CN113735788A

CN113735788A - Ibuprofen triazole thiol derivative and application thereof in preparation of novel coronavirus inhibitor

Info

Publication number: CN113735788A
Application number: CN202110627153.9A
Authority: CN
Inventors: 叶姣; 李明芳; 贺超凡; 胡艾希
Original assignee: Hunan University
Current assignee: Hunan University
Priority date: 2021-06-04
Filing date: 2021-06-04
Publication date: 2021-12-03

Abstract

本发明涉及结构式Ⅰ或Ⅱ所示的布洛芬三唑硫醇衍生物或布洛芬三唑硫酮衍生物、其制备方法、药物组合物及其在制备新型冠状病毒3CL蛋白酶抑制剂的应用。

布洛芬三唑硫酮是布洛芬三唑硫醇衍生物的互变异构体。其中R选自：氢、氘、C1～C2烷基、C3～C7直链或C3～C7支链烷基；Z选自：氢、4‑氟、4‑羟基、2‑(2,6‑二氯苯氨基)、4‑异丁基、3‑氟‑4‑苯基、3‑苯氧基、3‑苯甲酰基、4‑(2‑甲基烯丙氨基)或4‑(2‑氧代环戊甲基)；Y¹、Y²和Y⁴选自：氢、氘、C1～C2烷基、硝基、氨基、氟、氯、溴、碘、羟基、甲氧基或乙氧基；Y³选自：氢、氘、C1～C2烷基、羟基、乙氧基、硝基、氨基、甲氨基、二甲氨基、乙酰氨基、氟、氯、溴或碘；Y⁵选自：氢、氘、C1～C2烷基、硝基、氨基、氟、氯、溴或碘。The present invention relates to ibuprofen triazole thiol derivatives or ibuprofen triazole thione derivatives represented by structural formula I or II, their preparation methods, pharmaceutical compositions and their applications in preparing novel coronavirus 3CL protease inhibitors .

Ibuprofen triazole thione is a tautomer of ibuprofen triazole thiol derivatives. Wherein R is selected from: hydrogen, deuterium, C1～C2 alkyl, C3～C7 straight chain or C3～C7 branched alkyl; Z is selected from: hydrogen, 4-fluorine, 4-hydroxyl, 2-(2,6- dichloroanilino), 4-isobutyl, 3-fluoro-4-phenyl, 3-phenoxy, 3-benzoyl, 4-(2-methallylamino) or 4-(2- oxocyclopentylmethyl); Y ¹ , Y ² and Y ⁴ are selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxy, methoxy or ethoxy base; Y ³ is selected from: hydrogen, deuterium, C1-C2 alkyl, hydroxyl, ethoxy, nitro, amino, methylamino, dimethylamino, acetamido, fluorine, chlorine, bromine or iodine; Y ⁵ is selected from : hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine or iodine.

Description

Ibuprofen triazole thiol derivative and application thereof in preparation of novel coronavirus inhibitor

Technical Field

The invention relates to a novel compound, a preparation method and application thereof, in particular to an ibuprofen triazole mercaptan derivative or an ibuprofen triazole thioketone derivative and application thereof in preparation of a novel coronavirus 3CL protease inhibitor.

Background

Guo Chang Bin et al [ Chemicals, 2005, 63(09):841-848] described that ibuprofen, which was found to lack a structural fragment occupying the lateral pocket of COX-2 and was therefore not selective for both isoenzymes, was introduced into the 3-position of the phenyl ring of ibuprofen in order to occupy the lateral pocket of COX-2 and increase binding to COX-2, using the Autodock program to mimic the conformation of ibuprofen in which it binds to COX-1 and COX-2, and compared to the structure of the crystalline complex of the COX-2 selective inhibitor SC-558 with COX-2, to obtain a COX-2 selective inhibitor.

Shanbhag et al [ J Pharmaceutical Sciences, 1992, 81(2): 149-154 ] describe that gastrointestinal irritation of ibuprofen is primarily due to the carboxyl group on the ibuprofen molecule, making ibuprofen a prodrug, which increases patient compliance. The ibuprofen is prepared into eugenol ester, the eugenol ester has no volatility and irritation of eugenol, and gastrointestinal irritation of the ibuprofen can be reduced [ Shenyang pharmaceutical science university report, 2006,23(2), 70-73; eur J Pharmaceutical Sciences,2002,17(3), 121-. Bhat et al (Joseph J.1989, 61(4): 134-136) describe the synthesis of a series of ibuprofen derivatives by esterification of ibuprofen with ROH, wherein the sulfonamide derivatives of ibuprofen exhibit activity against Canadian molds.

Chinese invention patent [ ZL 201010143067.2; zl201210106644.x ] describes the anti-inflammatory and antidepressant activity of ibuprofen-2-arylmorpholineethyl ester (1):

4- (arylmethyleneamino) -3-alkyl-1H-1, 2, 4-triazole-5 (4H) -thione (2) and its biological activity are summarized below:

siddiqui et al [ organic Journal of Chemistry,2005,21(2):317-]3-phenyl-4-benzylmethyleneamino-1, 2, 4-triazolethiones (3) are described to have certain analgesic and anti-inflammatory activities when R is 4-Cl or 4-NO₂The analgesic and anti-inflammatory activity is better than that of the control drug diclofenac sodium.

Gowda et al [ European Journal of Medicinal Chemistry, 2011, 46: 4100-4106]Disclosed is a benzothiazinone derivative 4 containing triazolethione, which is tested for its in vivo anti-inflammatory activity at a concentration of 20mg/kg and found to be when X ═ O, Ar ═ 4-HOC₆H₄Or 4-NO₂C₆H₄When the drug is used, the anti-inflammatory effect is slightly inferior to that of indometacin.

Continent et al [ chemical notification, 2012,75 (4): 361-364] describe the fungicidal activity of 5-benzyl-1, 2, 4-triazole-3-thiol (5). 3-benzyl-1H-1, 2, 4-triazole-5 (4H) -thione is a tautomer of 5-benzyl-1, 2, 4-triazole-3-thiol.

Etc. [ E-Journal of Chemistry,2010,7(S1): S458-S464]3- (1-phenylethyl) -1,2, 4-triazole-5-sulfur is describedFungicidal activity of ketone (6). 3- (1-phenylethyl) -1H-1,2, 4-triazole-5 (4H) -thione is a tautomer of 5- (1-phenylethyl) -1,2, 4-triazole-3-thiol.

Chinese invention patent No. CN109053606A, 2018.12.21 discloses; CN109053607A, 2018.12.21 publication ] has described 4- (4-hydroxyphenylmethyleneamino) -1H-1,2, 4-triazole-5 (4H) -thione [7, 8: use of heterocylic chem, 2019, 56,2192 for the preparation of influenza virus neuraminidase inhibitors. 3-alkyl-1H-1, 2, 4-triazole-5 (4H) -thiones are tautomers of 5-alkyl-1, 2, 4-triazole-3-thiols.

Wherein R is¹Selected from: hydrogen, C₁～C₂Alkyl radical, C₃～C₇Straight chain or C₃～C₇A branched alkyl group; phenyl, 4-fluorophenyl; x is selected from: H. methyl, ethyl, amino or hydroxy; r is selected from: hydrogen, methoxy, ethoxy, C₃～C₄Straight-chain alkoxy or C₃～C₄A branched alkoxy group; y is selected from: phenyl, 4-hydroxyphenyl or 4-methoxyphenyl, fluoromethyl, difluoromethyl or trifluoromethyl.

Sujith et al [ European Journal of Medicinal Chemistry, 2009,44: 3697-]Synthesizing 5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol (9) by taking ibuprofen as a raw material, wherein Y ═ H, 4-Cl, 4-Br and 4-CH₃、4-NO₂And 2,6-Cl₂In vivo anti-inflammatory activity shows that the anti-inflammatory activity of the ibuprofen can be enhanced by introducing 1,2, 4-triazole mercaptan into the ibuprofen molecule, and when R is 4-Cl, the anti-inflammatory activity is the best and is better than that of ibuprofen. Martin et al [ International Journal of Pharmaceutical Assembly and Research,2019,1(2):47-51]5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol 9, in which Y ═ H, 4-Cl,4-OH, 4-OCH, has been reported to have some antibacterial activity₃、4-OH-3-OCH₃、4-N(CH₃)₂And 3,4,5- (OCH)₃)₃. Dhall et al [ J.Heterocyclic chem.,2018,55:2859-2869]The synthesis of 5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol 9, wherein Y ═ H,2-Cl,2-Br,2-OCH, is also reported₃,3-NO₂,4-Cl,4-Br,4-OH,4-OCH₃And 4-N (CH)₃)₂. 3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione is a tautomer of 5- (1- (4-isobutylphenyl) ethyl)) -1,2, 4-triazole-3-thiol.

Naser et al [ International Journal of Pharmaceutical Sciences and Research,2017,8(4): 1598-. 3- (1- (3-fluoro-4-biphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione is a tautomer of 5- (1- (3-fluoro-4-biphenyl) ethyl) -1,2, 4-triazole-3-thiol (10).

