Patent Publication Number: US-5021421-A

Title: 2-(1-Piperazinyl)-4-phenylcycloalkanopyridine derivatives, processes for the production thereof, and pharmaceutical composition containing the same

Description:
This invention relates to novel 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives having psychotropic activity, processes for the production thereof, and a pharmaceutical composition containing the said compound as an active ingredient. 
     PRIOR ART 
     There have hitherto been known some 2-(1-piperazinyl)-4-arylpyridine derivatives and related compounds which have pharmacological activities. For example, U.S. Pat. No. 4,469,696 [Japanese First Publication (Kokai) No. 58-963] discloses 2-(1-piperazinyl)-4-arylpyridine derivatives, however, the compounds disclosed therein are merely the compounds having an aryl group or a 2-furyl group at 5-position of pyridine ring, structure of which is completely different from that of the compounds of the present invention. Besides, the pharmacological activity of these compounds disclosed in the above reference is lipid absorption-inhibitory action which is also completely different from that of the compounds of the present invention. It is clear from the experiments by the present inventors, whereby the 4,5-bis-(4-fluorophenyl)-6-methyl-2-(4-phenyl-1-piperazinyl)pyridine disclosed in the above mentioned U.S. patent did not show any psychotropic activity, that is, it shows no inhibitory effect on an apomorphine-induced vomiting, which can be an index for anti-psychotic drug and no binding property to dopamine (D 2 ) and serotonin (S 2 ) receptors. 
     Moreover, a pyridine derivative having a piperazinyl group and a phenyl group at 2-position and 4-position of pyridine ring thereof respectively, 2-[4-(4-methylbenzyl)-1-piperazinyl]-4-phenylpyridine has been reported to have a weak activity as an anti-psychotic drug or as a neuroleptic drug, [cf: U.S. Pat. No. 4,831,034, Japanese First Publication (Kokai) No. 63-48267]. However, the structure of this compound is obviously different from that of the compounds of the present invention in respect to that this compound does not form the condensed ring between 5- and 6-positions of pyridine ring. 
     BRIEF DESCRIPTION OF THE INVENTION 
     The present inventors have extensively searched for compounds having an activity on the central nervous system and have found that novel 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives of the formula (I) disclosed hereinafter have excellent psychotropic activity and are useful as an anti-psychotic drug or an anti-anxiety drug and further as a drug for the treatment of cerebral insufficiency diseases. 
     An object of the invention is to provide novel 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives having excellent psychotropic activity. Another object of the invention is to provide processes for the production of these compounds. A further object of the invention is to provide a pharmaceutical composition being useful as an anti-psychotic or anti-anxiety drug etc. containing said compound as an active ingredient. These and other objects and advantages of the invention will be apparent to those skilled in the art from the following description. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The novel 2-(1-piperazinyl)-4-phenylcycloalkanopyridine derivatives of the present invention have the following formula (I): ##STR2## wherein n is 3, 4, 5, 6 or 7, 
     R 1  is a hydrogen atom, C 1  -C 10  alkyl, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 8  cycloalkyl, C 3  -C 6  cycloalkyl-(C 1  -C 4 )alkyl, hydroxy-(C 2  -C 6 ) alkyl, C 1  -C 3  alkoxy-(C 2  -C 6 ) alkyl, acyloxy-(C 2  -C 6 ) alkyl, unsubstituted or substituted aroyl-(C 1  -C 6 ) alkyl, unsubstituted or substituted aryl, heteroaryl, or acyl, 
     R 2  and R 3  are the same or different and are each a hydrogen atom, a halogen atom, C 1  -C 6  alkyl, C 1  -C 6  alkoxy, trifluoromethyl, or hydroxy, 
     R 4 , R 5  and R 6  are the same or different and are each a hydrogen atom, C 1  -C 6  alkyl, or phenyl, or two of R 4 , R 5  and R 6  combine to form a sigle bond or C 1  -C 3  alkylene, 
     R 7  and R 8  are the same or different and are each a hydrogen atom or C 1  -C 3  alkyl, 
     m is 2 or 3, 
     or an acid addition salt thereof. 
     The salt of the compounds of the formula (I) includes salts of inorganic acids (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), and salts of organic acids (e.g. maleate, fumarate, citrate, oxalate, tartrate, lactate, benzoate, methanesulfonate, etc.). Besides, these salts may optionally be present in the form of a hydrate, and hence, the compounds of the present invention include also these hydrate compounds. 
     Besides, when the compounds of the formula (I) contain asymmetric carbons, these compounds include stereoisomers, a mixture thereof, and a racemic mixture, which are also included as the active compound in the present invention. 
     In the present specification and claims, the groups in the formulae denote the following groups. 
     The &#34;alkyl&#34; and &#34;alkyl moiety&#34; and &#34;alkylene&#34; include straight chain or branched chain alkyl groups or alkylene groups. 
     The &#34;alkyl&#34; includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, and the like. 
     The &#34;alkylene&#34; includes methylene, ethylene, propylene, and the like. 
     The &#34;halogen atom&#34; includes fluorine, chlorine, bromine, and iodine. 
     The &#34;alkoxy&#34; includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentyloxy, hexyloxy, and the like. 
     The &#34;cycloalkyl&#34; includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. 
     The &#34;cycloalkyl-alkyl&#34; includes cyclopropylmethyl, cycylobutylmethyl, cyclopentylmethyl, and the like. 
     The &#34;hydroxyalkyl&#34; includes 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl, and the like. 
     The &#34;alkoxyalkyl&#34; includes methoxymethyl, methoxyethyl, ethoxyethyl, and the like. 
     The &#34;alkenyl&#34; includes vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, and the like. 
     The &#34;alkynyl&#34; includes ethynyl, propargyl, and the like. 
     The &#34;aryl&#34; includes phenyl, naphthyl, and the like. The &#34;unsubstituted or substituted aryl&#34; includes aryl groups having no substituent or one or two substituents selected from halogen atom, C 1  -C 3  alkyl, C 1  -C 3  alkoxy, and trifluoromethyl, and the examples are phenyl, 4-fluorophenyl, and the like. 
     The &#34;unsubstituted or substituted aroylalkyl&#34; includes aroylalkyl groups in which the aryl moiety is the above-mentioned unsubstituted or substituted aryl, and the examples are benzoylmethyl, p-fluorobenzoylpropyl, and the like. 
     The &#34;heteroaryl&#34; means a monocyclic or bicyclic heterocyclic group containing at least one hetero atom selected from nitrogen, oxygen and sulfur, for example, furyl, thienyl, pyridyl, pyrimidyl, isoquinolyl, and the like. 
     The &#34;acyl&#34; includes C 1  -C 4  alkanoyl, C 5  -C 6  cycloalkylcarbonyl, a benzoyl group which may optionally be substituted by halogen, C 1  -C 3  alkyl or C 1  -C 3  alkoxy, a heteroarylcarbonyl group in which the heteroaryl moiety is the above-mentioned heteroaryl, and the examples are formyl, acetyl, propionyl, butyryl, cyclohexanecarbonyl, benzoyl, benzoyl, nicotinoyl, isonicotinoyl, 4-fluorobenzoyl, furoyl, thenoyl, and the like. 
     The &#34;acyloxyalkyl&#34; includes acyloxyalkyl groups in which the acyl moiety is the above-mentioned acyl, and the examples are 2-acetyloxyethyl, 3-acetoxypropyl, benzoyloxyethyl, and the like. 
     Among the compounds of the formula (I) of the present invention, preferred compounds are those of the formula (I) wherein R 1  is a hydrogen atom, C 1  -C 10  alkyl, C 3  -C 8  cycloalkyl, hydroxy-(C 2  -C 6 ) alkyl, C 1  -C 3  alkoxy-(C 2  -C 4 ) alkyl, C 2  -C 4  alkanoyloxy-(C 2  -C 6 ) alkyl, a benzoyl-(C 2  -C 5 ) alkyl group in which the phenyl moiety may optionally be substituted by halogen, C 1  -C 3  alkyl or C 1  -C 3  alkoxy, C 2  -C 4  alkenyl, C 2  -C 4  alkynyl, pyridyl, pyrimidyl, C 2  -C 5  alkanoyl or furoyl, R 2  and R 3  are the same or different and are each hydrogen atom, halogen atom, methyl or methoxy, R 4 , R 5  and R 6  are the same or different and are each a hydrogen atom or C 1  -C 4  alkyl, or two of them combine to form C 1  -C 2  alkylene, R 7  and R 8  are the same or different, and are each hydrogen atom or C 1  -C 3  alkyl, and m is 2, and an acid addition salt thereof. 
     Further preferred compounds of the present invention are the compounds of the formula (I) wherein R 1  is a hydrogen atom, C 1  -C 8  alkyl, C 3  -C 8  cycloalkyl, hydroxy-(C 2  -C 6 )alkyl, C 1  -C 2  alkoxy-(C 2  -C 3 ) alkyl, acetyloxy-(C 2  -C 4 ) alkyl, C 3  -C 4  alkenyl, or C 2  -C 3  alkanoyl, R 2  and R 3  are the same and both are hydrogen atom or halogen atom, or one of them is hydrogen atom and the other is halogen atom, methyl, or methoxy, and an acid addition salt thereof. More preferred compounds of the present invention are the compounds of the formula (I) wherein R 2  and R 3  are the same or different and are each a hydrogen atom or a fluorine atom, and an acid addition salt thereof. 
     Particularly preferred compounds are the compounds of the following formula (I-1): ##STR3## wherein n 1  is 3, 6 or 7, 
     R 11  is hydrogen atom, C 1  -C 8  alkyl, C 3  -C 6  cycloalkyl, hydroxy-(C 2  -C 4 ) alkyl, C 1  -C 2  alkoxy-(C 2  -C 3 ) alkyl, or C 3  alkenyl, 
     R 21  and R 31  are the same or different and are each a hydrogen atom or a fluorine atom, 
     R 71  and R 81  are the same or different and are each a hydrogen atom or C 1  -C 3  alkyl, or an acid addition salt thereof, and of the following formula (I-2): ##STR4## wherein n 2  is 4 or 5, 
     R 12  is a hydrogen atom, C 1  -C 8  alkyl, C 3  -C 8  cycloalkyl, hydroxy-(C 2  -C 4 ) alkyl, C 1  -C 2  alkoxy-(C 2  -C 3 ) alkyl or C 3  alkenyl, 
     R 22  and R 32  are the same or different and are each a hydrogen atom or a fluorine atom, 
     R 42 , R 52  and R 62  are the same or different and are each a hydrogen atom or C 1  -C 4  alkyl, or two of them combine to form C 1  -C 2  alkylene, or an acid addition salt thereof. 
     Especially most preferred compounds in the present invention are the compounds of the formula (I-1) wherein n 1  is 6, R 11  is C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl, or hydroxy-(C 2  -C 4 )alkyl, R 21  and R 31  are the same or different and are each a hydrogen atom or a fluorine atom substituted at 2- or 4-position, R 71  and R 81  are each a hydrogen atom, and a salt thereof, and the compounds of the formula (I-2) wherein n 2  is 5, R 12  is C 1  -C 6  alkyl, C 3  -C 6  cycloalkyl or hydroxy-(C 2  -C 4 ) alkyl, R 22  and R 32  are the same or different and are each a hydrogen atom or a fluorine atom substituted at 2- or 4-position, R 42 , R 52  and R 62  are all hydrogen atoms, or two of them combine to form C 1  -C 2  alkylene, and another one is a hydrogen atom, and an acid addition salt thereof. 
     The most preferred compounds of the present invention are the compounds of the following formula (I-3): ##STR5## wherein R 13  is methyl, ethyl, propyl, butyl, pentyl or hydroxyethyl, and R 33  is a hydrogen atom or a fluorine atom, and a salt thereof. 
     Specifically preferred compounds of the present invention are as follows. 
     2-(4-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]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[b]pyridine 
     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[b]pyridine 
     2-(4-n-Pentyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     2-[4-(2-Hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     The compounds of the present invention can be prepared, for example, by the following processes. 
     (1) Process A 
     The compounds of the formula (I) are prepared by reacting a compound of the formula (II): ##STR6## wherein X is a leaving atom or group, and R 2 , R 3 , R 4 , R 5 , R 6  and n are as defined above, with a compound of the formula (III): ##STR7## wherein R 1 , R 7 , R 8  and m are as defined above. 
     The leaving atom or group X in the formula (II) denotes any atom or group which can leave off in the form of HX under the reaction conditions together with the hydrogen atom bonded to the nitrogen atom at 4-position of 1-substituted piperazines or homopiperazines. Examples of the leaving atom or group are halogen atoms, lower alkythio groups (e.g. methylthio, ethylthio, propylthio, butylthio, etc.), arylsulfonyloxy groups (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, etc.), and alkylsulfonyloxy groups (e.g. methanesulfonyloxy, etc.). 
     The reaction of the compound of the formula (II) and the compound of the formula (III) is carried out in an appropriate solvent or without using any solvent under atmospheric pressure or under pressure. Suitable examples of the solvent are aromatic hydrocarbons (e.g. toluene, xylene, etc.), ketones (e.g. methyl ethyl ketone, etc.), ethers (e.g. dioxane, diglyme, etc.), alcohols (e.g. ethanol, isopropyl alcohol, butanol, etc.), N,N-dimethylformamide, dimethylsulfoxide. The reaction is preferably carried out in the presence of a basic substance. Suitable examples of the basic substance are alkali metal carbonates (e.g. sodium carbonate, potassium carbonate, etc.), alkali metal hydrogen carbonates (e.g. sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), tertiary amines (e.g. triethylamine, etc.), but an excess amount of the compound of the formula (III) may be used instead of using the basic substance. When the compound of the formula (III) is in the form of a hydrate, the hydrate may be used. The reaction temperature is usually in the range of 40° to 200° C. The starting compound (II) can be prepared in the procedure as described in Reference Examples 1 to 94 hereinafter or in a similar process. 
     (2) Process B 
     The compounds of the formula (I) wherein R 1  is a hydrogen atom can be prepared by hydrogenolysis of a compound of the formula (I-4): ##STR8## wherein R 14  is unsubstituted or substituted benzyl or benzyloxycarbonyl (the substituent on the phenyl ring of said benzyl and benzyloxycarbonyl is a member selected from lower alkyl, lower alkoxy and halogen atoms), and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m and n are as defined above. 
     The hydrogenolysis of the compounds of the formula (I-4) is usually carried out by a conventional catalytic reduction in a solvent such as alcohols (e.g. ethanol, etc.) at room temperature under atmospheric pressure. The compounds of the formula (I-4) can be prepared by the same process as the above-mentioned Process A. The compounds of the formula (I-4) wherein R 14  is benzyloxycarbonyl can alternatively be prepared by a conventional process from a compound of the formula (I) wherein R 14  is methyl or benzyl having optionally a substituent. 
     (3) Process C 
     The compounds of the formula (I) wherein R 1  is a hydrogen atom can also be prepared by reacting a compound of the formula (I-5): ##STR9## wherein R 15  is methyl or unsubstituted or substituted benzyl (the substituent on the phenyl ring of the benzyl is a member selected from lower alkyl, lower alkoxy and halogen atoms), and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m and n are as defined above, with ethyl chlorocarbonate or 1-chloroethyl chlorocarbonate to give a compound of the formula (I-6): ##STR10## wherein R 16  is ethoxycarbonyl, 1-chloroethoxycarbonyl, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m and n are as defined above, or a compound of the formula (I-7): ##STR11## wherein R 17  is acyl, and R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m and n are as defined above, followed by hydrolysis of the compound of the formula (I-6) or (I-7). 
     The hydrolysis of the compound of the formula (I-6) or (I-7) is usually carried out by a conventional method, for example, by heating the compound in an appropriate solvent such as ethanol which is miscible with water in the presence of a basic substance (e.g. sodium hydroxide, potassium hydroxide, etc.) or an acid (e.g. hydrochloric acid, sulfuric acid, etc.). The hydrolysis of the compound of the formula (I-6) wherein R 16  is 1-chloroethoxycarbonyl is usually carried out by heating the compound in methanol. The compounds of the formulae (I-5) and (I-7) can be prepared by the same process as the above-mentioned Process A. 
     (4) Process D 
     The compound of the formula (I) wherein R 1  is a group other than a hydrogen atom can be prepared by reacting a compound of the formula (I-8): ##STR12## wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , m and n are as defined above, with a compound of the formula (IV): 
     
         R.sup.18 --Z                                               (IV) 
    
     wherein Z is a reactive residue of an alcohol, and R 18  is the same as R 1  except a hydrogen atom. 
     The reactive residue of an alcohol represented by the group Z includes, for example, a halogen atom (e.g. chlorine, bromine, iodine, etc.), lower alkylsulfonyloxy (e.g. methanesulfonyloxy, etc.), arylsulfonyloxy (e.g. benzenesulfonyloxy, p-toluenesulfonyloxy, etc.). 
     The reaction of the compound of the formula (I-8) and the compound of the formula (IV) is usually carried out in an appropriate solvent. Suitable examples of the solvent are aromatic hydrocarbons (e.g. benzene, xylene, etc.), ketones (e.g. methyl ethyl ketone, etc.), ethers (e.g. dioxane, etc.), N,N-dimethylformamide. The reaction is preferably carried out in the presence of a basic substance. The basic substance includes the same substances as used in the above Process A. The reaction temperature is usually in the range of 30° to 150° C. The compounds of the formula (I-8) can be prepared by the same processes as the above-mentioned Processes A to C. 
     When the compounds of the formula (I) prepared by the Processes A and D have a hydroxyl group in the structure thereof, they can be converted into corresponding ester derivatives or ether derivatives by reacting the compound with an appropriate acylating agent or a lower alkylating agent. These reactions are usually carried out by a conventional method. 
     The compounds of the formula (I) prepared by the above mentioned Processes can be isolated and purified from the reaction mixture by a conventional method. 
     The compounds of the formula (I) of the present invention are obtained in the form of a free base or a salt or a hydrate depending on the kinds of the starting compound, the kinds of reaction, the reaction conditions, and the like. When the compounds are obtained in the form of a salt, they can be converted into the corresponding free base by a conventional method, for example, by treating them with a basic substance such as an alkali metal hydroxide. Besides, when the compounds are obtained in the form of a free base, they can be converted into the corresponding salt by a conventional method, for example, by treating them with various acids. 
     The compounds of the formula (I) of the present invention show inhibitory effect on exploratory activity, antagonistic effect on apomorphine-induced vomiting, binding property to dopamine (D 2 ) and serotonin (S 2 ) receptors, increasing effect on concentration of brain monoamine metabolites, and little toxicity. Accordingly, the compounds of the present invention are useful as an anti-psychotic (neuroleptic) drug or an anti-anxiety (anxiolytic) drug. 
     Furthermore, the compounds of the formula (I) of the present invention show excellent improving effect in some animal models of memory impairment. Accordingly, the compounds of the present invention are also useful as a medicament for the treatment of various symptoms of cerebral insufficiency. 
     The compounds of the present invention which show potent antagonistic effect on apomorphine-induced vomiting, binding property to serotonin (S 2 ) and dopamine (D 2 ) receptors, and increasing effect on concentration of brain monoamine metabolites are, for example, the following compounds and a pharmaceutically acceptable salt thereof. 
     (1) 2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (2) 2-(4-Ethyl-1-piperazinyl)-4-(2,4-difluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (3) 2-(4-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (4) 2-(4-Methyl-1-piperazinyl)-4-(2,4-difluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (5) 2-(4-n-Propyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (6) 2-(4-n-Butyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (7) 2-(4-n-Pentyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (8) 2-[4-(2-Hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     (9) 2-(1-Piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyrindine 
     (10) 2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyrindine 
     (11) 2-[4-(2-Hydroxyethyl)-1-piperazinyl]-4-(4-fluoro-phenyl)-6,7-dihydro-5H-1-pyrindine 
     (12) 2-(4-Ethyl-1-piperazinyl)-4-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 
     (13) 2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 
     (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-5H-6,9-methanocyclohepta[b]pyridine 
     (17) 2-(4-Ethyl-1-piperazinyl)-4-(4-fluoro-phenyl)-6,7,8,9- tetrahydro-5H-5,8-methanocyclohepta[b]pyridine 
     The compounds of the present invention which have excellent improving effects on behavioral and/or memory deficites induced by scopolamine or cycloheximide are, for example, the following compounds and a pharmaceutically acceptable salt thereof. 
     (1) 2-(1-Piperazinyl)-4-phenyl-6,7-dihydro-5H-1-pyrindine 
     (2) 2-(1-Piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyridine 
     (3) 2-(1-Piperazinyl)-4-phenyl-5,6,7,8-tetrahydroquinoline 
     (4) 2-(1-Piperazinyl)-4-(4-fluorophenyl)-5,6,7,8-tetrahydroquinoline 
     (5) 2-(1-Piperazinyl)-4-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 
     The pharmacological activities of the representative compounds of the present invention are illustrated by the following Experiments. 
     In the Experiments, the following compounds, which are disclosed in the above mentioned U.S. Pat. No. 4,469,696, were used as reference. 
     Test Compound A (disclosed in Example 4): 
     4,5-Bis-(4-fluorophenyl)-6-methyl-2-(4-phenylpiperazino)pyridine 
     Test Compound B (disclosed in Example 1): 
     4,5-Bis-(4-methoxyphenyl)-6-methyl-2-(4-phenylpiperazino)pyridine 
     Test Compound C (disclosed in Example 2): 
     4,5-Bis-(4-hydroxyphenyl)-6-methyl-2-(4-phenylpiperazino)pyridine 
     EXPERIMENT 1 
     Inhibitory Effect on Exploratory Activity 
     A group of 5 male mice (Std-ddy strain, 20-25 g) was used. Two hours after oral administration of the test compound, mice were placed individually in a test box (23×35×30 cm) on Animex activity meter (Farad Co.). Immediately thereafter, activity counting was started and lasted for three minutes. The mean counts of the compound-treated group were compared with those of the corresponding control (non-dosed) group, and the percent inhibition was calculated. The results are shown in Table 1. 
     
                       TABLE 1                                                     
______________________________________                                    
Inhibitory effect on exploratory activity                                 
Test      Inhibitory   Test      Inhibitory                               
compound  ratio (%)    compound  ratio (%)                                
______________________________________                                    
Ex.                                                                       
1b*       83.7          83       53.5                                     
2a        77.5         106       74.9                                     
31        62.5         107       53.2                                     
36        68.4         111       74.0                                     
38        58.9         112       73.2                                     
53        68.1         114       81.9                                     
57        77.2         122       81.3                                     
71        61.9         123       72.2                                     
75        78.9         125       57.9                                     
76        87.6         127       80.3                                     
______________________________________                                    
 *The compound of Example 1b (hereinafter, the same)                      
 
    
     EXPERIMENT 2 
     Antagonistic Effect on Apomorphine-induced Vomiting: 
     A group of 3-4 dogs (Beagle, 8-15 kg) was used for examining effects on the test compounds on apomorphine-induced vomiting, a known test for evaluating neuroleptic drugs. 
     Each dog was given a subcutaneous injection of apomorphine hydrochloride (0.3 mg/kg) two hours after the treatment of the test compounds. Then, the frequency of oral vomiting was counted for one hour. The mean counts of the compound-treated group were compared with those of the corresponding control (non-dosed) group, and the percent inhibition was calculated. The results are shown in Table 2. 
     
                       TABLE 2                                                     
______________________________________                                    
Antagonistic effect on apomorphine-induced                                
vomiting                                                                  
Test   Dose     Inhibitory                                                
                          Test  Dose   Inhibitory                         
comp.  (mg/kg)  ratio (%) comp. (mg/kg)                                   
                                       ratio (%)                          
______________________________________                                    
Ex.                       Ex.                                             
1a.sup.1                                                                  
       0.2      100       73    1.0    100                                
1b     0.3      88        76    0.3    71                                 
2b     0.2      100       77    0.5    61                                 
6      1.0      89        82    1.0    100                                
7      1.0      80        88    3.0    94                                 
15     3.0      100       112   0.2    94                                 
25     3.0      100       114   0.2    89                                 
27     3.0      47        116   1.0    100                                
29     3.0      63        118   0.3    94                                 
36     0.5      81        121   0.5    93                                 
37     0.3      80        122   0.5    100                                
43     1.0      96        135   1.0    100                                
56     0.5      85        A.sup.2                                         
                                3.0    11                                 
66     1.0      95        B.sup.2                                         
                                3.0    13                                 
71     3.0      84        C.sup.2                                         
                                3.0    16                                 
______________________________________                                    
 .sup.1 The compound of Example 1a (hereinafter, the same)                
 .sup.2 The compounds disclosed in the U.S. Pat. No. 4,469,696            
 
    
     EXPERIMENT 3 
     In Vitro Binding Property to Dopamine (D 2 ), Serotonin (S 1 , S 2 ) and Adrenaline (α 1 ) Receptors: 
     Dopamine (D 2 ), serotonin (S 1 , S 2 ) and adrenaline (α 1 ) receptor binding assays were carried out according to the methods of I. Creese et al. [Eur. J. Pharmacol., 46, 377 (1977), S. J. Peroutka et al. [Mol. Pharmacol. 16, 687 (1979)], J. E. Leysen et al. [Mol. Pharmacol., 21, 301 (1982)] and D. C. U&#39;Prichard et al. [Mol. Pharmacol., 13, 454 (1977)], respectively. 
     Crude synaptosome fractions were prepared from some brain regions in rats for receptor sources. Radioactive ligands used were [ 3  H] spiperone (D 2 ), [ 3  H] serotonin (S 1 ), [ 3  H] ketanserin (S 2 ) and [ 3  H] WB-4101 (α 1 ). The binding assay was performed by incubating aliquots of synaptosome fraction in buffer solution (final volume: 1 ml) containing a [ 3  H] labelled ligand and a test compound. The assay was terminated by rapid filtration through Whatman GF/B glass fiber filters attached to a cell-harvester (Brandel) and radioactivity on the filters was counted in a Packard Triscarb scintillation counter. Specific binding was calculated as a difference between amounts of radioactivity in the presence and absence of an unlabelled ligand [spiperone (D 2 ), serotonin (S 1 ), methysergide (S 2 ) and prazosin (α 1 )]. The IC 50  value of the test compounds (concentration causing 50% inhibition of [ 3  H] ligand specific binding) was determined by probit analysis. The results are shown in Table 3. 
     
                       TABLE 3                                                     
______________________________________                                    
Binding property to dopamine (D.sub.2),                                   
sertonin (S.sub.1, S.sub.2) and adrenaline (α.sub.1)                
receptor                                                                  
Test       IC.sub.50 (nM)                                                 
compound   D.sub.2  S.sub.1  S.sub.2                                      
                                    α.sub.1                         
______________________________________                                    
Ex.                                                                       
1a.sup.1   24       --       9.9    83                                    
1b         46       --       7.0    92                                    
2a         24       --       28     88                                    
6          19       1500     7.6    6.9                                   
7          30       --       9.5    --                                    
15         58       1700     19     35                                    
23         96       2900     7.7    320                                   
25         77       2600     2.3    120                                   
71         25       --       14     13                                    
73         18       --       2.4    4.6                                   
86         730      1400     81     530                                   
87         270       820     28     94                                    
88         70        670     9.1    65                                    
92         300      1900     27     380                                   
96         660      4900     62     1100                                  
97         260      4100     5.1    890                                   
103        140      --       41     --                                    
A.sup.2    &gt;10000   --       &gt;10000 &gt;10000                                
B.sup.2    &gt;10000   --       --     --                                    
C.sup.2    &gt;10000   --       --     --                                    
______________________________________                                    
 .sup.1 The compound of Example 1a (hereinafter, the same)                
 .sup.2 The compounds disclosed in the U.S. Pat. No. 4,469,696            
 
    
     EXPERIMENT 4 
     Increasing Effect on Concentration of Brain Monoamine Metabolites 
     A group of 5 male mice (Std-ddy strain, 25-30 g) was used for examining effect of the test compounds on concentration of brain monoamine metabolites. It is generally accepted that an increase in each monoamine is mainly caused by each monoamine receptor blockade. 
     Mice were killed by decapitation 2 hours after treatment with the test compounds. Brains were quickly taken out, homogenized in 1N formic acid-acetone solution, and centrifuged in a refrigerated ultracentrifuge. The supernatant was evaporated by blowing with N 2  gas. Then, the residue was again resolved in 0.01 N acetic acid, and served for determining concentration of dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), a norepinephrine metabolite, 3-methyl-4-hydroxyphenylethylene glycol (MOPEG), and a serotonin metabolite, 5-hydroxyindole-3-acetic acid (5-HIAA) concentrations by HPLC with electrochemical detection. The effect of the test compounds on concentration of each monoamine metabolite is shown as % of control (level of non-dosed animals=100) in Table 4. 
     
                       TABLE 4                                                     
______________________________________                                    
Increasing effect on the concentration of                                 
monoamine metabolites                                                     
Test     Dose              (%)                                            
compound (mg/kg)  DOPAC    HVA   MOPEG  5-HIAA                            
______________________________________                                    
EX.                                                                       
1b*      1        235      212   118    102                               
2b       2        364      271   --     --                                
6        10       321      242   115    103                               
15       10       277      235   118    108                               
23       10       344      320   115    145                               
24       10       290      317   139    150                               
25       1        272      207   106    113                               
26       10       344      263   --     --                                
27       10       208      193   --     --                                
29       10       296      274   --     --                                
35       10       165      170   --     --                                
37       3        268      203   143     95                               
39       10       307      233   117     97                               
42       10       258      211   --     --                                
44       10       272      210   --     --                                
46       10       296      235   --     --                                
49       10       197      195   --     --                                
52       10       233      216   --     --                                
54       2        251      250   --     --                                
55       2        379      240   --     --                                
56       10       302      249   106    110                               
59       2        246      236   126    106                               
66       2        311      308   111    116                               
68       2        206      181   --     --                                
84       10       237      216   --     --                                
87       10       180      194   117    136                               
88       10       329      209   136    120                               
92       10       208      192   121    139                               
96       10       201      194   115    127                               
97       10       232      176   125    128                               
104      10       344      247   160     97                               
117      10       242      210   133    100                               
118      3        302      250   129    110                               
121      10       312      215   --     111                               
122      2        306      229   --     100                               
124      10       292      238   102    107                               
131      1        319      224   --     --                                
132      10       333      209   --     --                                
138      2        236      173   --     --                                
139      10       267      206   --     --                                
______________________________________                                    
 *The compound of Example 1b (hereinafter, the same)                      
 
    
     EXPERIMENT 5 
     Improving Effect on Scopolamine-induced Deficit of Spontaneous Alternation Behavior 
     A group of 15-25 male mice (Std-ddY strain, 22-28 g) was used for evaluating effect of the test compounds on scopolamine-induced deficit of spontaneous alternation in a T-maze, which is a known animal model of memory impairment due to hypofunction of the cholinergic nervous system. The T-maze used consists of a stem and two arms which are 25 cm long, 5 cm wide and 10 cm high. The first 10 cm of the stem and last 10 cm of each arm are divided by sliding doors into start and goal boxes. 
     A test compound and scopolamine hydrobromide (1 mg/kg) were intraperitoneally administered to each mouse, and after 30 minutes a test of spontaneous alternation task in the T-maze was continuously repeated for 8 trials. Commonly, naive mice alternate each (right and left) goal box in turn, but scopolamine-treated animals tend to enter the same goal box repeatedly. The effect of the test compounds was expressed as % improvement (complete improvement to the alternation level of non-dosed mice=100%). The results are shown in Table 5. 
     
                       TABLE 5                                                     
______________________________________                                    
Improving effect on scopolamine-induced                                   
deficit of spontaneous alternation behavior                               
Test           Dose     Improvement                                       
compound       (mg/kg)  (%)                                               
______________________________________                                    
Ex.                                                                       
 86*           10.0     47.6                                              
87              0.5     48.0                                              
                2.0     60.0                                              
88             10.0     37.0                                              
97             10.0     32.0                                              
______________________________________                                    
 *The compound of Example 86 (hereinafter the same)                       
 
    
     EXPERIMENT 6 
     Improving Effect on Cycloheximide-induced Amnesia of Passive Avoidance Response 
     Anti-amnesic effect of the test compounds was examined using mice given cycloheximide, which is a known amnesia-inducing agent. 
     A group of 15-20 male mice (Std-ddY strain, 27-33 g) was subjected to training and retention trials for a passive avoidance task in a step-down apparatus (30×30×50 cm) with a grid floor and a wooden platform (4×4×4 cm) in a center of the floor. In the training trial, each mouse was first placed on the platform. When the mouse stepped down on the grid floor, an electric shock (1 Hz, 0.5 sec, 60 VDC) was delivered to the feet for 15 seconds. Immediately after the training trial, cycloheximide (60 mg/kg, s.c.) and a test compound (i.p.) were administered. The retention trial was carried out 24 hours thereafter, the time from placing again each mouse placed on the platform until stepping down on the grid floor (step-down latency) was measured. The step-down latency in the retention trial was markedly shortened by treatment of cycloheximide (amnesia). The effect of test compounds was assessed by % improvement (complete improvement to the latency level of non-dosed animals=100%). The results are shown in Table 6. 
     
                       TABLE 6                                                     
______________________________________                                    
Improving effect on cycloheximide-induced                                 
amnesia of passive avoidance response                                     
Test           Dose     Improvement                                       
compound       (mg/kg)  (%)                                               
______________________________________                                    
Ex.                                                                       
 87*           0.5      48                                                
               2.0      77                                                
88             2.0      60                                                
92             2.0      44                                                
               10.0     78                                                
96             0.5      81                                                
               2.0      64                                                
97             0.5      38                                                
               2.0      36                                                
______________________________________                                    
 *The compound of Example 87 (hereinafter the same)                       
 
    
     EXPERIMENT 7 
     Acute Toxicity 
     A group of 5 male mice (Std-ddy strain, 25-30 g) was used. The test compound was orally administered to the test animal in the form of a 0.5% tragacanth solution or suspension, and for 7 days after the administration of the test compound, the lethality of animals was observed. The results are shown in Table 7. 
     
                       TABLE 7                                                     
______________________________________                                    
Acute toxicity                                                            
Test        Dose     Number of dead animals                               
compound    (mg/kg)  Number of test animals                               
______________________________________                                    
Ex.                                                                       
1a*         500      0/5                                                  
1b          500      0/5                                                  
2b          500      0/5                                                  
6           500      0/5                                                  
25          500      0/5                                                  
76          500      0/5                                                  
______________________________________                                    
 *The compound of Example 1a (hereinafter, the same)                      
 
    
     The compounds of the present invention can be administered either in oral route, parenteral route or intrarectal route, but preferably in oral route. The dose of the compounds may vary depending on the kinds of the compounds, administration routes, severity of the disease and age of patients, but is usually in the range of 0.01 to 50 mg/kg/day, preferably 0.01 to 5 mg/kg/day. 
     The compounds of the present invention are usually administered in the form of a conventional pharmaceutical preparation in admixture with a conventional pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent includes the conventional pharmaceutically acceptable carriers or diluents which do not react with the compounds of the present invention. Suitable examples of the carrier or diluent are lactose, glucose, mannitol, sorbitol, dextrin, cyclodextrin, starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, calcium carboxymethyl cellulose, ion exchange resin, methyl cellulose, gelatin, acacia, pullulan, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, light silicic anhydride, magnesium stearate, talc, tragacanth, bentonite, veegum, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium laurylsulfate, glycerin, glycerin fatty acid ester, anhydrous lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol, water, and the like. The pharmaceutical preparation includes tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections, suppositories, and the like. These preparations can be prepared by a conventional method. The liquid preparations may be in the form that they are dissolved or suspended in water or any other conventional medium when used. The tablets, granules and fine granules may be coated with a conventional coating agent. The injections are usually prepared by dissolving the compound of the present invention in water, but occasionally in a physiological saline solution or glucose solution, which is optionally incorporated with a buffer or a preservative. The pharmaceutical preparations may also contain other pharmaceutically active compounds. 
     The present invention is illustrated by the following Reference Examples, Examples and Preparations, but should not be construed to be limited thereto. The compounds are identified by elementary analysis, mass spectrum, IR spectrum, UV spectrum, NMR spectrum, and the like. 
     In the Reference Examples and Examples, the following abbreviations may occasionally be used. 
     Me: methyl 
     Et: ethyl 
     t-Bu: tertiary butyl 
     Ph: phenyl 
     A: ethanol 
     AC: acetonitrile 
     AT: acetone 
     CF: chloroform 
     D: N,N-dimethylformamide 
     E: diethyl ether 
     EA: ethyl acetate 
     HX: hexane 
     IP: isopropyl alcohol 
     M: methanol 
     MC: methylene chloride 
     PE: petroleum ether 
     T: toluene 
     W: water 
     Besides, the solvent shown in brackets as to the melting point in the following Reference Examples and Examples means a solvent for recrystallization. 
     REFERENCE EXAMPLE 1 
     Preparation of 4-phenyl-5,6,7,8-tetrahydro-2(1H)-quinolinone 
     A mixture of benzoylacetonitrile (25 g), cyclohexanone (25 g) and 75% polyphosphoric acid (250 g) is stirred at 50° C. for 30 minutes and further at 110° C. for 1.5 hour. After cooling, the reaction mixture is poured into ice-water and thereto is added diethyl ether (300 ml). The mixture is stirred and the precipitated crystals are collected by filtration. The crystals are recrystallized from N,N-dimethylformamide-ethanol to give the desired compound (27 g), m.p. 285°-288° C. 
     REFERENCE EXAMPLES 2 TO 46 
     In the same manner as described in Reference Example 1 except that the corresponding starting materials are used, there are obtained the compounds as shown in the following Tables 8 and 9. 
     
                       TABLE 8                                                     
______________________________________                                    
 ##STR13##                                                                
Ref.                       Melting point                                  
                                     Solvent for                          
Ex.  n      R.sup.2  R.sup.3                                              
                           (°C.)                                   
                                     recrystallization                    
______________________________________                                    
 2   3      H        H     221-223   M                                    
 3   3      4-F      H     258-265   M                                    
 4   3      3-F      H     234-235   A                                    
 5   3      2-F      H     210-212   A-W                                  
 6   3      4-OMe    H     243-245   M                                    
 7   3      4-F      2-F   235-245   A                                    
 8   4      4-F      H     287-288   D-A                                  
 9   4      3-F      H     253-255   A                                    
10   4      2-F      H     174-176   M                                    
11   4      4-OMe    H     239-242   M                                    
12   5      H        H     280-281   M                                    
13   5      4-F      H     245-246   M                                    
14   5      3-F      H     273-275   M                                    
15   5      2-F      H     251-252   A-W                                  
16   5      4-OMe    H     258-260   M                                    
17   5      2-OMe    H     245-247   A                                    
18   5      4-Me     H     253-258   M                                    
19   5      4-Cl     H     251-255   D-W                                  
20   5      2-Cl     H     262-263   D-W                                  
21   5      4-F      2-F   233-235   A                                    
22   6      H        H     265-266   M                                    
23   6      4-F      H     235-238   IP                                   
24   6      3-F      H     260-270   A                                    
25   6      2-F      H     245-247   IP                                   
26   6      4-F      3-F   255-261   M                                    
27   6      4-F      2-F   240-243   M                                    
28   6      6-F      2-F   254-256   A                                    
29   6      4-OMe    H     267-271   M                                    
30   6      4-Me     H     265-275   A                                    
31   6      4-Cl     H     284-287   M                                    
32   6      3-Cl     H     248-250   A                                    
33   6      4-Br     H     286-292   M                                    
34   7      4-F      H     241-243   EA                                   
______________________________________                                    
 
    
     
                       TABLE 9                                                     
______________________________________                                    
 ##STR14##                                                                
 Ex.Ref.                                                                  
      ##STR15##      R.sup.3                                              
                           R.sup.3                                        
                               (°C.)pointMelting                   
                                      recrystallizationSolvent            
______________________________________                                    
                                     for                                  
35                                                                        
      ##STR16##     H     H   275-279                                     
                                     M                                    
36                                                                        
      ##STR17##     F     H   270-275                                     
                                     M                                    
37                                                                        
      ##STR18##     F     H   255-257                                     
                                     M                                    
38                                                                        
      ##STR19##     F     H   278-284                                     
                                     M                                    
39                                                                        
      ##STR20##     F     H   266-267                                     
                                     M                                    
40                                                                        
      ##STR21##     F     H   --     --                                   
41                                                                        
      ##STR22##     H     H   272-276                                     
                                     M                                    
42                                                                        
      ##STR23##     F     H   273-277                                     
                                     M                                    
43                                                                        
      ##STR24##     H     H   220-225                                     
                                     IP                                   
44                                                                        
      ##STR25##     F     H   263-274                                     
                                     A                                    
45                                                                        
      ##STR26##     F     F   --     --                                   
46                                                                        
      ##STR27##     F     H   &gt;300   M                                    
______________________________________                                    
 
    
     REFERENCE EXAMPLE 47 
     Preparation of 4-(4-fluorophenyl)-1,5,6,7,8,9-hexahydro-2H-6,9-methanocyclohepta[b]pyridin-2-one 
     Bicyclo[3.2.1]octan-2-one (2 g) and 4-fluorobenzoylacetonitrile (2.6 g) are dissolved in 1,1,2,2-tetrachloroethane (5 ml) and thereto is added 75% polyphosphoric acid (25 g). The mixture is stirred at 80° C. for 30 minutes, at 100° C. for 1 hour, and further at 130° C. for 30 minutes. After cooling, the reaction mixture is poured into ice-water and neutralized with potassium carbonate. The precipitated crystals are collected by filtration and washed successively with water and ethyl acetate. The resultant is recrystallized from methanol to give the desired product (2.7 g), m.p.&gt;300° C. 
     REFERENCE EXAMPLE 48 
     Preparation of 4-(4-fluorophenyl)-1,5,6,7,8,9-hexahydro-2H-5,8-methanocyclohepta[b]pyridin-2-one 
     In the same manner as described in Reference Example 47 except that the corresponding starting materials are used, there is obtained the desired compound. 
     REFERENCE EXAMPLE 49 
     Preparation of 2-chloro-4-(4-fluorophenyl)-5,6,7,8-tetrahydroquinoline: 
     A mixture of 4-(4-fluorophenyl)-5,6,7,8-tetrahydro-2(1H)-quinoline (18.7 g) and phenylphosphonic dichloride (29 ml) is stirred at 170° C. for 1 hour. After cooling, the reaction mixture is dissolved in chloroform (200 ml) and the mixture is added dropwise into ice-water with stirring over a period of about 30 minutes. The mixture is made alkaline by dropwise addition of conc. aqueous ammonia thereto. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is recrystallized from isopropanol-petroleum ether to give the desired product (15.1 g), m.p. 111°-112° C. 
     REFERENCE EXAMPLES 50 TO 94 
     In the same manner as described in Reference Example 49 except that the corresponding starting materials are used, there are obtained the compounds as shown in Table 10 and 11. 
     
                       TABLE 10                                                    
______________________________________                                    
 ##STR28##                                                                
Ref.                       Melting point                                  
                                     Solvent for                          
Ex.  n      R.sup.2  R.sup.3                                              
                           (°C.)                                   
                                     recrystallization                    
______________________________________                                    
50   3      H        H     86-87     IP-PE                                
51   3      4-F      H     144-146   A                                    
52   3      3-F      H     55-57     IP                                   
53   3      2-F      H     Oil       --                                   
54   3      4-OMe    H     Oil       --                                   
55   3      4-F      2-F   Oil       --                                   
56   4      H        H     86-88     A                                    
57   4      3-F      H     84-86     A                                    
58   4      2-F      H     84-85     IP-PE                                
59   4      4-OMe    H     104-106   A                                    
60   5      H        H     71-72     IP                                   
61   5      4-F      H     84-85     PE                                   
62   5      3-F      H     Oil       --                                   
63   5      2-F      H     89-90     A                                    
64   5      4-OMe    H     75-76     A                                    
65   5      4-Me     H     66-67     A                                    
66   5      4-Cl     H     117-118   MC-HX                                
67   5      4-F      2-F   55-56     IP                                   
68   6      H        H     96-97     IP-PE                                
69   6      4-F      H     136-137   A                                    
70   6      3-F      H     110-111   A                                    
71   6      2-F      H     81-82     IP                                   
72   6      4-F      3-F   137-138   A                                    
73   6      4-F      2-F   74-75     IP                                   
74   6      6-F      2-F   83-84     IP                                   
75   6      4-OMe    H     147-150   MC-HX                                
76   6      4-Me     H     142-143   M                                    
77   6      4-Cl     H     183-185   CF-T                                 
78   6      3-Cl     H     100-101   A                                    
79   6      4-Br     H     Oil       --                                   
80   7      4-F      H     60-68     E                                    
______________________________________                                    
 
    
     
                       TABLE 11                                                    
______________________________________                                    
 ##STR29##                                                                
 Ex.Ref.                                                                  
      ##STR30##      R.sup.2                                              
                           R.sup.3                                        
                               (°C.)pointMelting                   
                                      recrystallizationSolvent            
______________________________________                                    
                                     for                                  
81                                                                        
      ##STR31##     H     H    94-95 IP                                   
82                                                                        
      ##STR32##     F     H    94-95 A                                    
83                                                                        
      ##STR33##     F     H    74-75 IP                                   
84                                                                        
      ##STR34##     F     H   102-104                                     
                                     MC-HX                                
85                                                                        
      ##STR35##     H     H   109-110                                     
                                     A                                    
86                                                                        
      ##STR36##     F     H   159-162                                     
                                     CF-A                                 
87                                                                        
      ##STR37##     F     H    83-84 IP                                   
88                                                                        
      ##STR38##     F     H   --     --                                   
89                                                                        
      ##STR39##     H     H    63-65 IP-PE                                
90                                                                        
      ##STR40##     F     H    74-76 IP                                   
91                                                                        
      ##STR41##     F     F   Oil    --                                   
92                                                                        
      ##STR42##     F     H   132-135                                     
                                     MC-HX                                
93                                                                        
      ##STR43##     H     H   Oil    --                                   
94                                                                        
      ##STR44##     F     H    92-94 MC-HX                                
______________________________________                                    
 
    
     EXAMPLE 1 
     Preparation of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     A mixture of 2-chloro-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (2.0 g), N-ethylpiperazine (2.4 g), and potassium iodide (1.1 g) is stirred at 170° C. for 5 hours. After cooling, the reaction mixture is dissolved in ethyl acetate and water. The organic layer is washed with water and extracted with 5% hydrochloric acid. The extract is made alkaline with potassium carbonate, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 
     (a) The residue is recrystallized from acetonitrile to give the desired product (1.2 g), m.p. 123°-124° C. 
     This product obtained in the above (a) is converted to the following salt thereof by treating the product with various acids. 
     (b) Dimaleate, m.p. 165°-167° C. (ethanol) 
     (c) Dihydrochloride·1/2 hydrate, m.p. 215°-222° C. (acetone) 
     (d) Fumarate, m.p. 228°-230° C. (ethanol) 
     (e) Citrate, m.p. 184°-187° C. (ethanol) 
     EXAMPLE 2 
     Preparation of 2-(4-ethyl-1-piperazinyl)-4-(2,4-difluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b] pyridine 
     A mixture of 2-chloro-4-(2,4-difluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (10 g), N-ethylpiperazine (11 g), and potassium iodide (5.4 g) is stirred at 170° C. for 5 hours. After cooling, the reaction mixture is dissolved in chloroform and 5% aqueous potassium carbonate solution. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 
     (a) The residue is dissolved in toluene, and subjected to silica gel column chromatography. The fractions eluted with toluene and a mixture of toluene-ethyl acetate (1:1) are collected, and recrystallized from isopropyl alcohol to give the desired product (5.5 g), m.p. 124°-125° C. 
     (b) The product obtained in the above (a) is treated with a solution of maleic acid in ethanol to give the dimaleate of the desired product, m.p. 133°-135° C. (ethanol). 
     EXAMPLE 3 
     Preparation of 2-(4-ethyl-1-piperazinyl)-4-phenyl-5,6,7,8-tetarahydroquinoline 
     A mixture of 2-chloro-4-phenyl-5,6,7,8-tetrahydroquinoline (1.0 g), N-ethylpiperazine (1.2 g), and potassium iodide (0.66 g) is stirred at 170° C. for 15 hours. After cooling, the reaction mixture is dissolved in chloroform, and 5% aqueous potassium carbonate solution. The organic layer is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oily residue is subjected to basic alumina column chromatography. The fractions eluted with toluene and a mixture of toluene and ethyl acetate (9:1) are collected, and treated with a solution of maleic acid in ethanol. The resulting maleate product is recrystallized from ethanolethyl acetate to give the dimaleate of the desired product (0.45 g), m.p. 139°-142° C. 
     EXAMPLES 4-77 
     In the same manner as described in Example 3 except that the corresponding starting materials are used, there are obtained the compounds as shown in Tables 12 and 13. 
     
                                           TABLE 12                                
__________________________________________________________________________
 ##STR45##                                                                
                               M.p. Sol.                                  
Ex.                                                                       
   n  R.sup.2                                                             
          R.sup.3                                                         
              R.sup.1                                                     
                     Q         (°C.)                               
                                    recry.                                
__________________________________________________________________________
4  3  H   H   Et     3/2 Maleate                                          
                               132-136                                    
                                    A                                     
5  3  H   H   CH.sub.2 CH.sub.2 OH                                        
                     Maleate   178-183                                    
                                    A                                     
6  3  4-F H   Et     Dimaleate 164-166                                    
                                    A                                     
7  3  4-F H   CH.sub.2 CH.sub.2 OH                                        
                     1/2 Fumarate                                         
                               207-210                                    
                                    M                                     
8  3  3-F H   Et     Dimaleate 124-126                                    
                                    A                                     
9  3  3-F H   CH.sub.2 CH.sub.2 OH                                        
                     Maleate.1/4 H.sub.2 O                                
                               182-185                                    
                                    A                                     
10 3  2-F H   Et     Maleate.1/5 H.sub.2 O                                
                               189-191                                    
                                    A                                     
11 3  2-F H   CH.sub.2 CH.sub.2 OH                                        
                     Maleate.1/2 H.sub.2 O                                
                               186-188                                    
                                    A                                     
12 3  4-OMe                                                               
          H   Et     Dimaleate 174-176                                    
                                    A                                     
13 3  4-OMe                                                               
          H   CH.sub.2 CH.sub.2 OH                                        
                     Dioxalate 183-187                                    
                                    M                                     
14 4  H   H   CH.sub.2 CH.sub.2 OH                                        
                     Dimaleate 129-131                                    
                                    A                                     
15 4  4-F H   Et     Dimaleate 146-148                                    
                                    A                                     
16 4  4-F H   CH.sub.2 CH.sub.2 OH                                        
                     Dimaleate 149-151                                    
                                    A                                     
17 4  3-F H   Et     Dimaleate 133-136                                    
                                    M                                     
18 4  3-F H   CH.sub.2 CH.sub.2 OH                                        
                     Dioxalate 180-182                                    
                                    M                                     
19 4  2-F H   Et     Dimaleate 148-150                                    
                                    A                                     
20 4  2-F H   CH.sub.2 CH.sub.2 OH                                        
                     Dioxalate.1/4 H.sub.2 O                              
                               169-172                                    
                                    A                                     
21 4  4-OMe                                                               
          H   Et     Dimaleate 179-181                                    
                                    A                                     
22 4  4-OMe                                                               
          H   CH.sub.2 CH.sub.2 OH                                        
                     Dioxalate.1/4 H.sub.2 O                              
                               160-165                                    
                                    A                                     
23 5  H   H   Et     Dimaleate 150-152                                    
                                    IP                                    
24 5  H   H   CH.sub.2 CH.sub.2 OH                                        
                     1/2 Fumarate                                         
                               142-144                                    
                                    A                                     
25 5  4-F H   Et     Dimaleate 150-152                                    
                                    A                                     
26 5  4-F H   CH.sub.2 CH.sub.2 OH                                        
                     1.7 Oxalate                                          
                               180-182                                    
                                    A                                     
27 5  3-F H   Et     Dimaleate 138-140                                    
                                    A                                     
28 5  3-F H   CH.sub.2 CH.sub.2 OH                                        
                     Maleate.1/4 H.sub.2 O                                
                               155-158                                    
                                    IP                                    
29 5  2-F H   Et     Oxalate   231-234                                    
                                    A-M                                   
30 5  2-F H   CH.sub.2 CH.sub.2 OH                                        
                     1/2 Fumarate.1/4 H.sub.2 O                           
                               163-164                                    
                                    M                                     
31 5  4-Cl                                                                
          H   Et     --        150-151                                    
                                    MC-A                                  
32 5  4-OMe                                                               
          H   Et     Dimaleate 162-164                                    
                                    A                                     
33 5  4-OMe                                                               
          H   CH.sub.2 CH.sub.2 OH                                        
                     Fumarate.1/2 H.sub.2 O                               
                               190-195                                    
                                    A-M                                   
34 5  4-Me                                                                
          H   Et     Dimaleate 180-183                                    
                                    A                                     
35 5  4-Me                                                                
          H   CH.sub.2 CH.sub.2 OH                                        
                     Dimaleate.1/4 H.sub.2 O                              
                               151-153                                    
                                    IP                                    
36 6  H   H   Et     Fumarate  236-238                                    
                                    M                                     
37 6  4-F H   CH.sub.2 CH.sub.2 OH                                        
                     Dimaleate 135-137                                    
                                    A                                     
38 6  4-F H                                                               
               ##STR46##                                                  
                     --        167-168                                    
                                    A-AT                                  
39 6  4-F H                                                               
               ##STR47##                                                  
                     --        165-167                                    
                                    M                                     
40 6  4-F H                                                               
               ##STR48##                                                  
                     --        156-157                                    
                                    A-AT                                  
41 6  4-F H                                                               
               ##STR49##                                                  
                     --        206-208                                    
                                    M-AT                                  
42 6  3-F H   Et     Dimaleate 153-155                                    
                                    A                                     
43 6  2-F H   Et     Fumarate  201-204                                    
                                    A                                     
44 6  4-Cl                                                                
          H   Et     --        133-135                                    
                                    CF-IP                                 
45 6  4-Cl                                                                
          H   CH.sub.2 CH.sub.2 OH                                        
                     --        156-158                                    
                                    CF-A                                  
46 6  3-Cl                                                                
          H   Et     --        114-115                                    
                                    IP                                    
47 6  3-Cl                                                                
          H   CH.sub.2 CH.sub.2 OH                                        
                     Oxalate   210-212                                    
                                    M                                     
48 6  4-Br                                                                
          H   Et     --        134-136                                    
                                    A                                     
49 6  4-OMe                                                               
          H   Et     --        113-114                                    
                                    MC-HX                                 
50 6  4-OMe                                                               
          H   CH.sub.2 CH.sub.2 OH                                        
                     HCl.3/4 H.sub.2 O                                    
                               153-156                                    
                                    A-E                                   
51 6  4-Me                                                                
          H   Et     Dimaleate 163-164                                    
                                    A                                     
52 6  4-Me                                                                
          H   CH.sub.2 CH.sub.2 OH                                        
                     Oxalate   207-209                                    
                                    A                                     
53 6  4-F 2-F CH.sub.2 CH.sub.2 OH                                        
                     Dioxalate.1/10 H.sub.2 O                             
                               169-172                                    
                                    A                                     
54 6  4-F 3-F Et     --        105-106                                    
                                    AC                                    
55 6  6-F 2-F Et     --        104-105                                    
                                    AC                                    
56 7  4-F H   Et     Fumarate  184-189                                    
                                    A-E                                   
__________________________________________________________________________
 
    
     
                                           TABLE 13                                
__________________________________________________________________________
 ##STR50##                                                                
 Ex.                                                                      
    ##STR51##                                                             
              R.sup.2                                                     
                R.sup.1                                                   
                       Q        M.p. (°C.)                         
                                      Sol. recry.                         
__________________________________________________________________________
57                                                                        
    ##STR52##                                                             
             H Et     Dimaleate                                           
                               138-140                                    
                                     A                                    
58                                                                        
    ##STR53##                                                             
             H CH.sub.2 CH.sub.2 OH                                       
                      Dimaleate                                           
                               140-141                                    
                                     A                                    
59                                                                        
    ##STR54##                                                             
             F Et     Dioxalate.1/4 H.sub.2 O                             
                               126-127                                    
                                     A                                    
60                                                                        
    ##STR55##                                                             
             F CH.sub.2 CH.sub.2 OH                                       
                      Fumarate 160-161                                    
                                     A                                    
61                                                                        
    ##STR56##                                                             
             H Et     --       130-131                                    
                                     A                                    
62                                                                        
    ##STR57##                                                             
             H CH.sub.2 CH.sub.2 OH                                       
                      --       162-163                                    
                                     A                                    
63                                                                        
    ##STR58##                                                             
             F Et     Fumarate 212-215                                    
                                     M-A                                  
64                                                                        
    ##STR59##                                                             
             F Et     Dimaleate                                           
                               141-142                                    
                                     IP                                   
65                                                                        
    ##STR60##                                                             
             F CH.sub.2 CH.sub.2 OH                                       
                      Dimaleate.1/2 H.sub.2 O                             
                               120-122                                    
                                     A                                    
66                                                                        
    ##STR61##                                                             
             F Et     Fumarate 209-211                                    
                                     M-A                                  
67                                                                        
    ##STR62##                                                             
             F CH.sub.2 CH.sub.2 OH                                       
                      HCl      200-203                                    
                                     A-E                                  
68                                                                        
    ##STR63##                                                             
             F Et     --       107-108                                    
                                     IP                                   
69                                                                        
    ##STR64##                                                             
             F CH.sub.2 CH.sub.2 OH                                       
                      Dioxalate.1/4 H.sub.2 O                             
                               125-126                                    
                                     A                                    
70                                                                        
    ##STR65##                                                             
             F Et     Fumarate 203-204                                    
                                     A                                    
71                                                                        
    ##STR66##                                                             
             H Et     Dimaleate.1/4 H.sub.2 O                             
                               173-176                                    
                                     A                                    
72                                                                        
    ##STR67##                                                             
             H CH.sub.2 CH.sub.2 OH                                       
                      Dimaleate                                           
                               140-142                                    
                                     A                                    
73                                                                        
    ##STR68##                                                             
             F Et     Dimaleate                                           
                               163-169                                    
                                     IP                                   
74                                                                        
    ##STR69##                                                             
             F CH.sub.2 CH.sub.2 OH                                       
                      Dimaleate                                           
                               159-161                                    
                                     A                                    
75                                                                        
    ##STR70##                                                             
             F Et     Fumarate 234-236                                    
                                     M-A                                  
76                                                                        
    ##STR71##                                                             
             F Et     Fumarate 216-219                                    
                                     M-A                                  
77                                                                        
    ##STR72##                                                             
             F Et     Fumarate.1/4 H.sub.2 O                              
                               226-230                                    
                                     M-A                                  
__________________________________________________________________________
 
    
     EXAMPLES 78-85 
     In the same manner as described in Example 3 except that the corresponding starting materials are used, there are obtained the following compounds. 
     (Example 78) 
     2-(4-Methyl-1-homopiperazinyl)-4-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine maleate, m.p. 187°-189° C. (ethanol) 
     (Example 79) 
     2-(4-Butanoyl-1-homopiperazinyl)-4-(4-fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine, oily product 
     (Example 80) 
     2-(4-Methyl-1-homopiperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine dimaleate, m.p. 141°-143° C. (ethanol) 
     (Example 81) 
     2-(4-Benzoyl-1-homopiperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine, oily product 
     (Example 82) 
     2-[4-(2-Methoxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine dimaleate, m.p. 119°-120° C. (acetonitrile) 
     (Example 83) 
     2-(3-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine, m.p. 138°-141° C. (isopropyl alcohol-hexane) 
     (Example 84) 
     2-(3,5-Dimethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 1/2 fumarate, m.p. 262°-266° C. (decomposed) (methanol) 
     (Example 85) 
     2-(1-Homopiperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine maleate, m.p. 198°-200° C. (ethanol) 
     EXAMPLE 86 
     Preparation of 2-(1-piperazinyl)-4-phenyl-5,6,7,8-tetrahydroquinoline 
     A mixture of 2-(4-benzyl-1-piperazinyl)-4-phenyl-5,6,7,8-tetrahydroquinoline (m.p. 105°-107° C., 2.1 g) obtained in the same manner as in Example 3, chloroethyl chloroformate (0.86 g) and methylene chloride (40 ml) is refluxed for 1 hour. The reaction mixture is concentrated under reduced pressure, and methanol (40 ml) is added to the residue. The mixture is refluxed for 30 minutes and concentrated under reduced pressure. The resulting residue is dissolved in water, washed with diethyl ether, neutralized with potassium carbonate, and extracted with chloroform. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. To the residue is added a solution of maleic acid in ethanol. The resulting maleate product is recrystallized from ethanol to give the dimaleate of the desired product (1.2 g), m.p. 150°-151° C. 
     EXAMPLES 87-110 
     In the same manner as described in Example 86 except that the corresponding starting materials are used, there are obtained the compounds as shown in Tables 14 and 15. 
     
                       TABLE 14                                                    
______________________________________                                    
 ##STR73##                                                                
                                   Melting                                
                                          Solvent                         
                                   point  for re-                         
Ex.  n     R.sup.2 R.sup.3                                                
                        Q          (°C.)                           
                                          crystaln.                       
______________________________________                                    
87   3     H       H    Maleate    175-179                                
                                          A                               
88   3     4-F     H    Dimaleate  152-155                                
                                          A                               
89   3     3-F     H    Maleate    176-179                                
                                          A                               
90   3     2-F     H    Maleate    186-188                                
                                          A                               
91   3     4-OMe   H    Dimaleate  148-149                                
                                          A                               
92   4     4-F     H    Dimaleate.1/4 H.sub.2 O                           
                                   143-145                                
                                          A                               
93   4     3-F     H    Dimaleate.1/4 H.sub.2 O                           
                                   148-151                                
                                          A                               
94   4     2-F     H    Dimaleate  136-137                                
                                          A                               
95   4     4-OMe   H    Dioxalate.1/4 H.sub.2 O                           
                                   210-213                                
                                          M                               
96   5     H       H    Maleate    173-176                                
                                          A                               
97   5     4-F     H    Dimaleate  144-147                                
                                          A                               
98   5     3-F     H    Maleate    173-175                                
                                          A                               
99   5     2-F     H    Maleate    173-180                                
                                          A                               
100  5     4-Cl    H    Maleate.1/4 H.sub.2 O                             
                                   176-178                                
                                          M-A                             
101  5     4-OMe   H    Dimaleate  133-137                                
                                          IP                              
102  5     4-Me    H    Dimaleate.3/4 H.sub.2 O                           
                                    95-97 IP                              
103  6     H       H    Dimaleate.1/4 H.sub.2 O                           
                                   124-127                                
                                          A                               
104  6     4-F     H    Maleate    186-190                                
                                          A                               
105  6     4-Me    H    Fumarate   218-221                                
                                          A                               
106  6     4-F     2-F  1/2 Fumarate.1/2 H.sub.2 O                        
                                   177-179                                
                                          A                               
______________________________________                                    
 
    
     
                                           TABLE 15                                
__________________________________________________________________________
 ##STR74##                                                                
 Ex.                                                                      
    ##STR75##                                                             
              R.sup.2                                                     
                 Q          (°C.)Melting point                     
                                   recrystaln.Solvent for                 
__________________________________________________________________________
107                                                                       
    ##STR76##                                                             
             H  Dimaleate.1/4 H.sub.2 O                                   
                           147-149                                        
                                  A                                       
108                                                                       
    ##STR77##                                                             
             H  3/2 Oxalate.1/2 H.sub.2 O                                 
                           178-181                                        
                                  M                                       
109                                                                       
    ##STR78##                                                             
             F  1/2 Fumarate.1/10 H.sub.2 O                               
                           181-186                                        
                                  A                                       
110                                                                       
    ##STR79##                                                             
             H  Maleate    207-208                                        
                                  A                                       
__________________________________________________________________________
 
    
     EXAMPLE 111 
     Preparation of 2-(4-methyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyrindine 
     A mixture of 2-(1-piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyrindine (2 g), 37% aqueous formaldehyde solution (0.66 g), formic acid (0.68 g) and water (15 ml) is refluxed for 20 minutes. After cooling, the reaction mixture is made alkaline with diluted aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. To the residue is added a solution of maleic acid in ethanol, and the resulting maleate product is recrystallized from ethanol to give the maleate of the desired compound, m.p. 135°-137° C. 
     EXAMPLES 112-117 
     In the same manner as described in Example 111 except that the corresponding starting materials are used, there are obtained the following compounds. 
     (Example 112) 
     2-(4-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine dimaleate, m.p. 136°-138° C. (ethanol) 
     (Example 113) 
     2-(4-Methyl-1-piperazinyl)-4-(4-methylphenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine dimaleate, m.p. 152°-154° C. (ethanol) 
     (Example 114) 
     2-(4-Methyl-1-piperazinyl)-4-(2,4-difluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine, m.p. 132°-133° C. (ethanol) 
     (Example 115) 
     2-(4-Methyl-1-piperazinyl)-4-(4-fluorophenyl)-6-methyl-5,6,7,8-tetrahydroquinoline dimaleate, m.p. 161°-164° C. (ethanol) 
     (Example 116) 
     2-(3,4-Dimethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine fumarate 1/4 hydrate, m.p. 173°-175° C. (ethanol-diethyl ether) 
     (Example 117) 
     2-(cis-3,5-Dimethyl-4-methyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine fumarate, m.p. 208°-210° C. (methanol-ethanol) 
     EXAMPLE 118 
     Preparation of 2-(4-n-propyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     A mixture of 2-(1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (1.4 g), n-propyl bromide (0.56 g), potassium carbonate (0.68 g), potassium iodide (0.1 g) and methanol (50 ml) is refluxed for 15 hours. The reaction mixture is concentrated under reduced pressure and thereto is added water. The mixture is extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. To the residue is added a solution of maleic acid in ethanol, and the resulting maleate product is recrystallized from ethanol to give the dimaleate of the desired compound (0.6 g), m.p. 149°-152° C. 
     EXAMPLES 119-126 
     In the same manner as described in Example 118 except that the corresponding starting materials are used, there are obtained the compounds as shown in the following Table 16. 
     
                       TABLE 16                                                    
______________________________________                                    
 ##STR80##                                                                
                                M.p.   Solvent, for                       
Ex.  n     R.sup.1      Q       (°C.)                              
                                       recrystal.                         
______________________________________                                    
119  3     (CH.sub.2).sub.3 OH                                            
                        Maleate 174-178                                   
                                       A                                  
120  3                                                                    
            ##STR81##   Maleate 215-218                                   
                                       A                                  
121  6                                                                    
            ##STR82##   Dimaleate                                         
                                154-155                                   
                                       A                                  
122  6     (CH.sub.2).sub.3 CH.sub.3                                      
                        --       89-90 A                                  
123  6     (CH.sub.2).sub.4 CH.sub.3                                      
                        Maleate 213-217                                   
                                       A-M                                
124  6     (CH.sub.2).sub.5 CH.sub.3                                      
                        Maleate 196-197                                   
                                       A                                  
125  6     CH.sub.2 CHCH.sub.2                                            
                        1/4 H.sub.2 O                                     
                                109-110                                   
                                       AC                                 
126  6     CH.sub.2 C CH                                                  
                        --       75-77 HX                                 
______________________________________                                    
 
    
     EXAMPLE 127 
     Preparation of 2-(4-n-propyl-1-piperazinyl)-4-(2,4-difluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     In the same manner as described in Example 118 except that the corresponding starting materials are used, the desired product is obtained, m.p. 108°-109° C. (ethanol). 
     EXAMPLE 128 
     Preparation of 2-[4-(2-furoyl)-1-piperazinyl]-4-phenyl-5,6,7,8-tetrahydroquinoline 
     A mixture of 2-(1-piperazinyl)-4-phenyl-5,6,7,8-tetrahydroquinoline (1.2 g), 2-furancarboxylic acid (0.46 g), chloroform (40 ml) and 1-(3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0.79 g) is stirred at 25° C. for 2 hours. The reaction mixture is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene and subjected to silica gel column chromatography. The fractions eluted with toluene and toluene-ethyl acetate (9:1) are collected and recrystallized from ethanol to give the desired product (0.4 g), m.p. 128°-130° C. 
     EXAMPLE 129 
     Preparation of 2-[4-(2-furoyl)-1-piperazinyl]-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyrindine 
     In the same manner as described in Example 128 except that the corresponding starting materials are used, the desired product is obtained, m.p. 165°-166° C. (ethanol). 
     EXAMPLE 130 
     Preparation of 2-(4-ethyl-1-piperazinyl)-4-(4-hydroxyphenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     2-(4-Ethyl-1-piperazinyl)-4-(4-methoxyphenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (1.3 g) is dissolved in 48% hydrobromic acid (10 ml) and the mixture is stirred at 120° C. for 2 hours. After cooling, water is added thereto and the mixture is neutralized with 1N aqueous sodium hydroxide solution and sodium hydrogen carbonate. The resulting precipitate is collected by filtration, washed with water, and recrystallized from methanol to give the desired product (0.6 g), m.p. 250°-253° C. 
     EXAMPLE 131 
     Preparation of 2-(4-ethyl-1-piperazinyl)-4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine 
     In the same manner as described in Example 3 except that the corresponding starting materials are used, there is obtained the oxalate ·1/2 hydrate of the desired product, m.p. 225°-227° C. (methanol). 
     EXAMPLE 132 
     Preparation of 2-(4-ethyl-1-piperazinyl)-4-(2,4-difluorophenyl)-6,7-dihydro-5H-1-pyrindin 
     In the same manner as described in Example 3 except that the corresponding starting materials are used, there is obtained the maleate of the desired product, m.p. 195°-196° C. (ethanol). 
     EXAMPLE 133 
     Preparation of 2-(4-cyclopropyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     In the same manner as described in Example 3 except that the corresponding starting materials are used, there is obtained the desired product, m.p. 125°-128° C. (ethanol). 
     EXAMPLE 134 
     Preparation of 2-[4-(4-fluorophenyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     In the same manner as described in Example 3 except that the corresponding starting materials are used, there is obtained the desired product, m.p. 130°-131° C. (methanol). 
     EXAMPLE 135 
     Preparation of 2-(4-ethyl-1-piperazinyl)-4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro-5,8-methanoquinoline 
     In the same manner as described in Example 3 except that the corresponding starting materials are used, there is obtained the oxalate ·1/2 hydrate of the desired product, m.p. 234°-238° C. (ethanol). 
     EXAMPLE 136 
     Preparation of 2-(cis-3,5-dimethyl-4-methyl-1-piperazinyl)-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyrindine 
     In the same manner as described in Example 111 except that the corresponding starting materials are used, there is obtained the fumarate ·1/4 hydrate of the desired product, m.p. 204°-208° C. (methanol-ethanol). 
     EXAMPLE 137 
     Preparation of 2-{4-[3-(4-fluorobenzoyl)propyl]-1-piperazinyl}-4-(4-fluorophenyl)-6,7-dihydro-5H-1-pyrindine 
     In the same manner as described in Example 118 except that the corresponding starting materials are used, there is obtained the desired product, m.p. 115°-116° C. (ethanol). 
     EXAMPLE 138 
     Preparation of 2-[4-(3-hydroxypropyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     In the same manner as described in Example 118 except that the corresponding starting materials are used, there is obtained the dioxalate ·1/4 hydrate of the desired product, m.p. 136°-138° C. (methanol). 
     EXAMPLE 139 
     Preparation of 2-[4-(2-acetoxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     A mixture of 2-[4-(2-hydroxyethyl)-1-piperazinyl]-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine (1.5 g), acetic anhydride (0.6 g), triethylamine (0.7 g) and ethyl acetate (30 ml) is refluxed for 2 hours. After cooling, the reaction mixture is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is dissolved in toluene and the mixture is subjected to silica gel column chromatography. The fractions eluted with toluene and toluene-ethyl acetate (1:1) are collected and thereto is added a solution of maleic acid in ethanol. The resulting maleate product is recrystallized from ethanol to give the maleate of the desired product (0.65 g), m.p. 187°-191° C. 
     EXAMPLE 140 
     Preparation of 2-(4-cyclopropylmethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine 
     In the same manner as described in Example 118 except that the corresponding starting materials are used, there is obtained the desired product, m.p. 109°-110° C. (methylene chloride-hexane). 
     The preparation of the pharmaceutical composition of the present invention is illustrated by the following Preparations. 
     
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Preparation 1                                                             
Preparation of capsules:                                                  
Components                Amount                                          
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2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-                             
                          5 g                                             
6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine                               
dimaleate                                                                 
Corn starch               57 g                                            
Lactose                   10 g                                            
Crystalline cellulose     25 g                                            
Hydroxypropyl cellulose   2 g                                             
Light silicic anhydride   0.5 g                                           
Magnesium stearate        0.5 g                                           
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     According to a conventional method, the above components are mixed and granulated, and the granules thus obtained are packed in capsules (1000 capsules) to give capsules containing the granules of 100 mg per one capsule. 
     
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Preparation 2                                                             
Preparation of tablets:                                                   
Components               Amount                                           
______________________________________                                    
2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-                             
                          5 g                                             
5,6,7,8,9,10-hexahydrocycloocta[b]pyridine                                
dimaleate                                                                 
Corn starch              20 g                                             
Lactose                  30 g                                             
Crystalline cellulose    30 g                                             
Hydroxypropyl cellulose   5 g                                             
Low sustituted hydroxypropyl cellulose                                    
                         10 g                                             
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     According to a conventional method, the above components are mixed and granulated, and the granules thus obtained are mixed with light silicic anhydride and magnesium stearate, and the mixture is tabletted to give tablets containing the active ingredient of 5 mg per one tablet. 
     
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Preparation 3                                                             
Preparation of powders:                                                   
Components               Amount                                           
______________________________________                                    
2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-                             
                          5 g                                             
5,6,7,8,9,10-hexahydrocycloocta[b]pyridine                                
dimaleate                                                                 
Corn starch              173 g                                            
Lactose                  300 g                                            
Hydroxypropyl cellulose   20 g                                            
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     According to a conventional method, the above components are mixed, granulated and screened, and the granules thus obtained are mixed with an appropriate amount of light silicic anhydride to give powders (100 triturations). 
     
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Preparation 4                                                             
Preparation of injections:                                                
Components               Amount                                           
______________________________________                                    
2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-                             
                          5 g                                             
5,6,7,8,9,10-hexahydrocycloocta[b]pyridine                                
dimaleate                                                                 
D-Sorbitol               45 g                                             
1N Aqueous solution of maleic acid                                        
                         q.s.                                             
or sodium hydroxide                                                       
Distilled water for injection                                             
                         q.s.                                             
Totally                  1000 ml                                          
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     The above active ingredient and D-sorbitol are mixed with distilled water for injection, and thereto is added 1N aqueous solution of maletic acid or sodium hydroxide to adjust the solution to pH 4.0. The solution is filterd with a membrane filter (pore size, 0.22 μm) and packed in ampoule (content 10 ml). The ampoule is sealed by melting and sterilized with high pressure steam at 121° C. for 20 minutes to give injection solutions. 
     
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Preparation 5                                                             
Preparation of lyophilized preparation:                                   
Components               Amount                                           
______________________________________                                    
2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-                             
                          5 g                                             
5,6,7,8,9,10-hexahydrocycloocta[b]pyridine                                
dimaleate                                                                 
D-Mannitol               45 g                                             
1N Aqueous solution of maleic acid                                        
                         q.s.                                             
of sodium hydroxide                                                       
Distilled water for injection                                             
                         q.s.                                             
Totally                  1000 ml                                          
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     The above active ingredient and D-mannitol are mixed with distilled water for injection, and thereto is added 1N aqueous solution of maleic acid or sodium hydroxide to adjust the solution to pH 4.0. The solution is filtered with a membrane filter (pore size, 0.22 μm) and packed in a vial (content 10 ml). The vial is sealed with a rubber stopper in halfway and subjected to lyophilization, that is, pre-freezing, primary drying at -50° C., secondary drying at -20° C., and then final drying at 20° C. After completely sealed with a rubber stopper within a chamber, the vial is covered with a flip-off cap to give a lyophilized preparation.