JPH07196647A - Cycloalkanopyridine derivative and psychotropic medicine containing the same derivative as active ingredient - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a psychotropic medicine having antagonism on both of a dopamine D2 receptor and a serotonin S3 receptor and thereby exhibiting excellent treating effect also on a negative symptom of schizophrenia. CONSTITUTION:A compound of formula I (R<1> is H, a cycloalkyl, etc.; R<2> is phenyl or a heteroaryl; R<2> is H or a lower alkyl; m is 2 or 3; n is 3-7) or its salts, e.g. 4-(4-ethyl-l-piperazinyl)-2-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H- cyclohepta[b]pyridine. The compound is obtained by reacting, e.g. a compound of formula II with a compound of the formula R<2> COOY (Y is a lower alkyl), reacting the resultant compound with ammonia gas, converting the product into a compound of formula III (X is an eliminating atom or an eliminating group) by phosphorus tribromide and reacting the compound of formula III with a compound of formula IV at 40-200 deg.C in the presence of a base such as sodium carbonate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cycloalkanopyridine derivative having an antagonistic effect on dopamine D ₂ receptor and serotonin S ₂ receptor and a psychotropic drug containing the same.

[0002]

2. Description of the Related Art British Patent No. 2052481 discloses 4
-(4'-Isopropylanilino) -2-phenyl-
4-Substitution such as 5,6,7,8-tetrahydroquinoline
It is described that 5,6,7,8-tetrahydroquinoline derivatives have a bactericidal action on bacteria, fungi and algae.

[0003]

Heretofore, phenothiazine derivatives such as chlorpromazine and butyrophenone derivatives such as haloperidol have been used as antipsychotic drugs.
The antipsychotic effects of these drugs are believed to be based on dopamine D ₂ receptor antagonism. However, although these drugs are effective for positive symptoms such as hallucinations and delusions, they are not necessarily effective for negative symptoms such as autism and apathy. In addition, extrapyramidal disorders occur as a side effect of these drugs, which is a great obstacle to treatment.

Recently, it has been reported that a compound having an antagonistic effect on the serotonin S ₂ receptor as well as the dopamine D ₂ receptor shows a favorable effect not only on the positive symptoms but also on the negative symptoms of schizophrenia. [Meco, G. et al: Cur
r. Ther. Res., 46 (5), 876-883 (1989)]. In addition, it has been reported that an antipsychotic drug having a serotonin S ₂ receptor antagonistic effect reduces side effect of extrapyramidal system [Bleich, A. et al .: Schizophr. Bull., 14 (2), 297]. -315 (1
988)].

Therefore, a compound having a strong antagonistic effect on both the dopamine D ₂ receptor and the serotonin S ₂ receptor can be a new type of useful antipsychotic drug which makes up for the shortcomings of conventional antipsychotic drugs. There is a nature.

Further, a compound having a strong antagonistic effect on both dopamine D ₂ receptor and serotonin S ₂ receptor is a compound other than schizophrenia in which dopamine and serotonin are involved, such as depression, depression, It is expected to be useful as a therapeutic agent for mental disorders such as anxiety.

The present inventors have conducted extensive studies to obtain a novel compound having an antagonistic effect on both dopamine D ₂ receptor and serotonin S ₂ receptor, and as a result, substituted or unsubstituted phenyl group at the 2-position. Or a heteroaryl group,
The inventors have found that a cycloalkanopyridine derivative having a piperazine or homopiperazine moiety at the 4-position is suitable for this purpose, and completed the present invention.

[0008]

According to the present invention, a cycloalkanopyridine derivative represented by the following formula (I), a pharmaceutically acceptable acid addition salt thereof, and a psychotropic drug containing the same as an active ingredient Will be provided.

[0009]

[Chemical 2]

[Wherein R ¹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a cycloalkyl (lower) alkyl group or a phenyl moiety is selected from halogen, lower alkyl and lower alkoxy 1 Or a phenyl (lower) alkyl group which may be substituted with two, and R ² is a phenyl group or heteroaryl group which may be substituted with one or two selected from halogen, lower alkyl and lower alkoxy. R ³ represents a hydrogen atom or a lower alkyl group, m represents 2 or 3, and n represents 3, 4, 5, 6 or 7. ]

The pharmaceutically acceptable acid addition salts of the compound represented by formula (I) include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like. Inorganic acid salts and maleic acid salts, fumarates, oxalates, citrates, tartrates, lactates, benzoates, methanesulfonates and the like. Since the compound represented by the formula (I) and its acid addition salt may exist in the form of a hydrate, these hydrates are also included in the compound of the present invention.

In the formula (I), when R ³ is a lower alkyl group, at least one asymmetric carbon atom is present, and depending on the kind of R ¹ and / or R ^2, an asymmetric carbon atom is present. I have something to do. In these cases, the compounds of formula (I) may exist in more than one stereoisomeric form. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are explained below.

