Compounds and methods for inducing chondrogenesis

Patent metadata

Field	Value
Publication number	US-9452170-B2
Application number	US-201414210198-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 15, 2013
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

Described herein are compounds and compositions for the amelioration of arthritis or joint injuries by inducing mesenchymal stem cells into chondrocytes.

First claim

What is claimed is:

1. A method of (a) ameliorating arthritis or joint injury in a mammal, the method comprising administering to a joint of the mammal a composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof; or (b) inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof:

wherein
each R 1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO 2 , SR 4 , S(O)R 4 , SO 2 R 4 , NR 4 R 11 , or CO 2 R 4 ;
n is 0, 1, 2, 3, or 4;
m is 1, 2, 3, or 4;
B is CO 2 R 4 , CH 2 CO 2 H, CH 2 CO 2 R 4 , or optionally substituted phenyl;
Y is a bond, —(CR 5 R 6 )—, —(CR 7 R 8 )(CR 9 R 10 )—, or —(CR 7 R 8 )(CR 9 R 10 )X—;
X is O or CR 5 R 6 ;
R 2 is halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, haloalkyl, SO 2 R 4 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ;
each R 3 is independently selected from H, CN, halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, SO 2 R 4 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , and C(═NOR 4 )R 4 ;
or R 3 together with an adjacent R 3 or with R 2 form a ring;
each R 4 is independently selected from H and optionally substituted alkyl;
each R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected from H, halo, optionally substituted alkyl, OH, CO 2 R 4 , NR 4 R 11 , and optionally substituted alkoxy; and
R 11 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ;
provided that
a) if Y is a bond and R 3 is H, then R 2 is selected from C(O)NR 4 R 11 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , and C(═NOR 4 )R 4 ; and
R 2 is not p-CH 2 OR 4 , p-CH 2 CH 2 OH, or p-CH 2 CH 2 CH 2 OH; and

b) the compound is not selected from

2. A method of (a) ameliorating arthritis or joint injury in a mammal, the method comprising administering to a joint of the mammal a composition comprising a therapeutically effective amount of a compound of Formula Ib, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof; or (b) inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of a compound of Formula Ib, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof:

wherein
each R 1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO 2 , SR 4 , S(O)R 4 , SO 2 R 4 , NR 4 R 11 , or CO 2 R 4 ;
n is 0, 1, 2, 3, or 4;
B is CO 2 R 4 ;
R 2 is C(O)NR 4 R 11 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ;
R 3 is H;
X is O or CR 5 R 6 ;
each R 4 is independently selected from H and optionally substituted alkyl;
each R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is independently selected from H, halo, optionally substituted alkyl, OH, NR 4 R 11 , and optionally substituted alkoxy; and
R 11 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ;
provided that if n is 0, then R 2 is not p-CH 2 OR 4 , p-CH 2 CH 2 OH, or p-CH 2 CH 2 CH 2 OH.

3. A method of (a) ameliorating arthritis or joint injury in a mammal, the method comprising administering to a joint of the mammal a composition comprising a therapeutically effective amount of a compound of Formula Ic, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof; or (b) inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of a compound of Formula Ic, or a pharmaceutically acceptable salt, solvate, polymorph, ester, N-oxide, or stereoisomer thereof:

wherein
each R 1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO 2 , SR 4 , S(O)R 4 , SO 2 R 4 , NR 4 R 11 , CO 2 H, or CO 2 R 4 ;
n is 0, 1, 2, 3, or 4;
m is 1, 2, 3, or 4;
B is CO 2 R 4 ;
Y is —(CR 5 R 6 )—;
C is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiazolyl, isoxazolyl, or pyrazolyl;
X is O or CR 5 R 6 ;
R 2 is halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, haloalkyl, SO 2 R 4 , SO 2 NH 2 , SO 3 H, (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , or C(═NOR 4 )R 4 ;
each R 3 is independently selected from H, CN, halo, C(O)R 4 , CO 2 R 4 , C(O)NR 4 R 11 , alkyl, optionally substituted alkoxy, haloalkyl, SO 2 R 4 , (CR 7 R 8 )OR 4 , (CR 7 R 8 )NR 4 R 11 , (CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )OR 4 , X(CR 7 R 8 )(CR 9 R 10 )NR 4 R 11 , (CR 7 R 8 )C(O)R 4 , (CR 7 R 8 )C(O)OR 4 , (CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )C(O)R 4 , X(CR 7 R 8 )C(O)OR 4 , X(CR 7 R 8 )C(O)NR 4 R 11 , X(CR 7 R 8 )(CR 9 R 10 )C(O)R 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)OR 4 , X(CR 7 R 8 )(CR 9 R 10 )C(O)NR 4 R 11 , (CR 7 R 8 )NR 4 SO 2 R 4 , and C(═NOR 4 )R 4 ;
or R 3 together with an adjacent R 3

Assignees

• California Inst Biomedical Res
• Scripps Research Inst

Inventors

• Schultz Peter G
• Chatterjee Arnab K
• Zhu Shoutian
• Payette Joshua
• Yoon Hongchul
• Yang Baiyuan

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• C07C317/40

  Y being a hydrogen or a carbon atom · CPC title

• C07C233/66

  having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups · CPC title