CN106478521A - A kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof - Google Patents

A kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof Download PDF

Info

Publication number
CN106478521A
CN106478521A CN201610886791.1A CN201610886791A CN106478521A CN 106478521 A CN106478521 A CN 106478521A CN 201610886791 A CN201610886791 A CN 201610886791A CN 106478521 A CN106478521 A CN 106478521A
Authority
CN
China
Prior art keywords
dmso
hiv
nmr
diarylmiazines
pyh
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610886791.1A
Other languages
Chinese (zh)
Inventor
朱园园
古双喜
卢欢欢
巨修练
薛萍
张旬
肖婷
王子君
梅海霞
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan Institute of Technology
Original Assignee
Wuhan Institute of Technology
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wuhan Institute of Technology filed Critical Wuhan Institute of Technology
Priority to CN201610886791.1A priority Critical patent/CN106478521A/en
Publication of CN106478521A publication Critical patent/CN106478521A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention belongs to pharmaceutical technology field is and in particular to a kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof, it has such as structural formula I, or structure formula II, or the structure shown in structure formula III：Wherein in structural formula I, R is monosubstituted base or multi-substituent；Described substituent group is fluorine atom, chlorine atom, bromine atoms, methyl, methoxyl group, trifluoromethyl or cyano group.Beneficial effects of the present invention are as follows：The noval chemical compound of present invention design synthesis has preferable HIV 1 cellular level inhibitory activity, part of compounds is better than the marketed drug Sustiva as reference, Nevirapine, zidovudine and moral Laevolac and determines to the inhibitory activity of HIV 1 this important Strain of IIIB, close with etravirine；And the selectivity of part of compounds is high, toxicity very little, can be used for being further developed as anti-AIDS drug.

