Hydrobromide of benzodiazepine derivative, preparation method and uses thereof

一种氢溴酸盐、氢溴酸的技术，应用在医药化学领域，能够解决临床使用不便、药物剂量不准确、长时间震荡溶解等问题

Active Publication Date: 2018-09-07
CHENGDU BRILLIANT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] It can be seen from the above table that no matter whether it is remimazolam free base or known salt derivatives of remimazolam, the water solubility is not higher than 11mg / ml, and it is only in the slightly soluble range, which will increase Its safety risk in clinical use requires long-term shaking and dissolution during clinical reconstitution, and there may be residual insoluble raw materials, resulting in inaccurate drug dosage and potential safety risks. In addition, this drug is used for general anesthesia For indications with large demand, the amount of diluent will be increased, which will cause extreme inconvenience in clinical use
Therefore, the solubility of known salt derivatives of remimazolam is a big disadvantage, which needs to be further improved.

Method used

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  • Hydrobromide of benzodiazepine derivative, preparation method and uses thereof
  • Hydrobromide of benzodiazepine derivative, preparation method and uses thereof
  • Hydrobromide of benzodiazepine derivative, preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] The preparation of the hydrobromide III crystal form of embodiment 1 formula (I) compound

[0070] Accurately weigh 1.8g of the compound of formula (I) in a 100mL there-necked flask, add 8.2mL of isopropanol and stir to make it all dissolve, then dissolve 0.83g of 47% aqueous hydrobromic acid in 6.3mL of isopropanol, and drop Add it to the isopropanol solution of the compound of formula (I), stir and crystallize, filter, and dry under reduced pressure at 55°C to obtain the hydrobromide salt of the compound of formula (I).

[0071] The X-ray diffraction spectrum figure of this crystal is shown in the attached figure 1 , DSC and TGA spectra see attached figure 2 , with a melting point of 163° C., defining this crystal form as the hydrobromide III crystal form of the compound of formula (I).

Embodiment 2

[0072] Embodiment 2: the preparation of the hydrobromide α crystal form of formula (I) compound

[0073] The hydrobromide III crystal form compound can undergo crystal transformation in a non-flowing gas with a certain humidity to obtain the α crystal form, especially in air with a humidity above 75%, through the mediation of the gas phase interface, the crystal form transformation occurs . The advantage of this method is that it is not mediated by solvent, no loss occurs, and no solvent residue is introduced.

[0074] Specifically, 200 mg of the hydrobromide salt III crystal form compound of the compound of formula (I) in Example 1 was left open for 20 hours under the condition of 50-55°C-RH75%. The X-ray diffraction spectrum figure of this crystalline sample is shown in image 3 , determine that the product is formula (I ) compound hydrobromide α crystal form. IC: The content of bromide ions is 15.74%, and the ratio of hydrobromic acid to salt is confirmed to be 1:1; solv...

Embodiment 3

[0075] Embodiment 3: the preparation of the hydrobromide α crystal form of formula (I) compound

[0076] Put 500 mg of the hydrobromide III crystal form compound of the compound of formula (I) in the above Example 1, and place it under the condition of 55-60°C-RH75% for 60 hours. The X-ray diffraction spectrogram and the DSC spectrogram of the crystalline sample are studied and compared, and it is determined that the product is the hydrobromide α crystal form of the compound of formula (I).

[0077] X-ray diffraction spectrum see Figure 4 , at about 6.96, 8.24, 10.48, 12.77, 13.61, 13.85, 15.20, 16.05, 16.28, 17.70, 19.40, 20.80, 22.85, 23.23, 24.05, 24.92, 25.55, 26.25, 27.79, 28.45, 30.7 attached Figure 5 , showing a melting point of 170°C, the sample contains 4.3% free water due to no further drying after crystallization at 75% humidity, which is reflected in a weight loss platform at 60.78-79.45°C on TGA; in addition, the DVS spectrum shows a certain It has the abilit...

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Abstract

The present invention provides the hydrobromide of 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazole[1,2-a][1,4]benzodiazepine-4-yl]methyl propionate, and a related crystal form thereof, and a preparation method and uses of the hydrobromide. According to the present invention, the solubility (more than 100 mg / ml) of the hydrobromide is extremely excellent and is significantly superior to other currently commercial or developed salt products of the compound, the hydrobromide is particularly suitable for the preparation of injections, the stability of various crystal forms is relatively good,and the hydrobromide has good practical value and market prospects.

Description

technical field [0001] The present invention relates to a kind of benzodiazepine The hydrobromide salt of the derivative and its preparation method and application belong to the field of medicinal chemistry. Background technique [0002] Remimazolam, its structure is shown in formula (I), chemical name is 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazo[1,2 -a][1,4]benzodiazepine -4-yl] propionate methyl ester. [0003] [0004] It is currently known that the compound is a short-acting central nervous system (CNS, Central Nervous System) inhibitor, and has effects including sedative hypnosis, anxiolytic, muscle relaxation and anticonvulsant. At present, it is mostly used for intravenous administration in the following clinical treatment programs: such as preoperative sedation, anxiolysis and amnesia during surgery; conscious sedation during short-term diagnostic, surgical or endoscopic procedures; administration of other anesthetics and analgesia as a component for...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61K31/5517A61P25/20A61P25/22A61P21/02A61P25/08A61P23/00A61K9/08A61K9/19
CPCA61K47/26A61K9/0019A61K9/08A61K9/19C07D487/04C07B2200/13A61K31/5517A61P21/02A61P23/00A61P25/08A61P25/20A61P25/22
Inventor 黄浩喜卓国清商国宁梁臻储婷陈翠翠罗鸣李英富苏忠海
Owner CHENGDU BRILLIANT PHARMA CO LTD
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