WO2007059116A2 - Geldanamycin derivatives and pharmaceutical compositions thereof - Google Patents

Geldanamycin derivatives and pharmaceutical compositions thereof Download PDF

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Publication number
WO2007059116A2
WO2007059116A2 PCT/US2006/044165 US2006044165W WO2007059116A2 WO 2007059116 A2 WO2007059116 A2 WO 2007059116A2 US 2006044165 W US2006044165 W US 2006044165W WO 2007059116 A2 WO2007059116 A2 WO 2007059116A2
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Prior art keywords
optionally substituted
compound
hydrochloride
geldanamycin
demethoxygeldanamycin
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PCT/US2006/044165
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French (fr)
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WO2007059116A3 (en
Inventor
Chunlin Tao
Hongna Han
Xiaowen Sun
Tapas De
Neil P. Desai
Patrick Soon-Shiong
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Abraxis Bioscience, Inc.
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Publication of WO2007059116A2 publication Critical patent/WO2007059116A2/en
Publication of WO2007059116A3 publication Critical patent/WO2007059116A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • GM is a benzoquinone ansamycin polyketide isolated from Streptomyces hygroscopicus. See DeBoer et al., Antibiot., 1970, 23, 442.
  • geldanamycin Although originally discovered by screening microbial extracts for antibacterial and antiviral activity, geldanamycin was later found to be cytotoxic to certain tumor cells. It is reported that geldanamycin exerts its antiproliferative and anti-cancer effect by binding with the heat shock protein 90 (Hsp90) chaperone and, in turn, altering the translocation properties of the tumor suppressor protein p53. See Stebbins et al., Cell, 1997, 239; Sepehrnia et al., J. Biol. Chem., 1996, 271, 15,084; Dasgupta et al., Experimental Cell Research, 1997, 29, 231.
  • Hsp90 heat shock protein 90
  • Hsp90 is essential for the stability and function of several oncogenic proteins associated with key sites of genetic deregulation in human cancer. It is known to be over-expressed in human tumors and has the potential to inhibit the hallmark traits of cancer such as cell growth, signaling apoptosis avoidance, limitless proliferation, angiogenesis, and metastasis. See Sreedhar et al, Pharmacology & Therapeutics, 2004, 101, 227.
  • geldanamycins and other Hsp90 inhibitors have been shown to prevent binding of protein substrates to Hs ⁇ 90 and to inhibit the ATP-dependent release of chaperone-associated protein substrates. See Scheibel et al. 7 Proc. Nat 7. Acad. Sci. USA, 1999, 96, 1297.
  • the geldanamycin-induced loss of these proteins leads to selective disruption of certain regulatory pathways and results in growth arrest at specific phases of the cell cycle. (See Muise-Heimericks et al., J Biol. Chem., 1998, 273, 29864), apoptosis, and/or differentiation of cells. Seerissavskaya et al., Cancer Res., 1999, 59, 3935.
  • geldanamycin as a specific inhibitor of Hsp90, was found to diminish specific wild-type p53 binding to the p21 promoter sequence. See McLean et al., Biochem Biophys Res Commun. 2004, 321(3), 665. Consequently, these inhibitors decrease p21 mRNA levels, which lead to a reduction in cellular p21 AVafl protein, the latter being known to induce cell cycle arrest. A minor decrease in p53 protein levels following the treatment of human fibroblasts with the inhibitors suggests the potential involvement of Hsp90 in the stabilization of wild-type p53.
  • geldanamycin was found to induce Hsp70 and prevent alpha-synuclein aggregation and toxicity in vitro. See McLean et al., Biochem Biophys Res Commun. 2004, 321(3), 665.
  • Hsp90 inhibitors An important property of Hsp90 inhibitors is their ability to cause simultaneous combinatorial blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic client proteins. See Workman P., Trends MoI Med. 2004 10(2), 47. Bedin et al. reported that geldanamycin induces MAPK-independent cell cycle arrest by inhibiting the chaperone function of the Hsp90 protein through competition for ATP binding. See Bedin et al., J. Int. J. Cancer 2004, 9(5), 43. The antiproliferative effect of geldanamycin has been attributed to destabilization of the Raf-1 protein, one of the targets of Hsp90, and to the resulting inhibition of MAPIC Li et al.
  • geldanamycin exhibits broad-spectrum antiviral activity, including HSV-I and severe acute respiratory syndrome coronavirus. Li et al., Antimicrob. Agents Chemother. 2004, 48(3), 867. HSV-I replication in vitro was significantly inhibited by geldanamycin with a 50% inhibitory concentration of 0.093 ⁇ M which was also a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 ⁇ M. The therapeutic index of geldanamycin was found to be over 3700. [0006] Mandler et al. reported that conjugating geldanamycin to the anti-HER2 mAb Herceptin in targeted cancer therapy resulted in a greater antitumor effect than Herceptin alone.
  • Analogues of geldanamycin have been synthesized in an attempt to increase the bioavailability and reduce the toxicity associated with the natural product.
  • analogues 17-allylaminogeldanamycin (17-AAG), which is currently in phase II clinical trials at the National Cancer Institute.
  • 17-AAG has shown reduced hepatotoxicity while maintaining Hsp90 binding. This compound was selected for clinical studies based on its in vitro activity against chemorefractory tumors and novel biological actions. Like geldanamycin, 17-AAG has limited aqueous solubility. This property requires the use of a solubilizing carrier, most commonly Cremophore®, a polyethoxylated castor oil; however Cremophore® can produce serious side reactions in some patients.
  • a deficiency of the previous generation of ansamycins is that they exhibit one or more poor pharmacological properties, e.g., metabolic instability, poor bioavailability, and/or difficult formulation ability, particularly for in vivo intravenous administration.
  • the invention provides compounds, as well as intermediates thereof and methods for their preparation, and compositions (including pharmaceutical compositions) that are useful in the treatment of diseases or conditions characterized by undesired cellular proliferation or hyperproli feration.
  • the invention further provides methods of using the compounds and compositions described herein.
  • the invention provides a compound or pharmaceutically acceptable salt thereof having the formula (I):
  • W represents: O, N-OH, N-O-COR 1 0 , or N-O-X-Rn;
  • X is selected from the group consisting of a substituted or unsubstituted (Ci- Cio) alkyl or (Ci-Cio) alkenyl or (Ce-Qo) aryl;
  • Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R 8 )(R 9 ), N(R 8 )(R 9 ), CO 2 R 1 O , wherein R 8 and R 9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (C 1 -C 20 ) alkyl, optionally substituted (C 2 -C 20 ) heteroalkyl, optionally substituted (C2-C 20 ) alkenyl, optionally substituted (C 2 -C20) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalky
  • Rs is selected from the group consisting of an optionally substituted (Q -C 20 ) alkyl, optionally substituted (Ci-C 20 ) heteroalkyl, optionally substituted (C 2 -C 20 ) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted (Ce-C 20 ) aryl, optionally substituted (C 3 -C 20 ) heteroaryl, optionally substituted (C 7 -C 20 ) arylalkyl, optionally substituted (C 4 -C 20 ) heteroarylalkyl, optionally substituted (C 3 -C 20 ) cycloalkyl, optionally substituted (C 2 - C 20 ) cycloheteroalkyl, N(R 8 )(R 9 ); -OR, o , -SR 10 , -N(Rg)-C(O)R 10
  • compositions for administration to a mammalian subject includes a plurality of particles of the compound having formula I and the average size of the particles is no greater than about 500 nm, or no greater than 200 nm.
  • a method of treating a disease or condition characterized by undesirable cellular proliferation or hyperproliferation is provided.
  • a compound of formula (I) is administered to an individual in need thereof in an amount sufficient to treat a disease or condition characterized by undesired cellular proliferation or hyperproliferation.
  • the invention provides method of manufacture of a medicament containing the compounds and compositions having formula I. rThe medicament may be useful in the treatment of conditions as described herein. Further, the compositions described herein (including pharmaceutical compositions), are also intended for use in the manufacture of a medicament for use in treatment of the conditions and, in accordance with the methods, described herein.
  • the invention provides benzoquinone ansamycins and compositions thereof, and further provides methods for using these novel compounds as single-agent and, in combination therapies with known compounds or in combinations of two or more of the compounds of formula (I) for the treatment of cancer and/or other diseases or conditions characterized by undesired cellular hyperproliferation.
  • the present invention relates to compounds of the formula I as well as pharmaceutically-acceptable salts and prodrugs thereof, hereinafter referred to as the active compounds derivatized from ansamycins or as compounds of formula (I).
  • the invention comprises compounds of formula (I)
  • W represents: O or N-OH, N-O-COR 10 , or N-O-X-Rn; wherein
  • X represents substituted or unsubstituted (Ci-Cio) alkyl or (Ci-Cio) alkenyl or (C ⁇ -Cio) aryl;
  • Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(Rs)(R 9 ), N(Rs)(R 9 ), CO 2 R 1 Oj wherein Rg and R9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (C 1 -C 20 ) alkyl, optionally substituted (C 2 -C20 heteroalkyl, optionally substituted (C 2 -C20) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalky
  • R 5 is indepently selected from the group consisting of optionally substitated (C1-C 20 ) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C 2 - C 2 Q) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C 2 - C20) alkynyl, optionally substituted (Ce-C 2 O) aryl, optionally substituted (C 3 -C 20 ) heteroaryl, optionally substituted (C 7 -C 20 ) arylalkyl, optionally substituted (C 4 -C 2O ) heteroarylalkyl, optionally substituted (C 3 -C 2O ) cycloalkyl, optionally substituted (C 2 - C20) cycloheteroalkyl, N(R 8 )(R 9 ), -OR, ⁇ !
  • R 5 is NH-OH 5 NH-O-COR 10 , or NH-O-X-R 1 1 , wherein X, R 1 0 and Rj ] are defined as the above
  • Rn and R5 incorporate one or more OfR 8 , R 9 . or R] 0 , that each occurence of R 8 , R9, or R 10 may be independently selected and may be the same or different from other occurrences Of R 8 , R 9 , and R 10 .
  • W may be selected from N-OH, N-O-COR] 0 , or N-O-X-Rn
  • R5 may selected from the group consisting OfN(R 8 )(Rp); -OR ]0 , -SR 1 0, -N(Rg)-C(O)R 10 , - N(Rs)-C(O)-OR 10 , -N(Rg)-C(O)-N(R 8 )(R 10 ), -N(Rs)-C(S)OR 10 , -N(Rg)-C(S)-OR 10 , and - N(Re)-C(S)-N(Re)(R 1 O), and Rg 3 R9 and R 10 , Rn, X as defined above and are independently selected.
  • R 5 may be selected from the group consisting of N(R 8 )(R 9 ); -OR 10 , -SR 10 , -N(Rg)-C(O)R 10 , -N(Rg)-C(O)-OR 10 , -N(Rg)-C(O)-N(R 8 )(R, 0 ), - N(Rs)-C(S)OR 10 , -N(Rg)-C(S)-OR 1 0 , and -N(Rs)-C(S)-N(R 8 )(R 1 o).
  • R 5 may be selected from N(R 8 )(R 9 ), and W is selected from N-O-COR 10 .
  • R$ may be selected from N(R 8 )(R 9 ), and W is selected from N-O-X-Rn.
  • R5 may be NH 2
  • W may be selected from N-OH, N-O-X-Rn.
  • R5 is NH 2
  • W may be selected from N-OH, N-O-X- R 11 .
  • R 5 is OCH 3
  • W may be selected from N-OH, N- O-X-R ⁇ .
  • halo refers to fluoro, chloro, bromo or iodo.
  • (C1-C 20 ) alkyl refers to an alkyl, substituted straight or branched chain alkyl or alkylenyl group, having from 1-20 carbon atoms.
  • the alkyl group has, for example, 1-10 carbon atoms.
  • alkyl group examples include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 1 -methylpentyl, 4- methylpentyl, heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl, 3-ethylpentyl, octyl, 2- methylheptyl, 6-methylheptyl, 2-ethylhexyl, 2-ethyl-3 -methylpentyl, 3-ethyl-2-methylpentyl, nonyl, 2-methyloctyl, 7-methyloctyl, 4-ethylheptyl, 3-ethyl-2-methylhexyl., 2-ethyl-l
  • (C 2 -C 20 ) alkenyl represents an alkenyl group, having from 2 to 20 carbon atoms, and may be a straight or branched chain group, natural or unnatural fatty acid. It may have 1 or more double bonds, for example, from 2 to 6, double bonds.
  • Examples of such groups include the vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 8-nonenyl, 1- nonenyl, 1-decenyl, 9-decenyl, 8-tridecenyl, cis-8-pentadecenyl, trans-8-pentadecenyl, 8- heptadecenyl, 8-heptadecenyl, 8,11-heptadecadieyl, 8,11,14-heptadecatrienyl,
  • (C 1 -Cs) alkoxy refers to an alkoxy group with one to eight carbon alkyl groups, and the alkyl moiety thereof generally corresponds to the Ci-C 2O alkyl groups described above and can be selected therefrom.
  • alkoxy groups are those derived from straight or branched chain lower alkyl groups with 1 -8 carbon atoms, and include, for example, methoxy, ethoxy n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, cyclohexyloxy, n-heptyloxy, n-octyloxy and 2-ethylhexyloxy.
  • (C 3 -C 2O ) aryl refers to an aromatic or heteroaromatic ring, including by way of example, phenyl, naphthyl, furanyl, imidazolyl and thionyl.
  • the aryl ring can be substituted with substituents selected from the group consisting of halo, Ci- Ce alkyl or C 1 -Ce alkoxy, or alkyl amino.
  • Examples include 4-chlorophenyl, 2 -fluorophenyl, 4-fluorophenyl, 3-flouro ⁇ henyl, 4-methylphenyl, 4-ditrifluorohenyl, 2-ethylphenyl, 3-n-propylphenyl, 4- isopropyl-phenyl, 4-n-butylphenyl, 4-t-butylphenyl, 4-sec-butylphenyl, 4- dimethylaminophenyl, 3,4-dimethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4- isopropoxyphenyl, 3-isobutoxyphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-furan, 2-pyridyl, 3- pyridyl, 2-thiophenyl, 3-thiophenyl, 1 -naphthyl, 2-naphthyl, 2-indolyl, and the like, and the aryl mo
  • heterocyclic group examples include alicyclic heterocyclic groups, aromatic heterocyclic groups, and the like, such as pyridonyl, pyrrolidonyl, uracilyl, dioxolnyl, pyrrolyl, tetrazolyl, pyrrolidinyl, thienyl, morpholino, thiomorpholino, piperazinyl, pyrazolidinyl, piperidino, pyridyl, hompiperazinyl, pyrazolyl, pyrazinyl, indolyl, isoindolyl, furyl, piperidyl, quinolyl, phthalazinyl, imidazolidinyl, imidazolinyl, pyrimidinyl, and the like.
  • heterocylic group moiety in the carbonyl bound to a heterocyclic ring has the same meaning as defined above, and examples of the entire group containing carbonyl include furoyl, thenoyl, nicotinoyl, isonicotinoyl, and the like.
  • Examples of the nitrogen containing heterocyclic group formed by R 8 and R 9 with the adjoining N and the nitrogen containing heterocyclic group formed by R 8 and R 9 with the adjoining N include pyrrolidyl, morpholiiio, thiomorpholino, piperazinyl, pyrazolidinyl, pyrazolinyl, piperidino, homopiperazinyl, indolinyl, isoindolinyl, perhydroazepinyl, perhydroazocinyl, indolyl, isoindolyl, and the like.
  • OR 10 , SR 10 and N(R 8 )(R 9 ) refer to the alkyl groups substituted with oxygen, sulfur and nitrogen.
  • Some examples of the alkyl group substituted with oxygen, sulfur or nitrogen include methoxymethyl, ethoxymethyl, propoxymethyl, n-butoxymethyl, 2- methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 3-methoxypro ⁇ yl, 3-ethoxypropyl, 3- propoxypropyl, 4-methoxybutyl, 4-propoxybutyl, dimethoxymethyl, 2,2-dimethoxyethyl, diethoxymethyl, 2,2-diethoxyethyl, dipropoxymethyl, 2,2-dipropoxyethyl, methylthiomethyl, ethylthiomethyl, propylthiomethyl, n-butylthiomethyl, 2-methylthiolethyl, 2-ethylthiolethyl, 2-propylthiole
  • COR 1 o refers to carboxylic acid, ester, or amide, wherein R 1 o generally correspond to the C 1 -C 20 alkyl groups discussed above and can be selected therefrom.
  • alkylamino group are those derived from hydrogen, and straight or branched chain lower alkyl groups with 1 -6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and hexyl groups.
  • Suitable pharmaceutically-acceptable salts of compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically-acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, acetic acid, citric acid, tartaric acid, phosphoric acid, carbonic acid, and the like.
  • a pharmaceutically-acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, acetic acid, citric acid, tartaric acid, phosphoric acid, carbonic acid, and the like.
  • pharmaceutically-acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically-acceptable base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ammonia, alkylamines, and the like.
  • a pharmaceutically-acceptable base such as lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ammonia, alkylamines, and the like.
  • X represents substituted or unsubstituted (C]-Cg) alkyl or alkenyl or (Cg-Cio) ar yl > wherein R 1 i represents hydrogen, hydroxyl, halogen, cyanide, or CON(R 8 )(R 9 ), N(R 8 )(R 9 ), CO 2 R 1 o; wherein R 8 and R 9 are each independently selected from the group consisting of hydrogen, (Ci-C 8 ) alkyl, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl and (C 2 -Cz) alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio,
  • N(R 8 )(R 9 ) is selected from the group consisting of methoxyamine, O-ethylhydroxyamine, O- allylhydroxyamine, 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine O-t-butylhydroxylamine, O-(Carboxymethyl)hydroxylamine, hemihydrochloride, O-aminohomoserine, aminoguanidine, 2-(aminooxy)-N,N-dimethylethanamine, O-phenylhydroxylamine, O- benzylhydroxylamine, hydrazine, methylhydrazine, 1,1-dimethy .hydrazine, acethydrazide, 2- hydroxyethylhydrazine, semicarbazide, 3-hydrazinopropanenitrile,carbohydrazide, 1- piperidinamine, butanohydrazide, 4-morpholinamine, phenylhydrazine; ammonia
  • the invention provides compounds of formula (I) wherein
  • W is N-O-H or N-O-COR 1 O, wherein R 1 o is selected from the group consisting of (Ci-Cs) alkyl, amino(Ci-C 8 ) alkyl, dimethylamino (Ci-Cs) alkyl, cyclo (Cj-C 8 ) alkyl, phenyl and naphthyl; R 1 and R- together form a single bond, R 3 , R 4 , R ⁇ , R 7 , Yi, Y 2 and Y3 are each hydrogen; and,
  • R 5 is OR 14 or N(R 8 )(R 9 ) wherein: i. when R 5 is OR 14 , R 14 is hydrogen or optionally substituted (C]- C 8 )alkyl; ii. when R5 is N(R 8 )(R 9 ), R 8 is hydrogen and R 9 is selected from the group consisting of (Ci-C 8 ) alkyl, (Ci-C 8 ) alkoxy, (C 3 -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl and (C 2 -Cs) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, alkylthio, optionally substituted amino, hydroxyl, (Q-Cs) alkoxyl, carboxyl, amidino, acylamino, (C 2 -C
  • R 5 when R 5 is N(R 8 )(R 9 ), Rg and R9, together with the nitrogen to which they are attached, may form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino and acylamino; or iv.
  • R 5 is selected from -OR 10 , -SR] 0 , -N(R 8 )-C(0)R ⁇ o, -N(R 8 )- C(O)-OR 10 , -N(Rs)-C(O)-N(R 8 )(R 10 ), -N(Rg)-C(S)OR 10 , -N(Rg)-C(S)-OR 10 , - N(Rg)-C(S)-NR 8 R 1 O (wherein Rg and R 1 o are independently selected from the group consisting of H, optionally substituted (C1-C 20 ) alkyl, optionally substituted (C1-C 20 ) heteroalkyl, optionally substituted (C2-Q20) alkenyl, optionally substituted (C2-C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl
  • W is N-O-H or N-O-COR 1 0, wherein R 1 o is selected from the group consisting of (C)-C 8 ) alkyl, amino (Ci-C 8 ) alkyl, dimethylamino (Ci-C 8 ) alkyl, cyclo (C3-C8) alkyl, phenyl and naphthyl; R 1 and R 2 together form a single bond; R 3 , R ⁇ , R 7 , Yi, Y 2 and Y 3 are each hydrogen; R 4 is fluoro, or , and
  • R 5 is OR] 4 or N(R 8 )(R 9 ) wherein i. when R 5 is OR) 4 , Rj 4 is hydrogen or optionally substituted (Ci-C 8 ) alkyl; ii. when R 5 is N(R 8 )(R 9 ), R 8 is hydrogen and R9 is selected from the group consisting of (Ci-Cs) alkyl, (C 1 -C 8 ) alkoxy, (C3-C 8 ) cycloalkyl, (Qz-Cs) alkenyl and (C 2 -C 8 ) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, optionally substituted
  • R 8 and R 9 together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino and acylamino; iv.
  • R 5 is selected from -OR 10 , -SR 10 , -N(R 8 )-C(O)R 10 , -N(R 8 )- C(O)-OR 10 , -N(Rg)-C(O)-N(R 8 )(R 10 ), -N(Rs)-C(S)OR 10 , -N(Rs)-C(S)-OR 10 , - N(Rs)-C(S)-N(R 8 )(R 1 O )
  • R 8 and R 10 are independently selected from the group consisting of H, optionally substituted (C1-C 20 ) alkyl, optionally substituted (C1-C 20 ) heteroalkyl, optionally substituted (C2-C 20 ) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C2-C 20 ) alkynyl, optionally substituted aryl, optionally substituted heteroaryl,
  • C. W is N-O-H or N-O-COR 10 , wherein R 1 o is selected from the group consisting of (Q-C 8 ) alkyl, amino(Ci-Cs) allcyl, dimethylamino (Ci-C 8 ) alkyl, cyclo (Ci-Cs) alkyl, phenyl and naphthyl; R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , Vi, Y 2 and Y 3 are each hydrogen; and
  • R 5 is OR
  • R 5 is N(R 8 )(Rp)
  • Rg and R 9 together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-Cs) alkylthio, substituted or unsubstituted amino, hydroxyl, (C 1 -C 8 ) alkoxyl, carboxyl, amidino and acylamino; or iv.
  • R 5 is selected from -OR 10 , -SR 10 , -N(Rg)-C(O)R 10 , -N(R 8 )- C(O)-OR 10 , -N(Rs)-C(O)-NR 8 R 10 , -N(Rg)-C(S)OR 1 0 , -N(R 8 )-C(S)-OR, o , - N(Rs)-C(S)-NRsR 1 O (wherein R 8 and R 1 o are selected from the group consisting of H, optionally substituted (C 1 -C 20 ) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted ary
  • W is N-O-H or N-O-COR 10 , wherein Rj 0 is selected from the group consisting of (Ci-Cs) alkyl, amino (Ci-Cs) alkyl, dimethylamino (Ci-C 8 ) alkyl, cyclo (C 3 -C 8 ) alkyl, phenyl and naphthyl; R u R 2 , R 3 , R 6 , R 7 , Yi, Y 2 and Y 3 are each hydrogen; R 4 is fhioro or OR] 0 and
  • R 3 is OR 14 or N(R 8 )(R 9 ) wherein: i. when R 5 is OR] 4 , Rj 4 is hydrogen or optionally substituted (C)-Cs) alkyl; ii. when R 5 is N(R 8 )(R 9 ), R 8 is hydrogen and R 9 is selected from the group consisting of (Ci-C 8 ) alkyl, (Ci-Cs) alkoxy, (C 3 -Cs) cycloalkyl, (C 2 -C 8 ) alkenyl and (C 2 -C 8 ) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-Cs) alkylthio, optionally substituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino, acyla
  • R 5 is N(R 8 )(R 9 )
  • R 8 and R 9 together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C]-Cs) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; or iv.
  • R 5 is selected from -OR 10 , -SR 10 , -N(Rg)-C(O)R] 0 , -N(R 8 )- C(O)-OR 10 , -N(Rg)-C(O)-N(R 8 )(R 1 O), -N(Rg)-C(S)OR 10 , -N(Rs)-C(S)-OR 10 , - N(Rg)-C(S)-N(R 8 )(R 1 O) (wherein Rg and R 1 o are independently selected from the group consisting of H, optionally substituted (C1-C 20 ) alkyl, optionally substituted (C1-C 20 ) heteroalkyl, optionally substituted (C 2 -C 20 ) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted hetero
  • R 5 is NH-O-X-R 1 i, wherein X and R 1 1 is defined as aboveE.
  • W is N-O-X-Rn; wherein X represents substituted or unsubstituted (Ci-Ci 0 ) alkyl or (Ci-Cio) alkenyl or (Ce-Ci 0 ) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R 8 )(Rg), N(Rg)(Rg), CO 2 R 1 0, wherein Rg and R9 are independently selected from the group consisting of H, optionally substituted (C]-C 2 O) alkyl, optionally substitated (C 2 -C20) heteroalkyl optionally 7 substituted (C2-C20) alkenyl, optionally substituted (C 2 -C20) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted ary
  • R ⁇ and R 2 together form a single bond, Rj, R 4 , R O , R7, Yi, Y 2 and Y 3 are each hydrogen;
  • R 5 is OR i4 or N(Rg)(R 9 ), wherein i. when R 5 is OR] 4 , R] 4 is hydrogen or optionally substituted (C]-C 8 ) alkyl; ii. when R 5 is N(R 8 )(R ⁇ , R 8 is hydrogen and R 9 is selected from the group consisting Of (Ci-C 8 ) alkyi, (C 1 -Cs) alkoxy, (C3-C8) cycloalkyl, (C 2 -Cs) alkenyl and (C 2 -Cs) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1 -C 8 ) alkylthio, optionally substituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino, acylamin
  • R 5 is N(Rs)(Rg), R 8 and R 9 , together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C]-Cs) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino and acylamino; or iv.
  • R 5 is selected from -OR 1 0 , -SR 1 0 , -N(R 8 )-C(O)R 10 , -N(R 8 )- C(O)-OR 10 , -N(Rs)-C(O)-N(R 8 )(R 10 ), -N(Rj)-C(S)OR 10 , -N(Rs)-C(S)-OR 10 , - N(Rs)-C(S)-N(R 8 )(R 1 0) (wherein R 8 , and R 1 o are independently selected from the group consisting of H, optionally substituted (Q-C 20 ) alkyl, optionally substituted (C 1 -C 20 ) heteroalkyl, optionally substituted (C 2 -C 20 ) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted aryl
  • W is N-O-X-Rn; wherein X represents substituted or unsubstituted (Ci -C 10 ) alkyl or (Ci-Cio) alkenyl or (C ⁇ -Cio) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R 8 )(Rg), N(R 8 )(R 9 ), CO 2 R 1 O, wherein R 8 and R 9 are independently selected from the group consisting of H, optionally substituted (C 1 -C 20 ) alkyl, optionally substitated (C 2 -C20) heteroalkyl optionally 7 substituted (C 2 -C 20 ) alkenyl, optionally substituted (C2-C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl
  • R 5 is OR H or N(R 8 )(R?) wherein i. when R 5 is R 14 O, R 14 is hydrogen or optionally substituted (Ci-Cs) alkyl; ii. when R5 is N(Rg)(R ⁇ , Rg is hydrogen and R9 is selected from the group consisting of (Ci-Cs) alkyl, (Ci-C 8 ) alkoxy, (C3-C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl and (C 2 -C 8 ) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, optionally substituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino, acylamino, (C 2
  • R 5 is N(R 8 )(R ⁇ , Rs and R 9 , together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; or iv.
  • R 5 is selected from -OR 10 , -SR 10 , -N(Rs)-C(O)R 10 , -N(R 8 )- C(O)-OR 10 , -N(Rs)-C(O)-N(R 8 )(R 10 ), -N(Rg)-C(S)OR 10 , -N(Rg)-C(S)-OR 10 , - N(Rs)-C(S)-N(Rg)(R 1 0) (wherein R 8 and R 1 o are independently selected from the group consisting of H, optionally substituted (C 1 -C 20 ) alkyl, optionally substituted (C 1 -C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C 2 -C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl
  • W is N-O-X-Ru; wherein X represents substituted or unsubstituted (Ci- Cio) alkyl or (Ci-C 1 o) alkenyl or (C ⁇ -Cio) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R 8 )(R 9 ) 5 N(R 8 )(R 9 ), CO 2 R 1 O, wherein R 8 and R 9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (C 1 -C 20 ) alkyl, optionally substitated (C2-C20) heteroalkyl optionally 7 substituted (C 2 -C 20 ) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally
  • R 4 is hydrogen or optionally substituted (Ci-C 8 ) alkyl; ii. when R 5 is N(R 8 )(R 9 ), R 8 is hydrogen and R 9 is selected from the group consisting of (Ci-C 8 ) alkyl, (Ci-C 8 ) alkoxy, (C 3 -C 1 ) cycloalkyl, (C 2 -C 8 ) alkenyl and (C 2 -C 8 ) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C]-C 8 ) alkylthio, optionally substituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino, acylamino, (C 2 -Ce) heterocycloalkyl and (C
  • R 5 is N(R 8 )(R 9 ) 3 R 8 and R 9 , together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-Cs) alkyl thio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; iv.
  • R 5 is selected from -OR 10 , -SR 10 , -N(Rg)-C(O)R 10 , -N(Rg)- C(O)-OR 10 , -N(Rg)-C(O)-N(R 8 )(R 10 ), -N(Rs)-C(S)OR 10 , -N(Rs)-C(S)-OR 10 , - N(Rs)-C(S)-N(Rg)(R 1 O )
  • R 8 , and R 10 are independently from the group consisting of H, optionally substituted (Ci-C 20 ) alkyl, optionally substituted (C 1 -C 20 ) heteroalkyl, optionally substituted (C 2 -C 20 ) alkenyl, optionally substituted (C 2 -C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted aryl, optionally substituted hetero
  • H. W is N-O-X-R 1 1; wherein X represents substituted or unsubstituted (Ci- C 10 ) alkyl or (CJ -CJ O ) alkenyl or (C 6 -Ci O ) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R 8 )(R 9 ), N(R 8 )(R 9 ), CO 2 R 10 , wherein R 8 and R 9 are independently selected from the group consisting of H, optionally substituted (C 1 -C 20 ) alkyl, optionally substituted (C 2 -C 20 ) heteroalkyl optionally 7 substituted (C 2 -C 20 ) alkenyl, optionally substituted (C2-C 20 ) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylal
  • R 14 is hydrogen or (Ci-C 8 ) alkyl; ii. when R 5 is N(R 8 )(R 9 ), R 8 is hydrogen and R 9 is selected from the group consisting of (Ci-Cs) alkyl, (Ci-C 8 ) alkoxy, (C J -C 8 ) cycloalkyl, (C 2 -C 8 ) alkenyl and (C 2 -C 8 ) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, optionally substituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino, acylamino, (C 2 -Ce) heterocycloalkyl and (C 2 -Ce) hetero
  • R5 is N(Rg)(Rg)
  • Rs and R 9 together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; or iv.
  • R 5 is selected from -OR 1 0, -SR 10 , -N(Rs)-C(O)R 1 0, -N(R 8 )- C(O)-OR 10 , -N(Rg)-C(O)-N(R 8 )(R 1 0 ), -N(Re)-C(S)OR 10 , -N(Rs)-C(S)-OR 10 , - N(Rg)-C(S)-N(Re)(R 1 O)
  • R 8 and R 10 are independently selected from the group consisting of H, optionally substituted (C 1 -C 2O ) alkyl, optionally substituted (C 1 -C 20 ) heteroalkyl, optionally substituted (C 2 -C 20 ) alkenyl, optionally substituted (C2-C 20 ) heteroalkenyl, optionally substituted (C 2 -C 20 ) alkynyl, optionally substituted aryl, optionally substituted heteroaryl,
  • compounds of the invention are selected from the group consisting of compounds of the formula ⁇ , wherein
  • W represents: O or N-OH, or N-O-COR 10 , or N-O-X-R n ;
  • X represents substituted or unsubstituted (Ci-Cio) alkyl or (C I -CJ O ) alkenyl or (Ce- C 1 0) aryl;
  • Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(Rg)(R 9 ), N(R 8 )(R ⁇ ,
  • R 8 and R 9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (CJ-C 20 ) alkyl, optionally substituted (C 2 - C20) heteroalkyl optionally 7 substituted (C2-C20) alkenyl, optionally substituted (C 2 -C20) heteroalkenyl, optionally substituted (C 2 -C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or R 8 is selected from the group consisting of H, optionally substituted C 1 -C ⁇ alkyl, optionally substituted Cs-Cs aryl, and optionally substituted C 5 -C 8 heteroaryl, or R 8 , together with R9, forms an optionally substituted 4-7 membered heterocyclic or carbo
  • R] R 2 , R3, Re, R7, Yi, Y2 and Y3 are each hydrogen,
  • R 4 is OH or OR 1 o wherein R 1 o is selected (Ci-Cs) alkyl, amino (Ci-C 8 ) alkyl, protected amino (Ci-C 8 ) alkyl, phenyl and naphthyl; and
  • R 5 is independently N(R 8 )(R 9 ) wherein R 8 is hydrogen and R 9 is selected from hydrogen, (Ci-Ce) alkyl, (C 2 -Cs) alkenyl and (C 2 -Cs) alkynyl; wherein said alkyl, alkenyl and alkynyl groups are optionally substituted and said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C 8 ) alkylthio, optionally substituted amino, hydroxyl, (Ci-C 8 ) alkoxyl, carboxyl, amidino, acylamino, (C 2 -CO) heterocycloalkyl and (C 2 -Ce) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; or R 5 is N(Rg)(R 9 ) wherein Rs and R
  • R ⁇ and R 2 form a single bond;
  • R 3 , R 6 , R 7 , Yi, Y 2 and Y 3 are each H;
  • R 4 is hydroxyl;
  • R 5 is -OCH 3 (also referred to as "OMe” or "methoxy");
  • W is defined as described herein. In particular embodiments, W is as described in Table 1. In some embodiments, W is as described in Table 3. In certain embodiments, W is N-OH, N-O-COR 1 o, or N-O-X-Rn, wherein X, R 1 o and Rn are as described herein. In some embodiments, W is N-O-COR 10 , or N-O-X-R 1 i • In other embodiments, W is N-OH or N-O- COR 1 o. In certain embodiments, W is N-OH or N-O-X-R 1 i - In particular embodiments, W is N-O-COR 1 o. In some embodiments, W is N-O-X-Rj i . In others, W is N-OH.
