WO2002096366A2 - Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy - Google Patents

Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy Download PDF

Info

Publication number
WO2002096366A2
WO2002096366A2 PCT/US2002/017180 US0217180W WO02096366A2 WO 2002096366 A2 WO2002096366 A2 WO 2002096366A2 US 0217180 W US0217180 W US 0217180W WO 02096366 A2 WO02096366 A2 WO 02096366A2
Authority
WO
WIPO (PCT)
Prior art keywords
mono
residue
group
alkyl
aryl
Prior art date
Application number
PCT/US2002/017180
Other languages
French (fr)
Other versions
WO2002096366A3 (en
Inventor
Byron C. Robinson
Ian M. Leitch
Stephanie Greene
Stev Rychnovsky
Original Assignee
Miravant Pharmaceuticals, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Miravant Pharmaceuticals, Inc. filed Critical Miravant Pharmaceuticals, Inc.
Priority to CA002448562A priority Critical patent/CA2448562A1/en
Priority to JP2002592879A priority patent/JP2004532251A/en
Priority to AU2002344234A priority patent/AU2002344234B2/en
Priority to EP02744204A priority patent/EP1401506A4/en
Publication of WO2002096366A2 publication Critical patent/WO2002096366A2/en
Publication of WO2002096366A3 publication Critical patent/WO2002096366A3/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0036—Porphyrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention relates to metallotetrapyrrolic compounds having phototherapeutic properties utilizable in photodynamic therapy for photodetection and phototherapy of target tissues.
  • Photodynamic therapy is a new modality for the treatment of malignancies, diseased tissue, hyperproliferating tissues, normal tissues or pathogens.
  • PDT involves a localized or systemic administration of a photosensitizing compound followed by exposure of target tissue to photoactivating light.
  • the photoactivating light excites the photosensitizer which, in turn, interacts with singlet oxygen causing the production of cytotoxic oxygen species.
  • the interaction of the cytotoxic oxygen species with tissues in which the photosensitizer is localized causes a modification of the tissue, resulting in a desired clinical effect.
  • the tissue specificity of the resultant phototoxic damage is determined largely, although not entirely, by the relative concentrations of the photosensitizer in each tissue at the time of exposure to the photoactivating light.
  • the method of light delivery is also an important therapeutic factor.
  • photosensitizers accumulate to varying degrees within tissues depending on the pharmacokinetic and distribution profile of the photosensitizing compound and the cell types comprising the tissues.
  • the chemical factors that enable certain photosensitizers to accumulate at a target site to a greater degree than other photosensitizers is not well understood.
  • the biological factors that result in the preferential uptake of some photosensitizers in certain tissue types compared to others is not well understood either. It is clear, however, that each photosensitizer has its own distribution and pharmacokinetic properties within different tissues and these properties determine the relative usefulness of the drug for the desired therapy.
  • rigorous screening and biological evaluation in appropriate model systems is required to identify suitable photosensitizers that display the characteristics necessary within the diseased or target tissues for an effective therapy.
  • Atherosclerosis is a disease that causes thickening and hardening of the arteries, particularly the larger artery walls. It is characterized by lesions of raised fibrous plaque that form within the vessel lumen. The plaques are most prevalent in, but not limited to, abdominal aorta, coronary arteries and carotid arteries and increase progressively with age. Intravascular ultrasound in man has shown that the plaque has a dome-shaped, opaque, glistening surface that protrudes into the lumen of the vessel.
  • a lesion will typically consist of a central core of lipid and necrotic cell debris, capped by a collagen fibromuscular layer. Complicated lesions will also include calcified deposits, necrotic tissue, thrombosis and fibrin. The occlusion of vessel lumen caused by the plaque leads to reduced blood flow, higher blood pressure and ultimately ischemic heart disease, if untreated.
  • the treatment of coronary atherosclerosis presently consists of pharmacological drug therapy, bypass surgery, percutaneous angioplasty and/or stent deployment.
  • Drug therapy is primarily directed towards the control of hypertension (with vasodilators, diuretics, anti-adrenergic agents, angiotensin converting enzyme inhibitors etc) or stabilization of the plaque by lowering circulating lipid levels (with statins).
  • the goal of the drug therapy is to return the patient's arterial blood pressure and circulating cholesterol to normal levels and thereby reduce the stress on the patient's heart, kidneys and other organs.
  • drug therapy can have side effects and does not control progressive or acute atherosclerosis.
  • a thoracic bypass surgery may be performed, where a vein, usually from the patient's leg, is used to bypass the occluded coronary artery.
  • a vein usually from the patient's leg
  • One end of the vein is attached to the aorta, and the other end is attached to the occluded vessel just beyond the obstruction.
  • bypass surgery has become an accepted surgical procedure, it can present substantial morbidity risks, is expensive and generally requires extended hospital care.
  • the procedure is often limited to proximal vessels to the heart and the long-term prognosis is less than satisfactory. Roughly five percent of bypass grafts can be expected to occlude each year following the operation and the native vessel can also re-occlude as well, necessitating repeat procedures.
  • Percutaneous transluminal angioplasty consists of balloon expansion of vessels to dilate areas of obstruction and has been used since the late 980's in the treatment of atherosclerotic coronary and peripheral vascular occlusive disease. Advances in catheter design have allowed more complex and distal stenoses and occlusions of coronary vessels to be treated with PTA. While this endovascular procedure displays excellent immediate revascularization of treated vessels and has gained acceptance as a less invasive alternative to bypass surgery, balloon angioplasty simply redistributes the atherosclerotic stenoses.
  • Restenosis is the vessel's natural healing response that typically occurs in direct proportion to the magnitude of the balloon angioplasty injury.
  • the exact mechanisms responsible for the restenotic process are not fully understood and thus it is not surprising that at present there are no proven clinical therapies to prevent it.
  • recent studies in man and animals have shown that two events, intimal thickening and abnormal geometric remodeling, occur following PTA. Indeed, intravascular ultrasound and pathologic studies suggest that, in man, intimal thickening and vessel remodeling are responsible for approximately one-third and two-thirds of the total lumen loss, respectively.
  • Intimal thickening involves the recruitment of vascular smooth muscle cells (VSMC) and perhaps advential myofibroblasts to the intima, where they proliferate and secrete an extracellular matrix.
  • VSMC vascular smooth muscle cells
  • Stent deployment (metal scaffolding used to open vessels) is the only intervention that helps to reduce the effects of the vessel remodelling component of restenosis.
  • stents hold an artery open and significantly reduce acute closure - restenosis rates have been reduced with stents from 40% to 20-35% - it is clear that stents have not eliminated the problem.
  • Neointimal hyperplasia i.e., new tissue growth through the sides of the stents
  • Interventional cardiologists have tried to remove this proliferative tissue with rotational and directional atherectomy, cutting balloons, eximer lasers, and deployment of another stent (stent sandwich), but none of these has shown to be effective. It is estimated that 1.8 million coronary interventions alone (0.36 million PTA and 1.45 million stent procedures) are performed worldwide each year, so a method of reducing neointima formation remains an important goal.
  • Anti-restenosis treatments have focused on arresting the cell replication cycle and the proliferation of VSMC.
  • a number of gene therapy approaches have been used unsuccessfully to interfere with VSMC proliferation including the use of antisense involved in cell proliferation (e.g. c-myc), and the use of adenovirus to increase nitric oxide synthase and thereby increase nitric oxide, an inhibitor of VSMC proliferation. Poor delivery of the gene therapy to the target vessel and immune reactions to some delivery vectors, however, have been major drawbacks for this method.
  • vascular photodynamic therapy has shown promise for the prevention of injury-induced neointimal hyperplasia in animal studies and has entered phase l/ll clinical trials in man (Lutetium texaphyrin; Pharmacyclics).
  • a photosensitizer was administered intravenously or locally to a patient and, after a predetermined time that depends on the optimal localization of the drug, the photosensitizer reached the target vascular lesion and light of an appropriate wavelength was used to activate the drug.
  • photosensitizers have been developed largely for use in oncological applications, and have also been examined in the cardiovascular field, mostly in preclinical animal models.
  • photosensitizers include Photofrin, 5-amino-levulinic acid (protoporphyrin IX precursor), tin ethyl
  • the excitation light source for PDT (usually diode lasers or dye lasers) has historically been matched to the far-red absorption bandwidth of the photosensitizer to maximize light penetration through blood in the arteries. Indeed, the present inventors believe that all the tetrapyrrolic photosensitizers used in cardiovascular indications have been designed for long wavelength absorption of light to address this perceived issue.
  • the light is then delivered to the treatment site via radially emitting fibers, often enclosed in balloon catheters (with a variety of designs), to exclude as much of the blood as possible.
  • Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic, restenotic lesions and vein graft intimal hyperplasia) is fueled by more effective second-generation photosensitizers that are designed specifically for cardiovascular indications and technological advances in endovascular light delivery catheters. These molecules may be used adjunctively with other debulking procedures.
  • photosensitizers described above have been used to treat atheromatous plaques and some are able to display some inhibition of intimal hyperplasia in animal models, many if not all have characteristics that will limit the usefulness of these drugs in a clinical setting.
  • One particular concern is the half-life of the photosensitizer.
  • a photosensitizer delivered systemically with a long half-life may have phototoxic side effects if exposed to direct light, within days of the procedure.
  • wavelengths of light lower than 600nm offer significant advantages in PDT because such wavelengths have penetration characteristics that deliver the PDT effect to the target sites (media and adventicia layers of the vessel) and not to myocardial tissue. Thus, effective therapy can be afforded at the target site, while deeper tissues are shielded from a PDT response by blood absorption within these tissues.
  • Previously reported cardiovascular experiments performed to date on tetrapyrrolic molecules have been done at wavelengths > 620nm.
  • Experiments that we have performed in pig arteries with new photosensitizer candidates at light activation > 600nm have resulted in unacceptable levels of damage to myocardial or cardiac muscle tissue surrounding the treatment area.
  • chlorins, phthalocyanines and texaphyrin type photosensitizers in general have little absorption in the 500-600nm regions, and thus may be suboptimal with regard to light activation at green and yellow wavelengths in cardiovascular tissues.
  • protoporphyrin IX and photofrin do not display absorption maximas at 532nm, thus they may be inefficient at absorbing treatment light at this wavelength and have very low molar extinction coefficients at 575nm ( ⁇ 7000cm " 1 /M "1 ).
  • long wavelength photosensitizers by design have red absorption peaks, operating room lighting in an emergency situation may cause serious photosensitivity in light exposed tissues.
  • Blue lasers are available, and even though most of the photosensitizers that have been used in cardiovascular diseases have blue absorptions, the light output of these devices currently limits their applicability to high power light treatments. Also, blood attenuation of light in the blue region of the spectrum (350 to 460 nm) is significantly greater than in the green/yellow region (500 to 600 nm). Thus, photosensitizers being activated in the blue region may suffer larger therapeutic inconsistancies if small amounts of blood are present within the vessel treatment area. Should high power blue lasers come onto the market, it may be possible (although difficult) to overcome significant blood attenuation in the blue region, and perhaps effect a desired therapy.
  • the present invention is directed to certain metallated photosensitizers that have shown excellent efficacy in advanced animal model systems as well as preferred uptake in the target tissue, with excellent clearance characteristics and low toxicity. These compounds are expected to be useful not only in cardiovascular disease indications, but also for indications in dermatology, oncology, ophthalmology, urology, and in dentistry.
  • the present invention overcomes the disadvantages of the prior art by providing novel metallated functionalized phototherapeutic agents of the tetrapyrrolic type, which display excellent uptake into cardiovascular tissues of interest, show low systemic toxicity and low myocardial tissue toxicity on light activation, and are cleared rapidly from skin and other tissues.
  • phototherapeutic agents are based on tetrapyrrolic ring systems such as the porphyrins.
  • tetrapyrrolic compounds involving the coordination of a gallium ion into the central cavity of tetrapyrrolic compounds to produce a gallium tetrapyrrolic complex, unexpectedly markedly enhances the uptake and biological efficacy of the compounds as photosensitizers for PDT of cardiovascular diseases when compared to the corresponding tetrapyrrolic compounds having other metal types coordinated to their central cavity.
  • tetrapyrrolic macrocycles that coordinate gallium when administered topically or systemically show unexpected skin tissue responses, such as hair growth stasis and positive skin remodelling (deposition of collagen) following treatment with light. These effects are not observed with other metallotetrapyrrolic macrocycles. Therefore, a preferred embodiment of the invention is directed to certain tetrapyrrolic compounds metallated with gallium.
  • the invention also provides new methods of treating cardiovascular diseases with PDT utilizing light at shorter wavelengths with the new metallated porphyrins of the invention, thus minimizing damage to the myocardial or muscle tissue.
  • the invention further provides new photosensitizers that may be used in short wavelength applications in photodynamic therapy to treat diseases other than cardiovascular diseases.
  • the present invention in one aspect, provides phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula I which may be used in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
  • Ri - R ⁇ 2 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group,
  • R- ⁇ 3 is selected from H, a physiologically acceptable counter ion, a C1-C20 straight or branched chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons; (CH ) n OH, or (CH 2 ) n OR ⁇ 4 , where R is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R ⁇ 8 , R 19 and R 20 can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R- ⁇ s) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R ⁇ 8) Rig and R 2 o together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is
  • R 21 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 22 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 23 and R 2 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR 22 can also be an amino acid, an amino acid salt, an amino acid ester residue, and an amino acid amide residue; aryl or substituted aryl, which may optional
  • M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , ln 3+ , Ge 4+ , Si 4+ , Al 3+ , Zn 2+ , and Mg 2+1 wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
  • Ri and R 2 can be the same or different and can be selected from: CO 2 R 3 , where R 3 is selected from H, a physiologically acceptable salt, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons; CONH(R 4 ), CONHNH(R 4 ), CON(R 4 ) 2> COR 4 , or CON(R 4 )(R 5 ), where R 4 and R 5 can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-,
  • R 6 is selected from a C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
  • R 8 and Rg can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or
  • R 10 , Ru and R i2 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, an amino acid or a salt, ester or amide thereof (provided - NH(R- ⁇ o) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-io, Ru and R-t 2 together possess the atoms necessary to constitute an aromatic ring system, n is
  • R 13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 15 and R-i ⁇ can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; and aryl or substituted aryl, which may optionally bear one or more
  • M is preferably Ga 3+ , wherein associated with the co-ordinated gallium is a physiologically acceptable charge balancing counter ion, but M in formula IA can also be selected from Pt 2+ , Pd 2+ , Sn 4+ , ln 3+ , Ge 4+ , Si 4+ , Al
  • Ri and R 2 can be the same or different and can be selected from H,
  • CN CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
  • R 3 and R can be the same or different and are selected from:
  • R 5 is selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, ethers or polyethers, or a functional group of less than about 100,000 daltons;
  • R 6 and R 7 can be the same or different and can be selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons;
  • R 8 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
  • R ⁇ 2 and R 13 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester or amide thereof (provided -NH(R ⁇ 2 ) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-
  • R 15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 16 is a a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 17 and R18 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; and aryl or substituted aryl, which may optionally bear one or more substituent
  • M is Ga 3+ , wherein associated with the co-ordinated gallium is a physiologically acceptable charge balancing counter ion.
  • phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula II that may be useful as photosensitizers in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
  • Ri to Ru can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, cyan
  • R- ⁇ 2 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons; (CH 2 ) n OH, or (CH 2 ) n ORi 3 , where R- ⁇ 3 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; (
  • R 17 , R ⁇ 8 and R 19 can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-
  • R 21 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 22 and R23 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHA can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue, and n is an integer between 0 and 4;
  • R 8 -R9 7 R ⁇ 'Rio 1 ii- i2 and R-
  • M is a diamagnetic or paramagnetic photoactive metal ion preferably selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , ln 3+ , Ge 4+ , Si 4+ , Al 3+ , Zn 2+ , and Mg 2+ , wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
  • Ri-R ⁇ can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyan
  • R 7 where R is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
  • R 8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
  • R 12> R13 and R 14 can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Ri 3 ) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R- ⁇ 2 , R 13 and R 14 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a
  • R 15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; (CH 2 ) n NHCOR 16 or (CH 2 ) n NHNHCOR 16 , where R 16 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a
  • R 17 and R ⁇ 8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR 17 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue; aryl or substituted ary
  • M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , ln 3+ , Ge 4+ , Si 4+ , Al 3+ , Zn 2+ , Mg 2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
  • phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula III which may be useful in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
  • Ri to R ⁇ 0 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group,
  • Ru is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
  • 2 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
  • R 16 , R i7 and R 18 can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R ⁇ ) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where Ri 6 , R17 and R- ⁇ 8 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A
  • R 19 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 20 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 2 ⁇ and R 22 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR 21 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue; aryl or substituted aryl
  • R1-R2, R3-R4, R6-R7, Rs-Rg, R4-R5, R5- 6, Rg-R-io, and R10-R1 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
  • M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , ln 3+ , Ge 4+ , Si 4+ , Al 3+ , Zn 2+ , Mg 2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
  • R-i, R 2 , R 3 , R can be the same or different and can be selected from: a functional group of less than about 100,000 daltons;
  • R 5 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
  • R 6 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4; CONH(R 8 ), CONHNH(R 8 ), CO(R 8 ), CON(R 8 ) 2 , CON(R 8 )(R 9 ), (CH 2 ) n CONH(R 8 ), (CH 2 ) n CONHNH(R 8 ), (CH 2 ) n CON(R 8 ), (CH 2 ) n CON(R 8 ), (CH 2 ) n CON(R 8 ), (CH 2 ) n CON(R 8 ), (CH 2 ) n CON(
  • Rho, Ru and R 2 can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R- ⁇ o) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R 10 , Ru and R-
  • R 13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 15 and R ⁇ 6 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR 15 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue; aryl or substituted aryl, which may optional
  • M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , ln 3+ ,
  • phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IV which may be used in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
  • R- ⁇ -R 8 can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyan
  • R 9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
  • R 10 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • X is a halogen
  • Ru is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
  • R 14 , R i5 and R 16 can be the same or different and are selected from H, NH 2 , straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R 4 ) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R , R15 and Ri 6 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and
  • R 17 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • R 18 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
  • M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga 3+ , Pt 2+ , Pd 2+ , Sn 4+ , ln 3+ , Ge 4+ , Si 4+ , Al 3+ , Zn 2+ , Mg 2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
  • the metallotetrapyrrolic compounds of the invention are derived by various procedures from naturally occurring cyclic tetrapyrroles.
  • the naturally occuring cyclic tetrapyrrolic molecules have the basic ring structure shown in Table 1 herein and are particularly preferred as starting materials for the synthesis of compounds of formula I.
  • the metallotetrapyrrolic molecules of the invention are derived by the coupling of suitably substituted dipyrromethane, dipyrromethenes, biladienes, builirubins, pyrroles and functionalized aldehydes, or functionalized maleonitriles.
  • These cyclic tetrapyrroles have the basic ring structure shown in Table 2, and are particularly preferred as starting materials for the synthesis of the compounds of formulae ll-IV.
  • a method for detection and treatment of cardiovascular tissue or other tissue abnormalities in a patient comprises administering to the patient an effective amount of a metallotetrapyrrolic compound of the invention and exposing the tissue to light within the photoactivating spectrum of the particular tetrapyrrolic compound.
  • tetrapyrrole tetrapyrrolic molecule
  • porphyrin tetrapyrrolic molecule
  • porphyrin isomers such as porphycenes, isoporphycenes, hemiporphycenes, corroles, corrphycenes, and the like, provided they are capable of co-ordinating a metal ion.
  • porphyrins Included in the first class of metallated tetrapyrrolic compounds of the invention are those of the porphyrins.
  • Scheme 1 outlines an example of the synthesis of porphyrins of the invention derived from blood derived porphyrins, for example hematoporphyrin or hemin.
  • porphyrin classes can be synthesized by the routes shown.
  • hematoporphyrin can be modified by those skilled in the art by well known methods to give compounds (usually as their dimethyl esters) that possess defined functionality at R (Scheme 1 ).
  • R substituents most commonly utilized are vinyl (protoporphyrin IX) (2), ethyl (mesoporphyrin IX) (3), hydrogen (deuteroporphyrin IX) (4), CH(Oalkyl)CH 3 (hematoporphyrin ethers) (5), and halogens (halogenated deuteroporphyrin IX) (6).
  • Porphyrins that may be derived from plants are shown in Scheme 2.
  • porphyrins such as chloroporphyrin e6 (9), chloroporphyrin e4 (10), phylloporphyrin (11), rhodoporphyrin (7), pyrroporphyrin (8), pheoporphyrin a5 (13) and phylloerythrin (12) and compounds having similar ring systems.
  • Such compounds can be then modified according to the invention to increase their biological activity.
  • porphyrins While both blood and plant derived porphyrins are preferred as starting materials due to their commercial availably, a very large number of synthetic porphyrins are generally applicable to the invention.
  • Such porphyrins may be made by synthetic methods known to those skilled in the art, via coupling of pyrrolic precursors, dipyrromethanes, dipyrromethenes and biladienes to give
  • a second preferred class of compounds according to the invention are the mono-,di,-tri and tetra- azaporphyrins.
  • Schemes 3 - 7 outlines the synthesis of mono-, di- and tetra-azaporphyrins, examples of which are listed in Table 2.
  • Schemes 3 - 7 outline synthetic routes to novel tetrapyrrolic molecules of interest in treating diseases of the cardiovascular system and other diseases applicable to PDT. Such derivatives are of particular interest because all display absorption maximas at wavelengths at or near 400nm, 532nm and 575nm.
  • Mono-azaporphyrins are synthesized efficiently via the coupling of dibromobiladienes with sodium azide or via the reaction of oxyporphyrins with ammonia. Copper and metal free diazaporphyrins are obtained via the coupling of 5,5'-dibromopyrromethenes with sodium azide. Tetraazaporphyrins are synthesized most efficiently via the treatment of substituted maleonitriles with Mg powder or magnesium alcoxides. Such reactions are well known in the art and are outlined in detail by N. Kobayashi in "The Porphyrin Handbook" Editors, K.M. Kadish, K.M. Smith, R. Guilard, Volume 2, Chapter 13, Academic press, 2000, p. 301-360, the disclosure of which is incorporated by reference herein.
  • peripheral functionality of these compounds is important with respect to further derivatization to achieve the desired therapeutic effect. It is recognized that small changes in the peripheral functionality can have pronounced effects on the biological efficacy of the molecules as does metal coordination to the compounds. Some of these compounds for example, are shown in Table 3.
  • the new compounds of the invention are based on the porphyrin, mono-, di-, tri- and tetra-azaporphyrin ring systems that bear peripheral functionality on the ring system.
  • Such functionality includes esters, alcohols, amides, amines, ethers, and phosphates.
  • Such derivatives may also have at least one hydroxylated residue present, or an amine group on which at least one hydroxylated residue is present.
  • the new porphyrins themselves may be photodynamically active as metal free analogs and therefore useful as PDT agents.
  • metallated derivatives of these compounds are of particular interest in treatment of cardiovascular disease and normal or abnormal conditions of the hematological system, lymphatic reticuloendothelial system, nervous system, endocrine and exocrine system; skeletomuscular system including bone, connective tissue, cartilage and skeletal muscle; pulmonary system; gastrointestinal system including the liver; reproductive system; skin; immune system; cardiovascular system; urinary system; ocular system; auditory system;or olfactory system; where shorter wavelengths of light are necessary or advantageous to effect a desired therapy.
  • porphyrin derivatives coordinating gallium are very interesting as these have been demonstrated to have greater uptake and efficacy in eliminating smooth muscle cells from the media and intima portions of arteries in a variety of animal models, than do other metalloporphyrins with different metal centers.
  • the new compounds of the invention are based on the porphyrin, mono-, di-, tri- and tetra-azaporphyrin ring systems that bear peripheral functionality on the ring system.
  • Such functionality includes esters, alcohols, amides, amines, ethers, and phosphates.
  • Such derivatives may also have at least one hydroxylated residue present, or an amine group on which at least one hydroxylated residue is present.
  • the new porphyrins themselves may be photodynamically active as metal free analogs and therefore useful as PDT agents.
  • metallated derivatives of these compounds are of particular interest in treatment of cardiovascular disease and normal or abnormal conditions of the hematological system, lymphatic reticuloendothelial system, nervous system, endocrine and exocrine system; skeletomuscular system including bone, connective tissue, cartilage and skeletal muscle; pulmonary system; gastrointestinal system including the liver; reproductive system; skin; immune system; cardiovascular system; urinary system; ocular system; auditory system;or olfactory system; where shorter wavelengths of light are necessary or advantageous to effect a desired therapy.
  • porphyrin derivatives coordinating gallium are very interesting as these have been demonstrated to have greater uptake and efficacy in eliminating smooth muscle cells from the media and intima portions of arteries in a variety of animal models, than do other metalloporphyrins with different metal centers.
  • Schemes 3-7 outline chemistry that has been undertaken to produce photosensitizing agents according to the invention and are not intended to limit the scope of the invention. It should be noted that the functionality and position of the N and C meso atoms can be varied to produce analogs different from those shown. Additionally, the R groups in these schemes constitute functional groups that can be modified by techniques known to those skilled in the art based on the chemistry described herein without departing from the spirit or scope of the invention.
  • a number of metalloporphyrins and metallo azaporphyrin acids and salts were synthesized.
  • a suitable free base tetrapyrrole ester was metallated and the ester functionality hydrolyzed using either basic or acidic conditions.
  • Metal incorporation followed standard procedures well known in the art (see Johann Walter Buchler in "The Porphyrins", Ed. D. Dolphin, Academic Press, Chapter 10, 389-483).
  • Isolation of the metallotetrapyrrolic acids was achieved by acidifying the metallotetrapyrrolic salt with acetic acid after the ester hydrolysis step, and the precipitated porphyrin collected. Preparation of the corresponding salts was most readily achieved by dissolution of the acid metalloporphyrin with a stoichiometric amount of either KOH or NaOH.
  • Metallotetrapyrrolic amides were conveniently prepared using the metal free tetrapyrrolic acids.
  • the metal free tetrapyrrolic acid compound was suspended or dissolved in dichloromethane and subsequently refluxed after the addition of oxaylchloride for 1-2 hrs or less. Removal of the solvent under dry conditions, followed by dissolution in dry dichloromethane and addition of the desired amine, produced the corresponding amide.
  • Metallation was then achieved as described above. It was noted that in several instances where alcohol moieties were present on the molecule, attempts to metallate with gallium or indium or tin, using NaOAc as the proton scavenger, resulted in acetylation of the alcohol moiety. It was found convenient to hydrolyze the acetyl groups following the metallation process using K 2 C ⁇ 3 methanol/H 2 0 or dilute KOH/methanol/H 2 O.
  • ester functionalities on tetrapyrrolic molecules may be reacted with amines at high temperature to produce the corresponding amides. These, in turn, may be metallated to produce metalloporphyrins with absorptions ranging between 500 and 600nm.
  • the tetrapyrroles employed in the present invention to form the aforementioned amide bond include two major classes that are both well-known to those skilled in the art: 1) the carboxy or amino-containing tetrapyrroles derived by various means synthetically or from natural porphyrins; and 2) the carboxy-containing meso-tetraphenylporphyrins.
  • Exemplary tetrapyrroles valuable for the preparation of the compounds contemplated by the present invention are listed in Table 1.
  • a wide variety of functionality can be efficiently added to the macrocycles by way of the amide bond.
  • the amide bond is formed via coupling of a tetrapyrrolic carbonyl moiety with an amino alcohol such that mono-, di- or polyhydroxylated acyclic or cyclic, primary or secondary amides are formed.
  • various amino alcohols are valuable for the present invention, including 2- aminoethanol, 2-amino-1 ,3-propanediol, 2-amino-2-(hydroxymethyl)-1 ,3- propanediol, D-glucosamine and similar such amino alcohols.
  • amine containing tetrapyrroles may be coupled to carbonyl groups of a second functionalized compound thus forming compounds that are themselves amides.
  • ester reduction of metal free tetrapyrroles with lithium aluminium hydride produces the corresponding di-propyl alcohol derivatives.
  • These derivatives can then be directly metallated to give metalloporphyrin di- alcohol complexes as described above with due consideration given to the acetylation of the alcohol.
  • metalloporphyrin di- alcohol complexes as described above with due consideration given to the acetylation of the alcohol.
  • Pt tetrapyrroles it was found more convienient to metallate the tetrapyrrole first then undertake the reduction of the ester.
  • the di-alcohol porphyrins and azaporphyrins may be modified in a number of ways. For example, they may be protected with tosylchloride or a similar leaving group and reacted with amines to give functionalized amino porphyrins, or reacted with salts of alcohols, thiols or malonate esters to give functionalized esters, ethers or functionalized thioethers which may be modified accordingly.
  • the alcohol moiety may be replaced by a halogen (Scheme 3) and the subsequent mono or polyhalogenated tetrapyrrole reacted with lithium reagents to form corresponding adducts.
  • the mono- or polyhalogenated tetrapyrrole can be reacted with NaCN, which after treatment with HCI in methanol gives the corresponding tetrapyrrolic molecule with longer alkyl chain carboxylic acid or ester functionalities, which may be metallated. Also, such longer chain tetrapyrrolic esters may be made directly from biladienes routes.
  • the mono- or polyhalogenated tetrapyrrole can be reacted with PO(O-alkyl 3 ) producing -CH 2 PO(0-alkyl) 2 analogs that may be used directly or further modified by standard techniques.
  • dialcohol porphyrins and azaporphyrins can also be modified by reaction with acid chlorides and the like to form functionalized esters, by reaction with sulfonyl chlorides to produce the corresponding esters, or by reaction with phosphoryl chlorides to produce the corresponding phosphate esters or acids.
  • Final drug concentrations for light and dark experiments were 0.01 , 0.1 , 1.0, 3.0 and 5.0 ⁇ M. Twenty microliters of each concentration were added to six replicate wells to the light and dark plate. The plates were wrapped in aluminum foil to avoid photoactivation and mixed in a gyratory shaker for approximately 2 minutes. Both plates were incubated for 24 hours at 37° C, 5%CO 2 . After a 24 hour incubation, drug-containing media was aspirated from the plates. Each well was rinsed with 180 ⁇ l Hepes buffer salt solution (HBSS) then aspirated to remove the HBSS. 180 ⁇ l of fresh media were added (5% FBS/DMEM phenol-free) to each well.
  • HBSS Hepes buffer salt solution
  • Plate 1 was immediately light treated at a wavelength of 532 nm (metalloporphyrins and Pt azaporphyrins) or 575nm (metalloazaporphyrins) with a power setting of 354 mW and a fluence of 1.25 J/cm 2 for 7 min 22 seconds. Plate 2 was not light treated. Immediately after light treatment, 20 ⁇ l Alamar blue was added to each well in plate 1. Alamar blue was added to plate 2 immediately after fresh media was added. The plates were mixed on a gyratory shaker for 5 min.
  • the Light EC50 data compares photosensitizers for their ability to kill cells at various concentrations.
  • Photosensitizer normal skin response as well as skin healing response was evaluated using CD Hairless male rats. Photosensitizers were administered in an liposomal egg yolk phospholipid formulation at 1 , 1.5 and 2
  • gallium-containing tetrapyrroles very interesting with respect to ablation of superficial diseases including superficial cancers of the skin, barrets esophagus, early stage lung cancer, actinic keratosis, basal cell carcinomas and the like. While many tetrapyrrolic compounds are able to induce necrosis of the epidermal layer, only the gallium tetrapyrrolic compounds under specific drug/light and time dose combinations are able to induce necrosis of the epidermal layer or alternatively cause clearing of hyperkeratotic skin lesions with deposition of collagen formation (see following section) without necrosis of the skin. Such skin clearing is observed easily at lower drug doses (for example
  • the extent of epidermal and/or dermal involvement was determined via histological evaluation.
  • the grading parameters for histological evaluation included the degree of epidermal/dermal necrosis, the depth of necrosis, edema, and infiltration of heterophils in the epidermis/dermis.
  • Skin was also evaluated for collage, elastin, fibronectin and immune cells via immunohistochemistry.
  • Tissues collected for histopathology were placed in plastic embedding cassettes and immersed in 10% phosphate buffered formalin. Fixed tissues were paraffin-embedded and sectioned into approximately 4-8 ⁇ m thickness slices using a microtome. Slides were stained using hematoxylin and eosin or collagen/elastin stains and interpreted by a qualified veterinary pathologist blinded to the study groups.
  • the pale and fibrillar collagen was consistent with remodeling of the epidermis and represents a more immature connective tissue at the dermal/epidermal junction of the dermis. There was no difference in elastin fibers in cases with the previously described pale stroma at the dermal/epidermal junction as compared to sections that did not have the pale zone. In all sections examined, the dermis contained less than 5% elastin stained fibers. Based on these findings, a change in elastin fibers is not evident within the dermis.
  • gallium tetrapyrrolic compounds produces unique skin restructuring processes that were not observed for any of the other metal free or metallo tetrapyrrolic photosensitizers studied and may be particularly valuable for the treatment of epithelial or endothelial cell layers of tissues, scars, wound healing, psoriasis, chronic inflammatory diseases, eczema, immune modulated diseases, scleraderma, shingles, wrinkles, hair removal, actinic keratosis, carcinomas or sarcoma of the skin or other tissues, fungual infections, viral or bacterial infections, warts, arthritis, port wine stains, birth marks, stretch marks, hyper pigmentation, urticaria, allegenic reactions, chronic proliferative dermatitis, chronic ulcerative dermatitis, disorders of hair or hair follicles,
  • phospholipid formulation 120 - 240 min before light delivery.
  • the rats were anaesthetized with 3.5% isoflurane (Abbott Laboratories, IL, USA) and the femoral region of the right leg was shaved and cleaned. A small midline incision was made and a 1 cm region of the right femoral artery was surgically exposed and dissected from surrounding tissues.
  • a direct arteriotomy was performed and a light balloon catheter (Miravant Medical Technologies, Inc) was introduced into the vessel and advanced retrogradely into a non-manipulated region of the left common carotid artery via the abdominal aorta.
  • the light catheter was then inflated at 1 atmosphere, to the dimensions of 2 mm x 20 mm, and light was delivered to the carotid artery via a diffuser centered within the catheter.
  • the light dosimetry was fixed at 50 J/cm 2 fluence and 160 mW/cm 2 irradiance.
  • the right femoral artery was tied off and the skin wound was closed. Rats were sacrificed three days post treatment as this corresponds to the known peak time that vascular cells, e.g., VSMC and myofibroblasts, proliferate and migrate in response to an injury.
  • the swine model has been utilized in the preclinical evaluation of interventions to reduce restenosis for several reasons. Chief among these reasons are the similarities in (i) size and anatomy of the swine arteries to human arteries, that permits instrumentation and evaluation of results via catheters; and (ii) histopathological characteristics of the proliferative response following artery injury similar to that seen in humans. Furthermore, large animals including the swine have proven to be more predictive of success in reducing restenosis in humans than have small animal models.
  • An extensive literature search e.g., Weiner, B.H., et al. Circulation. 72:1081-1086, 1985; Schwartz, R.S., et al. Circulation.
  • Photosensitizers were administered systemically (at doses typically 2 - 3.5 mg/kg body weight, in a soybean phospholipid formulation) as a slow bolus injection in the ear vein. Drug treatments were followed (1 - 4hr later) by endovascular light treatment (50-250 J/cm 2 fluence and 100-300 mW/cm 2 irradiance) in uninjured coronary (50-250 J/cm 2 fluence and 100-300 mW/cm 2 irradiance) and iliac (50-350 J/cm 2 fluence and 100-450 mW/cm 2 irradiance) arteries.
  • endovascular light treatment 50-250 J/cm 2 fluence and 100-300 mW/cm 2 irradiance
  • iliac 50-350 J/cm 2 fluence and 100-450 mW/cm 2 irradiance
  • animals also received balloon injuries in the coronary arteries at the time of PDT treatment.
  • Angioplasty injuries in 2 coronary arteries were performed.
  • Vital signs and cardiovascular parameters such as ECG, HR, BP, were monitored together with arterio-angiograms for measurements of vessel patency.
  • water-soluble compounds may be synthesized in accordance with the invention that, given the correct pattern of peripheral substitution and functional group selection, may show activity. Additionally, higher drug doses may be required to effect a treatment. It is interesting to note that the water soluble gallium porphyrins and azaporphyrins do not display significant skin photosensitivity at the doses used, making them potentially particularly interesting and valuable compounds. For example, compounds 88 and 109 gave no observed normal skin response at the drug doses used. It has also been noted that significant acellularity occurs following PDT treatment of rat arteries with water soluble gallium azaporphyrins and gallium porphyrins at longer treatment times post injection (16, 24 hrs).
  • esters The most active compounds tested for the elimination of cells in the medial and adventitial layers of vascular vessels are the esters (Tables 3 and 4). The nature of the ester functionality has been shown to influence the biodistribution and skin pharmacokinetic profile of the molecules. A surprising observation is that in almost all of the cases, gallium tetrapyrrolic esters are efficient at depleting cell population densities in the medial and adventitial layers of vascular vessels, much more so than almost all other metal types.
  • propyl ester (122) at a drug dose of 1 ⁇ mol/Kg shows normal skin responses only
  • rhodoporphyrin dimethyl ester (123) is cleared more rapidly from the skin (6 hrs) than is gallium mesoporphyrin dimethyl ester (1) (48 hrs).
  • gallium mesoporphyrin dimethyl ester (1) gallium mesoporphyrin dimethyl ester (1)
  • gallium deuteroporphyrin dimethyl ester (4) have shown >80% and >75% average inhibition of intimal hyperplasia over the length of the injured artery in pig coronary arteries (Table 7; many treated artery sections show 100% inhibition).
  • methylamide derivative (121 ) shows normal skin responses to 48 hrs post drug injection in rats. Its methylamide derivative (121 ) on the other hand at identical drug and light doses shows normal skin responses up to 6 hrs and not beyond. Additionally the stability of the methyl amide derivative and the diethylamide derivative in liposomal formulations may be longer than the diester analog, which may prove to be valuable in the pharmaceutical development of such compounds. Notable also is the fact that some of the metallotetrapyrrolic amides show no normal skin response at the doses used, and do not appear to be efficient photosensitizers. Such compounds may be of immense value as radiodiagnostics (where radioactive gallium isotopes are used for example) or as fluorescence diagnostic agents.
  • methyl amide derivative (121 ) of gallium mesoporphyrin at 3 mg/Kg, and light fluence of 125J/cm 2 shows >75% average inhibition of intimal hyperplasia over the length of the injured artery in pig coronary arteries (Table 7; Many treated artery sections show 100% inhibition).
  • the pharmacological properties of the novel compounds according to the invention are substantially different from those of existing photosensitizers described to date in the literature.
  • the compounds investigated possess the following properties.
  • any porphyrinic molecule may be modified according to the invention to form the desired photoactive compounds with widely differing functionality as described in the literature (for example see “Porphyrins and Metalloporphyrins” ed. K. Smith, Elsevier, 1975, N.Y. and “The Porphyrins”, Ed D. Dolphin, Vol l-V, Academic Press, 1978; “The Porphyrin Handbook”, Ed. K. Kadish, K. M. Smith, R. Guilard, Academic Press, 1999 incorporated by reference). These compounds contain various and ranging
  • Examples of such functionality include functional groups having a molecular weight less than about 100,000 daltons and can be a biologically active group or organic in nature. Examples include, but are not limited to: (1) hydrogen; (2) halogen, such as fluoro, chloro, iodo and bromo (3) lower alkyl, such as methyl, ethyl, CH(CH 3 ) 2 , n- propyl, butyl, hexyl, heptyl, octyl, isopropyl, t-butyl, n-pentyl and the like groups; (4) lower alkoxy, such as methoxy, ethoxy, isopropoxy, n-butoxy, t-pentoxy and the like; (5) hydroxy; (6) carboxylic acid or acid salts, such as — CH2COOH, — CH ⁇ COONa, — CH 2 CH 2 COOH, — CH 2 CH 2 CO
  • biologically active group can be any group that selectively promotes the accumulation, elimination, binding rate, or tightness of binding in a particular biological environment.
  • one category of biologically active groups is the substituents derived from sugars, specifically: (1) aldoses such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, and talose; (2) ketoses such as hydroxyacetone, erythrulose, rebulose, xylulose, psicose, fructose, sorbose, and tagatose; (3) pyranoses such as glucopyranose; (4) furanoses such as fructo-furanose; (5) O-acyl derivatives such as penta-O-acetyl-
  • glucopyranoside (7) phenylosazones such as glucose phenylosazone; (8) sugar alcohols such as sorbitol, mannitol, glycerol, and myo-inositol; (9) sugar acids
  • gluconic acid such as gluconic acid, glucaric acid and glucuronic acid, ⁇ -gluconolactone, ⁇ -
  • esters such as ⁇ -glucose 1 -phosphoric acid, ⁇ -glucose 6-phosphoric acid, ⁇ -
  • sugars such as 2-deoxy-ribose, rhammose (deoxy-mannose), and fructose (6- deoxy-galactose); (12) amino sugars such as glucosamine and galactosamine; muramic acid and neuraminic acid; (13) disaccharides such as maltose, sucrose and trehalose; (14) trisaccharides such as raffinose (fructose, glucose, galactose) and melezitose (glucose, fructose, glucose); (15) polysaccharides (glycans) such as glucans and mannans; and (16) storage polysaccharides such as ⁇ -amylose,
  • amylopectin dextrins, and dextrans.
  • Amino acid derivatives are also useful biologically active substituents, such as those derived from valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, alanine, arginine, aspartic acid, cystine, cysteine, glutamic acid, glycine, histidine, proline, serine, tyrosine, asparagine and glutamine.
  • peptides particularly those known to have affinity for specific receptors, for example, oxytocin, vasopressin, bradykinin, LHRH, thrombin and the like.
  • nucleosides for example, ribonucleosides such as adenosine, guanosine, cytidine, and uridine; and 2'-deoxyribonucleosides, such as 2'- deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine.
  • ribonucleosides such as adenosine, guanosine, cytidine, and uridine
  • 2'-deoxyribonucleosides such as 2'- deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine.
  • ligand specific for a biological receptor refers to a moiety that binds a receptor at cell surfaces, and thus contains contours and charge patterns that are complementary to those of the biological receptor.
  • the ligand is not the receptor itself, but a substance complementary to it. It is well understood that a wide variety of cell types have specific receptors designed to bind hormones, growth factors, or neurotransmitters. However, while these embodiments of ligands specific for receptors are known and understood, the phrase "ligand specific for a biological receptor”, as used herein, refers to any substance, natural or synthetic, that binds specifically to a receptor.
  • Examples of such ligands include: (1) the steroid hormones, such as progesterone, estrogens, androgens, and the adrenal cortical hormones; (2) growth factors, such as epidermal growth factor, nerve growth factor, fibroblast growth factor, and the like; (3) other protein hormones, such as human growth hormone, parathyroid hormone, and the like; (4) neurotransmitters, such as acetylcholine, serotonin, dopamine, and the like; and (5) antibodies. Any analog of these substances that also succeeds in binding to a biological receptor is also included within the invention.
  • the steroid hormones such as progesterone, estrogens, androgens, and the adrenal cortical hormones
  • growth factors such as epidermal growth factor, nerve growth factor, fibroblast growth factor, and the like
  • other protein hormones such as human growth hormone, parathyroid hormone, and the like
  • neurotransmitters such as acetylcholine, serotonin, dopamine, and the like
  • antibodies Any
  • substituents tending to increase the amphiphilic nature of the compounds include, but are not limited to: (1) short or long chain alcohols, such as, for example, — C 12 H 24 -OH; (2) fatty acids and their salts, such as, for example, the sodium salt of the long-chain fatty acid oleic acid; (3) phosphoglycerides, such as, for example, phosphatidic acid, phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol, phosphatidyl 3'-0-alanyl glycerol, cardiolipin, or phosphatidyl choline; (4) sphingolipids, such as, for example, sphingomyelin; and (5) glycolipids, such as, for example, glycosyldiacylglycerols, cerebrosides, s
  • the compounds of the present invention can be administered to the host in a variety of forms adapted to the chosen route of administration, e.g., orally, intravenously, topically, intramuscularly or subcutaneously.
  • the active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with food.
  • the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least about 0.1 % of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may, for example, conveniently be between about 2 to about 60% of the weight of the administered product.
  • the amount of active compound in such therapeutically useful compositions is can be selected so that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound.
  • the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint, oil of winter
  • tablets, pills, or capsules may be coated with shellac, sugar or both.
  • a syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and formulations.
  • the active compound may also be administered parenterally or intraperitoneally.
  • Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporanous preparation of sterile injectable solutions, dispersions, or liposomal or emulsion formulations.
  • the form must be sterile and should be fluid to enable administration by a syringe.
  • the form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required additional ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and the freeze-drying technique, which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solutions thereof.
  • the new compounds of the invention may also be applied directly to tumors in the host whether internal or external, in topical compositions.
  • exemplary compositions include solutions of the new compounds in solvents, particularly aqueous solvents, most preferably water.
  • the present new compounds may be dispersed in the usual cream or salve formulations commonly used for this purpose (such as liposomes, ointments, gels, hydrogels, cremes and oils) or may be provided in the form of spray solutions or suspensions that may include a propellant usually employed in aerosol preparations.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • Any conventional media or agent that is compatible with the active ingredient can be used in the therapeutic compositions of the invention.
  • Supplementary active ingredients can also be incorporated into the compositions.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated. Each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of cardiovascular diseases, diseases of the skin, and cancers in living subjects.
  • the present invention provides a method of treating live cells, which includes, but is not limited to, animals such as humans and other mammals.
  • the "mammals” also include farm animals, such as cows, hogs and sheep, as well as pet or sport animals, such as horses, dogs and cats.
  • the dosage of the pharmaceutical compositions of the invention is dependent on the method of administration, the patient's age, severity of the disease, and the like.
  • the compounds of the invention may be taken parentally or orally, generally being administered intravasculariy, subcutaneously, or intramuscularly or interperitoneally.
  • the subject compounds may also be administered by inhalation, perivascular delivery, pericardial delivery (into perivascular sac), periadvential delivery (e.g., using a hydrogel wrap around the vessel), endovascular balloon catheters with micropores, channels, transmural injection ports, and the like.
  • an infusate can be placed and pressurized to facilitate intramural and transmural penetration into the target vessel.
  • Local delivery can also be enhanced by other mechanical and electrical means.
  • the depth of the penetration of the subject compounds by this local delivery method is a function of pressure in the perfused segment and the dwell time.
  • Delivery of the compounds of the invention may also be via antibody-drug conjugates, internalizing antibodies or antibody fragments conjugated to compounds into cells using endocytosis.
  • the subject compounds may also be impregnated into stent struts for local delivery.
  • the route of administration of these pharmaceutical preparations is not critical, but may be selected according to the dosage form, the patient's age, the severity of the disease to be treated and other factors.
  • the compounds of the invention may find use in conjunction with other interventions, diagnostics and therapies, where lower levels of other therapies having significant side effects may be used effectively to reduce the detrimental side effects.
  • Adjunctive interventions may include, but are not limited to: balloon angioplasty, invasive and non-invasive surgical procedures, stent deployment, cutting balloons, embolic protection devices, rotational and directional atherectomy, eximer lasers and the like.
  • Adjunctive therapies may include, but are ⁇ orfimited to: radiation therapy, chemotherapy, anti-platelet agents, vasodilators, antihypertensives, anti- arrhythmics, hyperthermia, cryotherapy, magnetic force, viral and non-viral gene therapy, pharmacogenetic therapy, antibodies, vaccines, glycoprotein llb/llla Inhibitors, growth factors, peptides, DNA delivery, nucleic acids, anticancer drugs, steroid hormones, anti-inflammatories, proteins, anti-apoptotic therapies, anti-sense agents, immunotoxins, immunomodulators, antibody-drug conjugates, anti-proliferative therapies, drug eluting stents containing pharmacologically active agents, transplant products and processes, prostaglandins and catheter based devices to detect vulnerable plaques, hormone products, chelating agents, diuretics, cardiac glycosides, bronchodilators, antibiotics, antivirals, antitioxins, cyclosporins,
  • Adjunctive diagnostics may include, but are not limited to: intra- vascular ultrasound imaging, angiography, quantitative vessel measurements and the use of radiological contrast agents, hormone products, chelating agents, diuretics, cardiac glycosides, bronchodilators, antibiotics, antivirals, antitoxins, cyclosporins, thrombolytic agents, interferons, blood products such as parental iron and hemin, anti-fungal agents, antianginals, anticoagulants, analgesics, narcotics, neuromuscular blockers, sedatives, bacterial vaccines, viral vaccines, DNA or RNA of natural or synthetic origin including recombinent RNA and DNA, cytokines and their antagonists/inhibitors, and chemokines and their antagonists/inhibitors.
  • the method of the invention can include administration of the particular metallotetrapyrrolic compound prior to, concomitant with, or subsequent to a particular adjunctive therapy.
  • a particular regimen is employed for administration, where a single bolus or plurality of doses may be administered to the patient.
  • the particular protocol will depend upon the nature of the tissue to be treated, the particular compound that is employed and the severity of the disease. Target tissue structure and function, carriers, endocytosis, and other cellular transport mechanisms may be important for particular compounds when determining the specific mode of delivery.
  • Administration will preferably be within about 3 days prior to vessel activation with an energy source, and desirably will be the same day as the treatment of the target vessel.
  • the compounds of the invention may be formulated in a variety of ways, depending upon the manner of the administration, the particular compound, the number of administrations, other drugs, the presence of other active components and the like.
  • the formulation will generally be in a physiologically acceptable form, using various carriers, such as water, deionized water, phosphate buffered saline, aqueous ethanol, vegetable oils, liposomes, emulsions, inclusion complex (cyclodextrans).
  • the formulation may be formulated as a slow release formulation, where the subject compounds may be encapsulated in a wide variety of carriers, may be administered as capsules, or as a prodrug.
  • Injectable solutions are usually administered intravenously, either alone or in a mixture with conventional fluids for parenteral infusion containing sugars, amino acids, saline and the like.
  • Local administration may be by injection at the site of the living cells, by insertion or attachment of a solid carrier at the site, or by direct, topical application of a viscous liquid.
  • solutions may be administered as is by the intramuscular, intradermal, subcutaneous or intraperitoneal route. Suppositories are administered rectally, and eye drops are instilled into the eye.
  • the delivery of the compounds of the invention to living cells may be enhanced by the use of controlled-release compositions.
  • the compounds of the invention may also be applied externally by introducing them into a spray together with a suitable propellant and, if desired, a solvent, as a fine powder together with a suitable filler, and as a cream in combination with known auxiliaries. Furthermore they may be used in the form of suppositories. They may also contain the required auxiliaries, such as fillers, lubricants, preservatives and emulsifying agents prepared by any method known per se.
  • compositions of the invention may also contain a pharmaceutically acceptable carrier, such as saline, buffered saline, 5% dextrose in water, borate-buffered saline containing trace metal, carboxymethyl cellulose, vegetable oil, DMSO, ethanol, and the like.
  • a pharmaceutically acceptable carrier such as saline, buffered saline, 5% dextrose in water, borate-buffered saline containing trace metal, carboxymethyl cellulose, vegetable oil, DMSO, ethanol, and the like.
  • Formulations may further include one or more excipients, preservatives, antioxidants, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, lubricants, fillers, stabilizers, and the like. Methods of formulation are well-known in the art and are disclosed, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (Gennaro, ed. 1990)
  • the solutions or suspensions are preferably sterilized and isotonic with blood.
  • all the diluents in conventional use in this field can be employed.
  • water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol , liposomes and polyoxyethylene sorbitan fatty acid esters may be used.
  • the pharmaceutical preparations may contain sodium chloride, glucose, lactose or glycerol in an amount sufficient to give isotonic solutions. It is also possible to add conventional solubilizing agents, buffers, soothing agents or local anesthetics, etc. Further, when appropriate, the pharmaceutical preparations may contain coloring materials, preservatives, perfumes, flavoring agents, sweetening agents and the like.
  • the proportion of the active ingredient compound in the pharmaceutical preparations of the invention is not critical, but may suitably be selected from a wide range. Generally, however, the proportion is preferably within the range of from about 0.01 to about 70% by weight.
  • the dosage will generally be in the range of about 0.01 to about 100 mg/kg.
  • the total amount of the compound administered per day will generally be in the range of 0.1 to 50 mg/kg/day, more usually in the range of about 0.25 to 25 mg/kg/day.
  • This dose may be in a single bolus or be divided up to be administered in portions to provide the desired level of the subject compound in the mammal.
  • Light doses appropriate to activate the compounds of the invention can be administered externally or internally to the target tissue.
  • a particular regimen is employed for light administration, where a single dose or plurality of dosimetries may be administered to the patient.
  • the particular protocol will depend upon the nature of the tissue to be treated, the particular compound that is employed and the severity of the disease.
  • Light delivery devices can be, for example, in the form of a balloon catheter, bare tip diffuser and the like for endovascular delivery of light to blood-carrying vessels.
  • the term light is to be considered in its broadest sense, encompassing all electromagnetic radiation.
  • Light suitable for use in activating the compounds of the invention will typically be produced by, for example, arc lamps, LEDs or lasers at a certain frequency in the visible spectrum or near infrared for typical PDT treatments. In particular, wavelengths between 400nm and 900nm, corresponding to laser diode activation, may also be used. Additionally dual photon excitation may also be used.
  • alkyl refers to substituted or unsubstituted, straight or branched chain groups, preferably having one to twenty, more preferably having one to six, and most preferably having from one to four carbon atoms.
  • C 1 -C2 0 alkyl represents a straight or branched alkyl chain having from one to twenty carbon atoms.
  • Exemplary C 1 -C 20 alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, and the like.
  • C ⁇ -C 20 alkyl includes within its definition the term "C 1 -C 4 alkyl.”
  • Such alkyl groups may themselves be ethers or thioethers, or aminoethers or dendrimers.
  • cycloalkyl represents a substituted or unsubstituted, saturated or partially saturated, mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms.
  • exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • An exemplary cycloalkyl is a C 5 - C 7 cycloalkyl, which is a saturated hydrocarbon ring structure containing from five to seven carbon atoms.
  • aryl refers to an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents.
  • aryl groups include, but are not limited to, phenyl, napthalenes, anthracenes, benzopyrenes, quinolines, benzoquinolines, benzoperylene, benzofluorenes, fluorenes, benzofurazans, benzodiphenylenes, benzofluoranthenes, benzanthracenes, benzacephenanthrylenes, bathophenanthrolines, indans, benzoquinolines, quinolines, pyrazines, quinolines, quinazoles, quinoxalines, imidazopyridines, indenes, indolines, thiazolines, benzopyrimidines, pyrimidines, benzimidazole, triazolopyrimidines, pyrazoles, tryptophans, phenanthrolines, benzooxadiazoles, benzoselenadiazole, benzocoumarins, chalcones, fluoranthenes, pyr
  • halogen represents chlorine, fluorine, bromine or iodine.
  • halocarbon or “haloalkyl” represents one or more halogens bonded to one or more carbon bearing groups.
  • heterohaloalkyl represents, for example, halogenated alkylethers, halogenated -alkyl amines, halogenated alkyl esters, halogenated alkyl amides, halogenated alkyl thioesters, halogenated alkyl thiols, where N, S, O, P atoms are present in the haloalkylated structure.
  • heteroalkyl represents, for example, ethers, alkylamines, alkylated thiols and alkylate phosphorus containing groups.
  • carrier represents a substituted or unsubstituted aromatic or a saturated or a partially saturated 5-14 membered monocyclic or polycyclic ring, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, wherein all the ring members are carbon atoms.
  • electronegative group is intended to mean a chemical group containing an electronegative element such as halogen, sulfur, nitrogen or oxygen.
  • a "heterocycloalkyl group” is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1 , 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted.
  • heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl,
  • heteroaryl group is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
  • ring atoms including 1 , 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted.
  • heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3- bjthianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, t
  • leaving group refers to any group that departs from a molecule in a substitution reaction by breakage of a bond.
  • Examples of leaving groups include, but are not limited to, halides, tosylates, arenesulfonates, alkylsulfonates, and triflates.
  • Suitable protecting groups are recognizable to those skilled in the art. Examples of suitable protecting groups can be found in T. Green & P. Wuts, Protective Groups in Organic Synthesis (2d ed. 1991), the disclosure of which is incorporated herein by reference in its entirety.
  • Suitable salt anions include, but are not limited to, inorganics such as halogens, pseudohalogens, sulfates, hydrogen sulfates, nitrates, hydroxides, phosphates, hydrogen phosphates, dihydrogen phosphates, perchlorates, and related complex inorganic anions; and organics such as carboxylates, sulfonates, bicarbonates and carbonates.
  • inorganics such as halogens, pseudohalogens, sulfates, hydrogen sulfates, nitrates, hydroxides, phosphates, hydrogen phosphates, dihydrogen phosphates, perchlorates, and related complex inorganic anions
  • organics such as carboxylates, sulfonates, bicarbonates and carbonates.
  • substituents for alkyl and aryl groups include mercapto, thioether, nitro (N0 2 ), amino, aryloxyl, halogen, hydroxyl, alkoxyl, and acyl, as well as aryl, cycloalkyl and saturated and partially saturated heterocycles.
  • substituents for cycloalkyl groups include those listed above for alkyl and aryl, as well as alkyl groups.
  • Exemplary substituted aryls include a phenyl or naphthyl ring substituted with one or more substituents, preferably one to three substituents, independently selected from halo, hydroxy, morpholino(C- ⁇ -C 2 o)alkoxycarbonyl,
  • halo(C ⁇ -C 2 o)alkyl which represents a straight or branched alkyl chain having at least one halogen atom attached to it.
  • exemplary halo(C ⁇ -C 2 o)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, trifluoromethyl, trifluoroethyl, and the like.
  • hydroxy (C ⁇ -C 2 o)alkyl which represents a straight or branched alkyl chain having from one to twenty carbon atoms with a hydroxy group attached to it.
  • exemplary hydroxy(C ⁇ -C 2 o)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl, and the like.
  • C1-C2 0 alkylthio(C ⁇ -C o)alkyl is a straight or branched C 1 -C20 alkyl group with a C 1 -C2 0 alkylthio group attached to it.
  • Exemplary C 1 -C 20 alkylthio(CrC 2 o)alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the like.
  • heterocycle(C C2o)alkyl is a straight or branched alkyl chain having from one to twenty carbon atoms with a heterocycle attached to it.
  • exemplary heterocycle(Cr C 2 o)alkyls include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3- thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl and the like.
  • aryl(C ⁇ -C 20 )alkyl which is a straight or branched alkyl chain having from one to twenty carbon atoms with an aryl group attached to it.
  • exemplary aryl(C ⁇ -C 2 o)alkyl groups include phenylmethyl, 2- phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl and the like.
  • the heterocycloalkyls and the heteroaryls can, for example, be substituted with 1 ,2 or 3 substituents independently selected from halo, halo(C- ⁇ - C2o)alkyl, C1-C20 alkyl, C-1-C20 alkoxy, carboxy, C-1-C20 alkoxycarbonyl, carbamoyl, -(C ⁇ -C 2 o)alkylcarbamoyl, amino, di(C ⁇ -C 2 o)alkylamino or a group having the structure -(CH 2 ) a -R 7 where a can be 1 , 2, 3, 4, 5 and R can be hydroxy, C 1 -C 20 alkoxy, carboxy, CrC 2u alkoxycarbonyl, amino, carbamoyl, C-r C 2 oalkylamino or di(C ⁇ -C 2 o)alkylamino.
  • substituents independently selected from halo, halo(C- ⁇ - C2
  • substituted heterocycloalkyls include, but are not limited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and 6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl.
  • substituted heteroaryls include, but are not limited to, 3-methylimidazolyl, 3-methoxy pyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl, 2-methyl- 1 ,2,3,4- tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1 ,2,3,4- isoquinolin-7-yl and the like.
  • a "pharmaceutically acceptable solvate” is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of the inventive compounds.
  • Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds prepared using water, isopropanol, ethanol, DMSO, and other excipients generally referred to as GRAS or likewise recognized by the food and Drug administration as acceptable ingredients.
  • GRAS organic radical species
  • the compounds of the invention may exist in different polymorph forms, such as stable and metastable crystalline forms (and solvates thereof) and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
  • a "pharmaceutically acceptable salt” is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.
  • pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, citrates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates,
  • a compound of the present invention is a base
  • the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, lactic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
  • an inorganic acid such as hydrochloric acid
  • a compound of the present invention is an acid
  • the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), or an alkali metal or alkaline earth metal hydroxide or the like.
  • suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary and tertiary amines; cyclic amines such as piperidine, morpholine and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
  • Example 1 Gallium chloride mesoporphyrin dimethyl ester
  • Mesoporphyrin dimethyl ester (610mg) was dissolved in acetic acid (75mL) and Gallium acetyl acetonate added (700mg). The solution was refluxed for 1 hr after which time a UV visible analysis of the molecule showed the metallation to be complete. The solvent was removed by rotary evaporation and the residue dissolved in dichloromethane (100mL). The dichloromethane layer was washed repeatedly with 1 N HCI and the organic layer collected and evaporated.
  • the crude reaction mixture was chromatographed on silica (5% methanol/dichloromethane) and the major pink fraction collected and evaporated.
  • the compound was redissolved in dichloromethane (100mL), the organic layer was washed repeatedly with 1 N HCI, dried over sodium sulfate and evaporated to ⁇ 20mL. Hexane was added (14mL) and the dichloromethane was removed by rotary evaporation. The precipitated solid was collected by filtration and dried.
  • Example 8 Gallium chloride 8, 13-desvinyl-3,7,12,17-tetramethylporphyrin- 2.18-di(3'-hvdro ⁇ ypropy0
  • the aqueous layer was extracted with dichloromethane (50ml) and the organic layer collected and evaporated to dryness.
  • the residue was dissolved in THF (20mL) and a solution of DDQ (227mg) in THF (10mL) was added dropwise at room temperature. The solution was stirred for 10 min at room temperature and the solution poured into a saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (2 x 50mL) and evaporated to dryness.
  • the crude residue was chromatographed on silica using 1 % acetone/dichloromethane as eluent and the major red porphyrin band collected. The fraction was evaporated to dryness and precipitated from dichloromethane/methanol.
  • Example 21 Gallium chloride 7,8,12.13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-dif propionic acid methyl ester
  • Example 22 Gallium chloride 7,8.12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl amide)
  • Example 23 Gallium chloride 7,8.12.13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(3'-hvdroxypropyl) [0182] To a slurry of LiAIH 4 (46mg) in dry THF (3mL) was added a solution of azaporphyrin dimethyl ester (example 21 ) (150mg) in dry THF(3mL).
  • the crude material was precipitated from DMSO/water to remove excess diethyl malonate.
  • the porphyrin was dissolved in DMSO and LiCI (200mg) added. The solution was heated to 80°C for 4 hrs, cooled and water was added to precipitate the porphyrin.
  • the crude porphyrin was purified on a silica gel column. The desired fraction was collected by eluting 2% methanol/methylene chloride, and then precipitated from hexane to give 8,13-diethyl-3,7, 12,17- tetramethylporphyrin-2,18-di(pentanoic acid methyl ester) (118 mg, 98% yield).
  • Example 28 Gallium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2,18-difpentanoic acid ethyl ester
  • Example 39 Gallium chloride 3,8-dibromodeuteroporphyrin dimethyl ester [0198] 3,8-Dibromodeuteroporphyrin dimethyl ester was prepared from deuteroporphyrin dimethylester (250 mg) according to literature procedures
  • Example 43 Gallium hydroxy 3,8-Bis-fN,N-dimethylam ⁇ noprop-2-en-3- vDdeuteroporphyrin dimethyl ester [0202] 3,8-Bis (N,N-dimethylaminoprop-2-en-3-yl)deuteroporphyrin dimethyl ester (120 mg) was prepared following literature procedures (Pandey, R.
  • Hematoporphyrin (1.0 g) was converted to hematoporphyrin dimethyl ether dimethyl ester following literature procedures ( Byrne, C. J., . et al,
  • Hematoporphyrin dimethyl ether dimethyl ester was dissolved in tetrahydrofuran (100 ml). A solution of potassium hydroxide (2 g) in methanol/water (5ml/5ml) was added. The reaction was stirred overnight at room temperature. Tetrahydrofuran was evaporated and residue dissolved in water (50 ml). The solution was neutralized by 1N HCI. The solid was filtered and dried to give hematoporphyrin dimethyl ether. Hematoporphyrin dimethyl ether was dissolved in tetrahydrofuran and cooled in an ice/water bath.
  • Triethylamine (3 ml) was added followed by ethyl chloroformate (2 mL). The reaction was stirred for 30 min then methylamine (10 ml, 2 M in THF) was added.
  • Example 46 Indium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2,18-di(butanoic acid methyl ester)
  • Example 48 Aluminum chloride 8,13-diethyl-3,7,12,17- tetramethylporphyrin-2,18-di(butanoic acid methyl ester)
  • Example 51 Tin(IV)dichloride 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(pentanoic acid ethyl ester)
  • Example 52 Indium chloride 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(pentanoic acid ethyl ester)
  • Example 55 Zinc 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18- di(pentanoic acid ethyl ester)
  • Example 56 Gallium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2.18-di(pentanoic acid propyl ester)
  • Example 57 Gallium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2,18-di(pentanoic acid methyl ester)
  • Example 70 Gallium hydroxy Mesoporphyrin di-(N,N- dimethylaminoethylamide)
  • Example 72 Indium chloride 8, 13-diethyl-3,7,12,17-tetramethylporphyrin- 2.18-di(3'-hvdroxypropyl)
  • Example 73 Aluminum chloride 8, 13-diethyl-3,7,12,17- tetramethylporphyrin ⁇ .l ⁇ -diO'-hvdroxypropyl)
  • Example 75 Indium chloride 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(3'-methoxypropyl)
  • Example 76 Indium hydroxy 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(3-(N-pyrrolidino)propyl)
  • Example 78 Gallium hydroxy 8,13-diethyl-3, 7,12,17 tetramethylporphyrin- 2,18-di((N-3'-hvdoxypropyl)-3-aminopropyl)
  • Example 79 Zinc 8,13-diethyl-3,7,12,17 tetramethylporphyrin-2,18-di((N, N- diethyl)-3-aminopropyl)
  • Example 80 Gallium chloride 3,7,12,17-tetramethylporphyrin-2,18-di((3'- diethylphosphono)propyl)
  • Example 81 Indium chloride 3,7,12,17-tetramethylporphyrin-2,18-di((3'- diethylphosphono)propyl)
  • Example 82 Tin(IV)dichloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl ester) [0243] The metal free azaporphyrin (125 mg) synthesized in example 21
  • Example 83 Indium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl ester)
  • Example 84 Aluminum chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl ester)
  • Example 87 Gallium chloride 7,8.12.13-tetraethyl-12.17-dimethyl-10- azaporphyrin-2,18-di(propionic acid)
  • Example 88 Gallium hydroxy 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid sodium salt)
  • Example 89 Gallium chloride 7.8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid ethyl ester)
  • Example 90 Tin (IV) dichloride 7,8,12.13-tetraethyl-12,17-dimethvMO- azaporphyrin-2,18-di(propionic acid methyl amide)
  • Example 91 Indium chloride 7,8.12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl amide)
  • Example 93 Aluminum chloride 7,8,12,13-tetraethyM 2,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl amide)
  • Example 95 Gallium chloride 7,8,12,13-tetraethyl-12. 7-dimethyl-10- azaporphyrin-2,18-di(propionic acid 2'-methoxyethyl amide)
  • Example 96 Platinum 7,8, 12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin- 2,18-di(propionic acid-2'-methoxyethyl amide)
  • Example 97 Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-3'-hvdroxypropyl amide)
  • Example 100 Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-2-ethoxyethanol amide)
  • Example 102 Gallium chloride 7,8.12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-2'-N,N-dimethylaminoethyl amide)
  • Example 103 Platinum 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-2'-N,N-dimethylaminoethyl amide)
  • Example 104 Indium chloride 7,8.12,13-tetraethyl-12,17-dimethvM 0- azaporphyrin-2,18-di(3'-hyroxypropyl)
  • Example 106 Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethvM0- azaporphyrin-2,18-di(3'-methoxypropyl)
  • Example 107 Indium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(3-methoxypropyl)
  • Example 108 Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(butanoic acid methyl ester)
  • Example 114 Gallium hydroxy 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(pentanoic acid sodium salt)
  • Example 116 Gallium chloride 3,7,14,17-tetramethyl-5,10-diazaporphyrin- 2,8,12,18-tetra(propionic acid methyl ester)
  • Example 118 Gallium chloride 3,7,14,17-tetramethyl-5,10-diazaporphyrin- 2,8,12,18-tetra (3'-hvdroxypropyl)
  • Diazaporphyrin (synthesized in example 116) (50 mg) was converted to the title compound following the procedure described in example 23.

Abstract

Metallotetrapyrrolic compounds having photherapeutics properties useful in photodetection and phototherapy of target issues, particularly porphyrins and azaporphyrins that including gallium in the central pyrrolic core. Also disclosed are methods of using metallotetrapyrrolic compounds for the treatment or detection of cardiovascular disease.

Description

METALLOTETRAPYRROLIC PHOTOSENSITIZING AGENTS FOR USE IN
PHOTODYNAMIC THERAPY
DESCRIPTION OF THE INVENTION
Field of the Invention
[001] This invention relates to metallotetrapyrrolic compounds having phototherapeutic properties utilizable in photodynamic therapy for photodetection and phototherapy of target tissues.
Background of the Invention
[002] Photodynamic therapy ("PDT") is a new modality for the treatment of malignancies, diseased tissue, hyperproliferating tissues, normal tissues or pathogens. PDT involves a localized or systemic administration of a photosensitizing compound followed by exposure of target tissue to photoactivating light. The photoactivating light excites the photosensitizer which, in turn, interacts with singlet oxygen causing the production of cytotoxic oxygen species. The interaction of the cytotoxic oxygen species with tissues in which the photosensitizer is localized causes a modification of the tissue, resulting in a desired clinical effect. The tissue specificity of the resultant phototoxic damage is determined largely, although not entirely, by the relative concentrations of the photosensitizer in each tissue at the time of exposure to the photoactivating light. The method of light delivery is also an important therapeutic factor.
[003] Following systemic administration, many photosensitizers accumulate to varying degrees within tissues depending on the pharmacokinetic and distribution profile of the photosensitizing compound and the cell types comprising the tissues. The chemical factors that enable certain photosensitizers to accumulate at a target site to a greater degree than other photosensitizers is not well understood. In addition, the biological factors that result in the preferential uptake of some photosensitizers in certain tissue types compared to others is not well understood either. It is clear, however, that each photosensitizer has its own distribution and pharmacokinetic properties within different tissues and these properties determine the relative usefulness of the drug for the desired therapy. Currently, rigorous screening and biological evaluation in appropriate model systems is required to identify suitable photosensitizers that display the characteristics necessary within the diseased or target tissues for an effective therapy.
[004] An emerging clinical role for photodynamic therapy is in the treatment of proliferative cardiovascular diseases such as atherosclerosis, restenosis and vein graft disease. Atherosclerosis is a disease that causes thickening and hardening of the arteries, particularly the larger artery walls. It is characterized by lesions of raised fibrous plaque that form within the vessel lumen. The plaques are most prevalent in, but not limited to, abdominal aorta, coronary arteries and carotid arteries and increase progressively with age. Intravascular ultrasound in man has shown that the plaque has a dome-shaped, opaque, glistening surface that protrudes into the lumen of the vessel. A lesion will typically consist of a central core of lipid and necrotic cell debris, capped by a collagen fibromuscular layer. Complicated lesions will also include calcified deposits, necrotic tissue, thrombosis and fibrin. The occlusion of vessel lumen caused by the plaque leads to reduced blood flow, higher blood pressure and ultimately ischemic heart disease, if untreated.
[005] The treatment of coronary atherosclerosis presently consists of pharmacological drug therapy, bypass surgery, percutaneous angioplasty and/or stent deployment. Drug therapy is primarily directed towards the control of hypertension (with vasodilators, diuretics, anti-adrenergic agents, angiotensin converting enzyme inhibitors etc) or stabilization of the plaque by lowering circulating lipid levels (with statins). The goal of the drug therapy is to return the patient's arterial blood pressure and circulating cholesterol to normal levels and thereby reduce the stress on the patient's heart, kidneys and other organs. Unfortunately, in some cases drug therapy can have side effects and does not control progressive or acute atherosclerosis.
[006] In the more serious instances of coronary atherosclerosis, a thoracic bypass surgery may be performed, where a vein, usually from the patient's leg, is used to bypass the occluded coronary artery. One end of the vein is attached to the aorta, and the other end is attached to the occluded vessel just beyond the obstruction. Although bypass surgery has become an accepted surgical procedure, it can present substantial morbidity risks, is expensive and generally requires extended hospital care. Moreover, the procedure is often limited to proximal vessels to the heart and the long-term prognosis is less than satisfactory. Roughly five percent of bypass grafts can be expected to occlude each year following the operation and the native vessel can also re-occlude as well, necessitating repeat procedures.
[007] Percutaneous transluminal angioplasty (PTA) consists of balloon expansion of vessels to dilate areas of obstruction and has been used since the late 980's in the treatment of atherosclerotic coronary and peripheral vascular occlusive disease. Advances in catheter design have allowed more complex and distal stenoses and occlusions of coronary vessels to be treated with PTA. While this endovascular procedure displays excellent immediate revascularization of treated vessels and has gained acceptance as a less invasive alternative to bypass surgery, balloon angioplasty simply redistributes the atherosclerotic stenoses. It has also been determined that in some cases acute closure of the vessel after PTA and accelerated arteriosclerosis, or restenosis (re-occlusion) occurred as often as 40% within 6 months post-procedure. These re-occlusions further increase both as a function of the number of lesions treated and the time post-angioplasty.
[008] Restenosis is the vessel's natural healing response that typically occurs in direct proportion to the magnitude of the balloon angioplasty injury. The exact mechanisms responsible for the restenotic process are not fully understood and thus it is not surprising that at present there are no proven clinical therapies to prevent it. Nevertheless, recent studies in man and animals have shown that two events, intimal thickening and abnormal geometric remodeling, occur following PTA. Indeed, intravascular ultrasound and pathologic studies suggest that, in man, intimal thickening and vessel remodeling are responsible for approximately one-third and two-thirds of the total lumen loss, respectively. Intimal thickening involves the recruitment of vascular smooth muscle cells (VSMC) and perhaps advential myofibroblasts to the intima, where they proliferate and secrete an extracellular matrix. Stent deployment (metal scaffolding used to open vessels) is the only intervention that helps to reduce the effects of the vessel remodelling component of restenosis. However, while stents hold an artery open and significantly reduce acute closure - restenosis rates have been reduced with stents from 40% to 20-35% - it is clear that stents have not eliminated the problem.
[009] Neointimal hyperplasia, i.e., new tissue growth through the sides of the stents, has created a new problem, in-stent restenosis. Interventional cardiologists have tried to remove this proliferative tissue with rotational and directional atherectomy, cutting balloons, eximer lasers, and deployment of another stent (stent sandwich), but none of these has shown to be effective. It is estimated that 1.8 million coronary interventions alone (0.36 million PTA and 1.45 million stent procedures) are performed worldwide each year, so a method of reducing neointima formation remains an important goal. Anti-restenosis treatments have focused on arresting the cell replication cycle and the proliferation of VSMC. A number of gene therapy approaches have been used unsuccessfully to interfere with VSMC proliferation including the use of antisense involved in cell proliferation (e.g. c-myc), and the use of adenovirus to increase nitric oxide synthase and thereby increase nitric oxide, an inhibitor of VSMC proliferation. Poor delivery of the gene therapy to the target vessel and immune reactions to some delivery vectors, however, have been major drawbacks for this method.
[010] Researchers have looked to cancer treatments for ideas and ionizing radiation (brachytherapy) and stents coated with anti-cancer drugs have recently been identified as treatment options. At present, the use of drug coated stents has been restricted to animal studies and the few reports of human therapy appear to confirm the feasibility of the procedure. However, the best way to truly understand the vascular effect of drug-coated stents is to conduct long term studies well after the drug is completely eluted from the stent because it may be associated with inflammation and fibrin deposition, as seen in some animal models. Several devices are now available for applying radiation to recurrent narrowings within coronary stents or in-stent restenoses. However, a study recently failed to show the effectiveness of beta radiation (Beta-Cath system clinical trial; Novoste, 2001 , Kuntz, et al, J. American College of Cardiology, Feb, 2001) in preventing renarrowing of de novo coronary lesions, i.e., lesions that have not yet been treated with either PTA or stenting. Moreover, in animal and human studies it has been found that if the dose of radiation is too high, there is no healing of the lumenal endothelial lining of the intima resulting in an increased risk of late-onset thrombosis. Conversely, if the dose is too low, then restenosis and arteriosclerosis could actually be accelerated. Other technologies are being developed including cryotherapy using hypothermia, for example. These products all have technical challenges. The efficacy in animal models to date has been unimpressive and each is still far from commercialization.
[011] There exists a need for better methods for treatment of atherosclerosis and restenosis. When considering a therapy to treat or prevent restenosis, one must consider the steps in the complicated biologic cascade with which the therapeutic agent (e.g., photosensitizer) is designed to interfere, where the target cells will be when the proposed treatment is to be applied, and what the least traumatic and most efficient route of administration of that agent is for the specific problem to be treated. The ultimate objective of any therapy is to inhibit neointima formation while also promoting the controlled healing of the vessel wall.
[012] Recently, vascular photodynamic therapy has shown promise for the prevention of injury-induced neointimal hyperplasia in animal studies and has entered phase l/ll clinical trials in man (Lutetium texaphyrin; Pharmacyclics). In this study, a photosensitizer was administered intravenously or locally to a patient and, after a predetermined time that depends on the optimal localization of the drug, the photosensitizer reached the target vascular lesion and light of an appropriate wavelength was used to activate the drug.
[013] Several photosensitizers have been developed largely for use in oncological applications, and have also been examined in the cardiovascular field, mostly in preclinical animal models. Such photosensitizers include Photofrin, 5-amino-levulinic acid (protoporphyrin IX precursor), tin ethyl
etiopurpurin (SnET2), Visudyne® (Benzoporphyrin derivative), Antrin®, Optrin®
(Lutetium texaphyrin), mono-aspartyl chlorin e6 (MACE), and pheophorbide PH1126. All of these synthetic compounds were designed specifically for the treatment of solid tumors. Specifically, many of these compounds were designed to have large absorptions in the 620-740nm range so as to optimize the photoactivation of the drug with a wavelength that will penetrate to the greatest depths possible in all tissue types. In particular, these drugs were designed to absorb outside of the blood absorption profile, thus ensuring efficient photoactivation in most tissue types.
[014] The excitation light source for PDT (usually diode lasers or dye lasers) has historically been matched to the far-red absorption bandwidth of the photosensitizer to maximize light penetration through blood in the arteries. Indeed, the present inventors believe that all the tetrapyrrolic photosensitizers used in cardiovascular indications have been designed for long wavelength absorption of light to address this perceived issue. The light is then delivered to the treatment site via radially emitting fibers, often enclosed in balloon catheters (with a variety of designs), to exclude as much of the blood as possible.
[015] Enthusiasm for photoangioplasty (PDT of vascular de novo atherosclerotic, restenotic lesions and vein graft intimal hyperplasia) is fueled by more effective second-generation photosensitizers that are designed specifically for cardiovascular indications and technological advances in endovascular light delivery catheters. These molecules may be used adjunctively with other debulking procedures. This enthusiasm revolves around at least four significant attributes of light-activated therapy: a) the putative selectivity and safety of photoangioplasty, b) the potential for atraumatic and effective stabilization of atheromatous plaque through a biological mechanism, c) the postulated capability to reduce or inhibit restenosis using minimally invasive clinically relevant interventional techniques, and d) the potential to treat long segments of abnormal vessel by simply using fibers with longer light-emitting regions.
[016] While several of the photosensitizers described above have been used to treat atheromatous plaques and some are able to display some inhibition of intimal hyperplasia in animal models, many if not all have characteristics that will limit the usefulness of these drugs in a clinical setting. One particular concern is the half-life of the photosensitizer. A photosensitizer delivered systemically with a long half-life (CASPc, Photofrin, SnET2) may have phototoxic side effects if exposed to direct light, within days of the procedure.
[017] A second even more pressing concern that has to date escaped many of the investigators testing new photosensitizers in cardiovascular disease is photochemically induced damage to "normal" myocardial tissue surrounding the artery due to non-selective photosensitizer uptake and long depths of light penetration, which activates the photosensitizer in the myocardial tissue. Historically, it has been believed that attenuation of the photosensitizer excitation light by blood would inhibit the use of wavelengths of light shorter than 600nm in the cardiovascular field. This may have been true several years ago when balloon catheter technology in PDT was not as advanced as it is today. New endovascular light ballon catheters, however, can remove most of the blood from the treatment area. This advance enables the use of short wavelengths of light that historically may have been attenuated by blood.
[018] The use of wavelengths of light lower than 600nm offers significant advantages in PDT because such wavelengths have penetration characteristics that deliver the PDT effect to the target sites (media and adventicia layers of the vessel) and not to myocardial tissue. Thus, effective therapy can be afforded at the target site, while deeper tissues are shielded from a PDT response by blood absorption within these tissues. Previously reported cardiovascular experiments performed to date on tetrapyrrolic molecules have been done at wavelengths > 620nm. Experiments that we have performed in pig arteries with new photosensitizer candidates at light activation > 600nm have resulted in unacceptable levels of damage to myocardial or cardiac muscle tissue surrounding the treatment area. This has major clinical implications to patients with existing ischemic myocardial or muscle tissue due to poor artery perfusion. Attempts to lower the light dosimetry in order to limit treatments to the target tissue (media/intima) leads to long treatment times and less efficacy. In addition, long treatment times in the artery exposes the patient to additional risks with inflation and deflation of the balloon devices. Importantly, the present inventors have demonstrated in pig arteries that effective treatment depths can be obtained with shorter wavelengths of light, while sparing underlying tissue damage.
[019] Thus, in our opinion, long wavelength absorbing molecules (> 600nm), unless highly selective to target myocardial and intimal tissues (which has not to date been reported with any photosensitizer in cardiovascular tissues), may cause unacceptable normal cardiac tissue damage. Therefore, it would appear that activation of lutetium texaphyrin, BPD-MA, MACE, CASPc, SnET2, and pheophorbide PH-II26 with red light may be of limited use in the treatment of cardiovascular disease, as all of these compounds have low energy "red" absorbtions by design (> 600nm). It should be noted also that chlorins, phthalocyanines and texaphyrin type photosensitizers in general have little absorption in the 500-600nm regions, and thus may be suboptimal with regard to light activation at green and yellow wavelengths in cardiovascular tissues. In addition, protoporphyrin IX and photofrin do not display absorption maximas at 532nm, thus they may be inefficient at absorbing treatment light at this wavelength and have very low molar extinction coefficients at 575nm (~7000cm" 1/M"1). Furthermore, because long wavelength photosensitizers by design have red absorption peaks, operating room lighting in an emergency situation may cause serious photosensitivity in light exposed tissues. Attempts to use red light filters on operating room lights to minimize tissue damage due to the red light penetration results in poor tissue contrast and sub-optimal lighting conditions, making surgical procedures under these conditions extremely difficult, if not impossible. Optical clarity is much better at shorter wavelengths (500-600nm) where the depth of light peneration is limited to a few mm of tissue penetration. [020] Another important consideration in the design of cardiovascular photosensitizers that absorb at shorter wavelengths is that they must have absorptions at wavelengths where excitation light devices emit maximally. At 532nm, efficient inexpensive diode lasers are available. At other wavelengths (besides blue) <600nm-only dye lasers exist to supply enough light power to undertake a PDT treatment. These are particularly useful at 580nm. Blue lasers are available, and even though most of the photosensitizers that have been used in cardiovascular diseases have blue absorptions, the light output of these devices currently limits their applicability to high power light treatments. Also, blood attenuation of light in the blue region of the spectrum (350 to 460 nm) is significantly greater than in the green/yellow region (500 to 600 nm). Thus, photosensitizers being activated in the blue region may suffer larger therapeutic inconsistancies if small amounts of blood are present within the vessel treatment area. Should high power blue lasers come onto the market, it may be possible (although difficult) to overcome significant blood attenuation in the blue region, and perhaps effect a desired therapy.
[021] For these reasons, there is a real need for "shorter wavelength" absorbing photosensitizer agents that do not display red absorptions, that are cleared rapidly from normal tissues (especially skin), and that are effective in the treatment of intimal hyperplasia, atheromatous plaques, peripheral artery disease, and vein graft hyperproliferation. Additionally, as more disease indications are realized, shorter wavelength light may be equally important in other PDT applications that only require short wavelength excitation to effect a therapy. Such applications may be in hollow organ disease (for example, lung cancers and barrets esophagus), and in diseases of the skin (for example, psoriasis, actinic keratosis, and acne vulgaris).
[022] The present invention is directed to certain metallated photosensitizers that have shown excellent efficacy in advanced animal model systems as well as preferred uptake in the target tissue, with excellent clearance characteristics and low toxicity. These compounds are expected to be useful not only in cardiovascular disease indications, but also for indications in dermatology, oncology, ophthalmology, urology, and in dentistry.
[023] The present invention overcomes the disadvantages of the prior art by providing novel metallated functionalized phototherapeutic agents of the tetrapyrrolic type, which display excellent uptake into cardiovascular tissues of interest, show low systemic toxicity and low myocardial tissue toxicity on light activation, and are cleared rapidly from skin and other tissues. These phototherapeutic agents are based on tetrapyrrolic ring systems such as the porphyrins.
[024] We have additionally discovered that a single chemical modification of tetrapyrrolic compounds involving the coordination of a gallium ion into the central cavity of tetrapyrrolic compounds to produce a gallium tetrapyrrolic complex, unexpectedly markedly enhances the uptake and biological efficacy of the compounds as photosensitizers for PDT of cardiovascular diseases when compared to the corresponding tetrapyrrolic compounds having other metal types coordinated to their central cavity. Additionally, tetrapyrrolic macrocycles that coordinate gallium when administered topically or systemically, show unexpected skin tissue responses, such as hair growth stasis and positive skin remodelling (deposition of collagen) following treatment with light. These effects are not observed with other metallotetrapyrrolic macrocycles. Therefore, a preferred embodiment of the invention is directed to certain tetrapyrrolic compounds metallated with gallium.
[025] The invention also provides new methods of treating cardiovascular diseases with PDT utilizing light at shorter wavelengths with the new metallated porphyrins of the invention, thus minimizing damage to the myocardial or muscle tissue.
[026] The invention further provides new photosensitizers that may be used in short wavelength applications in photodynamic therapy to treat diseases other than cardiovascular diseases.
SUMMARY OF THE INVENTION
[027] To achieve these and other advantages, and in accordance with the purpose of the invention, as embodied and broadly described herein, the present invention, in one aspect, provides phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula I which may be used in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
Figure imgf000014_0001
I In formula I, Ri - Rι2 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of molecular weight of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A , CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)O- alkoxy, CH(CH3)0-aryl; (CH2)nO-alkoxy, or (CH2)nO-alkyl; where n is an integer from 0 to 8;
C(X)2C(X)3ι where X is a halogen;
CO2R13, where R-ι3 is selected from H, a physiologically acceptable counter ion, a C1-C20 straight or branched chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons; (CH )nOH, or (CH2)nORι4, where R is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Ri5, (CHX)nCO2Ri5, or (CX2)nCO2Ri5, where X is a halogen and R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
CONH(R16), CONHNH(R16), CO(R16), CON(R16)2, CON(R16)(Rι7)
(CH2)nCONH(Ri6), (CH2)nCON(R16)2, (CH2)nCOR16, (CH2)nCON(R16)(R17), (CX2)nCONH(R16), (CX2)nCON(R16)2, (CX2)nCON(Rι6)(R17), (CX2)nCOR16, (CH2)nCONHNH(Rι6), (CX2)nCONHNH(Rι6), (CHX)nCONH(R16), (CHX)nCONHNH(R16), (CHX)nCO(R16), (CHX)nCON(R16)2, or (CHX)nCON(Rι6)(Ri7), where X is a halogen and R-ι6 and Rι7 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
S(Rιβ), (CH2)nS(R18), (CH2)nNH(R18), (CH2)nNHNH(Rι8), (CH2)nN(R18)2,
(CH2)nN(R18)(R19), or (CH2)nN(R18)(Ri9)(R2o)+A, where Rι8, R19 and R20 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-ιs) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where Rι8) Rig and R2o together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR2ι, (CH2)nPO(OR21)2, (CH2)nP02R21, or (CH2)nPOR2ι where R21 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR22, or (CH2)nNHNHCOR22) where R22 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R23, S02NHR23, S02N(R23)2, S02NHNHR23, SO2N(R23)(R2 ) or S02R23, where R23 and R2 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR22 can also be an amino acid, an amino acid salt, an amino acid ester residue, and an amino acid amide residue; aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and R1-R2, R -R5, R7-R8, R10-R11, R2-R3, R5- 6, R8-R9, and Rn-Rι2 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
[028] In formula I, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, and Mg2+1 wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
[029] In a preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IA:
Figure imgf000018_0001
IA
In formula IA, Ri and R2 can be the same or different and can be selected from: CO2R3, where R3 is selected from H, a physiologically acceptable salt, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons; CONH(R4), CONHNH(R4), CON(R4)2> COR4, or CON(R4)(R5), where R4 and R5 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR6, where R6 is selected from a C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R7, (CHX)nCO2R7, or (CX2)nCO2R7, where X is a halogen and R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R8), (CH2)nCO(R8), (CH2)nCONHNH(R8), (CH2)nCON(R8)2,
(CH2)nCON(R8)(R9), (CX2)nCONH(R8), (CX2)nCON(R8)2, (CX2)nCON(R8)(R9), (CHX)nCONH(R9), (CHX)nCONHNH(R9), (CHX)nCON(R9)2, or (CHX)nCON(R8)(R9), where X is a halogen, and R8 and Rg can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rio), (CH2)nS(Rιo), (CH2)nNH(Rιo), (CH2)nNHNH(R10), (CH2)nN(R10)2)
(CH2)nN(R10)(Ru), or (CH2)nN(Rio)(Rii)(Ri2)+A, where R10, Ru and Ri2 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, an amino acid or a salt, ester or amide thereof (provided - NH(R-ιo) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-io, Ru and R-t2 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4 and A is a physiologically acceptable counter ion;
(CH2)nOP02ORi3, (CH2)nPO(ORι3)2, (CH2)nP02R13) or (CH2)nPOR13 where R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi4 or (CH2)nNHNHCORι4, where R14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R15, S02NHR15, S02N(R15)2, S02NHNHR15, S02N(R15)(Rι6) or S02R15, where R15 and R-iβ can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; and aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
[030] In formula I A, M is preferably Ga3+, wherein associated with the co-ordinated gallium is a physiologically acceptable charge balancing counter ion, but M in formula IA can also be selected from Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al
3+, Mg2+, Zn2+ either with or without a physiologically acceptable charge balancing counter ion.
[031] In another preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IB:
Figure imgf000022_0001
IB
In formula IB, Ri and R2 can be the same or different and can be selected from H,
CN, CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R3 and R can be the same or different and are selected from:
C02R5, where R5 is selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, ethers or polyethers, or a functional group of less than about 100,000 daltons;
CONH(R6), CONHNH(R6), CON(R6)2, or CON(R6)(R7), where R6 and R7 can be the same or different and can be selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCθ2R9, (CHX2)nCO2R9, or (CX2)nCθ2R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)πCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2,
(CH2)nCON(R10)(Rιι), (CX2)nCONH(Rιo), (CX2)nCONHNH(R10), (CX2)πCON(R10)2, (CX2)nCON(R10)(Rn), (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, or (CHX)nCON(R10)(Rn), where X is a halogen, and Rio and Ru can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, also where NH(R-|0) is part of an amino acid, an amino acid salt, an amino acid ester, or an amino acid amide, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Ri2), (CH2)nS(Ri2), (CH2)nNH(Rι2), (CH2)nN(R12)2, (CH2)nN(R12)(R13),
(CH2)nN(Rι2)(Rι3)(Ri4)+A, where Rι2 and R13 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester or amide thereof (provided -NH(Rι2) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-|2, R-I3 and R-ι together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR15, (CH2)nPO(ORι5)2, (CH2)nP02R15, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCORι6, where R16 is a a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, S02NHR17, SO2N(R17)2, SO2NHNHR17, S02N(R17)(Rι8) or S02R17, where R17 and R18 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; and aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons.
[032] In formula 1B, M is Ga3+, wherein associated with the co-ordinated gallium is a physiologically acceptable charge balancing counter ion.
[033] In another aspect of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula II that may be useful as photosensitizers in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
Figure imgf000025_0001
II
In formula II, Ri to Ru can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of molecular weight less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion, CN, OH, CHO, COCH3, CO(alkyl), C02H, CO2Na, CO2K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0- alkoxy, CH(CH3)0-aryl; (CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R-|2, where R-ι2 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons; (CH2)nOH, or (CH2)nORi3, where R-ι3 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; (CH2)nCO2R 4, (CX2)nCO2R14, or (CHX)nC02Rι4, where X is a halogen and R14 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4; CONH(R15), CONHNH(R15), CO(R15), CON(R15)2, CON(R15)(Rι6),
(CH2)nCONH(R15), (CH2)nCONHNH(R15), (CH2)nCON(R15)2, (CH2)nCOR15, (CH2)nCON(R15)(R16), (CX2)nCONH(R15), (CX2)nCONHNH(R15), (CX2)nCON(R15)2, (CX2)nCON(R15)(R16), (CX2)nCOR15, (CHX)nCONH(R15), (CHX)nCONHNH(R15), (CHX)nCON(R15)2, (CHX)nCON(R15)(Rι6), or (CHX)nCORi5, where X is a halogen and R15 and R16 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R17), (CH2)nS(R17), (CH2)nNH(R17), (CH2)nNHNH(R17), (CH2)nN(R17)2,
(CH2)nN(R17)(Ri8)> or (CH2)nN(R17)(Rι8)(Ri9)+A, where R17, Rι8 and R19 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-|7) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R17, R18 and Rig together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion; (CH2)nOPO2OR20, (CH2)nPO(OR20)2, (CH2)nP02R2o, or (CH2)nPOR20 where R20 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR21 or (CH2)nNHNHCOR2ι, where R21 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R22, S02NHR22, S02NHNHR22, S02N(R22)2, S02N(R22)(R23) or SO2R22, where R22 and R23 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHA can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue, and n is an integer between 0 and 4; aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R-]-R2 , R3-R4 , R6-R7 , R9-R10 , R4-R5 . R5-R6 . R8-R9 7 Rθ'Rio 1 ii- i2 and R-|2-Rι may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
[034] In formula II, M is a diamagnetic or paramagnetic photoactive metal ion preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, and Mg2+, wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions. In a preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IIA
Figure imgf000029_0001
IIA
In formula IIA, Ri-Rβ can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)O-alkoxy, or CH(CH3)0-aryl; (CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R7, where R is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nCO2R9, (CHX)nC02R9, or (CX2)nCO2R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R10), CONHNH(R10), CO(R10), CON(R10)2, CON(Rio)(Rn),
(CH2)nCONH(R10)> (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10, (CH2)nCON(R10)(Rn), (CX2)nCONH(R10), (CX2)nCONHNH(R10)I (CX2)nCON(R10)2, (CX2)nCON(R10)(Rιι), (CX2)nCORιo, (CHX)nCONH(R10), (CHX)nCONHNH(Rio), (CHX)nCON(R10)2) (CHX)nCON(Rio)(Rn), or (CHX)nCORιo, where X is a halogen, and Rio and Ru can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(Ri2), (CH2)nS(Ri2), (CH2)nNH(R12), (CH2)nNHNH(R12), (CH2)nN(R12)2,
(CH2)nN(Ri2)(Ri3), or (CH2)nN(R12)(R13)(Ri4)+A, where R12> R13 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Ri3) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-ι2, R13 and R14 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR15, (CH2)nPO(ORι5)2) (CH2)nPO2R15, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; (CH2)nNHCOR16 or (CH2)nNHNHCOR16, where R16 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, S02NHR17, S02NHNHRi7, S02N(Rιr)2, S02N(Rι7)(Rιs) or SO2Rι7, where R17 and Rι8can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR17 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue; aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and R1-R2, R3-R4 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
[035] In formula IIA, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions. Additionally, and in accordance with the present invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula III which may be useful in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
Figure imgf000033_0001
III
In formula III, Ri to Rι0 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group having a molecular weight of about 100,000 daltons; CH=CHCH2N+(CH3)3 A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), CO2H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0- alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8; C(X)2C(X)3, where X is a halogen;
C02Rιι, where Ru is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORι2, where R-|2 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R13, (CHX)nCO2Ri3, or (CX2)nC02Rι3, where X is a halogen, and R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(Ru), CONHNH(Ru), CO(R ), CON(R14)2, CON(R14)(Rι5),
(CH2)nCONH(R14), (CH2)nCONHNH(R14), (CH2)nCON(R14)2, (CH2)nCOR14, (CH2)nCON(R14)(Ri5), (CX2)nCONH(R14)> (CX2)nCONHNH(Rι4), (CX2)nCON(R14)2> (CX2)nCON(R14)(R15), (CX2)nCOR14, (CHX)nCONH(R14), (CHX)nCONHNH(R14), (CHX)nCON(R14)2) (CHX)nCON(R14)(Rι5), or (CHX)nCORι , where X is a halogen, and Ru and R15 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rιβ), (CH2)nS(R16), (CH2)nNH(R16), (CH2)nNHNH(R16), (CH2)nN(R16)2,
(CH2)nN(Rι6)(Ri7), or (CH2)nN(Rι6)(Ri7)(Ri8)+A, where R16, Ri7 and R18 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Rιβ) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where Ri6, R17 and R-ι8 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02ORι9) (CH2)nPO(OR19)2, (CH2)nP02Ri9, or (CH2)nPOR19 where R19 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR20 or (CH2)nNHNHCOR20, where R20 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R2ι, S02NHR2ι, SO2NHNHR2ι, S02N(R2ι)2, S02N(R2ι)(R22) or S02R21, where R2ι and R22 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR21 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue; aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R1-R2, R3-R4, R6-R7, Rs-Rg, R4-R5, R5- 6, Rg-R-io, and R10-R1 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
[036] In formula III, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions. In a preferred embodiment of the invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IIIA:
Figure imgf000037_0001
IIIA
In formula IIIA, R-i, R2, R3, R can be the same or different and can be selected from: a functional group of less than about 100,000 daltons;
C02R5, where R5 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR6, where R6 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R7, (CHX)nC02R7, or (CX2)nC02R7, where X is a halogen, and R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4; CONH(R8), CONHNH(R8), CO(R8), CON(R8)2, CON(R8)(R9), (CH2)nCONH(R8), (CH2)nCONHNH(R8), (CH2)nCON(R8)2, (CH2)nCOR8, (CH2)nCON(R8)(R9), (CX2)nCONH(R8), (CX2)nCONHNH(R8), (CX2)nCON(R8)2, (CX2)nCON(R8)(R9), (CX2)nCOR8, (CHX)nCONH(R8), (CHX)nCONHNH(R8), (CHX)nCON(R8)2l (CHX)nCON(R8)(R9), or (CHX)nCOR8, where X is a halogen, and R8 and R9 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rιo), (CH2)nS(Rιo), (CH2)nNH(R10), (CH2)nNHNH(R10), (CH2)nN(R10)2,
(CH2)nN(R10)( Ru), or (CH2)nN(R10)(Rιι)(Rι2)+A, where Rio, Ru and R 2 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-ιo) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R10, Ru and R-|2 possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR13, (CH2)nPO(OR13)2, (CH2)nPO2R13> or (CH2)nPOR13 where R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi4 or (CH2)nNHNHCORι4, where R14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R15, S02NHR15l S02NHNHRi5, S02N(R15)2, S02N(R15)(Rι6) or S02R15, where R15 and Rι6 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR15 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue; aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons.
[037] In formula IIIA, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+,
Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions. Additionally, and in accordance with the present invention, provided are phototherapeutic compositions of metallo-tetrapyrrolic compounds of formula IV which may be used in photodynamic therapy or in a medicament for treatment of diseases such as cardiovascular diseases:
Figure imgf000040_0001
IV
In formula IV, R-ι-R8 can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ethers, polyethers, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8; C(X)2C(X)3, where X is a halogen;
C02R9, where R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORιo, where R10 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Rιι, (CHX)nC02Ru, or (CX2)nC02Ru, where X is a halogen, and Ru is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R12), CONHNH(R12), CO(Rι2), CON(R12)2, CON(R12)(R13),
(CH2)nCONH(R12), (CH2)nCONHNH(R12), (CH2)nCON(R12)2> (CH2)nCOR12, (CH2)nCON(R12)(R13), (CX2)nCONH(R12), (CX2)nCONHNH(R12),
(CX2)nCON(R12)2, (CX2)nCON(R12)(Ri3), (CX2)nCORι2, (CHX)nCONH(R12), (CHX)nCONHNH(Rι2), (CHX)nCON(R12)2, (CHX)nCON(Rι2)(Rι3), or (CHX)nCOR12, where X is a halogen, and R-ι2 and R-π can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R14), (CH2)nS(R14), (CH2)nNH(R14)) (CH2)nNHNH(Rι4), (CH2)nN(Rι4)2,
(CH2)nN(R14)(R15), or (CH2)nN(Rι4)(Rι5)(Ri6)+A, where R14, Ri5 and R16 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R 4) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R , R15 and Ri6 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02ORi7, (CH2)nPO(OR17)2, (CH2)nP02Ri7, or (CH2)nPORi7 where R17 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi8 or (CH2)nNHNHCORι8) where R18 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; S03Rιg, S02NHR19, S02NHNHR19, S02N(R19)2) SO2N(R19)(R20) or SO2R19, where R-ig and R2o can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHA can also be an amino acid, an amino acid salt, an amino acid ester residue; aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and A, B, C, and D can be the same or different and can be selected from N, CH, CR2o, where R20 is selected from a halogen, aryl, substituted aryl, heteroaryl, alkyl, haloalkyl, heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a functional group of less than about 100,000 daltons.
[038] In formula IV, M is a diamagnetic or paramagnetic metal ion, photoactive metal ions being preferably selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, Mg2+ wherein optionally associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
[039] In accordance with a preferred embodiment of the invention, the metallotetrapyrrolic compounds of the invention are derived by various procedures from naturally occurring cyclic tetrapyrroles. The naturally occuring cyclic tetrapyrrolic molecules have the basic ring structure shown in Table 1 herein and are particularly preferred as starting materials for the synthesis of compounds of formula I.
[040] In another preferred embodiment of the invention, the metallotetrapyrrolic molecules of the invention are derived by the coupling of suitably substituted dipyrromethane, dipyrromethenes, biladienes, builirubins, pyrroles and functionalized aldehydes, or functionalized maleonitriles. These cyclic tetrapyrroles have the basic ring structure shown in Table 2, and are particularly preferred as starting materials for the synthesis of the compounds of formulae ll-IV.
[041] In accordance with another embodiment of this invention, there is provided a method for detection and treatment of cardiovascular tissue or other tissue abnormalities in a patient. The method comprises administering to the patient an effective amount of a metallotetrapyrrolic compound of the invention and exposing the tissue to light within the photoactivating spectrum of the particular tetrapyrrolic compound.
[042] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[043] The terms "tetrapyrrole", "tetrapyrrolic molecule," and "porphyrin" are used herein to designate compounds having a cyclic structure wherein four pyrrolic ring systems are linked via either carbon or nitrogen atoms. Compounds within the scope of the invention include porphyrins, mono-, di-, tri- and tetra- azaporphyrins, and porphyrin isomers such as porphycenes, isoporphycenes, hemiporphycenes, corroles, corrphycenes, and the like, provided they are capable of co-ordinating a metal ion.
[044] Included in the first class of metallated tetrapyrrolic compounds of the invention are those of the porphyrins. Scheme 1 outlines an example of the synthesis of porphyrins of the invention derived from blood derived porphyrins, for example hematoporphyrin or hemin. Several porphyrin classes can be synthesized by the routes shown. In these examples, hematoporphyrin can be modified by those skilled in the art by well known methods to give compounds (usually as their dimethyl esters) that possess defined functionality at R (Scheme 1 ). The R substituents most commonly utilized are vinyl (protoporphyrin IX) (2), ethyl (mesoporphyrin IX) (3), hydrogen (deuteroporphyrin IX) (4), CH(Oalkyl)CH3 (hematoporphyrin ethers) (5), and halogens (halogenated deuteroporphyrin IX) (6). Porphyrins that may be derived from plants are shown in Scheme 2. Particularly advantageous are the porphyrins such as chloroporphyrin e6 (9), chloroporphyrin e4 (10), phylloporphyrin (11), rhodoporphyrin (7), pyrroporphyrin (8), pheoporphyrin a5 (13) and phylloerythrin (12) and compounds having similar ring systems. Such compounds can be then modified according to the invention to increase their biological activity.
Figure imgf000046_0001
Scheme 1. Blood Derived Porphyrins
Figure imgf000047_0001
Scheme 2. Plant Derived Porphyrins
[045] While both blood and plant derived porphyrins are preferred as starting materials due to their commercial availably, a very large number of synthetic porphyrins are generally applicable to the invention. Such porphyrins may be made by synthetic methods known to those skilled in the art, via coupling of pyrrolic precursors, dipyrromethanes, dipyrromethenes and biladienes to give
the desired porphyrins with widely ranging functionality at both the β and meso
positions. The synthesis of porphyrins via the coupling of pyrrolic intermediates is outlined in detail in chapters 1-3 in "The Porphyrin Handbook" Editors, K.M. Kadish, K.M. Smith, R. Guilard, Volume 1 , Academic press, 2000, pp. 1-148, the disclosure of which is incorporated by reference herein. Such functionality will be explained in detail shortly. This functionality may be modified by further chemical reactions. Such compounds may then be modified according to the invention to produce metalloporphyrins that absorb light at or about 400, 532 and 575nm. While these wavelengths are preferred, it is recognized that other wavelengths > 400nm and less than 600nm may be used to excite compounds that absorb in this region. Table 1 outlines some of the preferred porphyrins that may be used as starting materials in the development of these types of compounds.
Figure imgf000048_0001
Table 1.
Figure imgf000048_0002
Figure imgf000049_0002
Et = CH2CH3, V = -CH=CH2
[046] A second preferred class of compounds according to the invention are the mono-,di,-tri and tetra- azaporphyrins. Schemes 3 - 7 outlines the synthesis of mono-, di- and tetra-azaporphyrins, examples of which are listed in Table 2.
Figure imgf000049_0001
Table 2.
Figure imgf000049_0003
, 15-Diaza-coproporphyrin 11 N CH N CH Me PO PO Me Me PO PO Me ,15-diaza-mesoporphyrin III N CH N CH Me Et Me Et PO Me Me PO
AO = -CH2CO2H; PO = -CH2CH2CO2H, EO = -CH(OH)CH3, EOE = -CH(OR)CH3, Me = - CH3, Et = CH2CH3, V = -CH=CH2
[047] Schemes 3 - 7 outline synthetic routes to novel tetrapyrrolic molecules of interest in treating diseases of the cardiovascular system and other diseases applicable to PDT. Such derivatives are of particular interest because all display absorption maximas at wavelengths at or near 400nm, 532nm and 575nm.
[048] Mono-azaporphyrins are synthesized efficiently via the coupling of dibromobiladienes with sodium azide or via the reaction of oxyporphyrins with ammonia. Copper and metal free diazaporphyrins are obtained via the coupling of 5,5'-dibromopyrromethenes with sodium azide. Tetraazaporphyrins are synthesized most efficiently via the treatment of substituted maleonitriles with Mg powder or magnesium alcoxides. Such reactions are well known in the art and are outlined in detail by N. Kobayashi in "The Porphyrin Handbook" Editors, K.M. Kadish, K.M. Smith, R. Guilard, Volume 2, Chapter 13, Academic press, 2000, p. 301-360, the disclosure of which is incorporated by reference herein.
[049] The peripheral functionality of these compounds is important with respect to further derivatization to achieve the desired therapeutic effect. It is recognized that small changes in the peripheral functionality can have pronounced effects on the biological efficacy of the molecules as does metal coordination to the compounds. Some of these compounds for example, are shown in Table 3.
[050] The new compounds of the invention are based on the porphyrin, mono-, di-, tri- and tetra-azaporphyrin ring systems that bear peripheral functionality on the ring system. Such functionality includes esters, alcohols, amides, amines, ethers, and phosphates. Such derivatives may also have at least one hydroxylated residue present, or an amine group on which at least one hydroxylated residue is present. The new porphyrins themselves may be photodynamically active as metal free analogs and therefore useful as PDT agents. However, metallated derivatives of these compounds are of particular interest in treatment of cardiovascular disease and normal or abnormal conditions of the hematological system, lymphatic reticuloendothelial system, nervous system, endocrine and exocrine system; skeletomuscular system including bone, connective tissue, cartilage and skeletal muscle; pulmonary system; gastrointestinal system including the liver; reproductive system; skin; immune system; cardiovascular system; urinary system; ocular system; auditory system;or olfactory system; where shorter wavelengths of light are necessary or advantageous to effect a desired therapy. In particular, porphyrin derivatives coordinating gallium are very interesting as these have been demonstrated to have greater uptake and efficacy in eliminating smooth muscle cells from the media and intima portions of arteries in a variety of animal models, than do other metalloporphyrins with different metal centers. These findings are discussed in detail in the Biological section.
[051] The new compounds of the invention are based on the porphyrin, mono-, di-, tri- and tetra-azaporphyrin ring systems that bear peripheral functionality on the ring system. Such functionality includes esters, alcohols, amides, amines, ethers, and phosphates. Such derivatives may also have at least one hydroxylated residue present, or an amine group on which at least one hydroxylated residue is present. The new porphyrins themselves may be photodynamically active as metal free analogs and therefore useful as PDT agents. However, metallated derivatives of these compounds are of particular interest in treatment of cardiovascular disease and normal or abnormal conditions of the hematological system, lymphatic reticuloendothelial system, nervous system, endocrine and exocrine system; skeletomuscular system including bone, connective tissue, cartilage and skeletal muscle; pulmonary system; gastrointestinal system including the liver; reproductive system; skin; immune system; cardiovascular system; urinary system; ocular system; auditory system;or olfactory system; where shorter wavelengths of light are necessary or advantageous to effect a desired therapy. In particular, porphyrin derivatives coordinating gallium are very interesting as these have been demonstrated to have greater uptake and efficacy in eliminating smooth muscle cells from the media and intima portions of arteries in a variety of animal models, than do other metalloporphyrins with different metal centers. These findings are discussed in detail in the Biological section.
[052] Schemes 3-7 outline chemistry that has been undertaken to produce photosensitizing agents according to the invention and are not intended to limit the scope of the invention. It should be noted that the functionality and position of the N and C meso atoms can be varied to produce analogs different from those shown. Additionally, the R groups in these schemes constitute functional groups that can be modified by techniques known to those skilled in the art based on the chemistry described herein without departing from the spirit or scope of the invention.
Figure imgf000053_0001
X = I,Br
Figure imgf000053_0002
X = I,Br M = Cu, 2H
Magnesium alchoxide
Figure imgf000053_0004
Figure imgf000053_0003
Scheme 3. Azaporphyrin Syntheses
Figure imgf000054_0001
Scheme 4. Modification of Porphyrin (X=CR) and azaporphyrin (X=N) compounds
Figure imgf000055_0001
Scheme 5. Modification of Porphyrin (X=CR) and azaporphyrin (X=N) compounds
Figure imgf000056_0001
Scheme 6. Modification of Porphyrin (X=CR) and azaporphyrin (X=N) compounds
Figure imgf000057_0001
Scheme 7. Modification of Porphyrin (X=CR) and diazaporphyrin (X=N) compounds
Synthesis of Metallotetrapyrroles ) Acids and salts of metallopomhyrin and metalloazaporphynns.
[053] A number of metalloporphyrins and metallo azaporphyrin acids and salts were synthesized. In general, a suitable free base tetrapyrrole ester was metallated and the ester functionality hydrolyzed using either basic or acidic conditions. Metal incorporation followed standard procedures well known in the art (see Johann Walter Buchler in "The Porphyrins", Ed. D. Dolphin, Academic Press, Chapter 10, 389-483). Isolation of the metallotetrapyrrolic acids was achieved by acidifying the metallotetrapyrrolic salt with acetic acid after the ester hydrolysis step, and the precipitated porphyrin collected. Preparation of the corresponding salts was most readily achieved by dissolution of the acid metalloporphyrin with a stoichiometric amount of either KOH or NaOH.
B) Esters of Metalloporphyrins and Metalloazaporphynns.
[054] A large number of metalloporphyrins and metallo azaporphyrin esters were synthesized. In general, a suitable free base tetrapyrrole acid was esterified using the appropriate alcohol and mineral acid (5%, H2S0 ). Metallation of the ester tetrapyrrole was achieved as described above.
C) Amide derivatives of Metalloporphyrins and azaporphyrins.
[055] Metallotetrapyrrolic amides were conveniently prepared using the metal free tetrapyrrolic acids. The metal free tetrapyrrolic acid compound was suspended or dissolved in dichloromethane and subsequently refluxed after the addition of oxaylchloride for 1-2 hrs or less. Removal of the solvent under dry conditions, followed by dissolution in dry dichloromethane and addition of the desired amine, produced the corresponding amide. Metallation was then achieved as described above. It was noted that in several instances where alcohol moieties were present on the molecule, attempts to metallate with gallium or indium or tin, using NaOAc as the proton scavenger, resulted in acetylation of the alcohol moiety. It was found convenient to hydrolyze the acetyl groups following the metallation process using K2Cθ3 methanol/H20 or dilute KOH/methanol/H2O.
[056] Alternatively, ester functionalities on tetrapyrrolic molecules may be reacted with amines at high temperature to produce the corresponding amides. These, in turn, may be metallated to produce metalloporphyrins with absorptions ranging between 500 and 600nm.
Synthesis of functionalized metalloporphyrins and azaporphyrins.
[057] The tetrapyrroles employed in the present invention to form the aforementioned amide bond include two major classes that are both well-known to those skilled in the art: 1) the carboxy or amino-containing tetrapyrroles derived by various means synthetically or from natural porphyrins; and 2) the carboxy-containing meso-tetraphenylporphyrins. Exemplary tetrapyrroles valuable for the preparation of the compounds contemplated by the present invention are listed in Table 1.
[058] A wide variety of functionality can be efficiently added to the macrocycles by way of the amide bond. Of particular interest are the tetrapyrrolic macrocycles bearing alkylamide functionalities, amino acids or amides of amino alcohols. In the latter instance, the amide bond is formed via coupling of a tetrapyrrolic carbonyl moiety with an amino alcohol such that mono-, di- or polyhydroxylated acyclic or cyclic, primary or secondary amides are formed. Thus, various amino alcohols are valuable for the present invention, including 2- aminoethanol, 2-amino-1 ,3-propanediol, 2-amino-2-(hydroxymethyl)-1 ,3- propanediol, D-glucosamine and similar such amino alcohols. Alternatively, amine containing tetrapyrroles may be coupled to carbonyl groups of a second functionalized compound thus forming compounds that are themselves amides. A) Reduction of ester functionalities of porphyrins and azaporphyrins.
[059] In general, ester reduction of metal free tetrapyrroles with lithium aluminium hydride produces the corresponding di-propyl alcohol derivatives. These derivatives can then be directly metallated to give metalloporphyrin di- alcohol complexes as described above with due consideration given to the acetylation of the alcohol. In some instances, for example with Pt tetrapyrroles, it was found more convienient to metallate the tetrapyrrole first then undertake the reduction of the ester. 5) Reaction of di-propyl alcohol tetrapyrrole derivatives
[060] The di-alcohol porphyrins and azaporphyrins may be modified in a number of ways. For example, they may be protected with tosylchloride or a similar leaving group and reacted with amines to give functionalized amino porphyrins, or reacted with salts of alcohols, thiols or malonate esters to give functionalized esters, ethers or functionalized thioethers which may be modified accordingly. In addition, the alcohol moiety may be replaced by a halogen (Scheme 3) and the subsequent mono or polyhalogenated tetrapyrrole reacted with lithium reagents to form corresponding adducts. Examples of lithium reagents are Li(CH2)nCO2alkyl (where n = 1-4), and lithiated aromatic reagents. In this way tetrapyrrolic molecules with longer alkyl chain carboxylic acid or ester functionalities may be produced and metallated.
[061] Alternatively, the mono- or polyhalogenated tetrapyrrole can be reacted with NaCN, which after treatment with HCI in methanol gives the corresponding tetrapyrrolic molecule with longer alkyl chain carboxylic acid or ester functionalities, which may be metallated. Also, such longer chain tetrapyrrolic esters may be made directly from biladienes routes. [062] In another alternative, the mono- or polyhalogenated tetrapyrrole can be reacted with PO(O-alkyl3) producing -CH2PO(0-alkyl)2 analogs that may be used directly or further modified by standard techniques.
[063] The dialcohol porphyrins and azaporphyrins can also be modified by reaction with acid chlorides and the like to form functionalized esters, by reaction with sulfonyl chlorides to produce the corresponding esters, or by reaction with phosphoryl chlorides to produce the corresponding phosphate esters or acids.
[064] Similar reactions may be undertaken on tetrapyrrolic molecules in which more than two carboxylic acid functionalities are present, for example those compounds shown in Tables 1 and 2. Such reactions on mono-, di- and tetra-azaporphyrin compounds are particularly preferred as metallo-derivatives of such compounds have larger molar extinction coefficients than the porphyrins in the green and yellow region. Thus, these compounds theoretically may be more efficient photosensitizers because a larger cross-sectional area of light may be absorbed. While the above examples list several chemical modifications to the tetrapyrrolic compounds, other modifications known to those skilled in the art could be made to the tetrapyrrolic ring systems without departing from the spirit or scope of the invention. Biological evaluation of Photosensitizers
[065] Metalloporphyrins were examined for biological efficacy in a variety of in vitro and in vivo model systems. In Vitro cytotoxicity assay
[066] The in vitro biological evaluation of photosensitizers for their ability to photosensitize cells was performed using standard procedures. Using 5% FBS/ DMEM phenol-free media, wells (180 μl/ well) were plated with 5 x 104 V79 (Chinese Hamster Lung Fibroblasts) cells/ml into two 96 well plates. Plate 1 was light-treated and plate 2 served as a control. The plates were Incubated at 37° C, 5%CO2 for 3-5 hours. Standard solutions of the photosensitizers were dissolved in pre-filtered Dimethyl Sulfoxide (DMSO). Drug was diluted in 5% FBS DMEM phenol free medium. Final drug concentrations for light and dark experiments were 0.01 , 0.1 , 1.0, 3.0 and 5.0 μM. Twenty microliters of each concentration were added to six replicate wells to the light and dark plate. The plates were wrapped in aluminum foil to avoid photoactivation and mixed in a gyratory shaker for approximately 2 minutes. Both plates were incubated for 24 hours at 37° C, 5%CO2. After a 24 hour incubation, drug-containing media was aspirated from the plates. Each well was rinsed with 180 μl Hepes buffer salt solution (HBSS) then aspirated to remove the HBSS. 180 μl of fresh media were added (5% FBS/DMEM phenol-free) to each well. Plate 1 was immediately light treated at a wavelength of 532 nm (metalloporphyrins and Pt azaporphyrins) or 575nm (metalloazaporphyrins) with a power setting of 354 mW and a fluence of 1.25 J/cm2 for 7 min 22 seconds. Plate 2 was not light treated. Immediately after light treatment, 20 μl Alamar blue was added to each well in plate 1. Alamar blue was added to plate 2 immediately after fresh media was added. The plates were mixed on a gyratory shaker for 5 min.
[067] Both plates were incubated under dark conditions for 24 hours at 37° C, 5%C02. After 24 hour incubation, the plates were read on a plate reader spectrophotometer (Spectra Max 250) at wavelengths 570 and 600 nm. and the percentage of cell survival recorded. Tables 3, 4, 5, and 6 contain in vitro light
EC50 data for the new photosensitizers. The Light EC50 data compares photosensitizers for their ability to kill cells at various concentrations.
Photosensitizers that showed promise passed into the in-vivo animal models.
In Vivo
EVALUATION OF METALLOTETRAPYRROLIC PHOTOSENSITIZERS ON SKIN
[068] We tested metallo- and metal-free tetrapyrroles systemically (see following section) for normal skin response in relation to the pharmacodynamic distribution of the photosensitizers in CD hairless rats. The skin of CD hairless rats are poorly developed, often referred to as hyperkeratotic, with various sized cystic hair follicles containing concentric lamellar accumulations of keratinaceous material, which are often associated with enlarged sebaceous glands. It quickly became apparent that gallium tetrapyrroles induced a marked clearing of the hyperkeratotic lesions in the treatment areas on the hairless rats. In fact, this clearing could be induced without necrosis of the skin. No other metallotetrapyrrole type produced such effects. This observation led us to assess the metallotetrapyrrolic compounds for skin restructuring effects both topically and systemically and for their ability to reduce hair growth in the following animal models. A) Systemic In-Vivo normal skin response (CD Hairless rats)
[069] Photosensitizer normal skin response as well as skin healing response, was evaluated using CD Hairless male rats. Photosensitizers were administered in an liposomal egg yolk phospholipid formulation at 1 , 1.5 and 2
μmol/kg body weight formulation per dose group as a single bolus intravenous
injection given through a marginal tail vein using a 27 gauge needle and a 1 cc tuberculin syringe. Normal skin responses were evaluated by irradiating several spots on the skin of the rat with a 532nm laser (150 mW/cm2, 150J, 1 cm diameter) at 1 , 6, 24, 48, and 96 hrs post injection. Normal skin responses were evaluated and documented. The time at which the last spot is observed at the concentration injected is reported in the far right hand column in Tables 3, 4, 5 and 6. Skin samples were taken for histological evaluation at days 1 , 10, 20 and 22 post light treatment. Rats were housed under normal lighting and all study procedures involving the test article were conducted under light filtered through blue and green Roscolox light filters to prevent photoactivation or degradation of the drug. Systemic Results
[070] A total of 160 free base and metallotetrapyrrolic photosensitizers were evaluated in the model and, surprisingly, the only compounds that showed clearing of the hyperkeratotic lesions without normal skin responses or necrosis were the gallium-containing tetrapyrroles. Histologically, the skin responses observed were identical to that induced topically, which is explained in detail in the following section. Typically, in the metallo or free base tetrapyrroles studied,
at drug doses of 1.0, 1.5 or 2.0 μmol/kg, there were skin responses with light
treatment over the range of 1 to 96 hours post drug administration, depending on the skin pharmacokinetics of the molecules (see Tables 3, 4, 5, 6 for example). At the higher drug doses, indicated skin responses, included moderate eschar, mild purpura and mild to moderate halo with light treatment. In most instances, skin responses resulted in the formation of an escar, which healed over 14-20 days to give an excellent cosmetic effect. In general, optimal skin responses which included escar formation, resulted histologically in full epidermal necrosis,
extending in most cases to 300μm into the dermis. Such destruction of the skin
tissue makes these gallium-containing tetrapyrroles very interesting with respect to ablation of superficial diseases including superficial cancers of the skin, barrets esophagus, early stage lung cancer, actinic keratosis, basal cell carcinomas and the like. While many tetrapyrrolic compounds are able to induce necrosis of the epidermal layer, only the gallium tetrapyrrolic compounds under specific drug/light and time dose combinations are able to induce necrosis of the epidermal layer or alternatively cause clearing of hyperkeratotic skin lesions with deposition of collagen formation (see following section) without necrosis of the skin. Such skin clearing is observed easily at lower drug doses (for example
1 μmol/Kg) at treatment times of 24, 48 or 96 hrs post drug injection, which failed
to give escar, purpura or halo skin responses.
B) Topical In-Vivo normal skin response
[071] Topically applied Gallium tetrapyrroles (3, 15 and 66) dissolved at a concentration of 0.1-0.4% in several gel formulations (formulation ingredients: benzylalcohol 0-30%, oleyl alcohol 0-2%, hydroxypropylcellulose 0.5-2.0%, ethanol Qs (amount required to make the formulation to 100%)) were assessed for their ability to cause skin necrosis, hair removal and surface remodelling in the rat and guinea pig models using the following protocols. Data described below corresponds to a formulation where the formulation excipients were benzylalcohol 19.6%, oleyl alcohol 2%, hydroxypropylcellulose 1.5%, ethanol Qs (amount required to make the formulation to 100%). Guinea Pigs (Single Topical Dermal Application):
[072] 12 week old female albino Hartley guinea pigs (Simonsen:Sim HA) (n=3) were used to assess the effects of photodynamic therapy with the gallium tetrapyrroles in gel vehicle applied to the skin. Gallium tetrapyrroles in gel vehicle were administered at 0.1 mg/cm2 (0.45% w/w) to a total of 3 guinea pigs as a single application to 1 cm2 treatment areas (30 μl vehicle gel or formulated drug/spot) without subsequent occlusion. Light treatment at 400 J/cm2 was administered 24 hours post drug application. Skin responses were evaluated daily for 3 weeks after light treatment. The test site was clipped one day prior to treatment and as necessary for skin observations. Guinea pigs were housed and all study procedures involving the test article were conducted under light filtered through blue and green light filters to prevent photoactivation or degradation of the drugs. Sprague Dawley Rats (Single Topical Dermal Application);
[073] 12 week old male Sprague Dawley rats (Harlan) (n=11 ) were used to assess the effects of photodynamic therapy with gallium tetrapyrroles (121 , 15, 66) in gel vehicle applied to the skin. Gallium tetrapyrroles in gel vehicle were
administered at 0.14 (30μL), 0.28 (200μL), or 0.6 (30μL) mg/cm2 (0.45%, 0.45%,
2% w/w, respectively) to a total of 11 rats as a single application to 1 cm2 treatment areas (30-200 μl/treatment spot) with semi-occlusion. Light treatment at 400 J/cm2 was administered at 4 and 24 hours post drug application. Skin responses were evaluated up to 3 months post light treatment. The test site was clipped one day prior to treatment and as necessary for skin observations. Skin samples were taken for histological evaluation at days 1 , 10, 20 and 28 post light treatment. Rats were housed under normal lighting and all study procedures involving the test article were conducted under light filtered through blue and green filters to prevent photoactivation or degradation of the drugs.
HISTOLOGICAL EVALUATION
[074] The extent of epidermal and/or dermal involvement was determined via histological evaluation. The grading parameters for histological evaluation included the degree of epidermal/dermal necrosis, the depth of necrosis, edema, and infiltration of heterophils in the epidermis/dermis. Skin was also evaluated for collage, elastin, fibronectin and immune cells via immunohistochemistry. Tissues collected for histopathology were placed in plastic embedding cassettes and immersed in 10% phosphate buffered formalin. Fixed tissues were paraffin-embedded and sectioned into approximately 4-8 μm thickness slices using a microtome. Slides were stained using hematoxylin and eosin or collagen/elastin stains and interpreted by a qualified veterinary pathologist blinded to the study groups.
Topical Results:
GUINEA PIGS
[075] All three gallium tetrapyrroles behaved similarly in the topical animal models. Clearing (early scarring or extracellular matrix deposition) with very mild eschar formation was seen in the skin for approximately 7-14 days post light treatment. No other skin responses were noted. Hair regrowth was not affected.
HAIRLESS RATS
[076] With the exception of clearing of the hyperkeratotic skin (remodeling of epidermal / dermal skin) at 7 days post light treatment, there was no skin response in animals that were light treated 24 hours post drug administration topically. Clearing (early scarring or extracellular matrix deposition) was seen for up to 40 days post light treatment. Within the dermis at
the dermal/epidermal border, there was an approximately 75 μm thick zone of
increased cellularity consisting of spindle to stellate cells with oval nuclei consistent with fibroblasts. The stroma in this area was pale and eosinophilic compared to the underlying unaffected dermis. At the early light treatment time points, there was mild serocellular crust indicating epidermal necrosis.
SPRAGUE DAWLEY RATS
Using compound 3 topically, there was no skin response at 0.14 mg/cm2, however the time for hair regrowth was delayed for approximately 21 days. At 0.28 mg/cm2, clearing formation (early scarring or extracellular matrix deposition) of the skin was seen at 7 days post light treatment and persisted for at least 28 days. There were no other skin responses observed in animals treated at 0.28 mg/cm2. At 0.28 mg/cm2, hair regrowth was delayed in the treatment site for approximately 38 days post light treatment. At 0.6 mg/cm2, there were skin responses (small, slight eschar) for up to approximately 10 days post light treatment, followed by clearing formation (early scarring or extracellular matrix deposition) for at least 30 days and with variable clearing persisting for up to 3 months post light treatment.
[077] At 0.6 mg/cm2, hair did not regrow in the treatment site for approximately 38 days post light treatment. Within the dermis at the
dermal/epidermal border, there was an approximately 75 μm thick zone of
increased cellularity consisting of spindle to stellate cells with oval nuclei consistent with fibroblasts. The stroma in this area was pale and eosinophilic compared to the underlying unaffected dermis. At the higher drug doses, there was mild serocellular crust indicating epidermal necrosis. There were also scattered lymphocytes and neutrophils. No changes were noted in the hair follicle.
[078] The pale and fibrillar collagen was consistent with remodeling of the epidermis and represents a more immature connective tissue at the dermal/epidermal junction of the dermis. There was no difference in elastin fibers in cases with the previously described pale stroma at the dermal/epidermal junction as compared to sections that did not have the pale zone. In all sections examined, the dermis contained less than 5% elastin stained fibers. Based on these findings, a change in elastin fibers is not evident within the dermis.
[079] The epidermal changes found in this study are consistent for the three photosensitizers tested topically and for the systemically administered gallium tetrapyrroles. These changes are usually present following regrowth of the epidermis after necrosis or ulceration. However, based on the lack of gross necrosis or ulceration of the overlying epidermis in most cases, this change is most likely a direct affect of the treatment. The replacement of granulation tissue with scarring with no or minimal necrosis involves transitions in the composition of the extracellular matrix. Some of the growth factors that stimulate synthesis of collagen and other connective tissue molecules also modulate the synthesis and activation of metalloproteinases or other proteolytic enzymes. The net result of extracellular matrix synthesis versus degradation results in remodeling of the connective tissue framework, an important feature of both chronic inflammation and wound repair. Based on these observations, systemic or topical application of gallium tetrapyrrolic compounds produces unique skin restructuring processes that were not observed for any of the other metal free or metallo tetrapyrrolic photosensitizers studied and may be particularly valuable for the treatment of epithelial or endothelial cell layers of tissues, scars, wound healing, psoriasis, chronic inflammatory diseases, eczema, immune modulated diseases, scleraderma, shingles, wrinkles, hair removal, actinic keratosis, carcinomas or sarcoma of the skin or other tissues, fungual infections, viral or bacterial infections, warts, arthritis, port wine stains, birth marks, stretch marks, hyper pigmentation, urticaria, allegenic reactions, chronic proliferative dermatitis, chronic ulcerative dermatitis, disorders of hair or hair follicles, disorders of skin pigmentation, acne, cutaneous infections, skin tumors, seborrheic dermatitis, cutaneous vasculitis, erythema multiforme and nodosum. In Vivo rat corotid artery [080] The acute effects of metallated photosensitizers, in response to light activation, to cause depletion of cell populations in the medial and adventitial layers of vessels was measured in normal uninjured rat carotid arteries. Sprague Dawley rats (Harlan, IN, USA) received an intravenous injection of the test
substance (at doses typically 0.5 - 4 μmol/kg body weight, in a liposomal egg yolk
phospholipid formulation), 120 - 240 min before light delivery. Shortly before the light treatment, the rats were anaesthetized with 3.5% isoflurane (Abbott Laboratories, IL, USA) and the femoral region of the right leg was shaved and cleaned. A small midline incision was made and a 1 cm region of the right femoral artery was surgically exposed and dissected from surrounding tissues.
[081] A direct arteriotomy was performed and a light balloon catheter (Miravant Medical Technologies, Inc) was introduced into the vessel and advanced retrogradely into a non-manipulated region of the left common carotid artery via the abdominal aorta. The light catheter was then inflated at 1 atmosphere, to the dimensions of 2 mm x 20 mm, and light was delivered to the carotid artery via a diffuser centered within the catheter. The light dosimetry was fixed at 50 J/cm2 fluence and 160 mW/cm2 irradiance. After light treatment and removal of the catheter, the right femoral artery was tied off and the skin wound was closed. Rats were sacrificed three days post treatment as this corresponds to the known peak time that vascular cells, e.g., VSMC and myofibroblasts, proliferate and migrate in response to an injury.
[082] The area spanning both left and right carotid arteries and surrounding tissue was harvested, fixed, embedded in paraffin and sectioned. The tissues were stained with Hematoxylin and Eosin (Fisher Scientific, PA) and examined by light microscopy to histologically assess the cell population density in the medial and adventitial layers of the PDT-treated vessel wall. Tables 3, 4, 5 and 6 contain results expressed as the % maximum accellularity (depletion of cell population densities) for the molecules tested. Metallo azaporphyrins with Ga, Zn, Al, Sn were excited at 575nm, while Pt azaporphyrins were excited at 532nm.
Figure imgf000072_0001
Figure imgf000072_0002
Figure imgf000073_0001
Figure imgf000074_0002
Compounds in Table with no example number were tested but not synthesized in the Examples.
Some compounds in Table were synthesized in Examples but not tested.
Figure imgf000074_0001
Table 4. Azaporphyrins (nd = not done)
Example M R1 , R2, R4 R In Drug Max % Rat Normal No R3 Vitro dose Artery skin
Figure imgf000075_0002
Figure imgf000075_0001
75
Table 5. Plant derived gallium porphyrins
Figure imgf000077_0002
Figure imgf000077_0001
Table 6. Metallodiazaporphyrins
Figure imgf000077_0003
Figure imgf000078_0001
In Vivo Pig Coronary artery experiments
[083] Those photosensitizers showing excellent efficacy in the rat carotid artery model were evaluated in more detail in the pig coronary artery model (Waksman, R., Rodriguez, J.C., Robinson, K.A., Cipolla, G.D., Crocker, I.R., Scott, N.A., King, S.B., Wilcox, J.N., Circulation, 96, 1944-1952, 1997). If vascular PDT is to be proposed as a therapy to prevent restenosis in humans due to angioplasty or stenting, then it must first be shown to be effective in a large animal model such as the swine. Porcine coronary arteries are very similar to human coronary arteries with regard to size, neointima formation, and thrombosis in response to injury.
[084] The swine model has been utilized in the preclinical evaluation of interventions to reduce restenosis for several reasons. Chief among these reasons are the similarities in (i) size and anatomy of the swine arteries to human arteries, that permits instrumentation and evaluation of results via catheters; and (ii) histopathological characteristics of the proliferative response following artery injury similar to that seen in humans. Furthermore, large animals including the swine have proven to be more predictive of success in reducing restenosis in humans than have small animal models. An extensive literature search (e.g., Weiner, B.H., et al. Circulation. 72:1081-1086, 1985; Schwartz, R.S., et al. Circulation. 82:2190-2200, 1990; Vascular Brachytherapy, Veenendaal, The Netherlands: Nucletron B.V. 1996 pp. 1-382) supports the notion that restenosis after balloon injury in porcine coronaries is the best model when compared to restenosis in humans. Therapies investigated in other species still must be confirmed in the porcine model. Several articles reviewing the relevant animal models for the study of restenosis have concluded that although imperfect, as are all animal models, the porcine model is still the best from the standpoint of similarity to human disease, ease of use, and cost (e.g., Schwartz, R.S., Murphy, J.G., Edwards, W.D., Camrud, A.R., Vlietstra, R.E., and Holmes, D.R. Restenosis after balloon angioplasty: A practical proliferative model in the porcine coronary arteries. Circulation. 82:2190-2200, 1990; Karas, S.P., Gravanis, M.B., Santoian, E.G., Robinson, K.A., and King, S.B., 3d Coronary intimal proliferation after balloon injury and stenting in swine: an animal model of restenosis. J.Am.Coll. Cardiology 20:467-474, 1992).
[085] Photosensitizers were administered systemically (at doses typically 2 - 3.5 mg/kg body weight, in a soybean phospholipid formulation) as a slow bolus injection in the ear vein. Drug treatments were followed (1 - 4hr later) by endovascular light treatment (50-250 J/cm2 fluence and 100-300 mW/cm2 irradiance) in uninjured coronary (50-250 J/cm2 fluence and 100-300 mW/cm2 irradiance) and iliac (50-350 J/cm2 fluence and 100-450 mW/cm2 irradiance) arteries. In another set of experiments, animals also received balloon injuries in the coronary arteries at the time of PDT treatment. Angioplasty injuries in 2 coronary arteries were performed. Vital signs and cardiovascular parameters such as ECG, HR, BP, were monitored together with arterio-angiograms for measurements of vessel patency.
[086] For acute experiments done in uninjured arteries, 3-5 days after the PDT experiments, animals were sacrificed and serial sections of all relevant arteries (iliacs, & coronaries) were harvested in 10% formalin and processed for histological assessment. Results of PDT at this timepoint give us an insight into the selective cellular effects of PDT on VSMC and myofibroblasts which are known to be maximally proliferating and migrating at this same time in response to a vessel wall injury - such as an angioplasty.
[087] For longer term efficacy experiments (14 days after the PDT experiments) animals were sacrificed and serial sections of all relevant arteries (coronaries only) were harvested in 10% formalin and processed for histological assessment. Representative arterial segments underwent parafin embedding and sectioning for Hemoxylin & Eosin and/or elastin staining. Slides were prepared for microscopy histological analysis of the (i) acute cellular responses and (ii) inhibition of neointima formation following treatment. Once prepared, the slides were analyzed via microscopy for histomorphometry and effects such as medial wall acellularity, arterial wall and surrounding tissue cell death and proliferation. The results of acellularity (depletion of cell population densities) and inhibition of restenosis are shown in Table 7. Control arteries that were subjected to angioplasty balloon injury displayed extensive neointimal development at 14 days as typically seen in this model. In contrast, coronary arteries subjected to angioplasty balloon injury and treated with the test substances and light activation at the time of injury, had markedly reduced neointimal formation. The magnitude of the inhibition was greater than any other photosensitizer drug currently used by other groups in PDT (clinically or pre-clinically), and was on the order of that only previously seen with radiation in this model. Inhibition data is averaged over the injury length within the artery.
Table 7. Pig coronary artery data
Figure imgf000082_0001
Biological results of metalloporphyrins and metalloazaporphynns in Vitro and in restenosis animal models in Vivo.
[088] Before this study very little information was known about the uptake and biodistribution of metallotetrapyrrolic compounds biologically, either as their acids, salts, esters, amines or amides. In particular, nothing is known about the distribution of metalloporphyrins in cardiovascular diseases, nor has anyone assessed structure-activity relationships. The following summary of what has been determined is as follows. A) Acids and salts of metalloporphyrin and metalloazaporphynns.
[089] A number of metalloporphyrins and metallo azaporphyrin acids and salts were tested for efficacy. In vitro, several of these compounds show the ability to kill cells. However, it appears that the metallotetrapyrrolic salts at early treatment time points post-administration are slightly less efficacious at the same drug dose than the metallotetrapyrrolic acid compounds in vivo. For example, as shown in Table 3, the disodium salt (109) shows 10% accelularity at a four hour treatment point using the above described protocol, whereas its acid derivative shows 15% accelularity. A similar observation is seen between compounds 87 and 88 (30% and 10% respectively; Table 4). While this appears to be a general observation, it is highly probable that water-soluble compounds may be synthesized in accordance with the invention that, given the correct pattern of peripheral substitution and functional group selection, may show activity. Additionally, higher drug doses may be required to effect a treatment. It is interesting to note that the water soluble gallium porphyrins and azaporphyrins do not display significant skin photosensitivity at the doses used, making them potentially particularly interesting and valuable compounds. For example, compounds 88 and 109 gave no observed normal skin response at the drug doses used. It has also been noted that significant acellularity occurs following PDT treatment of rat arteries with water soluble gallium azaporphyrins and gallium porphyrins at longer treatment times post injection (16, 24 hrs). Examples of this are with compounds 109 and 88 (Table 4). It is important to note that the metal-free azaporphyrin carboxylic acid (first entry table 4) displays poor efficacy (0%, 4hrs) in the arterial rat model, even though in vitro it appeared to be a potent molecule. We have investigated several other free base porphyrins and all have poor efficacy in the arterial rat model at the time point, drug and light dose parameters used (compound nos. (7a), mesoporphyrin dimethyl ester, metal-free analogs of compounds (26) and (28)). Thus it appears that metallation of tetrapyrrolic macrocycles, especially with gallium, enhances efficacy significantly. B) Esters of Metalloporphyrins and azaporphyrins.
[090] The most active compounds tested for the elimination of cells in the medial and adventitial layers of vascular vessels are the esters (Tables 3 and 4). The nature of the ester functionality has been shown to influence the biodistribution and skin pharmacokinetic profile of the molecules. A surprising observation is that in almost all of the cases, gallium tetrapyrrolic esters are efficient at depleting cell population densities in the medial and adventitial layers of vascular vessels, much more so than almost all other metal types. For example, the superiority of the gallium complexes over other metal types are shown with compound (1) (Ga), as compared to compounds (31), (30), (33); compound (12)(Ga), as compared to compound (41 ); compound (26)(Ga), as compared to compounds (45), (47), (48), and (49) (the indium complex (46) is more potent than the gallium complex (26), however death occurs in the animals at 3X the therapeutic dose); compound (28) (Ga), as compared to compounds (51 ), (52), (53), (54), and (55); compound (121 ) (Ga), as compared to compounds (58), (59), and (60); compound (7) (Ga), as compared to compounds (72), (73), (7a), (74); and compound (21 )(Ga), as compared to compounds (82), (83), and (84). Additionally, in pig coronary artery models, no cardiotoxicity was observed with compounds (1), (4) or (121 ) at doses exceeding 20 mg/Kg. Among the other metal types that also look promising are the indium tetrapyrrolic ester compounds; however, we have found that there is significant toxicity with the indium porphyrins studied at drug doses close to that of the therapeutic dose. This may limit their usefulness as therapeutic agents administered intravenously. [091] As would be expected, changing the peripheral functionality on the gallium tetrapyrrolic macrocycles changes their pharmacokinetic and distribution profiles in vivo. In some derivatives changing the methyl esters to ethyl esters also reduces the clearance time from the skin of the molecule by a factor of 2. One such example where this is illustrated is a comparison of normal skin responses between gallium mesoporphyrin dimethyl ester (1 ) and gallium mesoporphyrin diethyl ester (2). The dimethyl ester (1 ) at a drug dose of 1
μmol/Kg shows normal skin responses to 48 hrs post drug injection in rats (Table
3). Its ethyl ester derivative on the other hand at identical drug and light doses shows normal skin responses up to 24 hrs and not beyond (Table 3). Another example is gallium deuteroporphyrin ethyl ester (5) and propyl ester (122). The
propyl ester (122) at a drug dose of 1 μmol/Kg shows normal skin responses only
to 6 hrs post drug injection in rats versus 48 hrs as seen for the ethyl ester derivative (5).
[092] Also surprising is that increasing the alkyl chain length of R2 (Table 3), e.g., from 0 carbon CH2 units (i.e., compound (1 ) a propionic acid ester side chain) to 5-CH2 units (compound (57)), also decreases the normal skin
response by a factor of 8 (6 hr spot only at 1 μmol/Kg), without a significant
decrease in biological activity (1 μmol/Kg gives 80% acellularity), when compared
to compound (1) (1 μmol/Kg, 95%). Another example of note is that gallium
rhodoporphyrin dimethyl ester (123) is cleared more rapidly from the skin (6 hrs) than is gallium mesoporphyrin dimethyl ester (1) (48 hrs). Such changes in biological responses in response to the functional modifications to tetrapyrrolic compounds have not previously been recognized. Two such gallium tetrapyrrolic esters, gallium mesoporphyrin dimethyl ester (1) and gallium deuteroporphyrin dimethyl ester (4) have shown >80% and >75% average inhibition of intimal hyperplasia over the length of the injured artery in pig coronary arteries (Table 7; many treated artery sections show 100% inhibition). The results with these test substances are comparable to that observed only with vascular brachytherapy and to our knowledge are dramatically better than any other photosensitizers described to date in vascular studies with PDT. C) Amide derivatives of Metalloporphyrins and azaporphyrins.
[093] Very little is known about the uptake and biodistribution of metallotetrapyrrolic amide molecules. Metallocomplexes of gallium tetrapyrrolic amides vary in biological activity. Simple amides such as -CONHCH3 and - CON(Et2) appear to generate excellent responses in cardiovascular tissues. In particular, it has been found that replacing the methyl ester functionality in certain tetrapyrrolic molecules with a methyl amide group (-CONHCH3) decreases the skin clearance of the new amide derivative in animals by a factor of approximately eight when compared to the parent ester tetrapyrrole. Longer amide alkyl chains result in longer skin clearance times (for example the dihexyl amide derivative shows a 96hr normal skin spot table 3). The shortening of the skin clearance time for a molecule will have major clinical implications to patients, as long periods of photosensitivity are particularly undesirable. One such example where this is illustrated is a comparison of normal skin responses between gallium mesoporphyrin dimethyl ester (1) and gallium mesoporphyrin N-
methylamide (121 ), Table 3. The ester compound at a drug dose of 1 μmol/Kg
shows normal skin responses to 48 hrs post drug injection in rats. Its methylamide derivative (121 ) on the other hand at identical drug and light doses shows normal skin responses up to 6 hrs and not beyond. Additionally the stability of the methyl amide derivative and the diethylamide derivative in liposomal formulations may be longer than the diester analog, which may prove to be valuable in the pharmaceutical development of such compounds. Notable also is the fact that some of the metallotetrapyrrolic amides show no normal skin response at the doses used, and do not appear to be efficient photosensitizers. Such compounds may be of immense value as radiodiagnostics (where radioactive gallium isotopes are used for example) or as fluorescence diagnostic agents. It should be noted that the methyl amide derivative (121 ) of gallium mesoporphyrin at 3 mg/Kg, and light fluence of 125J/cm2 shows >75% average inhibition of intimal hyperplasia over the length of the injured artery in pig coronary arteries (Table 7; Many treated artery sections show 100% inhibition). These results are comparable to that observed only with vascular brachytherapy and to our knowledge are dramatically better than any other photosensitizer described to date in vascular studies with PDT.
D) Metalloporphyrin and metalloazaporphyrin alcohols.
[094] Very little is known about the uptake and biodistribution of tetrapyrrolic alcohol molecules either, topically or in cardiovascular diseases. Gallium derivatives of these compounds (Table 3, (7), for example) are efficient at dramatically reducing the number of smooth muscle cells in the media and myofibroblasts in the adventitial layers of rat arteries, while other metal types (for example (72), (73), (74) appear to be less efficacious or more toxic). It is also interesting to note that the metal-free mesoporphyrin propyl alcohol derivative (7a; Table 3, for example) shows no efficacy in the rat arterial model at drug
doses up to 2μmol/Kg. E) Phosphate tetrapyrrole derivatives
[095] Only two phosphonate analogs of metallotetrapyrrolic complexes were synthesized and evaluated in vitro. Compared to the ester tetrapyrrolic macrocycles, neither compound was particularly outstanding, however the indium analog (81 ) is photodynamically active in vivo, and hence has potential as a photosensitizer of disease conditions.
[096] In summary, the pharmacological properties of the novel compounds according to the invention are substantially different from those of existing photosensitizers described to date in the literature. In particular, the compounds investigated possess the following properties.
(I) They are distributed and localized to vascular vessels following injections
(II) They are activated at wavelengths of 500-600 nm to cause selective biological effects in the target vascular tissue.
(III) Following light activation, they cause significant depletions of medial wall vascular smooth muscle cells and adventitial myofibroblast cells in the coronary and peripheral vasculature at a time-point when these cell types are known to be maximally proliferating and/or migrating in response to vessel wall injury.
(IV) They demonstrate markedly reduced neointimal formation in coronary arteries following angioplasty injury, the magnitude of which has only previously been demonstrated with radiation therapy.
(V) They have no adverse effects on heart rate, blood pressure or electrocardiogram at doses that inhibit vascular injury responses. (VI) Upon light activation, the photodynamic effect is localized to the treatment zone of the vascular vessel, while sparing underlying tissue including the myocardium surrounding the coronary arteries.
(VII) They show marked skin remodelling characteristics not observed with other photosensitizers without necrosis of the skin, depending on the time of treatment and dosimetry used.
(VIII) They are able to necrose skin or tissues at specific treatment times and light dosimetry.
[097] The scope of the present invention is not limited to the examples provided herein. As shown by the above examples, any porphyrinic molecule may be modified according to the invention to form the desired photoactive compounds with widely differing functionality as described in the literature (for example see "Porphyrins and Metalloporphyrins" ed. K. Smith, Elsevier, 1975, N.Y. and "The Porphyrins", Ed D. Dolphin, Vol l-V, Academic Press, 1978; "The Porphyrin Handbook", Ed. K. Kadish, K. M. Smith, R. Guilard, Academic Press, 1999 incorporated by reference). These compounds contain various and ranging
substituents on the β-pyrrole positions or meso-positions of the porphyrin ring,
either symmetrically or asymmetrically substituted on the ring. Examples of such functionality include functional groups having a molecular weight less than about 100,000 daltons and can be a biologically active group or organic in nature. Examples include, but are not limited to: (1) hydrogen; (2) halogen, such as fluoro, chloro, iodo and bromo (3) lower alkyl, such as methyl, ethyl, CH(CH3)2, n- propyl, butyl, hexyl, heptyl, octyl, isopropyl, t-butyl, n-pentyl and the like groups; (4) lower alkoxy, such as methoxy, ethoxy, isopropoxy, n-butoxy, t-pentoxy and the like; (5) hydroxy; (6) carboxylic acid or acid salts, such as — CH2COOH, — CH≥COONa, — CH2CH2COOH, — CH2CH2COONa, — CH2CH2CH(Br)COOH, — CH2CH2CH(CH3)COOH, — CH2CH(Br)COOH, — CH2CH(CH3)COOH, — CH(CI)CH2CH(CH3)COOH, — CH2CH2C(CH3)2COOH, — CH2CH2C(CH3)2COOK, — CH2CH2CH2CH2COOH, C(CH3)2COOH, CH(CI)2COOH and the like; (7) carboxylic acid esters, such as — CH2CH2COOCH3, — CH2CH2COOCH2CH3, — CH2CH(CH3)COOCH2CH3) — CH2CH2COOCH2CH2CH3, — CH2CH2CH2COOCH2CH2CH3, — CH2CH(CH3)COOCH2CH3, — CH2CH2COOCH2CH2OH, — CH2CH2COOCH2CH2N(CH3)2 and the like, particularly halogenated alkyl esters; (8) sulfonic acid or acid salts, for example, group I and group II salts, ammonium salts, and organic cation salts such as alkyl and quaternary ammonium salts; (9) sulfonylamides such as — S02NH(alkyl), — S02N(alkyl)2, — S02NH(alkyl-OH), — S02N(alkyl-OH)2, — S02NH(alkyl)-N(alkyl)2, — S02N(alkyl-N(alkyl)2)2, S02(NH(alkyl)-N(alkyl)3 +Z-) and the like, wherein T is a counterion, — SO2NHCH2CO2H, substituted and unsubstituted benzene sulfonamides and sulfonylamides of aminoacids and the like; (10) sulfonic acid esters, such as S03(alkyl), S03(alkyl-OH), S03(alkyl-N(alkyl)2), S03(alkyl- N(alkyl)3 +Z") and the like, wherein Z" is a counterion, SO3CH2CO2H, and the like; (11) amino, such as unsubstituted or substituted primary amino, methylamino, ethylamino, n-propylamino, isopropylamino, butylamino, sec-butylamino, dimethylamino, trimethylamino, diethylamino, triethylamino, di-n-propylamino, methylethylamino, dimethyl-sec-butylamino, 2-aminoethoxy, ethylenediamino, cyclohexylamino, benzylamino, phenylethylamino, anilino, N-methylanilino, N,N- dimethylanilino, N-methyl-N-ethylanilino, 3,5-dibromo-4-anilino, p-toluidino, diphenylamino, 4,4'-dinitrodiphenylamino and the like; (12) cyano; (13) nitro; (14) a biologically active group; (15) amides, such as — CH2CH2CONHCH3, — CH2CH2CONHCH2CH3, — CH2CH2CON(CH3)2, — CH2CH2CON(CH2CH3)2, — CH2CONHCH3, — CH2CONHCH2CH3, — CH2CON(CH3)2, — CH2CON(CH2CH3)2, — CH2CH2CONHSO2CH3; (16) iminium salts, for example CH=N(CH3)2 +Z" and the like, wherein Z" is a counterion); (17) boron containing complexes; (18) carbon cage complexes (e.g., C20 and the like); (19) polyfunctional carboxylic acid groups and their metal cluster complexes, for example metal complexes of polyfunctional carboxylic acid moieties such as of EDTA, DTPA and the like, crown ethers, cyclams, cyclens, and the like; (20) other porphyrin, chlorin, bacteriochlorin, isobacteriochlorin, azaporphyrin, tetraazaporphyrin, phthalocyanine, naphthalocyanine, texaphyrins, tetrapyrrolic macrocycles or dye molecules and the like; (21) alkynyl, including alkyl, aryl, acid and heteroatom substituted alkynes; (22) leaving or protecting groups; (23) aromatic ring systems (aryl) either substituted or not, such as phenyls, napthalenes, anthracenes, benzopyrenes, quinolines, benzoquinolines, benzoperylene, benzofluorenes, fluorenes, benzofurazans, benzodiphenylenes, benzofluoranthenes, benzanthracenes, benzacephenanthrylenes, bathophenanthrolines, indans, benzoquinolines, quinolines, pyrazines, quinolines, quinazoles, quinoxalines, imidazopyridines, indenes, indolines, thiazolines, bezopyrimidines, pyrimidines, benzimidazole, triazolopyrimidines, pyrazoles, tryptophans, phenanthrolines, benzooxadiazoles, benzoselenadiazole, benzocoumarins, chalcones, fluoranthenes, pyridoindoles, pentacenes, perylenes, phenatholines, phenazines, phenoxazines, phenoxathiins, phenothiazines, pyrroles, thiophenes, or heteroaromatics containing 5, 6, 7, 8, membered ring systems; 24) -NHCS groups or any other substituent that increases the hydrophilic, amphiphilic or lipophilic nature or stability of the compounds. It is recognized that such groups can affect the biological activity of the compounds in vivo.
[098] The term "biologically active group" can be any group that selectively promotes the accumulation, elimination, binding rate, or tightness of binding in a particular biological environment. For example, one category of biologically active groups is the substituents derived from sugars, specifically: (1) aldoses such as glyceraldehyde, erythrose, threose, ribose, arabinose, xylose, lyxose, allose, altrose, glucose, mannose, gulose, idose, galactose, and talose; (2) ketoses such as hydroxyacetone, erythrulose, rebulose, xylulose, psicose, fructose, sorbose, and tagatose; (3) pyranoses such as glucopyranose; (4) furanoses such as fructo-furanose; (5) O-acyl derivatives such as penta-O-acetyl-
α-glucose; (6) O-methyl derivatives such as methyl α-glucoside, methyl β-
glucoside, methyl α-glucopyranoside, and methyl-2,3,4,6-tetra-0-methyl-
glucopyranoside; (7) phenylosazones such as glucose phenylosazone; (8) sugar alcohols such as sorbitol, mannitol, glycerol, and myo-inositol; (9) sugar acids
such as gluconic acid, glucaric acid and glucuronic acid, δ-gluconolactone, δ-
glucuronolactone, ascorbic acid, and dehydroascorbic acid; (10) phosphoric acid
esters such as α-glucose 1 -phosphoric acid, α-glucose 6-phosphoric acid, α-
fructose 1 ,6-diphosphoric acid, and α-fructose 6-phosphoric acid; (11) deoxy
sugars such as 2-deoxy-ribose, rhammose (deoxy-mannose), and fructose (6- deoxy-galactose); (12) amino sugars such as glucosamine and galactosamine; muramic acid and neuraminic acid; (13) disaccharides such as maltose, sucrose and trehalose; (14) trisaccharides such as raffinose (fructose, glucose, galactose) and melezitose (glucose, fructose, glucose); (15) polysaccharides (glycans) such as glucans and mannans; and (16) storage polysaccharides such as α-amylose,
amylopectin, dextrins, and dextrans.
[099] Amino acid derivatives are also useful biologically active substituents, such as those derived from valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, alanine, arginine, aspartic acid, cystine, cysteine, glutamic acid, glycine, histidine, proline, serine, tyrosine, asparagine and glutamine. Also useful are peptides, particularly those known to have affinity for specific receptors, for example, oxytocin, vasopressin, bradykinin, LHRH, thrombin and the like.
[0100] Another useful group of biologically active substituents are those derived from nucleosides, for example, ribonucleosides such as adenosine, guanosine, cytidine, and uridine; and 2'-deoxyribonucleosides, such as 2'- deoxyadenosine, 2'-deoxyguanosine, 2'-deoxycytidine, and 2'-deoxythymidine.
[0101] Another category of biologically active groups that is particularly useful is any ligand that is specific for a particular biological receptor. The term "ligand specific for a biological receptor" refers to a moiety that binds a receptor at cell surfaces, and thus contains contours and charge patterns that are complementary to those of the biological receptor. The ligand is not the receptor itself, but a substance complementary to it. It is well understood that a wide variety of cell types have specific receptors designed to bind hormones, growth factors, or neurotransmitters. However, while these embodiments of ligands specific for receptors are known and understood, the phrase "ligand specific for a biological receptor", as used herein, refers to any substance, natural or synthetic, that binds specifically to a receptor. [0102] Examples of such ligands include: (1) the steroid hormones, such as progesterone, estrogens, androgens, and the adrenal cortical hormones; (2) growth factors, such as epidermal growth factor, nerve growth factor, fibroblast growth factor, and the like; (3) other protein hormones, such as human growth hormone, parathyroid hormone, and the like; (4) neurotransmitters, such as acetylcholine, serotonin, dopamine, and the like; and (5) antibodies. Any analog of these substances that also succeeds in binding to a biological receptor is also included within the invention.
[0103] Particularly useful examples of substituents tending to increase the amphiphilic nature of the compounds include, but are not limited to: (1) short or long chain alcohols, such as, for example, — C12H24-OH; (2) fatty acids and their salts, such as, for example, the sodium salt of the long-chain fatty acid oleic acid; (3) phosphoglycerides, such as, for example, phosphatidic acid, phosphatidyl ethanolamine, phosphatidyl choline, phosphatidyl serine, phosphatidyl inositol, phosphatidyl glycerol, phosphatidyl 3'-0-alanyl glycerol, cardiolipin, or phosphatidyl choline; (4) sphingolipids, such as, for example, sphingomyelin; and (5) glycolipids, such as, for example, glycosyldiacylglycerols, cerebrosides, sulfate esters of cerebrosides or gangliosides. It would be known to those skilled in the art what other substituents, or combinations of the subsituents described, would be suitable for use in the invention.
[0104] The compounds of the present invention, or their pharmaceutically acceptable salts, solvates, prodrugs, or metabolites, can be administered to the host in a variety of forms adapted to the chosen route of administration, e.g., orally, intravenously, topically, intramuscularly or subcutaneously. [0105] The active compound may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with food. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations should contain at least about 0.1 % of active compound. The percentage of the compositions and preparations may, of course, be varied and may, for example, conveniently be between about 2 to about 60% of the weight of the administered product. The amount of active compound in such therapeutically useful compositions is can be selected so that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 50 and 300 mg of active compound.
[0106] The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound may be incorporated into sustained-release preparations and formulations.
[0107] The active compound may also be administered parenterally or intraperitoneally. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
[0108] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporanous preparation of sterile injectable solutions, dispersions, or liposomal or emulsion formulations. In all cases the form must be sterile and should be fluid to enable administration by a syringe. The form must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.
[0109] Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required additional ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique, which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solutions thereof.
[0110] The new compounds of the invention may also be applied directly to tumors in the host whether internal or external, in topical compositions. Exemplary compositions include solutions of the new compounds in solvents, particularly aqueous solvents, most preferably water. Alternatively, for topical application particularly to skin tumors or psoriasis, the present new compounds may be dispersed in the usual cream or salve formulations commonly used for this purpose (such as liposomes, ointments, gels, hydrogels, cremes and oils) or may be provided in the form of spray solutions or suspensions that may include a propellant usually employed in aerosol preparations. [0111] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Any conventional media or agent that is compatible with the active ingredient can be used in the therapeutic compositions of the invention. Supplementary active ingredients can also be incorporated into the compositions.
[0112] It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated. Each unit contains a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of cardiovascular diseases, diseases of the skin, and cancers in living subjects.
[0113] The present invention provides a method of treating live cells, which includes, but is not limited to, animals such as humans and other mammals. The "mammals" also include farm animals, such as cows, hogs and sheep, as well as pet or sport animals, such as horses, dogs and cats. The dosage of the pharmaceutical compositions of the invention is dependent on the method of administration, the patient's age, severity of the disease, and the like. [0114] The compounds of the invention may be taken parentally or orally, generally being administered intravasculariy, subcutaneously, or intramuscularly or interperitoneally. The subject compounds may also be administered by inhalation, perivascular delivery, pericardial delivery (into perivascular sac), periadvential delivery (e.g., using a hydrogel wrap around the vessel), endovascular balloon catheters with micropores, channels, transmural injection ports, and the like.
[0115] For local catheter-based delivery of the compounds of the invention, an infusate can be placed and pressurized to facilitate intramural and transmural penetration into the target vessel. Local delivery can also be enhanced by other mechanical and electrical means. The depth of the penetration of the subject compounds by this local delivery method is a function of pressure in the perfused segment and the dwell time. Although little attention has been paid to the quantitative characteristics of the compounds of the invention in this setting, deposition of the substance should obey the principles governing transmural convection and diffusion.
[0116] Delivery of the compounds of the invention may also be via antibody-drug conjugates, internalizing antibodies or antibody fragments conjugated to compounds into cells using endocytosis. The subject compounds may also be impregnated into stent struts for local delivery. The route of administration of these pharmaceutical preparations is not critical, but may be selected according to the dosage form, the patient's age, the severity of the disease to be treated and other factors.
[0117] The compounds of the invention may find use in conjunction with other interventions, diagnostics and therapies, where lower levels of other therapies having significant side effects may be used effectively to reduce the detrimental side effects. Adjunctive interventions may include, but are not limited to: balloon angioplasty, invasive and non-invasive surgical procedures, stent deployment, cutting balloons, embolic protection devices, rotational and directional atherectomy, eximer lasers and the like.
[0118] Adjunctive therapies may include, but are ήorfimited to: radiation therapy, chemotherapy, anti-platelet agents, vasodilators, antihypertensives, anti- arrhythmics, hyperthermia, cryotherapy, magnetic force, viral and non-viral gene therapy, pharmacogenetic therapy, antibodies, vaccines, glycoprotein llb/llla Inhibitors, growth factors, peptides, DNA delivery, nucleic acids, anticancer drugs, steroid hormones, anti-inflammatories, proteins, anti-apoptotic therapies, anti-sense agents, immunotoxins, immunomodulators, antibody-drug conjugates, anti-proliferative therapies, drug eluting stents containing pharmacologically active agents, transplant products and processes, prostaglandins and catheter based devices to detect vulnerable plaques, hormone products, chelating agents, diuretics, cardiac glycosides, bronchodilators, antibiotics, antivirals, antitioxins, cyclosporins, thrombolytic agents, interferons, blood products such as parental iron and hemin, anti-fungal agents, antianginals, anticoagulants, analgesics, narcotics, neuromuscular blockers, sedatives, bacterial vaccines, viral vaccines, DNA or RNA of natural or synthetic origin including recombinent RNA and DNA, cytokines and their antagonists/inhibitors, chemokines and their antagonists/inhibitors,
[0119] Adjunctive diagnostics may include, but are not limited to: intra- vascular ultrasound imaging, angiography, quantitative vessel measurements and the use of radiological contrast agents, hormone products, chelating agents, diuretics, cardiac glycosides, bronchodilators, antibiotics, antivirals, antitoxins, cyclosporins, thrombolytic agents, interferons, blood products such as parental iron and hemin, anti-fungal agents, antianginals, anticoagulants, analgesics, narcotics, neuromuscular blockers, sedatives, bacterial vaccines, viral vaccines, DNA or RNA of natural or synthetic origin including recombinent RNA and DNA, cytokines and their antagonists/inhibitors, and chemokines and their antagonists/inhibitors.
[0120] The method of the invention can include administration of the particular metallotetrapyrrolic compound prior to, concomitant with, or subsequent to a particular adjunctive therapy. A particular regimen is employed for administration, where a single bolus or plurality of doses may be administered to the patient. The particular protocol will depend upon the nature of the tissue to be treated, the particular compound that is employed and the severity of the disease. Target tissue structure and function, carriers, endocytosis, and other cellular transport mechanisms may be important for particular compounds when determining the specific mode of delivery. Administration will preferably be within about 3 days prior to vessel activation with an energy source, and desirably will be the same day as the treatment of the target vessel.
[0121] The compounds of the invention may be formulated in a variety of ways, depending upon the manner of the administration, the particular compound, the number of administrations, other drugs, the presence of other active components and the like. The formulation will generally be in a physiologically acceptable form, using various carriers, such as water, deionized water, phosphate buffered saline, aqueous ethanol, vegetable oils, liposomes, emulsions, inclusion complex (cyclodextrans). In some instances the formulation may be formulated as a slow release formulation, where the subject compounds may be encapsulated in a wide variety of carriers, may be administered as capsules, or as a prodrug.
[0122] Thus, for instance, when they are provided in the form of tablets, pills, solutions, suspensions, emulsions, granules or capsules, the preparations are typically administered orally. Injectable solutions are usually administered intravenously, either alone or in a mixture with conventional fluids for parenteral infusion containing sugars, amino acids, saline and the like. Local administration may be by injection at the site of the living cells, by insertion or attachment of a solid carrier at the site, or by direct, topical application of a viscous liquid. Specifically, when necessary, solutions may be administered as is by the intramuscular, intradermal, subcutaneous or intraperitoneal route. Suppositories are administered rectally, and eye drops are instilled into the eye. The delivery of the compounds of the invention to living cells may be enhanced by the use of controlled-release compositions.
[0123] The compounds of the invention may also be applied externally by introducing them into a spray together with a suitable propellant and, if desired, a solvent, as a fine powder together with a suitable filler, and as a cream in combination with known auxiliaries. Furthermore they may be used in the form of suppositories. They may also contain the required auxiliaries, such as fillers, lubricants, preservatives and emulsifying agents prepared by any method known per se.
[0124] The pharmaceutical compositions of the invention may also contain a pharmaceutically acceptable carrier, such as saline, buffered saline, 5% dextrose in water, borate-buffered saline containing trace metal, carboxymethyl cellulose, vegetable oil, DMSO, ethanol, and the like. Formulations may further include one or more excipients, preservatives, antioxidants, solubilizers, buffering agents, albumin to prevent protein loss on vial surfaces, lubricants, fillers, stabilizers, and the like. Methods of formulation are well-known in the art and are disclosed, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (Gennaro, ed. 1990)
[0125] In preparing fluids for injection, the solutions or suspensions are preferably sterilized and isotonic with blood. For preparing such dosage forms, all the diluents in conventional use in this field can be employed. Thus, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol , liposomes and polyoxyethylene sorbitan fatty acid esters may be used. In this case, the pharmaceutical preparations may contain sodium chloride, glucose, lactose or glycerol in an amount sufficient to give isotonic solutions. It is also possible to add conventional solubilizing agents, buffers, soothing agents or local anesthetics, etc. Further, when appropriate, the pharmaceutical preparations may contain coloring materials, preservatives, perfumes, flavoring agents, sweetening agents and the like.
[0126] The proportion of the active ingredient compound in the pharmaceutical preparations of the invention is not critical, but may suitably be selected from a wide range. Generally, however, the proportion is preferably within the range of from about 0.01 to about 70% by weight.
[0127] Depending upon the manner of administration, the frequency of administration, as well the nature and the degree of the biological activity, the dosage will generally be in the range of about 0.01 to about 100 mg/kg. When administered parentally, the total amount of the compound administered per day will generally be in the range of 0.1 to 50 mg/kg/day, more usually in the range of about 0.25 to 25 mg/kg/day. This dose may be in a single bolus or be divided up to be administered in portions to provide the desired level of the subject compound in the mammal.
[0128] Light doses appropriate to activate the compounds of the invention can be administered externally or internally to the target tissue. A particular regimen is employed for light administration, where a single dose or plurality of dosimetries may be administered to the patient. The particular protocol will depend upon the nature of the tissue to be treated, the particular compound that is employed and the severity of the disease. Light delivery devices can be, for example, in the form of a balloon catheter, bare tip diffuser and the like for endovascular delivery of light to blood-carrying vessels.
[0129] As used herein, the term light is to be considered in its broadest sense, encompassing all electromagnetic radiation. Light suitable for use in activating the compounds of the invention will typically be produced by, for example, arc lamps, LEDs or lasers at a certain frequency in the visible spectrum or near infrared for typical PDT treatments. In particular, wavelengths between 400nm and 900nm, corresponding to laser diode activation, may also be used. Additionally dual photon excitation may also be used.
[0130] Although it has been described primarily with reference to presently preferred embodiments, one skilled in the art should recognize that various modifications and improvements are within the scope of this invention. It will be clearly understood that the invention in its general aspects is not limited to the specific details referred to herein.
Definitions [0131] As used in the present application, the following definitions apply:
[0132] The term "alkyl" as used herein refers to substituted or unsubstituted, straight or branched chain groups, preferably having one to twenty, more preferably having one to six, and most preferably having from one to four carbon atoms. The term "C1-C20 alkyl" represents a straight or branched alkyl chain having from one to twenty carbon atoms. Exemplary C1-C20 alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, and the like. The term "Cι-C20 alkyl" includes within its definition the term "C1-C4 alkyl." Such alkyl groups may themselves be ethers or thioethers, or aminoethers or dendrimers.
[0133] The term "cycloalkyl" represents a substituted or unsubstituted, saturated or partially saturated, mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. An exemplary cycloalkyl is a C5- C7 cycloalkyl, which is a saturated hydrocarbon ring structure containing from five to seven carbon atoms.
[0134] The term "aryl" as used herein refers to an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, napthalenes, anthracenes, benzopyrenes, quinolines, benzoquinolines, benzoperylene, benzofluorenes, fluorenes, benzofurazans, benzodiphenylenes, benzofluoranthenes, benzanthracenes, benzacephenanthrylenes, bathophenanthrolines, indans, benzoquinolines, quinolines, pyrazines, quinolines, quinazoles, quinoxalines, imidazopyridines, indenes, indolines, thiazolines, benzopyrimidines, pyrimidines, benzimidazole, triazolopyrimidines, pyrazoles, tryptophans, phenanthrolines, benzooxadiazoles, benzoselenadiazole, benzocoumarins, chalcones, fluoranthenes, pyridoindoles, pentacenes, perylenes, phenatholines, phenazines, phenoxazines, phenoxathiins, phenothiazines and the like.
[0135] The term "halogen" represents chlorine, fluorine, bromine or iodine. The term "halocarbon" or "haloalkyl" represents one or more halogens bonded to one or more carbon bearing groups. The term "heterohaloalkyl" represents, for example, halogenated alkylethers, halogenated -alkyl amines, halogenated alkyl esters, halogenated alkyl amides, halogenated alkyl thioesters, halogenated alkyl thiols, where N, S, O, P atoms are present in the haloalkylated structure. The term heteroalkyl represents, for example, ethers, alkylamines, alkylated thiols and alkylate phosphorus containing groups.
[0136] The term "carbocycle" represents a substituted or unsubstituted aromatic or a saturated or a partially saturated 5-14 membered monocyclic or polycyclic ring, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, wherein all the ring members are carbon atoms.
[0137] The term "electron withdrawing group" is intended to mean a chemical group containing an electronegative element such as halogen, sulfur, nitrogen or oxygen.
[0138] A "heterocycloalkyl group" is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, or 18 ring atoms, and which includes 1 , 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, wherein the radical is unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1 ,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1 ,3-dioxolanyl,
)
1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1 ,5,9-triazacyclododecyl, and the like.
[0139] A "heteroaryl group" is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
15, 16, 17, or 18 ring atoms, including 1 , 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3- bjthianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl and the like.
[0140] The term "leaving group" as used herein refers to any group that departs from a molecule in a substitution reaction by breakage of a bond. Examples of leaving groups include, but are not limited to, halides, tosylates, arenesulfonates, alkylsulfonates, and triflates.
[0141] Suitable protecting groups are recognizable to those skilled in the art. Examples of suitable protecting groups can be found in T. Green & P. Wuts, Protective Groups in Organic Synthesis (2d ed. 1991), the disclosure of which is incorporated herein by reference in its entirety.
[0142] Suitable salt anions include, but are not limited to, inorganics such as halogens, pseudohalogens, sulfates, hydrogen sulfates, nitrates, hydroxides, phosphates, hydrogen phosphates, dihydrogen phosphates, perchlorates, and related complex inorganic anions; and organics such as carboxylates, sulfonates, bicarbonates and carbonates.
[0143] Examples of substituents for alkyl and aryl groups include mercapto, thioether, nitro (N02), amino, aryloxyl, halogen, hydroxyl, alkoxyl, and acyl, as well as aryl, cycloalkyl and saturated and partially saturated heterocycles. Examples of substituents for cycloalkyl groups include those listed above for alkyl and aryl, as well as alkyl groups.
[0144] Exemplary substituted aryls include a phenyl or naphthyl ring substituted with one or more substituents, preferably one to three substituents, independently selected from halo, hydroxy, morpholino(C-ι-C2o)alkoxycarbonyl,
pyridyl (Cι-C20)alkoxycarbonyl, halo (CrC2o)alkyl, C1-C20 alkyl, C1-C20 alkoxy, carboxy, Cι-C20 alkocarbonyl, carbamoyl, N-(Cι-C2o)alkylcarbamoyl, amino, Cι-C2oalkylamino, di(Cι-C o)alkylamino or a group of the formula -(CH )a-R7 where a can be 1 , 2, 3, 4, 5 and R7 can be hydroxy, C1-C20 alkoxy, carboxy, d- C20 alkoxycarbonyl, amino, carbamoyl, C1-C20 alkylamino or di(Cι-C2o)alkylamino, sulfonic acids, sulfonic esters, sulfonic amides, amides, esters and the like.
[0145] Another substituted alkyl is halo(Cι-C2o)alkyl, which represents a straight or branched alkyl chain having at least one halogen atom attached to it. Exemplary halo(Cι-C2o)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, trifluoromethyl, trifluoroethyl, and the like.
[0146] Another substituted alkyl is hydroxy (Cι-C2o)alkyl, which represents a straight or branched alkyl chain having from one to twenty carbon atoms with a hydroxy group attached to it. Exemplary hydroxy(Cι-C2o)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl, and the like.
[0147] Yet another substituted alkyl is C1-C20 alkylthio(Cι-C o)alkyl, which is a straight or branched C1-C20 alkyl group with a C1-C20 alkylthio group attached to it. Exemplary C1-C20 alkylthio(CrC2o)alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the like.
[0148] Yet another exemplary substituted alkyl is heterocycle(C C2o)alkyl, which is a straight or branched alkyl chain having from one to twenty carbon atoms with a heterocycle attached to it. Exemplary heterocycle(Cr C2o)alkyls include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3- thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl and the like.
[0149] Yet another substituted alkyl is aryl(Cι-C20)alkyl, which is a straight or branched alkyl chain having from one to twenty carbon atoms with an aryl group attached to it. Exemplary aryl(Cι-C2o)alkyl groups include phenylmethyl, 2- phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl and the like.
[0150] The heterocycloalkyls and the heteroaryls can, for example, be substituted with 1 ,2 or 3 substituents independently selected from halo, halo(C-ι- C2o)alkyl, C1-C20 alkyl, C-1-C20 alkoxy, carboxy, C-1-C20 alkoxycarbonyl, carbamoyl, -(Cι-C2o)alkylcarbamoyl, amino,
Figure imgf000110_0001
di(Cι-C2o)alkylamino or a group having the structure -(CH2)a-R7 where a can be 1 , 2, 3, 4, 5 and R can be hydroxy, C1-C20 alkoxy, carboxy, CrC2u alkoxycarbonyl, amino, carbamoyl, C-r C2oalkylamino or di(Cι-C2o)alkylamino.
[0151] Examples of substituted heterocycloalkyls include, but are not limited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and 6-N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl. Examples of substituted heteroaryls include, but are not limited to, 3-methylimidazolyl, 3-methoxy pyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl, 2-methyl- 1 ,2,3,4- tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl-1 ,2,3,4- isoquinolin-7-yl and the like.
[0152] A "pharmaceutically acceptable solvate" is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of the inventive compounds.
[0153] Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds prepared using water, isopropanol, ethanol, DMSO, and other excipients generally referred to as GRAS or likewise recognized by the food and Drug administration as acceptable ingredients. [0154] In the case of solid formulations, it is understood that the compounds of the invention may exist in different polymorph forms, such as stable and metastable crystalline forms (and solvates thereof) and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
[0155] A "pharmaceutically acceptable salt" is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, citrates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1 ,4-dioates, hexyne-1 ,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, hydroxybutyrates, glycolates, tartrates, methanesulfoantes, propanesulfonates, naphthalene-1- sulfonates, naphthalene-2-sulfonates, and mandelates.
[0156] If a compound of the present invention is a base, the desired salt may be prepared by any suitable method known to the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, lactic acid, salicylic acid, pyranosidyl acids such as glucuronic acid and galacturonic acid, alpha-hydroxy acids such as citric acid and tartaric acid, amino acids such as aspartic acid and glutamic acid, aromatic acids such as benzoic acid and cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
[0157] If a compound of the present invention is an acid, the desired salt may be prepared by any suitable method known to the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), or an alkali metal or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary and tertiary amines; cyclic amines such as piperidine, morpholine and piperazine; and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
EXAMPLES
[0158] Preparation of compounds according to the invention is illustrated by reference to the following non-limiting examples. It will be appreciated by persons skilled in the art with the teachings of the examples and the rest of the specification (i) how the chemistry may be applied to other peripheral groups on tetrapyrrolic ring structures that fall within the scope of this invention and (ii) that other synthetic routes may be suitable for preparation of the desired compounds.
Example 1 : Gallium chloride mesoporphyrin dimethyl ester [0159] Mesoporphyrin dimethyl ester (610mg) was dissolved in acetic acid (75mL) and Gallium acetyl acetonate added (700mg). The solution was refluxed for 1 hr after which time a UV visible analysis of the molecule showed the metallation to be complete. The solvent was removed by rotary evaporation and the residue dissolved in dichloromethane (100mL). The dichloromethane layer was washed repeatedly with 1 N HCI and the organic layer collected and evaporated. The crude reaction mixture was chromatographed on silica (7.5% methanol/dichloromethane) and the major pink fraction collected and evaporated. The compound was redissolved in dichloromethane (100mL), the organic layer was washed repeatedly with 1 N HCI, dried over sodium sulfate and evaporated to ~10mL. Hexane was added (7mL) and the dichloromethane was removed by rotary evaporation. The precipitated solid was collected by filtration and dried. Yield of the title compound = 650mg. Example 2: Gallium chloride mesoporphyrin diethyl ester
[0160] Mesoporphyrin dimethyl ester (200mg) was refluxed in 5% sulfuric acid in ethanol (25 ml) for 6hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and solution neutralized with sodium bicarbonate. The solid was filtered, dried and crystallized from dichloromethane and ethanol. Yield of mesoporphyrin diethyl ester = 180 mg. This was then metallated as described in example 1. Yield of the title compound = 190 mg. Example 3: Gallium chloride mesoporphyrin dipropyl ester
[0161] Mesoporphyrin dimethyl ester (150 mg) was refluxed in 2% sulfuric acid in propanol (30 ml) for 6hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and solution neutralized with sodium bicarbonate. The solid was filtered and dried. Yield of mesoporphyrin dipropyl ester = 180 mg. This was then metallated as described in example 1. Yield of the title compound
= 190 mg.
Example 4: Gallium chloride deuteroporphyrin dimethyl ester
[0162] Deuteroporphyrin dimethyl ester (1 OOmg) was metallated as described in example 1. Yield of the title compound = 98mg.
Example 5. Gallium chloride deuteroporphyrin diethyl ester
[0163] Deuteroporphyrin diethyl ester (100mg) was metallated as described in example 1. Yield of the title compound = 100mg. Example 6. Gallium chloride deuteroporphyrin methylamide
[0164] Deuteroporphyrin (100)mg was converted to its methyl amide and metallated as described in example 121. Yield of the title compound = 98mg.
Example 7. Gallium chloride 8, 13-diethyl-3 ,12,17-tetramethylporphyrin- 2,18-dK3'-hydroxypropyl)
[0165] a) Mesoporphyrin IX dimethyl ester (1g) was dissolved in THF (600mL) and LiAIH4 (1g) was added. The solution was refluxed under argon for 1 hr, then cooled and the solution was quenched by the addition of ethylacetate (50mL). 3N HCI was added to the solution and the crude porphyrin precipitated by removal of the THF by rotary evaporation. The crude product was dissolved in methanol/dichloromethane (10%) and chromatographed on silica eluting with 10% methanol/dichloromethane. The major red fraction was collected and evaporated to dryness. b) A small amount of the product porphyrin (200mg) was dissolved in acetic acid and gallium acetyl acetonate added (200mg). The solution was refluxed for 2 hrs after which time a UV visible analysis of the molecule showed the metallation to be complete. The solvent was removed by rotary evaporation and the residue dissolved in THF (100mL). A solution of sodium hydroxide (0.1g) in water (2mL) was added and the solution warmed at 40°C until acetate hydrolysis was complete by TLC. The solvent was removed by rotary evaporation and the crude residue dissolved in dichloromethane. The crude reaction mixture was chromatographed on silica (5% methanol/dichloromethane) and the major pink fraction collected and evaporated. The compound was redissolved in dichloromethane (100mL), the organic layer was washed repeatedly with 1 N HCI, dried over sodium sulfate and evaporated to ~20mL. Hexane was added (14mL) and the dichloromethane was removed by rotary evaporation. The precipitated solid was collected by filtration and dried.
Yield of the title compound = 180mg.
Example 8. Gallium chloride 8, 13-desvinyl-3,7,12,17-tetramethylporphyrin- 2.18-di(3'-hvdroχypropy0
[0166] Deuteroporphyrin dimethyl ester (100mg) was converted to its propyl alcohol derivative according to example 7 and (70mg) was metallated and purified as described in example 7. Yield of the title compound = 65mg.
Example 9. 8.13-diethyl-3.7,12.17-tetramethylporphyrin-2.18-di(propyl-3'- toluenesulfonate)
[0167] 8J13-diethyl-3,7,12,17-tetramethylporphrine-2,18-di(3,- hydroxypropyl) (1g) was dissolved in dichloromethane (200mL) and pyridine (5ml) was added. The solution was chilled in an ice bath and toluene sulfonylchloride (3g) was added and the solution stirred at 4°C overnight. Water (200mL) was added and the organic layer separated. The organic layer was washed with 1N HCI, followed by water and separated. The solvent was dried over sodium sulfate, filtered and the solvent removed by rotary evaporation, and the crude residue dissolved in dichloromethane and washed with water several times. The organic layer was collected and evaporated to dryness. The crude porphyrin was pure enough to use without additional purification. Yield of the title compound = 800mg. Example 10. Gallium chloride 8.13-diethyl-3.7.12.17-tetramethylporphyrin- 2,18-di(3'-methoxypropyl)
[0168] Sodium (200mg) was added to a solution of methanol (dry, 10mL). After all the sodium had dissolved, the ditosylate compound produced in example 9 (120mg) in dry dichloromethane (10mL) was added and the resulting solution refluxed overnight protected from moisture. The solution was quenched with water (20mL) and the organic layer separated and washed with water (3X 50mL) with back extraction with dichloromethane. The organic layer was dried, filtered and the organic layer reduced in volume to ~10mL. Methanol (10mL) was added and the dichloromethane was removed by rotary evaporation. The precipitated porphyrin was collected by filtration and dried. This gave 8,13-diethyl-3,7,12,17- tetramethylporphyrin-2,18-di(propyl methyl ether) with sufficient purity to be used in the metallation step. Yield = 80mg.
[0169] To a solution of this porphyrin (80mg) in acetic acid (20mL) was added gallium acetoacetonate (80mg). The solution was refluxed for 1 hr after which the solvent was removed by rotary evaporation. The resulting solid was dissolved in dichloromethane and the crude reaction passed over silica, eluting with 5% methanol/dichloromethane. The major pink fraction was collected and the solvent removed by rotary evaporation. The solid was dissolved in dichloromethane (5mL) and hexane (5mL) was added. The dichloromethane was removed by rotary evaporation and the solid precipitate collected by filtration and dried. Yield of the title compound = 75mg. Example 11. Gallium chloride mesoporphyrin di-(2'-methoxyethyl amide)
[0170] Mesoporphyrin (310mg) was suspended in dichloromethane (20mL) and oxaylchloride (3mL) added to it. The solution was refluxed for 1 hr. The solvent was removed by rotary evaporation and dichloromethane (20mL) added, followed by 2-methoxyethyl amine (1mL). The reaction was stirred for 1hr, diluted with dichloromethane (50mL), washed with water, dried and evaporated. The residue was dissolved in dichloromethane (10mL) and methanol (10mL) was added. The dichloromethane was removed by rotary evaporation and the precipitated porphyrin collected by filtration and dried. Yield of mesoporphyrin IX methoxyethylamide = 300mg.
[0171] Mesoporphyrin methoxyethylamide (150mg) and gallium acetylacetonate (130mg) was heated in acetic acid (15mL) for 1.5 hr. The solvent was removed by rotary evaporation, dissolved in dichloromethane (100mL) and washed with 1.2N HCI (2 x 50mL), dried and evaporated. The residue was dissolved in dichloromethane (5mL) and chromatographed on silica, eluting first with 2.5-7.5% methanol/dichloromethane, followed by 10% methanol dichloromethane. The major red fraction was collected and evaporated to dryness. The solid was dissolved in dichloromethane (10ml) and a 1 :1 solution of ether and hexane (10mL) was added. The dichloromethane was removed by rotary evaporation and the red precipitate of the title compound collected by filtration and dried. Yield of the title compound = 155mg. Example 12. Gallium hydroxy 3,8-N,N-dimethylaminomethyl deuteroporphyrin dimethyl ester
[0172] 3,8-N,N-dimethylaminomethyl deuteroporphyrin dimethyl ester (100mg) was prepared as described in the literature (Pandey, R. K. et al, Tetrahedron 1992, 48, 7591 ) and metallated as described in example 1 , except that the final product was washed with 0.5% NaOH solution and not 1 N HCI. Yield of the title compound = 100mg. Example 13. Gallium chloride chloroporphyrin eβ trimethyl ester
[0173] Chloroporphyrin e6 trimethyl ester (1 OOmg) was metallated as described in example 1. Yield of the title compound = 107mg.
Example 14. Gallium chloride chloroporphyrin eβ dimethyl ester 12- methylamide
[0174] Meso-pheophorbide methyl ester (400mg) was dissolved in a solution of methyl amine in THF (2M, 100mL). The resulting solution was stirred at room temperature for 2 days. The solvent was removed by rotary evaporation and the residue was dissolved in dichloromethane (10mL). Methanol was added and the dichloromethane removed by rotary evaporation. The precipitated chlorin was collected by filtration and dried (400mg). The chlorin was dissolved in chloroform (20mL) and a methanolic solution of saturated zinc acetate (2ml) was added. The solution was heated for 1 hr at reflux and the solution poured into water (100ml). The aqueous layer was extracted with dichloromethane (50ml) and the organic layer collected and evaporated to dryness. The residue was dissolved in THF (20mL) and a solution of DDQ (227mg) in THF (10mL) was added dropwise at room temperature. The solution was stirred for 10 min at room temperature and the solution poured into a saturated sodium bicarbonate solution. The resulting mixture was extracted with dichloromethane (2 x 50mL) and evaporated to dryness. The crude residue was chromatographed on silica using 1 % acetone/dichloromethane as eluent and the major red porphyrin band collected. The fraction was evaporated to dryness and precipitated from dichloromethane/methanol. Yield of chloroporphyrin e6 dimethyl ester 12-methyl amide = 210mg. The chloroporphyrin e6 dimethyl ester 12-methyl amide was metallated as described in example 1 to give 215mg of gallium chloride chloroporphyrin e6 dimethyl ester 12-methyl amide. Example 15. Gallium chloride mesoporphyrin N,N-diethylamide
[0175] Mesoporphyrin (148mg) was converted to mesoporphyrin N,N- diethyl amide as described in example 11 , except that N,N-diethyl amine was used in place of 2-methoxyethylamine. Yield = 0.242mg. This material was metallated as described in example 1 to give the title gallium compound. Yield = 250mg. Example 16. Gallium chloride mesoporphyrin 2-ethoxyethanol amide
[0176] Mesoporphyrin dimethyl ester (200mg) was dissolved in dioxane (1 ml) and 2-(2-aminoethoxy)ethanol (3ml) was added. The solution was refluxed for 3 hrs at ~120°C. The solution was poured into brine and extracted with dichloromethane/5% methanol, dried and evaporated. The porphyrin was TLC pure. The amide porphyrin was then refluxed for 45 min in acetic acid (10mL) containing gallium acetylacetonate (200mg). The acetic acid was evaporated and the residue dissolved in THF (50mL) and a solution of KOH (1g in 5ml H20/5ml methanol) was added. The solution was stirred for 2 hrs at room temperature. The excess KOH was quenched with acetic acid and the solvent removed by evaporation. The residue was dissolved in dichloromethane and washed with 1 N HCI (2 x 75mL), dried and evaporated to dryness. The product was pure by TLC (7% methanol/dichloromethane). Yield of the title compound = 210mg. Example 19. Gallium chloride 5-azaprotoporphyrin IX dimethyl ester.
[0177] 5-azaprotoporphyrin IX dimethyl ester (Montforts, F-P., et al, Tet. Lett. 1992, 33, 1985) (1 OOmg) was metallated as described in example 1. Yield of the title compound = 110mg. Example 20. Gallium chloride 5-azamesoporphyrin IX dimethyl ester.
[0178] 5-azamesoporphyrin IX dimethyl ester (Singh, J. P., et al, Tet. Lett.
1995, 36, 1567) (100mg) was metallated as described in example 1. Yield of the title compound = 107mg.
Example 21. Gallium chloride 7,8,12.13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-dif propionic acid methyl ester)
[0179] To a solution of 5,5'-dicarboxy-3,3'-di(2-methoxycarbonylethyl)-
4,4'-dimethylpyrromethane (5g) in methanol (70mL) was added ammonium hydroxide (2.6ml) and the solution stirred until the dipyrromethane had dissolved.
2-bromo-5-formyl-3,4-diethylpyrrole (5.3g) and HBr (33%, 25mL) was added. The solution was stirred at room temperature for 2 hrs after which time the solid 1 ,19- dibromobiladiene was filtered and dried. Yield = 7.2g. A smaller amount of 1 ,19- dibromobiladiene (3g) was refluxed in methanol containing sodium azide (4g) for
4 hrs. The solvent was removed and the residue dissolved in dichloromethane and chromatographed on silica using dichloromethane as eluent. The major purple band was collected and evaporated to dryness. The compound was dissolved in dichloromethane (50mL) and methanol (50mL) added. The dichloromethane was removed by rotary evaporation and the precipitated azaporphyrin collected by filtration. Yield of 7,8,12,13-tetraethyl-12,17-dimethyl-
10-azaporphyrin-2,18-di(propionic acid methyl ester) = 1.7g. [0180] The azaporphyrin (1 OOmg) was metallated according to example
1. Yield of the title compound = 115mg.
Example 22. Gallium chloride 7,8.12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl amide)
[0181] The azaporphyrin synthesized in example 21 (150mg) was dissolved in THF (50mL) and KOH (500mg) in MeOH/water (5mL:5mL) was added. The solution was refluxed for 2 hrs. The solvent was evaporated and the residue dissolved in water (10mL) and neutralized with HCI. The precipitated solid was collected by filtration and dried. Yield of dicarboxylic acid azaporphyrin
= 110mg. The solid was suspended in dichloromethane (10mL) and THF
(100mL). Triethylamine (2mL) was added and the mixture stirred overnight at room temprature. The solution was cooled to 0°C and ethylchloroformate (1mL) was added. The solution was stirred for 30min and then a solution of methylamine in THF (2M, 15mL) was added. The solution was stirred at room temperature for 2 hrs and then the solvent was removed. The residue was dissolved in dichloromethane/methanol (10%) and chromatographed on silica eluting with 10% methanol/dichloromethane, followed by 15% methanol/dichloromethane. The major fraction was collected and evaporated to dryness. Yield of the 2,3,7,8-tetraethyl-12, 13-dimethyl-5-azaporphyrin-13, 17- propionic acid dimethyl amide was 68mg. The azaporphyrin was metallated as shown in Example 1 purified by column chromatography eluting with 10% methanol/dichloromethane followed by 15% methanol/dichloromethane. The title compound was precipitated from dichloromethane/hexane, filtered and dried.
Yield = 72mg.
Example 23. Gallium chloride 7,8.12.13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(3'-hvdroxypropyl) [0182] To a slurry of LiAIH4 (46mg) in dry THF (3mL) was added a solution of azaporphyrin dimethyl ester (example 21 ) (150mg) in dry THF(3mL).
The mixture was stirred at room temperature for 15 min and excess LiALH decomposed with 0.2N HCI. The solution was dissolved in dichloromethane
(50mL) and washed well with water (2 x 50mL). The organic layer was separated and dried over sodium sulfate, filtered and evaporated to dryness. The crude residue was chromatographed on silica using 5% MeOH/dichloromethane and the major purple band collected. The solvent was removed and the crude residue dried under vacuum. The material was pure by TLC. Yield of 7,8,12,13-tetraethyl-
12,17-dimethyl-10-azaporphyrin-2,18-di(3'-hydroxypropyl) = 103mg. The product was dissolved in acetic acid (20mL) and gallium acetylacetonate (125mg) was added. The solution was refluxed for 15 min, cooled and the solvent removed by rotary evaporation. The residue was dissolved in dichloromethane (50mL) and washed with water (50ml). The organic layer was collected and evaporated to dryness. The residue was dissolved in methanol (7mL) and K2C03 (90mg) was added. The solution was stirred for 5 hrs at room temperature. The solution was poured into water and extracted with dichloromethane. The dichloromethane layer was washed with 1 N HCI, dried over sodium sulfate, filtered and the solvent removed. The product was precipitated from dichloromethane/hexane to give the title compound, 76mg.
Example 24. 8,13-diethyl-3,7.12.17-tetramethylporphyrin-2,18-di(3'- cvanopropyl)
[0183] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(propyl-3'- toluenesulfonate) (example 9) (150 mg) in DMSO (30 ml) was added to sodium cyanide (100 mg). The mixture was warmed up slowly to just refluxing (about 30 minutes) under argon. TLC of the reaction solution indicated that the reaction was complete. Water (5 ml) was added and the porphyrin precipitate was collected and washed with water to remove any trace of DMSO. The solid was air dried to give 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3'- cyanopropyl) (84 mg, 85% yield).
Example 25. 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic acid methyl ester)
[0184] 8,13-diethyl-3,7, 12,17-tetramethylporphyrin-2, 18-di(3'- cyanopropyl) (50 mg) was dissolved in a solution of methanol (50 ml) saturated with dry hydrogen chloride gas, the solution was stirred at room temperature in the dark overnight. Water (100 ml) was added followed by aqueous ammonia hydroxide to neutralize the solution. The solution was then extracted with methylene chloride twice (2x100 ml), and the combined methylene chloride was washed with water, drained and dried over sodium sulfate. The crude material was purified on a silica gel column, eluted with 1% methanol/methylene chloride. The desired fraction was collected and evaporated to dryness to give 8,13- diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic acid methyl ester) (47 mg, 84% yield).
Example 26. Gallium chloride 8.13-diethyl-3,7.12,17-tetramethylporphyrin- 2,18-difbutanoic acid methyl ester)
[0185] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic acid methyl ester) (example 25) (47 mg) in AcOH (100 ml) was added to Ga (acac)3
(90 mg). The mixture was heated to reflux for one hour, and then cooled to room temperature. AcOH was evaporated to dryness and methylene chloride (100 ml) was added to dissolve the solid. The methylene chloride solution was washed with 1 N HCI solution once (100 ml), drained and dried over sodium sulfate.
Methylene chloride was evaporated and the porphyrin was precipitated from hexane. The precipitate was collected by filtration and air dried to give 54 mg of gallium chloride 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic acid methyl ester) (98% yield).
Example 27. 8.13-diethyl-3,7.12.17-tetramethylporphyrin-2.18-di(pentanoic acid ethyl ester)
[0186] 8, 13-diethyl-3,7,12, 17-tetramethylporphyrin-2,18-dipropanol ditosylate ester (example 9) (150 mg) in anhydrous THF (30 ml) was added to a solution of sodium hydride (150 mg)/diethyl malonate (1 g)/anhydrous THF (50 ml). The mixture was heated to reflux for 6 hours, and then cooled to room temperature. Aqueous HCI solution was added, and the solution was extracted with methylene chloride (3x100 ml). The combined methylene chloride layer was washed once with water, drained, dried over sodium sulfate, and evaporated to dryness. The crude material was precipitated from DMSO/water to remove excess diethyl malonate. The porphyrin was dissolved in DMSO and LiCI (200mg) added. The solution was heated to 80°C for 4 hrs, cooled and water was added to precipitate the porphyrin. The crude porphyrin was purified on a silica gel column. The desired fraction was collected by eluting 2% methanol/methylene chloride, and then precipitated from hexane to give 8,13-diethyl-3,7, 12,17- tetramethylporphyrin-2,18-di(pentanoic acid methyl ester) (118 mg, 98% yield).
Example 28. Gallium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2,18-difpentanoic acid ethyl ester)
[0187] 8, 13-diethyl-3,7, 12,17-tetramethylporphyrin-2, 18-di(pentanoic acid methyl ester (example 27) (50 mg) in AcOH (100 ml) was added to Ga(acac)3 (50 mg). The mixture was heated to reflux for 40 minutes, and then cooled to room temperature. AcOH was evaporated to dryness and methylene chloride was added to dissolve the solid. The methylene chloride solution was washed with 1 N HCI solution twice (2x100 ml), drained and dried over sodium sulfate. Methylene chloride was evaporated and the porphyrin was precipitated from hexane. The precipitate was collected by filtration and air dried to give Gallium chloride 8,13-diethyI-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid methyl ester) (55 mg, 95% yield). Example 29: Platinum mesoporphyrin dimethyl ester
[0188] Platinum chloride (750 mg) and sodium chloride (750 mg) were refluxed in propionic acid (300 ml) for 30 min. Mesoporphyrin dimethyl ester (525 mg) and sodium acetate (550 mg) were added to the solution and refluxing continued for 2h after which time a UV visible analysis of the molecule showed the metallation to be complete. After cooling to room temperature, water (100 ml) was added and the precipitate filtered over celite. The product was recovered from celite by dissolving it in dichloromethane (100 ml). Methanol (25 ml) was added. Dichloromethane was removed by rotary evaporation. The precipitated solid was collected by filtration and dried. Yield of the title compound = 670mg. Example 30. Aluminum chloride mesoporphyrin dimethyl ester
[0189] Mesoporphyrin dimethylester (100 mg) was dissolved in dichloromethane ( 20 mL) and cooled to -78 °C in a dry-ice/acetone bath. Trimethylaluminum in toluene ( 2 ml, 2 M) was added slowly via syringe. The reaction was stirred at -78 °C for 30 min after which time a UV visible analysis of the molecule showed the metallation to be complete. Excess trimethylaluminum was decomposed by adding methanol (2 mL). The reaction was allowed to warm to room temperature diluted with dichloromethane ( 30 mL) and washed repeatedly with 1 N HCI. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. The crude reaction product was chromatographed on silica (5-10% methanol/dichloromethane) and the major pink fraction collected and evaporated. The product was dissolved in dichloromethane (50 mL), washed with 1 N HCI, dried and precipitated from hexane. The precipitate was collected by filtration and air dried to give 0.092 g of Aluminum chloride mesoporphyrin dimethyl ester. Example 31. Indium chloride Mesoporphyrin dimethyl ester
[0190] Mesoporphyrin dimethyl ester (150 mg), indium chloride (150 mg) and sodium acetate (200 mg) were refluxed in acetic acid (20 ml) for 3 hrs after which time a UV visible analysis of the molecule showed the metallation to be complete. Acetic acid was evaporated to dryness. The crude reaction product was chromatographed on silica (5%methanol/dichloromethane) and the major pink fraction collected and evaporated. Yield of the title compound = 139 mg.
Example 32. Tin (IV) dichloride Mesoporphyrin dimethyl ester
[0191] Mesoporphyrin dimethyl ester (100 mg), tin (II) chloride (100 mg) and sodium acetate (100 mg) were refluxed in the presence of air in acetic acid (15 ml) for 2 hrs after which time a UV visible analysis of the molecule showed the metallation to be complete. The reaction was cooled to room temperature and diluted with water (20 ml). The crude reaction product was filtered, dissolved in dichloromethane and washed with 1 N HCI, dried on sodium sulfate and evaporated to dryness. The product was precipitated from dichloromethane and hexane. Yield of the title compound = 100 mg. Example 33. Zinc Mesoporphyrin dimethyl ester [0192] Mesoporphyrin dimethyl ester (200 mg) was dissolved in dichloromethane (50 ml). A solution of zinc acetate (250 mg) in methanol (50 ml) was added and the reaction refluxed for 1hr. Dichloromethane was evaporated on a rotary evaporation and the solid filtered and dried. Yield of the title compound = 200 mg. Example 34. Gallium chloride Mesoporphyrin di (2-fluoroethylester)
[0193] Mesoporphyrin dimethyl ester (150 mg) was transesterified as described in example 3, except that 2-fluoroethanol was used instead of propanol. The crude product was purified by chromatography over silica gel {5% methanol/dichloromethane). This was then metallated as described in example 1. Yield of the title compound = 140 mg.
Example 35. Gallium chloride Mesoporphyrin di (3-chloropropylester)
[0194] Mesoporphyrin dimethyl ester (150 mg) was transesterified as described in example 3 except that 3-chloropropanoI was used instead of propanol. The crude product was purified by chromatography over silica gel (5% methanol/dichloromethane). This material was then metallated as described in example 1. Yield of the title compound = 150 mg. Example 36. Gallium chloride Deuteroporphyrin di (3-chloropropylester)
[0195] Deuteroporphyrin dimethyl ester (150 mg) was transesterified as described in example 3, except that 3-chloropropanol was used instead of propanol. The crude product was purified by chromatography over silica gel (2% methanol/dichloromethane). This material was then metallated as described in example 1. Yield of the title compound = 150 mg. Example 37. Gallium chloride Deuteroporphyrin di (2-fluoroethylester)
[0196] Deuteroporphyrin dimethyl ester (150 mg) was transesterified as described in example 3, except that 2-fluoroethanol was used instead of propanol. The crude product was purified by chromatography over silica gel (5% methanol/dichloromethane). This material was then metallated as described in example 1. Yield of the title compound = 140 mg. Example 38. Gallium chloride Deuteroporphyrin di (2,2,2-trifluoroethylester)
[0197] Deuteroporphyrin dimethyl ester (120 mg) was transesterified as described in example 3 except that 2,2,2-trifluoroethanol was used instead of propanol. The crude product was purified by chromatography over silica gel (5% methanol/dichloromethane). This was then metallated as described in example 1. Yield of the title compound = 102mg.
Example 39. Gallium chloride 3,8-dibromodeuteroporphyrin dimethyl ester [0198] 3,8-Dibromodeuteroporphyrin dimethyl ester was prepared from deuteroporphyrin dimethylester (250 mg) according to literature procedures
(Bonnette, R. et al, J. Chem. Res (S), 1990, 138-139). It was metallated as described in example 1. Yield of the title compound = 275 mg.
Example 40. Gallium chloride 3,8-hvdroxymethyl deuteroporphyrin dimethyl ester
[0199] 3,8-Dihydroxymethyl deuteroporphyrin dimethyl ester was prepared following literature procedures ( Kenner, G. W. et al. J. Chem. Soc,
Chem. Commun. 1987, 109-1347-1348). It was metallated as described in example 23. Yield = 60%
Example 41. Platinum 3,8-Bis(dimethylaminomethyl) deuteroporphyrin dimethyl ester
[0200] Platinum deuteroporphyrin dimethyl ester (230 mg) and eschenmoser's salt (1.5 g) were refluxed in chloroform (50 ml) for 36hrs. The reaction mixture was diluted with dichloromethane (50 mL) and washed several times with 1 % triethylamine/water, dried over sodium sulfate and evaporated to dryness. The crude product was chromatographed over silica gel (15% MeOH/2% triethylamine/dichloromethane). The solvent was evaporated and the product precipitated from dichloromethane and hexane. Yield of the title compound = 190 mg. Example 42. Gallium chloride Protoporphyrin dimethyl ester
[0201] Protoporphyrin dimethyl ester (100 mg) was metallated as described in example 1. Yield of the title compound = 100 mg.
Example 43. Gallium hydroxy 3,8-Bis-fN,N-dimethylamιnoprop-2-en-3- vDdeuteroporphyrin dimethyl ester [0202] 3,8-Bis (N,N-dimethylaminoprop-2-en-3-yl)deuteroporphyrin dimethyl ester (120 mg) was prepared following literature procedures (Pandey, R.
K. et al, Tetrahedron 1992, 48, 7591 ) and metallated according to example 12.
The product was precipitated from dichloromethane and hexane. Yield of the title compound = 102 mg.
Example 44. Gallium chloride Hematoporphyrin dimethyl ether dKmethyl amide)
[0203] Hematoporphyrin (1.0 g) was converted to hematoporphyrin dimethyl ether dimethyl ester following literature procedures ( Byrne, C. J., . et al,
Tetrahedron Lett. 1988, 29, 1421 ). Hematoporphyrin dimethyl ether dimethyl ester was dissolved in tetrahydrofuran (100 ml). A solution of potassium hydroxide (2 g) in methanol/water (5ml/5ml) was added. The reaction was stirred overnight at room temperature. Tetrahydrofuran was evaporated and residue dissolved in water (50 ml). The solution was neutralized by 1N HCI. The solid was filtered and dried to give hematoporphyrin dimethyl ether. Hematoporphyrin dimethyl ether was dissolved in tetrahydrofuran and cooled in an ice/water bath.
Triethylamine (3 ml) was added followed by ethyl chloroformate (2 mL). The reaction was stirred for 30 min then methylamine (10 ml, 2 M in THF) was added.
After 3 hours of stirring at room temperature, tetrahydrofuran was evaporated.
The residue was dissolved in dichloromethane and the solution was washed with water, and dried over sodium sulfate. The crude product was chromatographed on silica gel (50-60% acetone/dichloromethane) to give hematoporphyrin dimethyl ether di(methylamide). This material was metallated as in example 1.
Yield of the title compound = 500 mg.
Example 45. Tin(IV) dichloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2,18-di(butanoic acid methyl ester) [0204] 8,13-diethyl-3,7, 12, 17-tetramethylporphyrin-2, 18-di(butanoic acid methyl ester) (example 25) (100mg) was metallated by the procedure described in example 32. Yield of the title compound = 107mg.
Example 46. Indium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2,18-di(butanoic acid methyl ester)
[0205] 8,13-diethyl-3,7, 12, 17-tetramethylporphyrin-2, 18-di(butanoic acid methyl ester) (example 25) (100mg) was metallated as described in example 31.
Yield of the title compound = 95 mg.
Example 47. Platinum 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18- dUbutanoic acid methyl ester)
[0206] 8,13-diethyl-3,7, 12, 17-tetramethylporphyrin-2, 18-di(butanoic acid methyl ester) (example 25)(100mg) was metallated by the procedure described in example 29. Yield of the title compound = 110 mg.
Example 48. Aluminum chloride 8,13-diethyl-3,7,12,17- tetramethylporphyrin-2,18-di(butanoic acid methyl ester)
[0207] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic acid methyl ester) (example 25) (100mg) was metallated by a similar procedure as described in example 30. Yield of the title compound = 95 mg.
Example 49. Zinc 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18- difbutanoic acid methyl ester)
[0208] 8 , 13-d iethyl-3 ,7,12,17-tetramethylporphyrin-2 , 18-di(butanoic acid methyl ester) (example 25) (100mg) was metallated by a similar procedure (how different?) as described in example 33. Yield of the title compound = 105 mg.
Example 50. Gallium 8,13-diethyl-3.7,12,17-tetramethylporphyrin-2,18- di(butanoic acid propyl ester)
[0209] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(butanoic acid methyl ester) (example 25) (150 mg) was transesterified using 1 -propanol in the presence of concentrated sulfuric acid following example 3 . It was metallated as described in example 1. Yield of the title compound = 140 mg.
Example 51. Tin(IV)dichloride 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(pentanoic acid ethyl ester)
[0210] 8,13-diethyl-3,7, 12, 17-tetramethylporphyrin-2, 18-di(pentanoic acid ethyl ester) (example 27) (100 mg) was metallated following the procedure described in example 32. Yield of the title compound = 95 mg.
Example 52. Indium chloride 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(pentanoic acid ethyl ester)
[0211] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid ethyl ester) (example 27) (100 mg, example 26) was metallated following the procedure described in example 31. Yield of the title compound = 100 mg.
Example 53. Platinum 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18- di(pentanoic acid ethyl ester)
[0212] 8,13-d iethyl-3, 7, 12, 17-tetramethylporphyrin-2, 18-di(pentanoic acid ethyl ester) (example 27) (100 mg) was metallated following the procedure described in example 29. Yield of the title compound = 95 mg.
Example 54. Aluminum chloride 8,13-diethyl-3,7,12,17- tetramethylporphyrin-2,18-di(pentanoic acid ethyl ester) [0213] 8,13-diethyl-3,7, 12, 17-tetramethylporphyrin-2, 18-di(pentanoic acid ethyl ester) (example 27) (150 mg) was metallated following the procedure described in example 30. Yield of the title compound = 110 mg.
Example 55. Zinc 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18- di(pentanoic acid ethyl ester)
[0214] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(pentanoic acid ethyl ester) (example 27) (100 mg) was metallated following the procedure described in example 3. Yield of the title compound = 95 mg.
Example 56. Gallium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2.18-di(pentanoic acid propyl ester)
[0215] 8,13-diethyl-3,7, 12,17-tetramethylporphyrin-2, 18-di(pentanoic acid methyl ester) (example 27) (150 mg) was transesterified using 1 -propanol in the presence of concentrated sulfuric acid as described in example 3. It was metallated as described in example 1. Yield of the title compound = 140 mg.
Example 57. Gallium chloride 8,13-diethyl-3,7, 12,17-tetramethylporphyrin- 2,18-di(pentanoic acid methyl ester)
[0216] Gallium 8,13-diethyl-3,7, 12, 17-tetramethylporphyrin-2, 18- di(pentanoic acid methyl ester) was prepared as described in example 27 except that dimethyl malonate was used instead of diethyl malonate. Yield of the title compound = 125 mg. Example 58. Tin(IV)dichloride Mesoporphyrin N-methylamide
[0217] Mesoporphyrin N-methylamide (example 3) (425 mg) was metallated as described in example 32. Yield of the title compound = 400 mg.
Example 59. Indium chloride Mesoporphyrin N-methylamide
[0218] Mesoporphyrin N-methylamide (example 3) (150 mg) was metallated as described in example 31. The crude product was chromatographed over silica gel (10-15% methanol/dichlorometahne) and precipitated from dichloromethane/hexane. Yield of the title compound = 108 mg. Example 60. Platinum Mesoporphyrin N-methylamide
[0219] Mesoporphyrin N-methylamide (example 3) (100 mg) was metallated as described in example 29. The crude product was chromatographed over silica gel (10% methanol/dichloromethane) and precipitated from dichloromethane/hexane. Yield of the title compound = 121 mg. Example 61. Aluminum chloride Mesoporphyrin N-methylamide
[0220] Mesoporphyrin N-methylamide (example 121 ) (150 mg) was metallated as described in example 30. The crude product was chromatographed over silica gel (10-15% methanol/dichloromethane) and precipitated from dichloromethane/hexane. Yield of the title compound = 108 mg. Example 62. Zinc Mesoporphyrin N,N-diethylamide
[0221] Mesoporphyrin (250 mg) was converted to mesoporphyrin N,N- diethyl amide as described in example 121 , except that N,N-diethyl amine was used in place of methylamine. Yield = 0.242mg. This material was metallated as described in example 1 to give the title gallium compound. Yield = 200 mg. Example 63. Zinc Mesoporphyrin 3-(N-morpholino)propylamide
[0222] Mesoporphyrin (250 mg) was converted to mesoporphyrin 3-(N- morpholino)propylamide as outlined in example 121 , except that N-(3- aminopropyl)morpholine was used in place of methylamine, Yield = 275 mg. This material was metallated as described in example 33 to give the title zinc compound. Yield of the title compound = 250 mg. Example 64. Zinc Mesoporphyrin 3-(4-pyridyl)propylamide
[0223] Mesoporphyrin (250 mg) was converted to Mesoporphyrin 3-(4- pyridyl)propylamide as outlined in example 121 , except that 4-(3- aminopropyl)pyridine was used in place of methylamine, Yield = 200 mg. This material was metallated as described in example 33 to give the title zinc compound. Yield = 175 mg. Example 65. Platinum Mesoporphyrin di(2-methoxyethylamide)
[0224] Mesoporphyrin di(2-methoxyethylamide) (example 11 , 150 mg) was metallated as described in example 29. Yield of the title compound = 70 mg. Example 66. Gallium chloride Mesoporphyrin di(3-hydroxypropylamide)
[0225] Mesoporphyrin dimethylester (100 mg) was heated in 3- aminopropanol (5 ml) at 110 °C for 2hrs. The reaction mixture was cooled to room temperature and diluted with water (25 mL). The solid was filtered and dried to give mesoporphyrin di(3-hydroxypropylamide), 105 mg. This material was then metallated as described in example 16. Yield of the title compound = 80 mg. Example 67. Platinum Mesoporphyrin di(3-hvdroxypropylamide)
[0226] Platinum mesoporphyrin (125 mg) was heated in 3- aminopropanol (5 mL) at 120 °C for 2hrs. The reaction mixture was cooled to room temperature and diluted with water (25 mL). The solid was filtered and washed with water and dried to give the title compound. Yield of the title . compound = 130 mg.
Example 68. Gallium chloride Deuteroporphyrin di(3-hvdroxypropylamide)
[0227] Deuteroporphyrin dimethylester (200 mg) was heated in 3- aminopropanol (6 ml) at 120 °C for 2hrs. The reaction mixture was cooled to room temperature and diluted with water (25 mL). The solid was filtered and dried to give 200 mg of deuteroporphrin di(3-hydroxypropylamide). This material was then metallated as described in example 16. Yield of the title compound = 140 mg. Example 69. Platinum Mesoporphyrin di(2-ethoxyethanolamide)
[0228] Platinum mesoporphyrin (125 mg) was heated in ((2-ethoxy)-2'- ethanol)amine (3 mL) and dioxane (1 ml) at 120 °C for 3hrs. The reaction mixture was cooled to room temperature, diluted with water (25 mL) and extracted with chloroform/methanol (3:1 ), dried and evaporated to dryness. The crude product was chromatographed over silica gel (5% methanol/dichloromethane). The product was precipitated from dichloromethane/ether/hexane. Yield of the title compound = 90 mg.
Example 70. Gallium hydroxy Mesoporphyrin di-(N,N- dimethylaminoethylamide)
[0229] Mesoporphyrin (315 mg) was converted to mesoporphyrin di(N,N- dimethylaminoethyl amide) as described in example 121 , except that N,N- dimethylaminoethylamine was used in place of methylamine. Yield = 320 mg. This was metallated as described in example 1 , except that the product was not washed with 1 N HCI but with NaOH. Yield of the title compound = 210 mg. Example 71. Platinum Mesoporphyrin di N,N-dimethylaminoethylamide)
[0230] Platinum mesoporphyrin (100 mg) was refluxed in N,N- dimethylaminoethylamine (5 mL) for 16hrs. The reaction mixture was cooled to room temperature and diluted with ether (25 mL). The solid was filtered, dried and purified by chromatography over alumina (grade III)
(5%methanol/dichloromethane). The product was precipitated using dichloromethane and hexane to give the title compound. Yield = 75 mg.
Example 72. Indium chloride 8, 13-diethyl-3,7,12,17-tetramethylporphyrin- 2.18-di(3'-hvdroxypropyl)
[0231] Mesoporphyrin dimethyl ester was reduced to the corresponding diol as described in example 7. This compound (100 mg) was metallated as described in example 7, except that instead of gallium acetylacetonate, indium chloride (100mg) and sodium acetate(δθmg) was used. Yield of the title compound = 100g.
Example 73. Aluminum chloride 8, 13-diethyl-3,7,12,17- tetramethylporphyrin^.lδ-diO'-hvdroxypropyl)
[0232] Aluminum mesoporphyrin dimethyl ester (example 30) (92 mg) was dissolved in dry tetrahydrofuran (50 ml). Lithium aluminum hydride (75 mg) was added to the reaction and the reaction mixture refluxed under an atmosphere of nitrogen for 1hr. The reaction was cooled to room temperature and 1 N HCI was added slowly to destroy excess LiAIH4. The solution was extracted with dichloromethane (3x50 ml), dried over sodium sulfate and solvent evaporated to dryness. The crude product was chromatographed on silica gel
(20%methanol/dichloromethane) to give the titled product. Yield = 75 mg.
Example 74. Platinum 8, 13-diethyl-3,7,12,17-tetramethylporphryin-2,18- diO'-hydroxypropyl)
[0233] Platinum mesoporphyrin dimethyl ester (example 29) (300 mg) was dissolved in dry tetrahydrofuran (50 ml). Lithium aluminum hydride (250 mg) was added to the reaction and the reaction mixture refluxed for 1hr. The reaction was cooled to room temperature and methanol (1 ml) was added slowly to destroy excess LiAIH4. The solution was diluted with 1 N HCI (50 ml) and extracted with dichloromethane (3x50 ml), dried over sodium sulfate and solvent evaporated to dryness. The crude product was chromatographed on silica gel
(10%methanol/dichloromethane) to give the title compound. Yield = 250 mg.
Example 75. Indium chloride 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(3'-methoxypropyl)
[0234] 8, 13-diethyl-3,7, 12,17-tetramethylporphyrine-2, 18-di(3'- methoxypropyl) (example 10) (100 mg) was refluxed for 2hrs. in acetic acid (15 ml) in the presence of indium chloride (100 mg) and sodium acetate (100 mg) after which time the UV-Vis analysis of the reaction indicated the metallation to be complete. Acetic acid was evaporated by rotary evaporation. The residue was dissolved in dichloromethane (25 ml) and washed with water followed by 1 N
HCI. The dichloromethane layer was separated, dried over sodium sulfate and evaporated to dryness. The product was precipitated from dichloromethane/hexane. Yield of the title compound = 70 mg.
Example 76. Indium hydroxy 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(3-(N-pyrrolidino)propyl)
[0235] 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(propyl-3'-p- toluenesulfonate_(example 9) (140 mg) was dissolved in dichloromethane (25 ml) and pyrrolidine (1 ml) was added. The reaction was stirred at.room temperature for 20 hrs. All the volatiles were removed by rotary evaporation and the product precipitated from dichloromethane and methanol. Yield of 8,13-diethyl-3,7,12,17- tetramethylporphyrin-2,18-di(3-(N-pyrrolidino)propyl) = 118 mg. This was then dissolved in acetic acid (10 ml), and indium chloride (100 mg) and sodium acetate (100 mg) were added. The reaction mixture was heated at reflux for 2hrs after which time a UV visible analysis of the molecule showed the metallation to be complete. Acetic acid was evaporated and the residue dissolved in dichloromethane (50 ml). The solution was washed with water followed by 1 N
NaOH and again water, dried over sodium sulfate and evaporated to dryness.
The product was precipitated from dichloromethane and hexane. Yield of the title compound = 90 mg.
Example 77. Platinum 8,13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-dif3- (N-pyrrolidino)propyl)
[0236] Platinum 8, 13-diethyl-3,7,12,17-tetramethylporphyrin-2,18-di(3- hydroxypropyl) (example 74) (200 mg) was converted to its corresponding tosylate following the procedure in example 9. Yield = 200 mg. This was dissolved in chloroform (50 ml), pyrrolidine (2 ml) was added and the reaction mixture was refluxed for 4hrs. All the volatiles were removed by rotoevaporation.
The crude product was chromatographed over silica gel (15%-25% methanol/1 % triethylamine/dichloromethane). The product precipitated when all the dichloromethane was removed from the fractions. It was filtered and dried to give the title compound. Yield = 158 mg.
Example 78. Gallium hydroxy 8,13-diethyl-3, 7,12,17 tetramethylporphyrin- 2,18-di((N-3'-hvdoxypropyl)-3-aminopropyl)
[0237] 8, 13-diethyl-3,7, 12, 17-tetramethylporphyrin-2, 18-di(propyl-3'-p- toluenesulfonate_(example 9) (150 mg) and 3-aminύpropanol were refluxed in chloroform for 6hrs. chloroform was evaporated and water added to the residue.
The solid was filtered, washed with water and dried to give 2,7,12,18 tetramethyl-
3,8-diethyl-13, 17-di((N-3'-hydoxypropyl)-3-aminopropyl)porphyrin. This was metallated with gallium acetylacetonate (150 mg) in refluxing acetic acid (100 ml).
Metallation was complete after 1 hr. as evidenced by UV-Vis analysis. Acetic acid was evaporated and the residue dissolved in THF (25 ml)/methanol (25ml). A solution of KOH (1g / 5 ml water) was added and the reaction refluxed for 4hrs. diluted with water (100 ml) and extracted with dichloromethane. The dichloromethane layer was dried and evaporated to dryness and the residue precipitated from dichloromethane and hexane. Yield of the title compound = 100 mg.
Example 79. Zinc 8,13-diethyl-3,7,12,17 tetramethylporphyrin-2,18-di((N, N- diethyl)-3-aminopropyl)
[0238] Mesoporphyrin N,N-diethylamide (example 15) (350 mg) was dissolved in THF (40 ml). Lithium aluminum hydride (1 g) was added to the solution and the reaction stirred for 1hr at room temperature. Excess LiAIH was destroyed with methanol. The reaction was diluted with water and extracted thoroughly with dichloromethane, dried and evaporated to give 8,13-diethyl-
3,7,12,17 tetramethylporphyrin-2,18-di((N, N-diethyl)-3-aminopropyl). Yield = 85 mg. This was dissolved in dichloromethane, a methanolic solution of zinc acetate
(5%, 5 ml) was added and the reaction refluxed for 1hr. The solution was washed with water, dried and evaporated to dryness. The crude product was chromatographed over silica gel (1 %triethylamine/33%hexane/
66%dichloromethane) to give the titled compound. Yield = 85 mg.
Example 80. Gallium chloride 3,7,12,17-tetramethylporphyrin-2,18-di((3'- diethylphosphono)propyl)
[0239] Deuteroporphyrin dimethyl ester (1.0g) was reduced to the corresponding diol following example 7. The diol was dissolved in pyridine (25 ml) and dichloromethane (100 ml) and cooled in an ice-water bath. Methane sulfonyl chloride (5 ml) was added slowly to the reaction. The reaction was stirred for 4hrs and washed with water and then 1 N HCI until the organic layer was free of pyridine. The organic layer was dried and evaporated to give the deuteroporphyrin dimesylate. Yield = 1.150 g. This was then suspended in acetone (200ml), and sodium iodide (2.5 g) was added and the reaction refluxed for 3hrs. Acetone was evaporated, and water (100 ml) was added to the residue and filtered. The solid was washed with water and methanol and dried to give the deuteroporphyrin diiodide. Yield = 1.10 g.
[0240] Deuteroporphyrin diiodide (850 mg) was refluxed in triethylphosphite (45 ml) for 3hrs. Excess triethyphosphite was evaporated under vacuum and the residue dissolved in dichloromethane and chromatographed over silica gel (2%, 3%, 5% methanol/dichloromethane). The major product was collected and precipitated from dichloromethane/ ether / hexane to give the deuteroporphyrin diphosphonate. Yield = 850 mg.
[0241] Deuteroporphyrin diphosphonate (700 mg) was metallated as described in example 1. The crude product was purified by chromatography on silica gel (5%, 10%, 15% methanol/dichloromethane). The major product was collected and crystallized from dichloromethane/ether/hexane to give the title compound. Yield = 492 mg.
Example 81. Indium chloride 3,7,12,17-tetramethylporphyrin-2,18-di((3'- diethylphosphono)propyl)
[0242] 3,7,12,17-tetramethylporphyrin-2, 18-di((3'- diethylphosphono)propyl) (example 80) (140 mg) was refluxed in acetic acid (10 ml) in the presence of indium acetylacetone (140 mg) for 45 min. Acetic acid was evaporated by rotary evaporation and the residue dissolved in dichloromethane
(75 mL). The dichloromethane solution was washed with 1 N HCI (2x 50 ml), dried and evaporated. The crude product was pure by TLC and was precipitated from dichloromethane/ether/hexane to give the title compound. Yield = 135 mg.
Example 82. Tin(IV)dichloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl ester) [0243] The metal free azaporphyrin (125 mg) synthesized in example 21
(prior to metallation) was metallated as described in example 32. Yield of the title compound = 100 mg.
Example 83. Indium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl ester)
[0244] The metal free azaporphyrin (125 mg) synthesized in example
21 (prior to metallation) was metallated as described in example 31. Yield of the title compound = 125 mg.
Example 84. Aluminum chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl ester)
[0245] The metal free azaporphyrin (125 mg) synthesized in example 21
(prior to metallation) was metallated as described in example 30. Yield of the title compound = 125 mg.
Example 85. Platinum 7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin- 2,18-di(propionic acid methyl ester)
[0246] The metal free azaporphyrin (100 mg) synthesized in example 21 (prior to metallation) was metallated as described in example 29. Yield of the title compound = 110 mg.
Example 86. Platinum 7.8,12,13-tetraethyH 2,17-dimethyl-10-azaporphyrin- 2,18-di(propionic acid potassium salt)
[0247] The platinum azaporphyrin (example 85) (100 mg) was dissolved in THF (25 ml), and KOH (100 mg) was dissolved in methanol/water (1 ml/1 ml) and added. The reaction was refluxed until hydrolysis was complete, 2hrs. THF was evaporated on a rotoevaporator and the residue dissolved in water. The solution was neutralized with 1 N HCI, and the solid filtered and dried to give the platinum azaporphyrin diacid. The diacid (100 mg) was dissolved in methanol (25 ml) then treated with 2 equivalents of KOH in methanol and stirred for 2hrs. All the solvent was evaporated to dryness to give the title compound. Yield of the title compound = 90 mg.
Example 87. Gallium chloride 7,8.12.13-tetraethyl-12.17-dimethyl-10- azaporphyrin-2,18-di(propionic acid)
[0248] Gallium azaporphyrin (example 21 ) (125 mg) was hydrolyzed to the corresponding disodium salt as described in example 86. The solution was neutralized with 1 N HCI, and the solid filtered and dried to give the gallium azaporphyrin diacid. Yield of the title compound = 100 mg.
Example 88. Gallium hydroxy 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid sodium salt)
[0249] Gallium azaporphyrin diacid (example 87) (100 mg) was converted to its disodium salt as described in example 86, except that NaOH was used instead of KOH. Yield of the title compound = 100 mg.
Example 89. Gallium chloride 7.8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid ethyl ester)
[0250] Azaporphyrin (example 21 ) (100 mg) was transesterified as described in example 2. Yield = 90 mg. This was metallated as described in example 1. Yield of the title compound = 95 mg.
Example 90. Tin (IV) dichloride 7,8,12.13-tetraethyl-12,17-dimethvMO- azaporphyrin-2,18-di(propionic acid methyl amide)
[0251] Azaporphyrin methylamide (example 22; prior to metallation) (110 mg) was metallated as described in example 32. Yield of the title compound =
120 mg.
Example 91. Indium chloride 7,8.12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl amide)
[0252] Azaporphyrin methylamide (example 22; prior to metallation) (100 mg) was metallated as described in example 31. Yield of the title compound =
120 mg.
Example 92. Platinum 7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin- 2,18-di(propionic acid methyl amide)
[0253] Azaporphyrin methylamide (example 22; prior to metallation) (110 mg) was metallated as described in example 29. Yield of the title compound =
120 mg.
Example 93. Aluminum chloride 7,8,12,13-tetraethyM 2,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid methyl amide)
[0254] Azaporphyrin methylamide (example 22; prior to metallation) (110 mg) was metallated as described in example 30. Yield of the title compound = 90 mg. Example 94. Gallium chloride 5-aza-mesoporphyrin IX dimethyl amide
[0255] 5-aza-mesoporphyrin IX (100mg) was converted to its methylamide and metallated as described in example 121. Yield of the title compound = 75 mg.
Example 95. Gallium chloride 7,8,12,13-tetraethyl-12. 7-dimethyl-10- azaporphyrin-2,18-di(propionic acid 2'-methoxyethyl amide)
[0256] Azaporphyrin dimethyl ester (example 21 ; prior to metallation)
(100 mg) was converted to the amide as described in example 66 except that 2- methoxyethylamine was used instead of 3-aminopropanol. Yield = 110 mg. This material was metallated as described in example 11. Yield of the title compound
= 95 mg.
Example 96. Platinum 7,8, 12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin- 2,18-di(propionic acid-2'-methoxyethyl amide)
[0257] 7,8,12,13-tetraethyl-12, 17-dimethyl-10-azaporphyrin-2, 18- di(propionic acid 2'-methoxyethyl amide) (example 95) (100 mg) was metallated as described in example 29. Yield=85%
Example 97. Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-3'-hvdroxypropyl amide)
[0258] Azaporphyrin dimethyl ester (example 21 ) (100 mg) was converted to the title compound as described in example 66. Yield = 110 mg.
Example 98. Platinum 7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin- 2,18-di(propionic acid-3'-hvdroxypropyl amide amide)
[0259] Platinum azaporphyrin dimethyl ester (example 85) (100 mg) was converted to the title compound as described in example 67. Yield = 110 mg. Example 99. Gallium chloride 5-azamesoporphyrin IX di(3'-hvdroxypropyl amide)
[0260] 5-azamesoporphyrin dimethyl ester (Singh, J. P., et al, Tet. Lett.
1995, 36, 1567) (100 mg) was converted to the title compound as described in example 66. Yield = 110 mg.
Example 100. Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-2-ethoxyethanol amide)
[0261] Azaporphyrin dimethyl ester (example 21 ) (100 mg) was converted to the title compound as described in example 16. Yield = 110 mg.
Example 101. Platinum 7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin- 2,18-di(propionic acid-2-ethoxyethanol amide)
[0262] Platinum azaporphyrin dimethyl ester (example 85) (100 mg) was converted to the title compound as described in example 69. Yield = 100 mg.
Example 102. Gallium chloride 7,8.12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-2'-N,N-dimethylaminoethyl amide)
[0263] Azaporphyrin (example 21 ) (150 mg) was converted to the titled compound as described in example 22 except that 2-N,N- dimethylaminoethylamine was used instead of methylamine. Yield = 100 mg.
Example 103. Platinum 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(propionic acid-2'-N,N-dimethylaminoethyl amide)
[0264] Platinum azaporphyrin dimethyl ester (example 85) (100 mg) was converted to the title compound as described in example 71. Yield = 100 mg.
Example 104. Indium chloride 7,8.12,13-tetraethyl-12,17-dimethvM 0- azaporphyrin-2,18-di(3'-hyroxypropyl)
[0265] 7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin-2, 18-di(3'- hyroxypropyl) (example 23) (125 mg) was metallated as described in example 31.
Yield of the title compound = 100 mg. Example 105. Platinum 7,8,12,13-tetraethyl-12,17-dimethyl-10-azaporphyrin- 2,18-di(3'-hyroxypropyl)
[0266] Platinum azaporphyrin dimethyl ester (150 mg) was reduced using LiAIH4 as described in example 74. Yield of the title compound = 120 mg.
Example 106. Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethvM0- azaporphyrin-2,18-di(3'-methoxypropyl)
[0267] Azaporphyrin diol (example 23) (200 mg) was converted to its methyl ether via the tosylate according to the procedure described in examples 9 and 10. Yield = 150 mg. This material was metallated following the procedure described in example 10. Yield of the title compound = 120 mg.
Example 107. Indium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(3-methoxypropyl)
[0268] Azaporphyrin diol (example 23) (200 mg) was converted to its methyl ether via the tosylate according to the procedure described in examples 9 and 10. Yield = 150 mg. This material was metallated following the procedure described in example 31. Yield of the title compound = 120 mg.
Example 108. Gallium chloride 7,8,12,13-tetraethyl-12,17-dimethyl-10- azaporphyrin-2,18-di(butanoic acid methyl ester)
[0269] 7,8, 12, 13-tetraethyl-12, 17-dimethyl-10-azaporphyrin-2, 18- di(butanoic acid methyl ester) was prepared from azaporphyrin dimethyl ester (example 21) following the procedure described in examples 7, 9, 25, 26. Yield = 500mg. Example 109. Gallium hydroxy mesoporphyrin disodium salt
[0270] Gallium chloride mesoporphyrin dimethyl ester (example 1 )
(125 mg) was converted to its sodium salt as described in example 86, except that 3 equivalents of NaOH were used instead of KOH. Yield of the title compound = 100 mg. Example 110. indium hydroxy mesoporphyrin disodium salt
[0271] Indium chloride mesoporphyrin dimethyl ester (example 31 ) (125 mg) was converted to its sodium salt as described in example 86, except that 3 equivalents of NaOH were used in the final step instead of KOH. Yield of the title compound = 100 mg. Example 111. Platinum mesoporphyrin disodium salt
[0272] Platinum mesoporphyrin dimethyl ester (example 29) (150 mg) was converted to its sodium salt as described in example 86, except that NaOH was used in the final step instead of KOH. Yield of the title compound = 100 mg. Example 112. Indium hydroxy Protoporphyrin disodium salt
[0273] Protoporphyrin dimethyl ester (150 mg) was metallated following the procedure described in example 31. This material was converted to the title compound as described in example 86, except that 3 equivalents of NaOH were used in the final step instead of KOH. Yield of the title compound = 110 mg. Example 113. Indium hydroxy Coproporphyrin III tetra sodium salt
[0274] Coproporphyrin III dimethyl ester (125 mg) was metallated following the procedure described in example 31. This material was converted to the title compound as described in example 110. Yield = 110 mg.
Example 114. Gallium hydroxy 8,13-diethyl-3,7,12,17-tetramethylporphyrin- 2,18-di(pentanoic acid sodium salt)
[0275] Gallium chloride 8, 13-diethyl-3,7, 12,17-tetramethylporphyrin-2, 18- di(pentanoic acid methyl ester) (200mg) (example 28) was converted to its disodium salt following the procedure described in example 86, except that 3 equivalents of NaOH were used in the final step instead of KOH. Yield = 180mg. Example 115. Gallium chloride Mesoporphyrin III dimethyl ester [0276] Mesoporphyrin III dimethyl ester was synthesized according to literature procedures (Grigg, R., et al, J. Chem. Soc, C, 1969, 176). This material (200 mg) was metallated as described in example 1. Yield of the title compound = 190 mg.
Example 116. Gallium chloride 3,7,14,17-tetramethyl-5,10-diazaporphyrin- 2,8,12,18-tetra(propionic acid methyl ester)
[0277] 3,3'-dimethyl-4,4'-di(methyl propionate)dipyrromethane (1.05 g) was dissolved in ethyl acetate (25 ml) and bromine (1.5 g) was added dropwise.
A dark brown precipitate was formed. The reaction was cooled and the solid filtered and dried. Yield of dibrominate dipyrromethane = 0.95 g. This material was dissolved in methanol (50 ml), and sodium azide (1 g) in water (5 mL) was added and the reaction refluxed for 3 days. UV/Vis analysis of the reaction showed the disappearance of the 429 nm peak (due to dipyrromethane) and appearance of two peaks at 545 nm and 620 nm. The solvent was evaporated and the residue chromatographed over silica gel (2-5% methanol/dichloromethane). The fast running blue/purple band, which was
3,7,14,17-tetramethyl-5, 10-diazaporphyrin-2,8, 12, 18-tetra(propionic acid methyl ester), was isolated. Yield 3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18- tetra(propionic acid methyl ester) = of 100 mg. This material was metallated as described in example 21. Yield, 75 mg. Example 117. Gallium chloride 3,7,14,17-tetramethyl-5,10-diazaporphyrin- 2,8,12,18-tetra propionic acid
[0278] Gallium chloride 3,7, 14,17-tetramethyl-5, 10-diazaporphyrin-
2,8,12,18-tetra(propionic acid methyl ester) (example 116) (50 mg) was hydrolyzed to the corresponding tetra acid as described in example 86. Yield of the title compound = 45 mg.
Example 118. Gallium chloride 3,7,14,17-tetramethyl-5,10-diazaporphyrin- 2,8,12,18-tetra (3'-hvdroxypropyl)
[0279] Diazaporphyrin (synthesized in example 116) (50 mg) was converted to the title compound following the procedure described in example 23.
Yield = 30 mg.
Example 119. Platinum 3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8, 12,18- tetra(propionic acid methyl ester
[0280] 3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18- tetra(propionic acid methyl ester) (synthesized in example 116) (50 mg) was metallated as described in example 29. Yield, of the title compound = 50 mg.
Example 120. Platinum 3,7,14,17-tetramethyl-5,10-diazaporphyrin-2,8,12,18- tetraO'-hydroxypropyl)
[0281] Platinum 3, 7,14, 17-tetramethyl-5,10-diazaporphyrin-2,8, 12,18- tetra(propionic acid methyl ester) (example 119) (50 mg) was reduced to the corresponding tetraalcohol as described in example 74. Yield of the title compound = 35 mg. Example 121 : Gallium chloride mesoporphyrin N-methyl amide
[0282] Mesoporphyrin (200mg) was suspended/dissolved in dichloromethane (25mL) and oxalylchloride (5mL) was added. The solution was refluxed for 1 hr under argon. The excess oxaylychloride and dichloromethane was removed by rotary evaporation and dichloromethane (50mL) was added, followed by a 2M solution of methylamine in THF (40mL). The solution was stirred for 2 hrs after which the solvent was removed by rotary evaporation. The residue was dissolved in 5% methanol/dichloromethane and chromatographed on silica using 5 % methanol/dichloromethane as the eluent. The major red fraction (mesoporphyrin dimethyl amide) was collected and evaporated to ~30mL and methanol (20mL) added. The dichloromethane was removed by rotary evaporation and the precipitated solid collected by filtration and dried. This compound was suspended in acetic acid (25mL) and gallium acetyl acetonate added (200mg). The solution was refluxed for 1.5 hrs after which time a UV/visible analysis of the molecule showed the metallation to be complete. The solvent was removed by rotary evaporation and the residue dissolved in dichloromethane (100mL). The dichloromethane layer was washed repeatedly with 1 HCI and the organic layer collected and evaporated. The crude reaction mixture was chromatographed on silica (5% methanol/dichloromethane) and the major pink fraction collected and evaporated. The compound was redissolved in dichloromethane (100mL), and the organic layer was washed repeatedly with 1 N HCI, dried over sodium sulfate and evaporated to ~20mL. Hexane was added (14mL) and the dichloromethane was removed by rotary evaporation. The precipitated solid was collected by filtration and dried. Yield of the title compound = 200mg. Example 122: Gallium chloride deuteroporphyrin di-propylester
[0283] Deuteroporphyrin dimethyl ester (200mg) was refluxed in 5% sulfuric acid in propanol (25 ml) for 6hrs. The reaction was cooled to room temperature, diluted with water (100 ml) and solution neutralized with sodium bicarbonate. The solid was filtered, dried and crystallized from dichloromethane and hexane. Yield of deuterporphyrin dipropyl ester = 180 mg. This was then metallated as described in example 1. Yield of the title compound = 190 mg. Example 123: Gallium chloride rhodoporphyrin di-methylester
[0284] Rhodoporphryin dimethyl ester (200mg) was synthesized according to the method outlined in "The Porphyrins and Metalloporphyrins" Ed. Kevin Smith, Chapter 19, Elsevier Scientific Publishing Co., 1975, page 777, and metallated according to example 1. Yield = 210mg.
[0285] It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds and methods of the present invetion without departing from the spirit or scope of the invention. Thus, it is intended that the present invention cover the modification and variations of this invention provided they fall within the scope of the appended claims and the equivalents.

Claims

WHAT IS CLAIMED IS:
1. A method of using a gallium porphyrin as a medicament to treat or detect diseases of the cardiovascular system, comprising administering to a patient an effective amount of a porphyrin compound that coordinates gallium in the central pyrrolic core, and irradiating said porphyrin compound with energy at a wavelength capable of exciting the molecule to achieve the desired detection or therapeutic effect.
2. A method of using a gallium mono-, di-, tri-, or tetra-azaporphyrin as a medicament to treat or detect diseases of the cardiovascular system, comprising administering to a patient an effective amount of a mono-, di-, tri-, or tetra-azaporphyrin compound that coordinates gallium in the central pyrrolic core, and irradiating said mono-, di-, tri-, or tetra-azaporphyrin compound with energy at a wavelength capable of exciting the molecule to achieve the desired detection or therapeutic effect.
3. A method of using a metallated porphyrin as a medicament to treat or detect diseases of the cardiovascular system, comprising administering to a patient an effective amount of a porphyrin compound that coordinates a metal in the central pyrrolic core, and irradiating said porphyrin compound with energy at a wavelength capable of exciting the molecule to achieve the desired detection or therapeutic effect.
4. The method of claim 3, wherein the coordinated metal is selected from Ag, Au, Al, Cd, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Ge, Gd, Hf, Ho, In, Ir, La, Lu, Mn, Mg, Mo, Ni, Nd, P, Pb, Pd, Pr, Pt, Rh, Ru, Sb, Sc, Si, Sm, Sn, Tc, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, W, Zn and Zr.
5. The method of claim 3, wherein the coordinated metal is selected from Si, Ga, Pt, Pd, Sn, In, Ge, Al, Zn, Y, and Mg.
6. A method of using a metallated mono-, di-, tri-, or tetra-azaporphyrin as a medicament to treat or detect diseases of the cardiovascular system, comprising administering to a patient an effective amount of a mono.-, di-, tri-, or tetra-azaporphyrin compound that coordinates a metal in the central pyrrolic core, and irradiating said mono-, di-, tri-, or tetra-azaporphyrin compound with energy at a wavelength capable of exciting the molecule to achieve the desired detection or therapeutic effect.
7. The method of claim 6, wherein the coordinated metal is selected from Ag, Au, Al, Cd, Ce, Co, Cr, Cu, Dy, Er, Eu, Fe, Ga, Ge, Gd, Hf, Ho, In, Ir, La, Lu, Mn, Mg, Mo, Ni, Nd, P, Pb, Pd, Pr, Pt, Rh, Ru, Sb, Sc, Si, Sm, Sn, Tc, Tb, Th, Ti, TI, Tm, U, V, Y, Yb, W, Zn and Zr.
8. The method of claim 6, wherein the coordinated metal is selected. from In, Pt, Pd, Sn, Al, Mg, Zn, Si, Ge, Y and Ga.
9. A method for the detection or treatment of tissues of the cardiovascular system, comprising administering to a patient, locally or systemically, an effective amount of a porphyrin or a mono-, di-, tri-, or tetra-azaporphyrin, that coordinates a metal in the central tetrapyrrolic core, and irradiating said porphyrin or azaporphyrin with energy at a wavelength capable of exciting the molecule to achieve the desired detection or therapeutic effect.
10. The method of claim 9, wherein said metal is selected from In, Pt, Pd, Sn,
Al, Mg, Zn, Si, Ge, Y, and Ga.
11.The method of claim 10, wherein said metal is Ga.
12. The method of claim 1 , wherein said porphyrin compound is selected from gallium (III) mesoporphyrin diacid, gallium (III) mesoporphyrin dimethyl ester, gallium (III) mesoporphyrin diethyl ester, and gallium (III) mesoporphyrin dipropyl ester, gallium (111) mesoporphyrin dibutyl ester, gallium (III) mesoporphyrin dipentyl ester, gallium (III) mesoporphyrin dihexyl ester, gallium (III) mesoporphyrin N,N-diethylamide, gallium (III) deuteroporphyrin diacid, gallium (III) deuteroporphyrin dimethyl ester, gallium (111) deuteroporphyrin diethyl ester, gallium (III) deuteroporphyrin dipropyl ester, gallium (III) deuteroporphyrin dibutyl ester, gallium (III) deuteroporphyrin dipentyl ester, gallium (III) deuteroporphyrin dihexyl
ester, and β-halogenated derivatives and salts thereof.
13. The method of claim 1 , wherein said porphyrin compound is selected from mesoporphyrin derivatives, deuteroporphyrin derivatives, coproporphyrin derivatives, uroporphyrin derivatives, pentacarboxyporphyrin derivatives, hematoporphyrin derivatives, protoporphyrin derivatives, hexacarboxyporphyrin derivatives, chloroporphyrin e6 derivatives, chloroporphyrin e4 derivatives, phylloporphyrin derivatives, rhodoporphyrin derivatives, pyrroporphyrin derivatives, pheoporphyrin a5 derivatives, and phylloerythrin derivatives.
14. A method of using a tetrapyrrolic macrocycle that coordinates gallium in the central pyrrolic core as a medicament to treat or detect diseases of the cardiovascular system wherein said gallium co-ordinating tetrapyrrolic macrocycle is selected from a porphyrin, a azaporphyrin, a diazaporphyrin, a triazaporphyrin, a corrole, a porphycene, a isoporphycene, a hemiporphycene, and a corrphycene.
15. The method of any of claims 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13 and 14 for treating a vessel wall or tissue adjoining the vessel wall, or material attached to the vessel wall of a patient's coronary, carotid or peripheral vasculature.
16. The method of claim 15 wherein said vessel is an artery or a vein.
17. The method of any of claims 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, and 14 wherein the cardiovascular disease is atherosclerosis, restenosis or graft disease.
18. The method of claim 9 wherein said therapeutic effect is observed on the group consisting of normal contractile phenotype vascular smooth muscle cells (VSMC), non-contractile synthetic phenotype VSMC, myofibroblasts, endothelial cells, macrophages, leukocytes, monocytes, erthyrocytes, platelets, (thrombocytes) or combinations thereof.
19. The method of claim 9, wherein said therapeutic effect is observed on fibronectin, vitronectin, collagen, elastin, fibrinogen, proteoglycans, or metalloproteinases.
20. The method of claim 9, wherein said treatment involves ablation, reduction and/or stabilization of the vessel wall plaque.
21. The method according to claim 9, wherein said treatment is of restenosis of occlusive tissue formation induced in the vessel wall or by vascular injury to the vessel wall.
22. The method of claim 21 wherein said restenosis is selected from vessel wall negative geometric remodelling, intimal thickening, increased intraluminal shear stress, dysfunctional or absent endothelium, periadventitial fibrosis, increased motor tone, fibrotic contracture, scar formation or combinations thereof.
23. The method of claim 21 wherein said injury is via balloon angioplasty.
24. The method of claim 21 wherein said injury is stent deployment.
25. The method of claim 21 wherein said injury is from an endovascular device.
26. The method of claim 21 wherein said occlusive tissue is foreign tissue.
27. The method of claim 21 wherein said occlusive tissue is host tissue.
28. The method of claim 21 wherein said occlusive tissue is from an injury via invasive or non-invasive surgical manipulation of the vessel.
29. The method of claim 28 wherein said surgical manipulation is selected from suturing, vascular access, anastomosis, bypass procedure, or shunt.
30. The method of claim 9 for treatment of arteriovenous shunts.
31. The method of any of claims 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13 and 14 further including the step of delivering an activatable agent into tissue of the vessel wall which, continues to act therapeutically with or without exposure to an energy source.
32. The method of claim 9 wherein said energy source is selected from light, ultrasound, magnetic force, electromagnetic radiation, LEDs or lasers in the UV/visible electromagnetic spectrum or near infrared.
33. The method of claim 9 wherein said energy is an illuminating step of wavelength between about 350 to about 900 nm on the tissue of the vascular vessel wall.
34. The method of claim 33 wherein said illuminating step comprises illuminating a plurality of times, each for a duration and in an area sufficient to impart a treatment effect within the vascular vessel wall.
35. A method for restructuring the epithelial or endothelial layers of skin comprising administering to a patient, either topically or systemically, a therapeutic amount of a tetrapyrrolic molecule that coordinates gallium in the central tetrapyrrolic core, and irradiating said molecule with energy at a wavelength capable of exciting the molecule to achieve the desired therapeutic effect.
36. The method of claim 35 wherein epithelial or endothelial cell layer restructuring results in a positive therapeutic response to scars, wound healing, psoriasis, chronic inflammatory diseases, eczema, immune modulated diseases, scleraderma, shingles, wrinkles, actinic keratosis, carcinomas or sarcoma of the skin or other tissues, fungual infections, viral or bacterial infections, warts, arthritis, port wine stains, birth marks, stretch marks, hyper pigmentation, urticaria, allegenic reactions, chronic proliferative dermatitis, chronic ulcerative dermatitis, disorders of hair or hair follicles, disorders of skin pigmentation, acne, cutaneous infections, skin tumors, seborrheic dermatitis, cutaneous vasculitis, erythema multiforme or nodosum.
37. A method for stopping or arresting hair growth comprising administering to a patient, either topically or systemically, a therapeutic amount of a tetrapyrrolic molecule that coordinates gallium in the central tetrapyrrolic core and irradiating said molecule with energy at a wavelength capable of exciting the molecule to achieve the desired therapeutic effect.
38. A method according to claim 37 wherein said gallium co-ordinating tetrapyrrole is selected from a mesoporphyrin derivative, deuteroporphyrin derivative, coproporphyrin derivative, uroporphyrin derivative, pentacarboxyporphyrin derivative, hematoporphyrin derivative, protoporphyrin derivative, hexacarboxyporphyrin derivative, chloroporphyrin e6 derivative, chloroporphyrin e4 derivative, phylloporphyrin derivative, rhodoporphyrin derivative, pyrroporphyrin derivative, pheoporphyrin a5 derivative, phylloerythrin derivative, azaporphyrin derivate, diazaporphyrin derivative, triazaporphyrin derivative and a tetraazaporphyrin derivative.
39. A method according to claim 37 wherein said gallium co-ordinating tetrapyrrole is selected from a mesoporphyrin amide derivative, deuteroporphyrin amide derivative, coproporphyrin amide derivative, uroporphyrin amide derivative, pentacarboxyporphyrin amide derivative, hematoporphyrin amide derivative, protoporphyrin amide derivative, hexacarboxyporphyrin amide derivative, chloroporphyrin e6 amide derivative, chloroporphyrin e4 amide derivative, phylloporphyrin amide derivative, rhodoporphyrin amide derivative, pyrroporphyrin amide derivative, pheoporphyrin a5 amide derivative phylloerythrin amide derivative, azaporphyrin amide derivate, diazaporphyrin amide derivative, triazaporphyrin amide derivative and a tetraazaporphyrin amide derivative.
40. The method of claim 37 wherein said gallium tetrapyrrole is formulated topically in a gel containing excipients selected from benzyl alcohol, oleyl alcohol, hydroxypropyl cellulose, ethanol and water.
41.The method of claim 40 where the formulation comprises benzyl alcohol 19.6%, oleyl alcohol 2%, hydroxypropylcellulose 1.5% and ethanol, 76.9%.
42. A method of using a gallium tetrapyrrole molecule for the detection or treatment of tissue comprising administering to a patient a therapeutic amount of a gallium tetrapyrrolic molecule either locally, systemically, intramuscularly or interperitoneally and irradiating said molecule with energy at a wavelength capable of exciting the molecule to achieve the desired therapeutic effect, whereby said tissue belongs to the hematological system, lymphatic reticuloendothelial system, nervous system, endocrine and exocrine system, skeletomuscular system including bone, connective tissue, cartilage and skeletal muscle, pulmonary system, gastrointestinal system including the liver, reproductive system, immune system, cardiovascular system, urinary system, auditory or olfactory system.
43. The method of claim 9 wherein the detected disease is atherosclerotic plaque.
44. The method of claim 22, wherein said stabilization involves collagen cross linking.
45. A method for the treatment of diseases of the cardiovascular system comprising administering to a graft tissue a therapeutic amount of a tetrapyrrolic molecule that coordinates gallium in the central tetrapyrrolic core and irradiating said graft with energy at a wavelength capable of exciting the tetrapyrrolic molecule, such that the graft tissue is made less immunogenic to the host.
46. The method of claim 9 wherein said administration of porphyrin or azaporphyrin is prior to, concomitant with, or subsequent to, administration of adjunctive interventions, diagnostics or therapies.
47. The method of claim 9 wherein said administration is a single bolus or plurality of doses administered to the patient.
48. A method of claim 9 wherein said local administration is selected from perivascular delivery, pericardial delivery into perivascular sac, periadventital delivery, intravascular delivery using elution from placed stents impregnated with porphyrin or azaporphyrin, endovascular delivery using balloon catheters with micropores or channels, or transmural injection ports pressurized and enhanced by mechanical and electrical means to facilitate intramural and transmural penetration of the prophyrin or azaprophyrin into the target tissue.
49. The method of claim 9 wherein said systemic administration is selected from parenterally, orally, intravasculariy, subcutaneously, intramuscularly, intradermal or by inhalation.
50. The method of claim 46 wherein said adjunctive interventions are selected from balloon angioplasty, invasive or non-invasive surgical procedures, stent deployment, cutting balloons, embolic protection devices, rotational and directional atherectomy, and eximer laserectomy.
51. A method according to claim 46 wherein said therapies are selected from radiation therapy, chemotherapy, anti-platelet agents, vasodilators, antihypertensives, anti-arrhythmics, sonotherapy, hyperthermia, cryotherapy, magnetic force, viral or non-viral gene therapy, pharmacogenetic therapy, antibodies, vaccines, glycoprotein llb/llla Inhibitors, growth factors, peptides, DNA delivery, nucleic acids, anticancer drugs, steroid hormones, anti-inflammatories, proteins, anti-apoptotic therapies, anti-sense agents, immunosuppressants, immunotoxins, immunomodulators, antibody-drug conjugates, anti-proliferative therapies, drug eluting stents containing pharmacologically active agents, hormone products, chelating agents, diuretics, cardiac glycosides, bronchodilators, antibiotics, antivirals, antitioxins, cyclosporins, thrombolytic agents, interferons, blood products such as parental iron and hemin, anti-fungal agents, antianginals, anticoagulants, analgesics, narcotics, neuromuscular blockers, sedatives, bacterial vaccines, viral vaccines, DNA or RNA of natural or synthetic origin including recombinant RNA and DNA, cytokines and their antagonists/inhibitors, chemokines and their antagonists/inhibitors, vitamins, and antioxidants.
52. The method of claim 46 wherein said diagnostics are selected from intravascular ultrasound radiofrequency imaging or elastography, angiography, radiological contrast agents, electromechanical mapping, fourier transform infrared microspectroscopy, optical coherance tomography, high resolution Magnetic Resonance, electron beam tomography, combined raman spectroscopy and particle induced x-ray emission, radionucleotide technology, fluorescence based optical analysis, and thermal mapping.
53. The method of claim 3 wherein said metallated porphyrin is formulated by encapsulation in carriers selected from water, deionized water, phosphate buffered saline, aqueous ethanol, glucose, amino acids, vegetable oils, liposomes, immunoliposomes, cyclodextrans, microspheres, nanoparticles, lipoproteins, micellular systems or combinations thereof.
54. The method of claim 53 wherein said formulation is selected from slow release, a prodrug, tablets, pills, solutions, suspensions, emulsions, granules or capsules.
55. The method of claim 1 , wherein the gallium porphyrin is a compound of the following formula I:
Figure imgf000165_0001
I wherein R-i - R12 can be the same or different and can be selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of molecular weight of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A , CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3ι CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0- alkoxy , CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl; where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
C02Ri3, where R-|3 is selected from H, a physiologically acceptable counter ion, a C1-C20 straight or branched chain alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)n H, or (CH2)nORi , where R14 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Ri5, (CHX)nC02R-ι5, or (CX2)nC02Rι5) where X is a halogen and R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R16), CONHNH(R16), CO(R16), CON(R16)2, CON(Rιβ)(Rιr)
(CH2)nCONH(R16), (CH2)nCON(R16)2, (CH2)nCORι6, (CH2)nCON(R16)(R17), (CX2)nCONH(R16), (CX2)nCON(R16)2, (CX2)nCON(R16)(R17), (CX2)nCOR16, (CH2)nCONHNH(Rι6), (CX2)nCONHNH(R16), (CHX)nCONH(R16),
(CHX)nCONHNH(R16), (CHX)πCO(Rι6), (CHX)nCON(R16)2, or (CHX)nCON(Rι6)(Ri7), where X is a halogen and Rι6 and R17 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, haloheteroalkyl, heteroalkyl, aryl, heteroaryl, •heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rιβ), (CH2)nS(Rι8), (CH2)nNH(R18), (CH2)nNHNH(Ri8), (CH2)nN(R18)2,
(CH2)nN(Rι8)(Ri9), or (CH2)nN(R18)(Rι9)(R2o)+A, where R18, R19 and R20 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Rι8) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-ι8, Rig and R2o together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR2ι, (CH2)nPO(OR2ι)2, (CH2)nP02R2i, or (CH2)nPOR2ι where R2ι is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR22, or (CH2)nNHNHCOR22, where R22 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R23, S02NHR23, S02N(R23)2, S02N(R23)(R24), S02NHNHR23, or S02R23, where R23 and R24 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR23 can also be an amino acid, an amino acid salt, or an amino acid ester residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R1-R2, R4-Rδ, R7-R8, R10-R11, R2-R3, Re-Re, Rβ-Rθ, and R11-R12 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons; and wherein
M is Ga3+, wherein associated with the co-ordinated gallium is a physiologically acceptable charge balancing counter ion.
56. The method of claim 1 , wherein the gallium porphyrin is a compound of the following formula IA:
Figure imgf000169_0001
IA wherein Ri and R2 can be the same or different and can be selected from: CO2R3, where R3 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
CONH(R4), CONHNH(R4), CON(R4)2, COR4, or CON(R4)(R5), where R4 and R5 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR6, where R6 is selected from a C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R7, (CHX)nC02R7, or (CX2)nC02R7, where X is a halogen and R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R8), (CH2)nCO(R8), (CH2)nCONHNH(R8), (CH2)nCON(R8)2,
(CH2)nCON(R8)(R9), (CX2)nCONH(R8), (CX2)nCON(R8)2, (CX2)nCON(R8)(R9), (CHX)nCONH(R9), (CHX)nCONHNH(R9), (CHX)nCON(R9)2, or (CHX)nCON(R8)(R9), where X is a halogen, and R8 and R9 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, heteroalkyl, haloalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rιo), (CH2)nS(Rιo), (CH2)nNH(R10), (CH2)nNHNH(R10), (CH2)nN(Rιo)2l
(CH2)nN(Rιo)(Rιι), or (CH2)nN(R10)(Rn)(Rι2)+A, where R10, Ru and R12 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocyclic, an amino acid or a salt, ester or amide thereof (provided - NH(R-ιo) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-ι0, Ru and Rι2 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4 and A is a physiologically acceptable counter ion;
(CH2)nOP02ORι3, (CH2)nPO(OR13)2, (CH2)nP02Rι3, or (CH2)nPOR13 where R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; (CH2)nNHCORi4 or (CH2)nNHNHCOR14, where R14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R15, S02NHR15, S02N(Rι5)2, S02N(Rι5)(Rι6), S02NHNHR15, or S02Rι5l , where R15 and Rιβ can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and wherein
M is Ga3+, wherein associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion.
57. A compound of the following formula IA:
Figure imgf000172_0001
wherein Ri and R2 may be the same or different and are selected from: CO2R3 where R3 is selected from a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
CONH(R4), CONHNH(R4), CON(R4)2, COR4, or CON(R4)(R5), where R4 and R5 are selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di-, or polyetheralkyl residue, or a mono, di- , or polyetheraryl residue, an amino acid residue, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons, with the proviso that R4 and R5 are not pentetic acid (DTPA), polyfunctional carboxyl compounds or cyclen functional groups that are capable of binding metal ions with atomic numbers of 20-32, 37-39, 42-51 or 57-83;
(CH2)nOH or (CH2)nOR6 where R6 is alkyl or heteroalkyl, aryl or heteroaryl, a mono, di or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R7, (CHX)nC02R7 or (CX2)nC02R7 where X is a halogen and R7 is H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, or a mono, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R8), (CH2)nCON(R8)2, (CH2)nCON(R8)(R9), (CX2)nCONH(R8),
(CX2)nCON(R8)2, or (CX2)nCON(R8)(R9) where X is a halogen, R8 and R9 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, a mono, di- , or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nNH(Rιo), (CH2)nN(Rιo)2, or (CH2)nN(Rιo)(Rιι), where R10 and Rn can be the same or different and are selected from H, straight or branched chain C1- C20 alkyl or heteroalkyl, a aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4; (Ri2) where R1 is selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons; with the proviso that R12 does not include a carboxyl group;
(CH2)nS(Rι3) where R-ι3 is selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4; (CH2)nOP02ORi4, (CH2)nPO(OR14)2, (CH2)nP02Ri4, or (CH2)nPORι4 where R14 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di- , or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi5 or (CH2)nNHNHCORι5 where R15 is a straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R16, S02NH R16, S02N(R16)2, S02N(R16)(Rι7), S02NHNHR16, or S02Rι6, where R-iβ and R17 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di- , or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; and wherein
M is Ga3+, wherein associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion; with the proviso that Ri and R2 are not both C02H or both C02CH3.
58. A compound of the following formula:
Figure imgf000176_0001
wherein Ri and R2 may be the same or different and are selected from:
C02R3 where R3 is a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
CONH(R4), CONHNH(R4), CON(R4)2, COR4, or CON(R4)(R5), where R4 and R5 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di- , or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, an amino acid residue, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH or (CH2)nOR6 where R6 is alkyl or heteroalkyl, aryl or heteroaryl, a mono, di or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R7 or (CX2)nC02R where X is a halogen and R7 is H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, or a mono, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4; (CH2)nCONH(R8), (CH2)nCON(R8)2, (CH2)nCON(R8)(R9), (CX2)nCONH(R8),
(CX2)nCON(R8)2, or (CX2)nCON(R8)(R9), where X is a halogen and where R8 and R9 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di- , or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4; with the proviso that when n=2, R8 or R9 is not pentetic acid (DTPA), a polyfunctional carboxyl compound or a cyclen functional group that is capable of binding metal ions with atomic numbers of 20-32, 37-39, 42-51 or 57-83;
(CH2)nNH(R10), (CH2)nN(R1o)2l or (CH2)nN(R10)(Rιι), where R10 and R can be the same or different and are selected from H, straight or branched chain C1- C20 alkyl or heteroalkyl, a aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
(CH2)nNH(R10), (CH2)nN(R10)2, or (CH2)nN(Rιo)(Rιι), where Ri0 and Rn can be the same or different and are selected from H, straight or branched chain C1- C20 alkyl or heteroalkyl, a aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4; S(R-i2) where R12 is selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nS(Ri3) where R-ι3 is selected from H, straight or branched chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
(CH2)nOPθ2θRι4, (CH2)nPO(ORi4)2, (CH2)nP02Ri4, or (CH2)nPOR14 where R14 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl or heteroalkyl, an aryl or heteroaryl, a mono, di- , or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di-, or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi5 where R15 is a straight or branched chain C1-C20 alkyl or heteroalkyl, aryl or heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R16, S02NHR16, S02N(R16)2, S02N(R16)(R17), S02Rι6, or S02NHNHR16 where R16 and Ri7 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl or heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue; a mono, di- , or polyetheralkyl residue, or a mono, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue or a functional group of less than about 100,000 daltons; and wherein
M is Ga3+, wherein associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion; with the proviso that Ri and R2 are not both (CH2)2C02H or both (CH2)2C02CH3.
59. The method of claim 1 , wherein the gallium porphyrin is a compound of the following formula 1B:
Figure imgf000179_0001
1 B wherein Ri and R2 can be the same or different and are selected from H, CN, CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R3 and R4 can be the same or different and are selected from: C02R5, where R5 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, ethers or polyethers, or a functional group of less than about 100,000 daltons; CONH(R6), CONHNH(R6), CON(R6)2, or CON(R6)(R7), where R6 and R7 can be the same or different and are selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R9, (CHX2)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2,
(CH2)nCON(R10)(Rn), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rn), (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, or (CHX)nCON(R10)(Rn), where X is a halogen, and R-to and R can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester, or amide thereof (provided NH(R-ιo) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Ri2), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nN(R12)2, (CH2)nN(R12)(Rι3), or (CH2)nN(R12)(Ri3)(Rι4)+A, where Rι , R13 and R-|4 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester or amide thereof (provided -NH(R-i2) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where R12, R13 and R together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02ORi5, (CH2)nPO(ORι5)2, (CH2)nP02Ri5, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCOR16, where R-i6 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, S02NHRι7, S02N(R17)2, S02N(R17)(R18), S02NHNHR17, or S02Rι7) where R1 and Rι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
All of the above which may bear one or more substituents selected from hydroxy groups, alkyl groups, carboxyl groups and their esters and amides, and sulfonic acid groups and their esters and amides; and wherein
M is Ga3+, wherein associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion.
60. The method of claim 1 , wherein the gallium porphyrin is a compound of the following formula:
Figure imgf000182_0001
wherein Ri and R2 can be the same or different and are selected from H, CN,
CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R3 and R can be the same or different and are selected from:
CO2R5, where R5 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, ethers or polyethers, or a functional group of less than about 100,000 daltons;
CONH(R6), CONHNH(R6), CON(R6)2, or CON(R6)(R7), where R6 and R7 can be the same or different and are selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R9, (CHX2)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2,
(CH2)nCON(R10)(Rn), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rn), (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, or (CHX)nCON(Rι0)(Rn), where X is a halogen, and Rι0 and Rn can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester, or amide thereof (provided NH(Rio) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rι2), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nN(R12)2, (CH2)nN(R12)(R13), or (CH2)nN(Ri2)(Ri3)(Ri4)+A, where R12, R13 and R14 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester or amide thereof (provided -NH(R-|2) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R12, R13 and R-ι4 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion; (CH2)nOP02OR15, (CH2)nPO(OR15)2, (CH2)nPθ2Rι5, or (CH2)nPORι5 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCOR16, where R16 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, S02NHR17, S02N(R17)2, S02N(R17)(Ri8),S02NHNHR17, or S02R-ι7, where R17 and Rι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
All of the above which may bear one or more substituents selected from hydroxy groups, alkyl groups, carboxyl groups and its esters and amides and sulfonic acid groups and their esters and amides; and wherein M is Ga3+, wherein associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion.
61. A compound of the following formula:
Figure imgf000186_0001
wherein Ri and R2 can be the same or different and are selected from H, methyl, CN, CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R3 and R4 may be the same or different and are selected from: CO2R5 where R5 is H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, ethers or polyethers, or a functional group of less than about 100,000 daltons; CONH(R6), CONHNH(R6), CON(R6) , or CON(R6)(R7), where R6 and R7 can be the same or different and are selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons; (CH2)nOH, or (CH2)nOR8, where R8 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC0 R9, (CHX2)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2,
(CH2)nCON(R10)(Rιι), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2j (CX2)nCON(R10)(Rn), (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(Rιo) , or (CHX)nCON(Rι0)(Rn), where X is a halogen, and Rio and Rn can be he same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester, or amide thereof (provided NH(R10) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rι2), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nN(R12)2, (CH2)nN(R12)(Rι3), or (CH2)nN(R12)(R13)(R14)+A, where R12, R13 and R 4 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester or amide thereof (provided -NH(Ri2) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where R12, R13 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPθ2θR15, (CH2)nPO(OR15)2, (CH2)nP02Ri5, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi6 or (CH2)nNHNHCOR16, where R16 is a a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03Ri7, S02NHR17, S02N(R17)2, S02N(R17)(Rι8),S02NHNHR17, or S02R17, where R-|7 and R-ι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons; Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; All of the above which may bear one or more substituents selected from hydroxy groups, alkyl groups, carboxyl groups and its esters and amides and sulfonic acid groups and their esters and amides; and wherein M is Ga3+, wherein associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion; with the proviso that when R-i and R2 = H or Et and n=2, R9 cannot be H or CH3, and when Ri and R2 = C1-C7 alkyl and n=2, one of R-ι0 or Rn cannot be a functional group that possesses pentetic acid (DTPA), polyfunctional carboxyl compounds or cyclen functional groups that are capable of binding metal ions with atomic numbers of 20-32, 37-39, 42-51 or 57-83;
62. A compound of the following formula IB:
Figure imgf000189_0001
wherein Ri and R2 may be the same or different and are selected from H, methyl, CN, CO-alkyl, haloalkyl, heteroalkyl, hydroxyhaloalkyl, ether haloalkyl, ester haloalkyl, a C1-C20 alkyl, or a halogen;
R3 and R may be the same or different and are selected from:
C02R5 where R5 is H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, ethers or polyethers, or a functional group of less than about 100,000 daltons;
CONH(R6), CONHNH(R6), CON(R6)2, or CON(R6)(R7), where R6 and R7 can be the same or different and are selected from H, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue; a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R9, (CHX2)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
(CH2)nCONH(R10), (CH2)nCONHNH(Rιo), (CH2)nCON(R10)2,
(CH2)nCON(Rιo)(Rιι), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rn), (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, or (CHX)nCON(Rι0)(Rn), where X is a halogen, and Rio and Rn can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester, or amide thereof (provided NH(Rι0) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(R12), (CH2)nS(R12), (CH2)nNH(Ri2), (CH2)nN(R12)2, (CH2)nN(R12)(R13), or (CH2)nN(R12)(R13)(R14)+A, where Rι2, R13 and R14 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, an amino acid or a salt, ester or amide thereof (provided -NH(R-|2) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where Rι2, R13 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion; (CH2)nOP02OR15, (CH2)nPO(OR15)2, (CH2)nP02R15, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi6 or (CH2)nNHNHCOR16, where R16 is a a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, S02NHR17, S02N(R17)2, S02N(R17)(R18), S02NHNHR17, or S02Rι7, where R-ι and Rι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, an amino acid residue, an amino acid salt, an amino acid ester residue, an amino acid amide residue, or a functional group of less than about 100,000 daltons;
All of the above which may bear one or more substituents selected from hydroxy groups, alkyl groups, carboxyl groups and its esters and amides and sulfonic acid groups and their esters and amides; and wherein M is a metal cation selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge3+, Si4+, Al 3+, Zn2+, and Y3+, with the proviso that the compound of formula IB cannot be zinc deuteroporphyrin dimethylester, zinc deuteroporphyrin, zinc [3,7,12,17-tetramethyl-2,18- dipropanolato(2-)]porphyrin, zinc [dimethyl 8-bromo-3,7,12,17-tetramethyl-2- 18-dipropanoato(2-)]porphyrin, zinc [2-(2-hydroxyethyl)-18-methyl-3,7, 12,17- tetramethyl-2,18-dipropanoato(2-)]porphyrin, zincate(l-) [2-[3,7,-dimethyl-9- (2,6,6-trimethyl-1 -cyclohexen-1 -yl-0-2,4,6,8-nonatetraenyl]3,7, 12,17- tetramethyl-2-18-dipropanoato(3-)]porphyrin, Indium deuteroporphyrin dimethyl ester, palladium deuteroprophyrin diethylester, tin deuteroporphyrin, tin deuteroprophyrin dimethyl ester, zinc [[methyl 18-[3-[[1-91 H-imidazol-4- ylmethyl0-2-methoxy-2-oxoethyl]amino]-3-oxopropyl]-3,7,12,17-2;18- propanoato(2-)]porphyrin, Indium 7, 12-diiododeuteroporphyrin dimethyl ester, Tin 7, 12-diiododeuteroporphyrin, Zinc 7, 12-dibromodeuteroporphyrin dimethyl ester, Zinc 7-bromodeuteroporphyrin dimethyl ester, Zinc 7- iododeuteroporphyrin dimethyl ester, Zinc 7, 12-diiododeuteroporphyrin dimethyl ester, Zinc 7, 12-dibromodeuteroporphyrin, palladium deuteroprophyrin, platinum [2,8, 12,17-tetramethyI-3,7-dipropyl- porphyrinato(2-), platinum deuteroprophyrin dimethyl ester, Zinc 2, 4- diiododeuteroporphyrin dimethyl ester, or Zinc 7, 12-diiododeuteroporphyrin dioctyl ester.
63. Compounds according to claim 62 wherein M is Ga3+, where associated with the coordinated gallium is a physiologically acceptable charge balancing counter ion; with the proviso that when Ri and R2 = H, R5 cannot be CH , and when Ri and R2 = C1-C7 alkyl and n=2, R10 or Rn cannot be a functional group that possesses pentetic acid (DTPA), polyfunctional carboxyl compounds or cyclen functional groups that are capable of binding metal ions with atomic numbers of 20-32, 37-39, 42-51 or 57-83.
64. The method of claim 2, wherein said gallium azaporphyrin is a compound of the following formula II:
Figure imgf000194_0001
II wherein Ri to R can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of molecular weight less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion, CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0- alkoxy, CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen; CO2R12, where Rι2 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORι3, where R-ι3 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Ri4, (CX2)nC02Ri4, or (CHX)nC02Rι4! where X is a halogen and R14 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R15), CONHNH(R15), CO(R15), CON(R15)2, CON(R15)(Rι6),
(CH2)nCONH(R15), (CH2)nCONHNH(R15), (CH2)nCON(R15)2, (CH2)nCOR15, (CH2)nCON(R15)(R16), (CX2)nCONH(R15), (CX2)nCONHNH(R15)( (CX2)nCON(R15)2, (CX2)nCON(R15)(R16), (CX2)nCOR15, (CHX)nCONH(R15), (CHX)nCONHNH(R15), (CHX)nCON(R15)2, (CHX)nCON(R15)(R16), or (CHX)nCORi5, where X is a halogen and R-i5 and Rιβ can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid salt, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Ri7), (CH2)nS(R17), (CH2)nNH(R17), (CH2)nNHNH(R17), (CH2)nN(R17)2,
(CH2)nN(Rι7)(Ri8), or (CH2)nN(Ri7)(Ri8)(Ri9)+A, where R17, R18 and R19 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R 7) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where Rι7, R-is and R19 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR2θ! (CH2)nPO(OR20)2, (CH2)nPO2R20, or (CH2)nPOR20 where R20 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR2ι or (CH2)nNHNHCOR21, where R21 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R22, S02NHR22, SO2NHNHR22, S02N(R22)2, S02N(R22)(R23), or S02R22, where R22 and R23 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR22 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
R1-R2 , R3-R4 > R6-R7 > R9-Rιo . R4-R5 . R5-R6 . Rδ-R9 > R9-Rιo , R11-R12 and R12-R1 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons; and wherein
M is Ga3+ where associated with the metal ion is a physiologically acceptable charge balancing counter ion.
65. The method of claim 2, wherein the gallium azaporphyrin is a compound of the following formula:
Figure imgf000198_0001
wherein R-I-RΘ can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
C02R7, where R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R9, (CHX)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R10), CONHNH(R10), CO(R10), CON(R10)2, CON(R10)(Rn),
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10, (CH2)n.CON(R10)(Rn), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rιι), (CX2)nCOR10, (CHX)nCONH(R10), (CHX)nCONHNH(Rio), (CHX)nCON(Rio)2l (CHX)nCON(R10)(Rn), or (CHX)nCOR-ιo, where X is a halogen, and Rio and Rn can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(Rι2), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nNHNH(R12), (CH2)nN(R12)2,
(CH2)nN(Rι2)(Rι3), or (CH2)nN(R12)(Rι3)(R14)+A, where R12, R13 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-|3) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where R12, R-I3 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR15, (CH2)nPO(OR15)2, (CH2)nP02Rι5, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCOR16, where R16 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; S03R17, S02NHR17, S02NHNHR17, S02N(R17)2, S02N(R17)(Rι8), or S02Rι7, where Rι7 and Rι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR17 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
R1-R2, R3-R4 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons; and wherein
M is Ga3+ where associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
66. A metalloazaporphyrin of the following formula:
Figure imgf000201_0001
wherein Ri-Rβ can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyI, CH(CH3)0-alkoxy , or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
C02R , where R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R9, (CHX)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R10), CONHNH(R10), CO(R10), CON(Rι0)2, CON(R10)(Rn),
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10, (CH2)nCON(R10)(Rιι), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rιι), (CX2)nCOR10, (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(Rιo)2, (CHX)nCON(R10)(Rn), or (CHX)nCORιo, where X is a halogen, and Rio and Rn can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(Ri2), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nNHNH(R12), (CH2)nN(R12)2,
(CH2)nN(Rι2)(R13), or (CH2)nN(R12)(Rι3)(Ri4)+A, where R12l R13 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R12) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where R-I2, R13 and Rι4 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR15, (CH2)nPO(OR15)2, (CH2)nP02Ri5, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORi6 or (CH2)nNHNHCOR16, where R16 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R17, S02NHR17, S02NHNHR17, S02N(R17)2, S02N(R17)(R18) or S02Rι7, where R1 and Rι8 are the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; R1-R2, R3-R4 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons;
M is Ga3+ wherein associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
67. The method of claim 2, wherein the gallium azaporphyin is a compound of the following formula IIA:
Figure imgf000205_0001
IIA wherein R δ can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy , or CH(CH3)0-aryl; (CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R7, where R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons; (CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; (CH2)nC02R9, (CHX)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R10), CONHNH(R10), CO(R10), CON(R10)2, CON(R10)(Rn),
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10, (CH2)nCON(R10)(Rn), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rn), (CX2)nCOR10, (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, (CHX)nCON(Rι0)(Rn), or (CHX)nCORιo, where X is a halogen, and Rio and Rn can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(Rι2), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nNHNH(R12), (CH2)nN(R12)2,
(CH2)nN(R12)(R13), or (CH2)nN(R12)(R13)(Rι4)+A, where R12, R13 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Rι3) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-ι2, R13 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR15, (CH2)nPO(OR15)2, (CH2)nP02Ri5, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCORι6, where R16 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03Ri7, S02NHR17, S02NHNHR17, S02N(Rι7)2, S02N(Rι7)(R18) or S02Rι , where R-ι7 and Rι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHRι can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide;
Aryl or substituted aryl, which may optionally bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and R1-R2, R3-R4 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons; and wherein
M is Ga3+ where associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
68. A compound of the following formula II:
Figure imgf000209_0001
wherein R-i to Rn can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3A , CH=N(alkyl)2A, N(alkyl)3 +A (where A is a charge balancing ion), CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0- alkoxy, or CH(CH3)0-aryl,
(CH2)nO-alkoxy, (CH2)nO-alkyl; where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
C02Rι2 where R-ι2 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono, di-, or polyhydroxyalkyl residue, a mono, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH )nOR-|3, where R13 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Rι , (CHX)nC02Ri4, or (CX2)nC02R14, where X is a halogen, and R1 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R15), CONHNH(R15), CO(R15), CON(R15)2, CON(R15)(R16),
(CH2)nCONH(R15), (CH2)nCONHNH(Rι5), (CH2)nCON(R15)2, (CH2)nCOR15, (CH2)nCON(R15)(R16), (CX2)nCONH(R15), (CX2)nCONHNH(R15), (CX2)nCON(Ri5)2, (CX2)nCON(R15)(R16), (CX2)nCOR15, (CHX)nCONH(R15), (CHX)nCONHNH(R15), (CHX)nCON(R15)2, (CHX)nCON(R15)(R16), or (CHX)nCORi5, where X is a halogen, and R15 and Rι6 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(Ri7), (CH2)nS(R17), (CH2)nNH(R17), (CH2)nNHNH(R17), (CH2)nN(R17)2,
(CH2)nN(R17)(Rι8), or (CH2)nN(R17)(R18)(Rι9)+A, where R17, R18 and R 9 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Rι ) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where Rι7, Rιs and Rι9 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPO2OR20, (CH2)nPO(OR2o)2, (CH2)nP02R2o, or (CH2)nPOR20 where R20 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR2ι or (CH2)nNHNHCOR2ι, where R21 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R22, S02NHR22, S02NHNHR22l S02N(R22)2, S02N(R22)(R23), and SO2R22 where R22 and R23 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR22 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
All of which may bear one or more substituents selected from hydroxy groups, alkyl groups, carboxyl groups and its esters and amides and sulfonic acid groups and their esters and amides; and wherein
M is a metal selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3÷, Ge3+, Si4+, Al3+, and Mg2+, wherein and where necessary associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions; where R-i-Rn may possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral; with the proviso that formula II excludes the following compounds:
Ri, R , Re, Rg are ethyl, R2, R3, R , R-to are Me, R5, R8, Rn are H, and M=Mg;
Ri, R4, R7, R9 are ethyl, R2, R3, R6, R10 are Me, R5, R8, Rn are H, and M=Zn;
Ri, R4, Re, R-io are ethyl, R2, R3, R7, R9 are Me, R5, R8, Rn are H, and M=Zn;
Ri, R4, R7, R9 are Me, R2, R3, Re, R10 are Et, R5, R8, Rn are H, and M=Zn;
Ri, R4, R6, R10 are Me, R2, R3, R7, Rg are Et, R5, R8, Rn are H, and M=Zn;
Ri, R3, R6, R10 are Me, R2, R4 are vinyl, R7, Rg are CH2CH2C02Me, R5, R8, Rn are H, and M=Zn;
Ri, R2, R3, R4, Re, R7, Rg, R10 are Me, R5, R8, R11 are H, and M=Zn;
Ri, R3, R7, R10 are ethyl, R2, R4, Re, Rg are Me, R5, R8, Rn are H, and M=Zn;
Ri, R3, R6, R10 are Me, R2, R4 are Et, R7, R9 are CH2CH2C02Me, R5, R8, Rn are H, and M=Zn or Pd;
Rι> R2, R3, 4, RΘ, R7, R9, R10 are Me, R5) R8, Rn are H, and M=Pd; and
Ri, R2, R3, R4, Rs, Re, R7, Rs Rg, R10, R11 are H and M=Zn.
69. A compound of the following formula:
Figure imgf000214_0001
wherein R Rβ can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R7, where R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R9, (CHX)nC02R9, or (CX2)nC02R9, where X is a halogen, and Rg is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R10), CONHNH(R10), CO(R10), CON(R10)2, CON(Rι0)(Rn),
(CH2)nCONH(R10), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10, (CH2)nCON(R10)(Rn), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rn), (CX2)nCOR10, (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10)2, (CHX)nCON(Rι0)(Rn), or (CHX)nCORιo, where X is a halogen, and R-io and Rn can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rι2), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nNHNH(R12), (CH2)nN(R12)2,
(CH2)nN(Rι2)(Rι3), or (CH2)nN(R12)(Rι3)(Ri4)+A, where Rι2, Rι3 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-|2) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where R12, Rι3 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02ORi5, (CH2)nPO(OR15)2, (CH2)nP02Ri5, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter-ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORιe or (CH2)nNHNHCOR16, where Rι6 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; S03Ri7, S02NHR17, S02NHNHR17, S02N(R17)2, S02N(R17)(R18), or S02Rι , where R-ι and Rι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHRι7 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
R1-R2, R3-R4 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons; and wherein
M is a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Y3+, Zn2+, and Mg2+ wherein associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions; with the proviso that when Ri and R3 are Me, R2 and R4 are vinyl, and R5 and R6 are (CH2)2C02Me, M cannot be Zn; and when Ri and R3 are Me, R2 and R4 are Et, and R5 and R6 are (CH2)2C02Me, M cannot be Zn2+, Pd2+, or Mn3+.
70. A compound of the following formula IIA:
Figure imgf000218_0001
IIA wherein Ri-Rβ can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R7, where R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR8, where R8 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R9, (CHX)nC02R9, or (CX2)nC02R9, where X is a halogen, and R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R10), CONHNH(R10), CO(R10), CON(R10)2, CON(R10)(Rn),
(CH2)nCONH(Rιo), (CH2)nCONHNH(R10), (CH2)nCON(R10)2, (CH2)nCOR10) (CH2)nCON(R10)(Rn), (CX2)nCONH(R10), (CX2)nCONHNH(R10), (CX2)nCON(R10)2, (CX2)nCON(R10)(Rn), (CX2)nCOR10, (CHX)nCONH(R10), (CHX)nCONHNH(R10), (CHX)nCON(R10) , (CHX)nCON(R10)(Rn), or (CHX)nCOR-ιo, where X is a halogen, and R-to and Rn can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(R12), (CH2)nS(R12), (CH2)nNH(R12), (CH2)nNHNH(Ri2), (CH2)nN(R12)2,
(CH2)nN(R1 )(Ri3), or (CH2)nN(R12)(R13)(Ri4)+A, where R12, R13 and R14 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-|2) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-|2, R-I3 and R14 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR15, (CH2)nPO(OR15)2, (CH2)nP02Ri5, or (CH2)nPOR15 where R15 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR16 or (CH2)nNHNHCOR16, where R 6 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; SO3R17, S02NHRi7, S02NHNHR 7, S02N(Rι7)2, S02N(Rι7)(Rιβ), or SO2R17, where Rι and Rι8 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR-i7 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
R1-R2, R3-R4 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons.
M is a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, Y3+, Mg2+ wherein associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions; with the proviso that when Ri and R3 are Me, R2 and R4 are vinyl, and R5 and R6 are C02Me, M cannot be Zn2+; and when R-] and R3 are Me, R2 and R4 are Et and R5 and R6 are C02Me, M cannot be Zn2+, Pd2+ or Mn3+.
71. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula III:
Figure imgf000222_0001
wherein Ri to Rι0 can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group having a molecular weight of about 100,000 daltons; CH=CHCH2N+(CH3)3 A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3ι CO(a)kyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0- alkoxy, or CH(CH3)Oaryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
CO2R11, where Rn is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORi2, where R12 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Ri3, (CHX)nC02Ri3, or (CX2)nC02Rι3, where X is a halogen, and R 3 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R14), CONHNH(R14), CO(R14), CON(Rι4)2, CON(R1 )(R15),
(CH2)nCONH(R14), (CH2)nCONHNH(R14), (CH2)nCON(R14)2, (CH2)nCOR14, (CH2)nCON(R14)(Ri5), (CX2)nCONH(R14), (CX2)nCONHNH(R14), (CX2)nCON(R14)2, (CX2)nCON(Rι4)(R15), (CX2)nCOR14, (CHX)nCONH(R14), (CHX)nCONHNH(R14), (CHX)nCON(R14)2, (CHX)nCON(R14)(R15), or (CHX)nCORι , where X is a halogen, and Rι and R15 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(Rιe), (CH2)nS(Ri6), (CH2)nNH(R16), (CH2)nNHNH(R16), (CH2)πN(Rι6)2,
(CH2)nN(R16)(Ri7), or (CH2)nN(Rι6)(Ri7)(Ri8)+A, where R16, Ri7 and R18 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Rι6) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where Rι6, R-17 and Rι8 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR19, (CH2)nPO(ORi9)2, (CH2)nP02Rιg, or (CH2)nPOR19 where Rι9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR2o or (CH2)nNHNHCOR2o, where R20 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; SO3R21, SO2NHR21, SO2NHNHR21, S02N(R2ι)2, Sθ2N(R2ι)(R22), or S02R2ι, where R2ι and R22 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR2ι can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
R1-R2, R3-R4, R6-R7, Rs-R9, R4-R5, Rs-Re, Rg-Rio, and R10-R1 may also possess the atoms necessary to form ring systems, either aromatic or not, which themselves may possess heteroatoms that may be charged or neutral or bear one or more functional groups of molecular weight equal to or less than about 100,000 daltons; and wherein
M is Ga3+, where associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
72. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula IIIA:
Figure imgf000226_0001
IIIA wherein Ri, R2, R3, R4 can be the same or different and are selected from:
C02R5, where R5 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORe, where R6 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R7, (CHX)nC02R7, or (CX2)nC02R7, where X is a halogen, and R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R8), CONHNH(R8), CO(R8), CON(R8)2, CON(R8)(R9), (CH2)nC0NH(R8), (CH2)nCONHNH(R8), (CH2)nCON(R8)2, (CH2)nCOR8, (CH2)nCON(R8)(R9), (CX2)nCONH(R8), (CX2)nCONHNH(R8), (CX2)nCON(R8)2, (CX2)nCON(R8)(R9), (CX2)nCOR8, (CHX)nCONH(R8), (CHX)nCONHNH(R8), (CHX)nCON(R8)2, (CHX)nCON(R8)(R9), or (CHX)nCOR8, where X is a halogen, and R8 and R9 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rιo), (CH2)nS(Rιo), (CH2)nNH(R10), (CH2)nNHNH(R10), (CH2)nN(R10)2,
(CH2)nN(Rιo)( Rn), or (CH2)nN(Rιo)(Rn)(Ri2)+A, where R10, Rn and R12 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R10) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where Rio, Rn and R-i2 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPθ2θR13, (CH2)nPO(ORι3)2, (CH2)nP02R13, or (CH2)nPOR13, where R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR14 or (CH2)nNHNHCOR14, where R-i4 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
SO3R15, S02NHR15, S02NHNHR15, S02N(R15)2, S02N(R15)(Rι6), or S02R15, where R15 and R16 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR15 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and wherein
M is a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+,
Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, AI3+, Zn2+, Y3+, Mg2+ wherein associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
73. A compound of formula IIIA:
Figure imgf000229_0001
IIIA wherein Ri, R2, R3 and R4 can be the same or different and are selected from: a straight or branched chain C1-C20 alkyl, C1-C20 cycloalkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or a polyhydroxyaryl residue;
C02R5, where R5 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nOR6, where Re is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02R7, (CHX)nC02R7, or (CX2)nC02R7; where X is a halogen, and R7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4; CONH(R8), CONHNH(R8), CO(R8), CON(R8)2, CON(R8)(R9), (CH2)nCONH(R8), (CH2)nCONHNH(R8), (CH2)nCON(R8)2, (CH2)nCOR8, (CH2)nCON(R8)(R9), (CX2)nCONH(R8), (CX2)nCONHNH(R8), (CX2)nCON(R8)2, (CX2)nCON(R8)(R9), (CX2)nCOR8, (CHX)nCONH(R8), (CHX)nCONHNH(R8), (CHX)nCON(R8)2, (CHX)nCON(R8)(Rg), or (CHX)nCOR8, where X is a halogen, and R8 and Rg can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S(Rιo), (CH2)nS(Rιo), (CH2)nNH(R10), (CH2)nNHNH(R10), (CH2)nN(R10)2,
(CH2)nN(Rιo)( Rn), or (CH2)nN(Rιo)(Rn)(Ri2)+A, where R10, Rn and R12 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Rι0) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, or where R10, Rn and R12 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR13, (CH2)nPO(OR13)2, (CH2)nP02R13, or (CH2)nPOR13 where R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; (CH2)nNHCORι4 or (CH2)nNHNHCORι4, where R14 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03Ri5, S02NHR15, S02NHNHR15, S02N(R15)2, S02N(R15)(Rιe), or S02Rι5, where R15 and R-ι6 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR15 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; M is a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, Y3+, and Mg2+ wherein associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions; with the proviso that when Ri and R2 are Et, and R3 and R4 are (CH2)2C02H or (CH2)2C02Me, M cannot be Fe3+; when Ri and R2 are (CH2)2C02Me, M cannot be Fe3+; and when R-i R2 R3 and R4 are butyl, M cannot be Cu2+.
74. A compound of formula III:
Figure imgf000232_0001
III wherein Rι-R4, Rβ-Rg, can be the same or different and can be selected from: H, halogen, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl;
C02Rn, where R is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH )nOH, or (CH )nORi2, where R12 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Rι3, (CHX)nC02Rι3, or (CX2)nC02R13, where X is a halogen, and R13 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R14), CONHNH(R14), CO(R14), CON(R14)2, CON(R14)(R15),
(CH2)nCONH(R14), (CH2)nCONHNH(R14), (CH2)nCON(R14)2, (CH2)nCOR14, (CH2)nCON(R14)(Ri5), (CX2)nCONH(R14), (CX2)nCONHNH(R14), (CX2)nCON(R14)2, (CX2)nCON(R14)(R15), (CX2)nCOR14, (CHX)nCONH(Rι4), (CHX)nCONHNH(R14), (CHX)nCON(Rι4)2, (CHX)nCON(R14)(Rι5), or (CHX)nCORi4, where X is a halogen, and Rn and R15 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(Rιe), (CH2)nS(Rιe), (CH2)nNH(R16), (CH2)nNHNH(Rι6), (CH2)nN(R16)2,
(CH2)nN(R16)(R17), or (CH2)nN(R16)(Ri7)(Rι8)+A, where R16, Ri7 and R18 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R16) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R16, R17 and Rι8 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR19, (CH2)nP0(0Rig)2, (CH2)nP02R19, or (CH2)nP0R19 where R19 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR20 or (CH2)nNHNHCOR20, where R20 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
S03R2ι, S02NHR21, SO2NHNHR21, S02N(R2ι)2, S02N(R2ι)(R22), or S02R2ι, where R21 and R22 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR21 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue; where R5 and R10 are aryl, heteroaryl or substituted aryl or substituted heteroaryl, which may bear one or more of the substituents selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0- alkoxy, or CH(CH3)0-aryl; M is a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Y3+, Zn2+, Mg2+ wherein associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
75. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula IV:
Figure imgf000236_0001
IV
wherein Rι-R8 can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl) , CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
C02R9, where R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORιo, where R10 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Rn, (CHX)nC02Rn, or (CX2)nC02Rn, where X is a halogen, and Rn is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R12), CONHNH(R12), CO(R12), CON(R12)2, CON(Rι2)(Rι3),
(CH2)nCONH(R12), (CH2)nCONHNH(R12), (CH2)nCON(R12)2, (CH2)nCOR12, (CH2)nCON(R12)(Ri3), (CX2)nCONH(R12), (CX2)nCONHNH(R12), (CX2)nCON(R12)2, (CX2)nCON(R12)(Rι3), (CX2)nCOR12, (CHX)nCONH(R12), (CHX)nCONHNH(R12), (CHX)nCON(R12)2, (CHX)nCON(Rι2)(Rι3), or (CHX)nCORi2, where X is a halogen, and R12 and R 3 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(R14), (CH2)nS(R14), (CH2)nNH(R14), (CH2)nNHNH(Rι4), (CH2)nN(R14)2,
(CH2)nN(Rι4)(Rι5), or (CH2)nN(Rι4)(Rι5)(Ri6)+A, where R14, R15 and R16 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(Rι ) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R14, R15 and R-iβ together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR17, (CH2)nPO(OR17)2, (CH2)nP02Ri7, or (CH2)nPOR17 where R17 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCORis or (CH2)nNHNHCORι8, where R18 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; S03Ri9, S02NHR19, S02NHNHR19, S02N(R19)2, SO2N(R19)(R20), or S02Rι9, where Rig and R20 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR19 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; and
A, B, C, and D can be the same or different and can be selected from N, CH, and
CR20, where R20 IS selected from a halogen, aryl, substituted aryl, heteroaryl, alkyl, haloalkyl, heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a functional group of less than about 100,000 daltons; and wherein
M is Ga3+, where associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
76. The method of claim 2, wherein the gallium azaporphyrin is a compound of formula IV:
Figure imgf000240_0001
IV
wherein R-ι-R8 can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl), CH=CHCH2N(CH3)2, or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
C02Rg, where Rg is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORιo, where Rio is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Rn, (CHX)nC02Rn, or (CX2)nC02Rn, where X is a halogen, and R is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R12), CONHNH(R12), CO(R12), CON(R12)2, CON(R12)(R13),
(CH2)nCONH(R12), (CH2)nCONHNH(R12), (CH2)nCON(Rι2)2, (CH2)nCOR12, (CH2)nCON(R12)(R13), (CX2)nCONH(R12), (CX2)nCONHNH(R12), (CX2)nCON(R12)2, (CX2)nCON(R12)(Ri3), (CX2)nCOR12, (CHX)nCONH(R12), (CHX)nCONHNH(R12), (CHX)nCON(R12)2, (CHX)nCON(R12)(R13), or (CHX)nCORι2, where X is a halogen, and Rι2 and R13 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(R14), (CH2)nS(R14), (CH2)nNH(R14), (CH2)nNHNH(R14), (CH2)nN(R14)2,
(CH2)nN(R14)(R15), or (CH2)nN(R14)(Ri5)(Rιe)+A, where Ri4, R15 and R16 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-i4) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where R-ι4, Ri5 and Rι6 together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOPθ2θR17, (CH2)nPO(OR17)2, (CH2)nP02Ri7, or (CH2)nPOR17 where R17 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR18 or (CH2)nNHNHCOR18, where R18 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; S03Rι9, S02NHRιg, S02NHNHR19, S02N(R19)2, SO2N(R19)(R20), or S02Rι9, where R-ig and R2o can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHRι9 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons; A, B, C, and D can be the same or different and can be selected from N, CH, and CR20, where R2o is selected from a halogen, aryl, substituted aryl, heteroaryl, alkyl, haloalkyl, heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a functional group of less than about 100,000 daltons; and wherein M is a diamagnetic or paramagnetic photoactive metal ion selected from Ga3+, Pt2+, Pd2+, Sn4+, ln3+, Ge4+, Si4+, Al3+, Zn2+, Y3+, and Mg2+, wherein associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions.
77. A compound of the following formula IV:
Figure imgf000244_0001
IV
wherein R-ι-R8 can be the same or different and are selected from: H, halide, substituted or unsubstituted alkyl, heteroalkyl, haloalkyl, heterohaloalkyl, cyclic alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, amide, ester, ether, polyether, alkoxy group, aryloxy group, haloalkoxy group, amino group, alkylcarbonyloxy group, alkoxycarbonyl group, aryloxycarbonyl group, azo group, arylcarbonyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy group, sulfinyl group, sulfonyl group, silil group, carbamoyl group, heterocyclic group, nitro group, nitroso group, formyloxy group, isocyano group, cyanate group, isocyanate group, thiocyanate group, isothiocyanate group, N(alkyl)2, N(aryl)2, CH=CH(aryl),
Figure imgf000244_0002
or a functional group of less than about 100,000 daltons; CH=CHCH2N+(CH3)3A, CH=N(alkyl)2A, or N(alkyl)3 +A, where A is a charge balancing ion; CN, OH, CHO, COCH3, CO(alkyl), C02H, C02Na, C02K, CH(CH3)OH, CH(CH3)0-alkyl, CH(CH3)0-alkoxy, or CH(CH3)0-aryl;
(CH2)nO-alkoxy, or (CH2)nO-alkyl, where n is an integer from 0 to 8;
C(X)2C(X)3, where X is a halogen;
Cθ2Rg, where R9 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons;
(CH2)nOH, or (CH2)nORιo, where R-|0 is selected from alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a protecting group, a mono-, di- , or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nC02Rιι, (CHX)nC02Rn, or (CX2)nC02Rn, where X is a halogen, and R is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 1 and 4;
CONH(R12), CONHNH(R12), CO(R12), CON(R12)2, CON(R12)(Rι3),
(CH2)nCONH(R12), (CH2)nCONHNH(R12), (CH2)nCON(R12)2, (CH2)nCOR12, (CH2)nCON(R12)(Rι3), (CX2)nCONH(R12), (CX2)nCONHNH(R12), (CX2)nCON(R12)2, (CX2)nCON(R12)(Ri3), (CX2)nCOR12, (CHX)nCONH(R12), (CHX)nCONHNH(R12), (CHX)nCON(R12)2, (CHX)nCON(R12)(R13), or (CHX)nCORι2, where X is a halogen, and R-ι2 and R13 can be the same or different and are selected from H, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, an amino acid, an amino acid ester, an amino acid amide, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and
4;
S(R14), (CH2)nS(R14), (CH2)nNH(R14), (CH2)nNHNH(R14), (CH2)nN(R14)2,
(CH2)nN(R14)(R15), or (CH2)nN(R14)(R15)(Ri6)+A, where Ri4, R15 and R16 can be the same or different and are selected from H, NH2, straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, aryl, heteroaryl, heterocycle, amino acids (provided -NH(R-i4) is part of the amino acid), a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, where Rι4, R-15 and R-iβ together possess the atoms necessary to constitute an aromatic ring system, n is an integer between 0 and 4, and A is a physiologically acceptable counter ion;
(CH2)nOP02OR17, (CH2)nPO(OR17)2, (CH2)nP02R17, or (CH2)nPORι7 where Rι7 is selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4;
(CH2)nNHCOR18 or (CH2)nNHNHCOR18, where R18 is a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocyclic, aryl, heteroaryl, or a functional group of less than about 100,000 daltons, and n is an integer between 0 and 4; S03Ri9, S02NHRιg, S02NHNHRi9, S02N(R19)2, SO2N(R19)(R20), or S02R 9, where Rι9 and R20 can be the same or different and are selected from H, a physiologically acceptable counter ion, a straight or branched chain C1-C20 alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, heterocycle, aryl, heteroaryl, a mono-, di-, or polyhydroxyalkyl residue, a mono-, di-, or polyhydroxyaryl residue, a mono-, di-, or polyetheralkyl residue, a mono-, di-, or polyetheraryl residue, or a functional group of less than about 100,000 daltons, and NHR19 can also be an amino acid, an amino acid salt, an amino acid ester residue, or an amino acid amide residue;
Aryl or substituted aryl, which may bear one or more substituents with a molecular weight of less than or equal to about 100,000 daltons;
A, B, C, and D can be the same or different and can be selected from N, CH, and
CR20, where R2o is selected from a halogen, aryl, substituted aryl, heteroaryl, alkyl, haloalkyl, heterohaloalkyl, hydroxyalkyl, hydroxyhaloalkyl, or a functional group of less than about 100,000 daltons; and wherein
M is Ga3+ where associated with the metal ion is the appropriate number of physiologically acceptable charge balancing counter ions; with the proviso that where Rι-R8 are all phenyl or H, and A-D are N, M cannot be
Ga3+.
78. The method of any of claims 55, 56, 59, 60, 64, 65, 67, 71 , 72, 75 and 76, wherein a mammal is treated for disturbances of vascular and perivascular cellular processes selected from proliferation, replication, migration, necrosis, apoptosis, adhesion, matrix deposition, signalling pathways, paracrine and autocrine functions, mediator release, contraction, relaxation, shrinkage, phenotype changes, angiogenesis, aggregation, healing, repair, regulation of surrounding tissue, metabolism and matrices.
PCT/US2002/017180 2001-05-31 2002-05-31 Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy WO2002096366A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002448562A CA2448562A1 (en) 2001-05-31 2002-05-31 Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy
JP2002592879A JP2004532251A (en) 2001-05-31 2002-05-31 Metallotetrapyrrole photosensitizers used in photodynamic therapy
AU2002344234A AU2002344234B2 (en) 2001-05-31 2002-05-31 Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy
EP02744204A EP1401506A4 (en) 2001-05-31 2002-05-31 Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US29534501P 2001-05-31 2001-05-31
US60/295,345 2001-05-31

