CN113735929A - Anti-coronavirus compound and preparation method and application thereof - Google Patents

Anti-coronavirus compound and preparation method and application thereof Download PDF

Info

Publication number
CN113735929A
CN113735929A CN202110825940.4A CN202110825940A CN113735929A CN 113735929 A CN113735929 A CN 113735929A CN 202110825940 A CN202110825940 A CN 202110825940A CN 113735929 A CN113735929 A CN 113735929A
Authority
CN
China
Prior art keywords
formula
compound
pharmaceutically acceptable
reaction
cov
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202110825940.4A
Other languages
Chinese (zh)
Inventor
陈华栋
邱炳林
钟宝香
李金林
黄志征
陈书红
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haihua Life Xiamen Technology Co ltd
Original Assignee
Haihua Life Xiamen Technology Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haihua Life Xiamen Technology Co ltd filed Critical Haihua Life Xiamen Technology Co ltd
Priority to CN202110825940.4A priority Critical patent/CN113735929A/en
Publication of CN113735929A publication Critical patent/CN113735929A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Biotechnology (AREA)
  • Virology (AREA)
  • Genetics & Genomics (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an anti-coronavirus compound and a preparation method and application thereof. The anti-coronavirus compound of the invention is a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure:

Description

Anti-coronavirus compound and preparation method and application thereof
Technical Field
The invention relates to an anti-coronavirus compound and a preparation method and application thereof.
Background
Coronaviruses (CoV) are widely present in nature and are RNA viruses with envelope, linear single-strand positive strand genome, which only infect vertebrates, are associated with a variety of diseases in humans and animals and can cause diseases in the respiratory, digestive and nervous systems of humans and animals. At present, 6 kinds of human-infecting coronavirus are known, namely human coronavirus HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1, severe acute respiratory syndrome coronavirus SARS-CoV and middle east respiratory syndrome coronavirus MERS-CoV, and SARS-CoV-2 is the 7 th known coronavirus which can infect human. Among them, SARS-CoV-2 is a coronavirus clearly at 31.12.2019, which causes a novel coronavirus pneumonia, and the incubation period is 1 to 14 days, and is mostly 3 to 7 days based on the current epidemiological investigation. It is mainly manifested as fever, dry cough and hypodynamia. A few patients have nasal obstruction, watery nasal discharge, pharyngalgia, myalgia and diarrhea. Severe patients often develop dyspnea and/or hypoxemia after one week of onset, and severe patients can rapidly progress to acute respiratory distress syndrome, septic shock, refractory metabolic acidosis, hemorrhagic coagulation dysfunction, multiple organ failure and the like. It is worth noting that the course of the disease of the heavy and critical patients may be low or medium fever, even without obvious fever. Mild patients only manifest low fever, slight asthenia, etc., and no manifestations of pulmonary inflammation. From the current accepted cases, the prognosis of most patients is good, and the disease condition of few patients is critical. The virus has extremely high infectivity, seriously influences the life of people all over the world and drives the sight of people all over the world. The development of drugs capable of treating or preventing coronaviruses is imminent, and efforts to find novel specific drugs for coronaviruses are being made day by day and night and are the focus of attention of the public.
Disclosure of Invention
The invention aims to provide an anti-coronavirus compound, a preparation method and application thereof, wherein the compound has high inhibitory activity on various viruses and has the potential of being used for preparing anti-coronavirus medicines. The purpose of the invention is realized by the following technical scheme:
a compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:
Figure BDA0003173795860000021
wherein:
R2is F or Cl;
R1is H, alkyl acyl, alkyl benzoyl or
Figure BDA0003173795860000022
A1And A2Each independently is a group of formula Ia:
Figure BDA0003173795860000023
wherein:
each Y2Independently is a bond, O or NR;
m2 is 0, 1 or 2;
each Rx is independently Ry or a group of formula Ib:
Figure BDA0003173795860000024
wherein:
each M1a, M1c, and M1d is independently 0 or 1;
m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8
Each Ry is independently H, R, -C (═ O) OR, OR-SC (═ O) R;
each R is independently H, (C1-C8) alkyl, or C6-C20 aryl.
The term "pharmaceutically acceptable salts" as used herein refers to non-toxic inorganic or organic acid and/or base addition salts, as described in "Salt selection for basic drugs", int.J.pharm. (1986),33, 201-217. The inorganic or organic acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, citric acid, fumaric acid, glucuronic acid, formic acid, acetic acid, oxalic acid, succinic acid, etc.
The compound of formula I, or a pharmaceutically acceptable salt thereof, is represented by any one of the following structural formulae:
Figure BDA0003173795860000031
an antiviral agent comprising as an active ingredient any one or more of said compound of formula I or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising any one or more of said compounds of formula I or pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable carrier or excipient.
A pharmaceutical composition comprising said compound of formula I or any one or more of its pharmaceutically acceptable salts and at least one pharmaceutically acceptable diluent.
A pharmaceutical composition comprising said compound of formula I or any one or more of its pharmaceutically acceptable salts and at least one other antiviral drug.
The medicine composition is injection, oral preparation, freeze dried powder for injection and suspending agent.
The compound of formula I or its pharmaceutically acceptable salt can be used for preparing medicines for treating and/or preventing symptoms or diseases caused by SARS coronavirus, novel coronavirus SARS-CoV-2 or MERS coronavirus.
A process for the preparation of said compound of formula I, comprising the process steps of:
(1) synthesis of intermediate a: dissolving material SM in organic solventUnder reducing agent conditions with SOCl2Reacting to obtain an intermediate A, wherein structural formulas of the material SM and the intermediate A are respectively as follows:
Figure BDA0003173795860000041
wherein R in each structure1Either F or Cl
(2) Synthesis of intermediate B: reacting the intermediate A obtained in the step (1) with O-trimethylsilyl-N4-benzoylcytosine to obtain an intermediate B, wherein the structural formula of the intermediate B is as follows:
Figure BDA0003173795860000042
(3) synthesis of intermediate C: and (3) carrying out deprotection reaction on the intermediate B obtained in the step (2) to obtain an intermediate C, wherein the structure of the intermediate C is as follows:
Figure BDA0003173795860000043
(4) synthesis of intermediate D: and (3) reacting the intermediate C obtained in the step (3) with acid anhydride for transesterification to obtain an intermediate D, wherein the structural formula of the intermediate D is as follows:
Figure BDA0003173795860000051
(5) synthesis of target compound E: carrying out hydroxylamination on the intermediate D obtained in the step (4) to obtain a target compound E, wherein the structural formula of the target compound E is as follows:
Figure BDA0003173795860000052
(6) synthesis of intermediate F: reacting the intermediate C obtained in the step (3) with SM3 under the condition of a Grignard reagent to obtain an intermediate F, wherein the structural formulas of SM3 and the intermediate F are respectively as follows:
Figure BDA0003173795860000053
(7) synthesis of target compound G: carrying out hydroxylamination on the intermediate F obtained in the step (6) to obtain a target compound G, wherein the structural formula of the target compound G is as follows:
Figure BDA0003173795860000061
the specific synthetic route is as follows:
Figure BDA0003173795860000062
compared with the prior art, the invention has the advantages that: the target compounds E1, E2, G1 and G2 of the invention have little toxic effect on Vero normal cells, but can obviously inhibit the infection of SARS-CoV-2 virus on normal cells, and have inhibition effect on novel coronavirus SARS-CoV-2 at the cell level, so the target compounds of the invention have the potential for preparing medicines for resisting novel coronavirus SARS-CoV-2. In addition, the target compounds E1, E2, G1 and G2 also have remarkable activity against coronavirus such as MERS-CoV and SARS-CoV, and the tested compounds E1, E2, G1 and G2 have higher selectivity than positive control drugs.
Detailed Description
The present invention will be described in detail with reference to the following examples:
a compound of formula I, or a pharmaceutically acceptable salt thereof, having the structure:
Figure BDA0003173795860000071
wherein:
R2is F or Cl;
R1is H, alkyl acyl, alkyl benzylAcyl or
Figure BDA0003173795860000072
A1And A2Each independently is a group of formula Ia:
Figure BDA0003173795860000073
wherein:
each Y2Independently is a bond, O or NR;
m2 is 0, 1 or 2;
each Rx is independently Ry or a group of formula Ib:
Figure BDA0003173795860000074
wherein:
each M1a, M1c, and M1d is independently 0 or 1;
m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8
Each Ry is independently H, R, -C (═ O) OR, OR-SC (═ O) R;
each R is independently H, (C1-C8) alkyl, or C6-C20 aryl.
The term "pharmaceutically acceptable salts" as used herein refers to non-toxic inorganic or organic acid and/or base addition salts, as described in "Salt selection for basic drugs", int.J.pharm. (1986),33, 201-217. The inorganic or organic acid is preferably hydrochloric acid, sulfuric acid, phosphoric acid, maleic acid, citric acid, fumaric acid, glucuronic acid, formic acid, acetic acid, oxalic acid, succinic acid, etc.
The compound of formula I, or a pharmaceutically acceptable salt thereof, is represented by any one of the following structural formulae:
Figure BDA0003173795860000083
the preparation method of the compound of the formula I comprises the following process steps:
(1) synthesis of intermediate a: dissolving material SM in organic solvent, and neutralizing SOCl under the condition of reducing agent2Reacting to obtain an intermediate A, wherein structural formulas of the material SM and the intermediate A are respectively as follows:
Figure BDA0003173795860000082
Figure BDA0003173795860000091
wherein R is1F or Cl;
(2) synthesis of intermediate B: reacting the intermediate A obtained in the step (1) with O-trimethylsilyl-N4-benzoylcytosine to obtain an intermediate B, wherein the structural formula of the intermediate B is as follows:
Figure BDA0003173795860000092
(3) synthesis of intermediate C: and (3) carrying out deprotection reaction on the intermediate B obtained in the step (2) to obtain an intermediate C, wherein the structure of the intermediate C is as follows:
Figure BDA0003173795860000093
(4) synthesis of intermediate D: and (3) reacting the intermediate C obtained in the step (3) with acid anhydride for transesterification to obtain an intermediate D, wherein the structural formula of the intermediate D is as follows:
Figure BDA0003173795860000094
(5) synthesis of target compound E: carrying out hydroxylamination on the intermediate D obtained in the step (4) to obtain a target compound E, wherein the structural formula of the target compound E is as follows:
Figure BDA0003173795860000101
(6) synthesis of intermediate F: reacting the intermediate C obtained in the step (3) with SM3 under the condition of a Grignard reagent to obtain an intermediate F, wherein the structural formulas of SM3 and the intermediate F are respectively as follows:
Figure BDA0003173795860000102
(7) synthesis of target compound G: carrying out hydroxylamination on the intermediate F obtained in the step (6) to obtain a target compound G, wherein the structural formula of the target compound G is as follows:
Figure BDA0003173795860000103
the specific operation method of the step (1) comprises the following steps:
adding SM and organic solvent, cooling, slowly dropping reducing agent, and keeping the temperature at-20 to-30 ℃ all the time in the dropping process. After the dropwise addition, the reaction is carried out for 5-6h under the condition of temperature adjustment, and the TLC spot plate raw material reaction is finished. Then 2N HCl is added, and the reaction is continued for 1-2 h. Adding catalyst, slowly dropping SOCl2Controlling the reaction temperature to be-10-0 ℃, after the dropwise addition is finished, slowly heating to 30-40 ℃, stirring overnight, after TLC (thin layer chromatography) monitoring shows that the raw materials are completely reacted, cooling the reaction liquid to-10-0 ℃, and adding H2And O, stirring for 1-2h, and separating the liquid. The organic layer was washed with a citric acid solution and a 10% KOH solution, respectively, and the resulting organic layer was concentrated by replacing the solvent with chlorobenzene to obtain a solution of intermediate a.
Wherein, the SM, the reducing agent and the SOCl2Is 1.0:1.0-1.5:1.0-10.0, more preferably 1.0:1.1: 5.0.
The organic solvent is DMF, NMP and toluene, preferably toluene;
the catalytic reagent is TEA and DMAP, preferably DMAP;
the reducing agent is Red-Al, LiAlH4, preferably Red-Al.
The specific operation method of the step (2) is as follows:
adding anhydrous SnCl into the intermediate A solution4And SM2 (O-trimethylsilyl-N4-benzoylcytosine. the reaction solution is heated and then reacted for a period of time under the temperature condition, TLC monitors that the raw materials are completely reacted, the reaction solution is cooled to room temperature, DCM and saturated sodium bicarbonate solution are added into the system, then the system is cooled, and H is slowly added into the system2And O, quenching the reaction. Then, the temperature is raised to the room temperature, and the mixture is stirred for 1 to 2 hours. Filter and wash the filter cake with DCM. And (3) layering the obtained filtrate, heating the obtained organic layer filtrate, cooling, stirring for 2-3h under the condition of the secondary temperature, and slowly separating out the intermediate B.
Wherein, the SnCl4And SM2 (O-trimethylsilyl-N4-benzoylcytosine) in a molar ratio of 1.0-3.0:1.0, more preferably 2.0: 1.0.
the temperature rise is 40-90 ℃, and more preferably 70-80 ℃.
The reaction time is 8-24h, and more preferably 10-12 h.
The specific operation method of the step (3) is as follows:
adding the intermediate B, anhydrous methanol and sodium methoxide. The reaction solution was warmed up, reacted at this temperature for a while, TLC monitored the disappearance of the reaction raw material, isobutyric acid was added to quench the reaction, the reaction solution was concentrated, and the residual solvent was replaced with IPA. Heating the obtained reaction solution to 80-85 ℃, then slowly cooling to 0-5 ℃, stirring for 2-3h, and slowly precipitating an intermediate C.
Wherein the molar ratio of the intermediate B to sodium methoxide is 1.0-5.0: 1.0 is more preferably 3.0: 1.0.
the reaction temperature is 40-70 ℃, more preferably 50-55 ℃.
The reaction time is 1-6h, more preferably 1-2 h.
The specific operation method of the step (4) is as follows:
adding the intermediate C, an organic solvent and a catalyst, stirring until a reaction solution is clear, and adding DBU. Reacting for a while at a certain temperature, slowly adding isobutyric anhydride, and stirring overnight at room temperature. And concentrating the reaction solution, and purifying by column chromatography to obtain an intermediate D.
Wherein, the molar ratio of the intermediate C, the catalyst and the DBU is 1.0-5.0: 1.0: 2.0-10.0, more preferably 3.3: 1.0: 2.1.
the organic solvent is NMP, DMSO, DMF, THF, toluene and acetonitrile, and more preferably acetonitrile.
The catalyst is DMAP, TEA is DMAP more preferably.
The temperature is 10-40 ℃, more preferably 25-30 ℃.
The reaction time is 1-6h, more preferably 2-3 h.
The specific operation method of the step (5) is as follows:
and adding an intermediate D and a hydroxylamine reagent into IPA aqueous solution, heating, reacting for a period of time under the temperature condition, detecting by TLC (thin layer chromatography) to show that the raw materials completely react, adding toluene, extracting, separating liquid, concentrating an organic layer, and performing column chromatography to obtain a target compound E.
Wherein the molar ratio of the intermediate D to the hydroxylamine reagent is 1.0: 1.0-5.0, more preferably 1.0: 3.2.
the hydroxylamine reagent is hydroxylamine sulfate and hydroxylamine hydrochloride, and more preferably hydroxylamine sulfate.
The temperature rise temperature is 40-90 ℃, and more preferably, the temperature rise temperature is 70-75 ℃.
The reaction time is 10-30h, more preferably 17-24 h.
The specific operation method of the step (6) is as follows:
and (3) reducing the temperature of the reaction system by using an intermediate C and an organic solvent, slowly adding a Grignard reagent at the temperature, stirring, slowly heating after the dropwise addition is finished, reacting for a period of time at the temperature, then cooling, adding SM3 into the reaction, stirring overnight, detecting by TLC (thin layer chromatography) that the raw materials are completely reacted, adding an HCl solution, adding toluene, separating the extraction solution, concentrating the organic layer, and carrying out column chromatography to obtain an intermediate F.
Wherein the molar ratio of the intermediate C to the Grignard reagent to the SM3 is 1.0: 1.0-3.0: 1.0-1.5, more preferably 1.0: 2.0: 1.3.
the organic solvent is NMP, DMSO, DMF, THF, toluene and acetonitrile, more preferably THF.
The temperature of the reaction system is-20-20 ℃, and more preferably-10-0 ℃.
The temperature rise is 0-40 ℃, and more preferably 20-25 ℃.
The reaction time is 1-6h, more preferably 2-3 h.
The Grignard reagent is t-BuMgCl, n-propyl magnesium bromide, isopropyl magnesium chloride and isobutyl magnesium chloride, and the t-BuMgCl is more preferable.
The specific operation method of the step (7) is as follows:
and adding an intermediate F and a hydroxylamine reagent into IPA aqueous solution, heating, reacting for a period of time under the temperature condition, detecting by TLC (thin layer chromatography) to show that the raw materials completely react, adding toluene, extracting, separating liquid, concentrating an organic layer, and performing column chromatography to obtain a target compound G.
Wherein, the molar ratio of the intermediate F to the hydroxylamine reagent is 1.0: 1.0-5.0, more preferably 1.0: 3.2.
the hydroxylamine reagent is hydroxylamine sulfate and hydroxylamine hydrochloride, and more preferably hydroxylamine sulfate.
The temperature rise temperature is 40-90 ℃, and more preferably, the temperature rise temperature is 70-75 ℃.
The reaction time is 10-30h, more preferably 17-24 h.
Example 1:
1.1 Synthesis of intermediate A1
Figure BDA0003173795860000131
In a 1L three-necked flask, solid SM (R) was added under nitrogen protection1F) (37.2g, 0.10mol), anhydrous toluene (300ml), and then Red-Al (70% THF solution, 34.6g, 0.12mol) was slowly added dropwise while the temperature was kept at-20 to-30 ℃. After the dropwise addition is finished, the reaction is carried out for 5-6h under the temperature condition, and the TLC spot plate raw material reaction is finished. Then, 30ml of 2N HCl was added, and the reaction was continued for 1 to 2 hours.
DMAP (13.4g, 0.11mol) was added and SOCl was slowly dropped2(59.5g,0.5mol), controlling the reaction temperature to be-10 to 0 ℃, after finishing dropping, slowly heating to reach the temperatureStirring overnight at 30-40 ℃, monitoring by TLC (thin layer chromatography) to show that the raw materials are completely reacted, cooling the reaction liquid to-10-0 ℃, and adding 100ml of H2And O, stirring for 1-2h, and separating the liquid. The organic layer was washed 2 times with a citric acid solution and a 10% KOH solution, respectively, and the resulting organic layer was concentrated by replacing the solvent with 100ml of chlorobenzene to obtain an A1 solution.
1.2 Synthesis of intermediate A2
Figure BDA0003173795860000141
In a 1L three-necked flask, solid SM (R) was added under nitrogen protection1Cl) (38.8g, 0.10mol), anhydrous toluene (300ml), reducing the temperature to-20 to-30 ℃, slowly dropping Red-Al (70% THF solution, 34.6g, 0.12mol), the temperature being kept at-20 to-30 ℃ throughout the dropping process. After the dropwise addition is finished, the reaction is carried out for 5-6h under the temperature condition, and the TLC spot plate raw material reaction is finished. Then, 30ml of 2N HCl was added, and the reaction was continued for 1 to 2 hours.
DMAP (13.4g, 0.11mol) was added and SOCl was slowly dropped2(59.5g,0.5mol), controlling the reaction temperature to be-10-0 ℃, after finishing dropping, slowly heating to 30-40 ℃, stirring overnight, after TLC monitoring shows that the raw materials are completely reacted, cooling the reaction liquid to-10-0 ℃, and adding 100ml of H2And O, stirring for 1-2h, and separating the liquid. The organic layer was washed 2 times with a citric acid solution and a 10% KOH solution, respectively, and the resulting organic layer was concentrated by replacing the solvent with 500ml of chlorobenzene to obtain an A2 solution.
Example 2:
2.1 Synthesis of intermediate B1
Figure BDA0003173795860000142
Adding anhydrous SnCl into the A1 solution4(78.1g,0.3mol) and SM2 (O-trimethylsilyl-N4-benzoylcytosine, 43.4g,0.15 mol). Heating the reaction solution to 70-80 deg.C, reacting for 10-12h under the temperature condition, monitoring by TLC that the reaction of raw materials is completed, cooling to room temperature, adding 100ml DCM and 100ml saturated bicarbonateIn sodium solution. Then the temperature of the system is reduced to 0-5 ℃, and 150ml of H is slowly added2And O, quenching the reaction. Then, the temperature is raised to the room temperature, and the mixture is stirred for 1 to 2 hours. Filtration and the filter cake washed 2 times with 100ml of DCM. The obtained filtrate is layered, the obtained organic layer filtrate is heated to 80-90 ℃, then cooled to 0-5 ℃, stirred for 2-3h under the temperature condition again, and solid is slowly separated out. Filtration and washing of the resulting solid with 200ml IPA dried to give 34.9g intermediate B1 as SM (R)1Yield ═ F) was 61.2%.
Mass spectrometry analysis:
MS(M+H):572.18.
2.2 Synthesis of intermediate B2
Figure BDA0003173795860000151
Adding anhydrous SnCl into the A2 solution4(78.1g,0.3mol) and SM2 (O-trimethylsilyl-N4-benzoylcytosine, 43.4g,0.15 mol). Heating the reaction solution to 70-80 ℃, reacting for 10-12h under the temperature condition, monitoring by TLC that the reaction of the raw materials is finished, cooling to room temperature, and adding 100ml of DCM and 100ml of saturated sodium bicarbonate solution into the system. Then the temperature of the system is reduced to 0-5 ℃, and 150ml of H is slowly added2And O, quenching the reaction. Then, the temperature is raised to the room temperature, and the mixture is stirred for 1 to 2 hours. Filtration and the filter cake washed 2 times with 100ml of DCM. The obtained filtrate is layered, the obtained organic layer filtrate is heated to 80-90 ℃, then cooled to 0-5 ℃, stirred for 2-3h under the temperature condition again, and solid is slowly separated out. Filtration and washing of the resulting solid with 200ml IPA dried to give 37.7g intermediate B2 as SM (R)1Cl) was obtained in 64.3% yield.
Mass spectrometry analysis:
MS(M+H):588.15
example 3
3.1 Synthesis of intermediate C1
Figure BDA0003173795860000161
To a 2L three-necked flask, intermediate B1(57.1g, 0.10mol), anhydrous methanol (500ml), and sodium methoxide (1.6g,0.03mol) were added. The reaction solution was warmed to 50-55 ℃ and reacted at this temperature for 1-2h, TLC monitored for disappearance of the reaction material, isobutyric acid (2.6g, 0.03mol) was added to quench the reaction, the reaction solution was concentrated, the residual solvent was replaced with 200ml of IPA, and then concentration was continued to a volume of about 150 ml. Heating the obtained reaction solution to 80-85 ℃, then slowly cooling to 0-5 ℃, stirring for 2-3h, and slowly separating out solids. Filtration and washing of the filter cake with 100ml IPA followed by drying gave 23.6g of intermediate C1 in 91.2% yield.
