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Benzodiazepine derivative and preparation method and application thereof

A benzodiazepine and derivative technology, applied in the field of pharmacy, can solve the problems of poor patient compliance, fast metabolism of flumazenil, and large toxic and side effects

Active Publication Date: 2021-07-09
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the disadvantages of flumazenil, such as fast metabolism, short half-life in vivo, low bioavailability and poor solubility, lead to the fact that it is only available in the form of injections in clinical practice.
However, the injection form has disadvantages such as poor patient compliance, large toxic and side effects, and high production costs, which limit the application of flumazenil and are not conducive to the development and development of new clinical indications of flumazenil

Method used

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  • Benzodiazepine derivative and preparation method and application thereof
  • Benzodiazepine derivative and preparation method and application thereof
  • Benzodiazepine derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] Example 1: (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine Preparation of -3-yl) methylnicotinate (FY0348)

[0065]

[0066] (8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine The synthetic route of -3-yl) methylnicotinate is shown in the following reaction formula.

[0067]

[0068] Step a: Preparation of N-(5-fluoro-2-nitrobenzoyl)-N-methylglycine methyl ester

[0069]

[0070] Weigh 5-fluoro-2-nitrobenzoic acid (20g, 108mmol), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 25g, 130mmol), 1 -Hydroxybenzotriazole (HOBT, 18g, 130mmol) was placed in a reaction flask (500ml), added dichloromethane (200ml) and stirred to dissolve, activated at room temperature for 30min; 108mmol), triethylamine (22g, 216mmol) were dissolved in dichloromethane (200ml), added to the reaction flask in sequence, and reacted at room temperature for 12h. Sampling by TLC to detect the reaction, the raw material poi...

Embodiment 2

[0085] Example 2: 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine - Preparation of 3-methyl acetate (FY0226)

[0086]

[0087] Referring to the preparation method and conditions of Example 1, 8-fluoro-3-hydroxymethyl-5,6-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzo Dinitrogen -6-ketone and acetyl chloride were used as raw materials for esterification and condensation to obtain 136 mg of white solid, yield: 75%. 1H NMR (400MHz, chloroform-d) δ (ppm): 7.88 (s, 1H, CH), 7.73 (dd, J = 8.8, 2.9Hz, 1H, ArH), 7.38 (s, 1H, ArH), 7.35– 7.28(m,1H,ArH),5.14(s,2H,CH 2 ),4.44(s,2H,CH 2 ),3.20(s,3H.CH 3 ),2.07(s,3H,CH 3 ). HRMS (ESI, m / z) calculated value C 15 h 14 FN 3 o 3 [(M+H)+], 304.10; experimental value 304.10.

Embodiment 3

[0088] Example 3: 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3- Preparation of methyl cyclopropanecarboxylate (FY0230)

[0089]

[0090] Referring to the preparation method and conditions of Example 1, 8-fluoro-3-hydroxymethyl-5,6-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzo Dinitrogen -6-ketone and cyclopropanoyl chloride were used as raw materials for esterification and condensation to obtain about 115 g of white solid, yield: 35%. 1H NMR (400MHz, chloroform-d) δ (ppm): 7.87 (s, 1H, CH), 7.74 (dd, J = 8.9, 2.7Hz, 1H, ArH), 7.38 (dd, J = 8.5, 4.7Hz, 1H, ArH), 7.35-7.27 (m, 1H, ArH), 5.17 (d, 2H, CH 2 ),4.43(d,2H,CH 2 ),3.20(s,3H,CH 3 ),1.65(dt,J=7.9,3.5Hz,1H,CH),1.05–0.95(m,2H,CH 2 ), 0.87 (dd, J=7.5, 3.3Hz, 2H, CH 2 ). HRMS (ESI, m / z) calculated value C 17 h 16 FN 3 o 3 [(M+H)+], 330.13; experimental value 330.13.

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Abstract

The invention discloses a benzodiazepine derivative as shown in a formula (I), enantiomers, diastereoisomers, racemes and mixtures thereof, pharmaceutically acceptable salts, crystalline hydrates and solvates thereof, a preparation method thereof, and application of the derivative in the preparation of antidotes of GABAA receptor agonists, post-anesthesia awakening agents, anti-epileptic drugs, anti-senile dementia drugs, ethanol poisoning antidotes and awakening agents for treating consciousness loss caused by unknown reasons.

Description

[0001] Citations from earlier applications [0002] This application requires that the application number submitted to the State Intellectual Property Office of China on March 29, 2021 is 202110330261.X, and the invention name is "a class of benzodiazepines Derivatives and their preparation methods and uses", the contents of which are fully incorporated herein by reference. technical field [0003] The invention belongs to the field of pharmacy, in particular to a class of benzodiazepines derivatives, and their use as benzodiazepines Drug use such as antidote for overdose of similar drugs, awakening agent after anesthesia, diagnostic agent for loss of consciousness caused by unknown reasons, etc. Background technique [0004] γ-aminobutyric acid (gamma-aminobutyric acid, GABA) is the main inhibitory neurotransmitter in the central nervous system, widely distributed in the brain and spinal cord. GABA mainly plays a role by binding to GABA receptors to generate biologica...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5517A61P39/02A61P25/08A61P25/28A61P25/00
CPCC07D487/04A61P39/02A61P25/08A61P25/28A61P25/00
Inventor 苏瑞斌何新华俞纲冯燕王娜马玉杰
Owner ACADEMY OF MILITARY MEDICAL SCI
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