WO1995006032A1 - Tyrosine kinase inhibitor - Google Patents

Abstract

A compound represented by general formula (I) and uses thereof. This compound inhibits strongly a tyrosine kinase and suppresses tumor cell growth, so that it is useful in the medicinal field and is expected to be usable particularly as an antitumoral agent.

Description

 Description Tyrosine kinase inhibitor Technical field

 The present invention is useful in the field of medicine, and more specifically, relates to a novel compound that inhibits the growth of tumor cells and exhibits an antitumor effect, and a use thereof.

 Background art

 In the field of cancer chemotherapy, many compounds have already been put into practical use as antitumor agents. However, its effect on various types of tumors is not always sufficient, and the problem of tumor cell resistance to these drugs complicates the clinical use of antitumor agents [47th Annual Meeting of the Japanese Cancer Association See General Assembly article, pages 12-15 (1988). Under these circumstances, there is a constant need for new anticancer substances in the field of cancer treatment. In particular, there is a need for a substance that overcomes the resistance to existing anticancer substances and is effective against the types of cancer that existing anticancer substances cannot sufficiently exert.

 In recent years, substances having a tyrosine kinase inhibitory activity have attracted attention as an antitumor substance of a new mechanism [Drugs ォ ob 'Future (Drugs of Future) 17, 119-131 (1992) and Journal of Natural Products, Vol. 55, pp. 1529-1560 (1992), etc.]. The present inventors have screened a wide range of microbial metabolites and found that a novel compound BE-23372M [(E) -3- (3,4-dihydroxy) having tyrosine kinase inhibitory activity and antitumor activity Benzylidene) -5- (3,4-dihydroxyphenyl-2 (3H) -furanone] was disclosed [see Japanese Patent Application Laid-Open No. 4-275284].

 DISCLOSURE OF THE INVENTION,

Chemical modification of the 2 (3H) -furanone antitumor substance disclosed in the previous patent application [Japanese Patent Application Laid-Open No. 4-275284] to create a compound having more excellent tyrosine kinase inhibitory activity and antitumor activity. This is the problem that the present invention seeks to solve. The present inventors have made a chemical modification to the 2 (3H) -furanone-based antitumor compound disclosed above to create a compound having further excellent tyrosine kinase inhibitory activity and antitumor activity. As a result of synthesizing a large number of derivatives and examining their tyrosine kinase inhibitory activity and antitumor activity, the following general formula [I]

 [In the formula, each symbol has the same meaning as in claim 1.] Have been found to be novel compounds having extremely excellent tyrosine kinase inhibitory activity and antitumor activity, and have completed the present invention.

 Next, the meaning of the abbreviations used in the present invention will be described.

 Me methyl group

 Etethyl group

 Pr propyl group

 Bu butyl group

 Ph phenyl group

 CDI Carbonidimidazole

 DCC Ν, Ν'-Dicyclohexylcarposimid

 DMA Ν, Ν-dimethylacetamide

 DME 1,2-dimethyl tokishetan

 DMF Ν, Ν-dimethylformamide

 DMPU Ν, Ν'-dimethylpropyleneurea

 DPPA diphenyl phosphoryl azide

 EDCI · HC1 Tretyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

 HEPES 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid

HMPA Hexamethylphosphate triamide HOBT · H ₂ 0 1 - hydroxy - 1H-Benzotoriazo Ichiru monohydrate

HOSu N-hydroxysuccinimide

 KHMDS potassium hexamethyldisilazane

 LDA Lithium diisopropylamide

LHMDS lithium hexamethyldisilazane

 NMM N-methylmorpholine

 THF tetrahydrofuran

 Next, definitions of various terms referred to in the description of this specification and specific examples thereof will be described.

 In this specification, the term “equivalent” means molar equivalent unless otherwise specified.

 As used herein, the term "lower" means no more than 6 unless the carbon number of the group to which the term is attached is specifically stated.

 The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and a sec-butyl group. Tert-butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, isohexyl group and the like.

 The lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as a vinyl group, a 1-propeninole group, an aryl group, a 1-butenyl group, and a 2-butenyl group. , 3-butenyl group, 1-methylvinyl group, 2-methyl-1-butenyl group and the like.

 The lower alkynyl group means a linear or branched alkynyl group having 2 to 6 carbon atoms, for example, ethynyl group, 2-propynyl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group Group, 2-hexynyl group and the like.

 The cycloalkyl group means a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group.

The cycloalkyl lower alkyl group means a cycloalkylalkyl group having 4 to 14 carbon atoms in which the lower alkyl group is substituted by the cycloalkyl group, for example, a cyclopropylmethyl group, a 1-cyclopropylethyl group, 2-cyclopro Pyrethyl, cyclobutylmethyl, 1-cyclobutylethyl, 2-cyclobutylethyl, cyclopentylmethyl, 1-cyclopentylethyl, 2-cyclopentylethyl, cyclohexylmethyl, 1-cyclohexylethyl And a 2-cyclohexylethyl group.

 The aryl group means a group having 6 to 12 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, a 4-nitrophenyl group, a 4-carboxyphenyl group, and a 4-methoxyphenyl group. .

 Ύ reel lower alkyl group means an arylalkyl group having 7 to 14 carbon atoms in which the aryl group is substituted for the lower alkyl group, for example, benzyl group, phenethyl group, 3-phenylpropyl group, Examples thereof include a 4-methoxybenzyl group, a 4-hydroxybenzyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group.

 The protected hydroxy group means a hydroxy group protected by a commonly used protecting group. Examples of the used protecting group include a lower alkyl group such as a methyl group and an ethyl group; for example, a trimethylsilyl group and a t-butyldimethyl group. A lower alkylsilyl group such as a silyl group; a lower alkoxymethyl group such as a methoxymethyl group and a 2-methoxyethoxymethyl group; a tetrahydroviranyl group; a benzyl group, a P-methoxybenzizole group, and a 2,4-dimethoxy group; Aryl lower alkyl groups such as benzyl group, 0-nitropentenyl group, p-nitropentenyl group, and trityl group; lower alkanol groups such as formyl group and acetyl group; t-butoxycarbonyl group; Lower alkyloxy such as 2-odoethoxycarbonyl and 2,2,2-trichloroethoxycarbonyl Rubonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyloxycarbonyl group, 2-methyl-2- Lower alkenyloxycarbonyl groups such as probenyloxycarbonyl group, 2-butenyloxycarboninole group and cinnamyloxycarbonyl group; for example, benzyloxycarbonyl group, P-methoxybenzyloxycarbonyl group; And aryl lower phenyloxycarbonyl groups such as nitrobenzyloxycarbonyl group and P-nitropentoxycarbonyl group.

The hydroxy lower alkyl group means a hydroxyalkyl group having 1 to 6 carbon atoms in which the lower alkyl group is substituted by 1 to 2 hydroxy groups. Droxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1,2-dihydroxyethyl group, 1-hydroxypropyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2,3 -Dihydroxypropyl group and the like. The protected hydroxy lower alkyl group means the lower alkyl group having 1 to 6 carbon atoms which is substituted by 1 to 2 protected hydroxy groups, for example, methoxymethyl group, benzyl group. Methoxymethyl group, 1-methoxetinole group, 2-benzyloxyshethyl group, 2-tetrahydroviranyloxymethyl group, 1,2-dimethoxethyl group, and 1,2-glycolone and In the case of 3-glycol, an isopropylidene group, a cyclohexylidene group, a benzylidene group, or the like can be used as a protecting group, and specifically, a 1,3-di-0-isopropylidene pentyl group, 1,2 -Di-0-cyclohexylideneethyl group, 2,3-di-0-isopropylidene oryl group.

 The lower alkoxy group means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy. A tert-butoxy group, a pentoxy group, an isopentyloxy group, a neopentyloxy group, a tert-pentyloxy group, a hexyloxy group, an isohexyloxy group, and the like.

 The lower alkenyloxy group means a linear or branched alkenyloxy group having 3 to 6 carbon atoms, such as an aryloxy group, a 2-butenyloxy group, a 3-butenyloxy group, a 4-pentenyloxy group, and the like. Is mentioned.

 The lower alkynyloxy group means a linear or branched alkynyloxy group having 3 to 6 carbon atoms, such as a propynyloxy group, a 2-butynyloxy group, a 3-butynyloxy group, and a pentynyloxy group. Can be

 The cycloalkyl lower alkoxy group means a cycloalkyl alkoxy group having 4 to 14 carbon atoms in which the lower alkoxy group is substituted by the cycloalkyl group, for example, a cyclopropyl methoxy group, a 1-cyclopropyl ethoxyquin group. And 2-cyclopropylethoxy group, cyclobutyl methoxy group, cyclopentyl methoxy group, cyclohexyl methoxy group and the like.

An aryloxy group means one having 6 to 12 carbon atoms, such as phenoxy, 4-methoxyphenyl, 4-carboxyphenoxy, 1-naphthyl And a 2-naphthyloxy group.

 The aryl lower alkoxy group refers to an aryl lower alkoxy group having 4 to 14 carbon atoms in which the lower alkoxy group is substituted by the aryl group. Examples thereof include a benzyloxy group, a phenethyloxy group, and a 4-methyl Examples include a toxicbenzyloxy group, a 4-carboxybenzyloxy group, a 1-naphthylmethyloxy group, and a 2-naphthylmethyl group.

 The lower alkanoyl group means an alkanoyl group having 1 to 6 carbon atoms, for example, formyl group, acetyl group, propionyl group, butyryl group, valeryl group, pivaloyl group, hexanoyl group and the like.

 A lower alkanoyloxy group means an alkanoyloxy group having 1 to 6 carbon atoms. And the like.

 The lower alkenyloxy lower alkyl group means the lower alkyl group substituted with the alkenyloxy group, such as a formyloxymethyl group, an acetyloxymethyl group, a 1-acetyloxyxethyl group. , 2-acetyloxyethyl, propionyloxymethyl, 1-propionyloxyethyl, 2-propionyloxyethyl, and the like.

 The lower alkoxy lower alkyl group means an alkoxyalkyl group in which the lower alkyl group is substituted by the lower alkoxy group, and examples thereof include a methoxymethyl group, a methoxethyl group, an ethoxymethyl group, and a propyloxymethyl group. Can be

 The aryloxy lower alkyl group means the lower alkyl group substituted with the aryloxy group, and examples thereof include a phenokinemethyl group, a 1-naphthyloxymethyl group, and a 2-naphthyloxymethyl group.

 Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The term "lower alkyl group" means the lower alkyl group substituted with 1 to 3 halogen atoms, and examples thereof include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group. Methyl Group, bromomethyl group, dibromomethyl group, tribromomethyl group, 1,2-difluoroethyl group, 1,2-dichloroethyl group, 1,2-dibromoethyl group, 2,3-difluoropropyl group, 2,3-dichloro group And a propyl group and a 2,3-dibromopropyl group.

 The protected carboxyl group means a carboxyl group protected by a commonly used protecting group. Examples of the used protecting group include a methyl group, an ethyl group, a propyl group, an isopropyl group and a t-butyl group. A lower alkyl group; for example, a halo-lower alkyl group such as a 2,2,2-trichloroethyl group or a 2,2,2-trifluoroethyl group; for example, an acetooxymethyl group, a propionyloxymethyl group, a vivaloyloxy group; Methyl-, 1-acetoxityl,;!-Loweralkanoyloxyalkyl, such as propionyloxyethyl, etc .; for example, 1- (methoxycarboxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1 -(Isopropoxycarbonyloxy) lower alkyl group such as ethyl group such as 2-ethyl group; for example, 2-propininole group Lower alkenyl groups such as 2-chloro-2-propyninole group, 3-methoxycarbonyl-2-propenyl group, 2-methyl-2-propenyl group, 2-butenyl group and cinnamyl group For example, benzyl, P-methoxybenzyl, 3,4-dimethoxybenzyl, 0-nitrobenzyl, p-nitrobenzyl, benzhydryl, bis (P-methoxyphenyl) methyl, etc. Aryl lower alkyl group; for example, (5-substituted-2-oxo-1, 3-dioxol-4-yl) such as (5-methyl-2-oxo-1,3-dioxo-1-yl) methyl group; Yl) methyl group; for example, lower alkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group; indanyl group, phthalidyl group, methoxymethyl group and the like.

 The carboxy lower alkyl group means the above-mentioned lower alkyl group substituted by a carboxy group, and examples thereof include a carboxymethyl group, a 2-carboxyethyl group, and a 3-carboxypropyl group.

The protected carbonyloxy lower alkyl group means the above lower alkyl group substituted by a carboxy group protected by the above protecting group, for example, methoxycarbonylmethyl group, benzyloxycarbonylmethyl group, Methoxycarbonylethyl group, 3-benzyloxycarbonylpropyl group, etc. Can be

 A carboxy lower alkenyl group means the above-mentioned lower alkenyl group substituted by a carboxy group, such as a 1-carboxyvinyl group, a 2-carboxyvinyl group, a 3-carboxy-2-propenyl group, etc. Is mentioned.

 The protected carboxy lower alkenyl group means the above lower alkenyl group substituted by a carboxy group protected by the above protecting group, for example, an I-methoxycarbonylvinyl group, a 2-methyl A methoxycarbonylvinyl group and a 3-benzyloxycarbonyl-2-propininole group.

The protected amino group means an amino group protected by a commonly used protecting group, and examples of the protecting group include an aryl lower alkylidene group such as a benzylidene group and a P-methoxybenzylidene group; Aryl lower such as p-methoxybenzyl group, 3,4-dimethoxybenzyl group, 0-nitrobenzyl group, p-nitrobenzyl group, benzhydryl group, bis (P-methoxyphenyl) methyl group and trityl group Alkyl group; for example, lower alkanol group such as formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group, and vivaloyl group; for example, phthalyl group; for example, chloroacetyl group, dichloroacetyl group, trichloroacetyl group Halo-substituted lower alkanol groups such as trifluoroacetyl group; phenylacetyl group Aryloxy lower alkyl groups such as phenoxyacetyl groups; lower alkyloxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, etc .; Halo-lower alkyloxycarbonyl groups such as ethoxycarbonyl group and 2,2,2-trichloroethoxycarbonyl group; for example, 2-propenyloxycarbonyl group, 2-chloro-2-propyloxycarbonyl group, Alkenyloxy such as 3-methoxycarbonyl-2-propenyloxycarbonyl, 2-methyl-2-propenyloxycarbonyl, 2-butenyloxycarbonyl, cinnamyloxycarbonyl Carbonyl group; for example, benzyloxycarbonyl group, o-dimethoxybenzyloxycarbonyl group, p-dioxobenzyloxy group Carbonyl group, Ariru lower alkyl O alkoxycarbonyl group such as full We phenethyl Ruo alkoxycarbonyl group; such as trimethylsilyl group, t-Buchirujime Chirushiriru group lower alkylsilyl group, etc., and further these appropriately sets It is also possible to combine.

 The amino lower alkyl group means the lower alkyl group substituted with an amino group, for example, an aminomethyl group, a 1-aminoethyl group, a 2-aminoethynole group, a 1-aminopropyl group, a 2-aminopropyl group, Examples thereof include a 3-aminopropyl group, a toamino-1-methylethyl group, a 2-amino-tomethylethynole group, a 1-aminobutyl group, a 2-aminobutyl group, a 3-aminobutyl group, and a 4-aminobutyl group.

 The protected amino lower alkyl group means the above lower alkyl group substituted by the amino group protected by the above protecting group, for example, benzyloxycarbonylaminomethyl group, 1-t-butoxycarbonyl group. Examples include a minethyl group, a 2-benzyloxycarbonylaminoethyl group, a 1-N-p-nitrobenzyloxycarbonyl-Nt-butyldimethylsilylaminopropyl group, and the like. What is an arylo group? It means up to 13 aroyl groups, for example, benzoyl group, 4-methoxybenzoyl group, 1-naphthoyl group, 2-naphthoyl group and the like.

 The aryloxy group means an aryloxy group having 7 to 13 carbon atoms, and examples thereof include a benzoyloxy group, a 4-methoxybenzoyloxy group, a 1-naphthoyloxy group and a 2-naphthoyloxy group.

 N-mono-lower alkyl rubamoyl means a carbamoyl group substituted with one of the above-mentioned lower alkyl groups, such as N-methylcarbamoyl, N-ethylcarbamoyl, N-propyl carbamoyl. , N-butylcarbamoyl group and the like.

 The term Ν, Ν-di-lower alkyl group refers to a group that is substituted with two identical or different lower alkyl groups, for example, Ν, Ν-dimethylcarbamoyl group, Ν-ethyl- Ν-methylcarbamoyl group, Ν, Ν-getylcarbamoyl group, Ν-ethynole-Ν-propylcanolebamoinole group and the like.

 The lower alkoxycarbonyl group means an alkoxycarbonyl group having the lower alkoxy group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and a propyloxycarbonyl group.

The lower alkenyloxycarbonyl group means an alkenyloxycarbonyl group having the lower alkenyloxy group, for example, aryloxyl. Examples include a bonyl group and a butenyloxycarbonyl group.

 The aryloxycarbonyl group means an aryloxycarbonyl group having the above-mentioned aryloxy group, for example, phenoxycarbonyl group, 1-naphthoxycarbonyl group, 2-naphthoxycarbonyl group and the like. Is mentioned.

 The aryl lower alkoxycarbonyl group means an aryl alkoxycarbonyl group having the aryl lower alkoxy group, such as a benzyloxycarbonyl group, a 1-naphthylmethoxycarbonyl group, and a 2-naphthylmethoxycarbonyl group. Can be

 The lower alkylsulfonyloxy group means an alkylsulfonyloxy group having the lower alkyl group, for example, a methanesulfonyloxy group, an ethanesulfonyloxy group, a propanesulfonyloxy group, an isopropanesulfonyloxy group, Butanesulfonyloxy group and the like.

 The perylsulfonyloxy group means an arylsulfonyloxy group having the aryl group, and examples thereof include a benzenesulfonyloxy group and a p-toluenesulfonyloxy group.

 The di-lower alkoxyphosphoryloxy group means a dialkoxyphosphoryloxy group having two of the above-mentioned lower alkyl groups, and examples thereof include a dimethoxyphosphoryloxy group and a ethoxyphosphoryloxy group.

 The N-mono lower alkylamino group means an amino group substituted with the lower alkyl group, such as an N-methylamino group, an N-ethylamino group, an N-propylamino group, an N-butylamino group, and the like. .

 The protected N-mono-lower alkylamino group means a protected amino group substituted with the lower alkyl group, for example, an N-methyl-Np-nitrobenzyl amino group, an N-acetyl-N-ethylamino group. And the like.

Ν, Ν-di-lower alkylamino group means an amino group substituted with the same or different two lower alkyl groups, for example, Ν, Ν-dimethylamino group, Ν-ethyl-Ν-methylamino group. , Ν, Ν-ethylamino group, Ν-ethyl-Ν-propylamino group, Ν, Ν-dipropylamino group, Ν, Ν-dibutylamino group and the like. The lower alkanoyl group means an amino group substituted with the lower alkanoyl group, for example, an acetylamino group, a propionylamino group, a butylamino group. A lumino group, a vivaloylamino group and the like.

 The aroylamino group means an amino group substituted with the aroyl group, and examples thereof include a benzoylamino group, a 1-naphthoylamino group, and a 2-naphthoylamino group.

O

 The N-lower alkylaminocarbonyloxy group means an aminocarboxy group substituted by the lower alkyl group, specifically, N-methylaminocarbonyl group, N-ethylaminocarbonyloxy group. And the like.

 The N, N-di-lower alkylaminocarbonyloxy group means an aminocarbonyl group substituted by the same or different two above-mentioned lower alkyl groups, specifically, Ν, Ν-dimethylaminocarbonyl And a Ν, Ν-dimethylaminocarbonyloxy group, a Ν-ethyl-Ν-methylaminocarbonyloxy group, a Ν, Ν-dipropylaminocarbonylcarbonyl group, and the like.

 The protected amidino group means an amidino group protected by a commonly used protecting group, and examples of the protecting group include a t-butoxycarbonyl group, a 4-methoxy-2,3,6-trimethylbenzenesulfonyl group, And the like.

 The protected guanidino group means a guanidino group protected by a commonly used protecting group. Examples of the protective group include t-butoxycarbonyl group, 4-methoxy-2,3,6-trimethylbenzenesulfonyl group, And a mouth group.

 Leaving groups are those commonly used in organic synthetic chemistry, and specifically include halogen atoms, tri-lower alkylammonium groups, methanesulfonyloxy groups, trifluoromethanesulfonyloxy groups, p- And a toluenesulfonyloxy group.

The compound of the present invention represented by the above formula [1] may be, for example, an inorganic acid salt such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, perchlorate or phosphate; Acid addition salts such as organic acid salts such as P-toluenesulfonate, benzenesulfonate, methanesulfonate, oxalate, succinate, tartrate, citrate, fumarate or maleate Or an alkali metal salt such as sodium salt, potassium salt, potassium salt or the like, or an alkaline earth metal salt, and particularly preferably a pharmaceutically acceptable non-toxic salt. The present invention The compound of the formula [1] may have stereoisomers depending on the mode of the substituent, but the present invention also includes all of these stereoisomers and a mixture thereof.

 Among the compounds of the present invention represented by the general formulas [la] to [lg], the compounds represented by [la] to [Id] can be synthesized, for example, according to the following scheme.

Y

3. R 'in [Deprotection] Scheme represents a hydrogen atom, a lower alkyl group, lower alkenyl group, a lower § Rukiniru group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a Ariru group or Ariru lower alkyl group, R ³ It is a hydrogen atom, a lower alkyl group, lower-grade alkenyl group, lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, Ariru group, Ariru lower alkyl group, a Arukanoiru group or a lower Aroiru group, R ⁴ is claim Has the same meaning as 1, and R ⁵ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group, an aryl lower alkyl group, a protected hydroxy lower group Alkyl group, lower alkoxy lower alkyl group, protected amino lower alkyl group Protected carboxy-lower alkyl group, Shiano lower alkyl group, Shiano group, a lower alkylsulfonyl group or a lower Al force Noi Le group, R ⁶ is other than a hydrogen atom have the same meanings as R ^3, R ⁷ is A lower alkyl group or an aryl lower alkyl group; Y and Z have the same meaning as in claim 1; Y ² and Z ² are the same or different and are a lower alkyl group, a lower alkenyl group, a lower alkyl group; Alkynyl group, cycloalkyl group, cycloalkynol lower alkyl group, aryl Alkyl group, aryl lower alkyl group, protected hydroxy group, protected hydroxy lower alkyl group, lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, aryloxy group, cycloalkyl lower alkoxy group, aryl lower Alkoxy group, lower alkanoyl group, lower alkanoyloxy group, lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, aryloxy lower alkyl group, halogen atom, halo lower alkyl group, protected carboxy lower alkyl group , Protected carboxy lower alkenyl, protected amino lower alkyl, aryloyl, aryloxy, protected carboxyl, carbamoyl, N-mono lower alkyl levamoyl, Ν, Ν-di-lower Alkyl Power Rubamo Group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, aryloxycarbonyl group, aryl lower alkoxycarbonyl group, lower alkylsulfonyloxy group, arylsulfonyloxy group, di-lower alkoxyphosphoryl Xyl group, protected amino group, protected 低 -mono-lower alkylamino group, Ν, ア ル キ ル -di-lower alkylamino group, lower alkanoylamino group, aryloamino group, aminocarbonyloxy group, Ν-lower alkyl group Aminocarbonyloxy group, Ν, Ν-di-lower alkyl Substituted by aminoaminocarbonyl group, lower alkyl group or heterocyclic group, piperidinylcarbonyloxy group, nitro group, protected 1 to 5 substitutions selected from the group consisting of an amidino group, a protected guanidino group and a cyano group A phenyl group which may have 1 to 3 substituents which may have 1 to 3 substituents selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. 5 to 10 containing atoms: a 10-membered heterocyclic group, wherein Υ ³ and Ζ ³ are the same or different and are a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, Aryl group, aryl lower alkyl group, hydroxy group, protected hydroxy group, hydroxy lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, aryloxy group, Cycloalkyl lower alkoxy group, aryl lower alkoxy group, lower alkoxy lower alkyl group, aryloxy lower alkyl group, pager Child, halo-lower alkyl group, a force Rubamoi Le group, Nyu- mono-lower alkyl force Rubamoiru group, New, Nyu- di-lower alkyl force Rubamoi , Lower alkylsulfonyloxy, arylsulfonyloxy, di-lower alkoxyphosphoryloxy, protected amino, protected N-mono lower alkylamino, Ν, Ν-dilower An alkylamino group, a lower alkanoylamino group, an aryloamino group, a Ν-lower alkylaminocarbonyloxy group, a Ν, Ν-dilower alkylaminocarbonyloxy group, a lower alkyl group or a heterocyclic group which may be substituted. A peridinylcarbonyloxy group, a nitro group, a protected amidino group, a protected guanidino group and a phenyl group optionally having 1 to 5 substituents selected from the group consisting of a cyano group, or 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom which may have 1 to 3 substituents selected from the group 5-10 membered heterocyclic group containing indicates, X represents a halogen atom, L is a leaving group.

 Here, in the present invention, as a protecting group for a functional group other than the above, as a protecting group for a glycol, a normal group such as an isopropylidene group, a cyclohexylidene group, or a benzylidene group may be selected and used according to the reaction conditions. Can be.

 As the protecting group for catechol, a usual one such as a methylene group, an isopropylidene group or a cyclohexylidene group can be selected and used according to the reaction conditions.

 Examples of the carbonyl protecting group include lower alkyl acetal groups such as an ethylene acetal group, a dimethyl acetal group, and a dimethyl ether group, a 1,3-dithiolan-2-yl group, and a 1,3-dithiane-2 group. An ordinary group such as -yl group can be selected and used according to the reaction conditions.

-The compound of the general formula [la] can be prepared by adding 1,3-dicarbonyl disulfide compound [2] and 1 to 5 equivalents of hydroxylamine or a hydrogen halide salt of hydroxylamine to water or methanol, ethanol, or propanol according to a conventional method. In an inert solvent such as lower alcohols or water-containing lower alcohols, etc., the reaction is carried out at a temperature from room temperature to the boiling point of the solvent for 1 hour to 2 days, and the ring is closed. The compound of the general formula [lb] can be prepared according to a conventional method by mixing 1,3-dicarboniuihide compound [2] with 1 to 5 equivalents of hydrazine or hydrazine hydrate without solvent, or water, or methanol, ethanol, propanol or the like. Lower alcohols, hydrous lower alcohols, Reaction in an inert solvent such as ethers such as THF and DME, lower fatty acid amides such as DMA and DMF, or water-containing lower fatty acid amides at a temperature from room temperature to the boiling point of the solvent for 1 hour to 2 days. After obtaining the compound of the general formula [3], aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as THF, DME and getyl ether, lower fatty acid amides such as DMA. 1 to 5 equivalents of secondary amine alkali metal salts such as LDA, LHMDS and KHMDS, and 1 to 5 equivalents of alkali metal hydrides such as lithium hydride, sodium hydride and hydrogenation hydride in an inert solvent. As needed, in the presence of an inorganic base such as sodium methoxide, sodium ethoxide, lower alkali metal alkoxide such as t-butoxycali, or an alkali metal such as sodium carbonate, carbon dioxide rim, etc. 1 to 10 equivalents of HMPA, DMPU, etc. Add a reaction auxiliary and add 1 to 5 equivalents of the compound of the general formula R ⁶ L and 0 ° C to the boiling point of the solvent, preferably 10 ° C to: After reacting at 100 ° C for 30 minutes to 2 days, if necessary To obtain deprotection.

 The compound [lb] is prepared by adding 1 to 10 equivalents of the substituted hydrazine compound of the general formula [4] to a 1,3-dicarbonitrile compound [2] without solvent or water or a lower compound such as methanol, ethanol or propanol. In an inert solvent such as alcoholic or hydrated lower alcoholic, ethers such as THF, 1,4-dioxane and DME, lower fatty acid amides such as DMA. DMF or hydrated lower fatty acid amides. It can be obtained by reacting at a temperature from room temperature to the boiling point of the solvent for 1 hour to 2 days, followed by deprotection if necessary.

