Targeting GLI proteins in human cancer by small molecules

Patent metadata

Field	Value
Publication number	US-9840470-B2
Application number	US-201414761230-A
Country	US
Kind code	B2
Filing date	Jan 22, 2014
Priority date	Jan 23, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

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. An isolated enantiomer of 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 a direct bond or C 1 -C 4 alkyl;
Z is C 1 -C 4 alkyl or aryl;
R 4 is —OH; and
R 5 is hydrogen or C 1 -C 6 alkyl;
and salts and stereoisomers thereof.

2. The compound of claim 1 , wherein the compound is a slower eluting enantiomer.

3. The compound of claim 1 , wherein the compound is a faster eluting enantiomer.

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

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

6. The compound of claim 1 , wherein R 2 is alkyl.

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

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

9. The compound of claim 1 , wherein Y is C 1 -C 4 alkyl and Z is C 1 -C 4 alkyl.

10. The compound of claim 9 , wherein 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 —.

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 the compound is

13. The compound of claim 12 , wherein the compound is a slower eluting enantiomer.

14. The compound of claim 12 , wherein the compound is a faster eluting enantiomer.

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

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

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

Assignees

• Univ California

Inventors

• He Biao
• Mann Michael
• Jablons David M

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D231/14

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• A61K31/5377

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