JP2711435B2 - Novel 2,3-dihydro-4H-1-benzopyran-4-one derivative or salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the general formula [1]

Embedded image [Wherein R ¹ represents a lower alkyl, lower alkenyl or aryl group optionally substituted with a halogen atom;
² represents a hydrogen atom, an alkyl group or an acyl group; R ³ represents
A hydrogen atom, a halogen atom, a cyano group, azido group, carboxyl group, hydroxyl group, formyl group or alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R ⁴ Is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, an acyl group, a hydroxyl group or an alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl,
Lower alkenyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic group, or formula

Embedded image Or expression

Embedded image (Wherein, R ⁶ represents a hydrogen atom, a hydroxyl group, a cyano group or an alkoxycarbonyl group, or an optionally substituted alkyl, cycloalkyl, phenyl, amino,
Acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group; R ⁷ represents a hydrogen atom, an optionally substituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group, or R ⁶ and R ⁷ are adjacent It represents a 3- to 7-membered optionally substituted heterocyclic group together with a nitrogen atom. R ⁵ represents an optionally substituted phenyl, thienyl, furyl or pyridyl group; and Z represents an oxygen atom, a sulfur atom or an imino group. 2,3-dihydro-4H-1
-Benzopyran-4-one derivatives or salts thereof.

[0002]

2. Description of the Related Art The following general formula [A] described in JP-A-2-49778

Embedded image [Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the meanings described above. The 4H-1-benzopyran-4-one derivative or a salt thereof represented by the formula [1] has excellent anti-inflammatory, antipyretic, analgesic, anti-arthritic and anti-allergic effects and exhibits excellent therapeutic effects. .

[0003]

There is a need for a useful intermediate for producing a 4H-1-benzopyran-4-one derivative represented by the general formula [A] or a salt thereof.

[0004]

Under these circumstances, the present inventors have conducted intensive studies and have found that the general formula [1]
The 2,3-dihydro-4H-1-benzopyran-4-one derivative represented by the formula or a salt thereof is useful for producing the 4H-1-benzopyran-4-one derivative represented by the general formula [A] or a salt thereof As a result, the present invention was completed. Hereinafter, the compound of the present invention will be described in detail.

[0005] In this specification, each term has the following meaning unless otherwise specified. An alkyl group is, for example, methyl, ethyl, n-propyl, iso-propyl, n-
Butyl, iso- butyl, tert- butyl, pentyl, hexyl, a C ₁ ~ ₈ alkyl group such as heptyl, and octyl; and cycloalkyl groups, for example, cyclopropyl, cyclobutyl, cyclopentyl, C _3, such as cyclohexyl and cycloheptyl ~ ₈ cycloalkyl groups;
A lower alkyl group is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-
The C ₁ ~ ₅ alkyl group such as butyl and pentyl; The lower alkenyl group, for example, vinyl, allyl, C ₂ ~ ₅ alkenyl group such as 1-propenyl and 1-butenyl; and alkoxy groups, for example, - O- alkyl group (the alkyl group denotes a C ₁ ~ ₈ alkyl group as described above.)
The; Acyl groups, e.g., formyl or acetyl, propionyl and C ₂ ~ ₈ alkanoyl or methoxalyl and alkoxyoxalyl group such as ethoxalyl such butyryl group, C ₃ ~ ₈ cycloalkylcarbonyl group or a benzoyl, such as cyclohexane carbonyl An alkoxycarbonyl group is, for example, a -COO alkyl group (an alkyl group is
Shows a C ₁ ~ ₈ alkyl groups mentioned above. The halogen atom, a fluorine atom, a chlorine atom, etc. bromine atom and an iodine atom;) in the alkylthio group, for example, -S- alkyl group (the alkyl group denotes a C ₁ ~ ₈ alkyl groups mentioned above. Alkylsulfinyl group means, for example, C ₁ such as methylsulfinyl and ethylsulfinyl;
~ ₄ alkylsulfinyl group; and alkylsulfonyl group, for example, a C ₁ - ₄ alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl; and aryl groups, e.g., groups such as phenyl and naphthyl;
An acylamino group is, for example, an -NH-acyl group (acyl group has the same meaning as described above); and an alkylamino group is, for example, -NH-alkyl group (the alkyl group is ₁ to ₈ alkyl groups).
A dialkylamino group is, for example,

[0006]

Embedded image (The alkyl group denotes a C ₁ ~ ₈ alkyl group as described above.)
A haloalkyl group includes, for example, chloromethyl, fluoromethyl, dichloromethyl, trifluoromethyl,
Halo-C such as dichloroethyl and trichloroethyl
_1-8 alkyl groups; and the alkylsulfonyloxy group,
For example, an alkylsulfonyl -O- group (an alkylsulfonyl group represents a C ₁ ~ ₄ alkylsulfonyl group described above.) The; The arylsulfonyloxy group, e.g., phenylsulfonyloxy and p- toluenesulfonyl group such as oxy the; and the lower alkynyl group, for example, C ₂ ~ ₅ alkynyl group and the like ethynyl and 2-propynyl; and heterocyclic group, for example, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, Benzimidazolyl, benzthiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4 -Triazolyl, tetrazolyl, pyridyl, quinolyl, isoxyl Ryl, pyrimidinyl, piperazinyl, pyrazinyl, pyridazinyl, 1,2,3,4-tetrahydroquinolyl, 1,2,4-triazinyl, imidazo [1,2-b] [1,2,4] triazinyl, pyrrolidinyl, morpholinyl And at least one selected from an oxygen atom, a nitrogen atom and a sulfur atom such as quinuclidinyl
A 4- to 6-membered or fused heterocyclic group containing two heteroatoms.

In the general formula [1], when R ⁶ and R ⁷ together with an adjacent nitrogen atom form a 3- to 7-membered heterocyclic group, examples of the heterocyclic group include: 3 such as azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl and pyrrol-1-yl
And a 7-membered nitrogen-containing heterocyclic group.

