Derivatives of pyrazine and their salts, pharmaceutical composition comprising these compounds

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazine of the general formula (I):

wherein R1 means hydrogen (H) or halogen atom; R2, R3 and R5 mean hydrogen atom (H); R4 and R6 mean hydroxy-group optionally protected with acetyl or benzoyl group; A means oxygen atom (O); n = 0; Y means oxygen atom (O), or their salts. Compounds show the excellent anti-viral activity and useful as a therapeutic agent in treatment of viral infections. Also, invention describes a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 2 tbl, 15 ex

 

The invention relates to new derivatives of pyrazine or their salts, pharmaceutical compositions containing these compounds.

Prerequisites to the creation of inventions

To antiviral agents, currently used in clinical practice, include acyclovir and vidarabine against herpes viruses, ganciclovir and foscarnet against viruses cytomegaly, and interferon, etc. against hepatitis viruses. In addition, against influenza virus undertake extensive prevention using vaccines, and for this purpose use of low molecular weight compounds such as hydrochloride amantadine and ribavirin. In addition, in recent times also used zanamivir.

On the other hand, as for the antiviral activity of analogues of nucleoside and nucleotide derived pyrazinone ring, for example, first it was reported that compounds of General formula:

where R7represents a hydrogen atom, a methyl group or a C10H21possess antiviral activity. However, this type of connection does not show activity against the virus Visna" [Nucleosides &Nucleotides, Vol.15, Nos.11 and 12, Pages 1849-1861 (1996)]. In addition, the analogs of nucleoside and nucleotide having pyrazinone ring, substituted carbamoyl group up with the x not yet been reported.

Problems associated with the use of amantadine, is that it does not show activity against influenza virus type b, although it is effective against influenza virus type a, because of its mechanism of action, resulting, perhaps, is the acquisition of drug resistance to this connection, which leads to the breakdown, etc. on the other hand, although ribavirin and exerts an inhibitory action with respect to the polymerase and is effective against influenza type a and type b, it does not show an adequate clinical effect when oral use.

Hence, it is necessary to develop antiviral agent, has a preventive effect against various viruses and especially against influenza virus, and exhibiting a therapeutic effect.

Description of the invention

To address the above challenges were performed extensive research. In the result it was found that the derived pyrazine represented by the following General formula [1]:

where R1represents a hydrogen atom or halogen atom; R2represents hydrogen; R3and R5represent hydrogen; R4and R6represent a substituted or unsubstituted, protected or unprotected guide is auxillou or amino group; And represents an oxygen atom; n is 0; and Y represents an oxygen atom

or its salt are excellent antiviral activity. On the basis of the obtained data was completed the present invention.

The present invention is described in detail below.

As used in this description, the terms shall have following meaning unless indicated otherwise. The term "halogen atom" means a fluorine atom, chlorine atom, bromine atom or iodine atom; "halogenated methyl group" means a mono-, di - or tizamidine halogenated methyl group, such as vermeil, chloromethyl, methyl bromide, iodomethyl, dichloromethyl, trifluoromethyl, trichloromethyl and the like; "halogenated carbonyl group" means percarbonates, chlorocarbonyl, brakebill or jokermorino group; a "lower alkyl group" means C1-5alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl and the like; "lower alkoxygroup" means C1-5alkoxygroup, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and the like; "lower alkoxycarbonyl group" means C1-5alkoxycarbonyl group, such as methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl n-butoxycarbonyl, isobutoxide, second-butoxycarbonyl, tert-butoxycarbonyl, pentyloxybenzoyl and the like; "lower alkylamino" means mono - or di-C1-5alkylamino, such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamine and the like; "lower alkyl group containing halogen" means C2-5alkyl group containing halogen, such as vermeil, chloromethyl, methyl bromide, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, chloropropyl and the like; "lower Alchemilla group" means C2-5alkenylphenol group, such as vinyl, allyl and the like; "cycloalkyl group" means3-6cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like; "aryl group" means a phenyl group, naftalina group or the like; and "heterocyclic group" means a 4 to 6 membered ring or a condensed heterocyclic group containing at least one heteroatom selected from oxygen atom, nitrogen atom and sulfur atom, such as azetidine, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolin, oxazolyl, isoxazolyl, furutani, pyrrolidinyl, pyrrolyl, imidazolidinyl, imidazolyl, pyrazolidine, pyrazoline, 1,3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazole is, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyranyl, morpholinyl, 1,2,4-triazinyl, benzothiazyl, naftotiekis, benzofuran, isobenzofuran, bromanil, indolizinyl, isoindolyl, indolyl, indazoles, purinol, hinely, ethanolic, phthalazine, naphthylidine, honokalani, hintline, cinnoline, phthalidyl, isopropanol, bromanil, indolinyl, isoindolyl, benzoxazolyl, triazolopyridine, tetrathyridia, tetraterpenes, diazolidinyl, thiadiazolidine, triazolopyridazines, benzimidazolyl, benzothiazolyl, 1,2,3,4-tetrahydroquinolin, imidazo[1,2-b][1,2,4]-triazinyl, hinokitiol and the like.

In those cases, when the connection according to the present invention and an intermediate compound containing a hydroxyl group, mercaptopropyl, amino group, karbamoilnuyu group or carboxyl group, these substituents may be protected by a known protective groups.

The terms "group monophosphoric acid", "group diphosphorous acid" and "group triphosphorous acid" means a group of the following General formula:

where k is 1, 2, and 3, respectively.

Protective groups for the group monophosphoric acid, diphosphorous acid and triphosphorous acid include all groups that are normally used for protection of the phosphate groups is islote. Examples of such groups include lower alkyl groups such as methyl, cyclopropylmethyl, tert-butyl, ethane-1,2-diyl and the like; lower alkyl groups containing halogen, such as 2,2,2-trichloroethyl, 2,2,2-trichloro-1,1-dimethylethyl, 2,2,2-tribromoethyl and the like; acyl-lower alkyl groups such as 1-acetylethyl and the like; cyano-lower alkyl groups such as 2-cyanoethyl and the like; lower alkylsulfonyl-lower alkyl group, such as 2-methylsulfonylmethyl and the like; arylsulfonyl-lower alkyl groups such as 2-phenylsulfonyl and the like; alkeneamine groups such as allyl and the like; aryl groups such as phenyl, o-hydroxyphenyl, o-chlorophenyl, p-chlorophenyl, 2,4-dichlorophenyl, p-nitrophenyl, 2-dimethylamino-4-nitrophenyl, 2-tert-butylphenyl, 2-chloromethyl-4-nitrophenyl, o-phenylene and the like; aryl-lower alkyl groups such as benzyl, o-nitrobenzyl, p-nitrophenolate and the like; heterocyclic groups, such as 8-chinolin, 5-chloro-8-chinolin and the like, etc. For protection can be used one or more kinds of the above-mentioned protective groups.

Protective groups for a carboxyl group may include all groups, usually used to protect the carboxyl group. Examples of such groups include lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-b is Teal and the like; aryl groups such as phenyl, naphthyl and the like; aryl-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 acetylenyl, benzoylmethyl, p-nitrobenzoyl, p-bromobenzoyl, p-methanesulfonylaminoethyl and the like; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl, 2-tetrahydrofuranyl and the like; lower alkyl groups containing halogen, such as 2,2,2-trichloroethyl and the like; lower alkyl-silyl-alkyl groups such as 2-(trimethylsilyl)ethyl and the like; aryloxyalkyl groups, such as acetoxymethyl, propionylacetate, pivaloyloxymethyl and the like; nitrogen-containing heterocycle-lower alkyl group, such as phthalimidomethyl, succinimide 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 benzoyloxymethyl and the like; lower alkylthio-lower alkyl group, such as methylthiomethyl, 2-methylthioethyl and the like; aaltio-lower alkyl groups, such as phenylthiomethyl and the like; lower alkeneamine group, such as 1,1-dimethyl-2-propenyl, 3-ethyl-3-butinyl, the allyl and the like, and lower alkyl-substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylenediamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilane, tert-butylmethylether and the like.

Protective groups for amino and lower alkylamino may include all groups, usually used to protect amino groups. Examples of such groups include acyl groups, such as trichlorocyanuric, tribromoethanol, benzyloxycarbonyl, p-nitrobenzenesulfonyl, o-bromobenzyloxycarbonyl, (mono-, di - and tri-)chloroacetyl, TRIFLUOROACETYL, phenylacetyl, formyl, acetyl, benzoyl, tert-aryloxyalkyl, tert-butoxycarbonyl, p-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, 4-(phenylazo)benzyloxycarbonyl, 2-furfurylalcohol, diphenylcarbinol, 1,1-dimethylpropanolamine, isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantanecarbonyl, 8-hinolincarbonova and the like; aryl-lower alkyl groups such as benzyl, diphenylmethyl, trityl and the like; aristocraty, such as 2-nitrophenylthio, 2,4-dinitrophenyl and the like; alkane - and Allensville groups, such as methanesulfonyl, p-toluensulfonyl and the like; di-lower alkylamino lowest alkylidene groups, such as N,N-dimethylaminomethylene the like; aryl-lower alkylidene groups, such as benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethyl and the like; nitrogen-containing heterocyclic alkylidene groups such as 3-hydroxy-4-pyridylmethylene and the like; cycloalkylation groups, such as cyclohexylidene, 2-ethoxycarbonylphenyl, 2-ethoxycarbonylphenyl, 2-acetylcyclohexanone, 3,3-dimethyl-5-oxocyclohexyl and the like; di-aryl or di-aryl-lower alkylphosphonyl groups, such as diphenylphosphoryl, dibenzoyltartaric 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 trimethylsilane group and the like.

