JPH09241241A - N-(1-substituted-4-piperidyl)benzamide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new benzamide derivative having a serotonin receptor- operating activity and useful for the therapy of chronic gastritis, gastric content retention, abdominal feeling of fullness, central nervous system disorders and urine-excretion system disorders. SOLUTION: This new derivative is expressed by formula I [R<1> , R<2> are each H, a halogen, a lower alkoxy, a lower alkyl; X is carbonyl, methylene; (n) is 1-3] or it salt, e.g. 4-amino-5-chloro-2-methoxy-N- 1-[3-[4-(2-methoxyphenyl) piperazin-1-yl]-3-oxo-1-propyl]piperidin-4-yl}benzamide oxalate salt. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III in the presence of a base (e.g. sodium carbonate) and, if necessary, further sodium iodide, potassium iodide, etc., in a solvent (e.g. N,N-dimethylformamide) at 0-l00 deg.C. The compound of formula I is orally administered at a daily dose of 0.01-1,000mg/adult.

Description

Detailed Description of the Invention

[0001]

The present invention relates to serotonin (5-HT
₄ ) Novel N- (1-substituted- ₄ ) having receptor agonistic activity
-Piperidyl) benzamide derivative or a pharmaceutically acceptable salt thereof, and more specifically, to an N- (1-substituted-4-piperidyl) benzamide derivative having a phenylpiperazinyl group.

[0002]

BACKGROUND OF THE INVENTION Cisapride and metoclopramide, which have 5-HT ₄ receptor agonistic activity, have a gastrointestinal tract motility-promoting action, and are effective in treating chronic gastritis, abdominal bloating, reflux esophagitis, abdominal indefinite complaints and pseudoileus. It is effective in treating symptoms. However, metoclopramide has been recognized as an extrapyramidal side effect due to its action on central dopamine D ₂ receptors.
Further, it has been revealed that Parkinson's symptom also appears in cisapride, and it is considered that a selective drug having no action on dopamine D ₂ receptor is desirable to overcome these problems. Also, 5-HT ₄
Receptors are known to be widely distributed in living organisms such as the cardiovascular system, central nervous system and urinary system in addition to the digestive system,
5-HT ₄ receptor agonists are also believed to be useful in these injuries. Examples of the piperidylbenzamide derivative relating to the present invention include, for example, Japanese Patent Publication No. 58-401.
No. 9, JP-B-59-6851, JP-A-53-53
Although disclosed in JP-A-77069, JP-A-62-126158 and JP-A-62-129279, there is no description of the compound of the present invention.

[0003]

SUMMARY OF THE INVENTION The present invention provides 5-HT ₄
It is an object of the present invention to provide a 5-HT ₄ receptor agonist which has a selective agonist activity on the receptor and has no central side effect.

[0004]

DISCLOSURE OF THE INVENTION As a result of intensive studies conducted by the present inventors in view of the above situation, N- (1-substituted-4-piperidyl) having a phenylpiperazinyl group was found.
It was found that a benzamide derivative or a pharmacologically acceptable salt thereof meets the above-mentioned problems, and completed the present invention. That is, the present invention relates to an N- (1-substituted-4-piperidyl) benzamide derivative represented by the following general formula [I] or a pharmaceutically acceptable salt thereof.

[0005]

Embedded image

[Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, and X represents a carbonyl group or a methylene group,
n represents 1 to 3. ] N- (1-substituted-4-
Piperidyl) benzamide derivative or a pharmaceutically acceptable salt thereof.

The halogen atom, lower alkoxy group and lower alkyl group of R ¹ and R ² in the above general formula [I] will be specifically described. The halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The lower alkoxy group can be a methoxy group, an ethoxy group, an n-propoxy group or an isopropoxy group.
The lower alkyl group means a linear or branched alkyl group having 1 to 4 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group.