  • R 1 and R 2 form a single bond;
  • R 3 , R 6 , R 7 , Yi, Y2 and Y 3 are each H;
  • R 4 is O-R 1 0, wherein R 1 ois hydrogen, acetyl, alkyl, -C(O) R 1 o (wherein R 1 o is as described herein), or aryl; and
  • R 5 and W are defined as described herein.
  • W is as described in Table 1.
  • W is as described in Table 3.
  • W is as defined in Table 1 or Table 3.
  • W is N-OH, N- O-COR 10 , or N-O-X-Rn, wherein X, R 1 o and Rn are as described herein.
  • W is N-O-COR 1 o, or N-O-X-R 1 1 .
  • W is N-OH or N-O- CORjo-
  • W is N-OH or N-O-X-R] 1 .
  • W is N-O-COR 1 o.
  • W is N-O-X-R 1 1 . In others, W is N-OH. In some embodiments, R 5 and W are as described in Table 3. In certain embodiments, R 5 is as described in Table 3. In some embodiments, R 5 , R 1 • and W are, independently, as defined in Table 3. In some embodiments, Rp is hydrogen, acetyl, or -C(O)R 1O (wherein R 1 o is as described herein). In certain embodiments, R 1 - is hydrogen, acetyl, or -C(O)R 1 O wherein R 1 o is optionally substutited alkyl. In particular embodiments R 1 o is unsubstutited alkyl.
  • R 1 o is a C1-C10 alkyl, C 6 -C 20 alkyl, CiO-Ci 8 alkyl, C12-C 1 8 alkyl or C 15 alkyl.
  • Rp is hydrogen or acetyl.
  • R]- is hydrogen.
  • R 1 • is acetyl.
  • compounds of the invention are selected from the compounds listed in Table 2, below:
  • the pharmacologically acceptable salts of formula (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like.
  • the acid addition salts include inorganic acid salts (for example, hydrochloride, hydrobromide, sulfate, phosphate, and the like), and organic acid salts (for example, formate, acetate, oxalate, benzoate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, succinate, lactate, and the like).
  • Examples of the metal salts include alkali metal salts (for example, lithium salt, sodium salt, potassium salt, and the like), alkaline earth metal salts (for example, magnesium salt, calcium salt, and the like), aluminum salts, zinc salts, and the like.
  • Examples of the ammonium salts include salts with ammonium, tetramethylammonium, and the like.
  • Examples of the organic amine addition salts include addition salts with morpholine, piperidine, and the like.
  • Examples of the amino acid addition salts include addition salts with glycine, phenylalanine, aspartic acid, glutamic acid, lysine, and the like.
  • a method of preparing the inventive compounds is provided.
  • the compounds of the present invention are generally prepared using geldanamycin as a starting material.
  • Compound (I) may contain various stereoisomers, geometric isomers, tautomeric isomers, and the like. All of possible isomers and their mixtures are included in the present invention, and the mixing ratio is not particularly limited.
  • the synthetic method of formula (I) mainly comprises 17-substituted geldanamycin production (Step 1), oxime formation (Step 2), acylation/carbamoylation/alkoxycarbonylation (Step 3), alkylation (Step 3), amidation/esterification (Step 4), and each compound of interest is produced by combining these reaction steps depending on the object.
  • Step 1 The general procedure for preparation of 17-substituted geldanamycin derivatives is shown in Step 1 and the geldanamycin derivatives can be prepared based on procedures known in the art, such those found in U.S. patent No. 4,621,989.
  • Compound (B) is prepared from geldanamycin by such known or modified procedures.
  • Formula (Ia) can be prepared by oxime formation of the quinone carbony] of geldanamycin from geldanamycin and its derivatives that can be prepared from the related starting materials.
  • formula (Ia) can be prepared by allowing compound (A) or compound (B) to react with compound (II) represented by the following formula H 2 N-O-R B a (II) (wherein Rja is a group in which COR 10 wherein R 1 o has the same meaning as described above) or an acid addition salt thereof.
  • reaction solvents include, but are not limited to, pyridine, chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, and the like, which may be used either alone or as a mixture thereof.
  • An exemplary solvent is pyridine.
  • suitable acids include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like. The acids may be used in an amount of 0.1 to 10 equivalents based on compound (A) or (B)..
  • the reaction can be carried out in the presence of a base, for example, an amine (e.g., pyridine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, or the like), an alkali metal, carbonate, or bicarbonate (e.g., sodium carbonate, potassium carbonate, or the like), in an amount of 1 equivalent or more based on the acid addition salt of formula (II).
  • a base for example, an amine (e.g., pyridine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, or the like), an alkali metal, carbonate, or bicarbonate (e.g., sodium carbonate, potassium carbonate, or the like), in an amount of 1 equivalent or more based on the acid addition salt of formula (II).
  • pyridine is used as both the amine and
  • Compound (Ib) can be prepared by the conversion of compound (A) or (B) to an oxime compound (C). The resulting hydroxy 1 group is subjected to acylation, carbamoylation, or alkoxycarbonylation.
  • Compound (C) can be prepared by allowing compound (A) or (B) to react with hydroxylamine or an acid addition salt thereof according to Step 1.
  • Compound (Ib) can be prepared by allowing compound (C) to react with compound (III) represented by the following formula R 1 o COQ (III) (wherein R] o has the same meaning as defined above), or with compound (IV) represented by the following formula R 1 o'NCO (IV) (wherein R 1 o' represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted pyridyl), in the presence of a base.
  • compound (III) represented by the following formula R 1 o COQ (III) (wherein R] o has the same meaning as defined above)
  • compound (IV) represented by the following formula R 1 o'NCO (IV) wherein R 1 o' represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted pyridyl
  • reaction solvent dichloromethane, ether, THF, DMF, and the like, may be used alone or as a mixture thereof.
  • base amines (for example, pyridine, triethylamine, diisopropylethylamine, or the like) may be used in an amount of 0.1 equivalent or more, for example, , 1 to 10 equivalents, based on compound (III) or (IV).
  • Compound (III) or (IV) is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, based on compound (C).
  • reaction is carried out at a temperature of -80 to 100° C, for example -60 to 0° C, when compound (III) is used, or at a temperature of 0 to 80° C. when compound (IV) is used. Each reaction completes after 10 minutes to 48 hours.
  • Compound (Ic) can be prepared by alkylation of the hydroxyl group of compound (C). The reaction may be carried out by allowing compound (C) to react with compound (V) represented by the following formula HOR 1 o (V) (wherein R 1 o has the same meaning as defined above) in the presence of a condensing agent.
  • reaction solvent toluene, THF, dichloromethane, and the like, may be used alone or as a mixture thereof.
  • condensing agent trivalent phosphorous compounds (for example, triphenylphosphine, tributylphosphine, or the like) and azo compounds (for example, diethyl azodicarboxylate (DEAD), 1 , 1 -(azodicarbonyl)di ⁇ iperidine, and the like) may be used alone or as a mixture thereof.
  • DEAD diethyl azodicarboxylate
  • Each of compound (C) and the condensing agent is used in an amount of 1 equivalent or more, for example 1 to 5 equivalents, based on compound (G).
  • the reaction is carried out at a temperature of -20 to 80° C, e.g., 0 to 30° C, and the reaction completes after 5 minutes to 48 hours.
  • Compound (Ic) can be prepared by converting compound (A) or (B) into oxime compound (D) in which a carboxyl group is introduced, and then the carboxyl group is subjected to amidation or esterif ⁇ cation (Step 3) [Where X-Rl 1; wherein X represents substituted or unsubstituted (Ci-Cio) alkyl or (Ci-C ⁇ o) alkenyl; R 1 i represents hydrogen, hydroxyl, halogen, cyanide, or CON(R S )(RO, N(R 8 )(R 9 ) or CO2R10, (wherein R 8 and R9 and R 1 o have the same meaning as defined above)].
  • Compound (D) can be prepared by allowing compound (A) or (B) to react with compound (VI) represented by the following formula H 2 N-O-X-CO 2 H (VI) (wherein X has the same meaning as defined above) or an acid addition salt thereof.
  • Compound (Ic) can be prepared by allowing compound (D) to react with compound (VII) represented by the following formula HNR 8 R9 (VII) (wherein R 8 and R9 have the same meaning as defined above) or an acid addition salt thereof, or with a compound (VIII) represented by the following formula HOR 10 (VIII) (wherein R 1 o has the same meaning as defined above), in the presence of a condensing agent.
  • VII compound represented by the following formula HNR 8 R9 (VII) (wherein R 8 and R9 have the same meaning as defined above) or an acid addition salt thereof, or with a compound (VIII) represented by the following formula HOR 10 (VIII) (wherein R 1 o has the same meaning as defined above), in the presence of a condensing agent.
  • EDCI l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • DCC N,N'-dicyclohexylcarbodiimide
  • l,r-carbonyldiimidazole or the like
  • an additive agents such as N-hydroxysucciniimide (HONSu), 4-(dimethylamino) pyridine (DMAP), 1- hydroxybenzotriazole hydrate (HOBt), or the like, in an amount of 0.1 to 5 equivalents based on compound (D).
  • reaction solvent dichloromethane, ether, THF, DMF, and the like, may be used alone or as a mixture thereof.
  • an acid addition salt of compound (VII) the reaction can be carried out in the presence of a base, such as an amine.
  • a base such as an amine.
  • amines include, but are not limited to, pyridine, triethylamine, diisopropylethylamine, or the like.
  • triethylamine is used, in an amount of 1 equivalent or more, for example, 1 to 10 equivalents, based on the acid addition salt of compound (VII).
  • Each of compound (VII) or an acid addition salt thereof or compound (VIII) and the condensing agent may be used in an amount of 1 equivalent or more, e.g., 1 to 5 equivalents, based on compound (D).
  • the reaction is carried out at a temperature of -20 to 80° C, for example, 0 to 40° C. Each reaction completes after 10 minutes to 48 hours.
  • tissue includes the blood and blood forming system including platelets, blood vessel wall, and bone marrow; the cardiovascular system including heart and vascular system; digestive and excretory system including alimentary tract, biliary tract, kidney, liver, pancreas and urinary tract; the endocrine system including adrenal gland, kidney, ovary, pituitary gland, renal gland, salivary gland, sebaceous gland, testis, thymus gland and thyroid gland; the musclar system; reproductive system, including breast, ovary, penis and uterus; the respiratory system including bronchus, lung and trachea; skeletal system including bones and joints; tissue, fiber, and integumentary system including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hair follicle, ligament, bone marrow, melanin, me
  • Compounds of the present invention often have a strong binding affinity for Hsp90.
  • a preferred method of determining the relative binding affinities is by comparing the concentration of the test compound at which 50% of the target -protein is bound (otherwise known as the ICso concentration level) in a competitive binding assay, the performance of which is routine for the skilled artisan.
  • the efficacy of the compounds of formula (I), or compositions thereof (including pharmaceutical compositions), as described herein, for use in the treatment of the diseases and/or conditions described herein can be determined using routine in vitro assays and in vivo animal models known to the one of skill in the art.
  • efficacy with respect to the possible use of the compounds for the treatement of cancer can utilitze well known in vitro assays for determining the cytotoxicty of particular compounds on certain types of cancer.
  • Numerous cancer cell lines and tumor models are availaiable to the skilled artisan, as, for example, the MX-I (human breast carcinoma) cell line described in Example 63.
  • Such in vitro assays and in vivo models can also be used to determine the efficacy of particular combinations of one or more of the compounds of formula (I) and/or additional combinations with other active agents described herein for use in the treatment of the conditions as described.
  • Geldanamycin analogs of Formula (I) in this invention can be used in accordance with the methods of the present invention to alter the function of hormone receptors, making it easier to inhibit the associated signal pathways using low levels of a second drug which targets the proteins involved in those signaling pathways. Such a combination therapy can be useful to reduce non-specific toxicity associated with therapy by reducing the level of the drug required.
  • the present invention provides compositions for treatment of individuals (e.g., mammals, etc.) in need thereof, comprising one or more of the compounds of formula (I) as described herein and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, preservatives, or other inactive ingredients, including combinations of two or more of the foregoing, known to skilled artisans and described further herein.
  • the composition comprises a single compound of formula (I).
  • the composition comprises at least 1 , at least 2, at least 3, or 2, 3, or 4 of the compounds of formula (I).
  • the compositions comprise a compound of formula (I), wherein the compound is a compound listed in Table 1 , Table 2, or Table 3.
  • the composition comprises a compound of Table 1.
  • the composition comprises a compound of Table 2.
  • the composition comprises a compound of Table 3.
  • compositions of matter that are formulations of one or more active drugs and a pharmaceutically-acceptable carrier.
  • the invention provides a composition for administration to an individual in need thereof, which may include a plurality of particles of the compound of formula I and a pharmaceutically acceptable carrier.
  • the average size of the particles is no greater than about 500 nm, no greater than 400 nm, no greater than 200 nm.
  • the average size of the particles is about 150 nm, about 200 nm, about 300 nm, about 350 nm, about 400 nm, about 450 nm, about 500 nm, from about 100 nm to about 550 nm, from about 150 nm to about 500 nm from about 150 nm to about 400 nm, from about 150 nm to about 350 nm, from about 150 nm to about 300 nm, from about 150 nm to about 250 nm; from about 200 nm to about 400 nm; or from about 200 nm to about 350 nm.
  • Average particle size can be determined by methods known to the skilled artisan, including such techniques as from the correlation function by using various algorithms using Photon Correlation Spectroscopy (PCS; Dynamic Light Scattering or Quasi-Elastic Light Scattering (QELS)). The particle size obtained by these techniques is comparable to the mean diameter determined by PCS.
  • PCS Photon Correlation Spectroscopy
  • QELS Quasi-Elastic Light Scattering
  • the compounds of the present invention may be administered as a composition, for example, as a pharmaceutical composition containing the compounds and a pharmaceutically-acceptable carrier or diluent.
  • the active materials can also be mixed with other active materials that do not impair the desired action and/or supplement the desired action.
  • the active materials, in accordance with the present invention may be administered by any acceptable route including, but not limited to, orally or parenterally ⁇ e.g., intravenously, intradermally, subcutaneously, intramuscularly, by an airborne delivery system, topically, etc.), in liquid or solid form.
  • composition unless clearly intended otherwise by the context of use, is inclusive of pharmaceutical compositions, whether or not explicitly so stated.
  • Oral compositions will generally include an inert diluent or an edible carrier. Such oral compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
  • the oral compositions may contain additional ingredients such as: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like
  • a lubricant such as magnesium stearate
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • tablets or pills may be coated with sugar, shellac, or other enteric coating agents.
  • a syrup may contain, in addition to the active ingredients, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically or veterinarally pure and non-toxic in the amounts used.
  • the active ingredient may be incorporated into a solution or suspension.
  • the solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents
  • antibacterial agents such as benzyl alcohol or methyl parabens
  • antioxidants such as ascorbic acid or sodium bisulfite
  • chelating agents
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • the pharmaceutical forms suitable for injectable use include sterile solutions, dispersions, emulsions, and sterile powders.
  • the final form should be stable under conditions of manufacture and storage. Furthermore, the final pharmaceutical form should be protected against contamination and should, therefore, be able to inhibit the growth of microorganisms such as bacteria or fungi.
  • a single intravenous or intraperitoneal dose can be administered. Alternatively, a slow long-term infusion or multiple short-term daily infusions may be utilized, typically lasting from 1 to 8 days. Alternate day dosing or dosing once every several days may also be utilized.
  • Sterile, injectable solutions may be prepared by incorporating a compound in the required amount into one or more appropriate solvents to which other ingredients, listed above or known to those skilled in the art, may be added as required.
  • Sterile injectable solutions may be prepared by incorporating the compound in the required amount in the appropriate solvent with various other ingredients as required. Sterilizing procedures, such as filtration, may then follow.
  • dispersions are made by incorporating the compound into a sterile vehicle which also contains the dispersion medium and the required other ingredients as indicated above.
  • exemplary methods include vacuum drying or freeze drying to which any required ingredients are added.
  • Suitable pharmaceutical carriers include sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide.per mole of castor oil; liquid acid; lower alkanols; oils such as corn oil; peanut oil, sesame oil and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrolidone) ; and the like, alone, or with suitable dispensing agents such as lecithin; polyoxyethylene stearate; and the like.
  • a suspending agent for example, sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrolidone)
  • the carrier may also contain adjuvants such as preserving stabilizing, wetting, emulsifying agents and the like together with the penetration enhancer.
  • adjuvants such as preserving stabilizing, wetting, emulsifying agents and the like together with the penetration enhancer.
  • the final form must be sterile and should also be able to pass readily through an injection device such as a hollow needle.
  • the proper viscosity may be achieved and maintained by the proper choice of solvents or excipients.
  • the use of molecular or particulate coatings such as lecithin, the proper selection of particle size in dispersions, or the use of materials with surfactant properties may be utilized.
  • compositions containing compounds of formula (I) and methods useful for the in vivo delivery of compounds of formula (I) in the form of nanoparticles. which are suitable for any of the aforesaid routes of administration.
  • United States Patent Nos. 5,916,596, 6,506,405 and 6,537,579 teach the preparation of nanoparticles from the biocompatible polymers, such as albumin.
  • methods for the formation of nanoparticles of the present invention by a solvent evaporation technique from an oil-in- water emulsion prepared under conditions of high shear forces (e.g., sonication, high pressure homogenization, or the like).
  • the methods may be practiced as a therapeutic approach toward the treatment of the conditions described herein.
  • the compounds of formula (I) and compositions may be used to treat the conditions described herein in individuals in need thereof, including humans.
  • the methods generally comprise administering to the individual an amount of a compound of formula (I) 5 or composition described herein, effective to treat the condition.
  • more than one compound of formula (I) may be administered, either concurrently with, prior to or after the administration of the first compound.
  • the compounds, if administered concurrently may be administered in the same or separate formulations.
  • the individual is a mammal, including, but not limited to, human, bovine, horse, feline, canine, rodent, or primate. In other embodiments, the individual is a human.
  • a pharmaceutically or therapeutically effective amount refers to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder.
  • a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause a tumor to shrink or to decrease the growth rate of the tumor, or suppress tumor growth, where the tumor is benign or malignant.
  • the compounds of the invention may be used to treat diseases associated with cellular proliferation or hyperproliferation, such as cancers which include but are not limited to tumors of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas.
  • cancers which include but are not limited to tumors of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas.
  • the compounds of the invention may also be used to treat cancers of the liver and biliary tree (particularly hepatocellular carcinoma), intestinal cancers, particularly colorectal cancer, ovarian cancer, small cell and non-small cell lung cancer, breast cancer, sarcomas (including fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma, ( osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma), neoplasms of the central nervous systems (particularly brain cancer), and lymphomas (including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma,
  • the compounds of formula (I) and compositions thereof described herein may be used alone or in conjunction with ⁇ e.g., prior to, concurrently with, or after) other modes of treatments (e.g., adjunctive cancer therapy, combined modality treatments).
  • other modes of treatments e.g., adjunctive cancer therapy, combined modality treatments.
  • other therapeutic agents e.g., cancer chemotherapeutic agents as described herein and known to those of skill in the art
  • surgery e.g., radiation therapy.
  • compositions described herein can be administered in conjunction with one or more of other anticancer agents or cytotoxic compounds as described herein and as know in the art, one or more additional agents to reduce the occurrence and/or severity of adverse reactions and/or clinical manifestations thereof, surgery (e.g., to remove a tumor or lymph nodes, etc.) or radiation.
  • surgery e.g., to remove a tumor or lymph nodes, etc.
  • radiation e.g., to remove a tumor or lymph nodes, etc.
  • the compositions may be administered before, concurrently, or after the radiation therapy or surgery.
  • the compositions, and formulations thereof, as described herein may be administered before, concurrently, or after the administration of one or more anticancer agents.
  • the compounds of formula (I) and compositions described herein may also be administered in conjunction with (e.g., prior to, concurrently with, or after) agents to alleviate the symptoms associated with the condition or the treatment regimen (e.g., agents to reduce vomiting, hair loss, immunosuppression, etc.).
  • agents to alleviate the symptoms associated with the condition or the treatment regimen e.g., agents to reduce vomiting, hair loss, immunosuppression, etc.
  • the compounds of formula (I) or compositions thereof may also be administered at more than one stage of (including throughout) the treatment regimen (e.g., after surgery and concurrently with and after radiation therapy, etc.).
  • the compositions are administered prior to or after surgery (e.g., removal of a tumor or lymph nodes, etc.). In other embodiments, the compositions are administered after surgery and prior to, concurrently with or after radiation therapy.
  • surgery and/or radiation therapy in conjunction with administration of the compositions described herein, and, optionally, additional one or more chemotherapeutic agents (e.g., either agents active against the disease or condition being treated, or effective to treat the adverse effects of the anti-disease agents), can be determined by an attending physician based on the individual and taking into consideration the various factors effecting the particular individual, including those described herein.
  • the invention also provides methods of treating a mammal afflicted with the above diseases and conditions.
  • the method includes administering one or more of the inventive compounds to the afflicted individual.
  • the methods may further include the administration of a second active agent, such as a cytotoxic agent, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors.
  • the second active agent may be co-administered in the same composition or in a second composition.
  • suitable second active agents include, but are not limited to, a cytotoxic drug such as Acivicin; Aclarubicin; Acodazole Hydrochloride; AcrQnine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedef ⁇ ngol; Chlorambucil
  • the compounds and compositions may be used at sub-cytotoxic levels in combination with other agents in order to achieve highly selective activity in the treatment of non-neoplastic disorders, such as heart disease, stroke and neurodegenerative diseases. See Whitesell et al., Curr Cancer Drug Targets. 2003, 3(5), 349-58.
  • die compounds useful in the methods of the invention are used to reduce the cellular levels of Hsp90 client proteins, which are then effectively inhibited by the second agent. Binding of the client proteins to Hsp90 stabilizes the client proteins and maintains them in a soluble, inactive form ready to respond to activating stimuli.
  • Hsp90 forms an integral part of the functional receptor complex along with several other proteins such as Hsp70, Hsp40, p23, hip, Hsp56, and immunophilins. Hsp90 appears to regulate the activity of the steroid receptor by maintaining the receptor in a high-affinity hormone-binding conformation.
  • the second active agent is a taxane, such as paclitaxel and docetaxel.
  • the inventive compound is administered with (i.e., co-administered or conjugated to) a therapeutic antibody.
  • the therapeutic antibody is one that is specific to a target of interest, such as a cancer cell.
  • the antibody may be an antibody, an antibody fragment, or a functional equivalent thereof.
  • the antibody may be polyclonal, monoclonal, humanized, or chimerized. Immunoconjugate preparation is well known to those of skill in the art. For examples of antibodies and their preparation, see Mandler et al. Cancer Res. 2004, 64(4), 1460, as well as U.S. Patent Nos. 4,867,962, 5,601 ,825, 6,391,913, and U.S.
  • the compounds of formula (I) and compositions as described herein may be administered to individuals in need thereof for the treatment of conditions as described herein in conjunction with the methods of use described herein.
  • the compounds of formula (I) and compositions described herein will generally be used in an amount sufficient to achieve the intended result, for example in an amount effective to treat or prevent the particular condition being treated.
  • the compound(s) and composition(s) may be administered therapeutically to achieve therapeutic benefit.
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.
  • an effective amount is an amount sufficient to reduce tumor growth (e.g., as measured by rate of increase of mean tumor volume prior to and/or after treatment). In certain embodiments, an effective amount is an amount sufficient to decrease mean tumor volume (e.g., where mean tumor volume after treatment is reduced compared to mean tumor volume prior to treatment).
  • the amount of compound or composition administered in order to administer an sufficient amount to treat the disease or condition will depend upon a variety of factors, including, for example, the particular condition being treated, the mode of administration, the severity of the condition being treated and the age and weight of the patient, the bioavailability of the composition, the adverse effects experienced by the individual being treated, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art in view of the teachings provided herein. Dosages may also be estimated using in vivo animal models.
  • the compound of formula (I), or composition thereof, that is administered is a compound listed in Table 1, Table 1, or Table 3.
  • the compound of formula (I), or composition thereof, which is administered is a compound of Table 1.
  • the compound of formula (I), or composition thereof, which is administered is a compound of Table 2.
  • the compound of formula (I), or composition thereof, which is administered is a compound of Table 3.
  • kits for administration of the compounds of formula (I) and compositions described herein are provided kits for administration of the compounds of formula (I) and compositions described herein.
  • kits may include a unit dosage amount of at least one compound of formula (I) or composition, as disclosed herein. Kits may further comprise suitable packaging and/or instructions for use of the compound or composition. Kits may also comprise a means for the delivery of the compound of formula (I) or composition, such as a syringe for injection or other device as described herein and known to those of skill in the art.
  • the compounds of formula (I) and compositions thereof may be assembled in the form of kits.
  • the kit may provide the compounds of formula (I) or compositions thereof and reagents to prepare a composition for administration.
  • the composition may be in a dry or lyophilized form, or in a solution, particularly a sterile solution.
  • the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation. Such diluents include those known to those of skill in the art and are additionally described herein.
  • the kit may also contain a device for administration or for dispensing the compositions, including, but not limited to syringe, pipette, or other device known to those of skill.
  • a device for administration or for dispensing the compositions including, but not limited to syringe, pipette, or other device known to those of skill.
  • the composition When in a wet form, the composition may be stored in an ampoule or other sterile sealed container, including those known to persons of skill in the art.
  • kits may include other therapeutic compounds for use in conjunction with the compounds described herein.
  • the therapeutic agents are other anticancer agents. These agents may be provided in a separate form, or mixed with the compounds of the present invention, provided such mixing does not reduce the effectiveness of either the additional therapeutic agent of the compositions and formulations described herein.
  • the kits may include additional agents for adjunctive therapy. For example, agents to reduce the adverse effects of the drug (e.g., anti-nausea agents, anti-alopecia agents, immuno- enhancing agents, etc.).
  • kits will include appropriate instructions for preparation and administration of the compound/composition, side effects of the compound/compositions, and any other relevant information.
  • the instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, or optical disc.
  • kits for treating an individual who suffers from or is susceptible to the conditions described herein comprising a first container comprising a dosage amount of the compound of formula (I) or compositions as disclosed herein, and instructions for use.
  • the container may be any of those known in the art and appropriate for storage and delivery of intravenous formulations.
  • the kit further comprises a second container comprising a pharmaceutically acceptable carrier, diluent, adjuvant, etc. for preparation of the composition to be administered to the Individual.
  • Kits may also be provided that contain sufficient dosages of the compounds of formula (I) or compositions as disclosed herein to provide effective treatment for an individual for an extended period, such as a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
  • Kits may also include multiple unit doses of the compounds of formula (I) and compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
  • the kit may comprise appropriately packaged oral dosage forms and instructions for use.
  • kits comprise a compound of formula (I) or a composition thereof, wherein the compound is a compound listed in. Table 1, Table 2, or Table 3.
  • the kits comprise a compound of formula (I) or a composition thereof, wherein the compound is a compound of Table 1.
  • the kits comprise a compound of formula (I) or a composition thereof, wherein the compound is a compound of Table 2.
  • the kits comprise a compound of formula (I) or a composition thereof, wherein the compound is of Table 3.
  • This example demonstrates the preparation of 17-methoxyamino-17- demethoxygeldanamycin (1) and 18-o-methyloximino geldanamycin (2).
  • This example demonstrates the preparation of 18-phenoxyiminogeldanamycin (9) and 17-phenoxyamino-17-demethoxygeldanamycin (8).
  • EXAMPLE 17 f 0.0148 This example demonstrates the preparation of preparation of 17-allyamino-l 7- demethoxygeldanamycin (17-AAG, 20).
  • Compound 44 was prepared by treating geldanamycin and commercial N- methylpropylamine in THF at room temperature.
  • Acetyl chloride (89.1 ⁇ L, 1.25 mmol) was added dropwise to a solution of 17- amino-17-demethoxy-l 8-allylo ⁇ yloximin.ogeldanamycin (50 mg, 0.083 mmol) in THF (4.16 mL) at 0° C.
  • the reaction mixture was heated to 55° C. and stirred for 6 hr.
  • the reaction was quenched with sat. Na2CO 3 solution and the mixture was extracted with CH 2 Cl 2 .
  • the combined organic extracts were washed with brine and dried over anhydrous MgSO 4 and the solvent was evaporated under reduced pressure.
  • Triflic anhydride (12.8 ⁇ L, 0.076 mmol) was added dropwise to a solution of 17- hydroxy-17-demethoxygeldanamycin (32 mg, 0.058 mmol) and diisopropylethylamine (19.3 ⁇ L, 0.12 mmol) in CH 2 Cl 2 (5.85 mL) at 0° C.
  • the reaction mixture was stirred at 0° C. for 15 min.
  • the reaction was quenched with sat. NaHC ⁇ 3 solution and the mixture was extracted with CH 2 CIj.
  • the combined organic extracts were washed with brine and dried over anhydrous MgSO* and the solvent was evaporated under reduced pressure.
  • This example demonstrates the preparation of 17-dodecylamino-17-demethoxyl- geldanamycin (62).
  • a solution of geldanamycin (358 mg, 0,64 mmol) and dodecylamine (710.6 mg, 3.83 mmol) in THF (42.6 mL) was stirred at room temperature for 3 hr. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (CH 2 Cl 2 ZMeOH, 100:1) to yield the compound 62 (95 mg, 21% yield) as a purple solid.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-200 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-200 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
  • the resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-200 nm (Z-average, Malvern Zetasizer).
  • the dispersion was further lyophilized for 48 hours.
  • the resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline.
  • the particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
  • This example demonstrates the in vitro growth inhibition for certain compounds of the invention on MX-I (human breast carcinoma) cells.
  • a cytotoxicity assay was quantitated using the Promega CellTiter Blue Cell Viability Assay. Briefly, cells (5000 cells/well) were plated onto 96-well microtiter plates in RPMI 1640 medium supplemented with 10% FBS and incubated at 37° C. in a humidified 5% CO 2 atmosphere. After 24 hrs., cells were exposed to various concentrations of compound in DMSO and cultured for another 72 hrs. 100 ul of media were removed and 20ul of Promega CellTiter Blue reagent were added to each well and shaken to mix. After 4 hours of incubation at 37° C. in a humidified 5% CO 2 atmosphere, the plates were read at 544ex/620em. The fluorescence produced is proportional to the number of viable cells. After plotting fluorescence produced against drug concentration, the IC 50 was calculated as the half-life of the resulting non-linear regression. The data is presented in Table 3.

Abstract

The invention provides novel geldanamycin derivatives and methods of their production. The invention also provides methods of treating a disease or condition associated with undesirable cellular proliferation using the same.

Description

GELDANAMYCIN DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF
BACKGROUND OF THE INVENTION
[0001] Geldanamycin (GM) is a benzoquinone ansamycin polyketide isolated from Streptomyces hygroscopicus. See DeBoer et al., Antibiot., 1970, 23, 442.
Figure imgf000002_0001
Geldanamycin
Although originally discovered by screening microbial extracts for antibacterial and antiviral activity, geldanamycin was later found to be cytotoxic to certain tumor cells. It is reported that geldanamycin exerts its antiproliferative and anti-cancer effect by binding with the heat shock protein 90 (Hsp90) chaperone and, in turn, altering the translocation properties of the tumor suppressor protein p53. See Stebbins et al., Cell, 1997, 239; Sepehrnia et al., J. Biol. Chem., 1996, 271, 15,084; Dasgupta et al., Experimental Cell Research, 1997, 29, 231.
