Cyclopamine lactam analogs and methods of use thereof

• US 7,964,590 B2
• Filed: 03/07/2008
• Issued: 06/21/2011
• Est. Priority Date: 03/07/2007
• Status: Expired due to Fees

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Discovery, Inc. (Infinity Pharmaceuticals, Inc.)
• Inventors: Tremblay, Martin, Grogan, Michael J., Castro, Alfredo C., Lescarbeau, Andre
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US12/044,878
• Publication Number:
  US 20080287420A1
• Time in Patent Office: 1,201 Days
• Field of Search: 514/215, 540/521, 540/578
• US Class Current: 514/215
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 215/06 having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
• CPC Class Codes: C07D 491/20 Spiro-condensed systems

Abstract

The present invention relates to steroidal alkaloids useful in the treatment of hedgehog pathway related disorders, particularly cancer.

Claims

1. A compound of formula 15:

2. The compound of claim 1, wherein A is —

N(R¹³)— and

B is C═

O.

3. The compound of claim 1, wherein R¹¹ and R¹² are each H.

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

5. The compound of claim 1, wherein R⁷ and R¹⁰ are each H.

6. The compound of claim 1, wherein B is —

N(R¹³)— and

A is C═

O.

11. A pharmaceutical composition comprising Compound or salt as claimed in claim 1, and at least one pharmaceutically acceptable excipient.

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

13. The method of claim 12, wherein said hyperproliferative disorder is cancer.

14. A method of antagonizing the hedgehog pathway in a subject, the method comprising administering to the subject an effective amount of the compound or salt as claimed in claim 1.

15. A method of treating a hematological cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1, wherein the hematological cancer is selected from multiple myeloma, acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and myelodysplastic syndrome.

16. A method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1, wherein the leukemia is selected from acute lymphocytic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia, and chronic lymphocytic leukemia.

17. A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1, wherein the cancer is selected from pancreatic cancer, medulloblastoma, multiple myeloma, myeloid leukemia, myelodysplastic syndrome, non-Hodgkins lymphoma, Hodgkin'"'"'s disease, and acute lymphocytic leukemia.

18. A method of treating pancreatic cancer comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1.

19. A method of treating chondrosarcoma comprising administering to a subject in need thereof a therapeutically effective amount of the compound or salt as claimed in claim 1.

7. A compound of formula 21:

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

CH₂—

.

9. The compound of claim 7, wherein said compound has formula 23:

10. A compound selected from the group consisting of: