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CN112174956B - 2-substituted-5-hexahydropyridazinone-4-carboxylic ester derivative and application thereof - Google Patents

2-substituted-5-hexahydropyridazinone-4-carboxylic ester derivative and application thereof Download PDF

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CN112174956B
CN112174956B CN201910602257.7A CN201910602257A CN112174956B CN 112174956 B CN112174956 B CN 112174956B CN 201910602257 A CN201910602257 A CN 201910602257A CN 112174956 B CN112174956 B CN 112174956B
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胡双华
林寨伟
崔柏成
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GUANGZHOU NANXIN PHARMACEUTICAL CO Ltd
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Abstract

The invention belongs to the field of medicines, and particularly relates to a 2-substituted-5-hexahydropyridazinone-4-carboxylic ester derivative, a compound thereof, and pharmaceutically acceptable salts and solvates thereof, wherein the compound comprises hydrates, polycrystals, prodrugs, cocrystals, tautomers and stereoisomers, and more particularly, the compound can be used as an anti-influenza medicine with a CEN (CeN-mediated isothermal amplification) inhibition effect.

Description

2-substituted-5-hexahydropyridazinone-4-carboxylic ester derivative and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a 2-substituted-5-hexahydropyridazinone-4-carboxylic acid amine derivative and application thereof. More specifically, the compound of the present invention can be used as an anti-influenza drug having a CEN inhibitory effect.
Background
Influenza is a highly contagious respiratory disease caused by influenza virus, wherein influenza A virus has the widest host range, can infect both birds and mammals, and is very easy to cause pandemics worldwide. Influenza viruses have developed 4 major influenza outbreaks in nearly a hundred years only (1918, 1957, 1968, 2009). Among them, the outbreak of "spanish influenza" (H1N 1) in 1918 directly caused about 5000 thousands of deaths, and is a large outbreak of influenza in which the number of deaths in human history is the greatest. Whereas the last outbreak of "Mexico influenza" (A/2009/H1N 1) in 2009 spread rapidly to 214 countries worldwide, only 12 months of the outbreak led to about 20 million deaths. Therefore, it is very important to develop a novel broad-spectrum anti-influenza virus drug for the prevention and early treatment of influenza virus infection. Typically, these new strains result from the transmission of existing influenza viruses from other animal species to humans.
The influenza virus is an RNA virus of Orthomyxoviridae (Orthomyxoviridae) and belongs to the genus influenza virus. Influenza viruses are mainly classified into three types, i.e., A, B and C, also called A, B and C, according to the antigenic and genetic properties of the viral particle Nucleoprotein (NP) and matrix protein (M). The three types of viruses have similar biochemical and biological characteristics. The virus particles are 80-120nm in diameter and are usually approximately spherical, but filamentous forms may occur. The virus is composed of three layers, the inner layer is the virus nucleocapsid, which contains Nucleoprotein (NP), P protein and RNA. NP is a soluble antigen (S antigen), has type specificity, and is antigenically stable. The P proteins (P1, P2, P3) may be polymerases required for RNA transcription and replication. The middle layer is virus envelope composed of one lipoid and one Membrane Protein (MP), and the MP has stable antigenicity and type specificity. The outer layer is a radial protuberance made of two different glycoproteins, hemagglutinin (H) and neuraminidase (N). H can cause erythrocyte agglutination, is a tool for adsorbing viruses on the surfaces of sensitive cells, N can hydrolyze mucus protein, and N-acetylneuraminic acid at the tail end of a receptor specific glycoprotein on the cell surface is a tool for separating viruses from the cell surface after the replication is finished. H and N both have variation characteristics, so that only the specific antigenicity of the strain exists, and the antibody has a protection effect.
Unusual for viruses, nucleic acids whose genomes are not single fragments; in contrast, the genome contains 7 or 8 segments of negative-sense RNA. The influenza a genome encodes 11 proteins: hemagglutinin (H), neuraminidase (N), nucleoprotein (NP), M1, M2, NS1, NS2 (NEP), PA, PB1-F2, and PB2.H and N are macromolecular glycoproteins outside the virion. HA is a lectin that mediates binding of the virus to the target cell and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells by cleaving sugars that bind to mature viral particles. Therefore, these proteins have been targets for antiviral drugs. Moreover, these proteins are antigens of antibodies that can be produced. Influenza a viruses are classified into subtypes based on antibody responses to H and N, forming the basis of H and N discrimination in, for example, H5N 1.
Because the influenza virus genome is small, the synthesis of its desired proteins is dependent on the translation system of the host cell. Thus, the messenger RNA (mRNA) of influenza virus needs to have both a 5 'CAP (CAP) structure and a 3' -poly (A) tail structure that can be recognized by the translation system of the host cell. Wherein the 5 'cap is "captured" by cleavage of the PA subunit endonuclease activity of the influenza RNA polymerase complex from the 5' end of the host cell precursor mRNA. This mode, known as "CAP-snatchinging", deprives the CAP CAP of host mRNA for transcription of viral self mRNA, is necessary for transcription initiation of influenza virus.
