JPH0967347A - Cyclic amine derivative and medicinal composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a compound having excellent antiemetic activity based on its potent serotonin S3 (5HT3 ) and dopamine D2 antagonistic action, thus useful for treating and preventing various digestive organ symptoms involved in various diseases and therapeutic methods. SOLUTION: This compound, a cyclic amine derivative, is expressed by formula I X is CH or N; Y is (CH2 )n , O, etc.; (n) is 1, 2 or 3; R1 is an alkyl, R2 is an alkoxyl; R3 is amino, a monoalkylamino, etc.; R4 is a halogen; wavy line means the steric configuration of the bound carbon atoms represents RS, R or S}, e.g. 5-chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl)-2-methoxy-4- methylaminobenzamide. The compound of formula I is obtained by reaction of a compound of formula II with a compound of formula II in a solvent such as benzene pref. at about -10 to 150 deg.C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to serotonin S ₃ (5
The present invention relates to a novel cyclic amine derivative represented by the following general formula (I) having a strong antagonistic effect on both receptors of -HT ₃ ) and dopamine D ₂ and a pharmaceutical composition containing these compounds.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 2-104572 describes that a compound represented by the following chemical formula 2 has a gastrointestinal function-enhancing action and is useful as an antiemetic agent or a gastrointestinal enhancer. .

[0003]

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The compound of the above chemical formula 2 does not include the compound of the present invention.

In Japanese Patent Laid-Open No. 4-210970, a compound represented by the following chemical formula 3 has a strong 5-HT ₃ receptor antagonistic action and a strong dopamine D ₂ receptor antagonistic action, and is effective for various vomiting. It is described as useful.

[0006]

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The compound of Chemical formula 3 differs from the compound of the present invention in that it has a cyclic diamine structure.

In Japanese Patent Publication No. 7-500590, a compound represented by the following chemical formula 4 is used as a 5-HT ₃ antagonist for the treatment or prevention of pain, vomiting, central nervous system disorder and gastrointestinal disorder. It is stated that it is possible.

[0009]

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The compound of Chemical formula 4 differs from the compound of the present invention in the cyclic amine moiety.

[0011]

DISCLOSURE OF THE INVENTION In order to obtain an antiemetic agent which is expected to be effective for various emesis by potently and well-balanced antagonism of both serotonin S ₃ and dopamine D ₂ receptors, As a result of earnest research on a cyclic amine derivative, it was found that the compound meets this purpose, and the present invention was completed.

[0012]

According to the present invention, there are provided a cyclic amine derivative represented by the following formula (I), a physiologically acceptable acid addition salt thereof, and a pharmaceutical composition containing the compound. It

[0013]

Embedded image [Wherein, X denotes CH or N, Y is - (CH ₂₎ n
-, -O- or -S- is meant, n is 1, 2 or 3, R ¹ is a lower alkyl group, R ² is a lower alkoxy group, R ³ is an amino group, A mono (lower) alkylamino group or a di (lower) alkylamino group is meant, R ⁴ is a halogen atom, and a wavy line (to) is RS, R or S when the configuration of the carbon atom to which it is bound is RS. Means that. However, X is CH and Y is -CH.
₂ -, - when a O- or -S-, R ³ denotes a mono (lower) alkylamino group. ]

The addition salt of the compound of the present invention represented by the formula (I) is preferably a physiologically acceptable salt, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, Inorganic acid salts such as phosphate, oxalate, maleate,
Examples thereof include organic acid salts such as fumarate, malonate, lactate, malate, citrate, tartrate, benzoate and methanesulfonate.

Since the compounds of formula (I) may exist as hydrates and solvates, these hydrates and solvates are also included in the compounds of the present invention.

The terms used in this specification are explained below.

The lower alkyl group and the lower alkyl moiety are
Unless otherwise specified, it means one having 1 to 6 carbon atoms, which may be linear or branched. "Halogen atom" means fluorine, chlorine, bromine or iodine, with chlorine and bromine being preferred. Specific examples of the "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, with ethyl being particularly preferred. Specific examples of the "lower alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy and butoxy, with methoxy being particularly preferred. The “mono (lower) alkylamino group” means an amino group having one lower alkyl moiety described above, and examples thereof include methylamino, ethylamino, propylamino, isopropylamino and butylamino, with methylamino being particularly preferable. preferable. The “di (lower) alkylamino group” means an amino group having two lower alkyl moieties described above, and examples thereof include dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, methylethylamino and methylpropylamino. Can be mentioned.

Among the compounds of the present invention, preferred are compounds of formula (I) in which R ¹ is an ethyl group, R ² is a methoxy group, and R ³ , R ⁴ , X and Y are as described above. Included are the same compounds and their physiologically acceptable acid addition salts.

Further preferred compounds are, in formula (I), X is CH, Y is —CH ₂ — or —O—, R ¹ is an ethyl group and R ² is a methoxy group. , R ³ is a methylamino group, and R ⁴ is the same as those mentioned above, and physiologically acceptable acid addition salts thereof.

Another more preferable compound is
In formula (I), X is N, Y is —CH ₂ —, R ¹ is an ethyl group, R ² is a methoxy group,
Examples include compounds in which R ³ is a methylamino group and R ⁴ is the same as those mentioned above, and physiologically acceptable acid addition salts thereof.

Particularly preferred compounds include, for example, the following compounds and physiologically acceptable acid addition salts thereof.

5-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-
Methylaminobenzamide,

5-chloro-N- (4-ethylhexahydro-1,4-oxazepin-6-yl) -2-methoxy-4-methylaminobenzamide, and

5-Bromo-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-6-
Methylamino-3-pyridinecarboxamide.

Specific examples of the compounds included in the present invention include:
In addition to the compounds of Examples described below, the following compounds and physiologically acceptable acid addition salts thereof are included.

5-Bromo-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-
Methylaminobenzamide, 5-chloro-N- (1-isopropyl-1H-hexahydroazepin-3-yl)
-2-methoxy-4-methylaminobenzamide, 5-
Bromo-N- (4-ethylhexahydro-1,4-oxazepin-6-yl) -2-methoxy-4-methylaminobenzamide, 5-chloro-N- (4-ethylhexahydro-1,4-thiazepine -6-yl) -2-methoxy-4-methylaminobenzamide, 5-bromo-N-
(4-Ethylhexahydro-1,4-thiazepine-6-
Yl) -2-methoxy-4-methylaminobenzamide, 5-chloro-N- (1-ethyl-1H-octahydroazonin-3-yl) -2-methoxy-4-methylaminobenzamide,

5-Bromo-2-methoxy-6-methylamino-N- (1-propyl-1H-hexahydroazepin-3-yl) -3-pyridinecarboxamide, 5-chloro-N- (4-ethylhexa) Hydro-1,4-oxazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide, 5-bromo-N- (4
-Ethylhexahydro-1,4-oxazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide, 5-chloro-N- (4-ethylhexahydro-1,4-thiazepine-6 -Yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide,
5-Bromo-N- (4-ethylhexahydro-1,4-
Thiazepin-6-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide, 5-bromo-N-
(1-Ethyl-1H-heptahydroazocin-3-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide, and 5-bromo-N- (1-ethyl-
1H-octahydroazonin-3-yl) -2-methoxy-6-methylamino-3-pyridinecarboxamide.

The compound of the present invention can be produced, for example, by the following method.

The compound of the present invention represented by the formula (I) has the following formula (II)

[0030]

[Chemical 6]

(Wherein R ² , R ³ , R ⁴ and X have the same meanings as described above) or a reactive derivative thereof and the following formula (III)

[0032]

[Chemical 7]

(In the formula, R ¹ , Y and the wavy line have the same meanings as described above.)

It can be produced by reacting with a compound represented by:

Examples of the reactive derivative of the compound of formula (II) include lower alkyl ester (especially methyl ester), active ester, acid anhydride and acid halide (especially acid chloride). Specific examples of the active ester include p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, and N-hydroxysuccinimide ester. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl chlorocarbonate such as ethyl chlorocarbonate and isobutyl chlorocarbonate, and chlorinated acid anhydride. Mixed anhydrides with aralkyl chlorocarbonates such as benzyl carbonate, mixed anhydrides with aryl chlorocarbonates such as phenyl carbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.

When the compound of formula (II) itself is used,
N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, N,
N'-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic anhydride, benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexa The reaction can be carried out in the presence of a condensing agent such as fluorophosphate.

The reaction of the compound of formula (II) or its reactive derivative with the compound of formula (III) is carried out in a solvent or without solvent. Examples of the solvent used include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, ethanol and isopropanol. Such alcohols, ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, ethylene glycol, water and the like can be mentioned, and these solvents can be used alone or in admixture of two or more. This reaction is carried out in the presence of a base, if necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, and sodium hydrogen carbonate. , Alkali hydrogen carbonate such as potassium hydrogen carbonate, or triethylamine, tributylamine, diisopropylethylamine,
Examples thereof include organic bases such as N-methylmorpholine, but an excess amount of the compound of the formula (III) can also serve.
The reaction temperature is usually about −30 ° C. to about 200 ° C., preferably about −
The temperature is 10 ° C to about 150 ° C.

The compound of the formula (II) in which X is CH can be prepared by a method known per se, for example, J. Med. Chem., 24 , 1224-1230 (1
It can be produced by the method described in 981) or a method analogous thereto.

The compound of formula (II) in which X is N can be produced, for example, by the method shown in the following chemical formula 8.

[0040]

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(In the formula, R means a lower alkyl group, and R
² , R ³ and R ⁴ have the same meanings as above. )

Step 1 in the above Chemical Formula 8 is carried out in ethers such as tetrahydrofuran at about -80 ° C to -60 ° C.
Then, 2,6-difluoropyridine is treated with a strong base, followed by reacting with carbon dioxide.
Is carried out by esterification according to a conventional method.
Step 3 is for example in alcohols such as ethanol,
The reaction is carried out by reacting about 2 equivalents of amines, which also serves as a trap for the acid formed, and step 4 is carried out in the presence of a suitable base.
It is carried out by reacting an alkoxide. Step 5
The halogenation of is carried out by reacting a halogenating agent such as N-chlorosuccinimide or N-bromosuccinimide in a halogenated hydrocarbon such as chloroform, and the hydrolysis in step 6 is carried out by a conventional method. .

The compound of the formula (III) in which Y is —CH ₂ — can be produced, for example, by the method shown in the following chemical formula 9.

[0044]

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(In the formula, Tr means a triphenylmethyl group, Z means a reactive ester residue of alcohol,
R ¹ and wavy line have the same meanings as above. )

Step 1 : The reaction of the compound of formula (A) with chlorotriphenylmethane is usually carried out in a suitable solvent in the presence of a base. As the solvent and the base to be used, the specific examples described in the above-mentioned production method of the compound of the present invention can be mentioned as they are. The reaction temperature is usually about -10 ° C to about 150 ° C,
It is preferably about 0 ° C to about 100 ° C.

Step 2 : The compound of formula (C) has the formula (B)
The compound can be produced by reducing the compound with a metal hydride such as diisobutylaluminum hydride, lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride. Specific examples of the solvent used include ethers such as diethyl ether and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as methylene chloride and chloroform. The reaction temperature is generally about -10 ° C to about 100 ° C, preferably about 0 ° C to about 50 ° C.
° C.

Step 3 : Compound of formula (C) and formula: R ^1-
The reaction with the R ¹ introducing agent represented by Z is usually carried out in a suitable solvent,
It is carried out in the presence of a base. Examples of the reactive ester residue of alcohol represented by Z include halogen atoms such as chlorine, bromine and iodine. Specific examples of the solvent include aromatic hydrocarbons such as benzene and toluene,
Examples thereof include ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, alcohols such as ethanol and isopropyl alcohol, acetonitrile, chloroform, ethyl acetate, dimethylformamide, dimethyl sulfoxide, or a mixed solution thereof. Specific examples of the base used include the specific examples described in the above-mentioned production method of the compound of the present invention. Usually about 0 ° C to about 200 ° C, preferably about
80 ° C to about 150 ° C.

Step 4 : The reaction of this step is usually carried out using a mineral acid such as dilute hydrochloric acid or dilute sulfuric acid in a suitable solvent. Specific examples of the solvent used include alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, acetone, acetonitrile,
Examples thereof include ethylene glycol or a mixed solution thereof. The reaction temperature is usually about 0 ° C to about 100 ° C.

The compound of formula (III ') can also be produced by exchanging the reduction reaction of step 2 and the R ¹ introduction reaction (alkylation reaction) of step 3 in the above chemical formula 9. That is, the compound of formula (B) can be converted to the compound of formula (D) by alkylating (step 2 ′) and then reducing (step 3 ′). In this case, in the alkylation reaction of step 2 ′, it is preferable to use a strong base such as sodium hydride instead of the base described in the production method of the compound of the present invention, and in the reduction reaction of step 3 ′, Is preferably sodium bis (2-methoxyethoxy) aluminum hydride.

The compound of formula (III) in which Y is-(CH ₂ ) ₂ --or-(CH ₂ ) ₃ --can be produced, for example, by the method shown in the following chemical formula 10.

[0052]

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(Wherein Z ¹ represents a halogen atom,
n'means 1 or 2 and R ¹ and Z mean the same as above. )

The step 1 in the above chemical formula 10 is the same as the step 2'in the modification of the method shown in the above chemical formula 9 using commercially available 2-azacyclooctanone or 2-azacyclononanone as the starting material. Can be done by Halogenation of step 2, for example, J.Am. Chem. Soc., 80, 6233
-6237 (1958),
Steps 3 and 4 are, for example, Helv. Chim. Acta, 41 ,
It can be performed according to the method described in 181-188 (1958).

The compound of the formula (III) in which Y is --O-- or --S-- can be produced, for example, by the method described in JP-A-2-104572 or a method analogous thereto.

In the compound of formula (III), the compound in which Y is —O— or its optically active substance can be produced, for example, by the method shown in the following chemical formula 11.

[0057]

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(In the formula, Tr, R ¹ and the wavy line have the same meanings as described above.)

The step 1 in the above chemical formula 11 can be carried out in the same manner as the step 1 in the chemical formula 9 using a commercially available serine methyl ester or an optically active substance thereof as a starting material. The amidation of step 2 can be carried out under reaction conditions to synthesize an amide compound from a usual ester,
For example, it can be carried out by reacting a lower alkylamine in a solvent such as chloroform or ethanol at about 0 ° C to about 150 ° C. The reduction in step 3 is performed by using a reducing agent such as borane-tetrahydrofuran complex in an ether such as diethyl ether or tetrahydrofuran at about −20.
It can be carried out by reacting at a temperature between 50 ° C and about 50 ° C.
The ring-closing reaction of step 4 can be carried out by reacting chloroacetyl chloride at about 0 ° C to about 30 ° C in the presence of a base in a halogenated hydrocarbon such as chloroform. The reduction in Step 5 can be carried out in the same manner as in Step 2 in Chemical Formula 9 above, and the deprotection in Step 6 can be carried out in the same manner as in Step 4 in Chemical Formula 9 above.

According to the method represented by the chemical formula 9,
The configuration of the starting compound (A) is retained in the final product represented by the formula (III ′). On the other hand,
The final product of formula (III ″) produced by the method shown in is racemic. Further, in the compound of the formula (III), the compound produced by the method described in JP-A No. 2-104572 and Y is —O— or —S— is also a racemate. These racemic compounds of formula (III) can be separated into two optical isomers according to a conventional method. For example,
This is carried out by forming a diastereomeric salt of a compound of the formula (III) with an optically active acid, and then separating the two diastereomeric salts, and then converting this into a free base.

According to the above method for producing the compound of formula (I), the configuration of the compound of formula (III) as the starting compound is retained in the compound of formula (I).

The compound of formula (I) having a desired configuration can also be obtained by subjecting the compound of formula (II) to a racemic mixture of the compound of formula (III) produced according to JP-A 2-104572 according to the above-mentioned production method. After reacting and producing, it can be produced by optical resolution according to a conventional method.

The compound of formula (I) produced by the above production method is isolated and purified by a conventional method such as chromatography, recrystallization and reprecipitation.

The compound of formula (I) can be obtained in the form of a free base or an acid addition salt, depending on the reaction and treatment conditions. The acid addition salt can be converted to a free base by a conventional method, for example, by treating with a base such as alkali carbonate or alkali hydroxide. On the other hand, the free base can be converted to an acid addition salt by treating it with various acids according to a conventional method.

The test results of the compound of the present invention and metoclopramide hydrochloride monohydrate (Compound A), which is a commercially available drug for improving gastrointestinal tract function, are shown below, and the characteristics of the pharmacological action of the compound of the present invention are described.

Test Example 1 : Inhibitory action against apomorphine-induced vomiting (action based on anti-dopamine D ₂ action): Apomorphine-induced vomiting using 3 to 4 beagle dogs (body weight 8 to 15 kg) per group The antagonism of the test compound was examined. This test is commonly used as a method for detecting dopamine blockers. A prescribed dose of the test compound dissolved or suspended in a 0.5% tragacanth solution was orally administered, and 2 hours later, apomorphine hydrochloride (0.3 mg / kg) was injected subcutaneously into the back, and then the number of vomits was counted for 1 hour. Vomiting number of test compound administration group was calculated percent inhibition compared to that of the control group, 50% inhibiting effective amount (ED ₅₀ value) was determined by probit method. The results are shown in Table 1.

Test Example 2 : von Bezold-Jarisch reflex inhibitory action (anti-5-HT ₃ action) This test was carried out by the method of Fozard et al. [Arch. Pharmacology, 326 ,
36-44 (1984)]. Male Wistar rats (body weight 250-350 g) were anesthetized with urethane (1.5 g / kg, intraperitoneal) and fixed in a dorsal position. Electrocardiogram (second lead)
Was derived and the heart rate was recorded on an oscilloscope via a heart rate tachometer. 2-Methylserotonin (5-HT ₃ agonist) was intravenously administered at 10-30 μg / kg, resulting in a transient decrease in heart rate, namely Von Bezold-Jaris
ch reflection occurs. A fixed amount of 2-methylserotonin was repeatedly administered at 15-minute intervals, and after a stable reaction was obtained, the test compound was intravenously administered 3 minutes before 2-methylserotonin administration. For the drug efficacy, the inhibitory rate of the reaction after the administration to the reaction before the administration of the test compound was calculated, and the effective dose (ED ₅₀ value) for inhibiting 50% was determined by the probit method. The results are shown in Table 1.

[0068]

[Table 1] ^* ) Means the compound of Example 1 (the same applies hereinafter).

As is clear from the above test results, the compound of formula (I) and its physiologically acceptable acid addition salt are excellent in their strong serotonin S ₃ (5-HT ₃ ) and dopamine D ₂ antagonism. It has anti-emetic action and low toxicity, and can be used as an anti-emetic agent for the treatment and prevention of various gastrointestinal symptoms associated with various diseases and treatment methods. Specifically, acute / chronic gastritis, reflux esophagitis, gastric / duodenal ulcer, gastric neuropathy, gastroptosis, postgastrectomy syndrome, scleroderma, diabetes, esophageal / biliary tract disease, periodic vomiting in children, For the treatment and prevention of nausea, vomiting, loss of appetite, abdominal distention, upper abdominal discomfort, abdominal pain, heartburn, vomiting, etc. in diseases such as upper respiratory tract infection, and treatment of irritable bowel syndrome, constipation, infant diarrhea. And can be used for prevention. Furthermore, it can be used for the treatment and prevention of nausea or vomiting during administration of various anticancer agents or levodopa preparations or during irradiation of radiation. Furthermore, it can be used as an antipsychotic agent or anxiolytic agent, and also for the treatment and prevention of intoxication of addictive drugs (morphine, nicotine, amphetamine, etc.).

The route of administration may be oral, parenteral or rectal administration. The dose varies depending on the type of compound, administration method, patient's symptom / age, etc.
50 mg / kg / day, preferably 0.1 to 10 mg / kg / day, when used as an antipsychotic agent, usually 1 to 100
mg / kg / day, preferably in the range of 3 to 50 mg / kg / day.

When the compound of formula (I) or physiologically acceptable acid addition salt is used for the above-mentioned pharmaceutical use, it is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. As the carrier for formulation, a substance which is commonly used in the field of formulation and which does not react with the compound of the present invention is used. Specifically, for example, citric acid, glutamic acid, glycine, lactose,
Inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, methyl paraoxybenzoate, propyl paraoxybenzoate, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, Hydroxypropyl starch, carboxymethyl cellulose calcium, ion exchange resin, methyl cellulose, gelatin, gum arabic, pullulan, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid Acid, magnesium stearate, talc, traga DOO, bentonite, Veegum, carboxyvinyl polymers, titanium oxide, sorbitan fatty acid esters, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oils, waxes,
Examples include propylene glycol, ethanol, benzyl alcohol, sodium chloride, sodium hydroxide, hydrochloric acid, water and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections and suppositories. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. Tablets and granules may be coated by a known method.

These preparations may contain the compound of formula (I) or a physiologically acceptable acid addition salt thereof in an amount of 0.01% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically valuable components.

[0074]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples, but the present invention is not limited to these Examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra and the like.

In the following Reference Examples and Examples,
The following abbreviations may be used to simplify the description.

[Recrystallization Solvent] A: ethanol, AT: acetone, E: diethyl ether, EA: ethyl acetate, HX: n-hexane, IP: isopropanol, PE: petroleum ether, T: toluene.

[Substituent] Me: methyl group, Et: ethyl group, Pr: n-propyl group, iPr: isopropyl group.

[NMR] J: binding constant, s: singlet, d: doublet, dd: doublet, t: triplet, q: quartet, m: multiplet, d-like : Double line.

Reference Example 1 --Preparation of 5-bromo-2-methoxy-6-methylamino-3-pyridinecarboxylic acid:

(1) 2,6-difluoropyridine 50
g was dissolved in 200 ml of tetrahydrofuran, and n was added at -70 ° C.
-Butyl lithium 1.6M Hexane solution 326 ml was added dropwise. After stirring for 1 hour at the same temperature, dry ice was added to the reaction mixture.
Add a small chunk of g. Then, after stirring for 30 minutes at the same temperature, the temperature was raised to about 5 ° C., and 500 ml of ice water was added. The reaction solution was washed twice with ethyl acetate, the aqueous layer was adjusted to pH 3 with concentrated hydrochloric acid, and extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration and recrystallized from diethyl ether-n-hexane to give 2,6
63 g of difluoro-3-pyridinecarboxylic acid were obtained.
170-171 ° C

(2) 63 g of the above product, 7 methanol
A mixture of 00 ml and 5 ml of concentrated sulfuric acid was heated under reflux for 20 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with ice water.
It was extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform to obtain methyl 2,6-difluoro-3-pyridinecarboxylate (64 g) as an oil.

(3) 38 g of the above product, ethanol 5
72 g of ethanol solution of 20% methylamine in 00 ml solution
Was added dropwise at -20 ° C to -25 ° C. After stirring at the same temperature for 5 hours, the temperature was raised to room temperature, and the reaction solution was concentrated under reduced pressure. Ice water was added to the concentrated solution, and the precipitated solid was collected by filtration, washed with water, dried, and then treated with diethyl ether-n-hexane (2:
Recrystallized from 3) to give 2-fluoro-6-methylamino-
15.7 g of methyl 3-pyridinecarboxylate was obtained. 156-159 ° C

(4) 15.7 g of the above product, methanol
To the 400 ml solution was added 19.1 g of potassium tert-butoxyside, and the mixture was heated under reflux for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure, and an aqueous solution of sodium hydrogen carbonate was added to the residue. The precipitated solid was collected by filtration, washed with water, dried and dried.
16.3 g of methyl methoxy-6-methylamino-3-pyridinecarboxylate was obtained. Melting point 120-122 ° C (n
-Recrystallized from hexane-diethyl ether)

(5) To a solution of 7.3 g of the above product in 70 ml of dimethylformamide was added 7.0 g of N-bromosuccinimide.
And heated at 80 ° C. for 4 hours. Ice water is added to the reaction solution,
The precipitated solid is collected by filtration, washed with water and dried, and then dried.
9.8 g of methyl-bromo-2-methoxy-6-methylamino-3-pyridinecarboxylate were obtained. Melting point 136 ~
138 ° C (recrystallized from n-hexane-diethyl ether)

(6) An aqueous solution containing 3.1 g of sodium hydroxide in 100 ml of a methanol solution of 20 g of the above product 200
Then, the mixture was heated and refluxed for 1.5 hours. After cooling, methanol was distilled off under reduced pressure, and the mixture was acidified with concentrated hydrochloric acid. The precipitated solid was collected by filtration, washed with water and dried to obtain the desired product 18.
9 g were obtained. 224-225 ° C

¹ H-NMR spectrum (DMSO-d ₆ , δppm):
2.92 (3H, d, J = 5Hz), 3.88 (3H, s), 7.08 (1H, d, J = 5
Hz), 7.98 (1H, s), 12.08 (1H, s)

Reference Example 2 --- Preparation of 5-chloro-2-methoxy-6-methylamino-3-pyridinecarboxylic acid:

N-chlorosuccinimide was used in place of the N-bromosuccinimide of Reference Example 1 (5), and the reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the desired product.

Reference Example 3 --5-chloro-2-isopropoxy-6-methylamino-
Preparation of 3-pyridinecarboxylic acid:

Isopropanol was used instead of methanol in Reference Example 1 (4), and N-chlorosuccinimide was used in place of N-bromosuccinimide in Reference Example 1 (5). I got the object.

Reference Example 4 -- Preparation of 5-chloro-6-dimethylamino-2-isopropoxy-3-pyridinecarboxylic acid:

Dimethylamine was used in place of the ethanol solution of 30% methylamine in Reference Example 1 (3), and Reference Example 1
Isopropanol was used in place of methanol in (4), and N was used in place of N-bromosuccinimide in Reference Example 1 (5).
-Using each of chlorsuccinimide, reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the target product.

Reference Example 5 --- Preparation of 3-amino-1-ethyl-1H-hexahydroazepine:

(1) α-amino-ε-caprolactam
125 g of triethylamine and 118 g of chloroform 600 m
l To the suspension, 288 g of chlorotriphenylmethane was added with stirring under ice cooling. The mixture was further stirred under the same conditions for 1 hour and then at room temperature for 2 hours. The precipitate was collected by filtration, washed sufficiently with acetone, dried and dried to form α-
330 g of triphenylmethylamino-ε-caprolactam
I got 240-241 ° C

(2) 100 g of the above product and iodoethane
To a solution of 65 g of dimethylformamide in 500 ml of solution, 12 g of 60% sodium hydride was gradually added with stirring at room temperature. After stirring for 4 hours under the same conditions, the mixture was poured into ice water. The reaction solution was extracted with diethyl ether, the extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration and dried to give 1-ethyl-3.
88 g of -triphenylmethylamino-1H-hexahydroazepin-2-one were obtained. Melting point 120-121 ° C

(3) 180 g of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene
800 ml of toluene was added thereto, and 83 g of the above product was added thereto with stirring under ice-cooling, followed by stirring under the same conditions for 1 hour.
Stirred at room temperature for another 2 hours. The reaction mixture is cooled with ice
After addition of an aqueous sodium hydroxide solution, the organic layer was separated. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. After the obtained oily residue was crystallized from ethanol, the crystals were collected by filtration, dried and dried.
65 g of ethyl-3-triphenylmethylamino-1H-hexahydroazepine were obtained. 85-86 ° C

(4) To a solution of 134 g of the above product in 30 ml of tetrahydrofuran was added 500 ml of 10% hydrochloric acid, and the mixture was allowed to stand at room temperature for 2 hours.
Stir for hours. The reaction solution was washed with diethyl ether, and then excess potassium carbonate was added to the aqueous layer, followed by extraction with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 48 g of the desired product as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.
04 (3H, t, J = 7.5Hz), 1.3-1.9 (8H, m), 2.42 (1H, dd,
J = 13.5Hz, J = 6.9Hz), 2.5-2.6 (4H, m), 2.70 (1H, d
d, J = 13.5, J = 3.5Hz), 2.98 (1H, m).

Reference Example 6 --Production of (R) 3-amino-1-ethyl-1H-hexahydroazepine:

Α-Amino-ε-in Reference Example 5 (1)
(R) -α-amino-ε-caprolactam was used instead of caprolactam, and the reaction and treatment were carried out in the same manner as in Reference Example 5 to obtain the desired product as an oil.

Reference Example 7 : Preparation of (S) -3-amino-1-ethyl-1H-hexahydroazepine:

Α-Amino-ε-in Reference Example 5 (1)
(S) -α-amino-ε-caprolactam was used instead of caprolactam, and the reaction and treatment were carried out in the same manner as in Reference Example 5 to obtain the desired product as an oil.

Reference Example 8 : Preparation of 3-amino-1-methyl-1H-hexahydroazepine:

Iodomethane was used instead of iodoethane in Reference Example 5 (2), and the reaction and treatment were carried out in the same manner as in Reference Example 5 to obtain the desired product as an oil.

Reference Example 9 : Preparation of 3-amino-1-ethyl-1H-heptahydroazocine:

(1) 2-azacyclooctanone 27 g
To a solution of iodoethane and 50 g of iodoethane in 250 ml of tetrahydrofuran, 10 g of 60% sodium hydride was gradually added while stirring under ice-cooling. After the reaction mixture was stirred at room temperature for 4 hours, it was poured into ice water and extracted with diethyl ether. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (100: 1) to give 1-ethyl-1H-heptahydro. Azocin-2-one
36 g were obtained as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.
15 (3H, t, J = 7Hz), 1.4-1.7 (6H, m), 1.82 (2H, m),
2.48 (2H, m), 3.38 (2H, q, J = 7Hz), 3.47 (2H, m).

(2) Chloroform of 25 g of the above product
34 g of phosphorus pentachloride was gradually added to a 200 ml solution while stirring under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. 0.4 g of iodine was added to this mixture with stirring under ice-cooling, then 25 g of bromine was slowly added dropwise under the same conditions, and the mixture was heated under reflux for 2 hours. After cooling, the solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate and then washed successively with water and an aqueous sodium thiosulfate solution. After drying the ethyl acetate solution over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (4:
The crystals obtained by elution and purification in 1) were recrystallized from n-hexane to give 3-bromo-1-ethyl-1H-heptahydroazocin-2-one and 3-chloro-1-ethyl-1H.
10 g of a mixture of -heptahydroazocin-2-one was obtained.

(3) A solution of 10 g of the above mixture, 12 g of sodium azide and 2.0 g of sodium iodide in 100 ml of dimethylformamide was stirred overnight at 80 ° C., poured into ice water and extracted with diethyl ether. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with n-hexane-ethyl acetate (4: 1) to give 3-azido-1-ethyl-1H-heptahydroazocin-2-one.
4.8 g were obtained as an oil.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.
18 (3H, t, J = 7Hz), 1.5-1.8 (6H, m), 2.2 (2H, m),
3.08 (1H, m), 3.28 (1H, m), 3.53 (1H, m), 3.76 (1
H, m), 4.0 (1H, dd, J = 10.5Hz, J = 5.6Hz).

(4) 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride 36.
100 ml of toluene was added to 4 g, and 4.8 g of the above product was added.
g was slowly added with stirring under ice cooling, the temperature was raised after the addition was completed, and the mixture was stirred at room temperature for 2 hours. Water and 48% aqueous sodium hydroxide solution were slowly added to the reaction solution while stirring under ice cooling, and the toluene layer was separated and extracted with diethyl ether. After drying the combined organic layers with anhydrous magnesium sulfate,
The solvent was evaporated under reduced pressure to give the desired product (3.8 g) as an oil.

Reference Example 10- (S) -6-Amino-4-ethylhexahydro-1,4
-Production of Oxazepine:

(1) 30 g of (D) -serine methyl ester / hydrochloride was suspended in 300 ml of chloroform, and 47 g of triethylamine and 5 g of chlorotriphenylmethane were added to the suspension.
4 g was added, and the mixture was stirred at 0 to 10 ° C for 2 hours. After washing the reaction solution with water, the solvent was evaporated under reduced pressure, 125 g of a 70% ethylamine aqueous solution and 120 ml of ethanol were added to the residue, and the mixture was heated under reflux for 24 hours. The solvent was evaporated under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted and purified with chloroform to obtain (R) -3-hydroxy-2-triphenylmethylamino-N-ethylpropionamide 29 g as crystals. Obtained.

¹ H-NMR spectrum (CDCl ₃ , δppm): 1.
09 (3H, t, J = 7Hz), 1.96 (1H, t, J = 5Hz), 2.77 (1H,
m), 2.95 (1H, m), 3.04-3.35 (3H, m), 3.57 (1H, m),
7.10-7.50 (16H, m)

(2) 7.0 g of the above product was dissolved in 70 ml of tetrahydrofuran, 19 ml of a 1M borane-tetrahydrofuran solution was added at room temperature, and the mixture was heated under reflux. The reaction solution was cooled to room temperature, 40 ml of methanol was added, and the mixture was heated under reflux for 1 hour again. After cooling, the solvent was distilled off under reduced pressure, and the residue was chloroform.
20 ml and 3.8 g of triethylamine were added, and 2.1 g of chloroacetyl chloride was added dropwise at 0 to 10 ° C. After stirring at 10 ° C for 1 hour, the solvent was distilled off under reduced pressure, and ethanol was added to the residue.
2 ml and 1.5 g of potassium hydroxide were added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, followed by extraction with diethyl ether, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified to obtain (S) -6-triphenylmethylamino-4-ethylhexahydro-3-oxo-1,4-oxazepine.
1.8 g was obtained as crystals.

(3) 0.7 g of the above product was added to 200 m of toluene.
2.5 g of 70% sodium bis (2-methoxyethoxy) aluminum hydride toluene solution was added at room temperature, and the mixture was stirred for 8 hours. After ice water was added to the reaction solution, the toluene layer was separated and the solvent was evaporated under reduced pressure to remove (S) -6-triphenylmethylamino-4-ethylhexahydro-
0.58 g of 1,4-oxazepine was obtained.

¹ H-NMR spectrum (CDCl ₃ , δppm): 0.
85 (3H, t, J = 7Hz), 1.72 (1H, dd, J = 6Hz, J = 12Hz),
2.18-2,68 (6H, m), 2.95 (1H, m), 3.40 (1H, dd, J = 5H
z, J = 14Hz), 3.60-3.75 (3H, m), 7.12-7.65 (15H, m)

(4) Using the above product, Reference Example 5 (4)
Reaction and treatment were carried out in the same manner as in (1) to obtain the desired product.

Reference Example 11-(R) -6-Amino-4-ethylhexahydro-1,4
-Production of Oxazepine:

Instead of (D) -serine methyl ester • hydrochloride of Reference Example 10 (1), (L) -serine methyl ester • hydrochloride was used, and the reaction and treatment were carried out in the same manner as in Reference Example 10 to give the desired product. Obtained.

Example 1 Preparation of 5-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide:

5-Chloro-2-methoxy-4-methylaminobenzoic acid 8.06 g, 3-amino-1-ethyl-1H
-Hexahydroazepine 5.3 g dichloromethane 100 m
l-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride with stirring at room temperature 7.88 g
Was added, and the mixture was stirred at room temperature for 24 hours. 100 ml of reaction mixture in water
The mixture was washed successively with 100 ml of 10% aqueous sodium hydroxide solution, the organic layer was dried over anhydrous magnesium, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (1: 1).
It was purified and recrystallized from ethanol to obtain 5.3 g of the desired product.

Melting point 141-143 ° C .; ¹ H-NMR spectrum (CDCl ₃ , δppm): 1.04 (3H, t, J
= 7Hz), 1.5-2,0 (6H, m), 2.45-2.9 (6H, m), 2.95 (3H,
d, J = 5Hz), 3.96 (3H, s), 4.28 (1H, m), 4.68 (1H, d-
like), 6.12 (1H, s), 8.12 (1H, s), 8.44 (1H, d-lik
e).

Example 2 -- Preparation of (R) -5-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide:

5-Chloro-2-methoxy-4-methylaminobenzoic acid 1.25 g dimethylformamide solution 10
0.98 g of N, N'-carbodiimidazole was added to ml with stirring at room temperature. After stirring this mixed solution at room temperature for 5 hours, 0.86 g of (R) -3-amino-1-ethyl-1H-hexahydroazepine was added, and the mixture was stirred at room temperature for one day. After completion of the reaction, the solvent was distilled off under reduced pressure, chloroform was added thereto, and the mixture was washed with 10% aqueous sodium hydroxide solution. After drying the chloroform layer over anhydrous magnesium,
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (20:
Elute and purify in 1) and recrystallize from ethyl acetate to obtain the desired product.
0.99 g was obtained. 114-115 ° C

Examples 3 to 19 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds of Tables 2 and 3 represented by Chemical formulas 12 and 13.

[0127]

[Chemical 12]

[0128]

[Table 2] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ (℃) Recrystallization Example R ⁴ R ³ R ¹ Y Melting point Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 3 ^* Cl NHMe Et CH ₂ 116-118 EA 4 Br NHMe Et CH ₂ 140 -142 T 5 Cl NHMe Me CH ₂ 176-177 AE 6 Cl NHEt Et CH ₂ 101-103 TE 7 Cl NHMe Et (CH ₂ ) ₂ Amorphous ────────────────── ────────────── 8 Cl NHMe Et O 147-148 EA 9 ^* Cl NHMe Et O 105-106 AE 10 ^** Cl NHMe Et O 101-103 EA 11 Br NHMe Et O 157 -159 IP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ^* : S body, ^** : R body

[0129]

Embedded image

[0130]

[Table 3] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ (℃) Recrystallization Example R ⁴ R ³ R ² Q Melting point Solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 12 Br NHMe OMe 125-127 PE 13 ^** Br NHMe OMe 117-119 PE 14 ^* Br NHMe OMe 120-121 HX-EA 15 Cl NHMe OMe 132-133 PE-E 16 Cl NHMe O-iPr HCl 94-98 AT 17 Cl NH ₂ OMe 139-142 E-IP 18 Cl NH ₂ OEt 90-94 PE -E 19 Cl NMe ₂ O-iPr HCl, 1 / 4H ₂ O <35 AT ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ^* : S body, ^** : R body

Formulation Example 1 : Preparation of tablets (5 mg tablets) 5-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide (5 g), lactose (80 g), corn starch (30 g), crystalline cellulose (25 g), hydroxypropyl cellulose (3 g), light anhydrous silicic acid (0.7 g)
), And magnesium stearate (1.3 g).

The above ingredients are mixed and granulated by a conventional method, and each tablet is tableted at 145 mg to give 1000 tablets.

Formulation Example 2 : Preparation of powder (1%) 5-Bromo-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-6-methylamino-3-pyridine Carboxamide (10 g), lactose (960 g)
), Hydroxypropyl cellulose (25 g), and light anhydrous silicic acid (5 g).

After mixing the above components by a conventional method, a powder is prepared.

[0135]

INDUSTRIAL APPLICABILITY As described above, the compound of the present invention represented by the formula (I) and its physiologically acceptable acid addition salt are strong serotonin S ₃ (5-HT ₃ ), and dopamine D ₂ It exhibits an excellent antiemetic action based on an antagonistic action, and can be used as an antiemetic agent for the treatment and prevention of various gastrointestinal symptoms associated with various diseases and treatment methods. Specifically, acute / chronic gastritis, reflux esophagitis, gastric / duodenal ulcer, gastric neuropathy, gastroptosis, postgastrectomy syndrome, scleroderma, diabetes, esophageal / biliary tract disease, periodic vomiting in children, For the treatment and prevention of anorexia, nausea, vomiting, abdominal distention, upper abdominal discomfort, abdominal pain, heartburn, vomiting, etc. in diseases such as upper respiratory tract infections, and treatment of irritable bowel syndrome, constipation, infant diarrhea And can be used for prevention. Furthermore, it can be used for the treatment and prevention of nausea or vomiting during administration of various anticancer agents or levodopa preparations or during irradiation of radiation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 401/12 223 C07D 401/12 223 413/12 213 413/12 213 417/12 213 417/12 213

Claims (8)

[Claims] 1. A cyclic amine derivative represented by the following chemical formula 1 or a physiologically acceptable acid addition salt thereof. Embedded image [Wherein, X denotes CH or N, Y is - (CH ₂₎ n
-, -O- or -S- is meant, n is 1, 2 or 3, R ¹ is a lower alkyl group, R ² is a lower alkoxy group, R ³ is an amino group, A mono (lower) alkylamino group or a di (lower) alkylamino group is meant, R ⁴ is a halogen atom, and a wavy line (to) is RS, R or S when the configuration of the carbon atom to which it is bound is RS. Means that. However, X is CH and Y is -CH.
₂ -, - when a O- or -S-, R ³ denotes a mono (lower) alkylamino group. ] 2. The compound according to claim 1, wherein R ¹ is an ethyl group, and R ² is a methoxy group, or a physiologically acceptable acid addition salt thereof. 3. X is CH and Y is —CH ₂ — or —
The compound according to claim 2, which is O-, and R ³ is a methylamino group, or a physiologically acceptable acid addition salt thereof. 4. X is N and Y is --CH _2- ,
The compound according to claim 2, wherein R ³ is a methylamino group, or a physiologically acceptable acid addition salt thereof. 5. 5-Chloro-N- (1-ethyl-1H-
Hexahydroazepin-3-yl) -2-methoxy-4
-Methylaminobenzamide or a physiologically acceptable acid addition salt thereof. 6. 5-Chloro-N- (4-ethylhexahydro-1,4-oxazepin-6-yl) -2-methoxy-4-methylaminobenzamide or a physiologically acceptable acid addition salt thereof. 7. 5-Bromo-N- (1-ethyl-1H-
Hexahydroazepin-3-yl) -2-methoxy-6
-Methylamino-3-pyridinecarboxamide or a physiologically acceptable acid addition salt thereof. 8. A pharmaceutical composition comprising the cyclic amine derivative according to any one of claims 1 to 7 or a physiologically acceptable acid addition salt thereof.