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Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phoshorylase

A compound, trifluoromethyl technology, applied in the field of pyrrolopyridine-2-carboxamide, can solve the problem of difficult treatment of non-insulin-dependent type II diabetes

Inactive Publication Date: 2009-04-22
PROSIDION LIMITED
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Insulin-dependent type 1 diabetes and non-insulin-dependent type 2 diabetes are difficult to treat despite clinically acceptable treatment options including diet, exercise, hypoglycemic drugs, and the availability of insulin

Method used

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  • Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phoshorylase
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  • Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phoshorylase

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specific Embodiment approach

[0131] According to the present invention, compounds of general formula (I) can be prepared as outlined in Scheme 1 below, wherein R1 , R 1’ , R 2 , R 3 、X 1 、X 2 、X 3 、X 4 , Y and Z are as above-mentioned definition to general formula (I):

[0132] Route 1:

[0133]

[0134] According to Scheme 1, compounds of general formula (I) can be prepared by reacting an appropriate pyrrolopyridine-2-carboxylic acid of general formula (II) or a protected or activated derivative thereof with an appropriate amine of general formula (III). Coupled to prepare. Compounds of general formula (II) can be obtained by the synthesis described in Scheme 3 and Scheme 5 below. Compounds of general formula (III) are generally commercially available or may be obtained by the syntheses described in schemes 8 and 9 .

[0135] Typically, a compound of general formula (II) or a protected or activated derivative thereof is combined with a compound of general formula (III) in the presence of a su...

Embodiment 182

[0417] Prepared according to Example 182 from tert-butyl 4-[methyl(2-nitrobenzenesulfonyl)amino]piperidine-1-carboxylate (Preparation 74). δ H (d 6 -DMSO): 8.44 (2H, m), 8.13 (2H, m), 4.20-7.07 (1H, m), 3.29-3.17 (2H, m), 3.03-2.90 (2H, m), 2.77 (3H, s ), 2.00-1.84 (2H, m), 1.51-1.43 (2H, m).

[0418] Preparation 76: 5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (1-(S)-(4-fluorobenzyl)-2-{4-[methyl(2-nitrate phenylsulfonyl)amino]piperidin-1-yl}-2-oxoethyl)amide

[0419]

Embodiment 231

[0420] From 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propanoic acid (Example 231) Example 230) and N-methyl-2-nitro-N-piperidin-4-ylbenzenesulfonamide hydrochloride (Preparation 75). m / z(ES + )=643.36[M+H] + .

[0421] Preparation 77: Thiomorpholine 1,1-dioxide

[0422]

[0423] To a solution of thiomorpholine (1.0 g, 9.69 mmol) in acetic acid (11.5 mL) cooled to 0 °C (ice bath) was added aqueous hydrogen peroxide (30% w / v, 4 mL) and the reaction was heated to 100 ℃ 16h. The mixture was cooled and the solvent was removed in vacuo, then the residue was triturated with methanol to give a white precipitate. The solid was filtered and washed with methanol to afford the title compound as an off-white powder. m / z(ES + )=136.06[M+H] + .

[0424] Preparation 78: Methyl piperidine-4-carboxylate hydrochloride

[0425]

[0426] To a cooled solution of anhydrous methanol (100 mL) was added acetyl chloride (7.1 mL, 0.1 mol) and the solu...

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Abstract

Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.

Description

technical field [0001] The present invention relates to pyrrolopyridine-2-carboxamides. In particular, the present invention relates to pyrrolopyridine-2-carboxamides as inhibitors of glycogen phosphorylase. Background technique [0002] Insulin-dependent type 1 diabetes and non-insulin-dependent type 2 diabetes are difficult to treat despite clinically acceptable treatment options including diet, exercise, hypoglycemic drugs, and the availability of insulin. Treatment is patient-dependent, so there is still a need for new hypoglycemic agents, especially those that are better tolerated and have fewer side effects. [0003] The liver and certain other organs produce glucose by breaking down glycogen or by synthesizing glucose from small molecule precursors—thus raising blood sugar levels. The breakdown of glycogen is catalyzed by glycogen phosphorylase. Thus, inhibition of glycogen phosphorylase ("GP") can reduce elevated blood glucose levels in diabetic patients. [0004...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D471/00C07D519/00A61K31/437A61P9/10
Inventor 斯图尔特·爱德华·布拉德利托马斯·马丁·克鲁勒彼得·约翰·默里马丁·詹姆斯·普罗克特罗伯特·约翰·罗利科林·彼得·萨姆布罗克史密斯杰勒德·休·托马斯卡伦·莱斯莉·斯科菲尔德
Owner PROSIDION LIMITED
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