US 2002/0165398 A1 · Modulators of protein tyrosine phosphatases (PTPases)

Abstract

The present invention provides novel compounds, novel compositions, methods of their use, and methods of their manufacture, where such compounds are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPase's) such as PTP1B, CD45, SHP-1, SHP-2, PTPα, LAR and HePTP or the like. The compounds are useful in the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimers disease and schizophrenia, and infectious diseases.

A compound of Formula 1

123
wherein
A is together with the double bond in Formula 1 furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, furazanyl or 1,2,3-triazolyl;
R1 is hydrogen, COR5, OR6, CF3, nitro, cyano, CH2OH, SO3H, SO2NR7R8, PO(OH)2, CH2PO(OH)2, CHFPO(OH)2, CF2PO(OH)2, C(═NH)NH2, NR7R8 or selected from the following 5-membered heterocycles:
124
wherein R12, R13, and R14 are independently hydrogen, C1-C6alkyl, aryl, arylC1-C6alkyl and the alkyl and aryl groups are optionally substituted;
R2 is COR5, OR6, CF3, nitro, cyano, SO3H, SO2NR7R8, PO(OH)2, CH2PO(OH)2, CHFPO(OH)2, CF2PO(OH)2, C(═NH)NH2, NR7R8, or selected from the following 5-membered heterocycles:
125
R3, R16 and R17 are independently hydrogen, halo, nitro, cyano, trihalomethyl, C1-C6alkyl, aryl, arylC1-C6alkyl, hydroxy, oxo, carboxy, carboxyC1-C6alkyl, C1-C6alkyloxycarbonyl, aryloxycarbonyl, arylC1-C6alkyloxycarbonyl, C1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, aryloxy, arylC1-C6alkyloxy, arylC1-C,alkyloxyC1-C6alkyl, thio, C1-C6alkylthio, C1-C6alkylthioC1-C6alkyl, arylthio, arylC1-C6alkylthio, arylC1-C6alkylthioC1-C6alkyl, NR7R8, C1-C6alkylaminoC1-Calkyl, arylC1-C6alkylaminoC1-C6alkyl, di(arylC1-C6alkyl)aminoC1-C6alkyl, C1-C6alkylcarbonyl, C1-C6alkylcarbonyl-C1-C6alkyl, arylC1-C6alkylcarbonyl, arylC1-C6alkylcarbonylC1-C6alkyl, C1-Calkylcarboxy, C1-C6alkylcarboxyC1-C6-alkyl, arylcarboxy, arylcarboxyC1-C6alkyl, arylC1-C6alkylcarboxy, arylC1-C6alkylcarboxyC1-C6alkyl, C1-C6alkylcarbonylamino, C1-C6alkylcarbonylaminoC1-C6alkyl, -carbonylNR7C1-C6alkylCOR11, arylC1-C6alkylcarbonylamino, arylC1-C6alkylcarbonylaminoC1-C6alkyl, CONR7R8, or C1-C6alkylCONR7R8 wherein the alkyl and aryl groups are optionally substituted and R., is NR7R8;
or C1-C6alkylNR7R8;
or, when R16 and R17 are hydrogen, R3 is
A-B-C-D-C1-C6alkyl, wherein
A is C1-C8alkyl, aryl or arylC1-C6alkyl;
B is amino, thio, SO, SO2 or oxo;
C is C1-C8alkyl, amino;
D is a chemical bond, amino or C1-C8alkyl wherein the alkyl and aryl groups are optionally substituted;
or
126
wherein R12, R13, and R14 are independently hydrogen, C1-C6alkyl, aryl, arylC1-C6alkyl and the alkyl and aryl groups are optionally substituted;
R4 is hydrogen, hydroxy, C1-C6alkyl, aryl, arylC1-C6alkyl, NR7R8, C1-C6alkyloxy;
wherein the alkyl and aryl groups are optionally substituted;
R5 is hydroxy, C1-C6alkyl, aryl, arylC1-C6alkyl, C1-C6alkyloxy, C1-C6alkyl-oxyC1-C6alkyloxy, aryloxy, arylC1-C6alkyloxy, CF3, NR7R8;
wherein the alkyl and aryl groups are optionally substituted;
R6 is hydrogen, C1-C6alkyl, aryl, arylC1-C6alkyl;
wherein the alkyl and aryl groups are optionally substituted;
R7 and R8 are independently selected from hydrogen, C1-C6alkyl, adamantyl, aryl, arylC1-C6alkyl, C1-C6alkylcarbonyl, arylcarbonyl, arylC1-C6alkylcarbonyl, C1-C6alkylcarboxy or arylC1-C6alkylcarboxy wherein the alkyl and aryl groups are optionally substituted;
or
R7 and R8 are taken together with the nitrogen to which they are attached forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system containing 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one C1-C6alkyl, aryl, arylC1-C6alkyl, hydroxy, oxo, C1-C6alkyloxy, arylC1-C6alkyloxy, C1-C6alkyloxyC1-C6alkyl, NR9R10 or C1-C6alkylaminoC1-C6alkyl, wherein R9 and R10 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;
or
R7 and R8 are independently a saturated or partial saturated cyclic 5, 6 or 7 membered amine, imide or lactam;
or a salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.

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Modulators of protein tyrosine phosphatases (PTPases)

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Modulators of protein tyrosine phosphatases (PTPases)

Life of this patent

Abstract

Claims37