JPH08169830A - 5-ht4 receptor agonist - Google Patents

Abstract

PURPOSE: To obtain a 5-HT4 receptor agonist containing a new diazabicyclo derivative as an active component and effective for the treatment of digestive system diseases. CONSTITUTION: This 5-HT4 receptor agonist contains a new diazabicyclo derivative of formula I (R is a 4-6C cycloalkyl) or its pharmaceutically permissible salt as an active component. The compound of formula I is especially preferably N-(endo-3,9-dimethyl-3,9-diazabicyclo[3,3,1]non-7-yl)-1-cyclobutylinda zol-3- carboxamide. The 5-HT4 receptor agonist is especially an agent for the treatment of digestive system diseases or an agent for promoting the motion of gastrointestinal tracts. The 5-HT4 receptor agonist contains the compound of formula I as an active component and is optionally incorporated with a pharmaceutically permissible medicinal additives. The compound of formula I can be produced by condensing a 4-6C cycloalkyl alcohol to a compound of formula II in the presence of a di(1-6C) alkyl azodicarboxylate and a tri- substituted phosphine.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel diazabicyclo derivative which is effective in treating digestive diseases and a 5-HT ₄ receptor agonist containing the derivative as an active ingredient.

[0002]

Background of the Invention Various causes, such as chronic gastritis, gastrectomy,
When the gastrointestinal motility function is abnormal due to peptic ulcer, diabetes, scleroderma, etc., reflux of gastric contents into the esophagus, delay of gastric emptying, and deterioration of small and large intestine function occur. As a result, symptoms such as nausea, vomiting, heartburn, loss of appetite, abdominal distention, upper abdominal discomfort, abdominal pain, constipation, and reflux esophagitis may be caused. Also, in diseases such as irritable bowel syndrome and pseudo-bowel obstruction, a decrease in gastrointestinal motility is considered to be one of the causes. Drugs for treating these symptoms and medical conditions include direct cholinergic agents (for example, acratonium napadisylate) and dopamine antagonists (for example, domperidone). However, it is known that these known drugs do not provide a sufficient therapeutic effect and have side effects such as diarrhea and extrapyramidal symptoms.

The movement of the digestive tract is regulated by the sympathetic nervous system and the parasympathetic nervous system. In the parasympathetic nervous system, acetylcholine is one of the most important neurotransmitters involved in the regulation of gastrointestinal motility. Release of acetylcholine from nerves present in the gastrointestinal plexus causes contraction of the gastrointestinal tract. Therefore, promoting release of acetylcholine from the gastrointestinal nerve enhances gastrointestinal motility. Recently, the presence of 5-HT ₄ receptors in the gastrointestinal tract is shown. This 5-HT ₄ receptor is reported to regulate the release of acetylcholine in the gastrointestinal nerve (Trends in Pharmacological Science, Vol. 13, 141).
~ 145, 1992). Therefore, a compound that acts on the 5-HT ₄ receptor in the digestive tract and promotes acetylcholine release can be a more effective gastrointestinal motility enhancer with fewer side effects.

Diazabicyclo derivatives are commercially available from Nikitskaya E.
S. et al. (J. Org. Chem. USSR (Engl.
nsl.), Vol. 1, 170-176, 1965), 5 of this compound group
HT ₃ receptor antagonism has been reported (EP 469449, WO
9205174, EP 558923, WO 9307147). However, there is no report that this compound group has 5-HT ₄ agonistic activity.

[0005]

A compound that acts on 5-HT ₄ receptors in the digestive tract and promotes acetylcholine release has such an effect because it can be a more effective gastrointestinal motility promoter with fewer side effects. Elucidation of compounds is required.

[0006]

[Means for Solving the Problems] The inventors of the present invention have conducted diligent research to clarify such problems, and as a result, the formula (II)

Embedded image The compound of the formula (I) is condensed with a cycloalkyl alcohol in the presence of a dialkylazodicarboxylate and a trisubstituted phosphine (eg, triphenylphosphine or tributylphosphine) to give a compound of the desired general formula
The compound described in (I) was obtained. When the pharmacological action of this compound was examined, a remarkable 5-
It has HT ₄ receptor agonistic activity and exerts gastrointestinal motility enhancing action, so that gastrointestinal symptoms associated with chronic gastritis, post-gastric resection syndrome, peptic ulcer, diabetes, scleroderma, reflux esophagitis, hypersensitivity The present invention was found to be effective in the treatment of gastrointestinal disorders including genital bowel syndrome and pseudoileus.

