EP1685094A1 - Hydroxamates connectes a l'acyluree et a la sulfonyluree - Google Patents

Hydroxamates connectes a l'acyluree et a la sulfonyluree

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Publication number
EP1685094A1
EP1685094A1 EP04775672A EP04775672A EP1685094A1 EP 1685094 A1 EP1685094 A1 EP 1685094A1 EP 04775672 A EP04775672 A EP 04775672A EP 04775672 A EP04775672 A EP 04775672A EP 1685094 A1 EP1685094 A1 EP 1685094A1
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
group
phenyl
ethyl
benzoyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP04775672A
Other languages
German (de)
English (en)
Other versions
EP1685094A4 (fr
Inventor
Ze-Yi Lim
Haishan Wang
Yan Zhou
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SBio Pte Ltd
Original Assignee
SBio Pte Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SBio Pte Ltd filed Critical SBio Pte Ltd
Publication of EP1685094A1 publication Critical patent/EP1685094A1/fr
Publication of EP1685094A4 publication Critical patent/EP1685094A4/fr
Withdrawn legal-status Critical Current

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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to hydroxamate compounds that are inhibitors of histone deacetylase. More particularly, the present invention relates to acylurea or sulfonylurea containing compounds and methods for their preparation. 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.
  • 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. Hum. Mol. Genet. 10, 693-698 (2001), De Ruijter A.J.M. et al, Biochem. J., 370, 737-749 (2003)].
  • 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.
  • HDAC inhibitors have become available for clinical evaluation [US6,552,065]. Additional
  • HDAC inhibitors have been reported to interfere with neurodegenerative processes, for instance, HDAC inhibitors arrest polyglutamine-dependent neurodegeneration [Nature, 413(6857): 739-43, 18
  • 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. [J. Biol. Chem. 1990; 265(18): 10230-10237;
  • HDAC inhibitors that would be expected to have useful, improved pharmaceutical properties in the treatment of diseases such as cancer, neurodegenerative diseases and inflammatory and/or immune system disorders.
  • the present invention provides compounds of the Formula (I)
  • R 1 is selected from the group consisting of H, d -C 6 alkyl and acyl
  • M is selected from the group consisting of O, S, NH, NR 4 , NOH and NOR 4 ;
  • R 2 is selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylk
  • R 3 is selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, al
  • G is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R 4 is independently selected from the group consisting of H, alkyl, alkenyi, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally substituted; or a pharmaceutically acceptable salt or prodrug thereof.
  • the present invention provides compounds having the Formula (2)
  • R 1 is selected from the group consisting of H, Ci -C 6 alkyl and acyl
  • L is a single bond or is a C C 5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein, the chain may optionally be interrupted by at least one of -0-, -S-, -S(O)- and -S(0) 2 - and the chain may optionally be substituted with one or more substituents independently selected from the group consisting of C C 4 alkyl;
  • Z is selected from the group consisting of a single bond, N(R 1 ), O, S, S(O) and S(O) 2 ;
  • A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene;
  • B is selected from the group consisting of a single bond, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, .optionally substituted alkylheteroarylene, optionally substituted C C 3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene and optionally substituted -(CH 2 ) m -C(0)-N(R 4 )- (CH 2 ) n -, wherein n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of O, S, NH, NR 4 , NOH and NOR 4 ;
  • R 2 is selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, ' arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino
  • R 3 is independently selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino,
  • G is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl; each R 4 is independently selected from the group consisting of H, alkyl, alkenyi, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl; each of which may be optionally substituted; or a pharmaceutically acceptable salt or prodrug thereof.
  • R 1 is selected from the group consisting of H, C ⁇ -C 6 alkyl and acyl L is a single bond or is a CrC 5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein, the chain may optionally be interrupted by at least one of -0-, -S-, -S(O)- and -S(0) 2 - and the chain may optionally be substituted with one or more substituents independently selected from the group consisting of C C 4 alkyl;
  • Z is selected from the group consisting of a single bond, N(R 1 ), O, S, S(O) and S(0) 2 ;
  • A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene;
  • B is selected from the group consisting of a single bond, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted d-C 3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene and optionally substituted -(CH 2 ) m -C(0)-N(R 4 )- (CH 2 ) n -, wherein n is an integer from 0 to 6, m is an integer from 0 to 6; M is selected from the group consisting of O,.S, NH, NR 4 , NOH and NOR 4 ;
  • R 2 is selected from the group consisting of H, Ci -C 10 alkyl, alkenyi, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C 4 -C 9 heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), arylalkyl (e.g. benzyl), heteroarylalkyl (e.g.
  • R 3 is selected from the group consisting of H, Ci -C ⁇ 0 alkyl, alkenyi, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C 4 -C 9 heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), arylalkyl (e.g. benzyl), heteroarylalkyl (e.g.
