CN114957279B - Dihydrothieno [2,3-e ] indazole compound, pharmaceutical composition and application - Google Patents
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Abstract
The invention provides dihydrothieno [2,3-e ]]Indazole compound, pharmaceutical composition and application thereof, dihydrothieno [2,3-e ]]Indazole compounds or pharmaceutically acceptable salts thereof have a structural formula shown in the specification. The invention also provides the dihydrothieno [2,3-e ]]The application of indazole compounds or pharmaceutically acceptable salts thereof in preparing medicines for resisting coronaviruses; use in the preparation of a 3CL protease inhibitor. The invention is found through a great deal of research that the dihydrothieno [2,3-e]The indazole compound has remarkable inhibition effect on 3CL protease and good affinity, and experiments show that the indazole compound has good inhibition effect on various coronaviruses including novel coronaviruses 2019-nCoV in vitro, and can be used for preparing anti-coronavirus medicines.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a dihydrothieno [2,3-e ] indazole compound, a pharmaceutical composition and application.
Background
Coronaviruses belong to the order of the genus coronaviridae, the family of coronaviridae, the genus coronaviridae, are a class of RNA viruses with a envelope and a linear single positive strand genome, and are a large class of viruses widely existing in nature. Coronaviruses infect vertebrates only, and are associated with a variety of diseases in humans and animals, which can cause respiratory, digestive and nervous system diseases in humans and animals. To date, a total of 6 human-infectious coronaviruses (HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HCoV-HKU1 and MERS-CoV) were found in addition to the novel coronavirus (2019-nCoV). Among them, the middle east respiratory syndrome coronavirus (MERS-CoV) and the severe acute respiratory syndrome coronavirus (SARS-CoV) have caused serious social effects. The new coronavirus pneumonia epidemic situation has been successed with anti-new coronavirus medicines, and has positive effects on epidemic control.
The 3CL protease (3 CLpro) is the main protease that cleaves and processes functional nonstructural proteins transcribed by RNA in the viral self-code, which is highly conserved in coronaviruses and is a better target for action against coronaviruses. At present, 3CL protease inhibitor Paxlovid developed by the American-type pyroxene company is approved, and experimental results show that the 3CL protease inhibitor Paxlovid has better antiviral effect, but because the peptide-like structure of the main drug is poor in vivo stability, ritonavir is required to slow down the metabolism and the decomposition of the main drug, and therefore 3CL protease inhibitor anti-coronavirus drugs with better effect still need to be developed.
Disclosure of Invention
The invention solves the technical problem of providing dihydrothieno [2,3-e ] indazole compounds, pharmaceutical compositions and application.
In order to solve the problems, the invention adopts the following technical scheme:
in one aspect, the invention provides dihydrothieno [2,3-e ] indazoles or pharmaceutically acceptable salts thereof, which have the structural formula shown in formula I:
wherein R is 1 Selected from: an alkyl group; alkyl groups containing heteroatoms; cyclic hydrocarbon groups; an aryl-substituted alkyl group or an aryl-substituted alkyl group bearing a substituent selected from the group consisting of alkoxy, alkyl, cycloalkyl, halogen, nitro, nitrile, hydroxy, and amino; phenyl or substituted phenyl, the substituents being selected from alkoxy, alkyl, cycloalkyl, halogen, nitro, nitrile, hydroxy or amino;
R 2 selected from: an alkyl group; alkoxy substituted alkyl;
R 3 selected from: phenyl or substituted phenyl, the substituents being selected from alkoxy, alkyl, cycloalkyl, halogen, nitro, nitrile, hydroxy or amino.
The term "pharmaceutically acceptable salts" as used herein refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art. Pharmaceutically acceptable non-toxic salts include, but are not limited to, the following: phosphates, sulfates, perchlorates, hydrochlorides, hydrobromides, hydroiodides, borates, bisulphates, persulfates, hemisulfates, nitrates, citrates, succinates, maleates, ascorbates, oxalates, tartrates, benzoates, formates, acetates, propionates, butyrates, valerates, caprates, enanthates, caprylates, malonates, succinates, glutarates, adipates, pivalates, alginates, aspartate, methanesulfonates, ethanesulfonates, propanesulfonates, butanesulfonates, benzenesulfonates, camphorates, camphorsulfonates, cyclopentylpropionates, glucates, digluconates, dodecylsulfate, fumarate, glucoheptonates, glycerophosphate, 2-hydroxy-ethanesulfonates, lactobionic aldehyde, lactates, laurates, lauryl sulfates, malates, 2-naphthalenesulfonates, nicotinates, oleates, palmitates, pectinates, 3-phenylpropionates, bitrates, stearates, thiocyanates, p-toluenesulfonates, and the like.
Wherein, the alkyl group containing a heteroatom means an alkyl group containing at least one heteroatom.
Heteroatoms include oxygen, nitrogen, sulfur, phosphorus, silicon, halogen. Wherein halogen comprises F, cl, br, I.
