WO1997019916A2 - Bisazo compounds, intermediates thereof, process for synthesizing the same and therapeutic agent for viral infection containing the same - Google Patents

Abstract

The present invention provides a bisazo compound of formula (A) useful as a therapeutic agent for viral infection such as AIDS, an amidonaphtholsulfonic acid compound useful as an intermediate thereof, a process for synthesizing such a compound and a therapeutic agent for viral infection comprising the bisazo compound. Formula (A): Ar?1-N=N-(Y1¿)-NH-CO-(X1)-CO-NH-(Y1')-N=N-Ar1', wherein Ar?1 and Ar1¿' represent an aryl group having 15 or less carbon atoms or a 5- or 6-membered ring heteroaryl group, (X1) represents a naphthylene or biphenylene group having 20 or less carbon atoms, (Y1) and (Y1') represent a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule.

Description

SPECIFICATION

Title of the Invention

B i s a z o compoun d s , i nte rmed iate s th e r eof , pr oce s s f o r synthesizing the same and therapeutic agent for viral infection containing the same

Background of the Invention

The present invention relates to a new bisazo compound useful as a therapeutic agent for viral infection, an amidonaphtholsulfonic acid compound useful as an intermediate thereof, a process for synthesizing such a compound and a therapeutic agent for viral infection.

Viral infections have an absolute majority in human infections. However, only some of therapeutic agents for viral infection are sufficiently effective for the practical medical treatment, while many effective therapeutic agents for microbis s are available. Under these circumstances, the development of the former is eagerly demanded. Among patients suffering from the viral infection, those having acquired immunodeficiency syndrome (AIDS) caused by HIV (human immunodeficiency virus) which is the current topic show serious symptoms and a high mortality. Thus, the development of a medicine having a remarkable therapeutic effect is eagerly demanded.

As for compounds having an anti-AIDS activity, some compounds having a sulfonic acid group are known [Life Sciences, 4J7, 993; Japanese Patent Unexammed Published Application (hereinafter referred to as "J. P. KOKAI") No. Hei 5-105626; WO 94/14763; and J. Med. Chem. , 38, 1635 (1995)]. However, the therapeutic effect of them are not always sufficient.

On the other hand, although many bisazo compounds derived from animonaphthols are known, known bis(amidonaphtholazo) compounds having amido group as the bonding group are only few. Although examples of these compounds are given in J. P. KOKAI Nos. Sho 63-63765, 199780 and 295685, the bisamides used as the divalent bonding groups are limited to those derived from unsubstituted terephthalic acid, unsubstituted isophthalic acid or ( 4 , 4 ' -dicarboxyphenyl )methane. Bisamides derived from 2 , 5-dialkoxyterephthalic acid, heterocyclic dicarboxylic acids, biphenyldicarboxylic acids or naphthalenedicarboxylic acids have been unknown. Further, the substituents of the azo group are limited to some phenyl groups. Compounds having an aromatic ring formed by condensing a hetero ring such as quinoline or a hetero-aro atic ring such as pyridine have been unknown at all. Also bis(sulfonic acid a idonaphtholazo) compounds have been unknown at all.

On the other hand, in the production of 2 , 5-dihydroxybenzene- 1 , 4-dicarboxy lie acid esters, some processes wherein a 2,5- dioxocyclohexane-l,4-dicarboxylic acid ester is oxidized are known from, for example, EP 0373959A2 (also for other examples, refer to this specification). Among these processes, a process wherein bromine is used as an oxidizing agent is advantageous from the viewpoint of the environmental pollution, since no heavy metal is necessitated. However, known processes have problems in the actual production on an industrial scale. For example, in a process wherein carbon disulfide is used as a solvent (Annalen 211, 327 and 355), the solvent cannot be easily handled on an industrial scale because of its low boiling point; and in a process wherein chloroform is used (J. Chem. Soc, 2908 (1969), a side reaction (halogenation reaction of the benzene ring) easily occurs.

Summary of the Invention

An object of the present invention is to provide a new bisazo compound and a new bisnaphthylamide compound as the intermediate thereof.

Another object of the present invention is to provide a new therapeutic agent for viral infection.

A further object of the present invention is to provide a process for producing the intermediate.

The present invention provides bisazo compounds represented by the following general formula (A), (B), (C), (D), (E) or (F):

general formula (A):

Ar¹-N=N-(Y^l J-NH-CO- ¹ )-CO-NH-(Y' ' )-N=N-Ar¹ '

general formula (B):

Ar^J-N=N-(Y² )-NH-CO-(X² )-CO-NH-(Y² ' )-N=N-Ar^J '

general formula (C):

Ar³-N=N-(Y³ )-NH-CO-(X³ )-CO-NH-(Y³ ' )-N=N-Ar⁵ '

general formula (D):

Ar⁴-N=N-(Y⁴ )-NH-CO-(X⁴ )-CO-NH-(Y⁴ ' )-N=N-Ar⁴ ' general formula (E):

Ar⁵-N=N-(Y⁵ )-NH-CO-<X⁵ )-CO-NH-(Y⁵ ' )-N=N-Ar⁵ '

general formula (F):

Ar⁶ -N=N-(Y⁶ )-NH-SO. -(X' )-S0. -NH-(Y⁶ *)-N=N-Ar^« '

wherein Ar¹ and Ar¹ 'represent independently from each other a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6-membered ring heteroaryl group, (X¹ ) represents a substituted or unsubstituted naphthylene or biphenylene group having 20 or less carbon atoms, (Y¹ ) and (Y¹ ' ) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule,

Ar² and Ar² * represent independently from each other a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6- membered ring heteroaryl group, (X² ) represents a substituted or unsubstituted, 5- or 6-membered ring heteroarylene group having 20 or less carbon atoms, (Y² ) and (Y² ' ) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule,

Ar³ and Ar³ 'represent independently from each other a substituted αr unsubstituted phenyl group having 15 or less carbon atoms, (X¹ ) represents a 1,4-(2,5-dialkoxyphenylene) group having 20 or less carbon atoms, (Y³ ) and (Y³ ') represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule, Ar⁴ and Ar⁴ ' represent independently from each other a substituted or unsubstituted naphthyl group having 15 or less carbon atoms, a 5- or 6- membered ring heteroaryl group or a phenyl group condensed with a hetero ring, (X⁴ ) represents a substituted or unsubstituted phenylene group having 20 or less carbon atoms, (Y⁴ ) and (Y⁴ ' ) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule,

Ar⁵ and Ar⁵ 'represent independently from each other 2-chlorophenyl group, 2-fluorophenyl group or a 2-alkoxyphenyl group having 15 or less carbon atoms, (X⁵ ) represents an unsubstituted phenylene group, (Y⁵ ) and (Y⁵ ') represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule,

Ar⁶ and Ar⁶ ' represent independently from each other a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6- membered ring heteroaryl group, (X⁶ ) represents a substituted or unsubstituted arylene or biphenylene group having 20 or less carbon atoms, (Y⁶ ) and (Y⁶ ') represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule.

The present invention also provides bisnaphthylamide compounds represented by the following general formula (G):

general formula (G)

(Y⁷ )-NH-CO-(X⁷ )-C0-NH-(Y⁷ ' )

wherein (X⁷ ) represents a l,4-(2, 5-dιalkoxyphenylene) group having 20 or less carbon atoms, (Y⁷ ) and (Y⁷ ' ) represent independently from each other a hydroxynaphthyl group having 15 or less carbon atoms.

The bisnaphthylamide compound can be obtained in a high yield by a process which comprises the steps of adding a solution of a corresponding dicarboxylic acid chloride in an organic solvent to an aqueous solution of an ammonaphtholsulfonic acid and conducting the reaction in two-phase system.

The 2 , 5-dιhydroxybenzene-l , 4-dιcarboxylιc acid ester can be obtained in a high yield by a process which comprises the step of oxidizing a 2 , 5-dιoxocyclohexane-l , 4-dιcarboxylιc acid ester with bromine in acetic acid.

The present invention further provides a therapeutic agent for viral infection which comprises a compound of the following general formula (N) as the active ingredient:

general formula (N):

Ar⁸ -N=N-(Y⁸ )-NH-(Z^β )-(X» )-( Z^β ' )-NH-(Y^β ' )-N=N-Ar^β '

whe re in Ar* and Ar' ' represent independentl y f rom each othe r a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6-membered ring heteroaryl group, (X⁸ ) represents a substituted or unsubstituted arylene or biphenylene group having 20 or less carbon atoms or a 5- or 6-membered ring heteroarylene group, (Y⁸ ) and (Y⁸ ' ) represent independently from each other an arylene group having 15 or less carbon atoms and ( Z⁸ ) and ( Z⁸ ' ) represent independently from each other CO or S0₂ with the proviso that at least 2 sulfo groups or pharmacologically acceptable salts thereof are contained in the molecule.

Detailed Description of the Invention

The detailed description will be made on the compounds of the present invention.

It is known that azo compounds generally have azo-hydrazo tautomers. Although the compounds are represented by the general formulae (A), (B), (C), (D), (E), (F) and (N) for the azo isomers in the present invention, hydrazo isomers of them are also included in the present invention.

The detailed description will be given on the compounds of the general formula (A).

The divalent bonding group represented by (X¹ ) is naphthylene or biphenylene group which may have a substituent. The substituents include organic substituents connected through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl , carboxyl , aryloxycarbonyl , alkoxycarbonyl, aryloxy, alkoxy, carbamoyl , heterocyclic-oxy , acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acyla ino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulf amoyl , sulfonyl and sulfinyl groups.

The bonding positions of the divalent bonding group represented by (X¹ ) are preferably not adjacent to each other.

The divalent bonding groups represented by (X¹ ) will be further illustrated below.

When (X¹ ) is biphenylene group, it is desirably bonded at 3- and 3' -positions or 4- and 4 ' -positions . The substituent is preferably hydroxyl group or an alkoxy group. The bonding group is preferably 4, 4 '-biphenylene group, 3 ,3 '-(4 , 4 '-dihydroxybiphenylene) group, 3,3'-(4, 4 ' -dimethoxybiphenylene ) group or 3 , 3 ' -( 4 , 4 ' -dipropoxybiphenylene ) group. The most desirable substituent is 4 , 4 '-biphenylene group.

When (X¹ ) is naphthylene group, it is desirably bonded at 1- and 4-positions, 1- and 5-positions or 2- and 6-positions. The substituent is preferably hydroxyl group or an alkoxy group having 4 or less carbon atoms. The bonding group is preferably 1 , 4-naphthylene , 1,5- naphthylene, 2 , 6-naphthylene, 2 , 6-( 1 , 5-dihydroxynaphthylene) or 2,6- (1,5-dimethoxynaphthylene) group. 1,4- or 2 , 6-naphthylene group is particularly preferred.

The naphthylene group represented by (Y¹ ) or (Y¹ ') may have a substituent such as an organic substituent bonded through a carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom or sulfonic acid group. The organic substituents are, for example, alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylammo, alkoxycarbonylamino, sulfonamido, lmido, alkylthio, arylthio, heterocyclic-thio, sulfa oyl, sulfonyl and sulfmyl groups.

Among these substituents, hydroxyl group or sulfo group is preferred.

In particular, the naphthylene group represented by (Y¹ ) or (Y¹ ' ) is that derived from 3-amιno-2-naphthol, 4-amιno-5-naphthol, 5- amιno-1-naphthol, J-acid, r -acid, S-acid, K-acid or H-acid.

The description will be made on the aryl group or 5- or 6- membered ring heteroaryl group represented by Ar¹ or Ar¹ ' .

When the substituent represented by Ar¹ or Ar¹ ' is an aryl group, the aryl group is preferably a substituted or unsubstituted phenyl or naphthyl group which may have an organic substituent bonded through a carbon, oxygen, nitrogen or sulfur atom or hydroxyl group, halogen atom or sulfonic acid group. The organic substituents are, for example, alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, lmido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfmyl groups.

The aryl group represented by Ar¹ or Ar¹ ' may be further condensed with a 5- or 6-membered ring hetero ring.

The substituents represented by Ar¹ or Ar¹ ' will be further illustrated below. The aryl groups represented by Ar¹ are, for example, phenyl, 4- tolyl , 4-methoxyphenyl , 2,4-xylyl, 2-chlorophenyl, 2-methoxyhenyl , 2- f luorophenyl , 2 , 4-dichlorophenyl , 2-chloro-4-methylphenyl , 2,3- dichlorophenyl , 4-carboxyphenyl , 1-naphthyl, l-( 8-sulfonaphthyl ) , l-(5- sulfonaphthyl) , 2-( 1-sulfonaphthyl ) , 2-( 6, 8-disulf onaphthyl ) , 2- (5, 7- disulfonaphthyl ) and 8-quinolyl groups.

When Ar¹ or Ar¹ ' is a substituted phenyl group, it preferably has an alkoxy group having 3 or less carbon atoms or a halogen atom at the 2-position. The alkoxy group is preferably methoxy or ethoxy group, and the halogen atom is preferably chlorine or fluorine atom. The fluorine atom is particularly preferred.

When Ar¹ or Ar¹ ' is a substituted phenyl group, it is preferably 2-methoxyphenyl, 2-ethoxyphenyl , 4-methyl-2-methoxyphenyl , 2- f luorophenyl , 2-chlorophenyl, 2,3-dichlorophenyl , 2, 4-dichlorophenyl , 2, 5-dichlorophenyl , 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl or 2-chloro-5-sulf ophenyl group. Among them, 2-f luorophenyl , 2- chlorophenyl , 2 , 4-dichlorophenyl or 2-methoxyphenyl group is more preferred. Particularly preferred is 2-chlorophenyl or 2,4- dichlorophenyl group.

When Ar¹ or Ar¹ ' is a phenyl group condensed with a hetero ring, the hetero ring is preferably a nitrogen-containing aromatic hetero ring. Further, the hetero ring is preferably a 6-membered ring. The phenyl groups condensed with the hetero ring include quinolyl , pyrazinophenyl and pyrimidinophenyl groups. Among them, quinolyl groups and particularly 8-quinolyl group is preferred.

When Ar¹ or Ar¹ ' is a naphthyl group, the most preferred substituent thereof is hydrogen or sulfo group. Such naphthyl groups are, for example, 1-naphthyl, l-(8-sulfonaphthyl) , l-(5-sulfonaphthyl) , 2- ( 1-sulfonaphthyl ) , 2- ( 6 , 8-disulfonaphthy1 ) and 2-{5,7- disulfonaphthyl) groups. Among them, 1-naphthyl, l-(5-sulfonaphthyl ) and 2-(6,8-disulfonaphthyl) groups are more preferred, and 1-naphthyl group is most preferred.

When Ar¹ or Ar¹ ' is the 5- or 6-membered ring heteroaryl group, the heteroaryl ring may be condensed with a benzene ring. Examples of the heteroaryl rings include imidazole, thiazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzothiazole, indole and quinoline.

When Ar¹ or Ar¹ ' is the 5- or 6-membered ring heteroaryl group, examples thereof include 3-(5-methylpyrazolyl), 2-pyridyl, 3-pyridyl, 2- pyrimidyl, 2-indolyl and 2-benzimidazolyl groups. Among them, pyridyl group is preferred and 2-pyridyl group is most desirable.

The compound represented by the general formula (A) contains at least 2 sulfo groups or salts thereof in the molecule. The number of the sulfo groups or salts thereof is preferably not more than 8, more preferably 4 to 6 and most preferably 4.

When the sulfo group forms a salt thereof, the cation selected in the production of the salt is particularly preferably a pharmacologically acceptable cation, though it is not particularly limited and it is selected depending on the use. Examples of the cation sources include alkali metals such as lithium, sodium and potassium, alkaline earth metals such as calcium, magnesium and barium, aluminum and substituted or unsubstituted ammonium. When the cation is a substituted ammonium, the ammonium may be any of primary, secondary, tertiary and quaternary ammoniums. The ammonium may have an organic substituent bonded through a carbon, oxygen, nitrogen or sulfur atom or hydroxyl group, halogen atom or sulfonic acid group. The organic substituents are, for example, alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylammo, alkoxycarbonylamino, sulfonamido, lmido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

In particular, the organic ammoniums are those derived from methylamine, ethylamme, 2-methoxyethylamιne , monoethanolamine , dimethylamme , diethy lamme , diethanolamine , t r lethylamine , triethanolamine , ethylenediamine, N,N-dιmethylethylenedιamme and pyπdine. They include, for example, benzyltrimethylammonium , cetyltrimethylammonium and tetrabutyl ammonium.

Cations capable of forming saltswith the sulfo group are preferably sodium, potassium, magnesium, calcium, barium, aluminum, triethanolammonium, tπethylammonium and pyridinium ions. Among them, sodium, potassium, calcium and triethanolammonium ions are particularly preferred.

In a desirable combination of (X¹ ) , (Y¹ ), (Y¹ '), Ar¹ and Ar¹ ' in the bisazo compound represented by the general formula (A), (X¹ ) is 1,4- or 2, 6-naphthylene group or 4, 4 '-biphenylene group, (Y¹ ) and (Y^l ') are a naphthylene group derived from H-acid or K-acid, and Ar¹ and Ar¹ ' are a phenyl group having a halogen atom or alkoxy group at the 2-posιtιon or 8-qumolyl group; or (X¹ ) is 1,4- or 2, 6-naphthylene group or 4,4'- biphenylene group, (Y¹ ) and (Y¹ ' ) are a naphthylene group derived from S-acid, and Ar¹ and Ar¹ ' are a sulfophenyl group having a halogen atom or alkoxy group at the 2-position.

In a more desirable combination of the groups in the bisazo compound represented by the general formula (A), (X¹ ) is 4,4'- biphenylene group, (Y¹ ) and (Y¹ ' ) are a naphthylene group derived from H-acid, and Ar¹ and Ar¹ ' are a phenyl group having a halogen atom or alkoxy group at the 2-position or 8-quinolyl group; or ( X¹ ) is 4,4'- biphenylene group, (Y¹ ) and (Y¹ ' ) are a naphthylene group derived from S-acid, and Ar¹ and Ar¹ are a sulfophenyl group having a halogen atom or alkoxy group at the 2-position.

In a particularly desirable combination of the groups in the bisazo compound represented by the general formula (A), (X¹ ) is 4,4'- biphenylene group, (Y¹ ) and (Y¹ ') are a naphthylene group derived from H-acid, and Ar¹ and Ar¹ ' are 2-chlorophenyl group or 8-quinolyl group; or (X¹ ) is 4 , 4 ' -biphenylene group, (Y^l ) and (Y¹ ' ) are a naphthylene group derived from S-acid, and Ar¹ and Ar¹ ' are 2-chloro-5-sulf ophenyl group.

The detailed description will be made on the bisazo compounds represented by the general formula (B).

The divalent heteroaromatic ring-bonding group represented by (X² ) is a f lve-me bered ring such as thiophene, furan, pyrrole, pyrazole, imidazole or thiazole or a six-membered ring such as pyridine, pyrazine, pyridazine or pyrimidine. These heteroaromatic rings may have a substituent. The substituents include organic substituents bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, i ido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

The bonding positions of the heteroaromatic bonding group represented by (X² ) are preferably not adjacent to each other.

The heteroaromatic bonding groups represented by (X² ) will be further illustrated below.

Preferred heteroaromatic bonding groups represented by (X² ) are, for example, 2, 4-thiophene, 2 , 5-thiohene, 2,5-furan, 2,4-pyrrole, 2,5- pyrrole, 3 , 5-pyrazole, 2 , 4-imidazole, 2, 4-thiazole, 2, 4-pyridine, 2,5- pyridine, 3 , 5-pyridine, 2 , 5-pyrazine, 2 , 6-pyrazine, 2 , 4-pyrimidine, 2 , 5-pyrimidine , 4 , 6-pyrimidine, 3 , 5-pyridazine and 3 , 6-pyridazine. Among them, those wherein the heteroaromatic ring is pyridine ring are more preferred, and 2, 5-pyridine is most preferred.

The substituents represented by Ar² , Ar² ', (Y² ) and (Y² ' ) are the same as those described above with reference to Ar¹ and (Y¹ ), respectively, in the above-described general formula (A), and the sulfo group contained in the molecule is the same as that described above with reference to the general formula (A).

In a desirable combination of Ar² , Ar² ', (Y² ) and (Y² ') in the bisazo compound represented by the general formula (B), (Y² ) and (Y² ' ) are a naphthylene group derived from H-acid or K-acid, and Ar² and Ar² ' are a phenyl group having a halogen atom or alkoxy group at the 2- position or 8-quinolyl group; or (Y² ) and (Y² ' ) are a naphthylene group derived from S-acid, and Ar² and Ar² ' are a sulfophenyl group having a halogen atom or alkoxy group at the 2-position.

Concretely, in a particularly desirable combination of the groups in the bisazo compound represented by the general formula (B), (X² ) is 2,5-pyridine group, (Y² ) and (Y² ') are a naphthylene group derived from H-acid, and Ar² and Ar² ' are 2-chlorophenyl group or 8- quinolyl group; or (X² ) is 2,5-pyπdine group, (Y² ) and (Y² ') are a naphthylene group derived from S-acid, and Ar² and Ar² ' are 2-chloro-5- sulfophenyl group.

The detailed description will be made on the bisazo compounds represented by the general formula (C).

The alkoxy group of the 1 , 4-( 2 , 5-dialkoxyphenylene ) group represented by (X³ ) is a substituted or unsubstituted, linear or branched alkoxy group having 8 or less carbon atoms. The substituents are preferably alkoxy groups such as methoxy, ethoxy and methoxyethoxy groups. The alkoxy groups are preferably those having 4 or less carbon atoms, and more preferably linear alkoxy groups having 3 or less carbon atoms such as methoxy and ethoxy groups. Among the preferred alkoxy groups suitable for the substituents of the above-described alkoxy groups, preferred are those having 3 or less carbon atoms such as methoxy and ethoxy groups. When the alkoxy group further has an alkoxy group, the total carbon atoms in the alkoxy groups is preferably 4 or less, and more preferably, the group is a primary alkoxy group.

More concretely, the alkoxy group in the l,4-(2, 5- dialkoxyphenylene) group represented by (X³ ) is preferably methoxy, ethoxy or methoxyethoxy group. It is particularly preferably methoxy or ethoxy group.

The phenyl group represented by Ar³ or Ar^J ' may have a substituent such as an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

The substituents represented by Ar³ or Ar³ ' will be further illustrated below.

The phenyl groups represented by Ar³ or Ar³ ' are, for example, phenyl, 4-tolyl, 4-methoxyphenyl , 2,4-xylyl, 2-chlorophenyl, 2- methoxyhenyl , 2-f luorophenyl , 2 , 4-dichlorophenyl , 2-chloro-4- methylphenyl, 2, 3-dichlorophenyl and 4-carboxyphenyl groups.

When Ar³ or Ar³ ' is a substituted phenyl group, it preferably has an alkoxy group having 3 or less carbon atoms or a halogen atom at the 2-position. The alkoxy group is preferably methoxy or ethoxy group, and the halogen atom is preferably chlorine or fluorine atom. The fluorine atom is particularly preferred.

Concretely, when Ar³ or Ar³ ' is a substituted phenyl group, it is preferably 2-methoxyphenyl, 2-ethoxyphenyl, 4-methyl-2-methoxyphenyl , 2-f luorophenyl , 2-chlorophenyl, 2,3-dιchlorophenyl , 2, 4-dichlorophenyl , 2, 5-dιchlorophenyl, 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl or 2-chloro-5-sulf ophenyl group. Among them, 2-f luorophenyl , 2- chlorophenyl , 2 , 4-dichlorophenyl or 2-methoxyphenyl group is more preferred. Particularly preferred is 2-chlorophenyl or 2,4- dichlorophenyl group.

The substituents represented by (Y³ ) or (Y³ ' ) are the same as those described above with reference to (Y¹ ) in the above-described general formula (A), and the sulfo group contained in the molecule is the same as that described above with reference to the general formula (A).

In a desirable combination of (Y³ ), (Y³ ' ), Ar^J and Ar³ ' m the bisazo compound represented by the general formula (C), (Y³ ) and (Y³ ' ) are a naphthylene group derived from H-acid or K-acid, and Ar³ and Ar³ ' are a phenyl group having a halogen atom or alkoxy group at the 2- position; or (Y³ ) and (Y³ ' ) are a naphthylene group derived from S-acid, and Ar³ and Ar³ ' are a sulfophenyl group having a halogen atom or alkoxy group at the 2-posιtιon.

Concretely, in a particularly desirable combination of the groups in the bisazo compound represented by the general formula (C), (X³ ) is 1 , 4 - ( 2 , 5-d lmethoxypheny lene ) group or l,4-(2,5- diethoxyphenylene ) group, (Y³ ) and (Y³ ') are a naphthylene group derived from H-acid, and Ar³ and Ar³ ' are 2-f luorophenyl group; or (X³ ) is 1,4- (2, 5-dimethoxyphenylene) group or 1 , 4-( 2 , 5-diethoxyphenylene ) group, (Y³ ) and (Y³ ' ) are a naphthylene group derived from S-acid, and Ar³ and Ar³ ' are 2-f luoro-5-sulfophenyl group.

The detailed description will be made on the bisazo compounds represented by the general formula (D).

The phenylene group represented by X⁴ may have a substituent. The substituent is an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulf amoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

The bonding positions of the phenylene group represented by (X⁴ ) are desirably not adjacent to each other, namely, they are preferably 1, 3-positions or 1, 4-positions.

The phenylene groups represented by (X⁴ ) will be further illustrated below.

The phenylene group represented by (X⁴ ) is preferably unsubstituted. When it is substituted, the substituent is preferably an alkoxy group and particularly preferably a 1, 4-( 2, 5-alkoxyphenylene ) group. The alkoxy groups are preferably substituted or unsubstituted linear or branched alkoxy groups having 8 or less carbon atoms. The substituents are preferably alkoxy groups such as methoxy, ethoxy and methoxyethoxy groups. The alkoxy groups are preferably those having 4 or less carbon atoms, and more preferably linear alkoxy groups having 3 or less carbon atoms such as methoxy and ethoxy groups. When the alkoxy group further has an alkoxy group, the number of the total carbon atoms in the alkoxy groups is preferably 4 or less, and more preferably, the group is a primary alkoxy group.

More concretely, the alkoxy group in the l,4-(2,5- dialkoxyphenylene) group represented by (X⁴ ) is preferably methoxy, ethoxy or methoxyethoxy group. It is particularly preferably methoxy or ethoxy group.

The description will be made on Ar⁴ and Ar⁴ ' , i.e. the substituted or unsubstituted naphthyl group, five- or six-membered heteroaryl group or phenyl group condensed with a hetero ring.

The substituent represented by Ar⁴ or Ar⁴ ' may have a substituent such as an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, ammo, sulf amoylamino , alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

When Ar⁴ or Ar⁴ ' is a naphthyl group, the substituent thereof is most preferably hydrogen or sulfo group. Such a naphthyl group is preferably, for example, 1-naphthyl, 1-( 8-sulfonaphthyl ) , l-(5- sulfonaphthyl), 2-(1-sulfonaphthyl) , 2-(6,8-dιsulfonaphthyl) or 2-(5,7- disulfonaphthyl) group. Among them, 1-naphthyl, l-(5-sulfonaphthyl) or 2-(6,8-dιsulfonaphthyl ) group is preferred, and 1-naphthyl group is particularly preferred.

When Ar⁴ or Ar⁴ ' is a five- or six-membered heteroaryl group, the heteroaryl ring may be condensed with a benzene-ring. Examples of the heteroaryl rings include lmidazole, thiazole, pyrazole, pyπdine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzothiazole, indole and qumoline.

When Ar⁴ or Ar⁴ ' is the 5- or 6-membered ring heteroaryl group, examples thereof include 3-(5-methylpyrazolyl) , 2-pyridyl, 3-pyrιdyl, 2- pyri idyl, 2-ιndolyl and 2-benzιmιdazolyl groups. Among them, pyridyl group is preferred and 2-pyridyl group is most desirable.

In the phenyl group condensed with a hetero ring, which is represented by Ar⁴ or Ar⁴ ' , the hetero ring is preferably a nitrogen- containing aromatic hetero ring and more preferably a six-membered ring. Phenyl groups condensed with such a hetero ring include quinolyl, pyrazinophenyl and pyrimidinophenyl groups. Among them, quinolyl group, particularly 8-quinolyl group, is preferred.

The substituent represented by (Y⁴ ) or (Y⁴ ') are the same as those described above with reference to (Y¹ ) in the above-described general formula (A), and the sulfo group contained in the molecule is the same as that described above with reference to the general formula (A).

In a desirable combination of (X⁴ ), (Y⁴ ), (Y⁴ '), Ar⁴ and Ar⁴ ' in the bisazo compound represented by the general formula (D), (X⁴ ) is 1, 4-phenylene group, (Y⁴ ) and (Y⁴ ') are a naphthylene group derived from H-acid or K-acid, and Ar⁴ and Ar⁴ ' are a 1-naphthyl, 2-pyridyl or 8-qumolyl group.

In a more desirable combination of the groups in the bisazo compound of the general formula (D), (X⁴ ) is 1,4-phenylene group, (Y⁴ ) and (Y⁴ ' ) are a naphthylene group derived from H-acid, and Ar⁴ and Ar⁴ ' are a 1-naphthyl or 8-quinolyl group.

In a particularly desirable combination of the groups in the bisazo compound represented by the general formula (D), (X⁴ ) is 1,4- phenylene group, (Y⁴ ) and (Y⁴ ' ) are a naphthylene group derived from H- acid, and Ar⁴ and Ar⁴ ' are 8-quinolyl group; or (X⁴ ) is 1,4-phenylene group, (Y⁴ ) and (Y⁴ ') are a naphthylene group derived from H-acid, and Ar⁴ and Ar⁴ ' are 8-quinolyl group.

The detailed description will be made on the compounds represented by the general formula (E).

(X⁵ ) represents an unsubstituted 1,4-phenylene group and Ar⁵ and Ar* ' represent 2-chlorophenyl, 2-fluorophenyl or 2-alkoxy group. The alkoxy group represented by Ar⁵ or Ar⁵ ' is preferably a linear or branched alkoxy group having 8 or less carbon atoms, and more preferably a linear alkoxy group having 4 or less carbon atoms. The alkoxy group is particularly preferably ethoxy or methoxy group.

The naphthylene group represented by (Y⁵ ) or (Y⁵ ' ) may have a substituent. The substituent is an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

Among these substituents, the hydroxyl and sulfo groups are preferred.

More concretely, the naphthylene group represented by (Y⁵ ) or (Y⁵ ') is that derived from J-acid,τ -acid, S-acid, K-acid or H-acid.

The naphthylene group represented by (Y⁵ ) or (Y⁵ ' ) is preferably that derived from K-acid or H-acid. It is most preferably naphthylene group derived from H-acid.

The sulfo group contained in the molecule of the compound represented by the general formula (E) is the same as that described above with reference to the general formula (A).

The detailed description will be made on the bisazo compounds represented by the general formula (F).

The divalent bonding group represented by (X⁶ ) is an arylene or biphenylene group. Such a bonding group may have a substituent. The substituent is an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulf amoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

The bonding positions of the divalent bonding group represented by (X* ) are desirably not adjacent to each other.

The more detailed description will be given on the divalent bonding group represented by (X⁶ ).

When the divalent bonding group represented by ( X* ) is an arylene group, it is preferably a substituted or unsubstituted phenylene group or substituted or unsubstituted naphthylene group.

When the divalent bonding group represented by (X⁴ ) is a phenylene group, the bonding positions of the phenylene group are desirably not adjacent to each other, namely, they are preferably Im¬ positions or 1 , 4-positions.

When the divalent bonding group represented by ( X⁶ ) is a naphthylene group, the bonding positions of the naphthylene group are preferably 1 , 4-positions , 1 , 5-positions or 2 , 6-positions . The substituents of this group is preferably a hydroxyl group or alkoxy group having 4 or less carbon atoms. The divalent bonding group is preferably 1,4 -naphthylene, 1, 5-naphthylene, 2, 6-naphthylene, 2,6-(l,5- dihydroxynaphthylene) or 2, 6- (1, 5-dimethoxynaphthylene) group. Among them, 1,4- or 2 , 6-naphthylene group is particularly preferred.

