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DPP-IV inhibitor with sulfonamide formamide piperazine structure

A technology based on alkyl and cyano groups, which can be used in medical preparations containing active ingredients, organic chemistry, organic active ingredients, etc., and can solve problems such as limited drug varieties

Active Publication Date: 2009-07-22
XUANZHU BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the variety of drugs is limited and cannot meet the clinical needs. There is an urgent need to develop more DPP-IV inhibitor drugs to meet the clinical needs.

Method used

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  • DPP-IV inhibitor with sulfonamide formamide piperazine structure
  • DPP-IV inhibitor with sulfonamide formamide piperazine structure
  • DPP-IV inhibitor with sulfonamide formamide piperazine structure

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0126] Example 1 (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,4,5-trifluorophenyl)methyl]-5-isopropylpyridine Preparation of oxazine

[0127] 9.2g (50mmol) (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine was dissolved in 300mL tetrahydrofuran, and then heated at -78°C within 30min Add 24mL (60mmol, 2.5N) of n-butyllithium / n-hexane solution dropwise, and keep stirring for 30min. Then add dropwise 9.9g (55mmol) of 2,4,5-trifluorobenzyl chloride in 50mL of tetrahydrofuran cold solution, - The reaction was stirred at 78°C for 5h. Add 100 mL of water at -78°C to quench the reaction, concentrate the reaction solution, add ethyl acetate and 1N hydrochloric acid to the residue, separate the aqueous layer, extract three times with ethyl acetate, combine the organic layers, wash with salt, dry over anhydrous magnesium sulfate, reduce Concentrate under reduced pressure and purify on a silica gel column (the eluent is a mixture of ethyl acetate and cyclohexane) to obtain 12 g of th...

Embodiment 2

[0128] Example 2 Preparation of (R)-N-2-tert-butoxycarbonyl-3-(2,4,5-trifluorophenyl)alanine methyl ester

[0129] 16.4g (50mmol) of (2R,5S)-2,5-dihydro-3,6-dimethoxy-2-[(2,4,5-trifluorophenyl)methyl]-5-iso Propylpyrazine was dissolved in 100mL of acetonitrile, then 100mL of 1N hydrochloric acid was added dropwise, and the reaction solution was stirred at room temperature for 24h. Methanol was added, concentrated to dryness, this operation was repeated three times, and then repeated once with toluene to obtain a solid. After the solid was dissolved in 400mL of dichloromethane, 50g of triethylamine was slowly added, and then 24g (110mmol) (Boc) was slowly added dropwise. 2 O. The reaction solution was stirred at room temperature for 8 h, and 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 on a silica gel column, ...

Embodiment 3

[0130] Example 3 Preparation of (R)-N-2-tert-butoxycarbonyl-3-(2,4,5-trifluorophenyl)alanine

[0131] Add 200mL tetrahydrofuran to 10g (30mmol) of (R)-N-2-tert-butoxycarbonyl-3-(2,4,5-trifluorophenyl)alanine methyl ester, cool in an ice bath, and then dropwise add 21.5 g (90mmol) lithium hydroxide aqueous solution 200mL, the reaction solution was stirred at room temperature for 15h. Concentrate under reduced pressure, and dissolve the residue with ethyl acetate, wash with saturated sodium bicarbonate and brine, and dry over anhydrous magnesium sulfate. The solvent was distilled off to obtain 7.7 g of solid, yield: 80.3%.

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Abstract

The invention pertains to the field of medical technology, particularly relating to a DPP-IV inhibitor with a sulfamido formamide piperazine structure shown in the general formula (I), pharmaceutically acceptable salt or an isomer thereof, wherein, R, R, R and Ar are defined as the instruction book; the invention also relates to a preparation method of the compounds, a pharmaceutical composition containing the compounds and applications of the compounds in the preparation of medicaments for treatment and / or prevention of diabetes, noninsulin-dependent diabetes, hyperglycemia, insulin resistance.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a DPP-IV inhibitor having a sulfonamidoformamide piperazine structure, a pharmaceutically acceptable salt or an isomer thereof, a preparation method of these compounds, and a pharmaceutical combination containing these compounds compounds, and the application of these compounds in the preparation of drugs 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 o...

Claims

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Application Information

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IPC IPC(8): C07D295/32A61K31/495A61P3/10
Inventor 黄振华
Owner XUANZHU BIOPHARMACEUTICAL CO LTD
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