JPH09291034A - Condensed pyridine compound and its use as medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a condensed pyridine compound useful as a therapeutic agent for Parkinson's disease, having affinity for a dopamin D3 receptor. SOLUTION: This compound is shown by formula I [R<1> and R<2> are each H, a halogen, etc.; R<3> is H, an alkyl, etc.; X is S(O)m ((m) is 0, 1 or 2), etc.; (n) is 0 or 1] such as 2-(4-ethylpiperazin-1-yl)-4-phenyl-7,8-dihydro-5H- thiopyrano[4,3-b]pyridine. The compound of formula I is obtained by reacting a compound of formula II (Y is a halogen) with a compound of formula II. The compound shows more affinity for a D3 receptor than to a D2 receptor.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel condensed pyridine compound having an affinity for a dopamine D ₃ (hereinafter also referred to as D ₃ ) receptor. More specifically, central agents,
Especially schizophrenia, schizoaffective disorder, organic mental disorder, emotional disorder, anxiety, sleep disorder, depression, psychotic depression, psychomotor dysfunction due to substance abuse or drug (cocaine etc.) dependence, addiction, personality disorder, Movement disorders such as Parkinson's disease or tardive dyskinesia, Parkinsonism due to tranquilizers, memory disorders, mania, circadian rhythm disorders, psychiatric disorders in children and adolescents, behavioral problems in the elderly, dementia, sexual disorders ( The present invention relates to a novel D ₃ receptor blocker useful as a therapeutic agent such as impotence), a side effect therapeutic agent for an existing anti-Parkinson's disease drug, or an antiemetic agent, particularly a therapeutic agent for gastrointestinal nausea and vomiting.

[0002]

2. Description of the Related Art Schizophrenia is said to occur in about 7 to 8 out of 1000 people during puberty to about 40 years old, and about half of them cause a clear change in personality. It is a serious mental disorder that makes social adjustment difficult. The main cause of the manifestation of this intractable disease is the excessive dopamine theory that excessive release of dopamine increases the concentration of dopamine in the synaptic cleft and causes abnormal excitation of dopamine nerve activity. Conventionally, phenothiazine derivatives such as chlorpromazine and butyrophenone derivatives such as haloperidol have been clinically used as antipsychotic drugs, but the antipsychotic effects of these drugs are considered to be based on the D ₂ receptor blocking effect. However, in the case of these typical antipsychotic drugs whose main action is D ₂ receptor blocker action, extrapyramidal symptoms (a tardive dyskinesia, acute dystonia, akathisia, etc.) that occur after acute administration and long-term continuous use. The occurrence of side effects such as and endocrine abnormalities (hyperprolactinemia, amenorrhea, etc.) has become a serious problem.

[0003] In 1979, the dopamine receptor was classified into two receptor subtypes by a pharmacological method based on the related form to adenylate cyclase [Nat (Nat
ure, 227, 93-96 (1979)].
That is, the D ₁ receptor type that activates adenylate cyclase through a promoting GTP-binding protein (Gs protein) to produce cyclic AMP and suppresses adenylate cyclase through an inhibitory G protein (Gi protein) It is a D ₂ receptor type that suppresses the production of cyclic AMP. Then, with the development of molecular biology, five different genes were newly cloned as dopamine receptors. These subtypes belong to the D ₁ family, D ₁ and D ₅ due to the similarity in homology and gene structure.
D ₂ belonging to the receptor and D ₂ family, D _3, D ₄ have been classified into receptor [Trends-in Pharmacology logical Sciences (Trends in Pharm
acol. Sci. ) Volume 15, p. 264 (199
4)].

D_ThreeReceptor
Cloned from a human cDNA library [ne
Nature, 347, 146 (1
990)]. D in the transmembrane region_Two75% homology with receptor
There is a logic, structurally D _TwoVery similar to the receptor
I have. D_TwoMany of the compounds that have an affinity for the receptor
Is D_ThreeIt also has affinity for receptors.

Also in terms of pharmacological properties, the D ₃ receptor has the same binding ligand affinity as the D ₂ receptor. On the other hand, receptor selectivity varies considerably depending on the drug. Conventional dopamine agonists generally show several times higher affinity for the D ₃ receptor than for the D ₂ receptor. The ratio of D ₂ receptor affinity (Ki value) / D ₃ receptor affinity (Ki value), which is the ratio thereof, is higher in atypical antipsychotic drugs such as sulpiride than in typical antipsychotic drugs such as haloperidol. Is known to be high [Natur (Natur
e), 347, 146 (1990)]. Also, dopamine has the highest affinity for the D ₃ receptor of the 5 subtypes. From the above points, it is highly possible that the D ₃ receptor is involved in the etiology of schizophrenia or the site of action of therapeutic agents.

Further, there are differences among subtypes in the brain distribution of dopamine receptors. That is, the D ₂ receptor is mainly distributed in the substantia nigra-striatum system, the midbrain-limbic system and the pituitary gland in the brain, while the D ₃ receptor is the midbrain-limb controlling emotional functions. It is localized in the limbic system and is known to be absent in the substantia nigra-striatal system and pituitary gland [Brain Research, vol.
03 (1991)]. Therefore, it is suggested that the D ₃ receptor blocker may be a central agent that does not exhibit side effects such as extrapyramidal symptoms and endocrine abnormalities observed in the D ₂ receptor blocker.

[0007] In addition, life science (Life Sc
), Volume 57, No. 21, PL (Pharma)
347-350 (1).
995), the D ₃ receptor agonist 7-hydroxy-N, N-di-n-propyl-2-aminotetralin (7-OH-DPAT) induces vomiting, which is S which is a D ₂ receptor and D ₃ receptor antagonist
It is described that (-)-ethiclopride has an inhibitory effect. This gives D
It has been suggested that a _3- receptor antagonist may serve as an antiemetic agent, particularly as a therapeutic agent for nausea and vomiting derived from the digestive tract.

Central agents having an affinity for the D ₃ receptor are described in, for example, US Pat. No. 5,395,835.
Naphthalamide derivatives with high affinity for the D ₃ receptor have been disclosed. In addition, international publication WO95 / 04713
The 2-aminoindan compound is disclosed in Japanese Patent Publication No. 6-5
JP-A-04054 discloses aminomethylphenylimidazole derivatives each having a D ₃ receptor affinity and as a therapeutic drug for mental disorders such as schizophrenia and depression, and movement disorders such as Parkinson's syndrome. Furthermore, International Publication WO94 / 03426, International Publication W
O95 / 04037, International Publication WO94 / 241
29, International Publication WO95 / 10504 and International Publication WO95 / 21165 disclose phenylpyrrole derivatives having affinity for the D ₃ receptor as therapeutic agents for mental disorders, and JP-A-7-33077.
No. 8 discloses that piperidino-1,4-oxazine compounds having a selective affinity for D ₃ receptors are useful for psychosis, depression and the like. International publication WO95 / 0
No. 8533 discloses an N- (3-pyrrolidinyl) benzamide derivative as a D ₃ receptor and / or dopamine D ₄
It is described that it has affinity for receptors and is useful as a central agent for schizophrenia and the like, and also acts as a hypotensive agent, a diuretic agent, etc. by acting on peripheral D ₃ receptors. .

Further, JP-A-3-7257, JP-A-4-103572, and JP-A-6-100556.
Japanese Patent Laid-Open No. 355580 discloses a 4-phenylpyridine derivative as a psychotropic drug, and Japanese Unexamined Patent Publication No. 4-103580 discloses a 4-phenylpyridine derivative as a hypotensive agent.
No. 5034 discloses 1,6-naphthyridine derivatives as central agents. However, the affinity of these compounds for the D ₃ receptor has not been investigated.

[0010]

The present invention provides a central agent having a higher affinity for D ₃ receptors than D ₂ receptors and having no side effects such as extrapyramidal symptoms and endocrine abnormalities. Especially schizophrenia, schizoaffective disorder, organic mental disorder, emotional disorder, anxiety, sleep disorder, depression, psychotic depression, psychomotor dysfunction due to substance abuse or drug (cocaine etc.) dependence, addiction, personality disorder, Movement disorders such as Parkinson's disease or tardive dyskinesia, Parkinsonism due to tranquilizers, memory disorders, mania, circadian rhythm disorders, psychiatric disorders in children and adolescents, problem behaviors in the elderly, dementia, sexual disorders ( Preventive or therapeutic drug (such as impotence), side effect drug to existing anti-Parkinson's disease drug,
Alternatively, the object is to provide a compound useful as an antiemetic agent, particularly as a therapeutic agent for gastrointestinal nausea and vomiting.

[0011]

As a result of intensive studies conducted by the present inventors in view of the above points, the novel condensed pyridine compound has a higher affinity for the D ₃ receptor than the D ₂ receptor. The present invention has been completed and the present invention has been completed.
That is, the present invention provides (1) the general formula

[0012]

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[Wherein R ¹ and R ² are the same or different and each represents hydrogen, halogen, cyano, nitro, amino, alkyl or alkoxy, and R ³ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, substituent Represents an aryl which may have a substituent, an arylalkyl which may have a substituent, an acyl or an alkoxycarbonyl, and -X- represents a formula -S (O) m- (in the formula, m is 0,
1 or 2 shows a) or -N (R ⁴⁾ - (wherein, R ⁴
Represents hydrogen, alkyl, arylalkyl which may have a substituent, heteroarylalkyl, acyl, alkylsulfonyl, carbamoyl or alkylcarbamoyl), and n represents 0 or 1. ] The condensed pyridine compound represented by these, or its pharmaceutically acceptable salt,
(2) General formula

[0014]

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[Wherein R ¹ and R ² are the same or different and each represents hydrogen, halogen, cyano, nitro, amino, alkyl or alkoxy, and R ³ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, substituent Represents aryl which may have a substituent, arylalkyl which may have a substituent, acyl or alkoxycarbonyl, m represents 0, 1 or 2, n represents 0 or 1
Is shown. ] The condensed pyridine compound according to (1) or a pharmaceutically acceptable salt thereof represented by the above formula (3),

[0016]

[Chemical 6]

[Wherein R ¹ and R ² are the same or different and each represents hydrogen, halogen, cyano, nitro, amino, alkyl or alkoxy, and R ³ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, substituent Represents an optionally substituted aryl, optionally substituted arylalkyl, acyl or alkoxycarbonyl, R ⁴ is hydrogen, alkyl, optionally substituted arylalkyl, heteroarylalkyl, acyl , Alkylsulfonyl, carbamoyl or alkylcarbamoyl). ] The condensed pyridine compound described in (1) or a pharmaceutically acceptable salt thereof represented by the above, and (4) the condensed pyridine compound described in (1) to (3) or a pharmaceutically acceptable salt thereof and a medicine (5) A pharmaceutical composition comprising the above acceptable carrier, (5) a pharmaceutical comprising the condensed pyridine compound according to (1) to (3) above or a pharmaceutically acceptable salt thereof, (6) above (1) to (3) ) condensed pyridine compound or D ₃ receptor blocker to a pharmaceutically acceptable salt thereof as an active ingredient articles described.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The group represented by each symbol in the present specification is described below. Halogen in R ¹ and R ² represents fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferable. The alkyl in R ¹ and R ² is a linear or branched alkyl having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, and is methyl, ethyl, propyl, isopropyl, butyl, isobutyl. , Tert-butyl, pentyl, hexyl, heptyl, octyl and the like, with methyl being particularly preferred.

The alkoxy in R ¹ and R ² is a linear or branched alkoxy having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, and is methoxy, ethoxy, propoxy or isopropoxy. , Butoxy, isobutoxy,
It represents tertiary butoxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy and the like.

Alkyl for R ³ has the same meaning as alkyl for R ¹ and R ² , and methyl and ethyl are particularly preferable. The hydroxyalkyl in R ³ is an alkyl having 1 to 4 carbon atoms (methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc.) substituted with hydroxy, and hydroxymethyl, 2- Hydroxyethyl, 1-hydroxyethyl, 3
-Hydroxypropyl, 2-hydroxypropyl, 4-
Hydroxybutyl and the like are shown, and 2-hydroxyethyl is particularly preferable.

Alkoxyalkyl in R ³ is alkyl having 1 to 4 carbons (synonymous with the above) and having 1 to 4 carbons.
Substituted by a single alkoxy (methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, etc.), which is methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, butoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 3-methoxypropyl, 4
-Indicates methoxybutyl and the like.

The aryl which may have a substituent in R ³ includes halogen (as defined above) as a substituent, haloalkyl (trifluoromethyl, trichloromethyl, 2,
2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.), alkyl having 1 to 4 carbon atoms (as defined above), and alkoxy having 1 to 4 carbon atoms (as defined above) 1 To phenyl or naphthyl which may have 3 to 3, specifically, phenyl, 4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-methylphenyl, 4-methoxyphenyl, naphthyl. , 4-chloro-1-naphthyl, 2-methyl-1-naphthyl, 4-methoxy-1-naphthyl and the like, and phenyl is particularly preferable.

The arylalkyl which may have a substituent in R ³ is alkyl having 1 to 4 carbon atoms (synonymous with the above) substituted with aryl (synonymous with the above), and further has a substituent. As 1 to 3 selected from halogen (synonymous with the above), haloalkyl (synonymous with the above), alkyl having 1 to 4 carbons (synonymous with the above), and alkoxy having 1 to 4 carbons (synonymous with the above). You may have. Specifically, benzyl, 2-phenylethyl, 1-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 4
-Chlorobenzyl, 4-fluorobenzyl, 4-trifluoromethylbenzyl, 4-methylbenzyl, 4-methoxybenzyl, 2- (4-chlorophenyl) ethyl, 2
-(4-fluorophenyl) ethyl, 2- (3-trifluoromethylphenyl) ethyl, 2- (4-methylphenyl) ethyl, 2- (4-methoxyphenyl) ethyl,
Examples thereof include 2-naphthylmethyl and diphenylmethyl, and benzyl is particularly preferable.

Acyl in R ³ is alkanoyl having 1 to 5 carbon atoms which may be substituted with aryl (as defined above) or cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), or benzoyl. Furthermore, the acyl has at least a substituent selected from halogen (as defined above), alkyl having 1 to 4 carbons (as defined above), and alkoxy having 1 to 4 carbons (as defined above) on the benzene ring. One may be provided, and the alkanoyl may be substituted with halogen (as defined above). Specifically, formyl, acetyl, propionyl, butyryl, pivaloyl,
Benzoyl, phenylacetyl, phenylpropionyl, phenylbutyryl, benzoyl, 1-naphthoyl,
2-naphthoyl, cyclohexanecarbonyl, trifluoroacetyl, 4-chlorobenzoyl, 4-fluorobenzoyl, 4-methylbenzoyl, 4-methoxybenzoyl, 4-chlorophenylacetyl, 4-fluorophenylacetyl, 4-methylphenylacetyl, 4- Examples include methoxyphenylacetyl.

Alkoxycarbonyl in R ³ is
The alkoxy part is an alkoxycarbonyl having 1 to 4 carbon atoms, and is methoxycarbonyl, ethoxycarbonyl,
Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl and the like are shown. The alkyl in R ⁴ has the same meaning as the alkyl in R ¹ and R ² , and methyl is particularly preferable.

The arylalkyl which may have a substituent in R ⁴ has the same meaning as the arylalkyl which may have a substituent in R ¹ and R ² , and particularly benzyl and 2-phenylethyl are preferable. The heteroarulealkyl in R ⁴ includes pyridylmethyl, 2-pyridylethyl, furylmethyl, 2-furylethyl, thienylmethyl, 2-thienylethyl and the like.

The acyl in R ⁴ has the same meaning as the acyl in R ³ , and acetyl, benzoyl, trifluoroacetyl, cyclohexanecarbonyl, 4-fluorobenzoyl, 1-naphthoyl and 2-naphthoyl are particularly preferable. The alkylsulfonyl in R ⁴ is an alkylsulfonyl having an alkyl part having 1 to 4 carbon atoms, and includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like, and methylsulfonyl is particularly preferable.

Alkylcarbamoyl in R ⁴ is
1 to 2 alkyl having 1 to 4 carbon atoms (as defined above)
Individually substituted carbamoyl includes methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl and the like, with dimethylcarbamoyl being particularly preferred.

The pharmaceutically acceptable salts of the compounds of the present invention include inorganic acids (hydrochloric acid, hydrobromic acid, iodic acid, phosphoric acid, nitric acid, sulfuric acid, carbonic acid, etc.), organic acids (formic acid, acetic acid, lactic acid, propion). Acid, malonic acid, malic acid, tartaric acid, mandelic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, etc.) Acid addition salts of. Further, the compound of the present invention can be converted into an oxalate salt for the purpose of crystallization. Furthermore, the hydrate of the compound of the present invention (monohydrate, 1/4
Hydrates, hemihydrates, 3/2 hydrates, 5/2 hydrates, etc.), solvates (ethanol solvates etc.), N-oxide compounds are also included in the present invention.

When the compound of the present invention has an asymmetric atom, at least two kinds of optical isomers exist. The present invention also includes these optical isomers and racemates thereof. The compound of the present invention can be synthesized by various publicly known methods, for example, it can be produced by the following method. Method 1

[0031]

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(In the formula, Y is halogen (chlorine, bromine, etc.)
And other symbols are as defined above. The compound represented by the general formula (I) of the present invention (hereinafter referred to as the compound (I)) is obtained by converting the compound represented by the general formula (IV) (hereinafter referred to as the compound (IV)) into the general formula (V). It can be obtained by reacting with a compound represented by (hereinafter referred to as compound (V)). The reaction is usually carried out at room temperature to 200 ° C. in the presence or absence of a solvent such as benzene, toluene, ethanol, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethylimidazolidinone and N-methyl-2-pyrrolidone.
Performed in ~ 48 hours. This reaction is preferably carried out in the presence of a base such as sodium carbonate, potassium carbonate or triethylamine, but it can be substituted by using an excess amount of compound (V). When a compound (IV) in which Y is chlorine or bromine is used, the reaction proceeds smoothly by adding potassium iodide or the like.

Method 2

[0034]

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[In the formula, Z represents a leaving group such as halogen (chlorine, bromine, iodine, etc.), acetoxy, methanesulfonyloxy, paratoluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and R ⁵ is alkyl, hydroxyalkyl, It represents alkoxyalkyl, aryl optionally having substituent (s), arylalkyl optionally having substituent (s), acyl or alkoxycarbonyl, and other symbols are as defined above. ] In the compound (I), R ³ is hydrogen, a general formula (V
A compound represented by the general formula (VII)
Compound (I ′) can be obtained by reacting with the compound represented by The reaction is carried out in the presence or absence of a solvent such as benzene, toluene, dioxane, tetrahydrofuran, chloroform, dichloromethane, dimethylformamide, dimethylsulfoxide, dimethylimidazolidinone and N-methyl-2-pyrrolidone.
Preferably in the presence of a base such as sodium carbonate, potassium carbonate or triethylamine, usually at room temperature to 180 ° C.
It takes 24 hours.

Method 3

[0037]

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(In the formula, each symbol has the same meaning as described above.) In the compound (I), a compound represented by the general formula (II-b) in which -X- is -SO- (hereinafter, compound (I
I-b)) is obtained by oxidizing the compound (I) represented by the general formula (II-a) in which -X- is -S-. This reaction is carried out in the presence of acetic acid, formic acid, chloroform, dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, water or the like as a solvent, and using an oxidizing agent such as hydrogen peroxide, metachloroperbenzoic acid, peracetic acid or sodium bromate. It can be carried out at 0 ° C to around the boiling point of the solvent. Furthermore, -X-
The compound represented by the general formula (II-c) in which is —SO ₂ — can be obtained by oxidizing the compound (II-b) by the same method as described above.

Method 3 ': In compound (II-b)
The optically active sulfoxide compound is disclosed in JP-A-3-25
It can be manufactured according to the method described in Japanese Patent No. 1586.

[0040]

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(In the formula, each symbol has the same meaning as defined above.) That is, the compound (II-b ¹ ) or the compound (II-
b ² ) is a compound (II-a) represented by the general formula Ti (OR) ₄ (XII) (wherein R is methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl or the like having 1 to 4 carbon atoms). Represented by alkyl), a chiral dialkyl tartrate ester (eg, (+)-diethyl tartrate, (−)-diethyl tartrate, (+)-diisopropyl tartrate, (−)-diisopropyl tartrate) and optionally Depending on the acid (hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, etc.)
In the presence of a tertiary hydroperoxide (tertiary butyl hydroperoxide, cumene hydroperoxide, tertiary amyl hydroperoxide, tertiary octyl hydroperoxide, etc.) be able to. This reaction is carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, benzene and toluene under a nitrogen atmosphere at -78 ° C to room temperature for 1 to 24 hours. The reaction may be carried out in the coexistence of water.

