WO2007107594A2 - Derives de trifluoroethanone substitues par un heterocycle a six chainons utilises comme inhibiteurs de la histone desacetylase (hdac) - Google Patents

Derives de trifluoroethanone substitues par un heterocycle a six chainons utilises comme inhibiteurs de la histone desacetylase (hdac) Download PDF

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WO2007107594A2
WO2007107594A2 PCT/EP2007/052712 EP2007052712W WO2007107594A2 WO 2007107594 A2 WO2007107594 A2 WO 2007107594A2 EP 2007052712 W EP2007052712 W EP 2007052712W WO 2007107594 A2 WO2007107594 A2 WO 2007107594A2
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independently selected
compound
alkyl
ring containing
optionally substituted
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WO2007107594A3 (fr
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Philip Jones
Jesus Maria Ontoria Ontoria
Carsten Schultz-Fademrecht
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Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • HDAC histone deacetylase
  • the present invention relates to 6 membered heterocycle substituted trifluoroethanone derivatives that are inhibitors of histone deacetylase (HDAC), particularly class II HDAC.
  • HDAC histone deacetylase
  • the compounds of the present invention are useful for treating cellular proliferative diseases, including cancer. Further, the compounds of the present invention are useful for treating neurodegenerative diseases, schizophrenia and stroke among other diseases.
  • nuclear DNA is ordered in a compact complex called chromatin.
  • the core of the complex is an octamer of highly conserved basic proteins called histones.
  • Histones H2A, H2B, H3 and H4 associate and DNA winds around the basic amino acids of the histones interacting with the negatively charged phosphate groups of the DNA.
  • One molecule of histone Hl is associated with each wound core which accommodates approximately 146 bp of DNA.
  • the cores are, in turn, packaged into a compact regular structure with about 200 bp of DNA between each core.
  • HDACs histone deacetylases
  • HATs histone acetyl transferases
  • HDACl 1 shares homologies with both classes, but is at the same time distinct from all the other ten subtypes.
  • HDAC inhibitors HDACi
  • the first generation of HDACi were discovered from cell-based functional assays and only later identified as HDAC class I/II inhibitors. Present HDAC inhibitors are pan-specific or poorly selective.
  • the class Ha HDACs contain a highly conserved C-terminal catalytic domain ( ⁇ 420 amino acids) homologous to yHDAl and an N-terminal domain with no similarity to other proteins.
  • the activity of the class Ha HDACs is regulated at several levels, including tissue-specific gene expression, recruitment of distinct cofactors and nucleocytoplasmic shuttling. Whereas most class I HDACs are ubiquitously expressed, class Ha HDACs are expressed in a restricted number of cell types.
  • HDAC inhibitors cause the induction of differentiation, growth arrest and/or apoptosis in a broad spectrum of transformed cells in culture and tumours in animals, including both haematological cancers and solid tumours. These inhibitory effects are believed to be caused, in part, by accumulation of acetylated proteins, such as nucleosomal histones, which appear to play a major role in regulation of gene transcription.
  • a proposed mechanism for the anti-tumour effects of HDAC inhibitors is that the accumulation of acetylated histones leads to activation (and repression) of the transcription of a select number of genes whose expression causes inhibition of tumour cell growth.
  • HDACs family of HDACs, including the varying functions of different HDACs and the range of HDAC substrates.
  • the development of selective HDAC inhibitors might be important in defining their biological role and potential as therapeutic agents. Clinically, the optimal dose, timing and duration of therapy, as well as the most appropriate agents to combine with HDAC inhibitors, are still to be defined.
  • the compounds of this invention are useful in the inhibition of histone deacetylase, particularly class II histone deacetylase.
  • the compounds are HDAC 4 and 6 inhibitors and may additionally be active against other HDAC subtypes such as HDAC 1 and 3.
  • the present invention provides compounds of formula (I):
  • each of A, B and D is independently N or CH; each of R 1 and R 2 is independently selected from hydrogen, C 2 _ 6 alkenyl, C 2 - 6 alkynyl, C 3 . 8 cycloalkyl, C ⁇ -ioaryl, C 6 -ioarylCi-6alkyl, C ⁇ -ioarylCi-ealkoxy, a 5, 6 or 7 membered saturated or partially saturated ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, or a 7-10 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more
  • each R 4 is halogen; hydroxy; cyano, Ci_ 6 alkyl; C 2 _i 0 alkenyl; C 2 .i 0 alkynyl; haloCi_ 6 alkyl; Ci- ⁇ alkoxy; mercaptoCi- ⁇ alkyl; haloCi- ⁇ alkoxy; Ci. ⁇ alkoxycarbonyl; nitro; N(R a ); N(R a )CON(R a ) 2 ; CON(R a ) 2; ; or a ring which
  • each R b is independently hydrogen, or a ring which is: C 3 _ 7 cycloalkyl; Ce-ioaryl; C 6 -ioarylCi_ 6 alkyl; C ⁇ -ioaryloxyCi.ealkyl; C 6 _i 0 arylcarbonyl; a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S; a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; or a 7-10 membered unsaturated or partially saturated heterocyclic ring containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more groups independently selected from halogen, cyano, Ci- ⁇ alkyl, Ci- ⁇ alkoxy,
  • B and D are both CH and A is N or CH.
  • R 1 is C 3 _ 8 cycloalkyl, C 6 -ioaryl, C 6 -ioarylCi. 6 alkyl, C 6 -ioarylCi_ 6 alkoxy, a 5, 6 or 7 membered saturated or partially saturated ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms, or a 7-10 membered saturated, partially saturated or unsaturated heterocyclic ring containing 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one or more independently selected R 3 groups; and
  • R 2 is hydrogen, C 2 - 6 alkenyl or C 2 -6alkynyl.
  • each of R 1 and R 2 is independently hydrogen, phenyl, benzyl, naphthyl, cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, diazepanyl, tetrahydrofuranyl, morpholinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, thienyl, furyl, pyridinyl, indolyl, quinolinyl, quinoxalinyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzodioxolyl, imidazopyridinyl, dihydrobenzodioxinyl, tetrahydroquinolinyl, tetrahydronaphthalenyl or indazolyl; any of which rings being
  • R 1 is independently phenyl, benzyl, naphthyl, cyclopropyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, diazepanyl, tetrahydrofuranyl, morpholinyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, thienyl, furyl, pyridinyl, indolyl, quinolinyl, quinoxalinyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzotriazolyl, benzodioxolyl, imidazopyridinyl, dihydrobenzodioxinyl, tetrahydroquinolinyl, tetrahydronaphthalenyl or indazolyl; any of which rings being optionally substituted by one or more
  • a particular R group is hydrogen.
  • each of R 1 is an optionally substituted cyclohexyl, phenyl or benzyl.
  • R 1 or R" when R 1 or R" is a ring it is optionally substituted by one, two or three R 3 groups.
  • the ring at R 1 or R 2 is unsubstituted or monosubstituted.
  • R 3 is halogen, S(O) r N(R b ) 2 , C ⁇ -ioaryl or a 6 membered saturated ring containing 1 or 2 heteroatoms independently selected from N, O and S.
  • R b is independently hydrogen, or a 5 membered heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, the ring being optionally substituted by one or more groups.
  • each R b is independently hydrogen, methyl or an optionally substituted isoxazolyl.
  • R b is a ring it is unsubstituted or substituted by one, two or three independently selected groups. More particularly, the ring at R b is disubstituted.
  • a preferred substituent on the R b ring is methyl.
  • R 3 groups are chlorine, phenyl, [(dimethylisoxazolyl)aminosulfonyl and morpholinyl.
  • R 3 groups are chlorine, phenyl, [(3,4-dimethylisoxazol-5-yl)amino]sulfonyl and morpholin-4-yl.
  • R 1 groups are benzyl, chlorobenzyl, phenylcyclohexyl, ⁇ [(dimethylisoxazolyl)amino] sulfonyl ⁇ phenyl and morpholinylphenyl.
  • Specific R 1 groups are benzyl, 4-chlorobenzyl, 4-phenylcyclohexyl, 4- ⁇ [(3,4-dimethylisoxazol-5- yl)amino]sulfonyl ⁇ phenyl and 4-(morpholin-4-yl)phenyl.
  • R 2 is hydrogen
  • Y and R 4 are as defined above.
  • R 1 together with NR 2 forms a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl and azoniaspiro[4.4]nonane; any of which rings being optionally substituted by one or more groups independently selected from Y-R 4 .
  • R 1 together with NR 2 forms a ring as attached to the A, B and D containing 6 membered ring selected from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 1 ,4-diazepan- 1-yl and 7-aza-2-azoniaspiro[4.4]nonane; any of which rings being optionally substituted by one or more groups independently selected from Y-R 4 .
  • 6 membered ring selected from azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 1 ,4-diazepan- 1-yl and 7-aza-2-azoniaspiro[4.4]nonane; any of which rings being optionally substituted by one or more groups independently selected from Y-R 4 .
  • R 1 together with NR 2 forms a ring which is optionally substituted by one, two or three groups independently selected from Y-R 4 .
  • the ring is monosubstituted or disubstituted.
  • n is 1 or 2.
  • R 4 is halogen, hydroxy, N(R a ) 2 or a ring which is: phenyl, naphthyl, oxadiazolyl, thiadiazolyl, pyridinyl, benzoxazolyl, benzothiazolyl, tetrahydroisoquinolinyl, isoquinolinyl or benzoisothiazolyl; any of which rings being optionally substituted by one or more groups independently selected from halogen, Ci_ 4 alkyl, amino, di(Ci. 4 alkyl)amino, pyridinyl and phenyl optionally substituted by haloCi_ 4 alkyl.
  • R 4 is hydroxy, N(R a ) 2 or a phenyl or napthyl ring optionally substituted by one or more groups independently selected from halogen, di(Ci. 4 alkyl)amino and Preferably, when R 4 is a ring it is unsubstituted or substituted by one, two or three independently selected groups. More preferably, the ring is unsubstituted or monosubstituted.
  • R 4 ring Specific substituents on the R 4 ring are fluorine, methoxy, chlorine, dimethylamino and trifluoromethyl.
  • R 4 groups are phenyl, naphthyl, fluorophenyl, methoxyphenyl, chlorophenyl, (dimethylamino)phenyl, hydroxy, diethylamino and (trifluoromethyl)phenyl.
  • R 4 is phenyl, 2-naphthyl, 4-fluorophenyl, 1 -naphthyl, 2-methoxyphenyl, 4- chlorophenyl, 4-(dimethylamino)phenyl, hydroxy, diethylamino or 4-(trifluoromethyl)phenyl.
  • each R a is independently hydrogen, methyl or ethyl.
  • r is zero or two. More particularly r is two.
  • the present invention provides compounds of formula I wherein: each of R 1 and R 2 is independently selected from hydrogen, C 2 . 6 alkenyl, C 2 - 6 alkynyl, C 3 . gcycloalkyl, C 6 -ioaryl, C 6 .ioarylCi- 6 alkyl, C 6 -ioarylCi.
  • A, B, D and R 3 are as defined above; or a pharmaceutically acceptable salt or tautomer thereof.
  • the present invention provides compounds of formula II:
  • T is NH or CH 2 ; when T is NH then w is 1, 2 or 3; when T is CH 2 then w is 0, 1 or 2; and
  • A, B, D, Y and R 4 are as defined above; or a pharmaceutically acceptable salt or a tautomer thereof.
  • Y-R 4 may be substituted at any substitutable position on the ring.
  • the present invention also includes within its scope N-oxides of the compounds of formula I above.
  • N-oxides may be formed on any available nitrogen atom.
  • the N-oxides may be formed by conventional means, such as reacting the compound of formula I with oxone in the presence of wet alumina.
  • the present invention includes within its scope prodrugs of the compounds of formula I above.
  • prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
  • a prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • the present invention includes within its scope solvates of the compounds of formula I and salts thereof, for example, hydrates.
  • the compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: EX. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention.
  • the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • the compounds may exist in different isomeric forms, all of which are encompassed by the present invention.
  • a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • the phrase "optionally substituted” should be taken to be equivalent to the phrase “unsubstituted or substituted with one or more substituents” and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents.
  • a substituent on a saturated, partially saturated or unsaturated heterocycle can be attached at any substitutable position.
  • alkyl is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci_6alkyl is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement.
  • Ci_ 6 alkyl specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, and so on.
  • Preferred alkyl groups are methyl and ethyl.
  • cycloalkyl means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • C3-7cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl- cyclopentyl, cyclohexyl, and so on.
  • cycloalkyl includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups.
  • cycloalkyl as defined in this embodiment includes cyclopropyl, methyl- cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7- dimethylbicyclo[2.2.1]heptyl and so on.
  • Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C 2 -6alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • Alkenyl groups include ethenyl, propenyl, butenyl and 2-methylbutenyl. Preferred alkenyl groups include ethenyl and propenyl.
  • C 2 -6alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon- carbon triple bonds may be present.
  • Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on.
  • Preferred alkynyl groups include ethynyl and propynyl
  • Alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl above. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. The preferred alkoxy groups are methoxy and ethoxy.
  • mercaptoCi-ealkyl represents a SH group attached through an alkyl group of indicated number. Examples of suitable mercaptoalkyl groups include CH 2 SH, CH 2 CH 2 SH and CH 2 CH 2 CH 2 SH.
  • haloCi- ⁇ alkyl and “haloCi- ⁇ alkoxy” mean a C ⁇ alkyl or Ci_ 6 alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms.
  • fluoroCi- ⁇ alkyl and fluoroCi_ 6 alkoxy groups in particular fluoroCi. 3 alkyl and fluoroCi.
  • alkoxy groups for example, CF 3 , CHF 2 , CH 2 F, CH 2 CH 2 F, CH 2 CHF 2 , CH 2 CF 3 , OCF 3 , OCHF 2 , OCH 2 F, OCH 2 CH 2 F, OCH 2 CHF 2 or OCH 2 CF 3 , and most especially CF 3 , OCF 3 and OCHF 2 .
  • the term "Ci- ⁇ alkylcarbonyl” or "Ci- ⁇ alkoxycarbonyl” denotes a C ⁇ alkyl or
  • Suitable examples of Ci. 6 alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and ter ⁇ -butylcarbonyl.
  • Examples of Ci. ⁇ alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. The terms and Ci.
  • alkylsulfamoyl shall be construed analogously, wherein the C ⁇ alkyl group is attached via a sulfonyl (SO 2 ) and sulfamoyl (NHSO 2 ) radical, respectively.
  • the rings present in the compounds of this invention may be monocyclic or multicyclic, particularly bicyclic.
  • the multicyclic rings may be fused or spiro linked.
  • C ⁇ -ioaryl is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene.
  • the preferred aryl group is phenyl or naphthyl, especially phenyl.
  • heterocycles of this invention are benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl, furyl, furazanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,
  • Further examples include octahydroindolizinyl, diazoniaspiro[4.4]nonanyl, hexahydropyrrolo[3,4-b]pyrrolyl, oxaazoniabicyclo[2.2.1 ]heptanyl, diazoniaspiro[3.3]heptanyl, diazoniaspiro[3.5]nonanyl, diazoniaspiro[4.5]decanyl, octahydropyrrolo[3,4- c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydrocyclopenta[c]pyrrolyl, dihydroindolyl, azoniaspiro[4.5]decanyl, diazoniabicyclo[2.2.2]octanyl, diazoniabicyclo[2.2.1 ]heptanyl, diazoniabicyclo[3.2.1]octanyl,
  • Preferred 5, 6 or 7 membered saturated or partially saturated hetereocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and diazepanyl.
  • Preferred 5 membered heteroaromatic rings are thienyl, thiazolyl, pyrazolyl, isoxazolyl, imidazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, furyl and pyrrolyl.
  • a preferred 6 membered heteraromatic ring is pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl.
  • halogen refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
  • Particular compounds within the scope of the present invention are: 2-[4-(2-naphthylsulfonyl)piperazin-l-yl]-5-(trifluoroacetyl)pyridinium trifluoroacetate; 2-[4-(2-naphthylsulfonyl)piperazin-l-yl]-5-(trifluoroacetyl)pyrimidin-l-ium trifluoroacetate; 2-(4-Hydroxy-4-phenylpiperidin- 1 -yl)-5-(trifluoroacetyl)pyridinium trifluoroacetate; 2-(4-phenyl- 1 ,4-diazepan- 1 -yl)-5-(trifluoroacetyl)pyridinium trifluoroacetate; 2-(4-phenylpiperidin- 1 -yl)-5 -(trifluoroacetyl)pyridinium trifluoroacetate;
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention as formed by reacting a basic instant compound with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like.
  • a pharmaceutically acceptable salt of this invention contains 1 equivalent of a compound of formula (I) and 1, 2 or 3 equivalent of an inorganic or organic acid. More particularly, pharmaceutically acceptable salts of this invention are the trifluoroacetate or the chloride salts, especially the trifluoroacetate salts.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, NjN'-dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine,
  • the compounds of the invention can be used in a method of treatment of the human or animal body by therapy.
  • the compounds of the invention find use in a variety of applications for human and animal health.
  • the compounds of the invention are histone deacetylase (HDAC) inhibitors useful in the treatment of cancer among other diseases.
  • HDACs catalyse the removal of acetyl groups from lysine residues on proteins, including histones and HDAC inhibitors show diverse biological functions including affecting gene expression, cell differentiation, cell cycle progression, growth arrest, and/or apoptosis. See J. Med. Chem. (2003) 46:5097 and Curr. Med. Chem. (2003) 10:2343.
  • the compounds of the invention are used to treat cellular proliferation diseases.
  • Disease states which can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), neurodegenerative diseases, schizophrenia and stroke.
  • the compounds, compositions and methods provided herein are particularly deemed useful for the treatment of cancer including solid tumors such as skin, breast, brain, cervical carcinomas, testicular carcinomas, etc.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancre
  • Ewing's sarcoma malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),
  • the term "cancerous cell” as provided herein includes a cell afflicted by any one of the above-identified conditions.
  • the present invention provides a compound of formula I for use in the manufacture of a medicament for treating cellular proliferation diseases.
  • the present invention also provides a method for the treatment of cellular proliferation diseases, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the compounds of the instant invention may also be useful in the treatment or prevention of neurodegenerative diseases, including, but not limited to, polyglutamine-expansion-related neurodegeneration, Huntington's disease, Kennedy's disease, spinocerebellar ataxia, dentatorubral- pallidoluysian atrophy (DRPLA), protein-aggregation-related neurodegeneration, Machado- Joseph's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, spongiform encephalopathy, a prion-related disease and multiple sclerosis (MS). See WO 02/090534 and WO 03/083067.
  • neurodegenerative diseases including, but not limited to, polyglutamine-expansion-related neurodegeneration, Huntington's disease, Kennedy's disease, spinocerebellar ataxia, dentatorubral- pallidoluysian atrophy (DRPLA), protein-aggregation-related neurodegeneration, Machado-
  • the present invention provides a compound of formula I for use in the manufacture of a medicament for treating or preventing neurodegenerative diseases.
  • the present invention also provides a method for treating or preventing neurodegenerative diseases, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the compounds of the invention may also be useful in the treatment or prevention of mental retardation, in particular "X chromosome-linked mental retardation” and "Rubinstein-Taybi syndrome”.
  • the present invention provides a compound of formula I for the manufacture of a medicament for treating or preventing mental retardation.
  • the present invention also provides a method for treating or preventing mental retardation, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the compounds of the invention may also be useful in the treatment or prevention of schizophrenia, see WO 02/090534.
  • the present invention provides a compound of formula 1 for the manufacture of a medicament for treating or preventing schizophrenia.
  • the present invention also provides a method for treating or preventing schizophrenia, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the compounds of the invention may also be useful in the treatment or prevention of inflammatory diseases, including, but not limited to stroke, rheumatoid arthritis, lupus erythematosus, ulcerative colitis and traumatic brain injuries. See Leoni et al (2002), PNAS, 99(5):2995-3000, Suuronen et ⁇ /.(2003) J. Neurochem, 87:407-416 and Drug Discovery Today (2005), 10:197-204.
  • the present invention provides a compound of formula I for the manufacture of a medicament for treating or preventing inflammatory diseases.
  • the present invention also provides a method for treating or preventing inflammatory diseases, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the compounds of the present invention are also useful in the inhibition of smooth muscle cell proliferation and/or migration and are thus useful in the prevention and/or treatment of restenosis, for example after angioplasty and/or stent implantation.
  • the present invention provides a compound of formula I for the manufacture of a medicament for treating or preventing restenosis.
  • the present invention also provides a method for treating or prevention restenosis, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • smooth muscle cell proliferation and/or migration is inhibited and restenosis is prevented and/or treated by providing a stent device having one or more of the compounds of the instant invention in or on the stent device, e.g. coated onto the stent device.
  • the stent device is designed to controllably release the compounds of the invention, thereby inhibiting smooth miscle cell proliferation and/or migration and preventing and/or treating restenosis.
  • Stenosis and restenosis are conditions associated with a narrowing of blood vessels. Stenosis of blood vessels generally occurs gradually over time. Restenosis, in contrast, relates to a narrowing of blood vessels following an endovascular procedure, such as balloon angioplasty and/or stent implantation, or a vascular injury.
  • Restenosis is typically caused by trauma inflicted during angioplasty, effected by, for example, ballon dilation, atherectomy or laser ablation treatment of the artery. For these procedures, restenosis occurs at a rate of about 30% to about 60% depending on the vessel location, lesion length and a number of other variables. This reduces the overall success of the relatively non-invasive balloon angioplasty and stenting procedures. Restenosis is attributed to many factors, including proliferation of smooth muscle cells (SMC).
  • SMC smooth muscle cells
  • SMC proliferation is triggered by the initial mechanical injury to the intima that is sustained at the time of balloon angioplasty and stent implantation.
  • the process is characterized by early platelet activation and thrombus formation, followed by SMC recruitment and migration, and, finally, cellular proliferation and extracellular matrix accumulation.
  • Damaged endothelial cells, SMCs, platelets, and macrophages secrete cytokines and growth factors which promote restenosis.
  • SMC proliferation represents the final common pathway leading to neointimal hyperplasia. Therefore, anti-proliferative therapies aimed at inhibiting specific regulatory events in the cell cycle may constitute the most reasonable approach to restenosis after angioplasty.
  • the compounds of the invention may also be used as immunosuppressants or immunomodulators and can accordingly be used in the treatment or prevention of immune response or immune-mediated responses and diseases such as systemic lupus erythematosus (SLE) and acute or chronic transplant rejection in a recipient of an organ, tissue or cell transplant, (see WO 05/013958).
  • SLE systemic lupus erythematosus
  • WO 05/013958 WO 05/013958
  • autoimmune diseases examples include autoimmune hematological disorders (including hemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), systemic lupus erythematosus, thyroiditis, Hashimoto's thyroiditis, polychondritis, sclerodoma, Wegener granulamatosis,dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, atopic dermatitis, vasculitis, Steven- Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (including ulcerative colitis and Crohn's disease) endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary Miliary cirrhosis, juvenile diabetes (diabetes mellitus type I), diabetes type II and the disorders associated therewith, uveitis
  • autoimmune hematological disorders
  • the present invention provides a compound of formula I for the manufacture of a medicament for the treatment or prevention of immune disorders.
  • the present invention also provides a method for treating or preventing immune disorders, which method comprises administration to a patent in need thereof of an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the compounds of the invention may also be useful in the treatment or prevention of other diseases such as diabetes, cardiovascular disorders, asthma, cardiac hypertrophy and heart failure, (see Cell (2002), 110:479-488).
  • the compounds of this invention may be administered to mammals, preferably humans, either alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice.
  • the compounds of this invention may be administered to animals.
  • the compounds can be administered orally or parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
  • compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid; binding agents, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents for example, microcrystalline cellulose, sodium crosscarmellose, corn starch, or alginic acid
  • binding agents for example starch, gelatin, polyvinyl-pyrrolidon
  • the tablets may be uncoated or they may be coated by known techniques to mask the unpleasant taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a water soluble taste masking material such as hydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delay material such as ethyl cellulose, cellulose acetate butyrate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinyl- pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • the pharmaceutical compositions of the invention may also be in the form of an oil- in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally occurring phosphatides, for example soy bean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
  • compositions may be in the form of a sterile injectable aqueous solutions.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injectable preparation may also be a sterile injectable oil-in- water microemulsion where the active ingredient is dissolved in the oily phase.
  • the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution then introduced into a water and glycerol mixture and processed to form a microemulation.
  • the injectable solutions or microemulsions may be introduced into a patient's blood stream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
  • a continuous intravenous delivery device may be utilized.
  • An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension for intramuscular and subcutaneous administration.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3 -butane diol.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non- irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • compositions, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical application shall include mouth washes and gargles.
  • the compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles and delivery devices, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Compounds of the present invention may also be delivered as a suppository employing bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • bases such as cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.
  • the daily dosage will normally be determined by the prescribing physician with the dosage generally varying according to the age, weight, sex and response of the individual patient, as well as the severity of the patient's symptoms.
  • a suitable amount of compound is administered to a mammal undergoing treatment for cancer.
  • Administration generally occurs in an amount between about 0.1 mg/kg of body weight to about 60 mg/kg of body weight per day, preferably of between 0.5 mg/kg of body weight to about 40 mg/kg of body weight per day.
  • the instant compounds are also useful in combination with known therapeutic agents and anticancer agents.
  • this invention provides combinations of compounds of formula (I) and known therapeutic agents and/or anti-cancer agents for simultaneous, separate or sequential administration.
  • instant compounds are useful in combination with known anti-cancer agents.
  • Combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6 th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers.
  • a person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • Such anti- cancer agents include, but are not limited to, the following: other HDAC inhibitors, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints.
  • the instant compounds are particularly useful when co-administered with radiation therapy.
  • HDAC inhibitors include suberoylanilide hydroxamic acid (SAHA), LAQ824, LBH589, PXDlOl, MS275, FK228, valproic acid, butyric acid and CI-994.
  • SAHA suberoylanilide hydroxamic acid
  • LAQ824 LBH589
  • PXDlOl PXDlOl
  • MS275 MS275
  • FK228, valproic acid butyric acid
  • CI-994 CI-994.
  • Estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381, LYl 17081, toremifene, fulvestrant, 4- [7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(l-piperidinyl)ethoxy]phenyl]-2H-l-benzopyran-3-yl]- phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and S ⁇ 646.
  • Androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • Examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • Retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, ⁇ -difluoromethylornithine, ILX23- 7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • Cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • cytotoxic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPXlOO, (trans, trans, trans)-bis-mu-(hexane-l,6-diamine)
  • proteasome inhibitors include but are not limited to lactacystin, bortezomib, epoxomicin and peptide aldehydes such as MG 132, MG 115 and PSI.
  • the compounds of the present invention may be used in combination with other HDAC inhibitors such as SAHA and proteasome inhibitors.
  • microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6- pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-L- valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237)
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6- ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5- kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-lH,12H- benzo[de]pyrano[3 ',4' :b,7]-indolizino[l ,2b]quinoline-l 0, 13(9H, 15H)dione, lurtotecan, 7-[2-(N- isopropylamino)ethyl]-(20S)camptothecin, B ⁇ P1350, BNPII lOO, BN80915,
  • inhibitors of mitotic kinesins are described in PCT Publications WO 01/30768, WO 01/98278, WO 02/056880, WO 03/050,064, WO
  • inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLP 1 , inhibitors of CE ⁇ P-E, inhibitors of MCAK, inhibitors of Kif 14, inhibitors of Mphosphl and inhibitors of Rab6-KIFL.
  • “Inhibitors of kinases involved in mitotic progression” include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK) (in particular inhibitors of PLK-I), inhibitors of bub-1 and inhibitors of bub-Rl.
  • Antiproliferative agents includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'-deoxycytidine, N- [5- (2,3-dihydro-benzofuryl)sulfonyl]-jV-(3,4-dichlorophenyl)ure
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • HMG-CoA reductase inhibitors refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. ⁇ os. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. ⁇ os. 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVAC ⁇ OL®; see U.S. Pat. ⁇ os.
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.
  • Prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-I geranylgeranyl-protein transferase type I
  • GGPTase-II geranylgeranyl-protein transferase type-II
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ.
  • Angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors FIt-I (VEGFRl) and FIk-I /KDR (VEGFR2), inhibitors of epidermal-derived, fibrob last-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- ⁇ , interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS (1992)
  • NSAIDs nonsteroidal anti-inflammatories
  • steroidal anti-inflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see Fernandez et al (1985) J. Lab. Clin. Med.
  • VEGF vascular endothelial growth factor
  • Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin. Chem. La. Med. (2000) 38:679-692). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost.
  • TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U,S, Ser. No. 60/349,925 (filed January 18, 2002).
  • Agents that interfere with cell cycle checkpoints refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • Such agents include inhibitors of ATR, ATM, the Chkl and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • “Inhibitors of cell proliferation and survival signaling pathway” refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR (for example those disclosed in WO 03/059951), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (for example BAY-43-9006 ), inhibitors of MEK (for example
  • Apoptosis inducing agents include activators of TNF receptor family members (including the TRAIL receptors).
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-I of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-I evaluated by cell or microsomal assays.
  • Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat.
