CN114507220B - Substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative and preparation method and application thereof - Google Patents
Substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative, and a preparation method and application thereof, and belongs to the technical field of medicine synthesis. The substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative provided by the invention has obvious inhibitory activity on the replication of influenza viruses, and preliminary toxicity research shows that the derivative has good drug forming property, which indicates that the derivative has good application prospect as an antiviral drug. The results of the examples show that the substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative provided by the invention has anti-IAV activity EC 50 1.20 to 11.45 mu M.
Description
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a1, 2, 4-triazole derivative with a substituted 4-phenyl-5-functionalized position, a preparation method and application thereof.
Background
Influenza A Virus (IAV) is a single-stranded negative-strand segmented RNA virus belonging to the orthomyxoviridae family. IAV infection is a serious respiratory infection that can cause respiratory tract infections, is one of the leading causes of morbidity and mortality in respiratory diseases, and has caused two pandemics of world flu (1918 and 2009). It is estimated that the flu causes 29.1 to 64.6 million deaths annually, with millions of severe cases. Influenza is caused by airborne transmission in most cases. While new or emerging IAV strains are likely to cause rapid, serious global epidemics, causing millions of deaths. Influenza B Virus (IBV) almost exclusively infects humans, and is less common than IAV because it has less genetic diversity and is susceptible to some degree of immunity to IBV in the early years.
Currently, there are only two major classes of anti-influenza drugs for influenza a and b viruses: m2 ion channel inhibitors, mainly adamantanes (including amantadine and rimantadine); neuraminidase inhibitors (including oseltamivir and zanamivir). However, the vast majority of influenza a strains are resistant to adamantanes, and there is also a growing increase in the strains that are resistant to oseltamivir and zanamivir. The FDA approved palosavir in 2018 for the treatment of uncomplicated acute influenza patients over 12 years of age, by inhibiting cap-dependent endonuclease in influenza virus. There are currently reports of influenza viruses resistant to barusavir. Therefore, the development of new anti-influenza antiviral drugs is urgently required.
Disclosure of Invention
In view of the above, the present invention aims to provide a substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative, and a preparation method and an application thereof, and the substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative provided by the present invention has a good anti-influenza virus effect.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a1, 2, 4-triazole derivative with a substituted 4-phenyl-5-site functionalized group, which has a structure shown in a formula 1:
in the formula 1, R 1 Hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;
R 2 hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;
R 3 hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino or hydroxyl;
R 4 is hydrogen, C1-C6 alkoxy or halogen;
said R is 3 、R 4 Independently of the substitution site(s) of (a) is one or more.
Preferably, the C1-C6 alkyl is C1-C6 straight-chain alkyl or C3-C6 branched-chain alkyl;
the C1-C6 alkoxy is C1-C6 straight-chain alkoxy or C3-C6 branched-chain alkoxy.
Preferably, when said R is 3 When the number of substitution sites is 1, said R 3 The substitution position of (A) is 2-position, 3-position or 4-position;
when said R is 3 When there are more than one substitution sites, the R is 3 The substituted position(s) of (b) is any of a plurality of positions from the 2-position to the 6-position.
The invention provides a preparation method of the substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative, which comprises the following steps:
carrying out a first substitution reaction on a compound with a structure shown in a formula a and hydrazine hydrate to obtain a compound with a structure shown in a formula b;
carrying out a second substitution reaction on the compound shown in the formula c and N, N-dimethyl thiocarbonyl chloride to obtain a compound shown in a formula d;
under the alkaline condition, carrying out cyclization reaction on a compound shown as a formula b and a compound shown as a formula d to obtain a compound shown as a formula e;
under the alkaline condition, carrying out a third substitution reaction on the compound with the structure shown in the formula e and the compound with the structure shown in the formula f to obtain a compound with the structure shown in the formula 1;
preferably, the temperature of the first substitution reaction is 60-100 ℃ and the time is 8-36 h.
Preferably, the temperature of the second substitution reaction is 80-120 ℃ and the time is 1-8 h.
Preferably, the temperature of the third substitution reaction is 20-80 ℃ and the time is 0.5-2 h.
Preferably, the alkaline agent providing the alkaline condition is one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide.
The invention provides application of the substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative in preparing anti-influenza virus medicaments.
The invention provides an anti-influenza virus medicine composition which comprises a1, 2, 4-triazole derivative with a substituted 4-phenyl-5-position functionalized structure shown in a formula 1 or a pharmaceutically acceptable salt of the 1,2, 4-triazole derivative with the substituted 4-phenyl-5-position functionalized structure shown in the formula 1.
The invention provides a substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative which has a structure shown in a formula 1. The substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative provided by the invention can inhibit RNA-dependent RNA polymerase of influenza virus, has obvious inhibitory activity on the replication of influenza virus, and has good drug forming property as shown by preliminary toxicity research, which indicates that the derivative has good application prospect as an antiviral drug. The results of the examples show that the substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative provided by the invention has anti-IAV activity EC 50 Is 1.20-11.45 mu M.
Detailed Description
The invention provides a1, 2, 4-triazole derivative with a substituted 4-phenyl-5-site functionalized group, which has a structure shown in a formula 1:
in the formula 1, R 1 Hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen; in the present invention, the C1-C6 alkyl group is preferably a C1-C6 straight-chain alkyl group or a C3-C6 branched-chain alkyl group; in the present invention, the C1 to C6 linear alkyl group is preferably a methyl group or an ethyl group, and the C3 to C6 branched alkyl group is preferably an isopropyl group or a tert-butyl group.
In the present invention, the C1 to C6 alkoxy group is preferably a C1 to C6 linear alkoxy group or a C3 to C6 branched alkoxy group; in the present invention, the C1-C6 linear alkoxy group is preferably a methoxy group or an ethoxy group, and the C3-C6 branched alkoxy group is preferably an isopropoxy group or a tert-butoxy group.
In the present invention, the halogen is preferably fluorine, chlorine, bromine or iodine.
In the formula 1, R 2 Hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen; in the present invention, the preferred species of the C1-C6 alkyl group, C1-C6 alkoxy group or halogen is the same as above, and thus, the description thereof is omitted.
In the formula 1, R 3 Is hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxyTrifluoromethyl, trifluoromethoxy, cyano, nitro, amino, or hydroxy. In the present invention, the halogen is preferably fluorine, chlorine, bromine or iodine; in the present invention, the C1-C6 alkyl group is preferably a C1-C6 straight-chain alkyl group or a C3-C6 branched-chain alkyl group; the C1-C6 alkoxy is preferably C1-C6 linear alkoxy or C3-C6 branched alkoxy. In the present invention, the C1-C6 linear alkyl group is preferably a methyl group or an ethyl group, and the C3-C6 branched alkyl group is preferably an isopropyl group or a tert-butyl group. In the present invention, the C1 to C6 linear alkoxy group is preferably a methoxy group or an ethoxy group, and the C3 to C6 branched alkoxy group is preferably an isopropoxy group or a tert-butoxy group.
In the formula 1, R 4 Is hydrogen, C1-C6 alkoxy or halogen; in the present invention, the C1 to C6 alkoxy group is preferably a C1 to C6 linear alkoxy group or a C3 to C6 branched alkoxy group; in the present invention, the C1-C6 linear alkoxy group is preferably a methoxy group or an ethoxy group, and the C3-C6 branched alkoxy group is preferably an isopropoxy group or a tert-butoxy group. In the present invention, the halogen is preferably fluorine, chlorine, bromine or iodine.
In the present invention, said R 3 、R 4 Independently of one or more of the substitution sites of (a).
In the present invention, when said R is 3 When the number of the substitution sites is 1, the R is 3 The substitution position of (A) is preferably the 2-position, 3-position or 4-position;
when said R is 3 When there are more than one substitution sites, the R is 3 The substitution position(s) is preferably any of a plurality of positions from 2-position to 6-position.
As a specific example of the present invention, the substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative has the structures shown in formulas 2 to 55, and is specifically shown in Table 1.
TABLE 1 Structure of substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivatives
The invention provides a preparation method of the substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative, which comprises the following steps:
carrying out a first substitution reaction on a compound with a structure shown in a formula a and hydrazine hydrate to obtain a compound with a structure shown in a formula b;
carrying out a second substitution reaction on the compound shown as the formula c and N, N-dimethyl thiocarbonyl chloride to obtain a compound shown as a formula d;
under the alkaline condition, carrying out cyclization reaction on a compound shown as a formula b and a compound shown as a formula d to obtain a compound shown as a formula e;
under the alkaline condition, carrying out a third substitution reaction on the compound with the structure shown in the formula e and the compound with the structure shown in the formula f to obtain a compound with the structure shown in the formula 1;
in the present invention, a compound having a structure represented by formula a is subjected to a first substitution reaction with hydrazine hydrate to obtain a compound having a structure represented by formula b.
In the present invention, the source of the compound having formula a is preferably commercially available or prepared by itself. When the compound having the formula a is prepared by itself, the preparation method is preferably prepared according to the method of European Journal of Medicinal Chemistry,2020, volume 186, 111861.
In the present invention, the molar ratio of the compound having the structure represented by formula a to hydrazine hydrate is preferably 1. In the present invention, the solvent for the first substitution reaction is preferably ethanol.
In the present invention, the temperature of the first substitution reaction is preferably 95 ℃ and the time is preferably 24 hours.
After the first substitution reaction, the present invention preferably performs a post-treatment on the obtained first substitution reaction liquid, and the post-treatment preferably includes the steps of:
and (3) sequentially removing the solvent from the first substitution reaction solution and performing reversed-phase column chromatography to obtain a pure compound product with the structure shown in the formula b.
In the present invention, the solvent is preferably removed by evaporating the solvent. In the present invention, the stationary phase of the reverse phase column chromatography is preferably C18 packing, and the elution phase is preferably methanol and water.
In the invention, the compound shown in the formula c and N, N-dimethyl thiocarbonyl chloride are subjected to secondary substitution reaction to obtain the compound shown in the formula d.
In the present invention, the molar ratio of the compound having the structure represented by formula c to N, N-dimethylthiocarbonyl chloride is preferably 1.8 to 1.2, more preferably 1.1. In the present invention, the solvent for the second substitution reaction is preferably toluene.
In the present invention, the temperature of the second substitution reaction is preferably 120 ℃ and the time is preferably 3 to 8 hours, and more preferably 4 to 6 hours.
In the present invention, after the second substitution reaction, the substitution reaction liquid obtained in the present invention is preferably subjected to a post-treatment, and the post-treatment preferably comprises the steps of:
and (3) sequentially carrying out solid-liquid separation on the second substitution reaction liquid, and concentrating and carrying out column chromatography on the obtained liquid to obtain a pure compound product with the structure shown in the formula d.
In the present invention, the solid-liquid separation is preferably performed by suction filtration, and the concentration is preferably performed by evaporation concentration. In the invention, the stationary phase of the column chromatography is preferably C18 packing, and the mobile phase is preferably methanol and water.
In the invention, a compound shown as a formula b and a compound shown as a formula d undergo a cyclization reaction under an alkaline condition to obtain a compound shown as a formula e.
In the present invention, the molar ratio of the compound represented by formula b to the compound represented by formula d is preferably 1. In the present invention, the solvent for the cyclization reaction is preferably absolute ethanol.
In the invention, the alkaline reagent providing the alkaline condition is one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide; in the invention, the alkali metal carbonate is preferably one or more of potassium carbonate, cesium carbonate, lithium carbonate and sodium carbonate; the alkali metal hydride is preferably sodium hydride; the alkali metal hydroxide is preferably one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide.
In the present invention, the molar ratio of the compound represented by formula b to the basic agent is preferably 1 to 5, more preferably 1.
In the invention, the compound shown in the formula b and the compound shown in the formula d are preferably refluxed and mixed, and then an alkaline reagent is added for cyclization. In the present invention, the time for the reflux mixing is preferably 3 hours.
In the present invention, the temperature of the cyclization reaction is preferably reflux temperature, and the time is preferably 1.5h.
In the present invention, after the cyclization reaction, in the present invention, it is preferable that the obtained cyclization reaction solution is subjected to solid-liquid separation, and the obtained solid is a compound having a structure represented by formula e. In the present invention, the solid-liquid separation method is preferably suction filtration.
In the invention, under alkaline conditions, the compound with the structure shown in the formula e and the compound with the structure shown in the formula f are subjected to a third substitution reaction to obtain the compound with the structure shown in the formula 1.
In the present invention, the molar ratio of the compound having the structure represented by formula e to the compound having the structure represented by formula f is preferably 1.8 to 1.
In the invention, the alkaline reagent providing the alkaline condition is one or more of alkali metal carbonate, alkali metal hydride and alkali metal hydroxide; in the invention, the alkali metal carbonate is preferably one or more of potassium carbonate, cesium carbonate, lithium carbonate and sodium carbonate; the alkali metal hydride is preferably sodium hydride; the alkali metal hydroxide is preferably one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide.
In the present invention, the molar ratio of the compound having the structure represented by formula e to the basic agent is preferably 1.
In the present invention, the solvent for the third substitution reaction is preferably N, N-dimethylformamide.
In the present invention, the temperature of the third substitution reaction is preferably room temperature, and the time is preferably 0.5 to 2 hours, and more preferably 1 hour.
In the present invention, after the third substitution reaction, the obtained third substitution reaction liquid is preferably subjected to a post-treatment in the present invention, and the post-treatment preferably includes:
and mixing the third substitution reaction liquid with water, and carrying out solid-liquid separation on the obtained mixed liquid to obtain a compound solid with the structure shown in the formula 1.
In the present invention, the solid-liquid separation method is preferably suction filtration.
In the invention, the substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative and the synthetic route are shown as the formula A:
the invention provides application of the substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative in preparing anti-influenza virus medicaments. In the present invention, the influenza virus preferably includes influenza a virus and/or influenza b virus.
The invention provides an anti-influenza virus pharmaceutical composition, which comprises a1, 2, 4-triazole derivative with a structure shown in formula 1 and functionalized at a substituted 4-phenyl-5-position or a pharmaceutically acceptable salt of the 1,2, 4-triazole derivative with the structure shown in formula 1 and functionalized at the substituted 4-phenyl-5-position.
In the present invention, the pharmaceutically acceptable salt preferably includes pharmaceutically acceptable salts derived from inorganic acids, organic acids or inorganic bases.
In the invention, the organic acid is preferably one or more of hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; the organic acid is preferably one or more of oxalic acid, maleic acid, succinic acid and citric acid.
In the invention, the inorganic base is preferably one or more of hydroxide, carbonate and bicarbonate of metal cation; the metal in the metal cation is preferably one or more of lithium, sodium, potassium, calcium, magnesium and aluminum.
The substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivatives provided by the present invention, and the preparation method and application thereof are described in detail in the following examples, but they should not be construed as limiting the scope of the present invention.
Example 1
Preparation of 3- (((5- ((2-cyanobenzyl) thio) -4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) methylene) thio) -1-methyl-1H-indole A1
1) Preparation of Compound 2
Compound 1 (2.5g, 10mmol) (prepared according to the method of European Journal of Medicinal Chemistry,2020, volume 186, 111861) was dissolved in 30mL of ethanol, and 80% hydrazine hydrate (7mL, 110mmol) was added thereto, and the mixture was refluxed at 95 ℃ for 24 hours. The solvent was evaporated and product 2 (2.3 g, 98%) was reverse phase column chromatographed.
1 H NMR(500MHz,DMSO)δ9.00(s,1H),7.61(d,J＝7.9Hz,1H),7.50(s,1H),7.46(d,J＝8.2Hz,1H),7.21(t,J＝1.2Hz,1H),7.13(t,1H),4.17(s,2H),3.77(s,3H),3.22(s,2H).
2) Preparation of Compound 4
Dissolving 2, 6-dimethylaniline (3.73g, 30.86mmol) in 30mL of anhydrous toluene, adding N, N-dimethylthiocarbonyl chloride (4.2g, 33.95mmol), refluxing at 120 ℃ for 3h, cooling to room temperature, filtering to obtain filtrate, concentrating and evaporating to dryness, and performing column chromatography to obtain colorless liquid, namely the product 4 (4.5g, 90%).
3) Preparation of Compound 5
Dissolving the compound 2 (2.88g, 12.27mmol) and the compound 4 (2g, 12.27mmol) in 25mL of absolute ethyl alcohol, refluxing for 3 hours until the raw materials disappear, cooling to room temperature, and performing suction filtration to obtain filtrate and evaporate to dryness; 20mL of a 2N aqueous solution of sodium hydroxide was added thereto, and the mixture was refluxed by 1.5mL. After cooling to room temperature, the product 5 (3.8g, 82%) was obtained by suction filtration.
1 H NMR(500MHz,DMSO)δ13.83(s,1H),7.47(d,J＝8.2Hz,1H),7.42(s,1H),7.39(t,J＝7.8Hz,1H),7.28(d,J＝7.6Hz,2H),7.24(d,J＝7.9Hz,1H),7.21(t,J＝7.6Hz,1H),7.07(t,J＝7.4Hz,1H),3.76(s,3H),3.53(s,2H),2.04(s,6H).
4) Preparation of Compound A1
Compound 5 (100mg, 0.26mmol) was dissolved in 2mL of anhydrous N, N-dimethylformamide, and cesium carbonate (129mg, 0.40mmol) and 2-cyanobenzyl bromide (51mg, 0.26mmol) were added and reacted at room temperature for 1 hour. The reaction was dropped into 50mL of water and the cake was taken by suction filtration as product A1 (111mg, 86%) with the precipitation of a large amount of white solid.
1 H NMR(500MHz,CDCl 3 )δ7.76(d,J＝7.8Hz,1H),7.62(d,J＝9.4Hz,1H),7.50(t,J＝3.8Hz,1H),7.35(d,J＝6.9,3.0Hz,2H),7.30(d,J＝8.1Hz,2H),7.27–7.20(m,2H),7.19(d,J＝7.6Hz,2H),7.09(t,J＝7.6Hz,2H),7.06(s,1H),4.69(s,2H),3.75(s,3H),3.70(s,2H),1.92(s,6H). 13 C NMR(101MHz,CDCl3)δ153.30,150.78,140.84,137.24,136.39,134.57,133.04,132.95,130.95,130.60,130.41,129.36,129.20(2C),128.29,122.39,120.27,118.86,117.20,112.70,109.75,102.03,33.98,33.09,30.35,29.74,17.79(2C).
Example 2
Preparation of 3- (((5- ((2-fluoro-6-chlorobenzyl) thio) -4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) methylene) thio) -1-methyl-1H-indole A2
Compound 5 (100mg, 0.26mmol) obtained in example 1 was dissolved in 2mL of anhydrous N, N-dimethylformamide, and cesium carbonate (129mg, 0.40mmol) and 2-fluoro-3-chlorobenzyl bromide (75mg, 0.26mmol) were added to react at room temperature for 1 hour. The reaction was dropped into 50mL of water and the cake was taken as product A1 (113mg, 83%) by suction filtration as a large amount of white solid precipitated out.
1 H NMR(500MHz,CDCl 3 )δ7.37(t,J＝7.6Hz,1H),7.33(t,2H),7.28(d,J＝5.4Hz,1H),7.22(d,J＝7.5Hz,3H),7.18(dd,J＝8.3,1.7Hz,1H),7.13(d,J＝7.6Hz,1H),7.10(s,1H),6.99(t,J＝8.1Hz,1H),4.77(s,2H),3.78(s,3H),3.76(s,2H),2.07(s,6H).
Example 3
Preparation of 3- (((5- ((4-methoxybenzyl) thio) -4- (2, 6-dimethylphenyl) -4H-1,2, 4-triazol-3-yl) methylene) thio) -1-methyl-1H-indole A3
Compound 5 (100mg, 0.26mmol) obtained in example 1 was dissolved in 2mL of anhydrous N, N-dimethylformamide, and cesium carbonate (129mg, 0.40mmol) and 4-methoxybenzyl bromide (52mg, 0.26mmol) were added and reacted at room temperature for 1h. The reaction was dropped into 50mL of water and the large amount of white solid precipitated and was filtered off with suction to give the filter cake as product A3 (122mg, 94%).
1 H NMR(500MHz,DMSO)δ7.45(d,J＝8.1Hz,1H),7.40(t,J＝7.7Hz,1H),7.34(s,1H),7.28(d,J＝2.8Hz,2H),7.26(d,J＝3.6Hz,2H),7.19(t,J＝7.6Hz,1H),7.14(d,J＝7.9Hz,1H),7.03(t,J＝7.4Hz,1H),6.84(d,J＝8.7Hz,2H),4.38(s,2H),3.75(s,3H),3.71(s,3H),3.68(s,2H),1.85(s,6H). 13 C NMR(101MHz,DMSO)δ159.11,152.53,150.59,137.40,136.36(2C),135.30,131.08,130.76,130.63(2C),129.46,129.41(2C),129.18,122.45,120.39,118.59,114.26(2C),110.90,101.01,55.56,35.38,33.11,30.18,17.68(2C)。
Example 4
Preparation of 3- (((5- ((3-chloro-4-trifluoromethoxybenzyl) thio) -4- (2, 6-dichlorophenyl) -4H-1,2, 4-triazol-3-yl) methylene) thio) -1-methyl-1H-indole A21
1) Preparation of Compound 7
Dissolving 2, 6-dichloroaniline (5.0 g, 30.86mmol) in 30mL of anhydrous toluene, adding N, N-dimethylthiocarbonyl chloride (4.2g, 33.95mmol), refluxing at 120 ℃ for 8h, cooling to room temperature, suction filtering to obtain filtrate, concentrating and evaporating to dryness, and performing column chromatography to obtain colorless liquid, namely a product 7 (6.3g, 64%).
2) Preparation of Compound 8
Dissolving the compound 2 (2.88g, 12.27mmol) and the compound 7 (2.5g, 12.27mmol) in 25mL of absolute ethyl alcohol, refluxing for 6 hours until the raw materials disappear, cooling to room temperature, and filtering to obtain filtrate and evaporating to dryness; 20mL of a 2N aqueous solution of sodium hydroxide was added thereto, and the mixture was refluxed by 1.5mL. Cool to room temperature and pump filter to yield product 8 (5.1g, 76%).
1 H NMR(500MHz,DMSO)δ13.90(s,1H),7.77(d,J＝8.2Hz,2H),7.69–7.63(m,1H),7.47(d,J＝8.2Hz,1H),7.41(s,1H),7.36(d,J＝7.9Hz,1H),7.21(t,J＝7.7Hz,1H),7.09(t,J＝7.5Hz,1H),3.77(s,3H),3.64(s,2H)。
3) Preparation of Compound A21
Compound 8 (110mg, 0.26mmol) was dissolved in 2mL of anhydrous N, N-dimethylformamide, and cesium carbonate (129mg, 0.40mmol) and 2-chloro-4-trifluoromethoxybenzyl bromide (75mg, 0.26mmol) were added to react at room temperature for 1h. The reaction was dropped into 50mL of water and the cake was taken by suction filtration as product A21 (134mg, 82%) with the evolution of a large amount of white solid.
1 H NMR(500MHz,DMSO)δ7.74(d,J＝8.2Hz,2H),7.66(t,1H),7.62(s,1H),7.46(dd,J＝12.5,8.3Hz,2H),7.40(d,J＝7.7Hz,1H),7.29(d,J＝3.0Hz,1H),7.26(d,J＝7.8Hz,1H),7.20(t,J＝7.6Hz,1H),7.05(t,J＝7.5Hz,1H),4.41(s,2H),3.78(s,2H),3.74(s,3H). 13 C NMR(101MHz,DMSO)δ153.14,150.39,143.61,143.59,139.56,137.44,135.51,133.94(2C),133.63,131.60,130.04(2C),129.91,129.14,128.37,126.16,123.49,122.43,120.39,118.51,110.94,100.39,35.32,33.11,30.18。
Example 5
Preparation of 3- (((5- ((2-trifluoromethyl-4-chlorobenzyl) thio) -4- (2, 6-dichlorophenyl) -4H-1,2, 4-triazol-3-yl) methylene) thio) -1-methyl-1H-indole A23
Compound 8 (110mg, 0.26mmol) obtained in example 4 was dissolved in 2mL of anhydrous N, N-dimethylformamide, and cesium carbonate (129mg, 0.40mmol) and 2-trifluoromethyl-4-chlorobenzyl bromide (71mg, 0.26mmol) were added and reacted at room temperature for 1 hour. The reaction was dropped into 50mL of water and the cake was taken by suction filtration as product A23 (129mg, 81%) as a large amount of white solid.
1 H NMR(500MHz,DMSO)δ7.77(d,J＝2.6Hz,2H),7.75(s,1H),7.72(dd,J＝8.2,2.2Hz,1H),7.67(d,J＝7.4Hz,1H),7.64(t,J＝6.5Hz,1H),7.45(d,J＝8.2Hz,1H),7.32(s,1H),7.27(d,J＝7.9Hz,1H),7.20(t,J＝7.6Hz,1H),7.06(t,J＝7.5Hz,1H),4.52(s,2H),3.81(s,2H),3.75(s,3H). 13 C NMR(101MHz,DMSO)δ153.36,150.04,137.44,135.57,134.41,134.39,134.33,133.92,133.68,133.53,133.21,130.07(2C),129.15,128.28,126.75,126.69,125.07,122.44,120.40,118.51,110.95,100.33,33.40,33.12,30.17.
Example 6
Preparation of 3- (((5- ((2-trifluoromethoxybenzyl) thio) -4-phenyl-4H-1, 2, 4-triazol-3-yl) methylene) thio) -1-methyl-1H-indole A64
1) Preparation of Compound 10
Aniline (2.9 g, 30.86mmol) is dissolved in 30mL of anhydrous toluene, N-dimethylthiocarbonyl chloride (4.2 g, 33.95mmol) is added, the mixture is refluxed at 120 ℃ for 4h, cooled to room temperature, filtered, concentrated and evaporated to dryness, and the colorless liquid obtained after column chromatography is the product 4 (3.5 g, 83%).
