Title of Invention	NITROGEN-CONTAINING HETEROCYLIC CARBOXAMIDE DERIVATIVES OR SALTS THEREOF AND ANTIVIRAL AGENTS COMPRISING THE SAME
Abstract	An antiviral agent comprising a nitrogen- containing heterocyclic carboxamide derivative represented by the following general formula: where in ring A represents a pyrazine, pyrimidine, pyridazine or triazine ring which may be substituted with one or more groups selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groups, alkenyl groups; cycloalkyl groups; hydroxyl groups;alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; arylthio groups; arylamino groups; cyano groups; nitro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkyl amino croups? eye loalkyl ammo groups; acyl groups; hydrazine groups; carboxyl groups; carbamoyl groups; thiocarbamoy1 groups, alkylcarbamoyl groups and heterocyclic groups; R1 represents O or O-H R2 represents a hydrogen atom, an acyl group or a substituted or unsubstituted C1-6 alkyl group substituted with carbamoyl or carboxy groups; and the broken line represents a single bend or a double bond; wherein the C1-6 alkyl group substituted with carbamoyl or carboxy groups of R2 may be Substituted with at least one substituent selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups, halogenoalkyl groups; alkenyl groups; cycloalkyl groups, hydroxyl groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; aryithio groups; arylamino groups; cyano groups; nxtro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkylamino groups; cycloalky1 amino groups; acyl groups; hydrazine groups; carboxyl groups; carbamoyl groups; triocarbamoyl groups; alkylcarbamoyl groups and hetero- cyclic groups or a salt thereof; wherein the salt represents salt of mineral acids ; salts of organic carboxylic acids; salts of sulfonic acids; salts of alkali metals; salts of alkaline earth metals; ammonium salts; and salts of nitrogen-containing organic bases.

Title of Invention

NITROGEN-CONTAINING HETEROCYLIC CARBOXAMIDE DERIVATIVES OR SALTS THEREOF AND ANTIVIRAL AGENTS COMPRISING THE SAME

Abstract

An antiviral agent comprising a nitrogen- containing heterocyclic carboxamide derivative represented by the following general formula: where in ring A represents a pyrazine, pyrimidine, pyridazine or triazine ring which may be substituted with one or more groups selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groups, alkenyl groups; cycloalkyl groups; hydroxyl groups;alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; arylthio groups; arylamino groups; cyano groups; nitro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkyl amino croups? eye loalkyl ammo groups; acyl groups; hydrazine groups; carboxyl groups; carbamoyl groups; thiocarbamoy1 groups, alkylcarbamoyl groups and heterocyclic groups; R1 represents O or O-H R2 represents a hydrogen atom, an acyl group or a substituted or unsubstituted C1-6 alkyl group substituted with carbamoyl or carboxy groups; and the broken line represents a single bend or a double bond; wherein the C1-6 alkyl group substituted with carbamoyl or carboxy groups of R2 may be Substituted with at least one substituent selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups, halogenoalkyl groups; alkenyl groups; cycloalkyl groups, hydroxyl groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; aryithio groups; arylamino groups; cyano groups; nxtro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkylamino groups; cycloalky1 amino groups; acyl groups; hydrazine groups; carboxyl groups; carbamoyl groups; triocarbamoyl groups; alkylcarbamoyl groups and hetero- cyclic groups or a salt thereof; wherein the salt represents salt of mineral acids ; salts of organic carboxylic acids; salts of sulfonic acids; salts of alkali metals; salts of alkaline earth metals; ammonium salts; and salts of nitrogen-containing organic bases.

Full Text	DESCRIPTION NITROGEN-CONTAINING HETEROCYCLIC CARBOXAMIDE DERIVATIVES OR SALTS THEREOF AND ANTIVIRAL AGENTS COMPRISING THE SAME TECHNICAL FIELD The present invention relates to antiviral agents comprising a nitrogen-containing heterocyclic carboxamide derivative or a salt thereof. BACKGROUND ART Nowadays, antiviral agents are selected and put to use in accordance with the objective viruses. For instance, Acyclovir and Vidarabine are used against herpes viruses; Gancicrovir and Foscarnet are used against cytomegalo virus; and interferon is used against hepatitis viruses. Influenza virus is a central virus of the cold syndrome, which has attacked human being periodically to cause many deaths amounting to tens millions. Although the number of deaths shows a tendency of decrease in the recent years owing to the improvement in hygienic and nutritive conditions, the prevalence of influenza is repeated every year, and it is apprehended that a new virus may appear to cause a wider prevalence. For prevention of influenza virus, vaccine is used widely, in addition to which low molecular weight substances such as Amantadine and Ribavirin are also used. Amantadine is used for prevention and treatment of influenza. Its function mechanism is said to consist in inhibiting the fusion between influenza virus and cell membrane, and it is effective against A- type influenza virus. Its problems are, however, that it is ineffective against B type influenza virus, its resistant virus appears, and it causes side effects such as nerve disturbance. Although Rimantadine which is a derivative of Amantadine has a more improved antiviral activity, the problem of side effect is not overcome by it. Ribavirin which is a guanosine derivative shows a viral RNA polymerase-inhibitory activity and is effective upon A type and B type influenza viruses. Its internal use, however, brings about no sufficient clinical effect. The present invention provides an antiviral agent exhibiting a preventive effect and a therapeutic effect against various viruses, especially influenza viruses. DISCLOSURE OF THE INVENTION The present inventors have conducted researches and studies on compounds showing an antiviral activity against various viruses, especially influenza viruses. As a result, it has been found that pyrazine carboxamide derivatives have an anti-influenza virus activity. The inventors conducted further studies to find that nitrogen-containing heterocyclic carboxamide derivatives represented by the following general formula [1]: wherein ring A represents a substituted or unsubsti- tuted pyrazine, pyrimidine, pyridazine or triazine ring; R1 represents 0 or OH; R2 represents a hydrogen atom, an acyl group or a substituted or unsubstituted carbamoylalkyl or carboxyalkyl group; and the broken line represents a single bond or a double bond; or salts thereof exhibit an excellent antiviral activity against A-, B- and C-type of influenza viruses and other various viruses, these compounds have low cytotoxicity and are useful as an antiviral agents of high safety, as well as that novel N-containing heterocyclic carboxamide derivatives represented by the following general formula [1a]: wherein ring A' represents a pyrazine ring substituted with a halogen atom, a hydroxyl group or an oxide group; R1 represents 0 or OH; R2 represents a hydrogen atom, an acyl group or a substituted or unsubstituted carbamoylalkyl or carboxyalkyl group; and the broken line represents a single bond or a double bond; or salts thereof exhibit an excellent antiviral activity. Based on these findings, the present invention has been accomplished. The present invention will be described in detail below. Unless otherwise indicated, the term "halogen atom" used in this specification means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; the term "alkyl group" means a straight or branched chain C1-6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like; the term "alkenyl group" means a straight or branched chain C2-6 alkenyl group such as vinyl, allyl and the like; the term "cycloalkyl group" means a C3-6 cycloalkyl group such as cyclopropyl, cyclopentyl, cyclohexyl and the like; the term "alkoxy group" means a straight or branched chain C1-6 alkyl-O- group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and the like; the term "cycloalkyloxy group" means a C3-6 cycloalkyl-O- group such as cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and the like; the term "alkylthio group" means a straight or branched chain C1-6 alkyl-S- group such as methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio and the like; the term "alkylamino group" means an amino group substituted with one or more straight or branched chain C1-6 alkyl groups such as methylamino, ethylamino, propylamine butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, dipentylamino and the like; the term "cycloalkylamino group" means a C3-6 cycloalkyl-NH- group such as cyclopropylamino, cyclopentylamino, cyclohexylamino and the like; the term "halogenoalkyl group" means a halogen-substituted C1-6 alkyl group such as trifluoromethyl, trichloro- methyl, chloromethyl and the like; the term "aryl group" means a phenyl group, a naphthyl group and the like; the term "aryloxy group" means an aryl-O- group such as phenyloxy, naphthyloxy and the like; the term "arylthio group" means an aryl-S- group such as phenylthio, naphthylthio and the like; the term "arylamino group" means an aryl-NH- group such as phenylamino, naphthylamino and the like; the term "acyl group" means a C2-5 alkanoyl group such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and the like and an aroyl group such as benzoyl, naphthoyl and the like; the term "alkoxycarbonyl group" means a straight or branched chain C1-6 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxy- carbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and the like; the term "alkylcarbamoyl group" means a carbamoyl group substituted with one or more straight or branched chain C1-6 alkyl groups such as methylcarbamoyl, dimethyl- carbamoyl and the like; the term "carbamoylalkyl group" means a straight or branched chain C1-6 alkyl group substituted with a carbamoyl group such as carbamoyl- methyl, carbamoylethyl, carbamoylisopropyl and the like; the term "carboxyalkyl group" means a straight or branched chain C1-6 alkyl group substituted with a carboxyl group such as carboxymethyl, carboxylethyl, carboxyisopropyl and the like; the term "heterocyclic group" means a 4-, 5- or 6-membered ring or a fused ring thereof having, as the hetero atoms constituting said ring, at least one heteroatoms selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom, such as oxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl and morpholinyl; and the term "oxide group" means an oxygen atom linked to a nitrogen atom in a ring. The term "lower" means that the number of carbon atoms is 1 to 6. The protecting group for carboxyl group includes any groups which can conventionally be used as a protecting group for carboxyl group. The examples thereof include alkyl groups such as methyl, ethyl, n- propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert- butyl and the like; aryl groups such as phenyl, naphthyl and the like; aralkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl and the like; acylalkyl groups such as acetylmethyl, benzoylmethyl, p- nitrobenzoylmethyl, p-bromobenzoylmethyl, p- methanesulfonylbenzoylmethyl and the like; oxygen- containing heterocyclic groups such as 2- tetrahydropyranyl, 2-tetrahydrofuranyl and the like; halogeno-alkyl groups such as 2,2,2-trichloroethyl and the like; alkylsilylalkyl groups such as 2- (trimethylsilyl)ethyl and the like; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxy- methyl and the like; nitrogen-containing heterocyclic alkyl groups such as phthalimidomethyl, succinimido- methyl and the like; cycloalkyl groups such as cyclohexyl and the like; alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, 2-(trimethylsilyl)ethoxy- methyl and the like; aralkoxyalkyl groups such as benzyloxymethyl and the like; alkylthioalkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthioalkyl groups such as phenylthiomethyl and the like; alkenyl groups such as 1,1-dimethyl-2- propenyl, 3-methyl-3-butenyl, allyl and the like; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropyl- silyl, tert-butyldimethylsilyl, tert- butyldiphenylsilyl, diphenylmethylsilyl, tert- butylmethoxyphenylsilyl and the like; etc. In general formula [1], ring A represents a pyrazine ring, a pyrimidine ring, a pyridazine ring or a triazine ring. More specifically, ring A represents any of the following structures: In the structures above, the mark 1 expresses the position of substitution with R1, and the mark 2 expresses the position of substitution with -C(=O)NHR2. The carbamoylalkyl or carboxyalkyl group represented by R2 may be substituted with at least one substituent selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groups; alkenyl groups; cycloalkyl groups; hydroxyl groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; arylthio groups; arylamino groups; cyano groups; nitro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkylamino groups; cycloalkylamino groups; acyl groups; hydrazino groups; carboxyl groups; carbamoyl groups; thiocarbamoyl groups; alkylcarbamoyl groups and heterocyclic groups. Of ring A represented by general formula [1], preferred are pyrazine ring, pyrimidine ring and triazine ring, and more preferred is pyrazine ring. The substituent on ring A includes groups selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groups; alkenyl groups; cycloalkyl groups; hydroxyl groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; arylthio groups; arylamino groups; cyano groups; nitro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkylamino groups; cycloalkylamino groups; acyl groups; hydrazino groups; carboxyl groups; carbamoyl groups; thiocarbamoyl groups, alkylcarbamoyl groups and heterocyclic groups. Ring A can have one or more of the above-mentioned substituents. Further, the substituent on ring A is preferably linked to carbon atom of the ring. The salt of the compound of general formula [1] includes any usually known salts formed at the site of basic groups such as amino group and salts formed at the site of acidic group such as hydroxyl and carboxyl groups. The salts formed at the site of basic group include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts of organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like, and salts of sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. The salts formed at the site of acidic group include salts of alkali metals such as sodium, potassium and the like; salts of alkaline earth metals such as calcium, magnesium and the like; ammonium salts; and salts of nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N- methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1- ephenamine, N,N'-dibenzylethylenediamine and the like. Among the salts mentioned above, preferred are pharmacologically acceptable ones. Typical compounds represented by general formula [1] are shown in Tables 1 to 4. In the tables shown below, the abbreviations have the following meanings: Me: methyl Et: ethyl iPr: isopropyl tBu: tert-butyl, Ph: phenyl Ac: acetyl Bz: benzoyl R2a: -CH(COOH)CH2COOH R2b: -CH(CH3)CONHCH(CH3)COOH The nitrogen-containing heterocyclic carboxamide derivatives represented by general formula [1] or salts thereof are commercially available or can be produced according to any of known processes or analogous processes or by a combination thereof. As the papers describing the production processes thereof, J. Am. Chem. Soc, 71, 78 (1949); J. Am. Chem. Soc, 78, 242-244 (1956); J. Heterocycl. Chem., 15(4), 665- 670 (1978); J. Chem. Soc., 1379 (1955); U.S. Patent No. 5,597,823; etc. can be referred to. More specifically, the nitrogen-containing heterocyclic carboxamide derivatives represented by general formula [1] or salts thereof can be produced according to the following Production Processes 1 to 3. Production Process 1 wherein R1, R2, ring A and broken line are as defined above, and R3 represents a protecting group for carboxyl group. (1-a) A compound of general formula [1] can be obtained by reacting a compound of general formula [2] with a compound of general formula [4]. The solvent which can be used in this reaction is not particularly limited, so far as it causes no adverse effect on the reaction. The examples of the solvent include alcohols such as methanol, ethanol, isopropyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents can be used in admixture. The compound of general formula [4] is used at least in an equimolar amount to the compound of general formula [2], and preferably in an amount of 1.0-5.0 mole per mole of the compound of general formula [2] . This reaction can be carried out usually at 0-100°C and preferably at 20-80°C, for a period of 5-24 hours and preferably for 30 minutes to 10 hours. (1-b) A compound of general formula [1] can be obtained by subjecting a compound of general formula [3] and a compound of general formula [4] to a dehydrating condensation reaction. The solvent which can be used in this reaction is not particularly limited, so far as it causes no adverse effect on the reaction. The examples of the solvent include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; and amides such as N,N- dimethylformamide, N,N-dimethylacetamide and the like. These solvents can be used in admixture. The compound of general formula [4] can be used at least in an equimolar amount to the compound of general formula [3] and preferably in an amount of 1.0- 2.0 mole per mole of the compound of general formula [3]. The dehydrating condensing agent which can be used in this reaction includes, for example, 1,3- dicyclohexyl carbodiimide, N,N'-carbonyl diimidazole, 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and the like. The dehydrating condensing agent can be used at least in an equimolar amount to the compound of general formula [3] and preferably in an amount of 1.0- 2.0 mole per mole of the compound of general formula [3]. This reaction can be carried out usually at 0-100°C and preferably at 20-60°C, for a period of 5 minutes to 24 hours and preferably for 30 minutes to 10 hours. Production Process 2 wherein R1, R2, ring A and broken line are as defined above, and R4 represents a lower alkyl group. A compound of general formula [1] can be obtained by subjecting a compound of general formula [5] to alkyl-ether scission. More specifically, in a case where R4 is a methyl group, the reaction can be carried out according to the description of PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, Second edition, JOHN WILEY & SONS, pp. 145- 199 (1991) or by an analogous method. Production Process 3 wherein R1, ring A and broken line are as defined above, and R2a represents an acyl group. A compound of general formula [1c] can be obtained by subjecting a compound of general formula [1b] to acylation in the presence of an acid- eliminating agent. The solvent which can be used in this reaction is not particularly limited, so far as it causes no adverse effect on the reaction. The examples of the solvent include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; water; etc. These solvents can be used in admixture. The acylating agent can be used at least in an equimolar amount to the compound of general formula [1b] and preferably in an amount of 1.0-2.0 mole per mole of the compound of general formula [1b]. The acid-eliminating agent used in this reaction includes, for example, pyridine, triethyl- amine, sodium hydrogen carbonate and the like. The acid-eliminating agent can be used at least in an equimolar amount to the compound of general formula [1b] and preferably in an amount of 1.0-2.0 mole per mole of the compound of general formula [1b]. This reaction can be carried out usually at 0-100°C and preferably at 20-60°C, for a period of 5 minutes to 24 hours and preferably for 30 minutes to 10 hours. In the Production Processes 1-3, the compounds of general formula [2], [3], [4], [5] and [1b] can be replaced with their salt, respectively. As the salts, the same ones as mentioned for the compound of general formula [1] can be used. Some of the compounds of general formulas [2], [3], [4], [5] and [1b] and salts thereof may have various isomers such as optical isomers and position isomers, and solvated products. In such cases, any of these isomers and solvates may be used in the present invention. The compound of general formula [1c] thus obtained can be converted to salts thereof. The salts include the same ones as mentioned for the compound of general formula [1]. The objective viruses of the antiviral agent comprising the nitrogen-containing heterocyclic carboxamide derivative represented by general formula [1] or salt thereof according to the present invention include A-, B- and C-type influenza viruses, papilloma virus, adenovirus, A type hepatitis virus, B type hepatitis virus, C type hepatitis virus, poliovirus, echovirus, Coxsackie virus, enterovirus, rhinovirus, rotavirus, Newcastle disease virus, mumps virus, vesicular stomatitis virus, and Japanese encephalitis virus. The antiviral agent of the present invention exhibits an especially high effect against influenza viruses., By combining the nitrogen-containing heterocyclic carboxamide derivatives of the present invention represented by general formula [1] or salts thereof with conventional known excipients, adjuvants and additives, pharmaceutical preparations such as solutions, suspensions, powders, granules, fine granules, tablets, capsules, syrups, elixirs, spirits, troches, gargles, aerosols, etc. can be obtained. These pharmaceutical preparations can be administered either orally or non-orally, namely by injection, percutaneous administration, intrarectal administra- tion, intranarial administration, etc. The method of administration, dosage and frequency of administration of the antiviral agent of the present invention can be properly selected depending upon the age, body weight and symptom of the patient. Usually 1 to 10 mg/kg of the nitrogen- containing heterocyclic carboxamide derivative or a salt thereof can be administered to an adult either at once or in several portions. Next, antiviral activity and cytotoxicity of the nitrogen-containing heterocyclic carboxamide derivatives of the present invention represented by general formula [1] or salts thereof will be explained. Sample: A nitrogen-containing heterocyclic carboxamide derivative represented by general formula [1] or a salt thereof was dissolved in dimethyl sulfoxide to prepare a solution having a concentration of 10 mg/mL. At the time of use, the solution was diluted with a culture medium to a predetermined concentration and then put to use. As the host cell of influenza virus, MDCK cell (canine kidney cell) was used. For the cytotoxicity test, Vero cell (monkey kidney cell) was used. Culture medium: In the multiplication of MDCK cell and Vero cell and in the cytotoxicity test using Vero cell, E'-MEM (product of Nissui) to which 10% fetal bovine serum had been added was used. In the measurement of antiviral activity, E'- MEM (product of Nissui) to which 1% bovine serum albumin had been added was used. Test Example 1 (Anti-influenza activity) MDCK cells were seeded to a 6-well plate (product of CORNING) at 5 x 105 cells/well, and cultured overnight at 35°C in 5% CO2-air atmosphere. Then, the cultured MDCK cells on the plate was treated with influenza virus A/PR/8/34 strain diluted with a serum- free culture medium at the concentration of 200 PFU/mL, at 0.5 mL/well for one hour to achieve inoculation and adsorption. After completion of the inoculation and adsorption, an E'-MEM culture medium containing 0.6% Agar Noble, 1% bovine serum albumin and 3 μg/mL acetyltrypsin and also containing a test compound at a prescribed concentration was added to the cells. After sufficient coagulation, the plate was turned upside down, and cultured for 3 days. After completion of the culture, the alive cells were dyed with 1% Neutral Red. Then, the cells were fixed with 10% formalin. The agar medium was removed therefrom with running water. 25 Thereafter, the number of plaques was counted. The plaque inhibition rate was expressed in percentage calculated in comparison with control containing no test compound. The results are shown in Table 5, wherein the test compound number are the same as those in Tables 1 to 4. Test Example 2 (Cytotoxic activity) A culture medium containing a predetermined concentration of test compound was added to a 96-well plate (product of CORNING) in 100 μl/well. Then, Vero cells were adjusted to the concentration of 2 x 104 cells/mL with culture medium. The solution was added to the plate at 100 μL/well, and cultured at 37°C in 5% CO2-air atmosphere for 4 days. When the culture was completed, the number of alive cells was counted according to the XTT method [for example, see CANCER RESEARCH, Vol. 48, Pages 4827-4833 (1988)]. As a result, the 50% cell growth inhibitory concentration (IC50) of 3-hydroxy-2-pyrazinecarboxamide (compound No. 1) was 250 μg/mL or more. BEST MODE FOR CARRYING OUT THE INVENTION Next, the compound of the present invention is explained with reference to Referential Examples and Examples. The invention is by no means limited by these examples. In the eluent, the mixing ratios are all by volume. The carrier used in column chromatography was Silica Gel BW-127ZH (product of Fuji Silicia Chemical Co.), and the carrier used in the reverse phase column chromatography was LC-SORB SP-B-ODS (product of Chemco Co. ) . The symbol mark used in the Referential Examples and Examples has the following meaning: DMSO-d6 : Deuterated dimethyl sulfoxide Referential Example 1 In 6 mL of dichloromethane is suspended 0.30 g of methyl 3-hydroxy-2-pyrazinecaroxylate obtained according to the method described in literature [J. Heterocycl. Chem., 34, 27 (1997)]. To the suspension are successively added 0.54 mL of triethylamine and 0.29 g of glycine methyl ester hydrochloride. The resulting mixture is stirred at ambient temperature for 5 hours. After cooling, the solvent is distilled off under reduced pressure. The residue is purified by reverse phase column chromatography (eluent: water) to obtain 0.16 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)- carbonyl]amino}acetate. IR(KBr) cm-1: 1750, 1735, 1685 NMR(DMSO-d6) δ value: 3.67(3H,s), 4.12(2H,d,J=6Hz), 7.70-8.30(2H,m), 9.60-10.10(1H,m), 13.10(1H,brs) Referential Example 2 In 100 ml of concentrated sulfuric acid is dissolved 17.00 g of methyl 6-bromo-3-amino-2- pyrazinecarboxylate obtained according to the method described in literature [J. Am. Chem. Soc, 2798-2800 (1949)]. At an ice-cooled temperature, 10.11 g of sodium nitrite is added to the suspension, which is stirred for 30 minutes. The reaction mixture is poured into 920 mL of methanol, and heated under reflux for 5 hours. The reaction mixture is cooled and then concentrated under reduced pressure. The residue thus obtained is added to a mixture of 500 mL of ice water and 600 mL of chloroform and separated into layers. The organic layer is washed successively with saturated aqueous solution of sodium hydrogen carbonate, water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure to obtain 6.30 g of methyl 6-bromo-3-methoxy-2- pyrazinecarboxylate. IR(KBr) cm-1: 1734 NMR(CDCl3) δ value: 3.97(3H,s), 4.06(3H,s), 8.37(lH,s) Referential Example 3 In a nitrogen atmosphere, 11.38 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate is dissolved in 227 rnL of toluene. To the solution are successively added 10.32 g of benzophenone-imine, 0.42 g of tris(dibenzylideneacetone) dipalladium, 0.86 g of (s)- (-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 6.20 g of sodium t-butoxide. The resulting mixture is stirred at 80°C for one hour. The reaction mixture is cooled and filtered. The filtrate is purified by column chromatography (eluent: toluene:ethyl acetate = 20:1). The oily product thus obtained is dissolved in 140 mL of tetrahydrofuran, 7 mL of 2 mol/mL hydrochloric acid is added thereto and the resulting solution is stirred at ambient temperature for 15 minutes. The resulting reaction mixture is added to a mixture of 200 mL of chloroform and 50 mL of water, and alkalified with 1 mol/mL of sodium hydroxide, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: toluene:ethyl acetate =1:1) to obtain 3.64 g of methyl 6-amino-3-methoxy-2- pyrazinecarboxylate. IR(KBr) cm-1: 1716,1670 NMR(DMSO-d6) δ value: 3.80(3H,s), 3.82(3H,s), 7.20(2H,brs), 7.77(lH,s) Referential Example 4 In 70 mL of methanol is dissolved 3.50 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate. Gaseous ammonia is introduced to saturate the solution with ammonia. The solution is stirred at ambient temperature for 14 hours. The solvent is distilled off from the reaction mixture under reduced pressure to obtain 3.1 g of 6-amino-3-methoxy-2- pyrazinecarboxamide. IR(KBr) cm-1: 1684 NMR(DMSO-d6) : 3.79(3H,s), 5 . 87 (2H,brs) , 7 . 30-7 . 75 (3H,m) Referential Example 5 In a nitrogen atmosphere, 1.50 g of 6-amino- 3-methoxy-2-pyrazinecarboxamide is dissolved in 12 rnL of 70% pyridine hydrofluoride under ice-cooling. Then, 0.71 g of sodium nitrite is added thereto at -50°C, and the resulting solution is stirred at 10°C for 1 hour. The resulting reaction mixture is stirred at ambient temperature for an additional 1 hour. Thereafter, a mixture of 50 mL of ice water and 100 mL of chloroform is added thereto and the resulting mixture is separated into layers. The organic layer is washed with saturated aqueous solution of sodium chloride and saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure to obtain 1.29 g of 6-fluoro-3-methoxy-2- pyrazinecarboxamide. IR(KBr) cm-1: 1706 NMR(DMSO-d6) : 3.95(3H,s), 7 . 55-8 .15 (2H,m) , 8.39(1H,d,J=8.3Hz) Referential Example 6 In 100 mL of methanol is suspended 1.96 g of methyl 5-amino-3-methoxy-2-pyrazinecarboxylate obtained according to the method described in literature (JP-A- 50-105675). The resulting suspension is saturated with ammonia by introducing gaseous ammonia thereinto at -20°C. Then, the solution thus obtained is allowed to react at 95°C for 24 hours in a stainless steel-made closed vessel. After cooling, the solvent is distilled off under reduced pressure to obtain 1.57 g of 5-amino- 3-methoxy-2-pyrazinecarboxamide. IR(KBr) cm-1: 1654, 1637 NMR(DMSO-d6) δ value: 3.82(3H,s), 7 . 00 (3H, brs) , 7.30(1H,brs), 7.43(1H,s) Referential Example 7 In a nitrogen atmosphere, 0.5 g of 5-amino-3- methoxy-2-pyrazinecarboxamide is dissolved in 9 mL of 70% pyridine hydrofluoride under ice-cooling. Then, 0.23 g of sodium nitrite is added thereto at -70°C, and the resulting solution is heated to a temperature of -10°C in 30 minutes. Further, the solution is stirred at ambient temperature for 30 minutes. A mixture of 30 mL of ice water and 100 mL of chloroform is added thereto and the resulting mixture is separated into layers. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform:methanol = 10:1) to obtain 0.37 g of 5- fluoro-3-methoxy-2-pyrazinecarboxamide. IR(KBr) cm-1: 1705 NMR(DMSO-d6) δ value: 3.94(3H,s), 7.65(1H,brs), 7.85 (1H,brs), 8.12(1H,d,J=8.3Hz) Example 1 In 3 mL of methanol is suspended 0.6 g of methyl 6-bromo-3-hydroxy-2-pyrazinecarboxylate obtained according to the method described in literature [J. Med. Chem., 1969, 12(2), 285-287]. Then, 6 mL of 25% aqueous ammonia is added thereto and the resulting solution is stirred at ambient temperature for 17 hours. The reaction mixture is adjusted to pH 3 by adding 6 mol/L hydrochloric acid. The solvent is distilled off under reduced pressure. Isopropyl ether and water are added to the residue and filtered to obtain 0.33 g of 6-bromo-3-hydroxy-2- pyrazinecarboxamide. IR(KBr) cm-1: 1700, 1665 NMR(DMSO-d6) δ value: 7.50 (2H, brs) , 8.08(lH,s), 9.95(1H,brs) Example 2 In 10 mL of dimethylformamide is suspended 0.5 g of 3,5-dihydroxy-1,2,4-triazine-6-carboxylic acid obtained according to the method described in literature (JP-A-54-79292). Then, 2.06 g of N,N'- carbonyldiimidazole is added thereto, and the resulting solution in stirred at ambient temperature for 6 hours. The reaction mixture is cooled with ice, saturated with gaseous ammonia, and then stirred for 15 minutes at the same temperature as above. The deposited crystals are collected by filtration to obtain 0.37 g of 3,5-dioxo- 2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. IR(KBr) cm-1: 1732, 1710, 1685, 1656 NMR(DMSO-d6) δ value: 7.75(1H,s), 7.97(1H,s), 12.20- 12.80(2H,m) Example 3 In 5 mL of acetic anhydride is suspended 0.5 g of 3-hydroxy-2-pyrazinecarboxamide. The resulting solution is stirred at 110°C for 1 hour. The deposited crystals are collected by filtration to obtain 0.5 g of N2-acetyl-3-hydroxy-2-pyrazinecarboxamide. IR(KBr) cm-1: 1725, 1695, 1655 NMR(DMSO-d6) δ value: 2.25(3H,s), 7 . 53 (1H, d, J=4Hz) , 7.69(1H,d,J=4Hz), 11.70(1H,brs) Example 4 In 5 mL of 25% aqueous ammonia is suspended 0.25 g of methyl 6-chloro-3-hydroxy-2- pyrazinecarboxylate obtained according to the method described in literature [J. Med. Chem., 285-287 (1969)]. The suspension is stirred at ambient temperature for 1 hour. The deposited crystals are collected by filtration to obtain 0.18 g of 6-chloro-3- hydroxy-2-pyrazinecarboxamide. IR(KBr) cm-1: 1652 NMR(DMSO-d6) : 7 . 22 (2H, brs) , 7.91(1H,s), 10 . 40 (1H, brs) Example 5 In 50 mL of tetrahydrofuran is suspended 1.00g of 3-hydroxy-2-pyrazinecarboxamide. Then, 3.5 mL of triethylamine and 1.67 mL of benzoyl chloride are successively added thereto. The resulting solution is stirred at 60°C for 5 hours and cooled. The deposited crystals are collected by filtration. The crystals thus obtained are suspended in a mixture of 8 mL of water and 1 mL of 1 mol/mL hydrochloric acid, stirred at ambient temperature for 30 minutes, and collected by filtration to obtain 0.41 g of N2-benzoyl-3-hydroxy-2- pyrazinecarboxamide. IR(KBr) cm-1: 1735 NMR(DMSO-d6) δ value: 7.20-8.40(7H,m), 12.60(1H,brs) According to the same method as above, N2- (2,2-dimethylpropanoyl)-3-hydroxy-2-pyrazinecarboxamide is obtained. IR(KBr) cm-1: 1725 NMR(DMSO-d6) δ value: 1.21(9H,s), 7.49 (1H, d, J=2Hz), 7.95(lH,d,J=2Hz), 14.80(1H,brs) Example 6 In 0.5 mL of 47% aqueous solution of hydrogen bromide is dissolved 0.05 g of 3-methoxy-2- pyrazinecarboxamide-4-oxide obtained according to the method described in literature [Eur. J. Med. Chem., 15(2), 157-163 (1980)]. The solution is stirred at 45°C for 2 hours. The deposited crystals are collected by filtration and washed successively with ethanol and diethyl ether to obtain 0.03 g of 3-hydroxy-2- pyrazinecarboxamide-4-oxide. IR(KBr) cm-1: 1695 NMR(DMSO-d6) δ value: 7.19 (1H,d, J=6Hz), 7.56(lH,d,J=6Hz), 7.70(lH,brs), 7.95(1H,brs), 10.75(1H,brs) Example 7 In 4 mL of methanol is suspended 0.19 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)carbonyl]- amino}acetate. The suspension is saturated with ammonia by introducing gaseous ammonia thereinto under ice-cooling for 30 minutes. The resulting mixture is stirred at the same temperature as above for 1 hour and then at ambient temperature for 15 hours. The solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in a mixture of 4 mL of water and 1 mL of methanol. To the resulting solution is added 0.9 mL of 1 mol/L hydrochloric acid. The deposited crystals are collected by filtration to obtain 0.16 g of N2-(2-amino-2-oxoethyl)-3-hydroxy-2- pyrazinecarboxamide. IR(KBr) cm-1: 1675 NMR(DMSO-d6) δ value: 3.90(1H,d,J=5Hz), 7.10(1H,brs), 7.40(lH,brs), 7.60-8.40(2H,m), 9.50(1H,brs), 13.0(1H,brs) Example 8 In a nitrogen atmosphere, 1.51 g of sodium iodide is dissolved in 22 mL of acetonitrile. Then, 1.10 g of trimethylsilyl chloride is added thereto. The resulting solution is stirred at ambient temperature for 20 minutes. Then, 0.43 g of 6-fluoro- 3-methoxy-2-pyrazinecarboxamide is added thereto. The resulting solution is stirred at the same temperature as above for 18 hours. Then, a mixture of 10 mL of water and 200 mL of chloroform is added to the reaction mixture, and separated into layers. The organic layer thus obtained is washed successively with 5% aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: hexane:ethyl acetate =2:1) to obtain 0.06 g of 6-fluoro-3-hydroxy- 2-pyrazinecarboxamide. IR(KBr) cm-1: 1685, 1670, 1656 NMR(CDCl3): 5.40-7.80 (2H,m), 8.31 (1H, d, J=7.82Hz), 12.33(1H,s) Example 9 In 24 mL of concentrated sulfuric acid is suspended 4.00 g of 3-hydroxy-2-pyrazinecarboxamide. To the suspension is added 3.09 g of potassium nitrate under ice-cooling. The resulting mixture is stirred at 40°C for 3 hours. The reaction mixture is poured into 240 mL of water, and the deposited crystals are collected by filtration. The crystals thus obtained are suspended in 80 mL of water and heated under reflux for 30 minutes. After cooling, the crystals are collected by filtration to obtain 2.45 g of 3-hydroxy- 6-nitro-2-pyrazinecarboxamide. IR(KBr) cm-1: 1705, 1685, 1655 NMR(DMSO-d6) δ value: 8.10 (lH,brs), 8.30 (1H,brs), 8.96(1H,s) Example 10 In 2.1 mL of water is suspended 0.5 g of 2- aminomalonamide. Under ice-cooling, 0.43 g of ethyl glyoxalate is added to the suspension, which is then stirred for 40 minutes. Then, 0.85 mL of 5 mol/mL sodium hydroxide is added to the resulting suspension, which is then stirred at the same temperature as above for 40 minutes. The reaction mixture is adjusted to pH 12 by adding 1 mol/L sodium hydroxide, and once made into a solution. The solution is then adjusted to pH 2 by adding 6 mol/mL hydrochloric acid. The deposited crystals are collected by filtration and washed successively with water and 50% (w/w) ethanol to obtain 0.15 g of 3,5-dihydroxy-2-pyrazinecarboxamide. IR(KBr) cm-1: 1660 NMR(D2O) δ value: 6.97(1H,s) Example 11 In 2.0 mL of water are suspended 0.65 mL of diethyl-2-oxomalonate and 0.5 g of 2-aminomalonamide. Under ice-cooling, 0.85 mL of 5 mol/mL sodium hydroxide is added thereto. The resulting solution is stirred for 40 minutes. Then, at ambient temperature, 2.55 mL of 5 mol/mL sodium hydroxide is added to the solution, which is then stirred for an additional 30 minutes. Ethanol is added to the reaction mixture and the precipitate is collected by filtration to obtain 0.24 g of 3,5-dihydroxy-6-ethoxycarbonyl-2- pyrazinecarboxamide. IR(KBr) cm-1: 1655, 1735 NMR(D2O) δ value: 1.17(3H,t,J=7Hz), 4.15(2H,q,J=7Hz) Example 12 In a mixture of 1.0 mL of water and 1.0 mL of ethanol is suspended 0.13 g of 3,5-dihydroxy-6- ethoxycarbonyl-2-pyrazinecarboxamide. At ambient temperature, 0.34 mL of 5 mol/mL sodium hydroxide is added to the suspension, which is then stirred for 16 hours. The reaction mixture is adjusted to pH 2 by adding 1 mol/mL hydrochloric acid. The deposited crystals are collected by filtration and washed with water to obtain 0.07 g of 3,5-dihydroxy-6-carboxy-2- pyrazinecarboxamide. IR(KBr) cm-1: 1650 Example 13 In a nitrogen atmosphere, 0.09 g of 5-fluoro- 3-methoxy-2-pyrazinecarboxamide is suspended in 3.6 mL of acetonitrile. Then, 0.16 g of sodium iodide and 0.11 g of chlorotrimethylsilane are successively added to the suspension, which is then stirred at ambient temperature for 20 hours. Then, 2 mL of water and 40 mL of chloroform are added to the reaction mixture and separated into layers. The organic layer is separated, washed successively with 5% (w/v) aqueous solution of magnesium thiosulfate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure. The residue thus obtained is purified by column chromatography (eluent: chloroform) to obtain 0.01 g of 5-fluoro-3-hydroxy-2- pyrazinecarboxamide. IR(KBr) cm-1: 1670 NMR(CDCl3) δ value: 5.80(1H,s), 7.45(1H,brs), 7.93(1H,d,J=7.8Hz), 12.93(1H,s) Example 14 In 5 mL of ethanol is dissolved 0.1 g of ethyl 5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine- 6-carboxylate obtained according to the method described in literature (J. Am. Chem. Soc, 1956, 78, 1258-1259). At ambient temperature, gaseous ammonia is introduced into the solution for 30 minutes to saturate the solution with ammonia. After allowing the solution to stand at the same temperature as above for 15 hours, the resulting crystals are collected by filtration. The crystals thus collected are washed with three 5 mL portions of ethanol to obtain 0.05 g of 5-oxo-3-thioxo- 2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide. IR(KBr) cm-1: 1654 NMR(DMSO-d6) δ value: 3.30(4H,brs) Example 15 According to the method described in literature (International Patent Application: WO 98130549), 6-oxo-1,6-dihydro-5-pyrimidinecarboxamide is obtained. Example 16 According to the method described in literature (Chemische Berichte, 1964, 97, 3349-3353), 3-OXO-2,3-dihydro-4-pyridazinecarboxamide is obtained. Example 17 In 5 mL of ethanol is dissolved 0.06 g of ethyl 5-OXO-4,5-dihydro-1,2,4-triazine-6-carboxylate. At 10°C, the solution is saturated with ammonia by introducing gaseous ammonia thereinto for 20 minutes. The solution is allowed to stand at ambient temperature for 15 hours, and the resulting crystals are collected by filtration. The crystals thus obtained are washed successively with two 2 mL portions of ethanol and then two 1 mL portion of methanol to obtain 0.03 g of 5-oxo- 4,5-dihydro-1,2,4-triazine-6-carboxamide. IR(KBr) cm-1: 1654 NMR(DMSO-d6) δ value: 3.60(1H,brs), 7.44(1H,brs), 8.39(1H,s), 9.74(1H,brs) Example 18 In 4 mL of dimethyl sulfoxide is dissolved 0.4 g of methyl 3-hydroxy-2-pyrazinecarboxlate. Then, 0.27 g of L-aspartic acid and 0.85 mL of triethylamine are successively added to the solution, which is then stirred at 50°C for 6 hours. The deposited crystals are filtered off, and the filtrate is concentrated under reduced pressure. Then, 2 mL of water and 0.2 mL of methanol are added to the resulting residue. The precipitate formed is collected by filtration to obtain 0.09 g of (2S)-2-{[(3-oxo-3,4-dihydro-2-pyrazinyl)- carbonyl]amino}-butanedioic acid. IR(KBr) cm-1: 1695, 1680, 1665 NMR(DMSO-d6) δ value: 2.83(2H,d,J=5Hz), 4.50-5.00(1H,m), 7.60-8.05(2H,m), 9.95(lH,d,J=9Hz), 12.90(3H,brs) Example 19 In 5 mL of dimethyl sulfoxide is dissolved 0.42 g of L-alanyl-L-alanine trifluoroacetate. Then, 1.07 mL of triethylamine and 0.71 g of methyl 3- hydroxy-2-pyrazinecarboxylate are successively added to the solution, which is then stirred at 40°C for 17 hours. The solvent is distilled off under reduced pressure, and 2 mL of water was added to the residue thus obtained. The deposited product is collected by filtration and purified by column chromatography [eluent: chloroform:methanol = 30:1) to obtain 0.035 g of (2S)-2-[((2S)-2-{[(3-oxo-3,4-dihydro-2- pyrazinyl)carbonyl]amino}-propanoyl)amino]propanoic acid. IR(KBr) cm-1: 1665, 1675, 1655 NMR(DMSO-d6) δ value: 1.28 (3H, d, J=7Hz), 1.32(3H,d,J=7Hz), 3.95-4.95(2H,m), 5.1(2H,brs), 7.71(1H,d,J=3Hz), 7.87(1H,d,J=3Hz), 8.32(1H,d,J=7Hz), 9.9(1H,brs) INDUSTRIAL APPLICABILITY An antiviral agent comprising the nitrogen- containing heterocyclic carboxamide derivative represented by general formula [1] or a salt thereof is useful for preventing and treating virus-infections and especially influenza virus-infections. WE CLAIM: i. An antiviral agent comprising a nitrogen-containing heterocyclic carboxamide derivative represented by the following general formula: wherein ring A represents a pyrazine, pyrimidine, pyridazine or triazine ring which may be substituted with one or more groups selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groups; alkenyl groups; cycloalkyl groups; hydroxyl groups; alkoy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups, alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; aryithio groups, arylamino groups; cyano groups; nitro groups; amino groups; unsubstituted or substituted with one or more acyi groups; alkylamino groups; cycloalkylamino groups; acyl groups; hydrazino groups; cartoxyl groups; carbamoyl groups, thiocarbamoy1 groups, alkylcarbamoyl groups and heterocyclic groupe such as herein described; R1 represents O or OH; R2 represents a hydrogen atom, an acyl group or a substituted or unsubstituted C1-6 alkyl substituted with carbamoyl or carboxy groups} and the broken line represents a single bond or a double bond; wherein the C1-6 alkyl group substituted with carbamoyl or carboxy groups of R2 tray be substituted with at least one substituent selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with hydroxy1, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groupe, alkenyl groups; cycloalkyl groups, hydroxyl groups; alkoxy groups} cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; arylthio groups; arylamino groups; cyano groups; nitro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkylamino groups; cycloalkylamino groups; acyl groups; hydrazino groups; carboxyl groups; carbamoyl groups; thiocarbamoyl groups? alkylcarbamoyl groupe and heterocyclic groups such as herein described; or a salt thereof; wherein the salt represents salts of mineral acids? salts of organic carboxylic acids; salts of sulfonic acids? salts of alkali metals; salts of alkaline earth metals; ammonium salts; and salts of nitrogen-containing organic bases. 2. An antiviral agent as claimed in claim 1, wherein said ring A is s. pyrazine, pyrimidine or triazins ring which may be substituted with one or more groups selected from the group consisting of halogen atoms; alkyl groups unsubstituted or subbstituted with one or more hydroxyl , alkoxy, alkylthio, aryl , amino or alkylamino groups; halogenoalkyl groups; alkenyl groups; cycoalkyl groups; hydroxyl groups, alkoxy groups; cycloalkyloxy groups; alkaxycarbonyl groups; mereapto groups, alkylthio groups unsubstitutsd or substituted with one or more aryl groups; aryl groups; aryloxy groups; aryithio groups; arylamino groups; cyano groups; nitro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkyiamino groups; cycloaikylamino groups acyl groups; hydrazine groups; carboxyl groups; carbamoyl groups, thiocarbamoyl groups, alkylcarbamoyl groups and hetero- cyclic groups. 3. An antiviral agent as claimed in claim 2, wherein said rinc A is a pyrazine ring which may be substituted with one or more groups selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with one or more hydrexyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halcoanoalkyl groups; alkenyl groups; cycloakyl groups; hydroxyl groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbanyl groups mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; aryithio groups; arylamino groups; cyano groups? nitro groups amino groups unsubstituted or substituted with one or more acyl groups; alkylamino groups, cycloalkylamino groups; acyl groups; hydrazino groups; carboxyl groups; carbamoyl groups; thicrarbamoyl groups, alkylcarbamoyl groups and heterocyclic groups. 4. An antiviral agent as claimed in any one of claims 1 to 3, wherein tne virus is influenza virus, papilloma virus, aderovirus. A type hepatitis virus, B type hepatitis virus, C type hepav.itis virus, poliovirus, echovirus, Coxsasckie virus, enterovirus, rhinovirus, rotavirus, Newcastle disease virus, mumps virus, vesicular stomatitis virus or Japanese encephalitis virus. 5. An antiviral agent as claimed in claim 4 wherein said virus is irfluenza virus. 6. An nitrogen-containing heterocyclic carboxamide derivative represented by the following general formula: wherein ring A' represents a pyrazine ring substituted with a 1 halogen atom, a hydroxyl group or an oxido group; R represents O or OH; R represents a hydrogen atom, an acyl group or a substituted or unsubst ituted C alkyl group substituted with carbamoyl or carboxy groups; and the broken line represents a single bond or a double bond; wherein the C1-6 alkyl group substituted with carbamoyl or carboxy groups of R2 may be substituted with at least one substituent selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groups; alkenyl groups; cycoalkyl groups; hydroxyl groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubsbstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; arylthio groups; arylamina groups; cyano groups; nitro groups; amino groups unsubtituted or substituted with one or more acyl groups; alkylamino groups; cycloalkylamino groups; acyl groups; hydrazino groups; carboxyl groups; carbmoyl groups; thiocarbamoyl groups; alkylcarbamoyl groups and heterocyclic groups or a salt thereof; wherein the salt reresents salts of mineral acids; salts of organic carboxylic acids, salts of sulfonic acids; salts of alkali metal, salts of alciline earth metals; ammonium salts; and salts of nitrogen- containing organic bases. 7. A nitrogen—containing heterocyclic carboxamide derivative as claimed in claim 6 wherein said ring A' is a pyrazine ring substituted with a halogen atom; and R2 represents a hydrogen atom. An antiviral agent comprising a nitrogen-containing heterocyclic carboxamide derivative represented by the following general formula: where in ring A represents a pyrazine, pyrimidine, pyridazine or triazine ring which may be substituted with one or more groups selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenoalkyl groups, alkenyl groups; cycloalkyl groups; hydroxyl groups;alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; arylthio groups; arylamino groups; cyano groups; nitro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkyl amino croups? eye loalkyl ammo groups; acyl groups; hydrazine groups; carboxyl groups; carbamoyl groups; thiocarbamoy1 groups, alkylcarbamoyl groups and heterocyclic groups; R1 represents O or O-H R2 represents a hydrogen atom, an acyl group or a substituted or unsubstituted C1-6 alkyl group substituted with carbamoyl or carboxy groups; and the broken line represents a single bend or a double bond; wherein the C1-6 alkyl group substituted with carbamoyl or carboxy groups of R2 may be Substituted with at least one substituent selected from the group consisting of halogen atoms; alkyl groups unsubstituted or substituted with hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups, halogenoalkyl groups; alkenyl groups; cycloalkyl groups, hydroxyl groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups unsubstituted or substituted with one or more aryl groups; aryl groups; aryloxy groups; aryithio groups; arylamino groups; cyano groups; nxtro groups; amino groups unsubstituted or substituted with one or more acyl groups; alkylamino groups; cycloalky1 amino groups; acyl groups; hydrazine groups; carboxyl groups; carbamoyl groups; triocarbamoyl groups; alkylcarbamoyl groups and hetero- cyclic groups or a salt thereof; wherein the salt represents salt of mineral acids ; salts of organic carboxylic acids; salts of sulfonic acids; salts of alkali metals; salts of alkaline earth metals; ammonium salts; and salts of nitrogen-containing organic bases.

Full Text

DESCRIPTION
NITROGEN-CONTAINING HETEROCYCLIC CARBOXAMIDE
DERIVATIVES OR SALTS THEREOF AND ANTIVIRAL
AGENTS COMPRISING THE SAME
TECHNICAL FIELD
The present invention relates to antiviral
agents comprising a nitrogen-containing heterocyclic
carboxamide derivative or a salt thereof.
BACKGROUND ART
Nowadays, antiviral agents are selected and
put to use in accordance with the objective viruses.
For instance, Acyclovir and Vidarabine are used against
herpes viruses; Gancicrovir and Foscarnet are used
against cytomegalo virus; and interferon is used
against hepatitis viruses.
Influenza virus is a central virus of the
cold syndrome, which has attacked human being
periodically to cause many deaths amounting to tens
millions. Although the number of deaths shows a
tendency of decrease in the recent years owing to the
improvement in hygienic and nutritive conditions, the
prevalence of influenza is repeated every year, and it
is apprehended that a new virus may appear to cause a
wider prevalence.
For prevention of influenza virus, vaccine is
used widely, in addition to which low molecular weight

substances such as Amantadine and Ribavirin are also
used.
Amantadine is used for prevention and
treatment of influenza. Its function mechanism is said
to consist in inhibiting the fusion between influenza
virus and cell membrane, and it is effective against A-
type influenza virus. Its problems are, however, that
it is ineffective against B type influenza virus, its
resistant virus appears, and it causes side effects
such as nerve disturbance. Although Rimantadine which
is a derivative of Amantadine has a more improved
antiviral activity, the problem of side effect is not
overcome by it. Ribavirin which is a guanosine
derivative shows a viral RNA polymerase-inhibitory
activity and is effective upon A type and B type
influenza viruses. Its internal use, however, brings
about no sufficient clinical effect.
The present invention provides an antiviral
agent exhibiting a preventive effect and a therapeutic
effect against various viruses, especially influenza
viruses.
DISCLOSURE OF THE INVENTION
The present inventors have conducted
researches and studies on compounds showing an
antiviral activity against various viruses, especially
influenza viruses. As a result, it has been found that
pyrazine carboxamide derivatives have an anti-influenza

virus activity. The inventors conducted further
studies to find that nitrogen-containing heterocyclic
carboxamide derivatives represented by the following
general formula [1]:

wherein ring A represents a substituted or unsubsti-
tuted pyrazine, pyrimidine, pyridazine or triazine
ring; R1 represents 0 or OH; R2 represents a hydrogen
atom, an acyl group or a substituted or unsubstituted
carbamoylalkyl or carboxyalkyl group; and the broken
line represents a single bond or a double bond;
or salts thereof exhibit an excellent antiviral
activity against A-, B- and C-type of influenza viruses
and other various viruses, these compounds have low
cytotoxicity and are useful as an antiviral agents of
high safety, as well as that novel N-containing
heterocyclic carboxamide derivatives represented by the
following general formula [1a]:

wherein ring A' represents a pyrazine ring substituted
with a halogen atom, a hydroxyl group or an oxide
group; R1 represents 0 or OH; R2 represents a hydrogen
atom, an acyl group or a substituted or unsubstituted
carbamoylalkyl or carboxyalkyl group; and the broken
line represents a single bond or a double bond; or
salts thereof exhibit an excellent antiviral activity.
Based on these findings, the present invention has been
accomplished.
The present invention will be described in
detail below.
Unless otherwise indicated, the term "halogen
atom" used in this specification means a fluorine atom,
a chlorine atom, a bromine atom or an iodine atom; the
term "alkyl group" means a straight or branched chain
C1-6 alkyl group such as methyl, ethyl, n-propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
pentyl and the like; the term "alkenyl group" means a
straight or branched chain C2-6 alkenyl group such as
vinyl, allyl and the like; the term "cycloalkyl group"
means a C3-6 cycloalkyl group such as cyclopropyl,
cyclopentyl, cyclohexyl and the like; the term "alkoxy
group" means a straight or branched chain C1-6 alkyl-O-
group such as methoxy, ethoxy, n-propoxy, isopropoxy,
n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy
and the like; the term "cycloalkyloxy group" means a C3-6
cycloalkyl-O- group such as cyclopropyloxy,
cyclopentyloxy, cyclohexyloxy and the like; the term

