Compounds and methods for inducing chondrogenesis

Patent metadata

Field	Value
Publication number	US-11045476-B2
Application number	US-201916685555-A
Country	US
Kind code	B2
Filing date	Nov 15, 2019
Priority date	Mar 15, 2013
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

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 IIb, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 IIb, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 , NHR 5 , NR 4 R 5 , CO 2 H, or CO 2 R 4 ;
n is 0, 1, 2, 3, or 4;
B is NHC(O)R 2 ;
R 2 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, or optionally substituted alkyl;
R 4 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, optionally substituted aralkyl, or optionally substituted alkyl;
R 5 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ;
A is SO 2 NR a R b ; and
each R a and R b is independently optionally substituted alkyl or together with the N to which they are attached make a ring.

2. The method of claim 1 , wherein each R a and R b is independently optionally substituted alkyl.

3. The method of claim 1 , wherein R a and R b together with the N to which they are attached make a ring.

4. The method of claim 1 , wherein R 2 is optionally substituted phenyl.

5. The method of claim 1 , wherein the phenyl of R 2 is monosubstituted or disubstituted.

6. The method of claim 5 , wherein substitution on the phenyl of R 2 is independently selected from F, Cl, CO 2 H, CN, OCH 3 , C(O)CH 3 , CF 3 , CH 3 , CH 2 OH, CH 2 CH 2 OH, and CH 2 CH 2 CH 2 OH.

7. The method of claim 1 , wherein the compound is:

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

8. 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 III, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 III, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer 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 , NHR 5 , NR 4 R 5 , CO 2 H, or CO 2 R 4 ;
n is 0, 1, 2, 3, or 4;
X is O or NH and A is CH—CR 3 R 4 —C(O)R 2 ; or
X is NR 6 and A is C(O) or CH 2 ;
R 2 is optionally substituted aryl or optionally substituted heteroaryl;
each R 3 and R 4 is independently H or optionally substituted alkyl;
R 5 is H, optionally substituted alkyl, C(O)R 4 , C(O)OR 4 , C(O)NR 4 R 4 , or SO 2 R 4 ; and
R 6 is optionally substituted phenyl;
provided that
if n is 0, A is CHCH 2 C(O)R 2 and X is O, then R 2 is not

and
if A is C(O) or CH 2 , then X is NR 6 and R 6 is not

9. The method of claim 8 , wherein R 2 is phenyl and the phenyl of R 2 is monosubstituted or disubstituted.

10. The method of claim 9 , wherein substitution on the phenyl is independently selected from F, Cl, CO 2 H, CN, OCH 3 , C(O)CH 3 , CF 3 , CH 3 , CH 2 OH, CH 2 CH 2 OH, and CH 2 CH 2 CH 2 OH.

11. The method of claim 8 , wherein n is 0 or 1.

12. The method of claim 11 , wherein R 1 is independently selected from Cl, F, CH 2 OH, CH 2 NH 2 , OCH 3 , OCF 3 , OCHF 2 , CN, NO 2 , CO 2 H, and CO 2 CH 3 .

13. The method of claim 8 , wherein the compound is

or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof.

Assignees

• Scripps Research Inst

Inventors

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

Classifications

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · 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

• C07D231/40

  Acylated on said nitrogen atom · CPC title

• C07C317/40

  Y being a hydrogen or a carbon atom · CPC title

• A61K31/54 Primary

  having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame · CPC title