CN103467393A - Triazole enol-ketone disubstituted calyx 4 aromatic hydrocarbon compounds and preparation method and application thereof - Google Patents
Triazole enol-ketone disubstituted calyx 4 aromatic hydrocarbon compounds and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to triazole enol-ketone disubstituted calyx 4 aromatic hydrocarbon compounds represented in formula (1) and a preparation method and application of the triazole enol-ketone disubstituted calyx 4 aromatic hydrocarbon compounds. R and R1 are defined in an instruction book. According to the preparation method, P-tert-butylphenol is used as raw materials to synthesized into tert-butyl calix 4 arene, and calix 4 marene is obtained through the removal of tertiary butyl. The tert-butyl calix 4 arene, the calix 4 arene and halogenated acetic ester react to obtain 25, 27-di (ethyoxyl carbonyl methylene)-26, 28-dyhydroxy-( tertiary butyl) calyx 4 arene, and condensation is carried out with 1-substituted benzyl-4-acetyl-5-methyl-1H-1,2,3-triazole to obtain the triazole enol-ketone disubstituted calyx 4 aromatic hydrocarbon compounds. The triazole enol-ketone disubstituted calyx 4 aromatic hydrocarbon compounds have a retaining function on HIV-1 integrase.
Description
Technical field
The present invention relates to two cup 4 arene compounds that replace of a class Diniconazole-one, preparation method and as the application of HIV-1 integrase inhibitor.
Background technology
Acquired immune deficiency syndrome (AIDS) (Acquired immunodeficiency syndrome, AIDS) is to be infected and caused by human immunodeficiency virus (Human immunodeficiency virus, HIV).According to WHO(World Health Organization) epidemiology statistics, whole world accumulative total infected by HIV person reaches more than 7,000 ten thousand people, by the end of the year 2010, existing HIV the infected alive and aids patient be 3,400 ten thousand people approximately, but, it is very fast that the HIV infection population increases, newly-increased case 2,700,000 in 2010 only, dead 1,800,000 examples! Due to the infection that lacks effective vaccine and prevent HIV, find effectively and inverase that the developing countries can afford, be the task of top priority of AIDS-treating medicine research field.
Up to the present, U.S. FDA (Food and Drug Administration) approved 26 kinds of compounds medicine as acquired immune deficiency syndrome (AIDS), ratified in addition 5 kinds of compound preparations by these ingredients.Current highly efficient anti-virus therapy (Highly Active Antiretroviral Therapy commonly used clinically, HAART), take reverse transcriptase inhibitors and proteinase inhibitor as main types of drugs, can effectively reduce plasma viral load, extend HIV the infected's asymptomatic stage.Yet the variation of HIV-1 gene has caused the appearance of multidrug resistant disease strain.In addition, some toxic side effect of antiviral have also limited the application of HAART.Because being widely used of reverse transcriptase inhibitors and proteinase inhibitor medicine makes HIV produce resistance to it, long-term, high-dose is used also can produce serious toxic side effect, and increasing patient can't accept the treatment of these inverases constantly.Therefore find new action target spot and formulate an urgent demand that the medicine of high curative effect, high bioavailability and high security is inverase research.The HIV-1 intergrase is that the HIV-1 proviral DNA is integrated into requisite a kind of enzyme in host cell gene group process, due to the enzyme analogue that there is no identical function in human body, the medicine that acts on intergrase will can not damage normal cell, thereby reduce drug toxicity.Therefore, the HIV-1 intergrase is that research is efficient, a desirable target of the anti-AIDS drug of low toxicity.
Numerous bibliographical informations diketone acid and derivative thereof show intergrase had to stronger inhibition activity at cell levels, as compound S-1360, L870,810, MK-0518 and GS-9137 etc.Basically all contain α in these diketone acids and derivant structure thereof, γ-diketone pharmacophore structure fragment, experiment shows that such integrase inhibitor is mainly α in " chain transfer " process, γ-diketone structure fragment and IN – DNA form inner complex under the catalysis of divalent-metal ion, thereby have blocked the integration process of host DNA and viral DNA.U.S. FDA approval Isentress(diketone acid derivative MK-0518) as integrase inhibitor, in 2007, go on the market.
In recent years, Calixarene Derivatives and the interest that more and more causes the investigator with the anti-microbial activity that compound was had, antitumour activity and the antiviral activity etc. of calixarene platform design.Reported that as far back as 1994 (WO Patent9403164,1994) such as Hwang cup [4] arene derivatives shows restraining effect preferably to HIV and simplexvirus simultaneously.The calixarene compound that Coveney etc. (U.S.2005,113,454,2005) report builds with Resorcinol, Phloroglucinol has higher inhibition activity to HIV fusion process and intergrase.Recently, (the Bioorg.Med.Chem. such as Maxime, 2010,18:36 – 45) and (Bioorg.Med.Chem.Lett. such as Lun, 2010,20:2137 – 2139) reported that respectively Calixarene Derivatives shows good inhibition activity to HIV virus, there is no that to test cell toxicity or toxicity are very low simultaneously.
The 1,2,3-triazoles compound is the compounds that development in recent years is got up, and due to its unique structure and chemical property, at numerous areas such as organic chemistry, pharmaceutical chemistry and materials chemistries, has wide application scenario.Particularly aspect pharmaceutical chemistry, as there are many application antibiotic, antianaphylaxis, anti-HIV, the aspect such as antitumor.Therefore, the sequestering action mechanism that suppresses the intergrase activity according to diketoacids, using cup [4] aromatic hydrocarbons as the lead compound design platform, build α at cup [4] aromatic hydrocarbons lower edge, γ-diketone pharmacophore structure fragment is introduced the 1,2,3-triazoles ring simultaneously, design has been synthesized two cup 4 arene compounds that replace of a class Diniconazole-one as the HIV-1 integrase inhibitor, there is not yet at present bibliographical information both at home and abroad.
Summary of the invention
The purpose of this invention is to provide two cup 4 arene compounds that replace of a class Diniconazole-one, preparation method and as the application of HIV-1 integrase inhibitor.
The invention provides two cup 4 arene compounds that replace of a class Diniconazole-one that formula (I) means,
Wherein, mean-H of R or t-Bu-,
R
1mean:
R wherein
2expression-H ,-F ,-Cl ,-CH
3, can be at ortho position, a position or contraposition.
The compounds of this invention all has the Inhibition of HIV-1 integrase restraining effect.
The two preparation methods that replace cup 4 arene compounds of a class Diniconazole-one provided by the present invention comprise the following steps:
(a) under nitrogen protection, the p-tert-butylphenol meaned with formula (II) reacts in sodium hydroxide solution with formaldehyde, be warming up to water reaction in 115～120 ℃ of minutes 1～2 hour, continue subsequently heating reflux reaction 3-4 hour in phenyl ether solution, obtain that formula (III) means to tert-butyl-calix [4] aromatic hydrocarbons, the ratio of p-tert-butylphenol, formaldehyde and sodium hydroxide amount of substance is 22:23～28:1;
(b) under nitrogen protection, formula (III) compound is reacted in toluene solution with phenol and aluminum trichloride (anhydrous), reaction 4-12 hour under room temperature, obtain cup [4] aromatic hydrocarbons that formula (IV) means, the ratio of formula (III) compound, phenol and aluminum trichloride (anhydrous) amount of substance is 2:2:1～2;
(c) under nitrogen protection, by formula (III) compound or formula (IV) compound and halogenated acetic acids ester under inorganic or organic bases and catalyzer exist in organic solvent heating reflux reaction 24-48 hour, obtain 25 of formula (V) expression, 27-bis-(ethoxy carbonyl methylene radical)-26, 28-dihydroxyl-cup [4] aromatic hydrocarbons, formula (III) compound or formula (IV) compound, the ratio of the amount of halogenated acetic acids ester and alkaloid substance is 1:2～4:2～3, wherein the halogenated acetic acids ester is ethyl bromoacetate, methyl bromoacetate, methyl chloroacetate, ethyl chloroacetate, inorganic and organic bases is salt of wormwood, cesium carbonate, potassium tert.-butoxide, sodium hydride, catalyzer is potassiumiodide, organic solvent used is acetonitrile, acetone, N, dinethylformamide, methyl-sulphoxide,
Wherein, mean-H of R or t-Bu-.
(d) under condition of ice bath; formula (VI) 1-substituted benzyl-4-ethanoyl-5-methyl isophthalic acid H-1; 2; the 3-triazole is reacted in the organic solvent neutralization bases; then add formula (V) compound; slowly be heated to reflux, reaction times 3-8 hour, obtain formula as claimed in claim 1 (I) compound again.Formula (V) compound, 1-substituted benzyl-4-ethanoyl-5-methyl isophthalic acid H-1, the ratio of the amount of 2,3-triazole and alkaloid substance is 1:2～3:4～6, and alkali used is sodium methylate, sodium ethylate, sodium hydride, organic solvent used is methyl alcohol, ethanol, DMF, tetrahydrofuran (THF);
Wherein, R
2described with claim 1.
