Compounds and methods for inducing chondrogenesis

Patent metadata

Field	Value
Publication number	US-10166237-B2
Application number	US-201615256230-A
Country	US
Kind code	B2
Filing date	Sep 2, 2016
Priority date	Mar 24, 2011
Publication date	Jan 1, 2019
Grant date	Jan 1, 2019

Abstract

The present invention provides compounds and compositions for the amelioration of arthritis and joint injuries by inducing mesenchymal stem cells into chondrocytes.

First claim

What is claimed is:

1. A method for stimulating chondrocyte proliferation and cartilage production in cartilaginous tissues in a mammal, the method comprising administering to the mammal a composition comprising a therapeutically effective amount of a compound of formula I:

wherein
each of ring A and ring B are independently selected from the group consisting of cycloalkyl, aryl and heteroaryl;
each R 1 and R 2 is independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 heteroalkyl, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl-CN, C 1-6 alkylhydroxy, —OR 2a , —NR 2b R 2d , C 1-6 alkyl-NR 2b R 2d , —C(O)R 1a , —C(O)R 2d , —C(O)OR 2a , C 1-6 alkyl-C(O)OR 2b , —OC(O)R 2b , —OC(O)OR 2b , —C(O)NR 2a R 2b , —C(O)N(OH)R 2b , —NR 2b C(O)R 2c , C 1-6 alkyl-NR 2b C(O)R 2c , —NR 2b C(O)OR 2c , C 1-6 alkyl-NR 2b C(O)OR 2c , —OC(O)NR 2b R 2c , —NR 2b C(O)NR 2b R 2c , —NR 2b C(NR 2b )N R 2b R 2c , —C(O)NR 2b C(O)R 2b , C 1-6 alkyl-NR 2b C(O)NR 2b R 2c , —SR 2a , —SO 2 R 2b , —SO 2 OR 2b ,—SO 2 NR 2b R 2d , —NR 2b SO 2 R 2b , —P(O)(OR 2b ) 2 , —B(OR 2b ), —CN, —NO 2 , —N 3 , heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-heterocycloalkyl, C 1-6 alkyl-aryl, C 1-6 alkyl-O-aryl, C 1-6 alkyl-heteroaryl, and heteroaryl-aryl, and wherein the heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 to 2 R 2a groups;
R 1a is selected from the group consisting of —OR 1b and —NR 1b R 1c ;
R 1b and R 1c are each independently selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-aryl, and C 1-6 alkyl-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with from 1 to 4 Rid groups;
each R 1d is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 alkoxy, and —NO 2 ;
each R 2a is independently selected from the group consisting of H, C 2-6 alkenyl, C 2-6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-cycloalkyl, C 1-6 alkyl-heterocycloalkyl, C 1-6 alkyl-aryl and C 1-6 alkyl-heteroaryl, optionally substituted with 1 to 2 R 2b groups;
each R 2b and R 2c is independently selected from the group consisting of H, and C 1-6 alkyl;
each R 2d is independently selected from the group consisting of H, C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-cycloalkyl, C 1-6 alkyl-heterocycloalkyl, C 1-6 alkyl-aryl and C 1-6 alkyl-heteroaryl, each optionally substituted with 1 to 2 R 2b groups;
each of L 1 and L 2 are independently selected from the group consisting of a bond, C 1-6 alkylene, C 2-6 alkenylene, C 1-6 alkylene-O—, —O—C 1-6 alkylene, C 1-6 alkylene-NR 3a —, —NR 3a —C 1-6 alkylene, —C(O)—, C 1-6 alkylene-C(O)—, —C(O)—C 1-6 alkylene-NH—, —NH—C 1-6 alkylene-C(O)—, —C(O)N H—, —NHC(O)—, C 1-6 alkylene-NHC(O)—, —SO 2 NH—, —NHSO 2 —, —NHC(O)NH—, cycloalkylene, —N═N—, and —C(R 3a )═N(R 3c )—, wherein the alkylene group is optionally substituted with from 1-4 R 3b groups; R 3a is selected from the group consisting of H, and C 1-6 alkyl;
each R 3b is independently selected from the group consisting of H, C 1-6 alkyl, halogen, —OR 3a and —NR 3a R 3a ;
R 3c is absent or —OH;
alternatively, L 2 is combined with R 1 , L 1 is combined with L 2 , L 1 is combined with R 2 , two R 1 groups on adjacent ring atoms, or two R 2 groups on adjacent ring atoms are combined to form a 5-6 membered heterocycloalkyl with from 1 to 3 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl with from 1 to 3 heteroatoms selected from N, O and S, and optionally substituted with from 1 to 3 groups selected from the group consisting of H, C 1-6 alkyl and oxo;
subscripts m and n are each an integer from 1 to 3;
wherein:
(a) L 1 is a bond, L 2 is —C(O)NH—, ring B is phenyl, and at least one R 2 is —CN or phenyl, or
(b) at least one R 1 is —C(O)OH, ring A is phenyl, L 2 is —C(O)NH—, and L 1 is a bond or C 1-6 alkylene, or
(c) each of ring A and ring B is phenyl, at least one R 1 is —C(O)OH or combined with L 2 , and at least one R 2 is selected from the group consisting of H, —CN and —C(O)OH;

wherein when R 1 is —CO 2 H, subscript n is 1, ring A is phenyl, L 2 is —C(O)NH—, L 1 is a bond, ring B is phenyl, subscript m is 1, and R 2 is phenyl, then the phenyl of R 2 is substituted with C 1-6 alkyl,
or salts and isomers thereof, thereby stimulating chondrocyte proliferation and cartilage production in the cartilaginous tissues in the mammal.

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

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

wherein
each R 1 is independently selected from the group consisting of C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 heteroalkyl, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkyl-CN, C 1-6 alkylhydroxy, —OR 2a , —NR 2b R 2d , C 1-6 alkyl-NR 2b R 2d , —C(O)R 1a , —C(O)R 2d , —C(O)OR 2a , C 1-6 alkyl-C(O)OR 2b , —OC(O)R 2b , —OC(O)OR 2b , —C(O)NR 2a R 2b , —C(O)N(OH)R 2b , —NR 2b C(O)R 2c , C 1-6 alkyl-NR 2b C(O)R 2c , —NR 2b C(O)OR 2c , C 1-6 alkyl-NR 2b C(O)OR 2c , —OC(O)NR 2b R 2c , —NR 2b C(O)NR 2b R 2c , —NR 2b C(NR 2b )N R 2b R 2c , —C(O)NR 2b C(O)R 2b , C 1-6 alkyl-NR 2b C(O)NR 2b R 2c , —SR 2a , —SO 2 R 2b , —SO 2 OR 2b , —SO 2 NR 2b R 2d , —NR 2b SO 2 R 2b , —P(O)(OR 2b ) 2 , —B(OR 2b ), —CN, —NO 2 , —N 3 , heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-heterocycloalkyl, C 1-6 alkyl-aryl, C 1-6 alkyl-O-aryl, C 1-6 alkyl-heteroaryl, and heteroaryl-aryl, and wherein the heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 to 2 R 2a groups;
each of R 2a , R 2b , R 2c and R 2d are independently selected from the group consisting of H and C 1-6 alkyl; and
ring A is selected from the group consisting of phenyl, biphenyl and pyridyl,
wherein when ring A is phenyl and at least one R 1 is —C(O)OH, then subscript n is 2 or 3.

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

wherein
R 1 is selected from the group consisting of C 1-6 alkyl and —C(O)OR 2b ; and
R 2 is selected from the group consisting of —CN and Ph.

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

wherein
each R 2 is independently selected from the group consisting of H, C 1-6 haloalkoxy, C 1-6 alkyl-NR 2b R 2d , —C(O)OR 2b , —C(O)N(OH)R 2b , C 1-6 alkyl-NR 2b C(O)OR 2c , C 1-6 alkyl-NR 2b C(O)NR 2b R 2c , —SO 2 OR 2b , —PO 3 H, —CN, aryl, heteroaryl, and C 1-6 alkyl-O-aryl;
ring B is selected from the group consisting of cyclohexyl, phenyl, imidazole, oxazole, thiazole, pyrimidine, and pyrazine; and
L 1 is selected from the group consisting of a bond and —CH 2 —;
wherein
when R 2 is C 1-6 alkyl-NR 2b R 2d , then one of R 2b and R 2d is C 1-6 alkyl,
when R 2 is —C(O)OH, then L 1 is —CH 2 — or ring B is cyclohexyl, or both,
when R 2 is —CN, then L 1 is —CH 2 — or ring B is cyclohexyl, or both, and
when ring B is 2-thiazole, R 2 is unsubstituted phenyl.

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

Assignees

• Scripps Research Inst

Inventors

• Schultz Peter
• Bouchez Laure

Classifications

• A61K31/277

  having a ring, e.g. verapamil · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• C07D215/14

  Radicals substituted by oxygen atoms · CPC title

• C07D295/135

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title