US 7,019,026 B1 · Modulators of Protein Tyrosine Phosphatases (PTPases)

Abstract

Disclosed are novel compounds, novel compositions, methods of their use, and methods of their manufacture, where such compounds of Formula 1 are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPases) such as PTP1B, CD45, SHP-1, SHP-2, PTPα, LAR and HePTP or the like, wherein n, m, X, Y, R1, R2, R3, R4, R5 and R6 are defined more fully in the description. The compounds are useful in the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, and other diseases.

A compound of Formula I

wherein
n is 1 or 2;
m is 1 or 2,
Y is O, SO or SO2
R1 is COOH, COOC1–C6alkyl, COOarylC1–C6alkyl, COOC1–C6alkylcarbonyloxyC1–C6alkyl, COOC1–C6alkylcarbonyloxyarylC1–C6alkyl;
R2 is hydrogen;
R3 is hydrogen, C1–C6alkyl, arylC1–C6alkyl, C1–C6alkylcarbonyloxyC1–C6alkyl or C1–C6alkylcarbonyloxyarylC1–C6alkyl;
R4 is hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, provided R4 does not represent a heterocyclic ring;
wherein the alkyl and aryl groups are optionally substituted as defined below;
R5, is hydrogen, trihalomethyl, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkyloxycarbonyl, aryloxycarbonyl, arylC1–C6alkyloxycarbonyl, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, aryloxyC1–C6alkyl, arylC1–C6alkyloxyC1–C6-alkyl, NR7R8, C1–C6alkylaminoC1–C6alkyl, arylC1–C6alkylaminoC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkylcarbonylC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylcarbonylC1–C6alkyl, C1–C6alkylcarboxyC1–C6alkyl, arylcarboxyC1–C6alkyl, arylC1–C6alkylcarboxyC1–C6alkyl, C1–C6alkylcarbonylamino, C1–C6alkylcarbonyl-aminoC1–C6alkyl, -carbonylNR8C1–C6alkylCOR10, wherein R10 is NR7R8 or C1–C6alkylNR7R8, arylC1–C6alkylcarbonylamino, arylC1–C6alkylcarbonylaminoC1–C6alkyl, CONR7R8, C1–C6alkylCONR7R8, or arylaminocarbonylaminoC1–C6alkyl, provided R6 does not represent a heterocyclic ring;
wherein the alkyl and aryl groups are optionally substituted as defined below;
R6 is hydrogen, trihalomethyl, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkyloxycarbonyl, aryloxycarbonyl, arylC1–C6alkyloxycarbonyl, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, aryloxyC1–C6alkyl, arylC1–C6alkyloxyC1–C6-alkyl, NR7R8, C1–C6alkylaminoC1–C6alkyl, arylC1–C6alkylaminoC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkylcarbonylC1–C6alkyl, arylC1–C6alkylcarbonyl, arylC1–C6alkylcarbonylC1–C6alkyl, C1–C6alkylcarboxyC1–C6alkyl, arylcarboxyC1–C6alkyl, arylC1–C6alkylcarboxyC1–C6alkyl, C1–C6alkylcarbonylamino, -carbonylNR8C1–C6alkylCOR10, wherein R10 is NR7R8, or C1–C6alkylNR7R8, arylC1–C6alkylcarbonylamino, arylC1–C6alkylcarbonylaminoC1–C6alkyl, CONR7R8, or arylaminocarbonylaminoC1–C6alkyl;
wherein the alkyl and aryl groups are optionally substituted as defined below;
R7 and R9 are are independently a saturated or partially saturated cyclic 5, 6 or 7 membered amine, imide or lactam or are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy wherein the alkyl and aryl groups are optionally substituted as defined below;
or
R7 and R8 together with the nitrogen to which they are attached form a saturated, partially saturated or aromatic monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulphur, wherein the ring system is optionally substituted with at least one C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, C1–C6alkyloxy, C1–C6-alkyloxyC1–C6alkyl, C1–C6alkyl-aminoC1–C6alkyl or NR11R12, wherein R11 and R12 are independently selected from hydrogen, C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkylcarbonyl, arylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy or arylC1–C6alkylcarboxy;
wherein the alkyl and aryl groups are optionally substituted as defined below;
wherein the optionally substituted alkyl groups are substituted with one or more groups independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, hydroxy, oxo, COOR3, C1–C6alkyl, C1–C6alkyloxy, aryloxy, arylC1–C6alkyloxy, C1–C6alkylamino arylamino, arylC1–C6alkylamino, di(arylC1–C6alkyl)amino, C1–C6alkylcarbonyl, arylC1–C6alkylcarbonyl, C1–C6alkylcarboxy, arylcarboxy, arylC1–C6alkylcarbonyl, C1–C6alkylcarbonylamino, —C1–C6alkylaminoCOR13, wherein R13 is C1–C6alkyl, aryl, arylC1–C6alkyl, C1–C6alkyloxy, aryloxy, arylC1–C6alkyloxy;
arylC1–C6alkylcarbonylamino tetrahydrofuranyl, morpholinyl piperazinyl, or a saturated or partially saturated cyclic 5, 6 or 7 membered amine, imide or lactam, and
wherein the optionally substituted aryl groups are substituted with a group selected from halo, nitro, cyano, trihalomethyl, C1–C6alkyl, aryl, arylC1–C6alkyl, hydroxy, C1–C6alkyloxy, C1–C6alkyloxyC1–C6alkyl, aryloxy, arylC1–C6alkyloxy, arylC1–C6alkyloxyC1–C6alkyl, C1–C6alkylamino, C1–C6alkylaminoC1–C6alkyl, arylamino, arylC1–C6alkylamino, arylC1–C6alkylaminoC1–C6alkyl, di(arylC1–C6alkyl)aminoC1–C6alkyl, C1–C6alkylamino, arylC1–C6alkylcarbonylC1–C6alkyl, arylC1–C6alkylcarbonyl, arylC1–C6alkylcarbonylC1–C6alkyl, C1–C6alkylcarboxy, C1–C6alkylcarboxyC1–C6alkyl, arylC1–C6alkylcarboxy, arylC1–C6alkylcarboxyC1–C6alkyl, C1–C6alkylcarbonylamino, C1–C6alkylcarbonylaminoC1–C6alkyl, arylC1–C6alkylcarbonylamino, or arylC1–C6-alkylcarbonylaminoC1–C6alkyl;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, a racemic mixture, or any tautomeric form, or prodrug thereof.

18 more elements

Modulators of Protein Tyrosine Phosphatases (PTPases)

Life of this patent

Modulators of Protein Tyrosine Phosphatases (PTPases)

Life of this patent

Abstract

Claims74