Antidiabetic agents

Abstract

A compound of the formula wherein R1 is: R5 is: and n, m, Z, R8, R9, R10 and R11 are as defined herein, useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly, myocardial ischemia.

Description

BACKGROUND OF THE INVENTION The present invention relates to substituted 1H-(indole-2-carboxamides and 6H-thieno[2,3-b]pyrrole-5-carboxamides which are antidiabetic agents and as such are useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia. This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidinediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satis...

Examples

preparation 1

Methyl 2,3-dihydroxy benzoate

A mixture of 92.472 g (0.6 mol) of 2,3-dihydroxybenzoic acid (FW 154.12; Aldrich cat.# 12,620-9; RSO # 9449), 100 mL of anhydrous methanol and 3 mL of concentrated sulfuric acid was heated to reflux for 36 hrs. After cooling down, reaction mixture was concentrated down to approximately ⅓ of its volume and poured on ice. A precipitate that formed was washed thoroughly with cold water, filtered off and dried in the desiccator over calcium sulfate. Yield 98.4 g of off-white solid (98%). This was used without further purification.

LC MS: AP+ 169, AP− 167.

preparation 2

3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester

A flame dried 1 L-flask was charged with 82.7 grams (0.6 mol) of finely ground and flame dried potassium carbonate and 200 mL of absolute dimethylformamide and kept under-nitrogen gas. This reaction mixture was then stirred and warmed up to 40° C. A 47.23 g (29.7 mL, 0.3 mol) of 1-bromo-3-chloropropane was then added to the reaction flask rapidly followed by 50.445 g (0.3 mol) of methyl 2,3-dihydroxy benzoate (C-2). The reaction was then heated to 100° C. (110° C. was the temp. of an oil bath) under reflux condenser for 6 hrs. After cooling, the reaction was filtered to remove all the solids, solids washed with 50 mL of, DMF and filtrate concentrated on the rotary evaporator. The residue was then partitioned between water and ethyl acetate. The organic layer was then washed with 200 mL of 1N NaOH to remove any starting material, followed by 5% HCl, 5% NaHCO3, water and brine. Dried with magnesium sulfate. Filtered...

preparation 3

8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (C-4) and 9- Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (C-5)

A 17.15 g (0.0825 mol) of (3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester; C-3) was dissolved in a mixture of 65 mL of glacial acetic acid and 65 mL of acetic anhydride. The reaction mixture was heated to 45° C. and treated with a solution of 12 mL of 90% HNO3 (fuming) inl2 mL of glacial acetic acid dropwise. The reaction was then heated to 45-50° C. for 4 hours under reflux condenser. When cooled down, the reaction mixture was poured on a mix of ice and water and the yellow precipitate collected on a filter. Washed with water and dried on air. Crude 17.6 grams (this product was a mixture of the meta- (about 30%). and paranitration (about 60%) products. This was used without further purification. LC MS: AP− 253 (for the mixture)

BACKGROUND OF THE INVENTION The present invention relates to substituted 1H-(indole-2-carboxamides and 6H-thieno[2,3-b]pyrrole-5-carboxamides which are antidiabetic agents and as such are useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia. This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidinediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satis...

Examples

preparation 1

Methyl 2,3-dihydroxy benzoate

A mixture of 92.472 g (0.6 mol) of 2,3-dihydroxybenzoic acid (FW 154.12; Aldrich cat.# 12,620-9; RSO # 9449), 100 mL of anhydrous methanol and 3 mL of concentrated sulfuric acid was heated to reflux for 36 hrs. After cooling down, reaction mixture was concentrated down to approximately ⅓ of its volume and poured on ice. A precipitate that formed was washed thoroughly with cold water, filtered off and dried in the desiccator over calcium sulfate. Yield 98.4 g of off-white solid (98%). This was used without further purification.

LC MS: AP+ 169, AP− 167.

preparation 2

3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester

A flame dried 1 L-flask was charged with 82.7 grams (0.6 mol) of finely ground and flame dried potassium carbonate and 200 mL of absolute dimethylformamide and kept under-nitrogen gas. This reaction mixture was then stirred and warmed up to 40° C. A 47.23 g (29.7 mL, 0.3 mol) of 1-bromo-3-chloropropane was then added to the reaction flask rapidly followed by 50.445 g (0.3 mol) of methyl 2,3-dihydroxy benzoate (C-2). The reaction was then heated to 100° C. (110° C. was the temp. of an oil bath) under reflux condenser for 6 hrs. After cooling, the reaction was filtered to remove all the solids, solids washed with 50 mL of, DMF and filtrate concentrated on the rotary evaporator. The residue was then partitioned between water and ethyl acetate. The organic layer was then washed with 200 mL of 1N NaOH to remove any starting material, followed by 5% HCl, 5% NaHCO3, water and brine. Dried with magnesium sulfate. Filtered...

preparation 3

8-Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (C-4) and 9- Nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (C-5)

A 17.15 g (0.0825 mol) of (3,4-Dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester; C-3) was dissolved in a mixture of 65 mL of glacial acetic acid and 65 mL of acetic anhydride. The reaction mixture was heated to 45° C. and treated with a solution of 12 mL of 90% HNO3 (fuming) inl2 mL of glacial acetic acid dropwise. The reaction was then heated to 45-50° C. for 4 hours under reflux condenser. When cooled down, the reaction mixture was poured on a mix of ice and water and the yellow precipitate collected on a filter. Washed with water and dried on air. Crude 17.6 grams (this product was a mixture of the meta- (about 30%). and paranitration (about 60%) products. This was used without further purification. LC MS: AP− 253 (for the mixture)

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