JPH0499768A - 4-(4-phenylpyridin-2-yl)piperazine-1-oxide derivative - Google Patents

Abstract

NEW MATERIAL:A 4-(4-phenylpyridin-2-yl)piperazine-1-oxide derivative shown by formula I [R1 is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, hydroxy(lower)alkyl or lower alkoxy(lower)alkyl; R2 and R3 are H, halogen, lower alkyl or lower alkoxy; R4 and R5 are H, lower alkyl or R4 and R5 may be bonded to form lower alkylene; n is 3-7] and a salt thereof. EXAMPLE:1-Ethyl-4-[4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta[ b]pyridin-2- yl]piperazine-1-oxide. USE:A drug having psychotropic action and inhibitory action on central nervous system. PREPARATION:A compound shown by formula II is oxidized to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention provides novel and useful 4-(4-
Phenylpyridin-2-yl)piperazine-1-oxyto derivatives.

OBJECTS OF THE INVENTION The present invention provides novel compounds having excellent psychotropic effects, particularly central nervous system depressant effects.

Structure and Effects of the Invention According to the present invention, - Wuwei (1) ha [wherein R1 is a lower alkyl group, a cycloalkyl group, a cycloalkyl (lower) alkyl group, a hydroxy (lower)
means an alkyl group or a lower alkoxy (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, R4 and R5 are the same or different and mean a hydrogen atom, It means an atom or a lower alkyl group, or may be taken together to form a lower alkylene group, and n means an integer from 3 to 7. ] 4-(4-phenylpyridin-2-yl)piperazine-1-oxyto derivatives and salts thereof are provided.

The salts of the compound represented by formula (I) are preferably physiologically acceptable salts, such as hydrochloride.

Inorganic acid salts such as hydroiodide, sulfate, phosphate, etc., and organic acid salts such as citrate, maleate, fumarate, tartrate, benzoate, lactate, methanesulfonate, etc. There are several examples. 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, at least two types of stereoisomers may exist. These stereoisomers, mixtures and racemates thereof are included in the compounds of the present invention.

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. "As the lower alkyl group J, for example, methyl, ethyl.

Examples include propyl, isopropyl, butyl, pentyl, hexyl, etc. Examples of the "cycloalkyl group" include cyclopropyl and cyclobutyl.

Examples include cyclopentyl, cyclohexyl, and cyclohebutyl. Examples of the "cycloalkyl (lower) alkyl group" include cyclopropylmethyl and cyclohexylmethyl. Examples of the [hydroxy (lower) alkyl group] include 2-hydroxyethyl and 3-hydroxypropyl. The "lower alkoxy (lower) alkyl group" is, for example, 2-methoxyethyl.

Examples include 2-ethoxyethyl, 3-methoxypropyl, and 3-ethoxopropyl. [Halogen atoms J include fluorine, chlorine, bromine, and iodine. Examples of the "lower alkoxy group" include methoxy, nidoxy, propoxy, isopropoquino, and butoxy.

Examples of the "lower alkylene group" include methylene and ethylene.

Specific examples of the compound represented by formula (I) include the following, in addition to the compounds in Examples described below.

