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US 2001/0041715 A1Published application
Biphenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia
AssigneeAmerican Home Products Corporation
InventorsMichael S. Malamas, Richard E. McDevitt, Folake O. Adebayo
Life of this patent
Estimating the term…
Abstract
This invention provides substituted compounds of the general formulae: 1 wherein B and E are C or N; D, G and W are O, S, or N; or salt forms thereof, and methods and pharmaceutical compositions for their use in treating disorders related to insulin resistance or hyperglycemia.
Claims79
A compound of formula I having the structure
- 18
- wherein
- A is
- 19
- B is carbon or nitrogen;
- D is oxygen, sulfur, or nitrogen;
- E is carbon or nitrogen;
- Y is a bond, methylene, C(O), or CH(OH);
- R1 is alkyl containing 1 to 12 carbons, aryl of 6-12 carbon atoms, arylalkyl of 7-15 carbon atoms, halogen, carboxaldehyde, trifluoromethyl, alkoxy of 1-6 carbon atoms, 2,2-dimethyl-1,3-benzodioxole, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms which is mono-, di-, or tri-substituted with halogen, trifluormethyl, or alkoxy of 1-6 carbon atoms;
- Het is
- 20
- G is oxygen, sulfur or nitrogen;
- R2 and R2a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl;
- R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, trifluoromethyl, alkoxy of 1-6 carbon atoms, nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, —NR7(CH2)mCO2H, pyrrolidinone, a heterocycic ring containing 5 to ring 7 atom rings having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur, 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;
- R5 is hydrogen, alkyl of 1-6 carbon atoms, —CH(R8)R9, —C(CH2)nCO2R10, —C(CH3)2CO2R10, —CH(R8)(CH2)nCO2R10, —CH(R8)C6H4CO2R10
- R6 is alkylene of 1 to 3 carbon atoms
- R7 is hydrogen or alkyl of 1 to 6 carbon atoms,
- R8 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid, or Q-alkyl wherein the alkyl moiety contains 1-6 carbon atoms;
- Q is
- 21
- W is oxygen, sulfur, or nitrogen;
- R9 is —CO2R12, —CONHR12, tetrazole, —PO3R12;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 7-15 carbon atoms, or aralkyl of 7-15 carbon atoms;
- R12 is hydrogen, alkyl, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;
- m=1-3;
- n =1-6;
- with the proviso that when R1 is halogen, Y is a bond;
- or a pharmaceutically acceptable salt thereof.
25 more elements
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 compound of formula I having the structure
- 25
- wherein
- A is
- 26
- B is carbon or nitrogen;
- D is oxygen, sulfur, or nitrogen;
- E is carbon or nitrogen;
- Y is a bond, methylene, C(O), or CH(OH);
- R1 is alkyl containing 1 to 12 carbons, aryl of 6-12 carbon atoms, arylalkyl of 7-15 carbon atoms, halogen, carboxaldehyde, trifluoromethyl, alkoxy of 1-6 carbon atoms, 2,2-dimethyl-1,3-benzodioxole, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms which is mono-, di-, or tri-substituted with halogen, trifluormethyl, or alkoxy of 1-6 carbon atoms;
- Het is
- 27
- G is oxygen, sulfur or nitrogen;
- R2 and R2a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl;
- R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, trifluoromethyl, alkoxy of 1-6 carbon atoms, nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, —NR7(CH2)mCO2H, pyrrolidinone, a heterocycic ring containing 5 to ring 7 atom rings having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur, 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;
- R5 is hydrogen, alkyl of 1-6 carbon atoms, —CH(R8)R9, —C(CH2)nCO2R10, —C(CH3)2CO2R10, —CH(R8)(CH2)nCO2R10, —CH(R8)C6H4CO2R10
- R6 is alkylene of 1 to 3 carbon atoms
- R7 is hydrogen or alkyl of 1 to 6 carbon atoms,
- R8 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid, or Q-alkyl wherein the alkyl moiety contains 1-6 carbon atoms;
- Q is
- 28
- W is oxygen, sulfur, or nitrogen;
- R9 is —CO2R12, —CONHR12, tetrazole, —PO3R12;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 7-15 carbon atoms, or aralkyl of 7-15 carbon atoms;
- R12 is hydrogen, alkyl, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;
- m=1-3;
- n=1-6;
- with the proviso that when R1 is halogen, Y is a bond;
- or a pharmaceutically acceptable salt thereof.
25 more elements
A method of treating or inhibiting type II diabetes in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure
- 29
- wherein
- A is
- 30
- B is carbon or nitrogen;
- D is oxygen, sulfur, or nitrogen;
- E is carbon or nitrogen;
- Y is a bond, methylene, C(O), or CH(OH);
- R1 is alkyl containing 1 to 12 carbons, aryl of 6-12 carbon atoms, arylalkyl of 7-15 carbon atoms, halogen, carboxaldehyde, trifluoromethyl, alkoxy of 1-6 carbon atoms, 2,2-dimethyl- 1,3-benzodioxole, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms which is mono-, di-, or tri-substituted with halogen, trifluormethyl, or alkoxy of 1-6 carbon atoms;
- Het is
- 31
- G is oxygen, sulfur or nitrogen;
- R2 and R2a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl;
- R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, trifluoromethyl, alkoxy of 1-6 carbon atoms, nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, —NR7(CH2)mCO2H, pyrrolidinone, a heterocycic ring containing 5 to ring 7 atom rings having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur, 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;
- R5 is hydrogen, alkyl of 1-6 carbon atoms, —CH(R8)R9, —C(CH2)nCO2R10, —C(CH3)2CO2R10, —CH(R8)(CH2)nCO2R10, —CH(R8)C6H4CO2R10
- R6 is alkylene of 1 to 3 carbon atoms
- R7 is hydrogen or alkyl of 1 to 6 carbon atoms,
- R8 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid, or Q-alkyl wherein the alkyl moiety contains 1-6 carbon atoms;
- Q is
- 32
- W is oxygen, sulfur, or nitrogen;
- R9 is —CO2R12, —CONHR12, tetrazole, —PO3R12;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 7-15 carbon atoms, or aralkyl of 7-15 carbon atoms;
- R12 is hydrogen, alkyl, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;
- m=1-3;
- n=1-6;
- with the proviso that when R1 is halogen, Y is a bond;
- or a pharmaceutically acceptable salt thereof.
