JPH0899957A - New quinolone or naphthylidone compound or salt thereof, and antiherpes viral agent consisting thereof - Google Patents

Abstract

PURPOSE: To obtain a new compound having excellent antiherpes viral activity, thus useful as a medicinal effective for infectious diseases due to herpes simplex virus, herpes zoster virus, cytomegalovirus, etc. CONSTITUTION: This compound, a quinolone or naphthylidone compound (salt thereof), is expressed by formula I [R<1> is a (substituted) alkenyl, cycloalkyl, aryl or heterocyclic group; R<2> is amino, an alkylamino, (substituted) acylamino, etc.; X is H or a halogen; R<3> is a (substituted) aryl or heterocyclic group; A is N or CH], e.g. 3-amino-1-(4-fluorophenyl)-7-(pyridin-4-yl)-1,4-dihydro-4- oxyquinoline. The compound of formula I is obtained by coupling reaction between a compound of formula II (X<1> is Cl, Br or I) and an organotin compound in the presence of a Pd-catalyst to form a compound of formula III which is, in turn, subjected to nitro group reduction followed by alkylation, acylation, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to the general formula [1] [Wherein R ¹ represents an optionally substituted alkenyl, cycloalkyl, aryl or heterocyclic group; R ² represents
An optionally protected amino or alkylamino group or an optionally substituted acylamino or alkylsulfonylamino group; X is a hydrogen atom or a halogen atom; R ³ is an optionally substituted aryl or heterocycle The formula group; A represents N or CH. ] A novel quinolone or naphthyridone compound exhibiting an antiviral action represented by the above or a salt thereof, and an anti-herpesvirus agent comprising the same are provided. The anti-herpes virus agent here means an agent effective against infections caused by herpes simplex, herpes zoster virus, cytomegalovirus, or the like.

[0002]

2. Description of the Related Art Japanese Patent Publication No. 53-18600 is 8-ethyl-2.
Disclosed is that-(1-piperazino) pyrido [2,3-d] pyrimidin-5-one hydrochloride has anti-inflammatory activity. Further, JP-A-59-95287 discloses pyrido [2,3-d].
It is disclosed that the pyrimidine derivative has an action of increasing the contractility of the heart. Furthermore, recently, Antiviral Chemistry
& Chemotherapy), Volume 5, Issue 3, pages 169-175 (199
4 years), 8-alkyl-2- (pyridin-4-yl) pyrido [2,3-d] pyrimidin-5 (8H) -one was reported to be effective against AIDS virus. . On the other hand, at present, nucleic acid derivatives represented by acyclovir are widely used as anti-herpes virus agents. Acyclovir has been found to have excellent clinical effects on infectious diseases caused by herpes simplex virus and herpes zoster virus, but the emergence of resistant virus has become a problem in AIDS patients and the like. In addition, ganciclovir is used for infectious diseases caused by cytomegalovirus of the same herpesvirus genus, but serious side effects such as neutropenia and thrombocytopenia pose a problem.

[0003]

Therefore, the development of new anti-herpesvirus agents other than nucleic acid systems is desired.

[0004]

Under the circumstances, the inventors of the present invention have made earnest studies, and as a result, the general formula [1] [Wherein R ¹ represents an optionally substituted alkenyl, cycloalkyl, aryl or heterocyclic group; R ² represents
An optionally protected amino or alkylamino group or an optionally substituted acylamino or alkylsulfonylamino group; X is a hydrogen atom or a halogen atom; R ³ is an optionally substituted aryl or heterocycle The formula group; A represents N or CH. ] It was found that the quinolone or naphthyridone derivative represented by the formula] or a salt thereof has excellent anti-herpesvirus activity, and the present invention has been completed. Hereinafter, the compound of the present invention will be described in detail.