"alkylthio group" means a straight or branched chain C1-6
alkyl-S- group such as methylthio, ethylthio, n-
propylthio, isopropylthio, n-butylthio, isobutylthio,
sec-butylthio, tert-butylthio, pentylthio and the like;
the term "alkylamino group" means an amino group
substituted with one or more straight or branched chain
C1-6 alkyl groups such as methylamino, ethylamino,
propylamine butylamino, pentylamino, hexylamino,
dimethylamino, diethylamino, methylethylamino,
dipropylamino, dibutylamino, dipentylamino and the
like; the term "cycloalkylamino group" means a C3-6
cycloalkyl-NH- group such as cyclopropylamino,
cyclopentylamino, cyclohexylamino and the like; the
term "halogenoalkyl group" means a halogen-substituted
C1-6 alkyl group such as trifluoromethyl, trichloro-
methyl, chloromethyl and the like; the term "aryl
group" means a phenyl group, a naphthyl group and the
like; the term "aryloxy group" means an aryl-O- group
such as phenyloxy, naphthyloxy and the like; the term
"arylthio group" means an aryl-S- group such as
phenylthio, naphthylthio and the like; the term
"arylamino group" means an aryl-NH- group such as
phenylamino, naphthylamino and the like; the term "acyl
group" means a C2-5 alkanoyl group such as formyl,
acetyl, propionyl, butyryl, isobutyryl, valeryl and the
like and an aroyl group such as benzoyl, naphthoyl and
the like; the term "alkoxycarbonyl group" means a
straight or branched chain C1-6 alkoxycarbonyl group such

as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
isopropoxycarbonyl, n-butoxycarbonyl, isobutoxy-
carbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl,
pentyloxycarbonyl and the like; the term
"alkylcarbamoyl group" means a carbamoyl group
substituted with one or more straight or branched chain
C1-6 alkyl groups such as methylcarbamoyl, dimethyl-
carbamoyl and the like; the term "carbamoylalkyl group"
means a straight or branched chain C1-6 alkyl group
substituted with a carbamoyl group such as carbamoyl-
methyl, carbamoylethyl, carbamoylisopropyl and the
like; the term "carboxyalkyl group" means a straight or
branched chain C1-6 alkyl group substituted with a
carboxyl group such as carboxymethyl, carboxylethyl,
carboxyisopropyl and the like; the term "heterocyclic
group" means a 4-, 5- or 6-membered ring or a fused
ring thereof having, as the hetero atoms constituting
said ring, at least one heteroatoms selected from the
group consisting of oxygen atom, nitrogen atom and
sulfur atom, such as oxetanyl, thietanyl, azetidinyl,
furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl,
imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl,
benzofuranyl, benzothiazolyl, pyridyl, quinolyl,
pyrimidinyl and morpholinyl; and the term "oxide group"
means an oxygen atom linked to a nitrogen atom in a
ring. The term "lower" means that the number of carbon
atoms is 1 to 6.
The protecting group for carboxyl group

includes any groups which can conventionally be used as
a protecting group for carboxyl group. The examples
thereof include alkyl groups such as methyl, ethyl, n-
propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-
butyl and the like; aryl groups such as phenyl,
naphthyl and the like; aralkyl groups such as benzyl,
diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl,
bis(p-methoxyphenyl)methyl and the like; acylalkyl
groups such as acetylmethyl, benzoylmethyl, p-
nitrobenzoylmethyl, p-bromobenzoylmethyl, p-
methanesulfonylbenzoylmethyl and the like; oxygen-
containing heterocyclic groups such as 2-
tetrahydropyranyl, 2-tetrahydrofuranyl and the like;
halogeno-alkyl groups such as 2,2,2-trichloroethyl and
the like; alkylsilylalkyl groups such as 2-
(trimethylsilyl)ethyl and the like; acyloxyalkyl groups
such as acetoxymethyl, propionyloxymethyl, pivaloyloxy-
methyl and the like; nitrogen-containing heterocyclic
alkyl groups such as phthalimidomethyl, succinimido-
methyl and the like; cycloalkyl groups such as
cyclohexyl and the like; alkoxyalkyl groups such as
methoxymethyl, ethoxymethyl, 2-(trimethylsilyl)ethoxy-
methyl and the like; aralkoxyalkyl groups such as
benzyloxymethyl and the like; alkylthioalkyl groups
such as methylthiomethyl, 2-methylthioethyl and the
like; arylthioalkyl groups such as phenylthiomethyl and
the like; alkenyl groups such as 1,1-dimethyl-2-
propenyl, 3-methyl-3-butenyl, allyl and the like;

substituted silyl groups such as trimethylsilyl,
triethylsilyl, triisopropylsilyl, diethylisopropyl-
silyl, tert-butyldimethylsilyl, tert-
butyldiphenylsilyl, diphenylmethylsilyl, tert-
butylmethoxyphenylsilyl and the like; etc.
In general formula [1], ring A represents a
pyrazine ring, a pyrimidine ring, a pyridazine ring or
a triazine ring. More specifically, ring A represents
any of the following structures:

In the structures above, the mark *1 expresses the
position of substitution with R1, and the mark *2
expresses the position of substitution with -C(=O)NHR2.
The carbamoylalkyl or carboxyalkyl group
represented by R2 may be substituted with at least one
substituent selected from the group consisting of
halogen atoms; alkyl groups unsubstituted or
substituted with hydroxyl, alkoxy, alkylthio, aryl,

amino or alkylamino groups; halogenoalkyl groups;
alkenyl groups; cycloalkyl groups; hydroxyl groups;
alkoxy groups; cycloalkyloxy groups; alkoxycarbonyl
groups; mercapto groups; alkylthio groups unsubstituted
or substituted with one or more aryl groups; aryl
groups; aryloxy groups; arylthio groups; arylamino
groups; cyano groups; nitro groups; amino groups
unsubstituted or substituted with one or more acyl
groups; alkylamino groups; cycloalkylamino groups; acyl
groups; hydrazino groups; carboxyl groups; carbamoyl
groups; thiocarbamoyl groups; alkylcarbamoyl groups and
heterocyclic groups.
Of ring A represented by general formula [1],
preferred are pyrazine ring, pyrimidine ring and
triazine ring, and more preferred is pyrazine ring.
The substituent on ring A includes groups selected from
the group consisting of halogen atoms; alkyl groups
unsubstituted or substituted with one or more hydroxyl,
alkoxy, alkylthio, aryl, amino or alkylamino groups;
halogenoalkyl groups; alkenyl groups; cycloalkyl
groups; hydroxyl groups; alkoxy groups; cycloalkyloxy
groups; alkoxycarbonyl groups; mercapto groups;
alkylthio groups unsubstituted or substituted with one
or more aryl groups; aryl groups; aryloxy groups;
arylthio groups; arylamino groups; cyano groups; nitro
groups; amino groups unsubstituted or substituted with
one or more acyl groups; alkylamino groups;
cycloalkylamino groups; acyl groups; hydrazino groups;

carboxyl groups; carbamoyl groups; thiocarbamoyl
groups, alkylcarbamoyl groups and heterocyclic groups.
Ring A can have one or more of the above-mentioned
substituents. Further, the substituent on ring A is
preferably linked to carbon atom of the ring.
The salt of the compound of general formula
[1] includes any usually known salts formed at the site
of basic groups such as amino group and salts formed at
the site of acidic group such as hydroxyl and carboxyl
groups. The salts formed at the site of basic group
include salts of mineral acids such as hydrochloric
acid, hydrobromic acid, sulfuric acid and the like;
salts of organic carboxylic acids such as tartaric
acid, formic acid, citric acid, trichloroacetic acid,
trifluoroacetic acid and the like, and salts of
sulfonic acids such as methanesulfonic acid,
benzenesulfonic acid, p-toluenesulfonic acid,
mesitylenesulfonic acid, naphthalenesulfonic acid and
the like. The salts formed at the site of acidic group
include salts of alkali metals such as sodium,
potassium and the like; salts of alkaline earth metals
such as calcium, magnesium and the like; ammonium
salts; and salts of nitrogen-containing organic bases
such as trimethylamine, triethylamine, tributylamine,
pyridine, N,N-dimethylaniline, N-methylpiperidine, N-
methylmorpholine, diethylamine, dicyclohexylamine,
procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-
ephenamine, N,N'-dibenzylethylenediamine and the like.

Among the salts mentioned above, preferred are
pharmacologically acceptable ones.
Typical compounds represented by general
formula [1] are shown in Tables 1 to 4.
In the tables shown below, the abbreviations
have the following meanings:
Me: methyl
Et: ethyl
iPr: isopropyl
tBu: tert-butyl,
Ph: phenyl
Ac: acetyl
Bz: benzoyl
R2a: -CH(COOH)CH2COOH
R2b: -CH(CH3)CONHCH(CH3)COOH

The nitrogen-containing heterocyclic
carboxamide derivatives represented by general formula
[1] or salts thereof are commercially available or can
be produced according to any of known processes or
analogous processes or by a combination thereof. As
the papers describing the production processes thereof,
J. Am. Chem. Soc, 71, 78 (1949); J. Am. Chem. Soc,
78, 242-244 (1956); J. Heterocycl. Chem., 15(4), 665-
670 (1978); J. Chem. Soc., 1379 (1955); U.S. Patent No.
5,597,823; etc. can be referred to.
More specifically, the nitrogen-containing
heterocyclic carboxamide derivatives represented by
general formula [1] or salts thereof can be produced
according to the following Production Processes 1 to 3.

Production Process 1

wherein R1, R2, ring A and broken line are as defined
above, and R3 represents a protecting group for carboxyl
group.
(1-a) A compound of general formula [1] can be
obtained by reacting a compound of general formula [2]
with a compound of general formula [4].
The solvent which can be used in this
reaction is not particularly limited, so far as it
causes no adverse effect on the reaction. The examples
of the solvent include alcohols such as methanol,
ethanol, isopropyl alcohol and the like; halogenated
hydrocarbons such as dichloromethane, chloroform,
dichloroethane and the like; aromatic hydrocarbons such
as benzene, toluene, xylene and the like; ethers such
as dioxane, tetrahydrofuran, anisole, diethylene glycol
diethyl ether, dimethyl cellosolve and the like;

nitriles such as acetonitrile and the like; amides such
as N,N-dimethylformamide, N,N-dimethylacetamide and the
like; and sulfoxides such as dimethyl sulfoxide and the
like. These solvents can be used in admixture.
The compound of general formula [4] is used
at least in an equimolar amount to the compound of
general formula [2], and preferably in an amount of
1.0-5.0 mole per mole of the compound of general
formula [2] .
This reaction can be carried out usually at
0-100°C and preferably at 20-80°C, for a period of 5-24
hours and preferably for 30 minutes to 10 hours.
(1-b) A compound of general formula [1] can be
obtained by subjecting a compound of general formula
[3] and a compound of general formula [4] to a
dehydrating condensation reaction.
The solvent which can be used in this
reaction is not particularly limited, so far as it
causes no adverse effect on the reaction. The examples
of the solvent include ethers such as dioxane,
tetrahydrofuran, anisole, diethylene glycol diethyl
ether, dimethyl cellosolve and the like; halogenated
hydrocarbons such as dichloromethane, chloroform,
dichloroethane and the like; and amides such as N,N-
dimethylformamide, N,N-dimethylacetamide and the like.
These solvents can be used in admixture.
The compound of general formula [4] can be

used at least in an equimolar amount to the compound of
general formula [3] and preferably in an amount of 1.0-
2.0 mole per mole of the compound of general formula
[3].
The dehydrating condensing agent which can be
used in this reaction includes, for example, 1,3-
dicyclohexyl carbodiimide, N,N'-carbonyl diimidazole,
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide and the
like.
The dehydrating condensing agent can be used
at least in an equimolar amount to the compound of
general formula [3] and preferably in an amount of 1.0-
2.0 mole per mole of the compound of general formula
[3].
This reaction can be carried out usually at
0-100°C and preferably at 20-60°C, for a period of 5
minutes to 24 hours and preferably for 30 minutes to 10
hours.
Production Process 2

wherein R1, R2, ring A and broken line are as defined
above, and R4 represents a lower alkyl group.
A compound of general formula [1] can be
obtained by subjecting a compound of general formula
[5] to alkyl-ether scission.
More specifically, in a case where R4 is a
methyl group, the reaction can be carried out according
to the description of PROTECTIVE GROUPS IN ORGANIC
SYNTHESIS, Second edition, JOHN WILEY & SONS, pp. 145-
199 (1991) or by an analogous method.
Production Process 3

wherein R1, ring A and broken line are as defined above,
and R2a represents an acyl group.
A compound of general formula [1c] can be
obtained by subjecting a compound of general formula
[1b] to acylation in the presence of an acid-
eliminating agent.
The solvent which can be used in this
reaction is not particularly limited, so far as it
causes no adverse effect on the reaction. The examples
of the solvent include ethers such as dioxane,

tetrahydrofuran, anisole, diethylene glycol diethyl
ether, dimethyl cellosolve and the like; aromatic
hydrocarbons such as benzene, toluene, xylene and the
like; halogenated hydrocarbons such as dichloromethane,
chloroform, dichloroethane and the like; amides such as
N,N-dimethylformamide, N,N-dimethylacetamide and the
like; water; etc. These solvents can be used in
admixture.
The acylating agent can be used at least in
an equimolar amount to the compound of general formula
[1b] and preferably in an amount of 1.0-2.0 mole per
mole of the compound of general formula [1b].
The acid-eliminating agent used in this
reaction includes, for example, pyridine, triethyl-
amine, sodium hydrogen carbonate and the like.
The acid-eliminating agent can be used at
least in an equimolar amount to the compound of general
formula [1b] and preferably in an amount of 1.0-2.0
mole per mole of the compound of general formula [1b].
This reaction can be carried out usually at
0-100°C and preferably at 20-60°C, for a period of 5
minutes to 24 hours and preferably for 30 minutes to 10
hours.
In the Production Processes 1-3, the
compounds of general formula [2], [3], [4], [5] and
[1b] can be replaced with their salt, respectively. As
the salts, the same ones as mentioned for the compound
of general formula [1] can be used.

Some of the compounds of general formulas
[2], [3], [4], [5] and [1b] and salts thereof may have
various isomers such as optical isomers and position
isomers, and solvated products. In such cases, any of
these isomers and solvates may be used in the present
invention.
The compound of general formula [1c] thus
obtained can be converted to salts thereof. The salts
include the same ones as mentioned for the compound of
general formula [1].
The objective viruses of the antiviral agent
comprising the nitrogen-containing heterocyclic
carboxamide derivative represented by general formula
[1] or salt thereof according to the present invention
include A-, B- and C-type influenza viruses, papilloma
virus, adenovirus, A type hepatitis virus, B type
hepatitis virus, C type hepatitis virus, poliovirus,
echovirus, Coxsackie virus, enterovirus, rhinovirus,
rotavirus, Newcastle disease virus, mumps virus,
vesicular stomatitis virus, and Japanese encephalitis
virus. The antiviral agent of the present invention
exhibits an especially high effect against influenza
viruses.,
By combining the nitrogen-containing
heterocyclic carboxamide derivatives of the present
invention represented by general formula [1] or salts
thereof with conventional known excipients, adjuvants
and additives, pharmaceutical preparations such as

solutions, suspensions, powders, granules, fine
granules, tablets, capsules, syrups, elixirs, spirits,
troches, gargles, aerosols, etc. can be obtained.
These pharmaceutical preparations can be administered
either orally or non-orally, namely by injection,
percutaneous administration, intrarectal administra-
tion, intranarial administration, etc.
The method of administration, dosage and
frequency of administration of the antiviral agent of
the present invention can be properly selected
depending upon the age, body weight and symptom of the
patient. Usually 1 to 10 mg/kg of the nitrogen-
containing heterocyclic carboxamide derivative or a
salt thereof can be administered to an adult either at
once or in several portions.
Next, antiviral activity and cytotoxicity of
the nitrogen-containing heterocyclic carboxamide
derivatives of the present invention represented by
general formula [1] or salts thereof will be explained.
Sample: A nitrogen-containing heterocyclic
carboxamide derivative represented by general formula
[1] or a salt thereof was dissolved in dimethyl
sulfoxide to prepare a solution having a concentration
of 10 mg/mL. At the time of use, the solution was
diluted with a culture medium to a predetermined
concentration and then put to use.
As the host cell of influenza virus, MDCK
cell (canine kidney cell) was used. For the

cytotoxicity test, Vero cell (monkey kidney cell) was
used.
Culture medium: In the multiplication of
MDCK cell and Vero cell and in the cytotoxicity test
using Vero cell, E'-MEM (product of Nissui) to which
10% fetal bovine serum had been added was used.
In the measurement of antiviral activity, E'-
MEM (product of Nissui) to which 1% bovine serum
albumin had been added was used.
Test Example 1 (Anti-influenza activity)
MDCK cells were seeded to a 6-well plate
(product of CORNING) at 5 x 105 cells/well, and cultured
overnight at 35°C in 5% CO2-air atmosphere. Then, the
cultured MDCK cells on the plate was treated with
influenza virus A/PR/8/34 strain diluted with a serum-
free culture medium at the concentration of 200 PFU/mL,
at 0.5 mL/well for one hour to achieve inoculation and
adsorption. After completion of the inoculation and
adsorption, an E'-MEM culture medium containing 0.6%
Agar Noble, 1% bovine serum albumin and 3 μg/mL
acetyltrypsin and also containing a test compound at a
prescribed concentration was added to the cells. After
sufficient coagulation, the plate was turned upside
down, and cultured for 3 days. After completion of the
culture, the alive cells were dyed with 1% Neutral Red.
Then, the cells were fixed with 10% formalin. The agar
medium was removed therefrom with running water.

25
Thereafter, the number of plaques was counted. The
plaque inhibition rate was expressed in percentage
calculated in comparison with control containing no
test compound.
The results are shown in Table 5, wherein the
test compound number are the same as those in Tables 1
to 4.

Test Example 2 (Cytotoxic activity)
A culture medium containing a predetermined
concentration of test compound was added to a 96-well

plate (product of CORNING) in 100 μl/well. Then, Vero
cells were adjusted to the concentration of 2 x 104
cells/mL with culture medium. The solution was added
to the plate at 100 μL/well, and cultured at 37°C in 5%
CO2-air atmosphere for 4 days. When the culture was
completed, the number of alive cells was counted
according to the XTT method [for example, see CANCER
RESEARCH, Vol. 48, Pages 4827-4833 (1988)].
As a result, the 50% cell growth inhibitory
concentration (IC50) of 3-hydroxy-2-pyrazinecarboxamide
(compound No. 1) was 250 μg/mL or more.
BEST MODE FOR CARRYING OUT THE INVENTION
Next, the compound of the present invention
is explained with reference to Referential Examples and
Examples. The invention is by no means limited by
these examples.
In the eluent, the mixing ratios are all by
volume.
The carrier used in column chromatography was
Silica Gel BW-127ZH (product of Fuji Silicia Chemical
Co.), and the carrier used in the reverse phase column
chromatography was LC-SORB SP-B-ODS (product of Chemco
Co. ) .
The symbol mark used in the Referential
Examples and Examples has the following meaning:
DMSO-d6 : Deuterated dimethyl sulfoxide

Referential Example 1
In 6 mL of dichloromethane is suspended 0.30
g of methyl 3-hydroxy-2-pyrazinecaroxylate obtained
according to the method described in literature [J.
Heterocycl. Chem., 34, 27 (1997)]. To the suspension
are successively added 0.54 mL of triethylamine and
0.29 g of glycine methyl ester hydrochloride. The
resulting mixture is stirred at ambient temperature for
5 hours. After cooling, the solvent is distilled off
under reduced pressure. The residue is purified by
reverse phase column chromatography (eluent: water) to
obtain 0.16 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)-
carbonyl]amino}acetate.
IR(KBr) cm-1: 1750, 1735, 1685
NMR(DMSO-d6) δ value: 3.67(3H,s), 4.12(2H,d,J=6Hz),
7.70-8.30(2H,m), 9.60-10.10(1H,m), 13.10(1H,brs)
Referential Example 2
In 100 ml of concentrated sulfuric acid is
dissolved 17.00 g of methyl 6-bromo-3-amino-2-
pyrazinecarboxylate obtained according to the method
described in literature [J. Am. Chem. Soc, 2798-2800
(1949)]. At an ice-cooled temperature, 10.11 g of
sodium nitrite is added to the suspension, which is
stirred for 30 minutes. The reaction mixture is poured
into 920 mL of methanol, and heated under reflux for 5
hours. The reaction mixture is cooled and then
concentrated under reduced pressure. The residue thus

obtained is added to a mixture of 500 mL of ice water
and 600 mL of chloroform and separated into layers.
The organic layer is washed successively with saturated
aqueous solution of sodium hydrogen carbonate, water
and saturated aqueous solution of sodium chloride and
dried over anhydrous magnesium sulfate. Then, the
solvent is distilled off under reduced pressure to
obtain 6.30 g of methyl 6-bromo-3-methoxy-2-
pyrazinecarboxylate.
IR(KBr) cm-1: 1734
NMR(CDCl3) δ value: 3.97(3H,s), 4.06(3H,s), 8.37(lH,s)
Referential Example 3
In a nitrogen atmosphere, 11.38 g of methyl
6-bromo-3-methoxy-2-pyrazinecarboxylate is dissolved in
227 rnL of toluene. To the solution are successively
added 10.32 g of benzophenone-imine, 0.42 g of
tris(dibenzylideneacetone) dipalladium, 0.86 g of (s)-
(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and
6.20 g of sodium t-butoxide. The resulting mixture is
stirred at 80°C for one hour. The reaction mixture is
cooled and filtered. The filtrate is purified by
column chromatography (eluent: toluene:ethyl acetate =
20:1). The oily product thus obtained is dissolved in
140 mL of tetrahydrofuran, 7 mL of 2 mol/mL
hydrochloric acid is added thereto and the resulting
solution is stirred at ambient temperature for 15
minutes. The resulting reaction mixture is added to a

mixture of 200 mL of chloroform and 50 mL of water, and
alkalified with 1 mol/mL of sodium hydroxide, and the
organic layer is separated. The organic layer is
washed with saturated aqueous solution of sodium
chloride, dried over anhydrous magnesium sulfate, and
the solvent is distilled off under reduced pressure.
The residue thus obtained is purified by column
chromatography (eluent: toluene:ethyl acetate =1:1) to
obtain 3.64 g of methyl 6-amino-3-methoxy-2-
pyrazinecarboxylate.
IR(KBr) cm-1: 1716,1670
NMR(DMSO-d6) δ value: 3.80(3H,s), 3.82(3H,s),
7.20(2H,brs), 7.77(lH,s)
Referential Example 4
In 70 mL of methanol is dissolved 3.50 g of
methyl 6-amino-3-methoxy-2-pyrazinecarboxylate.
Gaseous ammonia is introduced to saturate the solution
with ammonia. The solution is stirred at ambient
temperature for 14 hours. The solvent is distilled off
from the reaction mixture under reduced pressure to
obtain 3.1 g of 6-amino-3-methoxy-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1684
NMR(DMSO-d6) : 3.79(3H,s), 5 . 87 (2H,brs) , 7 . 30-7 . 75 (3H,m)
Referential Example 5
In a nitrogen atmosphere, 1.50 g of 6-amino-

3-methoxy-2-pyrazinecarboxamide is dissolved in 12 rnL
of 70% pyridine hydrofluoride under ice-cooling. Then,
0.71 g of sodium nitrite is added thereto at -50°C, and
the resulting solution is stirred at 10°C for 1 hour.
The resulting reaction mixture is stirred at ambient
temperature for an additional 1 hour. Thereafter, a
mixture of 50 mL of ice water and 100 mL of chloroform
is added thereto and the resulting mixture is separated
into layers. The organic layer is washed with
saturated aqueous solution of sodium chloride and
saturated aqueous solution of sodium hydrogen
carbonate, and dried over anhydrous magnesium sulfate.
Then, the solvent is distilled off under reduced
pressure to obtain 1.29 g of 6-fluoro-3-methoxy-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1706
NMR(DMSO-d6) : 3.95(3H,s), 7 . 55-8 .15 (2H,m) ,
8.39(1H,d,J=8.3Hz)
Referential Example 6
In 100 mL of methanol is suspended 1.96 g of
methyl 5-amino-3-methoxy-2-pyrazinecarboxylate obtained
according to the method described in literature (JP-A-
50-105675). The resulting suspension is saturated with
ammonia by introducing gaseous ammonia thereinto at
-20°C. Then, the solution thus obtained is allowed to
react at 95°C for 24 hours in a stainless steel-made
closed vessel. After cooling, the solvent is distilled

off under reduced pressure to obtain 1.57 g of 5-amino-
3-methoxy-2-pyrazinecarboxamide.
IR(KBr) cm-1: 1654, 1637
NMR(DMSO-d6) δ value: 3.82(3H,s), 7 . 00 (3H, brs) ,
7.30(1H,brs), 7.43(1H,s)
Referential Example 7
In a nitrogen atmosphere, 0.5 g of 5-amino-3-
methoxy-2-pyrazinecarboxamide is dissolved in 9 mL of
70% pyridine hydrofluoride under ice-cooling. Then,
0.23 g of sodium nitrite is added thereto at -70°C, and
the resulting solution is heated to a temperature of
-10°C in 30 minutes. Further, the solution is stirred
at ambient temperature for 30 minutes. A mixture of 30
mL of ice water and 100 mL of chloroform is added
thereto and the resulting mixture is separated into
layers. The organic layer is washed with saturated
aqueous solution of sodium chloride and dried over
anhydrous magnesium sulfate. The solvent is distilled
off under reduced pressure. The residue thus obtained
is purified by column chromatography (eluent:
chloroform:methanol = 10:1) to obtain 0.37 g of 5-
fluoro-3-methoxy-2-pyrazinecarboxamide.
IR(KBr) cm-1: 1705
NMR(DMSO-d6) δ value: 3.94(3H,s), 7.65(1H,brs),
7.85 (1H,brs), 8.12(1H,d,J=8.3Hz)

Example 1
In 3 mL of methanol is suspended 0.6 g of
methyl 6-bromo-3-hydroxy-2-pyrazinecarboxylate obtained
according to the method described in literature [J.
Med. Chem., 1969, 12(2), 285-287]. Then, 6 mL of 25%
aqueous ammonia is added thereto and the resulting
solution is stirred at ambient temperature for 17
hours. The reaction mixture is adjusted to pH 3 by
adding 6 mol/L hydrochloric acid. The solvent is
distilled off under reduced pressure. Isopropyl ether
and water are added to the residue and filtered to
obtain 0.33 g of 6-bromo-3-hydroxy-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1700, 1665
NMR(DMSO-d6) δ value: 7.50 (2H, brs) , 8.08(lH,s),
9.95(1H,brs)
Example 2
In 10 mL of dimethylformamide is suspended
0.5 g of 3,5-dihydroxy-1,2,4-triazine-6-carboxylic acid
obtained according to the method described in
literature (JP-A-54-79292). Then, 2.06 g of N,N'-
carbonyldiimidazole is added thereto, and the resulting
solution in stirred at ambient temperature for 6 hours.
The reaction mixture is cooled with ice, saturated with
gaseous ammonia, and then stirred for 15 minutes at the
same temperature as above. The deposited crystals are
collected by filtration to obtain 0.37 g of 3,5-dioxo-

2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.
IR(KBr) cm-1: 1732, 1710, 1685, 1656
NMR(DMSO-d6) δ value: 7.75(1H,s), 7.97(1H,s), 12.20-
12.80(2H,m)
Example 3
In 5 mL of acetic anhydride is suspended 0.5
g of 3-hydroxy-2-pyrazinecarboxamide. The resulting
solution is stirred at 110°C for 1 hour. The deposited
crystals are collected by filtration to obtain 0.5 g of
N2-acetyl-3-hydroxy-2-pyrazinecarboxamide.
IR(KBr) cm-1: 1725, 1695, 1655
NMR(DMSO-d6) δ value: 2.25(3H,s), 7 . 53 (1H, d, J=4Hz) ,
7.69(1H,d,J=4Hz), 11.70(1H,brs)
Example 4
In 5 mL of 25% aqueous ammonia is suspended
0.25 g of methyl 6-chloro-3-hydroxy-2-
pyrazinecarboxylate obtained according to the method
described in literature [J. Med. Chem., 285-287
(1969)]. The suspension is stirred at ambient
temperature for 1 hour. The deposited crystals are
collected by filtration to obtain 0.18 g of 6-chloro-3-
hydroxy-2-pyrazinecarboxamide.
IR(KBr) cm-1: 1652
NMR(DMSO-d6) : 7 . 22 (2H, brs) , 7.91(1H,s), 10 . 40 (1H, brs)

Example 5
In 50 mL of tetrahydrofuran is suspended
1.00g of 3-hydroxy-2-pyrazinecarboxamide. Then, 3.5 mL
of triethylamine and 1.67 mL of benzoyl chloride are
successively added thereto. The resulting solution is
stirred at 60°C for 5 hours and cooled. The deposited
crystals are collected by filtration. The crystals
thus obtained are suspended in a mixture of 8 mL of
water and 1 mL of 1 mol/mL hydrochloric acid, stirred
at ambient temperature for 30 minutes, and collected by
filtration to obtain 0.41 g of N2-benzoyl-3-hydroxy-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1735
NMR(DMSO-d6) δ value: 7.20-8.40(7H,m), 12.60(1H,brs)
According to the same method as above, N2-
(2,2-dimethylpropanoyl)-3-hydroxy-2-pyrazinecarboxamide
is obtained.
IR(KBr) cm-1: 1725
NMR(DMSO-d6) δ value: 1.21(9H,s), 7.49 (1H, d, J=2Hz),
7.95(lH,d,J=2Hz), 14.80(1H,brs)
Example 6
In 0.5 mL of 47% aqueous solution of hydrogen
bromide is dissolved 0.05 g of 3-methoxy-2-
pyrazinecarboxamide-4-oxide obtained according to the
method described in literature [Eur. J. Med. Chem.,
15(2), 157-163 (1980)]. The solution is stirred at 45°C

for 2 hours. The deposited crystals are collected by
filtration and washed successively with ethanol and
diethyl ether to obtain 0.03 g of 3-hydroxy-2-
pyrazinecarboxamide-4-oxide.
IR(KBr) cm-1: 1695
NMR(DMSO-d6) δ value: 7.19 (1H,d, J=6Hz),
7.56(lH,d,J=6Hz), 7.70(lH,brs), 7.95(1H,brs),
10.75(1H,brs)
Example 7
In 4 mL of methanol is suspended 0.19 g of
methyl 2-{[(3-hydroxy-2-pyrazinyl)carbonyl]-
amino}acetate. The suspension is saturated with
ammonia by introducing gaseous ammonia thereinto under
ice-cooling for 30 minutes. The resulting mixture is
stirred at the same temperature as above for 1 hour and
then at ambient temperature for 15 hours. The solvent
is distilled off under reduced pressure. The residue
thus obtained is dissolved in a mixture of 4 mL of
water and 1 mL of methanol. To the resulting solution
is added 0.9 mL of 1 mol/L hydrochloric acid. The
deposited crystals are collected by filtration to
obtain 0.16 g of N2-(2-amino-2-oxoethyl)-3-hydroxy-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1675
NMR(DMSO-d6) δ value: 3.90(1H,d,J=5Hz), 7.10(1H,brs),
7.40(lH,brs), 7.60-8.40(2H,m), 9.50(1H,brs),
13.0(1H,brs)

Example 8
In a nitrogen atmosphere, 1.51 g of sodium
iodide is dissolved in 22 mL of acetonitrile. Then,
1.10 g of trimethylsilyl chloride is added thereto.
The resulting solution is stirred at ambient
temperature for 20 minutes. Then, 0.43 g of 6-fluoro-
3-methoxy-2-pyrazinecarboxamide is added thereto. The
resulting solution is stirred at the same temperature
as above for 18 hours. Then, a mixture of 10 mL of
water and 200 mL of chloroform is added to the reaction
mixture, and separated into layers. The organic layer
thus obtained is washed successively with 5% aqueous
solution of sodium thiosulfate and saturated aqueous
solution of sodium chloride, and dried over anhydrous
magnesium sulfate. The solvent is distilled off under
reduced pressure. The residue thus obtained is
purified by column chromatography (eluent: hexane:ethyl
acetate =2:1) to obtain 0.06 g of 6-fluoro-3-hydroxy-
2-pyrazinecarboxamide.
IR(KBr) cm-1: 1685, 1670, 1656
NMR(CDCl3): 5.40-7.80 (2H,m), 8.31 (1H, d, J=7.82Hz),
12.33(1H,s)
Example 9
In 24 mL of concentrated sulfuric acid is
suspended 4.00 g of 3-hydroxy-2-pyrazinecarboxamide.
To the suspension is added 3.09 g of potassium nitrate
under ice-cooling. The resulting mixture is stirred at

40°C for 3 hours. The reaction mixture is poured into
240 mL of water, and the deposited crystals are
collected by filtration. The crystals thus obtained
are suspended in 80 mL of water and heated under reflux
for 30 minutes. After cooling, the crystals are
collected by filtration to obtain 2.45 g of 3-hydroxy-
6-nitro-2-pyrazinecarboxamide.
IR(KBr) cm-1: 1705, 1685, 1655
NMR(DMSO-d6) δ value: 8.10 (lH,brs), 8.30 (1H,brs),
8.96(1H,s)
Example 10
In 2.1 mL of water is suspended 0.5 g of 2-
aminomalonamide. Under ice-cooling, 0.43 g of ethyl
glyoxalate is added to the suspension, which is then
stirred for 40 minutes. Then, 0.85 mL of 5 mol/mL
sodium hydroxide is added to the resulting suspension,
which is then stirred at the same temperature as above
for 40 minutes. The reaction mixture is adjusted to pH
12 by adding 1 mol/L sodium hydroxide, and once made
into a solution. The solution is then adjusted to pH 2
by adding 6 mol/mL hydrochloric acid. The deposited
crystals are collected by filtration and washed
successively with water and 50% (w/w) ethanol to obtain
0.15 g of 3,5-dihydroxy-2-pyrazinecarboxamide.
IR(KBr) cm-1: 1660
NMR(D2O) δ value: 6.97(1H,s)

Example 11
In 2.0 mL of water are suspended 0.65 mL of
diethyl-2-oxomalonate and 0.5 g of 2-aminomalonamide.
Under ice-cooling, 0.85 mL of 5 mol/mL sodium hydroxide
is added thereto. The resulting solution is stirred
for 40 minutes. Then, at ambient temperature, 2.55 mL
of 5 mol/mL sodium hydroxide is added to the solution,
which is then stirred for an additional 30 minutes.
Ethanol is added to the reaction mixture and the
precipitate is collected by filtration to obtain 0.24 g
of 3,5-dihydroxy-6-ethoxycarbonyl-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1655, 1735
NMR(D2O) δ value: 1.17(3H,t,J=7Hz), 4.15(2H,q,J=7Hz)
Example 12
In a mixture of 1.0 mL of water and 1.0 mL of
ethanol is suspended 0.13 g of 3,5-dihydroxy-6-
ethoxycarbonyl-2-pyrazinecarboxamide. At ambient
temperature, 0.34 mL of 5 mol/mL sodium hydroxide is
added to the suspension, which is then stirred for 16
hours. The reaction mixture is adjusted to pH 2 by
adding 1 mol/mL hydrochloric acid. The deposited
crystals are collected by filtration and washed with
water to obtain 0.07 g of 3,5-dihydroxy-6-carboxy-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1650

Example 13
In a nitrogen atmosphere, 0.09 g of 5-fluoro-
3-methoxy-2-pyrazinecarboxamide is suspended in 3.6 mL
of acetonitrile. Then, 0.16 g of sodium iodide and
0.11 g of chlorotrimethylsilane are successively added
to the suspension, which is then stirred at ambient
temperature for 20 hours. Then, 2 mL of water and 40
mL of chloroform are added to the reaction mixture and
separated into layers. The organic layer is separated,
washed successively with 5% (w/v) aqueous solution of
magnesium thiosulfate and saturated aqueous solution of
sodium chloride and dried over anhydrous magnesium
sulfate. Then, the solvent is distilled off under
reduced pressure. The residue thus obtained is
purified by column chromatography (eluent: chloroform)
to obtain 0.01 g of 5-fluoro-3-hydroxy-2-
pyrazinecarboxamide.
IR(KBr) cm-1: 1670
NMR(CDCl3) δ value: 5.80(1H,s), 7.45(1H,brs),
7.93(1H,d,J=7.8Hz), 12.93(1H,s)
Example 14
In 5 mL of ethanol is dissolved 0.1 g of
ethyl 5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine-
6-carboxylate obtained according to the method
described in literature (J. Am. Chem. Soc, 1956, 78,
1258-1259). At ambient temperature, gaseous ammonia is
introduced into the solution for 30 minutes to saturate

the solution with ammonia. After allowing the solution
to stand at the same temperature as above for 15 hours,
the resulting crystals are collected by filtration.
The crystals thus collected are washed with three 5 mL
portions of ethanol to obtain 0.05 g of 5-oxo-3-thioxo-
2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxamide.
IR(KBr) cm-1: 1654
NMR(DMSO-d6) δ value: 3.30(4H,brs)
Example 15
According to the method described in
literature (International Patent Application: WO
98130549), 6-oxo-1,6-dihydro-5-pyrimidinecarboxamide is
obtained.
Example 16
According to the method described in
literature (Chemische Berichte, 1964, 97, 3349-3353),
3-OXO-2,3-dihydro-4-pyridazinecarboxamide is obtained.
Example 17
In 5 mL of ethanol is dissolved 0.06 g of
ethyl 5-OXO-4,5-dihydro-1,2,4-triazine-6-carboxylate.
At 10°C, the solution is saturated with ammonia by
introducing gaseous ammonia thereinto for 20 minutes.
The solution is allowed to stand at ambient temperature
for 15 hours, and the resulting crystals are collected
by filtration. The crystals thus obtained are washed

