JPH03170431A - Treating agent for heart disease - Google Patents

Abstract

PURPOSE:To obtain a strong treating agent for heart disease containing a condensed triazine derivative or salt thereof, having excellent long-acting property and antagonistic activity against serotonin 2 receptor. CONSTITUTION:The objective treating agent containing a compound expressed by formula I[R<1> and R<2> are H, alkyl or aryl which may be replaced; (n) and (m) are 0-6; A is 5-7 membered ring; Q is formula II (R<3> is H, OH or aryl which may be replaced; R<4> to R<6> are H, halogen, alkyl, alkoxy or trihalogenomethyl), formula III (Ar<1> and Ar<2> are aryl which may be replaced or aromatic heterocyclic residue which may be replaced)] or salt thereof, e.g. 3-[2-[4-(4-fluorobenzoly) piperidine-1-yl]ethyl]6,7,8,9-tetrahydro-2H-pyrido[1,2-a]-1,3,5-triazi ne-2,4(3H)-dione. The treating agent is especially effective on prevention or treatment of ischemic heart disease.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a compound of formula (I) [wherein R1 is selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenmethyl group] An aryl group that may be substituted with one or more substituents, R2 is substituted with one or more substituents selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenomethyl group. n and m each represent an optionally substituted aryl group,
6 is an integer, A represents a 5- to 7-membered ring, which ring shares one nitrogen atom and is fused with all 4 triazine rings, and in addition to the nitrogen atom at the fused portion, a nitrogen atom, an oxygen atom, and It may contain one or two heteroatoms selected from sulfur atoms, or it may contain one or more double bonds, and Q is represented by the following general formula (!■)fl4 (wherein, R3 is a hydrogen atom, a hydroxyl group or an aryl group which may be substituted with one or two substituents selected from a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group and a trihalogenomethyl group, R4R5 and R6 are each a hydrogen atom, a halogen atom, an alkyl group, represents an alkoxy group or a trihalogenomethyl group) or a group represented by the following general formula (III) (wherein Ar' and Ar' are a halogen atom, a hydroxyl group, an alkoxy group, an alkyl group, and a trihalogenomethyl group, respectively) represents an aryl group or an aromatic heterocyclic residue which may be substituted with 1 to 3 substituents selected from the following. The present invention relates to a preventive and therapeutic agent for heart diseases containing a condensed triazine derivative or a salt thereof as an active ingredient.

[Prior Art] β-blockers are used as therapeutic agents for heart diseases such as angina pectoris, myocardial infarction, and heart failure. Calcium blocker. Cardiotropes are known.

As for therapeutic agents for this disease, research has been carried out in recent years on drugs having serotonin 2 receptor antagonistic action, but no drug with sufficient efficacy has yet been found.

[Problems to be Solved by the Invention] The present inventors have completed the present invention as a result of intensive studies to find a serotonin 2 receptor antagonist that has an excellent effect on heart diseases as described above.

[Structure of the Invention] The present invention relates to a prophylactic and therapeutic agent for heart diseases, which contains a condensed triazine derivative of formula (I) or a salt thereof as an effective ingredient.

The heart disease related to the present invention is angina pectoris. myocardial infarction,
Possible causes include heart failure and arrhythmia.

Next, the substituents in formula (!) will be explained below.

Alkyl groups include methyl, ethyl, isobrobyl,
1 carbon number such as n-propyl, tertiary butyl, n-butyl, etc.
I can list ~6 things. Examples of halogen atoms include fluorine, chlorine, bromine, and iodine.

Examples of the alkoxy group include those having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, and poxy. Examples of the A ring fused to the triazine ring include pyridine, pyrazine, virol, biperidine, homopiveridine,
Virolidine, viperazine, homoviperazine, birimidine, thiazole, virazole, oxazole, isothiazole, isoxazole, triazole, triazine, 1
．． Examples include 5- to 7-membered aromatic or aliphatic heterocycles such as 4-oxazine, 1.3-oxazine, 1.4-thiazine, and 1.3-thiazine. Examples of the aryl group include phenyl, naphthyl, biphenyl, and the like. Examples of the aromatic heterocyclic residue in the substituent of formula (IIT) include biridyl, pyridinyl, chenyl, furyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, and the like.

In the compound of formula (I), ring A is biveridine, homopiveridine or thiazole, the sum of m and n is an integer of 0 to 6, and Q is of formula (11') (wherein R31 is hydrogen or a hydroxyl group, (X means a halogen atom) or a group represented by the formula (m') (in the formula, XI and X2 each mean a halogen atom) be able to.

Salts of the compound of formula (1) include acid addition salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or organic sulfonic acids such as methanesulfonic acid, pencenesulfonic acid, and toluenesulfonic acid, and tartaric acid and maleic acid. , fumaric acid, malic acid,
Examples include acid addition salts of organic carboxylic acids such as oxalic acid, lactic acid, and citric acid.

Next, a method for producing the condensed triazine derivative represented by formula (I) will be explained.

+IV) (In the formula, R', R2, A, n, m and Q are the same as above.

) That is, a compound represented by formula (IV) is dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, etc. by formula (IV).
The desired formula (1) is obtained by reacting the compound represented by V) with various dehydrating reagents, such as a mixture of triphenylphosphine and azodicarboxylic acid dialkyl ester, at a temperature from 0°C to the boiling point of the solvent. Compounds of can be produced.

Further, the compound of formula (IV) is represented by the following formula (VT)R'Xs- (C}12). -CH- (CH2) --
Q ('/I) (where x3 is a halogen atom,
paratoluenesulfonyloxy group or methanesulfonyloxy group, R', n, m and Q are the same as above), and an equimolar or more amount of an alkali carbonate such as potassium carbonate or sodium carbonate, hydrogen Alkali hydrides such as sodium chloride, potassium hydride or triethyl hydride, l. 8-diazabicyclo[5,4.0]
The formula (I
) can be produced. In this reaction, it is also possible to add a catalytic amount of alkali iodide such as sodium iodide or potassium iodide.

Next, the intermediate represented by formula (TV) will be explained.

2H-Virido[1.2-8]-1.3.5- in the compound
triazine-2.4(3H) monodione (West German Patent Publication No. 1922837), 2H-bilyodo[1.2-al
-1.3.5-}Ryazine-2.4(3H) monodione (
Synthesis, p. 892, 1985), 5-methyl-
2H one year old xazolo[3.2-a]-1.3.5-}-riazine-2. 4 (3H)-dione (British Patent No. 1
328205), 8-methylimidazo [1. 2-a
l −1. 3. 5-triazine-2.4 (3H
,8H) monodione (Journal of Organ
ic Che-mistry, 43.4774.197
Some of the compounds are known, such as
The compound can be produced by referring to the methods disclosed in these documents.

Generally, the compound of formula (rv) can be produced by the following method.

(VIE) (ff)(
In the formula, R2 and A are the same as above. ) That is, the compound of formula (IV) is produced by reacting the compound of formula (VII) with phenoxycarbonyl isocyanate in a solvent such as dimethylformamide, tetrahydrofuran, dioxane, etc. at a temperature from 0°C to the boiling point of the solvent. be able to.

The compound of formula (1) was orally administered to rats for 10 consecutive days, and its toxicity was examined. No deaths were observed even after oral administration of aoomg/kg, indicating that the compound of formula (1) and its salts are safe. was confirmed to be high.

The compound of formula (I) or a salt thereof can be formulated into a dosage form such as a tablet, powder, capsule, or injection, and is usually administered orally, subcutaneously, intramuscularly, or intravenously.

The dosage of the compound of formula (I) or a salt thereof is usually in the range of 30 to 2000 mg/day per person for oral administration.

<Effects of the Invention> The compound of formula (1) and its salt have a strong and long-lasting serotonin 2 receptor antagonistic effect, and are also useful in experimental models of heart diseases accompanied by ischemic changes, such as myocardial infarction models. ,
It has shown excellent effects in improving cardiac function, myocardial necrosis, preventing thrombosis in coronary arteries, and improving cardiac microcirculation in angina models. Therefore, the compound of formula (1) or a salt thereof is excellent as a preventive or therapeutic agent for heart diseases, especially heart diseases accompanied by ischemic changes.

Hereinafter, the present invention will be explained by reference examples and examples, but the present invention is not limited thereto.

Reference example 1 3-[2-(4-(4-fluorobenzoyl)+A 11 ro)No-i-no+1.1
-f: t+ snow to1 ctoo - etrahydro-2H-pyrid [1.2-a] -1.3.5
-triazine-2,4(3}1) monodione (1)
6,7,8.9-tetrahydro2H-pyrido [1.2
-a] -1.3.5 -triazine-2.4(3
H) To an ethanol solution of sodium ethoxide prepared from 0.83 g of sodium monodione metal and 40 ml of absolute ethanol, 4.8 g of 2-amino-3.4.5.8-tetrahydropyridine hydrochloride was added under water cooling, and the mixture was heated to 30 mL at room temperature. The mixture was stirred for a minute. After removing insoluble matter by filtration, the filtrate was dried under reduced pressure. Add 30 ml of tetrahydrofuran to the residue, suspend it, and add 5.9 g of phenoxycarbonyl isocyanate to 10
It was dripped in minutes. After leaving it at room temperature overnight, the precipitated crystals were collected by filtration, and 1.4 g was obtained. Further, the filtrate was dried under reduced pressure, and the residue was applied to a silica gel column (100 g), and after elution with chloroform containing 5% methanol, 2.04 g of crystals were obtained. Combined with the previous crystals, 3.44 g of colorless crystals of the title compound
I got it.

Nh A +oc-+oq? 1 Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6) δ
: 1.6-1.9 (4H, m), 2.65 (2
H, t) 3.84 (2H, t) , 11.39 (1
1{,b). Infrared absorption spectrum v (KBr) cm
1': 3450, 3200, 3070, 1700, 15
90,1490,1440,1390. Calculated value (zero) as elemental analysis C7H9N302: C, 50.30; }1, 5.43;
N, 25.14. Actual value (%): C, 5Q. 37
．． H, 5.45; N, 24.91. (2) 37 [
2-[4-(4-fluorobenzoyl)biveridin-1-yl]ethyl-6.7,8.9-tetrahydro-2H-pyrido[1.2-a-1.3.5-triazine-2.4( 3H) monodione 8,7,8.9-tetrahydride-2H-pyrido[i
4-a-1.3.5-triazine-2.4 (3H
) monodione 34.1 g, 4-(4-fluorobenzoyl)-1-(2-hydroxyethyl)piveridine 5
1.2 g and 56.1 g of triphenylphosphine were suspended in 900 ml of tetrahydrofuran, and 38 g of azodicarboxylic acid diethyl ester was added dropwise over 15 minutes while cooling with water. After stirring for 20 minutes in chamber 7, the solvent was distilled off under reduced pressure.
500 ml of ethyl acetate was added to the residue and extracted with IN monohydrochloric acid. This 1N monohydrochloric acid extract was made alkaline by adding potassium carbonate and extracted with chloroform. It was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was crystallized from ethanol, and then recrystallized from a mixture of methanol and ethanol to obtain colorless crystals of the target compound.
7g was obtained.

Melting point 170-172°C Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.2 (IOH, m), 2.26 (2H, t)
,2.81 (2}1,t) ,3.0-3.3 (
3H,m) ,3.84 (2}1,t) ,4.06
(2H, t) ,7.13 (2H, t) . 7.9
5 (2H, dd). Infrared absorption spectrum ν (KBr) cm-': 173
0,1670,1600,1490,1450,141
0. Calculated value (zero) as elemental analysis CztH2sFN4Ch: (:, 62.99; H, 6.29. N, 13
．． 99. Actual value): C, Ii2.68. H, 6.
2B. N, 13.83. Reference Example 2 3-[2-[4-(4-fluorobenzoyl)viveridin-1-ylcoethylco6.7,8.9-tetrahydro-2H-pyrido[1.2-acotriazine-2.
4(3H) monodione hydrochloride 3-[2-[4-(4
-fluorobenzoyl)biveridin-1-yl]ethylco6.7,8.9-tetrahydro-2H-pyrido[1
．． 2-a]-1.3.5-triazine-2.4
(3H)-dione 33. Og in hot ethanol 150m
1 and added 5 ml of concentrated hydrochloric acid. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 27.4 g of colorless crystals of the title compound.

