WO1998018473A1 - Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase - Google Patents
Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase Download PDFInfo
- Publication number
- WO1998018473A1 WO1998018473A1 PCT/US1997/019230 US9719230W WO9818473A1 WO 1998018473 A1 WO1998018473 A1 WO 1998018473A1 US 9719230 W US9719230 W US 9719230W WO 9818473 A1 WO9818473 A1 WO 9818473A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutically acceptable
- compound
- hiv
- formula
- alkyl
- Prior art date
Links
- 0 *C(NNC1=NC(CCCC2)C2C(C2CCCCC2)=NC1)=O Chemical compound *C(NNC1=NC(CCCC2)C2C(C2CCCCC2)=NC1)=O 0.000 description 5
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/20—Nitrogen atoms
Definitions
- a retrovirus designated human immunodeficiency virus is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system.
- This virus was previously known as LAV, HTLV-JHI, or ARV.
- a common feature of retrovirus replication is the insertion by virally-encoded integrase of proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid cells.
- Integration is believed to occur in three stages: cleavage of two nucleotides from the 3' termini of the linear proviral DNA; covalent joining of the recessed 3' OH termini of the proviral DNA at a staggered cut made at the host target site; repair synthesis by host enzymes.
- Nucleotide sequencing of HIV shows the presence of a poi gene in one open reading frame [Ratner, L. et al., Nature, 313, 277(1985)].
- Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an integrase and an HIV protease [Toh, H. et al, EMBO J. 4, 1267 (1985); Power, M.D. et al., Science, 231 , 1567 (1986); Pearl, L.H. et al, Nature, 329, 351 (1987)].
- antiviral compounds act as inhibitors of HIV and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.
- Applicants demonstrate that the compounds of this invention are inhibitors of HIV integrase, probably by inhibiting catalysis rather than preventing assembly.
- the particular advantage of the present invention is highly specific inhibition of HIV integrase.
- the compounds of the present do not inhibit a variety of other protein- nucleic acid interactions, including enzymatic reactions involving HIV reverse transcriptase, DNase I, Eco RI endonuclease, or mammalian polymerase ⁇ , as well as other related interactions, e.g., involving HIV TAT protein.
- Compounds of formula I are disclosed. These compounds are useful in the inhibition of HIV integrase, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, pharmaceutically acceptable salts or hydrates (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.
- This invention is concerned with compounds of formula
- X and Y are independently H, CI, Br or F;
- R is aryl or heterocycle, either of which is unsubstituted or substituted with amino, azido, Cl-4 alkyl, phenyloxy, Cl-4 alkoxy, halo, nitro, phenyl or halophenyl, provided that:
- R is not 4-cinnolinyl
- X and Y are independently H, CI or Br; R is aryl or heterocycle, either of which is unsubstituted or substituted with Cl-4 alkyl, or Cl-4 alkoxy, provided that: when R is 5-methyl-4-imidazolyl, X is H; or pharmaceutically acceptable salts thereof.
- X and Y are independently H, CI, or Br;
- R is unsubstituted or substituted with one or more of Cl-4 alkyl; nitro; Cl -4 alkoxy or halo-Cl-4 alkyl, n is 3 to 6, or a pharmaceutically acceptable salt thereof.
- a particular subclass of this class is directed to tautomers of structural formula (I) wherein: X and Y are hydrogen; R is aryl, pyrazinyl, pyridyl, imidazolyl, pyrimidinyl, quinolinyl, any of which R substituents are unsubstituted or substituted with Cl-4 alkyl, or pharmaceutically acceptable salts thereof.
- the present invention further relates to a method of inhibiting HIV integrase comprising administering to a mammal, most particularly a human, an effective amount of a compound of formula (I).
- the present invention also has as an object the method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS or ARC in subject in need of such treatment, comprising administering to the mammal, most particularly a human, an effective amount of a compound of structural formula (I).
- Yet another object of the present invention is to provide pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
- the present invention also relates to the use of a compound of structural formula (I) for the preparation of a medicament useful for the treating infection by HIV, or of treating AIDS or ARC in a subject in need of such treatment, and for prevention infection of HIV in an exposed subject.
- the compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as racemates, racemic mixtures or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention.
- variable e.g., R, etc.
- its definition at each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
- alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
- Halogen or “halo” as used herein, means fluoro, chloro, bromo and iodo.
- aryl is intended to mean phenyl (Ph) or naphthyl.
- heterocycle or heterocyclic represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
- the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
- heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, mo holinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimid
- the pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.
- bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)
- R is heterocycle or aryl, unsubstituted or substituted with amido, azido, C1 -4alkyl, phenyloxy, C1-4alkoxy, halo, nitro, phenyl, or halophenyl
- 2-amino-5-chlorobenzophenone is reacted with glycine esters to give A.
- Thiation is carried out by subsequent reaction with Lawesson's reagent, which upon further reaction with RCON2H3, affords compounds of formula C of the present invention. See also Sternbach, L.H., et al, J. Org. Chem.27, 3788(1962).
- R is aryl or heterocycle, either of which is unsubstituted or substituted with amino, azido, C ⁇ _4 alkyl, phenyloxy, Cl -4 alkoxy, halo, nitro, phenyl or halophenyl.
- R is aryl or heterocycle, either of which is unsubstituted or substituted with amino, azido, Cl-4 alkyl, phenyloxy, Cl-4 alkoxy, halo, nitro, phenyl or halophenyl.
- Schemes HI and IV illustrate how to derivatize the hydrazide group by either EDC (l-(3-dimethylamionopropyl)-3- ethylcarbodiimide hydrochloride) -mediated coupling to a carboxylic acid or direct acylation with an acid chloride.
- EDC l-(3-dimethylamionopropyl)-3- ethylcarbodiimide hydrochloride
- the compounds of the present inventions are useful in the inhibition of HIV integrase, treatment of infection by human immunodeficiency virus (HIV) and the treatment of consequent pathological conditions such as AIDS.
- Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV.
- the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by e.g., blood transfusion, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.
- the compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.
- the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds.
- the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV integrase, e.g., by competitive inhibition.
- the compounds of this invention are commercial products to be sold for these purposes.
- the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
- administering should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need of treatment.
- a method of treating and a pharmaceutical composition for treating HIV infection and AIDS involves administering to a patient in need of such treatment a therapeutically-effective amount of a compound of the present invention.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- the present invention also has the objective of providing suitable systemic, oral, parenteral and topical pharmaceutical formulations for use in the methods of treatment of the present invention.
- the compositions containing the compound of the present invention for use in the treatment of the above-noted hyperandrogenic conditions can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for systemic administration.
- the compounds can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions.
- compositions may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts.
- the compositions may also be administered as a nasal spray or as a suppository.
- these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners/flavoring agents known in the art.
- these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.
- compositions When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
- the injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterally-acceptable diluents or solvents, such as mannitol, 1,3- butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
- suitable non-toxic, parenterally-acceptable diluents or solvents such as mannitol, 1,3- butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.
- these compositions When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
- a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.
- the compounds of this invention can be administered orally to humans in a dosage range of 1 to 1000 mg kg body weight in single or divided doses.
- One preferred dosage range is 0.1 to 200 mg/kg body weight orally in single or divided doses.
- Another preferred dosage range is 1.0 to 100 mg/kg body weight orally in single or divided doses.
- compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
- the present invention is also directed to combinations of the HrV integrase inhibitor compounds with one or more agents useful in the treatment of AIDS.
- the compounds of this invention may be effectively administered, whether at periods of pre- exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, antiinfectives, or vaccines, such as those in the following table.
- administration refers to both concurrent and sequential administration of the active agents.
- Ribavirin (Costa Mesa, CA) positive, LAS, ARC
- Interleukin-2 (Nutley, NJ) in combination lmmunex w/AZT
- Tumor Necrosis Genentech ARC in combination Factor; TNF (S. San Francisco, CA) w/gamma Interferon
- Isethionate (IM & (Rosemont, IL)
- Indinavir is an inhibitor of HIV protease and is the sulfate salt of N- (2(R)-hydroxy-l(S)-indanyl)-2(R)-phenylmethyl-4-(S)-hydroxy-5- (l-(4-(3-pyridyl-methyl)-2(S)-N'-(t-butylcarboxamido)- piperazinyl))-pentaneamide ethanolate. Its synthesis is set forth in U.S. 5,413,999. Indinavir is generally administered at a dosage of 800 mg three times a day.
