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Dihydroquinozolinone antiport process blocking agent, and preparation method and application thereof

A technology of medicinal salts and hydrogen atoms, which can be used in anti-toxic agents, anti-viral agents, pharmaceutical formulations, etc., and can solve the problems that limit the practicality of Retro-2cycl and its structural derivatives

Active Publication Date: 2019-10-25
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This problem greatly limits Retro-2 cycl The practicability of its structural derivatives is the main problem faced by this type of compound

Method used

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  • Dihydroquinozolinone antiport process blocking agent, and preparation method and application thereof
  • Dihydroquinozolinone antiport process blocking agent, and preparation method and application thereof
  • Dihydroquinozolinone antiport process blocking agent, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0098] Preparation Example 1: Preparation of 5-(2-methylthiazol-4-yl)thiophene-2-carbaldehyde (Intermediate 6)

[0099]

[0100] step 1

[0101] In a 250ml three-necked flask, add 5-acetyl-2-thiophenecarboxylic acid (5g, 29.4mmol), 120ml of methanol, 1.5ml of N,N-dimethylformamide (DMF), slowly drop chlorinated chlorinated acid at room temperature Sulfone (12.24g, 102.9mmol), reflux reaction for 5h after completion of dropwise addition. After the reaction is completed, cool down, adjust the pH to neutral with saturated sodium bicarbonate, add water to dilute, a large amount of solids precipitate, add water until the solids no longer increase, and filter with suction to obtain gray solid crude 5-acetyl-2-thiophenecarboxylic acid methyl ester , weighed 4.75g after drying, and the yield was 87.4%.

[0102] step 2

[0103] Put the dried methyl 5-acetyl-2-thiophenecarboxylate (4.75g, 25.7mmol) into a 100ml three-necked flask, add copper bromide (11.48g, 51.4mmol) and 150ml ...

preparation example 2

[0110] Preparation 2: Preparation of 5-fluoro-N-(2-methoxyphenyl)-2-(methylamino)benzamide (intermediate 10)

[0111]

[0112] step 6

[0113] In a 150ml round bottom flask, add 2-amino-5-fluorobenzoic acid (3.35g, 21.6mmol), triphosgene (8.34g, 28.1mmol), 75ml of tetrahydrofuran, DMF0.75ml, and react at 60°C. After the reaction is completed, The solvent was evaporated to dryness to obtain a yellow-brown solid, which was washed with a small amount of ethyl acetate to obtain 5-fluoroisatoic anhydride. Yellow solid 3.42g, yield 87.5%.

[0114] step 7

[0115] In a 100ml round bottom flask, add 5-fluoroisatoic anhydride (3.42g, 18.9mmol) and DMF35ml successively, cool to 0°C, add sodium hydride (60%, 0.9g, 22.68mmol) under stirring, and control the temperature at 0- Reacted at 5°C for 30 minutes, then raised to room temperature, added iodomethane (3.21g, 22.68mmol) and reacted overnight. After the reaction was completed, the reaction system was dropped into ice water, and...

preparation example 3

[0119] Preparation Example 3: Preparation of N-(2-methoxyphenyl)-2-(methylamino)benzamide (Intermediate 15)

[0120]

[0121] Using anthranilic acid instead of 2-amino-5-fluorobenzoic acid, according to the operation of Preparation Example 2, intermediate 15 was obtained with a total yield of 43% 1H-NMR

[0122] (DMSO-d6, 400MHz), δppm 9.25 (1H, s), 7.71 (2H, ddd, J = 7.8Hz, 3.9Hz, 1.5Hz), 7.49 (1H, d, J = 5.2Hz), 7.44-7.31 ( 1H, m), 7.17 (1H, td, J = 7.8Hz, 1.7Hz), 7.08 (1H, dd, J = 8.2Hz, 1.3Hz), 6.95 (1H, td, J = 7.6Hz, 1.3Hz), 6.78-6.55 (2H, m), 3.82 (3H, s), 2.79 (3H, d, J=4.7Hz). ESI-MS (+Q), 257.12 (M+H + ), 279.10 (M+Na + ).

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Abstract

The invention belongs to the field of pharmaceutical and chemical industry, and relates to dihydroquinozolinone antiport process blocking agent, and a preparation method and application thereof, in particular to a novel dihydroquinozolinone antiport process blocking agent compound, a medicinal salt, isomer, hydrate and solvate thereof, application of the compound and the medicinal salt, isomer, hydrate and solvate thereof to preparation of drugs for preventing and / or first aiding diseases caused by ribosome-inactivating proteins, and application of the compound and the medicinal salt, isomer,hydrate and solvate thereof to preparation of drugs for preventing and / or curing diseases caused by enterovirus, filoviridae or polyomavirus. The compound can effectively resist II-type ribosome-inactivating protein poisoning and / or the diseases caused by enterovirus, filoviridae or polyomavirus.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a dihydroquinazolone-type reverse transport process blocker, a preparation method and application thereof. Specifically, the present invention relates to novel dihydroquinazolone-type reverse transport process blocker compounds, their pharmaceutically acceptable salts, their isomers, their hydrates or their solvates, and their preparations for preventing and / or their use in medicines for emergency treatment of diseases caused by ribosome inactivating proteins, and their use in the preparation of medicines for preventing and / or treating diseases caused by enteroviruses, filoviruses or polyomaviruses. Background technique [0002] Ribosome Inactivating Protein (RIP) is a general term for a class of glycosylated or deglycosylated proteins with N-glycosidase activity, which are divided into three types according to their structure and mechanism of action, of which type II ...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D417/14C07D417/04C07C237/40A61P39/02A61P31/14A61K31/517A61K31/519
CPCA61P31/14A61P39/02C07C237/40C07D417/04C07D417/14C07D471/04Y02A50/30
Inventor 李松李行舟赵旭钟武肖军海郑志兵谢云德周辛波王晓奎曹瑞源王玉霞庄笑梅张文鹏
Owner ACADEMY OF MILITARY MEDICAL SCI
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