JPH1095781A - Arylpiperidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound exhibiting a high affinity to a dopamine D4 receptor without generating an extrapyramidal motor disturbance and having an antipsychotic effect. SOLUTION: This arylpiperidine derivative is a compound of formula I D is C or N; E is CH or N; G is O, S, N or NH; Y is H or a halogen; (n) is 1-4; R<1> is formula II [R<2> is H, a 1-5C alkyl, etc.; Ar is a (substituted) phenyl, etc.], etc.}, e.g. 2-amino-4-(4-fluorophenyl)-5- 2-[4-(6-fluorobenzofuran-3-yl) piperidin-1-yl] ethyl}thiazole. Further, in order to obtain the compound, e.g. it is preferable to halogenate a keto derivative of formula III (Z is Cl, etc.) by a halogenating agent, then react with a thiourea derivative of formula IV, and then react the obtained compound with a piperidine derivative of formula V in an inert solvent in the (non) presence of a base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an arylpiperidine derivative having an antipsychotic effect.

[0002]

2. Description of the Related Art Antipsychotic drugs are used in the treatment of schizophrenia and in behavioral problems in cerebrovascular disorders and senile dementia (aggressive actions,
It is also used to treat mental excitement, wandering, and delirium. However, the conventional dopamine D ₂ receptor antagonist, which is an antipsychotic, has a serious problem of extrapyramidal disorders, which are side effects. On the other hand, the structure and properties of the dopamine D ₄ receptor recently discovered are close to those of the dopamine D ₂ receptor, and the major difference lies in its distribution in the brain. The distribution of dopamine D ₄ receptor in the brain is present in high concentrations in the frontal cortex of the cerebral cortex, which is associated with the onset of schizophrenia, and is low in the striatum involved in the development of extrapyramidal disorders. Therefore, dopamine D ₄
Receptor antagonists are different from dopamine D ₂ receptor antagonists,
It is extremely likely that it will be a new drug for the treatment of schizophrenia without the extrapyramidal side effect (Nature, 350 , 610-
614 (1991); Nature, 358 , 109 (1992); Nature, 365
, 393 (1993); Nature, 365 , 441-445 (1993)).

One such compound is clozapine (clozapin).
pine). Affinity for dopamine D ₄ receptors clozapine has been reported to be higher than the affinity for the dopamine D ₂ receptor (Nature, 350, 610-614 (1991 )).
Further, in clinical trials of clozapine, it has been reported that, unlike dopamine D ₂ receptor antagonists, it is effective for drug-resistant schizophrenia and negative symptoms, and has little extrapyramidal dysfunction (Arch. Gen. Psych). ., 45 , 789-796 (1988)). However, clozapine has been reported to have a blood disorder called agranulocytosis, and deaths have been reported (Summary and Clinical D
ata.Sandoz, Canada Inc. (1990)). Therefore, a dopamine D ₄ receptor antagonist having no such side effects is highly useful as a therapeutic agent for schizophrenia and the like, which is extremely unlikely to cause extrapyramidal disorders.

[0004]

An object of the present invention is to provide a dopamine D ₄ receptor antagonistic compound having an antipsychotic effect without causing extrapyramidal disorders.

[0005]

Means for Solving the Problems As a result of intensive studies on aryl piperidine derivatives, the present inventors have found novel aryl piperidine derivatives having high affinity for dopamine D ₄ receptor, and have completed the present invention. is there. The present invention has the general formula (I)

Embedded image [In the formula, D represents a carbon atom or a nitrogen atom, E represents a CH group or a nitrogen atom, G represents an oxygen atom, a sulfur atom, a nitrogen atom or an NH group, Y represents a hydrogen atom or a halogen atom, n represents an integer of 1 to 4,

R ¹ has the formula (i):

Embedded image (Wherein R ² is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms,
An amino group, a monoalkylamino group having 1 to 5 carbon atoms, a hydroxyl group, an alkoxycarbonyl group having a total of 2 to 6 carbon atoms,
A carbamoyl group, a carboxyl group or a metal salt of a carboxyl group; and Ar represents a substituted or unsubstituted phenyl group or a thienyl group. ), Formula (ii);

Embedded image (Wherein, R ³ represents an alkyl group having 1 to 5 carbon atoms, X ¹
And X ² are different from each other and represent a nitrogen atom or an NH group;
Ar is the same as above. ), Formula (iii);

[0007]

Embedded image (Wherein X ³ and X ⁴ are different from each other and represent a nitrogen atom or an NH group, and Ar is the same as described above); or formula (iv);

Embedded image (Wherein R ⁴ is a hydrogen atom, a mercapto group, and has 1 to 5 carbon atoms)
Wherein Ar is the same as defined above. ). Or a pharmaceutically acceptable salt thereof.

In the present invention, the substituted phenyl group includes a halogen atom, an alkyl group having 1 to 5 carbon atoms,
5 represents a phenyl group having one or two substituents arbitrarily selected from an alkoxy group or a trifluoromethyl group, for example, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, Chlorophenyl group, 4-bromophenyl group, 3,4-dichlorophenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, 2-trifluoromethylphenyl Group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, etc., and as the halogen atom, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and as the alkyl group having 1 to 5 carbon atoms, , Linear, branched or cyclic alkyl groups such as methyl, ethyl, propyl, Propyl group, a butyl group, an isobutyl group,
sec-butyl group, t-butyl group, cyclopropylmethyl group,
It represents a pentyl group, an isopentyl group or the like.

