Small organic molecule regulators of cell proliferation

• US 8,273,747 B2
• Filed: 11/02/2007
• Issued: 09/25/2012
• Est. Priority Date: 11/02/2006
• Status: Active Grant

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Brunton, Shirley Ann, Guicherit, Oivin M., Kruse, Lawrence I.
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US11/982,709
• Publication Number:
  US 20080193423A1
• Time in Patent Office: 1,789 Days
• Field of Search: 514/469, 514/252.1, 514/275, 549/435, 544/297, 544/405
• US Class Current: 514/252.1
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 compound. 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 patched pathway or agonizing smoothened or hedgehog activity.

Claims

1. A compound represented by general formula (V):

2. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient;

wherein the composition is optionally suitable for oral or topical administration.

3. The compound of claim 1, wherein the compound is selected from the following:

4. The compound of claim 3, wherein the compound is

5. The compound of claim 3, wherein the compound is

6. The compound of claim 3, wherein the compound is

7. The composition of claim 2, wherein the compound is selected from the following:

8. The composition of claim 7, wherein the compound is

9. The composition of claim 7, wherein the compound is

10. The composition of claim 7, wherein the compound is

11. A method for promoting the formation or proliferation of hair follicles comprising contacting cells in vitro with an effective amount of a compound of claim 1.

12. The method of claim 11, wherein the compound further comprises a pharmaceutically acceptable excipient.

13. The method of claim 11, wherein the compound is

14. The method of claim 11, wherein the compound is

15. The method of claim 11, wherein the compound is

16. The method of claim 11, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 mM or less.

17. The method of claim 11, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 μ

M or less.

18. The method of claim 11, wherein the compound agonizes hedgehog mediated signal transduction with an ED₅₀ of 1 nM or less.

19. The method of claim 11, further comprising

implanting the cells in a patient.

20. The method of claim 19, wherein the patient displays male or female pattern baldness.

21. The method of claim 19, wherein the patient has alopecia.

22. The method of claim 21, wherein the amount of cells implanted is suitable for treating alopecia in the patient.

23. The method of claim 11, wherein the cells are contacted with an effective amount of the compound to increase trichogenicity of the cells.

24. The compound of claim 1, wherein the compound is further characterized by one or more of the following:

R¹ is methoxy;

R¹ is fluoro;

R¹ is ethoxy;

at least one of Y² or Y⁴ is F;

Y² and Y⁴ are F;

Y² is F and Y⁴ is H;

Z is a substituted or unsubstituted aryl ring;

Z is a substituted or unsubstituted phenyl ring;

Z is a substituted or unsubstituted heteroaryl ring;

Z is a substituted or unsubstituted pyridine, pyrimidine, pyrazine, pyridazine, triazine, tetrazine, pyrrole, pyrazole, or imidazole ring;

Z is a substituted or unsubstituted pyridine, pyrimidine, or pyrazine ring;

Z is a substituted or unsubstituted pyridine ring;

Z is a substituted or unsubstituted 4-pyridine ring;

Z is a substituted or unsubstituted 3-pyridine ring;

Z is a substituted or unsubstituted 2-pyridine ring;

Z is a substituted or unsubstituted 5-pyrimidine ring;

Z is a substituted or unsubstituted 2-pyrimidine ring;

Z is a substituted or unsubstituted 2-pyrazine ring;

Z is unsubstituted;

Z is substituted with one or more electron withdrawing groups;

Z is substituted with one or more groups selected from halogen, lower alkyl, lower alkenyl, —

CN, azido, NR^XR^X;

—

CO₂OR^X, —

C(O)—

NR^XR^X, —

C(O)—

R^X, —

NR^X—

C(O)—

R^X, —

NR^XSO₂R^X, —

SR^X, —

S(O)R^X, —

SO₂R^X, —

SO₂NR^XR^X, —

(C(R^X)₂)—

OR^X, —

(C(R^X)₂)_n—

, NR^XR^X, and —

(C(R^X)₂)_n—

SO₂R^X;

wherein R^X is, independently for each occurrence, H or lower alkyl; and

n is, independently for each occurrence, an integer from 0 to 2;

Z is substituted with one or more groups selected from halogen, —

CN, azido, —

CO₂OR^X, —

C(O)—

NR^XR^X, and —

C(O)—

R^X;

or

Z is substituted with fluoro.

25. A composition comprising a compound of claim 24 and a pharmaceutically acceptable excipient, wherein the composition is optionally suitable for oral or topical administration.

26. The compound of claim 1, wherein the compound is one of

27. A composition comprising a compound of claim 26 and a pharmaceutically acceptable excipient, wherein the composition is optionally suitable for oral or topical administration.

28. A method for promoting the formation or proliferation of hair follicles comprising contacting cells in vitro with an effective amount of a compound of claim 24.

29. A method for promoting the formation or proliferation of hair follicles comprising contacting cells in vitro with an effective amount of a compound of claim 26.

30. The compound of claim 24, wherein R¹ is selected from the group consisting of ethoxy and methoxy.

31. The compound of claim 24, wherein Z is a substituted or unsubstituted phenyl ring or a substituted or unsubstituted pyridine ring.