JPH09301971A - 6-methoxy-1H-benzotriazole-5-carboxamide compound - Google Patents

Abstract

(57) [Abstract] [PROBLEMS] To provide a gastrointestinal function improving drug having both antiemetic action and gastrointestinal function enhancing action. SOLUTION: 6-methoxy-1H represented by the following formula 1
-A benzotriazole-5-carboxamide compound or a physiologically acceptable acid addition salt thereof. Embedded image [In the formula, R ¹ is a C _{1 to} C ₄ alkyl group or (C _{3 to} C ₆
A cycloalkyl) methyl group, R ² is a hydrogen atom,
A C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group or a (C ₃ -C ₆ cycloalkyl) methyl group, and n
Means 1, 2 or 3 and the wavy line (~) means that the configuration of the carbon atom to which it is attached is RS, R or S. ]

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 6-methoxy-1H-benzotriazole-5-carboxamide compound characterized by excellent antiemetic action and digestive tract hyperactivity action and weak central inhibitory action. More specifically, it relates to a 6-methoxy-1H-benzotriazole-5-carboxamide compound in which the nitrogen atom of the amide moiety is substituted with a 7-, 8- or 9-membered 1-substituted-azacycloalkan-2-ylmethyl group.

[0002]

[Prior art]

US Pat. No. 3,839,330 discloses the following chemical formula 2.
It is disclosed that the compound represented by the formula (4) has an antiemetic action, but the publication does not specifically describe the compound of the present invention.

[0004]

Embedded image

(In the formula, B is an alkyl group or alkenyl group having 1 to 5 carbon atoms, R is an alkyl group having 1 to 5 carbon atoms, n is 1 or 2, and m is a number of 4 or less.)

[0006]

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 intensive studies by the present inventors, 6-methoxy-1H in which the nitrogen atom of the amide moiety is substituted with a 1-substituted-azacycloalkan-2-ylmethyl group having a 7, 8 or 9 membered ring. The present invention was completed by discovering that the central inhibitory effect is weak although the benzotriazole-5-carboxamide compound has both excellent antiemetic effect and gastrointestinal function enhancing effect.

[0008]

According to the present invention, a 6-methoxy-1H-benzotriazole-5-carboxamide compound represented by the following formula (I) and a physiologically acceptable acid addition salt thereof are provided. To be done.

[0009]

Embedded image

[Wherein R ¹ represents a C ₁ -C ₄ alkyl group or a (C ₃ -C ₆ cycloalkyl) methyl group, and R ²
Means a hydrogen atom, a C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group or a (C ₃ -C ₆ cycloalkyl) methyl group, n means 1, 2 or 3, and a wavy line (~ ) Is the configuration of the carbon atom to which it is attached is RS, R or S
Means that ]

Examples of physiologically acceptable acid addition salts of the compound of formula (I) include 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 formula (I) and physiologically acceptable acid addition salts thereof may exist as hydrates or solvates, these hydrates and solvates are also included in the present invention.

The compound in which R ² is a hydrogen atom in the formula (I) may exist in the form of a tautomer represented by the formula (I ′) or the formula (I ″). Variants are also included in the compounds of the invention.

[0013]

Embedded image [In formula, Az means the group represented by Chemical formula 5.

[0014]

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

In the following description, the structures of the compounds of the present invention are represented by the formula (I), and chemical names will also be named based on them.

The terms used in this specification are explained below.

Specific examples of the "alkyl group" include methyl,
Examples include ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl. “Cycloalkyl group” means cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The “cycloalkylmethyl group” means a methyl group substituted with the above cycloalkyl group, and specific examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,
Cyclohexylmethyl may be mentioned. Specific examples of the "lower alkanoyl group" include formyl, acetyl and propionyl, with acetyl being particularly preferred.

Preferred among the compounds of the present invention are the compounds of formula (I) in which R ¹ is an ethyl group or a cyclopropylmethyl group, and R ² and n are the same as those mentioned above, and their physiological activities. Acid-acceptable acid addition salts.

More preferred compounds are compounds of the formula (I) in which R ² is a hydrogen atom, a methyl group or an ethyl group, and R ¹ and n are the same as those mentioned above, and physiologically acceptable compounds thereof. Acid addition salts may be mentioned.

Regarding the size of the azacycloalkane ring, a 7-membered ring, that is, a compound in which n is 1 in the formula (I) is preferable.

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

N-[(1-ethyl-1H-hexahydroazepin-2-yl) methyl] -6-methoxy-1H-
Benzotriazole-5-carboxamide and N-
[(1-Ethyl-1H-heptahydroazocin-2-yl) methyl] -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide.

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

6-methoxy-N-[(1-propyl-1
H-hexahydroazepin-2-yl) methyl] -1H
-Benzotriazole-5-carboxamide, N-
[(1-Cyclopropylmethyl-1H-hexahydroazepin-2-yl) methyl] -6-methoxy-1H-benzotriazole-5-carboxamide, N-[(1-
Cyclopropylmethyl-1H-hexahydroazepine-
2-yl) methyl] -6-methoxy-1-methyl-1H
-Benzotriazole-5-carboxamide, 1-ethyl-N-[(1-ethyl-1H-hexahydroazepin-2-yl) methyl] -6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropyl -N-[(1-ethyl-1H-hexahydroazepine-
2-yl) methyl] -6-methoxy-1H-benzotriazole-5-carboxamide, 1-cyclopropylmethyl-N-[(1-ethyl-1H-hexahydroazepin-2-yl) methyl] -6-methoxy -1H-benzotriazole-5-carboxamide,

N-[(1-cyclopropylmethyl-1H
-Heptahydroazocin-2-yl) methyl] -6-methoxy-1H-benzotriazol-5-carboxamide, N-[(1-ethyl-1H-heptahydroazocin-2-yl) methyl] -6- Methoxy-1-methyl-1
H-benzotriazole-5-carboxamide, N-
[(1-Cyclopropylmethyl-1H-heptahydroazocin-2-yl) methyl] -6-methoxy-1-methyl-1H-benzotriazole-5-carboxamide,

N-[(1-ethyl-1H-octahydroazonin-2-yl) methyl] -6-methoxy-1H-
Benzotriazole-5-carboxamide, N-[(1
-Cyclopropylmethyl-1H-octahydroazonin-2-yl) methyl] -6-methoxy-1H-benzotriazol-5-carboxamide, N-[(1-ethyl-1H-octahydroazonin-2-yl) ) Methyl]-
6-Methoxy-1-methyl-1H-benzotriazole-5-carboxamide, and N-[(1-cyclopropylmethyl-1H-octahydroazonin-2-yl) methyl] -6-methoxy-1-methyl- 1H-benzotriazole-5-carboxamide.

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

In the production method (a) , the compound of the formula (I) in which R ² is a hydrogen atom has the following formula (II)

[0029]

[Chemical 6]

(Wherein R ^2a represents a hydrogen atom or a lower alkanoyl group) or a reactive derivative thereof, and the following formula (III)

[0031]

[Chemical 7]

(Wherein R ¹ , n and the wavy line have the same meanings as described above) and a compound represented by the formula (II) in which R ^2a is a lower alkanoyl group is used. Can be produced by hydrolyzing the product.

Examples of the reactive derivative of the compound of the 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, pentachlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, 1-hydroxybenzotriazole ester, 8-hydroxyquinoline ester, 2-hydroxyphenyl ester, 2-
Hydroxy-4,5-dichlorophenyl ester may be mentioned. 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.

When the compound of formula (II) 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 formula (II) or its reactive derivative with the compound of formula (III) 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, and specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium bicarbonate. Examples thereof include alkali bicarbonates such as potassium bicarbonate, and organic bases such as triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine, but an excess amount of the compound of the formula (III) can also serve. 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.

When the corresponding product is obtained by the reaction of the compound of the formula (II) in which R ^2a is a lower alkanoyl group with the compound of the formula (III), the product is hydrolyzed to give the compound of the formula (I). ), R ² can be converted to a compound in which R ² is a hydrogen atom.

This hydrolysis reaction can be carried out by a conventional method, for example, by bringing it into contact with water under acidic or basic conditions in a suitable solvent. As the solvent, for example, alcohols such as methanol, ethanol, isopropyl alcohol, dioxane, water or a mixed solution thereof is used. Specific examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as formic acid, acetic acid, propionic acid and oxalic acid. Specific examples of the base 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.

When a compound in which R ^2a is a lower alkanoyl group is used in the formula (II), the acetyl group is eliminated by using silica gel, and R ² in the formula (I) is used.
It can be easily converted into a compound in which ² is a hydrogen atom.

The compound of the formula (II) and its reactive derivative are described in, for example, JP-A-51-80858 (US Pat. No. 4,039,6).
No. 72 specification) or a method analogous thereto.

The production method of the compound of formula (III) is described below.

The compound of the formula (III) can be produced, for example, by the method shown in the following chemical formula 8.

[0042]

Embedded image

(In the formula, Pht means a phthalimido group, X means a reactive ester residue of alcohol, R
¹ and n mean the same as above. )

Step 1 : The reaction of the compound of formula (A) with nitromethane is carried out according to Indian. J. Chem., Vol. 14B, 400 (197).
According to the method described in 6), it is usually carried out without solvent or in a suitable solvent. The reaction temperature is generally about 80 ° C to about 130 ° C, preferably about 90 ° C to about 110 ° C. The compound of formula (A), which is a raw material compound, is commercially available or can be produced from a commercially available product by a method known per se.

Step 2 : The compound of formula (C) has the formula (B)
Can be produced by catalytic reduction using a catalyst such as platinum oxide, palladium carbon, Raney nickel under atmospheric pressure or under pressure. Specific examples of the solvent used include alcohols such as methanol and ethanol. The reaction temperature is usually about -10 ° C to about 100 ° C.
C., preferably about 0.degree. C. to about 50.degree.

Step 3 : The reaction of the compound of formula (C) with carboethoxyphthalimide is usually carried out in a suitable solvent. Specific examples of the solvent include ethers such as tetrahydrofuran and dioxane. The reaction temperature is
It is usually about 0 ° C to about 100 ° C, preferably about 10 ° C to about 50 ° C.

Step 4 : Compound of formula (D) and formula: R ^1-
The reaction with the R ¹ introducing agent represented by X 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 X include a halogen atom such as chlorine, bromine and iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, and an arylsulfonyloxy group such as benzenesulfonyloxy. Can be mentioned. Specific examples of the solvent include aromatic hydrocarbons such as benzene and toluene, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, alcohols such as ethanol and isopropyl alcohol, acetonitrile and chloroform. , Ethyl acetate, dimethylformamide, dimethylsulfoxide, or a mixture thereof. Specific examples of the base used include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali carbonates such as sodium carbonate and potassium carbonate, or triethylamine. , Tributylamine, diisopropylethylamine,
Organic bases such as N-methylmorpholine are mentioned.
When X is chlorine or bromine in the R ¹ introducing agent, the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. The reaction temperature varies depending on the type of R ¹ introducing agent used, usually from about 0 ° C. ~ about 200 ° C., preferably about 80 ° C. ~ about 0.99 ° C..

Step 5 : The deprotection reaction of the compound of formula (E) is carried out in the presence of hydrazine in a suitable solvent. Examples of the solvent used include alcohols such as methanol and ethanol. Reaction temperature is usually 20 ℃ ~ 80 ℃
It is.

The final product of the formula (III ') produced by the method shown in the above chemical formula 8 is racemic. The racemic compound of formula (III) can be resolved into two optical isomers according to a conventional method. For example, by treating a compound of formula (III) with an optically active acid to form a diastereomeric salt, and then separating the two diastereomeric salts, which are then converted to the free bases. .

Process (b) The compound of formula (I) has the following formula (IV)

[0051]

Embedded image

It can be produced by diazotizing the compound represented by the formula (wherein R ¹ , R ² , n and wavy line have the same meanings as described above).

The ring closure reaction of the compound of formula (IV) 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-closing reaction with nitrous acid, sodium nitrite is usually added to an aqueous solution of a compound of formula (IV) or an acid addition salt thereof after adding an excess of a mineral acid (eg hydrochloric acid) or an organic acid (eg acetic acid). Is performed 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-closing reaction with an alkyl nitrite, it is usually carried out by reacting a compound of the formula (IV) or an acid addition salt thereof (for example, hydrochloride or acetate) with an alkyl nitrite in a suitable 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 (IV) can be produced, for example, by the method represented by the following chemical formula 10.

[0055]

Embedded image

(In the formula, Z means a halogen atom,
R ² , Az and wavy line have the same meanings as above. )

Step 1 : The reaction of the compound of formula (F) or its reactive derivative with the compound of formula (III) can be carried out in the same manner as in the production method (a). The compound of the formula (F) which is a raw material compound is, for example, Helv. Chim. Acta, 40 ,
369-372 (1957).

Step 2 : Compound of formula (G) 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 : Reduction of the compound of formula (H) is carried out according to a conventional method. For example, by treating the compound of formula (H) 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, it is also carried out by hydrogenating the compound of formula (H) in the presence of a catalyst in a suitable solvent. 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 formula (IV) 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 configurations of the compounds of the formula (III) and the compound of the formula (IV), which are the starting compounds, are retained in the product 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 formula (I) is selected from the 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.

The results of pharmacological tests for representative compounds of the present invention are shown below.

Test Example : Inhibitory effect on apomorphine-induced vomiting--A group of 3 to 4 Beagle dogs (body weight 8 to 15 kg) was used.
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. The compound of Example 1 suppressed 92.7% at the dose of 1 mg / kg.

Since the compound of formula (I) and its physiologically acceptable acid addition salt have both excellent antiemetic action and gastrointestinal function enhancing action and weak central inhibitory action, they improve gastrointestinal function. It can be used as a drug for the treatment and prevention of various gastrointestinal dysfunction associated with various diseases and treatments. Specifically, acute / chronic gastritis, reflux esophagitis, gastric / duodenal ulcer,
Appetite in diseases such as gastric neuropathy, gastroptosis, postoperative paralytic ileus, senile ileus, postgastrectomy syndrome, scleroderma, diabetes, esophageal / biliary tract disorders, periodic vomiting in children, upper respiratory tract infections, etc. It can be used for treatment and prevention of depression, nausea, vomiting, abdominal bloating, upper abdominal discomfort, abdominal pain, heartburn, vomiting, etc., and treatment and prevention of irritable bowel syndrome, constipation, infant diarrhea. 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.

The route of administration may be oral, parenteral or rectal administration. The dose varies depending on the kind of compound, administration method, patient's symptoms and age, etc., but usually 0.01 to 30 mg / kg / day, preferably 0.1 to 10 m
g / kg / day.

When the compound of formula (I) or a physiologically acceptable acid addition salt thereof is used for the above-mentioned medicinal use, it is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. As a pharmaceutical carrier, it is commonly used in the pharmaceutical field,
A substance that does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, sorbitol, cyclodextrin, starch, partially pregelatinized starch, sucrose,
Magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, calcium carboxymethyl cellulose, 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, magnesium stearate, talc, tragacanth, bentonite, veegum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purification Lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, water, propylene glycol, ethanol, sodium chloride, sodium hydroxide, hydrochloric acid, citric acid, benzyl alcohol, glutamic acid, glycine,
Examples include methyl paraoxybenzoate, propyl paraoxybenzoate 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.

[0071]

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. Compounds are identified by elemental analysis value, mass spectrum, UV spectrum, IR spectrum, N
It was performed by MR spectrum and the like.

Reference Example 1 --Preparation of 2-aminomethyl-1-ethyl-1H-hexahydroazepine:

(1) A mixture of 25 g of 1-azacyclohexane-2-methoxyiminoether and 12 g of nitromethane was heated under reflux for 24 hours. After cooling, the precipitated solid was collected by filtration, washed with ether and dried to obtain 22.0 g of 2-nitromethylidene-1H-hexahydroazepine.

(2) 10 g of the above product, 10 g of methanol
To 0 ml of solution, add 1.0 g of platinum oxide and carry out medium pressure catalytic reduction at room temperature. After the theoretical amount of hydrogen had been absorbed, the catalyst was filtered off. The filtrate was evaporated under reduced pressure, and the obtained residue was distilled under reduced pressure to give 2-aminomethyl-1H-hexahydroazepine 5.7.
g was obtained as an oil. Boiling point 65-70 ℃ / 2 mmHg

(3) 10.4 g of carboethoxyphthalimide in 100 ml of tetrahydrofuran containing 6.7 g of the above product
Was added and the mixture was stirred at room temperature for 36 hours. The mixture was diluted with water, extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel chromatography, and eluted and purified with chloroform-methanol (9: 1) to give 2-phthalimidomethyl-.
3.6 g of 1H-hexahydroazepine was obtained as an oil.

(4) To a solution of 1.0 g of the above product in 50 ml of methyl ethyl ketone, 1.6 g of potassium carbonate and 0.93 ml of ethyl iodide were added, and the mixture was heated under reflux for 5 hours. The solvent was distilled off under reduced pressure, the residue was diluted with water and then extracted with chloroform. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was subjected to silica gel chromatography, eluted with chloroform-methanol (9: 1) and purified to give 1-ethyl-2-phthalimidomethyl-1H-hexahydroazepine (0.95 g) as an oil.

(5) 2.0 g of ethanol 2 of the above product
To the 0 ml solution, 0.42 g of hydrazine monohydrate was added, and the mixture was heated with stirring for 2 hours. The solvent was distilled off under reduced pressure, 1N hydrochloric acid was added to the residue, and the precipitated solid was filtered off. The filtrate was neutralized, then salted out with potassium carbonate, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.1 g of the desired product as an oil.

Reference Example 2 --Production of 2-aminomethyl-1-ethyl-1H-heptahydroazocine:

1-azacyclooctane-2-methoxyiminoether was used in place of 1-azacyclohexane-2-methoxyiminoether in Reference Example 1, and the same reaction and treatment as in Reference Example 1 was carried out to obtain the desired product. .

Example 1 N-[(1-ethyl-1H-hexahydroazepine-2
Preparation of -yl) methyl] -6-methoxy-1H-benzotriazole-5-carboxamide:

6-Methoxy-1H-benzotriazole-5-carboxylic acid 1.35 g of dimethylformamide 30
1.1 g of N, N'-carbonyldiimidazole was added to the ml solution, and the mixture was stirred at room temperature for 8 hours. To the reaction solution was added 2-aminomethyl-1-ethyl-1H-hexahydroazepine (1.1 g), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, chloroform-methanol (9: 1) and 1%.
The product was eluted and purified with a mixed solution of aqueous ammonia, and recrystallized from ethanol-acetone to obtain 1.35 g of the desired product. Melting point
158 to 159 ℃

Example 2 N-[(1-Ethyl-1H-heptahydroazocine-2
Preparation of -yl) methyl] -6-methoxy-1H-benzotriazole-5-carboxamide:

2-Aminomethyl-1- in Example 1
2-Aminomethyl-1-ethyl-1H-heptahydroazonin was used in place of ethyl-1H-hexahydroazepine and reacted and treated in the same manner as in Example 1 to obtain the target product as an oil.

[0084]

The compound of the present invention represented by the formula (I) and its physiologically acceptable acid addition salt have both excellent antiemetic action and gastrointestinal function enhancing action, and central inhibitory action. Since it is weak, it can be used as a gastrointestinal function improving drug for the treatment and prevention of various gastrointestinal dysfunction associated with various diseases and treatments.

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Claims (1)

[Claims] 1. A 6-methoxy-1H compound represented by the following chemical formula 1.
-A benzotriazole-5-carboxamide compound or a physiologically acceptable acid addition salt thereof. Embedded image [In the formula, R ¹ is a C _{1 to} C ₄ alkyl group or (C _{3 to} C ₆
A cycloalkyl) methyl group, R ² is a hydrogen atom,
A C ₁ -C ₄ alkyl group, a C ₃ -C ₆ cycloalkyl group or a (C ₃ -C ₆ cycloalkyl) methyl group, and n
Means 1, 2 or 3 and the wavy line (~) means that the configuration of the carbon atom to which it is attached is RS, R or S. ]