JPH0645600B2 - 1,4-diazacycloalkane derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel and useful 1,4-diazacycloalkane derivative having calcium antagonistic activity and the like, and salts thereof.

2. Description of the Related Art In recent years, as the physiology of in vivo calcium has been elucidated, calcium antagonists having various chemical structures have been marketed or studied. As typical examples, prenilamine-based, verapamil-based, nifedipine-based or diltiazem-based compounds are known.

OBJECT OF THE INVENTION The present invention provides a new type of calcium channel blocker which does not belong to any system of conventional calcium channel blockers. The present invention also provides a novel compound having an antiallergic action.

According to the present invention, the general formula (I) [Wherein R ₁ is And A represents a benzene ring or a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together form a single bond, -O-,
-S -, - CH = CH - , - CH 2 CH 2 -, - CH 2
O- or R ₂ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ₃ represents a phenyl (lower) alkyl group, a phenyl (lower) alkenyl group or a diphenylmethyl group in which an alkyl moiety is substituted with hydroxy. A naphthyl group, an aromatic heterocyclic group optionally substituted with lower alkyl or lower alkoxycarbonyl, a benzoyl (lower) alkyl group, an aroyl group, a phenyloxycarbonyl group, a phenyloxysulfonyl group or a phenylsulfonyl group, R ₄ and R ₅ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a lower alkylthio group or a cyano group, and W represents a carbonyl group or a sulfonyl group, X means an alkylene group, a means 2 or 3, and b Means an integer of 0 to 2. However, the phenyl moiety and naphthyl group in the above definition may be optionally substituted with a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a trifluoromethyl group or a lower alkoxy group, and the A ring is In the case of a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together And R ₄ represents a hydrogen atom. ] The 1,4-diaza cycloalkane derivative represented by these and its salt are provided.

As the salts of the compound represented by the formula (I), physiologically acceptable salts are preferable, and for example, inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate. salt,
And oxalate, maleate, fumarate, lactate,
Organic acid salts such as malate, citrate, tartrate, benzoate and methanesulfonate can be mentioned. Since the compounds of formula (I) and salts thereof may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

The compounds of formula (I) optionally have one or more asymmetric carbon atoms and optionally one asymmetric sulfur atom, and therefore may exist as stereoisomers. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are explained below.

The lower alkyl group, lower alkoxy group, lower alkylthio group or alkylene group may be linear or branched, but is preferably linear. Halogen atom means fluorine, chlorine, bromine, iodine, but fluorine, chlorine,
Bromine is preferred, especially fluorine. The lower alkyl group means one having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl and butyl, with methyl being preferable. The lower alkoxy group means one having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy and the like, with methoxy being preferred. The lower alkylthio group means one having 1 to 6 carbon atoms, and examples thereof include methylthio, ethylthio, propylthio, isopropylthio and the like, with methylthio being preferred. The alkylene group means one having 1 to 10 carbon atoms, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and heptamethylene. Examples of the unsubstituted or substituted phenyl (lower) alkyl group in which the alkyl moiety is substituted with hydroxy include 2-hydroxy-2-phenylethyl, 2-hydroxy-3-phenylpropyl, 2-hydroxy-2- (4
-Fluorophenyl) ethyl and the like. The unsubstituted or substituted phenyl (lower) alkenyl group means that the alkenyl moiety has 3 to 5 carbon atoms, for example, cinnamyl, o-, m- or p-fluorocinnamyl, o.
-, M- or p-chlorocinnamyl, o-, m- or p-methylcinnamyl and the like can be mentioned. Examples of the aromatic heterocyclic group optionally substituted with lower alkyl or lower alkoxycarbonyl include 2-thiazolyl, 2- or 4-pyridyl, 3-methyl-2-pyridyl, 3-ethoxycarbonyl-2-pyridyl, 2-pyrimidinyl, 6-methyl-4pyrimidinyl, 2-quinolyl and the like can be mentioned. Examples of the aroyl group include benzoyl, 2-naphthoyl, 2-furoyl, 2-thenoyl and the like.

The compounds of formula (I) and their physiologically acceptable salts are
Since it has an excellent calcium antagonism, it is useful for prevention and treatment of ischemic cardiovascular disorder and / or hypertension. The compound of formula (I) in which R ₃ is a 2-pyridyl group also has an excellent antiallergic effect, and thus, it is effective in treating allergic diseases such as bronchial asthma, allergic rhinitis, urticaria and atopic dermatitis. It is useful for prevention and treatment.

Among the compounds of the present invention, the preferred one as a calcium antagonist is that the ring A in formula (I) is a benzene ring, and Y and Z together form -S-, -CH = CH-,- CH ₂ CH ₂ − or And R ₂ is a hydrogen atom, R ₃ is a cinnamyl group, a 2-pyridyl group, a 2-pyrimidinyl group or a 2-quinolyl group, and one of R ₄ and R ₅ is a hydrogen atom,
The other is a hydrogen atom or a methyl group, W is a carbonyl group, X is - (CH ₂₎ n- and, n is an integer of 1 to 5, in a is 2, b is 0 to 2 integer A compound and its physiologically acceptable salts.

Particularly suitable compounds include, for example, the following compounds and physiologically acceptable salts thereof.

11- [4- (4-Cinnamyl-1-piperazinyl) butyrylamino] -6,11-dihydrodibenzo [b, e] thiepine, 11- [4- (4-Cinnamyl-1-piperazinyl) butyrylamino] -2-methyl -6,11-Dihydrodibenzo [b, e] thiepine, and 5- [4- (4-cinnamyl-1-piperazinyl) butyrylamino] -5H-dibenzo [a, d] cycloheptene Also within the compounds of the invention Suitable examples of the antiallergic agent include the following compounds and physiologically acceptable salts thereof.

11- [4- [4- (2-pyridyl) -1-piperazinyl] butyrylamino] 6,11-dihydrodibenzo [b,
e] Oxepin, and 5- [4- [4- (2-pyridyl) -1-piperazinyl] butyrylamino] -5H-dibenzo [a, d] cycloheptene The compound of the present invention can be produced, for example, by the following method.

Method (a): General formula (II) (In the formula, R ₁ , R ₂ , W and X have the same meanings as described above, and V means a reactive ester residue of alcohol.) And a compound represented by the general formula (III) (In the formula, R ₃ and a mean the same as above.) The compound represented by the general formula (I) can be obtained by reacting with the compound represented by the formula.

Examples of the reactive ester residue of alcohol represented by V in the formula (II) include halogen atom such as chlorine, bromine and iodine, lower alkylsulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy,
Arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy are mentioned.

The reaction between the compound of formula (II) and the compound of formula (III) is carried out without solvent or in a suitable solvent, and specific examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene. Examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, alcohols such as ethanol and isopropyl alcohol, acetonitrile and dimethylformamide. These solvents may be used alone or in admixture of two or more. This reaction is preferably carried out in the presence of a base, and specific examples of the base include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, triethylamine and tri-n. Examples thereof include organic bases such as -butylamine, diisopropylethylamine and N-methylmorpholine, but an excess amount of the compound of the formula (III) can also serve. Further, when a compound in which V is chlorine or bromine in the formula (II) is used, the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. Reaction temperature is usually about 0 ℃
To about 200 ° C, preferably about 40 ° C to about 160 ° C.

Method (b): General formula (IV) (In the formula, R ₁ and R ₂ have the same meanings as described above.)
And a compound represented by the general formula (V) (In the formula, R ₃ , X and a have the same meanings as described above.) By reacting with a compound represented by the following formula or a reactive derivative thereof, W in the formula (I) is a carbonyl group. The compound can be obtained.

Examples of the reactive derivative of the compound of the formula (V) include active ester, acid anhydride and acid halide (particularly acid chloride). Specific examples of the active ester include p
-Nitrophenyl ester, 2,4,5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester and the like. As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with a carbonic acid monoalkyl ester such as ethyl carbonate and isobutyl carbonate, and a phenyl carbonate. Examples thereof include mixed acid anhydrides with carbonic acid monoaryl esters, mixed acid anhydrides with isovaleric acid, alkanoic acids such as pivalic acid, and the like.

When the compound of formula (V) is used, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-
The reaction can be carried out in the presence of a condensing agent such as 1,2-dihydroquinoline.

The reaction between the compound of formula (IV) and the compound of formula (V) or its reactive derivative is usually carried out in a solvent. The solvent to be used should be appropriately selected according to the type of raw material compound, but for example, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane, methylene chloride,
Examples thereof include halogenated hydrocarbons such as chloroform, ethyl acetate, acetonitrile, dimethylformamide, dimethylsulfoxide, water, etc. These solvents may be used alone or in admixture of two or more. This reaction is carried out in the presence of a base as needed, and specific examples of the base include the specific examples of the base described in the method (a) part as they are. The reaction temperature will differ depending on the types of starting compounds used, but it is usually about 0 ° C to about 150 ° C.
Is.

The compound of formula (I) produced by each of the above production methods is isolated by a conventional method such as chromatography, recrystallization or reprecipitation.
Refined.

The compound of formula (I) can be obtained in the form of a free base or a salt, or a hydrate or a solvate, depending on the selection of starting compounds, reaction / treatment conditions and the like. The salt can be converted to the free base by a conventional method, for example, by treating with a base such as alkali carbonate. On the other hand, the free base can be converted into a salt by treating it with various acids according to a conventional method.

Hereinafter, the pharmacological effects of the compounds of the present invention will be described by showing the results of pharmacological tests on the representative compounds of the present invention, diltiazem hydrochloride which is a commercially available calcium antagonist, and tranilast which is a commercially available antiallergic agent.

Test Example 1 Calcium antagonism This test was carried out by the method of Godfraind et al. [Br.J.Pharmac., 36 , 549.
~ 560 (1969)].

A spiral incision was made on the isolated thoracic aorta of a male Wistar rat weighing 250 to 300 g, with a width of 3 to 4 mm and a length of about 3 mm.
A 30 mm arterial section specimen was prepared. 95% O ₂ + 5% CO ₂
Aerated with mixed gas of 10 ml, Krebs
The specimen was suspended in bicarbonate solution and a tension of 1 g was applied. The contraction response of the specimens was recorded by ink-writing oscillography via a tension-displacement transducer.

First, the solution in the Magnus tank with the sample suspended is Ca Including
High K⁺Replace with Krebs bicarbonate solution and remove.
After inducing polarization, CaCl_TwoIs added cumulatively,
Ca A dose-contraction curve was determined according to. Then the test compound
Perform a similar experiment in the presence of Ca Dose-contraction
Seeking the line, Van Rossum's method [Arch.int.Pharmacodyn.,
143, 299-330 (1963)] according to
A_TwoWas calculated. Note that pA_TwoAnd Ca Dose by
-Twice the contraction curve (in the absence of the test compound) on the high concentration side
Inverse of the molar concentration of test compound required to translate
It is a numerical value defined by logarithm.

The results are shown in Table 1. The numerical values in the table represent the average value ± standard error of 3 to 6 samples.

Test Example 2 Inhibition of passive skin anaphylaxis (PCA)
This test is performed by the method of Perper et al. [J.Pharmacol.Exp.Ther.,193
(2), 594-602 (1975)].

The method of Levine et al. [Int.Arch.Allergy Appl.Immuno] was applied to two abdominal sites of male Wistar rats (body weight 130 to 180 g).
L., 39 , 156-168 (1970)], and intradermally injected with 0.1 ml of a diluted solution of anti-ovalbumin mouse antiserum.
After 48 hours, 1 ml of a 0.5% Evans blue solution containing 2 mg of ovalbumin was injected into the tail vein. Dye injection 30
After a lapse of time, the rat was killed and the abdominal skin was peeled off, and then the area and color tone of the pigment spot were measured. The average value of the measured values of the pigment spots at two locations was used as the reaction value of each rat. Test compound is 0.5
% Tragacanth aqueous solution was dissolved or suspended and orally administered 1 hour before injection of the dye.

The inhibition rate was determined by comparing the reaction value of the test compound administration group with that of the 0.5% tragacanth aqueous solution (vehicle) administration group.

The compounds of Examples 4, 8, 9, 11, 14 and 15 were all
A dose of 80 mg / kg showed an inhibition rate of 50% or more. On the other hand, tranilast showed a suppression rate of 29.5% at the dose of 320 mg / kg.

The route of administration of the compound of formula (I) and its physiologically acceptable salts may be oral, parenteral or rectal administration, with oral administration being preferred. The dose is usually 0.05 to 30 mg / kg / day, although it varies depending on the kind of compound, administration method, patient's symptoms, age and the like. The compound of formula (I) or a salt thereof is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. Specific examples of the preparation include tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections, inhalants, patches, suppositories and the like.

