JPH1072439A - Pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new pyridine derivative selectively acting on a peripheral- type benzodiazepine receptor. SOLUTION: This new pyridine derivative is shown by formula I [X is O or NR4 ; R1 is H, an alkyl, etc.; R2 is an alkyl, a cloalkyl or a (substituted) phenyl; R. and R. are each H or a lower alkyl; R5 and R6 are each H, a lower alkyl, etc.; A is a (substituted) phenyl or (substituted) heteroaryl], e.g. N-(4- chlorophenyl)-N-methyl-2 (2,3-dimethyl-6-phenyl-4-pyridyloxy)acetamide. The compound of formula I in which is NR4 is obtained by reaction of a compound of formula II (Z is an eliminable group) with a compound of formula III under normal or a higher pressure in the presence of a base such as sodium carbonate. This new compound is useful as a preventive or therapeutic agent for anxiety- related diseases, depression, central diseases such as epilepsy, and ctirculatory diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel pyridine derivative which selectively acts on a peripheral benzodiazepine receptor, more specifically, a 2-aminoacetic acid amide moiety or a 2-oxyacetic acid amide moiety at the 4-position of the pyridine ring, The present invention relates to a pyridine derivative having a phenyl group or a heteroaryl group at the 2-position (or 6-position) of a pyridine ring.

[0002]

BACKGROUND OF THE INVENTION The central nervous system of mammals, including humans, has three
There are three benzodiazepine (hereinafter sometimes abbreviated as “BZ”) recognition sites, each of which has a “central type (ω ₁ , ω
₂₎ "and" peripheral-type (omega ₃₎ "is referred to as benzodiazepine receptor (hereinafter, respectively" BZomega ₁ receptor ",
"BZomega ₂ receptor" and also referred to as "BZomega ₃ receptor"). Among them, peripheral BZ receptors show ubiquitous distribution (kidney, liver, heart, etc.) in peripheral tissues and organs, and especially endocrine organs such as adrenal glands and testes, mast cells, lymphocytes, macrophages, platelets Recently, since it is present in high density in cells deeply involved in the inflammation immune system,
Interest in its physiological role is growing. On the other hand, in the brain, it is abundant in the mitochondrial membrane of glial cells and is involved in the uptake of cholesterol into the mitochondrial membrane. It is thought to affect the biosynthetic pathway. Therefore, stimulation of peripheral BZ receptors promotes neurosteroid production in the brain,
γ-aminobutyric acid (hereinafter sometimes abbreviated as “GABA”) is thought to affect the Cl ion channel opening process via a binding mechanism to a neurosteroid-specific recognition site present in a receptor. [Romeo, E. et al.
J. Pharmacol. Exp. Ther., 262 , 971-978 (1992)].

A compound having a non-BZ skeleton and selectively exhibiting affinity for a peripheral BZ receptor is disclosed in JP-A-58-20.
Since it was reported in 1756, a considerable number has been reported in patent applications and the like. However, none of the compounds have been put to practical use as pharmaceuticals.

[0004] The following compounds are known as compounds having a non-BZ skeleton and exhibiting selective affinity for peripheral BZ receptors.

Japanese Patent Application Laid-Open No. Sho 62-5946 discloses that amides represented by the following formula (2) bind to peripheral BZ receptors,
It is described as being useful as an anxiolytic, antispasmodic and antianginal, and a therapeutic agent for immunodeficiency symptoms.

[0006]

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In the above chemical formula 2, A is a nitrogen atom or ＣC
The H-, B is a nitrogen atom or = CH-, Z is attached at the ortho or para position relative to B, phenyl, thienyl, pyridyl and the like, chain _{-X- (CH 2) n- (CHR} )
m-CONR ₁ R ₂ is bonded at the ortho or para position with respect to B, and X represents —NR ₄ —, oxygen, sulfur and the like (the definition of other substituents is omitted).

JP-A-2-32058 discloses that 4-amino-3-carboxyquinolines represented by the following formula 3 have an affinity for peripheral BZ receptor in vitro and in vivo, and It is stated that it can be used as a prophylaxis and treatment of vascular diseases, or as an antiallergic agent, and for the prevention or treatment of infectious symptoms, or the treatment of anxiety symptoms.

[0009]

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In the above chemical formula 1, one of the symbols A, B, C and D is N, the other is CH, or A, B, C and D are each CH, R ₁₀ is hydrogen, C ₁ -C ₄ (Phenyl is optionally substituted with halogen, C ₁ -C ₃ alkoxy, alkyl or thioalkyl, nitro, trifluoromethyl or hydroxy) (the definition of other substituents is omitted) .

[0011]

SUMMARY OF THE INVENTION The present inventors have found that BZω
As a result of intensive studies to obtain compounds that act selectively and strongly on the _three receptors, they have found that the pyridine derivative represented by the formula (I) described below meets this purpose, and have completed the present invention.

[0012]

According to the present invention, there are provided a pyridine derivative represented by the following formula (I) and a physiologically acceptable acid addition salt thereof.

[0013]

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[Wherein, X represents —O— or —NR ₄ —, R ₁ represents a hydrogen atom, an alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl group, and R ₂ represents an alkyl group. , A cycloalkyl group or an unsubstituted or substituted phenyl group; R ₃ and R ₄ are the same or different and each represent a hydrogen atom or a lower alkyl group;
₅ and R ₆ may be the same or different and each represent a hydrogen atom or a lower alkyl group, or R ₅ and R ₆ may together form-(CH ₂ ) n-, wherein n represents 3, 4, 5 or 6, and A represents an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group. ]

The physiologically acceptable acid addition salts of the compounds of the formula (I) are defined as the physiologically acceptable acid addition salts of the compounds of the formula (I) when they have a basicity sufficient to form an acid addition salt. And the like; for example, inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate and phosphate, and maleate, fumarate and oxalic acid Organic salts such as salt, citrate, tartrate, lactate, benzoate, methanesulfonate and the like can be mentioned. Since the compound represented by the formula (I) and the acid addition salt thereof may exist in the form of a hydrate and / or a solvate, these hydrates and solvates are also included in the compound of the present invention. Is done.

The compounds of the formula (I) optionally have one or more asymmetric carbon atoms and can give rise to geometric isomerism. Thus, the compounds of formula (I) may optionally exist in more than one stereoisomeric form. These stereoisomers,
The mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are described below.

"Alkyl group" means a group having 1 to 10 carbon atoms unless otherwise specified, and may be linear or branched. The lower alkyl group and the lower alkyl moiety mean those having 1 to 6 carbon atoms unless otherwise specified, and may be linear or branched. Specific examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. As the lower alkyl group for R ₃ , R ₄ , R ₅ and R ₆ , those having 1 to 4 carbon atoms are preferred. Specific examples of the “lower alkoxy group” include methoxy, ethoxy, propoxy and butoxy.
The "lower alkenyl group" means a group having 3 to 6 carbon atoms having one double bond other than between the 1-2 position, and examples include allyl and 2-butenyl. "Cycloalkyl group" means a group having 3 to 8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl and cyclooctyl are mentioned. The “cycloalkyl (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted by the above “cycloalkyl group”, and examples thereof include cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl. "Halogen atom" means fluorine, chlorine,
It means bromine and iodine.

"Unsubstituted or substituted phenyl group"
Substituted with one or two selected from a halogen atom, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, trifluoromethyl, amino, mono- or di (C ₁ -C ₃ ) alkylamino, cyano and nitro Phenyl; 2-, 3- or 4-chlorophenyl; 2-, 3- or 4-bromophenyl;
2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl; 2
-, 3- or 4-methoxyphenyl; 2-, 3- or 4
2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-dimethylaminophenyl; 2
-, 3- or 4-cyanophenyl; 2-, 3- or 4-
Nitrophenyl. Preferred specific examples of "unsubstituted or substituted phenyl group" include phenyl, 4- or 3-chlorophenyl, 4- or 3-bromophenyl,
4- or 3-fluorophenyl and 4-methoxyphenyl can be mentioned.

