Inhibitors of histone deacetylase

• US 7,595,343 B2
• Filed: 09/12/2002
• Issued: 09/29/2009
• Est. Priority Date: 09/14/2001
• Status: Expired due to Fees

• Current Assignee: 92229129 Quebec Inc.
• Original Assignee: MethylGene, Inc. (Bristol-Myers Squibb Company)
• Inventors: Vaisburg, Arkadii, Frechette, Sylvie, Raeppel, Stephane, Leit, Silvana, Delorme, Daniel, Bouchain, Giliane, Woo, Soon Hyung, Moradei, Oscar
• Primary Examiner(s): Balasubramanian; Venkataraman
• Application Number:
  US10/242,304
• Publication Number:
  US 20040106599A1
• Time in Patent Office: 2,574 Days
• Field of Search: 564/155, 564/161, 514/617, 514/231.5, 544/60, 544/113, 544/196, 544/264, 544/283, 544/353, 544/358, 544/50, 546/155, 546/161
• US Class Current: 514/617
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 15/18 containing at least one group with formula
• CPC Class Codes: C07C 233/44 having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/80 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/38 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 235/56 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/20 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 237/22 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 237/40 having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 255/58 containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
• CPC Class Codes: C07C 255/59 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 2603/18 Fluorenes; Hydrogenated fluorenes
• CPC Class Codes: C07C 275/34 having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/36 with at least one of the oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. N-aryloxyphenylureas
• CPC Class Codes: C07C 311/42 : to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 323/32 : having at least one of the nitrogen atoms bound to an acyclic carbon atom of the carbon skeleton
• CPC Class Codes: C07C 323/36 : the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 323/44 : X or Y being nitrogen atoms
• CPC Class Codes: C07C 323/60 : with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
• CPC Class Codes: C07C 381/00 : Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 : with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 239/91 : with aryl or aralkyl radicals attached in position 2 or 3
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 251/18 : with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
• CPC Class Codes: C07D 251/52 : with an oxygen or sulfur atom attached to the third ring carbon atom
• CPC Class Codes: C07D 251/54 : Three nitrogen atoms
• CPC Class Codes: C07D 263/14 : with radicals substituted by oxygen atoms
• CPC Class Codes: C07D 263/24 : with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 265/36 : condensed with one six-membered ring
• CPC Class Codes: C07D 271/06 : 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 277/42 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 277/74 : Sulfur atoms substituted by carbon atoms
• CPC Class Codes: C07D 277/82 : Nitrogen atoms
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 307/12 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 307/28 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 311/56 : without hydrogen atoms in position 3
• CPC Class Codes: C07D 311/58 : other than with oxygen or sulphur atoms in position 2 or 4
• CPC Class Codes: C07D 333/36 : Nitrogen atoms
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 473/40 : with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C07F 7/081 : comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
• CPC Class Codes: C07F 7/0812 : comprising a heterocyclic ring

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.

Claims

1. A compound of structural formula (2a):

2. The compound according to claim 1 wherein:

R⁶ is H;

W is V-L³-;

L³ is —

NH—

CH—

or —

CH—

NH—

;

V is phenyl optionally substituted with from 1 to 3 moieties independently selected from halo, hydroxy, C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyl-oxy or -thio (particularly methoxy or methylthio), wherein each of the hydrocarbyl moieties are optionally substituted with one or more moieties independently selected from halo, nitroso, amino, sulfonamido, and cyano; and

Ar^a is phenyl and the amino moieties to which it is bound are ortho to each other.

3. The compound according to claim 1 wherein V is an optionally substituted ring moiety selected from the group consisting of the following:

4. The compound according to claim 1 wherein W is selected from the group consisting of the following:

5. The compound according to claim 1 wherein the A and Ar^a rings are not further substituted.

6. The compound according to claim 1 selected from the group consisting of the following combinations, in which, unless expressly displayed otherwise, Ar^a is phenyl:

7. The compound according to claim 6 wherein the amide nitrogen and the amino nitrogen bound to Ar^a are ortho to each other.

13. A composition comprising a compound according to any one of claim 1-7 or 8-10 and a pharmaceutically acceptable carrier.

14. A method of treating or inhibiting colon cancer, the method comprising administering to a patient in need thereof a effective amount of a compound according to any one of claims 1-7 and 8-12, or a pharmaceutical composition thereof.

8. The compound of formula (3b):

9. The compound according to claim 8 wherein Y, Z and W are one of the following combinations

10. The compound according to claim 8 wherein Y, Z and W are one of the following combinations

11. A compound selected from the group consisting of the following and their pharmaceutically acceptable salts:

12. A histone deacetylase inhibitor selected from the group consisting of the following compounds and their pharmaceutically acceptable salts:

15. 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):