Small Molecule Inhibitors of Dusp6 and Uses Therefor

Patent metadata

Field	Value
Publication number	US-2016355459-A1
Application number	US-201615243089-A
Country	US
Kind code	A1
Filing date	Aug 22, 2016
Priority date	Mar 20, 2009
Publication date	Dec 8, 2016
Grant date	—

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

What is claimed is:

1 . 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 a secondary or tertiary amine group; R3 is one or more independently of H, halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN; and R4 is ═O or —OH, wherein
when both R1 and R3 are H,
R4 is —OH, or
R3 is one or more independently of halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN, and

when R1 is H and R4 is ═O, R3 is one or more independently of halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN,
or a pharmaceutically-acceptable salt thereof.

2 . The compound of claim 1 in which R2 is a C 4-10 cycloalkylamine.

3 . The compound of claim 1 in which R2 is one of cyclopentylamine and cycloheptylamine.

4 . The compound of claim 1 consisting essentially of a (−) enantiomer of the compound.

5 . The compound of claim 1 having the formula:

6 . The compound of claim 1 in which R4 is ═O.

7 . The compound of claim 6 in which R2 is one of 4-t-Boc-cyclohexylamine, thiamorpholine, piperazine, methyl piperazine, acetyl piperazine, cyclopentylamine, cycloheptylamine and di-C 1-4 -alkylamine.

8 . The compound of claim 1 in which R4 is —OH.

9 . The compound of claim 1 , wherein R1 is 3,4-di-halo.

10 . The compound of claim 1 , wherein R1 is 3,4-dichloro.

11 . The compound of claim 1 , wherein R2 is one of C 4-10 cycloalkylamine, 4-t-Boc-cyclohexylamine, thiamorpholine, piperazine, methyl piperazine, acetyl piperazine, phenylamine, piperidine, morpholine, biotin, and di-C 1-4 -alkylamine.

12 . A composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable excipient.

13 . A method of inhibiting dual specificity phosphatase 6 (Dusp6)-induced dephosphorylation of extracellular signal-related kinase (ERK), comprising contacting a cell 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 H, halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN; and R4 is ═O or —OH, wherein
when both R1 and R3 are H,
R4 is —OH, or
R3 is one or more independently of halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN, and

when R1 is H and R4 is ═O, R3 is one or more independently of halo, C 1-3 alkyl, C 1-3 alkoxyl or —CN,
or a pharmaceutically-acceptable salt thereof, in an amount effective to inhibit dephosphorylation of ERK by Dusp6.

14 . The method of claim 13 , wherein R3 is halo.

15 . The method of claim 14 , where R3 is Br.

16 . The method of claim 13 , wherein R2 is a C 4-10 cycloalkylamine.

17 . The method of claim 13 , wherein R2 is one of cyclopentylamine and cycloheptylamine.

18 . The method of claim 13 , wherein R1 is H, R2 is one of cyclopentylamine, cyclohexylamine, and cycloheptylamine, and R3 is Br.

19 . The method of claim 18 , wherein R2 is cyclohexylamine.

20 . The method of claim 13 , wherein the compound has the structure:

Assignees

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

Inventors

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

Classifications

• A61K31/135

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

• C07D495/04 Primary

  Ortho-condensed 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

• C07C211/42

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