Cyclohexylamines, phenylamines and uses thereof

• US 8,242,142 B2
• Filed: 08/18/2009
• Issued: 08/14/2012
• Est. Priority Date: 08/19/2008
• Status: Expired due to Fees

• Current Assignee: Peking University Shenzhen Graduate School, Regents of the University of California (University of California)
• Original Assignee: Peking University Shenzhen Graduate School, Regents of the University of California (University of California)
• Inventors: Lin, Shuo, Yang, Zhen
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US12/543,480
• Publication Number:
  US 20100048637A1
• Time in Patent Office: 1,092 Days
• Field of Search: 514/337, 546/281.1
• US Class Current: 514/337
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond

Abstract

Compounds having the formula I, their methods of synthesis, and pharmaceutically acceptable salts of certain of them are provided in which the variables have the definitions described herein.

Compositions including the compounds having the formula I-A in which the variables have the definitions described herein, and methods of using the compositions for the treatment of certain diseases mediated by the up-regulation of Smo are also disclosed.

Claims

1. A compound of formula I

2. The compound of claim 1 wherein R¹ is hydrogen.

3. The compound of claim 1 of formula IA

4. The compound of claim 1 of formula I-B

5. The compound of claim 1 of formula I-C

6. The compound of claim 1 of formula I-D

7. The compound of claim 1 of formula I-E

8. The compound of claim 7 of formula I-F

9. The compound of claim 8, wherein R² is —

CH₂—

CH₂—

CH₃ or —

CH₂—

CH═

CH₂.

10. The compound of claim 8, wherein R² is —

CH₂—

CH₃.

11. A composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier, excipient, or diluent.

12. A method of treatment comprising administering a therapeutically effective amount of the compound of claim 2 to a subject having a cancer mediated by an up-regulation of Hedgehog signaling wherein the cancer is basal cell carcinoma or medulloblastoma.

13. The method of claim 12 wherein the up-regulation of Hedgehog signaling is an up-regulation of Smoothened.

14. A method of synthesizing the compound of formula I of claim 1 comprising

contacting a compound of formula II-A

15. The method of claim 14, wherein R² is —

CH₂—

CH₃, CH₂—

CH₂—

CH₃, or —

CH₂—

CH═

CH₂.

16. The method of claim 14, wherein the N-protecting group is t-butyloxycarbonyl, Cbz, pivaloyl, acetyl, or benzyl.

17. The method of claim 14, wherein the base is a hydride.

18. The method of claim 14 further comprising removing the N-protecting group to provide the compound of formula I wherein R¹ is hydrogen.

19. The method of claim 18, wherein the N-protecting group is removed by contacting the compound of formula I with an acid selected from HCl and CF₃CO₂H.