"Unsubstituted or substituted heteroaryl group"
Is a 5- to 6-membered monocyclic heteroaryl group containing at least one nitrogen atom, oxygen atom or sulfur atom which may be substituted by C ₁ -C ₃ alkyl or trifluoromethyl, or 5 A 6-membered to 6-membered bicyclic heteroaryl group, such as 2-, 3- or 4-pyridyl; 5-methyl-2-pyridyl; 2- or 3-thienyl; 2- or 3-furyl; 2-methyl-3-furyl; 2
2- or 3-pyrazinyl; 1-pyrazolyl; 2-imidazolyl; 2-thiazolyl; 2-isoxazolyl; 5-methyl-3-isoxazolyl; quinolyl; isoquinolyl.

Preferred among the compounds of the present invention are those wherein R ₁ is a lower alkyl group, R ₂ is a lower alkyl group or an unsubstituted or substituted phenyl group in the formula (I), and R ₃ , R ₅ , R ₆ , A and X are the same as described above, and physiologically acceptable acid addition salts thereof.

More preferred compounds of the present invention are those wherein R ₁ is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group in the formula (I), and R ₂ is a propyl group, an isopropyl group, A butyl group, a phenyl group or a phenyl group substituted with halogen or methoxy, R ₃ is a hydrogen atom, R ₅ is a methyl group, an ethyl group or a hydroxymethyl group, and R ₆ is a methyl group or an ethyl group. Or R ₅ and R ₆ together-
(CH ₂ ) ₄ —, wherein A is a phenyl group or a phenyl group substituted with halogen or methoxy,
X is the same compound as described above, and a physiologically acceptable acid addition salt thereof.

As specific examples of the compounds included in the present invention,
In addition to the compounds of the Examples described later, the compounds of Tables 1 and 2 represented by the following formula 5 and physiologically acceptable acid addition salts thereof can be mentioned.

The following abbreviations may be used in Tables 1 and 2 of the present specification, and in the following Reference Examples and Examples for the sake of simplicity.

Me: methyl group, Et: ethyl group, Pr: propyl group, i-Pr: isopropyl group, Bu: butyl group, Hex: hexyl group, Ph: phenyl group, CH _2- △: cyclopropylmethyl group.

Thus, for example, Ph-4-Cl represents a 4-chlorophenyl group, and 3-furyl-2-Me represents a 2-methyl-3-furyl group.

[0027]

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[0028]

[Table 1] _{━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ R 1 R 2 R 5 R} 6 A X ━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━ Et Et Me Me Ph-4-Cl NH Pr Pr Me Me Ph-4-Cl NH Pr Pr Me Me Ph- 4-OMe NH Pr Pr Me Me Ph-4-Cl NMe i-Pr i-Pr Me Me Ph NH Bu Bu Me Me Ph-3-Cl NH Bu Bu Me Me Ph-4-F NH Me Ph Me Me Ph- 4-Cl NH Me Ph Me Me Ph-4-OMe NH Me Ph-2-Cl Me Me Ph NH Me Ph-4-F Me Me Ph NH Me Ph-2-F Me Me Ph NH Et Ph Me Me Ph- 4-Cl NH Et Ph-4-Cl Me Me Ph NH ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0029]

[Table 2] Table 1 continued _{━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ R 1 R 2 R 5 R} 6 A X ━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Pr Pr Me Me 4-poly NH Pr Pr Me Me 2-thienyl NH Pr Pr Me Me 3- Ruffle NH Pr Pr H Me Ph NH Pr Pr Me H Ph NH Pr Pr Et Me Ph NH CH ₂ CH = CH ₂ Ph Me Me Ph NH CH _2- △ Ph Me Me Ph-4-OMe NH Et Et Me Me Ph- 4-Cl O Pr Pr Me Me Ph-4-Cl O Pr Pr Me Me Ph-4-OMe O Pr Pr H Me Ph NH Pr Pr Me H Ph NH Pr Pr Et Me Ph NH Pr Pr-(CH ₂ ) ₃ -Ph NH Pr Pr-(CH ₂ ) ₃ -Ph-4-Cl O Me Ph-(CH ₂ ) ₅ -Ph-4-Cl NH Me Ph-(CH ₂ ) ₅ -Ph-4-OMe O Me Ph -(CH ₂ ) ₆ -Ph NH Me Ph-(CH ₂ ) ₆ -Ph-4-Cl O ━━━━━━━━━━━━━━━━━━━━━━━━━━ ━━━━

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

Production method (a) : In the formula (I), X is-
The compound represented by NR ₄ — is represented by the following formula (II)

[0032]

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(Wherein, Z represents a leaving atom or a leaving group, and R ₆ , R ₅ and A have the same meanings as described above.)

