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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

[0227] Embodiment 1 Preparation of Compound 1 of the present invention

[0228]

[0229] 1. Preparation of (R)-1-(1-Phenylethyl)-1H-imidazole-5-carbonyl chloride (1b)

[0230]

[0231] In an ice-water bath at 0°C, inject (COCl) 2 (2 mL) was slowly added to a solution of 1b-2 (200 mg, 0.92 mmol) in dichloromethane (20 mL) at a rate of 1 mL / min, and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure to obtain white solid 1b (220 mg, crude product).

[0232] 2. Preparation of target compound 1

[0233]

[0234] In an ice-water bath at 0°C, the 1b prepared in the previous step was added to (S)-5-hydroxymethyldihydrofuran-2-one (107mg, 0.92mmol) and triethylamine (2.81g, 27.8mmol) dichloro methane (30 mL) solution, after the addition was completed, the reaction was continued for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was separated by silica gel column ch...

Embodiment 2

[0236] Embodiment 2 Preparation of Compound 2 of the present invention

[0237]

[0238] In an ice-water bath at 0°C, add (S)-(-)-4-hydroxymethyl-2(5H)-furanone (65mg, 0.56mmol) and triethylamine (113mg, 1.12 mmol) in dichloromethane (5mL) solution, the reaction was continued for 1 hour after the addition was complete. The reaction solution was concentrated under reduced pressure to obtain the crude product, which was separated by silica gel column chromatography, using any ratio of ethyl acetate / petroleum ether (v / v) in the range of 1 / 10 to 1 / 1 as the eluent, TLC (acetic acid Ethyl ester / petroleum ether (v / v)=1 / 1) was detected, and the fraction with Rf=0.4-0.5 was collected to obtain colorless oily compound 2 (20 mg, two-step reaction yield 12%). ESI[M+H] + =313.2

[0239] 1 H NMR (400MHz, d 6 -DMSO)δ8.34(s,1H),7.73–7.71(d,J=0.8Hz,1H),7.59(s,1H),7.36–7.32(m,2H),7.29–7.27(m,1H) ,7.17–7.15(m,2H),6.24–6.22(m,1H),6.18–6.16(m,1H), 5.47(d,J=1.6Hz,1H),4.57(dd,J=12.0,3.2Hz ...

Embodiment 3

[0240] Embodiment 3 Preparation of Compound 3 of the present invention

[0241]

[0242] Compound 3 was prepared by using compound 1b (234 mg, 1.0 mmol) and (S)-3-hydroxy-γ-butyrolactone (102 mg, 1.0 mmol) as raw materials, and compound 3 was synthesized according to the method of Example 1. ESI[M+H] + =301.2

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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): C07D405/12C07D405/14C07D409/12A61P25/20A61P23/00A61P25/08A61K31/4178
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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