・1-ethyl-4-(4-(4-fluorophenyl)-
5,6,7,8-tetrahydro-5,8methanoquinolin-2-yl]piperazine-1-oxyto1-ethyl-4-(4-(2,4-difluorophenyl)-5,6,7,8-tetrahydro -5゜8-methanoquinoline-2-ylcopiperazine-1=oxide l-ethyl-4-(1-(4-fluorophenyl) -
6,7,8,9-tetrahuman 0-5H-cyclohebuta (
b) Pyridin-2-yl]piperane-1-oxyto-l-ethyl-4-(4-(2,4-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohebuta[b) Pyridine- 2-ylcopiperazine-1-oxide 1-ethyl-4-(4-(4-fluorophenyl) -
6,7,8,9-tetrahydro-58-6゜9-methanocyclohebuta(b)pyridin-2-yl]piperazine-1-oxide 1-ethyl-4-(4-(4-fluorophenyl)-6
,7,8,9-tetrahydro-58-5゜8-methanocyclohebuta(b)pyridin-2-ylcopiperazine-1
-oxyto-l-ethyl-4-(4-(4-fluorophenyl)) -
6,7,8,9,10,11-hexahydro-5H-cyclonona(b) pyridin-2-ylcopiperazine-1-
Oxyto 1-ethyl-4-(4-phenyl-5,6,7°8.9
．． 10-hexahydrocycloocta(b)pyridine-2
-yl) piperazine-1-oxide l-methyl-4-(
4-(4-fluorophenyl) -5,6,7,8,9
,10-hexahydrocycloocta(b)pyridine-2
-ylcopiperazine-1-oxide 1-propyl-4-(4-(4-fluorophenyl')
-5,6,7,8,9,10-hexahydrocycloocta(b) pyridin-2-ylcopiperazine-1-oxide l-butyl-4-(4-(4-fluorophenyl)-5
,6,7,8,9,10-hexahydrocycloocta(
b) Pyridin-2-ylcopiperazine-1-oxide l-cyclopropylmethyl-4-(4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocycloocta(b) pyridin-2-yl]piperazine-1-oxide l-pentyl-4-(4-(4-fluorophenyl)-
5,6,7,8,9,10-hexahydrocycloocta(b) pyridin-2-ylcopiperazine-1-oxide 1-(3-hydroxypropyl)-4-(4-(4-fluorophenyl) -5,6,7,8,9゜lO-hexahydrocycloocta(b) pyridin-2-ylcopiperazine-1-oxide 1-(2-methoxyethyl')-4-
[4-(4-fluorophenyl) -5,6,7,8,
9,10-hexahydrocycloocta(b)pyridine-
2yl]piperazine-1-oxide 1-ethyl-4-(4-(2-fluorophenyl) -
5,6,7,8,9,10-hexahydrocycloocta(b) pyridin-2-ylcopiperazine-1-oxide l-ethyl-4-(4-(3,4-difluorophenyl)-5 ,6,7,8,9,10-hexahydrocycloocta[b]pyridin-2-ylcopiperazine-1-oxide 1-ethyl-4-(4-(2,6-difluorophenyl) -5, 6,7,8,9,10-hexahydrocycloocta(b) pyridin-2-ylcopiperazine-1-oxide l-methyl-4-(4-(2,4-difluorophenyl)-5,6, 7,8,9,10-hexahydrocycloocta(b) pyridin-2-ylcopiperazine-1-oxide l-propyl-4-(4-(2,4-difluorophenyl) -5,6,7, 8,9,10τhexahydrocycloocta(b)pyridin-2-yl]piperazine=1-
Oxides Preferred among the compounds of the present invention are compounds of formula (1) in which one of R2 and R3 is a fluorine atom, and the other is a hydrogen atom or a fluorine atom, and physiologically acceptable salts thereof. More preferably, R1 is a methyl group, an ethyl group, or a propyl group.

Butyl group, pentyl group or 2-hydroxyethyl group, R
Examples include a fluorine atom at the 2nd or 4th position, a hydrogen atom at R3 or a fluorine atom at the 2nd position, a hydrogen atom at both R4 and R6, a compound at n or 6, and physiologically acceptable salts thereof.

The compound 2〇) is, for example, -Wuwei (II) (in the formula, R,
, R2, R, , R4, R, and n have the same meanings as defined above. ) It can be produced by oxidizing the compound represented by the following in accordance with a conventional method. This reaction is usually carried out by treating the compound of formula (n) with an oxidizing agent in a suitable solvent. As the oxidizing agent, oxidizing agents commonly used in N-oxytation reactions can be used, such as hydrogen peroxide, peracetic acid, perbenzoic acid, and 2m-chloroperbenzoic acid.

Examples include organic peroxides such as monoperphthalic acid. The amount of the oxidizing agent used is stoichiometric to slightly excess relative to the compound of formula Cl0). The solvent is appropriately selected depending on the type of oxidizing agent, such as water, alcohols such as methanol and ethanol, ketones such as acetone, ethers such as diethyl ether and dioxane, chloroform, Examples include halogenated hydrocarbons such as methylene chloride and ethylene chloride, and aromatic hydrocarbons such as benzene and toluene. The reaction temperature varies depending on the type of oxidizing agent and is usually in the range of 0 to 100°C.

The compound of formula (1) is isolated and purified by conventional methods. The compound of formula (1) thus obtained can be converted into a salt by treatment with various acids according to conventional methods.

The raw material compound represented by formula (n) was prepared in Reference Examples 1゜8 and 1.
It can be manufactured by the method shown in No. 5 or a method similar thereto.

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.

Test Example 1: Effect on suppressing exploratory behavior Five ddY male mice weighing 20 to 25 g were used in each group. A test compound suspended in 0.5% tragacanth was orally administered (10 μL/kg), and 2 hours later, mice were placed one by one in an upper chamber cage (23 x 35 x 30 cm) using an Animex locomotor analyzer (Farad) and incubated for 3 minutes. The amount of exploratory behavior 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. The results are shown in Table 1.

Test Example 2 Suppressing effect of apomorphine on vomiting The suppressive effect of the test compound on vomiting induced by apomorphine was investigated using 3 to 4 peagle-sized animals (8 to 15 kg) per group.

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

(The following is a blank space) Table 1 Effect of suppressing exploratory behavior (1) and suppressing effect of vomiting caused by apomorphine (II) Means the compound of Example 1 (see below).

As is clear from the results of the above pharmacological tests, the compound of formula (1) and its physiologically acceptable salts exhibit excellent psychotropic effects, especially central nervous system depressant effects, and are also weakly toxic. It can be used as a psychotic drug. The route of administration may be oral, parenteral or rectal, but oral administration is preferred. The dosage of the compound of formula (I) or its salt depends on the type of compound.

Varies depending on administration method, patient's symptoms, age, etc., usually 0
．． 1 to 100 μ/kg/day. The compound of formula (1) or a salt thereof is usually administered in the form of a preparation prepared by mixing it with a pharmaceutical carrier. These formulations may also contain other ingredients of therapeutic value.

Specific examples of dosage forms include tablets, capsules, granules, powders, syrups, suspensions, injections, and suppositories. These formulations are prepared according to conventional methods.

The present invention will be explained in more detail below by reference examples and examples, but the present invention is not limited to these examples. Compounds are identified using elemental analysis values, mass spectra, and IR spectra.

This was performed using NMR spectroscopy, etc. In addition, the following abbreviations are used in the tables in Reference Examples and Examples to simplify the description.

A: Ethanol AC Niacetonitrile CF: Chloroform E Nidiethyl ether HX, Hexane A: Isopropyl alcohol M: Methanol MC: Methylene chloride T: Toluene Reference example 1 4-(4-fluorophenyl) -5,6,7゜8 ',
9.10-hexahydrocycloocta(b)pyridine-
Preparation of 2CIH)-one: 5 g of 4-fluorobenzoylacetonitrile.

A mixture of 4.6 g of cyclooctanone and 25 g of polyphosphoric acid is stirred at 120° C. for 2 hours. After cooling, the reaction solution was poured into ice water, diethyl ether was added thereto, and 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 Reference Examples 2-7 Using the corresponding raw material compounds, reactions and treatments were carried out in the same manner as in Reference Example 1, and the compounds shown in Table 2 were obtained by recrystallization from methanol.

Table 2 9° Reference Example 8 2-chloro-4-(4-fluorophenyl) 5, 6.
7. 8. 9. 10-Hexahydrone cloocta(b) Production of pyridine 4-(4-fluorophenyl)-5,6,7°8.9.
10-hexahydrocycloocta(b) pyridine-2(
5.2 m of phenylphosphonic acid dichloride to 5 g of IH)-one
1 and 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. Melting point: 136-137°C Reference Examples 9-14 Using the corresponding starting compounds, the compounds in Table 3 were obtained by reacting and treating in the same manner as in Reference Example 8.

Table 3 Reference example 15 2-(4-ethylpiperazinyl) (4-fluorophenyl) -5,6,7,8,9゜l
Preparation of O-hexahydrocycloocta(b) pyridine: 2-chloro-4-(4-fluorophenyl)-5,6,
A mixture of 5 g of 7,8,9,10-hexahydrocycloocta[b]pyridine and 5.9 g of N-ethylpiperazine is stirred at 170-180°C for 12 hours. After cooling, ethyl acetate and dilute hydrochloric acid are added to the reaction mixture, the aqueous layer is separated, made basic with an 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. The residue was dissolved in chloroform and subjected to silica gel column chromatography, eluting with chloroform. The eluate was concentrated, and the residue was recrystallized from ethanol to obtain 3.8 g of the desired product.

Melting point 123-124°C Reference Examples 16-22 Using the corresponding raw material compounds, the reaction was carried out in the same manner as in Reference Example 15.
Processing gives the compounds in Table 4.

Example 1 1-ethyl-4-(4-(4-fluorophenyl)-5
,6,7,8,9,10-hexahydrocycloocta(
b) Production of pyridin-2-ylcopiperazine-1-oxide: 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9°10-hexa Hydrocycloocta(b) 2 g of pyridine is dissolved in 20% of chloroform, and 0.94 g of m-chloroperbenzoic acid is gradually added while stirring under ice and water. After stirring for 1 hour, an aqueous sodium thiosulfate solution is added and stirring is continued.

The organic layer is separated, washed with an aqueous potassium carbonate solution and then with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.

The residue was subjected to silica gel column chromatography, and the part eluted with ethyl acetate-methanol (20:1) was concentrated and recrystallized from diethyl ether to obtain 1/4 of the target product.
1.4 g of hydrate are obtained.

Melting point: 168-170°C Examples 2-8 Using the corresponding starting compounds, the compounds shown in Table 5 are obtained by reacting and treating in the same manner as in Example 1.

(Margin below)

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R_1 is a lower alkyl group, a cycloalkyl group,
It means a cycloalkyl (lower) alkyl group, a hydroxy (lower) alkyl group, or a lower alkoxy (lower) alkyl group, and 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. , R_4 and R_5 are the same or different and represent a hydrogen atom or a lower alkyl group, or may be taken together to form a lower alkylene group, and n represents an integer of 3 to 7. ] 4-(4-phenylpyridin-2-yl)piperazine-1-oxide derivative and its salts.