WO2011035417A1 - Composés se fixant à la hsp-90, compositions de ceux-ci et leur utilisation dans le traitement de maladies auto-immunes et inflammatoires - Google Patents

Composés se fixant à la hsp-90, compositions de ceux-ci et leur utilisation dans le traitement de maladies auto-immunes et inflammatoires Download PDF

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WO2011035417A1
WO2011035417A1 PCT/CA2010/001482 CA2010001482W WO2011035417A1 WO 2011035417 A1 WO2011035417 A1 WO 2011035417A1 CA 2010001482 W CA2010001482 W CA 2010001482W WO 2011035417 A1 WO2011035417 A1 WO 2011035417A1
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compound
mmol
disease
added
hydrogen
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PCT/CA2010/001482
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Patrick Bureau
Jean-Hugues Fournier
James B. Jaquith
Alain Laurent
Yannick Rose
Mélanie PROULX
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Aegera Therapeutics Inc.
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Publication of WO2011035417A1 publication Critical patent/WO2011035417A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the heat shock protein 90 family including HSP90 alpha, HSP90 beta, HSP90 N, GRP94 and TRAP- 1 (herein generically referred to as HSP90), are essential molecular chaperones that participate in folding of newly synthesized proteins and stabilization and refolding of stress-denatured client proteins.
  • HSP90 client proteins A large number of HSP90 client proteins have been identified many of which are involved in cellular signaling. Consequently, inhibition of HSP90 is widely regarded as a promising therapeutic approach for the treatment of diseases and conditions characterized by inappropriate cellular signaling and stress responses including cancer, neurodegeneration, inflammation and autoimmune disease.
  • HSP90 and analogues are relatively large proteins that have characteristic
  • Crystallography studies revealed a pocket in the N-terminal domain with sequence homology to type II topoisomerases and MutL mismatch repair proteins which co- crystallized with ATP/ADP and established that the N-terminal region is a binding site for adenine nucleotides (Prodromou, C. et al., Cell, 1997, 90( 1 ): 65-75). Additionally,
  • HSP90 has a middle segment that participates in client protein binding and a c-terminal domain that is responsible for dimerization and binding of some natural products including novobiocin (Pearl, L. H. and Prodromou, C, Annu Rev Biochem, 2006, 75: 271 - 94).
  • HSP90 is one of the most abundant cellular proteins comprising 1 -2% of total cellular protein (Iwasaki, M. et al., Biochim Biophys Acta, 1989, 992( 1 ): 1 -8).
  • HSP90 alpha and HSP90 beta are dimeric cytosolic proteins whereas GRP94 and TRAP- 1 reside in the endoplasmic reticulum and mitochondria respectively.
  • HSP90 binds to a series of co-chaperones in an ATP dependent manner, thereby modulating the structure of client proteins. ATP binding regulates the conformation of HSP90 modulating interactions with client proteins (Richter, K., et al., ./ Biol Chem, 2008, 283(26): 17757-65).
  • HSP90 exerts its cellular function through selectively chaperoning, or promoting conformational changes and domain rearrangements in a wide range of client proteins including nuclear hormone receptors (Pratt, W. B. and Toft, D. O., Exp Biol Med
  • HSP90 protein kinases
  • Inflammation and autoimmune diseases are characterized by cellular events that are mediated through signaling proteins many of which are HSP90 clients.
  • the NF- kappaB pathway plays an important role in inflammation and autoimmune disease (Vallabhapurapu, S. and Karin, ⁇ ., ⁇ . Rev. Immunol. , 2009, 27: 693-733).
  • Components of the NF-kappaB pathway including RIP, IKK and NIK, have been shown to be HSP90 client proteins and inhibition of HSP90 results in degradation of these proteins and blocks activation of the canonical and non-cannonical NF-kappaB pathways (Broemer, M., D. et al., Oncogene, 2004, 23(31 ): 5378-86; Lewis, J. et al., ./. Biol. Chem. , 2000, 275( 14): 10519-26; and Qing, G. and Xiao, G., ./. Biol. Chem., 2005, 280( 1 1 ): 9765-8).
  • MAP kinases such as p38 and JNK
  • p38 and JNK have been shown to play key regulatory roles in the production of pro-inflammatory cytokines and downstream signaling events leading to joint inflammation and destruction in arthritis (Thalhamer, T. et al., Rheumatology (Oxford), 2008, 47(4): 409- 14).
  • Inhibition of HSP90 leads to deactivation and
  • HSP90 client proteins Vasilevskaya, I. A. et al., Mol. Pharmacol., 2004, 65( 1 ): 235-43; Salehi, A.H. et al., Chem. Biol , 2006, 13(2): 213-23; and Wax, S. et al., Arthritis Rheum. , 2003, 48(2): 541 -50). Regulation of mast cell function by the tyrosine kinase KIT is also sensitive to HSP90 inhibition (Fumo, G. et al., Blood, 2004, 103(3): 1078-84).
  • HSP90 plays a role in the function of both the innate and adaptive immune systems.
  • Data indicate that HSP90 alpha and beta are important for MHC class I and II presentation (Houlihan, J. L. et al., J. Immunol. , 2009, 182( 12): 7451 -7458; Kunisawa, J. and Shastri, N., Immunity, 2006, 24(5): p. 523-34).
  • GRP94 which is elevated in rheumatoid arthritis (Huang, Q. Q. et al., J.
  • HSP90 HSP90 in inflammation and autoimmune disease.
  • Pharmacological inhibition of HSP90 has been effective in preclinical models of sepsis, multiple sclerosis and uveitis (Dello Russo, C. et al., J.
  • HSP70 has been implicated in inflammatory bowel disease (IBD).
  • IBD inflammatory bowel diseases
  • Compounds inducing HSP70, such as inhibitors of HSP90 may be useful in the prevention and treatment of inflammatory bowel diseases (IBD) such as Crohn's disease and colitis (see Hu, S.; et al Am. J. Physiol. Gastrointest. Liver Physiol. (2009) G 1003- C lO l 1 ; and Tanaka, K-T, et al J. Biol. Chem. (2007) 282; 32, 23240-23252).
  • HSP90 in Cancer HSP90 has been closely investigated as a target in oncology due to it's central role in the function of key protein networks that become dysregulated in cancer (for reviews see Pearl, L. H., Curr. Opin. Genet. Dev. , 2005, 15( 1 ): 55-61 ; Neckers, L., Trends Mol. Med. , 2002, 8(4 Suppl): S55-61 ; Arslan, M.A. et al., Curr. Cancer Drug Targets, 2006, 6(7): 623-34; and Li, Y. et al., Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy, 2009, 12( 1 ): 17-27).
  • HSP90 In tumor cells, HSP90 is required for pathways that promote cell survival and proliferation. HSP90 regulates the function of oncogenic protein kinases such as AKT, ErbB2, Cdk4 and B-raf . Inhibition of HSP90 results in rapid dephosphorylation and inactivation of kinases such as AKT leading to cancer cell death (Georgakis, G. V. et al., Clin. Cancer Res. , 2006, 12(2): 584- 90). Cytotoxicity studies have demonstrated that HSP90 inhibitors have anti-cancer properties against a wide range of tumor cell lines. HSP90 inhibitors have been shown to be effective in multiple preclinical xenograft cancer models (Bao, R. et al., Clin.
  • HSP90 inhibitors may have utility in CNS disease. Inhibition of HSP90 has been shown to protect neurons from amyloid beta- induced toxicity (Ansar, S. et al., Bioorg. Med. Chem. Letters, 2007, 17(7): 1984- 1990) as well as reducing the extent of aberrant mutant Tau phosphorylation in neurons (Luo, W. et al., Proc. Natl. Acad. Sci. U S A, 2007, 104(22): 951 1 -6); which suggests that HSP90 inhibitors may be useful in the treatment of Alzheimer's disease.
  • HSP90 inhibition may be active through the modulation of disease-related proteins such as alpha-synuclein and LRRK2 (Putcha, P. et al. JPET 2010, 332:849-857; Hurtado-
  • HSP90 inhibition has been shown to decrease the release of inflammatory signals from microglia suggesting a possible therapeutic benefit in diseases characterized by neuroinflammation such as multiple sclerosis, stroke, Parkinson' s disease, Alzheimer' s disease, Huntington' s disease and ALS (Dello Russo et al. Neurochem., 2006, 99: 1351 - 1362).
  • HSP90 inhibition may be useful in treatment of stroke;
  • Geldanamycin a prototypic HSP90 inhibitor, has been shown to be protective in rat models of focal cerebral ischemia.
  • Geldanamycin is also neuroprotective in a cellular model of amyotropic lateral sclerosis (Batulan, Z. et al., Neurobiol. Dis. , 2006, 24(2): 213-25). Additionally, improved cellular processing of peripheral myelin protein 22 in response to HSP90 inhibitors suggests that HSP90 inhibition may be useful in the treatment of hereditary demyelinating neuropathies such as Charcot-Marie-Tooth disease (Rangaraju, S. et al., Neurobiology of Disease, 2008, 32( 1 ): 105- 1 15). HSP90 has also been implicated in retinitis pigmentosa (Tam et al. Hum. Mol. Gen, 2010).
  • HSP90 may be a useful target in the treatment of viral and parasitic infections including rotavirus (Dutta, D. et al., Virology, 2009, 391 (2): 325- 33), influenza (Chase, G. et al., Virology, 2008, 377(2): 431 -9), HCV (Nakagawa, S. et al., Biochem. Biophys. Res. Commun. , 2007, 353(4): 882-8) as well as plasmodium
  • the invention relates to compounds having a structure of Formula 1 , or a pharmaceutically acceptable salt thereof
  • A is selected from Al
  • each X is independently selected from CR and N, preferably selected such that no more than two occurrences, and more preferably no more than one occurrence, of X are N;
  • R is selected from -CN and C(0)NH 2 ;
  • R 1 is NH 2 ;
  • each R is independently selected from hydrogen, halogen, -N0 2 , -CN, alkyl, alkenyl, alkynyl, -OR 3 , -NR 4 R 5 , -S(0) m R 3 , -C(0)R 3 , -C(0)OR 3 , -C(0)NR 4 R 5 , - S(0) 2 NR 4 R ' ⁇ aryl, heteroaryl, carbocyclyl, and heterocyclyl;
  • each R', R 4 , and R is independently selected from hydrogen, -alkyl-R 6 , carbocyclyl, heterocyclyl, heteroaryl, and aryl; or
  • R 4 and R together are alkylene, thereby forming a ring
  • R 6 is selected from hydrogen, hydroxy, alkoxy, -NHC(0)alkyl, -NHS0 2 alkyl, amino, and heterocyclyl;
  • n is an integer from 0 to 2;
  • D is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl;
  • E is selected from carbocyclyl and heterocyclyl.
  • the invention relates to pharmaceutical compositions comprising a compound of Formula 1 and a pharmaceutically acceptable carrier or diluent.
  • the invention relates to methods for the treatment of a disease or condition selected from autoimmune and inflammatory diseases (e.g., arthritis, multiple sclerosis, lupus, and uveitis), sepsis, cancer, neurological diseases (e.g., neurological diseases (e.g., neurological disorders), and/
  • Alzheimer' s disease Huntington's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, Kuru, Creutzfeldt-Jakob disease (CJD), peripheral neuropathies and Charcot-Marie-Tooth disease), inflammatory bowel disease (IBD) such as Crohn's disease and colitis, viral infection (e.g., rotavirus, influenza, and hepatitis C), and parasitic infections (e.g., plasmodium falciparum and filarial nematodes) comprising administering a compound of Formula 1.
