JPH037257A - Pyridine derivative and psychotropic agent containing the derivative as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R is H or lower alkyl; W is H or lower alkyl; Y is lower alkyl; W and Y, together with the pyridine ring, form group expressed by formula II (n is 3-7; R4 to R6 are H, lower alkyl, phenyl, etc.); Ar is aryl or heteroaryl; R2 and R3 are H, halogen, lower alkyl, hydroxy, etc.; R1 is H, aklyl, etc.; R7 and R8 are H or lower alkyl; m is 2 or 3]. EXAMPLE:2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10- hexahydrocycloocta[b]pyridine. USE:A psychotropic, anti-anxiety agent and ameliorant for cerebral function. PREPARATION:A compound expressed by formula III (X is leaving atom or group) is reacted with a compound expressed by formula IV in the presence of a base without or in a solvent (e.g. toluene) at 40-200 deg.C to afford the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyridine derivative useful as a medicine and a new medicine containing it as an active ingredient.

US Patent Department No. 4,469,696 (Japanese Patent Publication No. 58-96
No. 3) contains several 2-(1-piperazinyl)-4-
A group of compounds of allylpyridine derivatives are disclosed. However, the compounds specifically disclosed therein are only those having an aryl group or 2-furyl group at the 5-position of the pyridine ring, and their structures are clearly different from the compounds of the present invention. Furthermore, the pharmacological action of these compounds is related to lipid absorption inhibiting action, and is completely different from the pharmacological action of the compounds of the present invention.

In addition, 2-[4-(4-methylbenzyl)-1-piperazinyl]-4-phenylpyridine, a pyridine derivative having a piperazinyl group at the 2-position and a phenyl group at the 4-position of the pyridine ring, is an antipsychotic or a neuroleptic. It has been reported that it has a weak medicinal effect (U.S. Patent Department 4, 8
31,034 and JP-A-83-48267).

As a result of intensive research into drugs that act on the central nervous system, the present inventor found that they have significant psychotropic effects and are useful as antipsychotics or anxiolytics, as well as as brain function improving drugs. discovered a pyridine derivative and completed the present invention.

The present invention has a general formula (I) [wherein R means a hydrogen atom or a lower alkyl group, W means a hydrogen atom or a lower alkyl group, and Y means a lower alkyl group, Alternatively, W and Y together with the pyridine ring form the following ring (WY), where n means 3, 4, 5.6 or 7, and R
4, R, and R6 are the same or different and mean a hydrogen atom, a lower alkyl group, or a phenyl group, or R4,
Any two of R5 and R6 together mean a single bond or a lower alkylene group.

R2 and R3 are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, or a trifluoromethyl group.

means a cyan group, nitro group or amino group, R1 is a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a lower alkoxy (lower) alkyl group,
Cycloalkyl (lower) alkyl group, aryl (lower) alkyl group which may have a substituent, acyloxy (
(lower) alkyl group, lower alkanoyl (lower) alkyl group, arylcarbonyl (lower) alkyl group which may have a substituent, lower alkenyl group, lower alkynyl group.

It means an aryl group, heteroaryl group or acyl group which may have a substituent, and R7 and R8 are the same or different and mean a hydrogen atom or a lower alkyl group.

m means 2 or 3. ] The present invention relates to pyridine derivatives represented by these and their acid addition salts, and psychotropic agents containing these compounds as active ingredients.

Examples of the acid addition salt of the compound represented by formula (1) include hydrochloride, hydrobromide, hydroiodide, and sulfate.

Examples include inorganic acid salts such as phosphates, and organic acid salts such as maleates, fumarates, oxalates, citrates, tartrates, lactates, benzoates, and methanesulfonates.

Since the compounds of formula (1) and their acid addition salts may exist in the form of hydrates, these hydrates are also included in the compounds of the present invention.

When the compound represented by formula (1) contains an asymmetric carbon, stereoisomers, mixtures thereof, and racemates are included in the compounds of the present invention.

Terms used in this specification will be explained below.

The alkyl group, lower alkyl group, lower alkyl moiety, or lower alkylene group may be linear or branched. "Alkyl group" means one having 1 to 10 carbon atoms, and a specific example is methyl.

Ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl, pentyl.

Examples include isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like.

"Lower alkyl group" means an alkyl group mentioned above having 1 to 6 carbon atoms, unless otherwise specified. "
Specific examples of the "lower alkylene group" include methylene, ethylene, propylene, tetramethylene, and the like. "
"Halogen atom" means fluorine, chlorine, bromine, and iodine. Specific examples of the "lower alkoxy group" or the lower alkoxy moiety include those in which the alkyl moiety is methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. A "cycloalkyl group" or a cycloalkyl moiety means one having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohebutyl.

Examples include cyclooctyl. “Hydroxy (lower)
"Alkyl group" means a lower alkyl group substituted with a hydroxy group, and specific examples include 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, and 4-hydroxybutyl. .

Examples include 2-hydroxybutyl. "Lower alkoxy (lower) alkyl group" means a lower alkyl group substituted with lower alkoxy, and specific examples include 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2゜3-dimethoxy Propyl, 4-methoxybutyl.

Examples include 2-methoxybutyl. The term "cycloalkyl (lower) alkyl group" means a lower alkyl group substituted with cycloalkyl, and includes, for example, cyclopropylmethyl, cyclopentylmethyl, cyclohexylethyl, and the like.

"Lower alkanoyl (lower) alkyl group" means a lower alkyl group substituted with an alkanoyl group having 2 to 6 carbon atoms, and includes, for example, acetylmethyl, acetylethyl, propionylethyl, and the like. "Lower alkenyl group" refers to a group having 3 to 2 carbon atoms and 1 to 2 double bonds.
6, such as propenyl, allyl, butenyl, etc. Examples of the "lower alkynyl group" include engineered tinyl and propargyl. Specific examples of the "aryl group" or aryl moiety include phenyl, naphthyl, and the like. A "heteroaryl group" or a heteroaryl moiety is a nitrogen atom.

It means a monocyclic or bicyclic ring containing at least one oxygen atom or sulfur atom, such as furyl.

Examples include thienyl, pyridyl, pyrimidyl, isoquinolyl, and the like. "Aryl group which may have a substituent" or an aryl moiety which may have a substituent is one in which the aryl part is unsubstituted or has 1 to 2 halogen atoms, lower alkyl, hydroxy group, means substituted with a lower alkoxy group, trifluoromethyl group, cyan group, nitro group or amino group, such as phenyl, 2-
3- or 4-fluorophenyl, 2-. 3- or 4-chlorophenyl, 2.3- 2.4-. 2゜5-. 2,6
- or 3,4-difluorophenyl.

2-93- or 4-methylphenyl, 2-. 3- or 4
-methoxyphenyl, 2-. Examples include 3- or 4-trifluoromethylphenyl.

"Aryl (lower) alkyl group which may have a substituent" means one having an aryl moiety which may have the above-mentioned substituent, such as benzyl, 2-. 3-
or 4-fluorobenzyl.

2-3- or 4-chlorobenzyl, 2.3-2.4-.
2.5-. 2,6- or 3,4-difluorobenzyl,
2-. 3- or 4-methylbenzyl, 2-. 3- or 4
-methoxybenzyl, 2,3- or 4-trifluoromethylbenzyl, and the like. "Arylcarbonyl (lower) alkyl group which may have a substituent" means a group having an aryl moiety which may have a substituent as described above, such as benzoylethyl, 4-fluorobenzoylpropyl etc. "Acyl group" or acyl moiety refers to lower alkanoyl group, cycloalkylcarbonyl group, and halogen atom.

means a heteroarylcarbonyl group in which the benzoyl group or heteroaryl moiety optionally substituted with lower alkyl or lower alkoxy is the same as the above-mentioned heteroaryl, for example formyl.

acetyl, propionyl, cyclohexanecarbonyl,
Benzoyl, 4-fluorobenzoyl, nicotinoyl,
Examples include isonicotinoyl, furoyl, thenoyl and the like. "Acyloxy (lower) alkyl group" means one having the above-mentioned acyl moiety, and specific examples thereof include acetyloxyethyl, benzoyloxyethyl, and the like.

- Among the compounds of the present invention represented by formula (I), R is a hydrogen atom, R+ is a hydrogen atom, Cl-Cl
0 alkyl group, 03 Cs cycloalkyl group, hydroxy 02 C8 alkyl group, C, -03 alkoxy C2-C
, alkyl group, C2C5 acyloxy02C8 alkyl group, benzoyl C optionally substituted with a halogen atom
2-Cl5 alkyl group, C2C4 alkenyl group, C2-
C, alkynyl group, C2C11 alkanoyl group, pyridyl group, pyrimidyl group or furoyl group, R2 and R3 are the same or different, and are a hydrogen atom or a halogen atom.

C1C: l alkyl group or C1-03 alkoxy group, Rt and R8 are the same or different, and hydrogen atom or C1C:
Examples include compounds in which t is a C3 alkyl group and m is 2, and acid addition salts thereof.

More preferably, R3 is a hydrogen atom.

C, -C, alkyl group, C3-C8 cycloalkyl group.

Hydroxy C2-06 alkyl group, ClG2 alkoxy C2-03 alkyl group, acetyloxy C2-C4 alkyl group, C3-C4 alkenyl group or C2-C5 alkanoyl group, R2 and R3 are the same and both are hydrogen atoms or halogen atoms. or one of them is a hydrogen atom and the other is a halogen atom, a methyl group or a methoxy group, and R4, Rs and R6 are the same or different,
Compounds that are a hydrogen atom or a Cl-C4 alkyl group, or two of these together are a ClC2 alkylene group, and acid addition salts thereof.

More preferable examples include compounds in which R2 and R3 are the same or different hydrogen atoms or fluorine atoms, and acid addition salts thereof.

More preferable examples include the following general formula (1-1) and the following general formula (1-2) (where nl means 3, 6 or 7, and R+ + is a hydrogen atom, C, -C, alkyl Base.

03C, means a cycloalkyl group, hydroxy C2-C4 alkyl group, ClO2 alkoxy C2-C5 alkyl group or C3 alkenyl group, and R21 and R31 are the same -
or differently means a hydrogen atom or a fluorine atom, and R7+ and R81 are the same or different and represent a hydrogen atom or a C
1O3 means an alkyl group. ) and acid addition salts thereof, and (wherein R2 means 4 or 5, R12 is a hydrogen atom, C, -C, alkyl group, C3-08
Cycloalkyl group, hydroxyC2-C.

Alkyl group, C,-02 alkoxy 02 C3 alkyl group or C3 alkenyl group.

R22 and R3□ are the same or different and mean a hydrogen atom or a fluorine atom; R4□, R5□ and R8□ are the same or different and are a hydrogen atom or a CI C4 alkyl group, or any of these The two together mean a C1-02 alkylene group. ) and its acid addition salts.

Particularly preferred in formula 1 (r-1) is n,
is 6, Rll is C, -C, alkyl group, C3Ce
is a cycloalkyl group or a hydroxy C2-C4 alkyl group, R2 and R3I are the same or different and are a hydrogen atom or a fluorine atom bonded to the 2- or 4-position,
Compounds in which R71 and R8 are hydrogen atoms, and acid addition salts thereof.

In addition, in formula (1-2), R1□ is a C+08 alkyl group, a C3Ca cycloalkyl group, or a hydroxyC
2-Cialkyl group, R2゜ and R3゜ are the same or different and are a hydrogen atom or a fluorine atom bonded to the 2-position or the 4-position, and R4゜, R5□ and R6□ are all hydrogen atoms. Examples include compounds in which one or two of these groups are a ClC2 alkylene group and the other is a hydrogen atom, and acid addition salts thereof.

The most preferred one is the following general formula (1-3) (wherein R13 means a methyl group, ethyl group, propyl group, butyl group, pentyl group or hydroxyethyl group, R33
means a hydrogen atom or a fluorine atom. ) and its acid addition salts.

These compounds specifically include 2-(4-methyl-1-
piperazinyl)-4-(4-fluorophenyl)-5,
6,7,8,9,10-hexahydrocycloocta[b
l pyridine.

2-(4-methyl-1-piperazinyl)-4-(2,4
-difluorophenyl)-5,6,7゜8.9.10-
Hexahydrocycloocta[b]pyridine.

2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9°10-hexahydrocycloocta[blpyridine.

2-(4-ethyl-1-piperazinyl)-4-(2,4
-difluorophenyl)-5,6,7゜8.9.10-
Hexahydrocycloocta[b]pyridine.

2-(4-n-propyl-1-piperazinyl)-4-(
4-fluorophenyl)-5,6,7゜8.9.10-
Hexahydrocycloocta[b]pyridine.

2-(4-n-propyl-1-piperazinyl)-4-(
2,4-difluorophenyl)-5,6°7.8,9.
10-hexahydrocycloocta[b]pyridine.

2-(4-n-butyl-1-piperazinyl)-4-(4
-fluorophenyl)-5,6,7,8°9.10-hexahydrocycloocta[blpyridine.

2-(4-n-pentyl-1-piperazinyl)-4-(
4-fluorophenyl)-5,6,7゜8.9.10-
hexahydrocycloocta[blpyridine and 2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl) = 5.6,7,
8,9.10-hexahydrocycloocta[b]pyridine and the like.

(The following is a blank space) The compound of the present invention can be produced, for example, by the following method.

(1) Compound (I) of the present invention is a compound represented by the general formula (wherein, X means a leaving atom or a leaving group) and the general formula (III) (wherein, R1, R7, R8 and m have the same meanings as above.) It can be obtained by reacting with the compound represented by:

The leaving atom or leaving group represented by X in formula (Il) means an atom or group that can leave in the form of HX together with the hydrogen atom of the NH moiety of the compound of formula (III) under reaction conditions. , for example, halogen atoms such as chlorine, bromine, and iodine, lower alkylthio groups such as methylthio and ethylthio, lower alkylsulfonyl groups such as methanesulfonyl, lower alkylsulfonyloxy groups such as methanesulfonyloxy, benzenesulfonyloxy, p -Arylsulfonyloxy groups such as toluenesulfonyloxy.

The reaction between the compound represented by the general formula (II) and the compound represented by the general formula (■ir) is carried out without a solvent or in a suitable solvent under normal pressure or increased pressure.

Specific examples of solvents include aromatic hydrocarbons such as toluene and xylene, ketones such as methyl ethyl ketone,
Examples include ethers such as dioxane and diglyme, alcohols such as ethanol, isopropyl alcohol, and butanol, N,N-dimethylformamide, and dimethyl sulfoxide. This reaction is preferably carried out in the presence of a base, and a specific example of the base is sodium carbonate.

Alkali carbonates such as potassium carbonate, alkali bicarbonates such as sodium bicarbonate 7 potassium bicarbonate.

Examples include tertiary amines such as triethylamine,
An excess amount of the compound represented by the general formula (II+) can also serve as the compound. In addition, when the compound represented by the general formula (lI[) exists in the form of a hydrate, the reaction temperature which can also be used in that form is usually 40 to 200°C.

Starting compound (II) can be produced by the methods shown in Reference Examples 1 to 106 or a method analogous thereto.

(2) The compound (1) of the present invention in which R1 is a hydrogen atom.

A compound represented by the general formula (1-4) (wherein, R14 means a benzyl group or ben, in which the aryl moiety may be substituted with a lower alkyl group, a lower alkoxy group, or a halogen atom.) It can be produced by hydrolysis.

Hydrolysis of the compound represented by the general formula (1-4) can be carried out by conventional method 2, for example, by carrying out catalytic reduction at normal temperature and normal pressure using an alcohol such as ethanol as a solvent. The compound of the present invention represented by the general formula ([-4) can be prepared by the production method of (1), or the compound (+-4) of the present invention in which R14 is a benzyloxycarbonyl group can be prepared by
It can be obtained by a conventional method from the compound (1) of the present invention in which R14 is a methyl group or an optionally substituted benzyl group.

(3) The compound (1) of the present invention in which R is a hydrogen atom,
Further, benzyl W, Y and m in the general formula (1-5) which may be substituted with a lower alkyl group, a lower alkoxy group or a halogen atom have the same meanings as above. ) is obtained by reacting the compound represented by the general formula (r
-8) (In the formula, Rte is an ethoxycarbonyl group, -R, R2, R3, R7, R8, W, Y and m have the same meanings as above.) (In the formula, R16 is a methyl group or Hydrolysis of a compound represented by an aryl moiety or a compound whose RIR is a 1-chloroethoxycarbonyl group in the general formula ((-7)R8) is usually carried out by heating, for example in methanol. The compounds of the present invention represented by general formulas (1-5) and (1-7) can be obtained by the production method (1).

(4) The compound of the present invention in which R+ is a group other than a hydrogen atom has the general formula (1-8) R2, P-3, R7, Rs, W, Y and m have the same meanings as above. ) It can be produced by hydrolyzing the compound represented by:

Hydrolysis of the compounds represented by general formulas (1-6) and (1-7) can be carried out using a conventional method, for example, using a suitable solvent such as ethanol that is miscible with water, and a base such as sodium hydroxide or potassium hydroxide. , or by heating in the presence of an acid such as hydrochloric acid or sulfuric acid.Y and m! , t@ have the same meaning. ) and the general formula Hv) Rts Z (IV) (wherein, 2 means a reactive residue of alcohol, R18
means the same as R7 above except for a hydrogen atom. ) can be produced by reacting with the compound represented by

Examples of the reactive ester residue of alcohol represented by formula 2 include halogen atoms such as chlorine, bromine, and iodine;
Examples include lower alkylsulfonyloxy groups such as methanesulfonyloxy, and arylsulfonyloxy groups such as benzenesulfonyloxy and p-)luenesulfonyloxy.

The reaction between the compound represented by the general formula (1-8) and the compound represented by the general formula (IV) is usually carried out in a suitable solvent, and a specific example of the solvent is benzene.

Aromatic hydrocarbons such as xylene, ketones such as methyl ethyl ketone, ethers such as dioxane, N
, N-dimethylformamide is preferably carried out in the presence of a base, and specific examples of the base include those mentioned in the production method section of (1). The reaction temperature is usually 30 to 150°C.

The compounds of the present invention represented by general formula (1-8) are (1) to
It can be obtained by the production method (3).

When the compound of the present invention obtained by the production methods (1) and (4) has a hydroxy group in its structure, the compound can be converted into a corresponding one by reacting with an appropriate acylating agent or lower alkylating agent. It can be converted into an ester derivative or an ether derivative. These reactions are carried out according to conventional methods.

The compound of the present invention represented by general formula (I) produced by each of the above-mentioned production methods is isolated and purified according to conventional methods.

The compound of the present invention represented by the general formula (1) can be obtained in the form of a free base, a salt, or a hydrate depending on the selection of raw material compounds, reaction conditions, treatment conditions, etc. Salts can be converted to the free base in conventional manner by treatment with a base such as an alkali hydroxide. On the other hand, the free base can be converted into a salt by treatment with various acids according to conventional methods.

The compound of the present invention represented by the general formula (N) has an exploratory behavior suppressing effect, an apomorphine-induced emesis suppressing effect, and a dopamine D2
It also exhibits a serotonin S2 receptor binding action and an action to increase monoamine metabolites in the brain, and has low toxicity, so it is useful as an antipsychotic or anxiolytic. Furthermore, it has shown excellent ameliorating effects in various memory impairment model experiments, and is useful as a brain function improving drug for various functional disorders in the central nervous system.

Serotonin 82 has a strong suppressive effect on apomorphine-induced vomiting
．． Examples of compounds that exhibit dopamine D2 receptor binding activity or dopamine metabolite increasing activity include the following compounds and physiologically acceptable salts thereof.

(1) 2-(4-ethyl-1-piperazinyl)-4
-(4-fluorophenyl)-5,6,7°8.9.1
0-hexahydrocycloocta[b]pyrindine (2) 2-(4-ethyl-1-piperazinyl)-4
-(2,4-difluorophenyl)-5,6°7.8,
9.10-hexahydrocycloocta[b]pyrindine (3) 2-(4-methyl-1-piperazinyl)-4
-(4-fluorophenyl)-5,6,7°8.9.1
0-hexahydrocycloocta[blpyridine.

(4) 2-(4-methyl-1-piperazinyl)-4
-(2,4-difluorophenyl)-5,6°7.8,
9.10-hexahydrocycloocta[blpyridine.

(5) 2-(4-n-propyl-1-piperazinyl)-
4-(4-fluorophenyl)-5,6°7.8,9.
10-hexahydrocycloocta[blpyridine.

(6) 2-(4-n-butyl-1-piperazinyl)-4
-(4-fluorophenyl)-5,6°7.8,9.1
0-hexahydrocycloocta[blpyridine.

(7) 2-(4-n-benthyl-1-piperazinyl)-
4-(4-fluorophenyl)-5,6°7.8,9.
10-hexahydrocycloocta[blpyridine.

(8) 2-[4-(2-hydroxyethyl)-1-
piperazinyl]-4-(4-fluorophenyl)-5,
6,7,8,9,10-hexahydrocycloocta[b
] Pyrindine (9) 2-(1-piperazinyl)-4-(4-fluorophenyl)-6,7-sihydro-5H-1-pyrindine.

(10) 2-(4-ethyl-1-piperazinyl)-
4-(4-fluorophenyl)-6,7-sihydro 5
8-1-pyrindine.

(11) 2-[4-(2-hydroxyethyl)-1
-piperazinyl]-4-(4-fluorophenyl)-6
,7-sihydro5H-1-pyrindine.

(12) 2-(4-ethyl-1-piperazinyl)-
4-phenyl-6,7,8,9-tetrahydro-5H-
cyclohebuta[b]pyrindine (13) 2-(4-
Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7,8゜9-tetrahydro-5H-cyclohebuta[b]pyrindine (14) 2-(4-ethyl-1-piperazinyl)-
4-(4-fluorophenyl)-5,6,7°8-tetrahydro-5,8-methanoquinoline.

