Mediators of hedgehog signaling pathways, compositions and uses related thereto

• US 9,173,869 B2
• Filed: 04/28/2010
• Issued: 11/03/2015
• Est. Priority Date: 09/16/1999
• Status: Expired due to Fees

• Current Assignee: Curis, Inc.
• Original Assignee: Curis, Inc.
• Inventors: Rubin, Lee, Guicherit, Oivin M.
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US12/769,112
• Publication Number:
  US 20110077256A1
• Time in Patent Office: 2,015 Days
• Field of Search: 544/287, 544/290, 514/262.3, 514/252.16, 514/252.17, 514/266.3
• US Class Current: 1/1
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/517 ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 239/91 with aryl or aralkyl radicals attached in position 2 or 3

Abstract

The present invention makes available methods and reagents for inhibiting aberrant growth states resulting from hedgehog gain-of-function by contacting the cell with a hedgehog antagonist, such as a small molecule, in a sufficient amount to aberrant growth state, e.g., to agonize a normal ptc pathway or antagonize hedgehog activity.

Claims

1. A compound of the formula (II):

2. The compound of claim 1, wherein R₁ and R₂ are, independently, substituted or unsubstituted phenyl.

3. The compound of claim 1, wherein R₈ is H or lower alkyl.

4. A compound of claim 1, wherein

R₁ and R₂, independently for each occurrence, are H, lower alkyl, substituted or unsubstituted —

(CH₂)_n aryl or substituted or unsubstituted —

(CH₂)_n heteroaryl, provided that, when R₁ is substituted or unsubstituted —

(CH₂)_n aryl, n is 0.

5. A compound of claim 4 wherein

n is 0-5;

p is 0-3;

R¹ is phenyl or pyridine; and

W is a substituted or unsubstituted benzene ring.

6. A compound of claim 5 wherein the aryl group in —

(CH₂)_n aryl for R₈ is benzene, and the heteroaryl group in —

(CH₂)_n heteroaryl for R₈ is pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine or pyrimidine, each such aryl or heteroaryl group optionally substituted by halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydoxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, carboxyl, alkylthio, sulfonamido, —

CF₃, or —

CN; and

the substituents when W is a substituted benzene are halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, carboxyl, alkylthio, sulfonamido, —

CF₃, or —

CN.

7. A compound of claim 5 wherein L adjacent to R₂ is absent.

8. A method of treating medulloblastoma, comprising administering to a patient a compound of claim 1.

9. A method of treating basal cell carcinoma comprising administering to a patient a compound of claim 1.

10. A compound of claim 1 in the form of a separated enantiomer.

11. A compound of claim 10 in the R configuration.

12. A compound of claim 10 in the S configuration.

13. A compound of claim 1 wherein the aryl group in —

(CH₂)_naryl is benzene, and the heteroaryl group in —

(CH₂)_n heteroaryl is pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine or pyrimidine.