  • ALS Amyotrophic Lateral Sclerosis
  • CJD Creutzfeldt-Jakob disease
  • IBD inflammatory bowel disease
  • viral infection e.g., rotavirus, influenza, and hepatitis C
  • parasitic infections e.g., plasmodium falciparum and filarial nematodes
  • the invention relates to compounds having a structure of Formula 1 , or a pharmaceutically acceptable salt thereof
  • A is selected from A 1 (wherein 1 -6 and 1 -8, respectively refer to positions on the ring);
  • each X is independently selected from CR 2 and N;
  • R is selected from -CN and -C(0)NH 2 ;
  • R 1 is NH 2 ;
  • each R 2 is independently selected from hydrogen, halogen, -NO2, -CN, alkyl, alkenyl, alkynyl, -OR 3 , -NR 4 R 5 , -S(0) m R 3 , -C(0)R 3 , -C(0)OR 3 , -C(0)NR 4 R 5 , - S(0)2NR 4 R , aryl, heteroaryl, carbocyclyl, and heterocyclyl;
  • each R', R 4 , and R is independently selected from hydrogen, -alkyl-R 6 , carbocyclyl, heterocyclyl, aryl and heteroaryl; or
  • R 4 and R together are alkylene, thereby forming a ring
  • R 6 is selected from hydrogen, hydroxy, alkoxy, -NHC(0)alkyl, -NHSC ⁇ alkyl, amino, and heterocyclyl; m is an integer from 0 to 2;
  • D is selected from aryl, heteroaryl, carbocyclyl and heterocyclyl;
  • E is selected from carbocyclyl and heterocyclyl.
  • A is Al , wherein each occurrence of X is independently
  • A is Al , wherein one or two occurrences of X are N.
  • R 2 is other than hydrogen
  • X' is CR 2 wherein R 2 is -NR 4 R ⁇ R 4 is hydrogen and R is carbocyclyl or heterocyclyl.
  • X' is CR 2 wherein R 2 is -NR 4 R ⁇ R 4 is hydrogen and R is heterocyclyl.
  • X ' is CR 2 wherein R 2 is -NR 4 R ⁇ R 4 is hydrogen and R is carbocyclyl-R 7 wherein
  • R 7 is selected from -OR 14 , -NR 12 R 1 3 , -C(0)NR 12 R 13 , -S0 2 NR 12 R 13 ,
  • each R 12 and R 1 ' is independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl; or
  • R 12 and R 1 ' together form a substituted or unsubstituted heterocyclyl ring system
  • R and R ' are selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl.
  • the carbocyclyl group of carbocyclyl-R 7 is a trans 1 -4 disubstituted 6-membered ring.
  • R 7 is a six-membered ring. In certain such embodiments, R 7 is preferably located at the 4- position of the carbocyclyl ring relative to the point of attachment to A. In certain embodiments as described above where X' is CR 2 , wherein R 2 is - NR 4 R ⁇ R 4 is hydrogen and R is carbocyclyl-R 7 , other occurrences of R 2 in Formula 1 are independently selected from hydrogen or halogen.
  • R 2 is - NR 4 R ⁇ R 4 is hydrogen and R is heterocyclyl
  • other occurrences of R 2 in Formula 1 are independently selected from hydrogen or halogen.
  • A is selected from
  • A is A2, wherein each occurrence of X is independently
  • A is A2, wherein one or two occurrences of X are N.
  • R when X is CR is other than hydrogen.
  • R 2 is selected from hydrogen, halogen, -CN, alkyl, -OR', -NR 4 R ⁇ -SCOj m R', and -C(0)NR 4 R ⁇ In certain such embodiments, R 2 is selected from hydrogen and NR 4 R ⁇
  • R 2 is selected from
  • R 2 is selected from In certain embodiments wherein A is Al and X' is CR 2 , R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is
  • R 2 is selected from
  • R 2 is selected from
  • R 2 is selected from
  • R when A is A2 at least one occurrence of R , preferably R ' when X", X or X s is CR ⁇ ' , more preferably R when X is CR , is selected from alkyl, halogen, -OR', and -S(0) m R ⁇
  • R 2 is alkyl, preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.
  • At least one occurrence of R 2 is halogen, preferably Br or F. In certain alternative such embodiments, at least one occurrence of R 2 are -OR'. In certain such embodiments, R 2 is selected from -0(CH 2 ) 2 OCH 3 , -0(CH 2 )2N(CH 3 )2, -0(CH 2 ) 2 OH, and OEt. In certain alternative such embodiments, at least one occurrence of R 2 is -S(0) m R 3 . In certain such embodiments, R 2 is selected from
  • B is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • Q is selected from -C(O)-, and -S(0) n -; and n is an integer from 1 to 2.
  • D is aryl or heteroaryl, preferably phenyl, pyridyl, thienyl, thiazolyl, oxazole, or isoxazole.
  • D is carbocyclyl, preferably cyclopentyl or cyclohexyl.
  • B is selected from
  • B is selected from
  • B is selected such that the D ring is one of the D rings specified in the previous paragraph and the E ring is one of the E rings specified in the paragraph prior to that.
  • Another aspect of the present invention provides a synthetic intermediate compound represented by Formula 2:
  • LG represents a leaving group, such as alkoxy, aralkoxy, or another group that can be, for example, displaced by an amine to form an amide or sulfonamide.
  • LG is alkoxy.
  • Another aspect of the present invention provides a synthetic intermediate compound represented by Formula 3:
  • Another aspect of the present invention provides a synthetic intermediate compound represented by Formula 4:
  • Another aspect of the present invention provides a synthetic intermediate compound represented by Formula 5:
  • Another aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula 1 and a pharmaceutically acceptable carrier, diluent or excipient.
  • Another aspect of the present invention provides a method of treating a proliferative disorder or a disease state, the method comprising administering to a subject in need thereof an amount of a compound or pharmaceutical composition as described above sufficient to treat the proliferative disorder or disease state.
  • Another aspect of the present invention provides a method of modulating HSP function, the method comprising contacting a cell with a compound of the present invention in an amount sufficient to modulate the binding of a HSP client protein to HSP90, thereby modulating the HSP function.
  • Another aspect of the present invention provides a method of modulating HSP function, the method comprising a) contacting a cell with a compound of the present invention in an amount sufficient to modulate HSP90 function, thereby b) affecting protein folding, stability and aggregation.
  • Another aspect of the present invention provides a probe, the probe comprising a compound of Formula 1 labeled with a detectable label or an affinity tag.
  • the probe comprises a residue of a compound of Formula 1 covalently conjugated to a detectable label.
  • detectable labels include, but are not limited to, a fluorescent moiety, a chemiluminescent moiety, a paramagnetic contrast agent, a metal chelate, a radioactive isotope-containing moiety, or biotin.
  • the term "affinity tag” means a ligand or group, linked either to a compound of the present invention or to an HSP domain, that allows the conjugate to be extracted from a solution.
  • the term "probe” means a compound of the invention which is labeled with either a detectable label or an affinity tag, and which is capable of binding, either covalently or non-covalently, to an HSP domain.
  • the probe When, for example, the probe is non-covalently bound, it may be displaced by a test compound.
  • the probe When, for example, the probe is bound covalently, it may be used to form cross-linked adducts, which may be quantified and inhibited by a test compound.
  • the invention relates to methods for the treatment of a disease or condition selected from autoimmune diseases and inflammation (e.g., arthritis, multiple sclerosis, lupus, and uveitis), sepsis, cancer, neurological diseases (including neurodegenerative diseases, such as Alzheimer's disease, Huntington' s disease,
  • Parkinson' s disease Amyotrophic Lateral Sclerosis (ALS), Gerstmann-Straussler- Scheinker syndrome, fatal familial insomnia, peripheral neuropathies, Charcot-Marie- Tooth syndrome, and prion-related diseases such as Kuru, Creutzfeldt-Jakob disease (CJD), and bovine spongiform encephalopathy), inflammatory bowel disease (IBD) such as Crohn' s disease and colitis, viral infection (e.g., rotavirus, influenza, and hepatitis C), and parasitic infections (e.g., plasmodium falciparum and filarial nematodes) comprising administering a compound of Formula 1 .
  • the invention relates to a method for treating cancer comprising administering a compound of Formula 1 .
  • the cancer is selected from
  • Another aspect of the invention provides a conjoint therapy wherein one or more other therapeutic agents are therapies are administered with compounds as described herein.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential, or separate dosing of the individual components of the treatment.
  • the present invention also relates to the use of the compounds of the present invention in combination with radiation therapy and/or one or more additional agents such as those described in WO 03/09921 1 , which is hereby incorporated by reference.
  • additional agents include, but are not limited to the following:
  • an estrogen receptor modulator a) an estrogen receptor modulator; b) an androgen receptor modulator; c) a retinoid receptor modulator; d) a cytotoxic agent; e) an antiproliferative agent; f) a prenyl-protein transferase inhibitor; g) an HMG-CoA reductase inhibitor; h) an HIV protease inhibitor; i) a reverse transcriptase inhibitor; j) an angiogenesis inhibitor; k) a PPAR- ⁇ agonist; 1) a ⁇ - ⁇ agonist; m) an inhibitor of inherent multidrug resistance; n) an anti-emetic agent; o) an agent useful in the treatment of anemia; p) an agent for the treatment of neutropenia; q) an immunologic-enhancing drug; r) a proteasome inhibitor (e.g., Velcade or MG 132); s) an HDAC inhibitor (e.g., sodium butyrate, phenyl buty
  • Additional combinations may also include agents which reduce the toxicity of the aforesaid agents, such as hepatic toxicity, neuronal toxicity, nephrotoxicity and the like.
  • Vinca alkaloids that can be used in combination with compounds of the invention to treat cancer and other neoplasms include, but are not limited to, vincristine, vinblastine, vindesine, vinflunine, vinorelbine, and anhydrovinblastine.
  • Taxanes and Other Microtubule Stabilizing Compounds Taxanes including, but not limited to, paclitaxel, doxetaxel, RPR 109881 A, SB- T- 1213, SB-T- 1250, SB-T- 101 187, BMS-275183, BRT 216, DJ-927, MAC-321 , IDN5109, and IDN5390, may be used in combination with the compounds of the invention to treat cancer and other neoplasms.
  • Taxane analogs e.g., BMS- 184476, BMS- 188797
  • functionally related non-taxanes e.g., epothilones (e.g., epothilone A, epothilone B (EPO906), deoxyepothilone B, and epothilone B lactam (BMS-247550)
  • epothilones e.g., epothilone A, epothilone B (EPO906), deoxyepothilone B, and epothilone B lactam (BMS-247550)
  • eleutherobin discodermolide, 2-epi-discodermolide, 2-des-methyldiscodermolide, 5- hydroxymethyldiscodermolide, 19-des-aminocarbonyldiscodermolide, 9( 13)- cyclodiscodermolide, and laulimalide
  • discodermolide 2-epi-discodermolide
  • microtubule stabilizing compounds that can be used in combination with the compounds of the invention to treat cancer and other neoplasms are described in U.S. Pat.
  • chemotherapeutic agents that may be administered with a compound of the present invention are listed in the following Table:
  • Additional combinations may also include agents which reduce the toxicity of the aforesaid agents, such as hepatic toxicity, neuronal toxicity, nephrotoxicity and the like.
  • RA non-steroidal anti-inflammatory drugs
  • analgesics corticosteroids
  • corticosteroids corticosteroids
  • disease-modifying antirheumatic drugs Further combinations may include Kineret, Actemra,
  • Hydroxychloroquine PlaquenilTM
  • Sulfasalazine AzulfidineTM
  • Leflunomide AravaTM
  • Tumor Necrosis Factor Inhibitors such as etanercept (EnbrelTM), adalimumab (HumiraTM), and infliximab (RemicadeTM)
  • T-cell costimulatory blocking agents such as abatacept (OrenciaTM)
  • B cell depleting agents such as rituximab (RituxanTM
  • Interleukin- 1 (IL- 1 ) receptor antagonist therapy such as anakinra (KineretTM)
  • intramuscular gold and other immunomodulatory and cytotoxic agents
  • azathioprine ImuranTM
  • cyclophosphamide and cyclosporine A (NeoralTM, SandimmuneTM).
  • p38 inhibitors JAK inhibitors, SYK inhibitors, ERK inhibitors, FMS inhibitors, cKIT inhibitors, anti-TNF agents, anti-CD2() MAbs, anti-IL/ILR targeting agents such as those which target IL- 1 , IL-5, IL-6
  • MS such as RemicadeTM, EnbrelTM, HumiraTM, KineretTM, OrenciaTM, RituxanTM and TYSABRITM (natalizumab) and CopaxoneTM (glatiramer acetate).
  • Compounds prepared as described herein can be administered in various forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art.
  • the compounds may be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, they may be formulated as injections
  • suppositories For application by the ophthalmic mucous membrane route, they may be formulated as eye drops or eye ointments. These formulations can be prepared by conventional means, and if desired, the active ingredient may be mixed with any conventional additive or excipient, such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and/or a buffer.