- hydrazide V 0.061 gms (0.44 mmol) of hydrazide V were heated to 80°C in a mixture of 1.5 mL of CHCI3 and 1.5 mL of EtOH for 16 hrs and then allowed to cool. The residue was concentrated to dryness and partitioned between CHCI3 and H2O. The water layer contained pure pyrazine hydrazide starting material by TLC and was discarded. The CHCI3 layer, which contained some undissolved solid, was concentrated to give a yellow solid. Trituration of this with EtOAc yielded a colorless solid which was the desired product VI.
- EXAMPLE 6 Oral Composition
- 50 mg of a compound of the present invention is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gelatin capsule.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP97911906A EP0949926A4 (en) | 1996-10-31 | 1997-10-27 | Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase |
CA002269135A CA2269135A1 (en) | 1996-10-31 | 1997-10-27 | Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase |
AU49173/97A AU4917397A (en) | 1996-10-31 | 1997-10-27 | Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2934896P | 1996-10-31 | 1996-10-31 | |
US60/029,348 | 1996-10-31 | ||
GB9624375.3 | 1996-11-22 | ||
GBGB9624375.3A GB9624375D0 (en) | 1996-11-22 | 1996-11-22 | Benzodiazepine hydrazide derivatives as inhibitors of HIV integrase |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998018473A1 true WO1998018473A1 (en) | 1998-05-07 |
Family
ID=26310468
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/019230 WO1998018473A1 (en) | 1996-10-31 | 1997-10-27 | Benzodiazepine hydrazide derivatives as inhibitors of hiv integrase |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0949926A4 (en) |
AU (1) | AU4917397A (en) |
CA (1) | CA2269135A1 (en) |
WO (1) | WO1998018473A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000059867A1 (en) * | 1999-03-30 | 2000-10-12 | Pharmacor Inc. | Hydroxyphenyl derivatives with hiv integrase inhibitory properties |
WO2000068235A1 (en) * | 1999-05-12 | 2000-11-16 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health & Human Services, The National Institutes Of Health | Thiazepine inhibitors of hiv-1 integrase |
EP1083897A1 (en) * | 1998-06-03 | 2001-03-21 | Merck & Co., Inc. | Hiv integrase inhibitors |
US6313177B1 (en) | 1999-04-30 | 2001-11-06 | Pharmacor Inc. | D-mannitol derivatives as HIV aspartyl protease inhibitors |
US6362165B1 (en) | 1999-03-30 | 2002-03-26 | Pharmacor Inc. | Hydroxyphenyl derivatives with HIV integrase inhibitory properties |
WO2004039803A2 (en) * | 2002-10-31 | 2004-05-13 | Pfizer Inc. | Hiv-integrase inhibitors, pharmaceutical compositions, and methods for their use |
US7015212B1 (en) | 1999-05-12 | 2006-03-21 | The United States Of America As Represented By The Department Of Health And Human Services | Thiazepine inhibitors of HIV-1 integrase |
US7468375B2 (en) | 2004-04-26 | 2008-12-23 | Pfizer Inc. | Inhibitors of the HIV integrase enzyme |
US7582624B2 (en) | 2002-09-20 | 2009-09-01 | Arrow Therapeutics Limited | Benzodiazepine derivatives and pharmaceutical compositions containing them |
US7692014B2 (en) | 2004-04-26 | 2010-04-06 | Pfizer, Inc. | Inhibitors of the HIV integrase enzyme |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4102881A (en) * | 1970-03-27 | 1978-07-25 | Takeda Chemical Industries, Ltd. | Benzodiazepine derivatives |
US4820834A (en) * | 1984-06-26 | 1989-04-11 | Merck & Co., Inc. | Benzodiazepine analogs |
