JP3023691B2 - 3-substituted condensed triazine derivatives - Google Patents

Description

The present invention has a strong serotonin 2 receptor antagonism,
Useful as pharmaceuticals used in the prevention and treatment of various diseases related to serotonin 2 receptor, for example, the prevention or treatment of circulatory system diseases such as ischemic heart disease and cerebrovascular disease, and the treatment of mental illness such as depression and schizophrenia. And an intermediate for producing a 3-substituted condensed triazine derivative or an acid addition salt thereof.

[Problems to be solved by conventional technology and invention]

Serotonin is a kind of biogenic amine having strong platelet aggregation, vasoconstriction, etc., and is also involved in neurotransmission. Serotonin is known to act via serotonin receptors on blood vessels, platelets, and the like. It is known that serotonin receptors include serotonin 1 receptor, serotonin 2 receptor and the like. In cases such as myocardial infarction where endothelial cells in coronary vessels are damaged, serotonin causes the formation of blood clots through the contraction of blood vessels via the serotoni 2 receptor, leading to blood supply to the myocardial ischemia. It is thought that it has been further reduced. For this reason, attention has been paid to this point, and attempts to use serotonin 2 receptor antagonists as drugs for ischemic diseases of the heart and brain have been progressing, and have a serotonin 2 receptor antagonistic action, and are useful as pharmaceuticals. There is a need to provide compounds.

[Means for solving the problem]

Under such circumstances, the present inventors have conducted intensive studies and as a result, the following general formula (II) Wherein R is a hydrogen atom, an alkyl group or a halogen atom,
An aryl group which may be substituted with one or more substituents selected from an alkoxyl group, an alkyl group and a trihalogenomethyl group; n and m each represent an integer of 0 to 2; Represents a 5- to 7-membered ring which may contain one or two heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to the nitrogen atom of the part, and may contain one or more double bonds. Q is the following general formula (III) (Wherein, R ¹ represents a hydrogen atom, a hydroxyl group or a halogen atom, a hydroxyl group, an alkyl group, an alkoxyl group and an aryl group which may be substituted with one or more substituents selected from a trihalogenomethyl group, R ² , R ³ and R ⁴ each represent a hydrogen atom, a halogen atom, an alkyl group, an alkoxyl group or a trifluoromethyl group.) Or a group represented by the following general formula (IV) (Wherein, Ar ¹ and Ar ² each represent a halogen atom, a hydroxyl group,
It represents an aryl group or an aromatic heterocyclic residue which may be substituted with one or three substituents selected from an alkyl group, an alkoxyl group and a trihalogenomethyl group. ) Represents a group represented by. The novel condensed triazine derivative (II) represented by the formula (I) and an acid addition salt thereof have a highly selective and highly active serotonin 2 receptor antagonistic activity, and are used for the prevention and treatment of the above-mentioned circulatory diseases and the like. Was found to be useful. At the same time, they have found that the following novel compound (I) can be suitably used as an intermediate for producing the above-mentioned condensed triazine derivative (II), and thus completed the present invention.

That is, the present invention provides the following general formula (I) (Wherein, R, m, n and ring A have the same meaning as described above;
X is a hydroxyl group, a halogen atom, an alkylsulfonyloxy group, a trifluoromethanesulfonyloxy group or an arylsulfonyloxy group optionally substituted by one or more substituents selected from a halogen atom, an alkoxyl group, an alkyl group and a nitro group Means The present invention provides a 3-substituted condensed triazine derivative represented by the following formula:

Next, the substituents in the formulas (I) to (IV) will be described below.

Examples of the alkyl group include a methyl group, an ethyl group, an isopropyl group, an n-propyl group, and a
6 are mentioned. Examples of the alkoxyl group include those having 1 to 6 carbon atoms such as a methoxyl group, an ethoxyl group, a propoxyl group and a butoxyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. As the aryl group, a phenyl group,
Examples include a naphthyl group and a biphenyl group. A ring, piperidine ring, homopiperidine ring, pyrrolidine ring,
Pyridine ring, pyrimidine ring, pyrazine ring, pyrrole ring,
Examples include a thiazole ring, an oxazole ring, a pyrazole ring, an isothiazole ring, an isoxazole ring, a piperazine ring, and a morpholine ring.

As the 3-substituted condensed triazine derivative (I) of the present invention, in formula (I), ring A is a piperidine ring, a homopiperidine ring, a pyrrolidine ring or a thiazole ring;
Compounds in which the sum of is an integer of 1 to 2 are preferred.

Among the 3-substituted condensed triazine derivatives (I) of the present invention, in the general formula (I), the compound (Ia) wherein X is a hydroxyl group and X is a halogen atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group or an arylsulfonyl Compound (Ib) which is an oxy group can be produced, for example, according to the following reaction formula.

(Wherein, R, m, n and ring A have the same meaning as described above;
Ar represents an aryl group which may be substituted with one or more substituents such as a halogen atom, an alkyl group, an alkoxyl group and a nitro group, and Y represents a halogen atom, an alkylsulfonyloxy group, a trifluoromethanesulfonyloxy group or a halogen atom And an arylsulfonyloxy group optionally substituted with one or more substituents selected from an alkoxyl group, an alkyl group and a nitro group. That is, compound (V) was added to an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, or dimethylformamide in the presence of triethylamine, dimethylaniline, 1,8-
Aryloxycarbonyl chloride is reacted in the presence of a base such as diazabicyclo- [5.4.0] -7-undecene with a solvent used at a temperature from 30 ° C to a boiling point of 30 ° C to obtain a compound (VI). Then, the compound (VI) and the compound (VII) are reacted in an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, or dimethylformamide at a temperature from room temperature to the boiling point of the solvent used, or Heating compound (VI) and compound (VII) at a temperature of 40 to 200 degrees Celsius to give compound (Ia)
Is obtained.

Further, the compound (Ia) thus obtained was treated with tetrahydrofuran, benzene, toluene, acetonitrile,
In an organic solvent such as chloroform, dichloromethane, dioxane, and dimethylformamide, pyridine, triethylamine, dimethylaniline, 1,8-diazabicyclo [5.4.
[0] alkylsulfonyl chloride, optionally substituted arylsulfonyl chloride, trifluoromethanesulfonyl chloride in the presence of a base such as -7-undecene at a temperature of from 30 to 50 degrees Celsius depending on the solvent used. And the like, to give a sulfonyl ester (Ib). Further, the compound (Ia) is used in an organic solvent such as benzene, toluene, chloroform and dichloromethane, or without using such a solvent.
By reacting with a halogenating reagent such as thionyl chloride, phosphorus oxychloride, and thionine bromide, Y of the general formula (Ib)
Is a halogen atom.

Compound (Ib) can also be produced according to the following reaction formula.

(In the formula, R, m, n, A ring, Ar and Y have the same meanings as described above.) That is, compound (VII) includes tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, dimethylformamide and the like. Aryloxycarbonyl isocyanate (VIII) in an organic solvent at a temperature from zero degree Celsius to the boiling point of the solvent used
To give compound (IX). In an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, or dimethylformamide, triphenylphosphine and diethyl azodicarboxylate at a temperature from 30 degrees Celsius to the boiling point of the solvent used. Compound (Ib) can be obtained by condensing with compound (X).

Further, compound (Ib) can also be produced according to a synthetic route shown in the following reaction formula.

(Wherein, R, m, n, ring A, Ar and Y have the same meanings as described above.) That is, compound (IX) is obtained from chlorocarbonyl isocyanate (XI) and compound (XII) by West German Patent DE-34090.
Compound (XIII) produced by the method described in 65 [Chem. Abstr., 104 , 50897j (1985)] in an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, and dimethylformamide at room temperature. To the compound (VII) at a temperature up to the boiling point of the solvent used.

Further, the compound (XIII) is tetrahydrofuran,
Benzene, toluene, acetonitrile, chloroform,
In an organic solvent such as dichloromethane, dioxane, or dimethylformamide, the compound (X) is reacted with the compound (X) at a temperature ranging from 30 ° C. to the boiling point of the solvent depending on the solvent used to form a compound (XIV). Deriving compound (Ib) by reacting with compound (VII) in an organic solvent such as, acetonitrile, chloroform, dichloromethane, dioxane, dimethylformamide, etc., at a temperature ranging from 30 degrees Celsius below zero to the boiling point of the solvent depending on the solvent used. Can be. Compound (XIV) can be obtained by converting compound (XV) into an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, or dimethylformamide in the form of triethylamine, dimethylaniline, 1,8
By reacting with aryloxycarbonyl chloride in the presence of a base such as -diazabicyclo [5.4.0] -7-undecene to give compound (XVI) and in the same manner by reacting another molecule of aryloxycarbonyl chloride. Can also be manufactured.

The compound (Ib) of the present invention obtained as described above can be converted to a compound (II) which is a serotonin 2 receptor antagonist, for example, according to the following reaction formula.

(Wherein, R, m, n, ring A, Y, R ¹ , R ² , R ³ , Ar ¹ , Ar ²
And Q have the same meaning as described above. That is, the compound (Ib) of the present invention is prepared in an organic solvent such as tetrahydrofuran, benzene, toluene, acetonitrile, chloroform, dichloromethane, dioxane, or dimethylformamide in triethylamine, dimethylaniline, 1,8-diazabicyclo [5.4.0] -7-. The compound (II) is reacted in the presence of an organic base such as undecene or the like, or an inorganic base such as anhydrous sodium carbonate, anhydrous potassium carbonate, sodium hydride, or potassium hydride at a temperature from room temperature to the boiling point of the solvent used. Can be manufactured.

〔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 6,7,8,9-tetrahydro-2H-pyrido [1,2-
a] -1,3,5-Triazine-2,4 (3H) -dione A solution of sodium ethoxide in 0.83 g of sodium metal and 40 ml of absolute ethanol was added to an ethanol solution of 2-amino-3,4,5 under ice-cooling. Then, 4.8 g of 6,6-tetrahydropyridine hydrochloride was added, and the mixture was stirred at room temperature for 30 minutes. After filtering off the insoluble matter,
The filtrate was evaporated to dryness under reduced pressure. The residue was suspended by adding 30 ml of tetrahydrofuran, and 5.9 g of phenoxycarbonyl isocyanate was added dropwise over 10 minutes while stirring with ice cooling. The resulting crystals were allowed to stand overnight at room temperature, and the precipitated crystals were collected by filtration to obtain 1.4 g of the title compound as colorless crystals. The filtrate was further dried under reduced pressure, and the residue was subjected to silica gel column chromatography (100 g). After elution with a mixed solution of methanol and chloroform, 2.04 g of crystals was obtained. The crystals were combined with the above crystals to give 3.44 g of the title compound as colorless crystals.

mp 185-187 ° C. _{NMR (DMSO-d 6) δ} : 1.6-1.9- (4H, m), 2.65 (2H, t),
3.65 (2H, t), 11.39 (1H, b). IRν (KBr) cm ^-1 : 3450,3200,3070,1700,1590,1490,144
0,1390. Elemental analysis Calculated as C ₇ H ₉ N ₃ O ₂ Calculated value (%): C, 50.30; H, 5.43; N, 25.14 Observed value (%): C, 50.37; H, 5.45; N, 24.91 Reference Example 2 7,8-dihydro-2H, 6H-pyrrolo [1,2-a]
-1,3,5-Triazine-2,4 (3H) -dione In the same manner as in Reference Example 1, colorless crystals of the title compound were obtained from 2-iminopyrrolidine hydrochloride and phenoxycarbonyl isocyanate.

mp 201-202 ° C. _{NMR (DMSO-d 6) δ} : 2.87 (2H, t), 2.07 (2H, t), 3.82
(2H, t), 11.25 (1H, bs). IRν (KBr) cm ^-1 : 3430,3210,3080,1740,1710,1690,163
0,1440,1410. Elemental analysis Calculated as C ₆ H ₇ N ₃ O ₂ Calculated value (%): C, 47.06; H, 4.61; N, 27.44 Observed value (%): C, 47.15; H, 4.40; N, 27.33 Reference Example 3 7,8,9,10-Tetrahydro-2H, 6H-1,3,5-triazino [1,2-a] azepine-2,4 (3H) -dione In the same manner as in Reference Example 1, 3,4,5,6-tetrahydro-7
A colorless powder of the title compound was obtained from -amino-2H-azepine hydrochloride and phenoxycarbonyl isocyanate.

