CA2486303A1 - Histone deacetylase inhibitors based on alpha-ketoepoxide compounds - Google Patents

Histone deacetylase inhibitors based on alpha-ketoepoxide compounds Download PDF

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Publication number
CA2486303A1
CA2486303A1 CA002486303A CA2486303A CA2486303A1 CA 2486303 A1 CA2486303 A1 CA 2486303A1 CA 002486303 A CA002486303 A CA 002486303A CA 2486303 A CA2486303 A CA 2486303A CA 2486303 A1 CA2486303 A1 CA 2486303A1
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alkyl
compound
alkoxy
hydroxyl
hydrocarbon chain
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CA002486303A
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French (fr)
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CA2486303C (en
Inventor
Hsuan-Yin Lan-Hargest
Robert J. Kaufman
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Errant Gene Therapeutics LLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Abstract

Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, for example, an alpha-ketoepoxide group, such as an alpha-ketothio 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, autosomal dominant disorders, e.g., spinal muscular atrophy and Huntington's disease, genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy, or to stimulate hematopoietic cells ex vivo.

Claims (21)

1. A compound having the formula (I):
wherein A is a cyclic moiety selected from the group consisting of C3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C4-14 cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; or A is a saturated branched C3-12 hydrocarbon chain or an unsaturated branched C3-12 hydrocarbon chain optionally interrupted by -O-, -S-, -N(R a)-, -C(O)-, -N(R a)-SO2-, -SO2-N(R a)-, -N(R a)-C(O)-O-, -O-C(O)-N(R a)-, -N(R a)-C(O)-N(R
b)-, -O-C(O)-, -C(O)-O-, -O-SO2-, -SO2-O-, or -O-C(O)-O-, where each of R a and R
b, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl;
each of Y1 and Y2, independently, is -CH2-, -O-, -S-, -N(R c)-, -N(R c)-C(O)-O-, -N(R c)-C(O)-, -C(O)-N(R c)-, -O-C(O)-N(R c)-, -N(R c)-C(O)-N(R d)-, -C(O)-, -C(NR c)-, -O-C(O)-O-, or a bond; each of R c and R d, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;
L is a straight C4-12 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 being optionally substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, hydroxyl, halo, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, nitro, cyano, C3-5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C1-4 alkylcarbonyloxy, C1-4 alkyloxycarbonyl, 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;
X1 is O or S; and each of R g, R h, and R i, independently, is hydrogen or C1-6 alkyl;
provided that when each of Y1 and Y2, independently, is a bond or CH2, A is unsubstituted phenyl or heterocyclyl, and L is C4-7, L has at least one double bond or at least one triple bond, and when each of Y1 and Y2 is a bond, A is unsubstituted phenyl, and L is C4, L is not a diene;
or a salt thereof.
2. The compound of claim 1, wherein each of R g, R h, and R i are hydrogen.
3. The compound of any of claims 1 and 2, wherein X1 is O.
4. The compound of any of claims 1-3, wherein each of Y1 and Y2, independently, is -CH2-, -O-, -N(R c)-, or a bond.
5. The compound of any of claims 1-4, wherein L is a C4-12 hydrocarbon chain optionally substituted with C1-2 alkyl, C1-2 alkoxy, hydroxyl, -NH2, -NH(C1-2 alkyl), or -N(C1-2 alkyl)2.
6. The compound of any of claims 1-5, wherein L is a C5-12 hydrocarbon chain substituted with C1-2 alkyl, C1-2 alkoxy, hydroxyl, -NH2, -NH(C1-2 alkyl), or -N(C1-2 alkyl)2.
7. The compound of any of claims 1-6, wherein L is a C5-10 hydrocarbon chain substituted with C1-2 alkyl, C1-2 alkoxy, hydroxyl, -NH2, -NH(C1-2 alkyl), or -N(C1-2 alkyl)2.
8. The compound of any of claims 1-7, wherein L is a C6-8 hydrocarbon chain substituted with C1-2 alkyl, C1-2 alkoxy, hydroxyl, -NH2, -NH(C1-2 alkyl), or -N(C1-2 alkyl)2.
9. The compound of any of claims 1-8, wherein L contains at least one double bond, at least one triple bond, or at least one double bond and one triple bond.
10. The compound of any of claims 1-9, wherein L is an unsaturated hydrocarbon chain containing at least one double bond.
11. The compound of claim 10, wherein the double bond is in trans configuration.