-
1997
- 1997-10-27 WO PCT/US1997/019230 patent/WO1998018473A1/en not_active Application Discontinuation
- 1997-10-27 AU AU49173/97A patent/AU4917397A/en not_active Abandoned
- 1997-10-27 CA CA002269135A patent/CA2269135A1/en not_active Abandoned
- 1997-10-27 EP EP97911906A patent/EP0949926A4/en not_active Withdrawn
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4102881A (en) * | 1970-03-27 | 1978-07-25 | Takeda Chemical Industries, Ltd. | Benzodiazepine derivatives |
US4820834A (en) * | 1984-06-26 | 1989-04-11 | Merck & Co., Inc. | Benzodiazepine analogs |
Non-Patent Citations (2)
Title |
---|
COLLECTION CZECHOSLOVAK CHEM. COMMUN., 1988, Vol. 53, No. 1, VEJDELEK Z. et al., "Potential Anxiolytics and Hypnotics: 1-(Alkanesulfonamidoalkyl)-6-Aryl-8-Halogen o-s-Triazolo[4,3-a]-1,4-Benzodiazepines and Related Compounds", pages 132-44. * |
See also references of EP0949926A4 * |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1083897A1 (en) * | 1998-06-03 | 2001-03-21 | Merck & Co., Inc. | Hiv integrase inhibitors |
EP1083897A4 (en) * | 1998-06-03 | 2003-01-02 | Merck & Co Inc | Hiv integrase inhibitors |
US6362165B1 (en) | 1999-03-30 | 2002-03-26 | Pharmacor Inc. | Hydroxyphenyl derivatives with HIV integrase inhibitory properties |
WO2000059867A1 (en) * | 1999-03-30 | 2000-10-12 | Pharmacor Inc. | Hydroxyphenyl derivatives with hiv integrase inhibitory properties |
US6313177B1 (en) | 1999-04-30 | 2001-11-06 | Pharmacor Inc. | D-mannitol derivatives as HIV aspartyl protease inhibitors |
US7015212B1 (en) | 1999-05-12 | 2006-03-21 | The United States Of America As Represented By The Department Of Health And Human Services | Thiazepine inhibitors of HIV-1 integrase |
WO2000068235A1 (en) * | 1999-05-12 | 2000-11-16 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health & Human Services, The National Institutes Of Health | Thiazepine inhibitors of hiv-1 integrase |
US8119630B2 (en) | 2002-09-20 | 2012-02-21 | Arrow Therapeutics Limited | Benzodiazepine derivatives and pharmaceutical compositions containing them |
US7582624B2 (en) | 2002-09-20 | 2009-09-01 | Arrow Therapeutics Limited | Benzodiazepine derivatives and pharmaceutical compositions containing them |
NL1024676C2 (en) * | 2002-10-31 | 2005-12-14 | Pfizer | HIV integrase inhibitors, pharmaceutical preparations and methods for their use. |
US7135482B2 (en) | 2002-10-31 | 2006-11-14 | Agouron Pharmaceuticals, Inc. | HIV-integrase inhibitors, pharmaceutical compositions, and methods for their use |
US7368571B2 (en) | 2002-10-31 | 2008-05-06 | Pfizer Inc | HIV-Integrase inhibitors, pharmaceutical compositions and methods for their use |
WO2004039803A3 (en) * | 2002-10-31 | 2004-09-16 | Pfizer | Hiv-integrase inhibitors, pharmaceutical compositions, and methods for their use |
WO2004039803A2 (en) * | 2002-10-31 | 2004-05-13 | Pfizer Inc. | Hiv-integrase inhibitors, pharmaceutical compositions, and methods for their use |
US7468375B2 (en) | 2004-04-26 | 2008-12-23 | Pfizer Inc. | Inhibitors of the HIV integrase enzyme |
US7692014B2 (en) | 2004-04-26 | 2010-04-06 | Pfizer, Inc. | Inhibitors of the HIV integrase enzyme |
Also Published As
Publication number | Publication date |
---|---|
EP0949926A4 (en) | 2001-01-17 |
EP0949926A1 (en) | 1999-10-20 |
AU4917397A (en) | 1998-05-22 |
CA2269135A1 (en) | 1998-05-07 |
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