Method 4

[0043]

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(In the formula, R ⁶ represents a protecting group for an amino group such as benzyl and ethoxycarbonyl, and other symbols have the same meanings as described above.) In compound (I), -X- is -N (R ⁴ )-, N is 1, and R ⁴ is hydrogen, the compound represented by the general formula (III-b) (hereinafter, referred to as compound (III-b)) is
It can be obtained by deprotecting the compound represented by formula (III-a) (hereinafter referred to as compound (III-a)). In the compound (III-a), R
^{When 6} is benzyl, it can be carried out by catalytic hydrogenation in the presence of platinum, palladium or the like in a solvent such as methanol or ethanol, or by hydrogenolysis using hydrazine. The reaction is usually from room temperature to 100 ° C
It takes 10 minutes to 24 hours. In addition, the compound (II
In I-a), when R ⁶ is ethoxycarbonyl, the presence of a base such as sodium hydroxide or potassium hydroxide or the presence of an acid such as hydrochloric acid or sulfuric acid in the presence of a water-miscible solvent such as methanol or ethanol. Lower, room temperature ~ 9
It can be carried out by hydrolysis at 0 ° C.

Method 5

[0046]

[Chemical 12]

[Wherein Z represents a leaving group such as halogen (chlorine, bromine, iodine, etc.), methanesulfonyloxy, paratoluenesulfonyloxy, trifluoromethanesulfonyloxy, etc., and R ⁷ has an alkyl group or a substituent. Optionally represents arylalkyl, heteroarylalkyl, acyl, alkylsulfonyl, carbamoyl or alkylcarbamoyl, and other symbols are as defined above. ] In the compound (I), -X- is ^{-N (R 4) -, n} =
When 1, R ⁴ is alkyl, optionally substituted arylalkyl, heteroarylalkyl, acyl, alkylsulfonyl, carbamoyl or alkylcarbamoyl, the compound of formula (III-b) and the general formula (VII
It can be obtained by reacting the compound represented by I). The reaction is benzene, toluene, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, dimethylimidazolidinone, N-
It is carried out in a solvent such as methyl-2-pyrrolidone or the like, preferably in the presence of a base such as sodium carbonate, potassium carbonate or triethylamine, usually at room temperature to 180 ° C. for 1 to 24 hours.

The compound (IV) which is a raw material for synthesizing the compound of the present invention can be produced by the following method. Method 6

[0049]

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(In the formula, symbols have the same meanings as described above.) The compound (IV) is a compound represented by the general formula (IX) (hereinafter referred to as compound (IX)), for example, phenylphosphonic dichloride. , Halogenated with a halogenating agent such as phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide. The reaction is usually performed in the absence of a solvent at 100 to 200 ° C. for 1 to 10 hours.

Method 7

[0052]

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(In the formula, symbols have the same meanings as above.) The compound (IX) is obtained by reacting the compound represented by the general formula (X) with the compound represented by the general formula (XI). To be The reaction is usually 5 in polyphosphoric acid.
It is carried out at 0 to 200 ° C. for 1 to 24 hours. The compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method. When the obtained product is a racemate, it can be resolved into a desired optically active substance, for example, by fractional recrystallization of a salt with an optically active acid or by using a column packed with an optically active carrier. it can. Individual diastereomer can be separated by a known means such as fractional crystallization or column chromatography. Moreover, an optically active substance can also be produced by using an optically active raw material compound. Stereoisomers can be isolated by a recrystallization method, a column chromatography method, or the like.

The condensed pyridine compound of the present invention or a pharmaceutically acceptable salt thereof has a higher affinity for the D ₃ receptor as compared with the D ₂ receptor, and is associated with extrapyramidal disorders, endocrine disorders (hyperprolactinemia). , Amenorrhea, etc.) is expected as a central agent with reduced side effects, such as schizophrenia, schizoaffective disorder, organic mental disorder, emotional disorder, anxiety, sleep disorder, depression, psychotic depression, substance abuse Or psychomotor dysfunction due to drug (cocaine etc.) dependence, addiction, personality disorder,
Movement disorders such as Parkinson's disease or tardive dyskinesia, Parkinsonism due to tranquilizers, memory disorders,
Prophylactic or therapeutic drug for mania, circadian rhythm disorder, psychiatric disorder in children and adolescents, problem behavior in the elderly, dementia, sexual disorder (impotence, etc.), side effect drug for existing anti-Parkinson's disease drug, or It is useful as an antiemetic, especially as a therapeutic drug for nausea and vomiting derived from the digestive tract.

When the compound of the present invention is used as a medicine, the compound of the present invention is a pharmaceutically acceptable carrier (excipient, binder,
Disintegrating agents, flavoring agents, flavoring agents, emulsifiers, diluents, solubilizing agents, etc.), tablets, pills, capsules, obtained by formulating a pharmaceutical composition obtained by a conventional method.
It can be administered orally or parenterally in the form of granules, powders, syrups, emulsions, elixirs, suspensions, solutions, injections, drops, suppositories and the like.

In the present specification, parenteral means subcutaneous injection,
It includes intravenous injection, intramuscular injection, intraperitoneal injection, or drip method. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to methods known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally administrable diluent or solvent, such as an aqueous solution. The acceptable vehicles or solvents that can be used are:
Examples include water, Ringer's solution, and a saline solution. Furthermore, aseptic non-volatile oil can also be used as a solvent or suspending solvent. Any non-volatile oil or fatty acid can be used for this purpose, including natural or synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi-synthetic mono-, di- or triglycerides. Although suppositories for rectal administration are solid at room temperature such as non-irritating excipients suitable for the drug and cocoa butter and polyethylene glycols,
It is a liquid at the temperature in the intestinal tract, and can be manufactured by mixing with a substance that melts in the rectum and releases a drug.

Examples of solid dosage forms for oral administration include powders, granules, tablets, pills and capsules described above. In such dosage forms, the active ingredient compound is at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starches, agar, alginates, chitins, chitosans, pectins, It can be mixed with tragacanth gums, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides. Such dosage forms may also, as usual, contain further additives, for example inert diluents, lubricants such as magnesium stearate, preservatives such as parabens, sorbines, ascorbin. Examples thereof include acids, α-tocopherols, antioxidants of cypress coconut, disintegrators, binders, thickeners, buffers, sweetening agents, flavoring agents, perfume agents and the like. Tablets and pills can also be manufactured with enteric coating. Examples of the drug for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like,
They may contain inert diluents commonly used in the art, such as water.

Dosage depends on age, body weight, general health condition,
These factors and other factors are taken into consideration depending on the sex, diet, administration time, administration method, excretion rate, drug combination, and the degree of the medical condition being treated for the patient at that time or other factors. The compound of the present invention, its optical isomer or a pharmaceutically acceptable salt thereof has low toxicity and can be safely used,
The daily dose varies depending on the condition and weight of the patient, the type of compound, the route of administration, etc., but is, for example, parenterally subcutaneously, intravenously or rectally about 0.01 to 50 m
g / person / day, preferably 0.01 to 20 mg / person / day, and orally about 0.01 to 150 mg / person / day.
It is preferable to administer daily, preferably 0.01 to 100 mg / person / day.

[0059]

[Examples] The present invention will be specifically described below with reference to examples of preparation of raw materials, examples and formulation examples, but the present invention is not limited thereto. Raw material preparation example 1

[0060]

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2 g of tetrahydrothiopyran-4-one,
A mixture of 2.5 g of benzoylacetonitrile and 25 ml of 75% polyphosphoric acid was stirred at 100 to 110 ° C for 2 hours. After cooling, the reaction solution was poured into ice water and stirred, and then the precipitated crystals were collected by filtration. The crystals collected by filtration were dissolved in chloroform, washed with water, and dried over magnesium sulfate. This is concentrated and the residue is purified by silica gel column chromatography to give 4-phenyl-1,5,7,8-
Tetrahydrothiopyrano [4,3-b] pyridine-2-
1.2 g of on was obtained. Melting point 275 ° C. Raw material preparation example 2

[0062]

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Tetrahydrothiopyran-4-one 20
g, 4-fluorobenzoylacetonitrile 34 g, 7
A mixture of 200 ml of 5% polyphosphoric acid was added at 100 to 110 ° C.
It was stirred for 1.5 hours. After cooling, the reaction solution was poured into ice water, stirred, and then extracted with chloroform. Wash the organic layer with water,
After drying over magnesium sulfate, the mixture was concentrated. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give 4- (4-
10 g of fluorophenyl) -1,5,7,8-tetrahydrothiopyrano [4,3-b] pyridin-2-one were obtained. Melting point 285-292 ° C. Raw material preparation example 3

[0064]

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Tetrahydrothiopyran-4-one 10
g, 4-chlorobenzoylacetonitrile 13.9 g,
100-110 of a mixture of 100 ml of 75% polyphosphoric acid
Stirred at C for 5 hours. After cooling, the reaction solution was poured into ice water, stirred, and then extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give 4- (4-chlorophenyl) -1,5,7,8-tetrahydrothiopyrano [4,3-b] pyridin-2-one. 4 g was obtained. Melting point 254 to 257 ° C. (decomposition) Raw material preparation example 4

[0066]

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Tetrahydrothiopyran-4-one 10
g, 4-methylbenzoylacetonitrile 12.3 g,
100-110 of a mixture of 120 ml of 75% polyphosphoric acid
Stirred at C for 2 hours. After cooling, the reaction solution was poured into ice water, stirred, and then extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give 4- (4-methylphenyl) -1,5,7,8-tetrahydrothiopyrano [4,3-b] pyridin-2-one 4 0.4 g was obtained. Melting point 232-235 ° C. (decomposition) Raw material preparation example 5

[0068]

