Combination therapy for type II diabetes or syndrome X

A method for treatment of Syndrome X or type II diabetes in a mammal, the method comprising administering to a mammal in need thereof:

• a) a pharmaceutically effective amount of a biguanide agent;
• and
• b) a pharmaceutically effective amount of a PTPase inhibiting compound of formula I:
• 7
• wherein
• Ar is
• 8
• A is hydrogen, halogen, or OH;
• B and D are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR1R1a, —NR1COR1a, —NR1CO2R1a, cycloalkylamino of 3-8 carbon atoms, morpholino, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-3-yl, —COR1b or OR;
• R is hydrogen, alkyl of 1-6 carbon atoms, —COR1, —(CH2)nCO2R1, —CH(R1a)CO2R1, —SO2R1, —(CH2)mCH(OH)CO2R1, —(CH2)mCOCO2R1, —(CH2)mCH═CHCO2R1, or —(CH2)mO(CH2)oCO2R1;
• R1 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, or CH2CO2R1′;
• R1′ is hydrogen or alkyl of 1-6 carbon atoms
• E is S, SO, SO2, O, or NR1c;
• X is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, CN, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, aryloxy;
• arylalkoxy, nitro, amino, NR2R2a, NR2COR2a, cycloalkylamino of 3-8 carbon atoms, morpholino, alkylsulfanyl of 1-6 carbon atoms, arylsulfanyl, pyridylsulfanyl, 2-N,N-dimethylaminoethyl-sulfanyl, —OCH2CO2R2b or —COR2c;
• Y is hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, hydroxyaralkyl of 6-12 carbon atoms, —OR3, SR3, NR3R3a, —COR3b, morpholine or piperidine;
• R1a, R1c, R2, R2aR3, R3a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, or aryl;
• R1b is alkyl of 1-6 carbon atoms or aryl;
• R2b is hydrogen, alkyl of 1-6 carbon atoms;
• R2c and R3b are each, independently, alkyl of 1-6 carbon atoms, aryl, or aralkyl of 6-12 carbon atoms;
• C is hydrogen, halogen or OR4;
• R4 is hydrogen, alkyl of 1-6 carbon atoms, —CH(R5)W, —C(CH3)2CO2R6, 5-thiazolidine-2,4-dione, —CH(R7)(CH2)mCO2R6, —COR6, —PO3(R6)2, —SO2R6, —(CH2)pCH(OH)CO2R6, —(CH2)pCOCO2R6, —(CH2)pCH═CHCO2R6, or —(CH2)pO(CH2)qCO2R6;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, aralkyl of 6-12 carbon atoms, aryl, —CH2(1H-imidazol-4-yl), —CH2(3-1H-indolyl), —CH2CH2(1,3-dioxo-1,3-dihydro-isoindol-2-yl), —CH2CH2(1-oxo-1,3-dihydro-isoindol-2-yl), —CH2(3-pyridyl), —CH2CO2H, or —(CH2)nG;
• G is NR6aR7a, NR6aCOR7a,
• 9
• W is CO2R6, CONH2, CONHOH, CN, CONH(CH2)2CN, 5-tetrazole, —PO3(R6)2, —CH2OH, —CONR6bCHR7b, —CH2NR6bCHR7bCO2R6, —CH2OCHR7bCO2R6—CH2Br, or —CONR6bCHR7bCO2R6;
• R6, R6a, R7, R7a are each, independently, is hydrogen, alkyl of 1-6 carbon atoms, or aryl;
• R6b is hydrogen or —COR6c;
• R6c is alkyl of 1-6 carbon atoms or aryl;
• R7b is hydrogen, alkyl of 1-6 carbon atoms, or hydroxyalkyl of 1-6 carbon atoms;
• Z1 and Z2 are each, independently, hydrogen, halogen, CN, alkyl of 1-6 carbon atoms, aryl, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, nitro, amino, —NR1R1a, —NR1COR1a, cycloalkylamino of 3-8 carbon atoms, morpholino, or OR8, or Z1 and Z2 may be taken together as a diene unit having the formula —CH═CR9—CR10═CR11—;
• R8 is hydrogen, alkyl of 1-6 carbon atoms, or aryl;
• R9, R10, and R11 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl, halogen, hydroxy, or alkoxy of 1-6 carbon atoms
• m is 1 to 4
• n is 1 or 2;
• p is 1 to 4;
• q is 1 to 4;
• or a pharmaceutically acceptable salt thereof;
• and
• c) optionally, a pharmaceutically effective amount of a sulfonylurea agent, or a pharmaceutically acceptable salt form thereof.