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WO2002076941A2 - Inhibiteurs de l'histone deacetylase - Google Patents

Inhibiteurs de l'histone deacetylase Download PDF

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Publication number
WO2002076941A2
WO2002076941A2 PCT/US2002/008836 US0208836W WO02076941A2 WO 2002076941 A2 WO2002076941 A2 WO 2002076941A2 US 0208836 W US0208836 W US 0208836W WO 02076941 A2 WO02076941 A2 WO 02076941A2
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Prior art keywords
alkyl
compound
alkoxy
hydroxyl
hydroxylalkyl
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PCT/US2002/008836
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English (en)
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WO2002076941A3 (fr
Inventor
Hsuan-Yin Lan-Hargest
Robert J Kaufman
Norbert L. Wiech
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Circagen Pharmaceutical
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Priority claimed from US09/812,945 external-priority patent/US7312247B2/en
Priority claimed from US09/812,944 external-priority patent/US6495719B2/en
Priority claimed from US10/025,947 external-priority patent/US8026280B2/en
Application filed by Circagen Pharmaceutical filed Critical Circagen Pharmaceutical
Priority to EP02719311A priority Critical patent/EP1408946A4/fr
Priority to CA2442366A priority patent/CA2442366C/fr
Priority to AU2002250401A priority patent/AU2002250401A1/en
Publication of WO2002076941A2 publication Critical patent/WO2002076941A2/fr
Publication of WO2002076941A3 publication Critical patent/WO2002076941A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/52—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen
    • C07C57/58—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings
    • C07C57/60—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing halogen containing six-membered aromatic rings having unsaturation outside the rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/42—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings having unsaturation outside the rings
    • 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
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to enzyme inhibitors, and more particularly to histone deacetylase inhibitors.
  • BACKGROUND DNA in the nucleus of the cell exists as a hierarchy of compacted chromatin structures.
  • the basic repeating unit in chromatin is the nucleosome.
  • the nucleosome consists of a histone octomer of proteins in the nucleus of the cell around which DNA is twice wrapped.
  • the orderly packaging of DNA in the nucleus plays an important role in the functional aspects of gene regulation. Covalent modifications of the histones have a key role in altering chromatin higher order structure and function and ultimately gene expression.
  • the covalent modification of histones occurs by enzymatically mediated processes, such as acetylation.
  • HDAC histone deacetylase
  • acetylation of histone-DNA activates transcription of DNA's message, an enhancement of gene expression.
  • Histone deacetylase can reverse the process and can serve to repress gene expression. See, for example, Grunstein, Nature 389, 349-352 (1997); Pazin et al, Cell 89, 325-328 (1997); Wade et al., Trends Biochem. Sci. 22, 128-132 (1997); and Wolffe, Science 272, 371-372 (1996).
  • Histone deacetylase is a metallo-enzyme with zinc at the active site.
  • Compounds having a zinc-binding moiety such as, for example, a hydroxamic acid group or a carboxylic acid group, can inhibit histone deacetylase.
  • Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, and genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy.
  • a method of inhibiting histone deacetylation activity in cells includes contacting the cells with an effective amount of a compound of formula (I), thereby treating one or more disorders mediated by histone deacetylase, and determining whether the level of acetylated histones in the treated cells is higher than in untreated cells under the same conditions.
  • the compound of formula (I) can be the following:
  • A is a cyclic moiety selected from the group consisting of C 3 . 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 4 . 14 cycloalkenyl, 4-14 membered heterocycloalkenyl, aryl, or heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; or A is a saturated branched C 3 .
  • 12 hydrocarbon chain optionally interrupted by -O-, -S-, -N(R a )-, -C(O)-, -N(R a )-SO 2 -, -SO 2 -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R , -N(R a )-C(O)-N(R b )-, -O-C(O)-, -C(O)-O-, -O-SO 2 -, -SO 2 -O-, or -O-C(O)-O-, where each of R a and R , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated
  • Each of Y 1 and Y 2 is -CH 2 -, -O-, -S-, -N(R C )-, -N(R c )-C(O)-O-, -O-C(O)-N(R , -N(R c )-C(O)-N(R d )-, -O-C(O)-O-, or a bond, and each of R c and R d , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L is a straight C 2 .
  • hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond; said hydrocarbon chain being optionally substituted with CM alkyl, C - 4 alkenyl, C 2 . 4 alkynyl, CM alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3 - 5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, . 4 alkylcarbonyloxy, C 1 .
  • alkyloxycarbonyl CM alkylcarbonyl, or formyl; and further being optionally interrupted by -O-, -N(R e )-, -N(R e )-C(O)-O-, -O-C(O)-N(R e )-, -N(R e )-C(O)-N(R f )-, or -O-C(O)-O-; each of R e and R f , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L is a C 2 . 3 hydrocarbon containing no double bonds and X 2 is -OR 1 , Y 1 is not a bond and Y 2 is not a bond.
  • a method of inhibiting histone deacetylase in cells comprising contacting the cells with an effective amount of a compound of formula (I), supra, and determining whether the level of acetylated histones in the treated cells is higher than in untreated cells under the same conditions.
  • A is phenyl optionally substituted with alkyl alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, or amino.
  • Each of Y 1 and Y 2 is -CH 2 -, -O-, -S-, -N(R C )-, or a bond; where R c is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L is a straight C 2 .
  • hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond, the hydrocarbon chain being optionally substituted with - alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, CM alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3 - 5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, CM alkylcarbonyloxy, CM alkyloxycarbonyl, C alkylcarbonyl, or formyl; and further being optionally interrupted by -O-, -N(R e )-, -N(R e )-C(O)-O-,
  • R e and R f independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • X 1 is O or S.
  • L is a C 2 . 3 hydrocarbon containing no double bonds and X is -OR , Y is not a bond and Y 2 is not
  • a method of treating a histone deacetylase-mediated disorder includes administering to a subject in need thereof a therapeutically effective amount of compound of formula (I), supra.
  • X 2 can be -OR 1 , -NR 3 -OR 1 , -C(O)-OR 1 , -CHR -OR 1 , or -O-CHR 4 -O-C(O)-R 5
  • X 2 can be -OR 1 , -NR 3 -OR 1 , or -O-CHR 4 -O-C(O)-R 5
  • each of Y 1 and Y 2 independently, can be -CH 2 -, -O-, -N(R C )-, or a bond
  • L can be a saturated hydrocarbon chain, such as a C 3 . 8 hydrocarbon chain substituted with d. 2 alkyl, C ⁇ alkoxy, hydroxyl, -NH 2 , -NH(C 1 )
  • L can be an unsaturated hydrocarbon chain containing at least one double bond and no triple bond, such as an unsaturated C 4 - 8 hydrocarbon chain substituted with C ⁇ _ 2 alkyl, d- alkoxy, hydroxyl, -NH 2 , -NH(C ⁇ - 2 alkyl), or -N(C ⁇ . 2 alkyl) 2 .
  • L can be an unsaturated hydrocarbon chain containing at least one double bond and one triple bond, such as an unsaturated C 4 .
  • A can be a C 5 - 8 cycloalkenyl or 5-8 membered heteroalkenyl containing at least one double bond.
  • A can be phenyl, naphthyl, indanyl, or tetrahydronaphthyl, or A can be phenyl optionally substituted with alkyl alkenyl, alkynyl, alkoxy, hydroxyl, , hydroxylalkyl, halo, haloalkyl, or amino.
  • A can contain only double bonds.
  • A is a cyclic moiety selected from the group consisting of C - ⁇ cycloalkyl, 3-14 membered heterocycloalkyl, C 4 . 14 cycloalkenyl, 3-14 membered heterocycloalkenyl (e.g., C 3 . 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 4 . 8 cycloalkenyl, 3-8 membered heterocycloalkenyl), monocyclic aryl, or monocyclic heteroaryl.
