JPH09169743A - Hexahydro-1h-1,4-diazepine derivative, its production and medicine thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a new hexahydro-1H-diazepine derivative, having excellent antiarrhythmic actions, especially class III type antiarrhythmic actions and useful as a preventing and therapeutic agent for various cardiopathies, especially arrhythmia such as atrial fibrillation. SOLUTION: This compound of formula I (R<1> is H, amino, etc.; R<2> is OH, a halogen, etc.; R<3> is H, an alkyl, etc.) or its salt, e.g. 1-acetyl-6-hydroxy-4-[(4- nitrophenyl)sulfonyl]hexahydro-1H-1,4-diazepine. The compound is obtained by initially reacting a compound of the formula R<3a> -Hal (R<3a> is H, an acyl, etc.; Hal is a halogen) with a 6-acyloxyhexahydro-1H-1,4-diazepine of formula II (R is an alkyl, an aryl, etc.), as necessary, in the presence of a base as a dehydrohalogenating agent, then hydrolyzing the resultant product in a 10% aqueous solution of hydrochloric acid and subsequently reacting the prepared intermediate with a compound of formula III, as necessary, in the presence of a base.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel hexahydro-1H-1,4-diazepine derivative and a pharmacologically acceptable salt thereof, a method for producing the same and a pharmaceutical use thereof. More specifically, a novel hexahydro-1H-1,4-diazepine useful for treating various heart diseases, particularly arrhythmia (for example, atrial fibrillation, ventricular fibrillation, etc.) and thereby preventing sudden death. The present invention relates to a derivative and a pharmacologically acceptable salt thereof, a method for producing the derivative, and a pharmaceutical use thereof.

[0002]

[Prior Art and Problems to be Solved by the Invention] Antiarrhythmic drugs include Vaughan Williams
According to the mechanism of action class I, II, III and
Classified as type IV. Currently the most widely prescribed antiarrhythmic drugs are Class I. This type of drug is dominated by sodium channel inhibition and is further subdivided therein by its effect on action potential duration.
However, these class I antiarrhythmic drugs have no effect on ventricular arrhythmias that cause sudden death, and also report shortening of the life expectancy of patients who are considered to be due to their arrhythmogenic action or myocardial depressant action. And anxiety about this type of antiarrhythmic drug is increasing. On the other hand, a pure class III antiarrhythmic drug is considered not to cause a decrease in myocardial function or induction of arrhythmia due to inhibition of action potential transmission as seen in class I antiarrhythmic drugs. Many developments are in progress.
However, amiodarone, a class III antiarrhythmic drug currently on the market, is highly toxic and its use is significantly limited. In addition, the existing drug sotalol has a strong side effect of β-blocker action, and it cannot be said that it is a satisfactory class III antiarrhythmic drug.

Conventionally, a 6-amido-1,4-substituted hexahydro-1H-1,4-diazepine derivative has been disclosed in Japanese Patent Application Laid-Open No.
It is disclosed as a serotonin 3 receptor antagonist in Japanese Patent Publication No. 92959 and Japanese Patent Publication No. 6-55738. However, there is no report that it has a structure like the following compounds of the present invention and acts on heart diseases.

The object of the present invention is to provide a novel compound having excellent antiarrhythmic activity and the like, which is useful as a drug, a method for producing the same, and a pharmaceutical use thereof, particularly a class in which toxicity is remarkably reduced.
It is to provide a novel antiarrhythmic drug of type III.

[0005]

Means for Solving the Problems As a result of intensive studies by the present inventors in order to achieve the above object, the present invention has been accomplished. That is,
The present invention relates to a compound of the formula (I)

[0006]

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[In the formula, R ¹ represents a hydrogen atom, an amino group, a nitro group or —NHSO ₂ CH ₃ , R ² represents a hydroxyl group,
—OC (O) —R ⁴ (R ⁴ represents an alkyl group, an aryl group or a heteroaryl group, and the aryl group and the heteroaryl group have an alkyl group, an alkoxy group, a halogen atom, —NHSO ₂ CH ₃ , and a nitro group and may have a substituent group selected from amino group) or a halogen atom, R ³ is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, the formula (1), (2),
(3), (4) or (5)

[0008]

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(In the formula, R ⁵ represents an alkylene group, and R ⁶
Represents a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, —NHSO ₂ CH ₃ , a nitro group or an amino group, and R ⁷ represents a hydrogen atom or an alkyl group). ] Hexahydro-1H-1,4 represented by
-Diazepine derivative (hereinafter, also referred to as compound (I)) or a pharmaceutically acceptable salt thereof, and a method for producing the same.

The present invention further relates to a pharmaceutical composition containing the compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient. Further, the present invention relates to a preventive or therapeutic agent for heart disease, particularly an preventive or therapeutic agent for arrhythmia (eg, atrial fibrillation, ventricular fibrillation, etc.)

Each symbol used in the present invention will be described below. The alkylene group for R ⁵ preferably has 1 to 4 carbon atoms and may be linear or branched. For example, methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, t-butylene,
Examples thereof include methylmethylene, and more preferably methylene and ethylene.

Examples of the halogen atom in R ² , R ⁶ , R ^2b and Hal include fluorine, chlorine, bromine and iodine. Preferably, R ² and R ^2b are chlorine, R ⁶ is fluorine, and Hal is chlorine or bromine.

R^Three, R^Four, R⁶, R⁷, R^3a, R^3b, R
The alkyl group in preferably has 1 to 5 carbon atoms.
And may be linear or branched, such as methyl,
Chill, n-propyl, isopropyl, n-butyl, iso
Butyl, t-butyl, 1-methylpropyl, n-plier
And isopentyl, neopentyl and the like.
R ^Three, R^3a, R^3bThen, more preferably methyl or ethyl
And n-propyl, isopropyl and isopentyl.
And more preferably methyl and ethyl. R^Four, R
⁶, R⁷, R is more preferably methyl.

The acyl group in R ³ , R ^3a and R ^3b preferably has 1 to 5 carbon atoms and may be linear or branched, for example formyl, acetyl, ethylcarbonyl, n-propylcarbonyl, Isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, t
-Butylcarbonyl, 1-methylpropylcarbonyl and the like can be mentioned, and acetyl is more preferable.

The alkoxy group for R ⁶ preferably has 1 to 5 carbon atoms and may be linear or branched. For example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t. -Butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, neopentyloxy and the like can be mentioned, and methoxy and ethoxy are more preferable.

The alkoxycarbonyl group in R ³ , R ^3a and R ^3b preferably has 2 to 6 carbon atoms and may be linear or branched, for example, methoxycarbonyl,
Ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, 1-methylpropoxycarbonyl, n-pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl and the like. And more preferably ethoxycarbonyl and t-butoxycarbonyl.

Examples of the aryl group for R ⁴ , R and Ar include phenyl and naphthyl, with phenyl being preferred. Examples of the heteroaryl group for R ⁴ , R and Ar include furyl, thienyl, pyrrolyl,
Pyridyl, pyrazolyl, imidazolyl, oxazolyl,
Examples include isoxazolyl, pyridazyl, pyrimidinyl, pyrazinyl, indolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, quinolyl, isoquinolyl and benzofuranyl. Ar is preferably pyridyl or quinolyl.

Further, the aryl group and the heteroaryl group in R ⁴ , R and Ar may have a substituent on the ring, and the substituent is an alkyl group (as described above),
Examples thereof include an alkoxy group (the same as the above), a halogen atom (the same as the above), —NHSO ₂ CH ₃ , a nitro group, an amino group and the like.

The pharmaceutically acceptable salt of the compound (I) of the present invention, when the compound (I) has a free base, can be directly obtained by neutralizing the free base. These pharmacologically acceptable salts include inorganic acid addition salts (for example, salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, sulfamic acid, nitric acid, etc.), organic acid addition salts (for example, methane). Sulfonic acid, acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid,
Citric acid, salicylic acid, lactic acid, salts with naphthalenesulfonic acid, etc.) and the like.

The compound (I) of the present invention includes all possible stereoisomers and mixtures thereof. In particular, it includes any optical isomer.

Among the compounds (I) of the present invention, R¹Is -NH
SO_TwoCH_ThreeA compound of R^ThreeIs a hydrogen atom or -C
(O) CH_ThreeA compound of R¹Is -NHSO_TwoC
H_Three, R ^TwoIs a hydroxyl group and R^ThreeIs a group represented by formula (1 ')
A compound of R¹Is -NHSO _TwoCH_Three, R^TwoIs -O
C (O) CH_Three, And R^ThreeIs a group represented by the formula (1 ′)
Compounds and the like are preferred.

Although the bonding position of the substituent R ¹ is not particularly limited, it is preferably in the para position.

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be produced by the methods shown in the following reaction process diagrams 1 to 5 and the like.

Reaction Process FIG. 1 shows a method for producing the compound (VIII) of the present invention.

[0025]

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[In the formula, each symbol has the same meaning as described above. ]

First, the diazepine compound (II) or (II
Compound (V) can be produced by reacting any of I) with halide (IV) in a solvent or in the absence of a solvent, if necessary, in the presence of a base as a dehydrohalogenating agent. .

The organic solvent used in the reaction is
Any substance may be used as long as it does not inhibit the reaction, for example,
Alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; benzene, toluene,
Examples thereof include aprotic apolar solvents such as xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc., preferably alcohol solvents, particularly ethanol.

Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine and triethylamine, and triethylamine is preferable. The reaction is usually performed in the range of cooling to the reflux temperature of the solvent, preferably 70 to 100 ° C. The reaction time is usually 1 to 102 hours, preferably 72
~ 96 hours.

Next, the compound (VI) can be produced by subjecting the compound (V) to a hydrolysis reaction.

A conventional method is used for the hydrolysis reaction. For example, the conditions may be either acidic conditions or alkaline conditions. Acid (for example, inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid) and an inert solvent (for example, water) are used under acidic conditions. Under alkaline conditions, a base (for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate such as sodium carbonate and potassium carbonate) and an inert solvent (for example, water)
Is used. It is preferably under acidic conditions, particularly 10% hydrochloric acid aqueous solution.

Under any of the conditions, the reaction is usually carried out in the range of cooling to the reflux temperature of the solvent, and the reaction temperature is 80 to 100.
C is preferred. The reaction time is usually 1 to 24 hours,
It is preferably 3 to 7 hours.

Then, the compound (VI) and the compound (VII) are
By reacting in the presence of a base as a dehydrohalogenating agent in a solvent or without a solvent, if necessary, a compound
(VIII) can be produced.

The organic solvent used in the reaction is
Any substance may be used as long as it does not inhibit the reaction, for example,
Alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; benzene, toluene,
Examples thereof include aprotic apolar solvents such as xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc., preferably alcohol solvents, particularly methanol.

Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like, and preferably triethylamine. The reaction is usually performed in the range of cooling to the reflux temperature of the solvent, preferably 15 to 40 ° C. The reaction time is usually 1 to 24 hours, preferably 10 to 18 hours.

Among the compounds (II) used as starting materials in the production method, for example, compounds in which R is a methyl group are described in Journal of Organic Chemistry (J. Org. Chem.), Vol. 36, page 1711, 1971. It is a known compound in years and can be produced by the method represented by the following reaction formula.

[0037]

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[In the formula, Ts represents a tosyl group, Et represents an ethyl group, and Ac represents an acetyl group. ]

The compound (III) used as a starting material in the production method can be produced by the following method.

[0040]

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[In the formula, R has the same meaning as described above. That is, the compound (III) can be produced by treating the compound (II) with a base in a solvent.

As the organic solvent used in the reaction,
Any substance may be used as long as it does not inhibit the reaction, for example,
Alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; benzene, toluene,
Xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, aprotic apolar solvents such as dioxane, and the like, preferably alcoholic solvents, aprotic apolar solvents, especially methanol or chloroform. is there.

Examples of the base used include liquid ammonia, triethylamine, pyridine and the like, and liquid ammonia is preferred. The reaction is usually performed in the range from under cooling to the reflux temperature of the solvent at -5 to 10 ° C.
Is preferred. The reaction time is usually 10 minutes to 6 hours, preferably 15 to 45 minutes.

Further, in the compound (IV) used as a starting material in the production method, for example, R ^3a is N-
The compound in which a methylbenzimidazol-2-yl group and Hal is a bromine atom is described in Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 35, 70.
It is a known compound on page 5, 1992, and can be produced by the method represented by the following reaction formula.

[0045]

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Reaction Process FIG. 2 shows the compound (X) of the present invention,
A method for producing (XI), (XII), (XIIa), and (XIIb) is shown.

[0047]

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[In the formula, each symbol has the same meaning as described above. ]

The compound (X) is obtained by reacting the compound (IX) with either the diazepine compound (II) or (III) in a solvent or without a solvent, if necessary, in the presence of a base as a dehydrohalogenating agent. It can be produced by reacting with.

The organic solvent used in the condensation reaction may be any one as long as it does not inhibit the reaction, for example, methanol, ethanol, isopropanol, n-.
Alcoholic solvents such as butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide; benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, Examples thereof include aprotic nonpolar solvents such as dioxane, and preferably aprotic nonpolar solvents, particularly chloroform.

Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine and triethylamine, and triethylamine is preferable. The reaction is usually performed in the range of cooling to the reflux temperature of the solvent, preferably 15 to 45 ° C. The reaction time is usually 1 to 48 hours, preferably 20 to 30 hours.

Then, the compound (X) is subjected to a hydrolysis reaction to produce the compound (XI).

A conventional method is used for the hydrolysis reaction. For example, the conditions may be either acidic conditions or alkaline conditions. An acid (for example, an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid) and an inert solvent (for example, water) are used under acidic conditions. As for alkaline conditions,
A base (for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate such as sodium carbonate and potassium carbonate) and an inert solvent (for example water) are used. It is preferably under acidic conditions, especially 10
% Aqueous hydrochloric acid solution.

Under any of the conditions, the reaction is usually carried out in the range from cooling to the reflux temperature of the solvent, and the reaction temperature is 80 to 100.
C is preferred. The reaction time is usually 1 to 24 hours,
It is preferably 1 to 3 hours.

The compound (XII) can be produced by reacting the compound (XI) with a halide (XX) in a solvent or without a solvent, if necessary, in the presence of a base.

The organic solvent used in the reaction is
Any substance may be used as long as it does not inhibit the reaction, for example,
Alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; benzene, toluene,
An aprotic apolar solvent such as xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; or a mixed solvent thereof, and the like can be mentioned, preferably methanol, chloroform, or a mixture of methanol and chloroform. It is a solvent.

Examples of the base used include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine and triethylamine, with triethylamine being preferred. The reaction is usually carried out in the range of cooling to the reflux temperature of the solvent at 50-8.
0 ° C. is preferred. The reaction time is usually 1 to 24 hours, preferably 1 to 6 hours.

The compound (XIIa) can be produced by reacting the compound (XI) with the aromatic vinyl compound (XIII) in the presence of sodium acetate in a solvent or without solvent.

As the organic solvent used in the reaction,
Any substance may be used as long as it does not inhibit the reaction, for example,
Water; methanol, ethanol, isopropanol, n-
Alcoholic solvents such as butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide; benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, Examples thereof include an aprotic nonpolar solvent such as dioxane; or a mixed solvent thereof, and a mixed solvent of an alcohol solvent and water is preferable, and a mixed solvent of methanol and water is particularly preferable. The reaction is usually carried out in the range from cooling to the reflux temperature of the solvent, and the reflux temperature of the solvent is preferred. The reaction time is usually 1 to 48 hours, preferably 6 to 24 hours.

Examples of the method for producing the compound (XIIb) include a method for producing the compound (XI) by a reductive amination reaction using an aromatic aldehyde (XIV) and a reducing agent.

The organic solvent used in the reduction reaction may be any one as long as it does not inhibit the reaction, and examples thereof include methanol, ethanol, isopropanol and n-.
Examples thereof include alcohol solvents such as butanol, and methanol is preferable.

Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium aluminum hydride,
Examples thereof include borane-t-butylamine complex salt, and preferably sodium cyanoborohydride.

The reaction is usually carried out in the range from cooling to the reflux temperature of the solvent, preferably 20 to 80 ° C. The reaction time is usually 1 to 48 hours, preferably 12 to 36 hours.

Of the compounds (IX) used as starting materials in the method for producing compound (X), for example, CH ₃ S
Compounds in which O ₂ NH— is in the 4-position and Hal is a chlorine atom are compounds of Indian Journal of Chemistry, Volume 23B, 2
It is a known compound on page 49, 1984 and the like, and can be produced by the method represented by the following reaction formula.

[0065]

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Reaction Process FIG. 3 shows the compound (XVI) of the present invention,
A method for producing (XVII), (XVIII), (XIX) and (XXII) is shown.

[0067]

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[In the formula, each symbol has the same meaning as described above. ]

Compounds (XVI) and (XVII) are
V) and either diazepine compound (II) or (III) in a solvent or without a solvent, if necessary, in the presence of a base as a dehydrohalogenating agent to give a mixture of the two. It can be manufactured. Separation of the compound (XVI) and the compound (XVII) thus produced from the mixture can be easily carried out by silica gel column chromatography or the like.

The organic solvent used in the condensation reaction may be any one as long as it does not inhibit the reaction, and examples thereof include methanol, ethanol, isopropanol and n-.
Alcoholic solvents such as butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide; benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, Examples thereof include aprotic apolar solvents such as dioxane, preferably aprotic apolar solvents, particularly dichloromethane.

Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like, with preference given to triethylamine. The reaction is usually carried out in the range from cooling to the reflux temperature of the solvent, and the reflux temperature of the solvent is preferred. The reaction time is usually 1 to 24 hours, preferably 12 to 24 hours.

The compound (XVII) is a compound (XVI) or a compound (XVII).
It can be produced by hydrolyzing a mixture of VII) (that is, hydrolyzing compound (XVI)).

A conventional method is used for the hydrolysis reaction. For example, the conditions may be either acidic conditions or alkaline conditions. An acid (for example, an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid) and an inert solvent (for example, water) are used under acidic conditions. As for alkaline conditions,
A base (for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate such as sodium carbonate and potassium carbonate) and an inert solvent (for example water) are used. It is preferably under acidic conditions, especially 10
% Aqueous hydrochloric acid solution.

Under any of the conditions, the reaction is usually carried out in the range from cooling to the reflux temperature of the solvent, and the reaction temperature is 80 to 100.
C is preferred. The reaction time is usually 1 to 24 hours,
It is preferably 12 to 24 hours.

Compound (XVIII) is obtained by adding an alkylating agent, an acylating agent or an alkoxycarbonylating agent to compound (XVII) in a solvent or without a solvent, and if necessary, the presence of a base as a dehydrohalogenating agent. It can be produced by reacting under.

As the organic solvent used in the reaction,
Any substance may be used as long as it does not inhibit the reaction, for example,
Alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; benzene, toluene,
Xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, aprotic apolar solvents such as dioxane, and the like, preferably alcohol solvents, aprotic apolar solvents, especially methanol or dichloromethane. is there.

Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like, with preference given to triethylamine.

The alkylating agent, the acylating agent, and the alkoxycarbonylating agent are represented by the formula (XXIII) R ^3b -Hal (XXIII) [wherein each symbol has the same meaning as defined above]. ] The halide represented by these, an acid anhydride, etc. are mentioned.

Examples of the alkylating agent include methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, propyl iodide, propyl bromide, isopropyl iodide, isopropyl bromide, butyl iodide, butyl bromide. , T-butyl iodide, t-butyl bromide, 1-methyl-1-iodopropane, 1-methyl-1-bromopropane, pentyl iodide, pentyl bromide, isopentyl iodide, isopentyl bromide, neopentyl iodide , Neopentyl bromide, benzyl chloride, benzyl bromide, 2-picolyl chloride, 2-picolyl bromide, 3-picolyl chloride, 3-picolyl bromide, 4-picolyl chloride, 4-picolyl bromide, 2- (2-chloroethyl) pyridine, 2- (2-bromoethyl) pyridine, 3- (2-chloroethyl) pyridine, 3- (2-butane) Moechiru) pyridine, 4- (2
Chloroethyl) pyridine, 4- (2-bromoethyl) pyridine, 2- (2-chloroethyl) -6-methylpyridine, 2- (2-bromoethyl) -6-methylpyridine,
2-chloromethylquinoline, 2-bromomethylquinoline, 1-bromide-2-methylbenzimidazole (the aryl group and the heteroaryl group have an alkyl group, an alkoxy group, a halogen atom, -NHSO ₂ CH ₃ , nitro group on the ring). Group and an optionally substituted substituent selected from amino groups) and the like.