(15) 2-(4-ethyl-1-piperazinyl)-
4-(2,4-difluorophenyl)-5,6°7.8
-Tetrahydro-5,8-methanoquinoline.

(16) 2-(4-ethyl-1-piperazinyl)-
4-(4-fluorophenyl)-6,7,8°9-tetrahydro-58-6,9-methanocyclohebuta[blpyridine and (17)2-(4-ethyl-1-piperazinyl)-4-
(4-Fluorophenyl)-6,7,8゜9-tetrahydro-5H-5,8-methanocyclohebuta[b]pyridine Excellent improvement in scopolamine- and cycloheximide-induced behavioral and memory disorders. Compounds that exhibit this action include, for example, the following compounds and their physiologically acceptable salts.

(1) 2-(1-piperazinyl)-4-phenyl-
6,7-Sihydro5H-1-pyrindine.

(2) 2-(1-piperazinyl)-4-(4-fluorophenyl)-6,7-sihydro-5H-1-pyrindine.

(3) 2-(1-piperazinyl)-4-phenyl-
5,6,7,8-tetrahydroquinoline.

(4) 2-(1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8-tetrahydroquinoline and (5) 2-(1-piperazinyl)-4-(4-fluorophenyl) -6,7,8,9-tetrahydro-5H
-Cyclohebbuta[b]pyridine The results of pharmacological experiments on representative compounds of the present invention are shown below to clarify the usefulness of the compounds of the present invention.

Test 11 - 2 Suppression of exploratory behavior Five ddY male mice weighing 20 to 25 g were used in each group. Two hours after oral administration of the test compound suspended in 0.5% tragacanth (1.0 mg/kg), mice were placed one by one in an upper chamber cage (23 x 35 x 30 cm) using an Animex locomotor analyzer (Farad). 3
The amount of exploration activity per minute was measured. The average value of the amount of exploratory behavior (counts/3 minutes) of the test compound administration group was determined and compared with that of the 5 control groups to calculate the inhibition rate. The results are shown in Table 1.

(Leaving space below) Table 1 Test of exploratory behavior suppression effect 11th grade - 42 Suppression of vomiting by apomorphine Group 1 3 to 4 Peagle dogs (8 to 15 kg) were used.

The antagonistic effects of test compounds on apomorphine-induced emesis were investigated. This test is commonly used to detect antipsychotic drugs.

Two hours after oral administration of the test compound, apomorphine hydrochloride (0
, 3 mg/kg) was administered subcutaneously to the back, and the number of vomitings was counted for 1 hour thereafter. The inhibition rate was calculated by comparing the frequency of vomiting in the test compound administration group with that of the control drug.

The results are shown in Table 2.

(Hereinafter in the margin) Table 2 Suppressing effect of emesis by apomorphine Table 2 (continued) Means the compound of Ladle Example 1a (the same applies hereinafter).

(The following is a blank space) Experiment - Dopamine D 21 Serotonin S, S2 and adrenaline α, receptor binding action (in vitro receptor binding assay) 1. Creese et al. [Eur, J. Pharma
col, 4B, 377 (1977)],
S., J., Peroutka et al. [Mo1. Pbar
-macol, 16.687 (1979)]
, J.E., Leysen et al. [Mo1. Pha
rmacol, 21.301 (1982)]
[Mo1. P
dopamine D2 + serotonin S2 and adrenergic alpha 1 receptor binding tests were carried out, respectively, according to the method of Phys.

A crude synabbutoseme membrane fraction prepared from rat brain was used as a receptor specimen, and also as a labeled ligand.

[3H] subiveron (D2), [3Hl serotonin (8
1), [3H]ketanserin (S2) and [3H]WB
-4101 (αI) was used. After incubating a buffer solution (final volume: 1 ml) containing the receptor specimen and each labeled ligand for a certain period of time in the presence of various concentrations of the test drug, the radioactive nogand bound to the receptor was harvested using a self-harvester (Brundell). Separated on a filter using a commercially available product. The total binding amount was determined by measuring the radioactivity on the filter using a liquid scintillation counter. In addition, the amount of binding in the presence of excess unlabeled ligands [subiperone (D2), serotonin (S+), methycelcito (S2), and prazosin (α1)] measured at the same time was defined as the nonspecific binding amount, and this was defined as the total binding amount. The amount of specific binding was determined by subtracting the amount. The test drug inhibits specific binding of the labeled ligand by 50
The concentration that inhibits the concentration by % was calculated by the probit method, and the results are shown in Table 3.

(Left below) Table 3 Dopamine D2. Serotonin 81.82 and adrenergic α1 receptor binding effect test t4 Effect on increasing monoamine metabolites in the brain Using 5 td-ddY male mice (25-30 g) per group,
The effect of the test compound on increasing monoamine metabolites in the brain was investigated. This effect is thought to primarily represent the degree of receptor inhibition of each monoamine.

Brains were removed 2 hours after oral administration of the test compound, homogenized with IN formic acid-acetone, and then cooled.

The supernatant was obtained by centrifugation. After this was evaporated to dryness with nitrogen gas, 0. 3, 4, which is a metabolite of dopamine, was dissolved in old N acetic acid and analyzed by high performance liquid chromatography with an electrochemical detector.
-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), a metabolite of noradrenaline 3
-Methoxy-4-hydroxyphenylethylene glycol (MOPEG) and 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin, were measured. The % increase in each monoamine metabolite by test drug (control = 100) was calculated and shown in Table 4.

h) means the compound of Example 1a (same below) Table 4 Increase in monoamine metabolites in the brain Table 4 (continued) (Margin below) Zero) means the compound of Example 1b (the same applies hereinafter).

ffi Suppressive effect on hyperlocomotion induced by scopolamine 1 group of 5 male 5td-ddY mice (22-28g
) was used to examine the antagonistic effects of test compounds on scopolamine-induced hyperlocomotion. In this exam,
Compounds that have acetylcholine nerve activating or central nervous system depressing effects show positive effects.

The test compound was orally administered to the mice, and 90 minutes later, each mouse was placed in a measurement cage (25 x 35 x 30 am). After 30 minutes, scopolamine hydrobromide (l m
g/kg) was administered intraperitoneally, and immediately after that, the amount of exercise for 30 minutes was measured using an Animex activity meter.
Measured at The case where scopolamine hyperlocomotion was completely antagonized was taken as 100%, and the % of antagonism of each test compound was calculated. The results are shown in Table 5.

(Left below) Table 5 Suppressive effect on scopolamine-induced hyperlocomotion (Left below) Table 5 (Continued) (Left below) Enkyosho-1 Improving effect on scopolamine-induced spontaneous alternation behavior disorder Decreased acetylcholine nerve function The effects of test compounds were investigated using a scopolamine-induced spontaneous alternation behavior disorder model as a model of memory impairment.

5td-ddY male mice (22
-28g) to scopolamine hydrobromide (1mg/kg)
The test compound was administered intraperitoneally, and 30 minutes later, a T-maze (passage width 5 CHI, length 25 cm, height 10
cm, guillotine doors were installed at the entrances of the start box and the left and right goal boxes). Eight consecutive trials were conducted to select the left and right goal boxes. Mice have a habit of selecting the left and right goal boxes alternately, but animals treated with scopolamine increase the number of times they enter the same goal box as in the previous trial (spontaneous alternation behavior disorder).
The case where this spontaneous alternation behavior disorder was improved to a normal level was taken as 100%, and the % of the improving effect of each test compound was calculated.

The results are shown in Table 6.

Table 6 induced by scopolamine Improvement effect on spontaneous alternation behavior disorder It means the compound of Example 86 (the same applies hereinafter).

(Left below) Tests - Improving effect on passive avoidance disorder induced by 1-cycloheximide Cycloheximide is known to cause amnesia in animals. Therefore, we investigated the effects of test compounds on the amnesia-inducing effect of cycloheximide using the passive avoidance response of mice as an indicator.

1ot5-20 5td-ddY male mice (27
Training and retention trials were performed using a step-down passive avoidance response measuring device (30 x 30 x 50 cm, with a 4 x 4 x 4 cm platform set in the center of the grid floor) using a 4 x 4 x 4 cm platform. In the training trial,
The mouse was placed on the platform, and an electric shock (I Hz) was given for 15 seconds immediately after the mouse landed on the floor grid.
, 0.5 sec, 60 VD[:) was applied. In the retention trial (24 hours after training), the mouse was placed on the platform again and the time it took to land on the floor grid (
Step-down latency) was measured. Cycloheximide (
80 rng/kg, s, c,) and test compound (i
, p, ) were administered immediately after the end of the training trial. Animals treated with cycloheximide have significantly reduced step-down latencies on retention trials (amnestic effect). The case where this latency reduction is improved to the normal level is defined as 100%,
The % improvement effect of each test compound was calculated. The results are shown in Table 7.

(Margin below) Table 7 induced by cycloheximide Improving effect on passive avoidance response disorder n) means the compound of Example 87 (the same applies hereinafter).

(Leaving space below) Trial 1 set example-8 Acute toxicity 1 group of 5 5td-ddY male mice (25-30g
), a test compound dissolved or suspended in a 0.5% tragacanth solution was administered lightly, and the presence or absence of death was observed for 7 days after administration. The results are shown in Table 8.

Table 8 Acute toxicity It means the compound of Example 1a (the same applies hereinafter).

The route of administration of the compounds of the present invention is oral administration.

Parenteral administration or rectal administration may be used, but oral administration is preferable, and the dosage depends on the type of compound.

Although it varies depending on the administration method, patient's symptoms and age, etc., it is usually 0.
．． Old to 50 B/kg/day, preferably 0. Old ~ 5mg
/kg/day. The compounds of the present invention are usually administered in the form of a formulation prepared by mixing with a pharmaceutical carrier.

As a pharmaceutical carrier, a substance commonly used in the pharmaceutical field and which does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, sorbitol, dextrin, cyclodextrin, starch,
White sugar, magnesium aluminate metasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxybutylene starch, calcium carboxymethylcellulose, ion exchange resin.

Methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone.

Polyvinyl alcohol, light silicic anhydride, magnesium stearate, talc, tragacanth, bentonite, vegum, carboxyvinyl polymer titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanolin, glycerogelatin.

Polysorbate, macrogol, vegetable oil, wax.

Examples include propylene glycol and water. Dosage forms include tablets, capsules, granules, and fine granules.

Examples include powders, syrups, suspensions, injections, and halves. These formulations are prepared according to conventional methods. In the case of a liquid preparation, it may be dissolved or suspended in water or other suitable medium before use.

In addition, tablets, granules, and fine granules may be coated by a well-known method.In the case of injections, they are prepared by dissolving the compound of the present invention in water, but if necessary, physiological saline or It may be dissolved in a glucose solution, and a buffer or preservative may be added.

These formulations may also contain other ingredients of therapeutic value.

In order to explain the present invention more specifically, reference examples,
Although Examples and Formulation Examples are given below, the present invention is not limited to these Examples. The compounds were identified by elemental analysis, mass spectra, R spectra, UV spectra, NMR spectra, etc. Furthermore, in the following Reference Examples and Examples, the following abbreviations may be used to simplify the description.

C tr -B u h C T F A Methyl group Ethyl group n-Propyl group tart-Butyl group Phenyl group Ethanol Acetonitrile Acetone Chloroform N, N-dimethylformamide Diethyl ether: Ethyl acetate HX: Hexane IP = Isopropyl alcohol M: Methanol MC: Methylene chloride PE: Petroleum ether T: Toluene W: Water Note that the solvent in parentheses shown at the melting point in Reference Examples and Examples means a recrystallization solvent.

(Left space below)
H)-Production of quinolinone: 25 g of penzoylacetonitrile, 2 cyclohexanone
5 g, 250 g of 75% polyphosphoric acid at 50°
Stir for 30 minutes at 110°C and 1.5 hours at 110°C.

After cooling, pour one reaction solution into ice water and add 300 ml of diethyl ether.
After stirring, the precipitated crystals are collected by filtration. N, N
Recrystallization from -dimethylformamide-ethanol yields 27 g of the desired product.

Melting point: 285-288°C 11 -1 D50 Using the corresponding raw material compounds, the compounds shown in Tables 9 and 10 are obtained by reacting and treating in the same manner as in Reference Example 1.

(Leaving space below) Table 9 Table 9 (continued) Table 10 Table 10 (continued) Table 10 (continued) Reference J[-11 4-(4-fluorophenyl)-1,5,6°7. 8.
Preparation of 9-hexahydro-2H-6,9-methanocyclohebuta[bl pyridin-2-one: bicyclo[3,2,
Dissolve 2 g of 11 octan-2-one and 2.6 g of 4-fluorobenzoylacetonitrile in 5 ml of 1.1,2.2-tetrachloroethane, and add 25 g of 75% polyphosphoric acid.
and then at 80°C for 30 minutes and at 100°C for 1 hour.
Stir for 30 minutes at 130°C. After cooling, the reaction solution was poured into ice water, neutralized with potassium carbonate, and the precipitated crystals were collected by filtration.

The crystals were washed with water and then with ethyl acetate, and then recrystallized from methanol to obtain 2.7 g of the desired product.

Melting point: 300°C or higher 52 4-(4-fluorophenyl)-1,5,6°7.8.
Production of 9-hexahydro-2H-5,8-methanocyclohebut[bl]pyridicin-one: Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Reference Example 51 to obtain the desired product.

Reference AJ [-reduced 1 4-(4-fluorophenyl)-3-methyl-5,6,
Production of 7,8,9,10-hexahydrocycloocta[b]pyridin-2-one: Using the corresponding raw material compound,
The desired product is obtained by reaction and treatment in the same manner as in Reference Example 1.

Melting point 268-272°C (ethanol) Production of moxibustion base-51 4-(2-thienyl)-5,6,7,8,9°10-hexahydrocycloocta[b]pyridin-2-one : Using the corresponding raw material compound, react and treat in the same manner as in Reference Example 1 to obtain the desired product.

Melting point 222-227°C (methyl ethyl ketone) 1 base-15 2-chloro-4-(4-fluorophenyl)-5,6,
Production of 7,8-tetrahydroquinoline: 4-(4-fluorophenyl)-5,6,7°8-tetrahydro-2(
A mixture of 18.7 g of IH)-quinolinone and 29 ml of phenylphosphonic dichloride is stirred at 170° C. for 1 hour. After cooling, the reaction solution was dissolved in 200 ml of chloroform,
The mixture was added dropwise to ice water under stirring over about 30 minutes, and concentrated aqueous ammonia was gradually added to make it basic. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropyl alcohol-petroleum ether to obtain 15.1 g of the desired product.

Melting point 111-112℃ Reference 56-104 Reaction and reaction were carried out in the same manner as in Reference Example 55 using the corresponding raw material compounds.
Processing gives the compounds shown in Tables 11 and 12.

(Margins below) Table 11 (vc) (Margins below) Table 12 (continued) Table 12 (continued) Table 12 (continued) (Margins below) (Margins below) -Production of chloro-4-(4-fluorophenyl)-3-methyl-5,6,7,8,9,10-hexahydrocycloocta[b] and lysine: Using the corresponding raw material compounds, Reference Example 55 React and process in the same manner as above to obtain the desired product.

Melting point 107-108°C (methanol-water) 1 basis
1 min 1 2-chloro-4-(2-thienyl)-5,6°7.8,
9. Production of 10-hexahydrocycloocta[b-copyridine: Using the corresponding raw material compound, reaction and reaction were carried out in the same manner as in Reference Example 55.
Process to obtain an oily target.

(Leaving space below) Actual ■1-Upper 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9゜10-hexahydrocycloocta[bl Production of pyridine: 2-chloro-4-(4-fluorophenyl)-5,6,
7,8,9,10-hexahydrocycloocta[bl pyridine 2.0 g, N-ethylpiperazine 2.4 g
, 1.1 g of potassium iodide is stirred at 170° C. for 5 hours. After cooling, the reaction solution was dissolved in ethyl acetate and water, and the organic layer was washed with water, extracted with 55% hydrochloric acid, made basic with potassium carbonate, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and dried under reduced pressure. Concentrate.

(a) Recrystallize the residue from acetonitrile to obtain the desired product 1.
Obtain 2g.

Melting point: 123-124° C. elegans is treated with each dilute acid to obtain various salts of the target product obtained in (a).

(b) Simaleate melting point 185-167°C (ethanol) (c) Dihydrochloride/half hydrate melting point 215-222°C (acetone) (d) Fumarate melting point 228-230°C ( Ethanol) (e) Citrate Melting point 184-187°C (Ethanol)
-difluorophenyl)-5,6,7゜8.9.10-
Hexahydrocycloocta[b]copyridine production: 2-chloro-4-(2,4-difluorophenyl)-5
,6,7,8,9,10-hexahydrocycloocta[
b] Copyridine 10gt N-ethylpiperazine 11
gt A mixture of 5.4 g of potassium iodide was heated to 170 ”C
Stir for 5 hours. After cooling, the reaction solution was diluted with chloroform and 5
% potassium carbonate aqueous solution, and the organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

(a) Dissolve the residue in toluene, apply column chromatography using silica gel, collect the eluted portion with toluene and a mixture of toluene-ethyl acetate (1:1), and recrystallize from isopropyl alcohol to obtain the desired product. Things 5.5
get g.

Melting point: 124-125°C (b) The target product obtained in (a) is treated with an ethanol solution of maleic acid to obtain the target product, simalate. Melting point 133-135°C (ethanol) 5 plates = 1 Production of 2-chloro-4-ethyl-1-piperazinyl)-4-phenyl-5,6,7,8-tetrahydroquinoline: 2-chloro-4-phenyl -5,6,7,8-tetrahydroquinoline 1.0 g, N-ethylpiperazine 1.
2g of potassium iodide and 0.88g of potassium iodide at 170°
Stir at C for 15 hours. After cooling, the reaction solution is dissolved in chloroform and a 5% aqueous potassium carbonate solution, and the organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil was subjected to column chromatography using basic alumina and toluene and toluene-ethyl acetate (9:1).
) was collected, converted into a maleate salt with an ethanol solution of maleic acid, and recrystallized from ethanol-ethyl acetate to obtain 0.45 g of the target simalate salt.
get. Melting point: 139-142°C
1- Using the corresponding raw material compounds, react and treat in the same manner as in Example 3 to obtain the compounds shown in Tables 13 and 14.

Table 13 (margins below) Table 13 (continued) Table 13 (continued) (margins below) (margins below) Table 13<viki) Table 14 R,) Table 13 (continued) Table 14 ( (continued) (blank below) Table 14 (continued) Table 14 (continued) (blank below) 78-85 Using the corresponding raw material compounds, the following compounds were obtained by reacting and treating in the same manner as in Example 3.

(Fire base 11 engineering 2-(4-methyl-1-homopiperazinyl)-4-(4
-fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohebuta[bl pyridine maleate: melting point 187-189°C (ethanol) (fushidan-yuyu) 2-(4-butanoyl- 1-homopiperazinyl)-4-
(4-Fluorophenyl)-6,7,8゜9-tetrahydro-5H-cyclohebuta[bll pyridine Oily substance (Backyard■-Ying Liao) 2-(4-Methyl-1-homopiperazinyl)-4-(4
2- (4 -benzoyl-1-homopiperazinyl)-4
-, (4-fluorophenyl)-5,6,7°8.9.
10-hexahydrocycloocta[b]pyridine di oily substance (夾五性-ls) 2- [4-(2-methoxyethyl)-1-piperazinyl] -4-(4-fluorophenyl)-5゜6 .7,
8,9.10-hexahydrocycloocta[bl pyridine cimalate: Melting point 119-120°C (acetonitrile) (Omizo [
) 2-(3-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,3゜9.10-hexahydrocycloocta[b]pyridine: Melting point 138-141'C (Isopropyl alcohol-
hexane) (Fire Gosara-84) 2-(3,5-dimethyl-1-piperazinyl)-4-(
4-fluorophenyl)-5,6,7゜8,9.10-
Hexahydrocycloocta[b]pyridine 1/2 fumarate: Melting point (decomposition) 262-266°C (methanol) (Fire Gosara - Migo) 2-(1-Homopiperazinyl)-4-(4- 2-(1-piperazinyl)- 4-phenyl-5゜6.7
．． Production of 8-tetrahydroquinoline: 2-(4-benzyl-1-piperazinyl)- obtained in the same manner as in Example 3.
4-phenyl-5,6°7.8-tetrahydroquinoline (melting point 105-107'C) 2.1 g + 0.86 g of chloroethyl chloroformate and 40 methylene chloride
ml of the mixture is heated under reflux for 1 hour and then concentrated under reduced pressure. Add 40 ml of methanol to the residue, heat under reflux for 30 minutes, and then concentrate under reduced pressure. The residue is dissolved in water, washed with diethyl ether, neutralized with potassium carbonate, and extracted with chloroform. After washing with water and drying with anhydrous sodium sulfate,
The solvent is removed under reduced pressure. A solution of maleic acid in ethanol is added to the residue to obtain a maleate salt, which is then recrystallized from ethanol to obtain 1.2 g of the desired simalate salt. Melting point 1
50-151'c 87-110 Reaction and reaction were carried out in the same manner as in Example 86 using the corresponding raw material compounds.
Processing gives the compounds shown in Tables 15 and 16.

(Left below) Table 15 Table 15 (continued) (Left below) Table 16 RQ 夾蓬m 2-(4-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7-sihydro Production of 5H-1- and rinsin: 2-(1-piperazinyl)-4-(4-fluorophenyl)-6,7-hydro 5H-1-pyrindine 2 g
, 37% formalin 0.66 gt formic acid 0.68
A mixture of g and 15 ml of water is heated to reflux for 20 minutes. After cooling, the reaction mixture was made basic with dilute aqueous sodium hydroxide solution and extracted with ethyl acetate. After washing with water and drying with anhydrous sodium sulfate, it is concentrated under reduced pressure.

An ethanol solution of maleic acid is added to the residue to obtain a maleate salt, and the target maleate salt is obtained by recrystallization from ethanol. Melting point: 135-137°C 112-117 Using the corresponding raw material compound, the following compound is obtained by reacting and treating in the same manner as in Example 111.

