Substituted aminopropenyl piperidine or morpholine derivatives as novel inhibitors of histone deacetylase

• US 8,377,935 B2
• Filed: 11/22/2011
• Issued: 02/19/2013
• Est. Priority Date: 05/18/2005
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Van Brandt, Sven Franciscus Anna, Angibaud, Patrick Ren, Marconnet-Decrane, Laurence Franoise Bernadette, Pilatte, Isabelle Nolle Constance
• Primary Examiner(s): ZAREK, PAUL E
• Application Number:
  US13/302,930
• Publication Number:
  US 20120157456A1
• Time in Patent Office: 455 Days
• Field of Search: 514/249, 514/258.1, 514/318, 544/242, 544/336, 546/112, 546/192
• US Class Current: 514/249
• 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

This invention comprises the novel compounds of formula (I)

wherein R¹, R², R³, R⁴, 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 as claimed in claim 1, wherein

X is N;

Y is O or CH;

R¹ is phenyl;

R² is —

CH₂OH or methyl;

R³ is hydrogen, C_1-6alkylcarbonyl or C_1-6alkylsulfonyl;

R⁹ is —

NH₂;

R¹⁰ is hydrogen; and

R¹¹, R¹² and R¹³ are each independently hydrogen.

3. A compound as claimed in claim 1, wherein

X is N;

each Y is CH;

n is 1;

R¹ is phenyl;

R² is —

CH₂OH or methyl;

R³ is hydrogen or C_1-6alkylsulfonyl; and

R⁴ is hydroxy.

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

5. A process of preparing a pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1 comprising:

mixing a pharmaceutically acceptable carrier and a compound of claim 1.

6. A method for treating proliferative diseases in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A combination of an anti-cancer agent and a compound as claimed in claim 1.

8. A process for preparing a compound of claim 1, comprising

a) reacting an intermediate of formula (II) with an appropriate acid, yielding a compound of formula (I), wherein R⁴ is hydroxy, herein referred to as a compound of formula (I-a, or

11. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound of claim 2.

12. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound of claim 3.

14. A combination of an anti-cancer agent and a compound of claim 2.

15. A combination of an anti-cancer agent and a compound of claim 3.

9. A compound of formula (VIII),

10. A process for preparing a compound as claimed in claim 9, comprising

a) converting compounds of formula (VIII), wherein R² is —

CH₂OH, herein referred to as compounds of formula (VIII-a), into compounds of formula (VIII), wherein R² is other than —

CH₂OH, herein referred to as compounds of formula (VIII-b), via art-known reactions or functional group transformations, or

13. A method for the treatment of proliferative diseases in a subject, said method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound that is