Just because "CAP-snatching" is a key element in the replication cycle of influenza virus, and because there is no similar mechanism and corresponding protease in host cells, inhibitors against "CAP-snatching" endonuclease can selectively block the transcription process of influenza virus without affecting the host cells, i.e. have CAP-dependent endonuclease (CEN) inhibition. This mechanism then becomes a potential anti-influenza drug target.
The existing means for preventing and treating influenza virus infection mainly comprise influenza vaccine inoculation and anti-influenza virus medicine application. Vaccination with influenza is the primary prophylactic method and is highly effective, but it has the major disadvantage of having to be injected once a year and of being less effective against adults and young children with low immunity and high risk of illness. Furthermore, if the predicted influenza vaccine species are incorrect, the efficacy of the vaccine will be reduced to 25%. Thus, anti-influenza virus drugs are the first line of treatment for influenza.
To date, FDA approved anti-influenza virus drugs for clinical use fall into two general categories: 1) M2 ion channel blockers including amantadine and rimantadine; 2) Neuraminidase inhibitors, mainly oseltamivir and zanamivir, and peramivir and ranimivir, which have been approved in several countries. In addition, the anti-influenza drugs currently approved only in japan on the market are the RNA inhibitors faviravir and xoflurza. Because the influenza viruses which are epidemic at present are resistant to the amantadine drugs (S31N mutation occurs in a virus NS gene), the amantadine drugs are no longer the first choice drugs recommended by WHO for preventing and treating influenza. Neuraminidase inhibitor drugs are the main choice for antiviral therapy of influenza patients, however, researchers have successively found drug-resistant strains of H1N1, H5N1, H3N2 and B that are resistant to oseltamivir, indicating that their resistance remains of great concern.
Documents 1to 5 report the structure and structure-activity relationship of flutamide (flutimide) and 2, 4-dioxobutyric acid derivatives as CEN inhibitors. CN201080036154 discloses synthesis of 3-hydroxy-4-pyridone derivatives as CEN inhibitors, antiviral action, in particular biological activity for inhibiting influenza virus proliferation. CN201680027747 discloses methods of synthesis of aza-pyridone compounds as CEN inhibitors and amelioration and/or treatment of diseases and/or disorders including influenza virus infection. WO2017072341A1 discloses the use of pyrimidinone derivatives as CEN inhibitors in the field of antiviral.
The above compounds still have some defects in terms of drug-forming property, and therefore, research and development of novel anti-influenza drugs having CEN inhibitory effect is still very urgent for scientists.
The literature:
1.Tetrahedron Lett 1995，36(12)，2005；
2.Tetrahedron Lett 1995，36(12)，2009。
3.Antimicrobial Agents And Chemotherapy，Dec.1994，p.2827－2837
4.Antimicrobial Agents And Chemotherapy，May 1996，p.1304－1307
5.J.Med.Chem.2003，46，1153－1164
disclosure of Invention
The invention provides a novel compound serving as an influenza virus RNA polymerase inhibitor, in particular to a novel compound with a CEN (cancer cell protein) inhibition function and a general formula I, and the compound and a composition thereof can be used for preparing medicaments for preventing, treating or relieving virus infection diseases of patients.
In one aspect, the invention relates to a compound shown as a general formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers and stereoisomers,
Figure BDA0002119614180000031
wherein R is 1 : is H or-C (= O) Y 1 、-C(＝O)-O-Y 1 、-(CH 2 )-O-(C＝O)-Y 1 、-(CH 2 )-O-(C＝O)-O-Y 1 、 -(CHCH 3 )-O-(C＝O)-Y 1 And- (CHCH) 3 )-O-(C＝O)-O-Y 1 ；
Y 1 Is optionally substitutedC 1-10 Alkyl, optionally substituted C 3-8 Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, mono-substituted amino group, di-substituted amino and-C (R) * ) 2 NHR ** (ii) a And each R * And R ** Independently is hydrogen or optionally substituted C 1-6 An alkyl group;
R 2 and R 3 Can be independently H and C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN、-COOR * 、-OR * 、 -(CH 2 )qNR * R ** ,-C(O)-NR * R ** ；R 2 And R 3 May be linked to form a ring to form an optionally substituted cycloalkyl group, an optionally substituted heterocyclyl group and an optionally substituted cycloalkenyl group; r * And R ** Independently H and optionally substituted C 1-6 An alkyl group; q is 0to 6;
R 4 is a structure shown in the following formula
Figure BDA0002119614180000032
R 9 And R 10 Is optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents are independent C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN、-COOR * 、-OR * 、-(CH 2 )qNR * R ** ,-C(O)-NR * R ** ；R * And R ** Independently H and optionally substituted C 1-6 Alkyl, q is 0to 6;
R 9 and R 10 Can be connected to form the structure shown as follows:
Figure BDA0002119614180000041
wherein n and m may independently be 0to 3, Q is CR * R ** 、NR * 、O、S、SO、SO 2 ；R * And R ** Independently H and optionally substituted C 1-6 An alkyl group;
R 5 is H or is selected from optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted heterocyclic group, optionally substituted C 3-8 Cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 6 ,R 7 can be independently H and C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN、-COOR * 、-OR * 、 -(CH 2 )qNR * R ** ,-C(O)-NR * R ** ，R 7 And R 8 May be linked to form a ring to form an optionally substituted cycloalkyl, an optionally substituted heterocyclyl and an optionally substituted cycloalkenyl; r * And R ** Independently H and optionally substituted C 1-6 An alkyl group; q is 0to 6;
R 8 : is H, C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN、-COOR * 、-OR * 、-(CH 2 )qNR * R ** ,-C(O)-NR * R ** ；
R * And R ** Independently H and optionally substituted C 1-6 An alkyl group; q is 0to 6.
In another aspect, the present invention provides a pharmaceutical composition, which comprises an effective amount of the compound of the present invention, and the compound is represented by formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers,
Figure BDA0002119614180000042
wherein,
R 1 : is H;
R 2 and R 3 Can be independently H or C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN、-COOR * 、-OR * ；R 2 And R 3 Optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted cycloalkenyl may be formed, R * Independently H and optionally substituted C 1-6 An alkyl group;
R 4 is a structure shown in the following formula
Figure BDA0002119614180000051
R 9 And R 10 Are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure BDA0002119614180000052
wherein n and m may independently be 0to 3, Q is CR * R ** 、NR * 、O、S、SO、SO 2 ；R * And R ** Independently H and optionally substituted C 1-6 An alkyl group;
R 5 is H or is selected from optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted heterocyclic group, optionally substituted C 3-8 A cycloalkyl group;
R 6 ,R 7 can be independently H and C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN；
R 8 : can be independently H or C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN。
In another aspect, the present invention provides a pharmaceutical composition, which comprises an effective amount of the compound of the present invention, and the compound is represented by formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers,
Figure BDA0002119614180000053
wherein R is 1 : is H;
R 2 and R 3 Can be independently H or C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN；
R 4 Is a structure shown in the following formula
Figure BDA0002119614180000054
R 9 And R 10 Are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure BDA0002119614180000061
wherein n and m may independently be 0-3, Q is O, S, SO 2 ；
R 5 Is H, or optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted heterocyclic group, optionally substituted C 3-8 A cycloalkyl group; wherein the substituents may be independent C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN；
R 6 ,R 7 Can be independently H and C 1-6 An alkyl group; r 9 : can be independently H or C 1-6 An alkyl group.
In another aspect, the present invention provides a pharmaceutical composition, which comprises an effective amount of the compound of the present invention, and the compound is represented by formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers,
Figure BDA0002119614180000062
wherein R is 1 : is H;
R 2 and R 3 Can be independently C 1-6 Alkyl, halogen, -CF 3 、-CN；
R 4 Is a structure shown in the following formula
Figure BDA0002119614180000063
R 9 And R 10 Are optionally substituted aryl, and optionally substituted heteroaryl groups, which may be linked to form the structure shown below:
Figure BDA0002119614180000071
wherein n and m can independently be 0-3, Q is O, S;
R 5 is H or is selected from optionally substituted C 1-8 Alkyl, optionally substituted C 2-8 Alkenyl, optionally substituted heterocyclic group, optionally substituted C 3-8 A cycloalkyl group; wherein the substituents may be independent C 1-6 Alkyl, -C (O) -C 1-6 Alkyl, halogen, -CF 3 、-CN；
R 6 ,R 7 Can be independently H and C 1-6 An alkyl group; r is 9 : can be independently H or C 1-6 An alkyl group.
In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.
In some embodiments, the pharmaceutical compositions provided herein further comprise one or more additional therapeutic agents.
In still other embodiments, the additional therapeutic agent is selected from an anti-influenza virus agent or a vaccine.
In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.
In other embodimentsThe pharmaceutical composition of the present invention may comprise one or more agents that inhibit replication of influenza virus infection selected from the group consisting of neuraminidase inhibitors, M2 protein inhibitors, polymerase inhibitors, PB 2 Inhibitors, immunomodulators.
In still other embodiments, the pharmaceutical composition of the invention, wherein the additional therapeutic agent is Amantadine (Amantadine), rimantadine (Rimantadine), oseltamivir (Oseltamivir), zanamivir (Zanamivir), peramivir (Peramivir), laninamivir (Laninamivir), laninamivir Octanoate (Laninamivir octoate), favipiravir (Favipiravir), arbidol (Arbidol), ribavirin (ribivirin), beraprost (Beraprost), stafurazolin, ingauweilin (Ingavirin), influenza (flase), drugs No. 1422050-75-6, JNJ-872, S-033188, influenza vaccines (e.g., flumisst, quadvalvalent, quadvianvent), or combinations thereof.
In another aspect, the invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the prevention, alleviation or treatment of a viral infectious disease in a patient.
In some embodiments, the viral infection is an influenza viral infection.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for the inhibition of cap-dependent endonuclease (CEN).
Unless otherwise indicated, the present invention includes all compounds of the present invention and pharmaceutically acceptable salts, solvates, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers thereof.
In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The compounds of the present invention also include the salt forms thereof, which are not necessarily pharmaceutically acceptable salts, but may be used for the preparation and/or purification of the compounds of the present invention and/or intermediates used in the isolation of isomers of the compounds of the present invention.
The compounds of the invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the invention also includes solvated and unsolvated forms thereof.
Alternatively, the compounds of the invention may contain several asymmetric centers or their racemic mixtures as generally described. The invention further comprises racemic mixtures, partial racemic mixtures and isolated enantiomers and diastereomers.
The compound of the present invention may exist in the form of one of possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, and the present invention may further comprise isomers, rotamers, atropisomers, tautomers or mixtures of isomers of the compound of the present invention, or isomers, rotamers, atropisomers, tautomers or partial mixtures or separated isomers, rotamers, atropisomers, tautomers.
In another aspect, the invention relates to methods of preparation, isolation and purification of compounds encompassed by formula I.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and all patent publications cited throughout the disclosure of the present invention are hereby incorporated by reference in their entirety.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated to be employed or used in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
The terms "subject" and "patient" as used herein are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails or turkeys), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a domestic animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, a "patient" refers to a human.
All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50.
Depending on the choice of starting materials and processes, the compounds according to the invention may be present in the form of one of the possible isomers or of a mixture thereof, for example as pure optical isomers, or as isomer mixtures, for example as racemic and diastereoisomeric mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules with water.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valeric acid salts, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl radical) 4 A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to counterion formation, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1-8 Sulphonates and aromatic sulphonates.
The term "prodrug" as used in the present invention,represents a compound which is converted in vivo into a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C) 1-24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those phosphate esters which are phosphorylated via the parent hydroxy group.
Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configurations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. The substituents on the atoms having an unsaturated double bond may be present in the- (Z) -or- (E) -form, if possible.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the present invention, within the examples. It will be appreciated that the terms "optionally substituted" and "unsubstituted or substituted by" \8230; substituted by one substituent "and" substituted or unsubstituted "may be used interchangeably. The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally," whether or not preceded by the term "substituted," indicates that one or more hydrogen atoms in a given structure are unsubstituted or specifically substitutedSubstituted by substituent groups. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, F, cl, br, I, CN, N 3 、OH、NH 2 、NO 2 Oxo (= O), C 1-12 Alkyl radical, C 1-6 Haloalkyl, C 1-6 Alkoxy radical, C 1-6 Alkylamino radical, C 2-6 Alkenyl radical, C 2-6 Alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkyl-C 1-4 Alkylene radical, C 3-12 Carbocyclic radical, C 3-12 carbocyclyl-C 1-4 Alkylene, heterocyclic group of 3 to 12 atoms, (heterocyclic group of 3 to 12 atoms) -C 1-4 Alkylene radical, C 6-10 Aryl radical, C 6-10 aryl-C 1-4 Alkylene, heteroaryl of 5 to 16 atoms or (heteroaryl of 5 to 16 atoms) -C 1-4 An alkylene group.
In each part of this specification, substituents for the disclosed compounds are disclosed in terms of group type or range. It is specifically contemplated that each separate subcombination of the various members of these groups and ranges is encompassed by the invention. For example, the term "C 1-6 Alkyl "in particular denotes independently disclosed methyl, ethyl, C 3 Alkyl radical, C 4 Alkyl radical, C 5 Alkyl and C 6 An alkyl group; the term "heteroaryl of 5-10 atoms" especially refers to heteroaryl of 5 atoms, heteroaryl of 6 atoms, heteroaryl of 7 atoms, heteroaryl of 8 atoms, heteroaryl of 9 atoms and heteroaryl of 10 atoms, which are independently disclosed.
The term "alkyl" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical containing from 1to 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, n-heptyl, n-octyl, and the like, wherein the alkyl groups may independently be unsubstituted or substituted with one or more substituents described herein.
The term "alkyl" and its prefix "alkane", as used herein, are intended to encompass both straight and branched saturated carbon chains.
The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 3-6 ring carbon atoms that is saturated, having one or more points of attachment to the rest of the molecule. In some embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, e.g., C 3-6 A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 5 to 6 ring carbon atoms, e.g., C 5-6 A cycloalkyl group; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can be independently unsubstituted or substituted with one or more substituents as described herein.
The term "heterocyclyl" may be used alone or as a majority of a "heterocyclylalkyl" or "heterocyclylalkoxy" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur, and oxygen, wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein the ring system has one or more attachment points to the rest of the molecule. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. In some embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 to 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 to 8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.
Examples of heterocyclyl groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl. In heterocyclic radicals of-CH 2 Examples of-groups substituted by-C (= O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Bridging heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
The term "aryl" may be used alone or as a majority of "arylalkyl" or "arylalkoxy" and refers to monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, each ring contains 3 to 7 ring atoms, and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl group may be independently unsubstituted or substituted with one or more substituents described herein.