The ratio of above-mentioned steps (c) Chinese style (III) compound or formula (IV) compound, halogenated acetic acids ester and inorganic or organic bases amount of substance is 1:2～4:2～3.Wherein the halogenated acetic acids ester is ethyl bromoacetate, methyl bromoacetate, methyl chloroacetate, ethyl chloroacetate, preferably ethyl bromoacetate, ethyl chloroacetate; Inorganic or organic bases is salt of wormwood, cesium carbonate, potassium tert.-butoxide, sodium hydride, and preferably salt of wormwood is as alkali; Catalyzer is potassiumiodide, and organic solvent used is acetonitrile, acetone, DMF, methyl-sulphoxide, and preferably acetonitrile, acetone are as reaction solvent.
In above-mentioned steps (d), the ratio of the amount of substance of formula V compound and formula (VI) compound is 1:2～3:4～6.Alkali is sodium methylate, sodium ethylate, sodium hydride, and preferably sodium hydride is as alkali; Organic solvent used is methyl alcohol, ethanol, DMF, tetrahydrofuran (THF), and preferably tetrahydrofuran (THF) is as reaction solvent.
The inventive method is used industrial common reagent and conventional working condition, the reaction conditions gentleness, and step is simple.
The chemical equation of the compounds of this invention is:
Embodiment
Embodiment 1:25,27-bis-((3Z)-4-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the 28-dihydroxyl-to the preparation of tert-butyl-calix [4] aromatic hydrocarbons (1)
(a) to the preparation of tert-butyl-calix [4] aromatic hydrocarbons
Add p-tert-butylphenol 5.0g(33.3mmol in reaction flask), 0.12g/mL NaOH solution 0.5mL and 36% formaldehyde 3.2mL(41.4mmol), logical N
2, stir lower intensification rapidly, in 115 ℃～120 ℃ minutes water reaction 1.0h～1.5h, stopped reaction when question response liquid becomes cellular wax (stopped logical N
2).Add phenyl ether 80mL after being cooled to room temperature, under stirring, in 260 ℃ of reactions, treat that foam fades away, again logical N
2with the moisture content in dispensing system as far as possible, question response liquid deepens until stop logical N after chocolate
2, then back flow reaction 2h.Reaction solution adds ethyl acetate 100mL after being cooled to room temperature, standing after stirring at room 30min.Filter, filter cake is water, ethyl acetate and acetic acid washing respectively, and the dry white powder that obtains, obtain white crystal 2.97g with the toluene recrystallization.Yield: 55%; Fusing point: 343 ℃～345 ℃.
(b) 25,27-bis-(ethoxy carbonyl methylene radical)-26, the 28-dihydroxyl-to the preparation of tert-butyl-calix [4] aromatic hydrocarbons
Under nitrogen protection, be equipped with in the there-necked flask of 50mL acetone and add 5,11,17,23-tert-butyl-calix [4] aromatic hydrocarbons (2mmol), ethyl chloroacetate (4.4mmol), K
2cO
3(2.4mmol), KI(1mmol), backflow 24h, TLC detects raw material and disappears.Decompression steams most of solvent, adds the hydrochloric acid of 30mL10%, stirs, and then uses chloroform (20mL * 3) to be extracted, and merges organic phase, and dried over mgso is concentrated, adds 30mL methyl alcohol, separates out a large amount of precipitations.Filter, precipitation is used the chloroform/methanol recrystallization, obtains white powder 1.30g. productive rate after drying: 79%; Fusing point: 250 ℃～252 ℃;
1H?NMR(400MHz,CDCl
3):δ=0.97(s,18H,ArC(CH
3)
3),1.26(s,18H,ArC(CH
3)
3),1.34(t,6H,J=7.2Hz,-OCH
2CH
3),3.32(d,4H,J=13.2Hz,ArCH
2Ar),4.30(q,4H,J=7.2Hz,-OCH
2CH
3),4.45(d,4H,J=13.2Hz,ArCH
2Ar),4.72(s,4H,ArOCH
2-),6.81(s,4H,ArH),7.02(s,4H,ArH),7.05(s,2H,ArOH).
(c) 25,27-bis-((3Z)-4-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the 28-dihydroxyl-to the preparation of tert-butyl-calix [4] aromatic hydrocarbons
Under nitrogen protection and ice bath, by 0.09g(60%, 2.1mmol) sodium hydride is dissolved in the tetrahydrofuran solution of 5mL drying; drip 0.43g(2mmol) 1-benzyl-4-ethanoyl-5-methyl isophthalic acid H-1,2,3-triazole is dissolved in the tetrahydrofuran solution of 5mL drying; drip and finish, continue to stir 15min.Then drip 0.82g(1mmol) 25,27-bis-(ethoxy carbonyl methylene radical)-26,28-dihydroxyl-tert-butyl-calix [4] aromatic hydrocarbons is dissolved in to the tetrahydrofuran solution of 5mL drying, drip and finish, and stirring heating refluxes, and TLC shows that raw material disappears.Cooling, reaction mixture is poured in the frozen water that contains the 1mL concentrated hydrochloric acid into to ethyl acetate (15mL * 3) extraction, salt water washing, anhydrous magnesium sulfate drying, precipitation, obtain thick product, ethyl acetate/petroleum ether (1:9) rapid column chromatography, obtain white solid 0.36g, yield: 31%.Fusing point: 155～158 ℃;
1H?NMR(400MHz,CDCl
3):δ=0.96(s,18H,C(CH
3)
3),1.33(s,18H,C(CH
3)
3),2.44(s,6H,CH
3),3.42(d,4H,J=13.2Hz,ArCH
2Ar),4.45(d,4H,J=13.2Hz,ArCH
2Ar),4.75(s,4H,ArOCH
2),5.56(s,4H,ArCH
2),6.85(s,2H,COCH),6.90(s,4H,ArH),7.12(s,4H,ArH),7.18-7.21(m,4H,ArH),7.30-7.36(m,6H,ArH),7.78(s,2H,ArOH),15.31(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.7,181.5,150.8,149.8,147.3,141.3,141.1,136.4,134.3,132.5,129.0,128.3,127.4,127.1,125.7,125.0,96.7,75.7,51.6,33.9,33.8,31.8,31.6,30.9,9.36;
MS(ESI):m/z=1157.8[M-H]
-.
Embodiment 2:25,27-bis-((3Z)-4-(1-is to luorobenzyl-5 methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the 28-dihydroxyl-to the preparation of tert-butyl-calix [4] aromatic hydrocarbons (2)
(a), (b) step is with embodiment 1.
(c) Raw be 1-to luorobenzyl-4-ethanoyl-5-methyl isophthalic acid H-1,2,3-triazole, other steps are with embodiment 1, productive rate: 36%.
Fusing point: 205～208 ℃;
1H?NMR(400MHz,CDCl
3):δ=0.95(s,18H,C(CH
3)
3),1.32(s,18H,C(CH
3)
3),2.44(s,6H,CH
3),3.43(d,4H,J=13.2Hz,ArCH
2Ar),4.42(d,4H,J=13.2Hz,ArCH
2Ar),4.75(s,4H,ArOCH
2),5.52(s,4H,ArCH
2),6.85(s,2H,COCH),6.90(s,4H,ArH),7.10-7.16(m,8H,ArH),7.30-7.37(m,4H,ArH),7.85(s,2H,ArOH),15.33(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.9,181.3,150.8,149.8,147.2,141.4,141.0,136.3,134.4,132.7,132.4,129.2,128.5,127.3,125.7,125.0,96.8,75.6,50.9,34.0,33.8,31.8,31.6,30.9,9.37;
MS(ESI):m/z=1193.6[M-H]
-.
Embodiment 3:25,27-bis-((3Z)-4-(1-p-chlorobenzyl-5 methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the 28-dihydroxyl-to the preparation of tert-butyl-calix [4] aromatic hydrocarbons (3)
(a), (b) step is with embodiment 1.
(c) Raw is 1-p-chlorobenzyl-4-ethanoyl-5-methyl isophthalic acid H-1,2,3-triazole, and other steps are with embodiment 1, productive rate: 42%.
Fusing point: 205～208 ℃;
1H?NMR(400MHz,CDCl
3):δ=0.95(s,18H,C(CH
3)
3),1.32(s,18H,C(CH
3)
3),2.44(s,6H,CH
3),3.49(d,4H,J=13.2Hz,ArCH
2Ar),4.50(d,4H,J=13.2Hz,ArCH
2Ar),4.75(s,4H,ArOCH
2),5.52(s,4H,ArCH
2),6.68-6.73(m,4H,ArH),7.01(d,4H,J=7.6Hz,ArH),7.12-7.17(m,8H,ArH),7.36(d,4H,J=8.4Hz,ArH),8.11(s,2H,COCH),8.15(s,2H,ArOH),15.19(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.6,181.6,153.7,153.3,151.9,141.1,136.4,134.5,133.2,132.7,129.3,128.6,127.6,125.8,119.0,118.7,97.0,75.7,51.0,34.0,33.8,31.8,31.5,30.9,9.30;
MS(ESI):m/z=1225.6[M-H]
-.
Embodiment 4:25,27-bis-((3Z)-4-(1-is to xylyl-5 methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the 28-dihydroxyl-to the preparation of tert-butyl-calix [4] aromatic hydrocarbons (4)
(a), (b) step is with embodiment 1.
(c) Raw be 1-to xylyl-4-ethanoyl-5-methyl isophthalic acid H-1,2,3-triazole, other steps are with embodiment 1, productive rate: 31%.
Fusing point: 151～154 ℃;
1H?NMR(400MHz,CDCl
3):δ=0.96(s,18H,C(CH
3)
3),1.31(s,18H,C(CH
3)
3),2.32(s,6H,CH
3),2.43(s,6H,CH
3),3.42(d,4H,J=13.2Hz,ArCH
2Ar),4.44(d,4H,J=13.2Hz,ArCH
2Ar),4.76(s,4H,ArOCH
2),5.52(s,4H,ArCH
2),6.86(s,2H,COCH),6.92(s,4H,ArH),7.11-7.17(m,7H,ArH),7.29-7.37(m,4H,ArH),7.85(s,2H,ArOH),15.33(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.6,181.1,150.8,149.7,147.2,141.4,141.0,136.2,134.3,132.7,132.3,129.2,128.4,127.3,125.4,125.0,96.8,75.6,50.9,34.0,33.8,31.8,31.6,30.9,21.1,9.35;
MS(ESI):m/z=1185.3[M-H]
-.
Embodiment 5:25,27-bis-((3Z)-4-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the preparation of 28-dihydroxyl-cup [4] aromatic hydrocarbons (5)
(a) step is with embodiment 1.
(b) preparation of cup [4] aromatic hydrocarbons
Reaction conditions is anhydrous, has HCl to generate, and need use device for absorbing tail gas.N
2under protection, in tri-mouthfuls of round-bottomed flasks of 100mL, add the 40mL dry toluene, 4.5g (6.8mmol) 5,11,17,23-tert-butyl-calix [4] aromatic hydrocarbons, 3.0g (32mmol) phenol, the anhydrous AlCl of 4.7g (35mmol)
3, 25 ℃ of magnetic agitation 4h, reaction system color flavescence gradually deepens, and TLC monitoring reaction raw material point disappears.Then reactant is poured in the dilute hydrochloric acid that 80mL concentration is 0.2mol/L, solution becomes oyster white and emits a large amount of heat.Separate organic phase, after removing toluene under reduced pressure, add the methyl alcohol of 40mL, separate out a large amount of white precipitates, standing after magnetic agitation 10min, filter to obtain crude product, obtain 2.1g.With the white solid 1.9g of methylene chloride/methanol recrystallization, productive rate: 66.7%.Fusing point 315-318 ℃;
(c) 25,27-bis-(ethoxy carbonyl methylene radical)-26, the preparation of 28-dihydroxyl-cup [4] aromatic hydrocarbons
Under nitrogen protection, be equipped with in the there-necked flask of 50mL acetonitrile and add 1.21g(2.8mmol) cup [4] aromatic hydrocarbons 2,0.65mL(5.7mmol) ethyl bromoacetate, 0.44g(3.1mmol) K
2cO
3, backflow 24h, TLC detects raw material and disappears.Filter, decompression steams most of solvent, join in the mixing solutions of 30mL methylene dichloride and 20mL10% hydrochloric acid, stir layering, then use methylene dichloride (10mL * 2) to be extracted, merge organic phase, washing, dried over mgso, concentrated, slightly for product, ethyl acetate/dichloromethane (1:8) rapid column chromatography obtains white crystal 0.95g, and productive rate is 57%.Fusing point: 164 ℃～166 ℃;
1H?NMR(400MHz,CDCl
3):δ=1.35(t,6H,J=7.2Hz,-OCH
2CH
3),3.39(d,4H,J=13.6Hz,ArCH
2Ar),4.33(q,4H,J=7.2Hz,-OCH
2CH
3),4.47(d,4H,J=13.6Hz,ArCH
2Ar),4.72(s,4H,-OCH
2CO-),6.63-6.66(m,4H,ArH),6.89(d,4H,J=7.2Hz,ArH),6.89(d,4H,J=7.2Hz,ArH),7.59(s,2H,ArOH);
(d) 25,27-bis-((3Z)-4-(1-benzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the preparation of 28-dihydroxyl-cup [4] aromatic hydrocarbons.
