5, 7-diphenyl-5H-thiazole [3, 2-a] pyrimidine-3-acetamide derivatives and application

A technology of thiazolo and pyrimidine, applied in the field of medicine, can solve the problems that cannot meet the needs of tumor survival and growth, nutrition cannot reach tumor cells through diffusion, and tumor tissue degeneration

Active Publication Date: 2017-10-10
河北戴桥医药科技有限公司
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

At the beginning of solid tumor formation, there is no angiogenesis, and the nutrition of tumor cells is mainly obtained through diffusion. When the distance between the cells and capillaries is more than 200 μm, the nutrition will not be able to reach the tumor cells through diffusion. When the number of tumor cells reaches 1×10 7 After a period of time, the nutrients obtained by diffusion can no longer meet the needs of tumor survival and growth. At this time, if there is no new angiogenesis, the tumor tissue will degenerate.

Method used

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  • 5, 7-diphenyl-5H-thiazole [3, 2-a] pyrimidine-3-acetamide derivatives and application
  • 5, 7-diphenyl-5H-thiazole [3, 2-a] pyrimidine-3-acetamide derivatives and application
  • 5, 7-diphenyl-5H-thiazole [3, 2-a] pyrimidine-3-acetamide derivatives and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Preparation of 5-(4-chlorophenyl)-7-(4-methoxyphenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid

[0017] Add 0.1 mol of 4-chlorobenzaldehyde, 0.1 mol of thiourea, 0.11 mol of 4-methoxyacetophenone, 0.1 mol of trimethylchlorosilane and 30 mL of acetonitrile into a 250 mL round bottom flask, stir, and reflux for 10 h. Cool, filter with suction, and recrystallize the filter cake from absolute ethanol to obtain yellow crystal 4-(4-chlorophenyl)-6-(4-methoxyphenyl)-3,4-dihydropyrimidine-2(1H) - Thione, yield 63%. ESI-MS (m / z): 331.2 (M+H) + .

[0018] Add 0.05mol 4-(4-chlorophenyl)-6-(4-methoxyphenyl)-3,4-dihydropyrimidine-2(1H)-thione into 10mL of 10% KOH solution, then drop Add 0.05mol 4-ethyl chloroacetoacetate, heat the reaction for 1h, dilute with ice water, a large number of crystals precipitate, and dry to obtain 4-[4-(4-chlorophenyl)-6-(4-methoxyphenyl)- 1,2,3,4-tetrahydropyrimidine-2-thio]-3-oxobutanoic acid ethyl ester, yield 48%.

[0019] 0.02m...

Embodiment 2

[0022] 2-[5-(4-Chlorophenyl)-7-(4-methoxyphenyl)-N,N-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-yl] - Preparation of acetamide (L1)

[0023] 10mmol dimethylamine hydrochloride, 10mmol [5-(4-chlorophenyl)-7-(4-methoxyphenyl)-5H-thiazolo[3,2-a]pyrimidin-3-yl]- Add acetic acid, 20mL dichloromethane into the round bottom flask, then add 12mmolEDCI, 12mmolHOBt and 10mmol triethylamine. 3 , washed with saturated NaCl solution, dried and separated by column chromatography to obtain a white solid with a yield of 40%.

[0024] 1 H-NMR (300MHz, DMSO), δ (ppm): 7.47 (2H, d, J = 8.7Hz), 7.38 (2H, d, J = 8.4Hz), 7.22 (2H, d, J = 8.7Hz), 6.82 (2H, d, J = 8.4Hz), 6.73 (H, d), 6.32 (H, s), 6.21 (H, d), 4.28 (2H, s), 3.82 (3H, s), 3.12 (3H , s), 3.06 (3H, s); ESI-MS (m / z): 440.1 (M+H) + .

Embodiment 3

[0026] 2-[5-(4-Chlorophenyl)-7-(4-methoxyphenyl)-N,N-diethyl-5H-thiazolo[3,2-a]pyrimidin-3-yl] - Preparation of acetamide (L2)

[0027] Dimethylamine hydrochloride was replaced with diethylamine, and the synthesis method was referred to Example 2, and the yield was 32%.

[0028] 1 H-NMR (300MHz, DMSO), δ (ppm): 7.50 (2H, d, J = 8.4Hz), 7.36 (2H, d, J = 8.4Hz), 7.25 (2H, d, J = 8.7Hz), 6.80 (2H, d, J = 8.4Hz), 6.72 (H, d), 6.32 (H, s), 6.20 (H, d), 4.28 (2H, s), 3.84 (3H, s), 3.48 (2H , m), 3.32 (2H, m), 1.18 (3H, t), 1.08 (3H, t); ESI-MS (m / z): 468.1 (M+H) + .

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Abstract

The invention discloses 5, 7-diphenyl-5H-thiazole [3, 2-a] pyrimidine-3-acetamide derivatives of ageneral formula I described in the application or their hydrates and salts, including their stereoisomers or tautomers acceptable by pharmacy, wherein R1 and R2 informula I are independently hydrogen or methyl or halogen or hydroxyl or methoxy or acetyl orpropionyl or nitro or alkoxy; R3 and R4 are independently selected from the alkyl of C1-C6, or R3 and R4 together with the nitrogen atoms whichR3 and R4 are connected to build up pyrryl, piperidyl, morpholine, N-methyl piperazine, and N-(4-brominephenylpiperazine).The 5, 7-diphenyl-5H-thiazole and [3, 2-a] pyrimidine-3-acetamide derivatives are used as inhibitors of vascular endothelial growth factor receptor neuraminidase for the treatment and prevention of various cancers.

Description

technical field [0001] The present invention belongs to the technical field of medicine, and in particular relates to 5,7-diphenyl-5H-thiazolo[3,2-a]pyrimidine-3-acetamide derivatives and their preparation methods and as vascular endothelial growth factor receptor- 2 A tyrosine kinase inhibitor for use in the treatment and prevention of various cancers. Background technique [0002] Malignant tumors are one of the major diseases that threaten human health in today's society. In 1971, Folkman proposed that the occurrence and development of tumors are closely related to angiogenesis. Tumor growth and metastasis depend on oxygen and essential nutrients provided by angiogenesis. At the beginning of solid tumor formation, there is no angiogenesis, and the nutrition of tumor cells is mainly obtained through diffusion. When the distance between the cells and capillaries is more than 200 μm, the nutrition will not be able to reach the tumor cells through diffusion. When the number ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D513/04A61P35/00
CPCC07D513/04
Inventor 刘斯婕王欣郭瑞霞周冉雷霓马媛媛
Owner 河北戴桥医药科技有限公司
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