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Substituted imidazole formate type derivative and application thereof

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

Active Publication Date: 2019-05-17
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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  • Substituted imidazole formate type derivative and application thereof
  • Substituted imidazole formate type derivative and application thereof
  • Substituted imidazole formate type derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0280] Embodiment 1 Preparation of Compound 1 of the present invention

[0281]

[0282] 1. Preparation of 3-(Hydroxymethyl)cyclobutane-1-carbonitrile (1-1)

[0283]

[0284] 3-Methylenecyclobutylcarbonitrile (5.59g, 60mmol) was dissolved in THF (150mL), the system was lowered to 0°C with an ice-water bath, and 9-BBN (0.5M / THF, 144mL, 72mmol) was added to Add dropwise to the system at a rate of 2 mL / min, and control the temperature below 0°C, and continue stirring at this temperature for 1 hour, then naturally warm the system to room temperature, and continue the reaction for 4 hours. The H of sodium perborate (24.54g, 300mmol) 2 O (200 mL) solution was added dropwise to the system at a rate of 5 mL / min, and stirred at room temperature for 12 hours. After the reaction was monitored by TLC, the reaction was complete, suction filtered, the filter cake was washed with ethyl acetate (3×50mL), the filtrate was extracted with ethyl acetate (3×50mL), and the combined organic ...

Embodiment 2

[0369] Embodiment 2 Preparation of compound 40 of the present invention

[0370]

[0371] The preparation method of compound 40 was similar to that of compound 1, and it was prepared according to the method of general operation A.

[0372] The intermediate compound 40-1 was obtained by condensation reaction of 1H-imidazole-5-carboxylic acid and methyl 2-cyclopentanone carboxylate, and then reacted with S-phenylethanol to obtain the target compound 40 (24 mg). ESI[M+H] + =341.2

[0373] 1 H NMR (400MHz, CDCl 3 )δ7.97(s,1H),7.88(s,1H),7.41–7.29(m,3H),7.25–7.16(m,2H), 6.31(q,J=7.2Hz,1H),3.59(s ,3H),2.73–2.61(m,4H),2.04–1.94(m,2H),1.90(d,J=7.1Hz, 3H).

[0374] The preparation of the following compounds 41-51 is similar to the compound 40 in Example 2, prepared according to the method of general operation A, and condensing 1H-imidazole-5-carboxylic acid with the corresponding five-membered ring alcohol to obtain 1H-imidazole-5-carboxylic acid ester Intermediate, and then r...

Embodiment 3

[0396] Embodiment 3 Preparation of compound 52 of the present invention

[0397]

[0398] The preparation method of compound 52 was similar to that of compound 1, and it was prepared according to the method of general procedure A.

[0399] The intermediate compound 52-1 was obtained by condensation reaction of 1H-imidazole-5-carboxylic acid and ethyl 2-cyclohexanone carboxylate, and then reacted with S-phenylethanol to obtain the target compound 52 (215 mg). ESI[M+H] + =369.4

[0400] 1 H NMR (400MHz, CDCl 3 )δ7.90(s,1H),7.88(s,1H),7.44–7.30(m,3H),7.27–7.20(m,2H), 6.36(q,J=6.6Hz,1H),4.19–3.90 (m,2H),2.44(t,J=6.0Hz,2H),2.32–2.24(m,2H),1.89(d,J=7.1Hz,3H),1.83–1.73(m,2H),1.73– 1.64(m,2H),0.99(t,J=7.1Hz,3H).

[0401] The preparation of the following compounds 53-73 is similar to the compound 52 in Example 3, prepared according to the method of general operation A, and condensing 1H-imidazole-5-carboxylic acid with the corresponding six-membered ring alcohol to obtain 1H-i...

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Abstract

The invention discloses a compound shown as a formula I or a stereoisomer thereof or pharmaceutically acceptable salts thereof or a solvate thereof or a prodrug thereof or a metabolic product thereofor a deuterated derivative thereof. The compound is a substituted imidazole formate type derivative with a novel structure and belongs to the field of pharmaceutical chemistry. The invention further discloses application of the substituted imidazole formate type derivative to preparation of drugs with calming, hypnosis and / or anesthetic effects and application of the substituted imidazole formatetype derivative to preparation of drugs capable of controlling status epilepticus. The compound disclosed by the invention has a relatively good inhibition effect on a central nervous system and provides a new choice for clinically screening and / or preparing the drugs with the calming, hypnosis and / or anesthetic effects and capable of controlling the status epilepticus. The formula I is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a substituted imidazole carboxylate derivative and its application. 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 action strength is 4 times that of barbital sodium and 12 times that of thiopental sodium, and the induction of general anesthesia is fast, and the recovery and recovery after administration are a...

Claims

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Application Information

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IPC IPC(8): C07D233/90C07D405/12C07D403/12A61K31/4174A61K31/4178A61P23/00A61P25/20A61P25/08
CPCY02P20/55
Inventor 马海军王昌华解振彪
Owner CHENGDU MFS PHARMA CO LTD
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