Piperazine derivative, preparation thereof and use thereof in medicine

A kind of pharmacy and compound technology, applied in the field of dipeptidyl peptidase IV inhibitors

Inactive Publication Date: 2009-07-01
SHANGHAI HENGRUI PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] However, although several DPPIV inhibitors have been disclosed, there is still no long-acting drug, and there is still a need for DPPIV inhibitors with improved properties

Method used

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  • Piperazine derivative, preparation thereof and use thereof in medicine
  • Piperazine derivative, preparation thereof and use thereof in medicine
  • Piperazine derivative, preparation thereof and use thereof in medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0121] (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazole Methyl [1,5-a]pyrazine-1-carboxylate hydrochloride

[0122]

[0123]

[0124] first step

[0125] 2,2-Dimethyl-5-[2-(2,4,5-trifluoro-phenyl)-acetyl]-[1,3]dioxane-4,6-dione

[0126] 2,2-Dimethyl-[1,3]dioxane-4,6-dione (5.69g, 39.5mmol) was dissolved in 400mL dichloromethane under stirring, and 2 was added under ice-cooling, 4,5-Trifluorophenylacetic acid 1a (7.15g, 37.6mmol) and p-dimethylaminopyridine (7.35g, 60.2mmol), slowly add 250mL of 1-(3-dimethylamino-propyl)-3-ethyl Base-carbodiimide hydrochloride (8.28g, 43.2mmol) dichloromethane suspension, stirred at room temperature for 36 hours, with 5% potassium bisulfate solution (250mL × 7) and saturated sodium chloride solution ( 250mL×2) Wash the reaction solution, dry it with anhydrous magnesium sulfate, filter it with suction, and concentrate the filtrate under reduced pressure to obtain the title product 2,2-di...

Embodiment 2

[0179] (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo [1,5-a]pyrazine-1-carboxylic acid (2-methylsulfonyl-ethyl)-amide hydrochloride

[0180]

[0181] first step

[0182] (R)-7-[3-tert-butoxycarbonyl-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetra Hydrogen-imidazo[1,5-a]pyrazine-1-carboxylic acid

[0183] (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8 -Tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester 1n (2.0g, 3.5mmol) was dissolved in 50mL methanol under stirring, added 30mL4N sodium hydroxide solution, and reacted at room temperature for 1 Hours later, follow the reaction by thin-layer chromatography, the raw materials disappeared, add 2N hydrochloric acid to adjust the pH of the reaction solution to about 3, extract the reaction solution with ethyl acetate (50mL×4), combine the organic phases, dry with anhydrous magnesium sulfate, and fi...

Embodiment 3

[0195] (R)-3-Amino-1-[1-(morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine- 7-yl]-4-(2,4,5-trifluorophenyl)-butan-1-one hydrochloride

[0196]

[0197] first step

[0198] (R)-[3-[1-(morpholine-4-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl ]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-tert-butyl carbamate

[0199] (R)-7-[3-tert-butoxycarbonyl-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8- Tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (60 mg, 0.109 mmol), morpholine (19 mg, 0.218 mmol) and bis(2-oxo-3-oxazolidinyl) Phosphinoyl chloride (53.5mg, 0.218mmol) was dissolved in 5mL of dichloromethane with stirring, triethylamine (0.1mL, 0.65mmol) was added, and reacted overnight at room temperature. The reaction was tracked by thin-layer chromatography. The raw materials basically disappeared, and the reaction was evaporated to dryness. liquid, and the resulting residue was purified by silica gel colu...

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Abstract

The invention relates to piperazidine derivatives shown in a general formula (I), a preparation method thereof, a medicine composition containing the derivatives, and use of the medicine as a therapeutic agent, in particular dipeptidyl peptidase-4 inhibitor, wherein the definitions of various substitutional groups in the general formula (I) are the same as those in the description.

Description

technical field [0001] The present invention relates to a new piperazine derivative represented by general formula (I), its preparation method and pharmaceutical composition containing the derivative, and its use as a therapeutic agent, especially as a dipeptidyl peptidase IV inhibitor use. Background technique [0002] Diabetes mellitus is a metabolic disease of multiple etiologies characterized by chronic hyperglycemia accompanied by disturbances in carbohydrate, fat and protein metabolism due to defects in insulin secretion and / or action. Diabetes is a very old disease. It is caused by the absolute or relative lack of insulin in the human body, which causes the blood glucose concentration to rise, and then a large amount of sugar is excreted from the urine, resulting in polydipsia, polyuria, polyphagia, weight loss, and dizziness. , fatigue and other symptoms. [0003] Permanent or uncontrolled hyperglycemia leads to increased morbidity and mortality. Often abnormal gl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4985A61P3/10A61P3/04
CPCC07D487/04A61P3/04A61P3/10A61P5/48A61P43/00
Inventor 邓炳初杨方龙范江冯虎王阳杨韬
Owner SHANGHAI HENGRUI PHARM CO LTD
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