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

Inactive 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

[0224] Embodiment 1 Preparation of Compound 1 of the present invention

[0225]

[0226] 1, the preparation of 1-ethynyl cyclobutanol (1-2)

[0227]

[0228] Cyclobutanone (1-1) (700.6mg, 10.0mmol) was dissolved in anhydrous THF (10mL) solution, the reaction system was replaced with nitrogen, and the temperature was lowered to 0°C with an ice-water bath. At 0°C, propargylmagnesium bromide (26 mL, 1.3 mol / L inTHF, 13 mmol) was slowly added to the system over 25 minutes with a syringe, and reacted at room temperature for two hours. The complete reaction was monitored by TLC, the reaction system was terminated with saturated ammonium chloride solution (30mL), extracted with dichloromethane (3×10mL), the combined organic phases were washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and extracted Filtered and concentrated under reduced pressure to obtain colorless oily crude product 1-2, which was directly used in the next reaction without further puri...

Embodiment 2

[0233] Embodiment 2 Preparation of Compound 2 of the present invention

[0234]

[0235] 1. Preparation of 3-(1-Ethoxyvinyl)oxetan-3-ol(2-2)

[0236]

[0237] 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. Lithium (20 mL, 1.0 mol / L inpentane, 20 mmol) was slowly added to the system within 5 minutes, and the temperature was kept below -70°C during the addition. After adding tert-butyllithium, continue to react 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 place the 3-oxoheterocyclic Butanone (720.6 mg, 10.0 mmol) in anhydrous THF (20 mL) was slowly added to the reaction system over 10 minutes. The reaction system was naturally warmed to room temperature, and the reaction was ...

Embodiment 3

[0242] Embodiment 3 Preparation of Compound 3 of the present invention

[0243]

[0244] 1. Preparation of 3-Ethynyloxetan-3-ol (3-2)

[0245]

[0246]Dissolve vinyl ethyl ether (3-1) (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. Lithium (20 mL, 1.0 mol / L inpentane, 20 mmol) was slowly added to the system within 5 minutes, and the temperature was kept below -70°C during the addition. After adding tert-butyllithium, continue to react 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 place the 3-oxoheterocyclic Butanone (720.6 mg, 10.0 mmol) in anhydrous THF (20 mL) was slowly added to the reaction system over 10 minutes. The reaction system was naturally warmed to room temperature, and the reaction was continue...

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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): C07D405/12C07D233/90C07D409/12A61P25/20A61P23/00A61P25/08A61K31/4178A61K31/4164
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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