Nitrogenous heterocyclic carboxamide derivatives or salts thereof and antiviral agents containing them

Description

(57) Extract The subject of the invention is the ,NHR2 o nitrogen-containing heterocyclic carboxamide derivatives of the general formula — wherein the A-ring is a substituted or unsubstituted pyrazine-pyrimidine-, pyridazine- or triazine-ring; R1 is oxygen or hydroxy; R2 is a hydrogen atom, an acyl group or a substituted or unsubstituted carbamoylalkyl or carboxyalkyl group; and the dotted line represents a single bond or a double bond — or salts thereof, and pharmaceutical compositions containing these compounds useful for the prevention and treatment of viral infections, especially influenza virus infection. * *φ * X Φ Λ Φ Φ φ φ * .* φφ φφ φφ ψ **ΦΧ Φ X Φ φ· φ χ. φί φ Φ ♦ ♦ φφ Φφφ φφ *X Χφφφ S,S.6>&K. éssbídéms ÖgWrök fcmh H-iÖ&t B»á&pe<-W^ em möíPm AOdÖbf brr *módb 7L995 / BE / ŰM is an opportunity for hetetoic Xusos kurhomsides with trogen content. aa ^Λ<~Αι>Φ:Κ 4·>·λ,..· .·><_ -...-Λ Φ··φ.^.> ÍU.'.vil ^· v>» ·.. \%χ... v.vss.ss<'ss^· · «.·Αχν»'φ· 'νν V· t Φ <· <55 W_--J»_ --W_. new and e»&«t fea^taXssató vÍxus^XXe,u>s ' 5 BASIC ft VERSION X Λ Jt .κ.'ν<· Λ kj· The invention relates to the use of nitrogen-containing heterocyclic carboxyamine compounds or their salts, and to antiviral agents and novel compounds containing the compounds. Nowadays, antiviral agents are selected and used in accordance with the viruses they infect. For example, acyclovir and valsartan are used against herpes viruses, gancivir and foscarnet are used against cytomegalovirus, and interferon is used against hepatitis viruses. The influenza virus is the central virus of the common cold syndrome, which has periodically attacked the world and caused tens of millions of deaths. Although the number of deaths has shown a decreasing trend in recent years due to improvements in hygiene and nutrition, the frequency of influenza recurs every year, and it is possible that a new virus may appear and cause a wider spread. Vaccines are widely used to prevent influenza virus infection, and in addition, small molecule drugs such as amantadine and ribavirin are also used. Amantadine is used to prevent and treat influenza. Its mechanism of action is said to be to inhibit the fusion between influenza virus and the cell membrane, and it is effective against influenza A virus. However, it has the problems of being ineffective against influenza B virus, « , Av-b It is known that resistant viruses appear in the body and cause side effects such as neurological disorders. Although rimantadine, a derivative of aramafiain, has better antiviral activity, this does not offset the problem of side effects. Ribavirin, a guanosine derivative, is effective against viral RNA polymerase and is effective against influenza A and B viruses. However, its internal use does not produce sufficient clinical effect. The invention provides an antiviral agent that exhibits preventive and therapeutic effects against various viruses, especially influenza viruses, The inventors have conducted research and studies on compounds that have shown antiviral activity against various viruses, especially influenza viruses. As a result, it has been found that pyrazine carboxamide derivatives have anti-influenza virus activity. The inventors have conducted further studies to determine that nitrogen-containing heterocyclic carboxamide derivatives of the general formula ....... in which The ring is a pyrazine, pyrimidine™, pyridazine or triazine ring optionally substituted with at least one group, wherein the ring is substituted with at least one group selected from the group consisting of the following substituents; halogen atom; alkyl group which is unsubstituted or substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylsatinoisophorphthal; haloalkylisophor; alkenyl-; ?; a;sms.k>kS;svuesf cycloalkyl··; hl droxy. 1 -; alkoxy-; olcloei közi. -; alkoxycarbonyl~; mercaptc group; unsubstituted or one or more arylgrouptsl substituted alkylthio group; aryl group; aryloxy group; arylthio group; arylaxnino group; cyano group; nitro group; unsubstituted or one or more acylsoprt substituted ardncscport; alkylamino-? cycloal kll -amino-; acyl·; hydrezino-; carboxyl-; carbamyl-; thiocarbamyl-; alkylcarbameyl-isoprt and heterocyclic groups; R1 is 0 or OH; represents a hydrogenated acyl group or an unsubstituted or substituted carbamoylalkyl or carboxyalkyl group; and the dotted line represents a single or double bond; where Hl substituent carbamyl-alkyl or carboxy-alkyl group may optionally be substituted with at least one substituent selected from the following group; halogen atom; cetyl group substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogen alkyl group; cycloalkyl group; cycloalkyl group; hydroxyl group; alkoxy group; cycloalkoxy group; alkoxycarbonyl group; mercapto group; alkylthio group unsubstituted or substituted with one or more groups; aryl group; aryloxy group; aryl-alkyl group; arylamino group; cyano group; nitro group; amino group unsubstituted or substituted with one or more acyl groups; alkylarsino group; cycloalkylamino group; acyl group; hydrazino group; carboxyl group; carbamoyl group; thiocarbamoyl group; alkylcarbamoyl group and heterocyclic groups -...... φφ ·$· ·» χ ♦ ι or these show excellent antiviral activity against influenza viruses of types 3 and 6 and some other viruses, the compounds have low cytotoxicity and can be used as safe antiviral drugs, and the new nitrogen-containing heterocyclic carboxamine derivatives of the general formula — in which Ring A' is a pyrazine ring substituted with a halogen group, a hydroxy group or an oxo group; lake means 0 or HC— group; R represents a hydrogen atom, a carbamoyl-(C1-6 alkyl) or carboxy-(C1-6 alkyl) group substituted on the z-5 carbon atom; and the dotted line represents a single bond or a double bond; where R represents a carbamoyl-(C1-6 alkyl) or carboxy-(C1-6 alkyl) group optionally substituted with at least one azo substituent selected from the following group: halogen atom; (C1-6 alkyl) group unsubstituted or substituted with one or more hydroxyl, (C1-6 alkoxy), (C1-6 alkyl) thio, phenyl, naphthyl, amino or (C1-6 alkyl) amino groups; halo-(C1-6 alkyl) group; (C2-6 alkyl) group; (C6-6 alkyl) group (carbon cycloalkyl) group; hydroxyl group; (C1-6 alkoxy) group; {C3-6 cycloalkoxy) group? (C1-6 alkoxy) carbon group; mercapto group; substituted or one or more ? I MS-í'BSC'Mjsvs^yaf *·<*·· φ f eη 1 1 - or na tt 1. 1 -t sweep fta I. substituted U-6 carbon al.k.ii} ~thio.o~group: phenyl or naphthyl group; phenoxy or naphthyloxy group; phenylthio or naltrexylthio group; phenylamino or nathylamino group; cyano; nitro group substituted or one or more amino groups substituted on 2 carbon atoms by a target group; (1-6 carbon atom cycloalkyl)-amino group; acyl group with 2-5 carbon atoms; hydrazino-; carboxyl-; carbamyl-; phenylcarbamoyl···? Heterocyclic groups containing a (1-6 carbon alkyl)carbamoyl group and a 4-, 5- or 6-membered ring or a fused ring consisting of ethene, which heterocyclic groups are selected from the following groups; oxetanol-, phenyl-, azefenyl-, furyl-, pyrrolyl-, phenyl-, oxazolyl-, isoxazolyl-, imidazolyl-, thiazolyl-, xythiazyl-, pyrrolidinyl-, benzofuranyl-, benzothiazolyl-, paryl-, quinolinyl-, pyrimidinyl-, and xtorfolinyl--or their salts exhibit excellent antiviral activity. We implement the invention based on carbon observations. The invention will be described in detail below. Unless otherwise indicated, the term "alkyl" as used herein means a fluorine, chlorine, bromine or iodine atom; the term "alkyl" means a straight or branched alkyl group containing 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and the like; the term "alkenyl" means a straight or branched alkenyl group containing 2-6 carbon atoms, such as vinyl, allyl, and the like; the term "cycloalkyl" means a cycloalkyl group containing 3-6 carbon atoms, such as cyclopropyl, cyclopentyl, dicyclohexyl, and the like; The term "alkoxy" means a straight or branched chain alkoxy group, for example methoxy, ethoxy, propoxy.-, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and the like; the term "cycloalkoxy group" means a cycloalkoxy group having 3 to 6 carbon atoms, for example, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and the like; "alkylthio" means a straight or branched chain alkyl group containing 1-6 carbon atoms, such as methylthio, ethylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio and the like; "alkylamino" means a straight or branched chain alkyl group containing 1-6 carbon atoms substituted with one or more straight or branched chain alkyl groups, such as methylamino, ethylamino, prop.ylamino, butylamino, pentylamino, hexylamino, dimethylamino, ethylamino, methylethylamino, dipropylamino, dibutylamino, diphatylamino, and the like; "cycloalkylamino" means a cycloalkylamino group having 3 to 6 carbon atoms, such as cyclopropylamino, cyclopentylamino, cyclohexylamino and the like; "halogenated alkyl" means a halogen-substituted alkyl group having 1 to 6 carbon atoms, such as trifluoromethyl, trichloromethyl, chloromethyl and the like; "aryl" means a phenyl, naphthyl and the like; "aryloxy" means an aryloxy group, such as phenyloxy, naphthyloxy and the like; "arylthio" means an arylthio group, such as phenylthio. 71. SOS / SK *·<·>« X'X Φν , ·>$ χ *Αχ * χ « £·..··' ,$.·. Λ ·> X < > $ * * * * * ..·'' ν< **«# $*Χ<· ·* «* naphthylthio-salt and the like; as "aryl-^sino-salt" means an ar i 1-amino group, for example phenylamino-, naphthylamino-salt and the like; "Acyl group" means an alkanol group having 2 to 5 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and the like, and an aroyl group, such as benzoyl, naphthoyl and the like; "alkoxycarbonyl group" means a straight or branched chain alkoxycarbonyl group having 1 to 6 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl and the like; "alkylcarbamoyl group" means a carbamoyl group having one or more straight or branched chain substituted with an alkyl group containing 1-6 carbon atoms, for example methylcarbamoyl, dimethylcarbamoyl.yl group and the like; "carbamoylalkyl group" means a straight or branched chain alkyl group having 1 to 6 carbon atoms substituted with a carbamoyl group, such as carbamoylmethyl, carbamoylethyl, carbamoylisopropyl group and the like; "carboxyalkyl group" means a straight or branched chain alkyl group having 1 to 6 carbon atoms substituted with a carboxyl group, such as carboxymethyl, carboxyethyl, carboxyisopropyl group and the like; "heterocyclic group" means a 4-, 5- or 6-membered ring or a fused ring thereof, which contains at least one heteroatom, such as oxygen, nitrogen and sulfur, as the heteroatoms forming the above-mentioned ring, such as cxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, ? essen® ί-·.**>' ί* ν>· *·**« 4 . ί « ν ί * $ χ ν .. * ·> * * * ..-§' *.<** * #€*$ κ JK * χ,δζοίϋ-, isoxazolyl-, imidazole-, thiazolyl-, isothiazolyl-, pyrrolidinyl-, benzothiazolyl-, benzothiazolyl-, pyridyl-, quinolyl-, pyrimidine-group; and the ,, ox ido-group means an oxygen atom attached to the nitrogen atom in the ring - The term "short-carbon" means that the number of carbon atoms is between 1 and 6. The protecting group for the carboxy group may be any group conventionally used as a protecting group for the carboxy group. Examples of groups include alkyl groups such as methyl, ethyl, propyl, isopropyl, 1,1-dimethyl-propyl, butyl, tert-butyl and the like; product groups such as phenyl, nsftyl 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, benzoyl-acetyl, p-nitrobenzoylmethyl, p-bromobenzoylmethyl, p-methenesulfonyl-benzylmethyl and the like; oxygen-containing heteroalkyl groups such as 2-tetrahydropyranyl, 2-tetrahydrofuryl and the like; halo gen-alkyl groups, such as 2,2,2-trimethylsilyl group and the like; (alkyl-silyl)-alkyl esters, such as 2-(trimethylsilyl)-ethyl group and the like; acyl-alkyl esters, such as acetoxy-~jnet.yl", propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocyclic alkyl groups, such as phthalimidomethyl, succinimido-acetyl and the like; cycloalkyl groups, such as cyclohexyl and the like; alkoxyalkyl groups, such as methoxymethyl, ethoxymethyl, (2-(trimethylsilyl)ethoxy]methyl and the like; araicon!