JPH043397B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD The present invention relates to a novel 1,5-benzoxathiepine derivative useful as a medicine and a method for producing the same. Problems to be Solved by the Prior Art and the Invention As a result of intensive research to create a compound that has a specific serotonin S ₂ receptor blocking effect, the present inventors have found that it has only an excellent serotonin S ₂ receptor blocking effect. Calcium antagonistic effect, cerebral vasospasm relieving effect,
It also has renal circulation improving, diuretic and antithrombotic effects, and is effective against ischemic heart diseases such as angina pectoris and myocardial infarction, cerebral circulation disorders such as blood clots, hypertension, cerebral vasospasm, and transient ischemic attacks. The present invention has been completed by successfully producing a new 1,5-benzoxathiepine derivative useful as a prophylactic or therapeutic agent. Means for solving the problems The present invention is based on the 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 (i) hydrogen, (ii) C _3-8 cycloalkyl group, halogen, Hydroxy group, lower alkoxy group, lower alkanoyloxy group, mono- or di-lower alkylamino group,
Lower alkyl group optionally substituted with C _3-8 cycloalkylamino group, lower alkanoylamino group, benzamide group, lower alkylthio group, carbamoyl group, N-lower alkylcarbamoyl group, or N,N-dilower alkylcarbamoyl group , (iii) a lower alkyl group, a lower alkoxy group, a lower alkanoylamino group, or a cycloalkyl group optionally substituted with a hydroxy group, or (iv) a halogen, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, or an amino group. represents a phenyl-lower alkyl group which may be substituted with a group, a nitro group or a hydroxy group, or R ₃ and R ₄ together with the adjacent nitrogen atom represent a 5- to 7-membered cyclic amino group, and the cyclic amino group may be substituted with the following (a) to (j), (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) phenyl-lower alkanoyl group, (i) phenyl-lower alkenoyl group, or (j) 5- to 7-membered group containing 1 to 3 nitrogen atoms. Heterocyclic group (however, (b) to (e), (g) to (i)
may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylene dioxy group, amino group, nitro group or hydroxy group), X is (i) hydrogen, (ii) lower alkyl, ( iii) lower alkanoyl group, (iv) hydroxyl lower alkyl group, (v) lower alkanoyloxy lower alkyl group, (vi) phenyl-lower alkyl group, (vii) phenyl group, (viii) lower alkoxycarbonyl group, (ix) phenyl-lower alkoxycarbonyl group, (x) a lower alkyl group, a carbamoyl group optionally substituted with a phenyl group or a phenyl-lower alkyl group, or () a carboxyl group (provided that the phenyl group in (vi) and (vii) may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group or hydroxy group), and Y is >C=O or >CH-OR ₅ (formula Among them, R ₅ is (i) hydrogen, (ii) lower alkanoyl group, (iii) phenyl-lower alkanoyl group, or (iv) (a′) lower alkyl group, (b′) phenyl group, or (c′) phenyl. - a carbamoyl group optionally substituted with a lower alkyl group (provided that (iii),
The phenyl groups in (iv), (b'), and (c) may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group, or hydroxy group). ), m is an integer of 0 to 2, n is an integer of 1 to 6] and salts thereof, and preventive and therapeutic agents for ischemic heart disease, thrombosis, hypertension, and cerebral circulation disorder. It provides: Regarding the above formula (), examples of halogen represented by R ₁ or R ₂ include fluorine, chlorine, bromine,
Examples include iodine. Examples of the lower alkyl group represented by R ₁ or R ₂ include alkyl groups having about 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert- _butyl .
Examples of the lower alkoxy group represented by _R2 include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,
Examples include alkoxy groups having about 1 to 4 carbon atoms such as tert-butoxy. As for R ₁ and R ₂ , it is more preferable that one of them is hydrogen and the other is lower alkoxy, and it is even more preferable that the lower alkoxy group is bonded to the 7-position of the benzoxathiepine skeleton. Examples of the lower alkyl group represented by R ₃ or R ₄ include alkyl groups having about 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. For example, C _3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), halogen (e.g., fluorine, chlorine,
bromine), hydroxy, lower (C _1-4 ) alkoxy (e.g., methoxy, ethoxy, propoxy, butoxy), lower (C _1-5 ) alkanoyloxy (e.g., acetoxy, propionyloxy, butyryloxy, pivaloyloxy), mono- or di- Lower (C _1-4 ) alkylamino (e.g., methylamino, dimethylamino, methylethylamino), C _3-8 cycloalkylamino (e.g., cyclopentylamino,
cyclohexylamino), lower (C _1-5 ) alkanoylamino (e.g., acetamide, propionamide), benzamide, lower (C _1-4 ) alkylthio (e.g., 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), or the like. Examples of the cycloalkyl group represented by R ₃ or R ₄ include cyclopropyl, cyclobutyl,
Examples include cycloalkyl groups having about 3 to 8 carbon atoms such as cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and the cycloalkyl group is, for example, a lower (C _1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl ), lower (C _1-4 ) alkoxy groups (e.g., methoxy, ethoxy,
propoxy, isopropoxy, butoxy),
It may be substituted with a lower (C _1-5 )alkanoylamino group (eg, acetamido), a hydroxy group, or the like. Examples of the phenyl lower alkyl group represented by R ₃ or R ₄ include benzyl, phenethyl, 3-
Examples include phenyl-lower (C _1-4 ) alkyl groups such as phenylpropyl, α-methylbenzyl, α-ethylbenzyl, α-methylphenethyl, β-methylphenethyl, β-ethylphenethyl, etc., and the phenyl in the phenyl-lower alkyl group The base is 1
or three such as halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), lower (C _1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl, etc.), lower (C _1-4 ) alkoxy groups (e.g., methoxy,
(ethoxy, propoxy, isopropoxy, butoxy, etc.), methylenedioxy group, amino group, nitro group, hydroxy group, etc. 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,
Examples include 4,5-trimethoxybenzyl, 4-ethylbenzyl, and 4-chlorobenzyl. Examples of the 5- to 7-membered cyclic amino group formed by R ₃ and R ₄ together with the adjacent nitrogen atom include a cyclic amino group which may have a heteroatom such as nitrogen, oxygen, or sulfur in addition to the nitrogen atom. Examples include pyrrolidinyl, morpholino, piperidyl, piperazinyl, homopiperazinyl, and the like.
The cyclic amino group may have a substituent at a substitutable position, such as lower ( _1-4 ) alkyl (e.g., methyl, ethyl, propyl, butyl), phenyl group, phenyl- lower alkyl group, diphenyl-lower alkyl group, triphenyl-lower alkyl group, lower alkanoyl group,
benzoyl group, phenyl-lower alkanoyl group,
Examples include a phenyl-lower alkenoyl group and a 5- to 7-membered heterocyclic group containing 1 to 3 nitrogen atoms. The phenyl group as a substituent is one to three such as halogen (e.g., fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl), lower ( C _1-4 ) alkoxy group (e.g., hetoxy, ethoxy,
(propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy group, etc. Also,
Examples of the phenyl-lower (C _1-4 ) alkyl group, diphenyl-lower (C _1-4 ) alkyl group, and triphenyl-lower (C _1-4 ) alkyl group used as substituents include benzyl, phenethyl, benzhydryl, etc. . Examples of the lower (C _1-4 ) alkanoyl group as a substituent include acetyl, propionyl, butyryl, phenyl-lower (C _1-4 )
Examples of the alkenoyl group include cinnamoyl. phenyl-lower alkyl group,
The phenyl group in diphenyl-lower alkyl group, triphenyl-lower alkyl group, benzoyl group, phenyl-lower alkanoyl group, and phenyl-lower alkenoyl group contains 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl), lower (C _1-4 ) alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino may be substituted with a group, a nitro group, a hydroxy group, etc. Examples of the 5- to 7-membered heterocycle containing 1 to 3 nitrogen atoms as a substituent include pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, and azepinyl. As for R ₃ and R ₄ , it is more preferable that R ₃ and R ₄ together with the adjacent nitrogen atom form a cyclic amino group substituted with a phenyl group, and even more preferable that they are piperazinyl substituted with a phenyl group. Examples of the lower alkyl group represented by X include alkyl groups having about 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. Examples of the lower (C _1-4 ) alkanoyl group include acetyl, propionyl, butyryl, and the like. Examples of the hydroxy lower alkyl group include groups such as hydroxymethyl. Examples of the lower (C _1-5 ) alkanoyl group of the lower alkanoyloxy lower alkyl group include acetyl, propionyl, butyryl, etc.
Examples of the lower alkanoyloxy lower alkyl group include acetyloxymethyl, propionyloxymethyl, and butyryloxymethyl. Examples of the phenyl-lower (C _1-4 ) alkyl group include benzyl, and the phenyl group has one to three halogens (e.g., fluorine, chlorine, bromine, iodine), lower (C _1-4 ) alkyl group (e.g., methyl, ethyl, propyl, butyl), lower (C _1-4 ) alkoxy group (e.g., methoxy,
ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group,
It may be substituted with a hydroxy group or the like. The phenyl group represented _by C _1-4 ) alkoxy group (e.g., methoxy, ethoxy, propoxy,
(isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy group, etc. Examples of the lower (C _1-4 ) alkoxycarbonyl group represented by It will be done. Examples of the phenyl-( _1-4 ) lower alkoxycarbonyl group represented by X include benzyloxycarbonyl. X may be a carbamoyl group, and the amino group of the carbamoyl group may be substituted with one or two lower (C _1-4 ) alkyl, phenyl, phenyl-lower (C _1-4 ) alkyl, etc. good.
X is preferably a lower alkoxycarbonyl group or a phenyl-lower alkoxycarbonyl group, and more preferably a lower alkoxycarbonyl group. Examples of the lower alkanoyl group represented by R ₅ include lower alkanoyl groups having about 1 to 6 carbon atoms such as acetyl, propionyl, butyryl, valeryl, and pivaloyl. Examples of the phenyl-lower (C _1-6 ) alkanoyl group represented by R ₅ include benzoyl, phenyl acetyl, phenylpropionyl, etc., and the phenyl group of the phenyl-lower alkanoyl group has 1 to 3 halogens ( e.g., fluorine, chlorine, bromine, iodine),
Lower (C _1-4 ) alkyl groups (e.g., methyl, ethyl,
(propyl, butyl), lower (C _1-4 ) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group, nitro group, hydroxy group, etc. R ₅ may be carbamoyl, and the amino group of the carbamoyl group is lower (C _1-4 ) alkyl (e.g., methyl, ethyl, propyl, butyl), phenyl, phenyl-lower (C _1-4 ) It may be substituted with alkyl (eg, benzyl, phenethyl), etc. The phenyl group and the phenyl group of the phenyl-lower alkyl group include 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), lower (C _1-4 )alkyl groups (e.g., methyl, ethyl, propyl). , butyl), lower (C _1-4 ) alkoxy groups (e.g.
methoxy, ethoxy, propoxy, isopropoxy, butoxy), methylenedioxy group, amino group,
It may be substituted with a nitro group, a hydroxy group, etc. Preferably, Y is hydroxymethylene. Depending on the value of m, the sulfur atom in formula () can be, for example, sulfide, sulfoxide,
Forms sulfone. Among these, it is preferable that m is 0. The group -( _CH2 )n- in formula () is, depending on the value of n,
For example, it forms methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene. Among them, trimethylene is preferred.
Examples of salts of compound () include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate; for example, acetate, tartrate, citrate,
Examples include pharmacologically acceptable salts such as salts with organic acids such as fumarate, maleate, toluenesulfonate, and methanesulfonate. Among the compounds (), the formula [In the formula, R ₆ is 1 to 3 halogens, lower (C _1-4 ) alkyl group, lower (C _1-4 ) alkoxy group,
R ₂ ′ is a lower (C _1-4 ) alkoxy group, and X′ is a lower (C _1-4 ) alkoxy group. A compound represented by [representing a carbonyl group] and a pharmacologically acceptable salt thereof are preferred. The compound of the present invention () has the formula Compounds and formulas represented by [In the formula, each symbol has the same meaning as above] [In the formula, n, R ₃ and R ₄ have the same meanings as above, W
represents a halogen or a group represented by the formula R-SO ₂ -O- (R represents lower (C _1-4 ) alkyl, phenyl or p-tolyl). It can be produced by subjecting it to an acylation or carbamoylation reaction following a post-reduction reaction or a reduction reaction after a condensation reaction. The condensation reaction is usually carried out in the presence of a base,
Examples of the base include inorganic bases such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium methoxide, sodium hydride, and lithium diisopropylamide, and organic bases such as triethylamine, pyridine, and 1.8-diazabicyclo[5.4.0]-7-undecene. Examples include amines. At this time, the reaction can be conveniently carried out using, for example, sodium iodide, potassium iodide, etc. as a catalyst. The above reaction is usually carried out in an organic solvent (e.g. acetone, 2-butanone, acetonitrile,
N,N-dimethylformamide, methylene chloride, benzene, toluene, tetrahydrofuran,
dioxane), and the reaction temperature is -20℃ ~
It can be carried out at +150°C, preferably about +20°C to +120°C. In addition, as means for reducing the compound () in the formula () obtained by the condensation reaction, in which Y is >C=O, examples include lithium aluminum hydride, lithium borohydride, cyanolithium borohydride, hydride Sodium boron,
Sodium cyanoborohydride, tritert hydride
- Reduction with metal hydride compounds such as butoxylithium aluminum, reduction with alcohols such as sodium metal and magnesium metal, catalytic reduction using metals such as platinum, palladium, and rhodium or their condensates with arbitrary carriers as catalysts, iron, Reduction of metals such as zinc with acids such as hydrochloric acid or acetic acid, electrolytic reduction, reduction with reductases, reduction with borohydride compounds such as diborane, or complexes of borohydride compounds such as borane-trimethylamine with amines, etc. Reaction conditions can be mentioned. The above reaction is usually carried out in the presence of water or an organic solvent (e.g. methanol, ethanol, ethyl ether, dioxane, methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature depends on the reducing means. It varies depending on the situation, but generally -20℃
~+100°C is preferable. Furthermore, as an acylation or carbamoylation reaction after condensation reduction,
This can be carried out using a conventional acylation or carbamoylation reaction of alcohol derivatives. As a means for such an acylation reaction, for example, a reactive derivative of an organic acid (acid anhydride, acid halide, etc.) corresponding to R ₅ is mixed with an organic base such as pyridine, triethylamine, N,N-dimethylaniline, sodium carbonate, It can be obtained by reaction in the presence of an inorganic base such as potassium carbonate or sodium hydrogen carbonate. The above reaction is usually carried out in an organic solvent (e.g. methanol, ethanol, ethyl ether,
Dioxane, methylene chloride, toluene, dimethylformamide, pyridine), and the reaction temperature is generally about -20°C to +100°C. In addition, the carbamoylation reaction can be carried out, for example, by reacting an alcohol derivative obtained by a reduction reaction with an isocyanate corresponding to R ₅ (e.g., methyl isocyanate, ethyl isocyanate, phenyl isocyanate, p-chlorophenyl isocyanate). I can do it. The above reaction is usually carried out in a suitable organic solvent (e.g., methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran,
methylene chloride, chloroform, toluene,
N,N-dimethylformamide);
The reaction temperature is generally preferably about -20°C to +150°C. Furthermore, the compound of the present invention () can be expressed by, for example, the formula Compounds and formulas represented by [Symbols in the formula have the same meanings as above] It can be obtained by reacting with an amine represented by the formula [wherein R ₃ and R ₄ have the same meanings as above]. The reaction between compound () and amines () can be carried out using an appropriate organic solvent (e.g. methanol, ethanol,
The reaction can be carried out in dioxane, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, methylene chloride, dimethyl sulfoxide, and any mixed solvent thereof. The reaction temperature is preferably about 0°C to +150°C, and in order to increase the reaction rate, organic bases such as triethylamine, pyridine, N,N-dimethylaniline, and inorganic bases such as potassium carbonate, sodium carbonate, and sodium bicarbonate are used. may be used as a catalyst. After the reaction, the compound in which Y is >C=O is subjected to the above reduction method or the acylation or carbamoylation reaction following the reduction reaction, whereby Y in formula () is >CH −OR ₅ can be led to the compound. Furthermore, the compound of the present invention () can be expressed by, for example, the formula It can also be produced by condensing the compound () with a compound represented by the formula [wherein each symbol has the same meaning as above] under reductive conditions. The reductive conditions include, for example, catalytic reduction using metals such as platinum, palladium, Raney nickel, rhodium, and mixtures thereof with arbitrary carriers as catalysts, such as lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, Reduction with metal hydride compounds such as sodium borohydride and sodium cyanoborohydride,
Reduction of metallic sodium, metallic magnesium, etc. with alcohols, metals such as iron, zinc, and hydrochloric acid,
Examples of reaction conditions include reduction with an acid such as acetic acid, electrolytic reduction, and reduction with a reductase.
The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, ethyl ether, dioxane,
(methylene chloride, chloroform, benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies depending on the reduction method, but is generally -20℃ to +
About 100°C is preferable. Although the purpose of this reaction can be sufficiently achieved at normal pressure, the reaction may be carried out under increased pressure or reduced pressure if necessary. Compounds of the invention () can also be used, for example, with the formula It can also be produced by subjecting a compound represented by the formula [wherein each symbol has the same meaning as above] to a reaction that reduces the amide group. For the reduction reaction, reduction means such as lithium aluminum hydride, sodium dihydro-bis[2-methoxyethoxy]aluminate, sodium acetoxyborohydride, aluminum hydride, diborane, and 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 reduction means, but is generally preferably about -20°C to +120°C. In addition, in the reduction reaction, in formula (), X is, for example, a lower alkoxycarbonyl group, phenyl-
A carbamoyl group optionally substituted with a lower alkoxycarbonyl group, a lower alkyl group, a phenyl group or a phenyl-lower alkyl group,
In the case where Y is >C=O, these functional groups can be reduced simultaneously, or the desired amide can be reduced by protecting the carbonyl group or selecting a reducing agent as necessary. It is also possible to reduce only the group. A sulfoxide or sulfone compound in which m is 1 or 2 in formula () can also be produced by oxidizing the corresponding sulfide compound. The oxidation reaction is carried out, for example, by the action of an organic peracid (eg, metachloroperbenzoic acid, peracetic acid) or an inorganic oxidizing agent (eg, hydrogen peroxide, periodic acid). The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, dioxane, dichloromethane), and is usually carried out at a temperature range of -20°C to +100°C. The object compound () of the present invention thus obtained can be separated and purified from the reaction mixture using conventional separation and purification methods, such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography. It can then be isolated. In formula (), for example, if Y is > CH−OR ₅ ,
At least two stereoisomers may be present. Both of these individual isomers and mixtures thereof are naturally included within the scope of the present invention, and these isomers can also be produced individually if desired. For example, by carrying out the above reaction using single isomers of starting compounds () and (), a single optical isomer of compound () can be obtained, or two or more types of products can be obtained. In the case of a mixture of isomers, this can be done by conventional separation methods,
For example, each isomer can be isolated by a method of forming a salt with an optically active acid (e.g., camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, malic acid, etc.), or by separation means such as various chromatography and fractional recrystallization. It can also be separated into the body. The starting compounds (), (), () and () can be produced, for example, by the method shown in the following reaction formula. (i) Compound () (a) X is optionally substituted with a phenyl group, lower alkoxycarbonyl group, phenyl-lower alkoxycarbonyl group, carboxyl group or lower alkyl group, phenyl group or phenyl-lower alkyl group; In the case of a carbamoyl group that may be (b) When X is a lower alkyl group, lower alkanoyl group, hydroxy lower alkyl group, lower alkanoyloxy lower alkyl group or phenyl-lower alkyl group (c) When X is hydrogen In the above reaction formula, Hal represents halogen (eg, bromine, chlorine), and other symbols have the same meanings as above. In formula (), X is a phenyl group, a lower alkoxycarbonyl group, a phenyl-lower alkoxycarbonyl group, a carboxyl group or a lower alkyl group,
When producing a compound that is a carbamoyl group optionally substituted with a phenyl group or a phenyl-lower alkyl group, first, compound () is used as a raw material compound in a suitable organic solvent (e.g., acetone, acetonitrile, benzene, toluene, methylene Compound (XII) can be obtained by reacting with compound () in chloride, N,N-dimethylformamide) and then reacting with compound (XI). In this reaction, it is usually preferable to coexist with a base such as potassium carbonate or sodium hydrogen carbonate to accelerate the reaction rate, and the reaction rate is usually
The temperature is preferably about 0°C to +120°C. A compound in which m is 1 or 2 in formula () can be produced by oxidizing compound (XII). The oxidation reaction is carried out, for example, by the action of an organic peracid (eg, metachloroperbenzoic acid, peracetic acid) or an inorganic oxidizing agent (eg, hydrogen peroxide, periodic acid). The above reaction is usually carried out in the presence of water or an organic solvent (eg, methanol, ethanol, dioxane, dichloromethane), and is usually carried out at a temperature range of about -20°C to +100°C.
Further, in formula (), a compound where m is 0 can be used in the next reaction without being subjected to the oxidation reaction. The ring-closing reaction to obtain compound () from compound () is usually carried out in an organic solvent (e.g., N,N-dimethylformamide, acetonitrile, methanol, dimethyl sulfoxide) and a base (e.g., sodium methoxide, sodium ethoxy The process proceeds conveniently in the presence of sodium chloride, potassium tert-butoxide, sodium hydride). The reaction temperature is usually preferably about -20°C to +100°C. When the compound () is obtained as an alkali metal salt in the above reaction, the compound () can be isolated by a conventional method after neutralization with, for example, acetic acid, hydrochloric acid, sulfuric acid, or the like. In formula (), X is a lower alkyl group, a lower alkanoyl group, a hydroxy lower alkyl group, a lower alkanoyloxy lower alkyl group, or a phenyl group.
In the case of a lower alkyl group, after the compound () is reacted with the compound (XI) to obtain the compound (), if necessary, the compound () is led to the compound (), subjected to a ring-closing reaction, and after introducing X. Compound () can be obtained by subjecting it to an ester group removal reaction. The reaction between compound () and (XI) is compound ()
It can be carried out in the same manner as the reaction of and ().
When compound () is introduced into compound (), it can be carried out in the same manner as the method for introducing compound (XII) into compound (). Also, () → ()
The ring-closing reaction can be carried out in the same manner as the reaction ()→(). The reaction between compounds () and () is carried out using a base (e.g., sodium carbonate, It can be carried out in the presence of potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium methoxide, triethylamine, pyridine).
At this time, the reaction can be made to proceed smoothly by adding, for example, an iodine compound such as potassium iodide or sodium iodide as a catalyst. The reaction is usually preferably carried out at a temperature of about -20°C to +150°C. The reaction of () → () follows the usual ester group removal reaction, and the compound () is mixed with a salt ( For example, the process proceeds by coexisting sodium chloride, lithium chloride, calcium chloride, sodium bromide) and heating at about +50°C to +160°C. In the formula (), when X is hydrogen, the compound ()
Compound (XI) can be obtained by subjecting it to a reaction similar to the reaction ()→(). In addition, compound () is obtained by reacting compound () with compound (XII) using compound () as a raw material compound, and then oxidizing the sulfur atom as necessary to obtain compound (), which is subjected to the same ring-closing reaction as above, and then It can also be produced by subjecting the resulting compound () to a conventional hydrolysis reaction. The reaction between compounds () and () can be carried out in the same manner as the reaction between compounds () and (). compound() is compound()
can be obtained by subjecting it to a reduction reaction. In the reduction reaction, for example, lithium aluminum hydride, lithium borohydride, lithium cyanoborohydride, sodium borohydride, sodium cyanoborohydride, trihydride, etc.
Reduction with metal hydride compounds such as tert-butoxylithium aluminum; catalytic reduction using a mixture of metals such as sodium metal, magnesium metal, and alcohols; metals such as platinum, palladium, and rhodium, or mixtures thereof with arbitrary carriers;
Reduction of metals such as iron and zinc with acids such as hydrochloric acid and acetic acid, electrolytic reduction, reduction with reductases, reduction with borohydride compounds such as diborane, or complexes of borohydride compounds such as borane-trimethylamine and amines. The following reaction conditions can be mentioned. The above reaction is usually carried out in water or in an organic solvent (e.g. methanol, ethanol, ethyl ether,
Dioxane, methylene chloride, chloroform,
(benzene, toluene, acetic acid, dimethylformamide, dimethylacetamide), and the reaction temperature varies depending on the reduction means, but is generally preferably about -20°C to +100°C. The reaction ()→() can be carried out using a conventional acylation or carbamoylation reaction of alcohol derivatives. As a means for the acylation reaction, for example, a reactive derivative of an organic acid corresponding to R ₅ (e.g., acid anhydride, acid halide) is combined with an organic base (e.g., pyridine, triethylamine, N,N-dimethylaniline) or It can be obtained by reacting with compound () 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 (e.g. methanol, ethanol, ethyl ether, dioxane, methylene chloride, toluene, dimethylformamide,
pyridine), and the reaction temperature is generally -
The temperature is preferably about 20°C to +100°C. In addition, in the carbamoylation reaction, for example, an alcohol derivative () obtained by a reduction reaction is added with an isocyanate corresponding to R ₅ (e.g., methyl isocyanate, ethyl isocyanate, phenyl isocyanate, p
-chlorophenyl isocyanate). The above reaction is usually carried out in a suitable organic solvent (e.g. methanol, ethanol, acetonitrile, dioxane, tetrahydrofuran, methylene chloride, chloroform, toluene, N,N-
The reaction temperature is generally preferably about -20°C to +150°C. The reaction between compound () and (XI) can be carried out in the same manner as the reaction between compound () and (). Compound () is compound (
) with dilute mineral acids (e.g., hydrochloric acid, sulfuric acid). Compound () can be produced in the same manner as the reduction reaction of compound (XII) from () to (), and ()
→() reaction is ()→()
It can be carried out in the same manner as the reaction. compound () is compound () (XII)
→It can be obtained by subjecting it to a reaction similar to the reaction in (). The reaction between compounds () and () can be carried out in the same manner as the reaction between compounds () and (). The reaction ()→() is similar to the reaction ()→(), and the reaction ()→(L) is ()→
It can be carried out in the same manner as the reaction in (). In the method for producing the above compound () and its intermediates, the compound used in the reaction may be an inorganic acid salt such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc., as long as it does not interfere with the reaction. Organic acid salts such as acetate, tartrate, citrate, fumarate, maleate, toluenesulfonate, methanesulfonate; metal salts such as sodium, potassium, calcium, aluminum salts; For example, 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. Effect The compound of the present invention, that is, 1 represented by the formula (),
5-Benzoxathiepine derivatives have specific serotonin S ₂ receptor blocking effects, calcium antagonistic effects,
It exhibits cerebral vasospasm relieving effect, renal circulation improving effect, diuretic effect and antithrombotic effect, such as ischemic heart disease such as angina pectoris and myocardial infarction, thrombosis and hypertension, cerebral vasospasm and transient ischemic attack. It is useful as a preventive or therapeutic agent for cerebral circulation disorders such as. The compound of the present invention has low toxicity, good absorption even when administered orally, and excellent stability, so when used as the above-mentioned medicine,
It can be safely administered orally or parenterally by itself or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents in the form of pharmaceutical compositions such as powders, granules, tablets, capsules, and injections. can be administered. The dosage varies depending on the condition of the target disease and the route of administration, but for example, when administered to adult patients for the purpose of treating ischemic heart disease or hypertension, a single dose of oral administration is usually approximately 0.1 to 10 mg/Kg. In particular, a dose of about 0.3 to 3 mg/Kg is preferred, and for intravenous administration, a single dose of about 0.003 to 0.1 mg/Kg, particularly 0.01 to 0.1 mg/Kg.
The dose is preferably about 0.1 mg/Kg, and it is desirable to administer these doses about 1 to 3 times a day depending on the symptoms. In addition, when compound () is administered to adult patients for the purpose of treating cerebral circulation disorders, oral administration usually
A dose of about 0.1 to 50 mg/Kg is preferably about 0.3 to 30 mg/Kg, and for intravenous administration, a dose of about 0.003 to 10 mg/Kg is preferable.
mg/Kg, especially preferably about 0.01 to 1 mg/Kg,
It is desirable to administer these doses about 1 to 3 times a day depending on the symptoms. EXAMPLES The present invention will be explained in more detail by referring to Reference Examples, Examples, and Preparation Examples below, but the present invention is not limited thereto. Reference example 1 2-mercapto-4-methoxyphenol 44.7
g, 88 g of methyl bromoacetate to 350 g of acetone
ml, add 88 g of anhydrous potassium carbonate, and heat at room temperature for 5 hours, followed by heating under reflux for 5 hours. After cooling, inorganic substances are removed by filtration, and the filtrate is distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain 65 g of colorless crystals of methyl 4-methoxy-2-methoxycarbonylmethylthiophenoxy acetate. Melting point 78℃ Elemental analysis value C ₁₃ H ₁₆ O ₆ S Calculated value: C 51.99; H 5.37 Actual value: C 52.18; H 5.37 Reference example 2 Methyl 4-methoxy-2-methoxycarbonylmethylthiophenoxy acetate 94.4 g N,
Dissolve in 300 ml of N-dimethylformamide and add 28% sodium methoxide 67 while stirring under ice cooling.
Drop g. After stirring for 1 hour, the precipitate was poured into ice water containing dilute hydrochloric acid, collected by filtration, washed with water, dried, and recrystallized from ethyl acetate-hexane, yielding methyl 7.
-methoxy-3-oxo-3,4-dihydro-
58.7 g of colorless crystals of 2H-1,5-benzoxathiepine-4-carboxylate are obtained. melting point 79
-81℃ Elemental analysis value C ₁₂ H ₁₂ O ₅ S Calculated value: C 53.72; H 4.51 Actual value: C 53.72; H 4.40 Reference example 3 2-Mercapto-4-methoxyphenol 28
g, 25 g of chlordiethylacetamide in acetone
Dissolve in 300ml, add 25g of anhydrous potassium carbonate,
Stir for 3 hours at room temperature under nitrogen flow. Next, 28 g of methyl bromoacetate and 25 g of anhydrous potassium carbonate are added, and the mixture is heated under reflux for 5 hours. After cooling, inorganic substances were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1:1) to obtain methyl 2-diethylcarbamoylmethylthio-4-
Colorless oil of methoxyphenoxyacetate 45
get g. Elemental analysis value C ₁₆ H ₂₃ NO ₅ As S Calculated value: C56.29; H6.79; N4.10 Actual value: C56.23; H6.77; N4.18 Reference example 4 Methyl 2-diethylcarbamoylmethylthio-4 -Dissolve 43g of methoxyphenooxyacetate in 160ml of N,N-dimethylformamide,
Add 30 g of 28% sodium methoxide dropwise under ice cooling and stirring in a nitrogen stream. After stirring for 6 hours, the mixture was poured into ice water containing 15 ml of acetic acid and extracted with ethyl acetate. The organic layers are combined, washed with water, dried, and then the solvent is distilled off under reduced pressure. The resulting residue is purified by column chromatography on silica gel (eluent: hexane:ethyl acetate = 1:1). Recrystallization from ethyl acetate yields 7-methoxy-3-oxo-
Colorless prism crystals of 3,4-dihydro-2H-1,5-benzoxathiepine-4-diethylcarboxamide are obtained. Melting point 112-113℃ Elemental analysis value C ₁₅ H ₁₉ NO ₄ Calculated value: C58.23; H6.19; N4.53 Actual value: C58.17; H6.06; N4.54 Reference example 5 2-mercapto -4-methoxyphenol 60
g, 67g of chloracetonitrile to 600ml of acetone
and add 125 g of anhydrous potassium carbonate while stirring under a nitrogen stream at room temperature. Stir at room temperature for 3 hours and then heat under reflux for 5 hours. After cooling, inorganic substances were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give 2-cyanomethylthio-4
- Obtain colorless prism crystals of methoxyphenooxyacetonitrile. Yield 65g. Melting point 53-54℃ Elemental analysis value C ₁₁ H ₁₀ N ₂ O ₂ S Calculated value: C56.39; H4.30; N11.96 Actual value: C56.57; H4.32; N11.78 Reference example 6 2 -Cyanomethylthio 30 g of 4-methoxyphenoxyacetonitrile is dissolved in 120 ml of N,N-dimethylformamide, and 30 g of 28% sodium methoxide is added dropwise under ice cooling and stirring in a nitrogen stream. After stirring for 2 hours, the precipitate was poured into ice water containing 12 g of acetic acid, collected by filtration, washed with water, and recrystallized from chloroform to give 3-amino-7-methoxy-
Colorless prism crystals of 2H-1,5-benzoxathiepine-4-carbonitrile are obtained. Yield 19.5g. Melting point 203-205℃ Reference example 7 6.0 g of 3-amino-7-methoxy-2H-1,5-benzoxathiepine-4-carbonitrile was suspended in 60 ml of ethanol, 18 ml of concentrated hydrochloric acid was added, and the temperature was 80-90.
Stir for 30 min at °C. After cooling, the precipitated ammonium chloride was filtered off, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to give 7-methoxy-3-oxo-3,4-dihydro-2H-1,
Colorless prism crystals of 5-benzoxathiepine-4-carbonitrile are obtained. Yield 5.1g. Melting point 132-133℃ Elemental analysis value C ₁₁ H ₉ NO ₃ S Calculated value: C56.16; H3.86; N5.95 Actual value: C56.08; H3.79; N5.85 Reference example 8 7-methoxy Dissolve 15 g of -3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carbonitrile in 200 ml of methanol,
Saturate with dry hydrogen chloride and leave at room temperature for 4 days.
Add 10 ml of water to the reaction solution, leave it overnight, and concentrate under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) and the raw material
6.0g was recovered and the methyl obtained in Reference Example 2
7-Methoxy-3-oxo-3,4-dihydro-
6.0 g of 2H-1,5-benzoxathiepine-4-carboxylate are obtained. Reference example 9 Methyl 7-methoxy-3-oxo-3,4-
Stir a mixture of 2.0 g dihydro-2H-1,5-benzoxathiepine-4-carboxylate, 1.96 g 1-chloroacetyl 4-phenylpiperazine, 0.6 g potassium iodide, 1.24 g anhydrous potassium carbonate, and 30 ml methyl ethyl ketone. Heat under reflux for 30 minutes. Inorganic substances are removed by filtration, the filtrate is concentrated under reduced pressure, the resulting residue is dissolved in ethyl acetate, washed with water, dried, and the solvent is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent:
Hexane:ethyl acetate = 2:1→1:1), recrystallized from ethyl acetate-hexane, and purified with methyl 7-methoxy-3-oxo-4-[2-oxo-2-(4-phenylpiperazine). 2.1 g of colorless crystals of -1-yl)ethyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate are obtained. Melting point 146-148℃ IR spectrum (KBr) cm ^-1 : 1740, 1640 NMR spectrum (CDCl ₃ ) δ: 4.78ppm
(2H, double doublet, C ₄ CH ₂ CO−) Elemental analysis value as C ₂₄ H ₂₆ N ₂ O ₆ S Calculated value: C61.26; H5.57; N5.95 Actual value: C61.40; H5.60 ;N5.90 Reference Examples 10-19 Methyl 3-
When oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylates and halides are condensed, the compounds shown in Table 1 are obtained.

【table】

[Table] Reference Example 20 Methyl 4-diethylcarbamoylmethyl-7-methoxy-3-oxo-3,4 obtained in Reference Example 11
-dihydro-2H-1,5-benzoxathiepine-4-carboxylate 1.0g in methanol 15ml
Add 0.2 g of sodium borohydride little by little while stirring under ice-cooling. When spots of starting material disappear on TLC, the reaction solution is concentrated under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layers are combined, washed with water, dried, and then the solvent is distilled off under reduced pressure. The resulting residue is separated and purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 1:1), and is eluted first. Methyl trans-4-diethylcarbamoylmethyl-3-
Hydroxy-7-methoxy-3,4-dihydro-
0.117 g of colorless needles of 2H-1,5-benzoxathiepine-4-carboxylate are obtained. melting point
120−123℃. (Recrystallization solvent: ethyl acetate-n-hexane) Elemental analysis value As C ₁₈ H ₂₅ NO ₆ S Calculated value: C56.38; H6.57; N3.65 Actual value: C56.50; H6.73; N3. 61 From the subsequently eluted fraction, methyl cis-
0.587 g of 4-diethylcarbamoylmethyl-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate is obtained. Recrystallization from ethyl acetate-n-hexane gives colorless columnar crystals. Melting point 120-122℃ Elemental analysis value C ₁₈ H ₂₅ NO ₆ As S Calculated value: C56.38; H6.57; N3.65 Actual value: C56.54; H6.71; N3.65 Reference example 21 Reference example 20 The compound obtained in Reference Example 9 was reduced with sodium borohydride in the same manner as above to obtain two isomers of methyl cis and trans-3-.
Hydroxy-7-methoxy-4-[2-oxo-
2-(4-phenylpiperazin-1-yl)ethyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate is obtained. Cis isomer: Recrystallize from ethyl acetate to obtain colorless needles. Melting point 213-215℃. Mass spectrum m/e: 472 (M ⁺ ) Elemental analysis value as C ₂₄ H ₂₈ N ₂ O ₆ S Calculated value: C61.77; H5.97; N5.93 Actual value: C60.87; H5.84; N5 .86 Trans isomer hydrochloride: Recrystallize from methanol and ether to obtain colorless needles. Melting point 170-180℃
(Decomposition) Elemental analysis value C ₂₄ H ₂₈ N ₂ O ₆ S・HCl・1/2
As H ₂ O Calculated value: C55.64; H5.83; N5.40 Actual value: C55.38; H5.73; N5.44 Reference example 22 Methyl 4-(1,3-dioxolane obtained in Reference example 10) -2-yl)ethyl-7-methoxy-3-
2.0 g of oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate are stirred with 2.0 g of lithium chloride, 0.3 ml of water and 20 ml of dimethyl sulfoxide at 100 DEG C. for 5 hours.
After cooling, add water and extract with ethyl acetate. The organic layers were combined, washed with water, dried, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: hexane-ethyl acetate = 2:1), and 4-(1,3 -dioxolan-2-yl)
Ethyl-7-methoxy-3,4-dihydro-2H
A colorless oil of -1,5-benzoxathiepin-3-one is obtained. IR spectrum (neat) cm ^-1 : 1730 NMR spectrum (CDCl ₃ ) δ: 1.6 ~ 2.3 (4H,
multiplet), 3.70ppm (3H, singlet, OCH ₃ ), 3.7
~4.2 (4H, multiplet), 4.60 (2H, do ublet),
4.6-5.0 (2H, multiplet) Mass spectrum m/e: 310 (M ⁺ ) Reference example 23 Methyl 2-
Methoxycarbonylmethylthiophenoxy acetate is obtained. Recrystallize from hexane-ethyl acetate to obtain colorless prism crystals. Melting point 65-66℃ Elemental analysis value C ₁₂ H ₁₄ O ₅ S Calculated value: C53.32; H5.22 Actual value: C53.20; H5.29 Reference example 24 Methyl 2-methoxycarbonyl obtained in Reference example 23 Methylthiophenoxy acetate was treated in the same manner as in Reference Example 2 to obtain methyl, 3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-
A colorless oil of 4-carboxylate is obtained. Elemental analysis value as C ₁₁ H ₁₀ O ₄ S Calculated value: C55.45; H4.23 Actual value: C55.33; H4.41 Reference example 25 Methyl 7-methoxy-3-oxo-3,4-
Dihydro-2H-1,5-benzoxathiepine-4-carboxylate 30g, 1-bromo-3-
A mixture of 50 g of chloropropane, 46 g of anhydrous potassium carbonate, 10 g of potassium iodide, 1.0 g of tetrabutylammonium iodide and 300 ml of acetonitrile is heated under reflux for 4 hours. After cooling, inorganic substances are removed by filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, washed with water, dried, and the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate: methylene chloride =
10:1:10). Recrystallization from ethanol yields methyl 4-(3-chloropropyl)-7-
Methoxy-3-oxo-3,4-dihydro-2H
Colorless prismatic crystals of -1,5-benzoxathiepine-4-carboxylate are obtained. Yield 17g. Melting point 64-65℃ Elemental analysis value C ₁₅ H ₁₇ ClO ₅ As S Calculated value: C52.25; H4.97 Actual value: C52.33; H5.10 Reference example 26 Methyl 4-(3-chloropropyl)-7 -methoxy-3-oxo-3,4-dihydro-2H-1,
17 g of 5-benzoxathiepine-4-carboxylate was dissolved in 200 ml of tetrahydrofuran, 2.8 g of borane trimethylamine complex and 12 g of boron trifluoride etherate were added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, ice water and dilute hydrochloric acid were added to the residue, and the mixture was extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 1:1).
13 g of a colorless oil of (3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate are obtained. Elemental analysis value as C ₁₅ H ₁₉ ClO ₅ S Calculated value: C51.95; H5.52 Actual value: C52.08; H5.48 Mass spectrum m/e: 346, 348 (M ⁺ ) Reference example 27 Reference example 1 2-mercapto-4- in the same manner as
Methyl phenol and methyl bromoacetate to methyl 2-methoxycarbonylmethylthio-
4-methylphenoxy acetate is obtained. Recrystallizes from methanol to form colorless prismatic crystals. Melting point 45-46℃ Elemental analysis value C ₁₃ H ₁₆ O ₅ S Calculated value: C54.92; H5.67 Actual value: C55.10; H5.70 Reference example 28 4-chloro in the same manner as Reference example 1 -Methyl 4-chloro-2-methoxycarbonylmethylthiophenoxy acetate is obtained from 2-mercaptophenol and methyl bromoacetate. Recrystallize from ethyl acetate-hexane to obtain colorless prism crystals. Melting point 76-77℃ Elemental analysis value C ₁₂ H ₁₃ ClO ₅ As S Calculated value: C47.30; H4.30 Actual value: C47.40; H4.29 Reference example 29 Methyl 2-methoxycarbonylmethylthio-
Reference example 2: 8.9g of 4-methylphenoxy acetate
By the same method as above, 5.8 g of methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate was obtained as a colorless oil. MS (m/e): 252 (M ⁺ ) IR spectrum (neat) cm ^-1 : 1730 to 1750 (-C
=O) NMR spectrum (CDCl ₃ ) δ: 2.22 (3H, s,
C ₇ −CH ₃ ), 3.80 (3H, s, C ₄ −COO CH ₃ ), 4.62
(2H, dd, C ₂ -H), 4.80 (1H, s, C ₄ -H) Reference Example 30 Methyl 7 From 4-chloro-2-methoxycarbonylmethylthiophenoxy acetate in the same manner as Reference Example 2 -Chloro-3-oxo-
Colorless needles of 3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate are obtained. Melting point 92-97℃ Elemental analysis value C ₁₁ H ₉ O ₄ As SCl Calculated value: C48.45; H3.33 Actual value: C48.45; H3.06 Reference example 31 Methyl 7-methyl-3-oxo-3, 4-dihydro-2H-1,5-benzoxathiepine-
Methyl 4-(3-chloropropyl)- was added to 4.1 g of 4-carboxylate in the same manner as in Reference Example 25.
7-methyl-3-oxo-3,4-dihydro-
2.0 g of a colorless oil of 2H-1,5-benzoxathiepine-4-carboxylate is obtained. MS (m/e): 328, 330 (M ⁺ ) IR spectrum (neat) cm ^-1 : 1760, 1730 (C=
O) NMR spectrum (CDCl ₃ ) δ: 2.20 (3H, s,
C ₇ −CH ₃ ), 3.70 (3H, s, C ₄ −COO CH ₃ ), 4.62
(2H, dd, C ₂ -H) Reference example 32 Methyl 4-(3-chloropropyl)-7-methyl-3-oxo-3,4-dihydro-2H-1,
2.0 g of 5-benzoxathiepine-4-carboxylate was reacted in the same manner as in Reference Example 20 to obtain methyl trans-4-(3-chloropropyl)-3-hydroxy-7-methyl-3,4-dihydro- 2H−1,
0.7 g of colorless oil of 5-benzoxathiepine-4-carboxylate and methyl cis-4-(3-
Colorless oil of (chloropropyl)-3-hydroxy-7-methyl-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate
Get 1.2g. Trans form IR spectrum (neat) cm ^-1 : 3540 (OH), 1720
(C=O) NMR spectrum (CDCl ₃ ) δ: 2.24 (3H, s,
C ₇ −CH ₃ ), 3.55 (3H, s, C ₄ −COO CH ₃ ) cis form IR spectrum (neat) cm ⁻¹ : 3520 (OH), 1730
(C=O) NMR spectrum (CDCl ₃ ) δ: 2.28 (3H, s,
_C7 - _CH3 )3.78(3H,s, _C4 -COO CH3 ) Reference example 33 Methyl 7-chloro-3-oxo-3,4- _dihydro -2H-1,5-benzoxathiepine-
Methyl 7-chloro-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H was obtained from 4-carboxylate in the same manner as in Reference Example 25.
A colorless oil of -1,5-benzoxathiepine-4-carboxylate is obtained. IR spectrum (neat) cm ^-1 : 1760, 1730 (C=
O) NMR spectrum (CDCl ₃ ) δ: 3.68 (3H, s,
C ₄ -COO CH ₃ ), 4.62 (2H, dd, C ₂ -H) Reference example 34 Methyl 7-chloro-4-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,
5-Benzoxathiepine-4-carboxylate was treated in the same manner as in Reference Example 20 to give methyl 7-chloro-4-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5 -Trans and cis forms of benzoxathiepine-4-carboxylate are obtained as colorless oils, respectively. Trans form Colorless oil IR spectrum (neat) cm ^-1 : 3520 (OH), 1720
(C=O) NMR spectrum (CDCl ₃ ) δ: 3.60 (3H, s,
C ₄ −COO CH ₃ ) Cis colorless oil IR spectrum (neat) cm ^-1 : 3520 (OH), 1730
(C=O) NMR spectrum (CDCl ₃ ) δ: 3.80 (3H, s,
C ₄ COO CH ₃ ) Reference Example 35 Methyl obtained in Reference Example 25 4-(3-chloropropyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-
A mixture of 5.0 g of 4-carboxylate, 30 ml of dimethyl sulfoxide, 0.3 ml of water and 1.5 g of lithium chloride is stirred at 100° C. for 5 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: hexane: ethyl acetate =
2:1) and purified with 4-(3-chloropropyl)-
7-Methoxy-3,4-dihydro-2H-1,5
-Colorless oil of benzoxathiepin-3-one
Get 2.0g. Elemental analysis value as C ₁₃ H ₁₅ ClO ₃ S Calculated value: C54.45; H5.27 Actual value: C54.60; H5.20 Mass spectrum (m/e): 286, 288 (M ⁺ ) Reference example 36 Reference 4-(3-chloropropyl)-7 obtained in Example 35
-methoxy-3,4-dihydro-2H-1,5-
Dissolve 0.8 g of benzoxathiepin-3-one in a solution of 2 ml of tetrahydrofuran and 10 ml of methanol, add 0.1 g of sodium borohydride under ice cooling, and stir for 1 hour. The reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the mixture was shaken. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and the solution is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (eluent = hexane:
0.68 g of colorless oil of 4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol get. Elemental analysis value as C ₁₃ H ₁₇ ClO ₃ S Calculated value: C54.03; H5.93 Actual value: C54.37; H6.13 Reference example 37 Methyl cis-4-(3-chloropropyl)-3
-Hydroxy-7-methoxy-3,4-dihydro-
Dissolve 3.5 g of 2H-1,5-benzoxathiepine-4-carboxylate in 50 ml of methanol,
Add 10 ml of 1N sodium hydroxide and stir at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, 50 ml of water was added, insoluble matter was extracted with ether, the alkaline layer was neutralized with diluted hydrochloric acid, and the precipitated oil was dissolved in 80 ml of ethyl acetate.
Extract with The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. Residue n-
Crystallized from hexane and ethyl acetate, cis-
4-(3-chloropropyl)-3-hydroxy-7
2.1 g of -methoxy-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylic acid are obtained.
Melting point: 175-178℃ (colorless prismatic crystal). Elemental analysis value C ₁₄ H ₁₇ O ₅ Calculated value as SCl C, 50.53; H, 5.15 Actual value C, 50.69; H, 5.07 Reference example 38 Cis-4-(3-chloropropyl)-3-hydroxy-7-methoxy −3.4-dihydro-2H−1.5−
Dissolve 1.0 g of benzoxathiepine-4-carboxylic acid in 5 ml of pyridine, add 4 ml of acetic anhydride, and let stand at room temperature for 5 hours. Pour the reaction solution into 20 ml of water and extract with ethyl acetate (2 x 20 ml). The ethyl acetate layer is washed with dilute hydrochloric acid, then water, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to give cis-3-acetoxy-4-(3-chloropropyl)-
0.95 g of crystals of 7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylic acid are obtained. Recrystallize from ethyl acetate and n-hexane to obtain colorless prism crystals. Melting point 163-165℃ Elemental analysis value C ₁₆ H ₁₉ O ₆ Calculated value as SCl C, 51.27; H, 5.11 Actual value C, 51.44; H, 5.17 Reference example 39 Cis-3-acetoxy-4-(3-chloro (propyl)-7-methoxy-3.4-dihydro-2H-1.5
-Benzoxathiepine-4-carboxylic acid 0.8g,
While stirring a mixture of 0.27 g of benzylamine and 6 ml of NN-dimethylformamide under ice cooling, 0.52 g of diethyl cyanophosphate and 0.45 ml of triethylamine are added. After keeping at the same temperature for 10 minutes, stir at room temperature for another 3 hours. The reaction solution was poured into water, the precipitated crystals were filtered, washed with water and then with ethyl acetate, resulting in cis-3-acetoxy-4-(3-
0.57 g of crystals of (chloropropyl)-7-methoxy-3.4-dihydro-2H-1.5-benzoxathiepine-4-N-benzylcarboxamide are obtained. Recrystallization from ethyl acetate gives colorless flakes with a melting point of 224-226°C. Mass spectrum, m/e463, 465 (M ⁺ ) Elemental analysis value C ₂₃ H ₂₆ NO ₅ Calculated value as SCl C, 59.54; H, 5.65; N, 3.02 Actual value C, 59.81; H, 5.48; N, 2.83 Implemented Example 1 Methyl 7-methoxy-3-oxo-3,4-
Dihydro-2H-1,5-benzoxathiepine-4-carboxylate 10g, 3-(4-phenylpiperazin-1-yl)propyl chloride
9.8g, anhydrous potassium carbonate 6.2g, potassium iodide
A mixture of 3.0 g and 150 ml of methyl ethyl ketone is heated under reflux and stirred for 25 hours. After cooling, inorganic substances were removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and dried. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: hexane-ethyl acetate =
3:1) and purified with methyl 7-methoxy-3-
Oxo-4-[3-(4-phenylpiperazine-1)
-yl)propyl]-3,4-dihydro-2H-
1,5-Benzoxathiepine-4-carboxylate is obtained. Recrystallize from methanol to form white crystals. Melting point 110-112℃. Yield 2.1g Elemental analysis value as C ₂₅ H ₃₀ N ₂ O ₅ S Calculated value: C63.31; H6.43; N5.95 Actual value: C63.50; H6.37; N5.71 Example 2-3 Implementation Methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5
-Benzoxathiepine-4-carboxylate and an alkyl halide are reacted to obtain the compounds shown in Table 2.

[Table] Example 4 Methyl 4-(4-bromobutyl)-7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-4 obtained in Reference Example 13
- A mixture of 1.7 g of carboxylate, 1.37 g of N-phenylpiperazine, 0.7 g of potassium iodide, 1.2 g of anhydrous potassium carbonate and 30 ml of acetonitrile is stirred under heating under reflux for 1.5 hours. After cooling, inorganic substances are removed by filtration.
The filtrate was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, dried, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane-ethyl acetate = 2:1), and purified with methyl 7-methoxy-
3-Oxo-4-[4-(4-phenylpiperazin-1-yl)butyl]-3,4-dihydro-2H-
1.0 g of a colorless oil of 1,5-benzoxathiepine-4-carboxylate is obtained. Hydrochloride White crystals, melting point 155-165°C (decomposed). Elemental analysis value C ₂₆ H ₃₂ N ₂ O ₅ S・2.HCl・1/2H ₂ O
Calculated value: C55.12; H6.22; N4.95 Actual value: C55.30; H6.19; N4.96 Example 5-11 In Reference Examples 12-15 by the same method as Example 4. The compounds shown in Table 3 are obtained by a substitution reaction between the obtained halide and amines.

【table】

[Table] Example 12 Methyl 7-methoxy-3-oxo-4-[3-(4-phenylpiperazine-1-) obtained in Example 1
yl)propyl]-3,4-dihydro-2H-1,
Dissolve 38 g of 5-benzoxathiepine-4-carboxylate in a mixed solvent of 40 ml of tetrahydrofuran and 200 ml of methanol, and add 3.7 g of sodium borohydride little by little while stirring under ice cooling. After the reaction is completed, the solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The organic layers were combined, washed with water, dried, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent:
Hexane-ethyl acetate-methanol = 20:10:
Separate and purify in step 1). From the first eluting fraction, methyl trans-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazine-1
-yl)propyl]-3,4-dihydro-2H-
12 g of a colorless oil of 1,5-benzoxathiepine-4-carboxylate are obtained. IR spectrum (neat) cm ^-1 : 3520, 1720 NMR spectrum (CDCl ₃ ) δ: 3.45 (3H,
singlet, OCH ₃ ), 3.60 (3H, singlet, OCH ₃ ) As a hydrochloride, it becomes a white powder. Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₅ S・2HCl・1/2H ₂ O Calculated value: C54.15; H6.36; N5.05 Actual value: C54.27; H6.20; N4.89 Continued The methyl cis-
3-hydroxy-7-methoxy-4-[3-(4-
phenylpiperazin-1-yl)propyl]-3,
18 g of a colorless oil of 4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate are obtained. IR spectrum (neat) cm ^-1 : 3530, 1740 NMR spectrum (CDCl ₃ ) δ: 3.60 (3H,
singlet, OCH ₃ ), 3.62 (3H, singlet, OCH ₃ ) As hydrochloride Melting point 165-175℃ (decomposition) Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₅ S・2HCl・1/2H ₂ O Calculated value: C54.15; H6.36; N5.05 Actual value: C54.02; H6.33; N5.00 Example 13-22 The compound obtained in Example 2-11 was hydrogenated in the same manner as in Example 12. Reduction with sodium boronate gives the compounds shown in Table 4.

【table】

【table】

[Table] Example 23 Methyl obtained in Reference Example 21 cis-3-hydroxy-7-methoxy-4-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]-3,4
-Dihydro-2H-1,5-benzoxathiepine-4-carboxylate (0.5 g) and sodium borohydride (0.1 g) were suspended in 15 ml of tetrahydrofuran, and while stirring, 0.19 g of acetic acid was added dropwise to prepare hydrogenated monoacetoxylate. Add to a solution of sodium boron in tetrahydrofuran and heat under reflux for 20 hours.
The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 1:1) to obtain methyl cis-
3-hydroxy-7-methoxy-4-[2-(4-
phenylpiperazin-1-yl)ethyl]-3,
0.2 g of a colorless oil of 4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate is obtained. As a hydrochloride, it becomes a white powder. Elemental analysis value C ₂₄ H ₃₀ N ₂ O ₅ S・2HCl・1/4H ₂ O Calculated value: C53.77; H6.11; N5.23 Actual value: C53.67; H6.19; N5.35 Implemented Example 24 Methyl obtained in Reference Example 21 cis-3-hydroxy-7-methoxy-4-[2-oxo-2-(4-phenylpiperazin-1-yl)ethyl]3,4-
0.7 g of dihydro-2H-1,5-benzoxathiepine-4-carboxylate is added to a mixture of 0.24 g of lithium aluminum hydride and 50 ml of ethyl ether and heated under reflux for 2 hours. After cooling, add 0.25 ml of water, 0.25 ml of 15% sodium hydroxide solution,
Add 0.75ml of water and stir for 30 minutes. The precipitate is filtered, washed with ethyl acetate, and the filtrates are combined and concentrated under reduced pressure. Recrystallization of the residue from ethyl acetate gives
cis-4-hydroxymethyl-7-methoxy-4
Colorless prismatic crystals of -[2-(4-phenylpiperazin-1-yl)ethyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol
Get 0.5g. Melting point 153-156℃ Elemental analysis value C ₂₃ H ₃₀ N ₂ O ₄ Calculated value: C64.16; H7.02; N6.51 Actual value: C64.30; H7.10; N6.48 Example 25 Reference Methyl cis-4-diethylcarbamoylmethyl-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepine- obtained in Example 20
4-carboxylate was treated as in Example 24 to give cis-4-(2-diethylaminoethyl)-4
-Hydroxymethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepine-
A colorless oil of 3-ol is obtained. IR spectrum (neat) cm ^-1 : 3400 NMR spectrum (CDCl ₃ ) δ: 1.00ppm (6H,
triplet, 2CH ₃ ), 1.75 (2H, m), 2.45 (6H, m),
3.58 (3H, singlet, OCH ₃ ), 3.60 (2H, double
doublet, CH ₂ OH), 3.90 (2H, singlet, -O-
C H ₂ -C-OH) Example 26 4-(1,3-dioxolane- obtained in Reference Example 22)
1-yl)ethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepine-3
Dissolve 0.8 g of -one in 20 ml of methanol, and add sodium borohydride little by little while stirring. When spots of the raw material disappear on thin layer chromatography, add 1N sodium hydroxide solution and extract with ethyl acetate. The organic layers are combined, washed with water, dried, and then the solvent is distilled off under reduced pressure. 5 ml of dioxane, 2 ml of water and 40 mg of p-toluenesulfonic acid are added to the resulting residue and stirred at room temperature for 8 hours. Add water to the reaction solution and extract with ethyl acetate.
The organic layers were combined and the solvent was distilled off under reduced pressure. To the resulting residue were added 10 ml of acetonitrile and 400 mg of 4-phenylpiperazine, and the mixture was stirred at room temperature for 20 hours. Then sodium cyanoborohydride 200
mg and 5 ml of methanol are added and stirred for an additional 10 hours. Add 1N sodium hydroxide to the reaction solution,
Extract with ethyl acetate. The organic layers are combined, washed with water, dried, and then the solvent is distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent:
Hexane-ethyl acetate-methanol = 10:10:
1) to obtain 7-methoxy-4-[3-(4
-phenylpiperazin-1-yl)propyl]-
200 mg of 3,4-dihydro-2H-1,5-benzoxathiepin-3-ol is obtained as a colorless oil.
As a hydrochloride, it becomes a white powder. Elemental analysis value C ₂₃ H ₃₀ N ₂ O ₃ S・2HCl・1/2H ₂ O Calculated value: C55.63; H6.70; N5.64 Actual value: C55.73; H6.61; N5.64 Implemented Example 27 0.7 g of cis-4-(2-diethylaminoethyl)-4-hydroxymethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol obtained in Example 25 Dissolve in 10 ml of pyridine, add 6 ml of acetic anhydride, and leave at room temperature for 3 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution and then with water, dried, and then the solvent was distilled off under reduced pressure.
-acetoxy-4-acetoxymethyl-7-methoxy-4-(2-diethylaminoethyl)-3,4
0.66 g of a colorless oil of -dihydro-2H-1,5-benzoxathiepine is obtained. Ethanol hydrochloride. Recrystallization from ethyl ether gives white crystals. Melting point 177-179℃ Elemental analysis value C ₂₁ H ₃₁ NO ₆ S・HCl・1/5H ₂ O Calculated value: C54.19; H7.01; N3.06 Actual value: C54.27; H7.05; N3 .06 Example 28 The compound obtained in Example 12 was acetylated in the same manner as in Example 27 to give methyl cis-3-acetoxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl). ) propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate is obtained. It is recrystallized from ethyl acetate-n-hexane to become colorless prism crystals. Melting point 168
-170℃The structure of this product can be determined by X-ray crystal analysis. Elemental analysis value as C ₂₇ H ₃₅ N ₂ O ₆ S Calculated value: C63.01; H6.66; N5.44 Actual value: C63.01; H6.69; N5.40 Example 29 Obtained in Example 12 The compound was reduced with lithium aluminum hydride in the same manner as in Example 24 to give cis-4-hydroxymethyl-7-methoxy-4-[3
-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol is obtained. Recrystallization from ethyl acetate gives colorless needles. Melting point 163-165℃ Elemental analysis value C ₂₄ H ₃₂ N ₂ O ₄ Calculated value: C64.84; H7.25; N6.30 Actual value: C64.76; H7.31; N6.39 Example 30 Implementation Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathie obtained in Example 12 Dissolve 160 mg of pin-4-carboxylate in 5 ml of methanol,
Add 3 ml of 1N sodium hydroxide and stir at 60°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 5 liters of water.
ml, adjust the pH to 3-4 with 1N hydrochloric acid, and cool.
The precipitate was collected by filtration, washed with acetone and dried to give cis-3-hydroxy-7-methoxy-4-[3-(4
-phenylpiperazin-1-yl)propyl]-
0.13 g of white crystals of 3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylic acid are obtained. Melting point 250-260℃ (decomposition) Elemental analysis value C ₂₄ H ₃₀ N ₂ O ₅ S・H ₂ O Calculated value: C60.48; H6.77; N5.88 Actual value: C60.27; H6.73; N5.66 Example 31 Methyl obtained in Example 12 cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H- Dissolve 0.3 g of 1,5-benzoxathiepine-4-carboxylate in 5 ml of N,N-dimethylformamide, and add phenyl isocyanate.
After adding 0.08 g and 0.1 ml of triethylamine and stirring at room temperature for 3 hours, the reaction solution was poured into water and extracted with ethyl acetate. After washing the organic layer with water and drying, it was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
The portion eluted with a mixed solvent of hexane:ethyl acetate = 3:1 to 1:1 was collected and evaporated under reduced pressure to obtain methyl cis-7-methoxy-3-phenylcarbamoyloxy-4-[3-(4- Phenylpiperazine
1-yl)propyl]-3,4-dihydro-2H-
0.4 g of a colorless oil of 1,5-benzoxathiepine-4-carboxylate is obtained. Add hydrochloric acid-ethanol solution to obtain 0.3 g of powdered hydrochloride. Elemental analysis value C ₃₂ H ₃₇ N ₃ O ₆ S・2HCl・1/2H ₂ O Calculated value: C57.05; H5.99; N6.23 Actual value: C56.78; H5.96; N6.37 Implemented Example 32 Methyl 3-oxo-3,4- obtained in Reference Example 24
Dihydro-2H-1,5-benzoxathiepine-4-carboxylate was condensed with 3-(4-phenylpiperazin-1-yl)-propyl chloride in the same manner as in Example 1, and methyl 3-oxo -[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate is isolated as the hydrochloride salt. Recrystallize from methanol to form white crystals. Melting point 176-178℃ Elemental analysis value C ₂₄ H ₂₈ N ₂ O ₄ S・HCl・1/2H ₂ O Calculated value: C59.67; H6.26; N5.80 Actual value: C59.49; H6.33 ;N5.79 Example 33 Methyl 3-oxo-[3-(4
-phenylpiperazin-1-yl)propyl]-
Example of 3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate hydrochloride
It was reduced with sodium borohydride in the same manner as in 12, and subjected to silica gel column chromatography (eluent: hexane-ethyl acetate-methanol = 10:
10:1) to obtain the trans isomer from the first eluting fraction and the cis isomer from the eluting fraction. Methyl cis-3-hydroxy-4-[3-(4
-phenylpiperazin-1-yl)propyl]-
3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate dihydrochloride. Recrystallized from methanol-ethyl acetate to give colorless plate crystals. Melting point 196-198℃ Elemental analysis value C ₂₄ H ₃₀ N ₂ O ₄ As S・2HCl Calculated value: C55.92; H6.26; N5.43 Actual value: C55.73; H6.15; N5.51 Methyl trans -3-hydroxy-4-[3
-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate dihydrochloride. White powder (amorphous powder). Elemental analysis value C ₂₄ H ₃₀ N ₂ O ₄ S・2HCl・1/3H ₂ O Calculated value: C55.28; H6.31; N5.37 Actual value: C55.29; H6.49; N5.11 Implemented Example 34 Cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazine-1) obtained in Example 30
-yl)propyl]-3,4-dihydro-2H-
1,5-Benzoxathiepine-4-carboxylic acid
Dissolve 0.12g in 3ml of ethanol and add diethyl sulfate.
Add 50 mg and 100 mg of sodium hydrogen carbonate, and heat under reflux for 3 hours. Pour the reaction solution into water and extract with ethyl acetate. After washing the organic layer with water and drying, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: hexane-ethyl acetate =
1:1) and purified with ethyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5- Benzoxathiepine-4-
Obtain 50 mg of a colorless oil of the carboxylate. As a hydrochloride, it forms a white powder (amorphous powder). Elemental analysis value C ₂₆ H ₃₄ N ₂ O ₅ S・2HCl・1/4H ₂ O Calculated value: C55.36; H6.52; N4.97 Actual value: C55.30; H6.64; N4.94 Implemented Examples 35-36 The compounds shown in Table 5 are obtained from the compound obtained in Reference Example 12 in the same manner as in Example 4.

[Table] Examples 37-38 The compounds of Examples 35 and 36 are reduced in the same manner as in Example 12 to obtain the compounds shown in Table 6.

【table】

[Table] Example 39 Methyl cis-4-(3-chloropropyl)-3-hydroxy-7-methoxy- obtained in Reference Example 26
14 g of 3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate was heated under reflux for 20 hours with 9.0 g of 4-phenylpiperazine, 9.0 g of anhydrous potassium carbonate, 0.5 g of potassium iodide, and 100 ml of acetonitrile. do. After cooling, inorganic substances are removed by filtration, the filtrate is concentrated under reduced pressure, the residue is dissolved in ethyl acetate, the organic layer is washed with water, and after drying, the solvent is distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent; hexane; ethyl acetate:methanol = 10:10:1), and the resulting oil was crystallized as a hydrochloride, resulting in the methyl compound obtained in Example 12. cis-3-hydroxy-7-methoxy-4-
Colorless crystals of [3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate dihydrochloride are obtained. Yield 8g. When this product is recrystallized from 50% ethanol, methyl cis-3-hydroxy-7-methoxy-4-
Colorless prismatic crystals of [3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate monohydrochloride are obtained. Melting point 154-155℃ (measured with Yanagimoto micro melting point analyzer) Melting point 132-133℃ (decomposition) (measured using the melting point measurement method described in the Japanese Pharmacopoeia) Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₅ S・HCl・As 2H ₂ O Calculated value: C55.09; H6.84; N5.14 Actual value: C55.46; H6.77; N5.09 IRν ^KBr _nax cm ^-1 : 3600-3300, 1735, 1720, 1600,
1480, 1250 NMR ( _d6 -DMSO) δ: 1.3-1.8ppm (12H),
3.68ppm (3H, singlet), 3.75ppm (3H, singlet)
3.8-4.3ppm (3H), 6.7-7.4ppm (8H) Example 40-48 Methyl cis-4- by the same method as Example 39
The compounds shown in Table 7 were produced by the substitution reaction of (3-chloropropyl)-3-hydroxy-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate with various amines. get.

【table】

[Table] Example 49 Methyl 7-methyl-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-
1.7 g of 4-carboxylate was converted into 3-(4-phenylpiperazin-1-yl) in the same manner as in Example 1.
By reacting with propyl chloride, methyl 7-
Methyl-3-oxo-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4
- Obtain 0.9 g of a colorless oil of carboxylate. Mass spectrum (m/e): 454 (M ⁺ ) IR spectrum ν ^Neat _nax cm ^-1 : 1760, 1730 (C=0) NMR spectrum (CDCl ₃ ) δ: 2.22 (3H, s,
C ₇ −CH ₃ ), 3.72 (3H, s, C ₄ −COOCH ₃ ), 4.62
(2H, dd, C ₂ -H) White crystals are obtained as hydrochloride. Melting point 140-150℃ (decomposition) Elemental analysis value C ₂₅ H ₃₀ N ₂ O ₄ S・2HCl・1/2H ₂ O Calculated value: C, 55.96; H, 6.20; N, 5.22 Actual value: C, 56.11; H, 6.19; N, 5.11 Example 50 Methyl 7-chloro-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepine-
4-carboxylate was reacted with 3-(4-phenylpiperazin-1-yl)propyl chloride in the same manner as in Example 1 to form methyl 7-chloro-3-oxo-4-[3-(4-phenyl). enylpiperazin-1-yl)propyl]-3,4-dihydro-
2H-1,5-benzoxathiepine-4-carboxylate is obtained. It forms white crystals as a hydrochloride. Melting point 197−199℃ Elemental analysis value C ₂₄ H ₂₇ N ₂ O ₄ SCl・2HCl・1/4H ₂ O
Calculated value: C, 52.18; H, 5.38; N, 5.07 Actual value: C, 52.11; H, 5.11; N, 4.98 Example 51 Methyl 7-Methyl-3-oxo-4[3-(4
-phenylpiperazin-1-yl)propyl]-
Example 12: 0.9 g of 3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate
methyl trans-3-hydroxy-7-methyl-4-[3-
(4-phenylpiperazin-1-yl)propyl]
-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate colorless oil
0.3 g and methyl cis-3-hydroxy-7-methyl-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5
0.43 g of a colorless oil of benzoxathiepine-4-carboxylate is obtained. Trans form IR spectrum (neat) cm ^-1 : 3550 (OH), 1730
(-C=O) NMR spectrum (CDCl ₃ ) δ: 2.25 (3H, s,
_C7 - _CH3 )3.52(3H, _s , _C4 -COO CH3 ) White crystals are obtained as hydrochloride. Melting point 145-155℃ Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₄ S・2HCl・1/4H ₂ O Calculated value: C, 56.23; H, 6.51; N, 5.25 Actual value: C, 56.39; H, 6.53 ;N, 5.24 Cis IR spectrum (neat) cm ^-1 : 3540 (OH), 1740
(C=O) NMR spectrum (CDCl ₃ ) δ: 2.35 (3H, s,
_C7 - _CH3 ), 3.75 (3H, s, _C4 -COO CH3 ₎ A white powder is obtained as the hydrochloride. Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₄ S・1.5HCl Calculated value: C, 58.73; H, 6.60; N, 5.48 Actual value: C, 58.68; H, 6.96; N, 5.31 Example 52 Methyl 7- Chloro-3-oxo-4-[3-
(4-phenylpiperazin-1-yl)propyl]
-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate was reduced with sodium borohydride in the same manner as in Example 12, and methyl 7-chloro-3-hydroxy-4-[3 -(4-
phenylpiperazin-1-yl)propyl]-3,
Cis and trans isomers of 4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate are obtained. Trans isomer Forms white crystals as hydrochloride. Melting point 150-160℃ (decomposition point) Elemental analysis value C ₂₄ H ₂₉ N ₂ O ₄ SCl, 2HCl Calculated value: C, 52.42; H, 5.68; N, 5.09 Actual value: C, 52, 24; H, 5.76 ;N, 4.97 Cis isomer Forms white crystals as hydrochloride. Melting point 205−207℃ Elemental analysis C ₂₄ H ₂₉ N ₂ O ₄ SCl, 2HCl, 1/2H ₂ O
Calculated value: C51.57; H, 5.77; N, 5.01 Actual value: C51.77; H, 5.79; N, 4.97 Example 53 Methyl cis-4-(3-chloropropyl)-3
-Hydroxy-7-methyl-3,4-dihydro-
0.3 g of 2H-1,5-benzoxathiepine-4-carboxylate was reacted with 4-phenylpiperidine in the same manner as in Example 39 to give methyl cis-3-hydroxy-7-methyl-4-[ 3
0.3 g of colorless oil of -(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate is obtained. IR spectrum (neat) cm ^-1 : 3530 (OH), 1740
(C=O) NMR spectrum (CDCl ₃ ) δ: 2.22 (3H, s,
_C7 - _CH3 )3.72(3H,s, _C4 -COO _CH3 ) becomes a white powder as a hydrochloride. Elemental analysis value C ₂₆ H ₃₃ NO ₄ S・HCl・1/2H ₂ O Calculated value: C, 62.32; H, 7.04; N, 2.80 Actual value: C, 62.41; H, 7.06; N, 2.70 Example 54 Methyl cis-4-(3-chloropropyl)-3
-Hydroxy-7-methyl-3,4-dihydro-
2H-1,5-benzoxathiepine-4-carboxylate was reacted with N-methyl-2-(3,4-dimethoxyphenyl)ethylamine in the same manner as in Example 39 to obtain methyl cis-3-hydroxy. -7-methyl-4-{3-[N-methyl-2
-(3,4-dimethoxyphenyl)ethylamino]
propyl}-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate is obtained. As a hydrochloride, it becomes a white powder. Elemental analysis value C ₂₆ H ₃₄ NO ₆ S・HCl・1/2H ₂ O Calculated value: C, 58.36; H, 6.97; N, 2.62 Actual value: C, 58, 21; H, 7.21; N, 2.49 Implemented Example 55 4-(3-chloropropyl)-7 obtained in Reference Example 36
-methoxy-3,4-dihydro-2H-1,5-
Benzoxathiepin-3-ol 500mg, N-
Phenylpiperazine 500mg, potassium iodide 50mg,
A mixture of 400 mg of potassium carbonate and 10 ml of N,N-dimethylformamide is stirred at 80°C for 8 hours. Add water to the reaction solution and extract with ethyl acetate.
The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent = hexane: ethyl acetate; methanol = 10:10:1), and the resulting colorless oil was converted into a salt salt and recrystallized from methanol-acetone. cis obtained in example 26
7-Methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]3,4-dihydro-
A white powder of 2H-1,5-benzoxathiepin-3-ol dihydrochloride is obtained. Elemental analysis value C ₂₃ H ₃₀ N ₂ O ₃ S・2HCl・1/2H ₂ O Calculated value: C, 55.64; H, 6.70; N, 5.64 Actual value: C, 55.95; H, 6.53; N, 5.47 400MHzNMR -Spectrum (d ₆ -DMSO)
δ: 3.206ppm (1H, multiplet, J=8.1, 3.8,
4.6Hz, _C4 -H), 3.776ppm (1H, double
doublet, J=12.2, 8.5Hz, C2 _- H), 4.017ppm
(1H, double doublet, J=12.2, 3.8Hz, C ₂ −
H), 4.152ppm (1H, double triplet, J=8.5,
3.8, 3.8Hz, _C3 -H). Example 56 7-methoxy-3-oxo obtained in Reference Example 4
Dissolve 1.8 g of 3,4-dihydro-2H-1,5-benzoxathiepine-4-diethylcarboxamide in 15 ml of ethanol, and add sodium borohydride.
Add 0.3g and stir for 5 hours. The reaction solution was poured into ice water, made acidic with dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent = ethyl acetate:hexane = 1:1) to obtain 3-hydroxy-7-methoxy-3,4-
Colorless oil of dihydro-2H-1,5-benzoxathiepine-4-diethylcarboxamide
Get 1.48g. IRν ^neat _nax cm ^-1 : 3400, 1635 300 mg of this product was reduced with sodium monoacetoxyborohydride in a tetrahydrofuran solution in the same manner as in Example 23, and then subjected to column chromatography on silica gel (eluent = methylene chloride: methanol = 10:1). The obtained oil was converted into a hydrochloride salt, recrystallized from methanol-ethyl acetate,
138 mg of pale yellow prismatic crystals of cis 4-diethylaminomethyl-7-methoxy-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol hydrochloride are obtained. Melting point 160-162℃ 400MHz NMR spectrum ( _d6 -DMSO) δ:
3.719ppm (1H, double doublet, J=12.5, 8.31
Hz, _C2 -H), 3.819ppm (1H, double triplet,
J=7.8, 3.9, 3.9Hz, _C4 -H), 4.121ppm (1H,
double doublet, J=12.5, 3.9Hz, C ₂ −H),
4.297ppm (1H, double triplet, J=8.3, 3.9,
3.9Hz, C ₃ -H) Elemental analysis value C ₁₅ H ₂₃ NO ₃ As S・HCl Calculated value: C, 53.96; H, 7.25; N, 4.20 Actual value: C, 54.11; H, 7.44; N, 4.13 Implemented Example 57 0.15 g of methyl cis-7-chloro-4-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate was mixed with Example 39. In a similar manner, N-methyl-2-(3,4-dimethoxyphenyl)
By reacting ethylamine, methyl cis-7-
Chlor-3-hydroxy-4-{3-[N-methyl-2-(3,4-dimethoxyphenyl)ethylamino]propyl}-3,4-dihydro-2H-1,
0.06 g of 5-benzoxathiepine-4-carboxylate oil is obtained. As a hydrochloride, it becomes a white powder. Elemental analysis value C ₂₅ H ₃₂ NO ₆ SCl, HCl, 1/2H ₂ O
Calculated value: C, 54.05; H, 6.17; N, 2.52 Actual value: C, 54.05; H, 6.04; N, 2.57 Example 58 Methyl cis-3-hydroxy-7-methoxy-4-[3-(4 -phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H-1,
Optical resolution of 5-benzoxathiepine-4-carboxylate (±) methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazine-1)
-yl)propyl]-3,4-dihydro-2H-
1.3 g of 1,5-benzoxathiepine-4-carboxylate and S-(+)-1,1'-binaphthyl-2,2'-diylhydrodiene phosphate
Dissolve 1.0 g in 50 ml of methanol and then concentrate under reduced pressure. The residue was dissolved in acetone-methanol, left in the refrigerator overnight, and the precipitate was collected by filtration. The obtained crystals were recrystallized three times from acetone-methanol to obtain white crystals. [α] ²⁵ _D +175.5° (C = 1.01, methanol) Suspend this product in methylene chloride, add 1N sodium hydroxide, and shake. The organic layer was washed with 1N sodium hydroxide and then with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Dissolve the resulting colorless oil in ethanol, add dilute hydrochloric acid,
Concentrate under reduced pressure. The residue was treated with methanol-ether to give (-)methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazin-1-yl)propyl]-3,4-dihydro-2H- A white powder of 1,5-benzoxathiepine-4-carboxylate dihydrochloride is obtained. [α] _D −102.0° (C=0.54 in methanol) Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₅ S・2HCl・1/2H ₂ O Calculated value: C, 54.15; H, 6.36; N, 5.05 Actual measurement Value: C, 53.98, H, 6.18; N, 4.83 Example 59 Same as Example 58 (±) Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazine-1- yl)propyl]-3,4-
The salt of dihydro-2H-1,5-benzoxathiepine-4-carboxylate and R-(-)-1,1'-binaphthyl-2,2'-diylhydrodiene phosphate was dissolved from acetone-methanol to Recrystallize twice to obtain white crystals of [α] ²⁵ _D -172° (C=1.03, methanol). After treating the obtained salt with 1N-sodium hydroxide, (+)methyl cis-3-hydroxy-7-methoxy-4-[3-
(4-phenylpiperazin-1-yl)propyl]
A white powder of -3,4-dihydro-2H-1,5-benzoxathiepine-4-carboxylate hydrochloride is obtained. [α] _D +110.8° (c=0.48 in methanol) Elemental analysis value C ₂₅ H ₃₂ N ₂ O ₅ S・2HCl・1/2H ₂ O Calculated value: C, 54.15; H, 6.36; N, 5.05 Actual value: C, 54.11; H, 5.93; N, 4.80 Example 60 Cis-3-acetoxy-4-(3-chloropropyl)-7-methoxy-3,4-dihydro-2H-
1.5-Benzoxathiepine-4-N-benzylcarboxamide 0.3g, N-phenylpiperazine
0.13g, potassium iodide 0.1g, potassium carbonate 0.12g,
A mixture of 4 ml of N,N-dimethylformamide
Stir at 70℃ for 2 hours. Pour the reaction solution into 20 ml of ice water, extract with ethyl acetate, wash with water, and dry over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with ethyl acetate and n-hexane to give cis-3-acetoxy-7-methoxy-4-[3-
(4-phenylpiperazin-1-yl)propyl]
97 mg of crystals of -3,4-dihydro-2H-1,5-benzoxathiepine-4-N-benzylcarboxamide are obtained. Melting point 178-180℃ (recrystallized from ethyl acetate, white powder) Mass spectrum m/e589 (M ⁺ ) Elemental analysis value C ₃₃ H ₃₉ N ₃ O ₅ S, as 1/4H ₂ O Calculated value: C, 66.70 ; H, 6.70; N, 7.07 Actual value: C, 66.75; H, 6.63; N, 6.87 If the melting point in Reference Examples and Examples is not otherwise specified, the value measured with the Yanagimoto micro melting point measuring device is show. Preparation Example When the compound of the present invention () is used as a therapeutic agent for ischemic heart disease, it can be used, for example, in the following formulation. 1 tablet (1) Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazine-
1-yl)propyl]-3,4-dihydro-
2H-1,5-Benzoxathiepine-4-
Carboxylate hydrochloride 10g (2) Lactose 90g (3) Corn starch 29g (4) Magnesium stearate 1g 1000 tablets 130 Mix ingredients (1), (2) and 17g of (3) to make 7g of ingredient
Granulate it with the paste made from (3), add 5g of ingredient (3) and ingredient (4) to the granules, and compress the mixture with a compression tablet machine to give 10 mg of ingredient (1) per tablet.
1000 tablets with a diameter of 7 mm are manufactured. 2 Capsules (1) Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazine-
1-yl)propyl]-3,4-dihydro-
2H-1,5-Benzoxathiepine-4-
Carboxylate/hydrochloride 10g (2) Lactose 135g (3) Fine cellulose powder 70g (4) Magnesium stearate 5g 1000 capsules 220 Mix all ingredients and put into gelatin capsule No. 3 (No.
10 revised Japanese Pharmacopoeia) to produce 1000 capsules containing 10 mg of ingredient (1) per capsule. 3 Injection (1) Methyl cis-3-hydroxy-7-methoxy-4-[3-(4-phenylpiperazine-
1-yl)propyl]-3,4-dihydro-
2H-1,5-Benzoxathiepine-4-
Carboxylate/tartrate 10g (2) Sodium chloride 9g (3) Chlorobutanol 5g Dissolve all ingredients in 1000ml of distilled water, dispense 1ml each into 1000 brown ampoules, and replace with nitrogen gas. The entire process is performed under sterile conditions. Effects of the Invention The effects of the compound () of the present invention will be explained below by showing experimental examples. Experimental Example 1 Serotonin S ₂ -ceptor blocking effect of the compound of the present invention (in vitro) [Experimental method] Bevan &Osher's method (Agents Action, 2
The experiment was carried out using a method modified from the following (Vol., p. 257, 1972). That is, a pig heart obtained immediately after being sacrificed at a slaughterhouse was stored on ice, and the left circumflex coronary artery was isolated and collected within 3 hours. Coronary artery about 3mm
Obtain a ring-shaped blood vessel specimen cut widthwise, and collect 20ml of
In a double-walled organ bath containing Krebs-Henseleit solution,
Suspension was performed using a pair of suspension needles. One end of the suspension needle was fixed to the bottom of the organ bath, and the other end was connected to a strain transducer, and the contraction of the porcine coronary artery ring preparation was measured isometrically and recorded on a polygraph recorder. The organ bath was kept at 37°C and Krebs−
The Henseleit liquid was fully saturated with a mixed gas of 97% O ₂ +3% CO ₂ . The composition of Krebs-Henseleit liquid is
NaCl 118.3, KCl4.7, KH ₂ PO ₄ 1.2, CaCl ₂・
2H ₂ O 2.58, MgSO ₄・7H ₂ O 1.15, NaHCO ₃ 25,
Glucose is 11.1mM. After the tension of the blood vessel specimen stabilized 1 to 2 hours after specimen preparation, a tension of 2 g was applied, and serotonin 10 ^-6 M (final concentration) was added to the organ bath approximately every hour to observe contraction. . When the vascular response to 2-3 serotonin additions was stable, test compounds were added at various concentrations 10 minutes prior to the next serotonin addition. The effect of blocking serotonin action was calculated from the magnitude of serotonin-induced contraction before and after addition of the test compound. [Experimental Results] The experimental results regarding this compound are shown in Table 8.

[Table] Experimental Example 2 The serotonin S ₂ -ceptor blocking effect was measured in the same manner as in Experimental Example 1. The results are shown in Table 9.

[Table] Experimental Example 3 Serotonin pressor suppressing effect by oral administration of the compound of the present invention [Experimental method] An experiment was conducted using male beagle dogs weighing 10 to 14 kg. Prior to the experiment, polyethylene tubes were placed in the femoral artery and vein for measurement of systemic blood pressure and intravenous administration of drugs.
i.e. pentobarbital sodium (30
(mg/Kg intravenous administration) Surgery was performed aseptically under anesthesia, polyethylene tubes were placed in the femoral artery and vein, and the tube plugs were rotated. The other end was guided subcutaneously to the back and led out of the body through the skin. Experiments were conducted 2 to 3 days after surgery. That is,
An intraarterial indwelling polyethylene tube was connected to a pressure transducer, and systemic blood pressure was measured and continuously recorded with a polygraph recorder. Serotonin 3~
When 30 μg/Kg was administered intravenously through an intravenously indwelling polyethylene tube, a transient pressor response was observed in a dose-dependent manner.
A reproducible pressor response was observed when administered repeatedly every minute. Therefore, 30 μg/Kg of serotonin was used to examine the effects of oral administration of the compound of the present invention. serotonin 2 to 3 times every 30 minutes
After intravenously administering 30 μg/Kg and confirming that a stable pressor response was obtained, the compound of the present invention ()
[Example 12 (cis form/dihydrochloride)] at 0.1, 0.3 and
After oral administration of 1.0 mg/Kg, the magnitude of the pressor response to serotonin was investigated. [Experimental Results] The experimental results are shown in Table 10. Example 12
The compound (cis form, dihydrochloride) sustainedly suppressed serotonin hypertension in a dose-dependent manner at doses of 0.1 mg/Kg or higher.

[Table] Experimental example 4 Calcium antagonism [Experimental method] After removing the mesentery of spontaneously hypertensive rats (14 weeks old, male), the mesenteric artery was heated at 37°C.
The Krebs-Henseleit solution was perfused at a rate of approximately 4 ml/min, and the perfusion pressure was measured at the same time (perfusion pressure: approximately 40 mm
Hg). KCl10 as an indicator of calcium antagonism
The inhibitory effect on the perfusion pressure increase response when mg/specimen was injected into the mesenteric artery was used. The compound is KCl
It was infused intra-arterially for 30 minutes prior to injection. [Experimental Results] The results are shown in Table 11. The increase in perfusion pressure due to KCl when the compound of Example 12 (cis form/dihydrochloride) was not treated (control) was 73±20 (average of 8 cases) mmHg.
Value after compound treatment (%) when this value is taken as 100%
However, the compound of Example 12 (cis) showed 10 ^-7 to 3
At ×10 ^-6 M, KCl showed a significant dose-dependent pressor suppressing effect.

[Table] Experimental Example 5 Diuretic Effect [Experimental Method] Spontaneously hypertensive rats (13 weeks old, male) were used in groups of 5 rats. The drug was suspended in a small amount of gum arabic and physiological saline and administered orally in a volume of 25 ml/Kg. The control group received only physiological saline containing gum arabic. After administration, the rats were placed in a metabolic cage for urine collection, and urine was collected for 5 hours. Urine volume and urine
Na ⁺ K ⁺ excretion was measured. Na ⁺ and K ⁺ were measured using a flame photometer (Hitachi 205DT). [Experimental Results] The results are shown in Table 12. The compound of Example 12 (cis form/dihydrochloride) was orally administered at 3 mg/Kg to increase urine volume,
Shows a tendency to promote Na ⁺ and K ⁺ excretion, 10mg/Kg
At 30 mg/Kg, there was a significant increase in urine volume, and at 30 mg/Kg there was a significant increase in urine volume, Na ⁺ and K ⁺ .

[Table] Experimental Example 6: In vivo antithrombotic effect in the coronary circulation of anesthetized dogs [Experimental method] Mongrel adult dogs were used under pentobarbital anesthesia under thoracotomy. Folts for intracoronary thrombus formation and its evaluation
[Circulation 54 , p. 365 (1976)] was followed. In other words, a cannula is inserted into the left circumflex coronary artery, and arterial blood is guided and circulated from the left common carotid artery.
Coronary blood flow was measured using an electromagnetic blood flow meter. In addition, a plastic constrictor with an inner diameter of approximately 1 mm was attached to the circumflex coronary artery to narrow the coronary artery. Thrombus formation was determined from periodic decreases and increases in coronary blood flow, and the antithrombotic effect was evaluated from the effect of the drug on the frequency of thrombus formation. The test drug was administered intravenously. [Experimental results] When a constrictor was attached to the circumflex coronary artery,
Coronary blood flow gradually decreases from 20 to 30 ml/min to several
After decreasing to ml/min, it suddenly increases. Various decreases and increases in coronary blood flow were observed periodically, with a frequency of 5 to 15/15 minutes. The compound of Example 12 (cis form/dihydrochloride) was 1 μg/
Kg intravenously administered or higher dose-dependently suppressed periodic changes in coronary blood flow (Table 13). That is,
The compound of Example 12 (cis form/dihydrochloride) was tested in vivo.
It inhibited thrombus formation caused by impaired intravascular blood flow.

[Table] Experimental Example 7 Relaxing effect on cerebral vasospasm after experimental subarachnoid hemorrhage [Experimental method] Six beagle dogs weighing 10-14 kg were used. Pentobarbital anesthesia (30mg/
Kg, intravenous administration), a polyethylene cannula was previously placed chronically in the right vertebral artery. For each cerebral angiogram, 10 ml of the contrast agent iodamide glutamine was injected through a chronically indwelling cannula under pentobarbital anesthesia. I went. Subarachnoid hemorrhage was caused by injecting 5 ml of fresh autologous blood collected from the leg vein into the cisterna magna using a spinal needle under pentobarbital anesthesia two days after cannula placement. Cerebral angiography was performed before subarachnoid hemorrhage and on days 3, 6, and 13 after hemorrhage.
The basilar artery diameter was measured from the radiograph. The animals were divided into two groups of three, one group was used as a control, and the other group was used as a control.
39 (monohydrochloride) of the compound was administered. The compound was orally administered at 30 mg/Kg on the day of subarachnoid hemorrhage, and 1 mg/Kg was administered intravenously immediately after subarachnoid hemorrhage.
30 mg/Kg was orally administered every day until 13 days later. [Experimental Results] Table 14 shows the diameter of the basilar artery before subarachnoid hemorrhage and the change in diameter after subarachnoid hemorrhage. Approximately 40 and 60 days after subarachnoid hemorrhage in the control group, respectively.
% basilar artery diameter decreased and cerebral vasospasm was observed. On the other hand, in the compound-treated group, the decrease in basilar artery diameter was slight, and the degree of decrease was significantly lower than in the control group.

[Table] Experimental Example 8 Renal Circulation Improving Effect [Experimental Method] Beagle dogs (normal blood pressure) weighing 9-14 kg were used. A laparotomy was performed along the abdominal midline under pentobarbital anesthesia. To measure renal blood flow, the left renal artery was dissected and an electromagnetic blood flow meter probe was attached. In addition, to measure systemic blood pressure, a polyethylene tube was retrogradely inserted into the abdominal aorta and fixed. The lead wires of the blood flow meter probe and the other end of the polyethylene tube were passed subcutaneously and exposed to the back of the neck. After more than one week had passed after the surgery, the animals were subjected to experiments without anesthesia. Renal blood flow was measured using an electromagnetic flowmeter, and systemic blood pressure was measured using a pressure transducer. Heart rate was also measured by driving a pulse rate tachometer with blood pressure pulse waves. The drug [Example 39 (monohydrochloride)] was administered orally, but repeated administrations to the same solid were administered at intervals of 3 days or more. [Experimental Results] When lactose (10 mg/Kg, number of cases: 7) was orally administered as a control in this experimental system, there was no change in systemic blood pressure, heart rate, or renal blood flow during the 7-hour observation period. Administration of 3 and 10 mg/Kg of the drug slightly lowered systemic blood pressure in a dose-dependent manner but had no effect on heart rate. However, these doses significantly increased renal blood flow by up to approximately 23 and 46%, respectively, and the effect persisted over the 7 hours observed. The results are shown in Table 15.

〔experimental method〕

The test drug was orally administered to 5-week-old male Jcl:Wistar rats, and then observed for 14 days to examine acute toxicity. [Experimental results] The LD ₅₀ value of Example 39 (monohydrochloride) is approximately 2100 mg/Kg
It was hot.

Claims (1)

[Claims] 1 formula [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxyl group, lower alkyl group, or lower alkoxy group, and R ₃ and R ₄ each represent (i) hydrogen, (ii) C _3-8 cycloalkyl group , halogen, hydroxyl group, lower alkoxy group, lower alkanoyloxy group, mono- or di-lower alkylamino group, C _3-8 cycloalkylamino group, lower alkanoylamino group, benzamide group, lower alkylthio group, carbamoyl group, N-lower a lower alkyl group optionally substituted with an alkylcarbamoyl group or an N,N-dilower alkylcarbamoyl group; (iii) a cycloalkyl group optionally substituted with a lower alkyl group, a lower alkoxy group, a lower alkanoylamino group or a hydroxyl group; represents an alkyl group, or (iv) a phenyl-lower alkyl group optionally substituted with a halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group or hydroxyl group, or R ₃ and R ₄ represents a 5- to 7-membered cyclic amino group together with the adjacent nitrogen atom, and this cyclic amino group may be substituted with the following (a) to (i): (a) 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) 5- to 7-membered heterocyclic group containing 1 to 3 nitrogen atoms (provided that (b) to (e), (g) to (i)
may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylene dioxy group, amino group, nitro group or hydroxyl group), X is (i) hydrogen, (ii) lower alkyl group, (iii) lower alkanoyl group, (iv) hydroxyl lower alkyl group, (v) lower alkanoyloxy lower alkyl group, (vi) phenyl-lower alkyl group, (vii) phenyl group, (viii) lower alkoxycarbonyl group, (ix ) phenyl-lower alkoxycarbonyl group, (x) a lower alkyl group, a carbamoyl group optionally substituted with a phenyl group or a phenyl-lower alkyl group, or () a carboxyl group (however, phenyl in (vi) and (vii) The group may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylene dioxy group, amino group, nitro group or hydroxyl group), and Y is >C=0 or >CH-OR ₅ ( In the formula, R ₅ is (i) hydrogen, (ii) lower alkanoyl group, (iii) phenyl-lower alkanoyl group, or (iv) (a′) lower alkyl group, (b′) phenyl group, or (c′) Carbamoyl group optionally substituted with phenyl-lower alkyl group (however, (iii),
(iv), b'), and (c') phenyl groups may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group, or hydroxyl group)
), m is an integer of 0 to 2, n is an integer of 1 to 6] or a salt thereof. 2. The compound according to claim 1, wherein R ₁ and R ₂ are each hydrogen, halogen, lower alkyl group or lower alkoxy group. 3. The compound according to claim 1, wherein R ₁ and R ₂ are each hydrogen or a lower alkoxy group. 4 R ₃ and R ₄ are each (i) hydrogen, (ii) lower alkyl group, (iii) C _3-8 cycloalkyl group, or (iv) halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino a phenyl-lower alkyl group optionally substituted with a radical, a nitro group or a hydroxyl group, or together with the adjacent nitrogen atom represents a morpholino, piperazinyl or piperidyl group, which morpholino, piperazinyl or piperidyl group is (a) a lower Alkyl, (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) 5- to 7-membered heterocyclic group containing 1 to 3 nitrogen atoms (however, (b) to (e), (g) to (i)
The group may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group, or hydroxyl group), Claim 1 which may be substituted with Compounds described. 5 R ₃ and R ₄ together with the adjacent nitrogen atom represent a piperazinyl group, and the 4th position is substituted with a halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group or hydroxyl group. The compound according to claim 1, to which a good phenyl group is bonded. 6 R ₃ and R ₄ together with adjacent nitrogen atoms are 4
-Phenylpiperazinyl compound according to claim 1. 7. The compound according to claim 1, wherein X is hydrogen, carboxyl group, lower alkoxycarbonyl group, hydroxymethyl group or lower alkanoyloxymethyl group. 8. The compound according to claim 1, wherein X is a lower alkoxycarbonyl group. 9 Y is >C=O or >CH-OR ₅ (wherein R ₅
is (i) hydrogen, (ii) a lower alkanoyl group, or (iii) a carbamoyl group optionally substituted with a lower alkyl group, a phenyl group, or a phenyl-lower alkyl group. compound. 10. The compound according to claim 1, wherein Y is hydroxymethylene. 11. The compound according to claim 1, wherein m is 0. 12. The compound according to claim 1, wherein n is an integer of 2 to 6. 13. The compound according to claim 1, wherein n is 3. 14. The compound according to claim ₁ , wherein R 1 is hydrogen and R ₂ is a lower alkoxy group. 15. The compound according to claim 1, wherein R ₁ is hydrogen and R ₂ is a lower alkoxy group bonded to the 7-position of the benzoxathiepine ring. 16 formula 2. The compound according to claim 1, wherein R ₆ represents a phenyl group, R ₂ ' represents a lower alkoxy group, and X' represents a lower alkoxycarbonyl group. 17 Claim 1 in which R ₂ ' is methoxy
Compound according to item 6. 18. The compound according to claim 16, wherein X' is methoxycarbonyl. 19 formula [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxyl group, lower alkyl group, or lower alkoxy group, and R ₃ and R ₄ each represent (i) hydrogen, (ii) C _3-8 cycloalkyl group , halogen, hydroxyl group, lower alkoxy group, lower alkanoyloxy group, mono- or di-lower alkylamino group, C _3-8 cycloalkylamino group, lower alkanoylamino group, benzamide group, lower alkylthio group, carbamoyl group, N-lower a lower alkyl group optionally substituted with an alkylcarbamoyl group or an N,N-dilower alkylcarbamoyl group; (iii) a cycloalkyl group optionally substituted with a lower alkyl group, a lower alkoxy group, a lower alkanoylamino group or a hydroxyl group; represents an alkyl group, or (iv) a phenyl-lower alkyl group optionally substituted with a halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group or hydroxyl group, or R ₃ and R ₄ represents a 5- to 7-membered cyclic amino group together with the adjacent nitrogen atom, and this cyclic amino group may be substituted with the following (a) to (j): (a) lower alkyl; (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) a phenyl-lower alkenoyl group or (j) a 5- to 7-membered heterocyclic group containing 1 to 3 nitrogen atoms (however, (b) to (e), (g) to (i)
may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylene dioxy group, amino group, nitro group or hydroxyl group), X is (i) hydrogen, (ii) lower alkyl group, (iii) lower alkanoyl group, (iv) hydroxy lower alkyl group, (v) lower alkanoyloxy lower alkyl group, (vi) phenyl-lower alkyl group, (vii) phenyl group, (viii) lower alkoxycarbonyl group, (ix ) phenyl-lower alkoxycarbonyl group, (x) lower alkyl group, phenyl group, or carbamoyl group optionally substituted with phenyl-lower alkyl group, or () carboxyl group (with the exception of phenyl groups in (vi) and (vii)) may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylenedioxy group, amino group, nitro group or hydroxyl group), and Y is >C=O or >CH-OR ₅ (formula Among them, R ₅ is (i) hydrogen, (ii) lower alkanoyl group, (iii) phenyl-lower alkanoyl group, or (iv) (a′) lower alkyl group, (b′) phenyl group, or (c′) phenyl. - a carbamoyl group optionally substituted with a lower alkyl group (provided that (iii),
The phenyl groups of (iv), (b′), and (c′) are further halogen, lower alkyl group, lower alkoxy group,
(optionally substituted with a methylenedioxy group, an amino group, a nitro group or a hydroxyl group), m is an integer of 0 to 2, and n is an integer of 1 to 6] A prophylactic and therapeutic agent for ischemic heart disease, thrombosis, hypertension or cerebral circulation disorder, comprising: 20 formula [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxyl group, lower alkyl group, or lower alkoxy group, and X is (i) hydrogen, (ii) lower alkyl group, (iii) lower alkanoyl group, ( iv) hydroxy lower alkyl group, (v) lower alkanoyloxy lower alkyl group, (vi) phenyl-lower alkyl group, (vii) phenyl group, (viii) lower alkoxycarbonyl group, (ix) phenyl-lower alkoxycarbonyl group, (x) A lower alkyl group, a phenyl group, or a carbamoyl group optionally substituted with a phenyl-lower alkyl group, or () a carboxyl group (however, the phenyl group in (vi) and (vii) may also be a halogen or lower alkyl group). , a lower alkoxy group, a methylenedioxy group, an amino group, a nitro group, or a hydroxyl group), and m represents an integer of 0 to 2] and the formula [In the formula, R ₃ and R ₄ are each (i) hydrogen, (ii) C _3-8 cycloalkyl group, halogen, hydroxyl group, lower alkoxy group, lower alkanoyloxy group, mono- or di-lower alkylamino group, C a lower alkyl group optionally substituted with a _3-8 cycloalkylamino group, lower alkanoylamino group, benzamide group, lower alkylthio group, carbamoyl group, N-lower alkylcarbamoyl group or N,N-dilower alkylcarbamoyl group, (iii) a lower alkyl group, a lower alkoxy group, a lower alkanoylamino group, or a cycloalkyl group optionally substituted with a hydroxyl group; or (iv) a halogen, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, or an amino group. , a phenyl-lower alkyl group optionally substituted with a nitro group or a hydroxyl group, or R ₃ and R ₄ together with adjacent nitrogen atoms represent a 5- to 7-membered cyclic amino group, and this cyclic amino group Optionally substituted with the following (a) to (j): (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) containing 1 to 3 nitrogen atoms 5 to 7-membered heterocyclic group (however, (b) to (e), (g) to (i)
The group may be further substituted with halogen, lower alkyl group, lower alkoxy group, methylene dioxy group, amino group, nitro group or hydroxyl group), n represents an integer of 1 to 6, and W represents halogen or Formula R-SO ₂ -O- (wherein R is a lower alkyl group,
phenyl group or p-tolyl group)] to a condensation reaction, a reduction reaction after the condensation reaction, or an acylation or carbamoylation reaction following the reduction reaction after the condensation reaction. , characterized by the expression [In the formula, Y is >C=O or >CH-OR ₅ (wherein, R ₅ is (i) hydrogen, (ii) lower alkanoyl group, (iii) phenyl-lower alkanoyl group, or (iv) (a ′) lower alkyl group, (b′) phenyl group, or (c′) carbamoyl group optionally substituted with phenyl-lower alkyl group (however, (iii),
The phenyl groups of (iv), (b′), and (c′) are further halogen, lower alkyl group, lower alkoxy group,
(optionally substituted with a methylenedioxy group, an amino group, a nitro group, or a hydroxyl group), and other symbols have the same meanings as above] or a method for producing a salt thereof. 21 formula [In the formula, R ₁ and R ₂ each represent hydrogen, halogen, hydroxyl group, lower alkyl group, or lower alkoxy group, and X is (i) hydrogen, (ii) lower alkyl, (iii) lower alkanoyl group, (iv ) hydroxyl lower alkyl group, (v) lower alkanoyloxy lower alkyl group, (vi) phenyl-lower alkyl group, (vii) phenyl group, (viii) lower alkoxycarbonyl group, (ix) phenyl-lower alkoxycarbonyl group, ( x) A lower alkyl group, a phenyl group, or a carbamoyl group optionally substituted with a phenyl-lower alkyl group, or () a carboxyl group (however, the phenyl group in (vi) and (vii) may further include a halogen, a lower alkyl group, may be substituted with a lower alkoxy group, methylenedioxy group, amino group, nitro group or hydroxyl group), and Y is >C=O or >CH-OR ₅ (in the formula, R ₅ is (i) substituted with hydrogen, (ii) a lower alkanoyl group, (iii) a phenyl-lower alkanoyl group, or (iv) a (a′) lower alkyl group, (b′) a phenyl group, or (c′) a phenyl-lower alkyl group; Carbamoyl group (however, (iii),
The phenyl groups of (iv), (b′), and (c′) are further halogen, lower alkyl group, lower alkoxy group,
), m represents an integer of 0 to 2, n represents an integer of 1 to 6, W represents halogen or Formula R- _SO2 -O- (wherein,
R represents a group represented by a lower alkyl group, a phenyl group, or a p-tolyl group] and a compound represented by the formula [In the formula, R ₃ and R ₄ are each (i) hydrogen, (ii) C _3-8 cycloalkyl group, halogen, hydroxyl group, lower alkoxy group, lower alkanoyloxy group, mono- or di-lower alkylamino group, C a lower alkyl group optionally substituted with a _3-8 cycloalkylamino group, lower alkanoylamino group, benzamide group, lower alkylthio group, carbamoyl group, N-lower alkylcarbamoyl group or N,N-dilower alkylcarbamoyl group, (iii) a lower alkyl group, a lower alkoxy group, a lower alkanoylamino group, or a cycloalkyl group optionally substituted with a hydroxyl group; or (iv) a halogen, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, or an amino group. , a phenyl-lower alkyl group optionally substituted with a nitro group or a hydroxyl group, or R ₃ and R ₄ together with adjacent nitrogen atoms represent a 5- to 7-membered cyclic amino group, and this cyclic amino group (a) lower alkyl, (b) phenyl group, (c) phenyl-lower alkyl group, (d) diphenyl-lower alkyl group, (e) triphenyl, which may be substituted with the following (a) to (j) -lower alkyl group, (f) lower alkanoyl group, (g) benzoyl group, (h) phenyl-lower alkanoyl group, (i) phenyl-lower alkenoyl group, or (j) 5 to 7 containing 1 to 3 nitrogen atoms. Heterocyclic groups with members (however, (b) to (e), (g) to (i)
The group may be further substituted with a halogen, a lower alkyl group, a lower alkoxy group, a methylenedioxy group, an amino group, a nitro group or a hydroxyl group). do, expression A method for producing a compound represented by the formula [wherein each symbol has the same meaning as above] or a salt thereof.