JPH0747574B2 - Pyridine derivative and psychotropic agent containing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel pyridine derivative having a psychotropic action and a novel drug containing the derivative as an active ingredient.

2. Description of the Related Art U.S. Pat. No. 4,469,696 (JP-A-58-963) discloses several 2- (1-piperazinyl) -4-arylpyridine derivatives. However, the compounds specifically disclosed therein are only compounds having an aryl group or a 2-furyl group at the 5-position of the pyridine ring, and the structure is clearly different from the compound of the present invention. Moreover, the pharmacological action of these compounds relates to the lipid absorption inhibitory action and is completely different from the pharmacological action of the compounds of the present invention.

In addition, 2- [4- (4-methylbenzyl) -1-piperazinyl] -4-phenylpyridine, a pyridine derivative having a piperazinyl group at the 2-position and a phenyl group at the 4-position of the pyridine ring, is an antipsychotic agent or neuroleptic agent. It has been reported to have a weak action as an agent (US Pat. No. 4,831,
034 and JP-A-63-48267).

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention As a result of intensive studies of drugs acting on the central nervous system, the present inventors have a remarkable psychotropic effect, and are useful as an antipsychotic agent or anxiolytic agent, and further useful as a brain function improving agent. The present invention has been completed by finding a new pyridine derivative.

MEANS FOR SOLVING THE PROBLEMS AND EFFECTS The present invention provides a compound represented by the general formula (I) [In the formula, n means 3, 4, 5, 6 or 7, Is an aryl group or a heteroaryl group, R is a hydrogen atom or a lower alkyl group, R ₁ is a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a lower alkoxy (lower) alkyl group ，
Cycloalkyl (lower) alkyl group, optionally substituted aryl (lower) alkyl group, acyloxy (lower) alkyl group, lower alkanoyl (lower) alkyl group, optionally substituted arylcarbonyl (Lower) alkyl group, lower alkenyl group, lower alkynyl group, optionally substituted aryl group, heteroaryl group or acyl group, wherein R ₂ and R ₃ are the same or different and each is a hydrogen atom, halogen atom,
A lower alkyl group, a lower alkoxy group, a hydroxy group, a trifluoromethyl group, a cyano group, a nitro group or an amino group, and R ₄ , R ₅ and R ₆ are the same or different and each is a hydrogen atom,
Means a lower alkyl group or a phenyl group, or
Any two of R ₄ , R ₅ and R ₆ together form a single bond or a lower alkylene group, and the rest represent a hydrogen atom, a lower alkyl group or a phenyl group, and R ₇ and R ₈ Are the same or different and each represents a hydrogen atom or a lower alkyl group, and m represents 2 or 3. ] The present invention relates to a pyridine derivative represented by: and a physiologically acceptable acid addition salt thereof, and a psychotropic drug containing these compounds as active ingredients.

Physiologically acceptable acid addition salts of the compound represented by formula (I) include hydrochloride, hydrobromide, hydroiodide,
Inorganic acid salts such as sulfate and phosphate, and organic acid salts such as maleate, fumarate, oxalate, citrate, tartrate, lactate, benzoate and methanesulfonate. To be Since the compounds of formula (I) and their acid addition salts may exist in the form of hydrates, these hydrates are also included in the compounds of the present invention.

When the compound of formula (I) has an asymmetric carbon atom, at least two stereoisomers may exist. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are explained below.

Unless otherwise specified, "lower" has 1 to 6 carbon atoms.
Means The alkyl group, lower alkyl group or lower alkyl moiety, or lower alkylene group may be linear or branched. "Alkyl group" has 1 to 10 carbon atoms
And specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, Examples include n-octyl, n-nonyl, n-decyl and the like. "Lower alkylene group"
Specific examples of include methylene, ethylene, trimethylene, propylene, tetramethylene, and the like. "Halogen atom" means fluorine, chlorine, bromine, and iodine. Specific examples of "lower alkoxy group" or lower alkoxy moiety include methoxy, ethoxy, n-propoxy,
Examples include isopropoxy, n-butoxy, isobutoxy and the like. The “cycloalkyl group” or the cycloalkyl moiety means one having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
“Hydroxy (lower) alkyl group” means a lower alkyl group in which a carbon atom other than the 1-position is substituted with a hydroxy group, and specific examples include 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl. , 2,3
-Dihydroxypropyl, 4-hydroxybutyl, 2-hydroxybutyl and the like can be mentioned. The "lower alkoxy (lower) alkyl group" means a lower alkyl group substituted by a lower alkoxy group, and specific examples include 2
-Methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2,3-dimethoxypropyl, 4-methoxybutyl, 2
-Methoxybutyl and the like. The “cycloalkyl (lower) alkyl group” means a lower alkyl group substituted by a cycloalkyl group, and examples thereof include cyclopropylmethyl, cyclopentylmethyl, 2-cyclohexylethyl and the like. "Lower alkanoyl (lower) alkyl group" means a lower alkyl group substituted by an alkanoyl group having 2 to 6 carbon atoms,
Examples thereof include acetylmethyl, 2-acetylethyl, 2-propionylethyl and the like. The "lower alkenyl group" means one having 1 to 2 double bonds and having 3 to 6 carbon atoms, and examples thereof include allyl and 2-butenyl.
The "lower alkynyl group" means one having a triple bond and having 3 to 6 carbon atoms, and examples thereof include propargyl and the like. Specific examples of the "aryl group" or the aryl moiety include phenyl, naphthyl and the like. “Heteroaryl group” or heteroaryl moiety means a nitrogen atom,
It means a monocyclic or bicyclic one containing at least one oxygen atom or sulfur atom, and examples thereof include furyl, thienyl, pyridyl, pyrimidinyl and isoquinolyl.
The “aryl group optionally having substituent (s)” or the aryl moiety optionally having substituent (s) means that the aryl moiety is unsubstituted or 1 to 2 halogen atoms, lower alkyl groups, hydroxy groups, A lower alkoxy group, a trifluoromethyl group, a cyano group, a nitro group or an amino group is substituted, for example, phenyl, 2-, 3- or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl. , 2,3
-, 2,4-, 2,5-, 2,6- or 3,4-difluorophenyl, 2
-, 3- or 4-methylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- or 4-trifluoromethylphenyl and the like can be mentioned.

The "aryl (lower) alkyl group optionally having substituent (s)" means a lower alkyl group substituted by the above-mentioned aryl group optionally having substituent (s), for example, benzyl, 2- , 3- or 4-fluorobenzyl, 2-, 3-
Or 4-chlorobenzyl, 2,3-, 2,4-, 2,5-, 2,6-or
3,4-difluorobenzyl, 2-, 3- or 4-methylbenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4
-Trifluoromethylbenzyl and the like can be mentioned. The "arylcarbonyl (lower) alkyl group optionally having substituent (s)" is a lower alkyl group in which the aryl moiety is substituted with the arylcarbonyl group which is the above-mentioned aryl moiety optionally having substituent (s). Means 2-benzoylethyl, 3- (4-fluorobenzoyl) propyl and the like. An "acyl group" or an acyl moiety is a lower alkanoyl group, a cycloalkanecarbonyl group, a halogen, a benzoyl group optionally substituted with lower alkyl or lower alkoxy, or a heteroaryl moiety which is the same as the above-mentioned heteroaryl. It means an arylcarbonyl group, and examples thereof include acetyl, propionyl, cyclohexanecarbonyl, benzoyl, 4-fluorobenzoyl, nicotinoyl, isonicotinoyl, furoyl, thenoyl and the like. The “acyloxy (lower) alkyl group” means a lower alkyl group in which a carbon atom other than the 1-position is substituted with an acyloxy in which the acyl moiety is the above-mentioned acyl moiety, and specifically, 2-acetoxyethyl, 2 -Benzoyloxyethyl etc. are mentioned.

Among the compounds of the present invention represented by the general formula (I), preferable ones include Is a phenyl group, R is a hydrogen atom, R ₁ is a hydrogen atom, C ₁ -C ₁₀ alkyl group, C ₃ -C ₈ cycloalkyl group, hydroxy (C ₂ -C ₆ ) alkyl group, C _1- C ₃ alkoxy (C ₂
-C ₄₎ alkyl group, C ₂ -C ₃ alkanoyloxy (C ₂ -
C ₆ ) alkyl group, benzoyl (C ₂ -C ₅ ) alkyl group in which phenyl moiety may be substituted with halogen atom, C ₃ −
A C ₄ alkenyl group, a C ₃ -C ₄ alkynyl group, a C ₂ -C ₅ alkanoyl group, a pyridyl group, a pyrimidinyl group or a furoyl group, wherein R ₂ and R ₃ are the same or different and a hydrogen atom, a halogen atom, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy group, R ₇ and R ₈ are the same or different and each represents a hydrogen atom or a C ₁ -C ₃
Examples thereof include compounds that are alkyl groups and m is 2, and physiologically acceptable acid addition salts thereof.

More suitable one is R, R ₇ , R ₈ and m are the same as those mentioned in the above preferable compounds, and R ₁ is a hydrogen atom, a C ₁ -C ₈ alkyl group, C ₃
-C ₈ cycloalkyl group, hydroxy (C ₂ -C ₆₎ alkyl group, C ₁ -C ₂ alkoxy (C ₂ over C ₃₎ alkyl group, acetoxy (C ₂ -C ₄₎ alkyl group, C ₃ -C ₄ alkenyl group or C ₂ -
A C ₃ alkanoyl group, R ₂ and R ₃ are the same and both are a hydrogen atom or a halogen atom, or one is a hydrogen atom and the other is a halogen atom, a methyl group or a methoxy group, R ₄ , R ₅ and R ₆ are the same or different and are a hydrogen atom or a C ₁ -C ₄ alkyl group, or any two of them are combined to form a C ₁ -C ₂ alkylene group, and the rest A compound in which is a hydrogen atom or a C ₁ -C ₄ alkyl group, and physiologically acceptable acid addition salts thereof.

More suitable is R, R ₁ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ and m are the same as those mentioned in the above preferred compounds, and R ₂ and R ₃ are the same or different and each is a hydrogen atom or fluorine. And compounds that are atoms and their physiologically acceptable acid addition salts.

More preferred are those represented by the following general formula (I-1) [In the formula, n ₁ means 3, 6 or 7, and R ₁₁ is a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₃ -C ₆ cycloalkyl group, a hydroxy (C ₂ -C ₄ ) alkyl group, C ₁ -C ₂ Alkoxy (C ₂ -C ₃ ) alkyl group or allyl group, R
₂₁ and R ₃₁ are the same or different and represent a hydrogen atom or a fluorine atom, and R ₇₁ and R ₈₁ are the same or different and represent a hydrogen atom or a C ₁ -C ₃ alkyl group. ] The compound and its physiologically acceptable acid addition salt represented by these, and the following general formula (I-2) [In the formula, n ₂ means 4 or 5, and R ₁₂ is a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₃ -C ₈ cycloalkyl group, a hydroxy (C ₂ -C ₄ ) alkyl group, C ₁ -C ₂ alkoxy (C ₂ -C ₃ ) means an alkyl group or an allyl group, R
₂₂ and R ₃₂ are the same or different and represent a hydrogen atom or a fluorine atom, and R ₄₂ , R ₅₂ and R ₆₂ are the same or different and are a hydrogen atom or C ₁
-C ₄ or refers to an alkyl group, or C ₁ -C ₂ form an alkylene group any two of these together, the rest is a hydrogen atom or a C ₁ -C ₄ alkyl group. ] And a physiologically acceptable acid addition salt thereof.

Particularly preferred are those of the formula (I-1) in which n ₁ is 6 and R ₁₁ is C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group or hydroxy (C ₂ -C ₄ ). An alkyl group, R
_A compound in which one of ₂₁ and R ₃₁ has a 2-position, the other has a 4-position, and R ₇₁ and R ₈₁ are both hydrogen atoms; and physiologically acceptable acid addition salts thereof; 1-2), R ₁₂ is C ₁ -C ₆ alkyl group, C ₃ -C ₆ cycloalkyl group or hydroxy (C ₂ -C ₄ ).
It is an alkyl group, and one of the bonding positions of R ₂₂ and R ₃₂ is 2
Position, the other bonding position is the 4-position, and R ₄₂ , R ₅₂ and R ₆₂ are all hydrogen atoms, or any two of them are taken together to form a C ₁ -C ₂ alkyl group. Formed,
The compound and the physiologically acceptable acid addition salt thereof with the rest being hydrogen atoms can be mentioned.

The most preferable one is the following general formula (I-3). (In the formula, R ₁₃ is methyl group, ethyl group, n-propyl group, n-
It means a butyl group, an n-pentyl group or a 2-hydroxyethyl group, and R ₃₃ means a hydrogen atom or a fluorine atom. ) And a physiologically acceptable acid addition salt thereof.

Specific examples of the most preferable compound include 2- (4-methyl-1-piperazinyl) -4- (4-fluorophenyl)
-5,6,7,8,9,10-Hexahydrocycloocta [b] pyridisi, 2- (4-methyl-1-piperazinyl) -4- (2,4-
Difluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridici, 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] pyridici, 2- (4-n-propyl-1-piperazinyl) -4-
(4-Fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridici, 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 and 2- [4- (2-hydroxyethyl) -1-piperazinyl] -4- (4- Fluorophenyl) -5,6,7,8,9,10-
Hexahydrocycloocta [b] pyridine as well as their physiologically acceptable acid addition salts are mentioned.

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

(1) The compound (I) of the present invention has the general formula (II) (In the formula, X means a leaving atom or a leaving group, R, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and n have the same meanings as above. ) And a compound represented by the general formula (III) (Wherein R ₁ , R ₇ , R ₈ and m have the same meanings as described above.) And can be produced.

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

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

Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ketones such as methyl ethyl ketone, ethers such as dioxane and diglyme, alcohols such as ethanol, isopropyl alcohol and butanol, N, N. -Dimethylformamide, dimethylsulfoxide. This reaction is preferably carried out in the presence of a base. Specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, and primary solvents such as triethylamine. Examples thereof include triamines, but an excess amount of the compound represented by the general formula (III) can also be used. In addition, when the chemical compound represented by the general formula (III) exists in the form of a hydrate, it can be used in that form. The reaction temperature is usually 40 to 200 ° C. Raw compound (I
I) can be produced by the method shown in Reference Examples 1 to 98 or a method analogous thereto.

(2) The compound (I) of the present invention in which R ₁ is a hydrogen atom is
General formula (I-4) (In the formula, R ₁₄ represents a lower alkyl group, a lower alkoxy group or a benzyl group which may be substituted with a halogen atom, or a benzyloxycarbonyl group, _{R, R 2, R 3,} R 4, R 5, R 6, R 7, R 8, m and n mean the same thing supra. ) The compound represented by can be produced by hydrogenolysis.

The hydrogenolysis of the compound represented by the general formula (I-4) can be carried out by a conventional method, for example, by using an alcohol such as ethanol as a solvent and carrying out catalytic reduction at room temperature and atmospheric pressure. . The compound of the present invention represented by the general formula (I-4) can be produced by the production method of (1) or the compound (I-4) of the present invention in which R ₁₄ is a benzyloxycarbonyl group:
It can be obtained by a conventional method from the compound (I) of the present invention in which R ₁₄ is a methyl group or an optionally substituted benzyl group.

(3) The compound (I) of the present invention in which R ₁ is a hydrogen atom also has the general formula (I-5) (In the formula, R ₁₅ represents an ethoxycarbonyl group, a 1-chloroethoxycarbonyl group or an acyl group, _{R, R 2, R 3,} R 4, R 5, R 6, R 7, R 8, m and n mean the same thing supra. ) It can also be produced by hydrolyzing a compound represented by.

Hydrolysis of the compound represented by the general formula (I-5) is carried out by a conventional method, for example, using a suitable solvent such as ethanol miscible with water, a base such as sodium hydroxide or potassium hydroxide, or hydrochloric acid, sulfuric acid or the like. It can be carried out by heating usually in the presence of the acid. A compound of the formula (I-5) in which R ₁₅ is a 1-chloroethoxycarbonyl group can also be converted into a compound of the formula (I) in which R ₁ is a hydrogen atom by heating in, for example, methanol. In the compound of the formula (I-5) in which R ₁₅ is an ethoxycarbonyl group or a 1-chloroethoxycarbonyl group, R ₁₅ may be a methyl group or a phenyl moiety substituted with a lower alkyl group, a lower alkoxy group or a halogen atom. It can be obtained by reacting the compound (I) of the present invention, which is a good benzyl group, with the corresponding chloroformates according to a conventional method. The compound of the present invention in which R ₁₅ is an acyl group in formula (I-5) can be obtained by the production method of (1).

(4) In the formula (I), R ₁ is a group other than a hydrogen atom, an aryl group which may have a substituent, a heteroaryl group and an acyl group. (In the formula, _{R, R 2, R 3,} R 4, R 5, R 6, R 7, R 8, m and n mean the same thing supra. ) And a compound represented by the general formula (IV) R ₁₆ -Z (IV) (wherein Z represents a reactive ester residue of an alcohol, R ₁₆ may have a hydrogen atom or a substituent, A good aryl group, a heteroaryl group, and an acyl group, which means the same as the above-mentioned R ₁ ).

Examples of the reactive ester residue of alcohol represented by Z in the above formula (IV) include halogen atom such as chlorine, bromine and iodine, lower alkylsulfonyloxy group such as methanesulfonyloxy, benzenesulfonyloxy, p -Arylsulfonyloxy groups such as toluenesulfonyloxy.

The reaction between the compound represented by the general formula (I-6) and the compound represented by the general formula (IV) is usually carried out in a suitable solvent, and specific examples of the solvent include benzene and xylene. Aromatic hydrocarbons, ketones such as methyl ethyl ketone, ethers such as dioxane, and N, N-dimethylformamide. This reaction is preferably carried out in the presence of a base, and specific examples of the base include the specific examples described in the production method part (1) as they are. The reaction temperature is usually 30 to 150 ° C.

The compound of this example represented by the general formula (I-6) is
It can be obtained by the production methods (1) to (3).

Further, some of the compounds of the compound (I) of the present invention can be produced by the methods shown below.

The compound of the present invention in which R ₁ is a methyl group can be produced by reacting the compound of the present invention in which R ₁ is a hydrogen atom with formic acid and formalin.
This is specifically shown in III.

The compound of the present invention in which R ₁ is an acyl group can be produced by reacting the compound of the present invention in which R ₁ is a hydrogen atom with a corresponding carboxylic acid or a reactive derivative thereof. Example 128 is specifically shown.

The compound of the present invention in which R ₁ is an acyloxy (lower) alkyl group can be produced by reacting the compound of the present invention in which R ₁ is a hydroxy (lower) alkyl group, with a corresponding acid anhydride, This method is concretely shown in Example 139 described later.

The compound of the present invention in which R ₂ or R ₃ is a hydroxy group can be produced by hydrolyzing the compound of the present invention in which R ₂ or R ₃ is a lower alkoxy group with hydrobromic acid. The method is specifically shown in Example 130 described later.

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

The compound of the present invention represented by the general formula (I) can be obtained in the form of a free base, an acid addition salt or a hydrate depending on the selection of starting compounds, reaction and treatment conditions and the like. The acid addition salt can be converted to the free base by a conventional method, for example, by treating with a base such as alkali hydroxide. On the other hand, the free base can be converted into an acid addition salt by treating it with various acids according to a conventional method.

The compound of the present invention represented by the general formula (I) and a physiologically acceptable acid addition salt thereof have an effect of suppressing exploratory behavior, an effect of suppressing apomorphine-induced emesis, dopamine D ₂ or serotonin.
Since it exhibits an S ₂ receptor binding action, an action of increasing monoamine metabolites in the brain, and low toxicity, it is useful as an antipsychotic agent or anxiolytic agent. Furthermore, it shows an excellent improving effect in various memory impairment model experiments, and is useful as a brain function improving agent for various functional disorders in the central nervous system.

Strong inhibitory effect on apomorphine-induced vomiting, serotonin S ₂ ,
Examples of the compound exhibiting dopamine D ₂ receptor binding action or dopamine metabolite increasing action include the following compounds and physiologically acceptable acid addition salts 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-fluorophenyl) -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-5
H-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-5
H-6,9-methanocyclohepta [b] pyridine and (17) 2- (4-ethyl-1-piperazinyl) -4-
(4-Fluorophenyl) -6,7,8,9-tetrahydro-5
H-5,8-methanocyclohepta [b] pyridine Compounds having excellent improving effects on behavioral disorders and memory disorders induced by scopolamine and cycloheximide include, for example, the following compounds and physiologically acceptable compounds thereof. Acid addition salts may be mentioned.

(1) 2- (1-piperazinyl) -4-phenyl-6,
7-dihydro-5H-1-pyrindine, (2) 2- (1-piperazinyl) -4- (4-fluorophenyl) -6,7-dihydro-5H-1-pyrindine, (3) 2- (1- Piperazinyl) -4-phenyl-5,
6,7,8-Tetrahydroquinoline, (4) 2- (1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8-tetrahydroquinoline and (5) 2- (1-piperazinyl) -4- (4-Fluorophenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine The results of pharmacological experiments on representative compounds of the present invention are shown below, and the compounds of the present invention are shown. Clarify the usefulness of.

Test Example 1 Inhibitory Behavior Inhibitory Action Five Std-ddY male mice each weighing 20 to 25 g were used in each group. Oral administration of test compound suspended in 0.5% tragacanth (10 mg / kg), and 2 hours later, one mouse at a time in a cage (23 × 35 × 30c) on Animex momentum measuring device (Farad).
m), and the amount of exploratory activity for 3 minutes was measured. The amount of exploratory behavior of the test compound administration group was measured. The average value of the search activity amount (count / 3 minutes) of the test compound administration group was calculated, and compared with that of the control group to calculate the inhibition rate. The results are shown in Table 1.

Test Example 2 Inhibitory Effect of Apomorphine on Vomiting Using 3 to 4 Beagle dogs (8-15 kg) per group, the antagonistic effect of the test compound on apomorphine-induced vomiting was examined. This test is commonly used as a method for detecting antipsychotic agents.

Two hours after oral administration of the test compound, apomorphine hydrochloride (0.
3 mg / kg) was subcutaneously administered to the back, and the number of vomiting for 1 hour was counted thereafter. The suppression rate was calculated by comparing the vomiting frequency of the test compound administration group with that of the control group. The results are shown in Table 2.

Test Example 3 Dopamine D ₂ , Serotonin S ₁ , S ₂ and Adrenergic α ₁ Receptor Binding Action (In Vitro Receptor Binding Assay) I. Creese et al. [Eur. J. Pharmacol., 46 , 377 (1977)],
SJPeroutka et al. [Mol.Pharmacol., 16 , 687 (1979)], JELeysen et al [Mol.Pharmacol., 21 , 301 (1982)] and DCU'Prichard et al [Mol.Pharmacol., 13 , 454 (1).
977).] And dopamine D ₂ ,
Serotonin S ₁ , S ₂ and adrenergic α ₁ receptor binding tests were performed.

A crude synaptosome membrane fraction prepared from rat brain was used as a receptor sample, and [ ³ H] spiperone (D ₂ ), [ ³ H] serotonin (S ₁ ), and [ ³ H] ketanserin (S ₂ ) were used as labeled ligands. ) And [ ³ HWB-4101 (α ₁ ). After incubating a receptor sample and a buffer solution containing each labeled ligand (final volume: 1 ml) for a certain period of time in the presence of various concentrations of test compounds, the radioligand bound to the receptor was used with a cell harvester (Brandell). Separated on a filter. The radioactivity on the filter was measured with a liquid scintillation counter to determine the total amount bound. In addition, unlabeled ligands [spiperone (D ₂ ), serotonin (S ₁ ), methysergide (S ₂ ) were measured simultaneously.
And prazosin (α ₁ )] in the presence of excess, the amount of specific binding was determined by subtracting this amount from the total amount of binding. The concentration at which the test compound inhibits the specific binding of the labeled ligand by 50% (IC ₅₀ value) was calculated by the probit method, and the results are shown in Table 3.

Test Example 4 Brain Monoamine Metabolite Increasing Action Using 5 male Std-ddY mice (25-30 g) per group, the brain monoamine metabolite increasing action of the test compound was examined.
This effect is believed to primarily represent the degree of receptor inhibition of each monoamine.

Two hours after oral administration of the test compound, the brain was removed and 1N formic acid-
After homogenizing with acetone, it was cooled and spun down to obtain a supernatant. This was evaporated to dryness with nitrogen gas, dissolved in 0.01N acetic acid, and analyzed by high-performance liquid chromatography with an electrochemical detector, 3,4-dihydroxyphenylacetic acid (DOPAC), a metabolite of dopamine, and homovanillic acid ( HVA), 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), a metabolite of noradrenaline, and 5-hydroxyindole-3-acetic acid (5-HIAA), a metabolite of serotonin, were measured. The% increase of each monoamine metabolite (control = 100) was calculated by the test compound and is shown in Table 4.

Test Example 5 Inhibitory effect of hyperactivity induced by scopolamine Using 5 male Std-ddY mice (22-28 g) per group, the antagonistic effect of the test compound on hyperactivity induced by scopolamine was examined. In this test, a compound having an acetylcholine nerve activating action or a central nerve depressant action shows a positive effect.

The test compound was orally administered to the mice, and 90 minutes later, each mouse was placed in a measuring cage (25 × 35 × 30 cm). Thirty minutes after that, scopolamine hydrobromide (1 mg / kg) was intraperitoneally administered, and immediately after that, the exercise amount for 30 minutes was measured by an Animex exercise amount measuring device. When scopolamine hyperkinesia was completely antagonized, the percentage of antagonism of each test compound was calculated as 100%. The results are shown in Table 5.

Test Example 6 Ameliorating Effect of Scopolamine-Induced Spontaneous Alternation Behavior Disorder The effect of the test compound was examined by using a scopolamine spontaneous alternation disorder model as a model of memory disorder based on hypofunction of acetylcholine nerve function.

1 group of 15 to 25 Std-ddY male mice (22-28 g) were intraperitoneally administered with scopolamine hydrobromide (1 mg / kg) and the test compound, and 30 minutes later, the T maze (passage width 5 cm, 25 cm long,
At the height of 10 cm, guillotine doors were installed at the entrances of the start box and the left and right goal boxes), the left and right goal box selection trials were performed eight times in succession. Mice have an oral habit of alternately selecting left and right goal boxes, but scopolamine-treated animals increase the number of times they enter the same goal box as the previous trial (spontaneous alternation behavior disorder). When the spontaneous alternation behavior disorder was improved to a normal level, it was regarded as 100%, and the% improvement effect of each test compound was calculated. The results are shown in Table 6.

Test Example 7 Cycloheximide-induced improvement of passive avoidance reaction disorder Cycloheximide is known to cause amnesia in animals. Therefore, the effect of the test compound on the amnestic effect of cycloheximide was examined using the passive avoidance reaction of mice as an index.

Step-down type passive avoidance reaction measuring device (30 × 30 × 50) using 15 to 20 Std-ddY male mice (27-33 g) per group
cm, and a platform of 4 × 4 × 4 cm was installed in the center of the floor of the grid) for training and holding trials. In the training trial, the mouse was placed on the platform, and the shock shock (1 Hz, 0.
5sec, 60VDC) was given. In the retention trial (24 hours after training), the mouse was placed on the platform again and the time to step onto the floor grid (step-down latency) was measured. Cycloheximide (60 mg / kg, sc) as well as test compound (ip) were administered immediately after the end of the training trial. Animals treated with cycloheximide have significantly reduced step-down latencies in retention trials (amnestic effect). When the reduction in latency was improved to a normal level, it was defined as 100%, and the% improvement effect of each test compound was calculated. The results are shown in Table 7.

Test Example 8 Acute toxicity A group of 5 male Std-ddY mice (25-30 g) was used.
A test compound dissolved or suspended in a 5% tragacanth solution was orally administered, and the death was observed for 7 days after the administration. The results are shown in Table 8.

The administration route of the compound of the present invention may be oral administration, parenteral administration or rectal administration, but oral administration is preferred. The dose will vary depending on the type of compound, administration method, patient symptoms and age, etc., but is usually 0.01 to 50 mg / kg / day,
It is preferably 0.01 to 5 mg / kg / day. The compound of the present invention is usually administered in the form of preparation prepared by mixing with a carrier for preparation. As the carrier for formulation, a substance which is commonly used in the field of formulation and which does not react with the compound of the present invention is used. Specifically, for example, lactose, glucose, mannitol, sorbitol, dextrin, cyclodextrin, starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl cellulose calcium, ion Exchange resin, methylcellulose, gelatin, gum arabic, pullulan, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, tragacanth, bentonite, veegum,
Carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin,
Examples thereof include fatty acid glycerin ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propylene glycol and water.

Examples of dosage forms include tablets, capsules, granules, fine granules, powders, syrups, suspensions, injections and suppositories. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another suitable medium before use. The tablets, granules and fine granules may be coated by a known method. In the case of an injectable preparation, it is prepared by dissolving the compound of the present invention in water, but it may be dissolved in physiological saline or glucose solution, if necessary, and a buffer or a preservative may be added. Good. These formulations may also contain other therapeutically valuable ingredients.

In order to explain the present invention more specifically, the following reference examples,
Examples and formulation examples are given, but the present invention is not limited to these examples and the like. The compounds are identified by elemental analysis, mass spectrum, IR spectrum, UV spectrum, N
It was performed by MR spectrum and the like. In addition, the following abbreviations may be used for simplification of description in the following Reference Examples and Examples.

Me: methyl group Et: ethyl group Pr: n-propyl group t-Bu: tert- butyl group Ph: phenyl group 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 WT: Water The solvent in parentheses shown at the melting point in Reference Examples and Examples is recrystallized. Means a solvent.

Reference Example 1 Preparation of 4-phenyl-5,6,7,8-tetrahydro-2 (1H) -quinolinone: A mixture of 25 g of benzoylacetonitrile, 25 g of cyclohexanone and 250 g of 75% polyphosphoric acid at 50 ° C. for 30 minutes at 110 ° C.
Stir for 1.5 hours. After cooling, the reaction solution is poured into ice water, 300 ml of diethyl ether is added, the mixture is stirred, and the precipitated crystals are collected by filtration. Recrystallization from N, N-dimethylformamide-ethanol gives 27 g of the desired product.

Melting point 285 to 288 ° C. Reference Examples 2 to 46 Using the corresponding starting compounds, reaction and treatment were carried out in the same manner as in Reference Example 1 to obtain the compounds shown in Tables 9 and 10.

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] Octane-2-one (2 g) and 4-fluorobenzoylacetonitrile (2.6 g) were dissolved in 1,1,2,2-tetrachloroethane (5 ml), 75% polyphosphoric acid (25 g) was added, and the mixture was heated at 80 ° C for 30 minutes at 100 ° C. Stir for 1 hour at 130 ° C for 30 minutes. After cooling, the reaction solution is poured into ice water, neutralized with potassium carbonate, and the precipitated crystals are collected by filtration. The crystals are washed with water and then with ethyl acetate and then recrystallized from methanol to obtain 2.7 g of the desired product.

Melting point 300 ° C or higher Reference Example 48 Preparation of 4- (4-fluorophenyl) -1,5,6,7,8,9-hexahydro-2H-5,8-methanocyclohepta [b] pyridin-2-one: The target compound is obtained by reacting and treating in the same manner as in Reference Example 47 using the corresponding starting material compound.

Reference Example 49 4- (4-fluorophenyl) -3-methyl-5,6,7,8,
9,10-Hexahydrocycloocta [b] pyridine-2-
Production of On: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Reference Example 1 to obtain the target product.

Melting point 268 to 272 ° C (ethanol) Reference Example 50 Preparation of 4- (2-thienyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridin-2-one: Corresponding raw material compound Is used and reacted and treated in the same manner as in Reference Example 1 to obtain the desired product.

Melting point 222 to 227 ° C. (methyl ethyl ketone) Reference Example 51 2-chloro-4- (4-fluorophenyl) -5,6,7,8
-Production of tetrahydroquinoline: A mixture of 18.7 g of 4- (4-fluorophenyl) -5,6,7,8-tetrahydro-2 (1H) -quinolinone and 29 ml of phenylphosphonic dichloride is stirred at 170 ° C for 1 hour. . After cooling
The reaction solution was dissolved in 200 ml of chloroform, added dropwise to stirring ice water for about 30 minutes, and concentrated ammonia water was gradually added to form a basic solution.The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure. The residue is recrystallized from isopropyl alcohol-petroleum ether to obtain 15.1 g of the desired product.

Reference Examples 52 to 96 Using the corresponding starting material compounds, the same reaction and treatment as in Reference Example 51 were performed to obtain the compounds shown in Tables 11 and 12.

Reference Example 97 Preparation of 2-chloro-4- (4-fluorophenyl) -3-methyl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: Using the corresponding starting compound, Reaction and treatment are carried out in the same manner as in Reference Example 51 to obtain the desired product.

Melting point 107-108 ° C (methanol-water) Reference Example 98 Preparation of 2-chloro-4- (2-thienyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: Corresponding The starting compound is reacted and treated in the same manner as in Reference Example 51 to obtain an oily target product.

Example 1 Preparation of 2- (4-Ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: 2-chloro -4- (4-fluorophenyl) -5,6,7,8,
9,10-Hexahydrocycloocta [b] pyridine 2.0g, N
-A mixture of 2.4 g of ethylpiperazine and 1.1 g of potassium iodide is stirred at 170 ° C for 5 hours. After cooling, the reaction solution was dissolved in ethyl acetate and water, the organic layer was washed with water, and then extracted with 5% hydrochloric acid,
The mixture is made basic with potassium carbonate, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

(A) Recrystallization of the residue from acetonitrile to give the desired product 1.
Get 2g.

Melting point 123-124 ° C. This is treated with various acids to obtain various salts of the target compound obtained in (a).

(B) Dimaleic acid salt, melting point 165-167 ° C (ethanol) (c) Dihydrochloride / hemihydrate, melting point 215-222 ° C (acetone) (d) Fumarate, melting point 228-230 ° C (e) Quen Acid salt Melting point 184 to 187 ° C (ethanol) Example 2 2- (4-Ethyl-1-piperazinyl) -4- (2,4-
Preparation of difluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: 2-chloro-4- (2,4-difluorophenyl) -5,6,
7,8,9,10-Hexahydrocycloocta [b] pyridine 10
A mixture of 11 g of g, N-ethylpiperazine and 5.4 g of potassium iodide is stirred at 170 ° C. for 5 hours. After cooling, the reaction solution is dissolved in chloroform and a 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 was dissolved in toluene and subjected to column chromatography using silica gel. The fractions eluted with toluene and toluene-ethyl acetate (1: 1) were collected and recrystallized from isopropyl alcohol to obtain 5.5 g of the desired product. To get

Melting point: 124-125 ° C (b) The desired product obtained in (a) is treated with an ethanol solution of maleic acid to obtain the desired dimaleate salt. Melting point 133-135 ° C (ethanol) Example 3 Preparation of 2- (4-ethyl-1-piperazinyl) -4-phenyl-5,6,7,8-tetrahydroquinoline: 2-chloro-4-phenyl-5, A mixture of 1.0 g of 6,7,8-tetrahydroquinoline, 1.2 g of N-ethylpiperazine and 0.66 g of potassium iodide is stirred at 170 ° C. for 15 hours. After cooling, the reaction solution 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 residual oily substance was subjected to column chromatography using basic alumina, and the fractions eluted with toluene and toluene-ethyl acetate (9: 1) were collected and converted to a maleate salt with an ethanol solution of maleic acid, followed by ethanol. Recrystallized from ethyl acetate, the desired dimaleate salt
Obtain 0.45 g. Melting point 139 to 142 ° C. Examples 4 to 77 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the compounds shown in Tables 13 and 14.

Examples 78 to 85 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the following compounds.

Example 78 2- (4-Methyl-1-homopiperazinyl) -4- (4
-Fluorophenyl) -6,7,8,9-tetrahydro-5H-
Cyclohepta [b] pyridine maleate: Melting point 187-189 ° C. (ethanol) (Example 79) 2- (4-butyryl-1-homopiperazinyl) -4-
(4-Fluorophenyl) -6,7,8,9-tetrahydro-5
H-cyclohepta [b] pyridine: oily substance (Example 80) 2- (4-methyl-1-homopiperazinyl) -4- (4
-Fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine dimaleate salt: melting point 141-143 ° C (ethanol) (Example 81) 2- (4-benzoyl- 1-homopiperazinyl) -4-
(4-Fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: oily substance (Example 82) 2- [4- (2-methoxyethyl) -1-piperazinyl ] -4- (4-Fluorophenyl) -5,6,7,8,9,10-
Hexahydrocycloocta [b] pyridine dimaleate: mp 119-120 ° C (acetonitrile) (Example 83) 2- (3-methyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6 , 7,8,9,10-Hexahydrocycloocta [b] pyridine: Melting point 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: Melting point (decomposition) 262-266 ° C (methanol) (Example 85) 2 -(1-Homopiperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine maleate: melting point 198-200 ° C (ethanol) Example 86 2- (1-Piperazinyl) -4-phenyl-5,6,7,8-
Preparation of tetrahydroquinoline: 2- (4-benzyl-1-) obtained in the same manner as in Example 3.
Piperazinyl) -4-phenyl-5,6,7,8-tetrahydroquinoline (melting point 105-107 ° C) 2.1 g, 1-chloroethyl chloroformate 0.86 g and methylene chloride 40 ml were heated under reflux for 1 hour and then under reduced pressure. Concentrate. Methanol in the residue
After adding 40 ml and heating under reflux for 30 minutes, concentrate under reduced pressure.
The residue is dissolved in water, washed with diethyl ether, neutralized with potassium carbonate, and extracted with chloroform. After washing with water and drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. To the residue is added maleic acid in ethanol to give a maleate salt, which is then recrystallized from ethanol to produce the desired dimelate salt.
Get 1.2g. Melting point 150 to 151 ° C. Examples 87 to 110 Using the corresponding starting materials, the reaction and treatment were carried out in the same manner as in Example 86 to obtain the compounds shown in Tables 15 and 16.

Example 111 Preparation of 2- (4-methyl-1-piperazinyl) -4- (4-fluorophenyl) -6,7-dihydro-5H-1-pyrindine: 2- (1-piperazinyl) -4- (4 A mixed article of -fluorophenyl) -6,7-dihydro-5H-1-pyrindine 2g, 37% formalin 0.66g, formic acid 0.68g and water 15ml is heated to reflux for 20 minutes. After cooling, the reaction solution is made basic with dilute aqueous sodium hydroxide solution and extracted with ethyl acetate. Wash with water, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. An ethanol solution of maleic acid is added to the residue to give a maleate salt, which is recrystallized from ethanol to obtain the desired maleate salt. Melting point 135 to 137 ° C. Examples 112 to 117 Reactions were performed in the same manner as in Example 111 using the corresponding starting compounds.
Treatment gives the following compound:

Example 112 2- (4-Methyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine dimaleate : Melting point 136 to 138 ° C (ethanol) (Example 113) 2- (4-methyl-1-piperazinyl) -4- (4-methylphenyl) -5,6,7,8,9,10-hexahydrocyclo Octa [b] pyridine dimaleate: melting point 152-154 ° C. (ethanol) (Example 114) 2- (4-methyl-1-piperazinyl) -4- (2,4-
Difluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: melting point 132-133 ° C (ethanol) (Example 115) 2- (4-methyl-1-piperazinyl)- 4- (4-fluorophenyl) -6-methyl-5,6,7,8-tetrahydroquinoline dimaleate: melting point 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: melting point 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: mp 208-210 ° C (methanol-ethanol) Example 118 2- (4-n-propyl-1-piperazinyl) -4-
Preparation of (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: 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.
A mixture of 68 g, potassium iodide 0.1 g and methanol 50 ml was added.
Heat at reflux for 15 hours. The reaction solution is concentrated under reduced pressure, water is added, the mixture is extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. An ethanol solution of maleic acid is added to the residue to give a maleate salt, which is then recrystallized from ethanol to obtain 0.6 g of the desired dimaleate salt.

Melting point 149-152 ° C Examples 119-126 Reactions were carried out in the same manner as in Example 118 using the corresponding starting compounds.
Treatment gives the compounds shown in Table 17.

Example 127 2- (4-n-propyl-1-piperazinyl) -4-
Production of (2,4-difluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: Reaction was carried out in the same manner as in Example 118 using the corresponding starting compound.
Process to obtain the desired product.

Melting point 108-109 ° C (ethanol) Example 128 2- [4- (2-Furoyl) -1-piperazinyl] -4
Preparation of -phenyl-5,6,7,8-tetrahydroquinoline: 2- (1-piperazinyl) -4-phenyl-5,6,7,8-
Tetrahydroquinoline 1.2 g, 2-furancarboxylic acid 0.46 g,
After stirring a mixture of 40 ml of chloroform and 0.79 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride at room temperature for 2 hours, the reaction solution was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To do. The residue was dissolved in toluene, subjected to silica gel column chromatography, and the fractions eluted with toluene and toluene-ethyl acetate (9: 1) were collected and recrystallized from ethanol to give the desired product.
Get 4g.

Melting point 128-130 ° C Example 129 2- [4- (2-Furoyl) -1-piperazinyl] -4
-(4-Fluorophenyl) -6,7-dihydro-5H-1
-Production of pyrindine: using the corresponding starting compound, reacting in the same manner as in Example 128
Process to obtain the desired product.

Melting point 165-166 ° C (ethanol) Example 130 2- (4-Ethyl-1-piperazinyl) -4- (4-hydroxyphenyl) -5,6,7,8,9,10-hexahydrocycloocta [b ] Pyridine production: 2- (4-ethyl-1-piperazinyl) -4- (4-methoxyphenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine 1.3 g 48 Dissolve in 10 ml of% hydrobromic acid and stir at 120 ° C. for 2 hours. After cooling, add water, neutralize with 1N aqueous sodium hydroxide solution and sodium bicarbonate, collect the precipitate by filtration, wash with water and recrystallize from methanol to obtain 0.6 g of the desired product.
To get Melting point 250-253 ° C Example 131 2- (4-Ethyl-1-piperazinyl) -4- (2,4-
Difluorophenyl) -6,7,8,9-tetrahydro-5H-
Production of Cyclohepta [b] pyridine: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired oxalate salt / hemihydrate.

Mp 225-227 ° C (methanol) Example 132 2- (4-Ethyl-1-piperazinyl) -4- (2,4-
Production of difluorophenyl) -6,7-dihydro-5H-1-pyrindine: Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the desired maleate salt.

Melting point 195-196 ° C (ethanol) Example 133 2- (4-cyclopropyl-1-piperazinyl) -4-
Production of (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the desired product. To get

Melting point 125-128 ° C (ethanol) Example 134 2- [4- (4-fluorophenyl) -1-piperazinyl] -4- (4-fluorophenyl) -5,6,7,8,9,10-
Production of hexahydrocycloocta [b] -pyridine: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired product.

Melting point 130-131 ° C (methanol) Example 135 2- (4-Ethyl-1-piperazinyl) -4- (2,4-
Difluorophenyl) -5,6,7,8-tetrahydro-5,8-
Production of methanoquinoline: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired oxalate salt / hemihydrate.

Melting point 234-238 ° C (ethanol) Example 136 2- (cis-3,5-Dimethyl-4-methyl-1-piperazinyl) -4- (4-difluorophenyl) -6,7-dihydro-5H-1- Production of pyrindine: Reaction was carried out in the same manner as in Example 111 using the corresponding starting compound.
By treatment, the target fumarate salt ¼ hydrate is obtained.

Melting point 204-208 ° C (methanol-ethanol) Example 137 2- [4- [3- (4-fluorobenzoyl) propyl] -1-piperazinyl] -4- (4-fluorophenyl) -6,7-dihydro- Production of 5H-1-pyrindine: Reaction was carried out in the same manner as in Example 118 using the corresponding starting compound.
Process to obtain the desired product.

Melting point 115-116 ° C (ethanol) Example 138 2- [4- (3-hydroxypropyl) -1-piperazinyl] -4- (4-fluorophenyl) -5,6,7,8,9,10
-Production of hexahydrocycloocta [b] -pyridine: Reaction was carried out in the same manner as in Example 118 using the corresponding starting compound.
By processing, the desired dioxalate salt 1/4 hydrate is obtained.

Melting point 136-138 ° C (methanol) Example 139 2- [4- (2-acetoxyethyl) -1-piperazinyl] -4- (4-fluorophenyl) -5,6,7,8,9,10-
Preparation of hexahydrocycloocta [b] pyridine: 2- [4- (2-hydroxyethyl) -1-piperazinyl] -4- (4-fluorophenyl) -5,6,7,8,9,10-
A mixture of 1.5 g of hexahydrocycloocta [b] pyridine, 0.6 g of acetic anhydride, 0.7 g of triethylamine and 30 ml of ethyl acetate is heated under reflux for 2 hours. After cooling, the reaction solution is washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in toluene and subjected to column chromatography using silica gel, toluene and toluene-ethyl acetate (1:
The portion eluted in 1) is collected, an ethanol solution of maleic acid is added to give a maleate salt, and recrystallized from ethanol to obtain 0.65 g of the desired maleate salt.

Melting point 187-191 ° C Example 140 2- (4-Cyclopropylmethyl-1-piperazinyl)
Production of 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine: Reaction was carried out in the same manner as in Example 118 using the corresponding starting compound.
Process to obtain the desired product.

Melting point 109-110 ° C. (methylene chloride-hexane) Examples 141-156 Using the corresponding starting materials, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the compounds shown in Table 18.

Example 157 Preparation of 2- (4-benzyl-1-piperazinyl) -6-methyl-4-phenyl-5,6,7,8-tetrahydroquinoline: Reaction was performed in the same manner as in Example 3 using the corresponding starting compound.・ Process to obtain the desired product.

Melting point 137-138 ° C (ethanol) Example 158 2- (4-benzyl-1-piperazinyl) -6-tert-
Production of butyl-4-phenyl-5,6,7,8-tetrahydroquinoline: Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the desired product.

Melting point 141-142 ° C (ethanol) Example 159 2-[(4-fluorobenzyl) -1-piperazinyl]
-4- (4-fluorophenyl) -6,7-dihydro-5H
-Production of pyrindine: using the corresponding starting compound, reacting in the same manner as in Example 118
By treatment, the desired dimaleate salt is obtained. Melting point 164-167
C. (Ethanol) Example 160 2- (4-Ethyl-1-piperazinyl) -4- (4-fluorophenyl) -3-methyl-5,6,7,8,9,10-hexahydrocycloocta [b ] Production of Pyridine: Using the corresponding starting compound, the reaction and treatment are carried out in the same manner as in Example 3 to obtain the desired product.

Melting point 125-126 ° C (acetonitrile) Example 161 2- (4-Ethyl-1-piperazinyl) -4- (2-thienyl) -5,6,7,8,9,10-hexahydrocycloocta [b] Production of Pyridine: Using the corresponding starting compound, the reaction and treatment were carried out in the same manner as in Example 3 to obtain the target 3/2 oxalate 1/5 hydrate. Melting point
163-167 ° C (Ethanol) Formulation Example 1 Capsule 2- (4-Ethyl-1-piperazinyl) -4- (4-fluorophenyl) -6,7,8,9-tetrahydro-5H-cyclohepta [b] pyridine・ Dimaleate ……………… 5g Corn starch ……………… 57g Lactose …………… 10g Crystalline cellulose …………… 25g Hydroxypropylcellulose …………… 2g Light anhydrous silicic acid ………… 0.5 g Magnesium stearate 0.5 g According to a conventional method, the above ingredients are mixed and granulated into 1000 capsules to prepare 100 mg capsules.

Formulation Example 2 Tablet 2- (4-Ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine dimaleate ... ………… 5g Corn starch ……………… 20g Lactose ……………… 30g Crystalline cellulose ……………… 30g Hydroxypropyl cellulose ……………… 5g Low-substituted hydroxypropyl cellulose ……………… 10g According to the method, the above components are mixed and granulated, and then light anhydrous silicic acid and magnesium stearate are added, and then tablets each containing 5 mg of the active ingredient are prepared.

Formulation Example 3 Powder 2- (4-ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine dimaleate ... ………… 5g Corn starch ………… 173g Lactose ………… 300g Hydroxypropylcellulose ………… 20g According to the usual method, after mixing, granulating and sizing the above ingredients, light anhydrous silicic acid was added. Add an appropriate amount and mix up to 100 times.

Formulation Example 4 Injection 2- (4-Ethyl-1-piperazinyl) -4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine dimaleate …………… 5g D-sorbitol ………… 45g 1N Maleic acid or 1N sodium hydroxide aqueous solution ………… Amount of distilled water for injection ……………… Amount of total 1000ml Main drug and D-sorbitol for injection Mix with distilled water, 1N
After dissolving by adding maleic acid or 1N sodium hydroxide aqueous solution and adjusting the pH to 4.0, filter through a membrane filter with a pore size of 0.22 μm, fill each 10 ml ampoule, melt and sterilize by high pressure steam sterilization at 121 ° C for 20 minutes. , Manufacture solution casting.

Formulation Example 5 Lyophilizer 2- (4-Ethyl-1-piperazinyl) -4- (4-fluorophenyl) 5,6,7,8,9,10-hexahydrocycloocta [b] pyridine dimaleate …………… 5g D-mannitol ………… 45g 1N maleic acid or 1N sodium hydroxide aqueous solution ………… Amount of distilled water for injection ………… Amount of total 1000ml Main drug and D-mannitol for injection Mix with distilled water, 1N
After dissolving by adding maleic acid or 1N sodium hydroxide aqueous solution and adjusting the pH to 4.0, filter through a membrane filter with a pore size of 0.22 μm, fill each vial with 10 ml and half-cap the rubber stopper, then pre-freeze, − Temporary drying at 50 ° C, secondary drying at -20 ° C, freeze-drying under conditions of 20 ° C, capping in the chamber, taking out, and flip-off cap to produce a freeze-dried preparation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 401/12 213 239 405/12 215 221 409/04 221 (72) Inventor Kiyoshi Furukawa Shiga Shiga Prefecture 2-12-4 Onomizuaki, Shiga-gun, Gunma (72) Inventor Yoshiaki Ochi 4-7 Fujigaoka, Sanda City, Hyogo Prefecture 17

Claims (7)

[Claims] 1. A general formula [In the formula, n means 3, 4, 5, 6 or 7, Is an aryl group or a heteroaryl group, R is a hydrogen atom or a lower alkyl group, R ₁ is a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a lower alkoxy (lower) alkyl group ，
Cycloalkyl (lower) alkyl group, optionally substituted aryl (lower) alkyl group, acyloxy (lower) alkyl group, lower alkanoyl (lower) alkyl group, optionally substituted arylcarbonyl (Lower) alkyl group, lower alkenyl group, lower alkynyl group, optionally substituted aryl group, heteroaryl group or acyl group, wherein R ₂ and R ₃ are the same or different and each is a hydrogen atom, halogen atom,
A lower alkyl group, a lower alkoxy group, a hydroxy group, a trifluoromethyl group, a cyano group, a nitro group or an amino group, and R ₄ , R ₅ and R ₆ are the same or different and each is a hydrogen atom,
Means a lower alkyl group or a phenyl group, or
Any two of R ₄ , R ₅ and R ₆ together form a single bond or a lower alkylene group, and the rest represent a hydrogen atom, a lower alkyl group or a phenyl group, and R ₇ and R ₈ Are the same or different and each is a hydrogen atom or a lower alkyl group, and m is 2 or 3. ] The pyridine derivative represented by these, or its physiologically acceptable acid addition salt. 2. General formula [In the formula, n ₁ means 3, 6 or 7, and R ₁₁ is a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₃ -C ₆ cycloalkyl group, a hydroxy (C ₂ -C ₄ ) alkyl group, C ₁ -C ₂ Alkoxy (C ₂ -C ₃ ) alkyl group or allyl group, R
₂₁ and R ₃₁ are the same or different and represent a hydrogen atom or a fluorine atom, and R ₇₁ and R ₈₁ are the same or different and represent a hydrogen atom or a C ₁ -C ₃ alkyl group. ] The pyridine derivative represented by these, or its physiologically acceptable acid addition salt. 3. General formula [In the formula, n ₂ means 4 or 5, and R ₁₂ is a hydrogen atom, a C ₁ -C ₈ alkyl group, a C ₃ -C ₈ cycloalkyl group, a hydroxy (C ₂ -C ₄ ) alkyl group, C ₁ -C ₂ alkoxy (C ₂ -C ₃ ) means an alkyl group or an allyl group, R
₂₂ and R ₃₂ are the same or different and represent a hydrogen atom or a fluorine atom, and R ₄₂ , R ₅₂ and R ₆₂ are the same or different and are a hydrogen atom or C ₁
-C ₄ or refers to an alkyl group, or C ₁ -C ₂ form an alkylene group any two of these together, the rest is a hydrogen atom or a C ₁ -C ₄ alkyl group. ] The pyridine derivative represented by these, or its physiologically acceptable acid addition salt. 4. A general formula (In the formula, R ₁₃ is methyl group, ethyl group, n-propyl group, n-
It means a butyl group, an n-pentyl group or a 2-hydroxyethyl group, and R ₃₃ means a hydrogen atom or a fluorine atom. ) A pyridine derivative represented by or a physiologically acceptable acid addition salt thereof. 5. 2- (4-Ethyl-1-piperazinyl)-
4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine or a physiologically acceptable acid addition salt thereof. 6. A psychotropic agent comprising the pyridine derivative according to any one of claims (1) to (5) or a physiologically acceptable acid addition salt thereof as an active ingredient. 7. 2- (4-Ethyl-1-piperazinyl)-
An antipsychotic agent comprising 4- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocycloocta [b] pyridine or a physiologically acceptable acid addition salt thereof as an active ingredient.