And a compound represented by the following formula (III):

[0035]

Embedded image HN (R ₄ ) -CH (R ₃ ) -CON (R ₁ ) (R ₂ ) (III)

(In the formula, R ₁ , R ₂ , R ₃ and R ₄ mean the same as described above.)

The compound can be produced by reacting with a compound represented by the following formula:

The leaving atom or leaving group represented by Z in the formula (II) is an atom or group capable of leaving in the form of HZ together with a hydrogen atom in the NH moiety of the compound of the formula (III) under the reaction conditions. A halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyl And arylsulfonyloxy groups such as oxy.

The reaction between the compound represented by the formula (II) and the compound represented by the formula (III) is carried out at normal pressure or under pressure in the absence of a solvent or in a suitable solvent.

Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene; ketones such as methyl ethyl ketone and methyl isobutyl ketone; dioxane;
Examples include ethers such as diglyme, alcohols such as ethanol, isopropanol and butanol, acetonitrile, dimethylformamide, and dimethylsulfoxide. This reaction is preferably performed in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and tribasic amines such as triethylamine. Triamines can be mentioned, but they can also serve as excess of the compound of the formula (III). The reaction temperature varies depending on the type of the starting compound, the reaction conditions, etc., but is usually about 40 to
At about 200 ° C, preferably from about 100 ° C to about 170 ° C.

The starting compound (II) can be produced by a method known per se, for example, the method described in JP-A-7-196647 and the method described in Reference Example 7 below, or a method analogous thereto.

The compound of the formula (III), which is the other starting compound in the present production method, can be prepared by a method known per se, for example, the method described in JP-A-2-32058 and Reference Example 14 below, or a method analogous thereto. Can be manufactured.

Production method (b) : In the formula (I), X is-
The compound represented by O- is represented by the following formula (IV)

[0044]

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(Wherein R ₅ , R ₆ and A have the same meanings as described above) and the following formula (V)

[0046]

Embedded image Z ₁ —CH (R ₃ ) —CON (R ₁ ) (R ₂ ) (V)

(Wherein Z ₁ represents a halogen atom;
₁ , R ₂ and R ₃ have the same meanings as described above. )

The compound can be produced by reacting with a compound represented by the following formula:

The reaction of the compound of the formula (IV) with the compound of the formula (V) can be carried out in the presence of a base, without a solvent or in a suitable solvent under normal pressure or pressure. As the solvent used, for example, toluene, xylene, dimethoxyethane,
1,2-dichloroethane, acetone, methyl ethyl ketone, dioxane, diglyme, ethyl acetate, dimethylformamide, dimethyl sulfoxide. Examples of the base include sodium hydride, triethylamine, potassium carbonate, and sodium carbonate. The reaction temperature is usually about -10 ° C to about 150 ° C, preferably about 10 ° C to about 70 ° C.

The starting compound (IV) can be produced by a method known per se, for example, the method described in JP-A-7-196647 and Reference Example 1 described below, or a method analogous thereto.

The compound of the formula (V) can be produced by a method known per se, for example, the method described in JP-A-62-64 and Reference Example 11 described later, or a method analogous thereto.

The product obtained by each of the above-mentioned production methods is isolated by a conventional method such as chromatography, recrystallization and reprecipitation.
It can be purified. The compound of the formula (I) having a sufficient basicity to form an acid addition salt can be converted into an acid addition salt by treating with a variety of acids according to a conventional method.

Various stereoisomers of the compound of the formula (I) can be separated and purified according to a conventional method such as chromatography. The test results of representative compounds of the present invention are shown below, and the characteristics of the pharmacological action of the compounds of the present invention will be described.

