Small molecule inhibitors of Dusp6 and uses therefor

Patent metadata

Field	Value
Publication number	US-9439877-B2
Application number	US-201514795056-A
Country	US
Kind code	B2
Filing date	Jul 9, 2015
Priority date	Mar 20, 2009
Publication date	Sep 13, 2016
Grant date	Sep 13, 2016

Abstract

Compounds that stimulate fibroblast growth factor production, and thus cell growth are provided. Also provided are compositions comprising the compounds and methods of using the compounds. The compounds can be used to treat wounds, to expand cell populations, such as hematopoietic cells, or to grow tissue in vitro, among other uses.

First claim

We claim:

1. A method of repairing a cardiac muscle defect in a patient, comprising contacting a cardiac cell of the patient with a compound having the formula:

in which R1 represents one or more independently of H, halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN; R2 is a secondary or tertiary amine group; R3 is one or more independently of halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN; and R4 is ═O or —OH, or a pharmaceutically acceptable salt thereof, in an amount effective to increase FGF secretion by the cell.

2. The method of claim 1 , wherein the cardiac cell is a cardiomyocyte.

3. The method of claim 2 , wherein the method further comprises obtaining one or more cardiomyocytes cells from a patient and contacting the one or more cardiomyocytes in vitro with the compound to expand the cardiomyocytes.

4. The method of claim 1 , wherein the defect is a congenital defect.

5. The method of claim 1 , wherein the defect is a wound.

6. The method of claim 1 , wherein R3 is halo.

7. The method of claim 6 , where R3 is Br.

8. The method of claim 1 , wherein R2 is a C 4-10 cycloalkylamine.

9. The method of claim 1 , wherein R2 is one of cyclopentylamine and cycloheptylamine.

10. The method of claim 1 , wherein R1 is H, R2 is one of cyclopentylamine, cyclohexylamine, and cycloheptylamine, and R3 is Br.

11. The method of claim 10 , wherein R2 is cyclohexylamine.

12. The method of claim 1 , wherein the compound consists essentially of a (−) enantiomer.

13. The method of claim 1 , wherein the compound has the formula:

14. The method of claim 1 , wherein R4 is ═O.

15. The method of claim 14 , wherein R2 is one of 4-t-Boc-cyclohexylamine, thiamorpholine, piperazine, methyl piperazine, acetyl piperazine, cyclopentylamine, cycloheptylamine and di-C 1-4 -alkylamine.

16. The method of claim 1 , wherein R4 is —OH.

17. The method of claim 1 , wherein R1 is 3,4-di-halo.

18. The method of claim 1 , wherein R1 is 3,4-dichloro.

19. The method of claim 1 , wherein the compound has the structure:

20. A method of repairing a damaged or deficient cardiac muscle in a patient, comprising contacting a cardiomyocyte of the patient with a compound having the formula:

or a pharmaceutically acceptable salt thereof, in an amount effective to increase levels of phosphorylated ERK or to decrease levels of de-phoshoprylated ERK in the cardiomyocyte.

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Day Billy W
• Tsang Waikok Michael
• Korotchenko Vasiliy N

Classifications

• C07D495/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/135 Primary

  having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)} · CPC title

• C07C211/42

  with six-membered aromatic rings being part of the condensed ring systems · CPC title

• C07C225/20 Primary

  having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton · CPC title