Inhibitors of histone deacetylase

• US 6,541,661 B1
• Filed: 11/22/2000
• Issued: 04/01/2003
• Est. Priority Date: 11/23/1999
• Status: Expired

• Current Assignee: 92229129 Quebec Inc.
• Original Assignee: MethylGene, Inc.
• Inventors: Lavoie, Rico, Ruel, Rejean, Delorme, Daniel, Thibault, Carl, Abou-Khalil, Elie
• Primary Examiner(s): McGarry, Sean
• Assistant Examiner(s): ZARA, JANE J
• Application Number:
  US09/718,265
• Time in Patent Office: 860 Days
• Field of Search: 560/318, 560/319, 560/4, 560/19, 560/24
• US Class Current: 560/318
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/10 Antimycotics
• 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: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 259/06 having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 259/10 having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 311/13 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 311/21 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/29 having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 311/44 having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07D 213/76 to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 215/36 Sulfur atoms C07D215/24 takes precedence
• CPC Class Codes: C07D 285/135 Nitrogen atoms
• CPC Class Codes: C07D 307/46 Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
• CPC Class Codes: C07D 307/54 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
• CPC Class Codes: C07D 307/91 : Dibenzofurans; Hydrogenated dibenzofurans
• CPC Class Codes: C07D 333/34 : Sulfur atoms
• CPC Class Codes: C07D 333/62 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero 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. An inhibitor of histone deacetylase represented by the formula

2. The inhibitor of claim 1, wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —

O—

M, M being H or a pharmaceutically acceptable cation.

3. The inhibitor of claim 2, wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.

4. The inhibitor of claim 1, wherein Y¹ is C₁-C₆ alkylene.

5. The inhibitor of claim 1, wherein Y¹ is C₁-C₃ alkylene.

6. The inhibitor of claim 1, wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.

7. The inhibitor of claim 6, wherein the phenylene is 4-phenylene.

8. The inhibitor of claim 1, wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.

9. The inhibitor of claim 8, herein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, halo, nitro, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, carboxy, and amino.

10. The inhibitor of claim 1, wherein m is zero.

11. An inhibitor of histone deacetylase represented by the formula

12. The inhibitor of claim 11, wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —

O—

M, M being H or a pharmaceutically acceptable cation.

13. The inhibitor of claim 12, wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.

14. The inhibitor of claim 11, wherein Y² is a chemical bond.

15. The inhibitor of claim 11, wherein Y² is C₁-C₃ alkylene.

16. The inhibitor of claim 11, wherein Y² is C₁-C₂ alkylene.

17. The inhibitor of claim 11, wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.

18. The inhibitor of claim 17, wherein the phenylene is 4-phenylene.

19. The inhibitor of claim 11, wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.

20. The inhibitor of claim 19, wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, halo, nitro, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, carboxy, and amino.

21. The inhibitor of claim 11, wherein one or two saturated carbons in L² are substituted with a substituent independently selected from the group consisting of C₁-C₆ alkyl, C₆-C₁₀ aryl, amino, oxo, hydroxy, C₁-C₄ alkoxy, and C₆-C₁₀ aryloxy.

22. The inhibitor of claim 21, wherein the substituent is oxo or hydroxy.

23. The inhibitor of claim 11, wherein L² is C₁-C₆ saturated alkylene, and no carbon atom of the alkylene is replaced by a heteroatom moiety.

24. The inhibitor of claim 11, wherein one carbon atom of the Y² alkylene is replaced by a heteroatom moiety selected from the group consisting of O;

NR′

, R′

being alkyl, acyl, or hydrogen;

S;

S(O);

or S(O)₂.

25. The inhibitor of claim 24, wherein L² is selected from the group consisting of —

S—

(CH₂)_n, —

S(O)—

(CH₂)_n—

, and —

S(O)₂—

(CH₂)_n—

, wherein n is 0, 1, 2, 3, or 4.

26. An inhibitor of histone deacetylase represented by the formula

27. The inhibitor of claim 26, wherein Z is selected from the group consisting of 2-anilinyl, 2-pyridyl, 1,3,4-thiadiazol-2-yl, and —

O—

M, M being H or a pharmaceutically acceptable cation.

28. The inhibitor of claim 27, wherein Z is 1,3,4-thiadiazol-2-yl which is substituted at the 5-position with a substituent selected from the group consisting of thiol, trifluoromethyl, amino, and sulfonamido.

29. The inhibitor of claim 26, wherein Y³ is selected from the group consisting of —

CH═

CH—

, —

C(CH₃)═

CH—

, and —

CH═

C(CH₃)—

.

30. The inhibitor of claim 26, wherein Ar is substituted or unsubstituted phenylene, which optionally may be fused to an aryl or heteroaryl ring, or to a saturated or partially unsaturated cycloalkyl or heterocyclic ring, any of which may be optionally substituted.

31. The inhibitor of claim 30, wherein the phenylene is 4-phenylene.

32. The inhibitor of claim 26, wherein Cy is selected from the group consisting of phenyl, naphthyl, thienyl, benzothienyl, and quinolyl, any of which may be optionally substituted.

33. The inhibitor of claim 32, wherein the phenyl, naphthyl, thienyl, benzothienyl, or quinolyl is unsubstituted or is substituted by one or two substituents independently selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₆-C₁₀ aryl, (C₆-C₁₀)ar(C₁-C₆)alkyl, halo, nitro, hydroxy, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl, carboxy, and amino.

34. An inhibitor of histone deacetylase selected from the group consisting of