Disclosure of Invention

The invention aims to provide an ibuprofen triazole mercaptan derivative or an ibuprofen triazole thioketone derivative, a preparation method thereof, a pharmaceutical composition and application in preparing a novel coronavirus 3CL protease inhibitor.

In order to solve the technical problem, the invention provides the following technical scheme:

the first aspect of the technical scheme of the invention provides ibuprofen triazole thiol derivatives or ibuprofen triazole thione derivatives shown as structural formula I or II:

the ibuprofen triazolethione derivatives are tautomers of the corresponding ibuprofen triazolethiol derivatives, as follows.

Wherein R is selected from: hydrogen, deuterium, C₁～C₂Alkyl radical, C₃～C₇Straight chain or C₃～C₇A branched alkyl group;

z is selected from: hydrogen, 4-fluoro, 4-hydroxy, 2- (2, 6-dichlorophenylamino), 4-isobutyl, 3-fluoro-4-phenyl, 3-phenoxy, 3-benzoyl, 4- (2-methylallylamino) or 4- (2-oxocyclopentylmethyl);

Y¹selected from: hydrogen, deuterium, C₁～C₂Alkyl, nitro, amino, fluoro, chloro, bromo, iodo, hydroxy, methoxy or ethoxy;

Y²selected from: hydrogen, deuterium, C₁～C₂Alkyl, nitro, amino, fluoro, chloro, bromo, iodo, hydroxy, methoxy or ethoxy;

Y³selected from: hydrogen, deuterium, C₁～C₂Alkyl, hydroxy, ethoxy, nitro, amino, methylamino, dimethylamino, acetylamino, fluoro, chloro, bromo or iodo;

Y⁴selected from: hydrogen, deuterium, C₁～C₂Alkyl, nitro, amino, fluoro, chloro, bromo, iodo, hydroxy, methoxy or ethoxy;

Y⁵selected from: hydrogen, deuterium, C₁～C₂Alkyl, nitro, amino, fluoro, chloro, bromo or iodo.

The first aspect of the technical scheme of the invention also provides ibuprofen triazole thiol derivatives which are selected from the following compounds:

the second aspect of the technical scheme of the invention provides a preparation method of ibuprofen triazole thiol derivatives, which is characterized in that the preparation reaction is as follows:

R¹selected from: hydrogen, C₁～C₂Alkyl radical, C₃～C₇Straight chain or C₃～C₇A branched alkyl group;

Y⁵selected from: hydrogen, deuterium, C₁～C₂Alkyl, nitro, amino, fluoro, chloro, bromo, iodo;

z is selected from: hydrogen, 4-fluoro, 4-hydroxy, 2- (2, 6-dichlorophenylamino), 4-isobutyl, 3-fluoro-4-phenyl, 3-phenoxy, 3-benzoyl, 4- (2-methylallylamino) or 4- (2-oxocyclopentylmethyl).

In a third aspect of the present invention there is provided a pharmaceutical composition comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the ibuprofen triazole thiol derivative and a pharmaceutically acceptable salt 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 and liniment; 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.

The fourth aspect of the technical scheme of the invention provides the ibuprofen triazolethiol derivative (I) or the ibuprofen triazolethiol derivative (II) and the pharmaceutically acceptable salt thereof, and the application of the pharmaceutical composition in the aspect of preparing the novel coronavirus 3CL protease inhibitor:

the beneficial technical effects are as follows:

the ibuprofen triazole mercaptan derivative (I) or the ibuprofen triazole thioketone derivative (II) is a novel compound with novel coronavirus 3CL protease inhibitory activity; can be used for preparing medicine for treating novel coronavirus.

Detailed Description

The following examples are intended to illustrate the invention without further limiting it.

Example 1

(E) Preparation of (E) -4- (4-hydroxy-3-methoxyphenylmethyleneamino) -5-benzyl-1, 2, 4-triazole-3-thiol

Refluxing 4-amino-3-benzyl-1H-1, 2, 4-triazole-5 (4H) -thione and 2.2mmol of vanillin for 5H, performing suction filtration, washing with dichloromethane or ethanol, performing ethanol recrystallization, and drying to obtain a white solid (E) -4- (4-hydroxy-3-methoxyphenyl methyleneamino) -5-benzyl-1, 2, 4-triazole-3-thiol with the yield of 71.8% and m.p.189-191 ℃.¹H NMR(400MHz,DMSO-d₆)δ:3.87(s,3H,OCH₃),4.15(s,2H,CH₂),6.94(d,J＝8.0Hz,1H,C₆H₃),7.34-7.26(m,6H,C₆H₃,C₆H₅),7.44(s,1H,C₆H₃2-H),9.66(s,1H,N＝CH),10.05(s,1H,OH),13.84(s,1H,NH)；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 2

(E) Preparation of (E) -4- (4-hydroxy-3-methoxyphenylmethyleneamino) -5-p-fluorobenzyl-1, 2, 4-triazole-3-thiol

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 (E) -4- (4-hydroxy-3-methoxyphenyl methyleneamino) -5-p-fluorobenzyl-1, 2, 4-triazole-3-thiol with the yield of 83.7 percent and m.p.210-212 ℃.¹H NMR(400MHz,DMSO-d₆)δ:3.85(s,3H,OCH₃),4.12(s,2H,CH₂),6.91(d,J＝8.0Hz,1H,C₆H₃),7.13(t,J＝8.4Hz,2H,C₆H₄),7.27(d,J＝8.0Hz,1H,C₆H₃),7.35-7.31(m,2H,C₆H₄),7.40(s,1H,C₆H₃2-H),9.62(s,1H,N＝CH),10.01(s,1H,OH),13.80(s,1H,NH)。

Example 3

(E) Preparation of (E) -4- (4-hydroxy-3-methoxyphenylmethyleneamino) -5-p-hydroxybenzyl-1, 2, 4-triazole-3-thiol

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 (E) -4- (4-hydroxy-3-methoxyphenyl methyleneamino) -5-p-hydroxybenzyl-1, 2, 4-triazole-3-thiol with the yield of 84.3% and m.p.213-215 ℃.¹H NMR(400MHz,DMSO-d₆)δ:3.85(s,3H,OCH₃),3.97(s,2H,CH₂),6.66(d,J＝8.0Hz,2H,C₆H₄),6.91(d,J＝8.0Hz,1H,C₆H₃2-H),7.06(d,J＝8.0Hz,2H,C₆H₄),7.27(d,J＝8.0Hz,1H,C₆H₃),7.42(s,1H,C₆H₃2-H),9.30(s,1H,N＝CH),9.59(s,1H,OH),10.01(s,1H,OH),13.75(s,1H,NH)。

Example 4

(E) Preparation of (E) -4- (4-hydroxy-3-ethoxyphenylmethyleneamino) -5-p-hydroxybenzyl-1, 2, 4-triazole-3-thiol

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 (E) -4- (4-hydroxy-3-ethoxyphenyl methyleneamino) -5-p-hydroxybenzyl-1, 2, 4-triazole-3-thiol with the yield of 70.3% and m.p.222-224 ℃.¹H NMR(400MHz,DMSO-d₆)δ:1.39(t,3H,CH₃),3.97(s,2H,CH₂),4.09(q,2H,OCH₂),6.66(d,J＝8.0Hz,2H,C₆H₄),6.92(d,J＝8.0Hz,1H,C₆H₃),7.06(d,J＝8.0Hz,2H,C₆H₄),7.25(d,J＝8.0Hz,1H,C₆H₃),7.40(s,1H,C₆H₃2-H),9.31(s,1H,N＝CH),9.58(s,1H,OH),9.93(s,1H,OH),13.75(s,1H,NH)。

Example 5

Preparation of 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione

4.6g (20.0mmol) of ibuprofen is dissolved in 50mL of acetonitrile, 3.2g (24.0mmol) of HOBt and 4.6g (24.0mmol) of EDCI are sequentially added, stirring is carried out at room temperature for 3h, then 5.1g (80mmol) of hydrazine hydrate is added under ice bath, after one and a half hour, ethyl acetate (3X 20mL) is extracted, sodium bicarbonate is washed, anhydrous sodium sulfate is dried, suction filtration and desolventization are carried out, and a white solid crude product is obtained and is directly used for the next reaction.

2.2g (10.0mmol) of the crude product in the previous step, 0.8g (15.0mmol) of potassium hydroxide are dissolved in 20mL of ethanol, a mixed solution of 1.2g (15.0mmol) of carbon disulfide and 4mL of ethanol is added dropwise in ice bath, after the dropwise addition is finished, the mixture is returned to room temperature and stirred for 2 hours, solid is separated out, filtered and dried; dissolving the solid in 1.9g (30.0mmol) of 80% hydrazine hydrate, refluxing until the reaction is complete, cooling, adjusting the pH value to 1 with dilute hydrochloric acid, separating out the solid, performing suction filtration, washing with water, drying, and recrystallizing with methanol to obtain a white solid, namely 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione, wherein m.p.179-181 ℃, and the yield is 68.7%.

Example 6

(E) Preparation of (E) -4- (benzylideneamino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

According to the literature [ International Journal of Pharmaceutical efficacy and Research,2019,1(02):47-51]The preparation method comprises the following steps: 0.28g (1.0mmol) of 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 0.11g (1.0mmol) of benzaldehyde are reacted and recrystallized to obtain (E) -4- (benzylideneamino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol, m.p. 99-201, and the yield is 82%.¹H NMR(400MHz,DMSO-d₆)δ:1.11-1.14(m,9H,CH₃+2×CH₃),2.40～2.09(m,1H,CH),2.50(d,2H,CH₂),3.71(q,1H,CH),7.39～8.00(m,9H,Ar-H),9.84(s,1H,N＝CH),13.41(s,1H,SH)。

Example 7

(E) Preparation of (E) -4- ((3-nitrobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

0.28g (1.0mmol) 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazoleDissolving 5- (4H) -thione and 0.17g (1.1mmol) of 3-nitrobenzaldehyde in 3mL of acetic acid, refluxing for 4.5H, cooling, separating out a solid, and performing suction filtration to obtain a white solid (E) -4- ((3-nitrobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol, wherein m.p.189-190 ℃ and the yield is 48.8%;¹H NMR(400MHz，DMSO-d₆)δ：0.72-0.75(m，6H，2×CH₃)，1.59(d，J＝7.1Hz，3H，CHCH ₃)，1.65-1.74(m，1H，CHCH₂)，2.34(d，J＝7.1Hz，2H，CH₂) 4.43(q, J ═ 7.1Hz, 1H, CH), 7.05(d, J ═ 7.9Hz, 2H, benzene ring), 7.16(d, J ═ 7.9Hz, 2H, benzene ring), 7.82-8.55(m, 4H, benzene ring), 10.14(s, 1H, NCH), 14.03(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.85，22.42，22.49，29.99，36.23，44.59，122.77，126.98，127.42，129.63，131.22，134.43，135.00，139.19，140.13，148.71，154.10，159.80，162.14。

example 8

(E) Preparation of (E) -4- ((4-nitrobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

By the method of example 7, 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione was reacted with 4-nitrobenzaldehyde to give (E) -4- ((4-nitrobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol as a white solid in 80.6% yield m.p.196 to 196 ℃;¹H NMR(400MHz，DMSO-d₆)δ：0.80-0.70(m，6H，2×CH₃)，1.59(d，J＝7.1Hz，3H，CHCH ₃)，1.77-1.66(m，1H，CHCH₂)，2.35(d，J＝7.0Hz，2H，CHCH ₂)，4.45(q，J＝7.1Hz，1H，CHCH₃) 7.06(d, J ═ 7.9Hz, 2H, phenyl ring), 7.17(d, J ═ 7.9Hz, 2H, phenyl ring), 8.02(d, J ═ 8.7Hz, 2H, phenyl ring), 8.32(d, J ═ 8.6Hz, 2H, phenyl ring), 10.23(s, 1H, NCH), 14.05(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.88，22.46，22.53，29.99，36.09，44.58，124.55，127.45，129.63，129.91，138.66，139.11，140.16，149.84，154.25，159.12，162.10。

example 9

(E) Preparation of (E) -4- ((4-hydroxy-3-methoxybenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

According to the method of example 7, 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione was reacted with vanillin to obtain (E) -4- ((4-hydroxy-3-methoxybenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol as a white solid, m.p.180 to 182 ℃, yield 29.2%;¹H NMR(400MHz，DMSO-d₆)δ：0.76-0.79(m，6H，2×CH₃)，1.56(d，J＝7.1Hz，3H，CHC ₃H)，1.69-1.76(m，1H，CHCH₂)，2.35(d，J＝7.0Hz，2H，CHC ₂H)，3.83(s，3H，OCH₃)，4.34(q，J＝7.1Hz，1H，CHCH₃) 6.85-7.30(m, 7H, benzene ring), 9.44(s, 1H, OH), 9.98(s, 1H, NCH), 13.84(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.88，22.51，22.57，30.02，36.17，44.61，55.99，110.26，115.91，123.81，124.90，127.46，129.54，139.27，140.05，148.55，151.75，153.80，161.92，163.81。

example 10

(E) Preparation of (E) -4- ((2-chlorobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione was reacted with o-chlorobenzaldehyde as in example 7 to give (E) -4- ((2)-chlorobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol, m.p.161-162 ℃ with a yield of 52.7%;¹H NMR(400MHz，DMSO-d₆)δ：0.74-0.77(m，6H，2×CH₃)，1.59(d，J＝7.1Hz，3H，CHC ₃H)，1.68-1.75(m，1H，CHCH₂)，2.35(d，J＝7.1Hz，2H，CHCH ₂)，4.45(q，J＝7.1Hz，1H，CHCH₃) 7.06(d, J ═ 7.9Hz, 2H, phenyl ring), 7.16(d, J ═ 7.9Hz, 2H, phenyl ring), 7.44-7.92(m, 4H, phenyl ring), 10.59(s, 1H, NCH), 14.02(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.94，22.46，22.52，30.02，36.10，44.59，127.41，127.92，128.24，129.60，130.34，130.65，134.31，135.45，139.34，140.09，154.32，156.71，161.95。

example 11

(E) Preparation of (E) -4- ((4-chlorobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

By the method of example 7, 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione was reacted with 4-chlorobenzaldehyde to give (E) -4- ((4-chlorobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol as a white solid in a yield of 45.1% m.p.163 to 165 ℃;¹H NMR(400MHz，DMSO-d₆)δ：0.83-0.75(m，6H，2×CH₃)，1.60(d，J＝7.1Hz，3H，CHC ₃H)，1.71-1.77(m，1H，CHCH₂)，2.37(d，J＝7.0Hz，2H，CHC ₂H)，4.41(q，J＝7.1Hz，1H，CHCH₃) 7.07(d, J ═ 7.5Hz, 2H, phenyl ring), 7.16(d, J ═ 7.7Hz, 2H, phenyl ring), 7.61(d, J ═ 7.6Hz, 2H, phenyl ring), 7.81(d, J ═ 7.8Hz, 2H, phenyl ring), 9.85(s, 1H, NCH), 13.98(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.86，22.47，22.55，30.00，36.10，44.58，127.44，129.58，129.68，130.53，131.52，137.65，139.12，140.11，153.99，161.81，162.01。

example 12

(E) Preparation of (E) -4- ((4-bromobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

According to the method of example 7, 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione reacts with 4-bromobenzaldehyde to obtain white solid (E) -4- ((4-bromobenzylidene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol, m.p.140-142 ℃, yield 53.6%;¹H NMR(400MHz DMSO-d₆)δ：0.74-0.77(m，6H，2×CH₃)，1.57(d，J＝7.1Hz，3H，CHC ₃H)，1.66-1.75(m，1H，CHCH₂)，2.35(d，J＝7.1Hz，2H，CHCH ₂)，4.39(q，J＝7.1Hz，1H，CHCH₃) 7.04(d, J ═ 7.9Hz, 2H, phenyl ring), 7.13(d, J ═ 7.9Hz, 2H, phenyl ring), 7.75-7.68(m, 4H, phenyl ring), 9.82(s, 1H, NCH), 13.95(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.85，22.48，22.55，30.00，36.10，44.58，126.66，127.44，129.58，130.66，131.85，132.62，139.11，140.11，154.00，161.85，162.00。

example 13

(E) Preparation of (E) -4- ((3-hydroxy-4-methoxybenzylidene) amino) -5- (1- (4-isobutyl-2-phenyl) ethyl) -1,2, 4-triazole-3-thiol

The reaction of 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione with 3-hydroxy-4-methoxybenzaldehyde as in example 7 gave (E) -4- ((3-hydroxy-4-methoxybenzylidene) amino) -5- (1- (4-isobutyl-2-phenyl) ethyl) -1,2, 4-triazole-3-thiol as a white solid in m.p.140-142 ℃ yield53.6％；¹H NMR(400MHz，DMSO-d₆)δ：0.83-0.75(m，6H，2×CH₃)，1.57(d，J＝7.0Hz，3H，CH₃)，1.70～1.76(m，1H，CH)，2.35(d，J＝6.9Hz，2H，CH₂)，3.84(s，3H，OCH₃) 4.32(q, J ═ 7.0Hz, 1H, CH), 7.01 to 7.28(m, 7H, phenyl ring), 9.40(s, 1H, OH), 9.47(s, 1H, NCH), 13.85(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.83，22.54，22.59，30.00，36.04，44.62，56.18，112.24，113.65，123.16，125.14，127.49，129.55，139.02，140.12，147.39，152.34，153.79，161.92，164.41。

example 14

(E) Preparation of (E) -4- ((3-bromo-4-methoxybenzylidene) amino) -5- (1- (4-isobutyl-2-phenyl) ethyl) -1,2, 4-triazole-3-thiol

By the method of example 7, 4-amino-3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione was reacted with 3-bromo-4-methoxybenzaldehyde to give (E) -4- ((3-bromo-4-methoxybenzylidene) amino) -5- (1- (4-isobutyl-2-phenyl) ethyl) -1,2, 4-triazole-3-thiol as a white solid in m.p.153-155 ℃ yield of 27.5%;¹H NMR(400MHz，DMSO-d₆)δ：0.75-0.78(m，6H，2×CH₃)，1.56(d，J＝7.1Hz，3H，CHC ₃H)，1.69-1.76(m，1H，CHCH₂)，2.35(d，J＝7.1Hz，2H，CHC ₂H)，3.93(s，3H，OCH₃)，4.36(q，J＝7.1Hz，1H，CHCH₃) 7.05(d, J ═ 7.9Hz, 2H, phenyl ring), 7.12(d, J ═ 7.9Hz, 2H, phenyl ring), 7.22-7.94(m, 3H, phenyl ring), 9.61(s, 1H, NCH), 13.91(s, 1H, SH);¹³C NMR(101MHz，DMSO-d₆)δ：19.84，22.50，22.56，30.02，36.18，44.62，57.18，111.89，113.31，126.43，127.42，129.56，130.75，132.63，139.22，140.08，153.86，159.05，161.77，162.01。

example 15

(E) Preparation of (E) -4- ((arylmethylene) amino) -5- (1- (4-isobutylphenyl) ethyl) -1,2, 4-triazole-3-thiol

Example 16

Example 17

Example 18

Preparation of 4-amino-3- (1- (3-fluoro-4-biphenylyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione

Prepared according to the literature [ Bioorganic & Medicinal Chemistry,2016,24(4):858-872 ].

Example 19

(E) Preparation of (4- (((4- (dimethylamino) benzylidene) amino) -5- (1- (3-fluoro-4-biphenylyl) ethyl) -1,2, 4-triazole-3-thiol

According to the literature [ International Journal of Pharmaceutical Sciences and Research,2017,8(4):1598]Preparation method of 0.31g (1mmol) of 4-amino-3-, (1- (3-fluoro-4-biphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 0.15g (1mmol) of 4- (dimethylamino) benzaldehyde are reacted for 6H to obtain red solid (E) -4- (((4- (dimethylamino) benzylidene) amino) -5- (1- (3-fluoro-4-biphenyl) ethyl) -1,2, 4-triazole-3-thiol, m.p. 116-118 ℃, the yield is 70%,¹H-NMR(400MHz,DMSO-d₆)δ:1.18(d,3H,CH₃),4.55(q,1H,CH),6.77-8.57(m,12H,Ar-H),9.68(s,1H,CH＝N),14.10(s,1H,SH)。

example 20

(E) Preparation of (E) -4- ((arylmethylene) amino) -5- (1- (3-fluoro-4-biphenylyl) ethyl) -1,2, 4-triazole-3-thiol

Example 21

Anti-novel coronavirus 3CL protease activity of ibuprofen triazole thiol derivatives

1 principle of experiment

The detection principle is as follows, using Fluorescence Resonance Energy Transfer (FRET): edans is a fluorescence Donor (Donor), Dabcyl is a fluorescence Acceptor (Acceptor) or a quenching group (Quencher), absorption spectra of the two fluorophores have certain overlap, and when the distance between the two fluorophores is proper (generally 7-10nm), fluorescence energy is transferred from the Donor to the Acceptor, so that the fluorescence intensity of the Donor fluorescent molecule is attenuated. Edans and Dabcyl are attached to both ends of the natural substrate of the 2019-nCoV Mpro/3CLpro protease, i.e., Dabcyl-KTSAVLQSGFRKME-Edans. When the 2019-nCoV Mpro/3CLpro protease does not cleave the substrate, the two groups are close enough to undergo fluorescence resonance energy transfer, i.e., Dabcyl can quench the fluorescence of Edans and no fluorescence can be detected; when the substrate is cut by the 2019-nCoV Mpro/3CLpro protease, the head and the tail of the polypeptide are separated, the two groups are separated, the fluorescence of the Edans is not quenched by the Dabcyl any more, and the fluorescence of the Edans can be detected, so that the enzyme activity of the 2019-nCoV Mpro/3CLpro protease can be detected very sensitively by fluorescence detection. If an Inhibitor (Inhibitor) of 2019-nCoV Mpro/3CLpro is added into the reaction system, the generation of fluorescence is inhibited, and the fluorescence intensity is inversely proportional to the inhibition effect of the Inhibitor, so that the inhibition effect of the 2019-nCoV Mpro/3CLpro protease Inhibitor can be detected. The maximum excitation wavelength of Edans is 340nm and the maximum emission wavelength is 490 nm.

2 method of experiment

2.1 preparation of samples and Positive drugs

A proper amount of inhibitor sample to be tested and a positive drug Ebselen are taken and prepared into a solution with proper concentration by DMSO.

2.2 Assay Reagent preparation

Appropriate amounts of Assay Reagent were prepared based on sample size (with relevant controls). Each 1. mu.l of 2019-nCoV Mpro/3CLpro was formulated with 92. mu.l of Assay Buffer to allow detection of one sample.

2.3 sample detection

Example samples were tested in 96-well black plates, with 93. mu.l of Assay Reagent, 5. mu.l of sample added to each sample well, 93. mu.l of Assay Reagent and 5. mu.l of solvent DMSO added to the model well, and 93. mu.l of Assay Buffer and 5. mu.l of solvent DMSO added to the blank. Shaking with oscillator for 1min, and mixing well. Add 2. mu.l of Substrate rapidly to each well, shake for 1min using a shaker, mix well. Incubated at 37 ℃ in the dark for 15-20 minutes and then subjected to fluorescence measurement using a multifunctional enzyme label. The excitation wavelength was 340nm and the emission wavelength was 490 nm.

3 detecting the sample

Example samples; the positive control drug was ebselen (ebselen).

4 Activity results

2019-nCoV Mpro/3CLpro protease inhibitory activity in the reaction system was evaluated at a sample detection concentration of 50. mu.g/ml. Re-screening the compound with the inhibition rate of more than 50%, repeating for 3 times, and calculating the IC according to the re-screening result₅₀Values, preferred experimental results are shown in table 1.

Table 1 Compound (50)0. mu.g/mL) inhibitory activity against 2019-nCoV Mpro/3CLpro protease and IC₅₀(μg/mL)

Y	Inhibition rate/%)	IC₅₀，μg/mL
			3-NO₂	72.36±7.99	31.5±8.64
3-OCH₃-4-OH	91.28±2.45	23.84±3.59
			2-Cl	97.37±2.07	14.78±2.53
4-Cl	66.28±2.92	34.14±5.04

The ibuprofen triazole thiol derivative has the activity of resisting novel coronavirus 3CL protease, and can be used for preparing novel coronavirus 3CL protease inhibitors. Can be used for preparing medicine for treating novel coronavirus.

Claims

1. A class of ibuprofen triazole thiol derivatives or ibuprofen triazole thione derivatives and pharmaceutically acceptable salts thereof as shown in structural formula I or II:

The ibuprofen triazole thione derivatives are tautomers of the corresponding ibuprofen triazole thiol derivatives;

Wherein, R is selected from: hydrogen, deuterium, C1～C2 alkyl, C3～C7 straight chain or C3～C7 branched alkyl;

Z is selected from: hydrogen, 4-fluoro, 4-hydroxy, 2-(2,6-dichloroanilino), 4-isobutyl, 3-fluoro-4-phenyl, 3-phenoxy, 3- Benzoyl, 4-(2-methylallylamino) or 4-(2-oxocyclopentylmethyl);

Y ¹ is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

Y ² is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

Y ³ is selected from: hydrogen, deuterium, C1-C2 alkyl, hydroxyl, ethoxy, nitro, amino, methylamino, dimethylamino, acetamido, fluorine, chlorine, bromine or iodine;

Y ⁴ is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

Y ⁵ is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine or iodine.

2. the described ibuprofen triazole thiol derivative of claim 1, is characterized in that it is selected from following compound:

3. the preparation method of the described ibuprofen triazole thiol derivative of claim 1 is characterized in that its preparation reaction is as follows:

Wherein, R ¹ is selected from: hydrogen, C ₁ -C ₂ alkyl, C ₃ -C ₇ straight chain or C ₃ -C ₇ branched chain alkyl;

The definitions of R, Z, Y ¹ to Y ⁵ are as described in claim 1 .

4. the application of ibuprofen triazole thiol derivative and pharmaceutically acceptable salt thereof in the preparation of novel coronavirus 3CL protease inhibitor according to claim 1 or 2.

5. the application of the described ibuprofen triazole thiol derivative and pharmaceutically acceptable salt thereof in the preparation of novel coronavirus medicine of claim 1 or 2.

6. A pharmaceutical composition comprising at least one compound of claim 1 or 2 and a pharmaceutically acceptable carrier.