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Tetrazole derivative, preparation, pharmaceutical composition containing tetrazole derivative and application of tetrazole derivative

A technology of tetrazole derivatives, which is applied in the field of preparation of tetrazole derivatives, can solve problems such as lack of treatment strategies

Pending Publication Date: 2022-05-06
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A variety of drugs have been explored in clinical trials and animal models, but effective therapeutic strategies are still lacking
In addition, there is no preventive drug for neuroprotective agents against acute ischemic stroke, so new compounds with new structural characteristics and new mechanisms of action are needed, and this field has a broad market and clinical needs

Method used

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  • Tetrazole derivative, preparation, pharmaceutical composition containing tetrazole derivative and application of tetrazole derivative
  • Tetrazole derivative, preparation, pharmaceutical composition containing tetrazole derivative and application of tetrazole derivative
  • Tetrazole derivative, preparation, pharmaceutical composition containing tetrazole derivative and application of tetrazole derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] Example 1. Synthesis of Intermediates 1-3

[0153]

[0154] Add raw material 1-1 (13.2g, 0.1mol), NBS (N-bromosuccinimide) (44.5g, 0.25mol), AIBN (azobisisobutyronitrile) (720mg, 3mmol), carbon tetrachloride (20ml), heated to reflux for 16h, cooled to room temperature, and concentrated under reduced pressure to remove carbon tetrachloride to obtain a mixture containing intermediate 1-2. Add water and ethanol (100ml: 100ml) to the mixture, react at 70 degrees Celsius for 4h, extract with ethyl acetate to obtain an organic phase, dry over anhydrous sodium sulfate, concentrate under reduced pressure and evaporate to dryness ethyl acetate, the obtained crude product is subjected to silica gel column chromatography (acetic acid Ethyl ester: petroleum ether = 1:50-1:10) was purified to obtain about 8.4 g of white to pale yellow crystalline intermediate 1-3, with a yield of 40% and a purity of more than 99%. HRMS:m / z(ESI)calcd for C 8 h 6 N 2 O[M+H] + 147.05found: 147....

Embodiment 2

[0155] Embodiment 2: the synthesis of intermediate 1-5

[0156]

[0157] Step 1: add intermediate 1-3 (2.8g, 20mmol), ethylene glycol (6.2g, 0.1mol), toluene (20ml), p-toluenesulfonic acid (275mg, 1.6mmol) to reflux in a single-necked bottle, Use a water separator to remove water until the water volume in the water separator no longer increases, and cool to room temperature. Saturated sodium bicarbonate solution was added until the water layer was neutral or alkaline, the water layer was separated, and the organic layer was concentrated under reduced pressure to obtain 4.5 g of light yellow oily semi-solid intermediate 1-4. Yield 89%. The purity is greater than 99%.

[0158] Step 2: Add intermediate 1-4 (0.7g, 3.93mmol), sodium azide (1.28g, 19.65mmol), ammonium chloride (1.05g, 19.65mmol), and DMF (10ml) into a single-necked flask, Heat to reflux for 12 hours, cool to room temperature, add 1N hydrochloric acid to quench, stir at room temperature for 1 hour, TLC confirms...

Embodiment 3

[0159] Embodiment 3: the synthesis of intermediate 2-3

[0160]

[0161] With reference to the steps of Example 1, 5-(trifluoromethyl)-2-methylbenzonitrile 2-1 (18.5 g, 0.1 mol) was used as raw material to obtain 15.2 g of solid 2-3 with a yield of 76% and a purity greater than 99%, HRMS: m / z (ESI) calcd for C 9 h 4 f 3 NO[M+H] + 200.02found: 200.25.

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Abstract

The invention discloses a tetrazole derivative with a structure as shown in a general formula I. The invention also discloses a composition containing the tetrazole derivative and application of the composition in preparation of drugs for preventing and resisting cerebral apoplexy. Through multiple experiments, the inventor of the invention proves that the compound has an obvious inhibition effect on ADP-induced platelet aggregation activity, and has an outstanding damage protection effect on neuron-like cells induced and differentiated by OGD / R fetal mouse primary cortical neuronal cells and neuroblastoma cells (N2A); for a focal cerebral ischemia animal model constructed by transient middle cerebral artery occlusion through a suture method, the compound has a good anti-cerebral apoplexy drug effect and good rat oral pharmacokinetic property. Therefore, the compound disclosed by the invention can be used as a neuroprotective agent to be applied to medicines for treating and preventing cerebral apoplexy.

Description

technical field [0001] The invention relates to the field of medicines, in particular to tetrazole derivatives, preparation methods, pharmaceutical compositions containing them and their use in the preparation of drugs for preventing and combating cardiovascular and cerebrovascular diseases, improving cardiovascular and cerebrovascular circulation disorders or antithrombotics. application. Background technique [0002] Stroke is one of the common cardiovascular and cerebrovascular diseases and has become the leading cause of disability and the second leading cause of death among adults worldwide. The incidence of ischemic stroke accounts for about 80% of the total stroke, which seriously threatens human health. In the past decade, research has focused on exploring more effective treatment strategies to reduce stroke-related death and disability. A variety of drugs have been explored in clinical trials and animal models, but effective therapeutic strategies are still lackin...

Claims

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Application Information

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IPC IPC(8): C07D257/04C07D401/04A61P9/10A61P9/00A61P25/00A61P7/02A61K31/41A61K31/4439
CPCC07D257/04C07D401/04A61P9/10A61P9/00A61P25/00A61P7/02Y02P20/55
Inventor 车金鑫董晓武金一真庄宇昕陈斌辉聂文文童乐仙
Owner ZHEJIANG UNIV
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