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TRPC6 inhibitor with anti-gastric cancer activity, and preparation method and application thereof

A technology of use and alkyl, applied in the field of pyrazolo[1,5-a]pyrimidine derivatives and their treatment of gastric cancer, can solve the problems of inability to find activity and oral availability, low oral availability, and high in vivo clearance rate , to achieve good in vitro anti-proliferative effect, excellent inhibitory effect, and simple synthesis effect

Active Publication Date: 2017-10-17
YANTAI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The compound has a good inhibitory effect on gastric cancer cells MKN45 and AGS, and the compound can inhibit cell growth in the G2 / M phase, and has a certain effect on nude mice inoculated with gastric cancer, but the onset is slow and the cycle is long, requiring continuous Effects can be seen after 7 weeks of administration
David G.W. reported the inhibitors of TRPC3 and TRPC6 in 2013, and the compounds they synthesized had IC of hTRPC3 and hTRPC6 50 The value can reach the nanomolar level, but in the in vivo test, it was found that the oral availability of this series of drugs is very low, and the clearance rate in the body is too high. Although a series of structural modifications, it is still impossible to find a better activity and oral availability. a structure at the level of

Method used

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  • TRPC6 inhibitor with anti-gastric cancer activity, and preparation method and application thereof
  • TRPC6 inhibitor with anti-gastric cancer activity, and preparation method and application thereof
  • TRPC6 inhibitor with anti-gastric cancer activity, and preparation method and application thereof

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Experimental program
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Effect test

specific Embodiment approach

[0057] The specific embodiment operates according to the following preparation method.

[0058] (1) When R 1 = R 2 When =H, prepare according to the following route:

[0059]

[0060] 1) Preparation of compound 4: dissolve compounds 1 and 2 in a small amount of dichloromethane, reflux at 100°C for 8-24 hours, cool to room temperature, and then add the reaction solution to hydrazine hydrochloride dissolved in 50% EtOH In the solution, reflux overnight at 80°C, cool to room temperature after the reaction, and wash with saturated NaHCO 3 The solution was basified, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, spin-dried, and recrystallized with petroleum ether and ethyl acetate to obtain a white to light yellow solid, namely compound 4.

[0061] 2) Dissolving compound 4 and compound 5 in anhydrous acetic acid, heating to reflux, and completing the reaction after 8-24 hours. Cool to room temperature, spin dry the s...

Embodiment 1

[0075] Preparation of Compound 8-1: R 1 = R 2 =H, R 4 = F, R 5 =OH,X 1 =X 2 =CH.

[0076] (1) Preparation of Compound 4: Dissolve Compound 1 (43.2mL), 2 (43.8mL) in dichloromethane (20mL) and then reflux at 100°C for 24 hours. After cooling to room temperature, add the reaction solution to into a solution of hydrazine hydrochloride dissolved in 50% EtOH (100mL), refluxed overnight at 80°C, cooled to room temperature after the reaction, and washed with saturated NaHCO 3 Basified, extracted with ethyl acetate (3*150mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried, recrystallized with petroleum ether and ethyl acetate to obtain a white solid, compound 4 (44.6g, 82%)

[0077] (2) Compound 4 (45.8 g) and compound 5 (36.4 mL) were dissolved in anhydrous acetic acid (300 mL), heated to reflux, and the reaction was completed after 24 hours. Cool to room temperature and spin dry the solvent. Add deionized water (300mL), and adjust...

Embodiment 2

[0081] Preparation of Compound 12-1: R 1 = R 2 =-Et, R 4 = CF 3 , R 5 =Cl,X 1 =X 2 =CH.

[0082] (1) Preparation of Compound 4: Dissolve Compound 1 (43.2mL), 2 (43.8mL) in dichloromethane (20mL) and then reflux at 100°C for 24 hours. After cooling to room temperature, add the reaction solution to into a solution of hydrazine hydrochloride dissolved in 50% EtOH (100mL), refluxed overnight at 80°C, cooled to room temperature after the reaction, and washed with saturated NaHCO 3 Basified, extracted with ethyl acetate (3*150mL), washed with saturated brine, dried over anhydrous sodium sulfate, filtered and spin-dried, recrystallized with petroleum ether and ethyl acetate to obtain a white solid, compound 4 (44.6g, 82%)

[0083](2) Compound 4 (21.8 g) and compound 5 (18.2 mL) were dissolved in anhydrous acetic acid (150 mL), heated to reflux, and the reaction was completed after 20 hours. Cool to room temperature and spin dry the solvent. Add deionized water (150mL), adj...

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Abstract

The invention provides a pyrazolo-[1,5-a] pyrimidine derivative. The invention further provides activity screening results of the cell level and the target level of the compound and an anti-tumor application of the compound for treating diseases or symptoms, such as gastric cancer, lung cancer, cervical cancer, breast cancer or colon cancer. The invention further provides a relevant experiment for the cell level of the compound. The cell level comprises an inhibitory test on a TRPC6 channel and growth inhibitory activity on gastric cancer cells.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and relates to a pyrazolo[1,5-a]pyrimidine derivative and its application for treating gastric cancer. Through high-throughput screening and subsequent structural modification, the present invention has discovered a series of pyrazolo[1,5-a]pyrimidines as the basic skeleton, which have excellent TRPC6 inhibitory effects, and have good inhibitory effects on gastric cancer cells and gastric tumors. effect compound. Background technique [0002] According to the latest report of the World Health Organization, the incidence of gastric cancer ranks fifth in the incidence of malignant tumors in the world, and its mortality rate ranks third, second only to lung cancer and liver cancer. The new cases of gastric cancer in China account for more than 40% of the world's new cases every year. Compared with the lower incidence of gastric cancer in Europe and the United States and the higher diagnosis rate of...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P35/00
CPCC07D487/04
Inventor 王洪波洪学传傅风华颜春洪吕振斌雷蕾马金波翟蓉郭梦琪
Owner YANTAI UNIV
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