Cyclopamine analogues and methods of use thereof

• US 7,230,004 B2
• Filed: 08/26/2005
• Issued: 06/12/2007
• Est. Priority Date: 08/27/2004
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Discovery, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Foley, Michael A., Porter, James R., Castro, Alfredo C., Adams, Julian, Tremblay, Martin R., Nevalainen, Marta, Janardanan Nair, Somarajan Nair
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US11/213,534
• Publication Number:
  US 20060074030A1
• Time in Patent Office: 655 Days
• Field of Search: 514/278, 546/18, 546/15
• US Class Current: 514/278
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 491/04 Ortho-condensed systems

Abstract

The present invention provides compositions and methods for modulating smoothened-dependent pathway activation. The present invention provides analogs of cyclopamine that can be used to counteract the phenotypic effects of unwanted activation of a hedgehog pathway, such as resulting from hedgehog gain-of-function, Ptc loss-of-function or smoothened gain-of-function mutations. The compounds of the present invention are particularly useful in treating cancers.

Claims

1. A compound of Formula 1:

2. The compound of claim 1, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are hydrogen.

3. The compound of claim 1, wherein R¹ is hydroxyl, sugar, —

OP(L)(OR²⁰)₂, —

X—

C(L)—

R²¹, or —

X—

C(L)—

X—

R²¹;

or R¹ and R² taken together, along with the carbon to which they are bonded, form —

C(O)—

.

4. The compound of claim 1, wherein R⁴ and R⁵ taken together form a double bond.

5. The compound of claim 4, wherein R¹ and R² taken together, along with the carbon to which they are bonded, form —

C(O)—

.

6. The compound of claim 1, wherein R¹ is hydroxyl and R² is H.

7. The compound of claim 6, wherein R⁵ and R⁶ taken together form a double bond;

or R⁵ and R⁶ taken together form a group represented by 1b;

8. The compound of claim 1, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

9. The compound of claim 1, wherein R⁵ and R⁶ taken together form a double bond and R¹⁰ and R¹¹ taken together form a double bond.

10. The compound of claim 5, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

11. The compound of claim 6, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

12. The compound of claim 1, wherein R⁸ and R⁹ are hydrogen;

or R⁸ and R⁹ taken together, along with the carbon to which they are bonded, is —

C(O)—

.

13. The compound of claim 1, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

14. The compound of claim 2, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

15. The compound of claim 5, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

16. The compound of claim 6, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

19. The compound of claim 1, which has the formula:

39. A pharmaceutical composition, comprising a compound of claim 1;

and a pharmaceutically acceptable excipient.

17. A compound of the formula:

18. A compound selected from the group consisting of:

20. A compound of Formula 2:

21. The compound of claim 20, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are hydrogen.

22. The compound of claim 20, wherein R¹ is hydroxyl, sugar, —

OP(L)(OR²⁰)₂, —

X—

C(L)-R²¹, or —

X—

C(L)—

X—

R²¹;

or R¹ and R² taken together, along with the carbon to which they are bonded, form —

C(O)—

.

23. The compound of claim 20, wherein R⁴ and R⁵ taken together form a double bond.

24. The compound of claim 23, wherein R¹ and R² taken together, along with the carbon to which they are bonded, form —

C(O)—

.

25. The compound of claim 20, wherein R¹ is hydroxyl and R² is H.

26. The compound of claim 25, wherein R⁵ and R⁶ taken together form a double bond;

or R⁵ and R⁶ taken together form a group represented by 1b;

27. The compound of claim 20, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

28. The compound of claim 20, wherein R⁵ and R⁶ taken together and R¹⁰ and R¹¹ taken together form a group represented by 1b;

29. The compound of claim 24, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

30. The compound of claim 25, wherein R¹⁰ and R¹¹ taken together form a double bond;

or R¹⁰ and R¹¹ taken together form a group represented by 1b;

31. The compound of claim 20, wherein R⁸ and R⁹ are hydrogen;

or R⁸ and R⁹ taken together, along with the carbon to which they are bonded, is —

C(O)—

.

32. The compound of claim 20, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

33. The compound of claim 21, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

34. The compound of claim 24, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

35. The compound of claim 25, wherein R¹² is H, alkyl, cycloalkyl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, hydroxyl, alkoxyl, —

[(W)—

N(R²¹)C(O)]_qR²¹, —

[(W)—

N(R²¹)SO₂]_qR²¹, —

[(W)—

C(O)N(R²¹)]_qR²¹, —

[(W)—

O]_qR²¹, —

[(W)—

C(O)]_qR²¹, or —

[(W)—

C(O)O]_qR²¹.

38. The compound of claim 20, which has the formula:

36. A compound of the formula:

37. A compound selected from the group consisting of: