JPH09301972A - N-(1-substituted-azacycloalkan-3-yl)carboxamide derivative and medicinal composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having both of excellent antiemetic action and alimentary canal function-accentuating action, having weak central nervous system depressant action and useful as an alimentary canal function improving medicine used for treating and preventing alimentary canal function abnormality. SOLUTION: This compound is represented by formula I [R<1> is a lower alkyl, a cycloalkyl, etc.; R<2> and R<3> form a group of formula II (R6 and R7 are each H or a lower alkyl) together with adjacent carbon atom and R<4> is H or R<3> and R<4> form a group, etc., of formula III together with adjacent carbon atom and R<2> is H or a halogen; (n) is 1-3; the wavy line represents that configuration of carbon which bonds is RS, R or S] or its acid addition salt, e.g. 7- chloro-N-(1-ethyl-1H-hexahydroazepin-3-yl)-4-methoxy-1H-benzotriazol-5- carboxamide. The compound of formula I is obtained by reacting a compound of formula IV with a compound of formula V.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel carboxamide derivative characterized by a combination of excellent antiemetic action and gastrointestinal function enhancing action and weak central inhibitory action, more specifically, a nitrogen atom in the amide moiety is 7, 8- or 9-membered ring 1-
Lower alkoxy-1H-benzotriazole carboxamide derivative substituted with substituted-azacycloalkan-3-yl group or lower alkoxy-1H- (or -3H-)
The present invention relates to a benzimidazole carboxamide derivative and a pharmaceutical composition containing the same.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 2-104572 describes that a compound represented by the following formula 4 has a gastrointestinal function-enhancing action and is useful as an antiemetic agent or a gastrointestinal function-enhancing agent. .

[0003]

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[Wherein R ₁ represents a lower alkyl group or an aryl (lower) alkyl group which is unsubstituted or has a substituent, R ₂ represents a hydroxy group, an alkoxy group or the like, R ₃ represents an amino group, A di-substituted amino group or an acylamino group is meant, R ₄ is a halogen atom, or R ₃ and R ₄ may be taken together to form —NH—N═N—, and R ₅ is hydrogen. Means an atom or a lower alkyl group, X means a single bond or a lower alkylene group, Y means a single bond, —CH ₂ —, —O—, —S—, —NR ₆ — and the like, and n is Means 0 or 1; the dashed line means the double bond which is optionally present when Y is —CH ₂ — and n is 0. However, when (i) Y is -NR ₆ -or a single bond, n means 0, and (ii) when Y is -O-, n
Means 1 and (iii) when Y is a single bond or —CH ₂ — and n is 0, R ₁ means an unsubstituted or substituted aryl (lower) alkyl group, and (iv ) N
When is 0, X means a lower alkylene group. ]

The above-mentioned publication only discloses a structure in which R ² and R ³ together in formula (I) below are —N═N—NH—.

[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 antiemetic action and gastrointestinal function enhancing action. Therefore, it has long been used as a gastrointestinal function improving drug for various digestive system diseases or various digestive disorders associated with treatment. It is used in the treatment and prevention of organic symptoms. 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. The number of patients suffering from gastrointestinal indefinite complaints is increasing due to complication of social life, advent of aging society, etc.
Moreover, the development of a compound having both an excellent antiemetic action and a gastrointestinal function enhancing action is desired.

As a result of intensive studies by the present inventors, lower alkoxy-1H- in which the nitrogen atom of the amide moiety is substituted with a 7-, 8- or 9-membered 1-substituted-azacycloalkan-3-yl group. Although the benzotriazole carboxamide derivative or the lower alkoxy-1H- (or -3H-) benzimidazole carboxamide derivative has both excellent antiemetic action and gastrointestinal hyperactivity action, it was found that the central depressant action is weak. Completed the invention.

[0008]

The present invention provides a carboxamide derivative represented by the following formula (I), a physiologically acceptable acid addition salt thereof, and a pharmaceutical composition containing the same.

