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Derivatives and salts of diamino dihydrotriazine, and preparation method, composition and application thereof

A technology of diaminodihydrotriazine and derivatives, which is applied in the fields of drug combination, active ingredients of heterocyclic compounds, organic chemistry, etc. Influence, compound structure modification limitations, etc.

Active Publication Date: 2014-03-26
SHANGHAI INST OF PHARMA IND CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Ma Xiang and others have synthesized a series of diaminodihydrotriazine compounds with spiro ring structure (Xiang Ma, Renee Ser-Peng Woon, Antiproliferative Activity Against MCF-7Breast Cancer Cells by Diamino-Triazaspirodiene Antifolates, Chem.Biol.Drug Des.2009;74:322–326), and performed corresponding biological activity tests, which involved compound 1, compound 2, and compound 3 as shown below, but did not study triazine spiroheterocyclic compounds in the above reports There is no research report on the structure-activity relationship of diaminodihydrotriazine spiroheterocyclic compounds in the prior art, so the structural modification of this type of compounds is always subject to certain restrictions, and it is difficult to find out their structures For the impact of activity, therefore, the research on this kind of compound needs to be further deepened

Method used

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  • Derivatives and salts of diamino dihydrotriazine, and preparation method, composition and application thereof
  • Derivatives and salts of diamino dihydrotriazine, and preparation method, composition and application thereof
  • Derivatives and salts of diamino dihydrotriazine, and preparation method, composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0175] 1-Bromo-3-phenoxypropane

[0176] Phenol (4.7g, 0.05mol), 1,3-dibromopropane (50g, 0.25mol), and potassium carbonate (10g, 0.075mol) were mixed in 100ml of acetonitrile, and reacted at 80°C for 9 hours. When the phenol is consumed as monitored by TLC, stop the reaction, place it at room temperature, remove the solid by suction filtration, concentrate the filtrate under reduced pressure, add 100ml of chloroform, wash the chloroform layer twice with 0.2N aqueous sodium hydroxide solution (100ml*2), wash with anhydrous magnesium sulfate to dry. Distilled under reduced pressure, under the pressure of 0.48mbar, the fraction at 76-78°C was taken to obtain 6.7g of colorless oil, with a yield of 62.2%. References for specific methods (Hideki Kubota, Toshihiro Watanabe. Synthesis and pharmacological evaluation of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel specific bradycardic agents. Bioorganic & Medicinal Chemistry, 2004, 12:871-882).

[0177] Compounds of gen...

Embodiment 2

[0179] 1-bromo-3-(2’,4’-dichlorophenoxy)propane

[0180] 2,4-dichlorophenol (8.2g, 0.05mol), 1,3-dibromopropane (50g, 0.25mol), and potassium carbonate (10g, 0.075mol) were mixed in 100ml of acetonitrile and reacted at 80°C for 8 hours. When the phenol is consumed as monitored by TLC, stop the reaction, place it at room temperature, remove the solid by suction filtration, concentrate the filtrate under reduced pressure, add 100ml of chloroform, wash the chloroform layer twice with 0.2N aqueous sodium hydroxide solution (100ml*2), wash with anhydrous magnesium sulfate to dry. Distilled under reduced pressure, under 0.3mbar pressure, the fraction at 106-108°C was taken to obtain 8.5g of colorless oily substance, with a yield of 60.5%.

Embodiment 3

[0182] 1-Bromo-3-(4’-methoxyphenoxy)propane

[0183]4-Methoxyphenol (6.2g, 0.05mol), 1,3-dibromopropane (50g, 0.25mol), and potassium carbonate (10g, 0.075mol) were mixed in 100ml of acetonitrile, and reacted at 80°C for 9 hours. When the phenol is consumed as monitored by TLC, stop the reaction, place it at room temperature, remove the solid by suction filtration, concentrate the filtrate under reduced pressure, add 100ml of chloroform, wash the chloroform layer twice with 0.2N aqueous sodium hydroxide solution (100ml*2), wash with anhydrous magnesium sulfate to dry. Distilled under reduced pressure, under 0.5mbar pressure, the fraction at 98-102°C was taken to obtain 8.1g of colorless oily substance, with a yield of 66.1%.

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Abstract

The invention discloses derivatives and salts of damino dihydrotriazine, and a preparation method, a composition and application thereof. According to the invention, the preparation method of the damino dihydrotriazine derivative and the damino dihydrotriazine salt can be realized by adopting a method I or a method II, wherein the method I includes the step of obtaining a general formula I compound prepared through the reaction between a general formula IV compound and a general formula V compound, while the method II includes the step of mixing a general formula VIII compound with a general formula II compound under an acidic condition, and obtaining the compound shown in the general formula I through a cyclization reaction of the mixture. The invention also provides application of derivatives and salts of the damino dihydrotriazine in preparation of human dihydrofolate reductase inhibitors, preventing and curing drugs for tumor or bacterial infection diseases. The invention further provides a drug composition, which comprises an effective amount of the derivatives and / or salts of the damino dihydrotriazine, as well as pharmaceutically acceptable carriers. According to the invention, spiro heterocyclic ring derivatives of the damino dihydrotriazine have an excellent inhibitory activity on human dihydrofolate reductase, tumor cells and bacteria.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemical synthesis, and in particular relates to a diaminodihydrotriazine derivative with a spiro ring structure, a salt thereof, a preparation method, a composition containing the same and an application thereof. Background technique [0002] Dihydrofolate reductase (DHFR) is an important drug target in the biological metabolism of folic acid. Dihydrofolate reductase is a key enzyme in the biological metabolism of folic acid. Its main function is to catalyze the reduction of dihydrofolate to tetrahydrofolate in vivo, and tetrahydrofolate is an essential coenzyme in the process of DNA synthesis. The structure of DHFR inhibitors is similar to the substrate of dihydrofolate reductase, which can competitively bind to DHFR, hinder the combination of DHFR and normal substrates, inhibit its catalytic reduction activity, and make it difficult to convert dihydrofolate into tetrahydrofolate. Interfering...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/107C07D495/10A61K31/53A61P35/00A61P31/04A61P35/02A61P37/02A61P19/02A61P19/04
CPCC07D491/107C07D495/10
Inventor 周晓天周伟澄
Owner SHANGHAI INST OF PHARMA IND CO LTD
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