[0002] Inhibition of Hsp90 results in interference in multiple signaling pathways that mediate cancer growth and cell survival. Hsp90 is essential for the stability and function of several oncogenic proteins associated with key sites of genetic deregulation in human cancer. It is known to be over-expressed in human tumors and has the potential to inhibit the hallmark traits of cancer such as cell growth, signaling apoptosis avoidance, limitless proliferation, angiogenesis, and metastasis. See Sreedhar et al, Pharmacology & Therapeutics, 2004, 101, 227.
[0003] Geldanamycin was thought to exert its anti-cancerous effects by tight binding of the N-terminus pocket of Hsp90s. See Stebbins, C. et al., Cell, 1997, 89, 239. Further, ATP and ADP have both been shown to bind this pocket with low affinity and to have weak ATPase activity. See Proronlou, C. et al., Cell, 1997, 90, 65; Panaretou et al., EMBOJ, 1998, 17, 4829. In vitro and in vivo studies have demonstrated that occupancy of this N-terminal pocket by geldanamycins and other Hsp90 inhibitors alters Hsρ90 function and inhibits protein folding. At high concentrations, geldanamycins and other Hsp90 inhibitors have been shown to prevent binding of protein substrates to Hsρ90 and to inhibit the ATP-dependent release of chaperone-associated protein substrates. See Scheibel et al.7 Proc. Nat 7. Acad. Sci. USA, 1999, 96, 1297. The geldanamycin-induced loss of these proteins leads to selective disruption of certain regulatory pathways and results in growth arrest at specific phases of the cell cycle. (See Muise-Heimericks et al., J Biol. Chem., 1998, 273, 29864), apoptosis, and/or differentiation of cells. See Vasilevskaya et al., Cancer Res., 1999, 59, 3935.
[0004] Recently, geldanamycin, as a specific inhibitor of Hsp90, was found to diminish specific wild-type p53 binding to the p21 promoter sequence. See McLean et al., Biochem Biophys Res Commun. 2004, 321(3), 665. Consequently, these inhibitors decrease p21 mRNA levels, which lead to a reduction in cellular p21 AVafl protein, the latter being known to induce cell cycle arrest. A minor decrease in p53 protein levels following the treatment of human fibroblasts with the inhibitors suggests the potential involvement of Hsp90 in the stabilization of wild-type p53. More recently, geldanamycin was found to induce Hsp70 and prevent alpha-synuclein aggregation and toxicity in vitro. See McLean et al., Biochem Biophys Res Commun. 2004, 321(3), 665.
[0005] An important property of Hsp90 inhibitors is their ability to cause simultaneous combinatorial blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic client proteins. See Workman P., Trends MoI Med. 2004 10(2), 47. Bedin et al. reported that geldanamycin induces MAPK-independent cell cycle arrest by inhibiting the chaperone function of the Hsp90 protein through competition for ATP binding. See Bedin et al., J. Int. J. Cancer 2004, 9(5), 43. The antiproliferative effect of geldanamycin has been attributed to destabilization of the Raf-1 protein, one of the targets of Hsp90, and to the resulting inhibition of MAPIC Li et al. found that geldanamycin exhibits broad-spectrum antiviral activity, including HSV-I and severe acute respiratory syndrome coronavirus. Li et al., Antimicrob. Agents Chemother. 2004, 48(3), 867. HSV-I replication in vitro was significantly inhibited by geldanamycin with a 50% inhibitory concentration of 0.093 μM which was also a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350μM. The therapeutic index of geldanamycin was found to be over 3700. [0006] Mandler et al. reported that conjugating geldanamycin to the anti-HER2 mAb Herceptin in targeted cancer therapy resulted in a greater antitumor effect than Herceptin alone. See Mandler et al. Cancer Res. 2004, 64(4), 1460. Geldanamycin also was to enhance the radiation sensitivity of human tumor cells by inhibiting the EGFR signal transduction system and the Akt signaling pathway. SeeMachida et al., Int. J. Radial Biol. 2003, 79(12), 973.
[0007] Despite its therapeutic potential as an anticancer agent, initial studies have indicated that the bioavailability of geldanamycin must be enhanced and the toxicity associated with the natural product reduced before significant progress can be made with respect to the therapeutic use of geldanamycin. The association of hepatotoxicity with the administration of geldanamycin led to its withdrawal from Phase I clinical trials. As with several other promising anticancer agents, geldanamycin also has poor water solubility that makes it difficult to deliver in therapeutically effective doses.
[0008] Analogues of geldanamycin have been synthesized in an attempt to increase the bioavailability and reduce the toxicity associated with the natural product. Among the more successful analogues is 17-allylaminogeldanamycin (17-AAG), which is currently in phase II clinical trials at the National Cancer Institute.
Figure imgf000004_0001
[0009] 17-AAG has shown reduced hepatotoxicity while maintaining Hsp90 binding. This compound was selected for clinical studies based on its in vitro activity against chemorefractory tumors and novel biological actions. Like geldanamycin, 17-AAG has limited aqueous solubility. This property requires the use of a solubilizing carrier, most commonly Cremophore®, a polyethoxylated castor oil; however Cremophore® can produce serious side reactions in some patients.
[0010] A deficiency of the previous generation of ansamycins, such as geldanamycin and 17-AAG, is that they exhibit one or more poor pharmacological properties, e.g., metabolic instability, poor bioavailability, and/or difficult formulation ability, particularly for in vivo intravenous administration.
[0011] Therefore, there is a need for preparations and synergists of anti-cancer compounds that allow for administration of doses significantly below the maximum tolerated dose while maintaining therapeutic effectiveness, as well as appropriate dosing schedules for combination therapy. The present invention provides these and other advantages.
BRIEF SUMMARY OF THE INVENTION
[0012] The invention provides compounds, as well as intermediates thereof and methods for their preparation, and compositions (including pharmaceutical compositions) that are useful in the treatment of diseases or conditions characterized by undesired cellular proliferation or hyperproli feration. The invention further provides methods of using the compounds and compositions described herein.
[0013] In one embodiment, the invention provides a compound or pharmaceutically acceptable salt thereof having the formula (I):
Figure imgf000005_0001
(I) wherein
W represents: O, N-OH, N-O-COR1 0, or N-O-X-Rn; wherein
X is selected from the group consisting of a substituted or unsubstituted (Ci- Cio) alkyl or (Ci-Cio) alkenyl or (Ce-Qo) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R8)(R9), N(R8)(R9), CO2R1 O, wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (C1 -C20) alkyl, optionally substituted (C2-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or Rs is selected from the group consisting of H, optionally substituted (C]-Ce) alkyl, optionally substituted (Cs-C8) aryl, and an optionally substituted (Cs-Cs) heteroaryl, or R8, together with R9 forms an optionally substituted 4-7 membered heterocyclic or carbocyclic ring; R1 o is selected from the group consisting of H, an optionally substituted (Cr C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C2O) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted (C6-C20) aryl, optionally substituted (C3-C20) heteroaryl, optionally substituted (C7-C2o) arylalkyl, optionally substituted (C4-C20) heteroarylalkyl, optionally substituted (C3-C20) cycloalkyl, and an optionally substituted (C2-C20) cycloheteroalkyl; R1 and R2 are each a hydrogen or R1 and R2 together form a single bond;
R3, R4, Re, R7, Yi, Y2, Y3 are independently selected from the group consisting H, halo, -OH, O-alkyl, O-acetyl, -O-aryl, OC(O)R]0, -SO2-R]0, and -NHR10, or together form oxo (=O), or hydroxylamino alkoxyimine or aryloxyimine, thioketo; or R3 and R4 or Yi and Y2 form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(Ci -C4) alkylpiperidinyl and N-(Ci-C4) piperazinyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting Of (Ci-C8) alkyl, halo, nitro, amino, azido and (Ci- Cs) alkoxyl, wherein R10 is, independently, as defined above; and
Rs is selected from the group consisting of an optionally substituted (Q -C20) alkyl, optionally substituted (Ci-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted (Ce-C20) aryl, optionally substituted (C3-C20) heteroaryl, optionally substituted (C7-C20) arylalkyl, optionally substituted (C4-C20) heteroarylalkyl, optionally substituted (C3-C20) cycloalkyl, optionally substituted (C2- C20) cycloheteroalkyl, N(R8)(R9); -OR,o, -SR10, -N(Rg)-C(O)R10, -N(Rg)-C(O)-OR10, - N(Rs)-C(O)-N(R8)(R10), -N(Rg)-C(S)OR10, -N(Rg)-C(S)-OR10, and -N(Rg)-C(S)- N(R8)(R]0).wherein when W is O, R5 is NH-OH, NH-O-COR]0, or NH-O-X-Rn. [0014] In another aspect is provided that includes a composition containing the compound of formula (I) and a pharmaceutically-acceptable carrier.
[0015] In another embodiment, a composition for administration to a mammalian subject is provided. The composition includes a plurality of particles of the compound having formula I and the average size of the particles is no greater than about 500 nm, or no greater than 200 nm.
[0016] In yet another aspect, a method of treating a disease or condition characterized by undesirable cellular proliferation or hyperproliferation is provided. In this method, a compound of formula (I) is administered to an individual in need thereof in an amount sufficient to treat a disease or condition characterized by undesired cellular proliferation or hyperproliferation.
[0017] In a further aspect, the invention provides method of manufacture of a medicament containing the compounds and compositions having formula I. rThe medicament may be useful in the treatment of conditions as described herein. Further, the compositions described herein (including pharmaceutical compositions), are also intended for use in the manufacture of a medicament for use in treatment of the conditions and, in accordance with the methods, described herein.
[0018J Unless otherwise noted, the compounds as described herein are intended for use in the methods of treatment and may be incorporated in the compositions, pharmaceutical compositions, and kits.
[0019] These and other advantages are described more fully below.
DETAILED DESCRIPTION OF THE INVENTION
10020] The invention provides benzoquinone ansamycins and compositions thereof, and further provides methods for using these novel compounds as single-agent and, in combination therapies with known compounds or in combinations of two or more of the compounds of formula (I) for the treatment of cancer and/or other diseases or conditions characterized by undesired cellular hyperproliferation. The present invention relates to compounds of the formula I as well as pharmaceutically-acceptable salts and prodrugs thereof, hereinafter referred to as the active compounds derivatized from ansamycins or as compounds of formula (I). [002Ij In a first aspect, the invention comprises compounds of formula (I)
Figure imgf000008_0001
(D
and pharmaceutically-acceptable salts thereof, wherein
W represents: O or N-OH, N-O-COR10, or N-O-X-Rn; wherein
X represents substituted or unsubstituted (Ci-Cio) alkyl or (Ci-Cio) alkenyl or (Cβ-Cio) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(Rs)(R9), N(Rs)(R9), CO2R1Oj wherein Rg and R9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (C1-C20) alkyl, optionally substituted (C2-C20 heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or Rs is selected from the group consisting of H, optionally substituted Ci-Cs alkyl, optionally substituted Cs-C8 aryl, and optionally substituted Cs-Cs heteroaryl; or R8, together with R9 forms an optionally substituted 4-7 membered heterocyclic or carbocyclic ring; R1o is selected from the group of H, optionally substituted (C1-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (Ci-C2Q) alkynyl, optionally substituted (C6-C20) aryl, optionally substituted (C6-C20) aryl, optionally substituted (C3-C20) heteroaryl, optionally substituted (C7-C2O) arylalkyl, optionally substituted (C4-C20) heteroarylalkyl, optionally substituted (C3-C20) cycloalkyl, optionally substituted (C2-C20) cycloheteroalkyl; R1 and R2 are both hydrogen or Rj and R2 together form a single bond; R.3, R), Re, R-7, Yi, Y2, Y3 are independently selected from the group consisting of H, halo, -OH, O-alkyl, O-acetyl, -O-aryl, OC(O)R10, -SO2-R10, OR10 and -NHR10, or together form oxo (=O), or hydroxylamino alkoxyimine oτ aryloxyimine, thioketo; or R3 and R4 or Yi and Y2 form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1-C4) alkylpiperidinyl and N-(Ci-C4) piperazinyl; where said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C]-C8) alkyl, halo, nitro, amino, azido and (Ci-Cs) alkoxyl;
R5 is indepently selected from the group consisting of optionally substitated (C1-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2- C2Q) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2- C20) alkynyl, optionally substituted (Ce-C2O) aryl, optionally substituted (C3-C20) heteroaryl, optionally substituted (C7-C20) arylalkyl, optionally substituted (C4-C2O) heteroarylalkyl, optionally substituted (C3-C2O) cycloalkyl, optionally substituted (C2- C20) cycloheteroalkyl, N(R8)(R9), -OR,θ! -SR10, -N(R8)-C(O)R,0, -N(Rs)-C(O)-OR10, - N(Rg)-C(O)-N(R8)(R10), -N(Rg)-C(S)OR10, -N(Rg)-C(S)-OR10, -N(Rg)-C(S)-NR8R10, wherein R8, R9, and R10 are defined as above; and
[0022) When W is O, R5 is NH-OH5 NH-O-COR10, or NH-O-X-R1 1 , wherein X, R1 0 and Rj ] are defined as the above
[0023] It is intended that where both Rn and R5 incorporate one or more OfR8, R9. or R]0, that each occurence of R8, R9, or R10 may be independently selected and may be the same or different from other occurrences Of R8, R9, and R10.
[0024] In one embodiment, W may be selected from N-OH, N-O-COR]0, or N-O-X-Rn, and R5 may selected from the group consisting OfN(R8)(Rp); -OR]0, -SR10, -N(Rg)-C(O)R10, - N(Rs)-C(O)-OR10, -N(Rg)-C(O)-N(R8)(R10), -N(Rs)-C(S)OR10, -N(Rg)-C(S)-OR10, and - N(Re)-C(S)-N(Re)(R1 O), and Rg3 R9 and R10, Rn, X as defined above and are independently selected.
[0025] In yet another embodiment, R5 may be selected from the group consisting of N(R8)(R9); -OR10, -SR10, -N(Rg)-C(O)R10, -N(Rg)-C(O)-OR10, -N(Rg)-C(O)-N(R8)(R, 0), - N(Rs)-C(S)OR10, -N(Rg)-C(S)-OR1 0, and -N(Rs)-C(S)-N(R8)(R1 o). Alternately, R5 may be selected from N(R8)(R9), and W is selected from N-O-COR10.
[0026] In another embodiment, R$ may be selected from N(R8)(R9), and W is selected from N-O-X-Rn.
[0027] In yet another embodiment, R5 may be NH2, and W may be selected from N-OH, N-O-X-Rn.
[0028] In another embodiment, R5 is NH2, and W may be selected from N-OH, N-O-X- R11.
[0029] In yet another embodiment, R5 is OCH3, and W may be selected from N-OH, N- O-X-Rπ.
[0030] The following definitions refer to the various terms used above and throughout the disclosure.
[0031] The term "halo" refers to fluoro, chloro, bromo or iodo.
[0032] The term "(C1-C20) alkyl" refers to an alkyl, substituted straight or branched chain alkyl or alkylenyl group, having from 1-20 carbon atoms. In view of availability of alkylating reactants, the alkyl group has, for example, 1-10 carbon atoms. Illustrative of the alkyl group include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 3-methylbutyl, 2,2-dimethylpropyl, 1,1-dimethylpropyl, hexyl, 1 -methylpentyl, 4- methylpentyl, heptyl, 1-methylhexyl, 2-methylhexyl, 5-methylhexyl, 3-ethylpentyl, octyl, 2- methylheptyl, 6-methylheptyl, 2-ethylhexyl, 2-ethyl-3 -methylpentyl, 3-ethyl-2-methylpentyl, nonyl, 2-methyloctyl, 7-methyloctyl, 4-ethylheptyl, 3-ethyl-2-methylhexyl., 2-ethyl-l- methylhexyl, decyl, 2-methykionyl, 8-methylnonyl, 5-ethyloctyl, 3-ethyl-2-methylheptyl, 3,3-diethylhexyI, undecyl, 2-methyldecyl, 9-methyldecyl, 4-ethylnonyl, 3,5-dimethylnonyl, 3-propyloctyl, 5-ethyl-4-methyloctyl, 1-pentylhexyl, dodecyl, 1-methylundecyl, 10- methylundecyl, 3-ethyldecyl, 5-propylnonyl, 3,5-diethyloctyl, tridecyl, 1 1 -methyldodecyl, 7- ethylundecyl, 4-propyldecyl, 5-ethyl-3-methyldecyl, 3-pentyloctyl, tetradecyl, 12- methyltridecyl, 8-ethyldodecyl and 6-propylundecyl groups.
[0033] The term "(C2-C20) alkenyl" represents an alkenyl group, having from 2 to 20 carbon atoms, and may be a straight or branched chain group, natural or unnatural fatty acid. It may have 1 or more double bonds, for example, from 2 to 6, double bonds. Examples of such groups include the vinyl, allyl, 1-propenyl, isopropenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3- hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 8-nonenyl, 1- nonenyl, 1-decenyl, 9-decenyl, 8-tridecenyl, cis-8-pentadecenyl, trans-8-pentadecenyl, 8- heptadecenyl, 8-heptadecenyl, 8,11-heptadecadieyl, 8,11,14-heptadecatrienyl, 4,7,11,14- nonadecatetraenyl and 2,6-dimethyl-8-(2,6,6-trimethyl- 1 -cyclohexen- 1 -yl)- 1 ,3,5,7- nonatetτaen-1-yl, cis-10-nonadecaenyl, 10,13-nonadecadienyl, cis-7,10,13-nonadecatrienyl, 5,8,11,14-nonadecatetraenyl, nonadecapentaenyl.
[0034] The term "(C1-Cs) alkoxy" refers to an alkoxy group with one to eight carbon alkyl groups, and the alkyl moiety thereof generally corresponds to the Ci-C2O alkyl groups described above and can be selected therefrom. Examples of alkoxy groups are those derived from straight or branched chain lower alkyl groups with 1 -8 carbon atoms, and include, for example, methoxy, ethoxy n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy, cyclohexyloxy, n-heptyloxy, n-octyloxy and 2-ethylhexyloxy.
[0035] The term "(C3-C2O) aryl" refers to an aromatic or heteroaromatic ring, including by way of example, phenyl, naphthyl, furanyl, imidazolyl and thionyl. The aryl ring can be substituted with substituents selected from the group consisting of halo, Ci- Ce alkyl or C1-Ce alkoxy, or alkyl amino. Examples include 4-chlorophenyl, 2 -fluorophenyl, 4-fluorophenyl, 3-flouroρhenyl, 4-methylphenyl, 4-ditrifluorohenyl, 2-ethylphenyl, 3-n-propylphenyl, 4- isopropyl-phenyl, 4-n-butylphenyl, 4-t-butylphenyl, 4-sec-butylphenyl, 4- dimethylaminophenyl, 3,4-dimethylphenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4- isopropoxyphenyl, 3-isobutoxyphenyl, 4-t-butoxyphenyl, 4-nitrophenyl, 2-furan, 2-pyridyl, 3- pyridyl, 2-thiophenyl, 3-thiophenyl, 1 -naphthyl, 2-naphthyl, 2-indolyl, and the like, and the aryl moiety of aryl and arylcarbamoyl have the same meaning.
[0036] Examples of the heterocyclic group include alicyclic heterocyclic groups, aromatic heterocyclic groups, and the like, such as pyridonyl, pyrrolidonyl, uracilyl, dioxolnyl, pyrrolyl, tetrazolyl, pyrrolidinyl, thienyl, morpholino, thiomorpholino, piperazinyl, pyrazolidinyl, piperidino, pyridyl, hompiperazinyl, pyrazolyl, pyrazinyl, indolyl, isoindolyl, furyl, piperidyl, quinolyl, phthalazinyl, imidazolidinyl, imidazolinyl, pyrimidinyl, and the like. The heterocylic group moiety in the carbonyl bound to a heterocyclic ring has the same meaning as defined above, and examples of the entire group containing carbonyl include furoyl, thenoyl, nicotinoyl, isonicotinoyl, and the like. Examples of the nitrogen containing heterocyclic group formed by R8 and R9 with the adjoining N and the nitrogen containing heterocyclic group formed by R8 and R9 with the adjoining N (said heterocyclic group may further contain O, S or other N) include pyrrolidyl, morpholiiio, thiomorpholino, piperazinyl, pyrazolidinyl, pyrazolinyl, piperidino, homopiperazinyl, indolinyl, isoindolinyl, perhydroazepinyl, perhydroazocinyl, indolyl, isoindolyl, and the like.
[0037] The terms "OR10, SR10 and N(R8)(R9)" refer to the alkyl groups substituted with oxygen, sulfur and nitrogen. Some examples of the alkyl group substituted with oxygen, sulfur or nitrogen include methoxymethyl, ethoxymethyl, propoxymethyl, n-butoxymethyl, 2- methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 3-methoxyproρyl, 3-ethoxypropyl, 3- propoxypropyl, 4-methoxybutyl, 4-propoxybutyl, dimethoxymethyl, 2,2-dimethoxyethyl, diethoxymethyl, 2,2-diethoxyethyl, dipropoxymethyl, 2,2-dipropoxyethyl, methylthiomethyl, ethylthiomethyl, propylthiomethyl, n-butylthiomethyl, 2-methylthiolethyl, 2-ethylthiolethyl, 2-propylthiolethyl, 3 -methyl thiopropyl, 3-ethylthiopropyl, 3-propylthiopropyl, 4- methylthiobutyl, 4-propylthiobutyl, aminomethyl, dimethylaminomethyl, (N- acetyl)methylaminomethyl, diethylaminomethyl, dipropylaminomethyl, dibutylaminomethyl, dimethylaminoethyl, diethylaminoethyl, dipropylaminoethyl, and dibutylaminoethyl groups.
[0038] The term "COR1o" refers to carboxylic acid, ester, or amide, wherein R1o generally correspond to the C1-C20 alkyl groups discussed above and can be selected therefrom. Some examples of the alkylamino group are those derived from hydrogen, and straight or branched chain lower alkyl groups with 1 -6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl and hexyl groups.
[00391 The term "-N(Rg)-C(O)Ri0, -N(Rg)-C(O)-OR10, -N(Rg)-C(O)-N(R8)(R10), -N(R8)- C(S)OR10, -N(Rs)-C(S)-OR10, -N(Rs)-C(S)-N(R8)(R10)," wherein R8 and R10 are the same or different, and each represents hydrogen, hydroxyl, alkyl, cycloalkyl, alkoxy, aryl, heterocyclic group, alkanoyl, or N(R8)(R1 0) together represent a substituted or unsubstituted aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridonyl, substituted or unsubstituted pyrrolidonyl, substituted or unsubstituted uracilyl, substituted or unsubstituted piperidyl, substituted or unsubstituted piperidino, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted morpholino, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted thiomorpholino, substituted or unsubstituted dioxolanyl, cyclic imido (a group formed by removing hydrogen bound to an imido N atom). [0040] The term "Pharmaceutically-acceptable salt" refers to a salt of one or more compounds. Suitable pharmaceutically-acceptable salts of compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically-acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, benzoic acid, acetic acid, citric acid, tartaric acid, phosphoric acid, carbonic acid, and the like. Where the compounds carry one or more acidic moieties, pharmaceutically-acceptable salts may be formed by treatment of a solution of the compound with a solution of a pharmaceutically-acceptable base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, tetraalkylammonium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, ammonia, alkylamines, and the like.
[00411 In certain embodiments, when W is present as N-O-X-R1 i, X represents substituted or unsubstituted (C]-Cg) alkyl or
Figure imgf000013_0001
alkenyl or (Cg-Cio) aryl> wherein R1 i represents hydrogen, hydroxyl, halogen, cyanide, or CON(R8)(R9), N(R8)(R9), CO2R1 o; wherein R8 and R9 are each independently selected from the group consisting of hydrogen, (Ci-C8) alkyl, (C3-C8) cycloalkyl, (C2-C8) alkenyl and (C2-Cz) alkynyl; wherein said alkyl, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, optionally substituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, and (d-Cδ) heterocycloalkyl and (C2-Ce) heterocycloaryl groups selected from the group comprising imidizaloly, furyl, tetrahydrofuryl; and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; or R8 and R9 together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl and pyrrolidinyl. In some embodiments, N(R8)(R9) is selected from the group consisting of methoxyamine, O-ethylhydroxyamine, O- allylhydroxyamine, 0-(tetrahydro-2H-pyran-2-yl)hydroxylamine O-t-butylhydroxylamine, O-(Carboxymethyl)hydroxylamine, hemihydrochloride, O-aminohomoserine, aminoguanidine, 2-(aminooxy)-N,N-dimethylethanamine, O-phenylhydroxylamine, O- benzylhydroxylamine, hydrazine, methylhydrazine, 1,1-dimethy .hydrazine, acethydrazide, 2- hydroxyethylhydrazine, semicarbazide, 3-hydrazinopropanenitrile,carbohydrazide, 1- piperidinamine, butanohydrazide, 4-morpholinamine, phenylhydrazine; ammonia, methylamine, ethylamine, propylamine, butylamine, pentylamine, hexylamine, heptylamine, octylamine, allylamine, β-hydroxyethylamine, β-chloroethylamine, β-glycoxyethylamine, aminobutylamine, adamantylmethylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooctylamine, benzylamine, phenethylamine, ethyleneamine,- pyrrolidine, piperldine, dimethylamine, arninoethylamine, diglycolamine, β- morpholinoethylamine, β-piperidinoethylamine, picolylamine, β-pyrrolidinoethylamine, β- pyridinylethylamine, β-methoxyethylamine, and β-N-methylaminoethylamine.
[00421 In certain embodiments the invention provides compounds of formula (I) wherein
A: W is N-O-H or N-O-COR1O, wherein R1o is selected from the group consisting of (Ci-Cs) alkyl, amino(Ci-C8) alkyl, dimethylamino (Ci-Cs) alkyl, cyclo (Cj-C8) alkyl, phenyl and naphthyl; R1 and R- together form a single bond, R3, R4, R^, R7, Yi, Y2 and Y3 are each hydrogen; and,
R5 is OR14 or N(R8)(R9) wherein: i. when R5 is OR14, R14 is hydrogen or optionally substituted (C]- C8)alkyl; ii. when R5 is N(R8)(R9), R8 is hydrogen and R9 is selected from the group consisting of (Ci-C8) alkyl, (Ci-C8) alkoxy, (C3-C8) cycloalkyl, (C2-C8) alkenyl and (C2-Cs) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto,
Figure imgf000014_0001
alkylthio, optionally substituted amino, hydroxyl, (Q-Cs) alkoxyl, carboxyl, amidino, acylamino, (C2-C6) heterocycloalkyl and (C2-Cn) heterocycloaryl and, if comprising more than two carbon atoms, may be branched, cyclic, unbranched, or combinations of branched, cyclic and unbranched groups; or iii. when R5 is N(R8)(R9), Rg and R9, together with the nitrogen to which they are attached, may form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino and acylamino; or iv. when R5 is selected from -OR10, -SR]0, -N(R8)-C(0)Rιo, -N(R8)- C(O)-OR10, -N(Rs)-C(O)-N(R8)(R10), -N(Rg)-C(S)OR10, -N(Rg)-C(S)-OR10, - N(Rg)-C(S)-NR8R1O (wherein Rg and R1o are independently selected from the group consisting of H, optionally substituted (C1-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-Q20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. when R5 is NH-O-X-Rn, wherein X and Rn is defined as above.
B: W is N-O-H or N-O-COR10, wherein R1o is selected from the group consisting of (C)-C8) alkyl, amino (Ci-C8) alkyl, dimethylamino (Ci-C8) alkyl, cyclo (C3-C8) alkyl, phenyl and naphthyl; R1 and R2 together form a single bond; R3, R^, R7, Yi, Y2 and Y3 are each hydrogen; R4 is fluoro, or , and
R5 is OR]4 or N(R8)(R9) wherein i. when R5 is OR)4, Rj4 is hydrogen or optionally substituted (Ci-C8) alkyl; ii. when R5 is N(R8)(R9), R8 is hydrogen and R9 is selected from the group consisting of (Ci-Cs) alkyl, (C1-C8) alkoxy, (C3-C8) cycloalkyl, (Qz-Cs) alkenyl and (C2-C8) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, optionally substituted
< amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, (C2-Ce) heterocycloalkyl, (C2-CO) heterocycloaryl, and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; or iii. when R5 is N(Rg)(R?), R8 and R9, together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino and acylamino; iv. when R5 is selected from -OR10, -SR10, -N(R8)-C(O)R10, -N(R8)- C(O)-OR10, -N(Rg)-C(O)-N(R8)(R10), -N(Rs)-C(S)OR10, -N(Rs)-C(S)-OR10, - N(Rs)-C(S)-N(R8)(R1 O) (wherein R8 and R10 are independently selected from the group consisting of H, optionally substituted (C1-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. when R5 is NH-O-X-R1 1 , wherein X and R1 1 are as defined above.
C. W is N-O-H or N-O-COR10, wherein R1o is selected from the group consisting of (Q-C8) alkyl, amino(Ci-Cs) allcyl, dimethylamino (Ci-C8) alkyl, cyclo (Ci-Cs) alkyl, phenyl and naphthyl; R1, R2, R3, R4, R6, R7, Vi, Y2 and Y3 are each hydrogen; and
R5 is OR|4 OrN(R8)(R9) wherein i. when R5 is ORH, RI4 is hydrogen or optionally substituted (Ci-C8) alkyl; ii. when R5 is N(Rg)(R9), Rg is hydrogen and R9 is selected from the group consisting Of (Ci-C8) alkyl, (Ci-C8) alkoxy, (C3-Cs) cycloalkyl, (C2-Cs) alkenyl and (C2-Cs) alkynyl; wherein said alkyl, alkoxy, alketiyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C1 -C8) alkylthio, optionally substituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino, acylamino, (C2-C6) heterocycloalkyl and (C2-Cg) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; or iii. when R5 is N(R8)(Rp), Rg and R9, together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-Cs) alkylthio, substituted or unsubstituted amino, hydroxyl, (C1 -C8) alkoxyl, carboxyl, amidino and acylamino; or iv. when R5 is selected from -OR10, -SR10, -N(Rg)-C(O)R10, -N(R8)- C(O)-OR10, -N(Rs)-C(O)-NR8R10, -N(Rg)-C(S)OR1 0, -N(R8)-C(S)-OR,o, - N(Rs)-C(S)-NRsR1O (wherein R8 and R1o are selected from the group consisting of H, optionally substituted (C1-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycioheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. when Rs is NH-O-X-Rn3 wherein X and R11 are as defined above..
D: W is N-O-H or N-O-COR10, wherein Rj0 is selected from the group consisting of (Ci-Cs) alkyl, amino (Ci-Cs) alkyl, dimethylamino (Ci-C8) alkyl, cyclo (C3-C8) alkyl, phenyl and naphthyl; Ru R2, R3, R6, R7, Yi, Y2 and Y3 are each hydrogen; R4 is fhioro or OR]0 and
R3 is OR14 or N(R8)(R9) wherein: i. when R5 is OR]4, Rj4 is hydrogen or optionally substituted (C)-Cs) alkyl; ii. when R5 is N(R8)(R9), R8 is hydrogen and R9 is selected from the group consisting of (Ci-C8) alkyl, (Ci-Cs) alkoxy, (C3-Cs) cycloalkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-Cs) alkylthio, optionally substituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, (C2-C&) heterocycloalkyl and (C2-Cg) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; or iii. when R5 is N(R8)(R9), R8 and R9, together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C]-Cs) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; or iv. when R5 is selected from -OR10, -SR10, -N(Rg)-C(O)R]0, -N(R8)- C(O)-OR10, -N(Rg)-C(O)-N(R8)(R1O), -N(Rg)-C(S)OR10, -N(Rs)-C(S)-OR10, - N(Rg)-C(S)-N(R8)(R1O) (wherein Rg and R1o are independently selected from the group consisting of H, optionally substituted (C1-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. . when R5 is NH-O-X-R1 i, wherein X and R1 1 is defined as aboveE. W is N-O-X-Rn; wherein X represents substituted or unsubstituted (Ci-Ci0) alkyl or (Ci-Cio) alkenyl or (Ce-Ci0) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R8)(Rg), N(Rg)(Rg), CO2R10, wherein Rg and R9 are independently selected from the group consisting of H, optionally substituted (C]-C2O) alkyl, optionally substitated (C2-C20) heteroalkyl optionally 7 substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl;
Rι and R2 together form a single bond, Rj, R4, RO, R7, Yi, Y2 and Y3 are each hydrogen; and
R5 is OR i4 or N(Rg)(R9), wherein i. when R5 is OR]4, R]4 is hydrogen or optionally substituted (C]-C8) alkyl; ii. when R5 is N(R8)(R^, R8 is hydrogen and R9 is selected from the group consisting Of (Ci-C8) alkyi, (C1-Cs) alkoxy, (C3-C8) cycloalkyl, (C2-Cs) alkenyl and (C2-Cs) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C 1-C8) alkylthio, optionally substituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, (C2-Cg) heterocycloalkyl and (C2-CO) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; or iii. when R5 is N(Rs)(Rg), R8 and R9, together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C]-Cs) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino and acylamino; or iv. when R5 is selected from -OR1 0, -SR1 0, -N(R8)-C(O)R10, -N(R8)- C(O)-OR10, -N(Rs)-C(O)-N(R8)(R10), -N(Rj)-C(S)OR10, -N(Rs)-C(S)-OR10, - N(Rs)-C(S)-N(R8)(R1 0) (wherein R8, and R1o are independently selected from the group consisting of H, optionally substituted (Q-C20) alkyl, optionally substituted (C 1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. when R5 is NH-O-X-Rn, wherein X and Rn is defined as above.
