Naproxen triazolethione derivatives and their application in the preparation of COVID-19 virus inhibitors

Abstract

The present invention relates to naproxen triazolethione derivatives or naproxen triazolethiol derivatives represented by structural formula I or II, preparation methods, pharmaceutical compositions, and their use in the preparation of novel coronavirus 3CL protease inhibitors. #imgabs0# wherein R is selected from the group consisting of hydrogen, deuterium, C1-C2 alkyl, C3-C7 straight-chain or C3-C7 branched alkyl; Z is selected from the group consisting of hydrogen, 6-methoxy, 5-chloro-6-methoxy, 5-amino-6-methoxy, and 6-ethoxy; and Y 1 、Y 2 and Y 4 is selected from the group consisting of: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy; Y 3 is selected from the group consisting of: hydrogen, deuterium, C1-C2 alkyl, hydroxy, ethoxy, nitro, amino, methylamino, dimethylamino, acetylamino, fluorine, chlorine, bromine or iodine; Y 5 Selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine.

Description

Technical Field

[0001] The present invention relates to a new class of compounds, their preparation methods and applications, specifically naproxen triazolethione derivatives or naproxen triazolethiol derivatives and their applications in the preparation of novel coronavirus 3CL protease inhibitors. Background Art

[0002] Chinese Patent [ZL200610123902.X, 2008] describes the anti-inflammatory activity of naproxen-2-aryl morpholine ethyl ester (1):

[0003]

[0004] Chinese Patent [CN 107286133 B, May 10, 2019] describes the application of 3-aryl-1,2,4-triazole-5(4H)-thioneimine derivatives (2) in influenza virus neuraminidase inhibitors:

[0005]

[0006] In the formula, Z is selected from: N or CH; X is selected from: H, C1-C2 alkyl, C3-C4 straight-chain alkyl or branched-chain alkyl;

[0007] Y 1 、Y 2 、Y 4 are selected from: hydrogen, C1-C2 alkyl, hydroxy, methoxy or ethoxy; Y 3 is selected from: hydrogen, C1-C2 alkyl, hydroxy, ethoxy, nitro, amino, methylamino, dimethylamino, acetylamino, fluorine, chlorine, bromine or iodine; Y 5 is selected from: hydrogen or C1-C2 alkyl.

[0008] Siddiqui et al. [Oriental Journal of Chemistry, 2005, 21(2): 317-322] describe that 3-phenyl-4-benzylideneamino-1,2,4-triazolethione compounds (3) have certain analgesic and anti-inflammatory activities. When R = 4-Cl or 4-NO2, the analgesic and anti-inflammatory activities are better than the control drug diclofenac sodium.

[0009]

[0010] Gowda et al. [European Journal of Medicinal Chemistry, 2011, 46: 4100-4106] disclosed benzothiazinone derivatives 4 containing triazolethione, and tested their in vivo anti-inflammatory activity at a concentration of 20 mg / kg. It was found that when X = O, Ar = 4-HOC6H4 or 4-NO2C6H4, their anti-inflammatory effect was slightly inferior to indomethacin.

[0011]

[0012] Lu Wenting et al. [Chemistry Bulletin, 2012, 75(4): 361-364] described the bactericidal 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.

[0013]

[0014] et al. [E-Journal of Chemistry, 2010, 7(S1): S458-S464] described the bactericidal activity of 3-(1-phenylethyl)-1,2,4-triazole-5-thione Schiff base (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.

[0015]

[0016] Chinese invention patents [CN109053606A, published on December 21, 2018; CN109053607A, published on December 21, 2018] have described the application of 4-(4-hydroxyphenylmethyleneamino)-1H-1,2,4-triazole-5(4H)-thione [7, 8: J. Heterocyclic Chem., 2019, 56, 2192] in the preparation of influenza virus neuraminidase inhibitors. 3-alkyl-1H-1,2,4-triazole-5(4H)-thione is a tautomer of 5-alkyl-1,2,4-triazole-3-thiol.

[0017]

[0018] Among them, R 1Selected from: hydrogen, C1-C2 alkyl, C3-C7 straight-chain or C3-C7 branched-chain alkyl; phenyl, 4-fluorophenyl; X is selected from: H, methyl, ethyl, amino or hydroxy; R is selected from: hydrogen, methoxy, ethoxy, C3-C4 straight-chain alkoxy or C3-C4 branched-chain alkoxy; Y is selected from: phenyl, 4-hydroxyphenyl or 4-methoxyphenyl, fluoromethyl, difluoromethyl or trifluoromethyl.

[0019] El-Husseiny et al. [Eur. J. Med. Chem. 2018, 158: 134] designed and synthesized 4-((arylmethylene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (9) with naproxen as the skeleton, which has good anti-cancer and anti-inflammatory effects, where Y = H, 3-Br and 4-OH. When R = 4-OH, compound 9 has excellent inhibitory activity against COX-2 enzyme, and its IC 50 is 0.40 μmol / L. Monther et al. [Int J Pharm Pharm Sci, 2017, 9(7): 66-71] synthesized (S)4-((arylmethylene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione [(S)-9] with (S)-naproxen as the raw material, where Y = H, 4-Br, 4-NO2 and 4-OH; in vivo anti-inflammatory activity showed that introducing an electron-donating group (4-OH) at the para-position of the benzene ring can increase the anti-inflammatory activity of naproxen derivatives. 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.

[0020]

[0021] Sujith et al. [European Journal of Medicinal Chemistry, 2009, 44: 3697–3702] synthesized 4-((arylmethylene)amino)-3-(1-(4-isobutylphenyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (10), where R = H, 4-Cl, 4-Br, 4-CH3, 4-NO2, and 2,6-Cl2. In vivo anti-inflammatory activity indicated that introducing 1,2,4-triazolethione into the ibuprofen molecule could enhance its anti-inflammatory activity. When R = 4-Cl, the anti-inflammatory activity was the best, superior to ibuprofen. Martin et al. [International Journal of Pharmaceutical Education and Research, 2019, 1(2): 47-51] reported that 4-((arylmethylene)amino)-3-(1-(4-isobutylphenyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione 10 had certain antibacterial activity, where R = H, 4-Cl, 4-OH, 4-OCH3, 4-OH-3-OCH3, 4-N(CH3)2, and 3,4,5-(OCH3)3. Dhall et al. [J. Heterocyclic Chem., 2018, 55: 2859-2869] also reported 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-OCH3, 3-NO2, 4-Cl, 4-Br, 4-OH, 4-OCH3, and 4-N(CH3)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.

[0022]

[0023] Naser et al. [International Journal of Pharmaceutical Sciences and Research, 2017, 8(4): 1598-1605] reported the synthesis of 4-((arylmethylene)amino)-3-(1-(3-fluoro-4-biphenyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (11). 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.

[0024] Summary of the Invention

[0025] The technical problem to be solved by the present invention is to provide naproxen triazolethione derivatives or naproxen triazolethiol derivatives, their preparation methods, pharmaceutical compositions and uses.

[0026] To solve the technical problems of the present invention, the present invention provides the following technical solutions:

[0027] The first aspect of the technical solution of the present invention provides a class of naproxen triazolethione derivatives or naproxen triazolethiol derivatives represented by the following structural formula I or II:

[0028]

[0029] The naproxen triazolethiol derivatives are tautomers of the corresponding naproxen triazolethione derivatives, and the same applies hereinafter.

[0030] Wherein, R is selected from: hydrogen, deuterium, C1-C2 alkyl, C3-C7 straight-chain or C3-C7 branched-chain alkyl;

[0031] Z is selected from: hydrogen, 6-methoxy, 5-chloro-6-methoxy, 5-amino-6-methoxy, 6-ethoxy;

[0032] Y 1 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

[0033] Y 2 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

[0034] Y 3 is selected from: hydrogen, deuterium, C1-C2 alkyl, hydroxyl, ethoxy, nitro, amino, methylamino, dimethylamino, acetylamino, fluorine, chlorine, bromine or iodine;

[0035] Y 4 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

[0036] Y 5 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine.

[0037] The first aspect of the technical solution of the present invention also provides a class of naproxen triazolethiones, selected from the following compounds:

[0038]

[0039] The second aspect of the technical solution of the present invention provides a preparation method of naproxen triazolethione derivatives, which is characterized in that its preparation reaction is as follows:

[0040]

[0041] Wherein, R 1 is selected from: hydrogen, C1-C2 alkyl, C3-C7 straight-chain or C3-C7 branched-chain alkyl;

[0042] R is selected from: hydrogen, deuterium, C1-C2 alkyl, C3-C7 straight-chain or C3-C7 branched-chain alkyl;

[0043] Z is selected from: hydrogen, 6-methoxy, 5-chloro-6-methoxy, 5-amino-6-methoxy, 6-ethoxy;

[0044] Y 1 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

[0045] Y 2 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

[0046] Y 3 is selected from: hydrogen, deuterium, C1-C2 alkyl, hydroxyl, ethoxy, nitro, amino, methylamino, dimethylamino, acetylamino, fluorine, chlorine, bromine or iodine;

[0047] Y 4 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine, iodine, hydroxyl, methoxy or ethoxy;

[0048] Y 5 is selected from: hydrogen, deuterium, C1-C2 alkyl, nitro, amino, fluorine, chlorine, bromine or iodine.

[0049] The third aspect of the technical solution of the present invention is to provide a pharmaceutical composition containing the compound described in the first aspect and its pharmaceutically acceptable salt. The pharmaceutical composition contains a therapeutically effective amount of the naproxen triazolethione of the present invention and its pharmaceutically acceptable salt, and optionally contains a pharmaceutical carrier. The pharmaceutical carrier mentioned herein refers to a commonly used pharmaceutical carrier in the pharmaceutical field; the pharmaceutical composition can be prepared according to the methods well known in the art. By combining the compound of the present invention and its pharmaceutically acceptable salt with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants, any dosage form suitable for human or animal use can be made. The content of the compound of the present invention and its pharmaceutically acceptable salt in the pharmaceutical composition is usually 0.1% - 95% by weight percentage.

[0050] The compounds of the present invention, their pharmaceutically acceptable salts or pharmaceutical compositions containing them can be administered in unit dosage forms, and the administration routes can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0051] The dosage forms for administration can be liquid dosage forms, solid dosage forms or semi-solid dosage forms. Liquid dosage forms can be solutions (including true solutions and colloidal solutions), emulsions (including O / W type, W / O type and multiple emulsions), suspensions, injections (including aqueous injections, powder injections and infusions), eye drops, nasal drops, lotions and liniments, etc.; solid dosage forms can be tablets (including ordinary tablets, enteric-coated tablets, buccal tablets, dispersible tablets, chewable tablets, effervescent tablets, orally disintegrating tablets), capsules (including hard capsules, soft capsules, enteric-coated capsules), granules, powders, pellets, dripping pills, suppositories, films, patches, aerosols (powder aerosols), sprays, etc.; semi-solid dosage forms can be ointments, gels, pastes, etc.

[0052] The compounds of the present invention and their pharmaceutically acceptable salts can be made into ordinary preparations, as well as sustained-release preparations, controlled-release preparations, targeted preparations and various particulate drug delivery systems.

[0053] In order to make the compounds of the present invention and their pharmaceutically acceptable salts into tablets, various excipients well-known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. Diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; wetting agents can be water, ethanol, isopropanol, etc.; binders can be starch paste, dextrin, syrup, honey, glucose solution, microcrystalline cellulose, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, etc.; lubricants and glidants can be talc powder, silicon dioxide, stearates, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0054] The tablets can also be further made into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer tablets and multi-layer tablets.

[0055] To prepare the administration unit in the form of a capsule, the active ingredient, the compound of the present invention and its pharmaceutically acceptable salts can be mixed with a diluent and a glidant, and the mixture can be directly placed into a hard capsule or a soft capsule. Alternatively, the active ingredient, the compound of the present invention and its pharmaceutically acceptable salts can be first made into granules or pellets with a diluent, a binder and a disintegrant, and then placed into a hard capsule or a soft capsule. The varieties of diluents, binders, wetting agents, disintegrants and glidants used for preparing tablets of the compound of the present invention and its pharmaceutically acceptable salts can also be used for preparing capsules of the compound of the present invention and its pharmaceutically acceptable salts.

