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 have not yet found the unique advantages of etomidate (such as high efficiency, safety) and eliminated its adverse effects 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

[0240] Embodiment 1 Preparation of Compound 1 of the present invention

[0241]

[0242] At room temperature, dioxane hydrochloride solution (4M, 0.15mL) was added dropwise at a rate of 1ml / min in dichloromethane (10mL) of 1-1 (150mg, 0.81mmol), and reacted at room temperature for 5 minutes , 1b (190 mg, 0.81 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction system was concentrated under reduced pressure, purified by preparative TLC (methanol / dichloromethane (v / v)=1 / 10) and the fraction with Rf=0.4-0.6 was collected to obtain colorless oily compound 1 (15 mg, yield 6%) . ESI[M+H] + =299.2

[0243] 1 H NMR (400MHz, d 6 -DMSO)δ8.38(s,1H),7.77(s,1H),7.33(t,J=7.3Hz,2H),7.28-7.26(m,1H),7.16(d,J=7.2Hz,2H ),6.15(q,J=7.2Hz,1H),1.89(s,3H),1.85(d,J=7.2Hz,3H),1.59–1.44(m,2H),1.35–1.10(m,2H) .

Embodiment 2

[0244] Embodiment 2 Preparation of Compound 2 of the present invention

[0245]

[0246] 1. Preparation of 1-(1-Ethoxyvinyl)cyclobutan-1-ol(2-2)

[0247]

[0248] Dissolve vinyl ethyl ether (2-1) (3.60g, 50.0mmol) in anhydrous THF (20mL), replace the reaction system with nitrogen, and cool down to -78°C with dry ice acetone under the protection of nitrogen. Basallithium (20 mL, 1.0 mol / L inpentane, 20 mmol) was slowly added to the system at a rate of 1 mL / min, and the temperature was kept below -70°C during the addition. After adding tert-butyllithium, continue to maintain the reaction at -78°C for 15 minutes, then replace the dry ice acetone bath with an ice-water bath, continue the reaction for 15 minutes, then use a dry ice acetone bath to lower the temperature to -78°C, and cyclobutanone (700.9 mg, 10.0 mmol) in anhydrous THF (20 mL) was slowly added to the reaction system at a rate of 1 mL / min. The reaction system was naturally warmed to room temperature, and the ...

Embodiment 3

[0256] Embodiment 3 Preparation of Compound 3 of the present invention

[0257]

[0258] 1. Preparation of 1-(3-Hydroxyoxetan-3-yl)ethan-1-one(3-2)

[0259]

[0260] At room temperature, HCl (0.1mol / L) (45mL) was added to 3-1 (288mg, 2mmol) in THF / H 2 O (45mL, 4 / 1) solution. The reaction system was stirred at room temperature for 15 minutes, monitored by TLC for complete reaction, extracted with dichloromethane (3×10 mL), combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, suction filtered, and concentrated under reduced pressure to obtain Colorless oily mixture 3-2, the product was directly used in the next reaction without further purification

[0261] 2. Preparation of target compound 3

[0262]

[0263] Compound 3 was prepared by using compound 1b-2 (324mg, 1.50mmol) and 3-2 as raw materials according to the method of general operation A, and the crude product was purified by preparative TLC (ethyl acetate / petr...

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PUM

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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 a...

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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