JPH0764840B2 - Fused hetero 7-membered ring compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel fused 7-membered heterocyclic compound useful as a medicine.

Problems to be Solved by Conventional Techniques and Inventions The present inventors have earnestly studied to create a compound having a specific serotonin S ₂ receptor blocking action, and as a result, an excellent serotonin S ₂ receptor blocking action, brain It has vasospasm relieving action and antithrombotic action, and prevents or treats ischemic heart diseases such as angina and myocardial infarction, cerebral circulation disorders such as thrombosis and hypertension, cerebral vasospasm and transient ischemic attack. The present invention has been completed by successfully producing a novel fused 7-membered heterocyclic compound useful as an agent.

Means for Solving the Problems [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy, and R ₃ and R ₄ each represent hydrogen or an optionally substituted lower alkyl, cycloalkyl or aralkyl group. Or forms a ring, which may be substituted with an adjacent nitrogen atom, and X is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or optionally esterified or amidated Represents a carboxyl group, Y represents> C═O or> CH—OR ₅ (in the formula, R ₅ represents hydrogen, acyl or optionally substituted carbamoyl), and A represents an oxygen atom or a sulfur atom. , E
Represents an oxygen atom or methylene, and G represents a lower alkylene. However, when A is a sulfur atom, E represents methylene] or a salt thereof.

With respect to the above formula (I), examples of the halogen represented by R ₁ or R ₂ include fluorine, chlorine, bromine and iodine.

The lower alkyl group represented by R ₁ or R ₂ is methyl,
Examples thereof include alkyl groups having about 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, etc. Examples of the lower alkoxy group represented by R ₁ or R ₂ include methoxy, ethoxy, propoxy, Isopropoxy, butoxy, isobutoxy, sec-butoxy, t
Examples thereof include alkoxy groups having 1 to 4 carbon atoms such as ert-butoxy. More preferably, both R ₁ and R ₂ are hydrogen, or one of them is hydrogen and the other is lower alkoxy, and when _one of R ₁ and R ₂ is a lower alkoxy group, the lower The case where the alkoxy group is bonded to the para position of E (meta position of A) is preferable.

The lower alkyl group represented by R ₃ or R ₄ is methyl,
Examples thereof include an alkyl group having 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, and the alkyl group is, for example, C
_3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), halogen (eg, fluorine, chlorine,
Bromine), hydroxy, lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, propoxy, butoxy), lower (C _1-5 ).
Alkanoyloxy (eg, acetoxy, propionyloxy, butyryloxy, pivaloyloxy), mono- or di-lower (C _1-4 ) alkylamino (eg, methylamino, dimethylamino, methylethylamino), C _3-8 cycloalkylamino (eg , Cyclopentylamino, cyclohexylamino), lower (C _1-5 ) alkanoylamino (eg, acetamide, propionamide), benzamide, lower (C
_1-4 ) Alkylthio (eg, methylthio, ethylthio, propylthio, butylthio), carbamoyl, N-lower (C _1-4 ).
It may be substituted with alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl), N, N-dilower (C _1-4 ) alkylcarbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl) and the like.

Examples of the cycloalkyl group represented by R ₃ or R ₄ include cyclopropyl, cyclobutyl, cyclopentyl,
Examples thereof include cycloalkyl groups having about 3 to 8 carbon atoms such as cyclohexyl, cycloheptyl, cyclooctyl, and the cycloalkyl groups are, for example, lower (C _1-4 ) alkyl groups (eg, methyl, ethyl, propyl, butyl, etc.) ， Lower
It may be substituted with a (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), a lower (C _1-5 ) alkanoylamino group (eg, acetamide), a hydroxy group, etc. .

Examples of the aralkyl group represented by R ₃ or R ₄ include phenyl, such as benzyl, phenethyl, 3-phenylpropyl, α-methylbenzyl, α-ethylbenzyl, α-methylphenethyl, β-methylphenethyl and β-ethylphenethyl. And a lower (C _1-4 ) alkyl group, wherein the phenyl group in the phenyl-lower alkyl group is 1 to 3
Such as halogen (eg, fluorine, chlorine, bromine, iodine, etc.), lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl, butyl, etc.), lower (C _1-4 ) alkoxy group (eg , Methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), methylenedioxy group, amino group,
It may be substituted with a nitro group, a hydroxy group or the like. Examples of such substituted phenyl-lower alkyl groups include, for example, 2- (4-chlorophenyl) ethyl, 2-
(4-hydroxyphenyl) ethyl, 2- (4-methoxyphenyl) ethyl, 2- (3,4-dimethoxyphenyl) ethyl, 2- (3,4,5-trimethoxyphenyl) ethyl, 2-
(3,4-Methylenedioxyphenyl) ethyl, 2- (p-
Tolyl) ethyl, 3,4-dimethoxybenzyl, 3,4-methylenedioxybenzyl, 3,4,5, -trimethoxybenzyl, 4
-Ethylbenzyl, 4-chlorobenzyl and the like can be mentioned.

Examples of the ring formed by R ₃ and R ₄ together with the adjacent nitrogen atom include a cyclic amino group which may have a hetero atom such as nitrogen, oxygen and sulfur in addition to the nitrogen atom, and examples thereof include pyrrolidinyl, morpholinyl, Included are 5- to 7-membered cyclic amino groups such as piperidyl, piperazinyl and homopiperazinyl. The cyclic amino group may have a substituent at a substitutable position, and examples of the substituent include lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl, butyl), aryl, aralkyl, Examples include acyl and heterocycle. Examples of the aryl group as a substituent include a phenyl group, and the phenyl group is 1 to 3 such as halogen (eg, fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (eg, Methyl, ethyl, propyl, butyl), lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy group, etc. May be. Further, aralkyl as a substituent includes, for example, phenyl-lower (C _1-4 ) alkyl such as benzyl and phenethyl, diphenyl-lower (C _1-4 ) alkyl such as benzhydryl and triphenyl-lower (C _1-4 ). Examples include alkyl. Examples of acyl as a substituent include lower (C _1-4 ) alkanoyl (eg, acetyl, propionyl,
Butyryl) and other lower (C _1-4 ) fatty acid residues, benzoyl,
Phenyl-lower (C _1-4 ) alkanoyl, phenyl-lower (C
_1-4 ) Aromatic organic acid residues such as alkenoyl (eg, cinnamoyl) and the like. The aralkyl group and the phenyl group in the aromatic organic acid residue are 1 to 3 such as halogen (eg, fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl). ，
Butyl), lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy group and the like. Examples of the hetero ring as a substituent include a 5- to 7-membered ring containing 1 to 3 nitrogen atoms such as pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl and azepinyl.

As R ₃ and R ₄ , the case where R ₃ and R ₄ together with the adjacent nitrogen atom form a ring substituted with aryl is more preferable, and the case where it is piperazinyl substituted with aryl is more preferable.

Examples of the lower alkyl group represented by X include methyl,
Examples thereof include alkyl groups having about 1 to 4 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, which are substituted with, for example, oxo, hydroxy, acyloxy, aryl and the like. Good. Examples of the lower alkyl group substituted with oxo include lower (C _1-4 ) alkanoyl such as acetyl, propionyl and butyryl. Examples of the lower alkyl group substituted with hydroxy include groups such as hydroxymethyl. Examples of the acyl group as the acyloxy group include acyl groups derived from lower fatty acids such as lower (C _1-5 ) alkanoyl (eg, acetyl, propionyl, butyryl), and examples of the lower alkyl group substituted with the acyloxy group include , Acetyloxymethyl, propionyloxymethyl, butyryloxymethyl and the like. The lower alkyl group substituted with aryl includes, for example, lower (C _1-4 ) alkyl substituted with a phenyl group such as benzyl, and the phenyl group has 1 to 3 halogen atoms (eg, fluorine, chlorine, Bromine, iodine), lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl, butyl), lower (C
_1-4 ) It may be substituted with an alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy group and the like.

Examples of the aryl group represented by X include a phenyl group, and the phenyl group is 1 to 3 such as halogen (eg, fluorine, chlorine, bromine, iodine), lower (C _1-4 ).
Alkyl group (eg, methyl, ethyl, propyl, butyl), lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy It may be substituted with a group or the like.

Examples of the esterified carboxyl group represented by X include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec.
Examples include lower (C _1-4 ) alkoxycarbonyl such as -butoxycarbonyl and tert-butoxycarbonyl, and phenyl-lower (C _1-4 ) alkoxycarbonyl such as benzyloxycarbonyl.

Examples of the amidated carboxyl group represented by X include a carbamoyl group, and the amino group of the carbamoyl group is 1 or 2 lower (C _1-4 ) alkyl, phenyl, phenyl-lower (C _{1- 4} ) It may be substituted with alkyl or the like. As X, an esterified carboxyl group is preferable, and a lower alkoxycarbonyl group is more preferable.

Examples of the acyl group represented by R ₅ include lower alkanoyl groups having about 1 to 6 carbon atoms such as acetyl, propionyl, butyryl, valeryl and pivaloyl, and phenyl derived from aromatic carboxylic acids such as benzoyl, phenylacetyl and phenylpropionyl. An acyl group such as lower (C _1-6 ) alkanoyl and the like, and when the aromatic is a phenyl group in the aromatic carboxylic acid, the phenyl group is 1 to 3 such as halogen (eg, fluorine, chlorine, Bromine, iodine), lower (C _1-4 ) alkyl group (eg, methyl, ethyl, propyl, butyl), lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), It may be substituted with a methylenedioxy group, an amino group, a nitro group, a hydroxy group or the like.

Examples of the optionally substituted carbamoyl group represented by R ₅ include carbamoyl, and the amino group of the carbamoyl group is lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl, butyl), phenyl , Phenyl-lower
It may be substituted with (C _1-4 ) alkyl (eg, benzyl, phenethyl) and the like. The phenyl group and the phenyl group of the phenyl-lower alkyl group are 1 to 3 such as halogen (eg, fluorine, chlorine, bromine, iodine), lower (C
_1-4 ) Alkyl group (eg, methyl, ethyl, propyl, butyl), lower (C _1-4 ) alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, It may be substituted with a nitro group, a hydroxy group or the like. Y is preferably hydroxymethylene.

When A is a sulfur atom, sulfide, depending on the oxidation state,
It forms a sulfoxide or sulfone, with sulfide being preferred.

Examples of the lower alkylene group represented by G include alkylene groups having about 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, and among them, ethylene, trimethylene, tetramethylene and pentamethylene. Is preferred, and trimethylene is most preferred. Examples of the salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate and phosphate, for example, acetate, tartrate, citrate, fumarate, maleate. , Pharmacologically acceptable salts such as salts with organic acids such as toluene sulfonate and methane sulfonate. Compound (I)
Among the formulas [Wherein R ₆ is substituted with 1 to 3 halogens, a lower (C _1-4 ) alkyl group, a lower (C _1-4 ) alkoxy group, a methylenedioxy group, an amino group, a nitro group or a hydroxy group. Optionally a phenyl group, R ₂ ′ is hydrogen or lower (C _1-4 ).
An alkoxy group, X'represents a lower (C _1-4 ) alkoxycarbonyl group, A and E have the same meanings as defined above, and a pharmacologically acceptable salt thereof is preferable.

Examples of the compound of the present invention include the compounds shown in Table 1.

The compound (I) of the present invention has, for example, the formula [Wherein each symbol has the same meaning as defined above] and a compound represented by the formula [Wherein G, R ₃ and R ₄ are as defined above, W is a halogen or a group represented by the formula R-SO ₂ -O- (R is a lower group)
_{Represented by} (C _1-4 ) alkyl, phenyl or p-tolyl], condensation reaction, reduction reaction after condensation reaction or reduction reaction after condensation reaction followed by acylation or carbamoylation reaction It can be manufactured by attaching to.

The condensation reaction is usually carried out in the presence of a base, and examples of the base include inorganic carbonates such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium methoxide, sodium hydride, lithium diisopropylamide, triethylamine, pyridine, 1 , 8-diazabicyclo 〔5,4,
0] -7-undecene and other organic amino compounds. At this time, for example, sodium iodide, potassium iodide or the like can be used as a catalyst to conveniently proceed the reaction. The above reaction is usually carried out in an organic solvent (eg, acetone, 2-butanone, acetonitrile, N, N-dimethylformamide, methylene chloride, benzene, toluene, tetrahydrofuran, dioxane) at a reaction temperature of -20 ° C to + 150 ° C. , Preferably at + 20 ° C to + 120 ° C.

In the formula (I) obtained by the condensation reaction, Y is> C =
Examples of the means for reducing the compound (I) that is O include lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, and tri-tert-hydride.
-Reduction with metal hydrogen compounds such as butoxylithium aluminum, reduction with sodium salts, metal magnesium, etc. and alcohols, catalytic reduction using a catalyst such as platinum, palladium, rhodium, etc. or a mixture thereof with any carrier, iron, Reduction with metals such as zinc and acids such as hydrochloric acid and acetic acid, electrolytic reduction, reduction with reductase, reduction of borohydride compounds such as diborane or borohydride compounds such as borane-trimethylamine with complexes with amines, etc. The reaction conditions can be raised. The above reaction is usually water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride,
Chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies depending on the reducing means, but generally -20
C. to + 100.degree. C. are preferable. Further, the acylation or carbamoylation reaction after condensation reduction can be carried out by using a usual means for acylation or carbamoylation reaction of an alcohol derivative. As means for such an acylation reaction, for example, a reactive derivative of an organic acid corresponding to R ₅ (an acid anhydride, an acid halide, etc.) can be treated with pyridine,
It can be obtained by reacting in the presence of an organic base such as triethylamine and N, N-dimethylaniline, and an inorganic base such as sodium carbonate, potassium carbonate and sodium hydrogen carbonate. The above reaction is usually carried out in an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, toluene, dimethylformamide, pyridine), and the reaction temperature is generally preferably about -20 ° C to + 100 ° C. The carbamoylation reaction can be obtained, for example, by reacting the alcohol derivative obtained by the reduction reaction with an isocyanate corresponding to R ₅ (eg, methyl isocyanate, ethyl isocyanate, phenyl isocyanate, p-chlorophenyl isocyanate). . The above reaction is usually carried out in a suitable organic solvent (eg, methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, methylene chloride, chloroform, toluene, N, N).
-Dimethylformamide), and the reaction temperature is generally preferably about -20 ° C to + 150 ° C.

The compound (I) of the present invention has, for example, the formula [In the formula, W'represents halogen or a group represented by the formula R'-SO ₂ -O- (in the formula, R'represents lower (C _1-4 ) alkyl, phenyl or p-tolyl), and And symbols have the same meaning as above] It can be obtained by reacting with an amine represented by the formula [wherein R ₃ and R ₄ are as defined above]. Compound (I
The reaction of V) with amines (V) is carried out in a suitable organic solvent (eg,
Methanol, ethanol, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide,
It can be carried out in methylene chloride, dimethyl sulfoxide and any mixed solvent thereof. The reaction temperature is preferably about 0 ° C to + 150 ° C. In order to increase the reaction rate, for example, organic bases such as triethylamine, pyridine, N, N-dimethylaniline such as potassium carbonate,
An inorganic base such as sodium carbonate or sodium hydrogen carbonate may be used as a catalyst.

After the reaction, in the formula (I), Y is> CH in the formula (I) by subjecting the compound in which Y is> C═O to the above-mentioned reduction method or the acylation or carbamoylation reaction following the reduction reaction. It can lead to compounds that are -OR ₅ . In addition, the compound (I) of the present invention has, for example, the formula [Wherein G'represents an alkylene group having one less methylene than the lower alkylene group represented by G, and other symbols have the same meanings as those defined above], and the compound (V) is condensed under reducing conditions. It can also be manufactured by

Examples of the reductive conditions include catalytic reduction using a metal such as platinum, palladium, Raney nickel, rhodium or a mixture thereof with an arbitrary carrier, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, Reduction with metal hydrogen compounds such as sodium borohydride and sodium cyanoborohydride, reduction with sodium and metal magnesium and alcohols with alcohols, reduction with metals such as iron and zinc and acids such as hydrochloric acid and acetic acid, electrolytic reduction, reduction Reaction conditions such as reduction with an enzyme can be mentioned. The above reaction is usually water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform,
It is carried out in the presence of benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature is generally -20 ° C to + 100 ° C, although it varies depending on the reducing means. This reaction can achieve the desired purpose at atmospheric pressure, but may be carried out under increased pressure or reduced pressure depending on the circumstances.

The compound (I) of the present invention also has, for example, the formula It can also be produced by subjecting a compound represented by the formula [wherein each symbol has the same meaning as defined above] to a reaction for reducing an amide group. For the reduction reaction, for example, a reducing means such as lithium aluminum hydride, sodium dihydro-bis [2-methoxyethoxy] aluminate, sodium acetoxyborohydride, aluminum hydride, diborane, or alkylborane can be used. The above reaction is usually carried out in the presence of an organic solvent (eg, ethyl ether, tetrahydrofuran, dioxane, toluene, benzene), and the reaction temperature varies depending on the reducing means, but generally-
20 ° C to + 120 ° C is preferable. In the reduction reaction, in the formula (VII), when X is, for example, an esterified or amidated carboxyl and Y is> C = O, these functional groups can be simultaneously reduced. However, only the desired amide group can be reduced by protecting the carbonyl group or selecting a reducing agent if necessary.

The compound in which A is sulfoxide or sulfone in the formula (I) can also be produced by oxidizing the corresponding sulfide compound. The oxidation reaction is carried out, for example, by reacting an organic peracid (eg, metachloroperbenzoic acid, peracetic acid) and an inorganic oxidizing agent (eg, hydrogen peroxide, periodate). The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, dioxane, dichloromethane), and usually carried out in the temperature range of -20 ° C to + 100 ° C.

The thus-obtained object compound (I) of the present invention can be obtained from the reaction mixture by using usual means for separation and purification such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography and thin layer chromatography. It can be isolated. In formula (I), for example, Y is> CH-OR
_{When 5} , there may be at least two stereoisomers. All of these individual isomers and mixtures thereof are naturally included in the scope of the present invention, and if desired, these isomers can be individually produced. For example, a single optical isomer of the compound (I) can be obtained by carrying out the above reaction using a single isomer of each of the starting compounds (IV) and (VI), and In the case of a mixture of two or more kinds of isomers, this is separated by a usual separation method, for example, a method of forming a salt with an optically active acid (eg, camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, malic acid, etc.) or various chromatographies. It is also possible to separate each isomer by a separation means such as grafting and fractional recrystallization.

The starting compounds (II), (IV), (VI) and (VII) can be produced, for example, by the method shown in the following reaction formula.

(I) Compound (II) (a) When X is an optionally substituted aryl or an optionally esterified or amidated carboxyl (B) When X is an optionally substituted alkyl group (C) When X is hydrogen (Ii) Compound (IV) (Iii) Compound (VI) (Iv) Compound (VII) In the above reaction formula, Hal represents halogen (eg, bromine, chlorine), and other symbols have the same meanings as described above.

The ring closure reaction to obtain (IX) from compound (VIII) is usually carried out in an organic solvent (eg, toluene, xylene) and a base (eg, sodium methoxide, sodium ethoxide, potassium tertiary butoxide, hydrogenation). sodium)
Favorably proceeds in the presence of. Reaction temperature is usually + 20 ℃
About + 200 ° C is preferable. In the above reaction, the compound (I
When X) is obtained as an alkali metal salt, compound (XI) can be isolated by a usual method after neutralizing with, for example, acetic acid, hydrochloric acid, sulfuric acid and the like.

In the formula (II), when X is a lower alkyl which may be substituted, the compound (X) obtained by the above method (i)-(a) is alkylated and then subjected to a reaction for removing an ester group. The compound (VIII) can be obtained by

The reaction between the compounds (X) and (XI) is carried out in a suitable organic solvent (eg, acetone, 2-butanone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, benzene, toluene, tetrahydrofuran) with a base (eg, carbonic acid). Sodium, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium methoxide, triethylamine, pyridine) can coexist. At this time, the reaction can be smoothly promoted by adding an iodine compound such as potassium iodide or sodium iodide as a catalyst. Usually, the reaction temperature is preferably about -20 ° C to + 150 ° C.

The reaction of (VII) → (VIII) follows the usual reaction for removing an ester group, and the compound (VII) in an appropriate organic solvent (eg, dimethyl sulfoxide, N, N-dimethylformamide, N, N-dimethylacetamide) , Salt (eg sodium chloride,
Lithium chloride, calcium chloride, sodium bromide) are coexistent and heated at about + 50 ° C to + 160 ° C to proceed.

In the formula (II), when X is hydrogen, the compound (X) is converted to (VII)
→ Compound (XIV) can be obtained by subjecting it to a reaction similar to the reaction of (VIII).

The reaction between the compounds (IX) and (XV) can be carried out in the same manner as the reaction between the compounds (X) and (XI). Compound (XVII) can be obtained by subjecting compound (XVI) to a reduction reaction. In the reduction reaction, reduction with a metal hydrogen compound such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, tritert-butoxylithium aluminum hydride,
Reduction with sodium, metal magnesium, etc. and alcohols, catalytic reduction using a mixture of metals such as platinum, palladium, rhodium, etc. and their arbitrary carriers as a catalyst,
Reduction with metals such as iron and zinc and acids such as hydrochloric acid and acetic acid,
Reaction conditions such as electrolytic reduction, reduction with a reductase, reduction with a borohydride compound such as diborane, or reduction with a complex of a borohydride compound such as borane-trimethylamine and amines can be mentioned. The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature is adjusted by a reducing means. Different but generally -20 ℃ ～ ＋ 10
About 0 ° C is preferable.

The reaction of (XVII) → (XVIII) can be carried out by using a usual means of acylation or carbamoylation of an alcohol derivative. As the means of the acylation reaction, for example, a reactive derivative of an organic acid corresponding to R ₅ (eg, acid anhydride, acid halide) is treated with an organic base (eg, pyridine, triethylamine, N, N-dimethylaniline) or It can be obtained by reacting with compound (XVII) in the presence of an inorganic base (eg, sodium carbonate, potassium carbonate, sodium hydrogen carbonate).

The above reaction is usually carried out in an organic solvent (eg, ethyl ether, dioxane, methylene chloride, toluene, dimethylformamide, pyridine), and the reaction temperature is generally preferably about -20 ° C to + 100 ° C. The carbamoylation reaction can be obtained, for example, by reacting the alcohol derivative (XVII) obtained by the reduction reaction with an isocyanate corresponding to R ₅ (eg, methyl isocyanate, ethyl isocyanate, phenyl isocyanate, p-chlorophenyl isocyanate). be able to. The above reaction is usually carried out in a suitable organic solvent (eg, acetonitrile, dioxane, tetrahydrofuran, methylene chloride, chloroform, toluene, N, N-dimethylformamide), and the reaction temperature is generally about -20 ° C to + 150 ° C. preferable.

The reaction between compounds (IX) and (XIX) is
It can be carried out in the same manner as the reaction of I). Compound (XX
I) can be obtained by hydrolyzing compound (XX) with a dilute mineral acid (eg, hydrochloric acid, sulfuric acid). Compound (XXIII) can be produced by the same procedure as compound (XXII) reduction reaction (XVI) → (XVII), and (XXIII)-(XXIV) reaction is (XVII) → (XVIII) reaction. It can be performed in the same manner as. Compound (XXV) is obtained by converting compound (XXIV) into (XX) → (XX
It can be obtained by subjecting it to a reaction similar to the reaction of I).

The reaction between compounds (IX) and (XXVI) is the same as compounds (X) and (XI)
It can be carried out in the same manner as the reaction of.

The reaction of (XXVII) → (XXVIII) is the same as the reaction of (XVI) → (XVII), and the reaction of (XXVIII) → (XXIX) is (XVI).
The reaction can be performed in the same manner as the reaction I) → (XVIII).

In the above-mentioned method for producing compound (I) and its intermediate, the compound used in the reaction is an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., as long as it does not interfere with the reaction. For example, organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate, etc., metal salts such as sodium salt, potassium salt, calcium salt, aluminum salt, etc. It may be used in the form of a salt such as a salt with a base such as a triethylamine salt, a guanidine salt, an ammonium salt, a hydrazine salt, a quinine salt or a cinchonine salt.

The present invention also provides intermediates (IV) and salts thereof which are useful for producing compound (I). Expression (I
Halogen is preferred as W'in V).

Action The compound of the present invention, ie, the compound represented by the formula (I) and a salt thereof, is a serotonin S ₂ receptor specific for animals, particularly mammals (eg, human, pig, dog, cat, rabbit, guinea pig, rat). It exhibits blocking action, cerebral vasospasm relieving action and antithrombotic action, and ischemic heart disease such as angina and myocardial infarction, thrombosis and hypertension, cerebral circulation disorder such as cerebral vasospasm and transient ischemic attack. It is useful as a preventive or therapeutic agent. Since the compound of the present invention has low toxicity, is well absorbed even by oral administration, and is excellent in stability, when used as the above-mentioned drug, itself or an appropriate pharmacologically acceptable carrier, excipient, diluent It can be safely administered orally or parenterally as a pharmaceutical composition such as powder, granules, tablets, capsules and injections. The dose varies depending on the condition of the target disease and the route of administration, but when administered to adult patients for the purpose of treating ischemic heart disease or hypertension, for example, oral administration usually gives a dose of about 0.1.
~ 10mg / Kg, especially 0.3 ~ 3mg / Kg is preferable, and in the case of intravenous administration, the dose is about 0.003 ~ 0.1mg / Kg, especially 0.01 ~ 0.1mg / K
About g is preferable, and it is desirable to administer these doses about 1 to 3 times a day depending on the symptoms.

When compound (I) is administered to an adult patient for the purpose of treating cerebral circulatory disorder, it is usually orally administered in a single dose of about 0.1-50 m
g / Kg is preferably about 0.3 to 30 mg / Kg, and a single dose of about 0.003 to 10 mg / Kg, especially about 0.01 to 1 mg / Kg is preferable for intravenous administration, and these doses should be about 1 to 1 daily depending on the symptoms. Three
It is desirable to administer it once.

EXAMPLES The present invention will be described in more detail below with reference to Reference Examples, Examples and Preparation Examples, but the present invention is not limited thereto.

Reference Example 1 Methyl 3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate 5.0 g, 1-bromo-3-chloropropane 7.1 g, potassium iodide 1.5 g, potassium carbonate 6.3 g and A mixture of 60 ml of acetonitrile is heated to reflux for 4 hours. After cooling, the inorganic substances are removed by filtration, the filtrate is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. Column chromatography of the residue on silica gel (eluent: hexane:
Purified with ethyl acetate = 8: 1 → 2: 1) and methyl 2- (3-
5.5 g of colorless oil of chloropropyl) -3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate are obtained. Recrystallization from ethanol gives 4.4 g of colorless prism crystals. Melting point 75-77 [deg.] C.

Elemental analysis C ₁₅ H ₁₇ Calculated _{ClO 4: C, 60.71; H} , 5.77 Found: C, 60.51; H; 5.72 .

Reference Example 2 Methyl 2- (3-chloropropyl) -obtained in Reference Example 1
2.0 g of 3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate is suspended in 30 ml of methanol and sodium borohydride is added little by little while stirring under ice cooling. After the reaction is completed, water is added and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1 → 1: 1). From the first eluted fraction, methyl 2- (3-chloropropyl) -3-hydroxy-2,3,4,5-tetrahydro-
A colorless oil of 1-benzoxepin-2-carboxylate (isomer A) is obtained. Mass spectrum m / e 298,300 (M
⁺ ).

NMR (CDCl ₃ ) δ: 2.0 (6H, multiplet), 3.0 (2H, multipl
et), 3.5 (2H, triplet, ClC H _2- ), 3.70 (3H, s, OCH ₃ ), 4.
_{18 (1H, multiplet, C 3} -H). Then, from the fractions eluted, methyl 2- (3-chloropropyl) -3-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate (B
0.66 g of crystals of the isomer) are obtained. Recrystallization from ethyl acetate-hexane gives colorless prism crystals. Melting point 107-109 [deg.] C.

Elemental analysis C ₁₅ H ₁₉ Calculated _{ClO 4: C, 60.30; H} , 6.41 Found: C, 60.29; H; 6.49 . Reference Example 3 4.1 g of 60% sodium hydride was suspended in 150 ml of xylene, and then 0.3 ml of tert-butanol was added to
A solution of 10 g of 2-methoxycarbonylmethyloxyphenoxyacetate in 100 ml of xylene is added dropwise at 140-150 ° C (8 hours are required). 7 g of acetic acid is added to the reaction solution and the precipitate is filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1 → 2: 1) to give methyl 3-oxo-3,3.
6.5 g of a colorless oil of 4-dihydro-2H-1,5-benzoxepin-2-carboxylate is obtained. Mass spectrum m /
e: 222 (M ⁺ ).

NMR (CDCl ₃ ) δ: 3.75 (3H, singlet, OCH ₃ ), 4.68 (2H, do
_{uble doublet, C 4 -H),} 5.32 (1H, singlet, C 2 -H). Reference Example 4 Methyl 3-oxo-3,4-dihydro-2 obtained in Reference Example 3
H-1,5-benzodioxepin-2-carboxylate 5.
5g, 1-Bromo-3-chloropropane 7g, potassium iodide
A mixture of 1.7 g, potassium carbonate 6.25 g, and acetonitrile 70 ml is heated to reflux for 3 hours. The inorganic substances are removed by filtration, the filtrate is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and dried, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1), and methyl 2- (3
-Chloropropyl) -3-oxo-3,4-dihydro-2H
2.5 g of a colorless oil of -1,5-benzodioxepin-2-carboxylate is obtained. Mass spectrum m / e = 298,300 (M
⁺ ).

NMR (CDCl ₃ ) δ: 3.66 (3H, singlet, OCH ₃ ), 4.62 (2H, do
uble doublet, C ₄ -H).

Reference Example 5 Methyl 2- (3-chloropropyl) -obtained in Reference Example 5
2.5 g of 3-oxo-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate is dissolved in 20 ml of methanol, and sodium borohydride is added little by little while stirring under ice cooling. After the reaction is completed, water is added to the reaction solution and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 3: 1 → 1: 1). From the first eluting fraction, methyl 2-
1.75 g of colorless oil of (3-chloropropyl) -3-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate (isomer A) is obtained.

Mass spectrum m / e: 300,302 (M ⁺ ). NMR (CDCl ₃ ) δ: 3.21 (4H, multiplet), 3.3 (2H, triple
t, ClC H _2- ), 3.70 (3H, singlet, OCH ₃ ), 4.2 (3H, multipl
et).

Then, from the fractions eluted, methyl 2- (3-chloropropyl) -3-hydroxy-3,4-dihydro-2H-
1,5-benzodioxepin-2-carboxylate (B
0.44 g of colorless oil of (isomer) is obtained. Mass spectrum: m /
e: 300,302 (M ⁺ ).

NMR (CDCl ₃ ) δ: 1.9 (4H, multiplet), 3.42 (2H, triple
t, ClC H _2- ), 3.80 (3H, singlet, OCH ₃ ).

Reference Example 6 To a mixture of 10 g of methyl 3- (2-hydroxyphenyl) propionate, 9.5 g of trimethylenediamine and 45 ml of N, N-dimethylformamide, 7.4 g of N, N-dimethylthiocarbamoyl chloride was added 15 ml of N, N-dimethylformamide.
The solution dissolved in is added dropwise with stirring. After stirring at room temperature for 15 hours, pour the reaction solution into ice water and extract with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 4: 1) to obtain 11 g of methyl 3- (2-N, N-dimethylthiocarbamoyloxyphenyl) propionate as a colorless oil. .

_{NMR (CDCl 3) δ: 2.2~3.1} (4H, multiplet), 3.28,3.38
_{(6H, 2singlet N (CH 3} ) 2).

Reference Example 7 To 2.0 g of methyl 3- (2-N, N-dimethylthiocarbamoyloxyphenyl) propionate obtained in Reference Example 6 was added.
Stir at 0-270 ° C for 30 minutes. After cooling, column chromatography on silica gel (eluent: hexane: ethyl acetate =
2: 1), a pale yellow oily product of methyl 3- (2-N, N-dimethylcarbamoylthiophenyl) propionate.
Get 1.4g. Mass spectrum m / e: 267 (M ⁺ ). NMR (CDCl ₃ ) δ: 2.3 to 3.3 (4H, multiplet), 2.98 (6H, s
inglet, N (CH ₃ ) ₂ ) 3.58 (3H, singlet, OCH ₃ ). Reference Example 8 1.1 g of methyl 3- (2-N, N-dimethylcarbamoylthiophenyl) propionate obtained in Reference Example 7 was dissolved in 10 ml of ethanol, 0.58 g of potassium hydroxide was added, and the mixture was heated under reflux for 5 hours. After cooling, the reaction solution was concentrated under reduced pressure, 10 ml of water was added to the residue to dissolve it, 0.63 g of methyl bromoacetate and 2 ml of acetone were added, and the mixture was stirred at room temperature for 4 hours. To the reaction mixture, add a solution of 0.62 g of dimethylsulfate in 4 ml of acetone and add 60
Stir at ℃ for 15 hours. The reaction mixture is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 3:
Purified in 1), 0.6 g of methyl 3- (2-methoxycarbonylmethylthiophenyl) propionate colorless oil
To get Mass spectrum m / e: 268 (M ⁺ ). NMR (CDCl ₃ ) δ: 2.4-3.3 (4H, multiplet), 3.62, 3.64
(6H, 2singlet, OCH ₃ ). Reference Example 9 60 g of oily sodium hydride (0.8 g) was suspended in toluene (50 ml), tert-butanol (0.05 ml) was added, and the mixture was placed in a nitrogen stream at 130 ° C.
Methyl 3- (2-
A solution of 2.1 g of methoxycarbonylmethylthiophenepropionate dissolved in 50 ml of toluene is added dropwise little by little (8 hours are required). After cooling, 2 ml of acetic acid is added and the precipitate is filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 4:
Purification in 1) gives 1.5 g of a colorless oil of methyl 3-oxo-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate.

Mass spectrum m / e: 236 (M ⁺ ).

NMR (CDCl ₃ ) δ: 2.6-3.4 (4H, multiplet), 3.62 (3H, 2
_{singlet, OCH 3), 4.2 (} 1H, singlet, C 2 -H). Reference Example 10 Methyl 3-oxo-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate obtained in Reference Example 9.
A mixture of 5 g, 1-bromo-3-chloropropane 3.0 g, potassium iodide 0.5 g, potassium carbonate 1.7 g and acetonitrile 20 ml is stirred at 80-85 ° C. for 5 hours. After cooling, the inorganic substances are filtered, the filtrate is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane: methylene chloride: ethyl acetate = 15: 1).
0: 1) and methyl 2- (3-chloropropyl)
1.1 g of colorless oil of -3-oxo-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate is obtained. Mass spectrum m / e: 312,314 (M ⁺ ).

NMR (CDCl ₃ ) δ: 1.7-3.6 (10H, multiplet), 3.65 (3H,
singlet, OCH ₃ ).

Reference Example 11 Methyl 2- (3-chloropropyl) -obtained in Reference Example 10
1.0 g of 3-oxo-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate in tetrahydrofuran
It is dissolved in a mixed solvent of 3 ml and 12 ml of methanol, and 0.1 g of sodium borohydride is added little by little while stirring under ice cooling. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1).
2- (3-chloropropyl) -3-hydroxy-2,3,4,
0.8 g of an oil of 5-tetrahydro-1-benzothiepine-2-carboxylate (confirmed to be a cis isomer by X-ray analysis) is obtained. Recrystallization from ethyl acetate gives colorless prism crystals. Melting point 108-110 ° C.

Elemental analysis value Calculated as C ₁₅ H ₁₉ ClO ₃ S: C, 57.23; H, 6.08 Found: C, 57.27; H, 6.11 Reference Example 12 N, N-Dimethylthiocarbamoyl chloride 7.5 g was added to a mixture of methyl 3- (2-hydroxy-4-methoxyphenyl) propionate 11 g, trimethylenediamine 0.5 g and N, N-dimethylformamide 45 ml. A solution dissolved in 15 ml of dimethylformamide is added dropwise with stirring. After stirring at room temperature for 13 hours, the reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting residue is stirred at 280-290 ° C for 1 hour. After cooling, add 60 ml of ethanol to the reaction product to dissolve it, add 3.6 g of potassium hydroxide, and add 5
Heat to reflux for hours. Then methyl bromoacetate 3.9g
And stir at room temperature for 4 hours. Then dimethyl sulfate 4.
Add 0 g and 30 ml of acetone and stir at 60 ° C for 10 hours.
The reaction mixture is concentrated under reduced pressure, water is added to the residue and the mixture is extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1) and methyl 3- (4-
4.0 g of methoxy-2-methoxycarbonylmethylthiophenyl) propionate are obtained. Then, 0.8 g of 60% oily sodium hydride was suspended in 50 ml of toluene, 0.05 ml of tert-butanol was added, and the mixture was heated to 130 ° C. in a nitrogen stream, and methyl 3- (4-methoxy-2-methoxycarbonylmethylthiophenyl) was added. A solution prepared by dissolving 2.2 g of propionate in 50 ml of toluene is added dropwise little by little (8 hours).
After cooling, 2 ml of acetic acid was added to the reaction mixture and the mixture was stirred, and then the precipitate was filtered off. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate =
3: 1) and methyl 8-methoxy-oxo-2,3,
1.3 g of 4,5-tetrahydro-1-benzothiepine-2-carboxylate are obtained. Then methyl 8-methoxy-
A mixture of oxo-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate 1.0 g, 1-bromo-3-chloropropane 2.5 g, potassium iodide 0.3 g, potassium carbonate 1.5 g and acetonitrile 20 ml was added to 85 Stir at ℃ for 5 hours. After cooling, the inorganic substances were removed by filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: hexane: methylene chloride: ethyl acetate = 15: 10: 1).
Purified with methyl 2- (3-chloropropyl) -8-
Methoxy-3-oxo-2,3,4,5-tetrahydro-1-
0.9 g of benzothiepine-2-carboxylate is obtained. Methyl 2- (3-chloropropyl) -8-methoxy-3
-Oxo-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate 0.7 g was dissolved in a mixed solvent of 10 ml of methanol and 3 ml of tetrahydrofuran, and 0.1 g of sodium borohydride was gradually added while stirring under ice cooling. Added. After stirring for 1 hour, pour the reaction solution into ice water,
Extract with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1) and methyl 2- (3-chloropropyl) -3-hydroxy-8-methoxy-2,3,4,5- Tetrahydro-1-
Benzothiepine-2-carboxylate is obtained.

Reference Example 13 15 g of methyl 3- (4-methoxy-2-methoxycarbonylmethyloxyphenyl) propionate was added to toluene 2
A solution dissolved in 00 ml, 60% oily sodium hydride 5.6 g
Was suspended in 200 ml of toluene, 0.4 ml of tertiary butanol was added, and the mixture was added dropwise to the suspension heated and refluxed with stirring for 8 hours. Heat to reflux for 30 minutes and let stand overnight. 10 ml acetic acid
It is poured into ice water containing water, the organic layer is separated, washed with water and dried, and then the solvent is distilled off under reduced pressure. Column chromatography of the residue on silica gel (eluent: hexane: ethyl acetate = 4: 1)
Purified with methyl 3-oxo-8-methoxy-2,3,4,5
-9.5 g of a colorless oil of tetrahydro-1-benzoxepin-2-carboxylate are obtained. Then methyl 3-
Oxo-8-methoxy-2,3,4,5-tetrahydro-1-
A mixture of 7.4 g of benzoxepin-2-carboxylate, 10.9 g of 1-bromo-3-chloropropane, 1.5 g of potassium iodide, 10 g of anhydrous potassium carbonate and 300 ml of acetonitrile is heated under reflux for 5 hours while stirring. After cooling, the inorganic substances were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate = 8:
Purified in 1) and methyl 2- (3-chloropropyl) -8
-Methoxy-3-oxo-2,3,4,5-tetrahydro-1
9 g of benzoxepin-2-carboxylate oil
To get Then methyl 2- (3-chloropropyl) -8
-Methoxy-3-oxo-2,3,4,5-tetrahydro-1
-9 g of benzoxepin-2-carboxylate is dissolved in 100 ml of methanol, and 0.6 g of sodium borohydride is added little by little while stirring under ice cooling. The reaction mixture is concentrated under reduced pressure, water is added to the residue and the mixture is extracted with ethyl acetate. The organic layer was washed with water, dried, evaporated to remove the solvent under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 3: 1). Methyl trans-2- Colorless oil of (3-chloropropyl) -3-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate 3.
Get 3g.

mass-spectrum m / e: 328,330 (M ⁺ ). Then, from the fractions eluting, methyl cis-2- (3
-Chloropropyl) -3-hydroxy-8-methoxy-
2,3,4,5-Tetrahydro-1-benzoxepin-2-
3.4 g of a carboxylate oil is obtained.

mass-spectrum m / e: 328,330 (M ⁺ ) Example 1 Methyl 2- (3-chloropropyl) -obtained in Reference Example 1
A mixture of 0.5 g of 3-oxo-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate, 0.6 g of N-phenylpiperazine and 0.27 g of potassium iodide is heated at 85 ° C. for 3 hours. After cooling, add water and extract with ethyl acetate.
The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 2: 1 → 1: 1) and methyl 3
-Oxo-2- [3- (4-phenylpiperazine-1-
Yield) propyl] -2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate colorless oil 0.55
get g. Recrystallization from ethanol-ether as a hydrochloride with ethanolic hydrochloric acid gives 0.5 g of colorless needles. Melting point 165-167 [deg.] C.

Elemental analysis value C ₂₅ H ₃₀ N ₂ O ₄・ 2HCl ・ 1 / 4H ₂ O Calculated value: C, 60.06; H, 6.55; N, 5.60 Actual value: C, 59.86; H, 6.36; N, 5.45 Example 2 Methyl 2- (3-chloropropyl) -obtained in Reference Example 10
85-90 a mixture of 3-oxo-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate 0.15 g, N-phenylpiperazine 0.18 g and potassium iodide 0.1 g.
Stir at ℃ for 4 hours. Water is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 2: 1) and methyl 3-oxo-2- [3- (4-phenylpiperazin-1-yl) propyl] -2, 3,4,5-tetrahydro-
70 mg of 1-benzothiepine-2-carboxylate crystals
To get Recrystallization from ethyl acetate-hexane gives colorless needle crystals. Melting point 101-103 ° C.

Elemental analysis value Calculated as C ₂₅ H ₃₀ N ₂ O ₄ S: C, 68.46; H, 6.89; N, 6.39 Actual value: C, 68.44; H, 6.84; N, 6.51 Example 3 Obtained in Reference Example 2 Methyl 2- (3-chloropropyl)-
3-Hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate (A isomer) 0.9 g, N
-Phenylpiperazine 1.07 g and potassium iodide 0.6 g
Stir the mixture at 90 ° C. for 3 hours. After cooling, add water and extract with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. Column chromatography of the residue on silica gel (eluent: hexane: ethyl acetate = 3: 1 → 1: 3)
And methyl 3-hydroxy-2- [3- (4-
Phenylpiperazin-1-yl) propyl] -2,3,4,5
0.68 g of crystals of tetrahydro-1-benzoxepin-2-carboxylate (isomer A) are obtained. Recrystallization from ethyl acetate-hexane gives colorless needle crystals. Melting point 98-99
° C.

Elemental analysis value Calculated as C ₂₅ H ₃₂ N ₂ O ₄ : C, 70.73; H, 7.60; N, 6.60 Actual value: C, 70.83; H, 7.63; N, 6.51 Methyl obtained in Example 4 Reference Example 2 2- (3-chloropropyl)-
0.36 g of 3-hydroxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate (B isomer),
N-phenylpiperazine 0.43 g and potassium iodide 0.2 g
The mixture was stirred at 90 ° C. for 3 hours, treated as in Example 3, and treated with methyl 3-hydroxy-2- [3- (4-phenylpiperazin-1-yl) propyl] -2,3,4,5-. 0.18 g of crystals of tetrahydro-1-benzoxepin-2-carboxylate (isomer B) are obtained. Recrystallization from ethyl acetate-hexane gives colorless needle crystals. Melting point 112-113
° C.

Elemental analysis C ₂₅ H ₃₂ N ₂ O ₄ Calculated: C, 70.73; H, 7.60 ; N, 6.60 Found: C, 70.99; H, 7.74 ; N, methyl obtained in 6.49 Example 5 Example 5 2- (3-chloropropyl)-
3-Hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate (A isomer) 0.5 g, N-
A mixture of 0.54 g of phenylpiperazine and 0.28 g of potassium iodide was stirred at 90 ° C. for 3 hours and treated in the same manner as in Example 3 to prepare methyl 3-hydroxy-2- [3- (4-phenylpiperazin-1-yl). 0.43 g of crystals of propyl] -3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate are obtained. Recrystallization from ethyl acetate-hexane gives white crystals. Melting point 143-144 [deg.] C.

Elemental analysis value Calculated as C ₂₄ H ₃₀ N ₂ O ₅・ 1 / 4H ₂ O: C, 66.87; H, 7.13; N, 6.50 Measured value: C, 66.94; H, 6.97; N, 6.47 Refer to Example 6 Methyl 2- (3-chloropropyl) -obtained in Example 5
3-Hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate (B isomer) 0.44 g, N
-Phenylpiperazine 0.5 g and potassium iodide 0.25 g
Stir the mixture at 90 ° C. for 3 hours. The reaction solution was used in Example 3.
Methyl 3-hydroxy-2- [3-
(4-Phenylpiperazin-1-yl) propyl] -3,
0.33 g of crystals of 4-dihydro-2H-1,5-benzodioxepin-2-carboxylate (B isomer) are obtained. Recrystallization from ethyl acetate-hexane gives white crystals. Melting point 113
-115 ° C.

Elemental analysis value Calculated as C ₂₄ H ₃₀ N ₂ O ₅ : C, 67.59; H, 7.09; N, 6.57 Actual value: C, 67.48; H, 7.04; N, 6.62 Methyl obtained in Example 7 Reference Example 11 Cis-2- (3-chloropropyl) -3-hydroxy-2,3,4,5-tetrahydro-1-
A mixture of 0.3 g of benzothiepine-2-carboxylate, 0.37 g of N-phenylpiperazine and 0.15 g of potassium iodide is stirred at 85-90 ° C for 6 hours. The reaction mixture was treated in the same manner as in Example 3 to give methyl cis-3-hydroxy-2- [3
-(4-phenylpiperazin-1-yl) propyl]-
0.25 g of crystals of 2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate are obtained. Recrystallization from ethyl acetate-hexane gives colorless prism crystals. Melting point 152-154
° C.

Elemental analysis value Calculated as C ₂₅ H ₃₂ N ₂ O ₃ S: C, 68.15; H, 7.32; N, 6.36 Actual value: C, 68.40; H, 7.34; N, 6.36 Example 8 Obtained in Example 2 Methyl 3-oxo-2- [3- (4-
Phenylpiperazin-1-yl) propyl] -2,3,4,5
0.2 g of tetrahydro-1-benzothiepine-2-carboxylate are dissolved in 20 ml of methanol and 50 mg of sodium borohydride are added little by little with stirring. After stirring for 1 hour, water is added and the mixture is extracted with ethyl acetate. The organic layer was washed with water, dried and evaporated under reduced pressure to remove the solvent, and the residue was recrystallized from ethyl acetate-hexane to give methyl 3-hydroxy-2- [3- (4-phenylpiperazine-) obtained in Example 7. 1-yl) propyl] -2,3,4,5-tetrahydro-
Crystal of 1-benzothiepine-2-carboxylate 0.15
get g. Melting point 152-154 [deg.] C.

Example 9 Methyl 2- (3-chloropropyl) -3-hydroxy-2,3,4,5-tetrahydro-1-obtained in Reference Example 2
Benzoxepin-2-carboxylate (B isomer)
0.3 g, N-methyl-3,4-dimethoxyphenethylamine
Methyl obtained by treating a mixture of 0.4 g and 0.1 g of potassium iodide at 90 ° C. for 3 hours and treating in the same manner as in Example 3.
3-Hydroxy-2- [3- (N-methyl-3,4-dimethoxyphenethylamino) propyl] -2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate as a hydrochloride, white powder Becomes

Elemental analysis value Calculated as C ₂₆ H ₃₅ NO ₆・ 2HCl ・ 1 / 2H ₂ O: C, 57.88; H, 7.10; N, 2.60 Actual value: C, 57.76; H, 6.92; N, 2.71 Example 10 Reference Methyl 2- (3-chloropropyl) -3-hydroxy-8-methoxy-2,3,4,5-tetrohydro-1-benzothiepine-2-carboxylate obtained in Example 12
0.3 g, N-phenylpiperazine 0.5 g and potassium iodide
Stir 0.1 g of the mixture at 90 ° C for 5 hours. The reaction mixture was treated in the same manner as in Example 3 to give methyl 3-hydroxy-8-methoxy-2- [3- (4-phenylpiperazin-1-yl) propyl] -2,3,4,5-tetrahydro-1. Benzothiepine-2-carboxylate is obtained. It becomes a white powder as the hydrochloride.

Elemental analysis value Calculated as C ₂₆ H ₃₄ N ₂ O ₄ S ・ 2HCl ・ 1 / 2H ₂ O: C, 60.00; H, 7.17; N, 5.38 Found: C, 59.83; H, 7.25; N, 5.21 Example 11 Methyl 2- (3-chloropropyl) -obtained in Reference Example 12
3-Hydroxy-8-methoxy-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate 0.7 g, N
0.5 g of (4-hydroxyphenyl) piperazine and N,
A mixture of 2 ml N-dimethylacetamide is stirred at 90 ° C. for 6 hours. Water is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate: methanol = 20: 20: 1), recrystallized from ethyl acetate and methyl 3-hydroxy-2-
0.3 g of colorless needles of {3- [4-hydroxyphenyl) piperazin-1-yl] propyl} -8-methoxy-2,3,4,5-tetrahydro-1-benzothiepine-2-carboxylate are obtained. Melting point 120-124 ° C (recrystallized from ethyl acetate) Elemental analysis value Calculated as C ₂₆ H ₃₄ N ₂ O ₅ S ・ H ₂ O: C, 61.88; H, 7.19; N, 5.55 Found: C, 61.81; H, 7.24; N, 5.71 Example 12 Methyl trans-2- (3-chloropropyl) -3-
Hydroxy-8-methoxy-2,3,4,5-tetrahydro-
1-benzoxepin-2-carboxylate 1.0 g, N-
A mixture of 1.1 g of phenylpiperazine and 0.25 g of potassium iodide is stirred at 90 ° C for 2.5 hours. Water is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate: methanol = 30: 20: 1) and methyl trans-3-hydroxy-8-methoxy-2- [3- (4-phenylpiperala). Zin-1-yl) propyl] -2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate pale yellow oil 1.0 g
To get White crystals are obtained as the hydrochloride. Melting point 140-155 ° C
(Decomposition point) Elemental analysis _{C 26 H 34 N 2 O 5} · 2HCl Calculated: C, 59.20; H, 6.88 ; N, 5.31 Found: C, 59.12; H, 6.96 ; N, 5.23 Example 13 Methyl Cis-2- (3-chloropropyl) -3-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1-
A mixture of 1.0 g of benzoxepin-2-carboxylate, 1.1 g of N-phenylpiperazine and 0.25 g of potassium iodide was added to 90%.
Stir at 2.5 ° C. for 2.5 hours, treat as in Example 12, and treat with methyl.
Cis-3-hydroxy-8-methoxy-2- [3- (4
-Phenylpiperazin-1-yl) propyl-2,3,4,5
A colorless prism crystal of tetrahydro-1-benzoxepin-2-carboxylate (confirmed to be a cis isomer by X-ray analysis) is obtained. Mp 126 - 128 ° C. (ethyl acetate - hexane to) Elemental analysis C ₂₆ H ₃₄ N ₂ O ₅ Calculated: C, 68.70; H, 7.54 ; N, 6.16 Found: C, 68.42; H, 7.62 N, 6.02 Example 14 Methyl cis-2- (3-chloropropyl) -3-hydroxy-8-methoxy-2,3,4,5-tetrahydro-1-
Benzoxepin-2-carboxylate 0.7g, N- (4
A mixture of 0.5 g of -hydroxyphenyl) piperazine and 2 ml of N, N-dimethylacetamide is stirred at 90 ° C for 6 hours. Water is added to the mixture and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate: methanol = 20: 20: 1) and methyl cis-3-hydroxy-2- {3- [4- (4-hydroxyphenyl) piperazine. -1-yl] propyl]
A viscous liquid of -8-methoxy-2,3,4,5-tetrahydro-1-benzoxepin-2-carboxylate is obtained.
It becomes a white powder as the hydrochloride.

Elemental analysis value Calculated as C ₂₆ H ₃₄ N ₂ O ₆・ 2HCl ・ H ₂ O: C, 55.61; H, 6.82; N, 4.99 Measured value: C, 55.78; H, 7.13; N, 4.78 Dispensing example Invention When compound (I) is used as a therapeutic agent for ischemic heart disease, for example, it can be used by the following formulation.

1. tablets Ingredients (1), (2) and 17g of (3) were mixed and granulated with a paste made from 7g of ingredient (3), to which 5g of ingredient (3) and ingredient (4) were added and the mixture Is compressed with a compression tablet machine to produce 1,000 tablets having a diameter of 7 mm and containing 10 mg of the component (1) per tablet.

Effect of the Invention Experimental Example 1 Serotonin S ₂ -receptor-blocking action of the compound of the present invention (in
In vitro) [Experimental method] Bevan &Osher's method (Agents Actions, Volume 2, 257, 197)
2 years) was modified. That is, the pig heart obtained immediately after slaughter at the slaughterhouse was stored under ice cooling, and the circumflex branch of the left coronary artery was separated and collected within 3 hours. A ring-shaped blood vessel specimen was obtained by slicing a coronary artery into slices each having a width of about 3 mm, and the suspension was suspended in a double-walled organ bath containing 20 ml of Krebs-Henseleit solution using a pair of suspending needles. One of the suspending needles was fixed to the bottom of the organ bath and the other was connected to a strain transducer, and the contraction of the porcine coronary ring specimen was measured isometrically and recorded on a polygraph recorder. Organ bath is 37 ℃
The Krebs-Henseleit solution was sufficiently saturated with 97% O ₂ -3% CO ₂ mixed gas. Krebs-Henseleit solution composition of _{NaCl 118.3, KC1 4.7, KH 2} PO 4 1.2, CaCl 2 · 2H 2 O 2.58, M
gSO ₄ .7H ₂ O 1.15, NaHCO ₃ 25, glucose 11.1 mM.

After 1 to 2 hours from the preparation of the sample, after the tension of the blood vessel sample became stable, a tension of 2 g was given, and serotonin 10 ^-6 M (final concentration) was added to the organ bath about every 1 hour to see contraction. . 2 to
When the vascular response to three serotonin additions was stable,
The test compound was added to various concentrations 10 minutes before the next addition of serotonin. The blocking effect of serotonin action was calculated from the magnitude of contraction by serotonin before and after the addition of the test compound.

[Experimental Results] The experimental results for this compound are shown in Table 2.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location C07D 321/10 337/08 405/12 213 409/12 213

Claims (11)

[Claims] 1. A formula [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy, and R ₃ and R ₄ each represent hydrogen or an optionally substituted lower alkyl, cycloalkyl or aralkyl group. Or forms a ring, which may be substituted with an adjacent nitrogen atom, and X is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or optionally esterified or amidated Represents a carboxyl group, Y represents> C═O or> CH—OR ₅ (in the formula, R ₅ represents hydrogen, acyl or optionally substituted carbamoyl), and A represents an oxygen atom or a sulfur atom. , E
Represents an oxygen atom or methylene, and G represents a lower alkylene. Provided that when A is a sulfur atom, E represents methylene] or a salt thereof. 2. The compound according to claim 1, wherein R ₁ and R ₂ are both hydrogen, or one of them is hydrogen and the other is a lower alkoxy group. 3. R ₃ or R ₄ is (i) hydrogen or (ii), respectively.
C _3-8 cycloalkyl, halogen, hydroxy, lower alkoxy, lower alkanoyloxy, mono- or di-lower alkylamino, C _3-8 cycloalkylamino, lower alkanoylamino, benzamide, lower alkylthio, carbamoyl, N-lower alkylcarbamoyl or N, N-
Lower alkyl optionally substituted with di (lower alkyl) carbamoyl, (iii) lower alkyl group, lower alkoxy group, lower alkanoylamino group or C _3-8 cycloalkyl group optionally substituted with hydroxy group, or
(Iv) halogen, lower alkyl group, lower alkoxy group,
Phenyl in which the phenyl group may be substituted with a methylenedioxy group, amino group, nitro group or hydroxy group
A lower alkyl group, or R ₃ and R ₄ together form a cyclic amino group which may contain a nitrogen atom, an oxygen atom or a sulfur atom in addition to the nitrogen atom together with the adjacent nitrogen atom, The cyclic amino group includes (a) lower alkyl group, (b) phenyl group, (c) phenyl-lower alkyl group, (d) diphenyl-lower alkyl group, (e) triphenyl-lower alkyl group, (f). Lower alkanoyl group,
(G) benzoyl group, (h) phenyl-lower alkanoyl group, (i) phenyl-lower alkenoyl group or (j) optionally substituted with a 5 to 7 membered heterocycle containing 1 to 3 nitrogen atoms, When the substituent of the cyclic amino group has a phenyl group, the phenyl group is halogen,
The compound according to claim 1, which may be substituted with a lower alkyl group, a lower alkoxy group, a methylenedioxy group, an amino group, a nitro group or a hydroxy group. 4. R ₃ and R ₄ together with an adjacent nitrogen atom form a cyclic amino group which may contain a nitrogen, oxygen or sulfur atom in addition to the nitrogen atom. The compound according to claim 1, wherein the group is substituted with a phenyl group which may be substituted with a halogen, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, an amino group, a nitro group or a hydroxy group. 5. X is substituted with phenyl optionally substituted with (i) hydrogen, (ii) oxo, hydroxy, lower alkanoyloxy or halogen, lower alkyl, lower alkoxy, methylenedioxy, amino, nitro or hydroxy. Optionally substituted lower alkyl group, (iii) halogen, lower alkyl, lower alkoxy, methylenedioxy, amino, phenyl group optionally substituted by nitro or hydroxy, (iv) lower alkoxycarbonyl group, (v) The compound according to claim 1, which is a carbamoyl group in which the amino group may be substituted with a phenyl-lower alkoxycarbonyl group or (vi) lower alkyl, phenyl or phenyl-lower alkyl. 6. The compound according to claim 1, wherein X is a lower alkoxycarbonyl group or a phenyl-lower alkoxycarbonyl group. 7. R ₅ is (i) a lower alkanoyl group, (ii) a phenyl-lower alkanoyl group or (iii) a lower alkyl, a carbamoyl group in which an amino group may be substituted with phenyl or phenyl-lower alkyl. And R ₅ has a phenyl group, the phenyl group may be substituted with halogen, lower alkyl, lower alkoxy, methylenedioxy, amino, nitro or hydroxy. 8. The compound according to claim 1, wherein Y is hydroxymethylene. 9. Formula [Wherein R ₆ represents a phenyl group which may be substituted with 1 to 3 halogens, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, an amino group, a nitro group or a hydroxy group, and R ₂ ′ represents Hydrogen or a lower alkoxy group, X'represents a lower alkoxycarbonyl group, and A and E have the same meanings as in claim 1] or a salt thereof. The compound according to item 1. 10. A formula [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy, and R ₃ and R ₄ each represent hydrogen or an optionally substituted lower alkyl, cycloalkyl or aralkyl group. Or forms a ring, which may be substituted with an adjacent nitrogen atom, and X is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or optionally esterified or amidated Represents a carboxyl group, Y represents> C═O or> CH—OR ₅ (in the formula, R ₅ represents hydrogen, acyl or optionally substituted carbamoyl), and A represents an oxygen atom or a sulfur atom. , E
Represents an oxygen atom or methylene, and G represents a lower alkylene. Provided that when A is a sulfur atom, E is methylene] or a salt thereof.
S ₂ receptor blocker. 11. A formula [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy, and R ₃ and R ₄ each represent hydrogen or an optionally substituted lower alkyl, cycloalkyl or aralkyl group. Or forms a ring, which may be substituted with an adjacent nitrogen atom, and X is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or optionally esterified or amidated Represents a carboxyl group, Y represents> C═O or> CH—OR ₅ (in the formula, R ₅ represents hydrogen, acyl or optionally substituted carbamoyl), and A represents an oxygen atom or a sulfur atom. , E
Represents an oxygen atom or methylene, and G represents a lower alkylene. Provided that when A is a sulfur atom, E represents methylene] or a salt thereof, a therapeutic agent for ischemic heart disease or cerebral circulation disorder.