™. X .O3íi / S£ ΦΦΧ < -alkyl groups, such as benzyloxymethyl group and the like; {alkylthio} -silyl groups, such as (methylthio) -methyl-# 2~ {methylthioh-ethyl group and the like; (arylthio)-alkyl groups, such as. (phenylthio)-methyl group and the like; alkenyl groups, such as 1f1-dimethyl-2-propenyl 1~# S-methyl-S-hutenyl, allyl group and the like; substituted silyl groups# for example trimethylsilyl-, triethylsilyl-, triisopropylsilyl-, diethyl-isopropylsilyl-, tert-butyl-dxmethylsilyl-, tert-butyl-dimetilsilyl-, tert-butyl-diphenylsilyl-, tert-butyl-diphenylsilyl-, tert-butyl-diphenylsilyl-, tert-butyl-diphenylsilyl-, tert-butyl-diphenylsilyl-, tert-butyl-diphenylsilyl-, tert-butyl-diphenylsilyl-, etc., In the general formula {1}, the a-ring represents a pyrazine ring, a pyrimidine ring, a pyridazine ring, or a triazine ring. More specifically, the a-ring is one of the following structures: .N ..N THE N' Γ2 N *1 In the above structures, the *I notation indicates the position of substitution with íC# and the *2 notation indicates the position of substitution with a group of general formula ™C fo:ö) bHBs. The carbamoylalkyl or carboxyalkyl group represented by R may be substituted with at least one of the following substituents: halogenated groups; unsubstituted or substituted hydroxy, alkylthio, aryl, amino or alkylaromatic groups; substituted alkyl groups; halogenated alkyl groups; alkene groups; cycloalkyl groups; hydroxyl groups; alkoxy groups; alkylalcohol groups; oxycarbonyl groups; mercapto groups; unsubstituted or substituted alkylthio groups with one or more substituents; aryl groups; aryloxy groups; arylthio groups; alkyloyl groups; cyano groups; nitro groups; amino groups which are unsubstituted or substituted with one or more alkyl groups; alkylamino groups; cycloalkylamino groups; acyl groups; hydroxy groups; carboxyl groups; carbamoyl groups; thiocarbamoyl groups; alkylcarbamoyl groups and other groups. The preferred form of the A-ring of the general formula Ar Gr is the pyrazine, pyrimidine and triazoin ring, and more preferably the apiranyl ring, the substituents on the As A-ring can be selected from the following groups; halogen atoms; alkyl groups unsubstituted or substituted with one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; halogenated alkyl groups; the X-ring groups; cycloalkyl groups; hydroxy groups; alkoxy groups; cycloalkoxy groups; alkoxycarbonyl groups; octacapto groups; alkylthio groups unsubstituted or substituted with one or more substituents; 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 *Α φ > χ « * * φφ * tok; carbo-esoports; carhamoyl groups; thio-carbamoyl groups; alkyl-carbamoyl groups and heterocyclic groups. Furthermore, the substituent on the A-ring is preferably attached to the carbon atom of the ring, The salt of the compound of the general formula (1) may be any of the generally known salts formed on basic groups, for example, amino groups, and salts formed on acidic groups, for example, hydroxy- and carboxy groups. The salts formed on basic groups include mineral acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts of organic carboxylic acids, for example, tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; and salts of carboxylic acids, for example, methanesulfonic acid, benzoic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. The salts formed on acidic groups may include salts of alkali metals, for example, sodium, potassium and the like; salts of alkali metals, for example, calcium, magnesium and the like; ammonium and nitrogen-containing organic bases, for example trimethylamine, trimethylamine, tributylamine, pyridine, d,h~-dimethylaniline, dmet.yl-piperidine, n-methylmorpholine, diethylamine, dinichohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, db'-dibenzylethylenediamine and the like. Many of the aforementioned salts are preferred and are pharmacologically acceptable. Typical compounds of general formula (!) are shown in Tables 1-4. ->· * * « The following tables summarize the results of 1.1 and β, and the following Ma aa: ssa txk, . v. s- A·-Bü: terc-putxx AC { SCÖtíi Sz: ben.töi.1 E2a: ~CH (COOH? CHjCOOH R2b : ~CH (CH·,) CONHCH (CH, j COÖH .ai <· * * φ X, table Szára G, G;5 5 4 R 1 s CH CH NB 2 N CH CH NO H 3 14 CH CH N Ab 4 N CH 14 Bz 5 H CH CH HC (O) tBu SN CH CH H CH2COHH2 7 CH e~ci CHr NHSH H CHC HCB C~B C-OCa NH XX H CH C-OSt 14 H 12 19 CH COiPr HH X3 N CH C-Ö-cyclopropiX 14 H ia H CH C-BHM® 14 H 15 s8 . CH C-NMe? HH X6 N CH C-NH-o i ki oprop X1 BB 17 N CH C-BH&c HH 18 14 CH C-HHBz HH X9 14 CH C-HHHh BH 20 H CH C-SH BH 21 N CH C-SMe 14 CH H2· CO '7 N H1 Ό ; C-CÖOMe HH 24 H CH C-COOHt 19 H 25 14 CH C-COHK2 H fí 2 b 14 CH C-CSBH, HB 14 CH C'-CCHXfe BH 28 14 CH C~COHMe2 0 H C40 K-30 N1 CH e 31 s9 CH C-CCI3 HH 32 H CH C-CF3 HH 33 H CK C-CH^CI HH 34 14 CH C-CH2~SMe 14 H 35 14 CH C-CH?-ÖMe HH 30 14 CH C-CiU-Ph CBH 14 H c3h C-CH2-OH HH 39 B CH C~CH?~NHrie BH 40 N CH C--CBTMCHz HK :ΐ. ím / S8 IC Oil ΦΦΦΧ X* >> Φ XX ΦΦΦΧ Φ χφ ϕ 2. Table Szám '($ A <·· C3 O 7 8 41 b CH C-Ph b H 42 b CH C“plrldin~3“íl b H 43 3 CH O£urán~2-.il b B 44 b CH C—tiofen-z-il b H 45 b CH Otiazoi-z-i I b H 46 b CH C ~p.l r ro I idin -1 - i 1 b H 4? b CH C-pipsriáin-l-il b H 48 b CH C-mórfölin-4-11 M H 49 6 CH C-Cb b H 50 b CH C-bCj b H öl 8 CH e-Bz b H 62 8 CH C-Ac b H 53 b OCObH2 c-mh2· b H . 54 b C-bH2 C-COOH b H 55 b ObH? C~COOMe b H 56 b C-Cl C-CöQMe b H 57 b C-OMe C-be b H 58 b C-COOH C-MO b H 58 b OCOOH ONHMe b H 60 b OCŐOMe C-Cl b H 61 b C-COObe C-p ipa r i dl η -1 -1.1 b H 62 b oomo C-Cb b H 63 H OMe OMe b H 64 b c-Ph C-Ph b H 65 b C-F CH b H 66 N C-Cl CH b H 67 b C-Br CH b H 68 b C-OH CH b H 68 b OOMe CH b H 70 b c-cst CH b H 71 b C-0-i?r CH b H 72 b C-c1k1οprop11 CH b H 7 3 b OOFh CH b H 74 b C-bH? CH b H 75 b C-bHMe CK b H 7 6 b C-bMo? CH H H 77 b C-Gikiopropii CH b H 78 b C-HHHh CH b H 7 8 b ObHAc CH b H 80 H C-bHBz CH b H rí 3> tábládat Száz· G1 GZ 1.71¾ R2 81 F C~COOMe CH F H 82 F c~cf3 CH F H 83 0 C-Ph CH F H 84 F C~piridin~4'-il CH F H 88 F C-CF CH F K 88 F C~FO? CH F H 87 CH F CB. F H 88 CH F C-M© F H 83 CH F C-St F H 30 CH F C~i8r F H 91 CH F C-F F H 92 CH F C-Cl F H 98 CK F C-Hr F H 94 CH F C-Ph F H 35 CH F C-OH F H 98 CH F C~OH© F H 97 CH F C-C8C F H 98 CH H C~OiPr F H 99 CH F C-SH F H 100 CH F C-SFe F H 101 CH F C“S“CK2Ph F H 102 CH F O-SPh F H 10 3 CH F C-HHz F H 103 CH F C-HHHe F H 109 CH F C~NPte2 F H 108 CH N C-piperldín-l-il F H 107 CH F C-FH-Ph F H 108 C-OH F C-SH F H 109 C~OH F C-HH;J F 8 110 C~Me F C-ÖH F H 111 F CH N CH H 112 F C-F H CH H 113 F C~C1. H CH H 114 F C-F H C-Fe H 115 F C-Cl F C-St H 116 F C~0Fe F C-OH H 117 N C~FH.? F C-OH H 118 F C-FHAc F C-OH H 119 F C~SH F C-OH H 120 0 C~SHte F C-OH H »X φ ΦΦ Φ X ** ΧΦΦ * φφ φ Φ X * φ φ 9, táblázat Szám A G;? rá 64 R2 121 b Cráfe b C~bHMe H 122 X C-Ph b C-CH B 123 b C-Me b C~öB R 124 b C~Me b C-S-'Ph K 125 Ν C~P2e b C~C1 H 126 b C-Me b C~0Me H 127 b C~Me b C~ÖPh H 128 b C-Me b C-morfolin-4-il H 1.29 CB CH b b H 130 CH C-OK b b H 131 CH C~Me b b H Ζ 0 b CH b b H 133 b C~C1 b b H 134 b C~Me b b H 135 b C-OMe b b H 13 6 b e~bHg b b H 137 23 C-bbAo b b H 138 b C--piriáin~4'”il b b H 139 b b CH b H 140 b b C~Hr b H 141 b b C~OH b H 142 b b C-öiPr b H 19 3 b b C-bBPh b H 144 b b C~ti&2ol~2-“il 29 H 29 5 b b c-sh b H 148 29 b C-SKe b H 147 N b C-Cl b H 148 b b C~bHbH2 b B 149 b b C~Ph b b 150 b b Opirídín-2~ii Í9 H 151 b 23 C~tiofen~2~.il b B 152 b b CráCbfe b H 153 b b C-We2 b H 154 b CB e-F b H 155 b CH CH b R2n 156 b CH CH b R2a ΦΦΧ* ** Φφ Φ Φ Φ X χ Φ Φ X φφφ φ Ά Λ$Φ* ΦφΦφ Nitrogen-containing heterocyclic carboxamide derivatives of the general formula Π,ί or their salts are commercially available, or can be prepared by any known method or analogous methods or combinations thereof. As publications describing the preparation methods, reference may be made to the following: [J. Am. Chem. Soc., 71, 78 {1343); J,. Chem. SOC., 78, 242-244 (1958); 1. Hetex'ocycl. Chem., 15(4), Ű85-67Ö (1978); J, Chem. Soc.,· 1379 (1,955); USP 8,597,823: et al. (3) wherein R:, R?, Λ-ring and the meaning of the dotted line are as defined above, and R? represents a protecting group for the carboxy group, fi-a) Bgy A compound of general formula (1) can be prepared by reacting a compound of general formula (2) with a compound of general formula (4). The solvent used in this reaction is not particularly limited as long as it does not have an adverse effect on the reaction. Examples of the solvent include alcohols such as methanol, ethanol, isopropyl alcohol and the like; halogenated hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride and the like; aromatic hydrocarbons such as benzalkonium chloride, toluene, xylene and the like; ethers such as dioxane, tetrahydrofurane, anisole, diethylene glycol diethyl ether, dimethyl cellulose and the like; nitriles such as acetonitrile and the like; amides such as N,N-dimethylformamide, b,N-dimethylacetamide and the like; and sulfoxides such as dimethyl sulfoxide and the like. These solvents can also be used as a mixture. The compound of general formula (4) is used in at least an equimolar amount, preferably in an amount of 1.0 to 5.0 mol / mol, based on the compound of general formula (2). This reaction can be carried out at a temperature of between 0 and 100°C, preferably between 20 and 00°C, for a period of between 5 minutes and 24 hours, preferably between 30 minutes and 10 hours. The compound of general formula (1) can also be prepared by a dehydration condensation reaction of a compound of general formula (3) and a compound of general formula (4). The solvent used in this reaction is not particularly limited as long as it does not have an adverse effect on the reaction. Examples of the solvent include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellulose and the like; halogenated hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride and the like; and amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like. The solvents may also be used as a mixture. The compound of general formula (4) is used in at least an equimolar amount, preferably in an amount of 1.0-2.0 mol / mcl, to the ι-r β #»*♦· *·.< Χ* ** * * * ♦ * * * Φ * * ·» « *> X XX * ·» «X *·.' Ψ-ΧΧ-ΐ ***« Λ ψ* calculated for the compound of general formula (3). The dehydrating condensing agent used in this reaction may be, for example, 1,3-acetic acid hexyl-carbohydrate. <Iiísdd, h,N’-ka.rboníl-diimidazoi, 1-éti 1~3~ C3’~dimetil~amíno~propií) -karbodíimíd és hasonlók» The dehydrating condensing agent is used in at least an equimolar amount, preferably in an amount of 1.0-2.0 mol / mol, based on the compound of general formula (3)» This reaction can be carried out generally at a temperature between 0 and 100°C, preferably between 20 and 00°C, for a period of time between 5 minutes and 24 hours, preferably between 30 minutes and 10 hours. 2, reaction scheme wherein E1, E2, A-ring and the dashed line are as defined below, and I represents a lower alkyl group. A compound of general formula (1) can also be prepared by alkyl ether cleavage of a compound of general formula (5). Specifically, in the case where R* is a methyl group, the reaction can be carried out according to the description in Protective Groups in Organic Syntheses (2nd ed. John Wiley and Sons, 145-199 (1991)) or an analogous procedure. * ·Χ φ· φ .. roaculovasiat *Φ*Χ ·χ* φ φ φ * * *Λ' Φ*« •ν actlezes .-Γ ·<'* χ / Χ / in which. á.:, The meaning of the ~ring and the dashed line was defined above, and R2* is a sci swept of. means* A compound of formula (Ic) can be prepared by reacting a compound of formula (Ia) in the presence of an antacid. The solvent used in this reaction is not particularly limited as long as it does not have an adverse effect on the reaction. Examples of the solvent include: ethers such as dioxane, tetrahydrofuran, benzene, diethylene glycol diethyl ether, diethyl ether, and the like; aromatic hydrocarbons such as benzene, toluene, xylene, and the like; halogenated hydrocarbons such as methylene dichloride, chloroform, ethylene dichloride, and the like; amides such as 5,3,N-dimethylformamide, N,3,N-dimethylacetamide, and the like; water, etc. These solvents may also be used as a mixture. The alysing agent is used in at least an equimolar amount, preferably in an amount of 1.0-2.0 mol / mol, based on the compound of general formula (ib). The acid scavenger used in this reaction may be, for example, pyridine, triethylamine, sodium bicarbonate and the like. The acid-binding agent is used in at least an equimolar amount, preferably in an amount of 1.0-2.0 mol / mol, based on the compound of general formula IIb). as»s / se The reaction can generally be carried out at a temperature between 0 and 100°C, preferably between 20 and 60°C, for a period of time between 5 minutes and 24 hours, preferably between 30 minutes and 10 hours. In the reaction schemes 1-3, the compounds of general formula (2), (3), (4), (51) and (Ibi) can also be replaced by their salts. As for the salts, the same ones mentioned for the compounds of general formula (11) can be used. Some of the general compounds (2), (3), (4), (5) and (6) and their salts may have different isomers, for example optical isomers and positional isomers, as well as solvated forms. In such cases, any of these isomers and solvates may be used in the invention. The compounds of general formula (I) thus obtained are converted into their salts. The salts may be the same as those mentioned for the compounds of general formula (1). Viruses that can be targeted by the antiviral agent comprising the nitrogen-containing heterocyclic carboxamide compound of the general formula (1) or its salt according to the invention include the following: influenza viruses A, B and C, papilloma virus, adenovirus, hepatitis A virus, hepatitis 3 virus, hepatitis C virus, poliovirus, echovirus, Coxsackievirus, enterovirus, rhinovirus, rotavirus, Newcastle disease virus, mumps virus, vesicular stomatitis virus and Japanese encephalitis virus. The antiviral agents according to the invention show particularly high efficacy against influenza viruses. The general formula (1) of the invention is nitrogen-containing 71.SS5 / 8S IA X ΦΦΦ By combining heterocyclic carboxamide