Preferably, R 1 Wherein the heteroatom-containing alkyl is selected from the group consisting of: straight or branched chain alkanyl-substituted alkyl; heterocyclyl-substituted alkyl.
The alkyl heterogroup refers to an alkyl group which is connected with an alkyl group through a heteroatom; heterocyclic means that the heterocyclic group is attached to the alkyl group through a heteroatom.
Further preferably, R 1 Wherein the linear or branched alkyl hetero group is a linear or branched alkoxy group; the heterocyclic group is an azaheterocyclic group.
Further preferably, the azacyclyl is a five-or six-membered azacyclyl.
R of the invention 1 、R 2 、R 3 The alkyl refers to saturated hydrocarbon radicals, and is hydrocarbon radicals formed by removing one hydrogen atom in alkane molecules; the alkyl group is preferably a linear or branched C1-18 alkyl group; the alkyl group is further preferably a linear or branched C1-8 alkyl group.
Alkoxy according to the invention means O-alkyl, alkyl being as defined above; the alkyl in the alkoxy group is preferably a C1-10 alkyl group; further preferred are C1-6 alkyl groups; the alkoxy group is most preferably methoxy or ethoxy.
The cyclic hydrocarbon group refers to hydrocarbon groups containing saturated or unsaturated cyclic carbon chain structures; the cyclic hydrocarbon group is preferably a saturated or unsaturated C3-12 cyclic hydrocarbon group; the cyclic hydrocarbon group is further preferably a saturated or unsaturated C3-6 cyclic hydrocarbon group.
The aromatic groups are preferably monovalent aromatic carbocyclic groups containing 6 to 12 carbon atoms and having a single ring or multiple condensed rings.
PreferablyR in formula I 2 Is alkyl.
Preferably, R in formula I 2 Is methyl.
Preferably, R in formula I 3 Is phenyl.
Preferably, the structural formula of the dihydrothieno [2,3-e ] indazole compound is selected from the following formulas II to VI:
in another aspect, the invention provides a pharmaceutical composition comprising the dihydrothieno [2,3-e ] indazole compound described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
The pharmaceutically acceptable excipients include excipients, diluents, lubricants, wetting agents, emulsifiers, suspending agents, preservatives, sweeteners, flavoring agents and the like, which are well known to those of ordinary skill in the art. Other active compounds may optionally be included in the pharmaceutical compositions of the present invention to provide for the integrated treatment of certain specific diseases.
The pharmaceutical composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powder for injection and the like. The various dosage forms of the composition may be formulated so as to provide immediate, sustained or delayed release of the active ingredient to the patient following administration of the composition by employing procedures well known in the art.
In still another aspect, the present invention provides a method for preparing the dihydrothieno [2,3-e ] indazole compound or a pharmaceutically acceptable salt thereof, comprising the following steps:
s1, dissolving 2-acetylcyclohexane-1, 3-dione in a solvent, cooling to 0-5 ℃, adding phenylhydrazine, reacting for 2-6 hours at 10-30 ℃, and separating a reaction product to obtain an intermediate 1 shown in the following formula VII;
s2, adding phosphorus oxychloride into N, N-dimethylformamide under the protection of inert gas and in an ice bath environment, adding the intermediate 1, stirring and reacting for 10-60min, heating to 70-90 ℃ and reacting for 30-150min, and separating a reaction product to obtain an intermediate 2 shown in the following formula VIII;
s3, adding sodium into absolute ethyl alcohol, stirring until the sodium is dissolved, adding ethyl thioglycolate and the intermediate 2, reacting for 12-18 hours, and separating a reaction product to obtain an intermediate 3 shown in the following formula IX;
s4, adding the intermediate 3 into a mixed solution of tetrahydrofuran and sodium hydroxide solution, reacting for 12-36 hours at 70-90 ℃, and separating a reaction product to obtain an intermediate 4 shown in the following formula X;
s5, dissolving the intermediate 4 in dry dichloromethane, adding oxalyl chloride and N, N-dimethylformamide, reacting for 30-90min, and concentrating the reaction solution to obtain a concentrated product; dissolving the concentrated product in tetrahydrofuran, adding the tetrahydrofuran containing a compound with the following formula XI, then adding triethylamine, reacting for 12-18h, and separating the reaction product to obtain the dihydrothieno [2,3-e ] indazole compound;
in step S1, the solvent is preferably absolute ethanol.
In step S1, the reaction product is isolated by filtration.
In the step S2, the method for separating the reaction product is that the reaction product is added into a 25% NaOAc solution, ethyl acetate is adopted for extraction, organic phases are combined, then anhydrous sodium sulfate is adopted for drying and then concentration is carried out, the concentrated product is separated and purified by silica gel column chromatography to obtain the intermediate 2, and the eluent is petroleum ether-ethyl acetate with the volume ratio of (5:1-3:1).
In step S3, the reaction product is isolated by filtration.
In step S4, the method for separating the reaction product is: the reaction product was treated to acidity with hydrochloric acid solution and then filtered to give the intermediate 4.