12. The compound of any of claims 1-11, wherein L is an unsaturated hydrocarbon chain containing at least two double bonds.
13. The compound of any of claims 1-12, wherein A is a C5-8 cycloalkenyl, 5-8 membered heteroalkenyl, phenyl, naphthyl, indanyl, or tetrahydronaphthyl optionally substituted with alkyl alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, or amino.
14. The compound of any of claims 1-13, wherein A is a phenyl optionally substituted with alkyl alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, or amino.
15. The compound of claim 1, wherein A is phenyl, Y1 is a bond, and L is a C6-12 hydrocarbon chain containing three double bonds and the carbon adjacent to Y1 is substituted with phenyl.
16. The compound of claim 1, wherein A is phenyl, Y1 is a bond, and L is a C3-12 hydrocarbon chain and the carbon adjacent to Y1 is substituted with two phenyl groups.
17. The compound of claim 1, wherein the compound is 1-oxiranyl-7-phenyl-2,4,6-heptatrien-1-one, or 1-oxiranyl-7-phenoxy-2,4,6-heptatrien-1-one.
18. A method of inhibiting histone deacetylation activity in cells comprising contacting the cells with an effective amount of a compound containing an alpha-ketoepoxide group, wherein the compound is not trapoxin, thereby treating one or more disorders mediated by histone deacetylase or stimulating hematopoietic cells ex vivo, and determining whether the level of acetylated histones in the treated cells is higher than in untreated cells under the same conditions.
19. The method of claim 18, wherein the compound is of formula (I):
wherein A is a cyclic moiety selected from the group consisting of C3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C4-14 cycloalkenyl, 3-8 membered heterocycloalkenyl, aryl, and heteroaryl; the cyclic moiety being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl; or A is a saturated branched C3-12 hydrocarbon chain or an unsaturated branched C3-12 hydrocarbon chain optionally interrupted by -O-, -S-, -N(R a)-, -C(O)-, -N(R a)-SO2-, -SO2-N(R a)-, -N(R a)-C(O)-O-, -O-C(O)-N(R a)-, -N(R a)-C(O)-N(R
b)-, -O-C(O)-, -C(O)-O-, -O-SO2-, -SO2-O-, or -O-C(O)-O-, where each of R a and R
b, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; each of the saturated and the unsaturated branched hydrocarbon chain being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl;
each of Y1 and Y2, independently, is -CH2-, -O-, -S-, -N(R c)-, -N(R c)-C(O)-O-, -N(R c)-C(O)-, -C(O)-N(R c)-, -O-C(O)-N(R c)-, -N(R c)-C(O)-N(R d)-, -C(O)-, -C(NR c)-, -O-C(O)-O-, or a bond; each of R c and R d, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl;
L is a straight C3-12 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 being optionally substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, hydroxyl, halo, amino, thio, alkylthio, arylthio, aralkylthio, acylthio, nitro, cyano, C3-5 cycloalkyl, 3-5 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C1-4 alkylcarbonyloxy, C1-4 alkyloxycarbonyl, 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;
X1 is O or S; and each of R g, R h, and R i, independently, is hydrogen or C1-6 alkyl;
provided that when each of Y1 and Y2, independently, is a bond or CH2, A is unsubstituted phenyl or heterocyclyl, and L is C4-6, L has at least one double bond or at least one triple bond;
or a salt thereof.
20. The method of any of claims 18 or 19, wherein the disorder is selected from the group consisting of cancer, hemoglobinopathies, thalassemia, sickle cell anemia, cystic fibrosis, protozoan infection, spinal muscular atrophy, Huntington's disease, alpha-1 anti-trypsin, retrovirus gene vector reactivation, wound healing, hair growth, peroxisome biogenesis disorder, and adrenoleukodystrophy.
21. The method of any of claims 18 or 19, wherein the disorder is cancer, cystic fibrosis, or adrenoleukodystrophy.
CA2486303A 2002-05-22 2003-05-21 Histone deacetylase inhibitors based on alpha-ketoepoxide compounds Expired - Fee Related CA2486303C (en)

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US38208902P 2002-05-22 2002-05-22
US60/382,089 2002-05-22
PCT/US2003/015839 WO2003099272A1 (en) 2002-05-22 2003-05-21 Histone deacetylase inhibitors based on alpha-ketoepoxide compounds

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EP (1) EP1511477A4 (en)
AU (1) AU2003243272A1 (en)
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