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Cyano-vinyl substituted benzodiaryl pyrimidine compound and preparation method and application thereof

A technology of benzodiarylpyrimidines and compounds, which is applied in the field of benzodiarylpyrimidines and their preparation, can solve problems such as poor patient response rate, limited clinical use, and drug inactivation, and achieve low cytotoxicity, Significant anti-HIV-1 activity, the effect of improving biological activity

Active Publication Date: 2019-12-03
FUDAN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

They have disadvantages such as poor water solubility (ETR, <<1μg / mL; RPV, 20ng / mL), low patient response rate (ETR, 36.5%; RPV, 27.3%), and side effects caused by long-term use
On the other hand, the amino acid mutation on the reverse transcriptase will make the original effective drug inactive, that is, the generation of drug-resistant HIV strains, which is also an important problem that limits its clinical use

Method used

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  • Cyano-vinyl substituted benzodiaryl pyrimidine compound and preparation method and application thereof
  • Cyano-vinyl substituted benzodiaryl pyrimidine compound and preparation method and application thereof
  • Cyano-vinyl substituted benzodiaryl pyrimidine compound and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Embodiment 1: the synthesis of trans-3-(4-((2-chloroquinazoline-4-) amino)-3,5-dimethylphenyl)acrylonitrile

[0037]

[0038] Trans-3-(4-amino-3,5-dimethylphenyl)acrylonitrile (334.8mg, 10mmol), 2,4-dichloroquinazoline (258.7mg, 13mmol), palladium acetate (112mg, 0.5 mmol), 2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl (394mg, 1mmol), potassium phosphate (6.37g, 30mmol) in N,N-dimethylformamide (80 mL) was heated at 140° C. for 12 hours under nitrogen protection. TLC showed the reaction was complete. Diluted with ethyl acetate (10 mL), washed with saturated sodium carbonate solution (10 mL×2), water (10 mL×2), and saturated brine (10 mL×2) successively, and dried the organic phase over anhydrous sodium sulfate overnight. Filtration, concentration, and column chromatography gave the desired solid.

[0039] Yield 23%, white solid; 1 H NMR (400MHz, DMSO-d 6 )δ10.15(s,1H,NH),8.54(d,J=8.1Hz,1H,ArH),7.89(t,J=7.6Hz,1H,ArH),7.72(d,J=8.2Hz,1H ,ArH),7.68–7.58(m...

Embodiment 2

[0044] Example 2: trans-4-((6-chloro-4-((4-(2-cyanovinyl)-2,6-difluorophenyl)amino)quinazoline-2-)amino)benzene Nitrile Synthesis. The structural formula of this compound is:

[0045]

[0046] Compound II trans-3-(4-((2,6-dichloroquinazoline-4-)amino)-3,5-difluorophenyl)acrylonitrile (2mmol), p-aminobenzonitrile (4mmol, 472mg ) in n-butanol (5 mL) was refluxed for 6-8 hours. Insoluble matter was precipitated in the reaction solution, filtered, washed with dichloromethane (5mL×3), and dried to obtain compound I trans-4-((6-chloro-4-((4-(2-cyanovinyl)- 2,6-Difluorophenyl)amino)quinazoline-2-)amino)benzonitrile.

[0047] Yield 41%, white solid, melting point >325°C; 1 H NMR (400MHz, DMSO-d 6 )δ11.61(s,1H,NH),10.76(s,1H,NH),8.84(s,1H,ArH),8.07(s,2H,ArH),7.96(d,J=8.6Hz,1H, ArH), 7.82–7.69 (m, 2H, ArH and olefinic H), 7.53 (s, 4H), 6.81 (d, J=16.8Hz, 1H, olefinic H). 13 CNMR (101MHz, DMSO-d 6 )δ160.18, 153.38, 147.77, 142.99, 136.15, 135.04, 134.80, 133.15, 129.23, 128.31...

Embodiment 3

[0048] Example 3: trans-4-((6-chloro-4-((4-(2-cyanovinyl)-2-fluoro-6-methylphenyl)amino)quinazoline-2-)amino ) Synthesis of benzonitrile. The structural formula of this compound is:

[0049]

[0050] The operation method is the same as above. Yield 52%, yellow solid, melting point 278-282°C. 1 H NMR (400MHz, DMSO-d 6 )δ10.98(s,1H,NH),10.56(s,1H,NH),8.81–8.74(m,1H,NH),8.04–7.52(m,9H,Ar Handolefinic H),6.36(d,14.2Hz ,1H,olefinic H),2.31(s,3H,CH 3 ). 13 C NMR (101MHz, DMSO-d 6 )δ160.29, 157.06, 149.47 (d, J C-F =2.5Hz), 143.22, 139.19, 135.79, 134.84, 133.44 (d, J C-F =11.7Hz), 133.17, 129.01, 126.65 (d, J C-F =2.1Hz), 124.20, 120.54, 119.51, 118.96, 112.63 (d, J C-F =22.0Hz), 112.17, 99.10, 18.12 (d, J C-F =2.3Hz).HRMScalcd for C 25 h 16 ClFN 6 [M+H] + :455.1182,found:455.1168.HPLC analysis:t R = 19.25 min, 95.01%.

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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a cyano-vinyl substituted benzodiaryl pyrimidine compound and a preparation method and application thereof. The compound disclosed by the invention is the cyano-vinyl substituted benzodiaryl pyrimidine compound, and further comprises pharmaceutically acceptable salts, hydrates and solvates, polycrystals or cocrystals thereof as well as precursors and derivatives with the same biological function. The invention further discloses a preparation method of the cyano-vinyl substituted benzodiaryl pyrimidine compound and application of a composition containing one or more compounds in related drugs for treating acquired immune deficiency syndrome and the like. In-vitro cell-level anti-HIV-1 activity experimentsshow that the small molecules have high anti-HIV-1 biological activity, can remarkably inhibit virus replication in MT-4 cells infected by HIV-1 virus, and have low cytotoxicity.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a benzodiarylpyrimidine compound substituted with a vinylcyanide group and a preparation method and application thereof. [0002] The series of compounds are HIV-1 non-nucleoside reverse transcriptase inhibitors, which not only have strong biological activity, but also have low cytotoxicity and high selection coefficient. Background technique [0003] AIDS (acquired immunodeficiency syndrome) is caused by the human immunodeficiency virus (HIV). HIV reverse transcriptase (RT) plays an important role in the viral life cycle and is an important target for the design of anti-HIV-1 drugs. RT inhibitors can be divided into nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Nucleoside reverse transcriptase inhibitors compete with the substrate to act on the RT active site, which has the disadvantages of poor s...

Claims

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Application Information

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IPC IPC(8): C07D239/94C07D239/95A61K31/517A61P31/18
CPCC07D239/94C07D239/95A61P31/18
Inventor 陈芬儿韩胜庄春林
Owner FUDAN UNIV
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