That is, according to the present invention, the following general formula
(I)

[Chemical 4] 5-H containing a compound represented by the formula (wherein R is a C ₄ -C ₆ cycloalkyl group) or a pharmaceutically acceptable salt thereof
A T ₄ receptor agonist is provided. Examples of the C ₄ -C ₆ cycloalkyl group of R in the general formula (I) of the above diazabicyclo derivative of the present invention include cyclobutyl, cyclopentyl,
Examples thereof include a cyclohexyl group.

The compound represented by the general formula (I) of the present invention is
For example, by condensing 3-methyl-3-azapentane-1,5-dial obtained by hydrolyzing N, N-bis (2,2-dialkoxyethyl) methylamine with methylamine and acetonedicarboxylic acid. To produce 3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonan-7-one, oxime the carbonyl group on the diazabicyclo ring, and then reduce the oxime to endo-7- Amino-3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane is produced, the amino compound thus obtained and 1H-indazole-3-carboxylic acid, or a reactive derivative thereof. And react with N-
(Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1H-indazole-
3-carboxamide, and further condensed with this compound and a C ₃ -C ₆ cycloalkyl alcohol, or 1- (C ₃
To C ₆ cycloalkyl) indazole-3-carboxylic acid or a reactive derivative thereof can be obtained. In addition, 3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonan-7-one is 2,6 obtained from methyl 4-bromocrotonate and methylamine.
It can also be synthesized by Dieckmann condensation of -bismethoxycarbonylmethyl-1,4-dimethylpiperazine. The reaction scheme of this series of reactions is as follows.

[0009]

Embedded image

Further, the conditions and the like of this manufacturing method will be described in detail. N, N-bis (2,2-dialkoxyethyl)
Methylamines such as N, N-bis (2,2-dimethoxyethyl) methylamine and N, N-bis (2,2-diethoxyethyl) methylamine react with haloacetaldehyde dialkyl acetal and methylamine in the presence of a base. Can be obtained. Examples of the haloacetaldehyde dialkyl acetal include bromoacetaldehyde dimethyl acetal, bromoacetaldehyde diethyl acetal, chloroacetaldehyde dimethyl acetal, chloroacetaldehyde diethyl acetal, and the like, and the base includes sodium hydroxide, potassium hydroxide,
Pyridine, dimethylaminopyridine, triethylamine and the like can be mentioned, and sodium hydroxide and potassium hydroxide are preferably used.

The reaction is 0.5 mol to 10 mol of haloacetaldehyde dialkyl acetal with respect to 1 mol of methylamine.
Mol, preferably 2 to 5 mol, base 0.5 mol to
Use 10 moles, preferably 2-5 moles, at 0 ° C.
To 200 ° C, preferably room temperature to 150 ° C. As the solvent, alcohol (methanol, ethanol, propanol, ethylene glycol, etc.) is preferably used.

3,9-Dimethyl-3,9-diazabicyclo [3.3.1] nonan-7-one is N, N-bis (2,2).
3-Dimethyl-3-azapentane-1,5 obtained by hydrolyzing -dimethoxyethyl) methylamine in the presence of an acid
It can be obtained by a condensation reaction of dial, methylamine and acetonedicarboxylic acid. Examples of the acid used for hydrolysis include hydrochloric acid, sulfuric acid, bromic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, oxalic acid and the like, and hydrochloric acid is preferably used.

The reaction is carried out between the freezing point and the boiling point of the solvent, preferably at a temperature of 20 ° C to 100 ° C. Examples of the solvent used include water, methanol-water, chloroform-water, acetone and the like. The reaction is N, N
The acid is used in an amount of 0.5 mol to 10 mol, preferably 3 mol to 5 mol, based on 1 mol of bis (2,2-dimethoxyethyl) methylamine. In addition, 3-methyl-3-
Azapentane-1,5-dial is N, N-bis (2,
It can also be obtained by acid hydrolysis of 2-diethoxyethyl) methylamine according to the above method.

In the next condensation reaction, 0.5 mol to 10 mol of methylamine, preferably 1 mol to 3 mol, is added to 1 mol of 3-methyl-3-azapentane-1,5-dial to give acetonedicarboxylic acid. It is carried out using an amount of 0.5 mol to 10 mol, preferably 1 mol to 3 mol. The reaction is carried out between the freezing point and the boiling point of the solvent, preferably at a temperature of 0 ° C to 40 ° C.

Examples of the solvent used include alcohol (methanol, ethanol, propanol, etc.), water and the like. In addition, as a buffering agent, carboxylic acid (formic acid, acetic acid,
(Citric acid, etc.) or salt (disodium hydrogen phosphate, sodium dihydrogen phosphate, etc.) can be used, and pH
As a regulator, inorganic acids (hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, etc.) and bases (sodium hydroxide, potassium hydroxide, triethylamine, pyridine, etc.) can be used.

3,9-Dimethyl-3,9-diazabicyclo [3.3.1] nonane-7-one oxime is 3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane-
It can be obtained by reacting 7-one with hydroxylamine hydrochloride in the presence of a base. Specific examples of the base include pyridine, dimethylaminopyridine, triethylamine and 1,8-diazabicyclo [5.4.0] undeca.
7-ene (DBU) and the like.

Hydroxylamine hydrochloride is used in an amount of 0.5 mol to 10 mol, preferably 0.1 mol, based on 1 mol of 3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonan-7-one.
It is carried out using 9 mol to 2 mol amount, 0.5 mol to 10 mol base, and preferably 0.9 mol to 3 mol amount. The reaction is carried out at 0 ° C to the boiling point of the solvent, preferably room temperature to the boiling point of the solvent.

Examples of the solvent used include alcohols (methanol, ethanol, propanol, etc.). The synthesis of endo-7-amino-3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane was carried out in the presence of Raney nickel under hydrogen gas atmosphere under the atmosphere of 3,9-dimethyl-3,9-diazabicyclo [3. It can be obtained by reducing nonane-7-one oxime.

In the reduction reaction of oxime, 2 mol to 50 mol, preferably 5 mol to 20 mol of ammonium acetate is used with respect to 1 mol of oxime, and Raney nickel is used in an amount of 0.01 to 10 times the weight of oxime, preferably. Is used in an amount of 0.02 to 2 times, and the hydrogen gas pressure is from normal pressure to 150 kg / c.
m ^2, preferably ^{10kg / cm 2 ~100kg / cm 2} , the reaction temperature is room temperature to 200 DEG ° C., it is preferably carried out at 100 ° C. from room temperature. The solvent used is alcohol (methanol,
Ethanol, propanol, etc.).

The compound represented by the formula (II) is endo-7-
Amino-3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane is reacted with a reactive derivative of a carboxylic acid, or in the presence of a condensing agent such as a carbodiimide derivative or a dialkylphosphoryl cyanide. It can be obtained by reacting an acid. Specific examples of the reactive derivative of carboxylic acid include diindazolo [2,3-a] [2 ',
3'-d] pyrazine-7,14-dione, 1H-indazole-3-carboxylic acid chloride and the like.

End-7-amino-3,9-dimethyl-
The reaction of 3,9-diazabicyclo [3.3.1] nonane with a reactive derivative of a carboxylic acid is carried out by endo-7-amino-
3,9-Dimethyl-3,9-diazabicyclo [3.3.
1] The reactive derivative of carboxylic acid is used in an amount of 0.1 mol to 10 mol, preferably 0.25 mol to 2 mol, per 1 mol of nonane. The reaction is carried out between the freezing point and the boiling point of the solvent, preferably at a temperature of 0 ° C to 40 ° C.

The solvent used is a hydrocarbon (pentane,
Hexane, heptane, cyclohexane, petroleum ether,
Benzene), halogenated hydrocarbons (carbon tetrachloride, chloroform, methylene chloride, etc.), ethers (ethyl ether, THF, dioxane, etc.), esters (ethyl acetate, etc.), acetone, DMF, nitromethane, DMS
O, HMPA, pyridine, etc., but DMF, D
MSO and the like are preferably used. In addition, this reaction is a base (dimethylaminopyridine, triethylamine, pyridine, potassium carbonate, sodium carbonate, etc.) as necessary.
Can be used.

Specific examples of the carboxylic acid include 1H-indazole-3-carboxylic acid. Specific examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride, diethylphosphoryl cyanide, diphenylphosphoryl azide, and propanephosphonic anhydride.

End-7-amino-3,9-dimethyl-
The condensation reaction between 3,9-diazabicyclo [3.3.1] nonane and carboxylic acid is carried out by using 1 mol of endo-7-amino-3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane. Carboxylic acid 0.1 mol to 10 mol, preferably 0.5 mol to 2 mol, condensing agent 0.1 mol to 10 mol,
It is preferably carried out using an amount of 0.5 to 2 mol.
In addition, this reaction is carried out in an amount of 0.5 mol to 2 mol of 1
-Hydroxybenzotriazole and N-hydroxysuccinimide can be used.

The reaction is carried out between the freezing point and the boiling point of the solvent, preferably at a temperature of 0 ° C to 40 ° C. Solvents used include hydrocarbons (pentane, hexane, heptane, cyclohexane, petroleum ether, benzene, etc.), halogenated hydrocarbons (carbon tetrachloride, chloroform, methylene chloride, etc.), ethers (ethyl ether, THF, dioxane, etc.), Examples thereof include esters (ethyl acetate and the like), acetone, DMF, DMSO, nitromethane and the like, and methylene chloride, DMF and the like are preferably used.

N- (endo-3,9-dimethyl-3,9-
Diazabicyclo [3.3.1] non-7-yl) -1-R
-Indazole-3-carboxamide derivative is N-
(Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1H-indazole-
It can be obtained by condensing 3-carboxamide and C ₄ -C ₆ cycloalkyl alcohol. Specific examples of the C _{4 to} C ₆ cycloalkyl alcohol include cyclobutanol,
Examples include cyclopentanol and cyclohexanol.

The reaction was carried out by reacting 1 mol of N- (endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1H-indazole-3-carboxamide with di ( C ₁ -C ₆ ) Alkylazodicarboxylate 0.5 mol to 2 mol, preferably 0.8 mol to 1.2 mol, trisubstituted phosphine 0.5 mol to 2 mol, preferably 0.8 mol. the 1.2 molar amount, C ₄ -C ₆ cycloalkyl alcohol 0.5 to 2 moles, preferably carried out using 0.8 moles to 1.2 molar amounts.

Specific examples of the di (C ₁ -C ₆ ) alkylazodicarboxylate include diethylazodicarboxylate and diisopropylazodicarboxylate, and specific examples of the trisubstituted phosphine include triphenylphosphine. , Tributylphosphine and the like. The reaction is carried out between the freezing point and the boiling point of the solvent, preferably at a temperature of 0 ° C to 40 ° C. As the solvent, ether (ethyl ether, THF, dioxane, etc.), DMF, etc. are preferably used.

Specific examples of the compound of the present invention thus obtained are listed below. N- (End-3,9
-Dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1-cyclobutylindazole-3-carboxamide, N- (endo-3,9-dimethyl-3,9)
-Diazabicyclo [3.3.1] non-7-yl) -1-
Cyclopentylindazole-3-carboxamide, N
-(Endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1-cyclohexylindazole-3-carboxamide.

The above-mentioned compounds of the present invention have a remarkable stimulatory effect on digestive tract motility via the 5-HT ₄ receptor, as shown in the following examples, and are therefore useful as therapeutic agents for digestive diseases. is there.

The compound represented by the general formula (I) of the present invention can be optionally converted into an addition salt with a pharmaceutically acceptable acid, and these acid addition salts are also included in the scope of the present invention. It Examples of acid addition salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid,
Oxalic acid, malic acid, maleic acid, tartaric acid, lactic acid, fumaric acid, malonic acid, suberic acid, methanesulfonic acid, p-
Examples thereof include salts with organic acids such as toluenesulfonic acid.

When the compound represented by the general formula (I) is used as a medicine, it can be made into various dosage forms. That is, this preparation can be orally administered in the form of liquid preparation such as tablets, dragees, hard capsules, soft capsules, solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of injection solution.

In preparing these formulations, conventional additives for formulation such as excipients, stabilizers, preservatives,
A solubilizer, a wetting agent, an emulsifying agent, a lubricant, a sweetening agent, a coloring agent, a flavoring agent, a tonicity adjusting agent, a buffering agent, an antioxidant and the like can be added to prepare a formulation.

The administration method and dose of the gastrointestinal motility function adjusting agent of the present invention are not particularly limited and may be appropriately selected depending on various dosage forms, patient's sex, and degree of disease. The dose is 0.1 to 1000 mg, preferably 1 to 100 mg.

The present invention will be further described below with reference to examples, but these are merely for explaining the present invention and do not limit the present invention.

Production Example 1 N, N-bis (2,2-dimethoxyethyl) methylamine

[Chemical 6] Potassium hydroxide (166 g, 2.96 mol) was dissolved in ethylene glycol (500 g), and methylamine hydrochloride (50.0 g, 0.74 mol) and bromacetaldehyde dimethyl acetal (300 g, 1.78 m) were added under water cooling.
ol) was added. Then, the mixture was heated under reflux for 3 hours. After the reaction was completed, water (500 ml) was added and chloroform (500 ml x
Extracted in 3). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated by column chromatography (florisil, hexane) to give the title compound (61 g). bp 80-85 ° C (3 mmHg) ¹ H NMR (CDCl ₃ ) δ 2.39 (s, 3H), 2.63 (d, J = 5Hz, 4H),
3.37 (s, 12H), 4.50 (t, J = 5Hz, 2H)

Production Example 2 3,9-Dimethyl-3,9-diazabicyclo [3.3.1]
Nonan-7-on

[Chemical 7] Distilled water (630 ml) and concentrated hydrochloric acid (101 ml, 1.21 mol) were added to N, N-bis (2,2-dimethoxyethyl) methylamine (61 g, 0.30 mol), and the mixture was heated under reflux for 1 hr. Then, an aqueous sodium hydroxide solution (sodium hydroxide: 48.5 g; water: 200 ml) was added under ice cooling (this is designated as solution A). On the other hand, solution A was added to a separately prepared solution of disodium phosphate dodecahydrate (114.4 g) and citric acid (54.1 g) in water (709 ml) at room temperature with stirring. Furthermore, methylamine hydrochloride (3
5.9 g, 0.53 mol), acetone dicarboxylic acid (85.
8 g, 0.59 mol) were added sequentially. Then, an aqueous sodium hydroxide solution was added to adjust the pH to 5, and the mixture was stirred for 15 hours. Concentrated hydrochloric acid (175 ml) was added dropwise to this reaction solution under ice cooling, the aqueous layer was washed with ethyl acetate (1000 ml × 2), sodium hydroxide (126 g) was added to the aqueous layer, and chloroform (1000 ml × 3) was added. Extracted. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain a residue (2
3 g) was separated by column chromatography (Florisil, ethyl acetate) to obtain a crude product. This was recrystallized from hexane to give the title compound (6.2 g). mp 72-73 ° C ¹ H NMR (CDCl ₃ ) δ 2.02 (d, J = 13 Hz, 2H), 2.20 (s, 3H),
2.43 (dd, J = 2Hz, 11Hz, 2H), 2.48 ~ 2.63 (m, 2H), 2.5
8 (s, 3H), 2.63 to 2.82 (m, 2H), 3.13 to 3.22 (m, 2H) IR (KBr) 2950, 2920, 2790, 2760, 1719, 1702, 1462,
1343, 1264, 1203, 1182, 1078, 820cm ^-1

Production Example 3 3,9-Dimethyl-3,9-diazabicyclo [3.3.1]
Nonane-7-one oxime

Embedded image 3,9-Dimethyl-3,9-diazabicyclo [3.3.1]
Pyridine (12 ml) and hydroxylamine hydrochloride (4.81 g, 69.2 mmol) were added to a solution of nonan-7-one (11.3 g, 67.2 mmol) in ethanol (130 ml),
The mixture was heated under reflux for 30 minutes. Potassium carbonate (25.
5 g) and water (12.6 ml) were added and the mixture was stirred for 2 hours. After distilling off ethanol, chloroform (100 ml x 3)
The organic layer was extracted, dried over potassium carbonate, and concentrated under reduced pressure to give the title compound (10.8 g). ¹ H NMR (CDCl ₃ ) δ 2.16 (s, 3H), 2.20 to 2.46 (m, 5H),
2.51 (s, 3H), 2.55 to 2.73 (m, 2H), 2.92 to 3.07 (m, 3H),
7.30 ~ 7.80 (br, 1H)

Production Example 4 End-7-amino-3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane

[Chemical 9] 3,9-Dimethyl-3,9-diazabicyclo [3.3.1]
Nonane-7-one oxime (2.79 g, 15.2 mmol)
Ammonium acetate (15 ml) in ethanol (30 ml)
g) and Raney nickel ethanol suspension (5 ml) were sequentially added, and the autoclave was operated under a hydrogen gas atmosphere of 50 atm.
The mixture was stirred at 0 ° C for 7 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. A 10% aqueous sodium hydroxide solution (20 ml) was added to the residue, which was then filtered through Celite, and the filtrate was extracted with chloroform (50 ml × 3). The organic layer was dried over potassium carbonate and concentrated under reduced pressure to give the title compound (2.27 g)
I got This product was used in the next reaction without purification. ¹ H NMR (CDCl ₃ ) δ 1.34 (d, J = 15Hz, 2H), 2.25 (s, 3H),
2.46 (s, 3H), 2.20 ~ 2.50 (m, 5H), 2.58 (d, J = 11Hz, 2
H), 2.73 to 2.86 (m, 2H), 2.70 to 3.20 (br, 2H), 3.08 (t, J = 7Hz, 1H)

Production Example 5 N- (endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1H-indazole-3-carboxamide

[Chemical 10] Endo-7-amino-3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane (1.40 g, 8.18 mmo
l) was dissolved in pyridine (40 ml), catalytic amounts of dimethylaminopyridine and 1H-indazole-3-carboxylic acid chloride (2.20 g, 12.2 mmol) were sequentially added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the pH was adjusted to 1 with diluted hydrochloric acid. Ethyl acetate (50 ml x
After washing with 2), the aqueous layer was adjusted to pH 11 or higher with sodium hydroxide and extracted with chloroform (100 ml × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (SiO ₂ , chloroform-ethanol = 10: 1). The obtained crude product was recrystallized from a chloroform-hexane mixed solvent to obtain the title compound (0.40 g). mp 219 to 221 ° C ¹ H NMR (CDCl ₃ ) δ 1.71 (s, 2H), 1.94 to 2.06 (m, 2H),
2.23 (s, 3H), 2.35 ~ 2.57 (m, 4H), 2.82 ~ 2.94 (m, 1H),
3.51 to 3.61 (m, 1H), 4.10 (d, J = 9Hz, 1H), 5.30 (q, J =
9Hz, 1H), 7.15 ~ 7.30 (m, 2H), 7.30 ~ 7.42 (m, 1H), 7.
78 (d, J = 3Hz, 1H), 8.15 ~ 8.25 (m, 1H), 8.73 ~ 8.87 (b
r, 1H) IR (KBr) 2920, 2975, 1650, 1455, 1175, 995, 750cm
^-1

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

[Chemical 11] N- (endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1H-indazole-3-carboxamide (2.00 g, 6.38 mmol), triphenylphosphine (3.35 g, 12.76 mmol),
And cyclopentanol (0.82g, 9.57mmol)
Diisopropyl azodicarboxylate (2.58 g, 12.76 mmol) was added to the DMF suspension in Example 2 at room temperature, and the mixture was stirred for 2 days. After completion of the reaction, the solvent was distilled off, and silica gel column chromatography (methanol-dichloromethane = 1:
9) and the title compound (1.53 g, 4.01 mm)
ol) was obtained. ¹ H NMR (CDCl ₃ ) δ 1.50 (d, J = 14Hz, 2H), 1.74 to 1.98
(m, 4H), 2.18 ~ 2.27 (m, 2H), 2.46 (s, 3H), 2.46 ~ 2.59
(m, 4H), 2.54 (s, 3H), 2.73 (d, J = 11Hz, 2H), 2.87 (b
s, 2H), 4.69 (td, J = 7Hz, 10Hz, 1H), 5.00 (m, 1H), 7.
24 (t, J = 7Hz, 1H), 7.37 (t, J = 7Hz, 1H), 7.44 (d, J = 9H
z, 1H), 8.43 (d, J = 8Hz, 1H), 10.68 (d, J = 11Hz, 1H) MS m / z 382 (M ⁺ )

The title compound was dissolved in ethyl acetate, and a 4N hydrochloric acid-ethyl acetate solution was added under ice cooling. The precipitated crystals were collected by filtration and dried under reduced pressure to give hydrochloride. mp 245 to 250 ° C. (decomposition) ¹ H NMR (D ₂ O) δ 1.68 to 1.83 (m, 2H), 1.84 to 1.95 (m, 2
H), 1.96 to 2.11 (m, 2H), 2.12 to 2.28 (m, 2H), 2.57 (s,
3H), 2.76 ~ 2.88 (m, 2H), 2.89 ~ 3.03 (m, 2H), 3.04 ~
3.21 (m, 2H), 3.11 (s, 3H), 3.76 (s, 2H), 4.58-4.70
(m, 1H), 5.08 (quintet, J = 8Hz, 1H), 7.36 (t, J = 8Hz,
1H), 7.49 (t, J = 7Hz, 1H), 7.63 (d, J = 9Hz, 1H), 8.13
(d, J = 8Hz, 1H) IR (KBr) 2950, 1657, 1648, 1546, 1536, 1203, 753cm
^{-1 In the same} manner, the following compound was obtained.

Example 2 N- (endo-3,9-dimethyl-3,9-diazabicyclo [3.3.1] non-7-yl) -1-cyclobutylindazole-3-carboxamide

[Chemical 12] ¹ H NMR (CDCl ₃ ) δ 1.51 (d, J = 15Hz, 2H), 1.91 to 2.00
(m, 2H), 2.46 to 2.61 (m, 6H), 2.53 (s, 3H), 2.55 (s, 3
H), 2.72 to 2.86 (m, 4H), 2.88 (s, 2H), 4.66 to 4.71 (m,
1H), 5.10 (m, 1H), 7.21 to 7.26 (m, 1H), 7.34 to 7.43 (m,
2H), 8.43 (d, J = 8Hz, 1H), 10.84 (d, J = 11Hz, 1H)

Further, a hydrochloride was prepared according to a conventional method. mp 184 to 186 ° C. ¹ H NMR (D ₂ O) δ 2.61 (s, 3H), 3.12 (s, 3H), 3.76 (s, 2
H), 4.64 to 4.67 (m, 1H), 5.16 (quintet, J = 8Hz, 1H),
7.31 ~ 7.35 (m, 1H), 7.45 ~ 7.57 (m, 2H), 8.09 ~ 8.13
(m, 1H) IR (KBr) 2950, 1650, 1620, 1527, 1480, 1194, 791,
760 cm ^-1

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

[Chemical 13] ¹ H NMR (CDCl ₃ ) δ 1.50 (d, J = 15Hz, 2H), 1.59 to 2.07
(m, 6H), 2.45 to 2.59 (m, 4H), 2.50 (s, 3H), 2.54 (s, 3
H), 4.38 ~ 4.45 (m, 1H), 4.65 ~ 4.71 (m, 1H), 7.21 ~ 7.
26 (m, 1H), 7.34 ~ 7.44 (m, 2H), 8.43 (d, J = 8Hz, 1H),
10.74 (d, J = 10Hz, 1H)

Further, a hydrochloride was prepared according to a conventional method. mp 181 to 183 ° C ¹ H NMR (D ₂ O) δ 1.78 to 2.06 (m, 6H), 2.56 (s, 3H), 3.1
1 (s, 3H), 3.74 (s, 2H), 4.45 ~ 4.58 (m 1H), 7.33 ~ 7.3
8 (m, 1H), 7.46-7.60 (m, 2H), 8.14 (d, J = 8Hz, 1H) IR (KBr) 2936, 1648, 1624, 1531, 1284, 1184, 753cm
^-1

Example 4 Compound 5-HT_FourReceptor activity depends on rat esophageal viscosity
It was measured by the method using the lamellar muscle plate (Naunyn-Schmiedeberg '
Arch. Pharmacol., Vol. 343, 439-446, 1991). La
The esophagus was removed from the pan and the muscularis mucosa was peeled off. Mix this
Combined gas (95% O₂5% CO₂) Supplied Tyrode's solution
Suspend in a tank, carbachol (1 x 10^-6Contracted by M)
I let you. After the contraction is stable, the compound is cumulatively administered to induce relaxation.
The slow response was measured. The results show that
Concentration that causes 50% relaxation of the contraction (ED ₅₀) Was asked.

[0048]

[Table 1] Compound ED ₅₀ [M] Example 1 1.91 × 10 ⁻⁶ Example 2 1.10 × 10 ⁻⁶ Example 3 2.95 × 10 ⁻⁶ Production Example 5 1.32 × 10 ^-4 Mosapride 3.47 × 10 ^-5

Example 5 The gastrointestinal motility promoting activity of the compound was measured by a method using guinea pig ileum. The ileum was removed from the guinea pig to prepare a longitudinal muscle sample having a length of about 2 mm. This is mixed gas (95
_{% O 2, 5% CO 2} ) suspended in Krebs-Henseleit solution tank was supplied, 1 ms, plus electrical stimulation of 0.1 Hz, was recorded contractile force to those isometric. The compound was dissolved in distilled water or dimethyl sulfoxide, and a concentration of 10 ⁻⁷ M was added to examine whether or not the contractile force was enhanced. Those in which an increase in contractile force was observed are represented by +, and those in which they were not observed are represented by-.

[0050]

[Table 2] Presence or absence of enhancement of compound contraction force Example 1 + Example 2 + Example 3 + Production Example 5-Mosapride-

Example 6 The LD ₅₀ of the compound of the present invention (Example 1) by oral administration in rats was 1000 mg / kg or more.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Hiroaki Sato Inventor Hiroaki Sato 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Pharmaceutical Research Institute (72) Haruhiko Kikuchi Oi-cho, Iruma-gun, Saitama 5-3-1, Tsurugaoka Nisshin Seifun Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Koichiro Hagiwara 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co. Ltd. Pharmaceutical Research Institute (72) Inventor Takeo Arai 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Seifun Co., Ltd. Pharmaceutical Research Laboratory (72) Inventor Setsuko Mino 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Seishin Flour Milling Co., Ltd. Pharmaceutical Research Laboratories (72) Inventor Yumiko Noguchi 5-3-1 Tsurugaoka, Oi-cho, Iruma-gun, Saitama Nisshin Flour Milling Co., Ltd. Pharmaceutical Research Laboratories

Claims (7)

[Claims] 1. A compound represented by the general formula (I): (Wherein R is a C ₄ -C ₆ cycloalkyl group) or a pharmaceutically acceptable salt thereof as an active ingredient,
A 5-HT ₄ receptor agonist comprising, if necessary, a pharmaceutically acceptable pharmaceutical additive. 2. N- (endo-3,9-dimethyl-3,9)
-Diazabicyclo [3.3.1] non-7-yl) -1-
5-HT ₄ receptor comprising a compound according to claim 1, which is cyclobutylindazole-3-carboxamide, or a pharmaceutically acceptable salt thereof as an active ingredient and, if necessary, a pharmaceutically acceptable pharmaceutical additive. Body agonist. 3. N- (endo-3,9-dimethyl-3,9)
-Diazabicyclo [3.3.1] non-7-yl) -1-
A 5-HT ₄ receptor comprising a compound according to claim 1, which is cyclopentylindazole-3-carboxamide, or a pharmaceutically acceptable salt thereof as an active ingredient and, if necessary, a pharmaceutically acceptable pharmaceutical additive. Agonist. 4. N- (endo-3,9-dimethyl-3,9)
-Diazabicyclo [3.3.1] non-7-yl) -1-
A 5-HT ₄ receptor comprising cyclohexylindazole-3-carboxamide, the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and optionally a pharmaceutically acceptable pharmaceutical additive. Agonist. 5. Formula (II): A compound represented by general formula (I), which comprises condensing a di (C ₁ -C ₆ ) alkylazodicarboxylate with a C ₄ -C ₆ cycloalkyl alcohol in the presence of a trisubstituted phosphine. Production method. 6. The 5-HT ₄ receptor agonist according to claim 1, which is a therapeutic agent for digestive system diseases. 7. The 5-HT ₄ receptor agonist according to claim 1, which is a gastrointestinal motility enhancer.