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Dihydroquinazolone-type reverse transport process blocker, its preparation method and use

A dihydroquinazoline and application technology, which is applied in the direction of anti-toxic agents, anti-viral agents, and pharmaceutical formulations, and can solve problems such as limiting the practicality of Retro-2cycl and its structural derivatives

Active Publication Date: 2020-10-23
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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  • Dihydroquinazolone-type reverse transport process blocker, its preparation method and use
  • Dihydroquinazolone-type reverse transport process blocker, its preparation method and use
  • Dihydroquinazolone-type reverse transport process blocker, its preparation method and use

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 methanol, 1.5ml N,N-dimethylformamide (DMF), and slowly dropwise add sodium chloride at room temperature. Sulfone (12.24g, 102.9mmol), reflux reaction for 5h after completion of dripping. After the reaction is completed, cool and adjust the pH to neutral with saturated sodium bicarbonate. After diluting with water, a large amount of solids will precipitate out. Add water until the solids no longer increase, and then filter with suction to obtain the crude gray solid methyl 5-acetyl-2-thiophenecarboxylate , Weighed 4.75g after drying, yield 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 solvent ethyl acetate 150ml, and r...

preparation example 2

[0110] Preparation Example 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 tetrahydrofuran, 0.75ml DMF, and react at 60℃. After the reaction is complete 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-fluoroisatinic anhydride. The yellow solid is 3.42 g, and the yield is 87.5%.

[0114] Step 7

[0115] In a 100ml round bottom flask, add 5-fluoroisatinic anhydride (3.42g, 18.9mmol), 35ml DMF, and cool to 0°C. Add sodium hydride (60%, 0.9g, 22.68mmol) while stirring, and control the temperature to 0- Reacted at 5°C for 30 minutes, then warmed to room temperature, added methyl iodide (3.21g, 22.68mmol) and reacted overnight. After the reaction was completed, the reaction system was dropped into ice water, a...

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, following 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 dihydroquinazolinone antitransport process blocker, its preparation method and application. Specifically, the present invention relates to novel dihydroquinazolinone antitransport process blocker compounds, their pharmaceutically acceptable salts, their isomers, their hydrates or their solvates, and their use in the preparation and prevention of And / or use in medicines for emergency treatment of diseases caused by ribosome inactivating proteins, and their use in preparing medicines for preventing and / or treating diseases caused by enterovirus, filovirus or polyoma virus. Background technique [0002] Ribosome Inactivating Protein (RIP) is a general term for a class of glycosylated or deglycosylated proteins with N-glycosidase activity. It is divided into three types according to the structure and mechanism of action, of which type II RIPs are all AB chain complexes conne...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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