mp 157-158 ° C. NMR (CDCl ₃ ) δ: 1.7 (6H, m), 2.8 (2H, m), 4.0 (2H,
m), 11.0 (1H, bs). IRν (KBr) cm ^-1 : 3520,3200-2800,1730,1670,1600,148
0,1420. Elemental analysis Calculated value for C ₆ H ₁₁ FN ₃ O ₂ (%): C, 53.03; H, 6.12; N, 23.19 Actual value (%): C, 53.27; H, 6.24; N, 23.03 Reference Example 4 6,7,8,9-Tetrahydro-2H-pyrido [1,2-
a] 1,3,5-Triazine-2,4 (3H) -dione 1.52 g of 2-amino-3,4,5,6-tetrahydropyridine was dissolved in 30 ml of acetonitrile, and 3.86 g of diphenylimididicarboxylate was dissolved. In addition, the mixture was stirred at room temperature for 2 hours.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (100 g), and eluted with a mixed solution of methanol and chloroform to obtain 1.97 g of the title compound as colorless crystals.

mp 185-187 ° C. _{NMR (DMSO-d 6) δ} : 1.6-1.9 (4H, m), 2.65 (2H, t), 3.
64 (2H, t), 11.39 (1H, b). IRν (KBr) cm ^-1 : 3450,3200,3070,1700,1590,1490,144
0,1390 Elemental analysis As C ₇ H ₉ N ₃ O ₂ Calculated value (%): C, 50.30; H, 5.43; N, 25.14 Observed value (%): C, 50.42; H, 5.53; N, 25.02 Reference example 5 to 9 In the same manner as in Reference Example 4, the compounds shown in Table 1 were obtained.

Reference Example 10 3-phenoxycarbonyl-3,4,5,6-tetrahydro-2H-1,3-oxazin-2-one 23.8 g of bis (tri-n-butyltin) oxide
After 4.8 g of -chloropropyl isocyanate was stirred at room temperature for 10 minutes, 15.0 g of hexamethylphosphoramide (HMPA) was added, and the mixture was stirred at 80 ° C for 1 hour. After cooling, 6.26 g of phenyl chloroformate was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled, 80 ml of hexane was added, and the precipitated crystals were collected by filtration to obtain 7.79 g of the title compound as colorless crystals.

mp 94-96 ° C NMR (CDCl ₃ ) δ: 2.19 (2H, m), 3.91 (2H, t), 4.38 (2H,
t), 7.1-7.5 (5H, m). IRν (KBr) cm ^-1 : 2924,1808,1788,1696,1488. Elemental analysis Calculated as C ₁₁ H ₁₁ NO ₄ (%): C, 59.72; H, 5.01; N, 6.33. Actual value (%) : C, 59.44; H, 5.09; N, 6.56. Example 1 3- (2-chloroethyl) -6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5 -Triazine-2,4 (3H) -dione 6,7,8,9-tetrahydro-2H- obtained in Reference Example 1 or 4
Pyrido [1,2-a] -1,3,5-triazine-2,4 (3H)-
2.00 g of dione, 1.13 g of 2-chloroethanol and 4.20 g of triphenylphosphine were dissolved in 40 ml of tetrahydrofuran, and 2.79 g of diethylazodicarboxylate were dissolved in 5 ml of tetrahydrofuran and added dropwise. After stirring for 1 hour, the reaction solution was dried under reduced pressure, and the residue was subjected to silica gel column chromatography (120 g), eluted with a mixture of methanol and chloroform, and crystallized from acetone and isopropyl ether to give 1.20 g of the title compound as colorless crystals I got

mp 61-63 ° C. _{NMR (CDCl 3) δ: 1.8-2.2} (4H, m), 2.83 (2H, t), 3.77
(2H, t), 3.85 (2H, t), 4.28 (1H, t). IRν (KBr) cm ^-1: 3390,2976,1730,1678,1594,1848 Elemental analysis C ₉ H ₁₂ ClN ₃ O ₂ Calculated (%):. C, 47.07 ; H, 5.26; N, 18.30; Cl , 15.44. Found (%): C, 47.35; H, 5.49; N, 18.21; Cl, 15.20. Example 2 3- (2-bromoethyl) -6,7,8,9-tetrahydro-2H-pyrido [ 1,2-a] -1,3,5-Triazine-2,4 (3H) -dione 6,7,8,9-Tetrahydro-2H- obtained in Reference Example 1 or 4
Pyrido [1,2-a] -1,3,5-triazine-2,4 (3H)-
Colorless crystals of the title compound were obtained in the same manner as in Example 1 from dione and 2-bromoethanol.

mp 64-66 ° C. NMR (CDCl ₃ ) δ: 1.8-2.1 (4H, m), 2.84 (2H, t-lik
e), 3.59 (2H, t), 3.86 (2H, t-like), 4.33 (1H, t). IRν (KBr) cm ^-1 : 3396,2976,1730,1678,1594,1484. Elemental analysis Calculated as C ₉ H ₁₂ BrN ₃ O ₂ (%): C, 39.44; H, 4.41; N, 15.33. Value (%): C, 39.66; H, 4.48; N, 15.25. Example 3 3- (2-bromoethyl) -6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1 , 3,5-Triazine-2,4 (3H) -dione (1) Phenyl N- (2-bromoethyl) carbamate 5.0 g of 2-bromoethylamine hydrobromide and 3.91 g of phenyl chloroformate are suspended in 50 ml of dichloromethane. The mixture became cloudy and 5.1 g of triethylamine was added dropwise with stirring under ice-cooling. 2
After stirring for an hour, water was added to the reaction solution, and the organic layer was separated. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and hexane was added to the residue to crystallize it.
33 g were obtained.

mp 57-60 ° C. _{NMR (CDCl 3) δ: 3.4} (4H, m), 5.6 (1H, b), 7.0-7.5 (5
H, m). (2) 3- (2-bromoethyl) -6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,
4 (3H) dione phenyl N- (2-bromoethyl) carbamate 2.
44 g and 1.64 g of phenyl chloroformate were suspended in 25 ml of acetonitrile, and 1.2 g of triethylamine was added dropwise with stirring under ice cooling. After stirring at the same temperature for 20 minutes, the mixture was stirred at room temperature for 3 hours. The reaction solution was evaporated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 20 ml of acetonitrile,
1.35 g of amino-3,4,5,6-tetrahydropyridine hydrochloride and 2.02 g of triethylamine were added, and the mixture was stirred at 60 ° C. for 45 minutes.
The reaction solution was evaporated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (90 g), eluted with a mixture of methanol and chloroform, and crystallized from acetone and isopropyl ether.
0.65 g of colorless crystals of the title compound were obtained.

mp 64-66 ° C. NMR (CDCl ₃ ) δ: 1.8-2.1 (4H, m), 2.84 (2H, t-lik
e), 3.59 (2H, t), 3.86 (2H, t-like), 4.33 (2H, t). Example 4 3- (2-hydroxyethyl) -6,7,8,9-
Tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione (1) 3-phenoxycarbonyl-2-oxazolidone 2-oxazolidone 5.0 g and phenylchloroformate 9.08 g was dissolved in dichloromethane 50 ml, and the mixture was stirred under ice-cooling.
6.07 g of triethylamine was added dropwise. After stirring for 20 minutes, 50 ml of water was added to the reaction solution, and the organic layer was separated. The solvent was distilled off under reduced pressure, hexane was added to the residue for crystallization, and the crystals were collected by filtration to obtain 9.89 g of the title compound as colorless crystals.

mp 157-160 ° C. _{NMR (DMSO-d 6) δ} : 4.0-4.2 (2H, m), 4.3-4.5 (2H,
m), 7.2-7.6 (5H, m). IRν (KBr) cm ^-1 : 3520,3200-2800,1730,1670,1600,148
. 0,1420 Elemental analysis C ₁₈ H ₉ FNO ₄ Calculated (%):. C, 57.97 ; H, 4.38; N, 6.76 Found (%): C, 57.78; H, 7.36; N, 6.78 (. 2) 3- (2-hydroxyethyl) -6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione sodium metal To a solution of sodium ethoxide in ethanol prepared from 0.46 g and absolute ethanol 20 ml was added 2-amino-3,4,5,6-tetrahydropyridine hydrochloride under ice cooling.
2.69 g was added and the mixture was stirred at room temperature for 40 minutes. After filtering off the insoluble matter,
The filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 30 ml of acetonitrile, and the 3-phenoxycarbonyl-2- obtained in the above (1) was dissolved.
4.14 g of oxazolidone was added and stirred at 60 ° C. for 1.5 hours.
The reaction solution was evaporated to dryness under reduced pressure, and the residue was subjected to silica gel column chromatography (120 g) to elute a mixture of methanol and chloroform to obtain 3.45 g of the title compound as colorless crystals.

mp 125-128 ° C. _{NMR (DMSO-d 6) δ} : 1.8-2.1 (4H, m), 2.69 (1H, s), 2.
82 (2H, t), 3.86 (4H, t-like), 4.14 (2H, t). IRν (KBr) cm ^-1 : 3292,2960,1730,1684,1602,1504,145
2,1416. Elemental analysis Calculated as C ₉ H ₁₃ N ₃ O ₃ Calculated (%): C, 51.18; H, 6.20; N, 19.89. Found (%): C, 50.83; H, 6.43; N, 19.64 Examples 5 to 8 In the same manner as in Example 4, the compounds shown in Table 2 were obtained.

Example 9 3- (2-methanesulfonyloxyethyl)
-6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,
3,5-triazine-2,4 (3H) -dione 3- (2-hydroxyethyl) -6,7, obtained in Example 4
8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5-
Dissolve 1.80 g of triazine-2,4 (3H) -dione and 1.20 g of triethylamine in 25 ml of acetonitrile, and stir under ice-cooling with stirring.
1.17 g of methanesulfonyl chloride was added dropwise. After stirring for 30 minutes, the reaction solution was evaporated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the title compound was a yellow caramel-like substance 2.34 g.
I got

_{NMR (CDCl 3) δ: 1.8-2.1} (4H, m), 2.8 (2H, t), 3.1 (3
H, s), 3.9 (2H, t), 4.3 (2H, t), 4.5 (2H, t). Example 10 3- [2- (4-methylbenzenesulfonyloxy) ethyl] -6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2, 4 (3H) -dione In the same manner as in Example 9, 3- (2-hydroxyethyl) -6,7,8,9-tetrahydro-2H-pyrido [1,2-a]
Light yellow crystals of the title compound were obtained from -1,3,5-triazine-2,4 (3H) -dione and 4-methylbenzenesulfonyl chloride.

_{NMR (CDCl 3) δ: 1.8-2.1} (4H, m), 2.44 (3H, s), 2.81
(2H, t-like), 3.83 (3H, t-lile), 4.3 (4H, m), 7.32
(2H, d), 7.77 (2H, dd). Example 11 3- (2-bromoethyl) -6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione diphenyl imide 2.57 g of dicarboxylate, 2-
Bromoethanol 1.50 g, triphenylphosphine 3.41 g
Then, 2.26 g of diethyl azodicarboxylate was added dropwise to a mixture of the mixture and 30 ml of tetrahydrofuran with stirring. After stirring for 2 hours, 0.98 g of 2-iminopiperidine was added, and the mixture was stirred at room temperature for 2 hours.
Stirred for hours. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (150 g), eluted with ethyl acetate, and crystallized from a mixture of acetone and isopropyl ether to obtain 0.92 g of the title compound as colorless crystals.

mp 64-66 ° C. NMR (CDCl ₃ ) δ: 1.8-2.1 (4H, m), 2.84 (2H, t-lik
e), 3.59 (2H, t), 3.86 (2H, t-like), 4.33 (1H, t). IRν (KBr) cm ^-1 : 3396,2976,1730,1678,1594,1484. Elemental analysis Calculated as C ₉ H ₁₂ BrN ₃ O ₂ (%): C, 39.44; H, 4.41; N, 15.33. Value (%): C, 39.58; H, 4.62; N, 15.13. Example 12 3- (1-hydroxypropan-2-yl)
-6,7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,
3,5-Triazine-2,4 (3H) -dione (1) 5-Methyl-3-phenoxycarbonyl-2-oxazolidone 5-methyl-2-oxazolidone and phenylchloroformone in the same manner as in Example 4 (1). Colorless crystals of the title compound were obtained from the mate.

mp 116-119 ° C. NMR (CDCl ₃ ) δ: 1.53 (3H, d), 4.0 (1H, m), 4.50 (2H,
m), 7.1-7.5 (5H, m). IR (KBr) cm ^-1: 3448,1812,1728,1592,1484 Calculated elemental analysis _{C 11 H 11 NO 4 (%} ):.. C, 59.72; H, 5.01; N, 6.33 Found (%) : C, 59.56; H, 5.08; N, 6.52. (2) 3- (1-hydroxypropan-2-yl) -6,
7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5
-Triazine-2,4 (3H) -dione 5- (5) obtained in the above (1) in the same manner as in Example 4 (2).
Colorless crystals of the title compound were obtained from methyl-3-phenoxycarbonyl-2-oxazolidone and 2-amino-3,4,5,6-tetrahydropyridine hydrochloride.

mp 109-112 ° C. _{NMR (DMSO-d 6) δ} : 1.40 (3H, d), 1.7-2.1 (4H, m), 2.
80 (2H, t), 3.34 (1H, s) 3.6-3.9 (3H, m), 4.09 (1H, d
d), 5.02 (1H, m). IR (KBr) cm ^-1: 3300,2948,2884,1680,1606,1490 Calculated elemental analysis _{C 10 H 15 N 3 O 3} (%):.. C, 53.32; H, 6.71; N, 18.65 Found Value (%): C, 53.26; H, 6.89; N, 18.82. Example 11 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6,7,8,9 -Tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione 3- (2-methanesulfonyloxyethyl) -6,7 obtained in Example 9 , 8,9-Tetrahydro-2H-pyrido [1,2-
a] Dissolve 3.3 g of 1,3,5-triazine-2,4 (3H) -dione in 25 ml of acetonitrile, add 1.01 g of triethylamine and 2.27 g of 4- (4-fluorobenzoyl) piperidine, and heat for 4 hours Refluxed. The reaction solution was evaporated to dryness under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (80 g), and eluted with a mixture of methanol and chloroform to give the title compound as yellow crystals.
2.17 g were obtained.

mp 170-172 ° C. _{NMR (CDCl 3) δ: 1.8-2.2} (10H, m), 2.26 (2H, t), 2.81
(2H, t), 3.0-3.3 (3H, m), 3.84 (2H, t), 4.06 (2H,
t), 7.13 (2H, t), 7.95 (2H, dd). IRν (KBr) cm ^-1 : 1730, 1670, 1600, 1490, 1450, 1410. Elemental analysis Calculated as C ₂₁ H ₂₅ FN ₄ O ₃ (%): C, 62.99; H, 6.29; N, 13.99. Value (%): C, 62.76; H, 6.32; N, 14.05. Example 12 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6,7,8,9 -Tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione hydrochloride 3- [2- [4- (4-fluoro Benzoyl) piperidin-1-yl] ethyl] -6,7,8,9-
1.0 g of tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione was dissolved in 30 ml of hot ethanol, and 1 ml of concentrated hydrochloric acid was added. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to give 0.8 g of colorless crystals of the title compound.

mp 256-259 ° C (decomposition). _{NMR (DMSO-d 6) δ} : 1.4-2.4 (8H, m), 2.86 (2H, t), 3.
1−4.0 (9H, m), 4.37 (2H, t), 7.30 (2H, t), 8.07 (2H, t)
dd). IRν (KBr) cm ^-1 : 3450,2940,2510,1730,1670,1600,148
0,1420. Elemental analysis: C ₂₁ H ₂₅ FN ₄ O ₃ .HCl Calculated value (%): C, 57.73; H, 6.00; N, 12.82. Observed value (%): C, 57.50; H, 5.82; N Reference Example 13 3- [2- [4- (4-Fluorobenzoyl) piperidin-1-yl] ethyl] -6,7,8,9-tetrahydro-2H-pyrido [1,2-a]- 1,3,5-Triazine-2,4 (3H) -dione maleate 3- [2- [4- (4-fluorobenzoyl) piperidin-1-yl] ethyl] -6, obtained in Reference Example 11. 7,8,9−
1.0 g of tetrahydro-2H-pyrido [1,2-a] -1,3,5-triazine-2,4 (3H) -dione was dissolved in 30 ml of methanol, and 0.29 g of maleic acid was added. The solution was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and recrystallized from ethanol to give 0.64 g of the title compound as colorless crystals.

mp 150-152 ° C (decomposition). _{NMR (DMSO-d 6) δ} : 1.6-2.1 (8H, m), 2.71 (2H, t), 2.
9-3.4 (4H, m), 3.5-3.8 (5H, m), 4.12 (2H, m), 6.06
(2H, s), 7.39 (2H, t), 8.10 (2H, dd). IRν (KBr) cm ^-1 : 3650-3300,2950,1730,1680,1600,148
5. Elemental analysis: C ₂₁ H ₂₅ FN ₄ O ₃ · C ₄ H ₄ O ₄ Calculated value (%): C, 58.13; H, 5.66; N, 10.85. Observed value (%): C, 58.28; H, 5.64; N, 10.87. Reference Example 14 3- [2- [4- [bis (4-fluorophenyl) methylene] piperidin-1-yl] ethyl] -6,
7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5
-Triazine-2,4 (3H) -dione 3- (2-methanesulfonyloxyethyl) -6,7,8,9-tetrahydro-2H-pyrido obtained in Example 9 in the same manner as in Reference Example 11. 1,2-a] -1,3,5-Triazine-2,4
(3H) -dione and 4- [bis (4-fluorophenyl)
-Methylene] -1- (2-hydroxyethyl) piperidine gave a yellow oil of the title compound.

NMR (CDCl ₃ ) δ: 1.8-2.0 (4H, m), 2.3 (4H, m), 2.5-
2.8 (8H, m), 3.8 (2H, t), 4.07 (2H, t), 6.96 (4H, d),
7.04 (4H, s). Reference Example 15 3- [2- [4- [bis (4-fluorophenyl) methylene] piperidin-1-yl] ethyl] -6,
7,8,9-tetrahydro-2H-pyrido [1,2-a] -1,3,5
-Triazine-2,4 (3H) -dione dihydrochloride 3- [2- [4- [bis (4-fluorophenyl) methylene] piperidin-1-yl] ethyl] -6,7 obtained in the above Reference Example 14. , 8,9-Tetrahydro-2H-pyrido [1,2-
a] A colorless powder of the title compound was obtained from -1,3,5-triazine-2,4 (3H) -dione in the same manner as in Reference Example 12.

mp 192-195 ° C. _{NMR (DMSO-d 6) δ} : 1.7-2.0 (4H, m), 2.5-2.9 (6H,
m), (6H, m), 3.0-3.4 (4H, m), 3.5-3.8 (4H, m), 4.
19 (2H, t), 7.18 (8H, d), 9.85 (1H, s), 11.41 (1H, b
s). IRν (KBr) cm ^-1 : 3450,2550,1760,1730,1620,1510,145
0. Elemental analysis _{C 27 H 28 F 2 N 4} O 2 · 2HCl Calculated (%):. C, 58.81 ; H, 5.48; N, 10.16 Found (%): C, 58.66; H, 5.72; N , 10.09. Test Example 1) Measurement of serotonin 2 receptor antagonistic activity A test compound was dissolved in purified water in male SD-SLC rats.
Oral administration at a dose of 0 mg / kg, and urethane (1 g / k
g, intraperitoneal administration) and α-chloralose (80 mg / kg, intraperitoneal administration). A polyethylene cannula was inserted into the carotid artery and blood pressure was recorded on a polygraph recorder via a pressure transducer. Sixty minutes after the administration of the test compound, serotonin (300 μg / kg) was intravenously injected and the pressor response was observed. The pressor inhibition rate was calculated from the pressor response of the control group to which purified water was administered and the pressor response of the test compound-administered group.
It was (hereinafter 5-HT ₂₎ antagonistic activity. The test results are shown in Table 3.

[Effects of the Invention] As described above, the 3-substituted condensed triazine derivative (I) of the present invention is useful as a production intermediate of compound (II), which is an excellent serotonin 2 receptor antagonistic substance.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07D 487/04 150 C07D 487/04 150 498/04 498/04 105 105 116 116 116 513/04 341 513/04 341 498/04 112T (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 471/04 C07D 487/04 C07D 498/04 C07D 513/04 CAPLUS (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The following general formula (I) (Wherein X is a hydroxyl group, a halogen atom, an alkylsulfonyloxy group, a trifluoromethanesulfonyloxy group or an aryl optionally substituted with one or more substituents selected from a halogen atom, an alkoxyl group, an alkyl group and a nitro group) A sulfonyloxy group, R represents a hydrogen atom, an alkyl group or a halogen atom, an alkoxy group, an aryl group which may be substituted with one or more substituents selected from an alkyl group and a trihalogenomethyl group,
m and n are each an integer of 0 to 2, and ring A may contain one or two heteroatoms selected from nitrogen, oxygen and sulfur in addition to the nitrogen in the condensed part with the triazine ring; A 5- to 7-membered ring which may contain one or more double bonds is shown. A) 3-substituted condensed triazine derivative represented by the formula: