Short-acting benzodiazepine derivatives, and preparation methods and uses thereof

A technology for compounds and polymorphs, applied in the field of benzodiazepine derivatives, can solve the problems of long time to regain sobriety, drug-drug interactions, etc.

Active Publication Date: 2017-06-27
SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, midazolam produces active metabolites in the body, which can lead to a longer recovery time for patients from midazolam-induced sedation and anesthesia
In addition, since the metabolism of midazolam is dependent on the hepatic enzyme cytochrome P4503A4, drug-drug interaction problems may arise if administered to patients with impaired hepatic function

Method used

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  • Short-acting benzodiazepine derivatives, and preparation methods and uses thereof
  • Short-acting benzodiazepine derivatives, and preparation methods and uses thereof
  • Short-acting benzodiazepine derivatives, and preparation methods and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0257] Example 1: 3-(8-bromo-1-methyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine -4-yl) methyl acrylate (compound 1)

[0258]

[0259] The first step: the preparation of 2-bromo-N-[4-bromo-2-(pyridin-2-ylcarbonyl)phenyl]acetamide (compound 1b)

[0260] The compound 2-(2-amino-5-bromo-benzoyl)pyridine (Compound 1a, 60 g, 0.22 mol) was dissolved in DCM (3 L) and NaHCO was added 3 (36.9 g, 0.44 mol). The mixture was cooled to 0°C, and bromoacetyl bromide (52.4 g, 0.26 mol) was slowly added dropwise. Stir at 0°C for 2 hours until TLC shows the reaction is complete. After the reaction solution was concentrated, the target product 2-bromo-N-[4-bromo-2-(pyridin-2-ylcarbonyl)phenyl]acetamide (compound 1b, 88 g, yield: 100.0%) was obtained.

[0261] The second step: 7-bromo-5-(pyridin-2-yl)-1H-benzo[e][1,4]diazepine Preparation of -2(3H)-one (compound 1c)

[0262] Compound 2-bromo-N-[4-bromo-2-(pyridin-2-ylcarbonyl)phenyl]acetamide (Compound 1b, 88 g, 0.22 mol)...

Embodiment 2

[0275] Example 2: (S)-3-(8-bromo-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,2-a][1,4]diazepine -4-yl) methyl propionate (compound 2s)

[0276]

[0277] The first step: (S)-5-((4-bromo-2-nicotinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid methyl ester (compound 2b) preparation of

[0278] Add HATU (45.6g, 0.12mol), N-methylmorpholine (20.2g, 0.2mol) and N-Boc-L-glutamic acid-5-methyl ester (16.1g , 0.1 mol), and the resulting mixture was allowed to react in an ice bath for 30 minutes, and then (2-amino-5-bromophenyl)(pyridin-2-yl)methanone (compound 2a, 27.7g, 0.1 mol) was added. After the TLC monitoring reaction was complete, water was added to the reaction system, extracted with ethyl acetate (20mL x 4), the ethyl acetate layer was evaporated to dryness, and the residue was purified by column chromatography to obtain the target product (S)-5-((4 -Bromo-2-nicotinoylphenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid methyl ester (compound ...

Embodiment 3

[0288] Example 3: (S)-3-(8-chloro-6-phenyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4] Diazepines -4-yl) methyl propionate (compound 3s)

[0289]

[0290] The first step: (S)-5-((2-benzoyl-4-chlorophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoic acid methyl ester (compound 3c ) preparation

[0291] (2-Amino-5-chlorophenyl)(benzyl)methanone (compound 3a, 5g, 0.022mol) and compound N-tert-butoxycarbonyl-L-glutamic acid-5-methyl ester (compound 3b, 6.32 g, 0.024 mol) was dissolved in DCM (50 mL). The mixture was cooled to 0 °C, DCC (4.99 g, 0.024 mmol) was added, and stirred for 24 hours. LCMS showed the reaction was complete. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was washed with water, dried and concentrated, and the residue was purified by silica gel column chromatography to obtain the target product (S)-5-((2-benzoyl -methyl 4-chlorophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (compound ...

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Abstract

The invention relates to benzodiazepine derivatives of formula I, used as a short-acting anesthetic, medicinal compositions containing the derivatives, pill case containing the medicinal compositions, preparation methods of the derivatives, anesthesia methods using the compositions, and uses of the compositions in the preparation of anesthesia medicines.

Description

technical field [0001] The present invention relates to benzodiazepines as short-acting anesthetics Derivatives, pharmaceutical compositions containing them, kits containing them, methods for their preparation, methods for anesthesia using them, and their use in the preparation of anesthetics. Background technique [0002] Benzodiazepine Derivatives (benzodiazepines) are GABA A Receptor (also called gamma-aminobutyric acid type A receptor) activator. GABA A The receptor is a gating receptor for chloride ion channels, which consist of two α and two β subunits (α2β2). There are GABA receptors on the β subunit. When GABA binds to it, the chloride ion channel opens, allowing chloride ions to flow inward, thereby hyperpolarizing nerve cells and producing an inhibitory effect. On the alpha subunit there are benzodiazepines receptors, when benzodiazepines When combined with it, is able to promote GABA and GABA A The binding of receptors increases the frequency of chlori...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5517A61P23/00A61P25/20A61P25/22A61P25/00
CPCC07D487/04A61K31/5517A61P23/00Y02P20/55A61K9/0019
Inventor 刘钢于华杨定菊杜静唐建川何婷曾宏宋宏梅苏东海刘薇王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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