WO1996013488A1 - Novel benzodiazepinone derivative and medicinal composition thereof - Google Patents

Abstract

A benzodiazepinone derivative represented by general formula (I) or a salt thereof, having a selective muscarine M2 receptor antagonism and being useful as a preventive or remedy for various diseases wherein muscarine M2 receptors participate, such as sick sinus syndrome including sinus bradycardia, sinus arrest and bradycardia-tachycardia syndrome, bradyarrhythmia including atrioventricular block and vagal bradycardia, and nervous syncope (carotid sinus anaphylaxis).

Description

 TECHNICAL FIELD The present invention relates to a novel benzodiazepinone derivative and a pharmaceutical composition thereof.

The present invention relates to a medicament, particularly a benzodiazepinone derivative or a salt thereof, and a pharmaceutical composition containing the compound. These materials have a Musca Li emissions M ₂ receptor antagonism excellent, preventing young properly diseases muscarinic Li down M Ri receptor is involved are useful in the treatment. Background art

 Bradyarrhythmia is a condition in which the pulse rate decreases due to functional or organic impairment of the cardiac conduction system. The main types of bradyarrhythmias are sinus insufficiency syndrome and atrioventricular block. Among them, sinus insufficiency syndrome, which accounts for about 50% of all bradycardia patients, is a disorder of the sinus node that plays the role of heart-knee pacemaker. Atrioventricular block is caused by damage to the atrioventricular node that connects the atrium and ventricle.

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

At present, artificial pacemakers are mainly used to treat bradyarrhythmias. Indications for artificial pacemakers include neuronal syncope (such as carotid sinus hypersensitivity), and some of these disorders, especially cardiac depression, have vagus nerves due to hyperconstriction of the heart and mental anxiety. It is the result of cerebral ischemia through over-delivery and transient cardiac arrest. Drugs for the treatment of bradyarrhythmias include the musculin antagonist, which suppresses vagal hyperexcitability, which is the cause of functional impairment, and the theophylline / S2 stimulant ゃ theophylline. In addition, the treatment of nervous syncope suppresses cardiac hyperconstriction. ^ Blockade drugs and disoviramide, which has a non-selective anticholinergic effect, and vagus Atotopin (Merck Index, 11th edition, p. 138; muscarinic antagonist), which suppresses Shinkyo S, has been used. In particular, muscarinic antagonists are expected to replace artificial pacemakers as chemical pacemakers.

Conventionally, compounds with muscarinic receptor antagonistic activity may cause tachycardia, anti-bradycardia, bronchodilation, suppression of gastrointestinal motility, suppression of acid secretion, b. Mydriasis, suppression of bladder atrophy, reduction of sweating, etc. Are known. It is known that there are at least three subtypes of this Muslin receptor. Mainly, M and receptors are present in the brain, etc., M ₂ receptors are present in the heart and the like, and M ₃ receptors are present in smooth muscle and glandular tissues.

 Many compounds that have an affinity for the Muslin receptor are known to date. In particular, atotopin has a strong affinity for muscarinic receptors and blocks its action, so it is used as an anti- bradycardic agent.

 The atotocin has almost the same affinity for all of the muscarinic receptor subtypes, o and Mg, and non-selectively antagonizes it (biological chemistry, 42 ( 5), 381 (1991)), which have side effects other than the intended effects, such as muscarinic receptor antagonism, effects on the central nervous system, effects on the center, nausea, urinary closure, constipation, and mydriasis This is known, and improvement has been desired.

In recent years, the study of subtypes of muscarinic Li down receptor, Micromax _2. Micromax ₃ compounds respectively selectively antagonize receptor has been investigated.

Among them, in particular compounds having a selective antagonism to Micromax ₂ receptor are expected effects such as KoJo pulse is and expected to other muscarinic Li emissions receptor-based side effects subtype antagonism is small You.

Incidentally, a compound having high central migration with Micromax ₂ receptor antagonism, diseases of the central nervous system, are expected to be particularly useful for the treatment of Alzheimer's disease and Parkinson's disease. For example, for Alzheimer's disease, by the blocking child choline agonizing presynaptic nerve Micromax ₂ inhibitory receptors (O over preparative. Receptors) in the central, Asechiru from nerve endings Increases choline release (Life science. Vol. 52 pp497-565 (1993)). In addition, Parkinson's disease is a useful therapeutic agent that has no atotopin-like side effects compared to conventional centrally acting anticholinergic drugs (non-selective musculin receptor antagonists). (NEW Pharmacology pp254-292 (1989)).

Is a compound having a selective M ₂ receptor antagonism are known conventionally, 5 having a substituted alkynyl carbonylation Le group in Japanese Patent Kokoku 5 68474 11th, 11- dihydric draw 6H- pyrido [2,3-b] [1,4] Benzodiazepin-16-one derivatives have been disclosed and included in this publication 11-[[2- (Jetylaminomethyl) 1-1-piperidinyl) [Acetyl] 1-5,11-dihydro 6H-pyrido [2,3-b] [1,4] benzodiazepin-16-one (AF-DX116) is a compound currently under development.

 As a patent disclosing a dibenzodiazepinone derivative, JP-A-3-291273 is cited. This publication describes a compound having the following general formula.

(In the formula, R ¹ , R ² , R ³ and n refer to the above publication)

 However, as described later, the structure of the compound of the present invention is different from that of the compound of the present invention in that the compound has a rubamoylpropionyl group on the 5-position nitrogen atom of the dibenzodiazepinone skeleton.

Despite the existence of these compounds, the creation of compounds that still have excellent muscarinic ₁₂ receptor selective antagonism is an important medical issue.

An object of the present invention has excellent Mus force Li emissions M ₉ receptor affinity having different chemical structure from the conventional compounds, and Mus force Li emissions M ₂ receptor antagonism It is to provide a compound having: Disclosure of the invention

The present inventors have compounds diary with the Mus force Li emissions M ₂ receptor antagonism, a result of intensive studies, the new force Rubamoirupuro Pio two Le based on Benzojiazepino down derivative excellent Mus force re having a 1-position and completed the present invention found to have a selective antagonism of emissions M ₂ receptors. That is, the present invention relates to a benzodiazepinone derivative represented by the following general formula (I) or a salt thereof.

(The symbols in the formula have the following meanings.

X: nitrogen atom or methine group

R ^{1 is a} hydrogen atom, a lower alkyl group which may be substituted, or cycloanolequinole 3

 R hydrogen atom, optionally substituted lower alkyl group, cycloalkyl group, aryl group or aralkyl group

A: Lower alkylene group

 Ring B: optionally substituted hydrocarbon ring group or 5- or 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms)

n: an integer from 1 to 5

Preferred compounds in the compound of the present invention include those represented by the above general formula (I) R ¹ is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group which may be substituted by a lower alkylthio group or a cycloalkyl group: or a cycloalkyl group;

R ² is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkyl group which may be substituted with a lower alkylthio group or a cycloalkyl group; a cycloalkyl group; an aryl group; Group,

 Ring B is an aryl group, a cycloalkyl group, or a 5- to 6-membered monocyclic heterocyclic group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms, and these ring groups are Alkenyl group; lower alkynyl group; halogen atom; hydroxyl group; mercapto group; lower alkylthio group; lower alkoxycarbonyl group; carboxy group; sulfonyl group; sulfinyl group; lower alkylsulfonyl group; lower alkylsulfinyl group; Mono- or di-lower alkyl group rubamoyl group; lower alkenyl group; lower alkenyl group; nitro group; cyano group; amino group; mono- or di-lower alkylamino group; 1-3 alkylenedioxy group; cycloalkyl group; aryl group; optionally substituted nitrogen-containing saturated ring group Or, optionally substituted lower alkyl group Wakashi Ku good Ben Zojiazepino emissions derivatives substituted with a lower alkoxy group or a salt thereof;

R ¹ is a hydrogen atom or a lower alkyl group,

R ² is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkyl group optionally substituted by a lower alkoxy group or a lower alkylthio group; a cycloalkyl group; an aryl group; or an aralkyl group;

Ring B may be substituted with a phenyl, naphthyl, lower alkyl or aryl group, C5-7 cycloalkyl group, furyl group, phenyl group, pyrrolyl group, imidazolyl group, thiazolyl group, isothia A zolyl group, a pyridyl group, a pyrimidinyl group, or a birazinyl group, wherein the funyl group is a halogen atom; a hydroxyl group; a mercapto group; Alkylthio group; lower alkoxycarbonyl group; carboxy group; carbamoyl group; mono or di-lower alkyl group rubamoyl group; nitro group; cyano group; amino group; mono or di-lower alkylamino group; 1-3 alkylenedioxy group; cycloalkyl group; aryl group; lower alkyl group, lower alkoxy group or nitrogen-containing saturated ring group which may be substituted with lower alkoxycarbonyl group; or halogen atom, hydroxyl group, phenyl. Benzodiazepinone derivative or a benzodiazepinone derivative which may be substituted with a lower alkyl group or a lower alkoxy group which may be substituted with a group, an amino group, or a mono- or di-lower alkylamino group salt ;

R ¹ is a lower alkyl group,

R ² is a hydrogen atom; a halogen atom or a lower alkyl group which may be substituted with a lower alkoxy group; a cycloalkyl group; or an aralkyl group;

 Ring B is a C5-7 cycloalkyl group, a phenyl group, or a phenyl group, which may be substituted with a fuunyl group, a naphthyl group, or an aryl group; the fuunyl group is a halogen atom; a hydroxyl group; A lower alkoxycarbonyl group; a nitro group; a mono or di-lower alkylamino group; a methylenedioxy group; a 5- to 7-membered nitrogen atom which may be substituted by a lower alkyl group or a lower alkoxycarbonyl group. A saturated alkyl group; a lower alkyl group optionally substituted with a halogen atom; or a benzodiazepinone derivative or a salt thereof, optionally substituted with a lower alkoxy group optionally substituted with a di-lower alkylamino group; A benzodiazepinone derivative or a salt thereof, wherein X is a nitrogen atom;

 A benzodiazepinone derivative which is a phenyl group substituted with a 5- to 7-membered nitrogen-containing saturated ring group, wherein ring B may be substituted with a lower alkyl group, or a salt thereof;

Benzodazepinone derivative or a phenyl group substituted with 1-piperazinyl group in which ring B may be substituted with a lower alkyl group or a derivative thereof Salt.

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

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

 Therefore, the term “lower alkyl group” in the present specification specifically includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isopropyl group, a sec-butyl group, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl Group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethyl group T-butyl 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 Pi And 1-ethyl-1 -methylpropyl and 1-ethyl-2-methylpropyl. It is preferably an alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group, an ethyl group, a propyl group, and an isopropyl 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 methylethylene group, a trimethylene group, a propylene group and the like. , 2-propylene, dimethylmethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-ethylethylene, 2-ethylethylene, 2 , 2-dimethylethylene group, 1,1-dimethylethylene group, ethylmethylmethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene 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, dimethylmethyl group, hexmethylene group, 1-methylpentamethylene group, 1,1 dimethylethyltramethylene group, 2,2-dimethyltetramethylene And the like. Preferably, it is an alkylene group having 1 to 3 carbon atoms, particularly preferably, a methylene group or an ethylene group.

 As the "cycloalkyl group", those having 3 to 8 carbon atoms are preferable, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloalkyl groups. And a heptyl group.

 The “hydrocarbon ring group” is a saturated or unsaturated, monocyclic or condensed hydrocarbon ring group, and is preferably an “aryl group” or a “cycloalkyl group”. Or "cycloalkynyl group".

 As the “aryl group”, an aryl group having 6 to 14 carbon atoms is preferable. Specifically, a phenyl group, a tril group, a xylyl group, a biphenyl group Phenyl, naphthyl, indenyl, anthryl, and phenanthryl; more preferably phenyl or naphthyl; and most preferably phenyl.

Examples of the “cycloalkenyl group” include those having 3 to 8 carbon atoms, specifically, 1-cyclopropenyl group, 2-cyclopropenyl group, 1-cyclobutenyl group, 2-cyclopropyl group. Cyclobutenyl group, 1-cyclopentenyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, 1-cyclohexenyl group, 2-cyclohexenyl group, 3-cyclohexenyl group, 1-cycloheptenyl group, 2 —Cycloheptenyl group, 3 —cycloheptenyl group, 1-cyclooctenyl group, 2 —cyclooctenyl group, 3-cyclooctenyl group, 4-cyclooctenyl group, 2,4 —cyclopentenyl group, 2,5 —six Rohexagenenyl group, 2,4—cycloheptagenyl group and 2,6—cycloheptagenyl group. The “aralkyl group” means a group in which any hydrogen of the above “lower alkyl group” is substituted with an aryl group. Examples thereof include phenylalkyl groups such as benzyl group, phenyl group, phenylpropyl group and phenylbutyl group, and naphthylalkyl groups such as naphthylmethyl group and naphthylethyl group.

 A “5- to 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen, sulfur or nitrogen atoms” is a group containing 1 to 4 heteroatoms consisting of oxygen, sulfur or nitrogen atoms. And a 6-membered monocyclic heteroaryl group. Specifically, a furyl group, a phenyl group, a thienyl group, a pyridine group, an imidazolyl group, a thiazolyl group, a pyrazolyl group, an isotizazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidyl group, and a pyridazinyl group. , Pyrazyl, triazolyl and tetrazolyl groups. Of these groups, a furyl group, a chenyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group, an isothiazolyl group, a pyridyl group, a pyrimidinyl group, a virazinyl group, and the like are preferable. A jyl group.

Specific examples of the substituent of the “optionally substituted lower alkyl group” for R ¹ and R ² include a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, and a cycloalkyl group. Preferred are a halogen atom, a hydroxyl group, a lower alkoxy group and a lower alkylthio group, and more preferred are a halogen atom and a lower alkoxy group.

Specific examples of the substituent of the “optionally substituted hydrocarbon ring group or a 5- or 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms” on the B ring Include a lower alkenyl group, a lower alkynyl group, a halogen atom, a hydroxyl group, a mercapto group, a lower alkylthio group, a lower alkoxycarbonyl group, a carboxy group, a sulfonyl group, a sulfinyl group, a lower alkylsulfonyl group, and a lower alkyl group. Rusulfinyl group, carbamoyl group, mono- or di-lower alkyl Kill force rubamoyl group, lower alkanoyl group, lower alkanoyloxy group, nitro group, cyano group, amino group, mono- or di-lower alkylamino group. Examples include a xy group, a cycloalkyl group, an aryl group, a nitrogen-containing saturated ring group which may be substituted, a lower alkyl group or a lower alkoxy group which may be substituted. Preferable are a halogen atom, a hydroxyl group, a mercapto group, a lower alkylthio group, a lower alkoxycarbonyl group. A carboxy group, a carbamoyl group, a mono- or di-lower-alkyl lbamoyl group, a nitro group, a cyano group. Mono- or di-lower alkylamino group, C13 alkylenedioxy group, cycloalkyl group, aryl group, lower alkyl group or lower alkoxy group Or a lower alkoxy group, a nitrogen-containing saturated ring group which may be substituted by a luponyl group, a halogen atom, a hydroxyl group, a phenyl group, or a di-lower alkylamino group. A lower alkyl group, a halogen atom or a hydroxyl group or a phenyl group or a lower alcohol which may be substituted with a di-lower alkylamino group; Particularly preferred are a halogen atom, a hydroxyl group, a lower alkylthio group, a lower alkoxycarbonyl group, a nitro group, a mono- or di-lower alkylamino group, a methylenedioxy group and a lower alkyl group. A 5- or 7-membered nitrogen-containing saturated ring group which may be substituted with a lower or lower alkoxycarbonyl group, a lower alkyl group which may be substituted with a halogen atom, or a di-lower alkylamino group. Is a lower alkoxy group which may be substituted.

The “lower alkoxy group” includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy) ) Group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 11-ethylpropoxy group, hexyloxy group, and the like. It is a toxic group. The term "lower alkylthio group" means a group in which a hydrogen atom in a mercapto group is substituted with the above lower alkyl group, and is a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group. Group, pentylthio group, hexylthio group and the like.

 “Halogen atom” means a fluorine, chlorine, bromine, or iodine atom.

 The “lower alkenyl group” is a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, a propyl group, a butenyl group, a methylpropyl group, a methylpropyl group. Group, dimethylvinyl group, pentenyl group, methylbutenyl group, dimethylpropyl group, ethylpropyl group, hexenyl group, dimethylbutenyl group, methylpentenyl group and the like.

 The “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes ethynyl, propynyl, petynyl, methylpropynyl, pentynyl, methylbutynyl. And a hexynyl group.

 “Lower alkoxycarbonyl” includes methoxycarbonyl, ethoxyquincarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl. Isobutoxycarbonyl, sec-butoxycarbonyl, tert-butyl Toxoxycarbonyl group, pentyloxy (amiroxy) carbonyl group, isopentyloxycarbonyl group, tert-pentyloxycarbonyl group, neopentyloxycarbonyl group, 2-methylbutoxycarbonyl group, 1, 2- Examples include a dimethylpropoxycarbonyl group, an 11-ethylpropoxycarbonyl group, and a hexyloxycarbonyl group.

Examples of the “lower alkylsulfonyl group” include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, a butylsulfonyl group, a pentylsulfonyl group, and a hexylsulfonyl group. Examples of the “lower alkylsulfinyl group” include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, an isopropylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group. No.

 “Mono- or di-lower alkyl group” refers to a carbamoyl group in which one or two hydrogen atoms in the group are substituted with the above lower alkyl group, and a methylcarbamoyl group. , Ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl and the like.

 Examples of the “lower alkanol group” include a formyl group, an acetyl group, a propionyl group, a butylyl group, a valeryl group and a bivaloyl group.

 The term “lower alkenyl group” means a group in which an oxygen atom is added to the carbonyl carbon of the above “lower alkenyl group”, specifically, a formyloxy group, an acetyloxy group, a propionyloxy group, These include petityloxy, valeryloxy, and vivaloyloxy.

 The “mono- or di-lower alkylamino group” means an amino group in which one or two hydrogen atoms in the amino group have been substituted with the above “lower alkyl group”, Examples thereof include a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group, a getylamino group, and a dipropylamino group.

 The “C 1-3 alkylenedioxy group” is one in which oxygen atoms are bonded to both sides of an alkylene chain having 1 to 3 carbon atoms, and examples thereof include a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group. And is preferably a methylenedioxy group.

Examples of the “lower alkyl group optionally substituted by a halogen atom” include a fluoromethyl group, a chloromethyl group, a bromomethyl group, a chloroethyl group, a dichloromethyl group, a bromochloromethyl group, and a trimethyl group. And a fluoromethyl group. Preferred is a trifluoromethyl group.

 The term “nitrogen-containing saturated ring group” means a saturated heterocyclic group containing one or two nitrogen atoms and optionally having an oxygen atom or a sulfur atom, and is preferably a 5-membered to 7-membered ring. It is a member ring. Specific examples include a pyrrolidinyl group, an imidazolidinyl group, a pyrazolidinyl group, a piperidyl group, a piperazinyl group, a morpholinyl group and the like, preferably a piperidyl group, a piperazinyl group, a morpholinyl group. Group. More preferably, these groups are linked to group A via a nitrogen atom.

 The “nitrogen-containing saturated ring group” may be substituted, and examples of the substituent include a lower alkyl group, a lower alkoxy group, and a lower alkoxycarbonyl group. Preferably, it is a lower alkyl group.

 Examples of the substituent in the “optionally substituted lower alkyl group or lower alkoxy group” include a halogen atom, a hydroxyl group, a phenyl group, an amino group, a mono- or di-lower alkyl group, and the like.

 The compound (I) of the present invention may have one or more asymmetric carbon atoms, and based on this, optical isomers such as (R) -form and (S) -form, racemic forms, diastereomers, etc. Exists. Also, depending on the type of substituent, it has a double bond, and there are geometric isomers such as (Z) -form and (E) -form. The present invention embraces all of the isomers or mixtures of these isomers.

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, lactic acid, lingic acid, quinic acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid. Acid addition salts with organic acids such as glutamic acid . Furthermore, the present invention 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. Hereinafter, a typical production method will be described. First manufacturing method;

 (First step)

(IV)

(In the formula, Ra represents ^a hydrogen atom or a carboxyl group-protecting group.) The amide compound represented by the general formula (IV) is represented by the general formula (II) and amide (II) or a salt thereof. It can be produced by condensing the carboxylic acid shown or a reactive derivative thereof according to a conventional method.

 Reactive derivatives of compound (III) include acid halides such as acid chloride and acid bromide; acid azide; N-hydroxybenzotriazole (HOBT); P-diphenyl and N-hydroxysk. Active esters with imides and the like; symmetrical acid anhydrides; mixed acid anhydrides with alkyl carbonates, P-toluenesulfonic acid and the like.

When compound (II) is reacted with a free carboxylic acid, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) pill, carposimid, 1,1-dicarbonyldiimidazole, N , N '— Bis (2-oxo-1-3-oxazolidinyl) phosphinate It is advantageous to carry out the reaction in the presence of a condensing agent such as lid, diphenylphosphoryl azide (DPPA).

 The reaction conditions vary slightly depending on the starting compound, especially the type of reactive derivative of the compound (化合物 Π), ', pyridine, tetrahydrofuran, dioxane, ether, N, N-dimethylformamide, benzene, toluene. Raw materials (II) and (III) in equimolar to raw materials in an organic solvent inert to the reaction, such as benzene, xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, acetonitrile, etc. It is advantageous to carry out the reaction using an excess of compound (III).

 During the reaction, depending on the type of reactive derivative or when using the salt of the starting compound (Π), trimethylamine, triethylamine, pyridine, picolin, lutidine, dimethylanilinine, N-methylmorpholine The method is carried out in the presence of a base such as an organic base such as phosphorus, or an inorganic base such as sodium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium hydroxide or potassium hydroxide. May be advantageous. Pyridines can also serve as solvents.

 The reaction temperature varies depending on the type of the reactive derivative. It is set as appropriate. Examples of the carboxyl-protecting group include lower alkyl groups such as methyl, ethyl, butyl, isopropyl, and tert-butyl.

Removal of the carboxyl-protecting group may be carried out according to a conventional method, and can be easily carried out, for example, by hydrolysis. (Second step)

Or

(Where A, B, X, R ¹ , R ² and n have the above-mentioned meanings, and R ^la and R ^2a are the same groups as the corresponding R ¹ and R ² or the amino groups, respectively. Means a protecting group.)

 The amide compound represented by the general formula (I), which is the compound of the present invention, is produced by condensing carboxylic acid (IV) or a reactive derivative thereof with the amine represented by the general formula (V) according to a conventional method. can do. Reactive derivatives of compound (IV) include acid halides such as acid chlorides and acid bromides; acid azides; N-hydroxybenzotriazole (HOBT), p-ditrophenyl and N-hydroxysk. Active esters with synimide and the like can be mentioned.

 This reaction can be carried out under the same conditions as in the method described in the first step.

“Amino group-protecting group” represented by R ^la and R ^2a which are the groups possessed by the compound of the formula (V) means a protecting group commonly used by those skilled in the art, and is typically an acyl group. As a protecting group for the amino group, a formyl group, Lower alkanoyl groups such as tyl group and propionyl group, lower alkoxycarbonyl groups such as methoxycarbonyl group, ethoxycarbonyl group, BOC, etc., lower alkane sulfonyl groups such as ethanesulfonyl group and ethanesulfonyl group, methoxyacetyl group, Aliphatic acetyl groups such as methoxypropionyl group, benzoyl group, benzyloxycarbonyl group and p-2-trobenzoyloxyl carbonyl group, or chenyl acetyl group, thiazolyl acetyl group, tetrazolyl acetyl group; And heterocyclic lower alkanol groups, azolylglyoxyloyl groups, and cyenylglyoxyoxyl groups.

 In addition, benzyl, p-nitrobenzoyl, benzhydryl, trityl and the like can be mentioned as protective groups for aralkyl amino groups. Furthermore, a tri-lower alkylsilyl group such as a trimethylsilyl group may be mentioned.

 Removal of the protecting group from the amino group may be carried out according to a conventional method. For example, when the protecting group is a tri-lower alkylsilyl group, etc., the removal can be easily performed by treating with water. When a protecting group such as a benzhydryl group, a p-methoxybenzyl group, a trityl group, a tert-butyl group, or a formyl group is used, a mixture of formic acid, trifluoroacetic acid, trifluoracetic acid / anisole, bromide, etc. It is easily removed by treatment with an acid such as a mixed solution of hydrochloric acid and acetic acid and a mixture of hydrochloric acid and dioxane.

The N-alkyl reaction of the amino compound from which the amino-protecting group has been removed is carried out by a conventional method such as reductive amination, substitution with a halogen compound, etc. to obtain the compound (I) of the present invention. ) Can be obtained.

(VIII) N,

R ”, (CH2) _m — iCHO

(Where A, B, X, R ¹ , R ² and R ^la , R ^2a have the same meaning as described above, and m represents an integer of 2 to 5.)

 The compound (I) of the present invention is obtained by condensing a carboxylic acid (IV) or a reactive derivative thereof with a hydroxy compound represented by the general formula (VI) according to a conventional method to give a compound represented by the general formula (VII). Then, it can be produced by oxidizing to an aldehyde compound represented by the general formula (VIII) and condensing it with an amine represented by the general formula (IX) according to a conventional method. The reaction between the compound represented by the general formula (IV) or a reactive derivative thereof and the compound represented by the general formula (VI) can be performed under the same conditions as in the method described in the first step of the first production method. is there. As the reactive derivative of the compound (VI), the same derivative as described in the second step of the first production method can be used.

Next, by oxidizing the compound represented by the general formula (VII), Although the compound represented by the formula (VIII) is obtained, in this reaction, dimethyl sulfoxy de (DMSO) oxidation. PCC (pyridinium Jiniumu Kurorokurome one DOO), PDC (Pirijiniumu dichromate), Cr0 ₃ pyridine, CuCr_rei_2 like Conventional methods such as chromic acid oxidation used are applied.

As a head-on condensation reaction between the aldehyde compound represented by the general formula (VIII) and the amine represented by the general formula (IX), after condensing (VIII) and (IX), LiAIH ₄ , NaBH ₄ , a method using a reducing agent such as NaBH ₃ CN, NaBH (OAc) 3 or BH3, catalytic reduction, reduction with TiCl _{4 and the} like.

Third manufacturing method;

R ^a OOC- (CH ₂ )

 Or its reactivity

 (ΠΙ)

(Where A, B, X, R ¹ , R ² , R ^la , R ^2a , R ^a and n have the above meanings.)

The amide compound of the present invention represented by the general formula (I) is According to a conventional method, boronic acid or its reactive derivative (III) and the compound represented by the general formula (V) are condensed first, and then the reaction product (X) is deprotected to produce the compound (XI). However, it can be produced by subjecting the compound (XI) and the amine represented by the compound ΠΙ) to a condensation reaction.

 The method of synthesizing compound (X) from carboxylic acid or its reactive derivative and the compound represented by general formula (V) is the same as in the second step of the first production method, and the reaction conditions and the like are the same as those in the second step. It is as described in.

 The reaction of deprotecting the compound (X) to give the compound (XI) may be carried out according to a conventional method for removing the protecting group of the carboxyl group, for example, it can be easily carried out by hydrolysis.

 The reaction for producing the compound (I) of the present invention by subjecting the compound represented by the general formula (XI) to a condensation reaction with the amine represented by the general formula (II) is the same as in the first step of the first production method. The reaction conditions and the like are the same as in the first step.

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

The compounds of the present invention, excellent Musca Li emissions M ₂ receptors have antagonism, preventing young properly for various diseases M ₂ receptors are involved are useful in the treatment. Sinus dysfunction group such as sinus bradycardia, sinus arrest, bradycardia tachycardia syndrome; bradyarrhythmia such as atrioventricular block and other vagus nerve-induced bradycardia, neural syncope (carotid sinus hypersensitivity) Sex)).

The compounds of the present invention also include compounds that can be preventive and therapeutic agents for central nervous diseases such as Alzheimer's disease and Parkinson's disease, or compounds that have antispasmodic activity on peripheral organs, particularly the colon and bladder. In particular, the present invention compounds compared to the M ₃ receptor is a smooth muscle Mus force Li down operation movement portion position, high selectivity for M ₂ receptor is the heart Mus force Li down operation movement portion position, Micromax ₃ receptor antagonists based on the action, b thirst, is particularly useful for bradyarrhythmias as less Micromax ₂ receptor antagonist of side effects, such as effects on the central. Affinity (Micromax M ₂ and M ₃₎ and M ₂ receptor antagonism against Musca Li down receptors of the compounds of the present invention was confirmed by the following tests.

 Muscarinic receptor affinity test (in vitro)

Wistar male rats (300-350 g) were asphyxiated and killed with carbon dioxide using dry ice, and then the cerebral cortex, heart, and submandibular gland were excised, and the membrane fraction was prepared by a conventional method. A specimen was obtained. Cerebral cortex membrane preparation is ³ H - ^pirenzepine with (Mjassay), il,臓膜specimens with ^{J H- quinuclidinyl benzilate (QNB) (} Moassay), submandibular gland membrane specimen ³ H- N-methyl with Scopolamine (NMS) (Mgassay) After incubation for 45 minutes each, the mixture was filtered using a WhatmanGF / B filter, and the radiation dose was measured using a liquid scintillation counter.

Nonspecific binding was determined by adding 2 x 10-5 Matropine simultaneously and incubating. In addition, HEPES buffer [4- (2-hydroxy-ethyl)-1-piperazinethane sulfonic acid 20 mM, NaCl lOOmM, MgCl ₉ lOmM, pH 7.5] was used for membrane preparation, compound preparation, and incubation. used.

Affinity for muscarinic Li down receptors of the compounds Cheng and Prusoff accordingly is labeled Rika "down de ^{3H- pirenzepine (Mj assay), J} H (Biochem.Phamacol, 22, 3099, 1973.) - QNB (M assay), the negative logarithm (pKi) of the dissociation constant calculated from the test compound portability (IC _{5 ()} ) which inhibits the binding of ³ H-NMS (M ₃ assay) by 50%. Table 1 shows the results of the linophil receptor affinity test. table 1

 Compound A: Japanese Patent Publication No. 5-68474 Example 32 compounds

 11-[[2- (Getylaminomethyl) — 1-Biberidinyl] acetyl] — 5, 11—Dihydro—6H-Bide [2,3-b]

[1, 4] Benzojiazebin - 6-one from above Mus force Li emissions affinity test results, the present invention compounds exhibit higher affinity to M ₂ receptor, yet another muscarinic Li down receptors, especially M ₃ receptors it was confirmed that a high M ₂ receptor selectivity as compared with. Muscarinic receptor antagonist test (in vivo)

1) MgAssay (Suppression of spinal cord destruction rat oxotremorine-induced bradycardia)

Using a male Wister rat (300 to 350 g), anesthesia with pentobarbiter was performed at 60 mgZkg ip, tracheal power, carotid power, left and right vagus nerve transection, and spinal cord destruction was performed. Under artificial respiration, the test compound or physiological saline was administered 15 minutes after administration of atenolol 10 mgZkg iv, and 15 minutes later, oxotremorine was cumulatively administered. The evaluation compound was administered iv from the femoral vein. The heart rate immediately before oxotremorine administration was set to 100%, and the dose-response curve was obtained by determining the rate of decrease in heart rate due to cumulative oxotremorine administration in the presence and absence of the test compound. Evaluation absence of compound and ED ₅ in (Con trolls) ₍₎ value (Okiso preparative Remori 50% heart rate reducing effect for the amount due down), from the ratio of the ED _{5 ()} value in the presence, dose- after calculating the rightward movement width of the curve (Dose- ratio), and Schild PLOu this deployment, determine the DR _10, it was expressed with a negative logarithmic value _{(pDR 10, mol / kg)} .

2) M ₃ Assay (Okiso door Remo Li emissions-induced rat saliva secretion inhibiting action)

Using a Wister male rat (300 to 350 g), urethane 1.2 gZkg 10 minutes after iP anesthesia, administer the test compound or physiological saline, and after 15 minutes, oxotremorin 0.8 mol / kg iv. Was administered. The saliva secreted for 5 minutes immediately after oxotremorine administration was collected, and the weight was used as the salivary secretion. The evaluation compound was administered i.v. from the femoral vein.

The salivary secretion of the control was defined as 100%, and the salivary secretion inhibition rate of the test compound was determined. The 50% inhibitory dose (ID _5Q value) was calculated and expressed as a negative logarithmic value (PIDKQ.mol / kg). . Table 2 shows the results of the above muscarinic receptor antagonist test (in vivo). Table 2

M2 / M3: Relative ratio compound of each compound when was the 1 M2ZM3 ratio Atorobin A: Kokoku 5 - than 68474 JP Example 32 Compound above Mus force Li down antagonistic test results, the compounds of the present invention M ₂ receptor high have binding shown, it was confirmed that further high M ₂ receptor selectivity as compared with the M ₃ receptors. Pharmaceutical preparations containing one or more of the compounds of the present invention or salts thereof as an active ingredient are prepared using carriers, excipients and other additives commonly used in pharmaceutical preparations.

 Examples of carriers and excipients for pharmaceuticals include solid or liquid emergency pharmaceutical substances. Examples of these include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, ethylen glycol, and other commonly used ones. Is exemplified.

 Administration is via tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous or intramuscular injections, suppositories, transdermals, inhalants, or intravesical injection. Any form of parenteral administration may be used. The dose is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject of administration, gender, etc. However, in the case of oral administration, the dose is usually about 0.1 to 0.1 mg / kg for adults per day. This may be administered once or in 2-4 divided doses. When given intravenously due to symptoms, it is usually administered once or more than once daily in the range of O.OO lmgZkg to lOmgZkg per adult.

Tablets, powders, granules and the like are used as the solid composition for oral administration according to the present invention. In such a solid composition, the one or more active substances may contain at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, poly, and the like. It is mixed with vinylpyrrolidone and magnesium aluminate. In a conventional manner, the composition may contain additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium glycerol glycolate, and lactose. It may contain stabilizing agents, solubilizing agents such as glutamate or aspartate. Tablets or pills may be sugar-coated such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, etc. May be coated with a film of an enteric substance.

 Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and commonly used inert diluents. , For example, purified water. Contains ethanol. This composition may contain, in addition to the inert diluent, auxiliaries such as wetting agents and suspending agents, sweeteners, flavoring agents, flavoring agents 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 water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80. is there. Such compositions may also include preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg, lactose), and solubilizing agents (eg, glutamate, aspartic acid). Adjuvants may be included. These are sterilized by, for example, filtration through a bacterial storage filter, blending of a bactericide or irradiation. They can also be used to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to examples. The compounds of the present invention are not limited to the compounds described in the following Examples, and may also be those represented by the above general formula (I), salts thereof, hydrates thereof, solvates thereof, geometrical and optical properties thereof. It includes all isomers and polymorphs.

The starting compounds of the compounds of the present invention include novel compounds, and the production examples of these compounds will be described as reference examples. Reference example 1 4-Morpholinobenzaldehyde A solution of 610 mg of dichloromethane (20 ml) in ice-cooled N, N'-ethylethyldiamine 1.85 g, acetic acid 2.74 g, triacetoxytridium borohydride (NaBH (OAc) 3 ) 2.02 g was added in sequence, and the mixture was returned to room temperature and stirred overnight. To the reaction solution was added a 1N aqueous sodium hydroxide solution (20 ml) to make it alkaline, and the mixture was extracted twice with chloroform (20 ml). After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (croral form: methanol: annmore water = 30: 1: 0.1). Then, 340 mg of N, N'-diethyl-N- (4-morpholinobenzyl) ethylenediamine was obtained as an oily substance.

Mass spectrometry value (mZz): EI 291 (M ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.03 (3Η, t), 1.08 (3H, t),

 2.50 (2H, q), 2.54-2.60 (4Η, m),

 2.66 (2H, t), 3.14 (4H, t),

 3.50 (2H, s), 3.86 (4H, t),

 6.86 (2H, d), 7.19 (2H, d) The following compounds of Reference Examples 2 to 9 were obtained in the same manner as in Reference Example 1. Reference example 2

 N, N * 1-ethyl-N- (4-pyrrolidinobenzyl) ethylenediamine

Mass spec (mZz): FAB 276 (MH ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.02 (3Η, t), 1.09 (3H, t),

1.97—2.01 (4Η, m), 2.47-2.68 (8Η, m), 3.27 (4Η, t), 3.48 (2Η, s), 6.52 (2H, d), 7.13 (2H, d) Reference example 3

 N, Ν '—Jetyl ー Ν— [4- (hexahidraw 1-abipinyl) benzyl] ethylenediamine

Mass spectrometry value (mZz): FAB 304 (MH ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.03 (3Η, t), 1.08 (3H, t),

 1.53-1.55 (4H, m), 1.78 (4H, s),

 2.50-2.67 (8H, m), 3.42-3.46 (6H, m),

6.62 (2H, d), 7.10 (2H, d) Reference example 4

 N, N '—Jetyl-N— [4- (4-Methyl-1-piperidinyl) benzyl] ethylenediamine

 Mass spectrometry value (mZz): FAB 304 (MH +)

Nuclear magnetic resonance spectrum (CDClg, TMS internal standard)

 δ 0.97 (3Η, t), 1.06 (3H, t), 1.12 (3Η, t), 1.30-1.38 (2Η, m), 1.45-1.54 (1Η, m), 1.73 (2H, d), 2.53-2.59 (4Η, m),

 2.64-2.71 (6Η, m), 3.50 (2H, s),

 3.62 (2H, d), 6.89 (2H, d), 7.16 (2H, d) Reference example 5

 N— [4 -— (4-t-butyloxycarbonyl-2--1-piperazinyl) benzyl] -N, N'-getylethylenediamine

 Mass spec (mZz): FAB 391 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.09 (3Η, t), 1.14 (3H, t),

 1.48 (9Η, s), 2.55-2.64 (4H, m),

2.69-2.72 (2H, m), 2.79 (2Η, m), 3.10-3.14 (4H, m), 3.53 (2H, s),

 3.56-3.60 (4Η, m), 6.89 (2Η, d),

 7.20 (2Η, d) Reference example 6

 Ν, Ν '— Jethyl-Ν— [4- (4-methyl-1-piperazinyl) benzyl] ethylenediamine

 Mass spec (mZz): FAB 305 (MH +)

Nuclear magnetic resonance spectrum (CDClg, TMS internal standard)

 δ: 0.96-1.10 (6Η, m), 2.35 (3H, s),

 2.52-2.68 (12H, m), 3.19 (4Η, t), 3.50 (2Η, s), 6.88 (2Η, d), 7.18 (2Η, d) Reference example 7

 ,, Ν '—Jetyl ー Ν— [4- (4-ethyl-1-piperazinyl) benzyl] ethylenediamine

 quality! : Analysis value (mZz): EI 318 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 0.98-1.14 (9Η, m), 2.45-2.68 (14H, m),

3.20 (4H, t), 3.49 (2Η, s), 6.88 (2H, d), 7.18 (2H, d) Reference Example 8

 Ν, Ν '—Jetyl— Ν— [4- (4-η-Propyl-1-1-pidinyl) benzyl] ethylenediamine

 Mass spectrometry value (mZz): FAB 333 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 0.80-1.28 (9Η, m), 1.96-2.05 (2H, m),

2.31— 2.80 (14H, m), 3.10-3.25 (4H, m), 3.50 (2H, s), 6.85 (2H, d), 7.20 (2H, d) Reference example 9

 N, Ν'-I-ethyl-N- [4- (1-methylthiethyl) -1-piradizinylbenzyl] ethylenediamine

 Mass spec (mZz): EI 332 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ 0.99-1.07 (6Η, m), 1.10 (6H, d),

 2.48-2.80 (13H, m), 3.18-3.20 (4H, m),

3.49 (2H, s), 6.87 (2H, d), 7.18 (2Η, d) Reference example 10 (1)

 To a mixed solution of 630 mg of a chloroacetaldehyde 40% τΚ solution in 630 mg of dichloromethane (10 ml) were sequentially added 660 mg of N-methyl-4-morpholinobenzylamine, 290 mg of acetic acid, and 1.07 g of triacetoxyborohydride under ice-cooling. The reaction solution was returned to room temperature, stirred for 2.5 hours, and then made alkaline with 1N sodium hydroxide. After extracting twice with black-mouthed form (10 ml), the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform form), and N- (2-chloroethyl) -N-methyl-41-morpholinobenzylamine 420 mg Was obtained as an oil.

Mass spectrometry value (m / z): EI 268 (M ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 2.27 (3Η, s), 2.73 (2Η, t), 3.15 (4H, t),

3.50 (2Η, s), 3.56 (2H, t), 3.86 (4H, t), 6.87 (2H, d), 7.21 (2H, d) Reference example 10 (2)

N— (2-chloroethyl) 1 N—methyl 4—morpholine To a solution of 380 mg of ethanol in ethanol (10 ml) was added 460 mg of aqueous solution of ethylamine 709, and the reaction mixture was stirred with 60 drops. After distilling off the solvent under reduced pressure, the resulting residue is crystallized from ether to give 300 mg of N'-ethyl-1-N-methyl-N- (4-morpholino) benzylethylenediamine hydrochloride in white color. Obtained as crystals.

 Mass spec (mZz): EI 277 (M +)

Nuclear magnetic resonance spectrum (CDClg, TMS internal standard)

 δ: 1.37 (3Η, t), 2.13 (3H, s),

 2.85-2.91 (4Η, m), 3.02-3.08 (2H, m), 3.13-3.15 (4Η, m), 3.56 (2H, s),

 3.86 (4Η, t), 6.87 (2Η, d), 7.24 (2Η, d) The following compounds of Reference Examples 11 to 14 were obtained in the same manner as in Reference Example 10 (2).

Reference Example 11

 N'-ethyl-N-methyl-N- (4-piperidino) benzylethylenediamine hydrochloride

 Mass spectrometry value (mZz): EI 275 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.33 (3Η, t), 1.57-1.60 (2H, m),

 1.68-1.72 (4H, m), 2.36 (3H, s),

 2.76 (4Η, q), 3.00 (2H, t), 3.15 (4H, t), 3.55 (2H, s), 6.89 (2H, d), 7.18 (2H, d) Reference Example 12

 Ν '-Ethyl-N-methyl-N- 4- (4-methyl-1-piperazinyl) benzylethylenediamine hydrochloride

 Mass spec (mZz): EI 290 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard) δ: 1.35 (3Η, t), 2.30 (3Η, s), 2.39 (3Η, s), 2.62-2.64 (4Η, m), 2.80-2.87 (4Η, m), 2.99 (2H, t), 3.23 ( 4H, t), 3.52 (2H, s), 6.89 (2Η, d), 7.21 (2Η, d) Reference example 13

 N'-Ethyl-N — [4- (1-ethyl-1-piperazinyl) benzyl] — N—Methylethylenediamine hydrochloride

 Mass spectrometry value (mZz): EI 304 (M +)

Nuclear magnetic resonance scan Bae click preparative Le (CDC1 _3, TMS internal standard)

 δ: 1.18 (3Η, t), 1.34 (3H, t), 2.30 (3Η, s), 2.55-2.59 (2H, m), 2.69-2.71 (4H, m), 2.79-2.86 (4H, m), 2.97-2.99 (2Η, m), 3.26-3.28 (4H, m), 3.52 (2H, s),

 6.89 (2H, d), 7.21 (2H, d) Reference Example 14

 N-cyclopropyl-N'-ethyl-N- (4-morpholine benzyl) ethylenediamine hydrochloride

 Mass spec (mZz): EI 303 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 6: 0.56-0.58 (2Η, m), 0.61 — 0.62 (2H, m), 1.29 (3H, t), 1.88-1.91 (1Η, m),

 2.73 (2H, q), 2.94 (2H, t), 3.00 C2H, t), 3.13 (4H, t), 3.72 (2H, s), 3.85 (4H, t), 6.87 (2H, d), 7.21 ( 2H, d) Reference example 15

Ν 'ェ ethyl チ ル Ν — (4 rufolinobenzyl) 1 Ν — (2, 2, 2—Trifluoroethyl) Ethylenediamine

 Mass spec (mZz): EI 345 (M +)

Nuclear magnetic resonance spectrum (CDCIQ, TMS internal standard)

 δ 1.07 (3Η, t), 1.80 (1H, brs),

 2.55 (2H, q), 2.66 (2Η, t),

 2.78 (2H, t), 3.07-3.16 (6Η, m),

 3.74 (2H, s), 3.85-3.87 (4Η, m),

 6.87 (2H, d), 7.19 (2Η, d) Reference example 16

 N'-Ethyl-N— (2-Methoxyxyl)-N-(4 morpholinobenzyl) Ethylenediamine

 Mass spec (mZz): EI 321 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.37 (3Η, t), 2.72 (2H, t),

 2.75-2.79 (2Η, m), 2.86 (2H, t),

 2.92 (2H, t), 3.11-3.16 (4H, m),

 3.40 (3H, s), 3.84-3.87 (4H, m),

 6.87 (2H, d), 7.18 (2H, d) Reference example 17

5,11 dihydro 6H-pyrido [2,3-b] [1,4] benzodiazepin-6-one Triethylamine 1.50 in a suspension of 3.0 g of dioxane (60 ml) heated to 80 g of dioxane solution (5 ml) and 2.46 g of dioxane solution (5 ml) of monoethyl succinate were simultaneously added dropwise. After reacting for 4 hours under reflux with heating, the solvent was distilled off under reduced pressure. To the resulting residue was added chloroform (25 ml) and water (25 ml). The precipitated crystals were filtered off, and the organic layer was separated. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel gel ram chromatography. The crude oil was purified by rough (cloth form: methanol = 100: 1) and the resulting oil was crystallized from methanol to obtain ethyl acetate.

 [11- (5,11-dihydro-6H-pyrid [2,3-b] [1,4] benzodiazepine-16-one) yl] 141-oxobutylate 2.94 g as white crystals Obtained.

 Melting point: 219-221

Elemental analysis (as a _{C 18 H 17 N 3 0 4} )

 C (%) H (%) N (%)

 Theoretical 63.71 5.05 12.38

 Experimental value 63.39 5.12 12.18 Reference example 18

 5, 10-Dihydro 11 H-Dibenzo [b, e] [1, 4] diazepin-11-one In 3.0 g of tetrahydrofuran solution (50 ml), 1.82 g of dimethylanilinine and monoethyl succinate 3.52 g was added.

After reacting at 80 ° C for 2 hours, 3.10 g of monoethyl succinate was added and stirred at 80 ° C overnight. The reaction solution was evaporated under reduced pressure, and the residue was dissolved in chloroform (50 ml). After washing with 0.1 N hydrochloric acid (50 ml) and saturated saline (50 ml), the organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1), and the obtained oily substance was purified from methanol. By crystallization, ethyl 4- [5- (5,10-dihydro-11H-dibenzo [b, e] [1,4] diazepine-11-one) yl] 14-oxobutyrate 3.49 g was obtained as white crystals.

 Melting point: 194-1196

Elemental analysis (as a _{C 19 H 19 N 2 0 4} )

 C (%) H (%) N (%)

Theoretical 67.45 5.36 8.28 Experimental value 67.17 5.36 8.14 Mass spectrometry value (mZz): FAB 339 (MH +) Reference example 19 '

 213.5 g of piperazine and 228 g of potassium carbonate were added to a dimethylformamide solution (1000 ml) of 100 g of 4-fluorobenzonitrile, and the mixture was stirred at 80 and 4.5 hours. After the precipitated salt was filtered off, the solvent was distilled off under reduced pressure, and the residue was crystallized from ethyl ether to obtain 59.9 g of 4- (1-piperidinyl) benznitrile as white crystals.

 Melting point: 80-81 ° C

 Mass spectrometry value (mZz): EI 187 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 2.37 (1H, brs), 3.02 (4H, t), 3.29 C4H, t), 6.85 (2Η, d), 7.48 (2H, d) Reference example 20

 41. To a solution of 18.72 g of benznitrile (250 ml) in bennitrile (250 ml) was added 7.55 g of acetone, 15.0 g of acetic acid, and 29.0 g of sodium triacetoxyborohydride under ice-cooling. The mixture was stirred at room temperature for 20 hours. The reaction mixture was cooled on ice, made alkaline by adding 1N sodium hydroxide, and extracted twice with chloroform (200 ml). The solvent was distilled off under reduced pressure after drying with magnesium sulfate. The residue was crystallized from hexane to give 21.0 g of 4- (4-1-isopropyl-1-piperidinyl) benzaldehyde as white crystals.

 Melting point: 88-90 ° C

 Mass spec (mZz): EI 229 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

δ: 1.08 (6Η, d), 2.65 (4H, t), 2.73 (1H, dt), 3.33 (4Η, t), 6.85 (2H, d), 7.48 (2H, d) Reference Example 21

 4-1 (4-Isopropyl-11-piperidinyl) Benznitrile To a solution of 9.1 g of toluene (64 ml) was added dropwise 64 ml of a diisobutylaluminum n-hexane solution under ice-cooling. The solution was stirred with 50 pieces for 1.5 hours. The reaction solution was returned to room temperature, water (50 ml) and ethyl acetate (100 ml) were added, and the deposited precipitate was removed using celite, and the ethyl acetate layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (closure form: methanol = 100: 1) and crystallized from diisopropyl ether. 6.84 g of, 4- (4-isopropyl-1-1-piperidinyl) benzaldehyde was obtained as yellow crystals.

 Melting point: 62-63

 quality! : Analysis value (mZz): EI 232 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.09 (6Η, d), 2.66 (4H, t), 2.73 (1Η, dt), 3.41 (4Η, t), 6.92 (2Η, d), 7.74 (2Η, d), 9.78 (1H, s) Reference Example 22

4-1 (4-Isopropyl-11-piperidinyl) benzaldehyde 6.80 g of a chloroform solution (50 ml) in ice-cooled 40% methylamine methanol solution 7.96 g, acetic acid 6.2 g, 9.8 g of sodium triacetoxyborohydride was added sequentially, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was clarified with 1N sodium hydroxide under ice cooling, and extracted four times with chloroform (50 ml). After combining the form layers of the mouth and drying over magnesium sulfate, the solvent was distilled off under reduced pressure to give N- [4- (4-Isopropyl-1-piperazinyl) benzyl] -N-methylamine. g was obtained as an oil. Mass spec (m / z): EI 247 (M ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ 1.08 (6Η, d), 2.42 (3H, s),

 2.66-2.69 (4Η, m), 2.71 (1Η, q), 3.17-3.20 (4Η, m), 3.68 (2Η, s),

 3.94 (1Η, brs), 6.88 (2Η, d), 7.20 (2H, d) Reference example 23

 N- [4- (4-Isopropyl-1-1-piperazinyl) benzyl] -N-methylamine 5.75 g of a 40% aqueous solution of chloroformate in 7.20 g of a chloroform solution (50 ml) under ice cooling. 3.52 g of acetic acid and 9.80 g of sodium triacetoxyborohydride were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. 1N sodium hydroxide was added to the reaction mixture, and the mixture was extracted twice with black-mouthed form to make it more viscous. After adjusting the form of the port, the mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (cloform form: methanol = 100: 1), and N— (2-chloroethyl) -N— [4— (4— 6.21 g of isopropyl-1-piperazinyl) benzyl] -N-methylamine were obtained as an oil.

 Mass spec (mZz): EI 309 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.09 (6Η, d), 2.26 (3H, s),

 2.68-2.75 (7Η, m), 3.19-3.22 (4H, m), 3.49 (2H, s), 3.55 (2H, t), 6.88 (2H, d), 7.18 (2Η, d) Reference example 24

N- (2-Chloroethyl) N— [4- (4-Isopropyl-11-piperazinyl) benzyl] —N-methylamine 5.94 g of ethanol 6.25 g of a 70% aqueous solution of ethyl ethylamine was added to the solution (40 ml), and the mixture was stirred at 60 for 2 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform (50 ml), 1N sodium hydroxide was added, and the mixture was extracted twice with chloroform. After drying the combined chloroform layer with magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol: ammonia water = 30: 1: 0.1). Then, 3.72 g of N'-ethyl-N- [4- (4-isopropyl-1-1-piperazinyl) benzyl] -1-N-methylamine was obtained as an oily substance.

 Mass spectrometry (m / z): FAB 319 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.08-1.17 (9Η, m), 1.96 (1H, brs),

 2.17 (3Η, s), 2.51 (2H, t),

 2.60 (2H, dd), 2.67-2.74 (7Η, m),

3.18-3.20 (4H, m), 3.42 (2H, s),

 6.87 (2H, d), 7.17 (2H, d) Reference example 25

5, 11—Dihydro 6Η—Pyrido [2,3-b] [1, 4] Benzodiazepin-6-one 80 g in a suspension of 3.0 g of dioxane (60 ml) under heating 80 g of a dioxane solution (5 ml) and 2.46 g of a dioxane solution (5 ml) of monoethyl succinate were simultaneously added dropwise. After reacting for 4 hours under reflux with heating, the solvent was distilled off under reduced pressure. To the resulting residue was added chloroform (25 ml) and water (25 ml), and after the precipitated crystals were removed, the organic layer was separated. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1), and the obtained oily substance was purified. By crystallization from methanol, ethyl 4- [11- (5,11 dihydro 6H-pyrido [2,3-b] [1,4] benzodiazepine-16-one) yl] 2.94 g of white soap B

 Melting point: 219-221

Elemental analysis (as _{C 19 H N N 3 0 4} )

 C (%) H (%) N (%)

 Theoretical 63.71 5.05 12.38

 Experimental value 63.39 5.12 12.18

Mass spectrometry value (mZz): FAB 340 (MH ⁺ ) Reference Example 26

 N, N '— To a solution of 6.0 ml of dimethyl ether in dichloromethane (60 ml) was added 2.0 g of fluorinated benzyl bromide under ice-cooling, and the reaction solution was cooled to room temperature. Stirred overnight. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution and water, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (clohol form: methanol: ammonia water = 30: 1: 0.1), and N, N'-Jetyl-N— (4-F 1.80 g of ethylenediamine was obtained as yellow crystals. Quality S analysis value (mZz): EI 224 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 0.95 (3Η, t), 1.15 (3H, t), 2.60 C2H, q), 2.62 (2Η, q), 2.64—2.69 (4H, m),

 3.53 (2H, s), 6.99 (2H, d), 7.27 (2H, d) The following compounds of Reference Examples 27 to 35 were obtained in the same manner as in Reference Example 26. Reference Example 27

 N, N 'monoethyl-N- (3-pyridylmethyl) ethylenediamine

 Mass spec (mZz): EI 207 (M +)

Nuclear magnetic resonance spectrum (CDCIQ, TMS internal standard)

6: 1.03 (3Η, t), 1.07 (3H, t), 2.51-2.67 (8H, m), 3.59 (2H, s),

 7.23-7.27 (1H, m), 7.64-7.65 (1H, m),

8.51 (2H, d) Reference example 28

 N — (2—Cross- mouth benzyl) 1 N, N'-Jetylethylene

Mass spec (mZz): EI 241 (M ⁺ )

Nuclear magnetic resonance scan Bae click preparative Le (CDCI _3, TMS internal standard)

 δ: 1.02-1.10 (6Η, m), 2.53-2.58 (4H, m),

2.64-2.68 (4H, m), 3.67 (2H, s),

7.17 (1H, t), 7.22 (1H, t), 7.37 (1H, d), 7.46 (1H, d) Reference Example 29

 N, N, 1-Jetyl-N — (2-naphthylmethyl) ethylene

 Mass spectrometry value (mZz): EI 255 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 0.98-1.14 (6Η, m), 2.42-2.68 (8H, m), 3.73 (2H, s), 7.38-7.52 (3H, m), 7.75-7.90 (4H, m) Reference example 30

 N, N '—Jethyl-N — (4-methylbenzyl)

Mass spectrometry value (mZz): EI 220 (M ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

6: 1.03 (3Η, t), 1.07 (3H, t), 2.33 (3Η, s), 2.51 (2H, q), 2.55 (3H, q), 2.58 (3H, t), 2.65 (3H, t), 3.53 C2H, s), 7.11 (2H, d), 7.18 (2H, d) Reference Example 31

 N, N '— Jethyl-N— (412 benzyl) ethylenediamine

Mass spectrometry value (mZz): FAB 251 (MH ⁺ )

Nuclear magnetic resonance spectrum (CDClg, TMS internal standard)

 δ: 1.04 (3Η, t), 1.09 (3H, t), 2.54 (2Η, q), 2.57 (2H, q), 2.62 (2H, t), 2.67 (2Η, t), 3.67 (2Η, s) , 7.50 (2Η, d), 8.16 (2Η, d) Reference example 32

Ν—Benziru Ν, N '—Jetyloo 1,3—Prono, ^0- diamine Mass spectrometry (mz): EI 220 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.04 (3Η, t), 1.08 (3H, t), 1.66 (2Η, m), 2.45-2.53 (4Η, m), 2.58-2.62 (4Η, m), 3.54 (2H, s), 7.21- 7.32 (5H, m) Reference example 33

 N- (4-bromobenzyl) -N, N'-Gethylethylenediamin

 Mass spectrometry (mZz): EI 286 (MH +)

Nuclear magnetic resonance spectrum (CDClq, TMS internal standard)

 δ: 1.02 (3Η, t), 1.08 (3H, t), 2.51 (2H, q), 2.54-2.59 (4Η, m), 2.65 C2H, t),

3.52 (2H, s), 7.19 (2Η, d), 7.42 (2Η, d) Reference example 34

 N, Ν '—Jetyl-Ν— (4-Methoxycarbonylbenzyl) ethylenediamine

 Mass analysis value (mZz): EI 252 (M +)

Nuclear magnetic resonance spectrum (CDCIQ, TMS internal standard)

 δ: 1.04 (3Η, t), 1.10 (3H, t), 2.51 (2Η, q), 2.56 (2Η, q), 2.60 (2Η, t), 2.65 (2Η, t), 3.64 (2H, s) , 3.93 (3H, s), 7.39 (2H, d), 7.97 (2H, d) Reference example 35

 N, N'-Jethyl-N— (4-Pyridylmethyl) ethylamine

Mass spectrometry value (mZz): EI 207 (M ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.00 (3Η, t), 1.12 (3H, t),

 2.42-2.70 (8H, m), 3.58 (2H, s),

 7.25 C2H, d), 8.53 (2H, d) Reference example 36

To a solution of 910 mg of benzaldehyde in dichloromethane (50 ml) was added 5.0 g of N, N'-dimethylethylenediamine, 2.60 g of acetic acid, and 5.47 g of sodium triacetoxyborohydride under ice-cooling. The mixture was returned to room temperature and stirred for 10 minutes. A 1N aqueous solution of sodium hydroxide (30 ml) was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (clo mouth form: methanol: ammonia water = 30: 1: 0.1), and purified by N, N'-Jetyl-N-benzyl diethylene 1.19 g of the amine were obtained as an oil.

 Mass spec (m / z): EI 206 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.04 (3Η, t), 1.07 (3H, t),

 2.50-2.58 (4Η, m), 2.60 (2Η, q)

 2.65 (2Η, q), 3.57 (2Η, s),

 7.21-7.32 (5Η, m) The following compounds of Reference Examples 37 to 57 were obtained in the same manner as in Reference Example 36. Reference Example 37

 N, N '—Jethyl-N—Phenylethylamine

 Mass spectrometry value (mZz): FAB 221 (MH +)

Nuclear magnetic resonance spectrum (CDC, TMS internal standard)

 δ: 1.05 (3Η, t), 1.09 (3H, t),

 2.38-2.90 (12H, m), 7.06-7.46 (5H, m) Reference example 38

 N, Ν'-Jetyl Ν— (4-Methoxybenzyl) Ethylenediamine

 Mass spectrometry value (mZz): EI 236 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 0.94-1.16 (6Η, m), 2.10 (1H, s),

 2.40-2.69 (8H, m), 3.50 (2H, s),

 3.77 (3H, s), 6.78-7.26 (4Η, m) Reference example 39

 N, N'-I-ethyl-N- (3-methoxybenzyl) ethylenediamine

Mass spectrometry (mZz): FAB 237 (MH +) Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 <5: 0.96-1.56 (6H, m), 2.37-2.64 (9H, m)

 3.54 (2H, s), 3.66 (3H, s),

 6.82 one 7.30 (4H, m) Reference example 40

 N-(4 1-benzyl benzyl) 1 N, N '— getylethylene

 Mass spectrometry (m / z): EI 240 (M +)

Nuclear magnetic resonance scan Bae click preparative Le (CDC1 _3, TMS internal standard)

 <5: 0.94-1.16 (6H, m), 2.14 (1H, s),

 2.39-2.75 (8H, m), 3.52 (2H, s),

 7.24 (4H, s) Reference example 41

 N-(3—Cross- mouth benzyl) N, N '— Jethylethylene

 Mass spec (mZz): FAB 241 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 <5: 1.00-1.21 (6H, m), 2.37 (1H, s),

 2.46-2.68 (8H, m), 3.58 (2H.s),

 7.24 one 7.40 (4H, m) Reference example 42

 N, N '— Jethyl-N — (3, 4—Methylenoxybenzil) Ethylenediamine

Mass spectrometry value (mZz): EI 250 (M ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

δ: 1.04 (3Η, t), 1.13 (3H, t), 2.54 (2 q, q), 2.60 (2H, q), 2.63 (2H, t), 2.70 (2H, t) 3.49 (2H, s), 5.93 (2H, s), 6.75 (2H, s) 6.82 (1H, s) Reference example 43

N, N'-Jethyl-N- (3-thenyl) ethylenediamine Mass spectrometry (mZz): EI 212 (M ⁺ )

Nuclear magnetic resonance spectrum (CDC1 _3, TMS internal standard)

 δ: 1.06 (3Η, t), 1.11 (3H, t), 2.55 (2H, q) 2.58-2.60 (2H, m), 2.61-2.64 (2H, m), 2.69 (2H, t), 3.62 (2H , S), 7.03 (1Η, d) 7.09 (1H, s), 7.28 (1H, d) Reference example 44

 N, '1-ethyl-N- (4-phenylcyclohexyl) ethylenamine

 quality! : Analytical value (mZz): EI 274 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3. TMS internal standard)

 6: 0.97, 1.05 (total 3Η. T, t),

 1.13-1.18 C3H, m) 1.39-1.51 (3H, m)

1.53-1.58 (1H, m) 1.64-1.70 (1H, m)

1.75-1.80 (1H, m) 1.87-1.89 (1H, m)

1.95-1.98 (1H, m) 2.01 one 2.07 (1H, m)

2.42-2.48 (1H, m) 2.55-2.79 (8H, m)

7.15-1 7.20 (2H, m) 7.26-1 7.31 (3H, m) Reference example 45

N, N '—Jetyl-N— (2-Methoxybenzyl) ethylenediamine Mass spectrometry value (mZz): FAB 237 (MH ⁺ )

Nuclear magnetic resonance spectrum (CDC1, TMS internal standard)

 δ: 0.95-1.15 (6Η, m), 1.62 (1H, s),

 2.41-2.65 (8H, m), 3.59 (2H, s),

 3.79 (3H, s), 6.78-7.38 (4H, m) Reference example 46

 N, N '— Jethyl-N— (4-dimethylaminobenzyl) ethylenamine

 Quality i Analysis value (mZz): EI 249 (M +)

Nuclear magnetic resonance scan Bae click preparative Le (CDC1 _3, TMS internal standard)

 δ: 1.05 (3Η, t), 1.09 (3H, t), 2.55 (2Η, q), 2.57 (2H, q), 2.62 (2H, t), 2.68 (2H, t), 2.96 (6H, s) , 3.49 (2H, s), 6.69 C2H, d), 7.15 (2Η, d) Reference example 47

