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N-substituted imidazole formate derivative and application thereof

An unsubstituted and deuterated technology, applied in the field of medicinal chemistry, can solve problems such as not found

Active Publication Date: 2019-05-21
CHENGDU MFS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And have found etomidate analogs such as dimethylmethoxycarbonyl metomidate (DMMM) and cyclopropyl methoxycarbonyl metomidate (CPMM) etc. successively, but still have not looked for not only retained the unique advantage of etomidate (such as efficient, safe), eliminated its adverse effect again. Compounds with inhibitory effects on adrenocortical function

Method used

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  • N-substituted imidazole formate derivative and application thereof
  • N-substituted imidazole formate derivative and application thereof
  • N-substituted imidazole formate derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0219] Embodiment 1 Preparation of compound 1 and compound 3 of the present invention

[0220]

[0221] 1. Preparation of 1-1(Ethyl 2-((tert-butyldiphenylsilyl)oxy)acetate)(1-2)

[0222]

[0223] In an ice-water bath at 0°C, tert-butyldiphenylchlorosilane (29.1g, 0.106mol) was added dropwise to ethyl glycolate (1-1) (10.0g, 96.1mmol), triethylamine (29.1 g, 0.288mol) and DMAP (1.17g, 9.61mmol) in dichloromethane (100mL) solution, the addition was completed in 30 minutes, then the temperature was naturally raised, and the reaction was stirred at room temperature for 4 hours. After the reaction solution was destroyed by adding water, the organic phase was separated, washed successively with 1N HCl, saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated under reduced pressure to obtain a crude product, which was separated by silica gel column chromatography and separated with ethyl acetate:petroleum ether ( Any ratio of v / v) in the ra...

Embodiment 2

[0237] Embodiment 2 Compound 2 of the present invention, the preparation of compound 4 and compound 6

[0238]

[0239] 1. Preparation of 1-(Hydroxymethyl)cyclopropanol (2-2)

[0240]

[0241] In an ice-salt bath at -10°C, the LiAlH 4 (3.72g, 98.0mmol) was added 10mmol every 1min, and was added into 2-1 (5.00g, 49.0mmol) in THF (50mL) solution in 10 times, and the reaction was continued for 2 hours after the addition was complete. After TLC monitors that the reaction is complete, under ice-salt bath, Na 2 SO 4 .10H 2 Add 1 g of O (10 g) every 1 min, and add it to the reaction system 10 times in total. After suction filtration, the filtrate is spin-dried, and separated by column chromatography (methanol / dichloromethane (v / v) at 1 / 50~1 / 10 Any ratio within the range), TLC (methanol / dichloromethane (v / v)=1 / 20) detection, collect Rf=0.2~0.3 part, obtain colorless oil 2-2 (1g, yield 23% ).

[0242] 2. Preparation of (R)-1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid (1...

Embodiment 3

[0259] Embodiment 3 Preparation of compound 5 of the present invention

[0260]

[0261] 1. Preparation of 1-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)cyclopropanol (5-1)

[0262]

[0263] At room temperature, 3,4-dihydro-2H-pyran (478mg, 5.68mmol), 2-2 (500mg, 5.68mmol) and pyridine p-toluenesulfonate (70.4mg, 0.28mmol) were added to di Chloromethane (10 mL) solution, react at room temperature for 2 hours. After TLC monitors that the reaction is complete, the reaction system is concentrated under reduced pressure, separated by gel column chromatography (ethyl acetate / petroleum ether (v / v) is in any ratio within the range of 1 / 10~1 / 1), TLC (acetic acid Ethyl ester / petroleum ether (v / v)=1 / 1) was detected, and fractions with Rf=0.3-0.4 were collected to obtain colorless oily compound 5-1 (510 mg, yield 52%).

[0264] 2. Preparation of target compound 5

[0265]

[0266] At room temperature, 5-1 (510mg, 2.96mmol), 1b-2 (640mg, 2.96mmol), EDCI (567mg, 2.96mmol), HOBT (400...

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Abstract

The invention discloses a compound as shown in the formula I, or a stereisomer, or pharmaceutically acceptable salt, or a solvate, or a prodrug, or a metabolite, or a deuterated derivative thereof. The compound is an N-substituted imidazole formate derivative with a novel structure and belongs to the field of medicinal chemistry. The invention also discloses application of the N-substituted imidazole formate derivative in the preparation of medicines with sedative, hypnotic and / or anesthetic effects, and application in the preparation of medicines capable of controlling the status epilepticus.The compound has a good inhibitory effect on the central nervous system, and provides a new selection for clinical screening and / or preparation of medicines with the sedative, hypnotic and / or anesthetic effects and capable of controlling the status epilepticus.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a novel structure of N-substituted imidazole carboxylate derivatives and the use of the compound in the preparation of drugs with sedative, hypnotic and / or anesthetic effects and in the preparation of drugs capable of controlling status epilepticus Applications. Background technique [0002] An imidazole derivative etomidate, the chemical name is R-(+)-1-(1-phenylethyl)-1-hydro-imidazole-5-ethyl carboxylate, which is a hypnotic intravenous general anesthetic , with a wide range of safety, it was 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; AcadEmerg Med. 2006; 13(4): 378-83. PubMed: 16531603). Etomidate is a non-barbiturate intravenous sedative drug, its ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D233/90A61P25/20A61P23/00A61P25/08A61K31/4178A61K31/4164
CPCC07D405/12C07D233/90C07D409/12A61P25/20A61P23/00A61P25/08C07D405/14Y02P20/55A61K31/415
Inventor 马海军王昌华
Owner CHENGDU MFS PHARMA CO LTD
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