In step S5, the method for separating the reaction product is: adding the reaction product into hydrochloric acid solution, extracting by adopting ethyl acetate, merging organic phases, washing the organic phases by adopting saturated sodium bicarbonate aqueous solution, drying by adopting anhydrous sodium sulfate, filtering, concentrating, and separating and purifying by using silica gel column chromatography to obtain the dihydrothieno [2,3-e ] indazole compound, wherein the eluent is petroleum ether-ethyl acetate with the volume ratio of (5:1-1:1).
Preferably, the preparation method of the dihydrothieno [2,3-e ] indazole compound or the pharmaceutically acceptable salt thereof comprises the following steps:
s1, dissolving 2-acetylcyclohexane-1, 3-dione in absolute ethyl alcohol, cooling to 0-5 ℃, slowly dropwise adding phenylhydrazine into the mixture, reacting for 4 hours at 25 ℃, and filtering to obtain an intermediate 1 shown in the following formula VII;
s2, dropwise adding phosphorus oxychloride into N, N-dimethylformamide under the protection of nitrogen and ice bath environment, stirring for 30min, then adding the intermediate 1 in batches, stirring for 30min, then heating to 80 ℃ for reaction for 90min, cooling to room temperature after the reaction is finished, adding the reaction product into a 25% NaOAc solution, extracting by adopting ethyl acetate, merging organic phases, drying by adopting anhydrous sodium sulfate, concentrating, separating and purifying the concentrated product by adopting a silica gel column chromatography to obtain the intermediate 2, wherein the eluent is petroleum ether-ethyl acetate with the volume ratio of (5:1-3:1);
s3, adding sodium into absolute ethyl alcohol, stirring until the sodium is dissolved, adding ethyl thioglycolate, continuously stirring for 15min, then adding the intermediate 2 into the reaction solution in three batches, stirring and reacting for 12-18h at 25 ℃,
after the reaction is finished, filtering the reaction liquid to obtain an intermediate 3;
s4, adding the intermediate 3 into a mixed solution of tetrahydrofuran and 1N sodium hydroxide solution, stirring and reacting for 24 hours at 80 ℃, cooling the reaction solution, treating the reaction solution to be acidic by adopting 1N hydrochloric acid solution, and filtering to obtain an intermediate 4;
s5, dissolving the intermediate 4 in dry dichloromethane, adding oxalyl chloride and N, N-dimethylformamide, stirring at 25 ℃ for reaction for 1h, and concentrating the reaction solution to obtain a concentrated solution; dissolving the concentrated solution in tetrahydrofuran, adding the tetrahydrofuran containing the compound of formula XI, then adding triethylamine, stirring and reacting for 12-18h, adding the reaction product into 1N hydrochloric acid solution, extracting by adopting ethyl acetate, merging organic phases, washing the organic phases by using saturated sodium bicarbonate aqueous solution, drying by using anhydrous sodium sulfate, filtering and concentrating, separating and purifying by using silica gel column chromatography to obtain the dihydrothieno [2,3-e ] indazole compound, wherein the eluent is petroleum ether-ethyl acetate with the volume ratio of (5:1-1:1).
In yet another aspect, the invention provides the use of a dihydrothieno [2,3-e ] indazole compound or a pharmaceutically acceptable salt thereof in the preparation of an anti-coronavirus medicament.
Preferably, the coronavirus is at least one of 2019-nCoV, HCoV-229E, HCoV-OC43, SARS-CoV and MERS-CoV.
In yet another aspect, the invention provides the use of a dihydrothieno [2,3-e ] indazole compound or a pharmaceutically acceptable salt thereof in the preparation of a 3CL protease inhibitor.
The 3CL protease is the main protease that cleaves and processes functional nonstructural proteins transcribed from RNA in the viral self-coding, which is highly conserved in coronaviruses, and is a better target for anti-coronaviruses. According to the invention, a great number of researches show that the dihydrothieno [2,3-e ] indazole compound has remarkable inhibition effect on 3CL protease and good affinity, and experiments show that the dihydrothieno [2,3-e ] indazole compound has good inhibition effect on various coronaviruses including novel coronaviruses 2019-nCoV in vitro, and can be used for preparing anti-coronavirus medicines.
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, a great number of researches show that the dihydrothieno [2,3-e ] indazole compound has remarkable inhibition effect on 3CL protease and good affinity, and experiments show that the dihydrothieno [2,3-e ] indazole compound has good inhibition effect on various coronaviruses including the current 2019-nCoV novel coronavirus in vitro, and can be used for preparing anti-coronavirus medicines.
Drawings
FIG. 1 is a graph showing the inhibitory effect of each group of samples in example 2 of the present invention on novel coronavirus 3CL protease;
FIG. 2 is a graph showing the tendency of Ebselen to dissociate from 3CL protein according to example 3 of the present invention;
FIG. 3 shows the steady state affinity K of Ebselen for 3CL protein in example 3 according to the invention D Fitting a curve;
FIG. 4 is a graph showing the tendency of sample A to bind to and dissociate from 3CL protein in example 3 of the present invention;
FIG. 5 shows the steady-state affinity K of sample A for 3CL protein in example 3 of the invention D Fitting a curve;
FIG. 6 is a graph showing the tendency of sample B to bind to and dissociate from 3CL protein in example 3 of the present invention;
FIG. 7 shows the steady-state affinity K of sample B for 3CL protein in example 3 of the invention D Fitting a curve;
FIG. 8 is a graph showing the tendency of sample C to bind to and dissociate from 3CL protein in example 3 of the present invention;
FIG. 9 shows the steady-state affinity K of sample C for 3CL protein in example 3 of the invention D Fitting a curve;
FIG. 10 is a graph showing the tendency of sample D to bind to and dissociate from 3CL protein in example 3 of the present invention;
FIG. 11 shows the steady-state affinity K of sample D for 3CL protein in example 3 of the invention D Fitting a curve;
FIG. 12 is a graph showing the tendency of sample E to bind to and dissociate from 3CL protein in example 3 of the present invention;
FIG. 13 shows the steady-state affinity K of sample E for 3CL protein in example 3 of the invention D Fitting a curve;
FIG. 14 is a graph showing the tendency of negative control to bind to and dissociate from 3CL protein in example 3 of the present invention;
FIG. 15 shows the steady-state affinity K of the negative control with 3CL protein in example 3 of the invention D Fitting a curve;
FIG. 16 is a graph showing the effect of each compound of example 6 of the present invention on anti-novel coronaviruses 2019-nCoV.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
In the following examples, the novel coronavirus Mpro/3CLpro inhibitor screening kit is provided by Beijing Biyun biotechnology Co., ltd; the rest of the experimental materials are all commercially available.
EXAMPLE 1 preparation of Dihydrothieno [2,3-e ] indazoles
Sample a: n- (3-pyrrolidin-1-propyl) -8-methyl-6-phenyl-4, 5-dihydrothieno [2,3-e ] indazole-2-carboxamide
Sample B: n- (3-methoxypropyl) -8-methyl-6-phenyl-4, 5-dihydrothieno [2,3-e ] indazole-2-carboxamide
Sample C: n- [3- (2-oxopyrrolidine-1-propyl) ] -8-methyl-6-phenyl-4, 5-dihydrothieno [2,3-e ] indazole-2-carboxamide
Sample D: n- [3- (4-propylpiperazinyl-1-propyl) ] -8-methyl-6-phenyl-4, 5-dihydrothieno [2,3-e ] indazole-2-carboxamide
Sample E: n- [2- (4-methylpiperidinyl-1-ethyl) ] -8-methyl-6-phenyl-4, 5-dihydrothieno [2,3-e ] indazole-2-carboxamide
Sample A, B, C, D, E was prepared by the reaction scheme of formula 1.
(1) Preparation of sample A
The preparation method of the sample A comprises the following steps:
s1, dissolving 2-acetylcyclohexane-1, 3-dione (15.4 g,0.1 mol) in absolute ethanol (250 mL), cooling to 0-5 ℃, slowly dropwise adding phenylhydrazine (9.84 mL,0.1 mol) into the mixture, reacting for 4 hours at room temperature (about 25 ℃), and filtering to obtain a white solid intermediate 1 (20.94 g, yield 92%); mass Spectrometry FT-MS (ESI) [ M+H ]] + m/z 227.1175, theoretical 227.1184;
s2, dropwise adding phosphorus oxychloride (10.5 g,68.5 mmol) into N, N-dimethylformamide (20 g,274 mmol) under the protection of nitrogen and ice bath environment, stirring for 30min, then adding the intermediate 1 (15.5 g,68.5 mmol) in batches, stirring for reaction for 30min, heating to 80 ℃ for reaction for 90min, cooling to room temperature after the reaction is finished, adding the reaction product into a 25% NaOAc solution, extracting by adopting ethyl acetate, merging organic phases, drying by adopting anhydrous sodium sulfate, concentrating, separating and purifying the concentrated product by adopting silica gel column chromatography to obtain the intermediate 2 (15.11 g, yield 81%), wherein an eluent is petroleum ether-ethyl acetate with the volume ratio of (5:1-3:1); mass spectrometry FT-MS (ESI) [ m+h ] +m/z 273.0785, theory 273.0795;
s3, adding sodium (1.2 g,0.052 mol) into absolute ethanol, stirring until the sodium is dissolved, adding ethyl thioglycolate (3.61 g,0.03 mol), continuously stirring for 15min, then adding the intermediate 2 (7.09 g,0.026 mol) into the reaction solution in three batches, stirring at room temperature of 25 ℃ for reaction overnight, and filtering the reaction solution after the reaction is finished to obtain an intermediate 3 (6.9 g, yield of 79%); mass spectrometry FT-MS (ESI) [ m+h ] +m/z 339.1162, theory 339.1167;
s4, adding the intermediate 3 (1.014 g,0.003 mmol) into a mixed solution of tetrahydrofuran (9 mL) and 15mL of 1N sodium hydroxide solution (4 g of sodium hydroxide is dissolved in 100mL of water), stirring and reacting for 24h at 80 ℃, cooling the reaction solution to room temperature, treating with 18mL of 1N hydrochloric acid solution to be acidic, and filtering to obtain an intermediate 4 (0.82 g, yield 88%); mass spectrum FT-MS (ESI) [ m+h ] +m/z 311.0848 theory 311.0854;
s5, dissolving the intermediate 4 (0.31 g,1 mmol) in dry dichloromethane (5 mL), dropwise adding oxalyl chloride (1.26 g,10 mmol), adding one drop of N, N-dimethylformamide, stirring at room temperature of 25 ℃ for reaction for 1h, and concentrating the reaction solution to obtain a concentrated solution; the concentrate was dissolved in tetrahydrofuran (5 mL), added to tetrahydrofuran containing 3- (pyrrolidin-1-yl) propan-1-amine (formula 2), then triethylamine (0.13 g,1.2 mmol) was added, stirred and reacted overnight, the reaction product was added to 30mL of 1N hydrochloric acid solution (diluted 12-fold with concentrated hydrochloric acid), the organic phases were combined after extraction with ethyl acetate three times, then the organic phases were washed three times with saturated aqueous sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel column chromatography with an eluent of petroleum ether-ethyl acetate in a volume ratio (5:1-1:1), to give sample a (0.315 g, 75% yield). 1 H NMR (600 mhz, dmso) delta 7.64 (s, 1H), 7.57-7.52 (m, 4H), 7.43-7.40 (m, 1H), 6.56 (brs, 1H), 3.24-3.21 (m, 2H), 3.07 (t, 2H, j=8.1 Hz), 2.67-2.65 (m, 4H), 2.93 (t, 2H, j=8.1 Hz), 2.48 (t, 2H, j=6.0 Hz), 2.39 (s, 3H), 1.85-1.83 (m, 4H), 1.79-1.74 (m, 2H). Mass Spectrometry FT-MS (ESI) [ M+H ]]+m/z 421.2053, theoretical 421.2062.
(2) Preparation of sample B
Steps S1 to S4 in the preparation method of sample B are the same as sample a.
S5, dissolving the intermediate 4 (0.31 g,1 mmol) in dry dichloromethane (5 mL), dropwise adding oxalyl chloride (1.26 g,10 mmol), adding one drop of N, N-dimethylformamide, stirring at room temperature of 25 ℃ for reaction for 1h, and concentrating the reaction solution to obtain a concentrated product; dissolving the concentrated product in tetrahydrofuran (5 mL), adding into tetrahydrofuran containing 3-methoxypropane-1-amine (formula 3), adding triethylamine (0.13 g,1.2 mmol), stirring for reaction overnight, adding the reaction product into 30mL1N hydrochloric acid solution (diluted 12 times with concentrated hydrochloric acid), extracting three times with ethyl acetate, mixing organic phases, washing the organic phases with saturated sodium bicarbonate aqueous solution three times, drying with anhydrous sodium sulfate, filtering, concentrating, separating and purifying with silica gel column chromatography, eluting with petroleum ether-ethyl acetate with volume ratio (5:1-1:1) to obtain sample B (0.274 g, yield 72%), 1 h NMR (600 mhz, dmso) delta 7.72 (s, 1H), 7.57-7.51 (m, 4H), 7.42-7.40 (m, 1H), 6.50 (brs, 1H), 3.49-3.44 (m, 4H), 3.35 (s, 3H), 3.07 (t, 2H, j=8.1 Hz), 2.93 (t, 2H, j=8.1 Hz), 2.39 (s, 3H), 1.88-1.84 (m, 2H). Mass Spectrometry FT-MS (ESI) [ M+H ]]+m/z 382.1578, theoretical 382.1589.
(3) Preparation of sample C
Steps S1 to S4 in the preparation method of sample C are identical to sample a.
S5, dissolving the intermediate 4 (0.31 g,1 mmol) in dry dichloromethane (5 mL), dropwise adding oxalyl chloride (1.26 g,10 mmol), adding one drop of N, N-dimethylformamide, stirring at room temperature of 25 ℃ for reaction for 1h, and concentrating the reaction solution to obtain a concentrated product; the concentrated product was dissolved in tetrahydrofuran (5 mL), added to tetrahydrofuran containing 3- (2-oxopyrrolidine) propane-1-amine (formula 4), then triethylamine (0.13 g,1.2 mmol) was added, stirred and reacted overnight, the reaction product was added to 30mL of 1N hydrochloric acid solution (diluted 12-fold with concentrated hydrochloric acid), the organic phases were combined after extraction with ethyl acetate three times, then the organic phases were washed three times with saturated aqueous sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel column chromatography with petroleum ether-ethyl acetate in a volume ratio (5:1-1:1) as eluent to give sample C (0.295 g, yield 68%). 1 H NMR (600 MHz, DMSO) delta 7.68 (s, 1H), 7.58-7.51 (m, 4H), 7.44-7.41 (m, 1H), 6.48 (brs, 1H), 3.51 (t, 2H, j=6.0 Hz), 3.31-3.24 (m, 4H), 3.07 (t, 2H, j=8.1 Hz), 2.93 (t, 2H, j=8.1 Hz), 2.78-2.76 (m, 2H), 2.32-2.28 (m, 2H), 2.41 (s, 3H), 1.84-1.80 (m, 2H). Mass Spectrometry FT-MS (ESI) [ M+H ]]+m/z 435.1840, theoretical 435.1849.
(4) Preparation of sample D
Steps S1 to S4 in the preparation method of sample D are the same as sample a.
S5, dissolving the intermediate 4 (0.31 g,1 mmol) in dry dichloromethane (5 mL), dropwise adding oxalyl chloride (1.26 g,10 mmol), adding one drop of N, N-dimethylformamide, stirring at room temperature of 25 ℃ for reaction for 1h, and concentrating the reaction solution to obtain a concentrated product; the concentrated product was dissolved in tetrahydrofuran (5 mL), added to tetrahydrofuran containing 3- (4-propylpiperazinyl) propane-1-amine (formula 5), then triethylamine (0.13 g,1.2 mmol) was added, and the reaction was stirred overnight, the reaction product was added to 30mL of a 1N hydrochloric acid solution (diluted 12-fold with concentrated hydrochloric acid), extracted three times with ethyl acetate, the organic phases were combined, washed three times with a saturated aqueous sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated, and purified by column chromatography on silica gel with an eluent of petroleum ether-ethyl acetate in a volume ratio of (5:1-1:1) to give sample D (0.334 g, yield 70%). Mass spectrum FT-MS (ESI) [ m+h ] +m/z 478.2643, theory 478.2635.
(5) Preparation of sample E
Steps S1 to S4 in the preparation method of sample E are identical to sample a.
S5, dissolving the intermediate 4 (0.31 g,1 mmol) in dry dichloromethane (5 mL), dropwise adding oxalyl chloride (1.26 g,10 mmol), adding one drop of N, N-dimethylformamide, stirring at room temperature of 25 ℃ for reaction for 1h, and concentrating the reaction solution to obtain a concentrated product; the concentrated product was dissolved in tetrahydrofuran (5 mL), added to tetrahydrofuran containing 2- (4-methylpiperidinyl) ethane-1-amine (formula 6), then triethylamine (0.13 g,1.2 mmol) was added, and the reaction was stirred overnight, the reaction product was added to 30mL of a 1N hydrochloric acid solution (diluted 12-fold with concentrated hydrochloric acid), extracted three times with ethyl acetate, the organic phases were combined, then washed three times with a saturated aqueous sodium hydrogencarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated, and separated and purified by silica gel column chromatography with an eluent of petroleum ether-ethyl acetate in a volume ratio of (5:1-1:1), to give sample E (0.334 g, yield 77%). Mass spectrum FT-MS (ESI) [ m+h ] +m/z 435.2225, theory 435.2213.
EXAMPLE 2 inhibition of 3Cl protease by dihydrothieno [2,3-e ] indazoles
1. Purpose of experiment
The in vitro enzyme inhibition of dihydrothieno [2,3-e ] indazoles on 3Cl proteases was evaluated.
2. Experimental method
Five dihydrothieno [2,3-e ] indazoles (sample A, B, C, D, E) and a DMSO solution of the positive inhibitor ebselen were diluted to final concentrations of 2mM,200mM,20mM,2mM, 0.2mM for use. The experiment sets a blank control group, a 100% enzyme activity control group, a positive inhibitor control group and a sample group, three compound wells are arranged at each concentration, 93ml Assay Buffer is added to the blank control wells according to the kit proportion, and 93ml Assay Reagent is added to the rest wells. The blank control group, the 100% enzyme activity control group and the positive inhibitor control group are respectively added with 5ml of DMSO solution, 5ml of positive inhibitor ebselen and 5ml of sample to be detected are respectively added into each hole of the sample group, the sample is placed in a SpectraMax i3x multifunctional enzyme labeling instrument, shaking and mixing are carried out uniformly, and after incubation is carried out for 10 minutes at 37 ℃, the autofluorescence value RFU0 of the sample is read. Placing the 96-well plate in a low-temperature environment, quickly adding 2ml of Substrate into each well, placing the wells in a SpectraMax i3x multifunctional enzyme labeling instrument, shaking and uniformly mixing, incubating for 10-20 minutes at 37 ℃ and reading the fluorescence value of each well after the values are stable.
Inhibition ratio (%) = [ RFU100% enzyme activity control- (RFU sample-RFU 0) ]/(RFU 100% enzyme activity control-RFU blank) ×100%
GraphPad Prism 9.0.0 calculated drug median inhibitory concentration (IC 50 )。
3. Experimental results
As shown in FIG. 1, the inhibition effect of each group of samples on the novel coronavirus 3CL protease is shown, and as can be seen from the graph, five dihydrothieno [2,3-e ] indazoles compounds all show remarkable enzyme inhibition effect on the novel coronavirus 3CL protease.
Example 3 Dihydrothieno [2,3-e ] indazoles affinity assay for coronavirus 3CL protease
1. Purpose of experiment
Evaluation of the affinity of dihydrothieno [2,3-e ] indazoles for coronavirus 3CL protease
2. Experimental method
3CLpro was coupled to the CM5 chip by hand under 1 XPBS buffer run, with a coupling yield of about 18000RU. The concentration of the small molecule sample is diluted in a gradient manner to 40mM, 20mM, 10mM, 5000nM, 2500nM, 1250nM, 625nM, 312.5nM, 156.25nM and 78.125nM by using 1.05 XPBS buffer containing 5% DMSO as a diluent, and the sample is covered by a rubber cap to prevent volatilization. Under the operation of 1.05XPBS buffer containing 5% DMSO, a Kinetics/afinity template under template in Biacore T200 Control Software is selected, parameters are set according to small molecule affinity, a program is operated, and an instrument is operated. After the operation is finished, data analysis is carried out by using Biacore T200 Evaluation Software, the obtained solvent correction curve is required to fall between-500 RU and +1000RU, the chi2 is less than 2, affinity model fitting can be carried out, and sample detection results with proper concentration are selected for fitting, so that a fitting curve and K are obtained D Values.
3. Experimental results
The protein small molecule interaction co-detection comprises 7 small molecule compounds including a positive control drug Ebselen and a negative control drug Brassinolide, 6 groups of positive data are detected, and a complete and ordered protein small molecule binding dissociation diagram and steady-state affinity K can be obtained D The complete results of the curve fitting are shown in fig. 2 to 15.
Table 1 below shows the positive control Ebselen, dihydrothieno [2,3-e ]]Interaction K of indazoles (sample A, B, C, D, E) with 3CL protein D Values. The reported 3CL protease inhibitor Ebselen served as a positive control.
From the above results, it is clear that dihydrothieno [2,3-e ] indazoles have good affinity with 3CL protease.
TABLE 1 interaction of 3CL proteins and small molecules K D Value of
EXAMPLE 4 inhibition of the Dihydrothieno [2,3-e ] indazoles on the HCoV-OC43 of the Normal coronavirus
1. Purpose of experiment
The inhibition of the HCoV-OC43 of the common coronavirus by the dihydrothieno [2,3-e ] indazoles was evaluated.
2. Experimental method
The drug effect of the drug against the common coronavirus HCoV-OC43 is measured by adopting a CPE method, and the experimental method is as follows: uniformly inoculating H460 cells with good growth state into 96-well cell culture plate, and placing in 5% CO 2 Culturing at 37deg.C for 24 hr. After observing the uniform growth of cells in each well, adding samples with different concentrations prepared by a maintenance solution, setting a cell control well and a virus control well, taking ribavirin as a positive control drug, and simultaneously infecting the sample well and the cell control well with a proper amount of 100 times of TCID (TCID) 50 Is a common coronavirus HCoV-OC43. Subsequently, it is subjected to 5% CO 2 Culturing at 37deg.C. The cytopathic degree of each group was observed and recorded daily until the viral control group had reached a degree of 4+. The half-Toxic Concentration (TC) of the sample on the cells was calculated by Reed-Muench method 50 ) And half-maximal Inhibitory Concentration (IC) against virus 50 ) And obtain a selection index (SI, si=tc 50 /IC 50 )。
3. Experimental results
Table 2 below shows the results of the compound anti-HCoV-OC 43 experiment. As can be seen from table 2, in this experiment, three compounds have significant inhibitory activity on the common coronavirus HCoV-OC43 in H460 cells and specific effective values can be found: sample A IC 50 At 7.70. Mu.M, SI at 3.0, selection indexHigher than the positive control drug ribavirin; sample B IC 50 11.11. Mu.M, SI 2.08; sample C IC 50 33.33. Mu.M, SI 1.73.
Results of experiments on compounds of Table 2 against the common coronavirus HCoV-OC43
EXAMPLE 5 inhibition of the Dihydrothieno [2,3-E ] indazoles on the HCoV-229E common coronavirus
1. Purpose of experiment
The inhibition of the common coronavirus HCoV-229E by dihydrothieno [2,3-E ] indazoles was evaluated.
2. Experimental method
Huh7 cells were inoculated into 96-well plates and placed in 5% CO 2 Culturing at 35 ℃. Infection with coronavirus 10 after 24 hours -3 Simultaneously adding a maintaining solution containing samples with different dilutions and positive control drugs, and simultaneously arranging a cell control hole and a virus control hole, wherein the concentration of CO is 5% 2 Culturing at 35 ℃. Observing cytopathic degrees (CPE) of each group when the virus control group has a pathological degree (CPE) of 4+, and calculating half-Toxic Concentration (TC) of the sample on cells by using a Reed-Muench method 50 ) And half-maximal Inhibitory Concentration (IC) against virus 50 )。
3. Experimental results
Table 3 below shows the results of the compound anti-HCoV-229E experiment. As can be seen from Table 3, in this experiment, dihydrothieno [2,3-e]The indazoles five compounds have obvious inhibitory activity on common coronavirus HCoV-229E in Huh7 cells and can obtain specific effective values: sample A had an IC50 of 7.70. Mu.M and SI of 7.5; sample B IC 50 23.11. Mu.M, SI 2.5; sample C IC 50 14.32. Mu.M, SI 4; sample D IC 50 3.08. Mu.M, SI of 10.8; sample E IC 50 3.7 mu M, SI is 27. Wherein, the selection index of the sample A and the sample D is higher than that of the positive control drug ribavirin.
Table 3 results of experiments on compounds against the common coronavirus HCoV-229E
EXAMPLE 6 inhibition of novel coronaviruses 2019-nCoV by dihydrothieno [2,3-e ] indazoles
1. Purpose of experiment
The inhibitory effect of dihydrothieno [2,3-e ] indazoles on novel coronaviruses 2019-nCoV was evaluated.
2. Experimental method
The drug effect of the drug against the new coronavirus is measured by adopting a nucleic acid quantitative method: vero cells were seeded at 10000/Kong Nongdu a day in advance into 96-well cell culture plates and the drug was formulated to 3 concentrations with DMEM maintenance solution of 2% fbs. Discarding cell culture supernatant, adding different concentrations of the drug to be tested (100 μl/well), 3 multiple wells per drug, and then supplementing 100TCID per well 50 Virus solution, and setting up virus control group and normal cell control group, placing 37 deg.C and 5% CO 2 Incubator culture. At 2 days post infection, 50 μl of cell supernatant was taken per well to extract nucleic acid, and the viral load was detected using quantitative RT-PCR.
3. Experimental results
Three concentrations were set for each group of compounds, the ordinate being the logarithm of the viral RNA replication amount based on 10, and number 0 being the viral control well, and the individual drug concentrations are shown in table 4.
TABLE 4 active compound numbering and concentration
FIG. 16 is a graph showing the effect of each of the above compounds on anti-novel coronaviruses 2019-nCoV. As can be seen from FIG. 16, the 30. Mu.M sample A, the 50. Mu.M sample B, the 50. Mu.M sample C, the 10. Mu.M sample D and the 10. Mu.M sample E all form a significant difference from the virus control group, and can significantly inhibit the replication of the novel coronavirus.
It is apparent that the above examples are given by way of illustration only and are not limiting of the embodiments. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. It is not necessary here nor is it exhaustive of all embodiments. While still being apparent from variations or modifications that may be made by those skilled in the art are within the scope of the invention.
Claims (6)
1. Dihydrothieno [2,3-e ] indazoles or pharmaceutically acceptable salts thereof, of formula II to VI:
2. a pharmaceutical composition comprising the dihydrothieno [2,3-e ] indazole compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant.
3. A process for the preparation of dihydrothieno [2,3-e ] indazoles according to claim 1 or pharmaceutically acceptable salts thereof, comprising the following steps:
s1, dissolving 2-acetylcyclohexane-1, 3-dione in a solvent, cooling to 0-5 ℃, adding phenylhydrazine, reacting for 2-6 hours at 10-30 ℃, and separating a reaction product to obtain an intermediate 1 shown in the following formula VII;
s2, adding phosphorus oxychloride into N, N-dimethylformamide under the protection of inert gas and in an ice bath environment, adding the intermediate 1, stirring and reacting for 10-60min, heating to 70-90 ℃ and reacting for 30-150min, and separating a reaction product to obtain an intermediate 2 shown in the following formula VIII;
s3, adding sodium into absolute ethyl alcohol, stirring until the sodium is dissolved, adding ethyl thioglycolate and the intermediate 2, reacting for 12-18 hours, and separating a reaction product to obtain an intermediate 3 shown in the following formula IX;
s4, adding the intermediate 3 into a mixed solution of tetrahydrofuran and sodium hydroxide solution, reacting for 12-36 hours at 70-90 ℃, and separating a reaction product to obtain an intermediate 4 shown in the following formula X;
s5, dissolving the intermediate 4 in dry dichloromethane, adding oxalyl chloride and N, N-dimethylformamide, reacting for 30-90min, and concentrating the reaction solution to obtain a concentrated product; dissolving the concentrated product in tetrahydrofuran, adding the tetrahydrofuran containing a compound with the formula XI, wherein the formula XI is selected from the following formulas (1) to (5), adding triethylamine, reacting for 12-18h, and separating the reaction product to obtain the dihydrothieno [2,3-e ] indazole compound;
4. the use of a dihydrothieno [2,3-e ] indazole compound according to claim 1 or a pharmaceutically acceptable salt thereof, for the preparation of an anti-coronavirus medicament.
5. The use according to claim 4, characterized in that:
the coronavirus is at least one of 2019-nCoV, HCoV-229E and HCoV-OC43.
6. The use of a dihydrothieno [2,3-e ] indazole compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a 3CL protease inhibitor.
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