CN111303046B - Biphenyl diaryl pyrimidine derivative containing chiral hydroxymethylene structure and preparation method and application thereof - Google Patents

Biphenyl diaryl pyrimidine derivative containing chiral hydroxymethylene structure and preparation method and application thereof Download PDF

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CN111303046B
CN111303046B CN202010172370.9A CN202010172370A CN111303046B CN 111303046 B CN111303046 B CN 111303046B CN 202010172370 A CN202010172370 A CN 202010172370A CN 111303046 B CN111303046 B CN 111303046B
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陈芬儿
庄春林
陈晓梅
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王佳琦
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl pyrimidine derivative containing a chiral hydroxymethylene structure, and preparation and application thereof. The biphenyl diaryl pyrimidine derivative with the chiral hydroxymethylene structure comprises medicinal salts, stereochemical isomers, hydrates and solvates, polycrystal or eutectic crystals, X-ray diffraction single crystals of a single enantiomer, precursors and derivatives with the same biological functions; the invention also discloses a preparation method thereof and application of a composition containing one or more compounds in preparation of related medicines for treating AIDS and the like. The in vitro cell level anti-HIV-1 activity experiment result shows that the small molecules have stronger anti-HIV-1 biological activity, can obviously inhibit virus replication in MT-4 cells infected by HIV-1 viruses, have lower cytotoxicity and are expected to become anti-HIV candidate drugs.

Description

Biphenyl diaryl pyrimidine derivative containing chiral hydroxymethylene structure and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a biphenyl diaryl pyrimidine derivative containing a chiral hydroxymethylene structure, a preparation method thereof and application thereof in related medicines for treating AIDS and the like.
Background
AIDS (Acquired immune deficiency syndrome), which is Acquired immune deficiency syndrome, is caused by immunodeficiency due to infection with Human immunodeficiency virus (HIV-l), thereby causing a series of serious epidemic diseases such as pathogenic infection and tumor. Since the first case was confirmed by the united states Centers for Disease Control (CDC) in 1981, aids has spread rapidly around the world, becoming a major public health problem worldwide, and has caused 3200 more than ten thousand deaths.
Reverse Transcriptase (RT) plays a key role in the life cycle of HIV virus replication, and is responsible for Reverse transcription of viral RNA into DNA-RNA hybrids and degradation of RNA in the hybrids to form single-stranded viral DNA, and then viral DNA is integrated into host cells by integrase, so that Reverse transcriptase becomes one of important targets for anti-AIDS drug design. Currently, more than half of the anti-HIV marketed drugs are Reverse Transcriptase Inhibitors (RTIs).
Among the existing anti-HIV-1 drugs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) play an important role in the clinical treatment of AIDS due to the advantages of high efficiency, low toxicity and the like, and become a main component of high-efficiency antiretroviral therapy (HAART). By the end of 2019, over 50 HIV-1 non-nucleoside reverse transcriptase inhibitors with different chemical structures have been discovered, 6 of which have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of AIDS, namely Nevirapine (NVP), Delavirdine (DLV), efavirenz (efavirenz, EFV), Etravirine (ETR), Rilpivirine (RPV) and Dorivirine (DOR). Currently clinically used NNRTIs are mainly second generation HIV inhibitors: diarylpyrimidines, Rilpivirine (RPV) and Etravirine (Etravirine, ETR). However, the rapid emergence of viral mutants, the poor water solubility (ETR, < <1 μ g/mL; RPV,20ng/mL) of these compounds, and the side effects caused by long-term administration limit their clinical use, and further development of novel highly potent non-nucleoside reverse transcriptase inhibitors with broad-spectrum antiviral activity and excellent pharmacokinetic properties has become one of the hot spots of research by medicinal chemists.
The invention aims to optimize the structure of diaryl pyrimidine non-nucleoside reverse transcriptase inhibitor and split chiral molecules, investigate the biological activity and pharmacological and toxicology of different single enantiomers, and obtain a novel high-efficiency non-nucleoside reverse transcriptase inhibitor with excellent antiviral activity and pharmacokinetic properties.
Disclosure of Invention
The invention aims to provide a biphenyl diaryl pyrimidine compound containing a chiral hydroxymethylene structure, which has strong biological activity and low cytotoxicity, and a preparation method and application thereof.
The invention provides a biphenyl diaryl pyrimidine derivative containing a chiral hydroxymethylene structure, which has the following structural formula:
Figure BDA0002409643790000021
wherein R1 and R2 are respectively and independently selected from hydrogen, cyano, amino, nitro, hydroxyl, halogen, C3-6 cycloalkoxy, C3-6 cycloalkamino, optionally substituted C1-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl or C1-6 alkoxy, carboxyl, ester group, amide group and sulfonamide group;
r3 and R4 are independently selected from hydrogen, cyano, amino, nitro, hydroxyl, halogen, sulfonic group, C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, C3-6 cycloalkoxy and C3-6 cycloalkylamino.
The biphenyl diaryl pyrimidine derivative containing the chiral hydroxymethylene structure also comprises medicinal salts, stereochemical isomers, hydrates and solvates, polycrystal or eutectic crystals and single-enantiomer X-ray diffraction single crystals, precursors and derivatives with the same biological functions.
The medicinal salt of the biphenyl diaryl pyrimidine derivative containing the chiral hydroxymethylene structure comprises hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, citrate, fumarate or malate.
The invention also provides a preparation method of the biphenyl diaryl pyrimidine derivative with the chiral hydroxymethylene structure, which comprises the following specific operation steps:
in a solvent, a carbon-based compound II is subjected to reduction reaction under the action of a reducing agent to obtain a racemate compound I, and then a single enantiomer with R and S configuration is obtained through chiral resolution; the general reaction formula and the resolution process for preparing the racemate are as follows:
Figure BDA0002409643790000022
the reaction conditions and the resolution method are as follows:
the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethyl acetate, etc.;
the reducing agent is one or more of borane, aluminum isopropoxide, sodium borohydride, potassium borohydride, lithium aluminum hydride and hydrogen;
the molar ratio of the compound II to the reducing agent is 1:2-1:5, and the optimal molar ratio is 1: 3;
the reaction temperature is 0-200 ℃, and the preferable reaction temperature is 20-50 ℃;
the reaction time is 1-4 h.
The resolution method used is one or more of crystallization resolution, chemical resolution, enzyme resolution and chromatographic resolution.
The invention also relates to a pharmaceutical composition comprising an effective amount of the above compound and a pharmaceutically acceptable carrier therefor. The invention also relates to application of the compound or the composition in preparation of drugs for preventing and treating AIDS.
The invention is based on the combination mode of biphenyl diaryl pyrimidine derivatives containing chiral hydroxymethylene structures and HIV reverse transcriptase, and combines computer-aided drug design, and introduces hydroxyl at the connecting arm to enhance the hydrogen bond interaction between the compound and the combination pocket. A biphenyl structure is introduced into the left wing of the pyrimidine ring, so that the pi-pi stacking effect between the compound and aromatic amino acid residues Tyr181 and Tyr188 in a binding pocket is enhanced. The cyano group on the left flank can deeply bind to the pocket to strengthen the binding force with the highly conserved amino acid residues Phe227 and Trp 229. In addition, the single enantiomer with a certain configuration is beneficial to effectively combining the molecule with a target, and the biological activity of the target compound against HIV virus strains is further improved. The in vitro cell level anti-HIV-1 activity experiment result shows that the series of compounds have more remarkable anti-HIV-1 activity and lower cytotoxicity. Wherein, all single enantiomers reflect that S configuration has better antiviral activity compared with R configuration, and the racemate activity is almost between two isomers.
Drawings
FIG. 1 and FIG. 2 show the structure of (R) - (+) -4X-ray single crystal.
Detailed Description
The invention will be better understood by the following examples of implementation, without however limiting the scope of the invention.
Example 1: preparation of the end product I
And (3) obtaining a racemate product Ras-1 by the compound II under the action of a reducing agent, and carrying out chiral resolution on the obtained racemate compound by using a proper resolution method to obtain a corresponding R enantiomer (R-1) and an R enantiomer (S-1). Wherein the reduction conditions are as follows: borane reagent reduction, aluminum alkoxide reagent reduction, sodium borohydride or potassium borohydride reduction, lithium aluminum hydride reduction, hydrogenation reduction under the catalysis of metals such as Pt, Pd, Ni and the like, and the like. The solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, ethyl acetate, etc.; the reaction temperature is 0-200 ℃, and the reaction time is 1-4 h. The resolution method is one or more of crystallization resolution, chemical resolution, enzyme resolution and chromatographic resolution.
The target compounds were prepared from starting materials containing different substituents by the methods described above, in part, as follows:
adding 4' - (2- (((4-cyanophenyl) amino) pyrimidine-4-carbonyl) -3' -methoxy- [1,1' -biphenyl ] -4-carbonitrile (1mmol) and sodium borohydride (3mmol) to methanol (40mL) at room temperature, stirring for 2 h.TLC shows that the reaction is complete the reaction is completed, pouring the reaction mixture into water (40mL), stirring for a while, and filtering to obtain the desired solid (racemate). on the basis of this, chiral resolution of the above-obtained racemate compound is performed by using a Supercritical Fluid Chromatography (SFC) resolution technique to obtain the corresponding single enantiomers of R configuration and S configuration.
Compound 1:
Figure BDA0002409643790000041
a white powdery solid; the yield is 95%; melting point: 195.6-197.8 deg.c (racemic modification), 234.8-236.2 deg.c (R configuration), 229.3-231.6 deg.c (S configuration).1H NMR(400MHz,DMSO-d6)δ:10.11(s,1H),8.56(d,J＝5.0Hz,1H),8.01–7.86(m,6H),7.64(d,J＝8.7Hz,2H),7.47(d,J＝7.7Hz,1H),7.39–7.29(m,2H),7.17(d,J＝5.0Hz,1H),6.12(s,1H),5.99(s,1H),3.92(s,3H).13C NMR(100MHz,DMSO-d6)δ:173.19,158.82,158.59,156.76,145.01,144.56,138.81,132.83,132.75,131.89,128.46,127.68,119.59,119.21,118.88,118.08,110.22,110.05,109.72,102.10,68.54,55.81.HRMS(ESI+):calcd for C26H20N5O2[M+H]+,434.1612；found,434.1605.HPLC(Agilent Eclipse XDB-C18,MeOH:H2O＝15:85,0.8mL/min,20℃,254nm):tr(Rac)＝9.46min,98.92％；tr(R)＝9.45min,98.84％；tr(S)＝9.45min,99.45％.Enantiomeric excess(ee)was determined by SFC(Daicel ChiralCel OJ-3,CO2:EtOH(0.05％DEA)＝60:40,2.5ml/min,35℃,254nm):tmajor(R)＝3.336min,tminor(R)＝2.398min,ee＝99.70％,
Figure BDA0002409643790000046
(c＝0.3,THF)；tmajor(S)＝2.390min,ee＝100.00％.
Figure BDA0002409643790000044
Figure BDA0002409643790000047
(c＝0.3,THF)。
Compound 2:
Figure BDA0002409643790000042
the operation is the same as above. A white powdery solid; the yield is 95%; melting point: 219.4-222.1 deg.C (racemic body), 221.9-223.6 deg.C (R configuration), 226.8-228.9 deg.C (S configuration).1H NMR(400MHz,DMSO-d6)δ:10.13(s,1H),8.61(d,J＝5.0Hz,1H),7.96–7.91(m,4H),7.90–7.83(m,3H),7.80–7.75(m,1H),7.67–7.57(m,3H),7.23(d,J＝5.0Hz,1H),6.53(d,J＝4.8Hz,1H),6.03(d,J＝4.5Hz,1H).13C NMR(100MHz,DMSO-d6)δ:171.74,159.06,158.86,144.80,142.72,140.89,139.10,132.97,132.90,132.74,129.84,127.69,127.49,125.99,119.51,118.71,118.22,110.66,110.45,102.25,71.33.HRMS(ESI+):calcd for C25H17ClN5O[M+H]+,438.1116,found,438.1111.HPLC(Agilent Eclipse XDB-C18,MeOH:H2O＝15:85,0.8mL/min,20℃,254nm):tr(Rac)＝10.26min,99.61％；tr(R)＝10.27min,97.03％；tr(S)＝10.25min,97.98％.Enantiomeric excess(ee)was determined by SFC(Daicel ChiralCel OD-3,CO2:EtOH(0.05％DEA)＝60:40,2.5ml/min,35℃,254nm):tmajor(R)＝2.728min,tminor(R)＝3.357min,ee＝98.82％,[α]20D＝+158.00(c＝0.1,DMSO:MeOH＝1:1)；tmajor(S)＝3.366min,tminor(S)＝2.751,ee＝97.88％.[α]20D＝-150.00(c＝0.1,DMSO:MeOH＝1:1)。