Further, as specific examples of the pharmacologically acceptable salt of the compound [I] of the present invention, any pharmaceutically acceptable salt can be used, but preferably, hydrochloride or hydrobromide is used. Mineral salts such as nitrates, sulfates, phosphates, oxalates, formic acid, acetates, lactates, succinic acids, fumarates, maleates, malates, tartrates, citrates, Organic acid salts such as aspartate and methanesulfonate can be mentioned. Furthermore, the compound [I] of the present invention can form hydrates and various solvates. A typical method for producing the compound [I] of the present invention is shown below.

[0009]

Embedded image

[Wherein R ¹ , R ² , X and n are the same as defined above. ]

That is, the compound [I] of the present invention comprises the compound [II] or a salt thereof and the compound represented by the above general formula [III] in a solvent, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, It can be produced by reacting in the presence of a base such as sodium methoxide, triethylamine and pyridine, and further in the presence or absence of sodium iodide, potassium iodide and the like. As the solvent, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, ethers such as tetrahydrofuran, diethyl ether, dioxane and dimethoxyethane, acetonitrile, dimethyl sulfoxide and the like can be preferably used. The reaction temperature is −20 ° C. to the boiling point of the solvent, but preferably 0 to
100 ° C. The reaction time varies depending on the reaction temperature, the type of raw material compound or the solvent, but is usually 0.5 hour to
50 hours is preferred.

Next, the compound [II] which is the starting material for the above reaction
And a typical method for producing the compound represented by the above general formula [III] is shown below. First, the production of the raw material compound [II] is
It can be carried out by the method of production step [A] from compound [IV] via compound [V] or the method of production step [B] via compound [VI].

[0013]

Embedded image

Production Process [A] The compound [V] can be produced by condensing the compound [IV] with 4-amino-1-ethoxycarbonylpiperidine. The condensation can be performed by a method using a suitable dehydrating agent, for example, a carbodiimide such as dicyclohexylcarbodiimide, or a method through a reactive derivative of the compound [IV]. Examples of the reactive derivative include acid anhydrides, acid halides, lower alkyl esters, active esters and mixed acid anhydrides. When a mixed acid anhydride is used, a mixed acid anhydride with methyl chlorocarbonate, ethyl chlorocarbonate, phenyl chlorocarbonate, benzyl chlorocarbonate and the like can be exemplified.

Next, compound [II] can be produced by reacting compound [V] in an alcohol such as methanol, ethanol or isopropyl alcohol in the presence of a base such as sodium hydroxide or potassium hydroxide. it can. Usually, the reaction temperature is preferably −20 ° C. to the boiling point of the solvent, and the reaction time is preferably 0.5 to 50 hours.

Production Process [B] The production of the compound [II] via the compound [VI] can be carried out according to the method described in JP-B-58-4019. On the other hand, the compound represented by the following general formula [III] can be produced by reacting the compound [VII] with the compound [VIII] or the compound [IX] according to the production process [C].

[0017]

Embedded image

[Wherein R ¹ , R ² , X and n are the same as defined above, and Z is a suitable leaving group such as chlorine atom, bromine atom, methanesulfonyloxy group, trifluoromethanesulfonyloxy group or p- Represents a toluenesulfonyloxy group and the like. ]

That is, when the compound [VIII] is used,
Compound in the presence or absence of a base such as triethylamine, pyridine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydroxide, sodium hydroxide, etc. in a solvent such as chloroform, methylene chloride, tetrahydrofuran, diethyl ether, dioxane, etc. By reacting with [VII], a compound represented by the above general formula [III] can be obtained. The reaction temperature is preferably −20 ° C. to the boiling point of the solvent, and the reaction time is preferably 0.5 to 50 hours. When using the compound [IX], acetonitrile, tetrahydrofuran, diethyl ether,
By carrying out the reaction in a solvent such as dioxane in the presence or absence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, etc. The compound represented by [III] can be obtained. The reaction temperature is preferably −20 ° C. to the boiling point of the solvent, and the reaction time is preferably 0.5 to 50 hours.

[0020]

The compound of the present invention and a pharmacologically acceptable salt thereof have a selective agonistic activity on the 5-HT ₄ receptor,
Since it does not show dopamine D ₂ receptor activity, it acts specifically on the 5-HT ₄ receptor. Therefore, it can be used for the treatment of chronic gastritis, gastric stasis, abdominal bloating, reflux esophagitis, abdominal indefinite complaints, pseudo-intestinal obstruction, central nervous system disorders, and urinary system.

When the compound of the present invention and a pharmacologically acceptable salt thereof are administered to humans for the purpose of treating or preventing the above-mentioned diseases, orally as a powder, granules, tablets, capsules, etc., It can be parenterally administered as an injection or a suppository. The clinical dose is appropriately determined by taking into consideration the symptoms, weight, age, sex, etc. of the patient to which it is applied, but when orally administered to an adult patient, it is usually about 0.01 to 1000 mg / human per day. It is possible to administer the amount of 0.1 to 500 mg / human in one to several divided doses.

In formulating, it can be manufactured by a conventional method using a usual pharmaceutical carrier. That is, in the case of producing a solid preparation for oral use, the main ingredient is an excipient and optionally a binder,
After adding disintegrant, lubricant, coloring agent, flavoring agent, etc.,
Powders, tablets, granules, capsules, etc. Here, as the excipient, for example, lactose, corn starch, glucose, sorbitol, crystalline cellulose, silicon dioxide, etc.,
As the binder, for example, polyvinyl alcohol, ethyl cellulose, methyl cellulose, acacia, tragacanth, shellac, hydroxypropyl starch, polyvinylpyrrolidone, etc., as the lubricant, for example, magnesium stearate, talc, polyethylene glycol, etc., as the disintegrating agent, For example, starch, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogen carbonate, calcium citrate and the like are used. As the flavoring agent, for example, cocoa powder, peppermint oil, cinnamon powder and the like are used. If necessary, these tablets and granules may be sugar-coated, gelatin-coated, or any other suitable coating may be applied. In addition, the preparation of an injection for parenteral administration can be carried out by a conventional method by adding a pH adjusting agent, a buffering agent, a stabilizer, a solubilizing agent and the like to the main drug as necessary.

[0023]

[Example 1]

4-amino-5-chloro-2-methoxy-N- {1-
[3- [4- (2-methoxyphenyl) piperazine-1
-Yl] -3-oxo-1-propyl] piperidine-4
Synthesis of 4-yl-5-benzamide oxalate 4-Amino-5-chloro-2-methoxy-N- (4-piperidyl) benzamide A solution of 1.0 g of N, N-dimethylformamide (10 ml) in 1- ( 3-Chloro-1-oxo-1-propyl) -4- (2-methoxyphenyl) piperazine 1.76 g, sodium carbonate 0.66 g and sodium iodide 47 mg were added, and 80
Stirred at C for 4 hours. After standing to cool, chloroform (200 m
1) was added, the mixture was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 3.9 g of a brown oily substance. This is subjected to silica gel column chromatography [developing solvent: chloroform / methanol = 30 /
1 → 15/1 (V / V)] to obtain 1.6 g (97%) of the free form of the title compound as a light brown oil.
This is dissolved in methanol and oxalic acid (3.1 mmo
1, 0.39 mmol) in methanol was added to obtain white crystals of oxalate. Recrystallization was performed with methanol-acetone to obtain 1.61 g of the title compound.

Mp143-147 ° C. IR (nujol
Method): 3392, 1724, 1640. MS m / z
(FAB): 530 (M ⁺ +1) (as free form). ¹
H-NMR (ppm, DMSO-d ₆ ) δ: 1.75-
1.95 (2H, m), 2.00-2.15 (2H,
m), 2.90-3.25 (8H, m), 3.30-
3.35 (2H, m), 3.38-3.55 (2H,
m), 3.60-3.70 (4H, m), 3.84 (3
H, s), 3.87 (3H, s), 3.95-4.10.
(1H, m), 5.85-6.20 (2H, m), 6.
52 (1H, s), 6.88-7.10 (4H, m),
7.66 (1H, s), 7.83 (1H, d, J = 6.
9 Hz) Elemental analysis (C ₁₃ H ₁₄ FN ₃ OS. (COOH) ₂ .1 / 2H ₂ O) Theoretical value (%): C, 55.37; H, 6.25; N, 11.13 Measured value ( %): C, 55.34; H, 6.16; N, 10.98

Similar to Example 1, the following Examples 2 to 1
6 compound was obtained. Example 2 4-amino-5-chloro-2-methoxy-N- [1-
[2- (4-phenylpiperazin-1-yl) -2-oxo-1-ethyl] piperidin-4-yl] benzamide oxalate mp 132-135 ° C. IR (nujol method): 336
8, 1710, 1660. MS m / z (FAB): 4
86 (M ⁺ +1) (as a free body)

Example 3 4-amino-5-chloro-2-methoxy-N- {1-
[2- [4- (2-methoxyphenyl) piperazine-1
-Yl] -1-ethyl] piperidin-4-yl} benzamide oxalate mp 200 ° C or higher. IR (nujol method): 3388,
1720, 1642. MS m / z (FAB): 502
(M ⁺ +1) (as a free body)

Example 4 4-amino-5-chloro-2-methoxy-N- {1-
[2- [4- (2-methoxyphenyl) piperazine-1
-Yl] -2-oxo-1-ethyl] piperidine-4-
Il} benzamide oxalate mp138-140 ° C. IR (nujol method): 336
4,1708,1638. MS m / z (FAB): 5
16 (M ⁺ +1) (as a free body)

Example 5 4-amino-5-chloro-2-methoxy-N- {1-
[3- [4- (2-methoxyphenyl) piperazine-1
-Yl] -1-propyl] piperidin-4-yl} benzamide oxalate mp131-133 ° C. IR (nujol method): 339
6,1705,1630. MS m / z (FAB): 5
16 (M ⁺ +1) (as a free body)

Example 6 4-amino-5-chloro-2-methoxy-N- {1-
[4- [4- (2-methoxyphenyl) piperazine-1
-Yl] -4-oxo-1-butyl] piperidine-4-
Il} benzamide mp 78-81 ° C. IR (nujol method): 3332,
1634. MS m / z (FAB): 544 (M ⁺⁺ )
1)

Example 7 4-amino-5-chloro-2-methoxy-N- [1-
[3- (4-phenylpiperazin-1-yl) -3-oxo-1-propyl] piperidin-4-yl] benzamide oxalate mp 126-129 ° C. IR (nujol method): 338
8, 1728, 1598. MS m / z (FAB): 5
00 (M ⁺ +1) (as a free body)

Example 8 4-amino-5-chloro-N- {1- [3- [4- (2
-Fluorophenyl) piperazin-1-yl] -3-oxo-1-propyl] piperidin-4-yl} -2-methoxybenzamide oxalate mp 151-154 ° C. IR (nujol method): 338
8, 1718, 1642. MS m / z (FAB): 5
18 (M ⁺ +1) (as a free body)

Example 9 4-amino-5-chloro-N- {1- [3- [4- (4
-Fluorophenyl) piperazin-1-yl] -3-oxo-1-propyl] piperidin-4-yl} -2-methoxybenzamide oxalate mp153-155 ° C. IR (nujol method): 334
8, 1706, 1652. MS m / z (FAB): 5
18 (M ⁺ +1) (as a free body)

Example 10 4-amino-5-chloro-N- {1- [3- [4- (2
-Chlorophenyl) piperazin-1-yl] -3-oxo-1-propyl] piperidin-4-yl} -2-methoxybenzamide oxalate mp 128-131 ° C. IR (nujol method): 334
0, 1716, 1634. MS m / z (FAB): 5
34 (M ⁺ +1) (as a free body)

Example 11 4-amino-5-chloro-N- {1- [3- [4- (3
-Chlorophenyl) piperazin-1-yl] -3-oxo-1-propyl] piperidin-4-yl} -2-methoxybenzamide oxalate mp173-176 ° C. IR (nujol method): 339
2,1708,1640. MS m / z (FAB): 5
34 (M ⁺ +1) (as a free body)

Example 12 4-amino-5-chloro-N- {1- [3- [4- (4
-Chlorophenyl) piperazin-1-yl] -3-oxo-1-propyl] piperidin-4-yl} -2-methoxybenzamide oxalate mp 184-187 ° C. IR (nujol method): 334
0, 1700, 1638. MS m / z (FAB): 5
34 (M ⁺ +1) (as a free body)

Example 13 4-amino-5-chloro-2-methoxy-N- {1-
[3- [4- (4-methoxyphenyl) piperazine-1
-Yl] -3-oxo-1-propyl] piperidine-4
-Yl} benzamide mp156-157 ° C. IR (nujol method): 341
2,3336,1642. MS m / z (FAB): 5
30 (M ⁺ +1)

Example 14 4-amino-5-chloro-2-methoxy-N- {1-
[3- [4- (2-methylphenyl) piperazine-1-
Iyl] -3-oxo-1-propyl] piperidine-4-
Il} benzamide oxalate mp 134-138 ° C. IR (nujol method): 334
4, 3224, 1636. MS m / z (FAB): 5
14 (M ⁺ +1) (as a free body)

Example 15 4-amino-5-chloro-2-methoxy-N- {1-
[3- [4- (2,4-Dimethylphenyl) piperazin-1-yl] -3-oxo-1-propyl] piperidin-4-yl} benzamide oxalate mp 132-136 ° C. IR (nujol method): 338
4, 3340, 1634. MS m / z (FAB): 5
28 (M ⁺ +1) (as a free body)

Example 16 4-amino-5-chloro-N- {1- [3- [4- (4
-Chloro-2-methylphenyl) piperazin-1-yl] -3-oxo-1-propyl] piperidin-4-yl} -2-methoxybenzamide oxalate mp 144-147 ° C. IR (nujol method): 334
4, 3224, 1638. MS m / z (FAB): 5
48 (M ⁺ +1) (as a free body)

Reference Example 1 4-amino-5-chloro-2-methoxy-N- [4-
Synthesis of (1-ethoxycarbonyl) piperidyl] benzamide 4-Amino-5-chloro-2-methoxybenzoic acid 5.1
After adding 2.78 g of triethylamine to a solution of 9 g of methylene chloride (50 ml), 2.85 g of ethyl chlorocarbonate was added dropwise under ice cooling. After stirring at 0 ° C. for 1 hour, ethyl 4
-Amino-1-piperidinecarboxylate 4.93 g
Methylene chloride (5 ml) solution of was added dropwise, the mixture was stirred for 1.5 hours, warmed to room temperature and stirred for 1 hour. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in ethyl acetate (250 ml). This is water (50 ml, 3 times), saturated saline (50 m
It was washed successively with l), dried and evaporated under reduced pressure to give an oil. This oily substance was crystallized with diethyl ether to obtain 8.6 g of the title compound as white crystals.

Mp 144-145 ° C. IR (nujol
Method): 3408, 1682, 1634, 1464. MS
m / z (FAB): 356 (M ⁺ +1). ¹ H-NMR
(Ppm, CDCl ₃ ) δ: 1.27 (3H, t), 1.
34-1.50 (2H, m), 1.97-2.04 (2
H, m), 2.98-3.09 (2H, m), 3.89.
(3H, s,), 4.01-4.21 (5H, m),
4.41 (2H, s), 6.29 (1H, s), 7.6
4 (1H, d), 8.09 (1H, s) Elemental analysis (C ₁₆ H ₂₂ ClN ₃ O ₄ ) Theoretical value (%): C, 55.01; H, 6.23; N, 11.81 Found (%): C, 54.06; H, 6.38; N, 11.72.

Reference Example 2 Synthesis of 4-amino-5-chloro-2-methoxy-N- (4-piperidyl) benzamide 4-amino-5-chloro-2-methoxy-N- [4-
31.5 g of potassium hydroxide was added to a suspension of 21.3 g of (1-ethoxycarbonyl) piperidyl] benzamide in isopropyl alcohol (600 ml), and the mixture was stirred for 29 hours under heating under reflux. After cooling, the insoluble matter was filtered off, and the filtrate was adjusted to pH 6 with diluted hydrochloric acid under cooling. The filtrate was evaporated to dryness under reduced pressure, chloroform (300 ml) and saturated saline were added, and then 40% aqueous sodium hydroxide solution was added to adjust the pH.
I made it 11 or more. After separating the chloroform layer, it was further extracted with chloroform (300 ml) three times. The combined chloroform layers were dried and evaporated under reduced pressure to give a brown powder. This was recrystallized from ethanol-ether to obtain 15.0 g of the title compound as light brown crystals.

Mp161-163 ° C. IR (nujol
Method): 3412, 3268, 1636. MS m / z
(FAB): 284 (M ⁺ +1). ¹ H-NMR (pp
m, DMSO-d ₆ ) δ: 1.27-1.48 (2H,
m), 1.73-1.80 (2H, m), 2.49-
2.53 (2H, m), 2.84-2.92 (2H,
m), 3.75-3.85 (4H, m,), 5.94.
(1H, s), 6.48 (1H, s), 7.67-7.
71 (2H, m)

Reference Example 3 1- (3-chloro-1-oxopropyl) -4- (2-
Synthesis of methoxyphenyl) piperazine To a solution of 3.0 g of 1- (2-methoxyphenyl) piperazine and 3.32 g of triethylamine in chloroform (100 ml) stirred with ice cooling was added a solution of 2.58 g of 3-chloropropionyl chloride in chloroform (20 ml). The mixture was added dropwise and stirred at room temperature for 1 hour. Chloroform (50 ml)
Was added, diluted, washed with saturated sodium hydrogen carbonate, water, and saturated saline in this order, and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure to obtain 4.7 g of a brown oily substance. This was subjected to silica gel chromatography [developing solvent: ethyl acetate / hexane = 1/1 (V / V)] to obtain white crystals. Further, recrystallization from ethyl acetate-hexane gave 3.7 g of the title compound.

Mp 94-96 ° C. IR (nujol
Method): 1650. MS m / z (FAB): 283 (M
⁺ +1). ¹ H-NMR (ppm, CDCl ₃ ) δ: 2.8
6 (2H, t, J = 7.0Hz), 3.01-3.09
(4H, m), 3.66 (2H, t, J = 4.8H
z), 3.60-3.90 (4H, m), 3.88 (3
H, s,), 6.87-7.10 ( 4H, m) Elemental analysis _{(C 14 H 19 ClN 2 O} 2) theory (%): C, 59.47; H, 6.77; N, 9.91 Found (%): C, 59.48; H, 6.91; N, 9.86.

[Formulation Example] The following mixture was uniformly mixed according to a conventional method and compressed into tablets to give tablets each containing 2 mg of the active ingredient. Compound of Example 1 2 mg Lactose 42 mg Crystalline cellulose 30 mg Corn starch 15 mg Hydroxymethyl cellulose 10 mg Magnesium stearate 1 mg

Test Example 1 5-HT ₄ Receptor Agonist Activity Baxter et al. Method (Naunyn-Schmied)
eberg's Arch. Pharmacol. , 343, 439-446, 1991),
The relaxation effect on carbachol contraction in rat esophageal mucosa was investigated. Approximately 2c of the proximal part of the rat esophagus
m was extracted and the inner smooth muscle plate of the esophageal mucosal muscle plate was separated from the outer layer to prepare a sample. The sample was mixed gas (95% O ₂ +
It was suspended in a Tyrode solution (37 ± 1 ° C.) that had been aerated with 5% CO ₂ . The sample was loaded with 0.25 g tension and the reaction was measured isometrically using an isometric transducer and recorded on a pen recorder. Carbachol (3 μM) was added to the sample to induce contraction, and after stable contraction was obtained, the test compound was cumulatively applied to observe the relaxation effect. The relaxation activity of the test compound is expressed as a percentage of the contraction height obtained in the presence of the test compound with respect to the contraction height by carbachol.
The concentration (EC ₅₀ value) of the test compound that suppressed% was calculated.
The results are shown in Table 1.

[0048]

[Table 1]

Test Example 2 Dopamine D ₂ Receptor Binding Action The method of Zahniser et al. (J. Pharmacol.
Exp. Ther. , 227, 592, 198
3 years), a dopamine D ₂ receptor binding test using [ ³ H] spiperone was performed. After decapitating an SD male rat, the whole brain was immediately removed, and the striatum was extracted under ice cooling. Ice-cold 50 mM Tris-HCl buffer (pH
7.5) was added and homogenized, and a receptor sample was obtained by ultracentrifugation. This receptor preparation was added with sodium chloride (120
mM), potassium chloride (5 mM), magnesium chloride (1 mM), calcium chloride (1 mM) containing ice-cooled 50
mM Tris-hydrochloric acid buffer, [ ³ H] spiperone (final concentration 0.5 nM) and a test compound were added, and the mixture was added at 60 at 25 ° C.
Incubated for minutes. Nonspecific binding amount is 10μ (S)-
It was obtained by adding (-)-sulpiride and performing the same operation. After the incubation, vacuum filtration was performed with a Whatman GF / C filter using a cell harvester. The radioactivity of this filter was measured using a liquid scintillation counter. The specific binding amount was calculated according to the following formula. Specific binding amount (dpm) = total binding amount (dpm) -nonspecific binding amount (dpm) The concentration of the test compound that inhibits the binding of [ ³ H] spiperone to the dopamine D ₂ receptor preparation by 50% It was expressed as an IC ₅₀ value. As a result, the IC ₅₀ value of the compound of the present invention was 1 μm.
It was M or more, and the binding power to the dopamine D ₂ receptor was weak.

[Test Example 3] Anti-dopaminergic activity test In the anti-dopaminergic activity experiment using rats, 100 or 1000 mg of the test compound was administered to SD male rats (4 mice per group).
Oral administration was carried out by observing general symptoms including catalepsy 1 hour after administration and eyelid drooping etc. up to 1 week after administration. For catalepsy, the rat's one forelimb was placed on a cylinder stand with a diameter of 5 cm and a height of 4 cm, and the resting time was scored (0 seconds: 0 point, 1-10 seconds: 1
Points, 11 to 20 seconds: 2 points, 21 to 30 seconds: 3 points, 31 seconds or more: 4 points).
The results are shown in Table 2.

[0051]

[Table 2]

Test Example 4 Acute Toxicity Test Male ddY male mice fasted overnight (5 weeks old, 8 mice per group)
1000 mg / kg of the compound of Example 6 suspended in a 0.5% aqueous solution of methylcellulose was orally administered to the above, and observation was performed for 1 week. As a result, no deaths were observed.

[0053]

From the above results, the compound of the present invention and the pharmacologically acceptable salt thereof have selective agonistic activity on 5-HT ₄ receptor and dopamine D ₂ receptor activity. Since it does not, it acts specifically on the 5-HT ₄ receptor. Therefore, chronic gastritis, gastric stasis, bloating,
It can be used to treat reflux esophagitis, abdominal indefinite complaints, symptoms of pseudo-ileus, central nervous system disorders and urinary system.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 31/495 AEN A61K 31/495 AEN (72) Inventor Akera Ikeda 2-305 Kokubun, Otsu City, Shiga Prefecture −15 (72) Inventor Hideyuki Kobayashi 9-206 Karabashi Biwacho, Minami-ku, Kyoto Prefecture, Kyoto Prefecture (72) Inventor Etsuko Chaki 667 Katsuragocho, Hikone City, Shiga Prefecture (72) Inventor Kazuyoshi Takahashi 60-3 Okamachi, Moriyama City, Shiga Prefecture

Claims (1)

[Claims] 1. A compound represented by the following general formula [I]: [Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkoxy group or a lower alkyl group, X represents a carbonyl group or a methylene group, and n is 1 to 1].
3 is represented. ] N- (1-substituted-4-piperidyl) benzamide derivative shown by these, or its pharmacologically acceptable salt.