Protective groups for hydroxyl group and mercaptopropyl may include all groups, usually used to protect the hydroxyl group. Examples of such groups include acyl groups, such as benzyloxycarbonyl, 4-nitrobenzenesulfonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzenesulfonyl, 3,4-dimethoxyphenylacetone, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, isobutylacetate, diphenylcarbinol, 2,2,2-trichlorocyanuric, 2,2,2-tribromoethyl, 2-(t is Immission)etoxycarbonyl, 2-(phenylsulfonyl)etoxycarbonyl, 2-(triphenylphosphonio)etoxycarbonyl, 2-furfurylalcohol, 1-adamantanecarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzyltoluene, 4-ethoxy-1-naphthaleneboronic, 8-hinolincarbonova, 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-trimethylsilylmethyl and the like; lower alkeneamine groups such as allyl and the like; aryl-lower alkyl groups such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl and the like; oxygen-containing and sulfur-containing heterocyclic groups, such as tetrahydrofuryl, tetrahydropyranyl, tetrahydropyranyl and the like; lower alkoxy and lower alkylthio-lower alkyl groups, such as methoxymethyl, methylthiomethyl, benzoyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloromethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl and the like; alkane - and Allensville groups, such as methanesulfonyl, p-toluensulfonyl and the like; substituted silyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylenediamine, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilane, tert-butylmethylether and the like; nesennye aryl group, such as hydroquinone, p-methoxyphenol and the like; enol-(simple)ester group, such as (2-methyl-3-oxo-1-cyclopenten-1-yl) and the like.

Protective groups for carbamoyl group may include all groups, usually used to protect carbamoyl group. Examples of such groups include aryl-lower alkyl groups such as benzyl, 4-methoxybenzyl, 2,4-dimethoxybenzyl and the like; lower alkoxyalkyl groups, such as methoxymethyl and the like; aryl-lower alkoxygroup, such as benzoyloxymethyl and the like; substituted silyl lower alkoxy-lower alkyl groups such as tert-butyldimethylsiloxy and the like; lower alkoxygroup, such as methoxy and the like; aryl-lower alkoxygroup, such as benzyloxy and the like; lower allylthiourea, such as methylthio, triphenylmethyl and the like; aryl-lower allylthiourea, such as benzylthio and the like; substituted silyl groups such as tert-butyldimethylsilyl and the like; aryl groups such as 4-methoxyphenyl, 4-methoxymethyl, 2-methoxy-1-naphthyl and the like; acyl groups such as trichlorocyanuric, TRIFLUOROACETYL, tert-butoxycarbonyl and the like, etc.

The substituents is a hydroxyl group represented by R3, R4, R5, R6, Z2, Z3, Z4and Z5which may be substituted, which may include protected or unprotected carboxyl group, lower alkyl group, lower alkoxycarbonyl group, aryl group, cycloalkyl group, lower alkenylphenol group, a lower alkyl group containing halogen, and heterocyclic group. For substitution can be used one or more types of substituents selected from the above substituents.

The substituents of the amino group represented by R3, R4, R5, R6, Z2, Z3, Z4and Z5which may be substituted may include substituted, protected or unprotected carboxyl, hydroxyl, amino and lower alkylamino, a lower alkyl group, lower alkoxygroup, lower alkoxycarbonyl group, aryl group, cycloalkyl group, lower Alchemilla group, a lower alkyl group containing halogen, and heterocyclic group. For substitution can be used by one or more substituents selected from the aforementioned groups.

Deputy phenylsulfanyl group, phenylsulfinyl group and phenylsulfonyl group represented by R22may include lower alkyl groups such as methyl, ethyl and the like.

Salts of compounds of the General formula [1] can normally include well-known salt formed by a basic group such as amino group, etc. and salts formed by the acid group, such as hydroxyl the group, phosphoryl group, carboxyl group, etc. Salts, formed the core group include, for example, salts of inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid and the like; salts of organic acids, such as tartaric acid, formic acid, citric acid, trichloroacetic acid, triperoxonane acid and the like, and salts of sulfonic acid, such as methanesulfonate, benzosulfimide, p-toluensulfonate, mesitylenesulfonyl, naphthalenesulfonate and the like. Salts formed by the acidic group include salts with alkali metal such as sodium, potassium and the like; salts with alkaline earth metal such as calcium, magnesium and the like; ammonium salt; and salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dimethylamine, dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-fenamin, N,N'-dibenziletilendiaminom and the like.

Of the salts mentioned above, preferred are pharmaceutically acceptable salts.

In some cases, compounds of General formulas [1] and their salts have isomers such as optical isomers, geometrical isomers and tautomers. In such cases, the present invention is engages these isomers and also includes solvated products, hydrates, and various crystalline forms.

Of the pharmaceutical compositions according to the present invention, the preferred pharmaceutical compositions are antiviral agents, and, in addition, the preferred antiviral compositions are agents against influenza virus, RS virus (rous sarcoma, AIDS virus, human papilloma virus, adenovirus, hepatitis a virus, hepatitis b virus, hepatitis C virus, polio virus, echo virus, Coxsackie virus, enterovirus, rhinovirus, rotavirus virus Kyokushinkai disease, mumps virus, vesicular stomatitis virus and Japanese encephalitis virus.

Even more preferred antiviral agents are those that are directed against rotavirus, RS virus and influenza virus. The most preferred anti-viral agent is an anti-influenza virus.

Of the compounds according to the present invention, the preferred compounds are such compounds in which R4and R6represents a protected or unprotected hydroxyl group, and their salts.

Even more preferred compounds include compounds in which R1means a hydrogen atom, a chlorine atom or a fluorine atom, and salts of these compounds; and p is impactfully compounds also include compounds such in which R1means a hydrogen atom or a fluorine atom, and salts of these compounds.

Among the compounds according to the present invention are typical, for example, such compounds listed in table I-1, where Bn represents a benzyl group, and "-" represents a simple link.

N[OP(O)HE]3
Table I-1
R1R2R3R4R5R6AnY
HHHOHHOHO0O
nHHOHHOHO0NH
HHHOHHOHO0S
6-FHHOHHOHO0O
6-FHHOHHOHO0 NH
6-ClHHOHHOHO0O
6-FHHOHHHO0O
HHHOHHHO0O
HHHOHHFO0O
6-FHHOHHNH2O0O
6-FHHNH2HOHO0O
6-FHHOHOHHO0O
HHHOHHNH2O0O
HHHNH2HOHO0O
HHHOHOHHO0O
HHHOHFHO0O
HHHOHN3HO0O
6-FHHN3HHO0O
6-FHHHHHO0O
6-F(HO)2POHOHHOHO0O
HHHN3HHO0O
HHHHHHO0O
H(HO)2POHOHHOHO0O
H (BnO)2POH.OHHOHO0O
6-FHHOHHOHCH20O
HHHOHHOHCH20O
HHHOHOHHCH20O
HHHHHHCH20O
HHH-H-CH20O
HHHOHHHO1O
HHHOHHOHO1O
6-FH[OP(O)OH]3HOHHOHO0O
HHOHHOHO0O
6-F[CH2=SNSN2O]P(O)HOHHOHO0O
H[CH2=SNSN2O]P(O)HOHHOHO0O

Below is described the method of obtaining the compounds according to the present invention.

Compounds according to the present invention can be obtained by the schemes of the method of synthesis from I-1 to I-4, below.

where R1, R3, R4, R5, R6, A, Y and n are as defined above; R8represents a lower alkyl group; Z1represents a hydrogen atom or a protective group for hydroxyl group; Z2, Z3, Z4and Z5that may be the same or different, represent a hydrogen atom, halogen atom, asiagraph, protected hydroxy-group or amino group; or Z3and Z5taken together, constitute a simple link.

(a) Compound of General formula [1A] or its salt can be obtained by removing the protective group of the who program of General formula [2A] or its salt.

The solvent used in this reaction is not limited, unless the solvent has no adverse effect on the reaction. Examples of the solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol 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; sulfoxidov, such as dimethyl sulfoxide and the like; water, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

As a reagent for removing the protective groups can be used reagents that are typically used to remove protection from hydroxyl group, amino group and phosphoric acid. However, preferred are base such as sodium methoxide, hydrogen gas, ammonia gas, aqueous ammonia, butylamine and the like; acids such as formic acid, aqueous solution of acetic acid, aqueous solution triperoxonane acid, hydrochloric acid and the like; palladium catalysts such as tetrakis-triphenylphosphine (0) and the like; phosphines such as tripe livostin and the like. These reagents to remove the protection can be used in combination or can be obtained in the reaction system. The reagent for removing the protection, use in the amount of at least 0.01 mol per mol of compound of General formula [2A] or its salt. If you prefer, you can use the reagent for removing protection, as a solvent.

The reaction unprotect usually carried out at a temperature of from -50°170°and preferably from -20°to 100°With, in the course of time from 1 minute to 100 hours and preferably for a time from 5 minutes to 50 hours.

(b) a Compound of General formula [1A], in which Y represents an oxygen atom, or its salt can be obtained by reaction of ammonolysis of the ester of carboxylic acid compounds of General formula [2b] or its salt in the presence or in the absence of a catalyst.

The solvent used in this reaction is not limited, if only he does not have a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like; NITRILES such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; alcohols such as methanol, ethanol, propane and the like; the sulfoxidov, such as dimethyl sulfoxide and the like; water, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents. The reaction can be carried out in the presence of reagents and conditions that are usually used in the ammonolysis reaction of aromatic esters of carboxylic acids. However, it is preferable to use ammonia gas, liquid ammonia or aqueous ammonia. These agents are used in amounts of at least 0.5 mol per mol of compound of the formula [2b] or its salt. You can also use these solvents as a solvent, if desired. The catalyst may be optionally used in this reaction include acid ammonium salts such as ammonium chloride; bases such as sodium methoxide, utility and the like; and amides of alkali metals such as sodium amide and the like. The catalyst is used in an amount of from 0.01 mol to 100 mol, and preferably from 0.01 to 20 mol per mol of compound of the formula [2b] or its salt.

The reaction is usually carried out at temperatures from -100°, 250°and preferably from -78°to 100°during the time from 1 minute to 72 hours and preferably from 30 minutes to 50 hours.

where R1, R3, R4R5R 6, R8, Z2, Z3, Z4, Z5, A, n and Y are as defined above; R9is a protected or unprotected group monophosphoric acid or acid chloride monophosphoric acid; and R12is a protected or unprotected group diphosphorous acid or trifosforny acid.

(a) Compound of General formula [2C] or its salt can be obtained by protecting compounds of General formula [2b] or its salt reagent in the presence or in the absence of acid catalyst or base.

The solvent used in this reaction is not strictly limited, if only he does not have a deleterious effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol 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; sulfoxidov, such as dimethyl sulfoxide and the like; ketones such as acetone and the like; water, etc. Listed solvents may be used as such or in the form of a mixture of two or more the solvents.

As the reagent is used such that o is commonly used to protect hydroxyl groups and amino groups, and preferably 2,2-dimethoxypropane, acetylchloride and benzoyl chloride. If desirable, these reagents can be obtained in the reaction system. The amount of the reagent is at least equimolar amount, and preferably 1.0 to 10 mol per mol of compound of the formula [2b] or its salt.

For the acid catalyst or base used in this reaction includes, for example, p-toluensulfonate, triethylamine and the like. A number of these compounds can be for both of 0.01-10 mol and preferably 0.05 to 10 mol per mol of compound of the formula [2b] or its salt.

The above reaction is usually carried out at a temperature of from -50°170°and preferably from 0°to 150°With the passage of time from one minute to 24 hours and preferably from 5 minutes to 10 hours.

(b) a Compound of General formula [2d] or its salt can be obtained (1) by the interaction of the compounds of General formula [2C] or its salt with fosforiliruyusciye reagent in the presence or in the absence of the additive according to the method described in Jikken Kadaku Koza, 4thEdition, Vol 22, Pages 313-438 (edited by the Chemical Society Japan (corporate juridical person), 1992) or by (2) the interaction of the compounds with positisiooni reagent and then with an oxidizing agent.

In method (1) the solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. When the minimum level of the solvent include aromatic hydrocarbons, such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like; NITRILES such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like; pyridine, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

As fosforiliruyusciye reagent can be used reagents that are commonly used to phosphorylation of hydroxyl groups. Examples of such fosforiliruyusciye agent include complex diesters of phosphoric acid, such as dimensionful and the like; dayevery phosphoric acid, such as S,S'-diphenyltetrazolium of monocyclohexyl and the like; anhydrides of phosphoric acid, such as the chloride phosphoryl, diallylmalonate and such etc. Fosforiliruyusciye reagent is used at least in equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of compound of the formula [2C] or its salt. To additives include, for example, azo compounds, such as diethyl ether azodicarboxylic acid diisopropyl ester of azodicarboxylic acid and the like; phosphines such as triphenylphosphine and the like; anhydrides is resolvability, such as anhydrides 2,4,6-triisopropylbenzenesulfonyl and such etc.; bases, such as pyridine, chloride tert-butyl magnesium and the like; etc. If desired, the additives can be used in combination. The additive is used at least in equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of compound of the formula [2C] or its salt.

The above reaction is usually carried out at a temperature of from -50°170°and preferably from 0°to 100°during the time from 1 minute to 72 hours, and preferably from 5 minutes to 24 hours.

In method (2) the solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like; NITRILES such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like; pyridine, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

As vospitaniya reagents can be applied is such reagents, which is usually used in the reaction of phosphatization hydroxyl group. Examples include phosphoramidite, such as diallyldimethylammonium and the like, and anhydrides of phosphorous acid, such as diallylphthalate and the like. Fastidisiosi reagent is used at least in equimolar amount and preferably in an amount of 1.0 to 3.0 mol per mol of compound of the formula [2C] or its salt. As additives used, for example, compounds tetrazole, such as 1H-tetrazole and the like, and bases, such as pyridine, kallidin and the like, and these additives can be used in combination, if desired. Additive used at least in equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of compound of the formula [2C] or its salt.

The oxidizing agents used in this reaction include, for example, peroxides such as m-chlormadinone acid, tert-butylhydroperoxide and the like, and halogen compounds such as iodine and the like. The oxidizing agent is used at least in equimolar amount and preferably in an amount of 1.0-5.0 mol per mol of compound of the formula [2C] or its salt.

The above reaction is usually carried out at temperatures from -78°to 100°and preferably at a temperature of from -50°C to 50°during the time from 1 minute to 24 hours and pre is respectfully from 5 minutes to 6 hours.

(C) a Compound of General formula [1b] or its salt can be obtained by the reaction according to method I-1(b), using the compound of General formula [2d] or its salt.

(d) a Compound of General formula [1C] or its salt can be obtained by the reaction according to method I-1(a), using the compound of General formula [1b] or its salt.

(e) a Compound of General formula [1b] or its salt can be obtained by the reaction according to method I-2(b), using the compound of General formula [1d] or its salt.

(f) the Compound of General formula [1E] or its salt can be obtained by the interaction of the compounds of General formula [1C] or its salt with fosforiliruyusciye agent in the presence or in the absence of a condensing reagent according to the method described, for example, in Chem. Rev., Vol.100, Pages 2047-2059 (2000).

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like; NITRILES such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like; pyridine, etc. Listed dissolve and can be used as a single solvent or a mixture of two or more solvents.

As fosforiliruyusciye reagent can be used such reagents, which are usually used for phosphorylation of the group monophosphoric acid. Examples of such fosforiliruyusciye agent include salts of phosphoric acid, such as phosphate tri-n-butylamine, pyrophosphate n-butylamine and the like, and these fosforiliruyusciye reagents can be synthesized in the reaction system, if desired. Fosforiliruyusciye reagent is used at least in equimolar amount and preferably in an amount of 1.0 to 10 mol per mol of the compounds of formula [1C] or its salt. As the condensing agent can be used, for example, imidazoles such as N,N-carbonyldiimidazole, N-Mei and the like, and amines, such as morpholine, Diisopropylamine and the like, and such amines can be used in combination, if desired. Condensing reagent is used at least in equimolar amount and preferably in an amount of 1.0-5.0 mol per mole of the compounds of formula [1C] or its salt.

The above reaction is carried out at a temperature of from -50°to 100°and preferably at a temperature of from 0°C to 50°during the time from 1 minute to 72 hours, and preferably from 5 minutes to 24 hours.

[Method of obtaining 3]

where R1, R8, A, n, Z1, Z , Z3, Z4and Z5are as defined above; Y1represents an oxygen atom or NH group, and R10represents a halogen atom, carbonyloxy or sulfonyloxy.

(a) Compound of General formula [2A] or its salt can be obtained by (1) the conversion of compounds of General formula [3A] or its salt in the compound of General formula [3b] or its salt according to a conventional method of sililirovanie in the presence or in the absence of additives and subsequent (2) the interaction of the obtained compound with a compound of General formula [4A] or its salt in the presence or in the absence of Lewis acid.

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like; NITRILES such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like; and halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane and the like. These solvents may be used in the form of the underwater solvent or a mixture of two or more solvents.

Similarbuy reagent used in the reaction (1)may be any similitude reagent, which is usually used for the conversion of the carbonyl group in silyl-enology simple ether. Examples of such reagents include 1,1,1,3,3,3-hexamethyldisilazane, N,O-bis(trimethylsilyl)ndimethylacetamide, trimethylsilane and the like. Similarbuy reagent is used at least in equimolar amount and preferably in an amount of 1.0 to 10.0 moles per mole of the compounds of formula [3A] or its salt.

To the additive, which if necessary can be used in this reaction includes, for example, ammonium sulfate and the like. Specified additive is used in an amount of 0.01-10.0 mol, preferably 0.05 to 5.0 mol per mol of compound of formula [3A] or its salt.

This reaction is usually carried out at a temperature of 0-200°and preferably at a temperature of 0-150°With the passage of time from 5 minutes to 24 hours and preferably from 5 minutes to 12 hours.

In reaction (2), the compound of the formula [4A] or its salt is used in amounts of 0.5 to 10 mol, and preferably 0.5 to 5 mol per mol of compound of formula [3A] or its salt.

To the Lewis acid, which if necessary can be used in this reaction includes, for example, trimethylsilyltrifluoroacetamide, chloride tin(IV)chloride titanium(IV), zinc chloride and the like. The Lewis acid is used, at m is re, in the amount of 0.5 mol and preferably in quantities of 0.5 to 10 mol per mol of compound of formula [3A] or its salt.

This reaction is usually carried out at a temperature of 0-100°and preferably at a temperature of 0-50°during the time from 1 minute to 72 hours, and preferably from 5 minutes to 24 hours.

(b) a Compound of General formula [2A] or its salt can be obtained by the interaction of the compounds of General formula [3A] or its salt with a compound of General formula [4b] or its salt in the presence or in the absence of additives using the base as a reagent, eliminating acidity.

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect 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, diethyl ether of diethylene glycol, dimethylethanol and the like; NITRILES such as acetonitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like, etc. Listed solvents can be used as a single solvent or a mixture of two and the and more solvents.

