HETEROCYCLIC CYCLOPAMINE ANALOGS AND METHODS OF USE THEREOF

• US 20080293755A1
• Filed: 03/07/2008
• Published: 11/27/2008
• Est. Priority Date: 03/07/2007
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Discovery, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Grogan, Michael J., Castro, Alfredo C., Tremblay, Martin
• Granted Patent: US 7,648,994 B2
• Time in Patent Office: Days
• US Class Current: 514/278
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 491/14 Ortho-condensed systems
• CPC Class Codes: C07D 513/14 Ortho-condensed systems

Abstract

The present invention relates to steroidal alkaloids that can be used in the treatment of hedgehog pathway related disorders, particularly cancer.

Claims

1. A compound of Formula 1a or 1b:

2. The compound of claim 1, wherein R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ are each H or alkyl.

3. The compound of claim 1, wherein R² and R³ taken together form a bond.

4. The compound of claim 1, wherein R⁴ and R⁵ are each H;

or R⁴ and R⁵ taken together form ═

O or ═

S.

5. The compound of claim 1, wherein Y is —

O—

or —

N(R²⁴)—

.

6. The compound of claim 1, wherein -T¹-T²-T³- represents —

CR²³—

N—

NR²⁴—

or —

CR²³—

NR²⁴—

N—

.

20. A pharmaceutical composition comprising a compound of claim 1, and at least one pharmaceutically acceptable excipient.

21. A method of treating a condition mediated by the hedgehog pathway, the method comprising administering to a subject an effective amount of a compound of claim 1.

22. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of a compound of claim 1.

23. A method of treating cancer in a subject comprising administering to a subject in need thereof therapeutically effective amount of a compound of claim 1.

24. The method of claim 23, wherein the cancer is a cancer of the central nervous system.

25. The method of claim 23, wherein the cancer is a cancer of the gastrointestinal tract system.

26. A method of inhibiting activation of a hedgehog pathway in a patient diagnosed with a hyperproliferative disorder, comprising administering to said patient a compound of claim 1 in an amount sufficient to reduce the activation of the hedgehog pathway in a cell of said patient.

7. A compound of formula 6a:

8. The compound of claim 7, wherein X is a bond or —

CH₂—

.

9. The compound of claim 7, wherein Y is —

O—

or —

N(R²⁴)—

.

10. The compound of claim 7, wherein -T¹-T²-T³- represents —

CR²³—

N—

NR²⁴—

or —

CR²³—

NR²⁴—

N—

.

11. The compound of claim 9, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

12. The compound of claim 7, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰.

13. A compound of formula 11b:

14. The compound of claim 13, wherein X is a bond or —

CH₂—

.

15. The compound of claim 13, wherein Y is —

O—

or —

N(R²⁴)—

.

16. The compound of claim 13, wherein -T¹-T²-T³- represents —

CR²³—

N—

NR²⁴—

or —

CR²³—

NR²⁴—

N—

.

17. The compound of claim 13, wherein R²⁴ is H, alkyl, or —

S(O)₂R²⁰.

18. The compound of claim 13, wherein R¹ is H, alkyl, hydroxyl, aralkyl, heteroaryl, heteroaralkyl, —

OR²⁰, —

C(O)R²⁰, —

CO₂R²⁰, —

C(O)N(R²⁰)(R²⁰), —

S(O)₂R²⁰, —

S(O)₂N(R²⁰)(R²⁰), —

[(W)—

C(O)]_pR²⁰, —

[(W)—

C(O)O]_pR²⁰, —

[(W)—

OC(O)]_pR²⁰, —

[(W)—

SO₂]_pR²⁰, —

[(W)—

N(R²⁰)SO₂]_pR²⁰, —

[(W)—

C(O)N(R²⁰)]_pR²⁰, —

[(W)—

O]_pR²⁰, —

[(W)—

N(R²⁰)]_pR²⁰, or —

[(W)—

S]_pR²⁰.

19. A compound selected from the group consisting of: