WO1996038422A1

WO1996038422A1 - Fused benzodiazepinone derivatives and medicinal composition of the same

Info

Publication number: WO1996038422A1
Application number: PCT/JP1996/001462
Authority: WO
Inventors: Toshihiro Watanabe; Akio Kakefuda; Akihiro Tanaka
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1995-05-31
Filing date: 1996-05-30
Publication date: 1996-12-05
Also published as: KR19990021835A; AU5844796A

Abstract

Fused benzodiazepinone derivatives represented by general formula (I) or salts thereof which have medicinal effects,in particular, preventive or therapeutic effects on heart diseases in which muscarine M2 receptors participate, wherein X represents CH or N; Y represents oxygen, NR4, S(O)¿n? or NR?5¿CO, wherein R?4 and R5¿ are the same of different and each represents hydrogen or lower alkyl; and n is an integer of from 0 to 2; A represents lower alkylene; R?1 and R2¿ are the same or different and each represents hydrogen, lower alkyl, cycloalkyl, optionally substituted aryl or optionally substituted aralkyl, or R?1 and R2¿ together with the nitrogen atom to which they are bonded may form a 4- to 9-membered nitrogen-containing saturated heterocycle optionally further containing one of oxygen, sulfur and nitrogen atoms and optionally having substituent(s); and R3 represents hydrogen, optionally substituted lower alkyl, hydroxy, lower alkoxy, nitro, halogeno, lower acyl or optionally substituted amino.

Description

Description Condensed benzodiazepinone derivatives and pharmaceutical compositions thereof

The present invention relates to a medicament, in particular, a condensed benzodiazepinone derivative or a salt thereof, and a pharmaceutical composition containing the compound. These materials are useful in the prevention or treatment of cardiac diseases involving muscarinic M ₂ receptor. Background art

Brain arrhythmia is a condition in which the pulse rate decreases due to a functional or organic disorder of the heart's conduction system. The main types of bradyarrhythmias are sinus insufficiency syndrome and atrioventricular block, of which about 50% of all bradycardia patients are caused by impairment of the sinus node, which acts as a cardiac pacemaker. The atrioventricular block is due to a failure of the atrioventricular node that connects the atrium and ventricle.

Patients with bradycardia have a low blood output from the heart, resulting in a lack of oxygen demand in the body, causing symptoms such as dizziness and convulsions, and can lead to death in severe cases.

At present, artificial pacemakers are mainly used to treat bradyarrhythmias. In addition, nervous syncope (vagal syncope, etc.) is indicated as a disease for which artificial pacemakers are indicated. The disease is a condition in which the vagus nerve is hyperexcited due to hyperconstriction of the heart and mental anxiety, resulting in syncope as a result of cerebral ischemia via transient cardiac arrest.

Drugs useful in these diseases include heart blockers, S-blockers, theophylline and disopyramide, which inhibit hyperconstriction of the heart, and atotopin (muscarinic receptors), which suppress vagal hyperexcitability, which causes functional disorders. Although an antagonist is used, a musculin receptor antagonist with particularly improved side effects is expected to replace an artificial pacemaker as a chemical pacemaker. Conventionally, compounds having a muscular phosphoric acid receptor antagonistic activity have been used in various forms such as tachycardia, anti-bradycardia, bronchial expansion, gastrointestinal motility suppression, acid secretion suppression, blood loss, mydriasis, bladder contraction suppression, sweat reduction It is known to cause physiological effects. It is known that there are at least three subtypes of this muscarinic receptor. Mainly receptors in the brain or the like, M ₂ receptors in the heart or the like, and M ₃ receptors are present in smooth muscle and glandular tissue.

Many compounds having affinity for the muscarinic receptor are known to date. Among them, atotopin has a strong affinity for muscarinic receptors and is used as an anti- bradycardic agent to block its action.

However, Atto port pin, M, is a subtype of muscarinic receptors, _2, has substantially the same affinity to all the M _3, the non-selective because it antagonizes the (biological chemistry, 4 2 (5 ), 38 1 (1991)). To prevent side effects such as bile, nausea, urinary retention, constipation, and mydriasis, which are thought to be caused by musculin receptor antagonism other than the intended anti-bradycardia effect. Was known to have. In particular, atotopin is known to have central side effects such as mental dysfunction due to its central migration, and its improvement has been demanded.

In recent years, subtypes of the muscarinic receptor have been studied, and compounds that selectively antagonize the ,, Μ ₂ , and M ₃ receptors have been studied.

Among them, in particular compounds having a selective antagonism to M ₂ receptor, it is expected effects such as KoJo pulse is and expected side effects based on the other muscarinic receptor subtypes antagonism is small.

Further, a compound having a low central nervous system is expected to act as a drug acting only on the heart without having any side effects of the central system, particularly, psychiatric disorders caused by receptors.

The compound having a KoJo pulse arrhythmia effect based on known prior art] i ₂ receptor antagonism, is known pyridinium Dobenzoji completion Zepinon derivative is fused base Nzojiazepinon derivatives having a substituted aminoalkyl carbonylation le radical I have. In other words, Japanese Patent Publication No. 5-684744 discloses a 5,1,1-dihydro-16H-pyrido [2,3-b] [1] having an 11-piperidinylalkylcarbonyl group at the 11-position. , 4] One Benzodiazepi 6-one derivatives are disclosed and included therein. 1 1 1 [[2- (Getylaminomethyl) 1 1 -piperidinyl] acetyl] 1, 5 1 1 1 [2,3-b] [1,4] Benzodazepin-1-one (AF-DX116) is a compound currently under development.

The condensed benzodiazepinone derivative of the present invention differs from these compounds in having a substituted phenylacetyl group, and is far superior in M ₂ selectivity and M ₂ receptor antagonism.

Further, regarding condensed benzodiazepinone derivatives having a substituted phenylacetyl group, Cohen VI et al. (Eur. J. Med. Chem. Vo 130, 61-69 (1 995)) states that M A dibenzodiazepinone derivative represented by the following general formula having _2- receptor antagonism has been disclosed and reported to be useful for central diseases such as Alzheimer's. However, there are no disclosures about the cardiac effects of these compounds, and their high central nervous potential may cause central nervous system side effects when used as a therapeutic agent for heart disease. Met.

(In the formula, n represents 2 to 5, R and R ₂ represent a lower alkyl group or the like.)

The compound of the present invention is a compound having a substituted funinyl acetyl group.

Hue via a conductor, i.e., an oxygen atom, a sulfur atom or a nitrogen atom, as described below. Is a fused benzodiazepinone derivative having a substituent

It is completely different from the compound of the literature in that it has a different structure, is superior in M ₂ selectivity, and particularly has a low central migration property.

An object of the present invention have a potent and selective Mus force phosphoric M ₂ receptor antagonism different in chemical structure from the conventional compounds, and less central migratory, compounds which have a cardiac-specific effects Is to provide. Disclosure of the invention

The present inventors have, per compound having a Mus force phosphoric M ₂ receptor antagonism, sharpness meaning studied a result, a substituted Fueniruasechiru group, i.e., bind to Fuweniru group via an oxygen atom, a sulfur atom or a nitrogen atom substituted have preventive and therapeutic effects of the novel condensation base Nzojiazepinon derivative excellent Mus force phosphoric M ₂ receptor involved heart disease with Fuweniruasechiru group substituted with a group at the 5-position, and Mii that low side effect The present invention has been completed.

That is, the present invention relates to a fused benzodiazepinone derivative represented by the following general formula (I) or a salt thereof.

(The symbols in the formula have the following meanings, X; CH or N

Y: an oxygen atom or a group represented by the formula NR ⁴ , S (0) 若しくは or NR ⁵ CO

R ⁴ , R ⁵ : same or different, hydrogen atom or lower alkyl group

n; integer from 0 to 2

A: lower alkylene group

R ¹ and R ^{2 are the} same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, or R ¹ is integrated with the nitrogen atom to be bonded, and may further contain any one of an oxygen atom, a sulfur atom and a nitrogen atom, and may form a 4- to 9-membered nitrogen-containing saturated heterocyclic group. The 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent R ³ : a hydrogen atom, a lower alkyl group which may have a substituent, a hydroxyl group, a lower alkyl group. Coxy group, nitro group, halogen atom, lower acyl group or amino group with substituents

Preferred compounds in the compound of the present invention include, in the above general formula (I), R ¹ and R ² are the same or different and are substituted with a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a substituent of the following group B. An aryl group, an aralkyl group which may be substituted with a substituent of the following group B, or a nitrogen atom bonded to R ¹ , and one of an oxygen atom, a sulfur atom and a nitrogen atom A 4- to 9-membered nitrogen-containing saturated heterocyclic group may be formed, and the 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent represented by the following group C. R ³ may be a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, a nitro group, a halogen atom, a lower acyl group or a group of the following group E which may be substituted with a substituent of the following group D. Mono- or di-substituted with Even though it is may Ryo amino group, a fused ben Zojiazepinon derivative or a salt thereof.

Group B: substituted with a halogen atom, a hydroxyl group, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, an amino group, a mono- or di-lower alkylamino group, a methylenedioxy group, or a lower alkyl group; Good 5 to 7 members A 5- to 7-membered nitrogen-containing saturated heterocyclic group which may be substituted with a lower saturated heterocyclic group or a lower alkoxycarbonyl group, or a lower alkyl group which may be substituted with a halogen atom,

Group C: a lower alkyl group, a lower alkoxy group, a lower alkylthio group, an aryl group which may be substituted with a substituent of Group B, an aryl group which may be substituted with a substituent of Group B An aryloxy group optionally substituted with a substituent of group B, an aralkyloxy group optionally substituted with a substituent of group B, an arylthio group optionally substituted with a substituent of group B, B A aralkylthio group, an amino group, a mono or di-lower alkylamino group, an arylamino group, or an aralkylamino group, which may be substituted with a group of substituents;

Group D: halogen atom, hydroxyl group or amino group,

Group E: a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, or a lower alkylsulfonyl group.

More preferred compounds are a 5- to 7-membered nitrogen-containing saturated heterocyclic group in which R ¹ and R ² are the same or different and may be substituted with a hydrogen atom, a lower alkyl group, a cycloalkyl group, or a lower alkyl group. An aryl group which may be substituted, an aryl group which may be substituted with a 5- to 7-membered nitrogen-containing saturated heterocyclic group which may be substituted with a lower alkyl group, or R ¹ and R ² May be integrated with the nitrogen atom to be bonded, and may further contain any one of an oxygen atom, a sulfur atom and a nitrogen atom, and may form a 4- to 9-membered nitrogen-containing saturated heterocyclic group. The 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent represented by the following group C1, wherein R ³ is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, A halogen atom, a lower acyl group or a group E group below A mono-amino group which may be substituted,

A fused benzodiazepinone derivative or a salt thereof.

Group C: lower alkyl group, lower alkoxy group, lower alkylthio group, aryl group, aralkyl group, aryloxy group, aralkyloxy group, arylthio group, aralkylthio group, amino group, mono or di-lower alkylamino group, arylamino group, Or an aralkylamino group, Group E: a lower alkyl group, a lower acyl group, a lower alkoxycarbonyl group, or a lower alkylsulfonyl group.

And X is CH. A condensed benzodiazepinone derivative or a salt thereof, Y is an oxygen atom, a condensed benzodiazepinone derivative or a salt thereof, or Y is a group represented by the formula NH CO. Its salts are particularly preferred.

The present invention relates to a pharmaceutical composition comprising a condensed benzodiazepinone derivative represented by the above general formula (I) or a salt thereof and a pharmaceutically acceptable carrier, particularly a heart disease involving a muscarinic M 2 receptor. It also relates to prophylactic or therapeutic agents. In particular, sinus insufficiency syndrome including sinus bradycardia, sinus arrest or bradycardia tachycardia syndrome or bradyarrhythmias including vagal excitability-induced bradycardia including atrioventricular blockade, neural syncope (carotid sinus hypersensitivity) And the like.

Hereinafter, the compound (I) of the present invention will be described in detail.

In the definition of the general formula in this specification, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Accordingly, the term “lower alkyl group” specifically refers to, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group , Neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3 — Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-Ethylbutyl group, 2-Ethylbutyl group, 1,1,2-Trimethylpropyl group, 1,2,2-Trimethylpropyl group, 1-Ethyl-1-methylpropyl Group, 1 Echiru 2-methylpropyl group and the like. Preferred are a methyl group and an ethyl group.

As the “lower alkylene group”, an alkylene group having 1 to 6 carbon atoms is preferable, and specifically, a methylene group, an ethylene group, a methylmethylene group, a trimethylene Group, propylene group, 2-propylene group, dimethylmethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, 2-ethylethyl group, 2,2-dimethylethylene group, 1,1-dimethylethylene group, ethylmethylmethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group Methylene group, 1,1-dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 2,3-dimethyltrimethylene group, 1, 2-dimethyltrimethylene group, 1,1,2-trimethylethylene group, getylmethylene group, hexamethylene group, 1-methylpemethylene group Tamechiren group, 1, -1-dimethyl tetramethylol alkylene group, 2, 2-dimethyl tetramethylene group and the like. Preferably, they are an ethylene group and a trimethylene group.

The "cycloalkyl group" preferably has 3 to 8 carbon atoms, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and the like. Preferably it is a cyclohexyl group.

The “aryl group_) means a carbocyclic aryl group unless otherwise specified, and specifically includes, for example, a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group and the like, preferably a phenyl group.

The “aralkyl group” means a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with the above “aryl group”. For example, when an aryl group is exemplified by a phenyl group, specifically, Benzyl group, phenyl group, 1-phenylethyl group, 3-phenylpropyl group, 2-phenylpropyl group, 1-phenylpropyl group, 1-methyl1-2-phenylethyl group, diphenylmethyl group (benzhydryl group), trityl group And the like. Preferred are a benzyl group and a phenethyl group.

Becomes the nitrogen atom to which binds with R ² and the "R ', te further oxygen atom, sulfur atom or nitrogen atom les, comprise one Zureka 1 les, and to also be 4-9 membered nitrogen-containing saturated Preferable specific examples of the “nitrogen-containing saturated heterocyclic group” in “May form a ring group” include those shown below.

The “halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom and the like. The term "lower acetyl group" means a lower alkyl group such as a formyl group and an acetyl group, a propionyl group, a butylyl group, an isobutyryl group, a valeryl group, an isovaleryl group, a bivaloyl group, and a hexanoyl group.

The substituent in the “aryl group optionally having substituent (s)” or the “aralkyl group optionally having substituent (s)” may be any as long as it is generally used as a substituent of an aryl group. It is preferably a substituent shown in the above group B, and more preferably a 5- to 7-membered nitrogen-containing saturated heterocyclic group which may be substituted with a lower alkyl group. One or more of these substituents may be substituted.

Here, the “5- to 7-membered nitrogen-containing saturated ring group” is a 5- to 7-membered ring of the above “nitrogen-containing saturated heterocyclic group”, preferably a pyrrolidyl group, a piperidyl group, or a morphonyl group And a piperazinyl group.

Becomes the nitrogen atom to which binds with R ² and the "R ', further oxygen atom, form a heterocyclic group a sulfur atom or to any one of comprise been 4 to be 9-membered nitrogen-containing saturated nitrogen atom The 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent, and the substituent may be a carbon atom or a nitrogen atom of a nitrogen-containing saturated heterocyclic ring. Any substituent may be used as long as it is used as a substituent of It is a substituent shown in the above-mentioned group C, and is more preferably a substituent shown in the above-mentioned group C1. Particularly preferred are a lower alkyl group, an aryl group, an aralkyl group, an aryloxy group, an arylamino group and an aralkyloxy group.

As the substituent in the `` lower alkyl group optionally having substituent (s) '' for R ³ , any group may be used as long as it is generally used as a substituent for a lower alkyl group. Group.

The substituent in the amino group J which may have a substituent in R ³ may be any of those usually used as a substituent of a nitrogen atom of an amino group, but is preferably a group of the group E The amino group may be mono- or di-substituted by any of these groups, and is preferably mono-substituted.

The "lower alkylthio group" and "lower alkoxy group" are each a group in which a hydrogen atom of a mercapto group or a hydroxyl group is substituted by the above-mentioned "lower alkyl group J", and is preferably a methylthio group, an ethylthio group, or Examples include a methoxy group and an ethoxyquin group.

The “mono- or di-lower alkylamino group” is a group in which one or two of the hydrogen atoms of the amino group are substituted with the above “lower alkyl group”, and is preferably a methylamino group, an ethylamino group, or a dimethylamino group. Clogged, getylamino group.

“Lower alkoxycarbonyl groups j include methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyl A straight-chain or branched alcohol having 1 to 6 carbon atoms, such as a oxycarbonyl group, an isopentyloxycarbonyl group, a neopentyloxycarbonyl group, a tert-pentyloxycarbonyl group, a hexyloxycarbonyl group, The term "lower alkylsulfonyl group" means a group in which a sulfur atom of a sulfonyl group is substituted by any of the above-mentioned "lower alkyl groups".

Specific examples of "aryloxy" and "arylthio" include phenoxy And ether or thioether residues derived from aromatic monocyclic or polycyclic hydrocarbon hydroxy or mercapto compounds such as (or phenylthio) and naphthyloxy (or thio) groups.

