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Benzodinitrogen medicine for sedation and hypnosis as well as preparation method and application of benzodinitrogen medicine

A technology of sedation and hypnosis and benzodiazepine, which is applied in the direction of drug combination, pharmaceutical formula, medical preparations containing active ingredients, etc., can solve the problems of reducing nerve excitability, returning patients to normal, drug accumulation, etc., to achieve easy relief Effect of waking up early, reducing side effects, and facilitating metabolism

Pending Publication Date: 2022-05-10
CHINA PHARM UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have found that when benzodiazepines When the dose of similar drugs exceeds the body's metabolism, it will cause an increase in the release of β-endorphin in the brain, act on the morphine receptors in the central nervous system and cardiovascular system, reduce the excitability of the nerves, and cause central nervous system and respiratory depression, blood pressure, and heart rate. Serious side effects such as slowing down
In addition, 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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  • Benzodinitrogen medicine for sedation and hypnosis as well as preparation method and application of benzodinitrogen medicine
  • Benzodinitrogen medicine for sedation and hypnosis as well as preparation method and application of benzodinitrogen medicine
  • Benzodinitrogen medicine for sedation and hypnosis as well as preparation method and application of benzodinitrogen medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0199] 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)

[0200]

[0201] The first step: (S)-5-((2-fluoro-benzoyl-4-chlorophenyl) amino)-4-((tert-butoxycarbonyl) amino)-5-oxopentanoic acid methyl ester ( Preparation of Compound 1c)

[0202] 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-...

Embodiment 2

[0215] 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)

[0216] 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

[0217] 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)

[0218] 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 benzodinitrogen medicine for sedation and hypnosis as well as a preparation method and application of the benzodinitrogen medicine. Belongs to the field of pharmaceutical chemistry. The benzodinitrogen compound disclosed by the invention has sedative, hypnotic and anti-anxiety activity, and has the characteristics of quick response, long action time, no accumulation and the like. In a mouse induced sedative-hypnotic experiment, the benzodiazepine derivative disclosed by the invention has the advantages that the onset time is equivalent to that of triazolam, the action duration of part of compounds is obviously shortened compared with that of triazolam, and the action duration of the other part of compounds is equivalent to that of diazepam; the related compounds are easy to metabolize into inactive products in vivo, are not accumulated, and do not accompany adverse symptoms such as sleepiness, addiction and the like. Therefore, the related compound and the pharmaceutical salt thereof can not only improve the difficulty in falling asleep, but also relieve the sleep disorder problem of easy and early waking, and have potential sedative, hypnotic and anxiety-resistant effects.

Description

technical field [0001] The present invention relates to benzodiazepines of formula (I) for sedative hypnosis Derivatives, pharmaceutical compositions containing them, kits containing them, methods for their preparation, methods for sedation and hypnosis using them, and their uses in the preparation of sedative, sleep-inducing and anti-anxiety drugs. Background technique [0002] In today's society, with the acceleration of people's lifestyles and the intensification of competition, sleep disorders / sleep sub-health has become a modern urban disease, which is widespread and seriously affects people's health and quality of life, and has become a social problem that cannot be ignored. With the development of society and economy, people's survival pressure is gradually increasing, and there are more and more people with insomnia, and the market demand for sedative, hypnotic and anti-anxiety drugs is also increasing year by year. The situation also increased. Therefore, finding...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5517A61P25/20A61P25/22
CPCC07D487/04A61P25/20A61P25/22
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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