Under nitrogen protection and ice bath, by 0.09g(60%, 2.1mmol) sodium hydride is dissolved in the tetrahydrofuran solution of 5mL drying; drip 0.43g(2mmol) 1-benzyl-4-ethanoyl-5 methyl isophthalic acid H-1,2,3-triazole is dissolved in the tetrahydrofuran solution of 5mL drying; drip and finish, continue to stir 5min.Then drip 0.60g(1mmol) cup [4] aromatic hydrocarbons-1, the 3-ethyl diacetate is dissolved in the tetrahydrofuran solution of 5mL drying, drips and finishes, and stirring heating refluxes, and TLC shows that raw material disappears.Cooling, reaction mixture is poured in the frozen water that contains the 1mL concentrated hydrochloric acid into to ethyl acetate (15mL * 3) extraction, salt water washing; anhydrous magnesium sulfate drying, precipitation, obtain thick product; ethyl acetate/petroleum ether (1:8) rapid column chromatography, obtain white solid 0.26g, yield: 28%; Fusing point: 177～180 ℃;
1H?NMR(400MHz,CDCl
3):δ=2.43(s,6H,CH
3),3.45(d,4H,J=13.2Hz,ArCH
2Ar),4.50(d,4H,J=13.2Hz,ArCH
2Ar),4.76(s,4H,ArOCH
2),5.52(s,4H,ArCH
2),6.70(t,4H,J=7.2Hz,ArH),7.00(d,4H,J=7.6Hz,ArH),7.12(d,4H,J=7.6Hz,ArH),7.19(d,4H,J=7.6Hz,ArH),7.34-7.40(m,6H,ArH),8.02(s,2H,COCH),8.10(s,2H,ArOH),15.20(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.4,181.8,153.8,152.1,141.5,136.6,134.7,133.6,129.6,129.0,128.5,128.3,127.7,127.3,126.0,119.0,96.9,75.6,51.6,31.6,9.31;
MS(ESI):m/z=933.4[M-H]
-.
Embodiment 6:25,27-bis-((3Z)-4-(1-is to luorobenzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the preparation of 28-dihydroxyl-cup [4] aromatic hydrocarbons (6)
(a) step is with embodiment 1, (b), (c) step is with embodiment 5.
(d) Raw be 1-to luorobenzyl-4-ethanoyl-5 methyl isophthalic acid H-1,2,3-triazole, other steps are with embodiment 5, productive rate: 25%.
Fusing point: 175～178 ℃;
1H?NMR(400MHz,CDCl
3):δ=2.43(s,6H,CH
3),3.43(d,4H,J=13.2Hz,ArCH
2Ar),4.44(d,4H,J=13.2Hz,ArCH
2Ar),4.75(s,4H,ArOCH
2),5.52(s,4H,ArCH
2),6.85(s,2H,COCH),6.90(s,4H,ArH),7.10-7.16(m,8H,ArH),7.30-7.37(m,4H,ArH),7.85(s,2H,ArOH),15.38(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.9,181.3,150.8,149.8,147.2,141.4,141.0,136.3,134.4,132.7,132.4,129.2,128.5,127.3,125.7,125.0,96.8,75.6,50.9,31.6,9.37;
MS(ESI):m/z=970.1[M-H]
-.
Embodiment 7:25,27-bis-((3Z)-4-(1-p-chlorobenzyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the preparation of 28-dihydroxyl-cup [4] aromatic hydrocarbons (7)
(a) step is with embodiment 1, (b), (c) step is with embodiment 5.
(d) Raw is 1-p-chlorobenzyl-4-ethanoyl-5 methyl isophthalic acid H-1,2,3-triazole, and other steps are with embodiment 5, productive rate: 36%.
Fusing point: 147～149 ℃;
1H?NMR(400MHz,CDCl
3):δ=2.44(s,6H,CH
3),3.49(d,4H,J=13.2Hz,ArCH
2Ar),4.50(d,4H,J=13.2Hz,ArCH
2Ar),4.75(s,4H,ArOCH
2),5.52(s,4H,ArCH
2),6.68-6.73(m,4H,ArH),7.01(d,4H,J=7.6Hz,ArH),7.12-7.17(m,8H,ArH),7.36(d,4H,J=8.4Hz,ArH),8.11(s,2H,COCH),8.15(s,2H,ArOH),15.19(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.6,181.6,153.7,153.3,151.9,141.1,136.4,134.5,133.2,132.7,129.3,128.6,127.6,125.8,119.0,118.7,97.0,75.7,51.0,31.5,9.30;
MS(ESI):m/z=1001.3[M-H]
-.
Embodiment 8:25,27-bis-((3Z)-4-(1-is to xylyl-5-methyl isophthalic acid H-1,2,3-triazole-4-yl)-4-hydroxyl-3-butene-2-one-1-methylene radical)-26, the preparation of 28-dihydroxyl-cup [4] aromatic hydrocarbons (8)
(a) step is with embodiment 1, (b), (c) step is with embodiment 5.
(d) Raw be 1-to xylyl-4-ethanoyl-5 methyl isophthalic acid H-1,2,3-triazole, other steps are with embodiment 5, productive rate: 23%.
Fusing point: 149～151 ℃;
1H?NMR(400MHz,CDCl
3):δ=2.32(s,6H,CH
3),2.39(s,6H,CH
3),3.46(d,4H,J=13.2Hz,ArCH
2Ar),4.48(d,4H,J=13.2Hz,ArCH
2Ar),4.72(s,4H,ArOCH
2),5.48(s,4H,ArCH
2),6.65(t,4H,J=7.6Hz,ArH),6.95(d,4H,J=7.6Hz,ArH),7.05-7.09(m,8H,ArH),7.13(d,4H,J=7.6Hz,ArH),7.97(s,2H,COCH),8.06(s,2H,ArOH),15.16(s,2H,OH);
13C?NMR(100MHz,CDCl
3):δ=187.2,181.9,153.7,152.1,141.1,138.2,136.4,133.2,131.3,129.7,129.3,128.5,127.7,127.2,125.7,118.7,96.9,75.7,51.5,31.5,21.1,9.36;
MS(ESI):m/z=961.4[M-H]
-.
Embodiment 9: the intergrase chain transfer reaction suppresses determination of activity
Reaction is carried out in 96 orifice plates, and cumulative volume is 50 μ L, and reaction buffer is: 25mmol/L PIPES, pH7.0,5%glycerol, 0.1g/L BSA.By testing sample and 800ng intergrase in the reaction buffer system 37 ℃ hatch 20min, subsequently, add the MnCl that final concentration is 10mmol/L
2, 1.5pmol donor dna and 1.5pmol target DNA, at 37 ℃ of reaction 1h.Add 51.5 μ L binding buffer liquid (10mmol/L Tris-HCl, pH7.6,2mol/L NaCl, 20mmol/L EDTA, 0.1%Tween20) and 1.5mL magnetic beads, mix latter 20 ℃ and hatch 15min.Microwell plate is placed in to 90s on the magnetic bead collector, abandons supernatant.PBST washes plate 3 times.Add the DigiTAb of 100 μ L with the alkali phosphatase enzyme mark of PBS1:5000 dilution, hatch 30min for 37 ℃, PBST washes plate 3 times, and magnetic bead is transferred in new microwell plate, adds 100mL chromogenic substrate (0.1mol/L Na
2cO
3, pH9.5,6.7mmol/L PNPP, 2mmol/L MgCl
2), measure the OD of 405nm place value.The negative contrast of DMSO that does not add sample is set in experiment, the Baicalein of 25 μ mol/L of take is the measurement result positive control, microplate reader is measured A value (absorbancy), (detailed method is shown in H.Q.He et al.A novel high-throughput format assay for HIV-1integrase strand transfer reaction using magnetic beads.Acta Pharma-cologica.Sinica. to calculate inhibiting rate by formula 100 * (1-dosing group A value/control group A value), 2008,29 (3): 397-404).Its determination of activity the results are shown in Table 1.
Table 1 the compounds of this invention suppresses intergrase determination of activity result
* the inhibiting rate of the compounds of this invention when 50 μ mol/L.
Claims (8)
1. two cup 4 arene compounds that replace of the class Diniconazole-one meaned by following general formula (I),
Wherein, mean-H of R or t-Bu-,
R
1mean:
R wherein
2expression-H ,-F ,-Cl ,-CH
3, can be at ortho position, a position or contraposition.
2. according to the compound of claim 1, it is characterized in that mean-H of R or t-Bu-.
3. according to the compound of claim 1, it is characterized in that R
1mean:
4. according to the compound of claim 3, it is characterized in that R
2expression-H ,-F ,-Cl ,-CH
3, can be at ortho position, a position or contraposition.
