WO1995003045A1

WO1995003045A1 - Accelerator for digestive tract movement

Info

Publication number: WO1995003045A1
Application number: PCT/JP1994/001170
Authority: WO
Inventors: Haruhiko Kikuchi; Hiroaki Satoh; Ruta Fukutomi; Kohei Inomata; Masashi Suzuki; Masahiro Ueno; Koichiro Hagihara; Takeo Arai; Haruko Eguchi; Yumiko Noguchi
Original assignee: Nisshin Flour Milling Co., Ltd.
Priority date: 1993-07-19
Filing date: 1994-07-18
Publication date: 1995-02-02
Also published as: JP3497863B2

Abstract

A 5-HT4 receptor agonist containing a diazabicyclo derivative represented by general formula (I) or a pharmaceutically acceptable acid-addition salt thereof as the active ingredient, which is efficacious as an accelerator for digestive tract movement, in particular, gastrointestinal movement; and a method of treating incompetence of digestive tract movement by administering the same, wherein R1 represents cyclopropylmethyl, allyl, isobutyl or 2-butenyl.

Description

Specification

Gastrointestinal motility enhancer

〔Technical field〕

The present invention is directed to Jiazabishikuro derivative or a pharmaceutically acceptable acid addition salt thereof as an active ingredient, about 5-HT ₄ receptor agonists.

The present invention relates to agents that promote by Ri gastrointestinal motility to act particularly 5-111 ₄ receptors of the gastrointestinal tract nervous system.

(Background technology)

As a conventional 5-HT ₄ receptor agonists, Mosapride, compounds having a base Nzuami de skeleton such Cisapride has been reported.

On the other hand, Jiazabishiku port derivative was first synthesized by Nikitskaya et (J. Org. Chem. USSR ( Engl. Transl.), 1965, 1, 170), 5- HT 3 have a receptor antagonism EP 469449, W0 9205174, W0 9307147 disclosed but, 5-HT ₄ are not known receptor agonism. , [Disclosure of the Invention].

An object of the present invention is to provide a 5-HT ₄ receptor agonist which is more effective and has fewer side effects.

Means for Solving the Problems As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that a diazavicic mouth derivative different from a benzamide skeleton or an acid addition salt thereof is effective as a 5-HT ₄ receptor agonist.

That is, the present invention provides a compound represented by the general formula (I):

(I)

(In the formula, represents a cyclopropylmethyl group, an aryl group, an isobutyl group or a 2-butenyl group) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. HT ₄ receptor agonists, more particularly gastrointestinal prokinetic agent.

To date, 5-HT receptors have been roughly classified into 5-HT h 5-HT ₂ and 5-HT ₃ receptors (Bradley et. Al., 1986, Neuropharmacology, 25, 563). 5-! ! Receptors have been shown to be present (Bockaert et. Al., 1992, Trends Pharmacol. Sci. 13, 141) _D- receptors are central nervous systems, such as the striatum, olfactory tubercle, pallidum, and lateral seat It is densely present in the nucleus or substantia nigra (Grossman et al., 1993, Br. J. Pharmacol. 109, 618), and in the peripheral nervous system such as the heart (Kaumann et. Al., 1990, Br. J. Pharmacol. 100, 879) or the gastrointestinal tract (Borman and Burleigh, 1993, Br. J. Pharmacol. 110, 927). Thus, 5 - HT ₄ receptor agonist by acting to such receptors can be a medicament for the treatment of diseases caused by the receptor.

For example, 5 in the gastrointestinal tract - HT ₄ receptor agonist is used as a gastrointestinal prokinetic agent. Gastrointestinal motility is regulated by the sympathetic and parasympathetic nervous systems. In the parasympathetic nervous system, acetylcholine is one of the most important neurotransmitters involved in regulating gastrointestinal motility. The release of acetylcholine from nerves present in the gut plexus causes the gastrointestinal tract to contract. Therefore, promoting the release of acetylcholine from the gastrointestinal nerve will enhance gastrointestinal motility. 5 - HT ₄ receptors have been reported to be free Adjusts the Asechiruko Li down in the digestive tract nerve (Ki lbinger and Wol f, 1992 , Naunyn- Schmiedeberg's Arch. Pharmacol. 345, 270) Therefore, drugs that act on this receptor to promote the release of acetylcholine are useful as gastrointestinal motility promoters in gastrointestinal motility disorders.

5-HT ₄ receptor agonist in the central nervous acts on 5-HT ₄ receptors in nerve cells, to increase cAMP in the cells has been reported (Trends Pharmacol. Sci. 1992, 13, 141 ). Nerve cells such as in the hippocampus, in order to be involved in memory and recognition, 5-HT ₄ receptor agonists by increasing the cAMP in these cells, memory and cognitive impairment therapeutic agent or dementia Can be a remedy for Furthermore, 5-HT ₄ receptor since there closely nigra and striatum, had there Hanchin tons chorea can be a therapeutic agent for voluntary movement disorders such as Parkinson's disease.

Thus, since the 5-HT ₄ receptor agonist acts on the 5-111 ₄ receptor and can be a useful drug for diseases of the central nervous system and the peripheral nervous system, the present inventors As a result of intensive studies to solve such problems, they have found that the following diazavicic mouth derivatives have remarkable 5-HT ₄ receptor agonist activity, and have completed the present invention.

The compound represented by the general formula (I) of the present invention has already been applied for a patent (Japanese Patent Application No. 5-13013) by the present inventors, and can be produced by various methods based on a well-known ladder reaction. can do.

That is, the compound represented by the general formula (I) basically has the following general formula (式)

(Π)

(Wherein has the meaning described above)

An amide-forming reactive derivative of indazole-3-carboxylic acid represented by (for example, 1- (cyclopropylmethyl) indazole-3-carbonylcarbonyl, 1-arylindazole-3-carbonylcarbonyl, 1-Isobutylindazole-3-carbonyl mouth, 1- (2-butenyl) indazole-3-carbonyl mouth) and the following formula (m)

3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane-7-amine represented by the following formula or a carbodiimide derivative (for example, dicyclohexylcarbodiimide, 1-ethyl-3-3- ( Indazole-3-carboxylic acid represented by the general formula (Π) and formula (III) in the presence of a condensing agent such as 3′-dimethylaminopropyl) carbodiimide hydrochloride) or cyanide getyl phosphate. 3,9-dimethyl-3,9-diazavincro [3.3.1] can be obtained by reacting nonan-7-amine.

Or the following formula (IV)

[2,3-a, 2 ', 3'-d] pyrazine-7, 14-di (1H-indazole-3-carboxylic acid dimer) is reacted with the compound represented by the above formula (ID) to obtain a compound represented by the formula (V)

And then R! -X (for example, cyclopropyl propyl methylbumid, aryl bromide, isobutyl bromide, crotyl bromide) in the presence of a base (for example, sodium hydride, n-butyllithium). In the presence of getyl azodicarboxylate and triphenylphosphine (or tributylphosphine) in the presence of E-OH 0H (for example, cyclopropanemethanol, aryl alcohol, isobutyl alcohol, Crotyl alcohol) to give a compound represented by the general formula (I). In the above formula, R, has the above-mentioned meaning, and X represents a halogen atom such as bromine or chlorine.

The diazabicyclononanamine derivative represented by the above formula (m) is a compound of N, N-bis (2,2-dialkoxyethyl) methylamine such as N, N-bis (2,2-dimethylmethicil). ) Methylamine is hydrolyzed to give 3-methyl-3-azapentanedial, which is then condensed with acetone dicarboxylic acid and methylamine to give 7-oxo-3,9-dimethyl-3,9-. Diazabicyclo [3.3.1] nonane, which was converted to oxime with hydroxylamine, then subjected to amino reduction by catalytic reduction to give 3,9-dimethyl-3,9-diazabicyclo [3.3.1. 1] It can be prepared by a reaction that produces nonane-7-amine. The 3,9-dimethyl-3,9-dazavinclo [3.3.1] nonane-7-amine obtained in this manner was converted to indazole-3 -Reacts with carboxylic acids or their amide-forming reactive derivatives.

The following series of reaction steps are shown in the following Scheme 1, taking the case where 1H-indazole-3-carbonic acid dimer is used as the amide-forming reactive derivative as an example.

The desired product thus produced can be obtained through washing, extraction and purification steps of the reaction mixture.

Reaction scheme

RO

KOH RO OR 1) Ha

+ MeNH

RO OR Me OR

2) CO _z H

O

(R = lower alkyl) C0 ₂ HeNH ₂ «HCI

(F ^ has the above meaning) Specific examples of the diazabicyclo derivative represented by the general formula (I) of the present invention produced from these reactions include:

N- [endo-1,3-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl] -1- (cyclopropylmethyl) indazol-3-3-carboxamide

N- [1-Endo 3,9-dimethyl-3,9-diazabicyclo [3.3,1] non-7-yl]-1-arylindazole-3-carboxamide

N- [End-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl]-1-isobutylindazole-3-hexylboxamide

N- [3,9-Dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl] -1- (2-butenyl) indazole-3-carboxamide

It is.

The acid addition salt of the compound represented by the general formula (I) of the present invention means a compound in which an acid is added to the nitrogen atom at the 3-position, the Z-position or the 9-position of the diazabicyclic ring in the general formula (I). These acid addition salts include pharmacologically acceptable salts, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and oxalate. Organic acid salts such as acid, maleate, fumarate, lactate, linate, citrate, tartrate, benzoate and methanesulfonate.

Further, the compound represented by the general formula (I) and the acid addition salt thereof may exist in the form of a hydrate or a solvate, and these hydrates and solvates are also included in the compound of the present invention. included. Examples of the diseases for which the 5-HT ₄ receptor agonist of the present invention is effective include central nervous diseases such as memory impairment, cognitive impairment, dementia, Huntington's disease, Parkinson's disease, heart diseases such as heart failure, and chronic gastritis. Gastrointestinal dysfunction associated with postgastrectomy syndrome, diabetes, scleroderma, etc., gastrointestinal disorders such as reflux esophagitis and irritable bowel syndrome.

The compounds of the present invention can be administered orally or parenterally in the form of conventional pharmaceutical preparations. Pharmaceutical preparations include tablets, capsules, troches, syrups, granules, powders, injections, suspensions and the like. The other agents in conjunction with bilayer tablets, _c further tablets may be multi-layered tablets, coated tablet conventional capsule shell optionally, for example, a sugar tablets, enteric coated tablets, be a film coat tablets Can also.

When a solid preparation is used, solid excipients such as lactose, sucrose, crystalline cellulose, corn starch, acacia, polyvinyl virolidone, hydroquinine propylcellulose, polyethylene glycol, stearate, magnesium stearate, Talc is used.

When a semi-solid preparation is used, vegetable or synthetic wax or fat is used.

When a liquid preparation is used, a liquid additive such as an aqueous sodium chloride solution, sorbitol, glycerin, olive oil, almond oil, propylene glycol, or ethanol is used.

The amount of active ingredient in these preparations is from 0.001 to 100% by weight of the preparation, suitably from 0.01 to 50% by weight on the platform of the preparation for oral administration, and In that case, it is 0.001 to 10% by weight.

There is no particular limitation on the administration method and dosage of the compound of the present invention. The dosage of the active ingredient per adult per day is 0.01 «9 ~: 100, although it is appropriately selected depending on the seed preparation form, the degree of the disease, the age of the patient, the sex, etc.

Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited thereto.

Example 1

N- [Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl] -1- (cyclopropylmethyl) indazolyl-3-carboxamide

N- [endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl] -1H-indazole-3-hexylboxamide (1.00 g-3.19 ol) After dissolving in DMF (30), 60% sodium hydride (0.1539, 3.83 mmol) was added under ice cooling, and the mixture was stirred for 30 minutes. Thereafter, cyclopropylmethyl bromide (3.83 mmol) was added at room temperature, and the mixture was stirred for 10 hours. The reaction solution was added to water (300), and the organic layer _c extracted with ethyl acetate (100 ^ x3) was washed with brine and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain a crude crystal. The crude crystals were recrystallized from ethyl acetate-hexane to give the title compound.

m.p. 136-137 ° C

, H NM (CDC £ ₃ ) <50.40 (m, 2H), 0.59 (m, 2H), 1.36 (m, 1Π), 1.50 (d, J = 15Hz, 2H), 2.44-2.51 (m, 2H), 2.48 (s, 3H), 2.53 (s, 3H), 2.59 (dd.J = 3Hz, 11Hz, 2H), 2.73 (d, J = llHz, 2H), 2.87 (bs, 2H), 4.26 (d, J = 7Hz, 2H), 4.64 (td, J = 7Hz, 11Hz, 1H), 7.20-7.25 (ra, 1H), 7.35-7.39 ( m, 2H), 8.42 (d, J = 8Hz, 1H), 11.13 (d, J = llHz, 1H)

Further, it was converted into a hydrochloride according to a conventional method.

m.p. 235-237 ° C (decomposition)

Example 2

N- (One end 3,9-dimethyl-3,9-diazabicyclo [3.3.1] nona-7-yl]-1-arylindazole -3 -hexylboxamide

Reaction of N- [endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-7-yl] -1H-indazole-3-3-carboxamide and aryl bromide according to Example 1 This was recrystallized from ethanol to obtain the title compound.

m.p. 163-164 ° C

Ή NMR (CDC 3) 51.48 (d, J = 15 Hz, 2H), 2.45 (s, 3H), 2.53 (s, 3H). 2.47 to 2.51 (m, 2H), 2.56 to 2.60 (m, 2H), 2.72 (d. J = llHz, 2H), 2.87 (bs, 2H), 4.62 (td, J = 7Hz, 10Hz, 1H). 4.99 (td, J = 2Hz, 5Hz _f 2H), 5.16 (dd, J = 2Hz .17Hz, 1H), 5.24 (dd, J = lHz, 10Hz, 1H), 6.03 (ddd, J = 5Hz, 10Hz, 17Hz, 1H), 7.20-7.29 (m, 1H), 7.36 ~ 7.40 (m, 2H), 8.42 (d, J = 8Hz, 1H), 11.22 (d _T J = 10Hz, 1H) IR (KBr) 2826, 2798, 1650, 1519, 1489, 1373, 1263, 1189, 788, 742cm- ¹

m.p. 129-130 ° C

Example 3

N- (Endo-3,9-dimethyl-3,9-diazavinclo [3.3.1] nona-7-yl]-1-isobutylindazole-3-carboxamide

Reaction of N- [endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl] -1H-indazole-3-carboxamide with isobutyl bromide according to Example 1 The residue was purified by silica gel chromatography (methanol: chloroform = 90: 10) to give the title compound.

^J H NMR (CDC ₃ ) (50.94 (d, J = 7 Hz, 6H), 1.49 (d, J = 15 Hz, 2H), 2.35 (septet, J = 7 Hz, 1H), 2.47 (s, 3H), 2.54 ( s, 3H), 2.45 ~ 2.61 (m, 4H), 2.73 (d, J = llHz, 2H), 2.87 (s, 2H), 4.15 (d, J = 7Hz, 2H), 4.64 (ddd.J = 3Hz , 7Hz, 10Hz, III), 7.21 to 7.26 (m, 2H), 7.38 (d, J = 3Hz.1H), 8.42 (d, J = 8Hz, 1H), 11.09 (d, J = llHz, 1H)

Further, it was converted into a hydrochloride according to a conventional method. mp 160-165 ° C (moisture absorption, decomposition)

lH NR (D ₂ 0) 50.89 (d, J = 7 Hz, 6H), 2.03 (d, J = 16 Hz, 2H), 2.24 to 2.32 (m, 1H), 2.57 (s, 3H), 2.79 to 2.87 (πι , 2H), 2.96 (d, J = 12 Hz, 2H), 3. ll (s, 3H), 3.16 (d, J = 14 Hz, 2H), 3.77 (s, 2H), 4.21 (d, J = 8 Hz) , 2H), 7.38 (t, J = 6Hz, 1H), 7.54 (t, J = 6Hz, 1H), 7.64 (d, J = 8Hz, 1H), 8.15 (d, J = 8Hz, 1H)

IR (KBr) 3402, 2958, 1649, 1639, 1534, 1196, 1165, 753 - 1 Example 4

N- [End-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl] -1- (2-butenyl) indazole-3-3-carboxamide

According to Example 1, N- [end-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non_7-yl] -1H-ingzol-3-hexyl poloxamide and crotyl bromide were reacted. The residue was purified by silica gel chromatography (methanol: chloroform = 95: 5) to give the title compound (transform: cis = 7: 3).

Ml NMR (CDC ₃ ) δ 1.48 (d, J = 15Hz, 2H), 1.70 (d, J = 5Hz, 2.1H), 1.85 (d, J = 6Hz, 0.9H), 2.46 (s, 3H), 2.54 (s, 3H), 2.44 to 2.61 (m, 4H), 2.73 (d, J = llHz, 2H), 2.87 (s, 210, 4.59 to 4.66 (m, 1H), 4.93 (d, J = 4Hz, 1.4 H), 5.05 (d, J = 6IIz, 0.611), 5.63 to 5.76 (m, 2H), 7.22 ~ 7, 26 (m, 1H), 7.35 ~ 7.41 (m, 1H), 8.41 (d, J = 8Hz, 1H), 11.18 (d, J = 10Hz, 1H)

m. p. 130 ° C (moisture absorption, decomposition)

'Η NMR (D ₂ 0) δ 1.70 (d, J = 5Hz, 2.1H), 1.83 (d, J = 6Hz, 0.9H), 2.02 (d, J = 16Hz, 2H), 2.54 (s, 3H) , 2.79 to 2.84 (m, 2H), 2.91 to 2.95 (m, 2H), 3.10 (s, 3H), 3.09 to 3.14 (m, 2H), 3.74 (s, 2H), 4.60 to 4.69 (m, 2H) 1H), 4.96 (d, J = 5Hz, 1.4H), 5.06 (d, J = 6Hz, 0.6H), 5.65-5.82 (m, 2H), 7.37 (t, J = 7Hz, 1H) , 7.52 (t, J = 7 Hz, 1H), 7.60 (d, J = 9 Hz, 1H), 8.13 (d, J = 8 Hz, 1H)

IR (KBr) 3400, 2940, 1656, 1651, 1627, 1527, 1489, 1179, 964, 755cm- ¹

Example 5

5-HT ₄ agonist activity

The 5-HT ₄ agonistic activity of the compound of the present invention was measured by the following two tests.

Test example 1) Activity on guinea pig ileum longitudinal muscle

The ileum was removed from a guinea pig and a longitudinal muscle specimen about 2 in length was prepared. This hung Krebs-Henseleit solution tank was supplied mixed gas _{(95% 0 2, 5%} C0 2), lms, and record the contraction force added to electrical stimulus of 0.1Hz to those isometric. Test compounds were dissolved in distilled water or DMS0, were tested using a concentration of 10- ⁷ M. The results were shown as an increase rate (%) of the contraction height after administration with respect to the contraction height due to electrical stimulation before administration of the test compound.

Test compounds are indicated by the numbers of the examples _n Test compound activity (%)

Compound 1 6.2%

Compound 2 11.2%

Acting force of the above compound - HT ₄ whether action or through the receptor, 5-HT ₄ receptor antagonist SDZ 205-557 (2 - Jechiruami Noechiru 4 - amino - 5 - chloro port - 2 - main butoxy benzoate ). That is, SDZ 205-557 was reported to be a 5-HT ₄ receptor antagonist in a test using the guinea pig ileum (Naunyn-Schmiedeberg's Arch. Pharmacol., 345, 387-393). , 1992). By thus examining whether contraction height increasing action using guinea pig ileum longitudinal muscle specimens of the above compounds are antagonized by SDZ 205-557, can be examined or affected etc. emergence through 5-HT ₄ receptor .

Shrinkage higher increasing activity of the compounds is antagonized by the use of SDZ 205-557 3 xl0- ⁷ M, the action force of the test compound - it became clear that through the HT ₄ receptor.

Test Example 2) Activity on rat esophageal mucosa

This was performed according to the method of Baxter et al. (Naunyn-Schmiedebergs Arch. Pharmacol., Vol 343, 439-446, 1991). That is, the esophagus was excised from the rat, and the mucosal muscle plate was peeled off. This hung Krebs Henseleit solution tank that supplied the mixed gas _{(95% 0 2, 5%} C0 2), after being deflated. Contraction was stabilized by carbachol ^{(1 χ 1 (Γ 6 Μ} ), a test compound The relaxation response was measured by cumulative administration, and the concentration was determined as the concentration (ED ₅₀ ) at which test compound administration caused 50% relaxation of levubacol contraction, and expressed as one log ED ₅₀ value (that is, the numerical value was The larger the value, the stronger the activity). Test compound activity (one log ED ₅₀ )

Compound 1 5.70

Compound 2 6.32

Compound 3 5.55

Compound 4 6.37

Mosapride 4. 46

Cisapride 5.51

The following shows that the compound of the present invention having 5-HT ₄ receptor agonist activity is useful as a therapeutic agent for gastrointestinal diseases by promoting gastrointestinal motility.

Example 6

Gastrointestinal hypermotility

The gastrointestinal motility enhancing effect of the compound of the present invention was measured by the following test.

Male dogs (10-14 and 9) were laparotomized under halothane anesthesia, and a force transducer on the stomach surface of the stomach, stomach, antrum, duodenum and ileum can be measured for cricoid muscle contraction. Was installed as follows. The lead of the transducer was led out of the body through the skin. The contraction wave signal obtained from each transducer was recorded on a computer via an amplifier, and the integrated value of the contraction wave was calculated to obtain a kinetic coefficient (Mobility Index). The experiment was performed using dogs with a recovery period of one month after the operation, and confirmed that normal fasting anal transmissible contraction (IMC) was obtained. After the dogs were fasted for a period of time, food was taken and postprandial contractions were measured. 60 minutes later, the compound of the present invention was intravenously administered, and the kinetic coefficient every 30 minutes was calculated. The results were calculated with the kinetic coefficient for 30 minutes before administration of the compound as 100. Was.

Hereinafter, the enhancement effect of the contractile force when Compound 2 (the compound of Example 2) 1 / is administered intravenously is represented as a kinetic coefficient.

Kinetic coefficient

Before administration 100

30 minutes after administration 314

60 minutes 271

90 minutes 228

120 minutes 206

150 minutes 192

180 minutes 196

Example 7

Gastric emptying promoting action

The gastric emptying promoting effect of the compound of the present invention was measured by the following test. After rats (200-250 ₉₎ were fasted overnight, previously semisolid diet weight was measured (Semi-sol id meal) 3 W was administered by a sonde into the stomach. The stomach was removed 60 minutes after administration, and the weight of the semi-solid food remaining in the stomach was calculated. The gastric emptying rate was calculated from the administered weight. The test compound was orally administered 60 minutes before administration of the semisolid diet. In addition, a group to which distilled water was administered was provided as a control group (control), and the acceleration rate was determined from the gastric emptying rate of the control group. Compound 2 (Compound of Example 2)

Concentration OgZ) Gastric emptying rate (%) Acceleration rate (%)

0.03 59.3 39.5

0.1 67.2 58.1

0.3 66.7 56.9 Compound 1 (Compound of Example 1)

Control 55.7

1.0 65.4 17.4

Cisapride

Control 48.8

0.1 50.9 4.3

0.3 47.6 -2.5

1.0 63.2 29.5

3.0 69.9 43.3

Toxicity test

The LD _5C of the compounds of the present invention was 9 or iv (rat) in all of the compounds.

Claims

'General formula (I)

Contract

(Wherein represents a cyclopropylmethyl group, an aryl group, an isobutyl group or a 2-butenyl group) or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. -HT ₄ receptor agonist.

2. The 5-receptor agonist according to claim 1, which is a gastrointestinal motility enhancer.

3. The 5-HT ₄ receptor agonist of claim 1, which is a gastrointestinal motility enhancer.

4. —General formula (I)

Wherein R _t represents a cyclopropylmethyl group, an aryl group, an isobutyl group or a 2-butenyl group, or a pharmaceutically acceptable acid addition salt thereof. A method for treating gastrointestinal motility dysfunction, comprising administering 0.01 _{ng to} 100 per day of an adult with gastrointestinal dysfunction.

5. The method according to claim 4, wherein the gastrointestinal motility dysfunction is gastrointestinal motility dysfunction.