Substituted 3-pyridyl indoles and indazoles as c17,20 lyase inhibitors

• US 20040236110A1
• Filed: 03/26/2004
• Published: 11/25/2004
• Est. Priority Date: 09/26/2001
• Status: Abandoned Application

• Current Assignee: Bayer Pharmaceuticals Corporation (Bayer AG)
• Original Assignee: Bayer Pharmaceuticals Corporation (Bayer AG)
• Inventors: Ladouceur, Gaetan H, Wong, Wai C, Burke, Michael, Bierer, Donald E
• Application Number:
  US10/491,214
• Publication Number:
  US 20040236110A1
• Time in Patent Office: Days
• US Class Current: 546/277.4
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 407/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The invention provides novel substituted 3-pyridyl indoles and indazoles and pharmaceutical compositions thereof. The invention also provides methods of use of substituted 3-pyridyl indoles and indazoles and pharmaceutical compositions thereof as inhibitors of lyases, e.g., the 17α-hydroxylase-C17,20-lyase enzyme. The invention further provides methods for the treatment of cancer in a subject, comprising administering a substituted 3-pyridyl indoles and indazoles or a pharmaceutical composition comprising a substituted 3-pyridyl indoles and indazoles to a subject. The cancer can be, e.g., prostate cancer or breast cancer.

Claims

1. A compound of the formula

2. A compound according to claim 1

wherein

R¹ represents

wherein R⁴ represents C_1-4 alkyl;

and

p is 0, 1, or 2;

provided that R³ is other than a pyridyl or an N-oxide-containing group;

or

wherein

R⁵ represents

CN,

halogen,

CHO, or

C(O)N(R⁶)₂ wherein R⁶ represents H or C_1-4 alkyl; and

q is 0, 1, or 2;

R² represents C_1-4 alkyl; and

m is 0, 1, or 2; and

R³ represents

wherein

R⁷ is C_1-4 alkyl or CN; and

r is 0, 1, or 2;

provided that R¹ is other than a pyridyl or an N-oxide-containing group;

wherein

R⁸ represents

CN,

halogen,

C_1-4 alkyl,

C_1-4 alkoxy,

NO₂,

CF₃,

C_1-4 acyl,

CO₂R⁹ wherein R⁹ is H or C_1-4 alkyl, or

3. A compound according to claim 1

wherein

R¹ represents

wherein R⁴ represents C_1-4 alkyl;

and

p is 0, 1, or 2;

provided that R³ is other than a pyridyl or an N-oxide-containing group;

or

wherein

R⁵ represents

CN,

halogen,

CHO, or

C(O)N(R⁶)₂ wherein R⁶ represents H or C_1-4 alkyl; and

q is 0, 1, or 2;

R² represents C_1-4 alkyl; and

m is 0, 1, or 2; and

R³ represents

wherein

R⁷ is C_1-4 alkyl or CN; and

r is 0, 1, or 2;

provided that R¹ is other than a pyridyl or an N-oxide-containing group;

wherein

R⁸ represents

CN,

halogen,

C_1-4 alkyl,

C_1-4 alkoxy,

NO₂,

CF₃,

C_1-4 acyl,

CO₂R⁹ wherein R⁹ is H or C_1-4 alkyl, or

4. A compound according to claim 1

wherein

R¹ represents

wherein R⁴ represents C_1-4 alkyl;

and

p is 0, 1, or 2;

or

provided that R³ is other than a pyridyl or an N-oxide-containing group;

R² represents C_1-4 alkyl; and

m is 0, 1, or 2; and

R³ represents

wherein

R⁷ is C_1-4 alkyl or CN; and

r is 0, 1, or 2;

5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

6. A method of inhibiting a lyase enzyme, comprising contacting said lyase enzyme with a compound of claim 1.

7. A method of inhibiting a 17α

-hydroxylase-C17,20-lyase, comprising contacting a 17α

-hydroxylase-C17,20-lyase with a compound of claim 1.

8. A method for treating a subject having a cancer associated with a 17α

-hydroxylase-C17,20-lyase, comprising administering to the subject a therapeutically effective amount of a compound of claim 1.

9. A method for treating prostate cancer in a subject, comprising administering to said subject a therapeutically effective amount of a compound of claim 1, such that the prostate cancer in the subject is treated.

10. A method for treating breast cancer in a subject, comprising administering to said subject a therapeutically effective amount of a compound of claim 1, such that the breast cancer in the subject is treated.

11. The method of any one of claims 8-10, wherein said subject is a primate, equine, canine or feline.

12. The method of any one of claims 8-10, wherein said subject is a human.

13. A compound of the formula

14. A compound according to claim 13

wherein

R¹⁵ represents

wherein R¹⁸ represents C_1-4 alkyl;

and

p is 0, 1, or 2;

or

provided that R¹⁷ is other than a pyridyl or an N-oxide-containing group;

R¹⁶ represents H; and

R¹⁷ represents

wherein

R¹⁹ is C_1-4 alkyl, and

r is 0, 1, or 2;

or

wherein

R²⁰ represents

halogen;

C_1-4 alkyl,

C_1-4 alkoxy,

NO₂,

CF₃, or

CO₂R²¹ wherein R²¹ is H or C_1-4 alkyl; and

s is 0, 1, or 2.

15. A compound according to claim 13

wherein

R¹⁵ represents

wherein R¹⁸ represents C_1-4 alkyl;

and

p is 0, 1, or 2;

R¹⁶ represents H; and

R¹⁷ represents

wherein

R¹⁹ is C_1-4 alkyl; and

r is 0, 1, or 2.

16. A pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier.

17. A method of inhibiting a lyase enzyme, comprising contacting said lyase enzyme with a compound of claim 13.

18. A method of inhibiting a 17α

-hydroxylase-C17,20 lyase, comprising contacting a 17α

-hydroxylase-C17,20 lyase with a compound of claim 13.

19. A method for treating a subject having a cancer associated with a 17α

-hydroxylase-C17,20 lyase, comprising administering to the subject a therapeutically effective amount of a compound of claim 13.

20. A method for treating prostate cancer in a subject, comprising administering to said subject a therapeutically effective amount of a compound of claim 13, such that the prostate cancer in the subject is treated.

21. A method for treating breast cancer in a subject, comprising administering to said subject a therapeutically effective amount of a compound of claim 13, such that the breast cancer in the subject is treated.

22. The method of any one of claims 19-21, wherein said subject is a primate, equine, canine or feline.

23. The method of any one of claims 19-21, wherein said subject is a human.