US2003083521A1PendingUtilityA1
Histone deacetylase inhibitors
Assignee: CIRCAGEN PHARMACEUTICAL A MARYPriority: Mar 27, 2001Filed: Dec 2, 2002Published: May 1, 2003
Est. expiryMar 27, 2021(expired)· nominal 20-yr term from priority
C07D 307/54C07C 259/06A61K 31/16C07C 57/60C07C 57/42
47
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Claims
Abstract
Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Inhibition of histone deacetylase can lead to the histone deacetylase-mediated transcriptional repression of tumor suppressor genes. For example, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, such as hematopoiesis, and genetic related metabolic disorders, such as, cystic fibrosis and adrenoleukodystrophy.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula (I):
wherein
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, monocyclic aryl, or monocyclic 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 H 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 b )—, —C(O)—O—, —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;
Y 2 is a bond;
L is an unsaturated straight C 4-12 hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond; said unsaturated hydrocarbon chain being optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C 1-4 alkylcarbonyloxy, C 1-4 alkyloxycarbonyl, C 1-4 alkylcarbonyl, or formyl; and further being optionally interrupted by —O—, —N(R g )—, —N(R g )—C(O)—O—, —O—C(O)—N(R g )—, —N(R g )—C(O)—N(R h )—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; each of R g and R h , independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl, wherein the carbon bonded to Y 2 is unsaturated, and provided that when L is a C 4-5 hydrocarbon chain and contains two double bonds, Y 1 is not CH 2 ;
R 1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and
R 2 is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group;
or a salt thereof.
2 . The compound of claim 1 , wherein R 1 is hydrogen.
3 . The compound of claim 1 , wherein R 2 is hydrogen.
4 . The compound of claim 1 , wherein each of R 1 and R 2 is hydrogen.
5 . The compound of claim 1 , wherein X 1 is O.
6 . The compound of claim 1 , wherein X 2 is O.
7 . The compound of claim 1 , wherein each of X 1 and X 2 is O.
8 . The compound of claim 1 , wherein Y 1 is —CH 2 —, —O—, —N(R a )—, or a bond.
9 . The compound of claim 1 , wherein Y 1 is a bond.
10 . The compound of claim 1 , wherein L is an unsaturated straight C 4-10 hydrocarbon chain substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, or amino.
11 . The compound of claim 1 , wherein L is an unsaturated straight C 5-8 hydrocarbon chain substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, or amino.
12 . The compound of claim 1 , wherein L is an unsaturated straight C 4-6 hydrocarbon chain.
13 . The compound of claim 1 , wherein L is an unsaturated straight C 5 hydrocarbon chain.
14 . The compound of claim 1 , wherein L is an unsaturated straight C 6 hydrocarbon chain.
15 . The compound of claim 1 , wherein L is an unsaturated straight C 4-10 hydrocarbon chain containing 2-5 double bonds optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
16 . The compound of claim 1 , wherein L is an unsaturated straight C 4-8 hydrocarbon chain containing 2-5 double bonds optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
17 . The compound of claim 1 , wherein L is —(CH═CH) m — where m is 2 or 3, L being optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
18 . The compound of claim 1 , wherein L is an unsaturated straight C 4-10 hydrocarbon chain containing 1-2 double bonds and 1-2 triple bonds, said hydrocarbon chain being optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
19 . The compound of claim 1 , wherein L is an unsaturated straight C 4-8 hydrocarbon chain containing 1-2 double bonds and 1-2 triple bonds, said hydrocarbon chain being optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
20 . The compound of claim 1 , wherein L is —C≡C—(CH═CH) n — where n is 1 or 2, L being optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
21 . The compound of claim 1 , wherein A is phenyl.
22 . The compound of claim 1 , wherein A is phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino.
23 . The compound of claim 22 , wherein L is an unsaturated straight C 4-6 hydrocarbon chain.
24 . The compound of claim 23 , wherein L is a saturated straight C 6 hydrocarbon chain.
25 . The compound of claim 24 , wherein each of R 1 and R 2 is hydrogen.
26 . The compound of claim 25 , wherein each of X 1 and X 2 is O.
27 . The compound of claim 26 , wherein Y 1 is —CH 2 —, —O—, 13 N(R a )—, or a bond.
28 . The compound of claim 22 , wherein L is an unsaturated straight C 4-8 hydrocarbon chain containing 2-5 double bonds; said hydrocarbon chain being optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
29 . The compound of claim 28 , wherein L is —(CH═CH) m —, where m is 2 or 3.
30 . The compound of claim 29 , wherein each of R 1 and R 2 is hydrogen.
31 . The compound of claim 30 , wherein each of Xand X 2 is O.
32 . The compound of claim 31 , wherein Y 1 is —CH 2 —, —O—, —N(R a )—, or a bond.
33 . The compound of claim 22 , wherein L is an unsaturated straight C 4-8 hydrocarbon chain containing 1-2 double bonds and 1-2 triple bonds; said hydrocarbon chain being optionally substituted with C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, or C 1-4 alkoxy.
34 . The compound of claim 33 , wherein L is —C≡C—(CH═CH) n —, where n is 1 or 2.
35 . The compound of claim 34 , wherein each of R 1 and R 2 is hydrogen.
36 . The compound of claim 35 , wherein each of X 1 and X 2 is O.
37 . The compound of claim 36 , wherein Y 1 is —CH 2 —, —O—, —N(R a )—, or a bond.
38 . The compound of claim 1 , said compound being 5-phenyl-2,4-pentadienoyl hydroxamic acid, N-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoyl hydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoyl hydroxamic acid, 5-phenyl-2-en-4-yn-pentanoyl hydroxamic acid, N-methyl-6-phenyl-3,5-hexadienoyl hydroxamic acid, or 7-phenyl-2,4,6-hepta-trienoylhydroxamic acid.
39 . The compound of claim 1 , said compound being 5-phenyl-2,4-pentadienoylhydroxamic acid.
40 . The compound of claim 1 , said compound being 7-phenyl-2,4,6-heptatrienoylhydroxamic acid.
41 . A compound of formula (II):
wherein
A is a cyclic moiety selected from the group consisting of monocyclic aryl or monocyclic heteroaryl; each of said cyclic moieties being optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino;
each of X 1 and X 2 , independently, 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 independently, is hydrogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, hydroxyl, halo, hydroxylC 1-4 alkyl, haloC 1-4 alkyl, or amino; and
each of a, b, c, d, and e, independently, is 0 or 1, and f is 0; provided that at least one of b, c, d, and e is not zero;
or a salt thereof.
42 . The compound of claim 41 , wherein R 1 is hydrogen.
43 . The compound of claim 41 , wherein R 2 is hydrogen.
44 . The compound of claim 41 , wherein each of R 1 and R 2 is hydrogen.
45 . The compound of claim 41 , wherein X 1 is O.
46 . The compound of claim 41 , wherein X 2 is O.
47 . The compound of claim 41 , wherein each of X 1 and X 2 is O.
48 . The compound of claim 41 , wherein a is 0.
49 . The compound of claim 41 , wherein c is 0.
50 . The compound of claim 41 , wherein each of a and f is 0.
51 . The compound of claim 41 , wherein the total number of b, c, d, and e is 3 or 4.
52 . The compound of claim 41 , wherein the total number of b, c, d, and e is 3 or 4.
53 . The compound of claim 41 , wherein each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 , independently, is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, hydroxylC 1-4 alkyl, or amino.
54 . The compound of claim 41 , wherein each of R 5 , R 6 , R 7 , and R 8 , independently, is hydrogen, C 1-4 alkyl, C 1-4 alkoxy, hydroxyl, hydroxylC 1-4 alkyl, or amino; and each of R 3 , R 4 , R 9 and R 10 , independently, is hydrogen.
55 . The compound of claim 41 , wherein each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is hydrogen.
56 . The compound of claim 41 , wherein A is phenyl.
57 . The compound of claim 41 , wherein A is phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino.
58 . The compound of claim 57 , wherein a is 0.
59 . The compound of claim 57 , wherein the total number of b, c, d, and e is 3 or 4; and a is 0.
60 . The compound of claim 59 , wherein each of R 1 and R 2 is hydrogen, and each of X 1 and X 2 is O.
61 . The compound of claim 60 , wherein each of R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 , independently, is hydrogen, C 1-4 alky, C 1-4 alkoxy, hydroxyl, hydroxylC 1-4 alkyl, or amino.Join the waitlist — get patent alerts
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