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Substituted pyrrolecarboxylate derivative and application thereof

An unsubstituted and deuterated technology, applied in the field of substituted pyrrole formate derivatives, can solve the problems of low anesthetic potency and limited clinical application.

Active Publication Date: 2019-07-12
CHENGDU MFS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the current carboetomidate has the potential to be an ideal general anesthetic drug, its anesthetic potency is too low to limit its possible clinical application

Method used

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  • Substituted pyrrolecarboxylate derivative and application thereof
  • Substituted pyrrolecarboxylate derivative and application thereof
  • Substituted pyrrolecarboxylate derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0242] Embodiment 1 Preparation of Compound 1 of the present invention

[0243]

[0244] 1. Preparation of (3-Methyloxetan-3-yl)methyl 1H-pyrrole-2-carboxylate (1-1)

[0245]

[0246] At room temperature, 1H-pyrrole-5-carboxylic acid (111.1 mg, 1.0 mmol), DCC (309.5 mg, 1.5 mmol) and DMAP (183.3 mg, 1.5 mmol) were dissolved in dichloromethane (2 mL), stirred at room temperature for 5 Minutes, then (3-methyloxetan-3-yl)methanol (153.2 mg, 1.5 mmol) was slowly added to the reaction system with a syringe, and stirred at room temperature overnight. The complete reaction of the system was monitored by TLC, the solvent was removed by concentration under reduced pressure, and methyl tert-butyl ether (5 mL) was added to stir, filtered with suction, the filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v)=1 / 1) ...

Embodiment 2

[0292] Embodiment 2 Preparation of Compound 22 of the present invention

[0293]

[0294] 1. Preparation of (3-Methyloxetan-3-yl)methyl 3-fluoro-1H-pyrrole-2-carboxylate (22-1)

[0295]

[0296] 3-Fluoro-1H-pyrrole-2-carboxylic acid (129.1 mg, 1.0 mmol), DCC (309.5 mg, 1.5 mmol) and DMAP (183.3 mg, 1.5 mmol) were dissolved in dichloromethane (2 mL) at room temperature , stirred at room temperature for 5 minutes, then slowly added (3-methyloxetan-3-yl)methanol (153.2 mg, 1.5 mmol) to the reaction system with a syringe, and stirred overnight at room temperature. The complete reaction of the system was monitored by TLC, the solvent was removed by concentration under reduced pressure, and methyl tert-butyl ether (5 mL) was added to stir, then filtered with suction, the filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate / petrol...

Embodiment 3

[0444] Embodiment 3 The preparation of compound 94 of the present invention

[0445]

[0446] 1. Preparation of S-(thietan-3-yl)5-fluoro-1H-pyrrole-2-carbothioate (94-1)

[0447]

[0448]5-Fluoro-1H-pyrrole-2-carboxylic acid (129.1 mg, 1.0 mmol), DCC (309.5 mg, 1.5 mmol) and DMAP (183.3 mg, 1.5 mmol) were dissolved in dichloromethane (2 mL) at room temperature , stirred at room temperature for 5 minutes, then slowly added thietane-3-thiol (159.3 mg, 1.5 mmol) to the reaction system with a syringe, and stirred overnight at room temperature. The complete reaction of the system was monitored by TLC, the solvent was removed by concentration under reduced pressure, and methyl tert-butyl ether (5 mL) was added to stir, filtered with suction, the filter cake was washed with methyl tert-butyl ether, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative TLC (ethyl acetate / petroleum ether (v / v)=1 / 1) and f...

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Abstract

The invention discloses a compound shown in a formula I, or a stereoisomer, or a pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative of the compound, and belongs to the field of medicinal chemistry. The compound is a substituted imidazolecarboxylate derivative with novel structure. The invention further discloses application of the substitutedimidazolecarboxylate derivative in preparation of drugs with effects of sedation, hypnosis and / or anesthesia and application of the substituted imidazolecarboxylate derivative in preparation of drugscapable of controlling status epilepticus, wherein the compound has good inhibition effects on the central nervous system, and a new choice is provided for clinically screening and / or preparing drugswith effects of sedation, hypnosis and / or anesthesia and drugs for controlling the status epilepticus.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a substituted pyrrole carboxylate derivative with a novel structure, and the application of the compound in the preparation of drugs with sedative, hypnotic and / or anesthetic effects and drugs capable of controlling status epilepticus . Background technique [0002] A kind of imidazole carboxylate derivative, i.e. etomidate, chemical name is R-(+)-1-(1-phenylethyl)-1-hydro-imidazole-5-ethyl carboxylate, is a hypnotic Intravenous general anesthetics have a large safety range and were once one of the commonly used drugs for anesthesia induction. The clinical application of imidazole derivatives has a history of 30 years (Br J Anaesth.1976; 48 (3): 213-6. PubMed: 1259887; Arch Int Pharmacodyn Ther.1975; 214 (1): 92-132. PubMed : 1156027; Acad Emerg Med. 2006; 13(4):378-83. PubMed: 16531603). Etomidate is a non-barbiturate intravenous sedative drug, its action strengt...

Claims

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Application Information

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IPC IPC(8): C07D405/12C07D207/34C07D409/12A61K31/401A61K31/4025A61P25/20A61P25/08A61P23/00
CPCC07D405/12C07D207/34C07D409/12A61P25/20A61P25/08A61P23/00
Inventor 马海军王昌华解振彪
Owner CHENGDU MFS PHARMA CO LTD
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