JP2643274B2 - Imidazo [1,2-a] pyridine derivative - Google Patents

Description

The present invention relates to a novel imidazo [1,2-a] pyridine derivative, an acid addition salt thereof, or a solvate thereof.

[Problems to be solved by conventional technology and invention]

So-called digestive instability complaints such as heartburn, abdominal distension, anorexia, upper abdominal discomfort, nausea and abdominal pain are manifested as main symptoms such as chronic gastritis and gastroptosis. The decrease in gastric emptying capacity associated with this is mentioned.

Conventionally, dopamine antagonists have been used to improve gastric motility, but side effects such as extrapyramidal symptoms have appeared, and their use has been limited.

Compounds having 5-HT (5-hydroxytryptamine) antagonism are commonly used to treat or prevent migraine, cluster headache, trigeminal neuralgia, antiemetic, especially vomiting and nausea associated with cancer treatment, anxiety and psychosis. Central disorders, such as
It is known to be useful in treating arrhythmias and the like. In recent years, it has become clear that compounds having a 5-HT antagonism do not exhibit side effects such as extrapyramidal symptoms and are effective in reducing gastric motility.

For example, compounds having an azabicyclo side chain and having 5-HT antagonistic activity include indole-3-ylcarboxylate endo-8-methyl-8-aza-bicyclo [3,2,1]
Oct-3-yl ester (JP-A-61-152628), endo-4-amino-5-chloro-2-methoxy-N- (1-azabicyclo- [3,3,1] -non-4-) Yl) -benzamide (JP-A-62-270583) and the like.

However, an application for a novel compound having better 5-HT antagonistic activity is desired.

[Means for solving the problem]

Therefore, the present inventors have searched for a compound that is different in structure from a conventional compound, has a 5-HT antagonistic effect, and is useful for gastric motility and the like, and as a result, has found a specific imidazo [1,2-a] It has been found that the intended purpose is achieved by the pyridine derivative, and the present invention has been completed.

That is, the gist of the present invention is represented by the general formula (I): Wherein Y is -O- or (In the formula, R ³ represents a hydrogen atom or an alkyl group.) A is a group represented by the formula (II), (III) or (IV), (In the formula, n represents an integer of 1 to 5, and R ⁴ represents a hydrogen atom, an alkyl group, a cycloalkyl group or an aralkyl group.)

R ¹ is hydrogen, alkyl, halogen, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, aralkyl, aralkyloxy, carboxyl, alkoxycarbonyl or alkoxycarbonyl Shows an alkyl group.

R ² represents a hydrogen atom, an alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, an amino group, an alkylamino group, a dialkylamino group, a nitro group, a mercapto group or an alkylthio group. [1,2-a] pyridine derivative, an acid addition salt thereof or a solvate thereof.

Hereinafter, the present invention will be described by referring to the imidazo of the present invention [1,2-
a] The pyridine derivative is represented by the general formula (I).

Wherein Y is -O- or (Wherein R is a hydrogen atom or a methyl group, an ethyl group, n-
And an alkyl group such as an alkyl group having 1 to 5 carbon atoms such as a propyl group, an i-propyl group, an n-butyl group, a t-butyl group, and an n-pentyl group. ), Preferably -O- or A represents a compound of formula (II), (III) or (IV) (Wherein, n represents an integer of 1 to 5, preferably 2 to 4,
R ⁴ is a hydrogen atom; having 1 to 1 carbon atoms as defined in the definition of R ³ above
5 represents an alkyl group such as an alkyl group; a cycloalkyl group such as a cyclopropyl group, a cyclopentyl group, or a cyclohexyl group; or an aralkyl group such as a benzyl group or a phenethyl group, and is preferably a methyl group, an ethyl group, or a benzyl group. R ¹ is a hydrogen atom; an alkyl group such as an alkyl group having 1 to 5 carbon atoms as defined in the definition of R ³ above; a halogen atom such as a fluorine atom, a chlorine atom, and a bromine atom; A fluoromethyl group; a hydroxyl group; a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, a t-butoxy group, an n-pentoxy group, etc. An alkoxy group such as an alkoxy group; an amino group; a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group,
an alkylamino group such as an amino group substituted with an alkyl group having 1 to 5 carbon atoms such as an n-butylamino group, an i-butylamino group, a t-butylamino group; a dimethylamino group, a diethylamino group, a dipropylamino group A dialkylamino group substituted with an alkyl group having 1 to 5 carbon atoms, such as an aralkyl group such as a benzyl group or a phenethyl group; an aralkyloxy group such as a benzyloxy group or a phenethyloxy group; a carboxyl group; a methoxycarbonyl group or an ethoxy group An alkoxycarbonyl group substituted with an alkoxy group having 1 to 5 carbon atoms such as a carbonyl group, an n-propyloxycarbonyl group, an i-propyloxycarbonyl group, or a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, an n-
An alkoxycarbonylalkyl group such as an alkyl group having 1 to 5 carbon atoms substituted with an alkoxycarbonyl group having 1 to 5 carbon atoms (carbon number of an alkoxy group) such as a butoxycarbonylmethyl group and a methoxycarbonylethyl group, , A methyl group, an ethyl group, and a methoxy group.

R ² is a hydrogen atom; an alkyl group, a halogen atom, an alkoxy group, an alkylamino group, an aralkyloxy group, or a dialkylamino group as described above; a hydroxyl group; an amino group; a nitro group; a mercapto group; , An n-propylthio group, an i-propylthio group, an n-butylthio group and the like, and an alkylthio group substituted with an alkyl group having 1 to 5 carbon atoms.

The compound of the present invention represented by the above general formula (I) can be obtained, for example, by subjecting a compound of the following formula (V) and a compound of the formula (VI) to a condensation reaction.

(In the formula (V), R ¹ and R ² have the same meanings as described above.) Or a reactive derivative in which a carboxyl group thereof is substituted with a highly reactive substituent.

H-YA (VI) (wherein Y and A have the same meanings as defined above) or a precursor thereof, for example, a compound wherein R ^{4 in} A is a benzyl group or an ethoxycarbonyl group .

In the general formula (I), Y is Can be obtained, for example, by the following method.

(1-1) A carboxyl group of the formula (V) is converted to N, N'-carbonyldiimidazole, N-hydroxysuccinimide,
It can be produced by reacting with pentachlorophenol or the like to produce an acid derivative having an appropriate reactivity and then reacting this with an amine represented by the formula (VI) in a solvent.

Examples of the solvent include dichloromethane, chloroform, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide and the like.

The reaction temperature is selected from the range of 0 to 200 ° C, preferably 10 to 130 ° C, and the reaction time is 20 minutes to 20 hours, preferably 30 minutes to
All you need to do for 10 hours.

(1-2) obtained by reacting the compound represented by the formula (V) with oxalyl chloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, etc. at 0 to 60 ° C for about 30 minutes to 2 hours. The compound can be produced by reacting an acid halide, preferably an acid chloride, with an amine represented by the formula (VI) in a solvent.

Examples of the solvent include dichloromethane, chloroform, benzene, toluene, tetrahydrofuran, N, N'-dimethylformamide and the like.If necessary, a tertiary amine such as triethylamine and pyridine or a heterocyclic amine is present, Alternatively, it may be used as a solvent. The reaction temperature is selected from the range of -30 to 80 ° C, preferably -10 to 40 ° C, and the reaction time is 5 hours or less, preferably 5 hours or less.
It may be done for a minute to two hours.

Further, in the general formula (I), a compound in which Y is represented by —O— can be obtained, for example, by the following method.

(2-1) The alcohol obtained by reacting the alcohol represented by the formula (VI) with n-butyllithium in a tetrahydrofuran solvent or with sodium halide in an N, N'-dimethylformamide solvent, for example. It can be produced by reacting an alkali metal salt such as a lithium salt or a sodium salt of an alcohol with the highly reactive acid derivative of the formula (V) described in the above (1-1) in a solvent.

Solvents include tetrahydrofuran, dioxane, N,
N'-dimethylformamide and the like are preferred, and the reaction is 10 to 1
It may be performed at 20 ° C. for about 30 minutes to 10 hours.

(2-2) An acid halide of the alkali metal salt of the alcohol represented by the formula (VI) described in the above (2-1) and the compound represented by the formula (V) described in the above (1-2), preferably It can be produced by reacting with acid chloride in a solvent.

As the solvent, tetrahydrofuran, dimethoxyethane, dioxane and the like are preferable, and the reaction may be carried out at −20 to 50 ° C. for 5 hours or less, preferably for about 5 minutes to 2 hours.

In the above reaction, it is considered that the configuration of the alcohol or amine represented by the formula (VI) is maintained as it is after the reaction. Further, the alcohol or amine represented by the formula (VI) can be reacted as necessary with a mixture of endo and exo isomers, and the endo or exo isomer can be separated by a conventional method such as chromatography or crystallization. .

When the precursor is used as the compound represented by the formula (VI), hydrogenation,
It can be deprotected by means such as ammonia-sodium or alkali hydrolysis.

The compound represented by the general formula (I) thus obtained can form an acid addition salt according to a conventional method.
Acids used to form the acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and acetic acid, oxalic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, Organic acids such as lactic acid are included.

In addition, an acid addition salt of the compound represented by the general formula (I) may be converted into an alcohol (methanol, ethanol, etc.), acetone (acetone, etc.), ethers (tetrahydrofuran, dioxane, etc.) of the compound according to a conventional method. Crystallization in an aqueous solution that may have been added to aid dissolution gives a solvate of the desired compound.

Hereinafter, the compound of the present invention represented by the general formula (I) will be exemplified.

1) 2-Methyl-imidazo [1,2-a] pyridine-3
-Carboxylic acid (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) ester-hydrochloride 2) 2-ethyl-imidazo [1,2-a] pyridine-3
-Carboxylic acid (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) ester-hydrochloride 3) 2-isopropyl-imidazo [1,2-a] pyridine-3-carboxylic acid (endo -8-Methyl-8-azabicyclo [3.2.1] oct-3-yl) ester-hydrochloride 4) Imidazo [1,2-a] pyridine-3-carboxylic acid (endo-8-methyl-8-azabicyclo [ 3.2.1] Oct-3-yl) ester-hydrochloride 5) 2-Trifluoromethyl-imidazo [1,2-a] pyridine-3-carboxylic acid (endo-8-methyl-8-azabicyclo [3.2.1 ] Oct-3-yl) ester-hydrochloride 6) 2,6-dimethyl-imidazo [1,2-a] pyridine-
3-carboxylic acid (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) ester-hydrochloride 7) 2-methyl-6-amino-imidazo [1,2-a]
Pyridine-3-carboxylic acid (endo-8-methyl-8-
Azabicyclo [3.2.1] oct-3-yl) ester-
Hydrochloride 8) 2-Methyl-6-nitro-imidazo [1,2-a]
Pyridine-3-carboxylic acid (endo-8-methyl-8-
Azabicyclo [3.2.1] oct-3-yl) ester-
Hydrochloride 9) 2-Methyl-8-methoxy-imidazo [1,2-
a] pyridine-3-carboxylic acid (endo-8-methyl-
8-Azabicyclo [3.2.1] oct-3-yl) ester-hydrochloride 10) 2-Methyl-8-benzyloxy-imidazo [1,
2-a] pyridine-3-carboxylic acid (endo-8-methyl-8-azabicyclo [3.2.1] oct-3-yl) ester-hydrochloride 11) 2-methyl-6-chloro-imidazo [1,2 -A]
Pyridine-3-carboxylic acid (endo-8-methyl-8-
Azabicyclo [3.2.1] oct-3-yl) ester-
Hydrochloride 12) N- (1-azabicyclo [2.2.2] oct-3-
Yl) 2-methyl-imidazo [1,2-a] pyridine-3
-Carboxamide-hydrochloride 13) N- (1-azabicyclo [2.2.2] oct-3-
Yl) -imidazo [1,2-a] pyridine-3-carboxamide-hydrochloride 14) 2-methyl-imidazo [1,2-a] pyridine-3
-Carboxylic acid (1-azabicyclo [2.2.2] oct-3
-Yl) ester-hydrochloride 15) N-((±) -1-azabicyclo [3.3.1] -non-4-yl) -2-methyl-imidazo [1.2-a] pyridine-3-carboxamide-hydrochloride The compound of the present invention has 5-HT as shown in Test Examples described later.
(5-Hydroxytryptamine) antagonist, which can be used for treating or preventing migraine, cluster headache, and trigeminal neuralgia. It can also be commonly used as an antiemetic, particularly for preventing vomiting and nausea associated with cancer treatment. Examples of such cancer treatments include the use of cytotoxic agents such as cisplatin, adriamycin, cyclophosphamide and radiation therapy. Compounds that are 5-HT antagonists are also effective in treating central disorders such as anxiety and psychosis, and arrhythmias.

Further, the compound of the present invention can be expected to have a gastric motility improving activity,
It is particularly useful for treating delayed gastric emptying, dyspepsia, bloating, esophageal reflux and gastrointestinal ulcers.

When the compound represented by the general formula (I) of the present invention, an acid addition salt thereof and a solvate thereof are used as a medicament, the compound is usually diluted with a solid or liquid carrier or excipient suitable for a medicament or a stabilizer. Used with agents. The form may take the form of tablets, capsules, oral solutions, powders, granules, troches, reconstitutable powders, injection or perfusion solutions or suspensions, suppositories and the like. Orally administrable compositions and dosage forms are generally suitable and preferred.

Tablets and capsules for oral administration are usually presented as unit dosages and contain conventional excipients such as binders, fillers, diluents, tablets, lubricants, disintegrating agents, coloring agents, flavoring agents and wetting agents. Contains excipients. Tablets can be coated according to methods well known in the art, for example, with an enteric coating.

Fillers suitable for use herein include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycolate. Suitable lubricants include, for example, magnesium stearate. Suitable lubricants as medicaments include:
For example, sodium lauryl sulfate is included. Oral solutions are provided, for example, in aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as a dry product which can be redissolved in water or a suitable vehicle before use. You. Such solvents are conventional additives, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, suspending agents such as aluminum stearate gel or hydrogenated edible fats,
Emulsifiers such as lecithin, sorbitan monooleate, gum arabic, non-aqueous (including edible oils) such as almond oil, rectified coconut oil, oily esters (e.g. esters of chrysin), propylene glycol, ethyl alcohol It can contain vehicles, preservatives such as methyl or ethyl esters of p-hydroxybenzoic acid, or sorbic acid, and if desired, conventional flavoring or coloring agents.

Tablets for oral administration are manufactured by conventional methods of mixing, filling or compressing. The active agent may also be distributed in these compositions using large amounts of fillers using a repeated blending operation.

For parenteral administration, fluid unit dosage forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and concentration, is either suspended or dissolved. Parenteral solutions are usually sterilized by dissolving the compound in a vehicle,
It is then prepared by filling into a suitable vial or ampoule and sealing. To enhance stability, the composition can be frozen and filled into vials and the water removed under vacuum and used.

Parenteral suspensions are prepared in substantially the same manner as parenteral solutions, except that the compound, instead of being dissolved, is suspended in a vehicle, sterilized by exposure to ethylene oxide, and then added to a sterile vehicle. It is manufactured by suspending in water.
If necessary, a surfactant, a wetting agent, and the like may be added so that the compound of the present invention has a uniform distribution.

In the present invention, a compound represented by the general formula (I) or an acid addition salt and a solvate thereof may further be used in mammals, such as humans, for defective gastrointestinal motility, vomiting, migraine, cluster headache and trigeminal neuralgia. It can be applied to the treatment or prevention of disorders related to.

Effective amounts for treating the above-mentioned disorders will vary with the relative efficacy of the compound of the present invention, the nature, extent and magnitude of the disorder being treated.

For example, when administered orally to an adult weighing 60 kg, the dose is usually 0.5 to 1000 mg of the compound of the present invention per day,
The dose is preferably 1 to 100 mg, and it is preferable to administer it in 1 to 4 divided doses per day.

The dose for intravenous injection is usually 300 mg or less, preferably 0.1 to 100 mg, and it is preferable to administer the dose once to several times a day.

〔The invention's effect〕

Since the compounds of the present invention have good 5-HT antagonistic activity, they treat or prevent migraine, cluster headache, trigeminal neuralgia, vomiting agents, especially vomiting and nausea associated with cancer treatment, anxiety and psychosis. It is useful in treating such central disorders and arrhythmias. In particular, the compound of the present invention is expected to have a gastric motility improving activity and is useful for treating delayed gastric emptying, dyspepsia, bloating, reflux in the esophagus and gastrointestinal ulcers.

〔Example〕

Hereinafter, the present invention will be described specifically with reference to Examples.
The present invention is not limited to these examples unless it exceeds the gist.

Example 1 2-Methyl-imidazo [1,2-a] pyridine-3-carboxylic acid (endo-8-methyl-8-azabicyclo [3.2.
1) Production of octo-3-yl) ester-hydrochloride 2.08 g of endo-8-methyl-8-azabicyclo [3.2.1] octan-3-ol (tropine) was dissolved in 10 ml of anhydrous tetrahydrofuran, and then 0 to 10 ° C. Then, 8.3 ml of a 15% -n-butyllithium-hexane solution was added dropwise with stirring. After stirring at room temperature for 40 minutes, the solvent was distilled off under reduced pressure, and 15 ml of anhydrous tetrahydrofuran was added to obtain a lithium salt solution of tropine.

2-methyl-imidazo [1,2-a] pyridine-3-carboxylic acid 2.0 g, N, N'-carbonyldiimidazole 2.21 g
Was added to 35 ml of tetrahydrofuran at room temperature. The mixture was heated and stirred at 50 ° C. for 1 hour to obtain imidazolide. To this solution, a lithium salt solution of tropine was added, and reacted at 50 ° C. for 2.5 hours.

After evaporating the solvent, chloroform was added and the mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was chromatographed on 75 g of silica gel with 3% methanol in chloroform as eluent,
The free title compound was obtained (mp 87-91 ° C). This was treated with ethyl acetate containing hydrogen chloride to give 0.81 g of the title compound (mp> 300 ° C.).

'H NMR (250 MHZ, DMSO-d ₆ ) δ: 9.25 (1H, d), 7.68 (1
H, d), 7.55 (1H, t), 7.19 (1H, t), 5.20 (1H, s),
3.88 (2H, s), 2.67-2.23 (11H, m) Example 2 Imidazo [1,2-a] pyridine-3-carboxylic acid (endo-8-methyl-8-azabicyclo [3.2.1] oct-
Preparation of 3-yl) ester-hydrochloride 2.49 g of endo-8-methyl-8-azabicyclo [3.2.1] octan-3-ol (tropine) are dissolved in 25 ml of anhydrous tetrahydrofuran and 15% at 5-12 ° C. 10.8 ml of n-butyllithium-hexane solution was added dropwise. After stirring at room temperature for 30 minutes and distilling off the solvent under reduced pressure, dimethylformamide (20 ml) was added to obtain a tropine lithium salt solution.

Imidazo [1,2-a] pyridine-3-carboxylic acid 2.2
g, N, N'-carbonyldiimidazole (2.68 g) were added to N, N-dimethylformamide (50 ml), and reacted at 60 ° C. for 1 hour to obtain imidazolide. To this solution, a tropine lithium salt solution was added dropwise at 65 ° C., and the mixture was stirred for about 30 minutes.

The solvent was distilled off under reduced pressure, the residue was dissolved in chloroform, washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was eluted by chromatography on 75 g of silica gel using chloroform containing 3% methanol as an eluent to obtain a free title compound (melting point: 136 to 140 ° C).

This was treated with hydrogen chloride-containing ethyl acetate to give 2.22 g of the title compound (melting point: 295 ° C. (decomposition)). ¹ H-NMR (250 MHz, DMSO-d ₆ ) δ: 9.26 (1H, d), 8.37 (1
H, s), 7.86 (1H, d), 7.60 (1H, t), 7.29 (1H, t),
5.22 (1H, s), 3.90 (2H, s), 2.70-2.11 (11H, m) Example 3 N- (1-azabicyclo [2.2.2] oct-3-yl)
Preparation of 2-methyl-imidazo [1,2-a] pyridine-3-carboxamide-hydrochloride 2.5 g of 2-methyl-imidazo [1,2-a] pyridine-3-carboxylic acid is added in portions to 10 ml of thionyl chloride And at room temperature
Stirred for 2.5 hours. Thionyl chloride was distilled off under reduced pressure, and the remaining crystals were washed with ethyl ether, filtered and dried to obtain 3.28 g of 2-methyl-imidazo [1,2-a] pyridine-3-carboxylic acid chloride-hydrochloric acid. Salt was obtained.

1-azabicyclo [2.2.2] octane-3-amine hydrochloride 1.49 g, triethylamine 5.73 ml chloroform 40m
l-methyl-2-imidazo [1,2-
a) pyridine-3-carboxylic acid chloride-hydrochloride 2.0 g
Was gradually added. Room temperature after 20 minutes, 1N after stirring for 2 hours
-Washed with sodium hydroxide solution and water and dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was eluted by column chromatography on 40 g of silica gel using chloroform containing 3% -methanol as an eluent to obtain a free title compound (melting point: 79 to 85 ° C).

This was treated with ethanolic hydrogen chloride to give the title compound 1.
06 g was obtained (melting point 290-295 ° C). ¹ H-NMR (250 MHz DMSO-d ₆ ) δ: 8.87 (1H, d), 8.20
(1H, d), 7.58 (1H, d), 7.40 (1H, t), 7.04 (H,
t), 4.36 (1H, m), 3.66-3.10 (6H, m), 2.60 (3H, m
s), 2.28-1.79 (5H, m) Example 4 N- (1-Azabicyclo (2.2.2) oct-3-yl)
Preparation of imidazo [1,2-a] pyridine-3-carboxamide-hydrochloride 3.0 g of imidazo [1,2-a] pyridine-3-carboxylic acid
Was added in portions to 12 ml of thionyl chloride under ice-cooling, a small amount of N, N-dimethylformamide was added, and the mixture was stirred at room temperature for 1.5 hours. Thionyl chloride was distilled off under reduced pressure, and the remaining crystals were washed with ethyl ether, decanted, and dried to give 3.96 g of imidazo [1,2-a] pyridine-3-carboxylic acid chloride-hydrochloride. .

1-azabicyclo [2.2.2] octane-3-amine hydrochloride 1.80 g, triethylamine 5.66 ml chloroform 45m
Then, 1.96 g of imidazo [1,2-a] pyridine-3-carboxylic acid chloride-hydrochloride was gradually added under ice-cooling and stirring. After 30 minutes at room temperature, after stirring for another 4 hours, 5%
The extract was washed with an aqueous solution of potassium carbonate and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the crystals were washed with n-hexane to obtain the free title compound (mp 166-168).
° C).

By treating this with ethanolic hydrogen chloride,
1.82 g of the title compound was obtained (melting point 290-296 ° C). ¹ H-NMR (250 MHz DMSO-d ₆ ) δ: 9.42 (1H, d), 9.91
(1H, d), 8.68 (1H, s), 7.75 (1H, d), 7.48 (1H,
t), 7.14 (H, t), 4.38 (1 H, m), 3.70-160 (11 H, m) Example 5 2-Methyl-imidazo [1,2-a] pyridine-3-carboxylic acid (1-azabicyclo [2.2.2] Production of oct-3-yl) ester-hydrochloride To 10 ml of N, N-dimethylformamide was added 0.41 g of 60% sodium hydride, and 1-azabicyclo [2.
2.2] Slowly add 1.30 g of octane-3-ol. 30
After one minute, the mixture was heated and stirred at 70 ° C. for another 30 minutes.

1.5 g of 2-methyl-imidazo [1,2-a] pyridine-3-carboxylic acid, 1.52 g of N, N'-carbonyldiimidazole
Was added to 40 ml of N, N-dimethylformamide and stirred at 65 ° C. for 1 hour to obtain imidazolide. To this solution was added the above 1-azabicyclo [2.2.2] octane-3-
An all sodium salt solution is added dropwise at 70 ° C., and the mixture is heated and stirred for 5 hours.

The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate,
After washing with water, the extract was dried over anhydrous magnesium sulfate and concentrated. The remaining crystals were crystallized from ethyl acetate-n-hexane to give the free title compound (melting point: 120-121 ° C).

This was treated with hydrogen acetate-containing ethyl acetate to give 1.32 g of the title compound. (Mp 267-270 ° C). ¹ H-NMR (250 MHz DMSO-d ₆ ) δ: 9.21 (1H, d), 7.74
(1H, d), 7.57 (1H, t), 7.22 (1H, t), 5.29 (1H,
m), 3.79-3.16 (7H, m), 2.65 (3H, s), 2.48-1.63
(5H, m) Example 6 N-((±) -1-azabicyclo [3.3.1] -non-4
Preparation of -yl) -2-methyl-imidazo [1,2-a] pyridine-3-carboxamide-hydrochloride (±) 4-amino-1-azabicyclo [3.3.1] -nonane 1.57 g, triethylamine 3.12 ml Methylene chloride 40m
dissolved in l. 2.35 g of 2-methylimidazo [1,2-a] pyridine-3-carboxylic acid chloride-hydrochloride obtained according to the method of Example 3 was gradually added under ice cooling. After 50 minutes, the temperature was raised to room temperature, and the mixture was further stirred for 1 hour. The crystals were dissolved in water, made alkaline with a 1N aqueous solution of sodium hydroxide, and extracted with chloroform. After washing with water, drying over anhydrous sodium sulfate and distilling off the solvent, the resulting crystals were crystallized from ethyl acetate-n-hexane to give the free title compound (melting point 154-156 ° C).

This was treated with ethanolic hydrogen chloride to give the title compound 0.1.
66 g were obtained (melting point> 300 ° C.). ¹ H-NMR (250 MHz, CD ₃ OD) δ: 8.83 (1 H, d), 7.45 (1 H,
d), 7.37 (1H, t), 6.95 (1H, t), 4.50 (1H, m), 3.6
0-3.40 (6H, m), 2.58 (3H, s), 2.44-1.70 (7H, m) Test example von Bezld-Jarish
Antagonism of reflex The compounds were evaluated for antagonism of the von Besold-Jalish reflex caused by 5-HT in anesthetized rats according to the following method.

Male rats (250-300 g) were anesthetized with urethane (1.5 g / kg, intraperitoneal), and the heart rate was recorded from an electrocardiogram. First, an appropriate amount of 5-HT (usually 4-6 μg / kg) was administered by intravenous route, and the change in heart rate was measured (A). The compound was then administered intravenously, followed by a 5-HT evoked response, and the change in heart rate was measured again (B). From these values, the inhibition rate for the control response was calculated by the following formula.

The results were as shown in Table 1.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display location A61K 31/435 AEN A61K 31/435 AEN (72) Inventor Satoshi Yamazaki Satoshi Kamoshida-cho, Midori-ku, Yokohama-shi, Kanagawa Prefecture 1000 Mitsubishi Chemical Industries Research Laboratory (72) Inventor Akihiro Tobe 1000 Kamoshita-cho, Midori-ku, Yokohama-shi, Kanagawa Prefecture Mitsubishi Chemical Industry Research Laboratory

Claims (1)

(57) [Claims] 1. A compound of the general formula (I): [In the above formula (I), Y is -O- or (In the formula, R ³ represents a hydrogen atom or an alkyl group.) A is a group represented by the formula (II), (III) or (IV), (In the formula, n represents an integer of 1 to 5, and R ⁴ represents a hydrogen atom, an alkyl group, a cycloalkyl group or an aralkyl group.) R ¹ is hydrogen, alkyl, halogen, trifluoromethyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, aralkyl, aralkyloxy, carboxyl, alkoxycarbonyl or alkoxycarbonyl Shows an alkyl group. R ² is a hydrogen atom, an alkyl group, a halogen atom, a hydroxyl group, an alkoxy group, an aralkyloxy group, an amino group,
It represents an alkylamino group, a dialkylamino group, a nitro group, a mercapto group or an alkylthio group. [1,2-a] pyridine derivatives, acid addition salts or solvates thereof.