5. a class Diniconazole-one according to claim 1 pair replaces the preparation methods of cup 4 arene compounds, it is characterized in that comprising the following steps:
(a) under nitrogen protection, the p-tert-butylphenol meaned with formula (II) reacts in sodium hydroxide solution with formaldehyde, be warming up to water reaction in 115～120 ℃ of minutes 1～2 hour, continue subsequently heating reflux reaction 3-4 hour in phenyl ether solution, obtain that formula (III) means to tert-butyl-calix [4] aromatic hydrocarbons, the ratio of p-tert-butylphenol, formaldehyde and sodium hydroxide amount of substance is 22:23～28:1;
(b) under nitrogen protection, formula (III) compound is reacted in toluene solution with phenol and aluminum trichloride (anhydrous), reaction 4-12 hour under room temperature, obtain cup [4] aromatic hydrocarbons that formula (IV) means, the ratio of formula (III) compound, phenol and aluminum trichloride (anhydrous) amount of substance is 2:2:1～2;
(c) under nitrogen protection, by formula (III) compound or formula (IV) compound and halogenated acetic acids ester under inorganic or organic bases and catalyzer exist in organic solvent heating reflux reaction 24-48 hour, obtain 25 of formula (V) expression, 27-bis-(ethoxy carbonyl methylene radical)-26, 28-dihydroxyl-(to the tertiary butyl) cup [4] aromatic hydrocarbons, formula (III) compound or formula (IV) compound, the ratio of the amount of halogenated acetic acids ester and alkaloid substance is 1:2～4:2～3, wherein the halogenated acetic acids ester is ethyl bromoacetate, methyl bromoacetate, methyl chloroacetate, ethyl chloroacetate, inorganic or organic bases is salt of wormwood, cesium carbonate, potassium tert.-butoxide, sodium hydride, catalyzer is potassiumiodide, organic solvent used is acetonitrile, acetone, N, dinethylformamide, methyl-sulphoxide,
Wherein, mean-H of R or t-Bu-.
(d) under condition of ice bath; formula (VI) 1-substituted benzyl-4-ethanoyl-5-methyl isophthalic acid H-1; 2; the 3-triazole is reacted with mineral alkali in organic solvent; then add formula (V) compound; slowly be heated to reflux, reaction times 3-8 hour, obtain formula as claimed in claim 1 (I) compound again.Formula (V) compound, 1-substituted benzyl-4-ethanoyl-5-methyl isophthalic acid H-1, the ratio of the amount of 2,3-triazole and alkaloid substance is 1:2～3:4～6, and alkali used is sodium methylate, sodium ethylate, sodium hydride, organic solvent used is methyl alcohol, ethanol, DMF, tetrahydrofuran (THF);
Wherein, R
2described with claim 1.
6. according to the method for claim 5, it is characterized in that the ratio of the amount of step (c) Chinese style (III) compound or formula (IV) compound, halogenide and alkaloid substance is 1:2～4:2～3.
7. according to the method for claim 5, it is characterized in that the ratio of the amount of substance of the middle formula V compound of step (d) and formula (VI) compound is 1:2～3:4～6.
8. the application of the two replacement cup of a class Diniconazole-one claimed in claim 14 arene compounds in preparation HIV-1 integrase inhibitor.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1367044A1 (en) * | 2002-05-31 | 2003-12-03 | Aids Care Pharma Limited | Calixarene-derivatives having anti-viral activity |
| US20050113454A1 (en) * | 2003-11-25 | 2005-05-26 | Aids Care Pharma Limited | Anti-viral compounds |
-
2013
- 2013-09-25 CN CN2013104595308A patent/CN103467393A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1367044A1 (en) * | 2002-05-31 | 2003-12-03 | Aids Care Pharma Limited | Calixarene-derivatives having anti-viral activity |
| US20050113454A1 (en) * | 2003-11-25 | 2005-05-26 | Aids Care Pharma Limited | Anti-viral compounds |
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| 杨发福等: "新型杯[4] 芳烃衍生物的合成及其氨基酸萃取性能", 《分子科学学报》 * |
| 罗再刚等: "25’27-二( α，γ-二酮苯丁氧基) -26’28-二羟基杯［4］芳烃的合成", 《化学研究与应用》 * |
| 罗再刚等: "含1,2,3-三唑环的α，γ-二酮衍生物的合成研究", 《化学研究与应用》 * |
| 罗再刚等: "新型对叔丁基杯［4］芳烃1，3-二酮衍生物的合成", 《合成化学》 * |
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