Description

A kind of Diarylmiazines HIV1-RT inhibitor and preparation method thereof
Technical field
The invention belongs to pharmaceutical technology field and in particular to a kind of Diarylmiazines HIV1-RT inhibitor and its Preparation method.
Background technology
Acquired immune deficiency syndrome (AIDS), is commonly called as acquired immune deficiency syndrome (AIDS) (english abbreviation is AIDS), by HIV (human immunodeficiency virus) (HIV) caused.Inhibition of HIV reproduction speed is very fast.HIV divides two kinds of hypotypes of HIV-1 and HIV-2, most of AIDS in the world Patient is HIV-1 infection.Reverse transcriptase (RT) plays irreplaceable effect in HIV-1 virus replicative cycle, is One of important target spot of inverase design.In inverase research, non-nucleoside reverse transcriptase inhibitor is efficient because of it The advantages of low toxicity, receives much concern.Non-nucleoside reverse transcriptase inhibitor through U.S. FDA approval listing has five kinds newly at present Chemical entities：Nevirapine, moral Laevolac are fixed, Efavirenz, etravirine and rilpivirine.Wherein, etravirine and a sharp Wei Woods is respectively provided with diaryl pyrimidine structure, and such compound is commonly referred to as Diarylmiazines HIV1-RT inhibitor (DAPYs).Pharmaceutical Chemist is found that many has the DAPYs of structure diversity at present.Classical DAPYs has one jointly Point is it is simply that the linker between pyrimidine ring and aromatic ring is all monatomic (O, N, S or C) linker.In view of molecular flexibility and structure As the importance to HIV1-RT inhibitor activity for the flexibility, the present invention designs a class and has diatomic linker (- C-O-) New diaryl pyrimidines.
Content of the invention
It is an object of the invention to by the linker between the pyrimidine ring of classical DAPYs and aromatic ring by traditional monatomic company Connect base (- X-, X are O, N, S or C) and transform flexible preferably diatomic linker (- CH as2- O-, diatomic refers to linker Main chain is carbon-oxygen diatomic), synthesis obtains a class and has new DAPYs, another object of the present invention is to proposing above-mentioned chemical combination The preparation method of thing.
The present invention solves above-mentioned technical problem and be employed technical scheme comprise that：A kind of Diarylmiazines HIV-1 reverse transcription Enzyme inhibitor is it is characterised in that have such as structural formula I, or structure formula II, or the structure shown in structure formula III：
Wherein in structural formula I, R is monosubstituted base or multi-substituent；Described substituent group be fluorine atom, chlorine atom, bromine atoms, Methyl, methoxyl group, trifluoromethyl or cyano group.
The preparation method of above-mentioned Diarylmiazines HIV1-RT inhibitor comprises the following steps：
With 2- (to cyano-aniline base) -4- chloropyrimide as raw material, under the effect and inert gas shielding of alkali, with benzylalcohol, One of them generation nucleophilic substitution of substituted benzyl alcohol, 1- naphthalene methanol or 2- naphthalene methanol obtains.
By such scheme, described alkali is sodium hydroxide or potassium hydroxide.
By such scheme, described solvent is dimethyl sulfoxide, dioxane, oxolane, DMF Mixed solvent with one of acetonitrile solvent or several solvent composition.Reaction equation and the corresponding compound of I are expressed as follows：
Beneficial effects of the present invention are as follows：The noval chemical compound of present invention design synthesis has preferable HIV-1 cellular level Inhibitory activity, to HIV-1IIIB, the inhibitory activity of this important Strain is better than the marketed drug as reference to part of compounds Sustiva, Nevirapine, zidovudine and moral Laevolac are fixed, close with etravirine；And the selectivity of part of compounds is high, Toxicity very little, can be used for being further developed as anti-AIDS drug.
Specific embodiment
Following examples explain the technology contents of the present invention further, but not as limiting the scope of the invention.
The general preparative methods of target compound：Weigh benzylalcohol (or substituted benzyl alcohol, or 1- naphthalene methanol, or 2- naphthalene methanol) (2.6mmol), sodium hydroxide (or potassium hydroxide) (1.6mmol) and (30 milliliters) addition two mouthfuls of flasks of 100mL of dimethyl sulfoxide In, stirring.Evacuation, nitrogen is protected.Then add 2- (to cyano-aniline base) -4- chloropyrimide (0.87mmol) molten in flask Solution in dimethyl sulfoxide (5～10mL) gained.Reactant is heated to 80 DEG C, stirs 12h, TLC detection display raw material reaction Finish.Next, with ethyl acetate (100mL) dilute reaction solution, and with saturated common salt water washing to aqueous phase pH ≈ 7.Organic faciess With anhydrous sodium sulfate drying, obtain crude product after concentration, through column chromatography (ethyl acetate/petroleum ether 1:30 is eluant) obtain target product Thing.Partly the structure yield of each target compound and characterize data are as follows：
Embodiment 1
Ⅰ-a:White solid, yield 67%, 207-209 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.21(s,1H, 4-CNArNH-),8.34(d,1H,PyH),7.90-7.39(m,8H,ArH),6.52(d,1H,PyH),5.52(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ169.16,159.40,159.29,145.17,134.18,133.35, 132.90,130.40,130.30,129.84,127.86,119.95,118.86,102.93,100.58,65.30.MS(ESI) 337.1(M+1)+.
Embodiment 2
Ⅰ-b:White solid, yield 40%, 203-205 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.16(s,1H, 4-CNArNH-),8.33(d,1H,PyH),7.90-7.39(m,8H,ArH),6.50(d,1H,PyH),5.44(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ169.23,159.28,159.00,145.05,139.32,133.53, 133.40,130.84,128.39,128.04,126.87,119.95,119.01,103.01,100.63,67.03.MS(ESI) 337.1(M+1)+.
Embodiment 3
Ⅰ-c:White solid, yield 67%, 209-211 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.12(s,1H, 4-CNArNH-),8.32(d,1H,PyH),7.93-7.45(m,8H,ArH),6.48(d,1H,PyH),5.43(s,2H,- CH2-).；13C NMR(150MHz,DMSO-d6)δ169.21,159.43,159.19,145.16,135.83,133.40, 133.09,130.22,128.91,119.98,118.88,102.90,100.60,67.02.MS(ESI)337.1(M+1)+.
Embodiment 4
Ⅰ-d:White solid, yield 66%, 199-201 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.16(s,1H, 4-CNArNH-),8.35(d,1H,PyH),7.91-7.30(m,8H,ArH),6.53(d,1H,PyH),5.49(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ169.13,159.41,159.31,145.16,135.77,133.37, 133.05,130.57,130.22,128.38,122.99,119.96,118.84,102.92,100.57,67.48.MS(ESI) 383.0(M+2)+.
Embodiment 5
Ⅰ-e:White solid, yield 66%, 190-192 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.13(s,1H, 4-CNArNH-),8.32(d,1H,PyH),7.92-7.35(m,8H,ArH),6.50(d,1H,PyH),5.44(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ169.16,159.42,159.24,145.13,139.61,133.39, 131.28,131.12,130.92,127.24,122.11,119.97,118.93,102.91,100.60,66.93.MS(ESI) 383.0(M+2)+.
Embodiment 6
Ⅰ-f:White solid, yield 57%, 179-181 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.12(s,1H, 4-CNArNH-),8.32(d,1H,PyH),8.31-7.43(m,8H,ArH),6.48(d,1H,PyH),5.42(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ169.98,169.20,159.56,159.42,159.20,158.79, 145.16,136.26,133.40,131.83,130.48,121.62,119.97,118.87,102.90,100.59,67.05, 54.09.MS(ESI)383.0(M+2)+.
Embodiment 7
Ⅰ-g:White solid, yield 54%, 185-187 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.14(s,1H, 4-CNArNH-),8.32(d,1H,PyH),7.95-7.22(m,8H,ArH),6.47(d,1H,PyH),5.49(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6) δ 169.17,161.70 (d, J=243.45Hz), 159.43,158.48, 145.24 (d, J=17.25Hz), 132.88,131.59 (d, J=8.85Hz), 131.53,130.60 (d, J=19.35Hz), 124.47 (d, J=8.55Hz), 123.58,119.97,119.20,118.30,102.98,101.08,100.06,62.08.19F NMR(564MHz,DMSO-d6)δ-118.32.MS(ESI)321.1(M+1)+.
Embodiment 8
Ⅰ-h:White solid, yield 70%, 224-226 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.13(s,1H, 4-CNArNH-), 8.33 (d, 1H, J=5.4Hz), 7.93-7.19 (m, 8H, ArH), 6.50 (d, 1H, J=5.4Hz), 5.45 (s,2H,-CH2-)；13C NMR(150MHz,DMSO-d6) δ 169.20,163.38 (d, J=241.65Hz), 159.42, (159.22,145.16,139.69 d, J=7.8Hz), 133.39,130.99 (d, J=8.4Hz), 124.25 (d, J= 2.4Hz), 119.97,118.90,115.30 (d, J=20.7Hz), 115.05 (d, J=21.75Hz), 102.89,100.62, 67.02.19F NMR(564MHz,DMSO-d6)δ-113.13.MS(ESI)321.1(M+1)+.
Embodiment 9
Ⅰ-i:White solid, yield 57%, 179-180 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.12(s,1H, 4-CNArNH-), 8.31 (d, 1H, J=5.4Hz), 7.92-7.19 (m, 8H, ArH), 6.47 (d, 1H, J=5.4Hz), 5.42 (s,2H,-CH2-)；13C NMR(150MHz,DMSO-d6) δ 169.27,163.14 (d, J=242.7Hz), 159.43, (159.13,145.20,133.41,132.99 d, J=2.85Hz), 130.85 (d, J=8.4Hz), 119.98,118.88, 115.81 (d, J=21.0Hz), 102.88,100.62,67.19.19F NMR(564MHz,DMSO-d6)δ-114.05.MS (ESI)321.1(M+1)+.
Embodiment 10
Ⅰ-j:White solid, yield 65%, 185-187 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.12(s,1H, 4-CNArNH-),8.32(d,1H,PyH),7.94-7.20(m,8H,ArH),6.48(d,1H,PyH),5.43(s,2H,- CH2-),2.33(s,3H,-CH3)；13C NMR(150MHz,DMSO-d6)δ169.43,159.46,159.10,145.24, 136.95,134.66,133.35,130.58,129.02,128.68,126.31,119.98,118.88,102.87,100.56, 66.45,18.91.MS(ESI)317.1(M+1)+.
Embodiment 11
Ⅰ-k:White solid, yield 64%, 168-170 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.11(s,1H, 4-CNArNH-),8.30(d,1H,PyH),7.95-7.14(m,8H,ArH),6.46(d,1H,PyH),5.39(s,2H,- CH2-),2.30(s,3H,-CH3)；13C NMR(150MHz,DMSO-d6)δ169.37,159.46,159.07,145.22, 138.06,136.62,133.37,129.10,128.99,128.80,125.51,119.99,118.91,102.85,100.62, 67.93,21.37.MS(ESI)317.1(M+1)+.
Embodiment 12
Ⅰ-l:White solid, yield 75%, 170-172 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.10(s,1H, 4-CNArNH-),8.30(d,1H,PyH),7.95-7.19(m,8H,ArH),6.45(d,1H,PyH),5.39(s,2H,- CH2-),2.29(s,3H,-CH3)；13C NMR(150MHz,DMSO-d6)δ169.38,159.45,159.05,145.23, 137.81,133.68,133.39,129.43,128.55,119.99,118.88,102.85,100.64,67.81,21.20.MS (ESI)317.1(M+1)+.
Embodiment 13
Ⅰ-m:White solid, yield 69%, 175-177 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.10(s,1H, 4-CNArNH-),8.31(d,1H,PyH),7.95-6.96(m,8H,ArH),6.47(d,1H,PyH),5.42(s,2H,- CH2-),3.82(s,3H,-OCH3)；13C NMR(150MHz,DMSO-d6)δ169.50,159.46,158.96,157.53, 145.29,133.34,130.07,129.67,124.33,120.70,119.98,118.85,111.28,102.84,100.68, 63.53,55.88.MS(ESI)333.2(M+1)+.
Embodiment 14
Ⅰ-n:White solid, yield 62%, 154-155 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.11(s,1H, 4-CNArNH-),8.31(d,1H,PyH),7.94-6.90(m,8H,ArH),6.48(d,1H,PyH),5.41(s,2H,- CH2-),3.74(s,3H,-OCH3)；13C NMR(150MHz,DMSO-d6)δ169.33,159.75,159.44,159.13, 145.20,138.29,133.38,130.04,120.47,119.97,118.89,113.94,113.89,102.86,100.63, 67.75,55.48.MS(ESI)333.2(M+1)+.
Embodiment 15
Ⅰ-o:White solid, yield 70%, mp189-191 DEG C；1H NMR(600MHz,DMSO-d6)δ10.07(s,1H,4- CNArNH-),8.30(d,1H,PyH),7.97-6.94(m,8H,ArH),6.40(d,1H,PyH),5.36(s,2H,-CH2-), 3.75(s,3H,-OCH3)；13C NMR(150MHz,DMSO-d6)δ169.40,159.64,159.45,159.00,145.26, 133.41,130.43,128.55,120.00,118.88,114.28,102.84,100.66,67.75,55.54.MS(ESI) 333.2(M+1)+.
Embodiment 16
Ⅰ-p:White solid, yield 46%, mp168-170 DEG C；1H NMR(600MHz,DMSO-d6)δ10.13(s,1H,4- CNArNH-),8.34(d,1H),7.92-7.57(m,8H,ArH),6.48(d,1H,PyH),5.59(s,2H,-CH2-)；13C NMR(150MHz,DMSO-d6)δ169.03,159.42,159.27,145.13,134.58,133.25,130.75,129.23, 127.34 (d, J=30.6Hz), 126.59 (d, J=5.25Hz), 126.55 (d, J=5.70Hz), 125.62 (d, J= 272.55Hz),119.91,118.89,102.98,100.53,64.44.19F NMR(564MHz,DMSO-d6)δ-58.75.MS (ESI)371.2(M+1)+.
Embodiment 17
Ⅰ-q:White solid, yield 48%, 168-170 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.13(s,1H, 4-CNArNH-),8.33(d,1H),7.93-7.63(m,8H,ArH),6.51(d,1H),5.54(s,2H,-CH2-)；13C NMR (150MHz,DMSO-d6)δ169.17,159.43,159.26,145.13,138.30,133.36,132.38,130.03, 129.75 (d, J=30.5Hz), 125.45 (d, J=270.9Hz), 125.17 (d, J=4.05Hz), 124.86 (d, J= 3.6Hz),119.94,118.94,102.93,100.56,67.05.19F NMR(564MHz,DMSO-d6)δ-61.15.MS (ESI)371.1(M+1)+.
Embodiment 18
Ⅰ-r:White solid, yield 72%, 155-157 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.11(s,1H, 4-CNArNH-),8.31-6.62(m,10H,ArH+PyH),5.36(s,2H,-CH2-),3.73(s,6H,-OCH3)；13C NMR (150MHz,DMSO-d6)δ169.31,160.96,159.43,159.14,145.20,139.03,133.37,119.97, 118.91,106.25,102.86,100.62,100.06,67.78,55.62.MS(ESI)363.3(M+1)+.
Embodiment 19
Ⅰ-s:White solid, yield 46%, 213-215 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.16(s,1H, 4-CNArNH-),8.35-6.56(m,9H,ArH+PyH),5.45(s,2H,-CH2-).13C NMR(150MHz,DMSO-d6)δ (168.93,162.71 d, J=243.75Hz), 159.37,145.13,138.36 (d, J=7.95Hz), 134.76 (d, J= 7.95Hz), 133.34,119.93,118.85,117.46 (d, J=22.05Hz), 117.08 (d, J=2.55Hz), 116.91 (d, J=23.85Hz), 102.98,100.59,66.94.19F NMR(564MHz,DMSO-d6)δ-114.12.MS(ESI) 401.0(M+2)+.
Embodiment 20
Ⅰ-t:White solid, yield 45%, 211-214 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.13(s,1H, 4-CNArNH-),8.33(d,1H,PyH),7.94-7.45(m,7H,ArH),6.47(d,1H,PyH),5.46(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6) δ 169.02,161.53 (d, J=250.35Hz), 159.37,159.26, (d, J=4.50Hz), 145.14,133.37,132.57 128.21 (d, J=3.45Hz), 123.41 (d, J=14.85Hz), (122.40 d, J=9.3Hz), 119.94,119.41 (d, J=24.15Hz), 118.91,102.98,100.56,61.59.19F NMR(564MHz,DMSO-d6)δ-115.03.MS(ESI)401.0(M+2)+.
Embodiment 21
Ⅰ-u:White solid, yield 27%, 252-254 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.15(s,1H, 4-CNArNH-),8.33(d,1H,PyH),8.08-7.49(m,8H,ArH),6.49(d,1H,PyH),5.91(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ169.39,159.48,159.20,145.19,133.69,133.30, 132.24,129.27,129.02,127.08,126.48,125.85,124.04,118.88,102.83,100.64, 66.24.MS(ESI)328.1(M+1)+.
Embodiment 22
Ⅰ-v:White solid, yield 35%, 220-222 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.13(s,1H, 4-CNArNH-),8.33(d,1H,PyH),8.00-7.51(m,8H,ArH),6.51(d,1H,PyH),5.61(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ168.98,159.07,158.77,144.79,133.97,132.99, 132.75,132.60,128.14,127.79,126.65,126.42,125.84,119.58,118.51,102.47,100.26, 67.60.
Embodiment 23
Ⅰ-w:White solid, yield 31%, 225-228 DEG C of mp；1H NMR(600MHz,DMSO-d6)δ10.18(s,1H, 4-CNArNH-),8.36(d,1H,PyH),7.96-7.57(m,8H,ArH),6.54(d,1H,PyH),5.62(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ168.59,158.99,144.70,139.56,133.56,133.25, 132.97,129.25,119.52,118.49,117.13,110.94,102.55,100.11,65.38.
Embodiment 24
Ⅰ-x:White solid, yield 70%, 178-180 DEG C of mp；1H NMR(400MHz,DMSO-d6)δ10.12(s,1H, 4-CNArNH-),8.32(d,1H,PyH),7.94-7.35(m,9H,ArH),6.49(d,1H,PyH),5.44(s,2H,- CH2-)；13C NMR(150MHz,DMSO-d6)δ169.28,159.44,159.20,145.16,136.99,134.91, 133.41,131.02,128.88,119.98,118.87,102.88,100.64,67.58.MS(ESI)303.64(M+1)+.
Embodiment 25
Ⅰ-y:White solid, yield 38%, 168-170 DEG C of mp；1H NMR(400MHz,DMSO-d6)δ10.13(s,1H, 4-CNArNH-),8.33(d,1H,PyH),8.09-7.49(m,11H,ArH),6.50(d,1H,PyH),5.92(s,2H,- CH2-).MS(ESI)353.2(M+1)+.
Embodiment 26
Ⅰ-z:White solid, yield 32%, 196-197 DEG C of mp；1H NMR(400MHz,DMSO-d6)δ10.11(s,1H, 4-CNArNH-),8.33(d,1H,PyH),8.00-7.51(m,11H,ArH),6.51(d,1H,PyH),5.61(s,2H,- CH2-).MS(ESI)353.1(M+1)+.
AntiHIV1 RT activity biological activity test is carried out to 26 target products of embodiment gained：
The anti HIV-1 virus determination of activity of cell in vitro level, mainly includes the inhibitory activity of the MT-4 cell to HIV And cytotoxicity two aspect.Method is described as follows：Make compound in the MT-4 cell of HIV, when infected by HIV is different Between, measure the cytopathic protective effect to HIV mutation for the medicine with mtt assay, calculate and make 50% cell avoid HIV induction Concentration medium effective concentration EC needed for cytopathy50, toxicity test is parallel with HIV (human immunodeficiency virus)-resistant activity experiment to be carried out, and is also in MT-4 In cell culture, measured with mtt assay and make 50% non-infected cells that cytopathic concentration (CC to occur50).
Materials and methods：The cytopathic suppression that the HIV (human immunodeficiency virus)-resistant activity of each compound is caused to HIV by medicine in cell Functioning efficiency is monitoring.Cell culture is carried out using MT-4 cell.Using Strain be HIV-1 Strain IIIB.
Concrete operations are as follows：By compound with using phosphate buffer saline solution to dilute after DMSO or water dissolution, by 3 × 105MT-4 cell 100 μ L this solution of each compound variable concentrations, in 37 DEG C of precultures lh, then adds in this compound The suitable viral dilution liquid of 100 μ L, cell is cultivated lh in 37 DEG C.Washing three times after, cell is suspended in again respectively containing Or do not contain in the culture medium of compound.Then, by cell in 5% carbon dioxide atmosphere, it is further cultured at 37 DEG C 7 days, and After infection, the 3rd day culture medium with containing or not contain compound is replaced and is supplemented culture fluid.Every kind of culture fluid condition is all heavy Multiple operation is twice.Viral cytopathic effect is all used daily reverse optical microscope monitor.For typical case, institute in this experiment Viral dilution liquid usually can lead to cytopathy on the 5th day after virus infection.Drug inhibition concentration is thin with drug on viral The effect of born of the same parents' pathological changes produces 50% inhibitory action and the concentration (CC to cell no direct toxicity simultaneously50).It is emphasized that when change Compound water solublity is poor, when needing could be dissolved with DMSO, DMSO specific concentration for water, generally below 10%, (DMSO In MT-4 cell culture medium, ultimate density is less than 2%).Because DMSO can affect the antiviral activity of test compound, right Also should parallel carry out containing same concentrations DMSO solution antiviral activity contrast blank experiment.In addition, DMSO ultimate density (1/ 1000) replicate required concentration in T cell well below impact HIV-1.
The EC that target compound suppresses HIV-1IIIB is listed in table 150、CC50.Marketed drug Nevirapine, Efavirenz and TMC125 is also tested concurrently as reference.Additionally, we are also tested for target compound I-a～I-x couple Inhibitory activity IC of HIV1-RT (HIV-1RT)50, it is shown in Table 1.
As shown in Table 1,26 compounds tested are respectively provided with preferable HIV-1 cellular level inhibitory activity, partization To HIV-1IIIB, the inhibitory activity of this important Strain is better than as the marketed drug Nevirapine of reference, in accordance with the law Wei compound Human relations, zidovudine and moral Laevolac are fixed, close with etravirine.And the selectivity of part of compounds is high, toxicity very little, can be used for It is further developed as anti-AIDS drug.

Claims (4)

1. a kind of Diarylmiazines HIV1-RT inhibitor is it is characterised in that have such as structural formula I, or structure formula II, Or the structure shown in structure formula III：
Wherein in structural formula I, R is monosubstituted base or multi-substituent；Described substituent group be fluorine atom, chlorine atom, bromine atoms, methyl, Methoxyl group, trifluoromethyl or cyano group.
2. Diarylmiazines HIV1-RT inhibitor described in claim 1 preparation method it is characterised in that include with Lower step：
With 2- (to cyano-aniline base) -4- chloropyrimide as raw material, under the effect and inert gas shielding of alkali, with benzylalcohol, replacement One of them generation nucleophilic substitution of benzylalcohol, 1- naphthalene methanol or 2- naphthalene methanol obtains.
3. the preparation method of Diarylmiazines HIV1-RT inhibitor as claimed in claim 2 is it is characterised in that institute The alkali stated is sodium hydroxide or potassium hydroxide.
4. the preparation method of Diarylmiazines HIV1-RT inhibitor as claimed in claim 2 is it is characterised in that institute The solvent stated is dioxane, oxolane, DMF, one of dimethyl sulfoxide and acetonitrile solvent or several Plant the mixed solvent of solvent composition.
CN201610886791.1A 2016-10-11 2016-10-11 A kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof Pending CN106478521A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610886791.1A CN106478521A (en) 2016-10-11 2016-10-11 A kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610886791.1A CN106478521A (en) 2016-10-11 2016-10-11 A kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof

Publications (1)

Publication Number Publication Date
CN106478521A true CN106478521A (en) 2017-03-08

Family

ID=58269775

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610886791.1A Pending CN106478521A (en) 2016-10-11 2016-10-11 A kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof

Country Status (1)

Country Link
CN (1) CN106478521A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110511211A (en) * 2019-08-30 2019-11-29 武汉工程大学 A kind of application of indazole piperidine pyrimidine class compound
CN111675661A (en) * 2020-06-28 2020-09-18 山东大学 Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing trans double bond and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0945443A1 (en) * 1998-03-27 1999-09-29 Janssen Pharmaceutica N.V. HIV inhibiting pyrimidine derivatives
CN102558070A (en) * 2002-05-13 2012-07-11 泰博特克药品有限公司 Microbicidal pyrimidine or triazine for preventing sexual HIV transmission

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0945443A1 (en) * 1998-03-27 1999-09-29 Janssen Pharmaceutica N.V. HIV inhibiting pyrimidine derivatives
CN102558070A (en) * 2002-05-13 2012-07-11 泰博特克药品有限公司 Microbicidal pyrimidine or triazine for preventing sexual HIV transmission

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GU S.X.ET AL.: "A novel family of diarylpyrimidines (DAPYs) featuring a diatomic linker: Design, synthesis and anti-HIV activities", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
LIANG，Y.H.ET AL.: "Synthesis and anti-HIV activity of 2-naphthyl substituted DAPY analogues as non-nucleoside reverse transcriptase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110511211A (en) * 2019-08-30 2019-11-29 武汉工程大学 A kind of application of indazole piperidine pyrimidine class compound
CN111675661A (en) * 2020-06-28 2020-09-18 山东大学 Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing trans double bond and preparation method and application thereof
CN111675661B (en) * 2020-06-28 2021-08-24 山东大学 Diaryl pyrimidine HIV-1 reverse transcriptase inhibitor containing trans double bond and preparation method and application thereof

Similar Documents

Publication Publication Date Title
Fu et al. New chalcone derivatives: synthesis, antiviral activity and mechanism of action
Xiong et al. Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 11: structural modulations of diaryltriazines with potent anti-HIV activity
AU2014340110B2 (en) Inhibitors of human immunodeficiency virus replication
Malpani et al. Efficient synthesis of 3H, 3′ H-spiro [benzofuran-2, 1′-isobenzofuran]-3, 3′-dione as novel skeletons specifically for influenza virus type B inhibition
Zeng et al. Hybrid diarylbenzopyrimidine non-nucleoside reverse transcriptase inhibitors as promising new leads for improved anti-HIV-1 chemotherapy
Xue et al. Synthesis and antiviral activity of some novel indole-2-carboxylate derivatives
Chen et al. Anti-AIDS agents. Part 56: Synthesis and anti-HIV activity of 7-thia-di-O-(−)-camphanoyl-(+)-cis-khellactone (7-thia-DCK) analogs
Romeo et al. Synthesis and biological evaluation of furopyrimidine N, O-nucleosides
Gu et al. Synthesis and structure–activity relationship of novel diarylpyrimidines with hydromethyl linker (CH (OH)-DAPYs) as HIV-1 NNRTIs
Sun et al. Optimization of 2, 4-diarylanilines as non-nucleoside HIV-1 reverse transcriptase inhibitors
CN106478521A (en) A kind of Diarylmiazines HIV 1 reverse transcriptase inhibitors and preparation method thereof
CN102558072B (en) 2-(4-alkylformyloxyphenylcarbonylmethylthio)pyrimidine compounds and application thereof
Sharma et al. Synthesis and antiviral activity of diverse heterocyclic scaffolds
CN108484508B (en) A kind of synthetic method of 5- trifluoromethyl uracil
CN106866628A (en) A kind of RTIs of aryl heteroaryl miazines HIV 1 and preparation method thereof
CN114213395B (en) Pyrimidone acyl piperazine compound and preparation method and application thereof
CN113248518B (en) Pyrimidine piperazine derivative and preparation method and application thereof
CN109369623A (en) 1,2,3 triazole diaryl pyrimidine derivatives of a kind of substitution and the preparation method and application thereof
CN105085410B (en) A kind of inhibitor of Diarylmiazines HIV 1 and preparation method thereof
Yu et al. Discovery of Dihydro‐Alkyloxy‐Benzyl‐Oxopyrimidines as Promising Anti‐Influenza Virus Agents
CN114507218B (en) Indole piperidine pyrimidine derivative and preparation method and application thereof
Vinoth et al. Synthesis of novel chalcones through palladium-catalyzed CO cross-coupling reaction of bromo-chalcones with ethyl acetohydroxamate and their antiplasmodial evaluation against Plasmodium falcipuram in vitro
Sun et al. Non‐nucleoside HIV Reverse Transcriptase Inhibitors, Part 6 [1]: Synthesis and Anti‐HIV Activity of Novel 2‐[(Arylcarbonylmethyl) thio]‐6‐arylthio DABO Analogues
CN109053613A (en) Diaryltriazine compound containing biphenyl structural and its preparation method and application
CN110511211B (en) Application of indazole piperidine pyrimidine compound

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20170308

RJ01 Rejection of invention patent application after publication