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Use and preparation of indazole compound

A compound, indazole technology, applied in the field of medicine, can solve the problems of long synthesis process and low yield, and achieve the effects of high yield, cerebral blood vessel protection, and neurological dysfunction improvement

Active Publication Date: 2012-01-25
浙江大果生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The synthesis process is long and the yield is low
However, there is no report about the substance being used to reverse the oxidative stress injury of vascular endothelial cells and protect against cerebrovascular injury.

Method used

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  • Use and preparation of indazole compound
  • Use and preparation of indazole compound
  • Use and preparation of indazole compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Example 1 Synthesis of 3-{2-[4N-(2-methyl-3-chlorophenyl)-1N-piperazinyl]ethyl}-5,6-dimethoxy-1H-ind by chemical synthesis azole hydrochloride

[0020] Step 1: Indazolylacetic acid synthesis

[0021] Put 669 mg of ethyl 2-amino-3,4-dimethoxycinnamate (I) into 3 ml of 2mol / L hydrochloric acid under ice-cooling conditions, and stir evenly. 1.5ml of 140g / L sodium nitrite aqueous solution was added dropwise thereto, and half an hour later, 4.5ml of 3.0mmol / L sodium sulfite aqueous solution was added and mixed thoroughly. Then add 6 mL of ethanol to it, stir and filter the crystals, wash with ethanol, dry under reduced pressure at 50°C for 4 hours, suspend it in 2mol / L 1.0mL hydrochloric acid, and stir at 60°C for half an hour. Adjust the pH to neutral with sodium acetate, collect the crystals by filtration, wash with water, and dry under reduced pressure at 50°C for 4 hours to obtain 248 mg of indazolylacetic acid (II).

[0022] Step 2: Synthesis of Indazolylacetamide

...

Embodiment 2

[0028] Example 2 Synthesis of 3-{2-[4N-(2-methyl-3-chlorophenyl)-1N-piperazinyl]ethyl}-5,6-dimethoxy-1H-ind by chemical synthesis Azole hydrochloride (V)

[0029] Step 1: Synthesis of Indazolylacetamide (III)

[0030] Get 4.724 g of the product indazole acid (II) obtained in step 1 in Example 1, add 50 mL of thionyl chloride therein, and after reflux for 1 hour, dissolve the residue in 100 mL of tetrahydrofuran, and add dropwise the solution containing 4.21g 1-1N-(2-methyl-3-chlorophenyl)piperazine in 10mL tetrahydrofuran solution, stirred at room temperature for 3 hours, then quenched by adding saturated aqueous sodium bicarbonate solution, extracted 4 times with 100mL ethyl acetate each time , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 8.2 g of the crude product of indazolylacetamide (III), with a yield of 96%.

[0031] Step 2: 3-{2-[4N-(2-Methyl-3-chlorophenyl)-1N-piperazinyl]ethyl}-5,6-dimethoxy-1H-in...

Embodiment 3

[0037] Example 3 3-{2-[4N-(2-methyl-3-chlorophenyl)-1N-piperazinyl]ethyl}-5,6-dimethoxy-1H-indazole hydrochloride Protective effect on vascular endothelial cell injury under hypoxia and low glucose oxidative stress injury

[0038] Drugs and Reagents

[0039] High-glucose DMEM and high-glucose DMEM medium were purchased from GIBICO Company in the United States, fetal bovine serum and newborn calf serum were purchased from Hangzhou Sijiqing Bioengineering Materials Research Institute, type I collagenase and tetrazolium blue were products of Sigma Company, and other reagents Both domestic and imported analytical reagents were used. The human umbilical vein endothelial EA.hy926 cell line used for cell culture in the experiment is an immortalized cell line.

[0040] cell culture

[0041] Human umbilical vein endothelial EA.hy 926 cells were cultured in high-glucose DMEM (containing 10% inactivated domestic fetal bovine serum) at 37°C, saturated air humidity, containing 5% CO 2 ...

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Abstract

The invention provides use of indazole compound 3-{2-[4N-(2-methyl-3- chlorphenyl)-1N-piperazinyl] ethyl}-5, 6-dimethoxy-1H-indazole hydrochloride in preparing medicines for curing cranial vascular diseases. Starting from 3, 4-dimethyl-6-aminoethyl caffeate, indazole acetic acid is obtained through nitrification ring reaction, indazole acetamide is obtained through bonding with piperazine side chain after acylchlorination, indazole amine is obtained after indazole acetamide is reduced by lithium tetrahydridoaluminate or sodium tetrahydridoborate, and the target compound is obtained through hydrochlorination and recrystallization. The indazole compound of the invention can reduce or block up the production and the secondary onset of ONOO, can reverse the oxidative stress damage of endothelial cells of blood vessels and can protect blood vessels of brain. The invention has the advantages that the preparation method is simple and convenient, the raw material cost is low and the yield is high.

Description

technical field [0001] The invention belongs to the technical field of medicine, and relates to the use of an indazole compound in the preparation of medicines. Especially for 3-{2-[4N-(2-methyl-3-chlorophenyl)-1N-piperazinyl]ethyl}-5,6-dimethoxy-1H-indazole hydrochloride Use in the preparation of drugs for the prevention and treatment of related cerebrovascular diseases caused by oxidative stress damage of vascular endothelial cells, and 3-{2-[4N-(2-methyl-3-chlorophenyl)-1N-piperazinyl] The preparation method of ethyl}-5,6-dimethoxy-1H-indazole hydrochloride. Background technique [0002] Cerebrovascular disease is a common and frequently-occurring disease that endangers human life and health. It has the characteristics of high morbidity rate, high disability rate, high mortality rate and high recurrence rate. The incidence of cerebrovascular disease is positively correlated with age, which increases with the aging of my country's population. Its incidence is on the ri...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/496C07D231/56A61P9/10
Inventor 韩峰张辰卢应梅楼宜嘉福永浩司
Owner 浙江大果生物医药科技有限公司
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