(Real[1U1.) 2-(4-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9゜10-hexahydrocycloocta[b]pyrine Zinsimalate: Melting point 136-138°C (ethanol) (5 books - 1
11) 2-(4-Methyl-1-piperazinyl)-4-methylphenyl)-5,6,7,8,9゜10-hexahydrocycloocta[b]pyrindinecymaleate: Melting point 152-154°C (ethanol) 011-1 Part 1) 2-(4-methyl-1-piperazinyl)-4-(2,4
-difluorophenyl)-5,8,7゜8.9.10-
Hexahydrocycloocta[b]pyrindine Melting point 132-133°C (ethanol) (Oyo U-Ko) 2-(4-methyl-1-piperazinyl)-4-(4-fluorophenyl)-6-methyl-5 ,6゜7.8-Tetrahydroquinoline cimaleate: Melting point 161-1
f34℃ (ethanol) (116) 2-(3,4-dimethyl-1-piperazinyl)-4-(
4-fluorophenyl)-5,6,7゜8.9.10-
Hexahydrocycloocta[b]pyrindine fumarate/l/4 hydrate: Melting point 173-175°C (ethanol-diethyl ether) (fire-J↓yu) 2-(cis-3,5 -dimethyl-4-methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,
7,8,9,10-hexahydrocycloocta[b]pyrindine fumarate: Melting point 208-210°C (methanol-ethanol) Direct flame dish-111 2-(4-n-propyl-1-piperazinyl) )-4-(
4-fluorophenyl)-5,6,7゜8.9.10-
Preparation of hexahydrocycloocta[b]pyridine: 2-(1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine, 4 g.

n-propylbromide 0.5 [3 g, potassium carbonate 0.
68 g, potassium iodide 0.1 g and methanol 50
The mixture of m1 is heated under reflux for 15 hours. The reaction solution is concentrated under reduced pressure, water is added, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. An ethanol solution of maleic acid is added to the residue to obtain a maleate salt, which is then recrystallized from ethanol to obtain 0.6 g of the target simalate salt.

Melting point: 149-152°C 119-126 Using the corresponding starting compounds, the compounds shown in Table 17 are obtained by reacting and treating in the same manner as in Example 118.

Table 17 (blank below) Fire source 1 unit 2-(4-n-propyl-1-piperazinyl)-4-(
2,4-difluorophenyl)-5,6°7.8,9.
Production of 10-hexahydrocycloocta[b-copyridine: Using the corresponding starting compound, the desired product is obtained by reacting and treating in the same manner as in Example 118.

Melting point 108-109°C (ethanol) [4-(2-furoyl)-1-piperazinyl]-
Production of 4-phenyl-5,6,7,8-tetrahydroquinoline: 2-(1-piperazinyl)-4-phenyl-5°6.7
．． 1.2 g of 8-tetrahydroquinoline, 0.48 g of 2-furancarboxylic acid, 40 ml of chloroform and 1-
After stirring a mixture of 0.79 g of (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride at room temperature for 2 hours, the reaction solution was washed with water and dried over anhydrous sodium sulfate.
The solvent is removed under reduced pressure.

The residue was dissolved in toluene, subjected to silica gel column chromatography, and dissolved in toluene and toluene-ethyl acetate (
9:1) was collected and recrystallized from ethanol to obtain 0.4 g of the desired product.

Melting point 128-130°C
4-(4-fluorophenyl)-6,7-sihydro 5
Production of H-1-pyrindine: Using the corresponding raw material compound, react and treat in the same manner as in Example 128 to obtain the target product.

Melting point 165-166°C (ethanol) Fire Gosho-11
Production of 2-(4-ethyl-1-piperazinyl)-4-(4-hydroxyphenyl)-5,6,7,8°9.10-hexahydrocycloocta[b]pyrindine: 2-(4- Dissolve 1.3 g of ethyl-1-piperazinyl)-4-(4-methoxyphenyl)-5,6,7,8,9゜10-hexahydrocycloocta[bl pyridine in 10 ml of 48% hydrobromic acid, Stir at 120°C for 2 hours. After cooling, water was added, neutralized with IN aqueous sodium hydroxide solution and sodium bicarbonate, and the precipitate was collected by filtration, washed with water, and recrystallized from methanol to obtain 0.6 g of the desired product. Melting point 25
0~253°C
-difluorophenyl)-6,7,8゜9-tetrahydro-5H-cyclohebuta[b]pyrindine Production: Using the corresponding raw material compound, react and treat in the same manner as in Example 3 to obtain the target oxalate salt. - Obtain hemihydrate.

Melting point: 225-227°C (methanol)
ll 2-(4-ethyl-1-piperazinyl)-4-(2,4
-difluorophenyl)-6,7-dihydro 5H-1
-Manufacture of pyrindine: Using the corresponding raw material compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the target maleate salt.

Melting point 195-196°C (ethanol) Eggplant 1
33 2-(4-cyclopropyl-1-piperazinyl)-4
-(4-fluorophenyl)-5,6,7°8.9.1
Production of 0-hexahydrocycloocta[b]pyrindine: Using the corresponding raw material compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired product.

Melting point 125-128°C (ethanol) Fire 5 books - Engineering 1
1 2- [4-(4-fluorophenyl)-1-piperazinyl] -4-(4-fluorophenyl)-5,6,7
, 8,9,10-hexahydrocycloocta[bl pyridine production: Using the corresponding raw material compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired product.

Melting point 130-131℃ (methanol) 2-(4-ethyl-1-piperazinyl)-4-(2,4
-Difluorophenyl)-5,6,7゜8-Tetrahydro-5,8-methanoquinoline production: Using the corresponding raw material compound, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the target oxalate 1/ A dihydrate is obtained.

Melting point 234-238°C (ethanol) Tip U 2-Ccis-3,5-dimethyl-4-methyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7-
Manufacture of Shihydro 5H-1-pyrindine: Using the corresponding raw material compounds, the reaction and treatment were carried out in the same manner as in Example 111 to obtain the target product, 74-eternal compound for fumarate.

Melting point 204-208°C (methanol-ethanol)
Five dog plates = soil 2- Production of [4-[3-(4-fluorobenzoyl)propyl]-1-piperazinyl]-4-(4-fluorophenyl)-6,7-hydro-5H-1-pyrindine : Using the corresponding raw material compound, react and treat in the same manner as in Example 118 to obtain the desired product.

Melting point 115-116°C (ethanol) under fire - upper 1 2- [4-(3-hydroxypropyl)-1-piperazinyl] -4-(4-fluorophenyl)-5,6,
Production of 7,8,9,10-hexahydrocycloocta[bl pyridine: Using the corresponding raw material compound, react and treat in the same manner as in Example 118 to obtain the target dioxalate quarter hydrate. get.

Melting point: 136-138°C (methanol)
2-[4-(2-acetoxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,
8,9,10-hexahydrocycloocta[b]pyrindine production: 2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,
8,9,10-hexahydrocycloocta[b]pyrindine, 5 g, acetic anhydride 0.8 g,) ethylamine 0.
A mixture of 7 g and 30 ml of ethyl acetate is heated under reflux for 2 hours. After cooling, the reaction solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The residue was dissolved in toluene, subjected to column chromatography using silica gel, the fraction eluted with toluene and toluene-ethyl acetate (1:1) was collected, and an ethanol solution of maleic acid was added to make the maleate salt. Recrystallize from to obtain 0.85 g of the target maleate salt.