derivatives or their salts with conventionally known excipients, enhancers and additives, pharmaceutical preparations such as solutions, suspensions, powders, granules, fine granules, tablets, capsules, syrups, elixirs, alcoholic preparations, pills, gargles, aerosols, etc. can be obtained. The pharmaceutical preparations can be administered either orally or non-orally, namely by injection, transdermally, rectally, nasally, etc. The administration method, dosage and frequency of administration of the antiviral agent of the invention can be selected appropriately depending on the age, body weight and symptoms of the patient. For an adult, generally 1-10 mg / kg of a nitrogen-containing heterocyclic carboxamide-0 derivative or its salt can be administered at one time or in multiple doses. The antiviral activity and cytotoxicity of the nitrogen-containing heterocyclic carboxamide derivatives of the general formula (1) or their salts according to the invention are described below. Example: The nitrogen-containing heterocyclic carboxamide derivative of the general formula (1) or its salt is dissolved in dimethyl sulfoxide to prepare a solution at a concentration of 10 mg / ml. When used, the solution is diluted with culture medium to a predetermined concentration and then used. MDCK cells (dog kidney cells) were used as the host cell for the influenza virus, and Beat cells (monkey kidney cells) were used for the A. cytotoxicity test. Culture medium: For the propagation of HDCK cells and Beater cells and for the cytotoxicity test with Beater cells, F'-MSM (Nissui ké♦ X <· >Χ< X sütmény) was used, to which 10% fetal calf serum was added. When measuring the antiviral effect, E'-MEH (Aíssu preparation) was used, to which 1% bovine serum albumin was added. Test example 1 (effect against laflu^aaa) MDCA cells were seeded onto a six-well plate (Corning) at 5 x 10 cells / well and cultured overnight at 38°C in a 5% carbon dioxide atmosphere. Then, the cultured MDCK cells on the plate were treated with A / R / A / A influenza virus diluted in serum-free medium at a concentration of 200 FFü / ml in a volume of 0.5 ml / well for one hour to achieve inoculation and adsorption. After inoculation and adsorption were complete, E / -MEM medium containing 0.6% Agar Doble, 1% bovine serum albumin, 3 pg / ml acetyltrypsin and the test compound at the prescribed concentration was added to the cells. After satisfactory coagulation, the plate was tilted upside down and incubated for 3 days. After the culture is complete, the cells are stained with 1% deuteral Red. The cells are then fixed with 10% formalin solution. The agar medium is removed with running water. After this, the plaques are counted.The degree of plaque inhibition is expressed as a percentage compared to a control sample containing no test compound. The results are presented in Table 5, in which the number of the test compound is the same as in Tables 1-4. < table number concentration of the added test compound (gg / ml) degree of inhibition (1) 1 1 91.9 2 100 32.4 9 100 50.0 41 100 25.0 65 1 100 SS 100 39.2 67 100 35.2 65 100 39.8 84 100 *> Test example 2 (cytotoxic effect) A medium containing a predetermined concentration of the compound to be tested is added to a perforated plate (made by Corning) in an amount of 100 μΙ / well. Then the medium is mixed with the Verő ?i..S3S / SS * V X ΦΦ φφ ​The concentration of Φ.ΧΦΦ ΧΦΦ* * cells is adjusted to 2 χ 1Ο':cells / ml~. The solution. 100 μΐ / butter is added to the plate and cultured at 37 *C~ in a 5% carbon dioxide-air atmosphere for 4 days. When the culture is complete, the viable cells are counted according to the XXT method [see for example; Cancer Research, 4 8, 4827-4833 (1988)]. As a result, it was found that the concentration (IC8) of 3-hydroxy-2-pyrazine-cataboxamide (Compound 1) that inhibited cell growth by 50% was 250 µg / ml or more. The compounds of the present invention will be described below with reference to the following examples and examples. The scope of the invention is in no way limited to these examples. In this eluent, mixing ratios are always understood in volume. The support used in column chromatography was Silica Gel 3W-1273H (Fuji. Siller a Chemical Co.}, and the support used in reverse phase column chromatography was LC-SORB SR-B-öDS (CChemco Co.}, Explanation of the notation used in the reference examples and examples: DbSO-d;m deuterated dimethylsulfoxide, X, reference example 0.30 g of l-hydroxy-z-pyrazinecarboxylic acid prepared according to the procedure described in the literature [J. Reterocyci, Chem., 34, 27 (1997}] is suspended in 8 ml of methylene dichloride. 0.54 ml of triethylamine and 0.29 g of glycine3S5 / M are added successively to the suspension. -methyl ester hydrochloride< The resulting mixture was stirred for 5 hours at room temperature. After cooling, the solvent was evaporated under reduced pressure. The residue was purified by reverse phase column chromatography (eluent: water) to give 0.18 g of methyl-2-{[(3-hydroxy-2-pyrazinyl)-carbonyl]-amino}-acetate. IR (KBr) evening 1750, 173S, 1885 ÖMR (DMSO-dg) S value: 3.87 (3.8,s|, 4.12 {2S, d, J~8Hz), 7.708.30 Í2B, mj, 9.80-10.10 (IS, m), 13.10 <1H, brs) Reference example 2 17.00 g of methyl 8-methyl-3-amino-2-pyrazinecarboxylate prepared according to the procedure described in the literature [J. Am. Chem. Sec., 2798-2800 (1949)} were dissolved in 100 ml of concentrated sulfuric acid. 10.11 g of sodium nitrite were added to the suspension at ice bath temperature and stirred for 30 minutes. The reaction mixture was poured into 320 ml of methanol and heated under reflux for 5 hours. The reaction mixture was cooled and then concentrated under reduced pressure. The residue thus obtained was added to a mixture of 500 ml of ice water and 800 ml of chloroform, and the phases were separated. The organic layer was then washed with saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure to obtain 8.30 g of methyl 8-bromo-3-methoxy-2-pyrazinecarboxylate. IR (KBr) cm'5·: .1734 h'MR (CDCip δ value: 3.97 (3H, s), 4.06 δH, a), 8.37 (1H, a) Reference example 3 11.38 g of methyl 8-ferroic acid 3-methoxy-2-pyrazinecarboxylate with nitrogen ·> « ·Ο· φνχχ. * * X * > ·>· φ is dissolved in 227 ml of toluene under an atmosphere. To the solution are added successively 10.32 g of benzophenone isidine, 0.42 g of tris(dibenzylideneacetone)dipalladium, 0.86 g of (S)-(-}-2,2'~.bis (diphenyl.'-phosphincd -1, l'-binaphthyl) and 6.20 g of sodium terebatovide. The resulting mixture is stirred for 1 hour at 60°C. 