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Novel benzodiazepine compound as well as preparation method and application thereof

A technology of benzodiazepines and compounds, which is applied in the field of preparation of sedative and anesthetic drugs, and can solve the problems of unable patients to return to normal, hindering development, drug accumulation, etc.

Pending Publication Date: 2021-02-12
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] In summary, benzodiazepines The use of narcotic drugs is often accompanied by dependence and addiction, and most of the drug metabolites still have certain drug effects, so that patients cannot quickly return to normal. Long-term use can easily lead to drug accumulation, which hinders its further development.

Method used

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  • Novel benzodiazepine compound as well as preparation method and application thereof
  • Novel benzodiazepine compound as well as preparation method and application thereof
  • Novel benzodiazepine compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0203] Example 1: (S)-3-(8-bromo-6-(pyridin-2-yl)-1-thioxo-2-2,4-dihydro-1H-benzo[f][1,2 ,4]triazol[4,3-a][1,4]diazepine -4-yl) methyl propionate (compound 1 tautomer)

[0204]

[0205] The first step: (S)-5-((2-fluoro-benzoyl-4-chlorophenyl) amino)-4-((tert-butoxycarbonyl) amino)-5-oxopentanoic acid methyl ester ( Compound 1c) Preparation:

[0206] 2-Amino-5-chloro-2'-fluorobenzophenone (compound 1a, 11.48g, 0.046mol) and compound N-tert-butoxycarbonyl-L-glutamic acid-5-methyl ester (compound 1b, 10 g, 0.038 mol) was dissolved in DCM (300 mL). The mixture was cooled to 0 °C, DCC (9.49 g, 0.046 mmol) was added, and stirred for 24 hours. LCMS showed the reaction was complete. The filtrate was taken by suction filtration and the reaction solvent was evaporated under reduced pressure, and the residual product was purified by column chromatography (petroleum ether / ethyl acetate, 4:1, v / v) to obtain a white solid (S)-5-((2-fluoro- Benzoyl-4-chlorophenyl)amino)-4-((tert-bu...

Embodiment 2

[0219] Example 2: (S)-3-(8-chloro-6-(2-chlorophenyl)-1-thio-2,4-dihydro-1H-benzo[f][1,2,4 ]triazol[4,3-a][1,4]diazepine Preparation of -4-yl)methyl propionate (compound 2 tautomer):

[0220] 1 H NMR (300MHz, DMSO-d 6 )δ:14.15(s,1H),8.46(d,J=8.8Hz,1H),7.87(d,J=7.4Hz,1H),7.66-7.50(m,4H),7.16(s,1H), 4.34(t, J=5.8Hz, 1H), 3.62(s, 3H), 2.70-2.45(m, 4H); 13 C NMR (75MHz, DMSO-d 6 )δ: 173.54, 167.16, 167.00, 153.68, 138.23, 132.42, 132.28, 132.12, 131.94, 131.73, 131.64, 131.07, 130.21, 128.52, 127.99, 127.966, 55.30, LC / z:447.2[M+H] + .

Embodiment 3

[0221] Example 3: (S)-3-(8-bromo-6-(pyridin-2-yl)-1-thioxo-2,4-dihydro-1H-benzo[f][1,2,4 ]triazol[4,3-a][1,4]diazepine Preparation of -4-yl) methyl propionate (compound 3 tautomer)

[0222] 1 H NMR (300MHz, DMSO-d 6 )δ: 14.17(s, 1H), 8.59(d, J=4.3Hz, 1H), 8.37(d, J=8.8Hz, 1H), 8.13(d, J=7.9Hz, 1H), 8.03-7.98( m,2H),7.60-7.54(m,2H),4.34(t,J=5.8Hz,1H),3.65(s,3H),2.70-2.45(m,4H); 13 C NMR (75MHz, CDCl 3 -d 1 )δ: 173.70, 167.81, 166.51, 157.68, 155.34, 149.03, 136.91, 134.69, 134.01, 132.24, 130.18, 126.91, 125.28, 124.90, 123.99, 55.09, 51.71, 360.18 :457.8[M+H] + .

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Abstract

The invention discloses a novel benzodiazepine compound as well as a preparation method and application thereof and belongs to the field of medicinal chemistry; the short-acting benzodiazepine derivative disclosed by the invention has the characteristics of quick acting, short acting time, strong depth, quick metabolism, quick awakening and the like. In anesthesia experiments on mice and rats, theshort-acting benzodiazepine derivative disclosed by the invention is equivalent to remimazolam in acting time, but the acting time and the waking time are remarkably shortened, the acting depth of part of compounds is obviously enhanced, and the short-acting benzodiazepine derivative has the characteristics of quicker acting speed, shorter acting time, higher acting strength, quicker metabolism,quicker waking speed and the like; in a long-term infusion anesthesia experiment on rats, compared with remimazolam, the short-acting benzodiazepine derivative has the advantages that the awakening time and the recovery time are obviously shortened, and the short-acting benzodiazepine derivative has the characteristics of quicker awakening, quicker recovery and the like.

Description

technical field [0001] The present invention relates to benzodiazepines of formula (I) as short-acting anesthetics Derivatives, pharmaceutical compositions containing them, kits containing them, methods for their preparation, methods of sedation and anesthesia using them, and their use in the preparation of sedative and anesthesia drugs. Background technique [0002] Anesthesia drugs can temporarily reversibly lose consciousness and pain in the body or parts of the body, and help patients reduce pain and other discomfort symptoms. They are essential auxiliary drugs for clinical operations. [0003] 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...

Claims

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Application Information

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IPC IPC(8): C07D487/04C07F9/6561A61K31/5517A61K31/675A61P25/20A61P23/00
CPCC07D487/04C07F9/6561A61P25/20A61P23/00Y02P20/55
Inventor 钱海石炜黄文龙李启飞蔡衍莫佳贤陈斌周嘉琪邹昱星
Owner CHINA PHARM UNIV
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