Targeting GLI proteins in human cancer by small molecules

Patent metadata

Field	Value
Publication number	US-9370521-B2
Application number	US-201214233504-A
Country	US
Kind code	B2
Filing date	Jul 20, 2012
Priority date	Jul 21, 2011
Publication date	Jun 21, 2016
Grant date	Jun 21, 2016

Abstract

The present disclosure provides compositions, pharmaceutical preparations and methods for the diagnosis and treatment of cancers expressing a GLI polypeptide. The disclosed compositions and pharmaceutical preparations may comprise one or more pyrazolyl-containing compounds, or an analog or derivative thereof.

First claim

What is claimed is:

1. A compound of formula (I):

wherein
each of X 1 and X 2 is independently N or C, wherein one of X 1 and X 2 is N and one of X 1 and X 2 is C, such that the ring N forms a double bond with whichever of X 1 and X 2 is C;
R 1 is aryl or substituted aryl;
R 2 is selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, and alkyl;
R 3 is aryl or substituted aryl;
Y is C 1 -C 4 alkyl and Z is C 1 -C 4 alkyl, such that Y and Z form —CH 2 ) 3 —C(CH 3 ) 2 —CH 2 —;
R 4 is —OH; and
R 5 is hydrogen or C 1 -C 6 alkyl;
and salts, hydrates, solvates, and prodrugs thereof.

2. The compound of claim 1 , wherein X 1 is N and X 2 is C.

3. The compound of claim 1 , wherein X 1 is C and X 2 is N.

4. The compound of claim 1 , wherein R 1 is aryl.

5. The compound of claim 1 , wherein R 2 is selected from aryl, substituted aryl, heteroaryl, and alkyl.

6. The compound of claim 1 , wherein R 2 is selected from heteroaryl and alkyl.

7. The compound of claim 1 , wherein R 3 is aryl.

8. The compound of claim 1 , wherein R 3 is substituted aryl.

9. The compound of claim 1 , wherein R 5 is hydrogen.

10. The compound of claim 1 , wherein R 1 is aryl, R 2 is heteroaryl, and R 3 is aryl.

11. The compound of claim 1 , wherein R 1 is aryl, R 2 is alkyl, and R 3 is substituted aryl.

12. The compound of claim 1 , wherein R 1 is aryl, R 2 is aryl, and R 3 is substituted aryl.

13. The compound of claim 1 , wherein R 1 is aryl, R 2 is substituted aryl, and R 3 is substituted aryl.

14. The compound of claim 1 , wherein the compound is 1,3-diphenyl-5-thiophen-3-yl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, having the structure:

15. The compound of claim 1 , wherein the compound is 3-(4-fluoro-phenyl)-1-phenyl-5-propyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, having the structure:

16. The compound of claim 1 , wherein the compound is 3-(4-fluoro-phenyl)-5-(3-fluoro-phenyl)-1-phenyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, having the structure:

17. The compound of claim 1 , wherein the compound is

(3-(4-fluoro-phenyl)-1,5-diphenyl-4,5-dihydro-1H-pyrazole-4-carboxylic acid (5-hydroxy-4,4-dimethyl-pentyl)-amide, Compound 5).

18. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a chemotherapeutic agent.

20. A pharmaceutical composition comprising:
(i) compound of claim 1 ; and
(ii) a therapeutic agent selected from erlotinib, pemetrexed, LY294002, SB431542, and cisplatin.

21. A method for treating a subject with a cancerous condition, the method comprising:
(a) administering to the subject a therapeutically effective amount of the compound of claim 1 ,
wherein the cancerous condition is characterized by expressing a GLI protein, and wherein the administering results in treatment of the subject.

22. A method for treating a subject with a cancerous condition, the method comprising:
(a) administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 18 ,
wherein the cancerous condition is characterized by expressing a GLI protein, and wherein the administering results in treatment of the subject.

23. The compound of claim 1 , wherein the compound is

Assignees

• He Biao
• Mann Michael
• Jablons David M
• Univ California

Inventors

• He Biao
• Mann Michael
• Jablons David M

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/5377 Primary

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/517

  ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine · CPC title

• A61K38/1709

  from mammals · CPC title

• C07D409/04

  directly linked by a ring-member-to-ring-member bond · CPC title