PL205150B1 - Novel pyrazine derivatives or salts thereof, pharmaceutical compositions containing the derivatives or the salts and intermediates for the preparation of both - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an improved method for chemically producing N-(13- methyltetradecyl)acetamide (capsiamide) which is an ingredient of Guinea pepper and has an analgesic action and an anti-inflammatory action. SOLUTION: This method for producing 13-methyltetradecylamine useful as an intermediate for synthesizing capsiamide, characterized by reacting a 5-halogenovaleronitrile as a starting raw material with triphenylphosphine, condensing the obtained phosphonium salt with 8-methyl-7-nonenal, and then reducing the obtained 13-cyano-2-methyltridecane-2,9-diene. The 13- methyltetradecylamine can be produced in a high yield. The method for producing the capsiamide, characterized by acetylating the 13-methyltetradecylamine with acetic anhydride. The capsiamide can be produced in a high yield.

Description

Description of the invention

The invention relates to a pyrazine derivative, a pharmaceutical composition and its use as an antiviral agent.

As currently clinically used antiviral agents, acyclovir and vidarabine for combating herpes virus, ganciclovir and foscarnet for controlling cytomegalovirus and interferon, etc. for controlling hepatitis virus can be mentioned. In addition, prevention by the use of an influenza virus vaccine is widely used, and low molecular weight compounds such as amantadine hydrochloride and ribavirin are also used for this purpose. Zanamivir has also been used recently.

On the other hand, it has been found that, for example, as regards the antiviral activity of nucleoside and nucleotide analogs containing a pyrazine ring as a base, compounds of the general formula:

narrow However, this type of compound does not show "Anti-visna virus activity [Nucleosides & Nucleotides, Vol. 15, Nos. 11 and 12, pp. 1849-1861 (1996)]". In addition, nucleoside and nucleotide analogs having a pyrazine ring substituted with a carbamoyl group have not been described so far.

The problems with amantadine are that, due to its mechanism of action, immunity to the virus may arise, it may cause nerve damage, and it is not effective against influenza B, even though it is effective against influenza A. On the other hand, although ribavirin has polymerase inhibitory activity and is effective against influenza A and B, yet when administered orally, it does not show a sufficient clinical effect.

Thus, it was desired to produce an antiviral agent having an infection prevention effect against various viruses, and in particular against influenza viruses, and having a therapeutic effect.

The present inventors conducted intensive research to solve the above problems. As a result, it was found that certain pyrazine derivatives or their salts have excellent antiviral activity. On this basis, the invention was accomplished.

The pyrazine derivative according to the invention is characterized in that it is represented by a general formula

hydrogen; R ⁴ and R ⁶ represent a hydroxyl group which may be optionally substituted with at least one group selected from the group consisting of a carboxyl group, a lower alkyl group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, a halogeno-lower alkyl group, and heterocyclic or optionally protected by one group selected from acyl groups, lower alkyl groups, lower alkenyl groups, arlow alkyl groups, oxygen- and sulfur-containing heterocyclic groups, lower alkoxy and lower alkyl, thio lower alkyl groups, alkane- or allenesulfonyl groups, enol ether groups; A is oxygen;

n is 0 and Y is an oxygen atom, or a salt of the derivative.

Preferably, in the given formula, R ⁴ and R ⁶ represent a hydroxyl group.

Preferably, in the given formula, R ¹ represents a hydrogen atom or a fluorine atom.

The pharmaceutical composition according to the invention is characterized in that it comprises a compound or a salt thereof as defined above.

A pharmaceutical composition containing a compound or a salt thereof as defined above in accordance with the invention is also characterized in that it serves as an antiviral agent.

Preferably, the composition is for use as an agent against influenza virus, RS virus, AIDS virus, papillomavirus, adenovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, polio virus, echo virus, coke virus. , enterovirus, rhinovirus, rotavirus, newcastle disease virus, mumps virus, vesicular stomatitis virus and Japanese encephalitis virus.

More preferably, the composition is for use as an anti-influenza virus agent.

More preferably, the composition is for use as an anti-hepatitis C virus agent.

Unless otherwise defined, terms used in this invention have the following symbols.

The term "halogen atom denotes a fluorine, chlorine, bromine or iodine atom; "Halogenated methyl group means a mono-, di- or tri-substituted halogenated methyl group such as fluoromethyl, chloromethyl, bromomethyl, iodomethyl, dichloromethyl, trifluoromethyl, trichloromethyl and the like;" The "halogenated carbonyl group" means a fluorocarbonyl, chlorocarbonyl, bromocarbonyl or iodocarbonyl group; "Lower alkyl group means a C1-5 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl groups and the like; "Lower alkoxy" means a C1-5 alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and the like; "Lower alkoxycarbonyl group means a C1-5 alkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl and the like-butoxycarbonyl group; "Lower alkylamino" means a mono- or di-C 1-5 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino and the like; "Halogen-lower lower alkyl group means a halogen C1-5 alkyl group such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichlorethyl, chloropropyl and the like;" "Lower alkenyl group means a C2-5 alkenyl group such as vinyl, allyl and the like; "Cycloalkyl group means a C3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; An aryl group means phenyl, naphthyl and the like; and "heterocyclic group is a 4- to 6-membered or fused heterocyclic group containing at least one atom selected from oxygen, nitrogen and sulfur, such as azetidinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1, 2,3-triazolyl, 1,2,4-triazolyl, thiatriazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, morpholinyl, 1,2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, chromenyl, indolizinyl, isoindolyl indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalidinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, triazolopyridinyl, triazinylpyridinyl, thimimopyridiazinyl, timimopyrazinyl, thimopyrazinyl, thiazinylopyrazinyl, quinazolinyl, cinnolinyl, phthalidinyl, isochromanyl, , benzimidazolyl, benzothiazolyl, 1,2,3,4-tetrahydroquinolyl, imidazo [1,2-b] [1,2,4] triazinyl, quinuclidinyl and the like.

In cases where the compound of the invention and its preparation intermediate include a hydroxyl group, a mercapto group, an amino group, a carbamoyl group or a carboxyl group, these substituents may be protected with known protecting groups.

As protecting groups for a carboxyl group, all groups conventionally useful for the protection of a carboxyl group can be mentioned. Examples of these groups include lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl and the like.

PL 205 150 B1; aryl groups such as phenyl, naphthyl and the like; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl, bis (p-methoxyphenyl) methyl and the like; acyl lower alkyl groups such as acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl, p-bromobenzylmethyl, p-methanesulfonylbenzoylmethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; halo-lower alkyl groups such as 2,2,2-trichloroethyl and the like; lower alkylsilylalkyl groups such as 2- (trimethylsilyl) ethyl and the like; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and the like; nitrogen-containing heterocyclic alkyl groups such as phthalimidomethyl, succinimidomethyl and the like; cycloalkyl groups such as cyclohexyl and the like; lower alkoxy lower alkyl groups such as methoxymethyl, methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and the like; aryl lower alkoxy lower alkyl groups such as benzyloxymethyl and the like; lower alkylthio lower alkyl groups such as methylthiomethyl, 2-methylthioethyl and the like; arylthio lower alkyl groups such as phenylthiomethyl and the like; lower alkenyl groups such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl, allyl and the like; lower alkyl-substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like.

As protecting groups for the amino and lower alkylamino groups, all groups conventionally used for protecting amino groups may be mentioned. Examples of such groups are acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di- and tri-) chloroacetyl, trifluoroacetyl, formyloxycarbonyl, tyloxycarbonyl, -butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenyl) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 8cylcylycarbonyl, 8-phthamancylycarbonyl, phthylphthoxycarbonyl similar; ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl and the like; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthio and the like; alkane- or allenesulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; di-lower alkylamino-lower alkylidene groups such as N, N-dimethylaminomethylene and the like; aryl-lower alkylidene groups such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-2-naphthylmethylene and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dimethyl-5-oxycyclohexylidene and the like; di-aryl or di-aryl lower phosphoryl groups such as diphenyl phosphoryl, dibenzyl phosphoryl and the like; oxygen-containing heterocyclic alkyl groups such as 5-methyl-2-oxo-2H-1,3-dioxol-4-ylmethyl and the like; and lower alkyl-substituted silyl groups such as trimethylsilyl and the like.

As protecting groups for a hydroxyl group, all groups conventionally used for protecting hydroxyl groups may be mentioned.

Examples include acyl groups such as benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 2, 2-carboxycarbonyl, isoproparboxycarbonyl, ispropoxycarbonyl. 2-trichloroethoxycarbonyl, 2,2,2-tribromethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, 1-adamantyloxycarbonyl, 4-adamantyloxycarbonyl, 4-adamantyloxycarbonyl, 4-vinyloxycarbonyl -ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl, benzoyl and the like; lower alkyl groups such as methyl, tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like; lower alkylene groups such as allyl and the like; ar-lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiopyranyl and the like; lower alkoxy and lower alkylthio lower alkyl groups such as methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and the like; alkane- or allenesulfonyl groups such as methanesulfonyl, p-toluenesulfonyl and the like; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl, tert-butylmethoxyphenylsilyl and the like; substituted aryl groups such as hydroquinone, p-methoxyphenol and the like; enol ether groups such as (2-methyl-3-oxo-1-cyclopentan-1-yl) and the like.

PL 205 150 B1

As protecting groups for a carbamoyl group, all groups conventionally used for the protection of carbamoyl groups can be mentioned.

Examples of such groups include ar-lower alkyl groups such as benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and the like; lower alkoxyalkyl groups such as methoxymethyl and the like; ar-lower alkoxy groups such as benzyloxymethyl and the like; substituted silyl lower alkoxy lower alkyl groups such as tert-butyldimethylsiloxymethyl and the like; lower alkoxy groups such as methoxy and the like; ar-lower alkoxy groups such as benzyloxy and the like; lower alkylthio groups such as methylthio, triphenylmethylthio and the like; ar-lower alkylthio groups such as benzylthio and the like; substituted silyl groups such as tert-butyldimethylsilyl and the like; aryl groups such as 4-methoxyphenyl, 4-methoxymethylphenyl, 2-methyl-1-naphthyl, 4-methoxymethylphenyl, 2-methoxy-1-naphthyl and the like; acyl groups such as trichloroethoxycarbonyl, trifluoroacetyl, tert-butoxycarbonyl and the like; e.t.c.

As substituents for the hydroxyl group R ⁴ , R ⁶ , Z ² , Z ³ , Z ⁴ and Z ⁵ which may be substituted, there may be mentioned protected or unprotected carboxyl group, lower alkyl group, lower alkoxycarbonyl group, aryl group, cycloalkyl group, a lower alkenyl group, a halo-lower alkyl group, and a heterocyclic group. One or more kinds of these substituents may be used as a substitution.

As a substituent for the amino group defined by Z ² , Z ³ , Z ⁴ and Z ⁵ that may be substituted, there may be mentioned protected or unprotected carboxyl, lower hydroxy, amino, and lower alkylamino, lower alkyl, lower alkoxy , a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, a halo-lower alkyl group, and a heterocyclic group. One or more kinds of these substituents may be used as a substitution.

As a substituent for the phenylsulfanyl group, the phenylsulfinyl group, and the phenylsulfonyl group of formula R ²² , lower alkyl groups such as methyl, ethyl and the like can be mentioned.

As the salts of the compounds of the general formulas [1] there can be mentioned the usual salts of a basic group such as amino, etc. and salts of an acidic group such as a hydroxyl group, a phosphoryl group, a carboxyl group, etc. The salts of the basic group include, for example, salts with a mineral acid such as hydrochloric, hydrobromic, sulfuric acid and the like; salts with an organic acid such as tartaric, formic, citric, trichloroacetic, trifluoroacetic and the like; and salts with sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like. The salts on the side of the acid group include salts with alkali metals such as sodium, potassium and the like; alkaline earth metal salts such as calcium, magnesium and the like; ammonium salts; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine,

N-methylmorpholine, diethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-e-phenethylamine, 1-ephenamine, N, N-dibenzylethylenediamine and the like.

Of the above-mentioned salts, pharmacologically acceptable salts are preferable.

In some cases, the compounds of general formulas [1] and their salts have isomers such as optical isomers, geometric isomers and tautomers. In such cases, the invention includes these isomers as well as solvated products, hydrates as well as various crystalline forms.

Among the pharmaceutical compositions according to the invention, preferred pharmaceutical compositions are those for use as antiviral agents, especially as agents for combating influenza virus, RS virus, AIDS virus, papillomavirus, adenovirus, hepatitis A virus, hepatitis virus. B virus, hepatitis C virus, polio virus, echo virus, coxackie virus, enterovirus, rhinovirus, rotavirus, newcastle disease virus, mumps virus, vesicular stomatitis virus, and Japanese encephalitis virus. More preferred are agents for controlling rotavirus, RS virus and influenza virus. The agent for combating the influenza virus can be mentioned as the most advantageous.

Among the compounds of the invention, those compounds in which R ⁴ and R ⁶ are protected or unprotected hydroxyl and salts of such compounds are preferred.

As more preferred compounds wherein R ¹ is hydrogen, chlorine or fluorine, or their salts, can be mentioned; as further more preferred compounds there may be mentioned those compounds in which R ¹ is a hydrogen atom or a fluorine atom or their salts.

Of the compounds of the invention, for example, those listed in Table I-1 are typical where "Bn is benzyl and" - is a bond.

PL 205 150 B1

T a b l i c a I-1

R ¹ R ² R ³ R ⁴ R ⁵ R ⁶ AND n Y H. H. H. OH H. OH ABOUT 0 ABOUT 6-F H. H. OH H. OH ABOUT 0 ABOUT 6-Cl H. H. OH H. OH ABOUT 0 ABOUT

The preparation of the compounds of the invention is described below.

The compounds of the invention can be prepared by the following Preparation Methods I-1 to 4. [Preparation Method I-1]

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , A, Y and n are as defined above; R ⁸ is a lower alkyl group; Z ¹ is a hydrogen atom or a protecting group for a hydroxyl group; Z ^2, Z ^3, Z ⁴ and Z ⁵ , which may be the same or different, are hydrogen, halogen, azido, protected hydroxyl or amino; or Z ³ and Z ⁵ taken together form a bond.

(a) The compound of general formula [1a] or a salt thereof can be produced by subjecting the compound of general formula [2a] or a salt thereof to de-protecting reaction.

PL 205 150 B1

The solvent used in this reaction is not particularly limited, unless exercising an adverse influence on the reaction. Examples of the solvent include 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-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water, etc. These solvents may be used alone or as a mixture of two or more.

As deprotecting agents, agents conventionally used to remove the protecting group of a hydroxyl group, an amino group, and a phosphoric acid group can be used. However, bases such as sodium methoxide, hydrogen gas, ammonia gas, liquid ammonia, butylamine and the like are preferably used; acids such as formic acid, aqueous acetic acid, aqueous trifluoroacetic acid, hydrochloric acid and the like; palladium catalysts such as tetrakis-triphenylphosphine palladium (O) and the like; phosphines such as triphenylphosphine and the like. These de-protecting agents can be used in combination, or they can be prepared in the reaction system. The de-protecting agent can be used in an amount of at least 0.01 mol per mol of the compound of general formula [2a] or salt thereof. The de-protecting agent can be used as a solvent if desired.

The de-protecting reaction is carried out usually at -50 ° C to 170 ° C and preferably from -20 ° C to 100 ° C, for a period of 1 minute to 100 hours and more preferably 5 minutes to 50 hours.

(b) The compound of general formula [1a] in which Y is an oxygen atom, or a salt thereof, can be produced by subjecting the compound of general formula [2b] or a salt thereof to the ammonolysis of a carboxylic acid ester in the presence or absence of a catalyst.

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include 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-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; water, etc. These solvents may be used singly or as mixtures of two or more. This reaction can be carried out in the presence of agents and under conventional conditions used in the ammonolysis of aromatic carboxylic esters. However, preference is given to using gaseous ammonia, liquid ammonia and aqueous ammonia. These agents are used in an amount of at least 0.5 mol per mol of the compound of formula [2b] or salt thereof. If desired, these agents can be used as a solvent. As the catalyst to be used in this reaction as desired, ammonium salts of acids such as ammonium chloride; bases such as sodium methoxide, butyllithium and the like; alkali metal amides such as sodium amide and the like. The catalyst is used in an amount of 0.01 to 100 moles and preferably 0.01 to 20 moles per mole of the compound of formula [2b] or salt thereof.

This reaction is carried out usually at -100 ° C to 250 ° C and preferably -78 ° C to 100 ° C, for a period of one minute to 72 hours and more preferably 30 minutes to 50 hours.

PL 205 150 B1

Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , Z ² , Z ⁴ , Z ⁵ , A, n and Y are as defined above; R ⁹ is a protected or unprotected mono-phosphoric acid group, or mono-phosphoric acid chloride; and R ¹² is a protected or unprotected phosphoric or tri-phosphoric acid group.

(a) The compound of general formula [2c] or salt thereof can be obtained by protecting the compound of general formula [2b] or salt thereof with an agent in the presence or absence of an acid catalyst or a base.

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include 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-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; ketones such as acetone and the like; water, etc. These solvents may be used alone or as a mixture of two or more.

As reagent, the usual hydroxyl and amino protecting agents can be used, preferably 2,2-dimethoxypropane, acetyl chloride and benzoyl chloride. If desired, these reagents can be prepared in the reaction system. The reagent is used at least in an equimolar amount and preferably 1.0-10 mol per mol of the compound of formula [2b] or salt thereof.

As the acid catalyst or base used in this reaction, for example, p-toluenesulfonic acid, triethylamine and the like can be mentioned. They can be used in an amount of 0.01-10 mol and preferably 0.05-10 mol per mol of the compound of formula [2b] or salt thereof.

This reaction is carried out usually at -50 ° C to 170 ° C and preferably at 0 ° C to 150 ° C, for a period of one minute to 24 hours and more preferably 5 minutes to 10 hours.

(b) The compound of general formula [2d] or salt thereof can be produced by (1) reacting the compound of general formula [2c] or salt thereof with a phosphorylating agent in the presence or absence of an excipient according to the method described in Jikken Kagaku Koza, 4th Edition, Vol 22, pages 313-438 (edited by Chemical Society Japan (corporate juricical person), 1992) or by (2) reaction with a phosphating agent followed by an oxidizing agent.

In the method (1), the solvent used in this reaction is not limited, as long as it has an adverse influence on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, aniso, diethylene glycol diethyl ether, dimethyl cellosolve and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; pyridine, etc. These solvents may be used alone or as a mixture of two or more.

As phosphorylating agents, reagents used for phosphorylation of the hydroxyl group can usually be used. Examples of such phosphorylating agents include phosphoric acid diesters such as dibenzyl phosphate and the like; phosphoric acid dithioesters such as monocyclohexylammonium S, S'-diphenylphosphorodithioate and the like; phosphoric acid chlorides such as phosphoryl chloride, diallylchlorophosphonate and the like, etc. The phosphorylating agent is used in an amount at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per 1 mol of the compound of formula [2c] and its salt. As excipients, for example, azo compounds such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and the like; phosphines such as triphenylphosphine and the like; allenesulfonic acid chlorides such as 2,4,6-triisopropylbenzenesulfonic acid chloride and the like; bases such as pyridine, tert-butylmagnesium chloride and the like. If desired, these additives may be used in combination. The excipient is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [2c] or salt thereof.

This reaction is carried out usually at -50 C to 170 C and preferably 0 C to 100 C, for a period of one minute to 72 hours and preferably 5 minutes to 24 hours.

In the method (2), the solvent used in this reaction is not limited, as long as it has an adverse influence on the reaction. Examples of the solvent include 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-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; pyridine and the like. These solvents may be used alone or as mixtures of two or more.

As phosphite agents, reagents used for phosphating a hydroxyl group can usually be used. Examples include phosphoramidates such as diallyl diisopropyl phosphoramidate and the like, and phosphoric acid chlorides such as diallyl chlorophosphate and the like. The phosphating agent is used in an amount at least in an equimolar amount and preferably in an amount of 1.0-3.0 mol per 1 mol of the compound.

Of formula [2c] and its salt. As additives, for example, tetrazole compounds such as 1H-tetrazole and the like, and bases such as pyridine, collidine and the like can be mentioned, and if desired, the additives can be used in combination. The additive is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [2c] or salt thereof.

As the oxidizing substances used in this reaction, for example, peroxides such as m-chloroperbenzoic acid, tert-butyl hydroperoxide and the like, and halogen compounds such as iodine and the like can be mentioned. The oxidizing agent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [2c] or salt thereof.

This reaction is carried out usually at -78 C to 100 C and preferably -50 C to 50 C, for a period of one minute to 24 hours and more preferably 5 minutes to 6 hours.

(c) The compound of general formula [1b] or salt thereof can be obtained by reacting according to Production Method I-1 (b), using the compound of general formula [2d] or salt thereof.

(d) The compound of general formula [1c] or salt thereof can be obtained by reacting according to Production Method I-1 (a), using the compound of general formula [1b] or salt thereof.

(e) The compound of general formula [1b] or salt thereof can be obtained by reacting according to Production Method I-2 (b), using the compound of general formula [1d] or salt thereof.

(f) The compound of general formula [1e] or salt thereof can be obtained by reacting the compound of general formula [1c] or salt thereof with a phosphorylating agent in the presence or absence of a condensing agent according to a procedure described, for example, in Chem. Rev., Vol. 100, pages 2047-2059 (2000).

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include 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-dimethylacetamide and the like; alcohols such as methanol, ethanol, propanol and the like; sulfoxides such as dimethyl sulfoxide and the like; pyridine, etc. These solvents may be used alone or as a mixture of two or more.

As phosphorylating agents, reagents commonly used for phosphorylation of the mono-phosphoric acid group can be used. Examples of such phosphorylating agents include phosphoric acid salts such as tri-n-butylammonium phosphate, n-butylammonium pyrophosphate and the like, and if desired, the phosphorylating agents can be synthesized by the reaction system. The phosphorylating agents are used at least in an equimolar amount and preferably in an amount of 1.0-10 mol per mol of the compound of formula [1c] or salt thereof. As the condensing agent, for example, imidazoles such as N, N-carbonyldiimidazole, N-methylimidazole and the like, and amines such as morpholine, diisopropylamine and the like can be used, and if desired, these amines can be used in combination.

The condensing agent is used at least in an equimolar amount and preferably in an amount of 1.05.0 mol per mol of the compound of formula [1c] or salt thereof.

This reaction is carried out usually at -50 ° C to 100 ° C and preferably at 0 ° C to 50 ° C, for a period of one minute to 72 hours and preferably 5 minutes to 24 hours.

[Manufacturing Method 3]

PL 205 150 B1

8 1 2 4 5 1 wherein R ¹ , R ⁸ , A, n, Z ¹ , Z ² , Z ⁴ and Z ⁵ are as defined above; Y ¹ is oxygen;

and R ¹⁰ is a halogen atom, a carbonyloxy group or a sulfonyloxy group.

(a) The compound of general formula [2a] or a salt thereof can be obtained by (1) converting the compound of general formula [3a] or a salt thereof into a compound of general formula [3b] or a salt thereof according to a conventional silylation method in the presence or in the presence of the absence of an additive, and then (2) by reacting it with a compound of general formula [4a] or a salt thereof in the presence or absence of Lewis acid.

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include 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-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like. These solvents can be used singly or as mixtures of two or more.

In reaction (1), a silylating agent conventionally used to convert a carbonyl group to a silyl enol ether may be used. Examples include 1,1,1,3,3,3-hexamethyldisilazane, N, O-bis (trimethylsilyl) acetamide, trimethylsilyl chloride and the like. The silylating agent is used at least in an equimolar amount and preferably in an amount of 1.0-10 mol per mol of the compound of formula [3a] or salt thereof.

As an additive which can be used as desired in this reaction, for example, ammonium sulfate can be mentioned. The amount of this material is 0.1-10.0 mol and preferably 0.05-5.0 mol, per mol of the compound of formula [3a] or salt thereof.

This reaction is carried out usually at 0-200 ° C and preferably at 0-150 ° C, for 5 minutes to 24 hours and preferably 5 minutes to 12 hours.

In the reaction (2), the compound of formula [4a] or salt thereof is used in an amount of 0.5-10 mol and preferably 0.5-5 mol per mol of the compound of formula [3a] or salt thereof.

As a Lewis acid that can be used in this reaction if desired, for example, trimethylsilyl trifluoromethanesulfonic acid, tin (IV) chloride, titanium (IV) chloride, zinc chloride and the like can be mentioned. The Lewis acid is used in an amount of at least 0.5 mol and preferably in an amount of 0.5-10 mol per mol of the compound of formula [3a] or salt thereof.

This reaction is carried out usually at 0-100 ° C and preferably at 0-50 ° C, for a period of one minute to 72 hours and preferably 5 minutes to 24 hours.

(b) The compound of general formula [2a] or salt thereof can be obtained by reacting the compound of general formula [3a] or salt thereof with a compound of general formula [4b] or salt thereof in the presence or absence of an excipient by using a base as deacidification agent.

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane 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-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used alone or as a mixture of two or more.

As the base used in this reaction, for example, inorganic and organic bases such as triethylamine, potassium tert-butoxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride and the like can be mentioned. In this reaction, the compound of general formula [4b] or salt thereof is used in an amount of 0.1-5 mol and preferably 0.2-2 mol per mol of the compound of general formula [3a] or salt thereof. In this reaction, the base is used in an amount of 0.1-10 mol and preferably 0.2-10 mol, per mol of the compound of general formula [3a] or salt thereof.

As additives which can be used in this reaction as desired, for example, palladium catalysts such as palladium tetrakis-triphenylphosphine and the like; phosphines such as triphenylphosphine and the like; polyethers such as 18-crown-6-ether and the like. The excipient is used in an amount of 0.01-10 mol and preferably 0.03-5.0 mol per mol of the compound of formula [3a] or salt thereof.

This reaction is carried out usually at -50 ° C to 170 ° C and preferably at 0 ° C to 120 ° C, for a period of one minute to 72 hours and preferably 5 minutes to 24 hours.

PL 205 150 B1

[Manufacturing Method I-4]

wherein R ¹ , A, n, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are as defined above.

A compound of general formula [2g] or a salt thereof can be obtained by reacting a compound of general formula [2f] or a salt thereof with a thionizing agent in the presence or absence of a base as described, for example, in Shin Jikken Kagaku Koza, Vol. 14, pp. 1819-1831 (edited by the Chemical Society Japan (corporate juricical person), 1978).

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane 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-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used singly or as mixtures of two or more.

As the thionizing agent, reagents which are conventionally used for the thionization of acid amides can be used. Examples include hydrogen sulfide gas, phosphorus pentasulfide, Lawson's reagent and the like. The thionizing agent is used in this reaction in an amount of 0.1-10 mol and preferably 0.2-5.0 mol per mol of the compound of general formula [2f] or his salt.

As the base used in this reaction, for example, mention bases such as ammonia, triethylamine, morpholine, pyridine, 4-dimethylaminopyridine and the like. In this reaction, the base is used in an amount of at least 0.01 mol per mol of the compound of formula [2f] or salt thereof. If desired, the base can be used as a solvent.

This reaction is carried out usually at -50 ° C to 170 ° C and preferably 0 ° C to 120 ° C, for a period of one minute to 24 hours and preferably 5 minutes to 6 hours.

Next, the method of producing the compounds of general formulas [2a], [2b], [3a '] and [3j] and their salts, which are the starting materials for the preparation of the compound of the invention, will be described.

Compounds of general formulas [2a], [2b], [3a '] and [3j] can be prepared by known methods and appropriate combinations of these methods. For example, these compounds can be prepared by the following Preparation Method I-A.

PL 205 150 B1

[Manufacturing Method I-A]

removing protecting group

wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , A, n, Z ¹ , Z ² , Z ³ , Z ⁴ , Z ⁵ and R ¹⁰ are as defined above.

(a) The compound of general formula [2e] or salt thereof can be obtained by reacting the compound of general formula [3c] or salt thereof with the compound of general formula [4a] or salt thereof according to Production Method I-3 (a).

(b) The compound of general formula [2e] or salt thereof can be obtained by reacting the compound of general formula [3c] or salt thereof with the compound of general formula [4b] or salt thereof according to Production Method I-3 (b).

(c) The compound of general formula [2b] or salt thereof can be obtained by reacting the compound of general formula [2e] or salt thereof according to Production Method I-1 (a).

Among the starting materials for the above-mentioned reactions, the compound of general formula [3c] or a salt thereof can, for example, be prepared according to J. Heterocyclic Chem., Vol. 34, No. 1, pp. 27-32 (1997) or J. Med. Chem., Vol. 12, No 2, pp. 285-287 (1969); the compound of general formula [4a] or a salt thereof can be produced according to, for example, J. Med. Chem., Vol 28, No. 7, pp. 904-910 (1985); and the compound of general formula [4b] or salt thereof can be produced according to J. Chem. Soc. PERKIN TRANS. 1, pp. 2419-2425 (1992), J. Med. Chem., Vol. 36, No. 14, pp. 2033-2040 (1993) or Bio. Med. Chem. Lett., Vol. 6, No. 13, pp. 1457-1460 (1996).

PL 205 150 B1

wherein R ⁸ is as defined above; R ^1a is halogen; R ¹¹ is a hydroxyl protecting group and X is a halogen other than a fluorine atom.

(a) The compound of general formula [3f] or salt thereof can be obtained by reacting the compound of general formula [3e] or salt thereof by using a diazotizing agent and an alcohol.

The solvents used in this reaction are not limited, so long as they adversely affect the reaction. Examples of the solvent include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like; 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; nitriles such as acetonitrile and the like; amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amine oxides such as triethylamine, N, N-dimethylaniline, pyridine N-oxide and the like; ketones such as acetone and the like; alcohols such as methanol, ethanol and the like; water, etc. If desired, these solvents may be used in admixture. The diazotizing agents used in the invention are not limited as long as they are conventionally used for the diazotization of aromatic amino compounds. However, alkali metal nitrites such as sodium nitrite and the like are preferably used. The diazotizing agent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of the compound of formula [3e] or salt thereof.

As the alcohol used in this reaction, for example, methanol and the like can be mentioned. The alcohol is used at least in an equimolar amount to the compound of formula [3e] or salt thereof. If desired, alcohol can also be used as a solvent.

This reaction is carried out usually at -70 ° C to 200 ° C and preferably at -50 ° to 100 ° C, for a period of one minute to 24 hours and preferably 30 minutes to 10 hours.

The compound of general formula [3g] or a salt thereof can be produced by (1) reacting a compound of general formula [3f] or a salt thereof with an imine in the presence of a catalyst and a base as a deacidifying agent according to a method disclosed in the literature [Tetrahedron Letters, Vol. 38, No. 36, pp. 6367-6370 (1997)] followed by (2) its hydrolysis in the presence of an additive.

In reaction (1), the solvents used are not limited, unless they adversely affect the reaction. Examples of the solvent include 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; etc. These solvents may be used alone or in a mixture of two or more.

In this reaction, the catalyst may be selected from a combination of a palladium-based catalyst such as palladium (II) acetate, tris (dibenzylidene-acetone) dipalladium and the like, a nickel catalyst such as bis (1,5-cyclooctadiene) nickel ( 0) and the like, and a phosphine ligand such as 1,1'-bis (diphenylphosphino) ferrocene, (s) - (-) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and the like. The catalyst is used in an amount of 0.001-1.0 mol and preferably 0.002-0.5 mol per mol of the compound of formula [3f] or salt thereof.

PL 205 150 B1

As the bases used in this reaction, alkali metal salts such as sodium tert-butoxide, cesium carbonate and the like can be mentioned. The base is used at least in an equimolar amount and preferably in an amount of 1.0-3.0 mol per mol of the compound of formula [3f] or salt thereof.

As the imine used in this reaction, for example, benzophenoneimine and the like can be mentioned. The imine is used at least in an equimolar amount and preferably in an amount of 1.0-3.0 mol per mol of the compound of formula [3f] or salt thereof.

This reaction is carried out usually at 0-120 ° C and preferably 5-100 ° C, for a period of one minute to 48 hours and preferably 5 minutes to 24 hours.

(2) In reaction (2), the solvents used are not limited, as long as they have an adverse effect on the reaction. Solvents used, for example, include ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol, ethanol and the like; water; etc. These solvents may be used alone or in a mixture of two or more.

As the auxiliary agents used in the reaction, for example, organic and inorganic acid salts such as sodium acetate, hydroxylamine hydrochloride, ammonium formate and the like; inorganic acids such as hydrochloric acid and the like; palladium catalysts such as palladium on carbon and the like. If desired, these additives can be used in combination. The additive is used in an amount of 0.01-50 mol and preferably 0.1-20 mol, per mol of the compound of general formula [3f] or salt thereof.

The reaction is carried out usually at 0-120 ° C and preferably 5-100 ° C, for a period of 1 minute to 48 hours and preferably 3 minutes to 24 hours.

(c) The compound of general formula [3h] or salt thereof can be obtained by reacting the compound of general formula [3g] or salt thereof according to Production Method I-1 (b).

(d) The compound of general formula [3i] or a salt thereof can be produced by subjecting the compound of general formula [3h] or a salt thereof to the de-amination of an amino group by using a diazotizing agent and the presence of an acid, in the presence or absence of an additional excipient in the manner of for example described in Fusso Kagaku Nyumon, pages 219-230 (edited by Nippon Gakujutsu Shinkokai, 155 Fluorine Chemistry Committee, 1997) followed by fluorination.

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. 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; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amine oxides such as triethylamine, N, N-dimethylaniline, pyridine, pyridine N-oxide and the like; ketones such as acetone and the like; water, etc. If desired, these solvents may be used in admixture.

The diazotizing agents used in this reaction may be in the form of any reagents when conventionally used for the diazotization of aromatic amino compounds. Preferably, examples of diazotizing agents are alkali metal salts of nitric acid such as sodium nitrate and the like. The diazotizing agent is used at least in an equimolar amount and preferably in an amount of 1.0-5.0 mol and more preferably 1.0-1.5 mol, per mol of the compound of formula [3h] or salt thereof.

The acid used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of acids include acids such as hydrochloric acid, hydrofluoroboric acid, hydrogen fluoride and the like; solutions of hydrogen fluoride in bases such as a solution of hydrogen fluoride in pyridine, etc. If desired, these acids can be used as a mixture.

In this reaction, the acid is used in an amount of at least 1 ml and preferably 1-50 ml per g of the compound of general formula [3h] or salt thereof, expressed as a volume / weight ratio.

As the additive used in the reaction, hydrofluoroboric acid, sodium tetrafluoride, ammonium fluoroborate and the like can be illustrated. The acid is used at least in an equimolar amount and preferably 1.0-20.0 mol per mol of the compound of formula [3h] or salt thereof.

This reaction is carried out usually at -70 ° C to 100 ° C and preferably at -60 ° C to 30 ° C, for a period of 50 minutes to 24 hours and preferably 1 hour to 10 hours.

(e) The compound of general formula [3i] or salt thereof can be obtained by reacting the compound of general formula [3f] or salt thereof according to Production Method I-1 (b).

(f) The compound of general formula [3a '] or salt thereof can be obtained by reacting the compound of general formula [3i] or salt thereof with a de-protecting agent.

PL 205 150 B1

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples include water; alcohols such as methanol, ethanol, propanol and the like; thioalcohols such as ethanethiol, thiophenol and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; ketones such as acetone, methyl ethyl ketone and the like; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; inorganic acids such as sulfuric acid, hydrochloric acid and the like; carboxylic acids such as acetic acid, trifluoroacetic acid and the like; sulfonic acids such as trifluoromethanesulfonic acid and the like; organic bases such as pyridine, triethylamine and the like; water, etc. These solvents may be used alone or as a mixture of two or more.

As de-protecting agents, agents which are conventionally used to remove the protecting group from a protected aromatic alcohol can be used. Preferably, trimethylsilyl iodide and the like can be mentioned. The production of the de-protecting agent in the reaction system is also acceptable. The de-protecting agent is used in an amount of 0.01-50 mol and preferably 0.1-30 mol, per mol of the compound of formula [3i] or salt thereof.

This reaction is carried out usually at -80 ° C to 200 ° C and preferably 0 ° C to 160 ° C, for a period of one minute to 48 hours and preferably 5 minutes to 20 hours.

The compound of general formula [3e] or a salt thereof, which is a starting material for the above-mentioned reaction, can be produced, for example, according to the method described in J. Am. Chem. Soc, Vol. 71, pp. 2798-2800 (1949).

[Manufacturing Method I-C]

wherein R ¹ is as defined above and R ¹³ is lower alkoxy or aryloxy.

(a) The compound of general formula [3k] or a salt thereof can be produced by reacting the compound of general formula [3l] or a salt thereof with an alcohol in the presence or absence of an acid catalyst or base according to the method described, for example, in Shin Jikken Kagaku Koza, Vol. 14, pages 1599-1602 (edited by the Chemical Society Japan (corporate juricical person), 1978).

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used alone or in a mixture of two or more.

As the alcohols used in the reaction, for example, methanol, ethanol, phenol and the like can be mentioned. The alcohol is used at least in an equimolar amount based on the compound of formula [3l] or salt thereof. If desired, alcohol can also be used as a solvent.

As the acid catalyst for this reaction, reagents conventionally used for the imidation of nitriles can be used. For example, hydrogen chloride and the like can be used for this purpose. The acid catalyst is used in an amount of at least 0.1 mol per mol of the compound of formula [3l] or salt thereof.

As the base used in this reaction, for example, metal alkoxides such as sodium methoxide, sodium ethoxide, sodium phenate and the like can be mentioned. If desired, these bases can also be prepared in the reaction system. In this reaction, the base is used in an amount of at least 0.01 mol and preferably 1.0-5.0 mol, per mol of the compound of formula [3L] or salt thereof.

PL 205 150 B1

This reaction is carried out usually at -78 C to 170 C and preferably -40 C to 120 C, for a period of one minute to 72 hours and preferably 5 minutes to 24 hours.

(b) The compound of general formula [3j] or salt thereof can be obtained by reacting the compound of general formula [3k] or salt thereof with a reagent according to a method described, for example, in Jikken Kagaku Koza, 4th Edition, Vol 14, pages 1614 -1617 (edited by Chemical Society Japan (corporate juricical person), 1978).

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane 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; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used singly or as mixtures of two or more.

As a reagent for this reaction, those reagents which are conventionally used for amidate amidates can be used. Examples of the reagent include gaseous ammonia, alcoholic ammonia, aqueous ammonia, and acid ammonium salts such as ammonium chloride and the like. The reagent is used at least in an equimolar amount based on the compound of formula [3k] or a salt thereof. If desired, the reagent is used as a solvent.

This reaction is carried out usually at -78 C to 170 C and preferably 0 C to 120 C, for a period of one minute to 72 hours and preferably 5 minutes to 24 hours.

[Manufacturing Method I-D]

1a, wherein R ^1a is as defined above.

(a) The compound of general formula [3m] or salt thereof can be obtained by reacting the compound of general formula [3n] or salt thereof with a diazotizing agent and with a hydroxylating agent in the presence or absence of an additive according to the method described in in Jikken Kagaku Koza, Vol 14, pages 537-538 (edited by Chemical Society Japan (corporate juricical person), 1977).

The solvent used in this reaction is not limited, unless exercising an adverse influence on the reaction. Examples of the solvent include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like; 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; nitriles such as acetonitrile and the like; amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like; sulfoxides such as dimethyl sulfoxide and the like; amines and amine oxides such as triethylamine, N, N-dimethylaniline, pyridine N-oxide, and the like; ketones such as acetone and the like; water, etc. These solvents can be used alone or as a mixture.

The diazotizing agents used in this reaction are not particularly limited as long as they are conventionally used for the deaminohydroxylation of aromatic amino compounds. Advantageously, alkali metal nitrites such as sodium nitrite and the like can be used. The diazotizing agent is used at least in an equimolar amount, preferably in an amount of 1.0-5.0 mol and more preferably in an amount of 1.0-2.0 mol, per mol of the compound of general formula [3n].

As the hydroxylating agent used in this reaction, for example, water and the like can be mentioned. The hydroxylating agent is used at least in an equimolar amount to the compound of formula [3h], although a hydroxylating agent can also be used as a solvent if desired.

As the additive used in this reaction, for example, copper salts such as copper sulfate and the like; inorganic bases such as sodium hydroxide, sodium carbonate and the like. The additive is used in an amount of 0.01-100 mol and preferably 0.1-50 mol, per mol of the compound of formula [3n].

PL 205 150 B1

This reaction is carried out usually at -70 ° C to 200 ° C, preferably -50 ° C to 100 ° C, for a period of one minute to 24 hours and more preferably 30 minutes to 10 hours.

(b) The compound of formula [3n] or salt thereof can be obtained by (1) reacting the compound of general formula [3o] or salt thereof with an electrophilic fluorinating agent in the presence or absence of an additive, exactly according to the method described in Fussoon Kagaku, pages 28-37 (edited by Kodansha Scientific, 1993) or by (2) reacting a compound of formula [3o] or a salt thereof with a fluorinating agent in the presence or absence of an additive according to a method as described, for example, in Jikken Kagaku Koza, Vol 14, pages 354-360 (edited by Chemical Society Japan (corporate juricical person), 1977).

In the method (1), the solvent used in this reaction is not limited, as long as it has an adverse influence on the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane, 1,1,2-trichlorotrifluoroethane and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol and the like; nitriles such as acetonitrile and the like; organic acids such as acetic acid, formic acid, trifluoroacetic acid and the like; inorganic acids such as hydrofluoric acid, sulfuric acid and the like; water, etc. These solvents may be used alone or as a mixture of two or more.

The electrophilic fluorinating agents used in this reaction are not limited, so far as are conventionally used in the addition of fluorine atoms to a carbon-carbon multiple bond. Examples of the preferred agents include gaseous fluorine, trifluoromethyl hypofluorite, acetyl hypofluorite, difluoroxenone, perchloryl fluoride, cesium fluorosulfate, N-fluoropyridinium triflate, N-fluoro-N-alkylallenesulfonamide, N-fluorosulfonamide sultame, N-fluorosaccharines (benzenesulfono) imide and N-fluoro-O-benzenedisulfonimide. Fluorine gas is the most preferred of these electrophilic fluorinating agents.

The electrophilic fluorinating agent is used in an amount of 0.05-50 mol and preferably 0.1-20 mol, per mol of the compound of formula [3o] or salt thereof.

The additives used in this reaction are not limited, as long as they are conventionally used in electrophilic fluorination reactions. Preferable examples are acid catalysts such as boron trifluoride, hydrofluoric acid and the like; organic and inorganic bases such as triethylamine, sodium fluoride and the like; halogens such as chlorine, bromine, iodine and the like. These excipients can be used singly or in a mixture of two or more. In this reaction, the excipient is used in an amount of 0.01-10 mol and preferably 0.1-10 mol, per mol of the compound of formula [3o] or salt thereof.

This reaction is carried out usually at -80 ° C to 170 ° C and preferably -80 ° C to 100 ° C, for a period of one minute to 72 hours and preferably 5 minutes to 48 hours.

(2) In the method (2), the solvents used in this reaction are not limited as long as they have an adverse effect on the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, fluorotrichloromethane, 1,1,2-trichlorotrifluoroethane and the like ethers such as diethyl ether, tetrahydrofuran, diethylene glycol diethyl ether, dimethyl cellosolve and the like; alcohols such as methanol and the like; nitriles such as acetonitrile and the like; organic acids such as acetic acid, formic acid, trifluoroacetic acid and the like; inorganic acids such as sulfuric acid and the like; water, etc. These solvents may be used alone or as a mixture of two or more.

The halogenating agents used in this reaction are not particularly limited as long as they are conventionally used for halogenating aromatics. Examples of these agents include bromine, chlorine, sulfuryl chloride, N-bromosuccinimide, N-chlorosuccinimide, and the like. The halogenating agent is used in an amount of 0.05-50 mol and preferably 0.1-20 mol, per mol of the compound of formula [3o] or salt thereof.

The additives used in this reaction are not particularly limited as long as they are conventionally used for halogenating aromatics. Examples include sodium bromide, lead tetraacetate, titanium (IV) chloride, aluminum chloride, silver sulfate and the like. These substances can be used alone or as a mixture of two or more. In this reaction, the additive is used in an amount of 0.01-10 mol and preferably 0.1-10 mol, per mol of the compound of formula [3o] or salt thereof.

This reaction is carried out usually at -80 C to 170 C and preferably -80 C to 100 C, for a period of one minute to 72 hours and more preferably 5 minutes to 48 hours.

In the processes for the preparation of the above-mentioned, all compounds can be used in the form of their salts. As salts, the salts described in the salt paragraph of the compound of general formula [1] can be used. If desired, these reactions can be conducted under an atmosphere of an inert gas such as nitrogen gas. The compound of general formula [1] or a salt thereof, which has been prepared as described above, can be converted into other compounds of general formula [1] or salts thereof by subjecting the compound to reactions such as oxidation, reduction, rearrangement, substitution, halogenation , dehydration, hydrolysis and the like or appropriate combination of these reactions.