[0009]

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[Wherein R ¹ represents a lower alkyl group, a cycloalkyl group, a cycloalkylmethyl group or a lower alkenyl group, and R ² and R ³ together with adjacent carbon atoms are represented by the following chemical formula 6] A group represented by the formula [A], R ⁴ represents a hydrogen atom,

[0011]

[Chemical 6]

(In the formula, R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group.) Alternatively, R ² represents a hydrogen atom or a halogen atom, and R
³ and R ⁴ together with adjacent carbon atoms each represent a group represented by the formula [B] or [C] of the following chemical formula 7,

[0013]

[Chemical 7]

(Wherein R ⁶ and R ⁷ are as defined above) R ⁵ is a lower alkyl group, n is 1, 2 or 3 and the wavy line (~) is Means that the configuration of the carbon atom to which is bonded is RS, R or S. ]

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 its physiologically acceptable acid addition salt may exist as a hydrate or a solvate, these hydrates and solvates are also included in the present invention. To be done.

A compound in which R ³ and R ⁴ together in formula (I) is a group represented by —NH—N═N— is represented by the following formula (I ′) or formula (I ″). These tautomers are also included in the compounds of the present invention, as they may exist in the form of tautomers.

[0018]

Embedded image (In the formula, Az means Chemical Formula 9,

[0019]

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

In the formula (I), R ³ and R ⁴ , or R ³ and R ² are taken together to form --NH--C (R ⁶ ) =
The compound which is a group represented by N- is represented by R in the formula (I).
³ and R ⁴ , or R ³ and R ² together are -N =
Can also be expressed as a C compound (R ⁶⁾ is -NH- group represented by. In this specification, it denotes a compound having such a structure as the former -NH-C (R ⁶⁾ = compound is a group represented by N-.

The terms used in this specification are explained below.

"Halogen atom" means fluorine, chlorine, bromine or iodine, with chlorine being particularly preferred. Specific examples of "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
Examples thereof include t-butyl, pentyl, and hexyl, and those having 1 to 3 carbon atoms are preferable. Specific examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The “cycloalkylmethyl group” means a methyl group substituted with the above-mentioned cycloalkyl group, and specific examples thereof include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl, with cyclopropylmethyl being preferred. . Specific examples of the "lower alkenyl group" include allyl and 2-butenyl.

Among the compounds of the present invention, preferred are compounds of formula (I) in which R ¹ is an ethyl group or a cyclopropylmethyl group, R ⁵ is a methyl group, and R ² , R ² .
^And compounds in which ³ , R ⁴ and n are the same as those mentioned above, and physiologically acceptable acid addition salts thereof.

A more preferred compound is, in formula (I), R ¹ is an ethyl group, R ² is a chlorine atom,
R ³ and R ⁴ are each a group represented by the formula [B] or [C] of the above Chemical Formula 7 together with adjacent carbon atoms,
Examples include compounds in which R ⁶ is a methyl group or an ethyl group, R ⁷ is a hydrogen atom, R ⁵ and n are the same as those described above, and physiologically acceptable acid addition salts thereof.

Particularly preferred compounds are those of formula (I) in which n is 1 and R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
Included are compounds where R ⁶ and R ⁷ are the same as above and physiologically acceptable acid addition salts thereof.

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

Particularly preferred compounds are specifically the following compounds and physiologically acceptable acid addition salts thereof.

7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-1H
-Benzotriazole-5-carboxamide, (R)-
7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-1H-benzotriazole-5-carboxamide, 7-chloro-N- (1
-Ethyl-1H-hexahydroazepin-3-yl)-
4-Methoxy-2-methyl-1H-benzimidazole-5-carboxamide, and (R) -7-chloro-N-
(1-Ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide.

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

7-chloro-N- (1-cyclopropylmethyl-1H-hexahydroazepin-3-yl) -4-
Methoxy-1H-benzotriazole-5-carboxamide, 7-chloro-N- (1-cyclopropylmethyl-
1H-hexahydroazepin-3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide, 7-chloro-N- (1-cyclopropyl-
1H-hexahydroazepin-3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide, 7-chloro-N- (1-allyl-1H-hexahydroazepin-3-yl)- 4-methoxy-1H
-Benzotriazole-5-carboxamide, 7-chloro-N- (1-allyl-1H-hexahydroazepine-
3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide, 7-chloro-4-
Ethoxy-N- (1-ethyl-1H-hexahydroazepin-3-yl) -1H-benzotriazole-5-carboxamide, 7-chloro-N- (1-ethyl-1H-
Hexahydroazepin-3-yl) -4-propoxy-
1H-benzotriazole-5-carboxamide, 7-
Chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-2-ethyl-1H-benzimidazole-5-carboxamide,

