Ketone-substituted heterocyclic compound and anesthetic effect thereof

A compound, unsubstituted technology, applied in the field of keto-substituted heterocyclic compounds

Active Publication Date: 2021-01-05
CHENGDU MFS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, with the clinical use, the disadvantages of e

Method used

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  • Ketone-substituted heterocyclic compound and anesthetic effect thereof
  • Ketone-substituted heterocyclic compound and anesthetic effect thereof
  • Ketone-substituted heterocyclic compound and anesthetic effect thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Embodiment 1 Preparation of Compound D1 of the present invention

[0121] Method A:

[0122]

[0123] 1. Preparation of Compound A-1

[0124]

[0125] (S)-1-phenylethan-1-ol (8.38g, 68.6mmol) was added to ethyl1H-pyrazole-5-carboxylate (7.4g, 52.8mmol) and PPh at 0°C in an ice-water bath 3 (20.8g, 79.3mmol) in THF (50mL) solution, then DEAD (13.8g, 79.2mmol) THF (150mL) solution was added dropwise to the reaction system at a rate of 2mmol / min, and slowly rose to Stir overnight at room temperature. After the reaction was complete as monitored by TLC, saturated brine (100 mL) was added to the reaction system, extracted with EtOAc (3×30 mL), the combined organic phases were washed with saturated brine (50 mL), anhydrous Na 2 SO 4 Dry, filter with suction, and concentrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=1 / 20~1 / 10), TLC (ethyl acetate / petroleum ether (v / v...

Embodiment 2

[0155] Embodiment 2 Preparation of Compounds D2~D10 of the present invention

[0156]

[0157] 1. Preparation of target compound D2

[0158]

[0159] At room temperature, the crude compound A-8 (1.4g, 4.08mmol), Na 2 CO 3 (865 mg, 8.16 mmol) was dissolved in MeOH (10 mL) and stirred overnight at room temperature. After the reaction was complete as monitored by TLC, saturated brine (20 mL) was slowly added to the reaction system, extracted with EtOAc (3×10 mL), and the combined organic phases were washed with anhydrous Na 2 SO 4 Dry, filter with suction, and concentrate under reduced pressure to obtain the crude product, which is purified by silica gel column chromatography (ethyl acetate / petroleum ether (v / v)=1 / 20~1 / 8), TLC (ethyl acetate / petroleum ether (v / v)=1 / 5) was monitored, and the fraction with Rf=0.5-0.6 was collected to obtain the target compound D2 (1.3 g, yield 95%). ESI[M+H] + =335.0

[0160] 1 H NMR (400MHz, CDCl 3)δ7.62(d,J=2.0Hz,1H),7.34–7.16(m,6H...

Embodiment 3

[0202] Embodiment 3 Preparation of Compounds D11-D12 of the present invention

[0203]

[0204] 1. Preparation of target compound D11

[0205]

[0206] At room temperature, the PTSA.H 2 O (1.2 g, 6.31 mmol) was added to a solution of compound D1 (600 mg, 1.97 mmol) in acetone (15 mL), and stirred at room temperature overnight. After the reaction was complete as monitored by TLC, ice water (10 mL) was added to the reaction system, extracted with EtOAc (3×15 mL), the combined organic phases were washed with saturated brine (10 mL), anhydrous Na 2 SO 4 Dry, filter with suction, and concentrate under reduced pressure to obtain a crude product. The crude product is purified by preparative TLC (ethyl acetate / petroleum ether (v / v)=1 / 3) and the fraction with Rf=0.4~0.6 is collected to obtain the target compound D11 (305 mg, Yield 60%). ESI[M+H] + =259.0

[0207] 1 H NMR (400MHz, CDCl 3 )δ7.67(d, J=2.1Hz, 1H), 7.44–7.16(m, 6H), 6.54(q, J=7.0Hz, 1H), 3.94(s, 3H), 1.95(d, J...

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PUM

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Abstract

The invention discloses a ketone-substituted heterocyclic compound and an anesthetic effect thereof. Specifically provided are a compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a deuterated derivative thereof. The ketone-substituted heterocyclic compound provided by the invention has a good central nervous system inhibition effect, can generate sedative, hypnotic and/or general anesthesia effects, and can control the epilepsy persistent state; the ketone-substituted heterocyclic compound also has the characteristics of quick response and quick recovery while maintaining excellent anesthetic activity; meanwhile, the ketone-substituted heterocyclic compound has almost no inhibition effect on the adrenal cortex function, has small side effects, solves the technical problems in the field, and provides a new choice for clinically screening and/or preparing sedative, hypnotic and/or general anesthesia medicines and medicines forcontrolling the epilepsy persistent state.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to a class of ketone-substituted heterocyclic compounds and the application of the compounds in the preparation of drugs for sedation, hypnosis and / or general anesthesia and drugs capable of controlling status epilepticus. Background technique [0002] Heterocyclic compounds refer to a class of cyclic organic compounds that contain atoms other than carbon (including but not limited to N, O, and S atoms) among the atoms constituting the ring. Heterocyclic compounds widely exist in nature, and most of the important compounds related to biology are heterocyclic compounds, such as nucleic acids, antibiotics, hormones, pigments and alkaloids. Heterocyclic compounds have various structures. Common heterocyclic compounds include furan and its derivatives, thiophene and its derivatives, pyridine and its derivatives, pyrrole and its derivatives, benzofuran and its derivatives, b...

Claims

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Application Information

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IPC IPC(8): C07D231/12C07D405/06C07D409/06C07D249/04C07D233/64C07D405/12C07D207/333C07D207/337C07D207/34A61P25/20A61P25/08A61P23/00A61K31/415A61K31/4155A61K31/4192A61K31/4164A61K31/4178A61K31/40A61K31/4025
CPCC07D231/12C07D405/06C07D409/06C07D249/04C07D233/64C07D405/12C07D207/333C07D207/337C07D207/34A61P25/20A61P25/08A61P23/00
Inventor 刘进张文胜马海军王昌华解振彪
Owner CHENGDU MFS PHARMA CO LTD
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