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Tetrahydrothiophen-3-one 25
g, 35 g of benzoylacetonitrile, and 250 ml of 75% polyphosphoric acid were stirred at 100 to 110 ° C. for 1.5 hours. After cooling, the reaction solution was poured into ice water, stirred, and then extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 5.4 g of 7-phenyl-3,4-dihydro-2H-thieno [3,2-b] pyridin-5-one. Melting point 228 ° C. (decomposition) Raw material preparation example 6

[0070]

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A mixture of 5 g of 1-ethoxycarbonyl-4-piperidone, 4.2 g of benzoylacetonitrile and 50 ml of 75% polyphosphoric acid was stirred at 100 to 110 ° C. for 1.5 hours. After cooling, the reaction solution was poured into ice water and stirred,
The precipitated crystals were filtered. The crystals collected by filtration were dissolved in ethyl acetate, washed with aqueous potassium carbonate solution, dried over magnesium sulfate, and concentrated. Diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration to give 6-ethoxycarbonyl-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one (2.9 g). Got Melting point 198 ° C. Raw material preparation example 7

[0072]

[Chemical 21]

20 g of 1-benzyl-4-piperidone, 15 g of benzoylacetonitrile, 30% of 75% polyphosphoric acid
0 ml of the mixture was stirred at 120-140 ° C. for 4.5 hours. After cooling, the reaction solution was poured into ice water, made basic with sodium hydroxide, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. By adding ethyl acetate to the obtained residue, 6
27 g of -benzyl-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2 (1H) -one
I got Melting point 227 ° C. (decomposition) Raw material preparation example 8

[0074]

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1-benzyl-4-piperidone 80 g, 4
2. A mixture of 70 g of fluorobenzoylacetonitrile and 500 ml of 75% polyphosphoric acid at 120-140 ° C.
Stir for 5 hours. After cooling, the reaction solution was poured into ice water, made basic with sodium hydroxide, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give 6-benzyl-4- (4-fluorophenyl)-.
114.2 g of 5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one were obtained. Melting point 209-
210 ° C (decomposition) Raw material preparation example 9

[0076]

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1-benzyl-4-piperidone 15.5
g, 4-chlorobenzoylacetonitrile 15 g, 75
A mixture of 100 ml% polyphosphoric acid was stirred at 120-150 ° C. for 4 hours. After cooling, the reaction solution was poured into ice water, made basic with sodium hydroxide, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give 6-benzyl-4- (4-chlorophenyl) -5,5.
6,7,8-Tetrahydro-1,6-naphthyridine-2
17.4 g of (1H) -one was obtained. Melting point 225-228
C. Raw material preparation example 10

[0078]

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1-benzyl-4-piperidone 15.5
g, 2-chlorobenzoylacetonitrile 15 g, 75
A mixture of 100% polyphosphoric acid was stirred at 120-150 ° C. for 4.5 hours. After cooling, the reaction solution was poured into ice water, made basic with sodium hydroxide, and extracted with chloroform.
The organic layer was washed with water, dried over magnesium sulfate, and concentrated. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give 6-benzyl-4- (2-chlorophenyl)-.
10 g of 5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one were obtained. Melting point 237-240
℃ (decomposition) Raw material preparation example 11

[0080]

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6-Ethoxycarbonyl-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one obtained in Preparation Example 6 3 g, sodium hydroxide 2 g, water A mixture of 10 ml and 30 ml of ethanol was stirred and refluxed for 17 hours. After cooling, the reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated to give 4-phenyl-5,6,7,8-tetrahydro-
1.8 g of 1,6-naphthyridine-2 (1H) -one was obtained. 245-248 ° C Decomposition Raw Material Preparation Example 12

[0082]

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4-phenyl-obtained in Raw Material Preparation Example 11
1.8 g of 5,6,7,8-tetrahydro-1,6-naphthyridine-2 (1H) -one, 1.1 g of methyl iodide,
1.1 g of potassium carbonate, 130 m of dimethylformamide
The mixture of 1 was stirred overnight at room temperature. The reaction mixture was concentrated, water was added, and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 0.74 g of 6-methyl-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one. Melting point 232-235 ° C. (decomposition) Raw material preparation example 13

[0084]

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4-phenyl-obtained in Raw Material Preparation Example 1
1,5,7,8-Tetrahydrothiopyrano [4,3-
b] A mixture of 1.2 g of pyridin-2-one and 2.5 ml of phenylphosphonic acid dichloride was stirred at 165 ° C. for 1 hour. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 2-chloro-4-phenyl-7,8-dihydro-5H-thiopyrano [4,3-
b] 1.2 g of pyridine was obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.81
-3.52 (m, 4H), 3.64 (s, 2H), 7.
01-7.76 (m, 6H) Raw material preparation example 14

[0087]

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3.5 g of 4- (4-fluorophenyl) -1,5,7,8-tetrahydrothiopyrano [4,3-b] pyridin-2-one obtained in Raw Material Preparation Example 2 and dichloride 150-160 of a mixture of 10 ml of phenylphosphonic acid
The mixture was stirred at ° C for 6.5 hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. Wash the organic layer with water,
After drying over magnesium sulfate, the mixture was concentrated. By purifying the residue by silica gel column chromatography, 2
-Chloro-4- (4-fluorophenyl) -7,8-dihydro-5H-thiopyrano [4,3-b] pyridine 3.
7 g were obtained.

¹ H-NMR (CDCl ₃ ) δ: 2.98
-3.02 (t, 2H, J = 6.6Hz), 3.23-
3.28 (t, 2H, J = 6.6Hz), 3.61
(S, 2H), 7.10-7.30 (m, 5H) Raw material preparation example 15

[0090]

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4- (4-chlorophenyl) -1,5,7,8-tetrahydrothiopyrano [4,3-b] pyridin-2-one obtained in Preparation Example 3 4.4 g, phenyl dichloride Mix a mixture of 18 ml of phosphonic acid at 160-170 ° C.
Stirred for 3.5 hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. By purifying the residue by silica gel column chromatography, 2-
Chloro-4- (4-chlorophenyl) -7,8-dihydro-5H-thiopyrano [4,3-b] pyridine 4.6 g
I got

¹ H-NMR (CDCl ₃ ) δ: 2.97
-3.02 (t, 2H, J = 6.6Hz), 3.23-
3.28 (t, 2H, J = 6.6Hz), 3.60
(S, 2H), 7.10 (s, 1H), 7.21-7.
47 (m, 4H) Raw material preparation example 16

[0093]

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4- (4-Methylphenyl) -1,5,7,8-tetrahydrothiopyrano [4,3-b] pyridin-2-one obtained in Preparation Example 4 4.4 g, dichloride Add a mixture of 15 ml of phenylphosphonic acid at 160-170 ° C.
Stirred for 2.5 hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. By purifying the residue by silica gel column chromatography, 2-
Chloro-4- (4-methylphenyl) -7,8-dihydro-5H-thiopyrano [4,3-b] pyridine 3.6 g
I got

¹ H-NMR (CDCl ₃ ) δ: 2.42
(S, 3H), 2.97-3.02 (t, 2H, J =
6.6 Hz), 3.23-3.28 (t, 2H, J =
6.6 Hz), 3.65 (s, 2H), 7.11-7.
29 (m, 5H) Raw Material Preparation Example 17

[0096]

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7-Phenyl-obtained in Raw Material Preparation Example 5
3,4-dihydro-2H-thieno [3,2-b] pyridin-5-one 3.7 g, phenylphosphonic acid dichloride 15
The ml mixture was stirred at 160-170 ° C. for 2 hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. After washing the organic layer with water and drying over magnesium sulfate,
Concentrated. The residue was purified by silica gel column chromatography to give 5-chloro-7-phenyl-
2,3-dihydrothieno [3,2-b] pyridine 1.5
g was obtained.

¹ H-NMR (CDCl ₃ ) δ: 3.31
-3.49 (m, 4H), 7.15 (s, 1H), 7.
43-7.57 (m, 5H) Raw material preparation example 18

[0099]

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6-Benzyl-4 obtained in Raw Material Preparation Example 7
-Phenyl-5,6,7,8-tetrahydro-1,6-
A mixture of naphthyridin-2 (1H) -one (27 g) and phenylphosphonic acid dichloride (90 ml) was added to the mixture at 160 to 170 ° C. for 2 times.
Stirred for hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, made basic with ammonia water, and then extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated to obtain 28.5 g of 6-benzyl-2-chloro-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine. . Melting point 147 to 148 ° C. Raw material preparation example 19

[0101]

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6-Benzyl-4 obtained in Raw Material Preparation Example 8
-(4-Fluorophenyl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one 40
15 g of a mixture of 50 ml of phenylphosphonic acid dichloride
The mixture was stirred at 0 to 160 ° C for 7 hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 60.7 g of 6-benzyl-2-chloro-4- (4-fluorophenyl) -5,6,7,8-tetrahydro-1,6-naphthyridine. . Melting point 128 to 131 ° C. Raw material preparation example 20

[0103]

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6-Benzyl-4 obtained in Raw Material Preparation Example 9
-(4-Chlorophenyl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one 17.
1 g of a mixture of 4 g and 30 ml of phenylphosphonic acid dichloride.
It stirred at 50-160 degreeC for 6 hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 6-benzyl-2-chloro-4- (4-chlorophenyl) -5,6,7,8-tetrahydro-1,6-naphthyridine 18.1 g.

¹ H-NMR (CDCl ₃ ) δ: 2.74
-2.79 (t, 2H, J = 6.6Hz), 3.02-
3.07 (t, 2H, J = 6.6Hz), 3.51
(S, 2H), 3.61 (s, 2H), 7.00 (s,
1H), 7.17-7.42 (m, 9H) Raw material preparation example 21

[0106]

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6-Benzyl-obtained in Preparation Example 10
4- (2-chlorophenyl) -5,6,7,8-tetrahydro-1,6-naphthyridin-2 (1H) -one 10
g, and a mixture of 20 ml of phenylphosphonic acid dichloride for 15
The mixture was stirred at 0 to 160 ° C for 7 hours. After cooling, the reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to obtain 6-benzyl-2-chloro-4- (2-chlorophenyl) -5,6,7,8-tetrahydro-1,6-naphthyridine 7.9 g.

