JP2681258B2 - Benzylamine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel benzylamine derivative or a salt thereof.

[0002]

2. Description of the Related Art The social structure of modern society and its mechanism are becoming more and more complicated, and people are increasingly exposed to various stresses. Amid such changes in social conditions, the number of people who suffer from stressful mental disorders, particularly depression and anxiety, has increased, which has become a major social problem.

Unlike typical depressions of the past, many of the modern depressions are relatively mild and tend to be protracted.
This depression is often difficult to distinguish from neurosis and tends to become chronic. And, the number of patients who have become chronic has become more and more neurotic, and in recent years there is an increasing trend (Clinical Psychiatry, Volume 21, No. 4, pp. 691-695, 199.
2 years).

As described above, with the increasing complexity of society, the picture of mental disorders has become more complicated. The following two points have been pointed out as recent characteristic changes.

(1) Among neuroses, depressive syndrome is mainly shown, and those which are difficult to distinguish from depression are increasing.

(2) Mild depression is included in those diagnosed with neurosis in the past. In particular, a mild depression patient occupies a considerable proportion of neurological disorders associated with anxiety attacks and anticipatory fears (Clinical Psychiatry, Vol. 21, No. 4, pp. 691-695). , 19
1992).

According to a concrete clinical study, when the symptoms of a patient diagnosed with major depression were analyzed, 72% had moderate worries, 62% had mental anxiety, and had physical anxiety (autonomy). Neurological and muscular symptoms) were 42%, fear attacks were 29%, fear symptoms were 19%, and threatening symptoms were 1.2% (Racagni, G., Smeraldi, edited by "An.
xious Depression ”, Ravenspress, New York,
(1987), and among depression patients, there is a high rate of those exhibiting anxiety symptoms.

[0008] Treatment of mental disorders having such complicated and various pathological conditions is currently carried out by selectively using antidepressants and anxiolytics depending on the symptoms, or by using both in combination. While this treatment may be effective, it is mostly pointed out to be inadequate. In particular, existing antidepressants are effective for endogenous depression, but poorly effective for depressive depression with a personality-related or neurotic color (Neuropsychopharmacology, Volume 9, No. 4, (Pp. 279-285, 1987), when anxiolytics are used in patients with anxiety symptoms in the background despite the existence of a depressive phase behind them, depression may be prolonged. (Clinical Psychiatry, Vol. 21, No. 4, pp. 691-695, 1992). Overuse of suicidal ideation and prolongation of depression are induced by easy use of antidepressants in clinical departments other than psychiatry (Neuropsychopharmacology, Vol. 9, No. 4, pp. 279-285, 1987).
(Year) and other problems are emerging.

Furthermore, existing antidepressants have (1) no immediate effect, require continuous administration for two weeks or more, (2) have unpleasant side effects such as anticholinergic action, (3) ineffective There is a problem that there is an example (efficiency 65%) (Neuropsychopharmacology, Vol. 11, No. 10, 753-76).
1 page, 1989) . In addition, anxiolytics have the problem that (1) there are side effects such as excessive sedation, somnolence, and muscle relaxation , and (2) there are many serious adverse symptoms such as dependence, withdrawal symptoms, and memory disorders. (Neuropsychopharmacology, Volume 11, Volume 9
No., pp. 709-719, 1989).

[0010] It is therapeutically effective to use antidepressants or anxiolytics that have many such side effects or adverse effects and are ineffective for the core symptoms of mental disorders in patients (single agent or combined use). It is speculated that it causes many trade-offs. Therefore, one agent is involved in the root of the disease state,
If a drug that exhibits both anti-anxiety effects is developed, it is considered that the above-mentioned problems in the current treatment will be solved.

Based on such knowledge, the inventors of the present invention have conducted extensive studies and found that the benzylamine derivative represented by the general formula (1) and its salt are excellent in both antidepressant and anxiolytic actions. They found that they are effective as antidepressant / anxiolytic agents, and completed the present invention here.

[0012]

The benzylamine derivative of the present invention is a novel compound which has not been published in the literature and has the general formula

[0013]

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[In the formula, R ¹ represents a lower alkyl group. R ²
Represents a cycloalkyl group. R ³ represents a halogen atom. ].

The benzylamine derivative of the present invention or a salt thereof has a characteristic of having both antidepressant and anxiolytic actions, and is effective as an excellent antidepressant / anxiolytic drug which meets the needs of the industry. , The compound of the present invention has a central nervous system activating action and a consciousness disorder improving action, and is used for head injury, cerebral hemorrhage, cerebral infarction, subarachnoid hemorrhage, drug poisoning, oxygen deficiency, oxygen deficiency accident, brain surgery and cardiac bypass surgery. Later consciousness disorder, and further aftereffects such as mental retardation, decreased attention, speech disorder, cognitive disorder,
It is useful as a therapeutic drug for learning disorders, movement disorders, decreased motivation, emotional disorders, etc., and also for the depressive state of senile dementia, delirium, language disorder, cognitive disorders, learning disorders, movement disorders, decreased attention, aging. It is also useful as a remedy for various symptoms such as memory disorders associated with. Furthermore, the compound of the present invention has a sigma receptor agonistic action, and is associated with stress-induced mental disorders such as depression, anxiety / neuropathy, psychosomatic disorder, anorexia nervosa, hypopituitarism, and high prolactin. It is also useful as a therapeutic drug for blood pressure, vascular dementia, hyperactivity syndrome, dementia / amnesia, Parkinson's disease, etc., and can also be used as an antidepressant, anxiolytic, psychosomatic disorder, and Parkinson's disease.

Further, the compound of the present invention is characterized by having antidepressant / anxiolytic action, central nerve activating action, consciousness disorder improving action and sigma receptor activating action even when it is orally administered.

Further, in a complicated modern society, many people are suffering from mental disorders (obsessive-compulsive disorder, etc.) due to stress (environmental stress) received from the surrounding environment. It is useful as a therapeutic agent.

Compounds similar in structure to the compounds of the invention are
For example, WO90 / 14334 (November 2, 1990)
Published 9th), WO91 / 09594 (7 July 1991)
Published on May 11, WO93 / 00313 (1993)
(Published January 7, 2013) and WO93 / 07113 (19)
Published April 15, 1993). In particular, WO
91/09594 and WO93 / 00313 disclose the general formula

[0019]

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[In the formula, Ar represents an aryl group or a heteroaryl group. The aryl group and the heteroaryl group are
Halogen atom such as chlorine atom, fluorine atom, bromine atom, iodine atom, trifluoromethyl group, C _{1 to} C ₆ alkoxy group, C _{2 to} C ₆ dialkoxymethyl group, C _{1 to} C ₆ alkyl group, Cyano group, C _{3 to} C ₁₅ dialkylaminoalkyl group, carboxy group, carboxamide group, C ₁ to
Haloalkyl group C _6, haloalkylthio group having C ₁ -C _6, allyl group, aralkyl group, cycloalkyl group C ₃ -C _6, an aroyl group, aralkoxy group, an acyl group of C ₂ -C _6, an aryl group, A substituted aryl group, a heteroaryl group, a substituted heteroaryl group, an aryl group fused with a substituted benzene ring, a substituted aryl group fused with a benzene ring, a heteroaryl group fused with a benzene ring, a substituted heteroaryl group fused with a benzene ring, C ₃ -C ₆ heterocycloalkyl group, C ₃ -C ₆ heterocycloalkyl group, an alkylthio group of C ₁ -C ₆ condensed with the benzene ring, C ₁ ~
C ₆ alkylsulfonyl group, C ₁ -C ₆ haloalkylsulfonyl group, C ₁ -C ₆ alkylsulfinyl group, C ₁ -C ₆ haloalkylsulfinyl group, arylthio group, C ₁ -C ₆ haloalkoxy group, Amino group,
C ₁ -C ₆ alkylamino group, a dialkylamino group of C ₂ -C _15, hydroxy group, a carbamoyl group, C ₁ -C
₆ N-alkylcarbamoyl groups, C _{2 to} C ₁₅ N, N
- dialkylcarbamoyl group, a nitro group or a C ₂ -C ₁₅
It may be substituted with a dialkylsulfamoyl group.

R ^a represents a hydrogen atom or a C ₁ -C ₆ alkyl group.

R ^b is different and represents a hydrogen atom, a C ₁ -C ₆ alkyl group, a hydroxy group, an amino group, a C ₁ -C ₆ alkylamino group or ═O.

R ^a and R ^b may together form a morpholino ring.

N represents 0 or an integer of 1 to 5.

W represents-(CH ₂ ) p- (p is an integer of 1 to 3) or -H H-.

V is-(CH ₂ ) q- (q is an integer of 1 to 6),-(CH ₂ ) r-C≡C- (CH ₂ ) r- (r is different from 0 or 1 to 3). _{integer), - (CH 2) r} -CH
_{= CH- (CH 2) r -} , - (CH 2) r-C (= O)
_{- (CH 2) r -,} - (CH 2) r-Y- (CH 2) r
- (Y is O or S) indicating the or an alkyl group of C ₁ -C _6.

Z represents a hydrogen atom, an aryl group, an aryl-substituted carboxyl group, a heteroaryl group or a cycloalkyl group. The aryl group, heteroaryl group and cycloalkyl group include halogen atoms such as chlorine atom, fluorine atom, bromine atom and iodine atom, trifluoromethyl group, C _1-
An alkoxy group having C _6, C ₂ -C dialkoxymethyl group of _6, alkyl group of C ₁ -C _6, a cyano group, a dialkylamino group of C ₃ -C _15, a carboxyl group, carboxamide group, C ₁ -C ₆ haloalkyl groups, C ₁ -C ₆ haloalkylthio groups, allyl groups, aralkyl groups, C _3-
Cycloalkyl group C _6, aroyl group, aralkoxy group, carboxyacyl group C ₂ -C _6, an aryl group, a substituted aryl group, a heteroaryl group, a substituted heteroaryl groups, C ₃ -C ₆ heterocycloalkyl groups, C _{1 to} C ₆ alkylthio group, C _{1 to} C ₆ alkylsulfonyl group,
C ₁ -C haloalkylsulfonyl group _6, an alkylsulfinyl group having C ₁ -C _6, haloalkylsulfinyl groups of C ₁ -C _6, an arylthio group, a haloalkoxy group C ₁ -C _6, an amino group, C ₁ -C ₆ alkylamino groups,
A C _{2 to} C ₁₅ dialkylamino group, a hydroxy group, a carbamoyl group, a C _{1 to} C ₆ N-alkylcarbamoyl group, a C _{2 to} C ₁₅ N, N-dialkylcarbamoyl group,
It may be substituted with a nitro group, a C ₂ -C ₁₅ dialkylsulfamoyl group or an orthomethylenedioxy group. ] A compound represented by the following is disclosed, and the compound is useful as a sigma receptor Reganto, a schizophrenia drug or other psychotropic drug, central nervous system disease, drug abuse,
It is taught that it can be used for the treatment of gastrointestinal disorders, hypertension, migraine headaches, peritonitis, depression and the like.

However, the above publications do not disclose the compound of the present invention. Moreover, the compound of the present invention is characterized by having both antidepressant and anxiolytic actions. Furthermore, the compound of the present invention is also characterized by being effective in improving consciousness disorder and treating obsessive-compulsive disorder.

More specifically, each group defined in the above general formula (1) is as follows.

As the lower alkyl group, for example, methyl,
Ethyl, propyl, isopropyl, butyl, tert-
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as butyl, pentyl and hexyl groups.

Cycloalkyl groups include cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl,
Examples thereof include cycloalkyl groups having 3 to 8 carbon atoms, such as cycloheptyl and cyclooctyl groups.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Among the compounds of the present invention, a compound in which R ¹ is a methyl group, an ethyl group, R ² is a cyclopropyl group, a cyclobutyl group, and R ³ is a chlorine atom is preferable, and R ^{1 is}
Is particularly preferably a methyl group, R ² is a cyclopropyl group, and R ³ is a chlorine atom.

The compounds of the present invention include the following compounds.

A compound of the general formula (1) in which R ¹ is a methyl group or an ethyl group or a salt thereof A compound of the general formula (1) in which R ¹ is a methyl group or a salt thereof R ² is a cyclopropyl group or a cyclobutyl group or a compound or compound or a salt thereof R ¹ is methyl in the general formula (1) a salt ^thereof, wherein R ³ is a chlorine atom in the general formula (1) a salt thereof R ² is a cyclopropyl group of a general formula (1) Group or ethyl group, R ² is a cyclopropyl group or a cyclobutyl group, R ³ is a chlorine atom, or a compound of the formula (1) or a salt thereof, R ³ is a chlorine atom, and the substitution position of R ³ is on the benzene ring. A compound of the general formula (1) or a salt thereof at the 4-position R ¹ is a methyl group or an ethyl group, R ² is a cyclopropyl group or a cyclobutyl group, R ³ is a chlorine atom, and the substitution position of R ³ is on the benzene ring. Of the general formula (1), which is the 4-position of Or a salt 3- (4-chloro-benzyloxy) -N- cyclopropylmethyl -N- methylbenzylamine 4- (4-chloro-benzyloxy) -N- cyclopropylmethyl -N- methylbenzylamine 2- (4- Chlorobenzyloxy) -N-cyclopropylmethyl - N-methylbenzylamine The compound of the present invention represented by the above general formula (1) can be produced by various methods, and preferred examples thereof include the following. It is manufactured by the method shown.

[0036]

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[In the formula, R ¹ , R ² and R ³ are the same as defined above. The reaction between the compound (2) and the compound (3) in Reaction Scheme-1 is carried out in the absence or presence of a dehydrating agent in a solvent-free or suitable solvent. As the solvent used here,
For example, alcohols such as methanol, ethanol and isopropanol, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, dimethylformamide, dimethylacetamide, N-methyl An aprotic polar solvent such as pyrrolidone or a mixed solvent thereof may, for example, be mentioned. As a dehydrating agent, for example, a desiccant used for dehydration of a normal solvent such as molecular sieve,
Examples thereof include mineral acids such as hydrochloric acid, sulfuric acid, and boron trifluoride, and organic acids such as p-toluenesulfonic acid. The reaction is
The reaction is usually performed at room temperature to 150 ° C, preferably at room temperature to 100 ° C, and the reaction is generally completed in about 5 minutes to 10 hours. The amount of the compound of general formula (3) to be used is not particularly limited, but it is usually at least an equimolar amount, preferably an equimolar to 2-fold molar amount with respect to the compound of the general formula (2). As the amount of the dehydrating agent to be used, it is generally preferable to use a large excess amount in the case of a desiccant, and to use a catalytic amount in the case of using an acid. The general formula thus obtained

[0038]

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[R ¹ , R ² and R ³ are the same as above. ]
The compound of 1 is subjected to the next reduction reaction without isolation.

Various methods can be applied to the reduction reaction of the compound of the general formula (A). For example, the conditions of catalytic hydrogenation of the compound of the general formula (9) described below can be used, but preferably a hydrogenation reducing agent is used. The reduction method used is preferably used. Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, diborane and the like, and the amount thereof is usually at least equimolar to the compound (2), preferably equimolar to 10 times. It is in the molar range. This reduction reaction is usually carried out using a suitable solvent such as water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, diethyl ether, diglyme and the like, and usually about -60 to 50.
C., preferably from -30.degree. C. to room temperature, for about 10 minutes to 5 hours. When lithium aluminum hydride or diborane is used as the reducing agent, it is preferable to use an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme.

[0041]

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[Wherein R ¹ , R ² and R ³ are the same as defined above.
X represents a halogen atom. R ⁴ and R ⁵ each represent a hydrogen atom or a lower alkyl group. ] Reaction of Compound (4) with Compound (5) and Compound (7)
The reaction of the compound (10) with the compound (10) is generally carried out in a suitable inert solvent in the presence or absence of a basic compound. Examples of the inert solvent used include benzene, toluene, aromatic hydrocarbons such as xylene, tetrahydrofuran, dioxane, ethers such as diethylene glycol dimethyl ether, lower alcohols such as methanol, ethanol, isopropanol, butanol, acetic acid, ethyl acetate, etc. Acetone, acetonitrile, dimethylsulfoxide, dimethylformamide, hexamethylphosphoric triamide and the like, or a mixed solvent thereof and the like can be mentioned. Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate, metal hydroxides such as sodium hydroxide and potassium hydroxide, sodium hydride, potassium, sodium, sodium amide, Metal alcoholates such as sodium methylate and sodium ethylate, pyridine,
N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, 1,5-diazabicyclo [4.3.0] nonene-5 (DBN), 1,8-diazabicyclo [5.4.0] undecene-7 (DBU),
1,4-diazabicyclo [2.2.2] octane (DA
And organic bases such as BCO). The ratio of the compound (4) to the compound (5) and the ratio of the compound (7) to the compound (10) are not particularly limited and may be appropriately selected within a wide range. It is preferable to use at least an equimolar amount, preferably an equimolar to 5-fold molar amount. The reaction is usually performed at about 0 to 200 ° C., preferably about 0 to 170 ° C., and generally the reaction is completed in about 30 minutes to 30 hours. In addition, alkali metal halogen compounds such as sodium iodide and potassium iodide may be added to these reaction systems.

The reaction between the compound (4) and the compound (6) is
It is carried out without solvent or in a suitable solvent in the presence of a reducing agent. As the solvent used here, for example, water, methanol, ethanol, alcohols such as isopropanol,
Examples thereof include ethers such as acetonitrile, formic acid, acetic acid, dioxane, diethyl ether, diglyme, and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene, and xylene; and mixed solvents thereof. Examples of the reducing agent include formic acid, fatty acid alkali metal salts such as sodium formate, sodium borohydride, sodium cyanoborohydride, hydride reducing agents such as lithium aluminum hydride, palladium-black, palladium-carbon, platinum oxide, platinum. black,
Examples thereof include catalytic reducing agents such as Raney nickel.

When formic acid is used as a reducing agent, the reaction temperature is usually room temperature to 200 ° C., preferably 50 to 150.
C. is appropriate, and the reaction is completed in about 1 to 10 hours. The amount of formic acid used is preferably a large excess with respect to compound (4).

When a hydrogenation reducing agent is used, the reaction temperature is usually about -30 to 100 ° C, preferably 0 to 70 ° C.
The reaction is appropriately performed, and the reaction is completed in about 30 minutes to 15 hours. The amount of the reducing agent to be used is generally about equimolar to about 20-fold molar amount, preferably about 1- to 6-fold molar amount, relative to compound (4). In particular, when lithium aluminum hydride is used as the reducing agent, it is preferable to use ethers such as diethyl ether, dioxane, tetrahydrofuran, and diglyme as solvents, and aromatic hydrocarbons such as benzene, toluene, and xylene.

When a catalytic reducing agent is used, it is usually in a hydrogen atmosphere at atmospheric pressure to 20 atm, preferably atmospheric pressure to 10 atm, or a hydrogen donor such as formic acid, ammonium formate, cyclohexene and hydrazine hydrate. In the presence of, the reaction is usually carried out at a temperature of about -30 to 100 ° C, preferably about 0 to 60 ° C, and the reaction is usually completed in about 1 to 12 hours. The amount of the catalytic reducing agent to be used is generally 0.1 to 40% by weight, preferably 1 to 40% by weight based on compound (4).
The content is preferably about 20% by weight.

The amount of the compound (6) used is usually at least an equimolar amount, preferably an equimolar amount to a large excess amount with respect to the compound (4).

The reaction between the compound (7) and the compound (8) is
It is carried out according to a usual amide bond formation reaction. The amide formation reaction is carried out by various known methods, for example, (a) mixed acid anhydride method, for example, carboxylic acid (8) is reacted with a halocarboxylic acid alkyl ester to form a mixed acid anhydride, which is reacted with amine (7). (B) Active ester method, for example, carboxylic acid (8) is used as an active ester such as p-nitrophenyl ester, N-hydroxysuccinimide ester, 1-hydroxybenzotriazole ester, and amine (7) is added thereto. Method of reacting; (c) Carbodiimide method; that is, carboxylic acid (8) to amine (7)
(D) a method of condensing benzene in the presence of an activator such as dicyclohexylcarbodiimide or carbonyldiimidazole;
Other methods, for example, a method in which carboxylic acid (8) is converted to a carboxylic acid anhydride with a dehydrating agent such as acetic anhydride, and this is reacted with amine (7), an ester of carboxylic acid (8) and a lower alcohol is converted to amine ( Method of reacting 7),
It can be carried out by a method of reacting an acid halide of carboxylic acid (8), that is, a carboxylic acid halide with amine (7). In addition, a method of activating a carboxylic acid (8) with a phosphorus compound such as triphenylphosphine or diethylchlorophosphate, and reacting this with an amine (7),
Further, the carboxylic acid (8) may be converted into an N-carboxyamino acid anhydride with phosgene or chloroformic acid trichloromethyl ester, and then this is reacted with the amine (7). Alternatively, the carboxylic acid (8) may be activated with an acetylene compound such as trimethylsilylethoxyacetylene and the amine (7) may be reacted therewith.

In the mixed acid anhydride method shown in (a) above, the mixed acid anhydride used is obtained by a conventional Schotten-Baumann reaction, and this is usually reacted with the amine (7) without isolation. Thus, the compound of the general formula (9) is produced. The Schotten-Baumann reaction is performed in the presence of a basic compound. As the basic compound used, a compound commonly used in the Schotten-Baumann reaction is used, and examples thereof include triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 4-dimethylaminopyridine, DBN, DBU and D.
Examples thereof include organic bases such as ABCO and inorganic bases such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like. The reaction is carried out at about -20 to 100 ° C, preferably 0 to 50 ° C for about 5 minutes to 10 hours, preferably about 5 minutes to 2 hours. The reaction between the obtained mixed acid anhydride and the amine (7) is about -20 to 150 ° C.
It is preferably carried out at 10 to 50 ° C. for about 5 minutes to 10 hours, preferably about 5 minutes to 5 hours. The mixed acid anhydride is generally a solvent commonly used in this kind of mixed acid anhydride method, specifically, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene. Ethers such as diethyl ether, dioxane, diisopropyl ether, tetrahydrofuran, dimethoxyethane, esters such as methyl acetate and ethyl acetate, 1,1,3,3-tetramethylurea, N, N-dimethylformamide, dimethyl sulfoxide , An aprotic polar solvent such as hexamethylphosphoric triamide, or a suitable solvent or mixed solvent, or in the absence thereof. As the halocarboxylic acid alkyl ester used in the production of the mixed acid anhydride, methyl chloroformate, methyl bromoformate,
Examples include ethyl chloroformate, ethyl bromoformate, isobutyl chloroformate and the like. The halocarboxylic acid alkyl ester is generally used in at least an equimolar amount, preferably about 1 to 1.5 times the molar amount of the amine (7). The amount of the carboxylic acid (8) used is usually at least equimolar to the amine (7), preferably about 1 to 1.5 times the molar amount.

In the active ester method shown in (b) above, for example, in the case of using N-hydroxysuccinimide ester, for example, in the presence or absence of a basic compound in a suitable solvent that does not affect the reaction. Done below. Further, a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide may be added to the reaction system of the reaction. Here, as the basic compound, any of the basic compounds used in the Schotten-Baumann reaction can be used, and in addition to them, sodium acetate,
Sodium benzoate, sodium formate, potassium acetate,
Alkali metal carboxylate such as lithium benzoate and cesium acetate, and alkali metal halide such as potassium fluoride and cesium fluoride can also be used. As the solvent, specifically, methylene chloride, chloroform, halogenated hydrocarbons such as dichloroethane, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, dioxane, tetrahydrofuran, ethers such as dimethoxyethane, Esters such as methyl acetate and ethyl acetate; aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and hexamethylphosphoric triamide; and mixed solvents thereof. The reaction is carried out at 0 to 150 ° C, preferably
It ends in ~ 30 hours. The amount of the N-hydroxysuccinimide ester used is usually at least equimolar, preferably equimolar to 2 times the molar amount of the amine (7).

The amine (7) and the carboxylic acid (8) are combined with triphenylphosphine, triphenylphosphine-2,2'-dipyridyldisulfide, diethylchlorophosphate, diphenylphosphinyl chloride, phenyl N-phenylphosphoramide. Compound (9) can also be obtained by reacting in the presence of a condensing agent for a phosphorus compound such as chlorate, diethyl cyanophosphate, and bis (2-oxo-3-oxazolidinyl) phosphinic chloride. As the basic compound used here, known compounds can be widely used, and examples thereof include sodium hydroxide and potassium hydroxide in addition to the basic compound used in the Schotten-Baumann reaction. Examples of the solvent include, in addition to the solvent used in the mixed acid anhydride method, pyridine, acetone, acetonitrile, etc., or a mixed solvent of two or more of the above solvents. The reaction is generally carried out at about -20 to 150 ° C, preferably at about 0 to 100 ° C, and is generally completed in 5 minutes to 30 hours. The amount of the condensing agent and the carboxylic acid (8) used is at least about equimolar, and preferably about equimolar to about 2 times the molar amount of the amine (7).

The compound (9) can also be obtained by reacting the amine (7) with the carboxylic acid (8) in the presence of a condensing agent. The reaction is carried out in a suitable solvent,
It is performed in the presence or absence of a catalyst. The solvents used here include dichloromethane, dichloroethane,
Halogenated hydrocarbons such as chloroform and carbon tetrachloride,
Examples thereof include acetonitrile and dimethylformamide. Examples of the catalyst used include organic bases such as dimethylaminopyridine and 4-piperidinopyridine, salts such as pyridinium tosylate, camphorsulfonic acid, and mercury oxide. Examples of the condensing agent include acetylene compounds such as trimethylsilylethoxyacetylene. The condensing agent is usually equimolar to 1 with respect to the amine (7).
It is good to use 0 times molar amount, preferably 2 to 6 times molar amount. The carboxylic acid (8) is usually used in an amount of at least about equimolar to the amine (7), preferably about equimolar to 2 times the molar amount. The reaction is usually carried out at about 0 to 150 ° C., preferably at about room temperature to about 100 ° C., and is completed in about 1 to 10 hours.

When the method of reacting a carboxylic acid halide with an amine (7) shown in (d) above is adopted, the reaction is carried out in the presence of a dehydrohalogenating agent in a suitable solvent. Usual basic compounds are used as the dehydrohalogenating agent. As the basic compound, known compounds can be widely used, and examples thereof include sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride and the like in addition to the basic compound used in the Schotten-Baumann reaction. As the solvent, other than the solvent used in the mixed acid anhydride method, for example, alcohols such as methanol, ethanol, propanol, butanol, 3-methoxy-1-butanol, ethyl cellosolve, methyl cellosolve, pyridine, acetone, acetonitrile and the like, or Examples thereof include a mixed solvent of two or more of the above solvents. The use ratio of the amine (7) and the carboxylic acid halide is not particularly limited and is appropriately selected within a wide range, but usually the latter is at least about equimolar amount, preferably equimolar to the former.
It is preferable to use about 5 times the molar amount. The reaction is usually carried out at -20.
The reaction is completed at about 180 ° C, preferably about 0 to 150 ° C, and generally about 5 minutes to 30 hours.

In the above, the carboxylic acid halide is produced, for example, by reacting the carboxylic acid (8) with a halogenating agent in the absence of a solvent or in the presence of a solvent. Any solvent can be used as long as it does not adversely affect the reaction.
For example, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride, ethers such as dioxane, tetrahydrofuran and diethyl ether, dimethylformamide, dimethylsulfoxide and the like can be mentioned. . As the halogenating agent, a normal halogenating agent that changes the hydroxyl group of the carboxy group to a halogen can be used.
Examples thereof include phosphorus pentabromide. The use ratio of the carboxylic acid (8) and the halogenating agent is not particularly limited and may be appropriately selected. However, when the reaction is carried out in the absence of a solvent, the latter is usually used in a large excess amount in the solvent and the latter. When carrying out the reaction in, the latter is usually at least equimolar to the former,
Preferably, a 2- to 4-fold molar amount is used. The reaction temperature (and reaction time) is not particularly limited either, but is usually from room temperature to 100
C., preferably at 50 to 80.degree. C. for about 30 minutes to 6 hours.

Various methods can be applied to the reaction of reducing the compound (9) to the compound (1), for example, catalytic hydrogenation in a suitable solvent in the presence of a catalyst. Examples of the solvent used include water, acetic acid, alcohols such as methanol, ethanol and isopropanol, hydrocarbons such as hexane and cyclohexane, ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran and diethyl ether, ethyl acetate and methyl acetate. And the like, aprotic polar solvents such as dimethylformamide, mixed solvents thereof, and the like. Examples of the solvent used include palladium, palladium-black, palladium-
Carbon, platinum, platinum oxide, copper chromite, Raney-nickel, etc. are used. The amount of catalyst used is represented by the general formula (9)
In general, it is preferable to use about 0.02 to 1 times the amount of the above compound. The reaction temperature is usually -20 to 100 ° C, preferably 0 to 70 ° C, the hydrogen pressure is usually 1 to 10 atm, and the reaction is generally completed in about 0.5 to 20 hours.

Although the above reducing conditions can be used, the reduction method using a hydrogenation reducing agent is preferably used.
Examples of the hydrogenation reducing agent used include lithium aluminum hydride, sodium borohydride, diborane and the like, and the amount thereof is usually at least equimolar to the compound (9), preferably equimolar to 10-fold molar. Is the range. This reduction reaction is usually carried out in a suitable solvent such as water,
Lower alcohols such as methanol, ethanol, isopropanol, tetrahydrofuran, diethyl ether,
Ethers such as diglyme, acetic acid, etc. are usually used,
200 ° C., preferably 0 to 170 ° C., for about 10 minutes
It takes about 10 hours. When lithium aluminum hydride or diborane is used as the reducing agent, an anhydrous solvent such as diethyl ether, tetrahydrofuran or diglyme is preferably used.

[0057]

Embedded image

[Wherein R ¹ , R ² and R ³ are the same as defined above. ] The reaction of the compound (11) and the compound (3) can be carried out by the reaction formula
2 can be carried out under the same conditions as the reaction between the compound (7) and the compound (8), but the amount of the compound used is not based on the amine (3) as shown in Reaction formula-2, but on the carboxylic acid. It is preferable to set the amount to (11).

The reduction reaction of compound (12) can be carried out under the same conditions as the reduction reaction of compound (9) of the above-mentioned reaction formula-2. Compound (12) can be produced, for example, by the method shown in the following Reaction scheme-4.

[0060]

Embedded image

[Wherein R ³ and X are the same as defined above. R ⁶ and R ⁷ each represent the group R ¹ or the group —CH ₂ R ² . However, when R ⁶ represents a group R ¹ , R ⁷ represents a group —CH ₂
Indicates R ^2, when R ⁶ represents a group -CH ₂ R ² is, R ⁷
Represents the group R ¹ . The reaction between the compound (11) and the compound (13) is carried out under the same conditions as in the reaction between the compound (11) and the compound (3) in the above Reaction Formula-3. The reaction between the compound (14) and the compound (15) is carried out under the same conditions as the reaction between the compound (4) and the compound (5) in the reaction formula-2.

Starting Compound (4) in Reaction Formula-2
Alternatively, (7) can be produced, for example, according to the method of the following reaction formula-5.

[0063]

Embedded image

[In the formula, R ³ and R ⁶ are the same as defined above. In the above Reaction Scheme-5, the compound (16) in which R ⁶ represents the group R ¹ is the compound (7), and R ⁶ is the group —CH ₂ R ²
The compound (16) showing is the compound (4). The compound (2) and the compound (13) are carried out under the same conditions as in the reaction of the compound (2) and the compound (3) in the reaction formula-1.

Starting compound (2) in the above reaction formula-1
And the raw material compound (1
1) can be produced, for example, according to the method shown in the following Reaction scheme-6.

[0066]

Embedded image

[In the formula, R ³ and X are the same as defined above. ] The reaction between the compound (17) and the compound (19) and the reaction between the compound (18) and the compound (19) can be carried out by the reaction formula-2.
The reaction is carried out under the same conditions as the reaction of compound (4) with compound (5) in.

Of the compounds of the present invention represented by the general formula (1), the compound having a basic group can be easily converted to an acid addition salt by reacting with a pharmaceutically acceptable acid. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, oxalic acid, acetic acid, succinic acid, malonic acid, methanesulfonic acid, maleic acid, fumaric acid, malic acid, tartaric acid, and citric acid. And organic acids such as benzoic acid.

The target compound of each step thus obtained can be easily isolated and purified by a conventional separation means. As the separation means, for example, a solvent extraction method,
The dilution method, recrystallization method, column chromatography, preparative thin layer chromatography and the like can be exemplified.

The compound of the general formula (1) is usually used in the form of a general pharmaceutical preparation. The preparation is prepared using a diluent or excipient such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant and a lubricant, which are usually used. Various forms can be selected as the pharmaceutical preparation depending on the purpose of treatment. Representative examples are tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.). In molding into tablets, those conventionally known in the art can be widely used as carriers, for example, lactose, sucrose, sodium chloride,
Glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate , Polyvinylpyrrolidone and other binders, disintegrators such as dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose , White sugar,
Disintegration inhibitors such as stearin, cocoa butter, hydrogenated oil, etc., absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate, humectants such as glycerin and starch, starch, lactose, kaolin, bentonite, colloidal silicic acid, etc. And a lubricant such as purified talc, stearate, boric acid powder, polyethylene glycol and the like. Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets. In molding into a pill form, those conventionally known in the art can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, gum arabic powder, Examples include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran agar. In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, esters of higher alcohols, gelatin, and semisynthetic glycerides. When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood, and when formed into the form of these solutions, emulsions and suspensions, they may be used as diluents. Any of those commonly used in the field can be used, and examples thereof include water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent and the like may be added. You may. Further, a coloring agent, a preservative, a flavor, a flavoring agent, a sweetening agent and the like and other pharmaceuticals may be contained in the pharmaceutical preparation as required.

The amount of the compound of the general formula (1) of the present invention or a salt thereof to be contained in the pharmaceutical preparation is not particularly limited and may be appropriately selected from a wide range.
The content is preferably 0% by weight.

The administration method of the above-mentioned pharmaceutical preparation is not particularly limited, and it is administered according to various preparation forms, age of the patient, sex and other conditions, degree of disease and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it may be administered intravenously alone or in a mixture with a normal replenisher such as glucose or amino acid, and if necessary, may be administered intramuscularly, intradermally, subcutaneously or intraperitoneally alone. Suppositories are administered rectally.

The dose of the above-mentioned pharmaceutical preparation is appropriately selected according to the usage, the age and sex of the patient, other conditions, the degree of disease, etc., but the amount of the compound of the general formula (1) or a salt thereof which is usually the active ingredient is About 0.2 to 200 per 1kg body weight per day
It is good to be about mg.

[0074]

[Examples] Formulation examples, reference examples, examples and pharmacological test results are listed below.

Formulation Example 1 4- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzylamine 5 mg Starch 132 mg Magnesium stearate 18 mg Lactose 45 mg Total 200 mg Tablets of the above composition in 1 tablet by a conventional method Was manufactured.

Formulation Example 2 2- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzylamine 150 mg Avicel (trade name, manufactured by Asahi Kasei Corporation) 40 g Corn starch 30 g Magnesium stearate 2 g Hydroxypropyl methylcellulose 10 g Polyethylene glycol-6000 3 g Castor oil 40 g Methanol 40 g The compound of the present invention, Avicel, corn starch and magnesium stearate are mixed and polished, and then tableted with a sugar-coated R10 mm kine. The obtained tablets are coated with a film coating agent comprising hydroxypropylmethylcellulose, polyethylene glycol-6000, castor oil and methanol to produce film-coated tablets.

Reference Example 1 To a solution of 1.2 g of 3-hydroxybenzaldehyde in 50 ml of N, N-dimethylformamide was added 2.4 g of 4-chlorobenzyl chloride and 2.1 g of potassium carbonate.
Stir at 0 ° C. for 3 hours. After cooling, this solution was separated with ethyl acetate-water, and the ethyl acetate layer was separated. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate = 10: 1) to obtain 1.9 g of 3- (4-chlorobenzyloxy) benzaldehyde.

Colorless needle-shaped ¹ H-NMR (CDCl ₃ ) δ ppm; 5.10 (2
H, s), 7.21 to 7.25 (1H, m), 7.38
(4H, s), 7.43 to 7.49 (3H, m), 9.
98 (1H, s).

Reference Example 2 To a solution of 10 g of 4-hydroxybenzoic acid in 100 ml of N, N-dimethylformamide, 29.1 g of 4-chlorobenzyl chloride and 25 g of potassium carbonate were added, and the mixture was stirred at 60 ° C. for 3 hours. After cooling, this solution was separated with ethyl acetate-water, and the ethyl acetate layer was separated. After washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was washed with n-hexane, collected by filtration, and then 50 ml of ethanol
Was suspended. 100 ml of 2N aqueous sodium hydroxide was added, and the mixture was stirred at room temperature for 4 days and then neutralized with concentrated hydrochloric acid. The precipitated crystals were collected by filtration and recrystallized from chloroform to give 4- (4-
16.7 g of chlorobenzyloxy) benzoic acid was obtained.

Colorless scale-like ¹ H-NMR (DMSO-d ₆ ) δ ppm; 5.14
(2H, s), 6.95 (2H, d, J = 8.5H
z), 7.47 (2H, d, J = 11 Hz), 7.52
(2H, d, J = 11 Hz), 7.87 (2H, d, J
= 8.5 Hz).

Reference Example 3 2- (4-chlorobenzyloxy) benzoic acid was obtained in the same manner as in Reference Example 2 using 2-hydroxybenzoic acid as a starting material.

Yellow prismatic ¹ H-NMR (CDCl ₃ ) δ ppm; 5.26 (2
H, s), 7.07 to 7,17 (2H, m), 7.39
(4H, s), 7.51 to 7.58 (1H, m), 8.
16 (1H, dd, J = 2.0Hz, J = 8.0H
z).

Reference Example 4 Using 3-hydroxybenzaldehyde as a starting material, the following compound was obtained in the same manner as in Reference Example 1.

3- (2-chlorobenzyloxy) benzaldehyde colorless granular ¹ H-NMR (CDCl ₃ ) δ ppm; 5.21 (2
H, s), 7.24 to 7.31 (3H, m), 7.39
~ 7.57 (5H, m), 9.98 (1H, s).

3- (3-chlorobenzyloxy) benzaldehyde colorless oil ¹ H-NMR (CDCl ₃ ) δppm; 5.10 (2
H, s), 7.22 to 7.33 (4H, m), 7.43
~ 7.52 (4H, m), 9.98 (1H, s).

3- (4-Fluorobenzyloxy) benzaldehyde Pink powdery ¹ H-NMR (CDCl ₃ ) δ ppm; 5.08 (2
H, s), 7.09 (2H, dd, J = 8.5 Hz, J
= 8.5 Hz), 7.22 to 7.26 (1H, m),
7.39 to 7.50 (5H, m), 9.98 (1H,
s).

3- (4-Bromobenzyloxy) benzaldehyde white powder ¹ H-NMR (CDCl ₃ ) δppm; 5.07 (2
H, s), 7.20 to 7.26 (1H, m), 7.30
~ 7.34 (2H, m), 7.42 ~ 7.55 (5H,
m), 9.97 (1H, s).

Reference Example 5 3- (4-chlorobenzyloxy) benzaldehyde 6
A solution of 2 g and 20 g of cyclopropylmethylamine in 750 ml of methanol was stirred at room temperature for 15 minutes. 12 g of sodium borohydride was gradually added to this solution under ice cooling. After the addition was completed, the mixture was stirred at the same temperature for 1 hour. The reaction solution was dissolved in 1 liter of chloroform, washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 81
g of 3- (4-chlorobenzyloxy) -N-cyclopropylmethylbenzylamine was obtained.

Yellow oily substance ¹ H-NMR (CDCl ₃ ) δ ppm; 0.06 to 0.
12 (2H, m), 0.44 to 0.51 (2H, m),
0.92-1.00 (1H, m), 1.55 (1H, m
m), 2.47 (2H, d, J = 7Hz), 3.79
(2H, s), 5.04 (2H, s), 6.81-6.
96 (3H, m), 7.24 (1H, dd, J = 8H
z, J = 8 Hz), 7.36 (4H, s).

Reference Example 6 In the same manner as in Reference Example 5 using appropriate starting materials, 3-
(4-chlorobenzyloxy) -N-methylbenzylamine was obtained.

Yellow oil ¹ H-NMR (CDCl ₃ ) δ ppm; 1.40 (1
H, bs), 2.45 (3H, s), 3.73 (2H,
s), 5.03 (2H, s), 6.82 to 6.95 (3
H, m), 7.24 (1H, dd, J = 8.0 Hz, J
= 8.0 Hz), 7.36 (4H, s).

Reference Example 7 To a solution of 2.1 g of 3- (4-chlorobenzyloxy) -N-methylbenzylamine and 3.4 ml of triethylamine in 50 ml of dichloromethane was added dropwise 1.0 ml of cyclobutylcarbonyl chloride under ice cooling. After stirring at room temperature for 1 hour, the reaction solution was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 3.1 g of 3- (4-chlorobenzyloxy) -N-cyclobutylcarbonyl-
N-methylbenzylamine was obtained.

Yellow oily substance ¹ H-NMR (CDCl ₃ ) δ ppm; 1.81-2.
53 (6H, m), 2.80, 2.90 (total 3H,
s), 3.20 to 3.48 (1H, m), 4.40,
4.54 (total 2H, s), 5.01 (2H, S), 6.
70 to 6.93 (3H, m), 7.19 to 7.33 (1
H, m), 7.35 (4H, s).

Reference Example 8 5 g of 4- (4-chlorobenzyloxy) benzoic acid was dissolved in 80 ml of thionyl chloride, heated under reflux for 1 hour, and thionyl chloride was distilled off under reduced pressure. The obtained residue was dissolved in 30 ml of dichloromethane, and this solution was added dropwise to a solution of 2.2 g of cyclopropylmethylamine and 10 ml of triethylamine in 100 ml of dichloromethane under ice cooling. 1 at room temperature
After stirring for an hour, the reaction solution was washed with 2N hydrochloric acid and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off.
Obtained 4.2 g of 4- (4-chlorobenzyloxy) -N-cyclopropylmethylbenzamide.

White powder ¹ H-NMR (CDCl ₃ ) δ ppm; 0.23 to 0.
30 (2H, m), 0.51 to 0.59 (2H, m),
1.00 to 1.15 (1H, m), 3.30 (2H, d
d, J = 5.5 Hz, J = 7.0 Hz), 5.07 (2
H, s), 6.09 to 6.21 (1H, m), 6.95.
˜7.00 (2H, m), 7.36 (4H, s), 7.
72-7.77 (2H, m).

Reference Example 9 2- (4-chlorobenzyloxy) -N-cyclopropylmethylbenzamide was obtained in the same manner as in Reference Example 8 using 2- (4-chlorobenzyloxy) benzoic acid as a starting material. .

White powder ¹ H-NMR (CDCl ₃ ) δ ppm; 0.02 to 0.
08 (2H, m), 0.29 to 0.37 (2H, m),
0.77 to 0.85 (1H, m), 3.22 (2H, d
d, J = 5.0 Hz, J = 7.0 Hz), 5.14 (2
H, s), 7.03 to 7.15 (2H, m), 7.38.
~ 7.48 (1H, m), 7.41 (4H, s), 7.
72 to 7.98 (1H, m), 8.24 (1H, dd,
J = 2.0 Hz, J = 8.0 Hz).

Reference Example 10 4- (4-chlorobenzyloxy) -N-cyclopropylmethylbenzamide (1.5 g) was dissolved in N, N-dimethylformamide (30 ml), and sodium hydride (0.25 g) was added.
g and stirred for 30 minutes at room temperature, then heated to 60 ° C,
It was stirred for another 30 minutes. After cooling with ice, 0.5 ml of methyl iodide was added to this solution, and the mixture was stirred overnight at room temperature. The reaction solution was separated with ethyl acetate-water, the ethyl acetate layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent was subjected to column chromatography (eluent;
Purify with dichloromethane: acetone = 50: 1),
Obtained 1.4 g of 4- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzamide.

Colorless oily substance ¹ H-NMR (CDCl ₃ ) δ ppm; 0.00-0.
40 (2H, m), 0.51 to 0.63 (2H, m),
0.88-1.11 (1H, m), 2.95-3.50
(5H, m), 5.05 (2H, s), 6.93-6.
97 (2H, m), 7.26 to 7.40 (2H, m),
7.37 (4H, s).

Reference Example 11 Reference example 1 using 2- (4-chlorobenzyloxy) -N-cyclopropylmethylbenzamide as a starting material
2- (4-chlorobenzyloxy)-
N-cyclopropylmethyl-N-methylbenzamide was obtained.

Slightly yellow oily substance ¹ H-NMR (CDCl ₃ ) δ ppm; −0.05 to
0.10, 0.23 to 0.37, 0.37 to 0.55
(Total 4H, m), 0.75 to 0.92, 0.92 to 1.
08 (total 1H, m), 2.88 to 3.25 (5H,
m), 5.07 to 5.14 (2H, m), 6.89 to
7.14 (2H, m), 7.25 to 7.45 (6H,
m).

Reference Example 12 The following compounds were obtained in the same manner as in Reference Example 5 using appropriate starting materials.

3- (2-chlorobenzyloxy) -N-
Cyclopropylmethylbenzylamine colorless oil ¹ H-NMR (CDCl ₃ ) δppm; 0.07-0.
13 (2H, m), 0.44 to 0.51 (2H, m),
0.92 to 1.10 (1H, m), 1.35 to 1.61
(1H, m), 2.48 (2H, d, J = 7.0H
z), 3.80 (2H, s), 5.17 (2H, s),
6.85-6.99 (3H, m), 7.25-7.32.
(3H, m), 7.38-7.42 (1H, m), 7.
55-7.59 (1H, m).

3- (3-chlorobenzyloxy) -N-
Cyclopropylmethylbenzylamine colorless oil ¹ H-NMR (CDCl ₃ ) δppm; 0.07-0.
12 (2H, m), 0.44 to 0.51 (2H, m),
0.50 to 1.08 (1H, m), 1.35 to 1.52
(1H, m), 2.48 (2H, d, J = 7.0H
z), 3.80 (2H, s), 5.04 (2H, s),
6.82-6.97 (3H, m), 7.21-7.30
(4H, m), 7.44 to 7.45 (1H, m).

3- (4-fluorobenzyloxy) -N
-Cyclopropylmethylbenzylamine colorless oil ¹ H-NMR (CDCl ₃ ) δppm; 0.07-0.
13 (2H, m), 0.44 to 0.51 (2H, m),
0.92 to 1.08 (1H, m), 1.40 to 1.70
(1H, m), 2.47 (2H, d, J = 7.0H
z), 3.80 (2H, s), 5.03 (2H, s),
6.83-6.97 (3H, m), 7.04-7.10.
(2H, m), 7.26 (1H, dd, J = 8.0H
z, J = 8.0 Hz), 7.38 to 7.44 (2H,
m).

3- (4-bromobenzyloxy) -N-
Cyclopropylmethylbenzylamine colorless oil ¹ H-NMR (CDCl ₃ ) δppm; 0.06-0.
12 (2H, m), 0.44 to 0.51 (2H, m),
0.91 to 1.06 (1H, m), 1.34 to 1.60
(1H, m), 2.47 (2H, d, J = 7.0H
z), 3.79 (2H, s), 5.02 (2H, s),
6.81 to 6.95 (3H, m), 7.20 to 7.33
(3H, m), 7.49 to 7.52 (2H, m).

Reference Example 13 The following compounds were obtained in the same manner as in Reference Example 8 using appropriate starting materials.

3- (4-chlorobenzyloxy) -N-
Cyclohexylmethylbenzamide white powdery ¹ H-NMR (CDCl ₃ ) δ ppm; 0.95-1.
11 (2H, m), 1.11 to 1.36 (3H, m),
1.56 to 1.90 (6H, m), 3.29 (2H, d
d, J = 6.5 Hz, J = 6.5 Hz), 5.06 (2
H, s), 6.18 to 6.29 (1H, m), 7.04
-7.09 (1H, m), 7.26 to 7.43 (3H,
m), 7.36 (4H, s).

3- (4-chlorobenzyloxy) -N-
Cyclopropylmethyl-N-propylbenzamide white powdery ¹ H-NMR (CDCl ₃ ) δppm; -0.01-
1.82 (10H, m), 3.00 to 3.63 (4H,
m), 5.05 (2H, s), 6.91 to 6.99 (3
H, m), 7.30 (1H, dd, J = 8.0 Hz, J
= 8.0 Hz), 7.35 (4H, s).

Reference Example 14 3- (4-chlorobenzyloxy) -N- in the same manner as in Reference Example 10 using 3- (4-chlorobenzyloxy) -N-cyclohexylmethylbenzamide as a starting material.
Cyclohexylmethyl-N-methylbenzamide was obtained.

Colorless oily substance ¹ H-NMR (CDCl ₃ ) δ ppm; 0.55 to 0.
72, 0.95 to 1.37, 1.52 to 1.85 (total 1
1H, m), 2.89, 3.04 (total 3H, s), 3.
06, 3.37 (total 2H, s), 5.05 (2H,
s), 6.92 to 6.99 (3H, m), 7.30 (1
H, dd, J = 8.5 Hz, J = 8.5 Hz), 7.3
6 (4H, s).

Example 1 80 g of 3- (4-chlorobenzyloxy) -N-cyclopropylmethylbenzylamine was added to 150 ml of formic acid and 3 g of formic acid.
Dissolve in a mixture of 150% 7% formaldehyde and dissolve in 3
Heated to reflux for an hour. After cooling to room temperature, 150 ml of concentrated hydrochloric acid was added to this solution, and the solvent was distilled off under reduced pressure. The obtained residue was separated with chloroform-aqueous sodium hydroxide, the chloroform layer was separated, washed with water, and then dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to obtain 86 g of 3- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzylamine as a brown oily substance.
I got

[0113] Of this, 3 g was made into hydrochloride and recrystallized from ethyl acetate to obtain 2.1 g of 3- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzylamine hydrochloride.

Colorless needles m. p. 119.0-121.0 ° C.

The compounds shown in Table 1 were obtained in the same manner as in Example 1 using appropriate starting materials.

[0116]

[Table 1]

Example 11 To a solution of 1.4 g of 4- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzamide in 50 ml of tetrahydrofuran was added 0.5 g of lithium aluminum hydride, and the mixture was heated under reflux for 3 hours. 2m water after cooling
1 was added and the mixture was stirred for 14 hours at room temperature. Filter the reaction,
The filtrate was partitioned with water-diethyl ether, the diethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the obtained residue was converted to oxalate, and recrystallized from ethanol to give 4- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzylamine oxalate 1 0.3 g was obtained.

White powder m. p. 154.0-154.5 ° C.

The compounds of Examples 1 and 3 to 10 were obtained in the same manner as in Example 11 using appropriate starting materials.

Example 12 4- (4-chlorobenzyloxy) benzaldehyde 6
To a solution of 2 g and 24 g of N-cyclopropylmethyl-N-methylamine in 750 ml of methanol, 12 g of sodium borohydride was gradually added under ice cooling, and after the addition was completed, the mixture was stirred for 1 hour at the same temperature. The reaction solution was dissolved in 1 liter of chloroform, washed with water, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the obtained residue was made into an oxalate,
Recrystallization from ethanol gave 84 g of 4- (4-chlorobenzyloxy) -N-cyclopropylmethyl-N-methylbenzylamine oxalate.

White powder m. p. 154.0 to 154.5 ° C Using the appropriate starting materials, the compounds of Examples 1 and 3 to 10 were obtained in the same manner as in Example 12.

Example 13 0.92 g of lithium aluminum hydride was added to a solution of 2.8 g of 3- (4-chlorobenzyloxy) -N-cyclobutylcarbonyl-N-methylbenzylamine in 50 ml of tetrahydrofuran, and the mixture was heated under reflux for 3 hours. . After cooling the reaction solution, 2 ml of water was added and stirred for 14 hours. After filtration, the filtrate was separated with water-diethyl ether, the diethyl ether layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a maleate salt, which was recrystallized from ethanol to give 1.9 g of 3- (4-chlorobenzyloxy).
-N-cyclobutylmethyl-N-methylbenzylamine maleate was obtained.

White powder m. p. 102.5-103.0 ° C.

The compounds of Examples 1 to 3 and 5 to 10 were obtained in the same manner as in Example 13 using appropriate starting materials.

Pharmacological test (1) Forced swimming test “Nature, Vol. 266, pp. 730-732 (1
977) ”and“ European Journal ”
of Pharmacology, Volume 47, 379
~ 391 page (1978) "was modified to carry out the experiment. That is, a transparent acrylic cylindrical water tank (inner diameter 2
Tap water (water temperature: approx. 25) at 9.5 cm and a height of 25 cm
C.) to a water depth of 11.3 cm, and male mice aged 7-8 weeks (weight: 30-35 g) are allowed to freely swim for 6 minutes,
The amount of swimming was measured. The amount of swimming was automatically measured by an infrared beam and a sensor that detects it, and the count was used as an index to indicate the depression state of the animal. That is, the higher the count number, the stronger the antidepressant action.

The mice were fasted 16 to 18 hours before the start of swimming, and the test compound and the solvent were orally administered 1 hour before the start of the experiment. The solvent used was 5% arabic gum physiological saline, and the test compound was suspended or dissolved in the solution before use. Control mice received only 5% gum arabic saline.

The results are shown in Table 2. Swimming amount in Table 2 (%)
Is the value when the control is 100%.

[0128]

[Table 2]

(2) Elevated plus maze test "Pharmacology Biochemistr"
y & Behavior, Volume 24, 525-52
Page 9 (1986) "and" Psychopharmac
92, 180-185 (198).
The test was conducted according to the method described in “7)”. The equipment consists of two facing open arms (25 x 5 cm; no walls around) and closed arms (25 x 5 cm; transparent acrylic walls 15 cm high on three sides) centered on a 5 x 5 cm platform. An acrylic maze with crosses was used. These four arms are 38c from the floor
Supported by a height of m. Four to five week old male mice (body weight: 20 to 24 g) fasted for 16 to 18 hours were placed on the open arms with their heads facing the open arms on the platform part of the device, and the mice in the device were kept for 5 minutes from that point. Observed behavior. There were two observation items: the number of times the robot entered the open arm and the number of times the robot entered the closed arm. As a parameter serving as an index of anxiolytic action, the frequency (%) of entering the open arm = the number of times of entering the open arm / (the number of times of entering the open arm + the number of times of entering the closed arm) × 100 was used. That is, the higher this value is, the stronger the anxiolytic effect is.

The test compound was suspended or dissolved in 5% gum arabic physiological saline and orally administered 1 hour before being placed in the device. Control mice received only 5% gum arabic saline.

The results are shown in Table 3. The numerical values of frequency (%) in Table 3 are values when the control is 100%.

[0132]

[Table 3]

(3) Evaluation of consciousness disorder improving effect in a head injury coma model "Nichijyo Izoku, Vol. 25, p. 202 (1977)" and "History of Medicine, Vol. 102, 867-" 869 pages (1
977)). That is, 4 to 5 week old male mice (weight 20 to 29 g)
After fasting for -20 hours, the head was fixed on a polystyrene foam pillow, and an acrylic columnar rod was dropped along the transparent plastic tube onto the crown of the mouse to give an impact. The observation of impaired consciousness was performed by observing the following two points. That is, there are two points, a time until the righting reflex is recovered from the coma after the impact (RR time) and a time until the spontaneous movement recovers (SM time). The test compound was suspended or dissolved in 5% gum arabic physiological saline and orally administered 1 hour before anesthesia loading. Control mice received only 5% gum arabic saline. The consciousness disorder improving effect of the test compound was evaluated by the ratio (% control) of the RR time or SM time of the test compound-administered mouse to the RR time or SM time of the control mouse. As a result, the compound of the present invention was found to have a significant consciousness disorder improving effect.

(4) Condition suppression test of mouse behavioral amount In this test, male ddy mice (7 to 8 weeks old, weight: 30 to 35 g) were used. 30x30x2 on the first day
Put the mouse in a transparent acrylic experiment box with a 9 cm grid on the floor, and shock it (AC100V × 3A,
(200 mse, 0.1 Hz) was applied from the floor grid for 6 minutes. On the second day, the mouse was returned again to the same device, and only the amount of activity was measured by the photoelectric momentum measuring device surrounding the device without giving an electric shock (condition suppression group). The mice in the control group were treated in the same manner as in the condition-suppressed group except that no electric shock was given on the first day. 5 test compounds
% Gum arabic-group suspended in physiological saline or dissolved only in physiological saline, orally administered 30 minutes to 1 hour before the measurement of the amount of activity on the second day, and administered with only each solvent (solvent control group) Compared to the parameters of. The parameters of this test correspond to the amount of activity on the second day (counting number of the measuring device).

In the above test, when a mouse that has undergone an electric shock is returned to the same place as when the electric shock was received again, the mouse remembers its environment, and this causes stress, resulting in a marked decrease in the amount of exercise. The compounds of the present invention were effective in restoring this decreasing momentum.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Atsushi Mori Atsushi Mori, 5-9 Miyake Building, 4-9-3 Sumiyoshi, Tokushima City, Tokushima Prefecture (72) Inventor Takao Nishi Taro Hachisu, Kitajima-cho, Itano-gun, Tokushima Prefecture 28 at 2

Claims (11)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a lower alkyl group. R ² represents a cycloalkyl group. R ³ represents a halogen atom. ] The benzylamine derivative represented by these, or its salt. Wherein R ¹ is a methyl group or an ethyl group, R ² starve
Chloropropyl or cyclobutyl group, R ³ is chlorine atom
And the substitution position of R ³ is the 4-position on the benzene ring.
Item 1. A benzylamine derivative or a salt thereof according to item 1. 3. 3- (4-chlorobenzyloxy) -N
-Cyclopropylmethyl-N-methylbenzylamine
Is its salt. 4. A benzylamine derivative according to claim 1.
And at least one selected from the group consisting of salts thereof.
Antidepressant / Anxiolytic agent that has. 5. The benzylamine derivative according to claim 1.
And at least one selected from the group consisting of salts thereof.
A central nerve activator having. 6. A benzylamine derivative according to claim 1.
And at least one selected from the group consisting of salts thereof.
A consciousness disorder improving agent. 7. A benzylamine derivative according to claim 1.
And at least one selected from the group consisting of salts thereof.
A sigma receptor agonist having. 8. A benzylamine derivative according to claim 3.
And at least one selected from the group consisting of salts thereof.
Antidepressant / Anxiolytic agent that has. 9. A benzylamine derivative according to claim 3.
And at least one selected from the group consisting of salts thereof.
A central nerve activator having. 10. A benzylamine derivative according to claim 3.
At least one selected from the group consisting of the body and its salts
Consciousness disorder improving agent contained. 11. A benzylamine derivative according to claim 3.
At least one selected from the group consisting of the body and its salts
A sigma receptor agonist containing.