CN113735787A - Naproxen triazolethione derivative and application thereof in preparation of novel coronavirus inhibitor - Google Patents

Naproxen triazolethione derivative and application thereof in preparation of novel coronavirus inhibitor Download PDF

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CN113735787A
CN113735787A CN202110626639.0A CN202110626639A CN113735787A CN 113735787 A CN113735787 A CN 113735787A CN 202110626639 A CN202110626639 A CN 202110626639A CN 113735787 A CN113735787 A CN 113735787A
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naproxen
methoxy
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叶姣
江婵
贺超凡
胡艾希
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Hunan University
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    • 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
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Abstract

The invention relates to a naproxen triazolethione derivative or a naproxen triazolethiol derivative shown in a structural formula I or II, a preparation method thereof, a pharmaceutical composition and application thereof in preparing a novel coronavirus 3CL protease inhibitor.
Figure DDA0003101466460000011
Wherein R is selected from: hydrogen, deuterium, C1-C2 alkyl, C3-C7 straight chain or C3-C7 branched chain alkyl; z is selected from: hydrogen, 6-methoxy, 5-chloro-6-methoxy, 5-amino-6-methoxy, 6-ethoxy; y is1、Y2And Y4Selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy; y is3Selected from: hydrogen, deuterium, C1-C2 alkyl,Hydroxy, ethoxy, nitro, amino, methylamino, dimethylamino, acetylamino, fluoro, chloro, bromo, or iodo; y is5Selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine and iodine.

Description

Naproxen triazolethione 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 a naproxen triazolethione derivative or a naproxen triazolethiol derivative and application thereof in preparation of a novel coronavirus 3CL protease inhibitor.
Background
The Chinese invention patent [ ZL200610123902.X, 2008] describes the anti-inflammatory activity of naproxen-2-aryl morpholine ethyl ester (1):
Figure BDA0003101466450000011
chinese invention patent No. [ CN 107286133B, 2019.5.10] describes the use of 3-aryl-1, 2, 4-triazole-5 (4H) -thioketimine derivative (2) in influenza virus neuraminidase inhibitors:
Figure BDA0003101466450000012
wherein Z is selected from: n or CH; x is selected from: H. c1～C2Alkyl radical, C3～C4Straight or branched chain alkyl;
Y1、Y2、Y4selected from: hydrogen, C1～C2Alkyl, hydroxy, methoxy or ethoxy; y is3Selected from: hydrogen, C1～C2Alkyl, hydroxy, ethoxy, nitro, amino, methylamino, dimethylamino, acetylamino, fluoro, chloro, bromo or iodo; y is5Selected from: hydrogen or C1～C2An alkyl group.
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.
Figure BDA0003101466450000013
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.
Figure BDA0003101466450000021
Continent et al [ chemical notification, 2012,75 (4): 361-364] describe the fungicidal activity of 3-benzyl-1, 2, 4-triazole-5-thione (5). 3-benzyl-1H-1, 2, 4-triazole-5 (4H) -thione is a tautomer of 5-benzyl-1, 2, 4-triazole-3-thiol.
Figure BDA0003101466450000022
Figure BDA0003101466450000025
Etc. [ E-Journal of Chemistry,2010,7(S1): S458-S464]The bactericidal activity of 3- (1-phenylethyl) -1,2, 4-triazole-5-thione Schiff base (6) is described. 3- (1-phenylethyl) -1H-1,2, 4-triazole-5 (4H) -thione is a tautomer of 5- (1-phenylethyl) -1,2, 4-triazole-3-thiol.
Figure BDA0003101466450000023
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.
Figure BDA0003101466450000024
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.
El-husselny et al [ eur.j.med.chem.2018, 158: 134]The 4- ((arylmethylene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thioketone (9) designed and synthesized by taking naproxen as a framework has good anticancer and anti-inflammatory effects, wherein Y is H, 3-Br and 4-OH, and when R is 4-OH, the compound 9 has excellent inhibitory activity on COX-2 enzyme and IC of the compound50It was 0.40. mu. mol/L. Monther et al [ Int J Pharm Sci,2017, 9 (7): 66-71]Synthesis of (S)4- ((arylmethylene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thioketone [ (S) -9) by using (S) -naproxen as raw material]Wherein Y is H, 4-Br, 4-NO2And 4-OH; the in vivo anti-inflammatory activity shows that the anti-inflammatory activity of the naproxen derivative can be increased by introducing an electron-donating group (4-OH) into the para position of a benzene ring. 3- (1- (6-methoxy-2-naphthyl) -1H-1,2, 4-triazole-5 (4H) -thione is a tautomer of 5- (1- (6-methoxy-2-naphthyl) -1,2, 4-triazole-3-thiol.
Figure BDA0003101466450000031
Sujith et al [ European Journal of Medicinal Chemistry, 2009,44: 3697-]Synthesizing 4- ((arylmethylene) amino) -3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thioketone (10) by taking ibuprofen as a raw material, wherein R is 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-triazolethione 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]It has been reported that 4- ((arylmethylene) amino) -3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione 10, wherein R ═ H, 4-Cl,4-OH, 4-OCH, has some antibacterial activity3、4-OH-3-OCH3、4-N(CH3)2And a combination of 3,4,5-(OCH3)3. Dhall et al [ J.Heterocyclic chem.,2018,55:2859-2869]The synthesis of 4- ((arylmethylene) amino) -3- (1- (4-isobutylphenyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione 10, where R ═ H,2-Cl,2-Br,2-OCH, was 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.
Figure BDA0003101466450000032
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.
Figure BDA0003101466450000033
Disclosure of Invention
The invention aims to provide a naproxen triazolethione derivative or a naproxen triazolethiol derivative, 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 of the present invention, there is provided a class of naproxen triazolethione derivatives or naproxen triazolethiol derivatives represented by structural formula i or ii:
Figure BDA0003101466450000041
the naproxen triazole thiol derivatives are tautomers of the corresponding naproxen triazole thione 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, 6-methoxy, 5-chloro-6-methoxy, 5-amino-6-methoxy, 6-ethoxy;
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, fluorine, chlorine, bromine, iodine.
In a first aspect of the present invention, there is also provided a class of naproxen triazolethiones selected from the following compounds:
Figure BDA0003101466450000042
the second aspect of the present invention provides a process for producing a naproxen triazolethione derivative, which is characterized in that the production reaction is as follows:
Figure BDA0003101466450000051
wherein R is1Selected from: hydrogen, C1～C2Alkyl radical, C3～C7Straight chain or C3～C7A branched alkyl group;
r is selected from: hydrogen, deuterium, C1～C2Alkyl radical, C3～C7Straight chain or C3～C7A branched alkyl group;
z is selected from: hydrogen, 6-methoxy, 5-chloro-6-methoxy, 5-amino-6-methoxy, 6-ethoxy;
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.
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 naproxen triazolethione of the present invention and pharmaceutically acceptable salts thereof, 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 naproxen triazolethione derivative (I) or the naproxen triazolethione derivative (II) and the pharmaceutically acceptable salt thereof, and the application of the pharmaceutical composition in the third aspect in the preparation of the novel coronavirus 3CL protease inhibitor:
Figure BDA0003101466450000061
the beneficial technical effects are as follows:
the naproxen triazolethione derivative (I) or the naproxen triazolethiol derivative (II) is a novel compound with the inhibitory activity of novel coronavirus 3CL protease; 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
Preparation of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione
Figure BDA0003101466450000071
4.6g (20.0mmol) naproxen is dissolved in 50mL acetonitrile, 3.2g (24.0mmol) HOBt and 4.6g (24.0mmol) EDCI are sequentially added, after stirring for 3h at room temperature, 5.1g (80mmol) 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 yellow solid crude product is obtained and is directly used for the next reaction.
2.4g (10.0mmol) of the crude product obtained in the previous step, 0.8g (15.0mmol) of potassium hydroxide are dissolved in 20mL of ethanol under ice bath, a mixed solution of 1.2g (15.0mmol) of carbon disulfide and 4mL of ethanol is added dropwise, after the dropwise addition is finished, the solution is returned to room temperature and stirred for 6 hours, solid is separated out, and the solution is 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, and drying to obtain a light yellow solid 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione, wherein m.p.206-208 ℃ and the yield is 70.0%;1HNMR(400MHz,DMSO-d6)δ：1.61(d,J＝7.2Hz,3H),3.85(s,3H,OCH3),4.47(q,J＝7.2Hz,1H,CH),5.43(s,2H,NH2),7.12-7.19(m,1H,Ar-H),7.28-7.32(m,1H,Ar-H),7.39(d,J＝8.5Hz,1H,Ar-H)),7.67(s,1H,Ar-H),7.75-7.84(m,2H,Ar-H),13.61(s,1H,NH).
example 2
(E) Preparation of (4) - ((3-nitrobenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione (I1)
Figure BDA0003101466450000072
Dissolving 1.0mmol of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 1.0mmol of 3-nitrobenzaldehyde in 3mL of acetic acid, refluxing for 3H, cooling, separating out a small amount of needle crystals, performing suction filtration, and separating out yellow solid I1 from the filtrate at m.p.181-183 ℃ with the yield of 32.3%;1H NMR(400MHz，DMSO-d6)δ：1.69(d，J＝6.8Hz，3H，CH3)，3.83(s，3H，OCH3) 4.61(q, J ═ 6.8Hz, 1H, CH), 7.10-8.56(m, 10H, phenyl ring + naphthyl ring), 10.17(s, 1H, NCH), 14.07(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.68，36.46，55.59，106.17，119.20，122.67，126.09，126.43，126.98，127.67，128.80，129.45，131.21，133.70，134.25，134.95，136.78，148.60，154.09，157.62，159.84，161.94。
example 3
(E) Preparation of (E) -4- ((4-nitrobenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione (I2)
Figure BDA0003101466450000081
According to the method of example 2, 1.0mmol of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 1.0mmol of 4-nitrobenzaldehyde react for 3 hours to obtain yellow solid I2, m.p.183-185 ℃, and the yield is 50%;1H NMR(400MHz，DMSO-d6)δ：1.74(d，J＝7.2Hz，3H，CH3)，3.88(s，3H，OCH3) 4.67(q, J ═ 7.2Hz, 1H, CH), 7.16-8.37(m, 10H, phenyl ring + naphthyl ring), 10.31(s, 1H, NCH), 14.14(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.67，36.38，55.60，106.18，119.22，124.54，126.13，126.48，127.67，128.80，129.53，129.90，133.70，136.74，138.51，149.81，154.29，157.63，159.11，161.89。
example 4
(E) Preparation of (4- ((4-hydroxy-3-methoxybenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione (I3)
Figure BDA0003101466450000082
According to the method of example 2, 1mmol of 4-yl-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 1.1mmol) of vanillin react for 30min to obtain a white solid I3, wherein m.p.163-165 ℃ and the yield is 39.2%;1H NMR(400MHz，DMSO-d6)δ：1.66(d，J＝7.2Hz，3H，CH3)，3.79(s，3H，OCH3)，3.85(s，3H，OCH3) 4.53(q, J ═ 7.2Hz, 1H, CH), 6.86-7.77(m, 9H, phenyl ring + naphthyl ring), 9.51(s, 1H, NCH), 10.04(s, 1H, OH), 13.93(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.89，26.81，36.46，55.62，55.96，106.19，110.19，115.91，119.18，123.78，124.91，126.00，126.66，127.50，128.85，129.47，133.69，137.03，148.54，151.72，153.76，157.61，161.96，163.65。
example 5
(E) Preparation of (E) -4- ((2-chlorobenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione (I4)
Figure BDA0003101466450000083
By the method of example 2, 0.5mmol4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 0.55mmol o-chlorobenzaldehyde react for 3H to obtain a white solid I4 with m.p.149-151 ℃ and the yield of 33.3%;1HNMR(400MHz，DMSO-d6)δ：1.66(d，J＝7.2Hz，3H，CH3)，3.82(s，3H，OCH3) 4.62(q, J ═ 7.2Hz, 1H, CH), 7.10-7.96(m, 10H, phenyl ring + naphthyl ring), 10.67(s, 1H, NCH), 14.05(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.83，36.38，55.61，106.21，119.23，126.10，126.50，127.61，127.91，128.26，128.84，129.50，130.32，130.65，133.70，134.33，135.41，136.95，154.31，156.43，157.63，161.81。
example 6
(E) Preparation of (4- ((3-bromo-4-methoxybenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione (I5)
Figure BDA0003101466450000091
According to the method of example 2, 1mmol of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 1.1mmol of 3-bromo-4-methoxybenzaldehyde are reacted for 30min to obtain a white solid I5, m.p.185-187 ℃, and the yield is 40.2%;1H NMR(400MHz，DMSO-d6)δ：1.66(d，J＝7.2Hz，3H，CH3)，3.84(s，3H，OCH3) 3.93(s, 3H, OCH3), 4.55(q, J ═ 7.2Hz, 1H, CH), 7.11-7.97(m, 9H, benzene ring + naphthalene ring), 9.68(s, 1H, NCH), 13.95(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.76，36.40，55.62，57.17，106.20，111.90，113.30，119.22，126.12，126.40，126.57，127.53，128.81，129.53，130.86，132.51，133.70，136.86，153.85，157.63，159.02，161.48，162.00。
example 7
(E) Preparation of (E) -4- ((4-chlorobenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione (I6)
Figure BDA0003101466450000092
According to the method of example 2, 1.0mmol of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 1.0mmol of 4-chlorobenzaldehyde are reacted for 3 hours to obtain a light yellow solid I6, wherein m.p.185-186 ℃ and the yield is 36.9%;1H NMR(400MHz，DMSO-d6)δ：1.67(d，J＝6.8Hz，3H，CH3)，3.83(s，3H，OCH3) 4.57(q, J ═ 6.8Hz, 1H, CH), 7.10-7.81(m, 10H, phenyl ring + naphthyl ring), 9.91(s, 1H, NCH), 14.00(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.76，36.37，55.60，106.18，119.22，126.13，126.60，127.54，128.82，129.52，129.69，130.53，131.52，133.71，136.77，137.61，153.99，157.63，161.38，162.02。
example 8
(E) Preparation of (I7) -4- ((3-hydroxy-4-methoxybenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione
Figure BDA0003101466450000101
According to the method of example 2, 1.0mmol of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 1.0mmol of isovanillin react for 3.5H to obtain a white solid I7, m.p.217-219 ℃, and the yield is 55%.1H NMR(400MHz，DMSO-d6)δ：1.66(d，J＝7.2Hz，3H，CH3)，3.84(s，6H，2×OCH3) 4.50(q, J ═ 7.2Hz, 1H, CH), 7.01-7.74(m, 9H, phenyl ring + naphthyl ring), 9.49(s, 2H, OH, NCH), 13.89(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.77，36.35，55.62，56.17，106.19，112.24，113.57，119.18，123.20，125.14，126.06，126.70，127.49，128.83，129.54，133.71，136.76，147.41，152.32，153.77，157.63，161.95，164.00。
example 9
(E) Preparation of (E) -4- ((4-bromobenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione (I8)
Figure BDA0003101466450000102
According to the method of example 2, 1.0mmol of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 1.0mmol of 4-bromobenzaldehyde react for 4H to obtain a white solid I8, m.p.191-193 ℃, and the yield is 21.4%;1H NMR(400MHz，DMSO-d6)δ：1.70(d，J＝6.8Hz，3H，CH3)，3.86(s，3H，OCH3) 4.59(q, J ═ 6.8Hz, 1H, CH), 7.13-7.78(m, 10H, phenyl ring + naphthyl ring), 9.93(s, 1H, NCH), 14.02(s, 1H, NH);13C NMR(101MHz，DMSO-d6)δ：19.76，36.37，55.62，106.21，119.21，126.13，126.60，126.62，127.54，128.83，129.52，130.66，131.87，132.63，133.72，136.77，154.00，157.65，161.48，162.04。
example 10
(E) Preparation of (E) -4- ((4-methoxybenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione
Figure BDA0003101466450000103
According to the literature [ heterocyclic Chemistry,2002,13(3):199-]The preparation method comprises the following steps: 0.3g (1mmol) of 4-amino-3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione and 0.14g (1.1mol) of 4-anisaldehyde are reacted for 2H, and acetic acid is recrystallized to obtain (E) -4- ((4-methoxybenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione, m.p.260-262 ℃, and the yield is 69%.1H NMR(400MHz,DMSO-d6)δ:1.60(d,3H,CH3),3.40(s,3H,OCH3)3.8(s,3H,OCH3),4.0(q,1H,CH),7.1–7.8(m,10H,Ar-H),10.1(br,2H,N＝CH+NH)。
Example 11
(E) Preparation of (E) -4- ((3-bromobenzylidene) amino) -3- (1- (6-methoxy-2-naphthyl) ethyl) -1H-1,2, 4-triazole-5 (4H) -thione
Figure BDA0003101466450000111
As per literature [ eur.j.med.chem.2018,158: 134] preparing the product.
Example 12
Anti-novel coronavirus 3CL protease activity of naproxen triazolethione 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-nCoVMpro/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-nCoVMpro/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-nCoVMpro/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.
Figure BDA0003101466450000121
TABLE 1 inhibitory Activity of the Compounds (50.0. mu.g/mL) on 2019-nCoVMpro/3CLpro protease and IC50(μg/mL)
Y Inhibition rate/%) IC50，μg/mL
4-NO2 86.29±4.46 3.28±0.38
3-OCH3-4-OH 90.06±2.53 2.99±0.08
2-Cl 80.44±6.65 5.72±0.18
3-Br-4-OCH3 67.17±2.35 23.79±4.94
The naproxen triazolethione derivative has the activity of resisting novel coronavirus 3CL protease, and can be used for preparing novel coronavirus 3CL protease inhibitors. The naproxen triazolethione derivative and the pharmaceutically acceptable salt thereof are applied to the preparation of novel coronavirus medicaments.

Claims (6)

1. A naproxen triazolethione derivative or a naproxen triazolethiol derivative shown as a structural formula I or II and pharmaceutically acceptable salts thereof:
Figure FDA0003101466440000011
the naproxen triazole thiol derivative is a tautomer of the corresponding naproxen triazole thione derivative;
wherein R is selected from: hydrogen, deuterium, C1～C2Alkyl radical, C3～C7Straight chain or C3～C7A branched alkyl group;
z is selected from: hydrogen, 6-methoxy, 5-chloro-6-methoxy, 5-amino-6-methoxy or 6-ethoxy;
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.
2. Naproxen triazolinethione derivatives according to claim 1, characterized in that they are chosen from the following compounds:
Figure FDA0003101466440000012
3. the process for preparing naproxen triazolinethione derivative according to claim 1, characterized in that it is prepared by the following reaction:
Figure FDA0003101466440000021
wherein R is1Selected from: hydrogen, C1～C2Alkyl radical, C3～C7Straight chain or C3～C7A branched alkyl group; r, Z, Y1～Y5Is as defined in claim 1.
4. Use of the naproxen triazolinethione derivative and pharmaceutically acceptable salts thereof according to claim 1 or 2 for the preparation of novel coronavirus 3CL protease inhibitors.
5. Use of the naproxen triazolinethione derivative and the pharmaceutically acceptable salts thereof according to claim 1 or 2 for the preparation of novel medicaments for coronaviruses.
6. A pharmaceutical composition comprising at least one compound of claim 1 or 2 and a pharmaceutically acceptable carrier.
CN202110626639.0A 2021-06-04 2021-06-04 Naproxen triazolethione derivative and application thereof in preparation of novel coronavirus inhibitor Pending CN113735787A (en)

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