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Benzotetrazole derivatives and preparation thereof, pharmaceutical compositions containing benzotetrazole derivatives and application of benzotetrazole derivatives

A technology for phenyltetrazolium and derivatives, which is applied in the field of phenyltetrazolium derivatives and preparation, and can solve the problems of limited administration route, poor physical and chemical properties, difficult preparation process and the like

Pending Publication Date: 2020-11-17
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Neuroprotective drugs include antioxidants, calcium channel antagonists and neurostimulants, among which the marketed drug has Enbipu (butylphthalide) of CSPC, which is a new drug independently developed by my country in the field of cerebrovascular disease. Early cerebral infarction has a certain therapeutic effect, but its therapeutic effect still has room for improvement, and butylphthalide is an oily compound with poor physical and chemical properties, difficult preparation process, and limited administration routes
[0003] 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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  • Benzotetrazole derivatives and preparation thereof, pharmaceutical compositions containing benzotetrazole derivatives and application of benzotetrazole derivatives
  • Benzotetrazole derivatives and preparation thereof, pharmaceutical compositions containing benzotetrazole derivatives and application of benzotetrazole derivatives
  • Benzotetrazole derivatives and preparation thereof, pharmaceutical compositions containing benzotetrazole derivatives and application of benzotetrazole derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0110] Embodiment 1. Synthesis of intermediate 4-1-3

[0111]

[0112]Add (20g, 0.1mol) raw material 4-1-1, (44.5g, 0.25mol) NBS (N-bromosuccinimide), (720mg, 3mmol) AIBN (azobisiso Butyronitrile), (20ml) carbon tetrachloride, heated to reflux for 16h, cooled to room temperature, concentrated under reduced pressure to remove carbon tetrachloride, and obtained a mixture containing intermediate 4-1-2. (400ml) water was added to the mixture, heated to reflux for 24h, extracted with ethyl acetate to obtain an organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure and evaporated to dryness of ethyl acetate, the resulting crude product was subjected to silica gel column chromatography (ethyl acetate:petroleum ether =1:50-1:10) to obtain about 8.4 g of white to pale yellow crystalline intermediate 4-1-3, with a yield of 40% and a purity of more than 99%. 1 H NMR 500MHz, CDCl 3 δ: 7.26 (d, 1H, ArH), 7.92 (dd, 1H, ArH), 7.98 (d, 1H, ArH), 10.31 (s,...

Embodiment 2

[0113] Embodiment 2: the synthesis of intermediate 4-1-5

[0114]

[0115] Step 1: Add (4.2g, 20mmol) intermediate 4-1-3, (6.2g, 0.1mol) ethylene glycol, (20ml) toluene, (275mg, 1.6mmol) p-toluenesulfonic acid in a single-necked flask and heat Reflux, use a water separator to remove water until the water volume in the water separator does not increase, 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 4-1-4. 1 HNMR (CDCl 3 )δ: 1.32 (m, 4H, CH 2 ), 5.77 (s, 1H, CH), 7.69 (d, 1H, ArH), 7.77 (dd, 1H, ArH), 7.87 (d, 1H, ArH). Yield 89%. The purity is greater than 99%.

[0116] Step 2: (1g, 3.93mmol) intermediate 4-1-4, (1.28g, 19.65mmol) sodium azide, (1.05g, 19.65mmol) ammonium chloride, and (10ml) DMF were added in a single-necked flask , heated...

Embodiment 3

[0117] Embodiment 3: the synthesis of intermediate 4-1a-3

[0118]

[0119] Referring to the steps of Example 1, using (15 g, 0.1 mol) 5-chloro-2-methyl-benzonitrile 4-1a-1 as raw material, 7.1 g of white solid 4-1a-3 was obtained with a yield of 43%. Purity greater than 99%, ESI(M+H) + =166.

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Abstract

The invention discloses benzotetrazole derivatives. The benzotetrazole derivatives have a structure represented by a general formula I or a general formula I'. In the general formula I or the generalformula I', R1 is a C3-C5 alkyl chain or a halogenated alkyl chain, R2 is one or a plurality of elements selected from H, Cl, F and Br or a combination of two or a plurality of elements selected fromH, Cl, F and Br, R3 is H, F or CH3, and R4 is a C1-C2 alkyl chain. The invention also discloses optical isomers of the derivatives, or pharmaceutically acceptable salts or solvates of the derivatives,or pharmaceutically acceptable salts or solvates of the optical isomers. The invention further discloses compositions containing the benzotetrazole derivatives and application of the compositions inpreparation of medicines for preventing and resisting cerebral apoplexy. Repeated experiments prove that the derivatives provided by the invention shows strong protective activity on OGD / R molded mouse primary cortical neuronal cells. Therefore, the derivatives disclosed by the invention can be applied as neuroprotective agents to medicines for treating and preventing cerebral apoplexy.

Description

technical field [0001] The present invention relates to the field of medicines, in particular to phenylbistetrazolium 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 antithrombosis in the application. Background technique [0002] Cerebral stroke is also called "stroke" or "cerebrovascular accident" (cerebral vascular accident, CVA). It is an acute cerebrovascular disease, which is a group of diseases that cause brain tissue damage due to the sudden rupture of blood vessels in the brain or the inability of blood to flow into the brain due to vascular obstruction, including ischemic stroke and hemorrhagic stroke. The incidence of acute ischemic stroke (cerebral ischemic stroke, CIS) is higher than that of hemorrhagic stroke, accounting for 60% to 70% of the total...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/04A61P9/00A61P9/10A61P25/00A61P7/02A61K31/41
CPCA61P7/02A61P9/00A61P9/10A61P25/00C07D257/04Y02P20/55
Inventor 庄宇昕金一真董晓武陈斌辉
Owner ZHEJIANG UNIV
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