As the acylating agent, for example, acetic anhydride,
Alkylcarboxylic acid anhydrides such as propionic anhydride, butyric anhydride, valeric anhydride; arylcarboxylic anhydrides such as benzoic anhydride (the aryl group is an alkyl group on the ring,
Alkoxy group, a halogen atom, -NHSO ₂ CH _3, may have a substituent group selected from nitro group and amino group); acetyl chloride, acetyl bromide, iodide acetyl, propionyl chloride, bromide, propionyl iodide Acyl halides such as propionyl chloride, butyric acid chloride, butyric acid bromide, butyric acid iodide, valeric acid chloride, valeric acid bromide, valeric acid iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide (the aryl group is a cyclic To an alkyl group, an alkoxy group, a halogen atom, —NHSO ₂ CH ₃ , a nitro group and an amino group may be substituted).

Examples of the alkoxycarbonylating agent include alkoxycarboxylic acid anhydrides such as n-propoxycarboxylic acid anhydride, n-butoxycarboxylic acid anhydride and t-butoxycarboxylic acid anhydride.

The reaction is usually carried out in the range from cooling to the reflux temperature of the solvent, and also from normal pressure to sealed tube. Preferably, the sealed tube state is 50 to 80 ° C.
The reaction time is usually 1 to 24 hours, preferably 8 to
16 hours.

The amino derivative (XIX) can be produced by reducing the compound (XVIII). Examples of the reduction method include Pd / carbon or Pt as a catalyst.
/ Method of using hydrogen in the presence of carbon or the like; Method of hydrogenation in the presence of Raney nickel; Sn / HCl, Sn /
A method using H ₂ SO ₄ , Fe / HCl, Fe / H ₂ SO ₄ or the like; a method using hydrogen sulfide in the presence of ammonia and the like can be mentioned. Preferably Pd / carbon or Pt
/ A method using hydrogen in the presence of carbon or the like; Sn / HCl
It is a method using.

As the organic solvent used in the reduction reaction,
Any substance may be used as long as it does not inhibit the reaction, for example,
Water; acetic acid, ethyl acetate; alcohol solvents such as methanol, ethanol, isopropanol, n-butanol;
Aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; aprotic apolar solvents such as benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc. Examples of the organic solvent include alcohol solvents, preferably ethanol.

The reaction is usually performed in the range of cooling to the reflux temperature of the solvent, preferably 20 to 80 ° C. The reaction time is usually 1 to 24 hours, preferably 30 minutes to 4 hours. Further, the reduction reaction using hydrogen gas is carried out in the pressure range of atmospheric pressure to 10 kg / cm ² and 3 to 4 kg / c.
m ² is preferred.

As the compound (XXII), a halogenated methanesulfonic acid or anhydrous methanesulfonic acid is used, and the compound (XIX) is converted into a solvent without solvent or in the presence of a base as a dehydrohalogenating agent if necessary. It can be produced by methanesulfonylation.

As the organic solvent used in the reaction,
Any substance may be used as long as it does not inhibit the reaction, for example,
Alcoholic solvents such as methanol, ethanol, isopropanol, n-butanol; aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; benzene, toluene,
Aprotic apolar solvents such as xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like can be mentioned, with no solvent being preferable.

Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine and triethylamine, and triethylamine is preferable. Examples of halogenated methanesulfonic acid include methanesulfonic acid chloride. The reaction is usually carried out in the range of cooling to the reflux temperature of the solvent, preferably 0 to 40 ° C. The reaction time is usually 1 to 24
Time, preferably 6-18 hours.

Reaction Process FIG. 4 shows a method for producing the compound (I ′) in which R ² in the formula (I) is R ^2a [—OC (O) —R ⁴ ].

[0090]

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[In the formula, each symbol has the same meaning as described above. ]

Compound (I ') can be produced by reacting compound (XXI) with or without an acylating agent in a solvent, if necessary in the presence of a base.

As the organic solvent used in the reaction,
Any substance may be used as long as it does not inhibit the reaction, for example,
Aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; aprotic apolar solvents such as benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc. And the like, and a solvent-free solvent is preferable.

Examples of the acylating agent include alkylcarboxylic acid anhydrides, arylcarboxylic acid anhydrides, and acyl halides. As the alkylcarboxylic acid anhydride,
For example, acetic anhydride, propionic anhydride, butyric anhydride,
Examples include valeric anhydride. Examples of the arylcarboxylic acid anhydride include benzoic anhydride and the like, and the aryl group is a substituent selected from an alkyl group, an alkoxy group, a halogen atom, —NHSO ₂ CH ₃ , a nitro group and an amino group on the ring. May have. Examples of the acyl halide include acetyl chloride, acetyl bromide,
Acetyl iodide, propionyl chloride, propionyl bromide, propionyl iodide, butyric acid chloride, butyric acid bromide, butyric acid iodide, valeric acid chloride, valeric acid bromide, valeric acid iodide, benzoyl chloride, benzoyl bromide, benzoyl iodide , Picolinoyl chloride, nicotinoyl chloride, isonicotinoyl chloride, etc., and the aryl group and the heteroaryl group are substituents selected from an alkyl group, an alkoxy group, a halogen atom, —NHSO ₂ CH ₃ , a nitro group and an amino group on the ring. May have.

The base used is pyridine, 4-
Examples thereof include dimethylaminopyridine and triethylamine, and triethylamine is preferable. The reaction is
Usually, it is carried out in the range from under cooling to the reflux temperature of the solvent,
80-150 degreeC is preferable. The reaction time is usually 1 to 24
Time, preferably 2-5 hours.

Reaction Process FIG. 5 shows a method for producing the compound (I ″) in which R ² in the formula (I) is R ^2b (halogen atom).

[0097]

Embedded image

[In the formula, each symbol has the same meaning as defined above. ]

The compound (I ″) can be obtained by halogenating the compound (XXI). For example, when R ^2b is a fluorine atom,
After converting the hydroxyl group of the compound (XXI) to an active ester such as methanesulfonic acid or trifluoromethanesulfonic acid or an active carboxylic acid ester such as benzoyloxy group, potassium fluoride or tris (dimethylamino) sulfonium difluorotrimethylsilcate or fluorine is used. Examples thereof include a method of treating with hydrogen fluoride and the like, and a method of using Yarobenco reagent. When R ^2b is a chlorine atom, a method using thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride or zinc chloride as a catalyst, hydrochloric acid, etc., and a method using Vilsmeier reagent or redone reagent, etc. Is mentioned. Further, when R ^2b is a bromine atom, a method using phosphorus tribromide, hydrobromic acid, bromine or the like, and a method using Vilsmeier reagent or redone reagent or the like can be mentioned.

As the organic solvent used in the reaction,
Any substance may be used as long as it does not inhibit the reaction, for example,
Aprotic polar solvents such as acetone, acetonitrile, N, N-dimethylformamide, dimethylsulfoxide; aprotic apolar solvents such as benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc. And the like, and preferably an aprotic apolar solvent, particularly chloroform. The reaction is usually performed in the range of cooling to the reflux temperature of the solvent, preferably at 40 to 80 ° C. The reaction time is usually 1-2.
It is 4 hours, preferably 6 to 18 hours.

The compounds obtained as described above can be separated and purified by subjecting them to known means such as concentration, extraction, chromatography and recrystallization.

The compound (I) of the present invention can also be used as an acid addition salt of a pharmacologically acceptable acid. The acid addition salt can be obtained by a generally known method. For example, a compound (I) having a free base or a solution thereof, a suitable acid or a solution thereof described above, an alcohol solvent (eg, methanol, ethanol, isopropanol, n-butanol, etc.), an aprotic polar solvent (eg, acetone). , Acetonitrile, N, N-dimethylformamide, dimethylsulfoxide, etc.), or an aprotic apolar solvent (eg, benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, etc.), etc. It is obtained by mixing in the solvent of. Also,
Mixtures of the above solvents may be used for better crystal precipitation. Furthermore, various isomers of the compound (I) can be produced by known methods.

The compound (I) of the present invention and pharmaceutically acceptable salts thereof can be administered to mammals (eg humans, dogs, cats,
It has an excellent antiarrhythmic action (particularly class III type antiarrhythmic action) against mice, rats, rabbits, etc.). Therefore, the compound (I) of the present invention and a pharmacologically acceptable salt thereof can be used for various heart diseases (for example, ischemic heart disease, heart failure during shock or surgery, myocardial disease, various arrhythmias associated with pericarditis, etc.). ) And the like, and is particularly useful as a prophylactic / therapeutic agent for tachyarrhythmia such as atrial fibrillation, atrial flutter, extrasystole, and ventricular fibrillation.

When the compound (I) of the present invention and a pharmacologically acceptable salt thereof are used as a medicine, a pharmacologically acceptable carrier (for example, liquid carrier, solid carrier, diluent, pharmaceutical technical aid) Etc.) and the like, for example, tablets, film-type tablets, sugar-coated tablets, capsule tablets, granules, powders, injections, transdermal preparations, suppositories, etc. to obtain a pharmaceutical composition, which can be orally, parenterally or locally Can be administered to. In addition, an effective amount of compound (I) or a pharmaceutically acceptable salt thereof is added to the above-mentioned preparation.

The dose of the compound (I) of the present invention and a pharmacologically acceptable salt thereof varies depending on the administration route, the symptoms of the patient, the body weight, the age, etc., and can be appropriately set according to the purpose of administration. . Usually, when orally administered to an adult, it is preferable to administer 0.001 to 50 mg / kg body weight / day, preferably 0.01 to 10 mg / kg body weight / day, divided into 1 to several times a day. When administered parenterally to an adult, it is preferable to administer 0.0001 to 5 mg / kg body weight / day, preferably 0.001 to 1 mg / kg body weight / day, divided into 1 to several times a day.

