CYCLOHEXYLAMINES, PHENYLAMINES AND USES THEREOF

• US 20100048637A1
• Filed: 08/18/2009
• Published: 02/25/2010
• Est. Priority Date: 08/19/2008
• Status: Active Grant

• Current Assignee: Peking University Shenzhen Graduate School, Regents of the University of California (University of California)
• Original Assignee: Peking University Shenzhen Graduate School
• Inventors: Yang, Zhen, Lin, Shuo
• Granted Patent: US 8,242,142 B2
• Time in Patent Office: Days
• 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 inhibiting Smoothened comprising contacting Smoothened with an effective amount of the compound of claim 2.

13. 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.

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

15. The method of claim 13, wherein the cancer is a solid tumor.

16. The method of claim 13, wherein the cancer is basal cell carcinoma or medulloblastoma.

17. A method of synthesizing the compound of formula I of claim 1 comprising contacting a compound of formula II-A

18. The method of claim 17, wherein R² is —

CH₂—

CH₃, CH₂—

CH₂—

CH₃, or —

CH₂—

CH═

CH₂.

19. The method of claim 17, wherein the N-protecting group is t-butyloxycarbonyl, Cbz, pivaloyl, acetyl, or benzyl.

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

21. The method of claim 17 further comprising removing the N-protecting group to provide the compound of formula I wherein R¹ is hydrogen.

22. The method of claim 21, wherein the N-protecting group is removed by contacting the compound of formula I with an acid selected from HCl and CF₃CO₂H.