[0008] The alkyl in R ^3, alkoxy, cycloalkyl, phenoxy, amino, carbamoyl and phenyl; alkyl in R ^4, alkoxy, alkylthio, phenylthio, amidino, lower alkenyl, lower alkynyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl , phenyl and heterocyclic group; alkyl in R ^6, cycloalkyl, phenyl, amino, acyl, carbamoyl, alkylsulfonyl, iminomethyl and amidino groups; alkyl in R ^7, alkoxy, cycloalkyl, phenyl and heterocyclic group; R heterocyclic group 3-7 membered ^{ring 6} and R ⁷ are formed together with the adjacent nitrogen atom; and R ⁵
A phenyl, thienyl, furyl and pyridyl group are a halogen atom, an alkoxy, an alkylthio, a phenoxy, a carboxyl, an acyl, an alkoxycarbonyl,
Selected from carbamoyl, sulfamoyl, cyano, alkylsulfonyl, hydroxyl, mercapto, acylamino, alkylamino, dialkylamino, alkyl, cycloalkyl, oxo, nitro, haloalkyl, amino, phenyl, alkoxycarbonylamino, hydroxyimino and heterocyclic groups It may be substituted with one or more substituents.

2,3-dihydro-4H- of the general formula [1]
The salts of the 1-benzopyran-4-one derivative include pharmaceutically acceptable salts, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts, triethylamine And salts with organic amines such as pyridine; salts with amino acids such as lysine, arginine and ornithine; salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; fumaric acid, maleic acid, malic acid and citric acid Salts with organic carboxylic acids such as; methanesulfonic acid,
and salts with sulfonic acids such as p-toluenesulfonic acid and naphthalenedisulfonic acid.

The compound of the present invention further includes all isomers (geometric isomers, optical isomers), hydrates, solvates and crystal forms. The 2,3-dihydro-4H-1-benzopyran-4-one derivative of the general formula [1] or a salt thereof can be produced, for example, by the following method.

[0011]

Embedded image

Embedded image

[0012] ^{[wherein, R 1, R 2, R} 3, R 4, R 5 and Z have the meanings mentioned above, R ⁸ is a lower alkyl group; R ⁹ is substituted R ^3a is a hydrogen atom as described for R ³ or an optionally substituted alkyl, cycloalkyl or phenyl group; R ^4a is a hydrogen atom as described for R ⁴ Atom, cyano, acyl or alkoxycarbonyl group or an optionally substituted alkyl or phenyl group or a formula

Embedded image (R ⁶ and R ⁷ have the meaning described above);
Means a halogen atom; Y means a halogen atom or a hydrogen atom; ~ means (E) isomer or (Z) isomer or a mixture thereof. The compounds of the general formulas [1-1] to [1-6] can also be obtained as salts, and examples of the salts include those similar to the salts of the compound of the general formula [1]. Hereinafter, each manufacturing method will be described.

(Production Method 1) The compound of the general formula [1] can be obtained by subjecting the compound of the general formula [4] to a ring closure reaction. In this reaction, a solvent may be used,
The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, benzene, xylene and the like can be used. However, the reaction can also be performed in the absence of a solvent. In this ring closure reaction, a condensing agent is used, and examples of the condensing agent include phosphorus pentoxide, polyphosphoric acid, zinc chloride, concentrated sulfuric acid, halogenosulfonic acid, sulfuric anhydride, and concentrated sulfuric acid-acetyl chloride. The amount of these condensing agents to be used is 1 to 50 times the molar amount of the compound of the general formula [4]. This reaction is usually 0-12
It may be carried out at 0 ° C. for 30 minutes to 24 hours. Further, after the compound of the general formula [4] is converted into a carboxylic acid halide using an acid halogenating agent such as thionyl chloride or phosphorus pentachloride, the Friedel-Crafts reaction is performed using a Lewis acid such as aluminum chloride. By doing so, the ring can be closed.

(Production Method 2) The compound of the general formula [1] can be obtained by reacting the compound of the general formula [8] with a reactive derivative of the compound of the general formula [9]. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane; N, N-dimethyl Examples include amides such as formamide and N, N-dimethylacetamide; and sulfoxides such as dimethyl sulfoxide. Further, an organic amine such as pyridine can be used as the solvent. This reaction can be carried out in the presence of a base, such as an alkali metal hydride such as sodium hydride or potassium hydride; an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide; Alkali metal carbonates such as sodium carbonate and potassium carbonate; and organic amines such as triethylamine and pyridine. Examples of the reactive derivative of the compound of the general formula [9] include an acid halide and an acid anhydride. The amounts of the base and the reactive derivative of the compound of the general formula [9] used are respectively 1 to 1.5 with respect to the compound of the general formula [8].
It is twice the mole. This reaction may be carried out at −30 to 150 ° C. for 30 minutes to 24 hours.

(Production method 3) The compound of the general formula [1-] is reacted with a halogenating agent to react the compound of the general formula [1-1].
2] can be obtained. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, methylene chloride,
Halogenated hydrocarbons such as 1,2-dichloroethane and chloroform; alcohols such as methanol and ethanol; esters such as ethyl acetate; organic carboxylic acids such as acetic acid and formic acid; Examples of the halogenating agent used in this reaction which may be used as a mixture include chlorine, bromine and sulfuryl chloride. The amount of the halogenating agent to be used is 0.9 to 1.1-fold the molar amount of the compound of the formula [1-1]. The reaction is usually carried out at 0 to 100 ° C, preferably at 10 to 40 ° C.
Then, it may be carried out for 30 minutes to 3 hours.

(Production Method 4) A compound of the general formula [1-3] is reacted with a compound of the general formula [10] in the presence of silver tetrafluoroborate to give a compound of the general formula [1-3] Can be obtained. In this reaction, the general formula [10]
May be used as a solvent. The amounts of silver tetrafluoroborate and the compound of the general formula [10] used in this reaction are 1 to 5 times and 10 to 100 times the mol of the compound of the general formula [1-2], respectively. It is. This reaction is usually carried out at 20 to 100 ° C. for 30 minutes to 24 hours.

(Production method 5) The compound of the general formula [1-4] is subjected to a thioetherification reaction in the presence of a base to give
The compound of the general formula [1-5] can be obtained. (i) A compound of the general formula [1-4] wherein Y is a halogen atom is reacted with a compound of the general formula R ⁹ SH [11] (R ⁹ has the above-mentioned meaning) in the presence of a base. And the compound of the general formula [1-5] can be obtained. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform; methanol, ethanol and the like; Alcohols; amides such as N, N-dimethylformamide; ketones such as acetone; ethers such as tetrahydrofuran and dioxane. These solvents may be used as a mixture of two or more kinds. Examples of the base used in this reaction include organic bases such as triethylamine and pyridine; alkali metals such as sodium metal and potassium; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium methoxide, sodium ethoxide and potassium tert. -Alkali metal alkoxides such as butoxide. The amounts of the base and the compound of the general formula [11] used are 1 to 10 times and 1 to 5 times the mole of the compound of the general formula [1-4], respectively. This reaction is usually 0-150 ° C
Then, it may be carried out for 30 minutes to 24 hours.

(Ii) Formula [1-4] wherein Y is a hydrogen atom
The compound of the general formula [1-5] can be obtained by reacting the compound of the formula with a base and then reacting with a thioetherating agent. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include ethers such as diethyl ether, tetrahydrofuran and dioxane; aromatic hydrocarbons such as benzene and toluene; Methylphosphoric triamide (HMPA) and the like may be mentioned, and these solvents may be used as a mixture of two or more kinds. Examples of the base used in this reaction include organic lithium compounds such as butyllithium, phenyllithium, lithium diisopropylamine, and lithium hexamethyldisilazane. Examples of the thioetherifying agent include disulfides such as dimethyl disulfide and diphenyl disulfide; methyl methanethiol sulfonate;
Thiol sulfonates such as methyl benzenethiol sulfonate; halogenated sulfenyls such as methylsulfenyl chloride and phenylsulfenyl chloride; The amount of base and thioetherifying agent used is
1 to 10 for the compound of the general formula [1-4]
It is twice the mole. This reaction is usually carried out at -78 to 0 ° C for 1 hour to
It should be carried out for 24 hours.

(Production Method 6) The compound of the general formula [1-1] is reacted with a halogenating agent in an amount of 2 to 2.5 times the amount of the compound of the general formula [1-1] to give the compound of the general formula [1-] 6] can be obtained. This reaction can be carried out in the same manner as described in Production method 3. When the raw material compound and the intermediate are used as a salt, examples of the salt include those similar to the salt of the compound of the general formula [1]. Next, the starting compound of the present invention can be produced, for example, by the following production method.

[0020]

Embedded image

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ^3a , R ^4a , X, Z and-have the meanings given above;
¹⁰ means an acyl group. The starting compounds and intermediates can also be used as salts, and examples of these salts include those similar to the salts of the compound of the general formula [1]. Hereinafter, each manufacturing method will be described.

(Production Method A) A compound of the general formula [4] can be obtained by reacting a compound of the general formula [2] with a compound of the general formula [3] in the presence of a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water,
N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide or water and an organic solvent (for example, N, N-dimethylformamide, dioxane,
Mixed solvents with methanol, ethanol, etc.). Examples of the base used in this reaction include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide; sodium hydride, hydrogen And alkali metal hydrides such as potassium iodide. Further, β-propiolactone or a derivative thereof may be used instead of the compound of the general formula [3]. The amounts of the base and the compound of the general formula [3] used are 1 to 10 times and 1 to 5 times the mole of the compound of the general formula [2], respectively. This reaction is usually carried out at 20 to 100 ° C. for 30 minutes to 24 hours. A 3-nitrophenol having an R ⁵ -Z- group (where R ⁵ and Z have the same meaning as described above) at the 4-position (see JP-A-57-203079) can be converted to a conventional nitro group by reduction. In addition, by performing the sulfonylation described in the above-mentioned production method 2, the compound of the general formula [2] as a raw material can be obtained.

(Production Method B) The compound of the general formula [6] is reacted with the compound of the general formula [3] according to the method of the production method A and the production method 1 described above.
The compound of the general formula [7] can be obtained by subjecting the compound of the general formula [6] to a ring closure reaction. The compound of the general formula [8] can be produced by subjecting the compound of the general formula [7] to a deacylation reaction in the presence of an acid catalyst. Examples of the solvent used for this reaction include water and a mixture of water and an organic solvent (eg, methanol, ethanol, dioxane, tetrahydrofuran, etc.). Examples of the acid catalyst used in this reaction include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as paratoluenesulfonic acid. The amount of the acid catalyst to be used is 0.1 to 50-fold the molar amount of the compound of the general formula [7]. This reaction may be carried out usually at 0 to 150 ° C. for 30 minutes to 24 hours.

Further, the compound of the present invention and the starting compound can be prepared, for example, by the known oxidation, reduction, dehydration, hydrolysis, halogenation, alkylation, acylation, amidation, alkylsulfonylation, alkenylsulfonylation,
By appropriately combining arylsulfonylation, esterification, iminoization, dealkylation, heterocyclic formation, and the like, other target compounds or other starting compounds can be derived.

The compound of the general formula [1] wherein R ³ , R ⁴ and R ⁵ are a formyl, acyl, cyano, carbamoyl or carboxyl group or a group substituted by these functional groups, It can be derived to the target compound. For example, a compound of the general formula [1] in which R ³ , R ⁴ and R ⁵ are a formyl group or a group substituted by formyl is a compound represented by the formula: Tetrahedron Letters [Tetrahedron.
t.] pp. 1187-1190 (1974); Synthetic Communications [Synth. Comm.] Volume 10, 889-
895 (1980), Tetrahedron 30
Volume, pages 3563-3568 (1974), Current Science [Curr. Sci.] Volume 49, pages 18-19 (1980), Tetrahedron Lett., Page 1955 ~
Page 1998 (1973), U.S. Patent Nos. 4,196,128 and 3,9
No. 06,005, R ³ according to the method described in such as Australian Patent No. 516,897, R ⁴ and R ⁵ are carboxyl, cyano, halogen, nitro or hydroxyl group as or substituted groups in these groups It can also be converted to some other desired compound. The compound of R ^3, R ⁴ and R ⁵ are radicals substituted with an acyl group or an acyl group the general formula [1] is generally known reaction, for example, by Witehhi (Wittig) reaction, R ³ , R ⁴ and R ⁵ can also be derived to the target compounds in which they are alkenyl groups or groups substituted with alkenyl groups.
This reaction is based on the Organic Reaction
action], Vol. 14, pp. 270-490. Alternatively, the acyl group can be derivatized to the corresponding alcohol by a Grignard reaction. This reaction is described in The Chemical Society of Japan, Experimental Chemistry, Vol. 18, Reaction of Organic Compounds, 363
Page to page 408 (Maruzen). Further, the compound of the general formula [1] in which R ³ , R ⁴ and R ⁵ are a carboxyl group or a group substituted by a carboxyl group is obtained by converting R ³ , R ⁴ and R ⁵ to amino or alkoxy by Curtius rearrangement. It is also possible to derive a target compound which is a carbonylamino group or a group substituted by an amino or alkoxycarbonylamino group. This reaction is described in Organic Reaction, Vol. 3, pp. 337-449.
It can be carried out according to the method described on page.

When the raw material compound or the target compound has a hydroxyl group, an amino group, a carboxyl group, or the like, these groups are, for example, protected groups in organic synthesis. TW Green (1981), John Wiley & Sons (1981)
s, Inc.)], and if necessary, the protecting group may be removed by a conventional method. Next, a method for producing the general formula [A] from the compound of the general formula [1] of the present invention will be described.

[0027]

Embedded image

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and Z have the meanings described above. ]

(Production Method A) The compound of the general formula [A] can be obtained by subjecting the compound of the general formula [1] to a dehydrogenation reaction. Examples of the dehydrogenation reaction include the following. (i) The compound of the general formula [A] can be obtained by reacting the compound of the general formula [1] with a dehydrogenating agent.
The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction.
Water; acetic acid; acetic anhydride; aromatic hydrocarbons such as benzene, toluene, and xylene; and ethers such as dioxane. As the dehydrogenating agent used in this reaction, for example, 2,3-dichloro-5,6-dicyano-
Examples thereof include 1,4-benzoquinone (DDQ), chloranil, trityl perchlorate, trityl fluoroborate, selenium dioxide, and palladium-carbon. The amount of the dehydrogenating agent used in this reaction is 0.5 to 5 moles per 1 mole of the compound of the general formula [1]. This reaction is usually 0-1
It may be carried out at 50 ° C. for 30 minutes to 72 hours.

(Ii) The compound of the general formula [A] can also be obtained by reacting the compound of the general formula [1] with a halogenating agent and then reacting with a base. The solvent used in the halogenation reaction is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, and chloroform; methanol, ethanol, and the like. Alcohols; esters such as ethyl acetate; organic carboxylic acids such as acetic acid and formic acid; and the like. These solvents may be used as a mixture of two or more kinds. Examples of the halogenating agent used in this reaction include chlorine, bromine, sulfuryl chloride and the like. The amount of the halogenating agent used is 0.9 to 1.1 based on the compound of the general formula [1].
It is twice the mole. The reaction is usually carried out at 0 to 100 ° C., preferably
It may be carried out at 10 to 40 ° C. for 30 minutes to 3 hours. Next, when a base is reacted with the obtained halogen compound, the solvent used is not particularly limited as long as it does not adversely affect the reaction. For example, methylene chloride, 1,2-
Halogenated hydrocarbons such as dichloroethane and chloroform; alcohols such as methanol and ethanol;
Amides such as N, N-dimethylformamide; pyridine; and the like, and these solvents may be used as a mixture of two or more kinds. Examples of the base used in this reaction include organic bases such as triethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, and alkali carbonates such as sodium carbonate and potassium carbonate. Can be The amount of the base to be used is 1- to 10-fold the molar amount of the compound of the formula [1]. This reaction is usually 0
It may be carried out at 〜100 ° C. for 30 minutes to 24 hours.

(Production method b) The compound of the general formula [A-1] is reacted with an alkali azide such as sodium azide or potassium azide or ammonium azide to give the compound of the general formula [A-1]. Obtainable.
This reaction is described in Chemical Abstracts (CA) Vol. 89, 4
It can be performed according to the method described in 3022p. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, water;
Amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfolane; nitriles such as acetonitrile; ketones such as acetone; sulfoxides such as dimethylsulfoxide; alcohols such as methanol and ethanol; tetrahydrofuran and dioxane And these solvents may be used as a mixture of two or more. The amount of the alkali azide or ammonium azide to be used is 1 to 5 moles per 1 mole of the compound of the formula [1-2]. This reaction may be usually performed at room temperature to 100 ° C. for 30 minutes to 12 hours.

(Production method c) The compound of the general formula [A-2] can be obtained by reacting the compound of the general formula [1-6] with a base. The solvent used in this reaction is not particularly limited as long as it does not adversely affect the reaction. For example, halogenated hydrocarbons such as methylene chloride, 1,2-dichloroethane, chloroform;
Alcohols such as methanol and ethanol; esters such as ethyl acetate; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide; pyridine; 2,6-lutidine and the like. You may mix and use more than one kind. Examples of the base used in this reaction include organic bases such as triethylamine, pyridine, 2,6-lutidine, and DBU; and alkali metal carbonates such as sodium carbonate and potassium carbonate. The amount of the base used is represented by the general formula [1]
-6] with respect to the compound of the formula [6]. This reaction may be usually carried out at 20 to 150 ° C. for 10 minutes to 24 hours.

[0033]

The compound represented by the general formula [1] of the present invention has excellent anti-inflammatory action, antipyretic analgesic action, anti-arthritic action and anti-allergic action, and exhibits excellent therapeutic effect. It is useful as an intermediate of the general formula [A].

[0034]

EXAMPLES Next, the present invention will be described with reference to Reference Examples and Examples, but the present invention is not limited thereto. The mixing ratios of the solvents are all volume ratios, and the carrier in column chromatography is silica gel [Kieselgel 60, Art. 7734 (Kieselgel 60, Ar
t.7734)] was used. The abbreviations used below have the following meanings. Me; methyl, Et; ethyl, i-Pr; isopropyl,
Ac; acetyl, IPA; isopropyl alcohol, I
PE: diisopropyl ether, Bz: benzoyl, D
MSO; dimethyl sulfoxide, ~; (E) form, (Z)
Body or a mixture thereof [] in the table indicates a recrystallization solvent.

Reference Example 1 (1) To 23.1 g of 3-nitro-4-phenoxyphenol, 120 ml of ethanol and 120 ml of water were added and dissolved by heating at 60 ° C. Then, 2.3 ml of 4N hydrochloric acid was added, and the reaction temperature was raised to 65 to 70 ° C.
16.8 g of iron powder is added in portions over 20 minutes. After the mixture was stirred at the same temperature for 30 minutes, the reaction solution was filtered while hot, 50 ml of water was added to the filtrate, and the mixture was allowed to cool. The precipitated crystal was collected by filtration to give 3-amino acid having a melting point of 156 to 157 ° C. -4-
16.5 g (82.1% yield) of phenoxyphenol are obtained. IR (KBr) cm ^-1 ; 3400, 3320, 1590, 1453, 1230 The compounds in Table 1 were obtained in the same manner.

[0036]

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[0037]

[Table 1]

(2) 20.1 g of 3-amino-4-phenoxyphenol and 23.7 g of pyridine are dissolved in 200 ml of methylene chloride. Under ice cooling, a solution of 12.6 g of methanesulfonyl chloride in 60 ml of methylene chloride is added dropwise over 30 minutes. The mixture was reacted at the same temperature for 2 hours, 200 ml of water was added thereto, and the pH was adjusted to 3 with 4N hydrochloric acid, and the organic layer was separated. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained crystals are recrystallized from benzene.
23.7 g (yield 84.9%) of 3-methylsulfonylamino-4-phenoxyphenol was obtained. IR (KBr) cm ^-1 ; 3440, 3250, 1318, 1215, 1150 Similarly, compounds in Tables 2 and 3 were obtained.

[0039]

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[0040]

[Table 2]

[0041]

[Table 3]

REFERENCE EXAMPLE 2 3-amino-4-phenoxyphenol (20.1 g) was treated with acetic acid (60 m).
After adding 30 ml of acetic anhydride under ice cooling, the mixture is stirred at 20 to 25 ° C. for 1 hour. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from toluene to obtain 22.6 g (93% yield) of 3-acetylamino-4-phenoxyphenol having a melting point of 151 to 153 ° C. IR (KBr) cm ^-1 ; 3440,3190,1665,1605,1540,1450,1238,12
Fifteen

Reference Example 3 (1) 8.0 g of sodium hydroxide was dissolved in 240 ml of water, and 24.3 g of 3-acetylamino-4-phenoxyphenol was added thereto.
Is dissolved. Then add 3-chloropropionic acid
10.9 g are added and the mixture is refluxed for 30 minutes. The reaction solution is cooled with water, and the precipitated crystals are filtered off. The filtrate is adjusted to pH 9 with 4N hydrochloric acid and washed twice with 50 ml each of ethyl acetate. The aqueous layer is separated, adjusted to pH 4 with 4N hydrochloric acid, and extracted with 200 ml of ethyl acetate. The extract is washed successively with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained crystals, and the precipitated crystals were collected by filtration to give 3- (3-acetylamino-4-phenoxyphenoxy) propionic acid having a melting point of 138 to 140 ° C. 10.0 g (31.7% yield) are obtained. IR (KBr) cm ^-1 ; 3270,1730,1630,1590,1540,1475,1425,12
20 NMR (d ₆ -DMSO) δ value; 2.00 (3H, s), 2.68 (2H, t, J = 6 Hz), 4.14
(2H, t, J = 6Hz), 6.50-7.92 (7H, m), 7.67 (1H, d, J = 2.4Hz),
9.22 (1H, bs)

(2) In the same manner as in Example 1 (2) described later,
The following compound was obtained. 7-acetylamino-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one Melting point: 214-215 ° C. (recrystallized from acetonitrile-ethyl acetate) IR (KBr) cm ⁻¹ ; 3305, 1700,1665,1615,1590,1520,1438,12
70,1245,1220 NMR (CDCl ₃ + d ₆ -DMSO) δ value; 2.16 (3H, s), 2.69 (2H, t, J = 6H
z), 4.49 (2H, t, J = 6Hz), 6.75-7.54 (5H, m), 7.19 (1H, s),
8.06 (1H, s), 9.32 (1H, bs)

Example 1 (1) 27.9 g of 3-methylsulfonylamino-4-phenoxyphenol was added to 250 ml of water in which 4 g of sodium hydroxide was dissolved.
Is dissolved. To this was added an aqueous solution of 10.9 g of 3-chloropropionic acid and 4 g of sodium hydroxide dissolved in 30 ml of water, and the mixture was refluxed for 30 minutes. After cooling the reaction solution with water, the pH is adjusted to 8 with 4N hydrochloric acid. 70 ml of ethyl acetate is added thereto, and the aqueous layer is separated. The aqueous layer was adjusted to pH 4 with 4N hydrochloric acid,
Extract with 100 ml of ethyl acetate. The extracted organic layer is washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. Then, the solvent is distilled off under reduced pressure, and diethyl ether is added to the obtained residue. If the precipitated solid is collected by filtration, 8.1 g of 3- (3-methylsulfonylamino-4-phenoxyphenoxy) propionic acid showing a melting point of 145 to 149 ° C.
(23.1% yield). IR (KBr) cm ^-1 ; 3250,1705,1482,1325,1210,1145 The following compounds were obtained in the same manner. -3- (3-methylsulfonylamino-4-phenoxyphenoxy) -3-methylpropionic acid Melting point: 121-124 ° C IR (KBr) cm ^-1 ; 3350,1710,1500,1335,1215,1155

(2) 3- (3-methylsulfonylamino-
3.51 g of 4-phenoxyphenoxy) propionic acid and 70 g of polyphosphoric acid are mixed and the mixture is stirred at 65-70 ° C. for 1.5 hours. The reaction solution was introduced into 300 ml of ice water, and ethyl acetate 2
Extract twice with 00 ml. The extracted organic layers are combined, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from methanol to give 2,3-dihydro-7-methylsulfonylamino- having a melting point of 143 to 144 ° C.
6-phenoxy-4H-1-benzopyran-4-one 1
8.7 g (56.1% yield) are obtained. IR (KBr) cm ^-1 ; 3120,1665,1610,1485,1440,1320,1265,12
15,1160,1135 NMR (CDCl ₃ ) δ value; 2.74 (2H, t, J = 6 Hz), 3.10 (3H, s), 4.53 (2
(H, t, J = 6Hz), 6.91 ~ 7.49 (7H, m), 7.40 (1H, s)

Example 2 3-Bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4
4.12 g of -one, 9.37 g of silver tetrafluoroborate and 100 ml of methanol are mixed and the mixture is refluxed for 4 hours. After cooling the reaction solution, the insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (eluent; toluene: ethyl acetate = 5: 1) to give 2,2.
3-dihydro-3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-
1.27 g (35% yield) of ON are obtained. Melting point: 139-141 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 ; 3230,1680,1610,1490,1450,1330,1260,12
10,1150

Example 3 3-Bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4
Dissolve 2.06 g of -one and 480 mg of methyl mercaptan in 50 ml of methylene chloride and add thereto triethylamine at 0-5 ° C.
2.02 g are added and the mixture is stirred at room temperature for 1 hour. The reaction solution is introduced into 30 ml of water, and the organic layer is separated. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (eluent; toluene: ethyl acetate = 50: 1) to give 2,3-dihydro-7-methylsulfonylamino-3-. 900 mg of methylthio-6-phenoxy-4H-1-benzopyran-4-one (47.4% yield) are obtained. Melting point: 126-128 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 3250,1690,1610,1480,1440,1340,1260,12
20,1160,1140

Example 4 (1) 79.7-Acetylamino-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one 29.7 g, ethanol 30 ml and 6N hydrochloric acid 300 ml were mixed. Reflux for hours. The reaction solution was introduced into 3 liters of ice water, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give a melting point.
7-Amino-2,3-dihydro-6 indicating 154-155 ° C.
Phenoxy-4H-1-benzopyran-4-one 23.5 g
(92.2% yield). IR (KBr) cm ^-1 ; 3470,3330,1655,1610,1570,1500,1460,13
20,1300,1255

(2) 7-amino-2,3-dihydro-6
Phenoxy-4H-1-benzopyran-4-one 25.5 g
Is dissolved in 200 ml of pyridine, and 12.6 g of methanesulfonyl chloride is added dropwise while maintaining the temperature at 20 to 25 ° C. After reacting the mixture at the same temperature for 12 hours, the solvent of the reaction solution is distilled off under reduced pressure. The obtained residue is ethyl acetate 200 ml
And 1N aqueous sodium hydroxide solution in 500 ml
Extract twice. The extracted aqueous layers are combined, adjusted to pH 4 with 4N hydrochloric acid, and extracted twice with 300 ml each of ethyl acetate. After the extracted organic layers were combined and washed sequentially with water and saturated saline,
Dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from methanol to give 2,2.
There are obtained 27.0 g (81.1% yield) of 3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. Physical properties of this compound (melting point and IR)
Was consistent with the physical properties of the compound obtained in Example 1 (2).
Similarly, compounds of Tables 4 to 7 were obtained.

[0051]

Embedded image

[0052]

[Table 4]

[0053]

Embedded image

[0054]

[Table 5]

[0055]

[Table 6]

[0056]

[Table 7]

Example 5 To 5.69 g of 3- (3-methylsulfonylamino-4-phenoxyphenoxy) -3-methylpropionic acid was added 100 g of polyphosphoric acid, and the mixture was stirred at 65 ° C. for 1 hour. Then, the reaction solution was introduced into 400 ml of ice water, and ethyl acetate 1 was added thereto.
After adding 50 ml, the organic layer is separated off. The solvent is distilled off under reduced pressure. The obtained residue was washed with 1N aqueous sodium hydroxide solution 1
This solution was washed with diethyl ether and adjusted to pH 4 with 4N hydrochloric acid.
And the organic layer is separated. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (eluent; toluene: ethyl acetate = 2
After purification in 5: 1), recrystallization from ethanol gives 2,
2.16 g (40% yield) of 3-dihydro-2-methyl-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one are obtained. Physical properties (melting point and IR) of this compound were consistent with those of the compound obtained in Example 4.

Example 6 2,3-dihydro-7-methylsulfonylamino-6
Phenoxy-4H-1-benzopyran-4-one 33.3 g
Is dissolved in 300 ml of chloroform. To this solution, 16.3 g of bromine is added dropwise over 30 minutes while maintaining the reaction temperature at 25-30 ° C. After completion of the dropwise addition, the mixture is stirred at 25 to 30 ° C. for 30 minutes, 100 ml of water is added thereto, and the organic layer is separated. The organic layer is washed successively with a 5% aqueous solution of sodium thiosulfate, water and saturated saline, and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 3-bromo-
2,3-dihydro-7-methylsulfonylamino-6-
Phenoxy-4H-1-benzopyran-4-one 40.1 g
(97.3% yield). Melting point: 137 to 140 ° C (recrystallized from toluene) IR (KBr) cm ^-1 ; 3250,1680,1610,1485,1325,1260,1205 NMR (CDCl ₃ ) δ value; 3.14 (3H, s), 4.54 to 4.70 (3H, m), 6.91
~ 7.38 (8H, m)

Example 7 2,3-dihydro-7-methylsulfonylamino-6
Phenoxy-4H-1-benzopyran-4-one 1.00 g
Is dissolved in 10 ml of a mixture of anhydrous tetrahydrofuran-hexamethylphosphoric triamide (7: 3). To this solution at -78 ° C was added 1,1,1,3,3,3-hexamethyldisilazane (1.17 g) and n-butyllithium (6.6 mmol) in 1,1,1,3,3,3-hexamethyldisilazane. 10 ml of a silazane-lithium salt in tetrahydrofuran solution are added, the mixture is stirred for 40 minutes, then at the same temperature 500 mg of methyl methanethiolsulfonate are added and the mixture is stirred for 15 minutes. Then, the reaction solution is heated to room temperature. The reaction solution was introduced into 80 ml of 2N hydrochloric acid under ice-cooling, and the mixture was diluted with 40 ml of ethyl acetate.
Extract twice with l each. The extracts are combined, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained oil was subjected to column chromatography (eluent: toluene: ethyl acetate = 5).
0: 1), 2,3-dihydro-7-methylsulfonylamino-3-methylthio-6-phenoxy-4
480 mg of H-1-benzopyran-4-one (39.6% yield) are obtained. The physical properties (melting point and IR) of this compound are shown in Example 4.
This was consistent with the physical properties of the compound obtained in (2).

Production Example 1 2,3-dihydro-7-methylsulfonylamino-6
Phenoxy-4H-1-benzopyran-4-one 3.33 g
And 2,3-dichloro-5,6-dicyano-1,4-
3.40 g of benzoquinone are added to 60 ml of dioxane and the mixture is refluxed for 12 hours. After cooling with water, the precipitate is filtered off and the solvent is distilled off under reduced pressure. The obtained residue is subjected to column chromatography (eluent; toluene: ethyl acetate = 5: 1).
Then, 2.68 g (81% yield) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one is obtained. Melting point: 216.7-217.6 ° C (recrystallized from acetonitrile) IR (KBr) cm ^-1 : 3110,1620,1585,1560,1485,1465,1440,13
20,1140 NMR (CDCl3 + d6-DMSO) δ value; 3.12 (3H, s), 6.24 (1H, d, J = 6
Hz), 6.98 to 7.53 (6H, m), 7.75 (1H, s), 7.90 (1H, d, J = 6Hz),
9.20 (1H, bs)

Production Example 2 2,3-dihydro-3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-
A mixture of 3.63 g of 4-one, 3.41 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 150 ml of dioxane is refluxed for 48 hours. After cooling the reaction solution and removing the precipitate by filtration, the solvent is distilled off under reduced pressure. The obtained residue is purified by column chromatography (eluent; toluene: ethyl acetate = 3: 1) to give 3-methoxy-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one. 1.91 g (52.9% yield) are obtained. Melting point: 164-166 ° C (recrystallized from ethanol) IR (KBr) cm ^-1 : 1610,1480,1460,1330,1260,1215,1175,11
40

Production Example 3 2,3-dihydro-7-methylsulfonylamino-3-
350 mg of methylthio-6-phenoxy-4H-1-benzopyran-4-one and 1.08 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added to 14 ml of dioxane.
Reflux for 9 hours. Then, the solvent was distilled off under reduced pressure,
The obtained residue is subjected to column chromatography (eluent;
Purification with toluene: ethyl acetate = 10: 1 yields 160 mg of 7-methylsulfonylamino-3-methylthio-6-phenoxy-4H-1-benzopyran-4-one (yield 45.7).
%). Melting point: 175-176 ° C (recrystallized from acetonitrile) IR (KBr) cm ^-1 : 3120,1600,1480,1420,1310,1210,1140

Production Example 4 In the same manner as in Production Example 1, Production Example 2 or Production Example 3, Table 8
~ 14 compounds were obtained.

[0064]

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[0065]

[Table 8]

[0066]

[Table 9]

[0067]

[Table 10]

[0068]

[Table 11]

[0069]

[Table 12]

[0070]

[Table 13]

[0071]

[Table 14]

Production Example 5 3-bromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4
40.1 g of -one is dissolved in 280 ml of N, N-dimethylformamide. Then 13.9 g of sodium azide are added and the mixture is stirred at 70-75 ° C. for 1 hour. The reaction solution is introduced into a mixed solvent of 1.5 l of water and 300 ml of ethyl acetate, adjusted to pH 0.1 with concentrated hydrochloric acid, and the aqueous layer is separated. The aqueous layer is washed with 200 ml of ethyl acetate, adjusted to pH 4.0 with a 10% aqueous sodium hydroxide solution, and extracted twice with 500 ml of ethyl acetate each. The extracted organic layers are combined, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethanol to give 3-amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4- mp showing a melting point of 162 to 163 ° C. 2.84 g of ON (82.1% yield) are obtained. IR (KBr) cm ^-1 ; 3440,3330,3180,1600,1580,1550,1480,14
65,1330,1205,1150 NMR (d ₆ -DMSO) δ value; 3.19 (3H, s), 5.50 ~7.00 (2H, br), 7.
04 ~ 7.49 (5H, m), 7.35 (1H, s), 7.62 (1H, s), 7.94 (1H, s)

Production Example 6 In the same manner as in Production Example 5, the compounds shown in Tables 15 and 16 were obtained.

[0074]

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[0075]

[Table 15]

[0076]

[Table 16]

Production Example 7 3.81 g of 3,3-dibromo-2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one were dissolved in 20 ml of pyridine, and this solution was added to 20 ml of pyridine. Reflux for minutes. The reaction solution is introduced into 200 ml of water, adjusted to pH 4 with concentrated hydrochloric acid, and extracted twice with 100 ml each of ethyl acetate. The extracted organic layers are combined, washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from acetonitrile to give 3-bromo-7 having a melting point of 215 to 216 ° C.
-Methylsulfonylamino-6-phenoxy-4H-1
3.30 g (82% yield) of benzopyran-4-one are obtained. IR (KBr) cm ^-1 ; 3100,3080,1635,1620,1485,1455,1335,11
55 NMR (d ₆ -DMSO) δ value; 3.23 (3H, s), 7.06 ~7.66 (5H, m), 7.
30 (1H, s), 7.72 (1H, s), 8.81 (1H, s), 10.07 (1H, s) In the same manner, the following compound was obtained. 3-chloro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one Melting point: 200-201 ° C (recrystallized from ethyl acetate-diisopropyl ether) IR (KBr) cm ^-1 ; 3220,3050 , 1645,1600,1560,1480,1450

Continued on the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI Technical display location A61K 31/445 ABG A61K 31/445 ABG C07D 311/24 C07D 311/24 311/36 311/36 405/12 213 405/12 213 257 257 409/12 311 409/12 311 (72) Inventor Hideka Nagaki 24-8 Okudacho, Toyama City, Toyama Prefecture (72) Inventor Tomoya Shimotori 175-3 Kosugi Kosugi, Toyama City, Toyama Prefecture (72) Inventor Shinji Makino 3490, Mikkaichi, Kurobe-shi, Toyama (56) References JP-A-57-203079 (JP, A) JP-A-61-251679 (JP, A)

Claims (11)

(57) [Claims] 1. A compound of the general formula [1] [Wherein R ¹ represents a lower alkyl, lower alkenyl or aryl group optionally substituted with a halogen atom;
² represents a hydrogen atom, an alkyl group or an acyl group; R ³ represents
A hydrogen atom, a halogen atom, a cyano group, azido group, carboxyl group, hydroxyl group, formyl group or alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, phenoxy, cycloalkyl, carbamoyl, amino or phenyl group; R ⁴ Is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a carboxyl group, an acyl group, a hydroxyl group or an alkoxycarbonyl group or an optionally substituted alkyl, alkoxy, alkylthio, phenylthio, lower alkynyl,
Lower alkenyl, sulfamoyl, alkylsulfinyl, alkylsulfonyl, amidino, phenyl or heterocyclic groups, or a compound of the formula Or the formula (Wherein, R ⁶ represents a hydrogen atom, a hydroxyl group, a cyano group or an alkoxycarbonyl group, or an optionally substituted alkyl, cycloalkyl, phenyl, amino,
Acyl, carbamoyl, alkylsulfonyl, iminomethyl or amidino group; R ⁷ represents a hydrogen atom, an optionally substituted alkyl, alkoxy, phenyl, cycloalkyl or heterocyclic group, or R ⁶ and R ⁷ are adjacent It represents a 3- to 7-membered optionally substituted heterocyclic group together with a nitrogen atom. R ⁵ represents an optionally substituted phenyl, thienyl, furyl or pyridyl group; and Z represents an oxygen atom, a sulfur atom or an imino group. 2,3-dihydro-4H-1
-A benzopyran-4-one derivative or a salt thereof. Wherein Z is an oxygen atom or a sulfur atom; R ⁵
Is a substituted phenyl or pyridyl group; R ¹ is a lower alkyl group or a lower alkenyl group optionally substituted with a halogen atom; R ² is a hydrogen atom or an acyl group; R ³ and R ⁴ are the same or different, a hydrogen atom, a carbamoyl group, a carboxyl group, a hydroxyl group or alkoxycarbonyl group or an optionally substituted alkyl, claim 1, wherein the alkoxy or phenyl group 2,3-dihydro - 4H-
1-benzopyran-4-one derivatives or salts thereof. 3. R ⁵ is an optionally substituted phenyl or pyridyl group; Z is an oxygen atom or a sulfur atom; R ¹ is a lower alkyl or lower alkenyl group optionally substituted by a halogen atom. R ² is a hydrogen atom or an acyl group; R ⁴ is (Wherein, R ⁶ represents a hydrogen atom, a hydroxyl group or an alkoxycarbonyl group or an optionally substituted alkyl, cycloalkyl, phenyl, acyl or carbamoyl group; and R ⁷ represents a hydrogen atom or an optionally substituted An alkyl group or R ⁶ and R ⁷ may be substituted together with an adjacent nitrogen atom.
It represents a 6-membered heterocyclic group. )); R ³
Is a hydrogen atom, a halogen atom, a cyano group, a carbamoyl group, a carboxyl group, a hydroxyl group or an alkoxycarbonyl group or an alkyl which may be substituted,
2. An alkoxy, amino or phenyl group.
2,3-dihydro-4H-1-benzopyran-4 as described
-One derivatives or salts thereof. 4. The 2,3-dihydro-4H-1-benzopyran-4-one derivative or a salt thereof according to claim 1, wherein Z is an oxygen atom. 5. The method according to claim 1, wherein R ¹ is a lower alkyl group.
2,3-dihydro-4H-1 according to any one of the above items
-A benzopyran-4-one derivative or a salt thereof. 6. The 2,3-dihydro-4H-1-benzopyran-4-one derivative or a salt thereof according to claim 1, wherein R ² is a hydrogen atom. 7. The 2,3-dihydro-4H-1-benzopyran-4-one derivative or a salt thereof according to claim 1, wherein R ³ is a hydrogen atom or an alkyl group. 8. R ⁴ is alkylthio optionally substituted, phenylthio, alkylsulfinyl, alkylsulfonyl or embedded image, Or (Wherein R ⁶ represents a hydrogen atom, a hydroxyl group or an alkoxycarbonyl group or an optionally substituted alkyl, cycloalkyl, phenyl, acyl, carbamoyl or alkylsulfonyl group; R ⁷ represents a hydrogen atom, Or an optionally substituted alkyl, alkoxy or heterocyclic group, or R ⁶ and R ⁷ together with an adjacent nitrogen atom represent a 3- to 7-membered optionally substituted heterocyclic group. 2.) a group represented by the formula:
2,3-dihydro-4H-1-benzopyran-4 as described
-One derivatives or salts thereof. 9. The 2,3-dihydro-4H-1-benzopyran-4-one derivative or a salt thereof according to claim 1, wherein R ⁴ is an alkylthio, formylamino or carbamoyl group. 10. The 2,3-dihydro-4H-1 according to claim 9, wherein R ⁵ is a phenyl group which may be substituted.
-A benzopyran-4-one derivative or a salt thereof. 11. R ⁵ is at least one substituent selected from a halogen atom, a hydroxyl group, an amino group, a carboxyl group, a haloalkyl group, an alkyl group, an alkoxy group, an alkoxycarbonyl group, an acylamino group and a carbamoyl group. The 2,3-dihydro-4H-1-benzopyran-4-one derivative or a salt thereof according to claim 10, which is a phenyl group which may be substituted.