Small organic molecule regulators of cell proliferation

• US 8,852,937 B2
• Filed: 08/20/2007
• Issued: 10/07/2014
• Est. Priority Date: 03/30/2000
• Status: Expired due to Fees

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Baxter, Anthony David, Boyd, Edward Andrew, Frank-Kamenetsky, Maria, Guicherit, Oivin, Porter, Jeffery, Price, Stephen, Rubin, Lee, Stibbard, John Harry Alexander
• Primary Examiner(s): Landau, Sharmila G.
• Assistant Examiner(s): MACAULEY, SHERIDAN R
• Application Number:
  US11/894,557
• Publication Number:
  US 20080207740A1
• Time in Patent Office: 2,605 Days
• Field of Search: 435/375
• US Class Current: 435/375
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: C07D 333/70 attached in position 2
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 containing three or more hetero rings

Abstract

The present invention makes available methods and reagents for modulating proliferation or differentiation in a cell or tissue comprising contacting the cell with a hedgehog agonist, such as the compounds depicted in FIGS. 32 and 33. In certain embodiments, the methods and reagents may be employed to correct or inhibit an aberrant or unwanted growth state, e.g., by antagonizing a normal ptc pathway or agonizing smoothened or hedgehog activity.

Claims

1. A method for agonizing the hedgehog pathway in a cell, comprising contacting the cell with a hedgehog agonist in an amount sufficient to modulate proliferation or differentiation of the cell, wherein the hedgehog agonist is represented in general formula (XI):

2. The method of claim 1, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

3. The method of claim 2, wherein the amine is a methylamino group.

4. The method of claim 1, wherein Cy′

is a 3-chloro-benzo(b)thien-2-yl, 3-fluoro-benzo(b)thien-2-yl, or 3-methyl-benzo(b)thien-2-yl group, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl.

5. The method of claim 4, wherein the benzo ring is a 1,4-difluorobenzene ring.

6. The method of claim 1, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

7. The method of claim 6, wherein Cy represents a substituted or unsubstituted cycloalkyl group.

8. The method of claim 6, wherein NR₂ represents a secondary amine.

9. The method of claim 7, wherein Cy′

is a 3-chloro-benzo(b)thien-2-yl, 3-fluoro-benzo(b)thien-2-yl, or 3-methyl-benzo(b)thien-2-yl group, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl.

10. The method of claim 9, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen and methyl.

11. The method of claim 10, wherein each R independently represents H or a lower alkyl.

12. The method of claim 8, wherein Cy′

is a 3-chloro-benzo(b)thien-2-yl, 3-fluoro-benzo(b)thien-2-yl, or 3-methyl-benzo(b)thien-2-yl group, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl.

13. The method of claim 12, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen and methyl.

14. The method of claim 13, wherein each R independently represents H or a lower alkyl.

15. The method of claim 1, wherein Cy represents a substituted or unsubstituted cycloalkyl group.

16. The method of claim 15, wherein NR₂ represents a secondary amine.

17. The method of claim 15, wherein Cy′

is a 3-chloro-benzo(b)thien-2-yl, 3-fluoro-benzo(b)thien-2-yl, or 3-methyl-benzo(b)thien-2-yl group, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl.

18. The method of claim 17, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen and methyl.

19. The method of claim 16, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

20. The method of claim 16, wherein each R independently represents H or a lower alkyl.

21. The method of claim 18, wherein each R independently represents H or a lower alkyl.

22. The method of claim 18, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

S(O₂)—

.

23. The method of claim 1, wherein NR₂ represents a secondary amine.

24. The method of claim 23, wherein Cy′

is a 3-chloro-benzo(b)thien-2-yl, 3-fluoro-benzo(b)thien-2-yl, or 3-methyl-benzo(b)thien-2-yl group, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, nitro, cyano, methyl, and ethyl.

25. The method of claim 24, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

26. The method of claim 23, wherein each R independently represents H or a lower alkyl.

27. The method of claim 25, wherein Cy represents a substituted or unsubstituted cycloalkyl group.

28. The method of claim 1, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

29. The method of claim 1, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

30. The method of claim 1, wherein the compound is administered to a patient as part of a therapeutic or cosmetic application.

31. The method of claim 30, wherein the therapeutic or cosmetic application is selected from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, and regulation of skin and hair growth.

32. The method of claim 1, wherein the cells are contacted with the compound in vitro.

33. The method of claim 1, wherein the cells are contacted with an effective amount of the compound to promote the formation, proliferation, or both of hair follicles.

34. The method of claim 1, further comprising

a) culturing the cells ex vivo to produce hair follicles;

and

b) implanting the hair follicles in a patient.

35. The method of claim 34, wherein the patient displays baldness.

36. The method of claim 34, wherein the patient has alopecia.

37. The method of claim 36, wherein the amount of hair implanted in step b) is suitable for treating alopecia in the patient.

38. The method of claim 1, wherein the hedgehog agonist interacts with smoothened.

39. The method of claim 1, wherein the hedgehog agonist disrupts interaction between patched and smoothened.

40. The method of claim 1, wherein the hedgehog agonist disrupts a patched-smoothened complex.