Tetrahydropyrimidone inhibitors of fatty acid binding protein and method

A compound of formula II

• enantiomers, diastereomers, or salts thereof wherein
• A is
• —R1,
• —(CR3R4)n—R1,
• —R5(CR3R4)p—R1,
• —(CR3R4)mR5(CR6R7)p—R1,
• —(CR3R4)n(CR6R7)p—R1,
• —S(O)R1,
• —S(O2)R1, or
• —NH(CR3R4)n—R1;
• R1 is substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkyl or cycloalkyl;
• B is
• —R2,
• —(CR3R4)n—R2,
• —R5(CR3R4)p—R2,
• —(CR3R4)mR5(CR6R7)p—R2,
• —(CR3R4)nR5(CR6R7)p—R2,
• —S(O)R2,
• —S(O2)R2, or
• —NH(CR3R4)n—R2;
• R2 is aryl, substituted aryl, cycloalkylalkyl, heteroaryl or substituted heteroaryl;
• R3 and R4 are the same or different and are independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, arylcarbonyl, aryl and heteroaryl, halo, hydroxy, alkoxy and aryloxy;
• R5 is a bond, O, NR8, S, SO, SO2, CO or CONH;
• R6 and R7 are the same or different and are independently H, alkyl, cycloalkyl, aryl, hydroxy, amino, halo, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, dialkylamino, arylamino, diarylamino, alkoxycarbonyl, alkylaminocarbonyl or alkylcarbonylamino;
• R8 is H, aryl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkyl or alkylcarbonyl;
• X* is —W, —(CR3R4)n—W, —O(CR3R4)n—W, —S(CR3R4)n—W, —NHC(═O)W, —CH═CHW, -(cycloalkylene)-W, or —N(R8)(CR3R4)n—W;
• Y is hydrogen, OH or alkenyl,
• or X* and Y taken together with the atom to which they are joined provide a group of the formula
• W is cyano, halogen, hydroxy, alkenyl, C(O)Cl, or C(O)H;
• n is an integer selected from 0 to 5;
• m is an integer selected from 1 to 5;
• and
• p is an integer selected from 0 to 4.

A method for treating insulin resistance, hyperglycemia, hyperinsulinemia, or elevated blood levels of free fatty acids or glycerol, obesity, hypertriglyceridemia, atherosclerosis, diabetic retinopathy, diabetic neuropathy or diabetic nephropathy which comprises administering to a mammalian species in need thereof an effective amount of of a compound of the following formula I

• enantiomers, diastereomers, or pharmaceutically acceptable salts thereof wherein
• A and B are the same or different and are independently
• —J,
• —(CR3RR4)n—J,
• —R5(CR3R4)p—J,
• —(CR3R4)mR5(CR6R7)p—J,
• —(CR3R4)n(CR6R7)p—J,
• —S(O)J where J is other than hydrogen,
• —S(O2)J where J is other than hydrogen, and
• —NH(CR3R4)n—J;
• J is independently R1 or R2;
• R1 and R2 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, cycloheteroalkyl and substituted cycloheteroalkyl;
• R3 and R4 are the same or different and are independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, arylcarbonyl, aryl and heteroaryl, halo, hydroxy, alkoxy and aryloxy;
• R5 is a bond, O, NR8, S, SO, SO2, CO or CONH;
• R6 and R7 are the same or different and are independently H, alkyl, cycloalkyl, aryl, hydroxy, amino, halo, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, dialkylamino, arylamino, diarylamino, alkoxycarbonyl, alkylaminocarbonyl or alkylcarbonylamino;
• R8 is H, aryl, arylcarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, alkyl or alkylcarbonyl;
• R9 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;
• R10 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;
• R11 is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aralkyl, substituted aralkyl, heteroaralkyl, substituted heteroaralkyl, cycloheteroalkyl and substituted cycloheteroalkyl;
• R12 and R13 are the same or different and are independently H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl;
• or R12 and R13 together with the nitrogen atom to which they are bonded together form an optionally substituted cycloheteroalkyl ring;
• X is selected from —Z, —(CR3R4)n—Z, —O—(CR3R4)p—Z, —S—(CR3R4)p—Z, —NHC(═O)Z, —CH═CHZ, -(cycloalkylene)-Z, or —N(R8)(CR3R4)n—Z;
• Y is H, alkyl, aryl, aralkyl, alkoxy, aryloxy, alkylthio, arylthio, hydroxy, —(CR3R4)n—CO2R9, —(CR3R4)n—CONR12R13, —NR3R4, aralkoxy, or heteroarylalkyl, provided that Y is other than hydroxy or NH2 when X is —O(CR3R4)p—Z, —S(CR3R4)p—Z, —NHC(═O)Z, or —N(R8)(CR3R4)n—Z;
• or X and Y, taken together with the atom to which they are joined, provide a group of the formula
• Z is CO2R9, SO3H, PO3R9R10, CONHOH, CONR12R13, (CR3R4)mOH, or tetrazole of the formula
• or its tautomer;
• n is an integer selected from 0 to 5;
• m is an integer selected from 1 to 5;
• and
• p is an integer selected from 0 to 4.