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Novel quinoline-4-carboxamide derivative, preparation method thereof, pharmaceutical composition containing novel quinoline-4-carboxamide derivative, and medical application of novel quinoline-4-carboxamide derivative

A formamide and compound technology, which is applied in the field of novel quinoline-4-carboxamide derivatives and their preparation, can solve problems such as compatibility stability, safety effects of metabolic drugs in vivo, etc.

Inactive Publication Date: 2015-06-03
CHENGDU MILITARY GENERAL HOSPITAL OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the combined application of drugs is easily affected by compatibility stability, in vivo metabolism, drug safety, etc., so it is necessary to develop a new type of single molecule with the above-mentioned dual effects

Method used

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  • Novel quinoline-4-carboxamide derivative, preparation method thereof, pharmaceutical composition containing novel quinoline-4-carboxamide derivative, and medical application of novel quinoline-4-carboxamide derivative
  • Novel quinoline-4-carboxamide derivative, preparation method thereof, pharmaceutical composition containing novel quinoline-4-carboxamide derivative, and medical application of novel quinoline-4-carboxamide derivative
  • Novel quinoline-4-carboxamide derivative, preparation method thereof, pharmaceutical composition containing novel quinoline-4-carboxamide derivative, and medical application of novel quinoline-4-carboxamide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0067] Preparation of compound (1): N-{3-[4-(5-chloro-2-methylphenyl)piperazinyl]propyl}-quinoline-4-carboxamide

[0068] (1) Quinoline-2,4-dicarboxylic acid: Weigh 1.0g (6.75mmol) of isatin and 0.7g (8.10mmol) of pyruvic acid and dissolve them in 25ml of 20% NaOH solution, set the microwave power to 110W, React for 10 minutes, stop the reaction, cool to room temperature, acidify with 1M hydrochloric acid solution to a pH value of about 2, a yellow solid precipitates, filter the solid with suction, wash thoroughly with water, and dry at 60°C for 12 hours to obtain the crude product of quinoline-2,4-dicarboxylic acid , dissolved in hot water, decolorized with activated carbon, filtered, and recrystallized to obtain 1.30 g of pure quinoline-2,4-dicarboxylic acid, with a yield of 89.2%. Mp: 235-240°C, 1 H NMR (DMSO- d 6 ): δ =8.81 (d, J = 7.6 Hz, 1H), 8.48 (s, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.95 (m, 1H), 7.86(m, 1H).

[0069] (2) Quinoline-4-carboxylic acid: Weigh 1.1g (5...

Embodiment 2

[0075] Preparation of compound (2): N-{3-[4-(5-chloro-2-methylphenyl)piperazinyl]propyl}-5-fluoroquinoline-4-carboxamide

[0076] (1) 5-Fluoro-quinoline-4-carboxylic acid: According to the method of Example 1, 4-fluoroisatin was prepared by microwave-catalyzed Pfitzinger reaction with pyruvic acid under alkaline conditions. Yield 83.4%, Mp: 265-269°C. 1 H NMR (DMSO- d 6 ): δ = 9.12 (d, J = 4.5 Hz, 1H), 8.73 (d, J = 8.7 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 8.0 (d, J = 4.5 Hz, 1H), 7.89-7.79 (m, 1H).

[0077] (2) N-{3-[4-(5-chloro-2-methylphenyl)piperazinyl]propyl}-5-fluoroquinoline-4-carboxamide: According to the method of Example 1, take 5-Fluoroquinoline-4-carboxylic acid to prepare 5-fluoroquinoline-4-formyl chloride, and then react with 3-[4-(5-chloro-2-methylphenyl)piperazinyl]propylamine, after deacidification prepared by acylation in the presence of sodium carbonate. Yield: 80.1%, Mp: 263-265°C. 1 H NMR (CDCl 3 ): δ = 1.64(m, 2H), 2.23(s, 3H), 3.10-3.22(m, 4...

Embodiment 3

[0079] Preparation of compound (3): N-{3-[4-(5-chloro-2-methylphenyl)piperazinyl]propyl}-5-trifluoromethylquinoline-4-carboxamide

[0080] According to the method of Example 1, take 5-trifluoromethyl-quinoline-4-formic acid to prepare 5-trifluoromethyl-quinoline-4-formyl chloride, and then combine with 3-[4-(5-chloro-2 -Methylphenyl) piperazinyl] propylamine reaction, prepared by acylation in the presence of acid-removing agent sodium carbonate. Yield: 82.7%. 1 H NMR (DMSO- d 6 ): δ = 1.47(br-s, 2H), 1.52(br-s, 2H), 2.36(s, 3H), 3.38(br-m, 4H), 3.29(q, J = 5.00 Hz, 2H), 3.35(d, J = 8.05Hz,2H), 7.15(m, 2), 7.26(d, J = 6.80 Hz,1H), 7.24(d, J = 8.10 Hz, 1H), 7.58(d, J = 1.92 Hz, 1H), 7.73(dd, J 1 = 8.22Hz, J 2 = 1.62Hz, 1H), 8.43(br-s, 1H,NH), 9.85(br-s, 1H).

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Abstract

The invention discloses a compound as shown in a formula I, a pharmaceutical salt or solvate and preparation method of the compound and application of the compound as a drug for preventing or treating posttraumatic stress disorder, anxiety and depressive disorder. In the formula I, R1, R2 and R3 are respectively and independently selected from hydrogen, a halogen atom, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, formamyl, substituted formamyl, a naphthenic base, a substituted naphthenic base, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; and L is a C1-C4 alkyl chain or a C1-C4 olefin chain, wherein the C1-C4 olefin chain contains cis and trans isomers.

Description

technical field [0001] The invention relates to a novel quinoline-4-carboxamide derivative and a preparation method thereof, and also relates to a pharmaceutical composition containing the derivative and the application of the derivative in medicine. Background technique [0002] Posttraumatic stress disorder (Posttraumatic Stress Disorder, PTSD) is a morbid mental reaction to severe traumatic events (such as combat trauma, traffic accidents, violent crimes, terrorist attacks, major infectious disease epidemics, and natural disasters, etc.) . According to the statistics of the American Psychiatry Association (APA), the overall prevalence rate of PTSD in the United States is 1-14%, with an average of 8%. 2 times that of men. According to statistics from the Institute of Psychology of the Chinese Academy of Sciences, six months after the Wenchuan earthquake, 12.7%-22.1% of the population suffered from post-traumatic stress disorder (PTSD), which brought heavy psychological, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/50A61K31/496A61P25/22A61P25/24
CPCC07D215/50
Inventor 顾建文祝辉匡永勤杨涛张新颜李运明欧珊
Owner CHENGDU MILITARY GENERAL HOSPITAL OF PLA
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