CN111000844B - Medicine for treating influenza virus infection - Google Patents
Medicine for treating influenza virus infection Download PDFInfo
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- CN111000844B CN111000844B CN201911320684.2A CN201911320684A CN111000844B CN 111000844 B CN111000844 B CN 111000844B CN 201911320684 A CN201911320684 A CN 201911320684A CN 111000844 B CN111000844 B CN 111000844B
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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Abstract
The invention relates to a medicament for treating influenza virus infection. Specifically, the invention provides a compound, or an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure shown in the formula I. The compound, or the isomer thereof, or the pharmaceutically acceptable salt thereof has a remarkable inhibitory effect on influenza virus, and is used for preventing and/or treating influenza virus infection.
Description
Technical Field
The invention relates to the field of medicaments, and particularly provides a medicament for treating influenza virus infection.
Background
The influenza virus belongs to the genus of influenza virus of the family Orthomyxoviridae (Orthomyxoviridae). Influenza viruses are classified into A, B, C types, depending on the antigenic and genetic properties of the virion Nucleoprotein (NP) and matrix protein (M). The influenza a virus genome consists of 8 single negative stranded RNAs of different sizes, designated segment 1 to segment 8, respectively. Influenza a viruses are further divided into 17H (H1-H17) and 10N (N1-N10) subtypes, depending on the surface glycoproteins Hemagglutinin (HA) and Neuraminidase (NA) of the virion. Human influenza viruses are predominantly of the H1, H2 and H3 subtypes. Most of the current highly pathogenic avian influenza which is seriously harmful are H5, H7 and H9 subtypes, wherein the lethality rate is highest by using the H5N1 subtype.
The entire life cycle of influenza virus needs to be completed in the cytoplasm and nucleus. The infection is initiated by the recognition and binding of the spike HA on the surface of the virion to a sialic acid receptor on the surface of the host cell, which binds the virion to the host cell as an endocytosed form. Under the acidic pH condition of endocytosis, the conformation of virus HA protein is changed, the fusion peptide at the N end of the light chain is exposed, and the virus envelope is fused with the cell membrane. The low pH environment also results in large amounts of H+Access to the interior of the virion via the M2 ion channel results in dissociation of the M1 protein from vRNP. The combined result of both is the release of the vRNP of the virion into the cytoplasm of the infected cell. vRNP subsequently translocates into the nucleus for gene transferAnd (3) replication and transcription of the genome, wherein the virus firstly synthesizes complementary RNA (cRNA) by taking the self RNA as a template during replication, and then synthesizes vRNA by taking the cRNA as a template. The mRNA produced by transcription is transferred from the nucleus to the cytoplasm and is translated into the structural and non-structural proteins of the virus. Part of the synthesized protein (such as NP) needs to be transferred into nucleus again to form vRNP with newly generated vRNA, vRNP begins to assemble into new virion with other virus protein after nucleus emergence, and newly generated progeny virus hydrolyzes glycoprotein on the cell surface through Neuraminidase (NA) to release N-acetylneuraminic acid, so that the virion is promoted to be released from the budding site.
The basic means for preventing and treating influenza are vaccine injection and drug therapy. The effectiveness of the vaccine is established by the similarity between the strain for preparing the vaccine and the influenza virus strain existing in the environment or about to cause epidemic, but the influenza virus is very easy to mutate, so that the prediction accuracy is difficult, and the prevention and treatment effect of the vaccine is greatly influenced. In the case of vaccine effectiveness difficult to grasp, the research of anti-influenza virus drugs is particularly important. While there are only four anti-influenza drugs currently approved by the FDA for marketing: amantadine, rimantadine, oseltamivir, zanamivir. The first two are M2 ion channel inhibitors, which inhibit viral replication by inhibiting the release of viral RNA into the cytoplasm. The latter two belong to inhibitors of NA activity, which inhibit viral replication by inhibiting the release and spread of viral particles. However, the development of new anti-influenza virus drugs is imminent due to problems such as development of viral resistance to these drugs and side effects caused by these drugs.
Therefore, there is a need in the art to develop a novel, highly effective, powerful medicament for the prevention and/or treatment of influenza virus infection.
Disclosure of Invention
The present invention aims at a drug capable of effectively preventing and/or treating influenza virus infection.
In a first aspect of the present invention, there is provided a use of a compound, or an isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention and/or treatment of influenza virus infection:
wherein the compound has the structure of formula I:
in formula I:
r1 and R2 are each independently substituted or unsubstituted C6-C20Aryl, or substituted or unsubstituted 5-20 membered heteroaryl;
r3, R4 and the carbon atoms to which they are commonly attached form a substituted or unsubstituted 3-12 membered heterocycloalkylene, substituted or unsubstituted C3-C10 cycloalkylene;
wherein any "substitution" means that one or more (preferably 1, 2, 3 or 4) hydrogen atoms on the group are substituted with a substituent selected from the group consisting of: halogen, C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C3-C6Halocycloalkyl, hydroxy, mercapto, amino, nitro, 3-8 membered heterocycloalkyl, C6-C12Aryl, or 5-8 membered heteroaryl;
the heteroaryl, heterocycloalkylene, and heterocycloalkyl each independently have 1-3 (preferably 1, 2, or 3) heteroatoms selected from N, O and S.
In another preferred embodiment, the heteroaryl, heterocycloalkylene, and heterocycloalkyl each independently have 1N heteroatom.
In another preferred embodiment, R1 and R2 are each independently substituted or unsubstituted C6-C20Aryl, or substituted or unsubstituted 5-12 membered heteroaryl.
In another preferred embodiment, R1 is substituted or unsubstituted C6-C20And (4) an aryl group.
In another preferred embodiment, R1 is substituted or unsubstituted C6-C12And (4) an aryl group.
In another preferred embodiment, R1 is a substituted or unsubstituted phenyl, or a substituted or unsubstituted naphthyl.
In another preferred embodiment, R1 is a halophenyl group, or a halonaphthyl group.
In another preferred embodiment, R1 is
In another preferred embodiment, R2 is a substituted or unsubstituted 5-12 membered heteroaryl.
In another preferred embodiment, R2 is a substituted or unsubstituted 5-8 membered heteroaryl.
In another preferred embodiment, R2 is pyridyl.
In another preferred embodiment, R2 is
In another preferred embodiment, R3, R4 and the carbon atoms to which they are commonly attached form a substituted or unsubstituted 5-10 membered heterocycloalkylene, or a substituted or unsubstituted C5-C8 cycloalkylene.
In another preferred embodiment, R3, R4 and the carbon atoms to which they are commonly attached form a substituted or unsubstituted 5-10 membered heterocycloalkylene.
In another preferred embodiment, R3, R4 and the carbon atoms to which they are commonly attached form a heterocyclohexyl group containing 1 or 2N atoms.
In another preferred embodiment, R3, R4 and the carbon atom to which they are commonly attached form
In another preferred embodiment, the heteroaryl, heterocycloalkylene, and heterocycloalkyl each independently have 1, 2, or 3 heteroatoms selected from N, O and S.
In another preferred embodiment, the compound has the structure of formula Ia:
wherein R5, R6 and R7 are independently zero, halogen and C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C3-C6A halocycloalkyl group;
r8 is C1-C4Alkyl radical, C1-C4Haloalkyl, C3-C6Cycloalkyl radical, C3-C6A halocycloalkyl group;
a is 1, 2, 3, 4 or 5;
b is 1, 2, 3 or 4;
c is 1, 2, 3, 4, 5 or 6.
In another preferred embodiment, a is 1.
In another preferred embodiment, R5 is halogen.
In another preferred embodiment, R6 is absent.
In another preferred embodiment, R7 is absent.
In another preferred embodiment, R8 is C1-C4An alkyl group.
In another preferred embodiment, R8 is methyl.
In another preferred embodiment, the compound has the structure of formula Ib:
wherein
R5 is halogen;
r8 is C1-C4Alkyl, or C3-C6A cycloalkyl group.
In another preferred embodiment, R5 is chloro.
In another preferred embodiment, R8 is methyl.
In another preferred embodiment, the compound is:
in another preferred embodiment, the compound is:
In another preferred embodiment, the influenza virus is an influenza a virus.
In another preferred embodiment, the influenza virus is an RNA virus or a DNA virus.
In another preferred embodiment, the influenza virus is an RNA virus.
In another preferred embodiment, the influenza a virus is an influenza H subtype and/or an influenza N subtype, and preferably, the influenza a virus is an influenza H1N1 subtype.
In another preferred embodiment, the influenza virus subtype H is an influenza virus subtype H1, H2, H3, H5, H7 and H9.
In another preferred embodiment, the influenza virus of subtype N is influenza virus subtype N1.
In another preferred embodiment, said preventing and/or treating influenza virus infection means:
(a) preventing and/or treating influenza virus infection by inhibiting binding of influenza virus to host cell membrane; and/or
(b) Influenza virus is prevented and/or treated by inhibiting the polymerase complex (vRNP) activity of influenza virus.
In another preferred embodiment, the dosage form of the drug is a solid preparation, a liquid preparation or a semisolid preparation.
In another preferred embodiment, the medicament is in the form of tablets, powder, pills, injections, capsules, films, suppositories, paste, granules, injections, infusion solutions and powder injections.
In a second aspect of the present invention, there is provided a pharmaceutical composition for the prophylaxis and/or treatment of influenza virus infection, said pharmaceutical composition comprising a compound according to the first aspect of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
In a third aspect of the invention, there is provided an in vitro non-therapeutic and non-diagnostic method of inhibiting influenza virus, said method comprising the steps of: contacting an influenza virus or an influenza virus-infected cell with a compound of the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, thereby inhibiting the influenza virus.
In a fourth aspect of the invention, there is provided a method of preventing and/or treating influenza virus infection by administering a compound according to the first aspect of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the second aspect of the invention to a subject in need of prevention and/or treatment of influenza virus infection.
Preferably, the subject includes human and non-human mammals (rodents, rabbits, monkeys, domestic animals, dogs, cats, etc.).
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is a graph showing the inhibitory effect of NSC 70933, ribavirin and DMSO, the compound of example 2, on H1N1 subtype influenza virus.
FIG. 2 shows the results of the inhibition of HA pseudovirus activity by NSC 70933 and DMSO, the compounds of example 3.
Fig. 3 shows the results of the inhibition of influenza vRNP activity by NSC 70933 and DMSO in example 4.
Detailed Description
The present inventors have surprisingly found, for the first time, a compound of formula I, or an isomer thereof, or a pharmaceutically acceptable salt thereof, through extensive and intensive studies. Experiments show that the compound has obvious inhibitory effect on influenza virus. The compounds of the present invention are effective in preventing and/or treating influenza virus infection. On the basis of this, the present invention has been completed.
Term(s) for
As used herein, the terms "comprises," "comprising," "includes," "including," and "including" are used interchangeably and include not only closed-form definitions, but also semi-closed and open-form definitions. In other words, the term includes "consisting of … …", "consisting essentially of … …".
As used herein, "R1", "R1"and" R1"has the same meaning as" and can be substituted for "another, and other similar definitions have the same meaning.
The term "alkyl" refers to a straight-chain (i.e., unbranched) or branched-chain saturated hydrocarbon group containing only carbon atoms, or a combination of straight-chain and branched-chain groups. When the alkyl group is preceded by a carbon atom number limitation (e.g. C) 1-C4Alkyl) means that the alkyl group contains 1 to 4 carbon atoms, e.g. C1-C4Alkyl refers to an alkyl group containing 1 to 4 carbon atoms, and representative examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.
The term "cycloalkyl" refers to a cyclic, bicyclic or polycyclic (fused, bridged or spiro) ring system group having a saturated or partially saturated unit ring. When a cycloalkyl group is preceded by a carbon atom number limitation (e.g. C)3-C6) When used, means that the cycloalkyl group has 3 to 6 carbon atoms. In some preferred embodiments, the term "C3-C6Cycloalkyl "refers to a saturated or partially saturated monocyclic or bicyclic alkyl group having 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, or the like.
The term "cycloalkylene" refers to a divalent cycloalkyl group (i.e., a divalent cycloalkyl group formed by removing hydrogens from the cycloalkyl group), wherein the cycloalkyl group is as defined above.
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, when the aryl group has a carbon atom number limitation as defined above, e.g., C6-C20Aryl means that the aryl group has 6 to 20 carbon atoms, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated or unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, and the point of attachment to the parent must be at a carbon atom on the ring having the conjugated pi-electron system. Representative examples of aryl groups include, but are not limited to: phenyl, naphthyl, or the like 。
The term "heteroaryl" refers to an aromatic heterocyclic system having one to more (preferably 1, 2, 3 or 4) heteroatoms, which may be monocyclic (monocyclic) or polycyclic (bicyclic, tricyclic or polycyclic) that are fused together or linked covalently, where the heteroatoms referred to herein include oxygen, sulfur and nitrogen. When heteroaryl is previously defined, examples of, for example, 5-membered heteroaryl include (but are not limited to): examples of pyrrole, furan, thiophene, imidazole, oxazole, thiazole, 6-membered heteroaryl include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine. The heteroaryl ring may be fused to an aryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring joined together with the parent structure is a heteroaryl ring.
The term "heterocycloalkyl", also known as heterocyclyl, refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent in which one or more ring atoms are selected from nitrogen, oxygen, or sulfur. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl. In the present invention, it is understood that 3-8 membered heterocycloalkyl means a membered heterocycloalkyl having 3-8 ring atoms.
The term "heterocycloalkylene" means a divalent heterocycloalkyl group (i.e., a divalent heterocycloalkyl group formed by removing hydrogen from a heterocycloalkyl group), wherein the heterocycloalkyl group is as defined above.
The term "halogen" refers to F, Cl, Br and I.
The term "halo" means that one or more hydrogens (preferably 1, 2, 3 or 4) in the group are replaced with a halogen, for example "haloalkyl" means that one or more hydrogens (preferably 1, 2, 3 or 4) on the alkyl group are replaced with a halogen.
The term "hydroxy" denotes-OH.
The term "mercapto" denotes-SH.
The term "amino" denotes-NH3。
The term "nitro" denotes-NO2。
Active ingredient
As used herein, "compounds of the invention" or "compounds of formula I" are used interchangeably and refer to compounds having the structure of formula I, or isomers thereof, or pharmaceutically acceptable salts thereof. It is to be understood that the term also includes mixtures of the above components, where in the compound, if a chiral carbon atom is present, the chiral carbon atom may be in the R configuration, also in the S configuration, or a mixture of both (e.g., a racemate).
The compound of the invention is as described in the first aspect of the invention.
The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention with an acid or base that is suitable for use as a pharmaceutical. Pharmaceutically acceptable salts include inorganic and organic salts. One preferred class of salts is that formed with acids of the compounds of the present invention, and suitable acids for forming salts include (but are not limited to): inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, phenylmethanesulfonic acid, benzenesulfonic acid, etc.; and acidic amino acids such as aspartic acid and glutamic acid. One preferred class of salts are metal salts of the compounds of the present invention formed with bases, suitable bases for forming the salts include (but are not limited to): inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and sodium phosphate, and organic bases such as ammonia, triethylamine and diethylamine.
The compound of formula I of the present invention can be converted into a pharmaceutically acceptable salt thereof by a conventional method, for example, a solution of the corresponding acid can be added to a solution of the above compound, and after complete salt formation, the solvent is removed to obtain the corresponding salt of the compound of the present invention.
Preferably, the compound is:
compound NSC 70933: from the NCI Diversity Set II library, and CAS: 5781-37-3.
Use of
The present invention provides a method for preventing and/or treating influenza virus infection. The compounds of the present invention can be used for the prevention and/or treatment of influenza virus infections. The compound can be prepared into a medicament for preventing and/or treating influenza virus infection, and the dosage form of the medicament can be solid preparation, liquid preparation or semisolid preparation. Typically, the dosage form of the medicine is tablets, powder, pills, injections, capsules, films, suppositories, paste, granules, injections, infusion solutions and powder injections.
The term "influenza virus" as used herein is synonymous with the meaning commonly understood by those skilled in the art, consisting of a nucleic acid molecule (DNA or RNA) and a protein or consisting of a protein only (e.g., a prion). The virus is small and simple in structure. Influenza viruses have no cellular structure and cannot replicate themselves because there is no fundamental system necessary to achieve metabolism. However, when it comes into contact with the host cell, its nucleic acid substance invades into the host cell, and a new virus is replicated by the latter replication system according to the instruction of the viral gene.
The influenza virus described herein is preferably an RNA virus (RNA virus). RNA viruses are a type of biological virus whose genetic material consists of ribonucleic acid (RNA ribonuclear acid), usually the nucleic acid is single-stranded (ssrnaingle-stranded RNA) and also double-stranded (dsRNA-stranded RNA).
In a specific embodiment, the influenza virus of the present invention is an influenza a virus. In a preferred embodiment, said influenza a virus is an influenza H subtype and/or an influenza N subtype virus. Typically, the influenza a virus is an influenza virus subtype H1N 1.
In another preferred embodiment, the influenza virus subtype H is an influenza virus subtype H1, H2, H3, H5, H7 and H9.
In another preferred embodiment, the influenza virus subtype N is influenza virus subtype N1.
In a preferred embodiment of the present invention, said preventing and/or treating influenza virus infection means:
(a) preventing and/or treating influenza virus by inhibiting the binding of influenza virus to host cell membrane; and/or
(b) Influenza virus is prevented and/or treated by inhibiting the polymerase complex (vRNP) activity of influenza virus.
The present invention also provides an in vitro non-therapeutic and non-diagnostic method of inhibiting influenza virus, said method comprising the steps of: influenza virus or an influenza virus-infected cell is contacted with a compound of the present invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof, thereby inhibiting influenza virus.
Compositions and methods of administration
The invention provides a composition for preventing and/or treating influenza virus infection. The composition includes (but is not limited to): pharmaceutical compositions, food compositions, dietary supplements, beverage compositions, and the like.
Typically, the composition is a pharmaceutical composition comprising a compound of the invention, or an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
In the present invention, the dosage form of the pharmaceutical composition includes (but is not limited to) oral preparations, injections, and external preparations.
Representative include (but are not limited to): tablet, injection, infusion solution, paste, gel, solution, microsphere, and pellicle.
The term "pharmaceutically acceptable carrier" refers to: one or more compatible solid, semi-solid, liquid or gel fillers which are suitable for human or animal use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant that the components of the pharmaceutical composition and the active ingredient of the drug are blended with each other and not significantly detract from the efficacy of the drug.
