JP2860689B2 - Pyrimidine derivatives - Google Patents

Description

The present invention is excellent in selectivity and has a strong serotonin 2 receptor antagonism, and prevents or treats various diseases related to serotonin 2 receptor, for example, ischemic The present invention relates to a novel pyrimidine derivative or a salt thereof, which is useful as a pharmaceutical for use in the prevention or treatment of cardiovascular diseases such as heart disease and cerebrovascular disease, and the treatment of mental illness such as depression and schizophrenia.

[Conventional technology]

Serotonin are abundant in platelets is blood components, thromboxane A ₂ and ADP, is released upon such a platelet stimulation collagen, stronger platelet aggregation Ya working cooperatively with these platelet aggregation agent and vasoconstrictor Causes vasoconstriction. In particular, vasoconstrictor action of serotonin is strong. Serotonin is known to act via serotonin receptors on blood vessels, platelets and the like.
Serotonin receptors include serotonin 1 receptor and serotonin 2 receptor, but when endothelial cells of coronary vessels are damaged such as in myocardial infarction, serotonin is mediated by serotonin 2 receptors. It causes contraction of blood vessels and promotes thrombus formation, which is one factor that reduces or interrupts blood supply to organs such as the myocardium and the brain. It is also known that serotonin exerts a stronger vasoconstrictive action when there is a lesion such as arteriosclerosis. Attention has been paid to such points at present, and attempts are being made to use serotonin 2 receptor antagonists as drugs for ischemic diseases of the heart and brain.

Known compounds having a serotonin 2 receptor antagonism include ketanserin, which is used in medicine, and ritanserin, irinderone, etc., which are not actually used in medicine.

[Problems to be solved by the invention]

Meanwhile, the conventional serotonin 2 receptor antagonist has a serotonin 1 receptor antagonistic action and a sympathetic alpha-1 receptor antagonistic action in addition to the main action of serotonin 2 receptor antagonistic action. Ketanserin is used in medicine as an antihypertensive, but its main function is sympathetic nerve alpha-1.
It also has an antagonistic action on various autakoid receptors. For example, ketanserin is said to be based on strong sympathetic alpha-1 antagonism in addition to serotonin 2 receptor antagonism. However, a strong hypotensive effect is not very favorable for patients with acute myocardial infarction.

Accordingly, an object of the present invention is to provide a compound having a potent and highly selective antagonism against serotonin 2 receptor.

[Means for solving the problem]

Under such circumstances, the present inventors have conducted intensive studies, and as a result, have found that the following pyrimidine derivative (I) has a potent and highly selective serotonin 2 receptor antagonism, and completed the present invention.

That is, the present invention provides the following general formula (I) [In the formula, ^one of R ¹ and R ² represents a hydrogen atom, a lower alkyl group or an aralkyl group, and the other has the following general formula (II) or (III) (In the formula, Q represents a linear or branched alkylene group having 1 to 8 carbon atoms, and R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group. Represents an alkoxyl group, R ⁷ represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a phenyl group), and R ³ and R ⁴ each represent a phenyl group and the other represents a hydrogen atom or an alkyl group Or an alkylene group having 3 to 4 carbon atoms such that they combine to form a 5- to 6-membered ring with two carbon atoms of the pyrimidine ring. ] And a salt thereof.

In the present invention, the lower alkyl group means either linear or branched, and examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Those having 1 to 6 carbon atoms such as a t-butyl group are exemplified. The alkoxyl group means either linear or branched, and examples thereof include those having 1 to 6 carbon atoms such as a methoxyl group, an ethoxyl group, a propoxyl group and a butoxyl group. As the alkylene group, ethylene, propylene,
Isopropylene, butylene, isobutylene and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Further, the salt of the pitamidine derivative (I) of the present invention includes:
Mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; organic sulfonic acids such as methanesulfonic acid, benzenesulfonic acid and toluenesulfonic acid; or tartaric acid, maleic acid, fumaric acid,
Acid addition salts with organic carboxylic acids such as malic acid, oxalic acid, lactic acid, citric acid and the like.

The pyrimidine derivative (I) of the present invention can be produced, for example, according to the following reaction formula.

(In the formula, ^one of R ¹ ′ and R ² ′ represents a hydrogen atom, a lower alkyl group or an aralkyl group, and the other represents a hydrogen atom,
X represents a halogen atom, a toluenesulfonyloxy group or a methanesulfonyloxy group, and R ^{3 to} R ⁷ and Q have the same meanings as described above. That is, the pyrimidine derivative (I) of the present invention is produced by reacting the piperidine derivative (V) or (VI) with the compound (IV) in the presence of a suitable base.

This reaction is usually performed using dimethylformamide, dimethylsulfoxide, acetonitrile, dimethylacetamide, N
The reaction is carried out in an organic solvent such as methylpyrrolidone and benzene at a temperature from room temperature to the boiling point of the solvent. As the base, sodium carbonate, potassium carbonate, triethylamine and the like are used. If necessary, the reaction may be carried out in the presence of an alkali iodide such as sodium iodide or potassium iodide in a catalytic amount or more.

The pyrimidine derivative (I) of the present invention can also be produced according to the following reaction formula.

(Wherein, R ^{5 to} R ⁷ and Q have the same meanings as described above.) That is, the pyrimidine derivative (I) of the present invention can also be obtained by reacting the compound (IV) with an alcohol (VII) or (VIII). ) Is manufactured.

This reaction is usually carried out in an organic solvent such as tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidone, benzene, etc. in the presence of triphenylphosphine and azodicarboxylic acid diester from 0 ° C to the boiling point of the solvent. Performed at temperatures up to

The pyrimidine derivative (I) of the present invention can also be produced according to the following reaction formula.

(In the formula, ^one of R ¹ ″ and R ² ″ represents a hydrogen atom, a lower alkyl group or an aralkyl group, and the other represents a group —Q—X, wherein R ^{3 to} R ⁷ , Q and X are the same as those described above. That is, the pyrimidine derivative (I) of the present invention can be produced by reacting the compound (IX) with the piperidine derivative (X) or (XI) in the presence of a suitable base.

This reaction is usually performed using dimethylformamide, dimethylsulfoxide, acetonitrile, dimethylacetamide, N
The reaction is carried out in an organic solvent such as methylpyrrolidone and benzene at a temperature from room temperature to the boiling point of the solvent. As the base, sodium carbonate, potassium carbonate, triethylamine and the like are used. If necessary, the reaction may be carried out in the presence of an alkali iodide such as sodium iodide or potassium iodide in a catalytic amount or more.

The thus obtained pyrimidine derivative (I) can be converted into an acid addition salt by a conventional method, if necessary, and can be isolated by a means known per se, for example, recrystallization, column chromatography and the like.

The raw material, pyrimidine derivative (IV) or (I
X) can be produced, for example, according to the following reaction formula.

Wherein R ¹ ′, R ² ′, R ¹ ″, R ² ″, R ³ and R ⁴ have the same meaning as described above, R ⁸ represents a lower alkyl group, and R ⁹ represents a lower alkyl group or aralkyl. And Y represents a halogen atom. [Action and Effect of the Invention] Test Example 1. Measurement of Serotonin 2 Receptor Antagonistic Activity The thoracic aorta was isolated from a male SD-SLC rat after carotid artery exsanguination, and 5 mm in width. The ring specimen was suspended from a Magnus apparatus (tension 1 g). Tension was recorded using a polygraph via FD-pickup. A Krebs-Henselite nutrient solution was used as the nutrient solution, and a mixture of 95% oxygen gas and 5% carbon dioxide gas was passed through the nutrient solution, and the temperature was maintained at 37 ° C. After 90 minutes of sample stabilization, vessels were contracted with 60 mM potassium chloride. Sixty minutes after washing the potassium chloride, serotonin was added cumulatively and the shrinkage height was measured. Further measuring the contraction height of the vessel for addition to serotonin 0.01~10μM of the compounds of the present invention obtained in Examples below After washing stabilization of the specimen was calculated pA ₂ value from that value. The test results are shown in Table 1.

Except using phenylephrine instead of measuring serotonin Test Example 2. sympathetic alpha 1 receptor antagonist activity in the same manner as in Test Example 1 to calculate the pA ₂ values. The results are shown in Table 1.

As is clear from Table 1, the pyrimidine derivative of the present invention has a strong serotonin 2 receptor antagonistic activity, and its action is excellent in selectivity with the alpha-1 receptor antagonistic activity.

In addition, the serotonin 2 receptor antagonism of the pyrimidine derivative of the present invention was persistent.

Therefore, the pyrimidine derivative of the present invention ischemic heart disease,
Prevention or treatment of cardiovascular diseases such as cerebrovascular disorders, depression,
It is useful as an active ingredient of a drug used for treating psychiatric disorders such as schizophrenia.

〔Example〕

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Reference Example 1. 6-methyl-5-phenyl-2,4 (1H, 3H)-
Pyrimidinedione [raw material (1)] (1) 2,3-dihydro-6-methyl-5-phenyl-2
-Thioxo-4 (1H) -pyrimidinone [Raw material (1a)] 21.0 g of ethyl 2-phenylacetoacetate and 9.0 g of thiourea were heated at about 180 ° C for 2.5 hours. After cooling, the mixture was suspended in methanol, adsorbed on silica gel, and the methanol was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (200 g), and eluted with chloroform containing 5% methanol. 21%).

(2) 6-methyl-5-phenyl-2,4 (1H, 3H) -pyrimidinedione [raw material (1)] 2,3-dihydro-6-methyl-5 obtained in the above (1)
Phenyl-2-thioxo-4 (1H) -pyrimidinone 3.39
g, monochloroacetic acid 5.2 g, methanol 80 ml and water 120 ml was heated to reflux overnight. After adding 3.0 g of monochloroacetic acid and heating under reflux for 6.5 hours, methanol was distilled off under reduced pressure.
The precipitated crystals were collected by filtration, and 2.96 g of the title compound as colorless crystals
(94% yield).

Reference Example 2. 6-isopropyl-5-phenyl-2,4 (1H,
3H) -Pyrimidinedione [raw material (2)] (1) Ethyl 4,4-dimethyl-2-phenylacetoacetate [raw material (2a)] 4,4-dimethyl-2-phenylacetoacetonitrile 6
4 g was dissolved in 135 ml of ethanol, and hydrogen chloride gas was passed at about 10 ° C. for 8 hours. After standing for 2 days, the mixture was concentrated under reduced pressure, and poured into a mixture of 66 g of sodium carbonate, 400 ml of water and 0.7 kg of ice with stirring. The mixture was extracted three times with 180 ml of ether and washed four times with 80 ml of 5% saline. The ether layer was ice-cooled, and a mixture of 17 g of concentrated sulfuric acid, 120 ml of water and 250 g of ice was added to separate an organic layer. The aqueous layer was heated at 50 ° C for 30 minutes, extracted with ether, further heated at 80-90 ° C, and extracted with ether. The combined ether layers were washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure (bp ₃ 123-124 ° C) to give the title compound as a colorless oil (44.9%).
g (56% yield) was obtained.

(2) 2,3-dihydro-6-isopropyl-5-phenyl-2-thioxo-4 (1H) -pyrimidinone [raw material (2
b)] Reference Example 1 (1) from ethyl 4,4-dimethyl-2-phenylacetoacetate and thiourea obtained in (1) above.
Colorless crystals of the title compound were obtained in the same manner as in the above method. Yield 27%.

(3) 6-isopropyl-5-phenyl-2,4 (1H, 3H)
-Pyrimidinedione [raw material (2)] Reference example 1 (2) from 2,3-dihydro-6-isopropyl-5-phenyl-2-thioxo-4 (1H) -pyrimidinone and monochloroacetic acid obtained in the above (2). Colorless crystals of the title compound were obtained in the same manner as in the above method. 86% yield.

Reference Example 3. 1-acetyl-5-phenyl-2,4 (1H, 3H)
-Pyrimidinedione [raw material (3)] 5-phenyl-2,4 (1H, 3H) -pyrimidinedione 1.0 g
Was suspended in 15 ml of acetic anhydride and heated under reflux for 5 hours. After cooling,
The colorless crystals are collected by filtration, and 0.64 g of the title compound as colorless crystals (yield 5
7%).

Reference Example 4. 1-benzoyl-5-phenyl-2,4 (1H, 3
H) -Pitamidinedione [raw material (4)] 5-phenyl-2,4 (1H, 3H) -pyrimidinedione 4.70
g was suspended in 60 ml of hexamethyldisilazane and heated under reflux for 2 hours. The residue that was concentrated to dryness under reduced pressure was acetonitrile 10
The solution was dissolved in 0 ml, and 9.0 ml of benzoyl chloride was added dropwise with stirring. After 1 hour, the colorless crystals are collected by filtration to give the title compound as colorless crystals.
5.81 g (80% yield) was obtained.

Reference Example 5. 1- (2-Iodoethyl) -5-phenyl-
2,4 (1H, 3H) -pyrimidinedione [raw material (5)] (1) 1- (2-acetoxyethyl) -5-phenyl-
2,4 (1H, 3H) - pyrimidinedione [material (5a)] 5-phenyl - (1H, 3H) - pyrimidine-dione 10.0g were suspended in hexamethyldisilazane _{100ml, (NH 2) 2 SO} 4 5mg
Was added and the mixture was heated under reflux for 2.5 hours. After cooling, the reaction mixture was evaporated to dryness under reduced pressure, and the obtained residue was heated to 190 to 200 ° C., and 9.02 g of -acetoxyethyl bromide was added dropwise under a nitrogen atmosphere over 35 minutes. After further heating to 200 ° C. for 1 hour, the mixture was cooled and 100 mg of 95% methanol was added. The reaction solution was evaporated to dryness under reduced pressure, 100 mg of chloroform was added to the residue, the insoluble material was removed by filtration, and the filtrate was evaporated to dryness under reduced pressure. The obtained residue was subjected to silica gel column chromatography (250 g) to give 3%
Elution was carried out with a mixture of methanol and chloroform. Crystallization from a mixture of methanol and ethanol gave 5.85 g (40% yield) of colorless crystals of the title compound.

(2) 1- (2-Hydroxyethyl) -5-phenyl-2,4 (1H, 3H) -pyrimidinedione [raw material (5b)] 1- (2-acetoxyethyl) -5 obtained in (2) Phenyl-2,4 (1H, 3H) -pyrimidinedione (5.84 g) was dissolved in methanol (80 ml) to give 90% sodium methoxide (1.66).
g was added and stirred at 50 ° C. for 1 hour. After cooling, methanol 50m
The mixture was diluted with 1 l, neutralized with DOWEX 50W (H ⁺ ), and the precipitate was collected by filtration to give 4.43 g (yield 90%) of the title compound as colorless needles.

(3) 1- (2-methanesulfonyloxyethyl) -5
-Phenyl-2,4 (1H, 3H) -pyrimidinedione [raw material (5c)] 1- (2-hydroxyethyl) -5 obtained in (3)
2.50 g of phenyl-2,4 (1H, 3H) -pyrimidinedione was dissolved in 20 ml of pyridine, and 1.60 g of methanesulfonyl chloride was added under ice cooling, followed by stirring for 2.5 hours. A small amount of aqueous methanol was added to the reaction solution, and the mixture was evaporated to dryness under reduced pressure. After the residue was crystallized from aqueous methanol, 3.12 g of colorless crystals of the title compound were obtained (yield 9
4%).

(4) 1- (2-iodoethyl) -5-phenyl-2,4
(1H, 3H) -pyrimidinedione [raw material (5)] 1- (2-methanesulfonyloxyethyl) -5-phenyl-2,4 (1H, 3H) -pyrimidinedione obtained in (4)
2.40 g was suspended in 50 ml of methyl ethyl ketone, 1.5 g of sodium iodide was added, and the mixture was heated under reflux for 1.5 hours. After cooling, the reaction solution was evaporated to dryness under reduced pressure, water was added to the residue, and pale yellow crystals were filtered to obtain 1.86 g (yield 67%) of the title compound.

Table 2 shows the physical property values of the raw material compounds obtained in Reference Examples 1 to 5.

Example 1. 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -5-phenyl-
2,4 (1H, 3H) -pyrimidinedione hydrochloride [Compound (1 ') of the present invention] (1) 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -5-phenyl-2,4 (1
(H, 3H) -pyrimidinedione [the present compound (1)] 1.78 g of the raw material (3) obtained in Reference Example 3, 2- [4- (4-
2.15 g of [fluorobenzoyl) piperidin-1-yl] ethanol and 2.61 g of triphenylphosphine were dissolved in 70 ml of dimethylformamide, and 1.73 g of diethyl azodicarboxylate was added dropwise over 15 minutes while stirring with ice cooling. After stirring for 2 hours, the solvent was distilled off under reduced pressure. Chloroform was added to the residue, and the insolubles were collected by filtration to recover 0.95 g (yield: 60%) of 5-phenyl-2,4 (1H, 3H) -pyrimidinedione. The filtrate was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (150 g), eluted with chloroform containing 4-5% methanol. After evaporating the solvent, crystallization from ethanol and 0.54 g of the title compound as colorless crystals were obtained. (14% yield).

(2) 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -5-phenyl-2,4 (1
(H, 3H) -pyrimidinedione hydrochloride [Compound (1 ') of the present invention]
The residue was dissolved in 0 ml and concentrated hydrochloric acid (3 ml) was added thereto, followed by drying under reduced pressure. The residue was collected by filtration from isopropyl alcohol, and recrystallized from isopropyl alcohol and methanol to give 0.55 g (81%) of colorless crystals of the title compound.

Example 2. 3- [3- [4- (4-Fluorobenzoyl) piperidin-1-yl] propyl] -5-phenyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride [Compound of the present invention (2 ')] (1) 3- [3- [4- (4-Fluorobenzoyl) piperidin-1-yl] propyl] -5-phenyl-2,4
(1H, 3H) -pyrimidinedione [Compound (2) of the present invention] Reference Example 4 was carried out in the same manner as in the method shown in Example 1 (1).
Colorless crystals of the title compound were obtained from the raw material (4) obtained in the above and 3- [4- (4-fluorobenzoyl) piperidin-1-yl] propanol. Yield 53%.

(2) 3- [3- [4- (4-Fluorobenzoyl) piperidin-1-yl] propyl] -5-phenyl-2,4
(1H, 3H) -pyrimidinedione hydrochloride [Compound (2 ′) of the present invention] The compound (2) of the present invention obtained in (1) was converted into a hydrochloride in the same manner as in the method shown in Example 1 (2), A colorless powder of the title compound was obtained. 87%).

Example 3. 3- [4- [4- (4-Fluorobenzoyl) piperidin-1-yl] butyl] -5-phenyl-
2,4 (1H, 3H) -pyrimidinedione hydrochloride [Compound (3 ') of the present invention] (1) 3- [4- [4- (4-fluorobenzoyl) piperidin-1-yl] butyl] -5-phenyl-2,4 (1
(H, 3H) -pyrimidinedione [Compound (3) of the present invention] 4.50 g of the raw material (4) obtained in Reference Example 4, 4-chloro-1-
1.83 g of butanol and 4.85 g of triphenylphosphine were dissolved in 100 ml of dioxane, and 2.85 ml of diethyl azodicarboxylate was added dropwise under ice-cooling and stirring, followed by stirring at room temperature for 80 minutes. The insoluble matter was removed by filtration and the residue was dried under reduced pressure. The residue was subjected to silica gel column chromatography (300 g), and eluted with chloroform containing 2% methanol. After evaporating the solvent under reduced pressure, the crude 3- (4-chlorobutyl) -5-phenyl-2,4 (1H, 3
7.22 g of H) -pyrimidinedione was obtained as a caramel-like substance. This was dissolved in 50 ml of N, N-dimethylformamide to give 4- (4-fluorobenzoyl) piperidine hydrochloride.
2.63 g, anhydrous potassium carbonate 1.46 g and sodium iodide 0.
After adding 40 g, the mixture was stirred at about 100 ° C. for 24 hours. After filtering off the insoluble matter, water was added, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (120 g), and eluted with chloroform containing 4-7% methanol to obtain 0.72 g (yield 10%) of the title compound as an oil.

(2) 3- [4- [4- (4-fluorobenzoyl) piperidin-1-yl] butyl] -5-phenyl-2,4 (1
(H, 3H) -Pyrimidinedione hydrochloride The compound of the present invention (3) obtained in (1) was converted into a hydrochloride in the same manner as in Example 1 (2) to give a colorless powder of the title compound. Yield 69%.

Example 4. 3- [2- [4- [Bis (4-fluorophenyl) methylene] piperidin-1-yl] ethyl] -5
-Phenyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride [Compound (4) of the present invention] 1.17 g of the raw material (4) obtained in Reference Example 4, 2- [4- [bis (4-fluorophenyl) methylene] piperidine-1-
Il) ethanol 1.45 g and triphenylphosphine 1.2
6 g was dissolved in 40 ml of N, N-dimethylformamide, and 0.84 g of diethyl azodicarboxylate was added dropwise under ice cooling. Three
After stirring for 0 minutes, the reaction solution was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (100 g), and eluted with chloroform. The obtained oil was dissolved in 30% of 10% ammonia-ethanol and left at room temperature for 30 minutes. The reaction solution was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (30 g), and eluted with chloroform containing 3% methanol. After evaporating the solvent under reduced pressure, 0.38 g of a colorless oil was obtained. This was dissolved in ethanol (30 ml), concentrated hydrochloric acid (0.1 ml) was added, and the mixture was concentrated under reduced pressure.
1%).

Example 5. 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6 methyl-5
Phenyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride 1/2
Hydrate [Compound of the present invention (5 ')] (1) 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6-methyl-5-phenyl-2,4 (1H, 3H) -pyrimidinedione [compound of the present invention ( 5)] The title compound was obtained from the raw material (1) obtained in Reference Example 1 and 2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethanol in the same manner as in Example 1 (1). To obtain colorless crystals. Yield 12%.

(2) 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6-methyl-5-phenyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride 1/2 Hydrate [Compound of the present invention (5 ')] The compound of the present invention (5) obtained in (1) is converted into a hydrochloride in the same manner as in Example 1 (2) to give a colorless powder of the title compound. Obtained. Yield 77%.

Example 6. 3- [3- [4- (4-Fluorobenzoyl) piperidin-1-yl] propyl] -6-methyl-
5-phenyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride monohydrate [Compound (6) of the present invention] From the raw material (1) obtained in Reference Example 1 and 3- [4- (4-fluorobenzoyl) piperidin-1-yl] propanol, colorless crystals of the title compound were obtained in the same manner as in Example 4. Yield 4%.

Example 7. 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6-isopropyl-5-phenyl-2,4 (1H, 3H) -pyrimidinedione hydrochloride monohydrate [Product of the present invention (7)] A colorless powder of the title compound was obtained from the raw material (2) obtained in Reference Example 2 and 2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethanol in the same manner as in Example 4. Yield 17%.

Example 8. 1- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -5-phenyl-
2,4 (1H, 3H) -pyrimidinedione hydrochloride hemihydrate [Compound (8) of the present invention] 1.86 g of the raw material (5) obtained in Reference Example 5 (4), 4- (4-
1.32 g of fluorobenzoyl) piperidine hydrochloride and 0.75 g of anhydrous potassium carbonate were suspended in 20 ml of N, N-dimethylformamide, and heated and stirred at 70 ° C. for 5 hours. After the reaction solution was dried under reduced pressure, 50 ml of water was added to the residue, extracted with 50 ml of chloroform, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silica gel (30 g), and eluted with chloroform containing 3% methanol. The residue was dissolved in ethanol and concentrated hydrochloric acid was added.
After adding 5 ml and drying under reduced pressure, the residue was crystallized from aqueous ethanol to give 0.56 g (yield 23%) of colorless crystals of the title compound.

Example 9. 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6-phenyl-
2,4 (1H, 3H) -pyrimidinedione hydrochloride [Compound (9 ') of the present invention] (1) 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6-phenyl-1,3-
Oxazine-2,4 (3H) -dione [Compound (9) of the present invention] 6-phenyl-1,3-oxazine-2,4 (3H) -dione
1.06 g, 1.76 g of triphenylphosphine and 1.1 ml of diethyl azodicarboxylate were dissolved in 40 ml of dioxane, and stirred under ice-cooling to give 2- [4- (4-fluorobenzoyl) piperidine-
1-yl] ethanol (1.45 g) was dissolved in dioxane (10 ml) and added dropwise. After stirring at room temperature for 40 minutes, the reaction solution was evaporated to dryness under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and n-hexane, and recrystallized from ethyl acetate to give 0.94 of the title compound as colorless crystals.
g (40% yield) was obtained.

(2) 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6-phenyl-2,4 (1
(H, 3H) -Pyrimidinedione hydrochloride [Compound of the present invention (9 ')] 1.86 g of the compound of the present invention (9) obtained in (1) was dissolved in 50 ml of a 15% ammonia-ethanol solution and heated under reflux for 15 minutes. After cooling, the precipitate was collected by filtration, dissolved in 20 ml of ethanol, 10 ml of 1 N hydrochloric acid was added, and the mixture was heated to 50 ° C. for 1 hour. After evaporating the solvent under reduced pressure, the residue was crystallized from a mixture of water and ethanol to obtain 1.60 g (82% yield) of colorless crystals of the title compound.

Example 10. 1- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6-phenyl-
2,4 (1H, 3H) -pyrimidinedione hydrochloride hemihydrate [Compound (10 ') of the present invention] (1) 1- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6-phenyl-2,4 (1
[H, 3H] -pyrimidinedione [the present compound (10)] 2- [4- (4-fluorobenzoyl) piperidine-
1-yl] ethylamine (2.97 g) and 6-phenyl-1,3-oxazine-2,4 (3H) -dione (4.0 g) were dissolved in a mixture of dioxane (60 ml) and water (10 ml), and the mixture was heated under reflux for 20 hours. After cooling,
The solvent was distilled off under reduced pressure, and the residue was crystallized from a mixture of methanol and chloroform to give 6-phenyl-1,3-oxazine-
0.67 g of 2,4 (3H) -dione was recovered, the mother liquor was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel (200 g) column chromatography, eluted with chloroform containing 3% methanol, and a mixed solution of methanol and chloroform. To give 0.73 g (15% yield) of colorless crystals of the title compound.

(2) 1- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6-phenyl-2,4 (1
(H, 3H) -pyrimidinedione hydrochloride hemihydrate [Compound of the present invention (10 ')] A method shown in Example 1 (2) using 0.73 g of the compound of the present invention (10) obtained in (1) above. In the same manner as in the above, 0.56 g (yield 69%) of colorless crystals of the title compound were obtained.

Example 11. 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H) -dione hydrochloride 1/2
Hydrate [the present compound (11 ')] (1) 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H) -dione [The present invention Compound (11)] 5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H)-
Colorless crystals of the title compound were obtained from dione and 2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethanol in the same manner as in Example 1 (1). Yield 12%.

(2) 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H,)-dione hydrochloride Hemihydrate [Compound of the Invention (11 ')] The compound of the invention (11) obtained in the above (1) was prepared in Example 1
It was converted into the hydrochloride in the same manner as in (2) to give colorless crystals of the title compound. Yield 71%.

Example 12. 1- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6,7-dihydro-1H-cyclopentapyrimidine-2,4 (3H, 5H) -dione hydrochloride Salt 1/2 hydrate [Compound of the present invention (12 ')] (1) 1- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6,7-dihydro-1H-
Cyclopentapyrimidine-2,4 (3H, 5H) -dione [the present compound (12)] 1.56 g of diethyl 2-oxocyclopentanecarboxylate
And 2.35 g of N- [2- [4- (4-fluorobenzoyl) -piperidin-1-yl] ethyl] urea at 140-150 ° C
For 3 hours. After cooling, the residue was dissolved in chloroform, applied to a silica gel (80 g) column, and eluted with chloroform containing 4% methanol to give 0.42 g of the free base of the title compound.
(14% yield).

(2) 1- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6,7-dihydro-1H-
Cyclopentapyrimidine-2,4 (3H, 5H) -dione hydrochloride
Hemihydrate [Compound of the Present Invention (12 ')] The compound of the present invention (12) obtained in the above (1) was prepared in Example 1
It was converted into the hydrochloride in the same manner as in (2) to give colorless crystals of the title compound. 74% yield.

Example 13. 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6,7-dihydro-1H-cyclopentapyrimidine-2,4 (3H, 5H) -dione hydrochloride Salt [the present compound (13 ')] (1) 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6,7-dihydro-1H-
Cyclopentapyrimidine-2,4 (3H, 5H) -dione [compound of the present invention (13)] The silica gel column of Example 12 (1) was further eluted with 5% methanol-containing chloroform to remove the free base of the title compound as colorless crystals. 0.34 g (yield 11%) was obtained.

(2) 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6,7-dihydro-1H-
Cyclopentapyrimidine-2,4 (3H, 5H) -dione hydrochloride [Compound (13 ')] The compound (13) of the present invention obtained in the above (1) was prepared in Example 1.
It was converted into the hydrochloride in the same manner as in (2) to give colorless crystals of the title compound. Yield 81%.

Example 14. 3- [2- (4-benzoylpiperidine-
1-yl) ethyl] -5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H) -dione hydrochloride [the compound of the present invention (1
Four)〕 5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H)-
In the same manner as in Example 4, colorless crystals of the title compound were obtained from dione and 2- (4-benzoyl) piperidin-1-yl) ethanol. 8% yield.

Example 15. 3- [2- [4- (4-Methoxybenzoyl) piperidin-1-yl] ethyl] -5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H) -dione hydrochloride 1 /
Dihydrate [the present compound (15)] 5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H)-
In the same manner as in Example 4, colorless crystals of the title compound were obtained from dione and 2- [4- (4-methoxybenzoyl) piperidin-1-yl] ethanol. Yield 12
%.

Example 16. 3- [2- [4- (3,4-Dimethoxybenzoyl) piperidin-1-yl] ethyl-5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H) -dione hydrochloride Salt 1 /
Dihydrate [the present compound (16)] 5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H)-
In the same manner as in Example 4, colorless crystals of the title compound were obtained from dione and 2- [4- (3,4-dimethoxybenzoyl) piperidin-1-yl] ethanol. yield
13%.

Example 17. 3- [2- [4-Bis (4-fluorophenyl) methylene] piperidin-1-yl] ethyl] -5,
6,7,8-tetrahydroquinazoline-2,4 (1H, 3H) -dione hydrochloride dihydrate [the present compound (17)] 5,6,7,8-tetrahydroquinazoline-2,4 (1H, 3H)-
In the same manner as in Example 4, colorless crystals of the title compound were obtained from dione and 2- [4- [bis (4-fluorophenyl) methylene] -piperidin-1-yl] ethanol. 8% yield.

Table 3 shows the physical property values of the compounds of the present invention obtained in Examples 1 to 17.
Shown in

Continuation of front page (56) References JP-A-61-227565 (JP, A) JP-A-64-52718 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 401 / 06 CA REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The following general formula (I) [In the formula, ^one of R ¹ and R ² represents a hydrogen atom, a lower alkyl group or an aralkyl group, and the other has the following general formula (II) or (III) (In the formula, Q represents a linear or branched alkylene group having 1 to 8 carbon atoms, and R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxyl group. And R ⁷ represents a hydrogen atom, a hydroxyl group, a lower alkyl group or a phenyl group.) R ³ and R ⁴ each represent a phenyl group and the other a hydrogen atom or an alkyl group Or an alkylene group having 3 to 4 carbon atoms such that they combine to form a 5- to 6-membered ring together with the two carbon atoms of the pyrimidine ring. ] The pyrimidine derivative represented by these, and its salt.