Inhibitors of histone deacetylase

• US 8,354,445 B2
• Filed: 05/11/2011
• Issued: 01/15/2013
• Est. Priority Date: 03/13/2007
• Status: Expired due to Fees

• Current Assignee: MethylGene, Inc.
• Original Assignee: MethylGene, Inc.
• Inventors: Frechette, Sylvie, Isakovic, Lubo, Paquin, Isabelle, Roy, Simon, Moradei, Oscar, Vaisburg, Arkadii
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US13/105,151
• Publication Number:
  US 20110212965A1
• Time in Patent Office: 615 Days
• Field of Search: 514/428, 548/566
• US Class Current: 514/428
• 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: C07D 207/14 Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• 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 405/12 linked by a chain containing hetero atoms as chain links

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. One aspect of the invention provides compounds of formula (1):

in which T, A and X are as described herein.

Claims

1. A compound of formula (1):

2. The compound according to claim 1, wherein T is NH₂.

3. The compound according to claim 1, wherein A is unsubstituted or optionally-substituted phenyl, thienyl, thiadiazolyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl or tetrazinyl.

4. The compound according to claim 1, wherein A is a 6-membered ring and the X—

and carbonyl moieties are arranged in a 1,4- manner relative to one another on the ring.

5. The compound according to claim 1, wherein A is unsubstituted or optionally-substituted arylene.

6. The compound according to claim 1, wherein A is unsubstituted phenylene.

7. The compound according to claim 1, wherein Z¹ is R⁵—

C(O)—

O—

, R¹²—

O—

C(O)—

N(R²)—

, R¹¹—

C(O)—

N(R²)—

, R¹⁵—

C(S)—

N(R²)—

, R¹⁵—

S—

C(O)—

N(R²)—

, R⁵—

N(R²)—

C(O)—

N(R²), R⁵—

N(R²)—

C(S)—

N(R²)—

, R⁸—

N(R²)—

C(O)—

O—

, R¹⁵—

O—

C(S)—

N(R²)—

, R¹⁵—

S—

C(S)—

N(R²)—

, R⁵—

N(R²)—

C(S)—

O—

, R⁵—

O—

C(S)—

N(R²)—

, R⁵—

S(O)_0-2—

N(R²)—

or R⁵—

N(R²)—

S(O)_0-2—

.

8. The compound according to claim 1, wherein Z¹ is R⁵—

C(O)—

O—

, R¹²—

O—

C(O)—

N(R²)—

, R¹¹—

C(O)—

N(R²)—

, R⁵—

N(R²)—

C(O)—

N(R²), R⁵—

N(R²)—

C(S)—

N(R²)—

, R⁸—

N(R²)—

C(O)—

O—

, R⁵—

N(R²)—

C(S)—

O—

, R⁵—

O—

C(S)—

N(R²)—

, R⁶—

O—

or R⁷—

N(R²)—

.

9. The compound according to claim 1, wherein Z¹ is R¹²—

O—

C(O)—

N(R²)—

.

10. The compound according to claim 1, wherein Z¹ is (C₁-C₆ hydrocarbyl)—

O—

C(O)—

N(R²)—

, and the (C₁-C₆ hydrocarbyl) is optionally substituted.

11. A compound, N-oxide, hydrate, solvate, pharmaceutically acceptable salt, complex or prodrug or a racemic mixture, diastereomer, enantiomer or tautomer thereof, according to claim 10, wherein Z¹ is R¹⁶—

O—

C(O)—

N(R²)—

, in which R¹⁶ is optionally-substituted (C₁-C₆ hydrocarbyl)-, optionally-substituted Ar—

(C₁-C₂ hydrocarbyl)-, optionally-substituted Het-(C₁-C₂ hydrocarbyl)-, optionally-substituted Hca-(C₀-C₂ hydrocarbyl)- or optionally-substituted Cak-(C₀-C₂ hydrocarbyl).

12. The compound according to claim 1, wherein n¹=1.

13. The compound according to claim 12, wherein the compound has an (S)-stereochemical configuration at the carbon to which Z¹ is connected.