2) Preparation of Compound 11
Dissolving the compound 2 (2.9g, 12.27mmol) and the compound 7 (1.7g, 12.27mmol) in 25mL of absolute ethyl alcohol, refluxing for 5h, removing the raw materials, cooling to room temperature, and carrying out suction filtration to obtain filtrate and evaporate to dryness; 20mL of 2N aqueous sodium hydroxide solution was added, and the mixture was refluxed at 1.5mL. After cooling to room temperature, the reaction mixture was filtered with suction to give product 11 (3.5g, 81%).
1 H NMR(500MHz,DMSO)δ13.65(s,1H),7.50(td,J＝5.2,1.8Hz,3H),7.46(d,J＝8.2Hz,1H),7.38(s,1H),7.31(t,2H),7.25(d,J＝7.9Hz,1H),7.20(t,J＝7.6Hz,1H),7.07(t,J＝7.5Hz,1H),3.75(s,3H),3.71(s,2H)。
3) Preparation of Compound A64
Compound 11 (92mg, 0.26mmol) was dissolved in 2mL of anhydrous N, N-dimethylformamide, and cesium carbonate (129mg, 0.40mmol) and 2-trifluoromethoxybenzyl bromide (66mg, 0.26mmol) were added and reacted at room temperature for 1h. The reaction was dropped into 50mL of water and the cake was taken by suction filtration as product A64 (129mg, 81%) as a large amount of white solid.
1 H NMR(500MHz,DMSO)δ7.49(t,J＝8.3Hz,2H),7.45(d,2H),7.42(d,J＝7.6Hz,2H),7.33(t,J＝7.8Hz,2H),7.28(s,1H),7.19(t,J＝7.6Hz,1H),7.11(d,J＝7.9Hz,1H),7.03(t,J＝7.6Hz,2H),6.99(d,J＝7.5Hz,1H),4.33(s,2H),3.84(s,2H),3.72(s,3H). 13 C NMR(101MHz,DMSO)δ153.97,149.93,147.10,137.37,135.64,133.02,132.04,130.21,130.13,129.97(2C),129.69,129.64,127.88,127.44(2C),122.36,120.74,120.35,119.24,118.53,110.80,100.54,33.05,31.34,30.44。
Performance testing
Evaluation of in vitro antiviral Activity and cytotoxicity test
293T-GLUC cells are taken as virus hosts, and the activity of the luciferase of the reporter gene carried by the influenza A virus is inhibited by a test sample.
Virus strain: infection of MDCK cells to obtain IAV (titer 10) 7 ) And storing at-80 ℃.
Sample treatment: samples were dissolved in DMSO to make appropriate initial concentrations and diluted with culture medium at 5 dilutions each.
The test method comprises the following steps: 293T-GLUC cells inoculated into 96-well plates, 5% CO 2 Incubated at 37 ℃ for 24 hours. The drug was added beforehand and incubated for 2 hours, and then the virus was inoculated with diluted provirus at MOI = 0.3. After 24 hours of culture, luciferase activity in the infected cells was measured, and the inhibition rate and EC of each sample were calculated 50 . The experiment was repeated three times and the results are shown in table 2.
The detection was carried out using CCK-8 (CellCountingkit-8) kit. HEK293T cells were seeded in 96-well plates at 2.5X 10 per well 4 Each cell was cultured in 100. Mu.L of 10% FBS-containing DMEM medium. After 24h of cell plating, 1. Mu.L of test compound was added to each well in a gradient and incubated at 37 ℃ for 24h. Adding 10 mu LCCK-8 reagent into each hole, continuously incubating for 1-2 hours at 37 ℃, and detecting the light absorption value of each hole at the wavelength of 450nm by using an Enspire2300 multifunctional microplate reader to calculate the half cytotoxicity concentration CC 50 (refers to the concentration of drug that causes 50% cell death). The experiment was repeated three times and the results are shown in table 2.
The inhibitory effect and toxicity of the partial derivatives of formula 1 of the present invention against influenza a virus are listed in table 2. Wherein the positive control drug ribavirin (ribavirin) is used as a comparative example.
In vitro anti-influenza virus activity and cytotoxicity of partial derivatives of Table 2
Experimental results show that all the test compounds in the table 1 have obvious inhibition effect on influenza A virus, and the activity of most compounds is superior to that of a positive control medicament ribavirin on a cellular level, which indicates that the structure has further research value.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (10)
1. A1, 2, 4-triazole derivative with a substituted 4-phenyl-5-position functionalized group has a structure shown in a formula 1:
in the formula 1, R 1 Hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;
R 2 hydrogen, C1-C6 alkyl, C1-C6 alkoxy or halogen;
R 3 hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, trifluoromethyl, trifluoromethoxy, cyano, nitro, amino or hydroxyl;
R 4 is hydrogen, C1-C6 alkoxy or halogen;
the R is 3 、R 4 Independently of the substitution site(s) of (a) is one or more.
2. The substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative of claim 1, wherein the C1-C6 alkyl is a C1-C6 straight-chain alkyl or a C3-C6 branched-chain alkyl;
the C1-C6 alkoxy is C1-C6 straight-chain alkoxy or C3-C6 branched-chain alkoxy.
3. The substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative of claim 1, wherein when R is 3 When the number of substitution sites is 1, said R 3 The substitution position of (A) is 2-position, 3-position or 4-position;
when said R is 3 When there are more than one substitution sites, the R is 3 The substitution position(s) is any of a plurality of positions from 2-position to 6-position.
4. A process for the preparation of a substituted 4-phenyl-5-functionalized 1,2, 4-triazole derivative according to any one of claims 1 to 3, comprising the steps of:
carrying out a first substitution reaction on a compound with a structure shown in a formula a and hydrazine hydrate to obtain a compound with a structure shown in a formula b;
carrying out a second substitution reaction on the compound shown as the formula c and N, N-dimethyl thiocarbonyl chloride to obtain a compound shown as a formula d;
under the alkaline condition, carrying out cyclization reaction on a compound shown as a formula b and a compound shown as a formula d to obtain a compound shown as a formula e;
under the alkaline condition, carrying out a third substitution reaction on the compound with the structure shown in the formula e and the compound with the structure shown in the formula f to obtain a compound with the structure shown in the formula 1;
5. the process according to claim 4, wherein the first substitution reaction is carried out at a temperature of 60 to 100 ℃ for 8 to 36 hours.
6. The process according to claim 4, wherein the second substitution reaction is carried out at a temperature of 80 to 120 ℃ for 1 to 8 hours.
7. The preparation method according to claim 4, wherein the temperature of the third substitution reaction is 20-80 ℃ and the time is 0.5-2 h.
8. The method according to claim 4 or 7, wherein the alkaline agent providing the alkaline condition is one or more of alkali metal carbonate, alkali metal hydride, and alkali metal hydroxide.
9. Use of the substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative as defined in any one of claims 1 to 3 or the substituted 4-phenyl-5-position functionalized 1,2, 4-triazole derivative prepared by the preparation method as defined in any one of claims 4 to 8 in the preparation of a medicament for treating influenza virus.
10. An anti-influenza virus pharmaceutical composition comprises a1, 2, 4-triazole derivative with a substituted 4-phenyl-5-position functionalized structure shown as a formula 1 or a pharmaceutically acceptable salt of the 1,2, 4-triazole derivative with the substituted 4-phenyl-5-position functionalized structure shown as the formula 1.
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| JP2005170939A (en) * | 2003-11-20 | 2005-06-30 | Takeda Chem Ind Ltd | Prophylactic/therapeutic agent for diabetes |
| CN1930132A (en) * | 2004-03-08 | 2007-03-14 | 惠氏公司 | Ion channel modulators |
| WO2009011850A2 (en) * | 2007-07-16 | 2009-01-22 | Abbott Laboratories | Novel therapeutic compounds |
| CN103209977A (en) * | 2010-09-28 | 2013-07-17 | 百时美施贵宝公司 | Novel piperazine analogs with substituted heteroaryl groups as broad-spectrum influenza antivirals |
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| JP2005170939A (en) * | 2003-11-20 | 2005-06-30 | Takeda Chem Ind Ltd | Prophylactic/therapeutic agent for diabetes |
| CN1930132A (en) * | 2004-03-08 | 2007-03-14 | 惠氏公司 | Ion channel modulators |
| WO2009011850A2 (en) * | 2007-07-16 | 2009-01-22 | Abbott Laboratories | Novel therapeutic compounds |
| CN103209977A (en) * | 2010-09-28 | 2013-07-17 | 百时美施贵宝公司 | Novel piperazine analogs with substituted heteroaryl groups as broad-spectrum influenza antivirals |
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| "Evaluation of selected 3D virtual screening tools for the prospective identification of peroxisome proliferator-activated receptor (PPAR)γ partial agonists";T. Kaserer等;《European Journal of Medicinal Chemistry》;20160806;第124卷;第49-62页 * |
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