JPH0641079A - Pyridine derivative - Google Patents

Abstract

PURPOSE:To provide the new compound exhibiting a low toxicity and useful, e.g. as an antipsychotic agent, an antianxiety agent and a medicine for improving cerebral functions. CONSTITUTION:A compound of formula I [W is H or a lower alkyl ; Y is a lower alkyl; Ar is a (hetero)aryl; R is H or a lower alkyl; R1 is H, a (cyclo) alkyl, a hydroxy(lower)alkyl, etc.; R2 and R3 are each H, a halogen, a lower alkyl, a lower alkoxy, hydroxy, trifluoromethyl, cyano, nitro or amino; R7 and R8 are each H or a lower alkyl; m is 2 or 3], e.g. 2-(4-ethyl-1-piperazinyl)--4-(4- fluorophenyl)-5,6-dimethylpyridine. In addition, the compound of formula I can be obtained by reacting a compound of formula II (X is an eliminable group) with a compound of formula III in the presence of a base such as triethylamine in a solvent such as toluene.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel pyridine derivative having a psychotropic action and a novel drug containing it as an active ingredient.

[0002]

2. Description of the Related Art U.S. Pat. No. 4,469,696 (JP-A-58-58)
No. 963) discloses several types of 2- (1-piperazinyl) -4.
-Arylpyridine derivatives are disclosed as having a lipid absorption inhibitory action. In addition, a pyridine derivative having a piperazinyl group at the 2-position of the pyridine ring and a phenyl group at the 4-position, 2
-[4- (4-Methylbenzyl) -1-piperazinyl]
It has been reported that -4-phenylpyridine has a weak action as an antipsychotic agent or a neuroleptic agent (see US Pat. No. 4,831,034 and JP-A-63-48267).

[0003]

DISCLOSURE OF THE INVENTION As a result of intensive studies of drugs acting on the central nervous system, the present inventors have a remarkable psychotropic effect, and as an antipsychotic agent or anxiolytic agent, further a brain function improving agent. As a result, they have found a pyridine derivative useful as the above and completed the present invention.

[0004]

[Means and Effects for Solving the Problems]

[0005]

[Chemical 2]

[In the formula, W means a hydrogen atom or a lower alkyl group, Y means a lower alkyl group, Ar means an aryl group or a heteroaryl group, and R means a hydrogen atom or a lower alkyl group. R ₁ is a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a lower alkoxy (lower) alkyl group, a cycloalkyl (lower) alkyl group, or an optionally substituted aryl (lower ) Alkyl group, acyloxy (lower) alkyl group, lower alkanoyl (lower) alkyl group, optionally substituted arylcarbonyl (lower) alkyl group, lower alkenyl group, lower alkynyl group, having substituent group be aryl group means a heteroaryl group or an acyl group, R ₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom, a lower Alkyl group, a lower alkoxy group, hydroxy group, trifluoromethyl group, cyano group,
A nitro group or an amino group, R ₇ and R ₈ are the same or different and each represents a hydrogen atom or a lower alkyl group, and m
Means 2 or 3. ] And a physiologically acceptable acid addition salt thereof and a psychotropic agent containing these compounds as active ingredients.

Physiologically acceptable acid addition salts of the compound represented by Chemical formula 2 include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate. And organic acid salts such as maleate, fumarate, oxalate, citrate, tartrate, lactate, benzoate and methanesulfonate. Since the compounds of Chemical formula 2 and their acid addition salts may exist in the form of hydrates, these hydrates are also included in the compounds of the present invention.

When the compound represented by Chemical formula 2 has an asymmetric carbon atom, at least two types of stereoisomers may exist. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are explained below.
Unless otherwise specified, "lower" has 1 to 6 carbon atoms.
Means The alkyl group, lower alkyl group or lower alkyl moiety, or lower alkylene group may be linear or branched. "Alkyl group" has 1 to 1 carbon atoms
0 means, specific examples include methyl, ethyl, n
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-
Octyl, n-nonyl, n-decyl and the like can be mentioned.
Specific examples of the "lower alkylene group" include methylene, ethylene, trimethylene, propylene, tetramethylene and the like.

"Halogen atom" means fluorine, chlorine, bromine and iodine. Specific examples of "lower alkoxy group" or lower alkoxy moiety include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy and the like can be mentioned. The “cycloalkyl group” or the cycloalkyl moiety means one having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

"Hydroxy (lower) alkyl group" means
It means a lower alkyl group substituted by a hydroxy group, and specific examples include 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-
Examples thereof include dihydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl and the like. The "lower alkoxy (lower) alkyl group" means a lower alkyl group substituted by a lower alkoxy group, and specific examples include 2
-Methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2,3-dimethoxypropyl, 4-methoxybutyl, 2-methoxybutyl and the like can be mentioned. “Cycloalkyl (lower) alkyl group” means a lower alkyl group substituted by a cycloalkyl group, for example, cyclopropylmethyl, cyclopentylmethyl, 2
-Cyclohexylethyl and the like can be mentioned. The "lower alkanoyl (lower) alkyl group" means a lower alkyl group substituted by an alkanoyl group having 2 to 6 carbon atoms, and examples thereof include acetylmethyl, 2-acetylethyl, 2-propionylethyl and the like. .

The "lower alkenyl group" means a double bond of 1
~ 2 having 3 to 6 carbon atoms, and examples thereof include allyl and 2-butenyl. The "lower alkynyl group" means one having a triple bond and having 3 to 6 carbon atoms, and examples thereof include propargyl and the like.

Specific examples of the "aryl group" or aryl moiety include phenyl, naphthyl and the like. The “heteroaryl group” or heteroaryl moiety means a monocyclic or bicyclic group containing at least one nitrogen atom, oxygen atom or sulfur atom, and is, for example, furyl, thienyl, pyridyl, pyrimidinyl, isoquinolyl and the like. Can be mentioned. The "aryl group which may have a substituent" or the aryl moiety which may have a substituent means that the aryl moiety is unsubstituted or one or two halogen atoms, a lower alkyl group or a hydroxy group. , A lower alkoxy group, a trifluoromethyl group, a cyano group, a nitro group or an amino group is substituted, for example, phenyl, 2-,
3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2,3-, 2,4-, 2,5-, 2,6
-Or 3,4-difluorophenyl, 2-, 3- or 4
-Methylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl and the like can be mentioned.

The "optionally substituted aryl (lower) alkyl group" means a lower alkyl group substituted by the above-mentioned optionally substituted aryl group, for example, benzyl. , 2-, 3- or 4-fluorobenzyl, 2-, 3- or 4-chlorobenzyl, 2,3
-, 2,4-, 2,5-, 2,6- or 3,4-difluorobenzyl, 2-, 3- or 4-methylbenzyl, 2
-, 3- or 4-methoxybenzyl, 2-, 3- or 4
-Trifluoromethylbenzyl and the like can be mentioned. The "arylcarbonyl (lower) alkyl group optionally having substituent (s)" is a lower alkyl group in which the aryl moiety is substituted with the arylcarbonyl group which is the above-mentioned aryl moiety optionally having substituent (s). Means 2-benzoylethyl, 3- (4-fluorobenzoyl) propyl and the like.

The "acyl group" or the acyl moiety is a lower alkanoyl group, a cycloalkanecarbonyl group, a benzoyl group optionally substituted with halogen, lower alkyl or lower alkoxy, or a heteroaryl moiety which is the same as the above-mentioned heteroaryl. A heteroarylcarbonyl group, for example acetyl, propionyl,
Examples thereof include cyclohexanecarbonyl, benzoyl, 4-fluorobenzoyl, nicotinoyl, isonicotinoyl, furoyl and thenoyl. "Acyloxy (lower)
The "alkyl group" means a lower alkyl group in which an acyl moiety is substituted with an acyloxy group which is the above-mentioned acyl moiety, and specific examples thereof include 2-acetoxyethyl, 2-benzoyloxyethyl and the like.

The compound of the present invention can be produced, for example, by the following method.

(1) The compound of Chemical formula 2 of the present invention is

[Chemical 3]

(Wherein X represents a leaving atom or a leaving group, and W, Y, Ar, R, R ₂ and R ₃ have the same meanings as described above) and the following. Conversion 4

[0019]

[Chemical 4]

It can be produced by reacting with a compound represented by the formula (wherein R ₁ , R ₇ , R ₈ and m have the same meanings as described above).

