WO2006101456A1 - Composes d'hydraxamate bicycliques contenant des heterocycles utiles en tant qu'inhibiteurs de l'histone desacetylase (hdac) - Google Patents

Composes d'hydraxamate bicycliques contenant des heterocycles utiles en tant qu'inhibiteurs de l'histone desacetylase (hdac) Download PDF

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WO2006101456A1
WO2006101456A1 PCT/SG2006/000065 SG2006000065W WO2006101456A1 WO 2006101456 A1 WO2006101456 A1 WO 2006101456A1 SG 2006000065 W SG2006000065 W SG 2006000065W WO 2006101456 A1 WO2006101456 A1 WO 2006101456A1
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cancer
compound according
alkyl
disease
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Weiping Deng
Dizhong Chen
Yifa Zhou
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S*Bio Pte Ltd
Yu, Niefang
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to hydroxamate compounds that are inhibitors of histone deacetylase (HDAC). More particularly, the present invention relates to bicyclic heterocyclic compounds and methods for their preparation and use. These compounds may be useful as medicaments for the treatment of proliferative disorders as well as other diseases involving, relating to or associated with enzymes having histone deacetylase activities.
  • HDAC histone deacetylase
  • chromatin a protein-DNA complex
  • histones which are the protein components.
  • Reversible acetylation of histones is a key component in the regulation of gene expression by altering the accessibility of transcription factors to DNA.
  • increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels of acetylation are associated with repression of gene expression (Wade P.A. et al. Hum. MoI. Genet., 2001 , 10:693-698., De Ruijter AJ. M. et al, Biochem. J., 2003, 370:737-749).
  • HDACs histone deacetylases
  • histone acetyltransferase Inhibition of HDACs results .in the accumulation of acetylated histones, which results in a variety of cell type dependent cellular responses, such as apoptosis, necrosis, differentiation, cell survival, inhibition of proliferation and cytostasis.
  • SAHA suberoylanilide hydroxamic acid
  • Trichostatin A is a reversible inhibitor of mammalian HDAC.
  • Trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDAC.
  • TSA trichostatin A
  • trapoxin B is a cyclic tetrapeptide, which is an irreversible inhibitor of mammalian HDAC.
  • HDAC inhibitors have become available for clinical evaluation (US6,552,065). Additional HDAC inhibiting compounds have been reported in the literature (Bouchain G. et al, J. Med. Chem., 2003, 46:820-830) and patents (WO 03/066579A2, WO 01/38322 A1 ). The in vivo activity of such inhibitors can be directly monitored by their ability to increase the amount of acetylated histones in the biological sample. HDAC inhibitors have been reported to interfere with neurodegenerative processes, for instance, HDAC inhibitors arrest polyglutamine-dependent neurodegeneration (Nature, 2001 , 413(6857): 739-43).
  • HDAC inhibitors have also been known to inhibit production of cytokines such as TNF, IFN, IL-1 which are known to be implicated in inflammatory diseases and/or immune system disorders.
  • cytokines such as TNF, IFN, IL-1 which are known to be implicated in inflammatory diseases and/or immune system disorders.
  • HDAC inhibitors that would be expected to have useful, improved pharmaceutical properties in the treatment of diseases such as cancer, neurodegenerative diseases, disorders involving angiogenesis and inflammatory and/or immune system disorders.
  • the present invention provides a compound of the formula (I):
  • V and V is a single or a double bond
  • V when the bond between V and V 1 is a double bond then V is CR 2 or N; V 1 is CR 2a or N;
  • V and V are not both N, and further wherein if V 1 is N then X is N;
  • V is CR 2 2 or NR 2 ;
  • V 1 is CR 2a 2 or NR 2 ;
  • X is N or CY
  • R 1 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkyl heteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, phenoxy, benzyl
  • R 1 is a group of the formula:
  • each R 20 , R 21 , R 22 , R 23 , R 24 and R 25 is independently selected from the group consisting of: H 1 halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alk
  • each R 26 and R 27 is independently selected from the group consisting of: H, halogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloaikenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, arylalkyloxy, hetero
  • n, o are integers independently selected from the group consisting of O, 1 , 2, 3 and 4;
  • R 2 is selected from the group consisting of: H, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloaikenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloal
  • R 2a is selected from the group consisting of: H, halogen, -CN, -NO 2 , -CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, arylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloal
  • R 2 and R 2a are joined such that when taken together with the two carbons to which they are attached they form a cyclic moiety
  • each Y is independently selected from the group consisting of: H, halogen, -CN, -NO 2 , 7 CF 3 , -OCF 3 , alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkoxyheteroaryl, alkenyloxy, alkynyloxy, cycloalkyloxy, cycloalkenyloxy, heterocycloalkyloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy, heterocycloalkenyloxy, aryloxy, heteroaryloxy,
  • p is an integer selected from O, 1 or 2
  • R 3 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl each of which may be optionally substituted;
  • R 4 is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl each of which may be optionally substituted;
  • Each R 5 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl each of which may be optionally substituted;
  • Each R 6 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl each of which may be optionally substituted;
  • Each R 7 and R 8 is independently selected from the group consisting of: H, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylheteroalkyl, heteroarylheteroalkyl, and acyl each of which may be optionally substituted;
  • Cy is C 1 -Ci 5 alkyl, aminoalkyl, heteroalkyl heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted;
  • L 1 is selected from the group consisting of CrC 5 alkyl or C 2 -C 5 alkenyl each of which may be optionally substituted;
  • W is selected from the group consisting of a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -N(R 9 )-, -C(O)N(R 9 )-, -SO 2 N(R 9 )-, -N(R 9 )C(0)-, -N(R 9 )SO 2 -, and -N(R 9 )-C(O)-N(R 10 )-;
  • Cy is C 1 -C 15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted;
  • L 1 and L 2 are the same or different and are independently C 1 -C 5 alkyl or C 2 -C 5 alkenyl each of which may be optionally substituted;
  • Cy is C 1 -C 15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted; k is O, 1 , 2, 3, 4 or 5;
  • W is selected from the group consisting of a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -N(R 9 )-, -C(O)N(R 9 )-, -SO 2 N(R 9 )-, -N(R 9 )C(O)-, -N(R 9 )SO 2 -, and -N(R 9 )-C(O)-N(R 10 )-;
  • L 1 and L 2 are the same or different and independently selected from CrC 5 alky] or C 2 -C 5 alkenyl each of which may be optionally substituted which may be optionally substituted;
  • W is selected from the group consisting of a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -N(R 9 )-, -C(O)N(R 9 )-, -SO 2 N(R 9 )-, -N(R 9 )C(O)-, -N(R 9 )SO 2 -, and -N(R 9 )-C(O)-N(R 10 )-;
  • R 9 and R 10 are the same or different and are independently selected from H, C 1 -C 6 alkyl, hydroxyalkyl, heteroalkyl, C 4 -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl and acyl each of which may be optionally substituted;
  • the bond between V and V 1 is a double bond providing compounds of formula (Ia):
  • the compound is a compound of formula (Ib):
  • R 1 , R 2 , R , R 3 , R 4 , Y, p and Z are as defined for compound of formula (I).