It is to be understood that, in the present invention, the carrier is not particularly limited and may be selected from materials commonly used in the art, or prepared by a conventional method, or commercially available. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g., methylcellulose, ethylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., tween), wetting agents (e.g., sodium lauryl sulfate), buffers, chelating agents, thickeners, pH adjusters, transdermal enhancers, colorants, flavors, stabilizers, antioxidants, preservatives, bacteriostats, pyrogen-free water, etc.
Typically, liquid dosage forms may contain, in addition to the active pharmaceutical ingredient, inert diluents commonly employed in the art such as water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butylene glycol, dimethylformamide and oils, especially cottonseed, groundnut, corn germ, olive, castor and sesame oils or mixtures of such materials and the like. In addition to these inert diluents, the compositions may also contain adjuvants such as wetting agents, emulsifying and suspending agents and the like
The pharmaceutical preparation should be compatible with the mode of administration. The agents of the invention may also be used with (including before, during or after) other co-therapeutic agents. In using the pharmaceutical composition or formulation, a safe and effective amount of the drug, typically at least about 10 micrograms/kg body weight, and in most cases no more than about 8 mg/kg body weight, preferably from about 10 micrograms/kg body weight to about 1 mg/kg body weight, is administered to a subject in need thereof (e.g., a human or non-human mammal). Of course, the particular dosage will depend upon such factors as the route of administration, the health of the patient, and the like, and is within the skill of the skilled practitioner.
The main advantages of the present invention include:
the invention discovers a series of compounds with broad-spectrum and excellent antiviral activity for the first time, the compounds have high-efficiency inhibitory action on influenza viruses, thereby preventing and/or treating influenza virus infection, and meanwhile, the compounds lay a material foundation for researching and developing new generation antiviral drugs, thereby having important academic value and practical significance.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Examples
The following are reagents, cells, kits, materials, influenza virus strains, vectors, and the like used in the examples:
PBS buffer (pH7.0-7.2): NaCl 8g, KCl 0.2g, Na2HPO4·12H2O 3.58g、KH2PO40.27g of ultrapure water was added thereto, and the volume was adjusted to 1L.
293T cells (human renal epithelial cells): ATCC, accession number CRL-11268.
DMEM Medium (Dulbecco's Modified Eagle's Medium): gibco Corp.
Transfection reagent PEI (operating as described in the instructions): polyscience, Inc.
Luciferase activity measurement kit: promega corporation.
Ribavirin (ribavirin): sigma Co.
Protease inhibitors: purchased from Roche corporation.
A/WSN/33 influenza virus strain (A/WSN/33 strain for short): is an Influenza A virus subtype H1N1 strain described in "Neumann G1, Watanabe T, Ito H, et al.Generation of Influenza A viruses from cloned cDNAs, PNAS,1999(16):9345-9350," entitled "Influenza viruses AyNy 33(H1N 1)" publicly available from Li-Tech Biotech, Inc., Zhejiang.
Plasmids expressing the PA gene of influenza virus, Plasmids expressing the PB1 gene of influenza virus, Plasmids expressing the PB2 gene of influenza virus, and Plasmids expressing the NP gene of influenza virus (i.e., "Plasmids expressing PA, PB1, PB2, and NP genes", "Plasmids for expressing non-tagged PB1, PB2, PAand NP" in the literature): generally described in "Zhang J, Liu T, Tong X, et al identification of novel vitamins inhibitors by antifluence A viruses specific reporter cell based screening. antibiotic Ras,2012(1): 48-54", publicly available from Li-En Biotech, Zhejiang.
pRL-TK plasmid: promega corporation.
pREP4 vector: the effect of plasmid transfection on the expression of the native beta 2-adrenoceptor of HEK293 and DDT 1-MF 2 cells is described in "Liyunfang, Zuoyi, Hourong et al, university report of Beijing: medical edition, 5 th 2001, "a article, publicly available from Zhejiang Lien Biotechnology Ltd.
pHH21 vector: described in "Neumann G1, Watanabe T, Ito H, et al, Generation of underfluenza A viruses from bound cDNAs, PNAS,1999(16): 9345-.
pNLLucE-R-HIV-Luc plasmid, pEWSN-HA plasmid and pCAGGS-NA plasmid: reference documents: junjie Zhang, Ting Liu, Xiamei Tong, Jinghua Yan, Xinn Ye, et al.identification of novel virus inhibition by fluorescence A virus specific reporter cell screening.2011; 93:48-54, publicly available from rien biotechnology limited, zhejiang.