Some of the compounds mentioned in the above production methods may have isomers such as optical isomers, geometric isomers, tautomers, etc. In some cases, these isomers can also be used in the invention, as well as solvated products, hydrates and various crystal forms can be used in the invention. After completion of the reaction, if desired, a given compound may take part in the next reaction without isolation.

Some of the compounds mentioned in the above-mentioned production processes may have an amino group, a hydroxyl group, or a carboxyl group. It is also possible, if desired, to protect these groups before and after the reaction to eliminate the protecting groups in a manner known per se.

The compound of general formula [1] or a salt thereof can be isolated, purified or recrystallized by conventional methods such as extraction, crystallization and / or column chromatography, etc.

The compound of the invention is formulated in combination with various pharmaceutical additives, such as an excipient, binder, disintegrant, disintegrant, anti-stick and release agent, lubricant, absorption-adsorption carrier, solvent, filler, isotonic agent. , dissolution aid, emulsifying agent, suspending agent, thickening agent, coating agent, absorption activator, gelling-coagulation activator, light stabilizer, preservative, moisturizing agent, emulsion-suspension-dispersion fixative, preservative color, anti-oxygen scavenger, sweetener, flavor, colorant, foaming agent, antifoam, analgesic, antistatic, buffering agent, pH adjusting agent, etc. and converted into pharmaceutical compositions such as center oral (tablet, capsule, powder, granules, microgranules, pill, suspension, emulsion, solution, syrup, etc.), injection, suppository, external agent (ointment, plaster, etc.), aerosol, etc.

The above-mentioned formulations are converted into pharmaceutical compositions by the usual methods.

Solid preparations for oral administration such as tablet, powder, granules and the like are prepared in the usual manner, including pharmaceutical additives for the preparation of solid preparations, including excipients such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous secondary calcium phosphate, partially gelatinized starch, corn starch, alginic acid and the like; binders such as simple syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, ethyl cellulose, sodium alginate, gum arabic, hydroxypropyl methyl cellulose, ethanol, hydroxypropyl, and the like; disintegrants such as dry starch, alginic acid, powdered agar, starch, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate, and the like; disintegrants such as stearyl alcohol, stearic acid, cocoa butter, hydrogenated oil and the like; antiblocking and anti-sticking agents such as aluminum silicate, calcium hydrogen phosphate, magnesium oxide, talc, silicic acid anhydride and the like; lubricants such as carbauba wax, light silicic acid anhydride, aluminum silicate, magnesium silicate, hydrogenated oil, hydrogenated vegetable oil derivatives, sesame oil, white beeswax, titanium oxide, dry aluminum hydroxide gel, stearic acid, calcium stearate, magnesium stearate, talc, calcium hydrogen phosphate, sodium lauryl sulfate, polyethylene glycol and the like; absorption activators such as quaternary ammonium salts, sodium lauryl sulfate, urea, enzymes and the like; absorption-adsorption vehicles such as starch, lactose, kaolin, bentonite, silicic acid anhydride, hydrogenated silicon dioxide, magnesium metasilicate-aluminate, colloidal silicic acid and the like, etc.

Thereafter, if desired, tablets can be converted into coated tablets such as sugar coated tablets, gelatin coated tablets, gastric soluble coated tablets, enteric coated coated tablets or water soluble coated coated tablets.

PL 205 150 B1

A capsule is prepared by mixing the above-mentioned pharmaceutical ingredients and filling a hard gelatin capsule, soft capsule etc. with the mixture thus obtained.

It is also possible to prepare an aqueous or oily suspension, solution, syrup or elixir by preparing a liquid preparation in a conventional manner from a pharmaceutical composition together with the above-mentioned additives for a liquid preparation, such as a solvent, filler, isotonizing agent, emulsifying agent, thickening agent, etc.

Suppositories can be prepared by adding a suitable absorption activator to polyethylene glycol, cocoa butter, lanolin, higher alcohol, higher alcohol ester, gelatin, semi-synthetic glyceride, Witepsol, or the like, and forming a mixture together with the pharmaceutical composition.

An injectable form is prepared by mixing a pharmaceutical composition with pharmaceutical additives for a liquid preparation, including diluents such as water, ethyl alcohol, Macrogol, propylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid. , sodium hydroxide and the like; pH adjusters and buffering agents such as sodium citrate, sodium acetate, sodium phosphate and the like; stabilizers such as sodium metabisulfite, ethylenediamine tetraacetic acid, thioglycolic acid, thiolactic acid and the like; isotonic agents such as sodium chloride, glucose, mannitol, glycerin and the like; dissolution aids such as sodium carboxymethylcellulose, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerin and the like; analgesics such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol and the like; local anesthetics; etc. and preparing the injectable mixture by the usual method.

The ointment in the form of a paste, cream or gel can be prepared by molding a pharmaceutical composition with a base such as white petroleum jelly, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite and the like; preservatives such as methyl para-oxybenzoate, ethyl para-oxybenzoate, propyl para-oxybenzoate and the like; stabilizers; wetting agents; etc., whereupon the mixture is formed into an ointment in the usual way.

A patch can be made by applying the above-mentioned ointment, cream, gel or paste to a conventional substrate in the usual manner. As a substrate, woven or non-woven fabrics made of cotton, staple fibers or chemical fibers can be used; and foam films or sheets made of soft polyvinyl chloride, polyethylene, polyurethane and the like.

The method of administering the above-mentioned pharmaceutical composition is not particularly specific, but can be properly selected depending on the form of the preparation, the age, sex and other conditions of the patient and the degree of symptoms in the patient.

The dose of the active ingredient of the pharmaceutical composition of the invention is appropriately selected depending on the method of application of the composition, the age and sex of the patient, the nature of the disease and other conditions. Usually, in terms of the active ingredient, the composition can be administered at a dose of 0.1-100 mg / kg / day for adults, in one or more portions.

Next, the antiviral and cytotoxic activity of the pyrazine derivatives of the general formula [1] according to the invention or their salts will be described.

Sample: The pyrazine derivative of general formula [1] or salt thereof was dissolved in dimethyl sulfoxide to make a 10 mg / ml solution. At the time of use, the solution was diluted with culture medium to the desired concentration and used.

Culture medium: During the propagation of MDCK cells (extracted from dog kidney), MA-104 (extracted from monkey kidney) and Hep-2 (isolated from human pharyngeal cells), E'-MEM was used with 10% fetal bovine serum added and a cytotoxicity assay was performed.

MDCK cells were used as the host cells of the influenza virus in the cytotoxicity assay. Rotavirus host cells were used as MA-104 cells and RS virus host cells were used as Hep-2 cells.

T e s t o te s 1 T h e activity against influenza virus

MDCK cells were plated in 6-well plate (manufactured by CORNING) at a density of 5 x 10 ⁵ cells / well and cultured overnight at 35 ° C under 5% carbon dioxide. Influenza virus (strain A / PR / 8/34) was diluted with serum free medium to 200 PFU / ml, infected and adsorbed at a rate of 0.5 ml / well for 1 hour. After infection and adsorption was complete, E'-MEM containing the test compound at a pre-concentration with 0.6% fine agar, 1% bovine serum albumin and 3 µg / ml acetylated trypsin was added. After

After sufficient coagulation, the plate was inverted and the culture continued for 3 days. After completion of culture, viable cells were stained with 1% Neutral Red, cells were fixed with 10% formalin, the agar medium was removed under running water, and the number of plaques was counted. The plaque inhibition rate was expressed as a percentage based on a control sample containing no test compound.

The results are shown in Table I-2, in which the numbers of the tested compounds correspond to the numbers in the Examples.

T a b e l a I-2

Example no Concentration of the compound added control (pg / ml) Braking speed (%) I-2 10 95 I-6 10 47 I-7 100 42

Then, in the same manner as in Test Example 1, the anti-influenza virus activity of nitrogen-containing heterocyclic carbamoyl derivatives of general formula [23], which can be derived from the compounds of the invention or salts of these derivatives, was assessed. As a test compound, 6-fluoro-3-hydroxy-2-pyrazinecarboxamide dissolved in dimethyl sulfoxide to a concentration of 10 mg / ml was used and diluted with the culture solution to a predetermined concentration just before use. As a result, the anti-influenza virus activity was found to be 100% in terms of the plaque inhibition rate at a concentration of the test compound of 1 µg / ml, and the excellence of the test compound as an antiviral agent was demonstrated.

T e s t o e s 2 [Activity against rotavirus]

MA-104 cells plated in 6-well plate (manufactured by CORNING) at a density of 5 x 10 ⁵ cells / well and cultured overnight at 37 ° C under 5% carbon dioxide.

Rotavirus (Ku strain) activated for 30 minutes. 10 µg / ml acetylated trypsin was diluted to 140 PFU / ml with serum-free culture solution and infected by adsorbing 0.5 ml / well for 1 hour. After the end of infection and adsorption, the infecting medium was removed and E'MEM medium containing 30 µg / ml of test compound, 5 µg / ml of trypsin and 0.4% agarose was added. Rotavirus infected MA-104 cells were grown for 3 days at 37 ° C in an atmosphere with 5% carbon dioxide, then 0.7% agarose containing 0.005% Neutral Red was applied and cultivation continued for 1 day under the conditions described above. After completion of the culture, the test plate was fixed with a 3% formaldehyde solution, the test medium solidified with agar was removed, and then the plaques were counted. The rate of rotavirus inhibition was calculated from the number of plaques in the compound-treated and untreated groups.

As a result, it was found that the compounds of Example 1-1 exhibit anti-rotavirus activity

T e s t o e s 3 [activity against RS virus [respiratory syncytial virus]

Hep-2 cells were spread in a 6-well plate (manufactured by CORNING) at a density of 5x10 ⁵ cells / well and grown overnight at 37 ° C under a condition of 5% carbon dioxide. RS virus (A-2 strain) was diluted to 140 PFU / ml with serum free medium, infected and adsorbed for 1 hour at 0.5 ml / well. After infection and adsorption were completed, the infecting medium was removed and E'-MEM containing 30 µg / ml of the test compound, 0.12% glutamine, 2% fetal bovine serum and 1% methylcellulose was added. Hep-2 cells infected with RS virus were cultured for 3 days at 35 ° C under a condition of 5% carbon dioxide. After completion of the culture, the test plate was fixed with a 3% formaldehyde solution, the test medium containing methylcellulose was removed. Then, the test plate was stained with 5% Giemza's solution and the number of plaques was counted. The RS virus inhibition rate was calculated from the number of plaques in the group of untreated and treated compounds.

As a result, the compound of Example 1-14 was found to be active against RS virus.

T e s t o w e s 4 (cytotoxic activity)

The medium containing the test compound at the predetermined concentration was added to a 96-well plate (from CORNING CO.) At 100 µl / well. Subsequently, a dispersion of MDCK cells was prepared at a concentration of 2 x 10 ⁴ cells / ml in medium, dispersed at 100 µl / well and cultured for 3 days at 37 ° C under a condition of 5% carbon dioxide. After

After culturing, the number of viable cells was counted by the XTT method [for example, CANCER RESEARCH, Vol. 48, pages 4,827-4,833 (1988), etc.].

As a result, it was found that all compounds listed in Table I-2 showed 50% inhibition of cell growth at a concentration of 100 µg / ml or higher (IC ₅₀ ).

BEST PERFORMANCE OF THE INVENTION

Thereafter, compounds of the invention and a method for the preparation of intermediates of the invention will be described in Reference Examples and Examples. This does not limit the invention in any way.

In the following Reference Examples and the Examples, all ratios in the eluent mixtures are defined as the "volume ratio." The carrier for the column chromatography was BW-127ZH Silica Gel (manufactured by Fuji Silysia Chemical Co.); the reverse phase chromatography vehicle was YMC.GEL ODS-AM 120-S50 (YMC CO., LTD.) and the ion exchange column chromatography vehicle was DEAE Cellulose (manufactured by Wako Pure Chemical Industries).

The abbreviation in the Reference Examples and Examples has the following meaning: DMSO-d6: deuterated dimethyl sulfoxide.

P r z k ł a d O d n i e s i e n i a I-1

17.0 g of methyl 3-amino-6-bromo-2-pyrazinecarboxylate was dissolved in 100 ml of concentrated sulfuric acid. 10.1 g of sodium nitrate were added under ice-cooling, and stirred for 30 minutes. The reaction mixture was poured into 920 ml of methanol and heated to reflux for 5 hours. After cooling the reaction mixture, the mixture was concentrated under reduced pressure, the residue thus obtained was added to a mixture of 500 ml of ice-water and 600 ml of chloroform, and the mixture thus obtained was separated into layers. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 6.30 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate was obtained in the form of a light yellow oily substance.

IR (KBr) cm ^-1 : 1735 ¹ H-NMR (CDCl 3) δ: 3.97 (3H, s), 4.06 (3H, s), 8.37 (1H, s).

P r z k ł a d O d n i e s i e n i a I-2

Under nitrogen gas, 11.4 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate was dissolved in 227 ml of toluene, and 10.3 g of benzophenonoimine, 0.42 g of tris (dibenzylideneacetate) dipalladium, 0.86 g ( s) - (-) - 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl and 6.20 g of sodium tert-butoxide. The mixture thus obtained was stirred at 80 ° C for 1 hour. After cooling the reaction mixture, it was filtered. The filtrate was purified by column chromatography [eluent: toluene: ethyl acetate = 20: 1]. The obtained oily substance was dissolved in 140 ml of tetrahydrofuran, 7 ml of 2 mol / L hydrochloric acid were added, and the mixture thus obtained was stirred at room temperature for 15 minutes. A mixture of 200 mL of chloroform and 50 mL of water was added to the reaction mixture, and then 1 mol / L sodium hydroxide was added to make the mixture basic, and the organic layer was separated. The organic layer thus obtained was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: toluene: ethyl acetate = 1: 1] to obtain 3.64 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate as a yellow colored oily substance.

IR (KBr ^-) cm ^-1: 1716, 1670 ¹ H-NMR (DMSO-d6) δ: 3.80 (3H, s), 3.82 (3H, s), 7.20 (2H, brs), 7.77 (IH, s).

P r z k ł a d O d n i e s i e n i a I-3

3.5 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate were dissolved in 70 ml of methanol. Ammonia gas was introduced into the solution to make a saturated solution, and the solution was stirred at room temperature for 14 hours. After removing the solvent from the reaction mixture under reduced pressure, 3.1 g of 6-amino-3-methoxy-2-pyrazinecarboxamide were obtained as a solid.

IR (KBr) cm ^-1: 1684 ¹ H-NMR (DMSO-d6) δ: 3.79 (3H, s), 5.87 (2H, brs), 7,30-7,75 (3H, m) .

PL 205 150 B1

P r z k ł a d O d n i e s i e n i a I-4

Under nitrogen gas, 1.50 g of 6-amino-3-methoxy-2-pyrazinecarboxamide was dissolved in 12 ml of a 70% fluoride-pyridine solution under ice cooling. Then, 0.71 g of sodium nitrate was added at -50 ° C, and the mixture thus obtained was stirred at 10 ° C for 1 hour. After the reaction mixture was stirred for an additional hour, a mixture of 50 ml of ice water and 100 ml of chloroform was added, and the mixture thus obtained was separated into its layers. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 1.29 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was obtained as a solid.

IR (KBr) cm ^-1: 1707 ¹ H-NMR (DMSO-d6) δ: 3.95 (3H, s), 7,55-8,15 (2H, m), 8.39 (12H, d, J = 8.3 Hz).

P r z k ł a d O d n i e s i e n i a I-5

Under nitrogen gas, 1.51 g of sodium iodide was dissolved in 22 ml of acetonitrile. After adding 1.10 g of trimethylsilyl chloride, the mixture thus obtained was stirred at room temperature for 20 minutes. Then, 0.43 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide was added, and the mixture thus obtained was stirred at the same temperature for 18 hours. The reaction mixture was added to a mixture of 10 ml of water and 200 ml of chloroform, and the mixture thus obtained was separated into its layers. The organic layer was washed successively with a 5% aqueous sodium thiosulfate solution and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: hexane: ethyl acetate = 2: 1] to obtain 0.06 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide as a white-colored solid.

IR (KBr) cm ^-1: 1685, 1658 ¹ H-NMR (CDCl3) δ: 5,40-7,80 (2H, m), 8.31 (1H, d, J = 7.8 Hz), 12 . 33 (IH, s).

P r z k ł a d O d n i e s i e n i a I-6

1.0 g of methyl 6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate was dissolved in 40 ml of dichloroethane. Under nitrogen gas, 1.0 mL of 1,1,1,3,3,3-hexamethyldisilizane and 0.54 mL of chlorotrimethylsilane were successively added and heated to 90 ° C for 2 hours. The mixture was allowed to cool and the solvent was removed under reduced pressure. The residue was dissolved in 30 ml of dichloroethane, and 2.68 g of β-D-ribofuranose 1-acetate-2,3,5-tribenzoate and 1.24 ml of tin (IV) chloride were successively added, and the mixture thus obtained was stirred at room temperature for 16 hours. . The reaction mixture was added to 30 ml of ice water and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution and separated into layers. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: hexane: ethyl acetate = 4: 1] to obtain 1.76 g of 4 - {(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5- [ Methyl (benzoyloxy) methyl] tetrahydro-2-furanyl} -6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxylate in the form of a yellow-colored oily substance.

IR (neat) cm ^-1: 1728 ¹ H-NMR (CDCl3) δ: 3.94 (3H, s), 4,5-4,9 (3H, m), 5,6-6,0 (2H, m), 6.3-6.5 (1H, m), 7.1-8.2 (16H, m).

P r z k ł a d O d n i e s i e n i a I-7

0.80 g 4 - {(2R, 3R, 4R, 5R) -3,4-bis (benzoyloxy) -5 - [(benzoyloxy) methyl] tetrahydro-2-furanyl} -6-chloro-3-oxo-3 Methyl 4-dihydro-2-pyrazinecarboxylate was suspended in 16 ml of methanol. While the suspension was cooled with ice, 0.73 g of a 28% methanolic sodium methoxide solution was added, and the mixture thus obtained was stirred at the same temperature for 1 hour. After the mixture was stirred at room temperature for an additional 3 hours, the pH of the mixture was adjusted to 7 with 6 mol / L hydrochloric acid, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: chloroform: methanol = 10: 1] to obtain 0.29 g of 6-chloro-4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) methyl tetrahydro-2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxylate in the form of a yellow-colored oily substance.

IR (neat) cm ^-1: 1728 ¹ H-NMR (CDCl3 + DMSO-d6) δ: 3,6-5,6 (11H, m), 5.99 (1H, s), 8.67 (1H, s).

Example I-1

1.0 g of 3-hydroxy-2-pyrazinecarboxamide was suspended in 5.0 ml of 1,1,1,3,3,3-hexamethyldisilazane. The suspension was heated to reflux for 30 minutes and allowed to stand

After cooling, the solvent was removed under reduced pressure. The residue was dissolved in 5.0 ml of dichloroethane under nitrogen gas, and 3.11 g of β-D-ribofuranose 1-acetate-2,3,5-tribenzoate and 0.50 ml of tin (IV) chloride were successively added, and the mixture thus obtained was stirred at room temperature for 22 hours. The reaction mixture was diluted with 30 mL of ethyl acetate and 20 mL of water, adjusting the pH to 8 with saturated aqueous sodium bicarbonate solution, filtering the precipitate and separating the organic layer. The organic layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography [eluent: ethyl acetate: methanol = 10: 1], then isopropyl ether was added and the solid was collected by filtration. Thus, 0.41 g of [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) benzoate was obtained. tetrahydro-2-furanyl] methyl in the form of a white solid.

IR (KBr) cm ^-1: 1734, 1685 ¹ H-NMR (CDCl3) δ: 4,6-5,1 (3H, m), 5.8-6.2 (3H, m), 6.39 ( 1H, d, J = 2.5Hz), 7.2-8.2 (17H, m), 8.95 (1H, br s).

P r x l a d I-2

0.37 g of [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetrahydro-2-furanyl] benzoate ] methyl was dissolved in 4 ml of methanol. While cooling the solution with ice, gaseous ammonia was introduced until saturation. The reaction mixture was stirred at room temperature for 15 hours and the solvent was removed under reduced pressure. Methanol was added to the residue and the precipitate was collected by filtration to give 0.12 g of 4 - [(2R, 3R, 4S, 5R) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo- 3,4-dihydro-2-pyrazinecarboxamide as a light brown solid.

IR (KBr) cm ^-1: 1654 ¹ H-NMR (DMSO-d6) δ: 3.73 (2H, dd, J = 5.4, 5.4 Hz), 3.8-4.2 (3H, m), 5.08 (1H, brs), 5.24 (1H, t, J = 5.4Hz), 5.61 (1H, brs), 5.92 (1H, s), 7.54 ( 1H, d, J = 4.2Hz), 7.71 (1H, brs), 8.27 (1H, d, J = 4.2Hz), 8.30 (1H, brs).

Example I-5

6-fluoro-3-hydroxy-2-pyrazinecarboxamide was treated in the same manner as in Example I-1 to give the benzoate [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2 -oxo-1 (2H) -pyrazinyl] -3,4-bis (benzoyloxy) tetrahydro-2-furanyl] methyl.

IR (KBr) cm ^-1: 1726, 1690 ¹ H-NMR (DMSO-d6) δ: 4,6-5,0 (3H, m), 5.9-6.1 (2H, m), 6. 33 (IH, s), 7.3-8.2 (17H, m), 8.53 (IH, br s).

Example I-6

0.15 g of [(2R, 3R, 4R, 5R) -5- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -3,4-bis (benzyloxy) tetrahydro benzoate -2-furanyl] methyl was dissolved in 2.0 ml of methanol. Then, 0.14 g of 28% methanolic sodium methoxide solution was added, and the mixture was stirred at an ice-cooled temperature for 20 minutes and then at room temperature for 30 minutes. The reaction mixture was acidified with 0.75 mL of 1 mol / L hydrochloric acid, and the solvent was removed under reduced pressure. After the residue was purified by column chromatography [eluent: chloroform: methanol = 5: 1], isopropanol and diethyl ether were added and the solid was collected by filtration to give 40 mg of 4 - [(2R, 3S, 4R, 5R) -3.4- dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide.

IR (KBr) cm ^-1 : 1686

E xample I-7

0.26 g of 6-chloro-4 - [(2R, 3R, 4S, 5S) -3,4-dihydroxy-5- (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3,4-dihydro-2 The methyl pyrazinecarboxylate was dissolved in 4 ml of methanol. While cooling the solution with ice, gaseous ammonia was introduced until saturation. The reaction mixture was stirred at ice-cooled temperature for 1 hour and then the solvent was removed under reduced pressure. After purification of the residue thus obtained by column chromatography [eluent: chloroform: methanol = 7: 1], 0.06 g of 6-chloro-4 - [(2R, 3S, 4R, 5R) -3,4-dihydroxy-5- was obtained. (hydroxymethyl) tetrahydro-2-furanyl] -3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a light yellow solid.

IR (KBr) cm ^-1 : 1693

PL 205 150 B1

Example I-8

Under a stream of nitrogen gas, 5.3 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide was suspended in 53 ml of acetonitrile. Then, 8.4 ml of N, O-bis (trimethylsilyl) acetamide was added at an ice-cooled temperature, and the mixture thus obtained was stirred at room temperature for

1.5 hours. While cooling the reaction mixture with ice, a solution of 9.4 g of (2R, 3R, 4R) -4,5-bis (acetyloxy) -2- (hydroxymethyl) tetrahydro-3-furanyl acetate prepared elsewhere according to the procedure described above was successively added to the reaction mixture. in Carbohydr. Res., Vol. 203, No., 9, pages 324-329 (1990) in 53 ml of acetonitrile and 7.2 ml of tin (IV) chloride, and the mixture thus obtained was stirred at room temperature for 20 minutes. The reaction mixture was poured into a mixture of 100 ml of 700 ml of ethyl acetate and 300 ml of saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. All layers were combined and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of methanol, 100 ml of 80% aqueous acetic acid solution was added, and the mixture thus obtained was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography [eluent: chloroform: methanol = 40: 1], chloroform and isopropyl ether were added, and the solid was collected by filtration to obtain 9.3 g of acetate (2R, 3R, 4R , 5R) -4- (acetyloxy) -2- [3- (aminocarbonyl) -5-fluoro-2-oxo-1 (2H) -pyrazinyl] -5- (hydroxymethyl) tetrahydro-3-furanyl as a solid light yellow in color.

IR (KBr) cm ^-1: 3411, 1752, 1686 ¹ H-NMR (DMSO-d6) δ: 2.04 (3H, s), 2.10 (3H, s), 3.64 (1H, ddd, J = 2.5, 5.0, 13Hz), 3.86 (1H, ddd, J = 2.5, 5.0, 13Hz), 4.29 (1H, d, J = 6.0Hz) , 5.35 (1H, t, J = 6.0Hz), 5.49 (1H, dd, J = 3.0, 5.0Hz), 5.65 (1H, t, J = 5.0 Hz), 6.11 (1H, d J = 3.0Hz), 7.96 (1H, brs), 8.42 (1H, d, J = 5.0Hz), 8.49 (1H, brs ).

The pyrazine derivatives or their salts according to the invention show excellent antiviral activity and are useful in the preparation of pharmaceuticals.

Claims (8)

Patent claims 1. Pyrazine derivative of the general formula Wherein R ¹ is hydrogen or halogen; R ² is hydrogen; R ³ and R ⁵ are hydrogen; R ⁴ and R ⁶ represent a hydroxyl group which may be optionally substituted with at least one group selected from the group consisting of a carboxyl group, a lower alkyl group, a lower alkoxycarbonyl group, an aryl group, a cycloalkyl group, a lower alkenyl group, a halogen lower alkyl group and a heterocyclic group or optionally protected by one selected from acyl groups, lower alkyl groups, lower alkenyl groups, ar-lower alkyl groups, oxygen- and sulfur-containing heterocyclic groups, lower alkoxy- and lower-alkylthio-lower alkyl groups, alkan- or allenesulfonyl, enol ether groups; A is oxygen; n is 0 and Y is an oxygen atom, or a salt of the derivative. 2. A derivative according to claim 1 ^{4. The} method of claim 1, wherein R 4 and R ⁶ are hydroxy. 3. The derivative according to claim 1 3. A compound according to claim 1 or 2, characterized in that R ¹ is hydrogen or fluoro. PL 205 150 B1 A pharmaceutical composition comprising a compound or salt thereof as defined in claim 1 1-3. 5. A pharmaceutical composition comprising a compound or salt thereof as defined in claim 1 1-3 for use as an antiviral agent. 6. A composition according to p. 5 for use as an agent against influenza virus, RS virus, AIDS virus, papillomavirus, adenovirus, hepatitis A virus, hepatitis B virus, hepatitis C virus, polio virus, echo virus, coxackie virus, enterovirus, rhinovirus , rotavirus, newcastle disease virus, mumps virus, vesicular stomatitis virus and Japanese encephalitis virus. 7. The composition according to p. 6 for use as an anti-influenza agent. 8. A composition as claimed in p. 6 for use as an agent against the hepatitis C virus.