14. The compound according to claim 1, wherein,

T is —

NH₂;

A is phenyl; and

X is

15. The compound according to claim 1, wherein,

T is —

NH₂;

A is phenyl; and

X is

16. The compound according to claim 1, wherein,

T is —

NH₂;

A is phenyl; and

X is

17. The compound according to claim 1, wherein,

T is —

NH₂;

A is phenyl; and

X is

18. The compound according to claim 1, wherein,

T is —

NH₂;

A is phenyl; and

X is

19. The compound according to claim 1, wherein

T is —

NH₂;

A is phenyl; and

X is

20. The compound according to claim 1, wherein

T is —

NH₂;

A is phenyl; and

X is

21. The compound according to claim 1, wherein

T is —

NH₂;

A is phenyl; and

X is

22. The compound according to claim 1, wherein

T is —

NH₂;

A is phenyl; and

X is

24. The compound according to claim 1, selected from the group consisting of:

(S)-Ethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-2-Methoxyethyl-1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate; and

(S)-N-(2-Aminophenyl)-4-(3-(pyridin-2-ylamino)pyrrolidin-1-yl)benzamide.

25. A composition comprising a compound according to claim 1 present in at least about 30% enantiomeric or diastereomeric excess.

26. The composition according to claim 25 wherein the compound is present in at least about 50% enantiomeric or diastereomeric excess.

27. The compositionaccording to claim 25 wherein the compound is present in at least 80% enantiomeric or diastereomeric excess.

28. The composition according to claim 25 wherein the compound is present in at least 90% enantiomeric or diastereomeric excess.

29. A composition comprising a compound according to claim 1 present as a substantially racemic mixture.

30. A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable, diluent, carrier or excipient.

31. A method of inhibiting histone deacetylase in a cell, the method comprising contacting the cell with one or more compounds according to claims 1, or a composition thereof.

32. A method for treating a cell proliferative disease or condition in an animal in need of such treatment, the method comprising administering to the animal a therapeutically effective amount of one or more compounds according to claim 1 or a composition thereof, wherein said cell proliferative disease or condition is selected from one or more of the group consisting of cancer, restenosis, and psoriasis.

33. The method according to claim 32 wherein the animal is a human.

23. A compound selected from the group consisting of:

(S)-2-(Dimethylamino)ethyl-1-(4-(2-aminophenylcarbamoyl)-phenyl)pyrrolidin-3-ylcarbamate;

(S)-Methyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Ethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-tert-Butyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Isobutyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Benzyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-N-(1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl)morpholine-4-carboxamide;

((S)-Pyridin-3-ylmethyl-1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-N-(2-Aminophenyl)-4-(3-(3-(pyridin-3-ylmethyl)ureido)pyrro lidin- 1 -yl) benzamide;

(S)-2-Methoxyethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(R)-2-Methoxyethyl 1-(5-(2-aminophenylcarbamoyl)pyridin-2-yl)pyrrolidin-3-yl carbamate;

(S)-N-(2-Aminophenyl)-4-(3-(3-(pyridin-3-ylmethyl)thioureido)pyrrolidin- 1-yl) benzamide;

(S)-O-Methyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamothioate;

(S)-2,2,2-Trifluoroethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)-pyrrolidin-3-ylcarbamate;

(S)-N-(2-Aminophenyl)-4-(3-(2-(dimethylamino) acetamido) pyrrolidin-1-yl)benzamide;

(S)-Pyridin-4-ylmethyl 1-(4-(2-aminophenyl carbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Pyridin-2-ylmethyl 1-(4-(2-aminophenyl carbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-3-(Dimethyl amino)propyl 1-(4-(2-amino phenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-Furan-3-ylmethyl1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(R)-1-Methylpyrrolidin-3-yl (S)-1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl carbamate;

(S)-1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl acetate;

(S)-N-(2-Aminophenyl)-4-(3-hydroxypyrrolidin-1-yl)benzamide;

(S)-1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl ethyl carbamate;

(S)-O-1-(4-(2-Aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl 2-morpholinoethylcarbamothioate;

(S)-N-(2-Aminophenyl)-4-(3-(dimethylamino)pyrrolidin-1-yl)benzamide;

(S)-N-(2-Aminophenyl)-4-(3-(phenylmethylsulfonamido)pyrrolidin-1-yl)benzamide;

(S)-2-morpholinoethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate;

(S)-methyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl(pyridin-3-ylmethyl) carbamate;

(S)-benzyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-yl(3,4,5-trimethoxybenzyl) carbamate;

(S)-isopropyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate;

(S)-cyclopropylmethyl 1-(4-(2-aminophenylcarbamoyl)phenyl)pyrrolidin-3-ylcarbamate;

(S)-tetrahydro-2H-pyran-4-yl 1-(4-(2-aminophenylcarb amoyl)phenyl)pyrro lidin-3-ylcarbamate, and

(R)-N-(2-Aminophenyl)-4-(3-hydroxypyrro lidin-1-yl)benzamide.