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5,7-Diphenyl-5h-thiazolo[3,2-a]pyrimidine-2-carboxamide derivatives and their applications

A thiazolo, 2-a technology, applied in the field of medicine, can solve the problems such as the inability to meet the needs of tumor survival and growth, the inability of nutrients to reach tumor cells through diffusion, and the degeneration of tumor tissue.

Active Publication Date: 2019-07-16
SHIJIAZHUANG UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • 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-thiazolo[3,2-a]pyrimidine-2-carboxamide derivatives and their applications
  • 5,7-Diphenyl-5h-thiazolo[3,2-a]pyrimidine-2-carboxamide derivatives and their applications
  • 5,7-Diphenyl-5h-thiazolo[3,2-a]pyrimidine-2-carboxamide derivatives and their applications

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Preparation of 5-(4-chlorophenyl)-7-(4-methoxyphenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid

[0016] 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) + .

[0017] 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 2-ethyl chloroacetoacetate, heat the reaction for 1h, dilute with ice water, a large number of crystals precipitate, and dry to obtain 2-(4-(4-chlorophenyl)-6-(4-methoxyphenyl)- 1,2,3,4-tetrahydropyrimidine-2-thio)-3-oxobutanoic acid ethyl ester, yield 45%.

[0018] 0.02...

Embodiment 2

[0021] 5-(4-chlorophenyl)-7-(4-methoxyphenyl)-N,N-dimethyl-3-methyl-5H-thiazolo[3,2-a]pyrimidine-2- Preparation of formamide (L1)

[0022] 10mmol dimethylamine hydrochloride, 10mmol 5-(4-chlorophenyl)-7-(4-methoxyphenyl)-3-methyl-5H-thiazolo[3,2-a]pyrimidine-2- Add formic acid and 20mL of dichloromethane into the round bottom flask, then add 12mmolEDCI, 12mmolHOBt and 10mmol of triethylamine. 3 , washed with saturated NaCl solution, dried and separated by column chromatography to obtain a white solid with a yield of 36%; 1 H-NMR (300MHz, DMSO), δ(ppm): 7.48 (2H, d, J = 8.7Hz), 7.40 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.7Hz), 6.84 (2H, d, J=8.4Hz), 6.73 (H, d), 6.21 (H, d), 3.83 (3H, s), 3.13 (3H, s), 3.02 (3H, s), 2.31 (3H , s); ESI-MS (m / z): 440.2 (M+H) + .

Embodiment 3

[0024] 5-(4-chlorophenyl)-7-(4-methoxyphenyl)-N,N-diethyl-3-methyl-5H-thiazolo[3,2-a]pyrimidine-2- Preparation of formamide (L2)

[0025] Dimethylamine hydrochloride was replaced with diethylamine, the synthetic method was referred to Example 2, and the yield was 39%; 1 H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J = 8.4Hz), 7.37 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.7Hz), 6.84 (2H, d, J = 8.4Hz), 6.72 (H, d), 6.20 (H, d), 3.84 (3H, s), 3.48 (2H, m), 3.32 (2H, m), 2.30 (3H , s), 1.19 (3H, t), 1.07 (3H, t), ESI-MS (m / z): 468.1 (M+H) + .

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Abstract

The invention discloses 3-methyl-5,7-diphenyl-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide derivatives shown in a formula I, or pharmaceutically acceptable hydrates or salts of the derivatives, i.e., stereoisomers or tautomers of the derivatives, wherein R1 and R2 in the formula I are respectively hydrogen, methyl, halogen, hydroxyl, methoxyl, acetyl, propionyl, nitro or alkoxy independently; R3 and R4 are independently selected from C1-C6 alkyl, or R3 and R4 form pyrrolyl, piperidinyl, morpholinyl, N-methylpiperazine and N-(4-bromophenyl piperazine) together with nitrogen atoms which are connected with the R3 and the R4. As vascular endothelial growth factor receptor tyrosine kinase inhibitors, the 3-methyl-5,7-diphenyl-5H-thiazolo [3,2-a]pyrimidine-2-carboxamide derivatives can be used for treating and preventing various cancers. The formula I is shown in the description.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to 3-methyl-5,7-diphenyl-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide derivatives and their preparation methods and as vascular endothelial A growth factor receptor-2 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 numbe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D513/04A61P35/00
CPCC07D513/04
Inventor 刘斯婕史兰香郭瑞霞王娟张宝华
Owner SHIJIAZHUANG UNIVERSITY
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