JP2544123B2 - Amine compound - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel and useful amine compound 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.

According to the present invention, the general formula (I) [Where 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 -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 hydrogen atom, a lower alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or 1 to 2 substituents. A cycloalkyl group having a group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a lower alkylthio group, an acyloxy group, an acylthio group, a disubstituted amino group, an acylamino group, a carboxy group, Lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, oxo group or acetalized or ketalized oxo group), saturated heterocyclic group, 1
~ A saturated heterocyclic group having 2 substituents (the substituents are a halogen atom, a hydroxy group, a nitro group, a lower alkyl group,
Lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or dilower alkylcarbamoyl group. Group), an aryl group, an aryl group having 1 to 4 substituents (the substituent is a halogen atom, a hydroxy group, a nitro group,
Lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group,
A carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a dilower alkylcarbamoyl group, and when two substituents are adjacent to each other, they may be combined to form an alkylenedioxy group) , A cycloalkenyl group condensed with an aryl group (the aryl part and / or the cycloalkenyl part may be substituted), a heteroaryl group, a heteroaryl group having 1 to 3 substituents (the substituent is a halogen atom,
Hydroxy group, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group , A lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group), a lower alkyl group having a substituent (the substituent is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkylthio group,
Oxo group, acetalized or ketalized oxo group, disubstituted amino group, acylamino group, acyloxy group, acylthio group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, dilower alkylcarbamoyl group, cyclo An alkyl group, a cycloalkyl group having 1 to 2 substituents, a saturated heterocyclic group, a saturated heterocyclic group having 1 to 2 substituents, an aryl group, an aryl group having 1 to 4 substituents, A heteroaryl group or a heteroaryl group having 1 to 3 substituents), a substituted alkenyl group or an alkynyl group (wherein the substituents are halogen atoms, hydroxy groups, lower alkoxy groups, lower alkylthio groups, acyloxy groups) Or an acylthio group), an acyl group, a lower alkoxycarbonyl group, carbamo Group, means a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group, R ₄ is an aryl group, an aryl group (said substituent is a halogen atom having 1 to 4 substituents, a hydroxy group, a nitro group,
Lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, A lower alkylcarbamoyl group or a dilower alkylcarbamoyl group, and when two substituents are adjacent to each other, they may be combined to form an alkylenedioxy group), a heteroaryl group or 1 to
Heteroaryl group having 3 substituents (the substituents are halogen atom, hydroxy group, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, amino group, lower alkylamino group, disubstituted amino group, acylamino Group, a cyano group, a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group), and R ₅ is the same or different and is a hydrogen atom, a halogen atom, a hydroxy group or a nitro group. Group, lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group,
A lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group, wherein R ₆ is the same or different and is a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a trifluoromethyl group, Lower alkoxy group, lower alkylthio group, acyloxy group or cyano group is meant, V is carbonyl group or sulfonyl group, W is alkylene group, X is a single bond, lower alkylene group, lower alkoxycarbonyl, carbamoyl , Lower alkylcarbamoyl, di-lower alkylcarbamoyl or (Wherein, R ₇ represents a hydrogen atom, a lower alkyl group or an acyl group, and d represents 1 or 2), or a lower alkylene group substituted by -CO- (in a ketalized form, may also be), - O -, - S -, - NR 8 - ( wherein, R ₈ represents a lower alkyl group or an acyl group), (In the formula, R ₇ means the same as above), -CH = CH-
And a lower alkylene group interrupted by a group selected from —C≡C— or bonded to R ₄ via these groups, a and b each represent an integer of 1 to 4, and c Is 0
It means an integer of 2.

However, when the A ring is a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together form a ring. And R ₆ represents a hydrogen atom. ] The amine compound and its salt represented by these are provided.

The salt of the compound represented by the formula (I) means a salt of the compound having the amino group or the substituted amino group in the formula (I). As the salts, physiologically acceptable salts are preferable, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and oxalate,
Organic acid salts such as maleate, fumarate, lactate, malate, citrate, tartrate, benzoate and methanesulfonate are listed. 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 compound 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 alkyl moiety, alkyl group, alkyl moiety, lower alkylene group or alkylene group may be linear or branched. "Lower alkyl group" means
"Alkyl group" having 1 to 6 carbon atoms means an alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl,
Examples include propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, 2-methylbutyl, 2,2-dimethylpropyl, hexyl, 2-ethylbutyl, heptyl, octyl, decyl and the like. The "lower alkoxy group" means one having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy and the like. The “alkenyl group” means an acyclic or cyclic group having 1 to 2 double bonds and having 3 to 10 carbon atoms, and includes, for example, allyl, 2-butenyl, 3-methyl-2-butenyl, 3- or 4-pentenyl, 2-, 3-, 4- or 5-hexenyl, cyclopentenyl, cyclohexenyl, cyclopentenylmethyl, cyclohexenylmethyl, 2,4-pentadienyl and the like can be mentioned. The "alkynyl group" means one having 3 to 10 carbon atoms, and examples thereof include 2-propynyl, 3-butynyl, 5-hexynyl and the like. "Cycloalkyl group" means one having 3 to 12 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples thereof include cycloheptyl, cyclooctyl, cyclododecyl, adamantyl, norbornyl, decahydronaphthyl and the like. The “halogen atom” means fluorine, chlorine, bromine, iodine, but fluorine, chlorine, bromine are preferable. The "acyl group" means an aliphatic carboxylic acid residue or an aromatic carboxylic acid residue having 1 to 7 carbon atoms, and includes, for example, formyl, acetyl, 2-methylacetyl, propionyl, butyryl, isobutyryl, benzoyl, naphthoyl. Etc. The “di-substituted amino group” means a di-lower alkylamino group or a cyclic amino group, and specific examples of the cyclic amino group include morpholino, 1-pyrrolidinyl, piperidino, 4-methyl-1-piperazinyl and the like.
Examples of the “aryl group” include phenyl, naphthyl and the like. "Heteroaryl group" means a nitrogen atom,
It means a monocyclic or bicyclic one containing at least one oxygen atom or sulfur atom, and examples thereof include furyl, thienyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, pyridyl, indolyl, isoquinolyl and the like. The “lower alkyl group having a substituent” means one having 1 to 2 of the above-mentioned substituents at any position, but the substituent is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkylthio group, When it is an oxo group, an acetalized or ketalized oxo group, an acyloxy group or an acylthio group, these substituents are bonded to a carbon atom other than the 1-position. The “saturated heterocyclic group” means a group derived from a cyclic ether, a cyclic thioether or a cyclic amine containing 1 to 2 nitrogen atoms, oxygen atoms or sulfur atoms, and examples thereof include tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, 1,3-or 1,4-
Dioxacyclohexyl, 2- or 3-pyrrolidinyl, 2-, 3- or 4-piperidinyl, 2- or 3-
Examples thereof include morpholinyl, 2- or 3-piperazinyl, and the nitrogen atom in the group derived from a cyclic amine may have a substituent such as a lower alkyl group, an aralkyl group, an acyl group or a lower alkoxycarbonyl group. Good. When R ₃ is a saturated heterocyclic group containing an oxygen atom or a sulfur atom, R ₃ is bonded to the nitrogen atom at a position other than the carbon atom adjacent to the oxygen atom or the sulfur atom. The "lower alkylene group" means one having 1 to 6 carbon atoms, and the "alkylene group" means one having 1 to 12 carbon atoms, for example, methylene, ethylene, methylmethylene, trimethylene, tetramethylene, pentamethylene. , Hexamethylene, heptamethylene, octamethylene, nonamethylene,
Examples include decamethylene and the like.

Suitable Among the compounds of the present invention, Y and Z in formula (I) together -S-, CH = CH -, - CH 2 CH
₂ −, And R ₂ is a hydrogen atom, one of R ₅ and R ₆ is a hydrogen atom, the other is a hydrogen atom, and the other is a hydrogen atom, a halogen atom, a hydroxy group, a lower alkyl group, a lower alkoxy group or a lower atom. an alkylthio group, V is a carbonyl group, W is - (CH ₂₎ n- and, n is an integer from 1 to 5, a and b are each 1 or 2, c is 0 to 2 integer A compound and its physiologically acceptable salts.

