Inhibitors of histone deacetylase

• US 7,253,204 B2
• Filed: 03/25/2005
• Issued: 08/07/2007
• Est. Priority Date: 03/26/2004
• Status: Active Grant

• Current Assignee: 92229129 Quebec Inc.
• Original Assignee: MethylGene, Inc.
• Inventors: Vaisburg, Arkadii, Frechette, Sylvie, Leit, Silvana, Moradei, Oscar, Raeppel, Stephane, Paquin, Isabelle, Delorme, Daniel, Isakovic, Ljubomir, Bouchain, Giliane, Gaudette, Frederic, Zhou, Zhihong
• Primary Examiner(s): Saeed; Kamal A.
• Assistant Examiner(s): CHU, YONG LIANG
• Application Number:
  US11/090,713
• Publication Number:
  US 20050245518A1
• Time in Patent Office: 865 Days
• Field of Search: 548/518, 548/523, 548/537, 514/422, 514/343, 514/408, 546/279.1
• US Class Current: 514/422
• 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 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 311/39 having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
• CPC Class Codes: C07D 209/42 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 213/38 having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 231/38 Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 235/16 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 237/20 Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 263/58 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 in position 2
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
• CPC Class Codes: C07D 307/84 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• 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 401/04 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 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

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 formula (2)

2. A compound according to claim 1 having S stereochemistry at C-3 position of the ring

3. A compound according to claim 1 having R stereochemistry at C-3 position of the ring

4. A compound according to claim 1, selected from the group consisting of:

N-(2-Amino-phenyl)-4-[3-(pyridin-3-ylamino)-pyrrolidin-1-yl]-benzamide;

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

(R)-N-(2-aminophenyl)-4-(3-(pyridin-3-ylamino)pyrrolidin-1-yl)benzamide;

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

(R)-N-(2-Aminophenyl)-4-(3-(pyridin-3-yloxy)pyrrolidin-1-yl)benzamide;

(S)-N-(1-(4-(2-Aminophenyl carbamoyl)phenyl)pyrrolidin-3-yl)nicotinamide;

(S)-N-(2-Aminophenyl)-4-(3-(pyridin-2-ylthio)pyrrolidin-1-yl)benzamide; and

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

5. A composition comprising a mixture of enantiomers of compounds of claim 1.

6. The composition of claim 5 wherein the mixture is racemic.

7. The composition of claim 5 wherein the mixture is enantiomerically enriched.

8. A composition comprising one or more compounds according to any one of claims 1-4 and a pharmaceutically acceptable carrier.