Inhibitors of histone deacetylase
AssigneeMethylGene Inc.
InventorsDaniel Delorme, Soon Hyung Woo, Arkadii Vaisburg, Oscar Moradei, Silvana Leit, Stephane Raeppel, Sylvie Frechette, Giliane Bouchain
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Abstract
The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.
Claims15
A compound of structural formula (2a):
- or a pharmaceutically acceptable salt thereof, wherein
- Ara is phenyl or thienyl;
- R6 is H, or C1-C6-alkyl;
- Y and Z are —CH═;
- W is (V′-L4)t-V-L3-;
- L3 is a direct bond, —C1-C6-hydrocarbyl, —(C1-C3-hydrocarbyl)m1-X′—(C1-C3-hydrocarbyl)m2, —NH—(C0-C3-hydrocarbyl), (C1-C3- hydrocarbyl)-NH—, or —NH—(C1-C3-hydrocarbyl)-NH—;
- m1 and m2 are independently 0 or 1;
- X′ is —N(R21)—, —C(O)N(R21)—, N(R21)C(O)—, —O—, or —S—;
- R21 is —H, V″—(C1-C6-hydrocarbyl)c;
- L4 is (C1-C6-hydrocarbyl)a-M-(C1-C6-hydrocarbyl)b;
- a and b are independently 0 or 1;
- M is —NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —SO2—, —NHSO2—, or —SO2NH—
- V, V′, and V″ are independently selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl;
- t is 0 or 1;
- or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- and
- wherein the A and Ara rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.
The compound of formula (3b):
- or pharmaceutically acceptable salt thereof, wherein Y and Z are CH and W is selected from the group consisting of:
- F,
- and
A compound selected from the group consisting of the following and their pharmaceutically acceptable salts:
A histone deacetylase inhibitor selected from the group consisting of the following compounds and their pharmaceutically acceptable salts:
- N-(2-Amino-phenyl)-4-(quinolin-2-
- ylsulfanylmethyl)-benzamide,
- N-(2-Amino-phenyl)-4-(4,6-dimethyl-
- pyrimidin-2-ylsulfanylmethyl)-benzamide,
- N-(2-Amino-phenyl)-4-(4-trifluoromethyl-
- pyrimidin-2-ylsulfanylmethyl)-benzamide,
- Biphenyl-4,4′-dicarboxylic acid bis-[(2-
- amino-phenyl)-amide],
- N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-
- dihydro-2H-thieno[3,2-d]pyrimidin-3-
- ylmethyl)-benzamide,
- N-(2-Amino-phenyl)-4-[bis-(3-
- trifluoromethoxy-benzyl)-amino]-
- benzamide, and
- N-(2-Amino-phenyl)-3-(4-{[1-(3-benzyl-
- 7-chloro-4-oxo-3,4-dihydro-quinazolin-2-
- yl)-ethylamino]-methyl}-phenyl)-
- acrylamide.
A method of treating or inhibiting colon cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of structural formula (2a):
- or a pharmaceutically acceptable salt thereof, said compound optionally administered together with a pharmaceutically acceptable carrier, wherein
- Ara is phenyl or thienyl;
- R6 is H, or C1-C6-alkyl;
- Y and Z are —CH═;
- W is halo;
- or W, the annular C to which it is bound, and Y together form a monocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl;
- and
- wherein the A and Ara rings are optionally further substituted with from 1 to 3 substituents independently selected from methyl, hydroxy, methoxy, halo, and amino.
Dependencies are inferred from the claim text.