  • a binder such as a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent, a coating agent, a cyclodextrin, and/or a buffer.
  • a daily dosage of from 0.01 to 2000 mg of the compound is recommended for an adult human patient, and this may be administered in a single dose or in divided doses.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • the precise time of administration and/or amount of the composition that will yield the most effective results in terms of efficacy of treatment in a given patient will depend upon the activity, pharmacokinetics, and bioavailability of a particular compound, physiological condition of the patient (including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication), route of administration, etc.
  • physiological condition of the patient including age, sex, disease type and stage, general physical condition, responsiveness to a given dosage, and type of medication
  • route of administration etc.
  • the above guidelines can be used as the basis for fine- tuning the treatment, e.g., determining the optimum time and/or amount of administration, which will require no more than routine experimentation consisting of monitoring the subject and adjusting the dosage and/or timing.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those ligands, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be
  • materials which can serve as pharmaceutically acceptable carriers include: ( 1 ) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch, potato starch, and substituted or unsubstituted ⁇ -cyclodextrin; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; ( 10) glycols, such as propylene glycol; ( 1 1 ) polyols, such as glycerin, sorbitol, mannitol
  • pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulphonate salts, and amino acid salts, and the like. (See, for example, Berge et al. ( 1 77)
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming
  • pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • suitable base such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring, and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: ( 1 ) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene
  • Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert matrix, such as gelatin and glycerin, or sucrose and acacia) and/or as mouthwashes, and the like, each containing a predetermined amount of a compound(s) as an active ingredient.
  • a composition may also be administered as a bolus, electuary, or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: ( 1 ) fillers or extenders, such as starches, cyclodextrins, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) we
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound(s) moistened with an inert liquid diluent.
  • Tablets, and other solid dosage forms may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes, and/or microspheres. They may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • opacifying agents include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents, and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming, and preservative agents.
  • Suspensions in addition to the active compound(s), may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compound(s) with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active agent.
  • Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound(s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants.
  • the active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required or beneficial.
  • the ointments, pastes, creams, and gels may contain, in addition to compound(s), excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound(s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • the compound(s) can be alternatively administered by aerosol. This is
  • aqueous aerosol e.g., aqueous aerosol, liposomal preparation, or solid particles containing the composition.
  • a nonaqueous (e.g., fluorocarbon propellant) suspension could be used.
  • Sonic nebulizers are preferred because they minimize exposing the agent to shear, which can result in degradation of the compound.
  • an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers.
  • the carriers and stabilizers vary with the requirements of the particular composition, but typically include nonionic surfactants (Tweens, Pluronics, sorbitan esters, lecithin, Cremophors), pharmaceutically acceptable co-solvents such as
  • Aerosols generally are prepared from isotonic solutions.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound(s) to the body.
  • dosage forms can be made by dissolving or dispersing the agent in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound(s) across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound(s) in a polymer matrix or gel.
  • compositions of this invention suitable for parenteral
  • administration comprise one or more compound(s) in combination with one or more pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents.
  • microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include tonicity-adjusting agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • various antibacterial and antifungal agents for example, paraben, chlorobutanol, phenol sorbic acid, and the like.
  • tonicity-adjusting agents such as sugars, sodium chloride, and the like into the compositions.
  • prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms can be made by forming microencapsulated matrices of compound(s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • agents may be given orally, parenterally, topically, or rectally. They are, of course, given by forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, infusion; topically by lotion or ointment; and rectally by suppositories. Oral administration is preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal,
  • systemic administration means the administration of a ligand, drug, or other material other than directly into the central nervous system, such that it enters the patient' s system and thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compound(s) may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally, and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compound(s), which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • compositions of this invention may be provided in an aqueous solution containing about 0.1 - 10% w/v of a compound disclosed herein, among other substances, for parenteral administration. Typical dose ranges are from about 0.01 to about 50 mg/kg of body weight per day, given in 1 -4 divided doses. Each divided dose may contain the same or different compounds of the invention.
  • the dosage will be an effective amount depending on several factors including the overall health of a patient, and the formulation and route of administration of the selected compound(s).
  • affinity tag means a ligand or group, linked either to a compound of the present invention or to an HSP domain, that allows the conjugate to be extracted from a solution.
  • alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc.
  • Representative alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec- butyl, (cyclohexyl)methyl, cyclopropylmethyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • alkenyl and alkynyl refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.
  • alkenyl groups include vinyl, propen-2-yl, crotyl, isopenten-2-yl, 1 ,3- butadien-2-yl), 2,4-pentadienyl, and 1 ,4-pentadien-3-yl.
  • Representative alkynyl groups include ethynyl, 1 - and 3-propynyl, and 3-butynyl.
  • alkyl substituents are lower alkyl groups, e.g., having from 1 to 6 carbon atoms.
  • alkenyl and alkynyl preferably refer to lower alkenyl and alkynyl groups, e.g., having from 2 to 6 carbon atoms.
  • alkylene refers to an alkyl group with two open valencies (rather than a single valency), such as -(CH 2 )i_io- and substituted variants thereof.
  • alkoxy refers to an alkyl group having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxy.
  • alkoxyalkyl refers to an alkyl group substituted with an alkoxy group, thereby forming an ether.
  • amide and “amido” are art-recognized as an amino- substituted carbonyl and includes a moiety that can be represented by the general formula:
  • R 9 , R 10 are as defined above.
  • Preferred embodiments of the amide will not include imides, which may be unstable.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by the general formulae:
  • R 9 , R 10 and R 10 each independently represent a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R 8 , or R 9 and R 10 taken together with the N atom to which they are
  • R represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocyclyl or a polycyclyl; and m is zero or an integer from 1 to 8.
  • R 9 or R 10 can be a carbonyl, e.g., R 9 , R 10 , and the nitrogen together do not form an imide.
  • R 9 and R 10 each independently represent a hydrogen, an alkyl, an alkenyl, or -(CH 2 ) m -R ⁇
  • the amino group is basic, meaning the protonated form has a pK a > 7.00.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • aryl as used herein includes 5-, 6-, and 7-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon.