The compound represented by the general formula [lc] is a glycine ester in an amount of 1 to 5 equivalents to the carboxylic acid compound represented by the general formula [5]. the solvent, methylene chloride, in an inert solvent such as a halogenated hydrocarbon, such as black hole Holm, to the boiling point of 0 ° Celsius to solvents, preferably 2 days 30 minutes 10 ° C~50 ^e C is 1 3 equivalents of DPPA, DCC, EDCI · HC1, after condensation in the usual manner as required condensing agent CDI, etc. is added an auxiliary agent such as HOBT · H ₂ 0, HOSu, the resulting compound with water or water-containing In water-containing lower alcohols such as methanol and ethanol.]: ~ 2 equivalents of inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate To give a compound of the general formula [7]. Erlenmeyer method [J ヱ ichi 'S' back (JSBuck) et al. According to Organic Synthesis, Vol. 2, p. 55, etc.], the compound of the general formula [7] is converted into 1 to 100 equivalents of a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or the like. Inorganic bases or sodium methoxides such as ~ 5 equivalents of secondary amialkali metal salts such as LDA, LHMDS, KHMDS, etc., and 1 ~ 5 equivalents of lithium metal hydrides such as lithium hydride, sodium hydride and lithium hydride. 1 to 10 equivalents of the general formula [8] in the presence of an alkali metal lower alkoxide such as oxide, sodium ethoxide, t-butoxycali or an alkali metal carbonate such as sodium carbonate or potassium carbonate [8] The compound is reacted with the carbonyl compound at a temperature from room temperature to the boiling point of the solvent for 1 hour to 1 day, and deprotected if necessary. The compound of the general formula [Id] is obtained by converting the carboxylic acid compound of the general formula [5] to a lower alkyl or aryl lower alkyl ester by an ordinary method, and then adding 1 to 5 equivalents of the amidoxime of the general formula [9] to 1 to 5 equivalents. 10 equivalents of alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium isopropoxide, t-butoxycali, etc. in a lower alcohol solvent such as methanol, ethanol, propanol, isopropanol, t-butanol The reaction is carried out at a temperature of from 0 ° C to the boiling point of the solvent for 30 minutes to 2 hours, and if necessary, deprotected.

—The compounds represented by the general formulas [le] to [lg] can be produced, for example, according to the following scheme.

Y ² -C0 ₂ H [5]

[Wherein Y, Ζ, Υ ¹ and R ⁴ have the same meaning as in claim 6, and Y ² and R ⁵ have the same meaning as described above. Y ⁴ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkynole lower alkyl group, an aryl group, an aryl lower alkyl group, a lower alkoxy group, a lower alkenyloxy group, a lower alkynyloxy group, an aryloxy group A cycloalkyl lower alkoxy group, an aryl lower alkoxy group, a lower alkoxy lower alkyl group, an aryloxy lower alkyl group, an N-mono-lower alkylamino group, an N, N-di-lower alkylamino group. Or a phenyl group optionally having 1 to 3 substituents, or 1 to 3 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents. A 5- to 10-membered heterocyclic group containing one heteroatom. R ⁸ and R ⁹ are the same or different and represent a lower alkyl group or an aryl lower alkyl group; R ¹⁰ has the same meaning as R ⁵ except for a hydrogen atom; and L represents a leaving group. ]

The compound of the general formula [Ie] is obtained by combining the compound of the general formula [20] with 1 to 5 equivalents of the compound of the general formula [8] and 1 to 30 equivalents of a lower fatty acid ammonium salt such as ammonium formate or ammonium acetate. 1 hour to 2 hours at room temperature to the boiling point of the reaction solvent in a lower fatty acid such as formic acid, acetic acid, propionic acid or the like at a temperature of 60 ° C to 110 ° C. React for days and deprotect if necessary.

 The compound of the general formula [Ie] may be deprotected, if necessary, from the compound of the general formula [20] to obtain 3 to 30 equivalents of a lower carboxylic anhydride such as acetic anhydride or propionic anhydride at 0 ° C to 100 ° C. C. Preferably, the reaction is carried out at 20.degree. 0 to 80 to 1 hour to 12 hours, and the compound of the general formula [21] is obtained by dehydration and ring closure to obtain a compound of the general formula [21]. Under 1 to 20 equivalents of a lower carboxylic anhydride such as acetic anhydride, propionic anhydride, butyric anhydride, 1 to 3 equivalents of a compound of the general formula [8] and 1 to 5 equivalents of an organic compound such as DBN or DBU. Base, 1 to 3 equivalents of metal hydride such as lithium hydride, sodium hydride, lithium hydride or 1 to 5 equivalents of metal salt of lower carboxylic acid, such as sodium acetate or acetate By reacting at 0 ° C to 150 ° C, preferably 20 ° C to 120 ° C for 5 minutes to 24 hours, and deprotecting if necessary. After the compound of the formula [If] is obtained, it is mixed with 1 to 100 equivalents of ammonia in water or a lower alcohol such as methanol or ethanol or a water-containing lower alcohol solvent at a temperature from room temperature to 70 ° C for 1 hour. (2) It can be obtained by reacting and deprotecting if necessary.

 The compound of the general formula [K] can be obtained by converting the compound of the general formula [20] to a lower carboxylic anhydride such as acetic anhydride, propionic anhydride or butyric anhydride in an amount of 1 to 20 equivalents, preferably in an inert gas atmosphere. Medium, 1 to 3 equivalents of the compound of the general formula [8] and 1 to 5 equivalents of an organic base such as DBN and DBU, and 1 to 3 equivalents of a metal hydride such as lithium hydride, sodium hydride, and potassium hydride Alternatively, the reaction is carried out at 0 ° C to 150 ° C, preferably 20 ° C to 120 ° C, for 5 minutes to 24 hours in the presence of 1 to 5 equivalents of a metal salt of a lower carboxylic acid such as sodium acetate or potassium acetate. Alternatively, it can be obtained by deprotection if necessary.

 Here, the starting compound 7-keto acid derivative [20] can be obtained, for example, by the Friedel-Crafts reaction of the compound [18] and the compound [19].

In this case, usually, in an inert solvent such as dichlorobenzene, nitrobenzene, carbon disulfide or the like, 1 to 5 equivalents, preferably 1 to 3 equivalents of aluminum chloride, zinc chloride, stannic chloride, relative to the compound [18] is used. -30 in the presence of a Lewis acid such as a boron trifluoride getyl ether complex. C to 100 ° C, preferably -10 ° C to 50 ° C, The reaction is carried out by reacting 1 to 5 equivalents, preferably 1 to 2 equivalents of compound [19] and compound [18] to compound [18] for 3 hours to 2 hours.

In addition, y-keto acid derivatives [20] were published by Masamune et al. [Angew. Chem. Int. Ed. In Engl. 18: 72-74 (1972 )] To the carboxylic acid compound of the general formula [5] in the presence of 1 to 3 equivalents of a carboxylic acid activator such as CDI in the presence of 1 to 5 equivalents, preferably 1.2 to 3 equivalents of the general formula [10] ], Ethers such as methyl ether, THF, 1,4-dioxane and DME, lower fatty acid amides such as DMF and DMA, and halogenated hydrocarbons such as dichloromethane and chromatoform. After reacting in an inert solvent at −15 ° C. to the boiling point of the solvent, preferably at 0 ° C. to 50 ° C. for 30 minutes to 2 days to obtain a 3-ketoester derivative [13], 1 to 5 equivalents of piperidine , Disopropylethylamine, DBU, DBN and other organic bases, 1-5 equivalents of LDA, LHMDS, KH Secondary amine alkali metal salts such as MDS, etc .:! To 5 equivalents of alkali metal such as lithium hydride, sodium hydride, potassium hydride, etc. Inorganic bases such as hydrides, or alkaline metal such as t-butyne hydride In the presence of a lower alkoxide or the like, 1 to 3 equivalents of the compound R1 ⁽⁾ L is added to an inert solvent such as DMF, benzene, toluene, THF, or DME at 0 ° C. to the boiling point of the solvent, preferably 10 ° C. The mixture was reacted at 30 ° C. to 70 ° C. for 30 minutes to 2 days to obtain a compound [14], and this compound was further added with 1 to 5 equivalents, preferably 1 to 2 equivalents of piperidine, diisopropylethylamine, DBU , DBN and other organic bases, 1 to 5 equivalents of LDA, LHMDS, KHMDS and other secondary aminal alkali metal salts, 1 to 5 equivalents of lithium hydride, sodium hydride, potassium hydride and other metal hydrides In the presence of an inorganic base such as e.g. In an inert solvent such as the compound of [15] and aromatic hydrocarbons such as benzene and toluene, ethers such as THF, 1,4-dioxane and DME, or lower fatty acid amides such as DMA and DMF, The reaction is carried out at 0 ° C. to the boiling point of the solvent, preferably at 10 ° C. to 100 ° C. for 30 minutes to 2 days to obtain a compound of the general formula [16]. For 2 days at 30 ° C to 120 ° C, preferably at 50 ° C to 100 ° C. [However, when R ⁵ is a hydrogen atom, it can be produced under the same reaction conditions as described above, except for the step of reacting compound [13] with compound R ^1QL . ] Also, the compound of the general formula [13] is According to the method of N. Cohen et al. [J. Org. Chem. 38, pp. 3229-3239], compound [11] is converted to a compound of the general formula 3-20 equivalents according to the method of J. Org. [12] with 1 to 5 equivalents, preferably 1 to 3 equivalents of an alkali metal hydride such as lithium hydride, sodium hydride, or lithium hydride; or an alkali metal hydride such as t-butoxycali. It can also be obtained by reacting for 1 hour to 2 hours at 50 ° C to the boiling point of the reaction solution in the presence of a metal lower alkoxide or the like.

Wherein R ', RR Υ, Ζ, Υ 1 and Zeta' have the same meanings as defined above. ]

 —The compound of general formula [lg] can be obtained, for example, by the following method. According to the method of A 丄 Kosak et al. [J. Am. Chem. Soc., Vol. 76, 4450-4454 (1954)], the general formula [20] was converted. The compound together with 1 to 3 equivalents of diphosphorus pentasulfide and 10 to 30 equivalents of an organic base such as pyridine, picoline, collidine, lutidine, etc., in a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride, etc. And reacting from room temperature to the boiling point of the reaction solvent for 1 hour to 1 day to obtain a compound of the general formulas [22] and Z or [23]. Hydrogen halide lower alcohol solutions such as methanolic hydrogen chloride solution, ethanolic hydrogen chloride solution, methanolic hydrogen bromide solution, ethanolic hydrogen bromide solution, and the compound of general formula [22] and / or general formula [23] The compound of the general formula [lg] can be obtained by reacting with 1 to 3 equivalents of the compound of the general formula [8] and performing deprotection if necessary.

The product obtained in each of the above steps can be obtained by a known purification method, such as Purification or isolation can be achieved by single or appropriate combination of chromatography, high performance liquid chromatography, thin layer chromatography, recrystallization, solvent extraction, precipitation, or distillation.

 Tyrosine kinase inhibitory activity

The tyrosine kinase inhibitory activity of the compound according to the present invention was measured as follows.

A431 cells, human epidermoid carcinoma cells, were seeded at a concentration of 5 x 10 ⁴ cells / 0.5 ml Z-well in a 24-well plate using a modified Dulbecco's MEM medium supplemented with 10% fetal bovine serum. % C0 ₂ in the presence 37 ° C and cultured for 6 days Ru to form a cell layer. After the cell layer was washed three times with 10mM HEPES · NaOHpH7.4 Dal Beck co Henhoi one guru MEM medium, the same medium 0.5 ml, and incubated for 30 minutes at 5% C0 ₂ present under 37 ° C, The compound of the present invention dissolved in DMSO is added to a final concentration of 50, 25, 12.5, 6.25 μg / ml (DMSO does not exceed a final concentration of 1%). After another 30 minutes, add human epidermal growth factor (from Yukinaga Pharmaceutical Co., Ltd.) to a final concentration of 200 ng / ml and continue culturing. After 5 minutes, discard the medium, wash the cell layer once with phosphate buffered saline, and dissolve with 0.2 ml of sample preparation buffer for SDS polyacrylamide electrophoresis. After separating a certain amount of the obtained cell lysate by SDS polyacrylamide electrophoresis, transfer it to a nitrocellulose filter using a semi-dry blotting apparatus. After blocking the obtained blocks in 3% buffered saline containing Tris-buffered saline and then reacting with an anti-phosphorylated cinnamomonoclonal antibody (PY-20, manufactured by ICN), Inhibition rate by detecting the tyrosine autophosphorylation of epidermal growth factor receptor induced in A431 cells by stimulation of human epidermal growth factor with a kitting detection kit (manufactured by Amersham) and quantifying with a densitometer Was calculated.

As a result, as shown in Table 1, the compounds according to the present invention exhibited excellent tyrosine kinase inhibitory activity. Table 1 Tyrosine kinase inhibitory activities

The compound according to the present invention inhibits the growth of tumor cells and has an anticancer effect.However, various forms can be selected as the administration form when the compound of the present invention is used as an antitumor agent, which is known in the art. Can be used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration. Pharmaceutical preparations include, for example, liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories. In addition, these preparations may optionally contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants. Examples of the additives include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, and talc.

 The dose of the compound of the present invention as a tyrosine kinase inhibitor differs depending on the administration method, the age and weight of the patient, the condition of the patient to be treated, and the like.A typical administration method for an adult is oral administration or non-administration. Oral administration to adult patients: 0.1 to 100 mg ZKg body weight per day for oral administration and 0.01 to 10 mg ZKg body weight per day for parenteral administration.

Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited thereto. The meanings of the abbreviations in NMR measurement are shown below.c

s: sink "let"

d: Doublet

t: triplet

q: Force note

m: Multiplet

br: Broad

 J: Coupling constant

 Hz: Hertz

 Reference example 1

 Synthesis of 1,4-di (3,4-dimethoxyphenyl) -1,3-butanedione

 To a solution of 2.00 g of 3,4-dimethoxyphenylacetic acid ethyl ester in 12 ml of anhydrous THF was added 1.80 g of 3,4-dimethoxyacetophenone and 407 mg of sodium hydride (60% suspension in mineral oil), and the mixture was heated under reflux for 20 minutes. After cooling the reaction solution to room temperature, 0.6 ml of acetic acid and 3 ml of water were added, the mixture was poured into ice water, and extracted three times with 50 ml of ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography (hexane: ethyl acetate = 3: 1). 1,4-di (3,4-dimethoxyphenyl)-1,3-butanedione

1.54 g are obtained as a white powder.

 Melting point: 78 ° C

FAB - MS (m / z, as ^{_{+ (C 2 .H 22 0 6}} + H)): 359

 Reference example 2

 Synthesis of 3- (3,4-dimethoxybenzoyl) propionic acid

According to the method of M. Rischmann et al. [Phytochemistry, Vol. 28, pp. 867-869 (1989)], 9.6 g of veratrol and 6.6 g of succinic anhydride were added to 60 ml of nitrobenzene under an argon atmosphere. Dissolve and add 18 g of aluminum chloride at 0 ° C with stirring over 30 minutes. After warming to room temperature, the mixture is stirred for 15 hours, and the reaction solution is poured into a mixture of 30 ml of concentrated hydrochloric acid and 160 ml of ice water. The precipitated pale yellow solid is collected by filtration, dissolved in 100 ml of 1N sodium hydroxide solution, washed twice with 50 ml of diethyl ether, and adjusted to pH 2 with concentrated hydrochloric acid at 0 ° C. Analysis The resulting colorless solid is washed twice with 100 ml of water and then twice with 100 ml of ethanol, and dried under reduced pressure to obtain 11.7 g of 3- (3,4-dimethoxybenzoyl) propionic acid as a colorless solid.

 Rf value: 0.23 (silica gel plate, n-hexane: ethyl acetate: acetic acid =

 50: 50: 1)

FAB- MS (m / z (C 12 H 14 0 5) + a) 238

 Reference example 3

 Synthesis of 3- (3,4-dimethoxybenzoyl) butyric acid

 Dissolve veratrol lg and methylsuccinic anhydride 826 mg in nitrobenzene 20 ml, cool to 0 ° C and add 1.9 g of aluminum chloride. After stirring at 0 ° C for 1 hour, warm to room temperature and stir for 12 hours. The reaction mixture is poured into a mixture of concentrated hydrochloric acid (20 ml) and water (40 ml), extracted with ethyl acetate, and the residue obtained by concentrating the organic layer is dissolved in 1N aqueous sodium hydroxide solution and washed twice with 50 ml of getyl ether. The aqueous layer is adjusted to pH 2 with 6N hydrochloric acid, extracted twice with 50 ml of ethyl acetate, and the organic layer is dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (Kokuchi.guchi-form, then Kuroguchi-form: methanol: formic acid = 200: 5: 1) to give 3- (3,4-dim. 473 mg of toxicbenzoyl) butyric acid are obtained. Reference example 4 '

 Synthesis of 5- (3,4-diacetoxypheninole) -2 (3H) -furanone

The (a) 3- (3,4-dimethyl Tokishibenzoiru) propionic acid 1.2g, was dissolved in acetic acid 15ml及beauty 50% hydrobromic acid 15ml, and stirred for 15 hours at 110 ^e C. The reaction mixture was cooled and concentrated under reduced pressure. A small amount of water was added to the resulting black-purple solid, the insolubles were collected by filtration, washed with ether, dried under reduced pressure, and dried under reduced pressure to give 3_ (3,4-dihydroxybenzoyl) propionic acid. 954 mg are obtained.

 Rf value: 0.46 (silica gel plate, methylene chloride: ethanol: formic acid =

 100: 10: 10)

Ή NMR (300 MHz, DMSO-d ₆ , δ ppm): 2.51 (2H, t, J = 6.3 Hz), 3.09 (2H, t, J = 6.3 Hz), 6.80 (lH, d, J = 8.1 Hz), 7.33- 7.38 (2H, m), 9.30 (1H, brs), 9.79 (lH.brs), 12.04 (lH.brs)

(b) 882 mg of 3- (3,4-dihydroxybenzoyl) propionic acid was added to acetic anhydride Dissolve in 10 ml and stir at 15 CTC for 3 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 5- (3,4-diacetoxyphenyl) -2 (3H) -furanone Obtain 430mg.

 Rf value: 0.40 (silica gel plate, hexane: ethyl acetate = 1: 1)

Ή NMR (300MHz, CDCl ₃ , δ ppm): 2.30 (3H, s), 2.31 (3H, s), 3.43 (2H, d, J = 3.0Hz), 5.78 (lH.t, J = 3.0Hz), 7.24 (lH, d, J = 8.7Hz), 7.43 (1H, d'J = 2.1 Hz), 7.49 (lH.dd.J = 2.1, 8.7Hz)

 Reference example 5

 Synthesis of 4-oxo-4- (2-pyridone_5-yl) butyric acid methyl ester

 (a) Synthesis of benzyl 6-benzyloxynicotinic acid ester

 6-Hydroxynicotinic acid (500 mg) and silver oxide (1.84 g) are suspended and stirred in toluene (30 ml). At room temperature, benzyl bromide (1.07 ml) is added, and the mixture is heated under reflux for 20 hours. After returning the reaction solution to room temperature, the insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 9) to give 6-benzyl. 680 mg of benzyl oxynicotinic acid ester are obtained.

 Rf value: 0.48 (silica gel plate, ethyl acetate: n-hexane = 1: 5)

(b) Synthesis of 6-benzyloxynicotinic acid

 Dissolve 500 mg of 6-benzyloxynicotinic acid benzyl ester in 5 ml of methanol, add 1 ml of 2N aqueous sodium hydroxide solution and stir for 30 minutes. Add 80 ml of ethyl acetate to the reaction mixture, and wash with 1N hydrochloric acid. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the obtained crystal was recrystallized from methanol to obtain 298 mg of 6-benzyloxynicotinic acid.

 Rf value: 0.15 (silica gel plate, ethyl acetate: n-hexane = 1: 5) (c) Synthesis of (6-benzyloxynicotinol) ethyl acetate

Dissolve 298 mg of 6-benzyloxynicotinic acid in 5 ml of DMF, add 232 mg of CDI, and stir at room temperature for 2 hours. Then, 616 mg of monoethyl malonate 1Z2 magnesium salt is added, and the mixture is stirred at room temperature for 15 hours. The reaction solution is concentrated under reduced pressure to about 1/5 volume, 80 ml of ethyl acetate is added, washed with 1N hydrochloric acid and then with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The residue obtained is purified by silica gel column chromatography. Separation and purification by oral chromatography (ethyl acetate: n-hexane = 1: 5) yielded 346 mg of (6-benzyloxynicotinol) ethyl acetate.

 Rf value: 0.80 (silica gel plate, ethyl acetate: n-hexane-1: 1) (d) Synthesis of 3-ethoxycarbonyl-3- (6-benzyloxynicotinol) ethyl propionate

 Under argon atmosphere, wash 54 mg of sodium hydride (60% mineral oil suspension) with n-hexane, add THF1 ml and stir. To this was added dropwise a solution of 340 mg of (6-benzyloxynicotinoyl) acetic acid ethyl ester in 4 ml of THF, and the mixture was heated under reflux for 1 hour. Return to room temperature, add 152/1 of ethyl bromoacetate, and heat again for 1 hour. The reaction solution is diluted with 80 ml of ethyl acetate, washed with 1N hydrochloric acid, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue is separated and purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 10) to obtain 403 mg of the title compound.

 Rf value: 0.28 (silica gel plate, ethyl acetate: n-hexane = 1: 5) (e) Synthesis of 4-oxo-4- (2-pyridone-5-inole) methyl butyrate

To 400 mg of 3-ethoxycarbonyl-3- (6-benzyloxynicotinoyl) propionate ethyl ester is added 10 ml of concentrated hydrochloric acid, and the mixture is heated under reflux for 15 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the obtained residue (220 mg) was dissolved in a 10% methanol solution of hydrochloric acid and stirred at room temperature for 30 minutes. The solvent is distilled off, and the resulting crystals are washed with ethyl acetate and n-hexane to obtain 215 mg of methyl 4-oxo-4 (2-pyridone-5-isole) butyrate.

 Ή-NMR (200 MHz, DMSO-d «, S ppm): 2.57 (2H, t, J = 6.3 Hz), 3.10 (2H, t, J = 6.3 Hz), 3.57 (3H, s), 6.36 (lH, d, J = 9.5Hz), 7.25 (lH, brs), 7.84 (lH, dd, J = 2.5,9.5Hz), 8.24 (lH, d, J = 2.5Hz)

 Example 1

 Synthesis of 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) isoxazole

 a. Synthesis of 3- (3,4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) isoxazole

1,4-di (3,4-dimethoxyphenyl) -1,3-butanedione obtained in Reference Example 1 Dissolve 10 mg of ethanol in 2 ml of ethanol, add a solution of 42 mg of hydroxylamine hydrochloride in 0.1 ml of water, and heat to reflux for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the resulting residue was dissolved in ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. Purification with 1 (hexane: ethyl acetate = 2: 1) yields 105 mg of 3- (3,4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) isoxazole.

 Melting point: 99-100 ° C

 b. Synthesis of 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) disoxazole

Dissolve 19.5 mg of 3- (3,4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) isoxazole in 2 ml of anhydrous methylene chloride and add 1 M boron tribromide in anhydrous methylene chloride at -78 ° C. Add 0.5 ml of methylene solution and stir for 12 hours to raise the temperature from -78 C to room temperature. The reaction mixture again - a 78 ^e C acetic acid Echiru 40ml and 0.01N HCl 10ml and added to separate liquid cooled to a residue after concentration under reduced pressure was added methanol 0.5ml organic layer was washed with water and saturated brine, anhydrous magnesium sulfate The residue obtained by drying and concentration under reduced pressure is purified by Sephadex ™ LH-20 column chromatography (methanol) to obtain 13.8 mg of the title compound as white crystals.

 Melting point: 205-206. C

High Resolution FAB- MS (mZz, as _{(C, 6 H 13 N0 5} + H):

 Calculated value: 300.0872

 Measured value: 300.0848

IR (KBr.cm- ¹ ): 3454,3388,1611,1593

Ή-NMR (300MHz, Acetone-d6, δ ppm): 3.92 (2H, s), 6.65 (lH.ddJ = 1.3Hz, 7.7Hz), 6.76 (lH, d, J = 0.6Hz), 6.79 (2H, d, J = 1.3 Hz), 6.91 (lH, d, J = 7.7 Hz), 7.20 (lH.dd.J = 1.3 Hz, 7.7 Hz) ₍ 7.29 (lH, d, J =

(1.3Hz)

 Example 2

 Synthesis of 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) villazol

a. 3- (3,4-Dimethoxybenzyl) -5- (3,4-Dimethoxyphenyl) pyrazo Synthesis

 Dissolve 201.5 mg of 1,4-di (3,4-dimethoxyphenyl) -1,3-butanedione and hydrazine hydrate 27; / 1 obtained in Reference Example 1 in 1.0 ml of ethanol, and heat to reflux for 1 hour. . After cooling the reaction solution to room temperature, the residue obtained by concentration under reduced pressure was dissolved in 40 ml of ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (hexane). : Ethyl acetate = 1: 3) to give 213 mg of 3- (3,4_dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) pyrazole.

_{FAB- MS (m / z ((} C 20 H 22 N 2 O 4 + H) as a ^+): 355

 b. Synthesis of 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxybenzyl) pyrazole

In the same manner as in Example 1, b, 19.8 mg of 3- (3,4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) pyrazole was dissolved in 2 ml of anhydrous methylene chloride, and 1M triodor was added with -78. Add 0.5 ml of anhydrous boron chloride in methylene chloride and stir for 12 hours. The reaction solution was cooled again to -78 ° C, 0.5 ml of methanol was added, and the mixture was concentrated under reduced pressure.40 ml of ethyl acetate and 10 ml of 0.01 N hydrochloric acid were added to the residue, and the mixture was separated.The organic layer was washed with water and saturated saline, and then anhydrous magnesium sulfate And concentrated under reduced pressure to give a residue, which is purified by Sephadex ^™ LH-20 column chromatography (methanol) to obtain 12.4 _mg of the title compound as white crystals.

High Resolution FAB- MS (m / z, as _{(C 16 H 14 N 2 0} 4 + H):

 Calculated value: 299.1032

 Measured: 299.1034

 IR (KBr.cm-: 3310,1611.1524

 Ή-NMR (300MHz, Acetone-d6, δ ppm): 3.83 (2H, s), 6.24 (lH, s), 6.61 (lH, dd, J = 1.2Hz, 7.3Hz), 6.65-6.75 (2H, m ), 6.81 (lH.dJ = 7.3Hz),

7.12 (lH, dd, J = 1.2Hz, 7.3Hz), 7.28 (lH, d, J = 1.2Hz)

 Hereinafter, the compounds of Examples 3 to 8 are synthesized by synthesizing a 1,3-diketone compound as a raw material in the same manner as in Reference Example 1, and cyclizing to a pyrazole derivative with hydrazine and deprotecting in the same manner as in Example 2. .

'Example 3. 5- (3,4-dihydroxybenzyl) -3- (4-hydroxybenzyl) pyrazol FAB-MS (as m / z, (C ₁₆ H ₁₄ N ₂ O ₃ + H) ⁺ ): 283

 Ή-NMR (300MHz, Acetone -de, δ ppm): 3.90 (2H, s), 6.25 (lH, s), 6.74-6.85 (3H, m), 7.10-7.15 (3H, m), 7.30 (lH. d)

 Example 4

5 - (3,4-dihydrazide Dorokishifueniru) -3- (3-hydroxycarboxylic benzyl) pyrazole FAB-MS (m / z, as _{+ (C 16 H "N 2} 0 3 + H)): 283

Ή-NMR (300MHz, CD ₃ OD, δ ppm): 3.90 (2H, s), 6.20 (lH, s), 6.59-6.78 (4H, m), 6.97-7.10 (3H, m)

 Example 5

 3- (3-arinole-4-hydroxybenzinole) -5- (3,4-dihydroxybenzinole) pyrazole

FAB- MS (m / z, as _{+ (C 19 H 18 N 2} 0 3 + H)): 323

Ή-NMR (300 MHz, CD ₃ OD, <5 ppm): 3.35 (2H, d-like), 3.85 (2H, s), 4.93-5.03 (2H, m), 5.93-6.03 (lH, m), 6.16 (lH, s), 6.69 (lH, d, J =

9Hz), 6.77 (lH, d, J = 9Hz), 6.87-7.00 (3H, m), 7.10 (lH.s)

 5- (3,4-dihydroxy-2-phenol) -3- (4-hydroxy-3-propylbenzyl) virazole

FAB- MS (m / z, as ^{_{+ (C 19 H 20 N 2}} O 3 + H)): 325

Ή-NMR (300MHz, CD ₃ OD, S ppm): 0.93. (3H, t, J = 8Hz), 1.54- 1.64 (2H, m), 2.53 (2H, t, J = 8Hz), 3.84 (2H, s), 6.16 (lH, s), 6.67 (1H, d, J = 8 Hz), 6.77 (lH, d, J = 8 Hz), 6.88 (lH, dd, J = 2 Hz, 8 Hz), 6.95 (lH, d , J = 2 Hz), 7.00 (lH.dd.J = 2 Hz, 8 Hz), 7.08 (lH, d, J = 2 Hz)

 5- (3,4-dihydroxyphenyl) -3- "3- (2,3-dihydroxypropyl)-4-hydroxybenzinole) 1 pyrazole

FAB-MS (mZz, (C ₁₉ H _{2, as} N ₂ O ₅ + H :): 357

(mZZ, as ^{_{+ (C 19 H 2 .H0 5}} + Na)): 379

Ή-NMR (300 MHz, CD ₃ OD, 6 ppm): 2.65-2.85 (2H, m), 3.40-3.52 (2H, m), 3.89 (2H, s), 3.85-3,95 (lH, m), 6.19 (lH.s), 6.69-6.80 (2H, m), 6.96 (lH.dd), 6.91-7.00 (2H, m), 7.10 (lH, d) Example 8

 3-"3- (2,3-dibromopropyl) -4-hydroxybenzyl]-'5- (3,4-dihydroxyphenyl) pyrazole

FAB- MS (m / z, as ^{_{+ (C 19 H I8 N 2}} 0 3 Br 2 + H)): 481

(m / z, as _{+ (C 19 H] 8 N} 2 0 3 Br 2 + Na)): 503 Ή- NMR (300MHz, CD 3 OD, δ ppm): 3.03 (lH, dd), 3.40 (lH, dd), 3.78 (2H, d), 3.86 (2H, s), 4.55-465 (lH, m), 6.19 (lH, s), 6.69-6.80 (2H, m), 6.95-7.02 (2H, m) , 7.02- 7.10 (2H, m)

 Example 9

 3- (3,4-dihydroxybenzinole) -5- (3,4-dihydroxyphenyl) -tri (2-pyridyl) pyrazole

Dissolve 358 mg of 1,4-di (3,4-dimethoxyphenyl) -1,3-butanedione and 164 mg of 2-hydrazinopyridine in Reference Example 1 in 10 ml of ethanol, and heat and reflux for 3.5 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure, and the resulting residue was purified by Sephadex® LH-20 column chromatography (form: methanol:: formic acid = 100: 10: 1) to give 3- (3, 289 mg of 4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) -1- (2-pyridyl) pyrazole was obtained, which was deprotected in the same manner as in Example 2-b) to give 98 _{mg of the} title compound. Get.

FAB- MS (m / z, as ^{_{+ (C 21 H I7 N 3}} 0 4 + H)): 376

 Ή-NMR (300 MHz, Acetone-de, δ ppm): 3.85 (2H, s), 6.22 (lH, s), 6.58 (lH, dd, J = 2.0 Hz, 8.3 Hz), 6.67-6.77 (4H, m ), 6.83 (lH, d, J = 2.4 Hz), 7.25-7.35 (lH, m), 7.61 (lH, d, J = 8.1 Hz), 7.80-8.00 (5H, m), 8.23-8.33 (lH, m)

 The compounds of Examples 10 to 12 are synthesized in the same manner as in Example 9.

 Example 10

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1- (8-quinolylmethyl) pyrazole

FAB- MS (m / z,

+ Η) ⁺ )): 440 Ή-NMR (300MHz, CD ₃ OD, δ pm): 3.35 (2H, s), 3.82 (2H, s), 5.92 (lH, s), 6.31-6.38 (lH, m), 6.39 (lH, s) , 6.52 (lH, s), 6.78 (lH, d, J = 8.4Hz), 6.87 (lH, d, J = 7.2Hz), 7.11 (lH.ddJ = 1.8Hz, 8.4Hz), 7.21 (lH, d , J = 1.8 Hz), 7.42 (lH.dJ = 7.2 Hz), 7.55 (lH.dd'J = 3.6 Hz, 8.1 Hz), 7.80 (lH, d, J = 1.0 Hz, 8.1 Hz), 8.31 (lH , dd, J = 1.8Hz,

8.1Hz), 8.91 (lH.ddJ = 1.2Hz, 3.6Hz)

 Example 11

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1-phenylphenazole

FAB- MS (m / z, as _{+ (C 22 H 18 N 2} O 4 + H)): 375

Ή-NMR (300 MHz, CD ₃ OD, δ ppm): 3.85 (2H, s), 6.19 (lH, s), 6.51 (lH, dd, J = 1.8Ηζ, 7.6Ηζ), 6.60 (lH, d, J = 1.8Hz), 6.61-6.69 (2H, m), 6.70 (lH, t, J = 7.6Hz), 6.74 (lH, d, J = 1.8Ηζ), 725-731 (2H, m ), 7.32 -7.40 (3H, m)

 Example 12

 3- (3,4-dihydroxybenzinole) -5- (3,4-dihydroxyphenyl) -1-methylpyrazole

FAB- MS (m / z, as ^{_{+ (C 17 H 16 N 2}} 0 4 + H)): 313

 Ή-NMR (300MHz, Acetone-de, δ ppm): 3.65- 3.80 (3H, m), 3.85-3.95 (2H, m), 6.25 (lH, s), 6.57-7.35 (6H, m)

 Example 13

 1-Arinole-3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenol) pyrazole

354 mg of 3- (3,4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) pyrazole obtained in Example 2-a) was dissolved in 5 ml of DMF, and sodium hydride (60% 80 mg of mineral oil suspension and 242 mg of aryl bromide were added, and the mixture was stirred at 80 ° C for 12 hours. The reaction mixture is cooled to room temperature, poured into ice water, neutralized with 1N hydrochloric acid, and extracted three times with 50 ml of ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 115 mg of the title compound. Profit You.

FAB- MS (m / z, as _{+ (C 19 H 18 N 2} 0 4)): 338

Ή-NMR (300MHz, CD ₃ OD, δ ppm): 3.84 (2H, s), 4.61 (2H, dd, J = 3.3Hz, 18.0Hz), 4.93 (lH.ddJ = 1.5Hz, 18.0Hz), 5.13 (lH.dd.J = 1.5Hz, 9.6Hz), 5.84-5.94 (lH, m), 6.23 (lH, s), 6.53 (lH'dd'J =

1.5Hz, 9.6Hz), 6.65-6.82 (3H, m), 7.05 (lH, dd, J = 1.8Hz, 6.7Hz), 7.16 (lH, d, J = 1.8Hz)

 Example 14

 Toracetyl-3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) pyrazole

177 mg of 3- (3,4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) pyrazole obtained in Example 2-a) is dissolved in 3 ml of pyridine, and 0.2 ml of acetic anhydride is added. Stir for hours. The reaction mixture was poured into ice water and extracted three times with acetic Echiru 20 ml, the organic layer with 1N hydrochloric acid, washed with saturated brine, dried over anhydrous magnesium sulfate燥, Sephadex ^TM LH-20 column residue is concentrated under reduced pressure, and the resulting Purification by chromatography (chloroform: methanol: formic acid = 100: 10: 1) affords 168 mg of the title compound, which is deprotected as in Example 2-b) to give 35 mg of the title compound.

FAB- MS (mZz, as _{+ (C 18 H 16 N 2} 0 5 + H)): 341

Ή-NMR (300 MHz, CD ₃ OD, δ ppm): 3.31 (3H, s), 4.04 (2H, s), 6.30

(lH, s), 6.76 (lH, s), 6.78-6.88 (2H, m), 6.96 (lH, s), 7.19 (lH'dd, J = 1.8Hz, 6.7Hz), 7.40 (lH, d, (J = 1.5Hz)

 Example 15

 3- (3.4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -4-methylpyrazole

100 mg of 1,4-di (3,4-dimethoxyphenyl) -1,3-butanedione obtained in Reference Example 1 was dissolved in 2 ml of toluene, 0.1 ml of methyl iodide and 70 mg of silver oxide were added, and the mixture was stirred at room temperature for 15 hours. After filtering off the insolubles, the solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1,4-di (3,4-dimethoxyphenyl). )-2-Methyl-1,3-butanedione 103 mg are obtained. Using this, the title compound is synthesized in the same manner as in Example 2.

FAB- MS (mZz, as _{+ (C 17 H 16 N 2} 0 4 + H)): 313

Ή-NMR (300MHz, CD ₃ OD, δ ppm): 2.00 (3H, s), 3.82 (2H, s), 6.52 (lH, dd, J = 1.8HzJ.6Hz), 6.60 (lH.dJ = 1.8Hz ), 6.67 (lH.dJ =

7.6Hz), 6.77-6.87 (2H, m), 6.96 (lH, d, J = 1.8Hz)

 Example 16

 (E)-4 (3,4-dihydroxybenzylidene)-2- (3,4-dihydroxybenzyl)-1,3 -year-old

 a. Synthesis of N- (3,4-dimethoxybenzoyl) glycine

 Dissolve 770 mg of glycineethyl estenole hydrochloride, 1.0 g of 3,4-dimethoxybenzoic acid, 1.20 g of DCC and 0.84 ml of triethylamine in 15 ml of anhydrous methylene chloride at 15 ° C, stir for 15 hours, and warm to room temperature. . After filtering off the insoluble matter, 200 ml of ethyl acetate was added, washed with 1N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and 1.16 g of the obtained residue was dissolved in 10 ml of methanol and 1N hydroxylated Add 1.1 ml of aqueous sodium solution and stir at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, adjusted to pH 3 with 1N hydrochloric acid, extracted twice with 50 ml of ethyl acetate, and the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue obtained was Sephadex ™ LH- Purify by 20 column chromatography (form: formanol: formic acid = 100: 10: 1) to obtain 390 mg of the title compound. b. (E) -4- (3,4-dihydroxybenzylidene) -2- (3,4-dihydroxyphenyl) -5-oxazolone

Dissolve 150 mg of N- (3,4-dimethoxybenzoyl) glycine and 210 mg of 3,4-dimethoxybenzaldehyde in 1 ml of acetic anhydride, add 25 mg of sodium hydride (60% mineral oil suspension), and add 1 hour at room temperature. The mixture was further stirred at 80 ° C for 2 hours. The reaction solution was poured into ice water, extracted three times with 5 ml of methylene chloride, and the organic layer was washed with a saturated aqueous solution of sodium carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The precipitated precipitate was dried to obtain 114 mg of (E) -4- (3,4-dimethoxybenzylidene) -2- (3,4-dimethoxyphenyl) -5-oxazolone, which was obtained in the same manner as in Example 2_b). Deprotection gave 35 mg of the title compound. Was.

 Melting point:> 270 ° C

High Resolution FAB- MS (m / z, as _{+ (C 16 H "N0 6} + H)):

 Calculated value: 314.0665

 Measured: 314.0689

IR (KBr.cm- ¹ ): 3304, 1758, 1650, 1605

 Ή-NMR (300MHz, Acetone-de, δ ppm): 6.94 (lH, d, J = 7.2Hz), 7.01 (lH, d, J = 7.2Hz), 7.13 (lH, s), 7,55 (lH .dd.J = 1.2HzJ.2Hz), 7.58 (lH, dd, J = 1.2Hz, 7.2Hz), 7.65 (lH, d, J = 1.2Hz), 8.15 (lH, d, J = 1.2Hz)

 Example 17

 (E) -2- (3,4-dihydroxyphenyl) -4- (4-hydroxybenzylidene)-1.3-oxazo mouth-5-one

 Synthesized in the same manner as in Example 16.

FAB- MS (mZz, as _{+ (C 16 H "N0 5} + H)): 298

 Ή-NMR (300MHz, Acetone-de, δ ppm): 6.98 (2H, d, J = 7.4Hz), 7.02 (lH, d, J = 7.4Hz), 7.10 (lH, s), 7.58 (lH, dd , J = 1.2Hz, 7.4Hz), 7.65 (lH, d, J = 1.2Hz), 8.21 (2H, d, J = 7.4Hz)

 Example 18

 3- (3,4-dihydroxybenzinole)-5- (3,4-dihydroxybenzoinole)-1,2,4-oxaziazol

 Dissolve 400 mg of 3,4-dimethoxypheninoleacetic acid ethyl ester and 200 mg of 3,4-dimethoxyphenylacetamidoxoxime in 2 ml of ethanol, add 71 mg of sodium ethoxide, and heat to reflux for 6 hours. After cooling to room temperature, the resulting precipitate is collected by filtration, washed with water, and dried in vacuo to give 3- (3,4-dimethoxybenzyl) -5- (3,4-dimethoxyphenyl) -1,2,4-oxadiazole. 165 mg were obtained, which was deprotected in the same manner as in Example 2-b) to obtain 84 mg of the title compound as white crystals.

 Melting point: 215-216 ° C

High Resolution FAB- MS (m / z, as _{+ (C 15 H 12 N 2} 0 5 + H)):

Calculated value: 301.0746 Measurement value: 301.0816

IR (KBr.cm- ¹ ): 3268,1623,1581

 Ή-NMR (300 MHz, Acetone-d6, δ ppm): 3.92 (2H, s), 6.68 (lH, dd, J

 1.3Hz, 7.0Hz), 6.75 (lH, d, J = 7.0Hz), 6.85 (lH, d, J = 1.3Hz), 6.99 (lH, d, J = 7.7Hz), 7.51 (lH, dd, J = 1.3Hz, 7.7Hz), 7.55 (lH, d, J =

(1.3Hz)

 Example 19

 (E) -3- 3-Hymethyl- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2,3-dihydropyrrole-5-one

Dissolve 238 mg of 3- (3,4-dimethoxybenzoyl) propionic acid, 180 mg of 3,4-dimethoxysetofphenone, 154 mg of ammonium acetate and 2 ml of acetic acid in 5 ml of toluene and heat to reflux for 5 hours. And extracted 3 times with acetic Echiru 20ml was added After cooling ice water to room temperature, the organic layer with saturated aqueous sodium hydrogen carbonate solution, washed with saturated brine, Sephadex the residue obtained by drying with anhydrous magnesium sulfate concentrated under reduced pressure ^R Purification by LH-20 column chromatography (cloth form: methanol: formic acid = 100: 10: 1) and (Ε) -3- [α-methyl- (3,4-dimethoxy) benzylidene] -5- ( 3,4-Dimethoxyphenyl) pyrrolidone 23 mg is obtained. This is deprotected in the same manner as in Example 2-) b to obtain 13.7 mg of the title compound.

High Resolution FAB- MS (m / z, as ^{_{+ (C 18 H 15 N0 5}} )):

 Calculated value: 325.0950

 Measured: 325.0938

 Ή-NMR (300 MHz, Acetone-de, δ ppm): 2.65 (3H, s), 6.03 (lH, d, J = 2.1 Hz), 6.85 (lH, d, J = 8.3 Hz), 6.90 (2H, d , J = l.lHz), 7.02 (1H, U = 1.1Ηζ), 7.08 (lH, dd, J = 2,2Hz, 8.3Hz), 7.15 (lH, d, J = 2.2Hz) 8.08 (lH , S), 8.14 (lH, s), 8.19 (lH, s), 8.31 (lH, s), 9.12 (lH, brs)

 (E)-3- (3,4-dihydroxybenzylidene)-5- (3,4-dihydroxyphenyl)-2.3-dihydropyrrole-5-one

 a. Synthesis of 5- (3,4-diacetoxyphenyl) -2 (3H) -furanone

3- (3,4-dihydroxybenzoyl) propionic acid 882mg, 3,4-dihydroxy Dissolve 696 mg of cibenzaldehyde and 164 mg of sodium acetate in 10 ml of acetic anhydride and stir at 150 ° C for 3 hours. The reaction solution is cooled to room temperature, poured into ice water, extracted three times with 20 ml of ethyl acetate, and the organic layer is washed with a saturated aqueous solution of sodium carbonate and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 3- (3,4-diacetoxybenzyl) -5- (3,4-diacetoxyphenyl) -2 ( 3H) -Furanone 430mg is obtained.

Ή-NMR (300MHz, CDCl ₃ , δ ppm): 2.30 (3H, s), 2.31 (3H, s), 3.43 (2H, d, J = 3.0Hz), 5.78 (1H, U = 3.0Hz), 7.24 (lH, d ₍ J = 8.7Hz), 7.43 (1H, d, J = 2.1Hz), 7.49 (lH, dd, J = 2.1Hz, 8.7Hz)

 b. Synthesis of (E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) pyrrolidone

 (E) -3- (3,4-Diacetoxybenzylidene) -5- (3,4-diacetoxyphenyl) -2 (3H) -Furanone 47.8 mg was dissolved in 25% aqueous ammonia 5 ml and dissolved at room temperature. Stir for hours. The residue obtained by concentration under reduced pressure is purified by Sephadex ™ LH-20 column chromatography (form: methanol: formic acid = 100: 10: 1) to obtain 4.5 mg of the title compound.

High Resolution FAB-MS (mZz, ⁺ binding by _{(C, 7 H 13 NO s} )):

 Calculated value: 311.0794

 Measured: 311.0774

IR (KBr.cm- ¹ ): 3266,1683,1606

 Ή-NMR (300 MHz, Acetone-de, δ ppm): 6.53 (lH, brs), 6.91 (2H, d, J = 8.3 Hz), 7.04 (lH, s), 7.17 (lH, dd, J = 2.1 Hz) , 8.3Hz), 7.23 (lH, dd, J = 2.1Ηζ, 8.3Ηζ), 7.31 (lH, d, J = 2.1Hz), 7.32 (lH.dJ = 2.1Hz), 8.17 (lH, brs), 8.28 (lH, brs), 8.43 (lH, brs), 8.52 (lH, brs), 9.24 (lH'brs)

 Synthesis of (E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene) -2 (3H) -furanone

(a) Synthesis of (E) -5- (3,4-dimethoxyphenyl) -3- (3-methoxybenzylidene) -2 (3H) -furanone Under argon atmosphere, lOOmg of 3- (3,4-dimethoxybenzoyl) propionic acid obtained in Reference Example 2 and m-anisaldehyde 1021 were dissolved in 1.5 ml of acetic anhydride, and sodium hydride (60 ml) was stirred at room temperature. 16.8 mg over 10 minutes. After stirring at room temperature for 60 minutes, heat to reflux for 2 hours, return to room temperature, add 10 ml of methylene chloride and 10 ml of water to the reaction solution, separate the organic layer, and separate the organic layer with a 0.1N aqueous solution of sodium hydroxide and saturated hydrogen carbonate. After washing with an aqueous sodium solution and then with a saturated saline solution and drying over anhydrous sodium sulfate, the solvent is distilled off, and the resulting brown oil is purified by silica gel gel chromatography (silica gel, 20 g, n-hexane: ethyl acetate). = 4: 1) to give (E) -5- (3,4-dimethoxyphenyl) -3- (4-methoxybenzylidene) -2 (3H) -furanone 43 mg as a yellow solid.

 Rf value: 0.48 (silica gel plate, n-hexane: ethyl acetate = 1: 1) (b) (E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene) -Synthesis of 2 (3H) -furanone

 Dissolve 48.8 mg of (E) -5- (3,4-Dimethoxyphenyl) -3- (3-methoxybenzylidene) -2 (3H) -furanone in 10 ml of anhydrous methylene chloride under an argon atmosphere, and add -78. While stirring at ° C, 1M boron tribromide methylene chloride solution 761 // 1 is added dropwise. After returning to room temperature and stirring for 15 hours, the mixture is cooled to -78 ° C, and 1 ml of anhydrous methanol is added with stirring. 100 ml of ethyl acetate and 50 ml of 0.01N hydrochloric acid were added to the reaction mixture, and the mixture was separated. The organic layer was washed with water and the solvent was distilled off under reduced pressure. The resulting red-yellow residue was subjected to silica gel gel chromatography (silica gel, 15 & chromatography). Purification by mouth form: methanol: formic acid = 100: 5: 1) yields a red-yellow solid containing the target compound. This was purified by Sephadex "^ LH20 force column chromatography (16 x 800 mm, black form: methanol: water = 5: 2: 2: 1) to give 21.1 mg of the title compound as a red-yellow solid. Get.

 Rf value: 0.32 (silica gel plate, black form: methanol: formic acid =

 100: 10: 10)

FAB- MS

As): 296

IR (KBr.cm- ¹ ): 3406, 1755, 1629, 1593, 1521, 1455, 1386, 1341, 1305, 1257,

 1194,1122

Ή-NMR (300MHz, acetone-d ₆ , δ ppm): 6.88-6.98 (lH, m), 6.95 (1H, d, J = 8.4Hz), 7.14 (lH, s), 7.21 (lH, s), 7.2 7.31 (lH, m), 7.28-7.33 (3H, m), 7.35 (lH, d, J = 1.8Hz )

 In the same manner as in Example 21, the compounds of the following Examples 22 to 86 were prepared by condensing a corresponding carbonyl compound of the general formula [8] and a 7-keto acid derivative of the general formula [21] in the presence of a base, followed by ring closure. It is synthesized by a method of treating with boron halide.

 Example 22

 (E) -3- (3,4-dihydroxybenzylidene) -5-phenyl-2 (3H) -furano _

FAB - MS (m / z, as ^{_{+ (C I7 H 12 0 4}} + H)): 281

 Ή-NMR (300 MHz, acetone-de, δ ppm): 6.96 (lH, d, J = 8.1 Hz), 7.27

(lH, s), 7.29 (lH, dd, J = 2.1,8.1Hz), 7.36 (lH, dJ = 2.1Hz), 7.38 (1H, s), 7.45-7.55 (3H, m), 7.82-7.92 ( 2H, m), 8.20 (lH, s), 8.74 (lH, s)

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxybenzylidene) -2 (3H) -furanone

 Rf value: 0.23 (silica gel plate, black form: methanol: formic acid =

 100: 10: 10)

FAB- MS (mZz, (C, 7 H 12 0 5; as): 296 '

 IR (KBr, cm— '): 3394,1740,1602,1578,1518,1455,1389,1260,1167,1116,

 945

 Ή-NMR OOOMHz.acetone- de, δ ppm): 6.94 (lH, d, J = 8.4Hz), 6.97 (2H, d, J = 8.4Hz), 7.18 (lH, s), 7.22 (lH, s) , 7.28 (lH.ddJ = 2.4, 8.4Hz), 7.33 (lH, d, J = 2.4Hz), 7.74 (2H, d, J = 8.4Hz)

 Example 24

 (E) -3- (3,4-dihydroxybenzylidene) -5- (4-hydroxyphenyl)-

2 (3H)-furanone

FAB- MS (m / z, as _{+ (C, 7 H 12 0} 5)): 296

Ή-NMR (300MHz, acetone-d ₆ , δ ppm): 6.90-7.00 (3H, m), 7.12-7.22 (2H, m), 7.18-7.28 (2H, m), 7.25 (lH.dd.J = 2.4, 8.1Hz), 7.33 (1H, d, J = 2.4Hz) Example 25

 Mixture of (E) and (Z) -5- (3,4-dihydroxyphenyl) -3- [4- (2,3-dihydroquin-propylpropyl) benzylidene 1-2 (3H) -furanone

FAB-MS (mZz, as ^{_{+ (C 2 .H 18 0 7}} )): 370

FAB- MS (m / z, as ^{_{+ (C 2 .H 18 0 7}} + Na)): 393

Ή-NMR (300MHz, acetone- d 6, δ ppm): 3.60-3.82 (3H, m), 3.98- 4.22 (4H, m), 4.67 (0.4H, s), 6.59 (0.4H, s), 6.92 (0.4H .J = 8.4Hz), 6.94 (0.6H, d, J = 8.1Hz), 7.03 (0.8H), 7.08 (1.2H), 7.15 (0.4H, dd, J = 3.3, 8.4Ηζ) ' 7 · 20 (0,6H, s), 7.21 (0.4H, d, J = 3.3Hz), 7.22 (0.4H, s), 7.24 (0.6H, s), 7.29 (0.6H, dd, J = 2.4 , 8.4Hz), 7.33 (0.6H, d, J = 1.8Hz), 7.81

(1.2H), 8.24 (lH, s), 8.25 (0.8H), 8.61 (0.6H, s)

 Example 26

 (E) -3- (2,4-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

FAB-MS (m / z, as _{+ (C 17 H 12 0 6} )): 312

NMR-NMR (300MHz, acetone-d ₆ , δ ppm): 6.45-6.55 (2H, m), 6.92 (1H, d, J = 8.4Hz), 7.11 (lH, s), 7.12 (lH, s), 7.25 (lH, dd, J = 1.8, 8.4Hz), 7.31 (lH, d, J = 1.8Hz), 7.79 (lH.dJ = 7.8Hz)

 Example 27

 (E) -3-[(E) -4- (2-carboxyvinyl) benzylidene 1-5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

FAB-MS (as mZz, (C ₂ .H ₁₄ O ₆ ) +): 350

Ή-NMR (300MHz, acetone-d ₆ , δ ppm): 6.63 (lH, d, J = 15.9Hz), 6.86 (lH, d, J = 7.8Hz), 7.25 (lH, d, J = 2.4Hz) , 7.26 (lH, s), 7.28 (lH, dd, J = 2.4, 7.8 Hz), 7.37 (lH, s), 7.64 (lH, d, J = 15.9 Hz), 7.78 (2H, d, J =

8.4 Hz), 7.88 (2H, d, J = 8.4 Hz), 9.26 (lH, brs), 9.80 (lH'brs)

 (E) -3- (2,3-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

FAB- MS (m / z, as ^{_{+ (C 17 H 12 0 6}} )): 312 _{Ή- NMR (300MHz, acetone- d 6} , δ ppm): 6.80 (lH.tJ = 7.8Hz), 6.94 (lH, d, J = 8.4Hz), 6.95 (lH, dd, J = 1.5,7.8Hz) , 7.11 (lH, d, J = 0.9Hz), 7.29 (lH, dd, J = 1.8,8.4Hz), 7.34 (lH, d, J = 1.8Hz), 7.38 (lH.dd.J = 0.9,7.8 Hz), 7.76 (lH, s)

 Example 29

 (E) -3- (2,6-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

_{FAB- MS (mZz, (C 17} H 12 0 6: as r): 312

_{Ή- NMR (300MHz, acetone- d 6} (δ ppm): 6.51 (2H, d, J = 7.8Hz), 6.79 (lH, d, J = 1.5Ηζ), 6 · 91 (lH, d, J = 8.4 Hz), 7.08 (lH, t, J = 8.4Hz), 7.16

(lH, dd, J = 1.8,7.8Hz), 7.21 (lH, d, J = 2.1Hz), 7.60 (lH, s)

 (E)-3- (3-Bromo-4-methoxybenzylidene) -5- (3,4-dihydroxyphenyl)-2 (3H)-Furanone

FAB- MS (mZz, as _{^ (C 18 H, 3 Br0} 5)): 388

FAB- MS (mZz, as ^{_{+ (C 18 H 18 0 5}} Br + Na)): 411

 Ή-NMR (300MHz, acetone- de, δ ppm): 3.99 (3H, s), 6.95 (lH.dJ = 8.1Hz), 7.20 (2H, s), 7.22 (lH.dJ = 8.?Hz), 7.29 (lH.dd, J = 2.2,8.1 Hz), 7.34 (lH, d, J = 2.2Hz), 7.87 (lH, dd, J = 2.1,8.7), 8.02 (lH, d, J = 2.4Hz)

 Example 31

 (E) -3- (3.4-Dihydroxybenzylidene) -5- (3-Hydroxyphenyl) -2 (3H) -Furanone

 Melting point: 243- 245 ° C

High Resolution FAB- MS (m / z, as _{+ (C I7 H 12 0 5} )):

 Calculated value: 296.0685

 Measured: 296.0675

IR (KBr.cm- ¹ ): 3322,1752,1734

 Example 32

(E-3- (3-dihydroxybenzylidene) _-5- (4-methylphenyl)-2 (3H) -Furanone

_{FAB- MS (m (C 18 H} 14 O 4) as a +): 294

 Ή-NMR (300 MHz, acetone-d6, δ ppm): 2.40 (3H, s), 6.95 (lH, d), 7.22- 7.38 (6H, m), 7.76 (2H, d-like), 8.30 (lH, brs), 8.72 (IH.brs) Example 33

 (E)-3- (3-arinole-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl)-2 (3H) -furanone

 Rf value: 0.20 (silica gel plate, black form: methanol: formic acid =

 100: 5: 1)

FAB- MS (m / z, as ^{_{+ (C 20 H 16 O 5}} )): 336

NMR-NMR (300 MHz, acetone-d ₆ , δ ppm): 3.44 (2H, d, J = 6.6 Hz), 5.00-5.10 (lH, m), 5.07-5.17 (lH, m), 6.00-6.15 (lH , M), 6.93 (lH.dJ = 8.4Hz), 6.99 (lH, d, J = 8.7Hz), 7.13 (lH, s), 7.21 (lH, s), 7.25 (1H, dd, J = 1.8, 8.1 Hz), 7.30 (lH, d, J = 2.1 Hz), 7.60 (lH, d, J = 2.1 Hz), 7.61 (lH, dd, J = 2.1, 8.7 Hz)

 Example 34

 (E)-3- (3,4-dihydroxybenzylidene)-5- (4-fluorophenyl)-2 (3H)-furanone

 Melting point:> 270 ° C

High Resolution FAB- MS (m_ / z, as ^{_{+ (C 17 HuF0 4))}} :

 Calculated value: 298.0641

 Measured: 298.0625

 IR (KBr.cm- '): 3292,1740,1620

 Ή-NMR (300MHz, acetone-de, δ ppm): 6.83 (lH, s), 6.96 (lH, d, J = 8.4Hz), 7.11 (lH, d, J = 1.7Hz), 7.13 (2H, t , J = 9.0Hz), 7.30 (lH, dd,

J = 1.7Hz, 8.4Hz), 7.39 (lH, s), 7.74 (2H, dd, J = 5.7Hz, 9.0Hz) Example 35

 (E) -5- (4-Carboxyphenyl) -3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone

Melting point:> 270 ° C High Resolution FAB-MS (m / z, (C 18 H 12 0 6: as r):

 Calculated value: 324.0634

 Measured: 324.0662

 IR (KBr.cm- '): 3466,1755,1689

 Ή-NMR (300MHz, acetone-de, δ ppm): 6.93 (lH, d, J = 8.1Hz), 7.30

(lH, dd, J = 2.4Hz, 8.1Hz), 7.32 (lH, s), 7.34 (lH, d, J = 2.4Hz), 7.53 (lH, s), 7.96 (2H, d, J = 8.7Hz ), 8.11 (2H, d, J = 8.7Hz)

 Example 36

 (E) -5- (3,4-dihydroxyphenyl)-3- (4-hydroxy-3-methoxyproponylbenzylidene)-2 (3H) -furanone

 FAB-MS (^ / ^, as (".?)): 354

 Ή-NMR (300 MHz, DMSO-de, δ ppm): 3.81 (3H, s), 6.78 (lH, d), 7.00 (lH, d-like), 7.12- 7.18 (4H, m), 8.04 (2H, s), 9.20 (lH, brs), 9.65 (lH'brs), 10.80 (lH.brs)

 Example 37

 (E) -3- "3- (2,3-dibromopropyl) -4-hydroxybenzylidene, -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

FAB-MS (mZz, as _{+ (C 2 .H 16 Br 2} 0 5)): 494

Ή-NMR (300MHz, acetone-d ₆₎ δ ppm): 3.20 (lH, dd, J = 8.4,14.1Hz), 3.91-3.99 (2H, m), 4.79 (lH, m), 5.76 (lH, dd , J = 4.1, 6.1Hz), 6.94

(lH, d, J = 8.4Hz), 7.02 (lH, d, J = 8.4Hz), 7.16 (lH, s), 7.22 (lH, s), 7.24 (lH, dd, J = 2.1,8.4Hz) , 7.30 (lH, d, J = 2.1Hz), 7.64 (lH.ddJ = 2.1,8.4Hz)

 Example 38

 (E) -5- (3-Carboxy-4-hydroxyphenyl) -3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone

FAB-MS (111 Bruno 2, as (〇 ^{_{18 ¾ 2 0 7) +)}} : 340

Ή-NMR (300MHz, acetone-d6, <5 ppm): 6.94 (lH, d), 7.10 (lH, d), 7.22 (lH, s), 7.28 (lH, dd), 7.31 -7.38 (2H, m ), 8.07 (lH, dd), 8.33 (lH, d) (E)-3- (3-carboxy-4-hydroxybenzylidene)-5- (3,4-dihydroxyphenyl)-2 (3H) -furanone

FAB- MS (mZz, as ^{_{+ (C 18 H 12 0 7}} )): 340

 Ή-NMR (300MHz, acetone-d6, δ ppm): 6.94 (lH, d), 7.00 (lH, d), 7.16 (lH, s), 7.24- 7.28 (2H, m), 7.35 (lH, d) , 7.96 (lH, dd-like), 8.30 (1H, d-like)

 Example 40

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-fluorobenzylidene)-2 (3H) -furanone

FAB- MS (m / z, as ^{_{+ (C 17 H "F0 4}} )): 298

 Ή-NMR OOOMHz.acetone-de, δ ppm): 6.95 (lH, d, J = 8.4Hz), 7.22 (lH, s), 7.23- 7.26 (2H, m), 7.27 (lH, s), 7.30 ( lH, dd, J = 2.4,8.4Hz), 7.35 (lH, d, J = 2.4Hz), 7.85-7.95 (2H, m), 8.44 (2H, brs)

 (E) -5- (3,4-dihydroxybenzene) -3- (3,4-difluorobenzoylidene)-

2 (3H)-furanone

FAB- MS (m ^/ / z, as ^{_{+ (C 17 H 1 .F 2}} 0 4)): 316

Ή-NMR (300 MHz ₍ acetone-d6, δ ppm): 6.95 (lH, d, J = 8.4Ηζ), 7 · 23 (lH, s), 7.28 (lH, s), 7.32 (lH.dd.J = 2.1,8.4Hz), 7.37 (lH, d, J = 2.1Hz), 7.39-7.49 (lH, m), 7.64--7.77 (IH.m), 7.78-7.88 (lH, m),

8.24 (lH, brs), 8.67 (lH, brs)

 Example 42

 (E) -3- (3,5-dichlorobenzylidene) -5- (3,4-dihydroxybenzoinole) -2 (3H) -furanone

FAB- MS (mZz, as _{+ (C I7 H 10 C1 2} 0 4): 349

 Ή-NMR (300MHz, acetone-d6, <5 ppm): 6.96 (lH.dJ = 8.4Hz), 7.20 (lH, s), 7.28 (lH, s), 7,34 (IH.ddJ = 1.8,8.4 Hz), 7.38 (lH.dJ = 1.8Hz), 7.53 (lH, t, J = 1.8Hz), 7.80 (2H, d, J = 1.8Hz), 8.31 (lH.s), 8.71 (lH, s)

Example 43 (E) -3- (3,4-dichlorobenzylidene) -5- (3,4-dihydroxyphenyl)-(3H) -furanone

 FAB-MS (as mZz C HuClsOJ): 348

 Ή-NMR (300MHz, acetone-d ^, δ ppm): 6.96 (lH'd'J = 8.4Hz), 7.22 (lH, s), 7.25 (lH, s), 7.32 (lH, dd, J = 1.8 , 8.4Hz), 7.36 (lH, d, J = 1.8

Hz), 7.67 (lH, d, J = 8.4 Hz), 7.83 (lH, dd, J = 2.4,8.4 Hz), 7.99 (IH, d, J = 2.4 Hz), 8.29 (lH, s), 8.71 ( lH, s)

 Example 44

 (E) -5- (3,4-dihydroxyphenyl) -3- (3,4,5-trihydrodroquinbenzylidene) -2 (3H) -furanone

 Rf value: 0.39 (silica gel plate, black form: methanol: formic acid =

 100: 30: 30 1)

 Ή-NMR (300 MHz, DMSO-d6, δ ppm): 6.78 (2H, s), 6.83 (lH, d, J = 9.3 Hz), 6.97 (lH, s), 6.99 (lH.s), 7.08-7.18 (2H, m)

 Example 45

 (E) -3- (2,5-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

 Rf value: 0.16 (silica gel plate, chlorovolume: methanol: formic acid =

 100: 10: 10)

FAB- MS (m / z, as ^{_{+ (C 17 H 12 0 6}} )): 312

Ή-NMR (300 MHz, acetone-d ₆ , 6 ppm): 6.81 (lH.dd.J = 2.7,8.4 Hz), 6.87 (lH, d, J = 8.4 Hz), 6.95 (lH, d, J = 8.4 Hz), 7.06 (lH, s), 7.28 (IH, dd, J = 2.1, 8.4Hz), 7.31 (lH.dJ = 2.7Hz), 7.32 (lH, d, J = 2.1Hz), 7.70 (lH, s), 7.94 (lH, s), 8.25 (lH, s), 8.58 (2H, s)

 Example 46

 (E) -3- (3,5-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

FAB-MS (mZz, as ^{_{+ (C 17 H 12 0 6}} )): 312

NMR-NMR (300MHz, acetone-de, <5ppm): 6.46 (lH, t, J = 1.8Hz), 6.95 (lH, d, J = 8.4Hz), 7.04 (lH, s), 7.12 (lH, s), 7.28 (lH, dd, J = 2.4,8.4 Hz), 7.33 (lH, d, J = 2.4Ηζ) 7.80 (2H, d, J = 1.8Hz)

 Example 47

 (E) -3- (3,5-Difluorobenzylidene) -5- (3,4-Dihydroxyphenyl)-(3H) -furanone

 FAB-MS (as !!!!! / ^^! ^): 316

Ή-NMR (300MHz, acetone-d ₆ , <5 ppm): 6.96 (lH'd'J = 8.4Hz), 7.05-7.15 (lH, m), 7.23 (lH, s), 7.31 (lH, s) 7.36 (lH.dd, J = 1.8,8.4Hz), 7.40 (lH, d, J = 1.8Hz), 7.42-7.52 (2H, m), 8.27 (lH, s), 8.72 (lH.s) 48

 (E) -5- (3,4-dihydroxyphenyl)-3- (6-methoxy-2-pyridylmethylidene)-2 (3H) -furanone

FAB- MS (mZz, as _{+ (C 17 H 13 NO 5} + H)): 312

Ή-NMR (300 MHz, acetone-d ₆ , δ ppm): 4.11 (3H, s), 6.82 (lH.dJ = 8.1 Hz), 6.96 (lH _f d, J = 8.4 Hz), 7.16 (lH, s) , 7.26 (lH, dd, J = 2.4,8.4 Hz), 7.30 (lH, d, J = 1.8Hz), 7.32 (lH.dJ = 7.5Hz), 7.67 (lH, d, J =

0.9Hz) 7.77 (lH, dd, J = 7.5, 8.1Hz),

 Example 49

 (E)-5- (3,4-dihydroxyphenyl) -3- (2-methoxy-5-pyridinolemethylidene)-2 (3H)-Furanone

FAB- MS (mZz, as ^{_{+ (C 17 H, 3 NO}} 5 + H)): 312

Ή-NMR (300 MHz, DMSO-d ₆ , <5 ppm): 3.93 (3H, s), 6.84 (lH.dJ = 8.4 Hz), 6.93 (lH, d, J = 8.4 Hz), 7.23 (lH, s ), 7.24 (lH, d, J = 2.4Hz), 7.25 (lH, dd, J = 2.4,8.4Hz), 7.34 (lH, s), 8.26 (lH, dd, J = 2.4,8.4Hz), 8.64 (lH, d, J = 2.4Hz)

 Example 50

 (E)-5- (3,4-dihydroxyphenyl) -3- (5-hydroxy-3-pyridylmethylidene) -2 (3H) -furanone

FAB-MS (as m / z. CdeHnNOs + H) ⁺ ): 298

Ή-NMR (300 MHz, DMSO-d ₆₎ δ ppm): 6.87 (lH, d, J = 8.1 Hz), 7.24 (1H, s), 7.25 (lH, d, J = 1.4 Hz), 7.28 (lH, dd, J = 1.4,8.1Hz), 7.29 (lH.s), 7.84 (lH.br), 8.24 (lH.br), 8.58 (lH, s)

 Example 51.

 Condensation of 3- (3,4-dimethoxybenzoyl) propionic acid and 4-diethoxyphosphoryloxybenzaldehyde in the same manner as in Example 21 to give (E) -3- (4-diethoxyphosphoryloxybenzylidene) -5- (3,4-Dimethoxyphenyl) -2 (3H) -furanone is obtained, which is similarly treated with boron tribromide, and the resulting reaction products are isolated to give compounds 51a, 51b and 51c, respectively.

 (51a) (E) -3- (4-Diethoxyphosphoryloxybenzylidene) -5- (3-hydroxy-4-methoxyphenyl) -2 (3H) -furanone

FAB- MS (mZz, as _{+ (C 22 H 23 0 8} P)): 446

 Ή-NMR (300MHz, acetone-d6, δppm): 1.33 (6H, dt, J = 0.9,6.9Hz), 4.23 (4H, dq, J = 6.9,8.4Hz), 7.08 (lH, d, J = 9.0Hz), 7.29 (lH, s), 7.31 (lH, s), 7.34-7.39 (4H, m), 7.85-7.95 (2H, m)

 (51b) (E) -3- (4-diethoxyquinoloxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

FAB- MS

As): 432

_{Ή- NMR (300MHz, acetone- d 6} , δ ppm): 1.34 (6H, dt, J = 0.9,6 · 9Ηζ), 4.23 (4H, dq, J = 6.9,8.4Hz), 6.94 (lH, d, J = 8.1Hz), 7.24 (lH, s), 7.27 (lH, s), 7.30-7.40 (4H, m), 7.88 (2H, d, J = 9.0Hz)

 (51c) (E) -5- (3,4-Dihydroxyphenyl) -3- (4-phosphonooxybenzylidene) -2 (3H) -furanone

FAB- MS (m / z, as ^{_{+ (C, 7 H 13 0}} 8 P)): 376

FAB- MS (m / z, as _{+ (C 17 H 13 0 8} P + Na)): 399

 Ή-NMR (300 MHz, DMSO-06, (ppm): 7.21 (lH, s), 7.24 (lH, s), 7.24- 7.30 (4H, m), 7.81 (2H, d, J = 8.4 Hz), 8.84 (lH, dt, J = 7.8Hz) Example 52

 (E)-3- (4-Arinole-3-hydroxybenzylidene)-5- (3,4-dihydroxyphenyl)-2 (3H)-Furanone

High Resolution FAB- MS (m / z, as _{+ (C 20 H 16 O 5} )):

Calculated value: 336.0998 Measured Value: 336.1014

Ή-NMR (300MHz _f acetone-d _6> δ ppm): 3.43 (2H, brd, J = 6.6Ηζ), 5.03 (lH, ddt, J = 1.0, 1.8, 10, 2Hz), 5.10 (lH, ddt, J = 11.8, 11.8, 16.8Ηζ), 602 (lH, ddt, J = 6.6, 10.2, 16.8Hz), 6.95 (lH, d, J = 7.8Hz), 7.11 (lH, s), 7.18 (lH, s), 7.21 (lH, d, J = 7.8 Hz), 7.27 (lH, dd, J = 2.4, 7.8Ηζ), 7

(lH, dd, J = 1.5, 7.8 Hz), 7.32 (lH, d, J = 2.4 Hz), 7.33 (lH, d, J = 1.5 Hz)

 (E) -5- (3,4-dihydroxyphenyl) -3- "4-hydroxy-3- (4-piperidinopyridinopyrinopropyl) benzylidene]-2 (3H) -furanone formate Methanol adduct

High Resolution FAB- MS (m / z, as _{+ (C 28 H 3 .N 2} O 7 + H)):

 Calculated value: 507.2131

 Measured value: 507.2166

 Ή-NMR (300MHz, DMSO-d6, δ ppm): 1.30-1.60 (8H, m), 1.70-1.80 (2H, m), 2.30-3.10 (7H, m), 3.90-4.30 (2H, m), 6.83 (1 H, dt, J = 8.7

Hz), 6.97 (lH, d, J = 8.4 Hz), 7.14 (lH, s), 7.19-7.23 (2H, m), 7.26 (1H, s), 7.52 (lH, d, J = 1.8 Hz), 7.58 (lH.dd.J = 1.8, 8.4Hz)

 Example 54

 (E) -5- (3,4-dihydroxyphenyl) -3- "3-hydroxy-4- (4-piperidinopyridino dipropionyloxy) benzylidene: 1-2-(3H) -furanone

High Resolution FAB-MS (m / z, as _{+ (C 28 H 3 .N 2} 0 7 + H)):

 Calculated value: 507.2131

 Measured value: 507.2108

 Ή-NMR (300 MHz, DMSO-de, δ ppm): 1.50-1.80 (8H, m), 2.03-2.13 (2H, m), 2.80-3.50 (7H, m), 4.00 -4.40 (2H, m), 6.83 (lH, d, J = 8.7

Hz), 7.01 (lH, d, J = 8.4Hz), 7.15 (lH, s), 7.16-7.26 (2H, m), 7.25 (1H, s), 7.53 (lH, d, J = 1.8Hz), 7.61 (lH.ddJ = 1.8,8.7Hz)

 Example 55

(E) -5- (3,4-Dihydroxyphenyl) -3- "4-hydroxy-3- (4-methylpiperazinocarbonyloxy) __ benzylidene; I-2 (3H) -furanone FAB- MS (m / z, as ^{_{+ (C 2 3H 22 N 2}} 0 7 + H)): 439

Ή-NMR (300MHz, DMSO-d _6> δ ppm): 2.60 (3H, s), 2.90 (4H, brs), 3.70 (2H, brs), 3.90 (2H, brs), 6.83 (lH, d, J = 8.4Hz), 6.97 (lH, brs), 7.00 (lH, d, J = 8.7Hz), 7.18-7.36 (3H, m), 7.45 (lH, d, J = 2.1Hz), 7.49 (lH, dd , J = 2.1,8.4Hz)

 Example 56

 (E) -3- "4- (4-Carboxyphenylsulfonyloxy) benzylidene]--(3,4-dihydroxyphenyl) -2 (3H) -furanone

 High resolution FAB-MS (as mZz.CwHUOsS):

 Calculated value: 480.0515

 Measurement value: 480.0496

 Ή- NMR OOOMHz.acetone-de, δ ppm): 6.95 (lH.d.J = 8.3Hz), 7.13-

7.23 (2H, m), 7.22 (lH, s), 7.23 (lH, s), 7.30 (1H, dd, J = 2.2,8.3Hz), 7.35 (1H, d, J = 2.2Hz), 7.81 -7.91 (2H, m), 8.00-8.10 (2H, m), 8.25-8.35 (2H, m)

 Example 57

 (E) -5- (4- (4-Carboxyphenylsulfonyloxy) phenyl 1-3- (3,4-dihydroxybenzylidene) -2 (3H) -Branone

High Resolution FAB- MS (mZz, as ^{_{+ (C 24 H 16 O 9}} S)):

 Calculated value: 480.0515

 Measured value: 480.0499

_{Ή- NMR (300MHz, acetone- d 6} , δ ppm): 6.95 (lH'd'J = 8.3Ηζ), 7 · 14-

7.24 (2H, m), 7.24-7.32 (2H, m), 7.36 (lH, s), 7.42 (lH.s), 7.82 -7.92 (2H, m), 8.03 (2H, s), 8.29 (2H, m s)

 Example 58

 Mixture of (E) and (Z) -5- (3,4-dihydroxyphenyl) -3- (2-phenylmethylidene) -2 (3H) -furanone

Ή-NMR (300 MHz, acetone-d ₆ , δ ppm): 6.64 (3 / 19H, s), 6.95 (lH, d, J = 8.4 Hz), 6.99 (16Z19H.S), 7.15-7.33 (3H, m ), 7.48 (16 / 19H, s), 7.54 (3 / 19H, s), 7.67 (lH, d, J = 4.2Hz), 7.78-7.88 (lH.m) Example 59

 (E) and (Z)-A mixture of 5- (3,4-dihydroxyphenyl) -3- (4-phenoxybenzylidene) -2 (3H) -furanone

High Resolution _{FAB- MS (m / z ((} C 23 H 16 0 5 + H) as a ^+):

 Calculated value: 373.1076

 Measured value: 373.1094

_{Ή- NMR (300MHz, acetone- d 6} , δ ppm): 6.88- 7.51 (12H, m), 7.87

(1.3H, d, J = 9.1Hz), 8.25 (0.7HJ = 9.1Hz)

 Example 60

 (E) -5- (3,4-dihydroxyphenyl)-3- (3-phenoxybenzylidene)-

2 (3H)-furanone

High Resolution FAB- MS (mZz, as ^{_{+ (C 23 H 16 0 5}} )):

 Calculated value: 372.0998

 Measured: 372.0984

 Ή-NMR (300MHz, acetone-d6, δ ppm): 6.96 (lH.d.J = 8.2Hz), 7.0-

7.35 (8H, m), 7.35-7.63 (5H, m)

 Example 61.

 (E) -3- (3,4-dihydroxybenzylidene) -5- (3-phenoxyphenyl) -2 (3H) -furanone

High Resolution FAB- MS (mZz, as _{+ (C 23 H 16 0 5} )):

 Calculated value: 372.0998

 Measured: 372.0997

 Ή- NMR OOOMHz.acetone- de, δ ppm): 6.94 (lH, d, J = 8.4Ηζ), 7.02 / 7.23 (4H, m), 7.25-7.57 (8H, m), 7.65 (lH, m )

 Example 62

 (E) -3- (3,4-dihydroxybenzylidene) -5- (4-phenyloxyphenyl) -2 (3H) -furanone

High Resolution FAB-MS (mZz, as ^{_{+ (C 23 H 16 O 5}} )):

 Calculated value: 372.0998

Measured: 372.1026 Ή-NMR (300MHz, acetone-d ₆₎ δ ppm): 6.95 (lH, d, J = 8.2Hz), 7.04-

7.55 (llH'm), 7.83-7.93 (2H, m), 8.48 (2H, brs)

 Example 63

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone

FAB-MS (111-2, (0 _{18 4} 0 ₅ ) ⁺ ): 310

Ή-NMR (300 MHz, CD ₃ OD, 5 ppm): 2.27 (3H, s), 6.84 (lH'd'J = 8.4 Hz), 6.87 (lH, d, J = 8.4 Hz), 6.97 (lH, s ), 7.21 (lH, s), 7.22 (lH, dd, J = 1.8, 8.4Hz), 7.23 (lH, s), 7.46 (lH.dd.J = 1.8, 8.4Hz), 7.48 (lH.s) Example 64

 (E) -5- (3,4-dihydroxyphenyl)-3- (3-nitrobenzylidene)-2 (3H) -furanone

FAB- MS (m / z, as _{+ (C 17 H "N0 6} )): 325

Ή-NMR (300 MHz, CD ₃ OD, 6 ppm): 6.86 (lH.dJ = 7.8 Hz), 7.01 (1H, d, J = 1.2 Hz), 7.24 (lH, dd, J = 1.8, 2.7 Hz), 7.27 (lH.ddJ = 2.7,8.1

Hz), 7.33 (lH, s), 7.72 (lH, t, J = 8.1 Hz), 8.11 (lH, ddd, J = 1.2,1.8,7.8 Hz), 8.24 (lH, ddd, J = 1.2,2.1, 8.1 Hz), 8.48 (lH.dd, J = 2.1, 2.1Hz)

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-fluoro-4-hydroxybenzylidene) -2 (3H) -furanone

 Ή-NMR (300MHz, acetone-de, δppm): 6.94 (IH.dJ = 8.1Hz), 7.11 (lH, t, J = 8.9Hz), 7.20 (lH, s), 7.24 (lH, s), 7.31 (lH, dd, J = 1.8, 8.4 Hz), 7.36 (lH, d, J = 1.8 Hz), 7.54 (lH.dd.J = 2.1, 8.4 Hz), 7.65 (1H, dd, J = 2.3, 12.2Hz)

 Example 66

 (E) -5- (3,4-dihydroxyphenyl) -3- (2-fluoro-3-hydroxybenzylidene) -2 (3H) -furanone

FAB-MS (mZz, as ^{_{+ (C 17 H "F0 5}} )): 314

Ή-NMR (300 MHz, CD ₃ OD, 5 ppm): 6.85 (lH, d, J = 8.4Ηζ), 6 · 89 (1Η, s), 6.98 (lH, ddd, J = 1.8, 1.8, 8.4Hz) , 7.10 (lH, ddd, J = 1.2,1.2,6.8Hz), 7.20 (lH, d, J = 1.8Hz), 7.23 (lH.dd.J = 6.8,8.4Hz), 7.28 (IH.ddd, J = 1.2,1.8,6.8Hz), 7.40 (lH, s)

 Example 67

 (E)-5- (3,4-dihydroxyphenyl)-3- (2,3-dimethyl-4-methoxybenzylidene)-2 (3H)-Furanone

 FAB-MS (as mZz CsoHwOs): 338

Ή-NMR (300 MHz, CD ₃ OD, <5 ppm): 2.19 (3H, s), 2.35 (3H, s), 3.88 (3H, s), 6.78 (lH, d, J = 1.8 Hz), 6.82 ( lH, d, J = 7.0 Hz), 6.94 (lH, d, J = 8.7 Hz), 7.16 (lH, s), 7.18 (lH, dd, J = 1.8, 8 JHz), 7.58 (lH, s), 7.59 (IH, dj = 7.0Hz)

 Example 68

 (E) -5- (3,4-dihydroxyphenyl)-3- (4-hydroxy-3-nitrobenzylidene) -2 (3H) -furanone

 Ή-NMR (300 MHz, acetone-de, δ ppm): 7.00 (lH, d, J = 8.8Ηζ), 7 · 28 (lH, d, J = 8.8 Hz), 7.23- 7.38 (2H, m), 7.52 (lH'dd.J = 2.2, 8.8Hz),

7.65 (lH, d, J = 2.2Hz), 8.51 (lH, dd, J = 2.2,8.8Hz), 9.22 (IH.dJ = 2.2Hz)

 Example 69 '

 (E)-5- (3,4-dihydroxyphenyl)-3- (2,3-dimethyl-4-hydroxybenzylidene)-2 (3H)-Furanone

 FAB-MS (as !!!!!, ^^^): 324

Ή-NMR (300 MHz, CD ₃ OD, δ ppm): 2.18 (3H, s), 2.33 (3H, s), 6.76 (IH, d, J = 7.0 Hz), 6.77 (lH, d, J = 1.8 Hz) ), 6.82 (IH.dJ = 8.7Hz), 7.15 (IH, s), 7.16 (lH, dd, J = 1.8,8.7Hz), 7.46 (lH, d, J = 7.0Hz), 7,58 (lH .s) Example 70

 (E)-5- (3,4-dihydroxyphenyl)-3- (2-fluoro-5-hydroxybenzylidene) -2 (3H)-Furanone

High Resolution FAB-MS (mZz, as _{+ (C 17 H "F0 5} )):

 Calculated value: 314.0591

Measured value: 314.0589 NMR-NMR (300 MHz, acetone-d ₆ , δ ppm): 6.96 (lH.dJ = 8.2 Hz), 6.90- 6.99 (lH, m), 7.06-7.14 (lH, m), 7.10 (lH, brs), 7.30 (lH, d, J = 2.3 Hz), 7.33 (lH, brs), 7.39 (lH.dJ = 2.3 Hz), 7.37-7.44 (lH, m) Example 71

 (E) -5- (3,4-Dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -Furanone

 Ή-NMR (300MHz, acetone-d6, <5 ppm): 2.25 (3H, s), 2.37 (3H, s), 6.79 (lH, s), 6.93 (lH, d, J = 8.1Hz), 7.08 ( lH, s), 7.26 (lH, dd, J = 2.1,8.1 Hz), 7.30 (lH, d, J = 2.1Hz), 7.44 (lH, s), 7.67 (lH, s)

 Example 72

 (E) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxy mouth xyphenyl) -2 (3H) -furanone

 FAB-MS (!!!!! ??? ^): 332

Ή-NMR (300 MHz, CD ₃ OD, S ppm): 6.81-6.83 (lH, m), 6.85 (lH, d, J = 4.5 Hz), 6.92 (lH, s), 7.21 (lH, s), 7.22 (lH, dd, J = 2.7,8.8Hz), 7.31

(lH, s), 7.48- 7.58 (lH.m)

 Example 73

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxy-4-trifluoromethylbenzylidene)-2 (3H) -furanone

 NMR-NMR (300 MHz, acetone-de, δ ppm): 6.92 (lH, d, J = 8.3Ηζ), 7.15

(lH, s), 7.25 (lH, dd, J = 2.3, 6.0 Hz), 7.34 (lH, d, J = 2.3 Hz), 7.32 to 7.37 (lH, m), 7.55 (lH, brs), 7.59 ( lH.dJ = 8.3Hz)

 Example 74

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-propylbenzylidene) -2 (3H) -furanone

High Resolution FAB- MS (m / z, as C ₂ .H ₁₈ 0 _5):

 Calculated value: 338.1154

 Measured: 338.1139

Ή-NMR (300MHz, acetone- ά ^, δ ppm): 0.97 (3H, t, J = 7.3Hz), 1.68 (2H, tq, J = 7.3,7.3Hz), 2.67 (2H, t, J = 7.3Hz) Hz), 6.93 (lH.dJ = 8.3Hz), 6.96 (lH, brd, J = 8.3Hz), 7.16 (lH, d, J = 0.9Hz), 7.21 (lH, brs), 7.26 (lH, dd, J = 2.1,8.3Hz), 7.31 (lH, d , J = 2.0Hz), 7.55- 7.62 (3H, m)

 (E) -3- (3,5-Dimethyl-4-hydroxybenzylidene) -5- (3,4-Dihydroxybenzyl) -2 (3H) -furanone

 FAB-MS (as mZz dsHwOs): 324

 Ή-NMR (300MHz, acetone-de, δ ppm): 2.32 (6H, s), 6.93 (lH, d, J = 8.4Hz), 7.17 (lH, s), 7.20 (lH, d, J = 1.2Hz ), 7.26 (lH.dd.J = 1.8,8.4 Hz), 7.32 (lH, d, J = 1.8 Hz), 7,50 (2H, s), 8.00 (lH, s), 8.25 (lH.brs) , 8.5 & (lH'brs)

 Example 76

 (E) -3- (3,5-ditert-f ', tinole-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

FAB-MS (mZz, as ^{_{+ (C 25 H 28 0 5}} )): 408

 Ή-NMR (300MHz, acetone-de, δ ppm): 1.35 (18H, s), 6.94 (lH.d.J =

1.5Hz), 6.97 (lH, d, J = 1.2Hz), 7.21 (2H, s), 7.25 (lH, dd, J = 2.1,8.4Hz), 7.29 (lH, s), 7.51 -7.61 (2H, m), 7.62 (lH, s), 7.94 (lH.s) Example 77

 (E) -5- (4,5-dihydroxy-2-methylphenyl) -3- (4-hydroxy-3- · methylbenzylidene) -2 (3H) -furanone

Ή-NMR (300 MHz, acetone-d6 + CDC13 ₍ δ ppm): 2.25 (3H, s), 2.43 (3H, s), 6.77 (lH, s), 6.79 (lH, s), 6.92 (lH, d , J = 7.8 Hz), 7.20 (lH, s), 7.22 (lH, s), 7.46 (lH, dd, J = 2.4, 7.8 Hz), 7.50 (lH.s)

 Example 78

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxy-4-methylbenzylidene) -2 (3H) -furanone

 Ή-NMR (300MHz, acetone-d6, (5ppm): 2.21 (3H, s), 6.91 (lH.d.J =

(8.3Hz), 7.08- 7.38 (7H, m)

 Example 79

XE) -5-(^ _ 4-dihydroxy 2- 2-methynolephen-2-le) 1--(4-hydroxy -3- Methylbenzylidene)-2 (3H)-Furanone

Ή-NMR (300MHz, acetone-d ₆ -CDCl _{3 (} δ ppm): 2.26 (3H, s), 2.44 (3H, s), 6.81 (lH, d, J = 8.4Hz), 6.88 (lH, s) , 6.96 (lH.dJ = 8.1Hz), 7.13 (lH, d, J = 8.4Hz), 7.22 (lH, s), 7.55 (lH, dd, J = 2.1,8.4Hz), 7.58 (IH, S)

 Example 80

 (E)-5- (3,4-dihydroxyphenyl)-3- (3-ethyl-4-hydroxybenzylidene)-2 (3H)-Furanone

High Resolution FAB- MS (m / z, as _{+ (C 19 H 16 0 5} )):

 Calculated value: 324.0998

 Measured Value: 324.1006

 Ή-NMR (300MHz, acetone-d6, δ ppm): 1.24 (3H, t, J = 7.5Hz), 2.71 (2H, q, J = 7.5Hz), 6.93 (lH, d, J = 8.1Hz), 6.97 (lH, d, J = 8.7 Hz), 7.17 (lH, s), 7.22 (lH, s), 7.26 (lH.ddJ = 2.4, 8.4 Hz), 7.32 (lH, d, J = 1.8 Hz), 7.57 (lH, dd, J = 2.1,8.4Hz), 7.62 (lH, d, J = 2.1Hz)

 Example 81

 (E) -3- (3,4-dihydroxybenzylidene) -5- (2,3,4-trihydroxyphenyl) -2 (3H) -furanone

High Resolution FAB- MS (mZz, as ^{_{+ (C 17 H 12 0 7}} )):

 Calculated value: 328.0583

 Measured: 328.0589

Ή-NMR (200 MHz, CD ₃ OD, δ ppm): 6.42 (lH, d, J = 8.7 Hz), 6.83 (IH, d, J = 8.1 Hz), 7.05 (lH, d, J = 8.7 Hz), 7.06 (lH, dd, J = 2.0,8.1Hz), 7.12 (lH, s), 7.18 (lH, d, J = 2.0Hz), 7.25 (lH.dJ = 0.9Hz)

 Example 82

 (E) -3- (4-Hydroxy-3-methylbenzylidene) -5- (3-Hydroxyphenyl) -2 (3H) -Furanone

FAB- MS (m / z, as _{+ (C 18 H 14 0 4} )): 294

Ή-NMR (300 MHz, DMSO-d6, δ ppm): 2.19 (3H, s), 6.79-6.89 (lH, m), 6.88 (lH, d, J = 8.7 Hz), 7.16--7.26 (lH, m) , 7.24 (lH, s), 7.29 (lH.t, J = 7.8Hz), 7.28-7.38 (lH, m), 7.51 (lH, s), 7.59 (lH.ddJ = 2.0,8.7 Hz), 7.65 (lH, d, J = 2.0Hz), 9.72 (lH.m) brs), 10.30 (lH.brs) Example 83

 (E)-3- (3-hydroxybenzylidene)-5- (3-hydroxyphenyl)-2 (3H)-furanone

 FAB-MS (as !!!! ^? ^): 280

FAB- MS

+ H) +): 281

Ή-NMR (300MHz, CD ₃ OD, δ ppm): 6.94-6.99 (2H, m), 7.31-7.41 (8H, m), 8.68 (2H, brs)

 Example 84

 (E) -3- (3-Fluoro mouth-4-hydroxybenzylidene) -5- (3-hydroxyphenyl) -2 (3H) -furanone

FAB- MS (mZz, as _{+ (C 17 H "F0 4} )): 298

 NMR-NMR (300 MHz, acetone-d6, δ ppm): 6.95 (lH, ddd, J = 1.2, 2.4, 7.8 Hz), 7.13 (lH, t, J = 8.8 Hz), 7.30 (lH, s), 7.28 -7.38 (2H, m), 7.40 (1H, dt, J = 1.2, 7.5Hz), 7.44 (lH, s), 7.53-7.63 (lH, m), 7.70 (lH, dd, J =

2.1, 12.3Hz), 8.64 (lH, br), 9.42 (lH, brs)

 Example 85

 Mixture of (E) and (Z) -3- (3,4-dihydroxybenzylidene) -5- (3-fluoro-4-hydroxybenzyl) -2 (3H) -furanone

High Resolution FAB-MS (mZz, as ^{_{+ (C 17 H "F0 5}} )):

 Calculated value: 314.0591

 Measured: 314.0573

 Ή-NMR (300 MHz, acetone-de, δ ppm): 6.83 + 6.94 (lH.dx 2, J = 8.3 Hz), 7.12 (lH, t, J = 8.5 Hz), 7.20 (lH, s), 7.25 ( lH, dd, J = 2.2,8.3Hz),

7.30 (lH, s), 7.38 (lH, d, J = 2.2Hz), 7.51 -7.57 (lH, m), 7.64 (lH, dd,

J = 2.2, 12.2Hz)

 Example 86

(E)-3- (3.4-dihydroxybenzylidene)-5- (3-hydroxy-4-methylphenyl)-2 (3H) -furanone High Resolution FAB- MS (mZz, as ^{_{+ (C 18 H "0 3}} )): 310 Calculated: 310.0841

 Measurement value: 310.0842

 Ή-NMR (300 MHz, acetone-de, <5 pm): 2.25 (3H, s), 6.94 (lH, d, J = 8.2 Hz), 7.19-7.23 (3H, m), 7.25 (1H, dd, J = 2.2, 8.2Hz), 7.29 (1H, dd,

J = 1.4, 5.5Hz), 7.32 (lH, d, J = 1.4Hz), 7.37 (lH, d, J = 1.9Hz)

 Synthesis of (E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -furanone

 (a) Synthesis of (E) -3- (3,4-diacetoxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -furanone

 100 mg of 3- (3,4-dimethoxybenzoyl) propionic acid, 70 mg of 3,4-dihydroxybenzaldehyde and 34.4 mg of sodium acetate are suspended in 0.2 ml of acetic anhydride and stirred at 80 ° C for 20 minutes. A small amount of methanol is added to the reaction mixture, and the precipitated yellow solid is collected by filtration. The obtained solid is washed with a small amount of methanol, and 96.1 mg of (E) -3- (3,4-diacetoxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -furanone is obtained. Obtained as a solid.

 Rf value: 0.31 (hexane: ethyl acetate = 1: 1)

FAB- MS (mZz, as ^{_{+ (C 23 H 20 O 8}} )) 424

 (b) Synthesis of (E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -furanone

 Dissolve 30 mg of (E) -3- (3,4-diacetoxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -furanone in 7 ml of acetone and stir at room temperature with 25% ammonia. Add 0.34 ml of Nya water. After stirring at room temperature for 3 hours, adjust the pH of the reaction solution to 2 with 2N hydrochloric acid at 0 ° C. After diluting the reaction solution with 50 ml of ethyl acetate and separating, the ethyl acetate layer is washed with water and the organic layer is concentrated under reduced pressure. The residue is purified by Sephadex ™ LH20 column chromatography (methylene chloride: methanol: ethanol: water = 5: 2: 2: 1) to give 24.7 mg of the title compound as a red-yellow solid.

High resolution FAB-MS (as mZz, C〗 ₉ H〗 ₆ Os):

Calculated value: 340.0947 Measured: 340.0935

 Ή-NMR (300MHz, acetone-d6, δ ppm): 3.88 (3H, s), 3.89 (3H, s), 6.94 (lH, d, J = 8.2Hz), 7.07 (lH, d, J = 8.9Hz) ), 7.18 (lH, s), 7.24 (lH'dd, J = 1.9,8.2Hz), 7.28 (lH, d, J = 0.9Hz), 7.33 (lH, d, J = 1.9Hz), 7.40-7.48 (2H, m), 8.29 (lH, s), 8.76 (lH, s)

 The compounds of Examples 88 to 90 were synthesized in the same manner as in Example 87.

 Example 88

 (E) -3- (3,4-dihydroxybenzylidene) -5- (4-methoxyphenyl) -2 (3H) -furanone

High Resolution FAB- MS (m / z, as _{+ (C 18 H 14 0 5} )):

 Calculated value: 310.0841

 Measured: 310.0859

 NMR-NMR (300MHz, acetone-de, δ ppm): 3.88 (3H, s), 6.94 (lH.dJ = 8.4Ηζ), 7.05 (2H, d, J = 8.4Hz), 7.19 (lH, s ), 7.22 (lH, s), 7.25 (1H, ddj = 1.8, 8.4 Hz), 7.34 (lH.dJ = 1.8 Hz), 7.81 (2H, d, J = 8.4 Hz)

 3- (4-Hydroxy-3-methoxybenzoinole) propionic acid was condensed with 3,4-dihydroxybenzaldehyde in the same manner as in Example 87 to give (E) -5- (4-acetoxy-3 -Methoxyphenyl) -3- (3,4-diacetoxybenzylidene) -2 (3H) -furanone, which was similarly treated with aqueous ammonia to give (E) -5- (4 -Acetoxy-3-methoxyphenyl) -3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone (compound 89a) and (E) -3- (3,4-dihydroxybenzylidene) -5- (4-Hydroxy-3-methoxyphenyl) -2 (3H) -furanone (Compound 89b) is obtained.

 89a (E) -5- (4-acetoxy-3-methoxyphenyl)-3- (3,4-dihydroxy benzylidene)-2 (3H) -furanone

High Resolution FAB- MS (111 Bruno 2,0: ₂ .¾ ₆ 0 ₇₎ as ^+):

 Calculated value: 368.0896

 Measured: 368.0878

Ή-NMR (200MHz, acetone-d6, δ ppm): 2.27 (3H, s), 3.91 (3H, s), 6.95 (lH, d, J = 8.3Hz), 7.18 (lH.dJ = 8.2Hz), 7.26 (lH, dd, J = 1.9,8.1Hz), 7.26 (lH, s), 7.34 (lH, d, J = 1.9Ηζ), 7 · 42 (lH, s), 7.47 (lH, dd, J = 1.9, 8.3Hz), 7.56 (lH, d, J = 1.8Hz)

 89b (E) -3- (3,4-dihydroxybenzylidene) -5- (4-hydroxy-3-methoxyphenyl) -2 (3H) -furanone

High Resolution FAB- MS (mZz, as ^{_{+ (C 18 H "0 6}} )):

 Calculated value: 326.0790

 Measured: 326.0804

 Ή-NMR (200 MHz, acetone-de, δ ppm): 3.93 (3H, s), 6.93 (lH, d, J = 8.3Hz), 6.94 (lH, d, J = 8.3Hz), 7.16 (lH, s ), 7.23 (lH, dd, J = 2.0,8.3

Hz), 7.24 (lH, s), 7.32 (lH, d, J = 2.0Hz), 7.39 (lH.ddJ = 1.9,8.3Hz), 7.45 (lH, d, J = 1.9Hz)

 Example 90

 (E) -5- (4-Hydroxy-3-methoxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone

High Resolution FAB-MS (mZz, as ^{_{+ (C 19 H 16 0 5}} )):

 Calculated value: 324.0998

 Measured Value: 324.1006

 Ή-NMR (300MHz, acetone-d6, δ ppm): 2.26 (3H, s), 3,93 (3H, s), 6.94 (lH, d, J = 8.1Hz), 6.95 (lH, d, J = 8.3Hz), 7.21 (lH, s), 7.28 (lH, d, J =

0.9Hz), 7.38 (lH, dd, J = 2.0, 8.1Hz), 7.41 (lH, d, J = 2.0Hz), 7.55 (1H, dd, J = 2.4, 8.3Hz), 7.62 (lH, d, (J = 2.4Hz), 8.24 (lH, s), 9.00 (lH.s)

 Synthesis of (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methoxybenzylidene) -2 (3H) -furanone

5- (3,4-Diacetoxyphenyl) -2 (3H) -furanone 110 mg, sodium sulphate 41 mg and 4-hydroxy-3-methoxybenzaldehyde 61 mg obtained in Reference Example 4 were added to acetic anhydride 2 ml. Dissolve and stir at 8 CTC for 30 minutes. 5 ml of methanol is added to the reaction mixture, and the precipitated yellow solid is collected by filtration. The obtained solid is washed with a small amount of methanol, and (E) -5- (3,4-acetoxyphenyl) -3- (4-hydroxy- There was obtained 35 mg of 3-methoxybenzylidene) -2 (3H) -furanone, which was deacetylated with aqueous ammonia in acetone in the same manner as in Example 87- (b) to give the title compound.

 FAB-MS (as !!!! no ^^): 326

 Ή-NMR (200MHz, acetone- de, <5 ppm): 4.00 (3H, s), 6.90 -7.00 (2H, m), 7.13-7.44 (6H, m)

 Example 92

 As in Example 91, the compound was synthesized from 5- (3,4-diacetoxyphenyl) -2 (3H) -furanone and 4-hydroxy-3-hydroxymethylbenzaldehyde.

 (E) -3- (3-Acetoxymethyl-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

FAB-MS

As): 368

FAB-MS (as mZz CsoHwO? + Na) ⁺ ): 391

Ή-NMR (300MHz, acetone-d ₆ , <5 ppm): 2.09 (3H, s), 5.19 (2H, s), 6.94 (lH, d, J = 8.4Hz), 7.04 (lH, d, J = 8.7Hz), 7.17 (lH, s), 7.23 (lH, s),

7.26 (lH, dd, J = 1.8, 8.4Hz), 7, 32 (lH, d, J = 1.8Hz), 7.72 (lH.dd.J = 2.4,8.4Hz), 7.81 (lH.d, J = 2.1Hz), 8.30 (lH, brs), 8.64 (lH, brs), 9.35 (lH, brs)

 Example 93

 (E) -3- (3-acetoxy) obtained by condensing 5- (3,4-diacetoxyphenyl) -2 (3H) -furanone and 3-hydroxy-4-methoxybenzaldehyde in the same manner as in Example 91. -4-Methoxybenzylidene) -5- (3,4-diacetoxyxyphenyl) -2 (3H) -furanone was similarly deprotected to give the compound (E) -3- (3-acetoxy-

4-Methoxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone (93a) and (E) -5- (3,4-dihydroxyphenyl)- 3- (3-hydroxy-

4-methoxybenzylidene)-2 (3H) -furanone (93b) is obtained.

 93 (a) (E) -3- (3-Acetoxy—4-methoxybenzylidene) — 5- (3,4-dihydroxyphenyl) -2 (3H) -furanone

High Resolution FAB-MS (mz, as C ₂₀ H _l6 O _7):

Calculated value: 368.0906 Measurement value: 368.0901

 Ή-NMR (200MHz, acetone-d6, δ ppm): 2.28 (3H, s), 3.92 (3H, s), 6.94 (lH, d, J = 8.3Hz), 7.16 (1H .J = 1.0Hz), 7.22 (lH, s), 7.22 (lH.dJ = 8.5Hz), 7.27 (lH, dd, J = 2.0,8.3Hz), 7.31 (lH.d, J = 2.0Hz), 7.61 (1H, d, J = 1.9Hz), 7.72 (lH.dd.J = 2.2, 8.5Hz)

 93 (b) (E) -5- (3,4-Dihydroxyphenyl) -3- (3-hydroxy-4-methoxybenzylidene) -2 (3H) -Furanone

High resolution FAB-MS (as m / z, (C _I8 H "0 ₆ ) +):

 Calculated value: 326.0790

 Measured: 326.0802

NMR-NMR (300 MHz, acetone-d ₆ , δ ppm): 3.93 (3H, s), 6.94 (lH.dJ = 8.1 Hz), 7.06 (lH, d, J = 8.1 Hz), 7.13-7.23 (2H, m), 7.31 (lH.dd.J = 1.8, 8.1 Hz), 7.31 (lH.dd.J = 2.4, 8.1 Hz), 7.34 (lH.dJ = 2.4 Hz), 7.35 (lH, d, J = 1.8 Hz), 7.97 (lH, s), 8.28 (lH, s), 8.61 (lH, s)

 Example 94

 Synthesis of (E) -3- (3,4-dihydroxybenzylidene) -5- (4-formylphenyl) -2 (3H) -furanone

 (a) A suspension of 300 mg of 4-formylbenzoic acid in 6 ml of anhydrous methylene chloride and 3 ml of anhydrous THF is added with 0.24 ml of 1,3-propanedithiol and 41 ml of boron trifluoride dimethyl ether complex. After stirring at room temperature for 20 hours, dilute the reaction solution with 50 ml of ethyl acetate. The organic layer is washed with 1N hydrochloric acid, water, and then with a saturated saline solution, and dried over anhydrous sodium sulfate. The colorless solid obtained by distilling off the solvent is washed with ether and dried under reduced pressure to obtain 435 mg of 4- (1,3-dithian-2-yl) benzoic acid as a colorless solid.

 Melting point: 202 ° C,

 Rf value: 0.47 (silica gel plate, black form: methanol: acetic acid = 50:

 5: 2)

FAB-MS (m / z (as _{C "H 12 0 2 S 2} + H) +): 241

IR (KBr.cm " ¹ ): 1667

(b) Dissolve 201 mg of 4- (1,3-dithiane-2-inole) benzoic acid in 5 ml of anhydrous THF And add 150 mg of CDI. After stirring at room temperature for 2 hours, 262 mg of monoethyl ester malonate 1Z2 magnesium salt was added, and after stirring at room temperature for 15 hours, the reaction solution was concentrated under reduced pressure.The resulting residue was dissolved in 40 ml of ethyl acetate, and 1N hydrochloric acid, water and saturated solution were added. Wash with aqueous sodium bicarbonate solution and saturated saline. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure, and the crude crystal obtained is washed with n-hexane and dried under reduced pressure to obtain 231 mg of 4- (1,3-dithian-2-yl) benzoyl acetic acid ethyl ester.

 Rf value: 0.35 (silica gel plate, n-hexane: ethyl acetate = 3: 1)

(c) Under an argon atmosphere, 31.2 mg of sodium hydride (60% mineral oil suspension) is washed with n-pentane, and suspended in 1 ml of anhydrous THF. Add a solution of 225 mg of 4- (1,3-dithian-2-yl) benzoinoleacetic acid ethyl ester in 1 ml of anhydrous THF and heat to reflux for 1 hour. The reaction solution is cooled to 0 ° C, 2 ml of ethyl bromoacetate is added with stirring, and the mixture is refluxed for 1 hour. The insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue obtained is dissolved in ether and washed with 1N hydrochloric acid, water and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 2- [4- ( 1,3-Dithiane-2-inole) benzoyl] 268 mg of getylester succinate as a colorless oil.

FABMS: (m / z (C 19 H 24 0 5 S 2) as a +): 396

_{(m / z (C 19 H} 24 0 5 S 2 + Na) as +): 419

 Rf value: 0.23 (silicone gel plate, n-hexane: ethyl acetate = 3: 1)

IR (neat) cm— ¹ : 1737,1692

 (d) To 56.8 mg of getyl ester 2- [4- (1,3-dithian-2-yl) benzoyl] is added 0.5 ml of concentrated hydrochloric acid, and the mixture is heated under reflux for 22 hours. After cooling to room temperature, the precipitated colorless solid was separated by filtration, washed with water, dried at 30 ° C under reduced pressure, and 36.9 mg of 3- [4- (1,3-dithian-2-yl) benzoyl] propionic acid was colorlessly purified. Obtained as a solid. Melting point: 154 ° C

 Rf value: 0.26 (silica gel plate, n-hexane: ethyl acetate: acetic acid = 25:

 25: 1)

As _{C 14 H 16 S 2 0 3} : Elemental analysis:

Calculated value C56.73.H5.44 Measured value C57.36.H5.68

High resolution FABMS (as m / z (C "H ₁₆ 0 ₃ S ₂ + H) ⁺ ):

 Calculated 297.0597

 Measured value 297.0619

IR (KBr) cm- ¹ : 1722, 1680

 (e) Suspension of 161.8 mg of 3- [4- (1,3-dithian-2-yl) benzoyl] propionic acid and 187.lmg of veratraldehyde in 1.6 ml of acetic anhydride was added to sodium hydride (60% mineral oil suspension). Add 24 mg of the mixture under stirring at room temperature, stir for 1 hour, and heat to reflux for 2 hours. After further stirring at room temperature for 15 hours, the reaction solution is separated with water and ethyl acetate, and the organic layer is washed with water, a 2N aqueous solution of sodium carbonate and then with a saturated saline solution, and then dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel gel chromatography (n-hexane: ethyl acetate = 5: 1) to obtain (E) -5- [4- (1,3- 57.8 mg of dithian-2-yl) phenyl] -3- (3,4-dimethoxybenzylidene) -2 (3H) -furanone are obtained as a yellow solid.

 Melting point: 180-181 ° C

Rf value: 0.24 (silica gel plate, hexane n-: acetate Echiru = 1: 1) High resolution FABMS: (m / z (C 23 H 22 0 4 S 2) as a +)

 Measured value 426.0985

 Calculated 426.0963

IR (KBr) cm- ¹ 1767

(f) (E) -5- [4- (1,3-Dithian-2-yl) phenyl] -3- (3,4-dimethoxybenzylidene) -2 (3H) -furanone 24.4 mg anhydrous Dissolve it in 2 ml of dichloromethane, and add 0.6 ml of 1M boron tribromide anhydrous methylene chloride solution with stirring at -78 ° C. After returning to room temperature with stirring for 15 hours, the mixture is cooled again to -78 ° C and 1 ml of anhydrous methanol is added. After returning to room temperature, the reaction solution is separated with 40 ml of ethyl acetate and 0.01N hydrochloric acid, and the organic layer is washed with water and then with a saturated saline solution and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by Sephadex ™ LH20 column chromatography (methanol), and purified by (E) -5- [4- (1,3-dithian-2-yl) phenyl ]-19.7 mg of 3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone are obtained as a yellow solid. FABMS: (as m / z (C ₂₁ H ₁₈ 〇 ₄ S ₂ )) 398

 Rf value: 0.36 (silica gel plate, black mouth form: methanol: formic acid =

 100: 10: 10)

 IR (KBrcm- '): 1749

 (g) (E) -5- [4- (1,3-dithian-2-yl) phenyl] -3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone 16.8 mg of THFlml To the solution are added a solution of 19 mg of silver arsenic acid and 0.2 ml of a 15% aqueous THF solution of boron trifluoride getyl ether complex 251, and the mixture is stirred at room temperature for 1.5 hours. 2 ml of ether was added to the reaction solution, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by Sephadex ™ LH20 column chromatography (methanol) and (E) -5- (4-formylphenyl) -3- (3,4-dihydroxybenzylidene) -2 (3H)- 8.0 mg of furanone are obtained as a yellow solid.

 Rf value: 0.33 (silica gel plate, black form: methanol: formic acid =

 100: 10: 10)

High Resolution FAB- MS (mZz, as ^{_{+ (C 18 H I2 0 5}} )):

 Calculated value: 308.0685

 Measured: 308.0675

 IR (KBr, cm—: 3269,1755,1692

Ή-NMR (300 MHz, acetone ₆ + CD ₃ OD, δ ppm): 6.88 (lH, d, J = 7.3 Hz), 7.25 (lH, dd, J = 1.4 Hz, 7.3 Hz), 7.27 (lH, d, J = 1.4Hz), 7.32 (lH.s),

7.51 (lH, s), 7.95- 8.05 (4H, m), 10.01 (lH, s)

 Example 95

 Synthesis of (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-hydroxymethylbenzylidene) -2 (3H) -furanone

(a) 5 g of 5-formylzalitinoleic acid is suspended in 100 ml of anhydrous methylene chloride, and 2.81 ml of 1,3-propanedithiol is added. Further, under stirring at 0 ° C, boron trifluoride dimethyl ether complex 703-1 is added, and the temperature is gradually returned to room temperature. After stirring for 15 hours, insoluble materials are collected by filtration. The solid collected by filtration is washed with methylene chloride and methanol to give 4.72 g of 5- (1,3-dithian-2-inole) salicylic acid as a colorless solid. The filtrate and the washings were combined, concentrated under reduced pressure, methanol was added to the residue, and the insolubles were collected by filtration. The solid collected by filtration was washed with methanol and dried under reduced pressure to give 2.07 g of 5- (1,3-dithian-2-yl) salicylic acid.

 Rf value: 0.40 (silica gel plate, methylene chloride: methanol: formic acid =

 100: 5: 1)

(b) 1.12 _g of lithium aluminum hydride was suspended in 45 _ml of anhydrous THF, and a solution of 4.72 g of 5- (1,3-dithian-2-inole) salitinoleic acid in 45 ml of anhydrous THF was added thereto while stirring at room temperature, followed by heating under reflux for 2 hours. Then, the mixture is cooled on ice, and 800 ml each of water and ethyl acetate and 200 ml of 2N hydrochloric acid are slowly added. The organic layer is washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained solid, and the insolubles were collected by filtration, washed with n-hexane and dried under reduced pressure, and 1.73 g of 5- (1,3-dithian-2-yl) salicyl alcohol was obtained as a colorless solid. obtain. The filtrate and the washing solution are combined, concentrated under reduced pressure, and the same operation is repeated to further obtain 2.05 g of the same compound.

 Rf value: 0.56 (silica gel plate, methylene chloride: methanol = 5: 1)

(c) Dissolve 5- (1,3-dithian-2-yl) salicyl alcohol l.OOg in 25 ml of anhydrous DMF, and stir at room temperature under stirring at room temperature, 1.24 ml of 1, dimethoxin chlorohexane, pyridinium p-toluenesulfonate Add 207 mg of salt and stir at room temperature for 15 hours and at 60 ° C for 1 hour. Pour the reaction mixture into 150 ml of water and extract with ethyl acetate (150 ml, 100 ml). The ethyl acetate layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1). This gives 1.30 g of 6- (1,3-dithyn-2-yl) benzo-1,3-dioxane-2-spiro-cyclohexane as a colorless oil.

 Rf value: 0.50 (silica gel plate, n-hexane: ethyl acetate = 4: 1)

(d) 6- (1,3-Dithian-2-yl) benzo-1,3-dioxane-2-spiro-cyclo 1.30 g of mouth hexane was dissolved in 50 ml of acetone. Under C stirring, 3.33 g of N-bromosuccinic acid imide and 20 ml of a 90% acetone aqueous solution are added. After stirring at 0 ° C for 5 minutes, 20 ml of a 10% aqueous sodium bisulfite solution is added, and the reaction solution is concentrated under reduced pressure. The residue is dissolved in 150 ml of ethyl acetate, and the ethyl acetate layer is washed with 5% aqueous sodium hydrogen carbonate solution and saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel gel chromatography (n-hexane: Ethyl succinate = 5: 1) to give 6-formylbenzo-1,3-dioxane-2-spiro-cyclohexane 8 mg as a colorless oil.

 Rf value: 0.45 (silica gel plate, n-hexane: ethyl acetate = 4: 1)

(e) 6-formylbenzo-1,6-dioxane-2-spiro-cyclohexane 60.3 mg, 5- (3,4-diacetoxyphenyl) -2 (3H) -furanone 47.8 mg and acetic acid suspended sodium 14.2mg acetic anhydride 0.1 ml, stirred for 3 hours at 80 ^e C. Dilute the reaction solution with 40 ml of ethyl acetate, and wash the ethyl acetate layer with water and saturated saline. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give (E) -5- (3, 4-Diacetoxyphenyl) -3-[(benzo-1,3-dioxane-2-spiro-cyclohexane-6-yl) methylidene] -2 (3H) -furanone 20.3 mg red Obtained as a yellow oil.

 Rf value: 0.64 (silica gel plate, n-hexane: ethyl acetate = 1: 1)

(f) (E) -5- (3,4-Diacetoxyphenyl) -3-[(benzo-1,3-dioxane-2-spiro-cyclohexane-6-yl) methylidene]- Dissolve 12.7 mg of 2 (3H) -furanone in 1 ml of acetone, add 39 ml of 25% aqueous ammonia with stirring at room temperature, and stir at room temperature for 2 hours. Adjust the pH of the reaction solution to 2 with 2N hydrochloric acid while stirring at 0 ° C, and stir at room temperature for an hour. Further, 0.1 ml of 2N hydrochloric acid was added, and the mixture was stirred at 50 ° C for 3 hours. The reaction solution was diluted with 20 ml of ethyl acetate, the ethyl acetate layer was washed with water, concentrated under reduced pressure, and the residue was subjected to Sephadex ™ LH20 column chromatography. Purification by chromatography (methylene chloride: methanol: ethanol: water = 5: 2: 2: 1) yields (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-hydroxy 1.6 mg of methylbenzylidene) -2 (3H) -furanone are obtained as a red-yellow solid.

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-hydroxymethylbenzylidene) -2 (3H) -furanone

High Resolution FAB-MS (mZz, as + (C ₁₈ H 〇 _6)):

 Calculated value: 326.0791

 Measured: 326.0810

Ή-NMR (200 MHz, acetone-de, δ ppm): 4.58 (lH.tJ = 5.7 Hz), 4.81 (lH, d, J = 5.7 Hz), 6.93 (lH, d, J = 8.3 Hz), 6.95 (lH, d, J = 8.3 Hz) lH, d, J = 8.4Hz), 7.15 (lH, d, J = 0.9Hz), 7.23 (lH, s), 7.26 (lH.dd.J = 2.0, 8.3Hz), 7.63 (1H, dd, J = 2.0, 8.4Hz), 7.79 (lH. d, J = 2.0 Hz), 8.35 (lH, s), 8.65 (lH, s), 9.17 (lH, s)

 Example 96

 Synthesis of (E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenone

 (a) Dissolve 3- (3,4-dimethoxybenzoyl) propionic acid (lg), pyridine (7.7 ml) and dinitropentasulfide (1.03 g) in chloroform (10 ml) and heat to reflux for 2 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 5- (3,4-dimethoxyphenyl). )-2 (3H) -Thiofenone is obtained as dark blue crystals.

Rf value: 0.57 (silica gel plate, hexane: acetic acid Echiru = 1: 1) FAB- MS ( mZz, as _{+ (C 12 H 12 0 3} S + H)): 237

IR (KBr'cm- ¹ ): 1707,1514,1265,1171,1144

 Ή-NMR (300MHZ.CDC13, δ ppm): 3.68 (2H, d, J = 2.9Hz), 3.91 (3H, s),

3.92 (3H, s), 6.01 (lH, t, J = 2.9Hz), 6.87 (lH, d, J = 8.1Hz), 6.97 (1H, d, J = 2.4Hz), 7.00 (lH, dd, J = 2.4, 8.1Hz)

 (b) Dissolve 200 mg of 5- (3,4-dimethoxyphenyl) -2 (3H)-^ offenone in 10 ml of 10% methanolic hydrochloric acid, add 148 mg of veratraldehyde, and stir at room temperature for 20 minutes. The brown crystals obtained by evaporating the solvent under reduced pressure were recrystallized (hexane: ethyl acetate = 1: 1) to give 3- (3,4-dimethoxybenzylidene) -5- (3,4-dimethoxyphenyl) )-2 (3H)-Thiophenone is obtained as dark orange crystals.

Rf value: 0.19 (silica gel plate, hexane: acetic acid Echiru = 2: 1) FAB- MS ( mZz, (C 21 H 2 .0 5 S: as): 384

 IR (KBr.cm- '): 1672, 1599, 1578, 1514, 1502, 1267, 1142

Ή-NMR (300 MHz, CDCl ₃ , δ ppm): 3.93 (3H, s), 3.94 (6H, s), 3.95 (3H, s), 6.81 (lH, d, J = 8.2 Hz), 6.97 (lH. dJ = 8.2Hz), 7.06 (lH.dJ = 2.2Hz), 7.15 (lH, dd, J = 2.2, 8.2Hz), 7.18 (lH, d, J = 2.2Hz), 7.20 (1H, d, J = 0.9Hz), 7.32 (lH, dd, J = 2.2, 8.2Hz), 7.39 (lH, s)

(c) 3- (3,4-Dimethoxybenzylidene)-5- (3,4-Dimethoxyphenyl)- Dissolve 165 mg of 2 (3H) -thiophenedone in 4 ml of methylene chloride, add 3 ml of 1M boron tribromide solution in methylene chloride at -78 ° C under a nitrogen stream, stir for 13 hours, and raise the temperature to room temperature. After adding 40 ml of water at −30 ° C. and extracting three times with 60 ml of ethyl acetate, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The dark red crystals obtained were separated into Sephadex ™ LH- Purify by 20 column chromatography to obtain the title compound as brown crystals.

 Rf value: 0.15 (silica gel plate, black mouth form: methanol: formic acid =

 100: 10: 10)

High Resolution FAB- MS (m / z, as ^{_{+ (C 17 H 12 0 5}} S)):

 Calculated value: 328.0405

 Measured value: 328.0400

 IR (KBr.cm): 3356,1651, 1603,1568,1510,1296,1265,1159

 Ή-NMR (300MHz, acetone-de, δ ppm): 6.92 (lH, d, J = 8.2Hz), 6.97 (lH, d, J = 8.2Hz), 7.01 (lH, d, J = 2.2Hz), 7.09 (lH, ddJ = 2.2,8.2Hz), 7.23 (lH, s), 7.28 (lH, dd, J = 2.2,8.2Hz), 7.39 (lH, d, J = 2.2Hz), 7.41

(lH, d, J = 0.9Hz)

 The compounds of Examples 97 to 115 were obtained in the same manner as in Example 96 by obtaining a 5-substituted-2 (3H) -thiophenone derivative and then condensing each with the corresponding carbonyl compound of the general formula (8) under acidic conditions. And, if necessary, deprotected with boron tribromide.

 Example 97

 (E) -5- (3,4-Dihydroxyphenyl) -3- (3-Fluoro-4-hydroxybenzylidene) -2 (3H) -thiophenone

FAB- MS (mZz, as ^{_{+ (C 17 H "F0 4}} S)): 330

Ή-NMR (300 MHz ₍ DMSO-d _6l δ ppm): 6.82 (lH, d, J = 8.1 Hz), 7.0 7.15 (3H, m), 7.21 (lH, s), 7.43 (lH, s), 7.59 (lH, dd, J = 1.8,8.4Hz), 7.74

(lH, dd, J = 1.8, 12.3Hz), 9.21 (lH, brs), 9.60 (lH'brs), 10.78 (1H, brs)

 Example 98

(E) -5- (3.4-dihydroxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) _- thiophenone FAB-MS (mZz. CwHpAS) '): 326

Ή-NMR (300 MHz, DMSO-d ₆ , δ ppm): 2.21 (3H, s), 6.84 (lH, d, J = 8.1 Hz), 6.94 (lH, d, J = 8.1 Hz), 7.10 (lH, dd, J = 2.4, 8.1Hz), 7.13 (1H, d, J = 2.4Hz), 7.22 (lH, s), 7.44 (lH, s), 7.63 (lH, s), 7.65 (lH, d, J = 8.1Hz)

 Example 99

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxybenzylidene)-(3H) -thionone

 Melting point: 208-216 ° C

FAB- MS (m / z, as _{(C, 7 H 12 0 4} S)): 312

Ή-NMR (300 MHz, CD ₃ OD, δ ppm): 6.81 (lH, d, J = 8.4 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.01 (lH, dd, J = 2.1, 8.3 Hz) ), 7.08 (lH, d, J = 2.1Hz), 7.24 (lH, s), 7.25 (lH, s), 7.62 (2H, d, J = 8.9Hz)

 Example 100

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene)-(3H) -thiophenone

 Melting point: 168-171. C

FAB - MS (mZz, as _{C 17 H 12 O 4 S)} : 312

Ή-NMR (300 MHz, CD ₃ OD, (ppm): 6.24 (lH, d, J = 8.0 Hz), 6.67 (1H, ddd, J = 2.0, 2.4, 8.0 Hz), 6.82 (lH.ddJ = 2.4, 8.0Hz), 6.89 (lH, d, J =

2.4Hz), 6.93- 6.99 (2H, m), 7.05-7.14 (3H, m)

 Example 101

 (E)-3- (3-aryl-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl)-2 (3H) -thiophenone

 Melting point: 156-158 ° C

FAB- MS (as _{m / z I C 2 oH 16} O 4 S): 352

Ή-NMR (300 MHz, CD ₃ OD, δ ppm): 3.21 (2H, d, J = 7.5 ·), 4.84 to 5.01 (2H, m), 5.76 to 5.92 (lH, m), 6.62 (lH, d , J = 8.0Hz), 6.68 (lH, d, J = 8.0Hz), 6.79 (lH, dd, J-2.0, 8.0Hz), 6.87 (lH, d, J = 2.0Hz), 7.03-7.13 (2H , m), 7.26-7.40 (2H, m) Example 102

 (E) -5- (3,4-Dihydroxyphenyl) -3- (3,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -thiophenone

FAB-MS (mZz, as _{+ (C 19 H 16 0 4} S)): 340

 Ή-NMR (300 MHz, DMSO-d6, δ ppm): 2.23 (6H, s), 6.82 (lH, d, J = 8.4)

Hz), 7.09 (lH, dd, J = 2.1, 8.4Hz), 7.13 (lH.d.J = 2.1Hz), 7.20 (1H, s), 7.43 (lH, s), 7.52 (2H, s)

 Example 103

 (E) -3- (3,5-di-tert-butynole-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenedone

FAB-MS

As): 424

 NMR-NMR (300 MHz, acetone-d6, δ ppm): 1.53 (18H, s), 6.79 (lH, s), 6.93 (lH, d, J = 8.4 Hz), 7.06 (lH, dd, J = 2.4, 8.4Ηζ), 7 · 17 (lH, d, J = 2.4Hz), 7.34 (lH, s), 7.35 (lH, s), 7.65 (2H, s), 8.28 (lH, s), 8.49 (lH .s) Example 104

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-propylbenzylidene) -2 (3H) -thiophenone

High resolution FAB-MS

And T):

 Calculated value: 354.0926

 Measured: 354.0936

 Ή-NMR (300 MHz, acetone-d6, δ ppm): 0.58 (3H, t, J = 7.3 Hz), 1.64-1.74 (2H, m), 2.68 (2H, t, J = 7.3 Hz), 6.91 (lH , d, J = 8.2Hz), 7.00 (1H, d, J = 8.3Hz), 7.08 (lH, dd, J = 2.2,8.2Hz), 7.20 (lH.dJ = 2.2Hz), 7.30 (lH, s ), 7.44 (lH, d, J = 1.0Ηζ), 7762 (lH, s), 7.65 (lH.s)

 Example 105

 (E) -5- (3,4-Dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -thiophenone

FAB-MS

As): 340

Ή-NMR (300MHz, acetone- d 6, δ ppm): 2.26 (3H, s), 2.35 (3H, s), 6.80 (1 H, s), 6.89 (1 H, d, J = 8.4Hz), 7.05 (1H, dd, J = 2.1, 8.4Hz), 7.16 (1H, d, J = 2.1Hz), 7.28 (lH, s), 7.51 (lH, s), 7.60 (lH, s), 8.22 (lH.brs), 8.48 (lH, brs), 8.83 (lH.brs)

 Example 106

 (E) -3- (2,3-Difluoro mouth-4-hydroxybenzylidene) -5- (3,4-Dihydroxy mouth xylphenyl) -2 (3H) -thiophenone

FAB-MS (mZz, as ^{_{+ (C, 7 H 10 F}} 2 O 4 S)): 348

Ή-NMR (200MHz, DMSO-d _6> <5 ppm): 6.82 (lH, d, J = 8.2Hz), 6.82-6.92 (lH, m), 7.08 (lH, dd, J = 2.2,8.2Hz) , 7.13 (lH, d, J = 2.2Hz), 7.23 (1H, s), 7.35 (lH.s), 7.67-7.77 (lH, m), 9.25 (lH, brs), 9.69 (2H, brs) Example 107

 (E) -3- (3-Fluoro mouth-4-hydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -thiophenone

FAB-MS (m / z, _{as, (C I9 H 15 F0 4} S)): 358

Ή-NMR (200MHz, acetone-d ₆ , δ ppm): 3.90 (3H, s), 3.88 (3H, s), 7.00-7.10 (lH, m), 7.07 (lH, s), 7.15 (lH, d , J = 8.4 Hz), 7.24 (lH, dd, J =

2.2,8.4Hz), 7.28 (lH, s), 7.40 (lH, d, J = 2.2Hz), 7.52-7.62 (lH.m), 7.67 (lH, dd, J = 2.2,12.2Hz)

 Example 108

 (E) -3- (3,5-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxypheninole) -2 (3H) -thiophenone

 Melting point: 211-213 ° C

FAB- MS

As): 348

 Ή-NMR (300 MHz, DMSO-de, δ ppm): 6.62 (1 HdJ = 8.3 Hz), 6.83 (1 H, ddj = 2.1, 8.3 Hz), 6.91 (lH, d, J = 2.1 Hz), 6.96 ( lH, s), 7.02 (lH.s), 7.12 (lH, d-like, J = 1.7Hz), 7.14 (lH, d-like, J = 1.7Hz)

 (E) -3- (3,4-dihydroxybenzylidene) -5- (4-hydroxyphenyl) -2 (3H) -thiophenone

FAB-MS (as π / ζ, (〇πΗ ₁₂ 0 ^) ⁺ ): 312

Ή-NMR (300 MHz, DMSO-d ₆ , δ ppm): 6.81-6.91 (3H, m), 7.17 (1H, s), 7.25 (lH, dd, J = 2.1,8.7 Hz), 7.30 (lH, d, J = 2.1 Hz), 7.43 (lH, s), 7.55 (2H, m), 9.38 (lH, brs), 9.95 (lH, brs), 10.02 (lH'brs) Example 110

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-2,3-dimethylbenzylidene) -2 (3H) -thiophenone

High resolution FAB-MS

As)

 Calculated value: 340.0769

 Measured value: 340.0750

NMR-NMR (300 MHz ₍ acetone-d ₆ , δ ppm): 2.21 (3H, s), 2.34 (3H, s), 6.89 (lH, d, J = 8.5 Hz), 6.89 (lH, d, J = 8.3 Hz), 7.04 (lH, dd, J = 2.3,8.3Hz),

7.16 (lH, d, J = 2.3Hz), 7.19 (lH, d, J = 1.0Hz), 7.50 (lH, d, J = 8.5Hz), 7.62 (lH, s), 8.24 (lH, s), 8.50 (lH, s), 8.91 (lH, s)

 Example 111

 (E) -3- (4-hydroxy-3-methylbenzylidene) -5- (4-hydroxyphenyl) -2 (3H) -thiophenedone

FAB-MS (mZz, as ^{_{+ (C 18 H 14 0 3}} S)): 310

 Ή-NMR (200 MHz, acetone-de, <5 ppm): 2.15 (3H, s), 6.94 (2H, dd, J = 2.2, 6.7 Hz), 6.98 (lH, dJ = 8.4 Hz), 7.28 (lH, s), 7.51 (lH, d, J = 1.0 Hz), 7.59 (2H, dd, J = 2.2,6.7Hz), 7.59-7.69 (2H, m)

 Example 112

 (E) -3- (2,3-difluoro-4-hydroxybenzylidene) -5- (4-hydroxyphenyl) -2 (3H) -thiophenedone

 FAB-MS (as mZz 'CnHwFzOsS)): 332

 Ή-NMR (200MHz, acetone -de, δ ppm): 6.96 (2H, dd, J = 2.1,6.8Hz), 6.98-7.08 (lH, m), 7.37 (lH, s), 7.44 (lH, s) , 7.62 (2H, dd, J = 2.1,6.8

Hz), 7.66- 7.76 (lH, m)

 Example 113

 (E) -3- (3,4-dihydroxybenzylidene) -5- (3-hydroxyphenyl) -2 (3H) -thiophenone

FAB-MS (as m / z, (C ₁₇ H _I2 0, S) ⁺ ): 312 Ή-NMR (200 MHz, DMSO-d ₆ , δ ppm): 6.78-6.88 (lH, m), 6.86 (1H, d, J = 8.2 Hz), 7.05 (1H. = 1.8 Hz), 7.11-7.21 (lH , m), 7.24-7.32 (4H, m), 7.53 (lH, s), 9.75 (3H, brs)

 Example 114

 (E) -3- (4-Hydroxyquin-3-methylbenzylidene) -5- (3-Hydroxyphenyl) -2 (3H) -Thiophenone

FAB-MS (mZz, as ^{_{+ (C 18 H 14 0 3}} S)): 310

 Ή-NMR (400MHz, DMSO-d6, δ ppm): 2.19 (3H, s), 6.78-6.88 (lH, m), 6.93 (lH, d, J = 8.4Hz), 7.03-7.13 (lH, m) , 7.17-7.27 (lH, m), 7.27 (lH, t, J = 8.0Hz), 7.13 (lH, s), 7.62 (lH, s), 7.65 (lH, d, J = 2.0Hz),

7.68 (lH, dd, J = 2.0,8.4Hz), 9.70 (lH, s), 10.39 (lH, s)

 Example 115

 (E) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (3-hydroxyphenyl) -2 (3H) -thiophenone

 FAB-MS (m / z, as (CnH.oFzOgS) +): 332

 NMR-NMR (200MHz, DMSO-de, δ ppm): 6.81-6.91 (lH.m), 6.91 -7.01 (lH.m), 7.05- 7.15 (lH, m), 7.17-7.27 (lH, m), 7.29 (lH.tJ = 7.6 Hz), 7.35 (lH, s), 7.54 (lH.s), 7.74 7.84 (lH, m), 9.74 (lH.s), 11.38 (lH, brs)

 Example 116

 (Z) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -4-methyl-2 (3H) -thiophenone

 (a) Dissolve 5 g of 3,4-dimethoxyacetophenone in 25 g of dimethyl carbonate and add 698 mg of sodium hydride (60% mineral oil suspension). After heating under reflux for 2 hours, cool to room temperature, add acetic acid to adjust the pH to 7, pour the reaction mixture into ice water, and extract twice with 100 ml of getyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained by evaporating the solvent was purified by silica gel chromatography (n-hexane: ethyl acetate = 2: 1) to give methyl 3,4-dimethoxybenzoylacetate 6.14. get g.

Ή-NMR (300 MHz, CDCl ₃ , δ ppm): 3.74 (3H, s), 3.92 (3H, s), 3.95 (3H, s), 3.97 (2H, s), 6.89 (lH.dJ = 8.7Hz), 7.52 (lH.dJ = 1.2Hz), 7.54 (lH, dd, J = 1.2, 8.7Hz)

 (b) To a suspension of 322 mg of sodium hydride (60% mineral oil suspension) in 20 ml of THF was added a solution of 3 g of methyl 3,4-dimethoxybenzoylacetate in 20 ml of THF, and the mixture was stirred at room temperature for 30 minutes. Further, 2.68 g of methyl iodide is added and the mixture is stirred at room temperature for 15 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was subjected to silica gel chromatography (n-hexane: ethyl acetate = 3: 1). Purification gives 1.8 g of methyl 2- (3,4-dimethoxybenzoyl) propionate.

Ή-NMR (300 MHz, CDCl ₃ , <5 ppm): 1.50 (3H, d, J = 6.8 Hz), 3.69 (3H, s),

3.93 (3H, s), 3.96 (3H, s), 4.38 (lH, q, J = 6.8Ηζ), 6.90 (lH, d, J = 8.7 Hz), 7.56 (lH, d, J = 1.8Hz) ), 7.62 (lH, dd, J = 1.8,8.7Hz)

 (c) To a suspension of sodium hydride (suspension in 60% mineral oil) (304 mg) in THF (20 ml) was added a solution of 1.6 g of methyl 2- (3,4-dimethoxybenzoyl) propionate in THF, and the mixture was heated under reflux for 1 hour. After cooling, further add 27 g of ethyl bromoacetate, reflux under heating for 2 hours, cool to room temperature, add water to the reaction solution, extract with ethyl acetate, and dry the ethyl acetate layer with anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure is purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1, then 3: 1) to give 3_ (3,4-dimethoxybenzoyl) -3-methyl 1.6 g of ethyl butylbutyrate is obtained.

Ή-NMR (300 MHz, CDCl _{3 (} <5 ppm): 1.23 (3H, t, J = 6.8 Hz), 1.69 (3H, s), 3.05 (2H, dd.J = 7.0,8.5 Hz), 3.70 (3H , S), 3.91 (3H, s), 3.93 (3H, s), 4.12 (2H, q, J = 6.8Hz), 6.83 (lH, d, J = 8.7Hz), 7.45-7.55 (2H, m)

(d) Dissolve 1.6 g of ethyl 3- (3,4-dimethoxybenzoyl) -3-methylcarbonylbutyrate in 100 ml of concentrated hydrochloric acid and heat to reflux for 12 hours. After cooling to room temperature, dilute the reaction mixture with water and extract with ethyl acetate. Extract the ethyl acetate layer twice with 50 ml of 0.5N aqueous sodium hydroxide solution. The aqueous layer was added with 6N hydrochloric acid under ice-cooling to adjust the pH to 2 or less, extracted with ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. And methanol: formic acid = 100: 5: 1) to give 3- (3,4-dimethoxybenzene). 285 mg of butyric acid are obtained.

Ή-NMR (300 MHz, CDCl _{3 (} δ pm): 1.28 (3H, d, J = 7.0 Hz), 2.51 (lH.dd.

 J = 6.8, 12.4Hz), 3.00 (lH.ddJ = 6.8, 12.4Hz), 3.88-3.98 (lH, m), 3.94 (3H, s), 3.96 (3H, s), 6.91 (lH.dJ = 8.7 Hz), 7.55 (lH.dJ = 1.8Hz), 7.63 (lH, dd.J = 1.8,8.7Hz)

 (e) Dissolve in 280 mg of 3- (3,4-dimethoxybenzoyl) butyric acid, 267 mg of diphosphorus pentasulfide, 5 ml of pyridine and 2.5 ml of chloroform, and heat to reflux at 130 ° C to 140 ° C for 2 hours. After cooling to room temperature, the reaction solution is poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer is washed with water and then with a saturated saline solution and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel chromatography (n-hexane: ethyl acetate = 3: 1) to give 5- (3,4-dimethoxyphenyl) -4-methyl-2 (5H)-147 mg of thiophenone are obtained.

Ή-NMR (300 MHz, CDCl ₃ , δ ppm): 1.94 (3H, s), 3.85 (3H, s), 3.89 (3H, s), 5.23 (lH, s), 6.10-6.20 (lH, m), 6.68 (lH, s), 6.83 (2H, s) (f) 5- (3,4-Dimethoxyphenyl) -4-methyl-2 (5H) -thiophenone lOOmg was dissolved in 5% of 10% hydrochloric acid methanol solution. And veratraldehyde (83 mg), and the mixture was stirred at room temperature for 20 minutes, and the solvent was distilled off under reduced pressure. The brown crystals obtained were recrystallized (hexane: ethyl acetate = 1: 1), and (Z) -5- ( 95 mg of 3,4-dimethoxyphenyl) -4-methyl-3- (3,4-dihydroxybenzylidene) -2 (3H) -thiophenedone are obtained as dark orange crystals.

(g) Dissolve 74 mg of (Z) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -4-methinole-2 (3H) -thiophenone in 5 ml of salt dimethylene, Under a nitrogen stream, at -78, add 0.6 ml of a 1 M solution of boron tribromide in anhydrous methylene chloride, and stir for 13 hours to warm to room temperature. - 30 Water 5ml added ^e C, put extracted with acetic Echiru, the organic layer was dried over magnesium sulfate to give a dark red crystal the solvent was distilled off under reduced pressure. The obtained crystals are purified by Sephadex ™ LH-20 column chromatography to obtain 55 _mg of the title compound as brown crystals.

FAB- MS as ^{+ (m / z, (C} I8 H) 4 0 5 S)): 342

Ή-NMR (300MHz, acetone-d6, δ ppm): 2.15 (3H, s), 6.84 (lH.dd.J = 2.4,8.1Hz), 6.88 (lH, d, J = 8.1Ηζ), 6 · 91 (lH.dJ = 8.1Hz), 6.96 (1H, d, J = 2.4Hz), 7.08 (lH, s), 7.52 (lH, dd, J = 1.8,8.1Hz), 8.04 (lH, d, J = 1.8Hz)

 The compounds of Examples 117 to 123 are synthesized in the same manner as in Example 116.

 Example 117

 (Z)-5- (3,4-dihydroquinphenyl)-3- (4-hydroxy-3-methylbenzylidene)-4-methyl-2 (3H) -thiophenedone

FAB- MS (mZz, as ^{_{+ (C 19 H 16 0 4}} S)): 340

Ή-NMR (300 MHz, acetone-d ₆ , δ ppm): 2.17 (3H, s), 2.24 (3H, s), 6.85 (lH, dd, J = 2.1, 8.1 Hz), 6.89 (lH, d, J = 8.4Hz), 6.93 (lH, d, J = 8.1Hz), 6.97 (lH, d, J = 2.1Hz), 7.12 (lH, s), 7.99 (lH, d, J = 2.1Hz), 8.08 ( (1H, dd, J = 2.1,8.4Hz)

 Example 118

 (E) and (Z)-A mixture of 5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone

FAB- MS _(m / z (as C ₁₈ H ₁₄ 04S): 326

 Example 119

 (Z)-5- (3,4-dihydroxypheninole) -3-(3,5-dimethinole-4-hydroxybenzylidene)-4-methyl-2 (3H) -thiophenone

High Resolution FAB- MS (m / z, ( C 20 H 18 O, S) as +):

 Calculated value: 354.0519

 Measured: 354.0915

Ή-NMR (200MHz, acetone-d ₆ , δ ppm): 2.16 (3H, s), 2.27 (6H, s), 6.85 (lH, dd, J = 2.0,8.1 Hz), 6.92 (lH, d, J = 8.1Hz), 6.96 (lH, d, J = 2.0Hz), 7.09 (lH, s), 7.93 (2H, s), 8.10 (lH, s), 8.19 (lH, s), 8.26 (lH.s ) Example 120

In the same manner as in Example 97, (Z) -3- (3-funoleo mouth-4-hydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -4-methyl-2 (3H) -thiophenone was used. After that, the product obtained by treatment with boron tribromide was isolated and purified to give (Z) -3- (3-fluoro-4--4-hydroxybenzylidene) -5- (3,4-dihydroxy (Droxyphenyl) -4-methyl-2 (3H) -thiophenone (Compound 120a) and (Z) -3- (3-Fluoro-4-hydroxy) Xybenzylidene) -5- (3-hydroxy-4-methoxyphenyl) -4-methyl-2 (3H) -thiophenone (Compound 120b) was obtained.

 120a) (Z) -5- (3,4-dihydroxyphenyl)-3- (3-fluoro-4-hydroxybenzylidene)-4-methinole-2 (3H) -thiophenone

High Resolution FAB- MS (mXz, as _{+ (C 18 H, 3 F0} 4 S)):

 Calculated value: 344.0519

 Measured: 344.0529

Ή-NMR (300 MHz, acetone-d ₆ , δ ppm): 2.16 (3H, s), 6.85 (lH, dd, J = 1.8, 8.4 Hz), 6.92 (lH.dJ = 8.1 Hz), 6.97 (lH, d, J = 2.4Hz), 7.05 (1H, dd, J = 8.7, 9.0Hz), 7.15 (lH, s), 7.71 -7.81 (lH, m), 8.22 (lH, s), 8.30

(lH, s), 8.33 (lH, dd, J = 1.8, 13.5Hz), 9.46 (lH.s)

 120b) (Z) -3- (3-Fluoro mouth-4-hydroxybenzylidene) -5- (3-Hydroxy-4-methoxyphenyl) -4-Methinole-2 (3H) -Thiophenone

High Resolution FAB-MS (mZz, as ^{_{+ (C 19 H I5 F0 4}} S)):

 Calculated value: 358.0675

 Measured: 358.0670

Ή-NMR (300 MHz, acetone-d ₆ , δ ppm): 2.17 (3H, s), 3.90 (3H, s), 6.94 (2H, m), 7.05 (lH.dJ = 7.8 Hz), 7.06 (lH, dd, J = 8.7,9.0Hz), 7.17 (1H, s), 7.72-7.82 (lH, m), 8.33 (lH.dd.J = 1.8,13.5Hz),

 Example 121

 As in Example 116, (Z) -3- (3,5-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -4-methyl-2 (3H) -thiophenedone After that, the product obtained by treatment with boron tribromide was isolated and purified to give (Z) -3- (3,5-difluoro-4-hydroxybenzylidene) -5- (3,4 -Dihydroxyphenyl) -4-methyl-2 (3H) -thiophenone (compound 121a) and (Z) -3- (3,5-difluoro-4-hydroxybenzylidene) -5- (3-hydroxy- 4-Methoxyphenyl) -4-methyl-2 (3H) -thiophenone (Compound 121b) was obtained.

 121a) (Z) -3- (3,5-diphneorolo- 4-hydroxybenzylidene)-5- (3,4-dihydroxyphenyl)-4-methinole-2 (3H) -thiophenone

High Resolution FAB- MS (m / z, as ^{_{+ (C 18 H 12 F 2}} 0 4 S)): Calculated value: 362.0478

 Measured: 362.0493

Ή-NMR (300 MHz, acetone-d ₆ , δ ppm): 2.16 (3H, s), 6.86 (lH.dd.J = 1.8,8.4 Hz), 6.93 (lH, d, J = 8.1 Hz), 6.98 ( lH, d, J = 1.8Hz), 7.12 (1H, s), 7.90 -8.00 (2H, m)

 121b) (Z) -3- (3,5-Difluoro mouth-4-hydroxybenzylidene) -5- (3-Hydroxy-4-methoxyphenyl) -4-Methyl-2 (3H) -Tiophenone

High Resolution FAB-MS (m ^/ z, as _{+ (C 19 H 14 F 2} 0 4 S)):

 Calculated value: 376.6581

 Measured: 376.6581

 Ή-NMR (300MHz, acetone-de, δ ppm): 2.17 (3H, s), 3.90 (3H, s), 6.91-7.01 (2H, m), 7.05 (lH, d, J = 8.7Hz), 7.15 (lH, s), 7.91-8.01 (2H, m) Example 122

 Mixtures of (E) and (Z) -5- (3,4-dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -4-methyl-2 (3H) -furanone

High resolution FAB-MS

As):

 Calculated value: 354.0926

 Measurement value: 358.0910 '

 NMR-NMR (300 MHz, acetone-d6, δ ppm): 1.80 + 2.12 (3H, sx 2), 2.13 + 2.18 (3H, sx 2), 2.22 + 2.28 (3H, sx 2), 6.69 + 6.73 (lH, sx 2), 6.82

(lH, dd, J = 1.9, 8.4Ηζ), 6.88 (lH, d, J-8.4Hz), 6.94 (lH.dJ = 2.0Hz), 7.07 + 7.78 (1H, SX 2), 7.22 + 7.58 (lH.sx 2), 8.20 + 8.21 (1H, sx2), 8.27 + 8.32 (lH.sx 2), 8.57 + 8.63 (lH, sx 2)

 Example 123

Mixtures of (E) and (Z) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (3, -dihydroxyphenyl) -4-methyl-2 (3H) -thiophanenone High resolution FAB-MS (m / 2, as ^{_{+ (C 18 H 12 F 2}} 0 4 S)):

 Calculated value: 362.0424

 Measured: 362.0394

NMR-NMR (300 MHz, acetone-d ₆ , δ ppm): 1.92 + 2.17 (3H, sx 2), 6.82- 6.98 (3H, m), 6.99 (lH, d, J = 1.9Hz), 7.11 (lH, s), 7.77-7.85 (lH.m), 8.28 + 8.29 (1H, SX 2), 8.39 + 8.46 (lH , sx 2), 9.70 + 9.77 (1H, sx 2)

 Example 124

 (E) -Synthesis of 3- (3,4-dihydroxybenzylidene) -5- (triphenyl-2-pyridone-5-inole) -2 (3H) -furanone

 (a) Dissolve 300 mg of methyl ester of 4-oxo-4- (2-pyridone-5-yl) butyrate obtained in Reference Example 5 in 5 ml of DMF, and add 80 mg of sodium hydride (60% mineral oil suspension), and then Add 275 / l of phenethyl bromide and stir at room temperature for 15 hours. The reaction solution is diluted with 80 ml of ethyl acetate and washed with water and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1) to give 4-oxo-4- (1-phenethyl). -2-pyridone-5-yl) Butyric acid methyl ester 136 mg is obtained.

The methyl ester 136mg was dissolved in methanol 5 ml, addition of 2N hydroxide sodium © anhydrous solution lml, stirred for 30 minutes at room temperature, adjust the _P H of the reaction solution to 2-3 with ice-cooling under 1N hydrochloric acid, acetic Echiru Extract with 80 ml. The organic layer is washed with a small amount of saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure to obtain 130 mg of 4-oxo-4- (1-phenyl-2-pyridone-5-yl) butyric acid. .

 Rf value: 0.15 (silica gel plate, methylene chloride: methanol = 30: 1)

Ή-NMR (200 MHz, DMSO-d6, δ ppm): 2.50 (2H, t), 2.90 (2H, t), 2.92 (2H, t), 4.18 (2H, t), 6.44 (lH, d), 7.15 -7.38 (5H, m), 7.82 (lH.dd), 8.48 (lH, d), 12.20 (lH.brs)

 (b) 130 mg of 4-oxo-4- (trifluoromethyl-2-pyridone-5-yl) butyric acid, 72 mg of veratraldehyde and 36 mg of sodium acetate were added to 0.5 ml of acetic anhydride.

Heat and stir at 80 ° C for 15 hours. After cooling the reaction solution to room temperature, it is diluted with 60 ml of ethyl acetate and washed with water and then with a saturated saline solution. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off, and the obtained residue was separated and purified by silica gel column chromatography (form: methanol = 100: 1) to give (E) -3- (3 , 4-Dimethoxybenzylidene) -5- (triphenethyl-2-pyridone-5-inole) -2 (3Η) -fura Non 160 mg is obtained.

 Rf value: 0.54 (Shiidani methylene: methanol = 30: 1)

FAB- MS (mZz, as ^{_{+ (C 26 H 23 N0 5}} )): 429

FAB- MS (m / z, as _{+ (C 2 6H 23 NO s} + H)): 430

 (c) Under an argon atmosphere, 32 mg of (E) -3- (3,4-dimethoxybenzylidene) -5- (1-phenethyl-2-pyridone-5-yl) -2 (3H) -furanone Dissolve in 3 ml of digmethylene and stir at -78 ° C. Add 1M boron tribromide anhydrous methylene chloride solution 380/1, stir for 5 minutes and then stir at room temperature for 30 minutes. After cooling to -78 ° C again, add 1 ml of methanol, return to room temperature, dilute with 30 ml of ethyl acetate, wash with water and then with saturated saline. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off. The resulting residue was separated by Sephadex ™ LH-20 column chromatography (chloroform: methanol: ethanol: water = 5: 2: 2: 1). Purify to give 27 mg of the title compound.

 Rf value: 0.51 (silica gel plate, methylene chloride: methanol: formic acid =

 300: 10: 1)

FAB- MS (m / z, as ^{_{+ (C 24 H 19 N05 +}} H)): 402

FAB- MS (mZz, as ^{_{+ (C 24 H 19 N0 5}} + Na)): 424

 Ή-NMR (300 MHz, acetone-de, δ ppm): 3.14 (2H, t, J = 7.8 Hz), 4.36 (2H, t, J = 7.8 Hz), 6.74 (lH, d, J = 9.0 Hz), 6.93 (lH, d, J = 8.4Hz), 7.17 (lH, s), 7.20-7.32 (7H, m), 7.51 (lH.dJ = 1.8Hz), 8.03 (lH.dd.J =

2.7,9.3Hz), 8.08 (lH.d.J = 2.7Hz)

 The compounds of Examples 125 to 134 were synthesized in the same manner as in Example 124 from methyl 4-oxo-4- (2-pyridone-5-yl) drank acid.

 Example 125

 (E) -5- (Tribenzyl-2-pyridone-5-inole) -3- (3,4-Dihydroxybenzylidene) -2 (3H) -furanone

FAB- MS (m / z, as _{+ (C 23 H 17 N0 5} + H)): 388

Ή-NMR (200 MHz, DMSO-d6, δ ppm): 5.19 (2H, s), 6.59 (lH, d), 6.85 (lH, d), 7.12 (lH, s), 7.18-7.38 (8H, m) , 8.02 (lH, dd), 8.29 (lH, d), 9.20 (lH, brs), 9.94 (lH.brs) Example 126

 (E)-3- (3,4-dihydroxybenzylidene) -5- "1- (4-hydroxybenzyl)-2-pyridone-5-inole,-2 (3H) -furanone

FAB- MS (mZz, as _{+ (C 23 H 17 N0 6} + H)): 404

 NMR-NMR (200MHz, DMSO-d6, δ ppm): 5.05 (2H, s), 6.55 (lH, d), 6.66-

6.76 (2H, m), 6.84 (lH, d), 7.10 (lH, s), 7.12-7.28 (5H, m), 7.96 (1H, dd), 8.22 (lH, d), 9.43 (2H, brs) , 9.92 (lH, brs)

 Example 127

 (E) -5- (1-cyclohexynolemethinoley 2-pyridone-1-5-inole) -1-3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone

FAB- MS (mZz, as ^{_{+ (C 23 H 23 N0 5}} + H)): 394

Ή-NMR (400 MHz, DMSO-d ₆ , δ ppm): 1.00-1.80 (l lH, m), 3.82 (2H, d), 6.55 (lH, d), 6.82 (lH.s), 7.05--7.15 ( 2H, m), 7.24 (lH, s), 7.95 (lH, dd), 8.06 (lH, d)

 Example 128

 (E) -5- (Tributyl-2-pyridone-5-inole)-3- (3,4-dihydroxybenzylidene)-2 (3H) -Furanone

FAB- MS (m / z, as _{+ (C 20 H 19 NO 5} + H)): 354

Ή-NMR (300MHz, CD ₃ OD, δ ppm): 0.95- 1.45 (7H, m), 4.04 (2H, t-like), 6.63 (1H, d, J = 9.3Hz), 6.86 (1H, d, J = 8.1 Hz), 7.04 (1H, s),

7.10- 7.20 (2H, m), 7.21 (lH, s), 7.93 (lH.dd.J = 2.1,9.9Hz), 8.06 (lH, d, J = 2.1Hz)

 Example 129

 (E) -3- (3,4-dihydroxybenzylidene) -5-Π- (3-phenylpropyl) -2-pyridone-5-inole 1-2 (3H) -furanone

FAB- MS (m / z, as ^{_{+ (C 25 H 21 N0 5}} + H)): 416

Ή-NMR (200 MHz, DMSO-d ₆ , δ ppm): 1.91-2.06 (2H, m), 2.62 (2H, t, J = 6.5 Hz), 3.99 (2H, tJ = 6.4 Hz), 6.54 (lH, d, J = 9.5 Hz), 6.85 (1H, d, J = 9.0 Hz), 7.11 (lH, s), 7.16- 7.28 (8H, m), 7.96 (lH.ddJ = 2.0, 9.5 Hz), 8.15 ( (lH, d, J = 2.0Hz) Example 130

 (E) -3- (3,4-dihydroxybenzylidene) -5-C1- (2-phenyloxethyl)--pyridone-5-inole Ί-2 (3H) —furanone

FAB-MS (mZz, as _{+ (C 24 H 19 N0 6} + H)): 418

 Ή-NMR (300 MHz, acetone-de, δ ppm): 4.35 (2H, t, J = 5.4 Hz), 4.47

(2H, t, J = 5.4Hz), 6.53 (lH, d, J = 9.3Ηζ), 6.92 (lH, s), 6.94-6.97 (3H, m), 7.11-7.21 (lH, m) , 7.17 (lH.s), 7.21 -7.33 (4H, m), 7.93 (lH.dd, J = 1.8,9.3Hz), 8.13 (lH, d, J = 1.8Hz), 8.58 (lH.brs)

 Example 131

 (E) -5- (1-Benzinole-2-pyridone-5-inole) -3- (4-Hydroxy-3-Methylbenzylidene) -2 (3H) -Furanone

FAB- MS (/ z, as _{+ (C 24 H 19 N0 4} )): 385

FAB-MS (mZz, as _{+ (C 24 H 19 N0 4} + H)): 386

 Ή-NMR (300MHz, acetone-d6, δ ppm): 2.24 (3H, s), 5.29 (2H, s), 6.57 (lH, d, J = 9.6Hz), 6.94 (lH, d, J = 8.1Hz) ), 7.19 (lH, s), 7.21 (lH, s),

7.30-7.47 (5H, m), 7.53 (lH, dd, J = 2.1,8.1Hz) ₍ 7.60 (lH, d, J = 2.1 Hz), 7.90 (lH, dd, J = 2.7,9,6Hz), 8.12 (lH.dJ = 2.7Hz), 9.08 (1H, brs)

 Example 132

 (E) -3- (3,4-dihydroxybenzylidene) -5- "1- (2-naphthylmethyl)-

2-pyridone-5-inole Ί-2 (3H) -furanone

FAB-MS (m / z, as _{(C 27 H 19 NO s)} +: 437

Ή-NMR (300MHz, CD ₃ OD, δ ppm): 5.20 (2H, s), 6.50 (lH, d, J = 8Hz), 6.65 (lH, d, J = 7Hz), 6.83 (lH, s), 7.20- 7.33 (4H, m), 7.58- 7.70 (6H, m), 7.75 (lH, dd, J = 2,8Hz), 8.00 (lH.dJ = 2Hz)

 Example 133

 (E) -5- (Tobenzil-2-pyridone-5-inole)-3- (3-Fluoro mouth-4-hydroxybenzylidene) -2 (3H) -Furanone

FAB- MS (m / z, as _{+ (C 23 H 16 FNO 4} + H)): 390

Ή-NMR (300 MHz, DMSO-d6, δ ppm): 5.19 (2H, s), 6.61 (lH, d, J = 9.6 Hz), 7.04 (lH, dd, J = 8.4,8.7Hz), 7.18 (lH, s), 7.28-7.35 (5H), 7.40 (lH, s), 7.51 (lH _> dd, J = 2.1 „8.7Hz ), 7.70 (lH, dd, J = 2.1, 12.6 Hz), 8.06 (lH, dd, J = 2.7, 9.6 Hz), 8.29 (lH, d, J = 2.7 Hz), 10.72 (lH.brs) 134

 CE) -3- (3,4-dihydroxybenzylidene) -5- (1-ethyl-2-pyridone-5-yl) -2 (3H) -furanone

FAB-MS (mZz, as + (C ₁₈ H ho N0 ₅ + H)): 326

 Ή-NMR OOOMHz.CDsOD, δ ppm): 1.37 (3H, t, J = 7.1 Hz), 4.10 (2H, q, J = 7.1 Hz), 6.64 (lH, d, J = 9.6 Hz), 6.86 (lH .dJ = 7.8Hz), 7.04 (1H, s), 7.10-7.20 (2H, m), 7.21 (1H, s), 7.94 (1H, dd, J = 2.4, 9.6Hz), 8.12

(lH, d, J = 2.4Hz)

 Example 135

 Synthesis of (E) -3- (3,4-dihydroxybenzylidene) -5- (triphenyl-2-pyridone-5-inole) -2 (3Η) -thiophenone

 (a) Dissolve 220 mg of 4- (tofunetyl-2-pyridone-5-inole) -4-oxobutyric acid and 1 ml of pyridine in 1.5 ml of chloroform and, in an argon atmosphere, 163 mg of pyridine of nitrine pentasulfide. Add 2 ml solution and heat to reflux for 1 hour. After cooling to room temperature, 40 ml of methylene chloride was added to the reaction solution, washed with 1N hydrochloric acid and then with a saturated saline solution, and the organic layer was dried over anhydrous sodium sulfate.The solvent was distilled off. Separation and purification by chromatography (chloroform: methanol = 100: 1) and preparative TLC (chromatographic form: methanol = 30: 1) yielded 5- (1-phenethyl-2-pyridone-5). To give 25 mg of -2 (3H) -thiophenone.

 Rf value: 0.53 (methylene chloride: methanol = 30: 1)

(b) Dissolve 25 mg of 5- (triphenyl-2-pyridone-5-yl) -2 (3Η) -thiophenone and 14 mg of veratraldehyde in 2 ml of a 10% methanolic hydrochloric acid solution, and then dissolve at room temperature for 15 minutes and then 80%. Heat to ° C and stir for 30 minutes. After cooling to room temperature, 25 ml of ethyl acetate was added to the reaction solution, washed with water and then with a saturated saline solution, and dried over anhydrous magnesium sulfate. The residue obtained after distilling off the solvent was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 3: 2), and then to preparative TLC (acetic acid). (E): 3- (3,4-Dimethoxybenzylidene) -5- (1-phenetinole-2-pyridone-5-inole) -2 (3H ) -Thiophenone 16.3 mg is obtained.

Rf value: 0.38 (ethyl acetate: _n- hexane = 4: 1)

FAB- MS (/ z, as _{+ (C 26 H 23 N0 4} S + H)): 446

 (c) Dissolve 9.8 mg of (E) -3- (3,4-dimethoxybenzylidene) -5- (triphenethyl-2-pyridone-5-inole) -2 (3H) -thiophenedone in 2 ml of methylene chloride. Under an argon atmosphere, add 1/1 of 1M boron tribromide anhydrous methylene chloride solution at -78 ° C, and stir at -78 ° C for 10 minutes and at room temperature for 30 minutes. After cooling again to -78 ° C, 0.5 ml of methanol was added, the reaction solution was returned to room temperature, diluted with 20 ml of ethyl acetate, washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure The resulting residue is separated and purified by Sephadex ™ LH-20 column chromatography (chloroform: methanol: ethanol: water = 5: 2: 2: 1) to obtain 5.5 mg of the title compound.

 Rf value: 0.36 (silica gel plate, methylene chloride: methanol: formic acid =

 300: 10: 1)

FAB-MS (mZz, as _{+ (C 24 H 19 N0 4} S + H)): 418

IR (KBr, cm- ⁾ ): 1651,1589,1506,1086

 Ή-NMR (200MHz, acetone-ds, δ ppm): 3.07 (2H, t, J = 7.5Hz), 4.27 (2H, t, J = 7.5Hz), 6.53 (lH, d, J = 9.6Hz), 6.95 (lH, d, J = 8.2Hz),

7.22-7.38 (9H, m), 7.58 (lH.d.J = 2.6Hz), 7.93 (lH, dd, J = 2.7,9.6

Hz), 8.65 (2H, brs)

 The compounds of Examples 136 to 138 were synthesized in the same manner as in Example 135.

 Example 136

 (E) -3- (3-Hydroxybenzylidene) -5- (triphenyl-2-pyridone-5-yl) -2 (3Η) -Thifuyunone

FAB-MS (m _/ z, as ^{_{+ (C 24 H 1 9N0 3}} S + H)): 402

Ή-NMR (300MHz, acetone-de, δ ppm): 3.07 (2H, t, J = 7.4Hz), 4.28 (2H, t, J = 7.4Hz), 6.52 (lH, d, J = 9.3Hz), 6.93- 6.99 (lH, m), 7.21- 7.34 (10H, m), 7.61 (lH.dJ = 2.7Hz), 7.92 (lH.ddJ = 2.7,9.3Hz) Example 137

 CE) -3- (2,3-Difluoro-4-hydroxybenzylidene) -5- (trifluoromethyl-2-pyridone-5-inole) -2 (3Η) -thiophenone

FAB- MS (m / z, as ^{_{+ (C 24 H 17 F 2}} N0 3 S + H)): 438

Ή-NMR (300 MHz, DMSO-d _{6 (} δ ppm): 2.95 (2H, U = 7.2 Hz), 4.18 (2H, t, J = 7.2 Hz), 6.53 (lH, d, J = 9.6 Hz), 6.84 (lH, t, J = 7.2Hz), 7.17-7.31 (6H, m), 7.34 (lH, s), 7.69 (lH, d, J = 2.7Hz), 7.66-7.76 (lH, m), 8.08 ( lH, dd, J = 2.7, 9.6Hz)

 Example 138

 (E) -3- (4-Hydroxy-3-methylbenzylidene) -5- (Triphenyl-2-pyridone-5-yl) -2 (3H) -Thiophenone

FAB- MS

+ H) +): 416

 Ή-NMR (300 MHz, DMSO-d6, δ ppm): 2.25 (3H, s), 2.95 (2H, t, J = 7.2 Hz), 4.18 (2H, t, J = 7.2 Hz), 6.53 (lH .dJ = 9.6Hz), 6.84 (lH, d, J = 8.4Hz), 7.23 (lH, s), 7.20-7.29 (6H, m), 7.41 (lH, s), 7.57-7.63 (1H, m) , 7.65 (lH, d, J = 2.7 Hz), 8.09 (lH, dd, J = 2.7, 9.6 Hz)

The numbers and structural formulas of the examples are shown below.

2 (continued)

Continued)

Industrial applicability

 The compound according to the present invention strongly inhibits tyrosine kinase and suppresses the growth of tumor cells, and thus is useful in the field of medicine, and is particularly expected to be used as an antitumor agent.

Claims

The scope of the claims

(1) General formula

 [I]

[Wherein the dotted line indicates that either the exocyclic or the intracyclic bond to which it is attached is a double bond and the other is a single bond, and W is = NR ² , an oxygen atom or a sulfur atom. X represents = NR ³ , nitrogen atom or = C = O, and represents ^ ⁴ or a nitrogen atom, and R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkynyl. R ² and R ³ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group or an aryl lower alkyl group. alkyl group, a cycloalkyl-lower alkyl group, a Ariru group, Ariru lower alk kill group, Arukanoiru group or a lower Aroinore group, R ⁴ is a hydrogen atom, a lower § alkyl group, a lower alkenyl group, lower alk Nyl group, cycloalkyl group, cycloalkynyl lower alkynole group, aryl group, arylno lower alkyl group, hydroxy lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy lower alkyl group, amino lower alkyl group, protected An amino lower alkyl group, a carboxy lower alkyl group, a protected carboxy lower alkyl group, a cyano lower alkyl group, a cyano group, a lower alkylsulfonyl group or a lower alkyl group; Y and Z are the same or different; Lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, cycloalkyl lower alkyl group, aryl group, aryl lower alkyl group, hydroxy group, protected hydroxy group, hydroxy lower alkyl group, protected Hydroxy low Alkyl group, a lower alkoxy group, a lower Arukeniruokishi group, a lower Arukiniruokishi group, Ariruokishi group, a cycloalkyl-lower alkoxy group, Ariru lower § alkoxy group, a lower Arukanoiru group, lower alkanoyloxy Noi Ruo alkoxy group, lower alk force Lower alkyl lower alkyl, lower alkoxy lower alkyl, aryloxy lower alkyl, halogen, halo lower alkyl, carboxy lower alkyl, protected carboxy lower alkyl, carboxy lower alkenyl, protected carboxy lower alkenyl Group, amino lower alkyl group, protected amino lower alkynole group, arylo group, arylooxy group, carboxyl group, protected carboxyl group, carbamoyl group, N-mono-lower alkyl carbamoyl group, Ν, Ν-di Lower alkyl group rubamoyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, aryloxycarbonyl group, aryl lower alkoxycarbonyl group, lower alkylsulfonyloxy group, arylsulfonyloxy group, Suphoryloxy group, di-lower alkoxy phosphoryloxy group, amino group, protected amino group, ア ル -aryl lower alkyloxycarbonylamino group, ァ -mono lower alkylamino group, protected Ν-mono lower alkylamino group, Ν, Ν-di-lower alkylamino group, lower alkanolamino group, aroylamino group, aminocarbonyloxy group, Ν-lower alkylaminocarbonyloxy group, Ν, Ν-dilower alkylaminocarbonyloxy group, Selected from the group consisting of piperidinyl carbonyloxy group, nitro group, amidino group, protected amidino group, guanidino group, protected guanidino group and cyano group which may be substituted with a lower alkyl group or a heterocyclic group. A phenyl group which may have 1 to 5 substituents, or a group having 1 to 3 substituents. May indicate a nitrogen atom, 5-10 membered heterocyclic group containing an oxygen atom and 1 to 3 heteroatom selected from the group consisting of sulfur atoms. (However, when both Υ and い ず れ are substituted phenyl groups, at least one of them has at least one hydroxy group.) Or a pharmaceutically acceptable salt thereof as an active ingredient Tyrosine kinase inhibitors.

(2) General formula

 I]

[Wherein the dotted line indicates that either the exocyclic or the intracyclic bond to which it is attached is a double bond and the other is a single bond, and W is = NR ² , an oxygen atom or a sulfur atom. X represents = NR ³ , a nitrogen atom or = C = 0, V represents CR ⁴ or a nitrogen atom, and R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a lower alkynyl group. , A cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group or an aryl lower alkyl group, wherein R ² and R ³ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, Ariru group, Ariru lower alk kill group, a Arukanoiru group or a lower Aroiru group, R ⁴ is a hydrogen atom, a lower § alkyl group, a lower alkenyl group, lower alkyl Alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, aryl group, aryl lower alkyl group, hydroxy lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy lower alkyl group, amino lower alkyl group, guamino Represents a protected amino lower alkyl group, a carboxy lower alkyl group, a protected carboxy lower alkyl group, a cyano lower alkyl group, a cyano group, a lower alkylsulfonyl group or a lower alkyl group, and Y and Z are the same or different. Lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, cycloalkyl lower alkyl group, aryl group, aryl lower alkyl group, hydroxy group, protected hydroxy group, hydroxy lower alkyl group, protection Hydroxy lower alkyl , Lower alkoxy, lower alkenyloxy, lower alkynyloxy, aryloxy, cycloalkyl lower alkoxy, aryl lower alkoxy, lower alkanoyl, lower alkanoyloxy, lower alkenyloxy lower alkyl , Lower alkoxy lower alkyl group, aryloxy lower alkyl group, halogen atom, halo lower alkyl group, carboxy lower alkyl group, protected carboxy lower alkyl group, carboxy lower alkyl Nyl group, protected carboxy lower alkenyl group, amino lower alkyl group, protected amino lower alkyl group, arylo group, arylooxy group, carboxyl group, protected carboxyl group, carbamoyl group, N-mono-lower alkyl group Carbamoyl group, Ν, Ν-di-lower alkyl group rubamoyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, aryloxycarbonyl group, aryl lower alkoxycarbonyl group, lower alkylsulfonyloxy group, aryl Sulfonyloxy group, phosphoryloxy group, di-lower alkoxyphosphoryloxy group, amino group, protected amino group, Ν-aryl lower alkyloxycarbonylamino group, Ν-mono-lower alkylamino group, protected Ν -Mono lower alkylamino group, Ν, Ν-di-low Alkylamino group, lower alkanoylamino group, aryloamino group, aminocarbonyloxy group, Ν-lower alkylaminocarbonyloxy group, Ν, Ν-dilower alkylaminocarbonyloxy group, lower alkyl group or hetero ring 1 to 5 substituents selected from the group consisting of piperidinyl carbonyloxy group, nitro group, amidino group, protected amidino group, guanidino group, protected guanidino group and cyano group which may be substituted with a group. Optionally containing a fuunyl group or 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom which may have 1 to 3 substituents 5 Represents a 10-membered heterocyclic group. (However, when both Υ and Ζ are substituted phenyl groups, at least one of them has at least one hydroxy group. Further, W is an oxygen atom, X is = C = 0, and V is ≡CR ⁴ , when R ¹ and R ⁴ are both hydrogen atoms and Y and Z are both 3,4-dihydroxy-open xylphenyl groups, W is an oxygen atom, X is = C = 0, When V is 3 CR ⁴ , R ¹ and R ⁴ are both hydrogen atoms and Y is a phenyl group, the Z force 2-hydroxyphenyl group, 4-hydroquinphenyl group, 4-hydroxy-3-methyl In the case of a toxicoxyl group, a 4-ethylinoamino-2-hydroxyphenyl group or a 3,5-dibromo-2-hydroxyphenyl group, W is an oxygen atom, X is C = 0, and ! ^ ⁴ and when R ¹ and R ⁴ are both hydrogen atoms and Y is a 4-methoxyphenyl group, Z is 2-hydrogen Xyphenyl, 5-chloro-2-hydroxyphenyl, 3,5-dibromo-2-hydroxyphenyl, 2,4-dihydroxyphenyl, 4-methylamino-2-hydroxyphenyl, 4-hydroxy In the case of a 3-methoxyethoxy group or a 3-ethoxy-4-hydroxyphenyl group, W is an oxygen atom, X is = C = 0, is! ^, R ¹ And when R ⁴ is both a hydrogen atom and Y is a 4-chlorophenyl group, and when Z is a 4-hydroxy-3-methoxyphenyl or 2-hydroxyphenyl group, W is an oxygen atom and X is = C = 0, a V Gayo CR ^4, when R ¹ and R ⁴ are both a hydrogen atom and Y is a 4-Buromofuweniru group, Z is 4-hydroxy - for 3 main Tokishifue two Le group, W Is an oxygen atom, X is C = 0, V is CR ³ , R ¹ and R ⁴ are both hydrogen atoms, and Y is a 4-methylphenyl group, and Z is 4-hydroxy- for 3 main Tokishifuweniru group, W is an oxygen atom, X is = C = 0, V is ≡ CR ^4, R ¹ and R ⁴ is a hydrogen atom and Y are both 4-isopropylidenediphenol When Z is a 4-hydroxy-3-methoxyphenyl group when R is a phenyl group, W is an oxygen atom, X is = C = O, and R ¹ and R ⁴ are both If Z when a hydrogen atom and Y is 4-Bifuweniru group is 2-hydroxy phenyl group, W is an oxygen atom, X is = C = 0, V is a three-CR ^4, R ¹ and When both R ⁴ are hydrogen atoms and Y is a 2-phenyl group, and Z is a 3-furyl group, W is an oxygen atom, X is C = 0, and V is CR ⁴ , R ¹ and R ⁴ are hydrogen and Y is 2-dibenzophenyl, Z is phenyl, 4-methoxyphenyl, 3,4-methylenedioxyphenyl, 2- Kurorofuweniru group, in the case of 4-Kurorofuweniru group or a 2-furyl group, W is a sulfur atom, X is = C = 0, ¥ is ≡01 ^4, R ¹ and R ⁴ are both hydrogen atoms And Y When Z is 2-hydroxyphenyl group, 5-chloro-2-hydroxyphenyl group or 2-hydroxy-3-methoxyphenyl group, W is a sulfur atom, and X is = C = a 0, V is ≡CR ^4, when R ¹ and R ⁴ are both a hydrogen atom and Y is a 4-Mechirufuweniru group, Z is 2-hydroxy-phenylene Honoré group or a 4 Hidorokin - 3- Except for methoxyphenyl group. )] Or a pharmaceutically acceptable salt thereof.

(3) General formula

 [I]

[Wherein the dotted line indicates that one of the exocyclic or intracyclic bonds to which it is attached is a double bond and the other is a single bond, V \ Mi = NR ² , an oxygen atom or X represents = NR ³ , nitrogen atom or = C = 0, ¥ represents ≡〇 or nitrogen atom, R 'represents hydrogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group , A cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group or an aryl lower alkyl group, wherein R ² and R ³ are the same or different and are a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl R ⁴ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkyl group, a cycloalkyl lower alkyl group, an aryl group, an aryl lower alkyl group, an alkanoinole group or a lower arylene group. Quinyl group, cycloalkyl group, cycloalkyl lower alkyl group, aryl group, aryl lower alkyl group, hydroxy lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy lower alkyl group, amino lower alkyl group, protected Represents an amino lower alkyl group, carboquine lower alkyl group, protected carboxy lower alkyl group, cyano lower alkyl group, cyano group, lower alkylsulfonyl group or lower alkyl group, and Y and Z are the same or different. , Lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, cycloalkyl lower alkyl group, aryl group, aryl lower alkyl group, hydroxy group, protected hydroxy group, hydroxy lower alkyl group, protected Hydroxy lower alkyl Lower group, lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, aryloxy group, cycloalkyl lower alkoxy group, aryl lower alkoxy group, lower alkanol group, lower alkanoyloxy group, lower alkenyloxy lower Alkyl group, lower alkoxy lower alkyl group, aryloxy lower alkyl group, halogen atom, halo lower alkyl group, carboxy lower alkyl group, protected carboxy lower alkyl group, carboxy lower alkyl Nyl group, protected carboxy lower alkenyl group, amino lower alkyl group, protected amino lower alkyl group, arylo group, arylooxy group, carboxyl group, protected carboxyl group, carbamoyl group, N-mono-lower alkyl group Carbamoyl group, Ν, Ν-di-lower alkyl group rubamoyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, aryloxycarbonyl group, aryl lower alkoxycarbonyl group, lower alkylsulfonyloxy group, aryl Sulfonyloxy group, phosphoryloxy group, di-lower alkoxyphosphoryloxy group, amino group, protected amino group, Ν-arinole lower alkyloxycarbonylamino group, Ν-mono-lower alkylamino group, protected Ν -Mono-lower alkylamino group, Ν, Ν-di Lower alkylamino group, lower alkanoylamino group, aryloamino group, aminocarbonyloxy group, ア ル -lower alkylaminocarbonyloxy group, Ν, Ν-dilower alkylaminoaminocarbonyl group, lower alkyl group or heteroalkyl group 1 to 5 substituents selected from the group consisting of piperidinylcarbonyloxy, nitro, amidino, protected amidino, guanidino, protected guanidino, and cyano which may be substituted with a telocyclic group Or a 1-3 heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents. And a 5- to 10-membered heterocyclic group. (However, when both Υ and Ζ are substituted phenyl groups, both of them have at least one hydroxy group. Also, W is an oxygen atom, X is = C = 0, and \ is {01} ⁴ , when R ¹ and R ⁴ are both hydrogen atoms and Y and Z are both 3,4-dihydroxyphenyl groups, W is an oxygen atom, X is C = 0, and When R ¹ and R ⁴ are both hydrogen atoms and Y is a 2-phenyl group, Z is a 3-furyl group, and W is an oxygen atom, and X is = C = 0. And when V is 3 CR ⁴ , R ¹ and R ⁴ are both hydrogen atoms and Y is 2-dibenzothenyl, Z is phenyl, 4-methoxyphenyl, 3,4- Excluding methylenedioxyphenyl, 2-chlorophenyl, 4-chlorophenyl or 2-furyl))] or a pharmaceutically acceptable salt thereof. .

 (Four)

3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) isooxo Sasol,

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1,2,4-oxadiazole,

 (E) -4- (3,4-dihydroxybenzylidene) -2- (3,4-dihydroxybenzyl)-1,3-oxazoguchi-5-one,

 (E) -2- (3,4-dihydroxyphenyl) -4- (4-hydroxyquinbenzylidene) -1,3-oxazochi-5-one,

 3- (3,4-dihydroxybenzinole) -5- (3,4-dihydroxyquinphenyl) pyrazole,

5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzyl) pyrazole, 3- (3-arinole-4-hydroxybenzyl) -5- (3,4-dihydroxyphenyl) pyrazole ,

 5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-propylbenzyl) pyrazole,

5- (3,4-dihydroxyphenyl) -3- 3- [3- (2,3-dihydroxypropyl) -4- 4-hydroxyphenyl] virazole,

 3- [3- (2,3-dibromopropyl) -4-hydroxyphenyl] -5- (3,4-dihydroxyphenyl) pyrazole,

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1- (2-pyridyl) pyrazole,

 1-arinole-3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) pyrazole,

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1- (8-quinolylmethyl) pyrazole,

1-acetinole-3- (3,4-dihydroxybenzinole) -5- (3,4-dihydroxyphene) pyrazole,

 3- (3,4-dihydroxybenzinole)-5- (3,4-dihydroxyphenyl)-trimethylvirazole and 5- (3,4-dihydroxybenzyl)-3- (3,4 -Dihydroxyphenyl)-1-methylvirazole mixture,

3- (3,4-dihydroxybenzinole) -5- (3,4-dihydroxybenzene)-4-methyl Ruvirazole,

 (E) -3- [α-methyl- (3,4-dihydroxy) benzylidene] -5- (3,4-dihydroxyphenyl) -2,3-dihydroxypyrroquinone-2-one;

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -2,3-dihydroxypyrrol-2-one,

 (Ε) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene) -2 (3Η) -furanone,

 (Ε) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxybenzylidene) -2 (3Η) -furanone,

(Ε) -3- (3,4-dihydroxybenzylidene) -5- (4-hydroxyphenyl) -2 (3Η) -furanone,

 (Ε) -3- [(E) -4- (2-carboxyvinyl) benzylidene] -5- (3,4-dihydroxy xyphenyl) -2 (3Η) -furanone,

 (Ε) -3- (2,3-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3Η) -furanone,

 (Ε) -3- (2,6-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3Η) -furanone,

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- (3-hydroxyphenyl) -2 (3Η) -furanone,

(Ε) -3- (3-aryl-4-hydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -2 (3Η) -furanone,

 (Ε) -5- (4-carboxyphenyl)-3- (3,4-dihydroxybenzylidene)-2 (3Η) -furanone,

 (Ε) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methoxycarbonylcarbonylbenzylidene) -2 (3Η) -furanone,

 (Ε) -3- [3- (2,3-dibromopropyl) -4-hydroxybenzylidene] -5- (3,4-dihydroxyphenyl) -2 (3Η) -furanone,

 (Ε) -5- (3-carboxy-4-hydroxyphenyl) -3- (3,4-dihydroxybenzylidene) -2 (3Η) -furanone,

(Ε) -3- (3-carboxy-4-hydroxybenzylidene) -5- (3,4-dihydroxy Shifuenil) -2 (3H) -Furanone,

 (E) -5- (3,4-dihydroxyphenyl)-3- (3,4,5-trihydroxybenzylidene) -2 (3H) -furanone,

 (E)-3- (2,5-dihydroxybenzylidene)-5_ (3,4-dihydroxybenzyl)-2 (3H)-furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (6-methoxy-2-pyridylmethylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2-methoxy-5-pyridylmethylidene) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- (5-hydroxy-3-pyridylmethylidene) -2 (3H) -furanone,

 (E) -3- (4-Jetoxyphosphoryloxybenzylidene) -5- (3-hydroxy-4-methoxyphenyl) -2 (3H) -furanone,

 (E) -3- (4-diethoxyphosphoryloxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-phosphonobenzylidene) -2 (3H) -furanone,

 (E)-3- (4-aryl-3-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- (4-methoxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- [4-hydroxy-3- (4-piberidinoviperidinocarbonyloxy) benzylidene] -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- [3-hydroxy-4- (4-piperidinobiperidinocarbonyloxy) benzylidene] -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- [4-hydroxy-3- (4-methylbiperazinocarbonyloxy) benzylidene] -2 (3H) -furanone,

(E) -3- [4- (4-carboxyphenylsulfonyloxy) benzylidene] -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

(E) -5- [4- (4-Carboxyphenylsulfonyloxy) phenyl] -3- (3, 4-dihydroxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-Dihydroxyphenyl) -3- (2-Chenylmethylidene) -2 (3H) -Furanone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (2-Chenylmethylidene) -2 (3H) -Furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-phenoxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- (3-funoleo mouth-4-hydroxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2-fluoro-3-3-hydroxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-nitrobenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2,3-dimethyl-4-hydroxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -furanone,

 (E) -3- (2,3-Diphnoleo-4--4-hydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxy-4-trifluoromethylbenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-propylbenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxy-2-methylphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- (3-ethyl-4-hydroquinbenzene Redene) -2 (3H)-furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (2,3,4-trihydroxyphenyl) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (4-hydroxy-3-methoxyphenyl) -2 (3H) -furanone,

 (E) -5- (4-hydroxy-3-methoxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methoxybenzylidene) -2 (3H) -furanone,

 (E) -3- (3-acetoxymethyl-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (4-formylphenyl) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-hydroxymethyltylbenzylidene) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenone,

(E) -5- (3,4-dihydroxyphenyl) -3- (3-funoleo mouth-4-hydroxybenzylidene) -2 (3H) -thiophenedone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroquin-3-methylbenzylidene) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxybenzylidene) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxybenzyl) -3- (3-hydroxybenzylidene) -2 (3H) -thiophenone,

 (E)-3- (3-arinole-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenone,

(E) -5- (3,4-dihydroxyphenyl)-3- (3,5-dimethyl-4-hydroxybe) Benzylidene) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroquinphenyl) -3- (4-hydroxy-3-propylbenzylidene) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -thiophenone,

 (E) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenedone,

 (E) -3- (3,5-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenone,

(E) -3- (3,4-dihydroxybenzylidene) -5- (4_hydroxyphenyl) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-2,3-dimethylbenzylidene) -2 (3H) -thiophenone,

 (E) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (4-hydroxyphenyl) -2 (3H) -thiophenedone,

 (Z) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -4-methyl-2 (3H) -thiophenedone,

(E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (3,5-dimethyl-4-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (3-fluoro-4--4-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -3- (3-fluoro- mouth-4-hydroxybenzylidene) -5- (3-hydroxy-4-methoxyphenylene) -4-methyl-2 (3H) -thiophenone,

(Z) -3- (3,5-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydro Xyphenyl) -4-methyl-2 (3H) -thiophenone,

 (Z) -3- (3-, 5-Diphnoleo-4--4-hydroxybenzylidene) -5- (3-hydroxy-

4-methoxyphenyl) -4-methyl-2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxyquinbenzylidene) -4-methyl-2 (3H) -thiophenone,

 (E) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -4-methyl-2 (3H) -thiophenone,

(Z) -3- (2,3-difluoro-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -4-methyl-2 (3H) -thiophenone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (phenethyl-2-pyridone-

5-yl) -2 (3Η) -furanone,

 (Ε) -5- (1-benzyl-2-pyridone-5-inole) -3- (3,4-dihydroxybenzylidene) -2 (3Η) -furanone,

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- [1- (4-hydroxybenzyl) -2-pyridone-5-inole] -2 (3Η) -furanone,

 (Ε) -5- (Tricyclohexylmethyl-2-pyridone-5-isle) -3- (3,4-dihydroxybenzylidene) -2 (3Η) -furanone,

(Ε) -5-α-butyl-2-pyridone-5-yl) -3- (3,4-dihydroxybenzylidene) -2 (3Η) -furanone,

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- [1- (3-phenylpropyl) -2-pyridone-5-inole] -2 (3Η) -furanone,

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- [1- (2-phenyloxetinole) -2-pyridone-5-yl] -2 (3Η) -furanone,

 (Ε) -5- (1-benzyl-2-pyridone-5-inole) -3- (4-hydroxy-3-methylbenzylidene) -2 (3Η) -furanone,

 (Ε)-3- (3,4-dihydroxybenzylidene) -5- [1- (2-naphthylmethyl) -2-pyridone-5-inole] —2 (3Η) —furanone,

(Ε) -5- (Tribenzyl-2-pyridone-5-inole) — 3_ (3-Fluoro-4-hydroxy Benzylidene)-2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (tretyl-2-pyridone-5-yl) -2 (3Η) -furanone,

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- (1-phenethyl-2-pyridone-5-yl) -1-2 (3Η) -thiofuunone,

 (Ε) -3- (3-hydroxybenzylidene) -5- (1-phenethyl-2-pyridone-5-yl) -2 (3Η) -thiophenone,

 (Ε) -3- (2,3-Difluoro mouth-4-hydroxybenzylidene) -5- (Triphenyl-

2- (pyridone-5-inole) -2 (3Η) -thiophenone or (Ε) -3- (4-hydroxy-3-methylbenzylidene) -5- (tophenethyl-2-pyridone-5-inole)- 3. The compound according to claim 2, which is 2 (3Η) -thiophenone, or a pharmaceutically acceptable salt thereof. (Five)

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenizole) isoxazole,

3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1,2,4-year-old oxadiazole,

 (Ε) -4- (3,4-dihydroxybenzylidene) -2- (3,4-dihydroxyphenyl) -5-oxazolone,

 (Ε) -2- (3,4-dihydroxyphenyl) -4- (4-hydroxybenzylidene) -5-year-old xazolone,

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) pyrazole,

 5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzyl) pyrazole, 3- (3-arinole-4-hydroxybenzyl) -5- (3,4-dihydroxyphenyl) pyrazole,

 5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-propylbenzyl) pyrazole,

 5- (3,4-dihydroxyphenyl) -3- [3- (2,3-dihydroxypropyl) -4-hydroxyphenyl] virazole,

3- [3- (2,3-dibromopropyl) -4-hydroxybenzoyl 1-5- (3,4-dihydrogen Roxyphenyl) pyrazole,

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1- (2-pyridyl) pyrazole,

 1-arinole-3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) pyrazole,

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1- (8-quinolylmethyl) pyrazole,

Triacetyl-3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) pyrazole,

3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -1-methylvirazole and 5- (3,4-dihydroxybenzyl) -3- (3,4 -Dihydroxyphenyl)-1-methylpyrazole mixture,

 3- (3,4-dihydroxybenzyl) -5- (3,4-dihydroxyphenyl) -4-methylvirazole,

(E) -3- [α-methyl- (3,4-dihydroxy) benzylidene] -5- (3,4-dihydroxyphenyl) -2,3-dihydroxypyrrol-2-one;

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2,3-dihydropyrroquinone-2-one,

 (Ε) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene)-2 (3Η) -furanone,

 (Ε) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxybenzylidene) -2 (3Η) -furanone,

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- (4-hydroxyphenyl) -2 (3Η) -furanone,

(Ε) -3- [(E) -4- (2-carboxyvinyl) benzylidene]-5- (3,4-diethyl oxyphenyl)-2 (3Η) -furanone,

 (Ε) -3- (2,3-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3Η) -furanone,

(Ε) -3- (2,6-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3Η) -furanone, (E) -3- (3,4-dihydroxybenzylidene) -5- (3-hydroxyphenyl) -2 (3H) -furanone,

 (E) -3- (3-arinole-4-hydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -2 (3H) -furanone,

(E) -5- (3-carboxy-4-hydroxyphenyl) -3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone,

 (E) -3- (3-carboxy-4-hydroxybenzylidene) -5- (3,4-dihydroxy cyclidenyl) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3,4,5-trihydroxybenzylidene) -2 (3H) -furanone,

 (E) -3- (2,5-dihydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

 (E) -3- (4-diethoxyphosphoroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- (4-phosphonobenzylidene) -2 (3H) -furanone,

 (E) -3- (4-aryl-3-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-methoxybenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- [4-hydroxy-3- (4-piberidi-nopiperidino-power ponyloxy) benzylidene] -2 (3H) -furanone, (E ) -5- (3,4-dihydroxyphenyl) -3- [4-hydroxy-3- (4-methylbiperazinocarbonyloxy) benzylidene] -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-fluoro-4--4-hydroxybenzylidene) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl) -3- (2-fluoro-3-hydroxybenzylidene) -2 (3H) -furanone, (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-nitrobenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl)-3- (2,3-dimethyl-4-hydroxybenzylidene)-2 (3H) -furanone,

(E) -5- (3,4-dihydroxyphenyl)-3- (2,5-dimethyl-4-hydroxybenzylidene)-2 (3H) -furanone,

 (E) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxy-4-trifluoromethylbenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-propylbenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -furanone,

(E) -5- (3,4-dihydroxy-2-methylphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-ethyl-4-hydroxybenzylidene) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (2,3,4-trihydroquinophenyl) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dimethoxyphenyl) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (4-hydroxy-3-methoxyphenyl) -2 (3H) -furanone,

(E) -5- (4-Hydroxy-3-methoxyphenyl) -3- (4-Hydroxy-3-methylbenzylidene) -2 (3H) -Furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methoxybenzylidene) -2 (3H) -furanone,

(E) -3- (3-acetoxymethyl-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -furanone, (E) -3- (3,4-dihydroxybenzylidene) -5- (4-formylphenyl) -2 (3H) -furanone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-hydroxymethyltylbenzylidene) -2 (3H) -furanone,

(E) -3- (3,4-dihydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3-fluoro-4--4-hydroxybenzylidene) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -thiophenenone,

 (E) -5- (3,4-dihydroxybenzyl) -3- (4-hydroxybenzylidene) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxybenzyl) -3- (3-hydroxybenzylidene) -2 (3H) -thiofunone,

(E) -3- (3-arinole-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (3,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -thiophenone, '

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-propylbenzylidene) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -2 (3H) -thiophenone,

 (E) -3- (2,3-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenenone,

(E) -3- (3,5-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-2,3-dimethylbenzylidene) -2 (3H) -thiophenone,

(E) -3- (2,3-difluoro-4-hydroxybenzylidene) -5- (4-hydroxyphenyl) -2 (3H) -thiophenone, (Z)-3- (3,4-dihydroxybenzylidene)-5- (3,4-dihydroxybenzylidene)-4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (4-hydroxy-3-methylbenzylidene) -4-methyl-2 (3H) -thiophenone,

(E) -5- (3,4-dihydroxyphenyl) -3- (3-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxybenzyl) -3- (3-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (3,5-dimethyl-4-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyl) -3- (3-fluoro-4-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -3- (3-fluoro-4-hydroxybenzylidene) -5- (3-hydroxy-4-methoxyphenyl) -4-methyl-2 (3H) -thiophenone,

(Z) -3- (3,5-difluoro mouth-4-hydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -4-methyl-2 (3H) -thiophenedone,

 (Z) -3- (3,5-difluoro mouth-4-hydroxybenzylidene) -5- (3-hydroxy-

4-methoxy-2) -4-methyl-2 (3H) -thiophenone,

 (E) -5- (3,4-dihydroxyphenyl) -3- (2,5-dimethyl-4-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (Z) -5- (3,4-dihydroxyphenyle) —3— (2,5-dimethinole—4-hydroxybenzylidene) -4-methyl-2 (3H) -thiophenone,

 (E) -3- (2,3-difluoro-4-hydroxybenzylidene) -5- (3,4-dihydroxybenzyl) -4-methyl-2 (3H) -thiophenedone,

(Z) -3- (2,3-difluoro_4-hydroxybenzylidene) -5- (3,4-dihydroxyphenyl) -4-methyl-2 (3H) -thiophenone,

 (E)-3- (3,4-dihydroxybenzylidene) -5- (1_Phenethyl-2-pyridone-

5-yl) -2 (3H)-furanone,

(E) -5- (Tribenzyl-2-pyridone-5-inole)-3- (3,4-dihydroxybenzylidene) -2 (3Η) -Furanone, (E) -3- (3,4-dihydroxybenzylidene) -5- [1- (4-hydroxybenzylinole) -2-pyridone-5-inole] —2 (3H) —furanone,

 (E) -5- (1-cyclohexylmethyl-2-pyridone-5-yl) -3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone,

(E) -5- (1-butyl-2-pyridone-5-inole) -3- (3,4-dihydroxybenzylidene) -2 (3H) -furanone,

 (E) -3-(3,4-dihydroxybenzylidene) _5- [1- (3-phenylpropyl) -2-pyridone-5-inole] _2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- [1- (2-phenyloxethyl) -2-pyridone-5-inole] -2 (3H) -furanone,

 (E) -5- (1-benzyl-2-pyridone-5-inole) -3- (4-hydroxy-3-methylbenzylidene) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- [1- (2-naphthylmethyl) -2-pyridone-5-inole] -2 (3H) -furanone,

(E) -5- (1-Benzyl-2-pyridone-5-inole) -3- (3-Fluoro-4-hydroxy benzylidene) -2 (3H) -furanone,

 (E) -3- (3,4-dihydroxybenzylidene) -5- (tretyl-2-pyridone-5-yl) -2 (3Η) -furanone,

 (Ε) -3- (3,4-dihydroxybenzylidene) -5- (triphenyl-2-pyridone-5-yl) -2 (3Η) -thiophenone,

 (Ε) -3- (3-Hydroxybenzylidene) -5- (Triphenethyl-2-pyridone-5-yl) -2 (3Η) -Thiophenone,

(Ε) -3- (2,3-Difluoro-4-hydroxybenzylidene) -5-hydroxy-phenyl-2-pyridone-5-inole) -2 (3Η) -thiophenone or (Ε) -3- 3. The compound according to claim 2, which is (4-hydroxy-3-methylbenzylidene) -5- (tophenethyl-2-pyridone-5-yl) -2 (3Η) -thiophenedone, or a pharmaceutically acceptable compound thereof. salt. (6) General formula

Wherein R ⁵ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group, an aryl lower alkyl group, a protected hydroxy lower alkyl group, a lower alkoxy group A lower alkyl group, a protected amino lower alkyl group, a protected carboxy lower alkyl group, a cyano lower alkyl group, a cyano group, a lower alkyl sulfonyl group or a lower alkyl group; Y ¹ represents a lower alkyl group; Lower alkenyl group, lower alkynyl group, cycloalkyl group, cycloalkyl lower alkyl group, aryl group, aryl lower alkyl group, protected hydroxy group, protected hydroxy lower alkyl group, lower alkoxy group, lower alkenyloxy group, Lower alkynyloxy group, aryl Alkoxy group, cycloalkyl lower alkoxy group, aryl lower alkoxy group, lower alkanol group, lower alkanoyloxy group, lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, aryloxy lower alkyl group, halogen atom, halo lower Alkyl group, protected carboxy lower alkyl group, protected carboxy lower alkenyl group, protected amino lower alkyl group, aroyl group, aroyloxy group, protected carboxyl group, carbamoyl group, N-mono-lower Alkyl group Rubamoinole group, N, N-di-lower alkyl group Lubamoyl group, lower alkoxycarbonyl group, lower alkenyloxycarbonyl group, aryloxycarbonyl group, aryl lower alkoxycarbonyl group, lower alkylsulfonyloxy Group, arylsulfonyloxy group, di-lower alkoxyphosphoryloxy group, protected amino group, N-aryl lower alkyloxycarbonylamino group, N-mono lower alkylamino group, protected N -Mono-lower alkylamino group, Ν, Ν-dilower alkylamino group, lower alkanoylamino group, aryloamino group, Ν-lower alkylaminocarbonyloxy group, Ν, Ν-dilower alkylaminocarbonyl group Piperidinylcarbonyloxy group, nitro group, protected amidino group, protected group which may be substituted with a oxy group, a lower alkyl group or a heterocyclic group. A nitrogen atom, an oxygen atom, which may have 1 to 5 substituents selected from the group consisting of an anidino group and a cyano group, and may have 1 to 3 substituents; And a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of: ] Is treated with diphosphorus pentasulfide to give a general formula

R ⁵ R ⁵

After obtaining a compound represented by the formula: wherein R ⁵ and Y ¹ are as defined above, under acidic conditions,

R ¹

 -71, 0

Wherein Z ¹ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group, an aryl lower alkyl group, a hydroxy group, a protected hydroxy group, a protected hydroxy group Lower alkyl group, lower alkoxy group, lower alkenyloxy group, lower alkynyloxy group, aryloxy group, cycloalkyl lower alkoxy group, aryl lower alkoxy group, lower alkanoyl group, lower alkanoyloxy group, lower alkanoy Roxy lower alkyl group, lower alkoxy lower alkyl group, aryloxy lower alkyl group, halogen atom, halo lower alkyl group, protected carboxy lower alkyl group, protected carboxy lower alkenyl group, protected amino lower alkyl group , Aryloyl, aryloxy, protected carboxyl, rubamoyl, N-mono-lower alkyl rubamoyl, Ν, Ν-di-lower alkyl rubamoyl, lower alkoxycarbonyl, lower alkenyloxycarbonyl , Aryloxycarbonyl group, aryl lower alkoxycarbonyl group, lower alkylsulfonyloxy group, arylaryl Honyloxy group, di-lower alkoxyphosphoryloxy group, protected amino group, N-aryl lower alkyloxycarbonylamino group, N-mono lower alkyl amino group, protected N-mono lower alkyl amino group, Ν, Ν- Substituted with di-lower alkylamino group, lower alkanoylamino group, aryloamino group, Ν-lower alkylaminocarbonyloxy group, Ν, Ν-dilower alkylaminocarbonyloxy group, lower alkyl group or heterocyclic group May have from 1 to 5 substituents selected from the group consisting of a piperidinylcarboxy group, a nitro group, a protected amidino group, a protected guanidino group and a cyano group. A phenyl group or 1 to 3 hetero atoms optionally having 1 to 3 substituents selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Shows a 5- to 10-membered heterocyclic group containing a terrorist atom. R ¹ represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group or an aryl lower alkyl group. A compound represented by the general formula:

Wherein R ¹ has the above-mentioned meaning, and R ⁴ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group, an aryl lower alkyl group, Lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy lower alkyl group, amino lower alkyl group, protected amino lower alkyl group, carboxy lower alkyl group, protected carboxy lower alkyl group, cyano lower alkyl group , A cyano group, a lower alkylsulfonyl group or a lower alkanoinole group, and Υ and Ζ are the same or different and are a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl. Group, aryl lower alkyl group, hydroquine group , Protected hydroxy group, hydroxy lower alkyl group, protected hydroxy lower alkyl group, lower alkoxy group, lower Lower alkenyloxy group, lower alkynyloxy group, aryloxy group, cycloalkyl lower alkoxy group, aryl lower alkoxy group, lower alkanol group, lower alkenyloxy group, lower alkenyloxy lower alkyl group, lower alkoxy lower alkyl group Group, aryloxy lower alkyl group, halogen atom, halo lower alkyl group, carboxy lower alkyl group, protected carboxy lower alkyl group, carboxy lower alkenyl group, protected carboxy lower alkenyl group, amino lower alkyl group, protected Amino lower alkyl group, aryloyl group, arylooxy group, carboxyl group, protected carboxyl group, carbamoyl group, N-mono lower alkyl group rubamoyl group, Ν, Ν-di lower alkyl group rubamoyl group, lower alkyl group Xycarbonyl group, lower alkenyloxycarbonyl group, aryloxycarbonyl group, aryl lower alkoxycarbonyl group, lower alkylsulfonyloxy group, arylsulfonyloxy group, phosphoryloxy group, di-lower alkoxyphosphoryloxy group , Amino, protected amino, 、 -aryl lower alkyloxycarbonylamino, Ν-mono-lower alkylamino, protected Ν-mono-lower alkylamino, Ν, Ν-di-lower alkylamino , Lower alkanoylamino, aryloamino, aminocarbonyloxy, Ν-lower alkylaminocarbonyloxy, Ν, Ν-dilower alkylaminocarbonyloxy, lower alkyl or heterocyclic Piperidinylcarbonyloxy group, nitro group, An amidino group, a protected amidino group, a guanidino group, a phenyl group optionally having 1 to 5 substituents selected from the group consisting of a protected guanidino group and a cyano group, or 1 to 3 A 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have one or more such substituents. 3. The method for producing a compound according to claim 2, which is represented by the formula: