Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia

A method of treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof which comprises administering to said mammal, a therapeutically effective amount of a compound of formula I having the structure

• wherein
• A is
• Q is
• B is nitrogen;
• D is oxygen, sulfur, or nitrogen;
• E is carbon or nitrogen;
• X is carbon, nitrogen, oxygen, or sulfur;
• Y is a bond, methylene, C(O), or CH(OH);
• Z is CH═CH, nitrogen, oxygen, or sulfur;
• the dashed line of Q represents an optional double bond;
• R1 is alkyl of 1 to 12 carbons, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms;
• Het is
• R7 is alkylene of 1 to 3 carbon atoms,
• G is oxygen, sulfur or nitrogen;
• R2 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, or trifluoromethyl;
• R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms, nitro, alkylsulfamide;
• arylsulfamide, cycloalkyl of 3-8 carbon atoms or a heterocyclic ring containing 5 to 7 ring atoms having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or aralkyl of 7-15 carbon atoms;
• R6 is hydrogen, —OR5, or —OCOR5;
• with the proviso that when R1 is halogen,
• Y is a bond,
• or a pharmaceutically acceptable salt thereof.

A method of treating type II diabetes in a mammal in need thereof which comprises administering to said mammal, a therapeutically effective amount of a compound of formula I having the structure

• wherein
• A is
• Q is
• B is nitrogen;
• D is oxygen, sulfur, or nitrogen;
• E is carbon or nitrogen;
• X is carbon, nitrogen, oxygen, or sulfur;
• Y is a bond, methylene, C(O), or CH(OH);
• Z is CH═CH, nitrogen, oxygen, or sulfur;
• the dashed line of Q represents an optional double bond;
• R1 is alkyl of 1 to 12 carbons, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms;
• Het is
• R7 is alkylene of 1 to 3 carbon atoms,
• G is oxygen, sulfur or nitrogen;
• R2 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, or trifluoromethyl;
• R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms, nitro, alkylsulfamide;
• arylsulfamide, cycloalkyl of 3-8 carbon atoms or a heterocyclic ring containing 5 to 7 ring atoms having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or aralkyl of 7-15 carbon atoms;
• R6 is hydrogen, —OR5, or —OCOR5;
• with the proviso that when R1 is halogen,
• Y is a bond,
• or a pharmaceutically acceptable salt thereof.

A method of modulating glucose levels in a mammal in need thereof which comprises administering to said mammal, a therapeutically effective amount of a compound of formula I having the structure

• wherein
• A is
• Q is
• B is nitrogen;
• D is oxygen, sulfur, or nitrogen;
• E is carbon or nitrogen;
• X is carbon, nitrogen, oxygen, or sulfur;
• Y is a bond, methylene, C(O), or CH(OH);
• Z is CH═CH, nitrogen, oxygen, or sulfur;
• the dashed line of Q represents an optional double bond;
• R1 is alkyl of 1 to 12 carbons, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms;
• Het is
• R7 is alkylene of 1 to 3 carbon atoms,
• G is oxygen, sulfur or nitrogen;
• R2 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, or trifluoromethyl;
• R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms, nitro, alkylsulfamide;
• arylsulfamide, cycloalkyl of 3-8 carbon atoms or a heterocyclic ring containing 5 to 7 ring atoms having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or aralkyl of 7-15 carbon atoms;
• R6 is hydrogen, —OR5, or —OCOR5;
• with the proviso that when R1 is halogen,
• Y is a bond,
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition which comprises a compound of formula I having the structure

• wherein
• A is
• Q is
• B is nitrogen;
• D is oxygen, sulfur, or nitrogen;
• E is carbon or nitrogen;
• X is carbon, nitrogen, oxygen, or sulfur;
• Y is a bond, methylene, C(O), or CH(OH);
• Z is CH═CH, nitrogen, oxygen, or sulfur;
• the dashed line of Q represents an optional double bond;
• R1 is alkyl of 1 to 12 carbons, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms;
• Het is
• R7 is alkylene of 1 to 3 carbon atoms,
• G is oxygen, sulfur or nitrogen;
• R2 is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, or trifluoromethyl;
• R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl, alkoxy of 1-6 carbon atoms, aryl of 6-10 carbon atoms mono-, di-, or tri-substituted with trifluoromethyl, alkyl of 1-6 carbon atoms or, alkoxy of 1-6 carbon atoms, nitro, alkylsulfamide;
• arylsulfamide, cycloalkyl of 3-8 carbon atoms or a heterocyclic ring containing 5 to 7 ring atoms having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur;
• R5 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or aralkyl of 7-15 carbon atoms;
• R6 is hydrogen, —OR5, or —OCOR5;
• with the proviso that when R1 is halogen,
• Y is a bond,
• or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.