Compound 3:
Figure BDA0002409643790000051
the operation is the same as above. A white powdery solid; the yield is 89%; melting point: 222.5-223.1 deg.C (racemic body), 161.5-163.3 deg.C (R configuration), and 189.9-191.2 deg.C (S configuration).1H NMR(400MHz,DMSO-d6)δ:10.13(s,1H),8.61(d,J＝5.0Hz,1H),7.95–7.90(m,4H),7.86(d,J＝8.7Hz,2H),7.70–7.56(m,5H),7.26(d,J＝5.0Hz,1H),6.48(d,J＝4.3Hz,1H),5.92(d,J＝4.1Hz,1H).13C NMR(100MHz,DMSO-d6)δ:172.25,160.02(d,J＝244.0Hz),158.99,158.83,144.85,142.91(d,J＝1.0Hz),139.63(d,J＝9.0Hz),132.89,132.78,130.65(d,J＝14.0Hz),129.70(d,J＝4.0Hz),127.65,123.11(d,J＝3.0Hz),119.52,118.73,118.19,113.91(d,J＝23.0Hz),110.62,109.94,102.27,68.67.HRMS(ESI+):calcd for C25H17FN5O[M+H]+,422.1412,found,422.1409.HPLC(Agilent Eclipse XDB-C18,MeOH:H2O＝15:85,0.8mL/min,20℃,254nm):tr(Rac)＝9.62min,97.31％；tr(R)＝9.30min,99.64％；tr(S)＝9.58min,99.73％.Enantiomeric excess(ee)was determined by SFC(Daicel ChiralCel OJ-3,CO2:EtOH(0.05％DEA)＝60:40,2.5ml/min,35℃,254nm):tmajor(R)＝2.766min,tminor(R)＝2.050min,ee＝99.60％,[α]20D＝+245.00(c＝0.1,DMSO:MeOH＝1:1)；tmajor(S)＝2.027min,ee＝100.00％.[α]20D＝-242.00(c＝0.1,DMSO:MeOH＝1:1)。
Compound 4:
Figure BDA0002409643790000061
the operation is the same as above. A white powdery solid; the yield is 91%; melting point: 184.3-185.6 deg.C (racemic body), 203.4-205.7 deg.C (R configuration), and 205.0-206.5 deg.C (S configuration).1H NMR(400MHz,DMSO-d6)δ:10.08(s,1H),8.58(d,J＝4.3Hz,1H),7.92–7.81(m,6H),7.65–7.55(m,4H),7.48(d,J＝7.8Hz,1H),7.24(d,J＝4.5Hz,1H),6.27(s,1H),5.86(s,1H),2.48(s,3H).13C NMR(100MHz,DMSO-d6)δ:173.23,158.83,158.76,144.89,144.42,142.22,137.12,136.51,132.82,128.85,128.15,127.44,124.55,119.57,118.92,118.25,110.12,109.92,102.26,71.79,19.45.HRMS(ESI+):calcd for C26H20N5O[M+H]+,418.1662,found,418.1665.HPLC(Agilent Eclipse XDB-C18,MeOH:H2O＝15:85,0.8mL/min,20℃,254nm):tr(Rac)＝9.93min,99.57％；tr(R)＝10.08min,98.06％；tr(S)＝10.12min,99.16％.Enantiomeric excess(ee)was determined by SFC(Daicel ChiralCel AD-3,CO2:EtOH(0.05％DEA)＝60:40,2.5ml/min,35℃,254nm):tmajor(R)＝8.089min,tminor(R)＝6.538min,ee＝98.98％,[α]20D＝+271.00(c＝0.1,DMSO:MeOH＝1:1)；tmajor(S)＝6.523min,tminor(S)＝8.193,ee＝99.68％.[α]20D＝-279.01(c＝0.1,DMSO:MeOH＝1:1)。
Compound 5:
Figure BDA0002409643790000062
the operation is the same as above. A white powdery solid; the yield is 93 percent; melting point: 202.5-203.9 deg.c (racemic body), 207.8-209.1 deg.c (R configuration) and 203.9-206.5 deg.c (S configuration).1H NMR(400MHz,DMSO-d6)δ:10.10(s,1H),8.63(d,J＝4.9Hz,1H),8.08(d,J＝7.3Hz,2H),8.01–7.92(m,4H),7.76(d,J＝8.3Hz,3H),7.55(d,J＝8.4Hz,2H),7.26(d,J＝4.9Hz,1H),6.65(d,J＝3.4Hz,1H),5.98(s,1H).13C