25 more elements
A method of modulating glucose levels in a mammal in need thereof which comprises administering to said mammal, a compound of formula I having the structure
- 33
- wherein
- A is
- 34
- B is carbon or nitrogen;
- D is oxygen, sulfur, or nitrogen;
- E is carbon or nitrogen;
- Y is a bond, methylene, C(O), or CH(OH);
- R1 is alkyl containing 1 to 12 carbons, aryl of 6-12 carbon atoms, arylalkyl of 7-15 carbon atoms, halogen, carboxaldehyde, trifluoromethyl, alkoxy of 1-6 carbon atoms, 2,2-dimethyl- 1,3-benzodioxole, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms which is mono-, di-, or tri-substituted with halogen, trifluormethyl, or alkoxy of 1-6 carbon atoms;
- Het is
- 35
- G is oxygen, sulfur or nitrogen;
- R2 and R2a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl;
- R3 and R4 are each;
- independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, trifluoromethyl, alkoxy of 1-6 carbon atoms, nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, —NR7(CH2)mCO2H, pyrrolidinone, a heterocycic ring containing 5 to ring 7 atom rings having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur, 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;
- R5 is hydrogen, alkyl of 1-6 carbon atoms, —CH(R8)R9, —C(CH2)nCO2R10, —C(CH3)2CO2R10, —CH(R8)(CH2)nCO2R10, —CH(R8)C6H4CO2R10
- R6 is alkylene of 1 to 3 carbon atoms
- R7 is hydrogen or alkyl of 1 to 6 carbon atoms,
- R8 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid, or Q-alkyl wherein the alkyl moiety contains 1-6 carbon atoms;
- Q is
- 36
- W is oxygen, sulfur, or nitrogen;
- R9 is —CO2R12, —CONHR12, tetrazole, —PO3R12;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 7-15 carbon atoms, or aralkyl of 7-15 carbon atoms;
- R12 is hydrogen, alkyl, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;
- m=1-3;
- n=1-6;
- with the proviso that when R1 is halogen, Y is a bond;
- or a pharmaceutically acceptable salt thereof.
26 more elements
A pharmaceutical composition which comprises a compound of formula I having the structure
- 37
- wherein
- A is
- 38
- B is carbon or nitrogen;
- D is oxygen, sulfur, or nitrogen;
- E is carbon or nitrogen;
- Y is a bond, methylene, C(O), or CH(OH);
- R1 is alkyl containing 1 to 12 carbons, aryl of 6-12 carbon atoms, arylalkyl of 7-15 carbon atoms, halogen, carboxaldehyde, trifluoromethyl, alkoxy of 1-6 carbon atoms, 2,2-dimethyl-1,3-benzodioxole, Het-alkyl wherein the alkyl moiety contains 1-6 carbon atoms, or aryl of 6-10 carbon atoms which is mono-, di-, or tri-substituted with halogen, trifluormethyl, or alkoxy of 1-6 carbon atoms;
- Het is
- 39
- G is oxygen, sulfur or nitrogen;
- R2 and R2a are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, halogen, trifluoromethyl;
- R3 and R4 are each, independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, trifluoromethyl, alkoxy of 1-6 carbon atoms, nitro, amino, carboalkoxy, carbamide, carbamate, urea, alkylsulfoamide, arylsulfoamide, cycloalkyl of 3-8 carbon atoms, —NR7(CH2)mCO2H, pyrrolidinone, a heterocycic ring containing 5 to ring 7 atom rings having 1 to 3 heteroatoms selected from oxygen, nitrogen, or sulfur, 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;
- R5 is hydrogen, alkyl of 1-6 carbon atoms, —CH(R8)R9, —C(CH2)nCO2R10, —C(CH3)2CO2R10, —CH(R8)(CH2)nCO2R10, —CH(R8)C6H4CO2R10
- R6 is alkylene of 1 to 3 carbon atoms
- R7 is hydrogen or alkyl of 1 to 6 carbon atoms,
- R8 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 6-12 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid, or Q-alkyl wherein the alkyl moiety contains 1-6 carbon atoms;
- Q is
- 40
- W is oxygen, sulfur, or nitrogen;
- R9 is —CO2R12, —CONHR12, tetrazole, —PO3R12;
- R10 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 7-15 carbon atoms, or aralkyl of 7-15 carbon atoms;
- R12 is hydrogen, alkyl, aryl of 6-12 carbon atoms, aralkyl of 7-15 carbon atoms;
- m=1-3;
- n=1-6;
- with the proviso that when R1 is halogen, Y is a bond;
- or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.
25 more elements
Dependencies are inferred from the claim text.