Dipeptidase-IV inhibitor sulfonyl urea derivates

A technology of compounds and compositions, applied in the field of dipeptidase-IV inhibitor sulfonylurea derivatives, capable of solving problems such as poor drug activity

Active Publication Date: 2009-04-29
BEIJING AOHE DRUG RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] However, gliclazide has severe persistent hypoglycemia and adverse reactions of liver and kidney dysfunction in clinical practice. At the same time, DPP-IV inhibitors have poor drug activity and cannot meet clinical needs. There is an urgent need to develop better anti-type II diabetes drugs to meet the clinical

Method used

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  • Dipeptidase-IV inhibitor sulfonyl urea derivates
  • Dipeptidase-IV inhibitor sulfonyl urea derivates
  • Dipeptidase-IV inhibitor sulfonyl urea derivates

Examples

Experimental program
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Effect test

Embodiment 1

[0152] Example 1 (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,5-difluorophenyl)methyl]-5-isopropylpyrazine preparation

[0153] Dissolve 9.2g (50mmol) (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine in 300ml tetrahydrofuran, then at -78°C for 30min Add 24ml (60mmol, 2.5N) of n-butyllithium / n-hexane solution dropwise, keep stirring for 30min, then dropwise add 8.9g (55mmol) of 2,5-difluorobenzyl chloride in 50ml of tetrahydrofuran cold solution, -78 Stir the reaction at ℃ for 5 hours, add 100ml of water at -78℃ to quench the reaction, concentrate the reaction solution, add ethyl acetate and 1N hydrochloric acid to the residue, separate the water layer, extract three times with ethyl acetate, combine the organic layers, wash with salt, and anhydrous Dry over magnesium sulfate, concentrate under reduced pressure, and purify on a silica gel column (the eluent is a mixture of ethyl acetate and cyclohexane) to obtain 10.8 g of the target compound as a solid, yield: 69.4%.

Embodiment 2

[0154] Example 2 Preparation of (R)-2-(tert-butoxycarbonyl)amino-3-(2,5-difluorophenyl)propionic acid methyl ester

[0155] 15.5g (50mmol) (2R,5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,5-difluorophenyl)methyl]-5-isopropyl Dissolve pyrazine in 100ml of acetonitrile, then add 100ml (1N) of hydrochloric acid dropwise, stir the reaction solution at room temperature for 24h, add methanol, concentrate to dryness, repeat this operation three times, and then repeat once with toluene to obtain a solid, which is used in 400ml After dichloromethane dissolves, slowly add 50g of triethylamine, then slowly add 24g (110mmol) (Boc) 2 O, the reaction solution was stirred at room temperature for 8 hours, the solid generated by the reaction was filtered off, the filtrate was diluted with dichloromethane, washed with 1N HCl solution and saturated brine respectively, dried over anhydrous magnesium sulfate, purified by a silica gel column, and the eluent was acetonitrile and petroleum The ether mixtur...

Embodiment 3

[0156] Example 3 Preparation of (R)-2-(tert-butoxycarbonyl)amino-3-(2,5-difluorophenyl)propionic acid

[0157] Add 200ml tetrahydrofuran to 9.5g (30mmol) of (R)-2-(tert-butoxycarbonyl)amino-3-(2,5-difluorophenyl)propionic acid methyl ester, cool in an ice bath, and then dropwise add 2.15g (90mmol) of lithium hydroxide in 200ml aqueous solution, the reaction solution was stirred at room temperature for 15h, concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated to obtain 6.9g Solid, yield: 76.2%.

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Abstract

The invention belongs to the technical field of medicine, and in particular relates to dipeptidyl peptidase IV inhibitor sulfonylurea derivatives of a general formula (I), pharmaceutically acceptable salts or isomers thereof, wherein R<1>, T<2>, R<3>, R<4>, R<5>, X and Y are as defined in the specification. The invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and application of the compounds to the preparation of drugs for the treatment and/or prevention of diabetes, non-insulin-dependent diabetes, hyperglycemia, and insulin resistance.

Description

1. Technical field [0001] The invention belongs to the field of medical technology, and in particular relates to dipeptidase-IV inhibitor sulfonylurea derivatives, pharmaceutically acceptable salts or isomers thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and The application of these compounds in the preparation of medicines for treating and / or preventing diabetes, non-insulin dependent diabetes, hyperglycemia and insulin resistance. 2. Background technology [0002] Diabetes is a systemic chronic metabolic disease caused by uncontrolled blood sugar levels higher than normal. Basically divided into four categories, including: type I (insulin-dependent), type II (non-insulin-dependent), other types and gestational diabetes. Type 1 and type 2 diabetes belong to primary diabetes, the two most common forms, caused by the interaction of genetic and environmental factors. The etiology of diabetes is very complex, but in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/4985A61P3/10A61P5/48
Inventor 黄振华赵红宇
Owner BEIJING AOHE DRUG RES INST
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