Patent EA-002365-B1 (EA)
Title: Combination of an aldose reductase inhibitor and a glycogen phosphorylase inhibitor
Inventor: MYLARI BANAVARA LAKSHMAN
IPC: A61K31/502
Filed: 1998-11-02
Abstract: 1. A pharmaceutical composition comprising a therapeutically effective amount of: a. an aldose reductase inhibitor; b. a glycogen phosphorylase inhibitor; and c. a pharmaceutical carrier. 2. A pharmaceutical composition for achieving an insulin sensitizing effect in a mammal comprising a. an amount of a first compound, said first compound being an aldose reductase inhibitor; and b. an amount of a second compound, said second compound being a glycogen phosphorylase inhibitor c. a pharmaceutically acceptable diluent or carrier wherein the amount of the first compound alone and the amount of the second compound alone is insufficient to achieve the insulin sensitizing effect and wherein the combine effect of the amounts of the first and second compound is greater than the sum of the insulin sensitizing effects achievable with the individual amounts of the first and second compound. 3. A pharmaceutical composition as recited in claim 1 or 2 wherein the aldose reductase inhibitor is 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5trifluoromethyl)-2-benzothiazolyl]methyl]-or a pharmaceutically acceptable salt thereof. 4. A pharmaceutical composition as recited in any of claims 1 to 3 wherein the glycogen phosphorylase is 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl- (2R)-hydroxy-3-( (3S)-hydroxypyrrolidin-1-yl)-3-oxopropyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-3-( (3S, 4S)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)- ((R)-hydroxy-dimethylcarbamoyl-methyl)-2-phenyl-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)- ( (R)-hydroxy-methoxy-methyl-carbamoyl)-methyl)-2-phenyl-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)- ((R)-hydroxy-[(2-hydroxy-ethyl)-methylcarbamoyl]-methyl)-2-phenyl-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2-(3-hydroxyimino-pyrrolidin-1-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]amide; 5-chloro-1H-indole-2-carboxylic acid [2-((3S,4S- dihydroxy-pyrrolidin-1-yl)-2-oxoethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-3-( (cis)-dihydroxypyrrolidin-1-yl)- (2R)-hydroxy-3-oxopropyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2- (cis-3, 4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)- (4-fluoro-benzyl)-2- (4-hydroxy-piperidin-1yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2- ( (3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [2-oxo-2-( (1RS)-oxo-thiazolidin-3-yl)-ethyl]amide; or 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide. 5. A pharmaceutical composition as recited in any of claims 1 to 4 wherein the amount of aldose reductase inhibitor is about 0.1 mg/kg about 20 mg/kg. 6. A pharmaceutical composition as recited in any of claims 1 to 5 wherein the amount of glycogen phosphorylase inhibitor is about 0.1 mg/kg about 15 mg/kg. 7. A method for treating a mammal having an insulin resistant condition comprising administering to said mammal a therapeutically effective amount of  a. an aldose reductase inhibitor, and b. a glycogen phosphorylase inhibitor. 8. A method as recited in claim 7 wherein the insulin resistant condition is diabetes, hyperinsulinemia, impaire glucose tolerance, hyperglycemia and/or hyperlipidema following meals, type 11 diabetes, altered body composition, reduction of lean body mass, obesity, hypertension, dyslipidemia, atherosclerosis, tissue ischemia, cardiovascular diseases, obesity, syndrome X, pregnancy, conditions of infection, uremia, hyperadrogenism, hypercortisolemia or other conditions of adrenocortical hormone excess, acromegly, growth hormone excess or polycystic ovarian disease. 9. A method for achieving an insulin sensitizing effect in a mammal which has an insulin resistant condition comprising administering to said mammal a. an amount of a first compound, said first compound being an aldose reductase inhibitor; and b. an amount of a second compound, said second compound being glycogen phosphorylase inhibitor, wherein the amount of the first compound alone and the amount of the second compound alone is insufficient to achieve said insulin sensitizing effect and wherein the combine effect of the amounts of the first and second compound is greater than the sum of the insulin sensitizing effects achievable with the individual amounts of the first and second compound. 10. A method of reducing tissue damage resulting from ischemia comprising administering to a mammal in need of such treatment a therapeutically effective amount of a. an aldose reductase inhibitor; and b. a glycogen phosphorylase inhibitor. 11. A method as recited in claim 10 wherein the tissue is cardia, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature or intestinal tissue. 12. A method as recited in any of claims 7 to 11 wherein the the aldose reductase inhibitor is 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[ [5-trifluoromethyl)-2benzothiazolyl] methyl]- or a pharmaceutically acceptable salt thereof. 13. A method as recited in any of claims 7 to 12 wherein the glycogen phosphorylase inhibitor is 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl- (2R)-hydroxy-3-( (3S)- hydroxypyrrolidin-1-yl)-3-oxopropyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl -3-((3S, 4S)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-((R)-hydroxy-dimethylcarbamoyl-methyl)-2-phenyl-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-((R)-hydroxy-methoxy-methyl-carbamoyl)- methyl)-2-phenyl-ethyl)-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)- ((R)- hydroxy-[(2-hydroxy-ethyl)-methylcarbamoyl]-methyl)-2-phenyl-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2- (3-hydroxyimino-pyrrolidin-1-yl)-2- oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [2-((3S,4S)-dihydroxy-pyrrolidin-1-yl)-2-oxoethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2-(cis-3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [2-(1,1-dioxo-thiazolidin-3-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylicacid [(1S)-benzy1-3-((cis)-dihydroxypyrrolidin-1-yl)-(2R)-hydroxy-3-oxopropyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzy1-3-((cis-3,4- dihydroxypyrrolidin-1-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [(1S)-(4-fluoro-benzyl)-2-(4-hydroxy-piperidin-1yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2-( (3RS)-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-amide; 5-chloro-1H-indole-2-carboxylic acid [2-oxo-2-( (1RS)-oxo-thiazolidin-3-yl)-ethyl]-amide; or 5-chloro-1H-indole-2-carboxylic acid [ (1S)-benzyl-2-(3-hydroxy-azetidin-1-yl)-2-oxo-ethyl]-amide. 14. A method as recited in any of claims 7 to 13 wherein the amount of aldose reductase inhibitor is about 0.1 mg/kg to about 20 mg/kg and the amount of glycogen phosphorylase inhibitor is about 0.1 mg/kg to about 15 mg/kg. 15. A method as recited in any of claims 7 to 14 wherein the mammal is a female or male human.