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, anthracene, and phenanthrene.
  • carbocycle and “carbocyclyl”, as used herein, refer to a non-aromatic substituted or unsubstituted ring in which each atom of the ring is carbon.
  • the terms “carbocycle” and “carbocyclyl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is carbocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Representative carbocyclic groups include cyclopentyl, cyclohexyl, 1 -cyclohexenyl, and 3- cyclohexen- 1 -yl, cycloheptyl.
  • carbonyl is art-recognized and includes such moieties as can be represented by the general formula:
  • X is a bond or represents an oxygen or a sulfur
  • R 1 1 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R or a pharmaceutically acceptable salt.
  • X is an oxygen and R 1 1 is not hydrogen
  • the formula represents an "ester”.
  • X is an oxygen
  • R 1 1 is a hydrogen
  • the formula represents a "carboxylic acid”.
  • heteroaryl includes substituted or unsubstituted aromatic 5- to 7- membered ring structures, more preferably 5- to 6-membered rings, whose ring structures include one to four heteroatoms.
  • heteroaryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, isoxazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • heteroatom as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.
  • heterocyclyl or “heterocyclic group” refer to substituted or unsubstituted non-aromatic 3- to 10-membered ring structures, more preferably 3- to 7- membered rings, whose ring structures include one to four heteroatoms.
  • heterocyclyl or “heterocyclic group” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Heterocyclyl groups include, for example, tetrahydrofuran, tetrahydropyran, piperidine, piperazine, pyrrolidine, morpholine, lactones, and lactams.
  • Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocycle, alkyl, alkenyl, alkynyl, and combinations thereof.
  • polycyclyl or “polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are "fused rings".
  • rings e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls
  • Each of the rings of the polycycle can be substituted or unsubstituted.
  • preventing is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.
  • a condition such as a local recurrence (e.g., pain)
  • a disease such as cancer
  • a syndrome complex such as heart failure or any other medical condition
  • prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount.
  • Prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population.
  • Prevention of pain includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population versus an untreated control population.
  • the term "probe” means a compound of the invention which is labeled with either a detectable label or an affinity tag, and which is capable of binding, either covalently or non-covalently, to an HSP90 domain.
  • the probe When, for example, the probe is non-covalently bound, it may be displaced by a test compound.
  • the probe When, for example, the probe is bound covalently, it may be used to form cross-linked adducts, which may be quantified and inhibited by a test compound.
  • substituted refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • Substituents can include, for example, a halogen, a hydroxyl, a carbon yl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood
  • treating includes reversing, reducing, or arresting the symptoms, clinical signs, and underlying pathology of a condition in manner to improve or stabilize a subject's condition.
  • Compounds of the invention also include all isotopes of atoms present in the intermediates and/or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Intermediate 1 -f may be prepared by reacting o- alkynyltrifluoroacetanilide intermediate 1 -d with aryl halide 1 -e in the presence of a ligand, a catalyst and a base. Treatment of intermediate 1 -f with an appropriate base provides intermediate 1 -g. Cyclized intermediate 1 -g can also be obtained from intermediate 1 -d in a one step-method under suitable conditions. Treatment of intermediate 1 -g with an amine of formula R 4 R NH provides intermediate 1 -h. Nitrile hydrolysis of intermediate 1 -h provides compounds of formula 1.
  • R 4 R NH provides nitrile intermediate 2-a which is then converted to the corresponding amide intermediate 2-b.
  • Intermediates 2-c may be prepared by reacting o- alkynyltrifluoroacetanilide intermediates 1 -d with aryl halide 2-b in the presence of a ligand, a catalyst and a base. Treatment of intermediate 2-c with an appropriated base provides compounds of formula 1. Compounds of formula 1 may also be obtained from intermediates 2-b and 1 -d in a one step-method under appropriated conditions.
  • intermediate 1 -a Treatment of intermediate 1 -a, preferentially a chlorine derivative, with intermediate 1 -b afford intermediate 3-a.
  • Sonogashira coupling reaction of aryl halide 1 - with terminal alkyne intermediate 3-a provides intermediate 3-b.
  • Treatment of intermediate 3-b with an appropriated base, ligand and catalyst provides polycyclic intermediate l -s.
  • intermediate 10-b (3.0 g, 1 .45 mmol) in EtOH was added 4- methylbenzenesulfonohydrazide (3.62 g, 1 .45 mmol) and the reaction was then stirred at room temperature for 20 minutes and 55 °C for 2 hours. Water and CH2CI2 were added; the organic layer was separated, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo to provide intermediate 10-c as colorless oil.
  • intermediate 12-b 950 mg, 2.74 mmol
  • DMSO 15.0 mL
  • MeOH 15 mL
  • NaOH I N 2.74 mL
  • 30% aqueous hydrogen peroxide 419 uL, 4.10 mmol
  • Saturated aqueous ammonium chloride and ethyl acetate were added, the organic layer was separated, the aqueous phase was extracted with ethyl acetate, the combined organic extracts were washed with brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo to provide intermediate 12-c as a white solid.
  • Step 2 13-c To a solution of intermediate 13-b (900 mg, 6.16 mmol) in CH 2 Cl 2 cooled to 0 °C were sequentially added DMSO ( 1 .96 mL, 27.7 mmol), DIPEA (4.29 mL, 24.63 mmol) and pyridine-SC complex (2.94 g, 18.47 mmol) in DMSO (2 mL) and the reaction was stirred at 0°C for 2 hours.
  • DMSO 1 .96 mL, 27.7 mmol
  • DIPEA 4.29 mL, 24.63 mmol
  • pyridine-SC complex 2.94 g, 18.47 mmol
  • intermediate 20-b (3.63 g, 12.73 mmol) in CH2CI2 cooled to 0 °C were sequentially added imidazole ( 1 .04 g, 15.27 mmol) and tert- butylchlorodimethylsilane (2.1 1 g, 14.0 mmol) and the reaction was then stirred at room temperature overnight. Water and ethyl acetate were added; the organic layer was separated, washed with 10% citric acid, saturated NaHCC and brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 20-c as a yellow oil.
