New dipeptidase-IV inhibitor compound

A compound, difluorophenyl technology, applied in the field of medicine, can solve the problems of limited varieties of DPP-IV inhibitors, unable to meet clinical needs, etc.

Active Publication Date: 2009-02-04
BEIJING AOHE DRUG RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The variety of DPP-IV inhibitors is limited and cannot meet the clinical needs, and there is an urgent need to develop more DPP-IV inhibitor drugs to meet the clinical needs

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Example 1 (2R, 5S)-2,5-dihydro-3,6-dimethoxy-2-[bis(4-fluoro-phenyl)]methyl]-5-isopropylpyrazine preparation

[0166] 18.4g (100mmol) (2S)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine was dissolved in 400ml tetrahydrofuran, and then heated at -78°C for 30min Add dropwise 48ml (120mmol, 2.5N) of n-butyllithium / n-hexane solution, keep stirring for 30min, then dropwise add 26.3g (110mmol) of 4-fluoro-diphenylchloromethane in 50ml of tetrahydrofuran cold solution, -78°C Stir the reaction for 5h, add 100ml of water at -78°C to quench the reaction, concentrate the reaction solution, partition the residue between ethyl acetate and 1N hydrochloric acid, extract the aqueous layer 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 (ethyl acetate:cyclohexane=1:20~1:10) to obtain 26.8 g of the target compound as colloidal solid, yield: 69....

Embodiment 2

[0167] Example 2 Preparation of (R)-N-2-(tert-butoxycarbonyl)-3,3-bis(4-fluorophenyl)alanine methyl ester

[0168] 38.6g (100mmol) of (2R,5S)-2,5-dihydro-3,6-dimethoxy-2-[bis(4-fluoro-phenyl)]methyl]-5-isopropyl Dissolve pyrazine in 200ml of acetonitrile, then add 200ml of 1N hydrochloric acid dropwise, stir the reaction solution at room temperature for 24 hours, add methanol, concentrate to dryness, repeat this operation three times, and then repeat it once with toluene to obtain a solid, which is treated with 700ml of dichloro Add 100g triethylamine after the methane dissolves, then add 52.3g (231.1mmol) (Boc) dropwise 2 O, the reaction solution was stirred at room temperature for 8 h, 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, and the eluents were acetonitrile and petroleum ether (...

Embodiment 3

[0169] Example 3 Preparation of (R)-N-2-(tert-butoxycarbonyl)-3,3-bis(4-fluorophenyl)alanine

[0170] Add 300ml tetrahydrofuran to 23.5g (60mmol) of (R)-N-2-(tert-butoxycarbonyl)-3,3-bis(4-fluorophenyl)alanine methyl ester, cool in an ice bath, and then dropwise add 4.12g (172.3mmol) 200ml aqueous solution of lithium hydroxide, 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 18g Solid, yield: 79.3%.

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Abstract

The invention belongs to the medicine technology field, which particularly relates to a new dipeptidase-IV inhibitor compound, the salt acceptable in pharmacy and the isomer thereof; wherein, the R<1>, R<2>, Ar, n, X or Y are defined in an introduction; The invention also relates to preparing methods of the compounds and the drug combination containing the compounds and the applications of the compounds in preparing the medicine for curing or preventing diabetes, non-insulin-dependent diabetes, hyperglycemia and insulin resistance.

Description

1. Technical field [0001] The present invention belongs to the technical field of medicine, and specifically relates to dipeptidase-IV (DPP-IV) inhibitor compounds, pharmaceutically acceptable salts and 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...

Claims

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Application Information

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