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2,4-di-substituted amido-6-substituted-[1,3,5]triazine or miazines compound, preparation method, pharmaceutical combination and use of the same

A two-substituted, compound technology, applied in the fields of medicinal chemistry and pharmacotherapy, can solve the problems of HIV virus resistance reverse transcriptase and protease inhibitors, side effects, false positives, and unclear mechanisms, and achieve inhibition of virus replication. Effect

Inactive Publication Date: 2008-08-20
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Although there have been more than ten years of research on IN inhibitors, there are currently no drugs on the market for IN inhibitors, and only a few have entered the clinic
The reason is that there are two main limitations: one is the limitation of the activity assay method: the determination based on cell culture cannot determine whether the compound directly acts on IN, and there are too many false positives in molecular level screening; the other is the limitation of structural biology. Restrictions: the crystal structure of IN and its DNA-substrate complex have not been determined, and there are still many mechanisms in the integration of this complex biochemical process that have not been clarified
[0016] At present, the treatment of AIDS mainly adopts the combination drug strategy, that is, the combination of HIV reverse transcriptase and protease inhibitors, but the drug resistance caused by HIV virus mutation and the toxic and side effects of reverse transcriptase and protease inhibitors in the course of treatment serious

Method used

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  • 2,4-di-substituted amido-6-substituted-[1,3,5]triazine or miazines compound, preparation method, pharmaceutical combination and use of the same
  • 2,4-di-substituted amido-6-substituted-[1,3,5]triazine or miazines compound, preparation method, pharmaceutical combination and use of the same
  • 2,4-di-substituted amido-6-substituted-[1,3,5]triazine or miazines compound, preparation method, pharmaceutical combination and use of the same

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] 4,6-dichloro-[1,3,5]triazin-2-ylaniline (II-1)

[0132]Dissolve 2.0 g of 2,4,6-trichloro-[1,3,5]triazine in 12 ml of dioxane, and slowly add aniline in acetone solution (1 g / 2 ml) with stirring in an ice bath ). After the dropwise addition was completed, 1.16 g of sodium carbonate was added at one time, and the mixture was stirred in an ice bath for 5 hours, then warmed up to room temperature and stirred for 2 hours. 150 ml of water was added dropwise to the reaction solution, stirred for 30 minutes, a large amount of solid was precipitated, filtered with suction, washed with water, and dried to obtain 2.48 g of a light yellow solid product with a yield of 95.4%. Mp 132-133°C (lit. 133-135°C). MS-EI 240 (M+, 100%).

Embodiment 2

[0134] (4-Chloro-6-morpholin-4-yl-[1,3,5]triazin-2-yl)aniline (III-1)

[0135] Dissolve 1.0 g of II-1 in 6 ml of dioxane, and slowly add a solution of morpholine in acetone (0.36 g / 1 ml) dropwise under cooling and stirring in an ice bath. After the dropwise addition, 0.438 g of sodium carbonate was added at one time, and the mixture was stirred in an ice bath for 2 hours, then warmed up to room temperature and stirred for 1 hour. 70 ml of water was added dropwise to the reaction solution, stirred for 30 minutes, a large amount of solid was precipitated, filtered with suction, washed with water, and dried to obtain 1.06 g of a light yellow solid product with a yield of 88.0%. Mp 193-195°C (lit. 198.5-199.5°C). 1H-NMR (400Hz, CDCl3) δ: 3.75 (4H, m), 3.85 (4H, m), 7.14 (1H, t), 7.18 (1H, br), 7.38 (2H, t), 7.52 (2H, t ).

Embodiment 3

[0137] (4-hydrazino-6-morpholin-4-yl-[1,3,5]triazin-2-yl)aniline (IV-1)

[0138] Put 0.5 g of III-1 into 15 ml of 85% hydrazine hydrate, reflux and stir for 2 hours, cool to room temperature, pump up, and wash with a small amount of absolute ethanol to obtain 0.4 g of off-white solid with a yield of 81.6%. Mp 170-171°C; MS-EI 287 (M+, 100%).

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Abstract

The invention relates to a novel 2, 4-disubstituted amino-6-substituted-(1, 3, 5) triazine or a 1, 3-pyrimidine derivative, the preparation method, a drug combination and the pharmacological usage; the structure general formula is shown as the formula (I), wherein, the definitions of R1, R2, R3, R4, R5, R6, A, B, X, Y and Z are described in an instruction. The compounds and a HIV-1 integrase have high binding activity and can effectively inhibit the binding of the integrase with a substrate in a substrate competition test. Therefore, the compounds are stronger HIV-1 integrase inhibitors, which are expected to be developed into new anti-HIV drugs.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry and pharmacotherapeutics, in particular to 2,4-disubstituted amino-6-substituted-[1,3,5]triazine or 1,3-pyrimidine compounds, their preparation method, containing such Pharmaceutical compositions and uses of compounds. Background technique [0002] Since the first AIDS (acquired immune deficiency syndrome) patient was discovered in the United States in 1981, AIDS has spread rapidly in more than 180 countries and regions around the world. At present, the total number of AIDS patients and virus carriers in the world has reached more than 42 million, of which nearly 1 million are in China, ranking second in Asia and 14th in the world. Moreover, in recent years, the number of AIDS cases in China has been increasing rapidly at an average annual rate of 30-40%, which has become an increasingly serious public security problem. [0003] As the pathogen of AIDS, HIV virus needs the participatio...

Claims

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Application Information

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IPC IPC(8): C07D251/54C07D239/50A61K31/505A61K31/53A61P31/18
CPCA61P31/18C07D239/48C07D239/50C07D251/18C07D251/54C07D401/04C07D413/04
Inventor 蒋华良沈旭郑永唐李剑柳红杜丽杨柳萌王睿睿王乙平陈凯先
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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