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Benzodiazepine* derivative and salts thereof and related crystal forms, preparation methods and uses thereof

A crystal and form technology, applied in the field of benzodiazepine* derivatives and their salts and related crystal form, preparation and application, can solve the problems of drug-drug interaction, long time recovery, etc., and achieve solvent residue Low, good solid state stability, the effect of ensuring safety

Active Publication Date: 2018-12-07
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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  • Benzodiazepine* derivative and salts thereof and related crystal forms, preparation methods and uses thereof
  • Benzodiazepine* derivative and salts thereof and related crystal forms, preparation methods and uses thereof
  • Benzodiazepine* derivative and salts thereof and related crystal forms, preparation methods and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0224] 3-(8-Chloro-1-cyclopropyl-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1 ,4] diazepine -4-base) the preparation of methyl propionate (compound of formula (I))

[0225]

[0226] The first step: 7-chloro-5-(2-fluorophenyl)-1H-benzo[e][1,4]diazepine - Preparation of 2(3H)-thione (compound B)

[0227] 7-Chloro-5-(2-fluorophenyl)-1H-benzo[e][1,4]diazepine -2(3H)-one (compound A, 5.0 g, 17.3 mmol) was dissolved in tetrahydrofuran (150 mL). Phosphorus pentasulfide (5.77g, 6.55mmol) was added, the mixture was heated to 78°C and reacted for 2 hours. Filtered, washed 3 times, added water to the filtrate, extracted 3 times with ethyl acetate, dried and concentrated, purified by column chromatography to obtain the target product 7-chloro-5-(2-fluorophenyl)-1H-benzo[ e][1,4]diazepine -2(3H)-thione (compound B, 4.2 g, yield: 79%).

[0228] MS m / z(ESI):305[M+H]+

[0229] The second step: 8-chloro-1-cyclopropyl-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazole[4,3-a]...

Embodiment 2

[0237] 3(S)-3-(8-chloro-1-cyclopropyl-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3 -a][1,4]diazepine Preparation of -4-yl) methyl propionate (compound of formula (Ia))

[0238]

[0239] The first step: (S)-5-((2-fluoro-benzoyl-4-chlorophenyl) amino)-4-((tert-butoxycarbonyl) amino)-5-oxopentanoic acid methyl ester ( Preparation of compound c)

[0240] 2-amino-5-chloro-2'-fluorobenzophenone (compound a, 20g, 0.083mol, commercially available) and N-tert-butoxycarbonyl-L-glutamic acid-5-methyl ester (compound b, 23 g, 0.088 mol, commercially available) was dissolved in dichloromethane (300 mL). The mixture was cooled to 0° C., dicyclohexylcarbodiimide (DCC, 18.2 g, 0.088 mmol) was added, and stirred for 24 hours. The liquid phase mass spectrometry (LCMS) test showed that the reaction was complete. The reaction solution was poured into ice water, extracted with ethyl acetate, the organic phase was washed 3 times with water, dried and concentrated to obtain the crude p...

Embodiment 3

[0253] Preparation and Characterization of Crystal B of Compound of Formula (Ia)

[0254] Crystal B of the compound of formula (Ia) was prepared as follows:

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PUM

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Abstract

The present invention relates to a crystalline form of a compound of formula (I) or formula (Ia), salts of the compound of formula (Ia) and crystal forms thereof, preparation methods thereof, pharmaceutical compositions comprising the same, and use thereof in the preparation of sedation, hypnosis, anxiolytic, muscle-relaxation or anticonvulsant medicines.

Description

technical field [0001] The present invention relates to 3-(8-chloro-1-cyclopropyl-6-(2-fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a ][1,4]diazepine -4-yl) methyl propionate (hereinafter referred to as "the compound of formula (I)") and its S-configuration compound 3 (S)-3-(8-chloro-1-cyclopropyl-6- (2-Fluorophenyl)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepine Crystal forms of methyl -4-yl)propionate (hereinafter referred to as "compound of formula (Ia)"), salts of the compound and crystal forms thereof, processes for their preparation, pharmaceutical compositions containing them, and their preparations Use in a sedative, hypnotic, anxiolytic, muscle relaxant or anticonvulsant drug. Background technique [0002] Benzodiazepine Benzodiazepines are short-acting central nervous system depressants with sedative, hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. This class of drugs can be used for intravenous administration in clinical regimens such as...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04C07C51/41C07C55/07C07C55/08A61K31/5517A61P25/20A61P25/22A61P25/08A61P21/02
CPCA61P21/02A61P25/08A61P25/20A61P25/22C07B2200/13C07D487/04
Inventor 刘钢唐建川胡昊唐毅梁勇于华王利春王晶翼
Owner SICHUAN KELUN BIOTECH BIOPHARMACEUTICAL CO LTD
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