SUBSTITUTED INDOLYL-ALKYL-AMINO-DERIVATIVES AS INHIBITORS OF HISTONE DEACETYLASE

• US 20110118291A1
• Filed: 10/05/2010
• Published: 05/19/2011
• Est. Priority Date: 01/19/2006
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Pilatte, Isabelle Nöelle Constance, Angibaud, Patrick René
• Granted Patent: US 8,163,765 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 401/14 containing three or more hetero rings

Abstract

This invention comprises the novel compounds of formula (1)

wherein R¹, R², R³, R⁴, R⁵, X and Y have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Claims

1. A compound of formula (I),

2. A compound according to claim 1 wherein

n is 1;

p is 0;

each Y is CH;

R¹⁰ is hydrogen;

R⁶, R⁷ and R⁸ are each independently hydrogen, R² is C_1-6alkyl and R³ is hydrogen or R² and R³ can be bridged with a methylene, ethylene or propylene bridge;

R⁴ is C_1-6alkyl; and

R⁵ is hydrogen.

3. A compound according to claims 1 and 2 wherein

n is 1;

m is 1 or 2;

p is 0;

each X is N;

each Y is CH;

R² and R³ are bridged with a methylene, ethylene or propylene bridge;

R⁴ is C_1-6alkyl; and

R⁵ is hydrogen.

4. A compound according to claims 1, 2 and 3 wherein said compound is compound No.2 and compound No. 3.

5. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claims 1 to 4.

6. A process of preparing a pharmaceutical composition as claimed in claim 5 wherein the pharmaceutically acceptable carriers and a compound as claimed in claims 1 to 4 are intimately mixed.

7. A compound as claimed in any of claims 1 to 4 for use as a medicine.

8. Use of a compound as claimed in any of claims 1 to 4 for the manufacture of a medicament for the treatment of proliferative diseases.

9. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in any of claims 1 to 4.

10. A process for preparing a compound as claimed in claim 1, characterized by

a) reacting an intermediate of formula (II) with an appropriate acid yielding a hydroxamic acid of formula (I), wherein R¹ is hydroxy, herein referred to as compounds of formula (I-a)

11. A compound of formula (A), in which Q is C_1-2alkyloxycarbonyl, hydroxycarbonyl or tetrahydropyranyloxyaminocarbonyl and n, m, p, X, Y, Z, R², R³, R⁴ and R⁵ are as defined for formula (I), and the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof.

12. A process for preparing a compound as claimed in claim 11, characterized by

a) reacting an intermediate of formula (III-a) with an intermediate of formula (VII) to form a compound of formula (A) in which Q is tetrahydropyranyloxyaminocarbonyl, represented by formula (II):