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3-Aryl-6-formamidopyrazolo[1,5-a]pyrimidine compounds and application thereof

A technology of carboxamide pyrazole and compound, applied in the field of medicine, can solve the problems of multi-drug resistance, need to combine medication, poor activity, etc., and achieve good anti-tuberculosis effect

Active Publication Date: 2017-06-20
SHAANXI SCI TECH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing anti-tuberculosis drugs have problems such as poor activity, multi-drug resistance, long treatment cycle, and the need for combination drugs. The clinical effect is increasingly unable to meet the needs of human beings.

Method used

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  • 3-Aryl-6-formamidopyrazolo[1,5-a]pyrimidine compounds and application thereof
  • 3-Aryl-6-formamidopyrazolo[1,5-a]pyrimidine compounds and application thereof
  • 3-Aryl-6-formamidopyrazolo[1,5-a]pyrimidine compounds and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] The synthetic process of compound (1) 2-dimethylaminomethylene-3-oxobutanoic acid ethyl ester in the above-mentioned synthetic route, its structural formula is as follows:

[0020]

[0021] Add ethyl acetoacetate (10.00g, 78.02mmol), N,N-dimethylformamide dimethyl acetal (DMFDMA) (13.75g, 115.39mmol) and p-toluenesulfonic acid ( 0.05g, 0.29mmol), reacted at 85°C for 2h, then heated up to 140°C and distilled under normal pressure to produce a colorless transparent liquid, until it could not be evaporated, then raised the temperature to 180°C, distilled under reduced pressure with an oil pump, and distilled a yellow transparent liquid Compound (1) 13.00 g, yield 90.93%. The product was used directly in the next step.

Embodiment 2

[0023] Synthetic process of compound (3) (2,7-dimethyl-3-(2,4-dichlorophenyl)-oxazolpyro[1,5-a]pyrimidine-6-carboxylic acid ethyl ester in the above synthetic route :

[0024]

[0025] Add N,N-dimethylmethyleneacetoacetate ethyl (2.98g, 16.10mmol), 3-methyl-4-(2,4-di Chlorophenyl)-5-aminopyrazole (3.00g, 12.40mmol), add 15mL of glacial acetic acid, reflux reaction for 6h after the reaction is completed, cool to room temperature, wash the precipitated solid with methanol, filter, and dry to obtain 3.02g of white solid Compound (3), the yield is 67.0%. mp150~152℃. 1H-NMR (CDCl 3 )δ: 8.91 (s, 1H, pyrimidine-H), 7.56 (d, J = 1.8Hz, 1H, Ar-H), 7.36 (dd, J = 8.4Hz&1.8Hz, 1H, Ar-H), 7.33 ( d,J=8.4Hz,1H,Ar-H),4.43(q,J=7.2Hz,2H,-CH 2 -),3.23(s,3H,pyrimidine-CH 3 ),2.46(s,3H,pyrazole-CH 3 ), 1.42(t, J=7.2Hz, 3H, -CH 2 CH 3 ); IRν: 2926, 1718, 1604, 1531, 1465, 1364, 1304, 1204, 1067, 810 cm-1.

Embodiment 3

[0027] Synthetic process of compound (4) 2,7-dimethyl-3-(2,4-dichlorophenyl)-pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (4) in the above synthetic route :

[0028]

[0029] Add pyrazolopyrimidine ester (1.00g, 2.76mmol) and lithium hydroxide (139mg, 3.31mmol) into a 100mL ground-mouth bottle, then add THF and H at a volume ratio of 3:1 2 8 mL of mixed solution of O, stirred at room temperature for 8 h, evaporated THF in the reaction liquid under reduced pressure, added 50 mL of water to the remaining liquid, acidified it with 1 mol / L hydrochloric acid to pH=3, filtered the solid powder that appeared in the solution, and washed the filter cake with water Several times, 881 mg of compound (4) was obtained with a yield of 95.4%. mp 238-242°C. 1H-NMR(DMSO-d6)δ:8.79(s,1H,pyrimidine-H),7.74(d,J=1.8Hz,1H,Ar-H),7.51(dd,J=8.4Hz&1.8Hz,1H, Ar-H), 7.46(d, J=7.8Hz, 1H, Ar-H), 3.59(br, 1H,-OH), 3.10(s, 3H, pyrimidine-CH 3 ),2.35(s,3H,pyrazole-CH 3 ); IRν: 3420, 1692, 1614, 1590, 14...

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Abstract

The invention belongs to the technical field of medicines, and concretely relates to 3-aryl-6-formamidopyrazolo[1,5-a]pyrimidine compounds and an application thereof. The compounds are six 2,7-dimethyl-3-aryl-6-formamidopyrazolo[1,5-a]pyrimidine compounds prepared by preparing ethyl 2-dimethylaminomethylene-3-oxobutyrate (1) through a reaction of ethyl acetoacetate and N,N-dimethylformamide dimethyl acetal and carrying out cyclization, hydrolysis and amidation on the compound (1) and 3-methyl-4-(2,4-dichlorophenyl)-5-aminopyrazole, and the structure of the compounds is characterized by nuclear magnetic resonance hydrogen spectrum and infrared spectroscopy. A result of detection of the compounds by an MABA method shows that the synthesized compounds have an inhibition effect on Mycobacterium tuberculosis H37Rv. A pharmacological activity screening detection result shows that parts of the compounds have a very good inhibition effect on the Mycobacterium tuberculosis H37Rv and Mycobacterium phlei M. phlei1180, and has good anti-tuberculosis exploitation and application prospect.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a 3-aryl-6-carboxamide pyrazolo[1,5-a]pyrimidine compound and its application. Background technique [0002] Tuberculosis (Tuberculosis, TB) is a highly contagious and fatal disease. It is mainly transmitted through the air, which has led to the widespread spread of this type of disease. According to the statistics of the World Health Organization (WHO), 2 billion people in the world are infected with tuberculosis, and there are about 20 million active tuberculosis patients, with 8-10 million new patients each year, and more than 2 million people die of tuberculosis every year , that is, one person dies of tuberculosis every 10 seconds. An uncured patient with active pulmonary tuberculosis can infect 10 to 15 people a year. There are 22 countries with serious tuberculosis epidemics in the world, and China is one of them. Among the countries with the largest number of TB patie...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P31/06
CPCC07D487/04
Inventor 卢久富靳玲侠季晓辉岳思羽赵蔡斌宋娟葛红光姜敏史娟
Owner SHAANXI SCI TECH UNIV
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