Report vector vNS-Luc: reference documents: junjie Zhang, Ting Liu, Xiamei Tong, Jinghua Yan, Xinn Ye, et al.identification of novel virus inhibition by fluorescence A virus specific reporter cell screening.2011; 93:48-54, publicly available from rien biotechnology limited, zhejiang.
The NSC 70933 compound has the following structure:
compound NSC 70933: from the NCI Diversity Set II library, and CAS: 5781-37-3.
Example 1 preparation of 293T-IAV-Luc cells
1. Construction of pREP4-IAV-Luc plasmid
1.1, artificially synthesizing a DNA fragment shown as a sequence 1SEQ ID NO. 1 in a sequence table (see a patent CN 106562957A). The sequence 1 consists of 1748 nucleotides, the 14 th to 58 th sites are marked as segment 1, the 59 th to 1711 th sites are firefly luciferase coding gene (reporter gene), the 1712 th and 1734 th sites are marked as segment 2, and the two ends are recognition site sequences of BsmB I. Wherein, the segment 1 and the segment 2 are promoters of NP protein of influenza virus, and under the condition of existence of influenza virus, the promoter positioned on the fusion plasmid can be started, and the firefly luciferase can be expressed.
1.2, cutting a DNA fragment shown in a sequence 1SEQ ID NO. 1 in a sequence table by using a restriction enzyme BsmBI, recovering the cut fragment, positively connecting the cut fragment with a large skeleton fragment of a pHH21 vector cut by the same enzyme, and naming the intermediate plasmid with correct sequencing verification as a pHH21-IAV-Luc plasmid. The pHH21-IAV-Luc plasmid was digested with NheI and PciI endonuclease (Takara), the digested fragments were recovered, the ends were filled with Klenow enzyme (purchased from Takara), and the fragments were ligated into pREP4 vector digested with PvuII endonuclease, and the recombinant plasmid whose sequencing was confirmed was named pREP 4-IAV-Luc.
2. Preparation of 293T-IAV-Luc cell
The recombinant plasmid pREP4-IAV-Luc was introduced into 293T cells to obtain recombinant cells, which were designated 293T-IAV-Luc cells.
Example 2 Compound NSC 70933 inhibits replication of influenza virus subtype H1N1
1. The A/WSN/33 strain, DMEM medium and the compound NSC 70933 are mixed to obtain a mixed solution. The mixture contained 0.5MOI virus and 50. mu. mol/L of compound NSC 70933.
2. 293T-IAV-Luc cells prepared in example 1 were uniformly plated on a 96-well plate (20000 cells per well), incubated at 37 ℃ for 12 hours, the supernatant was discarded, and the cells in the wells were washed with PBS buffer.
3. After completion of step 2, the 96-well plate was taken, the mixture obtained in step 1 (MOI ═ 0.5) was added thereto, and the mixture was incubated at 37 ℃ for 1 hour with standing, and the supernatant was discarded.
4. After completion of step 3, the 96-well plate was taken, DMEM medium containing 10% (by volume) fetal bovine serum and 50. mu. mol/L of compound NSC 70933 was added thereto, the mixture was left to stand at 37 ℃ for 12 hours, the supernatant was discarded, and the cells in the well were washed with PBS buffer.
5. And (4) after the step 4 is completed, adding the lysis solution in the luciferase activity measurement kit into the 96-well plate, standing and incubating for 30 minutes at 37 ℃, and taking the supernatant.
6. And (5) taking the supernatant obtained in the step (5), and detecting the expression level of the luciferase reporter gene by adopting a luciferase activity measurement kit.
Meanwhile, DMSO and ribavirin are adopted to replace a compound NSC 70933 to serve as a negative control (DMSO group) and a positive control (ribavirin group) in the experimental process respectively, the experimental group and the control group are subjected to three repeated tests, and the results are averaged.
Results
The inhibitory effect of compounds NSC 70933, ribavirin and DMSO on influenza virus subtype H1N1 is shown in table 1 and figure 1:
TABLE 1 inhibitory Effect of Compounds NSC 70933, ribavirin and DMSO on H1N1 subtype influenza Virus (fluorescein Gene expression level)
| Experimental group | | Ribavirin | NSC | 70933 |
| Parallel group 1 | 31384 | 938 | 1847 | |
| Parallel group 2 | 31508 | 906 | 1629 | |
| Parallel group 3 | 30665 | 719 | 1766 |
As can be seen from table 1 and fig. 1, compound NSC 70933 was able to significantly inhibit the activity of influenza virus subtype H1N 1.
Example 3 inhibition of HA pseudovirus Activity by Compound NSC 70933
3.1 preparation of HA pseudovirus
The 293T cells are inoculated to a cell culture dish, after the density reaches 80%, 6 mu g of pNLLucE-R-HIV-Luc plasmid, 6 mu g of pEWSN-HA plasmid and 6 mu g of pCAGGS-NA plasmid are co-transfected by virtue of a transfection reagent PEI, after 6 hours, a DMEM complete culture medium containing 10% (volume fraction) fetal calf serum is replaced, after 48 hours, the whole culture system is transferred to a 15ml centrifuge tube, cells are blown away, after one freeze thawing, the cells are filtered by a 0.22 mu m filter membrane, and filtrate is collected, namely virus liquid of the HA pseudovirus, and the virus liquid is stored at the temperature of 80 ℃ below zero.
3.2 Compound NSC 70933 inhibits the Activity of HA pseudovirus
1. 293T cells were plated uniformly on a 24-well plate (16 ten thousand cells per well), incubated at 37 ℃ for 15 hours with standing, and the supernatant was discarded.
2. After completion of step 1, the 24-well plate was taken, 100. mu.L of the virus solution of HA pseudovirus prepared in step one and 400. mu.L of DMEM medium containing compound NSC 70933 (so that the concentration of compound NSC 70933 in the system was 50. mu.M) were added to each well, incubated at 37 ℃ for 18 hours with standing, and the cells in the wells were washed with PBS buffer.
3. And (3) after the step 2 is completed, adding the lysis solution in the luciferase activity measurement kit into the 24-well plate, standing and incubating for 30 minutes at 37 ℃, and taking the supernatant.
4. And (3) taking the supernatant obtained in the step (3), and detecting the expression level of the luciferase reporter gene by adopting a luciferase activity measurement kit.
Meanwhile, DMSO was used as a negative control instead of compound NSC 70933 during the experiment. The experimental group and the control group were subjected to three replicates and the results were averaged.
Results
The results of inhibition of HA pseudovirus activity by compound NSC 70933 and DMSO are shown in table 2 and fig. 2:
table 2 inhibition results (fluorescein gene expression level) of HA pseudovirus activity by NSC 70933 and DMSO compound (n ═ 3)
| Experimental | DMSO | NSC | 70933 |
| Parallel group 1 | 1251 | 370 | |
| Parallel group 2 | 1256 | 392 | |
| Parallel group 3 | 1532 | 371 |
As can be seen from table 2 and fig. 2, compound NSC70933 significantly inhibits the activity of HA pseudovirus, indicating that compound NSC70933 can significantly inhibit the binding of influenza virus to host cell membrane, thereby preventing and/or treating influenza virus infection.
Example 4 inhibition of influenza Virus vRNP Activity by Compound NSC70933
1. 293T cells were uniformly plated on a 24-well plate, incubated at 37 ℃ for 14 hours, and the supernatant was discarded.
2. After completion of step 1, the 24-well plate was taken out, DMEM medium containing 50. mu. mol/L of the compound NSC70933 was added thereto, and the mixture was incubated at 37 ℃ for 1 hour with standing, and the supernatant was discarded.
3. After the completion of the step 2, a 24-well plate was taken, influenza virus PA, PB1, PB2 and NP gene plasmids and pRL-TK plasmids (the transfection dose of each well was 0.15. mu.g of each of influenza virus PA gene-expressing plasmid, influenza virus PB1 gene-expressing plasmid, influenza virus PB2 gene-expressing plasmid and influenza virus NP gene-expressing plasmid, 0.005. mu.g of pRL-TK internal reference plasmid, and 0.4ug of reporter vector vNS-Luc) were transfected with PEI, and incubated at 37 ℃ for 6 hours, and the supernatant was discarded.
4. After completion of step 3, a 24-well plate was taken, DMEM medium containing 10% (by volume) fetal bovine serum and 50. mu. mol/L NSC70933 was added thereto, the mixture was allowed to stand at 37 ℃ for 24 hours, the supernatant was discarded, and the cells in the well were washed with PBS buffer.
5. And (4) after the step 4 is finished, adding the lysis solution in the luciferase activity measuring kit into the 24-well plate, standing and incubating for 30 minutes at 4 ℃, and taking the supernatant.
6. And (5) taking the supernatant obtained in the step (5), and detecting the expression level of the luciferase reporter gene by adopting a luciferase activity measuring kit.
Meanwhile, DMSO was used as a negative control instead of compound NSC70933 during the experiment. The experimental group and the control group were subjected to three replicates, and the results were averaged.
As a result, the
The results of the inhibition of influenza virus vRNP activity by compound NSC70933 and DMSO are shown in table 3 and figure 3:
table 3 inhibitory effect of compounds NSC70933 and DMSO on influenza virus vRNP activity (fluorescein gene expression level) (n ═ 3)
| Experimental | DMSO | NSC | 70933 |
| Parallel group 1 | 117.6 | 94.8 | |
| Parallel group 2 | 117.6 | 96.7 | |
| Parallel group 3 | 115.9 | 101.2 |
As can be seen from table 3 and fig. 3, compound NSC70933 has a significant inhibitory effect on the activity of influenza virus polymerase complex, thereby preventing and/or treating influenza virus infection.
Conclusion
From examples 2-4 it can be seen that: the compound of the invention not only HAs an inhibition effect on HA-mediated virus invasion host cells, namely, the combination of influenza virus and host cell membranes, but also HAs an inhibition effect on the vRNP activity of the compound, which indicates that the compound NSC70933 can inhibit the replication of the virus at different stages, so that the possibility of the generation of drug resistance of the influenza virus is lower, and the possibility of the compound NSC70933 for drug formation is higher.
All documents mentioned in this application are incorporated by reference in this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes or modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the appended claims of the present application.
Sequence listing
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<120> a medicament for treating influenza virus infection
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Claims (9)
1. Use of a compound, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of influenza virus infection:
wherein the influenza virus is influenza A virus, and the influenza A virus is influenza virus subtype H1N 1;
the compounds have the following structure of formula Ib:
wherein
R5 is halogen;
r8 is C1-C4An alkyl group.
2. The use according to claim 1, wherein R5 is chloro.
3. The use according to claim 1, wherein R8 is methyl.
4. The use according to claim 1, wherein the compound is:
5. The use according to claim 1, wherein the compound is:
6. the use as claimed in claim 1, wherein the medicament is in the form of tablet, powder, pill, capsule, membrane, suppository, paste, granule, injection, infusion solution, powder for injection.
7. The use according to claim 1, wherein the prevention and/or treatment of influenza virus infection is:
(a) preventing and/or treating influenza virus infection by inhibiting the binding of influenza virus to host cell membrane; and/or
(b) Influenza virus is prevented and/or treated by inhibiting the polymerase complex activity of influenza virus.
8. The use according to claim 1, wherein the medicament is in the form of a solid, liquid or semi-solid formulation.
9. An in vitro non-therapeutic and non-diagnostic method of inhibiting influenza virus comprising the steps of: contacting an influenza virus or an influenza virus-infected cell with the compound of claim 1, or a pharmaceutically acceptable salt thereof, thereby inhibiting the influenza virus;
the influenza virus is A type influenza virus, and the A type influenza virus is H1N1 subtype influenza virus.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103239446A (en) * | 2013-05-13 | 2013-08-14 | 中国科学院武汉病毒研究所 | Application of chlorpheniramine maleate in preparation of medicaments for treating or preventing influenza virus |
| CN103251576A (en) * | 2013-05-13 | 2013-08-21 | 中国科学院武汉病毒研究所 | Application of diphenhydramine hydrochloride in preparation of medicines for treating or preventing influenza viruses |
| CN103893175A (en) * | 2014-04-18 | 2014-07-02 | 武汉胜达康生物科技有限公司 | Application of brompheniramine in preparation of medicine for treating or preventing influenza virus infection |
| CN110870864A (en) * | 2018-08-29 | 2020-03-10 | 复旦大学 | Application of carbinoxamine maleate in preparation of anti-influenza virus medicine |
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| EP0553191B1 (en) * | 1990-10-10 | 1995-05-17 | Schering Corporation | Pyridine and pyridine n-oxide derivatives of diarylmethyl- piperidines or piperazines, compositions and use thereof |
| UA80393C2 (en) * | 2000-12-07 | 2007-09-25 | Алтана Фарма Аг | Pharmaceutical preparation comprising an pde inhibitor dispersed on a matrix |
| US7985422B2 (en) * | 2002-08-05 | 2011-07-26 | Torrent Pharmaceuticals Limited | Dosage form |
| US7473432B2 (en) * | 2002-10-11 | 2009-01-06 | Idea Ag | NSAID formulations, based on highly adaptable aggregates, for improved transport through barriers and topical drug delivery |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103239446A (en) * | 2013-05-13 | 2013-08-14 | 中国科学院武汉病毒研究所 | Application of chlorpheniramine maleate in preparation of medicaments for treating or preventing influenza virus |
| CN103251576A (en) * | 2013-05-13 | 2013-08-21 | 中国科学院武汉病毒研究所 | Application of diphenhydramine hydrochloride in preparation of medicines for treating or preventing influenza viruses |
| CN103893175A (en) * | 2014-04-18 | 2014-07-02 | 武汉胜达康生物科技有限公司 | Application of brompheniramine in preparation of medicine for treating or preventing influenza virus infection |
| CN110870864A (en) * | 2018-08-29 | 2020-03-10 | 复旦大学 | Application of carbinoxamine maleate in preparation of anti-influenza virus medicine |
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