JPH1053528A - Medicine consisting of 6-methoxy-1h-benzotriazole-5-carboxamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine which possesses excellent antiemetic effect and pressor activity for alimentary canal and weak suppressing activity for central nervous system and is useful for treatment and prevention for functional abnormality of digestive organs by using a specific benzotriazole carboxamide derivative. SOLUTION: As this medicine, either of 6-methoxy-1H-benzotriazole-5- carboxamide derivatives of formula I (R<1> is ethyl or cyclopropylmethyl; R<2> is H, methyl or ethyl; (n) is 1-3; a wave line shows steric configuration, RS, R or S, at the carbon bonding with it) or its physiologically permissible acid- added salts or these hydrates are used. As the compound of formula I, (R)-N-(1- ethyl-1H-hexahydroazepine-3-yl)-6-methoxy-1-methyl-1H-benzotriazole-5- carboxamides are illustrated. The compound of formula I, e.g. a compound of formula I in which R<2> is H, is obtained via an intermediate of formula II (R<3> is a protecting group for amino group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel 6-methoxy-1H-benzotriazole-5-carboxamide derivative characterized by excellent antiemetic action and gastrointestinal function-enhancing action and weak central inhibitory action. More specifically, 6-methoxy-1H-benzotriazole-5-, in which the nitrogen atom of the amide moiety (-CONH-) is substituted by a 7, 8- or 9-membered 1-substituted-azacycloalkane-3-yl group. The present invention relates to a medicament comprising a carboxamide derivative.

[0002]

2. Description of the Related Art Japanese Patent Application Laid-Open 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 or gastrointestinal function-enhancing agent.

[0003]

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[Wherein, R ₁ represents a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group, and R ₂ represents a hydroxy group, an alkoxy group, an alkenyloxy group, a cycloalkyloxy group or a substituted R ₃ represents an amino group, a disubstituted amino group or an acylamino group, and R ₄ represents a halogen atom, wherein the substituent is a halogen atom, a hydroxy group or an oxo group. Or R ₃ and R ₄ may together form —NH—N ＝ N—, R ₅ represents a hydrogen atom or a lower alkyl group, and X represents a single bond or a lower alkylene group. And Y is a single bond, —CH ₂ —, —O
—, —S—, —SO—, —SO ₂ — or —NR ₆ —, wherein R ₆ is a lower alkyl group or an unsubstituted or substituted aryl (lower) alkyl group. Or together with R ₁ may form an ethylene group, n represents 0 or 1, and the dashed line represents a case where Y is -CH ₂ -and n is 0. Means an existing double bond. Where (i) Y is-
When it is NR ₆ -or a single bond, n means 0, and (i
i) when Y is -O-, n means 1; (iii) Y
Is a single bond or —CH ₂ — and n is 0, R
₁ represents an unsubstituted or substituted aryl (lower) alkyl group, and (iv) when n is 0, X represents a lower alkylene group. ]

However, the above publication discloses the combination of a 1H-benzotriazole skeleton represented by the following formula (I) used in the present invention and a nitrogen-containing 7-, 8- or 9-membered aliphatic ring. No specific disclosure is made of compounds having the compound, especially optically active substances and their pharmacological actions.

Japanese Patent Application Laid-Open No. 52-83737 discloses that a compound represented by the following chemical formula 3 has a strong inhibitory action on avoidance of conditions, an inhibitory action on stereotypical behavior of apomorphine and an inhibitory action on stereotyped methamphetamine. It is disclosed as being particularly useful as an antipsychotic.

[0007]

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Wherein A-CO is a 4-amino-5-chloro-2-methoxybenzoyl group, a 5-ethylsulfonyl-2-methoxybenzoyl group or a 2-methoxy-4,5
An azidobenzoyl group, B is an allyl group or a benzyl group with or without a substituent,
Means 1 or 2. ]

Also, Japanese Patent Application Laid-Open No. 52-100473 discloses the same about a compound represented by the following formula (4).

[0010]

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(Wherein R ¹ is a lower alkoxy group, R ² is a benzyl group having or not having a substituent, or m
Means 1 or 2. )

However, in the compounds represented by the formulas (3) and (4), the ring bonded to the amide (-CONH-) is a 5- or 6-membered ring, and the ring-forming nitrogen atom is an allyl group or a benzyl group. In that the compound is substituted with a group, the structure is different from that of the compound of the formula (I) described below, and the pharmacological action is completely different from that of the compound used in the present invention.

[0013]

SUMMARY OF THE INVENTION 4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide [generic name metoclopramide;
Merck Index, 11th edition, 6063 (1989)] has both an antiemetic effect and a gastrointestinal hyperactivity, and has been used as a gastrointestinal function improving drug for various digestive diseases or various digestive diseases associated with treatment since ancient times. It is used for treatment and prevention of organ dysfunction. However, metoclopramide has a central inhibitory action based on dopamine D ₂ receptor antagonism as a side effect, and thus has a clinically difficult use. As the number of patients suffering from unidentified complaints of the digestive system is increasing due to the complication of social life and the advent of an aging society, compounds with weak central inhibitory effects and excellent antiemetic and gastrointestinal hyperactivity The development of is desired.

As a result of extensive studies, the present inventors have found that the nitrogen atom of the amide moiety (-CONH-) is substituted with a 7-, 8- or 9-membered 1-substituted-azacycloalkane-3-yl group. 6-methoxy-1H-benzotriazole-5
Carboxamide derivatives, especially those having the configuration R (R)
Despite having excellent antiemetic action and gastrointestinal function-enhancing action, the -6-methoxy-1H-benzotriazole-5-carboxamide derivative was unexpectedly found to have a weak central inhibitory action, and completed the present invention. did.

[0015]

According to the present invention, there is provided a 6-methoxy-1H-benzotriazole-5-carboxamide derivative represented by the following formula (I) and a physiologically acceptable acid addition salt thereof. A medicament is provided.

[0016]

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Wherein R ¹ represents an ethyl group or a cyclopropylmethyl group; R ² represents a hydrogen atom, a methyl group or an ethyl group; n represents 1, 2 or 3; ) Indicates that the configuration of the carbon atom to which it is attached is R
It means S, R or S. ]

The physiologically acceptable acid addition salts of the compounds of the formula (I) include, for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate; And organic acid salts such as oxalate, maleate, fumarate, lactate, malate, citrate, tartrate, benzoate and methanesulfonate. Since the compound of the formula (I) and the acid addition salt thereof may exist as a hydrate or a solvate, these hydrates and solvates are also used as the compounds used in the present invention (hereinafter simply referred to as “the present invention”). Related compounds).

When the compound of formula (I) and the acid addition salt thereof are obtained as crystals, there may be several types of polymorphs, and these polymorphs are also included in the compounds according to the present invention. .

The compound of the formula (I) wherein R ² is a hydrogen atom may exist in the form of a tautomer represented by the formula (I ') or the formula (I "). Mutants are also included in the compounds according to the present invention.

[0021]

Embedded image [In the formula, Az means a group represented by Chemical formula 7.

[0022]

Embedded image (In the formula, R ¹ , n and wavy line mean the same as described above.)]

In the following description, the structure of the compound according to the present invention is represented by the formula (I), and the chemical names will be named accordingly.

In the present specification, "halogen atom" means fluorine, chlorine, bromine or iodine. Specific examples of “alkyl group” include methyl, ethyl, propyl,
Isopropyl is exemplified. Specific examples of the “alkoxy group” include methoxy, ethoxy, propoxy, and isopropoxy. Specific examples of the “lower alkanoyl group” include acetyl and propionyl. Specific examples of “lower alkoxycarbonyl group” include methoxycarbonyl and ethoxycarbonyl. As the “optionally substituted benzyl group”, the phenyl moiety may be substituted with one or two of the above-mentioned halogen atom, C _{1 to} C ₃ alkyl group and C _{1 to} C ₃ alkoxy group. Good benzyl groups are preferred, for example benzyl, 2-, 3
-Or 4-chlorobenzyl, 3-bromobenzyl, 4-
Examples include fluorobenzyl, 2,4- or 3,4-dichlorobenzyl, 4-methylbenzyl, 2-, 3- or 4-methoxybenzyl. Phenyl The term "which may be substituted benzyloxycarbonyl group", for example, a halogen atom described above, an alkyl group of C ₁ -C _3, with one or two such alkoxy group and nitro group of C ₁ -C ₃ A benzyloxycarbonyl group which may be partially substituted, for example, benzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl Is mentioned. "Amino group-protecting group" means a protecting group that can be eliminated by hydrolysis or hydrogenolysis, for example, the lower alkanoyl group, trifluoroacetyl, lower alkoxycarbonyl group, and optionally substituted benzyl group. And a benzyloxycarbonyl group which may be substituted, with benzyl and acetyl being particularly preferred.

As an intermediate for producing a compound in which R ² is a hydrogen atom in the formula (I), a compound of the following formula (II) can be mentioned.

[0026]

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(Wherein, R ¹ represents an ethyl group or a cyclopropylmethyl group, R ³ represents an amino-protecting group, and n and wavy lines represent the same as described above.)

Preferred examples of the compound represented by the above formula (I) include the following compounds and physiologically acceptable acid addition salts thereof.

N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, (R) -N- (1-ethyl-1H-hexahydroazepine -3-yl) -6
Methoxy-1H-benzotriazole-5-carboxamide, N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide, (R)- N-
(1-Ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide, 1-ethyl-N- (1-
Ethyl-1H-hexahydroazepin-3-yl) -6
-Methoxy-1H-benzotriazole-5-carboxamide, (R) -1-ethyl-N- (1-ethyl-1H
-Hexahydroazepin-3-yl) -6-methoxy-
1H-benzotriazole-5-carboxamide, N-
(1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazole-5
Carboxamide, N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-methyl-
1H-benzotriazole-5-carboxamide, N-
(1-Ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzotriazole-5
Carboxamide, (R) -N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6
Methoxy-1H-benzotriazole-5-carboxamide and (R) -N- (1-cyclopropylmethyl-
1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide.

Further preferred compounds include those in the above formula (I) wherein R ¹ is an ethyl group and R ² is a hydrogen atom or a methyl group.

With respect to the configuration, a compound in which the configuration of the carbon atom to which the wavy line is bonded in the formula (I) is RS or R is preferable, and a compound in which R is R is particularly preferable.

With respect to the size of the azacycloalkane ring, any of a 7-membered ring, an 8-membered ring and a 9-membered ring is preferable, but a 7-membered ring, that is, a compound of the formula (I) wherein n is 1 Is preferred.

Particularly preferred compounds among the above-mentioned compounds include the following compounds and their physiologically acceptable acid addition salts.

(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, and (R)-
N- (1-ethyl-1H-hexahydroazepine-3-
Yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide.

Specific examples of other suitable compounds included in the compounds according to the present invention in addition to the above-mentioned compounds include, for example, the following compounds and their physiologically acceptable acid addition salts.

(R) -N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, (R) -N-
(1-Ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1H-benzotriazole-5
Carboxamide, (R) -N- (1-ethyl-1H-heptahydroazocin-3-yl) -6-methoxy-1-
Methyl-1H-benzotriazole-5-carboxamide and (R) -N- (1-ethyl-1H-octahydroazonin-3-yl) -6-methoxy-1-methyl-
1H-benzotriazole-5-carboxamide.

The compound of the formula (I) can be produced, for example, by the following method.

Process (a) The compound of the formula (I) is prepared by reacting the compound of the following formula (III)

[0039]

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(Wherein R ^2a represents a protecting group for a hydrogen atom, a methyl group, an ethyl group or an amino group)

A compound represented by the following formula (IV):

[0042]

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(In the formula, R ¹ , n and wavy line mean the same as described above.)

By reacting with a compound represented by the formula (III), and in the case where a compound in which R ^2a is a protecting group for an amino group in the formula (III) is used, the intermediate (II) ) can be prepared a compound of formula (I) by converting the hydrogen atom to hydrolysis or hydrogenolysis to R ^2a.

Examples of the reactive derivative of the compound of the formula (III) include lower alkyl esters (especially methyl esters), active esters, acid anhydrides, acid halides (especially acid chlorides). [However, when a compound in which R ^2a is a hydrogen atom in the formula (III) is used, excluding acid anhydrides and acid halides] Specific examples of the active ester include p-nitrophenyl ester, 2,4,5- Trichlorophenyl ester, pentachlorophenyl ester, cyanomethyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester,
1-hydroxybenzotriazole ester, N-hydroxy-5-norbornene-2,3-dicarboximide ester, N-hydroxypiperidine ester, 8-
Examples include hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-hydroxy-4,5-dichlorophenyl ester, 2-hydroxypyridine ester, and 2-pyridylthiol 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 chlorocarbonate, mixed anhydrides with alkanoic acids such as isovaleric acid and pivalic acid Is mentioned.

As the protecting group for the amino group of R ^2a , for example, a protecting group which can be eliminated by hydrolysis or hydrogenolysis can be used. For example, a lower alkanoyl group, a trifluoroacetyl group, a lower alkoxycarbonyl group, And a benzyloxycarbonyl group which may be substituted, and acetyl is particularly preferred.

When the compound of the formula (III) itself is used,
N, N'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N'-carbonyldiimidazole, N,
The reaction can be carried out in the presence of a condensing agent such as N'-carbonyldisuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphorylazide, propanephosphonic anhydride. N, N'-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) as a condensing agent
When carbodiimide hydrochloride is used, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-1,2,3-benzotriazine-
4 (3H) -one, N-hydroxy-5-norbornene-2,3-dicarboximide and the like may be added and reacted.

The reaction of the compound of the formula (III) or a reactive derivative thereof with the compound of the formula (IV) is carried out in a solvent or without solvent. The solvent to be used should be appropriately selected according to the type of the raw material compounds and the like. For example, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, tetrahydrofuran and dioxane, methylene chloride, Halogenated hydrocarbons such as chloroform, alcohols such as ethanol and isopropyl alcohol, ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide,
Ethylene glycol and water are mentioned, and these solvents are used alone or in combination 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 bicarbonate. , Potassium bicarbonate, or an organic base such as triethylamine, tributylamine, diisopropylethylamine, or N-methylmorpholine, but can also serve as an excess of the compound of the formula (IV). The reaction temperature varies depending on the type of the starting compound used and the like.
The temperature is from -30C to about 200C, preferably from about -10C to about 150C.

In the formula (III), a compound wherein R ^2a is a protecting group for an amino group, for example, a lower alkanoyl group, a trifluoroacetyl group, a lower alkoxycarbonyl group or a benzyloxycarbonyl group which may be substituted; When the reaction with a compound of formula (IV) gives a compound of formula (I) wherein R ² is the corresponding protecting group,
The product is hydrolyzed to give R in formula (I)
It can be converted to a compound in which ² is a hydrogen atom. This hydrolysis reaction can be carried out according to a conventional method, for example, by contacting with water in an appropriate solvent under acidic or basic conditions. Examples of the solvent include methanol,
Alcohols such as ethanol and isopropyl alcohol, dioxane, water or a mixture thereof is used.
Specific examples of the acid for acidification include mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid, organic acids such as formic acid, acetic acid, propionic acid and oxalic acid, and silica gel. When a compound in which R ^2a is an acetyl group in the formula (III) is used, the acetyl group can be eliminated by using silica gel to easily convert to a compound in which R ² is a hydrogen atom. Further, specific examples of the base for making it basic include alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. The reaction temperature is usually about
20 ° C to about 100 ° C.

In the formula (III), a compound in which R ^2a is a protecting group for an amino group, for example, an optionally substituted benzyl group or an optionally substituted benzyloxycarbonyl group, and a compound of the formula (IV) When the reaction with the compound yields a compound of the formula (I) wherein R ² is the corresponding protecting group, the product is subjected to hydrogenolysis to give a compound of the formula (I) wherein R ² is a hydrogen atom Can be converted to This hydrogenolysis reaction can be performed according to a conventional method, for example, in a suitable solvent, palladium-carbon,
It is carried out by reacting with hydrogen in the presence of a catalyst such as Raney nickel. Examples of the solvent include methanol,
Alcohols such as ethanol, acetic acid, dioxane,
Tetrahydrofuran, water or a mixture thereof is used. The reaction temperature is usually about 0 ° C. to about 80 ° C., and the reaction is carried out under normal pressure or under pressure.

In the formula (III), compounds wherein R ^2a is a hydrogen atom or an amino-protecting group (lower alkanoyl, trifluoroacetyl, lower alkoxycarbonyl or optionally substituted benzyloxycarbonyl); The reactive derivative can be produced, for example, by the method described in JP-A-51-80858 (US Pat. No. 4,039,672) or a method analogous thereto.

In the formula (III), the compound wherein R ^2a is a protecting group for a methyl group, an ethyl group or an amino group (a benzyl group which may be substituted) is 4-chloro-2-methoxy-
Using 5-nitrobenzoic acid as a starting material, a suitable amine such as propylamine is converted to a corresponding amide using a suitable amine such as propylamine according to the method of Step 1 of Scheme 12, and then converted to the corresponding amide.
After introducing a methyl group, an ethyl group or an optionally substituted benzyl group into R ² by the methods of Steps 2 and 3, the product is reduced, and the corresponding 6- is prepared according to the method described in Production Method (b) described below. Methoxy-1H-benzotriazole-5
-Carboxamide derivatives can be produced and then hydrolyzed according to a conventional method.

The compound of the formula (IV) can be produced by the methods described in Reference Examples 1 to 7 below, or according to them.

Process (b) The compound of the formula (I) can be prepared by reacting the compound of the formula (V)

[0055]

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(Wherein, R ¹ , R ² , n and wavy line have the same meanings as described above). The compound can be produced by diazotizing to form a benzotriazole ring.

The ring closure reaction from the compound of formula (V) to the compound of formula (I) by diazotization is carried out under the conditions usually used for diazotization of aromatic amines. Examples of the diazotizing agent include sodium nitrite or alkyl nitrite such as tert-butyl nitrite and isoamyl nitrite. In the case of a ring closure reaction with nitrous acid, usually, an excess of a mineral acid (eg, hydrochloric acid) or an organic acid (eg, acetic acid) is added to an aqueous solution of the compound of the formula (V) or an acid addition salt thereof, and then sodium nitrite is added. By adding an aqueous solution of The reaction temperature is usually about -20C to about 60C, preferably about 0C to about 40C. In the case of a ring closure reaction with an alkyl nitrite, the compound of the formula (V) or an acid addition salt thereof (eg, hydrochloride, acetate) is usually reacted with an alkyl nitrite in an appropriate solvent. Done. Examples of the solvent include methanol, acetic acid, and acetic acid.
Dioxane, 1,2-dimethoxyethane, tetrahydrofuran, acetone and methylene chloride are used, and the reaction temperature is usually about 0 ° C to about 100 ° C, preferably about 30 ° C to about 80 ° C.

The starting compound represented by the formula (V) can be produced, for example, by a method represented by the following chemical formula (12).

[0059]

Embedded image

(Wherein Z represents a halogen atom;
² , Az and wavy lines mean the same as above. )

Step 1 : The reaction between the compound of the formula (J) or a reactive derivative thereof and the compound of the formula (IV) can be carried out in the same manner as in the production method (a). In addition, the compound of the formula (E) which is a starting compound is, for example, Helv. Chim. Acta, 40 ,
369-372 (1957).

Step 2 : Compound of formula (K) and formula: H ₂ N
Reaction of a compound represented by -R ² is carried out without a solvent or under a suitable solvent. Examples of the solvent to be used include alcohols such as methanol and ethanol, dimethylformamide, dimethylsulfoxide, and water. The reaction temperature is usually about 0 ° C to about 150 ° C.

Step 3 : The reduction of the compound of formula (L) is carried out according to a conventional method. For example, it is carried out by treating a compound of the formula (L) with a reducing agent in a suitable solvent. Specific examples of the reducing agent include a combination of a metal (for example, tin, zinc, iron) or a metal salt (for example, stannous chloride) and an acid (for example, hydrochloric acid, acetic acid). Monotin can be used alone as a reducing agent. Alternatively, the reaction is carried out by hydrogenating the compound of the formula (L) in a suitable solvent in the presence of a catalyst. Specific examples of the catalyst include palladium carbon, Raney nickel,
Platinum oxide is exemplified. The solvent to be used should be appropriately selected according to the reducing agent or the reducing means, and examples thereof include alcohols such as methanol and ethanol, ethyl acetate, acetone, acetic acid, dioxane, water and a mixture thereof. The reaction temperature varies depending on the reducing agent or the reducing means, but is usually about 10 ° C. to about 100 ° C., and preferably about 10 ° C. to about 50 ° C. in the case of catalytic reduction.

The resulting compound of the formula (V) can be used as a starting compound for the production method (b) without isolation and purification.

According to the production methods (a) and (b), the steric configurations of the starting compound, the compound of the formula (IV) and the compound of the formula (V), are retained in the product, the compound of the formula (I). ing. Therefore, a compound of formula (I) having a desired configuration can be obtained by using a raw material compound having a corresponding configuration or by using a racemic raw material compound. Can be produced by optical resolution according to a conventional method.

The compound produced by each of the above production methods is isolated by a conventional method such as chromatography, recrystallization and reprecipitation.
Purified.

The compound of the formula (I) can be obtained by selecting a starting compound,
It is 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.

[0068]

The test results of representative compounds among the compounds according to the present invention and metoclopramide hydrochloride monohydrate (compound A) which is a commercially available gastrointestinal tract function improving agent are shown below. Although described, the present invention is not limited to these test examples.

Test Example 1 : Inhibitory Effect on Apomorphine-Induced Vomiting-- Using 3-4 beagle dogs (8-15 kg body weight) per group, Ch
en and Ensor's method [J. Pharmacol. Exp. Ther., 98 , 245
-250 (1950)], the inhibitory effect of the test compound on apomorphine-induced emesis was examined.
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. The suppression rate was calculated by comparing the number of vomiting of the test compound administration group with that of the control group. Table 1 shows the results
Shown in

[0070]

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

As is evident from Table 1, almost all of the tested compounds of the present invention showed an emetic-inhibiting effect on apomorphine-induced emesis that was equal to or greater than that of metoclopramide hydrochloride monohydrate (Compound A). Was.

Test Example 2 : Enhancement of gastric emptying-This test was carried out by the method of Scarpignato et al. [Arch. Int. Pharmac.
odyn., 246 , 286-294 (1980)]. Male Wistar rats (weight 130-150 g) fasted for 18 hours and then contain 0.05% phenol red
1.5 ml of a 1.5% methylcellulose solution was orally administered. The stomach was removed 15 minutes after the administration, and the amount of phenol red remaining in the stomach was measured. The test compound was dissolved or suspended in a 0.5% tragacanth solution and orally administered 60 minutes before the administration of phenol red. The gastric emptying rate was calculated based on the amount of residual phenol red in the stomach, and the enhancement rate was determined by comparing with the gastric emptying rate of the control group. The number of animals used was 5 for the control group and the group administered with metoclopramide hydrochloride monohydrate (Compound A), and 4 for the others. Table 2 shows the results.

[0073]

[Table 2] ^* ) Means the compound of Example 2 (the same applies hereinafter).

As is clear from Table 2, all of the tested compounds according to the present invention exhibited gastric emptying-enhancing activity equal to or higher than that of metoclopramide hydrochloride monohydrate (Compound A).

Test Example 3 : Effect on Cholecystokinin or Morphine-Induced Delay in Gastric Emptying--This test was carried out by the method of Scarpignato et al. [Arch. Int. Pharmac.
odyn., 246 , 286-294 (1980)]. Male Wistar rats (body weight 130-150 g) were fasted for 18 hours and then contained 0.05% phenol red 1.
1.5 ml of a 5% methylcellulose solution was orally administered. Administration
After 15 minutes, the stomach was removed and the amount of phenol red remaining in the stomach was measured. The test compound 10, 30, or 100 mg / kg
Were respectively dissolved or suspended in a 0.5% tragacanth solution and orally administered 60 minutes before the administration of phenol red. Cholecystokinin 3 μg / kg or morphine 3 mg / kg was administered subcutaneously 5 minutes before phenol red administration to induce delayed gastric emptying. The number of animals used is 5-10. Table 3 shows the results
Shown in

[0076]

[Table 3] +: Slight to moderate improvement ++: remarkable improvement ±: no improvement ^* ) Means the compound of Example 2 (the same applies hereinafter).

As can be seen from Table 3, the compound of Example 2 showed 30% of the gastric emptying induced by cholecystokinin.
And 100 mg / kg dose showed significant improvement. For cholecystokinin or morphine-induced gastric emptying delay,
The compound of Example 7b was significantly improved at doses of 10, 30, and 100 mg / kg, and also showed a significant gastrointestinal hyperactivity in the gastric emptying induced by cholecystokinin or morphine. On the other hand, metoclopramide hydrochloride monohydrate (Compound A) did not show an improving effect on the gastric emptying delay induced by cholecystokinin or morphine at doses of 10, 30, and 100 mg / kg.

Test Example 4 : Gastrointestinal motility-promoting action of awake dogs: Pentobarbital sodium (Nembutal 30 mg bw) was used in four male and female beagle dogs (body weight: 10 to 12 kg) in each group.
t.) was anesthetized by intravenous administration, and the abdomen was opened aseptically. It
Oh et al. [Gastrointerol. Japan. 12 , 275-283 (197
7)], and tension transducer from the pylorus
The 3 cm proximal stomach vestibule, duodenum, upper jejunum, mid jejunum, and serosal muscular layer of the proximal colon at the end of the ileum were sewn in a direction in which the contraction of the circular muscle could be measured. For intragastric administration, a silicone tube (Fr. size 6.5) was inserted into the body of the stomach and fixed to the adjacent serosa. The transducer wire and intragastric tube were removed from the skin incision between the shoulder bones through the abdominal cavity and their outer ends were sewn to the incision near the skin. After the operation, a jacket-type protector was worn to protect the conductor and the tube. Dogs were housed in individual laboratory cages, fed food at 10 am, and had free access to water.

Test compound 3 or 10 mg / kg was suspended in 0.5% tragacanth solution and administered into the stomach through a silicone tube.

The compounds of Example 2 and Example 7b at doses of 3 and 10 mg / kg, respectively, exhibited an effect similar to the propagative strong contractile movement seen in the fasting period of awake dogs, and showed a marked gastrointestinal tract. It was found to have a function-enhancing effect. On the other hand, compound A did not show any propagative strong contraction movement.

Test Example 5 : Inhibitory effect on exploring behavior-- Five Std-ddY male mice (weight: 20 to 25 g) were used in each group. A test compound dissolved or suspended in a 0.5% tragacanth solution was orally administered, and two hours later, mice were individually animalized.
Ex-momentum measurement device (manufactured by Farad) Measurement cage (23 × 35
× 30 cm), and the amount of exploratory activity for 3 minutes was measured. The average value of the amount of exploratory activity (count / 3 minutes) in the test compound administration group was determined, the inhibition rate was calculated in comparison with that in the control group, and the dose (ID ₅₀ ) that inhibited by 50% was determined by the probit method.
Table 4 shows the results.

[0082]

[Table 4] ^* ) Means the compound of Example 1 (the same applies hereinafter).

As is clear from Table 4, all of the tested compounds of the present invention exhibited a much weaker inhibitory action on exploring behavior than metoclopramide hydrochloride monohydrate (Compound A). This result indicates that the central inhibitory action of these compounds according to the present invention is much weaker than that of compound A.

Test Example 6 : Acute toxicity—5 male Std-ddY mice (body weight 25 to 30 g) were used in each group. The test compound dissolved or suspended in a 0.5% tragacanth solution was orally administered, and death was observed for 7 days after the administration to determine a 50% lethal dose (LD ₅₀ ). Table 5 shows the results.

[0085]

[Table 5] ^* ) Means the compound of Example 2 (the same applies hereinafter).

As is clear from the above test results, the compound represented by the formula (I) and the physiologically acceptable acid addition salt thereof have excellent antiemetic action and gastrointestinal function-enhancing action. Regardless, since it has a weak central inhibitory effect and low toxicity, it can be used as a gastrointestinal tract function improving drug for treatment and prevention of various diseases and abnormalities of gastrointestinal function accompanying treatment. Specifically, acute / chronic gastritis, reflux esophagitis, gastric / duodenal ulcer, gastric neurosis, gastric ptosis, postoperative paralytic ileus, senile ileus, postgastrectomy syndrome, scleroderma, diabetes, esophagus / Anorexia, nausea, vomiting, bloating, upper abdominal discomfort, abdominal discomfort, abdominal pain, heartburn, vagueness, etc. in diseases such as liver and biliary tract diseases, periodic vomiting in children, upper respiratory tract infections, anorexia nervosa And for the treatment and prevention of irritable bowel syndrome, constipation, and diarrhea in infants. Furthermore, it can be used for treatment and prevention of nausea or vomiting during administration of various anticancer agents, morphine or levodopa preparations, or irradiation.

Among the compounds represented by the formula (I), the compound of Example 2, the compound of Example 7a and the compound of Example 7b exhibit particularly excellent gastrointestinal function improving activity.

The administration route may be any of oral administration, parenteral administration and rectal administration. The dose varies depending on the type of compound, the method of administration, the condition and age of the patient, but is usually 0.01 to 10 mg / kg / day, preferably 0.1 to 3 m / kg.
g / kg / day.

When the compound of formula (I) or a physiologically acceptable acid addition salt thereof is used for the above-mentioned medicinal purposes, it is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As a pharmaceutical carrier, it is commonly used in the pharmaceutical field,
In addition, a substance that does not react with the compound according to the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl Starch,
Carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, alginic acid, sodium alginate, light anhydrous silicic acid, stearic acid Magnesium, talc, tragacanth,
Bentonite, veegum, carboxyvinyl polymer,
Titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester,
Refined lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, water, propylene glycol, ethanol, sodium chloride, sodium hydroxide,
Hydrochloric acid, citric acid, benzyl alcohol, glutamic acid,
Glycine, methyl paraoxybenzoate, propyl paraoxybenzoate and the like can be mentioned.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, injections, cataplasms, suppositories and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method.

Compounds of the formula (I) in which R ² is a hydrogen atom are particularly advantageous for liquid preparations because of their good water solubility.

These preparations can 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.

Hereinafter, the compounds according to the present invention will be described more specifically. The identification of the compound is based on elemental analysis, mass spectrum, UV spectrum, IR spectrum, NM
The measurement was performed based on the R spectrum and the like.

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

[Recrystallization solvent] A: ethanol, E: diethyl ether.

[Substituents] Me: methyl group, Et: ethyl group, Δ: cyclopropyl group, Ph: phenyl group.

[NMR] J: coupling constant, s: singlet, d: doublet, dd: double doublet, t: triplet, q: quadruple, m: multiplet, br-s : Wide singlet.

[Others] ee: enantiomeric excess.

Reference Example 1 Production 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 concentrated 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% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride
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.
Stirred 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): 1.0
4 (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 2 Production of (R) -3-amino-1-ethyl-1H-hexahydroazepine:

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

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

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

Reference Example 4-(R) -3-amino-1-cyclopropylmethyl-1H
-Production of hexahydroazepine:

(1) 37 g of (R) -α-triphenylmethylamino-ε-caprolactam in 370 ml of toluene
Add 1M of diisobutylaluminum hydride at room temperature
1000 ml of a toluene solution was added dropwise and stirred for 16 hours. After completion of the reaction, water was added dropwise to decompose excess diisobutylaluminum hydride. The precipitated salt was removed by filtration, the filtrate was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to remove (R) -3-triphenylmethylamino-1.
34 g of H-hexahydroazepine were obtained as an oil.

(2) To a solution of 10 g of the above product in 100 ml of methyl ethyl ketone, 10.5 g of potassium carbonate and 5.1 g of cyclopropylmethyl bromide were added, and the mixture was heated under reflux for 5 hours. After the reaction was completed, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (10: 1) to give 10 g of (R) -1-cyclopropylmethyl-3-triphenylmethylamino-1H-hexahydroazepine as an oil. Obtained as a product.

(3) To a solution of 9.0 g of the above product in 10 ml of tetrahydrofuran was added 100 ml of 10% hydrochloric acid, and the mixture was stirred at room temperature for 5 hours. Wash the reaction with diethyl ether,
The aqueous layer was saturated with potassium carbonate and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 4.0 g of the desired product as an oil.

Reference Example 5 Production of 3-amino-1-cyclopropylmethyl-1H-hexahydroazepine:

Example 4 A reaction and treatment were carried out in the same manner as in Example 4 except that (R) -α-triphenylmethylamino-ε-caprolactam was replaced with α-triphenylmethylamino-ε-caprolactam. The title compound was obtained as an oil.

Reference Example 6 Production of 3-amino-1-ethyl-1H-heptahydroazocin:

(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): 1.1
5 (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) 25 g of the above product in chloroform
34 g of phosphorus pentachloride was gradually added to the 200 ml solution with stirring under ice cooling, and the mixture was stirred for 30 minutes under the same conditions. 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. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and washed with water and an aqueous solution of sodium thiosulfate in that order.
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: 1)
The resulting crystals were recrystallized from n-hexane to give 3-bromo-1-ethyl-1H-heptahydroazocin-2-one and 3-chloro-1-ethyl-1H-heptahydro. 10 g of a mixture of azocin-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 at 80 ° C. overnight, 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 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 , δ ppm): 1.1
8 (3H, t, J = 7Hz), 1.5-1.8 (6H, m), 2.2 (2H, m), 3.0
8 (1H, m), 3.28 (1H, m), 3.53 (1H, m), 3.76 (1H,
m), 4.0 (1H, dd, J = 10.5Hz, J = 5.6Hz).

(4) 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride36.
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, followed by stirring at room temperature for 2 hours. Water and a 48% aqueous sodium hydroxide solution were slowly added to the reaction mixture with stirring under ice-cooling, followed by extraction with diethyl ether. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.8 g of the desired product as an oil.

Reference Example 7 Production of 3-amino-1-ethyl-1H-octahydroazonin:

(1) 17 g of 2-azacyclononanone and 29 g of iodoethane, 200 m of 1,2-dimethoxyethane
To the solution, 6.0 g of 60% sodium hydride was gradually added with stirring at room temperature. After stirring for 4 hours under the same conditions, water was added and the mixture was extracted with chloroform. Wash the extract with water,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
1-ethyl-1H-octahydroazonin-2-one 2
0 g was obtained as an oil.

(2) To a solution of 20 g of the above product in 200 ml of tetrahydrofuran was added dropwise a solution of 2 M lithium diisopropylamide in 78 ml of tetrahydrofuran under ice-cooling.
Stirred for hours. The reaction solution was poured into dry ice, the obtained mixture was diluted with water, and this was washed with ethyl acetate.
The aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform.
After washing with saturated saline and drying over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to give 3-carboxy-1-ethyl-1.
14 g of H-octahydroazonin-2-one was obtained.
Melting point 109-110 ° C (recrystallized from diethyl ether-n-hexane)

(3) 12 g of acetone 100
12 ml of water and 7.0 ml of triethylamine were added to the ml solution. To this mixture, 30 ml of an acetone solution of 8.0 g of ethyl chlorocarbonate was added dropwise under ice-cooling, and the mixture was stirred for 30 minutes.
Stirred for hours. The reaction mixture was poured into ice water and extracted with diethyl ether. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 200 ml of toluene was added to the residue, and the mixture was heated and stirred at 70 ° C. When the foaming stopped, the temperature was raised to 100 ° C. and the mixture was stirred for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure.
120 ml was added with stirring under ice cooling, and the mixture was refluxed for 1.5 hours. The reaction mixture was washed with ethyl acetate, the aqueous layer was made alkaline with excess potassium carbonate, and extracted with chloroform. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 3-amino-1-.
8.5 g of ethyl-1H-octahydroazonin-2-one
Was obtained as an oil.

(4) 8.5 g of chloroform of the above product
To the 100 ml solution was added 7.0 ml of triethylamine, and under ice-cooling, 14 g of chlorotriphenylmethane was added little by little.
Stir at room temperature for 3 hours. The reaction mixture was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with ethyl acetate-n-hexane (1:10) to give 3-triphenylmethylamino-1-ethyl-1H.
-Octahydroazonin-2-one 14 g was obtained as a solid. 160-162 ° C (recrystallized from n-hexane-ethyl acetate)

(5) 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride 30
To 100 g of toluene, add 14 g of the above product
Was slowly added with stirring under ice-cooling, followed by stirring at room temperature for 24 hours. After cooling, a 2N aqueous solution of sodium hydroxide was added dropwise to the reaction solution, and a 48% aqueous solution of sodium hydroxide was added, followed by extraction with ethyl acetate. The extract was washed with water, washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted and purified with ethyl acetate-n-hexane (1:10) to obtain 13 g of 3-triphenylmethylamino-1-ethyl-1H-octahydroazonin.

(6) To a solution of 13 g of the above product in 3 ml of tetrahydrofuran was added 45 ml of 10% hydrochloric acid, and the mixture was stirred at room temperature for 5 hours. The reaction solution was washed with diethyl ether, the aqueous layer was made alkaline with excess potassium carbonate, and extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 5.0 g of the desired product as an oil.

Reference Example 8 Production of 4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

To a suspension of 14.7 g of 4-chloro-2-methoxy-5-nitrobenzoic acid, 300 ml of chloroform and 1 ml of dimethylformamide was added 22.7 g of thionyl chloride, and the mixture was heated under reflux for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of methylene chloride. 12.9 g of triethylamine and 3-amino-1-ethyl-
After adding 9.0 g of 1H-hexahydroazepine, at room temperature
Stir for 15 hours. The reaction solution was washed with water, 10% hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform-methanol (9: 1) to obtain 9.8 g of the desired product as a solid.

Reference Example 9 Preparation of (R) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

(R) -3-Amino-1-ethyl-1H-
The reaction was carried out in the same manner as in Reference Example 8 using hexahydroazepine.
Treatment gave the desired product as a solid.

Reference Example 10 Production of (S) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide:

(S) -3-Amino-1-ethyl-1H-
The reaction was carried out in the same manner as in Reference Example 8 using hexahydroazepine.
Treatment gave the desired product as a solid.

Reference Example 11 Production of 5-amino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide:

(1) 4-chloro-N- (1-ethyl-
1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide 4.9 g ethanol 100 m
To the solution, 50 ml of a 30% ethanol solution of methylamine was added, and the mixture was refluxed for 1.5 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the crystals were collected by filtration. The crystals are washed with water, dried and dried with N- (1-ethyl-1H-hexahydroazepine-
3.6 g of 3-yl) -2-methoxy-4-methylamino-5-nitrobenzamide were obtained.

(2) After dissolving 3.3 g of the above product in 200 ml of 20% aqueous methanol, 10% palladium on carbon was added, and catalytic reduction was carried out at normal pressure and room temperature. After the theoretical amount of hydrogen was absorbed, the palladium carbon was removed by filtration, and methanol in the filtrate was distilled off under reduced pressure to obtain an aqueous solution containing the desired product.

Reference Examples 12 to 15 -5 -amino-4-substituted amino-N- (1-ethyl-1H
-Hexahydroazepin-3-yl) -2-methoxy-
Production of benzamide or its optical isomer:

(R)-, having the same configuration as the target product
(S)-or (RS) -4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-
Using methoxy-5-nitrobenzamide and the corresponding amines, the reaction and treatment were carried out in the same manner as in Reference Example 11 to give
An aqueous solution of the compound shown in Table 6 was obtained.

[0140]

Embedded image

[0141]

[Table 6] ━━━━━━━━━━━━━━━━━ Reference example Configuration R ² １２ 12 R Me 13 S Me 14 RS Et 15 R Et ━━━━━━━━━━━━━━━━━

Reference Example 16 : 5-amino-4-benzylamino-N- (1-ethyl-
Preparation of 1H-hexahydroazepin-3-yl) -2-methoxybenzamide:

(1) 4-chloro-N- (1-ethyl-
1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide 2.0 g ethanol 50 ml
6.0 g of benzylamine was added to the solution, and the mixture was heated under reflux for 22 hours. After evaporating the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (12: 1) to give 4-benzylamino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy. 2.4 g of -5-nitrobenzamide were obtained as a solid.

(2) 6 ml of concentrated hydrochloric acid was added to 1.6 g of the above product
And ethanol (3 ml), a solution of stannous chloride dihydrate (2.6 g) in ethanol (3 ml) was added, and the mixture was stirred at 80 ° C. for 1 hour. After the completion of the reaction, ethanol was distilled off under reduced pressure to obtain an aqueous hydrochloric acid solution containing the desired product.

Reference Example 17 Production of 6-methoxy-1-methyl-1H-benzotriazole-5-carboxylic acid:

(1) 3-amino-1 in Reference Example 8
Using propylamine instead of -ethyl-1H-hexahydroazepine, the reaction and treatment were carried out in the same manner as in Reference Example 8 to give 4
-Chloro-2-methoxy-5-nitro-N- (1-propyl) benzamide was obtained as a solid.

(2) The above product was used in place of 4-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-5-nitrobenzamide in Reference Example 11 (1). The reaction was carried out in the same manner as in Reference Example 11 to give 5-amino-2-methoxy-4-methylamino-N- (1-propyl) benzamide as a solid.

(3) 5-amino-N- (1-ethyl-1H-hexahydroazepine-3 in Example 1 described later
-Yl) -2-methoxy-4-methylaminobenzamide was used and reacted and treated in the same manner as in Example 1 to give 6-methoxy-1-methyl-N- (1-
(Propyl) -1H-benzotriazole-5-carboxamide was obtained as a solid.

(4) 6.9 g of the above product and 100 m of concentrated hydrochloric acid
The mixture of l was heated at reflux for 5.5 hours. After cooling the reaction solution,
After concentration under reduced pressure, the precipitated crystals were collected by filtration, washed with water and dried to obtain 3.2 g of the desired product.

Example 1 N- (1-ethyl-1H-hexahydroazepine-3-
Preparation of yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

The 5-amino-N- obtained in Reference Example 11
After adding 5 ml of acetic acid to 40 ml of an aqueous solution containing about 3.0 g of (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide,
After cooling to ℃, 10 ml of an aqueous solution of 0.8 g of sodium nitrite was added and stirred at the same temperature for 1 hour. The reaction solution was made alkaline with an aqueous sodium hydroxide solution and then extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. The oil was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (9: 1), and the obtained solid was recrystallized from toluene-n-hexane to obtain 2.3 g of the desired product. Melting point 103-104 ° C

Example 2 Preparation of (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

The (R) -5-amino-N- (1-ethyl-1H-hexahydroazepine-3 obtained in Reference Example 12
-Yl) -2-methoxy-4-methylaminobenzamide in acetic acid solution was cooled to 5 ° C, and then sodium nitrite (6.6 g) in 50 ml aqueous solution was added dropwise. did. The reaction solution was made alkaline with an aqueous sodium hydroxide solution and then extracted with ethyl acetate.
The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. The oily product was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (9: 1), and the obtained solid was recrystallized from toluene-n-hexane to obtain the desired product.
g. Melting point 118-120 ° C [α] _D ²⁷ -70.6 ° (c = 1.0, ethanol)

Example 3 Preparation of (S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

The (S) -5-amino-N- (1-ethyl-1H-hexahydroazepine-3 obtained in Reference Example 13
-Yl) -2-methoxy-4-methylaminobenzamide was reacted and treated in the same manner as in Example 1, and the product was recrystallized from toluene-n-hexane to obtain the desired product. Melting point 119-120 ℃

Example 4 Preparation of 1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

The 5-amino-N- obtained in Reference Example 14
Using an aqueous solution of (1-ethyl-1H-hexahydroazepin-3-yl) -4-ethylamino-2-methoxybenzamide, the reaction and treatment were carried out in the same manner as in Example 1, and the product was converted from toluene-n-hexane. Recrystallization afforded the desired product. Melting point 84-85 ° C

Example 5 Preparation of (R) -1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

The (R) -5-amino-N- (1-ethyl-1H-hexahydroazepine-3 obtained in Reference Example 15
Using the aqueous solution of -yl) -4-ethylamino-2-methoxybenzamide, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the desired product as an oil. Mass spectrum (m / z): 346 (MH ⁺ )

Example 6 N- (1-Ethyl-1H-hexahydroazepine-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Production of carboxamide:

6-methoxy-1H-benzotriazole-5-carboxylic acid 0.85 g of dimethylformamide 10
0.78 g of N, N'-carbonyldiimidazole was added to the ml solution, and the mixture was stirred at room temperature for 6 hours. 3-amino-1 was added to the reaction mixture.
0.75 g of -ethyl-1H-hexahydroazepine was added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (10: 1), and recrystallized from ethanol-diethyl ether to obtain 1.3 g of the desired product. Obtained.

156-158 ° C. ¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.09 (3H, t, J =
7Hz), 1.5-2.1 (6H, m), 2.5-3.1 (6H, m), 3.83 (3H,
s), 4.4 (1H, m), 6.4 (1H, br-s), 7.07 (1H, s), 8.05
(1H, d, J = 8Hz), 8.78 (1H, s).

Example 7 Preparation of (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

(A) N, N'-carbonyldiimidazole was added to a solution of 10 g of 6-methoxy-1H-benzotriazole-5-carboxylic acid in 150 ml of dimethylformamide.
9.0 g was added, and the mixture was stirred at room temperature for 6 hours. (R)
8.8 g of -3-amino-1-ethyl-1H-hexahydroazepine was added, and the mixture was stirred at room temperature for 14 hours. After the reaction,
The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform-methanol (10: 1)
The residue was recrystallized from diethyl ether-n-hexane to obtain 12 g of the desired product. 127-128 ° C

(A ') The above-mentioned target substance was re-extracted with ethyl acetate
The desired product was obtained by recrystallization from n-hexane. Melting point 142
144144 ° C. [α] _D ²⁵ -71.9 ° (c = 1.0, methanol) The compound showed a retention time of 37.2 minutes by high performance liquid chromatography (HPLC) under the following conditions, and an optical purity of 99
% Ee or more. [HPLC conditions] HPLC column: SUMICHIRAL OA-4 manufactured by Sumika Chemical Analysis Service
900; 4.6 mm × 250 mm Mobile phase: n-hexane-methylene chloride-ethanol-trifluoroacetic acid (400: 100: 100: 0.6) Flow rate: 1.0 ml / min Temperature: 25 ° C. Detection: 230 nm

(B) The product obtained in the above (a) was treated with fumaric acid to obtain a fumarate, which was recrystallized from isopropyl alcohol-methanol to obtain a target 3/2 fumarate. 131-133 ° C

(B ') The product obtained in the above (a) was treated with fumaric acid to obtain a fumarate, which was recrystallized from isopropyl alcohol to obtain a target 3/2 fumarate. Melting point 162-163 ° C

(B ″) The product obtained in the above (a) is treated with fumaric acid to form a fumarate, which is recrystallized from ethanol-isopropyl alcohol to obtain the desired 3/2 fumarate / 1 / A tetrahydrate was obtained, mp 166-168 ° C.

(C) 1-acetyl-6-methoxy-1
To 31.5 g of H-benzotriazole-5-carboxylic acid, 20.3 g of triethylamine and 400 ml of ethyl acetate were added, and 17.5 g of ethyl chlorocarbonate was added dropwise at -7 to -10 ° C. After stirring at −5 ° C. to −7 ° C. for 2 hours, (R) -3-
Amino-1-ethyl-1H-hexahydroazepine 22.
8 g of ethyl acetate 80 ml solution was added dropwise, and after stirring for 1 hour,
Stirred at room temperature for 16 hours. The reaction solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. After 1000 ml of a mixed solution of chloroform-methanol (8: 1) was added to the residue, 180 g of silica gel was added, followed by stirring at room temperature for 16 hours. The silica gel was filtered off, washed with 1000 ml of a mixed solution of chloroform-methanol (5: 1), and the solvent was distilled off under reduced pressure to obtain 32 g of a crude product of the desired product.

To 24 g of the above crude product, 2.5 g of fumaric acid was added.
Use up to 3 times (22.5 g) isopropyl alcohol
Recrystallize from methanol to obtain the desired 3/2 fumarate 2
5 g were obtained. 131-133 ° C

Example 8 Preparation of (S) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

Instead of 3-amino-1-ethyl-1H-hexahydroazepine in Example 7, (S) -3-
Using amino-1-ethyl-1H-hexahydroazepine, the reaction and treatment were carried out in the same manner as in Example 7, then the product was treated with fumaric acid to form a fumarate, and the product was recrystallized from isopropyl alcohol to give the desired product. A 3/2 fumarate was obtained.
Melting point 156-158 ° C

Separately, the above product was treated with fumaric acid to form a fumarate, and recrystallized from ethanol-isopropyl alcohol to obtain the desired difumarate / hemihydrate. Melting point 148-151 ° C

The title compound was HP under the same conditions as in Example 7.
LC showed a retention time of 44.0 minutes, and the optical purity was 99% ee or more.

Examples 9-12 Instead of 3-amino-1-ethyl-1H-hexahydroazepine in Example 6, the corresponding 3-amino-1 was used.
Using the -substituted-azacycloalkanes, the reaction and treatment were conducted in the same manner as in Example 6 to obtain the compounds of Table 7 represented by Chemical Formula 14.

[0176]

Embedded image

[0177]

[Table 7] 例 Example Configuration R ¹ nQ Melting point (℃) Recrystallization solvent ９ 9 RS Et 2 1 / 4H ₂ O 169-171 E 10 RS Et 3 200-202 AE 11 RS CH ₂ △ 1 amorphous 12 R CH ₂ △ 1 amorphous ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━━━

Example 13 Preparation of (R) -N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide :

Using the corresponding starting compounds, Reference Examples 4 and 8
(R) -5 obtained by reaction and treatment in the same manner as in and 11.
Using an aqueous solution of amino-N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -2-methoxy-4-methylaminobenzamide, the reaction and treatment were carried out in the same manner as in Example 1 to obtain a product. Recrystallization from toluene gave the desired product. 127-128 ° C

Example 14 N- (1-ethyl-1H-heptahydroazocin-3-
Preparation of yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

6-methoxy-1H-benzotriazole-5-carboxylic acid and 3-amino-1 in Example 6
-Ethyl-1H-hexahydroazepine instead of 6-
Methoxy-1-methyl-1H-benzotriazole-5
Using -carboxylic acid and 3-amino-1-ethyl-1H-heptahydroazocin, respectively, the reaction and treatment were carried out in the same manner as in Example 6, and the product was recrystallized from ethanol-diethyl ether to obtain the desired product. . Melting point 116-118 ° C

Example 15 N- (1-Ethyl-1H-octahydroazonin-3-
Preparation of yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide:

6-methoxy-1H-benzotriazole-5-carboxylic acid and 3-amino-1 in Example 6
-Ethyl-1H-hexahydroazepine instead of 6-
Methoxy-1-methyl-1H-benzotriazole-5
The reaction and treatment were carried out in the same manner as in Example 6 using -carboxylic acid and 3-amino-1-ethyl-1H-octahydroazonin, respectively, and the product was recrystallized from ethyl acetate to obtain the desired product. Melting point 155-156 ° C

Example 16 Preparation of 1-benzyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide:

The 5-amino-4-benzylamino-N- (1-ethyl-1H-hexahydroazepin-3-yl) -2-methoxybenzamide obtained in Reference Example 16 was prepared.
6 ml of an aqueous hydrochloric acid solution containing 1.5 g and 30 ml of 5N hydrochloric acid and 70
Then, 1 ml of an aqueous solution of 0.29 g of sodium nitrite was added under ice cooling, and the mixture was stirred under the same conditions for 30 minutes and further at room temperature for 1 hour. The reaction solution was made alkaline with a 48% aqueous sodium hydroxide solution and then extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain an oil. This oil was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (20: 1), and the obtained solid was recrystallized from diethyl ether to obtain 1.1 g of the desired product.
136-137 ° C

Example 17-(R) -1-acetyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-
Preparation of benzotriazole-5-carboxamide:

To 31.5 g of 1-acetyl-6-methoxy-1H-benzotriazole-5-carboxylic acid, 20.3 g of triethylamine and 400 ml of ethyl acetate were added.
At -10 ° C, 17.5 g of ethyl chlorocarbonate was added dropwise. -5 ° C
After stirring at ~ -7 ° C for 2 hours, (R) -3-amino-1
A solution of 22.8 g of -ethyl-1H-hexahydroazepine in 80 ml of ethyl acetate was added dropwise, and the mixture was stirred at the same temperature for 1 hour and then at room temperature for 16 hours. The reaction solution was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 36 g of the desired product as a solid. 134 ~ 135
° C (recrystallized from ethyl acetate)

¹ H-NMR spectrum (CDCl ₃ , δ ppm): 1.
04 (3H, t, J = 7.0Hz), 1.5-2.1 (6H, m), 2.45-2.95 (6
H, m), 3.00 (3H, s), 4.09 (3H, s), 4.35 (1H, m),
7.76 (1H, s), 8.60 (1H, d, J = 9.0Hz), 8.95 (1H, s)

Example 18 : Preparation of tablet: (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5 Carboxamide (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).

After mixing and granulating the above components by a conventional method,
Tablets are produced at 145 mg per tablet to produce 1000 tablets.

Example 19 : Preparation of capsule: (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide-3 / 2 fumarate (10
g), lactose (160 g), corn starch (22
g), hydroxypropylcellulose (3.5 g), light anhydrous silicic acid (1.8 g), and magnesium stearate (2.7 g).

According to a conventional method, the above components are mixed and granulated.
Fill into capsules.

Example 20 : Preparation of powder: (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide 3 / 2 fumarate (10
g), lactose (960 g), hydroxypropylcellulose (25 g), and light anhydrous silicic acid (5 g).

According to a conventional method, after mixing the above components, the mixture is made into a powder.

Example 21 : Production of injection (10
Per 00 ampoule):

[0196]

[Table 8] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ · (R) -N- (1-ethyl) -1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide / 3/2 fumarate (10 g) sorbitol (100 g) water for injection (appropriate amount) ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Total volume 2000 ml ━━━━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━

(R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide / 3/2 fumarate and sorbitol were added to water for injection. After dissolving in part,
Add remaining water for injection to make up the total volume. The solution is filtered through a membrane filter (0.22 μm), the filtrate is filled into 2 ml ampules, which are then sterilized at 121 ° C. for 20 minutes.

[0198]

As described above, the compound represented by the formula (I) and a physiologically acceptable acid addition salt thereof have both an excellent antiemetic action and a gastrointestinal function-enhancing action, and Since it has a weak central inhibitory effect, it can be used as a gastrointestinal tract function improving drug for the treatment and prevention of various digestive dysfunctions associated with various diseases and treatments.

Claims (7)

[Claims] 1. A 6-methoxy-1H compound represented by the following chemical formula 1.
A benzotriazole-5-carboxamide derivative, a physiologically acceptable acid addition salt thereof, or a hydrate thereof. Embedded image [Wherein, R ¹ represents an ethyl group or a cyclopropylmethyl group, R ² represents a hydrogen atom, a methyl group or an ethyl group, n represents 1, 2 or 3, and a wavy line (〜) represents Means that the configuration of the carbon atom to which is bonded is RS, R or S. ] 2. (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide, N- (1-ethyl) -1H-hexahydroazepine-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Carboxamide, N- (1-ethyl-1H-hexahydroazepine-3-
Yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide, 1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole -5-carboxamide, (R) -1-ethyl-N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, N- (1-ethyl -1H-heptahydroazocin-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Carboxamide, N- (1-ethyl-1H-heptahydroazocin-3-
Yl) -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide, N- (1-ethyl-1H-octahydroazonin-3-
Yl) -6-methoxy-1H-benzotriazole-5
-Carboxamide, N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-benzotriazole-5-carboxamide, (R) -N- (1-cyclopropylmethyl-1H -Hexahydroazepin-3-yl) -6-methoxy-1H-
Benzotriazole-5-carboxamide, and (R)
-N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1-methyl-
A medicament comprising any compound selected from 1H-benzotriazole-5-carboxamide, a physiologically acceptable acid addition salt thereof, or a hydrate thereof. 3. (R) -N- (1-ethyl-1H-hexahydroazepin-3-yl) -6-methoxy-1H-
A medicament comprising any one of benzotriazole-5-carboxamide, a physiologically acceptable acid addition salt thereof, and a hydrate thereof. 4. The medicament according to claim 1, which is a gastrointestinal tract function improving agent. 5. A therapeutic agent for anorexia, nausea, vomiting, bloating, abdominal discomfort, abdominal pain or heartburn.
4. The medicament according to any one of 3. 6. The medicament according to claim 5, which is a therapeutic agent for anorexia, nausea, vomiting, abdominal distension, upper abdominal discomfort, abdominal pain or heartburn due to a decrease in digestive tract function. 7. The method according to claim 1, which is an antiemetic.
The medicament according to the item.