7-chloro-N- (1-ethyl-1H-heptahydroazocin-3-yl) -4-methoxy-1H
-Benzotriazole-5-carboxamide, 7-chloro-N- (1-cyclopropylmethyl-1H-heptahydroazocin-3-yl) -4-methoxy-1H-benzotriazole-5-carboxamide, 7-chloro- N
-(1-Ethyl-1H-heptahydroazocin-3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide, 7-chloro-N- (1-
Cyclopropylmethyl-1H-heptahydroazocine-
3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide, 7-chloro-N-
(1-Ethyl-1H-octahydroazonin-3-yl) -4-methoxy-1H-benzotriazol-5-
Carboxamide, and 7-chloro-N- (1-ethyl-
1H-octahydroazonin-3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide.

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

The compounds of formula formula (I) is represented by the following formula (II)

[0034]

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(Wherein R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above) or a reactive derivative thereof, and the following formula (III)

[0036]

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

Examples of the reactive derivative of the compound of the formula (II) include lower alkyl ester (especially methyl ester), active ester, acid anhydride, 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.

The compound of formula (II) can be produced by the method described in Reference Examples 4 to 8 below or a method analogous thereto.

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

In the formula (III), the compound in which n is 1 can be produced, for example, by the method shown in Chemical formula 12 below.

[0044]

[Chemical 12]

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

Step 1 : The reaction of the compound of formula (A) with chlorotriphenylmethane is usually carried out in a suitable solvent in the presence of a base. As the solvent and the base to be used, the specific examples described in the above production method (a) can be mentioned as they are. The reaction temperature is generally about -10 ° C to about 150 ° C, preferably about 0 ° C to about 100 ° C. In addition, as the R and S isomers of the formula (A), which are raw material compounds, commercially available racemates are used.
For example, optically resolving by the method described in J. Org. Chem., 44 , 4841-4847 (1979) or using optically active lysine, for example, according to the method described in Synthesis, 1978 , 614-616. You can

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

Step 3 : Compound of formula (C) 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 the specific examples described in the above production method (a) as they are. 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 4 : The reaction of this step is usually carried out using a mineral acid such as dilute hydrochloric acid or dilute sulfuric acid in a suitable solvent. Specific examples of the solvent used include alcohols such as methanol and ethanol, ethers such as diethyl ether and tetrahydrofuran, acetone, acetonitrile,
Examples thereof include ethylene glycol or a mixed solution thereof. The reaction temperature will differ depending on the types of starting compounds used, but it is usually about 0.degree. C. to about 100.degree.

The compound of formula (III ') can also be produced by exchanging the reduction reaction of step 2 and the R ¹ introduction reaction of step 3 in the above Chemical formula 12. That is, by introducing R ¹ into the compound of formula (B) (step 2 ′) and then reducing (step 3 ′), the compound of formula (D) can be obtained. In this case, it is preferable to use a strong base such as sodium hydride instead of the base described in the above-mentioned production method (a) in the reaction of step 2 ', and, for the reduction reaction of step 3', for example, hydrogen is used. Bis (2-methoxyethoxy)
Preference is given to using sodium aluminum.

In the formula (III), the compound in which n is 2 or 3 can be produced, for example, by the method represented by the following chemical formula 13.

[0052]

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(In the formula, Y means a halogen atom, and n '
Means 2 or 3, and R ¹ and X mean the same as above. )

The step 1 in the above chemical formula 13 is carried out in the same manner as the step 2'in the modification of the method shown in the above chemical formula 12, using commercially available 2-azacyclooctanone or azacyclononanone as the starting material. be able to. Step 2
The halogenation of, for example, J. Am. Chem. Soc., 80 , 6233-
6237 (1958), and steps 3 and 4 can be performed, for example, in Helv. Chim. Acta, 41 , 18
It can be performed according to the method described in 1-188 (1958).

The compound of the formula (III) can also be produced by the method represented by the following chemical formula 14.

[0056]

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

Step 1 in the above Chemical formula 14 can be carried out by generating an anion in the compound of formula (E) with a strong base in a suitable solvent and then reacting it with dry ice. The conversion of the carboxyl group to the amino group in step 2 is carried out by reacting the compound of formula (F) with ethyl chlorocarbonate and sodium azide in a suitable solvent, and then heating the resulting acyl azide body to form an isocyanate body, It can be carried out by reacting an acid. The triphenylmethylation in step 3, the reduction in step 4 and the deprotection of the triphenylmethyl group in step 5 can be carried out in the same manner as in step 1, step 2 and step 4 of the above Chemical formula 12, respectively.

The starting compound of the formula (E) can be produced by the method of step 1 of Chemical formula 13 using ε-caprolactam, 2-azacyclooctanone or 2-azacyclononanone as a starting material.

According to the method shown in Chemical formula 12, the configuration of the starting compound (A) is retained in the final product represented by the formula (III '). On the other hand, the final product of the formula (III ″) or (III ′ ″) produced by the method shown in Chemical formula 13 or Chemical formula 14 is a racemate. 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. .

According to the above production method, the configurations of the compound of formula (II) and the compound of formula (III) which are the starting compounds are retained in the compound of formula (I). Therefore, a compound of formula (I) having a desired configuration can be obtained by using a starting compound having a corresponding configuration or by using a starting compound which is a racemate.
It can be produced by producing a racemic compound of formula (I) and then performing 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 test results of the representative compound of the present invention and metoclopramide hydrochloride monohydrate (Compound A), which is a commercially available drug for improving gastrointestinal tract function, are shown below, and the characteristics of the pharmacological action of the compound of the present invention are explained. To do.

Test Example 1 : 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. Table 1 shows the results
Shown in

[0066]

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

Test Example 2 : Gastric emptying enhancing action--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.

[0068]

[Table 2] ^* ) Means the compound of Example 1 (the same applies hereinafter).

As is clear from the above test results, the compound of the formula (I) of the present invention and the physiologically acceptable acid addition salt thereof have both excellent antiemetic action and gastrointestinal function enhancing action. Despite the fact that it has a weak central inhibitory action and low toxicity, 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. Specifically, acute / chronic gastritis, reflux esophagitis, gastric / duodenal ulcer, gastric neuropathy, gastroptosis, postoperative paralytic ileus, senile ileus, post gastrectomy syndrome, scleroderma, diabetes, esophagus / esophagus Biliary disorders, periodic vomiting in children,
For the treatment and prevention of anorexia, nausea, vomiting, abdominal distention, upper abdominal discomfort, abdominal pain, heartburn, vomiting, etc. in diseases such as upper respiratory tract infections, and treatment of irritable bowel syndrome, constipation, infant diarrhea And can be used for prevention. Furthermore, it can be used for the treatment and prevention of nausea or vomiting during administration of various anticancer agents or levodopa preparations or during irradiation of radiation.

The route of administration may be oral, parenteral or rectal administration. The dose varies depending on the type of compound, administration method, patient's symptoms and age, etc., but is usually 0.01 to 30 mg / kg / day, preferably 0.1 to 5 m
g / kg / day.

When the compound of formula (I) or a physiologically acceptable acid addition salt thereof is used for the above-mentioned pharmaceutical use, it is usually administered in the form of a preparation prepared by mixing with a carrier for preparation. As 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.

[0074]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples, but the present invention is not limited to these Examples. Compounds are identified by elemental analysis value, mass spectrum, UV spectrum, IR spectrum, N
It was performed by MR spectrum and the like.

In the following Reference Examples and Examples,
The following abbreviations may be used to simplify the description. [NMR] J: binding constant, s: singlet, dd: double doublet, t: triplet, m: multiplet, br-s: broad singlet.

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

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

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

(3) 180 g of a 70% toluene solution of sodium bis (2-methoxyethoxy) aluminum hydride
Toluene (800 ml) was added thereto, and the above product (83 g) was added thereto with stirring under ice-cooling, and the mixture was stirred under the same conditions for 1 hour and further at room temperature for 2 hours. Water and 48% aqueous sodium hydroxide solution were added to the reaction solution under ice cooling, and 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. The obtained oily residue was crystallized with ethanol, the crystals were collected by filtration and dried to obtain 1-ethyl-3-triphenylmethylamino-1H-hexahydroazepine (65 g). 85-86 ° C

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

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

Reference Example 2 Preparation 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 Preparation 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 --Production of 6-methoxy-2-methyl-1H-benzimidazole-5-carboxylic acid:

(1) 4-acetylamino-5-amino-2-methoxybenzoic acid methyl hydrochloride 5.84 g of a toluene 100 ml solution was added with a catalytic amount of p-toluenesulfonic acid, and water was removed with Dean Stark. While heating and refluxing for 6 hours. After cooling the reaction solution, the precipitated crystals were collected by filtration,
After drying, 5.87 g of methyl 6-methoxy-2-methyl-1H-benzimidazole-5-carboxylic acid hydrochloride was obtained.

¹ H-NMR spectrum (DMSO-d ₆ , δppm):
2.77 (3H, s), 3.83 (3H, s), 3.90 (3H, s), 7.35 (1
H, s), 7.98 (1H, s).

(2) 2.3 g of sodium hydroxide was added to a mixed solution of 4.8 g of the above product, 50 ml of water and 20 ml of methanol, and the mixture was heated under reflux for 1.5 hours. After cooling the reaction solution, methanol was distilled off under reduced pressure, the resulting aqueous solution was washed with diethyl ether, adjusted to pH 4 with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 2.5 g of the desired product.

¹ H-NMR spectrum (DMSO-d ₆ , δppm):
2.47 (3H, s), 3.83 (3H, s), 7.08 (1H, s), 7.78 (1
H, s), 12.25 (1H, br-s).

Reference Example 5 : Preparation of 1,2-dimethyl-6-methoxy-1H-benzimidazole-5-carboxylic acid:

(1) Methyl 4-acetylamino-2-methoxy-5-nitrobenzoate (20.0 g) in 150 ml of anhydrous dimethylformamide was added to a solution of 60% sodium hydride (3.6%).
g was added, and the mixture was stirred at about 50 ° C for 20 minutes. After cooling to about 10 ℃,
Methyl iodide (21.2 g) was added, and the mixture was stirred at room temperature for 1 hr.
The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and then with saturated brine, the solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from isopropyl alcohol-diethyl ether to give 2-
19.8 g of methyl methoxy-4-[(N-methyl-N-acetyl) amino] -5-nitrobenzoate was obtained.

(2) 5.0 g of ethanol 1 of the above product
The 00 ml solution was catalytically reduced using 0.5 g of 5% palladium carbon. After absorbing the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated under reduced pressure to give 1,2-dimethyl-6-methoxy-
Methyl 1H-benzimidazole-5-carboxylate 2.5
g was obtained as a solid.

¹ H-NMR spectrum (DMSO-d ₆ , δppm):
2.49 (3H, s), 3.72 (3H, s), 3.77 (3H, s), 3.86 (3
H, s), 7.20 (1H, s), 7.80 (1H, s).

(3) 1,2-Dimethyl-6 was used instead of methyl 6-methoxy-2-methyl-1H-benzotriazole-5-carboxylate hydrochloride in Reference Example 4 (2).
A reaction was performed in the same manner as in Reference Example 4 (2) using 1.6 g of methyl-methoxy-1H-benzimidazole-5-carboxylate.
This was treated to obtain 0.7 g of the desired product.

¹ H-NMR spectrum (DMSO-d ₆ , δppm):
2.80 (3H, s), 3.92 (3H, s), 3.94 (3H, s), 7.66 (1
H, s), 7.97 (1H, s)

Reference Example 6 --- Preparation of 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid:

(1) 12.3 ml of concentrated sulfuric acid was added dropwise to 102 ml (d 1.52) of fuming nitric acid solution under ice cooling, and methyl 4-acetylamino-5-chloro-2-methoxybenzoate was added at 5 ° C or lower.
After adding 34 g little by little, it stirred at the same temperature for 5 minutes. The reaction solution was poured into ice water and the precipitated solid was collected by filtration. This was washed with water, dried and recrystallized from ethanol to give 4
23 g of methyl acetylamino-5-chloro-2-methoxy-3-nitrobenzoate was obtained.

(2) 18 g of ethanol 18 of the above product
Raney nickel was added to the 0 ml solution and catalytically reduced at medium pressure. After absorbing the theoretical amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to obtain 12.7 g of methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate.

(3) 4.0 g of the above product was added to 10 ml of concentrated sulfuric acid.
Was dissolved in 40 ml of ice water, and then an aqueous solution containing 1.52 g of sodium nitrite was added dropwise. After stirring for 1 hour under ice cooling, the mixture was heated under reflux for 16 hours. After cooling, the precipitated solid was collected by filtration, washed with water and dried to obtain 2.13 g of the desired product.
(Recrystallized from toluene)

Reference Example 7 : Preparation of 7 -chloro-4-methoxy-2-methyl-1H-benzimidazole-5-carboxylic acid:

(1) To a solution of 3.0 g of methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate obtained in Reference Example 6 (2) in 10 ml of toluene was added a catalytic amount of p-toluene sulfone. The mixture was refluxed for 1 hour while adding an acid and removing the produced water. After cooling, the precipitated solid was collected by filtration and
2.9 g of methyl -chloro-4-methoxy-2-methyl-1H-benzimidazole-5-carboxylate was obtained.

(2) 1.5 g of the above product, methanol 1
To a mixed solution of 0 ml-10 ml of water, add 0.7% of 48% sodium hydroxide.
4 g was added and the mixture was heated under reflux for 1.5 hours. Methanol was distilled off under reduced pressure, diluted with water and adjusted to pH 3 with concentrated hydrochloric acid. After water was distilled off under reduced pressure, the residue was dissolved in ethanol to remove insoluble materials. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from acetone to obtain 1.45 g of the desired product.

Reference Example 8 : Preparation of 7-bromo-4-methoxy-2-methyl-1H-benzimidazole-5-carboxylic acid:

4-Acetylamino-3 in Reference Example 7
Using methyl 4-acetylamino-3-amino-5-bromo-2-methoxybenzoate in place of methyl -amino-5-chloro-2-methoxybenzoate, reacting and treating in the same manner as in Reference Example 7 I got a thing.

Example 1 Preparation of 7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-1H-benzotriazole-5-carboxamide:

0.94 g of N, N'-carbonyldiimidazole was added to a solution of 1.2 g of 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid in 20 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 hours. 3 in the reaction solution
-Amino-1-ethyl-1H-hexahydroazepine
1.5 g was added and stirred at room temperature for 16 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was diluted with water and then extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform-methanol (7: 1), and recrystallized from ethanol-diethyl ether to obtain 1.9 g of the desired product. Melting point 172-
174 ° C

Example 2 -- Preparation of (R) -7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-1H-benzotriazole-5-carboxamide:

Instead of 3-amino-1-ethyl-1H-hexahydroazepine in Example 1, (R) -3-
Amino-1-ethyl-1H-hexahydroazepine was used, reacted and treated in the same manner as in Example 1, and recrystallized from toluene-diethyl ether to obtain the desired hemihydrate. Melting point 112-114 ° C

Example 3 N- (1-ethyl-1H-hexahydroazepine-3-
Preparation of yl) -6-methoxy-2-methyl-1H-benzimidazole-5-carboxamide:

Example 1 was replaced with 6-methoxy-2-methyl-1H-benzimidazole-5-carboxylic acid in place of 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid in Example 1. Reaction similar to
It was treated and recrystallized from acetone to obtain the desired 1/4 hydrate. Melting point 171-172 ° C

Example 4 N- (1-ethyl-1H-hexahydroazepine-3-
Preparation of (yl) -6-methoxy-1,2-dimethyl-1H-benzimidazole-5-carboxamide:

6-Methoxy-1,2-dimethyl-1H-benzimidazole-5-carboxylic acid was used in place of 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid in Example 1. The reaction and treatment were carried out in the same manner as in Example 1, and recrystallization from diethyl ether gave the target hemihydrate. Melting point 90-92 ℃

Example 5 7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-2-methyl-1H
-Preparation of benzimidazole-5-carboxamide:

Instead of 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid in Example 1, 7-chloro-4-methoxy-2-methyl-1H-benzimidazole-5-carboxylic acid was used. The reaction and treatment were carried out in the same manner as in Example 1, and recrystallization from diethyl ether-acetone gave the desired product. Melting point 162-165 ° C

Example 6- (R) -7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-2-methyl-1H-benzimidazole-5-carboxamide Manufacturing of:

Using the corresponding starting compound, reaction and treatment were carried out in the same manner as in Example 1, and recrystallization from diethyl ether gave the desired product. Melting point 176-178 ° C

Example 7 : 7-Bromo-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-2-methyl-1H
-Preparation of benzimidazole-5-carboxamide:

In place of 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid in Example 1, 7-bromo-4-methoxy-2-methyl-1H-benzimidazole-5-carboxylic acid was used. The reaction and treatment were conducted in the same manner as in Example 1 to obtain the desired product as an oil.

Example 8 Preparation of 7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-1,2-dimethyl-1H-benzimidazole-5-carboxamide :

Instead of 7-chloro-4-methoxy-1H-benzotriazole-5-carboxylic acid in Example 1, 7-chloro-4-methoxy-1,2-dimethyl-1 was used.
Using H-benzimidazole-5-carboxylic acid, the reaction and treatment were carried out in the same manner as in Example 1, and recrystallization from toluene-n-hexane gave the desired product. Melting point 124-125 ° C

Example 9 N- (1-ethyl-1H-hexahydroazepine-3-
Yl) -4-methoxy-1H-benzotriazole-5
-Production of carboxamide:

7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-1H
-To a solution of 0.3 g of benzotriazole-5-carboxamide in 10 ml of ethanol, 0.05 g of 10% palladium-carbon was added and catalytically reduced at a medium pressure. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography silica gel column chromatography, and chloroform-
Elute and purify with methanol (9: 1) and recrystallize from ethanol-diethyl ether to obtain 1/5 hydrate of the desired product.
0.15 g was obtained. Melting point 144-145 ° C

Formulation Example 1 : Preparation of tablets: 7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-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).

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

Formulation Example 2 : Preparation of powder: 7-chloro-N- (1-ethyl-1H-hexahydroazepin-3-yl) -4-methoxy-2-methyl-1H
-Benzimidazole-5-carboxamide (10 g),
Lactose (960 g), hydroxypropyl cellulose (25
g), and light anhydrous silicic acid (5 g).

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

[0128]

INDUSTRIAL APPLICABILITY As described above, the compound of the present invention represented by the formula (I) and the physiologically acceptable acid addition salt thereof have both excellent antiemetic action and gastrointestinal function enhancing action. In addition, since it has a weak central inhibitory effect, 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.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // (C07D 403/12 223: 12 235: 08) (C07D 403/12 223: 12 249: 18 )

Claims (5)

[Claims] 1. An N- (1-substituted-azacycloalkan-3-yl) carboxamide derivative represented by the following chemical formula 1 or a physiologically acceptable acid addition salt thereof. Embedded image [Wherein R ¹ represents a lower alkyl group, a cycloalkyl group, a cycloalkylmethyl group or a lower alkenyl group,
R ² and R ³ together with the adjacent carbon atoms mean a group represented by the formula [A] of the following chemical formula 2, and R ⁴ means a hydrogen atom, or (In the formula, R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom or a lower alkyl group.) Alternatively, R ² represents a hydrogen atom or a halogen atom, and R
³ and R ⁴ together with the adjacent carbon atoms mean a group represented by the formula [B] or [C] of the following chemical formula 3, (In the formulae, R ⁶ and R ⁷ have the same meanings as defined above.) R ⁵ means a lower alkyl group, n means 1, 2 or 3, and wavy line (∼) means that it is bonded. It means that the configuration of the carbon atom is RS, R or S. ] 2. The compound according to claim 1, wherein R ¹ is an ethyl group or a cyclopropylmethyl group, and R ⁵ is a methyl group. 3. R ¹ is an ethyl group, R ² is a chlorine atom, and R ³ and R ⁴ together with adjacent carbon atoms are the formulas [B] or [B] of Formula 3 in claim 1. C]
The compound according to claim 2, wherein R ⁶ is a group represented by, R ⁶ is a methyl group or an ethyl group, and R ⁷ is a hydrogen atom. 4. The compound according to claim 3, wherein n is 1. 5. The N- according to any one of claims 1 to 4.
A pharmaceutical composition comprising a (1-substituted-azacycloalkan-3-yl) carboxamide derivative or a physiologically acceptable acid addition salt thereof.