JPH04103572A - 4-phenyl-2-(1-piperazinyl)pyridine derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [X is CH2CO, CH2CH(OH) or CH=CH; R1 is lower alkyl; R<2> and R3 are H, halogen, lower alkyl or lower alkoxy (n) is 1-4] and a salt thereof. EXAMPLE:2-(4-Ethyl-1-piperazinyl)-4-(4-fluorophenyl)-10-hydroxy-5,6,7, 8,9,10- hexahydrocycloocta[b]pyridine. USE:A medicine having excellent psychotropic action and inhibitory action on central nervous system. PREPARATION:A compound shown by formula II (Y is halogen) is made to react with a piperazine compound shown by formula III in a solventless state or in a solvent (e.g. dimethyl sulfoxide) preferably in the presence of a base (e.g. triethylamine) at 40-200 deg.C to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel and useful 4-phenyl-2-(1-piperazinyl)pyridine derivatives having psychoactive effects and the like.

OBJECTS OF THE INVENTION The present invention provides 4-phenyl-2-(1-piperazinyl) fused pyridine derivatives having excellent psychotropic effects, particularly central nervous system depressant effects.

Structure and Effects of the Invention According to the present invention, general formula (I) [wherein X is a group: -CHICo-, -CH2Cl(O
H)- or -CH=CH-, R1 means a lower alkyl group, R2 and R3 are the same or different and mean a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, n means an integer from 1 to 4. ] 4-phenyl-2-(1-piperazinyl)pyridine derivatives and salts thereof are provided.

The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as inorganic acid salts such as hydrochloride, hydroiodide, sulfate, phosphate, and citrate. ,
Examples include organic acid salts such as maleate, fumarate, tartrate, benzoate, lactate, and methanesulfonate.

Since the compound of formula (I) and its salts may exist in the form of hydrates or solvates, these hydrates and solvates are also included in the compounds of the present invention.

When the compound represented by formula (1) has an asymmetric carbon atom, there exist at least two types of stereoisomers. These stereoisomers, mixtures thereof, and racemates are included in the present invention. Included in compounds.

Terms used in this specification will be explained below.

"Lower" means 1 to 6 carbon atoms, unless otherwise specified.
means. The lower alkyl group or lower alkyl moiety may be linear or branched. Examples of "lower alkyl groups" include methyl and ethyl.

Examples include propyl, isopropyl, butyl, pentyl, hexyl, etc. "Halogen atoms" include fluorine,
Examples include chlorine, bromine, and iodine.

An example of a "lower alkoxy group" is methoxy.

Examples include ethoxy, propoxy, isopropoxy, butoxy and the like.

Compounds of formula (I) are, for example, compounds of general formula (It) (wherein X
, R2, Ra and n have the same meanings as defined above, and Y means a halogen atom such as chlorine, bromine or iodine. ) and a piperazine compound represented by the general formula (I[) (wherein R1 has the same meaning as above).

The reaction between the compound of formula (It) and the compound of formula (III) is carried out without a solvent or in a suitable solvent under normal pressure or increased pressure. A specific example of the solvent is toluene.

Aromatic hydrocarbons such as xylene, ketones such as methyl ethyl ketone and methyl isobutyl ketone, ethers such as dioxane and diglyme, alcohols such as ethanol, isopropyl alcohol, and butanol, N,N-dimethylformamide , dimethyl sulfoxide and the like.

This reaction is preferably carried out in the presence of a base, and specific examples of the base include alkali carbonates such as sodium carbonate and potassium carbonate, alkali bicarbonates such as sodium bicarbonate and potassium bicarbonate, and alkali bicarbonates such as triethylamine. The triamine may be mentioned, but an excess amount of the compound of formula (I[) can also serve as the triamine.

In addition, when using a compound in which Y is chlorine or bromine in formula (II), the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. Reaction temperature is usually 40-200°C
It is.

Compounds of formula (I) in which X is a group: -CI(,C) may also include, for example, Tetrahedron, 34.1
651 (1978), by oxidizing a compound in which X or the group is CH2CH(OH)- in formula (I) using dimethyl sulfoxide.

In addition, the compound in which X in formula (I) is a group: -CH=CH- has the general formula (■') [wherein, L+ RK+ n and Y have the same meanings as above, and X' is a group CH, CH (halogen)-. It can also be produced by reacting the compound represented by the formula (I) with the compound represented by the formula (I). This reaction is carried out without a solvent or in a suitable solvent under normal pressure or increased pressure. A specific example of the solvent is toluene.

Examples include aromatic hydrocarbons such as xylene, ketones such as methyl ethyl ketone and methyl isobutyl ketone, ethers such as dioxane and diglyme, N,N-dimethylformamide, and dimethyl sulfoxide. 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 tertiary carbonates such as triethylamine. An excess of the compound of formula (I) may also serve as the amine. In addition, when using a compound in which halogen in X' and Y in formula (■') are chlorine or bromine, the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. do. The reaction temperature is usually 40-200'C.

The compound of formula (I) is isolated and purified by conventional methods. The compound of formula (I) thus obtained can be converted into a salt by treatment with various acids according to conventional methods.

The raw material compounds represented by formula (II) and formula (■') can be produced by the methods shown in Reference Examples 1 to 7, or by a method similar to these or Example 2.

The results of pharmacological tests on representative compounds of the present invention and chlorpromazine hydrochloride, a commercially available antipsychotic, will be shown below, and the pharmacological action of the compounds of the present invention will be explained. The compounds of the present invention used in the test are as follows.

A: 2-(4-ethyl-1-piperazinyl)-4-
(4-fluorophenyl)-5,6,7,8,9,10
-hexahydrocycloocta[blpyridin-10-one fumarate B: 2-(4-ethyl-1-piperazinyl)-4-
(4-Fluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohebuta[b]pyridin-9-one C: 2-(4-ethyl-1-piperazinyl)-4-(
4-Fluorophenyl)-5,6,7,8-tetrahydrocycloocta[bl pyridine fumarate Test Example 1 Inhibition of exploratory behavior Five ddY male mice weighing 20 to 25 g were used in each group. The test compound suspended in 0.5% tragacanth was orally administered (10 μL/kg), and 2 hours later, each mouse was placed in a measurement cage (23X35X30C1l+) on an Animex exercise measuring device (Farad). The amount of exploration activity per minute was measured. The average value of the amount of exploratory behavior (counts/3 minutes) of the test compound administration group was determined and compared with that of the control group to calculate the inhibition rate.

As a result, the inhibition rates of test compounds A, B, and C were 45%, 74%, and 58%, respectively. On the other hand, that of chlorpromazine hydrochloride was 46%.

Test Example 2 Brain dopamine metabolite increase effect Body weight 25-3
Five 0g ddY male mice were used in each group. 0.5
The test compound suspended in % tragacanth was orally administered (2
kg) L, the brain was removed after 2 hours, homogenized with IN formic acid-acetone, cooled and centrifuged to obtain the superior sulcus. After evaporating this to dryness with nitrogen gas, it was dissolved in 0.01N acetic acid and subjected to high performance liquid chromatography with an electrochemical detector.
The concentration of homovanillic acid (HVA), a metabolite of dopamine, was measured and expressed as a percentage of the control group.

As a result, the percentages of test compounds A, B and C were 185%, 208% and 198%, respectively, and these compounds caused a significant increase in HVA. On the other hand, that of chlorpromazine hydrochloride was 126%.

As is clear from the results of these pharmacological tests, formula (I)
The compounds and their physiologically acceptable salts exhibit excellent psychotropic effects, particularly central nervous system depressant effects, and have low toxicity, so they can be used, for example, as antipsychotic drugs. Administration routes for the compound of formula (I) and its salts include:
It may be administered orally, parenterally or rectally, with oral administration being preferred. The dosage depends on the type of compound.

Although it varies depending on the administration method, patient's symptoms, age, etc., it is usually 0.
．． 1 to 100 ■/kg/day. The compound of formula (I) or a salt thereof is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. As the pharmaceutical carrier, a substance commonly used in the pharmaceutical field and which does not react with the compound of formula (I) or its salt is used.

Specifically, for example, lactose, glucose, mannitol, cyclodextrin, starch, white sugar, crystalline cellulose,
Gelatin, gum arabic, hydroxypropylcellulose, hydroxypropylmethylcellulose, light silicic anhydride, magnesium stearate, talc, tragacanth, titanium oxide.

Examples include sorbitan fatty acid ester, vegetable oil, and water. Examples of dosage forms include tablets, capsules, granules, powders, syrups, suspensions, injections, and halves. These formulations are prepared according to conventional methods. These formulations may also contain other therapeutically valuable ingredients.

In order to explain the present invention more specifically, reference examples and examples are given below, but the present invention is not limited to these examples. The compounds were identified by elemental analysis, mass spectra, IR spectra, NMR spectra, etc.

Reference example 1 4-(4-fluorophenyl)-5,6,7,8,9,
10-hexahydrocycloocta[b]pyridine-2(
Preparation of IH)-one: A mixture of 5 g of 4-fluorobenzoylacetonitrile, 4.6 g of cyclooctanone and 25 g of polyphosphoric acid was
Stir at 0°C for 2 hours. After cooling, the reaction mixture was poured into ice water, diethyl ether was added thereto, the mixture was stirred, and the precipitate was collected by filtration. Recrystallization from isopropyl alcohol yields 5 g of the desired product.

Melting point: 235-238°C Using the corresponding raw material compounds, the following compounds are obtained by reacting and treating in the same manner as in Reference Example 1.

・4-(4-fluorophenyl)-1,5,6,7,8
,9-hexahydro-2H-cyclohebuta[blpyridin-2-one Melting point 245-246°C (recrystallized from methanol) 4-(4-fluorophenyl)-5,6,7
,8-tetrahydro-2(IH)-quinolinone Melting point 287-288°C (recrystallized from N,N-dimethylformamide-ethanol) ・4-(4-fluorophenyl)-1,5,6,7-tetrahydro- 28-1-pyrindin-2-one Melting point 258-265°C (recrystallized from methanol) -4
-(2,4-difluoroO'7/L7)-5
,6,7,8,9,10-hexahydrocycloocta[
b] Pyridin-2(IH)-one Melting point 240-24
3°C (recrystallized from methanol) -4-(2,6-difluoronia Fe:-)Iy) -5,6,7,8,9
,10-hexahydrocycloocta[blpyridine-2
(II()-one Melting point 254-256°C (recrystallized from ethanol) 4-phenyl-5,6,7,8,9,
10-hexahydrocycloocta[b]pyridine-2(
IH)-one Melting point 265-266°C (recrystallized from methanol) 4-(2,4-difluorophenyl)-1,
5,6,7,8,9-hexahyto' 0-2H-cyclobebuta[bl pyridin-2-one Melting point 233-23
5°C (recrystallized from ethanol) Reference Example 2 2-chloro-4-(4-fluorophenyl)-5,6,
7,8,9゜10-hexahydrocycloocta[bl Preparation of pyridine: 4-(4-fluorophenyl)-5,6
, 7, 8, 9, 1 To 5 g of hexahydrocycloocta[b]pyridin-2(IH)-one was added 5.2 ml of phenylphosphonic acid dichloride, and the mixture was stirred at 170°C for 1 hour.

After cooling, the reaction solution was dissolved in chloroform and gradually added dropwise to ice water while stirring. After making basic with aqueous ammonia, the organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 4.2 g of the desired product. Using the corresponding raw material compounds having a melting point of 136 to 137°C, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 2.

・2-chloro-4-(4-fluorophenyl)-6,7
,8,9-tetrahydro-5H-cyclohebuta[b]pyridine Melting point: 84-85°C (recrystallized from petroleum ether)
・2-chloro-4-(4-fluorophenyl)-5,6
,7,8-tetrahydroquinoline Melting point 111-11
2°C (recrystallized from isopropyl alcohol-petroleum ether) 2-chloro-4-(4-fluorophenyl)-
6,7-Sihydro 5H-1-pyrindine Melting point 14
4-146°C (recrystallized from ethanol) ・2-chloro-4-(2,4-difluorophenyl)-
5,6,7°8,9.10-hexahydrocycloocta[b]pyridine Melting point 74-75°C (recrystallized from isopropyl alcohol) ・2-4-(2,6-difluorophenyl)-
5,6,7°8,9.10-hexahydrocycloocta[blpyridine Melting point 83-84°C (recrystallized from isopropyl alcohol) ・2-chloro-4-phenyl-5,6,7,8,9, 1
0-hexahydrocycloocta[b]pyrindine point 96-97°C (recrystallized from isopropyl alcohol-petroleum ether) ・2-4-(2,4-difluorophenyl)-
6,7,8゜9-tetrahydro-5H-cyclohebuta [
bl pyridine melting point 55-56°C (recrystallized from isopropyl alcohol) Reference example 3 2-chloro-4-(4-fluorophenyl)-5,6,
7,8,9゜Production of 1-leaf hexahydrocycloocta[b]pyrindine 1-oxide: 2-chloro-4-(4-fluorophenyl)-5,6,
7,8,9° 1 g of 10-hexahydrocycloocta[b]pyrindine is dissolved in 60 rnI of chloroform, and 7.2 g of m-chloroperbenzoic acid is gradually added under water cooling. −
After leaving to stand overnight, an aqueous solution of 5 g of sodium thiosulfate was added dropwise with stirring under water cooling, and then an aqueous sodium carbonate solution was added dropwise and stirring continued. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography and chloroform-
The portion eluted with methanol (20:1) was recrystallized from methylene chloride-hexane to obtain 3.9 g of the desired product. Using raw materials corresponding to melting points of 184 to 185°C, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 3.

・2-chloro-4-(4-fluorophenyl)-6,7
,8,9-tetrahydro-5H-cyclohebuta[b]pyrindine 1-oxide Melting point 190-192°C (recrystallized from chloroform-toluene) ・2-chloro-4-(4-fluorophenyl)-6,7
-Sihydro 5H-1-pyrindin-1-oxide Melting point 229-230°C (recrystallized from chloroform-toluene) 2-chloro-4-(4-fluorophenyl)
-5,6,7,8-tetrahydroquinoline-1-oxide 2-chloro-4-phenyl-5,6,7,8,9,1
0-hexahydrocycloocta[b]pyrindine 1-oxide 2-chloro-4-(2,4-difluorophenyl)-5,6,7°8,9.1 hexahydrocycloocta[blpyridine-1 -Oxide 2-chloro-4-(2,6-difluorophenyl)-
5,6,7°8,9.10-hexahydrocycloocta[blpyridine=1-oxide・2-chloro-4-(2,4-difluorophenyl)-
6,7,8゜9-tetrahydro-5H-cyclohebuta[
bl pyridine-1-oxide reference example 4 2-chloro-4-(4-fluorophenyl)-10-acetoxy-5,6,7,8,9,10-hexahydrocycloocta [manufacture of bl pyridine: 2- Chloro-4-(4-fluorophenyl)-5,6,
7,8,9゜16.2 g of IO-hexahydrocycloocta[b]pyrindine 1-oxide was dissolved in 500 y of acetic anhydride.
d and heated at 140°C for 12 hours. The reaction solution was concentrated, the residue was subjected to medium pressure column chromatography on silica gel, and the portion eluted with hexane-ethyl acetate (20:1) was recrystallized from methylene chloride-hexane to obtain 3.7 g of the desired product. Melting point 111-113°C Using the corresponding raw material compound, the following compound was obtained by reacting and treating in the same manner as in Reference Example 4.

・2-chloro-4-(4-fluorophenyl)-9-acetoxy-6,7,8,9-tetrahydro-5H-cyclohebuta[b]pyrindine Melting point 104-106°C (
Recrystallized from methylene chloride-hexane) ・2-chloro-4-(4-fluorophenyl)-7-acedoxy6.7-sihydro-5H-1-pyrindine
Melting point 90-91°C (recrystallized from methylene chloride-hexane) 2-chloro-4-(4-fluorophenyl)-
8-acetoxy-5,6,7,8-tetrahydroquinoline/2-chloro-4-phenyl-10-acetoxy-5
, 6, 7, 8° 9.1 leaf to hexahydrocycloocta [b
] Pyrindine 2-chloro-4-(2,4-difluorophenyl)-10-acetoxyni 5.6.7.8.9.1
Kanohexahydrocycloocta[b]pyrindine 2-di-4-(2,6-difluorophenyl)-
10-acetoxy-5,6,7,8,9,10-hexahydrocycloocta[blpyridine 2-chloro-4-(2,4-difluorophenyl)-
9-acetoxy-6,7,8,9-tetrahydro-5H
-Cyclohebuta[b]pyringine Example 5 2-chloro-4-(4-fluorophenyl)-10-hydroxy-5,6,7,8,9,1 Kanohexahydrocycloocta[b]pyringine production : 2-chloro-4-(4-fluorophenyl)-10-acetoxy-5,6,7,8,9,10-hexahydrocycloocta[b]pyrindine, 9 g was dissolved in ethanol 28
Dissolved in rILl, IN aqueous sodium hydroxide solution 28-
Add and heat at 80°C for 30 minutes. The reaction solution was concentrated to about half its volume under reduced pressure, and the remaining solution was extracted with ethyl acetate. The extract is washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The residue was recrystallized from methylene chloride-hexane to obtain 3 g of the desired product.

Melting point: 132-134°C Using the corresponding raw material compound, the following compound is obtained by reacting and treating in the same manner as in Reference Example 5.

・2-Chloro-4-(4-fluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohebuta[b]pyrindine Melting point 64-67°C (regenerated from methylene chloride-hexane) Crystals) ・2-chloro-4-(4-fluorophenyl)-7-hydroxy-6.7-sihydro-5H-1-pyrindine
Melting point 155-156°C (recrystallized from methylene chloride-hexane) 2-chloro-4-(4-fluorophenyl)-8-hydroxy-5,6,7,8-tetrahydroquinoline 2-chloro-4- Phenyl-1 leaf hydroxy-
5,6,7,8゜9.10-hexahydrocycloocta[b]pyrindine 2-chloro-4-(2,4-difluorophenyl)-10-hydroxy-5,6,7,8,9
, 10-hexahydrocycloocta[b]pyrindine 2-di-4-(2,6-difluorophenyl)-
1 leaf hydroxy-5, 6, 7, 8, 9, 1 leaf hexahi F
Rocycloocta[b]pyrindine 2-chloro-4-(2,4-difluorophenyl)-
9-hydroxy-6,7,8,9-tetrahydro-5H
-cyclohebuta[blpyridine Reference Example 6 2,1O-dichloro-4-(4-fluorophenyl)-
5,6,7°8,9.10-hexahydrocycloocta[b]pyrindine production.

2-chloro-4-(4-fluorophenyl)-1-hydroxy-5,6,7,8,9,10-hexahydrocycloocta[b]pyrindine, 9 g to 20 y of chloroform
d, add 2 mt' of thionyl chloride, and heat to reflux. The reaction solution is concentrated under reduced pressure, toluene and an aqueous sodium bicarbonate solution are added to the residue, and the organic layer is separated, washed with water, dried over anhydrous sodium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, and the portion eluted with toluene-hexane (1:1) was recrystallized from methylene chloride-hexane to obtain 0.7 g of the desired product. Melting point 125
-127°C Using the corresponding raw material compounds, the following compounds were obtained by reacting and treating in the same manner as in Reference Example 6.

・2,9-dichloro-4-(4-fluorophenyl)-
6,7,8゜9-tetrahydro-5H-cyclohebuta [
b] Pyrindine 2,7-dichloro-4-(4-fluorophenyl)-6,7-sihydro 5H-1-pyrindine 2,8-dichloro-4-(4-fluorophenyl)-
5,6,7゜8-tetrahydroquinoline/2,10-dichloro-4-phenyl-5,6,7,8
,9,10-hexahydrocycloocta[blpyridine・2,10-dichloro-4-(2,4-difluorophenyl)-5゜6,7.8.9.10-hexahydrocycloocta[b]pyridine 2.10-dichloro-4-(2,6-difluorophenyl)-5゜6,7.8.9.10-hexahydrocycloocta[b]pyridine・2.9-dichloro-4-(2,4 -difluorophenyl)-6゜7,8.9-tetrahydro-5H-cyclohepta[blpyridine Example 1 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-1 Kano hydroxy -5, 6, 7, 8,
Preparation of 9,1 hexahydrocycloocta[bl pyridine: 2-di-4-4-(4-fluorophenyl)-10
-Hydroxy-5, 6, 7, 8, 9, 1 Kanohekisahito-
A mixture of cycloocta[b]pyringine, 5 g + 0.8 g of N-ethylpiperazine and 0.3 g of potassium iodide is stirred at 170° C. for 1.5 hours. After cooling, water is added to the reaction mixture and extracted with chloroform. Wash the extract with water,
After drying with anhydrous sodium sulfate, concentrate. The residue was subjected to silica gel column chromatography, and the portion eluted with ethyl acetate was converted into a fumarate salt by a conventional method, and recrystallized from methanol-ethanol to obtain the target fumarate salt.
Obtain 4g. Using raw materials corresponding to melting points of 234 to 237°C, reactions and treatments were carried out in the same manner as in Example 1 to obtain the following compounds.

・2-(4-ethyl-1-piperazinyl)-4-(4-
Fluorophenyl)-9-hydroxy-6,7,8,9
-Tetrahydro-5H-cyclohebuta[b]pyrindine fumarate Melting point 234-237°C (recrystallized from methanol-ethanol) ・2-(4-ethyl-1-piperazinyl)-4-(4-
fluorophenyl)-7-hydroxy-6.7-hydro-5H-1-pyrindine 2-(4-ethyl-1-piperazinyl)-4-(4-
Fluorophenyl)-8-hydroxy-5,6,7,8
-tetrahydroquinoline・2-(4-ethyl-1-piperazinyl)-4-phenyl-10-hydroxy-5,6,7,8,9,10-hexahydrocycloocta[blpyridine・2-(4-ethyl -1-piperazinyl)-4-(2,
4-difluorophenyl)-1 Kano hydroxy-5,6,
7,8,9,10hexahydrocycloocta[b]pyrindine 2-(4-ethyl-1-piperazinyl)-4-(
2,6-difluorophenyl)-1O-hydroxy-5
,6,7,8,9,10-hexahydrocycloocta[
bl pyridine 2-(4-ethyl-1-piperazinyl)
-4-(2,4-difluorophenyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine Example 2 2-(4-ethyl-1-piperazinyl)-4- (4-Fluorophenyl)-5,6,7,8,9,10-hexahydronecroocta[bl Preparation of pyridin-10-one: 0.16 g of oxalyl chloride was added to 100 ml of anhydrous methylene chloride.
A solution of 0.22 g of anhydrous dimethyl sulfoxide in anhydrous methylene chloride is added dropwise at an internal temperature of -60°C.

After 10 minutes, this solution was added with 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-10-hydroxy-5,6°7,8.9.10-hexahydrocycloocta[bl Pyridine 0.3g anhydrous methylene chloride 3-
The solution was added dropwise, and after 15 minutes triethylamine 0.59
Drop g. After 30 minutes, gradually add water at room temperature.
Stir for 30 minutes.

The organic layer is separated, dried over anhydrous sodium sulfate, concentrated, and the residue is subjected to silica gel column chromatography. The part eluted with ethyl acetate was converted to fumarate salt by a conventional method, and the target product was recrystallized from methanol-ethanol.
0.2 g of fumarate is obtained. Melting point: 206-209°C Using the corresponding raw material compounds, the following compounds are obtained by reacting and treating in the same manner as in Example 2.

・2-(4-ethyl-1-piperazinyl)-4-(4-
fluorophenyl)-6,7,8,9-tetrahydro-
5H-cyclohebuta[blpyridin-9-one 215
Hydrate melting point 174-175°C (recrystallized from methylene chloride-hexane) ・2-(4-ethyl-1-piperazinyl)-4-(4-
fluorophenyl)-6,7-cyhydro5H-1-pyrindin-7-one 2-(4-ethyl-1-piperazinyl)-4-(4-
fluorophenyl)-5,6,7,8-tetrahydroquinolin-8-one 2-(4-ethyl-1-piperazinyl)-4-phenyl-5,6°7,8.9.10-hexahydro cycloocta[b]pyrindin10-one 2-(4-ethyl-1-piperazinyl)-4-(2,
4-difluorophenyl)-5,6,7,8,9,10
-hexahydrocycloocta[b]pyrindine1-2-(4-ethyl-1-piperazinyl)-4-(2,
6-difluorophenyl)-5,6,7,8,9,to
-hexahydrocycloocta[b]pyrindin10-one 2-(4-ethyl-1-piperazinyl)-4-(2
,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohebuta[blpyridin-9-one Example 3 2-(4-ethyl-1-piperazinyl)-4-(4-fluoro Phenyl)-5,6,7,8-tetrahydrocycloocta[b]pyrindine production: 2.10-dichloro-4-(4-fluorophenyl)-
5,6,7°8,9.10-hexahydrocycloocta[blpyridine 0.6g, N-ethylpiperazine 1g
and 0.3 g of potassium iodide at 170°C.
Stir for an hour.

After cooling, add water to the reaction solution, extract with chloroform, wash with water,
After drying with anhydrous sodium sulfate, concentrate. The residue was subjected to silica gel column chromatography, and the portion eluted with ethyl acetate was converted into a fumarate salt by a conventional method, and recrystallized from methanol-ethanol to obtain the target fumarate salt.
Obtain 23g.

Melting point: 227-230°C Using the corresponding raw material compounds, the following compounds are obtained by reacting and treating in the same manner as in Example 3.

・2-(4-ethyl-1-piperazinyl)-4-(4-
fluorophenyl)-6,7-cyhydro5H-cyclohebuta[b1pyridine 2-(4-ethyl-1-piperazinyl)-4-(4-
fluorophenyl)-5H-1-pyrindine 2-(4-ethyl-1-piperazinyl)-4-(4-
Fluorophenyl)-5,6-cyhydroquinoline 2-
(4-ethyl-1-piperazinyl)-4-phenyl-5
,6゜7.8-tetrahydrocycloocta[blpyridine-2-(4-ethyl-1-piperazinyl)-4-(2
,4-difluorophenyl)-5,6,7,8-tetrahydrocycloocta[b]pyrindine2-(4-ethyl-1-piperazinyl)-4-(2,
6-difluorophenyl)-5,6,7,8-tetrahydrocycloocta[blpyridine 2-(4-ethyl-1-piperazinyl)-4-(2,
4-difluorophenyl)-6,7-dihydro5H-
Cyclohebbuta[b]pirinjin patent applicant

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, X is a group: -CH_2CO-, -CH_2CH(
OH)- or -CH=CH-, R_1 means a lower alkyl group, R_2 and R_3 are the same or different and mean a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, n means an integer from 1 to 4. ] A 4-phenyl-2-(1-piperazinyl)pyridine derivative and its salts.