The lower alkyl group, the lower alkyl moiety and the lower alkoxy group mean those having 1 to 6 carbon atoms, which may be linear or branched. Specific examples of the "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like. Specific examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned. "Hydroxy (lower) alkyl group" means
A carbon atom other than the 1-position of an alkyl group having 2 to 6 carbon atoms is substituted with a hydroxy group, for example, 2-
Hydroxyethyl, 3-hydroxypropyl and the like can be mentioned. The “cycloalkyl (lower) alkyl group” means a lower alkyl group substituted with the above cycloalkyl group, and specifically, cyclopropylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 2-cycloheptylethyl. , 2-cyclooctylethyl, 3-cyclohexylpropyl and the like. "Halogen atom"
Means fluorine, chlorine, bromine and iodine, with fluorine being particularly preferred. Specific examples of the "lower alkoxy group" include methoxy, ethoxy, propoxy, butoxy, isobutoxy and the like.

Specific examples of the "phenyl (lower) alkyl group in which the phenyl moiety may be substituted with one or two selected from halogen, lower alkyl and lower alkoxy" are benzyl, 2-, 3- or 4 -Fluorobenzyl, 2,4-, 2,6- or 3,4-difluorobenzyl, 2-, 3- or 4-chlorobenzyl,
2-, 3- or 4-bromobenzyl, 2-, 3- or 4-methylbenzyl, 2-, 3- or 4-methoxybenzyl, 2- (4-fluorophenyl) ethyl, 2- (2,4- Difluorophenyl) ethyl, 2-
(3-chlorophenyl) ethyl and the like can be mentioned. “1 selected from halogen, lower alkyl and lower alkoxy
Or specific examples of the "phenyl group which may be substituted with two" include phenyl, 2-, 3- or 4-fluorophenyl, 2,4-, 2,6- or 3,4-difluorophenyl, 2 -, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-3
-Or 4-methylphenyl, 2-, 3- or 4
-Methoxyphenyl and the like. The "heteroaryl group" means a monocyclic group which contains a nitrogen atom, an oxygen atom or a sulfur atom and may further contain one or more nitrogen atoms, for example, pyridyl, pyrimidinyl,
Examples thereof include thienyl, furyl, thiazolyl and isothiazolyl.

Preferred among the compounds of the present invention are, in the formula (I), R ² is a phenyl group which may be substituted with halogen, R ³ is a hydrogen atom and m is 2. , N is 3, 4, 5 or 6, and pharmaceutically acceptable acid addition salts thereof.

Among the compounds of the present invention, more preferred are the compounds represented by the following formula (I ') and pharmaceutically acceptable acid addition salts thereof.

[0018]

[Chemical 3]

(Wherein R ¹ 'represents a hydrogen atom, a methyl group, an ethyl group or a 2-hydroxyethyl group, R ⁴ represents a hydrogen atom or a fluorine atom, and n'represents 4, 5 or 6. means.)

Particularly preferred compounds are compounds of the formula (I ') in which R ¹ ' is a methyl group or an ethyl group, R ⁴ is a fluorine atom at the 4-position, and n'is 4 or 5, and pharmaceuticals thereof. It is a chemically acceptable acid addition salt.

Specific examples of particularly suitable compounds include, for example, the following compounds and pharmaceutically acceptable acid addition salts thereof.

4- (4-ethyl-1-piperazinyl)-
2- (4-fluorophenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine and

2- (4-fluorophenyl) -4- (4
-Methyl-1-piperazinyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine.

Specific examples of the compounds included in the present invention include:
In addition to the compounds of Examples described below, the following compounds and pharmaceutically acceptable acid addition salts thereof are included.

2- (4-fluorophenyl) -4- (4
-Propyl-1-piperazinyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine, 4-
(4-Cyclohexyl-1-piperazinyl) -2- (4
-Fluorophenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine, 4- (4-cyclohexylmethyl-1-piperazinyl) -2- (4-fluorophenyl) -6,7,8 , 9-tetrahydro-5
H-cyclohepta [b] pyridine,

2- (2,4-difluorophenyl) -4
-(4-Methyl-1-piperazinyl) -6,7,8,9
-Tetrahydro-5H-cyclohepta [b] pyridine,
4- (4-Ethyl-1-piperazinyl) -2- (2,6
-Difluorophenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine,

2- (4-chlorophenyl) -4- (4-
Methyl-1-piperazinyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine, 4- (4
-Ethyl-1-piperazinyl) -2- (4-methoxyphenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine,

2- (4-fluorophenyl) -6-methyl-4- (4-methyl-1-piperazinyl) -5,6
7,8-Tetrahydroquinoline, 4- (4-ethyl-1)
-Piperazinyl) -2- (4-fluorophenyl) -8
-Methyl-5,6,7,8-tetrahydroquinoline,

2- (4-fluorophenyl) -4- (4
-Methyl-1-homopiperazinyl) -6,7,8,9-
Tetrahydro-5H-cyclohepta [b] pyridine and 4- (4-ethyl-1-homopiperazinyl) -2- (4
-Fluorophenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine.

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

Process (a) : The compound of formula (I) is represented by the following formula (II)

[0032]

[Chemical 4]

(In the formula, X means a leaving atom or a leaving group, and R ² , R ³ and n have the same meanings as described above.)
And a compound represented by the following formula (III)

[0034]

[Chemical 5]

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

The leaving atom or leaving group represented by X in the formula (II) means an atom or a group capable of leaving in the form of HX together with the hydrogen atom of the NH moiety of the compound of the formula (III) under the reaction conditions. Means a halogen atom such as chlorine, bromine and iodine, a lower alkylthio group such as methylthio and ethylthio, a lower alkylsulfonyl group such as methanesulfonyl, a lower alkylsulfonyloxy group such as methanesulfonyloxy, trifluoro A trihalogenomethylsulfonyloxy group such as methylsulfonyloxy, an arylsulfonyloxy group such as benzenesulfonyloxy and p-toluenesulfonyloxy can be mentioned.

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

Specific examples of the solvent include toluene, aromatic hydrocarbons such as xylene, ketones such as methyl ethyl ketone and methyl isobutyl ketone, dioxane,
Examples thereof include ethers such as diglyme, ethanol, isopropyl alcohol, alcohols such as butanol, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. This reaction is preferably carried out in the presence of a base, and specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and triethylamine. Triamines can be mentioned, but it is possible to serve as an excess amount of the compound of the formula (III).
When a compound in which X is chlorine or bromine in the formula (II) is used, the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. If the compound of formula (III) is present in the form of a hydrate, it can also be used in that form.
The reaction temperature is usually 40 to 200 ° C.

The starting compound (III) is commercially available or can be produced by a conventional method using piperazine or homopiperazine as a starting material. In addition, the raw material compound (I
I) can be produced, for example, by the method shown in Chemical formula 6 below.

[0040]

[Chemical 6]

(In the formula, Y means a lower alkyl group, and R
² , R ³ , X and n have the same meanings as above. )

Step 1 is the method of Miles, ML et al. [J. Or.
g. Chem. 30 , 1007 (1965)] or a method analogous thereto. That is, first, the compound of the formula (A) and about 3 equivalents of sodium hydride are reacted in 1,2-dimethoxyethane under ice cooling, and then the compound of the formula (B) is added and heated to reflux. A compound of formula (C) can be obtained. When R ² in the formula (B) is a fluorine-substituted phenyl group, first, the compound of the formula (A) and an equivalent amount of sodium hydride are reacted in tetrahydrofuran under ice cooling. Then, it is preferable to add a strong base having a basicity stronger than sodium hydride [about 2 equivalents to the compound of formula (A)] to the compound of formula (B) and reacting at about -78 to 30 ° C. . Specific examples of the strong base in this case include metal amides such as sodium bis (trimethylsilyl) amide, sodium amide, potassium amide, lithium diisopropylamide, and n.
-Organolithium compounds such as butyllithium and phenyllithium are mentioned.

Formula (A) which is the starting compound in step 1
Alternatively, the compound of formula (B) is commercially available, or can be easily produced by a method known per se.

Step 2 is the method of Light, RJ et al. [J. Or
g. Chem., 25 , 538 (1960)] or a method analogous thereto. That is, it is carried out by dissolving the compound of the formula (C) in ethanol, blowing in ammonia gas, and then heating and refluxing.

Step 3, from the compound of formula (D) to formula (II)
The compound (1) is converted to a compound by a conventional method using phosphorus tribromide, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic acid anhydride and the like.

Process (b) : The compound of the formula (I) in which R ¹ is a hydrogen atom has the following formula (IV)

[0047]

[Chemical 7]

(Wherein R ¹¹ represents an ethoxycarbonyl group or a 1-chloroethoxycarbonyl group, and R ² ,
R ³ , m and n have the same meanings as above. It can be manufactured by hydrolyzing or solvolytically decomposing the compound represented by (4).

For the hydrolysis of the compound represented by the formula (IV), for example, a suitable solvent such as methanol or ethanol miscible with water is used, and a base such as sodium hydroxide or potassium hydroxide or hydrochloric acid or sulfuric acid is used. It is usually carried out by heating in the presence of an acid. A compound of the formula (IV) in which R ¹¹ is a 1-chloroethoxycarbonyl group can also be converted into a compound of the formula (I) in which R ¹ is a hydrogen atom by heating in, for example, methanol. R in formula (IV)
^The compound in which ¹¹ is an ethoxycarbonyl group or a 1-chloroethoxycarbonyl group is a compound in which R ¹ in the formula (I) is a methyl group or a benzyl group whose phenyl moiety may be substituted with halogen, lower alkyl or lower alkoxy. Can be obtained by reacting the corresponding chloroformic acid ester with a conventional method.

Process (c) : The compound of the formula (I) in which R ¹ is a methyl group has the following formula (V)

[0051]

[Chemical 8]

It is also produced by reductively methylating a compound represented by the formula (wherein R ² , R ³ , m and n have the same meanings as described above) with formic acid and formalin. be able to.

Methylation of the compound represented by the formula (V)
Usually, it can be carried out at 0 ° C to 200 ° C in the absence of solvent or in the presence of water. The compound of the formula (V) can be produced by the above production method (a) or (b)
Can be obtained by

The product obtained by each of the above production methods can be isolated and purified by a conventional method such as chromatography, recrystallization, reprecipitation and the like. The compound of formula (I) can be converted into an acid addition salt by treating with various acids according to a conventional method.

[0055]

In order to clarify the characteristics of the action of the compound of the present invention, the results of the pharmacological test for the representative compounds of the present invention are shown below.

Test Example 1 — Dopamine D ₂ and Serotonin S ₂ Receptor Binding Action (In Vitro Receptor Binding Assay) — Creese, I. et al. [See Eur. J. Pharmacol., 46 , 377 (1977)] and Leysen, JE et al. (Mol. Pharmacol., 21 , 301
(1982)], dopamine D ₂
And serotonin S ₂ receptor binding test was performed.

Crude synaptosome membrane fraction prepared from rat brain as a receptor sample, and as a labeled ligand,
[ ³ H] spiperone (for dopamine D ₂ receptors) and
[ ³ H] Ketanserin (for serotonin S ₂ receptor) was used.

After a receptor sample and a buffer solution (final volume: 1 ml) containing each labeled ligand were incubated in the presence of various concentrations of a test compound for a certain period of time, the radioligand bound to the receptor was treated with a cell harvester (Brandell). ) Was used for separation on the filter. The radioactivity on the filter was measured with a liquid scintillation counter to determine the total amount bound. In addition, the binding amount in the presence of unlabeled ligands [spiperone (for dopamine D ₂ receptor) and methysergide (for serotonin S ₂ receptor), which were measured simultaneously, was defined as the nonspecific binding amount, and this was subtracted from the total binding amount. Thus, the specific binding amount was determined.

The concentration at which the test compound inhibited the specific binding of the labeled ligand by 50% (IC ₅₀ ) was calculated by the probit method. The results are shown in Table 1.

[0060]

[Table 1] ^* Means the compound of Example 2 (the same applies hereinafter).

Test Example 2 —Exploratory Behavior Inhibitory Action— Five male STD-ddY mice each weighing 20 to 25 g were used in each group. The test compound suspended in 0.5% tragacanth was orally administered, and after 2 hours, one mouse was placed on a measuring cage (23 × 35) on an Animex momentum measuring device (Farad).
X30 cm) and the amount of exploratory activity for 3 minutes was measured. The average value of the search activity amount (count / 3 minutes) of the control group is 100.
%, The dose (ED ₅₀ value) of the test compound that suppresses the seeking activity by 50% is determined by the Litchfield-Wilcoxon method [Li
tchfield, JT JR. and Wilcoxon, F. (J. Pharmacol. E
xp. Ther., 96 , 99-113 (1949))]. The results are shown in Table 2.

[0062]

[Table 2] ^* Means the compound of Example 2 (the same applies hereinafter).

Test Example 3 — Inhibitory action against apomorphine-induced vomiting — Using 3 to 4 Beagle dogs (8 to 15 kg) per group, the inhibitory action of a test compound against apomorphine-induced vomiting investigated. This test is commonly used as a method for detecting antipsychotic drugs. Two hours after the oral administration of the test compound, apomorphine hydrochloride (0.3 mg / kg) was subcutaneously administered to the back, and the number of vomiting for 1 hour was counted thereafter. Table 3 shows the vomiting suppression rate against the number of vomiting in the control group as 100%.

[0064]

[Table 3] ^* Means the compound of Example 6 (the same applies hereinafter).

The compound of the formula (I) and pharmaceutically acceptable salts thereof (hereinafter sometimes referred to as "the compound of the present invention") are not limited to the dopamine D ₂ receptor but also to the serotonin S ₂ receptor. It also has a strong antagonistic effect,
It is a useful antipsychotic drug, which has a strong inhibitory effect on exploratory behavior and apomorphine-induced vomiting in animal experiments, and thus has an excellent effect not only on positive symptoms but also on negative symptoms of schizophrenia. In addition, it can be expected that side effects of the extrapyramidal system that are observed when conventional antipsychotic drugs are administered are reduced.

Further, the compound of the present invention is used for various diseases involving dopamine and serotonin, such as psychiatric disorders such as depression, depression, anxiety, Parkinson's disease, sleep disorders, migraine, nausea, vomiting, hypertension, It is also useful as a therapeutic agent for gastrointestinal disorders, asthma and urticaria, or as a platelet coagulation inhibitor.

The route of administration of the compound of the present invention may be oral administration, parenteral administration or rectal administration, but oral administration is preferred. The dose varies depending on the kind of compound, administration method, patient's symptoms and age, etc.
05-50 mg / kg / day, preferably 0.05-5 mg / kg
/ Day.

The compound of the present invention is usually administered in the form of preparation prepared by mixing with a carrier for preparation. As the carrier for formulation, a substance which is commonly used in the field of formulation and which does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl cellulose calcium, ion exchange resin. , Methyl cellulose, gelatin, gum arabic, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester , Sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanno Emissions, glycerogelatin, polysorbate, macrogol, vegetable oils, waxes, propylene glycol, water and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another appropriate medium before use. The tablets and granules may be coated by a known method. These formulations contain 0.1% or more of the compound of the present invention, preferably 1 to
It can be contained in a ratio of 70%. These formulations may also contain other therapeutically effective ingredients.

[0070]

EXAMPLES In order to describe the present invention more specifically, reference examples and examples will be given below, but the present invention is not limited to these examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, and NMR.
It was performed by spectrum and the like.

Reference Example 1 Preparation of 2-phenyl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-4 (1H) -one:

60% sodium hydride (15.5 g) was suspended in 1,2-dimethoxyethane (300 ml), and 2-acetylcyclooctanone (21.7 g) was gradually added while stirring under ice cooling. Next, 25.2 g of methyl benzoate was added, and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, 300 ml of diethyl ether was added to the residue to give a suspension, and this was added to ice water. Hydrochloric acid was added to this to acidify it, and the ether layer was separated. The ether solution was washed successively with water and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 100 ml of ethanol, and ammonia gas was bubbled into the solution for 20 minutes, and the mixture was heated under reflux for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 13.4 g of the desired product. Melting point 2
77-278 ° C

Reference Example 2 Preparation of 2 -phenyl-1,5,6,7,8,9-hexahydro-4H-cyclohepta [b] pyridin-4-one:

6.8 g of 60% sodium hydride was suspended in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred while cooling with ice.
8.7 g of 2-acetylcycloheptanone was gradually added. Then, 11.0 g of methyl benzoate was added, and the mixture was heated under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, 100 ml of diethyl ether was added to the residue to make a suspension, and this was added to ice water. After separating the aqueous layer and washing with diethyl ether,
Acidified with hydrochloric acid. This was extracted with diethyl ether, the ether solution was washed successively with water and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 40 ml of ethanol, ammonia gas was blown into this for 20 minutes, and the mixture was heated under reflux for 1 hour, and then the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 5.8 g of the desired product. Melting point 223-22
4 ° C

Reference Example 3 — 2-Phenyl-1,5,6,7-tetrahydro-4H-
Production of 1-pyrindin-4-one: 2 in Reference Example 2
-In place of acetylcycloheptanone, 2-acetylcyclopentanone was used, reacted and treated in the same manner as in Reference Example 2, and the product was recrystallized from ethanol to obtain the desired product.
Melting point 270-275 ° C (decomposition)

Reference Example 4 --2- (4-pyridyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine-4 (1H)-
Manufacturing On:

60% sodium hydride (17.3 g) was suspended in 1,2-dimethoxyethane (300 ml), and 2-acetylcyclooctanone (24.2 g) was gradually added while stirring under ice cooling. Then, 29.6 g of methyl isonicotinate was added, and the mixture was heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, 300 ml of diethyl ether was added to the residue to give a suspension, and this was added to ice water. The aqueous layer was separated, washed with diethyl ether, and then acidified with hydrochloric acid. This was washed again with diethyl ether and adjusted to pH 4 with aqueous sodium hydroxide solution. After extraction with diethyl ether, the ether solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 150 ml of ethanol, and ammonia gas was blown into the solution for 20 minutes, and the mixture was heated under reflux for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 5.9 g of the desired product. Melting point 285-286 ° C

Reference Example 5 : 2- (4-fluorophenyl) -5,6,7,8,9,
10-Hexahydrocycloocta [b] pyridine-4
Production of (1H) -one:

2.4 g of 60% sodium hydride was suspended in 46 ml of tetrahydrofuran, and 10.1 g of 2-acetylcyclooctanone was gradually added while stirring under ice cooling. Then 4
After adding 9.2 g of methyl-fluorobenzoate, 120 ml of 1.0 M sodium bis (trimethylsilyl) amide tetrahydrofuran solution was added dropwise, and the mixture was stirred at room temperature for 5 hours.
The reaction mixture was concentrated under reduced pressure, and diethyl ether and water were added to the residue. Hydrochloric acid was added to this to acidify it, and the ether layer was separated. The ether solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 100 ml of ethanol, and ammonia gas was bubbled into the solution for 20 minutes, and the mixture was heated under reflux for 1 hour. Then, the reaction mixture was concentrated under reduced pressure.
The residue was recrystallized from ethanol to obtain 4.6 g of the desired product.
Melting point 299-300 ° C

Reference Example 6--2- (4-fluorophenyl) -1,5,6,7,8,
Preparation of 9-hexahydro-4H-cyclohepta [b] pyridin-4-one:

0.8 g of 60% sodium hydride was suspended in 14 ml of tetrahydrofuran, and 3.1 g of 2-acetylcycloheptanone was gradually added with stirring under ice cooling. Then 4-
After adding 3.1 g of methyl fluorobenzoate, 40 ml of 1.0 M sodium bis (trimethylsilyl) amide tetrahydrofuran solution was added dropwise, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and diethyl ether and water were added to the residue. The aqueous layer was separated and washed with diethyl ether, and hydrochloric acid was added to this to acidify it. This was extracted with diethyl ether, the ether solution was washed successively with water and a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in 30 ml of ethanol, ammonia gas was bubbled into this for 20 minutes, and the mixture was heated under reflux for 1 hour, and then the reaction mixture was concentrated under reduced pressure.
The residue was recrystallized from ethanol to obtain 1.8 g of the desired product.
Melting point 253-255 ° C

Reference Examples 7 and 8 : Instead of 2-acetylcycloheptanone in Reference Example 6, 2-acetylcyclohexanone was used in Reference Example 7, and 2-acetylcyclopentanone was used in Reference Example 8, as in Reference Example 6. The product was recrystallized from ethanol to give the following compound.

Reference Example 7 : 2- (4-fluorophenyl) -5,6,7,8-tetrahydro-4 (1H) -quinolinone: melting point 278-27.
9 ° C

Reference Example 8 2- (4-Fluorophenyl) -1,5,6,7-tetrahydro-4H-1-pyrindin-4-one: melting point 27
0-272 ° C

Reference Example 9 --4-Bromo-2-phenyl-5,6,7,8,9,10
-Production of hexahydrocycloocta [b] pyridine:

2-phenyl-5,6,7,8,9,10
-Hexahydrocycloocta [b] pyridine-4 (1
H) -one (10 g) and phosphorus tribromide (20 ml) at 170 ° C.
The mixture was heated and stirred for an hour. The reaction mixture was dissolved in 50 ml of chloroform, and this was poured into ice water. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution, the organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted and purified with chloroform to obtain 8.6 g of oily desired product.

Reference Examples 10 to 17 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 9 and, if necessary, recrystallization from a suitable solvent gave the following compounds.

Reference Example 10 : 4-Bromo-2- (4-fluorophenyl) -5,6,6-
7,8,9,10-Hexahydrocycloocta [b] pyridine: oil

Reference Example 11 : 4-bromo-2- (4-pyridyl) -5,6,7,8,
9,10-Hexahydrocycloocta [b] pyridine:
Melting point 98-99 ° C (recrystallized from petroleum ether)

Reference Example 12 4-Bromo-2-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine: oil

Reference Example 13 : 4-Bromo-2- (4-fluorophenyl) -6,7,
8,9-Tetrahydro-5H-cyclohepta [b] pyridine: oil

Reference Example 14 4-Bromo-2-phenyl-5,6,7,8-tetrahydroquinoline: melting point 61-62 ° C. (recrystallized from petroleum ether)

Reference Example 15 : 4-Bromo-2- (4-fluorophenyl) -5,6,6-
7,8-Tetrahydroquinoline: melting point 59-60 ° C (recrystallized from petroleum ether)

Reference Example 16--4-Bromo-2-phenyl-6,7-dihydro-5H-
1-pyrindine: melting point 43-44 ° C (recrystallized from petroleum ether)

Reference Example 17 : 4-Bromo-2- (4-fluorophenyl) -6,7-
Dihydro-5H-1-pyrindine: melting point 92-93 ° C
(Recrystallized from diethyl ether)

Reference Example 18 Preparation of 2- (4-fluorophenyl) -4-trifluoromethylsulfonyloxy-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine:

2- (4-fluorophenyl) -5,6
1.3 g of 7,8,9,10-hexahydrocycloocta [b] pyridin-4 (1H) -one was dissolved in 26 ml of pyridine, and 0.56 ml of trifluoromethanesulfonyl chloride was added with stirring under ice cooling. After stirring for 1.5 hours at room temperature,
The reaction mixture was concentrated under reduced pressure. To the residue was added 4% aqueous sodium hydroxide solution (20 ml) and n-hexane (40 ml) and the mixture was stirred.
The organic layer was separated. This was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from petroleum ether to obtain 0.7 g of the desired product. Melting point 87-
88 ° C

Reference Example 19 --2- (4-Fluorophenyl) -4-trifluoromethylsulfonyloxy-6,7,8,9-tetrahydro-
Preparation of 5H-cyclohepta [b] pyridine:

In place of 2- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-4 (1H) -one in Reference Example 18, 2- (4 -Fluorophenyl) -1,5,6,7,
Using 8,9-hexahydro-4H-cyclohepta [b] pyridin-4-one, the reaction and treatment were carried out in the same manner as in Reference Example 18, and the product was recrystallized from petroleum ether to obtain the desired product. Melting point 68-69 ° C

Reference Example 20 : Preparation of 2-phenyl-4-trifluoromethylsulfonyloxy-5,6,7,8-tetrahydroquinoline:

A mixture of 2.3 g of 2-phenyl-5,6,7,8-tetrahydro-4 (1H) -quinolinone, 2.4 ml of trifluoromethanesulfonic anhydride and 50 ml of methylene chloride was stirred at room temperature for 4 hours. To the reaction mixture was added 4% aqueous sodium hydroxide solution (40 ml) and the mixture was stirred, and the organic layer was separated. This was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized from petroleum ether to obtain 3.2 g of the desired product. Melting point 58-59 ° C

Example 1 Preparation of 4- (4-ethyl-1-piperazinyl) -2-phenyl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine:

4-bromo-2-phenyl-5,6,7,
2.0 g of 8,9,10-hexahydrocycloocta [b] pyridine, 2.2 g of 1-ethylpiperazine and potassium iodide
10 mg of the mixture was heated with stirring at 170 ° C. for 16 hours. The reaction mixture was dissolved in chloroform, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with a chloroform-methanol (50: 1) mixed solution, and recrystallized from acetonitrile to obtain 1.4 g of the desired product. Melting point 93-94 ° C

Examples 2 to 18 : Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1, and the product was recrystallized from acetonitrile to give the following compound 9
The compounds of Table 4 represented by

[0105]

[Chemical 9]

[0106]

[Table 4] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example n R ¹ R ⁴ Melting point (° C.) ━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 2 6 Et F 128-129 3 6 CH ₂ Ph H 111 4 6 CH ₂ Ph F 126-127 5 5 Et H 112- 113 6 5 Et F 91-92 7 5 CH ₂ Ph H 83-85 8 5 CH ₂ Ph F 88-90 9 4 Et H 82-83 10 4 Et F 96-97 11 4 CH ₂ Ph H 131-132 12 4 CH ₂ Ph F 126-127 13 4 CH ₂ CH ₂ OH H 151-152 14 4 CH ₂ CH ₂ OH F 133-134 15 3 Et H 124-125 16 3 Et F 117-118 17 3 CH ₂ Ph H 114-115 18 3 CH ₂ Ph F 125-126 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 19 Preparation of 4- (4-ethyl-1-piperazinyl) -2- (4-pyridyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine :

In place of 4-bromo-2-phenyl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine in Example 1, 4-bromo-2- (4-
Pyridyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine was used and reacted and treated in the same manner as in Example 1 to obtain an oily target product. This was dissolved in ethanol, 2 equivalents of maleic acid was added, and the product was recrystallized from ethanol to obtain the desired dimaleic acid salt. Melting point 158-159 ° C (decomposition)

Example 20 --2- (4-fluorophenyl) -4- (4-methyl-1)
Preparation of -piperazinyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine:

2- (4-fluorophenyl) -4-trifluoromethylsulfonyloxy-5,6,7,8,
9,10-Hexahydrocycloocta [b] pyridine 0.
A mixture of 5 g and 0.62 g of 1-methylpiperazine was added at 140 ° C for 3 times.
The mixture was heated and stirred for an hour. 10 ml of 10% hydrochloric acid was added to the reaction mixture,
The insoluble material was filtered off. The filtrate was made alkaline with aqueous sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
The residue was recrystallized from acetonitrile to obtain 0.1 g of the desired product. Melting point 150-151 ° C

Example 21 Preparation of 2- (4-fluorophenyl) -4- (1-piperazinyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine:

2- (4-fluorophenyl) -4-trifluoromethylsulfonyloxy-5,6,7,8,
9,10-Hexahydrocycloocta [b] pyridine 0.
5 g, piperazine 0.53 g and dimethyl sulfoxide 2.5 ml
The mixture was heated and stirred at 110 ° C. for 4 hours. Water was added to the reaction mixture and the crystals were collected by filtration. The crystals were added to 10 ml of 10% hydrochloric acid, and the insoluble matter was filtered off. The filtrate was made alkaline with aqueous sodium hydroxide solution and extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Recrystallize the residue from acetonitrile to give the desired compound 0.1 g
Got Melting point 120-121 ° C

Example 22 Preparation of 2- (4-fluorophenyl) -4- (1-piperazinyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine:

2- (4-Fluorophenyl) -4-trifluoromethylsulfonyloxy-in Example 21
5,6,7,8,9,10-hexahydrocycloocta [b] pyridine instead of 2- (4-fluorophenyl) -4-trifluoromethylsulfonyloxy-6,6
7,8,9-Tetrahydro-5H-cyclohepta [b]
Reaction and treatment were carried out in the same manner as in Example 21 using pyridine, and the product was recrystallized from acetonitrile to obtain the target compound. Melting point 136-137 ° C

Example 23 Preparation of 4- (4-methyl-1-piperazinyl) -2-phenyl-5,6,7,8-tetrahydroquinoline:

A mixture of 2.3 g of 2-phenyl-4-trifluoromethylsulfonyloxy-5,6,7,8-tetrahydroquinoline and 3.2 g of 1-methylpiperazine was heated and stirred at 140 ° C. for 2 hours. The reaction mixture was dissolved in chloroform, washed with water, and then extracted with 10% hydrochloric acid. The aqueous layer was neutralized with an aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure.
The residue was dissolved in an ethanol solution of hydrochloric acid, diethyl ether was added to the residue for crystallization, and this was recrystallized from ethanol-diethyl ether to obtain 0.9 g of the desired dihydrochloride. Melting point 260-263 ° C (decomposition)

Example 24 2-Phenyl-4- (1-piperazinyl) -5,6
Preparation of 7,8,9,10-hexahydrocycloocta [b] pyridine:

4- (4-benzyl-1-piperazinyl)
-2-Phenyl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine 5.2 g, chloroformic acid 1-
1 ml of a mixture of 1.6 ml of chloroethyl and 50 ml of methylene chloride
After heating under reflux for an hour, the mixture was concentrated under reduced pressure. 50 ml of methanol was added to the residue, the mixture was heated under reflux for 30 minutes again, and then concentrated under reduced pressure. The residue was dissolved in water, washed with diethyl ether, neutralized with aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 2.2 g of the desired product. Melting point 111-112 ° C

Examples 25 to 29 : Using the corresponding starting compounds, the reaction was carried out in the same manner as in Example 24.
After treatment, the product was converted into a hydrochloride with an ethanol solution of hydrochloric acid in some cases to obtain the compound of Table 5 represented by the following chemical formula 10. The compound of Example 27 (b) was recrystallized from ethanol-diethyl ether, and all the remaining compounds were recrystallized from acetonitrile.

[0120]

[Chemical 10]

[0121]

[Table 5] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example n R ⁴ salt Melting point (° C.) ━━━━━━━━ ━━━━━━━━━━━━━━━━━━━━ 25 5 H-131-133 26 4 H 2 hydrochloride 276-282 27 (a) 4 F-131-133 27 (b) 4 F 2 hydrochloride 286-289 28 3 H-165-166 29 3 F-167-168 ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

Example 30 Preparation of 4- (4-methyl-1-piperazinyl) -2-phenyl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine:

4- (1-Piperazinyl) -2-phenyl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine 1.5 g, formic acid 5 ml and formalin 5 ml
The mixture was heated to reflux for 1 hour. The reaction mixture was neutralized with sodium hydroxide and extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Recrystallize the residue from acetonitrile to obtain the desired product
I got 1.1g. Melting point 120-121 ° C

Examples 31 to 35 : Reactions were carried out in the same manner as in Example 30 using the corresponding starting compounds.
By treatment, the compounds of Table 6 represented by the following chemical formula 11 were obtained.

[0125]

[Chemical 11]

[0126]

[Table 6] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example n R ⁴ melting point (° C.) recrystallization solvent ━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 152 Acetonitrile 35 3 F 106-108 Petroleum ether ━━━━━━━━━━━━━━━━━━━━━━━━━━━━━

[0127]

INDUSTRIAL APPLICABILITY As described above, the compound of the present invention has a strong antagonistic effect not only on the dopamine D ₂ receptor but also on the serotonin S ₂ receptor, so that it is not always effective as a conventional antipsychotic drug. It can be expected to show excellent therapeutic effects even on the negative symptoms of schizophrenia, which may not occur, and to reduce the occurrence of extrapyramidal side effects. Furthermore, the compound of the present invention is also useful as a therapeutic agent for various diseases other than schizophrenia involving dopamine and serotonin, for example, mental disorders such as depression, depression and anxiety.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/55 AAE C07D 215/46 221/04 405/04 215 221 409/04 215 221 417/04 215 221 // (C07D 401/04 213: 06 221: 04)

Claims (2)

[Claims] 1. A cycloalkanopyridine derivative represented by the following chemical formula 1 or a pharmaceutically acceptable acid addition salt thereof. [Chemical 1] [In the formula, R ¹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a cycloalkyl (lower) alkyl group or one or two phenyl moieties selected from halogen, lower alkyl and lower alkoxy. A phenyl (lower) alkyl group which may be substituted with, and R ² represents a phenyl group or a heteroaryl group which may be substituted with 1 or 2 selected from halogen, lower alkyl and lower alkoxy. , R ³ represents a hydrogen atom or a lower alkyl group, m represents 2 or 3, and n represents 3, 4, 5, 6 or 7. ] 2. A psychotropic drug containing the cycloalkanopyridine derivative according to claim 1 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient.