WO2005075466A1 - Thienyl-mercaptoketones substitues, et utilisation associee pour le traitement de maladies liees a l'activite enzymatique d'histone deacetylase - Google Patents

Thienyl-mercaptoketones substitues, et utilisation associee pour le traitement de maladies liees a l'activite enzymatique d'histone deacetylase Download PDF

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WO2005075466A1
WO2005075466A1 PCT/GB2005/000283 GB2005000283W WO2005075466A1 WO 2005075466 A1 WO2005075466 A1 WO 2005075466A1 GB 2005000283 W GB2005000283 W GB 2005000283W WO 2005075466 A1 WO2005075466 A1 WO 2005075466A1
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alkyl
heteroaryl
aryl
cycloalkyl
heterocycloalkyl
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PCT/GB2005/000283
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English (en)
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Walter Bordogna
Richard Bull
Jonathon Mark Sutton
Helen Katherine Smith
Hazel Joan Dyke
Stephen Price
Neil Victor Harris
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Argenta Discovery Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to substituted thienyl-mercaptoketones, their preparation and pharmaceutical compositions containing these compounds for treating diseases associated with histone deacetylase enzymatic activity.
  • DNA is tightly associated with histones to form a compact complex called chromatin.
  • the histones generally highly conserved across eukaryotic species, constitute a family of proteins which are rich in basic amino acids that contact the phosphate groups of DNA.
  • H2A, H2B, H3 and H4 There are different types of histones, including HI, H2A, H2B, H3 and H4.
  • Approximately 146 base pairs of DNA wrap around a histone core to make up a nucleosome particle, the repeating structural motif of chromatin.
  • Histone deacetylases are part of transcriptional corepressor complexes and play key roles in regulating chromatin structure.
  • Three different classes of human HDACs have been defined based on their homology to HDACs found in Saccharomyces cerevisiae.
  • Class I HDACs HDAC1, 2, 3, and 8 are related to the yeast transcriptional regulator RPD3.
  • Class II HDACs HDAC4, 5, 6, 7, 9, and 10 are similar to HDAl, another deacetylase in yeast.
  • Class III HDACs are related to the yeast silencing protein SIR2 and are dependent on NAD for enzymatic activity.
  • HDAC histone deacetylase
  • HATs histone acetyltransferases
  • histone deacetylases have been shown to regulate the activity of non-histone proteins through the modification of their acetylation level.
  • steroid receptors such as estrogen and androgen receptors [Wang et al, J. Biol. Chem. , 276:18375-83 (2001), Gaughan et al, J. Biol. Chem., 277: 25904-13 (2002)] transcription factors such as p53, E2F and myoD [Luo et al, Nature, 408:377-381 (2000); Ito et al, EMBO J, 19:1176-1179 (2001); Sartorelli et al, Mol. Cell, 4:725-734 (1999)], and cytoplasmic proteins such as ⁇ - tubulin [Hubbert et al, Nature, 417:455-458 (2002)].
  • HDAC HDAC-like oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency oxidative deficiency Yoshida and Beppu, Exper. Cell Res. ,177 -.122-131 (1988)]; and (iii) chlamydocin. Synthetic inhibitors include suberoyl anilide hydroxamic acid [Richon et al, Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998)] and phenylbutyrate [Johnstone RW Nat. Rev. Drug Discov., 1 :287-299 (2002)].
  • Trichostatin A has been shown to cause arrest of rat fibroblasts at both Gi and G 2 phases of the cell cycle, implicating HDAC in cell cycle regulation [Yoshida and Beppu, Exper. Cell Res., 177:122-131 (1988)].
  • Trichostatin A and suberoyl anilide hydroxamic acid have been shown to inhibit cell growth, induce terminal differentiation and prevent the formation of tumors in mice [Johnstone RW Nat. Rev. Drug Discov., 1:287-299 (2002)].
  • Trapoxin, trichostatin, and depudecin have been used to study gene regulation by HDAC- mediated chromatin remodeling [Christian A. Hassig, Stuart L. Schreiber, Curr. Opinion in Chem.
  • the present invention provides compounds of formula (I):
  • A represents optionally substituted monocyclic heteroaryl or phenyl
  • B represents optionally substituted heteroaryl, aryl, aryl-fused-heterocycloalkyl, heteroaryl-fused-cycloalkyl, heteroaryl-fused-heterocycloalkyl or aryl-fused-cycloalkyl, or B represents H when L represents a single bond;
  • L represents a single bond, alkylene, (CH 2 ) n X(CH 2 ) m; (CH 2 ) n X(CH 2 ) p Y(CH 2 ) m ;
  • X represents -O-, -NR 3 -, -CO-, -SO 2 -, -NR 3 CO-, -NR 3 SO 2 -, -CONR 3 -, -SO 2 NR 3 -, -NR 5 CONR 5a -;
  • Y represents -NR 3 - or -O-
  • R 1 represents H, COR 8 ;
  • R 2 represents halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, CN;
  • R represents H, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, or alkyl substituted by -OR 4 , -NR 5 R 6 , -NR 6 COR 7 , -NR 6 SO 2 R 7 , -CONR 5 R 6 or -SO 2 NR 5 R 6 ;
  • R 4 represents H, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl;
  • R 5 and R 5a represent H or alkyl;
  • R 6 represents H, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, heteroaryl, heterocycloalkyl or cycloalkyl
  • NR 5 R represents a cyclic amine
  • R 7 represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  • R 8 represents alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  • a second aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a disulphide, N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with a pharmaceutically acceptable carrier or excipient.
  • a third aspect of the invention is a compound of formula (I) or a disulphide, N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof for use in therapy.
  • a fourth aspect of the invention is the use of a compound of formula (I), or a disulphide, N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of a disease in which inhibition of histone deacetylase can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease.
  • a fifth aspect of the invention is a method for treating a disease in a patient in which inhibition of histone deacetylase can prevent, inhibit or ameliorate the pathology and/or symptomatology of the disease, which method comprises administering to the patient a therapeutically effective amount of compound of formula ⁇ ) or a disulphide, N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof.
  • a sixth aspect of the invention is a method of inhibiting histone deacetylase in a cell, comprising contacting a cell in which inhibition of histone deacetylase is desired with a compound of formula (I) or a disulphide, N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof.
  • a seventh aspect of the invention is a method of preparing a compound of formula (I) or a disulphide, N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof.
  • An eighth aspect of the invention is a method of making a pharmaceutical composition
  • a pharmaceutical composition comprising combining a compound of formula (I), or a disulphide, N-oxide, pharmaceutically acceptable salt, solvate or prodrug thereof, with a pharmaceutically acceptable carrier or excipient.
  • Histone deacetylase and "HDAC” are intended to refer to any one of a family of enzymes that remove acetyl groups from lysine residues of proteins including, but not limited to, histones, transcription factors, steroid receptors and tubulin. Unless otherwise indicated the term histone is meant to refer to any histone protein, including HI, H2A, H2B, H3, H4 and H5 from any species.
  • the histone deacetylase is a human HDAC, including, but not limited to, HDAC-1, HDAC-2, HDAC- 3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, and HDAC-10.
  • the histone deacetylase is derived from a protozoal or fungal source.
  • Patient includes both human and other mammals.
  • acyl means a -CO-alkyl group in which the alkyl group is as described herein.
  • exemplary acyl groups include -COCH 3 and -COCH(CH 3 ) .
  • acylamino means a -NR-acyl group in which R and acyl are as described herein.
  • exemplary acylamino groups include -NHCOCH 3 and -N(CH 3 )COCH 3 .
  • Alkoxy and “alkyloxy” means an -O-alkyl group in which alkyl is as defined below.
  • exemplary alkoxy groups include methoxy and ethoxy.
  • Alkoxycarbonyl means a -COO-alkyl group in which alkyl is as defined below.
  • exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • Alkyl as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably 1 to 6, carbon atoms, in the chain.
  • exemplary alkyl groups include methyl, ethyl, 1-propyl and 2-propyl.
  • Alkylamino means a -NH-alkyl group in which alkyl is as defined above.
  • exemplary alkylamino groups include methylamino and ethylamino.
  • Alkylene means an -alkyl- group in which alkyl is as defined previously.
  • exemplary alkylene groups include -CH 2 ⁇ , -(CH 2 ) 2 and -C(CH 3 )HCH 2 -.
  • Alkylsufinyl means a -SO-alkyl group in which alkyl is as defined above.
  • Exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl.
  • Alkylsufonyl means a -SO2-alkyl group in which alkyl is as defined above.
  • exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl.
  • Alkylthio means a -S-alkyl group in which alkyl is as defined above.
  • exemplary alkylthio groups include methylthio and ethylthio.
  • aminoacyl means a -CO-NRR group in which R is as herein described.
  • exemplary aminoacyl groups include -CONH 2 and -CONHCH 3 .
  • Aminoalkyl means an alkyl-NH 2 group in which alkyl is as previously described.
  • exemplary aminoalkyl groups include -CH NH 2 .
  • aminosulfonyl means a -SO -NRR group in which R is as herein described.
  • exemplary aminosulfonyl groups include -SO 2 NH and -SO 2 NHCH 3 .
  • Aryl as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms, such as phenyl or naphthyl, and in one embodiment preferably phenyl.
  • the aryl group may be substituted by one or more substituent groups.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Cj_4 alkyl moiety. Exemplary arylalkyl groups include benzyl, phenethyl and naphfhlenemethyl.
  • Arylalkyloxy means an aryl-alkyloxy- group in which the aryl and alkyloxy moieties are as previously described. Preferred arylalkyloxy groups contain a Cj_4 alkyl moiety. Exemplary arylalkyl groups include benzyloxy.
  • Aryl-fused-cycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein.
  • Exemplary aryl- fused-cycloalkyl groups include tetrahydronaphthyl and indanyl.
  • the aryl and cycloalkyl rings may each be sustitued by one or more substituent groups.
  • the aryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula (I) by any available carbon atom.
  • Aryl-fused-heterocycloalkyl means a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein.
  • Exemplary aryl-fused-heterocycloalkyl groups include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl.
  • the aryl and heterocycloalkyl rings may each be sustitued by one or more substituent groups.
  • the aryl- fused-heterocycloalkyl group may be attached to the remainder of the compound of formula (I) by any available carbon or nitrogen atom.
  • Aryloxy means an -O-aryl group in which aryl is described above.
  • Exemplary aryloxy groups include phenoxy.
  • Cyclic amine means an optionally substituted 3 to 8 membered monocyclic cycloalkyl ring system where one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR (where R is as described herein).
  • Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine.
  • the cyclic amine group may be substituted by one or more substituent groups.
  • Cycloalkyl means an optionally substituted saturated monocyclic or bicyclic ring system of from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms, and more preferably from 3 to 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkyl group may be substituted by one or more substituent groups.
  • Cycloalkylalkyl means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described.
  • Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmefhyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Dialkylamino means a -N(alkyl)2 group in which alkyl is as defined above. Exemplary dialkylamino groups include dimethylamino and diethylamino.
  • Disulphide means a compound of type R*-S-S-R* in which R*SH represents a compound of formula (I) .
  • Halo or halogen means fluoro, chloro, bromo, or iodo. Preferred are fluoro or chloro.
  • Haloalkoxy means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms.
  • exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy.
  • Haloalkyl means an alkyl group which is substituted by one or more halo atoms.
  • exemplary haloalkyl groups include trifluoromethyl.
  • Heteroaryl as a group or part of a group denotes an optionally substituted aromatic monocyclic or multicyclic organic moiety of from 5 to 14 ring atoms, preferably from 5 to 10 ring atoms, in which one or more of the ring atoms is/are element(s) other than carbon, for example nitrogen, oxygen or sulfur.
  • Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazmyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1,3,4-thiadiazolyl, fhiazolyl, thienyl and triazolyl groups.
  • the heteroaryl group may be substituted by one or more substituent groups.
  • the heteroaryl group may be attached to the remainder of the compound of formula (I) by any available carbon or nitrogen atom.
  • Heteroarylalkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • Heteroarylalkyloxy means a heteroaryl-alkyloxy- group in which the heteroaryl and alkyloxy moieties are as previously described. Preferred heteroarylalkyloxy groups contain a lower alkyl moiety. Exemplary heteroarylalkyloxy groups include pyridylmethyloxy.
  • Heteroaryloxy means a heteroaryloxy- group in which the heteroaryl is as previously described.
  • exemplary heteroaryloxy groups include pyridyloxy.
  • Heteroaryl-fused-cycloalkyl means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a cycloalkyl group, in which heteroaryl and cycloalkyl are as previously described.
  • Exemplary heteroaryl-fused-cycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl.
  • the heteroaryl and cycloalkyl rings may each be sustitued by one or more substituent groups.
  • the heteroaryl-fused-cycloalkyl group may be attached to the remainder of the compound of formula (I) by any available carbon or nitrogen atom.
  • Heteroaryl-fused-heterocycloalkyl means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which heteroaryl and heterocycloalkyl are as previously described.
  • Exemplary heteroaryl-fused-heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyridinyl and dioxolopyridinyl.
  • the heteroaryl and heterocycloalkyl rings may each be sustitued by one or more substituents groups.
  • the heteroaryl-fused-heterocycloalkyl group may be attached to the remainder of the compound of formula (I) by any available carbon or nitrogen atom.
  • Heterocycloalkyl means: (i) an optionally substituted cycloalkyl group of from 4 to 8 ring members which contains one or more heteroatoms selected from O, S or NR; (ii) a cycloalkyl group of from 4 to 8 ring members which contains CONR and CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl).
  • the heterocycloalkyl group may be substituted by one or more substituent groups.
  • the heterocycloalkyl group may be attached to the remainder of the compound of formula (I) by any available carbon or nitrogen atom.
  • Heterocycloalkylalkyl means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 4 carbon atoms in the chain, i.e. methyl, ethyl, propyl ("propyl or 'propyl) or butyl (“butyl, "butyl or ⁇ utyl).
  • R means hydrogen, alkyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heteroaryl or aryl.
  • Sulfonyl means a -SO 2 -alkyl group in which alkyl is as described herein.
  • exemplary sulfonyl groups include methanesulfonyl.
  • “Sulfonylamino” means a -NR-sulfonyl group in which R and sulfonyl are as described herein.
  • Exemplary sulfonylamino groups include -NHSO 2 CH 3 .
  • “Pharmaceutically acceptable salt” means a physiologically or toxicologically tolerable salt and include, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts.
  • pharmaceutically acceptable base addition salts that may be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g.
  • a compound of the invention contains a basic group, such as an amino group
  • pharmaceutically acceptable acid addition salts that may be formed include hydrochlorides, hydrobromides, phosphates, acetates, citrates, lactates, tartrates, malonates, mefhanesulphonates and the like.
  • Prodrug means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis, reduction or oxidation) to a compound of formula (I).
  • metabolic means e.g. by hydrolysis, reduction or oxidation
  • an ester prodrug of a compound of formula (I) containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule.
  • Suitable esters of compounds of formula (I) containing a hydroxy group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gentisates, isethionates, di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates, p-toluenesulphonates, cyclohexylsulphamates and quinates.
  • ester prodrug of a compound of formula (I) containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule [Examples of ester prodrugs are those described by F. J. Leinweber, Drug Metab. Res., 18:379 (1987)].
  • “Saturated” pertains to compounds and/or groups which do not have any carbon-carbon double bonds or carbon-carbon triple bonds.
  • cyclic groups referred to above namely, aryl, heteroaryl, cycloalkyl, aryl-fused- cycloalkyl, heteroaryl-fused-cycloalkyl, heterocycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl-fused-heterocycloalkyl and cyclic amine may be substituted by one or more substituent groups.
  • Suitable optional substituent groups include acyl (e.g. -COCH3), alkoxy (e,g, -OCH3), alkoxycarbonyl (e.g. -COOCH3), alkylamino (e.g.
  • alkylsulfmyl e.g. -SOCH3
  • alkylsulfonyl e.g. -SO 2 CH 3
  • alkylthio e.g. -SCH3
  • -NH 2 aminoalkyl (e.g. -CH2NH2)
  • arylalkyl e.g. -CH 2 Ph or -CH 2 -CH 2 -Ph
  • cyano dialkylamino (e.g. -N(CH3)2)
  • halo haloalkoxy
  • haloalkyl e.g.
  • alkyl e.g. -CH 3 or -CH2CH3
  • alkyl e.g. -CH 3 or -CH2CH3
  • -OH e.g. -CHO
  • -NO 2 aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl
  • aminoacyl e.g. - CONH 2 , -CONHCH 3
  • aminosulfonyl e.g. -SO 2 NH 2 , -SO 2 NHCH 3
  • acylamino e.g.
  • -NHCOCH 3 sulfonylamino
  • sulfonylamino e.g. -NHSO CH 3
  • heteroarylalkyl e.g. cyclic amine (e.g. morpholine)
  • aryloxy, heteroaryloxy, arylalkyloxy e.g. benzyloxy
  • heteroarylalkyloxy e.g. benzyloxy
  • Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and eso-forms, keto-, and enol-forms.
  • a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof.
  • such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques).
  • such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).
  • the group A is a monocyclic heteroaryl group, preferably containing 5 or 6 ring atoms.
  • the heteroatom(s) is/are selected from N, O and S atoms, and preferably from N atom(s).
  • A is selected from monocyclic heteroaryl groups containing 5 or 6 ring atoms including one or two nitrogen heteroatoms.
  • A is selected from pyrazolyl, imidazolyl, pyridinyl and pyrimidmyl.
  • A is selected from pyrazolyl, pyridinyl and pyrimidinyl.
  • the group A may be substituted or unsubstituted, and in one embodiment, A is unsubstituted. In an alternative embodiment, A is substituted and in this embodiment one or two substituent groups may be present.
  • the substituent groups are preferably selected from alkyl, alkoxy, haloalkyl, haloalkoxy, halogen and CN.
  • A is selected from pyrazolyl, imidazolyl, pyridinyl and pyrimidinyl optionally substituted with a substituent chosen from alkyl, alkoxy, haloalkyl, haloalkoxy, halogen and CN.
  • R 3 is selected from H or alkyl.
  • R 4 is selected from H or alkyl.
  • R is selected from alkyl.
  • R is selected from H and alkyl.
  • R 7 is selected from alkyl and aryl, particularly alkyl.
  • R 8 is selected from alkyl and aryl, particularly alkyl.
  • L represents a single bond
  • B represents heteroaryl and aryl.
  • the group B is selected from aryl and aryl-fused-heterocycloalkyl, particularly wherein said aryl is phenyl.
  • the aryl may be optionally substituted, preferably by one or two substituent groups.
  • Preferred substituent groups include halo, haloalkyl, alkoxy and acylamino.
  • n is 0, 1 or 2; in a further embodiment n is 0 or 1 ; and in a further embodiment n is 1.
  • m is 2 or 3.
  • m is 1 or 2.
  • m is 2.
  • p is 0, 1 or 2; in a further embodiment p is 0 or 1; and in a further embodiment p is 0.
  • the present invention provides compounds that inhibit HDAC activity according to the tests described in the literature and in the Biological Activity section of this document.
  • the therapeutic application of these compounds is pertinent to any disease that is known to be at least in part mediated by HDAC activity or whose symptoms are known to be alleviated by HDAC inhibitors (such as Trichostatin-A, suberoyl anilide hydroxamic acid, Trapoxin and depudecin).
  • HDAC inhibitors such as Trichostatin-A, suberoyl anilide hydroxamic acid, Trapoxin and depudecin.
  • these compounds could be beneficial for the treatment of cancer, psoriasis, fibroproliferative disorders (e.g. liver fibrosis), smooth muscle cell proliferation disorders (e.g.
  • immune modulation e.g. rheumatoid arthritis, autoimmune diabetes, lupus
  • the present invention is intended for the treatment of diseases caused by increased cell proliferation.
  • diseases caused by increased cell proliferation include, but are not limited to, primary and metastatic cancers of different origin (including those triggered by viral infections such as EBN, HIN, hepatitis B and C and KSHV), fibrosis of the liver, lung, kidney, heart and skin caused by myofibroblasts proliferation and increased production of extracellular matrix proteins [ ⁇ iki et al, Hepatology, 29:858-67 (1999)], inflammatory diseases and cardiomyocyte hypertrophy [Lu et al, P ⁇ AS, 97: 4070-4075 (2000)].
  • the invention is also aimed at the treatment of protozoal infections including, but not limited to, malaria, toxoplasmosis and coccidiosis.
  • the invention is aimed at the treatment of diseases caused by expanded polyglutamine repeats resulting in histone hypoacetylation including, but not limited to, neurodegenerative disorders such as Huntington's disease.
  • the compounds of formula (I) may be used or administered in combination with one or more additional drug(s) and/or procedures (such as radiotherapy in the case of cancer) useful in the treatment of the disorders mentioned above, the components being in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • the additional drug(s) may or may not be HDAC inhbitors.
  • the thienyl-mercaptoketones of the present invention may be prepared, for example, by the application or adaptation of methods described herein. They may also be prepared by known organic synthesis methods for example those described by R. C. Larock in Comprehensive Organic Transformations, NCH publishers, 1989. They may also be prepared by appropriate adaptation of any of the methods described in US patent 5,840,698 or those described by Campbell et al, Bioorg. Med. Chem. Lett. 1998, 8, 1157-1162 or Levin et al Bioorg. Med. Chem Lett. 1998, 8, 1163-1168.
  • Another method for the preparation of compounds of formula (I) or formula (II) involves the reaction of a compound of formula (IV) with an appropriate thiol, HSR 1 or HSR a .
  • X represents a suitable leaving group, such as a halogen, particularly bromine.
  • Compounds of formula (III) may be prepared by hydrolysis of compounds of formula (V) in which R b is a suitable protecting group, such as methyl or ethyl.
  • the hydrolysis may be carried out using a suitable base such as sodium hydroxide, in a protic solvent such as ethanol, at an appropriate temperature, such as ambient temperature.
  • a suitable base such as sodium hydroxide
  • a protic solvent such as ethanol
  • An alternative method for the preparation of compounds of (III) involves the hydrolysis of compounds of formula (VI).
  • the hydrolysis may be carried out using a suitable base, such as sodium hydroxide, in a protic solvent such as ethanol, at an appropriate temperature, such as the reflux temperature of the solvent.
  • hal means chloro, bromo or iodo.
  • a compound of formula (Nil) can be converted into a compound of formula (III) by any suitable method known to those skilled in the art, including the use of a palladium catalysed carbonylation reaction, or a halogen/lithium exchange followed by quenching with carbon dioxide.
  • the carbonylation reaction can be carried out using carbon monoxide in the presence of a suitable catalyst, such as bis(triphenylphosphine) palladium chloride and a suitable base, such as triethylamine in appropriate solvent(s), such as methanol and water.
  • the reaction may be carried out at any appropriate temperature and pressure, such as a temperature of HO C and a pressure of 10 bar.
  • the halogen/lithium exchange reaction may be carried out in the presence of a suitable lithium base, such as "butyl lithium, in an appropriate solvent such as tetrahydrofuran, at an appropriate temperature such as 0°C.
  • Compounds of formula (VI) may be prepared from compounds of formula (VI) by reaction with zinc cyanide in the presence of a palladium (0) catalyst, for example tetrakis (triphenylphospine)palladium (0), in an inert solvent, for example NN- dimethylfomiamide, at temperatures from about room temperature up to reflux temperature.
  • a palladium (0) catalyst for example tetrakis (triphenylphospine)palladium (0)
  • an inert solvent for example NN- dimethylfomiamide
  • Compounds of formula (IN) may be prepared from compounds of formula (NIII) by the use of suitable halogenating conditions.
  • suitable conditions for the preparation of compounds of formula (IN) in which X is bromine include the use of bromine or ⁇ - bromosuccinimide in a suitable solvent, such as acetonitrile.
  • Compounds of formula (VIII) can be prepared from compounds of formula (III) using any suitable method known to those skilled in the art. For eaxample, a compound of formula (III) can be converted in the corresponding Weinreb amide, which can then be treated with methylmagnesium bromide to provide a compound of formula (VIII).
  • Compounds of formula (VII) may be prepared from compounds of formula (IX) by reaction with an appropriate halogenating agent, such as bromine, iodine, N- chlorosuccini ide, iV-bromosuccinimide, or N-iodosuccinimide, in an approriate solvent, such as dichloromethane.
  • an appropriate halogenating agent such as bromine, iodine, N- chlorosuccini ide, iV-bromosuccinimide, or N-iodosuccinimide
  • Compounds of formula (V) may be prepared from compounds of formula (X), in which R c represents hydrogen, lower alkyl, or -B(OR c ) 2 represents a cyclic boronate ester, and a compound of formula (XI), in which "hal" and R are as previously defined.
  • the reaction may be performed in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), and a suitable base, such as cesium carbonate, in an appropriate solvent such as NN-dimethylformamide, at a suitable temperature, such as an elevated temperature, such as 80°C.
  • compounds of formula (III) may be prepared from compounds of formula (XII) and a compound of formula (X), and compounds of formula (VI) can be prepared starting from compounds of formula (XIII).
  • An alternative method for the preparation of compounds of formula (V) involves the reaction of a compound of formula (XIV), in which hal is as previously defined, with a compound of formula (XV) in which R b and R c are as previously defined.
  • the reaction may be performed in the presence of a suitable catalyst, such as tetrakis(triphenylphosphine)palladium (0), and a suitable base, such as cesium carbonate, in an appropriate solvent such as NN-dimethylformamide, at a suitable temperature, such as an elevated temperature, such as 80°C.
  • compounds of formula (III) may be prepared from compounds of formula (XVI) and a compound of formula (XIV), and compounds of formula (VI) can be prepared starting from compounds of formula (XVII).
  • Compounds of formula (XV), (XNI) and (XVII) may be commercially available, or may be prepared from compounds of formula (XI), (XII) or (XIII) respectively by conversion to a suitable organometallic reagent, such as a lithium or magnesium reagent and subsequent treatment with a suitable boron reagent, such as trimethylborate.
  • a suitable organometallic reagent such as a lithium or magnesium reagent
  • boron reagent such as trimethylborate
  • compounds of formula (XI), (XII) or (XIII) may be treated with a suitable boron reagent, such as bis(pinacolato)diboron, in the presence of a suitable catalyst, such as [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium, and a suitable base, such as potassium acetate, in an appropriate solvent, such as dioxane, at a suitable temperature, for example room temperature to the reflux temperature of the solvent.
  • a suitable boron reagent such as bis(pinacolato)diboron
  • a suitable catalyst such as [1,1 '- bis(diphenylphosphino)ferrocene]dichloropalladium
  • a suitable base such as potassium acetate
  • Compounds of formula (X) may be prepared from compounds of formula (XIV) using the procedures described above for the conversion of compounds of formula (XI), (XII) or (XIII) into compounds of formula (XV), (XVI) and (XVII).
  • primary amine (-NH2) groups may be alkylated using a reductive alkylation process employing an aldehyde or a ketone and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example 1,2-dichloroethane, or an alcohol such as ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • Secondary amine (-NH-) groups may be similarly alkylated employing an aldehyde.
  • primary amine or secondary amine groups may be converted into amide groups (-NHCOR' or -NRCOR') by acylation.
  • Acylation may be achieved by reaction with an appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reaction with an appropriate carboxylic acid in the presence of a suitable coupling agent such HATU (0-(7- azabenzotriazol-l-yl)-NNN',N'-tetramethyluronium hexafluorophosphate) in a suitable solvent such as dichloromethane.
  • a suitable coupling agent such as HATU (0-(7- azabenzotriazol-l-yl)-NNN',N'-tetramethyluronium hexafluorophosphate
  • amine groups may be converted into sulphonamide groups (- ⁇ HSO 2 R' or -NR"SO 2 R') groups by reaction with an appropriate sulphonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent such as dichloromethane.
  • Primary or secondary amine groups can be converted into urea groups (-NHCONR'R" or -NRCONR'R”) by reaction with an appropriate isocyanate in the presence of a suitable base such as triethylamine, in a suitable solvent, such as dichloromethane.
  • An a ine (-NH 2 ) may be obtained by reduction of a nitro f-NO 2 ) group, for example by catalytic hydrogenation, using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • a metal catalyst for example palladium on a support such as carbon in a solvent such as ethyl acetate or an alcohol e.g. methanol.
  • the transformation may be carried out by chemical reduction using for example a metal, e.g. tin or iron, in the presence of an acid such as hydrochloric acid.
  • amine (-CH 2 NH 2 ) groups may be obtained by reduction of nitriles (- CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support such as carbon, or Raney nickel, in a solvent such as an ether e.g. a cyclic ether such as tetrahydrofuran, at a temperature from -78°C to the reflux temperature of the solvent.
  • a metal catalyst for example palladium on a support such as carbon, or Raney nickel
  • Aldehyde groups may be converted to amine groups (-CH 2 NR'R")) by reductive amination employing an amine and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as ethanol, where necessary in the presence of an acid such as acetic acid at around ambient temperature.
  • a borohydride for example sodium triacetoxyborohydride or sodium cyanoborohydride
  • a solvent such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol such as ethanol
  • Aldehyde groups may be obtained by reduction of ester groups (such as -CO 2 Et) or nitriles (-CN) using diisobutylaluminium hydride in a suitable solvent such as toluene.
  • ester groups such as -CO 2 Et
  • -CN nitriles
  • aldehyde groups may be obtained by the oxidation of alcohol groups using any suitable oxidising agent known to those skilled in the art.
  • Ester groups (-CO 2 R') may be converted into the corresponding acid group (-CO 2 H) by acid- or base-catalused hydrolysis, depending on the nature of R. If R is t-butyl, acid- catalysed hydrolysis can be achieved for example by treatment with an organic acid such as trifluoroacetic acid in an aqueous solvent, or by treatment with an inorganic acid such as hydrochloric acid in an aqueous solvent.
  • Carboxylic acid groups may be converted into amides (-CONHR' or -CONR'R”) by reaction with an appropriate amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent such as dichloromethane.
  • a suitable coupling agent such as HATU
  • carboxylic acids may be homologated by one carbon (i.e -CO 2 H to - CH CO 2 H) by conversion to the corresponding acid chloride (-COC1) followed by Arndt- Eistert synthesis.
  • -OH groups may be generated from the corresponding ester (e.g. - CO 2 R'), or aldehyde (-CHO) by reduction, using for example a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • a complex metal hydride such as lithium aluminium hydride in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent such as methanol.
  • an alcohol may be prepared by reduction of the corresponding acid (-CO 2 H), using for example lithium aluminium hydride in a solvent such as tetrahydrofuran, or by using borane in a solvent such as tetrahydrofuran.
  • Alcohol groups may be converted into leaving groups, such as halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. -toluenesulfonyloxy group using conditions known to those skilled in the art.
  • halogen atoms or sulfonyloxy groups such as an alkylsulfonyloxy, e.g. trifluoromethylsulfonyloxy or arylsulfonyloxy, e.g. -toluenesulfonyloxy group
  • an alcohol may be reacted with thionyl chloride in a halogenated hydrocarbon (e.g. dichloromethane) to yield the corresponding chloride.
  • a base e.g. triethylamine
  • alcohol or phenol groups may be converted to ether groups by coupling a phenol with an alcohol in a solvent such as tetrahydrofuran in the presence of a phosphine, e.g. triphenylphosphine and an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • a phosphine e.g. triphenylphosphine
  • an activator such as diethyl-, diisopropyl, or dimethylazodicarboxylate.
  • ether groups may be" prepared by deprotonation of an alcohol, using a suitable base e.g. sodium hydride followed by subsequent addition of an alkylating agent, such as an alkyl halide.
  • Aromatic halogen substituents in the compounds may be subjected to halogen-metal exchange by treatment with a base, for example a lithium base such as "butyl or 'butyl lithium, optionally at a low temperature, e.g. around — 78°C, in a solvent such as tetrahydrofuran, and then quenched with an electrophile to introduce a desired substituent.
  • a base for example a lithium base such as "butyl or 'butyl lithium
  • a solvent such as tetrahydrofuran
  • an electrophile to introduce a desired substituent.
  • a formyl group may be introduced by using NN-dimethylformamide as the electrophile.
  • Aromatic halogen substituents may alternatively be subjected to metal (e.g.
  • Aromatic halogen substituents may also undergo nucleophilic displacement following reaction with an appropriate nucleophile such as an amine or an alcohol.
  • an appropriate nucleophile such as an amine or an alcohol.
  • such a reaction may be carried out at elevated temperature in the presence of microwave irradiation.
  • compounds of formula (I) in which A is heteroaryl containing an N-oxide group may be prepared by oxidation of compounds of formula (I) in which A is the corresponding non-oxidised heteroaryl.
  • Compounds of formula (VI) in which A represents a 3 -pyrazolyl may be prepared from the compound of formula (XX) by treatment with a hydrazine of formula (XXI), in which R represents H, BL-, or a group convertible to BL-, in a suitable solvent, such as a protic solvent, for example ethanol, at an appropriate temperature.
  • a suitable solvent such as a protic solvent, for example ethanol
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) transdermal or rectal administration or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • wetting agents
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • the active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form (e.g. in ampoules or in multi-dose containers, with an added preservative).
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, (e.g. sterile pyrogen-free water), before use.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • the active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, (e.g. containing conventional suppository bases such as cocoa butter or other glycerides).
  • the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, (e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas).
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • a proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above is 0.1 to 500 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
  • Method A Experiments performed on a Finnigan TSQ700 spectrometer with positive ion electrospray and single wavelength UV 254 nm detection using a Higgins Clipeus C18 5 ⁇ m 100 x 3.0 mm column and a 2 ml / minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system was held constant for a further 2 minutes.
  • Method B Experiments performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/Diode array detection using a Phenomenex Luna C18 (2) 30 x 4.6 mm column and a 2 ml / minute flow rate.
  • the solvent system was 95%» solvent A and 5% solvent B for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 0.50 minutes.
  • the reaction was quenched after 15 minutes by diluting with diethyl ether (100 mL) and pouring the reaction mixture into an aqueous solution of 5% Na 2 SO 3 /5% NaHCO (1:1), (250 mL).
  • the resulting mixture was extracted into dichloromethane (3 X 200 mL) and the combined organic extracts were filtered and concentrated in vacuo.
  • Crude bromoketone was used immediately and was therefore dissolved in THF (25 mL) and treated with Et 3 N (1.44 mL, 10.40 mmol) and thiolacetic acid (0.77 mL, 8.9 mmol) and stirred for 30 minutes at room temperature.
  • Reference example 1 1 -f 5 - ( 5 - [(Benzyl-methyl-aminol-methyl] -pyridin-2-yl ⁇ -thiophen-2-yl)-ethanone
  • Compounds are tested for their capacity to inhibit histone deacetylase activity (primary assay) and for their biological effects on growing cells (secondary assay).
  • Total lysates from K562 chronic human myelogenous leukemia cells are used as source of HDAC activity.
  • Cells are grown in RPMI media supplied with 10% FCS, harvested by centrifugation, washed once in PBS and resuspended at a density of 24xl0°7ml in HDA buffer (15mM Potassium phosphate pH 7.5, 5% glycerol, 0.2mM EDTA). After sonication, lysates are centrifuged at lOOOg for 20 minutes and the resulting supernatant is aliquoted and stored at -80°C.
  • commercially available HeLa nuclear extracts are used as source of histone deacetylase activity.
  • the assay was carried out for 30 minutes using 116 ⁇ M of a fluorescent substrate containing an acetylated lysine residue (BIOMOL).
  • a fluorescent substrate containing an acetylated lysine residue (BIOMOL).
  • the substrate can react with the added developer producing a fluorophore.
  • the amount of fluorophore produced is proportional to the HDAC activity in the sample and is quantified using a multiwell fluorimeter capable of excitation at 360nm and detection at 450nm.
  • Compounds are diluted in DMSO prior to addition to assay buffer, the final DMSO concentration in the assay being 1%.
  • the percent activity of the compounds in reducing histone deacetylase enzymatic activity is calculated as follows:
  • F s is the fluorescence at 450nm in the presence of the tested compound (Sample).
  • F c is the fluorescence at 450nm in the presence of vehicle 1 % DMSO (Control).
  • B is the fluorescence at 450nm in the absence of enzyme (Background fluorescence)
  • the IC 50 is defined as the concentration at which a given compound achieves 50% activity. IC 50 values are calculated using the XLfit software package (version 2.0.5).
  • MDA-MB-231 human mammary gland adenocarcinoma (ATCC) Both cell lines are free of Mycoplasma contamination (PCR Mycoplasma Detection Set, Takara).
  • MCF-7 are kept in MEM medium (Gibco) supplemented with 10% FCS and 1% Non Essential Amino Acids at 37°C in a 5% CO 2 humidified incubator.
  • MDA-MB-231 are kept in L-15 (Leibovitz) medium (Gibco) supplemented with 15% FCS at 37°C in a non-modified atmosphere, humidified incubator.
  • Cells are seeded in 96-well plates at a density of 20,000 cells/ml (3,000 cells/well) and after 24h they are exposed to different concentrations of compounds in 0.1% DMSO. Cells are grown for a further 72h, the media is removed and the cells are frozen at -80°C for at least 30 minutes and lysed in a solution containing the CyQUANT dye.
  • This is a fluorescent molecule that specifically binds nucleic acids and whose fluorescence is greatly enhanced upon binding nucleic acids. Therefore the fluorescence intensity is proportional to the number of cells present in each well and can be quantified using a multiwell fluorimeter by measuring the fluorescence of the solution at 520nm.
  • the percent activity of the compounds in reducing cell number is calculated as follows:
  • % activity ⁇ (A s - B) / (A c - B) ⁇ x 100
  • a s is the fluorescence at 520nm in the presence of the tested compound (Sample).
  • a c is the fluorescence at 520nm in the presence of vehicle 0.1% DMSO (Control).
  • B is the fluorescence at 520nm in the absence of cells (Background fluorescence).
  • IC 5 o is defined as the concentration at which a given compound achieves 50% activity.
  • IC 50 values are calculated using the XLfit software package (version 2.0.5).

Abstract

L'invention concerne un composé de la formule (I), dans laquelle A représente un hétéroaryle monocyclique facultativement substitué ou phényle, B représente hétéroaryle facultativement substitué, aryle, hétérocycloalkyle fusionné avec aryle, cycloalkyle fusionné avec hétéroaryle, hétérocycloalkyle fusionné avec hétéroaryle, ou cycloalkyle fusionné avec aryle, ou B représente H lorsque L représente une liaison unique; L représente une liaison unique, alkylène, (CH2)nX(CH2)m, (CH2)nX(CH2)pY(CH2)m; X représente -O-, -NR3-, -CO-, -SO2-, -NR3CO-, -NR3SO2-, -CONR3-, -SO2NR3-, -NR5CONR5a-; Y représente NR3- ou -O-; R1 représente H, COR8; R2 représente halogène, alkyle, haloalkyle, alkoxy, haloalkoxy, CN; R3 représente H, alkyle, arylalkyle, hétéroarylalkyle, hétérocycloalkylalkyle, cycloalkylalkyle, ou alkyle substitué par -OR4, -NR5R6, -NR6COR7, -NR6SO2R7, -CONR5R6 ou -SO2NR5R6; R4 représente H, alkyle, arylalkyle, hétéroarylalkyle, hétérocycloalkylalkyle, cycloalkylalkyle, aryle, hétéroaryle, hétérocycloalkyle ou cycloalkyle; R5 et R5a représentent H ou alkyle; R6 représente H, alkyle, arylalkyle, hétéroarylalkyle, hétérocycloalkylalkyle, cycloalkylalkyle, aryle, hétéroaryle, hétérocycloalkyle ou cycloalkyle ou NR5R6 représente une amine cyclique ; R7 représente alkyle, aryle, hétéroaryle, cycloalkyle, hétérocycloalkyle, arylalkyle, hétéroarylalkyle, cycloalkylalkyle ou hétérocycloalkylalkyle; R8 représente alkyle, aryle, hétéroaryle, cycloalkyle, hétérocycloalkyle, arylalkyle, hétéroarylalkyle, cycloalkylalkyle ou hétérocycloalkylalkyle ; n représente 0-3; m représente 0-3; p représente 1-3; et des disulfures correspondants, N-oxydes, des sels pharmaceutiquement acceptables, des solvants et des promédicaments de ceux-ci. L'invention porte aussi sur l'utilisation de ce composé dans le traitement d'une maladie grâce auquel l'inhibition d'histone déacétylase permet d'empêcher, d'inhiber ou d'améliorer la pathologie ou la symptomatologie de la maladie.
PCT/GB2005/000283 2004-02-03 2005-01-27 Thienyl-mercaptoketones substitues, et utilisation associee pour le traitement de maladies liees a l'activite enzymatique d'histone deacetylase WO2005075466A1 (fr)

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Cited By (3)

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Publication number Priority date Publication date Assignee Title
WO2007067994A1 (fr) * 2005-12-09 2007-06-14 Kalypsys, Inc. Inhibiteurs de l'histone désacétylase pour le traitement d'une maladie
WO2007067993A1 (fr) * 2005-12-09 2007-06-14 Kalypsys, Inc. Inhibiteurs d'histone desacetylase pour le traitement de maladies
WO2009021155A1 (fr) * 2007-08-09 2009-02-12 Alcon, Inc. Inhibiteurs d'histone désacétylase destinés à traiter les maladies dégénératives de l'oeil

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US4536517A (en) * 1983-04-25 1985-08-20 American Cyanamid Company Method of treating diabetes mellitus using arylglyoxals
WO2002026696A1 (fr) * 2000-09-29 2002-04-04 Prolifix Limited Composes d'acide carbamique comprenant un enchainement amide comme inhibiteurs hdac

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US4536517A (en) * 1983-04-25 1985-08-20 American Cyanamid Company Method of treating diabetes mellitus using arylglyoxals
WO2002026696A1 (fr) * 2000-09-29 2002-04-04 Prolifix Limited Composes d'acide carbamique comprenant un enchainement amide comme inhibiteurs hdac

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007067994A1 (fr) * 2005-12-09 2007-06-14 Kalypsys, Inc. Inhibiteurs de l'histone désacétylase pour le traitement d'une maladie
WO2007067993A1 (fr) * 2005-12-09 2007-06-14 Kalypsys, Inc. Inhibiteurs d'histone desacetylase pour le traitement de maladies
WO2009021155A1 (fr) * 2007-08-09 2009-02-12 Alcon, Inc. Inhibiteurs d'histone désacétylase destinés à traiter les maladies dégénératives de l'oeil

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