CN109053606B - 4- (4-hydroxyphenylmethyleneamino) -1,2, 4-triazole-5-thione and application thereof - Google Patents
4- (4-hydroxyphenylmethyleneamino) -1,2, 4-triazole-5-thione and application thereof Download PDFInfo
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- CN109053606B CN109053606B CN201811016751.7A CN201811016751A CN109053606B CN 109053606 B CN109053606 B CN 109053606B CN 201811016751 A CN201811016751 A CN 201811016751A CN 109053606 B CN109053606 B CN 109053606B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D249/12—Oxygen or sulfur atoms
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
Abstract
The invention provides a 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thioketone shown as a structural formula I, a preparation method thereof and application thereof in preparing influenza virus neuraminidase inhibitors:
wherein R is1Selected from: hydrogen, C1～C2Alkyl radical, C3～C7Straight chain or C3～C7Branched alkyl, fluoro, chloro, bromo, iodo; phenyl, 4-fluorophenyl; x is selected from: H. fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl; r is selected from: hydrogen, methoxy, ethoxy, C3～C4Straight-chain alkoxy or C3～C4A branched alkoxy group.
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thioketone and application thereof in preparing influenza virus neuraminidase inhibitors.
Background
4- (arylmethyleneamino) -3-alkyl-1H-1, 2, 4-triazole-5 (4H) -thione (1) and its biological activity are summarized below:
disclosure of Invention
The technical problem to be solved by the invention is to provide 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione, a preparation method, a pharmaceutical composition and application thereof.
In order to solve the technical problem, the invention provides the following technical scheme:
in a first aspect, the present invention provides a class of 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thiones having the formula i:
wherein R is1Selected from: c2Alkyl radical, C3～C7Straight chain or C3～C7Branched alkyl, fluoro, chloro, bromo, iodo; phenyl, 4-fluorophenyl; x is selected from: H. fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl; r is selected from: hydrogen, methoxy, ethoxy, C3～C4Straight-chain alkoxy or C3～C4A branched alkoxy group;
or, R1Selected from: c1～C2Alkyl radical, C3～C7Straight chain or C3～C7Branched alkyl, fluoro, chloro, bromo, iodo; phenyl, 4-fluorophenyl; x is selected from: fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl; r is selected from: hydrogen, methoxy, ethoxy, C3～C4Straight-chain alkoxy or C3～C4A branched alkoxy group.
The first aspect of the present invention also provides a class of 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thiones, selected from the following compounds:
in a second aspect of the present invention, there is provided a process for producing 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione, which comprises the following steps:
wherein R is1Selected from: c2Alkyl radical, C3～C7Straight chain or C3～C7Branched alkyl, fluoro, chloro, bromo, iodo; phenyl, 4-fluorophenyl; x is selected from: H. fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl; r is selected from: hydrogen, methoxy, ethoxy, C3～C4Straight-chain alkoxy or C3～C4A branched alkoxy group;
or, R1Selected from: c1～C2Alkyl radical, C3～C7Straight chain or C3～C7Branched alkyl, fluoro, chloro, bromo, iodo; phenyl, 4-fluorophenyl; x is selected from: fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl; r is selected from: hydrogen, methoxy, ethoxy, C3～C4Straight-chain alkoxy or C3～C4A branched alkoxy group.
In a third aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the first aspect and pharmaceutically acceptable salts thereof, said pharmaceutical composition comprising a therapeutically effective amount of a 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione and pharmaceutically acceptable salts thereof, according to the invention, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and the pharmaceutically acceptable salt thereof in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection. In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired. For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
In a fourth aspect of the present invention, there is provided a use of the 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione and pharmaceutically acceptable salts thereof according to the present invention and the pharmaceutical composition according to the third aspect for the preparation of influenza virus neuraminidase inhibitors:
wherein R is1Selected from: hydrogen, C1～C2Alkyl radical, C3～C7Straight chain or C3～C7Branched alkyl, fluoro, chloro, bromo, iodo; phenyl, 4-fluorophenyl; x is selected from: H. fluorine, chlorine, bromine, iodine, methyl, ethyl, amino or hydroxyl; r is selected from: hydrogen, methoxy, ethoxy, C3～C4Straight-chain alkoxy or C3～C4A branched alkoxy group.
The beneficial technical effects are as follows:
the 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione is a novel compound with influenza virus neuraminidase inhibitory activity.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-methyl-1H-1, 2, 4-triazole-5 (4H) -thione
0.26g (2.0mmol) of 4-amino-3-methyl-1H-1, 2, 4-triazole-5 (4H) -thione, 0.33g (2.2mmol) of vanillin and 3mL of acetic acid are subjected to reflux reaction for 4 hours, cooled, filtered, washed by dichloromethane or ethanol, recrystallized by ethanol and dried to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-methyl-1H-1, 2, 4-triazole-5 (4H) -thione, wherein the yield is 81.4 percent and m.p.229-231 ℃.1H NMR(400MHz,DMSO-d6)δ:13.64(s,1H,NH),9.98(s,1H,OH),9.60(s,1H,NCH),7.50(d,J＝1.8Hz,1H,C6H3 2-H),7.35(dd,J＝8.0,1.8Hz,1H,C6H3),6.96(d,J＝8.0Hz,1H,C6H3),3.88(s,3H,OCH3),2.36(s,3H,CH3).13C NMR(100MHz,DMSO-d6)δ:165.24,161.71,151.85,148.61,148.55,124.78,123.77,116.11,110.96,56.14,11.23。
Example 2
Preparation of 4- (4-hydroxyphenylmethyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione and 4-hydroxybenzaldehyde for 2.5H to obtain white solid 4- (4-hydroxyphenylmethyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione with the yield of 56.5 percent and m.p.247-250 ℃.1H NMR(400MHz,DMSO)δ:13.68(s,1H,NH),10.37(s,1H,OH),9.59(s,1H,NCH),7.75(d,J＝8.4Hz,2H,C6H4 2,6-H),6.92(d,J＝8.4Hz,2H,C6H4 3,5-H),2.70(q,J＝7.4Hz,2H,CH2),1.21(t,J＝7.4Hz,3H,CH3)。
Example 3
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thioketone and vanillin for 2.5H to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thioketone, wherein the yield is 80.1%, and m.p.193-195 ℃.1H NMR(400MHz,DMSO)δ:13.69(s,1H,NH),10.03(s,1H,OH),9.55(s,1H,NCH),7.47(s,1H,C6H3 2-H),7.33(d,J＝8.0Hz,1H,C6H3),6.93(d,J＝8.0Hz,1H,C6H3),3.85(s,3H,OCH3),2.72(q,J＝7.4Hz,2H,CH2),1.22(t,J＝7.4Hz,3H,CH3)。
Example 4
Preparation of 4- (4-hydroxy-3-ethoxyphenylmethyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thioketone and vanillin for 5.5H to obtain a white solid 4- (4-hydroxy-3-ethoxyphenyl methyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thioketone, wherein the yield is 62.1%, and m.p.183-185 ℃.1H NMR(400MHz,DMSO-d6)δ:13.70(s,1H,NH),9.97(s,1H,OH),9.56(s,1H,NCH),7.47(d,J＝1.9Hz,1H,C6H3 2-H),7.34(dd,J＝8.0,1.9Hz,1H,C6H3),6.96(d,J＝8.0Hz,1H,C6H3),4.11(q,J＝7.0Hz,2H,OCH2),2.73(q,J＝7.5Hz,2H,CH2),1.38(t,J＝7.0Hz,3H,OCH2CH3),1.23(t,J＝7.5Hz,3H,CH3)。
Example 5
Preparation of 4- (4-hydroxyphenylmethyleneamino) -3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the (S) -4-amino-3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 4-hydroxybenzaldehyde for 2.5H to obtain white solid 4- (4-hydroxyphenylmethyleneamino) -3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione with the yield of 83.3 percent and m.p.206-208 ℃.1H NMR(400MHz,DMSO)δ:13.81(s,1H,NH),10.38(s,1H,C6H44-OH),9.44(s,1H,NCH),7.78(d,J＝8.0Hz,2H,C6H4 2,6-H),6.93(d,J＝8.0Hz,2H,C6H43,5-H),5.60(s,1H,OH),4.86(q,J＝6.4Hz,1H,CH),1.45(d,J＝6.4Hz,3H,CH3)。
Example 6
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the (S) -4-amino-3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione and vanillin for 2.5H to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione, wherein the yield is 55.2%, and m.p.170-172 ℃.1H NMR(400MHz,DMSO)δ:13.80(s,1H,NH),10.03(s,1H,C6H34-OH),9.39(s,1H,NCH),7.50(s,1H,C6H3 2-H),7.35(d,J＝8.0Hz,1H,C6H3),6.93(d,J＝8.0Hz,1H,C6H3),5.60(s,1H,OH),4.86(q,J＝6.4Hz,1H,CH),3.85(s,3H,OCH3),1.45(d,J＝6.4Hz,3H,CH3)。
Example 7
Preparation of 4- (4-hydroxy-3-ethoxyphenylmethyleneamino) -3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the (S) -4-amino-3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione and vanillin for 4H to obtain a light yellow solid, namely 4- (4-hydroxy-3-ethoxyphenyl methyleneamino) -3- (1-hydroxyethyl) -1H-1,2, 4-triazole-5 (4H) -thione, wherein the yield is 81.2%, and m.p.154-156 ℃.1H NMR(400MHz,DMSO-d6)δ:13.78(s,1H,NH),9.91(s,1H,C6H34-OH),9.44(s,1H,NCH),7.51(d,J＝1.9Hz,1H,C6H3 2-H),7.36(dd,J＝8.0,1.9Hz,1H,C6H3),6.97(d,J＝8.0Hz,1H,C6H3),5.58(d,J＝5.8Hz,1H,OH),4.90(q,J＝6.7Hz,1H,CH),4.13(q,J＝6.9Hz,2H,OCH2),1.49(d,J＝6.7Hz,3H,CH3),1.40(t,J＝6.9Hz,3H,CH3)。
Example 8
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-propyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-propyl-1H-1, 2, 4-triazole-5 (4H) -thioketone and vanillin for 4H to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-propyl-1H-1, 2, 4-triazole-5 (4H) -thioketone, wherein the yield is 76.0%, and m.p.183-185 ℃.1H NMR(400MHz,DMSO)δ:13.70(s,1H,NH),10.03(s,1H,OH),9.55(s,1H,NCH),7.47(s,1H,C6H3 2-H),7.33(d,J＝8.0Hz,1H,C6H3),6.93(d,J＝8.0Hz,1H,C6H3),3.85(s,3H,OCH3),2.68(t,J＝7.3Hz,2H,C3H7 1-H),1.73-1.64(m,2H,C3H7 2-H),0.94(t,J＝7.3Hz,3H,C3H7 3-H)。
Example 9
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-pentyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-pentyl-1H-1, 2, 4-triazole-5 (4H) -thione and vanillin for 5H to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-pentyl-1H-1, 2, 4-triazole-5 (4H) -thione, wherein the yield is 62.5%, and m.p.162-164 ℃.1H NMR(400MHz,CDCl3)δ:10.67(s,1H,NH),10.02(s,1H,NCH),7.45(s,1H,C6H3 2-H),7.36(d,J＝8.0Hz,1H,C6H3),7.01(d,J＝8.0Hz,1H,C6H3),6.06(s,1H,OH),3.98(s,3H,OCH3),2.80(t,J＝7.3Hz,2H,C5H11 1-H),1.80-1.72(m,2H,C5H11 2-H),1.42-1.34(m,4H,C5H11 3,4-H),0.91(d,J＝5.9Hz,3H,CH3)。
Example 10
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-isopropyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-isopropyl-1H-1, 2, 4-triazole-5 (4H) -thione and vanillin for 5H to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-isopropyl-1H-1, 2, 4-triazole-5 (4H) -thione, wherein the yield is 60.0%, and m.p.155-157 ℃.1H NMR(400MHz,DMSO)δ:13.70(s,1H,NH),10.02(s,1H,OH),9.53(s,1H,NCH),7.47(s,1H,C6H3 2-H),7.34(d,J＝8.0Hz,1H,C6H3),6.93(d,J＝8.0Hz,1H,C6H3),3.84(s,3H,OCH3),3.15-3.09(m,1H,CH),1.25(d,J＝6.8Hz,6H,2CH3)。
Example 11
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-sec-butyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-sec-butyl-1H-1, 2, 4-triazole-5 (4H) -thione and vanillin for 5H to obtain a white solid, namely 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-sec-butyl-1H-1, 2, 4-triazole-5 (4H) -thione, wherein the yield is 73.9%, and m.p.157-159 ℃.1H NMR(400MHz,DMSO)δ:13.74(s,1H,NH),10.05(s,1H,OH),9.56(s,1H,NCH),7.49(d,J＝1.6Hz,1H,C6H3 2-H),7.36(dd,J＝8.4,1.6Hz,1H,C6H3),6.96(d,J＝8.4Hz,1H,C6H3),3.87(s,3H,OCH3),3.03-2.97(m,1H,CH),1.81-1.74(m,1H,CH2),1.63-1.56(m,1H,CH2),1.26(d,J＝7.2Hz,3H,CH3),0.88(t,J＝7.4Hz,3H,CH3)。
Example 12
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-benzyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-benzyl-1H-1, 2, 4-triazole-5 (4H) -thioketone and vanillin for 5H to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-benzyl-1H-1, 2, 4-triazole-5 (4H) -thioketone, wherein the yield is 71.8%, and m.p.189-191 ℃.1H NMR(400MHz,DMSO-d6)δ:13.84(s,1H,NH),10.05(s,1H,OH),9.66(s,1H,NCH),7.44(s,1H,C6H3 2-H),7.34-7.26(m,6H,C6H3,C6H5),6.94(d,J＝8.0Hz,1H,C6H3),4.15(s,2H,CH2),3.87(s,3H,OCH3)；13CNMR(100MHz,DMSO-d6)δ:164.03,161.86，151.82，150.67，148.61，135.69，129.37，128.95，127.32，124.95，123.81，116.03，110.48，56.06，31.21。
Example 13
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-p-fluorobenzyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-p-fluorobenzyl-1H-1, 2, 4-triazole-5 (4H) -thione and vanillin for 6H to obtain a white solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-p-fluorobenzyl-1H-1, 2, 4-triazole-5 (4H) -thione, wherein the yield is 83.7%, and m.p.210-212 ℃.1H NMR(400MHz,DMSO-d6)δ:13.80(s,1H,NH),10.01(s,1H,OH),9.62(s,1H,NCH),7.40(s,1H,C6H3 2-H),7.35-7.31(m,2H,C6H4),7.27(d,J＝8.0Hz,1H,C6H3),7.13(t,J＝8.4Hz,2H,C6H4),6.91(d,J＝8.0Hz,1H,C6H3),4.12(s,2H,CH2),3.85(s,3H,OCH3)。
Example 14
Preparation of 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-p-hydroxybenzyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-p-hydroxybenzyl-1H-1, 2, 4-triazole-5 (4H) -thione and vanillin for 6H to obtain a light yellow solid 4- (4-hydroxy-3-methoxyphenyl methyleneamino) -3-p-hydroxybenzyl-1H-1, 2, 4-triazole-5 (4H) -thione, wherein the yield is 84.3%, and m.p.213-215 ℃.1H NMR(400MHz,DMSO-d6)δ:13.75(s,1H,NH),10.01(s,1H,OH),9.59(s,1H,OH),9.30(s,1H,NCH)7.42(s,1H,C6H3 2-H),7.27(d,J＝8.0Hz,1H,C6H3),7.06(d,J＝8.0Hz,2H,C6H4),6.91(d,J＝8.0Hz,1H,C6H3 2-H),6.66(d,J＝8.0Hz,2H,C6H4),3.97(s,2H,CH2),3.85(s,3H,OCH3)。
Example 15
Preparation of 4- (4-hydroxy-3-ethoxyphenylmethyleneamino) -3-p-hydroxybenzyl-1H-1, 2, 4-triazole-5 (4H) -thione
Prepared as in example 1: refluxing the 4-amino-3-p-hydroxybenzyl-1H-1, 2, 4-triazole-5 (4H) -thione and vanillin for 6H to obtain a white solid, namely 4- (4-hydroxy-3-ethoxyphenyl methyleneamino) -3-p-hydroxybenzyl-1H-1, 2, 4-triazole-5 (4H) -thione, wherein the yield is 70.3%, and m.p.222-224 ℃.1H NMR(400MHz,DMSO-d6)δ:13.75(s,1H,NH),9.93(s,1H,OH),9.58(s,1H,OH),9.31(s,1H,NCH),7.40(s,1H,C6H3 2-H),7.25(d,J＝8.0Hz,1H,C6H3),7.06(d,J＝8.0Hz,2H,C6H4),6.92(d,J＝8.0Hz,1H,C6H3),6.66(d,J＝8.0Hz,2H,C6H4),4.09(q,2H,OCH2),3.97(s,2H,CH2),1.39(t,3H,CH3)。
Example 16
Anti-influenza virus neuraminidase activity of 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione
1. Principle of experiment
The compound MUNANA is a specific substrate of neuraminidase, metabolites generated under the action of neuraminidase can generate 450nm fluorescence under the irradiation and excitation of 360nm, and the change of fluorescence intensity can sensitively reflect neuraminidase activity. The enzymes are all from A/PR/8/34 (H)1N1) A viral strain.
2. Experimental methods
In an enzyme reaction system, a sample with a certain concentration and influenza virus NA are suspended in a reaction buffer solution (pH 6.5), a fluorescent substrate MUNANA is added to start the reaction system, and after incubation for 40 minutes at 37 ℃, a reaction stopping solution is added to stop the reaction. The fluorescence intensity values were determined under the parameters of an excitation wavelength of 360nm and an emission wavelength of 450 nm. The fluorescence intensity of the reaction system may reflect the activity of the enzyme. The inhibition rate of the compound on the NA activity can be calculated according to the reduction of the fluorescence intensity.
3. Detecting a sample: EXAMPLES Compounds
4. Active results
Preferred compounds have neuraminidase inhibition and IC at a concentration of 40.0. mu.g/mL in the reaction system50The values (. mu.g/mL) are shown in Table 1;
TABLE 1 inhibitory Activity of the Compound (40.0. mu.g/mL) on neuraminidase H1N1 and IC50(μg/mL)
| X | R1 | R | 40 μ g/mL, inhibition/% | IC50，μg/mL |
| H | H | OCH3 | 74.6±1.04 | 17.61±0.21 |
| H | CH3 | H | 58.58±0.48 | 30.04±0.55 |
| H | CH3 | OCH3 | 75.81±2.24 | 14.68±0.49 |
| H | CH3 | OC2H5 | 59.63±4.89 | 26.26±3.43 |
| H | C2H5 | OCH3 | 62.6±2.83 | 22.19±3.02 |
| H | n-C4H9 | OCH3 | 58.47±6.16 | 31.05±5.74 |
| H | C6H5 | OCH3 | 50.37±2.42 | 39.85±4.23 |
| H | 4-FC6H4 | OCH3 | 65.44±1.72 | 25.81±0.75 |
| H | 4-OHC6H4 | OCH3 | 74.59±4.15 | 18.11±1.34 |
| CH3 | CH3 | OCH3 | 64.77±2.25 | 19.47±2.26 |
| CH3 | CH3CH2 | OCH3 | 77.23±0.93 | 15.24±1.01 |
| OH | CH3 | H | 68.21±1.18 | 22.08±0.27 |
| OH | CH3 | OCH3 | 79.79±0.71 | 14.97±0.7 |
| OH | CH3 | OC2H5 | 75.67±0.47 | 15.58±0.84 |
4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione has anti-influenza virus neuraminidase activity, and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (6)
1. 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione having the chemical structure I:
r is selected from: hydrogen, methoxy, ethoxy, C3～C4Straight-chain alkoxy or C3～C4A branched alkoxy group; r1Selected from: phenyl or 4-fluorophenyl; x is selected from: ethyl, amino or hydroxy.
4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione selected from the following compounds:
3. the process for the preparation of 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione according to claim 1, characterised in that it is carried out as follows:
wherein R is1X and R are as defined in claim 1.
4. Use of 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione and pharmaceutically acceptable salts thereof, according to claim 1, in the preparation of influenza virus neuraminidase inhibitors.
5. Use of 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione according to claim 2, and pharmaceutically acceptable salts thereof, in the preparation of influenza virus neuraminidase inhibitors.
4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-benzyl-1H-1, 2, 4-triazole-5 (4H) -thione, 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-methyl-1H-1, 2, 4-triazole-5 (4H) -thione, 4- (4-hydroxyphenylmethyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione, 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione, methyl ethyl-5 (4H) -thione, methyl-3-methyl-1H, Use of 4- (4-hydroxy-3-ethoxyphenylmethyleneamino) -3-ethyl-1H-1, 2, 4-triazole-5 (4H) -thione, 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-propyl-1H-1, 2, 4-triazole-5 (4H) -thione or 4- (4-hydroxy-3-methoxyphenylmethyleneamino) -3-isopropyl-1H-1, 2, 4-triazole-5 (4H) -thione, and pharmaceutically acceptable salts thereof, in the preparation of influenza virus neuraminidase inhibitors.
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| 4-氨基-5-烃基-2, 4-二氢-3H-1, 2, 4-三唑-3-硫酮席夫碱的简便合成;吴太兴，等;《高等学校化学学报》;19981031;1617-1619 * |
| 5-苄基-4-氨基-3-巯基-1，2，4-三唑席夫碱合成与生物活性研究;陆文婷，等;《化学通报》;20121231;361-364，scheme1，化合物a * |
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