“Aralkyloxy group” or “aralkylthio group” means a group in which any hydrogen atom of the above “lower alkoxy group” or “lower alkylthio group” has been substituted with the above “aryl group”. Benzyloxy (or thio) group, phenethyloxy (or thio) group, 1-phenylethoxy (or ethylthio) group, 3-phenylloopoxy (or propylthio) group, 2-phenyloxypropyl (or propylthio) ) Group, 1-phenylloopoxy (or propylthio) group and the like.

“Arylamino group” or “aralkylamino group” refers to a group in which any hydrogen atom of an amino group is substituted with the above “aryl group” or “aralkyl group”. Specifically, a phenylamino group, Examples include a naphthylamino group, a benzylamino group, a phenethylamino group and the like.

The compound (I) of the present invention may have tautomers, geometric isomers, and optical isomers based on asymmetric carbon atoms, depending on the type of the substituent. The present invention includes all of these isomers, isolated or mixtures thereof.

The compound (I) of the present invention may form a salt with an acid. Such salts include mineral acids with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc., formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid Acid addition salts with organic acids such as acids, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid and the like can be mentioned. Furthermore, the present invention also includes hydrates of compound (I), solvates such as ethanol, and polymorphic substances.

[Manufacturing method]

The compound (I) of the present invention can be produced by applying various production methods. The typical manufacturing method is described below. (Method 1)

(I)

(Wherein, R ¹ , R ² , R ³ , A, X and Y have the above-mentioned meanings, and R ¹ ′ and R ² ′ are the same as R ¹ and R ² , or an amino-protecting group. And Ζ mean a halogen atom.)

The compound of the present invention represented by the general formula (I) is produced by reacting an alkyl halide (I) with an amino (ΒΙ).

In this reaction, compound (Μ) is equimolar to compound (H) in the absence of a solvent or in an organic solvent that does not participate in the reaction such as benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloroethane, methanol, or ethanol. It is advantageous to carry out the reaction at room temperature or under heating or by heating to reflux using a slight excess of mol. You.

In this reaction, secondary or tertiary bases such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, trimethylamine, triethylamine and dimethylamine, sodium iodide, sodium carbonate, sodium carbonate, hydrogencarbonate In some cases, the addition of an inorganic base such as sodium is advantageous for smoothly proceeding the reaction.

In order to suppress a side reaction, it is also possible to adopt a method in which a protecting group is introduced into the compound (10) to cause a reaction, and the protecting group is eliminated after the reaction. (Π0 is potassium imidophthalate, or a toluenesulfonyl group, an acetyl group, a phenacylsulfonyl group, a trifluoromethanesulfonyl group, a bisbenzenesulfonyl group, etc. It can be easily achieved by ordinary hydrolysis using hydrazine 1 τ hydrate.The term “protecting group J for the amino group” defined by R ¹ ′ and R ² ′ which are the groups of the compound of formula (Μ) It means a protecting group usually used by a trader, and is typically a lower alkanoyl group such as a formyl group, an acetyl group, a propionyl group, or the like as a protecting group for an acetyl group. Lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxyquincarbonyl group and BOC, lower alkanesulfonyl groups such as methanesulfonyl group and ethanesulfonyl group, methoxyacetyl group, methoxypropionyl group, benzoyl group, and benzyloquincarbonyl group An aliphatic acetyl group such as p-nitrobenzoyloxycarbonyl group, or a heterocyclic lower alkanoyl group such as a chenylacetyl group, a thiazolylacetyl group, a tetrazolylacetyl group, an azolylglycoxyloyl group, And a heterocyclic acyl group such as a chenylglyoxyloyl group.

Examples of the aralkyl-based amino-protecting group include a benzyl group, a p-nitrobenzyl group, a benzhydryl group, and a trityl group. Further, a tri-lower alkylsilyl group such as a trimethylsilyl group is exemplified.

The removal of the protecting group of the amino group may be carried out according to a conventional method. For example, when the protecting group is a tri-loweralkylsilyl group or the like, the removal can be easily performed by treating with water. Also, benzhydryl group, p-methoxybenzyl group, trityl group, ter If it is a protecting group such as t-butyl group or formyl group, it can be easily removed by treating it with an acid such as formic acid, trifluoroacetic acid, a mixture of trifluoroacetic acid and anisol, a mixture of hydrobromic acid and acetic acid, or a mixture of hydrochloric acid and dioxane. Is done.

Further, the compound (I) of the present invention can be obtained by performing an N-alkyl reaction by a conventional method such as reductive amination or substitution with a halogen compound on the amino compound after removing the protecting group for the amino group. it can.

(Method 2)

:

(Wherein R ′, R ² , R ³ , A, X, R ¹ ′, R ² ′ and Z have the above-mentioned meaning, and Y ² has 〇 or S.)

In the compound of the present invention, the compound wherein Y is an oxygen atom or a sulfur atom is hydroquine or It can also be obtained by reacting a thio compound (H ') with an alkyl halide (Iff').

This reaction is carried out in a solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile or dimethyl ether, in the presence of an inorganic base such as potassium carbonate or sodium hydrogen carbonate, usually at room temperature or under heating.

In this reaction, introduction and removal of a protecting group for an amino group can be carried out in the same manner as in Production Method 1. Also, if Y ² is S can also be led to compound Y is sulfoxide (so) or sulfone (S 0 ₂₎ by oxidation.

The compound (I) of the present invention thus produced is isolated or purified as it is or after subjecting it to a salt-forming treatment by a conventional method. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.

(Production method of raw material compounds)

The starting compound (I) of the present invention can be produced by the following method I or IT.

I. Method for producing a starting compound of the compound of the present invention (I) wherein Y is 0 or S (0) »

(i)

Hydrolysis

(Step b)

(W) (VI)

(Cor)

(Step c)

(Vtt)

(Wherein R ³ , A, X and Z have the above-mentioned meanings, R ′ is an ester residue, Y ² is 〇 or S, Y ³ is SO or S〇 ₂ and Z ′ is halogen In the compound (I) of the present invention, the starting compound (la) or (lb) of the compound in which Y is 〇 or S (0) „(n: 0 to 2) is represented by the above formula. , A ~ (! Produced by each process it can.

(Step a)

This step is a step of reacting a hydroxy or thio compound (W) with an alkyl halide (V) to obtain a compound (VI).

This reaction is carried out in a solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile, or dimethyl ether, in the presence of an inorganic salt group such as potassium carbonate or sodium hydrogen carbonate, usually at room temperature or under heating.

(Step b)

This step is a method for obtaining a compound (W) which is a carboxylic acid by hydrolyzing an ester compound (YD.)-This reaction is carried out by using a base such as sodium carbonate, sodium hydroxide, or trifluoroacetic acid; A conventional method of hydrolyzing in the presence of hydrochloric acid or the like can be applied.

(. Process)

This step is a step of obtaining an amide compound (Ia) by condensing amine 01) or a salt thereof with a carboxylic acid represented by the general formula (1) or a reactive derivative thereof according to a conventional method.

Reactive derivatives of compound (W) include acid halides such as acid chloride and acid promide; acid azide; N-hydroxybenzotriazol (HOBT); P-dinitrophenyl N-hydroxysuccinimi; And symmetrical acid anhydrides; mixed acid anhydrides with alkyl carbonic acid, p-toluenesulfonic acid, and the like. When the compound (W) is reacted with a free carboxylic acid, dicyclohexylcar positimide, 1-ethyl-3- (3-dimethylaminopropyl) carbopimid, 1,1 'monocarbonyldiimidazole, N, N' It is advantageous to carry out the reaction in the presence of a condensing agent such as —bis (2-oxo-3-oxo-subridinyl) phosphinic chloride, diphenylphosphoryl azide (DPPA).

The reaction conditions vary slightly depending on the starting compound, especially the type of reactive derivative of compound (W), but pyridine, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene, xylene, methylene chloride, The In an organic solvent inert to the reaction, such as chloroethane, chloroform, ethyl acetate, or acetonitrile, it is advantageous to react the starting compounds (II) and (VII) in equimolar amounts or the starting compound (W) in excess moles. is there.

Depending on the type of the reactive derivative or when using a salt of the raw material compound (Cor), an organic base such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, N-methylmorpholine, or carbonic acid is used in the reaction. It may be advantageous to carry out the reaction in the presence of a base such as potassium, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, an inorganic base such as 7j potassium oxide. Note that pyridin can also serve as a solvent.

The reaction temperature differs depending on the type of the reactive derivative and is set as appropriate.

(d process)

In this step, the raw material compounds (IT a) By mid Y ² is oxidizing a compound which is S, the present invention compound (I) Medium Y is sulfoxide (SO) or sulfone (S 0 ₂₎ at a reduction compound This is a step of obtaining a compound (lb).