Melting point 251i-259℃ (decomposition) Nuclear 6R gas resonance spectrum (heavy water) δ: 1.4-2.4 (8H, m), 2.86 (2
H, t), 3.1-4.0 (9H, m), 4.37 (
2. t). 7.30 (2}1,t) ,8.07
(2H, dd). Infrared absorption spectrum ν (KBr)
cm-' :3450.2940.2510,1730
, 1670, 1500, 1480, 1420. Calculated value as elemental analysis Cz+lhsFN403/HCI (Hori): C, 57.73. H, 6.00. N,1
2.82. Actual value (%): C, 57.50. L5
．． 82. N, 12.59 Reference Example 3 3-[2-[4-(4-fluorobenzoyl)biveridin-1-yl]ethyl]-1i,7,8.9-tetrahydro-2H-pyrido[1.2-a ] Triazine-2,4 (3}1) monodione maleate 3-[2-[4-(4-fluorobenzoyl)biveridin-1-yl]ethyl]-6 obtained in Reference Example 1 above.
7,8.9-tetrahydro-2H-pyride [1.2-a
] Triazine-2.4 (3}1)-dione 2.0
Dissolve g in 50 ml of methanol to obtain 0.58 maleic acid.
g was added. The solvent was concentrated under reduced pressure and the precipitated crystals were collected by filtration.
Recrystallization from 90% aqueous ethanol gave colorless crystals of the title compound.1. ．． 27g was obtained.

Melting point 180-183℃ (decomposition) Nuclear 6n gas resonance spectrum (dimethyl sulfoxide da
) δ: 1.6-2.1 (8H, m), 2.
71 (2}1,t) ,2.9-3.4? ．． 5-3.
8(5}1m). 4.12 (2H, m). 6.06 (2
H,s), 7.39 (2H.t), a. to(zH,d
d) Infrared absorption spectrum ν(κBr) cm-': 344
8.1734, 1677, 1596, 1494.145
Five element analysis C2■H2SFN403・C4H. Calculated value as 04 (phantom: C, 58.13; }!.5.66.
N, 10.85. Actual measurement value: C, 58.28.
}1,5.64; N,10.87.

Reference Example 4 3-[2-[4-(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7.8-dihydro-2
8,6H-pyrrolo[1.2-a]-1.3.5-triazine-2.4(3H) monodione (1) 7.8-dihydro2}1.6H-pyrrolo[1
．． 2-a]-1.3.5-triazine-2.4(
3H) Monodione Colorless crystals of the title compound were obtained from 2-iminopyrrolidine hydrochloride and phenoxycarbonyl isocyanate in the same manner as in Reference Example 1(l). Melting point 201-202℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 2.87 (2n, t). 2.07 (zo.
t), 3.82 (2H.t). 11.25 (1
}1, bs). Infrared absorption spectrum υ (KBr) crn-': 34
30.3210,3080.1?40,1710.18
90, 1630, 1440, 1410. Elemental analysis (:6}1? Calculated value (!k) as N302: C, 47.06. H, 4.61.
N, 27.44. Actual measurement value C'4"): C, 47.1
5; H, 4.40; N, 27.33. (2) 3-
[2-(4-(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7.8-dihydro-2H,BH
-pyrrolo[1.2-al-1.3.5-}-riazine-2.4(3H) monodione 7.8-dihydro28,6}1 obtained in Reference Example 4(l)
-Virolo(1.2-al-1.3.5-triazine-2.4(3H)ion and 4-(4-fluorobenzoyl)-1-(2-hydroxyethyl)piveridine in Reference Example 1(2) Condensation was carried out using triphenylphosine and azodicarboxylic acid diethyl ester in N,N-dimethylformamide in the same manner as described in , to obtain the caramel-like title compound.

Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.7-1.9 (4H, m), 2.1-2.5 (4H,
m), 2.68(2}1.t). 2.9-3.4 (5H
, m). 4.05 (4H, t-1ike) ,7.1
2 (2}1,t). 7.95 (2}1, dd). Reference Example 5 3-[2-[4-(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7.8-dihydro-2
8.8H-PyroO [1.2-a]-1.3.5-
}Ryazine-2.4(3H) monodione hydrochloride hemihydrate 3-[2-[4-
(4-fluorobenzoyl)piveridin-1-yl]ethyl]-7,8-dihydro28,6H-pyrrolo[1.
2-a]-1.3.5-triazine-2.4(3H
) 2.95 g of dione was dissolved in 50 ml of methanol, 2 ml of concentrated hydrochloric acid was added, and the mixture was dried under reduced pressure. The residue was crystallized from ethanol to obtain 2.30 g of the title compound as a colorless powder.

Melting point 253-255℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1.8-2.3 (6H.m). 2.91 (
2H. t). 3.0-3.5 (4H, m), 3.5-
4.0 (5H, m). 4.16 (2H, t), 7.37
(2H, t), 8.09 (2H, dd), 10.68
(1}1,b). Infrared absorption spectrum ν (KBr) am-': 35B
0,2940,2510, 1730.1680. 1
630, 1480, 1450, 1420. Elemental analysis Calculated value as CzoH23FN401HCl4/2H20 C9g): C, 55.62. H, 5.8
3; N, 12.97. Actual value (!k): C, 55.
69. H, 5-. 80. N, 12.83. Reference Example 6 3- [2- [4- (4-fluorobenzoyl>piveridin-1-yl]ethyl] -7.8.9.10-
Tetrahydro-28,6H -1.3.5-}-riadino[l,2-al azepine-2.4(3H)monosion (1) 7,I1,9.10-tetrahydro28,
6}! -1.3.5-triazino[1. 2-a]
Azevin-2.4 (3H) monodione monohydrate The title was obtained from 3,4,5.8-tetrahydro-7-amino-2H-azepine hydrochloride and phenoxycarbonyl isocyanate in the same manner as in Reference Example 1 (l). A colorless powder of the compound was obtained.

Melting point 157-158 ℃ Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.7
(6H,m) ,2.8 (21{,m)4.0(2
}1, m), 11.0 (LH, bS). Infrared absorption spectrum ν (KBr) cm-': 3520.3200
-2800.1730,1670, 1600,14
80,1420. Elemental analysis CaH+ IFN302・H20 Calculated value (%;): C, 4B. 24. H, 6.58; N,
21.09. Actual value <94): C, 48.33. H
, 6.42; N, 21.02. (2) 3- [2-
[4-(4-fluorobenzoyl)viveridin-1-
ylcoethyl] -7.8,9.10-tetrahydro-
2}1,6H-1.3.5-triazino[1,
2-al Azevin-2,4(3}1) One dione 7,8,9.10-tetrahydro2} produced in Reference Example 6(1) above! , 8H-triazino[1. 2-a
] Azevin-2,4(3H) monodione and 4-(4
-fluorobenzoyl)-1-(2-hydroxyethyl)biperidine was condensed using triphenylphosphine and azodicarboxylic acid diethyl ester in N,N-dimethylformade in the same manner as in Reference Example 1(2). Colorless crystals of the compound were obtained.

Melting point: 130-132°C Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.0 (10}1,m) ,2.0-2.4 (2
H. m), 2.69 (2H, t), 3.0-3.
3 (38, m), 4.0-4.2 (4H, m), 7
．． 13 (2H, t). 7.95 (2H, dd). Infrared absorption spectrum ν(κBr) cm-': 344
0,2950,1725,1670.1800,147
0,1440. Reference Example 7 3-[2-[4-(4-fluorobenzoyl)viveridin-1-ylcoethylco7.8,9.10-tetrahydro-28,6H-1.3.5-triazino[1.21a] Azepine-2.4(3H) monodione dihydrochloride 3-[2-[4-
(4-fluorobenzoyl)biperidin-1-yl]ethyl]-7.8,9.10-tetrahydro-28,8H
-1.3.5? Triazino [1. 2-a] Dissolve 3.83 g of azepine-2.4 (3H) dione in 50 ml of methanol, add 1.6 ml of concentrated hydrochloric acid,
It was dried under reduced pressure. After adding ethanol and concentrating under reduced pressure several times, it was crystallized from a mixture of ethanol and isobrobyl ether.
3.70 g of the title compound was obtained as a colorless powder.

Melting point 172-176 ℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d,)
δ: L. S-2.2 (10N, m) ,2.8 (
2H, m), 3.0-3.5 (4H, m), 3.
5-3.9 (3H, +n) ,4.0-4.2 (4
H, m) y7.37 (2H, t) ,8.12 (2
H, dd). 11.0(1}1,b). Infrared absorption spectrum v (KBr) cm-': 3450,29
40,2360,1770,1725.1680,16
10,1580,1450,1430.1230 Elemental analysis C2 H27FN403/2HG: Calculated value (
96): C, 54.21; H, 8.00; N, 1
1.50. Actual value (!t;) + C, 54.12; H
, 6.33; N 11.42. Reference Example 8 3-[3-[4-(4-fluorobenzoyl)biveridin-1-yl)probilco6.7,8.9tetrahydro-2H-pyrido[1.2-a]-1.3.5- Triazine-2.4(3H) monosion 6.7,8.9-tetrahydro 2H-pyrido [l,2-a] -1.3.5 - obtained in Reference Example 1(l) above
Triazine-2.4(3}1) monodione and 4-(4-fluorobenzoyl)-1-(3-hydroxyprobyl)
Piveridine was condensed with triphenylphosphine and azodicarboxylic acid diethyl ester in N,N-dimethylformamide in the same manner as in Reference Example 1(2) to obtain the title compound.

Nuclear magnetic coexcitation spectrum (deuterochloroform) δ: 1.5
-2.1 (12H, m). 2.50 (2H, t
) ,2.7-3.1 (4H,m) ,3.2 (I
H, m) ,3.85 (2H,t) ,4.02 (
2H,t) ,7.13 (2H,t)7.95 (2
}1, dd). Reference Example 9 3- [3- [4- (4-fluorobenzoyl) biveridin-1-yl] brovyl] -6.7, 8.9
-Tetrahydro-2H-pyrid [1.2-a] -1.
3.5-triazine-2.4(3}1) monodione maleate hemihydrate 3-[2-[4-(4-fluorobenzoyl)viveridine-1-] obtained in Reference Example 8 above yl]propylco6.7,8.9-tetrahydro-2H-pyrido[1,2
-al -1.3.5 -triazine-2.4(3}1
) 0.76 g of dione was dissolved in 100 ml of hot ethanol, and 0.21 g of maleic acid was added. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethanol to obtain 0.42 g of colorless crystals of the title compound.

Melting point 87-89℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: L. S-2.2 (10}1,m) ,2.70
(2H, t) , 2.9-3.3 (4H, m)
．． 3.4-4. 0 (7H, m) ,6.04 (2
H,s). 7.39 (2H,t) ,8.10(2
}1. dd). Infrared absorption spectrum ν(κBr) cm-': 345
0,2970,1730,. 1880.1600,14
90. Elemental analysis C22H27FN403/C4H40.
・Calculated value as 1/2H20 (U: C, 57.88.
H, 5.98; N, 10.38. Actual measurement information): C
, 57.50. H, 6.30. N, 10.18. Reference example 10 3- [2- [ 4- (4-fluorobenzoyl)
-4-hydroxypiperidin-1-yl]ethyl]-6
．． 7,8.9-tetrahydro-2H-pyrido[1.2-
a] -1.3.5 - triazine-2.4(3}1
) Dione 8,7,8.9 obtained in Reference Example 1(1) above
-Tetrahydro2H-pyrido [1.2-a] -1.
3.5-triazine-2,4(3}1) monodione and 4-(4-fluorobenzoyl)-4-hydroxy-1
-(2-hydroxyethyl)viveridine in Reference Example 1 (2)
) in the same way as N. Condensation was carried out using triphenylphosphine and azodicarboxylic acid diethyl ester in N-dimethylformamide to obtain colorless crystals of the title compound.

Melting point 217-220℃ Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.6
-2.0 (8M, m). 2.3-2.7 (81{
,m). 3.68 (2H, t). 3.87 (2
H, t). 5.68 (IH,s) ,7.28(
2H, t) , 8.24 (2H, dd) . Infrared absorption spectrum ν(κBr) cm-': 3450,29
50,1730,1670.160Q,1490,14
50,1410. Reference example 11 3- [2- [4- (4-fluorobenzoyl)-
4-hydroxybiveridin-1-yl]ethyl]-6.
7,8.9-tetrahydro-2H-pyrido [1.2-a
]-1.3.5-triazine-2.4(3H) monodione dihydrochloride hemihydrate 3-[2-(4-(4-fluorobenzoyl)-4 obtained in Reference Example 10 above) -Hydroxypiperidine-1-
Ilcoethylco6.7,8.9-tetrahydro-2H
-Pyrido(1.2-al-1.3.5-triazine-2.4 (311)) 0.80 g of dione was dissolved in 30 ml of methanol, 0.4 ml of concentrated hydrochloric acid was added, and the mixture was concentrated under reduced pressure. .

Ethanol was added to the residue and concentration under reduced pressure was repeated, and the precipitated crystals were collected by filtration and washed with acetone to obtain 0.68 g of colorless crystals of the title compound.

Melting point 178-184℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide 66)
δ: 1.6-2.4(B}I.m), 2.7(2}
1,t), 3.0-3.6(6H,m). 3.73(
2}1, t), 4.1 (2H, t), 7.2-7.
5 (3H, m), 8.77 (2}1, dd), 11
．． 0 (IH.b). Infrared absorption spectrum ν (KBr)
cm-': 3410, 3220, 2550, 1780
, 1730, 1680, 1610, 1580, 1440
．． Elemental analysis C2+HzsFN404・2Hcl4/2H2
Calculated value as 0 (“4): C, 50.60; H, 5
. aa; N, 1.1.24. Actual value (U: C, 50
．． 88; H, 5.81; N, 10.87. Reference example 1
2 3- [2-[4-(4-fluorobenzoyl)-4-phenylpiveridin-1-yl]ethyl]-6
．． 7,8.9-tetrahydro-2H-pyrido[1.2-
al-1.3.5-triazine-2.4(38) monodione 6,7,8.9-tetrahydro-2H-pyrido[1.2-a]-1 obtained in Reference Example 1(1). 3.5-triazine-2.4(3H) monodione and 4-(4-fluorobenzoyl)-4-phenyl-1-(2-hydroxyethyl)viveridine were treated with N,
condensation using triphenylphosphine and azodicarboxylic acid diethyl ester in N-dimethylformamide,
The title compound was obtained as an oil.

Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.9 (161{,m) ,3.8 (2H,t-
1ike) ,4.03 (2}1,t) ,6.89
(2H, t) , 7.26-7.48 (7H, m)
．． Reference Example 13 3- [2- [4- (4-fluorobenzoyl)-
4-phenylbiveridin-1-yl]ethyl]-6.7
, 8.9-tetrahydro-2H-pyrido [1. 2-
a]-1.3.5-triazine-2. 4 (3H
) Monodione dihydrochloride 172 elongated product 3-(2-[4-(4-fluorobenzoyl)-4-phenylbiveridin-1-yl]ethyl]-6.7,8. 9-tetrahydro-2H-
Virid[1.2-a]-1.3.5-triazine-2.4 (3H) monodione 0.75g methanol 3
After dissolving the solution in 0.0 ml and adding 0.3 ml of concentrated hydrochloric acid, the mixture was concentrated under reduced pressure.

Ethanol was added to the residue and vacuum concentration was repeated. The residue was recrystallized from a mixture of methanol and ethanol to obtain 0.52 g of the title compound as a colorless powder.

Melting point 203-210℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxy d6) δ
: 1.6-2.0 (4H, m), 2.4-3.1
(8}1,m) ,3.3 (2H,m) ,3.5
-3.7 (4H, m), 4.1 (2H, t).
7.1-7.7 (9H, m) 11.2 (IH, b)
．． Infrared absorption spectrum ν(KBr) c′′ :3410
,2960.2490.1770,1730,1680
, 1 [i20, 1580, 1500, 1440. Elemental analysis C27H29FN40,・2}1et・1/2H20
Calculated value as (interest: C, 58.07; H, 5.77
; N, 10.03. Actual value (*) + C, 58.28
．． H, 6.04. N. 9.70 Reference Example 14 3-[2-(4-(4-fluorobenzoyl)biperidin-1-yl]ethyl]-2H-pyrido[1.2
-a]-1.3.5-triazine-2.4(3H)
monodione dihydrochloride 2H-pyrido[1.2-al-1.3.5-triazine-2.4(3H) monodione 0.42 g, 4-(4-
Fluorobenzoyl)-1-(2-hydroxyethyl)
0.67 g of viveridine and 0.67 g of triphenylphosphine.
82 g was suspended in 10 ml of N,N-dimethylformamide, and 0.54 g of azodicarboxylic acid diethyl ester was added dropwise. After stirring at room temperature for 75 minutes, the reaction solution was dried under reduced pressure, and the residue was crystallized from ethanol. After filtering, 0.7 g of the base of the title compound was obtained. The obtained crystals were mixed with 30 m of ethanol.
After adding 0.2 ml of hydrochloric acid and concentrating under reduced pressure, the precipitate was collected by filtration to obtain 0.27 g of the title compound as a colorless powder.

Melting point 243-244℃ (decomposed) Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1.8-2.2 (4H, m), 2.88-3
．． 97 (7H, m), 4.38 (2Lt), 7.1
-7.5 (4H, m) 8.0 - 8.3 (3H, m), 8
．． [i9(IH, d). 11.02 (IH, bS). Infrared absorption spectrum ν (KBr) cm-': 3430
．． 2700-2200, 1730, 1680, 164
0,1590,1560,1440,1410. Elemental analysis C21H21FN40・2HC] Calculated value (1;
): C, 53.74; H, 4.94. N, 11.
94. Actual value <96>: C, 53.39. H, 4.
83. N, 11.83, Reference Example 15 3-[2-[4-(4-fluorobenzoyl)-biveridin-1-yl]ethyl]-2}1-thiazolo[
3.2-a] -1.3.5 - triazine-2.4
(31{) monodione 2H-thiazolo[3.2-a] -1.3.5-triazine-2.4(3H) monodione 1.69 g, 4-
2.51 g of (4-fluorobenzoyl)-1-(2-hydroxyethyl)piveridine and 2.89 g of triphenylphosphine were added to 40 ml of N,N-dimethylformamide.
1.92 g of azodicarboxylic acid diethyl ester was added dropwise to the suspension under water-cooling and stirring. After stirring at room temperature for 30 minutes, the reaction solution was dried under reduced pressure, and ethyl acetate was added to the residue and collected by filtration to obtain 3.0 g of colorless crystals of the title compound.

Melting point 184-187℃ Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.5
-1.9 (4H, m) , 2.2 (2H, m) ,
2.5 (28, m). 3.0 (2H, 10).
3.4 (IH, m) , :l. ! Is (2H, t)
,7.18<II{,d),7.34(2H,t)
,7.71 (IH.d) ,8.05 (2o.da)
．． Infrared absorption spectrum v (KBr) cm-': 34
50.307G, 2940, 2820, 1750. 1
67G, 1590.1550. Reference Example 16 3-[2-[4-(4-fluorobenzoyl)biperidin-1-yl]ethyl]-2H-thiazolo[3.
2-a]-1.3.5-triazine-2.4(3H)
Monodione hydrochloride hemihydrate 3-[2-[4-(4fluorobenzoyl)piveridin-1-yl]ethyl]-2 obtained in Reference Example 15 above
2.95 g of H-thiazolo[3.2-a]-1.3.5-triazine-2.4(3}1) monodione was suspended in methanol 50[+11], 2 ml of concentrated hydrochloric acid was added, and the crystals precipitated. was collected by filtration and recrystallized from hot water containing a small amount of methanol to obtain 2.08 g of the title compound as a colorless powder.

Melting point 278-280℃ (decomposed) Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1. Ii-2.2 (4}1,m) ,2.9
-3. 8 (7H, m), 4.24 (2H, t)
,7.23 (IH,d) ,7.38 (2H,t
)． 7.92 (IH, d). 8.11 (2H,
dd). Infrared absorption spectrum ν(KBr) cl”
:3/! 70, 1740, 1670, 1600, 158
0,1550,1420. Elemental analysis C+oH+aFN403S-}ICI・1
Calculated value as 72H20 (90: C, 50.95
．． H, 4.73: N, 12.51. Actual value (96
): C, 51.29. H, 4.88. N,
12.55. Reference Example 17 3-[2-[4-[bis(4-fluorophenyl)methylene]biveridin-1-yl]ethyl]-6.7
,8.9-tetrahydro-2}1- [1.2-8]
- 1.3.5-triazine-2.4(3H) monodione 6,7,8.9-tetrahydro 2}1-[1.2-a] obtained in Reference Example 1(l) - 1.3 .5-triazine-2.4(3}1)ion 1.87g, 4-
[Bis(4-fluorophenyl)methylene]-1-(2
3.64 g of (hydroxyethyl)viveridine and 3.15 g of triphenylphosphine were dissolved in 50 ml of N,N-dimethylformamide, and 2.1 g of azodicarboxylic acid diethyl ester was added dropwise to the solution under stirring while cooling with water. After stirring for 30 minutes,
The solvent was distilled off under reduced pressure, and the residue was purified using a silica gel column (180
g) and eluted with chloroform containing 3% methanol to obtain 1.38 g of the title compound as a yellow oil.

Nuclear magnetic resonance spectrum (deuterochloroform) δ: 1.8
-2.0 (4}1,m). 2.3 (4}1, m)
,2.5-2.8 (8}1,m). 3.8 (2
}1,t) ,4.07 (2H.t) ,6.96
(4H, d). 7.04 (4H, s). Reference Example 18 3-[2-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]ethyl]-8.7
, 8.9-tetrahydro-2H-pyrido [1. 2-
a]-1.3.5-triazine-2.4(3H) monodione dihydrochloric acid 3-[2-[4-[bis(4-fluorophenyl)methylene]viveridin-1 obtained in Reference Example 17 above
-yl]ethyl]-6.7,8.9-tetrahydro-2
1.38 g of 8-pyrido[1.2-al-1.3.5-triazine-2.4(3H) monodione was dissolved in 50 ml of methanol, 0.8 ml of concentrated hydrochloric acid was added, and the mixture was dried under reduced pressure. The residue was crystallized from a mixture of methanol and isoprobanol and then recrystallized to give the title compound as a colorless powder 1.

03g was obtained.

Melting point 192-195℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 1.7-2.0 (4H, m), 2.5-2.
9 (6H, m), 3.0-3.4 (4H, m)
,3.5-3.8 (4H,m) ,4.19 (2}
1,t) ,7.18 (8H,d) ,9.85 (
IH,s), 11.41 (IH,bs). Infrared absorption spectrum ν (KBr) cm”: 3450
．． 255G, 1760, 1730, 1620.151
0,1450. Elemental analysis CayH2aFJ402.2} Calculated value as ICI (k): C, 58.81; }1,5.
48; N, 10.16. Actual measurement value (X): (:,
58.85; H, 5.74; N, 10.11.
Reference Example 19 3-[2-[4-[bis(4-fluorophenyl)
Methylenecopiveridin-1-yl]ethylco7,8-
dihydro-2H,6H-pyrrolo[1,2-a]1,
3.5-Triazine-2. 4 (3H) Monodione 7.8-dihydro prepared in Reference Example 4(1) 28.6
H-pyrrolo[1,2-al-1.3.5-triazine-2.4(3}1)-dione and 1-(2-hydroxyethyl)-4-[bis(4-fluorophenyl)methylene] Piperidine was condensed with triphenylphosphine and azodicarboxylic acid diethyl ester in N,N-dimethylformamide in the same manner as in Reference Example 17 to obtain the title compound as an oil.

Nuclear magnetic resonance spectrum (deuterochloroform) δ: 2,.
2-2.5 (8H, m) ,2.5-2.8 (6}
1, m). 3.02 (2H,t) ,4.1 (4
8, m), 6.99 (8H, m). Reference Example 20 3-[2-[4-[bis(4-fluorophenyl)methylenecobiveridin-1-yl]ethyl]-7.8
-dihydro-2}1,6H-virolo[1,2-al
l,3.5-triazine-2.4(3}1) monodione dihydrochloride 3-[2-[4-[bis(
4-fluorophenyl)methylene]piperidin-1-ylcoethyl]-7.8-dihydro-28,6H-virolo[1.2-al-1.3.5-triazine-2
．． 2.44 g of 4(3H)-dione in 50 ml of methanol
1+nl of concentrated hydrochloric acid was added and the mixture was dried under reduced pressure. The residue was mixed with methanol and isoprobanol for 7 nights to crystallize.
Then, it was recrystallized to obtain the title compound as a colorless powder 1, Og.

Melting point 173-180℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 2.10 (2, m), 2.3-2.7 (4H,
m) 2.90 (2H, t). 2.9-3.4 (4H
,m) ,3.5-3.8(2H,m) ,3.88(
28,t) ,4.14 (2H,t) ,7.18
(8}1,d). 11.22 (IH,b). Infrared absorption spectrum ν (KBr) cm-': 3450,
1725, 1550, 1600, 1580, 1510
, 1450, 1420, 1220. Elemental analysis (value information calculated as 26H26F2N402・28Cl): C, 58.11. H, 5.2
5. N, 10.43. Actual value Samurai): C, 58.
O[i. H, 5.44. N, 10.63. Reference Example 21 3-[2-[4-[bis(4-fluorophenyl)methylene]biperidin-1-ylcoethyl]-28-
Thiazolo[3.2-a] -1.3.5-triazine-2,4(3H) Monodione hydrochloride 2H-thiazolo[3.2-a] -1.3.5-triazine-2,4(3H) one dione 1.0 g,
1-(2-hydroxyethyl)-4-[bis(
4-fluorophenyl)methylenecopiveridine 2.0g
and triphenylphosphine (1.86 g) were dissolved in 20 ml of N,N-dimethylformamide, and 1.25 g of azodicarboxylic acid diethyl ester was added dropwise to the solution under water cooling and stirring. 3
After stirring for 0 minutes, the solvent was distilled off under reduced pressure, and the residue was applied to a silica gel column (120 g) and eluted with chloroform containing 4% methanol. After removing the solvent under reduced pressure, the title compound?
2.05 g of an oily base was obtained. After dissolving this in 50+nl of ethanol and adding 0.5 ml of concentrated hydrochloric acid, the solvent was distilled off under reduced pressure. Ethanol was added and concentration under reduced pressure was repeated, and the precipitated crystals were collected by filtration to obtain 1.76 g of colorless crystals of the title compound.

Melting point 251-253℃ Nuclear magnetic resonance spectrum (dimethyl sulfoxide d6)
δ: 2.4-2.8 (4H, m), 2.5-2.
9 (4}1, m) , 3.6-3.8 (2H, m)
,4.22 (2H,t) ,7.18 (9H,m
) ,7.73 (1}1,cl) ,11.2 (I
H,b). Infrared absorption spectrum v (KBr) CO
I-': 3450, 2340, 1740.1B50,
1580.15501500,1420. Elemental analysis (calculated value (%) as: 2SH2■F2N402S'HCl: C, 58.08. H.4.
48; N, 10.84. Actual value (66): C,
57.94. H, 4.63. N, 10.84.
Example 1 1) Measurement of serotonin 2 receptor antagonistic activity Test compound was dissolved in purified ice and administered to SD-SLC male rats at 10 mg/k.
30 minutes later, urethane (Ig/
kg, intraperitoneal administration) and α-chloralose (80 m
g/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. 60 minutes after administering the test compound, serotonin (300μs/kg
) was injected intravenously and the pressor response was observed. The pressor suppression rate was calculated from the pressor response of the control group administered with purified ice and the pressor response of the test compound administration group, and was calculated as serotonin 2 (hereinafter referred to as 5-HT2).
It was defined as antagonistic activity. The test results are shown in Table 1 below.

2) Measurement of sympathetic alpha 1 receptor antagonist activity SD-S
Dissolve the test compound in purified water and inject 10 m
g/kg, and 30 minutes later, urethane (
Ig/kg, intraperitoneal administration) and α-chloralose (8
The mice were anesthetized with 0 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. 60 minutes after administering the test compound, phenylephrine (100
μs/kg) was intravenously injected and the pressor response was observed. The pressor suppression rate was calculated based on the pressor response value of the control group given purified ice and the pressor response value of the test compound administration group, and was defined as the sympathetic alpha 1 (hereinafter α1) antagonistic activity. The test results are shown in Table 1 below.

3) Mouse 4-day toxicity test The test compound was dissolved or suspended in 1% methylcellulose solution and administered to male ddy mice at a dose of 200 B/kH.
It was orally administered once a day for 4 consecutive days. The number of doses per group is 4.
The number of deaths was observed up to the next day after the final administration. The control group received 10ml/1% methylcellulose solution.
It was administered orally at a rate of 1.5 kg. The test results are shown in Table 1 below.

Table 1 Compound antagonistic properties of reference example 5'H'b α1 Toxicity (mortality rate) 2 93 3 93 l1 83 l8 93 20 83 21 93 9 l/5 3 9 0/5 0 6 0/5 l 3 Above table As is clear from the above, the compound of formula (I) exhibited a strong serotonin 2 receptor antagonism, and was also excellent in the selectivity and safety of the serotonin 2 receptor antagonism.

Example 2 Serotonin 2 Receptor Binding Activity Male SO rats were decapitated without anesthesia, the frontal cortex was isolated, and rough membrane markers were prepared. Using 3H-ketanserin as a labeled ligand. Methycel guide was used as a non-specific binding reagent. These reagents and the compound of formula (I) or its salt were dissolved in 5* methanol Tris buffer and incubated, followed by suction filtration on a GF/B Gaelas filter.

The radioactivity of 3H-ketanserin captured on the same filter was measured using a liquid scintillation counter. A Scatchard plot was created from this radioactivity value, and the dissociation constant and receptor density of the serotonin 2 receptor of the crude membrane marker were determined. Further, the 50* inhibitory concentration was determined from the receptor binding inhibition curve of the compound of formula (I) or a salt thereof, and the dissociation constant indicating the strength of binding to the serotonin 2 receptor was calculated. As a result, 3-[2-(4-(fluorobenzoyl)biperidin-1-yl]ethyl]-6.7,8.
9-tetrahydro-2H-pyrido[1.2-a] -
The dissociation constant of the hydrochloride of 1.3.5-triazine-2.4(3}1)-dione (hereinafter abbreviated as compound A) to the serotonin 2 receptor was 15 nM.

Example 3 Effect on acute myocardial infarction model Experimental materials and methods Experimental marker: An adult mongrel dog (weight 8-20 kg) was placed on a ventilator under anesthesia with bentobarbital (30 B/kg, intravenous administration), and then the chest was opened. did. The left anterior descending coronary artery was removed. A twenty-one-dollar platinum electrode was inserted to a depth of about 1 cm into the myocardium under the control of the left anterior descending coronary artery, and myocardial tissue blood flow was measured using the hydrogen gas clearance method. A polyethylene cannula was inserted into the femoral artery, and blood pressure and heart rate were recorded. Cannulas were inserted into the femoral artery and jugular vein, respectively.
For drug administration. It was used for blood collection. After stabilization of the experimental specimen, the left anterior descending coronary artery was ligated with an arterial clamp. Reperfusion was performed 2 hours after ligation. Thereafter, the heart was removed after observation for 4 hours.

The heart was perfused for 15 minutes by flowing 1% triphenyltetrazolium chloride solution from the anterior descending left coronary artery of the heart and retrogradely flowing 0.50 Evans blue solution from the aorta at a pressure of approximately 80 mm}Ig. Double stained. Then wash the heart. A 1 cm wide section was cut perpendicular to the long axis from the apex of the heart. Separate the myocardial infarction risk area and normal area of the left ventricle,
The wet weight of each was measured. The left ventricular weight (sum of myocardial infarction risk area and normal area) and risk area weight for each section were integrated to calculate the overall left ventricular weight and risk area weight. Furthermore, the area of the area that was not stained with Evans blue (cardiac infarction risk area) and the white remaining area that was not stained red with triphenyltetrazolium chloride (myocardial infarction area) within the myocardial infarction risk area was measured in each cross section. The ratio of myocardial infarction area to the entire left ventricle (myocardial infarction size) was calculated.

Drug administration: Drugs or saline were administered intravenously at lml/k from 20 minutes before left anterior descending coronary artery ligation until the end of the experiment.
It was infused at a rate of g/hr. The dose of the drug is lmg/
kg/hr. The experiment consisted of the following two groups.

l. Control group (11 cases): administration of raw saline2. Compound A hydrochloride administration group (12 cases) Experimental Results Table 2 Effect values in the acute myocardial infarction model indicate the mean and standard error.

*P<0.05 As is clear from the above table, after ligation and reperfusion of the left anterior descending coronary artery, the myocardial tissue blood flow in the control group was only about 6.
Although the recovery remained to 0*, the worsened myocardial blood flow was significantly recovered in the compound A deprived group compared to the control group. There was no difference in left ventricular weight and risk area weight between the two groups. The degree of injury inflicted on each heart appeared to be comparable. Under these conditions Compound A significantly reduced myocardial infarct size. Therefore, it has been revealed that Compound A has the effect of improving the microcirculatory disorder caused by ischemia and preventing myocardial death. Furthermore, the effect of Compound A on blood pressure was relatively mild.

therefore. Compound A has been shown to be a useful drug for the prevention or treatment of heart diseases associated with ischemia.

Example 4 Effect on angina model Experimental materials and methods Experimental specimen: An adult mongrel dog (weight 8-20 kg) was placed on a ventilator under anesthesia with bentobarbital (30 mg/kg, intravenous administration), and then the chest was opened. . The left anterior descending coronary artery was removed. A silicone tube for stenosis was placed on the left anterior descending coronary artery. A probe for measuring blood flow velocity was attached near it. Blood flow velocity was measured using a pulse Doppler blood flow meter. Coronary blood pressure was measured by inserting a cannula into a peripheral branch of the left anterior descending coronary artery beyond the stenotic site. A polyethylene cannula was inserted into the femoral artery, and blood pressure and heart rate were recorded. A cannula was inserted into the femoral vein and used for drug administration. After the specimen was stabilized, the left anterior descending coronary artery was narrowed so that its blood flow velocity decreased by 20* to create an angina-like condition in which the left anterior descending coronary artery blood velocity periodically decreased.

Administration of drug: One hour after the periodic decrease in the left anterior descending coronary artery blood flow velocity occurred, the maleate salt of Compound A was administered into the femoral vein at a dose of 0.1 B/kHz.

After that, changes in the condition in which the left anterior descending coronary artery blood flow velocity periodically decreased were observed. The effect of the drug was expressed as the number of times that periodic decreases in blood flow velocity occurred per hour before and after administration. The maleate salt of Compound A was used after being dissolved in saline.

Experimental results: Table 3 Effect in angina model Values indicate standard error of the mean.

Umbrella Umbrella P<0.01 (compared to before administration) As is clear from the above table. Administration of a low dose of Compound A significantly reduced the number of periodic decreases in coronary blood flow velocity compared to before administration, indicating that Compound A is effective in suppressing angina attacks.

Example 5 Toxicity values by oral administration to rats for 10 days Continuation of page 1 [Phase] Int. C.I. ' Identification code: Office serial number - 513/04 341 7822-4 (

Claims (1)

[Claims] The following general formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 is selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenomethyl group An aryl group that may be substituted with one or more substituents, and R^2 is one or more substituents selected from a hydrogen atom, an alkyl group, a halogen atom, an alkoxy group, an alkyl group, and a trihalogenomethyl group. an aryl group which may be substituted with , n and m each represent an integer of 0 to 6, A represents a 5- to 7-membered ring, the ring shares one nitrogen atom and is fused with a triazine ring, and In addition to the nitrogen atom in the condensation part, it may contain one or two heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, and may also contain one or more double bonds, and Q is represented by the following general formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R^3 is a hydrogen atom, a hydroxyl group, or a halogen atom,
An aryl group that may be substituted with one or two substituents selected from a hydroxyl group, an alkyl group, an alkoxy group, and a trihalogenomethyl group, and R^4, R^5, and R^6 are a hydrogen atom and a halogen atom, respectively. , represents an alkyl group, an alkoxy group or a trihalogenomethyl group. ) or the following general formula ▲ Numerical formula, chemical formula, table, etc. represents an aryl group or an aromatic heterocyclic residue which may be substituted with 1 to 3 substituents. ] A prophylactic and therapeutic agent for heart diseases containing a condensed triazine derivative or a salt thereof as an active ingredient.