JPH01258674A - Imidazo(1,2-a)pyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [Y is -O- or group shown by formula II (R<3> is H or alkyl); A is group shown by formula III (n is 1-5; R<4> is R<3>, cycloalkyl, etc.), group shown by formula IV or formula V; R<1> is R<3>, halogen, CF3, OH, alkoxy, amino, etc.; R<2> is R<3>, halogen, OH, alkoxy, aralkyloxy, amino, nitro, etc.]. EXAMPLE:2-Methyl-imidazo[1,2-a]pyridine-3-carboxylic acid (endo-8-methyl-8- azabicyclo[3,2,1]oct-3-yl)ester hydrochloride. USE:A drug. 5-HT antagonist. Useful for treating or preventing migraine, etc., antiemetic, especially preventing vomiting and bad heart related to treatment of cancer, remedying central nerve disorder, arrhythmia, etc. and useful for treating delayed gastric emptying, digestive ulcer, etc. PREPARATION:A compound shown by formula VI or a reactive derivative is condensed with a compound shown by formula VII or a precursor thereof in a solvent to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel imidazo CI, 2-a) pyridine derivative, an acid addition salt thereof or a solvate thereof.

[Problems to be solved by conventional technology and invention]

Heartburn, abdominal bloating, loss of appetite, upper abdominal discomfort, nausea,
So-called digestive complaints such as abdominal pain can be caused by chronic gastritis,
It appears as a main symptom of gastroptosis, and a major contributing factor is a decrease in gastric emptying capacity associated with gastric ataxia.

Conventionally, dopamine antagonists have been used to improve gastric motor function, but their use has been limited due to side effects such as extrapyramidal symptoms.

Compounds with z-HT (j-hydroxytryptamine) antagonistic activity are commonly used in the treatment or prevention of migraines, cluster headaches, trigeminal neuralgia, as antiemetics, especially in the prevention of vomiting and nausea associated with cancer treatment, and in the treatment of anxiety and psychosis. Central disorders such as
It is known to be useful in treating arrhythmia and the like.

Furthermore, in recent years, it has become clear that compounds having a j-HT antagonistic effect do not exhibit side effects such as extrapyramidal symptoms and are effective against a decline in gastric motor function.

For example, it has an azabicyclo side chain and! -HT antagonistic compounds include indol-3-ylcarboxylic acid endo-g-methyl-g-aza-bicyclo(3,2
,/ ) oct-3-yl ester (JP-A-Sho At-tr
2A21) %: "7 Dohiro-amino-!-chloro-2-methoxy N-(/-azabicyclo-(3,3,
/ )-Non-Hiro-yl)-benzamide (JP-A-Sho t2
-270!13 Publication) and the like are known.

However, even better! - It is desired to apply for a new compound having HT antagonistic activity.

[Means for solving problems]

Therefore, the present inventors discovered that the structure of the compound is different from that of conventional compounds.
As a result of searching for compounds that have j-HT antagonistic effects and are useful for gastric motility, we discovered that the desired purpose could be achieved with a specific imidazo[t,ra)pyridine derivative. The invention was completed.

That is, the gist of the present invention is - Formula (■): [wherein, Y represents 10- or -N- (wherein, R3 represents a hydrogen atom or an alkyl group].

A is a formula (If), (II[) or (1't/), (n
) (III) (IV) (where n
represents an integer of / and jt, and R4 represents a hydrogen atom, an alkyl group, a cycloalkyl group, or an aralkyl group. )
The group represented by is shown below.

R1 is a hydrogen atom, an alkyl group, a hydrogen atom, a trifluoromethyl group, a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, a carboxyl group, an alkoxycarbonyl group, or an alkoxy Indicates a carbonyl alkyl group.

R2 is a hydrogen atom, an alkyl group, a hydrogen atom,! Indicates a hydroxyl group, an alkoxy group, an oxy group, an amine group, an alkylamino group, a dialkylamino group, a nitro group, a mercapto group, or an alkylthio group. ], the imidazo(1,2-a)pyridine derivative, its acid addition salt, or its solvate.

In order to explain the present invention, the imidazo C1,2-
a) Pyridine derivatives have the general formula hydrogen atom or methyl group, ethyl group, n-propyl group, i-propyl group, n
-Butyl group, 1-butyl group, n-pentyl group, etc. carbon number/~j or (IV) (n) (III) (
IV) (wherein n represents an integer of /~!, preferably 2 to Hiroshi; R4 is a hydrogen atom; an alkyl group such as an alkyl group having a carbon number of /~! as shown in the definition of R3 above; cyclopropyl R1 is a hydrogen atom; ; Alkyl groups such as alkyl groups with carbon numbers/~ as shown in the definition of R3; fluorine atoms, chlorine atoms, bromine atoms, etc.; trifluoromethyl group; hydroxyl group; methoxy group, ethoxy group , n-propoxy group,
1-propoxy group, n-butoxy group, i-butoxy group,
Alkoxy groups such as alkoxy groups with carbon number/~j such as t-butoxy group and n-pentoxy group; Amino group; methylamino group, ethylamino group, propylamine group, inglobylamino group, n-butylamino group, Alkylamino groups such as amino groups substituted with alkyl groups having carbon numbers l to j such as i-butylamino groups and t-butylamino groups; carbon numbers/- such as dimethylamino groups, diethylamino groups, and dipropylamino groups; Dialkylamino group substituted with alkyl group etc. of 3; Aralkyl group such as benzyl group, phenethyl group; Aralkyloxy group such as benzyloxy group, phenethyloxy group; Carboxyl group; Methoxycarbonyl group, ethoxycarbonyl group, n-propyl group oxycarbonyl group,
Number of carbon atoms in i-propyloxycarbonyl group, etc./-Number of carbon atoms in alkoxycarbonyl group substituted with alkoxy group, etc., or methoxycarbonylmethyl group, ethoxycarbonylmethyl group, n-butoxycarbonylmethyl group, methoxycarbonylethyl group, etc. l~! (number of carbon atoms in alkoxy group) number of carbon atoms substituted in alkoxycarbonyl group l
-! represents an alkoxycarbonyl alkyl group such as an alkyl group, preferably a methyl group, an ethyl group, or a methoxy group.

R2 is a hydrogen atom; an alkyl group or group as described above; an amino group; a nitro group; a mercapto group; a methylthio group, an ethylthio group, an n-propylthio group, an i-propylthio group,
Indicates an alkylthio group substituted with an alkyl group having a carbon number of 1 to 2, such as n-butylthio group.

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

A compound represented by ((V) in which R1 and R2 have the same meanings as defined above) or a reactive derivative thereof in which the carboxyl group is substituted with a highly reactive substituent.

A compound represented by H-Y-A (M) (in the formula (■), Y and A have the same meanings as above) or a precursor thereof, for example R4 in A
is a benzyl group or an ethoxycarbonyl group.

Two compounds in which Y is -N- in the general formula (I) can be obtained, for example, by the following method.

(/-/) The carboxyl group of formula (V) is reacted with N,N'-carbonyldiimidazole, N-hydroxysuccinimide, pentachlorophenol, etc. to produce a suitable highly reactive acid derivative. It can be produced by reacting the amine represented by the formula (VT) in a solvent.

Examples of the solvent include dichloromethane, chloroborum, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and the like.

The reaction temperature is 0,200"C1, preferably 10-730℃
The reaction time may be 20 minutes to 10 hours, preferably 30 minutes to 10 hours.

(/-, z) A compound represented by formula (V) is reacted with oxalyl chloride, thionyl chloride, 1-non trichloride, phosphorus pentachloride, phosphorus tribromide, etc. at 0 to C for about 3Q minutes to 2 hours. an acid chloride, preferably an acid chloride (
It can be produced by reacting an amine represented by the formula Vl) in a solvent.

Examples of the solvent include dichloromethane, chloroform, benzene, toluene, tetrahydrofuran, N,N-dimethylformamide, etc. If necessary, a tertiary amine such as triethylamine or pyridine or a heterocyclic amine may be present. , or may be used as a solvent. The reaction temperature is -30-♂O℃, preferably -10~p
The temperature is selected from the range of 0°C, and the reaction time is 5 hours or less, preferably j minutes to 2 hours.

Further, a compound in which Y is represented by 10- in the general formula (1) can be obtained, for example, by the following method.

An alcohol obtained by reacting an alcohol represented by the formula L2-/)(Vl) with n-butyllithium in a tetrahydrofuran solvent or with sodium chloride in an N,N-dimethylformamide solvent, etc. Alkali metal salts such as lithium salts and sodium salts of alcohols,
It can be produced by reacting the highly reactive acid derivative of formula (V) described above (/-/) in a solvent.

As a solvent, tetrahydrofuran, dioxane, N, N
'-Dimethylformamide etc. are preferable, and the reaction time is 10~
1. It may be carried out at 20°C for about 30 minutes to 10 hours.

L2-, z) an alkali metal salt of an alcohol represented by formula (Vl) described in (2-/) above and an acid halide of a compound represented by formula (V) described in (1-2) above, preferably It can be produced by reacting with acid chloride in a solvent.

As the solvent, tetrahydrofuran, dimethoxyethane, dioxane, etc. are preferable, and the reaction time is -20~! 5 at O℃
Less than an hour, preferably! The reaction may be carried out for about minutes to 2 hours.

In the above reaction, it is thought that the configuration of the alcohol or amine represented by formula (■) is maintained as it is even after the reaction. In addition, the alcohol or amine represented by formula (■) can be reacted as a mixture of endo and exo isomers, if necessary, and the endo or exo isomers can be separated by a conventional method such as chromatography or crystallization. .

In addition, when the precursor is used as the compound represented by the formula (Vl), after the reaction in the above method, hydrogenation,
Deprotection can be carried out by means such as ammonia-sodium or alkaline 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 acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and acetic acid, citric acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, and tartaric acid. , lactic acid and other organic acids.

Alternatively, the acid addition salt of the compound represented by the general formula (I) can be prepared by adding alcohols (methanol, ethanol, etc.), acetones (acetone, etc.), ethers (tetrahydrofuran, dioxane, etc.), etc. to the compound according to a conventional method. A solvate of the desired compound can be obtained by crystallization in an aqueous solution, which may be added to aid solubility.

The compounds of the present invention represented by the general formula (1) are illustrated below.

/) Comethyl-imidazo[1,2-a)pyridine-3
-carboxylic acid (endo-?-methyl-♂-azabicyclo(3,2J)oct-3-yl)ester-hydrochloride 2) 2-ethyl-imidazo CI, 2-a) pyridine-3
-carboxylic acid (endo-♂-methyl-g-azabicyclol: 3.2./ :]]oct-3-yl ester-
Hydrochloride 3) 2-Isopropyl-imidazo[t,2-a)pyridine-3-carboxylic acid (endo-t-methyl-♂-azabicyclo(L2./)oct-3-yl)ester-hydrochlorideg)imidazo [/, 2-a) Pyridine-3-carboxylic acid (endo-g-methyl-?-azabicyclo (J, 2.
/] oct-3-yl) ester-hydrochloride j) 2-trifluoromethyl-imidazo (/, j -a]
Pyridine-3-carboxylic acid (endo-r-methyl-t-
Azabicyclo(3,2,/ )oct-3-yl)ester-hydrochloride 4) 2,6-dimethyl-imidazo[/, 2-a) Pyridine-3-carboxylic acid (endo-r-methyl-♂-azabicyclo (J, 2./]] Octo-3-yl ester-hydrochloride 7) 2-Methyl-6-amino-imidazo[l, 2-a
]Pyridine-3-carboxylic acid (endo-g-methyl-♂
-azabicyclo(3,L/)oct-3-yl)ester-hydrochloride ♂)2-methyl- to -nitroimidazo(/1,2-a)
) Hy'J-3-carboxylic acid (endo-g-methyl-?-azabicyclo(L2./ )oct-3-yl)ester-hydrochloride) 2-methyl-? -Methoxyimidazo [l, 2-a
"Jbi') gin-3-carboxylic acid (endo-g-methyl-?-azabicyclo(J,2./)oct-3-yl)ester-hydrochloride/θ) 2-mef-g-benzyloxy imidazo (i
, 2-a) Pyridine-3-carboxylic acid (endo-♂
-Methyl-r-azabicyclo(L2./)octo-3
-yl)ester-hydrochloride//)2-methyl-2-chloro-imidazo[l,2-a
) Pyridine-3-carboxylic acid (endo-?-methyl-r
-azabicyclo(3,2,/)oct-3-yl)ester-tl[/2)N-(/-azabicyclo[co,2.2)oct-3-yl)-2-methyl-imidazo[l, 2-a) Pyridine-3-carboxamide-hydrochloride/J) N-(/-azabicyclo[co,co,co]oct-3-yl)-imidazo(/,,2-a)pyridine-3-
Carboxamide hydrochloride/Hiro) 2-methyl-imidazo[t,za]pyridine-
3-carboxylic acid (/-azabicyclo [co, 2.2 ]]
Octo-3-yl ester-hydrochloride/! >N-((±) -/-azabicyclo(3,3,
7)-non-hiro-yl)-comethyl-imidazo(/,
2-a) Pyridine-3-carboxamide hydrochloride The compound of the present invention has tg-r-
It is an HT (!-hydroxytryptamine) antagonist and can be used to treat or prevent migraine, cluster headache, and trigeminal neuralgia. It can also be commonly used as an antiemetic, especially to prevent vomiting and nausea associated with cancer treatment.

Examples of such cancer treatments include the use of cytotoxic agents such as cisplatin, adriamycin, cyclophos-7amide, and radiation therapy.

j-) Compounds that are IT antagonists are also effective in the treatment of central disorders such as anxiety and psychosis, arrhythmia, and the like.

Furthermore, the compounds of the present invention are expected to have gastric motility-improving activity, and are particularly useful for treating delayed gastric emptying, indigestion, bloating, esophageal reflux, gastrointestinal ulcers, and the like.

When the compound represented by the general formula (I) of the present invention, its acid addition salt, and its solvate are used as a medicine, dilution with a solid or liquid carrier, excipient, stabilizer, etc., which is usually suitable for medicine. Use with agents etc. Its forms include tablets, capsules, oral solutions, powders, granules, troches,
They may take the form of resolvable powders, solutions or suspensions for injection and perfusion, suppositories, and the like. Orally administrable compositions and dosage forms are generally suitable and preferred.

Tablets and capsules for oral administration are usually presented in unit dosage form and include conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, colorants, flavoring agents, and wetting agents. Contains excipients. Tablets may be coated according to methods well known in the art, for example with enteric coatings.

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. Pharmaceutically suitable humectants include, for example, sodium lauryl sulfate.

Oral solutions include 1, for example, as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, etc.
It may be provided in dosage form or as a dry product which can be redissolved in water or a suitable medium before use. Such solutions may contain the usual additives, such as sorbitol, syrups, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, suspending agents such as aluminum stearate gel or hydrogenated edible fats, lecithin, nlupitan monooleate, Emulsifiers like gum arabic, almond oil, rectified coconut oil,
Preservatives such as oily esters (e.g. esters of chrycerin), propylene glycol, ethyl alcohol, non-aqueous media (which may also include edible oils), methyl or ethyl esters of p-hydroxybenzoic acid, or rubic acid. and, if desired, conventional flavoring or coloring agents.

Tablets for oral administration are manufactured by conventional methods of mixing, filling or tabletting. Iterative compounding operations may also be used to distribute the active agent in these compositions using large amounts of fillers.

For parenteral administration, liquid unit dosage forms are prepared containing a compound of the invention and a sterile vehicle. Depending on the vehicle and concentration, the compound may be suspended or dissolved. Parenteral solutions are usually prepared by dissolving the compound in a vehicle, filtering sterilization, then filling a suitable vial or ampoule and sealing. To increase stability, the composition can be frozen and then filled into vials and the water removed under vacuum before use.

Parenteral suspensions are prepared in substantially the same manner as parenteral solutions, except that the compound is suspended in a vehicle instead of being dissolved and sterilized by exposure to ethylene oxide.
It is further manufactured by suspending it in a sterile medium. A surfactant, wetting agent, etc. may be added as necessary to ensure uniform distribution of the compound of the present invention.

In the present invention, the compounds of general formula (I) or acid addition salts and solvates thereof may be used to treat impaired gastrointestinal motility, vomiting, migraines, cluster headaches and trigeminal headaches in mammals, such as humans. It can be applied to the treatment or prevention of disorders related to neuralgia.

Amounts effective to treat the disorders described above will vary depending on the relative efficacy of the compounds of the invention, the nature and severity of the disorder being treated, and the weight of the mammal.

For example, when orally administered to an adult with a body weight of 60#, the dose of the compound of the present invention is usually o3-iooo o3-iooo per day.
■, preferably /-100■, and this is l- per day.
It is preferable to administer the drug in divided doses.

When administered intravenously, the dose is usually 700 m7 or less,
Preferred doses are o, i to ioo■, and it is preferable to administer this in divided doses from once a day to several times a day.

〔Effect of the invention〕

Since the compounds of the invention have good j-HT antagonistic activity, they can be used in the treatment or prevention of migraines, cluster headaches, trigeminal neuralgia, as antiemetics, especially in the prevention of vomiting and nausea related to cancer treatment, in the treatment of anxiety and psychosis. It is useful in the treatment of central nervous system disorders, arrhythmia, etc. In particular, the compounds of the present invention are expected to have gastric motility-improving activity and are useful for treating delayed gastric emptying, indigestion, bloat, esophageal reflux, gastrointestinal ulcers, and the like.

〔Example〕

EXAMPLES The present invention will be specifically explained below using Examples, but the present invention is not limited to these Examples unless the gist thereof is exceeded.

Example/ Endo-r-methyl-r-azabicyclo[3°2,/]
Octane-3-ol (tropin) 2. Dissolve CH in toml of anhydrous tetrahydrofuran and heat at 0 to 70°C/j
(1) -n-butyllithium-hexane solution ♂, 3rt
tl was added dropwise under stirring. After stirring for 1.10 minutes at room temperature,
The solvent was distilled off under reduced pressure and anhydrous tetrahydrofuran/! m
A lithium salt solution of tropine was obtained.

Comethyl-imidazo[t,2-a3pyridine-3-carboxylic acid co,oy,N,N'-carbonyldiimidazole 2.2/r in tetrahydrofuran 33m at room temperature
Added to 1. The mixture was heated and stirred at t o 'c for 7 hours to obtain imidazolide. A lithium salt solution of tropine was added to this solution, and the mixture was reacted with jO''c for 2.5 hours.

After evaporating the solvent, chloroform was added, washed with water, dried over anhydrous magnesium sulfate, and concentrated.

The residue was chromatographed on silica gel 739 using trivalent methanol in chloroform as eluent to give the free title compound (melting point ♂
7-7/℃). When this is treated with ethyl acetate containing hydrogen chloride, O0♂/? The title compound was obtained (melting point: 300°C).

'HNMR (2jOMH7, DI! ISOda) δ:
Ta, 2 yo (lH, d), 7. +r(lH,d)
, 7.5 evening (lH,t), 7. / Ta (
l)(,t),! , 2 0('F(p
s), 3. rr (-zH% s), 2.67~ko,
23 (//H, m) Example 2 Endo-♂-methyl? -Azabicyclo [3゜ko, /]
Octane-3-ol (tropin) co,≠72 anhydrous tetrahydrofuran 2! , dissolved in l, ! , at 12℃/j
(1) -n-butyllithium-hexane solution/0. ♂
d was added dropwise. After stirring at room temperature for 30 minutes and distilling off the solvent under reduced pressure, dimethylformamide 2011 was added to obtain a lithium salt solution of tropine.

imidazo[/,2-a]pyridine-3-carboxylic acid2.
2? , N, N'-carbonyldiimidazole 2, t♂
2 was added to N,N-dimethylformamide jOtttl and reacted at to'c for 1 hour to obtain imidazolide. A lithium salt solution of tropine was added dropwise to this solution at +t'c,
Stirred for about 30 minutes.

The solvent was distilled off under reduced pressure, and the residue was washed with water dissolved in chloroform, dried over anhydrous magnesium sulfate, and concentrated. Silica gel 75 for the residue? The above was chromatographed using chloroform containing 3% methanol as an eluent to obtain the free title compound (melting point i36~l≠Q
℃).

Treatment of this with ethyl acetate containing hydrogen chloride gave the title compound 2.229 (melting point:
(Disassembly)).

'H-N, MR (2j OMHz, DMSO-da
) δ: Ri, 2 6 (/H, d), L
, 3 7 (/H, s), 7J4 (lH, d
), 7. go(lH,tL 7-2?(lH,t),!
, 22 (lH,S), ! , riO(2H,s),
2.70-2. / / (//H, m) Example 3 a] Preparation of pyridine-3-carboxamide-hydrochloride 2-methyl-imidazo [i, 2-a) Pyridine-3-carboxylic acid 2.3'? was added in portions to 10.1 liters of thionyl chloride, and the mixture was stirred at room temperature for 2.5 hours. Thionyl chloride was distilled off under reduced pressure, and the remaining crystals were washed with ethyl ether and dried temporarily.3. 2-methyl-imidazo(/,,?-a]pyridine-3-carboxylic acid chloride hydrochloride of λt2 was obtained.

/-azabicyclo[co, 2.2) octane-3-amine hydrochloride/, lI9? , triethylamine! ,73m1
was added to 10 ml of chloroform, and 2.02 ml of acomethyl-imidazo[i,2-a) pyridine-3-carboxylic acid chloride hydrochloride was gradually added under water cooling and stirring. 20
After a few minutes, the mixture was brought to room temperature and stirred for 2 hours.The mixture was washed with N-sodium hydroxide solution and water, and then washed with anhydrous sodium sulfate. After distilling off the solvent, the residue was purified using silica gel. 3 on top
Elution was performed by column chromatography using chloroform containing methanol as an eluent to obtain the free title compound (melting point: 7 - rsC).

This was treated with ethanolic hydrogen chloride to give the compounds in the table order.
6y was obtained (melting point: 0-22rC).

'HNMR (-2j OMHz DMSO-da)
δ:j', I7 (lH, d), L20 (lH, d
), 7.5r(tH,d), 7. ! O(/F(,t),
7, op (Hpt), p, 36 (lH, m)
, 3.66-3.10 (6H,m>, 2.tO(3H
.

S), CO, 2 lr-7,7F (YH, m) Example ≠ Imidazo [/, 2-a) Pyridine-3-carboxylic acid 3.
O? was added in portions to 12 ml of thionyl chloride under water cooling, and N
, add a small amount of N-dimethylformamide and prepare i, r at room temperature.
Stir for hours. Thionyl chloride was distilled off under reduced pressure, and the remaining crystals were washed with ethyl ether, decanted, and dried to give imidazo[i,za)pyridine-3-carboxylic acid chloride hydrochloride at a concentration of 3.96 ? Obtained.

l-Azabicyclo(2,2,23octane-3-amine hydrochloride ♂02, triethylamine 5.44d was dissolved in chloroform≠jrtl, and the mixture was cooled with water and stirred to imidazoate.
Heko a] Pyridine-3-carboxylic acid chloride-hydrochloride/? 4 S' was gradually added. After 30 minutes, the temperature was brought to room temperature, and after further stirring for ≠ hours! %-potassium carbonate aqueous solution and water, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the crystals were washed with n-hexane to obtain the free title compound (melting point tt, 6-/+lr''c).

Treatment of this with ethanolic hydrogen chloride gave the title compound 121 (melting point KotaQ-KotaA''C).
.

lHNMR (2j OMHz DMSOdo ) δ near, ≠ 2 (l H, d), ta,! F/(lH,d)
, fj r (/H, S), 7.7t (lH, d)
, 7.4CF (lH, t), 7.1e (H, t), LJ
r(/)(,m),j,70−/+0(
//H', m) Example j Production: Add 60% sodium hydride o,ttit to 10@l of N,N-dimethylformamide, and further add l-azabicyclo[co,2.2)octan-3-ol/, 3
θ? Add gradually. After 30 minutes, 3 more at 70”C.
The mixture was heated and stirred for 0 minutes.

2-Methyl-imidazoCI, 2-a) Pyridine-3-carboxylic acid i3 y,N,N'-carbonyldiimidazole/329 to N,N-dimethylformamide ltO,l
In addition, imidazolide was obtained by stirring at 6j'C for 1 hour. To this solution, add the above l-azabicyclo (2
,2,2) A sodium salt solution of octan-3-ol is added dropwise at 70°C, and the mixture is heated and stirred for 5 hours.

The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and concentrated. The remaining crystals were crystallized from ethyl acetate-〇-hexane to obtain the free title compound (melting point: 20-72/T).

By treating this with ethyl acetate containing hydrogen chloride, the title compound was converted to 32? Obtained.

(Melting point 2t7-27θ°C).

'H-NMR(-1F(7MHz DMSO-do
) δ: Ri, Co/(IH, d), 7.7≠(IH, d),
7.57 (tH, t), 7. ,z,z(IH,t),j
o, 2 ta (/H, m), 3
．． 7 Ta ~ 3. /t (7)4.

m), x, +t(3H+s), 2.11 r ~/, A
J (jH, m) Example 2 (±)-≠-amino/-azabicyclo(L3°/)-
Nonane/, j7f, triethylamine 3.12r! 11
was dissolved in 4tO@l of methylene chloride. Comethylimidazo[l,2-a) pyridine-3-carboxylic acid chloride hydrochloride obtained according to the method of Example 3,
It was added gradually under ice cooling.

After 10 minutes, the temperature was brought to room temperature, and the mixture was further stirred for 7 hours, and one portion of the resulting crystals was collected. The crystals were dissolved in water, made alkaline with /N-sodium hydroxide aqueous solution, and then extracted with chloroform. After washing with water, it was dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain crystals, which were crystallized from total ethyl acetate/n-hexane to obtain the free title compound (melting point/3L-116°C).

This was treated with ethanolic hydrogen chloride to give the title compound o,
t and ty were obtained (melting point>300°C).

IH-NMR (Co! OMHz, CD30D)
δ: Ll 3(IH, d), 7. ≠j(/)(,d)
, 7.37 (IH, t), 6.7 t (IH, tL Hiroshi,
Evening 0 (/H, m), 3.1.0-3. ≠O(gH,
m).

x, jr (J H, s), λ, ≠ Kuhachi 7 (7H
.

m) Test Example 7: Compounds were evaluated for antagonism of the 7-on-1 besol-to-year reflex evoked by j-HT in anesthetized rats according to the method described below.

A male rat (2!O~300f) was coated with urethane (/,!?
The animals were anesthetized with (intraperitoneal) injection, and their heart rate was recorded from an electrocardiogram. First, apply an appropriate amount of Yo-HT (usually ≠-6μ2
/#) was administered by intravenous route, and changes in heart rate were measured (A). The compound is then administered intravenously and then j
- An HT-induced response was caused, and changes in the number of heart beats were measured again (B). From these values, the inhibition rate relative to the control response was calculated using the following calculation formula.

The results were as shown in the table.

Table 1

Claims (1)

[Claims] (1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the above formula (I), Y is -O- or ▲There are mathematical formulas, chemical formulas, tables, etc.▼(In the formula, R^3 represents a hydrogen atom or an alkyl group). A has formula (II), (III) or (IV), ▲mathematical formula, chemical formula, table, etc.▼( I
) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) ▲ Mathematical formulas,
There are chemical formulas, tables, etc.▼(IV) (In the formula, n represents an integer from 1 to 5, R^4 is a hydrogen atom,
Indicates an alkyl group, cycloalkyl group or aralkyl group. ) represents a group. R^1 is a hydrogen atom, an alkyl group, a halogen atom, a trifluoromethyl group, a hydroxyl group, an alkoxy group, an amino group, an alkylamino group, a dialkylamino group, an aralkyl group, an aralkyloxy group, a carboxyl group, an alkoxycarbonyl group, or an alkoxy Indicates a carbonyl 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. ] An imidazo[1,2-a]pyridine derivative, an acid addition salt thereof, or a solvate thereof.