Cyclopamine analogues and methods of use thereof

• US 8,236,956 B2
• Filed: 12/15/2010
• Issued: 08/07/2012
• Est. Priority Date: 08/27/2004
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Adams, Julian, Castro, Alfredo C., Foley, Michael A., Janardanan Nair, Somarajan Nair, Nevalainen, Marta, Porter, James R., Tremblay, Martin R.
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US12/969,024
• Publication Number:
  US 20110166353A1
• Time in Patent Office: 601 Days
• Field of Search: 546/36, 546/41, 546/15
• US Class Current: 546/41
• 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 process comprising:

a. reacting a first compound of formula 2;

2. The process according to claim 1, wherein R¹³, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each hydrogen.

3. The process according to claim 1, wherein R¹ is hydroxyl, sugar, —

OP(L)(OR²⁰)₂, —

X—

C(L)-R²¹, or —

X—

C(L)-X—

R²¹, and R² is H;

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

C(O)—

.

4. The process according to claim 1, wherein R⁴ and R⁵ taken together form a double bond.

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

C(O)—

.

6. The process according to claim 3, wherein R¹ is hydroxyl and R² is H.

7. The process according to claim 6, wherein R⁵ and R⁶ taken together form a double bond.

8. The process according to claim 3, wherein R¹ is —

X—

C(L)-X—

R²¹.

9. The process according to claim 3, wherein R¹² is —

CO₂R²¹ and R²¹ is aralkyl.

10. The process according to claim 1, wherein R⁸ and R⁹ are each hydrogen, or R⁸ and R⁹ taken together, along with the carbon to which they are bonded, is —

C(O)—

.

11. The process according to claim 1, wherein the cyclopropanating agent is a 1,1-haloalkylmetal complex.

12. The process according to claim 11, wherein the 1,1-haloalkylmetal complex is formed from diiodomethane and Et₂Zn, and the cyclopropanation is conducted in dichloromethane.

13. The process according to claim 1, wherein the Lewis or Bronsted acid is selected from ZnI₂, BF₃, methanesulfonic acid, diaryloxyphosphoric acids, and HCl.

14. The process according to claim 1, wherein for the compound of formula 2, the second compound of formula 2, and the compound of formula 1:

R¹ is protecting group —

X—

C(L)-X—

R²¹, R² is H, R⁵ and R⁶ taken together form a double bond, and R¹² is protecting group —

CO₂-aralkyl,

further comprising removing the R₁ and R₁₂ protecting groups to form a second compound of formula 1 wherein R¹ is hydroxyl, R² is H, R⁵ and R⁶ taken together form a double bond, and R¹² is H.

15. The process according to claim 14, wherein the second compound of formula 1 is oxidized using Al(Oi-Pr)₃ to form a third compound of formula 1, wherein R¹ and R² taken together, along with the carbon to which they are bonded, form —

(C═

O)—

, R⁴ and R⁵ taken together form a double bond, and R¹² is H.