 N, N '— Jethyl-N— (4-hydroxybenzyl) ethylenediamine

 quality! : Analysis value (mZz): EI 221 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.05 (3H, t), 1.08 (3Η, t),

 2.53-2.62 (8H, m), 3.47 (2H, s),

 6.54 (2H, d), 7.05 (2H, d) Reference example 48

 N, N '— Jethyl-N— (2,3-dimethyl 4-methoxybenzyl) Ethylenediamine

Mass spectrometry value (m / z): EI 264 (M +) Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard) δ: 1.03 - 1.06 (6Η , m), 2.16 (3H, s),

 2.27 (3H, s), 2.46 C2H, q), 2.55 (2Η, q) 2.62 (4Η, s), 3.52 (2Η, s), 3.80 C3H, s) 5.30-5.40 (1Η, bs), 6.65 (1Η) , d), 7.02 (1Η, d) Reference example 49

 N, N'-Jethyl-N- (4-methylthiobenzyl) ethylenediamine

Mass spectrometry value (m / z): EI 252 (M ⁺ )

Nuclear magnetic resonance spectrum (CDCIQ, TMS internal standard)

 δ: 1.04 (3Η, t), 1.10 (3H, t), 2.45 (3Η, s), 2.54 (2Η, q), 2.57 (2Η, q), 2.62 (2Η, t), 2.71 (2Η, t) , 3.56 (2Η, s), 7.22 (4Η, s) Reference example 50

 Ν, Ν '—Jetyl ー Ν— (4-ethylbenzyl) ethylenediamine

 Mass spec (mZz): EI 234 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.05 (3Η, t), 1.07 (3H, t), 1.24 (3Η, t), 2.51-2.61 (4Η, m), 2.63-2.68 (6Η, m), 3.54 (2Η, s), 3.95 ( 1Η, bs), 7.13 (2Η, d), 7.21 (2Η, d) Reference example 51

Ν, Ν '—Jetyloo Ν— (4-Propoxybenzyl) ethylenamine Quality i analysis value (m / z): FAB 265 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 6: 1.02-1.05 (6Η, m), 1.08 (3H, t),

 1.80 (2H, dt), 2.50-2.67 (8Η, m), 3.51 (2H, s), 3.91 (3H, t), 6.84 (2H, d) 7.19 (2H, d) Reference example 52

 N, N '— Jethyl-N — (4 — trifluoromethylbenzyl) ethylenediamine

 Mass spec (mZz): EI 274 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.07 (3Η, t), 1.16 (3H, t), 2.58 C2H, q), 2.66 (2Η, q), 2.73 (2H, t), 2.79 (2H, t), 3.52 (1H, bs), 3.65 (2H, s), 7.44 (2H, d), 7.58 (2H, d) Reference example 53

 N-cyclohexylmethyl-N, N'-Jetylethylenediamine Mass spectrometry (mZz): EI 212 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 6: 0.80 (2Η, q), 0.98 (3H, t), 1.13 (3H, t),

 1.14-1.27 (2H, m), 1.37-1.44 (1H, m), 1.65-1.77 (6H, m), 2.16 (2H, d),

 2.48 (2H, q), 2.53 (2Η, t),

 2.65-2.71 (4Η, m) Reference example 54

N, Ν '—Jetyl ー Ν— (4-Isopropylbenzyl) ethylene Jimin

 Mass spec (mZz): EI 248 (M +)

Nuclear magnetic resonance scan Bae-vector (CDCI _3, TMS internal standard)

 δ: 0.98-1.14 (6Η, m), 1.20 (3H, s),

 1.28 (3Η, s), 2.39-2.64 (8Η, m), 2.71-3.03 (1Η, m), 3.54 (2H, s), 7.19 (4H, s) Reference example 55

 N, N—Dibenziru N'—Ethiethylethylenediamine

Mass spectrometry value (mZz): FAB 269 (MH ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.20 (3Η, t), 2.54 (2H, q), 2.75 (1Η, brs),

 2.86 (2H, t), 2.94 (2H, t), 3.66 C4H, s), 7.26-7.35 (10H, m) Reference Example 56

 N, N'-Jetyl-N- [4- (Pyridine) -benzyl] Ethylenediamine

 Mass spec (mZz): EI 289 (M +)

Nuclear magnetic resonance scan Bae click preparative Le (CDC1 _3, TMS內部standard)

 <5: 1.00 C3H, t), 1.11 (3H, t),

 1.50-1.81 (6H, m), 2.41-2.66 (8H, m), 3.07-3.28 (4H, m), 3.48 (2H, s),

 6.87 (2H, d), 7.16 (2H, d) Reference Example 57

N, N'-J-ethyl-N- (2-thenyl) ethylenamine Mass spectrometry (mZz): FAB 213 (MH +) Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.03 (3Η, t), 1.14 (3H, t),

 2.45-2.75 (8Η, m), 3.81 (2H.s),

 6.89-6.94 (2Η, m), 7.18 (1H, d) Reference example 58

 To a mixture of 3.3 g of a 40% aqueous solution of chloroacetaldehyde in 20 ml of dichloromethane, 2.0 g of N-methylbenzylamine, l.lg of acetic acid and 3.50 g of triacetoxyborohydride were sequentially added under ice-cooling. The reaction solution was returned to room temperature and stirred overnight. Then, a 1N aqueous sodium hydroxide solution (20 ml) was added to the reaction solution, and the organic layer was separated. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain 1.26 g of [N- (2-chloroethyl) -N-methyl] benzylamine.

 Mass spectrometry value (mZz): EI 183 (M +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 2.28 (3Η, s), 2.76 (2Η, t), 3.57 (2H, t),

 3.57 (2H, s), 7.24-7.30 (5Η, m) Reference example 59

 To a solution of 960 mg of [N- (2-chloroethyl) -N-methyl] benzylamine in ethanol (20 ml) was added 1.65 g of a 70% aqueous solution of ethylamine, and the reaction mixture was stirred at 60 overnight. After evaporating the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (cloth form: methanol = 30: 1). The obtained residue was crystallized from ether to give 430 mg of (N-benzyl-N'-ethyl-N-methyl) ethylenediamine hydrochloride as white crystals.

 Mass spectrometry value (mZz): EI 192 (M +)

Nuclear magnetic resonance spectrum (CDC1 _3, TMS internal standard) δ: 1.37 (3Η, t), 2.31 (3Η, s),

 2.84-2.91 (4Η, m), 3.00 C2H, t), 3.60 (2H, s), 7.27-7.34 (5H, m) In the same manner as in Reference Example 59, the following compounds of Reference Examples 60 and 61 were obtained. Was.

Reference Example 60

 N-Benziru N'-Ethyru N-Propyleneethylenediamine Mass spectrometry (mZz): FAB 221 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 0.85 (3Η, t), 1.05 (3H, t),

 1.30-1.62 (2Η, m) '1.86 (1H, brs), 2.32-2.60 (8H, m), 3.54 (2H, s),

 7.23-7.33 (5H, m) Reference example 61

N-benzyl- 一 -ethyl-N-isopropylethylenediene: mass spectrometry (mZz): EI 220 (M ⁺ )

Nuclear magnetic resonance spectrum (CDClg, TMS internal standard)

 δ: 1.14 (6Η, d), 1.19 (3H, t), 1.41 (1H, t) 2.55 (2Η, q), 2.73 (2H, t),

 2.93-2.96 (2Η, m), 3.05-3.09 (2Η, m) '3.61 (2H, s), 7.28-7.36 (5H, m) Reference example 62

N, Ν'-I-Jetyl-Ν— (4-hydroxybenzyl) ethylenediamine 560 mg of dioxane solution (4 ml) was added under ice-cooling with di-t-butyldicarbonate 660 mg, and the mixture was returned to room temperature and stirred for 3 hours. Reduce solvent After distillation under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and N'-t-butyloxycarbonyl-N, N'-Jethyl-N- (4- 520 mg of hydroxybenzyl) ethylenediamine was obtained as an oil.

 Mass analysis value (mZz): EI 323 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.02-1.05 (6Η, m), 1.42 C9H, s),

 2.52-2.56 (4H, m), 3.10-3.30 (4 (, m), 3.52 (2H, s), 6.75 (2H, d), 7.17 (2H, d) Reference example 63

Ν '1-t-butyloxycarbonyl N, N'-Getyl-Ν— (4—hydroxybenzyl) ethylenediamine 1,3 in 500 mL of 1N sodium hydroxide aqueous solution (4.7 ml) —Dibromoprono, 1.57 g of ⁰ , and 30 mg of tetrabutylammonium hydrogen sulfate were sequentially added, and the mixture was heated to 60%. After stirring the reaction solution for 3 hours, it was extracted twice with black-mouthed form. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (clo-form) to give N'-t-butyloxycarbonyl-N , 520 mg of, N'-ethyl-N- [4- (3-bromopropyloxy) benzyl] ethylenediamine was obtained as an oil.

 Mass spectrometry value (m / z): FAB 444 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.03-1.06 (6Η, m), 1.42 (9H, s),

 2.29-2.34 (2H, m), 2.42-2.53 (4H, m),

3.12-3.30 (4H, m), 3.53-3.62 (4H, m),

4.09 (2H, t), 6.84 (2H, d),

7.19 i 7.22 (2H, m) Reference Example 64

 N '-t-Butyloxycarbonyl N, N' -Jetyl-N- [4- (3-bromopropyloxy) benzyl] Ethylenediamine 520mg in ethanol solution (10ml) was added with 430mg of Jethylamine. Heated to 60 ° C. After stirring the reaction solution for 7 hours, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (cloth form: methanol: ammonia water = 30: 1: 0.1), and N'-t-butyloxycarbonyl was used. 'I-Jetyl-Ν— [4- (3-ethylaminopropyloxy) benzyl] 300 mg of ethylenediamine was obtained as an oily substance.

 Mass spec (mZz): FAB 436 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.02-1.25 (14H, m), 1.42 (9H, s),

 1.90— 2.08 (2Η, m), 2.51-2.70 (10Η, m),

3.10-3.27 (4H, m), 3.53 (2H, s),

 4.00 (2Η, t), 6.82 (2H, d), 7.21 (2H, d) Reference example 65

 N '— t-Butyloxycarbonyl Ν, Ν' 1-Jetyl- [— [4- (3-Jethylaminopropyloxy) benzyl] Ethylenediamin 300 mg, 4N hydrogen chloride-containing 1,4-dioxin solution 5 ml in 300 mg The mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with a 5% aqueous sodium hydrogen carbonate solution, and extracted twice with chloroform. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 270 mg of N- [4- (3- (ethylethylamino) propyloxybenzyl] -N, N'-getyl ethylenediamine as an oily substance. .

Mass spectrometry value (mZz): FAB 336 (MH ⁺ )

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

δ: 1.02-1.25 (14H, m), 1.90-2.08 (2H, m), 2.50-2.68 (10H, m), 3.11-3.29 (4H, m), 3.52 C2H, s), 4.01 (2H, t), 6.82 (2H, d), 7.23 (2H, d)

 4-ethyl [11- (5,11-dihydro-6 ヒ -pyrido [2.3-b] [1,4] benzodiazepine-16-one) yl] -14-oxobutyrate 300mg ethanol suspension To the solution (5 ml) was added dropwise 3 ml of a 1N aqueous solution of sodium hydroxide under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was ice-cooled, neutralized by adding 3 ml of 1 N hydrochloric acid, and the solvent was distilled off under reduced pressure. Toluene (10 ml) was added to the residue, and water was sufficiently removed by azeotropic distillation. To a DMF solution (10 ml) of the obtained residue was added ice-cooled 3-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HC1) 190 mg, N-hydroxybenztriazole (HOBT) 60 mg, N, N'-Diethyl-N- (4-morpholinobenzyl) ethylenediamine (260 mg) was added successively, and the mixture was stirred at room temperature for 5 hours. The solvent was distilled off under reduced pressure, and the obtained residue was mixed with ethyl acetate, and washed with a 5% aqueous sodium hydrogen carbonate solution and water. The organic layer is dried over magnesium sulfate, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel column chromatography (form: methanol: ammonia: aqueous ammonia = 30: 1: 0.1). The resulting oil was crystallized with ethyl acetate to give [1- [N-ethyl-N- [2- [N-ethyl-N- (4-morpholinobenzyl) amino]]. [Ethyl] caprbamoyl] propionyl] —5,11 dihydro-6H monopyrido [2,3-b] [1,4] benzodiazepin-16-one (345 mg) was obtained as white crystals.

 Melting point: 131-133

Elemental analysis value (as C ₃₃ H ₄₀ N ₆ O ₄ · 0.4H ₂ O)

 C (%) H (%) N (%)

Theoretical 66.96 6.95 14.20 Experimental value 66.82 6.77 14.22 The following compounds of Examples 2 to 14 were obtained in the same manner as in Example 1. Example 2

 11- [3— [N-Ethyl—N— [2 -— [N—Ethyl—N— [4- (1—pyrrolidinyl) benzyl] amino] ethyl] Powerbamoyl] propionyl]-5, 11 —Jihi Draw 6H—Pyrido [2,3—b] [1,4] Benzodiazepine 1—one

 Melting point: 123-126

Elemental analysis (C, © ₃ H ₄ () as N ₆ 0 © · 0.3H ₂ O)

 C (%) H (%) N (%)

 Theoretical 69.04 7.13 14.64

 Experimental value 69.08 7.00 14.68 Example 3

 11-1 [3— [N-ethyl-N— [2-[N-ethyl-N— [4- (hexahydro-1-azepinyl) benzyl] amino] ethyl] Powerbamoyl] propionyl] — 5 , 11—dihidro 6H—pyrid [2,3—b] [1,4] benzodiazepine 1—one

 Melting point: 167—168

Elemental analysis (as _{C 35 H 44 N 6 0 3} · 0 · 1Η 2 Ο)

 C (%) Η (%) Ν (%)

 Theoretical 70.23 7.44 14.04

 Experimental value 70.20 7.45 13.97 Example 4

11-1- [3- [Ν-ethyl- ー-[2-[Ν-ethyl-Ν-]-[4- (4-methyl-1-1-piridinyl) benzyl] amino] ethyl] potambyl] propionyl 1-5, 11—Jihi draw 6Η—Pyrido [2, 3— b] [1, 4] benzodiazepine 6-one

 Melting point: 154-156

Elemental analysis (as a _{C 35 H 44 N 6 0 3} )

 C (%) H (%) N (%)

 Theory 70.44 7.43 14.08

 Experimental value 70.23 7.38 14.12 Example 5

 11- [3— [N— (4-t-butyloxycarbonyl 1-piperazinylbenzyl) 1-N-ethylamino] ethyl] Powerlvamoyl] pu pionyl] 1-5,11-dihidro 6H C [2,3-b] [1,4] Benzodazepine 1-one

 Mass spectrometry value (m / z): FAB 684 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 0.96-1.09 (6Η, m), 1.49 (9H, s),

 2.51-2.59 (8Η, m), 3.02-3.10 (4H, m),

3.17-3.30 (4H, m), 3.50 (2H, d),

 3.52-3.60 (4Η, m), 6.85 (2H, d),

 7.18 (2H, d), 7.26-8.34 (8H, m)

 11- [3-[N-ethyl-N- [2-[N-ethyl-N- [4- (4-methyl-1-piperazinyl) benzyl] amino] ethyl] carbamoyl] propionyl] 1 5, 11— Jihi Draw 6H—pyrid [2,3—b] [1,4] benzodiazepine 1-one

 Melting point: 171-173

Elemental analysis _{(C 34 H 43 N? 0} 3 · 0.1H 2 O and with)

 C (%) H (%) N (%)

Theory 68.11 7.26 16.35 Experimental value 68.03 7.29 16.25 Example 7

 11- [3-[N-ethyl-N- [2-[N-ethyl-N- [4- (4-ethyl-1-piperazinyl) benzyl] amino] ethyl] Powerbambyl] propionyl] 1 5, 11—Jihi Draw 6H—Pyrido [2,3—b] [1,4] Benzodiazepine 1—one

 Melting point: 157-158

Elemental analysis (as _{C 35 H 45 N 7 0 3} · 0.2HoO)

 C (%) H (%) N (%)

 Theory 68.31 7.44 15.93

 Experimental value 68.22 7.44 15.98 Example 8

 11— [3— [N-ethyl-N— [2 -— [N-ethyl-N— [4 -— (4-n-propyl-1-11piperazinyl) benzyl] amino] ethyl] force rubamoyl] propionyl] -1 5 , 11 jihi draw 6H—pyrid [2,3-b] [1,4] benzodiazepine 1—one

 Melting point: 115-118

Elemental analysis (as _{C 36 H 47 N 7 0 3} )

 C (%) H (%) N (%)

 Theoretical 69.09 7.57 15.67

 Experimental value 68.94 7.66 15.54 Example 9

11-1- [3— [N-Ethyl—N— [2— [N—Ethyl-N— [4- (4-Isopropyl-1—Piperazinyl) benzyl] amino] ethyl] Power Lubamoyl] propionyl] 1 5 , 11—dihidro 6H—pyrid [2,3—b] [1,4] benzodiazepine 1—one Melting point: 119-121

Elemental analysis (as _{C 36 H 47 N 7 0 3} · 0.4H 2 O)

 C (%) H (%) N (%)

 Theoretical 68.31 7.61 15.49

 Experimental value 68.17 7.49 15.47 Example 10

 11— [3— [N-ethyl-N— [2 -— [N-methyl-N— (4-methylphosphorinobenzyl) amino] ethyl] dirubamoyl] propionyl] -5,11—dihydro 6H—pyrid [2,3-b] [1,4] benzodiazepine 1—on

 Melting point: 140-141 V

Elemental analysis (as _{C 32 H Q8 N 6 0 4} · 0.3H 2 O)

 C (%) H (%) N (%)

 Theory 66.72 6.75 14.59

 Experimental value 66.78 6.66 14.57 Example 11

 11-1- [3— [N-Ethyl-1-N— [2 -— [N-methyl-N— (4-piperidinobenzyl) amino] ethyl] potambyl] propionyl] 1.5,11-dihydro 6H — Pyrido [2,3—b] [1,4] benzodiazepine 1—on

 Melting point: 171-173

Elemental analysis _{(C 33 H 4 () N} 6 0 3 · 0 · 4Η 2 Ο and with)

 C (%) Η (%) Ν (%)

 Theory 68.82 7.14 14.59

Experimental value 68.75 6.97 14.54 Example 12 11— [3— [N-ethyl-N- [2 -— [N-methyl-N- [4-((4-methyl-1-1-piperazinyl) benzyl] amino] ethyl] dilvamoyl] propionyl] 1,5 11—Jihi Draw 6H—Pyrido [2,3—b] [1 4] Benzodiazepine 1—one

 Melting point: 143-145 V

Elemental analysis value (as C ₃₃ H ₄₁ N ₇ O · 0.5H ₂ O)

 C (%) H (%) N (%)

 Theory 66.87 7.14 16.54

 Experimental value 66.78 7.00 16.38 Example 13

 11-1- [N-ethyl-N- [2--N- [4- (4- (ethyl-1-piperazinyl) benzyl] -1-N-methyl] amino] ethyl] carbamoyl] propionyl] -5 ] 1 jihi draw 6H— pyrido [2 3-b] [1, 4] benzodiazepine 1-one

 Melting point: 150-152

Elemental analysis (as a _{C 34 H 43 N 7 0 3} )

 C (%) H (%) N (%)

 Theoretical 68.32 7.25 16.40

 Experimental value 68.07 7.22 16.37 Example 14

 11-1- [3— [N-ethyl-N— [2 [N-cyclopropyl-1-N— (4-morpholinobenzyl) amino] ethyl] pothambamoyl] propionyl] —5,11—dihydro-6H — Pyrido [2, 3— b] [1, 4] benzodiazepine 1-one

 Melting point: 135-137

Elemental analysis _{(C 34} H _{4 ()} as _{N 6 0 4 · 0.5H 2 O} )

C (%) H (%) N (%) Theory 67.42 6.82 13.87

 Experimental value 67.44 6.74 13.90 Example 15

 11- [3- [N- (4-t-Butyloxycarboxy 1-piperazinylbenzyl) -1-N-ethylamino] ethyl] power obtained in Example 5 Lubamoyl] propionyl] 1,5,11 —Dihydro 6H—Pyrido [2,3-b] [1,4] benzodiazepin-16-one 290 mg was dissolved in 10 ml of 1,4-dioxin solution containing 4N hydrogen chloride and stirred overnight at room temperature. . After evaporating the reaction solution under reduced pressure, the residue was dissolved in chloroform and washed with 5% aqueous sodium hydrogen carbonate solution and water. After the organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel chromatography (clo-form: methanol: ammonia water = 30: 1: 0.1), and purified by 11- [3- [N-ethyl-N- (1-piperazinylbenzyl) amino] ethyl] pothambmoyl] propionyl] 1.5,11 dihydro 6H-pyrido [2,3— b] [1,4] benzodiazepin-6-one 57mg was obtained.

 Mass analysis value (mZz): FAB 584 (MH +)

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

 δ: 0.90 (3Η, dt), 1.00 (3Η, dt),

 2.40-2.43 (4Η, m), 2.47-2.50 (4H, m), 2.77-2.82 (4H, m), 2.95-3.00 (4H, m), 3.12-3.25 (4H, m), 3.42 (2H, d ),

 6.81 (2H, d), 7.07-7.11 (2Η, m),

 7.41-8.31 (7H, m) The following compound of Example 16 (1) was obtained in the same manner as in Example 1. Example 16 (1)

11- [3— [N—ethyl-N— (2-hydroxyl) Moyl] propionyl] 1-5,11-dihidro 6H—pyrido [2,3-1b] [1,4] benzodiazepine-1 6-one

 quality! : Analysis value (mZz): FAB 383 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

 δ: 1.04-1.22 (3Η, m), 2.48-2.65 (2H, m), 2.80—3.03 (2H, m), 3.34-3.53 (4H, m), 3.60-3.75 (2H, m), 7.26-7.38 (1H, m), 7.40-7.70 (4H, m), 7.90-7.96 (1H, m), 8.34 (1H, s), 8.94-9.00 (1H, m) Example 16 (2)

To a solution of oxalyl chloride (170 mg) in methylene chloride (10 ml) under an argon atmosphere was added a solution of dimethyl sulfoxide (DMSO) IIOmg (1 ml) in methylene chloride (1 ml), and the mixture was stirred for 25 minutes. In addition, 11- [3- [N-ethyl-N- (2-hydroxicetyl) pothamamoyl] propionyl] obtained in Example 16 (1), 1,11-dihidroh 6H-pyri [2,3-b] [1,4] benzodiazepin-6-one A solution of 200 mg of methylene chloride (10 ml) was added and stirred for 25 minutes. Next, 290 mg of triethylamine (Et ₃ N) was added thereto at −78, and the mixture was returned to room temperature and stirred for 3 hours. To the reaction mixture were added [4-isopropyl-11-piperazinylbenzyl] amine, lOOmg, acetic acid (AcOH) 190mg, and sodium triacetoxyborohydride (NaBH (OAc) 3) 140mg in that order. After returning to room temperature and stirring for 1 hour, the reaction solution was made alkaline with a 1N aqueous solution of sodium hydroxide and extracted twice with methylene chloride (10 ml). The organic layer is dried over magnesium sulfate, the solvent is distilled off under reduced pressure, and the obtained residue is purified by silica gel gel chromatography (chromatography: methanol: ammonia water = 30: 1: 0.1). The resulting residue is crystallized from ethyl acetate and ether to give 11- [3— [N-ethyl-N— [2-—N— [4- (4-isopropyl-1—1-piperazine). Nyl) benzyl] amino] ethyl] lvamoyl] propionyl] -1,5,11-dihydro 6H-pyrido [2,3-b] [1,4] benzodiazepin-16-one 35 mg as white crystals Was.

 Melting point: 103-105

Elemental analysis (as _{C 34 H 43 N 7 0 3} · 0.5H 2 O)

 C (%) H (%) N (%)

 Theory 67.30 7.31 16.16

 Experimental value 67.15 7.40 15.93 Example 17

Ethyl 4- [11-1 (5,11-dihydro-6H-pyrido [2,3-b] [1,4] benzodiazepine-1-6-one) yl] 4-oxobutyrate 3.90 g ethanol suspension 1N sodium hydroxide (40m) was added dropwise to the suspension (40ml) under ice cooling, and the mixture was stirred at room temperature for 25 minutes. The reaction solution was cooled on ice, neutralized by adding 40 ml of 1N hydrochloric acid, and the solvent was distilled off under reduced pressure. Toluene (20 ml) was added to the residue, and water was sufficiently removed by azeotropic distillation. 1-Ethyl-3- (3-dimethylaminopropyl) hydroformamide hydrochloride (WSC HC1) 2.43 g, N-hydroxybenz Liasol (HOBT) 770 mg, N * -ethyl-N- [4- (4-Isopropyl-1-piperazinyl) benzyl] 3.67 g were sequentially added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 1N sodium hydroxide, extracted twice with chloroform, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform: methanol: ammonia water = 30: 1: 0.1) and recrystallized twice from isopropanol. 11-1- [3-[N- [2-[N-Ethyl-N- [4- (4-Isopropyl-1-1-piperazinyl) benzyl] -1-N-methylamino] ethyl] -lvamoyl] propionyl] — 5, 11—Dihydro-6H—Pyrido [2, 3—b] [1, 4] Ben 2.25 g of zodiazepin-1-one obtained as white crystals c

 Melting point: 178-180

Elemental analysis (as a _{C 35 H 45 N 7 0 3} )

 C (%) H (%) N (%)

 Theory 68.71 7.41 16.03

 Experimental value 68.51 7.39 15.92

 Quality i Analysis value (mZz): FAB 612 (MH +) Example 18

 Ethyl 4- [5— (5,10-dihydro-1H-dibenzo [b, e]

[1, 4] diazepine (111-one)) [yl] 14-oxobutyrate 4.2 ml of a 1N sodium hydroxide solution was added dropwise to a suspension of 420 mg of ethanol (8 ml) under ice-cooling and then at room temperature. The mixture was stirred for 45 minutes. The reaction solution was cooled on ice, and 4.2 ml of 1N hydrochloric acid was added to neutralize the mixture. The solvent was distilled off under reduced pressure. Toluene (10 ml) was added to the residue, and water was sufficiently removed by azeotropic distillation. 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC.HC1) 250 mg, N-hydroxybenz triazole (HOBT) was added to a methylene chloride solution (12 ml) of the obtained residue under ice-cooling. 150 mg, N, N'-dityl-N- (4-isopropyl-111-piperazinylbenzyl) ethylenediamine (380 mg) were sequentially added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with a 5% aqueous sodium hydrogen carbonate solution and saturated saline, and the organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (glo-form: methanol: ammonia water = 30: 1: 0.1), and the obtained residue was obtained. The oily substance was crystallized from ethyl acetate-hexane to give 5- [3- [N-ethyl-N- [2 -— [N-ethyl-N— [4- (4-isopropyl-1-pipera). Dinyl) benzyl] amino] ethyl] lvamoyl] propionyl] — 5,10-dihydro 11H-dibenzo [b, e] [1,4] dazepin-1 11-one 260 mg as white crystals Obtained. Melting point: 126-128

Elemental analysis (as a _{C 37 H 48 N 6 0 3} )

 C (%) H (%) N (%)

 Theory 71.12 7.74 13.45

 Experimental value 70.84 7.82 13.33

Mass spectrometry value (mZz): FAB 625 (MH ⁺ ) In the same manner as in Example 18, the following compounds of Examples 19 to 22 were obtained. Example 19

 5-[3-[N-ethyl] N— [2— [N— [4- (4-Isopropyl 1-piperazinyl) benzyl] -1-N-methylamino] ethyl] Power Lubamoyl] propionyl] 1 5 , 10—dihidro 11H—dibenzo [b, e] [1, 4] diazepine-one

Elemental analysis (as _{C 36 H 46 N 6 0 3} · 0.3H 9 O)

 C (%) H (%) N (%)

 Theory 70.17 7.62 13.64

 Experimental value 70.04 7.67 13.43

 Mass spectrometry value (mZz): FAB 611 (MH +) Example 20

 5-[3— [N-Ethyl-N— [2 -— [N-Ethyl-N— (4-molepholinobenzyl) amino] ethyl] Powerbamoyl] propionyl] 1, 5, 10—Dihydro 1H —Dibenzo [b, e] [1, 4] diazepine 11-one

 Quality analysis value (mZz): FAB 584 (MH +)

Nuclear magnetic resonance scan Bae-vector (CDC1 _3, TMS internal standard)

δ: 1.01-1.14 (6Η, m), 2.05-2.50 (2H, m), 2.53-2.57 (4H, m), 2.68-3.03 (2H, m), 3.11-3.15 (4H, m), 3.23—3.30 (4H, m), 3.50-1 3.53 (2H, m) 3.80-1 3.90 (4H, m) 6.83 (2Η, t), 7.10 Γ.13 (1H, m),

 7.16-1 7.31 (3H, m) 7.38-1 7.45 (2Η, m) 7.57-1 7.65 (2H, m) 7.96 (1H, s),

 8.18-1 8.30 (1H, m) Example 21

 5-[3— [N-ethyl-N— [2— [N-ethyl-N— [4- (4-ethyl-1 piperazinyl) benzyl] amino] ethyl] rubambayl] propionyl] 1 5, 10—Dihydro 11 H—Dibenzo [b, e] [1, 4] diazepine 1 11-one

 Mass spec (mZz): FAB 611 (MH +)

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

 δ: 0.88-1.04 (9Η, m), 2.42-2.67 (14H, m),

 3.08-3.46 (10H, m), 6.83-6.85 (2H, m), 7.11 (2Η, d), 7.19-7.83 (8H, m),

 10.60-10.70 (1Η, m) Example 22

 5— [3-N- [2— (N-benzyl-1-N-ethylamino) ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,10-dihidrone 11H—dibenzo [b, e] [1 , 4] Jazepine One

Mass spectrometry value (mZz): FAB 499 (MH ⁺ )

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

δ: 0.88-1.04 (6Η, m), 2.06-2.09 (1H, m), 2.44-2.51 (6H, m), 2.65-2.69 (1H, m), 3.12-3.15 (1H, m), 3.24-3.29 (3H, m), 3.54-3.56 (2H, m), 7.20-7.81 (13H, m), 10.60-10.66 (1H, m) Example 23

 4- (11— (5,11—dihydro 6H—pyrid [2,3—b] [1,4] benzodiazepine 16-one) yl] 14-oxobutylate 350 mg ethanol suspension 3.5 ml of 1N sodium hydroxide was added dropwise to the suspension (5 ml) under ice cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was cooled on ice, 3.5 ml of 1N hydrochloric acid was added for neutralization, and the solvent was distilled off under reduced pressure. To a DMF solution (10 ml) of the obtained residue was added 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride 220 mg under ice-cooling, N-hydroxybenztriazole 70 mg, [N, Ν ' —Jetyl-N— (4-fluorobenzyl)] Ethylenediamine (230 mg) was added successively, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed with a 5% aqueous sodium hydrogen carbonate solution and water. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (chlorophonolem: methanol = 30: 1). The obtained oily substance was crystallized from ethyl acetate-ether to give 11- [3- [N- [2- [N-ethyl-N- (4-fluorobenzyl) amino] ethyl] -1-N- [Ethylcarbamoyl] propionyl] —5,11—dihydro-6H—pyrido [2,3-b] [1,4] benzodiazepin-16-one 150 mg was obtained as white crystals. Melting point: 160-162

Elemental analysis (as a _{C 29 H 32 N 5 0 3} F · 0.2H 2 O)

C (%) H (·%) N (%) F () Theoretical value 66.83 6.27 13.44 3.65 Experimental value 66.64 6.26 13.46 3.67 Mass spectrometry value (mZz): FAB 518 (MH +) Examples 24 to 58 were obtained, Example 24 11-1- [3— [N— [2 -— [N-ethyl-N— (3-pyridylmethyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11-dihidroh 6H—pyrido [ 2, 3, -b] [1, 4] benzodiazepine 6-one

 Starting compound: N, N * -Jetyl-N- (3-pyridylmethyl) ethylenediamine

 Melting point: 152-154

Elemental analysis (as a _{C 28 H32N 6 0 3 · 0.2H} 2 O)

 C (%) H (%) N (%)

 Theoretical 66.70 6.48 16.67

 Experimental 66.55 6.48 16.69

 Mass spectrometry value (mZz): FAB 501 (MH +) Example 25

 11-1 [3-[N— [2— [N— (2-cyclobenzyl) -1-N-ethylamino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11-diphenyl Doro 6H—Pyrido [2,3-b] [1,4] Benzodiazepine 1—one

 Starting compound: N- (2-cyclobenzyl) -N.N'-Jetlje-Tylenediamine

 Melting point: 137-140,

Elemental analysis (as _{C 2 gH 32 N 5 0 3} Cl · 0.6H 2 O)

 C (%) H (%) N (%) C1 (%) Theoretical value 63.93 6.14 12.85 6.51 Experimental value 63.72 5.78 13.10 6.53 Mass spectrometry value (mZz): FAB 535 (MH +) Example 26

11 One [3— [N— [2— [N—Ethyl-N— (2-Naphthyl)) [No] ethyl] — N-ethylcarbamoyl] propionyl] -1,5,6-dihydro 6H—pyrido [2,3-b] [1,4] benzodiazepine-1 6-one

 Starting compound: N, N '—Jetyl—N— (2-Naphthyl) ethylenediamine

 Melting point: 102-105

Elemental analysis (as a _{C 33 H 35 N 5 0 3} )

 C (%) H (%) N (%)

 Theoretical 72.11 6.42 12.74

 Experimental value 71.96 6.36 12.76

Mass spectrometry value (mZz): FAB 550 (MH ⁺ ) Example 27

 11-1- [3- [N— [2- [N-Ethyl-N— (4-methylbenzyl) amino] ethyl] —N-ethylcarbamoyl] propionyl] -1,5,11-dihydro-6H— Pyrido [2,3-b] [1,4] benzodiazepine-6-one

 Starting compound: N, N'-Jethyl-N- (4-methylbenzyl) ethylenediamine

 Melting point: 155-157

Elemental analysis (C _{3 ()} as the _{H 35 N 5 0 3 · 0.2H} 2 O)

 C (%) H (%) N (%)

 Theoretical 69.66 6.90 13.54

 Experimental value 69.55 6.75 13.55

 Quality analysis of children (mZz): FAB 514 (MH +) Example 28

11-1- [3— [N— [2 -— [N-ethyl-N— (4-nitrobenzyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5 11—Dihydro 6H—Pyrido [2,3—b] [1,4] Benzodazepin 6—one

 Starting compound: N, N * -Jethyl-N- (4-nitrobenzyl) ethylenediamine

 Melting point: 129-133 V

Elemental analysis (as a _{C 29 H 32 N 6 0 5} · 0.1H 2 O)

 C (%) H (%) N (%)

 Theoretical 63.75 5.94 15.38

 Experimental value 63.59 5.79 15.24

Mass spectrometry value (mZz): FAB 545 (MH ⁺ ) Example 29

 11— [3— [N— [3— (N-benzyl-N-ethylethylamino) propyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11—dihydro-6H—pyridone [2, 3—b] [1, 4] benzodiazepine 6—one

 Starting compound: N-benzyl-N, N'-Jetyl-1,3-propanediamine

 Melting point: 127-129

Elemental analysis (C _{3 ()} as the H ₃₅ N ₅ 0 ₃₎

 C (%) H (%) N (%)

 Theoretical 70.15 6.87 13.63

 Experimental 69.90 6.81 13.69

 Mass spectrometry value (mZz): FAB 514 (MH +) Example 30

11— [3— [N- [2— [N— (4-bromobenzyl) -1-N-ethylamino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11 dihidro 6H—pyri C [2, 3-b] [1, 4] Benzodia 1 Sepin 6 — ON

 Starting compound: N — (4-bromobenzyl) — N, N '—

 Melting point: 170-171 ° C

Elemental analysis (as the _{C 2 nH 32 N 5 0 3} Br)

C (%) H (%) N (%) Br (%) Theoretical value 60.21 5.58 12.11 13.81 Experimental value 60.12 5.53 12.19 13.56 Mass spectrometry value (mZz): FAB 579 (MH ⁺ ) Example 31

 11 1 [3— [N— [2— [N—Ethyl-N— (4—Methoxycarbonylbenzyl) amino] ethyl] 1 N—Ethylcarbamoyl] propionyl] —5,11—Dihydro-1H— Pyrido [2,3-b] [], 4] benzodiazepine 1—one

 Starting compound: N, N'-Jetyl-N- (4-Methoxycarbonylbenzyl) ethylenediamine

 Melting point: 116-118

Elemental analysis (as a _{C 31 H 35 N 5 0 5} )

 C (%) H (%) N (%)

 Theory 66.77 6.33 12.56

 Experimental 66.83 6.29 12.52

 Mass spectrometry value (mZz): FAB 558 (MH +) Example 32

11 1 [3-[N— [2— [N-ethyl-N— (4-pyridylmethyl) amino] ethyl] — N-ethylcarbamoyl] propionyl] 1,5,11 —dihydro-6H-pyrido [2,3—b] [1,4] benzodiazepine 6—one Starting compound: N, N'-Jetyl-N- (4-pyridylmethyl) ethylenediamine

 Melting point: 152-154 X

Elemental analysis _{(C 28 H 32 N 6 0} 9 · 0.3Η 2 Ο and with)

 C (%) Η (%) Ν (%)

 Theoretical 66.46 6.49 16.61

 Experimental value 66.29 6.34 16.65

Mass spectrometry value (m / z): FAB 501 (MH ⁺ ) Example 33

 11- [3— [N— [2-(N-benzyl-N-ethylamino) ethyl] -1-N-ethylcarbamoyl] propionyl] 1-5,11-dihydro 1-6H—pyridone 2, 3, -b] [1, 4] Benzodazepine 1-6 years old

 Starting compound: N-benzyl-N, N'-Jethylethylenediamine Melting point: 157-160

Elemental analysis (as _{C 2 .H 33 N 5 0 3} · 0.4H 2 O)

 C (%) H (%) N (%)

 Theory 68.73 6.72 13.82

 Experimental 68.82 6.63 13.92

 Mass spectrometry value (mZz): FAB 500 (MH +) Example 34

 11-1- [3— [N-ethyl-N— [2 -— (N-ethyl-N-phenylethylamino) ethyl] caphambyl] propionyl] 1,5,11—dihydro 6H-pyrido [2,3 -b] [1, 4] Benzodazepine

Raw material compound: N, Ν'-Jetyl-Ν-Phenethylethylenediamine Melting point: 158-161

Elemental analysis (C ₃ () as the _{H 35 N 5 03 · 0.4H 2} O)

 C (%) H (%) N (%)

 Theoretical 69.18 6.93 13.45

 Experimental 69.25 6.75 13.47

 Mass spectrometry value (mZz): FAB 514 (MH +) Example 35

 11-1 [3— [N— [2— [N-ethyl-N— (4-methoxybenzyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] 1-5,11—dihydro-1H Pyrido [2,3—b] [1,4] benzodiazepine 1-one

 Starting compound: N, N * — Jethyl-N— (4-Methoxybenzyl) Ethylenediamine

 Melting point: 121 V

Elemental analysis value (as a _{CsoH ^ N ^ O · 0.1H 2} O)

 C (%) H (%) N (%)

 Theory 67.80 6.68 13.18

 Experimental value 67.70 6.54 13.25

 Mass spectrum (mZz): FAB 530 (MH +) Example 36

 11— [3— [N— [2— [N—ethyl-N— (3-methoxybenzyl) amino] ethyl] —N-ethylcarbamoyl] propionyl] —1,5—11 6H—Pyrido [2,3—b] [1,4] Benzodiazepine-one 6—one

 Starting compound: N, N '— Jethyl-N— (3-Methoxybenzyl) ethylenediamine

Melting point: 98-99 Elemental analysis _{(C 3 () H 35 N} 5 0 4 · 0 · 5Η 2 Ο and with)

 C (%) H (%) N (%)

 Theoretical 66.90 6.74 13.00

 Experimental value 66.86 6.57 13.12

 Mass spectrometry value (mZz): FAB 530 (MH +) Example 37

 11-1- [N- [2-[N- (4-cyclobenzyl) -1-N-ethylamino] ethyl] -1-N-ethylcarbamoyl] propionyl] 1-1,11 6H—pyrid [2,3-b] [1,4] benzodiazepine 1-one

 Starting compound: N— (4-chlorobenzyl) -1-N, N'—

 Melting point: 167-168. C

Elemental analysis _{(C 2 gH 32 N 5 0} 3 as a Cl · 0.1H ₂ O)

 C (%) H (%) N (%) C1 (%) Theoretical value 65.00 6.06 13.07 6.62 Experimental value 64.90 6.03 13.12 6.51 Mass spectrometry value (mZz): FAB534 (MH +) Example 38

 11— [3— [N— [2— [N— (3-cyclobenzyl) -1-N-ethylamino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11—dihidro 6H—Pyrido [2,3-b] [1,4] Benzodiazepine 1-one

 Starting compound: N— (3-chlorobenzyl) —N, N′—Jetlethylene diamine

 Melting point: 146-147

Elemental analysis (C ₂ 9H32N ₅ 0 ₃ as the C1 · 0.2H ₂ O) C (%) H (%) N (%) C1 (%) Theoretical 64.78 6.07 13.03 6.59 Experimental 64.68 5.96 13.06 6.67 Mass spectrometry (mZz): FAB534 (MH ⁺ ) Example 39

 11-1- [3- [N- [2-[N-Ethyl-N- (3,4-methylenedioxybenzyl) amino] ethyl] -1-N-ethylcarbamoyl] pionyl] -15,11-dihydro 6H—pyrid [2,3-b] [1,4] benzodiazepine 1—one

 Starting compound: N, N'-Jetyl-N- (3,4-methylenedioxybenzyl) Ethylenediamine

 Melting point: 130-132

Elemental analysis _{(C 3 oH «33N 5 0} 5 · 0,4H 9 O and with)

 C (%) H (%) N (%)

 Theoretical 65.42 6.18 12.71

 Experimental value 65.19 6.12 12.92

 Mass spectrometry value (mZz): FAB 544 (MH +) Example 40

 11-1 [3-[N— [2-[N-ethyl-N- (3-thenyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11-dihydro 6H—pyrid [2,3-b] [1,4] benzodiazepine-one

 Starting compound: N, N * —Jetyl—N— (3-Chenylmethyl) ethylenediamine

 Melting point: 160-161

Elemental analysis (as a _{Co 7 H Q1 N 5 0 3} S · 0.4H 2 O)

C (%) H (%) N (%) S (%) Theoretical value 63.23 6.25 13.66 6.25 Experimental value 63.16 6.16 13.62 6.33 Mass spectrometry value (mZz): FAB 506 (MH +) Example 41

 11— [3— [N— [2— [N-ethyl-N— (4-phenylcyclohexyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] —5,11—dihi draw 6H—pyrid [2,3—b] [1,4] benzodiazepine 1—on

 Starting compound: N, N'-Jetyl-N- (4-phenylcyclohexyl) ethylenediamine

 Melting point: 172-175

Elemental analysis (C _3/1 Η ₄₁ Ν ₅ Rei_3 · 0 · 6Η ₂ Ο and with)

 C (%) H (%) N (%)

 Theoretical 70.59 7.35 12.11

 Experimental value 70.29 7.11 12.18

Mass spectrometry value (mZz): FAB 568 (MH ⁺ ) Example 42

 11-1- [3— [N— [2 -— [N-Ethyl-N— (2-methoxybenzyl) amino] ethyl] —1-N-ethylcarbamoyl] propionyl] -15,11—Dihidro 6H—pyri C [2,3-b] [1,4] benzodiazepine 1-one

 Starting compound: N, N '— Jethyl-N— (2-Methoxybenzyl) Ethylenediamine

 Melting point: 119-120

Elemental analysis (C _{3 ()} as the H ₃₅ N ₅ 0 ₄₎

 C (%) H (%) N (%)

Theory 68.03 6.66 13.22 Experimental 67.75 6.68 13.11

Mass spectrometry value (mZz): FAB 530 (MH ⁺ ) Example 43

 11 1 [3— [N- [2- [N- (4-dimethylaminobenzyl) -1-N-ethylamino] ethyl] -1-N-ethylcarbamoyl] propionyl] 1-5,11—dihydro-6H— Pyrido [2,3-b] [1,4] benzodiazepine 1-on

 Starting compound: N— (4—dimethylaminobenzyl) —N, N′—diethylethylenediamine

 Melting point: 114-116

Elemental analysis value (as C ₃₁ Η ₃₈ Ν _{60 3} · 0.2H ₂ O)

 C (%) H (%) N (%)

 Theory 68.16 7.09 15.38

 Experimental value 67.88 7.02 15.38

 Mass spectrum (m / z): FAB 543 (MH +) Example 44

 11 1 [3— [N— [2— [N-ethyl-N— (4-hydroxybenzyl) amino] ethyl] 1-N-ethylcarbamoyl] propionyl] 1,5,11 dihidro 6H—pyrid [2,3-b] [1,4] benzodiazepine 1-one

 Starting compound: N, N '-getyl-N-(4-hydroxybenzyl) ethylenediamine

 Melting point: 156-157

Elemental analysis (as a _{C 29 H 33 N 5 0 4} )

 C (%) H (%) N (%)

 Theory 67.55 6.45 13.58

Experimental value 67.28 6.50 13.39 Mass spectrometry value (mZz): FAB 516 (MH +) Example 45

 11— [3— [N— [2— [N— (2,3-dimethyl-14-methoxybenzyl) -1-N-ethylamino] ethyl] —N-ethylcarbamoyl] propionyl] -15,11— Jihi Draw 6H—Pyrido [2,3-b] [1,4] Benzodazepine 1-one

 Starting compound: N, N '— getyl—N— (23-dimethyl-4 methoxybenzyl) ethylenediamine

 Melting point: 139-140

Elemental analysis (as a _{C 32 H 39 N 5 0 4} )

 C (%) H (%) N (%)

 Theory 68.92 7.05 12.56

 Experimental value 68.99 7.05 12.51

 Mass spectrum (mZz): FAB 558 (MH +) Example 46

 11-1- [3— [N— [2-[N-Ethyl-1-N— (4-methylthiobenzyl) amino] ethyl] -1-N-Ethylcarbamoyl] propionyl] 15,11—DihiDraw 6H—Pyri [2,3-b] [1,4] benzodiazepine 1-one

 Starting compound: N, N'-Jetyl-N- (4-methylthiobenzyl) ethylenediamine

 Melting point: 143-144

Elemental analysis (C _{3 ()} as H ₃₅ N ₅ 0 ₃ S)

C (%) H (%) N (%) S (%) Theoretical 66.03 6.46 12.83 5.88 Experimental 65.73 6.44 12.69 5.75 Mass spectrometry (mZz): FAB 546 (MH +) Example 47

 11-1 [3— [N— [2— [N-ethyl-N— (4-ethylbenzyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11 dihydro-6H—pyrido [ 2, 3, -b] [1, 4] benzodiazepin-6-one

 Starting compound: N, Ν'-diethyl チ ル — (4-ethylbenzyl) ethylenediamine

 Melting point: 144-146 ° C

Elemental analysis _{(C Q1 Hd 7 N 5 0.} · 0.1H 2 O and with)

 C (%) H (%) N (%)

 Theory 70.32 7.08 13.23

 Experimental value 70.18 7.09 13.20

quality! : Analysis value (mZz): FAB 528 (MH ⁺ )

 11-1- [3- [N- [2 -— [N- (4-Propyroxybenzyl) -1-N-ethylamino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11 6H—pyrid [2,3—b] [1,4] benzodiazepine 1—on

 Starting compound: N— (4-propyloxybenzyl) —N, N′—diethylethylenediamine

 Melting point: 135-137

Elemental analysis (as a _{Cq 2 H 39 N 5 0 4} )

 C (%) H (%) N (%)

 Theory 68.92 7.05 12.56

 Experimental value 68.85 7.00 12.50

Mass spectrometry value (mZz): FAB 558 (MH +) Example 49

 11— [3— [N- [2-[N-Ethyl-1-N— (4-trifluoromethylbenzyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11—DihiDraw 6H — Pyrido [2,3-b] [1,4] benzodiazepine-1-one

 Starting compound: N, Ν'-diethyl チ ル — (4-trifluoromethylbenzyl) ethylenediamine

 Melting point: 158-160Ό

Elemental analysis (as a _{C 3 oH 32 N 5 0 3} F 3)

 C (%) H (%) N (%) F (%) Theoretical 63.48 5.68 12.34 10.04 Experimental 63.33 5.72 12.30 9.97 Mass spectrometry (mZz): FAB 568 (MH +) Example 50

 11-1- [3— [N— [2-(N-cyclohexylmethyl-N-ethylamino)] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11-dihydro-6H-pyrido [ 2,3-b] [1,4] benzodiazepine 1 6-one

 Raw material compound: N-cyclohexylmethyl N, N'-Jetlhetylenediamine

 Melting point: 176-177

Elemental analysis (as a _{C 2g H 39 N 5 0 3} )

 C (%) H (%) N (%)

 Theoretical 68.88 7.77 13.85

 Experimental value 68.65 7.77 13.74

Mass spectrometry value (mZz): FAB 506 (MH +) Example 51 11- [3— [N- [2 -— [N-ethyl-N- (4-isopropylpyrbenzyl) amino] ethyl] -1-N-ethylcarbamoyl] propionyl] -15,11-dihi Draw 6H—Pyrido [2,3-b] [1,4] Benzodiazepine 1—one

 Starting compound: N, N'-Jetyl-N- [4- (2-methylethyl) benzyl] ethylenediamine

 Melting point: 145-147

Elemental analysis (as a _{C 32 H 39 N 5 0 3} · 0.2H 2 O)

 C (%) H (%) N (%)

 Theoretical 70.48 7.28 12.84

 Experimental value 70.37 7.14 12.80

Mass spectrometry value (mZz): FAB 542 (MH ⁺ ) Example 52

 11— [3— [N _ [2— (N, N—dibenzylamino) ethyl] -N-ethylcarbamoyl] propionyl] —5,11—dihidro 6H—pyrid [2,3—b] [1, 4] benzodiazepine 1-one

 Starting compound: N, N-dibenzyl-N'-ethylethylenediamine Melting point: 116-122

 Mass spectrometry value (m / z): FAB 562 (MH +)

Infrared absorption spectrum max (KBr) cm " ¹ : 3480, 1740, 1700, 1660, 1460, 1430, 1370, 1280, 1170 Example 53

 11-1 [3— [Ν- [2— [Ν-ethyl] ー — [4- (piperidinyl-111-yl) benzyl] amino] ethyl] —diethylcarbamoyl] propionyl] —5 11—Jihi Draw 6Η—Pyrido [2,3-b] [1,4] Benzodiazepine 1—one

Starting compound: N, N '—Jetil— N— [4— Yl) benzyl] ethylenediamine

 Melting point: 158-160

Elemental analysis (as a _{C 34 H 42 N 6 0 3} · 0.1H 2 O)

 C (%) H (%) N (%)

 Theoretical 69.86 7.28 14.38

 Experimental value 69.67 7.17 14.33

Mass spectrum (mZz): FAB 583 (MH ⁺ ) Example 54

 11- [3— [N- [2-[N-ethyl-N— (2-thenyl) amino] ethyl] —N-ethylcarbamoyl] propionyl] 1-5,11 dihydro-6H—pyri C [2, 3— b] [1, 4] Benzodazepine

 Ingredients: Ν, —'- Jethyl- ー-(2-Chenylmethyl) ethylenediamine

 Melting point: 156-157 ° C

Elemental analysis (as a _{C 27 H 31 N 5 0 3} S · 0.4H 2 O)

 C (%) H (%) N (%) S (%) Theoretical 63.23 6.25 13.66 6.25 Experimental 63.08 6.09 13.60 6.43 Mass spectrometry (mZz): FAB 506 (MH +) Example 55

11- [3— [N— [2-(N-benzyl-N-methylamino) ethyl] -1-N-ethylcarbamoyl] propionyl] -15,11-1 , 3-b] [1, 4] Benzodiazepine 1-Raw material: N-benzyl-N'-ethyl-N-methylethylenediamine Melting point: 164-166

Elemental analysis (as a _{C 28 H 31 N 5 0 3} · 0.6H 2 O)

 C (%) H (%) N (%)

 Theory 67.75 6.54 14.11

 Experimental value 67.72 6.36 14.09

 Mass spectrum (mZz): FAB 486 (MH +) Example 56

 11-1- [3— [N— [2 -— [N-benzyl-N-propylamino] ethyl] -1-N-ethylcarbamoyl] propionyl] -1,5,11-dihydro-6H—pyridone [2 , 3— b] [1, 4] Benzodazepine

 Starting compound: N-benzyl-N'-ethyl-N-propylethylenediamine

 Melting point: 152-153

Elemental analysis (C _{3 ()} as the _{H 35 N 5 0 3 · 0.6H} 2 O)

 C (%) H (%) N (%)

 Theory 68.71 6.96 13.35

 Experimental value 68.46 6.68 13.28

 Mass spectrometry value (mZz): FAB 514 (MH +) Example 57

 11-1 [3-[N-[2— [N-benzifree N-isopropylamino] ethyl] 1-N-ethylcarbamoyl] propionyl] 1-5,11-dihydro-6H-pyrido [2 , 3-b] [1, 4] benzodiazepine

 Starting compound: N-benzyl N'-ethyl-N- (2-methylethyl) ethylenediamine

Melting point: 189-191 V Elemental analysis _{(C 3 () H 35 N} 5 0 3 · 0 · 3Η 2 Ο and with)

 C (%) H (%) N (%)

 Theoretical 69.42 6.91 13.49

 Experimental 69.39 6.81 13.47

 Mass spectrum (mZz): FAB 514 (MH +) Example 58

 11 1 [3-[N — [2— [N — [4 1 (3 — cetiramino) propyloxybenzyl] 1 N—ethylamino] ethyl] 1 N —ethyl ethyl rubamoyl] propionyl] 1 5, 11 — dihydro 6H — pyrido [2, 3 — b] [1, 4] benzodiazepine 1 — on

 Starting compound: N— [4- (3-ethylethylamino) propyloxybenzil] -1-N, N'-Jetylethylenediamine

 Melting point: 99-100

Elemental analysis (as _{C 36 H 48 N 6 0 4} )

 C (%) H (%) N (%)

 Theory 68.76 7.69 13.36

 Experimental value 68.52 7.72 13.44

Quality i Analytical value (m / z): FAB 629 (MH ⁺ ) In the same manner as in Example 1, the following compounds of Example 59 and Example 60 were obtained. Example 59

 11 One [3— [N—Ethyru N— [2 丄 [N— (4-Morpholinobenzil) One N— (2,2,2-Trifluoroethyl) amino] ethyl] Caphambyl] propionyl ] 1, 11-Jihi draw 6H-Pyrid [2,3-b] [1,4] Benzodiazepine 1 -one

 Melting point: 153-155 V

Elemental analysis (as _{Cq 3 H 37 N 6 0 4} F 3 · 0.3H 2 O)

C (%) H (%) N (%) F (%) Theoretical value 61.54 5.88 13.05 8.85 Experimental value 61.34 5.78 13.02 8.75 Mass spectrometry value (mZz): FAB 639 (MH +) Example 60

 11-1- [3— [N-ethyl-N- [2-—N— (2-methoxyl) -1-N_ (4-morpholinobenzyl) amino] ethyl] -l-bamoyl] propionyl] -1,5— Jihi Draw 6H—Pyrido [2,3—b] [l, 4] Benzodiazepine 1—

 Melting point: 113-115 ° C

Elemental analysis (as a _{C 34 H 42 N 6 0 5} · 0.3H 2 O)

 C (%) H (%) N (%)

 Theory 65.85 6.92 13.55

 Experimental value 65.63 6.86 13.50

Mass spectrometry value (mZz): FAB 615 (MH +)

Hereinafter, the chemical structural formulas of the compounds obtained in the above Examples are listed.

 nPr: normal propyl group, iPr isopropyl group

tBu: tert-butyl group Table 4

iPr: Isopropyl group

Five

6

nPr: Normal propyl group, iPr: Isopropyl group The chemical structural formulas of the other compounds of the present invention (A-1 to 13, B-:! To 12) are described below. These compounds can be easily prepared in substantially the same manner as described in the above Examples and Preparation Methods, or by applying some modifications to these methods which are obvious to those skilled in the art.

iPr: Isopropyl group Table 8

Claims

The scope of the claims

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

(The symbols in the formula have the following meanings.

 X: nitrogen atom or methine group

R ^{1 is a} hydrogen atom, an optionally substituted lower alkyl group or cycloalkyl group

R ² : hydrogen atom, lower alkyl group which may be substituted, cycloalkyl group, aryl group or aralkyl group

 A: Lower alkylene group

 Ring B: optionally substituted hydrocarbon ring group or 5- to 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms

 n: integer from 1 to 5)

2. R ¹ is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group which may be substituted with a lower alkylthio group or a cycloalkyl group; or a cycloalkyl group;

R ² is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group or a lower alkyl group which may be substituted with a cycloalkyl group; a cycloalkyl group; Or an aralkyl group; Ring B is an aryl group, a cycloalkyl group, or a 5- to 6-membered monocyclic heteroaryl group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms. A lower alkynyl group; a lower alkynyl group; a halogen atom; a hydroxyl group; a mercapto group; a lower alkylthio group; a lower alkoxycarbonyl group; a carboxy group; a sulfonyl group; a sulfinyl group; a lower alkylsulfonyl group; Mono- or di-lower alkylcarbamoyl group; lower alkenyl group; lower alkenyl group; dinitro group; cyano group; amino group; Or di-lower alkylamino group; C 1-3 alkylenedioxy group; cycloalkyl group; aryl group; The benzodiazepinone derivative or the benzodiazepinone derivative according to claim 1, wherein the benzodiazepinone derivative may be substituted with 1 to 3 groups consisting of a nitrogen-containing saturated cyclic group; or an optionally substituted lower alkyl group or a lower alkoxy group. salt.

3. R ¹ is a hydrogen atom or a lower alkyl group;

R ² is a hydrogen atom; a halogen atom, a hydroxyl group, a lower alkoxy group or a lower alkyl group which may be substituted by a lower alkylthio group; a cycloalkyl group; an aryl group; or an aralkyl group;

Ring B may be substituted with a phenyl, naphthyl, lower alkyl or aryl group, a cycloalkyl group, a furyl group, a phenyl group, a pyrrolyl group, an imidazolyl group, a thiazolyl group. A sothiazolyl group, a pyridyl group, a bilimidinyl group, or a pyrazinyl group, wherein the phenyl group is a halogen atom; a hydroxyl group; a mercapto group; a lower alkylthio group; a lower alkoxycarbonyl group; Rubamoyl group; mono- or di-lower alkyl group rubamoyl group; nitro group; cyano group; amino group; mono- or di-lower alkylamino group; C13 alkylenedioxy group Cycloalkyl group; aryl group; lower alkyl group, lower alkoxy group or lower A nitrogen-containing saturated ring group which may be g-substituted by a lower alkoxycarbonyl group; or a halogen atom, a hydroxyl group, a phenyl group, an amino group, or a mono- or di-lower alkylamino group 3. The benzodiazepinone derivative or a salt thereof according to claim 2, which may be substituted with 1 to 3 groups consisting of a lower alkyl group or a lower alkoxy group which may be substituted with a group.

4. R ¹ is a lower alkyl group;

R ² is a hydrogen atom; a lower alkyl group which may be substituted with a halogen atom or a lower alkoxy group; a cycloalkyl group; or an aralkyl group;

 Ring B is a cycloalkyl group, a phenyl group, a phenyl group, or a phenyl group, which may be substituted with a phenyl group, a naphthyl group, or an aryl group; the phenyl group is a halogen atom; a hydroxyl group; a lower alkylthio group; A carbonyl group; a nitro group; a mono- or di-lower alkylamino group; a methylenedioxy group; a 5- to 7-membered nitrogen-containing saturated ring group which may be substituted with a lower alkyl group or a lower alkoxycarbonyl group; 4. A lower alkyl group which may be substituted with a halogen atom; or 1 to 3 groups comprising a lower alkoxy group which may be substituted with a di-lower alkylamino group. The benzodiazepinone derivative or a salt thereof according to the above.

5. The benzodiazepinone derivative or a salt thereof according to claim 1, wherein X is a nitrogen atom.

6. The benzodiazepinone derivative or a salt thereof according to claim 1, wherein ring B is a phenyl group substituted with a 5- to 7-membered nitrogen-containing saturated ring group which may be substituted with a lower alkyl group.

7. The benzodiazepinone derivative or a salt thereof according to claim 6, wherein ring B is a phenyl group substituted with a 1-piperazinyl group which may be substituted with a lower alkyl group.

8.11- [3— [N-ethyl-N— [2-[N-ethyl-N— [4 -— (4-ethyl-1-piperazinyl) benzyl] amino] ethyl] Power Lubamoyl] propionyl] — 5 6H—pyrid [2,3-b] [1,4] benzodiazepin-1-one or a salt thereof,

11-1- [3--N-ethyl-N- [2-[N-ethyl-N- [4- (4-isopropyl-1-piperazinyl) benzyl] amino] ethyl] caprolvayl] propionyl ] 1,5—Dihydro-6H—Pyrido [2,3—b] [1,4] Benzodiazepin-16-one or a salt thereof,

 11— [3— [N— [2— [N—ethyl-N— [4- (4-I-Pip-1—Pipera-Zinyl) benzyl] -1-N—Methylamino] ethyl] Pionyl] -1,5—dihydro-6H—pyrido [2,3—b] [1,4] benzodiazepin-16-one or a salt thereof,

 5-[3-[N-Ethyl-N-[2-[N-[4- (4-Isopropyl-1-1-piperazinyl) benzyl]]-N-methylamino] ethyl] Pionyl] — 5, 10-dihydro 11H — dibenzo [b, e] [1, 4] diazepin-11-one or a salt thereof,

 5-[3-[N-ethyl-N- [2-[N-ethyl-N- [4- (4-ethyl-1-piperazinyl) benzyl] amino] ethyl] force rubamoyl] propionyl] — 5, 10 — Jihi Draw 11H—Dibenzo [b, e] [1, 4] diazepin-1 11-one or its salt

9. A benzodiazepinone derivative represented by the following general formula (I) or a salt thereof Pharmaceutical composition containing

(The symbols in the formula have the following meanings.

 X: nitrogen atom or methine group

R ^{1 is a} hydrogen atom, a lower alkyl group which may have a substituent or a cycloalkyl group

R ² : hydrogen atom, lower alkyl group which may have a substituent, cycloalkyl group, aryl group or aralkyl group

 A: Lower alkylene group

 Ring B: 5- or 6-membered aromatic heterocyclic ring containing 1 to 4 oxygen, sulfur or nitrogen atoms as a carbon ring or hetero atom which may have a substituent.

 n: integer from 1 to 5)

10. The medicament according to claim 6, which is a muscarinic M2 receptor antagonist.

1 1. Sinus bradycardia, sinus arrest, or sinus dysfunction syndrome including bradycardia tachycardia syndrome, or bradyarrhythmia including vagal excitability-induced bradycardia including atrioventricular blockade, neural syncope (carotid artery) 11. The medicament according to claim 10, which is a prophylactic or therapeutic drug (including sinus hypersensitivity).