Melting point 187-1 old °C Fruit 1,000-11A''-2-(4-cyclopropylmethyl-1-piperazinyl)
-4-(4-fluorophenyl)-5゜6.7,8,9
．． Production of 10-hexahydrocycloocta[bl pyridine: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Example 118 to obtain the desired product.

Melting point 109-110°C (methylene chloride-hexane)
141-156 Using the corresponding starting compounds, the compounds shown in Table 18 are obtained by reacting and treating in the same manner as in Example 3.

(Leaving space below) Production of 15U 2-(4-benzyl-1-piperazinyl)-〇-methyl-4-phenylpyridine: Using the corresponding raw material compound, react and treat in the same manner as in Example 3 to obtain the desired product. Obtain maleate salt.

Melting point 168-171'C (ethanol) base - 51 Production of 2-(4-benzyl-1-piperazinyl)-6-methyl-4-phenyl-5,6,7,8-tetrahydroquinoline: Correspondence Using the raw material compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired product.

Melting point: 137-138°C (ethanol) Fire dish-159 2-(4-benzyl-1-piperazinyl)-6-ter
Production of t-butyl-4-phenyl-5,6,7,8-tetrahydroquinoline: Using the corresponding raw material compound, the desired product is obtained by reacting and treating in the same manner as in Example 3.

Melting point 141-142°C (ethanol) U juice-1
Production of 6dan 2-[(4-fluorobenzyl)-1-piperazinyl]-4-(4-fluorophenyl)-6゜7-sihydro-5H-pyrindine: Using the corresponding starting compound, the same procedure as in Example 118 was carried out. The target product, simalate, is obtained by reaction and treatment.

Melting point 164-167°C (ethanol) -161-1
66 Using the corresponding raw material compounds, the compounds shown in Table 19 are obtained by reacting and treating in the same manner as in Example 3.

(Margin below) Table 19 R.

Table 19 (Continued) (Margins below) JIL moxibustion 2-(4-ethyl-1-piperazinyl)-4(4-fluorophenyl)-3-methyl-5,6°7.8,9.1
Production of 0-hexahydrocycloocta[bl pyridine: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired product.

Melting point: 125-126°C (acetonitrile) Kyougogo-Kamikurodama 2-(4-ethyl-1-piperazinyl)-4-(2-thienyl)-5,6,7,8,9,10-hexahydrocyclo Production of octa[b]pyringine: Using the corresponding raw material compound, react and treat in the same manner as in Example 3 to obtain the desired product.
Dioxalate 115 hydrate is obtained.

Melting point 183-167°C (Ethanol) Capsule 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7,8,9-tetrahydro-5
H-cyclohebuta [bl pyridine cimaleate
・・・・・・・・・ 5g corn starch
・・・・・・・・・・・・ 57 g lactose ・・・
......10 g crystalline cellulose...
・・・・・・・・・ 25 g Hydroxypropyl cellulose ・・ 2 g Light silicic anhydride ・・
・・・・・・・・・ 0.5g Magnesium stearate ・・・・・・・・・ 0.5g According to the usual method, mix the above ingredients, make it into granules, fill 1000 capsules, and make 1 capsule. 100B capsules are manufactured.

Shell attachment tablet 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8゜9.10-hexahydrocycloocta[b]pyridine cymalein acid salt
・－・・・・・・・・・ 5g corn starch
・・・・・・・・・ 20 g lactose ・・・・
...30 g crystalline cellulose ...
・・・・・・・・・ 30 g Hydroxypropyl cellulose ・・・・ 5 g Low-substituted hydroxypropyl cellulose ・・・・−・ 10 g After mixing and granulating the above ingredients according to the usual method, light anhydrous silica was added. After adding acid and magnesium stearate, each tablet contains 5 B of the active ingredient.

Shell attachment-1 Powder 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8゜9, IO-hexahydrocycloocta[b]pyridine cymalein acid salt
・－・・・・・・・・・ 5g corn starch
・・・・・・－・・・・ 173 g lactose ・・・
・・・・・・・・・300g Hydroxypropyl cellulose ・・・・20g Mix the above ingredients according to the usual method,
After granulation and grading, an appropriate amount of light anhydrous silicic acid is added to make a 100x powder.

Knowledge-1 Injection 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8゜9.10-hexahydrocycloocta[b]pyridine cymalein acid salt
・－・・・・・・・・・ 5gD-Sorbitol
・・・・・・・・・・ 45 g IN maleic acid or IN sodium hydroxide aqueous solution ・・・・− Appropriate amount Distilled water for injection ・・・・・・・・・・・ Appropriate amount Total amount 1000 ml Main drug and D-sorbitol were mixed with distilled water for injection, and I
After adding and dissolving N maleic acid or IN sodium hydroxide aqueous solution and adjusting the pH to 4.0, the pore size was adjusted to 0.2.
Filtered through a 2 μm membrane filter and
llIl is filled into an ampoule, sealed, and sterilized with high-pressure steam at 121°C for 20 minutes to produce a solution.

Kenpaku-5 Freeze-drying agent 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8°9.10-hexahydrocycloocta[b]pyridine・Simalate
・・・・・・・・・・・・ 5gD-mannitol
・・・・・・−・・・ 45g IN maleic acid or IN
Sodium hydroxide aqueous solution ・・・・・・・・・ Appropriate amount of distilled water for injection ・・・・・・・・・ Appropriate amount of total volume 1000 ml Mix the main drug and D-mannitol with distilled water for injection,
After adding and dissolving N maleic acid or IN sodium hydroxide aqueous solution and adjusting the pH to 4.0.

Filter through a membrane filter with a pore size of 0.22 μm, fill 10 ml into a vial, half stopper with a rubber stopper, prefreeze, primary dry at -50°C, secondary dry at -20°C, and dry at 20°C. Patent applicant Yushibe Tsuboi, representative of Dainippon Pharmaceutical Co., Ltd., which features a lyophilized preparation that is freeze-dried under the following conditions, capped in a chamber, taken out, and covered with a flip-off cap.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R means a hydrogen atom or a lower alkyl group, W means a hydrogen atom or a lower alkyl group, and Y means a lower alkyl group. , or W and Y together with the pyridine ring form the following ring (WY), with the formula % (WY) where n means 3, 4, 5, 6 or 7, and R
_4, R_5 and R_6 are the same or different hydrogen atoms,
It means a lower alkyl group or a phenyl group, or any two of R_4, R_5 and R_6 taken together means a single bond or a lower alkylene group, and (2) means an aryl group or a heteroaryl group. R_2 and R_3 are the same or different and mean a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, a trifluoromethyl group, a cyano group, a nitro group, or an amino group, and R_1 is a hydrogen atom, an alkyl group, group, cycloalkyl group, hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, cycloalkyl (lower) alkyl group, aryl (lower) alkyl group which may have a substituent, acyloxy (lower) alkyl group group, lower alkanoyl (lower) alkyl group, arylcarbonyl (lower) alkyl group that may have a substituent, lower alkenyl group, lower alkynyl group, aryl group that may have a substituent, heteroaryl group or an acyl group, R_7 and R_8 are the same or different and represent a hydrogen atom or a lower alkyl group, and m represents 2 or 3. ] A pyridine derivative or an acid addition salt thereof. (2) A psychotropic agent containing the pyridine derivative or acid addition salt thereof according to claim (1) as an active ingredient.