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Compounds with neuroprotective effect, and preparation method and application thereof

A compound and unsaturated technology, applied in the field of biomedicine, can solve problems such as ineffective neuroprotective agents and complex pathogenesis of stroke

Active Publication Date: 2021-06-11
SHANGHAI ZHIMENG BIOPHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently commonly used neuroprotective agents include free radical scavengers, glutamate antagonists, calcium channel antagonists, cell membrane stabilizers, etc. However, due to the complexity of the pathogenesis of stroke, there is no neuroprotective agent with satisfactory clinical effect.

Method used

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  • Compounds with neuroprotective effect, and preparation method and application thereof
  • Compounds with neuroprotective effect, and preparation method and application thereof
  • Compounds with neuroprotective effect, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0179] The preparation of embodiment 1 compound 04013

[0180]

[0181] Step 1, Compound 2

[0182]To a solution of compound 1 (2.0 g, 14.5 mmol) in ethanol (20 mL) was slowly added dropwise thionyl chloride (20 mL) at 25°C. The reaction system was heated to 60°C and stirred overnight. Concentrated under reduced pressure, the residue was extracted with water (50mL) and ethyl acetate (50mL×2), the combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain white solid compound 2 (0.90g, yield: 37.5%)

[0183] Step 2. Compound 04006-1

[0184] A methanol (20 mL) solution of compound 2 (0.90 g, 5.4 mmol) and compound 3 (1.0 g, 5.0 mmol) was stirred at 25° C. for 1 hour, sodium cyanoborohydride (0.38 g, 6.0 mmol) was added, and stirred overnight. The reaction was quenched with aqueous sodium bicarbonate (100 mL), concentrated under reduced pressure to remove methanol, extracted with ethyl acetate (100 mL X 3), the combi...

Embodiment 2

[0190] The preparation of embodiment 2 compound 04015

[0191]

[0192] Step 1, compound 04015

[0193] To a solution of compound 04006-1 (0.2 g, 0.58 mmol) in ethyl acetate (10 mL) was added TCDI (thiocarbonyldiimidazole) (118 mg, 0.6 mmol) at 25°C, and stirred for 16 hours. The reaction solution was washed with water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified with a preparative plate to obtain compound 04015 (22 mg, yield: 10%).

[0194] MS(ESI): Calcd.for C 16 h 12 Cl 2 N 2 o 3 S 382; Found 383 [M+H] + .

[0195] HNMR (400MHz, CD 3 OD): δ8.83(s,1H),8.28(d,J=8.0Hz,1H),7.91(d,J=8.0Hz,1H),7.48(s,1H),7.07(s,1H), 4.83(s, 2H), 4.52(q, J=6.0Hz, 2H), 1.47(t, J=6.0Hz, 3H).

Embodiment 3

[0196] The preparation of embodiment 3 compound 04016

[0197]

[0198] Step 1, compound 04016

[0199] At 25°C, phosphorus oxychloride (0.55mL) was added to a solution of compound 04006-1 (200mg, 0.59mmol) and triethylamine (178mg, 1.76mmol) in toluene (10mL), and the reaction system was heated to React at 70°C for 16 hours. Concentrate under reduced pressure, add ethanol (20 mL) to the residue, and stir for half an hour. It was concentrated under reduced pressure, and the residue was purified by preparative chromatography to obtain 04016 (49.7 mg, yield: 19.6%).

[0200] MS(ESI): Calcd.for C 17 h 17 Cl 2 N 2 o 5 P 430; Found 431 [M+H] + .

[0201] HNMR (400MHz, CDCl 3 ): δ8.70(d, J=2.4Hz, 1H), 8.13-8.10(d, J=8.8Hz, 1H), 7.87-7.80(dd, d, J=8.8Hz, 2.0Hz, 1H), 7.43 (s,1H),7.15(d,J=2.4Hz,1H),4.88-4.70(m,2H),4.47(q,J=7.2Hz,2H),4.35-4.24(m,2H),1.47- 1.42(t,J=7.2Hz,3H),1.38-1.32(t,J=7.2Hz,3H).

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PUM

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Abstract

The invention relates to compounds with a neuroprotective effect, and a preparation method and application thereof. Specifically, the compounds disclosed by the invention have a structure as shown in a formula I, and the definitions of all groups and substituent groups are described in the specification. The invention also discloses the preparation method of the compounds and application of the compounds in neuroprotection.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to a class of compounds with neuroprotective effect and their preparation method and application. Background technique [0002] Stroke is an acute cerebrovascular disease, including ischemic and hemorrhagic stroke, and the incidence of ischemic stroke accounts for 60% to 70% of the total stroke. The characteristics of high residual rate. [0003] The molecular mechanism of neuroprotection and the development of neuroprotective drugs are one of the hot research fields in the treatment of stroke. Currently commonly used neuroprotective agents include free radical scavengers, glutamate antagonists, calcium channel antagonists, and cell membrane stabilizers. However, due to the complexity of the pathogenesis of stroke, there is no neuroprotective agent with satisfactory clinical effect. Due to the high incidence and great harm of stroke, it is of great significance to develop new neuroprote...

Claims

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Application Information

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IPC IPC(8): C07D413/04C07D413/14C07D498/10C07H13/10C07D413/12C07D263/58C07D265/18C07H1/00A61K31/536A61K31/537A61K31/423A61K31/424A61K31/706A61K31/675C07F9/6584A61P25/04A61P25/06A61P9/10A61P25/24A61P25/28A61P25/08A61P25/00A61P29/00
CPCC07D413/04C07D413/14C07D498/10C07H13/10C07D413/12C07D263/58C07D265/18C07H1/00C07F9/65846A61P25/04A61P25/06A61P9/10A61P25/24A61P25/28A61P25/08A61P25/00A61P29/00Y02P20/55A61K31/536A61K31/675A61K31/706A61K31/397A61K31/423C07F9/6584C07D493/04C07D413/10
Inventor 梁波陈焕明刘刚张志军夏天华波金秋
Owner SHANGHAI ZHIMENG BIOPHARMA CO LTD
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