F. W is N-O-X-Rn; wherein X represents substituted or unsubstituted (Ci -C 10) alkyl or (Ci-Cio) alkenyl or (Cβ-Cio) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R8)(Rg), N(R8)(R9), CO2R1O, wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted (C1-C20) alkyl, optionally substitated (C2-C20) heteroalkyl optionally 7 substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; R1 and R2 together foπn a single bond; R3, R^, R7, Yi, Y2 and Y3 are each hydrogen; R4 is fluoro, or OR1 o, and
R5 is ORH or N(R8)(R?) wherein i. when R5 is R14O, R14 is hydrogen or optionally substituted (Ci-Cs) alkyl; ii. when R5 is N(Rg)(R^, Rg is hydrogen and R9 is selected from the group consisting of (Ci-Cs) alkyl, (Ci-C8) alkoxy, (C3-C8) cycloalkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, optionally substituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, (C2-Cg) heterocycloalkyl and (C2-CO) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; iii. when R5 is N(R8)(R^, Rs and R9, together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; or iv. when R5 is selected from -OR10, -SR10, -N(Rs)-C(O)R10, -N(R8)- C(O)-OR10, -N(Rs)-C(O)-N(R8)(R10), -N(Rg)-C(S)OR10, -N(Rg)-C(S)-OR10, - N(Rs)-C(S)-N(Rg)(R10) (wherein R8 and R1o are independently selected from the group consisting of H, optionally substituted (C1-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. when Rs is NH-O-X-Rn, wherein X and Rn are as defined above.
G. W is N-O-X-Ru; wherein X represents substituted or unsubstituted (Ci- Cio) alkyl or (Ci-C1 o) alkenyl or (C^-Cio) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R8)(R9)5 N(R8)(R9), CO2R1O, wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (C1-C20) alkyl, optionally substitated (C2-C20) heteroalkyl optionally 7 substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; R1 , R2, R3, R4, R6, R7, Yi, Y2 and Y3 are each hydrogen; and R5 is OR14 or N(R8)(R9) wherein i. when R5 is R14O, R]4 is hydrogen or optionally substituted (Ci-C8) alkyl; ii. when R5 is N(R8)(R9), R8 is hydrogen and R9 is selected from the group consisting of (Ci-C8) alkyl, (Ci-C8) alkoxy, (C3-C1) cycloalkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (C]-C8) alkylthio, optionally substituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, (C2-Ce) heterocycloalkyl and (C2-C6) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic or unbranched or combinations of branched, cyclic and unbranched groups; iii. when R5 is N(R8)(R9)3 R8 and R9, together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-Cs) alkyl thio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; iv. when R5 is selected from -OR10, -SR10, -N(Rg)-C(O)R10, -N(Rg)- C(O)-OR10, -N(Rg)-C(O)-N(R8)(R10), -N(Rs)-C(S)OR10, -N(Rs)-C(S)-OR10, - N(Rs)-C(S)-N(Rg)(R1 O) (wherein R8, and R10 are independently from the group consisting of H, optionally substituted (Ci-C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. when Rs is NH-O-X-R1 1, wherein X and R11 is defined as above .
H. W is N-O-X-R11; wherein X represents substituted or unsubstituted (Ci- C10) alkyl or (CJ -CJO) alkenyl or (C6-CiO) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(R8)(R9), N(R8)(R9), CO2R10, wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted (C1-C20) alkyl, optionally substituted (C2-C20) heteroalkyl optionally 7 substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; R1 , R2, R3, Re, R7, Yi, Y2 and Y3 are each hydrogen; R4 is fluoro, or OR1o, and R5 is OR14 or N(R8)(R9) wherein i. when R5 is R14O, R14 is hydrogen or (Ci-C8) alkyl; ii. when R5 is N(R8)(R9), R8 is hydrogen and R9 is selected from the group consisting of (Ci-Cs) alkyl, (Ci-C8) alkoxy, (CJ-C8) cycloalkyl, (C2-C8) alkenyl and (C2-C8) alkynyl; wherein said alkyl, alkoxy, alkenyl and alkynyl are optionally substituted wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, optionally substituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, (C2-Ce) heterocycloalkyl and (C2-Ce) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; iii. when R5 is N(Rg)(Rg), Rs and R9, together with the nitrogen to which they are attached, form a heterocyclic residue selected from the group consisting of optionally substituted aziridinyl, azetidinyl and pyrrolidinyl wherein said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, substituted or unsubstituted amino, hydroxyl, (Ci-Cs) alkoxyl, carboxyl, amidino and acylamino; or iv. when R5 is selected from -OR10, -SR10, -N(Rs)-C(O)R10, -N(R8)- C(O)-OR10, -N(Rg)-C(O)-N(R8)(R1 0), -N(Re)-C(S)OR10, -N(Rs)-C(S)-OR10, - N(Rg)-C(S)-N(Re)(R1O) (wherein R8 and R10 are independently selected from the group consisting of H, optionally substituted (C1-C2O) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and. optionally substituted cycloheteroalkyl; or together form a 4-7 membered optionally substituted ring). v. when R5 is NH-O-X-Rn, wherein X and R11 are as defined above.
[00431 In particular embodiments, compounds of the invention are selected from the group consisting of compounds of the formula ϊ, wherein
W represents: O or N-OH, or N-O-COR10, or N-O-X-Rn; wherein
X represents substituted or unsubstituted (Ci-Cio) alkyl or (CI -CJO) alkenyl or (Ce- C10) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(Rg)(R9), N(R8)(R^,
wherein R8 and R9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (CJ-C20) alkyl, optionally substituted (C2- C20) heteroalkyl optionally 7 substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; or R8 is selected from the group consisting of H, optionally substituted C1-Cβ alkyl, optionally substituted Cs-Cs aryl, and optionally substituted C5-C8 heteroaryl, or R8, together with R9, forms an optionally substituted 4-7 membered heterocyclic or carbocyclic ring; wherein R1o is selected from the group optionally substitated (C]-C2O) alkyl, optionally substituted (C]-C2O) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted (Ce-C20) aryl, optionally substituted (C6-C20) aryU optionally substituted (C3-C2O) heteroaryl, optionally substituted (C7-C20) arylalkyl, optionally substituted (C4-C20) heteroarylalkyl, optionally substituted (C3-C20) cycloalkyl, optionally substituted (C2-C20) cycloheteroalkyl;
R], R2, R3, Re, R7, Yi, Y2 and Y3 are each hydrogen,
R4 is OH or OR1o wherein R1o is selected (Ci-Cs) alkyl, amino (Ci-C8) alkyl, protected amino (Ci-C8) alkyl, phenyl and naphthyl; and
R5 is independently N(R8)(R9) wherein R8 is hydrogen and R9 is selected from hydrogen, (Ci-Ce) alkyl, (C2-Cs) alkenyl and (C2-Cs) alkynyl; wherein said alkyl, alkenyl and alkynyl groups are optionally substituted and said substituents are selected from the group consisting of halo, cyano, mercapto, (Ci-C8) alkylthio, optionally substituted amino, hydroxyl, (Ci-C8) alkoxyl, carboxyl, amidino, acylamino, (C2-CO) heterocycloalkyl and (C2-Ce) heterocycloaryl and if comprising more than two carbon atoms may be branched, cyclic, unbranched or combinations of branched, cyclic and unbranched groups; or R5 is N(Rg)(R9) wherein Rs and R9, together with the nitrogen to which they are attached, form a 3 to 6 membered heterocycloalkyl or heterocycloaryl ring which is optionally substituted with one or more groups selected from hydroxyl, halo, cyano, (Ci-Ce) alkoxyl, (C]-CO) alkylthio, (C2-CO) heterocycloalkyl and (C2-Ce) heterocycloaryl; or Rs is R14O wherein Ru is optionally substituted (C]-C8) alkyl.
[0044] In certain embodiments of the compounds of formula (I)5 Rι and R2 form a single bond; R3, R6, R7, Yi, Y2 and Y3 are each H; R4 is hydroxyl; R5 is -OCH3 (also referred to as "OMe" or "methoxy"); and
[0045] W is defined as described herein. In particular embodiments, W is as described in Table 1. In some embodiments, W is as described in Table 3. In certain embodiments, W is N-OH, N-O-COR1o, or N-O-X-Rn, wherein X, R1o and Rn are as described herein. In some embodiments, W is N-O-COR10, or N-O-X-R1 i • In other embodiments, W is N-OH or N-O- COR1o. In certain embodiments, W is N-OH or N-O-X-R1 i - In particular embodiments, W is N-O-COR1o. In some embodiments, W is N-O-X-Rj i . In others, W is N-OH.
[0046] In certain embodiment of the compounds of formula (I), R1 and R2 form a single bond; R3, R6, R7, Yi, Y2 and Y3 are each H;
R4 is O-R10, wherein R1ois hydrogen, acetyl, alkyl, -C(O) R1o (wherein R1 o is as described herein), or aryl; and
[0047] R5 and W are defined as described herein. In particular embodiments, W is as described in Table 1. In some embodiments, W is as described in Table 3. In particular embodiments, W is as defined in Table 1 or Table 3. In certain embodiments, W is N-OH, N- O-COR10, or N-O-X-Rn, wherein X, R1o and Rn are as described herein. In some embodiments, W is N-O-COR1o, or N-O-X-R1 1. In other embodiments, W is N-OH or N-O- CORjo- In certain embodiments, W is N-OH or N-O-X-R] 1. In particular embodiments, W is N-O-COR1o. In some embodiments, W is N-O-X-R1 1. In others, W is N-OH. In some embodiments, R5 and W are as described in Table 3. In certain embodiments, R5 is as described in Table 3. In some embodiments, R5, R1 • and W are, independently, as defined in Table 3. In some embodiments, Rp is hydrogen, acetyl, or -C(O)R1O (wherein R1o is as described herein). In certain embodiments, R1- is hydrogen, acetyl, or -C(O)R1O wherein R1o is optionally substutited alkyl. In particular embodiments R1o is unsubstutited alkyl. In some embodiments, R1o is a C1-C10 alkyl, C6-C20 alkyl, CiO-Ci8 alkyl, C12-C18 alkyl or C15 alkyl. In some embodiments, Rp is hydrogen or acetyl. In other embodiments, R]- is hydrogen. In still other embodiments, R1 • is acetyl.
[0048] Compounds of formula (I) or pharmacologically acceptable salts thereof may exist in the form of addition products with water or various solvents, and these addition products are also included in the present invention. Examples of compounds of formula (I) are shown in Table 1. Table 1
Specific examples of formula (I)
Figure imgf000026_0001
Figure imgf000026_0002
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
[0049] In certain embodiments, compounds of the invention are selected from the compounds listed in Table 2, below:
Table 2
Figure imgf000036_0002
Figure imgf000037_0001
Figure imgf000038_0001
[0050] The pharmacologically acceptable salts of formula (I) include acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, and the like. Examples of the acid addition salts include inorganic acid salts (for example, hydrochloride, hydrobromide, sulfate, phosphate, and the like), and organic acid salts (for example, formate, acetate, oxalate, benzoate, methanesulfonate, p-toluenesulfonate, maleate, fumarate, tartrate, citrate, succinate, lactate, and the like). Examples of the metal salts include alkali metal salts (for example, lithium salt, sodium salt, potassium salt, and the like), alkaline earth metal salts (for example, magnesium salt, calcium salt, and the like), aluminum salts, zinc salts, and the like. Examples of the ammonium salts include salts with ammonium, tetramethylammonium, and the like. Examples of the organic amine addition salts include addition salts with morpholine, piperidine, and the like. Examples of the amino acid addition salts include addition salts with glycine, phenylalanine, aspartic acid, glutamic acid, lysine, and the like.
10051] In another embodiment, a method of preparing the inventive compounds is provided. The compounds of the present invention are generally prepared using geldanamycin as a starting material. Compound (I) may contain various stereoisomers, geometric isomers, tautomeric isomers, and the like. All of possible isomers and their mixtures are included in the present invention, and the mixing ratio is not particularly limited.
[0052] The synthetic method of formula (I) mainly comprises 17-substituted geldanamycin production (Step 1), oxime formation (Step 2), acylation/carbamoylation/alkoxycarbonylation (Step 3), alkylation (Step 3), amidation/esterification (Step 4), and each compound of interest is produced by combining these reaction steps depending on the object.
[0053] The general procedure for preparation of 17-substituted geldanamycin derivatives is shown in Step 1 and the geldanamycin derivatives can be prepared based on procedures known in the art, such those found in U.S. patent No. 4,621,989. Compound (B) is prepared from geldanamycin by such known or modified procedures.
Step 1
Figure imgf000039_0001
B [0054J As illustrated in Step 2, Formula (Ia) can be prepared by oxime formation of the quinone carbony] of geldanamycin from geldanamycin and its derivatives that can be prepared from the related starting materials. For example, formula (Ia) can be prepared by allowing compound (A) or compound (B) to react with compound (II) represented by the following formula H2N-O-RBa (II) (wherein Rja is a group in which COR10 wherein R1 o has the same meaning as described above) or an acid addition salt thereof.
[00551 Examples of suitable reaction solvents include, but are not limited to, pyridine, chloroform, dichloromethane, ethyl acetate, ether, tetrahydrofuran (THF), dimethylformamide (DMF), acetonitrile, and the like, which may be used either alone or as a mixture thereof. An exemplary solvent is pyridine. Examples of suitable acids include hydrochloric acid, acetic acid, trifluoroacetic acid, sulfuric acid, p-toluenesulfonic acid, camphorsulfonic acid, and the like. The acids may be used in an amount of 0.1 to 10 equivalents based on compound (A) or (B).. When an acid addition salt of formula (II) is used, the reaction can be carried out in the presence of a base, for example, an amine (e.g., pyridine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, N,N-diethylaniline, or the like), an alkali metal, carbonate, or bicarbonate (e.g., sodium carbonate, potassium carbonate, or the like), in an amount of 1 equivalent or more based on the acid addition salt of formula (II). In a particular embodiment, pyridine is used as both the amine and the solvent. The reaction is carried out at a temperature of -20 to 100° C5 for example, 20 to 80° C, and the reaction completes after 1 to 80 hours.
Step 2
Figure imgf000040_0001
(A) or (B) (Ia)
[0056] Compound (Ib) can be prepared by the conversion of compound (A) or (B) to an oxime compound (C). The resulting hydroxy 1 group is subjected to acylation, carbamoylation, or alkoxycarbonylation.
Figure imgf000041_0001
(A) or (B) (C) (Ib)
[0057] Compound (C) can be prepared by allowing compound (A) or (B) to react with hydroxylamine or an acid addition salt thereof according to Step 1.
[0058] Compound (Ib) can be prepared by allowing compound (C) to react with compound (III) represented by the following formula R1o COQ (III) (wherein R] o has the same meaning as defined above), or with compound (IV) represented by the following formula R1o'NCO (IV) (wherein R1o' represents substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted pyridyl), in the presence of a base.
[0059] As the reaction solvent, dichloromethane, ether, THF, DMF, and the like, may be used alone or as a mixture thereof. As the base, amines (for example, pyridine, triethylamine, diisopropylethylamine, or the like) may be used in an amount of 0.1 equivalent or more, for example, , 1 to 10 equivalents, based on compound (III) or (IV). Compound (III) or (IV) is used in an amount of 1 equivalent or more, preferably 1 to 10 equivalents, based on compound (C). The reaction is carried out at a temperature of -80 to 100° C, for example -60 to 0° C, when compound (III) is used, or at a temperature of 0 to 80° C. when compound (IV) is used. Each reaction completes after 10 minutes to 48 hours.
[0060] Compound (Ic) can be prepared by alkylation of the hydroxyl group of compound (C). The reaction may be carried out by allowing compound (C) to react with compound (V) represented by the following formula HOR1o (V) (wherein R1o has the same meaning as defined above) in the presence of a condensing agent.
[0061] As the reaction solvent, toluene, THF, dichloromethane, and the like, may be used alone or as a mixture thereof. As the condensing agent, trivalent phosphorous compounds (for example, triphenylphosphine, tributylphosphine, or the like) and azo compounds (for example, diethyl azodicarboxylate (DEAD), 1 , 1 -(azodicarbonyl)diρiperidine, and the like) may be used alone or as a mixture thereof. Each of compound (C) and the condensing agent is used in an amount of 1 equivalent or more, for example 1 to 5 equivalents, based on compound (G). The reaction is carried out at a temperature of -20 to 80° C, e.g., 0 to 30° C, and the reaction completes after 5 minutes to 48 hours.
[0062] Compound (Ic) can be prepared by converting compound (A) or (B) into oxime compound (D) in which a carboxyl group is introduced, and then the carboxyl group is subjected to amidation or esterifϊcation (Step 3) [Where X-Rl 1; wherein X represents substituted or unsubstituted (Ci-Cio) alkyl or (Ci-Cιo) alkenyl; R1 i represents hydrogen, hydroxyl, halogen, cyanide, or CON(RS)(RO, N(R8)(R9) or CO2R10, (wherein R8 and R9 and R1o have the same meaning as defined above)].
Step 3
Figure imgf000042_0001
[0063] Compound (D) can be prepared by allowing compound (A) or (B) to react with compound (VI) represented by the following formula H2 N-O-X-CO2H (VI) (wherein X has the same meaning as defined above) or an acid addition salt thereof.
[0064] Compound (Ic) can be prepared by allowing compound (D) to react with compound (VII) represented by the following formula HNR8 R9 (VII) (wherein R8 and R9 have the same meaning as defined above) or an acid addition salt thereof, or with a compound (VIII) represented by the following formula HOR10 (VIII) (wherein R1o has the same meaning as defined above), in the presence of a condensing agent.
[0065] As the condensing agent, l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), l,r-carbonyldiimidazole, or the like, may be used. Additionally, the reaction can be accelerated by adding an additive agents, such as N-hydroxysucciniimide (HONSu), 4-(dimethylamino) pyridine (DMAP), 1- hydroxybenzotriazole hydrate (HOBt), or the like, in an amount of 0.1 to 5 equivalents based on compound (D). As the reaction solvent, dichloromethane, ether, THF, DMF, and the like, may be used alone or as a mixture thereof. When an acid addition salt of compound (VII) is used, the reaction can be carried out in the presence of a base, such as an amine. Examples of amines include, but are not limited to, pyridine, triethylamine, diisopropylethylamine, or the like. In certain embodiments, triethylamine is used, in an amount of 1 equivalent or more, for example, 1 to 10 equivalents, based on the acid addition salt of compound (VII). Each of compound (VII) or an acid addition salt thereof or compound (VIII) and the condensing agent may be used in an amount of 1 equivalent or more, e.g., 1 to 5 equivalents, based on compound (D). The reaction is carried out at a temperature of -20 to 80° C, for example, 0 to 40° C. Each reaction completes after 10 minutes to 48 hours.
[0066] Those of ordinary skill, in view of the teachings provided herein, will appreciate additional modifications (e.g., choice of starting materials, reactants, temperature, reaction times, purification method, etc.) of the general methods provided above and the specific synthetic methods provided in the Examples, depending upon the selection of particular starting materials and final products desired. Compounds of formula (I) may also be further purified as described herein and, additionally, by methods known to those of skill in the art. Suitable purification methods include, for example, crystallization, HPLC, flash column chromatography, preparative thin layer chromatography, etc.
[0067] The lipophilic compounds of this invention will more easily pass through the cell membranes and distribute across tissues and the blood brain barrier. Such tissue includes the blood and blood forming system including platelets, blood vessel wall, and bone marrow; the cardiovascular system including heart and vascular system; digestive and excretory system including alimentary tract, biliary tract, kidney, liver, pancreas and urinary tract; the endocrine system including adrenal gland, kidney, ovary, pituitary gland, renal gland, salivary gland, sebaceous gland, testis, thymus gland and thyroid gland; the musclar system; reproductive system, including breast, ovary, penis and uterus; the respiratory system including bronchus, lung and trachea; skeletal system including bones and joints; tissue, fiber, and integumentary system including adipose tissue, cartilage, connective tissue, cuticle, dermis, epidermis, epithelium, fascia, hair follicle, ligament, bone marrow, melanin, melanocyte, mucous membrane, skin, soft tissue, synovial capsule and tendon.
[0068] Compounds of the present invention often have a strong binding affinity for Hsp90. A preferred method of determining the relative binding affinities is by comparing the concentration of the test compound at which 50% of the target -protein is bound (otherwise known as the ICso concentration level) in a competitive binding assay, the performance of which is routine for the skilled artisan.
[0069] The efficacy of the compounds of formula (I), or compositions thereof (including pharmaceutical compositions), as described herein, for use in the treatment of the diseases and/or conditions described herein can be determined using routine in vitro assays and in vivo animal models known to the one of skill in the art. For example, efficacy with respect to the possible use of the compounds for the treatement of cancer can utilitze well known in vitro assays for determining the cytotoxicty of particular compounds on certain types of cancer. Numerous cancer cell lines and tumor models are availaiable to the skilled artisan, as, for example, the MX-I (human breast carcinoma) cell line described in Example 63. Such in vitro assays and in vivo models can also be used to determine the efficacy of particular combinations of one or more of the compounds of formula (I) and/or additional combinations with other active agents described herein for use in the treatment of the conditions as described.
[0070] Given the teachings provided, the skilled artisan will be able to choose appropriate assays based on the condition or disease being targeted. Methods for testing the efficacy and toxicity (e.g., appearance of adverse effects during treatment) previously used to characterize geldanamycin and 17- AAG may also be used to characterize the compounds of formula (I). For example, the methods described in the references cited in the Background of Invention of the present specification (e.g., Li et al, ibid; Mandler et al, ibid; etc.).
[0071] Geldanamycin analogs of Formula (I) in this invention can be used in accordance with the methods of the present invention to alter the function of hormone receptors, making it easier to inhibit the associated signal pathways using low levels of a second drug which targets the proteins involved in those signaling pathways. Such a combination therapy can be useful to reduce non-specific toxicity associated with therapy by reducing the level of the drug required.
[0072] In another aspect, the present invention provides compositions for treatment of individuals (e.g., mammals, etc.) in need thereof, comprising one or more of the compounds of formula (I) as described herein and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, preservatives, or other inactive ingredients, including combinations of two or more of the foregoing, known to skilled artisans and described further herein. [0073] In certain embodiments of the compositions (including pharmaceutical compositions), the composition comprises a single compound of formula (I). In other embodiments, the composition comprises at least 1 , at least 2, at least 3, or 2, 3, or 4 of the compounds of formula (I).
[0074] In certain embodiments, the compositions comprise a compound of formula (I), wherein the compound is a compound listed in Table 1 , Table 2, or Table 3. In particular embodiments, the composition comprises a compound of Table 1. In certain embodiments the composition comprises a compound of Table 2. In another embodiment the composition comprises a compound of Table 3.
[0075] The present invention provides compositions of matter that are formulations of one or more active drugs and a pharmaceutically-acceptable carrier. In this regard, the invention provides a composition for administration to an individual in need thereof, which may include a plurality of particles of the compound of formula I and a pharmaceutically acceptable carrier. In certain embodiments, the average size of the particles is no greater than about 500 nm, no greater than 400 nm, no greater than 200 nm. In particular embodiments, the average size of the particles is about 150 nm, about 200 nm, about 300 nm, about 350 nm, about 400 nm, about 450 nm, about 500 nm, from about 100 nm to about 550 nm, from about 150 nm to about 500 nm from about 150 nm to about 400 nm, from about 150 nm to about 350 nm, from about 150 nm to about 300 nm, from about 150 nm to about 250 nm; from about 200 nm to about 400 nm; or from about 200 nm to about 350 nm.
[0076] Average particle size can be determined by methods known to the skilled artisan, including such techniques as from the correlation function by using various algorithms using Photon Correlation Spectroscopy (PCS; Dynamic Light Scattering or Quasi-Elastic Light Scattering (QELS)). The particle size obtained by these techniques is comparable to the mean diameter determined by PCS.
[0077] The compounds of the present invention may be administered as a composition, for example, as a pharmaceutical composition containing the compounds and a pharmaceutically-acceptable carrier or diluent. The active materials can also be mixed with other active materials that do not impair the desired action and/or supplement the desired action. The active materials, in accordance with the present invention, may be administered by any acceptable route including, but not limited to, orally or parenterally {e.g., intravenously, intradermally, subcutaneously, intramuscularly, by an airborne delivery system, topically, etc.), in liquid or solid form.
[0078] It is intended that, as used herein, the term "composition" unless clearly intended otherwise by the context of use, is inclusive of pharmaceutical compositions, whether or not explicitly so stated.
[0079] Oral compositions will generally include an inert diluent or an edible carrier. Such oral compositions may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the aforesaid compounds may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like.
[0080] The oral compositions may contain additional ingredients such as: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, corn starch and the like; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; and a sweetening agent such as sucrose or saccharin or flavoring agent such as peppermint, methyl salicylate, or orange flavoring. When the dosage unit form is a capsule, it may additionally contain a liquid carrier such as a fatty oil. Other dosage unit forms may contain other various materials which modify the physical form of the dosage unit, such as, for example, a coating. Thus, tablets or pills may be coated with sugar, shellac, or other enteric coating agents. A syrup may contain, in addition to the active ingredients, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors. Materials used in preparing these various compositions should be pharmaceutically or veterinarally pure and non-toxic in the amounts used.
[0081] For the purposes of parenteral therapeutic administration, the active ingredient may be incorporated into a solution or suspension. The solutions or suspensions may also include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. (0082] The pharmaceutical forms suitable for injectable use include sterile solutions, dispersions, emulsions, and sterile powders. The final form should be stable under conditions of manufacture and storage. Furthermore, the final pharmaceutical form should be protected against contamination and should, therefore, be able to inhibit the growth of microorganisms such as bacteria or fungi. A single intravenous or intraperitoneal dose can be administered. Alternatively, a slow long-term infusion or multiple short-term daily infusions may be utilized, typically lasting from 1 to 8 days. Alternate day dosing or dosing once every several days may also be utilized.
[0083] Sterile, injectable solutions may be prepared by incorporating a compound in the required amount into one or more appropriate solvents to which other ingredients, listed above or known to those skilled in the art, may be added as required. Sterile injectable solutions may be prepared by incorporating the compound in the required amount in the appropriate solvent with various other ingredients as required. Sterilizing procedures, such as filtration, may then follow. Typically, dispersions are made by incorporating the compound into a sterile vehicle which also contains the dispersion medium and the required other ingredients as indicated above. In the case of a sterile powder, exemplary methods include vacuum drying or freeze drying to which any required ingredients are added.
10084] Suitable pharmaceutical carriers include sterile water; saline, dextrose; dextrose in water or saline; condensation products of castor oil and ethylene oxide combining about 30 to about 35 moles of ethylene oxide.per mole of castor oil; liquid acid; lower alkanols; oils such as corn oil; peanut oil, sesame oil and the like, with emulsifiers such as mono- or di-glyceride of a fatty acid, or a phosphatide, e.g., lecithin, and the like; glycols; polyalkylene glycols; aqueous media in the presence of a suspending agent, for example, sodium carboxymethylcellulose; sodium alginate; poly(vinylpyrolidone) ; and the like, alone, or with suitable dispensing agents such as lecithin; polyoxyethylene stearate; and the like. The carrier may also contain adjuvants such as preserving stabilizing, wetting, emulsifying agents and the like together with the penetration enhancer. In all cases, the final form, as noted, must be sterile and should also be able to pass readily through an injection device such as a hollow needle. The proper viscosity may be achieved and maintained by the proper choice of solvents or excipients. Moreover, the use of molecular or particulate coatings such as lecithin, the proper selection of particle size in dispersions, or the use of materials with surfactant properties may be utilized. [0085] In accordance with the invention, there are provided compositions containing compounds of formula (I) and methods useful for the in vivo delivery of compounds of formula (I) in the form of nanoparticles., which are suitable for any of the aforesaid routes of administration.
[0086] United States Patent Nos. 5,916,596, 6,506,405 and 6,537,579 teach the preparation of nanoparticles from the biocompatible polymers, such as albumin. Thus, in accordance with the present invention, there are provided methods for the formation of nanoparticles of the present invention by a solvent evaporation technique from an oil-in- water emulsion prepared under conditions of high shear forces (e.g., sonication, high pressure homogenization, or the like).
|0087] As noted previously, in one aspect is provided a method of treatment of conditions as described herein using the compounds of formula (I) and/or compositions (including pharmaceutical compositions) as described herein.
[0088] In one embodiment, the methods may be practiced as a therapeutic approach toward the treatment of the conditions described herein. Thus, in certain embodiments, the the compounds of formula (I) and compositions may be used to treat the conditions described herein in individuals in need thereof, including humans. The methods generally comprise administering to the individual an amount of a compound of formula (I)5 or composition described herein, effective to treat the condition. In certain embodiments, more than one compound of formula (I) may be administered, either concurrently with, prior to or after the administration of the first compound. The compounds, if administered concurrently, may be administered in the same or separate formulations.
[0089] In some embodiments, the individual is a mammal, including, but not limited to, human, bovine, horse, feline, canine, rodent, or primate. In other embodiments, the individual is a human.
[0090] The terms, "pharmaceutically effective amount," "therapeutically effective amount" or "amount sufficient to achieve a therapeutic effect" refer to an amount of a compound or composition sufficient to treat a specified disorder, condition or disease or one or more of its symptoms and/or to prevent the occurrence of the disease or disorder. In reference to cancers, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause a tumor to shrink or to decrease the growth rate of the tumor, or suppress tumor growth, where the tumor is benign or malignant.
[0091] In accordance with the invention, the compounds of the invention may be used to treat diseases associated with cellular proliferation or hyperproliferation, such as cancers which include but are not limited to tumors of the nasal cavity, paranasal sinuses, nasopharynx, oral cavity, oropharynx, larynx, hypopharynx, salivary glands, and paragangliomas. The compounds of the invention may also be used to treat cancers of the liver and biliary tree (particularly hepatocellular carcinoma), intestinal cancers, particularly colorectal cancer, ovarian cancer, small cell and non-small cell lung cancer, breast cancer, sarcomas (including fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcoma, neuro-fibrosarcoma,( osteosarcoma, synovial sarcoma, liposarcoma, and alveolar soft part sarcoma), neoplasms of the central nervous systems (particularly brain cancer), and lymphomas (including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma).
[0092] The compounds of formula (I) and compositions thereof described herein, may be used alone or in conjunction with {e.g., prior to, concurrently with, or after) other modes of treatments (e.g., adjunctive cancer therapy, combined modality treatments). For example, in combination with other therapeutic agents (e.g., cancer chemotherapeutic agents as described herein and known to those of skill in the art), surgery, and/or radiation therapy. Where the condition being treated is cancer, the compositions described herein can be administered in conjunction with one or more of other anticancer agents or cytotoxic compounds as described herein and as know in the art, one or more additional agents to reduce the occurrence and/or severity of adverse reactions and/or clinical manifestations thereof, surgery (e.g., to remove a tumor or lymph nodes, etc.) or radiation. Where one or more of surgery or radiation are part of the treatment regimen, the compositions may be administered before, concurrently, or after the radiation therapy or surgery. Likewise, the compositions, and formulations thereof, as described herein may be administered before, concurrently, or after the administration of one or more anticancer agents. The compounds of formula (I) and compositions described herein may also be administered in conjunction with (e.g., prior to, concurrently with, or after) agents to alleviate the symptoms associated with the condition or the treatment regimen (e.g., agents to reduce vomiting, hair loss, immunosuppression, etc.). The compounds of formula (I) or compositions thereof may also be administered at more than one stage of (including throughout) the treatment regimen (e.g., after surgery and concurrently with and after radiation therapy, etc.).
[0093] In certain embodiments, the compositions are administered prior to or after surgery (e.g., removal of a tumor or lymph nodes, etc.). In other embodiments, the compositions are administered after surgery and prior to, concurrently with or after radiation therapy. The optimal combination of one or more of surgery and/or radiation therapy in conjunction with administration of the compositions described herein, and, optionally, additional one or more chemotherapeutic agents (e.g., either agents active against the disease or condition being treated, or effective to treat the adverse effects of the anti-disease agents), can be determined by an attending physician based on the individual and taking into consideration the various factors effecting the particular individual, including those described herein.
