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Dipeptidase inhibitor compound

A technology of compounds and compositions, applied in the field of medicine, can solve the problems of limited varieties of medicines

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

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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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0148] Example 1 7-[(R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propionyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1 ,2,4] Preparation of Triazolo[4,3-a]pyrazine

[0149]Throw 20.5g (100mmol) of (R)-2-(tert-butoxycarbonylamino)-3-hydroxy-propionic acid at room temperature, 13.5g (100mmol) HOBT (1-hydroxybenzotriazole), DMF100ml, Then 40g (150mmol) of DCC (dicyclohexylcarboimide) was added, and the reaction was stirred at room temperature for 2h. Remove the solid generated by the reaction by filtration, continue to add the filtrate to the reaction flask, add 19.2g (100mmol) 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazole And[4,3-a]pyrazine (see J.Med.Chem.2005, 48, 141-151 for its preparation method), raise the temperature and stir for 6h, after the reaction is complete, add 500ml of water to dilute, and precipitate a solid, and use methanol and dichloro The methane mixture was purified to obtain 30.4 g of the product, yield: 80.2%.

Embodiment 2

[0150] Example 2 7-[(R)-3-(tert-butoxycarbonylamino)-4-hydroxy-butyryl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1 ,2,4] Preparation of Triazolo[4,3-a]pyrazine

[0151] Referring to the preparation method of Example 1, throw (R)-3-(tert-butoxycarbonylamino)-4-hydroxy-butyric acid 21.9g (100mmol), 3-(trifluoromethyl)-5,6,7, 19.2 g (100 mmol) of 8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine. 7-[(R)-3-(tert-butoxycarbonylamino)-4-hydroxy-butyryl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2 , 4] Triazolo[4,3-a]pyrazine 29.4g, yield: 74.8%.

Embodiment 3

[0152] Example 3 7-[(R)-2-(tert-butoxycarbonylamino)-3-(N-2,4,5-trifluorophenoxy)-propionyl]-3-(trifluoromethane base)-5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazine

[0153] 27.3 g (72 mmol) of 7-[(R)-2-(tert-butoxycarbonylamino)-3-hydroxyl-propionyl]-3-(trifluoromethyl)-5,6,7,8-tetra Add hydrogen-[1,2,4]triazol[4,3-a]pyrazine into the dry reaction flask, then add 11.8g (80mmol) of 2,4,5-trifluorophenol, 18.9g (72mmol) Triphenylphosphine, 200ml tetrahydrofuran. Cool down to below 0° C. and then add 12.5 g (72 mmol) of diethyl azodicarboxylate in 30 ml of toluene. Insulated and stirred for 50 hours, after the reaction was completed, the solvent was recovered under reduced pressure, the residue was dissolved in ethyl acetate, washed once with 1N sodium hydroxide and saturated sodium chloride solution, and purified on a silica gel column (ethyl acetate / cyclohexane) to obtain Product 18.8g, yield: 51.2%.

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Abstract

The invention belongs to the medicine technology field, which more particularly relates to a dipeptidase inhibitor compound, the salt acceptable in pharmacy and the isomer thereof shown in the formula (I); wherein, the R<1>, Ar, X, m and n are defined in an introduction; The invention also relates to preparing methods of the compounds, 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 invention belongs to the field of medical technology, and specifically relates to dipeptidase inhibitor compounds, pharmaceutically acceptable salts thereof, isomers thereof, preparation methods of these compounds, pharmaceutical compositions containing these compounds, and the use of these compounds in the preparation of therapeutic and / or the application of drugs for the prevention of 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, b...

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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