  • intermediate 21 -b (2.0 g, 7.21 mmol) in DMF were sequentially added tBuOH (2.76 mL, 28.8 mmol), DMAP (352 mg, 2.88 mmol) and 1 ,3- diisopropylcarbodiimide (2.48 mL, 15.87 mmol) and the reaction was stirred at room temperature for 4 days. Water and ethyl acetate were added; the organic layer was separated, washed with 10% citric acid, saturated NaHCC and brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 21 -c as a white solid.
  • Step 1 A solution of intermediate 4-bromo-2-fluorobenzonitrile 30-a (25.0 g, 125.0 mmol), trans-4-aminocyclohexanol ( 14.4 g, 125.0 mmol) and triethylamine (52.3 mL, 375.0 mmol) in DMSO was heated at 150 °C overnight and then cooled to room temperature. Saturated aqueous ammonium chloride and ethyl acetate were added; the organic layer was separated, washed with saturated aqueous ammonium chloride and brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo. Diethyl ether and hexane were added to the residue and intermediate 30-b was collected by filtration as an off-white solid.
  • intermediate 30-b (31.4 g, 106.0 mmol) in DMSO/MeOH ( 1 : 1 , 304 mL) were sequentially added NaOH IN ( 106.0 mL, 106.0 mmol) and 30% aqueous hydrogen peroxide ( 16.30 mL, 160.0 mmol) and the reaction was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride and ethyl acetate were added, the organic layer was separated, washed with brine, dried over anhydrous MgS0 4 , filtered and concentrated in vacuo to provide intermediate 30-c as an off-white solid.
  • Fluorescence polarization based HSP90 binding assay was performed using modifications to previously described methods using full length HSP90 and a
  • geldanamycin-FITC probe see Llauger-Bufi, L. et al., Bioorg. Med. Chem. Lett. 13 (2003) 3975-3978. Briefly, geldanamycin-FITC probe was diluted into HFB buffer [20 mM HEPES (K) pH 7.3, 50 mM KC1, 1 mM DTT, 5 mM MgCl 2 , 20 mM Na 2 Mo0 4 , 0.01 % NP40, 0.1 mg/mL of Bovine gamma-globuline] to obtain a working concentration of 8 nM..
  • HFB buffer 20 mM HEPES (K) pH 7.3, 50 mM KC1, 1 mM DTT, 5 mM MgCl 2 , 20 mM Na 2 Mo0 4 , 0.01 % NP40, 0.1 mg/mL of Bovine gamma-globuline
  • HSP90 protein Hsp9() Native Protein, Stressgen, SPP-770
  • the final amount of protein used in the assay corresponds to the amount of protein necessary to obtain 80% of the maximum FP value in a 2 nM probe saturation experiment.
  • Assay were carried out in duplicates, into not treated black 96-well plate (Corning #3915), in a total volume of 100 ⁇ , for a final concentration of 2 nM of geldanamycin-FITC probe, various concentrations of compound and Hsp-90 protein into HFB buffer. Buffer only (blank) or probe only in buffer (G-factor) were also added to be used as controls for calibration.
  • the plate was left on a shaker at 4 °C for 3 hours and the FP values in mP were recorded using Genios Pro FP reader (TECAN).
  • Genios Pro FP reader TECAN
  • the measured FP values (mP) were then plotted against compound concentration and EC 50 , corresponding to the competitor concentrations where 50% of the tracer was displaced, calculated based on a sigomoidal dose-response (variable-slope) curve fit using GraphPad Prism version 4.02 for Windows, GraphPad Software, San Diego California USA, www.graphpad.com.
  • Colorectal carcinoma HCT1 16 cells (ATCC# CCL-247) were cultured as monolayers in 96 well plates at a density of 2000 cells per well in McCoy's 5a medium (HyClone) supplemented with 2.2 g/L sodium bicarbonate (Gibco), 10% FBS (HyClone) and 1 % penecillin/streptomycin (HyClone). After 24 hour incubation, triplicate wells were treated with various concentrations of compound. Cells were incubated in the presence of compound for 72 hours at 37 °C, 5% CO2. Metabolic viability of remaining cells was assessed by MTT (thiazolyl blue tetrazolium bromide, Sigma) assay.
  • MTT thiazolyl blue tetrazolium bromide
  • EC50 values (50% cell survival in the presence of compound as compared to untreated controls) were calculated from survival curves using BioAssay software (CambridgeSoft).
  • EC 50 and IC 50 A less than 100 nM; B between 100 and 1000 nM; C greater than 1000 nM.
  • Spleen cells from C57BL/6 (H-2b) and BALB/c (H-2d) were used as responder (R) and stimulator (S) cells, respectively.
  • Cells were plated in triplicate in 96-well flat microliter plates (Costar, Cambridge, MA) such that each well contained 2 x 10 R and 8 x 10 S cells. Cultures were incubated in the absence or presence of various
  • CSA cyclosporine A
  • 3H-TdR 3H-thymidine
  • Proliferation was measuring by counting the radioactivity on filter mats in a Wallac 1450 Microbeta TriLux scintillation counter (Turku, Finland).
  • Compound 13 blocked the mixed lymphocyte reaction between lymphocytes from two separate donor strains of mice with an EC 50 of less than 1 ⁇
  • mitogenlipopolysaccharide LPS, Leoli serotype ()127:B8) were purchased from Sigma. C57BL/6 spleen cells (2 x lOs/well in triplicate) were incubated in 96-well microliter plates with either medium, 5 J.lg/mL PHA, or 25 J.lg/mL LPS in the absence or presence of various concentrations of cyclosporine a (CSA), compound, or medium for 3 days at 37 °C in 5% CO 2 . For the final 16 hours of incubation, cultures were pulsed with 3H_TdR and then harvested using a Brandel 96-well cell harvester (Gaithersburg, MD).
  • CSA cyclosporine a
  • Compound 13 blocked in vitro proliferation of T cells in response to PHA with an EC50 of less than ⁇ ⁇ and blocked in vitro proliferation of B cells in response to LPS with an EC 50 of less than ⁇ ⁇ .
  • C57BL/6 spleen cells ( l () 6 /well in duplicate) were placed in 96-well microtiter plates in the presence of LPS at 800 ng/mL and the absence or presence of various concentrations of cylosporin A (CSA) or compound. Cultures were then incubated overnight at 37°C in 5% CO 2 . Supernatants were removed and frozen at -80 °C until assayed. TNF- ⁇ ELISA kits were obtained from eBioscience (San Diego, CA) and samples were assayed in duplicate according to kit instructions.