[0094] The invention also provides methods of treating a mammal afflicted with the above diseases and conditions. The method includes administering one or more of the inventive compounds to the afflicted individual. Thus, in certain embodiments, the methods may further include the administration of a second active agent, such as a cytotoxic agent, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and topoisomerase inhibitors. The second active agent may be co-administered in the same composition or in a second composition. Examples of suitable second active agents include, but are not limited to, a cytotoxic drug such as Acivicin; Aclarubicin; Acodazole Hydrochloride; AcrQnine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefϊngol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflomithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estraniustine Phosphate Sodium; Etanidazole; Ethiodized Oil 1 131; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-nl; Interferon Alfa-n3; Interferon Beta- 1 a; Interferon Gamma- 1 b; Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safmgol; Safingol Hydrochloride; Semustine; Simtrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazofurin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and Zorubicin Hydrochloride. In accordance with the invention, the compounds and compositions may be used at sub-cytotoxic levels in combination with other agents in order to achieve highly selective activity in the treatment of non-neoplastic disorders, such as heart disease, stroke and neurodegenerative diseases. See Whitesell et al., Curr Cancer Drug Targets. 2003, 3(5), 349-58. In this embodiment, die compounds useful in the methods of the invention are used to reduce the cellular levels of Hsp90 client proteins, which are then effectively inhibited by the second agent. Binding of the client proteins to Hsp90 stabilizes the client proteins and maintains them in a soluble, inactive form ready to respond to activating stimuli. Binding of a geldanamycin derivative to Hsp90 results in targeting the client protein to the proteasome, and subsequent degradation. For systems such as a steroid receptor, however, Hsp90 forms an integral part of the functional receptor complex along with several other proteins such as Hsp70, Hsp40, p23, hip, Hsp56, and immunophilins. Hsp90 appears to regulate the activity of the steroid receptor by maintaining the receptor in a high-affinity hormone-binding conformation. In a preferred embodiment, the second active agent is a taxane, such as paclitaxel and docetaxel.
[0095] In another preferred embodiment of the inventive method, the inventive compound is administered with (i.e., co-administered or conjugated to) a therapeutic antibody. The therapeutic antibody is one that is specific to a target of interest, such as a cancer cell. In this regard, the antibody may be an antibody, an antibody fragment, or a functional equivalent thereof. Further, the antibody may be polyclonal, monoclonal, humanized, or chimerized. Immunoconjugate preparation is well known to those of skill in the art. For examples of antibodies and their preparation, see Mandler et al. Cancer Res. 2004, 64(4), 1460, as well as U.S. Patent Nos. 4,867,962, 5,601 ,825, 6,391,913, and U.S. Published Patent Application Nos. 20060141545 and 20060233811, each of which is incorporated herein by reference.may be conjugated thereto. Such methods are known in the art (see). In a preferred method, the inventive compound is administered with trastuzumab.
[0096] As noted previously, the compounds of formula (I) and compositions as described herein may be administered to individuals in need thereof for the treatment of conditions as described herein in conjunction with the methods of use described herein.
[0097] The compounds of formula (I) and compositions described herein, will generally be used in an amount sufficient to achieve the intended result, for example in an amount effective to treat or prevent the particular condition being treated. The compound(s) and composition(s) may be administered therapeutically to achieve therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, notwithstanding that the patient may still be afflicted with the underlying disorder. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.
[0098] In some embodiments, where the condition being treated is a cancer, an effective amount is an amount sufficient to reduce tumor growth (e.g., as measured by rate of increase of mean tumor volume prior to and/or after treatment). In certain embodiments, an effective amount is an amount sufficient to decrease mean tumor volume (e.g., where mean tumor volume after treatment is reduced compared to mean tumor volume prior to treatment).
[0099] The amount of compound or composition administered in order to administer an sufficient amount to treat the disease or condition will depend upon a variety of factors, including, for example, the particular condition being treated, the mode of administration, the severity of the condition being treated and the age and weight of the patient, the bioavailability of the composition, the adverse effects experienced by the individual being treated, etc. Determination of an effective dosage is well within the capabilities of those skilled in the art in view of the teachings provided herein. Dosages may also be estimated using in vivo animal models.
[00100] In certain embodiments of the methods of treatment described herein, the compound of formula (I), or composition thereof, that is administered is a compound listed in Table 1, Table 1, or Table 3. In particular embodiments, the compound of formula (I), or composition thereof, which is administered, is a compound of Table 1. In certain embodiments the compound of formula (I), or composition thereof, which is administered, is a compound of Table 2. In another embodiment the compound of formula (I), or composition thereof, which is administered, is a compound of Table 3.
[00101] In another aspect are provided kits for administration of the compounds of formula (I) and compositions described herein.
[00102] In certain embodiments the kits may include a unit dosage amount of at least one compound of formula (I) or composition, as disclosed herein. Kits may further comprise suitable packaging and/or instructions for use of the compound or composition. Kits may also comprise a means for the delivery of the compound of formula (I) or composition, such as a syringe for injection or other device as described herein and known to those of skill in the art. {00103] Additionally, the compounds of formula (I) and compositions thereof may be assembled in the form of kits. The kit may provide the compounds of formula (I) or compositions thereof and reagents to prepare a composition for administration. The composition may be in a dry or lyophilized form, or in a solution, particularly a sterile solution. When the composition is in a dry form, the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation. Such diluents include those known to those of skill in the art and are additionally described herein.
[00104] The kit may also contain a device for administration or for dispensing the compositions, including, but not limited to syringe, pipette, or other device known to those of skill. When in a wet form, the composition may be stored in an ampoule or other sterile sealed container, including those known to persons of skill in the art.
[00105] The kits may include other therapeutic compounds for use in conjunction with the compounds described herein. In one embodiment, the therapeutic agents are other anticancer agents. These agents may be provided in a separate form, or mixed with the compounds of the present invention, provided such mixing does not reduce the effectiveness of either the additional therapeutic agent of the compositions and formulations described herein. Similarly the kits may include additional agents for adjunctive therapy. For example, agents to reduce the adverse effects of the drug (e.g., anti-nausea agents, anti-alopecia agents, immuno- enhancing agents, etc.).
[00106] The kits will include appropriate instructions for preparation and administration of the compound/composition, side effects of the compound/compositions, and any other relevant information. The instructions may be in any suitable format, including, but not limited to, printed matter, videotape, computer readable disk, or optical disc.
[00107] In a particular embodiment of the invention, kits for treating an individual who suffers from or is susceptible to the conditions described herein are provided, comprising a first container comprising a dosage amount of the compound of formula (I) or compositions as disclosed herein, and instructions for use. The container may be any of those known in the art and appropriate for storage and delivery of intravenous formulations. In certain embodiments the kit further comprises a second container comprising a pharmaceutically acceptable carrier, diluent, adjuvant, etc. for preparation of the composition to be administered to the Individual. 100108] Kits may also be provided that contain sufficient dosages of the compounds of formula (I) or compositions as disclosed herein to provide effective treatment for an individual for an extended period, such as a week, 2 weeks, 3, weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months or more.
[00109] Kits may also include multiple unit doses of the compounds of formula (I) and compositions and instructions for use and packaged in quantities sufficient for storage and use in pharmacies, for example, hospital pharmacies and compounding pharmacies.
[00110] In certain embodiments, the kit may comprise appropriately packaged oral dosage forms and instructions for use.
[00111] In particular embodiments of the kits described herein, the kits comprise a compound of formula (I) or a composition thereof, wherein the compound is a compound listed in. Table 1, Table 2, or Table 3. In particular embodiments, the kits comprise a compound of formula (I) or a composition thereof, wherein the compound is a compound of Table 1. In certain embodiments the kits comprise a compound of formula (I) or a composition thereof, wherein the compound is a compound of Table 2. In another embodiment the kits comprise a compound of formula (I) or a composition thereof, wherein the compound is of Table 3.
[00112] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.
EXAMPLE 1
100113] This example demonstrates the preparation of 17-methoxyamino-17- demethoxygeldanamycin (1) and 18-o-methyloximino geldanamycin (2).
[00114] To a solution of geldanamycin (100.0 rag, 0.1784 mmol) in pyridine was added o- methylhydroxyamine hydrochloride (148.9 mg, 1.78 mmol), and the mixture was then stirred at 80° C. overnight, and then removed the pyridine completely by vacuum. The residue was purified by column chromatography, eluting with CH2CVMeOH (40: 1 to 20:1) to give 2 as a yellow solid (35.4 mg, 32 % yield). 1H NMR (CDCl3, 500 MHz) δ 8.78 (s, IH, NH-22), 8.22 (s,1H , 19-H), 6.92 (d, J=11.6 Hz, ,1H 3-H), 6.56 (t, J=11.2 Hz, IH, 4-H), 5.91 (d, J=9.4 Hz3 IH, 9-H), 5.82 (t, J=10.6 Hz, 1,H 5-H), 5.17 (s, ,17H-H), 4.90 (brs, 2H, NH2), 4.30 (d, y=9.8 Hz,1H , 6-H), 4.21 (s, 3H, methoxyl 0-CH3), 4.01 (s, 3H, 17-O-CH3), 3.55 (t, /=14.9 Hz, IH, 12-H), 3.43 -3.40 (m, 1H, H-H), 3.35 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 2.76-2.73 (m, IH, 10-H)3 2.60-2.53 (m, 1,H 15-H), 2.42 (d, 7=11.7 Hz, IH, 15-H), 2.02 (s, 3H, 2-CH3), 1.84- 1.83 (m, 2H5 13-H), 1.62 (d, 3H, 7=1.2 Hz, 8-CH3), 1.63-1.60 (m, IH, 14-H), 1.00-0.97 (m, 6H, 10-CH3, 14-CH3); 13C NMR (HH23, CDCl3, 125 Hz) δ 183.6 (C-22), 168.3 (C-17), 160.6 (C-I), 155.9 (C-18), 145.6 (7-OCONH2), 135.2 (C-19, C-3), 133.8 (C-2), 133.1 (C-4), 132.8 (C-8), 126.9 (C-9), 126.5 (C-20), 126.2 (C-5), 102.3 (C- 16), 81.8 (C-6), 81.2 (C-7), 81.2 (C- 12), 72.2 (C-1 1), 64.3 (18-NOCH3), 63.6 (12-OC), 57.0 (17-OC), 56.6 (6-OC), 35.2 (C-15), 33.6 (C-13), 32.1 (C-IO), 27.3 (C-14), 22.9 (14-CH3), 12.7 (10-CH3), 12.5 (2-CH3), 12.1 (8- CH3); MS(ESI) Calcd. for C3OH43N3O9: 589, found 612 (MNa+), 588 (M-H)".
[00115] The second component was collected to give 1 as a red solid (9.6 mg, 10 %). 1H NMR (CDCl3, 500 MHz) δ 9.05 and 8.92 (s, IH, NH-22), 8.01 and 7.97 (s, IH, 19-H), 7.35 and 7.27 (s, 1H, NH-O), 6.94 (d, 7=11.8 Hz, IH, 3-H)3 6.57 (t, 7=1 1.3 Hz, IH, 4-H), 5.95 (t, 7=10.1Hz, 1H, 5-H), 5.85-5.78 (m, 15H 9-H), 5.17 (d, 7=3.1 Hz5 IH, 7-H), 4.80 (brs, 2H, NH2), 4.30 (d, 7=10.0 Hz, 1,H 6-H), 4.19 and 4.12 (s, 3H, methoxyl O-CH3)5 3.58-3.57 (m, 1H , 12-H), 3.46-3.42 (m, 1,H 11-H), 3.36 (s, 3H, OCH3), 3.25 (s, 3H, OCH3), 2.76-2.73 (m, IH, 10-H), 2.69-2.43 (m5 2H, 15-H), 2.02 (s, 3H, 2-CH3), 1.82-1.79 (m, 3H, 14-H, 13-H), 1.62 (s, 3H, S-CH3), 1.00-0.97 (m, 6H, 10-CH3, 14-CH3); MS(ESI) Calcd. for (C29H41N3O9): 575, found 598 (MNa+), 574 (M-H)".
EXAMPLE 2
[00116] This example demonstrates the preparation of 17-allyloxyamino-17- demethoxygeldanamycin (3) and 18-allyloxyiminogeldanamycin (4).
[00117] Compound 3 (11.9 mg, 11% yield, a yellow solid) and compound 4 (36.4 mg, 33 %, a red solid) were prepared from geldanamycin (100 mg, 0.178 mraol) and o- allylhydroxyamine hydrochloride (194.9 mg, 1.78 mmol) in the same manner as described in Example 1. 3: 1H NMR (CDCl3, 500 MHz) δ 9.07 and 8.94 (s, IH, NH-22), 8.05 and 8.01 (s, IH, 19-H), 6.93 (d, 7=11.8 Hz, 1,H 3-H)5 6.57 (t, 7=11.4 Hz, IH5 4-H)3 6.05-5.91 (m, 2H, 5-H and one vinyl proton), 5.82-5.78 (m, 1,H 9-H), 5.39-5.26 (m, 2H, two vinyl protons), 5.16 (s, IH, 7-H), 4.85 and 4.81 (d, J=5.9 Hz, 2H, allyl CH2), 4.80 (brs, 2H, NH2), 4.31 (d, 7=10.1 Hz,1H , 6-H), 3.62-3.52 (m, 1H, 12-H), 3.48-3.44(m, 4H, H-H and OCH3), 3.35 (s, 3H5 OCH3), 2.75-2.72 (m, 1H, 10-H), 2.68-2.42 (m, 2H, 15-H), 2.02 (s, 3H, 2-CH3), 1.95-1.82 (m, 3H, 14-H, 13-H), 1.79 (s, 3H, 8-CH3), 1.02-0.94 (m, 6H, 10-CH3, 14-CH3); MS(ESI) Calcd for C31H43N3O9: 601, found 623 (MNa+), 640 (MK+), 600 (M-H)".
[00118] 4: 1H NMR (CDCl3, 500 MHz) δ 8.80 (s7 1,H NH-22), 8.26 (s, ,11H9-H), 6.93 (d, 7=11.5 Hz, 1H, 3-H), 6.57 (t, 7= 11.4Hz, 1,H 4-H), 6.07-6.00 (m, IH, one vinyl proton), 5.92 (d, 7=9.3 Hz, 1H, 9-H), 5.82 (t, 7=10.4 Hz, 1H, 5-H), 5.31-5.29 (m, 2H, two vinyl protons), 5.18 (s, 1H, 7-H), 4.89 (d, /=5.9 Hz, 2H, allyl OCH2), 4.80 (brs, 2H, NH2), 4.30 (d, 7=9.9 Hz, 1H , 6-H), 4.01 (s, 3H, 17- OCH3), 3.56 (d, J=8.8 Hz, ,1H 12-H), 3.43 -3.42 (m, 1H , H-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.7 '4 (m, ,1H 10-H), 2.56(dd, /=10.6 and 12.8 Hz, 1H, 15-H), 2.42 (d, 7=12.7 Hz, 1,H 15-H), 2.03 (s, 3H3 2-CH3), 1.84- 1.83 (m, 2H, 13-H), 1.80 (s, 3H, 8-CH3), 1.59 (brs, IH, 14-H), 0.99 (d, /=7.0 Hz, 3H, 10- CH3), 0.95 (d, J=6.7 Hz, 3H, 14-CH3); MS(ESI) Calcd. for C32H45N3O9: 615, found 638 (MNa+), 614 (M-H)".
EXAMPLE 3
[00119] This example demonstrates the preparation of 18-terM3Utoxyirninogeldanamycin (S).
[00120] Compound 5 (yield 86%, a yellowish solid) was prepared from geldanamycin and o- tert-butylhydroxylamine hydrochloride in the same manner as described in Example 1. 1H NMR (CDCl3, 500 MHz) δ 8.84 (s, 1,H NH-22), 8.23 (s, IH, 19-H), 6.93 (d, J=11.5 Hz, IH, 3-H), 6.58 (t, J= 11.6Hz, 1,H 4-H), 5.93 (d, /=9.4 Hz, IH, 9-H), 5.82 (t, /=10.5 Hz, IH, 5-H), 5.18 (s, 1H, 7-H), 4.80 (brs, 2H, NH2), 4.31 (d, J=9.9 Hz, IH, 6-H), 4.05 (s, 3H, 17- OCH3), 3.58 (d, /=8.0 Hz, 1H, 12-H), 3.45 -3.42 (m, IH, H-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.78-2.74 (m, 1H, 10-H), 2.58(dd, 7=10.6 and 12.8 Hz, IH, 15-H), 2.43 (d, J=I 1.7 Hz,1H , 15-H), 2.04 (s, 3H, 2-CH3), 1.84-1.83 (m, 2H, 13-H), 1.80 (s, 3H, 8-CH3), 1.43 (s, 9H, tert-butyl-CH3), 1.59 (brs, 1,H 14-H), 0.99 (d, /=7.0 Hz, 3H, 10-CH3), 0.95 (d, /=6.7 Hz, 3H, 14-CH3); MS(ESI) Calcd. for C33H49N3O9: 631, found 654 (MNa+), 630(M-H)".
EXAMPLE 4
[00121] This example demonstrates the preparation of 18-250-butoxyiminogeldanamycin
(6)-
[00122] Compound 6 (yield 85%, a yellowish solid) was prepared from geldanamycin and <?-?5<?-butylhydroxyamine hydrochloride in the same manner as described in Example 1. 1H NMR (CDCl3, 500 MHz) δ 8.82 (s, ,1 NHH-22), 8.26 (s, IH, 19-H), 6.93 (d, /=11.7 Hz, IH, 3-H), 6.57 (t, /= 11.6Hz, 1H, 4-H), 5.92 (d, /=9.4 Hz, IH, 9-H), 5.82 (t, /=10.4 Hz, IH, 5-H), 5.18 (s, 1H, 7-H), 4.80 (brs, 2H, NH2), 4.30 (d,/=9.9 Hz, IH, 6-H), 4.20 (dd,/=4.1 and 10.7 Hz, 2H, 0-CH2), 4.01 (s, 3H, 17- OCH3), 3.56 (d, /=8.0 Hz, IH, 12-H), 3.45 -3.42 (m, IH, H-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.74 (rn, IH, 10-H), 2.57(dd, /=10.6 and 12.8 Hz, 1H, 15-H)3 2.43 (d, J=11.9 Hz, IH, 15-H)3 2.15-2.10 (m3 1H, wσ-butyl-CH), 2.04 (s, 3H, 2-CH3), 1.84-1.83 (m, 2H, 13-H), 1.80 (s, 3H, 8-CH3), 1.59 (brs, IH, 14-H), 0.99-0.91 (m, 12H, 10-CH3, 14-CH3, »O-butyl-CH3); MS(ESI) Calcd. for C33H49N3O9: 631, found 654 (MNa+), 630(M-H)".
EXAMPLE 5
[00123] This example demonstrates the preparation of 18-hydroxyiminogeldanamycin (7).
[00124) Compound 7 (yield 45%, a yellowish solid) was prepared from geldanamycin and hydroxylamine hydrochloride in the same manner as described in Example 1. 1H NMR (CD3OD, 500 MHz) δ 8.22 (s, IH, 19-H), 7.07 (brs, IH, 3-H), 6.61 (brs, IH, 4-H), 5.84 (brs, IH, 9-H), 5.58 (brs, 1H, 5-H)3 5.17 (s, IH, 7-H), 4.50 (brs, 1H, 6-H)3 4.00 (s, 3H, 17- OCH3), 3.54-3.52 (m, IH5 12-H), 3.48 -3.42 (m, IH, 11-H), 3.34 (s, 3H, OCH3), 3.30 (s, 3H, OCH3), 2.70 (brs, 1H, 10-H), 2.58(dd, 7=4.9 and 12.9 Hz, IH, 15-H), 2.36 (dd3 J=8.4 and 12.6 Hz, IH, 15-H), 2.01 (s, 3H, 2-CH3), 1.84 (brs, IH, 13-H), 1.72 (brs, IH, 13-H)3 1.72 (s, 3H, 8- CH3), 1.60-1.57 (m, IH, 14-H), 0.95 (m, 3H, 10-CH3), 0.94 (m, 3H, 14-CH3); MS(ESI) Calcd. for C29H4]N3O9: 575, found 598 (MNa+), 574(M-H)".
EXAMPLE 6
[00125] This example demonstrates the preparation of 18-phenoxyiminogeldanamycin (9) and 17-phenoxyamino-17-demethoxygeldanamycin (8).
[00126] Compound 9 (yield 66%, yellowish solid) and compound 8 (yield 15%, a reddish solid) were prepared from geldanamycin and phenoxyamine hydrochloride in the same manner as described in Example 1. 9: 1H NMR (CDCl3, 500 MHz) δ 8.87 (s, IH, NH-22), 8.47 (s, IH, 19-H), 7.40-7.37 (m, 4H, phenyl), 7.14 (t, J=7.0 Hz, IH, phenyl), 6.96 (d, J=I 1.7 Hz, IH, 3-H), 6.59 (t, J= 1 1.6Hz, IH, 4-H), 5.91 (d, J=9.4 Hz, IH, 9-H), 5.85 (t, J=10.4 Hz, IH, 5-H), 5.20 (s, IH, 7-H)5 4.80 (brs, 2H, NH2), 4.33 (d, J=9.7 Hz, IH, 6-H), 4.13 (s, 3H, 17- OCH3), 3.58 (d, =8.7 Hz, IIHH, 12-H), 3.45 -3.42 (m, IH, H-H), 3.37 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 2.79-2.76 (m, IH, 10-H), 2.61(dd, J=10.4 and 12.9 Hz, IH, 15-H), 2.49 (d, J=I 1.4 Hz, 1H, 15-H), 2.06 (s, 3H, 2-CH3), 1.85-1.84 (m, 2H, 13-H), 1.80 (s, 3H, 8-CH3), 1.68 1.58 (brs, 1H, 14-H), 1.00 (d, j=6.8 Hz, 3H, 10-CH3), 0.98 (d, J=6.4 Hz, 3H, 14-CH3); MS(ESI) Calcd. for C35H45N3O3: 651, found 674 (MNa+), 650(M-H)". [00127] 8: 1H NMR (CDCl3, 500 MHz) δ 9.00 (s, 1,H NH-22), 8.26 (s, 1,H 19-H), 7.43 (s, 1H, NH-O), 7.41 (d, J=7.5 Hz, 2H)1 7.29 (dd, J=0.8 and 8.8 Hz, 2H), 7.18 (t,J=7.3 Hz3 1H), 6.97 (d, ./=12.4 Hz, 1H, 3-H), 6.59 (t, J=11.6 Hz, 1H, 4-H), 5.93 (d, J=9.3 Hz, 1H, 5-H), 5.86 (t3 J=I 0.5 Hz, 1H, 9-H)3 5.19 (s, 1H5 7-H)54.80 (brs, 2H5 NH2), 4.36 (d, J=9.8 Hz, 1H, 6-H), 3.59 (m, 1H, 12-H), 3.45-3.43 (m, 1H, 1 1-H), 3.37 (s, 3H, OCH3), 3.28 (s, 3H, OCH3), 2.80- 2.77 (m, 1H, 10-H), 2.60-2.48 (m, 2H, 15-H), 2.06 (s, 3H, 2-CH3), 1.87-1.81 (m, 3H, 14-H, 13-H), 1.81 (s, 3H, 8-CH3), 1.02-0.99 (m, 6H, 10-CH3, 14-CH3); MS(ESI) Calcd. for C34H43N3O9: 637, found 660 (MNa+), 636 (M-H)-.
EXAMPLE 7
[00128] This example demonstrates the preparation of 18-benzyloxyiminogeldanamycin (10).
[00129] Compound 10 (yield 74%, a yellowish solid) was prepared from geldanamycin and o- benzylhydroxyamine hydrochloride in the same manner as described in Example 1. 1H NMR (CDCl3, 500 MHz) δ 8.80 (s, 1,H NH-22), 8.27 (s, 1H, 19-H), 7.41-7.31 (m, 5H, phenyl), 6.96 (d, J=11.7 Hz, 1H, 3-H), 6.57 (t, J= 11.7 Hz, 1H, 4-H), 5-91 (d, J=9.4 Hz, 1H, 9-H), 5.82 (t, J=10.5 Hz, 1H, 5-H), 5.41 (s, 2H, o-CH2-benzyl), 5.18 (s, 1H57-H), 4.80 (brs, 2H3 NH2), 4.30 (d, J=9.8 Hz5 1H, 6-H), 3.90 (s, 3H, 17- OCH3), 3.55 (d, J=8.9 Hz, 1,H 12- H)5 3.43 -3.41 (m, 1H, H-H), 3.35 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.74 (m, 1H, 10- H), 2.54 (dd, J=10.6and 12.8 Hz, 1H, 15-H)5 2.41 (d, J=11.6 Hz, 1H, 15-H), 2.02 (s, 3H3 2- CH3), 1.84-1.83 (m, 2H3 13-H), 1.79 (s, 3H, 8-CH3), 1.58 (brs, 1,H 14-H)5 0.98 (d, J=7.0 Hz, 3H, 10-CH3), 0.93 (d, J=6.7 Hz, 3H, 14-CH3); MS(ESI) Calcd. for C36H47N3O9: 665, found 688 (MNa+), 664(M-H)-.
EXAMPLE 8
[00130] This example demonstrates the preparation of 18-hexyloxyiminogeldanamycin (11).
[00131] Compound 11 (yield 81%, a yellowish solid) was prepared from Geldanamycin and o-hexanylhydroxylamine hydrochloride in the same manner as described in example 1. 1H NMR (CDC]3, 500 MHz) δ 8.81 (s, 1,H NH-22), 8.24 (s, 1,H 19-H)3 6.93 (d, J=11.5 Hz5 IH, 3-H), 6.58 (t, J= 11.5 Hz, 1H, 4-H), 5.92 (d, J=9.4 Hz, 1H, 9-H), 5.82 (t, J=10.5 Hz, 1H, 5-H), 5.18 (s, 1H, 7-H)5 4.80 (brs, 2H, NH2), 4.41 (t, 7=6.8 Hz, 2H3 18-C=N-O-CH2), 4.30 (d, ./=9.8 Hz, 1H, 6-H)5 4.01 (s, 3H, 17- OCH3), 3.56 (d, 7=7.6 Hz, IH, 1.1 -H), 3-45 -3.42 (m, 1H , 12-H)3 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.74 (m, 1H, 10-H), 2.57 (dd, ./=10.7 and 12.9 Hz3 1,H 15-H), 2.43 (d, 7=11.6 Hz, IH, 15-H), 2.04 (s, 3H, 2-CH3), 1.85- 1.84 (m72H, 13-H), 1.84-1.77 (m, 2H3 18-hexanyl-CH2), 1.79 (s3 3H, 8-CH3), 1.65 (brs3 1H, 14-H), 1.42-1.33 (m, 4H, 18-hexanyl), 0.98 (d, 7=7.0 Hz, 3H, 10-CH3), 0.93 (d, 7=6.7 Hz, 3H, 14-CHj), 0.92 (t, 7=7.2 Hz , 3H, 18-hexanyl-CH3); MS(ESI) Calcd. for (C34H5IN3O9): 645, found 668 (MNa+), 644(M-H)'.
EXAMPLE 9
[00132] This example demonstrates the preparation of 18-cyclopropylmethoxyimino geldanamycin (12).
[00133] Compound 12 (yield 89%, a yellowish solid) was prepared from geldanamycin and ø-cyclopropylcarbinylhydroxylamine hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.82 (s3 IH, NH-22), 8.28 (s, 1H, 19-H), 6.93 (d, 7=11.7 Hz, 1H, 3-H), 6.56 (t, 7= 11.7 Hz, ,14H-H), 5.93 (d, 7=9.5 Hz3 IH, 9-H), 5.82 (t, 7=10.5 Hz, 1H, 5-H), 5.18 (s, 1H, 7-H), 4.80 (brs, 2H3 NH2), 4.31 (d, 7=9.8 Hz, IH, 6-H), 4.23 (dd, 7=2.9 and 7.3 Hz, 2H, 18-C=N-O-CH2), 4.02 (s, 3H, 17- OCH3), 3.57 (d, 7=8.9 Hz, IH, 11-H), 3.45 -3.42 (m, 1H, 12-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H3 OCH3), 2.78-2.74 (m, IH, 10-H), 2.57 (dd, 7=10.7 and 12.9 Hz, IH, 15-H), 2.43 (d, 7=11.7 Hz, , 15-1HH), 2.04 (s, 3H, 2-CH3), 1.87 (m, 2H, 13-H)3 1.79 (s, 3H, 8-CH3), 1.60 (brs, , 14-H1)H, 1.28-1.24 (m, IH, 18-CH), 0.98 (d, 7=7.1 Hz3 3H, 10-CH3), 0.95 (d, 7=6.8 Hz, 3H, 14-CH3), 0.64-0.60 (m, 2H, 18-CH2), 0.37-0.35 (m, 2H, 18-CH2); MS(ESI) Calcd. for (C33H47N3O9): 629, found 652 (MNa+), 664(M+C1)\
EXAMPLE 10
[00134] This example demonstrates the preparation of 18-dodecyloxyiminogeldanamycin (13).
[0O135] Compound 13 (yield 87%, a yellowish solid) was prepared from geldanamycin and o- dodecanylhydroxylamine hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.81 (s, , N1HH-22), 8.24 (s, IH, 19-H), 6.93 (d, 7=11.9 Hz, IH, 3-H), 6.58 (t, J= 11.6 Hz, 1,H 4-H), 5.93 (d, J=9.4 Hz5 IH, 9-H), 5.82 (t, J=10.5 Hz, IH, 5-H), 5.18 (s, 1H, 7-H), 4.80 (brs, 2H, NH2), 4.41(t, J=6.8, 2H5 18-C=N-O-CH2), 4.30 (d, J=9.9 Hz, 1H, 6-H), 4.01 (s, 3H, 17- OCH3), 3.56 (d, J=9.2 Hz, IH, 11-H), 3.45 -3.42 (m, IH, 12-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.74 (m, IH, 10-H), 2.57 (dd, ./=10.5 and 12.7 Hz, 1H, 15-H), 2.42 (d, J=I 1.5 Hz, IH, 15-H), 2.04 (s, 3H, 2-CH3), 1.84- 1.83 (m, 2H, 13-H), 1.79 (s, 3H, 8-CH3), 1.58 (brs, IH, 14-H), 1.42-1.36 (m, 2H, 18-CH2), 1.32-1.25 (m, 18H, 18-(CH2)9), 0.98 (d, J=7.0 Hz, 3H, 10-CH3), 0.93 (d, J=6.7 Hz, 3H, 14- CH3), 0.89-0.85 (m, 3H, 18-CH3); MS(ESI) Calcd. for (C41H65N3O9): 743, found 766 (MNa+), 743(M-H)'.
EXAMPLE 11
[00136] This example demonstrates the preparation of 18-(4-nitrobenzyl)oxyimino geldanamycin (14).
[00137J 14 (yield 78%, a yellowish solid) was prepared from geldanamycin and o- (4- nitrobenzyl) hydroxylamine hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.81 (s, IH, NH-22), 8.29 (s, IH, 19-H), 8.25-8.22 (m, 2H, 18- benzyl), 7.55 (d, 2H, J=8.6 Hz, benyl), 6.93 (d, J=I 1.6 Hz, IH, 3-H), 6.57 (t, J= 11.5 Hz, 1 H, 4-H), 5.91 (d, .7=9.4 Hz, ,1H 9-H), 5.84 (t, J=10.4 Hz, IH, 5-H), 5.50 (s, 2H, o-CH2-benzyl), 5.18 (s, 1H, 7-H), 4.80 (brs, 2H, NH2), 4.30 (d, J=9.8 Hz, IH, 6-H), 3.87 (s, 3H, 17- OCH3), 3.55 (d, J=8.5 Hz, 1H, H-H), 3.43 -3.40 (m, 1,H 12-H), 3.35 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 2.11-2.14 (m, 1,H 10-H), 2.54 (dd, J=10.4 and 12.9 Hz, IH, 15-H), 2.43 (d, J=I 1.3 . Hz,1H , 15-H), 2.03 (s, 3H, 2-CH3), 1.83-1.82 (m, 2H, 13-H), 1.79 (s, 3H, 8-CH3), 1.58 (brs, 1H, 14-H), 0.98 (d, J=7.0 Hz, 3H, 10-CH3), 0.93 (d, J=6.7 Hz, 3H, 14-CH3); MS(ESI) Calcd. for (C36H46N4Oi I): 710, found 733 (MNa+), 709(M-H)'.
EXAMPLE 12
[00138] This example demonstrates the preparation of 18- o-cyclohexyloxyimino geldanamycin (15).