  • Inhibitors of COX-2 that are particularly useful in the instant method of treatment are 5-chloro-3-
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6- yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-l -[[3,5-dichloro-4-(4- chlorobenzoyl)phenyl]methyl]-lH-l,2,3-triazole-4-carboxamide,CM101, squalamine, combretastatin,
  • integrin blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the oc v ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ocv ⁇ 5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the 0Cy ⁇ 3 integrin and the oc v p5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ocy ⁇ j ⁇ v ⁇ 8 ; oq ⁇ i, «2 ⁇ L «5 ⁇ L «6 ⁇ l an d «6 ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3, ⁇ v ⁇ 5, ⁇ v ⁇ 6, « v ⁇ 8, «l ⁇ l, Ot2 ⁇ l, ⁇ 5 ⁇ l> ⁇ ⁇ l an d «6 ⁇ 4 integrins.
  • tyrosine kinase inhibitors include iV-(trifluoromethylphenyl)-5- methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the instantly claimed compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. (1998) 31:909-913; J. Biol. Chem. (1999) 274:9116-9121; Invest.
  • PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-OI l, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR- ⁇ 039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NPOI lO, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl- l,2-benzisoxazol-6-yl)oxy]-2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2- chloro-4-(4-fluor
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with anti- viral agents (such as nucleoside analogs including ganciclovir for the treatment of cancer. See WO 98/04290.
  • Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No.
  • a uPA/uPAR antagonist (Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis- Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August (1998) 5(8):1105-13), and interferon gamma (J Immunol (2000) 164:217-222).
  • the compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • a compound of the present invention may be used in conjunction with other antiemetic agents, especially neurokinin- 1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABA B receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.PatentNos.
  • neurokinin- 1 receptor antagonists especially 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABA B receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S.PatentNos
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • an anti-emesis agent selected from a neurokinin- 1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.
  • Neurokinin- 1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147; European Patent Publication Nos. EP 0 360 390, 0 394 989, 0 428 434, 0 429 366, 0 430 771, 0 436 334, 0 443 132, 0 482 539, 0 498 069, 0
  • the neurokinin- 1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(I -(i?)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4- triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.
  • a compound of the instant invention may also be administered with an agent useful in the treatment of anemia.
  • an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).
  • a compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia.
  • a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim.
  • a compound of the instant invention may also be administered with an immunologic- enhancing drug, such as levamisole, isoprinosine and Zadaxin.
  • an immunologic- enhancing drug such as levamisole, isoprinosine and Zadaxin.
  • a compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids).
  • bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.
  • the scope of the instant invention encompasses the use of the instantly claimed compounds in combination with a second compound selected from: other HD AC inhibitors, an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an anti- viral agent, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immuno logic- enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, an apoptosis inducing agent and a bisphosphonate.
  • a second compound selected from: other HD AC inhibitors,
  • administration means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment.
  • a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.)
  • administration and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • the angiogenesis inhibitor to be used as the second compound is selected from a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast- derived growth factor, an inhibitor of platelet derived growth factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, ⁇ -O-chloroacetyl-carbony ⁇ -fumagillol, thalidomide, angiostatin, troponin- 1, or an antibody to VEGF.
  • the estrogen receptor modulator is tamoxifen or raloxifene.
  • a method of treating cancer comprises administering a therapeutically effective amount of a compound of Formula I in combination with radiation therapy and/or in combination with a compound selected from: other HDAC inhibitors, an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an anti- viral agent, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, an apoptosis inducing agent and a
  • the invention further encompasses a method of treating or preventing cancer that comprises administering a therapeutically effective amount of a compound of Formula I in combination with a COX-2 inhibitor.
  • the instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a compound of Formula I and a compound selected from: other HDAC inhibitors, an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl- protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an anti- viral agent, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, an apoptosis inducing agent and a bisphosphonate.
  • a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a compound of Formula I and a compound selected from: other HDAC inhibitors, an estrogen receptor modulator, an and
  • reaction can be carried out under standard oxidizing conditions such as in the presence of an oxidizing agent such as Dess-Martin periodinane or Mn ⁇ 2 , generally in a solvent such as CHCl 3 or CH 2 Ck at about room temperature.
  • an oxidizing agent such as Dess-Martin periodinane or Mn ⁇ 2
  • a solvent such as CHCl 3 or CH 2 Ck at about room temperature.
  • a trifluoromethyl source such as TMSCF 3 may be used, generally in the presence of a fluoride source such as CsF or MBu 4 NF, in a solvent such as THF at about room temperature.
  • A, B, D, R 1 and R 2 are as defined above, X is halogen, such as bromine, chlorine or fluorine and R x is hydrogen or Ci_ 6 alkoxy.
  • the reaction is generally carried out in the presence of a base such as K 2 CO 3 , in a solvent such as MeCN at reflux.
  • a further reduction step can be carried out, generally under standard reduction conditions such as in the presence of a reductive agent such as DIBAL-H or in a two step procedure by reduction with a reductive agent such as LiAlH 4 , followed by oxidation in the presence of an oxidizing agent such as Mn ⁇ 2 , generally in a solvent such as CHCI3 or CH2CI 2 at about room temperature.
  • compounds of formula I can be prepared by reacting a compound of formula IC with a compound of formula IE:
  • A, B, D and X are as defined above.
  • the reaction is generally carried out in the presence of a base such as K 2 CO 3 and a solvent such as MeCN at reflux.
  • Compounds of formula IE can be prepared by reacting a compound of formula ID with a trifluoromethyl source, such as TMSCF 3 , generally in the presence of a fluoride source such as CsF or MBU 4 NF, in a solvent such as THF at about room temperature.
  • an oxidation reaction can be carried out under standard oxidizing conditions such as in the presence of an oxidizing agent such as Dess-Martin periodinane or Mn ⁇ 2 , generally in a solvent such as CHCI3 or CH 2 CI 2 at about room temperature.
  • any of the synthetic sequences described herein it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protecting Groups in Organic Synthesis, 3rd Edition, Greene, T. W. and Wuts, P. G. M.; Wiley Interscience, 1999 and Kocienski, P. J. Protecting Groups, Thieme, 1994.
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • the His-tagged HDAC 4 wild-type catalytic domain, was expressed in E. coli strain BL21 StarTM (DE3).
  • the cells were grown at 37°C in minimum medium supplemented with 1 g/1 ( 15 NFLi) 2 SC) 4 and 5 g/1 glucose, and lOO ⁇ M of ZnC ⁇ to an optical density of 0.8 at 600nm and induced with IPTG for 16 hr at 23°C. At 23°C more than 80% of the protein was soluble.
  • Bacterial pellets were resuspended in 25mM Hepes pH 7.5, 20OmM KCl, 0.5% NP-40, 20% glycerol ImM DTT and supplemented with Complete EDTA- free protease inhibitor. Subsequently bacterial pellets were lysed by microfluidizer, and centrifuged at 15000 rpm for 30min.
  • the soluble fraction was diluted 1 :1 with 25mM Hepes pH 7.5, 200 mM KCl, 1 mM DTT and was loaded directly on His Trap HP 5ml (Amersham Biosciences).
  • the protein was eluted at 20OmM Imidazole.
  • the fractions with HDAC 4 were diluted 1:3 with 25mM Hepes pH 7.5, 5% glycerol, 0.1% of NP-40, 1 mM DTT. Then the solution was loaded on a Resource Q equilibrated with 25mM Hepes pH 7.5, 10% glycerol, 5OmM KCl, 0.1% of NP-40, 1 mM DTT.
  • HDAC 4 was eluted with a salt gradient (0- 250)mM of KCl.
  • the product was fractionated by preparative SEC (G-75, Superdex 75 26/60 Amersham Biosciences) (25mM Hepes pH 7.5, 15OmM KCl, 0.1% of ⁇ -octyl glucopiranoside, 1 mM DTT) to give the final product.
  • Analytical SEC indicated that this product was monomeric.
  • the protein was concentrated at « 100 ⁇ M
  • HEK 293 cells 6 xl 0 6 cells/ 10 cm dish were transfected with 15 ug of plasmid DNA using Lipofectamine reagent (Invitrogen) according to the manufacturer's recommendations. After 24 hr, scrape cells in pre-cooled Ix PBS, centrifuge at 1500 x g for 5 min at 4°C, washed twice with Ix PBS, count cells, collect cell pellet by centrifugation and freeze at -8O 0 C.
  • Lipofectamine reagent Invitrogen
  • hypotonic lysis buffer_ (20 mM Hepes pH 7.9, 0.25 mM EDTA, 10% glycerol, 1 mM PMSF, Complete EDTA- free protease inhibitors cocktail from Boehringer) and incubated 15' on ice. Homogenize in Douncer 2 (25 strokes, B pestle), add to the homogenate 150 mM KCl and 0.5 % NP40 (isotonic lysis buffer: ILB). Sonicate twice for 30 sec (output 5/6, duty cycle 90, timer constant), then incubate 60 min on a rotating wheel at 4°C.
  • ILB centrifuge each time at 10000 rpm for 30 sec in an Eppendorf microfuge. Incubate slurry at RT for a few minutes before use. Use 10 ul of gel matrix for each 2 ug of flagged-HDAC6 in the soluble extract, mix gel matrix and soluble extract and incubate O/N on a rotating wheel at 4°C. Recover gel matrix by centrifugation and wash it once with ILB, twice with ILB containing 0.1% NP-40, and a further 2 times in elution buffer [50 mM Hepes pH 7.4, 5% glycerol, 0.01% Triton X-100, 100 mM KCl.
  • Elute protein by adding to the gel matrix 10 volumes of elution buffer containing 100 ug/ml of 3x FLAG peptide (F4799, SIGMA) and incubation for 60 min on a rotating wheel at RT; recover eluted protein by centrifugation.
  • Estimate flagged- HD AC6 concentration in the sample by anti-FLAG Western blot analysis (dilute eluted protein 30 folds with SDS-PAGE loading buffer and load 3, 10 and 30 ul, in parallel use 4, 8 and 16 ng of reference protein for quantification). Prepare 50 ul aliquots and snap freeze in liquid N 2 before storage at -80 0 C
  • TSA Stock TSA is provided as a 1OmM solution in 100% DMSO.
  • Assay buffer 25mM Tris/HCl pH8, 137mM NaCl, 2.7mM KCl, ImM MgCl 2 , O.lmg/ml BSA
  • Diluted substrate solution tert-Butyl [(15)-5-(trifluoroacetylamino)-l-[[(4-methyl-2-oxo-2H-l- benzopyran-6-yl) amino]carbonyl]pentyl]-carbarmc acid ester is diluted to 20OuM with Tris ImM p ⁇ 7.4 prior to each use. The final concentration in the assay is 2OuM.
  • Diluted developer solution The commercial 2OX developer concentrate (KI- 105, BioMol Research
  • Enzyme working solution Enzyme is diluted in 1.25x assay buffer prior to each use from a fresh aliquot of enzyme. The final concentration in the assay is 0.2 nM.
  • reaction is performed in 96-well microplate in a final volume of 50ul/well. Add 5ul of
  • DMSO/compound solution add 40ul of HDAC 4 enzyme in assay buffer and incubate 10' at RT. Start the reaction by adding 5ul of the 20OuM substrate solution and incubate 1 hr at 37°C. Stop the reaction by adding 50ul of developer/4uM TSA solution and incubate 30 min at RT. Measure the fluorescence at ex.360nM and em.460nM.
  • TSA stock TSA is provided as a 1OmM stock solution in 100% DMSO.
  • Assay buffer 2OmM Hepes pH 7.5, 137mM NaCl, 2.7mM KCl, ImM MgCl 2 , O.lmg/ml BSA
  • Diluted substrate solution The 5OmM Fluor-de-LysTM substrate (KI-104, BioMol Research Laboratories) is diluted to 15OuM with HDAC assay buffer prior to each use. The final concentration in the assay is 3OuM.
  • Diluted developer solution The commercial 2OX developer concentrate (KI- 105, BioMol Research Laboratories) is diluted 1:167 into HDAC assay buffer. 2uM [final] TSA to this solution increases its ability to stop the reaction.
  • HDAC 6 working solution The HDAC 6 enzyme is diluted in assay buffer prior to each use from a fresh aliquot of enzyme. The final concentration in the assay is 1-2 nM.
  • the reaction is performed in 96-well microplate in a final volume of 50ul/well. Add 5ul of DMSO/compound solution and then 35ul of HDAC 6 enzyme in assay buffer (or 35ul assay buffer in the negative controls) and incubate 10' at RT. Start the reaction by adding KM of the 15OuM substrate solution and incubate for 1 hr at 37°C. Stop the reaction by adding 50ul of developer/4uM TSA solution and incubate 30 min at RT. Measure the fluorescence at ex.36OnM and em.460nM.
  • BSA bovine serum albumin
  • DMSO dimethyl sulfoxide
  • DTT dithiothreitol
  • EDTA ethylenediaminetetraacetic acid
  • em emission
  • ex exitation
  • Hepes ((N-(2-Hydroxyethyl)piperazine)- N'-(2-ethanesulfonic acid)
  • ILB isotonic lysis buffer
  • IPTG Isopropyl-beta-D-thiogalactopyranoside
  • NP40 Nonidet P40
  • PBS Phosphate buffered saline
  • PMSF phenylmethylsulphonyl fluoride
  • RT room temperature
  • SEC size exclusion chromatography
  • TBS Tris buffered saline
  • Tris-HCl Tris Hydroxymethylaminoethane
  • TSA Trichostatin A
  • Step 3 2-r4-(2-naphthylsulfonyl)piperazm-l-yll-5-(trifluoroacetyl)pyridinium trifluoroacetate
  • Step 1 ⁇ 2-r4-(2-naphthylsulfonyl)piperazin-l -yllpyrimidin-5-vU methanol
  • a solution (0.1 M) of ethyl 2-[4-(2-naphthylsulfonyl)piperazin-l-yl]pyrimidine-5-carboxylate prepared as described in WO03/076422
  • the reaction mixture was stirred at RT for 30 min, then it was quenched by addition of water and NaOH 2N.
  • Step 2 2-r4-(2-naphthylsulfonyl)piperazin-l-vHpyrimidine-5-carbaldehyde
  • Step 4 2-r4-(2-naphthylsulfonyl)piperazin-l-yll-5-(trifluoroacetyl)pyrimidin-l-ium trifluoroacetate
  • the reaction mixture was stirred at RT for 2 h. Then, it was filtered through a pad of celite and washed off with CH 2 Cl 2 .
  • Step 2 2-(4-Hvdroxy-4-phenylpiperidin-l-yl)-5-(trifluoroacetyl)pyridinium trifluoroacetate
  • a solution (0.03 M) of 2,2,2-trifluoro-l-(6-fluoropyridin-3-yl)ethanone (from Step 1) in MeCN was treated with 4-phenylpiperidin-4-ol (1.2 eq.) and K 2 CO 3 (3.0 eq.)
  • the reaction mixture was heated to 75°C for 12 h. After cooling down, the reaction mixture was diluted with water and extracted with EtOAc.

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Abstract

La présente invention concerne des composés de formule (I) : ainsi que des sels et des tautomères pharmaceutiquement acceptables de ceux-ci. Les composés de la présente invention sont des inhibiteurs de la histone désacétylase(HDAC) et sont utiles pour traiter des maladies à prolifération cellulaire, y compris le cancer. Ils sont également utiles pour traiter les maladies neurodégénératives, la déficience mentale, la schizophrénie, les maladies inflammatoires, la resténose, les troubles immunitaires, le diabète, les maladies cardiovasculaires et l'asthme.
PCT/EP2007/052712 2006-03-21 2007-03-21 Derives de trifluoroethanone substitues par un heterocycle a six chainons utilises comme inhibiteurs de la histone desacetylase (hdac) WO2007107594A2 (fr)

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Publication number Priority date Publication date Assignee Title
US8017321B2 (en) 2004-01-23 2011-09-13 The Regents Of The University Of Colorado, A Body Corporate Gefitinib sensitivity-related gene expression and products and methods related thereto
CN103214413A (zh) * 2013-03-22 2013-07-24 郑州泰基鸿诺药物科技有限公司 一种含杂环的三氟甲基酮化合物及其制备方法
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9434994B2 (en) 2004-05-27 2016-09-06 The Regents Of The University Of Colorado, A Body Corporate Methods for prediction of clinical outcome to epidermal growth factor receptor inhibitors by non-small cell lung cancer patients

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WO2003076401A1 (fr) * 2002-03-13 2003-09-18 Janssen Pharmaceutica N.V. Derives d'amino-sulfonyle utilises comme inhibiteurs de l'histone deacetylase
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US20060058553A1 (en) * 2002-02-07 2006-03-16 Axys Pharmaceuticals, Inc. Novel bicyclic hydroxamates as inhibitors of histone deacetylase
WO2003075929A1 (fr) * 2002-03-13 2003-09-18 Janssen Pharmaceutica N.V. Inhibiteurs de l'histone déacétylase
WO2003076401A1 (fr) * 2002-03-13 2003-09-18 Janssen Pharmaceutica N.V. Derives d'amino-sulfonyle utilises comme inhibiteurs de l'histone deacetylase

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8017321B2 (en) 2004-01-23 2011-09-13 The Regents Of The University Of Colorado, A Body Corporate Gefitinib sensitivity-related gene expression and products and methods related thereto
US9434994B2 (en) 2004-05-27 2016-09-06 The Regents Of The University Of Colorado, A Body Corporate Methods for prediction of clinical outcome to epidermal growth factor receptor inhibitors by non-small cell lung cancer patients
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9499497B2 (en) 2012-11-20 2016-11-22 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
CN103214413A (zh) * 2013-03-22 2013-07-24 郑州泰基鸿诺药物科技有限公司 一种含杂环的三氟甲基酮化合物及其制备方法
CN103214413B (zh) * 2013-03-22 2015-05-13 郑州泰基鸿诺药物科技有限公司 一种含杂环的三氟甲基酮化合物及其制备方法

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