Small organic molecule regulators of cell proliferation

• US 7,115,653 B2
• Filed: 09/17/2002
• Issued: 10/03/2006
• Est. Priority Date: 03/30/2000
• Status: Expired due to Term

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Price, Stephen, Boyd, Edward Andrew, Frank-Kamenetsky, Maria, Rubin, Lee L., Stibbard, John Harry Alexander, Porter, Jeffery, Baxter, Anthony David, Guicherit, Oivin
• Primary Examiner(s): Saeed, Kamal A.
• Assistant Examiner(s): Coppins, Janet L.
• Application Number:
  US10/245,844
• Publication Number:
  US 20030139457A1
• Time in Patent Office: 1,477 Days
• Field of Search: 549/57, 549/58, 549/56, 514/443
• US Class Current: 514/443
• 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 compound represented in general formula (IX):

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

3. The compound of claim 2, wherein Cy is a cyclohexyl ring substituted with a pnmary or secondary amine.

4. The compound of claim 3, wherein the amine is a methylamino group.

5. The compound of any one of claims 1 or 3, wherein the benzo ring is substituted with from 1–

4 substituents selected from halogen, and methyl.

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

7. A pharmaceutical composition comprising a sterile excipient and a compound according to any one of claims 1 or 3–

4.

13. The compound of claim 1, wherein Cyis a substituted or unsubstituted piperidine ring.

14. The compound of claim 13, wherein the nitrogen in the piperidine ring is in a 1,4 relationship with Y.

15. The compound of claim 3, wherein the amine and Y are connected to Cy in a 1,4 relationship.

16. The compound of claim 15, wherein the amine and Y are in a frans relationship.

17. The compound of any one of claims 1, 2, or 13, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, or —

S(O)₂—

.

18. The compound of any one of claims 1, 2, or 13, wherein N in N(M_i)(M_i)(M_k) is bonded to exactly three carbon atoms.

19. The compound of any one of claims 1, 2, or 13, wherein M in —

Ar—

Y-M_i-N is present.

8. A pharmaceutical preparation comprising a sterile pharmaceutical excipient and a compound represented in general formula (I):

9. The pharmaceutical preparation of claim 8, wherein Y is absent from all positions.

10. The phhrmaeeutical preparation of claim 8, wherein M represents, independently for each occurrence, a substituted or unsubstituted methylene group.

11. The pharmaceutical preparation of claim 8, wherein X is selected from —

C(═

O)—

, —

C(═

S)—

, and —

(O₂)—

.

12. The pharmaceutical preparation of any one of claims 8–

9, wherein Cy is a cycloalkyl ring substituted with a primary, secondary, or tertiary amine.

20. The pharmaceutical preparation of any one of claims 8–

9, wherein Cy is a substituted or unsubstituted piperidine ring.

21. The pharmaceutical preparation of claim 20, wherein the nitrogen in the piperidine ring is in a 1,4 relationship with Y.

22. The pharmaceutical preparation of claim 12, wherein Cy is a substituted or unsubstituted cyclohexyl ring.

23. The pharmaceutical preparation of claim 12, wherein the amine and Y are connected to Cy in a 1,4 relationship.

24. The pharmaceutical preparation of claim 23, wherein the amine and Y are in a trans relationship.

25. The pharmaceutical preparation of claim 8, wherein N in N(M_i)(M_i)(X) is bonded to exactly three carbon atoms.

26. The pharmaceutical preparation of claim 12, wherein N in N(M_i)(M_i)(X) is bonded to exactly three carbon atoms.

27. The pharmaceutical preparation of claim 8, wherein M in Ar′

—

Ar—

Y-M_i-N is present.

28. The pharmaceutical preparation of claim 12, wherein M in Ar′

—

Ar—

Y-M_i-N is present.

29. The pharmaceutical preparation of any one of claims 10–

11, 25, or 27, wherein Y is absent from all positions.