Substituted indolyl alkyl amino derivatives as novel inhibitors of histone deacetylase

• US 8,524,728 B2
• Filed: 02/15/2011
• Issued: 09/03/2013
• Est. Priority Date: 07/28/2004
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Verdonck, Marc Gustaaf Celine, Angibaud, Patrick Ren, Roux, Bruno, Pilatte, Isabelle Nolle Constance, Ten Holte, Peter, Arts, Janine, Van Emelen, Kristof
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US13/027,793
• Publication Number:
  US 20110136841A1
• Time in Patent Office: 931 Days
• Field of Search: 544/331, 514/275
• US Class Current: 514/275
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• 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
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/056 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

This invention comprises the novel compounds of formula (I)

wherein R¹, R², R³, 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 method of treating ovarian cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of formula (I)

2. The method of claim 1 wherein in the compound of formula I

R⁴ is hydrogen, C_1-6alkyl, C_3-6cycloalkyl, C_3-6cycloalkylmethyl, —

C(═

O)—

CHR⁵R⁶ or —

S(═

O)₂—

N(CH₃)₂;

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylsulfonyl, or mono- or di(C_1-6alkyl)aminosulfonyl; and

R³ is hydrogen.

3. The method of claim 1 wherein in the compound of formula I

n is an integer with value 0 or 1;

X is independently N;

R⁴ is hydrogen or C_1-6alkyl;

R¹ is hydrogen, C_1-6alkyl or hydroxyC_1-6alkyl; and

R² is hydrogen, halo, C_1-6alkyl or C_1-6alkyloxy.

4. The method of claim 1 wherein in the compound of formula I

n is an integer with value 0 or 1;

R⁴ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyl or phenylC_1-6alkyl;

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylcarbonyl or C_1-6alkylsulfonyl; and

R² is hydrogen, halo, C_1-6alkyl, cyano, nitro or C_1-6alkyloxy.

5. The method of claim 1 wherein in the compound of formula I

n is an integer with value 1;

m is an integer with value 1;

X is independently N;

Y is independently NR⁴;

R⁴ is C_1-6alkyl;

R¹ is hydrogen;

R² is hydrogen or halo; and

R³ is hydrogen.

6. The method of claim 1 wherein in the compound of formula I

n is an integer with value 0 or 1;

R⁴ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyl or phenylC_1-6alkyl;

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylcarbonyl or C_1-6alkylsulfonyl; and

R² is hydrogen, halo, C_1-6alkyl, cyano, nitro, polyhaloC_1-6alkyl or C_1-6alkyloxy.

7. The method of claim 1 wherein in the compound of formula I

n is an integer with value 1;

m is an integer with value 1;

X is independently N;

Y is independently NR⁴;

R⁴ is C_1-6alkyl;

R¹ is hydrogen;

R² is hydrogen or halo; and

R³ is hydrogen.

8. The method of claim 7, wherein the compound of formula I is selected from the group consisting of

9. The method of claim 8, wherein the compound of formula I is

10. A method of inhibiting tumor cell growth in a subject having ovarian cancer comprising administering to the subject a therapeutically effective amount of the compound of formula (I),

11. The method of claim 10 wherein in the compound of formula I R⁴ is hydrogen, C_1-6alkyl, C_3-6cycloalkyl, C_3-6cycloalkylmethyl, —

C(═

O)13 CHR⁵R⁶ or —

S(═

O)₂-N(CH₃)₂;

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylsulfonyl, or mono- or di(C_1-6alkyl)aminosulfonyl; and

R³ is hydrogen.

12. The method of claim 10 wherein in the compound of formula I

n is an integer with value 0 or 1;

X is independently N;

R⁴ is hydrogen or C_1-6alkyl;

R¹ is hydrogen, C_1-6alkyl or hydroxyC_1-6alkyl; and

R² is hydrogen, halo, C_1-6alkyl or C_1-6alkyloxy.

13. The method of claim 10 wherein in the compound of formula I

n is an integer with value 0 or 1;

R⁴ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyl or phenylC_1-6alkyl;

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylcarbonyl or C_1-6alkylsulfonyl; and

R² is hydrogen, halo, C_1-6alkyl, cyano, nitro or C_1-6alkyloxy.

14. The method of claim 10 wherein in the compound of formula I

n is an integer with value 1;

m is an integer with value 1;

X is independently N;

Y is independently NR⁴;

R⁴ is C_1-6alkyl;

R¹ is hydrogen;

R² is hydrogen or halo; and

R³ is hydrogen.

15. The method of claim 10 wherein in the compound of formula I

n is an integer with value 0 or 1;

R⁴ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyl or phenylC_1-6alkyl;

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylcarbonyl or C_1-6alkylsulfonyl; and

R² is hydrogen, halo, C_1-6alkyl, cyano, nitro, polyhaloC_1-6alkyl or C_1-6alkyloxy.

16. The method of claim 10 wherein in the compound of formula I

n is an integer with value 1;

m is an integer with value 1;

X is independently N;

Y is independently NR⁴;

R⁴ is C_1-6alkyl;

R¹ is hydrogen;

R² is hydrogen or halo; and

R³ is hydrogen.

17. The method of claim 16, wherein the compound of formula I is selected from the group consisting of

18. The method of claim 17, wherein the compound of formula I is

19. The method of claim 10, wherein the tumor cell growth is caused by histone deacetylase (HDAC) activity.