  • Each of these cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl.
  • Each of X 1 and X 2 independently, is O or S.
  • Y 1 is -CH 2 -, -O-, -S-, -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R )-, -O-C(O)-, -C(O)-O-, -O-C(O)-O-, or a bond wherein each of R and R , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • Y 2 is -CH 2 -, -O-, -S-, -N(R , -N(R c )-C(O)-O-, -O-C(O)-N(R c )-, -N(R c )-C(O)-N(R )-, -O-C(O)-, -C(O)-O-, or -O-C(O)-O- wherein each of R c and R d , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L is (1) a saturated straight d- 12 hydrocarbon chain substituted with C alkyl, C 2 - 4 alkenyl, C - 4 alkynyl, C ⁇ - 4 alkoxy, halo, carboxyl, amino, nitro, cyano, C 3 .
  • R s and R h independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group
  • R 2 is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group.
  • hydroxamic acid-containing compounds have a structure of formula (I), supra.
  • A is a cyclic moiety selected from the group consisting of monocyclic aryl or monocyclic heteroaryl. Each of the cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino.
  • Each of X 1 and X 2 independently, is O or S.
  • Y 1 is -CH 2 -, -O-, -S-, -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R , -O-C(O)-, -C(O)-O-, -O-C(O)-O-, or a bond, where each of R a and R , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • Y 2 is -CH 2 -, -O-, -S-, -N(R C )-, -N(R c )-C(O)-O-, -O-C(O)-N(R c )-,
  • R c and R d independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L is (1) a saturated straight C 3 - 10 hydrocarbon chain substituted with C ⁇ - alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, d- 4 alkoxy, or amino, and further optionally interrupted by -O- or -N(R e )-, where R e is hydrogen, alkyl, hydroxylalkyl, or haloalkyl; or L is (2) an unsaturated straight C 4 .
  • R is hydrogen, R is hydrogen, X is O, X is O, or Y is
  • L can be a saturated straight C 4 . 10 hydrocarbon chain, or C 5 - 8 hydrocarbon chain (e.g., a saturated straight C 5 hydrocarbon chain, a saturated straight C 6 hydrocarbon chain, or a saturated straight C 7 hydrocarbon chain), substituted with C 1 - 4 alkyl, C 2 - alkenyl, C - 4 alkynyl, CM alkoxy, or amino, and further optionally interrupted by -O- or -N(R 0 )-.
  • L is an unsaturated straight C 4 - 10 hydrocarbon chain, or an unsaturated straight C 4 - 8 hydrocarbon chain, containing 2-5 double bonds, or 1-2 double bonds and 1-2 triple bonds, optionally substituted with CM alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, or C 1 . alkoxy, and further being optionally interrupted by -O- or -N(R g )-.
  • A can be phenyl, furyl, thienyl, pyrrolyl, or pyridyl or A can be phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino.
  • hydroxamic acid-containing compounds have a structure of formula (II):
  • A is a cyclic moiety selected from the group consisting of monocyclic aryl or monocyclic heteroaryl. Each of the cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino.
  • Each of X 1 and X 2 is O or S.
  • Each of R 1 and R 2 independently, is hydrogen, alkyl, hydroxylalkyl, or haloalkyl.
  • Each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is hydrogen, d- 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, C1-4 alkoxy, hydroxyl, halo, hydroxylC 1 - 4 alkyl, halod- 4 alkyl, or amino, and each of a, b, c, d, e, and f, independently, is 0 or 1. Note that at least one of b, c, d, and e cannot be zero. In certain embodiments, a is 0, f is 0, or the total number of b, c, d, and e is 3 or 4.
  • each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is hydrogen, d- 4 alkyl, d- 4 alkoxy, hydroxyl, hydroxyld- 4 alkyl, or amino.
  • Each of R 5 , R 6 , R 7 , and R 8 independently can be hydrogen, C 1 - 4 alkyl, CM alkoxy, hydroxyl, hydroxylC M alkyl, or amino,
  • Each of R 3 , R 4 , R 9 and R 10 independently, can be hydrogen.
  • hydroxamic acid-containing compounds have the structure of formula (I), supra.
  • A is a saturated branched C 3 - 14 hydrocarbon chain or an unsaturated branched C - 1 hydrocarbon chain optionally interrupted by -O-, -S-, -N(R a )-, -C(O)-, -N(R a )-C(O)-, -C(O)-N(R a )-, -N(R a )-SO 2 -, -SO 2 -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R )-, -O-C(O)-N(R )-, -O-C(O)-N(R )-, -O-C(O)-N(R )-, -
  • Each of the saturated and the unsaturated branched hydrocarbon chain is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl.
  • Each of X 1 and X 2 is O or S.
  • Each of Y 1 and Y 2 is -CH 2 -, -O-, -N(R C )-, -N(R c )-C(O)-O-, -O-C(O)-N(R c )-, -N(R c )-C(O)-N(R d )-, -O-C(O)-, -C(O)-O-, -O-C(O)-O-, or a bond, where each of R c and R d , independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L is a saturated straight C . 12 hydrocarbon or an unsaturated straight C . 12 hydrocarbon chain, said hydrocarbon chain being optionally substituted with C ⁇ - 4 alkyl, C - 4 alkenyl, C - 4 alkynyl, C alkoxy, hydroxyl, halo, carboxyl, amino. nitro, cyano, C 3 - 6 cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, CM alkylcarbonyloxy, CM alkyloxycarbonyl, CM alkylcarbonyl, formyl, C ⁇ alkylcarbonylamino, or C 1 .
  • R e and R independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and R is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group.
  • hydroxamic acid-containing compound of the present invention benzylthioglycoloylhydroxamic acid, N-methyl-5-phenyl-2,4- pentadienoylhydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4- methyl-5-phenyl-2,4-pentadienoylhydroxamic acid, 4-chloro-5-phenyl-2,4- pentadienoylhydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoylhydroxamic acid, 5-phenyl-2-en-4-yn-pentanoylhydroxamic acid, 5-(2-furyl)-2,4-pentadienoylhydroxamic acid, N-methyl-6-phenyl-3,5-hexadienoylhydroxamic acid, N-methyl-6-phen
  • carboxylic acid-containing compounds have a structure of formula
  • A is a cyclic moiety selected from the group consisting of C 3 - 14 cycloalkyl, 3-14 membered heterocycloalkyl, C 4 . 14 cycloalkenyl, 3-14 membered heterocycloalkenyl (e.g., C 3 . 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 4 - 8 cycloalkenyl, 3-8 membered heterocycloalkenyl), aryl, or heteroaryl.
  • the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl.
  • Each of X 1 and X 2 is O or S
  • each of Y 1 and Y 2 is -CH 2 -, -O-, -S-, -N(R , -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R b )-, -O-C(O)-O-, or a bond
  • each of R a and R b independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;
  • L is a straight C 3 - ⁇ 2 hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond.
  • the hydrocarbon chain is optionally substituted with CM alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, C M alkoxy, hydroxyl, halo, amino, nitro, cyano, C 3 - 5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, d- 4 alkylcarbonyloxy, C M alkyloxycarbonyl, C ⁇ - 4 alkylcarbonyl, or formyl; and is further optionally interrupted by -O-, -N(R C )-, -N(R c )-C(O)-O-, -O-C(O)-N(R c )-, -N(R c )-C(O)-
  • R° and R d independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L contains two or more double bonds, the double bonds are not adjacent to each other. Further, when L contains less than 6 carbon atoms in the hydrocarbon chain, Y 1 is not a bond.
  • A can be a C 5 - 8 cycloalkenyl or 5-8 membered heteroalkenyl containing at least two double bond
  • A can be phenyl, naphthyl, indanyl, or tetrahydronaphthyl, or A can be phenyl optionally substituted with alkyl alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, or amino.
  • carboxylic acid-containing compounds have a structure of formula (I), supra.
  • A is a cyclic moiety selected from the group consisting of aryl or heteroaryl. The cyclic moiety is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or
  • Each of X and X is O or S
  • L is a straight C 3 - 12 hydrocarbon chain optionally containing at least one double bond, at least one triple bond, or at least one double bond and one triple bond.
  • the hydrocarbon chain is optionally substituted with C M alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, d- alkoxy, or amino, and further optionally interrupted by -O- or -N(R C )-, where R° is hydrogen, alkyl, hydroxylalkyl, or haloalkyl.
  • R° is hydrogen, alkyl, hydroxylalkyl, or haloalkyl.
  • carboxylic acid-containing compounds have a structure of formula (I), supra.
  • A is a heteroaryl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino.
  • Each of X 1 and X 2 is O or S, and each of Y 1 and Y 2 , independently, is -CH 2 -, -O-, -S-, -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-,
  • L is a straight C 3 . 12 hydrocarbon chain optionally containing at least one double bond, at least one a triple bond, or at least one double bond and one triple bond.
  • the hydrocarbon chain is optionally substituted with CM alkyl, C 2 . 4 alkenyl, C 2 . 4 alkynyl, d- 4 alkoxy, or amino, and further optionally interrupted by
  • carboxylic acid-containing compounds have the structure of formula (I), supra.
  • A is a phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy,
  • Each of X and X is O or S
  • each of Y and Y 2 independently, is -CH 2 -, -O-, -S-, -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R )-, -O-C(O)-O-, or a bond.
  • Each of R a and R independently, being hydrogen, alkyl, hydroxylalkyl, or haloalkyl.
  • L is a straight C 3 .
  • hydrocarbon chain containing at least one double bond and one triple bond.
  • the hydrocarbon chain is optionally substituted with d- 4 alkyl, C 2 - 4 alkenyl, C 2 - 4 alkynyl, CM alkoxy, or amino, and further optionally interrupted by -O- or -N(R C )-, where R c is hydrogen, alkyl, hydroxylalkyl, or haloalkyl.
  • carboxylic acid-containing compounds have a structure of formula (I), supra.
  • A is a saturated branched C 3 - ⁇ 2 hydrocarbon chain or an unsaturated branched C 3 - 12 hydrocarbon chain optionally interrupted by -O-, -S-, -N(R a )-, -C(O)-, -N(R a )-SO 2 -, -SO 2 -N(R a )-, -N(R a )-C(O)-O-, -O-C(O)-N(R a )-, -N(R a )-C(O)-N(R b )-, -O-SO 2 -, -SO 2 -O-, or -O-C(O)-O-.
  • Each of R and R b is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • Each of the saturated and the unsaturated branched hydrocarbon chain is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl.
  • Each of X 1 and X 2 is O or S
  • each of Y 1 and Y 2 is -CH 2 -, -O-, -S-, -N(R C )-, -C(O)-, -N(R c )-SO 2 -, -SO 2 -N(R c )-, -N(R c )-C(O)-O-, -O-C(O)-N(R c )-, -N(R c )-C(O)-N(R d )-, -O-SO 2 -, -SO 2 -O-, -O-C(O)-O-, or a bond.
  • Each of R c and R d is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L is a straight C 2 . 12 hydrocarbon chain optionally containing at least one double bond, at least one a triple bond, or at least one double bond and one triple bond. The hydrocarbon chain is optionally substituted with C 1 .
  • R e and R f independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl.
  • L contains two or more double bonds, the double bonds are not adjacent to each other.
  • A must contain a heteroatom selected from the group consisting of O, S, or N or a double or triple bond.
  • A can be furyl, thienyl, pyrrolyl, or pyridyl.
  • X 1 can be O
  • X 2 can be O
  • each of Y 1 and Y 2 independently, can be -CH 2 -, -O-, -N(R a )-, or a bond.
  • L can be a saturated C 3 - 8 hydrocarbon chain optionally substituted with d- 2 alkyl, C ⁇ - 2 alkoxy, hydroxyl, -NH 2 , -NH(C 1 . 2 alkyl), or -N(d- 2 alkyl) 2 .
  • L can be an unsaturated C 4 - 8 hydrocarbon chain containing at least one double bond and no triple bond, at least one double bond and one triple bond, or only double bonds.
  • the unsaturated hydrocarbon chain can be optionally substituted with d- 2 alkyl, C ⁇ _ 2 alkoxy, hydroxyl, -NH 2 , -NH(d- alkyl), or -N(d- 2 alkyl) 2 .
  • the double bond can be in trans configuration.
  • carboxylic acid-containing compound of the present invention 4-chloro-5-phenyl-2,4-pentadienoic acid, 5-(4-dimethylaminophenyl)-2,4- pentadienoic acid, 5-(2-furyl)-2,4-pentadienoic acid, 5-phenyl-2-en-4-yn-pentanoic acid, 7- phenyl-2,4,6-heptatrienoic acid, and 8-phenyl-3,5,7-octatrienoic acid.
  • a salt of any of the compounds of the invention can be prepared.
  • a pharmaceutically acceptable salt can be formed when an amino-containing compound of this invention reacts with an inorganic or organic acid.
  • Some examples of such an acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid.
  • Examples of pharmaceutically acceptable salts thus formed include sulfate, pyrosulfate bisulfate, sulf ⁇ te, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, and maleate.
  • a compound of this invention may also form a pharmaceutically acceptable salt when a compound of this invention having an acid moiety reacts with an inorganic or organic base.
  • Such salts include those derived from inorganic or organic bases, e.g., alkali metal salts such as sodium, potassium, or lithium salts; alkaline earth metal salts such as calcium or magnesium salts; or ammonium salts or salts of organic bases such as morpholine, piperidine, pyridine, dimethylamine, or diethylamine salts. It should be recognized that a compound of the invention can contain cliiral carbon atoms. In other words, it may have optical isomers or diastereoisomers.
  • Alkyl is a straight or branched hydrocarbon chain containing 1 to 10 (preferably, 1 to 6; more preferably 1 to 4) carbon atoms.
  • alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- methylhexyl, and 3-ethyloctyl.
  • alkenyl and alkynyl refer to a straight or branched hydrocarbon chain containing 2 to 10 carbon atoms and one or more (preferably, 1-4 or more preferably 1-2) double or triple bonds, respectively.
  • alkenyl and alkynyl are allyl, 2- butenyl, 2-pentenyl, 2-hexenyl, 2-butynyl, 2-pentynyl, and 2-hexynyl.
  • Cycloalkyl is a monocyclic, bicyclic or tricyclic alkyl group containing 3 to 14 carbon atoms. Some examples of cycloalkyl are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl. Heterocycloalkyl is a cycloalkyl group containing at least one heteroatom (e.g., 1-3) such as nitrogen, oxygen, or sulfur. The nitrogen or sulfur may optionally be oxidized and the nitrogen may optionally be quaternized.
  • heteroatom e.g., 1-3
  • heterocycloalkyl examples include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, and morpholmyl.
  • Cycloalkenyl is a cycloalkyl group containing at least one (e.g., 1-3) double bond. Examples of such a group include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, and cyclooctenyl groups.
  • heterocycloalkenyl is a cycloalkenyl group containing at least one heteroatom selected from the group of oxygen, nitrogen or sulfur.
  • Aryl is an aromatic group containing a 5-14 ring and can contain fused rings, which may be saturated, unsaturated, or aromatic.
  • Examples of an aryl group include phenyl, naphthyl, biphenyl, phenanthryl, and anthracyl. If the aryl is specified as "monocyclic aryl,” if refers to an aromatic group containing only a single ring, i.e., not a fused ring.
  • Heteroaryl is aryl containing at least one (e.g., 1-3) heteroatom such as nitrogen, oxygen, or sulfur and can contain fused rings.