Test Example 1 Central (ω ₁ , ω ₂ ) and peripheral (ω ₃ ) benzodiazepine receptor binding test

[0055] Preparation of BZomega ₁ and omega ₂ receptor binding assay and receptor membrane preparation is, Stephens, a method of DN et al [J. Pha
rmacol. Exp. Ther., 253 , 334-343 (1990) conforms to], the preparation of BZomega ₃ receptor binding assay and receptor membrane preparation is, Schoemaker, method H [J. Pharmacol. Exp. The
r., 225 , 61-69 (1983)].

Receptor membrane preparations were prepared from the cerebellum, spinal cord or kidney of 7- to 8-week-old male Wistar rats by the following procedures.

To the cerebellum or spinal cord, a 20-fold volume of ice-cold buffer (50 mM Tris-citrate buffer, pH 7.1) was added and homogenized, followed by centrifugation at 40,000 g for 15 minutes. The obtained sediment was washed four times by the same operation, and then stored frozen at -60 ° C for 24 hours. After the frozen sediment was thawed, the precipitate obtained by washing and centrifugation with a buffer was centrifuged, and the sediment obtained was subjected to a binding test buffer I (50 mM Tris-HCl buffer containing 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, pH 7.
4) (1 g tissue wet weight / 40 ml) suspended in BZω ₁
Or used in binding experiments as omega ₂ receptor membrane preparation. On the other hand, 20 times the volume of ice-cold binding buffer II (100
50 mM sodium phosphate-potassium phosphate buffer containing 10 mM sodium chloride, pH 7.4) and homogenized.
The filtrate filtered through the quadruplicated gauze was centrifuged at 40,000 g for 20 minutes. The resulting sediment which was suspended in buffer II (1 g tissue wet weight / 100 ml) was used for the binding assay as BZomega ₃ receptor membrane preparation.

[0058] As the labeled ligand and unlabeled ligands, the BZomega ₁ and omega ₂ receptor binding assay ^[3 H] Ro 15-1
788 [final concentration _{(ω 1: 0.3 nM) (} ω 2: 1nM) ] and flunitrazepam (final concentration 10 [mu] M), the BZomega ₃ receptor binding assay with ^[3 H] Ro 5-4864 (final concentration 0.5 nM) Diazepam (100 μM final concentration) was used for each. Incubation conditions, in BZomega ₁ and omega ₂ receptor binding test
37 ° C. for 30 minutes, at 0 ℃ in BZomega ₃ receptor binding test 150
Minutes. Incidentally, BZω ₁ and omega ₂ receptor binding studies Bikyukurin (bicuculline: final concentration 100 [mu] M) were performed in the presence.

The receptor binding test was performed according to the following procedure. Test compounds of known concentrations in each test tube, tritium-labeled ligand, receptor membrane preparation, and buffer I or II for binding test
Was added to obtain a reaction solution having a total volume of 1 ml, and the reaction was started by adding a receptor membrane preparation. After the incubation, the reaction was stopped by filtering the labeled ligand bound to the receptor on a Whatman GF / B glass fiber filter using a cell harvester (Brandel, USA). Immediately, ice-cold buffer [omega ₁ and omega ₂ in 50 mM Tris - HCl buffer (pH 7.7); ω ₃ in buffer II] 3 in 5ml
Washed twice. Radioactivity transfers the filter to a vial,
After adding 10 ml of liquid scintillation cocktail (ACS-II, manufactured by Amersham, USA), the mixture was left for a certain period of time, and then measured with a scintillation counter. The specific binding amount was determined by subtracting the simultaneously measured non-specific binding amount in the presence of the unlabeled ligand from the total binding amount. The concentration at which the test compound inhibited the specific binding amount of the labeled ligand by 50% (IC ₅₀ value) was determined by the probit method. Table 3 shows the results
Shown in

[0060]

[Table 3] ^* Refers to the compound of Example 1 (the same applies hereinafter).

[0061] compounds and their physiologically acceptable acid addition salts of (I) (hereinafter, the compound may be referred to the present invention), and selective for BZomega ₃ receptor in vitro studies Because it shows remarkable affinity, anxiety-related diseases (neurosis, psychosomatic disorders, other anxiety disorders), central diseases such as depression, epilepsy, immune neurological diseases such as multiple sclerosis,
It is useful as a therapeutic or prophylactic for cardiovascular diseases such as angina pectoris and hypertension, or immune inflammatory diseases such as rheumatism.

The administration route of the compound of the present invention may be any of oral administration, parenteral administration and rectal administration. The dosage depends on the type of compound, administration method,
Depending on the age etc., it is usually 0.01-50 mg / kg /
Days, preferably 0.03 to 5 mg / kg / day.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch,
Partially pregelatinized starch, sucrose, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, carboxymethylcellulose calcium, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low substitution Degree hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate,
Light silicic anhydride, magnesium stearate, talc,
Carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin,
Fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, water, ethanol, polyoxyethylene hydrogenated castor oil (HCO), sodium chloride,
Examples include sodium hydroxide, hydrochloric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, citric acid, glutamic acid, benzyl alcohol, methyl paraoxybenzoate, ethyl paraoxybenzoate and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. In the case of a liquid preparation, it may be in the form of being dissolved or suspended in water or another appropriate medium at the time of use. Tablets and granules may be coated by a known method. In the case of an injection, the compound of the present invention is prepared by dissolving the compound in water. If necessary, the compound may be dissolved using an isotonic agent or a solubilizing agent. And a preservative may be added.

These preparations contain the compound of the present invention in an amount of 0.0
It can be contained at a rate of 1% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically effective ingredients.

[0066]

EXAMPLES The present invention will be described more specifically with reference to the following Reference Examples and Examples, but the present invention is not limited to these Examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, NMR spectra, and the like.

In the following Reference Examples and Examples,
The following abbreviations may be used to simplify the description.

[Recrystallization solvent] PE: petroleum ether, HX: n-hexane, IP: isopropanol.

Reference Example 1 Production of 2,3-dimethyl-6-phenyl-4 (1H) -pyridinone

31.6 g of about 60% sodium hydride (oily) was suspended in 500 ml of 1,2-dimethoxyethane, and 30 g of 3-methyl-2,4-pentanedione was stirred at 0 to 5 ° C.
Was gradually added. After stirring at room temperature for 30 minutes, 53.7 g of methyl benzoate was added again at 0 to 5 ° C., and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and 500 ml of diethyl ether was added to the residue to form a suspension, which was then added to ice water with stirring. The aqueous layer was separated, washed with diethyl ether, made acidic by adding concentrated hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and then with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 200 ml of ethanol residue
And ammonia gas is blown into it for 20 minutes.
Then, after heating under reflux for 1 hour, the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 21 g of the desired product. 249-251 ° C

Reference Examples 2 to 6 The corresponding starting compounds were used, reacted and treated in the same manner as in Reference Example 1, and recrystallized from ethanol to obtain the compounds of Table 4 represented by Chemical Formula 10.

[0072]

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[0073]

[Table 4]

Reference Example 7 Production of 2,3-dimethyl-6-phenyl-4-trifluoromethylsulfonyloxypyridine

2,3-dimethyl-6-phenyl-4 (1
H) -A mixture of 3 g of pyridinone and 30 ml of pyridine,
Trifluoromethylsulfonyl chloride 2.8 at 0-5 ° C
g was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours.
The reaction mixture was concentrated under reduced pressure. Water and n-hexane were added to the residue, the n-hexane layer was separated, washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the desired product 4 g was obtained as an oil.

Reference Examples 8 to 10 Using the corresponding starting compounds, the compounds were reacted and treated in the same manner as in Reference Example 7, and recrystallized from petroleum ether to obtain the compounds shown in Table 5 represented by Chemical Formula 11.

[0077]

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[0078]

[Table 5]

Reference Example 11 Production of 2-bromo-N, N-dipropylacetamide

To a mixture of 10.1 g of dipropylamine, 10.1 g of triethylamine and 80 ml of anhydrous diethyl ether,
Bromoacetyl chloride 15.8 g of anhydrous diethyl ether
A 40 ml solution was added dropwise while maintaining the reaction temperature at -40 ° C. After completion of the dropwise addition, the temperature was gradually raised, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure.
Purification by vacuum distillation gave 14 g of the desired product. Boiling point 1
00 ~ 103 ℃ / 1mmHg

Reference Examples 12 to 13 The corresponding compounds were reacted and treated in the same manner as in Reference Example 11 to obtain the following compounds.

Reference Example 12-2-bromo-N, N
-Dihexyl acetamide; oil

( Reference Example 13 )-2-bromo-N-
(4-chlorophenyl) -N-methylacetamide; melting point 52-53 ° C (recrystallized from isopropanol)

Reference Example 14 Production of 2-amino-N, N-dipropylacetamide

(1) A solution of 11 g of N-phthaloylglycyl chloride in 50 ml of methylene chloride was added dropwise to a mixture of 5 g of dipropylamine, 5 g of triethylamine and 50 ml of methylene chloride while maintaining the reaction temperature at 0 to 5 ° C. did. After completion of the dropwise addition, the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, the methylene chloride layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropanol to give 12.5 g of 2-phthalimido-N, N-dipropylacetamide. Melting point 99-100 ° C

(2) 12.5 g of the above product, hydrazine
A mixture of 4.3 g of monohydrate and 150 ml of ethanol was heated to reflux for 1 hour. After the reaction mixture was concentrated under reduced pressure, chloroform was added to the residue and the mixture was filtered.Water was added to the filtrate, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6.7 g of the desired product as an oil. Obtained.

Reference Example 15 2-amino-N- (4-
Production of (chlorophenyl) -N-methylacetamide

The reaction and treatment were carried out in the same manner as in Reference Example 14 using 4-chloro-N-methylaniline instead of dipropylamine in Reference Example 14 to obtain the desired product as an oil.

Example 1 Production of N- (4-chlorophenyl) -N-methyl-2- (2,3-dimethyl-6-phenyl-4-pyridyloxy) acetamide

2,3-dimethyl-6-phenyl-4 (1
H) -Pyridinone 1.2 g, 2-bromo-N- (4-chlorophenyl) -N-methylacetamide 1.6 g, anhydrous potassium carbonate 1.7 g and N, N-dimethylformamide 15
ml of the mixture was stirred at 60 ° C. for 3 hours. Water and chloroform were added to the reaction mixture, and the chloroform layer was separated,
The extract was washed with water, then with a saturated saline solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from isopropanol to obtain 2.0 g of the desired product. 141-142 ° C

Examples 2 to 8 The corresponding starting compounds were used and reacted and treated in the same manner as in Example 1 to obtain the compounds shown in Table 6 represented by Chemical Formula 12.

[0092]

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[0093]

[Table 6] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example _{R 5 R 6 R 1 R 2} R ₇ Melting point (℃) Recrystallization solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 2 Me Me Pr Pr H 81 -82 IP 3-(CH ₂ ) ₄ -Pr Pr H 120-121 IP 4-(CH ₂ ) ₄ -Hex Hex H 49-51 HX 5-(CH ₂ ) ₄ -Pr Pr 2-Me 80-82 PE 6- (CH ₂ ) ₄ -Pr Pr 4-Cl 97-98 IP 7-(CH ₂ ) ₄ -Pr Pr 4-F 105-106 IP 8-(CH ₂ ) ₄ -Me Ph-4-Cl H 115 -116 IP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Hex:-(CH ₂ ) ₅ CH ₃

Example 9 Production of 2- [5,6,7,8-tetrahydro-2- (2-methyl-3-furyl) -4-quinolyloxy] -N, N-dipropylacetamide

2,3-dimethyl-6 in Example 1
Instead of phenyl-4 (1H) -pyridinone,
6,7,8-Tetrahydro-2- (2-methyl-3-furyl) -4 (1H) -quinolone is converted to 2-bromo-N-
Using 2-bromo-N, N-dipropylacetamide instead of (4-chlorophenyl) -N-methylacetamide, the reaction and treatment were carried out in the same manner as in Example 1, and the product was re-dissolved from diethyl ether-n-hexane. Crystallization yielded the desired product. Melting point 76-77 ° C

Example 10 Production of N- (4-chlorophenyl) -N-methyl-2- (2,3-dimethyl-6-phenyl-4-pyridylamino) acetamide

1.8 g of 2,3-dimethyl-6-phenyl-4-trifluoromethylsulfonyloxypyridine
A mixture of 1.3 g of -amino-N- (4-chlorophenyl) -N-methylacetamide and 0.66 g of triethylamine was heated under reflux at 150 ° C for 3 hours with stirring. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from isopropanol to obtain 1.7 g of the desired product. Melting point 167-168 ° C

Examples 11 to 14 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 10 to obtain the compounds of Table 7 represented by Chemical Formula 13.

[0099]

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[0100]

Table 7 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example _{R 5 R 6 R 1 R 2} R 7 Melting point (℃) Recrystallization solvent ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 11 Me Me Pr Pr H 95-96 IP 12-(CH ₂ ) ₄ -Me Ph-4-Cl H 206-207 IP 13-(CH ₂ ) ₄ -Pr Pr H 117-118 IP 14-(CH ₂ ) ₄ -Pr Pr Cl 104-106 IP ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 15 --N- (4-chlorophenyl) -2- [5,6,7,8-tetrahydro-2- (2
-Methyl-3-furyl) -4-quinolyloxy] -N-
Production of methylacetamide

2,3-dimethyl-6 in Example 10
2- (2-methyl-3-furyl) instead of -phenyl-4-trifluoromethylsulfonyloxypyridine
-4-trifluoromethylsulfonyloxy-5,6
The reaction and treatment were carried out in the same manner as in Example 10 using 7,8-tetrahydroquinoline, and the product was recrystallized from isopropanol to obtain the desired product. 138-139 ° C

Embodiment 16 2- [5, 6, 7, 8-
Tetrahydro-2- (2-methyl-3-furyl) -4-
Production of [quinolyloxy] -N, N-dipropylacetamide

2,3-dimethyl-6 in Example 10
2- (2-methyl-3-furyl) instead of -phenyl-4-trifluoromethylsulfonyloxypyridine
-4-trifluoromethylsulfonyloxy-5,6
7,8-Tetrahydroquinoline is converted to 2-amino-N-
Using 2-amino-N, N-dipropylacetamide instead of (4-chlorophenyl) -N-methylacetamide, the reaction and treatment were conducted in the same manner as in Example 10, and the product was recrystallized from diethyl ether. I got something. Melting point 1
27-128 ° C

[0105]

The compound of the present invention represented by the formula (I)
It indicates selective and remarkable affinity for the peripheral-type BZomega ₃ receptors, anxiety-related disorders (neurosis, psychosomatic disorders, and other anxiety disorders), depression, central diseases such as epilepsy, angina It is useful as a therapeutic or prophylactic for cardiovascular diseases such as hypertension. Further, the compound of the present invention represented by the formula (I) is expected as a therapeutic or preventive agent for immune neurological diseases such as multiple sclerosis or immune inflammatory diseases such as rheumatism.

──────────────────────────────────────────────────の Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 31/44 ABN A61K 31/44 ABN 31/47 31/47 C07D 405/04 213 C07D 405/04 213 409/04 213 409/04 213

Claims (1)

[Claims] 1. A pyridine derivative represented by the following formula 1 or a physiologically acceptable acid addition salt thereof. Embedded image Wherein, X is -O- or -NR ₄ - means, R ₁ is represents a hydrogen atom, an alkyl group, a lower alkenyl group or a cycloalkyl (lower) alkyl, R ₂ is an alkyl group,
A cycloalkyl group or an unsubstituted or substituted phenyl group, R ₃ and R ₄ are the same or different and each represents a hydrogen atom or a lower alkyl group, and R ₅ and R ₆ are the same or different and are each a hydrogen atom Or a lower alkyl group, or R ₅ and R ₆ together
(CH ₂₎ may form a n-, n denotes 3, 4, 5 or 6 wherein, A is meant an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group. ]