IP Library › Granted Patent US 9,464,065

Granted Patent B2

US 9,464,065 · App. 14/007,306 · Granted Oct 11, 2016

Compounds and methods for inducing chondrogenesis

Inventors: Peter Schultz (La Jolla, CA); Laure Bouchez (Basel, CH)

Assignee: The Scripps Research Institute

C07D295/135 A61K31/4192 A61K31/423 A61K31/428 A61K31/47 A61K31/4965 A61K31/505 A61K31/5375 A61K31/593 A61K31/728 A61K36/54 A61K38/1816 A61K38/1825 A61K38/23 A61K38/39 A61K45/06 C07C233/75 C07C233/80 C07C233/81 C07C255/50 C07C255/57 C07C255/60 C07D209/48 C07D215/14 C07D241/24 C07D249/06 C07D257/04 C07D263/57 C07D277/46 C07D277/66 C12N5/0655 A61K9/0024

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Quick Facts

Patent No.: US 9,464,065
App. No.: 14/007,306
Granted: Oct 11, 2016
Kind: B2

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Abstract

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

Claims (156)

1. A method of 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:

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 )NR 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 R 1d 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 1-16 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)NH—, —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 ameliorating arthritis or joint injury in the mammal.

2. The method of claim 1 , wherein

(a) L 1 is a bond, L 2 is —C(O)NH—, ring B is phenyl, R 2 is —CN or phenyl, and subscript m is 1, or

(b) R 1 is —C(O)OH, subscript n is 1, ring A is phenyl, L 2 is —C(O)NH—, and L 1 is a bond or —CH 2 —, or

(c) each of ring A and ring B is phenyl, R 1 is —C(O)OH or combined with L 2 , subscript n is 1, and at least one R 2 is selected from the group consisting of H, —CN and —CO 2 H.

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

4. 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 )NR 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.

5. The method of claim 4 , wherein each R 1 is independently selected from the group consisting of —C(O)R 2d , —C(O)OR 2b , C 1-6 alkyl-C(O)OR 2b , —NR 2b C(O)OR 2c , —NR 2b C(O)NR 2b R 2c , —SO 2 OR 2b , —SO 2 NR 2b R 2d , —NR 2b SO 2 R 2b , and —CN.

6. The method of claim 4 , wherein each R 1 is independently selected from the group consisting of —CH 2 —C(O)OH, —C(O)Me, —NHC(O)NH 2 , —NHC(O)OMe, —NHSO 2 Me, —SO 2 NH 2 , —SO 2 NHMe, —SO 3 H, —C(O)OH, and —CN.

7. The method of claim 4 , wherein

ring A is phenyl; and

subscript n is 1.

8. The method of claim 4 , wherein

ring A is selected from the group consisting of biphenyl and pyridyl, or

subscript n is 2.

9. 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.

10. 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.

11. The method of claim 10 , wherein each R 2 is independently selected from the group consisting of H, —CH 2 NHCONH 2 , —CH 2 NHCOOMe, —CH 2 NHMe, —CH 2 OPh, 2-CN, 4-CN, —C(O)OH, —CONHOH, —OCF2H, —PO 3 H, —SO 3 H, phenyl, pyridyl, imidazole and tetrazole.

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

wherein

each R 2 is independently selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 alkylhydroxy, C 1-6 alkyl-NR 2b R 2d , —C(O)R 1a , —C(O)R 2d , —SO 2 NR 2b R 2d , —CN, -heterocycloalkyl, and aryl, wherein the aryl groups are optionally substituted with halogen;

alternatively, two R 2 groups on adjacent ring atoms can be combined to form a 5-membered heterocycloalkyl;

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 and C 1-6 alkyl;

ring B is selected from the group consisting of phenyl, thiazole and pyridyl; 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 both of R 2b and R 2d are H,

when R 2 is —C(O)OH, then L 1 is a bond and ring B is phenyl,

when R 2 is —CN, then L 1 is a bond and ring B is phenyl, and

when ring B is 2-thiazole, then R 2 is substituted phenyl.

13. The method of claim 12 , wherein

each R 2 is independently selected from the group consisting of H, Me, —Cl, —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —C(O)Me, —C(O)OH, —C(O)NH 2 , —CN, morpoholine, 3,4-difluorophenyl and —SO 2 NH 2 ; and

alternatively, two R 2 groups on adjacent ring atoms are combined to form a 1,3-dioxole or 1-methylpyrrolidine-2,5-dione.

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

wherein

R 1 is —C(O)OH;

each R 2 is independently selected from the group consisting of —CN and —C(O)OH;

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(O)—, C 1-6 alkylene-C(O)—, —C(O)—C 1-6 alkylene-NH—, —NH—C 1-6 alkylene-C(O)—, —NHC(O)—, —SO 2 NH—, —NHSO 2 —, and —NHC(O)NH—;

wherein at least one of L 1 and L 2 is selected from the group consisting of —C(O)—, C 1-6 alkylene-C(O)—, —C(O)—C 1-6 alkylene-NH—, —NH—C 1-6 alkylene-C(O)—, —NHC(O)—, —SO 2 NH—, —NHSO 2 —, and —NHC(O)NH—;

alternatively, L 2 is combined with R 1 , or L 1 is combined with R 2 , 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.

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

R 1a is selected from the group consisting of —OR 1b and —NR 1b R 1c ;

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 2 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 alkylamine, C 1-6 alkyl-CN, C 1-6 alkyl-OH, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-aryl, C 1-6 alkyl-heteroaryl, heteroaryl-aryl, —OR 2a , —NR 2b R 2d , —C(O)R 2d , —C(O)OR 2b , —OC(O)R 2b , —C(O)NR 2b R 2c , —NR 2b C(O)R 2c , —NR 2b C(O)OR 2c , —OC(O)NR 2b R 2c , —SO 2 R 2a , —SO 2 NR 2b R 2d , —CN, —NO 2 , and —N 3 , wherein the heterocycloalkyl, aryl and heteroaryl groups are optionally substituted with 1 to 2 R 2b groups;

alternatively, two R 2 groups on adjacent ring atoms are combined to form a 5 to 6 membered heterocyclic ring having from 1 to 3 heteroatoms each independently selected from the group consisting of 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;

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;

R 4 is independently selected from the group consisting of H, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, OH, —CO 2 H, and —NO 2 ;

L 1 is selected from the group consisting of a bond, C 1-6 alkylene, —C(O)—, —C 1-6 alkylene-NH—, —C 1-6 alkylene-NHC(O)—, and heteroarylene; and

X is selected from the group consisting of —CH— and —N—.

16. The method of claim 15 , wherein the compound has the structure:

wherein

each R 2 is independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, C 1-6 haloalkyl, C 1-6 alkyl-CN, C 1-6 alkyl-OH, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-aryl, C 1-6 alkyl-heteroaryl, heteroaryl-aryl, —OR 2a , —NR 2b R 2d , —C(O)R 2d , —OC(O)R 2b , —C(O)NR 2b R 2c , —NR 2b C(O)R 2c , —NR 2b C(O)OR 2c , —OC(O)NR 2b R 2c , —SO 2 R 2a , —SO 2 NR 2b R 2d , —CN, —NO 2 , and —N 3 , wherein the heterocycloalkyl, and aryl groups are optionally substituted with 1 to 2 R 2b groups;

wherein when R 2 is —CN, then subscript m is 1, R 1a is OH, R 4 is H, and L 1 is a bond.

17. The method of claim 15 , wherein the compound has the structure:

wherein

each R 2 is independently selected from the group consisting of C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkyl-CN, C 1-6 alkyl-OH, heterocycloalkyl, aryl, heteroaryl, C 1-6 alkyl-aryl, C 1-6 alkyl-heteroaryl, heteroaryl-aryl, —OR 2a , —NR 2b R 2d , —C(O)R 2d , —OC(O)R 2b , —C(O)NR 2b R 2c , —NR 2b C(O)R 2c , —NR 2b C(O)OR 2c , —OC(O)NR 2b R 2c , —SO 2 R 2a , —SO 2 NR 2b R 2d , —CN, —NO 2 , and —N 3 , wherein the heterocycloalkyl, and aryl groups are optionally substituted with 1 to 2 R 2b groups; and

L 1 is a bond,

wherein when R 2 is —CN, then subscript m is 1, R 1a is OH, and R 4 is H.

18. The method of claim 1 , wherein the compound is selected from the group consisting of:

19. The method of claim 1 , wherein the mammal has arthritis or joint injury.

20. The method of claim 1 , wherein the mammal does not have, but is at increased risk for, arthritis or joint injury.

21. The method of claim 1 , wherein the arthritis is selected from the group consisting of osteoarthritis, trauma arthritis, and autoimmune arthritis.

22. The method of claim 1 , wherein the mammal is selected from the group consisting of a human, a dog, a horse and a cat.

23. The method of claim 1 , wherein the composition further comprises a member selected from the group consisting of angiopoietin-like 3 protein (ANGPTL3), oral salmon calcitonin, SD-6010 (iNOS inhibitor), vitamin D3 (choliecalciferol), collagen hydrolyzate, FGF18, BMP7, avocado soy unsaponifiables (ASU) and hyaluronic acid.

24. A method of inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of a compound having the structure:

wherein

each of ring A and ring B are independently selected from the group consisting of cycloalkyl, aryl and heteroaryl;

R 1a is selected from the group consisting of —OR 1b and —NR 1b R 1c ;

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 2b and R 2c is independently 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;

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;

or salts and isomers thereof, thereby inducing differentiation of the stem cells into chondrocytes.

25. The method of claim 24 , wherein the method is performed in vitro.

26. The method of claim 24 , wherein the method is performed in vivo in a mammal and the stem cells are present in the mammal.

27. The method of claim 26 , wherein the mammal is a human, a dog, a horse or a cat.

28. A compound selected from the group consisting of:

29. The compound of claim 28 , selected from the group consisting of:

30. The compound of claim 28 , selected from the group consisting of:

31. A pharmaceutical composition comprising a compound of claim 28 and a pharmaceutically acceptable excipient.

32. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a pharmaceutically 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 )NR 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 R 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 ;

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 2b and R 2c is independently 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;

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;

or salts and isomers thereof.

33. The pharmaceutical composition of claim 32 , wherein the composition is formulated for intra-articular delivery.

34. The composition of claim 32 , further comprising a member selected from the group consisting of angiopoietin-like 3 protein (ANGPTL3), oral salmon calcitonin, SD-6010 (iNOS inhibitor), vitamin D3 (choliecalciferol), collagen hydrolyzate, FGF18, BMP7, avocado soy unsaponifiables (ASU) and hyaluronic acid.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 25, 2014

From: SCHULTZ, PETER; BOUCHEZ, LAURE

To: THE SCRIPPS RESEARCH INSTITUTE

Reel/Frame 032762/0717 →

Continuity (2)

Provisional Application 61467289 · Mar 24, 2011

Related Publication 20140113012A1 · Apr 24, 2014