NMR(101MHz,DMSO-d6)δ:172.12,159.24,158.85,144.78,142.79,141.87,138.01,133.04,132.72,131.22,131.10,127.96,127.59(q,J＝30.0Hz),124.23(q,J＝273.0Hz),123.98(q,J＝5.0Hz),119.51,118.76,118.22,110.89,110.61,102.33,70.32.HRMS(ESI+):calcd for C26H17F3N5O[M+H]+,472.1380,found,472.1381.HPLC(Agilent Eclipse XDB-C18,MeOH:H2O＝15:85,0.8mL/min,20℃,254nm):tr(Rac)＝10.38min,97.90％；tr(R)＝10.53min,99.81％；tr(S)＝10.58min,97.93％.Enantiomeric excess(ee)was determined by SFC(Daicel ChiralCel OD-3,CO2:EtOH(0.05％DEA)＝60:40,2.5ml/min,35℃,254nm):tmajor(R)＝1.577min,tminor(R)＝2.099min,ee＝99.64％,[α]20D＝+219.01(c＝0.1,DMSO:MeOH＝1:1)；tmajor(S)＝2.066min,tminor(S)＝1.562,ee＝97.80％.[α]20D＝-216.00(c＝0.1,DMSO:MeOH＝1:1)。
Compound 6:
Figure BDA0002409643790000071
the operation is the same as above. A white powdery solid; the yield is 92 percent; melting point: 263.3-265.9 deg.C (racemic body), 222.8-224.7 deg.C (R configuration), 223.3-225.7 deg.C (S configuration).1H NMR(400MHz,DMSO-d6)δ:10.10(s,1H),8.64(d,J＝5.0Hz,1H),8.02–7.93(m,4H),7.79(d,J＝8.6Hz,2H),7.64–7.53(m,4H),7.37(d,J＝5.0Hz,1H),6.64(d,J＝5.1Hz,1H),6.00(d,J＝4.6Hz,1H).13C NMR(100MHz,DMSO-d6)δ:172.28,161.05(dd,J＝247.0,10.0Hz),158.73,158.65,144.87,141.73,140.48(t,J＝10.0Hz),132.95,132.73,127.79,119.49(t,J＝9.0Hz),119.22,118.62,118.12,111.27,110.64(d,J＝26.0Hz),109.64,102.25,65.25.HRMS(ESI+):calcd for C25H16F2N5O[M+H]+,440.1317；found,440.1318.HPLC(Agilent Eclipse XDB-C18,MeOH:H2O＝15:85,0.8mL/min,20℃,254nm):tr(Rac)＝9.33min,98.13％；tr(R)＝9.37min,99.29％；tr(S)＝9.37min,99.41％.Enantiomeric excess(ee)was determined by SFC(Daicel ChiralCel OD-3,CO2:EtOH(0.05％DEA)＝60:40,2.5ml/min,35℃,254nm):tmajor(R)＝1.989min,tminor(R)＝3.425min,ee＝99.84％,
Figure BDA0002409643790000081
(c＝0.1,DMSO:MeOH＝1:1)；tmajor(S)＝3.408min,tminor(S)＝1.994min,ee＝99.84％.
Figure BDA0002409643790000082
(c＝0.1,DMSO:MeOH＝1:1)。
Compound 7:
Figure BDA0002409643790000083
the operation is the same as above. A white powdery solid; the yield is 87%; melting point: 168.9-171.5 deg.C (racemic modification), 236.1-236.7 deg.C (R configuration), and 237.6-238.5 deg.C (S configuration).1H NMR(400MHz,DMSO-d6)δ:10.01(s,1H),8.58(d,J＝5.0Hz,1H),7.95–7.85(m,4H),7.68(d,J＝8.6Hz,2H),7.56–7.40(m,4H),7.34(d,J＝5.0Hz,1H),6.25(s,1H),6.12(s,1H),2.37(s,6H).13C NMR(100MHz,DMSO-d6)δ:174.26,159.23,158.97,145.53,145.01,141.45,138.38,137.37,133.38,133.16,127.92,127.69,120.10,119.52,118.68,110.57,110.40,102.64,70.80,21.06.HRMS(ESI+):calcd for C27H22N5O[M+H]+,432.1819,found,432.1815.HPLC(Agilent Eclipse XDB-C18,MeOH:H2O＝15:85,0.8mL/min,20℃,254nm):tr(Rac)＝10.50min,97.42％；tr(R)＝10.53min,99.67％；tr(S)＝10.54min,98.32％.Enantiomeric excess(ee)was determined by SFC(Daicel ChiralCel OD-3,CO2:EtOH(0.05％DEA)＝60:40,2.5ml/min,35℃,254nm):tmajor(R)＝2.283min,tminor(R)＝3.293min,ee＝99.80％,
Figure BDA0002409643790000084
(c＝0.1,DMSO:MeOH＝1:1)；tmajor(S)＝3.296min,tminor(S)＝2.311,ee＝99.02％.
Figure BDA0002409643790000085
Figure BDA0002409643790000086
(c＝0.1,DMSO:MeOH＝1:1)。
Example 2: single enantiomer X-ray single crystal diffraction
The absolute configuration of a single enantiomer was confirmed by X-ray single crystal diffraction.
Preparation of single crystal: under room temperature or heating condition, the single enantiomer is completely dissolved in the solvent, and then the solution is relatively sealed and stands at room temperature to slowly volatilize the solvent until single crystal grows out. The solvent is one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, dichloromethane, dichloroethane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, ethyl acetate, n-hexane, cyclohexane and petroleum ether. The crystal growth time is 5-20 days. The following examples specifically illustrate the preparation method of the crystal and the X-ray single crystal diffraction results using the compound substituted by methyl on biphenyl as an example.
The compound (+) -4(2mg) substituted by a monomethyl on biphenyl was dissolved in 1ml of methanol at 50 c, after which the solvent was slowly evaporated under sealed conditions at room temperature, and after 15 days, a crystalline product was grown for confirmation of configuration by X-ray single crystal diffraction, with the following results:
TABLE 1 Crystal data and structure refinement for (R) - (+) -4
Figure BDA0002409643790000091
The structure of the (R) - (+) -4X-ray single crystal is shown in FIGS. 1 and 2.
Example 3: anti-HIV biological Activity assay
The anti-HIV virus activity at the cellular level in vitro was determined by the Rega drug research institute of Katholleke university, Belgium, and mainly included: inhibiting activity and cytotoxicity on HIV-infected MT-4 cells. The method comprises the following steps: the compound was allowed to infect HIV in MT-4 cells at different times, the protective effect of the drug on HIV-mutagenized cytopathic effects was determined by MTT method, and the half effective concentration EC required to protect 50% of the cells from HIV-induced cytopathic effects was calculated50Toxicity was measured in parallel with the anti-HIV activity test, and the concentration (CC) at which 50% of uninfected cells were cytopathic was measured by MTT method in MT-4 cell culture50) And calculating the selectivity index SI ═ CC50/EC50。
The material and the method are as follows:
the anti-HIV activity of each compound was monitored by the efficiency of the drug's inhibition of the cytopathic effects of HIV in cells. MT-4 cells were used for cell culture. The viral strains used were: HIV-1 strain IIIB and HIV-2 strain ROD.
The specific operation is as follows: dissolving the compound in DMSO or water, diluting with phosphate buffered saline solution, and mixing to obtain 3 × 10 solution5MT-4 cells were pre-incubated with 100. mu.L of each compound in different concentrations in this solution at 37 ℃ for 1h, and then 100. mu.L of an appropriate viral diluent was added to the compound and the cells were incubated at 37 ℃ for 1 h. After three washes, the cells are resuspended in culture medium with or without compound, respectively. Cells were then incubated at 5% CO2Incubate at 37 ℃ for 7 more days in an atmosphere and replace the supplemented medium with culture medium with or without compound on the third day post infection. The procedure was repeated twice for each broth condition. Cytopathic effects on the virus were monitored daily with a reverse optical microscope. Typically, the virus dilutions used in this experiment often lead to cytopathic effects the fifth day after virus infection. The inhibitory concentration of the drug is such that the drug produces a 50% inhibition of the viral cytopathic effect while having no direct toxicity to the cells (CC)50) And (4) showing. It is emphasized that, when the compounds are poorly water soluble and require DMSO to dissolve, the DMSO specific concentration is generally less than 10% relative to water (the final concentration of DMSO in the MT-4 cell culture medium is less than 2%). Since DMSO can affect the antiviral activity of the test compound, the antiviral activity of solutions containing the same concentration of DMSO should also be performed in parallel to the control blank. In addition, the final concentration of DMSO (1/1000) was much lower than the concentration required for HIV-1 replication in T cells.
The invention uses Nevirapine (NVP), Efavirenz (EFV) and Etravirine (ETravirine, ETV) which are marketed drugs as reference substances, and the result of the HIV inhibition activity of part of target compounds is shown in table 2 (the anti-HIV activity and cytotoxicity of racemates of compounds 1 to 7 and single enantiomers thereof in MT-4 cells).
Figure BDA0002409643790000101
TABLE 2[a]
Figure BDA0002409643790000111
aAll data represent the mean of at least three independent experiments;bEC50an effective concentration to protect 50% of the cells from viral infection;cCC50the drug concentration when 50% of cells are diseased;dSI selection index, CC50Value and EC50The ratio of the values is used for judging the safety range of the effect of the medicine.
Experimental results show that the compounds contained in the chemical general formula generally have stronger anti-HIV-1 virus activity, smaller cytotoxicity and higher selectivity index.
The present invention is not limited to the above examples.

Claims (6)

1. A biphenyl diaryl pyrimidine derivative containing a chiral hydroxymethylene structure is characterized in that the structural formula is as follows:
Figure DEST_PATH_IMAGE002
wherein R is1And R2Each independently selected from hydrogen;
R3and R4Are respectively and independently selected from hydrogen, cyano, amino, nitro, hydroxyl, halogen, sulfonic group and C1~6Alkyl radical, C1~6Alkoxy radical, C3~6Cycloalkyl radical, C3~6Cycloalkoxy, C3~6A cycloalkylamino group.
2. The preparation method of the biphenyl diarylpyrimidine derivatives containing chiral hydroxymethylene structure as claimed in claim 1, wherein the specific operation steps are as follows:
in a solvent, a carbon-based compound II is subjected to reduction reaction under the action of a reducing agent to obtain a racemate compound I, and then a single enantiomer with R and S configuration is obtained through chiral resolution; the general reaction formula and the resolution process for preparing the racemate are as follows:
Figure DEST_PATH_IMAGE004
the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, dichloromethane, dichloroethane, toluene, tetrahydrofuran, diethyl ether, isopropyl ether, methyl tert-butyl ether, and ethyl acetate;
the reducing agent is one or more of borane, aluminum isopropoxide, sodium borohydride, potassium borohydride, lithium aluminum hydride and hydrogen;
the molar ratio of the compound II to the reducing agent is 1:2-1: 5;
the reaction temperature is 0-200 ℃;
the reaction time is 1-4 h;
the resolution method used is one or more of crystallization resolution, chemical resolution, enzyme resolution and chromatographic resolution.
3. A biphenyldiarylpyrimidine derivative according to claim 1, which further comprises a pharmaceutically acceptable salt thereof, a stereochemically isomeric form thereof, and an X-ray diffraction single crystal of a single enantiomer thereof.
4. A biphenyldiarylpyrimidine derivative according to claim 3, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, acetate, methanesulfonate, p-toluenesulfonate, tartrate, citrate, fumarate and malate salts, and pharmaceutically acceptable prodrugs and derivatives thereof.
5. A pharmaceutical composition comprising an effective amount of a compound of any of claims 1 or 3 and a pharmaceutically acceptable carrier.
6. The use of the biphenyldiarylpyrimidine derivatives containing chiral hydroxymethylene structures as claimed in claim 1 for the preparation of a medicament for the prevention and treatment of AIDS.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101121698A (en) * 2007-09-13 2008-02-13 复旦大学 Diarylmiazines derivatives, preparation method and use thereof
CN109053591A (en) * 2018-07-04 2018-12-21 复旦大学 Diarylmiazines derivatives of biphenyl contenting structure and its preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101121698A (en) * 2007-09-13 2008-02-13 复旦大学 Diarylmiazines derivatives, preparation method and use thereof
CN109053591A (en) * 2018-07-04 2018-12-21 复旦大学 Diarylmiazines derivatives of biphenyl contenting structure and its preparation method and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Design of Biphenyl-Substituted Diarylpyrimidines with a Cyanomethyl Linker as HIV-1 NNRTIs via a Molecular Hybridization Strategy;Yuan Lei et al.;《Molecules》;20200226;第25卷(第5期);第1050号 *
Ligand-Based Design of Nondimethylphenyl-Diarylpyrimidines with Improved Metabolic Stability, Safety, and Oral Pharmacokinetic Profiles;Yali Sang et al.;《Journal of Medicinal Chemistry》;20191112;第62卷(第24期);第11430-11436页 *

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