[0056] To prepare an injection of the compound of the present invention and its pharmaceutically acceptable salts, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and appropriate solubilizers, cosolvents, pH adjusters and osmotic pressure regulators commonly used in the art can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin, etc.; the pH adjuster can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. When preparing a freeze-dried powder injection, mannitol, glucose, etc. can also be added as a support agent. In addition, if necessary, colorants, preservatives, fragrances, flavoring agents or other additives can also be added to the pharmaceutical preparation. To achieve the purpose of medication and enhance the therapeutic effect, the drugs or pharmaceutical compositions of the present invention can be administered by any well-known administration method.

[0057] The fourth aspect of the technical solution of the present invention is to provide the application of the naproxen triazolethione derivative (I) or naproxen triazolethiol derivative (II) of the present invention and its pharmaceutically acceptable salts, and the pharmaceutical composition described in the third aspect in the preparation of a novel coronavirus 3CL protease inhibitor:

[0058]

[0059] Beneficial technical effects:

[0060] The naproxen triazolethione derivative (I) or naproxen triazolethiol derivative (II) of the present invention is a class of new compounds with novel coronavirus 3CL protease inhibitory activity; it can be used for preparing drugs for treating novel coronavirus. Specific embodiments

[0061] The following examples are intended to illustrate the present invention rather than further limit the present invention.

[0062] Example 1

[0063] Preparation of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione

[0064]

[0065] 4.6 g (20.0 mmol) of naproxen was dissolved in 50 mL of acetonitrile. 3.2 g (24.0 mmol) of HOBt and 4.6 g (24.0 mmol) of EDCI were added successively. After stirring at room temperature for 3 h, 5.1 g (80 mmol) of hydrazine hydrate was added under an ice bath. After one and a half hours, it was extracted with ethyl acetate (3×20 mL), washed with sodium bicarbonate, dried with anhydrous sodium sulfate, filtered by suction, and the solvent was removed to obtain a crude yellow solid product, which was directly used for the next reaction.

[0066] 2.4 g (10.0 mmol) of the crude product from the previous step, 0.8 g (15.0 mmol) of potassium hydroxide were dissolved in 20 mL of ethanol under an ice bath. A mixture of 1.2 g (15.0 mmol) of carbon disulfide and 4 mL of ethanol was added dropwise. After the addition, the mixture was stirred at room temperature for 6 h, and a solid was precipitated. It was filtered by suction and dried; The solid was dissolved in 1.9 g (30.0 mmol) of 80% hydrazine hydrate, refluxed until the reaction was complete, cooled, and the pH was adjusted to 1 with dilute hydrochloric acid. A solid was precipitated, filtered by suction, washed with water, and dried to obtain light yellow solid 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione, m.p. 206 - 208 °C, yield 70.0%; 1 HNMR(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).

[0067] Example 2

[0068] Preparation of (E)-4-((3-nitrobenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (Ⅰ1)

[0069]

[0070] 1.0 mmol of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 1.0 mmol of 3-nitrobenzaldehyde were dissolved in 3 mL of acetic acid and refluxed for 3 h. After cooling, a small amount of needle-like crystals precipitated. The mixture was filtered by suction, and yellow solid I1 was precipitated from the filtrate, with a melting point of 181 - 183 °C and a yield of 32.3%; 1 H NMR (400 MHz, DMSO-d6) δ: 1.69 (d, J = 6.8 Hz, 3H, CH3), 3.83 (s, 3H, OCH3), 4.61 (q, J = 6.8 Hz, 1H, CH), 7.10 - 8.56 (m, 10H, benzene ring + naphthalene ring), 10.17 (s, 1H, NCH), 14.07 (s, 1H, NH); 13 C NMR (101 MHz, 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.

[0071] Example 3

[0072] Preparation of (E)-4-((4-nitrobenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (I2)

[0073]

[0074] According to the method of Example 2, 1.0 mmol of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 1.0 mmol of 4-nitrobenzaldehyde were reacted for 3 h to obtain yellow solid I2, with a melting point of 183 - 185 °C and a yield of 50%; 1 H NMR (400 MHz, DMSO-d6) δ: 1.74 (d, J = 7.2 Hz, 3H, CH3), 3.88 (s, 3H, OCH3), 4.67 (q, J = 7.2 Hz, 1H, CH), 7.16 - 8.37 (m, 10H, benzene ring + naphthalene ring), 10.31 (s, 1H, NCH), 14.14 (s, 1H, NH); 13CNMR (101 MHz, 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.

[0075] Example 4

[0076] (E)-4-((4-Hydroxy-3-methoxybenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (Ⅰ3) Preparation

[0077]

[0078] According to the method of Example 2, 1 mmol of 4-yl-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 1.1 mmol of vanillin were reacted for 30 min to obtain white solid Ⅰ3, m.p. 163 - 165 °C, yield 39.2%; 1 HNMR (400 MHz, DMSO-d6) δ: 1.66 (d, J = 7.2 Hz, 3H, CH3), 3.79 (s, 3H, OCH3), 3.85 (s, 3H, OCH3), 4.53 (q, J = 7.2 Hz, 1H, CH), 6.86 - 7.77 (m, 9H, benzene ring + naphthalene ring), 9.51 (s, 1H, NCH), 10.04 (s, 1H, OH), 13.93 (s, 1H, NH); 13 C NMR (101 MHz, 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.

[0079] Example 5

[0080] (E)-4-((2-Chlorobenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (Ⅰ4) Preparation

[0081]

[0082] According to the method of Example 2, 0.5 mmol of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 0.55 mmol of o-chlorobenzaldehyde were reacted for 3 h to obtain white solid I4, m.p. 149-151 °C, yield 33.3%; 1 HNMR (400 MHz, DMSO-d6) δ: 1.66 (d, J = 7.2 Hz, 3H, CH3), 3.82 (s, 3H, OCH3), 4.62 (q, J = 7.2 Hz, 1H, CH), 7.10-7.96 (m, 10H, benzene ring + naphthalene ring), 10.67 (s, 1H, NCH), 14.05 (s, 1H, NH); 13 CNMR (101 MHz, 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.

[0083] Example 6

[0084] Preparation of (E)-4-((3-bromo-4-methoxybenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (I5)

[0085]

[0086] According to the method of Example 2, 1 mmol of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 1.1 mmol of 3-bromo-4-methoxybenzaldehyde were reacted for 30 min to obtain white solid I5, m.p. 185-187 °C, yield 40.2%; 1 H NMR (400 MHz, DMSO-d6) δ: 1.66 (d, J = 7.2 Hz, 3H, CH3), 3.84 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 4.55 (q, J = 7.2 Hz, 1H, CH), 7.11-7.97 (m, 9H, benzene ring + naphthalene ring), 9.68 (s, 1H, NCH), 13.95 (s, 1H, NH); 1313C NMR (101 MHz, 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.

[0087] Example 7

[0088] Preparation of (E)-4-((4-chlorobenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (I6)

[0089]

[0090] According to the method of Example 2, 1.0 mmol of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 1.0 mmol of 4-chlorobenzaldehyde were reacted for 3 h to obtain a pale yellow solid I6, m.p. 185 - 186 °C, yield 36.9%; 1 1H NMR (400 MHz, DMSO-d6) δ: 1.67 (d, J = 6.8 Hz, 3H, CH3), 3.83 (s, 3H, OCH3), 4.57 (q, J = 6.8 Hz, 1H, CH), 7.10 - 7.81 (m, 10H, benzene ring + naphthalene ring), 9.91 (s, 1H, NCH), 14.00 (s, 1H, NH); 13 13C NMR (101 MHz, 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.

[0091] Example 8

[0092] Preparation of (E)-4-((3-hydroxy-4-methoxybenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (I7)

[0093]

[0094] According to the method of Example 2, 1.0 mmol of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 1.0 mmol of isovanillin were reacted for 3.5 h to obtain white solid I7, m.p. 217-219 °C, with a yield of 55%. 1 1H NMR (400 MHz, DMSO-d6) δ: 1.66 (d, J = 7.2 Hz, 3H, CH3), 3.84 (s, 6H, 2×OCH3), 4.50 (q, J = 7.2 Hz, 1H, CH), 7.01-7.74 (m, 9H, benzene ring + naphthalene ring), 9.49 (s, 2H, OH, NCH), 13.89 (s, 1H, NH); 13 13C NMR (101 MHz, 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.

[0095] Example 9

[0096] Preparation of (E)-4-((4-bromobenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione (I8)

[0097]

[0098] According to the method of Example 2, 1.0 mmol of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 1.0 mmol of 4-bromobenzaldehyde were reacted for 4 h to obtain white solid I8, m.p. 191-193 °C, with a yield of 21.4%; 1 1H NMR (400 MHz, DMSO-d6) δ: 1.70 (d, J = 6.8 Hz, 3H, CH3), 3.86 (s, 3H, OCH3), 4.59 (q, J = 6.8 Hz, 1H, CH), 7.13-7.78 (m, 10H, benzene ring + naphthalene ring), 9.93 (s, 1H, NCH), 14.02 (s, 1H, NH); 13CNMR (101 MHz, 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.

[0099] Example 10

[0100] Preparation of (E)-4-((4-Methoxybenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione

[0101]

[0102] Prepared according to the method in the literature [Heteroatom Chemistry, 2002, 13(3): 199 - 206]: 0.3 g (1 mmol) of 4-amino-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione and 0.14 g (1.1 mol) of 4-anisaldehyde were reacted for 2 h, and recrystallized from acetic acid 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 °C, yield 69%. 1 H NMR (400 MHz, 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).

[0103] Example 11

[0104] Preparation of (E)-4-((3-Bromobenzylidene)amino)-3-(1-(6-methoxy-2-naphthyl)ethyl)-1H-1,2,4-triazole-5(4H)-thione

[0105]

[0106] Prepared according to the method in the literature [Eur. J. Med. Chem. 2018, 158: 134].

[0107] Example 12

[0108] Antiviral Activity of Naproxen Triazole Thione Derivatives against Novel Coronavirus 3CL Protease

[0109] 1 Experimental Principle

[0110] The fluorescence resonance energy transfer (FRET) method was used for detection, and the principle was as follows: Edans is a fluorescence donor, and Dabcyl is a fluorescence acceptor or quencher group. The absorption spectra of these two fluorescence groups overlap. When the distance between these two fluorescence groups is appropriate (usually 7 - 10 nm), the fluorescence energy transfers from the donor to the acceptor, resulting in the attenuation of the fluorescence intensity of the donor fluorescence molecule itself. Edans and Dabcyl were connected to both ends of the natural substrate of 2019 - nCoV Mpro / 3CLpro protease, namely Dabcyl - KTSAVLQSGFRKME - Edans. When the 2019 - nCoV Mpro / 3CLpro protease did not cleave this substrate, the two groups were close enough for fluorescence resonance energy transfer to occur, that is, Dabcyl could quench the fluorescence of Edans and no fluorescence was detected. When the substrate was cleaved by the 2019 - nCoV Mpro / 3CLpro protease, the head and tail ends of the polypeptide separated, the two groups separated, and the fluorescence of Edans was no longer quenched by Dabcyl, so the fluorescence of Edans could be detected. In this way, the enzymatic activity of 2019 - nCoV Mpro / 3CLpro protease could be detected very sensitively through fluorescence detection. If an inhibitor of 2019 - nCoV Mpro / 3CLpro was added to the reaction system, the generation of fluorescence would be inhibited, and the fluorescence intensity was inversely proportional to the inhibitory effect of the inhibitor. In this way, the inhibitory effect of the 2019 - nCoV Mpro / 3CLpro protease inhibitor could be detected. The maximum excitation wavelength of Edans was 340 nm, and the maximum emission wavelength was 490 nm.

[0111] 2 Experimental Methods

[0112] 2.1 Preparation of Samples and Positive Drugs

[0113] An appropriate amount of the inhibitor sample to be measured and the positive drug Ebselen were taken and prepared into solutions with appropriate concentrations using DMSO.

[0114] 2.2 Preparation of Assay Reagent

[0115] Prepare an appropriate amount of Assay Reagent according to the sample quantity (including relevant controls). For every 1 μl of 2019-nCoV Mpro / 3CLpro, add 92 μl of Assay Buffer to prepare the Assay Reagent for detecting one sample.

[0116] 2.3 Sample Detection

[0117] The samples of the examples are detected in a 96-well black plate. Add 93 μl of Assay Reagent and 5 μl of the sample to each sample well in sequence, add 93 μl of Assay Reagent and 5 μl of the solvent DMSO to the model well, and add 93 μl of Assay Buffer and 5 μl of the solvent DMSO to the blank control. Use an oscillator to oscillate for 1 min to mix well. Quickly add 2 μl of Substrate to each well, and use an oscillator to oscillate for 1 min to mix well. After incubating in the dark at 37 °C for 15 - 20 minutes, perform fluorescence measurement using a multifunctional microplate reader. The excitation wavelength is 340 nm, and the emission wavelength is 490 nm.

[0118] 3 Detection of Samples

[0119] Samples of the examples; the positive control drug is ebselen.

[0120] 4 Activity Results

[0121] The inhibitory activity of 2019-nCoV Mpro / 3CLpro protease in the reaction system at a sample detection concentration of 50 μg / ml was evaluated. Compounds with an inhibition rate greater than 50% were re-screened, repeated 3 times, and their IC 50 values were calculated according to the results of the re-screening. The preferred experimental results are shown in Table 1.

[0122]

[0123] Table 1 Inhibitory activity and IC 50 (μg / mL)

[0124] Y Inhibition rate / % <![CDATA[IC 50 , μg / mL]]> <![CDATA[4-NO2]]> 86.29±4.46 3.28±0.38 <![CDATA[3-OCH3-4-OH]]> 90.06±2.53 2.99±0.08 2-Cl 80.44±6.65 5.72±0.18 <![CDATA[3-Br-4-OCH3]]> 67.17±2.35 23.79±4.94

[0125] Naproxen triazolethione derivatives have anti-SARS-CoV-2 3CL protease activity and can be used to prepare SARS-CoV-2 3CL protease inhibitors. Naproxen triazolethione derivatives and their pharmaceutically acceptable salts are used in the preparation of anti-SARS-CoV-2 drugs.

Claims

1. A naproxen triazolethione derivative and a pharmaceutically acceptable salt thereof as shown in structural formula I: in, R is selected from the group consisting of hydrogen, deuterium, C1-C2 alkyl, C3-C7 straight chain or C3-C7 branched chain alkyl; Z is selected from the group consisting of 6-methoxy or 6-ethoxy; Y 1 is selected from: hydrogen, deuterium, fluorine, chlorine, bromine or iodine; Y 2 is selected from: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methoxy or ethoxy; Y 3 is selected from: hydrogen, deuterium, hydroxy, ethoxy, nitro, fluorine, chlorine, bromine or iodine; Y 4 is selected from: hydrogen, deuterium, fluorine, chlorine, bromine, iodine, methoxy or ethoxy; Y 5 Selected from: deuterium, fluorine, chlorine, bromine or iodine.

2. A naproxen triazolethione derivative and a pharmaceutically acceptable salt thereof, characterized in that The naproxen triazolethione derivative is selected from the following compounds:

3. The method for preparing the naproxen triazolethione derivative according to claim 1, characterized in that Its preparation reaction is as follows: Among them, R 1 Selected from: hydrogen, C1-C2 alkyl, C3-C7 straight chain or C3-C7 branched alkyl; R, Z, Y 1 ~Y 5 The definition as in claim 1.

4. Use of the naproxen triazolethione derivative and pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of novel coronavirus 3CL protease inhibitors.

5. Use of the naproxen triazolethione derivative and pharmaceutically acceptable salt thereof according to claim 1 or 2 in the preparation of a novel coronavirus drug.

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

7. Use of naproxen triazolethione derivatives represented by Formula Ia and pharmaceutically acceptable salts thereof in the preparation of novel coronavirus drugs:

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