The alkoxy group having 1 to 5 carbon atoms is a linear or branched alkoxy group, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group,
Examples of a butoxy group, an isobutoxy group, a t-butoxy group, a pentoxy group, a 3-methylbutoxy group, and the like as a monoalkylamino group having 1 to 5 carbon atoms include a methylamino group, an ethylamino group, a propylamino group, and an isopropylamino group. Groups, such as a C1-5 alkylthio group, for example, a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, etc .; and a C2-6 alkoxycarbonyl group,
It represents a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, or the like. Further, as the pharmaceutically acceptable salt in the present invention, for example, sulfuric acid, hydrochloric acid,
Salts with mineral acids such as phosphoric acid, and salts with organic acids such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid, methanesulfonic acid, pamoic acid, decanoic acid, and enanthic acid.

The arylpiperidine derivative represented by the general formula (I) can be produced, for example, by the following method. Manufacturing method 1.

Embedded image (Wherein, Ar, n, D, E, G and Y are as defined above, and R ⁵ is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, an amino group, a monoalkylamino group having 1 to 5 carbon atoms) And Z
Represents a chlorine atom, a bromine atom or an iodine atom. )

A ketone derivative represented by the general formula (VI) is halogenated with a halogenating agent in an inert solvent, and then reacted with a thiourea derivative or a thioamide derivative represented by the general formula (V) in an inert solvent. Or by reacting a urea derivative or an amide derivative represented by the general formula (IV) with a sulfurizing agent to obtain a compound represented by the general formula (III), and isolating the compound (III), or General formula without releasing
By reacting the piperidine derivative represented by (II) in an inert solvent in the presence or absence of a base, the compound represented by the general formula (I
-1) An arylpiperidine derivative represented by the following formula (1) can be produced. The inert solvent used in this reaction may be any solvent that does not significantly inhibit the progress of this reaction.Examples include organic carboxylic acids such as acetic acid, chloroform, organic halogen compounds such as carbon tetrachloride, ethanol, isopropanol, and the like. Alcohols, ethers such as tetrahydrofuran and dioxane, hydrocarbons such as benzene and toluene, ketones such as acetone and methyl ethyl ketone;
Examples thereof include N-dimethylformamide, acetonitrile, water, and a mixed solvent thereof. Examples of the halogenating agent include chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, sulfuryl chloride and the like, and examples of the sulfurizing agent include phosphorus pentasulfide and Lawson's reagent. As the base, for example, organic amines such as triethylamine, diisopropylethylamine and pyridine, alcoholates such as sodium ethoxide, alkali metal amides such as sodium amide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogenated Examples thereof include inorganic bases such as sodium, and organic acid salts such as sodium acetate.

Manufacturing method 2.

Embedded image (In the formula, Ar, n, D, E, G, Y and Z are the same as described above, and M ¹ represents sodium, potassium or NH _4. )

A ketone derivative represented by the general formula (VI) is halogenated with a halogenating agent in the same manner as in Production Method 1, and then reacted with a thiocyanate represented by the general formula (VIII) in an inert solvent; By further treating with an acid, the compound represented by the general formula (V
The 2-hydroxythiazole derivative represented by II) can be produced. As the inert solvent used in this reaction, for example, organic carboxylic acids such as acetic acid, carbon tetrachloride, organic halogen compounds such as chloroform, ethanol, alcohols such as isopropanol, diethyl ether,
Examples thereof include ethers such as tetrahydrofuran, hydrocarbons such as toluene, N, N-dimethylformamide, acetonitrile, water, and a mixed solvent thereof. Then, as the acid for the acid treatment, for example, acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, and tosylic acid are used alone or in combination, and alcohols such as methanol and ethanol, dioxane and the like are used. May be reacted in ethers or water. Further, the 2-hydroxythiazole derivative represented by the general formula (VII) is isolated or not isolated, and the piperidine derivative represented by the general formula (II) is present in an inert solvent in the presence or absence of a base. The arylpiperidine derivative represented by the general formula (I-2) can be produced by the following reaction. As the inert solvent used in this reaction, for example, alcohols such as ethanol and isopropanol, ethers such as tetrahydrofuran and dioxane, hydrocarbons such as benzene and toluene, acetone,
Examples thereof include ketones such as methyl ethyl ketone, N, N-dimethylformamide, acetonitrile, water, and a mixed solvent thereof. As the base, for example, organic amines such as triethylamine, diisopropylethylamine and pyridine, alcoholates such as sodium ethoxide, alkali metal amides such as sodium amide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogenated Examples thereof include inorganic bases such as sodium and organic acid salts such as sodium acetate.

Manufacturing method 3.

Embedded image (In the formula, R ³ , Ar, n, D, E, G, Y and Z are the same as described above.)

The ketone derivative represented by the general formula (VI) is halogenated with a halogenating agent in the same manner as in Production Method 1, and then reacted with a thioamide derivative represented by the general formula (X) in an inert solvent. To a thiazole derivative represented by the general formula (IX), the thiazole derivative (IX) is isolated or not isolated, in a piperidine derivative represented by the general formula (II) and an inert solvent, The arylpiperidine derivative represented by the general formula (I-3) can be produced by reacting in the presence or absence of a base. As the inert solvent used in this reaction, for example, alcohols such as ethanol and isopropanol, ethers such as tetrahydrofuran and dioxane, hydrocarbons such as benzene and toluene, ketones such as acetone and methyl ethyl ketone,
Examples thereof include N, N-dimethylformamide, acetonitrile, water, and a mixed solvent thereof. As the base, for example, organic amines such as triethylamine, diisopropylethylamine and pyridine, alcoholates such as sodium ethoxide, alkali metal amides such as sodium amide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogenated Examples thereof include inorganic bases such as sodium and organic acid salts such as sodium acetate. Furthermore, the aryl piperidine derivative represented by the general formula (I-4) can be produced by treating the aryl piperidine derivative represented by the general formula (I-3) of the present invention with ammonia in an inert solvent. . As the inert solvent used in this reaction, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane,
Examples thereof include alcohols such as methanol and ethanol, acetonitrile and water.

Manufacturing method 4.

Embedded image (Wherein, R ³ , Ar, n, D, E, G and Y are as defined above, and M ² represents an alkali metal ion such as sodium, potassium, lithium, calcium, an alkaline earth metal ion or a hydrogen atom) .)

The arylpiperidine derivative represented by the general formula (I-3) is represented by the general formula (I-5) by hydrolyzing its ester group in an inert solvent in the presence of a base or an acid. Arylpiperidine derivatives can be produced. Examples of the inert solvent used in this reaction include ethers such as diethyl ether, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol,
Ketones such as acetone, organic carboxylic acids such as acetic acid,
N, N-dimethylformamide, water and the like can be exemplified. Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide and sodium carbonate.Examples of the acid include hydrochloric acid, hydrobromic acid, Examples thereof include inorganic acids such as sulfuric acid, and organic acids such as trifluoroacetic acid, formic acid, tosylic acid, and methanesulfonic acid.

Manufacturing method 5.

Embedded image (Wherein, R ³ , X ¹ , X ² , Ar, n, D, E, G, Y
And Z are the same as above. )

A ketone derivative represented by the general formula (VI) is halogenated with a halogenating agent in the same manner as in Production method 1, and an S-alkylisothiourea derivative represented by the general formula (XII) is added to a base in an inert solvent. The imidazole derivative represented by the general formula (XI) can be produced by reacting in the presence of Further, the imidazole derivative (XI) is represented by the general formula (I
By reacting the piperidine derivative represented by I) with an inert solvent in the presence or absence of a base, the compound represented by the general formula (I-
The arylpiperidine derivative represented by 6) can be produced. As the inert solvent used in this reaction, for example, alcohols such as ethanol and isopropanol,
Examples thereof include ethers such as tetrahydrofuran and dioxane, hydrocarbons such as benzene and toluene, ketones such as acetone and methyl ethyl ketone, N, N-dimethylformamide, acetonitrile, water, and a mixed solvent thereof. As the base, for example, organic amines such as triethylamine, diisopropylethylamine and pyridine, alcoholates such as sodium ethoxide, alkali metal amides such as sodium amide, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogenated Examples thereof include inorganic bases such as sodium and organic acid salts such as sodium acetate.

Manufacturing method 6.

Embedded image (Wherein, R ³ , X ³ , X ⁴ , Ar, n, D, E, G, Y
And Z are as defined above, and R ⁶ and R ⁷ together with a methyl group or an adjacent nitrogen atom represent a pyrrolidino group, a piperidino group, a morpholino group, an N-methylpiperazino group, or the like. )

The ketone derivative represented by the general formula (VI) is reacted with the piperidine derivative represented by the general formula (II) in the presence or absence of a base, in the presence or absence of an inert solvent. Thereby, the aminoketone derivative represented by the general formula (XIV) can be produced. Examples of the base used in this reaction include organic amines such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, and sodium hydride; and organic bases such as sodium acetate. Examples of the inert solvent include ethers such as diethyl ether, tetrahydrofuran, and dioxane; hydrocarbons such as benzene and toluene; and alcohols such as ethanol. Next, the aminoketone derivative represented by the general formula (XIV) and the N, N-dimethylformamide dialkylacetal derivative represented by the general formula (XIII) are reacted in the presence or absence of a cyclic amine in an inert solvent. By reacting, the enamine derivative represented by the general formula (XV) can be produced, and the aryl piperidine derivative represented by the general formula (I-7) can be produced by reacting the enamine derivative (XV) with hydrazine. . The cyclic amines used in this reaction include, for example, pyrrolidine, piperidine, morpholine, N
Examples of the inert solvent include ethers such as tetrahydrofuran and dioxane, hydrocarbons such as benzene and toluene, acetonitrile, and N, N-dimethylformamide. Examples of the inert solvent during the reaction with hydrazine include alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as toluene, N, N-dimethylformamide, acetonitrile, and the like.
Water or a mixed solvent thereof can be exemplified.

Manufacturing method 7.

Embedded image (Wherein, R ³ , R ⁶ , R ⁷ , Ar, n, D, E, G, Y
And Z are the same as above. )

The enamine derivative represented by the general formula (XV) is reacted with a mixture of formamide and ammonium formate, thiourea or an S-alkylisothiourea represented by the general formula (XII) in the presence or absence of a base. By reacting in an active solvent, an arylpiperidine derivative represented by the general formula (I-8) can be produced. Examples of the base used in the present invention include organic amines such as triethylamine, diisopropylethylamine and pyridine; inorganic bases such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide and sodium hydride; and organic bases such as sodium acetate. Examples of the inert solvent include organic carboxylic acids such as acetic acid, organic halogen compounds such as carbon tetrachloride and chloroform, alcohols such as ethanol and isopropanol, and ethers such as diethyl ether and tetrahydrofuran. , A hydrocarbon such as toluene, N, N-dimethylformamide, acetonitrile, water or a mixed solvent thereof.

The production examples of typical intermediate compounds of the present invention, the examples of the arylpiperidine derivatives represented by the general formula (I) of the present invention, and the test examples are shown below, but the present invention is not limited thereto. Not something. Production Example 1. 2-amino-5- (2-chloroethyl)-
4- (4-fluorophenyl) thiazole hydrobromide
Production of (Compound No. A-01) 4-Chloro-4′-fluorobutyrophenone 10.03
g was dissolved in 40 ml of acetic acid, 1 drop of 47% aqueous hydrobromic acid solution was added, and a solution of 8.07 g of bromine in 10 ml of acetic acid was added dropwise over 30 minutes. After the reaction mixture was stirred at room temperature for 1.5 hours, acetic acid was distilled off under reduced pressure.
0 ml and 3.81 g of thiourea were added, and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained crystals were recrystallized from ethanol to give 11.62 g of 2-amino-5- (2-chloroethyl) -4- (4-fluorophenyl) thiazole hydrobromide. Obtained. m. p. 185.0-187.0 ° C.

Production Example 2. 5- (2-chloroethyl)-
Preparation of 4- (4-fluorophenyl) thiazole hydrochloride (Compound No. A-10) 4-Chloro-4′-fluorobutyrophenone 10.03
g in 50 ml of carbon tetrachloride and 8.68 g of bromine in 1 ml.
It was dropped in 5 minutes. The reaction mixture was stirred at room temperature for 1.5 hours and concentrated under reduced pressure. The obtained residue was previously used for 1.
Formamide stirred under heating at 100 ° C. for 5 hours 2.36
g and 2.53 g of diphosphorus pentasulfide in a suspension of 100 ml of dioxane, followed by stirring at 100 ° C. for 5 hours while heating.
The reaction mixture was concentrated under reduced pressure, neutralized with a saturated aqueous solution of sodium hydrogen carbonate, and then the target product was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous sodium sulfate, and filtered to remove the desiccant.
The filtrate is concentrated under reduced pressure, and flash column chromatography (silica gel: Wako gel C200, developing solvent: n)
-Hexane-ethyl acetate = 10: 1). After treating this free base with a 4N solution of hydrogen chloride in ethyl acetate, recrystallization from isopropanol gave 3.10 g of 5- (2-chloroethyl) -4- (4-fluorophenyl) thiazole hydrochloride. m. p. 114.5-116.5 ° C.

Production Example 3 2-hydroxy-5- (2-
Preparation of (chloroethyl) -4- (4-fluorophenyl) thiazole (Compound No. A-11) 4-chloro-4′-fluorobutyrophenone 20.08
g was dissolved in 80 ml of chloroform, and a solution of 5.2 ml of bromine in 10 ml of chloroform was added dropwise over 30 minutes. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained residue was dissolved in 120 ml of ethanol, 9.80 g of potassium thiocyanate was added, and the mixture was heated under reflux with stirring for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the desired product was extracted with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, the desiccant was separated by filtration, and concentrated under reduced pressure. The obtained residue was heated and refluxed with stirring for 3 hours in a mixed solution consisting of 140 ml of acetic acid, 40 ml of water and 15 ml of sulfuric acid. After the reaction solution was concentrated under reduced pressure, the residue was poured into ice, and the desired product was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline,
After drying over anhydrous sodium sulfate, the desiccant was filtered off. After the filtrate was concentrated under reduced pressure, isopropyl ether was added to the obtained residue for crystallization, and the residue was recrystallized from n-hexane-ethyl acetate to give 2-hydroxy-5- (2-chloroethyl) -4-.
16.40 g of (4-fluorophenyl) thiazole was obtained. m. p. 140.0-141.5 ° C.

Production Example 4 5- (2-chloroethyl)-
Preparation of ethyl 4- (4-fluorophenyl) -2-thiazolecarboxylate (Compound No. A-12) 4-chloro-4′-fluorobutyrophenone 50.00
g was dissolved in 250 ml of carbon tetrachloride, and 41.30 g of bromine was dissolved.
Was added dropwise over 30 minutes. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The obtained residue and 33.20 g of ethyl thiooxamate were stirred in 250 ml of ethanol while heating under reflux for 15 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the desiccant was filtered off. It was concentrated below. The obtained residue is subjected to flash column chromatography (silica gel: Wako gel C200, developing solvent: n-hexane-ethyl acetate = 10: 1 to 9: 1).
And then recrystallized from diisopropyl ether.
29.14 g of ethyl-(2-chloroethyl) -4- (4-fluorophenyl) -2-thiazolecarboxylate was obtained. m. p. 81.5-82.5 ° C.

Production Example 5 2-methylthio-4 (5)-
Production of (2-chloroethyl) -5 (4)-(4-fluorophenyl) imidazole (Compound No. A-15) 4-chloro-4′-fluorobutyrophenone 2.00 g
Was dissolved in 5 ml of chloroform, and a solution of 0.52 ml of bromine in 1 ml of chloroform was added dropwise over 5 minutes. After the reaction mixture was stirred at room temperature for 1 hour, it was concentrated under reduced pressure. The obtained residue was dissolved in N, N-dimethylformamide (20 ml), S-methylisothiourea hydrochloride (3.50 g), anhydrous potassium carbonate (2.76 g) and sodium iodide (0.15 g)
Was added and heated to 80 ° C. and stirred for 1 hour. The reaction solution was poured into ice water, and the desired product was extracted with diethyl ether. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, the desiccant was separated by filtration, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (silica gel: Wakogel C200, developing solvent: n-hexane-ethyl acetate = 2: 1), and recrystallized from isopropyl ether to give 2-methylthio-4 (5). 1.13 g of-(2-chloroethyl) -5 (4)-(4-fluorophenyl) imidazole was obtained. m. p. 134.0-135.0 ° C.

Table 1 shows typical examples of compounds represented by the following general formula (A), which are intermediate compounds produced in the same manner as in Production Examples 1 to 5. The free base was obtained by neutralization with an aqueous sodium hydroxide solution or a saturated aqueous sodium hydrogen carbonate solution. Further, purification was performed by silica gel column chromatography as needed. General formula (A):

Embedded image

[0030]

[Table 1] Table 1 化合物 Compound number R ^{2 * 3} Ar ^{* 3} Z salt mp (° C.) recrystallization solvent _{^{* 1 ────────────────────────────────── A-01 NH 2}} 4 -F-Ph Cl HBr 185.0-187.0 EtOH A -02 NH 2 4-F-Ph Br HBr 162.0-164.0 EtOH A-03 NH 2 4-Cl-Ph Cl HBr 203.0-205.0 EtOH A-04 NH 2 4-Me -Ph Cl HBr 183.0-184.5 EtOH A-05 NH ₂ Ph Cl 128.0-129.0 PhCH ₃ A-06 NHMe 4-F-Ph Cl HCl 125.0-126.5 IPA A-07 Me 4-F-Ph Cl HCl 122.5-123.5 IPA A-08 Me 4-Me-Ph Cl HCl 141.0-143.0 IPA A-09 Me Ph Cl HCl 111.5-113.0 IPE A-10 H 4-F-Ph Cl HCl 114.5-116.5 IPA A-11 OH 4-F-Ph Cl 140.0-141.5 Hex-AcOEt A-12 CO ₂ Et 4-F-Ph Cl 81.5-82.5 IPE A-13 CO ₂ Et 4-Me-Ph Cl 79.0-80.0 IPE A-14 CO ₂ Et Ph Cl oil ^{* 2} ────────────────────────────────── * 1: Recrystallization solvent; EtOH = ethanol, PhCH ₃ = toluene, IPA = Isopropyl alcohol, IPE = diisopropyl ether, Hex = n-hexane, AcOEt = ethyl acetate. * 2: NMR (CDCl ₃ , δ (ppm)); 1.44 (3H, t), 3.44 (2H, d), 3.74 (2H, d), 4.49 (2H, q), 7.38-7.64 (4H, m) * 3: Me = methyl group, Et = ethyl group, Ph = phenyl group.

Example 1. 2-Amino-4- (4-fluorophenyl) -5- [2- [4- (6-fluorobenzofuran-3-yl) piperidin-1-yl] ethyl]
Preparation of thiazole (Compound No. B-01) 2-amino-5- (2-bromoethyl) -4- (4-fluorophenyl) thiazole hydrobromide 0.917
g, 4- (6-fluorobenzofuran-3-yl) piperidine hydrochloride (0.511 g), a mixture of 1.5 ml of diisopropylethylamine and 3 ml of methanol were stirred with heating under reflux for 12 hours. After cooling to room temperature, the reaction mixture was poured into water, and the desired product was extracted with chloroform. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, ether was added to the obtained residue, the crystals were collected by filtration, and recrystallized from ethanol to give 2-amino-4- (4-fluorophenyl) -5. 0.57 g of-[2- [4- (6-fluorobenzofuran-3-yl) piperidin-1-yl] ethyl] thiazole was obtained. m. p. 162.0-164.0 ° C.

Embodiment 2 FIG. 2-amino-4- (4-fluorophenyl) -5- [2- [4- (5-fluoro-1
H-benzotriazol-1-yl) piperidine-1-
Preparation of yl] ethyl] thiazole (Compound No. B-23) 2-amino-5- (2-bromoethyl) -4- (4-fluorophenyl) thiazole hydrobromide 0.917
g, 4- (5-Fluoro-1H-benzotriazole-
A mixture of 0.441 g of 1-yl) piperidine, 1 ml of diisopropylethylamine and 4 ml of methanol was stirred with heating under reflux for 12 hours. After cooling to room temperature, ethanol was added to the reaction mixture, and the crystals were collected by filtration. The obtained crystals were recrystallized from chloroform-ethanol to give 2-amino-4- (4-fluorophenyl) -5- [2- [4-
(5-Fluoro-1H-benzotriazol-1-yl) piperidin-1-yl] ethyl] thiazole 0.5
6 g were obtained. m. p. 234.0-235.0 ° C

Embodiment 3 FIG. 2-hydroxy-4- (4-
Preparation of fluorophenyl) -5- [2- [4- (6-fluorobenzofuran-3-yl) piperidin-1-yl] ethyl] thiazole (Compound No.B-06) 5- (2-chloroethyl) -2- Hydroxy-4- (4
-Fluorophenyl) thiazole 0.134 g, 4-
(6-fluorobenzofuran-3-yl) piperidine hydrochloride 0.11 g, diisopropylethylamine 0.28
of methanol and 0.5 ml of methanol while heating under reflux.
Stir for 5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by flash chromatography (silica gel: Merck Key Gelsell 60, 230 to 400 mesh, developing solvent: n-hexane-ethyl acetate = 2: 1). Recrystallized from ethyl acetate-hexane to give 2-hydroxy-4- (4-fluorophenyl) -5- [2- [4-
(6-Fluorobenzofuran-3-yl) piperidine-
1-yl] ethyl] thiazole (0.066 g) was obtained. m. p. 186.0-188.0 ° C

The following general formula obtained in the same manner as in Examples 1 to 3
Table 2 shows typical examples of the arylpiperidine derivative represented by (B). General formula (B):

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[0035]

[Table 2] Table 2 Compound No. R ^{2 * 2} Ar ^{* 2} DEGY mp (℃) (recrystallization solvent) ^{* 1} ─────────────────────── ──────────── B-01 NH ₂ 4-F-Ph C CH O 6-F 210.0-211.0 (EtOH) B-02 NH ₂ Ph C CH O 6-F 199.0-201.0 ( AcOEt-Hex) B-03 Me 4-F-Ph C CH O 6-F 121.0-123.0 (Ether) B-04 Me Ph C CH O 6-F 103.0-105.0 (AcOEt-Hex) B-05 H 4- F-Ph C CH O 6-F 130.0-132.0 (AcOEt-Ether) B-06 OH 4-F-Ph C CH O 6-F 186.0-188.0 (AcOEt-Hex) B-07 NH ₂ 4-F-Ph C CH S 6-F 216.0-218.0 (CHCl ₃ -EtOH) B-08 NH ₂ 4-F-Ph C CH NH H 203.0-203.5 (EtOH) B-09 NH ₂ 4-Me-Ph C CH NH H 99.0 -101.0 (AcOEt-Ether) B-10 Me 4-F-Ph C CH NH H 165.0-167.0 (AcOEt-Hex) B-11 Me 4-Me-Ph C CH NH H 138.0-141.0 (Ether) B-12 H 4-F-Ph C CH NH H 141.0-143.0 (AcOEt-Ether) B-13 MeNH 4-F-Ph C CH NH H 173.0-175.0 (Ether) B-14 CO ₂ Et 4-F-Ph C CH NH H 184.0-186.0 (EtOH) B-15 CO ₂ Et 4-Me-Ph C CH NH H 194.0-196.0 (AcOEt-Ether) B-16 CO ₂ Et Ph C CH NH H 182.0-183.0 (Ether) B- 17 CONH ₂ 4-F-Ph C CH NH H 20 6.0-209.0 (AcOEt-Ether) B-18 NH ₂ 4-F-Ph CNO 6-F 208.0-209.0 (EtOH-Hex) B-19 Me 4-F-Ph CNO 6-F 102.0-103.0 (EtOH-Hex _{) B-20 NH 2 4-} F-Ph CNS 6-F 203.0-204.0 (EtOH) B-21 NH 2 4-F-Ph CN NH 6-F 104.0-106.0 (EtOH) B-22 NH 2 4-F -Ph N CH N 5-F 282.0-284.0 (CHCl ₃ -EtOH) ───────────────────────────────── ─

[0036]

[Table 3] Table 2 (continued) Compound No. R ^{2 * 2} Ar ^{* 2} DEGY mp (℃) (recrystallization solvent) ^{* 1} ──────────────────── ─────────────── B-23 NH ₂ 4-F-Ph NNN 5-F 234.0-235.0 (CHCl ₃ -EtOH) B-24 NH ₂ 4-Cl-Ph NNN 5 -F 225.0-227.0 (CHCl ₃ -EtOH) B-25 Me 4-F-Ph NNN 5-F 145.0-146.0 (AcOEt-Hex) B-26 H 4-F-Ph NNN 5-F 144.0-146.0 (AcOEt -He ────────────────────────────────── * 1: Recrystallization solvent; EtOH = ethanol, AcOEt = acetic acid Ethyl, Hex = Hexane, CHCl ₃ = Chloroform, Ether = Ether * 2: Me = Methyl group, Et = Ethyl group, Ph = Phenyl group.

Example 4 2-Methylthio-4 (5)-
(4-fluorophenyl) -5 (4)-[2- [4-
Production of (5-fluoro-1H-benzotriazol-1-yl) piperidin-1-yl] ethyl] thiazole (Compound No. C-03) 2-methylthio-4 (5)-(2-chloroethyl) -5
(4)-(4-fluorophenyl) imidazole 0.1
41 g, 4- (5-fluoro-1H-benzotriazol-1-yl) piperidine 0.095 g, diisopropylethylamine 0.19 ml, and methanol 0.6 ml
Was stirred for 17 hours while heating under reflux. After cooling to room temperature, the solvent was distilled off under reduced pressure and flash chromatography (silica gel: Chromatorex NHDM1020,
Developing solvent: n-hexane-ethyl acetate = 1: 3). Recrystallization from ethanol-hexane gave 2-methylthio-4 (5)-(4-fluorophenyl) -5.
0.14 g of (4)-[2- [4- (5-fluoro-1H-benzotriazol-1-yl) piperidin-1-yl] ethyl] thiazole was obtained. m. p. 223.0-224.0 ° C

Table 3 shows typical examples of the arylpiperidine derivative represented by the general formula (C) obtained in the same manner as in Example 4. General formula (C):

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[0039]

[Table 4] Table 3 Compound R ^{3 * 2} X ¹ X ² Ar ^{* 2} DEGY mp (° C) No. (recrystallization solvent) ^{* 1} ─────────────────── ──────────────── C-01 Me N (NH) NH (N) 4-F-Ph C CH O 6-F 151.0-152.0 (AcOEt-Ether) C-02 Me N (NH) NH (N) 4-F-Ph C CH NH H 111.0-114.0 (AcOEt-Ether) C-03 Me N (NH) NH (N) 4-F-Ph NNN 5-F 223.0-224.0 (EtOH-Hex) ─────────────────────────────────── * 1: Recrystallization solvent; CHCl ₃ = Chloroform, EtOH = ethanol, AcOEt = ethyl acetate, Hex = n-hexane, Ether = ether. * 2: Me = methyl group, Ph = phenyl group.

Embodiment 5 FIG. Production of 5 (3)-(4-fluorophenyl) -4 (4)-[2- [4- (6-fluorobenzo [B] thiophen-3-yl) piperidin-1-yl] ethyl] pyrazole (1 ). 2- (4-fluorophenyl) -2- (3-
Chloropropyl) -1,3-dioxolane 1.5 g, 4
-(6-Fluorobenzo [b] thiophen-3-yl)
A mixture of 1.5 g of piperidine hydrochloride, 3.3 ml of diisopropylethylamine and 2.5 ml of methanol was stirred with heating under reflux for 25 hours. The reaction solution was partitioned between chloroform and a saturated aqueous solution of sodium hydrogen carbonate, and the aqueous layer was further extracted with chloroform. The organic layers were combined, washed with water and saturated saline, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to flash chromatography (silica gel: Merck Kieselgel 60 230-4).
00 mesh, developing solvent: n-hexane-ethyl acetate =
1: 2) to give 2- (4-fluorophenyl)-
2- [3- [4- (6-Fluorobenzo [b] thiophen-3-yl) piperidin-1-yl] propyl]-
0.71 g of 1,3-dioxolane was obtained. This was stirred at room temperature for 20 hours in a mixture of 3 ml of 1 N hydrochloric acid and 4 ml of tetrahydrofuran. The solvent was distilled off under reduced pressure, the residue was partitioned between ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure.
0 ml, and treated with 1 ml of 4N hydrogen chloride / 1,4-dioxane solution to give 6-fluoro-3- [1- [4
-(4-Fluorophenyl) -4-oxobutyl] piperidin-4-yl] benzo [b] thiophene hydrochloride.
54 g were obtained.

(2). 6-fluoro-3- [1- [4
-(4-Fluorophenyl) -4-oxobutyl] piperidin-4-yl] benzo [b] thiophene hydrochloride.
15 g, anhydrous potassium carbonate 0.05 g, N, N-dimethylformamide dimethyl acetal 0.36 g, pyrrolidine 0.25 g and N, N-dimethylformamide 0.1 g.
5 ml of the mixture was stirred in a 120 ° C. oil bath for 3.5 hours. After cooling the reaction solution to room temperature, it was partitioned between ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and washed three times with a saturated saline solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to give crude 6-fluoro-3.
-[1- [3- (1-pyrrolidinomethylene) -4- (4
-Fluorophenyl) -4-oxobutyl] piperidin-4-yl] benzo [b] thiophene was obtained. This was dissolved in 2 ml of methanol, and a 80% aqueous solution of hydrazine was added in 0.1 ml.
3 ml was added, and the mixture was heated under reflux for 2 hours. After the reaction solution was cooled to room temperature, it was separated with a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel: Chromatorex N).
HDM1020, developing solvent: n-hexane-ethyl acetate = 1: 2), recrystallization from ethyl acetate-ether, and 5 (3)-(4-fluorophenyl) -4 (4)
0.02 g of-[2- [4- (6-fluorobenzo [b] thiophen-3-yl) piperidin-1-yl] ethyl] pyrazole was obtained. m. p. 162.0-163.0 ° C

Embodiment 6 FIG. 6- (4-fluorophenyl) -5- [2- [4- (6-fluorobenzo [b] thiophen-3-yl) piperidin-1-yl] ethyl]
Preparation of pyrimidine The same operation as in Example 5 from 0.35 g of 6-fluoro-3- [1- [4- (4-fluorophenyl) -4-oxobutyl] piperidin-4-yl] benzo [b] thiophene hydrochloride 6-fluoro-3- [1- [3-
3.6 ml of formamide, 0.4 g of ammonium formate and 0.1 ml of water were added to (1-pyrrolidinomethylene) -4- (4-fluorophenyl) -4-oxobutyl] piperidin-4-yl] benzo [b] thiophene. , 180
The mixture was heated and stirred at 1.5 ° C for 1.5 hours. After the reaction solution was cooled to room temperature, it was separated with a saturated aqueous solution of sodium hydrogen carbonate and ethyl acetate, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined and washed with water and saturated saline. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (silica gel: Chromatorex NHD).
M1020, developing solvent: n-hexane-ethyl acetate =
2: 1) and recrystallized from ether to give 6- (4
-Fluorophenyl) -5- [2- [4- (6-fluorobenzo [b] thiophen-3-yl) piperidine-1
-Yl] ethyl] pyrimidine in an amount of 0.04 g. m. p. 123.0-124.0 ° C

Test Example [Receptor binding experiment] Dopamine D_FourReceptor binding experiment Human D as receptor sample_Four._TwoChai expressing receptor
Needs hamster ovary (CHO) cell membrane was used. [^ThreeH] as a labeled ligand [^ThreeH] Spiperone was used. [^ThreeH] The binding reaction using a labeled ligand is described in Eur. J. Phar
macol., 233, 173 (1993).
Was. Human D_Four._TwoReceptor binding test: human D_Four._TwoExpressed receptor
CHO cell membrane, ^ThreeH] Spiperone (0.5 nM) and
And 5 μm EDTA, 1.5 mM calcium chloride
Calcium, 5 mM potassium chloride and 120 mM sodium chloride
50 mM Tris-HCl buffer containing thorium (pH 7.
In 4), the reaction was carried out at 27 ° C. for 2 hours. After the reaction,
Suction filter (GF / B), and filter paper radioactivity
Is measured with a liquid scintillation spectrometer.
Was. When reacted in the presence of 10 μM haloperidol
The join of [^ThreeH] Non-specific binding of spiperone and total binding
The difference between and non-specific binding was defined as specific binding. When a certain concentration of [
^ThreeH] Spiperone and test drugs with varying concentrations
To obtain a suppression curve, and from this suppression curve,^ThreeH]
The concentration of the test drug that inhibits spiperone binding by 50% (I
C₅₀) And the results are shown in Table 4.

2. Dopamine D_TwoReceptor binding experiments. Rat striatal membrane was used as a receptor preparation. [^ThreeH] as a labeled ligand [^ThreeH] Using raclopride
Was. [^ThreeH] The binding reaction using a labeled ligand is described in Mol. Pharmac.
ol., 43, 749 (1993).
Was. Preparation of receptor preparation: Rat striatum was washed with 50 mM Tris-HCl
Homogenized with buffer (pH 7.4), 48,000
Centrifuge at xg and wash the precipitate once with Tris-HCl buffer
did. The precipitate is washed with 120 mM sodium chloride and 5 mM salt.
Potassium chloride, 2 mM calcium chloride and 1 mM chloride
50 mM Tris-HCl buffer containing magnesium (pH
7.4) to give a membrane preparation. Dopamine D_TwoReceptor binding experiment: membrane preparation (0.5 mg
Protein / ml), [ ^ThreeH] raclopride (1 nM) and
The test drug was reacted at 25 ° C. for 1 hour. After the reaction is complete,
Suction-filtered into a lath filter (GF / B) and radiated from filter paper
Performance measured with a liquid scintillation spectrometer
did. Reaction in the presence of 10 μM haloperidol
The bond of [^ThreeH] Non-specific binding of raclopride
The difference between binding and non-specific binding was defined as specific binding. Constant concentration
of[^ThreeH] laccloprid and the test drug at a different concentration
The reaction curve to obtain a suppression curve, and from this suppression curve
[^ThreeH] Concentration of test drug that inhibits raclopride binding by 50%
(IC₅₀) Was determined, and the results are shown in Table 4.

[0045]

[Table 5]

[0046]

The arylpiperidine derivative represented by the general formula (I) of the present invention has excellent affinity for dopamine D ₄ receptor, but has low affinity for dopamine D ₂ receptor, Because of its excellent separability, it is useful as an agent for preventing and treating diseases such as schizophrenia and cerebrovascular disorders and behavioral problems associated with senile dementia, and is also useful as a drug without side effects of extrapyramidal disorders It is.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 409/14 211 C07D 409/14 211 417/06 211 417/06 211 417/14 211 417/14 211 (72) Inventor Yoshida Masanori 345, Koyamada-cho, Kawachinagano-shi, Osaka Prefecture Nippon Agrochemicals Co., Ltd. (72) Inventor Atsuro Nakazato 3-24-1, Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. 3-24-1, Takada-ku Taisho Seiyaku Co., Ltd. (72) Inventor Shigeyuki Chaki 3-24-1, Takada, Toshima-ku, Tokyo Intra Taisei Seiyaku Co., Ltd. 3-24-1, Takada Taisho Pharmaceutical Co., Ltd.

Claims (1)

[Claims] 1. A compound of the general formula (I) [In the formula, D represents a carbon atom or a nitrogen atom, E represents a CH group or a nitrogen atom, G represents an oxygen atom, a sulfur atom, a nitrogen atom or an NH group, Y represents a hydrogen atom or a halogen atom, n represents an integer of 1 to 4; R ¹ is a group represented by the formula (i); (Wherein R ² is a hydrogen atom, an alkyl group having 1 to 5 carbon atoms,
An amino group, a monoalkylamino group having 1 to 5 carbon atoms, a hydroxyl group, an alkoxycarbonyl group having a total of 2 to 6 carbon atoms,
A carbamoyl group, a carboxyl group or a metal salt of a carboxyl group; and Ar represents a substituted or unsubstituted phenyl group or a thienyl group. ), Formula (ii); (Wherein, R ³ represents an alkyl group having 1 to 5 carbon atoms, X ¹
And X ² are different from each other and represent a nitrogen atom or an NH group;
Ar is the same as above. ), Formula (iii); (Wherein X ³ and X ⁴ are different from each other and represent a nitrogen atom or an NH group, and Ar is the same as described above), or formula (iv); (Wherein R ⁴ is a hydrogen atom, a mercapto group, and has 1 to 5 carbon atoms)
Wherein Ar is the same as defined above. ). Or a pharmaceutically acceptable salt thereof.