The leaving atom or leaving group represented by X in the chemical formula 3 means an atom or a group which can be eliminated in the form of HX together with the hydrogen atom of the NH moiety of the compound of the chemical formula 4 under reaction conditions,
For example, halogen atom such as chlorine, bromine and iodine, lower alkylthio group such as methylthio and ethylthio, lower alkylsulfonyl group such as methanesulfonyloxy, lower alkylsulfonyloxy group such as methanesulfonyloxy, benzenesulfonyloxy, p- Arylsulfonyloxy groups such as toluenesulfonyloxy are mentioned.

The reaction between the compound represented by Chemical formula 3 and the compound represented by Chemical formula 4 is carried out without solvent or in a suitable solvent under normal pressure or increased pressure.

Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ketones such as methyl ethyl ketone, ethers such as dioxane and diglyme, alcohols such as ethanol, isopropyl alcohol and butanol, Examples thereof include N, N-dimethylformamide and dimethyl sulfoxide. This reaction is preferably carried out in the presence of a base, and specific examples of the base include:
Alkali carbonate such as sodium carbonate, potassium carbonate,
Examples thereof include alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, and tertiary amines such as triethylamine, but an excess amount of the compound represented by Chemical formula 4 can be used. When the compound represented by Chemical formula 4 exists in the form of a hydrate, it can be used in that form. The reaction temperature is usually 40 to 200 ° C. The compound of Chemical formula 3 is the reference example 1.
It can be manufactured by the method shown in to 8 or a method similar thereto.

(2) The compound of Chemical formula 2 in which R ₁ is a hydrogen atom is

[Chemical 5]

(In the formula, R ₁₄ represents a benzyl group or a benzyloxycarbonyl group in which a phenyl moiety may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom, and W, Y, Ar, R, R ₂ , R ₃ , R ₇ ,
R ₈ and m mean the same as above. It can be produced by hydrogenolysis of the compound represented by the formula (1).

The hydrogenolysis of the compound represented by Chemical formula 5 can be carried out by a conventional method, for example, by using an alcohol such as ethanol as a solvent and carrying out catalytic reduction at room temperature and atmospheric pressure. The compound of the present invention represented by Chemical formula 5 may be the compound of Chemical formula 5 wherein R ₁₄ is a benzyloxycarbonyl group, wherein R ₁₄ may be a methyl group or a substituted group. It can be obtained by a conventional method from the compound of Chemical formula 2 which is a benzyl group.

(3) The compound of the present invention wherein R ₁ is a hydrogen atom.
The compound of

[Chemical 6]

(In the formula, R ₁₅ is an ethoxycarbonyl group, 1
-Means a chloroethoxycarbonyl group or an acyl group,
W, Y, Ar, R, R ₂ , R ₃ , R ₇ , R ₈ and m have the same meanings as described above. It can also be produced by hydrolyzing the compound represented by the formula (1).

Hydrolysis of the compound represented by Chemical formula 6 is carried out by a conventional method, for example, using a suitable solvent such as ethanol miscible with water, a base such as sodium hydroxide or potassium hydroxide, or an acid such as hydrochloric acid or sulfuric acid. It can be carried out by usually heating in the presence of. The compound of Chemical formula 6 in which R ₁₅ is a 1-chloroethoxycarbonyl group can also be converted to the compound of chemical formula 2 in which R ₁ is a hydrogen atom by heating in, for example, methanol. In the compound in which R ₁₅ is an ethoxycarbonyl group or a 1-chloroethoxycarbonyl group in Chemical formula 6, R ₁₅ is a methyl group or a benzyl group in which a phenyl moiety may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom. A compound of chemical formula 2,
It can be obtained by reacting the corresponding chloroformate with a conventional method. The compound in which R ₁₅ is an acyl group in Chemical formula 6 can be obtained by the production method of (1) above.

(4) The compound of the present invention in which R _{1 in} the chemical formula 2 is a group other than a hydrogen atom, an aryl group which may have a substituent, a heteroaryl group and an acyl group is represented by the following chemical formula 7

[Chemical 7]

(Wherein W, Y, Ar, R, R ₂ , R ₃ ,
R ₇ , R ₈ and m have the same meanings as above. ) Compound represented by

[Chemical 8] R ₁₆ -Z

(Wherein Z represents a reactive ester residue of alcohol, R ₁₆ represents a hydrogen atom, an aryl group which may have a substituent, a heteroaryl group, or an R ₁ group other than the acyl group described above. Which means the same as the above).

Examples of the reactive ester residue of alcohol represented by Z in the above chemical formula 8 include halogen atom such as chlorine, bromine and iodine, lower alkylsulfonyloxy group such as methanesulfonyloxy, benzenesulfonyloxy, Arylsulfonyloxy groups such as p-toluenesulfonyloxy are mentioned.

The reaction between the compound represented by Chemical formula 7 and the compound represented by Chemical formula 8 is usually carried out in a suitable solvent. Specific examples of the solvent include aromatic hydrocarbons such as benzene and xylene. And ketones such as methyl ethyl ketone, ethers such as dioxane, and N, N-dimethylformamide. This reaction is preferably carried out in the presence of a base, and specific examples of the base include the specific examples described in the above-mentioned production method (1) as they are. The reaction temperature is usually 30 to 150 ° C.

The compounds represented by the chemical formula 7 are the above (1) to
It can be obtained by the production method (3).

The compound of the present invention represented by Chemical formula 2 produced by each of the above-mentioned production methods is isolated and purified by a conventional method.

The compound of the present invention represented by the chemical formula 2 can be obtained in the form of a free base, an acid addition salt or a hydrate depending on the selection of starting compounds, reaction and treatment conditions and the like. Acid addition salt is a conventional method,
It can be converted to the free base by treatment with a base such as alkali hydroxide. On the other hand, the free base can be converted into an acid addition salt by treating it with various acids according to a conventional method.

The compound of the present invention represented by the chemical formula 2 and its physiologically acceptable acid addition salts have the following effects: exploratory behavior inhibitory action, apomorphine-induced emesis inhibitory action, dopamine D ₂ or serotonin S ₂ receptor binding action, Since it exhibits an action of increasing monoamine metabolites in the brain and has low toxicity, it is useful as an antipsychotic agent or anxiolytic agent. Furthermore, it shows an excellent improving effect in various memory impairment model experiments, and is useful as a brain function improving agent for various functional disorders in the central nervous system.

The results of pharmacological experiments on the representative compounds of the present invention are shown below to clarify the usefulness of the compounds of the present invention.

EXPERIMENTAL EXAMPLE 1 Inhibitory Behavior Inhibitory Action—5 male Std-ddY mice each weighing 20 to 25 g were used in each group. The test compound suspended in 0.5% tragacanth was orally administered (10 mg / kg), and after 2 hours, one mouse was placed on each Animex motility measuring device (Farad) in a measuring cage (23 × 35 × 30).
cm) and the amount of exploratory activity for 3 minutes was measured. The average value of the exploratory activity amount (count / 3 minutes) of the test compound administration group was calculated and compared with that of the control group to calculate the inhibition rate. The inhibition rate of the compound of Example 5 was 88.5%.

Test Example 2 Inhibitory effect of apomorphine on vomiting--Using 3 to 4 beagle dogs (8-15 kg) per group, the antagonistic effect of the test compound on apomorphine-induced vomiting was examined. This test is commonly used as a method for detecting antipsychotic agents. Two hours after oral administration of the test compound, apomorphine hydrochloride (0.3 mg / kg) was subcutaneously administered to the back,
After that, the number of vomiting for 1 hour was counted. The suppression rate was calculated by comparing the vomiting frequency of the test compound administration group with that of the control group.
The inhibition rate of the compound of Example 3 was 100% at the dose of 3.0 mg / kg.
Met.

Test Example 3 Dopamine D ₂ , Serotonin S ₁ , S ₂ and Adrenergic α ₁ Receptor Binding Action (in v
itro receptor binding assay) -I. Creese et al. [Eur. J. Pharmacol., 46, 377 (1977)], SJ Peroutka et al. [Mol. Pharmacol., 16, 687].
(1979)], JE Leysen et al. [Mol. Pharmacol., 2
1, 301 (1982)] and DC U'Prichard et al. [Mol.
Pharmacol., 13,454 (1977)],
Dopamine D ₂ , serotonin S ₁ , S ₂ and adrenergic α ₁ receptor binding tests were carried out, respectively.

Crude synaptosome membrane fraction prepared from rat brain as a receptor specimen, and as a labeled ligand,
[ ³ H] spiperone (D ₂ ), [ ³ H] serotonin (S ₁ ),
[ ³ H] Ketanserin (S ₂ ) and [ ³ H] WB-4101 (α
₁ ) was used. After incubating the receptor sample and the buffer solution containing each labeled ligand (final volume 1 ml) for a certain period of time in the presence of various concentrations of test compounds, the radioligand bound to the receptor was applied to the cell harvester (Brandell). Used to separate on a filter. The radioactivity on the filter was measured with a liquid scintillation counter to determine the total amount bound. In addition, the amount of binding in the presence of unlabeled ligands [spiperone (D ₂ ), serotonin (S ₁ ), methysergide (S ₂ ) and prazosin (α ₁ )] measured at the same time was defined as the nonspecific binding amount, and this was determined as The specific binding amount was determined by subtracting from the total binding amount. The concentration at which the test compound inhibits the specific binding of the labeled ligand by 50% (IC
₅₀ values) were calculated by the probit method.

IC ₅₀ of the compound of Example 3 for dopamine D ₂ , serotonin S ₂ and adrenergic α ₁ receptors
The values were 16, 27 and 5.4 nM, respectively.

Test Example 4 Intracranial monoamine metabolite increasing action: Using 5 male Std-ddY mice (25 to 30 g) per group, the increasing action of a test compound on a monoamine metabolite in the brain was examined.
This effect is believed to primarily represent the degree of receptor inhibition of each monoamine.

Two hours after oral administration of the test compound, the brain was removed, homogenized with 1N formic acid-acetone, and then cooled,
The solution was spun down to obtain a supernatant. This was evaporated to dryness with nitrogen gas, dissolved in 0.01N acetic acid, and subjected to high-performance liquid chromatography with an electrochemical detector, which was a metabolite of dopamine 3,
4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), which is a metabolite of noradrenaline, and 5- which is a serotonin metabolite.
The hydroxyindole-3-acetic acid (5-HIAA) concentration was measured. The% increase of each monoamine metabolite with the test compound (control = 100) was calculated and is shown in Table 1.

[0047]

[Table 1]

Test Example 5 Acute toxicity--Using 5 Std-ddY strain male mice (25 to 30 g) per group, 0.
Test compound 500 dissolved or suspended in 5% tragacanth solution 500
Orally administrated mg / kg, and observed death for 7 days after administration. As a result, in the compound-administered group of Example 3, all the patients survived even after 7 days.

The route of administration of the compound of the present invention may be oral administration, parenteral administration or rectal administration, but oral administration is preferred. The dose varies depending on the type of compound, administration method, patient's symptoms and age, etc., but is usually 0.01
-50 mg / kg / day, preferably 0.01-5 mg / kg / day. The compound of the present invention is usually administered in the form of preparation prepared by mixing with a carrier for preparation. As the carrier for formulation, a substance which is commonly used in the field of formulation and which does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, sorbitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl cellulose calcium, ion Exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, veegum, Carboxy vinyl polymer, titanium oxide, sorbitan fatty acid ester, lauryl sulfur Sodium, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oils, waxes, propylene glycol, water and the like.

Examples of the dosage form include tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections and suppositories. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. The tablets, granules and fine granules may be coated by a known method. In the case of an injectable preparation, it is prepared by dissolving the compound of the present invention in water, but it may be dissolved in physiological saline or glucose solution, if necessary, and a buffer or a preservative may be added. Good. These formulations may also contain other therapeutically valuable ingredients.

[0051]

EXAMPLES In order to describe the present invention more specifically, reference examples and examples will be given below, but the present invention is not limited to these examples. The compounds were identified by elemental analysis, mass spectrum, IR spectrum, UV spectrum, NMR spectrum and the like. In addition, the following abbreviations may be used for simplification of description in the following Reference Examples and Examples.

Me: methyl group, Et: ethyl group, Pr: n-propyl group, A: ethanol, E: diethyl ether, HX: hexane, IP: isopropyl alcohol, M: methanol.

Reference Example 1 --- 4- (4-Fluorophenyl) -5,6-dimethyl-2
Preparation of (1H) -pyridinone: 4-fluorobenzoylacetonitrile 22.3 g, 2-
Add a mixture of 80 ml butanone and 200 g 75% polyphosphoric acid.
Stir at 70 ° C for 30 minutes and 120 ° C for 1 hour. After cooling, the reaction solution is poured into ice water, 300 ml of diethyl ether is added, the mixture is stirred, and the precipitated crystals are collected by filtration and washed with water and then methanol. Recrystallize from methanol to obtain 21.8 g of the desired product. Melting point 290 ℃

Reference Examples 2 to 4 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the compounds shown in Table 2.

[0055]

[Table 2]

Reference Example 5 --- 2-chloro-4- (4-fluorophenyl) -5,6-
Preparation of dimethylpyridine: 4- (4-fluorophenyl) -5,6-dimethyl-2
A mixture of 21.5 g of (1H) -pyridinone and 78 g of phenylphosphonic dichloride is stirred at 170 ° C. for 3 hours. After cooling
The reaction solution is dissolved in chloroform and gradually added dropwise to stirring ice water. After gradually adding potassium carbonate to make it basic, the organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Subject to silica gel column chromatography, collect the eluate with chloroform and recrystallize from chloroform-n-hexane to obtain 18.8 g of the desired product.
To get Melting point 78-79 ° C

Reference Examples 6 to 8 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 5 to obtain the compounds shown in Table 3.

[0058]

[Table 3]

Example 1 Preparation of 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6-dimethylpyridine:
--2-chloro-4- (4-fluorophenyl) -5,6-
Dimethylpyridine 3.4 g, N-ethylpiperazine 8.2 g
And 2.4 g of potassium iodide are stirred at 170 ° C. for 14 hours. After cooling, water is added to the reaction solution and extracted with chloroform. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residual oily substance was subjected to silica gel column chromatography, and chloroform-methanol (20:
The fractions eluted in 1) are collected, made into a fumarate with a methanol solution of fumaric acid, and then recrystallized from methanol-ethanol to obtain 1.5 g of a target fumarate. Melting point 218〜
220 ° C

Examples 2 to 6 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the compounds shown in Table 4.

[0061]

[Table 4]

Example 7 Preparation of 2- (4-benzyl-1-piperazinyl) -6-methyl-4-phenylpyridine: Using the corresponding starting compound, reaction and treatment were carried out in the same manner as in Example 1, and ethanol was used. The desired maleate salt is obtained by recrystallization from the above. Melting point 168-171 ° C (ethanol)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical indication location // A61K 31/495 AAN 31/55 AAE AAM ABU (72) Inventor Mako Oka Taka Ibaraki, Osaka 17-26, Tamachi (72) Kiyoshi Furukawa, 2-12-4, Onomizuaki, Shiga-machi, Shiga-gun, Shiga Prefecture (72) 4--7, Fujigaoka, Sanda-shi, Hyogo Prefecture

Claims (1)

[Claims] 1. A pyridine derivative represented by Chemical formula 1 or a physiologically acceptable acid addition salt thereof. [Chemical 1] [Wherein W represents a hydrogen atom or a lower alkyl group, and Y represents
Means a lower alkyl group, Ar means an aryl group or a heteroaryl group, R means a hydrogen atom or a lower alkyl group, and R ₁ is a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group. Group, lower alkoxy (lower) alkyl group, cycloalkyl (lower) alkyl group, optionally substituted aryl (lower) alkyl group, acyloxy (lower) alkyl group, lower alkanoyl (lower) alkyl group, substituted Means an arylcarbonyl (lower) alkyl group which may have a group, a lower alkenyl group, a lower alkynyl group, an aryl group which may have a substituent, a heteroaryl group or an acyl group, R
₂ and R ₃ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a trifluoromethyl group, a cyano group, a nitro group or an amino group, and R ₇ and R ₈ are the same. Or, differently, it means a hydrogen atom or a lower alkyl group, and m means 2 or 3. ]