CN115124543B - Tricyclic pyridone compounds with antiviral activity and application thereof - Google Patents

Tricyclic pyridone compounds with antiviral activity and application thereof Download PDF

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CN115124543B
CN115124543B CN202210708764.0A CN202210708764A CN115124543B CN 115124543 B CN115124543 B CN 115124543B CN 202210708764 A CN202210708764 A CN 202210708764A CN 115124543 B CN115124543 B CN 115124543B
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tricyclic pyridone
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coronavirus
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陈明华
司书毅
李玉环
陈渝川
常珊珊
高荣梅
闫璧滢
肖同美
苏冰洁
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Abstract

The invention discloses tricyclic pyridone compounds with a structure shown in formula I or pharmaceutically acceptable salts thereof; the compound has anti-coronavirus activity and strong inhibition activity on coronaviruses. The invention also discloses application of tricyclic pyridone compounds shown in formula I or pharmaceutical salts thereof in preparing medicaments for treating related diseases caused by coronavirus and/or influenza virus infection. The invention also discloses the application of tricyclic pyridone compounds with the structure shown in the formula II or the pharmaceutical salts thereof in preparing medicaments for treating related diseases caused by coronavirus and/or influenza virus infection, wherein R is selected from R 1 Selected from H, CH 3 。

Description

Tricyclic pyridone compounds with antiviral activity and application thereof
Technical Field
The invention belongs to the technical field of natural medicines, and particularly relates to a tricyclic pyridone compound and medicinal salts thereof obtained from fermentation products in fungus Gibberella sp.1394, which are included in the technical field of microorganisms, a preparation method of the tricyclic pyridone compound and application of the tricyclic pyridone compound in resisting influenza virus and coronavirus related diseases.
Background
Coronaviruses are enveloped viruses, the virions are irregularly shaped, 60-220 nm in diameter, and the surface of the envelope has protrusions of envelope glycoproteins about 20nm a long and with enlarged distal portions, which are crowned. The positive-strand RNA of the viral genome is 27-31 kb in size, is an infectious nucleic acid, has a cap structure at the 5 'end and poly (A) at the 3' end, and has 7-10 genes. Coronaviruses are pathogens that severely affect the health of humans and animals, they enter human cells in fusion with the cytoplasmic membrane or endocytosis, mainly causing intestinal or respiratory diseases, which can be serious and life threatening.
Currently, there are mainly 7 coronaviruses (HCoV-229E, NL, OC43, HKU-1, SARS-CoV, MERS-CoV and SARS-CoV-2) that cause human diseases. HCoV-229E, NL63, OC43 and HKU-1 typically cause humans to experience common cold with mild upper respiratory symptoms, whereas SARS-CoV, MERS-CoV and more recently SARS-CoV-2 have more complex and more severe clinical symptoms and symptoms. In acute SARS-CoV-2 infection, patients often develop mild symptoms such as cough and fever. After the initial 2-14 day incubation period, most new patients with coronaries pneumonia develop pneumonia with dyspnea and hypoxia, and can develop acute respiratory disease. Mortality varies from 0.9% to 9.1% in different areas. SARS-CoV-2 is transmitted mainly by respiratory droplets and by close human-to-human contact, and asymptomatic carriers or asymptomatic carriers can also transmit viruses, creating a great challenge for the control of new coronaries. Therefore, antiviral drug and vaccine development is a major task to further control the current new coronary epidemic.
Candidate drugs for efficacy assessment of new coronatine pneumonia mainly include viral polymerase inhibitors, proteolytic enzyme inhibitors, helicase inhibitors, and host targeting agents. The drugs currently approved are: paxlovid, mo Napi Lavir (Monnpiravir), readefovir, ribavirin, faveravir, readefovir, abidol, etc., but the efficacy is yet to be further confirmed. Because coronaviruses are single-stranded RNA viruses, the coronaviruses have the characteristic of rapid mutation, and whether the existing wholesale medicines are effective on mutated strains is still to be further studied.
The natural medicine has rich resources, and the microorganism, the medicinal plant and the marine organism are all the time an important source of medicine lead and innovative medicine. Microbial secondary metabolites are favored by researchers because of their chemical structure diversity, broad biological activity, high reproducibility, and the ease of obtaining large amounts of samples by fermentation and the use of modern synthetic biology techniques.
Disclosure of Invention
The invention separates and purifies rice fermentation products of fungus Gibberella sp.1394, and identifies 5 tricyclic pyridone compounds, and an activity test result shows that the compounds have anti-coronavirus activity, have stronger inhibition activity on coronaviruses, have better application prospect, and are expected to be developed into novel medicines for resisting coronaviruses and influenza virus infection clinically.
The invention aims to provide tricyclic pyridone compounds or pharmaceutically acceptable salts thereof, wherein the structures of the tricyclic pyridone compounds are shown in formula I:
the molecular formula of the compound I is as follows: c (C) 30 H 47 NO 6 The molecular weight is: 517.
the pharmaceutical salt of the tricyclic pyridone compound shown in the formula I is a salt formed by the tricyclic pyridone compound shown in the formula I and inorganic acid, organic acid or amino acid.
The inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid or sulfonic acid; the amino acid is alanine, aspartic acid or lysine.
The sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid.
The invention also provides a preparation method of the tricyclic pyridone compound shown in the formula I, which comprises the following steps:
fermenting rice by fungus Gibberella sp.1394 to obtain rice fermented product, respectively extracting rice fermented product with 95% ethanol for 2 times and 50% ethanol for 1 time, filtering the extractive solution, concentrating under reduced pressure until no ethanol smell exists, to obtain crude extract water solution, extracting with ethyl acetate equal to the crude extract water solution in volume for 3 times, and concentrating under reduced pressure to obtain crude extract; performing normal phase silica gel chromatographic column chromatography on the crude extract, and performing gradient elution by using a dichloromethane-methanol system as an eluent to obtain 10 fractions which are respectively marked as Fr.1-Fr.10; taking Fr.10, dissolving with methanol, performing Flash column chromatography to obtain 6 subfractions, which are respectively denoted as Fr.10.1-Fr.10.6; fr.10.3 is taken and subjected to semi-preparative reverse phase high performance liquid chromatography (semi-preparative RP-HPLC) to obtain the tricyclic pyridone compound shown in the formula I.
Preferably, the extraction time is 30min each.
Preferably, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system is 100:0-0:100, specifically 50:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 1:1, 1:0.
Preferably, the mobile phase of Flash column chromatography is 5% -100% MeOH-H 2 O, carrying out gradient elution, wherein the flow rate of the mobile phase is 5 mL.min -1 . Specifically, the specification of the Flash column chromatography chromatographic column is SW-025-SP.
Preferably, the chromatographic column of the semi-preparative reverse phase high performance liquid chromatography is Capcell Pak C 18 MG II chromatographic column, specification is: 5 μm, 10X 250mm; the mobile phase was Acetonitrile (ACN): 0.1% trifluoroacetic acid (0.1% tfa) in water=69:31 (V: V), isocratic elution; the flow rate of the mobile phase was 1.5mL min -1 。
The invention also aims to provide the application of the tricyclic pyridone compounds shown in the formula I or the pharmaceutically acceptable salts thereof in preparing medicaments for treating related diseases caused by coronavirus and/or influenza virus infection.
The coronavirus is novel coronavirus (SARS-CoV-2) or variant strain thereof, and coronavirus HCoV-OC43.
Preferably, the application is the application in preparing medicines for resisting related diseases caused by coronavirus HCoV-OC43 infection.
The invention also aims to provide the application of tricyclic pyridone compounds with the structure shown in the formula II or the pharmaceutically acceptable salts thereof in preparing medicaments for treating related diseases caused by coronavirus and/or influenza virus infection:
wherein R is selected fromR 1 Selected from H, CH 3 。
Specifically, the tricyclic pyridone compounds of formula II are selected from the following compounds:
the molecular formula of the compound IIA is as follows: c (C) 28 H 41 NO 5 The molecular weight is: 471.
the molecular formula of the compound IIB is as follows: c (C) 29 H 43 NO 5 The molecular weight is: 485.
the molecular formula of the compound III is as follows: c (C) 28 H 43 NO 6 The molecular weight is: 489.
the molecular formula of the compound IV is as follows: c (C) 28 H 39 NO 4 The molecular weight is: 453.
the pharmaceutical salt of the tricyclic pyridone compound shown in the formula II is a salt formed by the tricyclic pyridone compound shown in the formula II and inorganic acid, organic acid or amino acid.
The inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid or sulfonic acid; the amino acid is alanine, aspartic acid or lysine.
The sulfonic acid is methanesulfonic acid or p-toluenesulfonic acid.
The coronavirus is novel coronavirus (SARS-CoV-2) or variant strain thereof, and coronavirus HCoV-OC43.
Preferably, the application is the application in preparing medicines for resisting diseases related to HCoV-OC43 infection of coronaviruses.
The invention also provides a preparation method of the tricyclic pyridone compound shown in the formula II, which comprises the following steps:
fermenting rice by fungus Gibberella sp.1394 to obtain rice fermented product, respectively extracting rice fermented product with 95% ethanol for 2 times and 50% ethanol for 1 time, filtering the extractive solution, concentrating under reduced pressure until no ethanol smell exists, to obtain crude extract water solution, extracting with ethyl acetate equal to the crude extract water solution in volume for 3 times, and concentrating under reduced pressure to obtain crude extract;
performing normal phase silica gel chromatographic column chromatography on the crude extract, and performing gradient elution by using a dichloromethane-methanol system as an eluent to obtain 10 fractions which are respectively marked as Fr.1-Fr.10;
fr.10 was taken and Flash column chromatography was performed with methanol dissolution with mobile phase 5% -100% MeOH-H 2 O, carrying out gradient elution, wherein the flow rate of the mobile phase is 5 mL.min -1 The method comprises the steps of carrying out a first treatment on the surface of the 6 subfractions were obtained, denoted fr.10.1-fr.10.6, respectively; taking Fr.10.3, and performing semi-preparative reverse phase high performance liquid chromatography (semi-preparative RP-HPLC) to obtain compounds of formulas IIA and IIB; taking Fr.10.2, and performing semi-preparative reverse phase high performance liquid chromatography (semi-preparative RP-HPLC) to obtain a compound III;
fr.5 was taken and Flash column chromatography was performed with methanol dissolution with mobile phase 5% -100% MeOH-H 2 O, carrying out gradient elution, wherein the flow rate of the mobile phase is 5 mL.min -1 The method comprises the steps of carrying out a first treatment on the surface of the 7 subfractions were obtained, denoted fr.5.1-fr.5.7, respectively; fr.5.7 was taken, dissolved in dichloromethane-methanol (1:1V: V), and eluted by Sephadex LH-20 column chromatography with dichloromethane-methanol (1:1V: V) as flow equality to obtain 7 subfractions, which were designated Fr.5.7.1-Fr.5.7.7, respectively; fr.5.7.2 was taken and subjected to reverse phase high performance liquid chromatography (semi-preparative RP-HPLC) to give compound IV.
Preferably, the extraction time is 30min each.
Preferably, the volume ratio of dichloromethane to methanol in the dichloromethane-methanol system is 100:0-0:100, specifically 50:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 1:1, 1:0.
Preferably, when preparing the compounds IIA and IIB, the chromatographic column of the semi-preparative reverse phase high performance liquid chromatography is Capcell Pak C 18 MG II chromatographic column, specification is: 5 μm, 10X 250mm; the mobile phase was Acetonitrile (ACN): 0.1% trifluoroacetic acid (0.1% tfa) in water=69:31 (V: V), isocratic elution; the flow rate of the mobile phase was 1.5mL min -1 。
Preferably, in preparing the compound III, the chromatographic column of the semi-preparative reverse phase high performance liquid chromatography is a Capcell Pak PFP chromatographic column, and the specification is as follows: 5 μm, 10X 250mm; the mobile phase was Acetonitrile (ACN): 0.1% trifluoroacetic acid (0.1% tfa) in water=68:32 (V: V), isocratic elution; the flow rate of the mobile phase was 1.5mL min -1 。
Preferably, in preparing the compound IV, the chromatographic column of the semi-prepared reversed phase high performance liquid chromatography is a Capcell Pak MG II chromatographic column, and the specification is as follows: 5 μm, 10X 250mm; the mobile phase was 78% acetonitrile in water (78% ACN-H) 2 O), isocratic elution.
The invention also aims to provide a medicine for treating related diseases caused by coronavirus infection and/or influenza virus, which is a pharmaceutical composition prepared by taking tricyclic pyridone compounds or pharmaceutical salts thereof shown in a formula I or tricyclic pyridone compounds or pharmaceutical salts thereof shown in a formula II as active ingredients and combining with one or more pharmaceutically acceptable carriers.
The pharmaceutical composition can be used for clinical treatment of coronavirus and influenza virus infection.
The tricyclic pyridone compounds of formula I or pharmaceutically acceptable salts thereof or the tricyclic pyridone compounds of formula II or pharmaceutically acceptable salts thereof can also be combined with known medicaments to form compound preparations for the treatment of coronavirus and influenza virus infections.
The medicine contains tricyclic pyridone compounds or medicinal salts thereof shown in the formula I or tricyclic pyridone compounds or medicinal salts thereof shown in the formula II in a weight ratio of 0.1-99.9%, and pharmaceutically acceptable carriers in the composition in a weight ratio of 0.1-99.9%.
The pharmaceutical composition is present in a pharmaceutically acceptable formulation. The preparation is tablet, capsule, granule, pill, powder, paste, suspension, injection, powder injection, suppository, cream, drop or patch. Wherein the tablet is sugar-coated tablet, film-coated tablet, enteric-coated tablet or slow-release tablet; the capsule is hard capsule, soft capsule and slow-release capsule; the powder injection is freeze-dried powder injection.
The effective dose of the tricyclic pyridone compound shown in the formula I or the pharmaceutically acceptable salt thereof or the tricyclic pyridone compound shown in the formula II is 0.1-1000 mg in each dose, wherein each dose refers to each preparation unit, such as each tablet of a tablet, each granule of a capsule, and each administration dose, such as 100mg.
The medicaments of the present invention may be used as solid carriers in the preparation of solid or semi-solid pharmaceutical preparations in the form of powders, tablets, dispersible powders, capsules, cachets, suppositories and ointments. The solid carrier which can be used is preferably one or more substances selected from diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, expanding agents and the like, or may be an encapsulating substance. In the powder formulation, 5 to 70% of the micronized active ingredient is contained in the carrier. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, low boiling waxes, cocoa butter and the like. Because of their ease of administration, tablets, powders, cachets, and capsules represent the most advantageous oral solid formulations.
When the medicament of the invention is prepared into liquid preparations, the liquid preparations comprise solutions, suspensions and emulsions. For example, parenteral injection formulations may be in the form of water or water-propylene glycol solutions, adjusted to their isotonicity, pH, etc., to adapt to the physiological conditions of the living body. The liquid preparation can also be prepared into a solution form in polyethylene glycol and an aqueous solution. An aqueous oral solution can be prepared by dissolving the active ingredient in water, and adding appropriate amounts of coloring agents, flavoring agents, stabilizers, and thickening agents. Aqueous suspensions suitable for oral use can be prepared by dispersing the micronized active ingredient in viscous materials such as natural and synthetic gums, methylcellulose, sodium carboxymethylcellulose, and other known suspending agents.
It is particularly advantageous to formulate the aforementioned drugs in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form of a formulation refers to physically discrete units suitable as unitary dosages, each unit containing a calculated predetermined quantity of active ingredient in order to produce the desired therapeutic effect. Such dosage unit forms may be in packaged form, such as tablets, capsules or powders in vials or bottles, or ointments, gels or creams in vials or bottles.
Although the amount of active ingredient contained in the dosage unit form may vary, it is generally adjusted to a range of 1 to 800mg depending on the potency of the active ingredient selected.
The person skilled in the art can determine the preferred dosage for a particular situation in a conventional manner. Generally, the amount to be treated is initially below the optimal dose of the active ingredient, and then the dosage is gradually increased until the optimal therapeutic effect is achieved. For therapeutic purposes, the total daily dose may be administered once or in divided doses.
Detailed Description
Embodiments of the present invention are applicable to the preparation of tricyclic pyridones from any microorganism, not limited to fungal fermentates. The following examples are set forth to aid those of ordinary skill in the art in better understanding the present invention and are not intended to limit the present invention in any way.
Example 1
Bacterial strain source:
fungus Gibberella sp.1394, china center for type culture Collection (China Pharmaceutical Culture Collection), accession number CPCC 400857.
And (3) strain fermentation:
inoculating activated fungus 1394 strain on PDA inclined plane, and culturing at 25deg.C in incubator for one week. The seed was slant-dug, crushed, inoculated into 3 conical flasks (specification: 500 mL) containing 100mL of PDB medium, and cultured with shaking at 25℃for 5 days as a seed solution. Taking 60 triangular flasks (specification: 500 mL), placing 100g of rice and 100mL distilled water into each triangular flask, sealing, sterilizing at 121deg.C for 15min, cooling, adding 10mL of the seed solution (60 bottles in total) into each triangular flask, and culturing at 25deg.C for 30 days to obtain fungal 1394 rice fermented product.
Extraction of fungal 1394 fermented product and extraction of extractum:
taking rice fermented product, respectively extracting with 95% ethanol for 2 times and 50% ethanol for 1 time under ultrasonic treatment for 30min, filtering the extractive solution, concentrating under reduced pressure until no alcohol smell exists to obtain crude extract water solution, extracting with ethyl acetate with volume equal to that of the crude extract water solution for 3 times, and concentrating the ethyl acetate layer under reduced pressure to obtain brown oily crude extract.
Separation, preparation and structural identification of compounds I, IIA, IIB, III and IV:
taking crude extract, separating by normal phase silica gel chromatographic column chromatography, selecting a methylene dichloride-methanol system, performing gradient elution according to the volume ratio of 50:1, 40:1, 35:1, 30:1, 25:1, 20:1, 15:1, 10:1, 5:1, 1:1 and 1:0, merging similar fractions according to TLC unfolding results, and then evaporating under reduced pressure to obtain 10 fractions which are respectively marked as Fr.1-Fr.10.
Fr.10 (1.3 g) was taken and dissolved in methanol and Flash column chromatography was performed (column format: SW-025-SP; mobile phase: 5% -100% MeOH-H) 2 O, gradient elution; flow rate: 5 mL/min -1 ) The separation finally gives 6 subfractions, designated Fr.10.1-Fr.10.6, respectively. Fr.10.3 was taken and subjected to semi-preparative RP-HPLC (chromatographic column: capcell Pak MG II column, specification: 5 μm; 4.6X1250 mm; mobile phase: 69% ACN-H) 2 O (0.1% tfa), isocratic elution; flow rate: 1.5 mL/min -1 ) Compounds I and II A, IIB are obtained. Fr.10.2 was taken and subjected to semi-preparative RP-HPLC (chromatographic column: capcell Pak PFP column, specification: 5 μm; 10X 250mm; mobile phase: 68% ACN-H) 2 O (0.1% tfa), isocratic elution; flow rate: 1.5 mL/min -1 ) Obtaining the compound III.
Fr.5 was taken and dissolved in methanol for Flash column chromatography (column size: SW-040-SP; mobile phase: 5% -100% MeOH-H) 2 O, gradient elution; flow rate: 5 mL/min -1 ) 7 subfractions were separated and designated Fr.5.1-Fr.5.7, respectively. Fr.5.7 was taken, dissolved in methylene chloride-methanol (volume ratio 1:1), eluted by Sephadex LH-20 column chromatography with methylene chloride-methanol (volume ratio 1:1) as flow equality, and fractions were combined according to TLC development results to give 7 subfractions, designated Fr.5.7.1-Fr.5.7.7, respectively. Fr.5.7.2 was taken and subjected to semi-preparative RP-HPLC (Capcell Pak MG II column; 5 μm; 10X 250mm; mobile phase: 78% ACN-H) 2 O, isocratic elution, flow rate: 1.5 mL/min -1 ) The compound IV is prepared.
Structural identification of Compound I
Compound I (named Fusaridon C) is a white amorphous powder, and HRESIMS suggests that its formula is C 30 H 47 NO 6 The unsaturation was 8. Compound I 1 H NMR spectra show an isolated aromatic proton [ delta ] H 7.71(1H,s, H-6)]A trisubstituted double bond proton [ delta ] H 5.02(1H,dd,J＝9.0,1.2Hz,H-13)]Three oxygen-linked methine protons [ delta ] H 4.57 (1 h, dd, j=12.0, 1.8hz, h-7), 3.23 (1 h, d, j=10.2 hz, h-11) and 4.50 (1 h, dd, j=6.6, 9.0hz, h-6')]Three isolated methyl protons [ delta ] H 3.32(3H,s,NCH 3 -1),3.10(3H,s,OCH 3 -4') and 3.04 (3H, s, OCH) 3 -4')]Methyl protons [ delta ] of four methines H 1.50(3H,d,J＝1.2Hz,CH 3 -20),0.84(3H,d,J＝6.6 Hz,CH 3 -21),0.80(3H,d,J＝6.6Hz,CH 3 -22) and 0.65 (3 h, d, j=6.6 hz, ch 3 -19)]Methyl proton [ delta ] of one methylene group H 0.79(3H,t,J＝7.2Hz,CH 3 -18)]And between 0.95 and 2.40 there are also some methylene and methylene proton resonance signals. The above hydrogen spectrum data combined with ultraviolet light spectrum suggest that the compound is presumed to be an N-methyl-2 pyridone compound, and the spectrum data is very similar to compound IIA (known compound). Careful analysis of NMR data comparing compounds I and IIA, differed in that the C-4' ketocarbonyl signal (delta) was absent in compound IIA in compound I C 207.7 But two more methoxy signals (delta) C 47.4 and 47.3) and 1 quaternary carbon signal (delta) C 98.9 From this, it can be deduced that the carbonyl group at C-4' position in the structure of the compound IIA is replaced by two methoxy groups in the compound I. 2 4' -OCH in HMBC spectra of Compound I 3 All related to C-4', further demonstrating the above reasoning, and thus determining the planar structure of Compound I.
The relative configuration of the partial chiral centers was determined by analysis of the coupling constant between protons of the compound and the ROESY-related signal. The signals associated with H-6 'and OH-1' in the ROESY spectrum indicate that H-6 'and-OH-1' are on the same side; the remote correlation signals for H-7 and H-11 indicate that H-7 and H-11 are on the same side, while the coupling constant between H-11 and H-10 is 9.6Hz, indicating that H-11 and H-10 are on the opposite side; chemical shift of C-20 is delta C 11.0, and no CH was observed in the ROESY spectrum 3 -a correlation signal between 20 and H-13, thereby indicating that the double bond between C-12 and C-13 is in trans configuration; according to C-21 (delta) C 20.9 And C-22 (delta) C 19.6) The difference in chemical shift between them was 1.3ppm, a minor difference indicating that C-21 and C-22 are in trans (Organ M G, bilokin Y V, svetosleav B.Approx. Toward the total synthesis of orevactaene. 2.Convergent and stereoselective synthesis of the C18-C31 domain of orevactaene.Evidece for the relative configuration of the side chain [ J)]J.org.chem.,2003,34 (2): 5176-5183.). The relative configuration of each moiety of compound I was determined.
TABLE 1 NMR data for Compound I
Note that: a Data were recorded at 600MHz for proton and at 150MHz for carbon in DMSO-d 6 .
structural identification of Compound IIA
The compound IIA is white amorphous powder, C 28 H 41 NO 5 ，ESI-MS m/z 472.3[M+H] + ； 1 H NMR(600 MHz,DMSO-d 6 ):δ H 7.73(1H,s,H-6),4.54(1H,dd,J＝2.4,11.4Hz,H-7),2.11(1H,m,H-8a), 1.34(1H,m,H-8b),1.77(1H,m,H-9a),1.18(1H,m,H-9b),1.45(1H,m,H-10),3.20(1H,d,J＝16.2Hz,H-11),5.00(1H,dd,J＝11.2,9.0Hz,H-13),2.41(1H,m,H-14),1.16(1H,m,H-15a), 1.00(1H,m,H-15b),1.28(1H,m,H-16),1.29(1H,m,H-17a),1.00(1H,m,H-17b),0.81(3H,t,J ＝6.6Hz,H-18),0.64(3H,d,J＝6.6Hz,H-19),1.46(3H,d,J＝1.2Hz,H-20),0.84(3H,d,J＝6.6Hz,H-21),0.79(3H,d,J＝6.6Hz,H-22),3.34(3H,s,H-23),2.29(1H,m,H-2′a),2.21(1H,m,H- 2′b),2.27(1H,m,H-3′a),1.74(1H,m,H-3′b),2.56(1H,dd,J＝16.2,4.2Hz,H-5′a),3.00(1H,dd,J＝16.8,4.8Hz,H-5′b)4.85(1H,t,J＝4.2Hz,H-6′),5.97(1H,s,OH-1′)； 13 C NMR(150MHz, DMSO-d 6 ):δ C 162.2(C-2),106.8(C-3),165.7(C-4),115.5(C-5),134.2(C-6),71.2(C-7),28.5(C- 8),32.5(C-9),31.4(C-10),90.1(C-11),134.2(C-12),134.2(C-13),28.9(C-14),44.5(C-15),31.2(C-16),28.1(C-17),11.0(C-18),17.6(C-19),10.7(C-20),20.9(C-21),19.5(C-22),37.1(C-23), 75.3(C-1′),32.6(C-2′),34.7(C-3′),207.7(C-4′),42.2(C-5′),90.1(C-6′)。
The structural formula of the compound IIA is as follows:
structural identification of the Compound IIB shown
Compound IIB is white amorphous powder, C 29 H 43 NO 5 ，ESI-MS m/z 486.3[M+H] + ； 1 H NMR(600 MHz,DMSO-d 6 ):δ H 7.71(1H,s,H-6),4.57(1H,dd,J＝12.0,2.4Hz,H-7),1.46(1H,m,H-8a), 1.98(1H,m,H-8b),1.33(1H,m,H-9a),1.85(1H,m,H-9b),1.46(1H,m,H-10),3.21(1H,d,J＝9.6Hz,H-11),5.02(1H,dd,J＝9.6,1.2Hz,H-13),2.42(1H,m,H-14),1.01(1H,m,H-15a),1.28 (1H,m,H-15b),1.38(1H,m,H-16),1.38(1H,m,H-17),0.80(3H,d,J＝6.6Hz,H-18),0.65(3H,d,J＝6.6Hz,H-19),1.48(3H,d,J＝1.2Hz,H-20),0.87(3H,d,J＝6.6Hz,H-21),0.78(3H,d,J＝ 7.2Hz,H-22),3.33(3H,s,H-23),5.31(1H,t,J＝4.8Hz,H-2′),2.53(1H,dd,J＝4.8Hz,16.2Hz,H-3′a),3.00(1H,dd,J＝5.4,16.2Hz,H-3′b),2.37(1H,m,H-5′a),2.07(1H,m,H-5′b),2.28(1H, m,H-6′a),2.22(1H,m,H-6′b),3.10(3H,s,OMe-1′)； 13 C NMR(150MHz,DMSO-d 6 ):δ C 162.3 (C-2),107.1(C-3),166.1(C-4),109.5(C-5),134.3(C-6),71.1(C-7),28.6(C-8),32.4(C-9),31.2(C-10),90.1(C-11),132.6(C-12),135.8(C-13),28.9(C-14),44.5(C-15),31.3(C-16),29.1(C-17), 11.0(C-18),17.6(C-19),10.7(C-20),20.9(C-21),19.5(C-22),37.3(C-23),81.7(C-1′),85.9(C- 2′),42.9(C-3′),207.5(C-4′),34.7(C-5′),31.4(C-6′),50.1(OMe-1′)。
The structural formula of the compound IIB is as follows:
structural identification of Compound III
Compound III is a milky amorphous powder, C 28 H 43 NO 6 ，ESI-MS m/z 490.1[M+H] + ； 1 H NMR(600 MHz,DMSO-d 6 ):δ H 9.88(1H,s,OH-4),7.58(1H,s,H-6),4.32(1H,dd,J＝5.4,9.6Hz,H-7),1.54 (1H,m,H-8a),2.00(1H,m,H-8b),1.33(1H,m,H-9a),1.82(1H,m,H-9b),1.66(1H,m,H-10),3.52(1H,d,J＝9.6Hz,H-11),5.18(1H,dd,J＝1.8,9.6Hz,H-13),2.38(1H,m,H-14),1.00(1H, m,H-15a),1.18(1H,m,H-15b),1.31(1H,m,H-16),1.00(2H,m,H-17),0.79(3H,t,J＝6.6Hz,H-18),0.69(3H,d,J＝6.6Hz,H-19),1.57(3H,d,J＝1.8Hz,H-20),0.87(3H,d,J＝6.6Hz,H- 21),0.79(3H,d,J＝6.6Hz,H-22),3.33(3H,s,H-23),2.47(1H,m,H-2′a),2.00(1H,m,H-2′b), 2.28(1H,dd,J＝5.4,13.8Hz,H-3′a),2.38(1H,dd,J＝5.4,13.8Hz,H-3′b),2.69(1H,dd,J＝13.8,11.4Hz,H-5′a),2.63(1H,dt,J＝13.8,6.6Hz,H-5′b),4.89(1H,dd,J＝13.8,6.6Hz,H-6′),9.88 (1H,OH-4)； 13 C NMR(150MHz,DMSO-d 6 ):δ C 160.5(C-2),108.7(C-3),161.0(C-4),114.7(C-5), 136.5(C-6),73.3(C-7),29.0(C-8),31.6(C-9),31.5(C-10),91.0(C-11),130.6(C-12),136.8(C-13),29.9(C-14),46.4(C-15),31.5(C-16),28.0(C-17),11.8(C-18),17.3(C-19),11.0(C-20),20.8 (C-21),19.6(C-22),36.5(C-23),77.0(C-1′),31.8(C-2′),36.1(C-3′),209.1(C-4′),44.4(C-5′), 69.9(C-6′)。
The structural formula of the compound III is as follows:
structural identification of Compound IV
Compound IV is a colorless gelatinous solid, C 28 H 39 NO 4 ，ESI-MS m/z 454.3[M+H] + ； 1 H NMR(600MHz, DMSO-d 6 ):δ H 9.69(1H,s,OH-4),7.55(1H,s,H-6),4.83(1H,dd,J＝1.8,11.4Hz,H-7),1.49(1H, m,H-8a),1.98(1H,m,H-8b),1.34(1H,m,H-9a),1.85(1H,m,H-9b),1.53(1H,m,H-10),3.27(1H,dd,J＝4.2,10.8Hz,H-11),5.20(1H,d,J＝9.6Hz,H-13),2.27(1H,t,J＝7.2Hz,H-14),1.01 (1H,m,H-15a),1.18(1H,m,H-15b),1.23(1H,m,H-16),1.01(1H,m,H-17a),1.22(1H,m,H-17b),0.79(3H,t,J＝7.2Hz,H-18),0.80(3H,d,J＝6.0Hz,H-19),0.86(3H,d,J＝6.6Hz,H-20), 1.56(3H,s,H-21),0.69(3H,d,J＝6.6Hz,H-22),3.37(3H,s,H-23),7.19(1H,d,J＝8.4Hz,H-2′), 6.75(1H,d,J＝8.4Hz,H-3′),9.41(1H,s,OH-4′),6.75(1H,d,J＝8.4Hz,H-5′),7.19(1H,d,J＝ 8.4Hz,H-6′)； 13 C NMR(150MHz,DMSO-d 6 ):δ C 160.2(C-2),108.7(C-3),160.9(C-4),112.8(C- 5),136.9(C-6),76.9(C-7),30.2(C-8),31.5(C-9),31.6(C-10),91.2(C-11),130.4(C-12),137.1(C-13),29.1(C-14),44.3(C-15),31.5(C-16),28.0(C-17),11.0(C-18),19.6(C-19),20.8(C-20), 11.3(C-21),17.3(C-22),36.1(C-23),124.5(C-1′),130.1(C-2′),114.9(C-3′),156.5(C-4′),114.9 (C-5′),130.1(C-6′)。
The structural formula of the compound IV is as follows:
example 2
Test items: test of coronavirus resistance of Compounds I to IV
The test principle is as follows: the degree of cytopathic effect (CPE) of the sample-inhibited virus was determined using H460 cells as the viral host.
Testing raw materials and methods:
virus strain: coronavirus HCoV-OC43, stored at-80 ℃.
Positive control drug: ribavirin (RBV), a company of the pharmaceutical industry, north of the lake (lot number 31712252).
Sample treatment: before use, the positive control medicine and the compounds I to IV are respectively prepared into mother solutions by DMSO, and then the mother solutions are used for 3-time dilution, 8 dilutions are respectively carried out.
The testing method comprises the following steps: h460 cells were inoculated into 96-well plates and placed in 5% CO 2 After incubation at 35℃for 24 hours, coronavirus infection was effected, with simultaneous addition ofThe maintenance solution containing samples with different dilutions and positive control drugs is provided with cell control wells (no coronavirus infection nor sample added) and virus control wells (no sample added) simultaneously, 5% CO 2 Continuously culturing at 35 ℃; when the virus control group lesion degree (CPE) reaches 4+, observing the cytopathic degrees (CPE) of each group, and calculating the half-lethal concentration (TC) of the sample on cells by using a Reed-Muench method 50 ) And half-maximal Inhibitory Concentration (IC) against virus 50 ) And calculates a selection index (si=tc 50 /IC 50 )。
CPE evaluation criteria: the cell death ratios are respectively marked as 4+ (cell death ratio 75% -100%), 3+ (cell death ratio 50% -75%), 2+ (cell death ratio 25% -50%), 1+ (cell death ratio 0% -25%), and 0+ (cell total survival).
The experimental results are shown in Table 1.
TABLE 1 results of anti-coronavirus test of Compounds I-IV

Claims (8)

1. Tricyclic pyridone compounds of the formula I or pharmaceutically acceptable salts thereof:
2. the tricyclic pyridone compound or pharmaceutically acceptable salt thereof according to claim 1, wherein: the pharmaceutical salt of the tricyclic pyridone compound is a salt formed by the tricyclic pyridone compound and inorganic acid, organic acid or amino acid; the inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid or sulfonic acid; the amino acid is alanine, aspartic acid or lysine.
3. A process for the preparation of tricyclic pyridones according to claim 1, wherein: comprising the following steps: fermenting rice by fungus Gibberella sp.1394 to obtain rice fermented product, respectively extracting rice fermented product with 95% ethanol for 2 times and 50% ethanol for 1 time, filtering the extractive solution, concentrating under reduced pressure until no ethanol smell exists, to obtain crude extract water solution, extracting with ethyl acetate equal to the crude extract water solution in volume for 3 times, and concentrating under reduced pressure to obtain crude extract; performing normal phase silica gel chromatographic column chromatography on the crude extract, and performing gradient elution by using a dichloromethane-methanol system as an eluent to obtain 10 fractions which are respectively marked as Fr.1-Fr.10; taking Fr.10, dissolving with methanol, performing Flash column chromatography to obtain 6 subfractions, which are respectively denoted as Fr.10.1-Fr.10.6; taking Fr.10.3, and performing semi-preparative reverse-phase high performance liquid chromatography to obtain tricyclic pyridone compounds shown in formula I;
the volume ratio of the dichloromethane to the methanol in the dichloromethane-methanol system is 100:0-0:100;
the mobile phase of Flash column chromatography is 5% -100% MeOH-H 2 O, carrying out gradient elution, wherein the flow rate of the mobile phase is 5 mL.min -1 ；
The chromatographic column of the semi-preparative reverse phase high performance liquid chromatography is Capcell Pak C 18 MG II chromatographic column, specification is: 5 μm, 10X 250mm; the mobile phase is acetonitrile, 0.1% trifluoroacetic acid aqueous solution=69:31 v:v, and isocratic elution is carried out; the flow rate of the mobile phase was 1.5mL min -1 。
4. The use of a tricyclic pyridone compound of claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease associated with a coronavirus infection.
5. The use according to claim 1, characterized in that: the application is the application in preparing medicaments for resisting related diseases caused by coronavirus HCoV-OC43 infection.
6. The application of tricyclic pyridone compounds or pharmaceutically acceptable salts thereof in preparing medicaments for treating related diseases caused by coronavirus HCoV-OC43 infection is shown in a structural formula II:
wherein R is selected from
R 1 Selected from CH 3 。
7. The use according to claim 6, characterized in that: the pharmaceutical salt of the tricyclic pyridone compound is a salt formed by the tricyclic pyridone compound and inorganic acid, organic acid or amino acid; the inorganic acid is hydrochloric acid or sulfuric acid; the organic acid is acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid or sulfonic acid; the amino acid is alanine, aspartic acid or lysine.
8. A medicine for treating diseases caused by coronavirus infection, which is a medicine composition prepared by taking the tricyclic pyridone compound or the pharmaceutical salt thereof as an active ingredient and matching with a pharmaceutically acceptable carrier.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107536833A (en) * 2017-10-24 2018-01-05 山东大学 A kind of application of pyridinone alkaloid of 4 hydroxyl 2 in antitumor product is prepared

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107536833A (en) * 2017-10-24 2018-01-05 山东大学 A kind of application of pyridinone alkaloid of 4 hydroxyl 2 in antitumor product is prepared

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Biomimetic conversion of ()-fusoxypyridone and ()-oxysporidinone to ()-sambutoxin: Further evidence for the structure of the tricyclic pyridone alkaloid, ()-fusoxypyridone;E. M. Kithsiri Wijeratne等;《Bioorganic & Medicinal Chemistry Letters》;第21卷;第2327页 *
Cytotoxic hexadepsipeptides and anti-coronaviral 4-hydroxy-2-pyridones from an endophytic Fusarium sp.;Shanshan Chang等;《Front. Chem.》;第01-09页 *

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