[00139] Compound 15 (yield 71%, a yellowish solid) was prepared from geldanamycin and o-cyclohexylhydroxyamine hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.83 (s, IH, NH-22), 8.26 (s, IH, 19-H), 6.93 (d, J=I 1.6 Hz, IH, 3-H), 6.56 (t, J= 11.6 Hz, IH5 4-H), 5.93 (d, J-9.4 Hz, IH, 9-H), 5.82 (t, 7=10.4 Hz, IH, 5-H), 5.18 (s5 IH, 7-H), 4.80 (brs, 2H5 NH2), 4.43-4.37 (m, IH, 18-cyclohexanyl-CH), 4.31 (d, J=9.9 Hz, IH, 6-H), 4.02 (s, 3H, 17- OCH3), 3.57 (d, J=9.0 Hz, IH, H-H), 3.45 -3.42 (m, IH, 12-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.7 '4 (m, IH5 10-H), 2.57 (dd, J=10.6 and 12.9 Hz, IH, 15-H), 2.44 (d, J=12.0 Hz, IH, 15-H), 2.03 (s, 3H, 2-CH3), 1.85- 1.81 (m, 2H, 13-H), 1.79 (s, 3H5 8-CH3), 1.64-1.62 (m, 6H, lδ-cyclohexanyl-CHa), 1.58 (brs, IH, 14-H), 1.41-1.25 (m, 4H, cyclohexanyl-CH2), 0.99 (d, J=7.0 Hz, 3H, 10-CH3), 0.94 (d, 7=6.6 Hz, 3H, 14-CH3); MS(ESI) Calcd. for (C35H5iN3O9): 657, found 680 (MNa+), 692(M+C1)\
EXAMPLE 13
[00140] This example demonstrates the preparation of 18-o-isopropoxyimino geldanamycin (16).
[00141] Compound 16 (yield 89%, a yellowish solid) was prepared from geldanamycin and o- propylhydroxylamine hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.82 (s, IH, NH-22), 8.24 (s, IH5 19-H)5 6.93 (d, J=11.8 Hz, IH, 3-H), 6.58 (t, J= 11.6 Hz, IH, 4-H), 5.92 (d, J=9.4 Hz, IH, 9-H), 5.82 (t, J=10.5 Hz, IH, 5- H), 5.19 (s, IH, 7-H), 4.80 (brs, 2H, NH2), 4.70-4.65 (m, IH5 18-C=N-O-CH2), 4.31 (d, J-9.9 Hz, IH, 6-H), 4.03 (s, 3H, 17- OCH3), 3.56 (d, J=7.9 Hz5 IH5 H-H)5 3.45 -3.42 (m5 IH5 12- H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.74 (m, IH, 10-H), 2.57 (dd, J=10.6 and 12.9 Hz, IH, 15-H), 2.43 (d, J=11.7 Hz, IH, 15-H), 2.04 (s, 3H, 2-CH3), 1.85-1.84 (m, 2H, 13-H), 1.79 (s, 3H, 8-CH3), 1.64 (brs, IH5 14-H), 1.42-1.36 (m, 6H, 18-CH3), 0.99 (d, J=7.0 Hz, 3H, 10-CH3), 0.95 (d, J=6.7 Hz, 3H5 14-CH3); MS(ESI) Calcd. for (C32H47N3O9): 617, found 640 (MNa+), 652(M+C1)".
EXAMPLE 14
[00142] This example demonstrates the preparation of 18-ethoxyimino geldanamycin (17).
[00143] Compound '17 (yield 78%, a yellowish solid) was prepared from geldanamycin and o- ethylhydroxylamine hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.80 (s, IH5 NH-22), 8.25 (s, IH, 19-H), 6.93 (d, J=11.6 Hz, IH, 3-H), 6.57 (t, J= 11.7 Hz, 1,H 4-H), 5.92 (d, J=9.5 Hz, IH, 9-H), 5.82 (t, J=10.5 Hz, IH, 5- H), 5.18 (s, 1H , 7-H), 4.80 (brs, 2H, NH2), 4.49-4.45 (m, 2H, 18-C=N-O-CH2), 4.30 (d, J=9.9 Hz,1H , 6-H), 4.02 (s, 3H, 17- OCH3), 3.56 (d, J=9.2 Hz, 1H, H-H)5 3.44 -3.42 (m, 1H, 12- H), 3.36 (s, 3H7 OCH3), 3.26 (s, 3H, OCH3), 2.11-2.1 A (m, 15H 10-H), 2.57 (dd, J=10.6 and 12.9 Hz, 1H, 15-H), 2.42 (d, J=11.7 Hz, 1H, 15-H), 2.03 (s, 3H, 2-CH3), 1.85-1.84 (m, 2H, 13-H), 1.79 (s, 3H, 8-CH3), 1.63 (brs, 1H, 14-H), 1.40 (t, J=7.0 Hz, 3H), 0.98 (d, J=7.0 Hz, 3H5 10-CH3), 0.94 (d, /=6.7 Hz, 3 H, 14-CH3); MS(ESI) Calcd. for (C3IH4SN3O9): 603, found 626 (MNa+), 638(M+C1)'.
EXAMPLE 15
[00144] This example demonstrates the preparation of 18-(3-methylbut-2-enyloxyimino)- geldanamyciri (18).
[00145] Compound 18 (yield 85%, a yellowish solid) was prepared from geldanamycin and σ- 3-methyl-2-butenylhydroxylamin.e hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.81 (s, 1,H NH-22), 8.24 (s, 1,H 19-H), 6.92 (d, J=1 1.5 Hz, 1H, 3-H), 6.57 (t, J= 11.3 Hz, 1H, 4-H), 5.92 (d, J=9.4 Hz, 1H, 9-H), 5.82 (t, J-10.6 Hz,1H , 5-H), 5.50-5.46 (m, 1H, 18-CH=C), 5.18 (s, 1H, 7-H), 4.90 (d, J=7.4 Hz, 2H, 18-C=N-O-CH2), 4.80 (brs, 2H,NH2), 4.30 (d, J=9.9 Hz, 1H, 6-H), 4.02 (s, 3H, 17- OCH3), 3.56 (d, J=8.1 Hz, 1H , 1 1-H), 3.45 -3.42 (m, 1H, 12-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.77-2.74 (m, 1H, 10-H), 2.57 (dd, J=10.6 and 12.9 Hz, 1H, 15-H), 2.42 (d, J=11.6 Hz,1H , 15-H), 2.03 (s, 3H, 2-CH3), 1.84 (m, 2H, 13-H), 1.79 (s, 3H, 18-CH3), 1.78 (s, 3H, 18-CH3), 1.77 (s, 3H, 8-CH3), 1.60 (brs, 1H, 14-H), 0.99 (d, J=6.9 Hz, 3H, 10-CH3), 0.94 (d, J=6.8 Hz, 3H5 14-CH3); MS(ESI) Calcd. for (C34H49N3O9): 643, found 666 (MNa+), 678(M+C1)'.
EXAMPLE 16
[00146] This example demonstrates the preparation of 18-(2- fluoroethoxyimino)geldanamycin (19).
[00147] Compound 19 (yield 56%, a yellowish solid) was prepared from geldanamycin and o- fluoroethylhydroxylamine hydrochloride in the same manner as described in example 1. 1H NMR (CDCl3, 500 MHz) δ 8.80 (s, 1,H NH-22), 8.27 (s, 1,H 19-H), 6.93 (d, J=11.7 Hz, 1H5 3-H)5 6.57 (t, J= 11.6 Hz, 1H, 4-H), 5.91 (d, /=9.4 Hz, 1H, 9-H), 5.83 (t, J-10.5 Hz, 1H5 5-H), 5.18 (s, IH, 7-H), 4.S0 (brs, 2H3 NH2), 4.79 (t, ./=3.8 Hz IIHH, 18-C=N-O-CH), 4.70- 4.66 (m, 2H, 18-CH2-F), 4.61 (t, 7=3.8 Hz, IH, 18-C=N-O-CH), 4.30 (d3 J=9.8 Hz, IH, 6-H), 4.01 (s, 3H, 17- OCH3), 3.56 (d, J=9.0 Hz, IH, H-H), 3.44 -3.41 (m, IH, 12-H), 3.36 (s, 3H, OCH3), 3.27 (s, 3H, OCH3), 2.78-2.74 (m, IH, 10-H), 2.56 (dd, J=10.6 and 12.9 Hz, IH, 15- H), 2.43 (d, J=11.7 Hz, IH5 15-H), 2.03 (s, 3H, 2-CH3), 1.84 (m, 2H, 13-H), 1.80 (s, 3H, 8- CH3), 1.63 (brs, IH, 14-H), 0.98 (d, J=7.0 Hz3 3H, 10-CH3), 0.94 (d, 7=6.7 Hz, 3H, 14-CH3); MS(ESl) Calcd. for (C31H44N3O9): 621, found 644 (MNa+), 620 (M-H)'.
EXAMPLE 17 f 0.0148] This example demonstrates the preparation of preparation of 17-allyamino-l 7- demethoxygeldanamycin (17-AAG, 20).
[00149] To a flame-dried three neck flask was added geldanamycin (1 g, 1.79 mmol) and anhydrous THF (32 mL). Under an atmosphere of argon allylamine (800 μL, 10.4 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 4 hours, upon which TLC indicated the disappearance of the starring material. The reaction mixture was condensed on a rotavapor to dryness. The resultant brownish oil was dissolved in 10 mL of isopropanol at 60° C. and stood at room temperature for at least 24 hrs until most of the desired product recrystallized from the solvent. After careful removal of the supernatant solution via a glass pipette, the solids were washed with cold ethyl ether and dried in vacuo to afford the desired product (985 mg, 94%). 1H NMR (CDCl3, 500 MHz): δ 9.16 (s, IH, NH-22), 7.30 (s, IH, 19-H), 6.95 (d, J= 11.2 Hz, IH, 3-H), 6.58 (t, J= 11.2 Hz, 1H, 4-H), 6.38 (s, IH, NH), 5.95-5.84 (m, 3H, H-5, H-9, one vinyl proton), 5.32-5.27 (m, 2H, H-9, two vinyl proton), 5.19 (s, IH, H-7), 4.80 (brs, 2H, NH2), 4.31 (d, J = 9.5 Hz, 1H, H-6), 4.15 (d, J = 4.5 Hz, 2H, allyl methylene protons), 3.56 (s, IH, H-12), 3.44 (d, J= 8.7 Hz, 1H, H-Il), 3.36 (s, 3H, OMe)5 3.27 (s, 3H, OMe), 2.75 (t, J= 7.1 Hz, IH, H-IO)52.65 (d, J= 14.0 Hz,1H , H-15), 2.36 (dd, J= 13^8, 10.8 Hz, IH, H-15), 2.02 (s, 3H, C2-Me), 1.75-1.65 (m, 3H, H-14, H-13), 1.61 (s, 3H, C8-Me), 1.12-0.95 (m, 6H, ClO-Me, C14-Me). ESI-MS: calcd. for C3iH43N3O8+Na (M+Na)+: 608. Found: 608. EXAMPLE 18
[00150] This example demonstrates the preparation of 17-allylamino- 18-allyloxyimino- 17- demethoxygeldanamycin (21).
[00151] To a solution of 17-AAG (50.0 mg, 0.0854 mmol) in pyridine 0.5 ml was added to o-allylhydroxyamine hydrochloride (93.5 mg, 0.854 mmol), and the mixture was then stirred at 80° C. overnight, and then removed the pyridine completely by vacuum. The residue was purified by column chromatography, eluting with CH2Cl2/MeOH (40: 1 to 20:1) to give 21 as reddish solid (45.0 mg, 82% yield). 1H NMR (CDCl3, 500 MHz) δ 9.06 (s, IH, NH-22), 8.06 (s, 1H, 19-H), 6.92 (d, J=11.6 Hz, IH, 3-H), 6.58 (t, J= 11.5Hz, IH, 4-H), 6.04-5.93 (m, 3H, 2 one vinyl proton, 9-H), 5.81 (t, 7=10.5 Hz, IH, 5-H), 5.36-5.24 (m, 4H, 2 two vinyl protons), 5.17 (s, IH, 7-H)1 4.80 (dt, J=5.9 and 1.1 Hz, 2H, allyl OCH2), 4.80 (brs, 2H, NH2), 4.31 (d, J=10.0 Hz, IH, 6-H), 4.13-4.12 (m, 2H, 17-ally- CH2), 3.56 (d, J=8.9 H IIHH, 12-H), 3.45 (d, J=9.4 Hz, IH, H-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.75-2.69 (m, 2H, 10- H and 15-H), 2.28(dd, J=10.8 and 14.1 Hz, IH, 15-H), 2.03 (s, 3H, 2-CH3), 1.86-1.74 (m, 6H, 13-H, 8-CH3 and 14-H), 0.99 (d, J=7.1 Hz, 3H, 10-CH3), 0.96 (d, J=7.4 Hz, 3H, 14-CH3); MS(ESI) Calcd. for C34H48N4O8: 640, found 663 (MNa+), 639 (M-H)'.
EXAMPLE 19
[00152] This example demonstrates the preparation of 17-allylamino-l 8-methoxyimino- 17-demethoxygeldanamycin (22).
[00153] Compound 22 (41.5 mg, 77 % yield, a reddish solid) was prepared from 17-AAG (51.5 mg, 0.088 mmol) and σ-methylhydroxyamine hydrochloride (73.4 mg, 0.88 mmol) in the same manner as described in Example 4: 1H NMR (CDCl35 500 MHz) δ 9.04 (s, IH, NH- 22), 8.02 (s, IH, 19-H), 6.91 (d, J-11.6 Hz, IH, 3-H), 6.57 (t, J= 11.6Hz, IH, 4-H), 5.97-5.90 (m, 2H, one vinyl proton, 9-H)3 5.81 (t, J=10.6 Hz, IH, 5-H), 5.32-5.25 (m, 2H, two vinyl protons), 5.17 (s, 1H, 7-H), 4.75 (brs, 2H, NH2), 4.30 (d,J=W.O Hz, IH5 6-H), 4.17-4.09 (m, 5H, 17-ally-CH2and N-O-CH3), 3.55 (dd, J=9.2 and 1.4 Hz3 1H, 12-H)3 3.46-3.43 (m, IH, H-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.74-2.69 (m, 2H, 10-H and 15-H), 2.32(dd, J=10.8 and 14.1 Hz3 1,H 15-H), 2.02 (s, 3H, 2-CH3), 1.86-1.73 (m, 6H3 13-H, 8-CH3 and 14- H), 1.00-0.97 (m, 6H, 10 and 14-CH3); MS(ESI) Calcd. for C32H46N4O8: 614, found 637 (MNa+), 613 (M-Hy. EXAMPLE 20
[00154] This example demonstrates the preparation of 17-allylamino- 18- carboxymethoxyimino- 17-demethoxygeldanamycin (23).
[00155] Compound 23 (12.6 mg, 22% yield, a reddish solid) was prepared from 17-AAG (51.5 mg, 0.088 mmol) and ø-carboxymethoxyhydroxyamine hemihydrochloride (96.2 mg, 0.88 mmol) in the same manner as described in Example 4: 1H NMR (CDCI3, 500 MHz) δ 9.05 (s, 1H. NH-22), 8.09 (s, 1,H 19-H), 6.90 (d, J=11.7 Hz, IH, 3-H)5 6.57 (t, J= 11.7Hz, IH, 4-H), 5.95-5.87 (m, 2H3 one vinyl proton, 9-H), 5.80 (t, 7=10.5 Hz7 IH, 5-H), 5.29-5.22 (m, 2H, two vinyl protons), 5.18 (s, 1,H 7-H), 4.82 (brs, 2H, NH2), 4.82. (s, 2H, carboxyl-O- CH2), 4.30 (d, J=10.0 Hz, 1,H 6-H), 4.10 (dd, J=1.4 and 5.5 Hz, 2H, 17-ally-CH2), 3.55 (d, j=9.1 Hz5 1H, 12-H)5 3.46-3.43 (m, ,1 HH-H), 3.35 (s, 3H5 OCH3), 3.26 (s, 3H, OCH3), 2.74- 2.67 (m, 2H, 10-H and 15-H)5 2.25 (dd, J=10.8 and 14.1 Hz, IH, 15-H), 2.02 (s, 3H, 2-CH3), 1.82-1.73 (m, 6H, 13-H, 8-CH3 and 14-H)5 0.99-0.95 (m5 6H, 10 and 14-CH3),- MS(ESI) Calcd. for C33H46N4O10: 658, found 681 (MNa+), 657 (M-H)- .
EXAMPLE 21
[00156] This example demonstrates the preparation of 17-cyclopentylamino-l 7- demethoxygeldanamycin (24).
[00157] To a flame-dried three neck flask was added geldanamycin (420 mg, 0.75 mmol) and anhydrous THF (30 mL). Under an atmosphere of argon cyclopentylamine (444 μL, 4.5 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 5 hrs, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant brownish oil was dissolved in 3 mL of isopropanol at 60° C. and stood at room temperature for at least 24 hours until most of the desired product recrystallized from the solvent. After careful removal of the supernatant solution via a glass pipette, the solids were washed with cold ethyl ether and dried in vacuo to afford the desired product (420 mg, 91 %). 1H NMR (CDCl3, 500 MHz): δ 9.19 (brs, 1H, NH-22), 7.27 (s, IH, H-19), 6.94 (d, J= 11.2 Hz, IH, H-3), 6.58 (t, J = 11.1 Hz, 1H, H-4), 6.30 (s, 15HNH), 5.91-5.85 (m, 2H, H-5, H-9), 5.18 (s, IH, H-7), 4.86 (brs, 2H, NH2), 4.30 (d, J= 9.5 Hz, 1,H H-6), 3.56 (brs, 2H, H-12, cyclopeπtyl), 3.47-3.42 (m,1H , H-I l), 3.36 (s, 3H3 OMe), 3.26 (s, 3H5 OMe), 2.74-2.65 (m, 2H, H-IO, H-15), 2.42 (t, J = 13.0 Hz, 1H, H-15), 2.02 (s, 3H3 C2-Me), 1.79 (s, 3H, C8-Me), 1.76-1.46 (m, 11 H, H-14, H-13, cyclopentyl), 1.00-0.95 (m, 6H). ESI-MS: calcd. for C33H47N3O8+Na (M+Na)+; 636. Found: 636.
EXAMPLE 22
[00158] This example demonstrates the preparation of 17-cyclopentylamino-18- allyloxyimino-17-demethoxygeldanamycin (25).
[001591 Compound 25 (36.6 mg, 67% yield, a reddish solid) was prepared from 17- cyclopentylamino-17-demethoxy geldanamycin (50.0 mg, 0.078 mmol) and o- allylhydroxyamine hydrochloride (85.2 mg, 0.78 mmol) in the same manner as described in Example 4: 1H NMR (CDCl3, 500 MHz) 9.08 (s, 1H, NH-22), 8.04 (s, IH, 19-H), 6.92 (d, J=11.7 Hz, 1H, 3-H), 6.60-6.55 (m, IH, 4-H), 6.04-5.95 (m, 2H, one vinyl proton, 9-H), 5.80 (t, J=10.7 Hz3 1H, 5-H)3 5.35-5.26 (m, 2H, two vinyl protons), 5.17 (s, 1H, 7-H)3 4.79 (dt, J=5.9 and 1.1 Hz5 2H3 allyl OCH2), 4.80 (brs3 2H3 NH2), 4.37-4.35 (m, 1H, 1.7-CH), 4.31 (d, J=9.6 Hz, 1H, 6-H), 3.56 (dd3./=9.3 and 1.5 Hz, 1H, 12-H)3 3.44 (dd3 J=9.3 and 2.8 Hz, 1H, 11-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.75-2.71 (m, 2H, 10-H and 15-H)3 2.25(dd, J=10.8 and 14.1 Hz3 1,H 15-H)3 2.02 (s, 3H, 2-CH3), 2.06-2.02 (m, 2H, 13-H), 1.87-1.51 (m, 12H, 8-CH3, 14-H and cyclopentyl 8H), 0.99 (d, J=6.9 Hz, 3H3 10-CH3), 0.96 (d, J=6.4 Hz, 3H3 14-CH3); MS(ESI) Calcd. TOr C36H52N4O8: 668, found 691 (MNa+), 667 (M-H)".
EXAMPLE 23
[00160] This example demonstrates the preparation of 17-cyclopentylamino-l 8- methoxyimino-17-demethoxygeldanamycin (26).
[00161] Compound 26 (44.3 mg, 85 % yield, a reddish solid) was prepared from 17- cyclopentylamino- 17-demethoxygeldanamycin (50.0 mg, 0.081 mmol) and o- methylhydroxyamine hydrochloride (68.1 mg, 0.81 mmol) in the same manner as described in Example 4: 1H NMR (CDCl3, 500 MHz) 9.06 (s, IH, NH-22), 8.00 (s, IH, 19-H), 6.91 (d, J=I 1.8 Hz, 1H, 3-H), 6.57 (t, J= 11.5Hz, ,14H-H)3 5.96 (d, J=9.5 Hz3 1H, 9-H)3 5.80 (t, ./=10.7 Hz, 1H, 5-H), 5.17 (s, 1,H 7-H), 4.80 (brs, 2H, NH2), 4.37-4.35 (m, IH, 17-CH), 4.31 (d, J=10.1 Hz, 1H, 6-H)3 4.10(s3 3H3 18-OCH3), 3.55 (d, J=9.3 Hz3 IH, 12-H), 3.46-3.44 (m, IH, 11-H), 3.36 (s, 3H, OCH3), 3.26 (s, 3H, OCH3), 2.75-2.71 (m, 2H, 10-H and 15-H), 2.28(dd, J=10.9 and 14.2 Hz, IH, 15-H), 2.10-2.06 (m, 2H5 13-H), 2.02 (s, 3H, 2-CH3), 1.87- 1.51 (m, 12H, 8-CH3, cyclopentyl 8Hand 14-H), 0.99 (d, J=7.0 Hz, 3H, 10-CH3), 0.96 (dd, ./=6.5 Hz, 3H, 14-CH3); MS(ESI) Calcd. for C34H50N4O8: 642, found 665 (MNa+), 641 (M- H)-.
EXAMPLE 24
[001621 This example demonstrates the preparation of 17-amino- 17- demethoxylgeldanamycin (27).
[00163] Amomia-MeOH solution (41.0 mL, 2M solution, 82.0 mmol) was added slowly to a solution of geldanamycin (920 mg, 1.64 mmol) in THF (54.7 mL) at room temperature and the mixture was stirred for 6 hr. Most of the solvent was removed under reduced pressure and then the mixture was charged into cold water. The mixture was brought to PH 3 with IN HCl and extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over anhydrous MgSθ4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 98:2, 90:5) to yield the compound 27 (0.79 g, 88% yield) as a purple solid. 1H ΝMR (500 MHz, CDCl3): δ
9.08 (s, IH), 7.21 (s, IH)36.92 (d, J= 11.5 Hz, IH), 6.54 (t, J= 11. Hz, IIHH), 5.88 (d, J= 9.1 Hz,1H ), 5.83 (t, J= 10.5 Hz3 1)H, 5.56 (br s, 2H), 5.12 (s, IH), 4.87 (br s, 2H), 4.28 (d, J =
9.9 Hz, 1H), 3.67 (d, J= 9.2 Hz, 1H), 3.42 (m, 1),H 3.35 (s, 3H), 3.25 (s, 3H), 2.75 (m, 2H), 2.01 (s, 3H), 2.00 (m, 1H), 1.87 (m, 1)H, 1.80 (s, 3H), 1.77 (m, 2H), 1.00 (d, J = 7.0 Hz, 3H), 0.97 (d, J= 6.5 Hz, 3H). MS (ESI): Calcd. for C28H39N3O8Na: 568, found 568 (M+Na)+.
EXAMPLE 25
[00164] This example demonstrates the preparation of 17-amino- 18-(2-fluoroethoxyimino) -17-demethoxygeldanamycin (28).
[00165J To a single neck flask was added 27 (70 mg, 0.12 mmol) and anhydrous pyridine (2 mL). Under an atmosphere of argon o-fluoroethylhydroxyamine hydrochloride (144 mg, 1.2 mmol) was added to the solution. The reaction mixture was stirred at 80° C. for 2 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant red oil was purified by flash column chromatography (methylene chloride : methanol, 97 : 3) to afford the desired product as a red solid (71.7 mg, 95%). 1H NMR (CDCl3, 500 MHz): δ 9.06 (s, IH), 8.00 (s, IH), 6.93 (d, J = 11.7 Hz, IH), 6.57 (t, J = 11.6 Hz, IH), 5.95 (d, J= 9.4 Hz, IH), 5.81 (t, J= 10.6 Hz3 IH), 5.19 (brs, 2H), 5.16 (s, IH), 4.80 (brs, 2H, NH2), 4.80-4.75 (m, IH), 4.67-4.64 (m, IH), 4.58 (t, J=AA Hz, IH), 4.53-4.52 (m, IH), 4.31 (d, J= 10.0 Hz, IH), 3.60 (d, J= 9.0 Hz, IH), 3.45-3.44 (m, IH), 3.36 (s, 3H), 3.26 (s, 3H), 2.76-2.67 (m, 3H), 2.02 (s, 3H), 1.96-1.88 (m, 2H), 1.81 (s, 3H), 1.71-1.60 (m, IH), 0.99 (d, J=6.9 Hz, 3H), 0.89 (t, J= 6.8 Hz, 3H). ESI- MS: calcd. for C30H43FN4O8+Na (M+Na)+: 629. Found: 629.
EXAMPLE 26
[00166] This example demonstrates the preparation of 17-amino-l 8- benzyloxyimino-17- demethoxygeldanamycin (29).
[00167] To a single neck flask was added 27 (70 mg, 0.12 mmol) and anhydrous pyridine (2 mL). Under an atmosphere of argon o-benzylhydroxylamine hydrochloride (90 mg, 0.62 mmol) was added to the solution. The reaction mixture was stirred at 80° C. for 2 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant red oil was purified by flash column chromatography (methylene chloride : methanol, 97 : 3) to afford the desired product as a red solid (64.9 mg, 82%). 1H NMR (CDCl3, 500 MHz): δ 9.12 (s, IH), 8.21 (s, IH), 7.38-7.36 (m, 2H), 7.27-7.27 (m, IH), 7.26 (s, IH), 7.16- 12 (m, IIHH), 6.98-6.95 (m, IH), 6.57 (t, J = 11.7 Hz, 1H), 5.95 (d, J = 9.4 Hz, 1)H3 5.83 (t, J = 10.6 Hz, IH), 5.30 (brs, 2H)1 5.18 (s, IH, H-7), 4.80 (brs, 2H, NH2), 4.32 (d, J = 10.0 Hz, IH), 3.63 (d, J = 8.4 Hz, IH)53.47-3.45 (m, IH), 3.37 (s, 3H), 3.26 (s, 3H), 2.78-2.72 (m, 2H), 2.06 (s, 3H), 2.04-1.90 (m, 2H), 1.85-1.78 (m, 2H), 1.81 (s, 3H), 1.03-1.00 (m, 6H). ESI-MS: calcd. for C34H44N4CV-Na (M+Na)+: 659. Found: 659.
EXAMPLE 27
[00168] This example demonstrates the preparation of 17-amino-l 8-(2- (dimethylamino)ethoxyimino- 17-demethoxygeldanamycin (30) .
[00169] To a single neck flask was added 27 (70 mg, 0.12 mmol) and anhydrous pyridine (2 mL). Under an atmosphere of argon o-dimethylaminoethoxylamine hydrochloride (88 mg, 0.62 mmol) was added to the solution. The reaction mixture was stirred at 80° C. for 2 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant red oil was purified by flash column chromatography (methylene chloride : methanol, 4 : 1) to afford the desired product as a red solid (34.3 mg, 44%). 1H NMR (CD3OD, 500 MHz): δ 7.83 (s, IH), 9.07 (d, J=9.1 Hz, IH), 6.64 (t, J=I 1.2 Hz, IH), 5.83 (m, IH), 5.68 (d, J = 9.8 Hz, IH), 5.12 (s, IH), 4.62-4.60 (m, 2H), 4.46 (d, J=8.9 Hz, IH), 3.61-3.59 (m, IH), 3.46 (brs, IH), 3.34 (s, 3H), 3.27 (s, 3H), 3.25-3.18 (m, 3H), 2.80 (s, IH), 2.75-2.72 (m, 4H), 2.54-2.51 (m, IH), 2.20-2.15 (m, IH)1 2.01 (s, 3H), 1.89-1.85 (m, 2H), 1.75-1.67 (m, 5H), 1.31 (t, J=7.3 Hz, IH), 1.00-0.96 (m, 6H). ESI-MS: calcd. for C32H49N5O8+^ (M+Na)+: 654. Found: 654.
EXAMPLE 28
[00170] This example demonstrates the preparation of 17-amino- 18-ethoxyimino- 17- demethoxygeldanamycin (31).
[00171 J To a single neck flask was added 27 (67 mg, 0.12 mmol) and anhydrous pyridine (2 mL). Under an atmosphere of argon σ-ethylhydroxyamine hydrochloride (88 mg, 0.62 mmol) was added to the solution. The reaction mixture was stirred at 80° C. for 2 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant red oil was purified by flash column chromatography (methylene chloride : methanol, 97:3) to afford the desired product as a red solid (65.3 mg, 93%). 1H NMR (CDCl3, 500 MHz): δ 9.07 (s, IH), 7.98 (s, IH), 6.93 (d, J=I 1.7 Hz, 1H), 6.57 (t, J = 11.6 Hz, )1,H 5.95 (d, J = 9.5 Hz, IH), 5.81 (t, J = 10.5 Hz, IH), 5.17 (s, 1H), 4.80 (brs, 2H, NH2)3 4.37 (dd, J = 7.2, 14.2 Hz, 2H), 4.31 (d, J=10.0 Hz, IH), 3.60 (d, J = 9.4 Hz, 1H), 3.46-3.44 (m, )1,H 3.36 (s, 3H), 3.25 (s, 3H)5 2.76-2.67 (m, 2H), 2.03 (s, 3H), 1.96-1.88 (m, 2H), 1.82-1.80 (m, 2H), 1.81 (s, 3H), 1.38 (t, J=7.2 Hz, 3H), 0.99 (d, J=6.9 Hz5 6H). ESI-MS: calcd. for C30H4^O8-I-Na (M+Na)+: 611. Found: 611.
EXAMPLE 29
[00172] This example demonstrates the preparation of 17-amino-18-hydroxyimino-17- demethoxygeldanamycin (32) [001731 To a single neck flask was added 27 (70 mg, 0.12 mmol) and anhydrous pyridine (2 mL). Under an atmosphere of argon hydroxyamine hydrochloride (87 mg, 1.2 mmol) was added to the solution. The reaction mixture was stirred at 80° C. for 2 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant red oil was purified by flash column chromatography (methylene chloride : methanol, 98:5) to afford the desired product as a red solid (42.3 mg, 61 %). 1H NMR (CD3OD, 500 MHz): δ 7.94 (s, IH), 7.08 (brs, IH), 6.64 (t, J = 11.2 Hz, IH), 5.81 (brs, IH), 5.71 (brs, IH), 5.09 (s, IH), 4.93-4.81 , IIHH), 4.46 (d, J=8.4 Hz7 1H), 3.63-3.60 (m, 1H), 3.44 (brs, 1)H, 3.35 (s, 3H), 3.26 (s, 3H), 2.73 (brs, IH), 2.53 (d, J=12.3 Hz, 1H), 2.19-2.14 (m, 1H), 2.01 (s, 3H), 1.85 (brs, ), 11H.75-1.67 (m, 6H), 0.99-0.96 (m, 6H). ESI-MS: calcd. TOr C24H40N4O8H-Na (M+Na)+: 583. Found: 583.
EXAMPLE 30
[00174] This example demonstrates the preparation of 17-(diethylamino)ethylarnino-l 7- demethoxygeldanamycin (33).
[00175] To a flame-dried three neck flask was added geldanamycin (300 mg, 0.54 mmol) and anhydrous THF (20 mL). Under an atmosphere of argon N,N-diethylaminoethyldiamine (0.7 ml, 5.4 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 1 hour, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The residue was recrystallized from isopropanol to afford the desired product as purple solid (270 mg, 78%). 1H NMR (CDCl3, 500 MHz): δ 9.21 (s, )1,H 7.25 (s, IH), 6.95 (d, /= 1 1.2 Hz, IH), 6.58 (t, J = 11.2 Hz, 1H), 5.95 (d, J= 9.7 Hz, 1)H, 5.86 (t, /= 11.2 Hz, IH), 5.18 (s, IH), 4.55 (brs, 2H), 4.33 (d, J= 10.0 Hz, 1H), 3.66 (m, 1)H, 3.58 (m, )1,H 3.44 (m, 2H), 3.36 (s, 3H, OMe), 3.27 (s, 3H, OMe), 2.72 (m, 4H), 2.57 (t, J = 7.1 Hz, 4H), 2.57 (m, IH), 2.03 (s, 3H, C2-Me), 1.78 (s, 3H), 1.75 -1.60 (m, 3H), 1.05 (t, /= 7.1 Hz, 6H), 0.95-0.86 (m, 6H). ESI-MS: calcd. for C34H52N4O8 +H (M+H)+: 645 and for C34H52N4O8+Na (M+Na)+: 667. Found: 645 and 667. EXAMPLE 31
[00176 J This example demonstrates the preparation of 17-(2-diethylamino)ethamino- 18- methoxyiminogeldanamycin (34).
[00177] To a solution of 18-<?-methyloximino geldanamycin 3 (20 mg, 0.034 mrnol) in THF was added N, N'- diethylethanediatnine (48 μL, 0.339 rήmol), and the mixture was then stirred at room temperature overnight, and then removed the THF completely by vacuum. The residue was purified by column chromatography, eluting with CFbClj/MeOH (98:2) to afford the desired product as red solid (24.5 mg, 98 % yield). 1H NMR (CDCl3, 500 MHz) δ 9.06 (s, IH, NH-22), 8.05 (s, IH, 19-H), 6.92 (d, J=11.6 Hz, IH, 3-H), 6.57 (t, J= 11.4Hz, IH, 4-H), 5.97 (d, J=9.4 Hz, IH, 9H), 5.81 (t, /=10.5 Hz, IH, 5-H)3 5.16 , IIHH, 7-H), 4.78 (brs, 2H, NH2), 4.30 (d, /=10.2 Hz, 1,H 6-H), 4.19-4.05 (m, 2H, 17-CH2), 4.1 l(s, 3H, 18- C=N-O-CH3), 3.58-3.55 (m, 1,H 11-H)5 3.45-3.43 (m, IH, 12-H), 3.35 (s, 3H, OCH3), 3.25 (s, 3H3 OCH3), 2.74-2.70 (m, 2H, 10-H and 15-H), 2.63(brs, IH, 15-H)3 2.02 (s, 3H, 2-CH3), 1.88-1.87 (m, 2H, 17-CH2), 1.79-1.71 (m, 6H, 13-H, 8-CH3 and 14-H), 1.30-1.25 (m, 4H, 17- CH2 χ2), 1.04-0.83 (m, 12H3 10 and 14-CH3, 17-CH3x2); MS(ESI) Calcd. FOr (C35H55N5O8): 673, found 696 (MNa+), 672 (M-H)".
EXAMPLE 32
[00178] This example demonstrates the preparation of 17-(2-hepthylamino)-l 7- demethoxygeldanamycin (35).
[00179] To a flame-dried three neck flask was added geldanamycin (490 mg, 0.88 mmol) and anhydrous THF (40 mL). Under an atmosphere of argon 2-heptylamine (795 μL, 4.5 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 8 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rota vapor to dryness. The resultant brownish, oil was dissolved in 5 mL of isopropaπol at 60° C. and stood at room temperature for at least 24 hours until most of the desired product recrystallized from the solvent. After careful removal of the supernatant solution via a glass pipette, the solids were washed with cold ethyl ether and dried in vacuo to afford the desired product (481 mg, 85%). 1H NMR (CDCl3, 500 MHz): δ 9.20 (s, 1,H NH-22), 7.28 (d, J= 5.4 Hz, 1H, H-19), 6.95 (d, /= 11.2 Hz,1H , H-3), 6.58 (t, J= 11.1 Hz, 1H, H-4), 6.35-6.25 (m, , 1 NHH), 5.91 (d, J= 9.5 Hz5 IH, H-9), 5.86 (t, J" = 10.5 Hz5 IH, H-5), 5.19 (brs, IH, H-7), 4.78 (brs, 2H, NH2), 4.30 (d, ./ = 9.5 Hz,1H , H-6), 4.12-3.98 (m, 1,H heptyl), 3.57 (d, J= 8.8 Hz, IH, H-12), 3.50-3.42 (m, IH, H- 1 1), 3.36 (s, 3H5 OMe), 3.26 (s, 3H, OMe), 2.76-2.69 (m, 2H, H-IO, H-15), 2.28-2.20 (m, IH, H-15), 2.02 (s, 3H5 C2-Me), 1.80 (s5 3H, Me), 1.70-1.75 (m, 2H, H-13), 1.59 (s, 3H5 Me), 1.42-1.32 (m, 1H, H-14), 1.35-1.20 (m5 8H, heptyl), 1.02-0.95 (m, 6H5 Me), 0.95 (t, J = 7.0 Hz5 3H, Me). ESI-MS: calcd. for C35H53N3O^Na (M+Na)+: 666. Found: 666.
EXAMPLE 33
[00180] This example demonstrates the preparation of 17-(2-hepthylamino)- 18- methoxyimino-17-demethoxygeldanamycin (36).
[00181] To a single neck flask was added 35 (75 mg, 0.12 mmol) and anhydrous pyridine (8 mL). Under an atmosphere of argon o-methylhydroxyamine hydrochloride (100 mg5 1.2 mmol) was added to the solution. The reaction mixture was stirred at 80° C. for 1 1 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant dark oil was purified by flash column chromatography (methylene chloride : methanol, 93 : 7) to afford the desired product as a light purple solid (63 mg, 76%). 1H NMR (CDCl3, 500 MHz): δ 9.07 (s, IH), 7.98 (s, IH), 7.51 (t, J = 1 1.1 Hz, 1)H, 6.91 (d, J = 11.2 Hz, IH), 6.61-6.55 (m, IH), 5.93 (d, J = 9.5 Hz,1H )5 5.84 (t, J = 10.5 Hz, )1,H 5.17 (brs, IH5 H-7), 4.78 (brs, 2H, NH2), 4.31 (d, J = 9.5 Hz,1H )5 4.12-3.98 (m, 2H), 4.11 (s, 3H), 3.57 (d, J = 8.8 Hz, IH), 3.50-3.42 (m, ), 3.361H (s, 3H)5 3.26 (s, 3H), 2.76-2.69 (m, 2H), 2.35-2.31 (m, IH), 2.02 (s, 3H), 1.79 (s, 3H)5 1.70-1.75 (m5 2H)5 1.58 (s, 3H), 1.42-1.32 (m, IH), 1.35-1.20 (m, 8H), 1.02-0.95 (m, 6H), 0.89 (t, J = 7.0 Hz5 3H). ESI-MS: calcd. for C36Hs6N4O8+Na (M+Na)+: 695. Found: 695.
EXAMPLE 34
[00182] This example demonstrates the preparation of 17-heptylamino-17- demethoxygeldanamycin (37).
[00183] To a flame-dried three neck flask was added geldanamycin (570 mg, 1.02 mmol) and anhydrous THF (30 mL). Under an atmosphere of argon heptylamine (893 μL, 6.1 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 24 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant brownish oil was dissolved in 5 mL of isopropanol at 60° C. and stood at room temperature for at least 24 hours until most of the desired product recrystallized from the solvent. After careful removal of the supernatant solution via a glass pipette, the solids were washed with cold ethyl ether and dried in vacuo to afford the desired product (532 mg, 81%). 1H NMR (CDCl3, 500 MHz): δ 9.20 (brs, lH, NH-22), 7.28 (s, IH, H-19), 6.95 (d, J= 11.0 Hz, IH, H-3), 6.59 (t, J= 11.0 Hz, IH, H-4), 6.30 (s, IH, NH), 5.91 (d, J = 9.4 , IIHH, H-9), 5.86 (t, J= 11.5 Hz, IH, H-5), 5.19 (s, 1H, H-7), 4.70 (brs, 2H, NH2), 4.31 (d, J- 9.5 Hz, IH, H-6), 3.58-3.54 (m, 2H, H- 12, H-heptyl), 3.47-3.42 (m, 2H5 H-I l, H-heptyl), 3.37 (s, 3H3 OMe), 3.27 (s, 3H, OMe), 2.74-2.72 (m, 1H, H-10), 2.67 (d, J= 12.8 Hz, 1, H H-15), 2.44 (t, /= 13.0 Hz, 1H, H-15), 2.03 (S, 3H, C2-Me), 1.70-1.30 (m, 13 H, H-14, H-13, heptyl), 1.60 (s, 3H, Me), 1.02 (d, J= . 6.9 Hz5 3H, Me), 0.96 (d, J= 7.1 Hz, 3H, Me), 0.88 (t, J = 7.0 Hz, 3H, heptyl). ESI-MS: calcd. for C35H53N3O8H-Na (M+Na)+: 666. Found: 666.
EXAMPLE 35
[00184] This examp Ie demonstrates the preparation of 17-methylaziridinyl- 17- demethoxygeldanamycin (38).
[00185] To a flame-dried three neck flask was added geldanamycin (425 rag, 0.75 mmol) and anhydrous THF (40 mL). Under an atmosphere of argon 2-methylaziridine (719 μL, 4.5 mmol) was added dropwise to the solution. The reaction mixture was stirred at room temperature for 7 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant brownish oil was dissolved in 4 mL of isopropanoi at 60° C. and stood at room temperature for at least 24 hours until most of the desired product recrystallized from the solvent. After careful removal of the supernatant solution via a glass pipette, the solids were washed with cold ethyl ether and dried in vacuo to afford the desired product (400 mg, 90%). 1H NMR (CDCl3, 500 MHz): δ 8.80 (brs, 1,H NH-22), 7.27 (s, IH, H-19), 6.93 (d, J= 11.0 Hz, IH, H- 3), 6.57 (t, J= 11.1 Hz, 1H, H-4), 5.89-5.81 (m, 2H, H-5, H-9), 5.19 (d, J = 4.4 Hz, IH, H-7), 4.80 (brs, 2H, NH2), 4.32 (d, J= 9.6 Hz, 1,H H-6), 3.58-3.50 (m, IH, H-12), 3.45-3.40 (m, 1H , H-11), 3.35 (s, 3H, OMe), 3.28 (s, 3H, OMe), 2.7S-2.71 (m, IH, H-10), 2.60-2.52 (m, 1H, H-15), 2.50-2.40 (m, 2H5 aziridinyl), 2.33-2.31 (m, IH, aziridinyl), 2.18 (d, J = 5.9 Hz, 1H, H-15), 2.02 (s, 3H, C2-Me), 1.60 (s, 3H5 C8-Me), 1.79-1.77 (m, 3H, H-14, H-13), 1.46 (t, J= 5.5 Hz, 3H, methyl), 1.32-1.30 (m, IH), 1.02-0.S9 (m, 6H, Me). ESI-MS: calcd. for C3iH43N3O8+Na (M+Na)+: 608. Found: 608.
EXAMPLE 36
[00186] This example demonstrates the preparation of 17-allylamino-l l-ø-palmitoyl-17- demethoxygeldanamycin (39).
[00187] To a solution of 17-AAG (260 mg, 0.44 mmol) in pyridine (10 mL) was added palmitoyl chloride (435 mg, 0.88 mol) at the room temperature under an atmosphere of argon. The mixture was heated to 65° C. and maintained at the same temperature for 6 hours. TLC showed the starting material disappeared. The reaction mixture was condensed on a rotavapor to dryness. The resultant residual was purified by flash column chromatography (Hexane: ethyl acetate, 1 : 1) to afford the desired product as a light purple oil (236 mg, 65%). MS(ESI) Calcd. for C47H73N3O9^-Na: 847, found: (M+Na+), 847.
EXAMPLE 37
[00188] This example demonstrates the preparation of 17-(PEGamino)- 17- demethoxygeldanamycin (40).
[00189] To a flame-dried three neck flask was added geldanamycin (150 mg, 0.27 mmol), anhydrous THF (20 mL) and DMF (3 mL). Under an atmosphere of argon NH2-PEG-NH2 (MW3400, 911 mg, 0.27 mmol) was added dropwise to the solution. The reaction mixture was stirred at 50° C. for 2 hours, upon which TLC indicated the disappearance of the starting material. The reaction mixture was condensed on a rotavapor to dryness. The resultant mixture was purified on the preparative HPLC to give the desired product as a light purple solid, which LC/MS indicated as the desired product.
EXAMPLE 38
[00190] This example demonstrates the preparation of 18-(2-dimethylamino)ethoxyimino- geldanamycin (41).
[00191] A suspension of geldanamycin (100 mg, 0.18 mmol) and 2-(aminooxy)-N,N- dimethylethanamine dihydrochloride (158 mg, 0.89 mmol) in pyridine (3.0 mL) was stirred at 80° C. for 2 hr. IJVNaOH solution (0.36 mL) was added and the mixture was stirred for further 4 hr. The mixture was cooled and treated with saturated NH4Cl solution and then extracted with CH2CI2. The combined organic extracts were washed with brine and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 98:2, 90:5, 75:5) to afford the desired product (45 mg, 39% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.79 (s, IH), 8.23 (s5 IH), 6.92 (d, J = 11.6 Hz, IH), 6.57 (t, J = 11.5 Hz, IH), 5.91 (d, J= 9.4 Hz, IH), 5.82 (t, J = 10.5 Hz, IH), 5.18 (s, IH), 4.80 (br s, 2H), 4.56 (t, J= 5.8 Hz, 2H), 4.30 (d, J= 9.9 Hz, IH), 4.02 (s, 3H), 3.55 (t, J= 7.2 Hz, IH), 3.42 (m, IH)5 3.35 (s, 3H), 3.26 (s, 3H)5 2.81 (t, J= 5.7 Hz, 2H), 2.75 (m, IH). 2.56 (dd, J= 10.5, 12.9 Hz, IH), 2.43 (dd, J== 1.3, 1 1.6 Hz, IH), 2.37 (s, 6H), 2.03 (s, 3H), 1.83 (m, 2H), 1.79 (s, 3H), 1.64 (m, IH), 0.98 (d, J= 7.0 Hz, 3H), 0.95 (d, J= 6.7 Hz5 3H). MS (ESI): Calcd. for C33H5ON4O9Na: 669, found 669 (M+Na)+.
EXAMPLE 39
[00192] This example demonstrates the preparation of 18-(2-(4-methylthiazol-5- yl)ethoxyimino)geldanamycin (42).
[00193] A solution of geldanamycin (86 mg, 0.15 mmol) and 2-[5-(4- methylthiazolo)]ethoxyamine hydrochloride (150 mg, 0.77 mmol) in pyridine (2.0 mL) was stirred at 80° C. for 2 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZTVIeOH, 98:2) to yield the compound 42 (68 mg, 63% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.80 (s, IH), 8.59 (s, IH), 8.25 (s, IH)5 6.93 (d5 J- 11.7 Hz, IH)5 6.57 (t, J= 11.3 Hz5 IH), 5.91 (d, J= 9.4 Hz, IH), 5.83 (t, J= .5 Hz, IIHH), 5.18 (s, IH), 4.80 (br s, 2H), 4.57 (t, J= 6.6 Hz, 2H), 4.31 (d, J = 9.8 Hz, IH), 3.94 (s, 3H), 3.55 (t, J = 7.4 Hz5 1H), 3.42 (m5 1H), 3.35 (s, 3H)5 3.27 (s, 3H), 3.26 (t, J= 6.6 Hz5 2H), 2.75 (m, IH), 2.55 (dd, J= 10.5, 13.0 Hz, 1H), 2.42 (s, 3H), 2.42 (t, J = 10.6 Hz, IH), 2.04 (s, 3H)5 1.83 (m, 2H), 1.79 (s, 3H), 1.64 (m, )1,H 0.99 (d, J= 7.0 Hz, 3H), 0.95 (d, J= 6.7 Hz, 3H). MS (ESI): Calcd. for C35H48N4O9SNa: 7235 found 723 (M+Na)+. EXAMPLE 40
[00194] This example demonstrates the preparation of 18-(2- (diethylammo)ethoxyimino)geldanamycin (43).
[00195] A solution of geldanamycin (100 mg, 0.178 mmol) and TvyV-diethyl-2- aminooxyethylamine dihydro chloride ( 183 mg, 0.89 mmol) in pyridine (3.0 mL) was stirred at 80° C. for 2 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 90:5, 75:5) to yield the compound 43 (86 mg, 72% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.79 (s, IHH), 8.21 (s, IH), 6.92 (d, J = 11.6 Hz, IH), 6.56 (t, J = 11.5 Hz, IH), 5.91 (d, J= 9.5 Hz, IH), 5.82 (t, J- 10.5 Hz5 IH), 5.17 (s, IH), 4.82 (br s, 2H), 4.54 (t, J= 6.2 Hz, 2H), 4.30 (d, J= 9.8 Hz, IH), 4.02 (s, 3H), 3.55 (t, J = 8.1 Hz, IH), 3.42 (m, IH), 3.35 (s, 3H), 3.26 (s, 3H), 2.93 (m, 2H), 2.75 (m, IH), 2.68 (q, J= 7.1 Hz, 4H), 2.56 (dd, J= 10.6, 12.9 Hz, IH), 2.43 (d, J= 12.6 Hz, IH), 2.02 (s, 3H), 1.83 (m, 2H), 1.79 (s, 3H), 1.63 (m, IH), 1.10 (t, J= 7.2 Hz, 6H), 0.98 (d, J= 7.0 Hz, 3H), 0.94 (d, J= 6.7 Hz, 3H). MS (ESI): Calcd. for C35H54N4O9Na: 697, found 697 (M+Na)+.
EXAMPLE 41
[00196] This example demonstrates the preparation of 17-propylamino-17- demethoxylgeldanamycin (44).
[00197] Compound 44 was prepared by treating geldanamycin and commercial N- methylpropylamine in THF at room temperature. 1H NMR (500 MHz, CDCI3): δ 9.19 (s, IH), 7.28 (s, IH), 6.96 (d, J= 11.8 Hz3 IH), 6.59 (t, J= 1.5 Hz, IIHH), 6.32 (br s, IH), 5.91 (d, J= 9.6 Hz5 IH), 5.86 (t, J= 10.6 Hz5 IH), 5.19 (s, IH), 4.75 (br s, 2H), 4.31 (d, J= 9.9 Hz,1H ), 3.54 (m, 2H), 3.44 (m, 2H), 3.37 (s, 3H), 3.27 (s, 3H), 2.74 (m, IH), 2.68 (d, J = 13.6 Hz, 1H), 2.43 (dd, J= 10.9, 13.9 Hz, 1)H, 2.03 (s, 3H), 1.80 (br s, SH), 1.69 (m, 3H), 1.05 (t, J= 6.9 Hz, 3H)5 0.97 (d, J = 6.5 Hz, 3H), 0.93 (d, J= 6.8 Hz, 3H). MS (ESI): Calcd. for C3IH45N3O8Na: 610, found 610 (M+Na)+.
EXAMPLE 42
[00198] This example demonstrates the preparation of 17-ethylamino- 17- demethoxylgeldanamycin (45). [00199] Compound 45 was prepared by treating geldanamycin and commercial iV~ ethylmethylamine in THF at room. 1H NMR (500 MHz5 CDCl3): δ 9.19 (s, IH), 7.28 (s, IH), 6.95 (d, J= 11.6 Hz, IH), 6.58 (t, J= 11.4 Hz IIHH), 6.23 (br IIHH), 5.91 (d, J= 9.5 Hz3 IH), 5.86 (t, J= 10.6 Hz, IH), 5.19 (s, IH), 4.82 (br s, 2H), 4.31 (d, J= 9.9 Hz, IH), 3.63 (m, IH), 3.57 (m, IH), 3.50 (m,lH), 3.45 (m, IH), 3.36 (s, 3H), 3.27 (s, 3H), 2.74 (m, IH), 2.68 (d, J = 13.4 Hz, IH), 2.43 (dd, J= 10.8, 13.9 Hz, IH), 2.02 (s, 3H), 1.80 (s, 3H), 1.78 (m, 2H), 1.72 (m, IH), 1.33 (t, J= 7.2 Hz, 3H), 1.00 (d, J= 6.9 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H). MS (ESI): Calcd. for C30H43N3O8Na: 596, found 596 (M+Na)+.
EXAMPLE 43
[00200] This example demonstrates the preparation of 17-amino- 17 -demethoxyl- 18- methoxyiminogeldanamycin (46).
[00201] A solution of 17-amino- 17-demethoxygeldanamycin (100 mg, 0.18 mmol) and methoxylamine hydrochloride (76.4 mg, 0.915 mmol) in pyridine (2.0 mL) was stirred at 800C for 1 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 100:2) to yield the compound 46 (97 mg, 92% yield) as a orange reddish solid. 1H NMR (500 MHz, CDCl3): δ 05 (s, IIHH), 7.97 (s, IH), 6.93 (d, J= 11.8 Hz, IH), 6.57 (t, J= 11.4 Hz, 1H), 5.96 (d, J= 9.4 Hz, 1)H, 5.80 (t, J= 10.6 Hz, IH), 5.19 (br s, 2H), 5.17 (s, 1H), 4.80 (br s, 2H), 4.31 (d,J= 10.1 Hz, )1,H 4.12 (s, 3H), 3.60 (d,J = 9.2 Hz, ), 1H 3.45 (m, 1H), 3.36 (s, 3H), 3.25 (s, 3H), 2.74 (m, IH), 2.68 (d, J= 14.1 Hz, IH), 2.02 (s, 3H), 1.92 (m, 2H), 1.80 (s, 3H), 1.79 (m, 2H), 1.00 (s, 3H), 0.99 (s, 3H). MS (ESI): Calcd. for C29H42N4O8Na: 597, found 597 (M+Na)+.
EXAMPLE 44
[00202] This example demonstrates the preparation of 17-amino- 17-demethoxy 1-18- allyloxyiminogeldanamycin (47).
[00203] A solution of 17-amino-17-demethoxygeldanamycin (100 mg, 0.18 mmol) and o- allylhydroxylamine hydrochloride (100.2 mg, 0.915 mmol) in pyridine (2.0 mL) was stirred at 80° C. for 1 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 100:2) to yield the compound 47 (103 mg, 94% yield) as a orange reddish solid. 1H NMR (500 MHz, CDCl3): δ 9.06 (s, IH), 8.00 (s, IH), 6.93 (d, J = 11.7 Hz, IH), 6.57 (t, 7= 11.5 Hz, 1 H), 6.01 (m, )1,H 5.95 (d, J = 9.4 Hz, IH), 5.80 (t, J= 10.6 Hz, IH), 5.35 (m, 1H), 5.28 (m, 1H), 5.16 (s, 1)H3 4.81 (m, 2H), 4.31 <d, J= 10.0 Hz, IH), 3.60 (d, J= 9.4 Hz, 1H), 3.45 (m, 1H), 3.36 (s, 3H), 3.25 (s, 3H), 2.74 (m, IH), 2.68 (d, J = 14.0 Hz, IH), 2.02 (s, 3H), 1.92 (m, 2H), 1.80 (s, 3H), 1.79 (m, 2H), 1.00 (s, 3H), 0.98 (s, 3H). MS (ESI): Calcd. for C3IH44N4O8Na: 623, found 623 (M+Na)+.
EXAMPLE 45
[00204] This example demonstrates the preparation of 17-propylamino-17-dernethoxyl-18- allyloxyiminogeldanamycin (48).
[00205] A solution of π-propylamino-π-demethoxygeldanamycin (40 mg, 0.068 mmol) and <9-allylhydroxylamine hydrochloride (74.4 mg, 0.68 mmol) in pyridine (2.0 mL) was stirred at 80° C. for 3 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 100:1) to yield the compound 48 (25 mg, 57% yield) as a reddish solid. 1H NMR (500 MHz, CDCl3): δ 9.08 (s, )1,H 8.04 (s, IH), 6.92 (d, J= 11.6 Hz, IH), 6.57 (t, J = 11.4 Hz, 1H), 6.01 (m, 1H), 5.96 (d, J= 11.1 Hz, 1)H, 5.81 (t, J= 10.6 Hz, IH), 5.34 (m, IH)5 5.28 (m, 1H), 5.17 (s, 1)H, 4.79 (d, J= 5.9 Hz, 2H), 4.31 (d, J= 10.1 Hz, IH), 3.57 (m, IH), 3.50 (m, 1H), 3.45 (m, 1H), 3.38 (m, 2H), 3.36 (s, 3H), 3.26 (s, 3H), 2.72 (m, IH), 2.34 (dd, J= 10.9, 14.0 Hz, 1H), 2.03 (s, 3H), 1.84 (m, IH), 1.80 (s, 3H), 1.77 (m, IH), 1.73 (m, IH), 1.65 (m? 2H), 0.99 (m, 9H). MS (ESI): Calcd. for C34H50N4O8Na: 665, found 665 (M+Na)+.
EXAMPLE 46
[00206] This example demonstrates the preparation of 17-amido-l 7-demethoxyl-l 8- methoxyiminogeldanamycin (49).
[00207] 3-Chloropropionyl chloride (15.4 μL, 0.16 mmol) was added to a solution of 17- amino-17-demethoxy-18-methoxyloximinogeldanamycin (42 mg, 0.073 mmol) in THF (3.65 mL) at 0° C. The reaction mixture was allowed to room temperature and stirred for 2 hr. Then the mixture was heated under reflux for further 2 hr. The reaction was quenched with sat. Na2CO3 solution and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2CkZMeOH, 90:10) to yield the compound 49 (25 mg, 51% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, IH)5 8.29 (s, IH), 7.63 (s, 1H ), 6.90 (d, J= 11.6 Hz, 1H)5 6.56 (t,J= 11.4 Hz, )15H 5.86 (d, J= 9.9 Hz, IH), 5.83 (t, J= 10.6 Hz, 1H), 5.16 (s, 1H), 5.01 (br s, 2H), 4.30 (d, J= 9.7 Hz, IH), 4.17 (s, 3H), 3.87 (m5 2H), 3.51 (m, 1H), 3.40 (m, 1H), 3.34 (s, 3H), 3.27 (s, 3H), 2.85 (m, 2H), 2.74 (m, IH), 2.63 (d, J = 12.0 Hz, 1H), 2.34 (dd, J= 10.3, 13.7 Hz, ),1H 2.03 (s, 3H), 1.80 (m, 2H), 1.78 (s, 3H), 1.67 (m, IH), 0.98 (d, J= 7.0 Hz, 3H), 0.88 (d, J= 6.6 Hz, 3H). MS (ESI): Calcd. for C32H45ClN4O9Na: 687, found 687 (M+Na)+.
EXAMPLE 47
[00208] This example demonstrates the preparation of 17-acetoamido-17-demethoxyl-l 8- allyloxyiminogeldanamycin (50).
[00209] Acetyl chloride (89.1 μL, 1.25 mmol) was added dropwise to a solution of 17- amino-17-demethoxy-l 8-allyloχyloximin.ogeldanamycin (50 mg, 0.083 mmol) in THF (4.16 mL) at 0° C. The reaction mixture was heated to 55° C. and stirred for 6 hr. The reaction was quenched with sat. Na2CO3 solution and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 100:2, 100:3) to yield the compound 50 (17 mg, 30% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.85 (s, IH)5 8.16 (s, IH), 7.22 (s, 1H), 6.55 (t, J= 11.4 Hz, 1H), 5.99 (m, 1)H, 5.80 (t, J= 9.8 Hz, )1,H 5.34 (m, IH), 5.28 (m, 1H), 5.20 (m, 2H), 4.92 (t, J= 12.0 Hz, )1,H 4.82 (d, J= 5.9 Hz, 2H), 4.42 (d, J = 9.0 Hz, 1H), 3.45 (m, 1H), 3.37 (s, 3H), 3.32 (s, 3H), 2.86 (m, IH), 2.49 (m, IH), 2.26 (m, I H), 2.15 (s, 3H), 2.03 (s, 3H), 1.86 (s, 3H), 1.83 (m, IH), 1.73 (s, 3H), 1.49 (m, IH), 1.01 (d, J= 6.5 Hz5 3H), 0.92 (d, J= 6.7 Hz, 3H). MS (ESI): Calcd. for C35H48N4Oi0Na: 707, found 707 (M+Na)+. EXAMPLE 48
[00210] This example demonstrates the preparation of 17-amido-l 7-demethoxyl-l 8- methoxyiminogeldanamycin (51).
[00211| A solution of 17-amide substituted geldanamycin (36 mg, 0.045 mmol) and methoxylamine hydrochloride (18.8 mg, 0.225 mmol) in pyridine (2.5 mL) and methanol (0.5 mL) was stirred at 80° C. for 2 hr. The mixture was cooled and sat. TS[HUCl solution was added. The mixture was extracted with CH2Cl2 and the combined organic extracts were washed with brine, dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 100:2) to yield the compound 51 (7 mg, 19% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.80 (s, IH), 8.31 (s, IH), 8.22 (s, IH), 7.85 (d, J = 7.6 Hz, 2H)5 7.54 (d, J = 7.3 Hz, 2H), 7.37 (m 2H), 7.32 (m 2H), 7.25 (m, IH)1 6.92 (d, J= 11.8 Hz, IH), 6.58 (t,J = 11.6 Hz, IH), 5.91 (d, J= 8.8 Hz, IH), 5.84 (t, J= 10.5 Hz, IH), 5.18 (s, IH), 4.75 (br s, 2H), 4.32 (d, J= 9.8 Hz, IH), 4.14 (s, 3H), 3.80 (m, IH)5 3.64 (s, 2H), 3.60 (s, 2H), 3.52 (t, J= 7.8 Hz, IH), 3.39 (m, IH), 3.33 (s, 3H), 3.28 (s, 3H), 2.73 (m, 2H), 2.53 (m, 2H), 2.40 (m, IH), 2.04 (s, 3H), 1. (m, IIHH), 1.80 (s, 3H), 1.73 (rn, IH), 1.69 (m, IH), 1.09 (m, 3H), 0.98 (d, J= 7.0 Hz, 3H), 0.91 (d, J= 6.5 Hz5 3H). MS (ESI): Calcd. for C46H59N5O9Na: 848, found 848 (MH-Na)+.
EXAMPLE 49
[00212] This example demonstrates the preparation of 17-methylsulfonyloxy-17- demethoxyl-geldanamycin (52).
100213] Triflic anhydride (12.8 μL, 0.076 mmol) was added dropwise to a solution of 17- hydroxy-17-demethoxygeldanamycin (32 mg, 0.058 mmol) and diisopropylethylamine (19.3 μL, 0.12 mmol) in CH2Cl2 (5.85 mL) at 0° C. The reaction mixture was stirred at 0° C. for 15 min. The reaction was quenched with sat. NaHCθ3 solution and the mixture was extracted with CH2CIj. The combined organic extracts were washed with brine and dried over anhydrous MgSO* and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 100:2) to yield the compound 52 (14 mg, 35% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.60 (s, 1H ), 7.57 (sa 1H), 6.92 (d, J = 12.1 Hz, IH), 6.55 (t, J= 11.3 Hz, IH), 5.96 (t, J= 9.6 Hz, IH), 5.59 (d, J= 9.7 Hz, IH)5 5.10 (s, IH)5 4.72 (br s, 2H)54.32 (d, J = 8.2 Hz, IH), 3.38 (s, 3H)5 3.35 (S5 3H), 3.31 (m, IH), 3.26 (m, IH), 2.81 (m, IH)5 2.59 (dd, J = 7.8, 13.1 Hz, IH), 2.49 (dd, J= 6.9, 13.3 Hz, IH)3 2.03 (s, 3H), 1.77 (s, 3H), 1.71 (m, 2H), 1.56 (m, IH)5 1.09 (d, J= 6.6 Hz, 3H), 0.89 (d, J= 7.0 Hz5 3H). MS (ESI): Calcd. for C29H37F3N2OnSNa: 701, found 701 (M+Na)+.
EXAMPLE 50
[00214] This example demonstrates the preparation of 17-hydroxy 1- 17-demethoxyl- 18- methoxyimmo-geldanamycin (53).
[00215] A solution of crude 17-hydroxy-17-demethoxygeldanamycin (78 mg, 0.14 mmol) and merhoxylamine hydrochloride (59.7 mg, 0.715 mmol) in pyridine (2.5 mL) was stirred at 80° C. for 1.5 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH9 100:2) to yield the compound 53 (34 mg, 41% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.93 (s, IH), 8.01 (s, IH)5 7.33 (s, IH), 6.93 (d, J= 11.7 Hz5 IH), 6.57 (t, J= 11.4 Hz, IH), 5.93 (d, J= 9.5 Hz, IH), 5.83 (t, J = 10. Hz, IIHH), 5.18 (s, IH)5 4.75 (br s, 2H), 4.31 (d5 J = 9.9 Hx, IH)74.18 (s, 3H), 3.58 (d, J= 8.8 Hz, IH)5 3.43 (m, IH), 3.36 (s, 3H), 3.27 (s, 3H), 2.76 (t, J= 7.4 Hz, IH), 2.52 (dd5 J= 10.3, 13.2 Hz, IH), 2.44 (d, J = 11.9 Hz5 IH), 2.03 (s, 3H), 1.85 (m, 2H), 1.80 (s5 3H), 1.67 (m, IH)5 0,99 (d5 J= 7.1 Hz5 3H), 0.97 (d, J= 7.2 Hz, 3H). MS (ESI): Calcd. for C29H4]N3O9Na: 598, found 598 (M+Na)+.
EXAMPLE Sl
[00216] This example demonstrates the preparation of 17-hydroxyl-l 7-demethoxyl- 18- allyoxyimino-geldanamycin (54).
[00217] A solution of crude 17-hydroxy- 17-demethoxygeldanamycin (86 mg, 0.16 mmol) and ø-allylhydroxylamine hydrochloride (86 mg, 0.78 mmol) in pyridine (2.5 mL) was stirred at 80° C. for 1.5 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2/MeOH, 100:2) to yield the compound 54 (38 mg, 40% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.94 (s, IH), 8.05 (s, IH), 7.34 (s, IH), 6.94 (d, J= 11.4 Hz5 IH)5 6.57 (t, J= 11.5 Hz, 1H), 6.01 (m, 1H), 5.93 (d, J= 9.4 Hz, )15H 5.83 (t, J= 10.5 Hz5 IH), 5.38 (m, IH), 5.32 (m, IH), 5.18 (s, IH)5 4.85 (d, J = 6.0 Hz, 2H), 4.80 (br s, 2H), 4.31 (d, / - 9.9 Hz, IH), 3.58 (d, J= 9.2 Hz, IH), 3.43 (m, IH), 3.36 (s, 3H), 3.26 (s, 3H), 2.76 (m, IH), 2.52 (dd, J = 10.3, 13.2 Hz, IH)3 2.44(d,J= 1 8 Hz, IIHH), 2.03 (s, 3H), 1.85 (m, 2H), 1.80 (S1 3H), 1.69 (m, )1,H 0.99 (d, J = 7.1 Hz, 3H), 0.97 (d, J= 7.0 Hz, 3H). MS (ESI): Calcd. for C3IH43N3O9Na: 624, found 624 (M+Na)+.
EXAMPLE 52
[00218] This example demonstrates the preparation of 17-ethoxyl~ 17-dermethoxyl- geldanamycin (55).
J0O219] A solution of sodium ethoxide (37.1 mg, 0.545 mmol) in ethanol (1.0 mL) was added dropwise to a mixture of geldanamycin (61 mg, 0.109 mmol) in ethanol (10.9 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The reaction was quenched with sat. NH4Cl solution and the mixture was extracted with CH2Cl2- The combined organic extracts were washed with brine and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 100:2) to yield the compound 55 (15 mg, 24% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3); δ 8.71 (s, IH), 7.28 (s, IH), 6.94 (d, J= 12.6 Hz, 1H), 6.57 (t, J= 11.4 Hz, )1,H 5.S8 (t, J= 10.3 Hz3 IH), 5.83 (t, J= 9.5 Hz,1H ), 5.19 (s, 1H), 4.78 (br s, 2H), 4.46 (in 2H), 4.31 (d, J= 9.4 Hz, IH), 3.53 (d, J= 8.5 Hz,1H ), 3.39 (m, 1H), 3.36 (s, 3H), 3.29 (s, 3H), 2.78 (m, IH), 2.52 (m, IH), 2.43 (m, IH), 2.03 (s, 3H), 1.79 (s, 3H), 1.78 (m, 2H), 1.63 (m, IH), 1.36 (t, J= 7.1 Hz7 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.97 (d, J= 5.1 Hz, 3H). MS (ESI): Calcd. for C30H42N2O9Na: 597, found 597 (MW-Na)+.
EXAMPLE 53
[00220] This example demonstrates the preparation of 17-ώσ-propoxyl- 17-demethoxyl- geldanamycin (56).
[00221] A mixture of sodium hydride (60% dispersion, 16.2 mg, 0.41 mmol) and isopropanol (2.3 mL) was stirred at room temperature for 10 min. Then this clear solution was added dropwise to a solution of geldanamycin (103 mg, 0.18 mmol) in THF (16.1 mL) at room temperature. The reaction mixture was stirred at room temperature for 40 min. The reaction was quenched with sat. NH4CI solution and the mixture was extracted with CH2CI2. The combined organic extracts were washed with brine and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CEbCl2ZMeOH, 100:1.5) to yield the compound 56 (25 mg, 23% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.72 (s, IH), 7.27 (s, IH), 6.94 (d, J= 11.6 Hz, 1H), 6.57 (t, /= 11.4 Hz, 1H), 5.88 (t, J= 10.4 Hz, )1,H 5.82 (d, J= 9.4 Hz,1H ), 5.23 (m, 1H), 5.19 (s, 1H), 4.78 (br s, 2H), 4.31 (d, J = 9.4 Hz5 IH), 3.53 (d, J= 9.1 Hz,1H )5 3.38 (m, 1H), 3.35 (s, 3H), 3.29 (s, 3H), 2.78 (m, IH), 2.50 (m, IH), 2.43 (m, IH), 2.03 (s, 3H), 1.79 (s, 3H), 1.77 (m, 2H), 1.68 (m, IH), 1.35 (d, J = 6.2 Hz, 3H)5 1.27 (d, J = 6.2 Hz, 3H), 0.97 (m, 6H). MS (ESI): Calcd. for C3SH44N2O9Na: 61 1, found 611 (M+Na)+.
EXAMPLE 54
[00222) This example demonstrates the preparation of 17-ethoxyl-l 7-demethoxyl-l 8- methoxyiminogeldanarnycin (57).
[00223] A solution of 17-ethoxy- 17-demethoxygeldanamycin (82 mg, 0.14 mmol) and methoxylamine hydrochloride (59.7 mg, 0.72 mmol) in pyridine (2.0 mL) was stirred at 80° C. for 2 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 100: 1.5) to yield the compound 57 (72 mg, 83% yield) as a yellow solid. 1H NMR (500 MHz5 CDCl3): δ 8.80 (s, 1)H, 8.22 (s, )1,H 6.93 (d, J= 11.8 Hz, ), 16H.57 (t, J= 11.6 Hz, 1H ), 5.92 (d, J= 9.5 Hz, 1H), 5.82 (t, J= 5.2 Hz, )15H 5.18 (s, ),14H.80 (br s, 2H), 4.29 (m, 3H), 4.20 (s, 3H), 3.56 (m, 1)H, 3.43 (m, IH), 3.36 (s, 3H), 3.26 (s, 3H)5 2.75 (m, IH), 2.58 (dd, J = 10.6, 12.9 Hz, 1)H, 2.43 (d, J= 11.6 Hz5 IH), 2.03 (s, 3H)5 ,1.84 (m, 2H)5 1.79 (s, 3H), 1.63 (m, 1H), 1.40 (t, J= 7.1 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H). MS (ESI): Calcd. for C3]H45N3O9Na: 626, found 626 (M+Na)+.
EXAMPLE 55
[00224] This example demonstrates the preparation of 17-ethoxyl-l 7-demethoxyl-l S- allyloxyirnino-geldanamycin (58).
[00225] A solution of 17-ethoxy- 17-demethoxygeldanamycin (66 mg, 0.115 mmol) and O- allylhydroxylamine hydrochloride (63.0 mg, 0.575 mmol) in pyridine (2.0 mL) was stirred at 80° C. for 2 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2CWMeOH, 100:1.5) to yield the compound 58 (49 mg, 68% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.81 (s, IH), 8.25 (s, IH), 6.93 (d, J = 11.7 Hz, IH), 6.57 (t, J= 11.4 Hz, IH), 6.03 (m, IH), 5.92 (d, J = 9.4 Hz, IH), 5.82 (t, J= 10.5 , IIHH), 5.36 (dd, J = 1.4, 17.2 Hz, IH), 5.29 (dd, J= 1.3, 10.4 Hz IIHH), 5.18 (s, IH), 4.88 (d, J= 5.9 Hz, 2H), 4.77 (br s, 2H), 4.29 (m, 3H), 3.56 (d, J= 9.2 Hz, IH)5 3.43 (m, IH), 3.36 (s, 3H), 3.26 (s, 3H), 2.76 (m, 1H), 2.58 (dd, J= 10.7, 12.8 Hz, 1)H. 2.43 (d, J= 12.8 Hz, IH), 2.03 (s, 3H), 1.84 (m, 2H), 1.80 (s, 3H)5 1.64 (m, IH), 1.38 (t, J= 7.1 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H), 0.96 (d, J= 6.7 Hz, 3H). MS (ESI): Calcd. for C33H47N3O9Na: 652, found 652 (M+Na)+.
EXAMPLE 56
[00226] This example demonstrates the preparation of 17-(dimethylamino)ethoxyl-17- demethoxyl-geldanamycin (58).
[00227] A mixture of sodium hydride (60% dispersion, 11.2 mg, 0.28 mmol) and NJV- dimethylethanolamine (0.5 mL) in THF (3.0 mL) was stirred at room temperature for 10 min. Then this clear solution was added dropwise to a solution of geldanamycin (104 mg, 0.19 mmol) in THF (15.6 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hr. The reaction was quenched with sat. NH4CI solution and the mixture was extracted with CH2CI2. The combined organic extracts were washed with brine and dried over anhydrous MgSO4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2CVMeOH, 100:5) to yield the compound 59 (64 mg, 56% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 7.28 (s, 1H), 6.94 (d, J= 13.2 Hz, IH), 6.57 (t, J= 11.4 Hz, IH), 5.88 (t, J = 10.2 Hz, 1H), 5.82 (d, J= 9.2 Hz, 1H), 5.18 (s, )1,H 4.77 (br s, 2H), 4.67 (m, IH), 4.46 (m, 1H ), 4.32 (d, J= 9.3 Hz, 1H), 3.54 (m, 1)H, 3.39 (m, IH), 3.36 (s, 3H)5 3.30 (s, 3H), 3.11 (m, 1H ), 2.78 (m, 2H), 2.47 (m, 2H), 2.36 (s, 6H). 2.03 (s, 3H), 1.79 (s, 3H), 1.77 (m, 2H), 1.72 (m, 1H)5 0.97 (m, 6H). MS (ESI): Calcd. for C32H48N3O9Na: 611, found 611 (M+Na)+. EXAMPLE 57
[00228] This example demonstrates the preparation of 17-dimethylaminoerhoxyl-l 7- demethoxyl- 18-methoxyiminogeldanamy cin (60) .
[00229] A solution of 17~dimethylaminoethoxy-l 7-demethoxygeldanamycin (39 mg, 0.063 mmol) and methoxylamine hydrochloride (52.6 mg, 0.63 nxrπol) in pyridine (3.0 rtiL) was stirred at 80° C. for 2.5 hr. The mixture was cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 10: 1) to yield the compound 60 (19 mg, 47% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 8.78 (s, IH), 8.23 (s, IH)7 6.92 (d, J= 11.5 Hz, IH), 6.57 (t, J = 1 1.5 Hz5 IH), 5.91 (d, J= 9.5 Hz, IH), 5.83 (t, J= 10.5 Hz, IH), 5.18 (s, IH), 4.75 (br s, 2H)5 4.37 (m, 2H)5 4.31 (d, J= 9.8 Hz, IH), 4.22 (s, 3H), 4.05 (m, IH), 3.55 (m, IH), 3.43 (m, IH), 3.35 (s, 3H), 3.26 (s, 3H), 2.86 (m, IH), 2.75 (m, IH), 2.56 (m, IH), 2.46 (m, 7H), 2.03 (s, 3H), 1.84 (m, 2H), 1.79 (s, 3H), 1.65 (m, IH), 0.99 (d, J= 6.9 Hz, 3H), 0.95 (d, J= 6.7 Hz, 3H). MS (ESI): Calcd. for C33H51N4O9: 647, found 647 (M+H)+.
EXAMPLE 58
[00230} This example demonstrates the preparation of 17-(l-chloropropan-2-yi)amino-17- demethoxylgeldanamycin (61).
(00231] Compound 61 (22% yield, a purple solid) was prepared from the treatment of 17- (2-methylaziridinyl)geldanamycin and o-phenylhydroxylamine hydrochloric acid in pyridine at 80° C. for 2 hr.1H NMR (500 MHz, CDCl3): δ 9.11 (s, 1 H), 7.30 (s, 1 H), 6.96 (d, J = 11.7 Hz, IH), 6.58 (t, J= 11.3 Hz, IH), 5.89 (d, J= 9.5 Hz, IH), 5.87 (t, J= 1 4Hz, IIHH)3 5.19 (s, 1H), 4.76 (br s, 2H), 4.31 (d, J= 9.8 Hz, IH), 3.74 (dd, J- 4.2, 11.5 Hz, IH), 3.65 (m, IH), 3.58 (m, 1H), 3.45 (m, 1H), 3.37 (s, 3H), 3.28 (s, 3H), 2.74 (m, 2H)5 2.17 (m, IH), 2.03 (s, 3H), t.80 (s, 3H)5 1.75 (m, 3H), 1.60 (m, IH)5 1.31 (d, J= 6.5 Hz, 3H), 1.00 (m, 6H). MS (ESI): Calcd. for C3IH44CIN3O8Na: 644, found 644 (M+Na)+.
EXAMPLE 59
[00232] This example demonstrates the preparation of 17-dodecylamino-17-demethoxyl- geldanamycin (62). [00233] A solution of geldanamycin (358 mg, 0,64 mmol) and dodecylamine (710.6 mg, 3.83 mmol) in THF (42.6 mL) was stirred at room temperature for 3 hr. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (CH2Cl2ZMeOH, 100:1) to yield the compound 62 (95 mg, 21% yield) as a purple solid. 1H NMR (500 MHz, CDCl3): δ 9.20 (s, IH), 7.28 (s, IH), 6.96 (d, J - 11.5 Hz, IH), 6.59 (t, J= 11.4 Hz, IH), 6.30 (br s, )1,H 5.91 (d, J- 9.5 Hz, IH)5 5.86 (t, J = 10.6 Hz, 1H), 5.19 (s, 1H), 4.78 (br s, 2H), 4.31 (d, J= 9.9 Hz, IH), 3.57 (m, 2H), 3.45 (m, 2H), 3.37 (s, 3H), 3.27 (s, 3H), 2.74 (m, IH), 2.68 (d, J= 13.4 Hz, IH), 2.43 (dd, J= 10.9, 13.8 Hz, 1H), 2.03 (s, 3H), 1.80 (s, 3H), 1.79 (m, 2H), 1.67 (m, 3H), 1.39 (m, 2H), 1.26 (m, 16H), 1.00 (d, J= 6.9 Hz, 3H), 0.97 (d, J= 6.7 Hz, 3H), 0.88 (t, J= 7.0 Hz, 3H). MS (ESI): Calcd. for C40H63N3O8Na: 737, found 737 (M+Na)+.
EXAMPLE 60
[00234] This example demonstrates the preparation of 18-o-methyloximino geldanamycin (2)-albumin compositions.
[00235] 53 mg 18-ø-methyloximino geldanamycin (as prepared in Example 1) is dissolved in 1.5 ml chloroform/ethanol (9/1). The solution is then added into 23.5 ml of human serum albumin solution (5% w/v). The mixture is homogenized for 5 minutes at low RPM (Vitris homogenizer model: Tempest LQ.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000- 40,000 psi while recycling the emulsion for at least 5 cycles. The resulting system was transferred into a Rotavap and solvent was rapidly removed at 400C, at reduced pressure (30 mm Hg), for 20-30 minutes. The resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-200 nm (Z-average, Malvern Zetasizer). The dispersion was further lyophilized for 48 hours. The resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline. The particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway. EXAMPLE 61
[002361 This example demonstrates the preparation of 18-allyloximinogeldanamycin (4)- albumin compositions.
[00237] 75 mg 18-allyloxxminogeldanamycin (as prepared in Example 2) is dissolved in 1.5 ml chloroform/ethanol (9/1). The solution is then added into 23.5 m] of human serum albumin solution (5% w/v). The mixture is homogenized for 5 minutes at low RPM (Vitris homogenizer model: Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000- 40,000 psi while recycling the emulsion for at least 5 cycles. The resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C, at reduced pressure (30 mm Hg), for 20-30 minutes. The resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-200 nm (Z-average, Malvern Zetasizer). The dispersion was further lyophilized for 48 hours. The resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline. The particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
EXAMPLE 62
[00238] This example demonstrates the preparation of 17-AAG-albumin compositions.
[00239] 100 mg 17-AAG (as prepared in Example 17) is dissolved in 3.0 ml chloroform /ethanol (9/1). The solution is then added into 27.0 ml of human serum albumin solution (5% w/v). The mixture is homogenized for 5 minutes at low RPM (Vitris homogenizer model: Tempest I.Q.) in order to form a crude emulsion, and then transferred into a high pressure homogenizer (Avestin). The emulsification was performed at 9000-40,000 psi while recycling the emulsion for at least 5 cycles. The resulting system was transferred into a Rotavap and solvent was rapidly removed at 40° C, at reduced pressure (30 mm Hg), for 20- 30 minutes. The resulting dispersion was translucent and the typical average diameter of the resulting particles was in the range 50-200 nm (Z-average, Malvern Zetasizer). The dispersion was further lyophilized for 48 hours. The resulting cake was easily reconstituted to the original dispersion by addition of sterile water or saline. The particle size after reconstitution was the same as before lyophilization. It should be recognized that the amounts, types and proportions of drug, solvents, proteins used in this example are not limiting in anyway.
EXAMPLE 63
[00240] This example demonstrates the in vitro growth inhibition for certain compounds of the invention on MX-I (human breast carcinoma) cells.
[00241] A cytotoxicity assay was quantitated using the Promega CellTiter Blue Cell Viability Assay. Briefly, cells (5000 cells/well) were plated onto 96-well microtiter plates in RPMI 1640 medium supplemented with 10% FBS and incubated at 37° C. in a humidified 5% CO2 atmosphere. After 24 hrs., cells were exposed to various concentrations of compound in DMSO and cultured for another 72 hrs. 100 ul of media were removed and 20ul of Promega CellTiter Blue reagent were added to each well and shaken to mix. After 4 hours of incubation at 37° C. in a humidified 5% CO2 atmosphere, the plates were read at 544ex/620em. The fluorescence produced is proportional to the number of viable cells. After plotting fluorescence produced against drug concentration, the IC50 was calculated as the half-life of the resulting non-linear regression. The data is presented in Table 3.
Table 3. Cytotoxicity of geldanamycin analogs
Figure imgf000089_0001
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
EXAMPLE 64
[00242] In this example, the EC50 for Her2 suppression in a breast cancer cell line was determined.
[00243] The EC50 for Her2 suppression by 17-methoxy-l S-oximinogeldanamycin derivatives on BT-474 breast cancer carcinoma was determined using a microliter cell-based assay as reported by Huezo et aV., Chemistry & Biology, 10: 629 (2003), each of which is incorporated by referenceas if fully set forth herein.
Table 4. EC50of geldanamycin analogs
Figure imgf000096_0001
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
[00244] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
(0024S] All references, including publications, patent applications, and patents, cited herein are hereby incorporated by reference to the same extent as if each reference were individually and specifically indicated to be incorporated by reference and were set forth in its entirety herein.
[00246] The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely ' intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
[00247] Particular embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of these embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Claims

CLAIM(S):
1. A compound or pharmaceutically acceptable salt thereof having the formula
(I)
Figure imgf000101_0001
(D wherein
W represents: O, N-OH, N-O-COR10, OrN-O-X-Rn; wherein
X is selected from the group consisting of a substituted or unsubstituted (Q- Cio) alkyl or (C1-C]o) alkenyl or (Cβ-Cio) aryl; Rn represents hydrogen, hydroxyl, halogen, cyanide, or CON(Rs)(Rs), N(Rg)(R9), CO2R10, wherein Rg and R9 are independently selected from the group consisting of H, optionally substituted amine, optionally substituted (C1-C20) alkyl, optionally substituted (C2-C2O) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, and optionally substituted cycloheteroalkyl; R8 is selected from the group consisting of H, optionally substituted (C]-C6) alkyl, optionally substituted (Cs-Cs) aryl, and an optionally substituted (C5- C8) heteroaryl, or together with R9 form an optionally substituted 4-7 membered heterocyclic or carbocyclic ring;
R1O is selected from the group consisting of H, an optionally substituted (Ci- C20) alkyl, optionally substituted (C1-C20) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkerryl, optionally substituted (C2-C20) alkynyl, optionally substituted (C6-C20) aryl, optionally substituted (C6-C20) aryl, optionally substituted (C3-C20) heteroaryl, optionally substituted (C7-C2Q) arylalkyl, optionally substituted (C4-C20) heteroarylalkyl, optionally substituted (C3-C20) cycloalkyl, and an optionally substituted (C2-C20) cycloheteroalkyl; R1 and R2 are each a hydrogen or R1 and R2 together form a single bond;
R3, R4, R6, R7, Yi, Yt, Y3 are independently selected from the group consisting H, halo, -OH, O-alkyl, O-acetyl, -O-aryl, OC(O) R10, -SO2-R1O, and -NHR10, or together form oxo (=O), or hydroxylamino alkoxyimine or aryloxyimine, thioketo; or R3 and R4 or Yi and Y2 form a heterocyclic residue selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, oxazolidinyl, morpholino, piperazinyl, 4-(C1-C4) alkylpiperidinyl and N-(C 1-C4) piperazinyl; and said alkyl, phenyl and naphthyl groups may be substituted with one or more residues selected from the group consisting of (C1-C8) alkyl, halo, nitro, amino, azido and (Ci- C8) alkoxyl; and
R5 is selected from the group consisting of an optionally substituted (C1-C20) alkyl, optionally substituted (C1-C2O) heteroalkyl, optionally substituted (C2-C20) alkenyl, optionally substituted (C2-C20) heteroalkenyl, optionally substituted (C2-C20) alkynyl, optionally substituted (C6-C20) aryl, optionally substituted (C3-C20) heteroaryl, optionally substituted (C7-C20) arylalkyl, optionally substituted (C4-C20) heteroarylalkyl, optionally substituted (C3-C20) cycloalkyl, optionally substituted (C2- C20) cycloheteroalkyl, N(R8)(R9); -OR10, -SR10, -N(R8)-C(O)R10, -N(R8)-C(O)-OR10, - N(Rg)-C(O)-N(R8)(R10), -N(R8)-C(S)OR10, -N(R8)-C(S)-OR10, and -N(Rg)-C(S)- N(R8)(R1o), wherein R8, R9 and R1o as as defined above and are independently selected, wherein when W is O, R5 is N-OH, N-O-COR10, or N-O-X-R1 1.
2. The compound of claim 1 wherein the compound is selected from the group consisting of 18-o-methyloximinogeldanamycin, 18-allyIoxyiminogeldanamycin, l8-teri~ butoxyiminogeldanamycin, 18-iso-butoxyiminogeldanamycin, 18- hydroxyiminogeldanamycin, 18-phenoxyiminogeldanamycin, 18- benzyloxyiminogeldanamycin, 18-hexyloxyimino geldanamycin, 18- cyclopropylmethoxyiminogeldanamycin, 18-dodecyloxyiminogeldanamycin, 18-(4- nitrobenzyl)oxyiminogeldanamycrn, 18-o-cyclohexyloxyimino geldanamycin, I8-0- isopropoxyimino geldanamycin, 18-ethoxyimino geldanamycin. 18-(3-methylbut-2- enyloxyimino)-geldanamycin, 18-(2-fluoroethoxyimino)geldanamycin, 17-allylamino- 18- allyloxyimino- 17-demethoxygeldanamycin, 17-allylamino- 18-methoxyimino- 17- demethoxygeldanamycin, 17-allylamino- 18-carboxymethoxyimino- 17- demethoxygeldanamycin, π-cyclopentylamino-lS-allyloxyimino-l?- demethoxygeldanamycin, 17-cyclopentylamino- 18-methoxyimino- 17- demethoxygeldanamycin, 17-amino-l 8-(2-fluoroethoxyimino) -17-demethoxygeldanamycin, 17-amino- 18- benzyloxyimino- 17-demethoxygeldanamycin, 17-amino-l 8-(2- (dimethylamino)ethoxyimino- 17-demethoxygeldanamycin, 17-amino- 18-ethoxyimino- 17- demethoxygeldanamycin, 17-(2-diethylamino)ethamino-l 8-methoxyiminogeldanamycin, 17- (2-hepthylamino)- 18-methoxyimino- 17-demethoxygeldanamycin, 18-(2- dimethylamino)ethoxyirnino-geldanamycin, 18-(2-(4-methylthiazol-5- yl)ethoxyimino)geldanamycin, 18-(2-(diethylamino)ethoxyimino)geldanamycin, 17-amino- 17-demethoxyl- 18-methoxyiminogeldanamycin, 17-amino- 17-demethoxyl- 18- allyloxyiminogeldanamycin, 17-propylamino- 17-demethoxyl- 18- allyloxyiminogeldanamycin, 17-amido- 17-demethoxyl- 18-methoxyiminogeldanamycin, 17- acetoamido- 17-demethoxyl- 18-allyloxyiminogeldanamycin, 17-amido- 17-demethoxyl- 18- methoxyiminogeldanamycin, 17-methylsulfonyloxy-17-demethoxyl-geldanamycin, 17- hydroxyl- 17-demethoxyl- 18-methoxyimino-geldanamycin, 17-hydroxyl- 17-demethoxyl- 18- allyoxyimino-geldanamycin, 17-ethoxyl- 17-demethoxyl- 18-methoxyiminogeldanamycin, 17- ethoxyl- 17-demethoxyl- 18-ally loxyimino-geldanamycin, 17-amino- 18-hydroxyimino- 17- demethoxygeldanamycin, and 17-dimethylaminoethoxyl-l 7-demethoxyl- 18- methoxyiminogeldanamycin,
3. The compound of claim 1, wherein the compound is selected from the group consisting of 17-methoxyamino- 17-demethoxygeldanamycin, 17-allyloxyamino- 17- demethoxygeldanamycin, 17-phenoxyaniino- 17-demethoxygeldanamycin, 17- cyclopentylamino- 17-demethoxygeldanamycin, 17-amino- 17-demethoxylgeldanamycin, 17- (diethylamino)ethylamino- 17-demethoxygeldanamycin, 17-(2-hepthylamino)- 17- demethoxygeldanamycin, 17-heptylamino- 17-demethoxygeldanamycin, 17-methylaziridinyl- 17-demethoxygeldanamycin, 17-allylamino- 11-o-palmitoyl-l 7-demethoxygeldanamycin, 17- (PEGamino)- 17-demethoxygeldanamycin, 17-propylamino- 17-demethoxylgeldanamycin, 17- ethylamino- 17-demethoxylgeldanamycin, 17-ethoxyl- 17-demethoxyl-geldanamycin, 11-iso- propoxyl-17-demethoxyl-geldanamycin, 17-(dimethylamino)ethoxyl- 17-demethoxylgeldanamycin, 17-(l-chloropropan-2-yl)amino-17-demethoxylgeIdanamycin, and 17- dodecylamino-17-demethoxyl-geldanamycin.
4. A pharmaceutical composition comprising the compound of any one of claims 1-3 and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition of claim 4, wherein the composition is suitable for delivery via routes of administration selected from the group consisting of oral, parenteral and combinations thereof.
6. The pharmaceutical composition of claim 5, wherein said composition is suitable for oral delivery and further comprises one or more ingredients selected from the group consisting of a diluent, an edible carrier, a binder, an excipient, a disintegrating agent, a lubricant, a glidant, and a sweetening agent.
7. The pharmaceutical composition of claim 5, wherein said composition is suitable for parenteral delivery and comprises one or more ingredients selected from the group consisting of a sterile diluent, antimicrobial agents, antioxidants, buffers, tonicity adjusting agents
8. A method for treating a disease or condition characterized by undesired cellular proliferation or hyperproliferation comprising administering a compound of any one of claims 1-3 to an individual in need thereof in an amount sufficient to treat a disease or condition characterized by undesired cellular proliferation or hyperproliferation.
9. The method of claim 8, wherein said disease or condition is cancer.
10. The method of claim 8, wherein said compound is administered as a single intravenous dose, a single intraperitoneal dose, a slow long-term infusion, multiple short-term daily infusions, or combinations of one or more thereof.
11. The method of claim 9, wherein said cancer is selected from the group consisting of cancers of the liver and biliary tree, intestinal cancers, colorectal cancer, ovarian cancer, small cell and non-small cell lung cancer, breast cancer, sarcomas, fibrosarcoma, malignant fibrous histiocytoma, embryonal rhabdomysocarcoma, leiomysosarcorna, neurofibrosarcoma, osteosarcoma, synovial sarcoma, liposarcoma, alveolar soft part sarcoma, neoplasms of the central nervous systems, brain cancer, and lymphomas, including Hodgkin's lymphoma, lymphoplasmacytoid lymphoma, follicular lymphoma, mucosa-associated lymphoid tissue lymphoma, mantle cell lymphoma, B-lineage large cell lymphoma, Burkitt's lymphoma, and T-cell anaplastic large cell lymphoma, and combinations thereof.
12. The method of claim 8, further comprising administering to said individual a second active agent selected from the group consisting of Acivicin; Aclarubicin; Acodazole Hydrochloride; AcrQnine; Adozelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Bropirimine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carubicin Hydrochloride; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cisplatin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Dexormaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziquone; Docetaxel; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Dromostanolone Propionate; Duazomycin; Edatrexate; Eflomithine Hydrochloride; Elsamitrucin; Enloplatin; Enpromate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Etanidazole; Ethiodized Oil 1 131; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flurocitabine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Gold Au 198; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ihnofosine; Interferon Alfa-2a; Interferon Alfa-2b; Interferon Alfa-nl; Interferon Alfa-n3; Interferon Beta- 1 a; Interferon Gamma- 1 b; Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liarozole Hydrochloride; Lometrexol Sodium; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melengestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Meturedepa; Mitindomide; Mitocarcin; Mitocromin; Mitogillin; Mitomalcin; Mitomycin; Mitosper; Mitotane; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxisuran; Paclitaxel; Pegaspargase; Peliomycin; Pentamustine; Peplomycin Sulfate; Perfosfamide; Pipobroman; Piposulfan; Piroxantrone Hydrochloride; Plicamycin; Plomestane; Porfϊmer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safrngol; Safingol Hydrochloride; Semustine; Sitntrazene; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiromustine; Spiroplatin; Streptonigrin; Streptozocin; Strontium Chloride Sr 89; Sulofenur; Talisomycin; Taxane; Taxoid; Tecogalan Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfϊn; Teniposide; Teroxirone; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Tiazoturin; Tirapazamine; Topotecan Hydrochloride; Toremifene Citrate; Trestolone Acetate; Triciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Vapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Vorozole; Zeniplatin; Zinostatin; and Zorubicin Hydrochloride.
13. The method of claim 12, wherein said second active agent is a taxane.
14. The method of claim 8, wherein said compound is administered with a therapeutic antibody.
15. The method of claim 14, wherein said therapeutic antibody is trastuzumab.
16. The method of claim 8, wherein said compound is administered orally, or parenterally.
17. The method of claim 16, wherein the compound is administered intramuscularly, transdermally or by an airborne delivery system.
18. The method of any one of claims 8-17, wherein step (a) is performed prior to, concurrently with, or after combined modality therapy.
19. The method of claim 18, wherein the combined modality therapy comprises chemotherapy, radiation therapy, or surgery.
20. The method of any one of claims 8-18, further comprising a step (b) wherein step (b) comprises administering to the individual one or more agents to reduce hair loss, vomiting, immune suppression, or nausea, and wherein step (b) is performed prior to, concurrently with, or after step (a).
21. The method of any one of claims 8-20, wherein the individual is a mammal.
22. The method of claim 21 , wherein the mammal is a human.
23. A composition for administration to an individual comprising a plurality of particles of the compound of any one of claims 1-3 and a carrier, wherein the average size of the particles is no greater than about 500 ran.
24. The composition according to claim 23, wherein the average size of the particles is no greater than about 200 nm.
25. A kit comprising a compound of any one of claims 1 -3, packaging and instructions for use.
26. The kit of claim 25 wherein the compound is contained in a first container and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers, or preservatives are contained in a second container.
27. A kit comprising the pharmaceutical formulation of any one of claims 4-7, packaging and instructions for use.
28. The kit according to any one of claims 25-29, further comprising means for delivery.
29. The kit according to claim 28, wherein the means for delivery is a syringe.
30. The kit according to any one of claims 25-29, wherein the compound is provided as a single unit dose.
31. The kit according to any one of claims 25-29, wherein the compound is provided in multiple single unit doses.
32. The use of a compound according to any one of claims 1-3 in the preparation of a medicament for the treatment of a disease or condition characterized by undesired cellular proliferation or hyperproliferation.
33. The compound of claim 1, wherein
W is selected from N-OH, N-O-COR10, or N-O-X-Rn9 and
R5 is selected from the group consisting of N(R8)(Rg); -OR1o, -SR10, -N(Rg)-C(O)R10, -N(Rg)-C(O)-OR10, -N(Rg)-C(O)-N(R8)(R10), -N(Rs)-C(S)OR10, -N(Rg)-C(S)-OR10, and - N(Rg)-C(S)-N(R8)(R10).
34. The compound of claim 33 , wherein R5 is N(R8)(R9), and W is N-OH.
35. The compound of claim 33, wherein R5 is N(R8)(R9), and W is N-O-COR10.
36. The compound of claim 33 , wherein R5 is N(R8)(R9), and W is N-O-X-R1 i .
37. The compound of claim 33 , wherein R5 is NH2, and W is N-OH or N-O-X- R11.
38. The compound of claim 33, wherein R5 is N(R8)(R9), R8 is hydrogen, R9 is defined above, and W is selected from N-OH or N-O-X-R1 1.
39. The compound of claim 33, wherein R5 is OCH3, and W is N-OH or N-O-X- R11.
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