  • R 4 is selected from the group consisting of C C alkyl, heteroalkyl, aryl, heteroaryl and acyl;
  • X and Y are the same or different and are independently selected from the group consisting of H, halo, C C 4 alkyl, N0 2 , OR 4 , SR 4 , C(0)R 5 , and NR 6 R 7 ;
  • R 5 is C C 4 alkyl
  • R 6 and R 7 are the same or different and are independently selected from the group consisting of H, C C6 alkyl, C 4 -C 9 cycloalkyl, C 4 -C 8 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroaryl alkyl.
  • Particularly preferred compounds of Formula (2) are those of Formula (2b) and (2c).
  • R 2 , X, Y, Z, A, B, R 3 and R 4 are the same as for Formula (2).
  • G and R 2 are as for Formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
  • G and R 2 are as for Formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
  • G and R 2 are as for Formula (I), or a pharmaceutically acceptable salt or prodrug thereof.
  • B is a single bond or CH 2
  • B is attached to meta or para position of phenylene relative to L and G is selected from aryl, heteroaryl, alkyl and alkoxyalkyl.
  • n is an integer from 1 to 8;
  • G is selected from aryl, heteroaryl, alkyl and heteroalkyl.
  • R 2 is selected from H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, arylheteroalkyl, heteroarylalkyl, and heteroarylheteroalkyl.
  • X is selected from H, halo, C C 4 alkyl, alkoxy, alkylamino; B is attached to meta or para position of phenylene relative to L.
  • n is an integer from 1 to 8
  • X is selected from H, halo, C C alkyl, alkoxy, alkylamino.
  • R 1 is preferably H or C C 4 alkyl, more preferably H or methyl, most preferably H.
  • M is preferably O or S, most preferably O.
  • Q is preferably S(0) 2 or CO, most preferably CO.
  • G is preferably optionally substituted aryl, more preferably optionally substituted phenyl, most preferably 4-methyl phenyl or phenyl.
  • R 2 is preferably selected from the group consisting of H, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, optionally substituted arylheteroalkyl, optionally substituted heteroarylalkyl, optionally substituted heteroarylheteroalkyl, optionally substituted cycloalkylalkyl and optionally substituted heterocycloalkylalkyl.
  • R 2 is selected from the group consisting of H, 2-
  • R 2 is selected from the group consisting of H, 2-(1H-indol-3- yl)-ethyl, 2-(2-methyl-1H-indol-3-yl)-ethyl, pyridin-3-ylmethyl, 3-hydroxy-propyl, 2-pyridin- 2-yl-ethyl, 2-pyridin-3-yl-ethyl, pyridin-2-ylmethyl, pyridin-3-ylmethyl, 2-pyridin-4-yl-ethyl, benzyl, 3-phenyl-propyl, 2-phenoxy-ethyl, 2-morpholino ethyl, 2-phenyl ethyl, 2-(4-bromo- phenyl)-ethyl, 2-(4-fluoro-phenyl)-ethyl, 3-imidazol-1 -yl-propyl, 2-(1 H-imidazol-4-yl)-ethyl,
  • R 2 is selected from the group consisting of H, 2-(1 H- indol-3-yl)-ethyl, 2-(2-methyl-1 H-indol-3-yl)-ethyl, 2-phenyl ethyl, 2-piperidin-1 -yl-ethyl and 2-pyrrolidin-1 -yl-ethyl.
  • R 3 is H.
  • Z is preferably a single bond.
  • A is preferably an optionally substituted arylene.
  • A is selected from the group consisting of 1 ,4-phenylene and 1 ,3-phenylene. It is particularly preferred that A is 1 ,4-phenylene.
  • B is selected from the group consisting of a single bond, methylene, ethylene, propylene, alkylarylene, and heteroalkylene.
  • B is methylene.
  • B is a bond.
  • B is ethylene.
  • B is propylene.
  • the identities of B, A, Z and L are such that the group BAZL is a group of formula -(CH 2 ) n - wherein n is an integer from 1 to 7.
  • identities of B, A, Z are such that the group BAZ is a group of formula -(CH 2 )- phenyl-
  • identities of B, A, Z and L are such that the group BAZL is selected from the group consisting of
  • each R 5 is independently selected from the group consisting of alkyl, alkenyi, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted;
  • 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.
  • Such compounds, salts, prodrugs and metabolites are at times collectively referred to herein as "HDAC inhibiting agents" or "HDAC inhibitors".
  • 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.
  • 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 preferably involves administration of a compound of Formula (2) more preferably a compound of Formula (2a) or (2b) or (2c), most preferably a compound of (2e) to (2r).
  • the disorder is preferably selected from the group consisting of but not limited to cancer (e.g. breast cancer, colon cancer, prostate cancer, pancreatic cancer, leukemias, lymphomas), 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 preferably 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 preferably an anti-cancer agent.
  • the agent preferably contains a compound of Formula (2) more preferably a compound of Formula (2a) or (2b) or (2c), most preferably a compound of (2e) to (2r).
  • 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.
  • the disorder is preferably a proliferative disorder, most preferably 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 (I).
  • the invention provides a method of treatment of a disorder, disease or condition that are mediated by deacetylase activity such as histone deacetylase including administration of a therapeutically effective amount of a compound of Formula (I).
  • the method preferably includes administration of a compound of Formula (2), more preferably a compound of Formula (2a) or (2b) or (2c), most preferably a compound of (2e) to (2r) as described herein.
  • the disorder is preferably 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 la Tourette syndrome, Diffuse Lewy body disease, Progressive supranuclear palsy, 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,
  • Candida Albicans Bacterial infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria, Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
  • Viral infections such as Herpes Simplex
  • Protozoal infections such as Malaria, Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
  • 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 preferably 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 provides amethod of modifying deacetylase activity including contacting the deacetylase with a compound of Formula (I).
  • the deacetylase activity is preferably histone deacetylase activity, even more preferably class I histone deacetylase activity.
  • the histone deacetylase is preferably HDAC1 or HDAC8.
  • 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 preferably includes administration of a compound of Formula (2) more preferably a compound of Formula (2a) or (2b) or (2c), most preferably a compound of (2e) to (2r) as described herein.
  • the neurodegenerative disorder is preferably 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 preferably 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 preferably 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 preferably includes administration of a compound of Formula (2) more preferably a compound of Formula (2a) or (2b) or (2c), most preferably a compound of (2e) to (2r) 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 present invention provides the use of a compound of Formula (I) to modify deacetylase activity, preferably histone deacetylase activity, even more preferably HDACI or HDAC8.
  • the invention also provides the use of a compound of Formula (I) to treat cancer.
  • the cancer is selected from a group including but not limited to breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.
  • the present invention also provides the use of a compound of Formula (I) in the preparation of a medicament for the treatment of hematologic malignancies.
  • the hematologic malignancy is preferably selected from the group consisting of B-cell lymphoma, T-cell lymphoma and leukemia.
  • the invention also provides a method for the treatment of a hematologic malignancy including administration of an effective amount of a compound of Formula (I).
  • the invention also provides an agent for the treatment of hematologic malignancy including a compound of Formula (I).
  • the invention also provides the use of a compound of Formula (I) in the preparation of a medicament for the treatment of solid tumors.
  • the solid tumor is preferably selected from the group consisting of breast cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer, colon cancer, pancreatic cancer and brain cancer.
  • the invention also provides a method of treatment of a solid tumor including administration of an effective amount of a compound of Formula (I).
  • the solid tumor is preferably selected from the group consisting of breast cancer, lung cancer, pancreatic cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer, colon cancer and brain cancer.
  • the invention also provides agents for the treatment of solid tumors including a compound of Formula (I).
  • the invention provides for the use of a compound of Formula (I) in the preparation of a medicament for the induction of cell death such as apoptosis of tumor cell.
  • the invention also provides a method of inhibiting tumor cell proliferation including the administration of a compound according to Formula (I).
  • the invention also provides a method of inhibiting the activity of histone deacetylase including contacting the histone deacetylase with an effective amount of a compound according to Formula (I).
  • the invention also provides the use of a compound of Formula (I) in the manufacture of medicaments for the induction of apoptosis of tumor cells.
  • the invention provides a method of inducing apoptosis in tumor cells including administration of an effective amount of a compound of Formula (I).
  • hydroxamate compounds for example acylurea/sulfhonylurea 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' 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 tumors including acoustic neuroma, neuroblastomas, glioma and other brain tumors, spinal cord tumors, breast cancers, colorectal cancers, colon cancer, advanced colorectal adenocarcinomas, 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 tumor, gall bladder cancer, genitourinary cancers including testicular cancer, penile cancer, prostate cancer, gynaecological cancers including cervical cancer,
  • Preferred cancers that may be treated by the compounds of the present invention include but are not limited to breast cancer, colon cancer, pancreatic cancer, lung cancer, ovarian cancer, prostate cancer, head and neck cancer, renal cancer, gastric cancer and brain cancer.
  • Preferred 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 e.g., peripheral T-cell lymphoma.
  • Preferred cancers that may be treated by compounds of the present invention include but are not limited to solid tumors and hematologic malignancies.
  • 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 la Tourette syndrome, Diffuse Lewy body disease, Progressive supranuclear palsy, Pick's disease, intracerebreal haemorrphage, Primary lateral sclerosis, Spinal muscular atrophy, Amyotrophic lateralsclerosis, 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, Rubeotic glaucoma, Intersititial keratitis, Diabetic retinopathy
  • Systemic Lupus Erythematosus Disease involving angiogenesis including cancer, psoriasis, rheumatoid arthritis; Psychological disorders including bipolar disease, schizophrenia, mainia, depression and dementia; Cardiovascular Diseases including heart failure, restenosis and arteriosclerosis; Fibrotic diseases including liver fibrosis, cystic fibrosis and angiofibroma; Infectious diseases including Fungal infections, such as
  • Candida Albicans Bacterial infections, Viral infections, such as Herpes Simplex, Protozoal infections, such as Malaria, Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
  • Viral infections such as Herpes Simplex
  • Protozoal infections such as Malaria, Leishmania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidiosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.
  • hydroxamate compounds of the present invention have the following structure (I):
  • R 1 is selected from the group consisting of H, Ci -C 6 alkyl and acyl
  • M is selected from the group consisting of O, S, NH, NR 4 , NOH and NOR 4 ;
  • R 2 is selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl; heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, al
  • R 3 is selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino, al
  • G is selected from the group consisting of optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; each R 4 is independently selected from the group consisting of H, alkyl, alkenyi, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; or a pharmaceutically acceptable salt or prodrug thereof.
  • R 1 is selected from the group consisting of H, C-i -C 6 alkyl and acyl;
  • L is a single bond or is a C C 5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein, the chain may optionally be interrupted by at least one of -0-, -S-, -S(O)- and -S(0) 2 - and the chain may optionally be substituted with one or more substituents independently selected from the group consisting of C C alkyl;
  • Z is selected from the group consisting of a single bond, N(R 1 ), O, S, S(O) and S(0) 2 ;
  • A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene;
  • B is selected from the group consisting of a single bond, optionally substituted acylamino, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted C ⁇ -C 3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene and optionally substituted -(CH2) m -C(0)-N(R )-(CH 2 ) n -, wherein n is an integer from 0 to 6, m is an integer from 0 to 6;
  • M is selected from the group consisting of O, S, NH, NR 4 , NOH and NOR 4 ;
  • R 2 is selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylk
  • R 3 is independently selected from the group consisting of H, halogen, alkyl, alkenyi, alkynyl, haloalkyl, haloalkenyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, cycloalkylheteroalkyl, heterocycloalkylheteroalkyl, heteroarylheteroalkyl, arylheteroalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyaryl, alkenyloxy, alkynyloxy, cycloalkylkoxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, arylalkyloxy, amino,
  • G is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted arylalkyl and optionally substituted heteroarylalkyl; each R 4 is independently selected from the group consisting of H, alkyl, alkenyi, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, heteroarylalkyl and acyl, each of which may be optionally substituted; or a pharmaceutically acceptable salt or prodrug thereof.
  • the compounds of Formula (2) are compounds of
  • R 1 is selected from the group consisting of H, Ci -C ⁇ alkyl and acyl
  • L is a single bond or is a C C 5 hydrocarbon chain which may contain 0 to 2 multiple bonds independently selected from double bonds and triple bonds and wherein, the chain may optionally be interrupted by at least one of -O-, -S-, -S(O)- and -S(0) 2 - and the chain may optionally be substituted with one or more substituents independently selected from the group consisting of C 1 -C 4 alkyl;
  • Z is selected from the group consisting of a single bond, N(R 1 ), O, S, S(O) and S(O) 2 ;
  • A is selected from the group consisting of a single bond, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted cycloalkylene and optionally substituted heterocycloalkylene;
  • B is selected from the group consisting of a single bond, optionally substituted acyl amino, optionally substituted aminoacyl, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted arylalkylene, optionally substituted heteroarylalkylene, optionally substituted alkylarylene, optionally substituted alkylheteroarylene, optionally substituted C C 3 alkylene, optionally substituted heteroalkylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene and optionally substituted -(CH 2 ) m -C(0)-N(R 4 )-(CH 2 ) n -, wherein n is an integer from 0 to 6, m is an integer from 0 to 6;
  • M is selected from the group consisting of O, S, NH, NR 4 , NOH and NOR 4 ;
  • R 2 is selected from the group consisting of H, Ci -C 10 alkyl, alkenyi, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C 4 -C 9 heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), arylalkyl (e.g. benzyl), heteroarylalkyl (e.g.
  • R 3 is selected from the group consisting of H, Ci -C 10 alkyl, alkenyi, heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, C -C 9 heterocycloalkylalkyl, cycloalkylalkyl (e.g., cyclopropylmethyl), arylalkyl (e.g. benzyl), heteroarylalkyl (e.g.
  • X and Y are the same or different and are independently selected from the group consisting of H, halo, C C 4 alkyl, N0 2 , OR 4 , SR 4 , C(0)R 5 , and NR 6 R 7 ;
  • R a is C r C 4 alkyl
  • R 6 and R 7 are the same or different and are independently selected from the group consisting of H, C ⁇ -C 6 alkyl, C -C 9 cycloalkyl, C 4 -C 9 heterocycloalkyl, aryl, heteroaryl, arylalkyl and heteroaryl alkyl.
  • 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 C-i-C- alkyl, more preferably C C ⁇ o alkyl, most preferably C C 6 unless otherwise noted.
  • suitable straight and branched CrC 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
  • “Dialkylamino” means a -N(alkyl) 2 group, in which the alkyl is as defined as above.
  • the alkyl group is preferably a C C 6 alkyl group.
  • Arylamino includes both mono-arylamino and di-arylamino unless specified.
  • Mono- arylamino means a group of formula aryl NH-
  • di-arylamino means a group of formula (aryl 2 ) N- where aryl is as defined herein.
  • Examples of acyl include acetyl, benzoyl, phenylacetyl.
  • Alkenyi 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 alkenyi group include, but are not limited to, ethenyl and propenyl.
  • Alkoxy refers to an -O-alkyl group in which alkyl is defined herein.
  • the alkoxy is a C C 6 alkoxy. Examples include, but are not limited to, methoxy and ethoxy.
  • alkenyloxy refers to an -O- alkenyi group in which alkenyi is as defined herein. Preferred alkenyloxy groups are C ⁇ -C 6 alkenyloxy groups.
  • Alkynyloxy refers to an -O-alkynyl group in which alkynyl is as defined herein. Preferred alkynyloxy groups are C C 6 alkynyloxy groups.
  • Alkoxycarbonyl refers to an -C(0)-0-alkyl group in which alkyl is as defined herein. The alkyl group is preferably a C C 6 alkyl group. Examples include, but not limited to, methoxycarbonyl and ethoxycarbonyl.
  • Alkylsulfinyl means a -S(0)-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(0) 2 -alkyl group in which alkyl is as defined above.
  • the alkyl group is preferably a C 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 trip 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 not limited to, ethynyl and propynyl.
  • Alkylaminocarbonyl refers to an alkylamino-carbonyl group in which alkylamino is as defined above.
  • Aminoacyl refers to the formula -C(0)-(CH 2 ) m -(CH)(NR 6 R 7 )-(CH 2 ) n -R 6 wherein R 6 and R 7 are as defined above, m and n are integers selected from 0 to 6.
  • 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.
  • the aryl group may be substituted by one or more substituent groups. When the aryl ring is divalent it has been referred to as "arylene" in this application.
  • Arylalkenyl means an aryl-alkenyl- group in which the aryl and alkenyi 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 contains a C 1 . 5 alkyl moiety.
  • Exemplary arylalkyl groups include benzyl, phenethyl and naphthelenemethyl.
  • 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, cyclobutyi, cyclopentyl, cyclohexyl and the like, unless otherwise specified.
  • alkyl and cycloalkyl substituents also applies to the alkyl portions of other substituents, such as without limitation, alkoxy, alkyl amines, alkyl ketones, arylalkyl, heteroarylalkyl, alkylsulfonyl and alkyl ester substituents and the like.
  • 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 cylcoheptylmethyl.
  • Heterocycloalkyl refers to a ring containing from at least one heteroatom selected from nitrogen, sulfur, oxygen, preferably from 1 to 3 heteroatoms. Each ring is preferably from 3 to 4 membered, more preferably 4 to 7 membered.
  • suitable 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 carbons atoms, more preferably 2 to 10 carbon atoms in the chain, wherein one or more of the carbon atoms have 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.
  • Cycloalkenyl means an optionally substituted non-aromatic monocyclic or multicyclic 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. The cycloalkenyl group may be substituted by one or more substituent groups.
  • Heteroaryl refers to a monocyclic, or fused polycyclic, aromatic heterocycle (ring structure preferably having a 5 to 10 member aromatic ring containing one or more heteroatoms selected from N, O and S).
  • Typical heteroaryl substituents include furyl, thienyl, pyrrole, pyrazole, triazole, thiazole, oxazole, pyridine, pyrimidine, isoxazolyl, pyrazine, indole, benzimidazole, and the like.
  • heteroaryl ring is divalent it has been referred to as "heteroarylene" in this application.
  • Heteroarylalkyl means a heteroaryl-alkyl group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.
  • “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-propyl or isopropyl) or butyl (n- butyl, isobutyl or tertiary-butyl.
  • “Sulfonyl” means a R-S0 2 - group in which the R is selected from aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, arylalkyl and heteroarylalkyl as described herein. G could be further substituted. Examples of sulfonyl include methanesulfonyl, benzenesulfonyl, 4- methylbenzenesulfonyl, naphthalene-2-sulfonyl, and the like.
  • inventive compounds 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 present invention. 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 hydroxyl group may be convertible by hydrolysis in vivo to the parent molecule.
  • 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.
  • an ester prodrug of a compound of formula I containing a carboxy group may be convertible by hydrolysis in vivo to the parent molecule. (Examples of ester prodrugs are those described by F. J.
  • Possible HDAC inhibiting agents include those having an IC 50 value of 5 ⁇ 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.
  • terapéuticaally effective amount is an amount sufficient to effect beneficial or desired clinical 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
  • 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 compounds can be incorporated into slow release or targeted delivery systems such as polymer matrices, liposomes, and microspheres.
  • 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, 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, carboxymethylceilulose, 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 alcohol and
  • 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 emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • 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 metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, 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., 265, 17174 (1990), J. Taunton et al, Science 1996 272: 408].
  • the histone deacetylase inhibitor interacts with and/or reduces the activity of more than one 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/or reduces the activity of predominantly one histone deacetylase, for example HDAC-1 , HDAC-3 or HDAC-8 which belongs to Class I HDAC enzymes [De
  • 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.
  • 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 in this invention can be used to treat pre-cancer conditions including myeloid dysplasia, endometrial dysplasia and cervical dysplasia.
  • compounds of the various embodiments disclosed herein may be useful for treating neurodegenerative diseases, and inflammatory diseases and/or immune system disorders.
  • the disorder is preferably 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 promotes differentiation, for example, cell cycle arrest in the G1 or G2 phase, and induce apoptosis SYNTHESIS OF DEACETYLASE INHIBITORS
  • the compounds of this invention 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 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 Edtion, Wiley- InterScience, 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- dimethyiformamide
  • 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.
  • Reverse-phase preparative HPLC was operated by using a C-
  • High-throughput mass-dependent (reverse- phase HPLC) purification system was operated by using a C ⁇ 8 column (5 urn, 19x50 mm) at flow rate of 30 mL/min and a linear gradient from 5 to 95% of CH 3 CN + 0.05% TFA over 9 min.
  • the fractions containing the desire product were lyophilized, or evaporated to dryness under vacuum to provide the dry compound, or evaporated to remove the volatile organic solvent then extracted with organic solvents (ethyl acetate or dichloromethane are commonly used, if necessary, the pH of the aqueous solution could also be adjusted in order to get free base, acid or the neutral compound).
  • organic solvents ethyl acetate or dichloromethane are commonly used, if necessary, the pH of the aqueous solution could also be adjusted in order to get free base, acid or the neutral compound).
  • NMR spectra were recorded on a Bruker AV400 instrument operating at 400 MHz, and 13 C-NMR spectra were recorded operating at 100 MHz. NMR spectra are obtained as CDCI 3 solutions (reported in ppm), using chloroform as the reference standard (7.26 ppm and 77.00 ppm), CD 3 OD (3.3 and 49.3 ppm), DMSO-d 6 (2.50 and 39.5 ppm), or an internal tetramethylsilane standard (0.00 ppm) when appropriate. Other NMR solvents were used as needed.
  • R is a linking moiety or equal to -B-A-Z-L- as defined for Formula (2), R" is R less one CH 2 , R 11 is a C-i -C 6 alkyl or benzyl, R 21 is R 2 less one CH 2 and R 2 is defined as for Formula (I).
  • the intermediate (2) in Scheme 1 could be prepared by (i) alkylation of amine (2a) with R 2 X (3a, X is halo, e.g., I " , Br “ , CI “ or a good leaving group), or (ii) reductive amination of amine (2a) with aldehyde (3b), or (iii) reductive amination of aldehyde (2b) with amine R 2 NH 2 (3c).
  • the ester (6) is hydrolyzed to the acid (6a).
  • the acid is subsequently converted to the hydroxamic acid (8) by either Method A or Method B.
  • Method A (i) the acid is converted to acid chloride by treating it with CICOCOCI, or SOCI 2 , or other reagents under neutral conditions (such as Ph 3 P with CBr 4 , or 2,4,6- Trichloro-[1 ,3,5]triazine); or (ii) the acid is converted to an active ester by reacting it with isobutyl chloroformate; (iii) the acid chloride or active ester is reacted with hydroxylamine or the O-protected hydroxylamine [e.g., O-benzylhydroxylamine, 0-(2,4-dimethoxy- benzyl)-hydroxylamine, 0, ⁇ /-bis-(2,4-dimethoxy-benzyl)-hydroxylamine, 0-(tetrahydro- pyran-2-yl)-hydroxylamine, 0-(ferf-butyl-dimethyl-silyl)-hydroxylamine] to give the hydroxamic acid or the O-protected
  • Method B Coupling the acid with hydroxylamine or O-protected hydroxylamine (R 12 ONH 2 ) with a coupling reagent, then followed by removing the protecting group by methods known in the literature. Synthesis of acylurea linked hydroxamic acid (9).
  • Acylurea linked hydroxamic acid (9) could be synthesized by methods analogous to those used for synthesis of sulfonylurea linked hydroxamic acid (8).
  • sulfonylurea linked hydroxamic acid (8) and acylurea linked hydroxamic acid (9) could also be synthesized by a synthetic route described in Scheme 4.
  • O- protected hydroxamate starting material amine (2c) or aldehyde (2d) are used to make the O-protected hydroxamate intermediate (2P) which is subsequently converted to the corresponding sulfonylurea (8a) and acylurea (9a). After removal the protecting group, sulfonylurea (8) and acylurea (9) are obtained.
  • R 13 is selected from R 11 or R 12 .
  • the product (6b) could be converted to the hydroxamic acid (8b) by using the similar condition as described for (8) in Scheme 1 , 2 or 4.
  • Scheme 5
  • 8-Amino-octanoic acid (2.116 g, 13.29 mmol) and methanol (50 mL) were added. The mixture was stirred and cooled in a dry-ice /acetone bath under nitrogen. SOCI 2 (1.5 mL, 20.7 mmol) was added via syringe, then the dry-ice bath was removed and the mixture was stirred at room temperature for 2.5 h. The solution was evaporated and the residue was added diethyl ether. The solid was filtered and dried under vacuum. 8-Amino-octanoic acid methyl ester hydrochloride was obtained as white solid (2.772 g, 99.8%).
  • 6-Amino-hexanoic acid methyl ester hydrochloride 0.555 g, 3.06 mmol
  • NaBH(OAc) 3 0.782 g, 3, .69 mmol
  • 3-Phenyl-propionaldehyde 0.47 mL, 3.21 mmol
  • dichloromethane 10 mL
  • triethylamine 0.43 mL, 3.09 mmol
  • 6-Amino-hexanoic acid (13.1 g, 100 mmoL) was dissolved in 10% aqueous Na 2 CO 3 solution (300 mL), then dioxane (200 mL) was added to the above solution.
  • Fmoc-Cl 26 g, 110 mmoL was added to the above mixture portion-wise, and the resultant reaction mixture was stirring for 12h.
  • the mixture was extracted with ether (150 mL X 2), and the aqueous portion was acidified by 6N HCl.
  • 6-(9H-Fluoren-9-ylmethoxycarbonylamino)-hexanoic acid 9.17 g, 25 mmoL
  • 0-(2,4- dimethoxy-benzyl)-hydroxylamine 36 g, 26 mmoL
  • DCM 250 mL
  • DCC 6.18 g, 30 mmoL
  • the resultant mixture was stirred for 3h at room temperature, then cooled to 0°C, filtered, and washed with DCM.
  • the organic solution was evaporated to dryness to give the crude [5-(2,4-dimethoxy- benzyloxycarbamoyl)-pentyl]-carbamic acid 9/7-fluoren-9-ylmethyl ester.
  • 6-(3-Benzoyl-thioureido)-hexanoic acid (2,4-dimethoxy-benzyloxy)-amide (crude fromSTEPI , 0.186 g equal to 0.27 mmoL) and Triethylsilane (0.05 mL) in DCM (1.7 mL) was added TFA (0.3 mL) at room temperature with stirring. After 20 min, the solution was evaporated to dryness and diluted with methanol and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC. 6-(3-Benzoyl- thioureido)-hexanoic acid hydroxyamide was obtained as a white solid (0.027 g, 32% overall yield).
  • Step 4 acylurea formation by reacting the above resin with benzoyl isocyanate.
  • the crude products were purified by High throughput mass-dependent HPLC purification system.
  • acyl isocyanates could be prepared according to the published literature methods.
  • acetyl isocyanate could be synthesized by reacting Et 3 SnNCO with acetyl bromide [Chauzov, V. A.; Baukov, Yu. I. Zhurnal Obshchei Khimii (1972), 42(8), 1868-9], or by reacting Bu 3 SnNCO with acetyl chloride [Kodama, H. et al. Jpn.
  • Recombinant GST-HDAC1 and GST-HDAC8 Protein expression and purification 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 10 8 PFU/ml.
  • the GST-HDAC1 protein or GST-HDAC8 protein was eluted by elution buffer containing 50 mM Tris, pH ⁇ .0, 150mM NaCl, 1 % Triton X-100 and 10mM or 20mM reduced Glutathione.
  • the purified GST-HDAC1 protein or purified GST-HDAC8 protein was dialyzed with HDAC storage buffer containing 10mM Tris, pH7.5, 100mM NaCl and 3mM MgCI 2 . 20% Glycerol was added to purified GST-HDAC1 protein or purified GST- HDAC8 before storage at -80°C.
  • Flur de lys Developer was added and the reaction was incubated for 10 min. Briefly, 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.).
  • the analytical software, Prism 3.0® (GraphPad Software Inc) has been used to generate
  • MB435 and MDA-MB231) were obtained from ATCC. Colo205 cells were cultivated in
  • MDA-MB231 cells were cultivated in RPMI 1640 containing 2 mM L-glutamine, 5%FBS.
  • MDA-MB435 cells were cultivated in DMEM containing 2 mM L-Glutamine, 5% FBS. Colo205 cells were seeded in 96-wells plate at 5000 cells per well respectively.
  • MB231 cells were seeded in 96-wells plate at 6000 cells per well. The plates were incubated at 37°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).
  • the cellular or growth inhibition activity results of representative compounds are shown in Table 4. These data indicate that compounds in this invention are highly active in inhibition of tumor cell growth. In addition, representative compounds have also demonstrated their ability to inhibit growth in other types of cancer cell lines including lung cancer cell lines (e.g. NCI-H522 and A549), prostate cancer cell line (e.g. PC3), leukemia cell line (e.g. HL-60), lymphoma cell line (e.g. Ramos) and pancreatic cancer cell line (MIAPaCA2) (data not shown).
  • lung cancer cell lines e.g. NCI-H522 and A549
  • prostate cancer cell line e.g. PC3
  • leukemia cell line e.g. HL-60
  • lymphoma cell line e.g. Ramos
  • MIAPaCA2 pancreatic cancer cell line
  • HDAC histone deacetylase
  • 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 separately using primary antibody specific for acetylated H3, acetylated H4 or acetylated H2A (Upstate Pte Ltd).
  • the detection antibody goat anti rabbit antibody conjugated with Horse radish peroxidase (HRP) was used according to the manufacturer instruction (Pierce Pte Ltd). After removing the detection antibody from the membrane, an enhanced chemiluminescent substrate for detection of HRP (Pierce Pte Ltd) was added onto the membrane.
  • 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 analysed 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 results of histone deacetylase assay are shown in Table 5.
  • the selective induction of apoptosis in proliferating cells such as tumor cells is one of the desirable approaches, and can be mediated by treatment with various anti-proliferative compounds
  • Programmed cell death or apoptosis is the cellular response to stress factors such as DNA damage introduced during conventional anti-cancer treatment.
  • Stress factors such as DNA damage introduced during conventional anti-cancer treatment.
  • necrosis a non-coordinated form of cell death called necrosis.
  • characteristic phenotypical cellular changes occur, which include the condensation of chromatin, the shrinkage of cells and finally the fragmentation of chromosomal DNA.
  • One of the very early changes caused by apoptotic events occurs in the phospholipids bilayer of the plasma membrane.
  • the phospholipid phosphatidylserine is translocated from the inner to the outer side of the plasma-membrane and, as a result, is exposed to the extracellular space.
  • One way of detecting early apoptotic cells is to determine the amount of phosphatidyl-serine at the extracellular side of the plasma- membrane which is accomplished by the standard flow cytometric method of Annexin V staining.
  • the phospholipids recognizing protein Annexin V binds with high affinity to these inverted and exposed phosphatidyl-serines.
  • Ramos Burkitt -lymphoma cells This cell line is one of the gold standard cell lines commonly used as a tissue culture model for B cell lymphoma. Representative compounds as indicated below were added to 80,000 cells per 500 ⁇ l growth medium (RPMI1640 medium supplemented with 2 mM L-Glutamine, 10% heat-inactivated FBS, 1mM Na- Pyruvate and 10 mM HEPES) in 24 well format at various concentrations. Two days after the start of treatment, cells were collected and subjected to the Annexin V staining protocol following the instructions of the manufacturer (BD Biosciences).
  • RPMI1640 medium supplemented with 2 mM L-Glutamine, 10% heat-inactivated FBS, 1mM Na- Pyruvate and 10 mM HEPES
  • PI propidium iodide
  • HL-60 cells which is an acute promyelocytic leukemia cell line (data not shown).
  • compounds disclosed in this invention can be used to treat cancers including hematologic malignancies (e.g. lymphoma and leukemia).
  • the efficacy of the compounds of the invention can then be determined using in vivo animal xenograft studies.
  • the animal xenograft model is one of the most commonly used in vivo cancer models.
  • mice Female athymic nude mice (Harlan), 12-14 weeks of age would be implanted subcutaneously in the flank with 5 x 10 6 cells of HCT116 or with 1 x 10 6 cells of Colo205 human colon carcinoma suspended in 50% Matrigel. When the tumor reaches the size 100 mm 3 , the xenograft nude mice would be paired-match into various treatment groups.
  • the selected HDAC inhibitors would be dissolved in appropriate vehicles, such as 10%DMA/10% Cremophore/80%water and administered to xenograft nude mice intraperitonelly by daily for 14 days. The dosing volume will be 0.2-ml/20g mouse.
  • Paclitaxol used as positive control, will be prepared for intravenous administration in 10%Ethanol/10%Cremophore/80%water.
  • the dosing volume for Paclitaxol will be 0.015- ml/g mouse.
  • Compounds in this invention that are tested would show significant reduction in tumor volume relative to controls treated with vehicle only.
  • the activity of histone deacetylase when measured shall be reduced and results in accumulation of acetylated histone relative to vehicle treated control group. The result will therefore indicate that compounds in this invention are efficacious in treating a proliferative disorder such as cancer.

Abstract

La présente invention concerne des composés d'hydroxamate qui sont des inhibiteurs de l'histone déacétylase. Plus particulièrement, cette invention concerne des composés contenant de l'acylurée et de la sulfonylurée, ainsi que des procédés permettant de les préparer. Ces composés peuvent être utiles en tant que médicaments pour traiter des troubles proliférants ainsi que d'autres maladies impliquant, liées ou associées aux enzymes présentant des activités d'histone déacétylase.
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CA2543570A1 (fr) 2005-05-06
TW200530166A (en) 2005-09-16
AU2004284030A1 (en) 2005-05-06
WO2005040101A1 (fr) 2005-05-06
MXPA06004735A (es) 2006-12-14
JP2007509930A (ja) 2007-04-19
AR046920A1 (es) 2006-01-04
EP1685094A4 (fr) 2007-08-22

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