In the present specification, unless otherwise specified, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the lower alkyl group is preferably methyl, ethyl, n-propyl, isopropyl, n−
A C _1-5 alkyl group such as butyl, isobutyl, sec-butyl, tert-butyl and pentyl; a lower alkoxy group is preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, s.
a C _1-5 alkoxy group such as ec-butoxy, tert-butoxy and pentyloxy; a lower alkylthio group is
Preferably, a C _1-5 alkylthio group such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and pentyl; an acyl group is preferably a formyl group. , C _2-5 alkanoyl groups such as acetyl and ethylcarbonyl and aroyl groups such as benzoyl and naphthylcarbonyl; acylamino groups are preferably C _2-5 alkanoylamino such as formylamino group, acetylamino and ethylcarbonylamino. A group and an aroylamino group such as benzoylamino and naphthylcarbonylamino; a lower alkoxycarbonyl group is preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
Isopropoxycarbonyl, n-butoxycarbonyl,
Isobutoxycarbonyl, sec-butoxycarbonyl, t
ert-butoxycarbonyl and pentyloxycarbonyl and other C _1-5 alkoxycarbonyl groups; hydroxy-lower alkyl groups are preferably hydroxy-C _1-5 alkyl groups such as hydroxymethyl, hydroxyethyl and hydroxypropyl; The alkylamino group is preferably methylamino, ethylamino, propylamino, butylamino, pentylamino, hexylamino, heptylamino, octylamino, dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino, dipentyl. amino, dihexyl amino, mono- or di -C _1-10 alkylamino groups, such as diheptylamino and dioctyl amino; the lower alkylamino group, preferably, methylamino, ethylamino, Puropirua Bruno, dimethylamino, mono- or di diethylamino and methylethylamino -
A C _1-5 alkylamino group; an amino-lower alkyl group is preferably an amino-C _1-5 alkyl group such as aminomethyl, aminoethyl and aminopropyl; a lower alkylamino-lower alkyl group is Preferably, mono- or di-C _1-5 alkylamino-C such as methylaminomethyl, methylaminoethyl, ethylaminomethyl, methylaminopropyl, propylaminoethyl, dimethylaminomethyl, diethylaminomethyl, diethylaminoethyl and dimethylaminopropyl. _1-5 alkyl group; a halogeno-lower alkyl group is preferably a halo such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl and chloropropyl. Geno-C _1-5 alkyl group; an alkenyl group is preferably a C _2-10 alkenyl group such as vinyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl; Preferably, a C _2-5 alkenyl group such as vinyl and allyl; a cycloalkyl group is
Preferably, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; a lower alkylsulfonyl group is preferably
C _1-5 alkylsulfonyl groups such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and pentylsulfonyl; and alkylsulfonylamino groups. Is preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, sec-
A linear or branched C _1-10 alkylsulfonylamino group such as butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, heptylsulfonylamino and octylsulfonylamino; a lower alkylsulfonylamino group And is preferably methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, isopropylsulfonylamino, n-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, tert-butylsulfonylamino, pentylsulfonylamino and the like. C _1-5 alkylsulfonylamino group of; lower alkylsulfamoyl group, preferably, methylsulfamoyl, ethylsulfamoyl, n- propylsulfamoyl Famo , Isopropylsulfamoyl, n-butylsulfamoyl, isobutylsulfamoyl, sec-butylsulfamoyl, tert-butylsulfamoyl, pentylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and ethylmethyl the aryl group, preferably a group such as phenyl and naphthyl; a mono- or di -C _1-5 alkylsulfamoyl group such as sulfamoyl group and a heterocyclic group, preferably, azetidinyl, thienyl , Furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, flazanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
Imidazolinyl, pyrazolidinyl, pyrazolinyl, 1,
3,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiatriazolyl, Pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, 1,
2,4-triazinyl, benzothienyl, naphthothienyl, benzofuryl, isobenzofuryl, chromenil, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl,
Cinolinyl, fteridinyl, isochromanyl, chromanyl, indolinyl, isoindolinyl, benzoxazolyl, triazolopyridyl, tetrazolopyridazinyl,
Tetrazolopyrimidinyl, thiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, benzimidazolyl, benzthiazolyl, 1,2,3,4-
Tetrahydroquinolyl, imidazo "1,2-b] [1,
It means a 4- to 6-membered or fused heterocyclic group containing at least one hetero atom selected from an oxygen atom, a nitrogen atom and a sulfur atom, such as 2,4] triazinyl and quinuclidinyl.

The substituent of the optionally substituted lower alkenyl, alkenyl, cycloalkyl, aryl or heterocyclic group for R ¹ is a halogen atom, a cyano group, an optionally protected carboxyl group or a protected group. Optionally hydroxyl group, optionally protected amino group, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, aryl group, cycloalkyl group, lower alkenyl group, halogeno-lower alkyl group and optionally protected A good lower alkylamino group may be mentioned, which may be substituted with one or more of these substituents.

The substituent of the optionally substituted acylamino, lower alkylsulfonylamino or alkylsulfonylamino group for R ² is a halogen atom,
Cyano group, optionally protected carboxyl group, optionally protected hydroxyl group, optionally protected amino group, lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, aryl group, cycloalkyl group, Lower alkenyl group, halogeno-lower alkyl group, optionally protected lower alkylamino group,
It may be substituted with one or more of these substituents.

The substituent of the optionally substituted aryl or heterocyclic group for R ³ is a halogen atom,
Lower alkyl group, lower alkenyl group, cycloalkyl group, aryl group, lower alkoxy group, lower alkylthio group, nitro group, cyano group, acyl group, optionally protected hydroxyl group, optionally protected hydroxy lower alkyl Group, optionally protected amino group, optionally protected lower alkylamino group, optionally protected amino lower alkyl group, optionally protected lower alkylamino-lower alkyl group, lower alkylsulfonyl Groups, carbamoyl groups, sulfamoyl groups and lower alkylsulfamoyl groups, which may be substituted with one or more of these substituents.

The protecting group for the carboxyl group includes all groups which can be used as a usual protecting group for the carboxyl group, and examples thereof include methyl, ethyl, n-propyl and iso-.
Propyl, 1,1-dimethylpropyl, n-butyl and
lower alkyl groups such as tert-butyl; aryl groups such as phenyl and naphthyl; al-groups such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl.
Lower alkyl group; acetylmethyl, benzoylmethyl,
Acyl-lower alkyl groups such as p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl;
Halogeno-lower alkyl groups such as 2,2,2-trichloroethyl; lower alkylsilylalkyl groups such as 2- (trimethylsilyl) ethyl; acyloxyalkyl groups such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl; phthalimidomethyl And nitrogen-containing heterocyclic-lower alkyl groups such as succinimidomethyl; cycloalkyl groups such as cyclohexyl; lower alkoxy-lower alkyl groups such as methoxymethyl, methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; benzyloxymethyl and the like. Al-lower alkoxy-lower alkyl group; lower alkylthio-lower alkyl group such as methylthiomethyl and 2-methylthioethyl; arylthio-lower alkyl group such as phenylthiomethyl; - dimethyl-2-propenyl, 3
Lower alkenyl groups such as -methyl-3-butynyl and aryl; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl And lower alkyl-substituted silyl groups.

The protecting group for amino, lower alkylamino, alkylamino, amino lower alkyl group and lower alkylamino-lower alkyl group includes all groups which can be used as usual amino protecting groups, for example trichloro. Ethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, Benzoyl, tert-amyloxycarbonyl,
tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, iso Acyl groups such as propoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl; al-lower alkyl groups such as benzyl, diphenylmethyl and trityl; 2-nitrophenylthio and 2, Arylthio groups such as 4-dinitrophenylthio; alkane- or arene-sulfonyl groups such as methanesulfonyl and p-toluenesulfonyl; N, N
-Di-lower alkylamino-lower alkylidene group such as dimethylaminomethylene; benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydroxy-1-naphthylmethylene-containing lower alkylidene group; 3- Nitrogen-containing heterocyclic alkylidene group such as hydroxy-4-pyridylmethylene;
Cycloalkylidene groups such as cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5-oxycyclohexylidene; diphenylphosphoryl and dibenzylphosphoryl Such as diaryl- or dial-lower alkylphosphoryl groups; 5-methyl-2-oxo-2H-
And oxygen-containing heterocyclic alkyl groups such as 1,3-dioxol-4-yl-methyl; and lower alkyl-substituted silyl groups such as trimethylsilyl.

Further, the protecting group for hydroxyl and hydroxy lower alkyl group includes all groups which can be used as a usual hydroxyl protecting group, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxy. Carbonyl, 4-
Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1
-Dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2-
(Trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonio) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzyl. Thiocarbonyl, 4-ethoxy-1-
Acyl groups such as naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; methyl, tert-butyl, 2, Lower alkyl groups such as 2,2-trichloroethyl and 2-trimethylsilylethyl; lower alkenyl groups such as allyl; benzyl, p-methoxybenzyl, 3,
Al-lower alkyl groups such as 4-dimethoxybenzyl, diphenylmethyl and trityl; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-
Lower alkoxy- and lower alkylthio-lower alkyl groups such as methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and 1-ethoxyethyl; alkyl- such as methanesulfonyl and p-toluenesulfonyl. And aryl-sulfonyl groups; and trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-
And lower alkyl-substituted silyl groups such as butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl.

As the salt of the compound of the general formula [1], there may be mentioned the commonly known salts of a basic group such as amino group or an acidic group such as hydroxyl or carboxyl group. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid;
With salts of organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid and trifluoroacetic acid; and with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid Examples of the salt, and as the salt in the acidic group, include salts with alkali metals such as sodium and potassium; salts with alkaline earth metal salts such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine, tributylamine, Pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine,
Examples thereof include salts with nitrogen-containing organic bases such as dicyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine and N, N′-dibenzylethylenediamine. In addition, when the compound of the general formula [1] or a salt thereof has isomers (for example, optical isomers, geometric isomers and tautomers), the present invention includes those isomers, It also includes solvates, hydrates and crystals of various shapes.

In the compound of the present invention, R ¹ may be substituted lower alkenyl, cycloalkyl, aryl or heterocyclic group; R ² may be optionally protected amino or lower alkylamino group or substituted And a quinolone which is an acylamino or lower alkylsulfonylamino group, or a compound which is a naphthyridone compound or a salt thereof is preferable, and further, cycloalkyl, aryl or heterocyclic group in which R ¹ may be substituted; R ³ is substituted Particularly preferred are quinolone or naphthyridone compounds which are optionally heterocyclic groups or compounds which are salts thereof.

Among the compounds of the present invention, as typical compounds,
The following compounds may be mentioned. * 3-amino-1- (4-fluorophenyl) -7-
(Pyridin-4-yl) -1,4-dihydro-4-oxoquinoline. 1- (4-fluorophenyl) -3-formylamino-7- (pyridin-4-yl) -1,4-dihydro-4
-Oxoquinoline * 1- (4-fluorophenyl) -3-formylamino-7- (imidazol-1-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine * 1- (2,4 -Difluorophenyl) -3-formylamino-7- (imidazol-1-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine.1- (2,4-difluorophenyl) -3-formyl Amino-7- (thiazol-2-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine. 1- (4-fluorophenyl) -3-formylamino-7- (thiazol-2-yl ) -1,4-Dihydro-
4-Oxoquinoline-3-amino-6-fluoro-1- (4-fluorophenyl) -7- (pyridin-4-yl) -1,4-dihydro-4-oxoquinoline-6-fluoro-1- ( 4-fluorophenyl) -3-
Formylamino-7- (pyridin-4-yl) -1,4
-Dihydro-4-oxoquinoline 6-fluoro-1- (4-fluorophenyl) -3-
Formylamino-7- (1H-imidazol-1-yl) -1,4-dihydro-4-oxo-1,8-naphthyridine. 1- (2,4-difluorophenyl) -6-fluoro-3-formylamino -7- (1H-imidazole-1
-Yl) -1,4-dihydro-4-oxo-1,8-naphthyridine

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be synthesized, for example, according to the route shown below.

[0016] [Wherein R ¹ , R ² , R ³ , A and X have the same meanings as described above; X ¹ is a chlorine, bromine or iodine atom; R ^3a is imidazole, pyrazole, triazole, N such as pyrrolidine, piperidine and piperazine
Alk represents a C1-6 alkyl group. ] General formulas [2], [3], [4], [5], [6],
Examples of the salt of the compound of [7], [7a] and [1a] include the same salts as described for the salt of the compound of general formula [1].

(Production Method 1) A compound of the general formula [7] or a salt thereof can be prepared by reacting a compound of the general formula [2] or a salt thereof with a general formula [2] in the presence or absence of silver oxide and a palladium catalyst. [3] Organotin compound or salt thereof or Organotin compound of general formula [4] or salt thereof and General formula [5]
It can be obtained by subjecting a compound of 1 or a salt thereof to a coupling reaction. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Examples thereof include ethers such as dimethyl cellosolve; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. You may use it in mixture of 2 or more types. Examples of the palladium catalyst used in this reaction include PdCl ₂ (PPh ₃ ) ₂ ,
Pd (PPh ₃ ) ₄ , PdCl ₂ [P (O-tolyl) ₃ ] ₂ , PdCl ₂ + 2P (OEt) ₃ and PdCl ₂ (PhCN) ₂ [Et represents an ethyl group and Ph represents a phenyl group] . ] Etc. are mentioned. The amount of the organotin compound of the general formula [3] or its salt used is equimolar or more, preferably 1.0 to 2.0 times the molar amount of the compound of the general formula [2] or its salt. The amount of the compound of [5] or a salt thereof to be used is equimolar or more, preferably, to the organotin compound of the general formula [4] or a salt thereof,
It may be 1.0-5.0 times mol. This coupling reaction is usually carried out under an atmosphere of an inert gas (eg, argon and nitrogen) at 50-170 ° C. for 1 minute-2.
It should be carried out for 4 hours.

The compound of the general formula [7a] or a salt thereof is obtained by adding the compound of the general formula [6] or a salt thereof to a base in the presence or absence of a copper catalyst. It can be obtained by using as a deoxidizing agent and reacting. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Examples thereof include ethers such as dimethyl cellosolve; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. You may use it in mixture of 2 or more types. Bases used in this reaction include inorganic or organic bases such as triethylamine, potassium-tert-butoxide, potassium carbonate, sodium carbonate and sodium hydride. Also,
Examples of the copper catalyst used in this reaction include copper powder, cuprous chloride, cuprous bromide and cuprous iodide.
The compound of the general formula [6] or a salt thereof may be used in an equimolar amount or more, preferably 1.0 to 3.0 times the molar amount of the compound of the general formula [2] or a salt thereof. This reaction is usually carried out at 50-250 ° C, preferably 100-200 ° C for 5
It may be carried out for minutes-24 hours, preferably 30 minutes-10 hours.

The compound of the general formula [1a] or a salt thereof is a compound of the general formula [7] or a salt thereof or a general formula [7a].
The compound or a salt thereof can be obtained by subjecting a nitro group reduction reaction that is usually performed.

The compound of the general formula [1] or a salt thereof can be obtained by subjecting the compound of the general formula [1a] or a salt thereof to an alkylation reaction, an acylation reaction, an alkylsulfonylation reaction and the like which are usually performed.

The compound of the general formula [1] or a salt thereof thus obtained is subjected to a known reaction such as oxidation, reduction, rearrangement, substitution, addition, halogenation, dehydration or hydrolysis. Or by combining them as appropriate, other compounds of the general formula [1] or salts thereof can be derived.

The general formula [1a] in the production method described above,
In the compound of [2], [3], [4], [5], [6], [7a] or [7] or a salt thereof, isomers (for example, optical isomers, geometric isomers and tautomers) Isomers, etc.), these isomers can be used, and solvates, hydrates and crystals of various forms can be used.

General formulas [2], [3], [4], [5],
In [6], [7a], [7] or [1a] or a salt thereof, a compound having an amino group, a hydroxyl group or a carboxyl group may be prepared by previously protecting these groups with an ordinary protecting group. After that, these protecting groups can be removed by a method known per se.

Next, a method for producing a compound of the general formula [2] or a salt thereof and a novel compound, an organotin compound of the general formula [4] or a salt thereof, which are raw materials for producing the compound of the present invention, will be explained. .

[0025] [In the formula, Ph represents a phenyl group, and R ¹ , X, X ¹ and Alk have the same meanings as described above. Examples of the salts of the compounds of the general formulas [8], [9], [10] and [11] include the same salts as those described for the salt of the compounds of the general formula [1].

(Production Method A) (1) The compound of the general formula [9] or a salt thereof can be prepared by the general formula [8] according to the method described in, for example, Synthesis, page 295 (1979). Can be obtained by reacting the compound of 1) or a salt thereof with nitromethane in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Examples thereof include ethers such as dimethyl cellosolve; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. You may use it in mixture of 2 or more types. In addition, examples of the base used in this reaction include potassium tert-butoxide and sodium hydride. The amounts of the base and nitromethane used may be equimolar or more, preferably 2 to 5 times the molar amount of the compound of the general formula [8] or a salt thereof. This reaction may be carried out usually at 0-50 ° C, preferably 10-30 ° C, for 5 minutes-30 hours.

(2) (a) A compound of the general formula [11] or a salt thereof is prepared by reacting a compound of the general formula [9] or a salt thereof with an orthoester in the presence of acetic anhydride, It can be obtained by reacting the compound of 10] or a salt thereof. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and for example, aromatic hydrocarbons such as benzene, toluene and xylene; dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and Ethers such as dimethyl cellosolve; alcohols such as methanol, ethanol and propanol; halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; and Examples thereof include sulfoxides such as dimethyl sulfoxide, and these solvents may be used alone or in combination of two or more. Examples of the orthoesters include methyl orthoformate and ethyl orthoformate, and the amounts thereof are preferably equimolar or more with respect to the compound of the general formula [9] or a salt thereof, respectively. Is 1 to 10 times by mole. The reaction of the compound of the general formula [9] or a salt thereof with the orthoester is usually at 0 to 150 ° C., preferably at 50 to 150 ° C.
Minutes to 50 hours may be carried out.

Then, the obtained reaction mixture and the general formula [1
0] or a salt thereof in the reaction of the general formula [1
The amount of the compound of [0] or salt thereof used may be equimolar or more with respect to the compound of general formula [9] or salt thereof. This reaction is usually performed at 0-100 ° C, preferably 10-6.
It may be carried out at 0 ° C for 20 minutes to 30 hours.

(B) Alternatively, the compound of the general formula [11] or its salt is obtained by reacting the compound of the general formula [9] or its salt with an acetal in the presence or absence of an acid anhydride. Then, it can also be obtained by reacting the compound of the general formula [10] or a salt thereof. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, and for example, (2)
The same solvents as those mentioned in (a) can be mentioned. Examples of the acid anhydride include acetic anhydride and the like. Examples of acetals include N, N-dimethylformamide dimethylacetal and N, N-dimethylformamide diethylacetal.
The amount used may be equimolar or more, preferably 1 to 5 times the molar amount of the compound of the general formula [9] or a salt thereof. This reaction may be carried out usually at 0-100 ° C., preferably 20-85 ° C. for 20 minutes-50 hours.

Then, in order to react the compound of the general formula [10] or its salt, the compound of the general formula [10] or its salt is equimolar or more to the compound of the general formula [9] or its salt. You can use it. This reaction is usually 0-100
It may be carried out at 20 ° C., preferably 10 to 60 ° C. for 20 minutes to 30 hours.

(3) The compound of the general formula [2] or a salt thereof can be obtained by subjecting the compound of the general formula [11] or a salt thereof to a ring closure reaction in the presence or absence of a fluoride salt or a base. be able to. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction, but for example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dioxane, anisole, diethylene glycol. Examples thereof include ethers such as dimethyl ether and dimethyl cellosolve; and sulfoxides such as dimethyl sulfoxide. These solvents may be used alone or in combination of two or more. Examples of the fluoride salt optionally used in this reaction include sodium fluoride and potassium fluoride, and examples of the base optionally used include sodium hydrogen carbonate, potassium carbonate, potassium tert. -Butoxide, sodium hydride and the like, and the amount thereof may be equimolar or more to the compound of the general formula [11] or a salt thereof, preferably 1.0 to 3.0 times by mole. Good. This reaction may be carried out usually at 0 to 180 ° C. for 5 minutes to 30 hours.

(4) An aryl tin compound of the general formula [4] or a salt thereof can be prepared by reacting an aryl halide compound of the general formula [2] or a salt thereof with, for example, bulletin of
The Chemical Society of Japan (Bull.Che
m.Soc.Jpn.), Vol. 56, pp. 3855-3856 (1983), and can be obtained by reacting with hexaalkyldistannane using a palladium catalyst. The solvent and the palladium catalyst used in this reaction are not particularly limited as long as they do not adversely affect the reaction, and specifically, the same ones as described in the production method 1 can be mentioned. The amount of hexaalkyldistannan used may be equimolar or more, preferably 1.0 to 3.0 times the molar amount of the aryl halide compound of the general formula [2] or a salt thereof. This reaction is usually at 40-160 ° C,
It may be carried out for 1 hour to 72 hours.

Furthermore, in the manufacturing route, general formulas [2], [3], [4], [5], [6], [7a],
When the compound of [7], [10] or [11] or a salt thereof has an amino group, a hydroxyl group or a carboxyl group, these groups should be protected with a usual protecting group in advance, and after the reaction, the compound itself These protecting groups can be removed by a known method.

In the above-mentioned manufacturing method, the general formula [1a],
[2], [3], [4], [5], [6], [7a],
The compound of [7], [8], [9], [10] or [11] or a salt thereof is an isomer (for example, an optical isomer,
Geometric isomers and tautomers, etc.), these isomers can be used, and solvates,
Hydrates and crystals of the desired shape can be used. After the completion of the reaction, the reaction target product may be directly used in the next reaction without isolation.

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

When the compound of the present invention is used as a medicine, excipients, carriers, diluents and the like which are usually used for formulation may be appropriately mixed, and these may be used in the form of tablets or capsules according to a conventional method. It can be administered orally or parenterally in the form of a preparation, powder, syrup, granule, pill, suspension, emulsion, liquid, powder preparation, suppository, ointment or injection. The administration method, dose and frequency of administration can be appropriately selected according to the patient's age, body weight and symptom, and usually for adults, oral or parenteral (for example, injection, infusion and rectal site administration). Administration etc.)
The daily dose may be 0.1-100 mg / kg divided into one to several divided doses.

Next, the pharmacological action of the representative compounds of the present invention will be explained. 1. Antiviral effect test method Herpes simplex virus Antiviral Research,
It was performed according to the in vitro plaque reduction method described in Vol. 22, pp. 175-188 (1993). That is, Vero cells were sufficiently grown in a 6-well culture plate, and the HSV-2 (G) strain was grown to 10%.
The cells were infected with 0 PFU / 0.5 ml. After the infection was completed, a medium containing various concentrations of the test compound was added, and the cells were cultured for 3 days. For the determination, plaques were counted after staining with methylene blue, and the 50% inhibition value (IC ₅₀ ) was calculated from the percentage relative to the control. The results are shown in Table 1.

[Table 1]

Cytomegalovirus test method Archives of Birology (Arch.Virol.),
The method was carried out according to the in vitro plaque reduction method described in Vol. 117, pp. 165-171 (1991). That is, HEL cells were sufficiently grown in a culture dish with a diameter of 60 mm, and CMV (towne) strain was treated with 100 PF.
Infected with U / 0.5 ml. After the infection was completed, a medium containing various concentrations of the test compound was added, and the cells were cultured for 8 days. The judgment is
After staining with methylene blue, plaques were counted, and the 50% inhibition value (IC ₅₀ ) was calculated from the percentage relative to the control. The results are shown in Table 2.

[Table 2]

[0039]

EXAMPLES Next, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited thereto. The mixing ratios in the eluents were all dose ratios, and silica gel 60, No. 7734 (manufactured by Merck) was used as a carrier in column chromatography. The symbols used in the reference examples and examples have the following meanings. TFA-d ₁ : Deuterated trifluoroacetic acid DMSO-d ₆ : Deuterated dimethyl sulfoxide

Reference Example 1 4-Bromo-2-fluorobenzoic acid (6.60 g) was suspended in 86 ml of methylene chloride to give N, N-dimethylformamide (0.60 m).
Add l and cool to 0 ° C. Then, 4.00 g of oxalyl chloride is added dropwise over 5 minutes. 4 at room temperature after dropping
After stirring for 0 minutes, the solvent is distilled off under reduced pressure. The residue obtained is dissolved in 100 ml of methylene chloride and phenol 3.0
Add g and cool to 0 ° C. Then, triethylamine
3.20 g was added dropwise, and the mixture was further stirred at room temperature for 1 hour. 30 ml of water is added to the reaction mixture, and the organic layer is separated. The obtained organic layer is washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Hexane was added to the obtained residue, and the crystals were collected by filtration to obtain 8.80 g of 4-bromo-2-fluorobenzoic acid phenyl ester as pale yellow crystals. IR (KBr) cm ^-1 : ν _{C = O} 1737 NMR (CDCl ₃ ) δ value: 7.10-8.25 (8H, m)

Reference Example 2 10.0 g of potassium tert-butoxide was dissolved in 100 ml of dimethyl sulfoxide, and 5.40 g of nitromethane at 10-20 ° C.
Is added dropwise over 20 minutes. Then, after stirring for 1 hour at 20 ° C, 4-bromo-2-fluorobenzoic acid phenyl ester dissolved in 20 ml of dimethyl sulfoxide 8.80 g
Is added dropwise at 10-20 ° C over 20 minutes. Then at 20 ℃
Stir for 30 minutes. The reaction mixture was poured into 100 ml of ice water in which 2.70 g of urea was dissolved, adjusted to pH 2 with 6N hydrochloric acid, and 400 ml of water.
Add. The precipitated crystals are collected by filtration to obtain 7.00 g of pale yellow crystals of 4'-bromo-2'-fluoro-2-nitroacetophenone. IR (KBr) cm ^-1 : ν _{C = O} 1696 NMR (DMSO-d ₆ ) δ value: 6.26 (2H, s), 7.57-8.04 (3H, m)

Reference Example 3 4.24 g of 4'-bromo-2'-fluoro-2-nitroacetophenone was dissolved in 42 ml of methylene chloride, and 3.3 ml of acetic anhydride was added.
0 g and 3.86 g of N, N-dimethylformamide dimethyl acetal are added, and the mixture is stirred at room temperature for 1 hour. Then 4
-Fluoroaniline (3.78 g) is added, the mixture is stirred at room temperature for 10 hours, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to column chromatography [eluent; hexane: ethyl acetate =
7: 1] for purification, yellow crystals of 1- (4-bromo-
3.19 g of 2-fluorobenzoyl) -2- (4-fluoroanilino) -1-nitroethylene are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1669 NMR (DMSO-d ₆ ) δ value: 5.41-9.14 (8H, m), 11.90 (1H, bs)

Reference Example 4 1- (4-Bromo-2-fluorobenzoyl) -2-
(4-Fluoroanilino) -1-nitroethylene 3.15 g
Was dissolved in 31 ml of N, N-dimethylformamide, 1.70 g of potassium carbonate was added, and the mixture was stirred at 60 ° C. for 30 minutes. After cooling the reaction mixture to room temperature, 300 ml of water was added and the precipitated crystals were collected by filtration to give colorless crystals of 7-bromo-1- (4-fluorophenyl) -3-nitro-1,4-dihydro-4-.
2.88 g of oxoquinoline are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1649 NMR (DMSO-d ₆ ) δ value: 7.13 (1H, d, J = 1.5Hz), 7.20-7.95 (5H,
m), 8.28 (1H, d, J = 8.8Hz), 9.14 (1H, s)

Example 1 (1) 7-Bromo-1- (4-fluorophenyl) -3
-Nitro-1,4-dihydro-4-oxoquinoline 2.83 g
Was suspended in 57 ml of toluene, and then 1.89 g of 4-trimethylstannylpyridine and 50.0 mg of tetrakis (triphenylphosphine) palladium (0) were added, followed by heating under reflux for 18 hours under a nitrogen atmosphere. The solvent was distilled off from the reaction mixture under reduced pressure, the obtained residue was purified by column chromatography [eluent; chloroform: acetone = 2: 1], diethyl ether was added, and crystals were collected by filtration. 1.97 g of colorless crystals of 1- (4-fluorophenyl) -3-nitro-7- (pyridin-4-yl) -1,4-dihydro-4-oxoquinoline are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1646 NMR (DMSO-d ₆ ) δ value: 7.26 (1H, d, J = 1.0Hz), 7.30-8.70 (10H,
m), 9.18 (1H, s)

(2) In the same manner as in (1), 6-fluoro-1- (4-fluorophenyl) -3-nitro-7-
(Pyridin-4-yl) -1,4-dihydro-4-oxoquinoline is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1653 NMR (DMSO-d ₆ ) δ value: 7.17 (1H, d, J = 5.9Hz), 7.30-7.95 (6H,
m), 8.21 (1H, d, J = 10.2Hz), 8.50-8.70 (2H, m), 9.20 (1H, s)

(3) Tin chloride (2) (3.20 g) was added to concentrated hydrochloric acid (48 m)
1- (4-fluorophenyl)-
1.93 g of 3-nitro-7- (pyridin-4-yl) -1,4-dihydro-4-oxoquinoline are added portionwise over 10 minutes and stirred at the same temperature for 1 hour. After cooling the reaction mixture, the pH was adjusted to 13 with a 5N aqueous sodium hydroxide solution, and the crystals were collected by filtration to give yellow crystals of 3-amino-1-.
1.40 g of (4-fluorophenyl) -7- (pyridin-4-yl) -1,4-dihydro-4-oxoquinoline are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1630 NMR (DMSO-d ₆ ) δ value: 4.62 (2H, bs), 7.10-7.85 (9H, m), 8.38
(1H, d, J = 8.3Hz), 8.60 (2H, d, J = 5.8Hz)

Example 2 In the same manner as in Example 1 (3), 3-amino-6-fluoro-1- (4-fluorophenyl) -7- (pyridine-
4-yl) -1,4-dihydro-4-oxoquinoline is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1621 NMR (DMSO-d ₆ ) δ value: 4.64 (2H, bs), δ: 7.07 (1H, d, J = 6.4H
z), 7.39-7.66 (7H, m), 8.01 (1H, d, J = 11.1Hz), 8.63 (2H, dd,
(J = 4.5Hz, 1.6Hz)

Example 3 1.10 g of formic acid and 1.23 g of acetic anhydride were heated and stirred at 40 ° C. for 2 hours. The reaction mixture is then treated with 3-amino-1- (4-
Fluorophenyl) -7- (pyridin-4-yl)-
A suspension of 0.20 g of 1,4-dihydro-4-oxoquinoline in 3 ml of methylene chloride is added at 20 ° C. After stirring for 10 minutes at the same temperature, 30 ml of diisopropyl ether is added and the crystals are collected by filtration. The obtained crystals were suspended in 5 ml of water, adjusted to pH 9 with a saturated aqueous solution of sodium hydrogen carbonate, and collected by filtration to give 3-formylamino-1- (4-fluorophenyl) -7- (pale yellow crystals as crystals. Pyridin-4-yl) -1,4-dihydro-4-oxoquinoline (0.15 g) is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1677,1625 NMR (DMSO-d ₆ ) δ value: 7.10-7.95 (8H, m), 8.20-8.75 (4H, m),
9.10 (1H, s), 9.91 (1H, bs)

Example 4 In the same manner as in Example 3, 6-fluoro-1- (4-fluorophenyl) -3-formylamino-7- (pyridin-4-yl) -1,4-dihydro-4-. Get oxoquinoline. IR (KBr) cm ^-1 : ν _{C = O} 1682,1621 NMR (DMSO-d ₆ ) δ value: 7.14 (1H, d, J = 6.3Hz), 7.32-8.71 (10H,
m), 9.10 (1H, s), 9.91 (1H, bs)

Example 5 0.20 g of 3-amino-1- (4-fluorophenyl) -7- (pyridin-4-yl) -1,4-dihydro-4-oxoquinoline was suspended in 3 ml of methanol to obtain acetic anhydride. 0.15g
Is added at 20 ° C., and the mixture is stirred at the same temperature for 2 hours. 30 ml of diisopropyl ether is added to the reaction mixture, and the crystals are collected by filtration.
The crystals obtained were suspended in 5 ml of water, adjusted to pH 9 with a saturated aqueous sodium hydrogen carbonate solution, and collected by filtration to give 3-acetylamino-1- (4-fluorophenyl) -7- (pale yellow crystals. Pyridin-4-yl) -1,4-dihydro-4-oxoquinoline (0.18 g) is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1685,1626 NMR (DMSO-d ₆ ) δ value: 2.15 (3H, s), 7.15-7.90 (11H, m), 9.05
(1H, s), 9.34 (1H, bs)

Example 6 0.20 g of 3-amino-1- (4-fluorophenyl) -7- (pyridin-4-yl) -1,4-dihydro-4-oxoquinoline was suspended in 4 ml of methylene chloride to give 20 At 0 ° C, 0.10 g of methanesulfonyl chloride and 0.07 g of pyridine are added and the mixture is stirred at the same temperature for 12 hours. 30 ml of diisopropyl ether is added to the reaction mixture, and the crystals are collected by filtration. The crystals obtained are suspended in 5 ml of water and saturated aqueous sodium hydrogen carbonate solution is added.
The pH was adjusted to 9 and the crystals were collected by filtration to give 3-methanesulfonylamino-1- (4-fluorophenyl) as pale yellow crystals.
-7- (Pyridin-4-yl) -1,4-dihydro-4
-0.15 g of oxoquinoline is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1626 NMR (DMSO-d ₆ ) δ value: 3.06 (3H, s), 7.10-8.75 (12H, m), 8.88
(1H, bs)

[0052]

INDUSTRIAL APPLICABILITY The quinolone or naphthyridone compound of the compound of the present invention or a salt thereof has excellent anti-herpesvirus activity and is useful as a medicine.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Nobuyuki Matsubara 285-4 Shinmachi Nakagawara, Toyama City, Toyama Prefecture (72) Inventor Kimoyasu Shiraki 2556-4 Gosukuhiromachi, Toyama City, Toyama Prefecture

Claims (8)

[Claims] 1. [Wherein R ¹ represents an optionally substituted alkenyl, cycloalkyl, aryl or heterocyclic group; R ² represents
An optionally protected amino or alkylamino group or an optionally substituted acylamino or alkylsulfonylamino group; X is a hydrogen atom or a halogen atom; R ³ is an optionally substituted aryl or heterocycle The formula group; A represents N or CH. ] The quinolone or naphthyridone compound represented by these, or those salts. 2. The quinolone or naphthyridone compound or a salt thereof according to claim 1, wherein R ² is an optionally protected amino or lower alkylamino group or an optionally substituted acylamino or lower alkylsulfonylamino group. 3. The quinolone or naphthyridone compound or a salt thereof according to claim 1 or 2, wherein R ¹ is an optionally substituted lower alkenyl, cycloalkyl, aryl or heterocyclic group. 4. The quinolone or naphthyridone compound according to claim 1, wherein R ¹ is an optionally substituted cycloalkyl, aryl or heterocyclic group; and R ³ is an optionally substituted heterocyclic group. Or their salt. 5. [Wherein R ¹ represents an optionally substituted alkenyl, cycloalkyl, aryl or heterocyclic group; R ² represents
An optionally protected amino or alkylamino group or an optionally substituted acylamino or alkylsulfonylamino group; X is a hydrogen atom or a halogen atom; R ³ is an optionally substituted aryl or heterocycle The formula group; A represents N or CH. ] The anti-herpesvirus agent containing the quinolone represented by this, or a naphthyridone compound, or those salts. 6. A quinolone or a naphthyridone compound or a salt thereof according to claim 5, wherein R ² is an optionally protected amino or lower alkylamino group or an optionally substituted acylamino or lower alkylsulfonylamino group. An anti-herpes virus agent contained. 7. An anti-herpesvirus agent containing the quinolone or naphthyridone compound or a salt thereof according to claim 5 or 6, wherein R ¹ is an optionally substituted lower alkenyl, cycloalkyl, aryl or heterocyclic group. . 8. A quinolone or naphthyridone compound according to claim 5, wherein R ¹ is an optionally substituted cycloalkyl, aryl or heterocyclic group; and R ³ is an optionally substituted heterocyclic group. Alternatively, an anti-herpesvirus agent containing a salt thereof.