CN112920136A - Compound and medical application thereof in novel coronavirus pneumonia - Google Patents
Compound and medical application thereof in novel coronavirus pneumonia Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, in particular to a compound and medical application thereof in novel coronavirus pneumonia, belongs to the technical field of pharmacy, and relates to application of the compound in preparation of a medicine for preventing and/or treating diseases related to the novel coronavirus pneumonia, wherein the compound is a compound shown in a formula I or a formula II or a pharmaceutically acceptable salt or ester thereof.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, in particular to a compound and medical application thereof in treating novel coronavirus pneumonia, and belongs to the technical field of pharmacy.
Background
Since the outbreak of COVID-19 caused by SARS-CoV-2, it has lost the lives of millions of people worldwide. Furthermore, despite prior outbreaks of zoonosis, antiviral drugs or vaccines against closely related coronaviruses, SARS-CoV-1 or MERS-CoV, have not been approved. For the design and development of COVID-19 antiviral drugs, it is still important to understand the replication cycle and key genomic elements. Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses. The two viral cysteine proteases 3CLpro and PLpro play a key role. 3CLpro is highly conserved among all coronaviruses and plays an important role in mediating viral replication and transcription, and therefore is considered as an ideal protein target for the development of broad-spectrum antiviral drugs. Cys145 and His41 are key residues of the catalytic site of 3 CLpro. Furthermore, there are several pockets in the active site of 3CLpro, such as the glutamine-specific S1 site, the hydrophobic S2 site and the small S4 site, which together provide ample opportunity for drug design. PLpro of SARS-CoV-2 can inhibit viral replication and reactivate the innate immune response. Similar to SARS-CoV PLpro, the active site of PLpro of SARS-CoV-2 contains the classical Cys-His-Asp ternary catalytic molecule, the side chain of Trp106 is located within the oxyanion pore, and the indole ring nitrogen is suggested to be involved in the stabilization of negatively charged tetrahedral intermediates generated throughout the catalytic process.
Disclosure of Invention
LY1 is a novel effective small molecule inhibitor and is a new antiviral drug candidate. The chemical name is 3- ((2- (piperazine-1-yl) phenyl) amino) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide, and the study shows that LY1 can effectively inhibit the virus activity of COVID-19 new crown pneumonia, and does not cause obvious toxicity under multiple effective doses. The structural formula is as follows:
LY1 can inhibit the activity of 3CLpro and PLpro, and can be used as the therapeutic drug for COVID-19 new coronary pneumonia.
The invention synthesizes a series of compounds which have similar structures and are effective to the new coronary pneumonia.
The invention provides a preparation method of a series of compounds, which is efficient, practical and economical, short in production period, high in yield and easy for industrial production.
The invention verifies the anti-new crown pneumonia activity of a series of compounds, systematically verifies the compound LY1, and provides potential drug molecules for anti-new crown drugs.
The technical scheme is as follows: in order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a compound having the formula
The technical scheme adopted by the invention is as follows:
in a first aspect, there is provided a compound of formula I or formula II, or a pharmaceutically acceptable salt or ester thereof:
wherein, the A ring can be a five, six or seven-membered saturated or unsaturated ring, one to two heteroatoms exist in the ring, and the heteroatom refers to N, O, S;
r1 is one or more substituents independently selected from hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxyacyl;
r2 is one or two substituents selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, and the halogen is fluorine, chlorine, bromine or iodine.
R3 is a substituent selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxy acyl, wherein the halogen refers to fluorine, chlorine, bromine or iodine.
R4 is one or more substituents selected from hydrogen, halogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, nitro, amino, carboxy or C1-C3 alkoxyacyl, aromatic, heteroaromatic, cyclic or heterocyclic, wherein halogen is fluorine, chlorine, bromine or iodine,
In some embodiments, ring A is pyrrolyl, imidazolyl, pyrazolyl, furanyl, tetrahydrofuranyl, thienyl, tetrahydrofuranyl, thiazolyl, phenyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, pyrrolyl, thiazolyl,
as the benzene ring, benzene rings are preferred. R1 is one or more substituents independently selected from hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, nitro, amino, carboxy or C1-C3 alkoxyacyl, preferably hydrogen.
R2 is one or two substituents selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkoxy acyl, wherein the halogen refers to fluorine, chlorine, bromine or iodine, and preferably is methyl.
R3 is a substituent selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxy acyl, wherein the halogen refers to fluorine, chlorine, bromine or iodine, and preferably hydrogen, methyl, hydroxyl and halogen.
R4 is one or more substituent groups selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxyacyl, aromatic, heteroaromatic, ring or heterocyclic ring,
halogen means fluorine, chlorine, bromine or iodine, preferably
On the basis of the above preferable formula, the compound is 3- ((2- (piperazine-1-yl) phenyl) amino) -5H-naphtho [1,8-cd ] isothiazole-5-ketone 1, 1-dioxide, which is called compound LY1 for short, and the structural formula is as follows
Pharmacological experiments prove that the compound has obvious inhibition effect on the new coronavirus.
One of the objects of the present invention is to provide a method for preparing compounds represented by the general formula I/II, wherein the synthetic route is as follows:
another object of the present invention is to provide a process for the preparation of compound LY1, the synthetic route being as follows: the preparation method of the compound LY1 is characterized in that the synthetic route is as follows:
the method comprises the following steps:
(1) (compound 1) 1-naphthalenesulfonyl chloride is subjected to substitution reaction to prepare (compound 2) 1-naphthalenesulfonamide;
(2) (compound 2) the 1-naphthalenesulfonamide is oxidized to prepare (compound 3)5, 8-dioxo-dihydronaphthalene;
(3) (compound 3) subjecting 5, 8-dioxo-dihydronaphthalene to substitution reaction with (compound 4) tert-butyl 4- (2-aminophenyl) piperazine-1-carboxylate to obtain (compound 5) (tert-butyl 4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylate);
(4) (Compound 5) (tert-butyl 4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylate) amino deprotection gives the title compound (Compound LY1)4- ((2- (piperazin-1-yl) phenyl) amino) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide.
Further, the step (1) specifically means: adding the compound 1 into a reactor containing a solvent, stirring, dropwise adding 0 ℃ ammonia water in an ice bath, after dropwise adding, tracking and detecting a reaction by a thin layer, after the reaction is finished, distilling under reduced pressure, separating out a solid, filtering, and drying in vacuum to obtain a compound 2.
Preferably, the solvent is one or more of aprotic solvents.
The step (2) specifically comprises the following steps: adding (compound 2) 1-naphthalene sulfonamide into a reactor containing an organic solvent, controlling the temperature to be 65-70 ℃ and stirring; dissolving ten times of equivalent ceric sulfate by using 2mol/L dilute sulfuric acid, controlling the temperature to be 65-70 ℃, stirring, slowly dropwise adding the solution into the system, timing from dropwise adding, stopping reaction after 25-35 minutes, standing, cooling, carrying out suction filtration, then adding dichloromethane into filtrate for extraction, taking a dichloromethane layer, and carrying out vacuum drying to obtain the 5, 8-dioxo-dihydronaphthalene. More preferably, the temperature is 65 ℃ and the reaction time is 27 minutes.
Further, in the step (2), the organic solvent is one or more of glacial acetic acid and trifluoroacetic acid.
The step (3) specifically comprises the following steps: dissolving the compound 3, the compound 4 and the catalyst by using glacial acetic acid, and stirring and reacting for 25-30 hours at normal temperature; distilling under reduced pressure to remove the solvent to obtain a crude product, and purifying the crude product to obtain a compound 5;
the catalyst is one or more of copper acetate monohydrate, cerium trichloride and triethylamine; more preferably copper acetate monohydrate.
The step (4) specifically comprises the following steps: removing amino protection from the compound 5 to obtain a compound LY 1; the method specifically comprises the following steps: dissolving the compound 5 by using an organic solvent dichloromethane, introducing hydrochloric acid gas, stirring at room temperature, and carrying out thin-layer tracking detection reaction; after the reaction is finished, filtering to obtain the compound LY 1.
In the step (4), the organic solvent is one or more of dichloromethane, chloroform and dioxane.
Preferably, in step (3), the crude product is purified to give compound 5, comprising:
adding absolute ethyl alcohol into the crude product, heating to boil at 110 ℃, monitoring the liquid phase, stopping heating after the reaction product is completely converted, naturally cooling and stirring for 6 hours, filtering to obtain a filter cake, performing column chromatography, adding 10 times of equivalent of organic solvent for complete dissolution, dropwise adding 25 times of equivalent of alcohol organic solvent, removing the organic solvent after rotary evaporation, and filtering to obtain a compound 5 after crystals are completely separated out.
Further, in the purification process, the organic solvent is one or more of dichloromethane and ethyl acetate, preferably dichloromethane; the alcohol organic solvent is one or more of methanol, ethanol and isopropanol, preferably isopropanol.
The preparation and purification method of the compound LY1 series compound provided by the invention has the advantages of simple preparation method, low cost and high yield, and the compound LY1 with good anti-tumor activity is conveniently prepared by taking naphthalenesulfonyl chloride as a raw material at lower cost.
In a third aspect, the use of the compounds in the preparation of a medicament for the prevention and/or treatment of diseases associated with novel coronavirus pneumonia is provided.
The compound inhibits the activity of 3CLpro and PLpro by high specificity, and is used as a medicament for treating novel coronavirus pneumonia.
Can be used as a medicine for treating diseases which are resistant to STAT3 inhibitor medicines or gemfibrotinib medicines and comprise colorectal cancer, lung cancer and novel coronavirus pneumonia.
Compound LY1 is particularly effective.
Drawings
FIG. 1 is a diagram: efficacy of LY1 on propagation of new coronaviruses was assessed by quantitative real-time RT-PCR, compound LY1 showed good anti-viral activity;
FIG. 2 is a diagram of: MTT method, cytotoxicity of compound LY1 was evaluated by MTT method, and CC50 value of compound LY1 was higher than 15 μ M. As shown in fig. 2. The experimental result shows that LY1 has excellent antiviral activity and less toxicity in vitro;
FIG. 3 is a diagram of: the Fluorescence Resonance Energy Transfer (FRET) protease determination result shows that LY1 can effectively inhibit the activity of SARS-CoV-23 CLpro and PLpro;
FIG. 4 is a diagram of: surface Plasmon Resonance (SPR) analysis results showed that LY1 mainly targets 3CLpro protein.
Detailed Description
To further illustrate the present invention, a series of examples are given below, which are purely illustrative and are intended to be a detailed description of the invention only and should not be understood as limiting the invention.
A compound and its preparation
Precursor preparation
1) Preparation of 1-naphthalenesulfonamides
Adding 1-naphthalene sulfonyl chloride (5g, 21.9mmol) into a 1L round-bottom flask containing 200ml of acetone, stirring, dropwise adding 240 ml of 0 ℃ ammonia water into an ice bath, detecting the reaction by tracking a thin layer after the dropwise adding is finished, distilling out an organic solvent and ammonia gas decomposed from the ammonia water under reduced pressure after the reaction is finished, separating out a solid, filtering, and drying in vacuum to obtain the 1-naphthalene sulfonamide (4.35g, the yield is 96.7%). The compound was used in the next reaction without further purification. The experimental data are as follows:
Mp 147～149℃.1H NMR(500MHz,DMSO-d6)δ:8.65(d,J＝8.5Hz,1H),8.19(d,J＝8.2Hz,1H), 8.14(d,J＝6.8Hz,1H),8.08(d,J＝7.4Hz,1H),7.76–7.59(m,5H).HR-MS(ESI)calcd for C10H9NO2S [M+Na]+230.0246,found 230.0244
2) preparation of 5, 8-dioxo-dihydronaphthalene
Ceric sulfate anhydride (160g, 677.45mmol) was dissolved in 750ml of 2mol/L dilute sulfuric acid, and the temperature was controlled at 65 ℃. Adding 1-naphthalene sulfonamide (10g, 48.49mmol) into a 500ml round bottom flask containing 200ml of glacial acetic acid, controlling the temperature to 65 ℃, stirring at the temperature, slowly dropwise adding the mixture into a ceric sulfate aqueous phase system, timing from the dropwise addition, monitoring by thin layer chromatography, stopping the reaction after 27 minutes, cooling the reaction liquid, filtering, extracting the filtrate with 1200ml of dichloromethane, drying to remove water, performing low-pressure rotary evaporation to obtain a light yellow solid, and performing vacuum drying to obtain 5, 8-dioxa-dihydronaphthalene (6.72g, yield 58.43%). Directly used in the next reaction without purification. The experimental data are as follows:
Mp 186～188℃.HR-MS(ESI)calcd for C10H7NO4S[M+Na]+259.9988,found 259.9989
example 1
1.1 preparation of (4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylic acid tert-butyl ester)
5, 8-dioxo-dihydronaphthalene (56.5g, 238.17mmol), tert-butyl 4- (2-aminophenyl) piperazine-1-carboxylate (60g, 217.90mmol) and copper acetate monohydrate (5.6g, 28.05mmol) were added to a 2L round-bottomed flask containing 1200ml of glacial acetic acid, reacted at 25 ℃ and stirred at that temperature for 26 hours; the solvent was removed by distillation under reduced pressure to obtain a crude product.
Adding 1500ml of absolute ethyl alcohol into the crude product, heating to boil at 110 ℃, monitoring the complete conversion of a reaction product by a liquid phase, stopping heating, naturally cooling and stirring for 6h, filtering to obtain a filter cake, removing general impurities after column chromatography, adding 10 times of equivalent of dichloromethane to completely dissolve, slowly dropwise adding 25 times of equivalent of isopropanol, removing the same amount of dichloromethane after low-pressure rotary evaporation at 33 ℃, separating out all crystals, filtering to obtain mauve crystals, and drying at low pressure to obtain the tert-butyl 4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalene-2-yl) amino) phenyl) piperazine-1-carboxylate with the purity of 97% (67.53g, yield 83%).
The experimental data are as follows:
Mp 189～190℃.1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.39(dd,J＝8.0,1.3Hz,1H),8.29(dd, J＝7.8,1.3Hz,1H),8.05(t,J＝7.8Hz,1H),7.46–7.40(m,3H),7.23(d,J＝4.2Hz,2H),6.12(s,1H), 3.45(t,J＝4.8Hz,4H),2.82(t,J＝5.0Hz,4H),1.40(s,9H).HR-MS(ESI)calcd for C25H28N4O6S,[M+Na] +535.1622,found 535.1619
1.2 preparation of 4- ((2- (piperazin-1-yl) phenyl) amine) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide
Tert-butyl (4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylate) (2g, 3.78mmol) was added to a 50ml round-bottom flask containing 2ml dichloromethane, followed by gaseous hydrochloric acid and detection of the reaction by thin-layer tracing; after the reaction, a filter cake was obtained by filtration, and 4- ((2- (piperazin-1-yl) phenyl) amine) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide was isolated by drying under reduced pressure (1.95g, yield 97%). The experimental data are as follows:
2.1 preparation of (1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) -nicotinic acid
5, 8-dioxo-dihydronaphthalene 1(237mg,1mmol), 5-aminonicotinic acid (172mg,1.2mmol) and copper acetate monohydrate (20mg,0.1mmol) were added to a 25ml round-bottom flask containing 5ml of glacial acetic acid, heated under reflux and reacted at this temperature with stirring for 3 hours; the solvent was distilled off under reduced pressure, and 3- (naphthalen-2-ylamino) -5H-naphthalen [1,8-cd ] isothiazol-5-one 1, 1-dioxide (221mg, yield 71%) was separated by liquid chromatography.
The experimental data are as follows
1H NMR(500MHz,DMSO):δ8.31(s,1H),8.04(d,J＝7.6Hz,1H),7.98(d,J＝2.5Hz,1H),7.94(d, J＝7.5Hz,1H),7.78(t,J＝7.5Hz,1H),7.44(s,1H),7.40(s,2H),5.62(s,1H),5.34(s,2H).HRMS(ESI) for C16H11N3O6SNa[M+Na]+:calcd,396.0266；found,396.0270.
Example 3
3.1 preparation of (4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylic acid tert-butyl ester)
5, 8-dioxo-dihydronaphthalene (0.5g, 2.11mmol), tert-butyl 4- (2-aminophenyl) piperazine-1-carboxylate (0.787g, 2.53mmol) and copper acetate monohydrate (42mg, 0.21mmol) were added to a 25ml round-bottom flask containing 12ml of glacial acetic acid, heated at 118 ℃ under reflux, and the reaction was stirred at this temperature for 3 hours; the solvent was removed by distillation under the reduced pressure, and the compound (tert-butyl 4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylate) (0.568g, yield 51%) was isolated by liquid chromatography. The experimental data are as follows:
Mp 189～190℃.1H NMR(500MHz,DMSO-d6)δ8.85(s,1H),8.39(dd,J＝8.0,1.3Hz,1H),8.29(dd, J＝7.8,1.3Hz,1H),8.05(t,J＝7.8Hz,1H),7.46–7.40(m,3H),7.23(d,J＝4.2Hz,2H),6.12(s,1H), 3.45(t,J＝4.8Hz,4H),2.82(t,J＝5.0Hz,4H),1.40(s,9H).HR-MS(ESI)calcd for C25H28N4O6S,[M+Na] +535.1622,found 535.1619
3.2 preparation of 4- ((2- (piperazin-1-yl) phenyl) amine) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide
Tert-butyl (4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylate) (200 mg, 0.378mmol) was added to a 10ml round-bottom flask containing 2ml dichloromethane, followed by 2ml trifluoroacetic acid, stirring at room temperature and detection of the reaction by thin-layer tracing; after the completion of the reaction, the solvent was distilled off under reduced pressure, and the compound was isolated by liquid chromatography to give 4- ((2- (piperazin-1-yl) phenyl) amine) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide (149mg, yield 95%). The experimental data are as follows:
example 4
Preparation of 7- ((4-hydroxyphenyl) amino) -5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide
5, 8-dioxo-dihydronaphthalene (100mg, 0.421mmol), 4-aminophenol (55.2mg, 0.506mmol) and copper acetate monohydrate (16.83mg, 0.084mmol) were charged into a 25mL round-bottomed flask, and 5mL of glacial acetic acid was added and dissolved, followed by reaction at room temperature for 3 hours, completion of the reaction, removal of the solvent by distillation under reduced pressure, and liquid chromatography to give 7- ((4-hydroxyphenyl) amino) -5, 8-dioxo-5, 8-dihydronaphthalene-1-sulfonamide.
The experimental data are as follows.
1H NMR(400MHz,DMSO)δ9.67(s,1H),)δ9.63(s,1H)8.39(dd,J＝8.0,1.3Hz,1H),8.07(dd,J ＝7.8,1.3Hz,1H),8.05(t,J＝7.8Hz,1H)7.23(d,J＝4.2Hz,2H))6.93(s,1H)7.23(d,J＝4.2Hz,2H), 5.88(S,H)HR-MS(ESI)calcd forC16H12N2O5S,[M+H]345.0467,found 345.0460
Example 5
5.1 preparation of 3- ((4- (diethylamino) phenyl) amino) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide
5, 8-dioxo-dihydronaphthalene 3(300mg, 1.26mmol), N-diethyl-p-phenylenediamine 4(249.26mg, 1.52mmol) and copper acetate monohydrate (20mg,0.1mmol) were added to a 100ml round-bottom flask containing 15ml glacial acetic acid and stirred at room temperature for 24 hours; the solvent was removed by distillation under the reduced pressure, and anhydrous ethanol was added thereto and heated, and then, condensed and refluxed, most of the solvent was distilled off and then filtered, and 3- ((4- (diethylamino) phenyl) amino) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide (37mg, yield 7.67%) was separated as a cake by column chromatography.
1H NMR(400MHz,DMSO-d6)δ9.66(s,1H),8.39(dd,J＝8.0,1.3Hz,1H),8.07(dd,J＝7.8,1.3Hz, 1H),8.05(t,J＝7.8Hz,1H)7.20(d,J＝8.9Hz 2H),6.78–6.70(d,J＝8.9Hz,2H),5.99(s,1H),3.37(d, J＝7.0Hz,4H),,1.11(t,J＝7.0Hz,6H).HR-MS(ESI)calcd forC20H19N3O3S,[M+H]382.1147,found 382.1147
Example 6
6.1 preparation of 3- ((2-aminophenyl) amino) -5H-naphthalen [1,8-cd ] isothiazol-5-one 1, 1-dioxide
5, 8-dioxo-dihydronaphthalene 1(237mg,1mmol) and 1, 2-diaminoaniline (130mg,1.2mmol) were added. Adding copper acetate monohydrate (20mg,0.1mmol) into a 50ml eggplant-shaped bottle containing 10ml glacial acetic acid, and stirring at room temperature for reaction for 16 hours; the solvent was removed by distillation under the reduced pressure, and 3- ((2-aminophenyl) amino) -5H-naphthalen [1,8-cd ] isothiazol-5-one 1, 1-dioxide (234mg, yield 72%) was measured by liquid chromatography
The experimental data are as follows; yellow powdery solid mp (262 ℃ -267 ℃).1H NMR(300MHz,DMSO)δ8.70(dd,J＝1.0 Hz,2H),8.24-7.90(m,7H),7.23(s,1H),6.43-6.58(m,1H)
HRMS(ESI)of C16H12N3O3S[M+H]+326.0
Example 7
7.1 preparation of 3- (4-fluoro-2- (trifluoromethyl) benzyl) -5H-naphthalen [1,8-cd ] isothiazol-5-one 1, 1-dioxide
5, 8-dioxo-dihydronaphthalene 1(100mg), 4-fluoro-2- (trifluoromethyl) aniline (90.6mg) and copper acetate monohydrate (28.4mg) were added to a 25ml round-bottomed flask containing 5ml of glacial acetic acid, and the reaction was heated under reflux and stirred at that temperature for 34 hours; after the reaction was completed, 47.6mg of the crude product was obtained (yield: 47.6%). And then adding DCM to dissolve the mixture, adding 5g of 100-mesh silica gel to prepare sand, and carrying out column chromatography separation and purification after sand preparation is finished. After the separation is finished, a primary purified product is obtained and is analyzed in LC-MS to obtain a product with 397 molecular weight, and the product can be further purified. Further purification by column chromatography gave 26.2mg (yield 26.2%) of the purified product 3- (4-fluoro-2- (trifluoromethyl) benzyl) -5H-naphthalen [1,8-cd ] isothiazol-5-one 1, 1-dioxide.
1H NMR(400MHz,DMSO-d6)δ10.20(s,1H),8.37(d,J＝7.6Hz,1H),8.26(d,J＝7.6Hz,1H),8.02 (t,J＝7.6Hz,1H),7.64(dd,J＝8.8,5.1Hz,3H),5.76(s,1H),HRMS(ESI)of C17H8F4N2O3S[M+H] 397.3152
Example 8
Preparation of 3- ((6-Fluoropyridin-3-yl) amino) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide
5, 8-dioxo-dihydronaphthalene (100mg, 0.421mmol), 2-fluoro-5-aminopyridine (56.71mg, 0.506mmol) and copper acetate monohydrate (16.83mg, 0.084mmol) were charged into a 25mL round-bottomed flask, and 5mL of glacial acetic acid was added and dissolved, and after completion of the reaction at room temperature for 3 hours, the solvent was distilled off under reduced pressure, and the 3- ((6-fluoropyridin-3-yl) amino) -5H-naphtho [1,8-cd ] isothiazol-5-one 1, 1-dioxide was obtained by liquid chromatography.
The experimental data are as follows
1H NMR(400MHz,DMSO-d6)δ9.87(s,1H),8.64(dd,J＝7.9,1.1Hz,1H)8.37(d,J＝7.6Hz,1H), 8.26(d,J＝7.6Hz,1H),8.02(t,J＝7.6Hz,1H)7.67(dd,J＝7.4,2.7Hz,1H)7.40(d,J＝7.4Hz,1H)6.06 (s,1H)HR-MS(ESI)calcd for C15H8FN3O3S,[M+H]330.02,found330.02
Example 9
9.1 preparation of N-methylnaphthalene-1-sulfonamide
Adding 1-naphthalene sulfonyl chloride (5g, 21.9mmol) into a 1L round-bottom flask containing 200ml of acetone, stirring, dropwise adding 240 ml of 0 ℃ methylamine into an ice bath, detecting the reaction by tracking a thin layer after the dropwise adding is finished, distilling out an organic solvent and ammonia gas decomposed from ammonia water under reduced pressure after the reaction is finished, separating out a solid, filtering, and drying in vacuum to obtain the N-methylnaphthalene-1-sulfonamide (4.82g, yield 95.66%). The compound was used in the next reaction without further purification.
9.2 preparation of N-methyl-5, 8-dihydronaphthalene-1-sulfonamide
Ceric sulfate anhydride (160g, 677.45mmol) was dissolved in 750ml of 2mol/L dilute sulfuric acid, and the temperature was controlled at 65 ℃. Adding N-methylnaphthalene-1-sulfonamide (10g, 48.49mmol) into a 500ml round bottom flask containing 200ml glacial acetic acid, controlling the temperature to 65 ℃, stirring at the temperature, slowly dropwise adding into a cerous sulfate aqueous phase system, timing from the dropwise addition, monitoring by thin layer chromatography, stopping the reaction after 27 minutes, cooling the reaction liquid, filtering, extracting the filtrate with 1200ml dichloromethane, drying to remove water, performing low-pressure rotary evaporation to obtain a light yellow solid, and performing vacuum drying to obtain the N-methyl-5, 8-dihydronaphthalene-1-sulfonamide (6g, yield 54.22%). Directly used in the next reaction without purification
9.34- (2- (((8- (N-methylsulfamoyl) -1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylic acid tert-butyl ester
N-methyl-5, 8-dihydronaphthalene-1-sulfonamide (56.5g, 238.17mmol), tert-butyl 4- (2-aminophenyl) piperazine-1-carboxylate (60g, 217.90mmol) and copper acetate monohydrate (5.6g, 28.05mmol) were added to a 2L round bottom flask containing 1200ml of glacial acetic acid, reacted at 25 ℃ and stirred at this temperature for 26 hours; the solvent was removed by distillation under reduced pressure to obtain a crude product.
Adding 1500ml of absolute ethyl alcohol into the crude product, heating to boil at 110 ℃, monitoring the complete conversion of a reaction product by a liquid phase, stopping heating, naturally cooling and stirring for 6h, filtering to obtain a filter cake, removing general impurities after column chromatography, adding 10 times of equivalent of dichloromethane to completely dissolve, slowly dropwise adding 25 times of equivalent of isopropanol, removing the same amount of dichloromethane after low-pressure rotary evaporation at 33 ℃, separating out all crystals, filtering to obtain mauve crystals, and drying at low pressure to obtain the tert-butyl 4- (2- (((8- (N-methylsulfamoyl) -1, 4-dioxo-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylate (54.33g, yield 78.32%).
9.4 preparation of N-methyl-5, 8-dioxa-7- ((2- (piperazin-1-yl) phenyl) amino) -5, 8-dihydronaphthalene-1-sulfonamide
Tert-butyl (4- (2- ((1, 4-dioxo-5-sulfamoyl-1, 4-dihydronaphthalen-2-yl) amino) phenyl) piperazine-1-carboxylate) (2g, 3.78mmol) was added to a 50ml round-bottom flask containing 20ml dichloromethane, followed by gaseous hydrochloric acid and detection of the reaction by thin-layer tracing; after the reaction, a filter cake was obtained by filtration, and N-methyl-5, 8-dioxa-7- ((2- (piperazin-1-yl) phenyl) amino) -5, 8-dihydronaphthalene-1-sulfonamide (1.82g, yield 98%) was isolated by drying under reduced pressure. The experimental data are as follows:
1H NMR(400MHz,Chloroform-d)δ8.58(s,1H),8.47(dq,J＝7.9,1.4Hz,2H),7.93(t,J＝7.8Hz,1H), 7.46(tq,J＝4.6,2.7Hz,1H),7.21(t,J＝3.4Hz,3H),6.65(s,1H),6.37(s,1H),3.17(t,J＝4.6Hz,4H), 2.93(dd,J＝5.9,3.4Hz,4H),2.80(d,J＝3.0Hz,3H),2.04(s,1H)HR-MS(ESI)calcd forC21H22N4O4S, [M+H]+427.1362,found 427.1361
second, pharmacological part (New coronavirus pneumonia)
1. Plasmids
The open reading frame of 3CLpro was cloned into pET28a vector between Nde I and Xho I cloning sites. This construct ensured that the expressed protein could be cleaved automatically by 3CLpro itself and could be treated with PreScission protease to remove the 6 xhis tag. For PLP construction, codon-optimized SARS-CoV-2nsp3 was inserted in aa746-1062 part into Nde I and EcoR I of pET28a, the peptide being fused to the N-terminal SAVLQ protein sequence. The first amino acid (Glu) was mutated to Ser to facilitate the digestion of PLP by 3CLpro to remove the N-terminal His-tag. All mutants were produced using KOD-plus-neo (TOYOBO, Osaka, Japan).
2. Production and purification of recombinant proteins
Constructs of 3CLpro and PLP were transformed into E.coli BL21(DE3) (Novagen) respectively for expression. For detailed information, individual clones were precultured overnight at 37 ℃ in LB medium containing kanamycin (50. mu.g/mL) to produce seed cultures. Then, the seed culture was inoculated at a ratio of 1% at a ratio of 0.5% isopropyl-D-thiogalactoside (IPTG) to produce sufficient culture to express the protein. After 12 hours of induced expression, cells were harvested by centrifugation at 5000rpm for 10 minutes at 4 ℃. The pellet was then resuspended in buffer a (20mM HEPES, 500mM NaCl, pH 7.5) before lysis by sonication. After sonication, the lysate was clarified by ultracentrifugation at 18000rpm for 1.5h at 4 ℃ and the supernatant was used for protein purification using a HisTrap FF column (GE Healthcare). The obtained protein was purified at 4 ℃ with PreScission protease at 20: molar alignment of 13 CLpro was lysed overnight and then further purified by gel filtration chromatography on a Superdex 200 column (GE Healthcare) equilibrated with buffer B (20mM HEPES, 100mM NaCl, 1mM DTT, pH 7.5). Thereafter, the eluted fractions were concentrated to 15mg/ml using Amicon (10 kDa cut-off, Millipore). The concentrated protein was then stored at-80 ℃ for crystallization and activity determination. For PLP purification, the ratio of 20: molar ratio of 1N-terminal His-tag was removed using 3 CLpro.
Inhibition assay for SARS-CoV-23 CLpro and PLP
Fluorescence Resonance Energy Transfer (FRET) protease assays were performed using Dabcyl-KLSAVLQSGFRKM-Edans-NH2 and CBZ-RLRGG-AMC as fluorogenic substrates, respectively. For 3CLpro inhibition assay, 100nM of 3CLpro recombinant protein (serial dilutions of compounds) was mixed in reaction buffer 1(50mM Tris-HCl, 1mM EDTA, pH 7.3) and incubated for 50h, the total volume after mixing was 50. mu.L, and 20. mu.M substrate was added to initiate the reaction. The fluorescence signals of the 320nm excitation and 405nm emission were then measured immediately every 3 seconds with a BioTek Synergy4 plate reader. For the PLP inhibition assay, a similar procedure was performed while monitoring the fluorescence signal at 340nm (excitation) and 450nm (emission). IC50 curves were calculated using GraphPad Prism 5.0 Software (GraphPad Software, inc., San Diego, CA, USA). IC50 values from three independent experiments are expressed as mean ± SD.
Antiviral assay of LY1
The African green monkey kidney Vero E6 cell line was obtained from the American type culture Collection (ATCC, No. 1586) and stored in Dulbecco's modified Eagle Medium (DMEM; Gibco Invitrogen) and supplemented with 10% fetal bovine serum (FBS; Gibco Invitrogen) and 1% penicillin-streptomycin (Gibco Invitrogen). Clinical isolates of SARS-CoV-2 (nCoV-2019BetacoV/WIV 04/2019) were propagated in Vero E6 cells and viral titers were determined as described previously (11). All infection experiments were performed at biosafety level 3 (BLS-3).
5.RT-PCR
Efficacy of LY1 on virus yield was assessed by quantitative real-time RT-PCR. Vero E6 cells were seeded in 96-well plates and infected with SARS-CoV-2 at an MOI of 0.05. After 2 hours of infection, the virus-containing medium was removed and the cells were treated with 0.1% DMSO as a control or 2.5-15 μ MLL 1. After 48 hours of treatment, the copy number of viral RNA in the cell supernatant was detected using real-time fluorescent quantitative PCR, which is indicated by the expression of RdRP, N and E.
Surface plasmon resonance analysis
SPR analysis
SPR analysis was performed on a BiaCore T200 System (GE Healthcare, Sweden). The target protein was diluted in 10mM sodium acetate and immobilized on a CM5 sensor chip by an amine coupling method. The samples were then diluted in running buffer (PBS). The drug passing through the analyte was then injected through the reference channel and the active channel at a flow rate of 30 μ L/min. Both association and dissociation times were set to 120 s. On Biacore T200 evaluation software, by Steady-State affinityAnd the model is affinity fitted by global fitting to obtain the equilibrium dissociation constant KD。
Example 1 in vitro antiviral Activity of LY1
The antiviral effect assessed by quantitative RT-PCR and immunofluorescent staining assay were used in parallel to demonstrate the in vitro antiviral ability of LY 1. We found that compound LY1 showed strong antiviral activity in the assembled compound library, reaching 100% inhibition at 30 μ M. Using an immunofluorescent staining assay, staining with anti-Nucleoprotein (NP) antibodies and DAPI, a significant reduction in NP was observed with LY1 under the microscope, as shown in figure 1. Compound LY1 showed good antiviral activity by quantitative real-time RT-PCR with an EC50 value of 3.93 μ M, see figure 2. Cytotoxicity of compound LY1 was assessed by MTT method and compound LY1 had CC50 value higher than 15 μ M. As shown in fig. 2. The experimental results show that LY1 has excellent antiviral activity and less toxicity in vitro.
Example 2 inhibition of the Activity of 3CLpro or PLpro by LY1
Purifying the fermentation liquid of Escherichia coli (E.coli) to obtain recombinant SARS-CoV-23 CLpro and PLpro. To measure the inhibitory potency of compound LY1 on 3CLpro or PLpro, a Fluorescence Resonance Energy Transfer (FRET) protease assay was performed using Dabcyl-KLSAVLQSGFRKM-Edans-NH2 and CBZ-RLRGG-AMC as fluorogenic substrates, respectively. As shown in FIG. 3, the inhibitory effect on 3CLpro and PLpro reached 94.4% and 88.6%, respectively, at a concentration of 10. mu.M. The result shows that the compound LY1 can effectively inhibit the activity of SARS-CoV-23 CLpro and PLpro. We used a Fluorescence Resonance Energy Transfer (FRET) -based cleavage assay to determine IC50Value, IC50The values were 0.51. mu.M and 2.97. mu.M, respectively.
Example 3 LY1 targeting primarily 3CLpro protein
To further determine 3CLpro and PLpro as potential targets, we then characterized the affinity between 3CLpro and PLpro and compound LY1 by Surface Plasmon Resonance (SPR) analysis. KDThe value was 0.51. mu.M, which indicates a strong binding affinity between 3CLpro and the lead compound LY1 (FIG. 4. however, Compound LY1 binds to PLpro-bound KDThe value was 2.97. mu.M. The results show that LY1 binds with less affinity to PLpro than 3CLpro (fig. 4). Therefore, we conclude that 3CLpro is the main target due to the high affinity between 3CLpro and the lead compound Y8.
Claims (9)
1. A compound is shown as formula I or formula II, or pharmaceutically acceptable salt or ester thereof:
wherein ring A is a five-, six-, or seven-membered saturated, unsaturated carbocyclic or heterocyclic ring, one to two heteroatoms are present in the heterocyclic ring, and each heteroatom is independently selected from N, O, S;
r1 is one or more substituents independently selected from hydrogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxyacyl;
r2 is a substituent selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy or C1-C3 alkoxy acyl, wherein the halogen refers to fluorine, chlorine, bromine or iodine;
r3 is a substituent selected from hydrogen, halogen, C1-C3 alkyl, hydroxyl, C1-C3 alkoxy, nitro, amino, carboxyl or C1-C3 alkoxy acyl, wherein the halogen refers to fluorine, chlorine, bromine or iodine;
r4 is one or more substituents selected from hydrogen, halogen, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, nitro, amino, carboxy or C1-C3 alkoxyacyl, an aromatic, heteroaromatic, carbocyclic or heterocyclic ring having one to two heteroatoms in the heterocyclic ring, each heteroatom independently selected from N, O, S; the halogen refers to fluorine, chlorine, bromine or iodine;
or R4 is selected from
2. The compound of claim 1,the A ring is selected from benzene ring, pyrrolyl, imidazolyl, pyrazolyl, furyl, tetrahydrofuryl, thienyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl,
Preferably a benzene ring.
3. A compound according to claim 1, wherein R1 is hydrogen.
4. A compound according to claim 1, wherein R2 is methyl.
5. The compound of claim 1, wherein R3 is hydrogen, methyl, hydroxy, halogen.
6. A compound according to claim 1, wherein R4 is a substituent, preferably
7. The compound of claim 1, wherein the compound of formula I is selected from the group consisting of:
8. the compound of claim 1, wherein the compound of formula II is selected from the group consisting of:
9. use of a compound according to any one of claims 1 to 8 for the preparation of a medicament for the prophylaxis and/or treatment of diseases associated with novel coronavirus pneumonias.
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