Compounds and methods for inducing chondrogenesis
AssigneesThe Scripps Research Institute, The California Institute for Biomedical Research
InventorsPeter G. SCHULTZ, Arnab K. CHATTERJEE, Shoutian ZHU, Joshua PAYETTE, Hongchul YOON, Baiyuan YANG
Life of this patent
Estimating the term…
Abstract
Described herein are compounds and compositions for the amelioration of arthritis or joint injuries by inducing mesenchymal stem cells into chondrocytes.
Claims38
-115. (canceled)
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, 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 I, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof:
- wherein
- each R1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO2, SR4, S(O)R4, SO2R4, NR4R11, CO2H, or CO2R4;
- n is 0, 1, 2, 3, or 4;
- m is 1, 2, 3, or 4;
- B is CO2R4, CH2CO2H, CH2CO2R4, or optionally substituted phenyl;
- Y is a bond, —(CR5R6)—, —(CR7R8)(CR9R10)—, or —(CR7R8)(CR9R10)X—;
- X is O or CR5R6;
- R2 is halo, C(O)R4, CO2R4, C(O)NR4R11, alkyl, optionally substituted alkoxy, haloalkyl, SO2R4, (CR7R8)OR4, (CR7R8)NR4R11, (CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R11)OR4, X(CR7R8)(CR9R10)NR4R11, (CR7R8)C(O)R4, (CR7R8)C(O)OR4, (CR7R8)C(O)NR4R11, X(CR7R8)C(O)R4, X(CR7R8)C(O)OR4, X(CR7R8)C(O)NR4R11, X(CR7R8)(CR9R10)C(O)R4, X(CR7R8)(CR9R10)C(O)OR4, X(CR7R8)(CR9R11)C(O)NR4R11, (CR7R8)NR4SO2R4, or C(═NOR4)R4;
- each R3 is independently selected from H, CN, halo, C(O)R4, CO2H, CO2R4, C(O)NR4R11, alkyl, optionally substituted alkoxy, SO2R4, (CR7R8)OR4, (CR7R8)NR4R11, (CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)NR4R11, (CR7R8)C(O)R4, (CR7R8)C(O)OR4, (CR7R8)C(O)NR4R11, X(CR7R8)C(O)R4, X(CR7R8)C(O)OR4, X(CR7R8)C(O)NR4R11, X(CR7R8)(CR9R10)C(O)R4, X(CR7R8)(CR9R10)C(O)OR4, X(CR7R8)(CR9R10)C(O)NR4R11, (CR7R8)NR4SO2R4, and C(═NOR4)R4;
- or R3 together with an adjacent R3 or with R2 form a ring;
- each R4 is independently selected from H and optionally substituted alkyl;
- each R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, optionally substituted alkyl, OH, CO2R4, NR4R11, and optionally substituted alkoxy;
- and
- R11 is H, optionally substituted alkyl, C(O)R4, C(O)OR4, C(O)NR4R4, or SO2R4;
- provided that
- a) if Y is a bond and m is 0, then R2 is selected from C(O)NR4R11, (CR7R8)OR4, (CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)NR4R11, (CR7R8)C(O)R4, (CR7R8)C(O)OR4, (CR7R8)C(O)NR4R11, X(CR7R8)C(O)R4, X(CR7R8)C(O)OR4, X(CR7R8)C(O)NR4R11, X(CR7R8)(CR9R10)C(O)R4, X(CR7R8)(CR9R10)C(O)OR4, X(CR7R8)(CR9R10)C(O)NR4R11, (CR7R8)NR4SO2R4, and C(═NOR4)R4;
- and
- R2 is not p-CH2OR4, p-CH2CH2OH, or p-CH2CH2CH2OH;
- and
- b) the compound is not selected from
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, 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 Ib, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof:
- wherein
- each R1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO2, SR4, S(O)R4, SO2R4, NR4R11, CO2H, or CO2R4;
- n is 0, 1, 2, 3, or 4;
- B is CO2R4;
- R2 is C(O)NR4R11, (CR7R8)OR4, (CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)NR4R11, (CR7R8)C(O)R4, (CR7R8)C(O)OR4, (CR7R8)C(O)NR4R11, X(CR7R8)C(O)R4, X(CR7R8)C(O)OR4, X(CR7R8)C(O)NR4R11, X(CR7R8)(CR9R10)C(O)R4, X(CR7R8)(CR9R10)C(O)OR4, X(CR7R8)(CR9R10)C(O)NR4R11, (CR7R8)NR4SO2R4, or C(═NOR4)R4;
- R3 is H;
- X is O or CR5R6;
- each R4 is independently selected from H and optionally substituted alkyl;
- each R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, optionally substituted alkyl, OH, NR4R11, and optionally substituted alkoxy;
- and
- R11 is H, optionally substituted alkyl, C(O)R4, C(O)OR4, C(O)NR4R4, or SO2R4;
- provided that if n is 0, then R2 is not p-CH2OR4, p-CH2CH2OH, or p-CH2CH2CH2OH.
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, 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 Ic, or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof:
- wherein
- each R1 is independently halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryloxy, CN, NO2, SR4, S(O)R4, SO2R4, NR4R11, CO2H, or CO2R4;
- n is 0, 1, 2, 3, or 4;
- m is 1, 2, 3, or 4;
- B is CO2R4;
- Y is —(CR5R6)—;
- C is aryl or heteroaryl;
- X is O or CR5R6;
- R2 is halo, C(O)R4, CO2R4, C(O)NR4R11, alkyl, optionally substituted alkoxy, haloalkyl, SO2R4, SO2NH2, SO3H, (CR7R8)OR4, (CR7R8)NR4R11, (CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)NR4R11, (CR7R8)C(O)R4, (CR7R8)C(O)OR4, (CR7R8)C(O)NR4R11, X(CR7R8)C(O)R4, X(CR7R8)C(O)OR4, X(CR7R8)C(O)NR4R11, X(CR7R8)(CR9R10)C(O)R4, X(CR7R8)(CR9R11)C(O)OR4, X(CR7R8)(CR9R10)C(O)NR4R11, (CR7R8)NR4SO2R4, or C(═NOR4)R4;
- each R3 is independently selected from H, CN, halo, C(O)R4, CO2H, CO2R4, C(O)NR4R11, alkyl, optionally substituted alkoxy, haloalkyl, SO2R4, (CR7R8)OR4, (CR7R8)NR4R11, (CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)OR4, X(CR7R8)(CR9R10)NR4R11, (CR7R8)C(O)R4, (CR7R8)C(O)OR4, (CR7R8)C(O)NR4R11, X(CR7R8)C(O)R4, X(CR7R8)C(O)OR4, X(CR7R8)C(O)NR4R11, X(CR7R8)(CR9R10)C(O)R4, X(CR7R8)(CR9R10)C(O)OR4, X(CR7R8)(CR9R10)C(O)NR4R11, (CR7R8)NR4SO2R4, and C(═NOR4)R4;
- or R3 together with an adjacent R3 or with R2 form a ring;
- each R4 is independently selected from H and optionally substituted alkyl;
- each R5, R6, R7, R8, R9, and R10 is independently selected from H, halo, optionally substituted alkyl, OH, CO2R4, NR4R11, and optionally substituted alkoxy;
- and
- R11 is H, optionally substituted alkyl, C(O)R4, C(O)OR4, C(O)NR4R4, or SO2R4;
- provided that the compound is not
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;
- or (b) inducing differentiation of mesenchymal stem cells into chondrocytes, the method comprising contacting mesenchymal stem cells with a sufficient amount of the compound, wherein the compound is selected from
- or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof.
A compound selected from
- or a pharmaceutically acceptable salt, solvate, polymorph, prodrug, ester, metabolite, N-oxide, stereoisomer, or isomer thereof.
Dependencies are inferred from the claim text.