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Substituted pyrazole formate derivative and application thereof

An unsubstituted and deuterated technology, applied in the field of substituted pyrazole carboxylate derivatives, can solve problems such as not found

Active Publication Date: 2020-01-24
CHENGDU MFS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

And have successively found etomidate analogues such as Dimethylmethoxycarbonyl metomidate (DMMM) and Cyclopropyl methoxycarbonyl metomidate (CPMM), but have not yet found that both retained 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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  • Substituted pyrazole formate derivative and application thereof
  • Substituted pyrazole formate derivative and application thereof
  • Substituted pyrazole formate derivative and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0228] Embodiment 1 Preparation of compound 1 and compound 2 of the present invention

[0229]

[0230] In an ice-water bath at 0°C, S-phenylethanol (2.3g, 18.8mmol) was added to ethyl 1H-pyrazole-5carboxylate (2.0g, 14.3mmol) and PPh 3 (5.6g, 21.4mmol) in THF (50mL) solution, then dropwise add DEAD (3.7g, 21.2mmol) in THF (10mL) solution, add dropwise to the system at a rate of 1mmol / min, slowly rise to Stir overnight at room temperature. After the completion of the reaction was monitored by TLC, saturated brine (50 mL) was added to the reaction system, extracted with ethyl acetate (3×15 mL), the combined organic phases were washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. Suction filtration, concentrated under reduced pressure to obtain the crude product, the crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=1 / 20~1 / 10), TLC (ethyl acetate / petroleum ether (v / v) / v)=1 / 2) was monitored, and the ...

Embodiment 2

[0235] Embodiment 2 The preparation of compound 3~compound 48 of the present invention

[0236]

[0237] At room temperature, NaOH (3.1 g, 77.5 mmol) was added in one portion to compound 1 (9.5 g, 38.9 mmol) in EtOH / H 2 O (25mL, 1 / 1 / 1) solution, stirred at 60°C for 1 hour. After the completion of the reaction was monitored by TLC, the reaction solution was concentrated, and water (20 mL) was added to the system. After adjusting the pH to 4-5 with 1N hydrochloric acid, it was extracted with dichloromethane (3×15 mL), and the combined organic phases were washed with anhydrous sodium sulfate Dry, filter with suction, and concentrate under reduced pressure to obtain compound A (6.7 g, yield 80%) as a white solid. ESI[M+H] + =217.1

[0238] 1 H NMR (400MHz, CDCl 3 )δ7.62(d, J=2.0Hz, 1H), 7.39–7.16(m, 5H), 7.00(d, J=2.0Hz, 1H), 6.56(q, J=7.0Hz, 1H), 1.93( d,J=7.1Hz,3H).

[0239] 2. Preparation of target compound 3-compound 48

[0240]

[0241] Preparation of Compound 3...

Embodiment 3

[0333] Embodiment 3 Preparation of compound 49 and compound 50 of the present invention

[0334]

[0335] 1. Preparation of Ethyl 3-nitro-1H-pyrazole-5-carboxylate (49-2)

[0336]

[0337] Dissolve 49-1 (50g, 318.3mmol) in ethanol (300mL) at room temperature, add thionyl chloride (49g, 412mmol) dropwise in an ice-water bath at 0°C, and react at 85°C for 10 hours after the addition is complete. After the reaction was complete as monitored by TLC, it was concentrated under reduced pressure to obtain a crude product, which was dissolved in dichloromethane (30 mL) and washed with saturated NaHCO 3 The aqueous solution was adjusted to pH=8, extracted with dichloromethane (3×30 mL), washed with saturated brine (50 mL), dried, filtered with suction, and the filtrate was concentrated to obtain compound 49-2 as a white solid (58.7 g, yield 99.6%). ESI[M+H] + =186.1

[0338] 2. Preparation of Ethyl 3-amino-1H-pyrazole-5-carboxylate (49-3)

[0339]

[0340] 49-2 (58.7 g, 317...

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Abstract

The invention discloses a compound shown in a formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound, or a solvate of the compound, or a prodrug of the compound, or a metabolite of the compound, or a deuterated derivative of the compound. The compound is a substituted pyrazole formate derivative with a novel structure and belongs to the field of pharmaceuticalchemistry. The invention also discloses an application of the substituted pyrazole formate derivative in preparing medicines with sedative, hypnotic and / or anaesthesia effects and in preparing medicines capable of controlling a continuous epilepsy state. The compound has a good inhibiting effect on central nervous system, and provides a new choice for clinically screening and / or preparing medicines which have sedative, hypnotic and / or anaesthesia effects and can control a continuous epilepsy state.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of substituted pyrazole carboxylate derivatives with novel structures, and the use of such compounds in the preparation of drugs with sedative, hypnotic and / or general anesthesia and drugs capable of controlling status epilepticus in the 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...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D231/14C07D405/12C07D409/12C07D231/16A61P25/20A61P25/08A61P23/00A61K31/415A61K31/4155
CPCC07D231/14C07D405/12C07D409/12C07D231/16A61P25/20A61P25/08A61P23/00
Inventor 马海军王昌华解振彪
Owner CHENGDU MFS PHARMA CO LTD
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