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

• US 8,138,198 B2
• Filed: 05/16/2006
• Issued: 03/20/2012
• Est. Priority Date: 05/18/2005
• Status: Active Grant

• Current Assignee: Isabelle Noëlle Constance Pilatte, Laurence Françoise Bernadette Marconnet-Decrane, Patrick René Angibaud, Sven Franciscus Anna Van Brandt
• Original Assignee: Isabelle Noëlle Constance Pilatte, Laurence Françoise Bernadette Marconnet-Decrane, Patrick René Angibaud, Sven Franciscus Anna Van Brandt
• Inventors: Angibaud, Patrick René, Marconnet-Decrane, Laurence Françoise Bernadette, Van Brandt, Sven Franciscus Anna, Pilatte, Isabelle Noëlle Constance
• Primary Examiner(s): Hui, San-Ming
• Assistant Examiner(s): ZAREK, PAUL E
• Application Number:
  US11/914,208
• Publication Number:
  US 20090221580A1
• Time in Patent Office: 2,135 Days
• Field of Search: 514/275, 544/332
• US Class Current: 514/275
• 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

each X is N;

Y is CH;

R¹ is phenyl;

R² is —

CH₂OH or methyl;

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

3. A compound as claimed in claim 1 wherein

each 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.

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

6. A process of preparing a pharmaceutical composition comprising mixing a pharmaceutically acceptable carrier and the compound as claimed in claim 1.

7. A combination of an anti-cancer agent and a compound as claimed in claim 1, wherein the compound of claim 1 is a HDAC inhibitor.

8. A process for preparing a compound as claimed in 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

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

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

12. A combination of an anti-cancer agent and a compound as claimed in claim 2, wherein the compound of claim 2 is a HDAC inhibitor.

13. A combination of an anti-cancer agent and a compound as claimed in claim 3, wherein the compound of claim 3 is a HDAC inhibitor.

4. A compound selected from the group consisting of:

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

14. A combination of an anti-cancer agent and a compound as claimed in claim 4, wherein the compound of claim 4 is a HDAC inhibitor.