New compound m-hydroxyphenyl tetrazine dicarbonamide, preparation and application thereof

A technology of hydroxyphenyl and dicarboxamide, which is applied to the new compound m-hydroxyphenyltetrazine dicarboxamide and the fields of preparation and application, can solve the problems of no antitumor activity and the like, and achieves easy availability of raw materials, simple preparation method, The effect of low production cost

Active Publication Date: 2012-10-03
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Afterwards, some 1,2,4,5-tetrazine compounds with specific structures have been reported to have antitumor activity, such as 3,6-bis(2-hydroxyl-5-chlorophenyl)-1 , 2,4,5-tetrazine (see Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett.2006, 16(14), 3702.), 1-isobutyryl -3,6-diphenyl-1,4-dihydro-1,2,4,5-tetrazine (see Rao, G.-W.; Hu, W.-X.Bioorg.Med.Chem.Lett .2005, 15(12), 3714.) and N 1 , N 4 -Bis(m-methylphenyl)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide (see Hu, W.-X.; Rao, G. -W.; Sun, Y.-Q.Bioorg.Med.Chem.Lett.2004, 14(5), 1177.), etc., but most 1,2,4,5-tetrazine compounds do not have antitumor active

Method used

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  • New compound m-hydroxyphenyl tetrazine dicarbonamide, preparation and application thereof
  • New compound m-hydroxyphenyl tetrazine dicarbonamide, preparation and application thereof
  • New compound m-hydroxyphenyl tetrazine dicarbonamide, preparation and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Example 1: N 1 , N 4 - Preparation of two (3-hydroxyphenyl)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide (I)

[0025] Dissolve 2.00 grams (17.8 mmol) of 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 2.16 grams (17.8 mmol) of N,N-xylidine In 50 milliliters of dichloromethane solution, prepare a preliminary solution (that is, a solution containing 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine and a basic catalyst), 250 milliliters 10.60 g (35.7 mmol) of bis(trichloromethyl)carbonate and 20 ml of dichloromethane were sequentially added into the three-necked flask, stirred at 0° C., and the preliminary solution was slowly added dropwise. After the addition was completed within 10 minutes, TLC followed and detected, and the reaction was refluxed for 4 hours. Then the temperature was lowered to 5° C., nitrogen gas was blown, and a solution obtained by dissolving 3.90 g (35.7 mmol) of m-hydroxyaniline in 20 ml of dichloromethane was added dropwise. After dripping, T...

Embodiment 2

[0026] Example 2: N 1 , N 4 - Preparation of two (3-hydroxyphenyl)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide (I)

[0027] Dissolve 2.00 g (17.8 mmol) of 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 0.98 g (12.4 mmol) of pyridine in 10 ml of methanol to prepare To form a preparatory solution, 3.54 g (11.9 mmol) of bis(trichloromethyl)carbonate and 10 ml of methanol were sequentially added to a 50 ml three-necked flask, stirred at -5°C, and the preparatory solution was slowly added dropwise. After the addition was completed within 10 minutes, TLC followed and detected, and the reaction was refluxed for 10 hours. Then the temperature was lowered to 6° C., nitrogen gas was blown, and a solution obtained by dissolving 5.84 g (53.5 mmol) of m-hydroxyaniline in 6 ml of ethanol was added dropwise. After dripping, TLC tracking detection, heating and reflux for 27 hours, distilled off methanol and ethanol, added 20 ml of chloroform to the residue, stirred and heated, re...

Embodiment 3

[0028] Example 3: N 1 , N 4 - Preparation of two (3-hydroxyphenyl)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide (I)

[0029] Dissolve 2.00 g (17.8 mmol) of 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine (II) and 0.91 g (7.4 mmol) of 4-dimethylaminopyridine in Prepare a preparatory solution in 40 ml of chloroform solution, add 4.30 g (14.5 mmol) of bis(trichloromethyl)carbonate and 20 ml of chloroform to a 100 ml three-necked flask successively, stir at -10°C, and slowly add the preparatory solution dropwise. After the addition was completed within 40 minutes, TLC followed and detected, and the reaction was refluxed for 8 hours. Then the temperature was lowered to 6° C., nitrogen gas was blown, and a solution obtained by dissolving 7.77 g (71.2 mmol) of m-hydroxyaniline in 10 ml of chloroform was added dropwise. After dripping, TLC tracking detection, heated to reflux for 12 hours, evaporated chloroform, and the residue was recrystallized with 20 milliliters of ethanol. Othe...

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Abstract

The invention discloses a new compound, N1,N4-di(3-hydroxyphenyl)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-dicarbonamide shown in formula (I), and preparation and application thereof. The preparation of the compound comprises the steps of using 3,6-dimethyl-1,6-dihydro-1,2,4,5-tetrazine and bis(trichloromethyl) carbonate as raw materials to react with m-hydroxyaniline in an organic solvent in the presence of alkaline catalyst. The compound provided by the invention is applied for preparing medicines for treatment and prevention of human gastric cancer, ovarian cancer, liver cancer, breast cancer or lung cancer. According to the invention, the compound is rational in design, easy in operation, low in production cost and easy to obtain raw materials, and is suitable for industrialized application, and a new choice for screening anti-tumor medicines is provided.

Description

(1) Technical field [0001] The present invention relates to a kind of new compound m-hydroxyphenyltetrazine dicarboxamide (being N 1 , N 4 -bis(3-hydroxyphenyl)-3,6-dimethyl-1,2,4,5-tetrazine-1,4-dicarboxamide) and its preparation method, and the compound in the preparation of prevention or Application in drugs for the treatment of tumor diseases. (2) Background technology [0002] Tetrazine compounds have many good physical properties, spectral properties and high reactivity, especially some tetrazine derivatives with special structures have obvious antiviral activity, antitumor activity, and can be used as pesticides and insecticides. For example, there are currently two varieties of pesticides (tetrafenazine and flufenazine) on the market, and one variety of medicine (the antineoplastic drug temozolomide) has been on the market. [0003] In 1978, it was reported that 3,6-diphenynyl-hexahydro-1,2,4,5-tetrazine had antitumor activity (see Eremeev, A.V.; Tikhomirova, D.A....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D257/08A61K31/395A61P35/00
Inventor 饶国武倪嘉斌章莉玲王翠
Owner ZHEJIANG UNIV OF TECH
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