¹ H-NMR (CDCl ₃ ) δ: 2.64
-2.87 (m, 2H), 3.03-3.08 (m, 2
H), 3.30-3.44 (m, 2H), 3.51-
3.65 (m, 2H), 6.99 (s, 1H), 7.1
2-7.49 (m, 9H) Raw material preparation example 22

[0109]

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6-methyl-4-phenyl-5,6,7,
8-Tetrahydro-1,6-naphthyridine-2 (1H)
A mixture of 0.7 g of -one and 3 ml of phenylphosphonic acid dichloride was stirred at 160 to 170 ° C for 3.5 hours. After cooling,
The reaction solution was dissolved in chloroform, poured into ice water, stirred, basified with aqueous ammonia, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate and then concentrated to obtain 0.7 g of 2-chloro-6-methyl-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine. . Melting point 90-93 ° C Example 1

[0111]

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2-Chloro-4 obtained in Raw Material Preparation Example 13
A mixture of 1.5 g of -phenyl-7,8-dihydro-5H-thiopyrano [4,3-b] pyridine, 5 ml of 1-ethylpiperazine and 0.9 g of potassium iodide was heated to 170 ° C.
For 9 hours. After cooling, water was added and the mixture was extracted with chloroform. After washing the organic layer with water and drying over magnesium sulfate,
Concentrated. The residue was purified by silica gel column chromatography to give 2- (4-ethylpiperazine-
1-yl) -4-phenyl-7,8-dihydro-5H-
Thiopyrano [4,3-b] pyridine was obtained. Oxalic acid was added to this to give an oxalate salt, which was then recrystallized from hydrous ethanol to obtain 1.3 g of the corresponding oxalate salt 1/4 hydrate. Melting point 215 to 217 ° C. (decomposition) Example 2

[0113]

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2- (4-Ethylpiperazin-1-yl) -4-phenyl-7,8-dihydro-5H-thiopyrano [4,3-b] pyridine oxalate.1 obtained in Example 1 To a solution of 0.5 g of tetrahydrate in 30 ml of acetic acid, 0.14 g of 30% hydrogen peroxide was added with stirring, and the mixture was stirred at room temperature for 2.
Stir for 5 hours. After water was added to the reaction solution, an excess amount of sodium hydrosulfite aqueous solution was added and concentrated.
Water was added to the residue, basified with potassium carbonate, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 2- (4-ethylpiperazin-1-yl) -4-phenyl-7,8-dihydro-5H-thiopyrano [4,3-b] pyridine-6-oxide. Got To this, add oxalic acid to make oxalate,
Recrystallization from methanol gave 0.1 g of the corresponding oxalate hemihydrate. Melting point 193-19
5 ° C. (decomposition) Example 3

[0115]

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2-Chloro-4 obtained in Raw Material Preparation Example 14
-(4-Fluorophenyl) -7,8-dihydro-5H
A mixture of 5 g of thiopyrano [4,3-b] pyridine, 15 g of piperazine, 3 g of potassium iodide and 10 ml of N-methyl-2-pyrrolidone was stirred at 120 to 130 ° C for 10 hours. After cooling, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated to give 2- (1-piperazinyl) -4- (4-fluorophenyl) -7,8-dihydro-5H-thiopyrano [4,3-b]. Pyridine was obtained. Oxalic acid was added to this to give an oxalate salt, which was then recrystallized from water-containing methanol to obtain 2.9 g of the corresponding oxalate salt. Melting point 21
6 to 218 ° C. (decomposition) Example 4

[0117]

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2-Chloro-4 obtained in Raw Material Preparation Example 14
-(4-Fluorophenyl) -7,8-dihydro-5H
A mixture of 2 g of thiopyrano [4,3-b] pyridine, 10 ml of 1-methylpiperazine and 1.2 g of potassium iodide was stirred at 140 to 145 ° C for 27 hours. After cooling, water was added and the precipitated crystals were collected by filtration. It was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. By purifying the residue by silica gel column chromatography, 4- (4-fluorophenyl) -2- (4-
Methylpiperazin-1-yl) -7,8-dihydro-5
H-thiopyrano [4,3-b] pyridine was obtained. To this, fumaric acid was added to give a fumarate, which was recrystallized from a mixed solvent of methanol and acetone to obtain 0.25 g of the corresponding fumarate. Melting point 189-191 ° C (decomposition) Example 5

[0119]

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4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) -obtained in Example 4
To a solution of 1.3 g of 7,8-dihydro-5H-thiopyrano [4,3-b] pyridine fumarate in 30 ml of acetic acid was added 0.45 g of 30% hydrogen peroxide under stirring, and the mixture was stirred at room temperature for 3 hours. . After water was added to the reaction solution, an excess amount of sodium hydrosulfite aqueous solution was added and concentrated. Water was added to the residue, basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) -7,
8-Dihydro-5H-thiopyrano [4,3-b] pyridine-6-oxide was obtained. Oxalic acid was added to this to give an oxalate salt, which was recrystallized from hydrous ethanol to obtain 0.6 g of the corresponding oxalate salt. Melting point 208-
211 ° C. (decomposition) Example 6

[0121]

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4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) -obtained in Example 5
7,8-Dihydro-5H-thiopyrano [4,3-b] pyridine-6-oxide oxalate 1.2 g of formic acid 20
While stirring, 0.6 g of 30% hydrogen peroxide solution was added to the ml solution, and the mixture was allowed to stand at room temperature overnight. After adding water to the reaction solution, an excess amount of an aqueous sodium thiosulfate solution was added and the mixture was concentrated. Water was added to the residue, basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and then recrystallized from ethyl acetate to give 4- (4-fluorophenyl) -2- (4-methylpiperazin-1-yl) -7,8-dihydro-5H-.
0.25 g of thiopyrano [4,3-b] pyridine-6,6-dioxide was obtained. Melting point 205-207 ° C (decomposition) Example 7

[0123]

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2-Chloro-4 obtained in Raw Material Preparation Example 14
-(4-Fluorophenyl) -7,8-dihydro-5H
A mixture of 2 g of -thiopyrano [4,3-b] pyridine, 10 ml of 1-ethylpiperazine and 1.2 g of potassium iodide was stirred at 140 to 145 ° C for 27 hours. After cooling, water was added and the precipitated crystals were collected by filtration. It was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 2- (4-ethylpiperazin-1-yl)-
4- (4-fluorophenyl) -7,8-dihydro-5
H-thiopyrano [4,3-b] pyridine was obtained. Oxalic acid was added to this to give an oxalate salt, which was recrystallized from methanol to obtain 1.4 g of the corresponding oxalate salt. Melting point 226-228 ° C (decomposition) Example 8

[0125]

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2-Chloro-4 obtained in Raw Material Preparation Example 15
-(4-chlorophenyl) -7,8-dihydro-5H-
A mixture of 4.7 g of thiopyrano [4,3-b] pyridine, 25 ml of 1-ethylpiperazine and 2.6 g of potassium iodide was stirred at 140 ° C. for 28 hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 4- (4-chlorophenyl) -2- (4-ethylpiperazin-1-yl) -7,8-dihydro-5H-thiopyrano [4,3-
b] Pyridine was obtained. To this, fumaric acid was added to give a fumarate, which was recrystallized from ethanol to obtain 3 g of the corresponding fumarate. Melting point 197-198 ° C (decomposition) Example 9

[0127]

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4- (4-chlorophenyl) -2- (4-ethylpiperazin-1-yl) -obtained in Example 8
To a solution of 5.2 g of 7,8-dihydro-5H-thiopyrano [4,3-b] pyridine fumarate in 50 ml of acetic acid was added 1.4 g of 30% hydrogen peroxide under stirring, and the mixture was stirred at room temperature for 6 hours. . After adding water to the reaction solution, an excess amount of sodium sulfite aqueous solution was added and the mixture was concentrated. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 4- (4-chlorophenyl) -2- (4-ethylpiperazin-1-yl)-.
7,8-Dihydro-5H-thiopyrano [4,3-b] pyridine-6-oxide was obtained. To this, fumaric acid was added to give a fumarate, which was recrystallized from a mixed solvent of ethyl acetate and ethanol to obtain 1.8 g of a corresponding 3/2 fumarate. Melting point 191-192 ° C (decomposition) Example 10

[0129]

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4- (4-chlorophenyl) -2- (4-ethylpiperazin-1-yl) -obtained in Example 9
A solution of 0.9 g of 7,8-dihydro-5H-thiopyrano [4,3-b] pyridine-6-oxide 3/2 fumarate in 20 ml of formic acid was stirred and 30% aqueous hydrogen peroxide 0.52 was added.
g was added and left overnight at room temperature. After adding water to the reaction solution, an excess amount of sodium sulfite aqueous solution was added and the mixture was concentrated. Water was added to the residue, basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and then concentrated to give 4- (4-chlorophenyl) -2- (4-ethylpiperazin-1-yl)-.
7,8-Dihydro-5H-thiopyrano [4,3-b] pyridine-6,6-dioxide was obtained. To this, fumaric acid was added to give a fumarate, which was recrystallized from ethanol to give 0.67 g of the corresponding fumarate hemihydrate.
I got Melting point 196-198 ° C (decomposition) Example 11

[0131]

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2-Chloro-4 obtained in Raw Material Preparation Example 16
-(4-Methylphenyl) -7,8-dihydro-5H-
A mixture of 3.6 g of thiopyrano [4,3-b] pyridine, 20 ml of 1-ethylpiperazine and 2.2 g of potassium iodide was stirred at 160 to 170 ° C for 18 hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. By purifying the residue by silica gel column chromatography, 2-
(4-Ethylpiperazin-1-yl) -4- (4-methylphenyl) -7,8-dihydro-5H-thiopyrano [4,3-b] pyridine was obtained. To this, fumaric acid was added to form a fumarate and recrystallized from ethanol to obtain 2.1 g of a corresponding fumarate hemihydrate. Melting point 170-172 ° C (decomposition) Example 12

[0133]

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2- (4-Ethylpiperazin-1-yl) -4- (4-methylphenyl) -obtained in Example 11
3,8-Dihydro-5H-thiopyrano [4,3-b] pyridine fumarate hemihydrate 3 g acetic acid 50 ml
While stirring, 0.96 g of 30% hydrogen peroxide solution was added to the solution,
Left at room temperature overnight. After adding water to the reaction solution, an excess amount of sodium sulfite aqueous solution was added and the mixture was concentrated. Water was added to the residue, basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and then recrystallized from ethyl acetate to give 2-
1.1 g of (4-ethylpiperazin-1-yl) -4- (4-methylphenyl) -7,8-dihydro-5H-thiopyrano [4,3-b] pyridine-6-oxide was obtained. Melting point 138-139 [deg.] C. Example 13

[0135]

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2-Chloro-4 obtained in Raw Material Preparation Example 14
-(4-Fluorophenyl) -7,8-dihydro-5H
-3.9 g of thiopyrano [4,3-b] pyridine, 25 ml of 1-piperazine ethanol, 2.2 g of potassium iodide
The mixture was stirred at 140-150 ° C for 18.5 hours.
After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. By purifying the residue by silica gel column chromatography, 4- (4-fluorophenyl) -2- (4- (2-
Hydroxyethyl) piperazin-1-yl) -7,8-
Dihydro-5H-thiopyrano [4,3-b] pyridine was obtained. Fumaric acid was added to this to give a fumarate, which was recrystallized from ethyl acetate to obtain 2.3 g of the corresponding fumarate. Melting point 167-169 ° C (decomposition) Example 14

[0137]

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4- (4-fluorophenyl) -2- {4- (2-hydroxyethyl) -1 obtained in Example 13
-Piperazinyl} -7,8-dihydro-5H-thiopyrano [4,3-b] pyridine-fumarate 0.4 g 0.43 g of acetic acid 5 ml was added to a solution of acetic acid 5 ml under stirring at room temperature. Stir for 8 hours. After adding water to the reaction solution,
An excess amount of sodium sulfite aqueous solution was added and concentrated. Water was added to the residue, basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 4- (4-fluorophenyl) -2- (4- (2-hydroxyethyl) -1-piperazinyl) -7,8-dihydro-5H-thiopyrano [4. 3-b] Pyridine-6-oxide was obtained. To this, fumaric acid was added to give a fumaric acid salt, which was then recrystallized from a mixed solvent of ethyl acetate and ethanol to obtain 0.16 g of the corresponding fumaric acid salt.

¹ H-NMR (DMSO-d ₆ ) δ: 2.
46-2.57 (m, 6H), 2.88-2.99.
(M, 4H), 3.20-3.81 (m, 8H), 7.
28-7.43 (m, 5H) Example 15

[0140]

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5-Chloro-7 obtained in Raw Material Preparation Example 17
A mixture of 5.5 g of phenyl-2,3-dihydrothieno [3,2-b] pyridine, 20 ml of 1-ethylpiperazine and 3.7 g of potassium iodide at 150 to 170 ° C. was used.
Stirred for hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 5- (4-ethylpiperazine-1-
Yl) -7-phenyl-2,3-dihydrothieno [3,
2-b] pyridine was obtained. To this, fumaric acid was added to form a fumarate, which was recrystallized from methanol to obtain 3.6 g of a corresponding fumarate. Melting point 189-190
C (decomposition) Example 16

[0142]

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4.6 g of 5- (4-ethylpiperazin-1-yl) -7-phenyl-2,3-dihydrothieno [3,2-b] pyridine fumarate obtained in Example 15
30 ml of hydrogen peroxide solution under stirring in 50 ml of acetic acid solution of 1.
6 g was added, and the mixture was stirred at room temperature for 4 hours. After adding water to the reaction solution, an excess amount of sodium sulfite aqueous solution was added and the mixture was concentrated. Water was added to the residue, basified with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 5- (4-ethylpiperazin-1-yl) -7-phenyl-2,3-dihydrothieno [3,2-b] pyridine-1-oxide. To this, fumaric acid was added to give a fumarate, which was then recrystallized from a mixed solvent of ethanol and acetone to obtain 2.1 g of the corresponding fumarate. Melting point 185-186
C (decomposition) Example 17

[0144]

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2-Chloro-6 obtained in Raw Material Preparation Example 22
-Methyl-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine (1.1 g), 1-ethylpiperazine (5 ml), and potassium iodide (0.7 g) were added to a mixture of 170 g.
Stirred at C for 8 hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 2- (4-ethylpiperazin-1-yl) -6-methyl-4-phenyl-5,6,6.
7,8-Tetrahydro-1,6-naphthyridine was obtained.
Oxalic acid was added to this to give an oxalate salt, which was recrystallized from methanol to obtain 0.4 g of the corresponding dioxalate monohydrate. Melting point 186-188 ° C (decomposition) Example 18

[0146]

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Starting material 6-benzyl-obtained in Preparation Example 18
A mixture of 13.5 g of 2-chloro-4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine, 30 ml of 1-ethylpiperazine and 9 g of potassium iodide was added to 15
Stirred at 0 ° C. for 12.5 hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-benzyl-2-
(4-Ethylpiperazin-1-yl) -4-phenyl-
5,6,7,8-Tetrahydro-1,6-naphthyridine was obtained. Oxalic acid was added to this to give an oxalate salt, which was then recrystallized from ethyl acetate to obtain 14 g of the corresponding dioxalate monohydrate. Melting point 142-143 ° C Example 19

[0148]

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6-benzyl-2-obtained in Example 18
(4-Ethylpiperazin-1-yl) -4-phenyl-
5,6,7,8-Tetrahydro-1,6-naphthyridine dioxalate monohydrate 16 g, 10% palladium carbon 6 g, hydrazine monohydrate 2.2 ml, ethanol 2
The 00 ml mixture was stirred and refluxed for 30 minutes. After cooling, the catalyst was filtered off and concentrated. Water was added to the residue and extracted with ethyl acetate. After washing the organic layer with water and drying over magnesium sulfate,
By concentrating, 2- (4-ethylpiperazine-1)
8 g of -yl) -4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine were obtained.

¹ H-NMR (CDCl ₃ ) δ: 1.12
(T, 3H), 2.46 (t, 2H), 2.55 (d
d, 4H), 2.86 (dd, 2H), 3.18 (d
d, 2H), 3.55 (dd, 4H), 3.74 (s,
2H), 6.37 (s, 1H), 7.24 to 7.28.
(M, 2H), 7.35 to 7.40 (m, 3H) Example 20

[0151]

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2- (4-Ethylpiperazin-1-yl) -4-phenyl-5,6,7,8 obtained in Example 19
1.2 g of tetrahydro-1,6-naphthyridine and 0.45 g of triethylamine were dissolved in 30 ml of chloroform, 0.6 ml of benzoyl chloride was added dropwise with stirring, and the mixture was left at room temperature overnight. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and recrystallized from a mixed solvent of ethyl acetate and diisopropyl ether to give 6-benzoyl-2- (4-ethylpiperazin-1-yl) -4-.
0.7 g of phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine was obtained. Melting point 142-144 ° C Example 21

[0153]

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2- (4-Ethylpiperazin-1-yl) -4-phenyl-5,6,7,8 obtained in Example 19
A mixture of tetrahydro-1,6-naphthyridine 1.3 g and acetic anhydride 5 ml was stirred at 80 ° C. for 5 hours. After cooling,
The reaction mixture was concentrated, water was added to the residue, the mixture was made basic with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-acetyl-2- (4-ethylpiperazine-1-
Yl) -4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine was obtained. Oxalic acid was added thereto to form an oxalate salt, which was then recrystallized from methanol to obtain 0.4 g of the corresponding dioxalate hemihydrate. Melting point 111-113 ° C Example 22

[0155]

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2- (4-Ethylpiperazin-1-yl) -4-phenyl-5,6,7,8 obtained in Example 19
1.5 g of tetrahydro-1,6-naphthyridine and 0.56 g of triethylamine were dissolved in 20 ml of chloroform, and 0.6 g of dimethylcarbamoyl chloride was added with stirring.
Was added dropwise, and the mixture was left at room temperature overnight. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-dimethylcarbamoyl-2- (4-ethylpiperazine-1-).
Yl) -4-phenyl-5,6,7,8-tetrahydro-1,6-naphthyridine was obtained. To this, oxalic acid was added to form an oxalate salt, which was then recrystallized from a mixed solvent of methanol and acetone to give the corresponding dioxalate salt
0.5 g of dihydrate was obtained. Melting point 168-169 [deg.] C. Example 23

[0157]

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2- (4-Ethylpiperazin-1-yl) -4-phenyl-5,6,7,8 obtained in Example 19
1 g of phenethyl bromide was added dropwise with stirring to a mixture of 1.5 g of tetrahydro-1,6-naphthyridine, 0.8 g of potassium carbonate and 30 ml of dimethylformamide, and then the mixture was stirred at 50 to 60 ° C. for 10 hours. The reaction solution was concentrated, water was added, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography, ethanol hydrochloride was added to give the hydrochloride, and the crystals were recrystallized from a mixed solvent of methanol and acetone to give 2- (4-ethylpiperazin-1-yl) -6-phenethyl-4-phenyl. -5
6,7,8-Tetrahydro-1,6-naphthyridine-2
0.9 g of hydrochloride monohydrate was obtained. Melting point 262-264
C (decomposition) Example 24

[0159]

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Starting material 6-benzyl-obtained in Preparation Example 19
2-chloro-4- (4-fluorophenyl) -5,6,
7,8-Tetrahydro-1,6-naphthyridine 8 g, 1
-Ethylpiperazine 40 ml, potassium iodide 3.8 g
The mixture was stirred at 130-140 ° C for 22 hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-benzyl-2- (4-ethylpiperazine-1-).
Yl) -4- (4-fluorophenyl) -5,6,7,
8-Tetrahydro-1,6-naphthyridine was obtained. To this, fumaric acid was added to give a fumarate, which was recrystallized from a mixed solvent of methanol and ethanol to obtain 6 g of a corresponding 3/2 fumarate. Melting point 218-220 ° C
(Disassembly) Example 25

[0161]

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6-benzyl-2-obtained in Example 24
(4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) -5,6,7,8-tetrahydro-1,
6-naphthyridine 3/2 fumarate 6.2 g, 10%
3 g of palladium carbon, 1.4 ml of hydrazine monohydrate,
A mixture of 80 ml of ethanol was stirred and refluxed for 1 hour. After cooling, the catalyst was filtered off, the mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure to give 2- (4
-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) -5,6,7,8-tetrahydro-1,6-
Obtained naphthyridine.

¹ H-NMR (CDCl ₃ ) δ: 1.14
(T, 3H), 2.42-2.57 (m, 6H), 2.
85 (t, 2H), 3.18 (t, 2H), 3.53-
3.57 (m, 4H), 3.72 (s, 2H), 6.3
4 (s, 1H), 7.05-7.28 (m, 4H) Oxalic acid was added to this to make an oxalate, which was then recrystallized from methanol to give the corresponding dioxalate.
5.4 g of hemihydrate was obtained. Melting point 164-166 ° C Example 26

[0164]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
-5,6,7,8-Tetrahydro-1,6-naphthyridine dioxalate dihydrate 2g, acetic anhydride 40m
The mixture of 1 was stirred at 80 ° C. for 1 hour. After cooling, the reaction mixture was concentrated, water was added to the residue, the mixture was made basic with potassium carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-acetyl-2- (4-ethylpiperazin-1-yl) -4-.
(4-Fluorophenyl) -5,6,7,8-tetrahydro-1,6-naphthylidene was obtained. To this, fumaric acid was added to form a fumarate, which was recrystallized from a mixed solvent of ethanol and acetone to obtain 1.6 g of a corresponding 3/2 fumarate. Melting point 187-189 ° C Example 27

[0166]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
2.1 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate hemihydrate and 0.6 g of triethylamine were dissolved in 40 ml of dichloromethane, and methylsulfonyl chloride 0 was added under stirring. After dropping 0.8 g, the mixture was left overnight at room temperature. Water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and then recrystallized from ethyl acetate to give 2- (4-ethylpiperazin-1-yl)-
1.1 g of 4- (4-fluorophenyl) -6-methylsulfonyl-5,6,7,8-tetrahydro-1,6-naphthyridine was obtained. Melting point 180-182 ° C (decomposition) Example 28

[0168]

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6-Benzyl-obtained in Preparation Example 20
2-chloro-4- (4-chlorophenyl) -5,6
7,8-Tetrahydro-1,6-naphthyridine 7 g, 1
-Ethylpiperazine 20 ml, potassium iodide 3.2 g
The mixture was stirred at 140 ° C. for 8.5 hours. After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-benzyl-4- (4-chlorophenyl) -2- (4-ethylpiperazin-1-yl) -5,6,7,8-tetrahydro-1,6. -Naphthyridine was obtained. Fumaric acid was added to this to give a fumarate, which was recrystallized from ethyl acetate and ethanol to obtain 1.7 g of a corresponding difumarate.

¹ H-NMR (DMSO-d ₆ ) δ: 1.
09-1.14 (t, 3H, J = 6.6Hz), 2.6
4-2.77 (m, 10H), 3.36 (s, 2H),
3.50-3.68 (m, 6H), 6.53 (s, 1
H), 7.21-7.50 (m, 9H) Example 29

[0171]

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6-Benzyl-obtained in Preparation Example 21
2-chloro-4- (2-chlorophenyl) -5,6
7,8-Tetrahydro-1,6-naphthyridine 7.9
A mixture of g, 1-ethylpiperazine 25 ml and potassium iodide 3.6 g was stirred at 140 ° C. for 13.5 hours.
After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-benzyl-4- (2-chlorophenyl) -2-.
(4-Ethylpiperazin-1-yl) -5,6,7,8
-Tetrahydro-1,6-naphthyridine was obtained. Oxalic acid was added thereto to form an oxalate salt, which was then recrystallized from ethanol and acetone to obtain 4.2 g of the corresponding dioxalate salt / 3/2 hydrate. Melting point 167-169 ° C
(Disassembly) Example 30

[0173]

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Starting material 6-benzyl-obtained in Preparation Example 19
2-chloro-4- (4-fluorophenyl) -5,6,
7,8-Tetrahydro-1,6-naphthyridine 8 g, 1
40 ml piperazine ethanol, potassium iodide 3.
8 g of the mixture was stirred at 140-150 ° C for 15 hours.
After cooling, water was added and the mixture was extracted with chloroform. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-benzyl-4- (4-fluorophenyl) -2.
-(4- (2-Hydroxyethyl) piperazin-1-yl) -5,6,7,8-tetrahydro-1,6-naphthyridine was obtained. To this, fumaric acid was added to form a fumarate, which was then recrystallized from methanol to give the corresponding 3
2.2 g of the / 2 fumarate salt was obtained. Melting point 211-212 ° C
(Disassembly) Example 31

[0175]

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6-benzyl-4-obtained in Example 30
(4-Fluorophenyl) -2- (4- (2-hydroxyethyl) -1-piperazinyl) -5,6,7,8-tetrahydro-1,6-naphthyridine.3 / 2 fumarate 5 g, 10% A mixture of 2.5 g of palladium carbon, 3 ml of hydrazine monohydrate and 100 ml of methanol was stirred and refluxed for 7 hours. After cooling, the catalyst was filtered off, the mixture was concentrated, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate, and then concentrated to give 4-
(4-Fluorophenyl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) -5,6,7,8-
3 g of tetrahydro-1,6-naphthyridine was obtained. Melting point 148-149 ° C Example 32

[0177]

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4- (4-Fluorophenyl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) -5,6,7,8-tetrahydro-obtained in Example 31
1,6-naphthyridine 1.5 g of tetrahydrofuran 5
0.45 g of acetic anhydride was added dropwise to the 0 ml solution with stirring, and the mixture was left at room temperature overnight. The reaction solution is concentrated, water is added,
It was made basic with potassium carbonate and extracted with chloroform.
The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give 6-acetyl-4- (4-fluorophenyl) -2- (4- (2-hydroxyethyl) piperazin-1-yl) -5,6,7,8. -Tetrahydro-
1,6-naphthyridine was obtained. To this, add oxalic acid to make oxalate, and recrystallize from ethanol to obtain the corresponding 3/2 oxalate hemihydrate 0.9 g.
I got Melting point 155-158 [deg.] C. (decomposition) Example 33

[0179]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
20 ml of a pyridine solution containing 0.3 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate hemihydrate and 5 mg of dimethylaminopyridine
To this, 0.14 g of benzoyl chloride was added under ice cooling, and 1
Stirred for hours. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 6-benzoyl-2- (4-ethylpiperazin-1-yl) -4- (4-fluorophenyl).
-5,6,7,8-Tetrahydro-1,6-naphthyridine was obtained. Oxalic acid was added to this to make an oxalate salt, which was then recrystallized from isopropyl alcohol to obtain 0.12 g of the corresponding 3/2 oxalate monohydrate. Melting point 122-124 ° C Example 34

[0181]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
A dichloromethane solution 20 containing 0.75 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate hemihydrate and 0.23 g of triethylamine 20.
0.55 g of trifluoroacetic anhydride was added to ml under ice cooling, and the mixture was stirred for 1 hour. After the reaction, the mixture was treated with an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to give 2- (4-ethylpiperazin-1-yl) -4- (4-fluorophenyl) -6-trifluoro. Acetyl-5,6,7,8-
Tetrahydro-1,6-naphthyridine was obtained. to this,
After adding oxalic acid to make oxalate, recrystallize from mixed solvent of methanol and acetone to give the corresponding 2
0.67 g of oxalate hemihydrate was obtained. Melting point 13
4-136 ° C Example 35

[0183]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
20 ml of a dichloromethane solution containing 0.5 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate hemihydrate and 0.2 g of triethylamine
Under ice-cooling, cyclohexylcarbonyl chloride 0.
10 ml of a solution of 25 g of dichloromethane was added. After the reaction, the mixture was treated with an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 6-
Cyclohexylcarbonyl-2- (4-ethylpiperazin-1-yl) -4- (4-fluorophenyl) -5,
6,7,8-Tetrahydro-1,6-naphthyridine was obtained. Oxalic acid was added thereto to form an oxalate salt, which was then recrystallized from methanol to obtain 0.4 g of a corresponding dioxalate salt. 163-165 ° C.

Example 36

[0186]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
A dichloromethane solution 20 containing 0.54 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate hemihydrate and 0.24 g of triethylamine 20.
0.3 ml of 4-fluorophenylcarbonyl chloride was added to ml under ice cooling, and the mixture was stirred for 1 hour. After the reaction, the mixture was treated with an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 2- (4-
Ethylpiperazin-1-yl) -4- (4-fluorophenyl) -6- (4-fluorophenylcarbonyl)-
5,6,7,8-Tetrahydro-1,6-naphthyridine was obtained. After adding oxalic acid to make oxalate,
Recrystallization from methanol gave 0.34 g of the corresponding dioxalate monohydrate. Melting point 178 ° C Example 37

[0188]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
A dichloromethane solution 20 containing 0.56 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate dihydrate and 0.25 g of triethylamine 20.
To 1 ml, under ice cooling, 0.37 g of 1-naphthoic acid chloride
10 ml of a dichloromethane solution of was added and stirred for 1 hour. After the reaction, the mixture was treated with an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 2- (4-ethylpiperazin-1-yl) -6-
(1-naphthoyl) -5,6,7,8-tetrahydro-
1,6-naphthyridine was obtained. To this, citric acid was added to form a citrate, which was then recrystallized from methanol to obtain 0.14 g of the corresponding citrate / hemihydrate. Melting point 164-166 ° C Example 38

[0190]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
A dichloromethane solution 20 containing 0.59 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate dihydrate and 0.27 g of triethylamine.
10 ml of a dichloromethane solution of 0.5 g of 2-naphthoic acid chloride was added to ml under ice-cooling, and the mixture was stirred for 1 hour.
After the reaction, the mixture was treated with an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure,
2- (4-Ethylpiperazin-1-yl) -6- (2-
Naphthoyl) -5,6,7,8-tetrahydro-1,6
-Naphthyridine was obtained. By adding citric acid to this to form a citrate, and recrystallizing from methanol,
0.64 g of the corresponding citrate hemihydrate was obtained.
Melting point 164-166 ° C Example 39

[0192]

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Starting material 6-benzyl-obtained in Preparation Example 19
2-chloro-4- (4-fluorophenyl) -5,6,
100 m 1,3-dimethyl-2-imidazolidinone solution containing 6 g of 7,8-tetrahydro-1,6-naphthyridine, 3 g of potassium iodide and 14.7 g of piperazine
1 was heated and stirred at 140 to 150 ° C. for 24 hours. After the reaction, the reaction solution was acidified with hydrochloric acid and extracted with ethyl acetate, and then the organic layer was removed. The aqueous layer was made basic with an aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6-benzyl-4- (4-fluorophenyl) -2- (1-piperazinyl) -5,6,7,8-tetrahydro-1,6-naphthyridine. Oxalic acid was added to this to give an oxalate salt, which was then recrystallized from methanol to obtain 4.6 g of the corresponding dioxalate hemihydrate. Melting point 2
51 ° C. (decomposition) Example 40

[0194]

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2- (4-Ethylpiperazin-1-yl) -4- (4-fluorophenyl) obtained in Example 25
A dichloromethane solution 20 containing 0.59 g of -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate dihydrate and 0.27 g of triethylamine.
Under ice-cooling, 10 ml of a dichloromethane solution containing 0.5 g of 1-naphthoic acid chloride was added to ml, and the mixture was stirred for 1 hour.
After the reaction, the mixture was treated with an aqueous potassium carbonate solution and extracted with chloroform. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure,
2- (4-Ethylpiperazin-1-yl) -4- (4-
Fluorophenyl) -6- (1-naphthoyl) -5,
6,7,8-Tetrahydro-1,6-naphthyridine was obtained. Citric acid was added to this to form a citrate salt, which was then recrystallized from methanol to give the corresponding citrate salt.
0.64 g of hemihydrate was obtained. Melting point 164-166 ° C Example 41

[0196]

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6-benzyl-4-obtained in Example 39
(4-Fluorophenyl) -2- (1-piperazinyl)
A dimethylformamide solution containing -5,6,7,8-tetrahydro-1,6-naphthyridine dioxalate hemihydrate 1 g, potassium carbonate 0.15 g and benzyl bromide 0.32 g was added at 60 ° C. The mixture was heated and stirred for 3 hours. After the reaction, the reaction solution was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, 2- (4-benzylpiperazin-1-yl)-
6-benzyl-4- (4-fluorophenyl) -5,
6,7,8-Tetrahydro-1,6-naphthyridine was obtained. Oxalic acid was added to this to give an oxalate salt, which was then recrystallized from methanol to obtain 0.26 g of the corresponding 5/2 oxalate hemihydrate. Melting point 186-1
88 ° C Example 42

[0198]

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Starting material 6-benzyl-obtained in Preparation Example 19
2-chloro-4- (4-fluorophenyl) -5,6,
7,8-Tetrahydro-1,6-naphthyridine 6.34
g, potassium iodide 9 g, potassium carbonate 1 g and 4-
Phenylpiperazine was heated and stirred at 160 to 170 ° C. for 4 hours. After the reaction, the reaction solution was treated with water and extracted with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography to give 6-benzyl-4- (4-fluorophenyl) -2- (4-phenylpiperazine-1-.
Yl) -5,6,7,8-tetrahydro-1,6-naphthyridine was obtained. Oxalic acid was added thereto to form an oxalate salt, which was then recrystallized from isopropyl alcohol to obtain 1 g of the corresponding oxalate hemihydrate.
A melting point of 160 to 162 ° C. or less, and examples of the formulation of the compound of the present invention or a pharmaceutically acceptable salt thereof as a medicine will be given.

Formulation Example 1 After thoroughly mixing 0.5 parts of the compound of Example 6, 25 parts of lactose, 35 parts of crystalline cellulose and 3 parts of corn starch,
Knead well with the binder prepared in 2 parts of corn starch.
This kneaded product is sieved with 16 mesh and placed in an oven at 50 ° C.
After drying with, it is sieved with 24 mesh. After thoroughly mixing the kneaded powder thus obtained with 8 parts of corn starch, 11 parts of crystalline cellulose and 9 parts of talc, the mixture is compressed into tablets to give tablets each containing 0.5 mg of the active ingredient.

Formulation Example 2 1.0 mg of the compound of Example 6 and 9.0 m of sodium chloride
g was dissolved in water for injection, filtered to remove the pyrogen, transferred to an ampoule under aseptic conditions, sterilized, and melt-sealed to give an injectable solution containing 1.0 mg of the active ingredient.

[0202]

The pharmacological activity of the compound of the present invention or a pharmaceutically acceptable salt thereof can be proved by the following experimental examples. Experimental Example 1: Affinity for D ₃ receptor; ³ H-YM09
Human D prepared from CCL1.3 derived from mouse fibroblasts into which the 151-2-binding human dopamine D ₃ receptor gene was introduced and expressed
₃ Receptor-expressing membrane is research biochemical international (Research Biochemica
I. International) Cat. N
o. Use D-152. This is a Tris-hydrochloric acid buffer solution 50 mM, sodium chloride 150 mM buffer solution (pH 7.
It is suspended in 4) and used for the experiment.

Next, YM09151-2 tritiated with a test compound at various concentrations was added to a synaptosome suspension.
[Nemonapride] (final concentration: 0.05 nM) is added, and the mixture is reacted at 30 ° C. for 60 minutes. After the reaction, the reaction liquid is changed to Whatman (What
man) GF / B glass filter (trade name) was suction-filtered, and after washing with 50 mM Tris-hydrochloric acid buffer solution, 120 mM sodium chloride, 5 mM potassium chloride buffer solution (pH 7.4), the radioactivity remaining on the filter Is measured with a liquid scintillation counter. Non-specific binding is determined in the presence of 10 ^-5 M spiperone. 5 of the test compound
The 0% inhibitory concentration (IC ₅₀ ) is calculated by non-linear regression to obtain the inhibition constant (Ki value).

Experimental Example 2: Affinity for Dopamine D ₂ Receptor; ³ H-Spiperone Binding Crude synaptic membrane preparation and binding experiments were performed in Crees (I. Cr).
Eese et al. [European Journal of Pharmacology (Eur. J. Pharmaco
l. ), 46, 377 (1977)]. The synaptosome fraction was separated from the rat striatum at 9-10 weeks, and 50 mM Tris containing 120 mM sodium chloride, 5 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, 10 ^-6 M purgerin and 0.1% ascorbic acid. -Suspended in hydrochloric acid buffer (pH 7.1) and used for the experiment.

Next, several concentrations of the test compound and tritiated spiperone (final concentration:
0.2 mM) is added and the mixture is reacted at 37 ° C. for 20 minutes. After the reaction, the reaction solution was added to Whatman GF / B.
After suction filtration with a glass filter (trade name) and washing the filter with 50 mM Tris-HCl buffer (pH 7.7), the radioactivity remaining on the filter is measured with a liquid scintillation counter. Non-specific binding 10 ^-4 M
Determined in the presence of (±) -sulpiride. 5 of the test compound
The 0% inhibitory concentration (IC ₅₀ ) is graphically determined, and the inhibition constant (Ki value) is determined.

Experimental Example 3: Inhibitory effect on quinpyrrole (D ₂ receptor and D ₃ receptor agonist) -induced vomiting Male beagle dogs weighing about 10 kg and female beagle dogs (Hazleton Research) weighing about 8 kg
Products, Inc. , Michigan, U
SA) is used. All experiments are performed in an environment where the animals are housed in individual cages at a temperature of 23 ± 2 ° C and a humidity of 55 ± 5%. The animals that had been fasted from the day before were fed with the solid feed for only 2 hours, and quinpirole was administered after the feeding was completed. Vomiting that develops within 1 hour after administration is observed to observe the time of first vomiting and the number of vomiting. The test compound is administered 30 minutes before quinpyrrole intravenously or orally 60 minutes before.

From various pharmacological experiments including the above pharmacological tests,
It is clear that the Fused Pyridine Compounds of the present invention or pharmaceutically acceptable salts thereof have a higher affinity for the D ₃ receptor as compared to the D ₂ receptor.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/495 AAN A61K 31/495 AAN ACP ACP ACV ACV ADR ADR C07D 471/04 104 C07D 471/04 104Z 113 113 495/04 105 495/04 105A 111 111 (72) Inventor Takafumi Nimura Address: 955 Address, Otomi, Yoshitomi-cho, Tsukigami-gun, Fukuoka Prefecture Yoshitomi Pharmaceutical Co., Ltd. 2nd Research Laboratory (72) Inventor Junichi Maeda Fukuoka No. 955, small holiday, Yoshitomi-cho, Tsukigami-gun, Yamaguchi Prefecture

Claims (6)

[Claims] 1. A compound of the general formula [Wherein R ¹ and R ² are the same or different and each represents hydrogen, halogen, cyano, nitro, amino, alkyl or alkoxy, and R ³ has hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or a substituent. Optionally aryl, optionally substituted arylalkyl, acyl or alkoxycarbonyl, -X-
(Wherein, m is 0, 1 or 2 showing a) or -N (R ⁴⁾ - - the formula -S (O) m (wherein, R ⁴ is hydrogen, alkyl, which may have a substituent Arylalkyl, heteroarylalkyl, acyl, alkylsulfonyl, carbamoyl or alkylcarbamoyl)),
Represents 0 or 1. ] The condensed pyridine compound represented by these, or its pharmaceutically acceptable salt. 2. A compound of the general formula [Wherein R ¹ and R ² are the same or different and each represents hydrogen, halogen, cyano, nitro, amino, alkyl or alkoxy, and R ³ has hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or a substituent. And optionally aryl, optionally substituted arylalkyl, acyl or alkoxycarbonyl, m is 0, 1 or 2, and n is 0 or 1. ] The condensed pyridine compound of Claim 1 represented by these, or its pharmaceutically acceptable salt. 3. A general formula: [Wherein R ¹ and R ² are the same or different and each represents hydrogen, halogen, cyano, nitro, amino, alkyl or alkoxy, and R ³ has hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, or a substituent. Optionally represents aryl, optionally substituted arylalkyl, acyl or alkoxycarbonyl, R ⁴ is hydrogen, alkyl, optionally substituted arylalkyl, heteroarylalkyl, acyl, alkylsulfonyl , Carbamoyl or alkylcarbamoyl). ] The condensed pyridine compound of Claim 1 represented by these, or its pharmaceutically acceptable salt. 4. A pharmaceutical composition comprising the condensed pyridine compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 5. A medicine comprising the condensed pyridine compound according to claim 1 or a pharmaceutically acceptable salt thereof. 6. A dopamine D ₃ receptor blocker comprising the condensed pyridine compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.