KR950008530B1 - Substituted benzamide derivatives, process for the preparation thereof, and pharmaceutical compositions, containing the same - Google Patents

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Description

Substituted benzamide derivatives, preparation method thereof and pharmaceutical composition containing same

The present invention relates to a novel substituted benzamide derivative having a digestive tract hyperactivity, a method for preparing the same, a method for using the same, and a pharmaceutical composition containing the compound as an active ingredient.

N-[(4-lower alkyl-2 (or 3) -morpholinyl) methyl] benzamide derivatives have reserpin antagonism, analgesic action, etc. and are useful as antidepressants or analgesics. No. 1987 (not audited).

On the other hand, 4-amino-5-chloro-N-[(2-diethylamino) ethyl] -2-methoxybenzamide (common name: metoclopride, Merck index, 10th edition, 6019 ( Since the mid-1960s, when a) was developed as an antiemetic or anti-digestive agent, various benzamide derivatives have been synthesized and their pharmacological properties have been investigated. However, no substituted benzamide derivatives with activity superior to that of metoclopramide as digestive tract dysfunctions have yet been found.

The present inventors have studied extensively to obtain novel substituted benzamide derivatives having excellent digestive tract hyperactivity, and the 2-position of the morpholine or hexahydro-1, 4-oxazepine group by the alkylene group of the nitrogen atom of the amide moiety It has been found that substituted benzamide derivatives bound to carbon atoms in C show a desired activity, and furthermore, some of these substituted benzamide derivatives show more potent digestive tract function but are more detrimental to the central nervous system than the effects of metoclopramide. It was found to indicate less.

It is an object of the present invention to provide novel substituted benzamide derivatives having good digestive tract hyperactivity. Another object of the present invention is to provide a method for preparing the compound. It is another object of the present invention to provide a pharmaceutical composition containing as an active ingredient the compound described above useful as an anti-digestive tract function.

These and other objects of the present invention will become apparent to those skilled in the art by the following description.

Substituted benzamide derivatives of the present invention are compounds having the following general formula.

Wherein R is hydrogen, C ₂ -C ₅ alkoxycarbonyl, benzyloxycarbonyl, heteroaryl is furyl, thienyl, pyridyl, or heteroaryl (C ₁ -C ₃₎ ) Alkyl, phenyl (C ₃ -C ₅ ) akenyl, or -T- (Y) pR ₆ , wherein T is a single bond or C ₁ -C ₆ alkylene, Y is oxygen, sulfur, or carbonyl, R ₆ is phenyl, each independently substituted with 1 to 5 members selected from the group consisting of halogen, C ₁ -C ₄ alkyl, trifluoromethyl, C ₁ -C ₄ alkoxy, nitro, cyano and amino , Naphthyl or diphenylmethyl, p is 0 or 1 but P is 0 if T is a single bond) and R ₁ is halogen, hydroxy, C ₁ -C ₁₂ alkoxy, C ₃ -C ₆ cycloalkyloxy , C ₃ -C ₈ alkenyloxy, C ₃ -C ₈ alkynyloxy, C ₂ -C ₈ alkoxy, C ₁ -C ₄ alkylthio, amino, substituted with one or two oxygen or carbonyl, C ₁ -C ₈ alkyl, phenyl (C Mono-substituted amino which is _1- C ₃ ) alkyl or C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkoxy wherein the carbon atom at a position other than 1-position is substituted with one hydroxy or amino, or the substituent is halogen, Cyano, C ₂ -C ₅ alkoxycarbonyl, phthalimido, C ₃ -C ₆ cycloalkyl, phenyl optionally substituted with one halogen, phenoxy optionally substituted with one halogen, or one halogen Optionally substituted benzoyl substituted C ₁ -C ₆ alkoxy, R ₂ is hydrogen, R ₃ is hydrogen, halogen, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₅ alkanoylamino, or nitro, R ₄ is hydrogen, halogen, nitro, sulfamoyl, C ₁ -C ₄ alkylsulfamonyl, or di (C ₁ -C ₄ alkyl) sulfamoyl, or R ₁ , R _2, R ₃ and R ₄ any two adjacent groups are combined to form a C ₁ -C ₃ alkylenedioxy group remaining number, each of the two And, R ₅ is hydrogen or C ₁ -C ₄ alkyl, X is C ₁ -C ₃ alkylene, and m and n are each 1 or 2, with the proviso that, R _2, R ₃ and R ₄ at least one lifter Dogs are not hydrogen.

The present invention also provides pharmaceutically acceptable acid addition salts, quaternary ammonium salts, and N-oxide derivatives of this compound.

Pharmaceutically acceptable acid addition salts of this compound (1) are, for example, inorganic acid addition salts (i.e. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.) and organic acid addition salts (i.e. oxalate, maleate, fumarate) , Lactate, maleate, citrate, tartarate, benzoate, bentansulfonate, and the like).

Pharmaceutically acceptable quaternary ammonium salts of compound (I) mean pharmaceutically acceptable ammonium salts of compounds of formula (I) wherein R is other than hydrogen, alkoxycarbonyl, or benzyloxy carbonyl, e.g. lower alkyl Halides (such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, etc.), lower alkyl lower alkylsulfonates (such as methylmethanesulfonate, ethylmethanesulfonate, etc.), lower alkyl arylsulfonates (such as methyl p-toluenesulfo Quaternary ammonium salts such as Nate et al.

N-oxide derivatives of compound (I) are those in which R is hydrogen, alkoxycarbonyl, benzyloxycarbonyl, thienyl alkyl, pyridyl alkyl, or -T'-SR ₆ (R ₆ is as defined above and T 'is alkyl Renim) and R ₁ is other than alkylthio, meaning an N-oxide derivative of the compound of formula (I).

Since compound (I), its acid addition salt, its quaternary ammonium salt, and its N-oxide derivative may optionally be present in the form of a hydrate or solvate, the hydrate and solvate are also included in the present invention.

Compounds of formula (I) contain one or more asymmetric carbon atoms, so the compounds exist in the form of various stereoisomers. The present invention also includes these stereoisomers and mixtures thereof and racemic compounds.

As used herein, the meanings of atoms or groups are as follows.

The alkyl group, alkyl moiety, alkylene group or alkylene moiety comprises a straight or branched chain group. "Alkoxycarbonyl" includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like. "Alkylene" includes, for example, methylene, ethylene, methylmethylene, trimethylene, propylene, dimethylmethylene, tetramethylene, pentamethylene, hexamethylene and the like. "Halogen" includes fluorine, chlorine, bromine, and iodine, with fluorine, chlorine and bromine being preferred. "Alkyl" includes, by way of example, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like. "Alkoxy" is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy, heptyloxy, octyl Oxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy and the like. "Cycloalkyl" includes, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. "Alkenyloxy" means a group having one double defect at a position other than a carbon atom adjacent to an oxygen atom, for example allyloxy, 2-butenyloxy, 3-butenyloxy, 3-methyl-2-butene Yloxy, 3- or 4-pentenyloxy, 4- or 5-hexenyloxy, 6-heptenyloxy and the like. "Alkynyloxy" means a group having one triple bond at a position other than a carbon atom adjacent to an oxygen atom, and includes, for example, 2-propynyloxy, 3-butynyloxy, 5-hexynyloxy, and the like. . "Alkoxy interrupted by one or two oxygen or carbonyl" is, for example, 2-methoxymethoxy, (2-methoxyethoxy) methoxy, 2, 2-dimethoxyethoxy, 2-oxopropoxy , 3-oxobutoxy and the like. "Alkanoylamino" includes, for example, acetyl amino, propionylamino, butyrylamino, isobutyrylamino, and the like.

(여기서 Y와 p는 상기 설명한 바와 같고, R₇은 수소, 플루오로, 염소 트리플루오로메틸, 시아노, 또는 니트로이고, q는 1 내지 4의 정수임), 펜타플루오로벤질, 2-니트로-4-클로로벤질, 1-페닐에틸 또는 나프틸메틸이고, R₁은 히드록시 C₁-C₁₀알콕시, C₅-C₆시클로알킬옥시, C₃-C₅알케닐옥시, C₃-C₅알키닐옥시, 1개의 카르보닐로 중단된 C₂-C₄알콕시, 1-위치 외의 위치에 있는 탄소원자가 1개의 히드록시로 치환된 C₂-C₅알콕시, 또는 치환기가 할로겐, 시아노, C₂-C₄알콕시 카르보닐, C₃-C₅시콜로알킬, 1개의 할로겐으로 선택적으로 치환된 페닐, 하나의 할로겐으로 선택적으로 치환된 페녹시, 또는 1개의 할로겐으로 선택적으로 치환된 벤조일인 치환 C₁-C₅알콕시이고, R₂는 수소이고, R₃은 아미노, 디(C₁-C₂알킬) 아미노, 또는 C₂-C₅알카노일아미노이고, R₅는 수소 또는 메틸이고, X는 메틸렌 또는 에틸렌이고 m은 1이고, n은 1 또는 2인 일반식(I)의 화합물, 그 약학적 허용 산부가염, 그 4급 암모늄염, 및 그 N-산화물 유도체이다.Among the compounds of the present invention, it is preferred that R is pyridylmethyl,-(CH2) q--(Y)

Where Y and p are as described above, R ₇ is hydrogen, fluoro, chlorine trifluoromethyl, cyano, or nitro, q is an integer from 1 to 4), pentafluorobenzyl, 2-nitro- 4-chlorobenzyl, 1-phenylethyl or naphthylmethyl, R ₁ is hydroxy C ₁ -C ₁₀ alkoxy, C ₅ -C ₆ cycloalkyloxy, C ₃ -C ₅ alkenyloxy, C ₃ -C ₅ alkynyloxy, a C ₂ -C ₄ alkoxy interrupted by one carbonyl, a 1-position carbon atom in a position other than the self-substituted by one hydroxy-C ₂ -C ₅ alkoxy group, or the substituent is halogen, cyano, C ₂ -C ₄ alkoxy carbonyl, C ₃ -C ₅ cycloalkyl, phenyl optionally substituted with one halogen, phenoxy optionally substituted with one halogen, or benzoyl optionally substituted with one halogen a C ₁ -C ₅ alkoxy, R ₂ is hydrogen, R ₃ is amino, di (C ₁ -C ₂ alkyl) amino, or C ₂ -C ₅ alkanoyl amino And, R ₅ is hydrogen or methyl, X is methylene or ethylene and m is 1, n is 1 or 2. A compound of formula (I), the pharmaceutically acceptable acid addition salts, the quaternary ammonium salts, and the N Oxide derivatives.

More preferred compounds are compounds of the following general formula, their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts, and their N-oxide derivatives.

Wherein R _a is pyridylmethyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, cyanobenzyl, or 3- (4-chlorophenoxy) propyl, and R _1a is C ₁ -C ₇ Alkoxy, cyclopentyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 2-oxopropoxy, 2-hydroxypropoxy, or 2-chloromethoxy, R ₃ ′ is amino, dimethyl Amino, or C ₂ -C ₃ alkanoylamino, R 5 ′ is hydrogen or methyl, and n is 1 or 2.

Particularly preferred compounds are compounds of the following general formula, pharmaceutically acceptable acid addition salts thereof, and N-oxide derivatives thereof.

Wherein R _b is pyridylmethyl, benzyl, fluorobenzyl, chlorobenzyl, or 3- (4-chlorophenoxy) propyl, and R _1b is methoxy, ethoxy, butoxy, isobutoxy, pentyloxy, Isopentyloxy, 3-methyl-2-butenyloxy, or 2-hydroxypropoxy.

Particular examples of particularly preferred compounds are the following compounds and their pharmaceutically acceptable acid addition salts.

4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide,

4-amino-5-chloro-2-ethoxy-N-[[4- (3-pyridyl) methyl-2-morpholinyl] methyl] benzamide,

4-amino-N-[(4-benzyl-2-morpholinyl] methyl] -5-chloro-2- (3-methyl-2-butenyloxy) benzamide,

4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -2-butoxy-5-chlorobenzamide,

4-amino-2-butoxy-5-chloro-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide,

4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-isopentyloxybenzamide,

4-amino-5-chloro-N-[[4- (2-chlorobenzyl) -2-morpholinyl] methyl] -2-ethoxybenzamide,

4-amino-N-[(4-benzyl-2-morpholinyl] methyl] -5-chloro-2-ethoxybenzamide,

4-amino-N- [4-benzyl-2-morpholinyl] methyl] -5-chloro-2-methoxybenzamide,

4-amino-5-chloro-N-[[4- (4-cyanobenzyl) -2-morpholinyl] methyl] -2-methoxybenzamide, and

4-amino-5-chloro-N-[[4- (3- (4-chlorophenoxy) propyl) -2-morpholinyl] methyl] -2-methoxybenzamide,

The compounds of the present invention can be prepared by several methods, for example by the following method.

Method (a):

The compound of general formula (I) can be prepared by reacting a compound of general formula (II) or a reactive derivative thereof with a compound of general formula (III).

Wherein R ₁ , R ₂ , R ₃ and R ₄ are as defined above.

Wherein R ₅ , X, m and n are as defined above and R ′ is the same as R except for hydrogen.

And when the compound of formula (I) wherein R is C ₁ -C ₅ alkoxycarbonyl, benzyloxycarbonyl, or benzyl is obtained, the above groups can be optionally removed from the product.

Reactive emulsions of compound (II) include, for example, active esters, acid anhydrides, acid halides (particularly acid chlorides), and lower alkyl esters. Suitable examples of active esters include p-nitrophenyl ester, 2, 4, 5-trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide, Ester, 1-hydroxy benzotriazole ester, N-hydroxy-5-norbornene-2, 3-dicarboxyimide ester, N-hydroxy piperidine ester, 8-hydroxyquinoline ester, 2-hydrate Hydroxyphenyl esters, 2-hydroxy-4, 5-dichlorophenyl esters, 2-hydroxypyridine esters, 2-pyridylthiol esters and the like. Acid anhydrides include symmetric acid anhydrides and mixed acid anhydrides. Suitable examples of mixed acid anhydrides include mixed acid anhydrides with alkyl chloroformate (such as ethyl formate, chloroformate isobutyl, etc.), mixed acid anhydrides with aralkyl chloroformate (such as benzyl chloroformate), and aryl chloroformate. Mixed acid anhydrides (such as phenyl chloroformate), and mixed acid anhydrides (such as isovaleric acid and pivalic acid) with alkanoic acid.

When compound (II) is used, the reaction may proceed in the presence of a condensing agent, which may be dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, 1-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline, and the like.

When dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride is used as a condensing agent, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydride Reagents such as oxy-4-oxo-3, 4-dihydro-1, 2, 3-benzotriamine, or N-hydroxy-5-norbornene-2, 3-dicarboxyimide are added to the reaction system. do.

The reaction of compound (II) or its reactive derivatives with compound (III) is carried out in a suitable solvent or without the use of a solvent. Suitable solvents are selected according to the type of starting compound, for example aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), ethers (such as diethylether, diisopropylether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (Such as dichloromethane, chloroform, etc.), ethyl acetate, acetonitrile, dimethilformamide, dimethyl sulfoxide, ethylene glycol, water, and the like. These solvents are used alone or in combination of water or more. If the acid is liberated in the course of the reaction, this reaction may optionally be carried out in the presence of a base. Suitable examples of bases include alkali metal bicarbonates (such as sodium bicarbonate, gallium bicarbonate, etc.), alkali metal carbonates (such as sodium carbonate, potassium carbonate, etc.), and organic bases (such as triethylamine, tributylamine, diisopropylethylamine, N Methyl morpholine). Compound (III) may be used in excess to form a base. The reaction temperature may vary depending on the type of starting compound, but is usually in the range of about -30 to 200 ° C, preferably about -10 to 150 ° C, and the reaction time is usually in the range of 1 to 48 hours.

When compound (II) has a functional group such as aliphatic amino that interferes with the reaction, it is preferable to block the functional group in advance with a suitable protecting group such as lower alkanoyl (such as acetyl). This protecting group can be removed after the reaction.

When a compound of formula (I) wherein R is C ₂ -C ₅ alkoxycarbonyl, benzyloxycarbonyl, or benzyl is obtained by the method (a), this group is removed so that R is hydrogen. To produce a compound. Removal of these groups can be done by conventional methods. For example, when R is alkoxycarbonyl, the product is hydrolyzed under alkaline conditions and when R is benzyloxycarbonyl or benzyl, the product is hydrolyzed. Hydrolysis under alkaline conditions is carried out by using a base in a suitable solvent. Solvents include, for example, alcohols (such as methanol, ethanol, isopropanol, etc.), dioxane, water, or mixtures thereof. Bases include, for example, alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, and the like). Hydrolysis is usually carried out at a temperature of about 50 to 100 ° C. for 0.5 to 24 hours. Hydrolysis can be done in a suitable solvent in the presence of a catalyst. Solvents include, for example, alcohols (such as methanol, ethanol, isopropanol, etc.), ethyl acetate, acetic acid, dioxane, water, or mixtures thereof. The catalyst is, for example, palladium on carbon. Hydrogen decomposition is usually carried out for 1 to 4 hours at a temperature of about 20 to 80 ℃.

When a compound of formula (I) wherein R ₃ is C ₂ -C ₅ alkanoylamino is obtained by the above method (a), the product is hydrolyzed under acidic or alkaline conditions, where R ₃ is amino. The compound of can be produced. Alkanoyl groups can be easily removed. For example, R ₃ may have to obtain the compound of the alkanoylamino The compound (Ⅱ) lower alkyl when the reaction with the compound (Ⅲ) at 120~150 ℃ ester, R ₃ is an amino of general formula (I) of the.

Many starting compounds (II) are known and described in literature, such as French Patents 1,307,995, US Patents 3,177,252, 3,342,826 and 3,892,802, British Patents 1,153,796, European Patents 76,530 and 102,195, and J. Chem. It is readily prepared by the methods disclosed in Soc., 1863, 4666. The novel compound (II) can also be prepared by this known method or by the methods disclosed in 80, 81 and 83 to 87 in the reference examples described below.

Starting compounds (III) are novel and can be prepared, for example, by the methods disclosed in Reference Examples 1, 3 to 6, 56, 58, 60 to 76 and 79 described below.

Method (b):

The compounds of formula (Ic) can be prepared by chlorinating the compounds of formula (IV) and then removing the alkanoyl groups from the product.

Wherein R _b is as defined above and R _1c is methoxy, ethoxy, butoxy, isobutoxy, pentyloxy, or isopentyloxy.

Wherein R _b and R _1c are as defined above and R ₃ ″ is alkanoyl amino of C ₂ -C ₅ .

Firstly the chlorination step can be carried out by known methods, for example by reacting compound (IV) with a chlorinating agent in a suitable solvent. Chlorinating agents include, for example, N-chlorosuccinimide, iodobenzene dichloride, t-butyl hypochlorite and the like. The solvent varies depending on the type of chlorinating agent and the like, and examples thereof include halogenated hydrocarbons (such as dichloromethane, chloroform, 1, 2-dichloroethane, etc.), ethers (such as tetrahydrofuran, etc.), acetonitrile, dimethylformamide, Pyridine and the like. Although reaction temperature changes with kinds of chlorinating agents etc., it is usually the range of about -20-100 degreeC, and reaction time is the range of 124 hours normally.

Removal of alkanoyl groups from chlorinated products is done by hydrolysis or by treatment with organic amines. Hydrolysis is carried out in a suitable solvent under acidic or alkaline conditions. Solvents include, for example, alcohols (such as methanol, ethanol, isopropanol, etc.), dioxane, water, or mixtures thereof. Acids include inorganic acids (such as hydrochloric acid), and bases include alkali metal hydroxides (such as sodium hydroxide, potassium hydroxide, etc.), alkali metal carbonates (such as sodium carbonate, potassium carbonate, etc.), and the like. Treatment of the chlorinated product with organic amines is done in the presence or absence of a solvent. Solvents include, for example, aromatic hydrocarbons (such as benzene, toluene, etc.), ethers (such as tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (such as dichloromethane, chloroform, etc.), alcohols (such as methanol, ethanol, isopropanol, etc.), ethyl acetate , Acetonitrile and the like. Organic amines include, for example, lower alkylamines (such as methylamine, ethylamine, etc.), di (lower alkyl) amines (such as dimethylamine, diethylamine, etc.), and the like. Removal of the alkanoyl group is usually carried out for 30 minutes to 8 hours at a temperature of about 20 to 100 ° C.

Starting compound (IV) is prepared, for example, by reacting a suitable 4-alkanoylamino-2-alkoxybenzoic acid or a reactive derivative thereof with the appropriate 2-aminomethyl-4-substituted morpholine in the same manner as in the above method (a). Can be.

Method (c):

It can also be prepared by reducing the compound of formula (V) to compound (Ic).

Wherein R _b and R _1c are as defined above.

The reduction reaction can be carried out by conventional methods, for example by reacting compound (V) with a reducing agent in a suitable solvent. Reducing agents include metals (eg, tin, zinc, iron, etc.) or combinations of metal salts (eg, tin chloride, etc.), acids (eg, hydrochloric acid, acetic acid, etc.), and the like. Tintin chloride may be used alone as a reducing agent. Alternatively, the reduction reaction can also be carried out by hydrogenating compound (V) in the presence of a catalyst in a solvent. Suitable examples of catalysts include palladium on carbon and the like. Suitable solvents are selected according to the type of reducing agent or reduction method and include, for example, alcohols (such as methanol, ethanol, isopropanol, etc.), ethyl acetate, acetic acid, dioxane, water or mixtures thereof.

The reaction temperature varies depending on the type of reducing agent or reduction method, but is usually in the range of about 10 to 100 ° C., and in the case of catalytic hydrogenation, the range of about 10 to 50 ° C. is preferable. The reaction time is usually in the range of 1 to 24 hours.

The starting compound (V), for example, reacts a suitable 2-alkoxy-5-chloro-4-nitrobenzoic acid or a reactive derivative thereof with the appropriate 2-aminomethyl-4-substituted morpholine in the same manner as in the above method (a). Can be prepared by 2-alkoxy-5-chloro-4-nitrobenzoic acid can be prepared, for example, by the method disclosed in British Patent No. 1,153,796.

Method (d):

Compound Rule (Ic) can also be produced by reacting a compound of the following general formula (VI) with a compound of the following general formula (VII).

Wherein R _b is as defined above.

ZR ₈ (Ⅶ)

Wherein R ₈ is methyl, ethyl, butyl, isobutyl, pentyl or isopentyl and Z is a reactive ester moiety of the alcohol.

In general formula, the reactive ester moiety of the alcohol defined by Z is, for example, a halogen source (such as chlorine, bromine or iodine), lower alkylsulfonyloxy (such as methanesulfonyloxy, ethanolsulfonyloxy, etc.), aryl Sulfonyloxy (such as benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy and the like), lower alkoxysulfonyloxy (such as methoxysulfonyloxy, ethoxysulfonyloxy and the like) and the like. .

The reaction is usually carried out in a suitable solvent in the presence of a base. Suitable examples of bases include alkali metal carbonates (such as sodium carbonate, potassium carbonate, etc.), quaternary ammonium hydroxides (such as tetrabutyl ammonium hydroxide, benzyltriethyl ammonium hydroxide, etc.), alkali metal alkoxides (such as sodium methoxide, potassium ethoxide, etc.). ), Alkali metal hydrides (such as sodium hydride, potassium hydride and the like). Suitable solvents are selected according to the type of starting compound, base, and the like, and examples thereof include dichloromethane, acetone, acetonitrile, methanol, ethanol, isopropanol, diglyme, dimethylformamide, dimethylacetamide, and the like. When a compound of the general formula (Z) wherein Z is chlorine or bromine is used, the reaction can proceed more smoothly by adding alkali metal iodide (such as sodium iodide, potassium iodide, etc.) to the reaction system.

Alternatively, the reaction can also be carried out in the presence of a strong base (such as sodium hydroxide, potassium hydroxide, etc.) and a phase transfer catalyst in a phase transfer solvent system such as dichloro methane-water. Suitable examples of phase transfer catalysts include tetrabutylammonium bromide, cetyltrimethylammonium bromide, benzyltri ethylammonium chloride, tetrabutylammonium sulfite and the like.

The reaction temperature varies depending on the type of starting compound and the like, but is usually in the range of about 5 to 150 캜, and the reaction time is usually in the range of 5 to 48 hours.

As the starting compound (VI), for example, 2-acetoxy-4-acetylamino-5-chlorobenzoic acid or a reactive derivative thereof is appropriate 2-aminomethyl-4-substituted morpholine in the same manner as in the method (a). And the resulting product can then be hydrolyzed to produce. Compound (VI) can also be prepared by demethylating the corresponding 2-methoxy compound with sodium ethanethiolate in dimethylformamide or with boron tribromide in dichloromethane.

Compound (I) prepared by the above methods can be separated and purified by conventional techniques, i.e. by chromatography, recrystallization or reprecipitation.

Compound (I) may be obtained in the form of an organic base, an acid addition salt, a hydrate, or a solvate depending on the kind of starting compound, reaction and treatment conditions, and the like. Acid addition salts can be converted to the free base by treating it with a base such as an alkali metal hydroxide or an alkali metal carbonate as usual. On the other hand, the free base can be converted into an acid addition salt by treating it with various acids as usual. For example, an acid addition salt of compound (I) is obtained by reacting a compound of formula (I) with an appropriate acid in a solvent and purifying the reaction product by recrystallization or reprecipitation. Solvents include, for example, chloroform, acetone, methanol, ethanol, isopropanol, water or mixtures thereof. The reaction temperature is usually in the range of about 0 to 80 캜, and the reaction time is usually in the range of 30 minutes to 48 hours.

Compounds of formula (I) wherein R is other than hydrogen, alkoxycarbonyl, or benzyloxycarbonyl are converted to their quaternary ammonium salt in a conventional manner. This quaternization reaction is carried out by reacting compound (I) with an appropriate quaternizing agent in the presence or absence of a solvent. Examples of the solvent include aromatic hydrocarbons (such as benzene, toluene, xylene, etc.), ketones (such as acetone, methyl, ethyl ketone, methyl isobutyl ketone, etc.), acetonitrile, or mixtures thereof. Although reaction temperature changes with kinds of compound (I) and a quaternization agent, it is usually the range of about 10-130 degreeC, and reaction time is the range of 1-72 hours normally.

Compounds of formula (I) wherein R is hydrogen, alkoxycarbonyl, benzyloxycarbonyl, thienylalkyl, pyridylalkyl, or R ₆ and T 'are -T'-SR ₆ as defined above are conventional It can be converted into its N-oxide derivative by the method. The N-oxidation reaction is carried out by reacting compound (1) with a suitable oxidizing agent in a solvent. Examples of the oxidizing agent include hydrogen peroxide and organic peracids (such as peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, etc.). Suitable solvents are selected depending on the type of oxidant, which is, for example, water, acetic acid, alcohols (such as methanol, ethanol, etc.), ketones (such as acetone, etc.), ethers (such as diethyl ether, dioxane, etc.), halogenated hydrocarbons (such as dichloro Methane, chloroform and the like). Although reaction temperature changes with kinds of oxidizing agent, it is the range of 0-100 degreeC normally, and reaction time is the range of 1-72 hours normally.

The pharmacological action of the compounds of the present invention is exemplified by the results of the following experiments, which were carried out on representative compounds of the present invention.

Reference compounds used in this experiment are as follows.

A: metoclopramide hydrochloride monohydrate, and

B: N-[(4-ethyl-2-morpholinyl) methyl] -2-methoxy-benzamide fumarate.

B is disclosed in Japanese Patent Laid-Open No. 90274/1978 described above.

Test Example 1; Gastric hyperactivity

This test was performed according to the method of Scarpignato et al. (See Arch. Int. Pharmacodyn., 246, 286-294 (1980)).

Before realizing a Wistar rat male weighing 130-150 g, starve for 18 hours and orally administer 1.5 ml of test food (1.5% methylcellulose solution containing 0.05% phenol red). 15 minutes after injection of the test food, the stomach is removed and the amount of phenol red remaining in the stomach is measured.

Test compounds dissolved or suspended in 0.5% tragacanth solution are administered orally 60 minutes prior to administration of the test food. The gastric emptying rate is calculated according to the amount of phenol red remaining in the stomach, and the action of the test compound is expressed in comparison with the meaning of the increase of the emptying rate. The number of animals used is 5 for the control group and the metoclophate hydrochloride monohydrate group and 4 for the other test compound group. The results are shown in Table 1.

Gastric emptying

TABLE 1

*) This means the compound of Example 1 (1) (hereinafter same).

As shown in Table 1, the compounds of the present invention showed potent gastric emptying at doses up to 2.0 mg / kg. This effect is stronger than that of metoclopramide hydrochloride monohydrate. Compound B, on the other hand, had no effect at the dose of 10.0 mg / kg.

Test Example 2; Acute Toxicity

DdY rat males weighing 18-25 g were used in groups of 10 each. Test compounds dissolved or suspended in 0.5% tragacanth solution were orally administered to the animals at predetermined doses. The number of dead for 7 days after the administration was observed and the results are shown in Table 2.

Test Example 3; Central action (CNS effect)

Three male ddY rats each weighing 18-25 g were used. According to the Irwin method (see Psychopharmacologia, 13. 222-257 (1968)), changes in general behavior and dissolution in 0.5% tragacanth solution or oral administration with 100 mg / kg of suspension test compound The disease state was observed. The overall strength of each analytical effect, such as during systemic stiffness, ptosis, and motion changes, was comprehensively determined, and the trend of the test compound for Chungju was shown in the following four-step evaluation.

- : no effect

+: Slightly effective

++: moderate effect

+++: has significant effect

TABLE 2

*) This means the compound of Example 1 (1) (hereinafter same).

As shown in Table 2, the CNS effect and acute toxicity of the compounds of the present invention are weaker than metoclolide hydrochloride monohydrate. These data suggest that the compound has a good separation point between the dose for gastric emptying and the dose for reverse CNS effect.

As will be apparent from the above experimental results, the compound of formula (I) and its pharmaceutically acceptable acid addition salts, quaternary ammonium salts, or N-oxide derivatives are useful as digestive tract inhibitors, because they have excellent anti-digestive action with less toxicity. Do. They can be used for the treatment and prevention of anorexia, nausea, vomiting, and bloating caused by diseases such as acute and chronic gastritis, gastric and duodenal ulcer, gastric neuropathy and gastric drainage, and for the treatment and prevention of esophageal, biliary tract disease and constipation. . Furthermore, they can also be used to treat and prevent nausea and vomiting when cisplatin and anticancer drugs are administered.

The compound of formula (I) and its pharmaceutically acceptable acid addition salts, quaternary ammonium salts, or N-oxide derivatives may be administered by oral administration, parenteral administration, or rectal administration. The dosage of Compound (I) and its pharmaceutically acceptable salts or N-oxide derivatives depends on the type of compound, the route of injection, the symptoms and the age of the patient, but is usually in the range of 0.001-20 mg / kg body weight per day on an adult basis. Preferably it is the range of 0.004-5 mg. This dosage may be administered twice or several times a day.

Compounds of formula (I) and pharmaceutically acceptable salts or N-oxide derivatives thereof are usually administered to a patient in the form of a pharmaceutical composition which is non-toxic and contains an effective amount of the compound. Pharmaceutical compositions are usually prepared by mixing the active compound (I), salts thereof, or N-oxide derivatives with conventional pharmaceutical carriers that are not reactive with the active compound (I), salts, or N-oxide derivatives. Suitable examples of carrier materials include lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium, aluminosilicate tetrahydrate, synthetic aluminum silicate, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium Carboxy methyl cellulose, ion exchange resin, methyl cellulose, gelatin, acacia, pullulan, hydroxypropyl cellulose, lower substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, hard silicic anhydride, Magnesium stearate, talc, tragacanth, bentonite, non-gum, carboxyvinyl polymer, titanium dioxide, sorbitan fatty acid ester, sodium lauryl sulfate, cacao butter, glycerin, saturated fatty acid glyceride, lanolin anhydride, glycerogelatin, Polysorbate, macro There are, vegetable oil, wax, propylene glycol, water and the like.

The pharmaceutical composition may be in the form of tablets, capsules, granules, microgranules, powders, syrup suspensions, suppositories, injections and the like. Such formulations may be prepared by conventional methods. Liquid formulations may be prepared by dissolving or suspending the active compound in water or other suitable medium when in use. Tablets, granules and microgranules can be coated according to conventional methods.

The pharmaceutical composition comprises, as an active ingredient, a compound of formula (I), a pharmaceutically acceptable salt thereof, or an N-oxide derivative thereof in an amount of 0.5% by weight or more based on the total weight of the composition, preferably in a ratio of 1 to 70% by weight. It contains. Furthermore, the composition may comprise one or more other therapeutically active compounds.

The invention is illustrated by the following examples and reference examples, but is not limited thereto. Identification of compounds is carried out by elemental analysis, mass spectrum, IR spectrum, NMR spectrum and the like.

In the Examples and Reference Examples, the following abbreviations are often used.

Me: Methyl

Et: ethyl

Pr: Profile

Ph: Phenyl

Ac: Acetyl

A: Ethanol

AC: acetone

AE: ethyl acetate

CH: Chloroform

DO: Dioxane

DM: Dichloromethane

E: diethyl ether

H: Hexane

IP: Isopropyl Alcohol

M: Methanol

PE: diisopropyl ether

T: toluene

Example 1

Preparation of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide:

(1) 4-amino-5-chloro-2-ethoxybenzoic acid (2.7 g) in a dichloromethane (50 ml) solution of 2-aminomethyl-4- (4-fluorobenzyl) morpholine (2.5 g); The mixture obtained by adding 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.4 g) is stirred at 25 ° C. for 4 hours. The reaction mixture is subsequently washed with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from ethanol to obtain the target product (2.0 g) having a melting point of 151 to 153 占 폚.

(2) The free base (2.0 g) obtained in (1) of this Example was dissolved in ethanol (50 ml), and 35% ethanol hydrochloric acid (5 ml) was added. The precipitates are collected and recrystallized from ethanol to obtain the hydrochloride (1.6 g) of the target having a melting point of 160 to 163 占 폚.

(3) The free base (7.0 g) obtained in the same manner as in Example (1) was dissolved in heated ethanol (100 ml), and citric acid monohydrate (3.8 g) was added. The mixture is heated to a clear solution, concentrated to 20 ml and cooled. The precipitates are collected and recrystallized from ethanol to obtain the citrate (8.6 g) of the target having a melting point of 143 to 145 占 폚.

(4) The solution obtained by dissolving the free base (10 g) obtained in the same manner as in (1) of this Example in a heated 10% citric acid aqueous solution (40 ml) is cooled. The precipitate is collected to give citrate dihydrate (1.1 g) of the desired product having a melting point of 110 to 113 占 폚.

Example 2

Preparation with 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (same as the compound of Example 1):

4-Amino-5-chloro-2-ethoxy benzoic acid (2.9 g) was added to dichloromethane (50 ml) to a stirred suspension, and triethylamine (1.6 g) was added at 25 ° C. The obtained mixture was cooled to -10 deg. C, and isobutyl chloroformate (2.0 g) was slowly added. The mixture is stirred at the same temperature for 1 hour and then a solution of dichloromethane (10 ml) of 2-aminomethyl-4- (4-fluorobenzyl) morpholine (3.0 g) is added. The reaction mixture was stirred at a temperature of -10 ° C to -5 ° C for 1 hour and then at 25 ° C overnight. The mixture is subsequently washed with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from ethanol to obtain the target product (4.1 g) having a melting point of 151 to 153 占 폚.

Example 3

Preparation of 4-amino-N- [3- (4-benzyl-2-morpholinyl) propyl] -5-chloro-2-methoxybenzamide:

To a mixture of 2- (3-aminopropyl) -4-benzylmorpholine (2.0 g), 4-amino-5-chloro-2-methoxybenzoic acid (1.7 g) and dichlorobetane (40 ml), 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.8 g) is added and the mixture is stirred at 25 ° C. for 4 hours. The reaction mixture is subsequently washed with water, 10% aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. After removing the chloroform eluting portion, the elution portion of methanol-chloroform (1: 9) is collected and evaporated to obtain an oily target product (2.5 g).

The free base thus obtained was dissolved in ethanol (50 ml) and an ethanol (10 ml) solution of oxalic acid (0.6 g) was added. The resulting solution is concentrated to about 10 ml and diethyl ether is added until turbidity appears. The precipitates are collected and recrystallized from ethanol to obtain the oxalate hemihydrate of the desired product having a melting point of 118 to 121 ° C.

Example 4

Preparation of 3, 4-methylenedioxy-N-[(4-benzyl-2-morpholinyl) methyl] benzamide:

The mixture was stirred under reflux for 1 hour in 3, 4-methylenedioxybenzoic acid (2.0 g), tanonyl chloride (1.7 g), dimethylformamide (1 drop), and chlorolom (25 ml). After removing chloroform under reduced pressure, toluene (20 ml) was added, and the solution obtained was evaporated under reduced pressure. The residue was dissolved in chloroform (25 ml) and triethylamine (10 ml) was added. To the mixture was added dropwise a solution of 2-aminomethyl-4-benzylmorpholine (2.5 g) in chloroform (25 ml) at 0 ° C. The reaction mixture was stirred at 25 ° C. overnight and then washed with water, 1N aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain the desired product (4.0 g). The free base thus obtained is treated with fumaric acid in heated isopropyl alcohol. The precipitates are collected and recrystallized from isopropyl alcohol to obtain 3/4 fumarate of the desired product having a melting point of 161 to 163 占 폚.

Example 5

Preparation of 4-amino-5-chloro-N-[(4-ethoxycarbonyl-2-morpholinyl) methyl-2-methoxybenzamide: 2-aminomethyl-4-ethoxycarbonylmorpholine ( 4-amino-5-chloro-2-methoxybenzoic acid (5.0 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.2 g) in a dichloromethane (100 ml) solution of 5.8 g) ) And the resulting mixture is stirred at 25 ° C. for 4 hours. The reaction mixture is subsequently washed with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. After removing the chloroform eluting portion, the elution portion of methanol-chloroform (1: 9) is collected and evaporated to obtain an oily target product (7.5 g).

The free base thus obtained was treated with oxalic acid substantially in the same manner as in the second term of Example 3 to obtain an oxalate of the desired product having a melting point of 140 to 151 占 폚 (recrystallized from ethanol-diethyl ether).

Example 6

Preparation of 4-amino-5-chloro-N-[[4- (4-cyanobenzyl) -2-morpholinyl] methyl] -2-methoxybenzamide: (1) 2-aminomethyl-4- To a dichloromethane (40 ml) solution of (4-cyanobenzyl) morpholine (1.5 g), 4-amino-5-chloro-2-methoxybenzoic acid (1.2 g) and 1-ethyl-3- (3-dimethyl The mixture obtained by the addition of anipropyl) carbodiimide hydrochloride (1.3 g) is stirred at 25 ° C. for 3 hours. The reaction mixture is subsequently washed with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain an oily target product.

(2) The free base obtained in (1) of this Example was dissolved in a small amount of ethanol, and a ethanol (20 ml) solution of fumaric acid (0.7 g) was added thereto. The resulting solution is concentrated to about 10 ml and cooled. The precipitates are collected and recrystallized from ethanol to obtain the fumarate of the desired product having a melting point of 163 to 167 ° C.

Example 7

Preparation of 4-acetylamino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide:

To a stirred mixture of 4-acetylamino-5-chloro-2-ethoxybenzoic acid (2.0 g), 2-aminomethyl-4- (4-fluorobenzyl) morpholine (1.6 g), and dichloromethane (20 ml) The mixture obtained by adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (15 g) is stirred at 25 ° C. for 1.5 hours. The reaction mixture is subsequently washed with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is recrystallized from ethanol to obtain the target product having a melting point of 161 to 163 캜.

Example 8

Preparation of 4-amino-N- [2- (4-benzyl-2-morpholinyl) ethyl] -5-chloro-2-ethoxybenzamide:

The desired product was substituted with 2-aminomethyl-4- (4-fluorobenzyl) morpholine of Example 1 (1), 2- (2-aminoethyl) -4 having a melting point of 149 to 151 캜 (recrystallized from methanol). Using benzylmorpholine, it is substantially prepared in the same manner as in Example 1 (1).

Example 9

Preparation of 4-amino-N- [2- (4-benzyl-2-morpholinyl) ethyl] -5-chloro-2-methoxybenzamide:

The desired product was substantially the same as in Example 6 (1) using 2- (2-aminoethyl) -4-benzylmorpholine instead of 2-aminomethyl-4- (4-cyanobenzyl) morpholine. Manufactured in the same manner as 1).

The free base thus obtained is treated in substantially the same manner as in Example 6 (2) to give hemifumarate 3/2 EtOH having a melting point of 68 to 72 ° C. (recrystallized from ethanol-diethyl ether).

Example 10

Preparation of 4-amino-N- [2- (4- (4-cyanobenzyl) -2-morpholinyl) ethyl] -5-chloro-2-methoxybenzamide:

The 1/4 hydrate of the desired product had a melting point of 180-182 ° C. (recrystallized from isopropyl alcohol) instead of 2-aminomethyl-4- (4-cyanobenzyl) morpholine of Example 6 (1). Prepared substantially the same way as in Example 6 (1) using 2-aminoethyl) -4- (4-cyanobenzyl) morpholine.

Example 11

Preparation of 2, 3-methyleneoxy-N-[[4-benzyl-2-morpholinyl) methyl] benzamide:

The desired product was 2-aminomethyl-4-benzyl, instead of 2-aminomethyl-4- (4-cyanobenzyl) morpholine and 4-amino-5-chloro-2-methoxybenzoic acid of Example 6 (1), respectively. Prepared substantially the same way as in Example 6 (1) using morpholine and 2, 3-methylenedioxybenzoic acid. The free base thus obtained is treated in substantially the same manner as in Example 6 (2) to obtain a fumarate quarter hydrate of the desired product having a melting point of 144 to 146 占 폚 (recrystallized from ethanol).

Example 12

Preparation of 5-chloro-N-[[4- [3- (4-chlorophenoxy) propyl] -2-morpholinyl] methyl] -4-dimethylamino-2-methoxybenzamide:

The hemihydrate of the target had a melting point of 128 to 130 instead of 2-aminomethyl-4- (4-cyanobenzyl) morpholine and 4-amino-5-chloro-2-methoxybenzoic acid of Example 6 (1), respectively. Substantially practiced using 2-aminomethyl-4- [3- (4-chlorophenoxy) propyl] morpholine and 5-chloro-4-dimethylamino-2-methoxybenzoic acid at ° C (recrystallized from ethanol) It is manufactured by the same method as Example 6 (1).

Reality 13

Preparation of 5-chloro-N-[[4- (4-cyanobenzyl) -2-morpholinyl] methyl] -4-dimethylamino-2-methoxybenzamide:

The target product was 5-chloro-4-dimethylamino-2-methoxy having a melting point of 161 to 163 캜 (recrystallized from ethanol) instead of the 4-amino-5-chloro-2-methoxybenzoic acid of Example 6 (1). It is prepared substantially in the same manner as in Example 6 (1) using benzoic acid.

Example 14

Preparation of 4-amino-5-chloro-N-[[4- (2-chlorobenzyl) -6-methyl-2-morpholinyl] methyl] -2-ethoxybenzamide:

(1) 4-amino-5-chloro-2-ethoxybenzoic acid (1.9) in dichloromethane (50 ml) solution of 2-aminomethyl-4- (2-chlorobenzyl) -6-methylmorpholine (2.2 g) g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (17 g) are added. The reaction mixture is stirred for 4 hours at 25 ° C., then washed with water, aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was chromatographed on silica gel with ethyl acetate-hexane-chloroform (1: 1: 1) to obtain an oily target (2.6 g).

(2) The free base (2.6 g) obtained in (1) of this Example is dissolved in ethanol (50 ml), and an ethanol (20 ml) solution of fumaric acid (1.5 g) is added. The resulting solution is concentrated to about 10 ml. The precipitates are collected and recrystallized from isopropyl alcohol to obtain the difumarate of the desired product having a melting point of 150 to 154 占 폚.

Example 15

Preparation of 4-amino-5-chloro-N-[[4- (2-chlorobenzyl) -5, 5-dimethyl-2-morpholinyl] -methyl] -2-ethoxybenzamide:

The objective was to instead of 2-aminomethyl-4- (2-chlorobenzyl) -6-methylmorpholine of Example 14 (1), 2-aminomethyl-4- having a melting point of 181 to 184 ° C (recrystallized from ethanol). (2-Chlorobenzyl) -5, 5-dimethylmorpholine was prepared substantially in the same manner as in Example 14 (1).

Example 16

Preparation of 4-amino-N-[(4-benzyl-hexahydro-1,4-oxazin-2-yl) methyl] -5-chloro-2-ethoxybenzamide:

The desired product used 2-aminomethyl-4-benzylhexahydro-1, 4-oxazepine in place of 2-inomethyl-4- (2-clobenzyl) -6-methylmorpholine of Example 14 (1) Is substantially prepared in the same manner as in Example 14 (1). The free base thus obtained is treated in substantially the same manner as in Example 14 (2) to obtain the fumarate of the desired product having a melting point of 180 to 183 ° C (recrystallized from isopropyl alcohol).

Example 17

Preparation of 4-amino-5-chloro-2-ethoxy-N-[(4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (compound as Example 1):

(1) A mixture of 4-acetylamino-5-chloro-2-methoxybenzoic acid ethyl ester (2.7 g) and 2-aminomethyl-4- (4-fluorobenzyl) morpholine (5.6 g) at 150 ° C Heat stir for 2 hours. After cooling, the reaction mixture is chromatographed on silica gel with chloroform to give the desired product having a melting point of 151 to 153 캜 (recrystallized from ethanol).

(2) The target product was prepared by using 4-amino-5-chloro-2-ethoxybenzoic acid methyl ester instead of the 4-acetylamino-5-chloro-2-ethoxybenzoic acid methyl ester of (1) of this Example. In the same manner as in Example (1).

Examples 18-155

Various compounds described in the following Tables 3 to 6 are prepared substantially in the same manner as Examples 1 to 7, 14, and 17 using the corresponding starting materials.

TABLE 3

TABLE 4

TABLE 5

TABLE 6

Example 156

Preparation of 4-amino-5-chloro-2-methoxy-N- (2-morpholinyl) benzamide:

(1) 4-amino-5-chloro-N-[(4-epoxycarbonyl-2-morpholinyl) methyl] -2-methoxybenzamide (6.1 g), potassium hydroxide (10.1 g) and isopropyl The mixture of alcohol (60 ml) is stirred at reflux for 3 hours. The reaction mixture is concentrated under reduced pressure, the residue is diluted with water and extracted with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is recrystallized from isopropyl alcohol to obtain the target product (1.4 g) having a melting point of 161 to 162 캜.

(2) 4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-methoxybenzamide (5.0 g), ethanol (100 ml), and acetic acid (20 nl) The mixture is hydrogenated to 10% palladium on carbon (0.5 g) at 25 ° C. After absorbing the calculated amount of hydrogen, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the desired product (3.8 g).

Example 157

Preparation of 4-acetylamino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (compound as Example 7):

To a solution of 4-acetylamino-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (4.0 g) in dimethylformamide (20 ml) The mixture obtained by adding chlorosuccinimide (1.3 g) is stirred at 70 ° C. for 2 hours. The reaction mixture is poured into iced water and extracted with diethyl ether. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is recrystallized from acetone to obtain the target product (3.1 g) having a melting point of 161 to 163 占 폚.

The starting material, 4-acetylamino-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide was prepared as the 4-amino-5 of Example 1 (1). Prepared substantially the same way as in Example 1 (1) using 4-acetylamino-2-ethoxybenzoic acid instead of -chloro-2-ethoxybenzoic acid.

Example 158

Preparation of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (compound as Example 1):

(1) 4-acetylamino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (2.0 g) with 10% hydrochloric acid ( 40 ml) of the mixture is refluxed for 1 hour and cooled. The reaction mixture is neutralized with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer is dried over magnesium sulfate and evaporated. The residue is recrystallized from ethanol to obtain the target product (1.4 g) having a melting point of 151 to 153 占 폚.

(2) The free base (1.0 g) obtained in Example (1) was dissolved in ethanol (25 ml) and 35% ethanol hydrogen chloride (3 ml) was added. The precipitates are collected and recrystallized from ethanol to obtain the hydrochloride (0.8 g) of the target having a melting point of 160 to 163 占 폚.

(3) The free base (1.0 g) obtained by the same method as in (1) of this Example was dissolved in heated ethanol (15 ml) and citric acid monohydrate (0.53 g) was added. The mixture is heated to a clear solution, concentrated to 3 ml and cooled. The precipitates are collected and recrystallized from ethanol to obtain the citrate (1.2 g) of the target having a melting point of 143 to 145 占 폚.

(4) The solution obtained by dissolving the free base (1.0 g) obtained in the same manner as in Example (1) of this Example in a heated 10% aqueous citric acid solution (40 ml) is cooled. The precipitate is collected to give citrate dihydrate (1.1 g) of the desired product having a melting point of 110 to 113 占 폚.

Examples 159-185

The compounds of Examples 18-22, 45-47, 52, 63-68, 79-81, 83, and 88-95 were substantially subjected to chlorination of the appropriate 4-acetylaminobenzamide derivatives in the same manner as in Example 157. As a result, 4-acetylamino-5-chlorobenzamide derivative obtained in the same manner as in Example 158 was prepared by hydrolysis.

Example 186

Preparation of 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide (compound as Example 1):

(1) stannous chloride dihydrate (5.4 g) to 5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] -4-nitrobenzamide (2.2 g), ethanol (30 ml), and ethyl acetate (30 ml) are added to a stirred mixture. The reaction mixture is stirred at 70 ° C. for 2 hours and concentrated. The residue is basified with aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is recrystallized from ethanol to obtain the target product (1.1 g) having a melting point of 151 to 153 占 폚.

The starting material, 5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] -4-nitrobenzamide, was prepared as described in Example 1 (1). Prepared substantially the same way as in Example 1 (1), using 5-chloro-2-ethoxy-4-nitrobenzoic acid instead of amino-5-chloro-2-ethoxybenzoic acid.

(2) The free base (1.0 g) obtained in Example (1) was dissolved in ethanol (25 ml) and 35% ethanol hydrogen chloride (3 ml) was added. The precipitates are collected and recrystallized from ethanol to obtain the hydrochloride (0.8 g) of the target having a melting point of 160 to 163 占 폚.

(3) The free base (1.0 g) obtained by the same method as in (1) of this Example was dissolved in heated ethanol (15 ml) and citric acid monohydrate (0.53 g) was added. The mixture is heated to a clear solution, concentrated to 3 ml and cooled. The precipitates are collected and recrystallized from ethanol to obtain the citrate (1.2 g) of the target having a melting point of 143 to 145 占 폚.

(4) The solution obtained by dissolving the free base (1.0 g) obtained in the same manner as in Example (1) of this Example in a heated 10% aqueous citric acid solution (40 ml) is cooled. The precipitate is collected to give citrate dihydrate (1.1 g) of the desired product having a melting point of 110 to 113 占 폚.

Examples 187-213

The compounds of Examples 18 to 22, 45 to 47, 52, 63 to 68, 79 to 81, 83 and 88 to 95 are prepared substantially in the same manner as in Example 186 using the corresponding 4-nitro compound.

Example 214

Preparation of 4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-hydroxybenzamide (compound as Example 124):

(1) 1-ethyl- in a mixture of 2-aminomethyl-4-benzylmorpholine (3.1 g), 2-acetoxy-4-acetylamino-5-chlorobenzoic acid (4.0 g), and dichloromethane (40 ml) The mixture to which 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (2.9 g) was added is stirred at 25 ° C. for 4 hours. The reaction mixture is subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in ethanol (80 ml) and 10% hydrochloric acid (30 ml) is added. The mixture is refluxed for 2 hours with stirring and concentrated under reduced pressure. The residue is neutralized with aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from isopropyl alcohol to obtain monohydrate (3.0 g) of the desired product having a melting point of 153 to 155 占 폚.

(2) To a stirred suspension of dimethylformamide (20 ml) of 60% sodium hydride (0.52 g) is added a solution of dimethylformamide (5 ml) of ethanethiol (0.81 g) under ice cooling. The mixture was stirred at 25 ° C. for 0.5 h and then 4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-methoxybenzamide (3.4 g) was added. Stir at 100 ° C. for 1 h. After cooling, the reaction mixture is evaporated under reduced pressure. The residue is diluted with water and washed with chloroform and neutralized with 10% hydrochloric acid. The precipitates are collected, washed with water and recrystallized from isopropyl alcohol to give monohydrate (2.3 g) of the desired product having a melting point of 153 to 155 占 폚.

The following compounds are prepared in substantially the same manner as in this example using the corresponding starting materials:

4-amino-5-chloro-N-[[4- (2-chlorobenzyl) -2-morpholinyl] methyl] -2-hydroxybenzamide having a melting point of 183 to 185 ° C. (recrystallized from ethanol),

4-amino-5-chloro-N-[[4- (3-chlorobenzyl) -2-morpholinyl] methyl] -2-hydroxybenzamide,

4-amino-5-chloro-N-[[4- (4-chlorobenzyl) -2-morpholinyl] methyl] -2-hydroxybenzamide,

4-amino-5-chloro-N-[[4- (2-fluorobenzyl) -2-morpholinyl] methyl] -2-hydroxybenzamide,

4-amino-5-chloro-N-[[4- (3-fluorobenzyl) -2-morpholinyl] methyl] -2-hydroxybenzamide,

4-amino-5-chloro-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] -2-hydroxybenzamide, oil,

4-amino-5-chloro-2-hydroxy-N- [4- (2-pyridyl) methyl-2-morpholinyl] methyl] benzamide,

4-amino-5-chloro-2-hydroxy-N-[[4- (3-pyridyl) methyl-2-morpholinyl] methyl] benzamide,

4-amino-5-chloro-2-hydroxy-N- [4- (4-pyridyl) methyl-2-morpholinyl] methyl] benzamide, and

4-amino-5-chloro-N-[[4- [3- (4-chlorophenoxy) propyl] -2-morpholinyl] methyl] -2-hydroxybenzamide.

Example 215

Preparation of 4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -2-butoxy-5-chlorobenzamide (compound as Example 88):

Tetra bromide in a stirring solution of 1N aqueous sodium hydroxide solution (32 ml) of 4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -5-chloro-2-hydroxybenzamide (4.0 g) A solution of dichloromethane (32 ml) of butylammonium (3.4 g) and butyl bromide (4.3 g) is added. The reaction mixture is stirred at 25 ° C. for 15 h and concentrated under reduced pressure. Ethyl acetate is added to the residue. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue is chromatographed on silica gel with ethanol-chloroform (5:95) to give the title compound (5.5 g). The free base thus obtained is dissolved in heated ethanol (20 ml) and fumaric acid (1.5 g) is added. The solution is stirred for a while. The precipitates are collected and recrystallized from ethanol to give the fumarate hemihydrate (4.6 g) of the target having a melting point of 188 to 190 占 폚.

Examples 216-242

The compounds of Examples 1, 18 to 22, 45 to 47, 52, 63 to 68, 79 to 81, 83 and 89 to 95 are prepared substantially in the same manner as in Example 2105 using the corresponding starting materials.

Example 243

Preparation of Iodide 2-[(4-amino-5-chloro-2-ethoxybenzoyl) inomethyl] -4- (2-chlorobenzyl) -4-methyl morpholinium:

To a solution of 4-amino-5-chloro-N-[(4- (2-chlorobenzyl) -2-morpholinyl] methyl] -2-ethoxybenzamide (2.4 g) in ethanol (100 ml) methyl iodide ( 4.0 g) are added and the mixture is stirred for 24 h at 25 ° C. An appropriate amount of charcoal is added to the reaction mixture and the mixture is heated for a while to filter The filtrate is concentrated to about 10 ml under reduced pressure The precipitates are collected from methanol Recrystallization yields a hemihydrate (1.6 g) of the desired product having a melting point of 184 to 188 占 폚.

Example 244

Preparation of 4-amino-5-chloro-N-[(4- (2-chlorobenzyl) -2-morpholinyl] methyl] -2-ethoxybenzamide N-oxide:

30% in methanol (150 ml) stirred solution of 4-amino-5-chloro-N-[[4- (2-chlorobenzyl) -2-morpholinyl] methyl] -2-ethoxybenzamide (4.0 g) Aqueous hydrogen peroxide (1.2 g) is added. After the mixture was heated to reflux for 8 hours, additional 30% aqueous hydrogen peroxide (1.2 g) was added and the reaction mixture was stirred at reflux for an additional 24 hours. The solvent is distilled off under reduced pressure, and chloroform and water are added to the residue. The mixture is stirred for about 30 minutes. The precipitate is collected from isopropyl alcohol-diisopropyl ether and recrystallized to obtain the desired product (0.6 g) having a melting point of 154 to 157 ° C.

The starting material used in the previous example is prepared as follows.

Reference Example 1

Preparation of 2-Aminomethyl-4-benzylmorpholine:

(1) A mixture of 4-benzyl-2-chloromethylmorpholine (86.4 g), phthalimide potassium salt (78.0 g) and dimethylformamide (700 ml) was stirred under reflux for 5 hours. Pour the reaction mixture into ice water. The obtained precipitate is collected and recrystallized from isopropyl alcohol to obtain N-[(4-benzyl-2-morpholinyl) methyl] phthalamide (107 g) having a melting point of 136 to 139 ° C. Starting material, 4-benzyl-2-chloromethylmorpholine, was prepared using the F. Loftus method [Syn. Prepared according to Commun., 10, 59-73 (1980).

(2) A mixture of the above phthalimide compound (67.2 g), 85% hydrazine hydrate (20.08) and ethanol (180 ml) was stirred under reflux for 30 minutes. The reaction mixture is filtered, the filtrate is diluted with water and extracted with chloroform. The organic layer is washed with a small amount of water and then with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain an oily target product (33.5 g). Treatment of free base with fumaric acid in heated ethanol yields the desired fumarate difumarate with a melting point of 166 to 170 ° C.

Reference Example 2

Preparation of 2-aminomethyl-4-phenylmorpholine:

The target material was substantially the same as in Reference Examples 1 (1) and (2) using 2-chloromethyl-4-phenylmorpholine instead of 4-benzyl-2-chloromethylformoline of Reference Example 1 (1). Prepared by the method.

Reference Example 3

Preparation of 2-Aminomethyl-4-benzylmorpholine:

(1) A mixture of 4-benzyl-2-chloromethylmorpholine (15.0 g), sodium azide (8.6 g) and dimethylformamide (150 ml) is stirred at 130 ° C. for 2 hours. The reaction mixture is diluted with water and extracted with diethyl ether. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain an oily 2-azidomethyl-4-benzylmorpholine (15 g).

(2) Toluene (40 ml) solution of 2-azidomethyl-4-benzylmorphlin (15 g) was stirred with toluene (60 ml) of 70% bis (2-methoxyethoxy) aluminum sodium hydride cooled to -5 ° C. Add dropwise to the solution. The reaction mixture is stirred at 25 ° C. for 15 hours, cooled to 10 ° C. and the excess reducing agent is decomposed by the careful addition of 10% aqueous sodium hydroxide solution. The organic layer is separated, subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After removing the solvent under reduced pressure, the target product is obtained as an oil (11 g).

Reference Example 4

Preparation of 2-acetylaminomethyl-4-benzylmorpholine:

A mixture of N-[(4-benzyl-2-morpholinyl) methyl] phthalimide (162 g), 85% hydrazine hydrate (43.3 g) and ethanol (100 ml) was stirred under reflux for 20 minutes. The reaction mixture is filtered and the filtrate is diluted with water and extracted with chloroform. The organic layer is separated, washed with a small amount of water, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The mixture obtained by the slow addition of acetic anhydride (98.3 g) to the filtrate is stirred at 25 ° C. for 2 hours. The reaction mixture is subsequently washed with aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure and the residue is recrystallized from toluene to obtain the target product (101 g) having a melting point of 110 to 111 캜.

Reference Example 5

Preparation of 2-acetylaminomethylmorpholine:

2-acetylaminomethyl-4-benzylmorpholine (120 g) is dissolved in a mixture of ethanol (1000 ml) and acetic acid (30 ml) and hydrogenated with 10% palladium on carbon (5 g) at about 60 ° C. After absorbing the calculated amount of hydrogen, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the oily target.

Reference Example 6

Preparation of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine:

A mixture of 2-acetylaminomethylmorpholine (7.0 g), 4-fluorobenzyl chloride (12 g), potassium carbonate (56 g), potassium iodide (1 g) and methyl ethyl ketone (100 ml) was stirred under reflux for 17 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is diluted with water and extracted with chloroform. The organic layer is separated, subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is recrystallized from toluene to obtain a target product (9 3 g) having a melting point of 120 to 122 占 폚.

Reference Examples 7-55

The various compounds listed in Table 7 were prepared in substantially the same manner as in Reference Example 6 using suitable alkylating agents in place of 4-fluorobenzyl chloride in Reference Example 6.

TABLE 7

Reference Example 56

Preparation of 2-aminomethyl-4- (4-fluorobenzyl) morpholine:

A 10% hydrochloric acid (50 ml) solution of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine (3.0 g) was stirred under reflux for 4 hours. The reaction mixture was adjusted to pH 11 with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure affords the oily target product.

Reference Example 57

Preparation of 2-aminomethyl-4-substituted morpholine:

The desired product used the products of Reference Examples 4, 7-18, 21-33, 38-41 and 53-55 instead of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine of Reference Example 56. It was prepared substantially in the same manner as in Reference Example 56.

Reference Example 58

Preparation of 2-aminomethyl-4- [3- (4-chlorophenoxy) propyl] morpholine:

A mixture of 2-acetylaminomethyl-4- [3- (4-chlorophenoxy) propyl] morpholine (3.3 g) and a 10% aqueous sodium hydroxide solution (60 ml) was stirred under reflux for 20 hours. The reaction mixture is extracted with chloroform, and the organic layer is subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure affords the oily target product.

Reference Example 59

Preparation of 2-aminomethyl-4-substituted morpholine:

The desired product was prepared according to the Reference Examples 19, 20, 34 to 37, 42 to 45, 47 to 52 and 55 instead of the 2-acetylaminomethyl-4- [3- (4-chlorophenoxy) morpholine of Reference Example 58. Using the product, it is substantially prepared in the same manner as in Reference Example 58.

Reference Example 60

Preparation of 2-aminomethyl-4-ethoxycarbonylmorpholine:

(1) To a toluene (200 ml) stirring solution of N-[(4-benzyl-2-morpholinyl) methyl] phthalimide (30.0 g), ethyl chloroformate (19.4 g) was added dropwise at 60 ° C, and the mixture was Stir at reflux for 1 hour. The reaction mixture is subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was recrystallized from isopropyl alcohol-diethyl ether to give N-[(4-ethoxycarbonyl-2-morpholinyl) methyl] phthalimide (27.8) having a melting point of 113 to 115 캜. g) is obtained.

(2) A mixture of N-[(4-ethoxycarbonyl-2-morpholinyl) methyl] phthalimide (10.0 g), 85% hydrazine hydrate (2.9 g) and ethane (10 ml) was refluxed for 10 minutes. Stir. The reaction mixture is filtered to extract the filtrate with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives an oily target (5.8 g).

Reference Example 61

Preparation of 4-benzyl-2-cyanomethylmorpholine:

A mixture of 4-benzyl-2-chloromethylmorpholine (225 g), potassium cyanide (13 g), potassium iodide (1 g) and dimethyl sulfoxide (40 ml) was stirred by heating at 120 DEG C for 5 hours. The reaction mixture is cooled, diluted with water and extracted with diefil ether. The organic layer was washed with water, dried over sodium sulfate and evaporated to give an oily target product (20 g).

Reference Example 62

Preparation of 2- (2-aminoethyl) -4-benzylmorpholine:

A solution of 4-benzyl-2-cyanomethylmorpholine (20 g) dissolved in a mixture of ethanol (160 ml) and 28% aqueous ammonia (10 ml) was hydrogenated with Raney nickel (2 g, wet) at 25 ° C. for 2 hours. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The remaining oil (16.5 g) is treated with an ethanol solution of maleic acid to obtain maleate, and the maleic acid is recrystallized from ethanol-acetethyl to give the sesquimalate of the target having a melting point of 123 to 125 ° C.

Reference Example 63

Preparation of 2- (2-hydroxyethyl) -4-benzylmorpholine:

A solution of diethyl ether (100 ml) of 2-ethoxycarbonylmethyl-4-benzylmorpholine (41 g) was added dropwise to a stirring suspension of diethyl ether (150 ml) of lithium aluminum hydride (59.2 g). The reaction mixture is stirred at 25 ° C. for 1 hour. The excess lithium aluminum hydride is decomposed by continued addition of ethyl acetate and water. The insoluble material is filtered off and the filtrate is evaporated to give the desired oily product (34.4 g). A starting material, 2-ethoxycarbonylmethyl-4-benzylmorpholine, is prepared according to the F. Loftus method [Syn. Commun., 10, 59-73 (1980)].

Reference Example 64

Preparation of 2- (2-acetoxyethyl) -4-benzylmorpholine:

Acetic anhydride (17.8 ml) is added dropwise to a mixture of 2- (2-hydroxyethyl) -4-benzylmorpholine (27.7 g), triethylamine (28 ml), and ethyl acetate (100 ml). The reaction mixture is stirred at 25 ° C. for 1 hour and evaporated under reduced pressure. The residue is dissolved in chloroform and chromatographed on silica gel. The fraction containing the target product is collected and evaporated to obtain an oily target product (29.1 g).

Reference Example 65

Preparation of 2- (2-acetoxyethyl) -4-benzyloxycarbonylmorpholine:

To a solution of acetonitrile (200 ml) of 2- (2-acetoxyethyl) -4-benzylmorpholine (29.1 g) was added dropwise benzyl chloroform (24.4 g). The reaction mixture is refluxed for 30 minutes to cool and evaporated under reduced pressure. The residue is chromatographed on silica gel. The eluate of hexane is discarded, and the following eluate of hexane-chloroform (1: 1) is collected and evaporated to obtain an oily target product (24.5 g).

Reference Example 66

Preparation of 2- (2-hydroxyethyl) -4-benzyloxycarbonylmorpholine:

A mixture of 2- (2-acetoxyethyl) -4-benzyloxycarbonylmorpholine (24,5 g), potassium hydroxide (8.9 g), ethanol (40 ml) and water (40 ml) was refluxed for 30 minutes and concentrated under reduced pressure. do. Water is added to the residue and the mixture is extracted with diethyl ether. The organic layer is washed with water, dried over sodium sulfate and evaporated to give an oily target product (15 g).

Reference Example 67

Preparation of 2- (2-chloroethyl) -4-benzyloxycarbonylmorpholine:

Thionyl chloride (16.4 ml) is added dropwise to a mixture of 2- (2-hydroxyethyl) -4-benzyloxycarbonylmorpholine (15 g), dimethylformamide (1 ml) and chloroform (50 ml). The mixture is refluxed for 2 hours, cooled and evaporated under reduced pressure to give the desired oily product (16 g).

Reference Example 68

Preparation of 2- (2-cyanoethyl) -4-benzyloxy carbonylmorpholine:

A mixture of 2- (2-chloromethyl) -4-benzyloxycarbonylmorpholine (16 g), potassium cyanide (6.3 g), potassium iodide (1 g) and dimethylformamide (50 ml) was stirred at 100 DEG C for 5 hours. Heat at After cooling, the reaction mixture is diluted with water and extracted with diethyl ether. The organic layer is dried over sodium sulfate and evaporated. The residue is crystallized from diethyl ether-hexane to obtain the target product (10.7 g) having a melting point of 59 to 60 ° C.

Reference Example 69

Preparation of 2- (2-cyanoethyl) morpholine:

A solution of 2- (2-cyanoethyl) -4-benzyloxycarbonylmorpholine (10.7 g) in ethanol (60 ml) was hydrogenated with 5% palladium on carbon (1 g) at 25 ° C. After absorbing the calculated amount of hydrogen, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the oily target (5.4 g).

Reference embodiment 70

Preparation of 2- (2-cyanoethyl) -4-benzylmorpholine:

A mixture of 2- (2-cyanoethyl) morpholine (5.4 g), benzyl chloride (5.4 g), potassium carbonate (5.4 g), potassium iodide (0.5 g) and methyl ethyl ketone (30 ml) was refluxed for 1 hour. Under heating. After cooling, the reaction mixture is filtered and the filtrate is concentrated. The solution which dissolved the residue in diethyl ether is extracted with dilute hydrochloric acid. The extract is basified with dilute sodium hydroxide in an aqueous solution and extracted with chloroform. The organic layer is dried over sodium sulphate and evaporated to give the title compound (8 g).

Reference Example 71

Preparation of 2- (3-aminopropyl) -4-benzylmorpholine:

A solution of 2- (2-cyanoethyl) -4-benzylmorpholine (8 g) in a mixture of ethanol (60 ml) and 28% aqueous ammonia (4 ml) was hydrogenated with Raney nickel at 25 ° C. After absorbing the calculated amount of hydrogen, the catalyst is filtered off. The filtrate is evaporated under reduced pressure to give the desired substance as an oil (7 g).

Reference Example 72

Preparation of 2- (2-chlorobenzyl) amino-1-methylethanol:

A mixture of 2-amino-1-methylethanol (25.0 g), 2-chlorobenzaldehyde (51.5 g), sodium bicarbonate (33.6 g), and ethanol (1000 ml) was stirred under reflux for 4 hours. The reaction mixture is cooled to 10 ° C. and the mixture obtained by adding small amount of sodium borohydride (13.9 g) is stirred at 25 ° C. for 1 hour. The solvent is removed under reduced pressure, the residue is diluted with water and extracted with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain an oily target product (55.0 g).

Reference Example 73

Preparation of 4- (2-chlorobenzyl) -2-chloromethyl-6-methylmorpholine:

A mixture of 2- (2-chlorobenzyl) amino-1-methylethanol (20.0 g) and epichlorohydrin (9.7 g) is stirred at 25 ° C. for 24 hours. The mixture obtained by adding 98% sulfuric acid (30 ml) to the reaction mixture is stirred at 150 ° C. for 30 minutes. After cooling, the reaction mixture is poured into ice water. The mixture is basified with aqueous sodium hydroxide solution and extracted with toluene. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain an oily target product (19.7 g).

Reference conducting 74

Preparation of N-[[4- (2-chlorobenzyl) -6-methyl-2-morpholinyl] methyl] phthalimide:

A mixture of 4- (2-chlorobenzyl) -2-chloromethyl-6-methylmorpholine (19.7 g), phthalamide potassium salt (14.6 g) and dimethylformamide (150 ml) is stirred at 150 ° C. for 5 hours. . The reaction mixture is poured into iced water and extracted with diethyl ether. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off to obtain an oily target product (26 g).

Reference Example 75

Preparation of 2-acetylaminomethyl-4- (2-chlorobenzyl) -6-methylmorpholine:

A mixture of N-[[4- (2-chlorobenzyl) -6-methyl-2-morpholinyl] methyl] phthalamide (26 g), 100% hydrazine hydrate (4.2 g) and ethanol (20 ml) was refluxed for 15 minutes. Stir. After filtering off the insoluble material, the filtrate is diluted with water and extracted with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. Acetic anhydride (14.7 g) is added to the filtrate and the mixture is stirred at 25 ° C. for 2 hours. The reaction mixture is subsequently washed with aqueous sodium hydroxide solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. After removing the solvent under reduced pressure, the residue was chromatographed on silica gel with ethyl acetate to obtain the target product (15 g) in the oil phase.

Reference Example 76

Preparation of 2-Aminomethyl-4- (2-chlorobenzyl) -6-methylmorpholine:

A 10% hydrochloric acid (60 ml) solution of 2-acetylaminomethyl-4- (2-chlorobenzyl) -6-methylmorpholine (3.0 g) was stirred under reflux for 2 hours. The reaction mixture is basified with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to obtain an oily target product (2 2 g).

Reference Example 77

Preparation of 2-aminomethyl-4- (2-chlorobenzyl) -5, 5-dimethylmorpholine:

2- (2-chlorobenzyl) amino-2-methylpropanol was substantially the same method as Reference Example 72 using 2-amino-2-methylpropanol instead of 2-amino-1-methylmethanol of Reference Example 72. Is prepared. This product is converted to the oily target in substantially the same manner as Reference Examples 73-76.

Reference Example 78

Preparation of 2-Aminomethyl-4-benzyl-hexahydro-1, 4-oxazepine:

3-benzylaminopropanol is prepared substantially in the same manner as Reference Example 72 using 3-aminopropanol and benzaldehyde instead of 2-amino-1-methylethanol and 2-chlorobenzaldehyde of Reference Example 72, respectively. This product is converted to the oily target in substantially the same manner as Reference Examples 73-76.

Reference Example 79

Preparation of 2-acetylaminomethyl-4- (4-fluorobenzyl) morpholine (compound as Reference Example 6):

A mixture of N- (4-fluorobenzyl) ethanolamine (10.0 g) and N- (2, 3-epoxypropyl) phthalimide (12.3 g) is stirred at 80 ° C. for 3 hours. 98% sulfuric acid (31.9 g) is gradually added to the reaction mixture, and the mixture is stirred at 150 ° C for 2 hours. Cool brown solution to 25 ℃ and pour into ice water. The mixture is basified with aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. Acetic anhydride (6.0 g) is added to the filtrate. The resulting mixture was stirred at 25 ° C. for 2 hours, then ice water was added followed by aqueous sodium hydroxide solution. The mixture is stirred at 25 ° C. for a while. The organic layer is separated, subsequently washed with water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated and the residue is recrystallized from toluene to give the desired product (8.8 g) having a melting point of 120 to 122 占 폚.

Reference Example 80

Preparation of 4-Amino-5-chloro-2-hexyloxy benzoic acid:

(1) A mixture of p-acetylaminosalicylic acid methyl ester (5,0 g), hexyl iodide (76 g), potassium carbonate (99 g), and dimethylformamide (20 ml) is stirred at 70 ° C for 30 hours. The reaction mixture is poured into iced water and extracted with diethyl ether. The organic layer was subsequently washed with aqueous sodium hydroxide solution, aqueous po and sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel with chloroform-methanol (20: 1) to give an oily 4-acetylamino-2-hexyloxybenzoic acid ethyl ester (4.9 g).

(2) A mixture obtained by adding N-chlorosuccinimide (1.4 g) to a stirring solution of 4-acetylamino-2-hexyloxybenzoic acid methyl ester (2.6 g) in dimethylformamide (20 ml) was stirred at 70 DEG C for 1 hour. Stir. The reaction mixture is poured into iced water and extracted with diethyl ether. The organic layer was subsequently washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to give an oily 4-acetylamino-5-chloro-2-hexyloxybenzoic acid methyl ester (2. 1 g).

(3) A mixture of 4-acetylamino-5-chloro-2-hexyloxybenzoic acid methyl ester (21 g), ethanol (10 ml), and water (30 ml) containing sodium hydroxide (2.6 g) under reflux for 4 hours. Heat. The solution obtained by distilling ethanol under reduced pressure is acidified with dilute hydrochloric acid and extracted with chloroform. The organic layer is treated in the same manner as in (2) of this Example to obtain the target product.

The various compounds used as starting materials in Examples 86-95 and 97-123 are prepared substantially in the same manner as in this reference example using appropriate reagents in place of hexyl iodide.

Reference Example 81

Preparation of 2-benzylamino-5-nitrobenzoic acid:

An ethanol (40 ml) solution of 2-chloro-5-nitrobenzoic acid (5.0 g) and benzylamine (15.0 g) was refluxed for 10 hours and then concentrated under reduced pressure. Water (100 ml) was added to the residue, and the resulting solution was stirred for 1 hour with acetic acid at a pH of about 4. The precipitates are collected and recrystallized from ethanol to obtain the target product (4.8 g) having a melting point of 238 to 248 캜.

Reference Example 82

Preparation of 2-hexylamino-5-nitrobenzoic acid:

The desired product was prepared in substantially the same manner as Reference Example 81 using hexylamine (recrystallized from diisopropyl ether-hexane) having a melting point of 161 to 163 ° C. instead of the benzylamine of Reference Example 81.

Reference Example 83

Preparation of 2-acetylamino-4-dimethylamino-5-nitrobenzoic acid:

G.E. Keyser and N.J. According to Leonard method (J. Org. Chem., 44, 2989-2994 (1979)), nitriding 2-acetylamino-4-chlorobenzoic acid (33.0 g) to 2-acetylamino-4-chloro-5-nitro Benzoic acid (30.0 g) is obtained A solution of nitric acid (11.3 g) and 40% aqueous dimethylamine solution (40 ml) in ethanol (100 ml) is refluxed for 5 hours and then evaporated under reduced pressure. The solution is adjusted with acetic acid to pH 4. The precipitates are collected and recrystallized from ethanol to give the desired product (8.6 g) having a melting point of 230 to 255 ° C.

Reference Example 84

Preparation of 2-ino-4-dimethylamino-5-nitrobenzoic acid:

A mixture of 2-acetylamino-4-dimethylamino-5-nitrobenzoic acid (6.5 g), concentrated hydrochloric acid (20 ml) and water (80 ml) is stirred at 100 ° C. for 30 minutes. After cooling, solid sodium hydroxide (5 g) and 10% aqueous sodium hydroxide solution are added until the mixture is clear. The resulting solution is adjusted to pH 4 with acetic acid. The precipitates are collected and recrystallized from methanol to obtain the target product (4.8 g) having a melting point of 240 to 250 ° C.

Reference Example 85

Preparation of 2-Amino-4-methylamino-5-nitrobenzoic acid:

A mixture of 2-acetylamino-4-chloro-5-nitrobenzoic acid (10.0 g) and 40% aqueous methylamine solution (60 ml) was stirred at 80 ° C. for 10 hours and then evaporated under reduced pressure. 40% aqueous methylamine solution (100 ml) was added to the residue, and the obtained solution was stirred at 80 ° C for 20 hours. After cooling, the mixture is diluted with water (50 ml) and the pH is adjusted to about 4 with acetic acid. The precipitates are collected and recrystallized from acetonitrile to obtain the desired product (7.6 g) having a melting point of 260 to 272 ° C.

Reference Example 86

Preparation of 2-fluoro-5-sulfamoylbenzoic acid:

A tetrahydrofuran (70 ml) solution of 5-chlorosulfonyl-2-fluorobenzoic acid (7.0 g) and 28% aqueous ammonia (20 ml) was stirred at 0 ° C. for 1.5 hours. The reaction mixture is poured into water (200 ml), acidified with concentrated hydrochloric acid and extracted with chloroform. The extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is washed with diethyl ether to give the desired product (5.0 g).

Reference Example 87

Preparation of 2-methylamino-5-dimethylsulfamoylbenzoic acid:

A mixture of 5-dimethylsulfamoyl-2-fluorobenzoic acid (10 g) and 40% ethylamine aqueous solution (85 ml) was refluxed for 24 hours and then evaporated under reduced pressure. The residue is adjusted to pH 4 with acetic acid. The precipitates are collected, washed with water and dried to afford the desired product (6.0 g).

Reference Example 88

Preparation of 2-cyclopropylamino-5-sulfamoylbenzoic acid:

The desired product is prepared substantially from 2-fluoro-5-sulfamoylbenzoic acid and cyclopropylamine in the same manner as in Reference Example 87.

Example 245

1,000 Congestion

4-amino-5-chloro-2-ethoxy-N-[(4- (4-fluorobenzyl) -2-morpholinyl] methyl]

Benzamide citrate… … … … … … … … … … … … … … … … 2 g

Cornstarch… … … … … … … … … … … … … … … … 28 g

Lactose… … … … … … … … … … … … … … … … 55 g

Microcrystalline cellulose... … … … … … … … … … … … … … … … 11 g

Hydroxypropyl cellulose... … … … … … … … … … … … … … … … 3 g

Lightweight silicic anhydride … … … … … … … … … … … … … … … 0.5g

Magnesium stearate … … … … … … … … … … … … … … … 0.5g

The ingredients are mixed by conventional methods, granulated to prepare 1,000 tablets each weighing 100 mg.

Example 246

About 1,000 Capsules

4-amino-5-chloro-2-ethoxy-N [[4- (3-pyridyl) methyl-2-morpholinyl] methyl]

Benzamide fumarate … … … … … … … … … … … … … … … 5 g

Cornstarch… … … … … … … … … … … … … … … … 103 g

Lactose… … … … … … … … … … … … … … … … 65 g

Hydroxypropyl cellulose... … … … … … … … … … … … … … … … 5 g

Lightweight silicic anhydride … … … … … … … … … … … … … … … 1 g

Magnesium stearate … … … … … … … … … … … … … … … 1 g

The ingredients are mixed by conventional methods, granulated and filled with 1,000 capsules.

Example 247

Fine granular

4-amino-N-[(4-benzyl-2-morpholinyl) methyl] -2-butoxy-5-chlorobenzamide

Fumarate Hemihydrate… … … … … … … … … … … … … … … … 10 g

Cornstarch… … … … … … … … … … … … … … … … 220 g

Lactose… … … … … … … … … … … … … … … … 730 g

Hydroxypropyl cellulose... … … … … … … … … … … … … … … … 30 g

Lightweight silicic anhydride … … … … … … … … … … … … … … … 10 g

The components are mixed by conventional methods and prepared in a microgranular form.

Claims (10)

A compound of formula (I) or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof, or wherein R is hydrogen, alkoxycarbonyl, thienylalkyl, pyridylalkyl or -TSR ₆ '(T and R ₆ ' Is an N-oxide derivative of the formula (I) compound wherein R ₁ is not alkylthio.

Wherein R is hydrogen, C ₂ -C ₅ alkoxycarbonyl, phenyl, diphenylmethyl, heteroarylfuryl, thienyl, pyridyl, or 1, 2-benzisoxazolyl heteroaryl (C ₁ -C ₃ ) alkyl, phenyl (C ₃ -C ₅ ) alkenyl, -TR ₆ (T is C ₁ -C ₆ alkylene, R ₆ is phenyl, phenyl substituted with ₁ to 3 C ₁ -C ₄ alkyl , Phenyl substituted with ₁ trifluoromethyl or C ₁ -C ₄ alkoxy, phenyl substituted with 1 halogen and 1 nitro, or naphthyl), T- (Y) pR ₆ '(T is As defined, Y is oxygen, sulfur, or carbonyl, R ₆ ′ is phenyl substituted with 1 to 5 halogen, p is 0 or 1), or —T— (Y ′) pR ₆ ″ ( T and p are as defined above, Y 'is oxygen, R ₆ "is phenyl substituted with nitro, cyano or aino) and R ₁ is halogen, hydroxy, C ₁ -C ₁₂ alkoxy, C ₃ -C ₆ cycloalkyloxy, C ₃ -C ₈ alkenyloxy, C ₃ -C ₈ eggs Kinyloxy, C ₂ -C ₈ alkoxy, C ₁ -C ₄ alkylthio, amino, interrupted by one or two oxygen or carbonyl, C ₁ -C ₈ alkyl, phenyl (C ₁ -C ₃ ) alkyl Or mono-substituted amino, which is C ₃ -C ₆ cycloalkyl, C ₂ -C ₆ alkoxy, in which the carbon atom at a position other than 1-position is substituted with one hydroxy or amino, or the substituent is halogen, cyano, C _3- C ₅ alkoxycarbonyl, phthalimido, C ₃ -C ₆ cycloalkyl, phenyl optionally substituted with one halogen, phenoxy optionally substituted with one halogen, or benzoyl optionally substituted with one halogen A substituted C ₁ -C ₈ alkoxy group, R ₂ is hydrogen, R ₃ is hydrogen, halogen, amino, C ₁ -C ₄ alkylamino, di (C ₁ -C ₄ alkyl) amino, C ₂ -C ₅ alkanoylamino, or nitro, R ₄ is Hydrogen, halogen, nitro, sulfamoyl, C ₁ -C ₄ alkylsulfamonyl, or di (C ₁ -C ₄ alkyl) sulfamoyl, or adjacent to any two of R ₁ , R ₂ , R ₃ and R ₄ The groups combine to form C ₁ -C ₃ alkylenedioxy and the remaining two groups are each hydrogen, R ₅ is hydrogen or C ₁ -C ₄ alkyl, X is C ₁ -C ₃ alkylene, and m and n Are each 1 or 2, provided that at least one of the R ₂ , R ₃ and R ₄ groups is not hydrogen. The compound of claim 1, wherein R is pyridylmethyl, -CH ₂ )

(R ₇ is hydrogen, trifluoromethyl, cyano, or nitro, q is an integer from 1 to 4),-(CH ₂ ) q- (Y)

(Y and p are as defined in claim 1, R7 'is fluorine or chlorine and q is as defined above), pentafluorobenzyl, 2-nitro-4-chlorobenzyl, 1-phenylethyl or naph Methylmethyl; R ₁ is hydroxy C ₁ -C ₁₀ alkoxy, C ₅ -C ₆ cycloalkyloxy, C ₃ -C ₅ alkenyloxy, C ₃ -C ₅ alkynyloxy, C ₂ -C terminated with 1 carbonyl ₄ alkoxy, C ₂ -C ₅ alkoxy in which the carbon atom at a position other than the 1-position is substituted with one hydroxy, or the substituent is halogen, cyano, C ₂ -C ₄ alkoxy carbonyl, C ₃ -C ₅ cyclo Substituted C ₁ -C ₅ alkoxy which is alkyl, phenyl optionally substituted with one halogen, phenoxy optionally substituted with one halogen, or benzoyl optionally substituted with one halogen; R ₂ is hydrogen; R ₃ is amino, di (C ₁ -C ₂ alkyl) amino or C ₂ -C ₅ alkanoylamino; R ₄ is chlorine; R ₅ is hydrogen or methyl; X is methylene or ethylene and m is 1; And n is 1 or 2, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof. The compound according to claim 1, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt, or N-oxide derivative thereof, having the following general formula (Ia).

Wherein R _a is pyridylmethyl, benzyl, fluorobenzyl, chlorobenzyl, trifluoromethylbenzyl, cyanobenzyl, or 3- (4-chlorophenoxy) propyl, and R _1a is C ₁ -C ₇ Alkoxy, cyclopentyloxy, 3-butenyloxy, 3-methyl-2-butenyloxy, 2-oxopropoxy, 2-hydroxypropoxy, or 2-chloroethoxy, R ₃ ′ is amino, dimethyl Amino, or C ₂ -C ₃ alkanoylamino, R ₅ ′ is hydrogen or methyl, and n is 1 or 2. N-oxide derivative of a compound of formula (Ib), wherein R _b is not pyridylmethyl, or a pharmaceutically acceptable acid addition salt thereof;

Wherein R _b is pyridylmethyl, benzyl, fluorobenzyl, chlorobenzyl, or 3- (4-chlorophenoxy) propyl and R _1b is methoxy, ethoxy, butoxy, isobutoxy, pentyloxy, Isopentyloxy, 3-methyl-2-butenyloxy, or 2-hydroxypropoxy. The compound according to claim 4, wherein the compound is 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide Compound or a pharmaceutically acceptable acid addition salt thereof, The compound of claim 1, or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt or N-oxide derivative thereof, and a pharmaceutically acceptable carrier or diluent, wherein the composition of the digestive tract dysfunction. A digestive tract dysfunction composition comprising the compound of claim 2 or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt or N-oxide derivative thereof and a pharmaceutically acceptable carrier or diluent. A digestive tract dysfunction composition comprising the compound of claim 3 or a pharmaceutically acceptable acid addition salt, quaternary ammonium salt or N-oxide derivative thereof and a pharmaceutically acceptable carrier or diluent. Digestive tract dysfunction composition comprising the compound of claim 4, or a pharmaceutically acceptable acid addition salt or N-oxide derivative thereof and a pharmaceutically acceptable carrier or diluent. A digestive tract dysfunction composition comprising the compound of claim 5 or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier or diluent.