Small organic molecule regulators of cell proliferation

• US 20020198236A1
• Filed: 09/26/2001
• Published: 12/26/2002
• Est. Priority Date: 03/30/2000
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Rubin, Lee, Price, Stephen, Guicherit, Oivin M., Boyd, Edward Andrew, Stibbard, John Harry Alexander, Porter, Jeffery, Baxter, Anthony David
• Granted Patent: US 6,683,192 B2
• Time in Patent Office: Days
• US Class Current: 514/324
• 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• 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 compound represented in general formula (IX):

2. The compound of claim 1, wherein Cy includes at least one sp³ hybridized atom.

3. The compound of claim 2, wherein Cy further includes at least one nitrogen atom in the ring, or an amino substituent on the ring.

4. The compound of claim 1, wherein Cy includes or is substituted with a primary, secondary, or tertiary amine.

5. The compound of claim 4, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

6. The compound of claim 5, wherein the amine is a methylamino group.

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

8. The compound of claim 7, wherein the benzo ring is a 1,4-difluorobenzene ring.

21. A pharmaceutical composition comprising a sterile excipient and a compound according to claim 1.

24. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a compound of claim 1.

25. The method of claim 21, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 mM or less.

26. The method of claim 21, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

27. The method of claim 21, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

28. The method of claim 21, wherein the cell is contacted with the hedgehog agonist in vitro.

29. The method of claim 21, wherein the cell is contacted with the hedgehog agonist in vivo.

9. A compound represented in general formula (X):

10. The compound of claim 9, wherein M_j includes a cycloalkyl ring having 5-7 ring atoms.

11. The compound of claim 10, wherein NR₂ represents NHMe.

12. The compound of claim 9, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

13. The compound of claim 12, wherein the amine is a methylamino group.

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

15. The compound of claim 14, wherein the benzo ring is a 1,4-difluorobenzene ring.

17. The compound of claim 16, wherein Cy is a cyclohexyl ring substituted with a primary or secondary amine.

18. The compound of claim 17, wherein the amine is a methylamino group.

19. The compound of claim 16, wherein the benzo ring is substituted with from 1-4 substituents selected from halogen, and methyl.

20. The compound of claim 19, wherein the benzo ring is a 1,4-difluorobenzene ring.

22. A pharmaceutical composition comprising a sterile excipient and a compound according to claim 9.

23. A pharmaceutical composition comprising a sterile excipient and a compound according to claim 16.

30. The method of claim 29, wherein the hedgehog agonist is administered 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. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a compound of claim 9.

33. The method of claim 32, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 mM or less.

34. The method of claim 32, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

35. The method of claim 32, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

36. The method of claim 32, wherein the cell is contacted with the hedgehog agonist in vitro.

37. The method of claim 32, wherein the cell is contacted with the hedgehog agonist in vivo.

38. The method of claim 32, wherein the hedgehog agonist is administered as part of a therapeutic or cosmetic application.

39. The method of claim 38, 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.

40. A method for modulating proliferation or differentiation of a cell, comprising contacting the cell with a compound of claim 16.

41. The method of claim 40, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 mM or less.

42. The method of claim 40, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

43. The method of claim 40, wherein the hedgehog agonist agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

44. The method of claim 40, wherein the cell is contacted with the hedgehog agonist in vitro.

45. The method of claim 40, wherein the cell is contacted with the hedgehog agonist in vivo.

46. The method of claim 40, wherein the hedgehog agonist is administered as part of a therapeutic or cosmetic application.

47. The method of claim 46, 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.

16. A compound represented in general formula (XI):