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Indazole/azaindazole-based diarylcarbamide/thiocarbamide-structure antineoplastic drug

An anti-tumor drug, the technology of heteroindazole, applied in the field of anti-tumor drugs, can solve the problems that have not yet been discovered.

Inactive Publication Date: 2011-08-17
JINAN HAILE MEDICAL TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But so far, no patents or other literature reports based on indazole (benzopyrazole) or azaindazole (pyrazolopyridine) (following formula Ia and Ib) compounds have been found

Method used

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  • Indazole/azaindazole-based diarylcarbamide/thiocarbamide-structure antineoplastic drug
  • Indazole/azaindazole-based diarylcarbamide/thiocarbamide-structure antineoplastic drug
  • Indazole/azaindazole-based diarylcarbamide/thiocarbamide-structure antineoplastic drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0082] Example 1: N-{4-[1-(5-azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (1):

[0083]

[0084] 5-azaindazole (0.96g, 8.0mmol), p-fluoronitrobenzene (1.13g, 8.0mmol), cesium carbonate (5.2g, 16.0mmol) were dissolved in DMF (20ml), stirred overnight at room temperature, and The reaction solution was poured into water for filtration, and the filter cake was washed with water to obtain the target product, which was directly used in the next reaction without purification.

[0085] SnCl 2 7.5g (32.0mmol) was dissolved in 70mL concentrated hydrochloric acid, 1.9g (8.0mmol) of nitrophenyl-5-azaindazole obtained in the above step was added, and the reaction was stirred overnight at room temperature. Adjust the pH to 9 with saturated sodium bicarbonate solution, and extract with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purified by column chromatography (ethyl acetate:petroleum ether=2:1...

Embodiment 2

[0087] Example 2: N-{4-[1-(5-azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]thiourea (2):

[0088]

[0089] Dissolve 6.4g (33mmol) of 4-chloro-3-(trifluoromethyl)aniline and 11.2g (100mmol) of triethylenediamine in 40mL of toluene, then cool to 0°C, and slowly add CS 2 7.6g (100mmol), stirred at room temperature for 10h, filtered, and the filter cake was washed with toluene. Dissolve the filter cake in 40 mL CHCl 3 , and then dropwise added triphosgene (BTC) 3.3g (11.0mmol) dissolved in 15ml CHCl at 0°C 3 The solution was stirred at room temperature for 1h, and then refluxed for 1h. Cool to room temperature and filter. The filtrate was concentrated, and column chromatography (DCM:PE=1:1) gave 3.0 g of 4-chloro-3-trifluoromethylphenyl isothiocyanate as a yellow oily liquid, with a yield of 38.5%.

[0090] Referring to the method of Example 1, 1-(4-aminophenyl)-5-azaindazole was synthesized. Dissolve 100mg (0.49mmol) of the above 1-(4-aminophenyl)-5-azaindazol...

Embodiment 3

[0091] Example 3: N-{[4-[1-(6-azaindazole)]phenyl}-N'-[4-chloro-3-trifluoromethylphenyl]urea (3):

[0092] With reference to the method in Example 1, 9.6 g (40.0 mmol) of p-nitrophenyl-6-azaindazole was used to replace p-nitrophenyl-5-azaindazole, and the ratio of other raw materials and the operation method were the same , 5.4 g of 1-(4-aminophenyl)-6-azaindazole was obtained, with a yield of 70%. With reference to the method in Example 1, 1-(4-aminophenyl)-5-azaindazole was replaced with 1-(4-aminophenyl)-6-azaindazole (100mg, 0.49mmol), other Raw material proportioning and operating method are identical, obtain N-{[4-[1-(6-azaindazole)] phenyl}-N'-[4-chloro-3-trifluoromethylphenyl] urea ( 3) 170 mg, yield 81%. HPLC: 100%, LC-MS (C 20 h 13 CIF 3 N 5 O, MW=431): M+1=432; See Table-1 for relevant spectral data.

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PUM

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Abstract

The invention belongs to the field of drugs, and relates to an antineoplastic drug, particularly an indazole / azaindazole-based diarylcarbamide / thiocarbamide-structure antineoplastic drug. The structural general formulae of the indazole / azaindazole-based diarylcarbamide / thiocarbamide-structure antineoplastic drug are disclosed as Formula (Ia) and (Ib), wherein Z is an N or C atom; W is an atom or group, such as O, S, NH, NOH, NCH or the like; M is O, S, N, CH or the like; n is 1 or 2; and Y and R are respectively halogen atom, H, R1, CF3, OCF3, OH, OR2, OCOR3, NH2, NHR4, NR52, NHCOR6, carboxy group, ester group, cyano-group, sulfhydryl group, alkylthio group, sulfuryl group, sulfoxide group, sulfo-group, sulfonate group, sulfamide group, ketone group, aldehyde group, nitro-group or nitroso-group. The pharmacological experiment proves that the drug has favorable antineoplastic effect on human lung cancer, human kidney cancer, human colon cancer, human liver cancer, human stomach cancer and human breast cancer.

Description

technical field [0001] The invention belongs to the field of drugs, and relates to an antitumor drug, in particular to an antitumor drug based on a diaryl urea or thiourea structure of indazole or azaindazole. Pharmacological experiments have proved that these drugs have good anti-tumor effects on human lung cancer, human kidney cancer, human colon cancer, human liver cancer, human gastric cancer, and human breast cancer. Background technique [0002] According to WHO statistics, in 2007, there were as many as 12 million newly diagnosed cancer patients in the world, and over the past few years, more than 7 million patients worldwide died of cancer every year. This figure is very close to the number of people who die from acute cardiovascular disease. Cancer is about to become the deadliest disease in the world. [0003] Renal cell carcinoma (RCC), a form of kidney cancer that arises from renal tubular cells. Renal cell carcinoma accounts for 90-95% of renal tumors, of whi...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07D231/56C07D213/81C07C309/30C07C303/32A61K31/4412A61K31/4375A61K31/416A61P35/00
CPCC07D231/56C07D471/04A61P35/00A61P35/04
Inventor 李文保
Owner JINAN HAILE MEDICAL TECH DEV
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