Publications (2)

Publication Number Publication Date
WO2002096366A2 true WO2002096366A2 (en) 2002-12-05
WO2002096366A3 WO2002096366A3 (en) 2003-03-20

Family

ID=23137301

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/017180 WO2002096366A2 (en) 2001-05-31 2002-05-31 Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy

Country Status (6)

Country Link
US (2) US6827926B2 (en)
EP (1) EP1401506A4 (en)
JP (1) JP2004532251A (en)
AU (1) AU2002344234B2 (en)
CA (1) CA2448562A1 (en)
WO (1) WO2002096366A2 (en)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1374897A1 (en) * 2002-06-21 2004-01-02 Health Research, Inc. Chlorin and bacteriochlorin-based difunctional aminophenyl DTPA and N2S2 conjugates
EP1374912A1 (en) * 2002-06-21 2004-01-02 Edwin L. Adair Use of metaloporphyrins for treatment of arteriosclerotic lesions
US6753160B2 (en) 2002-06-21 2004-06-22 Edwin L. Adair Method of using metaloporphyrins for treatment of arteriosclerotic lesions
EP1439842A1 (en) * 2001-06-01 2004-07-28 National Jewish Medical and Research Center Oxidant scavengers for treatment of diabetes or use in transplantation or induction of immune tolerance
WO2005000854A3 (en) * 2003-06-06 2005-05-12 Eukarion Inc Orally bioavailable low molecular weight metalloporphyrins as antioxidants
WO2006005924A1 (en) * 2004-07-13 2006-01-19 Psimei Pharmaceuticals Plc Porphyrin derivatives and their use in photon activation therapy
EP1762248A1 (en) * 2005-09-09 2007-03-14 CORIT Consorzio per la Ricerca sul Use of cobalt porphyrins in joint therapy with an immunosuppressant drug for treatment of transplant patients or autoimmune disorders
WO2007056440A1 (en) * 2005-11-07 2007-05-18 Titan Pharmaceuticals, Inc. Treatment and prevention of adverse liver conditions using gallium
JP2007517909A (en) * 2004-01-14 2007-07-05 ギリアード サイエンシーズ， インコーポレイテッド Lipid-based dispersions useful for drug delivery
US7820644B2 (en) 1999-01-25 2010-10-26 Aelous Pharmaceuticals, Inc. Substituted porphyrins
DE102010056443A1 (en) * 2010-12-28 2012-06-28 Universität Bremen New chlorin derivative useful as photosensitizer in photodynamic tumor therapy
US8416405B2 (en) 2008-08-08 2013-04-09 Chemimage Corporation Raman chemical imaging of implantable drug delivery devices
US8709473B1 (en) 2009-01-28 2014-04-29 Abbott Cardiovascular Systems Inc. Method of targeting hydrophobic drugs to vascular lesions
US9345904B2 (en) 2011-07-01 2016-05-24 Sbi Pharmaceuticals Co., Ltd. Photodynamic therapy using photosensitizing agent or 5-aminolevulinic acid
RU2617045C1 (en) * 2016-03-02 2017-04-19 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский технологический университет" Pharmaceutical composition for fluorescent diagnostics of pathological changes in skin and mucous membranes
US9993661B2 (en) 2008-04-04 2018-06-12 Immunolight, Llc. Modulating a biological activity of a target structure by energy generation in-situ within a medium
CN109575036A (en) * 2018-12-11 2019-04-05 怀化学院 Two ester type compound of Metal hematoporphyrins bis ether, catalyst and preparation method thereof and catalytic oxidation of cyclohexane method
US10391330B2 (en) 2007-11-06 2019-08-27 Immunolight, Llc Non-invasive systems and methods for in-situ photobiomodulation
US11382895B2 (en) 2008-05-23 2022-07-12 National Jewish Health Methods for treating injury associated with exposure to an alkylating species
CN115945220A (en) * 2023-03-15 2023-04-11 四川大学 Ir metal-based biocatalyst and preparation method and application thereof

Families Citing this family (126)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086460A2 (en) * 2002-04-05 2003-10-23 Candela Corporation High fluence rate activation of photosensitizers for dermatological applications
US20050163821A1 (en) * 2002-08-02 2005-07-28 Hsing-Wen Sung Drug-eluting Biodegradable Stent and Delivery Means
US20040077621A1 (en) * 2002-08-08 2004-04-22 Academia Sinica Antioxidants
GB2397067B (en) * 2002-12-23 2005-05-11 Destiny Pharma Ltd Porphin & azaporphin derivatives with at least one cationic-nitrogen-containing meso-substituent for use in photodynamic therapy & in vitro sterilisation
US20040176754A1 (en) * 2003-03-06 2004-09-09 Island Tobin C. Method and device for sensing skin contact
EP2604215B1 (en) * 2003-02-25 2017-10-11 Tria Beauty, Inc. Eye-safe dermatologic treatment apparatus and method
US7118563B2 (en) * 2003-02-25 2006-10-10 Spectragenics, Inc. Self-contained, diode-laser-based dermatologic treatment apparatus
WO2004077020A2 (en) * 2003-02-25 2004-09-10 Spectragenics, Inc. Skin sensing method and apparatus
WO2004075976A2 (en) 2003-02-25 2004-09-10 Spectragenics, Inc. Method and apparatus for the treatment of benign pigmented lesions
WO2004075731A2 (en) * 2003-02-25 2004-09-10 Spectragenics, Inc. Acne treatment device and method
EP1596747B1 (en) * 2003-02-25 2016-02-17 Tria Beauty, Inc. Eye-safe dermatologic treatment apparatus
EP1596744B1 (en) * 2003-02-25 2016-02-17 Tria Beauty, Inc. Self-contained, eye-safe hair-regrowth-inhibition apparatus and method
AU2004285412A1 (en) 2003-09-12 2005-05-12 Minnow Medical, Llc Selectable eccentric remodeling and/or ablation of atherosclerotic material
US7553326B2 (en) * 2003-11-24 2009-06-30 Sweet Richard M Method and apparatus for preventing dialysis graft intimal hyperplasia
US20050171436A1 (en) * 2004-01-09 2005-08-04 Clarke Richard H. Raman spectroscopy for monitoring drug-eluting medical devices
US8777935B2 (en) 2004-02-25 2014-07-15 Tria Beauty, Inc. Optical sensor and method for identifying the presence of skin
GB2415372A (en) 2004-06-23 2005-12-28 Destiny Pharma Ltd Non photodynamical or sonodynamical antimicrobial use of porphyrins and azaporphyrins containing at least one cationic-nitrogen-containing substituent
WO2006014530A2 (en) * 2004-07-07 2006-02-09 The General Hospital Corporation Imaging of enzyme activity
US8396548B2 (en) 2008-11-14 2013-03-12 Vessix Vascular, Inc. Selective drug delivery in a lumen
US9713730B2 (en) 2004-09-10 2017-07-25 Boston Scientific Scimed, Inc. Apparatus and method for treatment of in-stent restenosis
US9277955B2 (en) 2010-04-09 2016-03-08 Vessix Vascular, Inc. Power generating and control apparatus for the treatment of tissue
US7688440B2 (en) 2005-01-27 2010-03-30 Prescient Medical, Inc. Raman spectroscopic test strip systems
US7651851B2 (en) * 2005-01-27 2010-01-26 Prescient Medical, Inc. Handheld Raman body fluid analyzer
US7524671B2 (en) * 2005-01-27 2009-04-28 Prescient Medical, Inc. Handheld raman blood analyzer
US8066759B2 (en) * 2005-02-04 2011-11-29 Boston Scientific Scimed, Inc. Resonator for medical device
EP1848778B1 (en) 2005-02-18 2013-04-10 North Carolina State University De novo synthesis of bacteriochlorins
US20060222592A1 (en) * 2005-04-05 2006-10-05 Clemens Burda Nanoparticles and methods of manufacturing nanoparticles for electronic and non-electronic applications
US7595469B2 (en) * 2005-05-24 2009-09-29 Boston Scientific Scimed, Inc. Resonator for medical device
US7279664B2 (en) * 2005-07-26 2007-10-09 Boston Scientific Scimed, Inc. Resonator for medical device
US7304277B2 (en) * 2005-08-23 2007-12-04 Boston Scientific Scimed, Inc Resonator with adjustable capacitor for medical device
US7524282B2 (en) * 2005-08-29 2009-04-28 Boston Scientific Scimed, Inc. Cardiac sleeve apparatus, system and method of use
US8097609B2 (en) * 2005-10-20 2012-01-17 North Carolina State University Swallowtail motifs for imparting water solubility to porphyrinic compounds
EP1779891A1 (en) * 2005-10-28 2007-05-02 Abdula Kurkayev Method of activating a photosensitizer
US7423496B2 (en) * 2005-11-09 2008-09-09 Boston Scientific Scimed, Inc. Resonator with adjustable capacitance for medical device
US8170643B2 (en) * 2005-11-22 2012-05-01 Bsd Medical Corporation System and method for irradiating a target with electromagnetic radiation to produce a heated region
WO2007064842A2 (en) * 2005-11-30 2007-06-07 North Carolina State University Synthesis of chlorins and phorbines with enhanced red spectral features
WO2007064841A2 (en) 2005-11-30 2007-06-07 North Carolina State University Porphyrinic compounds for use in flow cytometry
US7465312B2 (en) 2006-05-02 2008-12-16 Green Medical, Inc. Systems and methods for treating superficial venous malformations like spider veins
US8019435B2 (en) 2006-05-02 2011-09-13 Boston Scientific Scimed, Inc. Control of arterial smooth muscle tone
US20090326435A1 (en) * 2006-05-02 2009-12-31 Green Medical, Inc. Systems and methods for treating superficial venous malformations like varicose or spider veins
WO2007130465A2 (en) * 2006-05-02 2007-11-15 Green Medical, Inc. Systems and methods for treating superficial venous malformations like spider veins
EP2455034B1 (en) 2006-10-18 2017-07-19 Vessix Vascular, Inc. System for inducing desirable temperature effects on body tissue
CA2666661C (en) 2006-10-18 2015-01-20 Minnow Medical, Inc. Tuned rf energy and electrical tissue characterization for selective treatment of target tissues
JP5479901B2 (en) 2006-10-18 2014-04-23 べシックス・バスキュラー・インコーポレイテッド Induction of desired temperature effects on body tissue
FR2914302A1 (en) * 2007-03-30 2008-10-03 Sanofi Pasteur Sa PROCESS FOR PREPARING PORPHYRIN DERIVATIVES, SUCH AS PROTOPORPHYRIN (IX) AND INTERMEDIATE SYNTHESIS
US8580845B2 (en) * 2007-06-29 2013-11-12 Board Of Regents, The University Of Texas System Functionalized expanded porphyrins
WO2009021225A1 (en) * 2007-08-08 2009-02-12 Spectragenics, Inc. Capacitive sensing method and device for detecting skin
WO2009129321A1 (en) * 2008-04-18 2009-10-22 Sonnemed Llc Compounds and methods for activated therapy
WO2009132355A1 (en) 2008-04-25 2009-10-29 Tria Beauty, Inc. Optical sensor and method for identifying the presence of skin and the pigmentation of skin
JP2011529492A (en) * 2008-07-30 2011-12-08 日東電工株式会社 Drug carrier
WO2010040063A1 (en) * 2008-10-03 2010-04-08 The Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Medical Center Treatment of hepatitis c infection with metalloporphyrins
CN102271603A (en) 2008-11-17 2011-12-07 明诺医学股份有限公司 Selective accumulation of energy with or without knowledge of tissue topography
US8802074B2 (en) 2008-11-26 2014-08-12 Board Of Regents, The University Of Texas System Polymers functionalized with ion-specific recognition elements
US20100227799A1 (en) * 2009-03-09 2010-09-09 Medtronic Vascular, Inc. Simultaneous photodynamic therapy and photo induced polymerization
US9192790B2 (en) 2010-04-14 2015-11-24 Boston Scientific Scimed, Inc. Focused ultrasonic renal denervation
US8473067B2 (en) 2010-06-11 2013-06-25 Boston Scientific Scimed, Inc. Renal denervation and stimulation employing wireless vascular energy transfer arrangement
US9408661B2 (en) 2010-07-30 2016-08-09 Patrick A. Haverkost RF electrodes on multiple flexible wires for renal nerve ablation
US9463062B2 (en) 2010-07-30 2016-10-11 Boston Scientific Scimed, Inc. Cooled conductive balloon RF catheter for renal nerve ablation
US9155589B2 (en) 2010-07-30 2015-10-13 Boston Scientific Scimed, Inc. Sequential activation RF electrode set for renal nerve ablation
US9084609B2 (en) 2010-07-30 2015-07-21 Boston Scientific Scime, Inc. Spiral balloon catheter for renal nerve ablation
US9358365B2 (en) 2010-07-30 2016-06-07 Boston Scientific Scimed, Inc. Precision electrode movement control for renal nerve ablation
US8974451B2 (en) 2010-10-25 2015-03-10 Boston Scientific Scimed, Inc. Renal nerve ablation using conductive fluid jet and RF energy
US9220558B2 (en) 2010-10-27 2015-12-29 Boston Scientific Scimed, Inc. RF renal denervation catheter with multiple independent electrodes
US9028485B2 (en) 2010-11-15 2015-05-12 Boston Scientific Scimed, Inc. Self-expanding cooling electrode for renal nerve ablation
US9089350B2 (en) 2010-11-16 2015-07-28 Boston Scientific Scimed, Inc. Renal denervation catheter with RF electrode and integral contrast dye injection arrangement
US9668811B2 (en) 2010-11-16 2017-06-06 Boston Scientific Scimed, Inc. Minimally invasive access for renal nerve ablation
US9326751B2 (en) 2010-11-17 2016-05-03 Boston Scientific Scimed, Inc. Catheter guidance of external energy for renal denervation
US9060761B2 (en) 2010-11-18 2015-06-23 Boston Scientific Scime, Inc. Catheter-focused magnetic field induced renal nerve ablation
US9023034B2 (en) 2010-11-22 2015-05-05 Boston Scientific Scimed, Inc. Renal ablation electrode with force-activatable conduction apparatus
US9192435B2 (en) 2010-11-22 2015-11-24 Boston Scientific Scimed, Inc. Renal denervation catheter with cooled RF electrode
US20120157993A1 (en) 2010-12-15 2012-06-21 Jenson Mark L Bipolar Off-Wall Electrode Device for Renal Nerve Ablation
US9220561B2 (en) 2011-01-19 2015-12-29 Boston Scientific Scimed, Inc. Guide-compatible large-electrode catheter for renal nerve ablation with reduced arterial injury
AU2012283908B2 (en) 2011-07-20 2017-02-16 Boston Scientific Scimed, Inc. Percutaneous devices and methods to visualize, target and ablate nerves
WO2013016203A1 (en) 2011-07-22 2013-01-31 Boston Scientific Scimed, Inc. Nerve modulation system with a nerve modulation element positionable in a helical guide
EP2765942B1 (en) 2011-10-10 2016-02-24 Boston Scientific Scimed, Inc. Medical devices including ablation electrodes
US9420955B2 (en) 2011-10-11 2016-08-23 Boston Scientific Scimed, Inc. Intravascular temperature monitoring system and method
US10085799B2 (en) 2011-10-11 2018-10-02 Boston Scientific Scimed, Inc. Off-wall electrode device and methods for nerve modulation
US9364284B2 (en) 2011-10-12 2016-06-14 Boston Scientific Scimed, Inc. Method of making an off-wall spacer cage
EP2768563B1 (en) 2011-10-18 2016-11-09 Boston Scientific Scimed, Inc. Deflectable medical devices
US9079000B2 (en) 2011-10-18 2015-07-14 Boston Scientific Scimed, Inc. Integrated crossing balloon catheter
EP2775948B1 (en) 2011-11-08 2018-04-04 Boston Scientific Scimed, Inc. Ostial renal nerve ablation
EP2779929A1 (en) 2011-11-15 2014-09-24 Boston Scientific Scimed, Inc. Device and methods for renal nerve modulation monitoring
US9119632B2 (en) 2011-11-21 2015-09-01 Boston Scientific Scimed, Inc. Deflectable renal nerve ablation catheter
US9265969B2 (en) 2011-12-21 2016-02-23 Cardiac Pacemakers, Inc. Methods for modulating cell function
WO2013096913A2 (en) 2011-12-23 2013-06-27 Vessix Vascular, Inc. Methods and apparatuses for remodeling tissue of or adjacent to a body passage
WO2013101452A1 (en) 2011-12-28 2013-07-04 Boston Scientific Scimed, Inc. Device and methods for nerve modulation using a novel ablation catheter with polymeric ablative elements
US9050106B2 (en) 2011-12-29 2015-06-09 Boston Scientific Scimed, Inc. Off-wall electrode device and methods for nerve modulation
US10660703B2 (en) 2012-05-08 2020-05-26 Boston Scientific Scimed, Inc. Renal nerve modulation devices
US10321946B2 (en) 2012-08-24 2019-06-18 Boston Scientific Scimed, Inc. Renal nerve modulation devices with weeping RF ablation balloons
EP2895095A2 (en) 2012-09-17 2015-07-22 Boston Scientific Scimed, Inc. Self-positioning electrode system and method for renal nerve modulation
US10398464B2 (en) 2012-09-21 2019-09-03 Boston Scientific Scimed, Inc. System for nerve modulation and innocuous thermal gradient nerve block
US10549127B2 (en) 2012-09-21 2020-02-04 Boston Scientific Scimed, Inc. Self-cooling ultrasound ablation catheter
JP6074051B2 (en) 2012-10-10 2017-02-01 ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ． Intravascular neuromodulation system and medical device
WO2014143571A1 (en) 2013-03-11 2014-09-18 Boston Scientific Scimed, Inc. Medical devices for modulating nerves
US9956033B2 (en) 2013-03-11 2018-05-01 Boston Scientific Scimed, Inc. Medical devices for modulating nerves
US9808311B2 (en) 2013-03-13 2017-11-07 Boston Scientific Scimed, Inc. Deflectable medical devices
JP6220044B2 (en) 2013-03-15 2017-10-25 ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ． Medical device for renal nerve ablation
CN105228546B (en) 2013-03-15 2017-11-14 波士顿科学国际有限公司 Utilize the impedance-compensated medicine equipment and method that are used to treat hypertension
US10265122B2 (en) 2013-03-15 2019-04-23 Boston Scientific Scimed, Inc. Nerve ablation devices and related methods of use
JP2016524949A (en) 2013-06-21 2016-08-22 ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ． Medical device for renal nerve ablation having a rotatable shaft
US9943365B2 (en) 2013-06-21 2018-04-17 Boston Scientific Scimed, Inc. Renal denervation balloon catheter with ride along electrode support
US9707036B2 (en) 2013-06-25 2017-07-18 Boston Scientific Scimed, Inc. Devices and methods for nerve modulation using localized indifferent electrodes
WO2015002787A1 (en) 2013-07-01 2015-01-08 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation
US10660698B2 (en) 2013-07-11 2020-05-26 Boston Scientific Scimed, Inc. Devices and methods for nerve modulation
EP3019106A1 (en) 2013-07-11 2016-05-18 Boston Scientific Scimed, Inc. Medical device with stretchable electrode assemblies
EP3049007B1 (en) 2013-07-19 2019-06-12 Boston Scientific Scimed, Inc. Spiral bipolar electrode renal denervation balloon
US10695124B2 (en) 2013-07-22 2020-06-30 Boston Scientific Scimed, Inc. Renal nerve ablation catheter having twist balloon
WO2015013205A1 (en) 2013-07-22 2015-01-29 Boston Scientific Scimed, Inc. Medical devices for renal nerve ablation
JP6159888B2 (en) 2013-08-22 2017-07-05 ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ． Flexible circuit with improved adhesion to renal neuromodulation balloon
US9895194B2 (en) 2013-09-04 2018-02-20 Boston Scientific Scimed, Inc. Radio frequency (RF) balloon catheter having flushing and cooling capability
CN105530885B (en) 2013-09-13 2020-09-22 波士顿科学国际有限公司 Ablation balloon with vapor deposited covering
WO2015057521A1 (en) 2013-10-14 2015-04-23 Boston Scientific Scimed, Inc. High resolution cardiac mapping electrode array catheter
US11246654B2 (en) 2013-10-14 2022-02-15 Boston Scientific Scimed, Inc. Flexible renal nerve ablation devices and related methods of use and manufacture
EP3057520A1 (en) 2013-10-15 2016-08-24 Boston Scientific Scimed, Inc. Medical device balloon
US9770606B2 (en) 2013-10-15 2017-09-26 Boston Scientific Scimed, Inc. Ultrasound ablation catheter with cooling infusion and centering basket
JP6259099B2 (en) 2013-10-18 2018-01-10 ボストン サイエンティフィック サイムド，インコーポレイテッドＢｏｓｔｏｎ Ｓｃｉｅｎｔｉｆｉｃ Ｓｃｉｍｅｄ，Ｉｎｃ． Balloon catheter comprising a conductive wire with flexibility, and related uses and manufacturing methods
CN105658163B (en) 2013-10-25 2020-08-18 波士顿科学国际有限公司 Embedded thermocouple in denervation flexible circuit
WO2015103617A1 (en) 2014-01-06 2015-07-09 Boston Scientific Scimed, Inc. Tear resistant flex circuit assembly
EP3102136B1 (en) 2014-02-04 2018-06-27 Boston Scientific Scimed, Inc. Alternative placement of thermal sensors on bipolar electrode
US11000679B2 (en) 2014-02-04 2021-05-11 Boston Scientific Scimed, Inc. Balloon protection and rewrapping devices and related methods of use
WO2016123841A1 (en) * 2015-02-03 2016-08-11 东南大学 Multimodality imaging preparation used for detecting senile dementia and cardio-cerebrovascular diseases and application thereof
US10035806B2 (en) 2015-10-06 2018-07-31 California Institute Of Technology Derivatized corroles and metallocorroles and their use as imaging and therapeutic agents
US10335608B2 (en) 2016-04-20 2019-07-02 Theralase Technologies, Inc. Photodynamic compounds and methods for activating them using ionizing radiation and/or other electromagnetic radiation for therapy and/or diagnostics
CN111848656B (en) * 2020-06-24 2023-03-14 天津大学 Ion-modified protoporphyrin gallium compound and preparation method and application thereof
CN112402632B (en) * 2020-11-24 2022-01-07 南京大学 Nanoscale coordination polymer for radiotherapy sensitization and preparation method and application thereof
US11896852B2 (en) 2020-12-21 2024-02-13 Xerox Corporation Closed-loop non-invasive transcranial stimulation and neural activity recording system and method

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5405957A (en) * 1992-10-30 1995-04-11 The University Of British Columbia Wavelength-specific photosensitive compounds and expanded porphyrin-like compounds and methods of use
US5552134A (en) * 1988-01-11 1996-09-03 University Of Toledo Uses of benzochlorins, verdins and porphyrin derivatives and of compositions containing such benzochlorins, verdins and porphyrin derivatives
US5672334A (en) * 1991-01-16 1997-09-30 Access Pharmaceuticals, Inc. Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans
US5849259A (en) * 1992-09-28 1998-12-15 Institut Fur Diagnostikforschung Gmbh 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical agents containing the latter and process for their production

Family Cites Families (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE84036T1 (en) 1985-10-23 1993-01-15 Nihon Mediphysics Co Ltd PORPHYRIN DERIVATIVES, THEIR PRODUCTION AND USE.
US5283255A (en) * 1987-01-20 1994-02-01 The University Of British Columbia Wavelength-specific cytotoxic agents
JP3191223B2 (en) 1991-10-04 2001-07-23 株式会社光ケミカル研究所 Porphyrin derivatives and their uses
US5948771A (en) * 1996-01-31 1999-09-07 The Trustees Of Columbia University In The City Of New York Method for treating heart failure using tetrapyrroles and metallotetrapyrroles
AU6028598A (en) 1997-01-09 1998-08-03 Emory University Non-iron metalloporphyrins and methods of use
NZ338031A (en) * 1997-05-07 2001-04-27 Qlt Phototherapeutics Inc Ethylene glycol esters of monohydrobenzoporphyrin derivatives as photoactive agents and their use in conducting photodynamic diagnosis
US5880145A (en) * 1997-05-07 1999-03-09 The University Of British Columbia Class of benzoporphyrin derivative photoactive compounds
US6136841A (en) 1998-06-02 2000-10-24 Schering Aktiengesellschaft 3-, 8-substituted deuteroporphyrin derivatives, pharmaceutical agents that contain the latter, process for their production and their use in photodynamic therapy and MRI diagnosis
AU1683901A (en) * 1999-11-17 2001-05-30 Qlt Inc. Use of pdt to inhibit intimal hyperplasia
WO2001097860A2 (en) * 2000-06-21 2001-12-27 Bristol-Myers Squibb Pharma Company Pharmaceuticals for the imaging of angiogenic disorders for use in combination therapy
WO2002096417A1 (en) * 2001-05-31 2002-12-05 Miravant Pharmaceuticals, Inc. Substituted porphyrin and azaporphyrin derivatives and their use in photodynamic therapy, radioimaging and mri diagnosis
EP1279676A1 (en) * 2001-07-19 2003-01-29 Institut Curie Porphyrin derivatives for photodynamic therapy
AU2002336637A1 (en) * 2001-10-03 2003-04-14 Miravant Pharmaceuticals, Inc. Chlorin photosensitizing agents for use in photodynamic therapy
AU2002336636A1 (en) * 2001-10-03 2003-04-14 Miravant Pharmaceuticals, Inc. Photosensitizing carbamate derivatives

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5552134A (en) * 1988-01-11 1996-09-03 University Of Toledo Uses of benzochlorins, verdins and porphyrin derivatives and of compositions containing such benzochlorins, verdins and porphyrin derivatives
US5672334A (en) * 1991-01-16 1997-09-30 Access Pharmaceuticals, Inc. Invivo agents comprising cationic metal chelators with acidic saccharides and glycosaminoglycans
US5849259A (en) * 1992-09-28 1998-12-15 Institut Fur Diagnostikforschung Gmbh 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical agents containing the latter and process for their production
US5405957A (en) * 1992-10-30 1995-04-11 The University Of British Columbia Wavelength-specific photosensitive compounds and expanded porphyrin-like compounds and methods of use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1401506A2 *

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8946202B2 (en) 1999-01-25 2015-02-03 Aeolus Sciences, Inc. Substituted porphyrins
US8470808B2 (en) 1999-01-25 2013-06-25 Jon D. Piganelli Oxidant scavengers for treatment of type I diabetes or type II diabetes
US7820644B2 (en) 1999-01-25 2010-10-26 Aelous Pharmaceuticals, Inc. Substituted porphyrins
US9289434B2 (en) 1999-01-25 2016-03-22 Aeolus Sciences, Inc. Substituted porphyrins
US8546562B2 (en) 1999-01-25 2013-10-01 James D. Crapo Substituted porphyrins
US8217026B2 (en) 1999-01-25 2012-07-10 Aeolus Sciences, Inc. Substituted porphyrins
EP1439842A1 (en) * 2001-06-01 2004-07-28 National Jewish Medical and Research Center Oxidant scavengers for treatment of diabetes or use in transplantation or induction of immune tolerance
EP1439842A4 (en) * 2001-06-01 2009-09-02 Nat Jewish Med & Res Center Oxidant scavengers for treatment of diabetes or use in transplantation or induction of immune tolerance
EP1679083A2 (en) * 2002-06-21 2006-07-12 Edwin L. Adair Use of metaloporphyrins for treatment of arteriosclerotic lesions
EP1679083A3 (en) * 2002-06-21 2006-08-02 Edwin L. Adair Use of metaloporphyrins for treatment of arteriosclerotic lesions
US6753160B2 (en) 2002-06-21 2004-06-22 Edwin L. Adair Method of using metaloporphyrins for treatment of arteriosclerotic lesions
EP1374897A1 (en) * 2002-06-21 2004-01-02 Health Research, Inc. Chlorin and bacteriochlorin-based difunctional aminophenyl DTPA and N2S2 conjugates
US7067276B2 (en) 2002-06-21 2006-06-27 Adair Edwin L Method of using metaloporphyrins for treatment of arteriosclerotic lesions
EP1374912A1 (en) * 2002-06-21 2004-01-02 Edwin L. Adair Use of metaloporphyrins for treatment of arteriosclerotic lesions
US7649091B2 (en) 2003-06-06 2010-01-19 Eukarion, Inc. Orally bioavailable low molecular weight metalloporphyrins as antioxidants
WO2005000854A3 (en) * 2003-06-06 2005-05-12 Eukarion Inc Orally bioavailable low molecular weight metalloporphyrins as antioxidants
JP2007517909A (en) * 2004-01-14 2007-07-05 ギリアード サイエンシーズ， インコーポレイテッド Lipid-based dispersions useful for drug delivery
WO2006005924A1 (en) * 2004-07-13 2006-01-19 Psimei Pharmaceuticals Plc Porphyrin derivatives and their use in photon activation therapy
US7816518B2 (en) 2004-07-13 2010-10-19 Psimei Pharmaceuticals, Plc Porphyrin derivatives and their use in photon activation therapy
GB2433070A (en) * 2004-07-13 2007-06-13 Psimei Pharmaceuticals Plc Porphyrin derivatives and their use in photon activation therapy
EP1762248A1 (en) * 2005-09-09 2007-03-14 CORIT Consorzio per la Ricerca sul Use of cobalt porphyrins in joint therapy with an immunosuppressant drug for treatment of transplant patients or autoimmune disorders
WO2007056440A1 (en) * 2005-11-07 2007-05-18 Titan Pharmaceuticals, Inc. Treatment and prevention of adverse liver conditions using gallium
US10391330B2 (en) 2007-11-06 2019-08-27 Immunolight, Llc Non-invasive systems and methods for in-situ photobiomodulation
US9993661B2 (en) 2008-04-04 2018-06-12 Immunolight, Llc. Modulating a biological activity of a target structure by energy generation in-situ within a medium
US10272262B2 (en) 2008-04-04 2019-04-30 Immunolight, Llc. Method for modulating a biological activity of a target structure by energy generation in-situ within a medium
US11382895B2 (en) 2008-05-23 2022-07-12 National Jewish Health Methods for treating injury associated with exposure to an alkylating species
US8416405B2 (en) 2008-08-08 2013-04-09 Chemimage Corporation Raman chemical imaging of implantable drug delivery devices
US8709473B1 (en) 2009-01-28 2014-04-29 Abbott Cardiovascular Systems Inc. Method of targeting hydrophobic drugs to vascular lesions
DE102010056443A1 (en) * 2010-12-28 2012-06-28 Universität Bremen New chlorin derivative useful as photosensitizer in photodynamic tumor therapy
DE102010056443A8 (en) * 2010-12-28 2012-11-08 Universität Bremen Chlorin derivatives and their use
US9345904B2 (en) 2011-07-01 2016-05-24 Sbi Pharmaceuticals Co., Ltd. Photodynamic therapy using photosensitizing agent or 5-aminolevulinic acid
RU2617045C1 (en) * 2016-03-02 2017-04-19 Федеральное государственное бюджетное образовательное учреждение высшего образования "Московский технологический университет" Pharmaceutical composition for fluorescent diagnostics of pathological changes in skin and mucous membranes
CN109575036A (en) * 2018-12-11 2019-04-05 怀化学院 Two ester type compound of Metal hematoporphyrins bis ether, catalyst and preparation method thereof and catalytic oxidation of cyclohexane method
CN109575036B (en) * 2018-12-11 2020-09-22 怀化学院 Metal hematoporphyrin diether diester compound, catalyst and preparation method thereof, and cyclohexane catalytic oxidation method
CN115945220A (en) * 2023-03-15 2023-04-11 四川大学 Ir metal-based biocatalyst and preparation method and application thereof

Also Published As

Publication number Publication date
WO2002096366A3 (en) 2003-03-20
US20050137180A1 (en) 2005-06-23
JP2004532251A (en) 2004-10-21
EP1401506A2 (en) 2004-03-31
AU2002344234B2 (en) 2007-11-08
US6827926B2 (en) 2004-12-07
EP1401506A4 (en) 2005-02-16
CA2448562A1 (en) 2002-12-05
US20030105069A1 (en) 2003-06-05

Similar Documents

Publication Publication Date Title
US6827926B2 (en) Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy
AU2002344234A1 (en) Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy
US6906050B2 (en) Substituted porphyrin and azaporphyrin derivatives and their use in photodynamic therapy, radioimaging and MRI diagnosis
O’Connor et al. Porphyrin and nonporphyrin photosensitizers in oncology: preclinical and clinical advances in photodynamic therapy
KR100286963B1 (en) Metal Complex of Water-soluble Texapyrine
JP5205264B2 (en) Perylenequinone derivatives and uses thereof
JPH10500659A (en) Texaphyrin metal complexes with improved functionality
JP2004532251A5 (en)
US20090035363A1 (en) Photoactive Compounds and Compositions and Uses Thereof
US5512559A (en) Method of treating cancer tumors with imine porphyrin compounds
CA2445068C (en) Azo compounds for type i phototherapy
PT2322173T (en) Cationic bacteriochlorophyll derivatives and uses thereof
EP1567147B1 (en) Water-soluble anionic bacteriochlorophyll derivatives and their uses
US20050020559A1 (en) Chlorin photosensitizing agents for use in photodynamic therapy
JP2005505514A (en) Dye-sulfenate for double phototherapy
US20080275232A1 (en) Chlorins possessing fused ring systems useful as photoselective compounds for photodynamic therapy
US20040266748A1 (en) Photosensitizing carbamate derivatives
JP2006503096A (en) Azo compounds for type I phototherapy
AU2008200847A1 (en) Metallotetrapyrrolic photosensitizing agents for use in photodynamic therapy
Kılıç Novel Near-Ir Photosensitizers for Photodynamic Therapy and Designing Heavy Atom Free Photosensitizers for the Photodynamic Therapy
Hui Evaluation of 151-Hydroxypurpurin-7-Lactone (G2) Derivatives, Boron Dipyrromethene (Bodipy) and Rosamine Analogues as Photosensitisers for Photodynamic Cancer Therapy

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG UZ VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2448562

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2002592879

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2002744204

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2002344234

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2002744204

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642