  • CSA cylosporin A
  • PBMCs Peripheral blood mononuclear cells
  • the isolated PBMCs were washed two times in phosphate buffered saline (PBS; pH 7.4).
  • PBS phosphate buffered saline
  • PBMC were resuspended in 37 °C RPMI media supplemented with 10% FBS and 0.1 % penicillin/streptavidin.
  • Viable PBMC cells were counted manually with a hemacytometer in presence of trypan blue and diluted to 1() 6 cells per ml in supplemented RPMI media.
  • PBMC are seeded at ⁇ ⁇ ⁇ cells per well in 48-well cell culture plate.
  • Various concentrations of compound diluted in RPMI media containing 10% FBS (30 uL) was added to PBMC and incubated 18 hours at 37 °C in humidified atmosphere in cell incubator.
  • LPS 25 uL, 2 ug/mL, Sigma
  • RPMI media supplemented with 10% FBS and 0.1 % P/S was added to PBMC and incubated at
  • PBMCs Peripheral Blood Mononuclear Cells
  • mice Female C57BL6 mice (5 per group) received 5 consecutive daily PO doses ( 10, 30, 60 or 100 mg/kg) of compound. Trunk blood was collected in vacutainer containing EDTA anticoagulant 24h after the final dose. Blood from mice of the same group was pooled and peripheral blood mononuclear cells (PBMC) were isolated with a density separation medium (Lympholyte-Mammal, Cedarlane) and lysed in RIPA buffer. HSP70 protein levels were measured using a commercial sandwich ELISA (R&D Systems).
  • PBMC peripheral blood mononuclear cells
  • mice Female Swiss mice (3 per group) received 5 consecutive daily PO doses of compound (60 or 100 mg/kg). Brains were collected 6 hours after the final dose, homogenized using a motorized pellet pestle and lysed in RIPA buffer. HSP70 protein levels were measured using a commercial sandwich ELISA (R&D Systems).
  • Compound 45 was shown to induce a dose dependent increase in HSP70 protein in brain homogenate (up to a 2 fold) demonstrating that compounds of formula 1 are capable of inducing HSP70 in the brain.
  • the concentration of compounds of formula 1 were determined in the plasma and brain homogenate of mice after treating CD- 1 mice with compound via IV or oral administration. Compound concentrations were
  • Dextran Sulphate sodium (DSS) model of colitis was assessed using acetonitrile extraction of compound from the appropriate matrix and calculation of drug concentrations using a spiked standard curve from the same matrix (ie. plasma or brain homogenate).
  • Compounds of formula 1 demonstrated good oral absorption (greater than 10 % F) and exposure in brain. These results indicate that compounds of formula 1 are orally available and can cross the blood brain barrier. Therefore compounds of formula 1 may be useful in the treatment of both peripheral and CNS related diseases and conditions.
  • mice Male, C57BL/6 mice (22-25 g) were treated with Vehicle (water) or Compound 33 ( 100 mg/kg, PO) starting on day 0, and continuing daily for the duration of the experiment.
  • DSS was provided ad lib as a 3% solution in the drinking water from day 1 through 7, after which time it was replaced with normal drinking water.
  • DAI Body weight and Disease Activity Index
  • Compound 33 was shown to significantly limit the DAI by approximately 85% and prevent significant body weight loss on day 8 on the experiment. This indicates that compound 33 was useful in limiting or preventing DSS induced colitis in the drug treated animals and that compounds of formula 1 may be useful in the treatment of inflammatory bowel disease (IBD) such as colitis.
  • IBD inflammatory bowel disease

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Abstract

L'invention porte sur des composés thérapeutiques qui se fixent à la HSP90. Les composés de la présente invention se fixent à la HSP90 et modifient l'aptitude à chaperonner des protéines HSP90. L'invention porte également sur des compositions pharmaceutiques comprenant ces composés et sur des procédés de traitement de maladies et de troubles tels qu'un cancer, une maladie auto-immune et d'autres maladies.
PCT/CA2010/001482 2009-09-25 2010-09-24 Composés se fixant à la hsp-90, compositions de ceux-ci et leur utilisation dans le traitement de maladies auto-immunes et inflammatoires WO2011035417A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012126084A1 (fr) * 2011-03-24 2012-09-27 Pharmascience Inc. Composés de liaison à hsp-90, compositions de ces composés, et utilisations de ces composés pour le traitement et la prévention d'infections fongiques
CN113735740A (zh) * 2021-08-30 2021-12-03 珠海润都制药股份有限公司 一种去甲基伊托必利亚硝胺的制备方法
WO2023077216A1 (fr) * 2021-11-02 2023-05-11 Bright Angel Therapeutics Inc. Inhibiteurs de la protéine de choc thermique 90 (hsp90) pour le traitement d'infections fongiques et leurs procédés d'utilisation

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WO2002094830A2 (fr) * 2001-05-23 2002-11-28 Merck Frosst Canada & Co. Derives de dihydropyrrolo[1,2-a]indole et de tetrahydropyrido[1,2-a]-indole utilises comme antagonistes des recepteurs de prostaglandine d2
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WO2002094830A2 (fr) * 2001-05-23 2002-11-28 Merck Frosst Canada & Co. Derives de dihydropyrrolo[1,2-a]indole et de tetrahydropyrido[1,2-a]-indole utilises comme antagonistes des recepteurs de prostaglandine d2
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012126084A1 (fr) * 2011-03-24 2012-09-27 Pharmascience Inc. Composés de liaison à hsp-90, compositions de ces composés, et utilisations de ces composés pour le traitement et la prévention d'infections fongiques
CN113735740A (zh) * 2021-08-30 2021-12-03 珠海润都制药股份有限公司 一种去甲基伊托必利亚硝胺的制备方法
WO2023077216A1 (fr) * 2021-11-02 2023-05-11 Bright Angel Therapeutics Inc. Inhibiteurs de la protéine de choc thermique 90 (hsp90) pour le traitement d'infections fongiques et leurs procédés d'utilisation

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