The term "heteroaryl" may be used alone or as a majority of "heteroarylalkyl" or "heteroarylalkoxy" and denotes monocyclic, bicyclic and tricyclic aromatic systems containing 5 to 16 ring atoms, or 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 8 ring atoms, or 5 to 7 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring contains one or more heteroatoms, wherein each ring contains 5 to 7 ring atoms, and wherein the heteroaryl group has one or more attachment points to the rest of the molecule. when-CH is present in the heteroaryl group 2 When it is a group, -CH 2 The-group may optionally be replaced by-C (= O) -. Unless otherwise indicated, the heteroaryl group may be attached to the rest of the molecule (e.g., the host structure in the formula) via any reasonable site (which may be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is a 5-14 atom composed heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 12 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 8 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodimentsIn the schemes, heteroaryl is a heteroaryl consisting of 5-7 atoms containing 1,2,3 or 4 heteroatoms independently selected from O, S and N; in other embodiments, heteroaryl is a 5-6 atom heteroaryl comprising 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g. 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g. 5H-tetrazolyl, 2H-tetrazolyl), triazolyl (e.g., 2-triazolyl, 5-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiodiazolyl, 1,3, 4-thiodiazolyl, 1,2, 5-thiodiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, but are in no way limited to these groups: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 4,5,6, 7-tetrahydrobenzofuranyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathiyl, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl, said heteroaryl group optionally being substituted with one or more substituents as described herein.
As used herein, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, which are known to those skilled in the art. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
The term "effective amount" of a compound of the invention refers to an amount that elicits the desired biological response. In the present invention, the biological response is expected to be inhibition of influenza virus replication, reduction in the amount of influenza virus or reduction or amelioration of the severity, duration, progression or onset of influenza virus infection, prevention of spread of influenza virus infection, prevention of recurrence, evolution, onset or progression of symptoms associated with influenza virus infection, or enhancement of the prophylactic or therapeutic effect of another anti-influenza infection therapy used. The exact amount of the compound to be administered to a subject will depend on the mode of administration, the type and severity of the infection and the characteristics of the subject, such as health, age, sex, weight and tolerance to drugs. The skilled artisan will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other antiviral agents, such as anti-influenza drugs, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages of approved agents are known and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition being treated and the amount of the compound described herein being used. In the case where amounts are not explicitly specified, an effective amount should be taken. For example, a compound of the invention may be administered to a subject at a dosage in the range of about 0.01-100 mg/body weight/day for therapeutic or prophylactic treatment.
The term "treatment" as used herein refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity, and/or duration of an influenza virus-mediated condition, or ameliorating one or more symptoms (particularly, one or more discernible symptoms) of an influenza virus-mediated condition as a result of administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the invention)).
In other embodiments, the present invention relates to a compound, but is in no way limited to, one of the following, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof: (specific Compound)
In another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention.
In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.
In some embodiments, the pharmaceutical compositions provided herein further comprise a second agent.
In still other embodiments, the second agent is one or more agents that inhibit replication of influenza virus infection selected from the group consisting of neuraminidase inhibitors, M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, zanamivir, oseltamivir, peramivir, laninamivir octanoate, fapiravir, immunomodulators, beraprost, ribavirin.
In another aspect, the invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a viral infectious disease in a patient.
In some embodiments, the viral infection is an influenza viral infection.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for the inhibition of cap-dependent endonuclease (CEN).
In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of the enantiomers of the compounds of the present invention.
Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrogenphosphate, polysilconate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.
Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from groups I to XII of the periodic Table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., na, ca, mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
Furthermore, the compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form, either inherently or by design, solvates with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.
Compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition which comprises a compound shown as a formula (I), a formula (I-a) or a formula (I-b) or a stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle.
Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or free of other adverse or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.
The pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or excipient, as described herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular intended dosage form, as used herein. In addition to conventional carrier vehicles which are incompatible with the compounds of the present invention, e.g., may produce undesirable biological effects or may deleteriously interact with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and its use are contemplated by the present invention.
Some examples of substances that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methyl cellulose, hydroxypropyl methyl cellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch) cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository waxes), oils (e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (e.g., propylene glycol or polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol and phosphate buffers, and other non-toxic compatible lubricants (e.g., sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifying agents, gelling agents, and the like, as judged by the formulator, coating agents, sweeteners and flavoring agents, preservatives and antioxidants may also be present in the composition.
The compounds or compositions of the present invention may be administered by any suitable means, and the above-described compounds and pharmaceutically acceptable compositions may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally as an oral or nasal spray, and the like, depending on the severity of the infection being treated.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used for the preparation of injections.
For example, injectable formulations can be sterilized by filtration through a bacterial-retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
To prolong the effect of the compounds or compositions of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.
Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard gel capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols.
The active compound may also be in the form of a microencapsulated form with one or more of the above-mentioned excipients. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to the inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
Formulations for topical or transdermal administration of the compounds of the present invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of a dermal patch that has the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the composition is administered orally, intraperitoneally, or intravenously.
The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated forms. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.
The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers which are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
For topical application, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or solutions in particular isotonic, pH adjusted, sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.
The pharmaceutical compositions may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.
The compounds for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be administered in a single daily dose or in multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
In summary, the present invention provides the use of said compound or said pharmaceutical composition for the manufacture of a medicament for the inhibition of cap-dependent endonuclease (CEN). The compound of the invention is suitable for being prepared into medicines with various dosage forms, and can be widely used for treating seasonal influenza, avian influenza, swine influenza and influenza virus mutant strains with drug resistance to tamiflu.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species, and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
Advantages of the compounds of the invention: compared with the existing similar compounds, the compound of the invention has larger difference in structure, not only can well inhibit influenza virus, but also has lower cytotoxicity, and more excellent in vivo pharmacokinetic property and in vivo pharmacodynamic property. In addition, compared with the existing similar compounds, the compound provided by the invention has better drugability.
Detailed Description
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula I, unless otherwise specified. The following reaction schemes and examples serve to further illustrate the context of the invention.
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Preparation examples
In the following preparation examples, the inventors described in detail the preparation of the compounds of the present invention by taking some of the compounds of the present invention as examples.
Example 1- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-yl) -5-hydroxy-4, 6-dioxo-2, 3,4, 6-tetrahydro-1H-pyrido [1,2-b ] pyridazine-3-carboxylic acid ethyl ester
Figure BDA0002119614180000191
Obtained by the following reaction formula:
step 1) Synthesis of Compound 2
Figure BDA0002119614180000201
A solution of a mixture of Compound 1 (200.0g, 812.3mmol, 1.00eq), iodoethane (228.0g, 1.46mol,116.9mL, 1.80eq) and DBU (185.5 g,1.22mol,183.7mL, 1.50eq) in DMF (1000 mL) was stirred at 20-30 ℃ for 1hr. TLC (PE: EA =1 f = 0.60) showed the reaction was complete the reaction mixture was poured into 4L of water and extracted with ethyl acetate (1000ml × 3). The organic layer was washed with saturated brine (1000ml × 2) and concentrated to give compound 2 (190.0 g,692.8mmol, yield 85.3%) as a yellow oil. HNMR conforms to the expected structure. 1 H NMR:(400MHz,CHLOROFORM-d)δ7.74(d,J＝5.6Hz,1H),7.51-7.44(m,2H), 7.39-7.29(m,3H),6.46(d,J＝5.6Hz,1H),5.36-5.23(m,2H),4.33(q,J＝7.2Hz,2H),1.31(t,J＝7.1Hz, 3H)。
Step 2) Synthesis of Compound 3
Figure BDA0002119614180000202
A solution of Compound 2 (190.0g, 692.8mmol, 1.00eq), t-butoxycarbonyl-N-amino-carbamate (137.3g, 1.04mol, 1.50 eq), and PPTS (522.3g, 2.08mol, 3.00eq) in DMA (2200 mL) was stirred at 50-60 ℃ for 1hr. TLC (PE: EA =1 f = 0.15) showed the reaction was complete. The mixture was poured into water, extracted with ethyl acetate (1000ml × 3), and the organic layer was washed with brine (500ml × 3), and then concentrated to dryness. The residue was purified by column chromatography (PE: EA = 20. HNMR conforms to the expected structure. 1 H NMR:(400MHz,CHLOROFORM-d)δ7.37-7.31 (m,2H),7.29-7.17(m,4H),6.29(d,J＝7.9Hz,1H),5.17(s,2H),4.18(q,J＝7.1Hz,2H),1.37(s,9H),1.18- 1.13(m,3H).
Step 3) Synthesis of Compound 4
Figure BDA0002119614180000211
A mixture of compound 3 (120.0g, 309.0mmol, 1.00eq), ethyl 2-acrylate (61.0g, 609.3mmol,66.2mL, 1.97eq), DIEA (47.9g, 370.7mmol,64.6mL, 1.20eq) and acetonitrile (1.2L) was stirred at 70-80 ℃ for 12hrs. TLC (PE: EA =1 f = 0.60) showed complete consumption of compound 3 the mixture was concentrated to dryness. The residue was subjected to column chromatography (SiO) 2 Petroleum ether/ethyl acetate =1001to 0/1) purified compound 4 (100.0 g,204.7mmol, yield 66.3% yield) as a yellow oil, which was used in the next reaction.
Step 4) Synthesis of Compound 5
Figure BDA0002119614180000212
To a solution of compound 4 (100.0 g,204.7mmol, 1.00eq) in ethyl acetate (200 mL) was added HCl/EtOAc (4M, 500mL, 9.77eq) dropwise at 20-30 ℃. The mixture was stirred at 20-30 ℃ for 2hrs. TLC (PE: EA =1 f = 0.09) showed the reaction was complete. The mixture was concentrated to dryness. The residue was saturated with Na 2 CO 3 The solution (200 mL) was adjusted to pH =8, extracted with ethyl acetate (200ml × 3), and the organic layer was concentrated to dryness to give compound 5 (80.0 g, crude) as a yellow oil. HNMR conforms to the expected structure. 1 H NMR:(400MHz,DMSO-d 6 ) δ7.84(d,J＝7.8Hz,1H),7.43-7.27(m,5H),6.88(t,J＝5.8Hz,1H),6.30(d,J＝7.7Hz,1H),5.09(s,2H),4.23 (q,J＝7.0Hz,2H),4.05(q,J＝7.1Hz,2H),3.62-3.56(m,1H),3.34(s,2H),3.21(q,J＝6.7Hz,2H),2.41(t, J＝6.8Hz,2H),1.19(td,J＝7.1,11.1Hz,6H).
