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WO2013041407A1 - Acides hydroxamiques et récepteurs hdac6 - Google Patents

Acides hydroxamiques et récepteurs hdac6 Download PDF

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Publication number
WO2013041407A1
WO2013041407A1 PCT/EP2012/067721 EP2012067721W WO2013041407A1 WO 2013041407 A1 WO2013041407 A1 WO 2013041407A1 EP 2012067721 W EP2012067721 W EP 2012067721W WO 2013041407 A1 WO2013041407 A1 WO 2013041407A1
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Prior art keywords
alkylene
phenyl
formula
alkyl
unsubstituted
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Inventor
Nigel Ramsden
Kathryn Bell
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Cellzome GmbH
Cellzome Ltd
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Cellzome GmbH
Cellzome Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
    • C07C311/12—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C07C311/13—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Definitions

  • the present invention relates to specific histone deacetylase (HDAC) inhibitors, including pharmaceutically acceptable salts, which are useful for modulating HDAC activity for modulating cellular activities such as signal transduction, cell proliferation, cell survival and cytokine secretion. More specifically the invention provides compounds which inhibit, regulate and/or modulate HDAC activity, in particular HDAC6 activity, and signal transduction pathways relating to cellular activities as mentioned above. Furthermore, the present invention relates to pharmaceutical compositions comprising said compounds, e.g. for the treatment of diseases such as immunological, inflammatory, autoimmune, allergic disorders, proliferative diseases such as cancer, neurodegenerative disorders or neurological diseases and processes for preparing said compounds.
  • diseases such as immunological, inflammatory, autoimmune, allergic disorders, proliferative diseases such as cancer, neurodegenerative disorders or neurological diseases and processes for preparing said compounds.
  • Histone deacetylases catalyse the removal of acetyl groups from lysine residues in histone amino termini, leading to chromatin condensation and changes in gene expression.
  • certain HDACs can deacetylate non-histone substrates, for example HDAC6 functions as a tubulin deacetylase.
  • HDAC6 functions as a tubulin deacetylase.
  • HDACs have been identified and subdivided into four classes based on their homology to yeast HDACs, their subcellular localization and their enzymatic activities.
  • the class I HDACs (1, 2, 3 and 8) are homologous to the yeast RPD3 protein, can generally be detected in the nucleus and show ubiquitous expression in human cell lines and tissues.
  • Class II HDACs (4, 5, 6, 7, 9 and 10) are similar to the yeast Hda proteins and can shuttle between the nucleus and the cytoplasm. HDAC6 can deacetylate the cytoskeletal protein a-tubulin.
  • the class III HDACs (SIRT1, 2, 3, 4, 5, 6 and 7) are homologues of the yeast protein Sir2 and require NAD + for their activity.
  • HDAC 11 is the sole member of class IV HDACs (Bolden et al, 2006. Nat. Rev. Drug Discov. 5(9):769-784).
  • HDACs are present within multisubunit protein complexes together with other components that influence the selectivity of HDAC inhibitors (Bantscheff et al, 2011. Nat. Biotechnol. 29(3):255-265).
  • HDAC6 functions as a tubulin deacetylase. HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules and localizes with the microtubule motor complex. In vivo the overexpression of HDAC6 led to a global deacetylation of alpha- tubulin, whereas a decrease in HDAC6 increased alpha-tubulin acetylation. In vitro, purified HDAC6 potently deacetylated alpha-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promoted chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. It was concluded that HDAC6 is a tubulin deacetylase which regulates important biologic processes beyond histone metabolism and gene transcription (Hubbert et al, 2002. Nature 417(6887):455-458).
  • HDAC6 plays a role in the function of Foxp3 + T-regulatory cells (Tregs). Diminished numbers or function of Foxp3 + Tregs can cause autoimmunity and allograft rejection.
  • Treatment of HDAC6-deficient and wild-type mice with HDAC-6 specific inhibitors revealed that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, for example experimental colitis and cardiac allograft rejection. Therefore inhibition of HDAC6 may promote Treg-dependent suppression of autoimmunity and transplant rejection (de Zoeten et al., 2011. Mol. Cell. Biol, 31(10):2066-2078).
  • HDAC6 is a target for protection and regeneration following injury in the nervous system. Damage of neurons leads to an increase in HDAC6 expression and inhibition of HDAC6 can promote survival and regeneration of neurons. Importantly, selectice inhibition of HDAC6 avoids cell death associated with non-selective HDAC inhibitors (pan-HDAC inhibitors). Therefore HDAC6 may be a promising target for the treatment of, for example, stroke, ischemia and spinal cord injury (Rivieccio et al., 2009. Proc. Natl. Acad. Sci. USA 106(46): 19599-604).
  • HDAC6 has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. Overexpression of HDAC6 correlates with tumorigenesis and improved cell survival. Previous work demonstrated that in multiple myeloma cells, inhibition of HDAC6 results in apoptosis (Aldana-Masangkay and Sakamoto, 2011. J. Biomed. Biotechnol. 875824).
  • HDAC6 was identified as a component of the aggresome in human cells (Kawaguchi et al, 2003. Cell 115 (6): 727-738). Aggregates of misfolded proteins are transported and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome, where they are processed. HDAC6 could bind both polyubiquitinated misfolded proteins and dynein motors, thereby recruiting misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 failed to clear misfolded protein aggregates from the cytoplasm, could not form aggresomes properly, and were hypersensitive to accumulation of misfolded proteins.
  • HDAC inhibitors are in preclinical development and clinical trials for the treatment of a wide variety of diseases including cancer, inflammatory, cardiac, and neurodegenerative diseases (Bolden et al., 2006. Nat. Rev. Drug Discov. 5(9):769-784; Haberland et al., 2009. Nat. Rev. Genet. 10(l):32-42). It is expected that the development of selective HDAC inhibitors targeting only one member of the HDAC family should lead to improved efficacy and drug safety compared to non-selective "pan-HDAC inhibitors" (Kalin et al., 2009. Curr. Opin. Chem. Biol. 13: 1-9; Balasubramanian et al, 2009. Cancer Lett. 280(2):211-21).
  • HDAC6 inhibitor that inhibits HDAC6 with greater potency than other HDACs such as HDACl , HDAC2 and HDAC3, may have advantageous therapeutic properties because inhibition of other HDACs may cause unwanted side effects (Bradner et al, 2010. Nat. Chem. Biol. 6(3):238-243; WO-A 2011/019393).
  • HDAC inhibitors have been reported in the literature which may be useful in the medical field, for example as anti-cancer or anti- inflammatory agents (WO-A 2001/38322; WO-A 2008/074132; Gupta et al, 2010. Bioorg. Med. Chem. Lett. 20(23):7067-7070).
  • HDAC6 inhibitors are known in the art (WO-A 2011/011186) there is a need for providing additional HDAC6 inhibitors having at least partially more effective pharmaceutically relevant properties, like activity, selectivity, and ADMET properties.
  • hydroxamic acid of formula (I) or a pharmaceutically acceptable salt thereof for use in a method for treating or preventing an immunological, inflammatory, autoimmune or allergic disorder or disease, or a transplant rejection, or a graft-versus host disease, or a neurogenerative disease, or neuron injury,
  • X is aryl, heteroaryl, cycloalkyl or heterocyclyl, any of which is unsubstituted or substituted, or H;
  • L is C1-C14 saturated alkylene or C2-Ci4-alkenylene, wherein the alkylene or alkenylene is unsubstituted or substituted, wherein one or two of the carbon atoms of the alkylene or alkenylene is replaced by NR', R' being hydrogen, alkyl, acyl, arylalkyl or, together with R, is (Ci-C 3 )-alkylene, and wherein one or two of the carbon atoms of the alkylene or alkenylene is optionally replaced with O, S, S(O), S(0) 2 or C(O); and
  • R is H or, together with R', (Ci-C 3 )-alkylene.
  • a compound of formula (I) for use as a medicament wherein the symbols and indices have the meanings given above, provided that if L is -S(0 2 )-NH ⁇ ( ⁇ denoting the bond to the phenyl ring) then X is unsubstituted phenyl, or cycloalkyl, or heterocyclyl.
  • x, y is 0, 1, 2 and x + y is 2 or 3;
  • w, m is independently 0 or 1 ;
  • L 1 is (Ci-C6)-alkylene or (C 2 -C 6 )-alkenylene, wherein the alkylene or alkenylene is unsubstituted or substituted;
  • Y 1 is -CO-, -S(0) 2 - , -0-CO-, -NR 3 -CO-;
  • R 3 is H, (C 1 -C 6 )-alkyl, phenyl or benzyl, each substituted or unsubstituted;
  • X is aryl, heteroaryl, cycloalkyl or heterocyclyl, any of which is unsubstituted, or H;
  • a pharmaceutical composition for treating or preventing an immunological, inflammatory, autoimmune or allergic disorder or disease, or a transplant rejection, or a graft-versus-host disease, or a neurodegenerative disorder, or neurological disease comprising a compound of formula (I) above or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a compound of formula (I) and the use of a hydroxamic acid of formula (I), wherein the symbols in formula (I) have the meanings given above, provided that if L is -S(0 2 )-NH ⁇ ( ⁇ denoting the bond to the phenyl ring) then X is unsubstituted phenyl, or cycloalkyl, or heterocyclyl, or a pharmaceutically acceptable salt thereof.
  • a hydroxamic acid of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating or preventing an immunological, inflammatory, autoimmune or allergic disorder or disease, or a transplant rejection, or a graft-versus-host disease, or a neurodegenerative disorder, or neurological disease, and the use of a hydroxamic acid of formula (I) or a pharmaceutically acceptable salt thereof, provided that if L is -S(0 2 )-NH ⁇ ( ⁇ denoting the bond to the phenyl ring) then X is unsubstituted phenyl, or cycloalkyl, or heterocyclyl, wherein the symbols in formula (I) have the meanings given above for the preparation of a medicament.
  • a method of treating or preventing a disease in a human comprising the step of administering to the human a therapeutically effective amount of a hydroxamic acid of formula (I) or a pharmaceutically acceptable salt thereof, wherein the symbols in formula (I) have the meanings given above, provided that if L is -S(0 2 )-NH ⁇ ( ⁇ denoting the bond to the phenyl ring) then X is unsubstituted phenyl, or cycloalkyl, or heterocyclyl, or a pharmaceutically acceptable salt thereof, or for treating or preventing an immunological, inflammatory, autoimmune or allergic disorder or disease, or a transplant rejection, or a graft-versus-host disease, or a neurodegenerative disorder, or neurological disease in a human, comprising the step of administering to the human a therapeutically effective amount of a hydroxamic acid of formula (I) above or a pharmaceutically acceptable salt thereof.
  • the invention includes all stereoisomeric forms of the compounds of the formula (I) and their salts. With respect to each chiral center, independently of any other chiral center, the compounds of formula (I) can be present in S configuration or substantially S configuration, or in R configuration or substantially R configuration, or as a mixture of the S isomer and the R isomer in any ratio.
  • the invention includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios.
  • compounds according to the invention which can exist as enantiomers can be present in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, and in the form of mixtures of the two enantiomers in all ratios including racemates.
  • the invention includes both the E form and Z form, or the cis form and the trans form, as well as mixtures of these forms in all ratios.
  • a compound which can occur in two or more stereoisomeric forms is a pure, or substantially pure, individual stereoisomer.
  • the preparation of individual stereoisomers can be carried out, for example, by separation of a mixture of isomers by customary methods, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials in the synthesis, or by stereoselective synthesis.
  • a derivatization can be carried out before a separation of stereoisomers.
  • the separation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula (I) or at the stage of a starting material or an intermediate during the synthesis.
  • the present invention also includes all tautomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts.
  • the invention also comprises the corresponding pharmaceutically acceptable salts of the compounds of formula (I), i.e. the physiologically and toxicologically acceptable salts.
  • the compounds of the formula (I) can be pharmaceutically acceptable salts, for example, alkali metal salts, alkaline earth metal salts or as ammonium salts. More specific examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, quaternary ammonium salts such as tetraalkylammonium salts, or acid addition salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain a basic group, i.e.
  • a group which can be protonated can be used according to the invention, for example, in the form of their addition salts with inorganic or organic acids.
  • suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, trifluoroacetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines or zwitterions.
  • the salts of the compounds of the formula (I) can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting the compound of the formula (I) with an organic or inorganic acid or base in a solvent or diluent, or by anion exchange or cation exchange from another salt.
  • the invention also includes all salts of the compounds of the formula (I) which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the invention furthermore includes all solvates of compounds of the formula (I), for example hydrates or adducts with alcohols, active metabolites of the compounds of the formula (I).
  • the compounds of the formula (I) may exist in crystalline or amorphous form. Furthermore, some of the crystalline forms of the compounds may exist as polymorphs, which are included within the scope of the present invention. Polymorphic forms of a compounds may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (ssNMR).
  • XRPD X-ray powder diffraction
  • IR infrared
  • Raman spectra Raman spectra
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • ssNMR solid state nuclear magnetic resonance
  • HDAC histone deacetylase
  • HDAC and "HDAC6” includes mutant forms of said HDACs.
  • Halogen or "halo” means fluoro, chloro, bromo and iodo, preferably fluoro, chloro and bromo, in particular fluoro and chloro.
  • C n -C m -alkyl refers to a branched or unbranched saturated hydrocarbon group having n to m, carbon atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1 , 1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbuty
  • C 2 -C m -alkenyl refers to a branched or unbranched unsaturated hydrocarbon group having 2 to m, e.g. 2 to 10 or 2 to 6 carbon atoms and a double bond in any position, such as ethenyl, 1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2- butenyl, 3-butenyl, 1 -methyl- 1-propenyl, 2-methyl- 1-propenyl, l-methyl-2-propenyl, 2- methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1-butenyl, 2- methyl- 1-butenyl, 3 -methyl- 1-butenyl, l-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl- 2-butenyl, 1 -methyl-3 -butenyl
  • C 2 -C m -alkynyl refers to a branched or unbranched unsaturated hydrocarbon group having 2 to m, e.g. 2 to 10 or 2 to 6 carbon atoms and containing at least one triple bond, such as ethynyl, propynyl, 1-butynyl, 2-butynyl, and the like.
  • C n -C m -haloalkyl refers to a straight-chain or branched alkyl group having n to m carbon atoms, where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example C 1 -C 4 - haloalkyl, such as chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl, 2,2- dichloro-2-
  • C 1 -C 4 - haloalkyl in particular comprises Ci-C 2 -fluoroalkyl, which is synonym with methyl or ethyl, wherein 1, 2, 3, 4 or 5 hydrogen atoms are substituted with fluorine atoms, such as fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2- difluoroethyl, 2,2,2-trifluoroethyl and pentafluoromethyl.
  • C n -C m -alkoxy and “C n -C m -alkylthio" refer to straight-chain or branched alkyl groups having n to m carbon atoms, (as mentioned above) bonded through oxygen or sulfur linkages, respectively, at any bond in the alkyl group.
  • Ci-C 4 -alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, isobutoxy and tert-butoxy
  • futher Ci-C 4 -alkylthio such as methylthio, ethylthio, propylthio, isopropylthio and n-butylthio.
  • C n -C m -haloalkoxy and “C n -C m -haloalkylthio” refer to straight-chain or branched alkyl groups having n to m carbon atoms, (as mentioned above) bonded through oxygen or sulfur linkages, respectively, at any bond in the alkyl group, where some or all of the hydrogen atoms in these groups may be replaced by halogen atoms as mentioned above, for example Ci-C 2 - haloalkoxy, such as chloromethoxy, bromomethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, dichlorofluoro- methoxy, chloro difluoromethoxy, 1-chloroethoxy, 1-bromoethoxy, 1-flu
  • Ci-C 2 -fluoroalkoxy and Ci-C 2 -fluoroalkylthio refer to Ci- C 2 -fluoroalkyl which is bonded to the remainder of the molecule via an oxygen atom or a sulfur atom, respectively.
  • Ci-C 4 -alkoxy-Ci-C 4 -alkyl refers to alkyl having 1 to 4 carbon atoms, e.g. like the specific examples mentioned above, wherein one hydrogen atom of the alkyl radical is replaced by a Ci-C4-alkoxy group.
  • C3-C m -cycloalkyl refers to a monocyclic 3- to m-membered saturated cycloaliphatic radicals, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.
  • aryl refers to an aromatic hydrocarbon radical such as naphthyl or in particular phenyl.
  • C 6 -Cio-aryl-Ci-C 6 -alkyl refers to a Ci-C 6 -alkyl group, e.g. as specified above, wherein one hydrogen atom of the alkyl radical is replaced by a C 6 -Cio- aryl group, e.g. benzyl.
  • heterocyclyl refers to a group which is a mono-, bi-, or polycyclic structure having preferably from 3 to 14, more preferred 3 to 7, in particular 5 or 6, atoms, wherein one or more atoms are selected from the group consisting of N, O, and S.
  • the ring structure is saturated, unsaturated or partially unsaturated, and is non-aromatic.
  • one or more rings may be aromatic; for example one ring of a bicyclic heterocycle or one or two rings of a tricyclic heterocycle may be aromatic, as in indan and 9, 10-dihydro anthracene.
  • Examples of 3-, 4-, 5-, 6- or 7-membered saturated heterocyclyl include:
  • oxiranyl aziridinyl, azetidinyl, 2 tetrahydrofuranyl, 3-tetrahydrofuranyl, 2 tetrahydro- thienyl, 3 tetrahydrothienyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 3 pyrazolidinyl, 4 pyrazolidinyl, 5-pyrazolidinyl, 2 imidazolidinyl, 4 imidazolidinyl, 2-oxazolidinyl, 4-oxazolidinyl, 5 oxazolidinyl, 3-isoxazolidinyl, 4 isoxazolidinyl, 5 isoxazolidinyl, 2 thiazolidinyl, 4-thia- zolidinyl, 5 -thiazolidinyl, 3 isothiazolidinyl, 4-isothiazolidinyl, 5 isothiazolidinyl, 1 ,2,4- ox
  • heteroaryl as used herein means a mono-, bi-, tri- or polycyclic group having 5 to 14 ring atoms, preferably 5, 6, 9 or 10 ring atoms; in particular 5 or 6 ring atoms, having 6, 10, or 14 pi electrons shared in a cyclic array; and having, in addition to carbon atoms, one or more heteroatoms selected from the group consisting of N, O, and S.
  • Examples of 5 or 6 membered heteroaryl are: 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5- oxazolyl, 2-thiazolyl, 4 thiazolyl, 5-thiazolyl, 2-imidazolyl, 4-imidazolyl, l,3,4-triazol-2- yl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl and 2-pyrazinyl.
  • Ci-C m -alkylene is divalent branched or preferably unbranched saturated aliphatic chain having 1 to m carbon atoms, for example -CH 2 -, CH 2 CH 2 , -CH(CH 3 )-, CH 2 CH 2 CH 2 , CH(CH 3 )CH 2 , CH 2 CH(CH 3 ), CH 2 CH 2 CH 2 CH 2 , CH 2 CH 2 CH 2 CH 2 CH 2 ,
  • unsubstituted or substituted means that the respective moiety is optionally substituted, i.e. that at least one hydrogen atom is replaced by a substituent.
  • the number of substituents on one group is from 1 to 4, more preferably 1 or 2, however, in the case of halogen substituents the number can be up to the possible maximum, e.g. in the case of a perfluoroalkyl group.
  • groups such as alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, heterocycle and aryl can themselves be optionally substituted by further non substituted substituents.
  • L in formula (I) is a group -(L 1 ) m -W-(L 2 ) n ⁇ , where
  • L 1 is Ci-C6-alkylene or C 2 -C 6 -alkenylene, wherein the alkylene or alkenylene is unsubstituted or substituted;
  • W is (Y ⁇ r -NR 1 or -NR 2 -(Y 2 ) S
  • Y 1 is -CO-, -S(0) 2 -, -0-CO-, -NR 3 -CO-;
  • Y 2 is -CO-, -S0 2 - or -CO-O- L 2 is Ci-C 6 -alkylene, Ci-C 6 -alkylene-0-, C 2 -C 6 -alkenylene, C 2 -C 6 -alkenylene-0-, wherein the alkylene or alkenylene is unsubstituted or substituted;
  • R 1 is H, Ci-C 6 -alkyl, phenyl, benzyl, each unsubstituted or substituted, or is, together with R, Ci-C3-alkylene
  • R 2 , R 3 is H, Ci-C 6 -alkyl, phenyl, benzyl, each unsubstituted or substituted, and
  • ⁇ denotes the bond to the 1 ,4-phenylene group.
  • X is preferably C 6 -Cio-aryl, Cs-Ce-heteroaryl, any of which is unsubstituted or substituted by one or more groups R a , or H.
  • R a is preferably Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, C 6 -Cio-aryl, C 6 -Cio-aryl-Ci-C 6 -alkyl, halogen, nitro, hydroxyl, Ci-C 6 -alkoxy, Ci-C 6 -haloalkoxy, Ci-C 6 -alkoxycarbonyl, carboxy, amino, CN, NHR b , NHCOR c , NHS0 2 R c , S0 2 R c , S0 2 NR b or CONHR b .
  • R b is preferably H or Ci-C 4 -alkyl.
  • R c is preferably Ci-C 4 -alkyl.
  • L is preferably a group -(L 1 ) m -W-(L 2 ) n ⁇ , where ⁇ denotes the bond to the 1,4- phenylene group.
  • L 1 is preferably Ci-C4-alkylene, which is linear or branched, and which is unsubstituted or substituted by one or more halogen atoms and/or OH.
  • m is preferably 0 or 1.
  • W is preferably -(Y ⁇ -NR 1 - or -NR 2 -(Y 2 ) S -.
  • Y 1 is preferably -CO- , -S(0) 2 - , -O-CO- or -NR 3 -CO-.
  • r is preferably 0 or 1.
  • Y 2 is preferably -CO- or -S(0) 2 - s is preferably 0 or 1.
  • L 2 is preferably Ci-C4-alkylene or Ci-C4-alkylene-0 ⁇ , either of which is linear or branched and either of which is unsubstituted or substituted by one or more halogen atoms and/or OH.
  • n is preferably 0 or 1.
  • R 1 is preferably H, C 1 -C4 alkyl, benzyl, phenyl or - together with R - Ci-C 2 -alkylene.
  • R 2 , R 3 is preferably H, Ci-C4-alkyl, phenyl or benzyl.
  • R is preferably H or - together with R 1 - Ci-C 2 -alkylene.
  • X is more preferred phenyl, which is unsubstituted or substituted by one to four groups R a , or H.
  • R a is more preferred F, CI, Br, CN, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -haloalkyl, C 1 -C 4 - haloalkoxy, NHR b , NHCOR c , NHS0 2 R c , S0 2 R c , S0 2 NHR b or CONHR b .
  • R b is more preferred H or Ci-C4-alkyl.
  • R c is more preferred Ci-C4-alkyl.
  • L is more preferred -(L ⁇ -W-CL 2 )-.
  • L 1 is more preferred linear or branched Ci-C4-alkylene.
  • m is more preferred 0 or 1.
  • W is more preferred -(Y NR 1 - or -NR 2 -(Y 2 ) S -.
  • Y 1 is more preferred -CO-, -S(0) 2 -, -O-CO- or -NR 3 -CO-.
  • r is more preferred 0 or 1.
  • Y 2 is more preferred -CO-, -S(0) 2 -. s is more preferred 0 or 1.
  • L 2 is more preferred linear or branched Ci-C 4 -alkylene, linear or branched C 1 -C 4 - alkylene-0 ⁇ .
  • n is more preferred 0 or 1.
  • R 1 is more preferred H, Ci-C4-alkyl, benzyl or - together with R - Ci-C 2 -alkylene.
  • R 2 , R 3 is more preferred H, Ci-C4-alkyl or benzyl.
  • R is more preferred H or - together with R 1 - Ci-C 2 -alkylene.
  • X is particularly preferred phenyl, which is unsubstituted or substituted by one to four groups R a , or H.
  • R a is particularly preferred F, CI, Br, CN, Ci-C 4 -alkyl, Ci-C 4 -alkoxy, Ci-C 4 -haloalkyl, Ci-C 4 -haloalkoxy, NHR b , NHCOR c , NHS0 2 R c , S0 2 R c , S0 2 NHR b or CONHR b .
  • R b is particularly preferred H or Ci-C4-alkyl.
  • R c is particularly preferred Ci-C4-alkyl.
  • L is particularly preferred -(L 1 ) m -W-(L 2 ) n -.
  • L 1 is particularly preferred -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH(CH 3 )-, -CH(CH 3 )- CH 2 - or -CH 2 -C(CH 3 ) 2 -.
  • m is particularly preferred 0 or 1.
  • w is particularly preferred -(Y')i-NR 1 - or -NR 2 -(Y 2 ) S -.
  • Y 1 is particularly preferred -CO-, S(0) 2 -, -O-CO- or -NR 3 -CO-.
  • r is particularly preferred 0 or 1.
  • Y 2 is particularly preferred -CO-.
  • s is particularly preferred 0 or 1.
  • L 2 is particularly preferred -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 -0-, -CH 2 -CH 2 - O- or -CH 2 -CH 2 -.
  • n is particularly preferred 0 or 1.
  • R 1 is particularly preferred H, CH 3 , benzyl or - together with R - -CH 2 - or -CH 2 -CH 2 -.
  • R 2 , R 3 is particularly preferred H, CH 3 , C 2 H 5 or benzyl.
  • R is particularly preferred H or - together with R 1 - -CH 2 - or -CH 2 -CH 2 -.
  • X is H or phenyl which is unsubstituted or substituted.
  • phenyl is unsubstituted or is substituted by one or two substituents independently selected from Ci-C 4 -alkyl, Ci-C 4 -haloalkyl, C 6 -Cio-aryl, C 6 -Cio-aryl-Ci-C 6 -alkyl, halogen, nitro, hydroxyl, Ci-C 6 -alkoxy, Ci-C 6 -alkoxycarbonyl, carboxy and amino.
  • the compound of formula (I) is a compound of formula
  • Preferred compounds of formula (II) are compounds of formulae (III) and (IV),
  • Prodrugs of the compounds of the present invention are also within the scope of the present invention.
  • Prodrug means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • Examples of a prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g.
  • Metabolites of compounds of formula (I) are also within the scope of the present invention.
  • metabolites refers to all molecules derived from any of the compounds according to the present invention in a cell or organism, preferably mammal.
  • the term relates to molecules which differ from any molecule which is present in any such cell or organism under physiological conditions
  • hydroxamic acids of formula (I) are partly known and partly novel.
  • compounds of formula (I) can be obtained by the synthetic routes disclosed in WO 01/38322 and WO 2008/074132.
  • the present invention provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient together with a pharmaceutically acceptable carrier, optionally in combination with one or more other pharmaceutical compositions.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally. Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
  • a pharmaceutical composition of the present invention may comprise one or more additional compounds as active ingredients like one or more compounds of formula (I) not being the first compound in the composition or HDAC6 inhibitors.
  • Further bioactive compounds may be steroids, leukotriene antagonists, cyclosporine or rapamycin.
  • the compounds of the present invention or pharmaceutically acceptable salt(s) thereof and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, this may occur separately or sequentially in any order.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation.
  • they When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula (I) is administered in combination with another drug or pharmaceutically active agent and/or that the pharmaceutical composition of the invention further comprises such a drug or pharmaceutically active agent.
  • drug or pharmaceutically active agent includes a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • Combined or “in combination” or “combination” should be understood as a functional coadministration, wherein some or all compounds may be administered separately, in different formulations, different modes of administration (for example subcutaneous, intravenous or oral) and different times of administration.
  • the individual compounds of such combinations may be administered either sequentially in separate pharmaceutical compositions as well as simultaneously in combined pharmaceutical compositions.
  • Suitable examples of pharmaceutically active agents which may be employed in combination with the compounds of the present invention and their salts for autoimmune therapy include: immunosuppresants such as amtolmetin guacil, mizoribine and rimexolone; anti-TNFa agents such as etanercept, infliximab, Adalimumab, Anakinra, Abatacept, Rituximab; tyrosine kinase inhibitors such as leflunomide; kallikrein antagonists such as subreum; interleukin 11 agonists such as oprelvekin; interferon beta 1 agonists; hyaluronic acid agonists such as NRD-101 (Aventis); interleukin 1 receptor antagonists such as anakinra; CD8 antagonists such as amiprilose hydrochloride; beta amyloid precursor protein antagonists such as reum
  • immunosuppresants such as amtolmetin guacil, mizoribine and rimex
  • proteasome inhibitors such as bortezomib (formerly PS-341) is envisaged.
  • the compounds of formula (I) can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally, for example, as liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of formula (I) are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • a therapeutically effective amount of a compound of the present invention will normally depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration.
  • an effective amount of a compound of formula (I) for the treatment of an inflammatory disease for example rheumatoid arthritis (RA) will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day.
  • the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a pharmaceutically acceptable salt, prodrug or metabolite thereof may be determined as a proportion of the effective amount of the compound of formula (I) per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician.
  • terapéuticaally effective amount means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • One aspect of the present invention is a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament.
  • Another aspect of the present invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treating or preventing a disease or disorder associated with HDAC6.
  • a disease or disorder associated with HDAC6 is defined as a disease or disorder where HDAC6 is involved.
  • the diseases or disorder associated with HDAC6 is an immunological, inflammatory, autoimmune, or allergic disorder or disease or a transplant rejection or a Graft-versus host disease.
  • HDAC6 plays a role in the function of Foxp3 + T-regulatory cells (Tregs). Diminished numbers or function of Foxp3 + Tregs can cause autoimmunity and allograft rejection.
  • Treatment of HDAC6-deficient and wild-type mice with HDAC-6 specific inhibitors revealed that HDAC6 inhibition promotes Treg suppressive activity in models of inflammation and autoimmunity, for example experimental colitis and cardiac allograft rejection. Therefore inhibition of HDAC6 may promote Treg-dependent suppression of autoimmunity and transplant rejection (de Zoeten et al, 2011. Mol. Cell. Biol, 31(10):2066-2078).
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing an immunological, inflammatory, autoimmune, or allergic disorder or disease or a transplant rejection or a Graft-versus host disease.
  • an autoimmune disease is a disease which is at least partially provoked by an immune reaction of the body against own components, e.g. proteins, lipids or DNA.
  • the autoimmune disease is selected from the group consisting of rheumatoid arthritis (RA), inflammatory bowel disease (IBD; Crohns's disease and ulcerative colitis), systemic lupus erythematosus (SLE), and multiple sclerosis (MS).
  • RA rheumatoid arthritis
  • IBD inflammatory bowel disease
  • SLE systemic lupus erythematosus
  • MS multiple sclerosis
  • RA Rheumatoid arthritis
  • RA is a chronic progressive, debilitating inflammatory disease that affects approximately 1% of the world's population.
  • RA is a symmetric polyarticular arthritis that primarily affects the small joints of the hands and feet.
  • pannus In addition to inflammation in the synovium, the joint lining, the aggressive front of tissue called pannus invades and destroys local articular structures.
  • IBD Inflammatory bowel disease
  • Crohn's disease involves most frequently the terminal ileum and colon, is transmural and discontinuous.
  • ulcerative colitis the inflammation is continuous and limited to rectal and colonic mucosal layers.
  • definitive classification of Crohn disease or ulcerative colitis cannot be made and are designated 'indeterminate colitis.
  • Both diseases include extraintestinal inflammation of the skin, eyes, or joints. Neutrophil-induced injuries may be prevented by the use of neutrophils migration inhibitors.
  • SLE Systemic lupus erythematosus
  • MS Multiple sclerosis
  • GVDH graft-versus-host disease
  • Transplant rejection includes, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea. It is known that T cells play a central role in the specific immune response of allograft rejection.
  • the disease or disorder associated with HDAC6 is a proliferative disease, especially cancer.
  • HDAC6 diseases and disorders associated especially with HDAC6 are proliferative disorders or diseases, especially cancer.
  • another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing a proliferative disease, especially cancer.
  • Cancer comprises a group of diseases characterized by uncontrolled growth and spread of abnormal cells. All types of cancers generally involve some abnormality in the control of cell growth, division and survival, resulting in the malignant growth of cells. Key factors contributing to said malignant growth of cells are independence from growth signals, insensitivity to anti-growth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, tissue invasion and metastasis, and genome instability (Hanahan and Weinberg, 2000. The Hallmarks of Cancer. Cell 100, 57-70).
  • cancers are classified as hematological cancers (for example leukemias and lymphomas) and solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • hematological cancers for example leukemias and lymphomas
  • solid cancers such as sarcomas and carcinomas (for example cancers of the brain, breast, lung, colon, stomach, liver, pancreas, prostate, ovary).
  • HDAC6 has become a target for drug development to treat cancer due to its major contribution in oncogenic cell transformation. Overexpression of HDAC6 correlates with tumorigenesis and improved cell survival. Previous work demonstrated that in multiple myeloma cells, inhibition of HDAC6 results in apoptosis (Aldana-Masangkay and Sakamoto, 2011. J. Biomed. Biotechnol. 875824).
  • multiple myeloma which is characterized by excess production of intracellular proteins. This includes relapsed and relapsed/refractory multiple myeloma.
  • the disease or disorder associated with HDAC6 is a neurodegenerative disorder or neurological disease.
  • another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing a neurodegenerative disorder or neurological disease.
  • HDAC6 is a target for protection and regeneration following injury in the nervous system. Damage of neurons leads to an increase in HDAC6 expression and inhibition of HDAC6 can promote survival and regeneration of neurons. Importantly, selective inhibition of HDAC6 avoids cell death associated with non-selective HDAC inhibitors (pan-HDAC inhibitors. Therefore HDAC6 may be a promising target for the treatment of for example stroke, ischemia and spinal cord injury (Rivieccio et al, 2009. Proc. Natl. Acad. Sci. USA 106(46): 19599-604).
  • HDAC6 was identified as a component of the aggresome in human cells (Kawaguchi et al., 2003. Cell 115 (6): 727-738). Aggregates of misfolded proteins are transported and removed from the cytoplasm by dynein motors via the microtubule network to an organelle termed the aggresome, where they are processed. HDAC6 could bind both polyubiquitinated misfolded proteins and dynein motors, thereby recruiting misfolded protein cargo to dynein motors for transport to aggresomes. Cells deficient in HDAC6 failed to clear misfolded protein aggregates from the cytoplasm, could not form aggresomes properly, and were hypersensitive to accumulation of misfolded proteins.
  • HDAC6 inhibitors may be useful to treat neurodegenerative disorders such as Huntingtons's, Alzheimer's, Parkinson's disease and Amyotrophic lateral sclerosis (ALS).
  • ALS Amyotrophic lateral sclerosis
  • Huntingtons's disease is a neurodegenerative disorder caused by a mutant form of the protein huntingtin with abnormally long glutamine repeats at the amino -terminus.
  • the mutant protein aggregates in neuronal cells and can cause nerve cell damage and toxicity.
  • Intracellular protein aggregates also occur in other neurodegenerative diseases, for example Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • the Tau protein is frequently found in brains of Alzheimer's patients and is thought to contribute to the formation of neurofibrillary tangles (for example in tauopathies such as fronto -temporal dementia).
  • Parkinson's disease is a neurodegenerative disease associated with the accumulation and aggregation of misfolded proteins. Preventing aggregation or disaggregating misfolded proteins may provide a therapeutic benefit by slowing or preventing the progression of PD.
  • ALS Amyotrophic lateral sclerosis
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prophylaxis of diseases and disorders associated with HDAC6.
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing an immunological, inflammatory, autoimmune, or allergic disorder or disease or a transplant rejection or a Graft-versus host disease.
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a proliferative disease, especially cancer.
  • Yet another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating a neurodegenerative disorder or neurological disease.
  • HDAC6 diseases and disorders associated with HDAC6 are as defined above.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of diseases and disorders associated with HDAC6, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of an immunological, inflammatory, autoimmune, or allergic disorder or disease or a transplant rejection or a Graft-versus host disease, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof a proliferative disease, especially cancer, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof one or more conditions selected from the group consisting of a neurodegenerative disorder or neurological disease, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need thereof a viral infection, wherein the method comprises the administration to said patient a therapeutically effective amount of a compound according to present invention or a pharmaceutically acceptable salt thereof.
  • HDAC6 diseases and disorders associated with HDAC6 are as defined above.
  • treating or “treatment” is intended to refer to all processes, wherein there may be a slowing, interrupting, arresting, or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • LCMS was carried out on a Waters uPLC-SQD system using a Waters Acquity UPLC BEH CI 8, 2.1 x 30 mm, 1.7 micron column at 40 °C. Column flow was 0.5 mL/min. Solvents used were water (0.1% formic acid) and acetonitrile (0.1% formic acid), with an injection volume of 3 ⁇ . Wavelength was monitored using photodiode array detection 210-400 nm. The mass spec data are gathered in positive or negative mode, scanning for masses between 150 and 700 amu.
  • LCMS was carried out on an Agilent 1 100 using a Gemini CI 8, 3 x 30 mm, 3 micron column. Column flow was 1.2 mL/min and solvents used were water (0.1% formic acid) and acetonitrile (0.1% formic acid) with an injection volume of 3 ⁇ ⁇ . Wavelengths were 254 and 210 nm.
  • Methyl 2-(4-hydroxyphenyl)acetate (275 mg) was stirred overnight at 50 °C in DMF (10 mL) with potassium carbonate (300 mg) and tert-butyl (3-bromopropyl)carbamate (395 mg). The reaction was cooled, diluted with ethyl acetate (20 mL) and then washed with 1 M aqueous sodium hydroxide (10 mL).
  • Methyl 2-(4-(benzamidomethyl)phenyl)acetate was dissolved in methanol (50 mL) and stirred at room temperature with 4 M aqueous sodium hydroxide (2 mL). After 4 h solvents were removed under reduced pressure and the residue was dissolved in water (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was washed with water (2 x 10 mL) and the combined aqueous phases were acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3 x 20 mL).
  • N-Benzyl-N-methyl-4-(2-oxo-2-(((tetrahydro-2H-pyran-2-yl)oxy)amino)ethyl)benzamide (D) was dissolved in 4 M hydrogen chloride in dioxane and allowed to stand at room temperature. After 2 h the solvents were removed under reduced pressure and the product triturated with ether to give N-benzyl-4-(2-(hydroxyamino)-2-oxoethyl)-N- methylbenzamide (1).
  • LCMS method A, (ES+) 299, RT 0.87 min.
  • tert-butyl 6-(2-((Benzyloxy)amino)-2-oxoethyl)-3,4-dihydroisoquinoline-2(lH)-carboxy- late (Q) was dissolved in methanol (5 mL) and stirred under hydrogen with 5% palladium on carbon for 5 h. The reaction was filtered through Celite and concentrated under reduced pressure to give tert-butyl 6-(2-(hydroxyamino)-2-oxoethyl)-3,4-dihydroisoquinoline- 2(lH)-carboxylate.
  • LCMS method B (ES+) 329 (MNa + ), RT 2.16 min.
  • test compounds are added directly into a cell lysate.
  • Various concentrations of test compounds were added to K-562 cell lysate samples and allowed to bind to the proteins contained in the lysate sample.
  • the affinity matrix was added to capture proteins not bound to the test compound.
  • the beads with captured proteins were separated from the lysate. Bead-bound proteins were then eluted and the presence of HDAC2 and HDAC6 was detected and quantified using specific antibodies and the Odyssey Infrared Detection system. Further experimental protocols can be found in WO2011/018241.
  • the beads were incubated at room temperature in darkness on an end- over-end shaker (Roto Shake Genie, Scientific Industries Inc.) for 16 - 20 h.
  • the coupling efficiency was determined by HPLC analysis of non-immobilized compound in the supernatant.
  • Non-reacted NHS-groups on the beads were blocked by incubation with aminoethanol at room temperature on the end-over-end shaker over night.
  • Beads were washed with 10 mL of DMSO and stored in z ' sopropanol at -20°C. These beads were used as the affinity matrix in the following experiments.
  • the affinity matrix was washed three times with 5 - 10 volumes of DP buffer (50 mM Tris-HCl pH 7.4, 5% Glycerol, 1.5 mM MgCl 2 , 150 mM NaCl, 1 mM Na 3 V0 4 , 0.4% NP- 40, 1 mM DTT). Beads were collected by centrifugation (2 min at 300 x g in a Herareus centrifuge) and finally resuspended in DP buffer to prepare a 2.1% beads slurry.
  • DP buffer 50 mM Tris-HCl pH 7.4, 5% Glycerol, 1.5 mM MgCl 2 , 150 mM NaCl, 1 mM Na 3 V0 4 , 0.4% NP- 40, 1 mM DTT.
  • Stock solutions of test compounds were prepared in DMSO corresponding to a 50-fold higher concentration compared to the final desired test concentration (e.g. a 10 mM stock solution was prepared for a final test concentration of 200 ⁇ ). This dilution scheme resulted in a final DMSO concentration of 2%.
  • K-562 cells (DSMZ Braunschweig, Germany; ACC 10) were either obtained from an external supplier (CIL SA, Mons, Belgium) or grown in one litre Spinner flasks (Integra Biosciences, 182101) in suspension in RPMI 1640 medium (Invitrogen, 21875-034) supplemented with 10%> Fetal Bovine Serum (Invitrogen, 10270-106). Cells were harvested by centrifugation and washed once with PBS buffer (Invitrogen, 14190-094). The harvested cells were directly subjected to cell lysis.
  • lysis buffer 50 mM Tris-HCl pH 7.4, 0.8% NP40, 5% glycerol, 150 mM NaCl, 1.5 mM MgCl 2 , 25 mM NaF, 1 mM sodium vanadate, 1 mM DTT supplemented with protease inhibitors (protease inhibitor cocktail, Roche Diagnostics, 1 873 580; 1 tablet per 25 mL buffer).
  • protease inhibitors protease inhibitor cocktail, Roche Diagnostics, 1 873 580; 1 tablet per 25 mL buffer.
  • the material was dounced 20 times using a mechanized POTTER S, transferred to 50 mL falcon tubes, incubated for 30 minutes rotating at 4 °C and centrifuged for 10 min at 20,000 x g at 4 °C (10,000 rpm in Sorvall SLA600, precooled). The supernatant was transferred to an ultracentrifuge- polycarbonate tube (Beckmann, 355654) and spun for 1 h at 145.000 x g at 4 °C (40.000 rpm in ⁇ 50.2, precooled). The supernatant was transferred to a fresh 50 mL falcon tube, the protein concentration was determined by a Bradford assay (BioRad) and samples containing 50 mg of protein per aliquot were prepared. The samples were immediately used for experiments or frozen in liquid nitrogen and stored frozen at -80 °C.
  • lysate aliquot containing 120 mg of protein was thawed in a 21 °C water bath and then kept at 4 °C.
  • the lysate was diluted by adding DP buffer supplemented with protease inhibitors to obtain a final protein concentration of 10 mg/mL and a final NP-40 concentration of 0.4 - 0.5% (weight/volume).
  • the filter plate was placed on top of a collection plate (Greiner bio-one, polypropylene microplate 384 well V-shape, 781 280) and the beads were eluted with 20 ⁇ .
  • elution buffer 100 mM Tris, pH 7.4, 4% SDS, 0.01% Bromophenol blue, 20% glycerol, 50 mM DTT.
  • the eluate was stored at -20 °C or directly used for spotting on a nitrocellulose membrane.
  • HDAC2 and HDAC6 in the eluates were detected and quantified by spotting on nitrocellulose membranes and using a first antibody directed against the protein of interest and a fluorescently labelled secondary antibody (anti-mouse or anti-rabbit IRDyeTM antibodies).
  • the Odyssey Infrared Imaging system from LI-COR Biosciences (Lincoln, Iowa, USA) was operated according to instructions provided by the manufacturer (Schutz-Geschiller et al, 2004. Quantitative, two-color Western blot detection with infrared fluorescence. Published May 2004 by LI-COR Biosciences, www.licor.com).
  • the nitrocellulose membranes (BioTrace NT; PALL, BTNT30R) were first blocked by incubation with Odyssey blocking buffer (LICOR, 927- 40000) for 1 h at room temperature. Blocked membranes were then incubated for 16 h at 4 °C with the first antibody diluted in Odyssey blocking buffer supplemented with 0.4%> Tween 20. Afterwards the membranes were washed three times for 5 min with 15 mL PBS buffer containing 0.1% Tween 20 (Sigma, T2700) at room temperature.
  • LICOR Odyssey blocking buffer
  • the membranes were incubated for 60 min at room temperature with the detection antibody (IRDyeTM labelled antibody from LI-COR) diluted in Odyssey blocking buffer (LICOR 927-40000) containing 0.2% Tween 20. Afterwards the membranes were washed four times for 5 min each with PBS buffer containing 0.1% Tween 20 at room temperature. Then the membrane was rinsed twice with PBS buffer to remove residual Tween-20. The membranes were then scanned with the Odyssey Infrared Imaging system. Fluorescence signals were recorded and analysed according to the instructions of the manufacturer. Concentration response curves were computed with BioAssay and Tibco Spotfire.
  • HeLa cells were treated with compounds over a range of concentrations. Cells were then lysed and the acetylation levels of tubulin and histone H4 (at lysine K5) were analysed in cell extracts by Western blotting. In parallel, the compound cytotoxicity was tested with a cell viability assay.
  • HeLa cells were grown in full medium in a 5% C0 2 atmosphere at 37°C.
  • Full medium Minimum essential medium (MEM) (Invitrogen (GIBCO), catalogue number 31095) containing 1 mM sodium pyruvate (Invitrogen (GIBCO), catalogue number 1 1360), 1 x non-essential amino acids (NEAA) (Lonza, catalogue number BE13-1 14E), and 10% fetal bovine serum (FBS) (Invitrogen (GIBCO), catalogue number 10270-106).
  • Assay medium Minimum essential medium (MEM) containing 1 mM Sodium pyruvate, 1 x NEAA, and 1.5% FBS.
  • HeLa cells were seeded at a density of 20,000 cells/well in a flat bottom 96-well tissue culture plate (MicrotestTM, BD-Falcon, catalogue number 353072) and cultured over night in full medium until they reached confluence. Wells containing medium without cells served as controls. The compound treatment was done in duplicate on two parallel plates. The first plate was used for the preparation of cell lysates for Western blot analysis. The second plate was used for the assessment of compound cytotoxicity with a MTT asay (Cell Proliferation Kit I, Roche Diagnostics GmbH, catalogue number 1 1465007001).
  • DMSO control wells received 10 of a 1 : 10 dilution of DMSO in assay medium resulting in a final DMSO concentration of 0.67% (DMSO controls).
  • Non-treated control wells received 10 ⁇ of assay medium. Plates were incubated at 37°C, 5% C0 2 for 4 h.
  • the supernatant was aspirated without disturbing the cell layer and 150 ⁇ , ice-cold phosphate buffered saline (1 x PBS, Invitrogen (GIBCO), catalogue number 20012-043) was added to each well.
  • the PBS was removed without disturbing the cell layer and 50 ⁇ , of 2 x sample buffer (100 mM Tris, pH 7.4, 4% SDS, 20% glycerol, 0.01% Bromphenol blue) were added to each well to lyse the cells.
  • the plate was incubated for 10 min at room temperature with shaking.
  • the cell lysis was controlled under the microscope (cells should be dissolved). The incubation was continued with shaking at 50 °C for 30 min.
  • the SDS-PAGE was run with MES running buffer (NP0002, Invitrogen, Carlsbad, CA, USA) at 140 V for approximately 90 min.
  • the proteins were then transferred onto an Immobilon®-FL PVDF membrane (Millipore, IPFL00013) using wet transfer for 2 h (Transfer buffer: 50 mM Trizma® base, 40 mM glycine, 0.04% SDS, 20% methanol).
  • the membrane was blocked by incubation in blocking buffer (Li-COR® Biosciences, 927-40000) for 1 h at room temperature with shaking. Then the membrane was incubated with the primary antibody diluted in blocking buffer, 0.1% Tween 20 for 16 h at 4 °C with shaking.
  • the primary antibody was removed and the membrane was washed three times for 10 minutes with PBST (PBS with 0.2% Tween 20). Then the secondary detection antibody diluted 1 : 10,000 in blocking buffer, 0.1% Tween 20, 0.02% SDS was added and incubated for 1 hour at room temperature with shaking. The secondary antibody was removed and the membrane was washed three times for 10 min in PBST. The membrane can be stored in PBS until scanned.
  • the membrane was scanned on a Li-COR® Biosciences Odyssey imager in the two channels for 680 nm and 780 nm and the signals were processed with the Li-COR® Biosciences Odyssey software (Schutz-Geschiller et al, 2004. Quantitative, two- color Western blot detection with infrared fluorescence. Published May 2004 by LI-COR® Biosciences, www.licor.com). Data were further analysed with the GraphPad Prism V.5 Software.
  • the second plate was used for a MTT assay according to the instructions of the manufacturer to determine compound cytoxicity (Cell Proliferation Kit I from Roche Diagnostics GmbH, catalogue number 1 1465007001).
  • ⁇ ⁇ ⁇ of the MTT reagent were added to each well, including wells that contain 140 assay medium but no cells. These control wells were used to measure the background signal of the assay medium.
  • the plate was incubated at 37 °C, 5% C0 2 for 4 h to allow the formation of formazan crystals. Then 100 of resolubilisation agent were added to dissolve the formazan crystals and the plate was incubated at 37 °C, 5% C0 2 for 16 h. Absorption was measured at 570 nm using a plate reader (LjL BiosystemsTM Analyst HT 96-384 plate reader). Wells without cells were used to assess the background signal. The average signal from untreated cells was used as 100% viability reference value.

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Abstract

Acide hydroxamique de formule (I) ou sel de qualité pharmaceutique de cet acide à utiliser dans le traitement ou la prévention d'un trouble ou d'une maladie à caractère immunologique, inflammatoire, auto-immune ou allergique, d'un rejet de transplantation, de la maladie de l'hôte contre le greffon, ou d'une maladie neuro-dégénérative, ou encore d'une lésion neuronale. Les symboles utilisés dans la formule ont les significations suivantes : X est aryle, hétéroaryle, cycloaryle ou hétérocyclyle, chacun des composés précédents pouvant être non substitué ou substitué, ou H; L est un alkylène saturé en C1-C14 ou un alcénylène en C2-C8, l'alkylène ou l'alcénylène étant non substitué ou substitué, où un ou deux des atomes de carbone d'alkylène ou d'alcénylène est remplacé par NR', R' étant hydrogène, alkyle, acyle, hydrogène, arylalkyle ou, conjointement avec R, est un alkylène en (C1-C3), et où un ou deux atomes de carbone d'alkylène ou d'acénylène est éventuellement remplacé par O, S(O), S(O)2 ou C(O); et R est H, ou conjointement avec R' alkylène en (C1-C3).
PCT/EP2012/067721 2011-09-19 2012-09-11 Acides hydroxamiques et récepteurs hdac6 Ceased WO2013041407A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20150106857A (ko) 2014-03-12 2015-09-22 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 신규 화합물 및 이를 포함하는 약제학적 조성물
EP2763531A4 (fr) * 2011-10-03 2015-11-18 Univ Columbia Nouvelles molécules qui inhibent sélectivement l'histone-déacétylase 6 par rapport à l'histone-déacétylase 1
WO2015175813A1 (fr) * 2014-05-14 2015-11-19 The Regents Of The University Of Colorado, A Body Corporate Acides hydroxamiques hétérocycliques comme inhibiteurs de protéine désacétylase et inhibiteurs doubles de protéine kinase-protéine désacétylase, et leurs procédés d'utilisation
JP2016531163A (ja) * 2013-09-20 2016-10-06 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Ｈｄａｃ６阻害物質を用いた、異常なリンパ球の機能に起因する疾患の治療
KR20170013186A (ko) 2015-07-27 2017-02-06 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 설프아마이드 유도체 화합물 및 이를 포함하는 약제학적 조성물
KR20170013187A (ko) 2015-07-27 2017-02-06 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 아마이드 유도체 화합물 및 이를 포함하는 약제학적 조성물
KR20170013836A (ko) 2015-07-27 2017-02-07 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 설폰아마이드 유도체 화합물 및 이를 포함하는 약제학적 조성물
KR20170017792A (ko) 2015-08-04 2017-02-15 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 유도체 화합물 및 이를 포함하는 약제학적 조성물
WO2020194272A1 (fr) * 2019-03-27 2020-10-01 2681603 Ontario Inc. Composés d'acide hydroxamique de phénylsulfonamide halogéné, compositions et leurs utilisations servant d'inhibiteurs sélectifs de hdac6
WO2020240493A1 (fr) 2019-05-31 2020-12-03 Chong Kun Dang Pharmaceutical Corp. Composés dérivés de 1,3,4-oxadiazole homophtalimide utilisés comme inhibiteur de l'histone désacétylase 6, et composition pharmaceutique les comprenant
WO2021154882A1 (fr) * 2020-01-27 2021-08-05 H. Lee Moffitt Cancer Center And Research Institute Inc. Lymphocytes t régulateurs humains inhibés par hdac6
CN116496178A (zh) * 2023-04-27 2023-07-28 合肥工业大学 具有丁香酸和氨基酸结构片段的化合物及其合成与用途
US11958844B2 (en) 2018-07-26 2024-04-16 Chong Kun Dang Pharmaceutical Corp. 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and pharmaceutical composition comprising the same
KR20240133645A (ko) 2023-02-28 2024-09-04 주식회사 종근당 옥사다이아졸 유도체 화합물 및 이를 포함하는 약제학적 조성물
US12466827B2 (en) 2020-02-25 2025-11-11 Chong Kun Dang Pharmaceutical Corp. 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same

Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (fr) 1999-11-23 2001-05-31 Methylgene, Inc. Inhibiteurs de l'histone deacetylase
WO2002026703A1 (fr) * 2000-09-29 2002-04-04 Prolifix Limited Composes d'acide carbamique comprenant une liaison ether et utiles en tant qu'inhibiteurs de hdac
WO2003070188A2 (fr) * 2002-02-15 2003-08-28 Sloan-Kettering Institute For Cancer Research Methode de traitement des maladies mediees par la thioredoxine (trx)
WO2005019162A1 (fr) * 2003-08-26 2005-03-03 Amorepacific Corporation Derives d'acide hydroxamique et leur methode de preparation
WO2005040101A1 (fr) * 2003-10-27 2005-05-06 S*Bio Pte Ltd Hydroxamates connectes a l'acyluree et a la sulfonyluree
WO2005055928A2 (fr) * 2003-12-02 2005-06-23 The Ohio State University Research Foundation Acides gras a chaine courte lies a un motif de chelation zn2+ utilises en tant que nouvelle classe d'inhibiteurs d'histone desacetylase
US20060293343A1 (en) * 2005-05-18 2006-12-28 Asahi Kasei Pharma Corporation Pyrimidine derivatives
WO2007058992A2 (fr) * 2005-11-14 2007-05-24 Novartis Ag Mutations et polymorphismes de hdac6
WO2008074132A1 (fr) 2006-12-19 2008-06-26 Methylgene Inc. Inhibiteurs de l'histone désacétylase et pro-médicaments à base de ceux-ci
WO2008076954A2 (fr) * 2006-12-15 2008-06-26 Novartis Ag Composés hétérocycliques et procédés d'utilisation de ceux-ci
WO2009026446A2 (fr) * 2007-08-21 2009-02-26 Arqule, Inc. Inhibiteurs des hdac
WO2009045385A1 (fr) * 2007-10-04 2009-04-09 Merck & Co., Inc. Composés n-hydroxy-naphtalène dicarboxamide et n-hydroxy-biphényl-dicarboxamide comme inhibiteurs de l'histone désacétylase
EP2100879A1 (fr) * 2008-03-13 2009-09-16 4Sc Ag Nouveaux composants d'acide hydroxamique tetrahydroisoquinoline/ isoindoline substitués N
WO2010151318A1 (fr) * 2009-06-22 2010-12-29 Millennium Pharmaceuticals, Inc. Acides hydroxamiques substitués et leurs utilisations
WO2011011186A2 (fr) 2009-07-22 2011-01-27 The Board Of Trustees Of The University Of Illinois Inhibiteurs de hdac et procédés thérapeutiques les utilisant
WO2011018241A1 (fr) 2009-08-14 2011-02-17 Cellzome Ag Procédés d’identification et de caractérisation de composés interagissant avec l’hdac
WO2011019393A2 (fr) 2009-08-11 2011-02-17 President And Fellows Of Harvard College Inhibiteurs de hdac classe- et isoforme-spécifiques et utilisations de ceux-ci
WO2011058582A1 (fr) * 2009-11-16 2011-05-19 Orchid Research Laboratories Ltd. Inhibiteurs d'histone déacétylase pour le traitement d'infections fongiques

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038322A1 (fr) 1999-11-23 2001-05-31 Methylgene, Inc. Inhibiteurs de l'histone deacetylase
WO2002026703A1 (fr) * 2000-09-29 2002-04-04 Prolifix Limited Composes d'acide carbamique comprenant une liaison ether et utiles en tant qu'inhibiteurs de hdac
WO2003070188A2 (fr) * 2002-02-15 2003-08-28 Sloan-Kettering Institute For Cancer Research Methode de traitement des maladies mediees par la thioredoxine (trx)
WO2005019162A1 (fr) * 2003-08-26 2005-03-03 Amorepacific Corporation Derives d'acide hydroxamique et leur methode de preparation
WO2005040101A1 (fr) * 2003-10-27 2005-05-06 S*Bio Pte Ltd Hydroxamates connectes a l'acyluree et a la sulfonyluree
WO2005055928A2 (fr) * 2003-12-02 2005-06-23 The Ohio State University Research Foundation Acides gras a chaine courte lies a un motif de chelation zn2+ utilises en tant que nouvelle classe d'inhibiteurs d'histone desacetylase
US20060293343A1 (en) * 2005-05-18 2006-12-28 Asahi Kasei Pharma Corporation Pyrimidine derivatives
WO2007058992A2 (fr) * 2005-11-14 2007-05-24 Novartis Ag Mutations et polymorphismes de hdac6
WO2008076954A2 (fr) * 2006-12-15 2008-06-26 Novartis Ag Composés hétérocycliques et procédés d'utilisation de ceux-ci
WO2008074132A1 (fr) 2006-12-19 2008-06-26 Methylgene Inc. Inhibiteurs de l'histone désacétylase et pro-médicaments à base de ceux-ci
WO2009026446A2 (fr) * 2007-08-21 2009-02-26 Arqule, Inc. Inhibiteurs des hdac
WO2009045385A1 (fr) * 2007-10-04 2009-04-09 Merck & Co., Inc. Composés n-hydroxy-naphtalène dicarboxamide et n-hydroxy-biphényl-dicarboxamide comme inhibiteurs de l'histone désacétylase
EP2100879A1 (fr) * 2008-03-13 2009-09-16 4Sc Ag Nouveaux composants d'acide hydroxamique tetrahydroisoquinoline/ isoindoline substitués N
WO2010151318A1 (fr) * 2009-06-22 2010-12-29 Millennium Pharmaceuticals, Inc. Acides hydroxamiques substitués et leurs utilisations
WO2011011186A2 (fr) 2009-07-22 2011-01-27 The Board Of Trustees Of The University Of Illinois Inhibiteurs de hdac et procédés thérapeutiques les utilisant
WO2011019393A2 (fr) 2009-08-11 2011-02-17 President And Fellows Of Harvard College Inhibiteurs de hdac classe- et isoforme-spécifiques et utilisations de ceux-ci
WO2011018241A1 (fr) 2009-08-14 2011-02-17 Cellzome Ag Procédés d’identification et de caractérisation de composés interagissant avec l’hdac
WO2011058582A1 (fr) * 2009-11-16 2011-05-19 Orchid Research Laboratories Ltd. Inhibiteurs d'histone déacétylase pour le traitement d'infections fongiques

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
ALDANA-MASANGKAY; SAKAMOTO, J. BIOMED. BIOTECHNOL., 2011, pages 875824
BALASUBRAMANIAN ET AL., CANCER LETT., vol. 280, no. 2, 2009, pages 211 - 21
BANTSCHEFF ET AL., NAT. BIOTECHNOL., vol. 29, no. 3, 2011, pages 255 - 265
BOLDEN ET AL., NAT. REV. DRUG DISCOV., vol. 5, no. 9, 2006, pages 769 - 784
BRADNER ET AL., NAT. CHEM. BIOL., vol. 6, no. 3, 2010, pages 238 - 243
GUPTA ET AL., BIOORG. MED. CHEM. LETT., vol. 20, no. 23, 2010, pages 7067 - 7070
HABERLAND ET AL., NAT. REV. GENET., vol. 10, no. 1, 2009, pages 32 - 42
HANAHAN; WEINBERG: "The Hallmarks of Cancer", CELL, vol. 100, 2000, pages 57 - 70
HUBBERT ET AL., NATURE, vol. 417, no. 6887, 2002, pages 455 - 458
KALIN ET AL., CURR. OPIN. CHEM. BIOL., vol. 13, 2009, pages 1 - 9
KAWAGUCHI ET AL., CELL, vol. 115, no. 6, 2003, pages 727 - 738
LAVOIE R ET AL: "Design and synthesis of a novel class of histone deacetylase inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, ELSEVIER SCIENCE, GB, vol. 11, no. 21, 1 January 2001 (2001-01-01), pages 2847 - 2850, XP002954135, ISSN: 0960-894X, DOI: 10.1016/S0960-894X(01)00552-2 *
RIVIECCIO ET AL., PROC. NATL. ACAD. SCI. USA, vol. 106, no. 46, 2009, pages 19599 - 604
SCHUTZ-GESCHWENDENER ET AL.: "Quantitative, two-color Western blot detection with infrared fluorescence", May 2004, LI-COR BIOSCIENCES
SCHUTZ-GESCHWENDENER ET AL.: "Quantitative, two-color Western blot detection with infrared fluorescence", May 2004, LI-COR@ BIOSCIENCES
ZOETEN ET AL., MOL. CELL. BIOL., vol. 31, no. 10, 2011, pages 2066 - 2078

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EP2763531A4 (fr) * 2011-10-03 2015-11-18 Univ Columbia Nouvelles molécules qui inhibent sélectivement l'histone-déacétylase 6 par rapport à l'histone-déacétylase 1
JP2016531163A (ja) * 2013-09-20 2016-10-06 アセチロン ファーマシューティカルズ インコーポレイテッドＡｃｅｔｙｌｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ，Ｉｎｃ． Ｈｄａｃ６阻害物質を用いた、異常なリンパ球の機能に起因する疾患の治療
EP3046559A4 (fr) * 2013-09-20 2017-03-22 Acetylon Pharmaceuticals, Inc. Traitement des maladies provoquées par une fonction lymphocytaire anormale avec un inhibiteur d'hdac6
KR20150106857A (ko) 2014-03-12 2015-09-22 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 신규 화합물 및 이를 포함하는 약제학적 조성물
US10287255B2 (en) 2014-03-12 2019-05-14 Chong Kun Dang Pharmaceutical Corp. Compounds as histone deacetylase 6 inhibitors and pharmaceutical compositions comprising the same
US9840520B2 (en) 2014-05-14 2017-12-12 The Regents Of The University Of Colorado, A Body Corporate Heterocyclic hydroxamic acids as protein deacetylase inhibitors and dual protein deacetylase-protein kinase inhibitors and methods of use thereof
WO2015175813A1 (fr) * 2014-05-14 2015-11-19 The Regents Of The University Of Colorado, A Body Corporate Acides hydroxamiques hétérocycliques comme inhibiteurs de protéine désacétylase et inhibiteurs doubles de protéine kinase-protéine désacétylase, et leurs procédés d'utilisation
US10508122B2 (en) 2014-05-14 2019-12-17 The Regents Of The University Of Colorado, A Body Corporate Heterocyclic hydroxamic acids as protein deacetylase inhibitors and dual protein deacetylase-protein kinase inhibitors and methods of use thereof
USRE47690E1 (en) 2014-05-14 2019-11-05 The Regents Of The University Of Colorado, A Body Corporate Heterocyclic hydroxamic acids as protein deacetylase inhibitors and dual protein deacetylase-protein kinase inhibitors and methods of use thereof
US20170081343A1 (en) * 2014-05-14 2017-03-23 The Regents Of The University Of Colorado, A Body Corporate Heterocyclic Hydroxamic Acids as Protein Deacetylase Inhibitors and Dual Protein Deacetylase-Protein Kinase Inhibitors and Methods of Use Thereof
KR20170013187A (ko) 2015-07-27 2017-02-06 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 아마이드 유도체 화합물 및 이를 포함하는 약제학적 조성물
KR20170013836A (ko) 2015-07-27 2017-02-07 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 설폰아마이드 유도체 화합물 및 이를 포함하는 약제학적 조성물
KR20170013186A (ko) 2015-07-27 2017-02-06 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 설프아마이드 유도체 화합물 및 이를 포함하는 약제학적 조성물
KR20170017792A (ko) 2015-08-04 2017-02-15 주식회사 종근당 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 유도체 화합물 및 이를 포함하는 약제학적 조성물
US11958844B2 (en) 2018-07-26 2024-04-16 Chong Kun Dang Pharmaceutical Corp. 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and pharmaceutical composition comprising the same
WO2020194272A1 (fr) * 2019-03-27 2020-10-01 2681603 Ontario Inc. Composés d'acide hydroxamique de phénylsulfonamide halogéné, compositions et leurs utilisations servant d'inhibiteurs sélectifs de hdac6
WO2020240493A1 (fr) 2019-05-31 2020-12-03 Chong Kun Dang Pharmaceutical Corp. Composés dérivés de 1,3,4-oxadiazole homophtalimide utilisés comme inhibiteur de l'histone désacétylase 6, et composition pharmaceutique les comprenant
US12440484B2 (en) 2019-05-31 2025-10-14 Chong Kun Dang Pharmaceutical Corporation 1,3,4-oxadiazole homophthalimide derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
WO2021154882A1 (fr) * 2020-01-27 2021-08-05 H. Lee Moffitt Cancer Center And Research Institute Inc. Lymphocytes t régulateurs humains inhibés par hdac6
US12466827B2 (en) 2020-02-25 2025-11-11 Chong Kun Dang Pharmaceutical Corp. 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and the pharmaceutical composition comprising the same
KR20240133645A (ko) 2023-02-28 2024-09-04 주식회사 종근당 옥사다이아졸 유도체 화합물 및 이를 포함하는 약제학적 조성물
CN116496178A (zh) * 2023-04-27 2023-07-28 合肥工业大学 具有丁香酸和氨基酸结构片段的化合物及其合成与用途

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