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Benzo[d]isothiazole-3-(2H)-one derivative, preparation method and application thereof

A technology of isothiazole and derivatives, which is applied in the field of preparation of brain neuroprotective agents, substituted benzo[d]isothiazol-3-one derivatives and its preparation, can solve the problem of low selectivity, high neurobehavioral toxicity, oral poor bioavailability

Inactive Publication Date: 2019-08-16
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The second technical problem to be solved in this application is to disclose the application of the above-mentioned benzo[d]isothiazol-3(2H)-one derivatives as brain neuroprotective agents in the treatment of ischemic stroke, so as to overcome the problems existing in the prior art. Induced hemorrhage, difficult to penetrate the blood-brain barrier, poor oral bioavailability, low selectivity and high neurobehavioral toxicity and other defects

Method used

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  • Benzo[d]isothiazole-3-(2H)-one derivative, preparation method and application thereof
  • Benzo[d]isothiazole-3-(2H)-one derivative, preparation method and application thereof
  • Benzo[d]isothiazole-3-(2H)-one derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 1-(2-Bromoethoxy)-4-methylbenzene

[0053] Put 26.8mmol of 4-methylphenol, 40.3mmol of 1,2-dibromoethane and 25ml of water in a 250ml eggplant-shaped bottle. After stirring, the temperature was raised to 95° C., and 4.8 ml of 25% sodium hydroxide solution was added dropwise. After the dropwise addition, continue to heat up to 100° C. and stir for 12 h, and monitor the reaction by TLC. After completion of the reaction, cool to room temperature, extract with 30ml of dichloromethane × 3, combine the dichloromethane layers, extract twice with 10ml of 5% sodium hydroxide solution, wash once with 10ml of saturated sodium chloride solution, and dry over anhydrous sodium sulfate for 12h. After filtration, the solvent was distilled off under reduced pressure to obtain a colorless liquid with a yield of 59.8%, and TLC showed a pure point.

Embodiment 2

[0055] 1-(2-(4-Methylphenyl)ethyl)piperazine

[0056] Put 16.8mmol of 1-(2-bromoethoxy)-4-methylbenzene, 50ml of methanol and 67.2mmol of piperazine in a 100ml eggplant-shaped flask, raise the temperature to 70°C and stir for 3h, and monitor the reaction by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure. Add 30ml of dichloromethane and 15ml of saturated sodium carbonate solution to dissolve, separate the layers, take the dichloromethane layer, wash twice with 20ml of saturated sodium bicarbonate solution, and once with 20ml of water, extract the organic phase with 20ml of 10% hydrochloric acid, and make the aqueous layer The pH is less than 3, keep the aqueous layer; use 10ml of 20% sodium hydroxide solution to adjust the pH to greater than 10, a solid precipitates, extract with 40ml of dichloromethane until the organic phase is free of spots, combine the organic phases, and dry over anhydrous sodium sulfate for 12h. After filtrati...

Embodiment 3

[0058] 2-(3-Oxybenzo[d]isothiazolin-2(3H)-yl)acetic acid

[0059] Put 33.07mmol of 1,2-benzisothiazol-3-one, 50ml of tetrahydrofuran and 66.14mmol of anhydrous potassium carbonate in a 250ml eggplant-shaped bottle, react in ice bath for 30min, add 33.07mmol of tert-butyl bromoacetate, and continue to The bath was reacted for 3h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was distilled off under reduced pressure. Add 30ml of dichloromethane and 15ml of trifluoroacetic acid, stir at room temperature for 5h, a white solid precipitates out. The crude product was obtained by suction filtration, and recrystallized from absolute ethanol to obtain a white solid with a yield of 85%, and TLC showed a pure point.

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Abstract

The invention relates to a benzo[d]isothiazole-3-(2H)-one derivative, a preparation method and application of the benzo[d]isothiazole-3-(2H)-one derivative. The compound is a free alkali or salt of acompound with a structure shown in a general formula (I). The salt is one of hydrochloride, hydrobromide, sulfate, trifluoroacetate, tartrate, lactate or mesylate; R1 independently represents "-CH2-CO-" or "-CH2-CH2-"; R2 independently represents "-CH2-CH2-O-" or "-CO-CH=CH-"; R3 independently represents hydrogen, halogens, a hydrocarbon group, a halogen-substituted hydrocarbon group, a nitro group, an amino group, a nitrile group, a hydroxyl group, an alkoxy group, an aryloxy group, a heterocycloalkoxy group, an aryl group, a substituted heterocyclic ring or a substituted aryl group. The invention also provides an application of the benzo[d]isothiazole-3-(2H)-one derivative in preparation of ischemic stroke treatment medicines.

Description

technical field [0001] The invention belongs to the field of pharmacy, and relates to a substituted benzo[d]isothiazol-3(2H)-one derivative, a preparation method thereof, and an application of the derivative in preparing a brain neuroprotective agent. Background technique [0002] Stroke is one of the diseases with the highest mortality and disability rate today, and nearly 80% of strokes are ischemic strokes. The survival of brain cells after a stroke depends on how much neurons are damaged, that is, how much blood flow to the brain that supplies cells with oxygen and nutrients is reduced. When ischemic stroke occurs, the cerebral blood flow in the ischemic core is severely reduced, and irreversible damage occurs to the brain tissue after 60-90 minutes; while the cerebral blood flow in the peripheral ischemic penumbra of the core is relatively reduced, but the cell metabolism Within a few hours after the occurrence of ischemia, the abnormal electrical activity and metaboli...

Claims

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Application Information

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IPC IPC(8): C07D275/04A61P9/10A61P25/00
CPCA61P9/10A61P25/00C07D275/04
Inventor 仲琰韩佳沛方甜甜陈俐颐
Owner SOUTHEAST UNIV
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