CN103965163A - Pyrimidine ring-containing quinolone derivatives as well as preparation method and application thereof - Google Patents

Pyrimidine ring-containing quinolone derivatives as well as preparation method and application thereof Download PDF

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CN103965163A
CN103965163A CN201410201093.4A CN201410201093A CN103965163A CN 103965163 A CN103965163 A CN 103965163A CN 201410201093 A CN201410201093 A CN 201410201093A CN 103965163 A CN103965163 A CN 103965163A
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CN103965163B (en
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陈芬儿
何秋琴
毛天绮
万正勇
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Fudan University
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

The invention belongs to the technical field of medicines and in particular relates to pyrimidine ring-containing quinolone derivatives as well as a preparation method and application thereof. A compound comprises pyrimidine ring-containing quinolone derivatives, pharmaceutical salts, hydrates and solvates of the pyrimidine ring-containing quinolone derivatives, polymorphic or eutectic substances of the pyrimidine ring-containing quinolone derivatives, and precursors and derivatives, with same biological functions, of the pyrimidine ring-containing quinolone derivatives. The invention further discloses a preparation method of the compound and application of a composition containing one or more compounds to preparation of related drugs for treating AIDS (acquired immune deficiency syndrome) and the like. A pharmacological experiment result shows that the compound has remarkable anti-HIV (human immunodeficiency virus)-1 virus activity and relatively low cell toxicity, and can effectively inhibit replication of MT-4 cells infected with HIV-1 viruses.

Description

Quinolone derivative containing pyrimidine ring and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a quinolone derivative containing a pyrimidine ring, and a preparation method and application thereof.
Background
Acquired immunodeficiency syndrome (AIDS), is an epidemic caused by infection with Human Immunodeficiency Virus (HIV). Since the first AIDS cases were confirmed by the American centers for disease control in 1981, the number of AIDS patients worldwide showed an explosive growth trend called "century plague".
HIV-1 Reverse Transcriptase (RT) and Integrase (IN) are key enzymes IN the viral replication process, the former Reverse transcribes viral RNA into viral DNA, the latter integrates viral DNA into host chromosomal cells, and RT and IN have become important targets for designing highly effective and low-toxicity anti-HIV drugs. Diaryl pyrimidine RT inhibitors have been noted as an important anti-HIV compound since the first report by Janssen 2001. Through a large number of structural modifications, a plurality of highly active HIV-1RT inhibitors have been obtained, representative compounds of Etravirine and Rilpivirine were approved by the U.S. FDA for marketing in 2008 and 2011, respectively. Because the quinolone compounds contain pyridonic acid structures, the quinolone compounds can be chelated with metal ions IN IN, so that good anti-HIV activity is exerted, and because the compounds are stable IN metabolism, the quinolone compounds are used as lead compounds to search for efficient, low-toxicity and anti-drug-resistance integrase inhibitors, which is a hot spot for currently developing anti-HIV drugs. Elvitegravir developed by tobacao corporation of japan has obtained us FDA approval for marketing in 2012.
Disclosure of Invention
The invention aims to provide a quinolone derivative containing pyrimidine ring, which has good anti-HIV-1 virus activity, small cytotoxicity and high selectivity index, and a preparation method and application thereof.
According to the hybridization principle and by combining with a computer-aided drug design theory, the diaryl pyrimidine RT inhibitor and the quinolone IN inhibitor are subjected to molecular hybridization to obtain a quinolone derivative containing a pyrimidine ring, so that the antiviral activity of a target object is further improved. Biological activity tests show that all compounds have anti-HIV-1 activity, and partial compounds have good HIV-1 activity and higher selectivity index.
The compound provided by the invention has the following structural general formula (I) or (II), and is marked as a compound I and a compound II:
wherein R is1Selected from hydrogen, C1～6Alkyl radical, C3～7Cycloalkyl radical, C1～6Alkoxy, C substituted by one or more halogen atoms1～6Alkyl radicals, C substituted by one or more halogen atoms2～6Alkenyl, C substituted by one or more halogen atoms3～6An alkynyl group;
R2selected from hydrogen, C1～6Alkyl radical, C3～7Cycloalkyl radical, C1～6Alkoxy, halogen atom;
R3is selected from C1～3An alkyl group;
x is selected from carbon atom, oxygen atom, nitrogen atom and sulfur atom.
The invention also includes pharmaceutically acceptable salts, hydrates and solvates thereof, polymorphs or co-crystals thereof, precursors and derivatives thereof having the same biological function.
The invention also provides a preparation method of the carbostyril derivative containing the pyrimidine ring, and the reaction route is as follows:
in the formula, PG is benzyl or 2, 4-dimethoxybenzyl;
the preparation method comprises the following specific operation steps:
(1) reacting substituted benzoyl chloride with 3- (N, N-dimethylamino) ethyl acrylate in toluene in the presence of triethylamine to generate an intermediate 1;
(2) reacting the intermediate 1 with various amines in an organic solvent to generate an intermediate 2;
(3) the intermediate 2 is subjected to ring closing under the action of alkali to generate an intermediate 3;
(4) reacting the intermediate 3 in an alkaline water solution for 3-8h, adjusting the pH value to 2-3 with acid water, filtering, and washing to obtain an intermediate 4;
(5) reacting the intermediate 4 in an alkaline aqueous solution for 8-72h, adjusting the pH value to 2-3 with acid water, filtering, and washing to obtain an intermediate 5;
(6) condensing the intermediate 5 and the compound III under an alkaline condition to obtain a required compound I; or,
(5) reacting intermediate 4 with (substituted) benzylamine or (substituted) benzylthiol with or without base to give intermediate 6;
(6) deprotection of intermediate 6 to give intermediate 7; condensing the intermediate 7 and the compound III under an acidic condition to obtain a required compound I;
(7) the compound I and trimethylsilyldiazomethane react in an organic solvent to generate the required compound II, or the compound I and C1-C3 alcohol generate the required compound II under the action of acid.
The preparation method of the compound III is disclosed in the document Bioorg, chem, Med2011,19, 5117-5124.
In step (2), the organic solvent is dichloromethane, chloroform, DMF, tetrahydrofuran, dioxane, DMSO, or C1-C4Alcohol, a single solvent or a mixed solvent of several solvents; the reaction temperature is 25-80 ℃.
In step (3) of the present invention, the base used is an alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, or an organic base such as triethylamine, DBU, DIEPA, and the organic solvent used is tetrahydrofuran, dioxane, DMF, DMSO, C1-C4Alcohol, a single solvent or a mixed solvent of several solvents; the reaction temperature is 25-110 ℃.
In step (4) of the present invention, the alkali used is an alkaline earth hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, and the organic solvent is C1-C4Alcohol, tetrahydrofuran, dioxane, DMF, DMSO, a single solvent or a mixed solvent of several solvents; the reaction temperature is 25-50 ℃; the reaction time is 3-8 h.
In the step (5), the alkali used is alkaline earth hydroxide, such as sodium hydroxide and potassium hydroxide, and the organic solvent is tetrahydrofuran, dioxane, DMF or DMSO, a single solvent or a mixed solvent of several solvents; the reaction temperature is 80-110 ℃; the reaction time is 8-72 h.
In step (6) of the present invention, the base used is an alkaline earth hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide, or an alkali metal carbonate such as sodium carbonate, potassium carbonate, cesium carbonate, or an organic base such as triethylamine, DBU, DIEPA, and the organic solvent used is DMF, tetrahydrofuran, dioxane, DMSO, C1-C4An alcohol; the reaction temperature is 60-110 ℃.
In step (5) of the present invention, the base used is alkaline earth hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide or calcium hydroxide, or alkali metal carbonate, such as sodium carbonate, potassium carbonate or cesium carbonate, or organic base, such as triethylamine, DBU or DIEPA, and the organic solvent is DMF, tetrahydrofuran, dioxane, DMSO or C1-C4Alcohol, a single solvent thereof, or a mixed solvent of several thereof.
In the step (6), the deprotection agent used in the deprotection reaction is trifluoroacetic acid, the reaction solvent is dichloromethane and THF, and the reaction temperature is 25-80 ℃; or the deprotection agent is Pd/hydrogen, Pt/hydrogen, Raney Ni/hydrogen, and the reaction solvent is C1-C4Alcohol and dioxane, the reaction pressure is 1-10atm, and the reaction temperature is 25-50 ℃.
The intermediate 7 is condensed with a compound III under acidic conditions by using an acidSOCl2、HCl、H2SO4、H3PO4The organic solvent is DMF, tetrahydrofuran, dioxane, DMSO, or C1-C4Alcohol, wherein the reaction temperature is 60-110 ℃.
In step (7), the organic solvent is DMF, tetrahydrofuran, dioxane, DMSO, or C1-C4Alcohol, wherein the reaction temperature is 0-25 ℃, and the reaction temperature is a single solvent or a mixed solvent of a plurality of solvents; the acid used is SOCl2、HCl、H2SO4、H3PO4The reaction temperature is 25-110 ℃.
The compound of the invention has novel structure, good anti-HIV-1 virus activity, smaller cytotoxicity and higher selectivity index. The invention also relates to a pharmaceutical composition comprising an effective amount of the above compound and a pharmaceutically acceptable carrier; the invention also relates to application of the compound or the composition in preparation of drugs for preventing and treating AIDS.
Detailed Description
The invention will be better understood by the following examples of implementation, but is not intended to limit the scope of the invention.
Example 1: preparation of intermediate 1
Substituted benzoic acid (18.1mmol), ethyl 3- (N, N-dimethylamino) acrylate (18.1mmol) and triethylamine (27.1mmol) are dissolved in 30mL of toluene, stirred at 90 ℃ for 4h, concentrated and subjected to column chromatography to obtain intermediate 1.
Ethyl2-(2,4-difluorobenzoyl)-3-(dimethylamino)acrylate(R2H): yield 65%, H1NMR(400MHz,CDCl3)δ7.79(s,1H),7.62-7.68(m,1H),6.89-6.93(m,1H),6.74-6.80(m,1H),3.98-4.03(q,J＝7.2Hz,2H),3.31(s,3H),2.89(s,3H),0.95-0.99(t,J＝7.2Hz,3H)。
Ethyl2-(5-bromo-2,4-difluorobenzoyl)-3-(dimethylamino)acrylate(R2Br): the yield thereof is 62 percent,1HNMR(400MHz,CDCl3)δ7.86–7.82(t,J＝7.2Hz,1H),7.80(s,1H),6.87-6.83(t,J＝8.4Hz,1H),4.05-3.99(q,J＝7.2Hz,2H),3.33(s,3H),2.87(s,3H),1.04-1.01(t,J＝7.2Hz,3H)。
Ethyl2-(2,4-difluoro-5-iodobenzoyl)-3-(dimethylamino)acrylate(R2i): the yield is 52 percent,1HNMR(400MHz,CDCl3)δ8.01-7.97(t,J＝7.2Hz,1H),7.78(s,1H),6.78(dd,J＝9.6,7.2Hz,1H),4.00(q,J＝7.2Hz,2H),3.31(s,3H),2.86(s,3H),1.01-0.97(t,J＝7.2Hz,3H)。
example 2: synthesis of intermediate 4
Intermediate 1(3mmol) and various substituted amines (3.6mmol) were stirred in THF (5mL) at 50 ℃ for 3h and concentrated to give intermediate 2 which was used directly in the next reaction without isolation and purification.
Intermediate 2(1.5mmol), K2CO3(2.3mmol) was added to DMF (10mL), stirred overnight at 60-90 deg.C, cooled, poured into ice water, filtered, washed with water to give intermediate 3, which was used in the next reaction without isolation and purification.
Intermediate 3(1mmol) was dissolved in THF (3mL), 10% aqueous NaOH (3mL) was added, the mixture was stirred at 45 ℃ overnight, after cooling, THF was spun off, the aqueous phase was adjusted to PH 2 with hydrochloric acid, filtered, washed with water and dried to give intermediate 4.
1-Ethyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝ethyl,R2H) yield 74％；1H NMR(400MHz,DMSO)δ15.07(s,1H),9.08(s,1H),8.48-8.44(dd,J＝8.8,6.4Hz,1H),8.00-7.97(dd,J＝10.8,1.6Hz,1H),7.58-7.54(td,J＝9.2,2.0Hz,1H),4.60-4.55(q,J＝7.2Hz,2H),1.42-1.38(t,J＝7.2Hz,3H)。
1-(sec-Butyl)-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝s-butyl,R2H) yield 70%;1H NMR(400MHz,CDCl3)δ14.83(s,1H),8.83(s,1H),8.64-8.60(dd,J＝9.0,6.8Hz,1H),7.42-7.39(dd,J＝10.8,1.6Hz,1H),7.38-7.26(m,1H),4.68-4.60(m,1H),2.06-1.97(m,2H),1.65-1.63(d,J＝6.8Hz,3H),1.01-0.96(t,J＝7.2Hz,3H)。
1-cyclopentyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝cyclopentyl,R2h) yield 81%;1H NMR(400MHz,CDCl3)δ14.83(s,1H),8.87(s,1H),8.62-8.58(dd,J＝9.0,6.4Hz,1H),7.47-7.44(dd,J＝10.8,2.0Hz,1H),7.34-7.27(m,1H),4.99-4.88(m,1H),2.46-1.85(m,8H)。
6-Bromo-1-methyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝ethyl,R2br) yield 84%;1H NMR(400MHz,DMSO)δ14.77(s,1H),9.04(s,1H),8.58-8.56(d,J＝7.6Hz,1H),8.07-8.05(d,J＝10.4Hz,1H),4.04(s,3H)。
6-bromo-7-fluoro-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝i-butyl,R2br) yield 77%;1H NMR(400MHz,DMSO)δ14.70(s,1H),9.02(s,1H),8.54-8.52(d,J＝7.2Hz,1H),8.22-8.19(d,J＝10.8Hz,1H),4.37-4.36(d,J＝7.2Hz,2H),2.21-2.08(m,1H),0.90-0.88(d,J＝6.8Hz,6H)。
6-Bromo-1-cyclohexyl-7-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝cyclohexyl,R2yield 92% when becoming Br;1H NMR(400MHz,DMSO)δ14.74(s,1H),8.88(s,1H),8.60-8.59(d,J＝8.0Hz,1H),8.41-8.38(d,J＝10.8Hz,1H),4.86-4.74(m,1H),2.11-1.29(m,10H)。
1-Ethyl-7-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝ethyl,R2yield 89%;1H NMR(400MHz,DMSO)δ14.78(s,1H),9.05(s,1H),8.69-8.68(d,J＝7.2Hz,1H),8.05-8.02(d,J＝10.8Hz,1H),4.56-4.51(q,J＝7.2Hz,2H),1.40-1.36(t,J＝7.2Hz,3H)。
7-Fluoro-6-iodo-4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid(R1＝n-propyl,R2yield 88%;1H NMR(400MHz,DMSO)δ14.78(s,1H),9.05(s,1H),8.71-8.69(d,J＝6.8Hz,1H),8.07-8.05(d,J＝10.8Hz,1H),4.48-4.45(t,J＝7.2Hz,2H),1.84-1.72(m,2H),0.92-0.89(t,J＝7.2Hz,3H)。
1-(tert-Butyl)-7-fluoro-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝t-butyl,R2yield 90%;1H NMR(400MHz,DMSO)δ14.75(s,1H),9.00(s,1H),8.83-8.82(d,J＝6.4Hz,1H),8.20-8.17(d,J＝10.8Hz,1H),1.85(s,9H)。
example 4: synthesis of intermediate 5
Dissolving the intermediate 4(1.0mmol) in DMSO solution (5mL), adding 12.5N NaOH solution (5mL), reacting at 80 ℃ for 1-2d, cooling, pouring into ice water, adjusting pH to about 2 with 6N HCl, filtering, washing with water, and drying to obtain intermediate 5. The product is used for the next reaction without separation and purification.
1-Ethyl-7-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝ethyl,R2H) yield 90%;1H NMR(400MHz,MeOD)δ8.87(s,1H),8.33-8.31(d,J＝8.8Hz,1H),7.15-7.10(m,2H),4.48-4.43(q,J＝6.8Hz,2H),1.55-1.51(t,J＝7.2Hz,3H)。
1-(sec-Butyl)-7-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝s-butyl,R2h) yield 93%;1H NMR(400MHz,MeOD)δ8.80(s,1H),8.33-8.31(d,J＝8.8Hz,1H),7.27-7.26(d,J＝1.2Hz,1H),7.11-7.09(dd,J＝8.8,1.2Hz,1H),4.90-4.86(m,1H),2.05-1.96(m,2H),1.61-1.60(d,J＝6.4Hz,3H),0.97-0.93(t,J＝7.6Hz,3H)。
1-Cyclopentyl-7-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝cyclopentyl,R2h) yield 90%;1H NMR(400MHz,MeOD)δ8.82(s,1H),8.34-8.32(d,J＝9.2Hz,1H),7.31-7.30(d,J＝1.6Hz,1H),7.13-7.11(dd,J＝8.8,1.2Hz,1H),5.17-5.11(m,1H),2.41-2.36(m,2H),2.07-1.91(m,6H)。
6-Bromo-1-methyl-7-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝methyl,R2yield 90% of Br;1H NMR(400MHz,DMSO)δ15.21(s,1H),11.99(s,1H),8.95(s,1H),8.39(s,1H),7.21(s,1H),3.98(s,3H)。
6-Bromo-7-hydroxy-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝i-butyl,R2yield 89% when becoming Br;1H NMR(400MHz,DMSO)δ15.18(s,1H),11.87(s,1H),8.92(s,1H),8.41(s,1H),7.29(s,1H),4.27-4.25(d,J＝7.2Hz,2H),2.25-2.11(m,1H),0.92-0.91(d,J＝6.8Hz,6H)。
6-Bromo-1-cyclohexyl-7-hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝cyclohexyl,R2yield 92% when becoming Br;1H NMR(400MHz,DMSO)δ15.19(s,1H),11.87(s,1H),8.78(s,1H),8.44(s,1H),7.46(s,1H),4.51-4.45(m,1H),2.10-1.32(m,10H)。
1-Ethyl-7-hydroxy-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝ethyl,R2yield 89%;1H NMR(400MHz,DMSO)δ15.23(s,1H),11.92(s,1H),8.96(s,1H),8.61(s,1H),7.19(s,1H),4.45-4.40(q,J＝7.2Hz,2H),1.43-1.39(t,J＝7.2Hz,3H)。
7-hydroxy-6-iodo-4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid(R1＝n-propyl,R2yield 88%;1H NMR(400MHz,DMSO)δ15.23(s,1H),11.86(s,1H),8.95(s,1H),8.61(s,1H),7.20(s,1H),4.37-4.33(t,J＝7.2Hz,2H),1.86-1.77(m,2H),0.94-0.90(t,J＝7.2Hz,3H)。
1-(tert-Butyl)-7-hydroxy-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid R1＝(t-butyl,R2yield 90%;1H NMR(400MHz,DMSO)δ15.18(s,1H),11.74(brs,1H),8.90(s,1H),8.67(s,1H),7.80(s,1H),1.84(s,9H)。
example 5: synthesis of intermediate 6
Dissolving the intermediate 4(1.0mmol) in DMSO (2mL), adding 2, 4-dimethoxybenzylamine (3.0mmol), reacting at 85 ℃ for 6h under the protection of N2, cooling, pouring into ice water, adjusting pH to about 5 with 6N HCl, filtering, washing with ethanol, and drying to obtain an intermediate 6.
7-((2,4-dimethoxybenzyl)amino)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylicacid(R1＝ethyl,R2H) yield 98%;1H NMR(400MHz,DMSO)δ16.01(brs,1H),8.78(s,1H),8.02-8.00(d,J＝9.0Hz,1H),7.44(s,1H),7.22-7.20(d,J＝8.4Hz,1H),6.96-6.94(d,J＝8.8Hz,1H),6.62-6.56(m,2H),6.50-6.47(dd,J＝8.4,2.0Hz,1H),4.38-4.27(m,4H),3.84(s,3H),3.73(s,3H),1.31-1.28(t,J＝6.8Hz,3H)。
example 6: synthesis of intermediate 7
Intermediate 6(5.0mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (15.0mmol) was added, and the mixture was stirred at room temperature for 5 h. After the reaction was completed, ice water (250mL) was poured in and vigorously stirred for 20min, and filtered. The filter cake was dried and poured into dichloromethane (500mL) for 10min with ultrasound, the insolubles were removed by filtration, and the dichloromethane was removed from the filtrate under reduced pressure to give intermediate 7.
7-Amino-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(R1＝ethyl,R2H), yield 94%,1H NMR(400MHz,DMSO)δ16.01(s,1H),8.79(s,1H),8.04-8.02(d,J＝8.8Hz,1H),6.88-6.86(d,J＝8.8Hz,1H),6.79(s,1H),6.50(s,2H),4.38-4.33(q,J＝7.2Hz,2H),1.42-1.38(t,J＝7.2Hz,3H)。
example 7: synthesis of the end product I
Adding the intermediate 5(1.0mmol), the compound II (1.05mmol) and K2CO3(2.5mmol) into DMF (10mL), stirring at 60-90 ℃ for 8-24 h, cooling, pouring into ice water, adjusting the pH value to 5-6 with glacial acetic acid, filtering, and purifying by dichloromethane/methanol column chromatography to obtain the final product I.
7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝ethyl,R2H) yield 42%; MP291-293 ℃;1H NMR(400MHz,DMSO)δ15.19(s,1H),10.15(s,1H),9.10(s,1H),8.55-8.53(d,J＝5.6Hz,1H),8.51-8.48(d,J＝8.8Hz,1H),8.04(s,1H),7.71-7.68(d,J＝8.8Hz,2H),7.62-7.59(dd,J＝8.8Hz,1.6Hz,1H),7.49-4.47(d,J＝8.8Hz,2H),6.77-6.75(d,J＝5.6Hz,1H),4.59-4.54(q,J＝6.8Hz,2H),1.35-1.31(t,J＝7.2Hz,3H)；ESI428[M+H]+。
1-(sec-Butyl)-7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝s-butyl,R2h): the yield is 49%; MP273-274 ℃;1H NMR(400MHz,DMSO)δ15.18(s,1H),10.15(s,1H),8.81(s,1H),8.54-8.53(d,J＝5.6Hz,1H),8.52-8.51(d,J＝8.8Hz,1H),8.19(s,1H),7.68-7.66(d,J＝8.8Hz,2H),7.61-7.59(dd,J＝1.2,8.8Hz,1H),7.48-7.46(d,J＝8.8Hz,1H),6.76-6.74(d,J＝5.6Hz,1H),5.07-4.99(m,1H),1.96-1.83(m,2H),1.48-1.46(d,J＝7.2Hz,3H),0.78-0.75(t,J＝7.2Hz,3H)；ESI456[M+H]+。
7-((2-((4-Cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-cyclopentyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝cyclopentyl,R2h) yield 51%; MP278-280 ℃;1HNMR(400MHz,DMSO)δ15.15(s,1H),10.16(s,1H),8.81(s,1H),8.55-8.54(d,J＝5.6Hz,1H),8.54-8.51(d,J＝9.2Hz,1H),8.20(s,1H),7.70-7.68(d,J＝8.8Hz,2H),7.64-7.62(d,J＝8.8Hz,1H),7.50-7.48(d,J＝8.8Hz,2H),6.77-6.76(d,J＝5.6Hz,1H),5.31-5.17(m,1H),2.21-1.73(m,8H)；ESI468[M+H]+。
6-Bromo-7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝methyl,R2yield 50% of Br; MP (moving Picture experts group)>300℃；1HNMR(400MHz,DMSO)δ14.84(s,1H),10.15(s,1H),9.09(s,1H),8.67(s,1H),8.56-8.55(d,J＝6.0Hz,1H),8.17(s,1H),7.63-7.61(d,J＝8.8Hz,2H),7.47-7.45(d,J＝8.4Hz,2H),6.82-8.80(d,J＝5.6Hz,1H),4.03(s,3H)；ESI492[M+H]+。
6-Bromo-7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝i-butyl,R2Yield 62% when becoming Br; MP286-289 deg.C;1HNMR(400MHz,DMSO)δ14.82(s,1H),10.17(s,1H),9.06(s,1H),8.68(s,1H),8.58-8.56(d,J＝5.6Hz,1H),8.28(s,1H),7.59-7.57(d,J＝8.8Hz,2H),7.44-7.42(d,J＝8.8Hz,2H),6.85-6.83(d,J＝5.6Hz,1H),4.37-4.35(d,J＝7.2Hz,2H),2.07-2.00(m,1H),0.80-0.79(d,J＝6.4Hz,6H)；ESI534[M+H]+。
6-Bromo-7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-cyclohexyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝cyclohexyl,R2yield 70% when becoming Br; MP301-303 ℃;1H NMR(400MHz,DMSO)δ14.82(s,1H),10.16(s,1H),8.93(s,1H),8.70(s,1H),8.58-8.57(d,J＝5.6Hz,1H),8.45(s,1H),7.64-7.62(d,J＝8.8Hz,2H),7.46-7.44(d,J＝8.8Hz,2H),6.85-6.83(d,J＝5.6Hz,1H),4.89-4.78(m,1H),2.10-1.22(m,10H)；ESI560[M+H]+。
7-((2-((4-Cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-ethyl-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝ethyl,R2yield 21%; MP306-308 ℃;1H NMR(400MHz,DMSO)δ14.90(s,1H),10.17(s,1H),9.10(s,1H),8.86(s,1H),8.57-8.56(d,J＝5.4Hz,1H),8.17(s,1H),7.62-7.60(d,J＝7.6Hz,2H),7.44-7.42(d,J＝8.0Hz,2H),6.82-6.80(d,J＝5.6Hz,1H),4.56-4.51(q,J＝6.8Hz,2H),1.31-1.28(t,J＝6.8Hz,3H)；ESI554[M+H]+。
7-((2-((4-Cyanophenyl)amino)pyrimidin-4-yl)oxy)-6-iodo-4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝n-propyl,R2yield 66% as compared with I); MP258-260 ℃;1HNMR(400MHz,DMSO)δ14.89(s,1H),10.17(s,1H),9.09(s,1H),8.87(s,1H),8.57-8.56(d,J＝5.6Hz,1H),8.18(s,1H),7.61-7.59(d,J＝8.4Hz,2H),7.44-7.42(d,J＝8.4Hz,2H),6.82-6.80(d,J＝5.6Hz,1H),4.48-4.45(t,J＝6.8Hz,2H),1.74-1.64(m,2H),0.82-0.78(t,J＝7.2Hz,3H)；ESI568[M+H]+。
1-(tert-Butyl)-7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝O,R1＝t-butyl,R2yield 69%; MP224-226 ℃;1HNMR(400MHz,DMSO)δ14.82(s,1H),10.14(s,1H),9.05(s,1H),8.91(s,1H),8.56-8.55(d,J＝5.6Hz,1H),8.28(s,1H),7.59-7.56(d,J＝8.4Hz,2H),7.42-7.40(d,J＝8.4Hz,2H),6.81-6.80(d,J＝5.6Hz,1H),1.79(s,9H)；ESI582[M+H]+。
adding the intermediate 7(1.0mmol), the compound II (1.5mmol) and 12N hydrochloric acid (0.3mL) into isopropanol (15mL), refluxing for 12h, cooling, filtering, adjusting to isoelectric point with 1N potassium hydroxide aqueous solution, filtering, washing with water, and drying to obtain the final product I.
7-((2-((4-Cyanophenyl)amino)pyrimidin-4-yl)amino)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid(X＝N,R1＝ethyl,R2H) yield 72%; MP (moving Picture experts group)>330℃；1H NMR(400MHz,DMSO)δ10.90(s,1H),10.41(s,1H),9.02(s,1H),8.35-8.32(d,J＝8.8Hz,1H),8.25-8.23(d,J＝6.0Hz,1H),8.12(s,1H),8.09-8.07(d,J＝8.8Hz,1H),7.87-7.85(d,J＝8.8Hz,2H),7.78-7.76(d,J＝8.8Hz,2H),6.62-6.61(d,J＝6.0Hz,1H),4.45-4.40(q,J＝7.2Hz,2H),1.36-1.33(t,J＝7.2Hz,3H)；ESI427[M+H]+。
Example 8: synthesis of the end product II
Compound I (0.5mmol) was dissolved in a mixed solvent of THF (30mL) and methanol (10mL), and a hexane solution of trimethylsilyldiazomethane (0.75mmol) was slowly added thereto, followed by stirring at room temperature for 24 hours. After the reaction was completed, the reaction mixture was cooled in an ice bath and 1% aqueous acetic acid solution was added dropwise until no gas was generated. 20mL of distilled water was added, and THF and methanol were distilled off under reduced pressure. Filtering and drying to obtain a final product II.
Methyl7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate(R1＝methyl,R2H): the yield is 87%; 290 dec;1H NMR(400MHz,DMSO)δ10.14(s,1H),8.74(s,1H),8.52-8.51(d,J＝5.6Hz,1H),8.36-8.34(d,J＝8.8Hz,1H),7.73-7.71(d,J＝8.8Hz,3H),7.50-7.48(d,J＝8.4Hz,2H),7.43-7.41(dd,J＝8.4,2.0Hz,1H),6.72-6.70(d,J＝5.6Hz,1H),3.88(s,3H),3.77(s,3H)；ESI428[M+H]+。
Methyl6-bromo-7-((2-((4-cyanophenyl)amino)pyrimidin-4-yl)oxy)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate(R1＝methyl,R2br): the yield is 85 percent; 304 dec;1H NMR(400MHz,DMSO)δ10.16(s,1H),8.77(s,1H),8.55-8.54(d,J＝5.6Hz,1H),8.51(s,1H),7.95(s,1H),7.65-7.63(d,J＝8.4Hz,2H),7.44-7.43(d,J＝8.4Hz,2H),6.80-6.78(d,J＝6.0Hz,1H),3.87(s,3H),3.78(s,3H)；ESI506[M+H]+。
example 10: anti-HIV biological Activity assay
anti-HIV activity at the cellular level in vitro was determined by the Rega research institute of kathlieke university, belgium, and mainly included: inhibiting activity and cytotoxicity on HIV-infected MT-4 cells. The method is described as follows: the protective effect of the drug on HIV-induced cytopathic effect was determined by MTT method in MT-4 cells infected with HIV at different times, the half effective concentration IC50 required to protect 50% of the cells from HIV-induced cytopathic effect was calculated, toxicity was determined in parallel with the anti-HIV activity assay, and the concentration to cause 50% of the uninfected cells to develop cytopathic effect was also determined by MTT method in MT-4 cell culture (CC-4 cells)50) And calculating the selectivity index SI ═ CC50/IC50。
The material and the method are as follows:
the anti-HIV activity of each compound is controlled by the efficiency of the drug's inhibitory effect on the cytopathic effect of HIV in cells. MT-4 cells were used for cell culture. The viral strains used were: HIV-1IIIB。
The specific operation is as follows:
dissolving the compound in DMSO or water, diluting with phosphate buffered saline solution, and mixing 3 × 105MT-4 cells were pre-incubated with 100uL of each compound at various concentrations in this solution at 37 ℃ for 1h, and then 100uL of appropriate virus diluent was added to the compound and the cells were incubated at 3Culturing at 7 deg.C for 1 h. After three washes, the cells were resuspended in culture medium with or without compound, respectively. Cells were then incubated at 5% CO2Incubate at 37 ℃ for 7 more days in the 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. The cytopathic effect on the virus was monitored daily by reverse light microscopy. Typically, the viral dilutions used in this assay often lead to cytopathic effects the fifth day after viral 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 compound is poorly water soluble and requires DMSO to dissolve, the specific DMSO concentration is generally less than 10% relative to water (the final DMSO concentration 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 the solutions containing the same concentration of DMSO should also be run in parallel to the control blank. In addition, the final concentration of DMSO (1/1000) was much lower than the concentration required to affect HIV-1 replication on T cells.
In the present invention, TMC125 and Elvitegravir were used as control substances, and the results of HIV inhibitory activity of some target compounds are shown in Table 1.
TABLE 1 anti-HIV-1 Activity
Experimental results show that the compounds contained in the general formula I generally have stronger anti-HIV-1 virus activity and smaller cytotoxicity.
Any one of the above compounds and conventional pharmaceutical carriers can be made into pharmaceutical composition for treating and preventing HIV infection diseases.

Claims (12)

1. A pyrimidine ring-containing quinolone derivative having the following structural formula (I) or (II):
wherein R is1Selected from hydrogen, C1~6Alkyl radical, C3~7Cycloalkyl radical, C1~6Alkoxy, C substituted by one or more halogen atoms1~6Alkyl radicalC substituted by one or more halogen atoms2~6Alkenyl, C substituted by one or more halogen atoms3~6An alkynyl group;
R2selected from hydrogen, C1~6Alkyl radical, C3~7Cycloalkyl radical, C1~6Alkoxy, halogen atom;
R3is selected from C1~3An alkyl group;
x is selected from carbon atom, oxygen atom, nitrogen atom and sulfur atom.
2. A process for preparing a quinolone derivative containing a pyrimidine ring according to claim 1, characterized by the following reaction scheme:
in the formula, PG is benzyl or 2, 4-dimethoxybenzyl;
the specific operation steps are as follows:
(1) reacting a substituted benzoyl chloride with 3-, (N, NReaction of ethyl (dimethylamino) acrylate in toluene in the presence of triethylamine to form an intermediate1；
(2) The intermediate is reacted with a catalyst1Reacting with various amines in organic solvent to generate intermediate2；
(3) The intermediate is reacted with a catalyst2Cyclization under the action of alkali to generate intermediate3；
(4) Intermediates3Reacting in alkaline water solution for 3-8h, adjusting pH to 2-3 with acid water, filtering, washing to obtain an intermediate4；
(5) Intermediates4Reacting in alkaline water solution for 8-72h, adjusting pH to 2-3 with acid water, filtering, and washing to obtain an intermediate5；
(6) Intermediates5And compoundsIIIUnder alkaline conditionsCondensing to obtain the required compoundI；
Or,
(5) intermediate4Reacting with (substituted) benzylamine or (substituted) benzylmercaptan under the condition of alkali or no alkali to obtain intermediate6；
(6) intermediate6Deprotection to give intermediates7(ii) a Intermediates7And compoundsIIICondensing under acidic condition to obtain the required compoundI；
(7) Compound (I)IReacting with trimethylsilyldiazomethane in organic solvent to generate the needed compoundIIOr a compoundIReacting with C1-C3 alcohol under the action of acid to generate the required compoundII。
3. The method according to claim 2, wherein in the step (2), the organic solvent is dichloromethane, chloroform, DMF, tetrahydrofuran, dioxane, DMSO, or C1-C4Alcohol, a single solvent or a mixed solvent of several solvents; the reaction temperature is 25-80 ℃.
4. The production method according to claim 2, characterized in that in the step (3), the base used is a carbonate of an alkali metal: sodium, potassium or cesium carbonate, or an organic base: triethylamine, DBU or DIEPA, the organic solvent is tetrahydrofuran, dioxane, DMF, DMSO, or C1-C4Alcohol, a single solvent or a mixed solvent of several solvents; the reaction temperature is 25-110 ℃.
5. The production method according to claim 2, characterized in that in the step (4), the base used is an alkaline earth hydroxide: lithium hydroxide, sodium hydroxide or potassium hydroxide, the organic solvent being C1-C4Alcohol, tetrahydrofuran, dioxane, DMF, DMSO, a single solvent or a mixed solvent of several solvents; the reaction temperature is 25-50 ℃; the reaction time is 3-8 h.
6. The production method according to claim 2, characterized in that in the step (5), the base used is an alkaline earth hydroxide: sodium hydroxide or potassium hydroxide, wherein the organic solvent is tetrahydrofuran, dioxane, DMF, DMSO, a single solvent thereof, or a mixed solvent of several solvents thereof; the reaction temperature is 80-110 ℃; the reaction time is 8-72 h.
7. The production method according to claim 2, characterized in that in the step (6), the base used is an alkaline earth hydroxide: lithium, sodium or potassium hydroxide, or alkali metal carbonates: sodium, potassium or cesium carbonate, or an organic base: triethylamine, DBU or DIEPA, the organic solvent is DMF, tetrahydrofuran, dioxane, DMSO, or C1-C4One kind of alcohol; the reaction temperature is 60-110 ℃.
8. The method according to claim 2, wherein in step (5), the base used is an alkaline earth hydroxide: lithium, sodium, potassium or calcium hydroxide, or alkali metal carbonates: sodium, potassium or cesium carbonate, or an organic base: triethylamine, DBU or DIEPA, and organic solvent selected from DMF, tetrahydrofuran, dioxane, DMSO, and C1-C4Alcohol, a single solvent thereof, or a mixed solvent of several thereof.
9. The method according to claim 2, wherein in step (6), the deprotection agent used in the deprotection reaction is trifluoroacetic acid, the reaction solvent is dichloromethane or THF, and the reaction temperature is 25-80 ℃; or the deprotection agent is Pd/hydrogen, Pt/hydrogen or Raney Ni/hydrogen, and the reaction solvent is C1-C4Alcohol or dioxane, the reaction pressure is 1-10atm, and the reaction temperature is 25-50 ℃;
intermediates7And compoundsIIICondensation reaction under acidic condition, the acid used is SOCl2、HCl、H2SO4、H3PO4The organic solvent is DMF, tetrahydrofuran, dioxane, DMSO, or C1-C4Alcohol, wherein the reaction temperature is 60-110 ℃.
10. The method according to claim 2, wherein in the step (7), the organic solvent is DMF, tetrahydrofuran, dioxane, DMSO, C1-C4Alcohol, wherein the reaction temperature is 0-25 ℃, and the reaction temperature is a single solvent or a mixed solvent of a plurality of solvents; the acid used is SOCl2、HCl、H2SO4Or H3PO4The reaction temperature is 25-110 ℃.
11. A pharmaceutical composition comprising an effective amount of the pyrimidine ring-containing quinolone derivative of claim 1 and a pharmaceutically acceptable carrier therefor.
12. Use of a quinolone derivative containing a pyrimidine ring according to claim 1 or a pharmaceutical composition according to claim 11 for the preparation of a medicament for the treatment and prevention of aids.
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CN111732573B (en) * 2020-05-16 2022-09-16 复旦大学 Quinolone acid-aminopyrimidine compound and preparation method and application thereof
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CN112159390B (en) * 2020-09-25 2022-07-19 西南大学 Synephrine fluoroquinolone derivative and preparation method and application thereof

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