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 was dissolved in 140 ml of tetrahydrofuran, 7 ml of 2 mol / ml hydrochloric acid solution was added, and the resulting solution was stirred at room temperature for 15 minutes. The resulting reaction mixture was added to a mixture of 200 ml of chloroform and 50 ml of water, and 1 mol / ml sodium hydroxide solution was added, and the organic phase was separated. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by column chromatography (eluent; toluene:ethyl acetate:::1:1). 3.64 g of methyl 6-amino-3-methoxy-2-pyrazine hydroxylate are obtained. IR (KBr) cm'd 1716, 1670 NMR (DHS0-6) δ value; 3.80 {3B, s), 3.82 (3H, s), 7.20 (2H, brs), 7.77 (1H, s) Reference Example 4: 3.50 g of methyl 6-amino-3-methyl-2-pyrazinecarboxylate was dissolved in methanol. The solution was saturated by introducing ammonia gas. The solution was stirred at room temperature for 14 hours. The solvent was evaporated from the reaction mixture under reduced pressure to obtain 3.1 g of 6-azindo-3-methyl-2-pyrazinecarboxiamide. IR (KBr) cm5; 1684 NMR (DdSO-d,,) : 3.73 (3H, s), 5.37 <2H, brs), 7.30-7.75 (3.H, m) H .«3VK8 Beat Reference Example S. '1.50 g of 8-amino-3-methoxy-2-pyrazinecarboxamide was dissolved in 12 ml of 70% pyridine-bifluorourea under a nitrogen atmosphere with ice-cooling. Then 0.7.1 g of sodium nitrate was added at -50 °C, and the resulting solution was stirred for 1 hour at 10 °C. The resulting reaction mixture was stirred for another 1 hour at room temperature. Then, a mixture of 50 ml of ice water and 100 ml of chloroform was added, and the phases of the resulting mixture were separated. The organic phase was washed with a saturated aqueous solution of sodium chloride and a saturated aqueous solution of sodium hydrogen carbonate, and dried over anhydrous sodium cesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain 1.29 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide. IR (KBr) cm'5·: 1706 PMR ÍDHSO-sh) : 3.05 (35, sl, 7.55-3.13 (25, m) , 8.39 (ÍR, d, 3-8.3Hz) 6» reference example According to the procedure described in the literature (jn~A~S0~lö557S) 1.99 g of me fii - 5 - am ί ηo - 3 ™me tovi -2-p ira zin - car b o x i '1 á to t is suspended in 100 ml of methanol. The suspension obtained is saturated with ammonia by introducing ammonia gas at -20 °C. The solution thus obtained is left to react at 95 °C for 24 hours in a closed, stainless steel apparatus. After cooling, the solvent is evaporated under reduced pressure to obtain 1.57 g of 5™amino“3~methoxy~2-pyrazine~carboxamide, IR(KBr) cm': 1854, 1637 NMR (DM3O~ds) δ value: 3.52 (3R, S), 7.00 (3H, hrs), 7.30 (1H, hrs), 7.43 (1R, s) n mss / ss Λ ΦΦΦ ΧΦ * * ΧΦΦφ ΦΦ ..water Φ Φ X Φ X χ φ ΦΦ Φ*φφ φφφφ Φ Φ* Reference Example 7: 0.5 g of 5-amino-3-methoxy-2-pyrrazinecarboxamide was dissolved in 9 ml of 70% pyridine hydrofluoride under an atmosphere of nitrogen with ice cooling. Then 0.23 g of sodium nitrite was added at ~7°C, and the resulting solution was warmed to -10°C over 30 minutes. The solution was then stirred at room temperature for 50 minutes. A mixture of 30 ml of ice water and 100 ml of chloroform was added, and the phases of the resulting mixture were separated. The organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue thus obtained was purified by column chromatography (eluent: chloroform:methanol ~ 10:1) to give 0.37 g of S-fluoro-1-methoxy-1™pyraz.1 n -carboxamide. IR (KSr) cm1: 1705 hMH (QdSO-dR δ value: 3.94 (3H, s), 7.05 UH, brs), 7.85 Uh, brs), 8.12 (IH, d, J~8, 3 Hz) The procedure described in the literature [u. bed. Chem., (1969), 12 (2), 205-287] sarin was prepared by suspending 0.6 g of methyl-6-bromo-3-hydroxy-2-pyrazinecarboxylate. in 3 ml of methanol. Then 6 ml of 25% aqueous ammonia solution were added, and the resulting solution was stirred for 17 hours at room temperature. The pH of the reaction mixture was The pH is adjusted to 3 by adding 6 mol / l hydrochloric acid solution. The solvent is evaporated off under reduced pressure. Isopropyl ether and water are added to the residue and after filtration 0.33 g of 6-chromo(TM) 3-hydroxy-2-pyrazinecarboxamide is obtained. ? ·. sos / ss IR (KBr) cm-1: 1700, 1665 MMR (DMSO~ds) h value: 7.50 (2.8, hrs) , 8.08 (18, s), 0.95 (1H, hrs) 0.5 g of 3,5-dihydroxy-1,2,4-triazine-6-carboxylic acid prepared according to the method described in the literature {J2-A-S4-79292} was suspended in 10 ml of dimethylformamide. Then 2.05 g of K, N'-carbonyldiinidazole were added, and the resulting solution was stirred for € hours at room temperature. The reaction mixture was cooled with ice, saturated with ammonia gas, and stirred for 15 minutes at the above temperature. The precipitated crystals were collected on a filter to obtain 0.37 g of 3,.5-diloxo-2 ,3,4,5-tetrahydro-1,2, 4-triazine-6-carboxamide. IR (KBr) om:b 1732, 1710, 1585, 1658 HMH (DMSO-dU 6 value; 7.75 (1K, s), 7.97 (1H, s), 12.20-12.80 (28, m) 0.5 g of 3-hydroxy-2-pyrazinecarboxamide is suspended in 5 ml of ethyl acetate. The resulting solution is stirred for 1 hour at 110°C. The precipitated crystals are collected on a filter to give 0.5 g of 5K-acetyl-3-hydroxy-2-pyrazinecarboxamide. IR (KBr) cafü 1725, 1695, 1655 NMR (DMS6-db S value: 2.25 (3R, a), 7.53 (18, d, 0-4 Hz), 7.69 (18, d, J™4 Hz), 11.70 (1H, hrs) Example 4 0.25 g of isoyl-O-chloro-3-hydroxy-2-pyrazinecarboxylate prepared according to the procedure described in the literature (»J. Med. Chem., 285-287 (1969)] is suspended in 5 ml of 25% aqueous ammoniaH ..-.3% / SS .·> > φ in solution. The suspension is stirred for 1 hour at room temperature. A. The precipitated crystals are collected on a filter to obtain 0.18 g of 6~chloro~.3~ -h 1 dr oxi -2 -pl re z 1 n~ carboxamido. IR (KBr) cm'h 1052 guard) 1.00 g of 3-hydroxy-2-pyrazinecarboxamide is suspended in 50 ml of tetrahydrofuran. Then 3.5 ml of triethylamine and 1.67 ml of benzene chloride are added successively. The resulting solution is stirred for 5 hours at 50 °C and then cooled. The precipitated crystals are collected on a filter. The crystals thus obtained are suspended in a mixture of 8 ml of water and 1 ml of 1 mol / l hydrochloric acid solution, stirred for 30 minutes at room temperature, and collected on a filter to obtain 0.41 g of N4-benayl-3-hydroxy-2-pyrazinecarboxamide, 1R (RB r) cm'Λ: 1 '? 3 5 HMR (DMSO-dJ δ value: 7.20-8.40 <7H, m), 12.00 (Ifí, fors) According to the same procedure as above, we prepare P~{2,2- di me ti 1 - prop ion i1) - 3 ~bi dr ox i - 2 ~ pl razin - car b o x am i do t. IRISH (KBr) om'h 1725 NMR (hHSO-d,) δ value: 1.21 (OK, s), 7.45 pH, d, ü-2 Hz), 7.95 (IH, d, o-2 Hz), 14.80 (IB, brp 0.05 g of 3-methoxy-2-pyrazine-, prepared according to the procedure described in the literature [Biz. 31 Med. Chem,, 15 (2), 157-153 (1930)]

Claims

-carboxamide i-oride is dissolved in 0.5 ml of 47% aqueous hydrogen bromide solution. The solution is stirred for 2 hours at 45 “C, A • <u .sos / ms x-x -χχ Λ $· Φ φ ΦΦ * * * Φ Φ* kivált kristályokat szűrőre gyűjtjük, és egymás után etanollal és dietil-éterrel mossuk, így 0,03 g 3-hidroxi-2-pirazin.“karboxamid~4~oxidot kapunk. ÍR (KBr) cm'U 16SS NME. (DMSO-dJ 8 érték: 7, IS (Xfí, d, Sz), 7,36 {Ifí, d, J««6 Hr), 7,70 UH, brs), 7,95 UH, brs), 10,7 5 (1H, brs). 0, IS g metil-2~{[(3-hidro.xi-2-pirazini.l)-karbon.il]-amino}-acetátot szuszpendálunk 4 mi metanolban. A szuszpenziót arrnnóniagáz bevezetésével 30 perc alatt telítjük jeges hűtés, mellett, A kapott elegyet 1 órán át a fenti hőmérsékleten, utána 15 órán át szobahőmérsékleten kevertetjük. Az oldószert csökkentett nyomáson iepároljuk. Az igy kapott maradékot feloldjuk 4 ml viz és 1 ml metanol elegyében. A kapott oldathoz hozzáadunk ö,S mi. 1 mol / i sósavoldatot. A kivált kristályokat szűrőre gyűjtve 0,16 g U~ (2-amlno-2“Oxoetii) -.3'“h.hydroxy-2'-pyrazinecarboxamide is obtained. IR (KSr) cm U 1675 NME <BMSQ~d{;) S érték: 3,90 UH, d, o-S Hz), 7,10 UH, brs), 7,40 UH, brs), 7,60-8,40 (2H, m), 9,50 (1H, brs), 13,0 U-K, brs). Nitrogén atmoszféra alatt 1,51 g nátrium-jodidot feloldunk 22 ml acetonitrilben. Utána hozzáadunk 1,10 g trimetil-sziiil-kloridot. A kapott oldatot 20 percen át kevertetjük. szobahőmérsékleten. Ezután hozzáadunk 5,43 g g~f.luor--3-.metox.i-2-pira.zin-karboxamidot. Δ kapott oldatot 18 érán ót kevertetjük a fentivel azonos hőmérsékleten. Ezután 10 ml víz és 200 ml kloroform elegyét adjuk a reakcióelegyhez, és a fázisokat elválasztjuk. Az ; : .«í5 / s:s Φ φφφ φ'φ ΦΦ *ΧΦΦ φ φ φ * * φ ΦΦ ΦΦΧΦ ΧΦΦΦ Így kapott szerves fázist egymás után mossuk nátriuni-tiossulfát 5%-os vizes oldatéval és nátrium-klorid telített vizes oldatával, és magnézium-szulfáton szárítjuk. Az oldószert csökkentett nyomáson ispároljuk. Az .The residue thus obtained was purified by column chromatography (eluent: hexane; ethyl acetate - 2:1) to give 0.06 g of 6-fluoro-3-hydroxy-2-pyrazine-carboxamide. IR (KBr) cm'1: 1685, 1370, 1656 NMR (C.OCi3): 5.40-7.00 (2H, ej, 8.31 (1H, d, »> 7.82 Hz}, 12.3.3 (Id, Si) 4.00 g of 3-hydroxy-2-pyrazine-carboxamide were suspended in 24 ml of concentrated sulfuric acid. 3.09 g of potassium nitrate were added to the suspension while cooling with ice. The resulting mixture was stirred for 3 hours at 40 °C. The reaction mixture was poured into 240 ml of water, and the precipitated 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 on a filter to give 2.45 g of 3-hydroxy-5-nitro-2-pyrazine-carbamide. IR (KBr) 0.45 h H, 1635, 1655 WR (μMSO-de § value: 8.10 (18, forsj , 8.30 (.IH, brs), 8.06 (IH, s> . Example 10 0.5 g of 2-amino-malonamide is suspended in 2.0 ml of water. While cooling with ice, 0.43 g of ethyl glyoxalate is added to the solution.to the suspension, which was then stirred for 40 minutes. To the resulting suspension was added. 0.85 ml of 5 mol / l sodium hydroxide solution, and then stirred for 40 minutes at the same temperature as above. The pH of the reaction mixture was adjusted to 12~rs with 1 mol / l sodium hydroxide solution Ah ΧΦΦΦ -X* X* ΦχΦφ Φφ χ φ χ χ φ <i· φ » Φ Φ * ΦΦΦ ΦΦΦ Φ Φ Φ Φ ΦΦ φΦΦφ ΦΦΦΦ X X* adagolásával, és ismét oldatba visszük. Az oldat pH-ját ezután 2~re állítjuk 6 mol / 1 sósavoldat adagolásával. A kivált kristályokat szűréstől összegyűjtjük, egymás után mossuk vízzel és 50 %-os (tömeg / tömeg) etanolial és igy 0,15 g 3, 5-dihidtoxi-.2-pirazi.n~ -karboxamídot kapunk. ÍR (KBr) cm'A 166Ü NMR CDjÖ) δ érték: 6,37 (1.H, s) 11. példa 0,65 ml dletii-z-oxo-malonátot és 0,5 g 2-amíno-maionamidot szuszpendálunk 2,0 m.l vízben. Jeges hűtés közben, hozzáadunk 0,85 ml 5 moi / i nátrium-hidroxid-oldatot. A kapott oldatot <0 percen át kevertetjük.Then 2.35 ml of 5 mol / l sodium hydroxide was added to the solution at room temperature and stirred for another 30 minutes. Ethanol was added to the reaction mixture and the precipitate was collected by filtration to give 0.24 g of 3,5-dihydroxy-6-{ethoxycarbonyl}-2-pyrazinecarboxamide. IR (KBr) cm1: 1555, 1735 NMR (D2O) δ value; 1.17 (3K, t, J-7 Hz), 4.15 (2H, q, o=*7 Hz) 0.13 g of 3,5-dihydroxy-5- (ethoxycarbonyl)-2-pyrazinecarboxamide was suspended in 1.0 ml of vis and 1.0 ml of ethanol. At room temperature, 0.34 ml of 5 mol / 'i sodium hydroxide solution was added to the suspension, which was then stirred for 16 h. The pH of the reaction mixture was adjusted to 2 by adding 1 mol / 1 hydrochloric acid. The precipitated crystals were collected on a filter and washed with water to give 0.07 g of 3,5-dihydroxy-6-carboxy-2-pyrazinecarboxamide. ÍR (KBr; cm''5': 1650 >. .«esne .ad' of Φ.φ·φφ φ·*>· -xx ί*** φφ φ * X Φ Φ Φ Φ * X Φ Φ VX φ Φ * Φ Φ -X φ Φφ ΦχίΧφ *φ*φ Φ xtf Under a nitrogen atmosphere, 0.09 g of 5-f.Fluoro-S-methoxy-S-pyrazine™ -carboxamide is suspended in 3.6 ml of acetonitrile. Then 0.16 g of sodium iodide and 0.31 g of chlorotrimethylsilyl are added successively to the suspension, which is then stirred for 20 hours at room temperature. Then 2 ml of water and 40 ml of chloroform are added to the reaction mixture / and the phases are separated. The organic phase is separated, washed successively with a 5% (w / w) aqueous solution of magnesium thiosulfate and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by column chromatography (eluent; chloroform) to give 0.01 g of 5-fluoro-3-hydroxy-2-pyrazine-carboxamide. IR (KBr) melt 1670 O (CDCl.;) § value: 5.80 UH, s), 7.45 <IH, brs), 7,93 (IB, d, J—?, 8 Hz), 12,93 <1B, s) , A szakirodalomban leírt eljárás (0. Am, Chem. Soc., (1956), 78, 1258-1259) 0.1 g of 5-oxo-3-thioxO-2,3,9,5-tetrahydro-l,2,4-triazine-6-carboxalate prepared according to the method is suspended in 5 ml of ethanol. The solution is saturated by passing ammonia gas into the solution for 30 minutes at room temperature. The solution is left to stand for 15 hours at the same temperature, and the crystals obtained are collected on a filter. The crystals thus collected are washed with 3x5 ml of ethanol to give 0.05 g of a-oxe-3-thiox-2, 3, 4, 5™tetrahydro-1,2,4-triazine-6-carboxamide. IR (KBr) tsar :3.654 NMR. (DMSO-d / § value; 3.30 (in, brs) 71.355 / 88 X « X φ **♦ ,Μ'Κ ν«.φφ X··· * * * φ φ * φ φ φ* φ*φφ The procedure described in the literature <W0 93 / 136549} szerint állítunk elő ú-oxo-lz S-dihidro-S-píri-mídin-karboxamidot. 16, példa WAWAWMMWA%WrtW,AWrt\ A szakirodalomban leire eljárás [Chemisohe Seriehte, 97, 3349-3353 Π9641] szerint állítunk elő 3-oxo-2,3-dididre--4-pi.ridazin-karboxamidot.

17. példa VV.-»VW»VVVVV^> 3^VVXVWWrtVWW. 0.06 g of ethyl 5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxylate is dissolved in 5 ml of ethanol.The solution was saturated at 10 °C for 20 min by introducing ammonia. The solution was left to stand at room temperature for 15 min and the resulting crystals were collected on a filter. The crystals were washed successively with 2 x 2 ml of ethanol and then 2 x 1 ml of methanol to give 0.03 g of 5-oxo-4,5-dihydro-1,2,4-triazine-6-carboxamide. IR (KBr1 cm'H 1654 NMR (DMSO-d,j δ value: 3.60 (1H, brs), 7.44 (1H, brs), 3.39 (1H, s), 9.74 (1H, brs) 0.4 g of methyl-3-hydroxy-2-pyrazinecarboxylate is dissolved in 9 ml of dimethylsulfoxide. Then 0.27 g of b-aspartic acid and 0.35 ml of triethylamine are added successively to the solution, which is then stirred for 6 hours at 60 *C.» The precipitated crystals are removed by filtration and the filtrate is concentrated under reduced pressure. 2 ml of water and 0.2 ml of methanol are added to the resulting residue. The precipitate formed is collected on a filter to give 2.02 g (2S> -2™([(3-oxo-3,4-dlhídro-2 -pyra zi η 11} -carhoni 1 j~amino} -succinic acid gate, ..3-d'UU· Φ- £,. ·> ., *•4 χ * s< * Φ ·φ > * ή, ·> ' φ *·,· ψ , ΙΕ (KBr) om'U 1695, 1680, 1665 NME (DMSO-dg) δ value: 2.83 (2H, d, US Hz), 4.50-5.00 UH, m), 7.60-8.05 Un, h0, 3.95 UH, d, U=9 Ha), 12.90 UH, era), 0.42 g of L-alanyl-L-alanxn-trifluoroacetate is dissolved. In 5 ml of olmethyl sulfoxide. To the solution are added successively 1.07 ml of triethylamine and 0.71 g of methyl-3-hydroxy~2-pyrazin-car.rhoKilOs, then stirred for 17 hours at 40 0C. The solvent is evaporated under reduced pressure, and 2 ml of water is added to the residue thus obtained. The precipitated product A is collected on a filter and purified by column chromatography (eluent: chloroform).rm:methanol — 30 U) is purified, thus 0.035 g (28) -2-[ (US) -2~{({3~oxo~3,4~díhxdro~2-pxrazinxl) ~ car rb ο σ', i 1] - am ino) -pr op i ok i 1) - a mi no] - pr op i on s av a fc kap unk„ ÍR (KBr) om-1: 1555, 1575, 1655 NME (EMSO-d,) δ value: 1.28 UH, d, >>? Hz), 1.32 (3H, d, 0-7 Hz), 3.95-4.95 (2H, m), 5.1 (2H, brs) , 7.71 UH, d, d-3 Hz), 7.87 UH, d, J-3 Hz), 5.32 UH, d, 0-7, Hz), 0.9 UH, brs) An antiviral agent comprising a nitrogen-containing heterocyclic carboxamide derivative of the general formula U) or a salt thereof is useful for the prevention and treatment of viral infections, and in particular influenza virus infections.

1. Nitrogen-containing heterocyclic carboxamide derivatives of the general formula (1) - in which the ring A is optionally substituted with at least one group by a pyrazine, pyridinium, pyrrolazine or triazine ring, where the ring is substituted with at least one group selected from the group of the following substituents: halogen; alkyl group substituted with one or more hydroxy, alkoxy, alkylthio, aryl, amino or alkyl-aromatic groups; halogen alkyl group; alkene group; cycloalkyl group; hydroxyl group; alkoxy group; alkyl carbonyl group; mercapto group; alkyl thio group substituted with one or more substituents; aryl group; φ φ φ φφ* arii-oxí-ceoporf; ar ί 1 -ti ο - c ο ο ρ ο rt; ar 11-amino-group; eianocoporf; rdtroosoport? ältäsitefleh or amino group substituted with one or more acyl groups; alklI-ami.no~group; cycloalkyl-amino-group; acyl-sweep; hydraeno-group; carboxyl-sweep car bamo i1c group; o ·· ka r P amo 11 - cs ορ ort; a 1kyl-carbamoyl-group and heterocyclic groups; R5· represents 0 or HO-group; ;V represents a hydrogen atom, an acyl group or a substituted or substituted carbamoyl-alkyl or carboxy-alkyl group; and the dotted line represents a single or double bond; where h is a carbamoyl-alkyl or carboxy-alkyl group, in the case of a given substituent, it may be substituted by at least one substituent selected from the following group: halogen atom; alkyl group unsubstituted or substituted by one or more hydroxyl, alkoxy, alkylthio, aryl, amino or alkylamino groups; n sveseoyava-íij haloalkyl group; alkenyl group; cycloalkyl group; hydroxyl group; alkoxy group; cycloalkyl group; alk oxy-car ronyl group; mercapto group; substituted or substituted with one or more aryl groups.alkylthio group; aryl group; aryloxy group; arylthio group; arylamino group; cyano group; nitro group; heliothione or amino group substituted with one or more acyl groups; alkylamino group; glycolylamino group; acryl group; hydrazino group; carboxyl group; carbamyl group; thiocarbamoyl group; a 1 ki 1 -carbamoyl group and heterocyclic groups -- or a salt thereof for use in therapy or prophylaxis, heterocyclic carboxamide derivatives according to claim 1, where ring A is a substituted pyrazine, pyrazine- or triazine ring according to claim 1.

3. Heterocyclic carboxyamide derivatives according to claim 2, wherein X is a ring, optionally substituted according to claim 1.

4. An antiviral agent comprising a heterocyclic carboxyamide derivative according to any one of claims 1-3, wherein a.virus influenza virus, papilloma virus, adenovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, poliovirus, echovirus, Coxsackie virus, enterovirus, rhinovirus, rotavirus, Bevacise disease virus, mumps virus, vesicular stomatitis virus or Japanese encephalitis virus, 5, The antiviral agent according to claim 4, wherein the virus is influenza virus, 8.Nitrogen-containing heterocyclic carboxamide derivatives of the general formula {la; in which the A*' ring represents a pyrazine ring substituted with halogen, hydroxyl or oxido group; R: represents 0 or HO group; Ib represents a hydrogen atom, a C2-C5 alkyl group or a carbamoyl-(C1-C5 alkyl)- or carboxy-;C1-C5 alkyl)-group' and φ φ the dotted line represents a single bond or a double bond? where R substituent is a carbamoyl-(C1-C6 alkyl)- or carboxy-(C1-C6 alkyl)-group in a given case?·! may be substituted with at least one substituent selected from the following group: balog ena tom.; unsubstituted or substituted by one or more hydroxyl, 1-6-alkyl, (1-6-alkyl)thio, phenyl, naphthyl, amino or (1-6-alkyl)amino groups; halogen-(1-6-alkyl)? (3-6-alkyl alkenyl) group; (3-6-alkyl cycloalkyl) group; hydroxyl group; (1-6-alkyl alkoxy) group; (3-6-alkyl cycloalkyl) group; (1-6-alkyl carbonyl) group; mercapto group; unsubstituted or substituted by one or more phenyl or naphthyl groups; phenyl or naphthyl isothioate; phenoxy or naphthyloxy group; phenyl or naphthyl group; phenylamino or naphthylamino group; cyano group; nitro group; substituted ethylene or one or more C3-5 alkyl groups; (C1-6 alkyl) -araiso group; (C3-6 cycloalkyl}-amino group;. 2-5 carbon atom acyl group; hydrazino group; carboxyl group; carbamoyl group; fluorocarbamoyl group? (l-δ carbon atom alkyl)-cataboH group and Heterocyclic groups containing 4-, 5- or δ-membered rings or fused rings consisting of 4-, 5- or δ-membered rings, which heterocyclic groups are selected from the following groups: oxetanyl, triphenyl, azefenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl, benzofuranyl, thiazolyl, pyrroyl, quinolinyl, pyrimidinyl, and morpholinyl groups - or salts thereof, 7, nitrogen-containing, halocyclic carboxamide derivatives according to claim 6, wherein ring A' represents a pyrazine ring substituted with a halogen atom; and ;h represents a hydrogen atom, S, the following compounds according to claim 1: δ-fluoro-3-hydroxy-2-pyrazine-carboxamide or its salts, fn < λ · ·» c & authorized; 'X....