[0106]

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

Reference Example 1 1-Acetyl-6-hydroxyhexahydro-1H-
1,4-Diazepine Journal of Organic Chemistry (J.O.
rg. Chem.), 36, 1711-1713, 197.
69 g of 6-acetoxyhexahydro-1H-1,4-diazepine dihydrobromide synthesized by the method described in 1 year
200 ml of chloroform suspension solution (215 mmol)
Under ice cooling, an excess amount of ammonia gas was directly blown into the flask.
After stirring at room temperature for 30 minutes and filtering, the filtered material was thoroughly washed with chloroform, and the filtrate and washings were combined and concentrated under reduced pressure to give 34 g of the title compound as a pale yellow oil.
(100%) obtained. MS (M / Z) EI: 159 (M ⁺ + 1), CI: 159 (M ⁺ +)
1) NMR (CDCl ₃ ) δ: 2.05,2.12 (s, 3H), 2.72-3.0
0 (m, 4H), 3.32-3.82 (m, 7H) IR (neat): 3300 (OH), 1630 (C = O) cm ^-1

Reference Example 2 1-Acetyl-6-hydroxy-4- (1-methylbenzimidazol-2-yl) hexahydro-1H-1,
4-Diazepine 2.79 g of 1-acetyl-6-hydroxyhexahydro-1H-1,4-diazepine synthesized in Reference Example 1 (1
7.6 mmol) and 30 ml of ethanol in a mixed suspension solution, 1.78 g (17.6 mmol) of triethylamine was added, and then Journal of Medicinal Chemistry (J. Med. Chem.), Vol. 35, 705-716.
2-Bromo-1-synthesized by the method described on page 1992.
3.72 g of methyl-1H-benzimidazole (17.
6 mmol) was added and the mixture was refluxed for 78 hours. After cooling, the mixture was concentrated and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried and concentrated, and the obtained residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 50: 1) to give 2.35 g (46%) of the title compound as an oil. Obtained. NMR (CDCl ₃ ) δ: 2.10 (s, 3H), 3.22-3.61 (m,
8H), 3.52 (s, 3H), 3.88-4.13 (m, 1H), 6.92-7.15 (m, 3
H), 7.20-7.40 (m, 1H) MS (M / Z) EI: 288 (M ⁺ ), CI: 289 (M ⁺ + 1)

Reference Example 3 6-Hydroxy-1- (1-methylbenzimidazol-2-yl) hexahydro-1H-1,4-diazepine 1 g (3.1 mmol) of the compound of Reference Example 2 and 20 ml of a 10% aqueous hydrochloric acid solution were added. The mixed solution was heated and stirred at 90 ° C. for 4 hours. After cooling, neutralize with 10% sodium hydroxide solution,
The aqueous layer was extracted three times with dichloromethane, the organic layer was concentrated, and the residue was purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 3: 1) to give 0.60 g of the title compound as an oil ( 7
9%). MS (M / Z) EI: 246 (M ⁺ ), CI: 247 (M ⁺ + 1)

Example 1 1-Acetyl-6-hydroxy-4-[(4-nitrophenyl) sulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 1), and 6-hydroxy-1
-[(4-Nitrophenyl) sulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 2) Journal of Organic Chemistry (J.O.
rg. Chem.), 36, 1711-1713, 197.
6-acetoxyhexahydro-1H-1,4-diazepine dihydrobromide prepared by the method described in 1 year 19.2
g (60 mmol) was suspended in 150 ml of dichloromethane, and 13.1 g (130 mm) of triethylamine under ice cooling.
ol) was added dropwise. Furthermore, 50 ml of a dichloromethane solution of 2.2 g (10 mmol) of p-nitrobenzenesulfonyl chloride was added dropwise under ice cooling. After stirring for 12 hours at room temperature,
The precipitated crystals were removed by filtration, the filtrate was washed with 50 ml of water, and the aqueous layer was extracted with dichloromethane. The organic layers were collected, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 50: 1) to give an Rf value =
0.77 g (22%) of the compound of Compound No. 1 which was 0.63 (chloroform: methanol = 9: 1) was obtained.

Melting point 187 to 188 ° C (methanol) MS (M / Z) CI: 344 (M ⁺ + 1) NMR (DMSO-d ₆ ) δ: 1.90 (s, 3H), 2.70-4.00
(m, 10H), 7.95 (d, J = 7.2Hz, 2H), 8.30 (d, J = 7.2Hz, 2H) Elemental analysis (C ₁₃ H ₁₇ N ₃ O ₆ S): Theoretical value: C, 45.47; H, 4.99; N, 12.24% Measured value: C, 45.42; H, 4.99; N, 12.16%

At the same time, 1.61 g (53%) of the compound No. 2 having an Rf value = 0.30 (chloroform: methanol = 9: 1) was obtained. Melting point 165 to 167 ° C (methanol) MS (M / Z) EI: 302 (M ⁺ + 1), CI: 302 (M ⁺ +)
1) NMR (DMSO-d ₆ ) δ: 2.35-3.60 (m, 11H), 7.7
0 (d, J = 7.2Hz, 2H), 8.10 (d, J = 7.2Hz, 2H) Elemental analysis (C ₁₁ H ₁₅ N ₃ O ₅ S): Theoretical value: C, 43.84; H, 5.02; N, 13.95% Measured: C, 43.75; H, 5.03; N, 13.89%

Also, 4.57 g of the compound of Compound No. 1
(13.3 mmol) suspended in 10% aqueous hydrochloric acid,
By hydrolyzing at 100 ° C. for 16 hours, cooling, adjusting to alkaline with a 10% sodium hydroxide aqueous solution, filtering the precipitated crystals, washing the crystals with water, and drying,
3.58 g (89%) of the compound of Compound No. 2 could be obtained. As a result of instrumental analysis, this was in agreement with the result obtained by the above method.

Example 2 6-Hydroxy-1-methyl-4-[(4-nitrophenyl) sulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 3) 3.61 g (12 mmol) of the compound No. 2 Was dissolved in 50 ml of methanol and triethylamine 2.4 was added.
2 g (24 mmol), 3.41 g of iodomethane (24
mmol) was added and the mixture was heated to 60 ° C. in a sealed tube overnight. After cooling, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 20: 1) to give the title compound as 2.
Obtained 24 g (59%).

Melting point 129-131 ° C (methanol) MS (M / Z) EI: 315 (M ⁺ ), CI: 316 (M ⁺ +1) NMR (CDCl ₃ ) δ: 2.47 (s, 3H), 2.71- 2.84 (m,
4H), 3.34-3.49 (m, 4H), 3.75-4.08 (m, 1H), 7.93 (d, J =
8.4Hz, 2H), 8.33 (J = 8.4Hz, 2H) Elemental analysis (C ₁₂ H ₁₇ N ₃ O ₅ S): Theoretical value: C, 45.70; H, 5.43; N, 13.33% Measured value: C, 45.57 H, 5.51; N, 13.15%

Example 3 1-Ethyl-6-hydroxy-4-[(4-nitrophenyl) sulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 4) 3.41 g (11. 3 mmo
l), 2.29 g of triethylamine (22.7 mmo
l), iodoethane (3.54 g, 22.7 mmol) and methanol (50 ml) were used to carry out the same operation as in Example 2 to give 3.16 g (85%) of the title compound.
%)Obtained.

Melting point 98 to 100 ° C. (methanol) MS (M / Z) EI: 329 (M ⁺ ), CI: 330 (M ⁺ +1) NMR (CDCl ₃ ) δ: 1.02 (t, J = 6.6 Hz, 3H), 2.65
(q, J = 6.6Hz, 2H), 2.35-3.13 (m, 4H), 3.30-3.66 (m, 4H),
3.79-4.03 (m, 1H), 7.89 (d, J = 9.0Hz, 2H), 8.26 (d, J =
9.0Hz, 2H) Elemental analysis (C ₁₃ H ₁₉ N ₃ O ₅ S): Theoretical value: C, 47.40; H, 5.81; N, 12.76% Measured value: C, 47.22; H, 5.79; N, 12.65%

Example 4 6-Hydroxy-1-isopropyl-4-[(4-nitrophenyl) sulfonyl] hexahydro-1H-1,4
-Diazepine (Compound No. 5) The same procedure as in Example 2 was performed using 3.61 g (12 mmol) of the compound of Compound No. 2, 1.62 g (16 mmol) of triethylamine, 1.97 g (16 mmol) of isopropyl bromide and 30 ml of methanol. By carrying out, 3.0 g (73%) of the title compound was obtained.

Melting point 104 to 107 ° C. (ethyl acetate) MS (M / Z) EI: 343 (M ⁺ ), CI: 344 (M ⁺ +1) Elemental analysis (C ₁₄ H ₂₁ N ₃ O ₅ S): Theory Value: C, 48.96; H, 6.16; N, 12.24% Measured value: C, 48.79; H, 6.15; N, 12.00%

Example 5 6-Hydroxy-1-isopentyl-4-[(4-nitrophenyl) sulfonyl] hexahydro-1H-1,4
-Diazepine (Compound No. 6) 0.8 g (2.65 mmol) of the compound of Compound No. 2 was used with an excess amount of isopentyl bromide as a solvent to give 10
Heated at 0 ° C. for 16 hours. After cooling, the excess reagent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 50: 1) to give 0.2 g (20.6%) of the title compound.
Obtained.

Melting point 86 to 88 ° C. (isopropyl ether) MS (M / Z) EI: 371 (M ⁺ ), CI: 372 (M ⁺ +1) Elemental analysis (C ₁₆ H ₂₅ N ₃ O ₅ S): Theory Value: C, 51.73; H, 6.78; N, 11.31% Measured value: C, 51.43; H, 6.76; N, 11.10%

Example 6 1- (tert-Butyloxycarbonyl) -6-hydroxy-4-[(4-nitrophenyl) sulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 7) Compound No. 2 20 ml of a dichloromethane solution of 4.8 g (22 mmol) of di-t-butyl dicarbonate in 100 ml of a dichloromethane solution of 6.02 g (20 mmol) and 2.2 g (22 mmol) of triethylamine under ice cooling.
1 was added dropwise. After stirring at room temperature for 24 hours, the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate and washed with 10% aqueous sodium hydroxide solution and then with water. The organic layer was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from methanol to obtain 5.94 g (74%) of the title compound.

Melting point 159-160 ° C. (methanol) NMR (CDCl ₃ ) δ: 1.40 (s, 9H), 2.85-3.24 (m,
2H), 3.30-3.80 (m, 5H), 3.92-4.22 (m, 2H), 7.92 (d, J =
9.0Hz, 2H), 8.30 (d, J = 9.0Hz, 2H) Elemental analysis (C ₁₆ H ₂₃ N ₃ O ₇ S): Theoretical value: C, 47.87; H, 5.78; N, 10.47% Measured value: C , 47.82; H, 5.76; N, 10.48%

Example 7 1-[(4-aminophenyl) sulfonyl] -4-ethyl-6-hydroxyhexahydro-1H-1,4-diazepine (Compound No. 8) Compound 1 of Compound No. 4 in 15 ml of absolute ethanol. .6
Add 9 g (5.1 mmol) and tin (II) chloride dihydrate 5.75 g (25.5 mmol) and add 3 at 70 ° C.
The mixture was heated and stirred for 0 minutes. After cooling, add 30 ml of cold water and add 5%
The solution was neutralized to pH = 7 to 8 with a sodium bicarbonate solution, extracted with chloroform, the organic layer was dehydrated and then concentrated under reduced pressure to obtain 1.18 g (77%) of the title compound.

Melting point 129 to 133 ° C. (ethanol) MS (M / Z) EI: 300 (M ⁺ + 1), CI: 300 (M ⁺ +)
1) NMR (CDCl ₃ ) δ: 0.95 (t, J = 8.4Hz, 3H), 2.56
(q, J = 8.4Hz, 2H), 2.48-2.78 (m, 4H), 3.15-3.30 (m, 4H),
3.52 (bs, 1H), 3.73-4.00 (m, 1H), 4.24 (bs, 1H), 6.63
(d, J = 10.2Hz, 2H), 7.50 (d, J = 10.2Hz, 2H) Elemental analysis (C ₁₃ H ₂₁ N ₃ O ₃ S): Theoretical value: C, 52.15; H, 7.07; N, 14.04 % Measured value: C, 52.09; H, 7.13; N, 14.01%

Example 8 1-[(4-aminophenyl) sulfonyl] -6-hydroxy-4-isopropylhexahydro-1H-1,4
-Diazepine (Compound No. 9) 3.0 g (8.7 mmol) of the compound of Compound No. 5, tin (II) chloride dihydrate 9.8 g (43.5 mmol),
The same operation as in Example 7 was carried out using 30 ml of absolute ethanol to obtain 1.87 g (69%) of the title compound.

Melting point 131-135 ° C. (ethanol) MS (M / Z) EI: 314 (M ⁺ + 1), CI: 314 (M ⁺ +)
1) NMR (CDCl ₃ ) δ: 0.98 (t, J = 6.0Hz, 6H), 2.60-
2.90 (m, 4H), 3.19-3.32 (m, 4H), 3.75-3.95 (m, 2H), 4.
32 (bs, 2H), 6.65 (d, J = 7.8Hz, 2H), 7.50 (d, J = 7.8Hz, 2
H) Elemental analysis (C ₁₄ H ₂₃ N ₃ O ₃ S): Theoretical value: C, 53.65; H, 7.40; N, 13.41% Measured value: C, 53.38; H, 7.43; N, 13.45%

Example 9 1-[(4-aminophenyl) sulfonyl] -6-hydroxy-4-isopentylhexahydro-1H-1,4
-Diazepine (Compound No. 10) 0.8 g (2.15 mmol) of the compound of Compound No. 6 was dissolved in 80 ml of ethanol, and 0.1% under nitrogen gas substitution.
0 g of 10% palladium-carbon (Pd-C) was added, and catalytic reduction was performed at a hydrogen gas pressure of 4.0 kg / cm ² for 2 hours. After completion of the reaction, filtration is performed, and the filtrate is concentrated,
0.8 g (quantitative) of the title compound was obtained as an oil. MS (M / Z) EI: 341 (M ⁺ ), CI: 342 (M ⁺ + 1)

Example 10 1-Acetyl-6-hydroxy-4- [4-[(methylsulfonyl) amino] phenylsulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 11) 1 synthesized in Reference Example 1 -Acetyl-6-hydroxyhexahydro-1H-1,4-diazepine 4.41 g (2
7.9 mmol) in chloroform / methanol mixed solution (4: 1) in 100 ml, Indian Journal
Of chemistry (Indian Journal of Chemistry),
Vol. 23B, p. 249, 3.75 g (14 mmol) of p-methylsulfonylaminobenzenesulfonyl chloride synthesized according to the method described in 1984 was added little by little under ice cooling. After stirring at room temperature for 24 hours, the solvent was concentrated under reduced pressure and purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 9: 1).
4.53 g (83%) of the title compound was obtained.

Melting point 80-88 ° C. MS (M / Z) CI: 392 (M ⁺ + 1) NMR (CDCl ₃ -CD ₃ OD) δ: 2.10-2.20 (m, 3)
H), 3.10 (s, 3H), 3.32-4.20 (m, 1H), 7.40 (d, J = 9.0Hz,
2H), 7.80 (d, J = 9.0Hz, 2H) Elemental analysis (C ₁₄ H ₂₁ N ₃ O ₆ S ₂ 0.5H ₂ O): Theoretical value: C, 41.99; H, 5.53; N, 10.49% measurement Value: C, 42.06; H, 5.48; N, 10.42%

Example 11 6-Hydroxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] hexahydro-1H-1,
4-diazepine hydrochloride (Compound No. 12) Compound of Compound No. 11 0.45 g (1.15 mmo
10 ml of 10% hydrochloric acid aqueous solution was added to l), and the mixture was heated and stirred at 100 ° C. After cooling for 1 hour, the precipitated crystals were removed by filtration, and the filtrate was neutralized with a 10% aqueous sodium hydroxide solution. The aqueous solution was evaporated under reduced pressure to dryness, the residue was hot extracted with acetone, the extracted organic layer was concentrated, and the resulting residue was subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 4: Purification in 1) gave 0.28 g (70%) of a crude oil. This was treated with a hydrochloric acid / ethanol solution to give the title compound.

Melting point 245-249 ° C. (2-propanol) MS (M / Z) CI: 350 (M ⁺ +1) NMR (DMSO-d ₆ -CDCl ₃ ) δ: 3.00-3.62
(m, 9H), 3.10 (s, 3H), 4.15 (bs, 1H), 7.35 (bs, 1H), 7.
40 (d, J = 9.0Hz, 2H), 7.72 (d, J = 9.0Hz, 2H) Elemental analysis (C ₁₂ H ₁₉ N ₃ O ₅ S ₂ HCl): Theoretical value: C, 37.35; H, 5.22; N, 10.89% Measured value: C, 37.20; H, 5.19; N, 10.77%

Example 12 6-Hydroxy-4-isopentyl-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 13) Compound 1g (Compound No. 10) 2.93 mmol) with a stoichiometric amount of methanesulfonyl chloride and a mixture of triethylamine, the excess reagent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; chloroform: methanol = 50: 1). Purification yielded 0.25 g (21%) of the title compound. Melting point 42-46 ° C (chloroform-d) MS (M / Z) CI: 420 (M ⁺ + 1)

Example 13 6-Hydroxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4-phenylmethylhexahydro-1H-1,4-diazepine (Compound No. 1
4) 0.94 g of benzyl bromide (5. 5 g) of 1.75 g (5 mmol) of the compound of Compound No. 12 and 0.56 g (5.5 mmol) of triethylamine in 50 ml of methanol solution.
5 mmol) was added and the mixture was refluxed for 1 hour. After cooling, the solvent was concentrated, dissolved in ethyl acetate and washed with water. The organic layer was concentrated, and the obtained residue was purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 20: 1) to give 1.
Obtained 85 g (84%).

Melting point 56-61 ° C. MS (M / Z) EI: 439 (M ⁺ ), CI: 440 (M ⁺ +1) NMR (CDCl ₃ ) δ: 2.45-2.90 (m, 4H), 3.07 (s ,
3H), 3.25-3.42 (m, 4H), 3.70 (s, 2H), 3.90-4.05 (m, 1
H), 5.30 (bs, 2H), 7.30 (s, 5H), 7.35 (d, J = 8.4Hz, 2
H), 7.78 (d, J = 8.4Hz, 2H) Elemental analysis (C ₁₉ H ₂₅ N ₃ O ₅ S ₂ 1 / 3H ₂ O): Theoretical value: C, 51.21; H, 5.81; N, 9.43% measurement Value: C, 51.24; H, 5.60; N, 9.36%

Example 14 1-[(4-Fluorophenyl) methyl] -6-hydroxy-4- [4-[(methylsulfonyl) amino] phenylsulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 15 ) 1.75 g (5 mmol) of the compound of Compound No. 12, 0.51 g (5 mmol) of triethylamine, 45 ml of chloroform, and 10 ml of methanol were mixed with p-chloride.
Fluorobenzyl 0.72 g (5 mmol) was added under ice cooling, and the mixture was refluxed for 1 hour. Furthermore, p-fluorobenzyl chloride 0.72 g (5 mmol), triethylamine 0.51
g (5 mmol) was added, and the mixture was refluxed for 6 hours. After cooling, the mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 20: 1) to obtain 2.15 g (94%) of the title compound.

Melting point 169-171 ° C. (methanol) MS (M / Z) EI: 457 (M ⁺ ), CI: 458 (M ⁺ +1) NMR (CDCl ₃ ) δ: 2.45-2.85 (m, 4H), 3.15 (s,
3H), 3.20-3.37 (m, 4H), 3.62 (s, 2H), 3.90-3.97 (m, 1
H), 4.80 (bs, 1H), 6.90 (d, J = 9.0Hz, 2H), 7.18 (d, J = 9.
0Hz, 2H), 7.20 (d, J = 8.4Hz, 2H), 7.60 (d, J = 8.4Hz, 2H) Elemental analysis (C ₁₉ H ₂₄ FN ₃ O ₅ S ₂ ): Theoretical value: C, 49.87; H, 5.29; N, 9.23% Measured value: C, 49.81; H, 5.30; N, 9.05%

Example 15 6-Hydroxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4-[(2-pyridyl)
Methyl] hexahydro-1H-1,4-diazepine dihydrochloride (Compound No. 16) Compound of Compound No. 12 0.63 g (1.8 mmo
1), 0.40 g (4 mmol) of triethylamine and 50 ml of chloroform were added with 0.33 g (2 mmol) of 2- (chloromethyl) pyridine hydrochloride at room temperature, and after refluxing for 3 hours, triethylamine 0.4 was further added.
0 g (4 mmol) was added and the mixture was refluxed for 24 hours. After cooling, it was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting solvent; dichloromethane: methanol = 19: 1) to obtain 0.26 g (33%) of a free salt of the title compound. NMR (CDCl ₃ ) δ: 2.70-3.02 (m, 4H), 3.04 (s,
3H), 3.26-3.42 (m, 4H), 3.82-4.00 (m, 1H), 3.88 (s, 2
H), 5.90 (bs, 1H), 7.02-7.24 (m, 2H), 7.24 (d, J = 8.4H
z, 2H), 7.45-7.68 (m, 1H), 7.62 (d, J = 8.4Hz, 2H), 8.42
(bd, J = 4.8Hz, 1H)

A part of this was converted to the hydrochloride by treating with hydrochloric acid / ethanol solution to obtain the title compound. Melting point 163 to 166 ° C (ethanol) MS (M / Z) SIMS: 441 (M ⁺ + 1) Elemental analysis (C ₁₈ H ₂₄ N ₄ O ₅ S ₂ 2HCl): Theoretical value: C, 42.10; H, 5.10; N, 10.91% Measured value: C, 42.36; H, 5.04; N, 10.99%

Example 16 6-Hydroxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4- [2- (2-pyridyl) ethyl] hexahydro-1H-1,4-diazepine dihydrochloride (Compound No. 17) In 20 ml of a mixed solution of methanol-water (1: 1), 2.09 g (6 mmol) of the compound of Compound No. 12, 1.26 g (12 mmol) of 2-vinylpyridine, 1.63 g of sodium acetate trihydrate. (12 mmol) was added and the mixture was refluxed for 24 hours. After cooling, the mixture was concentrated, the residue was dissolved in ethyl acetate and washed with water, and the organic layer was concentrated. The obtained residue was purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 19: 1) to obtain the free salt of the title compound. NMR (CDCl ₃ ) δ: 2.60-3.10 (m, 8H), 3.04 (s,
3H), 3.32-3.46 (m, 4H), 3.88-4.00 (m, 1H), 7.02-7.50
(m, 3H), 7.30 (d, J = 7.8Hz, 2H), 7.72 (d, J = 7.8Hz, 2H),
8.40 (bd, J = 3.6Hz, 1H)

This was treated with a hydrochloric acid / ethanol solution to obtain 1.65 g (56%) of the title compound. Melting point 176-179 ° C (ethanol) MS (M / Z) SIMS: 455 (M ⁺ + 1) Elemental analysis (C ₁₉ H ₂₆ N ₄ O ₅ S ₂ 2HCl): Theoretical value: C, 43.26; H, 5.35; N, 10.62% Measured: C, 43.17; H, 5.36; N, 10.62%

Example 17 6-Hydroxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4- [2- (6-methyl-2-pyridyl) ethyl] hexahydro-1H-1,4
-Diazepine dihydrochloride (Compound No. 18) 1.05 g (3 mmol) of the compound of Compound No. 12, 0.71 g (6 mmol) of 6-methyl-2-vinylpyridine in 10 ml of a mixed solution of methanol-water (1: 1), 0.82 g (6 mmol) of sodium acetate trihydrate was added, and the mixture was refluxed for 6 hours. Thereafter, the same post-treatment as in Example 16 was carried out to give 0.77 g of the free salt of the title compound.
(55%) obtained. NMR (CDCl ₃ ) δ: 2.45 (s, 3H), 2.66-3.02 (m,
10H), 3.06 (s, 3H), 3.52-3.70 (m, 2H), 3.85-4.00 (m, 1
H), 6.86 (d, J = 7.2Hz, 2H), 7.12-7.45 (m, 1H), 7.20 (d,
(J = 8.4Hz, 2H)

This was treated with a hydrochloric acid / ethanol solution to give 0.74 g of the title compound as yellow amorphous crystals.
(46%) was obtained. MS (M / Z) SIMS: 469 (M ⁺ + 1) Elemental analysis (C ₂₀ H ₂₈ N ₄ O ₅ S ₂ 2HCl 0.25H ₂ O): Theoretical value: C, 43.99; H, 5.63; N, 10.26 % Measured value: C, 43.93; H, 5.82; N, 10.30%

Example 18 6-Hydroxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4- [2- (4-pyridyl) ethyl] hexahydro-1H-1,4-diazepine dihydrochloride (Compound No. 19) In 30 ml of a mixed solution of methanol-water (1: 1), 3.85 g (10 mmol) of the compound of Compound No. 12, 2.10 g (20 mmol) of 4-vinylpyridine, 2.72 g of sodium acetate trihydrate. (20 mmol) was added and 18
Reflux for hours. Thereafter, the same post-treatment as in Example 16 was carried out to give 0.73 g (16
%)Obtained. NMR (CDCl ₃ ) δ: 2.80 (bs, 8H), 3.08 (s, 3H),
3.32 (bs, 4H), 3.82-4.05 (m, 1H), 7.08 (d, J = 6.6Hz, 2
H), 7.32 (d, J = 9.0Hz, 2H), 7.72 (d, J = 9.0Hz, 2H), 8.48
(d, J = 6.6Hz, 2H)

A part of this was converted into the hydrochloride by a conventional method to give the title compound. Melting point 146-150 ° C MS (M / Z) SIMS: 455 (M ⁺ + 1) Elemental analysis (C ₁₉ H ₂₆ N ₄ O ₅ S ₂ 2HCl H ₂ O): Theoretical value: C, 41.83; H, 5.54; N, 10.27% Measured: C, 41.71; H, 5.92; N, 10.18%

Example 19 6-Hydroxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4- (2-quinolylmethyl) hexahydro-1H-1,4-diazepine dihydrochloride (Compound No. 20) 1.75 g (5 mmol) of the compound of Compound No. 12, 2
-Quinoline carboxaldehyde 0.86 g (5.5 m
mol), 0.1 g of molecular sieve 4A and 10 ml of methanol were stirred at room temperature for 30 minutes.
Sodium cyanoborohydride 0.42g (6.6mm
ol) was added little by little and then refluxed for 24 hours. After cooling and concentrating, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 50: 1) to give 2.00 g (82%) of the free salt of the title compound. )Obtained. NMR (CDCl ₃ ) δ: 2.80-3.16 (m, 2H), 2.18 (s,
3H), 3.30-3.48 (m, 3H), 3.42 (s, 2H), 3.86-4.20 (m, 4
H), 7.28 (d, J = 9.0Hz, 2H), 7.64 (d, J = 9.0Hz, 2H), 7.40-
8.20 (m, 6H)

A part of this is converted into a hydrochloride by a conventional method,
It was used as the title compound. Melting point 146-150 ° C MS (M / Z) SIMS: 491 (M ⁺ + 1) Elemental analysis (C ₂₂ H ₂₆ N ₄ O ₅ S ₂ 2HCl): Theoretical value: C, 46.89; H, 5.01; N, 9.94 % Measured value: C, 47.10; H, 5.30; N, 10.02%

Example 20 1- (1-Methylbenzimidazol-2-yl) -4
-[4-[(Methylsulfonyl) amino] phenylsulfonyl] -6-hydroxyhexahydro-1H-1,4
-Diazepine (Compound No. 21) 0.60 g (2.44 mmo) of the compound synthesized in Reference Example 3
l), 0.51 g of triethylamine (4.9 mmo)
l), and p-chloride in a mixed solution of 15 ml of methanol.
Methylsulfonylaminobenzenesulfonyl 1.32g
(4.9 mmol) was added, and the mixture was stirred at room temperature for 12 hours.
After completion of the reaction, the mixture was concentrated, and the residue was purified by silica gel column chromatography (elution solvent; dichloromethane: methanol = 9: 1) to give the title compound as 1.1.
0 g (94%) was obtained.

Melting point 150 to 160 ° C. (2-propanol) MS (M / Z) EI: 479 (M ⁺ ), CI: 480 (M ⁺ +1) NMR (CDCl ₃ ) δ: 2.61-3.10 (m, 4H) ), 3.00 (s,
3H), 3.58 (s, 3H), 3.48-4.28 (m, 5H), 7.10-7.50 (m, 4
H), 7.23 (d, J = 9.0Hz, 2H), 7.64 (d, J = 9.0Hz, 2H) Elemental analysis (C ₂₀ H ₂₅ N ₅ O ₅ S ₂ 2.1H ₂ O): Theoretical value: C , 46.42; H, 5.69; N, 13.54% Measured value: C, 46.02; H, 5.20; N, 13.38%

Example 21 6-Chloro-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4-phenylmethylhexahydro-1H-1,4-diazepine hydrochloride (Compound No. 22) Compound No. 14 To 10 ml of a chloroform solution of 1.32 g (3 mmol) of the above compound was added thionyl chloride (3.57 g (3
0 mmol) was added and the mixture was refluxed for 12 hours. After cooling, the mixture was concentrated, methanol was added, the mixture was adjusted to weakly alkaline with 10% aqueous sodium hydroxide solution, and the residue obtained by concentrating this solvent was subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 50: 1). Was purified by 1.30 g (95%) of the free salt of the title compound.
%)Obtained.

NMR (CDCl ₃ ) δ: 2.42-3.30 (m, 7
H), 3.10 (s, 3H), 3.52-3.92 (m, 2H), 3.72 (s, 2H), 7.1
5 (s, 5H), 7.28 (d, J = 9.0Hz, 2H), 7.67 (d, J = 9.0Hz, 2H) A portion of this was treated with hydrochloric acid / ethanol to give the title compound. Melting point 189-191 ° C (methanol / ethanol) MS (M / Z) CI: 458 (M ⁺ +1) Elemental analysis (C ₁₉ H ₂₄ ClN ₃ O ₄ S ₂ HCl): Theoretical value: C, 46.15; H, 5.10; N, 8.50% Measured value: C, 46.32; H, 5.70; N, 8.43%

Example 22 6-acetoxy-1- [4-[(methylsulfonyl) amino] phenylsulfonyl] -4-phenylmethylhexahydro-1H-1,4-diazepine (Compound No. 2
3) Compound of Compound No. 14, 1.00 g (2.28 mmo)
A mixture of 1) and 5 ml of acetic anhydride was refluxed for 3 hours. After cooling, concentrate and dissolve the residue in chloroform.
The organic layer was washed with a 0% aqueous solution of potassium carbonate, dehydrated, and then concentrated. The obtained residue was subjected to silica gel column chromatography (elution solvent; dichloromethane: methanol = 1).
The title compound was purified to 0.9.
0 g (82%) was obtained.

Melting point 153-154 ° C. MS (M / Z) CI: 482 (M ⁺ + 1) NMR (CDCl ₃ ) δ: 1.98 (s, 3H), 2.68-2.98 (m,
4H), 3.05 (s, 3H), 3.18-3.56 (m, 5H), 3.66 (s, 2H), 4.
90 (bs, 1H), 7.22 (s, 5H), 7.30 (d, J = 9.0Hz, 2H), 7.72
(d, J = 9.0Hz, 2H ) Elemental analysis _{(C 21 H 27 N 3 O} 6 S 2): theoretical value: C, 52.37; H, 5.65 ; N, 8.73% measured value: C, 52.64; H, 5.83 ; N, 8.87%

Example 23 6-chloro-1-[(4-fluorophenyl) methyl]
-4- [4-[(methylsulfonyl) amino] phenylsulfonyl] hexahydro-1H-1,4-diazepine hydrochloride (Compound No. 24) Compound of Compound No. 15 1.00 g (2.19 mmo)
3.75 g (30 mmol) of thionyl chloride was added to a mixed solution of l) and 10 ml of chloroform, and the same operation as in Example 21 was carried out to obtain 0.63 g (60%) of the title compound.

Melting point 183-186 ° C. MS (M / Z) CI: 476 (M ⁺ + 1) NMR (CDCl ₃ ) δ: 2.40-3.30 (m, 4H), 3.12 (s,
3H), 3.44-3.52 (m, 3H), 3.72 (s, 2H), 3.70-4.00 (m, 2
H), 6.80 (d, J = 9.0Hz, 2H), 7.10 (dd, J = 9.0,2.4Hz, 2H),
7.34 (d, J = 8.4Hz, 2H), 7.65 (d, J = 8.4Hz, 2H) Elemental analysis (C ₁₉ H ₂₃ N ₃ O ₄ S ₂ ClF HCl): Theoretical value: C, 44.53; H, 4.72 ; N, 8.20% Measured value: C, 44.84; H, 5.37; N, 8.24%

Example 24 6-acetoxy-1-[(4-fluorophenyl) methyl] -4- [4-[(methylsulfonyl) amino] phenylsulfonyl] hexahydro-1H-1,4-diazepine (Compound No. 25 ) Compound of Compound No. 15, 1.94 g (4.25 mmo)
A mixture of l) and 10 ml of acetic anhydride was refluxed for 1 hour. Then, the same operations as in Example 22 were carried out to obtain 1.09 g (51%) of the title compound.

Melting point 132-139 ° C. MS (M / Z) CI: 500 (M ⁺ + 1) NMR (CDCl ₃ ) δ: 1.98 (s, 3H), 2.70-2.90 (m,
4H), 3.08 (s, 3H), 3.20-3.30 (m, 3H), 3.48-3.80 (m, 2
H), 3.68 (s, 2H), 6.82 (d, J = 9.0Hz, 2H), 7.14 (dd, J = 9.
0,3.6Hz, 2H), 7.30 (d, J = 9.0Hz, 2H), 7.68 (d, J = 9.0Hz,
2H) Elemental analysis (C ₂₁ H ₂₆ FN ₃ O ₆ S ₂ 2.25H ₂ O): Theoretical value: C, 46.70; H, 5.69; N, 7.78% Measured value: C, 46.73; H, 5.52; N, 7.72%

Example 25 6-acetoxy-1- (1-methylbenzimidazol-2-yl) -4- [4-[(methylsulfonyl) amino] phenylsulfonyl] hexahydro-1H-1,4
-Diazepine (Compound No. 26) Compound of Compound No. 21 0.47 g (0.98 mmo
A mixture of l) and 10 ml of acetic anhydride was refluxed for 2 hours. Then, the same operation as in Example 22 was carried out to obtain 0.22 g (43%) of the title compound.

Melting point 104-110 ° C. MS (M / Z) EI: 521 (M ⁺ ), CI: 522 (M ⁺ +1) NMR (CDCl ₃ ) δ: 2.00 (s, 3H), 3.05 (s, 3H) ),
3.50-3.88 (m, 12H), 7.15-7.50 (m, 4H), 7.35 (d, J = 9.0H
z, 2H), 7.78 (d , J = 9.0Hz, 2H) Elemental analysis _{(C 22 H 27 N 5 O} 6 S 2 0.75H 2 O): theory: C, 49.38; H, 5.37 ; N, 13.10 % Measured value: C, 49.66; H, 5.46; N, 13.11%

Pharmacological test Antiarrhythmic activity was 1-10 mg / kg in anesthetized guinea pigs.
The test compound was intravenously administered at a dose within the range of, and the effect on the electrocardiogram was measured (Study Example 1). In the electrocardiogram, QRS interval (initial sway interval), PR interval (sinoatrial chamber excitatory conduction time) and QTc time (heartbeat correction QT interval) were measured. Generally Class II
Compounds showing type I antiarrhythmic activity were identified by QR in the electrocardiogram.
QT without affecting S interval and PR interval
It is said that only the c time is selectively increased. On the other hand, the effect of the test compound on the left coronary artery ligation-reperfusion-induced acute ventricular fibrillation model in anesthetized rats was examined (Test Example 2). That is, the effect of the test compound on the incidence of symptoms such as extrasystole, ventricular tachycardia, ventricular fibrillation, and cardiac arrest that occurred in the treated rats was examined.

Test Example 1: Effects on guinea pig blood pressure, heart rate, and electrocardiogram: Hartley male guinea pigs 1 group 3 to 5 animals,
Urethane was anesthetized by intraperitoneal administration of 1 to 1.5 g / 10 ml / kg. The left jugular vein and artery were cannulated and used for drug (test compound) administration and blood pressure measurement, respectively. For blood pressure, a limb standard lead II was derived from an electrocardiogram via a pressure transducer and an amplifier, and each was simultaneously analyzed by introducing it into an ECG Processor (Softron, SBP-2). Changes in blood pressure were shown as mean blood pressure, and changes in electrocardiogram were measured by QRS interval, PR interval, QT interval (electrical ventricular systolic time) and QTc time. The changes in QRS interval, PR interval and QTc time after administration of the test compound in anesthetized guinea pigs are shown in Table 1 as a ratio relative to those before the administration of the test compound and are shown in Table 1.

[0162]

[Table 1]

As shown in Table 1, the compounds of the present invention, especially the compound of Compound No. 15 (Compound 15), were treated with DL as a control drug.
-Compared to sotalol, it has an excellent class by extending only QTc time without affecting QRS interval and PR interval.
It exhibited a type III antiarrhythmic-like effect.

Test Example 2: Effect on rat left coronary artery ligation-reperfusion-induced acute ventricular fibrillation model Ten Wistar male rats per group were intraperitoneally administered with pentobarbital sodium 50 mg / kg. An artificial ventilation cannula was orally inserted into the trachea. Clark et al. (J. Pharmacol. Meth., 3,
357 (1980)) artificial respiration (2 cc / 100 g, 5
5 times / min) Open the left chest with the 4th rib underneath, rupture the apex, expose the heart to the outside of the thorax, and use a suture with a needle to perform S
A thread was passed around the left coronary artery according to the method of elye et al. (Angiology, 11, 398 (1960)). The end of the thread passed through the polyethylene cannula and out of the thorax. After the heart was once placed in the thorax and left for about 10 to 15 minutes, tension was applied to the thread to ligate the left coronary artery. After ligation for 5 minutes, the tension was released and blood circulation was restarted. 3 just before ligation
The electrocardiogram was observed for 0 minutes. The drug (test compound) was intravenously administered 5 minutes before the left coronary artery ligation. Arrhythmias were evaluated by recording electrocardiogram of standard limb II leads, and extrasystoles, ventricular tachycardia, ventricular fibrillation, and cardiac arrest were observed, and the results were expressed as the appearance rate. The effect of the compound of the present invention on the model of left coronary artery ligation-reperfusion-induced acute ventricular fibrillation in anesthetized rats is shown in Table 2 as a comparison with physiological saline and DL-sotalol.

[0165]

[Table 2]

As shown in Table 2, compound No. 15 of the present invention
Of the compound showed similar antiarrhythmic activity to DL-sotalol used as a control drug.

Test Example 3: Mouse Acute Toxicity Test Compound 100, 50, 25 mg / kg of Compound No. 15 was intravenously administered to 2 groups of 1 male ICR mice that had been fasted overnight, and DL-sotalol hydrochloride was used as a control. Salt 12
Intravenous administration of 5, 62.5, 31.3 mg / kg, observation of symptoms from immediately after administration to 4 hours later, and
Life and death by the week were judged. Also, compound No. 15 of compound 500, 250, 125, 62.5, 31.3 m
g / kg (0.5% MC (methyl cellulose) suspension)
Was orally administered and examined in the same manner. These results are shown in Table 3,
4 and 5 respectively.

[0168]

[Table 3]

[0169]

[Table 4]

[0170]

[Table 5]

As shown in Tables 3, 4, and 5, the compound of Compound No. 15 of the present invention showed extremely low toxicity in intravenous administration as compared with DL-sotalol used as a control drug. It also showed extremely low toxicity upon oral administration.

Formulation Example 1 Capsules containing the following ingredients were produced by known pharmaceutical techniques.

[0173]

INDUSTRIAL APPLICABILITY The compound of the present invention and a pharmacologically acceptable salt thereof have excellent antiarrhythmic action (particularly class III antiarrhythmic action), and various heart diseases, especially arrhythmia (for example, atrial fibrillation). , Ventricular fibrillation, etc.).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 403/04 235 C07D 403/04 235

Claims (17)

[Claims] 1. A compound of the formula (I) [In the formula, R ¹ represents a hydrogen atom, an amino group, a nitro group, or
NHSO ₂ CH ₃ is shown, R ² is a hydroxyl group, —OC (O)
—R ⁴ (R ⁴ represents an alkyl group, an aryl group or a heteroaryl group, and the aryl group and the heteroaryl group have an alkyl group, an alkoxy group, a halogen atom, —N on the ring.
HSO ₂ CH ₃ , a nitro group and an amino group may have a substituent) or a halogen atom, and R ³ represents a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, a formula (1), (2), (3), (4) or (5) (In the formula, R ⁵ represents an alkylene group, R ⁶ represents a hydrogen atom,
Alkyl group, alkoxy group, halogen atom, -NHSO
₂ CH ₃ , a nitro group or an amino group, and R ⁷ represents a hydrogen atom or an alkyl group). ]
A hexahydro-1H-1,4-diazepine derivative represented by or a pharmaceutically acceptable salt thereof. 2. The hexahydro-1H-1,4-diazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ³ in the formula (I) is a hydrogen atom. 3. In the formula (I), R ³ is —C (O) CH.
Hexahydro-1H-1,4- according to claim 1, which is _3.
A diazepine derivative or a pharmacologically acceptable salt thereof. 4. In the formula (I), R ¹ is —NHSO ₂ C.
Hexahydro-1H-1,4 according to claim 1, which is H _3.
-Diazepine derivatives or pharmaceutically acceptable salts thereof. 5. In the formula (I), R ¹ is —NHSO ₂ C.
H ₃ and R ² are hydroxyl groups, and R ³ is of the formula (1 ′) [In the formula, R ⁶ represents a hydrogen atom, an alkyl group, an alkoxy group,
Halogen atom, -NHSO ₂ CH _3, a nitro group or an amino group. ] The hexahydro-1H-1,4-diazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by: 6. In the formula (I), R ¹ is —NHSO ₂ C.
H ₃ , R ² are —OC (O) CH ₃ , and R ³ is of the formula (1 ′) [In the formula, R ⁶ represents a hydrogen atom, an alkyl group, an alkoxy group,
Halogen atom, -NHSO ₂ CH _3, a nitro group or an amino group. ] The hexahydro-1H-1,4-diazepine derivative or the pharmaceutically acceptable salt thereof according to claim 1, which is a group represented by: 7. A formula (IV) R ^3a —Hal (IV) [wherein R ^3a is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, a formula (1), (2), (3) or ( 4) [Chemical 5] (In the formula, R ⁵ represents an alkylene group, R ⁶ represents a hydrogen atom,
Alkyl group, alkoxy group, halogen atom, -NHSO
₂ CH ₃ , a nitro group or an amino group, and R ⁷ represents a hydrogen atom or an alkyl group).
al represents a halogen atom. ] The compound represented by the formula (II): [In the formula, R represents an alkyl group, an aryl group or a heteroaryl group, and the aryl group or the heteroaryl group has an alkyl group, an alkoxy group, a halogen atom, or -NH on the ring.
It may have a substituent selected from SO ₂ CH ₃ , a nitro group and an amino group. ] 6-acyloxyhexahydro-1H-1,4-diazepine represented by or a formula
(III) [Chemical 7] [In the formula, R has the same meaning as described above. ] By reacting with 1-acyl-6-hydroxyhexahydro-1H-1,4-diazepine represented by the following formula (V): [In the formula, R ^3a and R are as defined above. ] And a compound represented by the formula (VI): [In the formula, R ^3a has the same meaning as described above. ] The compound of the formula (VII) [In the formula, R ¹ represents a hydrogen atom, an amino group, a nitro group, or
NHSO ₂ CH ₃ is shown, and Hal has the same meaning as above. ] The compound represented by the formula (VIII): [In the formula, R ¹ and R ^3a have the same meanings as described above. ] The manufacturing method of the compound represented by these. 8. Formula (IX): [In the formula, Hal represents a halogen atom. A compound represented by the formula (II) [In the formula, R represents an alkyl group, an aryl group or a heteroaryl group, and the aryl group or the heteroaryl group has an alkyl group, an alkoxy group, a halogen atom, or -NH on the ring.
It may have a substituent selected from SO ₂ CH ₃ , a nitro group and an amino group. ] 6-acyloxyhexahydro-1H-1,4-diazepine represented by or a formula
(III) embedded image [In the formula, R has the same meaning as described above. ] By reacting with 1-acyl-6-hydroxyhexahydro-1H-1,4-diazepine represented by the following formula (X): [In the formula, R has the same meaning as described above. ] The compound represented by the formula (XI) is characterized in that the compound is hydrolyzed. A method for producing a compound represented by the formula: 9. Formula (XI): And a compound represented by the formula (XX) R ³ —Hal (XX) [wherein R ³ is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, formulas (1), (2), and (3) ,
(4) or (5) (In the formula, R ⁵ represents an alkylene group, R ⁶ represents a hydrogen atom,
Alkyl group, alkoxy group, halogen atom, -NHSO
₂ CH ₃ , a nitro group or an amino group, and R ⁷ represents a hydrogen atom or an alkyl group).
al represents a halogen atom. ] The compound represented by the formula (XII): [In the formula, R ³ has the same meaning as described above. ] The manufacturing method of the compound represented by these. 10. Formula (XI):The compound represented by the formula (XII
I) Ar-CH = CH_Two (XIII) [In the formula, Ar represents an aryl group or a heteroaryl group.
However, the aryl group or heteroaryl group has an alkyl group on the ring.
Group, alkoxy group, halogen atom, -NHSO _TwoCH
_ThreeHaving a substituent selected from a nitro group and an amino group
May be. ] Reacting with a compound represented by
Characterized by the formula (XIIa):[Wherein, R^3cIs the formula (1 ″), (2 ″) or (3 ″)(Where R⁶Is a hydrogen atom, an alkyl group, an alkoxy group,
Halogen atom, -NHSO_TwoCH_Three, Nitro group or
A group represented by (denoting a mino group) is shown. ] Compound represented by
Method of manufacturing a product. 11. Formula (XI):The compound represented by formula (XIV) Ar-CHO (XIV) [wherein Ar represents an aryl group or a heteroaryl group] in a solvent.
However, the aryl group or heteroaryl group has an alkyl group on the ring.
Group, alkoxy group, halogen atom, -NHSO _TwoCH
_ThreeHaving a substituent selected from a nitro group and an amino group
May be. ] And a reductive amination
A reaction of the formula (XIIb)[Wherein, R^3dIs of formula (1 '), (2') or (3 ')(Where R⁶Is a hydrogen atom, an alkyl group, an alkoxy group,
Halogen atom, -NHSO_TwoCH_Three, Nitro group or
A group represented by (denoting a mino group) is shown. ] Compound represented by
Method of manufacturing a product. 12. The formula (XV): [In the formula, Hal represents a halogen atom. A compound represented by the formula (II) [In the formula, R represents an alkyl group, an aryl group or a heteroaryl group, and the aryl group or the heteroaryl group has an alkyl group, an alkoxy group, a halogen atom, or -NH on the ring.
It may have a substituent selected from SO ₂ CH ₃ , a nitro group and an amino group. ] 6-acyloxyhexahydro-1H-1,4-diazepine represented by or a formula
(III) [In the formula, R has the same meaning as described above. ] By reacting with 1-acyl-6-hydroxyhexahydro-1H-1,4-diazepine represented by the following formula (XVI): [In the formula, R has the same meaning as described above. ] And a compound represented by the formula (XVII): A mixture of the compounds represented by formula (XVII) The compound represented by formula (XVIII) is converted to a compound of formula (XVIII) by alkylation, acylation or alkoxycarbonylation. [Wherein R ^3b is an alkyl group, an acyl group, an alkoxycarbonyl group, a formula (1), (2), (3), (4) or (5) (In the formula, R ⁵ represents an alkylene group, R ⁶ represents a hydrogen atom,
Alkyl group, alkoxy group, halogen atom, -NHSO
₂ CH ₃ , a nitro group or an amino group, and R ⁷ represents a hydrogen atom or an alkyl group). ]
A compound represented by the formula (X
IX) [Chemical 34] [In the formula, R ^3b has the same meaning as described above. ] The compound represented by the formula [XXII] [In the formula, R ^3b has the same meaning as described above. ] The manufacturing method of the compound represented by these. 13. Formula (XXI): [In the formula, R ¹ represents a hydrogen atom, an amino group, a nitro group, or
NHSO ₂ CH ₃ is shown, and R ³ is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, formula (1),
(2), (3), (4) or (5) (In the formula, R ⁵ represents an alkylene group, R ⁶ represents a hydrogen atom,
Alkyl group, alkoxy group, halogen atom, -NHSO
₂ CH ₃ , a nitro group or an amino group, and R ⁷ represents a hydrogen atom or an alkyl group). ]
A compound represented by the formula (I ′) embedded image characterized by reacting the compound represented by the formula (I ′) with or without a solvent. [In the formula, R ¹ and R ³ have the same meanings as described above, and R ^2a represents -O.
^{C (O) -R 4 (R} 4 is an alkyl group, an aryl group or a heteroaryl group, said aryl group, the heteroaryl group is an alkyl group on the ring, an alkoxy group, a halogen atom, -NHSO ₂ CH _3, nitro A group and an amino group may have a substituent). ] The manufacturing method of the compound represented by these. 14. Formula (XXI): [In the formula, R ¹ represents a hydrogen atom, an amino group, a nitro group, or
NHSO ₂ CH ₃ is shown, and R ³ is a hydrogen atom, an alkyl group, an acyl group, an alkoxycarbonyl group, formula (1),
(2), (3), (4) or (5) (In the formula, R ⁵ represents an alkylene group, R ⁶ represents a hydrogen atom,
Alkyl group, alkoxy group, halogen atom, -NHSO
₂ CH ₃ , a nitro group or an amino group, and R ⁷ represents a hydrogen atom or an alkyl group). ]
A compound represented by the formula (I ″): [In the formula, R ¹ and R ³ have the same meanings as described above, and R ^2b represents a halogen atom. ] The manufacturing method of the compound represented by these. 15. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 16. The pharmaceutical composition according to claim 15, which is an agent for preventing or treating heart disease. 17. The pharmaceutical composition according to claim 15, which is an agent for preventing or treating arrhythmia.