Nuclear magnetic analysis:
1H-NMR (400MHz, DMSO-d 6): 9.02(1H, d),8.20(2H, s),7.88(1H, d),6.21(1H, d),4.87(1H, m),3.95(1H, m),3.45-3.78(2H, m),2.31(1H, s),2.08(1H, s),1.21-1.37(3H, d). Mass Spectrometry:
MS(M+H):260.10
3.2 Synthesis of intermediate C2
Figure BDA0003173795860000162
In a 2L three-necked flask, intermediate B2(58.7g, 0.10mol), anhydrous methanol (500ml), and sodium methoxide (1.6g,0.03mol) were added. The reaction solution was warmed to 50-55 ℃ and reacted at this temperature for 1-2h, TLC monitored for disappearance of the reaction material, isobutyric acid (2.6g, 0.03mol) was added to quench the reaction, the reaction solution was concentrated, the residual solvent was replaced with 200ml of IPA, and then concentration was continued to a volume of about 150 ml. Heating the obtained reaction solution to 80-85 ℃, then slowly cooling to 0-5 ℃, stirring for 2-3h, and slowly separating out solids. Filtration and washing of the filter cake with 100ml IPA followed by drying gave 24.8g of intermediate C2 in 90.4% yield.
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.97(1H,d),8.17(2H,s),8.07(1H,s),6.20(1H,d),4.74(1H,m),4.01(1H,m),3.41-3.75(2H,m),3.01(1H,s),2.01(1H,s),1.58(3H,s).
mass spectrometry analysis:
MS(M+H):276.07
example 4
4.1 Synthesis of intermediate D1
Figure BDA0003173795860000171
In a 250ml three-necked flask, intermediate C1(2.6g,10mmol), anhydrous acetonitrile (50ml), DMAP (0.36g,3mmol) were added, the reaction stirred until clear, and DBU (3.2g,21mmol) was added. The reaction was carried out at 25-30 ℃ for 2-3h, isobutyric anhydride (1.7g,11mmol) was slowly added, and the mixture was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (MeOH: CHCl)35:100) gave 2.3g of intermediate D1 in 70.0% yield.
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：9.10(1H,d),8.18(2H,s),7.81(1H,d),6.11(1H,d),4.78～4.98(2H,m),3.81～4.01(2H,m),2.59(1H,m),2.11(1H,s)1.34(3H,d).1.12(6H,d).
mass spectrometry analysis:
MS(M+H):330.14.
4.2 Synthesis of intermediate D2
Figure BDA0003173795860000181
In a 250ml three-necked flask, intermediate C2(2.7g,10mmol), anhydrous acetonitrile (50ml), DMAP (0.36g,3mmol) were added, the reaction stirred until clear, and DBU (3.2g,21mmol) was added. The reaction was carried out at 25-30 ℃ for 2-3h, isobutyric anhydride (1.7g,11mmol) was slowly added, and the mixture was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (MeOH: CHCl)3Yield 65.0% of intermediate D2 ═ 5: 100).
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.95(1H,d),8.15(2H,s),8.01(1H,s),6.17(1H,d),4.95～5.05(1H,m),4.56(1H,m),4.28(1H,d),4.20(1H,m),2.87(2H,m),1.51(3H,s).1.12(6H,d).
mass spectrometry analysis: MS (M + H):346.11.
Example 5
5.1 Synthesis of target Compound E1 (named Compound HH261)
Figure BDA0003173795860000182
A100 ml three-necked flask was charged with intermediate D1(3.3g, 10mmol) and hydroxylamine sulfate (5.3g,32mmol), 50ml of 70% IPA aqueous solution was added, the temperature was raised to 70-75 deg.C, the reaction was carried out at this temperature for 17-24h, TLC showed completion of the reaction of the starting materials, 50ml of toluene was added, extraction and liquid separation were carried out, the organic layer was concentrated, filtration and column chromatography (PE: EA: 3:1) gave 2.70g of the objective compound E1 (compound HH261) in 78.03% yield. Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.96(1H,d),8.64(1H,s),7.78(1H,d),6.31(1H,d),5.10(1H,m),4.61(1H,m),4.18～4.21(2H,m),2.93(1H,m)2.42(1H,s),2.20(1H,s),1.30(3H,d).1.12(6H,d).
mass spectrometry analysis: MS (M + H):346.13.
5.2 Synthesis of the object Compound E2 (named Compound HH262)
Figure BDA0003173795860000191
A100 ml three-necked flask is charged with the intermediate D2(3.4g, 10mmol) and hydroxylamine sulfate (5.3g,32mmol), 50ml of 70% IPA aqueous solution is added, the temperature is raised to 70-75 ℃, the reaction is carried out for 17-24h at the temperature, TLC detection shows that the raw materials are completely reacted, 50ml of toluene is added, extraction and liquid separation are carried out, an organic layer is concentrated, filtration and column chromatography (PE: EA: 3:1) are carried out, so that 2.68g of the target compound E2 (compound HH262) is obtained, and the yield is 75.5%.
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.93(1H,d),8.50(1H,s),8.03(1H,s),6.29(1H,d),5.01(1H,m),4.65(1H,m),4.24(1H,d),4.09(1H,m),2.90-2.93(2H,m)2.21(1H,s),1.60(3H,s).1.12(6H,d).
mass spectrometry analysis: MS (M + H):362.10
Example 6
6.1 Synthesis of intermediate F1
Figure BDA0003173795860000201
In a 100ml reaction flask, N2Protecting, adding intermediate C1(2.6g,10mmol) and anhydrous THF 100ml, reducing the temperature to-10-0 ℃, and slowly adding 1.7M t-BuMgCl (4.0g, 20mmol) under the temperature condition. Controlling the temperature of the system to be minus 10-0 ℃, after dropwise adding, stirring for 30min, slowly heating to 20-25 ℃, reacting for 2-3h under the temperature condition, then cooling to-10-0 ℃, adding SM3(5.9g,13mmol) into the reaction, stirring overnight, detecting that the raw materials are completely reacted by TLC, adding 30ml of 2N HCl solution, adding 50ml of toluene, extracting, separating liquid, concentrating an organic layer, and carrying out column chromatography (PE: EA is 4:1) to obtain 2.4g of an intermediate F1, wherein the yield is 45.8%.
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.94(1H,d),7.86(1H,d),7.52(2H,s),7.35(2H,m),7.21(3H,m),6.75(1H,br),6.30(1H,d),5.29(1H,m),4.98(1H,m),3.95-4.30(4H,m),2.01(1H,s),1.32-1.33(6H,m),1.19(6H,d)
mass spectrometry analysis: MS (M + H):529.18.
6.2 Synthesis of intermediate F2
Figure BDA0003173795860000202
In a 100ml reaction flask, N2 protected intermediate C2(2.7g,10mmol) and anhydrous THF 100ml are added, the temperature is reduced to-10-0 ℃, and 1.7M t-BuMgCl (4.0g, 20mmol) is slowly added under the temperature condition. Controlling the temperature of the system to be minus 10-0 ℃, after dropwise adding, stirring for 30min, slowly heating to 20-25 ℃, reacting for 2-3h under the temperature condition, then cooling to-10-0 ℃, adding SM3(5.9g,13mmol) into the reaction, stirring overnight, detecting that the raw materials are completely reacted by TLC, adding 30ml of 2N HCl solution, adding 50ml of toluene, extracting, separating liquid, concentrating an organic layer, and carrying out column chromatography (PE: EA is 4:1) to obtain 2.3g of an intermediate F2, wherein the yield is 42.6%.
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.95(1H,d),7.83(1H,s),7.48(2H,s),7.35(2H,m),7.21(3H,m),6.80(1H,br),6.29(1H,d),5.25(1H,m),4.96(1H,m),3.95-4.30(4H,m),2.68(1H,s),1.43(3H,s),1.33(3H,d),1.19(6H,d)
mass spectrometry analysis: MS (M + H):545.15.
Example 7
7.1 Synthesis of the object Compound G1 (designated as Compound HH263)
Figure BDA0003173795860000211
A100 ml three-necked flask was charged with intermediate F1(2.6G, 5mmol) and hydroxylamine sulfate (2.6G,16mmol), 30ml of 70% IPA aqueous solution was added, the temperature was raised to 70-75 deg.C, the reaction was carried out at this temperature for 17-24h, TLC showed completion of the reaction of the starting materials, 50ml of toluene was added, extraction and liquid separation were carried out, the organic layer was concentrated, filtration and column chromatography (PE: EA: 3:1) gave 1.8G of the objective compound G1 (compound HH263) in 68.5% yield.
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.93(1H,d),8.35(1H,s),7.78(1H,d),7.32(2H,m),7.19(3H,m),6.75(1H,br),6.28(1H,d),5.20(1H,m),4.95(1H,m),3.99-4.28(4H,m),2.25(1H,s),2.05(1H,s),1.32(6H,m),1.19(6H,d)
mass spectrometry analysis: MS (M + H):545.17
7.2 Synthesis of the object Compound G2 (designated as Compound HH264)
Figure BDA0003173795860000221
A100 ml three-necked flask was charged with intermediate F2(2.7G, 5mmol) and hydroxylamine sulfate (2.6G,16mmol), 30ml of 70% IPA aqueous solution was added, the temperature was raised to 70-75 deg.C, the reaction was carried out at this temperature for 17-24h, TLC showed completion of the reaction of the starting materials, 50ml of toluene was added, extraction and liquid separation were carried out, the organic layer was concentrated, filtration and column chromatography (PE: EA: 3:1) gave 1.7G of the target compound G2 (compound HH264) in 62.6% yield.
Nuclear magnetic analysis:
1H-NMR(400MHz,DMSO-d6)：8.95(1H,d),8.42(1H,s),7.82(1H,s),7.35(2H,m),7.21(3H,m),7.09(1H,s),6.80(1H,br),6.28(1H,d),5.31(1H,d),4.95(1H,m),4.53(1H,d),4.01-4.28(3H,m),2.15(1H,s),1.45(3H,s),1.32(3H,d),1.19(6H,d),
mass spectrometry analysis: MS (M + H):561.14.
Example 8 activity assay:
1) vero cells were seeded in 96-well plates at 37 ℃ with 5% CO2Culturing overnight in an incubator
2) To the plates were added compounds (25, 20, 15, 10, 5, 0.5, 0.05, 0.015. mu.M) at different concentrations
3) Incubate the plate in incubator for 24h
4) Add 10. mu.l of CCK8 solution to each well (care not to generate bubbles in the well which would affect the OD reading)
5) Incubating the culture plate in an incubator for 1-4h
6) Absorbance at 450nm was measured with a microplate reader
7) If OD is not to be measured temporarily, 10. mu.l of 0.1M HCl solution or 1% W/V SDS solution may be added to each well, and the plate may be covered and kept at room temperature in the absence of light. The absorbance did not change when measured over 24 hours.
Vitality calculation
Cell viability (%) ([ a (dosed) -a (blank) ]/[ a (0 dosed) -a (blank) ] × 100
A (dosing): absorbance of wells with cells, CCK-8 solution and drug solution
A (blank): absorbance of wells with media and CCK-8 solution without cells
A (0 dosing): absorbance of wells with cells, CCK-8 solution and no drug solution
Cell viability: cell proliferation Activity or cytotoxic Activity
Vero cells were loaded with different concentrations (25, 20, 15, 10, 5, 0.5, 0.05, 0.015. mu.M) of test compound at 37 ℃ with 5% CO2The incubator is treated for 1h, then SARS-CoV-2 virus with 0.1MOI is added, and the incubation is continued for 1h at 37 ℃. Subsequent washing of the cells with a blank mediumAdding the test compound with different concentrations (25, 20, 15, 10, 5, 0.5, 0.05 and 0.015 mu M) once, continuing to culture until the virus is infected for 24h, extracting RNA of a culture supernatant, detecting the change of the virus copy number by using absolute quantitative PCR, taking the virus copy number treated by the test compound with 0.015 mu M as a maximum infection value, and dividing the copy numbers of other concentrations by the copy number of a group with 0.015 mu M to obtain the virus replication ratio. Nonlinear fitting (% inhibition) is carried out on the data by utilizing graphpad 7.0 software to obtain the IC of the compound to be detected50。
Vero cells are added with different concentrations (25, 20, 15, 10, 5, 0.5, 0.05, 0.015 mu M) of a compound to be detected, cultured for 24 hours at 37 ℃, and then the activity of the cells is detected by using a CCK8 kit. Nonlinear fitting (% cell viability) is carried out on the data by utilizing graphpad 7.0 software to obtain CC of the compound to be detected50。
By SI ═ CC50/IC50(CC50: cytoxicity concentration, drug concentration IC at which 50% of cells were killed50: inhibition concentration, half maximal inhibitory concentration), the results were obtained by calculation, and the specific data are shown in table 1. The inventor also tests the anti-SARS-CoV virus activity of the compound by the method, and the SI values of the target compounds E1, E2, G1 and G2 are all more than 100. The inventors also tested the compounds for anti-MERS-CoV viral activity using the method described above and found that compounds E1, E2, G1 and G2 all had SI values greater than 100.
TABLE 1 anti-SARS-CoV-2 Virus Activity test results
Figure BDA0003173795860000231
Figure BDA0003173795860000241
As can be seen from the data: for those skilled in the art, higher SI values during drug screening indicate lower drug toxicity, and SI values during drug screening experiments are generally greater than10 is better, and the SI of the compounds E1, E2, G1 and G2 prepared by the invention is far more than 10, which shows that the compounds of the invention have obvious application prospect for anti-SARS-CoV-2, SARS-CoV and MERS-CoV virus medicaments, and can be further researched. In addition, the activity of the compounds E1, E2, G1 and G2 of the present invention, particularly the compound G1, was most remarkable, and the half inhibitory concentration IC thereof50The value is 0.24. mu.M, and the activity is stronger than that of chloroquine phosphate (median inhibitory concentration IC)50The value is 1.52 mu M), which shows that the compound of the invention has more virus inhibition effect than the positive control drug chloroquine phosphate, and is expected to be developed into a novel anti-novel coronavirus SARS-CoV-2, SARS-CoV and MERS-CoV drug.
The upper and lower limit values and interval values of the raw materials of the invention can realize the invention, and the enumerated raw materials can realize the invention, so the examples are not necessarily listed.
It is noted that all references or patents mentioned in this application are incorporated herein by reference as if each individual reference or patent were individually incorporated by reference. Further, it should be understood that the above-described specific embodiments and technical principles of the present invention, and after reading the above-described contents of the present invention, those skilled in the art may make various modifications and alterations to the present invention without departing from the scope of the present invention, and those equivalents also fall within the scope of the present invention.

Claims (8)

1. A compound of formula I, or a pharmaceutically acceptable salt thereof, characterized by: the compounds of formula I have the following structure:
Figure FDA0003173795850000011
wherein:
R2is F or Cl;
R1is H, alkyl acyl, alkyl benzoyl or
Figure FDA0003173795850000012
A1 and A2 are each independently a group of formula Ia:
Figure FDA0003173795850000013
wherein:
each Y2Independently is a bond, O or NR;
m2 is 0, 1 or 2;
each Rx is independently Ry or a group of formula Ib:
Figure FDA0003173795850000014
wherein:
each M1a, M1c, and M1d is independently 0 or 1;
m12c is 0, 1, 2, 3, 4, 5, 6, 7, 8
Each Ry is independently H, R, -C (═ O) OR, OR-SC (═ O) R;
each R is independently H, (C1-C8) alkyl, or C6-C20 aryl.
2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: the compound of formula I is represented by any one of the following structural formulae:
Figure FDA0003173795850000021
3. an antiviral agent characterized by: the antiviral agent comprises any one or more compounds of formula I as described in any one of claims 1-2 or a pharmaceutically acceptable salt thereof as an active ingredient.
4. A pharmaceutical composition characterized by: comprising any one or more compounds of formula I as defined in any one of claims 1-2 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
5. A pharmaceutical composition characterized by: comprising any one or several of the compounds of formula I as defined in any one of claims 1-2 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable diluent.
6. A pharmaceutical composition characterized by: comprising any one or more compounds of formula I as defined in any one of claims 1-2 or a pharmaceutically acceptable salt thereof and at least one further antiviral drug.
7. The pharmaceutical composition of claim 6, which is an injection, an oral preparation, a freeze-dried powder injection and a suspending agent.
8. Use of a compound of formula I according to any one of claims 1 or 2 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of symptoms or diseases caused by SARS coronavirus, novel coronavirus SARS-CoV-2 or MERS coronavirus.
CN202110825940.4A 2021-07-21 2021-07-21 Anti-coronavirus compound and preparation method and application thereof Pending CN113735929A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110825940.4A CN113735929A (en) 2021-07-21 2021-07-21 Anti-coronavirus compound and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110825940.4A CN113735929A (en) 2021-07-21 2021-07-21 Anti-coronavirus compound and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN113735929A true CN113735929A (en) 2021-12-03

Family

ID=78728921

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110825940.4A Pending CN113735929A (en) 2021-07-21 2021-07-21 Anti-coronavirus compound and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN113735929A (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106573011A (en) * 2014-06-24 2017-04-19 艾丽奥斯生物制药有限公司 Substituted nucleosides, nucleotides and analogs thereof
CN106604734A (en) * 2014-06-24 2017-04-26 艾丽奥斯生物制药有限公司 Substituted nucleosides, nucleotides and analogs thereof
CN107427529A (en) * 2014-12-26 2017-12-01 埃莫里大学 N4 OH cytidines and derivative and relative anti-viral uses
CN111372592A (en) * 2017-12-07 2020-07-03 埃默里大学 N4-hydroxycytidine and derivatives and antiviral uses related thereto
CN111393494A (en) * 2020-04-17 2020-07-10 广东帕派恩生物科技有限公司 Compound based on nucleotide structure, preparation method and application
CN111548384A (en) * 2020-03-29 2020-08-18 常州安蒂卫生物科技有限公司 Substituted N4-hydroxycytidine derivatives and prodrugs thereof for use in anti-novel coronavirus therapy
CN111728973A (en) * 2020-05-27 2020-10-02 中国医学科学院病原生物学研究所 Medicine for resisting novel coronavirus SARS-CoV-2 and its application
US10874687B1 (en) * 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
CN112778387A (en) * 2021-01-15 2021-05-11 杭州科巢生物科技有限公司 Molnupiravir crystal form A and preparation method thereof

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106573011A (en) * 2014-06-24 2017-04-19 艾丽奥斯生物制药有限公司 Substituted nucleosides, nucleotides and analogs thereof
CN106604734A (en) * 2014-06-24 2017-04-26 艾丽奥斯生物制药有限公司 Substituted nucleosides, nucleotides and analogs thereof
CN107427529A (en) * 2014-12-26 2017-12-01 埃莫里大学 N4 OH cytidines and derivative and relative anti-viral uses
CN111372592A (en) * 2017-12-07 2020-07-03 埃默里大学 N4-hydroxycytidine and derivatives and antiviral uses related thereto
US10874687B1 (en) * 2020-02-27 2020-12-29 Atea Pharmaceuticals, Inc. Highly active compounds against COVID-19
CN111548384A (en) * 2020-03-29 2020-08-18 常州安蒂卫生物科技有限公司 Substituted N4-hydroxycytidine derivatives and prodrugs thereof for use in anti-novel coronavirus therapy
CN111393494A (en) * 2020-04-17 2020-07-10 广东帕派恩生物科技有限公司 Compound based on nucleotide structure, preparation method and application
CN112724186A (en) * 2020-04-17 2021-04-30 广东帕派恩生物科技有限公司 Nucleotide compound for inhibiting virus
CN111728973A (en) * 2020-05-27 2020-10-02 中国医学科学院病原生物学研究所 Medicine for resisting novel coronavirus SARS-CoV-2 and its application
CN112778387A (en) * 2021-01-15 2021-05-11 杭州科巢生物科技有限公司 Molnupiravir crystal form A and preparation method thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHEAHAN, TIMOTHY P.ET AL.: "An orally bioavailable broad-spectrum antiviral inhibits SARS-CoV-2 and multiple endemic, epidemic and bat coronavirus", 《SCIENCE TRANSLATIONAL MEDICINE》 *
陈宁: "《氨基酸工艺学》", 30 June 2020, 中国轻工业出版社 *

Similar Documents

Publication Publication Date Title
US7223789B2 (en) Heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
CN113292565B (en) Nucleoside compound and preparation method and application thereof
CN108250122B (en) Sulfonamide-aryl amide compounds and pharmaceutical use thereof for treating hepatitis B
AU2008202641A1 (en) p-38 kinase inhibitors
CN101367749B (en) A set of mesidino mesitoyl derivant, preparation and application thereof
EP3965753A1 (en) Dhodh inhibitors and their use as antiviral agents
CN106892878B (en) Thiazole derivative and application thereof in inhibiting dihydroorotate dehydrogenase
WO2022268145A1 (en) Amide compound, and preparation method therefor and pharmaceutical use thereof
US6020488A (en) Small molecule inhibition of RNA/ligand binding
CN115721661A (en) Application of purine nucleoside medicament in preventing or treating coronavirus infectious diseases
CN112771048B (en) Inhibitors of influenza virus replication and intermediates and uses thereof
CN115135646A (en) Substituted polycyclic compounds, pharmaceutical compositions and uses thereof
CN113735929A (en) Anti-coronavirus compound and preparation method and application thereof
CN109503518B (en) Substituted biaryl amide compound and preparation method and application thereof
CN111057073A (en) 4-indole-2-arylamino pyrimidine compound and application thereof in inflammation treatment
CN114702501B (en) Imidazole peptide deformylase inhibitor with anti-tumor effect
CN114213395B (en) Pyrimidone acyl piperazine compound and preparation method and application thereof
CN110013483A (en) Thiazole simultaneously [3,2-a] pyrimidine -6- 6-carbonitrile derivatives be used for antibacterial purposes
CN113620903A (en) 4- (benzothiazole-2-yl) -N-substituted aniline compound and preparation method and application thereof
CN111825608A (en) Tetrahydroquinoline and tetrahydroisoquinoline compounds and application thereof
CN115141206B (en) Alpha-lipoic acid lycorine conjugate and preparation method and application thereof
CN109384727A (en) Phthalazines ketone compounds, preparation method, pharmaceutical composition and purposes
CN117658868A (en) Benzamide derivative and preparation method and application thereof
CN112694461B (en) Chromanone compound and preparation method and application thereof
CN114053394B (en) Application of novel compound in preparation of medicines for preventing and/or treating coronavirus infection

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20211203