In order to describe the present invention more specifically, reference examples and examples will be given below, but the present invention is not limited to these examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra and the like.

In addition, the following abbreviations may be used for simplification of the description in the following Reference Examples and Examples.

Me: Methyl group Et: Ethyl group ph: Phenyl group A: Ethanol AC: Acetone AE: Ethyl acetate CH: Chloroform E: Diethyl ether H: n-Hexane M: Methanol T: Toluene Reference Example 1 11- (5-chlorobare) Preparation of rilamino) -6,11-dihydrodibenzo [b, e] thiepine: 8.8 g of 11-amino-6,11-dihydrodibenzo [b, e] thiepine, 6.0 g of 5-chlorovaleric acid chloride and dioxane. 100 ml of the mixture are heated to reflux with stirring for 15 hours. The solvent is distilled off under reduced pressure, and the residue is recrystallized from ethanol to obtain 12.5 g of the desired product.

Melting point 155 to 156 ° C. Reference Examples 2 to 8 The following compounds are obtained by reacting and treating the corresponding starting compounds in the same manner as in Reference Example 1.

* 11- (3-chloropropionylamino) -6,11-dihydrodibenzo [b, e] thiepine * 1 / 5EtOH melting point
177 to 177.5 ° C (recrystallized from ethanol) 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] thiepine Melting point 189 to 190 ° C (recrystallized from ethanol) 11- (4 -Chlorobutyrylamino) -2-methyl-
6,11-Dihydrodibenzo [b, e] thiepine Melting point 188-190 ° C (recrystallized from ethyl acetate) 5- (5-chlorovalerylamino) -5H-dibenzo [a, d] cycloheptene Melting point 221-222 ° C (Recrystallized from chloroform) 5- (4-chlorobutyrylamino) -5H-dibenzo [a, d] cycloheptene Melting point 220-223 ° C (Recrystallized from toluene) 5- (3-chloropropionylamino) -5H -Dibenzo [a, d] cycloheptene melting point 220-223 ° C (recrystallized from ethanol-n-hexane) -5- (4-chlorobutyrylamino) -5H-10,11-
Dihydrodibenzo [a, d] cycloheptene Melting point 220-222 ° C. (recrystallized from toluene) Reference Example 9 11- (4-chlorobutyrylamino) -2-methyl-6,6
Preparation of 11-dihydrodibenzo [b, e] thiepine-5,5-dioxide: 11- (4-chlorobutyrylamino) -2-methyl-6.
5.0 g of 11-dihydrodibenzo [b, e] thiepine was dissolved in 100 ml of chloroform, and 12 g of m-chloroperbenzoic acid was added thereto under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. The reaction mixture is washed successively with 10% aqueous sodium hydroxide solution, water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off, and the residue was recrystallized from methanol to give the desired product (5.1 g).
To get

Melting point 203-204 ° C. Reference Example 10 Preparation of 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] thiepine-5,5-dioxide: Using the corresponding starting material, Reference Example 9 The reaction and treatment are performed in the same manner as in to obtain the target product. Melting point 215 to 227 ° C. (recrystallized from methanol) Reference Example 11 trans-11- (4-chlorobutyrylamino) -6,6
Production of a, 7,8,9,10,10a, 11-octahydrodibenzo [b, e] thiepine: (1) trans-6,6a, 7,8,9,10,10a, 11-octahydro-11 6 g of -oxodibenzo [b, e] thiepine
After melting and stirring a mixture of 40 g of ammonium formate and 220 ° C. for 2 hours, 40 g of ammonium formate was added, and 220 ° C.
Stir for an additional 2 hours. After cooling, add water to the reaction mixture,
The precipitated oily substance is extracted with toluene. The extract was washed with water and then concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform to remove trans-.
11-formamide-6,6a, 7,8,9,10,10a, 11
5 g of octahydrodibenzo [b, e] thiepine are obtained as an oil.

(2) A mixture of 5 g of the 11-formamide derivative, 40 ml of ethanol and 20 ml of concentrated hydrochloric acid is heated under reflux at 100 ° C. for 30 minutes. The reaction mixture is concentrated under reduced pressure, 10% aqueous potassium carbonate solution is added to the residue, and the precipitated oily substance is extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give trans-11-amino-6,6a, 7,8,9,10,
10a, 11-octahydrodibenzo [b, e] thiepine 4
g is obtained as an oil.

(3) 2.56 g of the above 11-amino compound, 50 ml of toluene and 4
A mixture of 1.9 g of chlorobutyric acid chloride is heated to reflux at 130 ° C. for 16 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 3.0 g of the desired product as an oil. Mass spectrum m / z: 337 (M ⁺ ) Example 1 Preparation of [4- [4- (2-pyridyl) -1-piperazinyl] butyrylamino] cyclohexylphenylmethane: (4-chlorobutyrylamino) cyclohexylphenylmethane 1.5 g, 1- (2-pyridyl) piperazine 2.
A mixture of 3 g, sodium iodide 3.8 g and dimethylformamide 30 ml is stirred at 60 ° C. for 15 hours. 10% after cooling
Aqueous potassium carbonate solution is added and extracted with chloroform. The extract is washed with water and then with saturated saline, and then dried over magnesium sulfate. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (100: 2) to obtain 1.3 g of the desired product. Melting point 130-132 ° C. (recrystallized from ethyl acetate-diethyl ether) Example 2 11- [4- (4-Cinnamyl-1-piperazinyl) butyrylamino] -6,11-dihydrodibenzo [b, e] thiepine dimalein Preparation of acid salt 3/4 hydrate: 1.0 g of 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] thiepine, 1.0 g of 1-cinnamylpiperazine, iodide A mixture of 3.0 g sodium and 20 ml dimethylformamide is stirred at 100 ° C. for 1 hour. After cooling, the reaction solution was treated in the same manner as in Example 1, the residue was subjected to silica gel column chromatography, and the portions eluted with chloroform-methanol (100: 3) were collected.
The solvent is distilled off. The residue is converted into maleic acid vinegar according to a conventional method and recrystallized from ethanol to obtain 0.8 g of the desired product.

Melting point 183-184 ° C Example 3 Preparation of 5- [4- [4- (2-pyrimidinyl) -1-piperazinyl] butyrylamino] -5H-dibenzo [a, d] cycloheptene: 5- (4-chlorobutyrylamino ) -5H-Dibenzo [a, d] cycloheptene 2.0 g, 1- (2-pyrimidinyl) piperazine 2.6 g, sodium iodide 4.8.
A mixture of g and 20 ml of dimethylformamide is stirred at 60 ° C. for 16 hours. After cooling, the reaction solution was treated as in Example 1,
The residue is subjected to silica gel column chromatography and eluted with chloroform-methanol (100: 3) to obtain 1.4 g of the desired product. Melting point 199-201 ° C (chloroform-
Recrystallization from ethyl acetate) Example 4 11- [4- [4- (2-pyridyl) -1-piperazinyl] butyrylamino] -6,11-dihydrodibenzo [b, e] oxepin 1/4 hydrate Preparation: 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] oxepin 2.0 g, 1- (2-pyridyl) piperazine 2.8 g, sodium iodide 4.8
g and 30 ml of dimethylformamide are stirred at 60 ° C. for 16 hours. After cooling, the reaction solution was treated as in Example 1,
The residue is subjected to silica gel column chromatography, the portions eluted with ethyl acetate are collected, the solvent is evaporated, and the residue is recrystallized from ethyl acetate-diethyl ether to obtain 1.3 g of the desired product. Melting point 141-143 ° C Example 5 11- [4- (4-Cinnamyl-1-piperazinyl) butyrylamino] -2-methyl-6,11-dihydrodibenzo [b, e] thiepin-5,5-dioxide dimaleic acid Preparation of salt / hemihydrate: 11- (4-chlorobutyrylamino) -2-methyl-6
11-dihydrodibenzo [b, e] thiepine-5,5-dioxide 2.5 g, 1-cinnamylpiperazine 1.5
g, 1.0 g of sodium iodide and 20 ml of dimethylformamide are stirred at 100 ° C. for 1 hour. 10% after cooling
Aqueous potassium carbonate solution is added and extracted with chloroform. The extract is washed with water and then with saturated saline, and then dried over magnesium sulfate. The solvent is distilled off, the residue is subjected to silica gel column chromatography, and the portion eluted with chloroform-methanol (100: 5) is collected. After distilling off the solvent, the residue is converted into a maleate salt by a conventional method and recrystallized from ethanol to obtain 2.0 g of the desired product. Melting point
174 to 176 ° C Example 6 11- [4- (4-Cinnamyl-1-piperazinyl) butyrylamino] -6,11-dihydrodibenzo [b, e] thiepin-5,5-dioxide dimaleate.1 / 2
Manufacture of hydrate: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Example 5 to obtain the desired product. Melting point 175 to 176 ° C. (recrystallized from ethanol) Example 7 trans-11- [4- [4- (2-pyridyl) -1-piperazinyl] butyrylamino] -6,6a, 7,8,9,
Preparation of 10,10a, 11-octahydrodibenzo [b, e] thiepine: trans-11- (4-chlorobutyrylamino) -6,6
a, 7,8,9,10,10a, 11-octahydrodibenzo [b, e] thiepine 3.0 g, 1- (2-pyridyl) piperazine 3.2 g and xylene 50 ml on a oil bath.
Heat at reflux for 16 hours at 0 ° C. After cooling, it is washed with a 10% aqueous potassium carbonate solution and then with water, and then dried over magnesium sulfate. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-toluene (1: 1) to obtain 1.8 g of the desired product as an oil.

Mass spectrum m / z: 464 (M ⁺ ) Example 8 Preparation of 5- [4- [4- (2-pyridyl) -1-piperazinyl] butyrylamino] -5H-dibenzo [a, d] cycloheptene: 5- A mixture of 2.4 g of amino-5H-dibenzo [a, d] cycloheptene, 2.9 g of 4- [4- (2-pyridyl) -1-piperazinyl] butyric acid, 2.3 g of dicyclohexylcarbodiimide and 50 ml of methylene chloride was prepared at room temperature. Stir for hours. The precipitate is filtered off, the filtrate is concentrated under reduced pressure, and the residue is recrystallized from chloroform-diethyl ether to obtain 2.0 g of the desired product. Melting point 171 to 173 [deg.] C. Examples 9 to 52 Using the corresponding starting compounds, reaction and treatment are carried out in the same manner as in Examples 1 to 8 to obtain the compounds shown in Tables 2 to 5.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07D 295/08 A 295/14 A 307/68 311/88 7252-4C 313/12 7252-4C 335 / 18 337/12 401/12 213 8829-4C 215 8829-4C 239 8829-4C 405/12 213 8829-4C 215 8829-4C 239 8829-4C 407/12 307 8829-4C 409/12 213 8829-4C 215 8829-4C 239 8829-4C 307 8829-4C 333 8829-4C 417/12 213 9051-4C 215 9051-4C 239 9051-4C // A61K 31/335 ADD 9360-4C 31/34 ABM 9360-4C 31/35 ABS 9360-4C 31/38 ABF 9360-4C 31/425 9360-4C 31/435 ABU 9360-4C 31/44 ACD 9360-4C 31/47 9360-4C 31/505 9360-4C 31/55 9360-4C 31 / 645 9360-4C

Claims (1)

[Claims] 1. A general formula [Wherein R ₁ is And A represents a benzene ring or a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together form a single bond, -O-,
_{-S-, -CH = CH -, -} CH 2 CH 2 -, - CH 2 O- or R ₂ represents a hydrogen atom, a lower alkyl group or a lower alkoxy group, and R ₃ represents a phenyl (lower) alkyl group, a phenyl (lower) alkenyl group or a diphenylmethyl group in which an alkyl moiety is substituted with hydroxy. A naphthyl group, an aromatic heterocyclic group optionally substituted with lower alkyl or lower alkoxycarbonyl, a benzoyl (lower) alkyl group, an aroyl group, a phenyloxycarbonyl group, a phenyloxysulfonyl group or a phenylsulfonyl group, R ₄ and R ₅ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a lower alkylthio group or a cyano group, and W represents a carbonyl group or a sulfonyl group, X means an alkylene group, a means 2 or 3, and b Means an integer of 0 to 2. However, the phenyl moiety and naphthyl group in the above definition may be optionally substituted with a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a trifluoromethyl group or a lower alkoxy group, and the A ring is In the case of a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together And R ₄ represents a hydrogen atom. ] The 1,4-diaza cycloalkane derivative and its salt represented by these.