6-methyl-thiazole triazole-5-formamide derivative and application

A technology of triazole and thiazolide, applied in the field of medicine, can solve the problems of tumor tissue degeneration, inability to meet the needs of tumor survival and growth, and inability of nutrients to reach tumor cells through diffusion.

Active Publication Date: 2017-12-08
河北戴桥医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 reach the tumor cells ...

Method used

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  • 6-methyl-thiazole triazole-5-formamide derivative and application
  • 6-methyl-thiazole triazole-5-formamide derivative and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] Preparation of 2-(4-chlorophenyl)-6-methyl-thiazole[3,2-b][1,2,4]triazole-5-carboxylic acid

[0017] Add 0.1 mol of thiosemicarbazide and 100 mL of dichloromethane into a 250 mL three-necked flask, stir to dissolve in an ice water bath, and then add 0.13 mol of pyridine. Slowly add 0.13 mol of 4-chlorobenzoyl chloride dropwise at 0-5°C for 20 minutes to complete the dropwise addition, and react at 15°C for 2 hours to complete the reaction. A large amount of white solid appears in the system, filter. The obtained white solid was dissolved in 80 mL of 5% by mass sodium hydroxide solution, heated to reflux for 2h, and cooled to room temperature. The pH was adjusted to 5-6 with 3.65% by mass dilute hydrochloric acid. A large amount of light yellow solid precipitated out and filtered. Recrystallize to obtain 18.3 g of 5-(4-chlorophenyl)-3-mercapto-1,2,4-triazole, with a yield of 86.7%, ESI-MS (m / z): 212.3 (M+H) + .

[0018] Add 0.06mol of 5-(4-chlorophenyl)-3-mercapto-1,2,4-tri...

Embodiment 2

[0022] N,N-Dimethyl-2-(4-chlorophenyl)-6-methyl-thiazolo[3,2-b][1,2,4]triazol-6-yl}-5- Preparation of formamide (L1) 10mmol dimethylamine hydrochloride, 10mmol 2-(4-chlorophenyl)-6-methyl-thiazole [3,2-b][1,2,4]triazole-5 -Formic acid, 20mL of dichloromethane were added to the round bottom flask, and then added 12mmol EDCI, 12mmol HOBt and 10mmol triethylamine, after 12h at room temperature, the reaction solution was used 5% HCl, 5% NaHCO 3 , Washed with saturated NaCl solution, dried and separated by column chromatography to obtain a white solid with a yield of 34%; 1 H-NMR (300MHz, DMSO), δ (ppm): 7.42 (2H, d, J = 8.7 Hz), 7.26 (2H, d, J = 8.7 Hz), 3.96 (3H, s), 3.02 (3H, s) ), 2.60(3H,s); ESI-MS(m / z): 321.2(M+H) + .

Embodiment 3

[0024] N,N-Diethyl-2-(4-chlorophenyl)-6-methyl-thiazolo[3,2-b][1,2,4]triazole-5-carboxamide (L2) Preparation

[0025] The dimethylamine hydrochloride was replaced with diethylamine, the synthesis method was referred to Example 2, and the yield was 36%.

[0026] 1 H-NMR (300MHz, DMSO), δ (ppm): 7.52 (2H, d, J = 9.0 Hz), 7.37 (2H, d, J = 9.0 Hz), 3.98 (2H, m), 3.32 (2H, m ),2.30(3H,s),1.18(3H,t),1.05(3H,t); ESI-MS(m / z):349.1(M+H) + .

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Abstract

The invention discloses a 6-methyl-thiazole [3,2-b] [1,2,4]-triazole-5-formamide derivative as shown in formula I or pharmaceutically acceptable hydrate and salt thereof, including stereisomer or tautomer thereof. In the formula I, R1 is hydrogen, methyl, halogen, hydroxy, methoxyl, acetyl, propionyl, nitryl or alkoxy; R2 and R3 are independently selected from C1-C6 alkyl; or R2, R3 and nitrogen atoms connected with R2 and R3 form pyrrolyl, piperidyl, morpholinyl, N-methyl piperazine and N-(4-bromophenyl) piperazine. The 6-methyl-thiazole [3,2-b] [1,2,4]-triazole-5-formamide derivative disclosed by the invention is used as a vascular endothelial growth factor protein tyrosine kinase inhibitor for treating and preventing various cancers.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to 6-methyl-thiazolo[3,2-b][1,2,4]-triazole-5-carboxamide derivatives, a preparation method thereof, and vascular endothelium Growth factor receptor tyrosine kinase inhibitor for the treatment and prevention of various cancers. Background technique [0002] Malignant tumors are one of the main diseases threatening human health in today's society. In 1971, Folkman proposed that the occurrence and development of tumors are closely related to angiogenesis. The growth and metastasis of tumors depend on the oxygen and necessary nutrients provided by angiogenesis. There is no angiogenesis at the beginning of solid tumor formation. The nutrition of tumor cells is mainly obtained through diffusion. When the cells are more than 200μm from the capillaries, the nutrition will not reach the tumor cells through diffusion. When the number of tumor cells reaches 1×10 7 After this, the nut...

Claims

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Application Information

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IPC IPC(8): C07D513/04A61P35/00
CPCC07D513/04
Inventor 刘斯婕王娟郭瑞霞史兰香张宝华
Owner 河北戴桥医药科技有限公司
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