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Triazolopyrimidine HIV-1 retrovirus inhibitor and its preparation method and application thereof

A reverse transcriptase inhibition, HIV-1 technology, applied in the field of medicine, can solve the problems of side effects, poor oral availability, etc.

Active Publication Date: 2013-10-23
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, the marketed drugs etravirine and rilpivirine, as typical representatives of the second-generation NNRTIs, have received extensive attention. However, due to the poor oral availability or side effects of these two drugs, further research is needed. Structural modifications to overcome the above problems

Method used

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  • Triazolopyrimidine HIV-1 retrovirus inhibitor and its preparation method and application thereof
  • Triazolopyrimidine HIV-1 retrovirus inhibitor and its preparation method and application thereof
  • Triazolopyrimidine HIV-1 retrovirus inhibitor and its preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Example 1.4-((5-(2,4,6-trimethylphenoxy)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino)benzonitrile (WL - Preparation of a1)

[0069] Add 5.0g (59.5mmol) of aminotriazole, 9.52g (59.5mmol) of diethyl malonate and 4.05g (59.5mmol) of NaOEt (prepared from Na and EtOH) into 50mL of anhydrous EtOH, stir, Reflux for 12h. The residual ethanol was distilled off, ice water was added, extracted three times with ethyl acetate, and diethyl malonate was removed. The aqueous layer was collected and acidified to pH=1 with concentrated HCl. Stand still in an ice bath to precipitate a large amount of white solid, filter, wash with water, and dry to obtain intermediate 1;

[0070] The prepared intermediate 16.08g (40mmol) was added to 57mL (600mmol) POCl 3 , stirred and refluxed at 95°C for 12h. Evaporate excess POCl 3 , add crushed ice after cooling, stir to remove residual POCl 3 . Join H 2 O and CH 2 Cl 2 Extraction was performed and the organic layer was collected. Take Na ...

Embodiment 2

[0074] Example 2.4-((5-(2,4,6-trichlorophenoxy)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino)benzonitrile ( Preparation of WL-a2)

[0075] The preparation method is as in Example 1, and the difference is: the trichlorophenol of 2mmol and the K of 4mmol 2 CO 3 Add it into an appropriate amount of DMF, stir at room temperature for 5 min, then add 2 mmol of intermediate 3, and react at 150° C. for 8-12 h. The product is a white solid, the total yield is 7%, mp: 258-260°C.

[0076] ESIMS: m / z431.3(M+1), 433.4(M+3), 435.3(M+5), 437.3(M+7).

[0077] IR(KBr,cm -1 ):3303(NH),2231(CN).

[0078] 1 H NMR (DMSO-d 6 ,400MHz)δ:10.16(s,1H,NH),8.48(s,1H,triazole-H),8.13(s,2H,OPh-H),7.96(d,2H,J=8.8Hz,Ph-H ), 7.84 (d, 2H, J=8.8Hz, Ph-H), 5.91 (s, 1H, pyrimidine-H).

Embodiment 3

[0079] Example 3.4-((5-(4-bromo-2,6-dimethylphenoxy)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl)amino) Preparation of benzonitrile (WL-a3)

[0080] The preparation method is as in Example 1, the difference is: 2mmol of 4-bromo-2,6-dimethylphenol and 4mmol of K 2 CO 3 Add it into an appropriate amount of DMF, stir at room temperature for 5 min, then add 2 mmol of intermediate 3, and react at 150° C. for 8-12 h. The product is a white solid, 8% overall yield, mp: 285°C (dec).

[0081] ESIMS: m / z435.4(M+1),437.4(M+3).

[0082] IR(KBr,cm -1):3358(NH),2218(CN).

[0083] 1 H NMR (DMSO-d 6 ,400MHz)δ:10.13(s,1H,NH),8.44(s,1H,triazole-H),7.98(d,2H,J=8.8Hz,Ph-H),7.82(d,2H,J=8.8 Hz, Ph-H), 7.60 (s, 2H, OPh-H), 5.71 (s, 1H, pyrimidine-H), 2.18 (s, 6H, CH 3 ).

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Abstract

The invention relates to a triazolopyrimidine HIV-1 retrovirus inhibitor and its pharmaceutically acceptable salt, ester or prodrug, its preparation method and an application of one compound or a composition of more compounds in the preparation of anti-AIDS drugs.

Description

technical field [0001] The invention relates to a derivative and its preparation method and application, in particular to a triazolopyrimidine HIV-1 reverse transcriptase inhibitor and its preparation method and application, belonging to the technical field of medicine. Background technique [0002] AIDS, also known as acquired immunodeficiency syndrome (Acquired immunodeficiency syndrome, AIDS), is an infectious disease caused by the pathogen of AIDS, human immunodeficiency virus (Human immunodeficiency virus, HIV), mainly T cell immune function deficiency . Since its discovery in the 1980s, AIDS has become one of the major infectious diseases that seriously endanger human health. At present, the most commonly used clinical method for preventing and treating AIDS is highly active antiretroviral therapy (Highly Active Antiretroviral Therapy, HAART). Although the implementation of this therapy has greatly improved the suppression efficiency of HIV virus, but because HIV viru...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61K31/519A61P31/18
Inventor 刘新泳王柳展鹏
Owner SHANDONG UNIV
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