successively with two 2 mL portions of ethanol and then
two 1 mL portion of methanol to obtain 0.03 g of 5-oxo-
4,5-dihydro-1,2,4-triazine-6-carboxamide.
IR(KBr) cm-1: 1654
NMR(DMSO-d6) δ value: 3.60(1H,brs), 7.44(1H,brs),
8.39(1H,s), 9.74(1H,brs)
Example 18
In 4 mL of dimethyl sulfoxide is dissolved
0.4 g of methyl 3-hydroxy-2-pyrazinecarboxlate. Then,
0.27 g of L-aspartic acid and 0.85 mL of triethylamine
are successively added to the solution, which is then
stirred at 50°C for 6 hours. The deposited crystals are
filtered off, and the filtrate is concentrated under
reduced pressure. Then, 2 mL of water and 0.2 mL of
methanol are added to the resulting residue. The
precipitate formed is collected by filtration to obtain
0.09 g of (2S)-2-{[(3-oxo-3,4-dihydro-2-pyrazinyl)-
carbonyl]amino}-butanedioic acid.
IR(KBr) cm-1: 1695, 1680, 1665
NMR(DMSO-d6) δ value: 2.83(2H,d,J=5Hz), 4.50-5.00(1H,m),
7.60-8.05(2H,m), 9.95(lH,d,J=9Hz), 12.90(3H,brs)
Example 19
In 5 mL of dimethyl sulfoxide is dissolved
0.42 g of L-alanyl-L-alanine trifluoroacetate. Then,
1.07 mL of triethylamine and 0.71 g of methyl 3-
hydroxy-2-pyrazinecarboxylate are successively added to

the solution, which is then stirred at 40°C for 17
hours. The solvent is distilled off under reduced
pressure, and 2 mL of water was added to the residue
thus obtained. The deposited product is collected by
filtration and purified by column chromatography
[eluent: chloroform:methanol = 30:1) to obtain 0.035 g
of (2S)-2-[((2S)-2-{[(3-oxo-3,4-dihydro-2-
pyrazinyl)carbonyl]amino}-propanoyl)amino]propanoic
acid.
IR(KBr) cm-1: 1665, 1675, 1655
NMR(DMSO-d6) δ value: 1.28 (3H, d, J=7Hz),
1.32(3H,d,J=7Hz), 3.95-4.95(2H,m), 5.1(2H,brs),
7.71(1H,d,J=3Hz), 7.87(1H,d,J=3Hz), 8.32(1H,d,J=7Hz),
9.9(1H,brs)
INDUSTRIAL APPLICABILITY
An antiviral agent comprising the nitrogen-
containing heterocyclic carboxamide derivative
represented by general formula [1] or a salt thereof is
useful for preventing and treating virus-infections and
especially influenza virus-infections.

WE CLAIM:
i. An antiviral agent comprising a nitrogen-containing
heterocyclic carboxamide derivative represented by the following
general formula:

wherein ring A represents a pyrazine, pyrimidine, pyridazine or
triazine ring which may be substituted with one or more groups
selected from the group consisting of halogen atoms; alkyl groups
unsubstituted or substituted with one or more hydroxyl, alkoxy,
alkylthio, aryl, amino or alkylamino groups; halogenoalkyl
groups; alkenyl groups; cycloalkyl groups; hydroxyl groups;
alkoy groups; cycloalkyloxy groups; alkoxycarbonyl groups;
mercapto groups, alkylthio groups unsubstituted or substituted with
one or more aryl groups; aryl groups; aryloxy groups; aryithio
groups, arylamino groups; cyano groups; nitro groups; amino
groups; unsubstituted or substituted with one or more acyi groups;
alkylamino groups; cycloalkylamino groups; acyl groups; hydrazino
groups; cartoxyl groups; carbamoyl groups, thiocarbamoy1 groups,

alkylcarbamoyl groups and heterocyclic groupe such as herein
described; R1 represents O or OH; R2 represents a hydrogen atom,
an acyl group or a substituted or unsubstituted C1-6 alkyl
substituted with carbamoyl or carboxy groups} and the broken line
represents a single bond or a double bond; wherein the C1-6
alkyl group substituted with carbamoyl or carboxy groups of R2
tray be substituted with at least one substituent selected from
the group consisting of halogen atoms; alkyl groups unsubstituted
or substituted with hydroxy1, alkoxy, alkylthio, aryl, amino or
alkylamino groups; halogenoalkyl groupe, alkenyl groups;
cycloalkyl groups, hydroxyl groups; alkoxy groups} cycloalkyloxy
groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups
unsubstituted or substituted with one or more aryl groups; aryl
groups; aryloxy groups; arylthio groups; arylamino groups; cyano
groups; nitro groups; amino groups unsubstituted or substituted
with one or more acyl groups; alkylamino groups; cycloalkylamino
groups; acyl groups; hydrazino groups; carboxyl groups; carbamoyl
groups; thiocarbamoyl groups? alkylcarbamoyl groupe and
heterocyclic groups such as herein described; or a salt thereof;
wherein the salt represents salts of mineral acids? salts of
organic carboxylic acids; salts of sulfonic acids? salts of
alkali metals; salts of alkaline earth metals; ammonium salts;
and salts of nitrogen-containing organic bases.

2. An antiviral agent as claimed in claim 1, wherein said
ring A is s. pyrazine, pyrimidine or triazins ring which may be
substituted with one or more groups selected from the group
consisting of halogen atoms; alkyl groups unsubstituted or
subbstituted with one or more hydroxyl , alkoxy, alkylthio, aryl ,
amino or alkylamino groups; halogenoalkyl groups; alkenyl groups;
cycoalkyl groups; hydroxyl groups, alkoxy groups; cycloalkyloxy
groups; alkaxycarbonyl groups; mereapto groups, alkylthio groups
unsubstitutsd or substituted with one or more aryl groups; aryl
groups; aryloxy groups; aryithio groups; arylamino groups; cyano
groups; nitro groups; amino groups unsubstituted or substituted
with one or more acyl groups; alkyiamino groups; cycloaikylamino
groups acyl groups; hydrazine groups; carboxyl groups; carbamoyl
groups, thiocarbamoyl groups, alkylcarbamoyl groups and hetero-
cyclic groups.
3. An antiviral agent as claimed in claim 2, wherein said
rinc A is a pyrazine ring which may be substituted with one or
more groups selected from the group consisting of halogen atoms;
alkyl groups unsubstituted or substituted with one or more
hydrexyl, alkoxy, alkylthio, aryl, amino or alkylamino groups;
halcoanoalkyl groups; alkenyl groups; cycloakyl groups; hydroxyl

groups; alkoxy groups; cycloalkyloxy groups; alkoxycarbanyl
groups mercapto groups; alkylthio groups unsubstituted or
substituted with one or more aryl groups; aryl groups; aryloxy
groups; aryithio groups; arylamino groups; cyano groups? nitro
groups amino groups unsubstituted or substituted with one or
more acyl groups; alkylamino groups, cycloalkylamino groups; acyl
groups; hydrazino groups; carboxyl groups; carbamoyl groups;
thicrarbamoyl groups, alkylcarbamoyl groups and heterocyclic
groups.
4. An antiviral agent as claimed in any one of claims 1 to 3,
wherein tne virus is influenza virus, papilloma virus,
aderovirus. A type hepatitis virus, B type hepatitis virus, C
type hepav.itis virus, poliovirus, echovirus, Coxsasckie virus,
enterovirus, rhinovirus, rotavirus, Newcastle disease virus,
mumps virus, vesicular stomatitis virus or Japanese encephalitis
virus.
5. An antiviral agent as claimed in claim 4 wherein said
virus is irfluenza virus.
6. An nitrogen-containing heterocyclic carboxamide derivative
represented by the following general formula:

wherein ring A' represents a pyrazine ring substituted with a
1
halogen atom, a hydroxyl group or an oxido group; R represents O
or OH; R represents a hydrogen atom, an acyl group or a
substituted or unsubst ituted C alkyl group substituted with
carbamoyl or carboxy groups; and the broken line represents a
single bond or a double bond; wherein the C1-6 alkyl group
substituted with carbamoyl or carboxy groups of R2 may be
substituted with at least one substituent selected from the group
consisting of halogen atoms; alkyl groups unsubstituted or
substituted with hydroxyl, alkoxy, alkylthio, aryl, amino or
alkylamino groups; halogenoalkyl groups; alkenyl groups;
cycoalkyl groups; hydroxyl groups; alkoxy groups; cycloalkyloxy
groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups
unsubsbstituted or substituted with one or more aryl groups; aryl
groups; aryloxy groups; arylthio groups; arylamina groups; cyano
groups; nitro groups; amino groups unsubtituted or substituted with
one or more acyl groups; alkylamino groups; cycloalkylamino
groups; acyl groups; hydrazino groups; carboxyl groups;
carbmoyl groups; thiocarbamoyl groups; alkylcarbamoyl groups
and heterocyclic groups or a salt thereof; wherein the salt
reresents salts of mineral acids; salts of organic carboxylic

acids, salts of sulfonic acids; salts of alkali metal, salts of
alciline earth metals; ammonium salts; and salts of nitrogen-
containing organic bases.
7. A nitrogen—containing heterocyclic carboxamide derivative
as claimed in claim 6 wherein said ring A' is a pyrazine ring
substituted with a halogen atom; and R2 represents a hydrogen
atom.

An antiviral agent comprising a nitrogen-containing
heterocyclic carboxamide derivative represented by the following
general formula:

where in ring A represents a pyrazine, pyrimidine, pyridazine or
triazine ring which may be substituted with one or more groups
selected from the group consisting of halogen atoms; alkyl groups
unsubstituted or substituted with one or more hydroxyl, alkoxy,
alkylthio, aryl, amino or alkylamino groups; halogenoalkyl
groups, alkenyl groups; cycloalkyl groups; hydroxyl groups;alkoxy
groups; cycloalkyloxy groups; alkoxycarbonyl groups; mercapto
groups; alkylthio groups unsubstituted or substituted with one or
more aryl groups; aryl groups; aryloxy groups; arylthio groups;
arylamino groups; cyano groups; nitro groups; amino groups
unsubstituted or substituted with one or more acyl groups;
alkyl amino croups? eye loalkyl ammo groups; acyl groups; hydrazine
groups; carboxyl groups; carbamoyl groups; thiocarbamoy1 groups,
alkylcarbamoyl groups and heterocyclic groups; R1 represents O
or O-H R2 represents a hydrogen atom, an acyl group or a

substituted or unsubstituted C1-6 alkyl group substituted with
carbamoyl or carboxy groups; and the broken line represents a
single bend or a double bond; wherein the C1-6 alkyl group
substituted with carbamoyl or carboxy groups of R2 may be
Substituted with at least one substituent selected from the
group consisting of halogen atoms; alkyl groups unsubstituted or
substituted with hydroxyl, alkoxy, alkylthio, aryl, amino or
alkylamino groups, halogenoalkyl groups; alkenyl groups;
cycloalkyl groups, hydroxyl groups; alkoxy groups; cycloalkyloxy
groups; alkoxycarbonyl groups; mercapto groups; alkylthio groups
unsubstituted or substituted with one or more aryl groups; aryl
groups; aryloxy groups; aryithio groups; arylamino groups; cyano
groups; nxtro groups; amino groups unsubstituted or substituted
with one or more acyl groups; alkylamino groups; cycloalky1 amino
groups; acyl groups; hydrazine groups; carboxyl groups; carbamoyl
groups; triocarbamoyl groups; alkylcarbamoyl groups and hetero-
cyclic groups or a salt thereof; wherein the salt represents
salt of mineral acids ; salts of organic carboxylic acids; salts
of sulfonic acids; salts of alkali metals; salts of alkaline
earth metals; ammonium salts; and salts of nitrogen-containing
organic bases.

Documents:

IN-PCT-2001-144-KOL-FORM-27.pdf

in-pct-2001-144-kol-granted-abstract.pdf

in-pct-2001-144-kol-granted-claims.pdf

in-pct-2001-144-kol-granted-correspondence.pdf

in-pct-2001-144-kol-granted-description (complete).pdf

in-pct-2001-144-kol-granted-examination report.pdf

in-pct-2001-144-kol-granted-form 1.pdf

in-pct-2001-144-kol-granted-form 18.pdf

in-pct-2001-144-kol-granted-form 2.pdf

in-pct-2001-144-kol-granted-form 26.pdf

in-pct-2001-144-kol-granted-form 3.pdf

in-pct-2001-144-kol-granted-form 5.pdf

in-pct-2001-144-kol-granted-priority document.pdf

in-pct-2001-144-kol-granted-reply to examination report.pdf

in-pct-2001-144-kol-granted-specification.pdf

in-pct-2001-144-kol-granted-translated copy of priority document.pdf

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Patent Number

226506

Indian Patent Application Number

IN/PCT/2001/144/KOL

PG Journal Number

51/2008

Publication Date

19-Dec-2008

Grant Date

17-Dec-2008

Date of Filing

05-Feb-2001

Name of Patentee

TOYAMA CHEMICAL CO. LTD.

Applicant Address

2-5, 3-CHOME, NISHISHINJUKU, SHINJUKU-KU, TOKYO

Inventors:

#	Inventor's Name	Inventor's Address
1	FURUTA YOUSUKE	255-18, HONGOMACHI, TOYAMA-SHI
2	EGAWA HIROOYUKI	612, KANAYAMASHINHIGASHI, TOYAMA-SHI

PCT International Classification Number

A61K 31/495

PCT International Application Number

PCT/JP99/04429

PCT International Filing date

1999-08-18

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	11/145922	1999-05-26	Japan
2	10/250441	1998-08-20	Japan