In this reaction, sulfide (S) can be obtained by oxidizing sulfide (S) with hydrogen peroxide or a peracid (such as metabenzo-perbenzoic acid or peracetic acid) under mild conditions. Sulfone (S 0 ₂ ) can be obtained under strong conditions in the presence of excess oxidizing agent.

(ii)

(Wherein, R ³ , X, Υ ² , and を have the meaning described above.)

In the compound (I) of the present invention, the starting compound (1 ′) of the compound in which Υ is 0 or S is obtained by condensing a compound (Cor) with a carboxylic acid derivative (vr) by an ordinary method. ') Can be obtained. The reaction can be carried out in the same manner as in the above (Step c).

I. Method for producing a starting compound of the compound of the present invention (I) wherein Y is NR ⁴ or NR ⁵ CO

(Ic) (Id) (Wherein, R ³ , A, X, Z, and Z have the above-mentioned meanings.) In the compound (I) of the present invention, the starting compounds (Ic) and (Hd) of the compound wherein Y is NR ⁴ or NR ⁵ CO ) Can be produced by each of the steps a to c in the above reaction formula. (Step a)

This step is a step of reacting compound (H) with compound (VIV) by an amidation reaction to obtain compound (X).

This reaction can be carried out in substantially the same manner as in the method described in the above I (step c).

(Step b)

This step is a step of obtaining a compound (XI) having an amino group by reducing the compound (X) having a nitro group.

The reduction can be carried out according to the usual methods of metal / metal salts (zinc, iron, stannous chloride, etc.) or catalytic reduction (catalyst: palladium Z-carbon, platinum oxide, Raney nickel, etc.).

(c-1 process)

In this step, the compound (XI) and the compound (II) are reacted by an amidation reaction, and the compound (He) (the starting compound of the compound in which Y is NR ⁵ CO in the compound (I) of the present invention) ) Can be obtained.

This reaction can be carried out in substantially the same manner as in the method described in the above I (step c). (c-2 processes)

In this step, the compound (XI) is reacted with the alkyl halide (V) to obtain a compound (Id) (a starting compound of the compound of the present invention, wherein Y is NR ⁴ ).

This reaction can be carried out in substantially the same manner as in the method described in the above I (step a).上の Business availability

The compounds of the present invention, Mel useful for the prevention or treatment of cardiac diseases M ₂ receptors are involved.

Sinus dysfunction syndromes such as sinus bradycardia, sinus arrest, bradycardia tachycardia syndrome; atrioventricular block It may be useful as a prophylactic and / or therapeutic agent for other bradyarrhythmias such as vagus nerve excitation-induced bradycardia, and neuronal syncope (such as carotid sinus hypersensitivity).

In particular, the present invention compounds compared to the M ₃ receptor, high selectivity for M ₂ receptor, Furthermore, since the central migratory low reduced side effects bradyarrhythmia such effects on B thirst Ya central Useful as a preventive and therapeutic agent.

Affinity (IV, M ₂ and M _3), KoJo pulse effect based on M ₂ receptor antagonism of Mus force phosphate receptor of the present invention compounds, and central migration was confirmed by the following tests.

Muscarinic receptor affinity test (inv i tro) _

Male Wister rats (300-350 g) were suffocated with carbon dioxide on dry ice and then excised from the cerebral cortex, heart and submandibular gland. . Cerebral cortex membrane preparation together with ^{3 H-pirenzepine}

(Mi assay), pericardium specimen with ³ H—qu i nu clidi ny lb en zi 1 ate (QNB) (M ₂ ass ay). Submandibular gland membrane specimen is ³ H—N-one methy lsc op ol (M ₃ assa) with amine (NMS) 45 minutes each after incubation, filtered using Watma nGF / B fi 1 ter, and measured the radiation dose with a liquid scintillation counter .

Non specificbindi ng was determined by inc ub ati on by simultaneously adding 2X 1 0 ^_5 M atro P ine respectively. In addition, the preparation of the membrane, the preparation of the compound, and the incubation were all performed in HEP ES buffer [4- (2-hyroxy—et hyl) -1 -piperzainet hanesulfon icacid 20 mM, Na C 110 mM, gC 121 OmM, pH 7.5] was used.

Affinity Mus force phosphate receptor of the compounds C he ng an d P r υ soff CB ioch em. Phama col., 22, 30 9 9, 1 973) Thus, a labeled ligand ³ H- ^pirenzepine ( M, ass ay),

The negative logarithm of the dissociation constant calculated from the test compound concentration (IC ₅ ) that inhibits the binding of ³ H-QNB (M ₂ assay) and ³ H-NMS ( ₃ assay) by 50% (p K i).

Table 1 shows the results of the above-mentioned affinity test for musculin receptor.

table 1

From the above muscarinic affinity test results, the present invention compounds exhibit higher affinity to M ₂ receptor, confirmed that yet other muscarinic receptors, a high M ₂ receptor selectivity, especially compared to the M ₃ receptor Was done.

Inhibition of bradycardia and salivary secretion based on musculin receptor antagonism (i n v i vo)

1) M ₂ As s ay (inhibition of spinal cord destruction in rat oxotremorine-induced bradycardia)

Pentobarbital 6 Omg / kg i.p. was used in male Wistar rats (300 to 350 g), anesthesia was performed, tracheal force neuration, carotid artery force neuration, left-right vagus nerve transection, and spinal cord destruction were performed. After 15 minutes of stabilization under artificial respiration, the test compound or physiological saline was administered 15 minutes after the administration of athenolol 1 OmgZkg i.v., and 15 minutes later, oxotremorine was cumulatively administered. The evaluation compound was administered i.v. through the femoral vein.

The heart rate immediately before oxotremorine administration was set at 100, and the rate of decrease in heart rate due to cumulative oxotremorine administration in the presence and absence of the test compound was determined to obtain a dose-response curve. Evaluation absence of compound and ED ₅₀ values in the (control) (50% heart rate reducing effect dose by Okisotoremori down), ED ₅ in the presence. From the ratio with the value, the dose After calculating the rightward movement width (Dos e- ratio) of the action curve, expand to Schi 1 dpiot, and DR ,. And expressed as a negative logarithmic value (pDR,., Mo 1 / kg).

2) M ₅ As s ay (Okisotoremorin induced rat salivary secretion inhibiting action)

Using Wister male rats (300-350 g), urethane 1.2 gZkg ip 10 minutes after anesthesia, administer the test compound or physiological saline, and 15 minutes later, administer oxotremorine 0.8 / mo 1 kg iv did. Saliva secreted for 5 minutes immediately after administration of okifutremorin was collected, and the weight was defined as the amount of saliva secreted. The evaluation compound was administered i.v. from the femoral vein.

The salivary secretion rate of the control compound was determined assuming the salivary secretion of the control as 100%, and the 50% inhibitory dose (ID _5. value) was calculated. The negative logarithmic value was expressed as (p I Dso, molZkg). did.

Table 2 shows the results of the above-mentioned musculin phosphoreceptor antagonism test (invivo). Table 2

M ₂ / Uz: Relative ratio compound of each compound when was a 1 M _{_2/3} ratio Atoropin A: Kokoku 5 - 68474 JP Example 32 Compound

1 1 1 [[2- (Jetylaminomethyl) 1 1-piperidinyl] acetyl] 1 5, 1 1-Dihydro-1 6H-pyrido [2, 3-b] [1, 4] Benzodiazepine 1 6-one from the above test results, the compounds of the present invention bradycardia inhibition by M ₂ receptor antagonism than the antisecretory action of saliva caused by M ₃ receptor antagonism even in V ivo The action was found to be much more potent. Therefore, the possibility of a preventive or therapeutic agent for heart disease side effects is reduced to attributable to the M ₃ receptor Russia渴等showed. Central migration test (awake mouse · oxotremorine-induced tremor suppression) _

Using an ICR male mouse (35 to 60 g), an evaluation compound or a solvent (physiological saline, etc.) was administered to the tail vein while awake (i.v. :). Fifteen minutes later, loxotremorine lmg / kg was administered subcutaneously on the back (s.c.), and behavior was observed 5, 10, and 15 minutes later.

All judgments were made by blind, and the behavior was scored as 5, 10, and 15 minutes after oxotremorine administration according to the following criteria. The largest score among the three observation times was used for the tree.

Evaluation criteria + + +: Very violent tremor.

+ +: A tremor that can be seen in a quiet state.

+: Trembling occurs when lifting with the base of the tail. Sat: Unclear distinction between locomotor activity and tremor.

Or, if you swing with the base of the tail, tremor will occur. I: No noticeable abnormal behavior.

The score in the absence of the evaluation compound (control) was taken as 100%, and the score in the presence of the evaluation compound was converted and expressed in%. Table 3 shows the results. Table 3

X: All cases died In the above-mentioned central migration test, attopin showed central migration from the administration of lmg / kg and suppressed the occurrence of tremor in the center, whereas the compound of the present invention showed 30 to 10 O mg There was no central effect even at high doses, indicating low central nervous system.

Therefore, it was shown that the compound of the present invention may be a prophylactic / therapeutic agent for heart diseases having low central side effects.

A preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient is prepared using carriers, excipients and other additives commonly used in the preparation of pharmaceuticals. Examples of carriers and excipients for pharmaceutical preparations include solid or liquid emergency pharmaceutical substances. Examples thereof include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylene glycol, and other commonly used ones. .

Administration is oral, such as tablets, pills, capsules, granules, powders, and liquids, or non-injection, such as intravenous or intramuscular injections, suppositories, transdermals, inhalants, or intravesical injections. Any form of oral administration may be used. The dose is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject, gender, etc., but in the case of oral administration, for adults, 0.0 mg / kg to 10 mg / kg / day. The dose is about g, and is administered once or in 2 to 4 divided doses. When given intravenously due to symptoms, it is usually administered once or more than once a day in the range of 0.001 mg zkg to 1 Omg / kg per adult.

Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicone. It is mixed with magnesium acid aluminate. In accordance with the usual methods, the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, and stabilizing agents such as lactose. Even if it contains a solubilizing agent such as glutamic acid or aspartic acid Good. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents, for example, purified Contains water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of the non-aqueous solution and drowning agent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 and the like. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). ,. These are sterilized by, for example, filtration through a bacteria storage filter, blending of a bactericide or irradiation. They can also be used to produce a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to examples. The compound of the present invention is not limited to the compounds described in the following Examples, and furthermore, the compound represented by the general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, its geometrical and optical isomers The crystal includes all polymorphs.

The starting compounds of the compound of the present invention include novel compounds. Production examples of these compounds will be described as reference examples.

Reference example 1a

(i) To a solution of 2.5 g of methyl 4-hydroxy-13-nitrophenylacetate in 30 ml of acetate nitrile (30 ml) was added 1.37 g of 1,3-dibromopropane and 3.37 g of carbonic acid 2.1 g, and stirred at 80 ° C. The insoluble material was removed by filtration, and the filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give methyl 4- (3-bromopropoxy) -3- 3.57 g of ditrophenyl acetate were obtained as a yellow oil.

Mass spectrometry value (mZz): (FAB) 332 (MH ⁺ )

Nuclear magnetic resonance scan Bae spectrum (CDC 1 _3, TMS internal standard)

δ: 2.22-2. 9 (m, 2H), 3.62 (s.2H), 3.66 (t, 2H, J = 6.2Hz), 3.72 (s, 3H), 4.25 (t. 2H. J = 5.7Hz) , 7.16 (d, 1H, J = 8.6Hz), 7.47 (dd. IH. J = 8.6, 2.5Hz). 7.79 (d, IH, J = 2.2Hz). (Ii) Methyl 4- (3-bromopropoxy) To a methanol solution (30 ml) of 6.98 g of 1,3-nitrophenyl acetate was added 31.5 ml of a 1N aqueous solution of sodium hydroxide at 0 ° C., followed by stirring at room temperature for 2 hours. The residue obtained after distilling off the solution under reduced pressure was acidified to pH with 1N hydrochloric acid. The organic layer was extracted with chloroform and dried over magnesium sulfate, and the organic layer was distilled off under reduced pressure. The obtained residue was solidified with hexane to give 6.44 g of 4- (3-bromopropoxy) -13-nitrophenylacetic acid. Obtained. Table 4 shows the structural formula and melting point.

Nuclear magnetic resonance scan Bae spectrum (CDC 1 _3, TMS internal standard)

δ: 2.22-2.49 (m, 2H) .3.65 (t.2H, J = 6.2Hz) .3.66 (s, 2H) .4.25 (t.2H, J = 5.8Hz) .7.07 (d, IH, J = 8.6Hz), 7.47 (dd, IH, J = 8.6.2.3Hz), 7.80 (d.IH.J = 2.2Hz).

Similarly, Reference Examples 1b to 1p in Table 4 were obtained.

Reference example 2a

4 To a solution of 6-42 g of di-oxane (50 ml) of 3- (3-bromopropoxy)-3-ditrophenylacetic acid was added 2.94 ml of thionyl chloride and one drop of N, N-dimethylformamide, and the mixture was heated to 70 ° C. . After reacting for 1 hour, the reaction solution was distilled off under reduced pressure. To a solution of the obtained residue in tetrahydrofuran (60 ml) was added 3.54 g of 11-oxo-10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepine and 2.05 ml of dimethylaniline. The mixture was stirred at 80 for 8 hours. The reaction solution was evaporated under reduced pressure, and the obtained residue was dissolved in chloroform. The solution was washed successively with a 0.1N aqueous hydrochloric acid solution, a sodium hydrogencarbonate aqueous solution, and a saturated saline solution. After drying the organic layer over magnesium sulfate, The filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and crystallized with ethanol to give 5-[[4- (3-bromopropoxy). 1,3-Ditrophenyl] acetyl] 1,5,10-Dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one and 5-[[4- (3- 5.57 g of a mixture of (propoquine) _- 3-ditrophenyl] acetyl] -5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepin-11,1-one was obtained as white crystals. Table 5 shows the structural formula and mass spectrometry values.

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ: 2.17-2.33 (m.2H), 3.58-3.72 (m, 4H) .4.16 (brs, 2H), 6.97 (d, IH, J = 7.9Hz), 7.13 (d, IH, J = 7.9Hz) .7.21-7.61 On, 8H), 7.96 (dd, IH, J = 7.9.1.2Hz), 8.57-8.81 (tn.1 H).

In the same manner or by further adding a conventional group modification reaction, Reference Examples 2b to 2r in Table 5 were obtained.

Reference example 3

43.1 g of trophenylacetic acid were dissolved in 62 ml of dichloromethane, and 2.98 ml of oxalyl dichloride and 0.05 ml of N, N-dimethylformamide were added thereto under ice-cooling, followed by returning to room temperature. After the completion of the foaming, the mixture was concentrated and azeotropically distilled three times with dichloromethane. After dissolving this in 10 ml of dichloromethane, 3.0 g of 11-oxo- 10, 11-dihydro- 15H-dibenzo [b, e] [1,4] diazepine and 2.16 m 1 of dimethylaniline were dissolved. Was added dropwise to a tetrahydrofuran solution. After the solution was refluxed for 6 hours, the solvent was distilled off. The obtained residue was dissolved in dichloromethane, washed with a 0.5N aqueous hydrochloric acid solution and saturated saline, dried over magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified on a silica gel column of solvent-based form-acetone (7: 3) silica gel and recrystallized from toluene to give 5-[(412-trophenyl) acetyl] —5,10-dihydro- 4.48 g of 11H-dibenzo [b, e] [1,4] dazepine-1 1-one light brown crystals were obtained. Melting point: 255-256 ° C Mass spec (mZz): (FAB) 374 (MH ⁺ )

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ: 3.77 (s, 2H) .7.96 (d, 1H), 8.09 (br, 2H).

Reference example 4

5-[(4-Nitrophenyl) acetyl] 1,5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine 111 g 4.2N N, N-dimethylformamide After dissolving in 84 ml, Raney nickel 8.4 ml was added, and hydrogenation was performed at normal temperature and normal pressure. After the completion of the hydrogen absorption, the catalyst was removed by filtration and concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and dried over magnesium sulfate. The residue obtained after distilling off the solvent was recrystallized from 2-propanol to give 5-[(4-aminophenyl) acetyl] -5,10-dihydro-11H-dibenzo [b, e] [1,4 3.1 g of pale brown crystal of diazepine-one was obtained.

Melting point: '1 81-1 82 ° C melting

Mass spec (mZz): (FAB) 344 (MH +)

Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

δ: 3.51 (br.2H), 6.46 (s, 1H), 6.71 (m, 1H), 7.56 (t, 1H), 7.95 (d, 1H), 8.4-8.9 (m, 1H).

Reference example 5

51-C (4-aminophenyl) acetyl] 1,5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine 1.1 g Dissolve 1.0 g in acetonitrile 2 Oml Then, 0.39 ml of 3-chloropropionyl chloride was added. The mixture was heated under reflux for 30 minutes and cooled with ice. The precipitated crystals are collected by filtration, washed with acetonitrile, dried under reduced pressure, and then dried under reduced pressure. 5-[[4- (3-chloropropionamide) phenyl] acetyl] —5,10-dihydro-11H— There were obtained 1.17 g of colorless crystals of dibenzo [b, e] [1,4] diazepine-11one.

Melting point:> 230

Mass spectrum (mZz): (FAB) 434 (H ⁺ ) Nuclear magnetic resonance scan Bae spectrum (CDC 1 _3, TMS internal standard)

δ: 2.770η.2Η), 3.60 (q, 2H), 3.85 (m, 2H), 6.8-7.0 (m.2H) .9.19 (s, IH), 9.6-10.Km, IH).

Reference example 6

5-[[4- (3-Bromopropylthio) phenyl] acetyl] —5,10—dihydro ー 1H—dibenzo [b, e] [1,4] diazepine 4- (3-chloropropionyl) phenyl] acetyl] 15, 10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one 600 mg of methylene chloride solution ( (10 ml) was added 260 mg of metabenzo-perbenzoic acid at 75 ° C and stirred for 30 minutes. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with methylene chloride (1 Oml × 2), and dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give 5-[[4- (3-bromopropylsulfinyl) phenyl] acetyl] 1,5—10—Dihydro-11 H—Dibenzo _ [b, e] [1,4] diazepine 111 and 5 -— [[4- (3-chloropropyl propylsulfiel) phenyl [Acetyl] 1,5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine A mixture of 111-one, 53 Omg was obtained.

Mass spec (m / z): (FAB) 497 (MH +) (Br), 453 (H +) (CD

Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

δ 1.96-2.10 (m, 1H) .2.20-2.36 (m.IH) .2.82-2.90 (m, IH) .2.93-3.100η, IH), 3.43-3.36 (m.2H), 3.70-3.78 (m, 2H), 7.12-7.95 (m, 12H).

Reference Example 7

5-[[4- (3-Bromopropylthio) phenyl] acetyl] -1,5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-1 1-one and 5— [ [4 -— (3-chloropropylthio) phenyl] acetyl] 1,5,10—dihydro 1 1 H—dibenzo [b, e] [1,4] diazepine 1 1 1 1 380 m To a solution of g in methylene chloride (1 Oml) was added 38 Omg of metabenzo-perbenzoic acid under ice-cooling, followed by stirring for 2 hours. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with methylene chloride (1 Oml × 2), and dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give 5-[[4- (3-bromopropylsulfinyl) phenyl] acetyl]. 1, 5, 10-dihydro-11H-dibenzo

[b, e] [1, 4] diazepine 1 1 1one and 5— [[4-1 (3-chloropropylsulfonyl) phenyl] acetyl] 1, 5, 1 0—dihydro-1 1 H—dibe 36 Omg of a mixture of benzo [b, e] [1,4] dazepine-11one was obtained. Mass spec (m / z): (FAB) 5 13 (MH +) (Br), 469 (MH +)

(C D

Nuclear magnetic resonance spectrum (DMSO—ds, TMS internal standard)

<5: 2.15-2.37 (m, 2H) .3.20-3.31 (m.2H), 3.55-3.62 (m, 2H), 3.75-3.82 (m, 2H). 7.10 (d, 1H), 7.20- 7.97 (m.9H).

Table 4

Table 5

Reference example Mass spectrometry value (m / z)

-R ³ one Y ² —A-X

No. (Br) / (CI)

2 a 1 N0 ₂ ④— 0 ^ ・ ^ CH (FAB) 510 (MH ⁺ ) / 466 (H ⁺ )

2 b 1 C2tl5 ④— CH (FAB) 493 (MH ⁺ ) / 449 (MH ⁺ )

2 c one H ④—

CH (FAB) 465 (MH ⁺ ) / 421 (H ⁺ )

2 d 1 H ③-0 CH (FAB) 451 (MH ⁺ ) / 407 (MH ⁺ )

2 e 1 H ② ー CH (FAB) 465 (MH ⁺ ) / 421 (MH ⁺ )

2 f i H ⑧ ー 0 ^ ・ ^ CH (FAB) 465 (MH ⁺ ) / 421 (MH ⁺ )

2 g one H ② ー CH (FAB) 451 (H ⁺ ) / 407 (MH ⁺ )

2 h one H ④—

CH (FAB) 451 (H ⁺ ) / 407 (MH ⁺ )

2 i -COCHs ④— 0 ^^^ CH (FAB) 507 (MH ⁺ ) / 463 (MH ⁺ )

2 j -H ④ -0 ^^ N (CI) 466 (H ⁺ ) / 422 (MH ⁺ )

2 k -Br ④— 0 ^-^ CH (FAB) 543 (MH ⁺ ) / 499 (MH ⁺ )

2 1 -0CH ₃ ④— Ο CH (FAB) 495 (MH ⁺ ) / 451 (H ⁺ )

2 m 1 CI ④0 CH (FAB) 499 (MH ⁺ ) / 455 (H ⁺ )

2 n -N0 ₂ ④— 0 ・ ^^ N (FAB) 511 (MH ⁺ ) / 467 (MH ⁺ )

2 o-COC2H6 ④ -0 ^^ CH (FAB) 521 (MH ⁺ ) / 477 (MH ⁺ )

2 P-CH2CH2CH3 ④0 ~ ^^ CH (FAB) 507 (MH ⁺ ) / 463 (MH ⁺ )

2 q one H ④-s / ^ \ CH (FAB) 481 (MH ⁺ ) / 437 (MH ⁺ )

2 r -F ④— 0 χ ^ ・ ^ CH (FAB) 483 (MH +) / 439 (MH ⁺ ) Example 1

5-[[4- (3-Clo-propionylamino) phenyl] acetyl] —5,10—dihydro — 11H—dibenzo [b, e] [1, 4] diazepine To an acetonitrile solution (86 ml) of g was added 10.3 ml of ethylamine and 32 mg of tetrabutylammonium bromide at room temperature. After heating the reaction solution to reflux for 1 hour, the solvent was concentrated under reduced pressure. The obtained residue was dissolved in chloroform, washed with a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was dissolved in 70 ml of ethanol, a 4 N hydrochloric acid-containing ethyl acetate solution (3.7 1 ml) was added, and the mixture was stirred under ice-cooling. The precipitated crystals are collected by filtration, washed with ethanol, and washed with 5-[[4- (3- (ethylaminopropionamide) phenyl] acetyl] -1,5,10-dihydro-11H-dibenzo [b, e] [1,4] Diazepine-111-one hydrochloride 4.71 g was obtained as colorless crystals. Melting point: 204- 206 ° C

Elemental analysis value (as C ₂₈ H ₃₀ N ₄ 0 ₃ 'HC 1 · Η ₂₀ )

C (%) Η (%) Ν (%) C 1 (%) Theoretical 64.05 6.33 10.67 6.75

Experimental 63.92 6.32 10.68 6.94

Mass spec (mZz): (FAB) 47 1 (MH ⁺ )

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

δ: 1.22 (t, 6H), 2.83 (t.2H), 3.12-3.15 (m.4H), 3.35-3.37 (m, 2H) .3.43-3.60

(m, 2H) .6.96 (d.2H) .7.14-7.27 (m, 2H) .7.38-7.49 (m, 4H), 7.54-7.78 (m.4H), 10.21

(brs, 1H) .10.58 (d.1H).

Example 2

5-[[4- (3-bromopropoxy) —3-nitrophenyl] acetyl] -1,5,10-dihydro-11H-dibenzo [b, e] [1,4] dazepine-1 1-one and 5- [[4- (3-chloropropoxyquine) -1-nitrophenyl] acetyl] — 5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine mixture Piperidine in 5.00 g of acetonitrile solution (25 ml) (5.0 6 ml) and sodium iodide (153 mg) were added, and the mixture was stirred at 80 ° C for 4 hours. After the solvent was concentrated under reduced pressure, the obtained residue was dissolved in chloroform, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (form: methanol: aqueous ammonia = 30: 1: 0.1) to give 5-[[3-nitro-1-4- (3-piperidinopropoxy) phenyl]. [Acetyl] -1,5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one 5.10 g was obtained as a yellow amorphous. Further, 7 Omg of this compound was dissolved in ethanol, and an appropriate amount of a dioxane solution containing 4N hydrochloric acid was added to form a hydrochloride, whereby 65 m of white crystals were obtained.

Mass spectrometry value (mZz): (FAB) 5 15 (MH +)

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard)

6: 1.38-1.50 (6H.m), 1.88 (2H.brs), 2.36 (6H.brs) .3.63-3.80 (2H, m), 4.16 (2H, brs), 7.23 (1H, d, J = 8.5Hz) .7.31-7.33 (2H, m) .7.47-7.50 (5H.m), 7.62-7.66 (1H, m), 7.79 (1H.d, J = 7.9Hz), 8.35 (1H.brs), 10.68 (1H, m).

Example 3

5-[[3-Nitro-1-41- (3-piperidinopropoxy) phenyl] acetyl] -1,5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-1 1 1 In 5.0 g of a methanol solution (80 ml) of 5.0 g, 525 mg of 10% palladium-carbon was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere at normal pressure. After filtering off insolubles, the celite filtrate was concentrated under reduced pressure to give 5-[[3-amino-41- (3-piberidinopropoxy) phenyl] acetyl] -15,10-dihydro-11H-dibenzo [b , e] [1, 4] Diazepine-11-one 5.47 g were obtained as pale yellow crystals. Mass spectrometry value (mZz): (FAB) 4 8 5 (MH ⁺ )

δ 1.37-1.38 (m, 2H) .1.46-1.51 (m.4H), 1.81-1.87 (m, 2H) .2.32 (brs.4H) .2.3 9 (t, 2H, J = 7.3Hz), 3.29- 3.43 (m.2H), 3.90 (t, 2H, J = 7.3Hz), 4.64-4.65 (m.2H), 6.09 (d, 1H, J = 7.3Hz) .6.39 (s.1H), 6.62 (d , 1H, J = 7.9Hz), 7.19-7.81 (m, 8H), 10.61 (brs, 1 H).

Example 4

5-C [3-amino-41- (3-piperidinopropoxy) phenyl] acetyl] — 5,10-dihydro-11H-dibenzo [b, e] [1, 4] diazepine-11-one 1.68 ml of acetic anhydride was added to 5.76 g of a pyridine solution (50 ml), and the mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was dissolved in chloroform (80 ml), washed successively with a 0.1 N aqueous sodium hydroxide solution and saturated saline, and then dried over magnesium sulfate. The residue obtained after evaporating the solvent under reduced pressure was purified by silica gel column chromatography (form: methanol = 30: 1), and 2- (3-piperidinopropoxy) -1-5-[[(1 1-oxo 5,10-dihydro-11H-dibenzo [b, e] [1,4] dazepine-15-yl) carbonyl] methyl] acetoanilide 6.5 1 g was obtained as an oil. The obtained oily substance is powdered from hexane to give 2- (3-piperidinopropoxy) -1-[[(11-oxo-5,10-dihydro-11H-dibenzo [b, e] [ 1, 4] dazepine-15-yl) carbonyl] methyl] acetanilide was obtained.

Elemental analysis (as _{_{_{C 3, H 34 N 4 0}}} 4 · 1.0H 2 O)

C (%) H (%) N (%)

Theoretical 68.36 6.66 10.29

Experimental value 68.06 6.59 10.0 9

Mass spectrum (mZz): (FAB) 527 (MH +)

Nuclear magnetic resonance spectrum (DMSO— _ds , TMS internal standard)

δ: 1.40-1.520η, 6Η) .1.92 (brs.2H), 2.08 (s, 3H), 2.40 (brs, 6H), 3.35-3.56 (m, 2H), 4.OKbrs.IH), 6.67 (brs , 1H), 6.90 (t, IH, J = 8.6 Hz), 7.19-7.77 (m.9H), 8.88 (brs, IH), 10.55-10.57 (m, IH).

2— (3-piperidinopropoxy) 1 5— [[(1 1 1 oxo 1 5,1 0—dihydro 1 1 H—dibenzo [b, e] [1, 4] diazepine 1— 4) Carbonyl] methyl] acetanilide 4.1 Standard solution in 3 g of methanol (200 ml) An ethyl acetate solution (2.3'5 ml) containing constant hydrochloric acid was added, and the mixture was evaporated under reduced pressure. By crystallization from ethanol, 2- (3-piperidinopropoxy) -l-[[(11-oxo-l, 5,10-dihydro-11H-dibenzo [b, e] [1, 4] Diazepine-5-yl) carbonyl] methyl] acetoanilide hydrochloride 4.18 g was obtained as a white crystal.

Elemental analysis value (as C ₃ , H ₃ 4N40 ₄ · HC 1 0.5H ₂₀ )

C (%) H (%) N (%) C 1 (%)

Theoretical 65.08 6.34 9.79 6.20

65.07 6.46 9.95 6.35

Mass spec (m / z) (FAB) 564 (MH +)

Example 5

5-[(4-Aminophenyl) acetyl] 1,5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine 1 1 1one 40 Omg was dissolved in hexamethylphosphoramide 8m1. 0.13 ml of 1,3-dibromopropane was added and reacted at 100 ° C. for 2 hours. After the temperature of the reaction solution was returned to room temperature, 0.83 ml of piperidine was added, and the reaction was carried out at 100 for 1 hour. The reaction solution was poured into water and extracted twice with chloroform. The extracts were combined, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography using a solvent system, chloroform-form-methanol-28% aqueous ammonia (15: 1: 0.1), and the 5- [4- [N — (3-Piveridino propylamino) 1-phenyl] acetyl] 1,5,10-dihydro-11H-dibenzo [b, el [1, 4] diazepine 11 1-one 1 15 Omg as foam Obtained.

Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

δ: 1.46 (br.2H), 1.60 (total 4H), 1.77 (t, 2H), 2.42 (total 6H), 3.12 (br.2H) .3.54 (br.2H), 4.74Cbr.IH), 6.45 ( 2H), 6.69 (br, IH), 7.24 (m, IH) .7.57 (m.IH) .7.7-8.1 (2H in total).

In the following table, for the above Examples 1 to 5 and another Examples 5 to 60 of the present invention, the compounds And the melting point are shown. The compounds of Examples 6 to 7 in the following table are the same as in Example 1, the compounds of Examples 8 to 50 are the same as in Example 2, and the compounds of Examples 51 to 52 are the same as in Example 3. Similarly, the compounds of Examples 53 to 60 were obtained in the same manner as in Example 4.

Table 6

⁰

The following table shows the nuclear magnetic resonance spectra of the compounds obtained as amorphous among the example compounds in the above table.

Table 7 Examples

Nuclear magnetic resonance scan Bae spectrum (DMS_〇- d _6, TM S internal standard) [delta]:

J 0.

0.95 (3H, t, J = 7.2 Hz), 1.02 (3H.t, J = 7.2 Hz), 1.81 (2H, t, J = 6.4 Hz), 2.35 (2H q, J = 7.2 Hz), 2.39-2.50 (6H.m), 3.05-3.08 (4H.m), 3.32 (2H.o

8 ヽ O l ゥ Cn OU ιτ ゥ CO_0 C fOU> τ O fio / OU 4- 1—Ω —

S, o.4o o.DU n.m, o.ϋό-ό.Όό, w, o.y ^ n.t, J = b.nZ ヽ ci

), 6.id (2H, d, J = 8.OHz), 6.82 (2H.d, J = 8.OHz), 6.87C2H.d, J = 8.4 Hz, 7.10 (2H , d, J = 8.8 Hz), 7.17-7.27 (2H.m), 7.36-7.46 (2H.m), 7.52-7.80 (4H, m), 10 . 58 (1H, s)

1.29 (6H.d), 1.33 (6H.d). 2. 10-2.22 (2H, m), 3.17-3.22 (2H, m). 3.59-

1 1 3.65 (2H, m), 4.00-4.09 (2H, m), 6.81 (2H.d), 6.91 (2H, d), 7.15-7.77 ( 8H, m), 10.59 (1H.s)

1.19 (3H, t.J = 7.3Hz), 2.06C2H.brs), 2.97-3.03 (4H.m). 3.45-3.58

3.97 (2H.brs). 4.18 (2H.brs). 6.75 (2H.brs), 6.91 (2H, d, J = 8.

6Hz), 7.20-7.76C13H, m), 10.57 (1H, brs)

1.02 (3H.t.J = 7.3Hz), 2.58 (2H.q.J = 7.3Hz), 2.79 (2H, t, J = 6.1Hz), 3.4

1 5 4-3. 67C4H, m), 3.96 (2H, brs), 6.40-6.90 (4H.m), 7.12-7. 63 (14H, m), 10.54 ( 1H, brs)

1.02 (6H.brs), 1.87 (2H, brs). 2.64 (6H, brs). 3.49-3. 62 (2H, m), 3.94

1 8 (2H, t, J = 6.1 Hz). 6.55 (2H.brs). 6.75-6.77 (7H.m), 7.12-7.53 (6H.m), 7 63-7.77 (3H, m), 10.55-10.58 (7H.m) Example

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard) 5:

IN 0.

0.98 (6H, t, J = 7.3Hz), 2.56 (4H, brs) 2.78 (2H, brs), 3.49-3.65 (2H, m) 丄 y, o. B4 ^ n. DrS, D. DO D OD ^^ n, lil, D, 0 D. ί ovln. Wf ί ΙΔ ί. (Ό Ό {\, m), 10.55-10.57 (lH, m)

20 0.96 (6H, brs) .2.50-2.80 (6H.m), 3.67-3.70 (2H, m) .3.98 (2H.brs),

D. ol ./o ZH. ΙΪ1 1U- DyUn »DrSy

0.98 (6H, brs), 2.56 (4H, brs) .2.78 (2H.brs), 3.3-3.61 (2H, m), 3.98

21 (2H, brs) .6 79 (2H, d, J = 7.3Hz), 6 89 (2H, d, J = 7.3Hz), 7, 19-727 (3H, m, 1.oi l. lo un, W, 1U. t) b, 丄 H, S

0.83 (6H.t, J = 7.3Hz), 1.39 (4H.brs), 1.80 (2H, brs), 2.32 (6H, brs),

25 3.42-3.56 (2H, m) .3.96 (2H.brs) .6.77-6.84 (4H, m), 7.19-7.76 (8H, m), 10.57 (1H, s)

1. OOU ^ H, t, J-b. Lnz, I. Ub-. L n, m, z. L v2H. Brs; 2.94-1 2.98

4 6 (4H.m), 3.23-3.25 (2H, m), 3.42-3.59 (2H.m) .4.02-4.03 (2H, m), 6.81 (2H.d, J = 7.9Hz), 6.92 (2H d.J = 8.5Hz), 7.19-7, 79 (8H.m), 9.25 (1H, br SJ, iu.byuH, s

1 70-1.77 (6H, m), 1 95-2.01 (2H, m), 2 80-2.83 (2H, m), 3.00 (2H, t),

A Q

0. UD o. Ίυ Δη, W _t 0.00 o. ΌΚΔΠ, Wf o. DU 0. Don, W * b. DO 1.

(12H, m), 10.60 (1H, brs)

49 1 65-1.76 (6H, m), 1 89 (1H, brs), 2, 05 (1H, brs), 3.66 (1H, dd), 3.79

(、 \ 丄 Π 、

, 7 f · 0-7-7 / β 0Π I ΔOUΓί, Π1 ノ, 11 nU. UOQTliHrif

0.98 (6H, brs) .1.8 C2H, brs) .2.54 (6H.brs) .3.33-3.44 (2H, m), 3.92

51 (2H, t, J = 6.9Hz), 4.62C2H, brs), 6.10 (1H.d, J = 7.8Hz), 6.62 (1H, d, J = 7.8Hz), 6.40C1H, d, J = 2 OHz), 7.19-7.82 (8H, m), 10.60-10.62 (1H, m) Hereinafter, the chemical structural formulas of the other compounds of the present invention (Examples A-1 to A-88) are shown in the form of tables. s myself 15 These compounds are in substantially the same manner as the method described in the embodiments and structures method, or, _c Table can be easily prepared by applying slight variations obvious to those skilled in these 8

Table 9

Table 10

<

>>

o

Example o.n R

One ^0v position

A— 45 ② 1 NE t ₂

③ 1 NE t ₂

A -47 ④ 1 NE t ₂

Α-48 ② 2 N E t 2

A-49 ③ 2 NE t 2

④ 2 NMe 2

E t

\ Z

A-51 ③ 1 N

1

B n

E t

\ Z

④ 2 N

1

B n

A -53 ② 2,0

A -54 ③ 20

④ 3 0 Table 11

Table 12

<<<<

Toutoto

O C

Example No. R * R ^b Y

A-67 H H-S

A-68 Me H S

A-69 H Me 0

H H NHCO

A-71 Me H 0

H Me S

H E t S

A-74 Me E t 0

A -75 Me E t S

H E t NHCO

E t E t 〇 Table 13

Example No. R ^s R ^b Y

A -78 H H S

A-79 Me H S

A -80 H Me 0

A-81 H H NHCO

A— 82 Me H 0

A-83 H Me S

A-84 H E t S

A— 85 Me E t 0

A-86 Me E t S

A-87 H E t NHCO

A— 88 E t E t 0 Table 14

Claims

1. a fused benzodiazepinone derivative represented by the following general formula (I) or a salt thereof

(I)

Enclosure

(The symbols in the formula have the following meanings.

X; GH or N

R ⁴ , R ⁵ : same or different, hydrogen atom or lower alkyl group

n; integer from 0 to 2

A: lower alkylene group

R ¹ and R ^{2 are the} same or different and are a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group optionally having a substituent, an aralkyl group optionally having a substituent, or R ′ R ² is integrated with the nitrogen atom to be bonded, and may further contain any one of an oxygen atom, a sulfur atom and a nitrogen atom, and may form a 4- to 9-membered nitrogen-containing saturated heterocyclic group. The 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent; R ³ ; a hydrogen atom, a lower alkyl group which may have a substituent, a hydroxyl group, a lower alkyl group; Coxy group, nitro group, halogen atom, lower acyl group or amino group having substituents

2. R ¹ and R ² are the same or different and are each substituted with a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group which may be substituted with a substituent of the following group B, or a substituent of the following group B. Or an optionally substituted aralkyl group, or R ¹ and R ² are integrated with the nitrogen atom to be bonded, and may further contain any one of an oxygen atom, a sulfur atom and a nitrogen atom. The saturated heterocyclic group may form a saturated heterocyclic group. The 4- to 9-membered nitrogen-containing saturated heterocyclic group may further have a substituent represented by the following group C, wherein R ³ is a hydrogen atom, It may be mono- or di-substituted by a lower alkyl group, a hydroxyl group, a lower alkoxy group, a nitro group, a halogen atom, a lower acyl group or a group of the following group E which may be substituted with a substituent of the group D. The condensed benzodiazole according to claim 1, which is an amino group. Pinon derivative or a salt thereof.

Group B: 5 to 7 which may be substituted with a halogen atom, hydroxyl group, lower alkylthio group, lower alkoxycarbonyl group, nitro group, amino group, mono or di-lower alkylamino group, methylenedioxy group, lower alkyl group 5 TJ 7-membered nitrogen-containing saturated heterocyclic group which may be substituted with a lower nitrogen-containing saturated heterocyclic group or a lower alkoxyl group, or a lower alkyl group which may be substituted with a halogen atom.

Group C: lower alkyl group, lower alkoxy group, lower alkylthio group, aryl group which may be substituted with substituent group B, aryl group which may be substituted with substituent group B, aralkyl group, Aryloxy group which may be substituted with a substituent, aralkyloxy group which may be substituted with a group B substituent, arylthio group which may be substituted with a group B substituent, group B substituent Or an aralkylthio group, an amino group, a mono or di-lower alkylamino group, an arylamino group, or an aralkylamino group.

Group D: a halogen atom, a hydroxyl group or an amino group.

3. R ', R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, heterocycle substituted by a lower alkyl group les, and to also be 5 to 7-membered nitrogen-containing saturated Optionally substituted with an aryl group or a lower alkyl group

An aralkyl group which may be substituted by a 5- to 7-membered nitrogen-containing saturated heterocyclic group, or a nitrogen atom bonded to R ′, and one of an oxygen atom, a sulfur atom and a nitrogen atom A 4- to 9-membered nitrogen-containing saturated heterocyclic group which may further contain a substituent represented by the following C 1 group. R ³ may be mono-substituted with a hydrogen atom, a lower alkyl group, a 7K acid group, a lower alkoxy group, a nitro group, a halogen atom, a lower acyl group, or a group of the following group E. 2. The fused benzodiazepinone derivative or a salt thereof according to claim 1, which is a good amino group.

Group C: lower alkyl group, lower alkoxy group, lower alkylthio group, aryl group, aralkyl group, aryloxy group, aralkyloxy group, arylthio group, aralkylthio group, amino group, mono or lower alkylamino group, arylamino group Or an aralkylamino group.

4. The fused benzodiazepinone derivative or a salt thereof according to claim 1, wherein X is CH.

5. The fused benzodiazepinone derivative or a salt thereof according to claim 1, wherein Y is an oxygen atom.

6. The fused benzodiazepinone derivative or a salt thereof according to claim 1, wherein Y is a group represented by the formula NHCO.

7.5-[[4- (3-Getylaminopropionamide) phenyl] acetyl]-5,10-dihydro-11H-dibenzo [b, e] [1, 4] diazepine

11. The fused benzodiazepinone derivative or a salt thereof according to claim 1, which is 1-one.

8. 2- (3-Piperidinopropoxy) 1 5— [[(11 1-oxo-1,5,10—dihydro-11H—dibenzo [b, e] [1,4] dazepine-1 5— 2. The condensed benzodiazene according to claim 1, wherein the benzodiazepyl is methyl acetoanilide. Pinone derivatives or salts thereof.

9. A pharmaceutical composition comprising the condensed benzodiazepinone derivative or a salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

1 0. Muscarinic M ₂ receptor prophylactic or therapeutic agent The pharmaceutical composition of the range 9 according claims are participating heart disease.

1 1. Sinus bradycardia, sinus dysfunction syndrome including sinus arrest or bradycardia tachycardia syndrome or bradyarrhythmias including vagal excitability-induced bradycardia including atrioventricular blockade, neural syncope (carotid sinus hypersensitivity) 10. The pharmaceutical composition according to claim 10, which is a prophylactic or therapeutic agent for: