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6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid or pharmaceutical salt, preparation and application

A carbonyl quinoline and medicinal salt technology, applied in the field of organic synthesis, can solve the problems of unsatisfactory prevention and treatment effects, low efficiency of anti-tumor drugs, narrow therapeutic window, etc., achieve excellent anti-tumor activity, easy post-processing, and simple steps Effect

Active Publication Date: 2016-01-13
河南省医药科学研究院
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Problems solved by technology

[0002] Existing anti-tumor drugs have disadvantages such as low efficiency, poor selectivity, drug resistance, narrow therapeutic window, etc., and the prevention and treatment effect is not ideal

Method used

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  • 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid or pharmaceutical salt, preparation and application
  • 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid or pharmaceutical salt, preparation and application
  • 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid or pharmaceutical salt, preparation and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] 6-Chloro-1-((1-(4-chlorophenyl)-1,2,3-triazol-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid (IV-1) synthesis

[0051]

[0052] (1) Synthesis of 2-((4-chloroaniline) methylene) diethyl malonate (I-1)

[0053] In a 100mL three-necked flask equipped with a thermometer and a reflux condenser, add 3.8g (0.030mol) of p-chloroaniline and 6.5mL (0.031mol) of diethyl ethoxymethylene malonate, add 15mL of toluene to dissolve, and heat To reflux, TLC tracking, developer V (ethyl acetate): V (petroleum ether) = 1:4, react for 6 hours, stop the reaction, stand at room temperature, filter with suction, and recrystallize from ethanol to obtain 2-((4-chloro Aniline) methylene) malonate (I-1), 7.56 g of white crystals, 87% yield, m.p.80-81°C, 1 HNMR (400MHz, CDCl 3 )δ: 8.46 (d, J = 13.2Hz, 1H, CHofVinylic,), 7.34 (d, J = 8.8Hz, 2H, Ar-H), 7.07 (d, J = 8.8Hz, 2H, Ar-H), 4.30(q, J=6.8Hz, 2H, CH 2 ,ofOCH 2 CH 3 ), 4.24 (q, J=7.2Hz, 2H, CH 2 ,ofOCH 2 CH 3 ), 1.38(t, J=7.2H...

Embodiment 2

[0061] 6-Methyl-1-((1-(4-chlorophenyl)-1,2,3-triazol-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid (IV-2) Synthesis

[0062]

[0063] According to the method for embodiment 1, p-toluene and diethyl ethoxymethylene malonate are condensed to obtain 2-((4-methylaniline) methylene) diethyl malonate: white solid, Yield 80.3%; Gould-Jacobs cyclization produced 6-methyl-4-carbonylquinoline-3-ethyl formate: white powder, yield 73.1%, and then with 4-bromomethyl-1-(4- Chlorophenyl)-1,2,3-triazole undergoes N alkylation reaction, NaOH hydrolysis and hydrochloric acid acidification to obtain 6-methyl-1-((1-(4-chlorophenyl)-1,2 ,3-triazol-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid (IV-2), white solid, yield 71.2%, m.p.223-224°C. The structure of IV-2 is characterized as follows: IR(cm -1 ) ν: 3470 (O-H), 3163 (quinoline=C-H), 3115 (triazole=C-H), 1745 (C=O, 1516, 1465 (C=C). 1 HNMR (400MHz, DMSO)δ:2.45(s,3H,-CH 3 ),5.65(s,2H,CH 2 of NCH 2 ),7.55(d,2H,ArH,J=7.2Hz),7....

Embodiment 3

[0065] 6-fluoro-1-((1-(4-chlorophenyl)-1,2,3-triazol-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid (IV-3) synthesis

[0066]

[0067]Using p-fluoroaniline as raw material, according to the method of Example 1, condensed with ethoxymethylene malonate diethyl ester to obtain 2-((4-fluoroaniline) methylene) malonate diethyl ester: white solid , yield 71.2%; Gould-Jacobs cyclization obtains 6-fluoro-4-carbonylquinoline-3-ethyl formate: white powder, yield 71.7%; and 4-bromomethyl-1-(4- Chlorophenyl)-1,2,3-triazole was subjected to N alkylation reaction, NaOH hydrolysis, and hydrochloric acid acidification to obtain 6-fluoro-1-((1-(4-chlorophenyl)-1,2, 3-triazol-4-yl)methyl)-4-carbonylquinoline-3-carboxylic acid (IV-3), white solid, yield 71.2%, m.p.218-219°C. The structural characterization of IV-3 is as follows: IR(cm -1 )ν: 3495(O-H), 3179(quinoline=C-H), 3125(triazole=C-H), 1753(C=O, 1530, 1470(C=C); 1 HNMR(400MHz,DMSO)δ:5.70(s,2H,CH 2 of NCH 2 ),7.60(d,2H,ArH,J=8...

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Abstract

The present invention belongs to the technical field of organic synthesis, and specifically discloses 6-substituted-1-((1-substituted phenyl-1,2,3-triazole-4-yl)methyl)-4-carbonylquinoline-3-carboxylic compounds or a pharmaceutical salt thereof, and preparation and application thereof. The general formula is shown in the specification, wherein R, R1, R2, R3, R4 and R5 are the same or different, each being selected from one of H, halogen, nitro, amino, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxyl, C1-C4 carboxyl and formyl. The preparation comprises: performing condensation between substituted phenyl as a raw material and diethyl ethoxymethylene malonate to produce an intermediate I, and performing Gould-Jacobs cyclization to produce an intermediate II; performing ''click chemistry'' between substituted phenyl azide and propargyl bromide to produce an intermediate III; and performing an N-alkylation reaction, alkaline hydrolysis and acidification between the intermediate II and the intermediate III to obtain a target product IV. The inventive compound or the pharmaceutically salt thereof has an excellent antitumor effect.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a 6-substituted-1-((1-substituted phenyl-1,2,3-triazol-4-yl)methyl)-4-carbonylquinoline-3 - Formic acid compounds or pharmaceutically acceptable salts thereof and their preparation and application. Background technique [0002] Existing antineoplastic drugs have disadvantages such as low efficiency, poor selectivity, drug resistance, narrow therapeutic window, etc., and the prevention and treatment effect is not ideal. [0003] Bioinformatics research has found that quinolone derivatives (see Fig. 1 for the basic structure) besides antibacterial, also have other biological activities such as anti-tumor and anti-virus. One of the "hot spot" structures. In addition to biological activities such as antibacterial, anti-tuberculosis, and anti-virus, 1,2,3-triazole compounds also have good anti-tumor activity. For example, Miller et al. combined 1,2,3-triazole and aromatic ...

Claims

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Application Information

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IPC IPC(8): C07D401/06A61P35/00A61P35/02
Inventor 邹敏马方陈慧平张长征张小俊赵志鸿王桂芳张壮丽张艳郑立运王宁王东阳王庆端
Owner 河南省医药科学研究院
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