  • heteroaryl are pyridyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, and benzthiazolyl.
  • the cyclic moiety can be a fused ring formed from two or more of the just-mentioned groups.
  • Examples of a cyclic moiety having fused rings include fluorenyl, dihydro- dibenzoazepine, dibenzocycloheptenyl, 7H-pyrazino[2,3-c]carbazole, or 9,10-dihydro-9,10- [2]buteno-anthracene.
  • Amino protecting groups and hydroxy protecting groups are well-known to those in the art.
  • the species of protecting group is not critical, provided that it is stable to the conditions of any subsequent reaction(s) on other positions of the compound and can be removed without adversely affecting the remainder of the molecule.
  • a protecting group may be substituted for another after substantive synthetic transformations are complete.
  • Examples of an amino protecting group include, but not limited to, carbamates such as 2,2,2-trichloroethylcarbamate or tertbutylcarbamate.
  • hydroxyl protecting group examples include, but not limited to, ethers such as methyl, t-butyl, benzyl, p- methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluor
  • an amino group can be unsubstituted (i.e., -NH 2 ), mono-substituted (i.e., -NHR), or di-substituted (i.e., -NR 2 ). It can be substituted with groups (R) such as alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl.
  • Halo refers to fluoro, chloro, bromo, or iodo.
  • Inhibition of a histone deacetylase in a cell is determined by measuring the level of acetylated histones in the treated cells and measuring the level of acetylated histones in untreated cells and comparing the levels. If the level of histone acetylation in the treated cells increases relative to the untreated cells, histone deacetylase has been inhibited.
  • disorders or physiological conditions may be mediated by hyperactive histone deacetylase activity.
  • a disorder or physiological condition that is mediated by histone deacetylase refers to a disorder or condition wherein histone deacetylase plays a role in triggering the onset thereof.
  • disorders or conditions include, but not limited to, cancer, hemoglobinopathies (e.g., thalassemia or sickle cell anemia), cystic fibrosis, protozoan infection, adrenoleukodystrophy, alpha- 1 anti-trypsin, retrovirus gene vector reactivation, wound healing, hair growth, peroxisome biogenesis disorder, and adrenoleukodystrophy.
  • a carboxylic acid-containing compound of the present invention can be prepared by any known methods in the art.
  • the resulting solution is stirred at the same temperature for an additional 30-45 minutes which is followed by the addition of a solution containing an aromatic acrylaldehyde in anhydrous THF over 1- 2 hours.
  • the reaction mixture is then warmed to room temperature and stirred overnight. It is then acidified (e.g., with HC1) which allows the organic phase to be separated.
  • the organic phase is then dried, concentrated, and purified (e.g., by recrystallization) to form an unsaturated carboxylic acid.
  • a Grignard reagent e.g., methyl magnesium iodide
  • a phosphorus oxychloride e.g., phosphorus oxychloride
  • carboxylic acid-containing compounds e.g., those containing a linker with multiple double bonds or triple bonds
  • Carboxylic acid-containing compounds described above can then be converted to hydroxamic acid-containing compounds according to the following scheme: X 1 CH 3 O
  • Triethylamine (TEA) is added to a cooled (e.g., 0-5°C) anhydrous THF solution containing the carboxylic acid.
  • Isobutyl chloroformate is then added to the solution having carboxylic acid, which is followed by the addition of hydroxylamine hydrochloride and TEA. After acidification, the solution was filtered to collect the desired hydroxamic acid-containing compound.
  • N-substituted hydroxamic acid can be prepared in a similar manner as described above.
  • the desired N-substituted hydroxamic acid can be collected after acidifying the reaction mixture after the reaction has completed (e.g., in 2-3 hours).
  • KOH/methanol basic condition
  • Desired products in the form of a potassium salt
  • L' contains an amino substituent, it can be first protected by a suitable amino protecting group such as trifluoroacetyl or tert-butoxycarbonyl prior to being treated with reagents such as butyllithium. See, e.g., T. W. Greene, supra, for other suitable protecting groups.
  • a compound produced by the methods shown above can be purified by flash column chromatography, preparative high performance liquid chromatography, or crystallization.
  • a pharmaceutical composition can be used to inhibit histone deacetylase in cells and can be used to treat disorders associated with abnormal histone deacetylase activity.
  • these disorders are cancers (e.g., leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, cervical cancer, renal cancer, prostate cancer, and breast cancer), hematological disorders (e.g., hemoglobinopathies, thalassemia, and sickle cell anemia) and genetic related metabolic disorders (e.g., cystic fibrosis, peroxisome biogenesis disorder, alpha-1 anti-trypsin, and adrenoleukodystrophy).
  • the compounds of this invention can also stimulate hematopoietic cells ex vivo, ameliorating protozoal parasitic infection, accelerate wound healing, and protecting hair follicles.
  • An effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al, Cancer Chemother. Rep. 50, 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 1970, 537. An effective amount of a compound described herein can range from about 1 mg/kg to about 300 mg/kg.
  • Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage, pre-treatment, or post-treatment, with other therapeutic treatments including use of other chemotherapeutic agents and radiation therapy.
  • Other chemotherapeutic agents that can be co-administered include, but not limited to, paclitaxel and its derivatives (e.g., taxotere), doxorubicin, L-asparaginase, dacarbazine, amascrine, procarbazine, hexamethylmelamine, mitoxantrone, and gemicitabine.
  • the pharmaceutical composition may be administered via the parenteral route, including orally, topically, subcutaneously, intraperitoneally, intramuscularly, and intravenously.
  • parenteral dosage forms include aqueous solutions of the active agent, in a iso tonic saline, 5% glucose or other well-known pharmaceutically acceptable excipient.
  • Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds. Because some of the compounds described herein can have limited water solubility, a solubilizing agent can be included in the composition to improve the solubility of the compound.
  • the compounds can be solubilized in polyethoxylated castor oil (Cremophor EL®) and may further contain other solvents, e.g., ethanol.
  • compounds described herein can also be entrapped in liposomes that may contain tumor-directing agents (e.g., monoclonal antibodies having affinity towards tumor cells).
  • a compound described herein can be formulated into dosage forms for other routes of administration utilizing conventional methods. For example, it can be formulated in a capsule, a gel seal, or a tablet for oral administration. Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose.
  • Tablets may be formulated in accordance with conventional procedures by compressing mixtures of a compound described herein with a solid carrier and a lubricant.
  • solid carriers include starch and sugar bentonite.
  • Compounds of this invention can also be administered in a form of a hard shell tablet or a capsule containing a binder, e.g., lactose or mannitol, a conventional filler, and a tableting agent.
  • the activities of a compound described herein can be evaluated by methods known in the art, e.g., MTT (3-[4,5-dimehtythiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, clonogenic assay, ATP assay, or Extreme Drug Resistance (EDR) assay.
  • MTT 3-[4,5-dimehtythiazol-2-yl]-2,5-diphenyltetrazolium bromide
  • clonogenic assay e.g., clonogenic assay, ATP assay, or Extreme Drug Resistance (EDR) assay.
  • EDR Extreme Drug Resistance
  • the EDR assay in particular, is useful for evaluating the antitumor and antiproliferative activity of a compound of this invention (see Example 28 below). Cells are treated for four days with compound of the invention.
  • Both untreated and treated cells are pulsed with tritiated thymidine for 24 hours. Radioactivity of each type of cells is then measured and compared. The results are then plotted to generate drug response curves, which allow IC 50 values (the concentration of a compound required to inhibit 50% of the population of the treated cells) to be determined.
  • the histone acetylation activity of a compound described herein can be evaluated in an assay using mouse erythroleukemia cells. Studies are performed with the DS19 mouse erythroleukemia cells maintained in RPMI 1640 medium with 25 mM HEPES buffer and 5% fetal calf serum. The cells are incubated at 37°C. Histones are isolated from cells after incubation for periods of 2 and 24 hours. The cells are centrifuged for 5 minutes at 2000 rpm in the Sorvall SS34 rotor and washed once with phosphate buffered saline.
  • the pellets are suspended in 10 ml lysis buffer (10 mM Tris, 50 mM sodium bisulfite, 1% Triton X-100, 10 mM magnesium chloride, 8.6% sucrose, pH 6.5) and homogenized with six strokes of a Teflon pestle.
  • the solution is centrifuged and the pellet washed once with 5 ml of the lysis buffer and once with 5 ml 10 mM Tris, 13 mM
  • EDTA pH 7.4.
  • the pellets are extracted with 2 x 1 mL 0.25N HC1.
  • Histones are precipitated from the combined extracts by the addition of 20 mL acetone and refrigeration overnight.
  • the histones are pelleted by centrifuging at 5000 rpm for 20 minutes in the Sorvall SS34 rotor. The pellets are washed once with 5 mL acetone and protein concentration are quantitated by the Bradford procedure. Separation of acetylated histones is usually performed with an acetic acid-urea polyacrylamide gel electrophoresis procedure. Resolution of acetylated H4 histones is achieved with 6,25N urea and no detergent as originally described by Panyim and Chalkley, Arch.
  • the procedure for densitometry involves digital recording using the Alpha hnager 2000, enlargement of the image using the PHOTOSHOP program (Adobe Corp.) on a MACINTOSH computer (Apple Corp.), creation of a hard copy using a laser printer and densitometry by reflectance using the Shimadzu CS9000U densitometer.
  • the percentage of H4 histone in the various acetylated states is expressed as a percentage of the total H4 histone.
  • concentration of a compound of the invention required to decrease the unacetylated H4 histone by 50% i.e., EC 50
  • concentration of a compound of the invention required to decrease the unacetylated H4 histone by 50% can then be determined from data obtained using different concentrations of test compounds.
  • Histone deacetylase inhibitory activity can be measured based on procedures described by Hoffmann et al., Nucleic Acids Res., 27, 2057-2058 (1999). See Example 30 below. Briefly, the assay starts with incubating the isolated histone deacetylase enzyme with a compound of the invention, followed by the addition of a fluorescent-labeled lysine substrate (contains an amino group at the side chain which is available for acetylation).
  • HPLC is used to monitor the labeled substrate.
  • the range of activity of each test compound is preliminarily determined using results obtained from HPLC analyses. IC 50 values can then be determined from HPLC results using different concentrations of compounds of this invention. All assays are duplicated or triplicated for accuracy.
  • the histone deacetylase inhibitory activity can be compared with the increased activity of acetylated histone for confirmation.
  • Compounds of this invention are also evaluated for effects on treating X-linked adrenoleukodystrophy (X-ALD), a peroxisomal disorder with impaired very long-chain fatty acid (VLCFA) metabolism.
  • X-ALD X-linked adrenoleukodystrophy
  • VLCFA very long-chain fatty acid
  • cell lines derived from human primary fibroblasts and (EBN-transformed lymphocytes) derived from X-ALD patients grown in RPMI are employed. Tissue culture cells are grown in the presence or absence of test compounds.
  • total lipids are extracted, converted to methyl esters, purified by TLC and subjected to capillary GC analysis as described in Moser et al., Technique in Diagnostic Biochemical Genetics: A Laboratory Manual (ed. A., H.F.) 177-191 (Wiley-Liss, New York, 1991).
  • C24:0 /3-oxidation activity of lyophoclastoid cells are determined by measuring their capacity to degrade [ 1 - 14 C]-C24:0 fatty acid to water-soluble products as described in Watkins et al., Arch. Biochem. Biophys. 289, 329-336 (1991).
  • the statistical significance of measured biochemical differences between untreated and treated X- ALD cells can be determined by a two-tailed Student's t-test. See Example 31 below.
  • CFTR cystic fibrosis
  • CFTR As CFTR exits the ER and matures through the Golgi stacks, its glycosylation is modified until it achieves a terminal mature glycosylation, affording it a molecular weight of around 170 kDa (Band C). Thus, the extent to which CFTR exits the ER and traverses the Golgi to reach the plasma membrane may be reflected in the ratio of Band B to Band C protein.
  • CFTR is immunoprecipitated from control cells, and cells exposed to test compounds. Both wt CFTR and ⁇ F508 CFTR expressing cells are tested. Following lysis, CFTR are immunoprecipitated using various CFTR antibodies.
  • Immunoprecipitates are then subjected to in vitro phosphorylation using radioactive ATP and exogenous protein kinase A. Samples are subsequently solubilized and resolved by SDS-PAGE. Gels are then dried and subject to autoradiography and phosphor image analysis for quantitation of Bands
  • B and C are determined on a BioRad personal fix image station. See Example 32 below.
  • compounds of this invention can be used to treat homozygous ⁇ thalassemia, a disease in which there is inadequate production of ⁇ globin leading to severe anemia. See Collins et al., Blood, 85(1), 43-49 (1995).
  • compounds of the present invention are evaluated for their use as antiprotozoal or antiparasitic agents.
  • the evaluation can be conducted using parasite cultures (e.g., Asexual P. falciparum). See Trager, W. & Jensen, J.B. Science 193, 673-675 (1976) .
  • Test compounds of the invention are dissolved in dimethyl sulfoxide (DMSO) and added to wells of a flat-bottomed 96-well microtitre plate containing human serum. Parasite cultures are then added to the wells, whereas control wells only contain parasite cultures. After at least one invasion cycle, and addition of labeled hypoxanthine monohydrochloride, the level of incorporation of labeled hypoxanthine is detected.
  • IC 50 values can be calculated from data using a non-linear regression analysis.
  • toxicity of a compound described herein is evaluated when a compound of the invention is administered by single intraperitoneal dose to test mice. See Example 33 below. After administration of a predetermined dose to three groups of test mice and untreated controls, mortality/morbidity checks are made daily. Body weight and gross necropsy findings are also monitored. For reference, see Gad, S. C. (ed.), Safety Assessment for Pharmaceuticals (Nan ⁇ ostrand Reinhold, New York, 1995).
  • Dimethylformamide (DMF, anhydrous, 25 mL) was cooled to 0-5°C and phosphorus oxychloride (16.4 mL) was added dropwise over a period of an hour. The resulting solution was added dropwise to a cooled (0-5°C) solution of 4-phenyl-2-methyl-3-buten-2-ol (0.14 mol) in 60 mL of anhydrous DMF over a period of an hour. The reaction mixture was then warmed to room temperature, gradually heated up to 80°C, stirred at 80°C for three hours and cooled to 0-5°C.
  • Butyllithium (135 mL of 2.5 N solution) was added to 600 mL of anhydrous tefrahydrofuran (THF) at -65°C.
  • the resulting solution was stirred at -65°C for an additional 30 minutes and then a solution of ⁇ -methyl-tr r ⁇ -cim amaldehyde (23.2 g) in 100 mL of anhydrous THF was added to the reaction at — 65°C over a period of 70 minutes.
  • the reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight.
  • the reaction was then acidified with 5% hydrochloric acid (125 mL) to a pH of 2.8.
  • the aqueous layer was extracted with 100 mL of ether twice and with 100 mL of ethyl acetate once.
  • the combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the crude material was dissolved in 100 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 25.8 g of the desired 4-methyl-5-phenyl-2,4-pentadienoic acid.
  • Butyllithium (50 mL of 2.5 N solution) was added to 250 mL of anhydrous tefrahydrofuran (THF) at -65°C.
  • the resulting solution was stirred at -65°C for an additional 40 minutes and then a solution of ⁇ -chloro- cinnamaldehyde (10.0 g) in 60 mL of anhydrous THF was added to the reaction at -65°C over a period of 95 minutes.
  • the reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight.
  • the reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight.
  • the reaction was then acidified with 6 N hydrochloric acid (5 mL) to a pH of 1.0.
  • the aqueous layer was extracted with 75 mL of ethyl acetate three times.
  • the combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the crude material was recrystallized with chloroform: ether (90:10) and then refrigerated overnight. The crystals were filtered and dried under vacuum to afford 1.1 g of the desired 5-phenyl-2-ene-4- pentynoic acid.
  • Butyllithium (24 mL of 2.5 N solution) was added to 120 mL of anhydrous tetrahydrofuran (THF) at -65°C.
  • THF tetrahydrofuran
  • the resulting solution was stirred at -65°C for an additional 30 minutes and then a solution of 7-dimethylaminocinnamaldehyde (5.0 g) in 80 mL of anhydrous THF was added to the reaction at -65°C over a period of 30 minutes.
  • the reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight.
  • Triphenylphosphine (178.7 g) and 3-chloropropionic acid (73.9 g) were mixed in a 1- liter 3 -neck round bottom flask equipped with a mechanical stirrer, reflux condenser with a nitrogen inlet and a thermocouple. The mixture was heated to 145°C under nitrogen and stirred for 2 hours. The reaction was then cooled to 70°C. Ethanol (550 mL) was added and the mixture was refluxed at 80°C until complete dissolution. The solution was cooled to room temperature and ether (900 mL) was added. The mixture was placed in the freezer overnight.
  • the reaction was then allowed to warm to room temperature and stirred overnight.
  • the reaction mixture was cooled to 0-5°C in an ice bath and water (1.6 liters) was added dropwise.
  • the aqueous solution was acidified with 12 N hydrochloric acid (135 mL) to a pH of 1 and extracted with ethyl acetate (1.6 liters) twice.
  • the combined organic layers was washed with water (1000 mL) three times, dried over anhydrous sodium sulfate and concentrated under vacuum to afford a yellow oil.
  • the crude oil was dissolved in 125 mL of methylene chloride and chromatographed on a Biotage 75L silica gel column and eluted with methylene chloride: ether (9:1).
  • l-Phenyl-2-buten-l-ol (135.88 g) was dissolved in 2300 mL of dioxane and treated with 2750 mL of dilute hydrochloric acid (2.3 mL of concentrated hydrochloric acid in 2750 mL of water) at room temperature. The mixture was stirred overnight and then poured into 4333 mL of ether and neutralized with 2265 mL of saturated aqueous sodium bicarbonate. The aqueous phase was extracted with 1970 mL of ether.
  • Dimethylformamide (DMF, anhydrous, 14 mL) was cooled to 0-5°C and phosphorus oxychloride (8.2 mL) was added dropwise over a period of 40 minutes.
  • the resulting solution was added dropwise to a cooled (0-5°C) solution of 4-phenyl-3-buten-2-ol (10 g) in 32 mL of anhydrous DMF over a period of an hour.
  • the reaction mixture was warmed to room temperature over a 35-minute period and then gradually heated up to 80°C over a period of 45 minutes.
  • the reaction was stirred at 80°C for three hours and then cooled to 0- 5°C.
  • Butyllithium (12.8 mL of 2.5 N solution) was added to 65 mL of anhydrous tetrahydrofuran (THF) at -65°C.
  • the resulting solution was stirred at -65°C for an additional 30 minutes and then a solution of 5-phenyl-
  • 2,4-pentadienal (2.4 g) in 15 mL of anhydrous THF was added to the reaction at -65°C. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. To the reaction was added 30 mL of water, acidified with 5% hydrochloric acid (14 mL) to a pH of 4.7 and then added an additional 20 mL of water. The aqueous layer was extracted with 10 mL of ether twice and with 10 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 50 mL of hot methanol and then refrigerated overnight.
  • the aqueous layer was extracted with ethyl acetate (280 mL) twice, acidified with 12 N hydrochloric acid (24 mL) to a pH of 1, extracted again with ethyl acetate (280 mL) twice.
  • the combined organic layers were washed with water
  • l-Phenyl-2-buten-l-ol (135.88 g) was dissolved in 2300 mL of dioxane and treated with 2750 mL of dilute hydrochloric acid (2.3 mL of concentrated hydrochloric acid in 2750 mL of water) at room temperature. The mixture was stirred overnight and then poured into 4333 mL of ether and neutralized with 2265 mL of saturated sodium bicarbonate. The aqueous phase was extracted with 1970 mL of ether.
  • the reaction mixture was warmed to room temperature over a 35-minute period and then gradually heated up to 80°C over a period of 45 minutes.
  • the reaction was stirred at 80°C for three hours and then cooled to 0- 5°C.
  • To the cooled reaction solution was added dropwise a solution of sodium acetate (40 g) in deionized water (100 mL) over a period of one hour.
  • the mixture was then reheated to 80°C, stirred at 80°C for an additional 10 minutes, cooled down to room temperature and extracted with ether (100 mL) twice.
  • Example 12 Synthesis of cinnamoylhydroxamic acid Triethylamine (TEA, 17.6 mL) was added to a cooled (0-5°C) solution of trans- cinnamic acid (15.0 g) in 200 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (16.4 mL). The reaction mixture was stirred for 30 minutes and hydroxylamine hydrochloride (17.6 g) was added followed by dropwise addition of 35 mL of TEA at 0-5°C. The reaction was allowed to warm to room temperature and stirred overnight.
  • TEA cinnamoylhydroxamic acid Triethylamine
  • Triethylamine (TEA, 29 mL) was added to a cooled (0-5°C) solution of 5-phenyl-2,4- pentadienoic acid (29.0 g) in 300 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (27.0 mL). The reaction mixture was stirred for 15 minutes and hydroxylamine hydrochloride (28.92 g) was added followed by dropwise addition of 58 mL of TEA over a period of 60 minutes at 0-5°C. The reaction was allowed to warm to room temperature and stirred overnight.
  • TEA Triethylamine
  • the reaction was then poured into 450 mL of a 1% (by weight) solution of citric acid and then extracted with 200 mL of methylene chloride twice and 500 mL of ether once. The solvents were removed under vacuum to give an oil.
  • the crude oil was crystallized with 200 mL of hot acetonitrile to give a tan solid.
  • the tan solid was recrystallized from 60 mL of hot acetonitrile to afford 12.5 g of the desired 5- phenyl-2,4-pentadienoylhydroxamic acid.
  • 5-Phenyl-2,4-pentadienoic acid chloride was dissolved in 50 mL of methylene chloride and added to a solution of 13.8 mL of 40% sodium hydroxide in 50 mL of water at 0-5°C. The resulting solution was stirred for two hours and then acidified to a pH of 4 with concentrated hydrochloric acid. The precipitate was collected by filtration and dried under vacuum to afford 4.2 g of N-methyl-5-phenyl-2,4-pentadienoylhydroxamic acid.
  • Triethylamine (TEA, 6.5 mL) was added to a cooled (0-5°C) solution of 4-methyl-5- phenyl-2,4-pentadienoic acid (7.0 g) in 75 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (6.0 mL) over a period of 60 minutes. The reaction mixture was stirred for 15 minutes and hydroxylamine hydrochloride (6.5 g) was added followed by dropwise addition of 13 mL of TEA over a period of 60 minutes at 0- 5°C. The reaction was allowed to warm to room temperature and stirred overnight.
  • TEA 4-methyl-5- phenyl-2,4-pentadienoic acid
  • Triethylamine (TEA, 2.5 mL) was added to a cooled (0-5°C) solution of 4-chloro-5- phenyl-2,4-pentadienoic acid (3.0 g) in 30 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (2.3 mL) over a period of 15 minutes. The reaction mixture was stirred for 30 minutes and hydroxylamine hydrochloride (2.5 g) was added followed by dropwise addition of 5.0 mL of TEA over a period of 60 minutes at 0-5°C. The reaction was allowed to warm to room temperature and stirred overnight.
  • TEA 4-chloro-5- phenyl-2,4-pentadienoic acid
  • Triethylamine (TEA, 0.8 mL) was added to a cooled (0-5°C) solution of 5-(p- dimethylaminophenyl)-2,4-pentadienoic acid (1.0 g) in 10 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (0.7 mL). The reaction mixture was stirred for 60 minutes and hydroxylamine hydrochloride (0.8 g) was added followed by dropwise addition of 1.6 mL of TEA at 0-5°C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 15 mL of water.
  • Triethylamine (TEA, 2.1 mL) was added to a cooled (0-5°C) solution of 5-(2-furyl)- 2,4-pentadienoic acid (2.0 g) in 15 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (2.0 mL) over a period of 30 minutes. The reaction mixture was stirred for 30 minutes and hydroxylamine hydrochloride (2.15 g) was added followed by dropwise addition of 4.2 mL of TEA over a period of 60 minutes at 0-5°C. The reaction was allowed to warm to room temperature and stirred overnight.
  • TEA Triethylamine
  • Triethylamine (TEA, 1.75 mL) was added to a cooled (0-5°C) solution of 6-phenyl- 3,5-hexadienoic acid (2.0 g) in 30 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (1.62 mL) over a period of 15 minutes. The reaction mixture was stirred for 15 minutes and hydroxylamine hydrochloride (1.74 g) was added followed by dropwise addition of 3.5 mL of TEA at 0-5°C. The reaction was allowed to warm to room temperature and stirred overnight.
  • TEA Triethylamine
  • 6-Phenyl-3,5-hexadienoic acid (1 g) was dissolved in 10 mL of tetrahydrofuran (THF) and treated with 0.9 g of l,l'-carbonyldiimidazole. The reaction was stirred for 30 minutes.
  • N-methylhydroxylamine hydrochloride (0.44 g) was neutralized with 0.29 g of sodium methoxide in 10 mL of THF and 5 mL of methanol and then filtered to remove the sodium chloride. N-methylhydroxylamine was then added to the reaction mixture and stirred overnight. The resulting mixture was partitioned between 25 mL of water and 50 mL of ethyl acetate.
  • the ethyl acetate layer was washed with 25 mL each of 5% hydrochloric acid, saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated under vacuum to afford 0.9 g of a viscous yellow oil.
  • the crude product was chromatographed on a Biotage 40S silica gel column and eluted with ethyl acetate :hexane (1:1). The fractions containing the desired product were combined and the solvent was removed under vacuum to yield 0.17 g of N-methyl-6-phenyl-3,5-hexadienoylhydroxamic acid.
  • Triethylamine (TEA, 24.1 mL) was added to a cooled (0-5°C) solution of 7-phenyl- 2,4,6-heptatrienoic acid (27.8 g) in 280 mL of anhydrous dimethylformamide. To this solution was added dropwise isobutyl chloroformate (22.5 mL) over a period of 75 minutes. The reaction mixture was stirred for 40 minutes and hydroxylamine hydrochloride (24.2 g) was added followed by dropwise addition of 48 mL of TEA over a period of 70 minutes at 0- 5°C. The reaction was allowed to warm to room temperature and stirred overnight.
  • TEA Triethylamine
  • the PC3 cell line was maintained in RPMI supplemented with 10% fetal calf serum and antibiotics. Cells were suspended in 0.12% soft agar in complete medium and plated (2,000 cells per well) in different drug concentrations onto a 0.4% agarose underlayer in 24- well plates. Plating calls on agarose underlayers supports the proliferation only of the transformed cells, ensuring that the growth signal stems from the malignant component of the tumor.
  • the model used in this assay was mouse erythroleukemia cells. Specifically, the level of acetylation of H4 histones in these erythroleukemia cells was monitored. H4 histones was chosen as the target due to the ease of resolution of the variably acetylated histones. Inhibition of histone deacetylase leads to increased (hyper)acetylation of histones.
  • Histones were isolated from cells after incubation for 2 or 24 hours. The cells were centrifuged for 5 minutes at 2,000 rpm in the Sorvall SS34 rotor and washed once with phosphate buffered saline. The pellets were suspended in 5 mL lysis buffer (10 mM Tris, 50 mM sodium bisulfite, l%Triton X-100, 10 mM magnesium chloride, 8.6% sucrose, pH 6.5) and homogenized with six strokes of a teflon pestle. The homogenizing tubes were rinsed with 5 mL lysis buffer.
  • the combined solutions were centrifuged and the pellets were washed once with 5 mL of the lysis buffer and once with 5 mL 10 mM Tris, 13 mM EDTA, pH 7.4.
  • the pellets were extracted with 2 x 1 mL 0.25N HC1. Histones were precipitated from the combined extracts by the addition of 20 mL acetone and refrigeration overnight.
  • the histones were pelleted by centrifuging at 5,000 rpm for 20 minutes in the Sorvall SS34 rotor. The pellets were washed once with 5 mL acetone and protein concentration was quantitated by the Bradford procedure.
  • Y tracking dye had run off the gel.
  • the gel was stained with Coomassie Blue R.
  • the most rapidly migrating protein band is the unacetylated H4 histone followed by bands with 1,2,3 and 4 acetyl groups which were quantitated by densitometry.
  • Densitometry was measured through digital recording using the Alpha Imager 2000.
  • Enlargement of the image was done using PHOTOSHOP (Adobe Corp.) on a MACINTOSH (Apple Corp.) computer. After creating a hard copy of the gel by using a laser printer, a
  • test compounds of the invention showed EC 50 values in micromolar concentration range.
  • Histone Deacetylation Assay The determination of the inhibition of histone deacetylase by compounds of the invention was based upon the procedure described by Hoffmann et al., Nucleic Acids Res. 27,
  • histone deacetylase was isolated from rat liver as previously described in Kolle, D. et al., Methods: A Companion to Methods in Enzymology 15, 323-331
  • the assay was performed in a final total volume of 120 ⁇ L consisting of 100 ⁇ L of 15 mM tris-HCl buffer at pH 7.9 and 0.25 mM EDTA, 10 mM NaCl, 10% glycerol, 10 mM mercaptoethanol and the enzyme.
  • the assay was initiated upon the addition of 10 ⁇ l of a test compound followed by the addition of a fluorescent-labeled lysine substrate to each assay tube in an ice bath for 15 minutes.
  • the tubes were transferred to a water bath at 37 °C for an additional 90 minutes.
  • Test compounds of the invention showed potent inhibition of histone deacetylase, having IC 50 values in the low micromolar concentration range (e.g., two test compounds showed IC 50 values of 1.7 ⁇ M and 1.8 ⁇ M).
  • Cell lines derived from X-ALD human patients were grown in RPMI supplemented with fetal calf serum (10%), penicillin (100 U/mL), streptomycin (100 U/mL) and glutamine (2mM). On day 0, cells were divided into two separate tissue culture flasks, and test compounds (2.5-250 ⁇ M final concentration, diluted from a 0.5 M stock solution in PBS, pH 7.6) was added to one flask. Cells in the second flask were grown in the absence of test compounds for the same length of time and served as controls. The media were changed every 3-4 days.
  • Biochemical Measurements As described above, tissue culture cells were grown in the presence or absence of test compounds, collected from tissue culture flasks using trypsin, washed twice with PBS and subjected to biochemical analysis. NLCFA measurements was conducted by extracting total amount of lipids, converted the lipids to methyl ester, purified by TLC, and subjected to capillary CC analysis as described in Moser et al., Technique in Diagnostic Biochemical Genetics: A Laboratory Manual (ed. A., H.F.) 177-191 (Wiley-Liss, New York, 1991).
  • C24:0 ⁇ - oxidation activity of lymphoblastoid cells was determined by measuring their capacity to degrade [1- 14 C]-C24:0 fatty acid to water-soluble products as described in Watkins et al, Arch. Biochem. Biophys. 289, 329-336 (1991).
  • the statistical significance of measured biochemical differences between untreated and treated X-ALD cells can be determined by a two-tailed Student's t-test.
  • CFTR is initially synthesized as a nascent polypeptide chain in the rough ER, with a molecular weight of around 120 kDa (Band A). It rapidly receives a core glycosylation in the ER, giving it a molecular weight of around 140 kDa (Band B). As CFTR exits the ER and matures through the Golgi stacks, its glycosylation is modified until it achieves a terminal mature glycosylation, affording it a molecular weight of around 170 kDa (Band C).
  • CFTR is immunoprecipitated from control cells, and cells exposed to test compounds. Both wt CFTR and ⁇ F508 CFTR expressing cells are tested. Following lysis, CFTR are immunoprecipitated using various CFTR antibodies. Immunoprecipitates are then subjected to in vitro phosphorylation using radioactive ATP and exogenous protein kinase A. Samples are subsequently solubilized and resolved by SDS-PAGE.
  • Test compounds of the invention were administered to three groups of 10 mice at 100, 300, and 1,000 mg/kg.
  • An additional group received vehicle (20% hydroxypropyl-/3- cyclodextrin aqueous solution) at 10 mL/kg.
  • Mortality/morbidity checks were made twice daily. Clinical observations were recorded predose and /or postdose on Day 1, and daily thereafter through Day 8. Body weights were recorded on the day of dosing (Day 1) and on Day 8. Mice were euthanized by CO asphyxiation and necropsied on Day 8 or upon death.

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Abstract

L'invention porte sur une histone déacétylase qui est une métalloenzyme avec zinc au niveau du site actif. Des composés ayant une fraction se liant au zinc telle qu'un groupe acide hydroxamique ou un groupe acide carboxylique peuvent inhiber l'histone déacétylase. L'inhibition de l'histone déacétylase peut réprimer l'expression génique, y compris l'expression des gènes relatifs à la suppression tumorale. Selon cette invention, l'inhibition de l'histone déacétylase peut être une alternative dans le traitement du cancer, des troubles hématologiques tels que les hémoglobinopathies et des troubles métaboliques liés aux gènes tels que la mucoviscidose et l'adrénoleucodystrophie.
PCT/US2002/008836 2001-03-27 2002-03-25 Inhibiteurs de l'histone deacetylase WO2002076941A2 (fr)

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EP1567142A4 (fr) * 2002-11-20 2005-12-14 Errant Gene Therapeutics Llc Traitement de cellules pulmonaires avec des inhibiteurs d'histone deacetylase
WO2006029818A3 (fr) * 2004-09-16 2006-05-11 Dsm Ip Assets Bv Nouvelles compositions cosmetiques
WO2006028972A3 (fr) * 2004-09-02 2006-06-08 Osi Pharm Inc Mercaptoamides en tant qu'inhibiteurs d'histone deacetylase
US7154002B1 (en) 2002-10-08 2006-12-26 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7169801B2 (en) 2003-03-17 2007-01-30 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7507828B2 (en) 2003-07-07 2009-03-24 Georgetown University Histone deacetylase inhibitors and methods of use thereof
US7611729B2 (en) 2001-09-10 2009-11-03 Lunamed Ag Dosage forms having prolonged active ingredient release
US7642253B2 (en) 2005-05-11 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7642275B2 (en) 2004-12-16 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7683185B2 (en) 2002-11-18 2010-03-23 Queen Mary & Westfield College Histone deacetylase inhibitors
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US8110577B2 (en) 2006-10-19 2012-02-07 Queen Mary & Westfield College Histone deacetylase inhibitors
JP2019189648A (ja) * 2019-07-08 2019-10-31 国立大学法人東京農工大学 シス桂皮酸類縁体、重力屈性調節剤
WO2021042814A1 (fr) * 2019-09-04 2021-03-11 中南大学 Agent de valorisation d'acide alkylethioéther éthyle hydroximique, son procédé de préparation et son utilisation
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US7611729B2 (en) 2001-09-10 2009-11-03 Lunamed Ag Dosage forms having prolonged active ingredient release
US7399884B2 (en) 2002-10-08 2008-07-15 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7154002B1 (en) 2002-10-08 2006-12-26 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7683185B2 (en) 2002-11-18 2010-03-23 Queen Mary & Westfield College Histone deacetylase inhibitors
EP1567142A4 (fr) * 2002-11-20 2005-12-14 Errant Gene Therapeutics Llc Traitement de cellules pulmonaires avec des inhibiteurs d'histone deacetylase
WO2004076386A3 (fr) * 2003-02-25 2004-10-28 Topotarget Uk Ltd Composes d'acide carbamique comprenant un groupe heteroaryle bicyclique utilises en tant qu'inhibiteurs de hdac
US8071620B2 (en) 2003-02-25 2011-12-06 Topotarget Uk Limited Carbamic acid compounds comprising a bicyclic heteroaryl group as HDAC inhibitors
AU2004215624B2 (en) * 2003-02-25 2011-06-02 Topotarget Uk Limited Hydroxamic acid compounds comprising a bicyclic heteroaryl group as HDAC inhibitors
JP2006518730A (ja) * 2003-02-25 2006-08-17 トポターゲット ユーケー リミテッド Ｈｄａｃインヒビターとしての、二環式ヘテロアリール基を含むカルバミン酸化合物
WO2004076386A2 (fr) 2003-02-25 2004-09-10 Topotarget Uk Limited Composes d'acide carbamique comprenant un groupe heteroaryle bicyclique utilises en tant qu'inhibiteurs de hdac
US7652036B2 (en) 2003-02-25 2010-01-26 Topotarget Uk Limited Carbamic acid compounds comprising a bicyclic heteroaryl group as HDAC inhibitors
US7169801B2 (en) 2003-03-17 2007-01-30 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7375228B2 (en) 2003-03-17 2008-05-20 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7381825B2 (en) 2003-03-17 2008-06-03 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7842835B2 (en) 2003-07-07 2010-11-30 Georgetown University Histone deacetylase inhibitors and methods of use thereof
US8748463B2 (en) 2003-07-07 2014-06-10 Georgetown University Histone deacetylase inhibitors and methods of use thereof
US7507828B2 (en) 2003-07-07 2009-03-24 Georgetown University Histone deacetylase inhibitors and methods of use thereof
US8067600B2 (en) 2003-07-07 2011-11-29 Georgetown University Histone deacetylase inhibitors and methods of use thereof
JP2008511679A (ja) * 2004-09-02 2008-04-17 オーエスアイ・ファーマスーティカルズ・インコーポレーテッド ヒストンデアセチラーゼ阻害剤としてのメルカプトアミド
WO2006028972A3 (fr) * 2004-09-02 2006-06-08 Osi Pharm Inc Mercaptoamides en tant qu'inhibiteurs d'histone deacetylase
WO2006029818A3 (fr) * 2004-09-16 2006-05-11 Dsm Ip Assets Bv Nouvelles compositions cosmetiques
US7642275B2 (en) 2004-12-16 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7642253B2 (en) 2005-05-11 2010-01-05 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7732475B2 (en) 2005-07-14 2010-06-08 Takeda San Diego, Inc. Histone deacetylase inhibitors
US7741494B2 (en) 2005-07-14 2010-06-22 Takeda San Diego, Inc. Histone deacetylase inhibitors
US8110577B2 (en) 2006-10-19 2012-02-07 Queen Mary & Westfield College Histone deacetylase inhibitors
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WO2021042814A1 (fr) * 2019-09-04 2021-03-11 中南大学 Agent de valorisation d'acide alkylethioéther éthyle hydroximique, son procédé de préparation et son utilisation
CN114805235A (zh) * 2022-05-09 2022-07-29 江苏中旗科技股份有限公司 一种多取代异恶唑烷酮及其中间体的合成制备方法
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