When the divalent bonding group represented by (X⁶ ) is a biphenylene group, the bonding positions of the biphenylene group are preferably 3,3 '-positions or 4,4'-positions. The substituents of this group is preferably a hydroxyl group or alkoxy group. The divalent bonding group is preferably 4 , 4 ' -bipheny1ene , 3,3 '-(4,4'- dihydroxybiphenylene) , 3,3 '-(4,4'-dimethoxybiphenylene) or 3,3 '-(4,4'- dipropoxybiphenylene) group. Among them, 4,4 '-biphenylene group is most preferred.

The substituents represented by Ar⁶ , Ar⁶ ' , (Y' ) and (Y⁶ ' ) are the same as those described above with reference to Ar¹ and (Y¹ ) in the above-described general formula (A), and the sulfo group contained in the molecule is the same as that described above with reference to the general formula (A).

In a desirable combination of (X^s ), (Y^s ), (Y^s '), Ar⁶ and Ar⁶ ' in the bisazo compound represented by the general formula (F), (X⁶ ) is 1,4- or 1,3-phenylene group, 1,4- or 2,6-naphthylene group or 4,4'- biphenylene group, (Y⁶ ) and (Y⁶ ' ) are a naphthylene group derived from H-acid or K-acid, and Ar* and Ar⁶ ' are a phenyl group having a halogen atom or alkoxy group at the 2-posιtιon or 8-quinolyl group; or (X⁶ ) is 1, 4- or 1,3-biphehylene group, 1,4- or 2,6-naphthylene group or 4,4'- biphenylene group, (Y⁶ ) and (Y* ' ) are a naphthylene group derived from S-acid, and Ar⁶ and Ar⁶ ' are a sulfophenyl group having a halogen atom or alkoxy group at the 2-position.

In a more desirable combination of the groups in the bisazo compound represented by the general formula (F), (X⁶ ) is 1,3-phenylene group or 4,4'-biphenylene group, (Y^« ) and (Y* ' ) are a naphthylene group derived from H-acid, and Ar⁶ and Ar⁶ ' are a phenyl group having a halogen atom or alkoxy group at the 2-position or 8-quinolyl group; or (X* ) is 1,3-phenylene group or 4,4 '-biphenylene group, (Y⁶ ) and (Y⁶ ' ) are a naphthylene group derived from S-acid, and Ar⁶ and Ar⁶ ' are a sulfophenyl group having a halogen atom or alkoxy group at the 2- position.

In a particularly desirable combination of the groups in the bisazo compound represented by the general formula (F), (X' ) is 4,4'- biphenylene group, (Y⁴ ) and (Y* ' ) are a naphthylene group derived from H-acid, and Ar⁶ and Ar⁶ ' are 2-chlorophenyl group or 8-quinolyl group; or (X⁶ ) is 4 , 4 '-biphenylene group, (Y⁶ ) and (Y⁶ ' ) are a naphthylene group derived from S-acid, and Ar* and Ar⁶ ' are 2-chloro-5-sulfophenyl group.

The most desirable combination of the groups in the bisazo compound represented by the general formula (F), (X⁶ ) is 4,4'- biphenylene group, (Y⁴ ) and (Y⁴ ' ) are a naphthylene group derived from H-acid, and Ar⁶ and Ar⁶ ' are 2-chlorophenyl group.

The detailed description will be made on the compounds represented by the general formula (G).

The 1,4-(2,5-dialkoxyphenylene) group represented by (X⁷ ) and naphthyl group represented by (Y⁷ ) or (Y⁷ ' ) are the same as the bonding group described above with reference to (X³ ) in the general formula (C) and naphthylene group described with reference to (Y³ ).

The description will be made on the compounds represented by the general formula (N), which is usable as active ingredient of a therapeutic agent for viral infection.

The divalent bonding group represented by (X⁸ ) is that having 1 to 20 carbon atoms such as an alkylene, vinylene, acetylene, arylene, biphenylene or heteroarylene group, which may be bonded through an ether group.

When the divalent bonding group represented by ( X⁸ ) is an alkylene group, it has 1 to 20 carbon atoms. The alkylene group is, for example, methylene, ethylene, propylene or butylene group. The bonding group may be bonded through an ether group. Such a bonding group may have a substituent. The substituent is an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

When the bonding group is a divalent hydrocarbon, it may form a ring such as 1,4-cyclohexylene.

The number of carbon atoms in the bonding group is preferably 1 to 8, more preferably 1 or 4 to 8, and particularly preferably 1 or 4 to 6.

When the bonding group is bonded through an ether group, the number of the total carbon atoms is preferably 3 to 5, and it is most preferably 2,2' -oxybis(ethylene) . The most preferred bonding group is 1 , 4-cyclohexylene.

When the divalent bonding group represented by (X⁸ ) is vmylene group, it preferably has a cis-conf iguration derived from fumaπc acid. When the divalent bonding group represented by (X⁸ ) is an arylene group, it is preferably phenylene or naphthylene group. The bonding group may be bonded through an ether group. Such a bonding group may have a substituent such as an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group or halogen atom. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, ureido, sulf amoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfmyl groups.

Among these substituents, alkoxy groups having 8 or less carbon atoms and halogen atoms are preferred. Among them, alkoxy groups having 4 or less carbon atoms and halogen atoms are more preferred; and fluorine and chlorine atoms are particularly preferred.

When the bonding group is bonded through the ether group, 4,4'- oxybιs( phenylene) is most preferred.

The bonding poisitions of the bonding group are preferably not adjacent to each other.

When the divalent bonding group represented by ( X⁸ ) is biphenylne group, it may have a substituent such as an organic substituent bonded to the biphenylene group through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom or sulfonic acid group. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

Among these substituents, hydroxyl group and alkoxy groups having 8 or less carbon atoms and halogen atoms are preferred; hydroxyl group, alkoxy groups having 4 or less carbon atoms and halogen atoms are more preferred; and fluorine and chlorine atoms are particularly preferred.

The bonding positions of the bonding group are preferably not adjacent to each other.

When the divalent bonding group represented by (X⁸ ) is an aromatic heterocyclic group, it is a five-membered ring such as thiophene, furan, pyrrole, pyrazole, i idazole or thiazole, or a six- membered ring such as pyridine, pyrazine, pyridazine or pyrimidine. Such an aromatic hetero ring may have a substituent. The substituents are, for example, an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom or sulfonic acid group. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulfamoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups. The bonding positions of the aromatic heterocyclic bonding group represented by (X⁸ ) are preferably not adjacent to each other.

The concrete description will be made on the aromatic heterocyclic bonding groups represented by (X⁸ ).

The preferred aromatic heterocyclic groups represented by (X⁸ ) are, for example, 2,4-thiophene, 2, 5-thiophene, 2,5-furan, 2,4-pyrrole, 2,5-pyrrole, 3 , 5-pyrazole, 2, 4-imidazole, 2, 4-thiazole, 2,4-pyridine, 2, 5-pyridine, 3 , 5-pyridine, 2, 5-pyrazine, 2,6-pyrazine, 2 , 4-pyrimidine, 2, 5-pyrimidine, 4 , 6-pyrimidine, 3 , 5-pyridazine and 3 , 6-pyridazine. The aromatic hetero ring is preferably pyridine ring, more preferably 2,5- pyridine.

The description will be made on the divalent bonding group (Y^» ) or (Y⁸ ' ) .

The arylene group represented by (Y⁸ ) or (Y⁸ ' ) is naphthylene or phenylene group which may have a substituent. The substituents are, for example, an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom or sulfonic acid group. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulf amoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

Among these substituents, hydroxyl group and sulfo group are preferred.

More concretely, the phenylene group represented by ( Y⁸ ) or (Y⁸ ' ) is that derived from, for example, 3-aminophenol or 3-amino-4- hydroxybenzenesulfonic acid.

Also, more concretely, the naphthylene group represented by (Y⁸ ) or (Y⁸ ' ) is that derived from, for example, 3-amino-2-naphthol , 4- amino-5-naphthol, 5-amino-l-naphthol , j-acid, r -acid, S-acid, K-acid or H-acid.

The arylene group represented by (Y⁸ ) or (Y⁸ ') is preferably naphthylene group, more preferably naphthylene group derived from S- acid, K-acid or H-acid.

The description will be made on the aryl group or five- or six- membered heterocyclic aryl group represented by Ar⁸ or Ar⁸ ' .

When the substituent represented by Ar⁸ or Ar⁸ ' is an aryl group, it is preferably a substituted or unsubstituted phenyl or naphthyl group which may have a substituent such as an organic substituent bonded through carbon, oxygen, nitrogen or sulfur atom, hydroxyl group, halogen atom, sulfonic acid group or the like. Examples of the organic substituents include alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulf amoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

The aryl group represented by Ar⁸ or Ar* ' may be further condensed with a five- or six-membered hetero ring.

The substituents represented by Ar⁸ or Ar⁸ ' will be further illustrated below. The aryl groups represented by Ar⁸ or Ar⁸ ' are, for example, phenyl, 4-tolyl, 4-methoxyphenyl , 2,4-xylyl, 2-chlorophenyl, 2- methoxyhenyl , 2-f luorophenyl , 2 , 4-dichlorophenyl , 2-chloro-4- methylphenyl , 2 , 3-dichlorophenyl , 4-carboxyphenyl , 1-naphthyl, l-(8- sulf onaphthyl ) , 1- ( 5-sulf onaphthyl ) , 2- ( 1-sulfonaphthyl ) , 2-(6,8- d sulf onaphthyl ) , 2- ( 5, 7-dιsulf onaphthyl ) and 8-quinolyl groups.

When Ar⁸ or Ar⁸ ' is a substituted phenyl group, it preferably has an alkoxy group having 3 or less carbon atoms or a halogen atom at the 2-posιtιon. The alkoxy group is preferably methoxy or ethoxy group, and the halogen atom is preferably chlorine or fluorine atom. The chlorine atom is particularly preferred.

Concretely, when Ar⁸ or Ar⁸ ' is a substituted phenyl group, it is preferably 2-methoxyphenyl, 2-ethoxyphenyl , 4-methyl-2-methoxyphenyl , 2-f luorophenyl , 2-chlorophenyl, 2,3-dιchlorophenyl , 2, 4-dichlorophenyl , 2, 5-dichlorophenyl , 2-chloro-4-methylphenyl, 2-chloro-5-methylphenyl or 2-chloro-5-sulf ophenyl group. Among them, 2-f luorophenyl , 2- chlorophenyl , 2 , 4-dichlorophenyl or 2-methoxyphenyl group is more preferred. Particularly preferred is 2-chlorophenyl or 2,3- dichlorophenyl group.

In the phenyl group condensed with a hetero ring and represented by Ar⁸ or Ar⁸ ' , the hetero ring is preferably a nitrogen-containing aromatic hetero ring which is more preferably a six-membered ring. Such phenyl groups condensed with a hetero ring include quinolyl, pyrazinophenyl and pyrimidinophenyl groups. Among them, quinolyl groups and particularly 8-quinolyl group is preferred.

When Ar⁸ or Ar⁸ ' is naphthyl group, the most preferred substituent thereof is sulfo group. Such naphthyl groups are, for example, 1-naphthyl, l-(8-sulfonaphthyl) , l-(5-sulfonaphthyl ) , 2-(l- sulfonaphthyl) , 2-( 6,8-disulfonaphthyl ) and 2-(5,7-disulfonaphthyl ) groups. Among them, 1-naphthyl, 1-(5-sulfonaphthyl ) and 2-(6, 8- disulfonaphthyl) groups are more preferred, and 1-naphthyl group is most preferred.

When Ar" or Ar⁸ ' is the 5- or 6-membered ring heteroaryl group, the heteroaryl ring may be condensed with a benzene ring. Examples of the heteroaryl rings include imidazole, thiazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, benzimidazole, benzothiazole, indole and quinoline.

When Ar⁸ or Ar⁸ ' is a 5- or 6-membered ring heteroaryl group, examples thereof include 3-(5-methylpyrazolyl) , 2-pyridyl, 3-ρyridyl, 2- pyrimidyl, 2-indolyl and 2-benzimidazolyl groups. Among them, pyridyl group is preferred and 2-pyridyl group is most desirable.

Although Ar⁸ and Ar⁸ ' , (Y⁸ ) and (Y⁸ '), and (Z⁸ ) and (Z⁸ ') may be the same or different from each other, they are preferably the same as each other. Particularly, both (Z⁸ ) and (Z⁸ ' ) are preferably carbonyl group.

The compound represented by the general formula (N) contains at least 2 sulfo groups or salts thereof in the molecule. The number of the sulfo groups or salts thereof is preferably not more than 8, more preferably 4 to 6 and most preferably 4.

The sulfo group in the compound may be free sulfonic acid group or a salt with a pharmacologically acceptable cation. The cation is not particularly limited and it is selected depending on the application conditions. The cations include ions of alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium, magnesium and barium, aluminum and substituted or unsubstituted ammonium.

When the cation is a substituted ammonium, the ammonium may be any of primary, secondary, tertiary and quternary ammoniums. The ammonium may have an organic substituent bonded through a carbon, oxygen, nitrogen or sulfur atom or hydroxyl group, halogen atom or sulfonic acid group. The organic substituents are, for example, alkyl, aryl, heterocyclic, cyano, acyl, carboxyl, aryloxycarbonyl, alkoxycarbonyl, aryloxy, alkoxy, carbamoyl, heterocyclic-oxy, acyloxy, carbamoyloxy, silyloxy, aryloxycarbonylamino, acylamino, anilino, ureido, amino, sulf amoylamino, alkoxycarbonylamino, sulfonamido, imido, alkylthio, arylthio, heterocyclic-thio, sulfamoyl, sulfonyl and sulfinyl groups.

In particular, the organic ammoniums are those derived from methylamine, ethylamine, 2-methoxyethylamine , monoethanolamine , dimethyl amine , diethylamine , diethanola ine , t rieth lamine , triethanolamine, ethylenediamine, N,N-dimethylethylenediamine, L-lysine, L-arginine, L-histidine, pyridine, etc. They include, for example, benzyltrimethylammonium, cetyltrimethylammonium and tetrabutylammonium.

The cations capable of forming salts with the sulfo group are preferably sodium, potassium, magnesium, calcium, barium, aluminum, triethanolammonium, triethylammonium, pyridinium, L-lysine, L-arginine and L-histidine ions. Among them, sodium, potassium, calcium and triethanolammonium ions are particularly preferred.

The concrete description will be made on a desirable combination of (X⁸ ), (Y⁸ ), (Y⁸ '), Ar⁸ and Ar⁸ '. In this case, both ( Z⁸ ) and ( Z⁸ ' ) are carbonyl group.

In a combination, (X⁸ ) is 1,4- phenylene, l,4-(2,5- diethoxyphenylene) or 4 , 4 ' -biphenylene, (Y⁸ ) and (Y⁸ ' ) are a bonding group derived from H-acid or K-acid, and Ar⁸ and Ar⁸ ' are phenyl, 2- chlorophenyl , 2-methoxyphenyl, 2,3-dichlorophenyl, 2, 4-dichlorophenyl, 2, 5-dichlorophenyl, 2-f luorophenyl, 2-chloro-4-methylphenyl or 8-quinolyl group.

In another combination, (X⁸ ) is 1,4- phenylene, l,4-(2,5- diethoxyphenylene) or 4 , 4 ' -biphenylene, (Y⁸ ) and (Y⁸ ' ) are a bonding group derived from S-acid, and Ar⁸ and Ar⁸ ' are 2-chloro-4-sulfophenyl , 2-methoxy-4-sulfophenyl or 2-f luoro-4-sulfophenyl group.

The description will be made on a more desirable combination of (X^s ), (Y⁸ ), (Y⁸ '), Ar⁸ and Ar⁸ ' in the general formula (N).

(X⁸ ) is 1,4- phenylene, 1 , 4- ( 2 , 5-diethoxyphenylene ) or 4,4'- biphenylene, (Y⁸ ) and (Y⁸ ' ) are a bonding group derived from H-acid or K-acid, and Ar⁸ and Ar⁸ ' are phenyl, 2-chlorophenyl, 2-methoxyphenyl, 2, 3-dichlorophenyl , 2 , 4-dichloropheny 1 , 2 , 5-d ichloropheny 1 , 2- f luorophenyl, 2-chloro-4-methylphenyl or 8-quinolyl group.

The description will be made on the most desirable combination of (X⁸ ), (Y⁸ ), (Y⁸ '), Ar⁸ and Ar⁸ ' in the general formula (N).

(X⁸ ) is 1,4- phenylene, (Y⁸ ) and ( Y⁸ ' ) are a bonding group derived from H-acid, and Ar⁸ and Ar⁸ ' are 2-chlorophenyl, 2,3- dichlorophenyl or 8-quinolyl group; (X⁸ ) is 4 , '-biphenylene, (Y* ) and (Y⁸ ' ) are a bonding group derived from H-acid, and Ar⁸ and Ar⁸ ' are 8- quinolyl group; (X⁸ ) is 1,4- phenylene, (Y⁸ ) and (Y⁸ ') are a bonding group derived from K-acid, and Ar⁸ and Ar⁸ ' are 2-chlorophenyl group; or (X⁸ ) is 1 , 4-{ 2, 5-diethoxyphenylene) group, (Y⁸ ) and (Y^{8 1} ) are a bonding group derived from H-acid, and Ar⁸ and Ar⁸ ' are phenyl group.

Examples of the compounds represented by the general formulae (A), (B), (C), (D), (E), (F), (G) and (N) are given below, which by no means limit the present invention.

O 97/19916

Ar'-N=N- (Y')- II(Z")- (X-)- Z" ^' J-NIKV )-N = N-Λr'

Ar"-N = N-(Y')-Nιl(Z")-(_n")-(Z"')-NII{Y"' )-N = N-Ar'

Ar'-N = N-(V")-N!l(Z")-(r ) - ( Z "^' ) -NIK Y" )-N = N-Ar"

Ar"-S = N-(y")-NH(Z")-(X")-CZ"^,)-MKY"^' ^-N = N-Ar"

Ar"-N = N-(Y") NH(Z") (X^β ) - { V ) -NH( Y" ) -N = N-Ar'

Ar^β-N-N-(Y")-NH(Z")-(X")-(Z^θ')-NH(Y"^' )-N=N-Ar'

Ar"-N=N-(Y")-NH(Z")-(X")-(Z"^,)-NH(Y" )-N=N-Ar'

Ar " - X = N- ( Y " ) -Nil ( Z " ) - ( X " ) - ( Z " ' ) - NH( Y " ) - N = N- Ar '

9916

Ar'-N=N-(Y")-Mι(Z^,)-(X")-(Z"')-NH(Y"' )-N=N-Λr^]

9916

Λr'-N=N-fY")-NH(Z")-(X')-ι IKY"' ) -N=N-Ar '

916

The description will be made on the processes for synthesizing the compounds of the present invention.

The process for synthesizing the compounds of the gereral formula (F) is as described below.

The compounds of the general formula (F) can be synthesized by a condensation reaction of a 2,5-dial oxybenzene-l,4-dicarboxylic acid chloride with an aminonaphtholsulfonic acid. It is desirable that the aminonaphtholsulfonic acid is used in the form of an aqueous solution thereof, the acid chloride is dissolved in an organic solvent hardly solulble in water and the reaction is conducted in two-phase system in the presence of a base.

The organic solvent used for the reaction is not particularly limited so far as the acid chloride is soluble therein. Preferred organic solvents are aromatic hydrocarbons such as toluene, chlorobenzene and dichlorobenzene, halogenated hydrocarbons such as dichloromethane and chloroform, and acetic acid esters such as ethyl acetate and butyl acetate. Among them, chlorobenzene, chloroform and ethyl acetate are more preferred, and chloroform is most preferred.

The base used for the reaction is also not particularly limited, so far as it is capable of neutralizing hydrochloric acid formed by the reaction. Examples of the bases include metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and magnesium hydroxide, metal carbonates such as sodium carbonate, potassium carbonate and calcium carbonate, metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and amines such as triethylamine, imidazole, pyridine and collidine. The reaction temperature is preferably 0 to 90"C , more preferably 10 to 70°C .

The 2 , 5-dialkoxybenzene-l , 4-dicarboxylic acid chlorides can be synthesized from corresponding carboxylic acids by an ordinary halogenation method (see, for example, "Shin Jikken Kagaku Koza 14, Synthesis and Reaction of organic compounds (II), 1106). The 2,5- dialkoxybenzene-1 , 4-dicarboxylic acids can be synthesized from 2,5- dihydroxybenzene-1, 4-dicarboxylic acid esters according to Austrian Patent No. 265244.

The description will be made on the process for synthesizing 2, 5-dihydroxybenzene-l, 4-dicarboxylic acid esters.

A 2, 5-dioxocyclohexane-l , 4-dicarboxylic acid ester is suspended in acetic acid, and the ester is reacted with 1.05 to 1.2 equivalents, per equivalent of the ester, of bromine at 0 to 70 °C , desirably 20 to 60°C .

The 2, 5-dioxocyclohexane-l , 4-dicarboxylic acid esters can be easily synthesized from diethylsuccinic acid according to J. P. KOKAI No. Sho 52-59135.

The description will be made on the process for synthesizing the compounds represented by the general formula (C).

Ar-NHj is converted into a diazonium compound under an acidic condition. The obtained product is mixed with a suspension of a corresponding compound represented by the general formula (G) in water at 0 to 30°C to easily synthesize the intended compound. Preferably, a water-soluble organic solvent such as tetrahydrofuran, dioxane, acetonitrile, dimethylformamide or dimethyl sulf oxide is added in an amount of preferably 2 to 50 % by volume, more preferably 5 to 40 % by volume.

The compounds represented by the general formulae (A), (B), (D), (E) and (F) can be synthesized in the same manner as that described above for the compound of the general formula (C).

The description will be made on the pharmacologically acceptable carrier or adjuvant contained in the pharmaceutical composition of the present invention together with the compound of the general formula (N) or tautomer thereof or pharmacologically acceptable salt thereof, as well as the form and dosage thereof. The use of the compound of the general formula (N) or tautomer thereof in combination with a pharmacologically acceptable carrier or adjuvant is preferable to the use thereof singly. Such a combination of them is preferably in the form of an ordinary preparation, for example, tablets, capsules, granules, liquid, syrup or injection which is to be administered orally or parentrally. The pharmaceutical composition of the present invention contains a specified pharmacologically acceptable carrir or adjuvant for this purpose. The pharmacologically acceptable carrier or adjuvant which can be contained in the pharmeceutical composition of the present invention is at least one member selected from the group consisting of physiological saline, buffers, inorganic salts, natural oils and fats, phospholipids , onosaccharides , monosacchar ide derivatives, ol igosacchar ides , oligosacchar ide derivatives, polysaccharides , polysaccharide derivatives, monohydric to trihydric alcohols and derivatives thereof, sugar alcohols and derivatives thereof, amino acids and derivatives thereof, polypeptide derivatives, polyethylene glycols, polyvinyl alcohols, polyvinylpyrrolidones , organic acids, organic acid salts, triethanolamine and dimethyl sulf oxide.

More concrete examples of the pharmacologically acceptable carriers and adjuvants contained in the pharmaceutical composition of the present invention include physiological saline, phosphate buffer, acetate buffer, magnesium silicate, silicic acid anhydride, magnesium metasilicate aluminate, calcium dihydrogenphosphate, natural oils and fats, polyoxyethylene-hardened castor oil, lecithin, glucose, galactose, mannose, sucrose, lactose, sucrose-fatty acid esters, cyclodextrin, starch, dextrin, hydroxypropylstarch , sodium starch glycolate, crysta l l ine ce l lulose , hydroxypropylce l lul ose , hydroxypropylmethylcellulose , methylcellulose , ethylcel lulose , carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, gum arabic powder, propylene glycol , glycerol, benzyl alcohol, triacylglycerols , diacylglycerols , monoacylglycerols , mannitol, sorbitol, sorbitol-f atty acid esters, amino acids and derivatives thereof, gluta ic acid-ethyl glutamate copoly er, gelatin, albumin, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, fatty acids having 8 to 20 carbon atoms, citric acid, tartaric acid, ascorbic acid, alkaline earth metal stearates, benzoic acid salts, triethanolamine and dimethyl sulfoxide. Among them, the carrier or adjuvant is preferably one or more members selected from the group consisting of physiological saline, phosphate buffer, acetate buffer, natural oils and fats, polyoxyethylene-hardened castor oil, lecithin, glucose, lactose, sucrose / fatty acid esters, cyclodextrin, propylene glycol, glycerol, triacylglycerols, sorbitol, amino acids and derivatives thereof, polyethylene glycol, fatty acids having 8 to 16 carbon atoms, triethanolamine and dimethyl sulfoxide.

It is to be understood that the pharmaceutical composition of the present invention may further contain other ingredients ordinarily used in this technical field depending on the kind of the composition, in addition to the above-described ingredients. For example, the composition suitable for the oral administration may contain additives such as a sweetening agent, thickening agent or flavor.

The dosage of the pharmaceutical composition of the present invention may usually be selected in the range of 0.1 to 100 mg/kg in terms of the active ingredient. The dosage will be easily determined by those skilled m the art depending on the dosage form, age and body weight of the patient and heaviness of disease. In an acute or chronic contagion, the composition may be administered twice or more times a day.

A further improved effects can be expected when the pharmaceutical composition of the present invention is used in combination with one or more other antiviral agents. Examples of other antiviral agents include nucleoside analogs, phosphonof or ate , Rifabutin, phosphonothioate oligodeoxynucleotide, Castanospermme and a -mterferon. The nucleoside analogs including 2 ' , 3 '-dideoxycytidine, 2' , 3 ' -dideoxyinosine and 3 ' -azιdo-2 ' , 3 ' -dideoxythymidme (AZT) are particularly effective. The following Examples will further illustrate the present invention.

Example 1

Synthesis of dimethyl 2, 5-dιhydroxybenzene-l, 4-dιcarboxylate:

228 g (1.00 mol) of dimethyl 2 , 5-dioxocyclohexane-l , 4- dicarboxylate was suspended in 1500 ml of acetic acid. 165 g (1.03 mol) of bromine was dropped into the resultant suspension while the internal temperature was kept at 20 to 25 °C . After the completion of the dropping followed by heating at 80 °C , the obtained mixture was stirred for about 1 hour. The disappearance of the starting material was confirmed by TLC, the reaction mixture was cooled and precipitates thus formed were collected by filtration. Yield: 217 g (96 %). (m.p.: 177 to 179°C ; recrystallized from methanol). The precipitates separated from the reaction liquid can be used for the subsequent reaction without purification.

Comparative Example

Synthesis of dimethyl 2, 5-dιhydroxybenzene-l, 4-dιcarboxylate:

11.4 g (0.050 mol) of dimethyl 2 , 5-dioxocyclohexane-l , 4- dicarboxylate was suspended in 70 ml of chloroform. 8.3 g (0.052 mol) of bromine was dropped into the resultant suspension at room temperature. After the completion of the dropping, the obtained mixture was stirred at room temperature for one hour until the yellow color of the solution had disappeared. According to TLC, the starting material did not completely disappear and the formation of two other components was recognized in addition to the intended product. When the quantity of bromine was increased so that the starting material would disappear, the formation of the two components was increased and spots of other by-products were increased.

Example 2

Synthesis of dimethyl 2,5-dιmethoxybenzene-l,4-dιcarboxylate:

1.13 g (5.0 mmol) of dimethyl 2 , 5-dιhydroxybenzene-l , 4- dicarboxylate, 1.52 g (11.0 mmol) of potassium carbonate and 1.39 g (11.0 mmol) of dimethyl sulfate were stirred together in 16 ml of DMF at 90 °C m nitrogen atmosphere for 3 hours. After the starting materials had disappeared, the reaction mixture was cooled to room temperature and poured into 200 ml of water. Crystals thus formed were collected by filtration. Yield: 0.81 g (64 %). (m.p. 144 to 145°C ; recrystallized from methanol) .

Example 3

Synthesis of 2, 5-dιmethoxybenzene-l , 4-dιcarboxylιc acid:

10.0 g (0.039 mol) of dimethyl 2 , 5-dιmethoxybenzene-l , 4- dicarboxylate, 15.6 g (0.236 mol) of 85 % KOH and 50 ml of methanol were heated under reflux for 2 hours. 50 ml of water was added to the reaction mixture, and the obtained mixture was stirred at 80 °C for 2 hours. Then the reaction mixture was cooled and acidified with concentrated hydrochloric acid. Crystals thus formed were collected by filtration. Yield: 8.61 g (97 %). (230°C , decomposition). Example 4

Synthesis of 2,5-dimethoxybenzene-l,4-dicarboxylic acid chloride:

Several drops of DMF (N,N-dimethylformamide) were added to a mixture of 0.226 g (1.0 mmol) of 2,5-dimethoxybenzene-l,4-dicarboxylic acid and 3 ml of thionyl chloride, and the resultant mixture was heated under reflux for 6 hours. Excess thionyl chloride was distilled off under reduced pressure to obtain a light yellow solid, which was used for the subsequent reaction without the purification.

Example 5

Synthesis of bisnaphthol compound G-l:

143 mg (0.42 mmol) of H-acid was suspended in 1 ml of water. A solution of 56 mg (0.21 mmol) of 2,5-dimethoxybenzene-l,4-dicarboxylic acid chloride in 1 ml of chloroform was added to the obtained suspension. A solution of 44.5 mg (0.42 mmol) of sodium carbonate in 0.5 ml of water was dropped into the obtained mixture under violent stirring at room temperature. After the completion of the addition followed by stirring at room temperature for additional 4 hours, chloroform was distilled off. The temperature was lowered to room temperature and pH was controlled at 2 or below with 2 N hydrochloric acid and the precipitates thus formed were collected by filtration. Yield: 130 mg (70 %). (m.p. > 300^*0 ).

In the same manner, compounds G-2 to G-6 can be synthesized.

Example 6 Synthesis of terephthaloyl bis-H-acid:

160 g (47 mmol) of H-acid and 20 g (50 mmol) of sodium hydroxide were dissolved in 750 ml of water. 750 ml of a solution of 50 g (30 mmol) of terephthaloyl chloride in THF was added to the aqueous solution under stirring at room temperature. The resultant mixture was stirred at room temperature for 1 hour, and the reaction liquid was heated to 70 to 80°C and stirred at that temperature for additional 1 hour. The reaction liquid was cooled to room temperature and then concentrated hydrochloric acid was added thereto to make the reaction mixture acidic. Precipitates thus formed were collected by filtration and thoroughly washed with hot water to obtain the intended product. Yield: 72 g (35 %).

The intermediates for the compounds represented by the general formulae (A), (B), (D) and (E) can be synthesized from corresponding carboxylic acids through acid chlorides in the same manner as that described above.

Example 7

Synthesis of bisazo compound C-l:

0.22 g (2.4 mmol) of aniline was dissolved in 16.8 ml of 0.5 N hydrochloric acid. 0.166 g of sodium nitrite was added to the resultant solution under cooling with ice, and the obtained mixture was stirred for 50 minutes to form a diazonium solution. Separately, 0.524 g (0.60 mmol) of bisnaphthol compound G-l was dissolved in 52 ml of 18 % aqueous tetrahydrofuran (THF) solution and then 1.48 g (18 mmol) of sodium acetate was added to the obtained solution. Precipitates were thus formed. The suspension was cooled to 0 °C , to which the diazonium solution prepared as described above was added at once. The obtained mixture was stirred at 0 °C for 1 hour 40 minutes, then at room temperature for 2 hours and finally at 60°C for 2 hour 20 minutes to complete the coupling reaction. Nitrogen gas was directly blown into the reaction mixture to concentrate it. 1.5 g of potassium acetate was added to the concentrate to conduct the salting out. The precipitate thus formed was collected by filtration. Yield: 0.56 g (83 %) (m.p. > 300^oC ).

The compounds represented by the general formulae (A), (B), (D), (E) and (N) can be synthesized in the same manner as that described above.

Example 8

Synthesis of bisazo compound F-5:

Synthesis of intermediate bisnaphthol:

7.5 g (22 mmol) of H-acid was suspended in 25 ml of water. A solution of 3.51 g (10 mmol) of 4,4 '-biphenyl disulfonyl chloride in 35 ml of chloroform was added to the suspension. A solution of 3.2 g (30 mmol) of sodium carbonate in 10 ml of water was dropped into the solution under vigorous stirring at room temperature. After the completion of the dropping followed by stirring at 50 °C for additional 2 hours, 0.86 g (20 mmol) of 93 % sodium hydroxide was added to the reaction mixture. The mixture thus obtained was stirred at 80"C for 2 hours while chloroform was distilled off. After cooling to room temperature followed by addition of concentrated hydrochloric acid, pH was adjusted to about 3. Crystals thus formed were collected by filtration. Yield: 5.1 g (54 %). (m.p. > 300 °C ).

Synthesis of bisazo compound F-5:

0.41 g (3.2 mmol) of o-chloroaniline was dissolved in 22.4 ml of 0.5 N hydrochloric acid. 0.22 g of sodium nitrite was added to the resultant solution under cooling with ice and the obtained mixture was stirred for 50 minutes to prepare a diazonium solution. Separately, 0.75 g (0.80 mmol) of the bisnaphthol compound synthesized as described above was dissolved in 69 ml of 18 % aqueous tetrahydrofuran (THF) solultion, and 2.0 g (24 mmol) of sodium acetate was added to the solution. The solultion was cooled to 0 °C and the diazonium solution was added thereto at once. The reaction mixture was stirred at 0 °C for 2 hours, then at room temperature for 2 hours and finally at 60°C for 2 hours to complete the coupling reaction. 2 g of potassium acetate was added to the reaction mixture, which was then concentrated by blowing nitrogen gas thereinto. The precipitates thus formed were collected by filtration. Yield: 0.81 g (79 %) (m.p. > 300 °C ).

The bisazo compounds represented by the general formula (F) can be synthesized in the same manner as that described above.

The following Examples will illustrate the pharmaceutical composition of the present invention. In the Examples, the term "active ingredient" means the above-described compound of the general formula (N), tautomer thereof or pharmacologically acceptable salt thereof. Pharmaceutical Composition Production Example 1

Active ingredient 50 mg

Potato starch 35 mg

Lactose 110 mg

Talc 4 mg

Magnesium stearate 1 mg

The active ingredient was pulverized. Lactose and potato starch were added to the powder and they were mixed together. A 10 % starch paste was added to the mixture and they were stirred to form granules. After drying followed by sizing of the granules, talc and magnesium stearate were mixed with them. The resultant mixture was tabletted by an ordinary method.

Pharmaceutical Composition Production Example 2

Active ingredient 50 mg

Glucose 200 mg

Water for injection suitable amount

The active ingredient and glucose were dissolved in the distilled water for injection to obtain a solution having a glucose content of 5 % . The solution was filtered through a bactericidal microporous filter into a sterile amber-colored glass ampoule (10 ml), which was then sealed to obtain an injection.

Pharmaceutical Composition Production Example 3 Active ingredient 500 mg Hydroxypropylmethylcellulose 120 mg

Lactose 50 mg

Povidone 30 mg

Magnesium stearate 7 mg

Th e a c t i v e i n g r e d i e n t wa s pu l v e r i z e d . Hydroxypropylmethylcellulose and lactose were added to the powder and they were mixed together. The mixture was granulated with an aqueous Povidone solution by wet granulation method. The granules were mixed with magnesium stearate, and the obtained mixture was compressed to obtain a pharmaceutical composition of controlled release type.

Pharmaceutical Composition Production Example 4

Active ingredient 10 mg

Decanoic acid 60 mg

Triethanolamine 0.5 ml

Purified water 10 ml

The purified water was added to decanoic acid and triethanolamine. The mixture was heated at 60 to 70°C to obtain a solution. The active ingredient was mixed in the solution to obtain a liquid composition.

Pharmaceutical Composition Production Example 5

Active ingredient 10 mg

Decanoic acid 60 mg

Triethanolamine 0.5 ml

Sodium carboxymethylcellulose 2 mg Purified water 10 ml

Decanoic acid, triethanolamine and sodium carboxymethylcellulose were thoroughly mixed together. Purified water was added to the mixture, and the obtained mixture was heated at 60 to 70°C to obtain a solution. The active ingredient was mixed in the solution to obtain a liquid composition.

Pharmaceutical Composition Production Example 6

Active ingredient 10 mg

Polyoxyethylene-hardened castor oil 60 80 mg

Medium-chain length fatty acid triglyceride 50 mg

Ethanol 30 mg

Propylene glycol 30 mg

The active ingredient was dissolved in ethanol. The polyoxyethylene-hardened castor oil 60, medium-chain length fatty acid triglyceride and propylene glycol were added to the solution. The dispersion thus obtained was fed into a hard gelatin capsule of size 4 to obtain a capsule.

ASSAY EXAMPLE 1 (Infection Syncytia Assay)

A cell culture based syncytia assay was used for the rapid and quantitative detection of compounds that can prevent fusion between virus, and/or virus infected cells with cells expressing CD4 , a glycoprotein of 55 kDa on the surface of the cells. As discussed above, it is believed that the main route for HIV infection into lymphocytes and macrophages is through CD4 (Fauci, Science, 239:617 (1988); Stein et al., Cell, 49:659 (1987); McClure et al . , EMBO J., 7:521 (1988); and Maddon et al . , Cell, 54:865 (1986)). CD4 interacts with the membrane expressed gpl20 on HIV-1 and HIV-1-ιnfected cells (Dalgleish et al . , Nature, 312:763 (1984); Klatzmann et al., Nature, 312:767 (1984); McDougal et al., Science, 231:382 (1986); and Maddon et al. , Cell, 47: 333 (1986)). This CD4-gpl20 interaction is essential for syncytia formation, a process of cell fusion that leads to giant cell aggregates and eventually the in vitro destruction of virus-mfected cells (Lifson et al . , Nature, 323:725 (1986); and Sodroski et al., Nature, 322:470 (1986)). Some have speculated that the process of syncytia formation recruits uninfected CD4 cells, and may be a factor in the decreased CD4 " cell counts in HIV-1 infected individuals. However, the exact mechanism and cell components involved with syncytia formation after the initial gpl20-CD4 binding are still unknown. An ELISA containing just the gpl20 and CD4 proteins alone is unable to provide additional components thought to be important in HIV-1 mfectivity and cell fusion, such as conformational changes of the proteins, newly exposed gp41 sites and other as yet unknown sites on the cell (Sattentau et al . , J. Exp. Med. , 174:407 (1991); and Gallaher, Cell, 50:327 (1987)). Therefore, the in vitro assay described below can be used to assess not only gpl20-CD4 binding, but all the necessary events needed for syncytia formation.

The HIV-1 mfectivity studies were conducted in MT2 cells. MT2 cells were grown in RPMI 1640 medium, 10% heat-inactivated fetal bovine serum (FBS). A stock solution of the test compound used in this invention in 100% DMSO was diluted into RPMI media. The major HIV-1 isolate used was RF provided by NIH AIDS research and reference reagent program. A major antiviral assay was developed to determine the antiviral activities of compounds (inhibitors).

The cells were infected with HIV-1 RF at multiplicity of infectivity (moi) of 0.001 in the absence of a compound for one hour. HIV-1 infected cells were washed once with PBS, resuspended in RPMI 1640, 10% FBS medium and distributed to 96-well culture dishes (5 x 10' cells per well) in the presence of inhibitor. The cell culture was maintained for five days and the virus spread was assessed by reading syncytia. The results obtained are shown in Table 1.

TABLE 1 Syncytia Inhibition Assay

Compound Inhibition (%) Inhibition (%) Inhibition (% ) 20 u g/ml 10 u g/ml 5 u g/ml

100 20

95 50

60 0

90 0

100 0

100 0

100 95

10 0

0 0

100 20

0 0

Comparative Compound 1

Most of the anti-syncytia assay data of the compounds used in this invention correlates with antiviral data. Although each absolute inhibition value is different between the two, the higher the anti- syncytia value, the higher the antiviral activity. Since gpl20/CD4 blocking activity does not correlate with the antiviral activity, this type of compound used in this invention likely blocks a step of the fusion process that occurs after CD4 binding.

ASSAY EXAMPLE 2 (Antiviral Assay)

The HIV-1 infectivity studies were conducted in MT2 cells and peripheral blood mononuclear cells (PBMC). MT2 cells were grown in RPMI 1640 medium, 10% heat-inactivated fetal bovine serum (FBS). PBMCs were stimulated with 4/a g/ml PHA for 48 hours in RPMI 1640. After HIV-1 infection, PBMCs were maintained in RPMI 1640, 10% FBS and 10 U/ml IL-2. A stock solution of the test compound used in this invention in 100% DMSO was diluted into RPMI media. The HIV-1 patient isolates used were 900029, 900285 and 910029. A major antiviral assay was developed to determine the antiviral activities of compounds (inhibitors).

The cells were infected with HIV-1 RF at multiplicity of infectivity ( oi) of 0.001 in the absence of a compound for one hour. HIV-1 infected cells were washed once with PBS, resuspended in RPMI 1640, 10% FBS medium and distributed to 96-well culture dishes (5 x 10^s cells per well) in the presence of inhibitor. The cell culture was maintained for seven days and the virus spread was assessed by HIV-1 p24 ELISA. The results obtained are shown in Table 2. TABLE 2 Inhibition Effect of the Compounds

N.D. : No data

The results in Table 2 indicate that the compounds used in the present invention exhibit an efficient inhibitory effect against HIV even in the presence of 50% Human Serum.

While the invention has been described in detail, and with reference to specific embodiments thereof, it will be apparent to one of ordinary skill in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

claim

1. A bisazo compound represented by the following general formula (A), (B), (C), (D), (E) or (F): general formula (A):

Ar¹-N=N-(Y¹)-NH-CO-(X¹ )-CO-NH-(Y^{1 '})-N=N-Ar^{1 '} general formula (B):

Ar²-N=N-(Y²)-NH-CO-(X²)-CO-NH-(Y^{2 '})-N=N-Ar^{2 '} general formula (C):

Ar³-N=N-(Y³ )-NH-CO-(X³ )-CO-NH-(Y^{3 '})-N=N-Ar^{3 '} general formula (D):

Ar⁴-N=N-(Y⁴)-NH-CO-(X⁴ )-CO-NH-(Y^{4 '})-N=N-Ar^4' general formula (E):

Ar⁵-N=N-(Y⁵ )-NH-CO-(X⁵ )-CO-NH-(Y^{5 '})-N=N-Ar^{5 '} general formula (F):

Ar⁶ -N=N-(Y⁶ )-NH-SO.-(X⁶)-SO₂-NH-(Y^{6 '})-N=N-Ar^{6 '} wherein Ar¹ and Ar^{1 '} represent independently from each other a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6-membered ring heteroaryl group, (X¹ ) represents a substituted or unsubstituted naphthylene or biphenylene group having 20 or less carbon atoms, (Y¹) and (Y^1') represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule,

Ar² and Ar^{2 '} represent independently from each other a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6- membered ring heteroaryl group, (X² ) represents a substituted or unsubstituted, 5- or 6-membered ring heteroarylene group having 20 or less carbon atoms, (Y² ) and (Y^{2 '}) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule,

Ar³ and Ar^{3 '} represent independently from each other a substituted or unsubstituted phenyl group having 15 or less carbon atoms, (X³) represents a 1,4-(2,5-dialkoxyphenylene) group having 20 or less carbon atoms, (Y³ ) and (Y^{3 '}) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule, Ar⁴ and Ar^4' represent independently from each other a substituted or unsubstituted naphthyl group having 15 or less carbon atoms, a 5- or 6-membered ring heteroaryl group or a phenyl group condensed with a hetero ring, (X⁴ ) represents a substituted or unsubstituted phenylene group having 20 or less carbon atoms, (Y⁴ ) and (Y^{4 '}) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule, Ar⁵ and Ar^{5 '} represent independently from each other 2-chlorophenyl group, 2-fluorophenyl group or a 2-alkoxyphenyl group having 15 or less carbon atoms, (X⁵ ) represents an unsubstituted phenylene group, (Y⁵) and (Y^{5 '}) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule,

Ar⁶ and Ar^{6 '} represent independently from each other a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6-membered ring heteroaryl group, (X⁶ ) represents a substituted or unsubstituted arylene or biphenylene group having 20 or less carbon atoms, (Y⁶ ) and (Y^{6 '}) represent independently from each other a naphthylene group having 15 or less carbon atoms with the proviso that at least 2 sulfo groups or salts thereof are contained in the molecule.

2. The bisazo compound set forth in claim 1, which is represented by the general formula (A).

3. The bisazo compound set forth in claim 1, which is represented by the general formula (B).

4. The bisazo compound set forth in claim 1, which is represented by the general formula (C).

5. The bisazo compound set forth in claim 1, which is represented by the general formula (D).

6. The bisazo compound set forth in claim 1, which is represented by the general formula (E).

7. The bisazo compound set forth in claim 1, which is represented by the general formula (F).

8. The bisazo compound set forth in claim 1, wherein at least one of Ar¹, Ar^{1 '}, Ar², Ar^{2 '}, Ar³ , Ar^{3 '}, Ar⁶ and Ar^6' is represented by the following general formula (H):

wherein X represents a halogen atom or linear or branched alkoxy group having 4 or less carbon atoms, and Y represents a hydrogen atom, linear or branched alkyl group having 4 or less carbon atoms, linear or branched alkoxy group having 4 or less carbon atoms, halogen atom, sulfo group or a salt thereof.

9. The bisazo compound ser forth in claim 1, wherein at least one of NH-(Y¹), NH-(Y^{1 '}), NH-(Y²), NH-(Y^{2 '}), NH-(Y³ ), NH-(Y^{3 '}), NH-(Y⁴), NH-(Y^{4 '}), NH-(Y⁵ ), NH-(Y^{5 '}), NH-(Y⁶ ) and NH-(Y^{6 '}) is represented by the following general formula (I) or (J):

wherein M represents a hydrogen atom or cation, or

wherein M represents a hydrogen atom or canon.

10. The bisazo compound set forth in claim 1, wherein ar least one of NH-(Y¹ ), NH-(Y^{1 '}), NH-(Y²), NH-(Y^{3 '}), NH-(Y³ ), NH-(Y^{3 '}), NH-(Y⁶) and NH-(Y^{6 '}) is represented by the following general formula (I), and and at least one of Ar¹ , Ar^{1 '}, Ar² , Ar^{2 '}, Ar³, Ar^{3 '}, Ar⁶ and Ar^{6 '} is represented by the following general formula (H):

wherein M represents a hydrogen atom or cation, and

wherein X represents a halogen atom or linear or branched alkoxy group having 4 or less carbon atoms, Y represents a hydrogen atom, linear or branched alkyl group having 4 or less carbon atoms, linear or branched alkoxy group having 4 or less carbon atoms or halogen atom.

11. The Disazo compound set forth in claim 1 , wherein at least one of NH-(Y¹), NH-(Y^{1 '}), NH-(Y²), NH-(Y^{3 '}), NH-(Y³), NH-(Y^{3 '}), NH-(Y⁶) and NH-(Y^{6 '}) is represented by the following general formula (J), and at least one of Ar¹ , Ar^{1 '}, Ar² , Ar^{2 '}, Ar³ , Ar^{3 '}, Ar⁶ and Ar^{6 '} is represented by the following general formula (M):

wherein M represents a hydrogen atom or cation, and

wherein X represents a halogen atom or linear or branched alkoxy group having 4 or less carbon atoms, and Y represents a hydrogen atom, a linear or branched alkyl group having 4 or less carbon atoms, linear or branched alkoxy group having 4 or less carbon atoms or halogen atom.

12. A bisamide compound represented by the following general formula (G):

general formula (G).

(Y⁷ )-NH-CO-(X⁷)-CO-NH-(Y^{7 '})

wherein (X⁷) represents a 1,4-(2,5-dialkoxyphenylene) group having 20 or less carbon atoms, (Y⁷ ) and (Y^{7 '}) represent independently from each other a hydroxynaphthyl group having 15 or less carbon atoms.

13. The bisamide compound set forth in claim 12, wherein at least one of NH-(Y⁷ ) and NH-(Y^{7 '}) is represented by the following general formula (K) or (L):

wherein M represents a hydrogen atom or cation, or

wherein M represents a hydrogen atom or cation.

14. A process for producing the bisamide compound represented by the general formula (G) set forth in claim 12, which comprises the steps of adding an acid chloride dissolved in an organic solvent to an aqueous solution of aminonaphtholsulfonic acid and conducting the reaction in two-phase system.

15. A process for producing 2,5-dihydroxybenzene-1,4-dicarboxylic acid esters, which comprises the steps of providing a 2,5-dioxocyclohexane-1,4-dicarboxylic acid ester and oxidizing the 2,5-dioxocyclohexane-1,4-dicarboxylic acid ester with bromine in acetic acid.

16. A therapeutic agent for viral infection, which comprises at least one of compounds represented by the following general formula (N):

Ar⁸ -N=N-(Y⁸)-NH-(Z⁸)-(X⁸)-(Z^{8 '})-NH-(Y^{8 '})-N=N-Ar^{8 '}

wherein Ar⁸ and Ar^{8 '} represent independently from each other a substituted or unsubstituted aryl group having 15 or less carbon atoms or a 5- or 6-membered ring heteroaryl group, (X⁸ ) represents a substituted or unsubstituted arylene or biphenylene group having 20 or less carbon atoms or a 5- or 6-membered ring heteroarylene group, (Y') and (Y^{8 '}) represent independently from each other an arylene group having 15 or less carbon atoms, and (Z⁸ ) and (Z^{8 '} ) represent independently from each other CO or SO₂ with the proviso that at least 2 sulfo groups or pharmacologically acceptable salts thereof are contained in the molecule.

17. The therapeutic agent for viral infection set forth in claim 16, wherein the viral infection is caused by a retrovirus.

18. The therapeutic agent for viral infection set forth in claim 17, wherein the retrovirus is HIV.

19. A therapeutic agent for viral infection, which comprises at least one of the compounds set forth in claim 9.

20. A therapeutic agent for viral infection, which comprises at least one of the compounds set forth in claim 10.

21. A therapeutic agent for viral infection, which comprises at least one of the compounds set forth in claim 11.

22. The therapeutic agent for viral infection set forth in claim 16, wherein the compounds represented by the general formula (N) is a bisazo compound represented by the following general formula (O):

wherein X represents a halogen atom or linear or branched alkoxy group having 4 or less carbon atoms, Y represents a hydrogen atom, a linear or branched alkyl group having 4 or less carbon atoms, linear or branched alkoxy group having 4 or less carbon atoms or halogen atom, M represents a hydrogen atom or cation, m represents 1 or 2, and n represents 0 or 1.

23. The therapeutic agent for viral infection set forth in claim 16, wherein the compounds represented by the general formula (N) is a bisazo compound represented by the following general formula (P):

wherein Ar⁹ represents a 2-chlorophenyl, 2,3-dichloropnenyl or 8- quinolyl group, and M represents a hydrogen atom or cation.

24 . The therapeutic agent for viral infection set forth in claim 16, wherein the compounds represented by the general formula (X) is a Pisazo compound represented by the following general formula (Q):

wherein M represents a hydrogen atom or cation,

25. The therapeutic agent for viral infection set forth in claim 16, wherein the compounds represented by the general formula (N) is a bisazo compound represented by the following general formula (R):

wherein M represents a hydrogen atom or cation.

26. The therapeutic agent for viral infection set forth in claim 16, wherein the compounds represented by the general formula (N) is a bisazo compound represented by the following general formula (S):

wherein M represents a hydrogen atom or cation.

27. The therapeutic agent for viral infection set forth in claim 16, which further comprises at least one pharmacologically acceptable carrier or adjuvant selected from the group consisting of physiological saline, buffers, inorganic salts, natural oils and fats, phospholipids, monosaccharides, monosaccharide derivatives, oligosaccharides, oligosaccharide derivatives, polysacchar ides, polysaccharide derivatives, monohydric to trihydric alcohols and derivatives thereof, sugar alcohols and derivatives thereof, amino acids and derivatives thereof, polypeptide derivatives, polyethylene glycols, polyvinyl alcohols, polyvinylpyrrolidones, organic acids, organic acid salts, triethanolamine and dimethyl sulfoxide.

28. The therapeutic agent for viral infection set forth in claim 27, wherein the pharmacologically acceptable carrier or adjuvant is at least one member selected from the group consisting of physiological saline, phosphate buffer, acetate buffer, magnesium silicate, silicic acid anhydride, magnesium metasilicate aluminate, calcium dihydrogenphosphate, natural oils and fats, polyoxyethylene-hardened castor oil, lecithin, glucose, galactose, mannose, sucrose, lactose, sucrose-fatty acid esters, cyclodextrin, starch, dextrin, hydroxypropylstarch, sodium starch glycolate, crystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,ethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, gum arabie powder, propylene glycol, glycerol, benzyl alcohol, triacylglycerols, diacylglycerols, monoacylglycerols, mannitol, sorbitol, sorbitol-fatty acid esters, amino acids and derivatives thereof, glutamic acid-ethyl glutamate copolymer, gelatin, albumin, polyethylene glycol, polyvinyl alcohol, polyvinylpyrrolidone, fatty acids having 8 to 20 carbon atoms, citric acid, tartaric acid, ascorbic acid, alkaline earth metal stearates, benzoic acid salts, triethanolamine and dimethyl sulfoxide.

29. The therapeutic agent for viral infection set forth in claim 28, wherein the pharmacologically acceptable carrier or adjuvant is at least one member selected from the group consisting of physiological saline, phosphate buffer, acetate buffer, natural oils and fats, polyoxyethylene-hardened castor oil, lecithin, glucose, lactose, sucrose-fatty acid esters, cyclodextrin, propylene glycol, glycerol, triacylglycerols, sorbitol, amino acids and derivatives thereof, polyethylene glycol, fatty acids having 8 to 16 carbon atoms, triethanolamine and dimethyl sulfoxide.