  • the compound is a compound of formula (Ic):
  • R , R , R 1 R , Y, p and Z are as defined for compound of formula (I).
  • the compound is a compound of formula (Id)
  • R 1 , R , R , R , Y, p and Z are as defined for compound of formula (I).
  • R 1 is selected from the group consisting of H, hydroxyalkyl, alkyl, heteroalkyl, alkoxyalkyl, arylalkyl, heteroarylalkyl, aminoalkyl, heterocycloalkylheteroalkyl, and heterocycloalkyl each of which may be optionally substituted as previously stated.
  • R 1 is selected from the group consisting of H, alkyl, heteroalkyl, alkoxyalkyl, and arylalkyl each of which may be optionally substituted as previously stated.
  • R 1 is selected from the group consisting of hydroxyalkyl, arylalkyl and heterocycloalkylalkyl each of which may be optionally substituted as previously stated.
  • R 1 is arylalkyl.
  • suitable arylalkyl groups include benzyl and phenethyl.
  • R 1 is selected from the group consisting of:
  • R 1 when R 1 is alkyl or heteroalkyl then it is not substituted by a cycloalkyl, aryl, heteroaryl, or heterocycloalkyl group.
  • R 1 are: H; methyl; (pyridin-2-yl)methyl; phenylmethyl, (pyridin-3- yl)methyl; (2-pyrollidin-1-yl-ethylamino)-methyl, ethyl; 2-hydroxy-ethyl; 2-(pyridin-2- yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-phenyl-ethyl; 2-carboxy-ethyl; 2-(morpholin-4-yl)-ethyl; 2-(piperidin-1-yl)-ethyl; 2-(pyrollidin-1-yl)-ethyl; 2-dimethylamino-ethyl; 3- dimethylamino-2-methyl-propyl, 2-diethylamino-ethyl; 2-methoxy-ethyl; propyl; 2,3-di- hydroxy-propyl; 3-hydroxy-propyl; 3-methoxy-propyl; prop
  • R 1 is a group of the formula: -(CR 20 R 21 ) m -(CR 22 R 23 ) n -(CR 24 R 25 ) o -NR 26 R 27 ;
  • R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , m, n and o are as defined in formula (I).
  • R 1 is a group of the formula:
  • R 1 is a group of the formula
  • R 1 is a group of the formula:
  • R 1 is a group of the formula: -CH 2 -C(CHa) 2 CH 2 -NR 26 R 27
  • R 26 and R 27 are each independently selected from the group consisting of H, or alkyl. If R 26 and R 27 are alkyl then in one embodiment they are independently selected from CrC 10 alkyl. In another embodiment they are independently selected from C 1 -C 6 alkyl. Examples of specific values of alkyl are methyl, ethyl, propyl, isopropyl, 2,2-dimethyl-propyl, butyl, isobutyl, tert-butyl, pentyl, 2,4,4-trimethyl-pentyl, and hexyl, each of which may be optionally substituted.
  • R 26 and R 27 together with the nitrogen to which they are attached from an optionally substituted heterocycloalkyl group, which in certain embodiment is a 5 or 6 membered heterocycloalkyl group.
  • an optionally substituted heterocycloalkyl group which in certain embodiment is a 5 or 6 membered heterocycloalkyl group.
  • heterocycloalkyl groups that may be formed by the combination of R 26 and R 27 include pyrrolidine and piperidine.
  • R 2 is selected from the group consisting of H, alkyl, hydroxyalkyl, alkoxyalkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, heterocycloalkylalkyl, heterocycloalkyl heteroalkyl, arylalkyl, heteroarylalkyl, aryl heteroalkyl, heteroarylheteroalkyl, and L, each of which may be optionally substituted as previously stated.
  • R 2 is an arylalkyl moiety.
  • suitable arylalkyl moieties include benzyl and phenethyl.
  • R 2 is an alkyl group which in one embodiment is selected from CrC-io alkyl. In another embodiment R 2 is selected from CrC ⁇ alkyl. Examples of specific values of alkyl are methyl, ethyl, propyl, isopropyl, 2,2-dimethyl-propyl, butyl, isobutyl, tert-butyl, pentyl, 2,4,4-trimethyl-pentyl, and hexyl, each of which may be optionally substituted.
  • R 2 is alkyl or heteroalkyl then it is not substituted by a cycloalkyl, aryl, heteroaryl, or heterocycloalkyl group.
  • R 2 include : H; methyl; (pyridin-2-yl)methyl; (pyridin-3-yl)methyl; ethyl; 2-hydroxy-ethyl; 2-(pyridin-2-yl)ethyl; 2-(pyridin-3-yl)ethyl; 2-phenyl-ethyl; 2-carboxy-ethyl; 2-(morpholin-4-yl)-ethyl; 2-(piperidin-1-yl)-ethyl; 2-(pyrollidin-1-yl)- ethyl; 2-dimethylamino-ethyl; 2-diethy!amino-ethyl; 2-methoxy-ethyl; propyl; 2,3-di- hydroxy-propyl; 3-hydroxy-propyl; 3-methoxy-propyl; 3-isopropoxy-propyl; 2,2-dimethyl- propyl; 3-dimethylamino-propyl; 3-dimethylamino-
  • R 2 and R 2a are joined such that together with the carbon atoms to which they are attached they form a cyclic group containing from 3 to 20 atoms in the cyclic moiety. In one form of this embodiment the R 2 and R 2a are joined such that together with the carbon atoms to which they are attached they form a cyclohexenyl group.
  • R 2a is selected from the group consisting of H, alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, heterocycloalkylalkyl, heterocycloalkyl heteroalkyl, arylheteroalkyl and L 1 each of which may be optionally substituted as previously stated.
  • R 2a is selected from the group consisting of heterocycloalkylalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl and arylheteroalkyl, each of which may be optionally substituted.
  • R 2a is alkyl or heteroalkyl then it is not substituted by a cycloalkyl, aryl, heteroaryl, or heterocycloalkyl group.
  • R 2a is an arylheteroalkyl group, a heterocycloalkylheteroalkyl group or a heteroarylheteroalkyl group and has the formula:
  • B is Aryl, heteroaryl or heterocycloalkyl.
  • r and s are integers independently selected from 0 to 6;
  • R 9 is selected from the group consisting of H, Ci-C 6 alkyl, hydroxyalkyl, heteroalkyl, C 4 - C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl and acyl each of which may be optionally substituted.
  • the group is an arylheteroalkyl group and has the formula: Ar-(CH 2 ) r -NR 9 -(CH 2 ) s —
  • r and s are integers independently selected from 0 to 6;
  • R 9 is selected from the group consisting of H, CrC ⁇ alkyl, hydroxyalkyl, heteroalkyl, C 4 - C 9 cycloalkyl, C 4 -Cg heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl and acyl each of which may be optionally substituted.
  • R 2a is a heterocycloalkylheteroalkyl group and has the formula:
  • r and s are integers independently selected from 0 to 6;
  • R 9 is selected from the group consisting of H, CrC 6 alkyl, hydroxyalkyl, heteroalkyl, C 4 - C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl and acyl each of which may be optionally substituted.
  • R 2a is:
  • Cy is CrC 15 alkyl, aminoalkyl, heteroalkyl heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted;
  • L 1 is selected from the group consisting of CrC 5 alkyl or C 2 -C 5 alkenyl each of which may be optionally substituted;
  • W is selected from the group consisting of a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -N(R 9 )-, -C(O)N(R 9 )-, -SO 2 N(R 9 )-, -N(R 9 )C(0)-, - N(R 9 )SO 2 -, and -N(R 9 )-C(O)-N(R 10 )-;
  • R 2a is a group of formulae:
  • Cy is CrC 15 alkyl, aminoalkyl, heterocycloalkyl, cycloalkyl, aryl, aryloxy or heteroaryl, each of which may be optionally substituted;.
  • L 1 is selected from the group consisting of C 1 -C 5 alkyl, which may be optionally substituted.
  • R 2a is a group of formula:
  • R 2a H; methyl; benzylamino-methyl; dibenzylamino- methyl; (3-phenylpropyl-amino)-methyl, pyrrolidin-1 -yl-methyl; [2-(4-fluoro-phenyl)- acetylamino]-methyl; 2-methyl-pyrollidin-1 -yl-methyl, [2-(4-methoxy-phenyl)- acetylamino]-methyl; (2-pyrollidin-1-yl-ethylamino)-methyl; (phenethylamino)methyl; 4- methoxy-benzylamino-methyl; (2-hydroxyethyl)-phenethyl-amino)-methyl; benzyloxy- methyl; phenylacetylamino-methyl; 1-amino-2-phenyl-ethyl; 2-benzylamino-ethyl; 2-(3- methoxy-phenyl)-eth
  • Each Y may be the same or different and is generally selected from the group consisting of H, halogen, CrC 4 alkyl, -CF 3 , -NO 2 , -C(O)R 6 , -OR 7 , -SR 7 , -CN and - NR 7 R 8 .
  • p is 1 the substitution is preferably at the 4 or 7 position of the ring. If p is 2 the substituents are preferably at the 4 and 7 position of the ring, p is preferably O.
  • R 3 is preferably H, CrC 6 alkyl, or acyl, more preferably H or CrC 4 alkyl, most preferably H;
  • R 4 is preferably H or C 1 -C 4 alkyl, most preferably H;
  • R 5 is preferably H, CrC 4 alkyl, heteroalkyl, or acyl, most preferably methyl;
  • R 6 is preferably H, CrC 4 alkyl, heteroalkyl or acyl, most preferably CrC 4 alkyl;
  • R 7 and R 8 are preferably selected from the group consisting of H, d-C ⁇ alkyl,
  • the embodiments disclosed are also directed to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • HDAC inhibiting agents or “HDAC inhibitors”.
  • the compounds disclosed are used to modify deacetylase activity, in some cases histone deacetylase activity and in some cases HDAC 8, or HDAC 1 activity.
  • the embodiments disclosed also relate to pharmaceutical compositions each comprising a therapeutically effective amount of a HDAC inhibiting agent of the embodiments described with a pharmaceutically acceptable carrier or diluent for treating cellular proliferative ailments.
  • effective amount indicates an amount necessary to administer to a host to achieve a therapeutic result, e.g., inhibition of proliferation of malignant cancer cells, benign tumor cells or other proliferative cells.
  • the invention also relates to pharmaceutical compositions including a compound of the invention with a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a method of treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis including administration of a therapeutically effective amount of a compound of formula (I).
  • the method includes administration of a compound of (Ia) (Ib), (Ic) or (Id) as described herein.
  • the disorder is selected from the group consisting of but not limited to cancer (e.g. breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemias, lymphomas, ovarian cancers, neuroblastomas, melanoma, inflammatory diseases/immune system disorders, angiofibroma, cardiovascular diseases (e.g. restenosis, arteriosclerosis), fibrotic diseases (e.g. liver fibrosis), diabetes, autoimmune diseases, chronic and acute neurodegenerative disease like disruptions of nerval tissue, Huntington's disease and infectious diseases like fungal, bacterial and viral infections.
  • the disorder is a proliferative disorder.
  • the proliferative disorder is cancer.
  • the cancer can include solid tumors or hematologic malignancies.
  • the invention also provides agents for the treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis including a compound of formula (I) as disclosed herein.
  • the agent is an anti-cancer agent.
  • the agent is an anti-angiogenesis agent.
  • the agent contains a compound of formula (Ia) (Ib) 1 (Ic) or (Id) as described herein.
  • the invention also relates to the use of compounds of formula (I) in the preparation of a medicament for the treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis.
  • a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis.
  • the disorder is a proliferative disorder.
  • the disorder is a cancer.
  • the compounds of the present invention surprisingly show low toxicity, together with a potent anti-proliferative activity.
  • the invention provides a method of treatment of a disorder, disease or condition that can be treated by the inhibition of histone deacetylase including administration of a therapeutically effective amount of a compound of formula
  • the method includes administration of a compound of formula (Ia) (Ib), (Ic) or (Id) as described herein.
  • the disorder is selected from the group consisting of but not limited to Proliferative disorders (e.g. cancer); Neurodegenerative diseases including Huntington's Disease, Polyglutamine diseases, Parkinson's Disease, Alzheimer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion , dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de Ia Tourette syndrome, Diffuse Lewy body disease, Pick's disease, Intracerebral haemorrhage Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-related macular degeneration, macular myopic degeneration
  • the invention also provides agents for the treatment of a disorder, disease or condition that can be treated by the inhibition of histone deacetylase including a compound of formula (I) as disclosed herein.
  • the agent is an anti-cancer agent.
  • the invention also relates to the use of compounds of formula (I) in the preparation of a medicament for the treatment of a disorder, disease or condition that can be treated by the inhibition of histone deacetylase.
  • the invention also provides a method for inhibiting cell proliferation including administration of an effective amount of a compound according to formula (I).
  • the invention provides a method of treatment of a neurodegenerative disorder in a patient including administration of a therapeutically effective amount of a compound of formula (I).
  • the method includes administration of a formula (Ia) (Ib), (Ic) or (Id) as described herein.
  • the neurodegenerative disorder is Huntington's Disease.
  • the invention also provides agents for the treatment of neurodegenerative disorder including a compound of formula (I) as disclosed herein.
  • the agent is an anti-Huntington's disease agent.
  • the invention also relates to the use of compounds of formula (I) in the preparation of a medicament for the treatment of a neurodegenerative disorder.
  • the neurodegenerative disorder is Huntington's Disease.
  • the invention provides a method of treatment of an inflammatory disease and/or immune system disorder in a patient including administration of a therapeutically effective amount of a compound of formula (I).
  • the method includes administration of a compound of formula (Ia), (Ib), (Ic) or (Id) as described herein.
  • the inflammatory disease and/or immune system disorder is rheumatoid arthritis.
  • the inflammatory disease and/or immune system disorder is Systemic Lupus Erythematosus.
  • the invention also provides agents for the treatment of inflammatory disease and/or immune system disorder including a compound of formula (I) as disclosed herein.
  • the invention also relates to the use of compounds of formula (I) in the preparation of a medicament for the treatment of inflammatory disease and/or immune system disorder.
  • the inflammatory disease and/or immune system disorder is rheumatoid arthritis.
  • the inflammatory disease and/or immune system disorder is Systemic Lupus Erythematosus.
  • the invention provides a method of treatment of eye disease mediated by HDAC inhibition in a patient including administration of a therapeutically effective amount of a compound of formula (I).
  • the method includes administration of a compound of formula (Ia), (Ib), (Ic) or (Id) as described herein.
  • the eye disease is macular degeneration.
  • the eye disease is glaucoma.
  • the eye disease is retinal degeneration.
  • the invention also provides agents for the treatment of eye disease mediated by HDAC inhibition including a compound of formula (I).
  • the eye disease is macular degeneration.
  • the eye disease is glaucoma.
  • the eye disease is retinal degeneration.
  • the invention also relates to the use of compounds of formula (I) in the preparation of a medicament for the treatment of eye disease mediated by HDAC inhibition.
  • the method preferably includes administration of a compound of formula (Ia), (Ib), (Ic) or (Id) as described herein.
  • the eye disease is macular degeneration.
  • the eye disease is glaucoma.
  • the eye disease is retinal degeneration.
  • hydroxamate compounds for example heterocycles containing hydroxamic acid in one of the substituents that may be inhibitors of deacetylases, including but not limited to inhibitors of histone deacetylases.
  • the hydroxamate compounds may be suitable for prevention or treatment of a disorder caused by, associated with or accompanied by disruptions of cell proliferation and/or angiogenesis when used either alone or together with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • An example of such a disorder is cancer.
  • 'cancer 1 is a general term intended to encompass the vast number of conditions that are characterised by uncontrolled abnormal growth of cells.
  • the compounds of the invention will be useful in treating various cancers including but not limited to bone cancers including Ewing's sarcoma, osteosarcoma, chondrosarcoma and the like, brain and CNS tumours including acoustic neuroma, neuroblastomas, glioma and other brain tumours, spinal cord tumours, breast cancers, colorectal cancers, advanced colorectal adenocarcinomas, colon cancers, endocrine cancers including adenocortical carcinoma, pancreatic cancer, pituitary cancer, thyroid cancer, parathyroid cancer, thymus cancer, multiple endocrine neoplasma, gastrointestinal cancers including stomach cancer, esophageal cancer, small intestine cancer, Liver cancer, extra hepatic bile duct cancer, gastrointestinal carcinoid tumour, gall bladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostate cancer, gynaecological cancers including cervical cancer
  • cancers examples include breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer (e.g. renal cell carcinoma), gastric cancer, colon cancer, colon cancer, colorectal cancer and brain cancer.
  • renal cancer e.g. renal cell carcinoma
  • gastric cancer e.g. gastric cancer
  • colon cancer e.g. colon cancer
  • colorectal cancer e.g. colorectal cancer and brain cancer.
  • cancers that may be treated by compounds of the present invention include but are not limited to B-cell lymphoma (e.g. Burkitt's lymphoma), leukemias (e.g. Acute promyelocytic leukemia), cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma.
  • B-cell lymphoma e.g. Burkitt's lymphoma
  • leukemias e.g. Acute promyelocytic leukemia
  • CCL cutaneous T-cell lymphoma
  • peripheral T-cell lymphoma peripheral T-cell lymphoma
  • the compounds may also be used in the treatment of a disorder involving, relating to or, associated with dysregulation of histone deacetylase (HDAC).
  • HDAC histone deacetylase
  • HDAC activity is known to play a role in triggering disease onset, or whose symptoms are known or have been shown to be alleviated by HDAC inhibitors.
  • disorders of this type that would be expected to be amenable to treatment with the compounds of the invention include the following but not limited to: Proliferative disorders (e.g.
  • Neurodegenerative diseases including Huntington's Disease, Polyglutamine diseases, Parkinson's Disease, Alzheimer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de Ia Tourette syndrome, Diffuse Lewy body disease, Pick's disease, Intracerebral haemorrhage Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic paraplegia, Progressive ataxia and Shy-Drager syndrome; Metabolic diseases including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-related macular degeneration, macular myopic degeneration, Rubeotic glaucoma, Interstitial keratitis, Diabetic retinopathy, Peter'
  • Halogen represents chlorine, fluorine, bromine or iodine.
  • Alkyl as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group, preferably a Ci-Ci 4 alkyl, more preferably C 1 -Ci 0 alkyl, most preferably C 1 -C 6 unless otherwise noted.
  • suitable straight and branched C 1 -C 6 alkyl substituents include methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, t-butyl, hexyl, and the like.
  • Alkylamino includes both monoalkylamino and dialkylamino, unless specified.
  • “Monoalkylamino” means a -NH-Alkyl group, in which alkyl is as defined above.
  • “Dialkylamino” means a -N(alkyl) 2 group, in which each alkyl may be the same or different and are each as defined herein for alkyl.
  • the alkyl group is preferably a Ci-C 6 alkyl group.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono- arylamino means a group of formula aryl NH- in which aryl is as defined herein
  • di- arylamino means a group of formula (aryl 2 ) N- where each aryl may be the same or different and each are as defined herein for aryl.
  • acyl means an alkyl-CO- group in which the alkyl group is as described herein.
  • examples of acyl include acetyl and benzoyl.
  • the alkyl group is preferably a C 1 -C 6 alkyl group.
  • Alkenyl as group or part of a group denotes an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched preferably having 2-14 carbon atoms, more preferably 2-12 carbon atoms, most preferably 2-6 carbon atoms, in the chain.
  • the group may contain a plurality of double bonds in the normal chain and the orientation about each is independently E or Z.
  • Exemplary alkenyl group include, but are not limited to, ethenyl and propenyl.
  • Alkoxy refers to an -O-alkyl group in which alkyl is defined herein. Preferably the alkoxy is a CrC ⁇ alkoxy. Examples include, but are not limited to, methoxy and ethoxy.
  • alkenyloxy refers to an -O- alkenyl group in which alkenyl is as defined herein.
  • Preferred alkenyloxy groups are CrC 6 alkenyloxy groups.
  • Alkynyloxy refers to an -O-alkynyl group in which alkynyl is as defined herein. Preferred alkynyloxy groups are CrC 6 alkynyloxy groups.
  • Alkoxycarbonyl refers to an -C(O)-O-alkyl group in which alkyl is as defined herein.
  • the alkyl group is preferably a Ci-C 6 alkyl group. Examples include, but not limited to, methoxycarbonyl and ethoxycarbonyl.
  • Alkylsulfinyl means a -S(O)-alkyl group in which alkyl is as defined above.
  • the alkyl group is preferably a CrC 6 alkyl group.
  • Exemplary alkylsulfinyl groups include, but not limited to, methylsulfinyl and ethylsulfinyl.
  • Alkylsulfonyl refers to a -S(O) 2 -alkyl group in which alkyl is as defined above.
  • the alkyl group is preferably a C 1 -C 6 alkyl group. Examples include, but not limited to methylsulfonyl and ethylsulfonyl.
  • Alkynyl as a group or part of a group means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which may be straight or branched preferably having from 2-14 carbon atoms, more preferably 2-12 carbon atoms in the chain, preferably 2-6 carbon atoms in the chain.
  • Exemplary structures include, but are not limited to, ethynyl and propynyl.
  • Alkylaminocarbonyl refers to an alkylamino-C(O)- group in which alkylamino is as defined above.
  • Cycloalkyl refers to a saturated or partially saturated, monocyclic or fused or spiro polycyclic, carbocycle preferably containing from 3 to 9 carbons per ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, unless otherwise specified. It includes monocyclic system such as cyclohexyl, bicyclic systems such as decalin, and polycyclic systems such as adamantane. "Cycloalkylalkyl” means a cycloalkyl-alkyl- group in which the cycloalkyl and alkyl moieties are as previously described. Exemplary monocycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.
  • Heterocycloalkyl refers to a saturated or partially saturated monocyclic, bicyclic or polycyclic ring containing at least a heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms in at least one ring. Each ring is preferably from 3 to 10 membered, more preferably 4 to 7 membered.
  • heterocycloalkyl substituents include pyrrolidyl, tetrahydrofuryl, tetrahydrothiofuranyl, piperidyl, piperazyl, tetrahydropyranyl, morphilino, 1 ,3-diazapane, 1 ,4-diazapane, 1 ,4-oxazepane, and 1 ,4-oxathiapane.
  • Heterocycloalkenyl refers to a heterocycloalkyl as described above but containing at least one double bond.
  • Heterocycloalkylalkyl refers to a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as previously described.
  • exemplary heterocycloalkylalkyl groups include (2-tetrahydrofuryl)methyl, (2-tetrahydrothiofuranyl)methyl.
  • Heteroalkyl refers to a straight- or branched-chain alkyl group preferably having from 2 to 14 carbon atoms, more preferably 2 to 10 atoms in the normal chain, one or more of which has been replaced by a heteroatom selected from S, O, and N.
  • exemplary heteroalkyls include alkyl ethers, secondary and tertiary alkyl amines, alkyl sulfides, and the like.
  • Aryl as a group or part of a group denotes (i) an optionally substituted monocyclic, or fused polycyclic, aromatic carbocycle (ring structure having ring atoms that are all carbon) preferably having from 5 to 12 atoms per ring.
  • aryl groups include phenyl, naphthyl, and the like; (ii) an optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a C 5-7 cycloalkyl or C 5-7 cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyl are as previously described.
  • Exemplary arylalkenyl groups include phenylallyl.
  • Arylalkyl means an aryl-alkyl- group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a Ci -5 alkyl moiety.
  • Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl.
  • Cycloalkenyl means an optionally substituted non-aromatic monocyclic or polycyclic ring system containing at least one carbon-carbon double bond and preferably having from 5-10 carbon atoms per ring.
  • Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl or cycloheptenyl.
  • heteroaryl either alone or part of another group refers to groups containing an aromatic ring (preferably a 5 or 6 membered aromatic ring) having 1 or more heteroatoms as ring atoms in the aromatic ring with the remainder of the ring atoms being carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen.
  • heteroaryl examples include thiophene, benzothiophene, benzofuran, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, naphtho[2,3-b]thiophene, furan, isoindolizine, xantholene, phenoxatine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1 H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, phenanthridine, acridine, phenazine, thiazole, isothiazole, phenothiazine, oxazole, isoxazole, furazane
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a C 1 to C 6 alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • “Lower alkyl” as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having 1 to 6 carbon atoms in the chain, more preferably 1 to 4 carbons such as methyl, ethyl, propyl (n-pr ⁇ pyl or isopropyl) or butyl (n-butyl, isobutyl or tertiary-butyl).
  • the positions for attachment of the acidic moiety are the 5- and 6-ring positions.
  • Some of the compounds of the disclosed embodiments may exist as single stereoisomers, racemates, and/or mixtures of enantiomers and /or diastereomers. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the subject matter described and claimed.
  • Formula (I) is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds.
  • each formula includes compounds having the indicated structure, including the hydrated as well as the non-hydrated forms.
  • the HDAC inhibiting agents of the various embodiments include pharmaceutically acceptable salts, prodrugs, and active metabolites of such compounds, and pharmaceutically acceptable salts of such metabolites.
  • “Pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds, and include pharmaceutically acceptable acid addition salts and base addition salts.
  • Suitable pharmaceutically acceptable acid addition salts of compounds of Formula I may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are hydrochloric, sulfuric, and phosphoric acid.
  • Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, fumaric, maleic, alkyl sulfonic, arylsulfonic.
  • Suitable pharmaceutically acceptable base addition salts of compounds of Formula I include metallic salts made from lithium, sodium, potassium, magnesium, calcium, aluminium, and zinc, and organic salts made from organic bases such as choline, diethanolamine, morpholine.
  • organic salts are: ammonium salts, quaternary salts such as tetramethylammonium salt; amino acid addition salts such as salts with glycine and arginine. Additional information on pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 19th Edition, Mack Publishing Co., Easton, PA 1995. In the case of agents that are solids, it is understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
  • 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 hydroxyl group are for example acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis- ⁇ -hydroxynaphthoates, gestisates, 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.
  • ester prodrugs are those described by FJ. Leinweber, Drug Metab. Res., 18:379, 1987).
  • Preferred HDAC inhibiting agents include those having an IC 50 value of 10 ⁇ M or less.
  • Administration of compounds within Formula (I) to humans can be by any of the accepted modes for enteral administration such as oral or rectal, or by parenteral administration such as subcutaneous, intramuscular, intravenous and intradermal routes. Injection can be bolus or via constant or intermittent infusion.
  • the active compound is typically included in a pharmaceutically acceptable carrier or diluent and in an amount sufficient to deliver to the patient a therapeutically effective dose.
  • the inhibitor compound may be selectively toxic or more toxic to rapidly proliferating cells, e.g. cancerous tumors, than to normal cells.
  • the term "therapeutically effective amount" or “effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations.
  • An effective amount is typically sufficient to palliate, ameliorate, stabilize ⁇ reverse, slow or delay the progression of the disease state.
  • a therapeutically effective amount can be readily determined by a skilled practitioner by the use of conventional techniques and by observing results obtained in analogous circumstances. In determining the effective amount a number of factors are considered including the species of the patient, its size, age, general health, the specific disease involved, the degree or severity of the disease, the response of the individual patient, the particular compound administered, the mode of administration, the bioavailability of the compound, the dose regimen selected, the use of other medication and other relevant circumstances.
  • the compounds of the invention can be administered in any form or mode which makes the compound bioavailable.
  • One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the condition to be treated, the stage of the condition to be treated and other relevant circumstances. We refer the reader to Remingtons Pharmaceutical Sciences, 19 th edition, Mack Publishing Co. (1995) for further information.
  • the compounds of the present invention can be administered alone or in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutically acceptable carrier diluent or excipient.
  • the compounds of the invention while effective themselves, are typically formulated and administered in the form of their pharmaceutically acceptable salts as these forms are typically more stable, more easily crystallised and have increased solubility.
  • compositions which are formulated depending on the desired mode of administration.
  • the present invention provides a pharmaceutical composition including a compound of Formula (I) and a pharmaceutically acceptable carrier, diluent or excipient.
  • the compositions are prepared in manners well known in the art.
  • kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pack or kit can be found a container having a unit dosage of the agent(s).
  • the kits can include a composition comprising an effective agent either as concentrates (including lyophilized compositions), which can be diluted further prior to use or they can be provided at the concentration of use, where the vials may include one or more dosages.
  • single dosages can be provided in sterile vials so that the physician can employ the vials directly, where the vials will have the desired amount and concentration of agent(s).
  • Associated with such container(s) can be various written materials such as instructions for use, or a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • the compounds of the invention may be used or administered in combination with one or more additional drug (s) that include chemotherapeutic drugs or HDAC inhibitor drugs and/or procedures (e.g. surgery, radiotherapy) for the treatment of the disorder/diseases mentioned.
  • additional drug s
  • the components can be administered in the same formulation or in separate formulations. If administered in separate formulations the compounds of the invention may be administered sequentially or simultaneously with the other drug (s).
  • the compounds of the invention may be used in a combination therapy. When this is done the compounds are typically administered in combination with each other. Thus one or more of the compounds of the invention may be administered either simultaneously (as a combined preparation) or sequentially in order to achieve a desired effect. This is especially desirable where the therapeutic profile of each compound is different such that the combined effect of the two drugs provides an improved therapeutic result
  • compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminium monostearate and gelatin.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, dragees, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
  • Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • the active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifier
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroskide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroskide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Dosage forms for topical administration of a compound of this invention include powders, patches, sprays, ointments and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required.
  • a preferred dosage will be a range from about 0.01 to 300 mg per kilogram of body weight per day.
  • a more preferred dosage will be in the range from 0.1 to 100 mg per kilogram of body weight per day, more preferably from 0.2 to 80 mg per kilogram of body weight per day, even more preferably 0.2 to 50 mg per kilogram of body weight per day.
  • a suitable dose can be administered in multiple sub-doses per day.
  • the compounds of the embodiments disclosed inhibit histone deacetylases.
  • the enzymatic activity of a histone deacetylase can be measured using known methodologies (Yoshida M. et al, J. Biol. Chem., 1990, 265:17174, J. Taunton et al, Science 1996, 272: 408).
  • the histone deacetylase inhibitor interacts with and/or reduces the activity of more than one known histone deacetylase in the cell, which can either be from the same class of histone deacetylase or different class of histone deacetylase..
  • the histone deacetylase inhibitor interacts and reduces the activity of predominantly one histone deacetylase, for example HDAC-1 , HDAC-2, HDAC-3 or HDAC-8 which belongs to Class I HDAC enzymes (De Ruijter AJ. M. et al, Biochem. J., 2003, 370:737-749).
  • HDACs can also target non-histone substrates to regulate a variety of biological functions implicated in disease pathogenesis. These non-histone substrates include Hsp90, ⁇ -tubulin, p53, NFkb and HIFIa (Drummond et al., Annu. Rev. Pharmacol. Toxicol. 2004, 45:495).
  • Certain preferred histone deacetylase inhibitors are those that interact with, and/or reduce the activity of a histone deacetylase which is involved in tumorigenesis, and these compounds may be useful for treating proliferative diseases.
  • Examples of such cell proliferative diseases or conditions include cancer (include any metastases), psoriasis, and smooth muscle cell proliferative disorders such as restenosis.
  • the inventive compounds may be particularly useful for treating tumors such as breast cancer, colon cancer, lung cancer, ovarian cancer, prostate cancer, head and/or neck cancer, or renal, gastric, pancreatic cancer and brain cancer as well as hematologic malignancies such as lymphoma and leukemias.
  • inventive compounds may be useful for treating a proliferative disease that is refractory to the treatment with other chemotherapeutics; and for treating hyperproliferative condition such as leukemias, psoriasis and restenosis.
  • compounds of this invention can be used to treat pre-cancer conditions or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the larynx, actinic and solar keratosis, seborrheic keratosis and keratoacanthoma.
  • pre-cancer conditions or hyperplasia including familial adenomatous polyposis, colonic adenomatous polyps, myeloid dysplasia, endometrial dysplasia, endometrial hyperplasia with atypia, cervical dysplasia, vaginal intraepithelial neoplasia, benign prostatic hyperplasia, papillomas of the
  • compounds of the various embodiments disclosed herein may be useful for treating neurodegenerative diseases, and inflammatory diseases and/or immune system disorders.
  • the disorder may be selected from the group consisting of cancer, inflammatory diseases and/or immune system disorders (e.g. rheumatoid arthritis, systemic lupus erythematosus), angiofibroma, cardiovascular diseases, fibrotic diseases, diabetes, autoimmune diseases, chronic and acute neurodegenerative disease like Huntington's disease, Parkinson's disease, disruptions of nerval tissue and infectious diseases like fungal, bacterial and viral infections.
  • the disorder is a proliferative disorder.
  • histone deacetylase inhibitors of the invention have significant antiproliferative effects and promote differentiation, cell cycle arrest in the G1 or G2 phase, and induce apoptosis.
  • the agents of the various embodiments may be prepared using the reaction routes and synthesis schemes as described below, employing the techniques available in the art using starting materials that are readily available.
  • the preparation of particular compounds of the embodiments is described in detail in the following examples, but the artisan will recognize that the chemical reactions described may be readily adapted to prepare a number of other agents of the various embodiments.
  • the synthesis of non-exemplified compounds may be successfully performed by modifications apparent to those skilled in the art, e.g. by appropriately protecting interfering groups, by changing to other suitable reagents known in the art, or by making routine modifications of reaction conditions.
  • a list of suitable protecting groups in organic synthesis can be found in T.W. Greene and P. G. M. Wuts' Protective Groups in Organic Synthesis, 3rd Edition, Wiley-lnterScience, 1999.
  • other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the various embodiments.
  • Reagents useful for synthesizing compounds may be obtained or prepared according to techniques known in the art.
  • THF Tetrahydrofuran
  • DMF N,N-dimethylformamide
  • the reactions set forth below were performed under a positive pressure of nitrogen, argon or with a drying tube, at ambient temperature (unless otherwise stated), in anhydrous solvents, and the reaction flasks are fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven-dried and/or heat-dried. Analytical thin-layer chromatography was performed on glass-backed silica gel 60 F 254 plates (E Merck (0.25 mm)) and eluted with the appropriate solvent ratios (v/v). The reactions were assayed by TLC and terminated as judged by the consumption of starting material.
  • the TLC plates were visualized by UV absorption or with a p-anisaldehyde spray reagent or a phosphomolybdic acid reagent (Aldrich Chemical, 20wt% in ethanol) which was activated with heat, or by staining in iodine chamber. Work-ups were typically done by doubling the reaction volume with the reaction solvent or extraction solvent and then washing with the indicated aqueous solutions using 25% by volume of the extraction volume (unless otherwise indicated). Product solutions were dried over anhydrous sodium sulfate prior to filtration, and evaporation of the solvents was under reduced pressure on a rotary evaporator and noted as solvents removed in vacuo. Flash column chromatography (Still et al, J. Org.
  • NMR spectra was recorded on a Bruker instrument operating at 400 MHz, and 13 C-NMR spectra was recorded operating at 100 MHz. NMR spectra are obtained as CDCb solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD 3 OD (3.4 and 4.8 ppm and 49.3 ppm), or an internal tetramethylsilane standard (0.00 ppm) when appropriate. Other NMR solvents were used as needed.
  • Mass spectra were obtained using LC/MS either in ESI or APCI. All melting points are uncorrected.
  • R 2 and each Y are hydrogens, and R 1 is either hydrogen or substituted.
  • R 1 is either hydrogen or substituted.
  • such compound(s) can be synthesized by analogous method illustrated in Scheme I starting with a substituted indole (e.g. 5-Bromo-1H-indole-3-carbaldehyde), which can be alkylated at the indole nitrogen under basic conditions to give II.
  • the N-alkylated indole derivative was then reacted with ethyl acrylate under Heck reaction condition to provide the desired alkenoic ester IV.
  • the aldehyde group in IV was then reacted with appropriate amine component (R 8 RgNH) to give the reductive amination product.
  • R 8 RgNH appropriate amine component
  • the reductive amination product is a secondary amine it can be further reacted with an appropriate aldehyde, or an appropriate alkyl halide to produce a tertiary amine.
  • the carboxylic ester group was converted to the hydroxamic acid derivative by reacting with appropriate hydroxylamine or N-alkyl hydroxylamine (NHR 3 OR 4 where R 3 and R 4 are defined as above in Formula I).
  • the hydroxamate compounds Vl were prepared by a known synthesis method (J. Med. Chem., 2002, 45:753-757).
  • Examples 1 , 2, 3, 10 &11 were synthesized according to Scheme I.
  • Compounds of Formula Ib for example Example 4, in which the indole nitrogen is not alkylated, can be successfully prepared by Scheme I.
  • a Heck reaction can be first performed on 5-Bromo-1 H-indole-3-carbaldehyde to give the indole acrylate, which is followed by N-alkylation of indole to give IV. Following a reductive amination IV is converted to the desired amine which can be converted to the desired hydroxamic acid.
  • Examples 6 - 9 were prepared by this alternative synthetic route.
  • compounds of general structure VIII could be prepared from indole aldehyde IV.
  • the aldehyde group can be reduced to the primary alcohol under mild reduction conditions, and the resulting alcohol can be subsequently converted to a good leaving group such as a bromide Vila by methods known in the literature.
  • the reactive Vila can be reacted with carbon nucleophiles or oxo anions or thiolates to give 1 ,3-substituted indoles VIIb, and subsequently to the desired hydroxamate VIII as depicted in Formula I.
  • 1 ,3-substituted indoles may be prepared by methodologies in which the 3-substituent is introduced during indole ring formation [Org Lett, 2004, 6:79-82] and in certain 3-substituents the substituents can be further modified.
  • Reagents and conditions (a) SnCI 2 (10 equiv), MeOH, 60 0 C. (b) 1. NaNO 2 , HCI. 2. SnCI 2 (10 equiv), MeOH. (c) TsOH, EtOH, reflux, (d) NH 2 OKHCI, MeONa, MeOH.
  • 2,3-substituted indole derivatives can be prepared by other methodologies which are known in the literature [J. Org. Chem, 1997, 62, 2676; J. Am. Chem. Soc, 1999, 121 :3791-3792]. These 2,3-substituted indoles can be extended to 1 ,2,3-substituted indoles of Formula I, by alkylation of the indole nitrogen. Examples 16, 18, 19 were prepared according to Scheme II.
  • the compounds of formula (Ib) may also be produced using the methodology in scheme (III).
  • Scheme IV illustrates the general procedure used for preparing compounds of formula Ic.
  • Such compound(s) can be synthesized by analogous method illustrated in Scheme IV starting with 5-bromoisatin (XVIII) which can be converted to indazole XIX by methods known in the literature.
  • the indazole carboxylate XIX was reacted with a primary or secondary amine together with a coupling agent such as PyBop to form the amide XX.
  • the indazole nitrogen was then alkylated by reaction with an alkyl halide XXI.
  • N-alkylated iridazole derivative XXII was then reacted with ethyl dcrylate XXIII under Heck reaction condition to provide the desired alkenoic ester XXIV which was subsequently converted to the hydroxamic acid XXV by a known synthesis method (J. Med. Chem., 2002, 45:753-757).
  • the carboxylic acid group in structure XIX can be transformed to corresponding aldehydes XXViI which can be further modified.
  • the aldehyde group can be reduced to the primary alcohol under mild reduction conditions, and the resulting alcohol can be subsequently converted to a good leaving group such as a bromide XXIX by methods known in the literature.
  • the reactive intermediate XXIX can be reacted with carbon nucleophiles or oxo anions or thiolates to give 1 ,3- substituted indazoles XXX as illustrated in Scheme V.
  • the hydroxamate compounds XXXVIII can be synthesized by the synthetic route shown in Scheme Vl.
  • the readily available 5-Bromo-3-nitro-pyridin-2-ol XXXII was converted to the 2-CI derivative XXXIII by treating with POCI 3 , and XXXIII was then reacted with an amine to give 5-Bromo-3-nitro-pyridin-2-amine XXXlV
  • the 2- amino compound was reacted with aldehyde and tin chloride, then followed by oxidation with Oxone to give compound XXXVI. Heck reaction of XXXVI and ethyl acrylate afforded compound XXXVII.
  • the hydroxamate compounds XXXVIII were obtained by a known synthesis method (J. Med. Chem., 2002, 45, 753-757).
  • hydroxamate compounds of Formula Id wherein the ⁇ , ⁇ - unsaturated hydroxamic acid is located adjacent to the pyridine nitrogen can be synthesized by the synthetic route shown in Scheme VII.
  • 5-Methoxy-6-nitro-pyridine-2- carboxylic acid methyl ester XXXX which could be prepared from XXXIX According to literature procedure (US 6448281 B1 ), can be treated with a corresponding amine to produce a 6-nitro-5- amine derivative of pyridine which after hydrogenation would give compound XXXXI .
  • Imidazole ring formation can be accomplished by treatment of XXXXI with corresponding aldehyde in the presence of Oxone to give compound XXXXII.
  • the desired ⁇ , ⁇ -unsatu rated ester XXXXIII can be introduced into XXXXII by performing Wittig or related reaction on XXXXlI, using appropriate reagents known in the literature to furnish the ⁇ , ⁇ -unsatu rated ester.
  • the hydroxamate compounds (XXXXIV) can be obtained by a known synthesis method (J. Med. Chem., 2002, 45, 753-757).
  • the titled compound (2) was prepared according to the procedures described in
  • Example 1 by using appropriate starting materials. Yield: 50% based on corresponding ester.
  • Solvent B Acetonitrile with 0.1% trifluoroacetic acid; UV 254): 1.64 min; MS(m/z): 419
  • the titled compound (3) was prepared according to the procedures described in Example 1 , by using appropriate starting materials. 52mg (0.14 mmol) of precursor ester, 90 mg (1.3 mmol) of hydroxylamine HCI salt were dissolved in 3 ml_ of dried MeOH and followed by adding 0.59 ml. (4.9 M in MeOH, 2.9 mmol) of sodium methoxide. The resulting solution was stirred at room temperature for 16 hours. The reaction was quenched by adding 1 M HCI and purified by reversed phase HPLC. 18mg of product was obtained. Yield: 35% based on corresponding ester.
  • the compound 5 was prepared according to the procedures described in the following. Intermediate a was alkylated with bromoethanol under basic condition to provide compound b, which was then transformed to corresponding hydroxamate according to procedure described previously to give 5.
  • the titled compound (6) was prepared according to the procedures described in
  • the titled compound (9) was prepared according to the procedures described in
  • the titled compound was prepared using the procedure outlined for example 9. Thus alkylation of indole nitrogen with appropriate alkyl halides, followed by Heck reaction, then by reductive amination with appropriate amines, and finally by converting the ester group to the desired hydroxamate.
  • the titled compound was prepared using the procedure outlined for Example 9. Thus alkylation of indole nitrogen with appropriate alkyl halides, followed by Heck reaction, then by reductive amination with appropriate amines, and finally by converting the ester group to the desired hydroxamate.
  • Human cDNA library was prepared using cultured SW620 cells. Amplification of human HDAC1 and HDAC8 coding region from this cDNA library was cloned separately into the baculovirus expression pDEST20 vector and pFASTBAC vector respectively (GATEWAY Cloning Technology, Invitrogen Pte Ltd). The pDEST20- HDAC1 and pFASTBAC-HTGST-HDAC8 constructs were confirmed by DNA sequencing. Recombinant baculovirus was prepared using the Bac-To-Bac method following the manufacturer's instruction (Invitrogen Pte Ltd). Baculovirus titer was determined by plaque assay to be about 1O 8 PFU/ml.
  • the GST-HDAC1 protein or GST-HDAC8 protein was eluted by elution buffer containing 50 mM Tris, pH ⁇ .O, 15OmM NaCI, 1 % Triton X-100 and 1OmM or 2OmM reduced Glutathione.
  • the purified GST-HDAC1 protein or purified GST- HDAC8 protein was dialyzed with HDAC storage buffer containing 1OmM Tris, pH7.5, 10OmM NaCI and 3mM MgCI 2 . 20% Glycerol was added to purified GST-HDAC1 protein or purified GST-HDAC8 before storage at -8O 0 C.
  • the assay has been carried out in 96 well format and the BIOMOL fluorescent-based HDAC activity assay has been applied.
  • the reaction composed of assay buffer, containing 25 mM Tris pH 7.5, 137 mM NaCI, 2.7 mM KCI, 1 mM MgCI 2 , 1 mg/ml BSA, tested compounds, an appropriate concentration of HDAC8 enzyme or HDAC1 enzyme, 200 ⁇ M Flur de lys p53 peptide substrate for HDAC8 enzyme or 500 ⁇ M Flur de lys generic substrate for HDAC1 enzyme and subsequently was incubated at room temperature for 2 h. Flur de lys Developer was added and the reaction was incubated for 10 min.
  • deacetylation of the substrate sensitizes it to the developer, which then generates a fluorophore.
  • the fluorophore is excited with 360 nm light and the emitted light (460 nm) is detected on a fluorometric plate reader (Tecan Ultra Microplate detection system, Tecan Group Ltd).
  • Colo205 Human cancer cell lines (e.g. Colo205) were obtained from ATCC. Colo205 cells were cultivated in RPM1 1640 containing 2 mM L-Glutamine, 5% FBS, 1.0 mM Na Pyruvate. Colo205 cells were seeded in 96-wells plate at 5000 cells per well. The plates were incubated at 37 0 C, 5% CO 2 , for 24 h. Cells were treated with compounds at various concentrations for 96 h. Cell growth was then monitored using CyQUANT® cell proliferation assay (Invitrogen Pte Ltd). Dose response curves were plotted to determine Gl 50 values for the compounds using XL-fit (ID Business Solution, Emeryville, CA).
  • Histone deacetylase (HDAC) inhibition is the increase in the acetylation level of histones.
  • Histone acetylation including H3, H4 and H2A can be detected by immuno-blotting (western-blot).
  • Colo205 cells approximately 5 x10 5 cells, were seeded in the previously described medium, cultivated for 24 h and subsequently treated with HDAC inhibitory agents and a positive control at 10 ⁇ M final concentration. After 24 h, cells were harvested and lysed according to the instruction from Sigma Mammalian Cell Lysis Kit. The protein concentration was quantified using BCA method (Sigma Pte Ltd).
  • the protein lysate was separated using 4-12% bis-tris SDS-PAGE gel (Invitrogen Pte Ltd) and was transferred onto PVDF membrane (BioRad Pte Ltd).
  • the membrane was probed using primary antibody specific for acetylated histone H3 (Upstate Pte Ltd).
  • the detection antibody, goat anti rabbit antibody conjugated with HRP was used according to the manufacturing instruction (Pierce Pte Ltd).
  • an enhanced chemiluminescent substrate for detection of HRP was added onto the membrane. After removing the substrate, the membrane was exposed to an X-ray film (Kodak) for 1 sec - 20 mins.
  • the X-ray film was developed using the X-ray film processor.
  • the density of each band observed on the developed film could be qualitatively analyzed using UVP Bioimaging software (UVP, Inc, Upland, CA). The values were then normalized against the density of actin in the corresponding samples to obtain the expression of the protein.
  • the efficacy of the compounds of the invention can then be determined using tumor xenograft studies.
  • the tumor xenograft model is one of the most commonly used in vivo cancer models.
  • mice Female athymic nude mice (Harlan), 12-14 weeks of age will be implanted subcutaneously in the flank with 5 x 10 6 cells of HCT116 human colon cancer cells, or with 5 x 10 6 cells of A2780 human ovarian cancer cells, or with 5 x 106 cells of PC3 prostate cancer cells.
  • the xenograft nude mice When the tumor reaches the size 100 mm 3 , the xenograft nude mice will be paired-match into various treatment groups.
  • the selected HDAC inhibitors will be dissolved in appropriate vehicles and administered to xenograft nude mice intraperitonelly or orally daily for 21 days.
  • the dosing volume will be 0.01 ml/ g body weight.
  • Paclitaxol which can be used as positive control, will be prepared for intravenous administration in an appropriate vehicle.
  • the dosing volume for Paclitaxol will be 0.01 ml/g body weight.
  • Compounds of this invention that are tested will show significant reduction in tumor volume relative to controls treated with vehicle only. Acetylated histone relative to vehicle treated control group when measured shall be accumulated. The result will therefore indicate that compounds of this invention are efficacious in treating a proliferative disease such as cancer.

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Abstract

La présente invention porte sur des composés d'hydroxamate inhibiteurs de l'histone désacétylase. Ladite invention concerne plus particulièrement des composés contenant des hétérocycles et leurs procédés de préparation. Ces composés peuvent être utiles en tant que médicaments pour le traitement de troubles prolifératifs et d'autres pathologies impliquant, liées à, ou associées à des enzymes présentant une activité histone désacétylase (HDAC).
PCT/SG2006/000065 2005-03-21 2006-03-20 Composes d'hydraxamate bicycliques contenant des heterocycles utiles en tant qu'inhibiteurs de l'histone desacetylase (hdac) WO2006101456A1 (fr)

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