Benzodiazepine compound as well as preparation method and pharmaceutical effect thereof

A compound and composition technology, applied in the field of chemical medicine, can solve the problems of by-product toxicity, high blood drug concentration, affecting the activity of drug metabolizing enzymes, etc.

Active Publication Date: 2020-12-29
WEST CHINA HOSPITAL SICHUAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, it has been reported that remimazolam has a lower potency than other sedative drugs, and it is necessary to increase the dosage in clinical application to increase the potential toxicity; meanwhile, the free base structure of remimazolam is unstable, and the by-products are quite toxic, and It will further affect the activity of drug-metabolizing enzymes in the body, causing problems such as high blood drug concentration and drug accumulation during continuous medication

Method used

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  • Benzodiazepine compound as well as preparation method and pharmaceutical effect thereof
  • Benzodiazepine compound as well as preparation method and pharmaceutical effect thereof
  • Benzodiazepine compound as well as preparation method and pharmaceutical effect thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0167] Embodiment 1, the preparation of intermediate 1 of the present invention

[0168]

[0169] At -40°C, add 5.25ml (29.83mmol, 4.4eq) 2-bromopyridine to a three-necked flask containing 20ml (27.12mmol, 4.0eq) n-butyllithium (2.5M) and 40ml anhydrous ether, and stir for 1 hour , and then added dropwise a solution containing 2.0g (6.78mmol, 1.0eq) of 2-amino-4,5-dibromobenzoic acid in 30ml of tetrahydrofuran, and reacted at 0°C for 3 hours. After the reaction of the raw materials was basically complete, ice water was added, extracted with ethyl acetate, dried and filtered over anhydrous sodium sulfate, concentrated under reduced pressure to obtain an oil, and 2.17 g of a yellow solid (Intermediate 1) was obtained by column chromatography.

[0170] The H NMR spectrum (deuterated chloroform) of the intermediate 1: δ8.78(d,1H),8.43(d,1H),8.07(d,1H),7.96–7.82(m,2H),6.87(d ,1H). MS: m / z: 355.90 (M+1).

Embodiment 2

[0171] Embodiment 2, the preparation of intermediate 2 of the present invention

[0172]

[0173] 2.0g (5.62mol, 1.0eq) 2-amino-4,5-dibromophenyl-pyridin-2-yl-methanone and 2.8g (10.72mmol, 1.9eq) (R)-2-tert-butoxy Carbonyl-amino-5-methoxy-5-oxopentanoic acid was dissolved in 30mL of dichloromethane (DCM), and 2.2g (10.68mmol, 1.9eq) of DCC (dicyclohexylcarbodiimide ), react overnight at room temperature. Point the board, and the raw materials basically react completely. The reaction solution was filtered and concentrated under reduced pressure, and 3.3 g of a light yellow oily substance (Intermediate 2) was obtained by column chromatography.

[0174] The H NMR spectrum of the intermediate 2 (deuterated chloroform): δ11.36(s, 1H), 8.74(d, J=4.8Hz, 1H), 8.57(d, J=9.0Hz, 1H), 7.99– 7.92(m,3H),7.67(dd,J=9.0,2.2Hz,1H),7.56–7.51(m,1H),5.42(d,J=6.6Hz,1H),4.35(s,1H),3.68 (s, 3H), 2.54–2.24 (m, 4H), 1.44 (s, 9H). MS: m / z: 600.28 (M+1).

Embodiment 3

[0175] Embodiment 3, the preparation of intermediate 3 of the present invention

[0176]

[0177] 3.3g (R)-4-((tert-butoxycarbonyl)amino)-5-((4,5-dibromo-2-pyridylphenyl)amino)-5-oxopentanoic acid methyl ester Dissolve in 20mL methanol, add 20mL HCl / MeOH solution (the volume ratio of HCl and MeOH is 1:1), and react overnight at room temperature. Point the board, and the raw materials basically react completely. Use directly in the next step without treatment.

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PUM

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Abstract

The invention provides a benzodiazepine compound as well as a preparation method and a pharmaceutical effect thereof, and belongs to the field of chemical medicines. The benzodiazepine compound is a compound shown as a formula I, or a salt thereof, or a stereoisomer thereof, or a solvate thereof, or a eutectic thereof, or a composition thereof. The compound is good in intravenous sedative anesthesia effect, the anesthesia effect of the compound is equivalent to or even superior to that of remimazolam, and specifically, the effective dosage is remarkably reduced, and the duration time and the recovery time are remarkably shortened. Meanwhile, in rat and mouse caudal vein anesthesia models, compared with remimazolam, the compound has remarkably improved waking quality. The compound providedby the invention has the advantages of fast onset, short duration, fast awakening and good tolerance during anesthesia, can be used for anesthesia induction, anesthesia maintenance and daytime operation anesthesia, and has a good application prospect.

Description

technical field [0001] The invention belongs to the field of chemical medicine, and in particular relates to a benzodiazepine compound, a preparation method thereof, and an action in medicine. Background technique [0002] Midazolam is the most commonly used benzodiazepine drug, which is relatively safe and acts mainly by binding to central γ-aminobutyric acid (GABAA) receptors. The onset is relatively rapid, and it has the effect of reducing intracranial pressure and brain metabolism. It is often used for pre-anesthesia administration, induction and maintenance of general anesthesia, adjuvant medication during spinal anesthesia and local anesthesia, diagnostic or therapeutic operations such as cardiovascular angiography, Sedation of ICU patients during cardioversion, bronchoscopy, gastrointestinal endoscopy, etc. However, because its metabolism depends on the liver and kidneys, long-term continuous infusion will cause drug accumulation in the body, usually causing adverse ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5517A61P23/00A61P25/20
CPCC07D487/04A61K31/5517A61P23/00A61P25/20C07D207/28C07D213/80C07C63/08C07C53/06C07C53/126C07C65/11C07C59/265C07C63/36C07C55/08C07C55/14C07C57/15C07C53/10C07C53/08C07C59/08
Inventor 柯博文刘进杨俊
Owner WEST CHINA HOSPITAL SICHUAN UNIV
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