The bases used in this reaction include, for example, inorganic and organic bases, such as triethylamine, tert-piperonyl potassium, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride and the like. When carrying out this reaction the compound of formula [4b] or its salt is used in an amount of 0.1-5 mol and preferably 0.2 to 2 mol per mol of compound of General formula [3A] or its salt. When carrying out this reaction, the base is used in an amount of 0.1-10 mol and preferably 0.2 to 10 mol per mol of compound of General formula [3A] or its salt.

To the additive, which if necessary can be used in this reaction include, for example, palladium catalysts such as tetrakis-triphenylphosphine and the like; phosphines such as triphenylphosphine and the like; polyethers, such as 18-crown-6-(simple)ether and the like. Specified additive is used in an amount of 0.01-10.0 mol, and preferably of 0.03 to 5.0 mol per mol of compound of formula [3A] or its salt.

This reaction is usually carried out at a temperature of from -50°170°and preferably at a temperature of from 0°to 120°during the time from 1 minute to 72 hours, and preferably from 5 minutes to 24 hours.

where R1, A, n, Z1, Z2, Z3, Z4and Z5are such to the to defined above.

The compound of General formula [2g] or its salt can be obtained by the interaction of the compounds of General formula [2f] or its salt with a reagent tonirovania in the presence or in the absence of a base as described, for example. Shin Jikken Called Koza, Vol 14, Pages 1819-1831 (edited by the Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect 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, diethyl ether of diethylene glycol, dimethylethanol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

As a reagent tonirovania can be used such reagents, which are usually used for tonirovania amides of the acids. Examples of such reagents include gaseous hydrogen sulfide, Diaspora pentasulfide, reagent Lawson etc. Reagent tonirovania used in this reaction in an amount of 0.1-10 mol and site is preferably 0.2 to 5.0 mol per mol of compound of General formula [2f] or its salt.

To the base used in this reaction include, for example, such grounds as ammonia, triethylamine, morpholine, pyridine, 4-dimethylaminopyridine and the like. When carrying out this reaction, the base is used at least in an amount of 0.01 mol per mol of compound of the formula [2f] or its salt. If desired, the base can be used as a solvent.

The above reaction is usually carried out at a temperature of from -50°170°and preferably from 0°to 120°during the time from 1 minute to 24 hours and preferably from 5 minutes to 6 hours.

Next will be described a method of obtaining compounds of General formula [2A], [2b], [3A'] and [3j] and their salts, which are the starting materials for producing the compounds according to the present invention.

Compounds of General formula [2A], [2b], [3A'] and [3j] can be obtained by well known methods or the appropriate combination of methods. For example, these compounds can be obtained according to the following method I-A.

where R1, R3, R4, R5, R6, R8, A, n, Z1, Z2, Z3, Z4, Z5and R10are as defined above.

(a) a Compound of General formula [2A] or its salt can be obtained by the interaction of the compounds of General formula [3C] or its salt with which an Association of the General formula [4A] or its salt according to the method of synthesis of I-3(a).

(b) a Compound of General formula [2A] or its salt can be obtained by the interaction of the compounds of General formula [3C] or its salt with a compound of General formula [4b] or its salt according to the method of synthesis of I-3(b).

(c) a Compound of General formula [2b] or its salt can be obtained by the reaction of compounds of General formula [2A] or its salt according to the method of synthesis I-1(a).

Among the raw materials for the implementation of the above reactions, the compound of General formula [3C] or its salt can be prepared by the method described in J. Heterocyclic Chem., Vol.34, No.1, Pages 27-32 (1997) or J. Med. Chem., Vol.12, No.2, Pages 285-287 (1969); a compound of General formula [4A] or its salt can be prepared by the method described in J. Med. Chem., Vol.28, No.7, Pages 904-910 (1985); and the compound of General formula [4b] or its salt can be prepared by the method described in J. Chem. Soc. PERKIN TRANS.1, Pages 2419-2425 (1992), J. Med. Chem., Vol.36, No.14, Pages 2033-2040 (1993) or Bio. Med. Chem. Lett., Vol.6, No.13, Pages 1457-1460 (1996).

where R8is as defined above; R1Arepresents a halogen atom; R11represents a protective group for hydroxyl group, and X represents a halogen atom other than fluorine atom.

(a) Compound of General formula [3f] or its salt can be obtained by the reaction of compounds of General formula [3E] or its salt using diastereomer reagent and the IRTA.

The solvents used in this reaction may be any solvent, if only they have no harmful effects 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, diethyl ether of diethylene glycol, dimethylethanol 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; sulfoxidov, such as dimethyl sulfoxide and the like; amines and aminoacid, such as triethylamine, N,N-dimethylaniline the 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 the form of a mixture. Diasterous reagents used in this invention, virtually unlimited, if they are usually used for the diazotization of aromatic amino compounds. However, preferably, when used nitrites of alkali metals such as sodium nitrite and the like. Diasterous reagent is used at least in equimolar amount and preferably in an amount of 1.0-5.0 mol per mole with the unity formula [3E] or its salt.

The alcohol used in this reaction includes, for example, methanol and the like. Alcohol is used at least in equimolar amount relative to the compound of the formula [3E] or its salt. Alcohol can also be used as solvent, if desired.

The above reaction is usually carried out at a temperature of from -70°to 200°and preferably at a temperature of from -50°to 100°during the time from 1 minute to 24 hours and preferably from 30 minutes to 10 hours.

(b) a Compound of General formula [3g] or its salt can be obtained (1) by the interaction of the compounds of General formula [3f] or its salt with Eminem in the presence of catalyst and substrate as a reagent promoting elimination of acidity, according to the method described in the literature [Tetrahedron Letters, Vol.38, No.36, Pages 6367-6370 (1997)], and (2) by hydrolysis in the presence of additives.

When carrying out the reaction (1) used solvents are not strictly limited, unless they have no harmful effects on the reaction. Examples of the solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like, etc. Listed solvents may be used as such or in the form of a mixture of the Vuh or more solvents.

For this reaction the catalyst may be selected from combinations of palladium catalyst such as palladium(II)acetate, Tris(dibenzylidene-acetone)dipalladium and the like, Nickel catalysts such as bis(1, 5cyclooctadiene)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 amounts of 0.001 to 1.0 mol, and preferably of 0.002 to 0.5 mol per mol of compound of the formula [3f] or its salt.

To the base used in this reaction include alkali metal salt such as tert-piperonyl sodium, cesium carbonate and the like. The base is used at least in equimolar amount and preferably in an amount of 1.0 to 3.0 mol per mol of compound of the formula [3f] or its salt.

To imino used in this reaction includes, for example, benzophenone and the like. Imin used at least in equimolar amount and preferably in an amount of 1.0 to 3.0 mol per mol of compound of the formula [3f] or its salt.

The above reaction is usually carried out at a temperature of 0-120°and preferably at a temperature of 5-100°during the time from 1 minute to 48 hours and preferably from 5 minutes to 24 hours.

(2) In carrying out reaction (2) is used solvents are not strictly limited the, if only they have no harmful effects on the reaction. Apply solvent, such as, for example, ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like; alcohols such as methanol, ethanol and the like; water, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

To the additive used in this reaction include, for example, salts of organic and inorganic acids, such as sodium acetate, hydrochloride, hydroxylamine, muravlensky ammonium and the like; inorganic acids such as hydrochloric acid and the like, and palladium catalysts such as palladium on uglevodoroda and the like.

These additives can be used in combination, if desired. The additive is used in an amount of 0.01-50 mol and preferably 0.1 to 20 mol per mol of compound of General formula [3f] or its salt.

The above reaction is usually carried out at a temperature of 0-120°and preferably at a temperature of 5-100°during the time from 1 minute to 48 hours and preferably from 3 minutes to 24 hours.

(C) a Compound of General formula [3h] or its salt can be obtained by the interaction of the compounds of General formula [3g] or its salt according to the method of synthesis I-1(b).

(a) Compound of General forms of the crystals [3i] or its salt can be obtained by the reaction of deamination of amino compounds of General formula [3h] or its salt using diastereomer reagent in the presence of acid, in the presence or in the absence of the additive according to the method described, for example, Fusso Depending Nyumon, Pages 219-230 (edited by Nippon Gakujutsu Shinkokai, 155 Fluorine Chemistry Committee, 1997), with subsequent fluorination reaction.

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of the solvents include ethers, such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol 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; sulfoxidov, such as dimethyl sulfoxide and the like; amines and aminoacid, such as triethylamine, N,N-dimethylaniline, pyridine, pyridine-N-oxide and the like; ketones such as acetone and the like; water; etc Listed solvents may be used in the form of a mixture, if desired.

Diastereomer reagents used in this reaction may be any of the reagents, if they are usually used for the diazotization of aromatic amino compounds. Preferred diastereomer reagents are, for example, alkali metal salts of nitrous acid such as sodium nitrite and the like. Diasterous reagent used in rainy least in equimolar amount, preferably in an amount of 1.0-5.0 mol, and furthermore preferably 1.0 to 1.5 mol per mol of compound of the formula [3h] or its salt.

The acid used in this reaction is not strictly limited, if only it does not have a deleterious effect on the reaction. Examples of acids include acids such as hydrochloric acid, barterisation acid, hydrogen fluoride and the like; solutions of hydrogen fluoride in the grounds, such as a solution of hydrogen fluoride in pyridine, etc. these acids may be used in the form of a mixture, if desired.

For this reaction the acid is used, at least in the amount of 1 ml, and preferably 1-50 ml per g of compound of General formula [3h] or its salt, which is determined based on the ratio of volume/weight.

To the additive used in this reaction is barterisation acid, tetraploid sodium, perborate ammonium and the like. The acid is used at least in equimolar amount, and preferably 1.0 to 20.0 mol per mol of compound of the formula [3h] or its salt.

The above reaction is usually carried out at a temperature of from -70°to 100°and preferably at a temperature of from -60°With 30°over time from 50 minutes to 24 hours and preferably from 1 hour to 10 hours.

(e) Connection of the soup formula [3i] or its salt can be obtained by the reaction of compounds of General formula [3f] or its salt according to the method of synthesis I-1(b).

(f) the Compound of General formula [3A'] or its salt can be obtained by the interaction of the compounds of General formula [3i] or its salt with a reagent that promotes the removal of the protective group.

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of the solvents include alcohols such as methanol, ethanol, propanol and the like; tosporte, such as ethanthiol, 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, diethyl ether of diethylene glycol, dimethylethanol and the like; simple thioethers such as dimethyl sulfide 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; sulfoxidov, such as dimethyl sulfoxide and the like; inorganic acids such as sulfuric acid, hydrochloric acid and the like; carboxylic acids such as acetic acid, triperoxonane acid and the like; sulfonic acids, such as triftoratsetata and the like; organic bases such as pyridine, treat the Lamin and the like; water, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

As a reagent, contributing to the removal of the protective group, can be used reagents that are typically used to remove protection from an aromatic alcohol. Preferably, you can use trimethylsilylmethyl and the like. Also acceptable is getting reagent facilitating the removal of the protective group in the reaction system. Reagent facilitating the removal of the protective group used in an amount of 0.01-50 mol and preferably 0.1 to 30 mol per mol of compound of the formula [3i] or its salt.

The above reaction is usually carried out at a temperature of from -80°to 200°and preferably at a temperature of from 0°160°With the passage of time from one minute to 48 hours and preferably from 5 minutes to 20 hours.

The compound of General formula [3E] or its salt, which are the starting material for the above-mentioned reaction can be obtained, for example, by the method described in J. Am. Chem. Soc., Vol.71, Pages 2798-2800 (1949).

[Method of obtaining I-C]

where R1is the same as defined above, and R13represents a lower alkoxygroup or alloctype.

(a) Compound of General formula [3k] or its salt can be obtained by the interaction of the compounds of General formula [3l] or its salt with an alcohol in the presence or in the absence of an acid catalyst or a base according to the method described, for example, Shin Jikken Called Koza, Vol.14, Pages 1599-1602 (edited by the Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of the solvents 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, diethyl ether of diethylene glycol, dimethylethanol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

The alcohol used in this reaction includes, for example, methanol, ethanol, phenol and the like. Alcohol is used at least in equimolar amount relative to the compound of the formula [3l] or its salt. The use of alcohol as a solvent is valid, if desired.

As the acid catalyst used in this reaction, use these reagents, which are usually used for limitirovaniya NITRILES. For these purposes it is possible to use, for example, hydrogen chloride and p is such. An acid catalyst is used in amount of at least 0.1 mol per mol of compound of the formula [3I] or its salt.

To the base used in this reaction include, for example, alkoxides of metals such as sodium methoxide, ethoxide sodium, phenoxide sodium and the like. It is acceptable to receive the specified grounds in the reaction system, if desired. For this reaction, the base is used in amounts of at least 0.01 mol, and preferably 1.0 to 5.0 mol per mol of compound of the formula [3I] or its salt.

The above reaction is usually carried out at temperatures from -78°170°and preferably at temperatures from -40°to 120°With the passage of time from one minute to 72 hours, and preferably from 5 minutes to 24 hours.

(b) a Compound of General formula [3j] or its salt can be obtained by the interaction of the compounds of General formula [3k] or its salt with the reagent according to the method described in Shin Jikken Called Koza, Vol.14, Pages 1614-1617 (edited by the Chemical Society Japan (corporate juridical person), 1978).

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of the solvents include aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as methylene chloride, chloroform, dig aratan and the like; ethers, such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxidov, such as dimethyl sulfoxide and the like, etc. Listed solvents may be used as such or in the form of a mixture of two or more solvents.

As indicated above, the reagent used in this reaction, use these reagents, which are usually used for amidinopropane of imidates. Examples of the above reagent include gaseous ammonia, alcoholic solution of ammonia, aqueous ammonia and ammonium salts of acids, such as ammonium chloride and the like. The reagent is used at least in equimolar amount relative to the compound of the formula [3k] or its salt. The use of the reagent as solvent is valid, if desired.

The above reaction is usually carried out at temperatures from -78°170°and preferably at a temperature of from 0°to 120°With the passage of time from one minute to 72 hours, and preferably from 5 minutes to 24 hours.

[Method of obtaining I-D]

where R1ais the same as defined above.

(a) Compound of General formula [3m] or its salt can be obtained interaction is m compounds of General formula [3n] or its salt with diasterous reagent and gidrauxiliruetsa reagent in the presence or in the absence of the additive according to the method described, for example, Shin Jikken Called Koza, Vol.14, Pages 537-538 (edited by the Chemical Society Japan (corporate juridical person), 1977).

The solvent used in this reaction is not strictly limited, unless the solvent has no adverse effect on the reaction. Examples of solvents include inorganic acids such as sulfuric acid, hydrochloric acid, nitric acid and the like; ethers such as dioxane, tetrahydrofuran, anisole, diethyl ether of diethylene glycol, dimethylethanol 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; sulfoxidov, such as dimethyl sulfoxide and the like; amines and aminoacid, such as triethylamine, N,N-dimethylaniline the pyridine-N-oxide and the like; ketones such as acetone and the like; water; etc Listed solvents may be used as such or in the form of a mixture.

Diasterous reagent used in this reaction is not strictly limited, if it is usually used for dezaminirovanie aromatic amino compounds. Preferably, when used nitrites of alkali metals such as sodium nitrite and the like. Diasterous reagent is used at least in equimolar number is the number, preferably in the amount of 1.0-5.0 mol, and furthermore preferably 1.0 to 2.0 mol per mol of compound of the formula [3n].

To hydroxyurea the reagent used in this reaction include, for example, water and the like. Hydroxyperoxy reagent is used at least in equimolar amount relative to the compound of the formula [3n], although hydroxyperoxy reagent can also be used as solvent, if desired.

To the additive used in this reaction include, for example, salts of copper, such as copper sulfate and the like; and 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 to 50 mol per mol of compound of the formula [3n].

The above reaction is usually carried out at a temperature of from -70°to 200°and preferably at a temperature of from -50°to 100°With the passage of time from one minute to 24 hours and preferably from 30 minutes to 10 hours.

(b) a Compound of General formula [3n] or its salt can be obtained (1) by the interaction of the compounds of General formula [3O] or its salt with an electrophilic fluorinating reagent in the presence or in the absence of additives and in more detail, according to the methodology described in Fusso no Depending, Pages 28-37 (edited by Kodansha Scientific, 1993) or (2) the interaction of the compounds of formula [3O] or its salt with a Gal who generouse reagent in the presence or in the absence of the additive according to the method described, for example, Shin Jikken Called Koza, Vol.14, Pages 354-360 (edited by the Chemical Society Japan (corporate juridical person), 1977).

In method (1) used solvents are not strictly limited, unless they have no harmful effects on the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, ferrichloride, 1,1,2-trichlorotrifluoroethane and the like; ethers such as diethyl ether, tetrahydrofuran, diethyl ether of diethylene glycol, dimethylethanol 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, triperoxonane acid and the like; inorganic acids such as hydrofluoric acid, sulfuric acid and the like; water; etc, These solvents may be used as such or in the form of two or more the solvents.

Electrophilic fluorinating reagents used in this reaction is not strictly limited, if they are usually used for the reactions of addition of fluorine atoms to carbon-carbon multiple bonds. Preferred examples of such reagents include gaseous fluorine, triftoratsetofenona, aceinhibitors, diversion, fluoride charnawati acid, cesium sulfatreat, triplet N-torpedine, N-fluoro-N-alkyl is insulfoam,

N-torahresource, N-Forbes(triftorbyenzola)imide, N-Forbes(benzolamide)imide and N-fluoro-O-sensordisplaylib. Of these electrophilic fluorinating reagents is preferred gaseous fluorine. Electrophilic fluorinating reagent is used in an amount of 0.05 to 50 mol and preferably 0.1 to 20 mol per mol of compound of the formula [3O] or its salt.

Additive, which if necessary can be used in this reaction is not strictly limited, if it is commonly used in reactions of electrophilic fluorination. Preferred examples of such additives include acid catalysts such as boron TRIFLUORIDE, hydrofluoric acid and the like; organic and inorganic bases, such as triethylamine, sodium fluoride and the like; and halogen such as chlorine, bromine, iodine and the like. These additives can be used as such or in the form of a mixture of two or more additives. In this reaction, the additive is used in an amount of 0.01-10 mol and preferably 0.1 to 10 mol per mol of compound of the formula [3O] or its salt.

The above reaction is usually carried out at a temperature of from -80°170°and preferably at a temperature of from -80°to 100°With the passage of time from one minute to 72 hours, and preferably from 5 minutes to 48 hours.

(2) In the method (2) used solvents are not strictly ogran Jenny, if only they have no harmful effects on the reaction. Examples of the solvent include halogenated hydrocarbons such as methylene chloride, chloroform, ferrichloride, 1,1,2-trichlorotrifluoroethane and the like; ethers such as diethyl ether, tetrahydrofuran, diethyl ether of diethylene glycol, dimethylethanol 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, triperoxonane acid and the like; inorganic acids such as sulfuric acid and the like; water; etc, These solvents may be used as such or in the form of a mixture of two or more solvents.

Halogenation reagents used in this reaction is not strictly limited, if they are usually used for the halogenation of aromatic compounds. Preferred examples of such reagents include bromine, chlorine, chloride Sulfuryl, N-bromosuccinimide, N-chlorosuccinimide and the like. The halogenation reagent is used in an amount of 0.05 to 50 mol and preferably 0.1 to 20 mol per mol of compound of the formula [3O] or its salt.

Additives, which are used if necessary in this reaction is not strictly limited, if they are usually used for the halogenation of aromatic compounds. Preferred approx the market additives include sodium bromide, the leads to compounds, which lead chloride titanium(IV)chloride, aluminium sulfate, silver and the like. These additives can be used as such or in the form of a mixture of two or more additives. In this reaction, the additive is used in an amount of 0.01-10 mol and preferably 0.1 to 10 mol per mol of compound of the formula [3O] or its salt.

The above reaction is usually carried out at a temperature of from -80°170°and preferably at a temperature of from -80°to 100°With the passage of time from one minute to 72 hours, and preferably from 5 minutes to 48 hours.

In the above-mentioned methods of producing compounds all compounds can be used in the form of their salts. As mentioned salts can be used such as salt, as described in the paragraph devoted to the salts of compounds of General formula [1]. If desired, the reaction can be conducted in an atmosphere of inert gas, such as nitrogen. The compound of General formula [1] or its salt, which were obtained by the above method can be converted into other compounds of General formula [1] or their salts implementation of known reactions, such as oxidation, reduction, rearrangement, substitution, halogenoalkane, dehydration, hydrolysis and the like, or the implementation of an appropriate combination of these reactions.

Some compounds that are referenced in the above SPO is obah obtain, may have isomers such as optical isomers, geometric isomers, tautomers, etc. In such cases, these isomers are also used in the present invention, as well as apply solvated products, hydrates and various crystal forms. After completion of the reaction, the target compound can be used in the next stage of the reaction without isolation, if desired.

Some compounds that are referenced in the above methods for their production, can have the amino group, hydroxyl group or carboxyl group. If you want, you can protect these groups using a conventional protective group after the reaction to remove the protective group method, well known in itself.

The compound of General formula [1] or its salt can be distinguished, clean or recrystallized conventional means, such as extraction, crystallization and/or column chromatography, etc.

The connection according to the present invention formulated with various pharmaceutical additives such as excipient, binding agent, baking powder, agent, preventing disintegration, antiadhesive and-caking agent, a lubricating agent, an absorption-adsorption media, solvent, filler, isotonic agent, the agent promotes dissolution, emulsifier, suspendisse agent, thickener, creating a coating agent, an absorption promoter, the promoter of the gelatin-coagulation, light, preservative, moisture-proofing agent, stabilizer emulsion-suspension-dispersion, totoproject, agent, preventing deoxygenate-oxidation, sweetening-flavouring agent, a colouring agent, a blowing agent, protivovospalitel, analgesic agent, an antistatic agent, a buffer agent, the agent regulating the pH, etc. and form a pharmaceutical composition, such as oral composition (tablet, capsule, powder, granule, fine granule, pill, suspension, emulsion, solution, syrup etc), injection, suppository, outer composition (ointment, plaster, etc.), aerosol, etc.

Based on the above compositions create pharmaceutical preparations according to conventional methods.

Solid preparations for oral administration such as tablet, powder, granule and the like, prepared according to the usual way together with pharmaceutical additives, intended for solid preparations, including fillers such as lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, crystalline cellulose, anhydrous secondary acidic calcium phosphate, partially pregelatinized starch, corn starch, alginic acid and the like; binding agents such as syrup, glucose solution, starch solution, gelatin solution, polyvinyl alcohol, polyvinyl simple ether, polyvinylpyrrolidone, carboxymethylcellulose, shellac, methylcellulose, ethylcellulose, sodium alginate, Arabic gum, hypromellose, hydroxypropylcellulose, water, ethanol and the like; disintegrating agents, such as dry starch, alginic acid, agar powder, starch, poperechnyy polyvinylpyrrolidone, Poperechnaya carboxymethylcellulose sodium, carboxymethylcellulose calcium, sodium salt chromalveolates acid and the like; reagents that prevent disintegration, such as stearyl alcohol, stearic acid, cocoa butter, oil and hydrogensource like; anti-adhesive and prevent caking agents, such as aluminium silicate, secondary acidic calcium phosphate, magnesium oxide, talc, silicic anhydride and the like; and lubricating agents, such as Carnauba wax, volatile silicic anhydride, aluminum silicate, magnesium silicate, hydrogenated oil derivatives, hydrogenated vegetable oil, sesame oil, white wax, titanium oxide, dry gel of aluminum hydroxide, stearic acid, calcium stearate, magnesium stearate, talc, secondary acidic calcium phosphate, sodium lauryl sulfate, polyeth lepicol and the like; the absorption promoters such as Quaternary ammonium salts, sodium lauryl sulfate, urea, enzymes and the like; absorption and adsorption media, such as starch, lactose, kaolin, bentonite, silicic anhydride, hydrated silicon dioxide, metasilicate-magnesium aluminate, colloidal silicic acid and the like, etc.

In addition, if desirable, the tablet can be manufactured in plain coated tablets, such as the pill with sugar coated tablet with a gelatin coating, the tablet from dissolving in the stomach coated tablet from dissolving in the intestines coated or tablet with a water-soluble film coating.

A capsule is prepared by mixing together the above-mentioned pharmaceutical ingredients and filling the mixture of hard gelatin capsules, soft capsules, etc.

In addition, aqueous or oily suspension, solution, syrup and elixir can be prepared by forming a pharmaceutical composition together with the above-mentioned additives, intended for cooking liquid drug, such as a solvent, a filler, an isotonic agent, emulsifier, stabilizer for suspension, thickening agent, etc. in the form of liquid preparation according to a conventional method.

The suppository can be prepared by adding the appropriate promoter abs is rbli to polyethylene glycol, the cocoa butter, lanolin, higher alcohol, higher air oxyacids, gelatine, the semisynthetic glycerides, Witepsol or the like, and mixing these ingredients together with the pharmaceutical composition with the formation of the suppository.

Injectable form is prepared by mixing the pharmaceutical composition and pharmaceutical additives, intended for the manufacture of the liquid preparation, including diluents, such as water, ethyl alcohol. Macrogol, polyethylene glycol, citric acid, acetic acid, phosphoric acid, lactic acid, sodium lactate, sulfuric acid, sodium hydroxide and the like; agents that regulate pH, and buffering agents such as sodium citrate, sodium acetate, sodium phosphate and the like; stabilizers such as sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolate acid, tomalachka acid and the like; isotonic agents such as sodium chloride, glucose, mannitol, glycerol and the like; agents that promote dissolution, such as carboxymethylcellulose sodium, propylene glycol, sodium benzoate, benzyl benzoate, urethane, ethanolamine, glycerol and the like; analgesic agent, such as calcium gluconate, chlorobutanol, glucose, benzyl alcohol and the like; local anesthetics; and so on, and education of the mixture in the form of an injection solution according to the usual methods for the U.

The ointment in the form of a paste, cream or gel can be prepared by forming a pharmaceutical composition with a base, such as white petrolatum, polyethylene, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicon, bentonite and the like; preservatives such as methyl ether, peroxybenzoyl acid, ethyl ester, peroxybenzoyl acid, propyl ester peroxybenzoyl acid and the like; stabilizers; wetting agents, etc., and education of the mixture in the form of ointments according to an ordinary method.

The patch can be manufactured using the above-mentioned ointment, cream, gel or paste deposited on a conventional substrate according to the conventional method. The substrate can be used for textile and atextile fabric and film or foam plates are made of soft vinyl chloride, polyethylene, polyurethane and the like.

The method of introducing the above-mentioned pharmaceutical composition is not limited to any specific, and can be, in fact, determined in accordance with the form of the drug, age, sex and other conditions of the patient, and the severity of symptoms in a patient.

The dose of the active ingredient of the pharmaceutical compositions according to the present invention is essentially determined on the basis of the method of applying the composition, age and sex of the patient, type of Soboleva what I and other conditions. Typically the song you can enter the dose on the basis of active ingredient 0.1 to 100 mg/kg/day for an adult, or as a single dose or as multiple parts of the doses.

The following describes the antiviral and cytotoxic activity of derivatives of pyrazine represented by the General formula [1] according to the present invention, or their salts.

Sample: derived pyrazine represented by the General formula [1]or its salt was dissolved in dimethyl sulfoxide to obtain a solution whose concentration was 10 mg/ml By the time of use, the solution was diluted to the desired concentration of the culture medium and used.

Cultural environment: minimum supporting culture medium (E-MEM) with added 10% fetal bovine serum used for the growth of MDCK cells (derived from dog kidney), MA-104 (derived from monkey kidney) and ner-2 (derived from tumors with pharyngeal cancer) and to test the cytotoxicity.

As the host cells of influenza virus and to test the cytotoxicity used MDCK cells. MA-104 cells used as host cells rotavirus and ner-2 cells used as host cells of rous sarcoma virus.

Test example 1 [Activity against influenza virus]

MDCK cells were placed in 6-well plate (produced by CORNING) with a density of 5×10 5cells/well and cultured overnight at 35°under conditions of 5% carbon dioxide. Influenza virus (strain A/PR/8/34) was diluted to 200 PFU/ml serum-free culture medium and infected cells, adsorption of the virus was carried out at a rate of 0.5 ml/well for one hour. At the end of the infection and adsorption in the wells was added E-MEM culture medium containing the test compound at a predetermined concentration together with 0.6% purified agar, 1% bovine serum albumin and 3 μg/ml acetylated trypsin. Once a sufficient coagulation tablet is turned upside down and were cultured for 3 days. After culturing the living cells were stained with 1% neutral red, the cells were fixed with 10% formalin, medium with agar was removed with running water, and the number of spots was counted.

The rate of inhibition of spots expressed in percentage relative to the control sample containing no test compound.

The results are shown in table I-2 presents the number of tested compounds is the same as in the examples.

Table I-2
Connection (Example)(%)
4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-f the wounded]-oxo-3,4-dihydro-2-pyrazinecarboxamide (I-2) 1095
4-[(2R,3R,43,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-fluoro-oxo-3,4-dihydro-2-pyrazinecarboxamide (1-4)1047
6-fluoro-3-hydroxy-2-pyrazinecarboxamide (1-5)10042
With the Concentration of added test compound, µg/ml;
(%) The rate of inhibition in %.

In addition, it was determined activity against influenza virus, show nitrogen-containing heterocyclic carbamaepine derivative represented by the General formula [23], which are derived from compounds according to the present invention, or salts of these derivatives, in the same manner as in test Example 1. Test compounds used 6-fluoro-3-hydroxy-2-pyrazinecarboxamide dissolved in dimethyl sulfoxide to form a solution with a concentration of 10 mg/ml, which was diluted culture solution to a predetermined concentration before use. The results showed that the activity against influenza virus was 100%, but the extent of inhibition at a concentration of test compound 1 µg/ml, which indicates that the test compound is excellent protivovirusny the m product.

Test example 2 [Activity against rotavirus]

MA-104 cells were placed in 6-well plate (produced by CORNING) with a density of 5×105cells/well and cultured overnight at 37°under conditions of 5% carbon dioxide. Rotavirus (strain Ku), activated acetylated trypsin with a concentration of 10 μg/ml for 30 minutes, diluted to 140 PFU/ml serum-free culture medium and infected cells, adsorption of the virus was carried out at a rate of 0.5 ml/well for one hour. After infection and adsorption infectious medium was removed and added E-MEM culture medium containing 30 μg/ml test compound, 5 μg/ml of trypsin and 1.4% agarose. MA-104 cells infected with rotavirus were cultured for 3 days at 37°under conditions of 5% carbon dioxide, and then layered 0.7% agarose solution containing 0.005% neutral red, and continued to cultivate in one day under the same conditions as described above. After culturing the tablet was fixed with 3%formaldehyde solution, solidified with agar culture medium was removed, and then counted the number of spots. The rate of inhibition against rotavirus was calculated based on the number of spots in the group of cells treated with the compound, and in the untreated group of cells.

As a result, the ATA has been shown the compound of example I-1 shows activity against rotavirus.

Test example 3 [Activity against RS virus (rous sarcoma) (respiratory syncytial virus)]

Ner-2 cells was dismissed on 6-hole tablet (produced by CORNING) with a density of 5×105cells/well and cultured overnight at 37°under conditions of 5% carbon dioxide. RS virus (strain a-2) was diluted to 140 PFU/ml serum-free culture medium and infected cells, adsorption of the virus was carried out at a rate of 0.5 ml/well for one hour. At the end of the infection and adsorption infectious medium was removed and wells were added to E'-MEM culture medium containing 30 μg/ml test compound, 0,12% glutamine, 2% fetal bovine serum and 1% methylcellulose. Ner-2 cells infected with RS virus was cultured for 3 days at 35°under conditions of 5% carbon dioxide. After culturing the tablet was fixed with 3% formaldehyde solution and culture medium containing methylcellulose were removed. After that, the tablet were stained with a 5% solution Giemza, and counted the number of spots. The rate of inhibition against RS virus was calculated based on the number of spots in the group of cells treated with the compound, and in the untreated group of cells.

Test example 4 (Cytotoxic activity)

Culture medium, terzidou test the connection with a predetermined concentration, added to 96-well plate (produced by CORNING CO.) when the amount of 100 µl/well. Next was preparing a dispersion of MDCK cells with a concentration of 2×104cells/ml in culture medium, was dissipated at a rate of 100 μl/well and were cultured for 3 days at 37°under conditions of 5% carbon dioxide. At the end of the cultivation counted the number of living cells by XTT method [for example, CANCER RESEARCH, Vol.48, Pages 4827-4833 (1988), etc].

The results showed that the concentration of all the compounds listed in table I-2 in which the observed growth inhibition of 50% of the cells (IC50at 100 µg/ml or higher.

PREFERRED embodiments of the INVENTIONS

Below are disclosed compounds according to the present invention and intermediate compounds according to the present invention with reference examples and examples according to the invention. The present invention is in no way limited to these examples.

In the examples below, mixed relations, which relate to Ellenton, all options in the "surround." As media for column chromatography was used silica gel BW-127ZH (produced by Fuji Silysia Chemical Co.); as media for reversed-phase chromatography was used YMC·GEL ODS-AM 120-S50 (YMC CO., LTD.) and media for ion exchange column is chromatographie was DEAE cellulose (produced by Wako Pure Chemical Industries).

Abbreviation used in the reference examples and examples according to the invention, has the following value:

DMSO-d6: deuterated dimethyl sulfoxide.

Reference example I-1

In 100 ml of concentrated sulfuric acid was dissolved 17.0 g of methyl 3-amino-6-bromo-2-pyrazinecarboxamide. Then to a solution, cooled with ice, was added to 10.1 g of sodium nitrite and stirred for 30 minutes. The reaction mixture was poured in 920 ml of methanol and heated at the boil under reflux for 5 hours. After cooling, the reaction mixture was concentrated under reduced pressure, the obtained residue was added to a mixture of 500 ml of ice water and 600 ml of chloroform, and the resulting mixture was separated into layers. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus received 6,30 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxamide in the form of an oily product is a light yellow color.

IR (KBR) cm-1: 1735

1H-NMR (CDCl3) δ: of 3.97 (3H, s)4,06 (3H, s)of 8.37 (1H, s).

Reference example I-2

In 227 ml of toluene was dissolved 11.4 g of methyl 6-bromo-3-methoxy-2-pyrazinecarboxamide in a current of nitrogen gas and consistently added 10.3 g of benzophenone is, 0,42 g of Tris(dibenzylideneacetone)diplodia, 0,86 g

(s)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and 6.20 g of tert-butoxide sodium. The mixture was stirred at 80°C for one hour. After cooling, the reaction mixture was filtered. The filtrate was purified column chromatography [eluent:toluene:ethyl acetate=20:1]. The obtained oily product was dissolved in 140 ml of tetrahydrofuran, was added 7 ml of 2 mol/l hydrochloric acid, and the mixture was stirred at room temperature for 15 minutes. Then to the reaction mixture was added a mixture of 200 ml of chloroform and 50 ml of water, and then was added 1 mol/l solution of sodium hydroxide to podselect the mixture, and the separated organic layer. The obtained organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The residue was purified column chromatography [eluent:toluene: ethyl acetate=1:1] to obtain of 3.64 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxamide in the form of an oily yellow product.

IR (KBR) cm-1: 1716, 1670

1H-NMR (DMSO-d6) δ: of 3.80 (3H, s), 3,82 (3H, s), 7,20 (2H, Sirs), to 7.77 (1H, s).

Reference example I-3

In 70 ml of methanol was dissolved 3.5 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxamide. After filing in a solution of ammonia gas for cooking nasishennokrasnie, the solution was stirred at room temperature for 14 hours. Removing the solvent from the reaction mixture under reduced pressure to give 3.1 g of 6-amino-3-methoxy-2-pyrazinecarboxamide in the form of a solid product.

IR (KBR) cm-1: 1684

1H-NMR (DMSO-d6) δ: with 3.79 (3H, s), by 5.87 (2H, Sirs), 7,30 to 7.75 (3H, m).

Reference example I-4

In the atmosphere of nitrogen gas in 12 ml of 70% solution of hydrogen fluoride-pyridine was dissolved 1.50 g of 6-amino-3-methoxy-2-pyrazinecarboxamide, cooling the solution with ice. Then was added 0.71 g of sodium nitrite at -50°and the resulting mixture was stirred at 10°C for one hour. After stirring the reaction mixture for a further one hour was added to a mixture of 50 ml of ice water and 100 ml of chloroform and the resulting mixture was separated into layers. The organic layer was washed saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. Thus received 1.29 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide in the form of a solid product.

IR (KBR) cm-1: 1707

1H-Yarm (DMSO-d6) δ: of 3.95 (3H, s), 7,55-of 8.15 (2H, m), 8,39 (1H, d, J=8,3 Hz).

Reference example I-5

In 22 ml of acetonitrile was dissolved 1.51 g of sodium iodide in the atmosphere of nitrogen gas. After addition of 1.10 g of tributyltinchloride the resulting mixture was stirred at room temperature over their 20 minutes. Then added 0,43 g of 6-fluoro-3-methoxy-2-pyrazinecarboxamide and the resulting mixture was stirred at the same temperature as described above for 18 hours. The reaction mixture was added to a mixture of 10 ml of water and 200 ml of chloroform and the resulting mixture was separated into layers. The organic layer is successively washed with 5% aqueous sodium thiosulfate solution and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified column chromatography [eluent:hexane:ethyl acetate=2:1] to obtain 0.06 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide in the form of a solid white product.

IR (KBR) cm-1: 1685, 1658

1H-NMR (CDCl3) δ: 5,40-7,80 (2H, m), 8,31 (1H, d, J=7.8 Hz), of 12.33 (1H, s).

Reference example I-6

In 40 ml of dichloroethane was dissolved 1.0 g of methyl 6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide. Then to the solution was sequentially added with 1.0 ml 1,1,1,3,3,3-hexamethyldisilazane and 0.54 ml of chlorotrimethylsilane in the atmosphere of nitrogen gas, and was heated at 90°C for 2 hours. The mixture was cooled, and the solvent was removed under reduced pressure. The residue was dissolved in 30 ml of dichloroethane, and then added 2,68 g β-D-ribofuranose-1-acetate-2,3,5-tribenzoate and 1,24 ml of tin chloride(IV), and the resulting mixture was stirred at room temperature for 16 hours the. The reaction mixture was added to 30 ml of ice water and brought to pH 8 with saturated aqueous sodium bicarbonate solution and separated into layers. The organic layer was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The obtained residue was purified column chromatography [eluent:hexane:ethyl acetate=4:1] to obtain of 1.76 g of methyl 4-{(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl)-6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide in the form of an oily yellow product.

IR (pure) cm-1: 1728

1H-NMR (CDCl3) δ: of 3.94 (3H, s), 4,5-4,9 (3H, m), 5,6-6,0 (2H, m), 6,3-6,5 (1H, m), of 7.1-8.2 (N, m).

Reference example I-7

In 16 ml of methanol is suspended 0,80 g of methyl 4-{(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-2-furanyl}-6-chloro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide. The suspension was cooled with ice, and at the same time was added 0.73 g of 28% methanolic solution of sodium methoxide and the resulting mixture was stirred at the same temperature as described above, in one hour. After stirring the mixture at room temperature for additional 3 hours, the mixture was brought to pH 7 with a solution of 6 mol/l hydrochloric acid and the solvent was removed under reduced pressure. The residue was purified to Nochnoi chromatography [eluent:chloroform:methanol=10:1] to obtain 0.29 grams of methyl 6-chloro-4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide in the form of an oily yellow product color.

IR (pure) cm-1: 1728

1H-NMR (CDCl3+DMSO-d6) δ: 3,6-5,6 (11H, m), of 5.99 (1H, s), 8,67 (1H, s).

Example I-1

5.0 ml of 1, 1,1,3,3,3-hexamethyldisilazane suspended 1.0 g of 3-hydroxy-2-pyrazinecarboxamide. The suspension was heated under reflux for 30 minutes and left to cool, and the solvent was removed under reduced pressure. The residue was dissolved in 5.0 ml of dichloroethane in the atmosphere of nitrogen gas, then added 3.11 g (3-0-ribofuranose-1-acetate-2,3,5-tribenzoate and 0.50 ml of tin chloride(IV) and the resulting mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with 30 ml ethyl acetate and 20 ml of water, brought to pH 8 with saturated aqueous sodium bicarbonate solution, the precipitate was filtered, and the organic layer was separated. The organic layer was sequentially washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified column chromatography [eluent:ethyl acetate:methanol=10:1], then was added isopropyl ether and the solid material was collected by filtration. Thus received 0,41 g [(2R,3R,4R,5R)-5-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-3,4-IP(benzoyloxy)tetrahydro-2-furanyl]methylbenzoate in the form of a solid white product.

IR (KBR) cm-1: 1734, 1685

1H-NMR (CDCl3) δ: 4,6-5,1 (3H, m), 5.8 and 6.2 (3H, m), to 6.39 (1H, d, J=2.5 Hz), 7,2-8,2 (17H, m), of 8.95 (1H, Sirs).

Example I-2

In 4 ml of methanol was dissolved 0,37 g [(2R,3R,4R,5R)-5-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methylbenzoate. While cooling the solution with ice filed ammonia gas until saturation. The reaction mixture was stirred at room temperature for 15 hours and the solvent was removed under reduced pressure. To the residue was added methanol and the precipitate was collected by filtration to obtain 0.12 g of 4-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide in the form of a solid light brown color.

IR (KBR) cm-1: 1654

1H-NMR (DMSO-d6) δ: of 3.73 (2H, DD, J=5,4, 5,4 Hz), 3,8-4,2 (3H, m)5,08 (1H, Sirs), of 5.24 (1H, t, J=5.4 Hz), 5,61 (1H, Sirs), of 5.92 (1H, s), 7,54 (1H, d, J=4, 2 Hz), 7,71 (1H, Sirs), of 8.27 (1H, d, J=4, 2 Hz), 8,30 (1H, Sirs).

Example I-3

6-Fluoro-3-hydroxy-2-pyrazinecarboxamide was treated in the same manner as in example I-1, obtaining [(2R,3R,4R,5R)-5-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-3,4-bis(benzoyloxy)tetrahydro-2-furanyl] methylbenzoate.

IR (KBR) cm-1: 1726, 1690

1H-NMR (DMSO-d6) δ: between 4.6-5.0 (3H, m), 5,9-6,1 (2H, m), 6,33 (1H, s), 7,3-8,2 (17H, m), 8,53 (1H, Sirs).

Example I-4

In 2.0 ml of methanol was dissolved 0.15 g of [(2R,3R,4R,5R)-5-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-Piras the Nile]-3,4-bis(benzoyloxy)tetrahydro-2-furanyl] methylbenzoate. Then to a solution, cooled with ice, was added 0.14 g of 28% methanolic solution of sodium methoxide and stirred at this temperature for 20 minutes and then at room temperature for 30 minutes. The reaction mixture was acidified with 0.75 ml of solution 1 mol/l hydrochloric acid and the solvent was removed under reduced pressure. After purification of the residue column chromatography [eluent:chloroform:methanol=5:1] added isopropanol and diethyl ether and the solid product was collected by filtration to obtain 40 mg

4-[(2R,3R,43,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarboxamide.

IR (KBR) cm-1: 1686

Example I-5

In 4 ml of methanol was dissolved 0.26 g of methyl 6-chloro-4-[(2R,3R,4S,5S)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide. Into a solution, cooled by ice, filed ammonia gas until saturation. The reaction mixture was stirred under ice cooling for one hour, and then the solvent was removed under reduced pressure. When cleaning column chromatography [eluent:chloroform:methanol=7:1] of the residue was obtained 0.06 g of 6-chloro-4-[(2R,3R,43,5R)-3,4-dihydroxy-5-(hydroxymethyl) tetrahydro-2-furanyl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide in the form of solid product is a light yellow color.

IR (KBR) cm-1: 1693

Example I-6

In 53 ml of acetonitrile added to 5.3 g of 6-fluoro-3-hydroxy-2-pyrazinecarboxamide in a current of nitrogen gas. Then, to the suspension was added to 8.4 ml of N,O-bis(trimethylsilyl) ndimethylacetamide, cooling the mixture with ice, and this mixture was stirred at room temperature for 1.5 hours. To the reaction mixture, cooled with ice, was sequentially added a solution of 9.4 g of (2R,3R,4R)-4,5-bis(atomic charges)-2-(hydroxymethyl)-tetrahydro-3-uranylacetate, previously synthesized by the method mentioned in Carbohydr. Res., Vol.203, No.9, Pages 324-329 (1990), in 53 ml of acetonitrile and 7.2 ml of tin chloride(IV), the resulting mixture was stirred at room temperature for 20 minutes. The reaction mixture was poured into a mixture of 100 ml of ethyl acetate and 300 ml saturated aqueous sodium bicarbonate solution, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. All organic layers were combined and dried over anhydrous magnesium sulfate, then the solvent was removed under reduced pressure. The residue was dissolved in 200 ml of methanol, was added 100 ml of 80% aqueous acetic acid, the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was purified column chromatography on silica gel [eluent:chloroform:methanol=40:1], was added chloroform and isopropyl ether and the solid product was collected by filtration receiving the receiving 9.3 g of (2R,3R,4R,5R)-4-(atomic charges)-2-[3-(aminocarbonyl)-5-fluoro-2-oxo-1(2H)-pyrazinyl]-5-(hydroxymethyl)tetrahydro-3-uranylacetate in the form of a solid product is light yellow in color.

IR (KBR) cm-1: 3411, 1752, 1686

1H-NMR (DMSO-d6) δ: 2,04 (3H, s)of 2.10 (3H, s)to 3.64 (1H, DDD, J=2,5, 5,0, 13 Hz), 3,86 (1H, DDD, J=2,5, 5,0, 13 Hz), the 4.29 (1H, d, J=6.0 Hz), to 5.35 (1H, t, J=6.0 Hz), 5,49 (1H, DD, J=3,0, 5.0 Hz), the 5.65 (1H, t, J=5.0 Hz), 6,11 (1H, d, J=3.0 Hz), of 7.96 (1H, Sirs), 8,42 (1H, D, J=5.0 Hz), 8,49 (1H, Sirs).

Industrial application

Derivatives pyrazine or their salts according to the present invention, namely compounds according to the present invention, have excellent antiviral activity and are used as pharmaceutical drugs.

1. Derived pyrazine represented by the following General formula:

where R1represents a hydrogen atom or a halogen atom;

R2represents hydrogen;

R3and R5represent hydrogen;

R4and R6represent a hydroxyl group optionally protected with acetyl or benzoline group;

And represents an oxygen atom;

n is 0; and

Y represents an oxygen atom

or its salt.

2. Derived pyrazine or its salt according to claim 1, where R4and R6represent a hydroxyl group.

3. Derived pyrazine or its salt according to claims 1 and 2, where R1represents a hydrogen atom or a fluorine atom.

4. The pharmacist is ical composition, which antiviral agent containing the compound or its salt according to any one of claims 1 to 3.

5. The pharmaceutical composition according to claim 4, where the virus is an influenza virus, RS virus (rous sarcoma), the AIDS virus, the human papilloma virus, adenovirus, hepatitis a virus, hepatitis b virus, hepatitis C virus, polio virus, echo virus, Coxsackie virus, enterovirus, rhinovirus, rotavirus, Newcastle disease virus, mumps virus, vesicular stomatitis virus and Japanese encephalitis virus.

6. The pharmaceutical composition according to claim 5, where the virus is an influenza virus.

7. The pharmaceutical composition according to claim 5, where the virus is a hepatitis virus C.



 

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