JPH07228573A - 2-phenylcycloalkanopyrimidine derivative - Google Patents

Abstract

(57) [Summary] [Structure] A 2-phenylcycloalkanopyrimidine derivative represented by the following chemical formula 1 and a pharmaceutically acceptable acid addition salt thereof. [Chemical 1] [Wherein R ¹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted phenyl (lower) alkyl group R ² and R ³ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ⁴ represents a hydrogen atom or a lower alkyl group, and m
Means 2 or 3 and n means 3, 4, 5, 6 or 7. [Effect] The compound of the present invention has an antagonistic action on serotonin S ₂ receptors and is therefore useful as a therapeutic drug for various diseases of the central nervous system in which serotonin is involved.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel 2-phenylcycloalkanopyrimidine derivative having an antagonistic effect on the serotonin S ₂ receptor.

[0002]

2. Description of the Related Art US Pat. Nos. 3,322,759 and 3,346,4
No. 52 publication discloses 2- (4-chlorophenyl) -4-N-.
(2-N, N-diethylaminoethyl) amino-5
6,7,8-Tetrahydroquinazoline, 4-N- (2-
5,6 such as N, N-dimethylaminoethyl) amino-2-phenyl-5,6,7,8-tetrahydroquinazoline
-Lower alkylene pyrimidine derivatives are described as having analgesic activity.

[0003]

A compound having a strong antagonistic action on the serotonin S ₂ receptor may be an antipsychotic drug effective for negative symptoms of schizophrenia and having less extrapyramidal side effects. Not only is there [Bleich, A. et al:
Schizophr. Bull., 14 (2), 297-315 (1988)], and other central nervous system diseases related to serotonin, such as anxiety, depression, Parkinson's disease, and sleep disorders. Expected to be.

The present inventors have conducted extensive studies to obtain a novel compound having a strong antagonistic action on the serotonin S ₂ receptor, and as a result, a piperazine or homopiperazine moiety at the 4-position of the pyrimidine ring The present invention has been completed by finding that a 2-phenylcycloalkanopyrimidine derivative having a substituted or unsubstituted phenyl group at the position meets this purpose.

[0005]

According to the present invention, a 2-phenylcycloalkanopyrimidine derivative represented by the following formula (I) and pharmaceutically acceptable acid addition salts thereof are provided.

[0006]

[Chemical 2]

[Wherein R ¹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl group or an unsubstituted or substituted phenyl (lower ) Means an alkyl group, R ² and R ³ are the same or different and each represent a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, R ⁴ means a hydrogen atom or a lower alkyl group, and m is Means 2 or 3, n is 3, 4,
Means 5, 6 or 7. ]

The pharmaceutically acceptable acid addition salts of the compound represented by formula (I) include, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and the like. Inorganic acid salts and maleic acid salts, fumarates, oxalates, citrates, tartrates, lactates, benzoates, methanesulfonates and the like. Since the compound represented by the formula (I) and its acid addition salt may exist in the form of hydrate and / or solvate, these hydrate and solvate are also included in the compound of the present invention. To be done.

In the formula (I), when R ⁴ is a lower alkyl group, at least one asymmetric carbon atom is present, and depending on the kinds of R ¹ , R ² and R ³ , the asymmetric carbon atom may be an asymmetric carbon atom. It may exist. In these cases, the compounds of formula (I) may exist in more than one stereoisomeric form. These stereoisomers, their mixtures and racemates are included in the compounds of the present invention.

The terms used in this specification are explained below.

The lower alkyl group, the lower alkyl moiety and the lower alkoxy group mean those having 1 to 6 carbon atoms, which may be linear or branched. Specific examples of the "lower alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like. Specific examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl,
Cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned. "Hydroxy (lower) alkyl group" means
A carbon atom other than the 1-position of an alkyl group having 2 to 6 carbon atoms is substituted with a hydroxy group, for example, 2-
Hydroxyethyl, 3-hydroxypropyl and the like can be mentioned. The “cycloalkyl (lower) alkyl group” means a lower alkyl group substituted with the above-mentioned cycloalkyl group, specifically, cyclopropylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 3-cyclohexylpropyl and the like. Is mentioned. The “halogen atom” means fluorine, chlorine, bromine, and iodine. Specific examples of the "lower alkoxy group" include methoxy, ethoxy,
Examples include propoxy, butoxy, isobutoxy and the like.
Specific examples of the "mono- or di-lower alkylamino group" include methylamino, dimethylamino, ethylamino,
Examples thereof include diethylamino and dipropylamino.

"Unsubstituted or substituted phenyl group" means
It means a phenyl group which may be substituted with 1 or 2 selected from halogen, lower alkyl, lower alkoxy, amino, mono- or di-lower alkylamino, nitro and cyano, and specific examples include phenyl, 2-, 3- or 4-fluorophenyl, 2,4-, 2,6- or 3,4-difluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-3 -Or 4-methylphenyl, 2
-, 3- or 4-methoxyphenyl, 2-, 3- or 4-aminophenyl, 2-, 3- or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- Alternatively, 4-nitrophenyl, 2-, 3- or 4-cyanophenyl and the like can be mentioned. The “unsubstituted or substituted phenyl (lower) alkyl group” means a lower alkyl group substituted with the above-mentioned unsubstituted or substituted phenyl group, and specific examples include benzyl, 2-, 3- or 4 -Fluorobenzyl, 2,4-, 2,6- or 3,4-difluorobenzyl, 2-, 3- or 4-chlorobenzyl, 2
-, 3- or 4-bromobenzyl, 2-, 3- or 4-methylbenzyl, 2-, 3- or 4-methoxybenzyl, 2-, 3- or 4-aminobenzyl, 2-, 3- or 4 -Methylaminobenzyl, 2
-, 3- or 4-dimethylaminobenzyl, 2-,
3- or 4-nitrobenzyl, 2-, 3- or 4-cyanobenzyl, 2- (4-fluorophenyl) ethyl, 2- (2,4-difluorophenyl) ethyl, 2
-(3-chlorophenyl) ethyl, 2- (4-nitrophenyl) ethyl, 2- (4-aminophenyl) ethyl,
2- (4-dimethylaminophenyl) ethyl, 2- (3
-Cyanophenyl) ethyl, 3- (2-methoxyphenyl) propyl and the like can be mentioned.

Preferred among the compounds of the present invention are the compounds of formula (I) in which R ² and R ³ are the same or different and each is a hydrogen atom or a halogen atom, and n is 3, 4, 5 or 6. And pharmaceutically acceptable acid addition salts thereof.

Among the compounds of the present invention, more preferred are the compounds represented by the following formula (I ') and pharmaceutically acceptable acid addition salts thereof.

[0015]

[Chemical 3]

(In the formula, R ¹ 'means a hydrogen atom, a methyl group, an ethyl group or a 2-hydroxyethyl group, R ² ' means a hydrogen atom or a fluorine atom, and n'is 4, 5 or 6 Means.)

More preferred compounds are compounds of the formula (I ') in which R ¹ ' is a hydrogen atom or a methyl group, R ² 'is a fluorine atom at the 4-position, and n'is 4 or 5, and a compound thereof It is a pharmaceutically acceptable acid addition salt.

Specific examples of particularly suitable compounds include the following compounds and their pharmaceutically acceptable acid addition salts.

2- (4-fluorophenyl) -4- (4
-Methyl-1-piperazinyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine,

2- (4-fluorophenyl) -4- (1
-Piperazinyl) -6,7,8,9-tetrahydro-5
H-cycloheptapyrimidine and

2- (4-fluorophenyl) -4- (4
-Methyl-1-piperazinyl) -5,6,7,8-tetrahydroquinazoline.

Specific examples of the compounds included in the present invention include:
In addition to the compounds of Examples described below, the following compounds and pharmaceutically acceptable acid addition salts thereof are included.

2- (4-fluorophenyl) -4- (4
-Propyl-1-piperazinyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine, 4- (4
-Cyclohexyl-1-piperazinyl) -2- (4-fluorophenyl) -6,7,8,9-tetrahydro-5
H-cycloheptapyrimidine, 4- (4-cyclohexylmethyl-1-piperazinyl) -2- (4-fluorophenyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine,

2- (2,4-difluorophenyl) -4
-(4-Methyl-1-piperazinyl) -6,7,8,9
-Tetrahydro-5H-cycloheptapyrimidine, 2-
(2,4-Difluorophenyl) -4- (1-piperazinyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine, 2- (2,6-difluorophenyl) -4- (4-methyl) -1-Piperazinyl) -6,
7,8,9-Tetrahydro-5H-cycloheptapyrimidine, 2- (2,6-difluorophenyl) -4- (1
-Piperazinyl) -6,7,8,9-tetrahydro-5
H-cycloheptapyrimidine,

2- (4-chlorophenyl) -4- (4-
Methyl-1-piperazinyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine, 2- (4-chlorophenyl) -4- (1-piperazinyl) -6,7,
8,9-Tetrahydro-5H-cycloheptapyrimidine, 2- (4-methoxyphenyl) -4- (4-methyl-1-piperazinyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine, 2 -(4-Methoxyphenyl) -4- (1-piperazinyl) -6,7,8,
9-tetrahydro-5H-cycloheptapyrimidine,

2- (4-fluorophenyl) -4- (4
-Methyl-1-homopiperazinyl) -6,7,8,9-
Tetrahydro-5H-cycloheptapyrimidine, 2-
(4-fluorophenyl) -4- (1-homopiperazinyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine,

4- (4-cyclohexyl-1-piperazinyl) -2- (4-fluorophenyl) -5,6,7,
8-tetrahydroquinazoline, 2- (2,4-difluorophenyl) -4- (4-methyl-1-piperazinyl)
-5,6,7,8-tetrahydroquinazoline, 2- (4
-Methoxyphenyl) -4- (1-piperazinyl)-
5,6,7,8-tetrahydroquinazoline, 2- (4-
Fluorophenyl) -4- (4-methyl-1-homopiperazinyl) -5,6,7,8-tetrahydroquinazoline,

2- (4-fluorophenyl) -6-methyl-4- (4-methyl-1-piperazinyl) -5,6
7,8-Tetrahydroquinazoline and 2- (4-fluorophenyl) -8-methyl-4- (1-piperazinyl)
-5,6,7,8-Tetrahydroquinazoline.

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

Process (a) : The compound of formula (I) is represented by the following formula (II)

[0031]

[Chemical 4]

(Wherein X represents a leaving atom or a leaving group, and R ² , R ³ , R ⁴ and n have the same meanings as described above) and a compound represented by the following formula (III: )

[0033]

[Chemical 5]

It can be produced by reacting with a compound represented by the formula (wherein R ¹ and m have the same meanings as described above).

The leaving atom or leaving group represented by X in the formula (II) means an atom or a group capable of leaving in the form of HX together with the hydrogen atom of the NH moiety of the compound of the formula (III) under the reaction conditions. Means a halogen atom such as chlorine, bromine or iodine, a lower alkylthio group such as methylthio or ethylthio, a lower alkylsulfonyl group such as methanesulfonyl, a lower alkylsulfonyloxy group such as methanesulfonyloxy, or trifluoromethane. Examples thereof include trihalogenomethanesulfonyloxy group such as sulfonyloxy, benzenesulfonyloxy, and arylsulfonyloxy groups such as p-toluenesulfonyloxy.

The reaction between the compound represented by the formula (II) and the compound represented by the 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 and methyl isobutyl ketone, dioxane,
Examples thereof include ethers such as diglyme, ethanol, isopropyl alcohol, alcohols such as butanol, acetonitrile, N, N-dimethylformamide, and dimethyl sulfoxide. 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 hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate, and triethylamine. Triamines may be mentioned, but an excess amount of the compound of the formula (III) can be used. When a compound in which X is chlorine or bromine in the formula (II) is used, the reaction proceeds smoothly by adding an alkali metal iodide such as sodium iodide or potassium iodide. When the compound represented by the 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.

The starting compound (III) is commercially available or can be prepared by a conventional method using piperazine or homopiperazine as a starting material. In addition, the raw material compound (I
I) can be produced, for example, by the method shown in Chemical formula 6 below.

[0039]

[Chemical 6]

(In the formula, Y means a chlorine atom or a bromine atom, and R ² , R ³ , R ⁴ , X and n have the same meanings as described above.)

Step 1 is for Ambelang, JC and Johnson,
The method of TB [J. Am. Chem. Soc., 61 , 632 (1939)] or a method similar thereto can be used. That is, the compound of formula (V) can be obtained by reacting the compound of formula (IV) with an equivalent amount of potassium thiocyanate in an aromatic hydrocarbon such as toluene at 40 to 150 ° C.
The compound of formula (IV) is commercially available or can be easily produced by a method known per se.

Step 2 can be carried out by the method of Huenig, S. and Huebner, K. [Chem. Ber., 95 , 937 (1962)] or a method analogous thereto. That is, the reaction is carried out by reacting the compound of formula (V) and the compound of formula (VI) in a halogenated hydrocarbon such as chloroform under ice cooling and then heating. The compound of formula (VI) is commercially available or can be easily produced by a method known per se.

Steps 3 and 4 can be carried out by the method of Carney, RWJ et al. [J. Org. Chem., 29 , 2887 (1964)] or a method analogous thereto. That is, it is carried out by dissolving the compound of formula (VII) in a lower alcohol such as ethanol, blowing in ammonia gas, and then heating.

From the compound of formula (VIII) in step 4,
The conversion of (II) into a compound is carried out by heating with phosphorus oxychloride, phosphorus tribromide, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride or the like.

Process (b) : The compound (I) of the present invention (provided that it is not a hydrogen atom or an unsubstituted or substituted phenyl group) has the following formula (IX)

[0046]

[Chemical 7]

(Wherein R ² , R ³ , R ⁴ , m and n have the same meanings as described above) and the following formula (X)

[0048]

[Chemical 8]

(Wherein Z represents a reactive ester residue of alcohol, R ¹¹ represents the same as R ¹ other than a hydrogen atom and an unsubstituted or substituted phenyl group). It can also be produced by reacting with.

Examples of the reactive ester residue of the alcohol represented by Z in the above formula (X) include halogen atoms such as chlorine, bromine and iodine, lower alkylsulfonyloxy groups such as methanesulfonyloxy and benzenesulfonyl. Oxy, arylsulfonyloxy groups such as p-toluenesulfonyloxy.

The reaction between the compound represented by the formula (IX) and the compound represented by the formula (X) is usually carried out in a suitable solvent. Specific examples of the solvent include benzene and xylene. Aromatic hydrocarbons, ketones such as methyl ethyl ketone, ethers such as dioxane, acetonitrile, N, N-dimethylformamide can be mentioned. 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 above production method (a) as they are. The reaction temperature is usually 30 to 150 ° C.

The compound represented by the formula (IX) can be obtained by the above production method (a). The compound represented by the formula (X) is commercially available, or can be easily produced by a method known per se.

Compounds of the formula (I) in which R ¹ is an aminophenyl group or an aminophenyl (lower) alkyl group can be obtained by the above production method (a) or (b), wherein R ¹ is a nitrophenyl group or a nitrophenyl group. It can also be produced by reducing a compound of formula (I) which is a (lower) alkyl group by a conventional method.

The product obtained by each of the above-mentioned production methods is isolated by a conventional method such as chromatography, recrystallization and reprecipitation.
It can be purified. The compound of formula (I) can be converted into an acid addition salt by treating it with various acids according to a conventional method.

[0055]

In order to clarify the characteristics of the action of the compound of the present invention, the results of the serotonin S ₂ receptor binding test of representative compounds of the present invention are shown below.

Test Example 1 Serotonin S ₂ Receptor Binding Action (In Vitro Receptor Binding Assay) Leysen, JE et al. [Mol. Pharmacol., 21 , 301 (1982)]
Reference], a serotonin S ₂ receptor binding test was performed.

Crude synaptosome membrane fraction prepared from rat brain as a receptor sample, and as a labeled ligand,
[ ³ H] Ketanserin was used.

After a receptor sample and a buffer solution (final volume: 1 ml) containing each labeled ligand were incubated in the presence of various concentrations of a test compound for a certain period of time, the radioligand bound to the receptor was treated with a cell harvester (Brandell). ) Was used for separation on the filter. The radioactivity on the filter was measured with a liquid scintillation counter to determine the total amount bound. Further, the binding amount in the presence of excess unlabeled ligand (methysergide) measured at the same time was defined as the nonspecific binding amount, and the specific binding amount was determined by subtracting this from the total binding amount.

The concentration at which the test compound inhibited the specific binding of the labeled ligand by 50% (IC ₅₀ ) was calculated by the probit method. The results are shown in Table 1.

[0060]

[Table 1] ^* Means the compound of Example 2 (the same applies hereinafter).

The compound of the formula (I) and pharmaceutically acceptable salts thereof (hereinafter sometimes referred to as "the compound of the present invention") have a strong antagonistic action on the serotonin S ₂ receptor. , Not only useful as a new type of antipsychotic drug effective against negative symptoms of schizophrenia and having less extrapyramidal side effects, but also other diseases of the central nervous system involving serotonin, such as anxiety and depression. It is also useful as a therapeutic drug for Parkinson's disease and sleep disorders.

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 varies depending on the kind of compound, administration method, patient's symptoms and age, etc.
05-50 mg / kg / day, preferably 0.05-5 mg / kg
/ Day.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a pharmaceutical carrier. 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, dextrin, cyclodextrin, starch, sucrose, magnesium aluminometasilicate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethyl cellulose, hydroxypropyl starch, carboxymethyl cellulose calcium, ion exchange resin. , Methyl cellulose, gelatin, gum arabic, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester , Sodium lauryl sulfate, glycerin, fatty acid glycerin ester, purified lanno Emissions, glycerogelatin, polysorbate, macrogol, vegetable oils, waxes, propylene glycol, water and the like.

Examples of the dosage form include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. The liquid preparation may be dissolved or suspended in water or another appropriate medium before use. The tablets and granules may be coated by a known method. These formulations contain 0.1% or more of the compound of the present invention, preferably 1 to
It can be contained in a ratio of 70%. These formulations may also contain other therapeutically effective ingredients.

[0065]

EXAMPLES In order to describe the present invention more specifically, reference examples and examples will be given below, but the present invention is not limited to these examples. The compounds were identified by elemental analysis values, mass spectra, IR spectra, and NMR.
It was performed by spectrum and the like.

Reference Example 1 Preparation of 4-Fluorobenzoyl Isothiocyanate:

A mixture of 50 g of 4-fluorobenzoyl chloride, 33.7 g of potassium thiocyanate and 80 ml of dry toluene was heated under reflux for 8 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by vacuum distillation to obtain 52.6 g of the desired product. Boiling point 93 ℃ / 3mmHg

Reference Example 2 --2- (4-fluorophenyl) -5,6,7,8,9,
10, -Hexahydro-4H-cycloocta [e]-
Preparation of 1,3-Oxazine-4-thione:

37.1 g of 4-fluorobenzoyl isothiocyanate was dissolved in 60 ml of chloroform, and a solution of 20 g of 1-morpholinocyclooctene in 20 ml of chloroform was added dropwise with stirring while maintaining the reaction temperature at 5 ° C. or lower.
After completion of dropping, the mixture was stirred at room temperature until the reaction temperature did not rise, and then heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from ethanol to obtain 10 g of the desired product. Melting point 104-105 ° C

Reference Examples 3 and 4-In place of 1-morpholinocyclooctene in Reference Example 2, 1-morpholinocycloheptene was used in Reference Example 3,
In Reference Example 4, 1-morpholinocyclohexene was used, reacted and treated in the same manner as in Reference Example 2, and the product was recrystallized from ethanol to obtain the following compound.

( Reference Example 3 )-2- (4-fluorophenyl) -4,5,6,7,8,
9-hexahydrocyclohepta [e] -1,3-oxazine-4-thione: melting point 139-140 ° C

Reference Example 4 2- (4-fluorophenyl) -5,6,7,8-tetrahydro-4H-1,3-benzoxazine-4-thione: melting point 149-151 ° C

Reference Example 5 : 2- (4-fluorophenyl) -5,6,7,8,9,
Preparation of 10-hexahydro-4 (3H) -cyclooctapyrimidinethione:

2- (4-fluorophenyl) -5,6
After blowing ammonia gas into a mixture of 10 g of 7,8,9,10-hexahydro-4H-cycloocta [e] -1,3-oxazine-4-thione and 200 ml of ethanol for 30 minutes, the mixture was stirred at 80 ° C for 30 minutes. did. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to obtain 9.2 g of the desired product. Melting point 189-192 ° C

Reference Examples 6 and 7 -2- (4-fluorophenyl) -5, in Reference Example 5
Instead of 6,7,8,9,10-hexahydro-4H-cycloocta [e] -1,3-oxazine-4-thione, in Reference Example 6, 2- (4-fluorophenyl) -4,
5,6,7,8,9-hexahydrocyclohepta [e]
-1,3-oxazine-4-thione was used as 2 in Reference Example 7.
Using-(4-fluorophenyl) -5,6,7,8-tetrahydro-4H-1,3-benzoxazine-4-thione, the reaction and treatment were carried out in the same manner as in Reference Example 5, and the product was converted from ethanol. Recrystallization gave the following compound.

Reference Example 6--2- (4-fluorophenyl) -3,5,6,7,8,
9-hexahydro-4H-cycloheptapyrimidine-4
-Thion: melting point 190-192 ° C

Reference Example 7 : 2- (4-Fluorophenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinethione: melting point 19
8 ~ 201 ℃

Reference Example 8 : 4-chloro-2- (4-fluorophenyl) -5,6,
Preparation of 7,8,9,10-hexahydrocyclooctapyrimidine:

2- (4-fluorophenyl) -5,6
9.2 g of 7,8,9,10-hexahydro-4 (3H) -cyclooctapyrimidinethione and 28 ml of phosphorus oxychloride
The mixture was heated to reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, ice water was added, and the mixture was stirred. The chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethanol to obtain 8.4 g of the desired product. Melting point 104-10
5 ° C

Reference Examples 9 and 10 --2- (4-fluorophenyl) -5, in Reference Example 8
Instead of 6,7,8,9,10-hexahydro-4 (3H) -cyclooctapyrimidinethione, in Reference Example 9 2- (4-fluorophenyl) -3,5,6,7,8,
9-hexahydro-4H-cycloheptapyrimidine-4
-Thion was reacted and treated in the same manner as in Reference Example 8 using 2- (4-fluorophenyl) -5,6,7,8-tetrahydro-4 (3H) -quinazolinethione in Reference Example 10 to obtain the product Was recrystallized from ethanol to obtain the following compound.

Reference Example 9 : 4-chloro-2- (4-fluorophenyl) -6,7,
8,9-Tetrahydro-5H-cycloheptapyrimidine: melting point 82-83 ° C

Reference Example 10 : 4-chloro-2- (4-fluorophenyl) -5,6,6
7,8-Tetrahydroquinazoline: melting point 96-97 ° C

Example 1 Preparation of 2- (4-fluorophenyl) -4- (1-piperazinyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidine:

A mixture of 4-chloro-2- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidine (2.5 g), anhydrous piperazine (2.2 g) and dimethyl sulfoxide (5 ml) was added at 110 ° C. It was heated to reflux for 1 hour. The reaction mixture was added to water, and the precipitated crystals were collected by filtration and washed with water, and the obtained crude crystals were dissolved in 20% hydrochloric acid. The insoluble material was filtered off, neutralized with aqueous sodium hydroxide solution, and extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was recrystallized from acetonitrile to obtain 1.3 g of the desired product. Melting point
126-127 ° C

Examples 2 to 4 In place of 4-chloro-2- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidine in Example 1, In 2, 4-chloro-2- (4-fluorophenyl) -6,7,8,9-
Tetrahydro-5H-cycloheptapyrimidine was used in Example 3 as 4-chloro-2- (4-fluorophenyl)-
5,6,7,8-Tetrahydroquinazoline, 4-chloro-2-phenyl-5,6,7, prepared in Example 4 according to the method described in J. Org. Chem., 29 , 2887 (1964).
8-Tetrahydroquinazoline was used in Example 1 respectively.
The following compounds were obtained by reacting and treating in the same manner as in.

Example 2 2- (4-Fluorophenyl) -4- (1-piperazinyl) -6,7,8,9-tetrahydro-5H-cycloheptapyrimidine: melting point 113-115 ° C. (acetonitrile) Recrystallized from)

Example 3 2- (4-fluorophenyl) -4- (1-piperazinyl) -5,6,7,8-tetrahydroquinazoline: melting point 145-146 ° C. (recrystallized from ethanol)

( Example 4 )-2-phenyl-4- (1-piperazinyl) -5,6,6
7,8-Tetrahydroquinazoline: melting point 255-26
3 ℃ (decomposition) (recrystallized from ethanol)

Example 5 : 2- (4-fluorophenyl) -4- (4-methyl-1)
Preparation of -piperazinyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidine:

A mixture of 2 g of 4-chloro-2- (4-fluorophenyl) -5,6,7,8,9,10-hexahydrocyclooctapyrimidine and 2.1 g of N-methylpiperazine at 110 ° C. for 3 hours. Heated and stirred. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, the chloroform layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Recrystallize the residue from ethanol to obtain 1.4 g of the desired product.
Got Melting point 133-134 ° C

Examples 6 to 13 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 5, and the product was recrystallized from ethanol to obtain the compounds of Table 2 represented by Chemical formula 9. .

[0092]

[Chemical 9]

[0093]

[Table 2] ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ Example n R ¹ R ² Melting point (° C.) ━━━━━━━ ━━━━━━━━━━━━━━━━━━━━━━━━━━━━ 6 5 Me F 141 to 142 7 4 Me F 144 to 145 8 4 CH ₂ CH ₂ OH F 119 to 120 9 4 CH ₂ Ph F 149 ~ 150 10 4 Me H 125 ~ 126 11 4 CH ₂ CH ₂ OH H 114 ~ 115 12 4 CH ₂ Ph H 131 ~ 132 13 4 Ph H 151 ~ 152 ━━━━━━━━━━━━ ━━━━━━━━━━━━━━━━━ Me: Methyl group, Ph: Phenyl group

Example 14 : 2- (4-fluorophenyl) -4- [4- [2- (4
-Nitrophenyl) ethyl] -1-piperazinyl]-
Preparation of 5,6,7,8-tetrahydroquinazoline:

2- (4-fluorophenyl) -4- (1
A mixture of -piperazinyl) -5,6,7,8-tetrahydroquinazoline (2.5 g), p-nitrophenethyl bromide (25 g), potassium carbonate (3.3 g) and acetonitrile (100 ml) was heated to reflux for 27 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with a mixed solution of chloroform-methanol (50: 1), and recrystallized from ethanol to obtain 2.0 g of the desired product. Melting point 150-153 ° C

Example 15- [4- [2- (4-aminophenyl) ethyl] -1-piperazinyl] -2- (4-fluorophenyl) -4-
Preparation of 5,6,7,8-tetrahydroquinazoline:

2- (4-fluorophenyl) -4- [4
-[2- (4-Nitrophenyl) ethyl] -1-piperazinyl] -5,6,7,8-tetrahydroquinazoline 1.
A mixture of 3 g, acetic acid 8 ml and 5% palladium carbon was stirred under a hydrogen atmosphere at room temperature for 1 hour, and then the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and then made alkaline with 10% aqueous sodium hydroxide solution. This was extracted with chloroform, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with a mixed solution of chloroform-methanol (100: 1), and recrystallized from ethanol to obtain 0.5 g of the desired product. Melting point 157-159 ° C

[0098]

INDUSTRIAL APPLICABILITY As described above, the compound of the present invention has a strong antagonistic effect on the serotonin S ₂ receptor, and therefore is effective for negative symptoms of schizophrenia and is an antipsychotic with less extrapyramidal side effects. Not only is it useful as a medicine,
It is also useful as a therapeutic drug for other central nervous system diseases involving serotonin, such as anxiety, depression, Parkinson's disease, and sleep disorders.

Claims (1)

[Claims] 1. A 2-phenylcycloalkanopyrimidine derivative represented by the following chemical formula 1 and a pharmaceutically acceptable acid addition salt thereof. [Chemical 1] [Wherein R ¹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy (lower) alkyl group, a cycloalkyl (lower) alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted phenyl (lower) alkyl group And R ² and R ³ are the same or different and each represents a hydrogen atom,
A halogen atom, a lower alkyl group or a lower alkoxy group, R ⁴ represents a hydrogen atom or a lower alkyl group,
m means 2 or 3 and n means 3, 4, 5, 6 or 7. ]