The compound of the present invention can be produced, for example, by the following method.

Method (a): (In the formula, R ₁ , R ₂ , V and W mean the same as above, and T
Means a reactive ester residue of alcohol. ) And a compound represented by the general formula (III) (In the formula, R ₄ means the same as the above, X ′ means the same as the above X other than a single bond, and R ₃ ′ means the same as the above R ₃ , but is unsubstituted. Or a substituted aryl group,
Except when it is an unsubstituted or substituted heteroaryl group, an acyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group. ) By reacting with a compound represented by
R ₃ is a group other than an unsubstituted or substituted aryl group, an unsubstituted or substituted heteroaryl group, an acyl group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group, and X is a single bond A compound that is a group other than can be obtained.

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

The reaction between the compound of formula (II) and the compound of formula (III) is
It 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, ketones such as methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, Examples thereof include alcohols such as ethanol and isopropyl alcohol, acetonitrile, dimethylformamide and the like. 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 sodium bicarbonate,
Examples thereof include alkali bicarbonates such as potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, and organic bases such as triethylamine and N-methylmorpholine, but an excess amount of the compound of the formula (III) may also serve. it can. When a compound in which T 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. The reaction temperature is usually about 0 ° C to about 20.
It is 0 ° C, preferably about 40 ° C to about 150 ° C. When a reactive amino group is present in R ₃ or R ₄ of the compound of formula (III), it is desirable that these groups be protected according to a conventional method and then eliminated after the reaction.

Method (b): (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 , R ₄ , W and X have the same meanings as described above.) By reacting with a compound represented by or a reactive derivative thereof, V in the formula (I) is a carbonyl group. Certain compounds can be obtained.

Examples of the reactive derivative of the compound of the formula (V) include active ester, acid anhydride, acid halide (especially acid chloride).
Can be mentioned. 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 can be mentioned. As the acid anhydride, a symmetrical acid anhydride or a mixed acid anhydride is used, and specific examples of the mixed acid anhydride include a mixed acid anhydride with a chloroformic acid alkyl ester such as ethyl chloroformate and isobutyl chloroformate, a chlorine acid. Examples thereof include mixed acid anhydrides with chloroformate aryl esters such as acid phenyl, mixed acid anhydrides with alkanoic acids such as isovaleric acid and pivalic acid.

When the compound of formula (V) is used, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1,2
It can be reacted in the presence of a condensing agent such as 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 the case requires, 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 from about -20 ° C to about 15
It is 0 ° C, preferably about 0 ° C to about 80 ° C. R ₁ of the compound of formula (IV) or R ₃ of the compound of formula (V) or
When a reactive amino group or carboxy group is present in R ₄ , these groups are preferably protected according to a conventional method and eliminated after the reaction.

When the product obtained by the production methods (a) and (b) has a hydroxy group, an amino group or a mono-substituted amino group in its structure, it can be converted into an acyl derivative by acylation according to a conventional method. it can.

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

The compound having an amino group or a substituted amino group in the formula (I) is obtained in the form of a free base or a salt, depending on the selection of the starting compound, reaction / treatment conditions and the like. The salts can be converted to the free bases by conventional methods, for example by treatment with a base such as alkali carbonate. On the other hand, the free base can be converted to a salt by treating it with various acids according to the usual method.

The compound of formula (I) and physiologically acceptable salts thereof have excellent calcium antagonistic activity, and thus are useful for the prevention and treatment of hypertension and / or ischemic cardiovascular disorder.

Below, the results of the pharmacological tests on the representative compounds of the present invention and on the commercially available calcium antagonist diltiazem hydrochloride are shown to explain the pharmacological action of the compounds of the present invention.

Test example Calcium antagonism This test is based on the method of Godfraind and Kaba [Br.J.Pharmac., 3
6 , 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. Vent a mixed gas of 95% O ₂ + 5% CO ₂ and suspend the sample in a Magnus tank containing 10 ml of Krebs bicarbonate solution kept at 37 ℃
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
Not high K⁺Replace with Krebs bicarbonate solution and remove
After inducing the pole, CaCl₂Is added cumulatively, and Ca To
A dose-contraction curve was determined by Then in the presence of the test compound
Perform a similar experiment and To obtain the dose-contraction curve according to
Van Rossum's method [Arch.int.Pharmacodyn.,143, 299 ~ 3
30 (1963)] and the calcium antagonistic pA₂Calculate
did. Note that pA₂And Ca Dose-contraction curve (test
(In the absence of the test compound) is translated by 2 times to the high concentration side.
Defined as the inverse logarithm of the molar concentration of the test compound required to
It is a numerical value.

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

As is apparent from Table 1, most of the compounds of the present invention tested exhibited a much stronger calcium antagonism than diltiazem hydrochloride.

Test Example 2 Antihypertensive Action in Spontaneously Hypertensive Rats (SHR) For experiments, 18-26 week-old male SHRs self-reproduced at Dainippon Pharmaceutical Co., Ltd. Research Institute [Okamoto-Aoki strain; Jap.Ci.
rcul.J., 27 , 282-293 (1963)] was used. Most animals had a mean blood pressure of 150-170 mmHg. Weeks and Jon
es method [Proc.Soc.Exp.Biol.Med., 104 , 646-648 (196
0)], a cannula (polyethylene tube manufactured by Clay Adams, PE-50, manufactured by US Clay Adams) in the abdominal aorta of rat
Embedded. The other end of the cannula was exposed and fixed on the back of the neck. One to four days later, the cannula was connected to a pressure transducer (manufactured by Nihon Kohden, MP-4T type), and blood pressure at awakening was measured by a direct method. On the day of the experiment, the blood pressure before administration was measured for 1 hour, and then the test compound suspended in a 0.5% tragacanth aqueous solution was orally administered (3.0 ml / kg), and the blood pressure was continuously measured for 5 hours thereafter. In addition, 2 to 5 animals per group were used.

Table 2 shows the maximum blood pressure reduction of the test compounds at the mean blood pressure. Most of the compounds of the present invention showed the maximum antihypertensive effect 30 to 60 minutes after administration.

As is clear from Table 2, all the compounds of the present invention
Oral administration of 10 to 30 mg / kg showed a clear antihypertensive effect. In contrast, diltiazem hydrochloride did not show a significant antihypertensive effect at 30 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 0.001 to 20 mg / kg / day, though it varies depending on the kind of compound, administration method, patient's symptoms, age and the like. The compound of the formula (I) or a salt thereof is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a substance which is commonly used in the pharmaceutical field and which does not react with the compound of formula (I) or a salt thereof is used. Specifically, for example, lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl cellulose calcium, ion exchange Resin, methyl cellulose, gelatin, gum arabic, pullulan, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth,
Bentonite, veegum, carboxyvinyl polymer,
Examples thereof include titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, cacao butter, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, water and the like. The dosage forms include tablets, capsules, granules, fine granules, powders, syrups, suspensions,
Examples include injections and suppositories. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. The tablets, granules and fine granules may be coated by a known method.

These preparations may contain the compound of formula (I) or a physiologically acceptable salt thereof in a proportion of 0.5% or more, preferably 1 to 70%. These formulations may also contain other therapeutically valuable ingredients.

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. In addition, the identification of the compound is the elemental analysis value,
Mass spectrum, IR spectrum, NMR spectrum, etc. were used.

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

Me: Methyl group Et: Ethyl group Ph: Phenyl group Ac: Acetyl group c-C _m H _2m-1 : m-membered cycloalkyl group A: Ethanol AE: Ethyl acetate CH: Chloroform E: Diethyl ether H: Hexane T : Toluene Reference Example 1 Production of 11- (5-chlorovalerylamino) -6,11-dihydrodibenzo [b, e] thiepine: 8.8 g of 11-amino-6,11-dihydrodibenzo [b, e] thiepine 5-chlorovaleric acid chloride 6.0 g and dioxane 10
0 ml of the mixture is heated to reflux with stirring for 15 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol to give the desired product 1
Get 2.5.

Melting point 155 to 156 ° C Reference Examples 2 to 27 Reactions were performed in the same manner as in Reference Example 1 using the corresponding starting compounds.
Treatment gives the compounds shown in Tables 3-5.

Reference Example 28 Preparation of 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] thiepine-5,5-dioxide: 11- (4-chlorobutyrylamino) -6,11- 5.0 g of dihydrodibenzo [b, e] thiepine was dissolved in 100 ml of chloroform, and 12 g of m-chloroperbenzoic acid was added thereto under ice cooling, followed by stirring at 0 ° C. for 1 hour. The reaction mixture is washed successively with 10% sodium hydroxide, water and saturated brine, and dried over magnesium sulfate. The solvent is distilled off, and the residue is recrystallized from methanol to obtain 5.1 g of the desired product. Melting point 215 to 227 ° C Reference Example 29 Preparation of 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] thiepin-5-oxide: 11- (4-chlorobutyrylamino) -6 10 g of 11,11-dihydrodibenzo [b, e] thiepine was dissolved in 500 ml of methylene chloride, 7.0 g of m-chloroperbenzoic acid was added thereto under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture is washed successively with 10% sodium hydroxide, water and saturated brine, and dried over magnesium sulfate. Methylene chloride was distilled off, and the residue was recrystallized from chloroform-hexane to obtain 8.0 g of the desired product.

Melting point 210-212 ° C Reference example 30 trans-11- (4-chlorobutyrylamino) -6,6a,
Production of 7,8,9,10,10a, 11-octahydrodibenzo [b, e] thiepine: (1) trans-6,6a, 7,8,9,10,10a, 11-octahydro-11-oxo After a mixture of 6 g of dibenzo [b, e] thiepine and 40 g of ammonium formate was melted and stirred at 220 for 2 hours,
Add 40 g ammonium formate and stir at 220 for an additional 2 hours. After cooling, water is added to the reaction mixture, and the oily substance that precipitates is extracted with toluene. The extract was washed with water, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with chloroform to give trans-11-formylamino-6,6a, 7,8,9,10,10a, 11-octa. 5 g of hydrodibenzo [b, e] thiepine are obtained as an oil.

(2) 5 g of the above 11-formylamino compound, 40 ml of ethanol
And a mixture of 20 ml of concentrated hydrochloric acid is heated to reflux at 100 ° C. for 30 minutes. The reaction solution is concentrated under reduced pressure, 10% potassium carbonate is added to the residue, and the precipitated oily matter is extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to give trans-11-amino-6,6a, 7,8,9,10,10a, 11-octahydrodibenzo [b, e] thiepine 4g. 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- (N-benzyl-N-cyclopropylamino) butyrylamino] diphenylmethane: (4-chlorobutyrylamino) diphenylmethane 2.0
A mixture of 4.0 g of g, N-benzyl-N-cyclopropylamine and 500 ml of xylene is heated to reflux with stirring for 6 hours.
To the reaction mixture was added 100 ml of toluene, 10% potassium carbonate,
After washing with water and saturated saline solution in that order, it is dried over magnesium sulfate. The solvent was evaporated, the residue was subjected to silica gel column chromatography, and the target compound was eluted with chloroform.
Get 1.5g. Melting point 107-109 ° C. (recrystallized from diethyl ether) Example 2 Preparation of [4- (N-benzyl-N-cyclopropylamino) butyrylamino] cyclohexylphenylmethane: (4-chlorobutyrylamino) cyclohexylphenylmethane 1.5 g , N-benzyl-N-cyclopropylamine
2.0g, sodium iodide 5g and dimethylformamide 15m
The mixture of 1 is stirred at 60 ° C. for 16 hours. After cooling, add 10
Add% potassium carbonate and extract with chloroform. The extract is washed successively with water and saturated brine and dried over magnesium sulfate. Chloroform is distilled off, and the residue is subjected to silica gel column chromatography and eluted with chloroform to obtain 1.2 g of the desired product.

Melting point 85-87 ° C (recrystallized from diethyl ether-hexane) Example 3 Preparation of 5- [5- (N-benzyl-N-butylamino) valerylamino] -5H-dibenzo [a, d] cycloheptene: 5- ( A mixture of 1.5 g of 5-chlorovalerylamino) -5H-dibenzo [a, b] cycloheptene, 1.5 g of N-benzyl-N-butylamine, 2.0 g of sodium iodide and 50 ml of dimethylformamide is stirred at 100 ° C. for 1.5 hours. The reaction mixture is treated in the same manner as in Example 2 to obtain 1.1 g of the desired product as an oil.

1.0 g of the above free base and 0.4 g of oxalic acid are dissolved in 5 ml of ethanol. This ethanol solution was added dropwise to 200 ml of diethyl ether with stirring, and the resulting precipitate was collected by filtration to obtain 1.0 g of the desired product, oxalate / 3/4 hydrate. Melting point 98-101 ° C Example 4 11- [4- [N-benzyl-N- (2-hydroxy-2
Preparation of -methylpropyl) amino] butyrylamino] -2-methyl-6,11-dihydrodibenzo [b, e] thiepine: 11- (4-chlorobutyrylamino) -2-methyl-6,
A mixture of 1.0 g of 11-dihydrodibenzo [b, e] thiepine, 1.0 g of N-benzyl-N- (2-hydroxy-2-methylpropyl) amine, 3.0 g of sodium iodide and 20 ml of dimethylformamide at 60 ° C. for 18 hours. Stir. The reaction mixture is treated in the same manner as in Example 2 to obtain 0.7 g of the desired product as an oil.

The above free base is treated in the same manner as in Example 3 to obtain the objective oxalate monohydrate. Melting point 87-90 ° C (reprecipitation from ethanol-diethyl ether) Example 5 11- [4- [N-benzyl-N- (2-hydroxybutyl) amino] butyrylamino] -6,11-dihydrodibenzo [b, e ] Thiepin production: 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] thiepine 2.0 g, N-benzyl-N- (2
-Hydroxybutyl) amine 2.0 g, sodium iodide 4.0
A mixture of g and 30 ml of dimethylformamide is stirred at 60 ° C. for 16 hours. The reaction mixture is treated in the same manner as in Example 2 to obtain 1.3 g of the desired product as an oil.

The above free base is treated in the same manner as in Example 3 to obtain the target oxalate salt 3/4 hydrate.

Melting point 90-92 ° C (reprecipitation from ethanol-diethyl ether) Example 6 11- [4- [N-benzyl-N-butylamino) butyrylamino] -6,11-dihydrodibenzo [b, e] thiepin-5, Preparation of 5-dioxide: 11- (4-chlorobutyrylamino) -6,11-dihydrodibenzo [b, e] thiepine-5,5-dioxide 2.0 g, N-benzyl-N-butylamine 2.0 g, iodide 3.0 g sodium
And a mixture of 15 ml of dimethylformamide are stirred at 60 ° C. for 20 hours. The reaction mixture was treated in the same manner as in Example 2 to give the desired product.
35 g are obtained as an oil. Mass spectrum m / z: 490
(M ⁺ ) Example 7 trans-11- [4- (N-benzyl-N-cyclopropylamino) butyrylamino] -6,6a, 7,8,9,10,10a, 11
-Preparation of octahydrodibenzo [b, e] thiepine: trans-11- (4-chlorobutyrylamino) -6,6
a, 7,8,9,10,10a, 11-octahydrodibenzo [b, e] thiepine 1.0 g, N-benzyl-N-cyclopropylamine 1.0 g
A mixture of and 50 ml of xylene is heated at reflux at 150 ° C. for 16 hours. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol (10
Elution at 0: 3) gave 0.6 g of the desired product as an oil. Mass spectrum m / z: 448 (M ⁺ ) The above free base is treated in the same manner as in Example 3 to obtain the target oxalate 5/4 hydrate. Melting point 88-90 ° C (reprecipitation from ethanol-diethyl ether) Example 8 11- [4- [N-benzyl-N- (2-tetrahydropyranylmethyl) amino] butyrylamino] -6,11-dihydrodibenzo [b] , e] Thiepin production: 4- [N-benzyl-N- (2-tetrahydropyranylmethyl) amino] butyric acid 2.0 g, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 2.2 g and dimethyl 11-amino-6,11 was added to a mixture of 20 ml of formamide.
Add 1.8 g of dihydrodibenzo [b, e] thiepine and stir at room temperature for 3 hours. The reaction solution is poured into water and extracted with toluene. The extract solution is washed with water and dried over magnesium sulfate. Toluene was distilled off, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain the desired product 2.
2 g are obtained as an oil.

The above free base is treated in the same manner as in Example 3 to obtain the target oxalate.3 / 2 hydrate. Melting point 90-93 ° C (reprecipitation from ethanol-diethyl ether) Example 9 11- [4- [N-benzyl-N-cyclopropylamino) butyrylamino] -N-methyl-6,11-dihydrodibenzo [b, e Preparation of thiepine: A mixture of 1.5 g of 4- (N-benzyl-N-cyclopropylamino) butyric acid, 1.5 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 30 ml of chloroform at 0 ° C. Stir for hours. To this was added 1.5 g of 11-methylamino-6,11-dihydrodibenzo [b, e] thiepine and the mixture was stirred at room temperature for 3 hours. The reaction solution is washed with water and then dried over magnesium sulfate. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with chloroform to obtain 2.0 g of the desired product as an oil. Mass spectrum m / z: 456 (M ⁺ ) Example 10 Preparation of 5- [4- (N, N-dibenzylamino) butyrylamino] -5H-dibenzo [a, d] cycloheptene: 4- (N, N A mixture of 1.0 g of dibenzylamino) butyric acid, 1 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 20 ml of chloroform is stirred at 0 ° C. for 1 hour. To this, 1.0 g of 5-amino-5H-dibenzo [a, d] cycloheptene was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution is washed with water and then dried over magnesium sulfate. The solvent is distilled off, and the residue is subjected to silica gel column chromatography and eluted with chloroform to obtain 1.2 g of the desired product. Melting point 13
9-140 ° C. (recrystallized from chloroform-hexane) Example 11 11- [4- [N-benzyl-N- (2-acetoxybutyl) amino] butyrylamino] -6,11-dihydrodibenzo [b, e] thiepine Preparation of 11- [4- [N-benzyl-N- (2-hydroxybutyl) amino] butyrylamino] -6,11-dihydrodibenzo [b, e] thiepine 1.0 g in pyridine 10 ml solution 0.5 g acetic anhydride. In addition, leave at room temperature overnight. The reaction solution is poured into water and extracted with toluene. The extract is washed with water and dried over magnesium sulfate, and the solvent is distilled off to obtain 0.9 g of the desired product as an oil.

The above free base is treated in the same manner as in Example 3 to obtain the target oxalate monohydrate. Melting point 81-84 ° C (reprecipitation from ethanol-diethyl ether) Examples 12-380 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Examples 1-11 to obtain the compounds shown in Tables 6-15.

Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 243/24 C07C 243/24 255/47 255/47 255/55 255/55 255/58 255/58 255 / 60 255/60 273/10 273/10 275/04 275/04 323/25 323/25 323/30 323/30 323/32 323/32 323/36 323/36 323/38 323/38 327/20 327 / 20 C07D 219/10 C07D 219/10 307/14 307/14 307/52 307/52 309/14 309/14 311/88 311/88 313/12 313/12 335/18 335/18 337/12 337 / 12 409/12 207 409/12 207 213 213 307 307 309 309 309 337 337 // A61K 31/135 ADD A61K 31/135 ADD 31/165 ABU 31/165 ABU 31/195 ABR 31/195 ABR 31/275 ABS 31/275 ABS 31/33 31/33 31/435 31/435 (72) Inventor Kunihiko Takeyama 112 Koyodai, Ikoma-shi, Nara

Claims (1)

(57) [Claims] 1. [Where R ₁ is The ring A means a benzene ring or a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z
There together, -O -, - S -, - CH = CH -, - CH 2 C
H 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 hydrogen atom, a lower alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, or 1 to 2 substituents. A cycloalkyl group having a group (the substituent is a halogen atom, a hydroxy group, a lower alkyl group, a cycloalkyl group, a lower alkoxy group, a lower alkylthio group, an acyloxy group, an acylthio group, a disubstituted amino group, an acylamino group, a carboxy group, Lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylcarbamoyl group, oxo group or acetalized or ketalized oxo group), saturated heterocyclic group, 1
~ A saturated heterocyclic group having 2 substituents (the substituents are a halogen atom, a hydroxy group, a nitro group, a lower alkyl group,
Lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group or dilower alkylcarbamoyl group. Group), an aryl group, an aryl group having 1 to 4 substituents (the substituent is a halogen atom, a hydroxy group, a nitro group,
Lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group,
A carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a dilower alkylcarbamoyl group, and when two substituents are adjacent to each other, they may be combined to form an alkylenedioxy group) , A cycloalkenyl group condensed with an aryl group (the aryl part and / or the cycloalkenyl part may be substituted), a heteroaryl group, a heteroaryl group having 1 to 3 substituents (the substituent is a halogen atom,
Hydroxy group, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group , A lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group), a lower alkyl group having a substituent (the substituent is a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkylthio group,
Oxo group, acetalized or ketalized oxo group, disubstituted amino group, acylamino group, acyloxy group, acylthio group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl group, dilower alkylcarbamoyl group, cyclo An alkyl group, a cycloalkyl group having 1 to 2 substituents, a saturated heterocyclic group, a saturated heterocyclic group having 1 to 2 substituents, an aryl group, an aryl group having 1 to 4 substituents, A heteroaryl group or a heteroaryl group having 1 to 3 substituents), a substituted alkenyl group or an alkynyl group (wherein the substituents are halogen atoms, hydroxy groups, lower alkoxy groups, lower alkylthio groups, acyloxy groups) Or an acylthio group), an acyl group, a lower alkoxycarbonyl group, carbamo Group, means a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group, R ₄ is an aryl group, an aryl group (said substituent is a halogen atom having 1 to 4 substituents, a hydroxy group, a nitro group,
Lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, A lower alkylcarbamoyl group or a dilower alkylcarbamoyl group, and when two substituents are adjacent to each other, they may be combined to form an alkylenedioxy group), a heteroaryl group or 1 to
Heteroaryl group having 3 substituents (the substituents are halogen atom, hydroxy group, nitro group, lower alkyl group, lower alkoxy group, lower alkylthio group, amino group, lower alkylamino group, disubstituted amino group, acylamino Group, a cyano group, a carboxy group, a lower alkoxycarbonyl group, a carbamoyl group, a lower alkylcarbamoyl group or a di-lower alkylcarbamoyl group), and R ₅ is the same or different and is a hydrogen atom, a halogen atom, a hydroxy group or a nitro group. Group, lower alkyl group, trifluoromethyl group, lower alkoxy group, lower alkylthio group, acyloxy group, amino group, lower alkylamino group, disubstituted amino group, acylamino group, cyano group, carboxy group, lower alkoxycarbonyl group, carbamoyl Group, lower alkylcarbamoyl group Or a di-lower alkylcarbamoyl group, wherein R ₆ is the same or different and is a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a lower alkylthio group, an acyloxy group or a cyano group. Group means V means carbonyl group or sulfonyl group, W means alkylene group, X means single bond, lower alkylene group, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, di-lower alkylcarbamoyl or (Wherein, R ₇ represents a hydrogen atom, a lower alkyl group or an acyl group, and d represents 1 or 2), or a lower alkylene group substituted by -CO- (in a ketalized form, may also be), - O -, - S -, - NR 8 - ( wherein, R ₈ represents a lower alkyl group or an acyl group), (In the formula, R ₇ means the same as above), -CH = CH-
And a lower alkylene group interrupted by a group selected from —C≡C— or bonded to R ₄ via these groups, a and b each represent an integer of 1 to 4, and c Is 0-2
Means an integer of. However, when the A ring is a cyclohexane ring, Y and Z both represent a hydrogen atom, or Y and Z together form a ring. And R ₆ represents a hydrogen atom. ] The amine compound and its salt represented by these.