Step 5) Synthesis of Compound 6
Figure BDA0002119614180000221
To a solution of t-BuOK (60.09g, 535.5mmol, 2.60eq) in THF (800 mL) was added dropwise a solution of compound 5 (80 g, 206.0mmol, 1.00eq) in THF (800 mL) at 0to 10 ℃. The mixture was stirred at 20-30 ℃ for 2hrs. TLC (EA: meOH =20 f = 0.50) indicating completion of the reaction. The mixture was poured into a saturated solution of citric acid (500 mL) and NaHCO 3 Adjusting to pH7-8, the organic layer was concentrated to dryness to give Compound 6 (50.0 g,146.0mmol, yield 70.9% yield) as a yellow solid. HNMR conforms to the expected structure. 1 H NMR: (400MHz,DMSO-d 6 )δ7.73(d,J＝7.6Hz,1H),7.47(br d,J＝7.0Hz,2H),7.35-7.27(m,3H),6.58(t,J＝8.3Hz, 1H),6.16(d,J＝7.7Hz,1H),5.08(s,2H),4.26(q,J＝7.1Hz,2H),3.70(d,J＝8.3Hz,2H),1.26(t,J＝7.1Hz, 3H).
Step 6) Synthesis of Compound 7
Figure BDA0002119614180000222
To a solution of compound 1a (8.00g, 30.3mmol, 1.00eq) and 6 (10.4g, 30.3mmol, 1.00eq) in ethyl acetate (100 mL) was added T at 20-30 deg.C 3 P (134.8 g,211mmol,126mL, 50% purity, 7.00 eq). The mixture was stirred at the temperature of 70-80 ℃ for 1.5hrs. TLC (Plate 1, petroleum ether: ethyl acetate =1 f = 0.3) show complete consumption of compound 7 reaction mixture cooled to 20-30 ℃, diluted with ethyl acetate (200 ml), washed with water (150ml x 3), anhydrous Na 2 SO 4 And (5) drying. Filtering, concentrating, passing the residue through silica gel column (SiO) 2 Petroleum ether/ethyl acetate = 1) to give compound 7 (16.0 g,27.2mmol, yield 89.8%) as a yellow solid. 1 H NMR:EW17959-13-P1A(400MHz,DMSO-d 6 )δ12.64-11.95(m,1H),7.52-7.30(m,8H),7.27-7.03(m,6H), 6.89-6.75(m,2H),5.76-5.69(m,1H),5.58(br d,J＝15.3Hz,1H),5.32(s,1H),5.22-5.11(m,3H),4.28- 4.19(m,1H),3.72-3.55(m,2H),1.09(t,J＝7.0Hz,3H).
Step 7) Synthesis of Compound 8
Figure BDA0002119614180000231
A mixture of Compound 7 (500mg, 849umol, 1.00eq), pd/C (50.0 mg,849umol,10.0%,1.00 eq) and MeOH (5.00 mL) was stirred at 20-30 ℃ under hydrogen (15 psi) for 1hr. LCMS (EW 17752-44-P1A, 5. Mu. 95AB, product: RT =0.964 mins) showed the expected m/z. The mixture was filtered and washed with EA (2.00 mL). The filtrate was concentrated to give the desired product 1 (50.0 mg,96.9umol, yield 11.4%, purity 96.6%) as a yellow solid, the structure of which was confirmed by HNMR and LCMS. HPLC purity 96.6%, product RT = 3.143mins. MS (ESI, M/z): 499.1[ (M + H) + ].1H NMR:(400MHz,DMSO-d 6 )δ7.41-6.74(m,7H),6.24(br d, J＝6.7Hz,1H),5.79-5.53(m,1H),5.45-5.31(m,1H),4.15-3.90(m,6H),1.13-1.02(m,3H).
Example 2: screening experiment of compound in vitro anti-influenza virus activity
In the following examples, the inventors conducted experiments using cytopathic effect (CPE) using a part of the compounds of the present invention as examples, and examined the antiviral activity of the compounds against influenza virus a/WSN/33 (H1N 1) and toxicity against MDCK cells.
The following acronyms are used throughout this embodiment
English abbreviation English full scale Chinese full scale
ATCC American Tissue Culture Collection American type culture Collection
CC 50 Concentration for 50％Cytotoxicity 50% cytotoxic concentration
CCK8 Cell Counting Kit 8 Cell counting kit 8
CPE Cytopathic Effect Cytopathic effect
DMSO Dimethyl Sulfoxide Dimethyl sulfoxide
EC 50 Concentration for 50％of Maximal Effect 50% effective concentration
ml Millilitre Milliliter (ml)
mM Millimolar Millimole per litre
MOI Multiplicity Of Infection Multiplicity of infection
OD Optical Density Optical density
μM Mircomolar Micromole per liter
μl Mircolitre Microlitre
1. Test materials
1.1 Compounds
The compounds were prepared as 20mM stock solutions based on 100% DMSO solution. Compounds were tested at 8 concentration points, 4-fold gradient dilution, duplicate wells. The initial test concentrations are shown in table 1.
TABLE 1 Compound information Table
Figure BDA0002119614180000241
1.2 cell lines
MDCK canine kidney cells were purchased from ATCC. The cells were cultured in EMEM medium (Sigma) supplemented with 10% fetal bovine serum (Hyclone), 2mM L-glutamine (Gibco), 1% non-essential amino acids (Gibco), 100U/ml penicillin and 100. Mu.g/ml streptomycin (Hyclone). OptiPRO SFM medium (Gibco) supplemented with 2mM L-glutamine, 1% non-essential amino acids, 100U/ml penicillin and 100. Mu.g/ml streptomycin was used as the test medium.
1.3 Virus strains
Influenza A/WSN/33 (H1N 1) strains were purchased from Virapur.
1.4 reagents
The main reagent used in the project is a cell viability detection kit CCK8 (Shanghai Liji biology)
1.5 instruments
The main instrument used in the project is a microplate reader SpectraMax340PC384 (Molecular Device).
2 test method
CPE refers to the phenomenon of massive proliferation of the virus in the host cell, leading to cytopathy and even death. By measuring cell viability, the CPE assay is widely used to determine the inhibitory activity of compounds against viruses that cause cytopathic effects. In this study, the in vitro inhibitory activity of compounds against influenza A/WSN/33 (H1N 1) was tested using the CPE assay. The virus assay is summarized in table 2.
TABLE 2 Experimental methods for antiviral Activity
Influenza virus strains Cells Compound treatment time (day)/end point method Positive control compound Detection reagent
A/WSN/33(H1N1) MDCK 5/CPE S-033447 CCK8
MDCK cells were plated at a density of 2,000 cells per well in 384-well cell culture plates and at 5% CO 2 And cultured overnight in an incubator at 37 ℃. The next day compounds (8 concentration points, 4-fold gradient dilution, double-well) and virus (MOI = 0.04) were added, respectively. The final concentrations of DMSO and pancreatin in the cell culture broth were 0.5% and 2.5. Mu.g/ml, respectively. Cells at 37 deg.C, 5% 2 The culture was continued for 5 days under these conditions until the rate of cell morbidity in virus control wells (cells infected with virus, no compound treatment) reached 80-95%. The cytotoxicity test and the antiviral test are carried out simultaneously, the test conditions are consistent, but no virus infection exists.
Cell viability was measured using the cell viability assay reagent CCK 8. The antiviral activity and cytotoxicity of the compound are represented by the inhibition rate (%) and cell viability (%) of the compound against the viral-induced cytopathic effect, respectively. The calculation formula is as follows:
Figure BDA0002119614180000251
Figure BDA0002119614180000252
note: sample well: compound treating the wells;
virus control wells: cells infected with virus, no compound treatment;
cell control wells: cells, no compound treatment or viral infection;
culture solution control wells: only the culture broth, without cells, viruses or compounds.
Nonlinear fitting analysis of the inhibition rate and cell viability rate of the compound was performed using GraphPad Prism (version 5) software to obtain the EC of the compound 50 And CC 50 The value is obtained.
3 results
The activity against influenza A/WSN/33 (H1N 1) and the cytotoxicity against MDCK of the compounds are summarized in Table 3.
TABLE 3 anti-influenza Virus Activity test results
Compound (I) EC 50 (μM)* CC 50 (μM)
Example 1 2.362 >50
*A＝1-1000nM；B＝1-10um；C＝10-50uM；D>50uM
As is clear from tables 1 and 2, the results of the experiments show that Compound 1 has excellent inhibitory activity against influenza A virus/WSN/33 (H1N 1).
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (5)

1. A compound, and pharmaceutically acceptable salts thereof, in particular:
Figure DEST_PATH_IMAGE002
。
2. a pharmaceutical composition comprising an effective amount of a compound of claim 1 and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.
3. Use of a compound of claim 1 and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment and/or prevention, alleviation or treatment of influenza virus infection.
4. The pharmaceutical composition of claim 2, further comprising a therapeutically effective amount of at least one other drug selected from the group consisting of: neuraminidase inhibitor, M2 protein inhibitor, polymerase inhibitor, PB 2 An inhibitor or an immunomodulator.
5. The composition of claim 4, wherein the at least one other drug is selected from zanamivir, oseltamivir, peramivir, laninamivir octanoate, fapiravir, beraprost, or ribavirin.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102803260A (en) * 2009-06-15 2012-11-28 盐野义制药株式会社 Substituted polycyclic carbamoylpyridone derivative
CN103228653A (en) * 2010-09-24 2013-07-31 盐野义制药株式会社 Substituted polycyclic carbamoyl pyridone derivative prodrug

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102803260A (en) * 2009-06-15 2012-11-28 盐野义制药株式会社 Substituted polycyclic carbamoylpyridone derivative
CN103228653A (en) * 2010-09-24 2013-07-31 盐野义制药株式会社 Substituted polycyclic carbamoyl pyridone derivative prodrug

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