JPH0546340B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel pyrimidine derivatives. More specifically, this invention has inotropic effect, antihypertensive effect,
The present invention relates to novel pyrimidine derivatives and pharmaceutically acceptable salts thereof, which have cerebral vasodilatory effects and platelet aggregation inhibitory effects, methods for producing them, and pharmaceutical compositions containing them. Certain pyrimidine derivatives with hypotensive and vasodilatory effects are described, for example, in European Patent Publication No. 001075. The pyrimidine derivative of this invention is a new compound and is represented by the following general formula [ ]. {In the formula, Z is

【formula】

[expression] and

[Formula] [In the formula, R ¹ and R ² are each hydrogen; alkenyl group; al (lower) alkyl group; or lower optionally substituted with epoxy group, hydroxyl group, amino group and/or lower alkylamino group alkyl group; R ⁵ means a lower alkyl group; R ³ is hydrogen; an aryl group optionally substituted with a lower alkyl group, a lower alkoxy group and/or a halogen atom; or a lower alkyl group a pyridyl group which may be substituted with; ^R4 is hydrogen; a lower alkyl group; or a phenyl group which may be substituted with a lower alkoxy group; Y is =O, =S or =N- ^R6 [in the formula, R ⁶ is a lower alkyl group; cyclo(lower) alkyl; alk(lower) optionally substituted with a lower alkoxy group
Alkyl group; means an N-containing unsaturated heterocyclic group which may be substituted with a lower alkyl group; or an aryl group which may be substituted with a hydroxyl group, a lower alkyl group, a halogen atom and/or a lower alkoxy group, The lower alkoxy substituent may be substituted with an epoxy group, a hydroxyl group, an amino group and/or a lower alkylamino group]. However, when R ³ is hydrogen, R ⁴ means a lower alkyl group or a phenyl group optionally substituted with a lower alkoxy group, R ¹ and R ² are each hydrogen or a lower alkyl group, and When R ³ is a phenyl group,
Y means =S or =N- ^R6 , ^R1 and ^R2
are each hydrogen or a lower alkyl group, R ³ is an aryl group substituted with a lower alkoxy group, and
When R ⁶ is an aryl group substituted with a lower alkyl group, R ⁴ means a lower alkyl group or a phenyl group optionally substituted with a lower alkoxy group. } For the target compound [], Z is the formula: A group represented by R ¹ and/or R ²
When is hydrogen, the pyrimidine moiety of the target compound [] can alternatively be represented by its tautomer. For example, when R ¹ and R ² are both hydrogen and Y is =N-R ⁶ , the compound [] is one of structural formulas (A) to (E) as shown below. It can be shown as (In the formula, R ³ , R ⁴ and R ⁶ each have the same meaning as before.) The target compound may exist in any of these tautomeric forms and may coexist as an equilibrium mixture. Thus, all of these tautomeric forms are included within the scope of this invention. Even in the case where Y is =O or =S, the pyrimidine moiety of the target compound [] includes its tautomers, which can be indicated by substantially the same tautomerism as explained above. However, in this specification, for convenience, the target compound [ ] is represented by the above formula (A). The object compound [] of this invention and its salt can be produced by the following production method. Manufacturing method 1 Manufacturing method 2 Manufacturing method 3 Manufacturing method 4 Manufacturing method 5 Manufacturing method 6 Manufacturing method 7 Manufacturing method 8 [In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁶ and Z each have the same meaning as before, one of R ¹ _a and R ² _a is hydrogen, the other is hydrogen; alkenyl group; or a lower alkyl group which may be substituted with an epoxy group, a hydroxyl group, an amino group and/or a lower alkylamino group; one of R ¹ _b and R ² _b is an alkenyl group; an al(lower) alkyl group or a lower alkyl group which may be substituted with an epoxy group, a hydroxyl group, an amino group and/or a lower alkylamino group; the other is hydrogen; an alkenyl group; an al(lower) alkyl group; or an epoxy group, a hydroxyl group, an amino group and /or a lower alkyl group which may be substituted with a lower alkylamino group; one of R ¹ _c and R ² _c is a lower alkyl group substituted with an epoxy group; the other is hydrogen; an alkenyl group; an al(lower) alkyl group or a lower alkyl group which may be substituted with an epoxy group, a hydroxyl group, an amino group and/or a lower alkylamino group; one of R ¹ _d and R ² _d is substituted with a hydroxyl group and an amino group or a lower alkylamino group a lower alkyl group, the other being hydrogen; an alkenyl group; an al (lower) alkyl group; or a lower alkyl group optionally substituted with a hydroxyl group, an amino group and/or a lower alkylamino group; R ⁷ is an alkenyl group; an al (lower) Alkyl group; or lower alkyl group optionally substituted with epoxy group, hydroxyl group, amino group and/or lower alkylamino group; R ⁸ is epoxy group, hydroxyl group, amino group and/or lower alkyl group;
or a lower alkyl group optionally substituted with a lower alkylamino group, R ⁸ _a is a lower alkyl group substituted with an epoxy group, R ⁸ _b is a lower alkyl group substituted with a hydroxyl group and an amino group or a lower alkylamino group , X is a leaving group, Ya is =O or =N-R ⁶ (in the formula, R ⁶ has the same meaning as before), Za is the formula:

[expression] or

[Formula] (In the formula, R ¹ , R ² and R ⁵ each have the same meaning as before). However, when R ³ is hydrogen, R ⁴ means a lower alkyl group or a phenyl group optionally substituted with a lower alkoxy group, R ¹ and R ² are each hydrogen or a lower alkyl group, and ^R3
is a phenyl group, Y is =S or =N-
R ⁶ means R ¹ and R ² are each hydrogen or a lower alkyl group, R ³ is an aryl group substituted with a lower alkoxy group, and R ⁶ is an aryl group substituted with a lower alkyl group, R ⁴ means a lower alkyl group or a phenyl group optionally substituted with a lower alkoxy group. ] In the above and following descriptions of this specification,
Preferred examples and explanations of various definitions encompassed within the scope of this invention are discussed in detail below. However, the definitions of R ¹ _a , R ¹ _b , R ¹ _c and R ¹ _d are
encompassed within the definition of R ¹ , the definitions of R ² _a , R ² _b , R ² _c and R ² _d are encompassed within the definition of R ² , and the definitions of R ⁸ _a and R ⁸ _b are also encompassed within the definition of R ⁸ , so R ¹ _a to ^{R 1} _d , R ² _a to R ² _d and R ⁸ _a to ^{R 8} _b
For suitable examples and explanations of R ¹ , R 2 and R 8 , please refer to the examples and explanations of R 1 , R ² and R ⁸ , respectively. "Lower" shall mean 1 to 6 carbon atoms unless otherwise specified. Suitable examples of lower alkyl groups for R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, Straight chain or branched alkyl groups such as hexyl and the like can be mentioned. The lower alkyl groups of R ¹ , R ² , R ⁷ and R ⁸ are epoxy groups, hydroxyl groups, amino groups and/or such as methylamino, ethylamino, propylamino, butylamino, tertiary butylamino, pentylamino, It may be substituted with a lower alkylamino group such as hexylamino. Suitable examples of lower alkyl groups having such substituents include epoxy-substituted lower alkyl groups such as 2,3-epoxypropyl, 3,4-epoxybutyl, 4,5-epoxypentyl, and 4,6-epoxyhexyl. Alkyl groups, such as hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 6-hydroxyhexyl, hydroxy-substituted lower alkyl groups, such as aminomethyl, 1-aminoethyl, 2-aminoethyl, 2- Aminopropyl, 3-aminopropyl, 4-aminobutyl, 5-aminopentyl,
Amino-substituted lower alkyl groups such as 6-aminohexyl, e.g. methylaminomethyl, dimethylaminomethyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 2-(methylamino)propyl, 3-(ethylamino) ) propyl, 3-(isopropylamino)propyl, 3-(tert-butylamino)propyl, 6-(hexylamino)hexyl, lower alkylamino-substituted lower alkyl groups, such as 2-hydroxy-3-methylaminopropyl, 3-hydroxy-2-methylaminopropyl, 2-hydroxy-3-isopropylaminopropyl, 3-butylamino-2-hydroxypropyl, 2-tert-butylamino-3-hydroxypropyl, 3-tert-butylamino Examples include hydroxy and lower alkylamino-substituted lower alkyl groups such as -2-hydroxypropyl. Suitable examples of alkenyl groups for R ¹ , R ² and R ⁷ include vinyl, allyl, propenyl, isopropenyl, butenyl, pentenyl and the like. Suitable examples of the alkyl group for R ¹ , R ² and R ⁷ include benzyl, phenethyl, 3-
Examples include phenylpropyl, benzhydryl, trityl, and the like. Suitable examples of aryl groups for R ³ and R ⁶ include:
Examples include phenyl and naphthyl. The aryl group of ^R3 is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy,
It may be substituted with a lower alkoxy group such as hexyloxy, a halogen such as chlorine, bromine, fluorine, iodine, and/or the lower alkyl group mentioned above. Suitable examples of the aryl group for ^R3 having such a substituent include 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-
Lower alkoxy-substituted phenyl groups such as trimethoxyphenyl, 2,3,4-trimethoxyphenyl, 2-ethoxyphenyl, 4-hexyloxyphenyl, e.g. 2-chlorophenyl, 4-chlorophenyl, 2,4-dichloro Phenyl, 3,4-dichlorophenyl, 2,6-dichlorophenyl, 2
-halogenated phenyl groups such as -bromophenyl, 2-bromo-4-chlorophenyl, e.g. 3-chloro-4-methoxyphenyl, 4-chloro-2-methoxyphenyl, 3-chloro-4,5-dimethoxyphenyl, Lower alkoxy and halogen substituted phenyls such as 2-bromo-4-ethoxyphenyl, e.g. p-tolyl, o-tolyl, 4-ethylphenyl, 4-hexylphenyl, 2,6-dimethylphenyl, 3,4-dimethylphenyl ,2,
Lower alkyl substituted phenyl groups such as 4,6-trimethylphenyl, e.g. 4-chloro-2-methylphenyl, 4-chloro-2-ethylphenyl, 2-
Lower alkyl and halogen-substituted phenyl groups such as bromo-3-methylphenyl, or e.g.
-Methyl-4-methoxyphenyl, 2-ethyl-
Examples include lower alkoxy and lower alkyl substituted phenyl groups such as 4-methoxyphenyl and 3-ethyl-4-ethoxyphenyl. Examples of the pyridyl group for ^R3 include pyridyl groups such as 2-pyridyl, 3-pyridyl, and 4-pyridyl, and pyridinio groups, and these pyridyl groups may be optionally substituted with the lower alkyl group. Suitable examples of the pyridyl group for ^R3 having such a substituent include 2-methylpyridyl, 3-ethylpyridyl, 3-ethyl-6-methylpyridyl, 1-methylpyridinio, 1-ethylpyridinio, and 1-hexylpyridyl. Examples include Ginio et al. The phenyl group of R ⁴ may be optionally substituted with a lower alkoxy group, and for suitable examples thereof, refer to those exemplified for the lower alkoxy-substituted phenyl group of R ³ . Suitable examples of the cyclo(lower) alkyl group for R ⁶ include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The aryl group of R ⁶ is a hydroxyl group, a lower alkyl group,
It may be optionally substituted with halogen and/or lower alkoxy, and among the substituents of these aryl groups, the lower alkoxy substituent may be substituted with an epoxy group, hydroxyl group, amino group and/or lower alkylamino group. good. Preferred examples of ^the aryl group for R ⁶ having such a substituent include lower alkyl-substituted phenyl groups, halogenated phenyl groups, and lower Mention may be made of alkyl- and halogen-substituted phenyl groups, lower alkoxy-substituted phenyl groups, or hydroxy-substituted phenyl groups such as, for example, 2-hydroxyphenyl, 3-hydroxyphenyl, and 4-hydroxyphenyl. The lower alkoxy moiety of the lower alkoxy-substituted phenyl group may be further substituted with an epoxy group, a hydroxyl group, an amino group and/or a lower alkylamino group. Suitable examples of lower alkoxy-substituted phenyl groups further having these substituents include 4-(2,3-epoxypropoxy) phenyl, 2-(hydroxymethoxy) phenyl, 4-(2-aminoethoxy)
Phenyl, 4-(3-methylaminopropoxy)
Phenyl, 4-(2-hydroxy-3-isopropylaminopropoxy) phenyl, 4-(3-tert-butylamino-2-hydroxypropoxy)
Examples include phenyl. Suitable examples of the ar(lower) alkyl group for R ⁶ include benzyl, phenethyl, 3-phenylpropyl, benzhydryl, trityl, and the like. This al(lower) alkyl group may be optionally substituted with the lower alkoxy group, and preferable examples of the al(lower) alkyl group having such a substituent include, for example, 4-methoxybenzyl,
Examples include lower alkoxy-substituted benzyl groups such as 2-ethoxybenzyl and 3,4-dimethoxybenzyl, and lower alkoxy-substituted benzhydryl groups such as 4-methoxybenzhydryl and 4,4'-dimethoxybenzhydryl. Suitable examples of the N-containing unsaturated heterocyclic group for R ⁶ include pyrrolyl, imidazolyl, imidazolinyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, isothiazolyl, such as 1,2,3-thiadiazolyl, 1,
5 or 6 such as thiadiazolyl, such as 2,4-thiadiazolyl, 1,3,4-thiadiazolyl, etc.
Examples thereof include N-containing unsaturated heterocyclic ring members. These N-containing unsaturated heterocyclic groups may be substituted with lower alkyl groups as exemplified above.
Suitable examples of N-containing unsaturated heterocyclic groups having such substituents include 4-methylpyridyl,
2,4,6-trimethylpyridyl, 5-methyl-
Examples include 1,3,4-thiadiazolyl. Suitable examples of leaving groups for X include, for example, chloride,
Examples include halides such as bromides and iodides, and sulfonates such as methanesulfonate, benzenesulfonate, and toluenesulfonate. Suitable pharmaceutically acceptable salts of the target compound [] are conventional non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, alkaline earth metal salts such as calcium salts, magnesium salts, etc. Metal salts, ammonium salts, such as trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts,
Organic base salts such as N,N'-dibenzylethylenediamine salts, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates, etc. These include organic acid salts, such as inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, and salts with amino acids such as arginine salt and ornithine salt. In this regard, compounds [a] to [
m] is included within the scope of compound [], so
For suitable salts of these compounds [a] to [m], reference can be made to the salts exemplified for the target compound [] above. The method for producing the target compound [] and its salt will be explained in detail below. Production Method 1 The target compound [a] and its salt can be produced by reacting the compound [] or a reactive derivative thereof in a carboxy group or a salt thereof with the compound [] or a salt thereof. Suitable salts of compounds [] and [] include the same salts as exemplified for compound []. Suitable reactive derivatives in the carboxy salt of compound [] include esters, acid halides, acid anhydrides, and the like. Suitable examples of reactive derivatives include acid halides such as acid chlorides and acid bromides; symmetric acid anhydrides; aliphatic carboxylic acids such as acetic acid and pivalic acid; substituted carboxylic acids such as dialkyl phosphoric acid and diphenyl phosphoric acid; mixed acid anhydrides with acids such as phosphoric acid; lower alkyl esters such as methyl esters, ethyl esters, propyl esters, hexyl esters, e.g. benzyl esters, benzhydryl esters, p-
Substituted or unsubstituted alkyl esters such as chlorobenzyl esters, such as phenyl esters, tolyl esters, 4-nitrophenyl esters, 2,4-dinitrophenyl esters, pentachlorophenyl esters, naphthyl esters, etc. substituted or unsubstituted aryl esters of N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-
Hydroxyphthalimide or 1-hydroxy-
Esters such as those with 6-chloro-1H-benzotriazole and the like may be mentioned. These reactive derivatives can be appropriately selected depending on the type of compound [] to be used. This reaction is usually carried out in conventional solvents such as water, methanol, ethanol, propanol, tetralin, tetrahydrofuran, dioxane, chloroform, toluene, dimethylformamide, dimethyl sulfoxide, or any organic solvent that does not adversely affect the reaction. For example, it can be carried out in any other organic solvent. This reaction is preferably carried out in the presence of an acid such as an inorganic acid such as hydrochloric acid, sulfuric acid or polyphosphoric acid, or an organic acid such as trifluoroacetic acid, benzenesulfonic acid or toluenesulfonic acid. In addition, this reaction can be performed using, for example, magnesium sulfate,
It can also be carried out in the presence of a dehydrating agent such as anhydrous zinc chloride, phosphorus pentoxide, zeolite, or silica gel, or under dehydrating conditions such as azeotropic dehydration. When compound [] is used in the form of free acid or salt, the reaction is preferably carried out in the presence of a customary condensing agent such as N,N-dicyclohexylcarbodiimide. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under or under heating. Production Method 2 The target compound [a] and its salt can be produced by reacting the compound [b] or its salt with the compound [] or its salt. Suitable salts for compound [] include the same salts as exemplified for compound []. This reaction is preferably carried out using an alkali metal hydride, such as sodium hydride, potassium hydride, etc.
Alkaline earth metal hydrides such as calcium hydride and magnesium hydride; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; e.g. sodium bicarbonate. ,
Alkali metal bicarbonate such as potassium bicarbonate,
For example, it is carried out in the presence of a base such as an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like. This reaction is usually carried out in a conventional solvent such as water, methanol, ethanol, propanol, tetrahydrofuran, dioxane, acetonitrile, methylene chloride, chloroform, benzene, dimethylformamide, dimethyl sulfoxide, or any organic solvent that does not adversely affect the reaction. It can be carried out in any other organic solvent as long as it is a solvent. These solvents are the raw material compound [b],
It can be appropriately selected depending on the type of base and compound [], especially the type of base to be used. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under heating. Production method 3 Target compound [d] and its salt can be produced by alkylating compound [b] or its salt. Since this reaction is carried out substantially in the same manner as Production Method 2, the description of Production Method 2 may be referred to for the reaction method and reaction conditions such as base, solvent, reaction temperature, etc. of this production method. Production method 4 Target compound [f] and its salt can be produced by reacting compound [e] or its salt with ammonia or lower alkylamine or their salt. Suitable salts of ammonia and lower alkylamine include the acid addition salts exemplified for compound []. Suitable examples of lower alkylamines used in this reaction include methylamine, ethylamine,
Propylamine, butylamine, tertiary butylamine, pentylamine, hexylamine, dimethylamine, diethylamine, dipropylamine,
Included are primary and secondary amines such as diisopropylamine, dibutylamine, dihexylamine, and the like. This reaction is usually carried out in conventional solvents such as water, methanol, ethanol, tetrahydrofuran, dioxane, methylene chloride, chloroform, benzene, dimethylformamide, dimethyl sulfoxide, but any organic solvent that does not adversely affect the reaction may be used. , or any other organic solvent. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under or under heating. Production method 5 The target compound [h] and its salt can be produced by reacting the compound [g] or its salt with phosphorus pentasulfide. This reaction is usually carried out in conventional solvents such as benzene, toluene, xylene, pyridine, tetrahydrofuran, dioxane, but it can also be carried out in any other organic solvent that does not adversely affect the reaction. I can do it. The reaction temperature is not particularly limited, and the reaction is usually carried out with or without heating. Production Method 6 The target compound [i] and its salt can be produced by reacting the compound [h] or its reactive derivative in a thioxo group or a salt thereof with the compound [ ] or its salt. Suitable salts for compound [] include the same salts as exemplified for compound []. This reaction typically involves methanol, ethanol, propanol, tetrahydrofuran, dioxane,
The reaction is carried out in a conventional solvent such as methylene chloride or dimethylformamide, but the reaction can be carried out in any other organic solvent that does not adversely affect the reaction. When the compound [] is a liquid, it can also be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually carried out at room temperature or under or under heating. The group -O-R ⁵ is the group Z of the starting compound [h]
, the lower alkyl moiety of R ⁵ may be eliminated in this production method to form a ketone compound. Suitable reactive derivatives of the thioxo group of compound [h] include, for example, S-methyl derivatives,
S- such as S-ethyl derivatives and S-octyl derivatives
Examples include alkyl derivatives, such as S-al(lower)alkyl derivatives such as S-benzyl derivatives, S-carboxy(lower)alkyl derivatives, or salts thereof. These reactive derivatives are suitable for the compound [
h] or a salt thereof, for example, alkyl halides such as methyl iodide, ethyl iodide, octyl bromide, al(lower) alkyl halides such as benzyl chloride, benzyl bromide, monochloroacetic acid, monobromoacetic acid, 3- It can be produced by reacting with an alkylating agent such as a halogenated (lower) fatty acid such as chloropropionic acid or a salt thereof. This reaction is carried out in substantially the same manner as Production Method 2, and therefore the description of Production Method 2 may be referred to for the reaction method and reaction conditions such as solvent and reaction temperature. Production method 7 Target compound [k] and its salt can be produced by reacting compound [j] or its salt with compound [] or its salt. Suitable salts of compound [] include the acid addition salts exemplified for compound []. This reaction is carried out substantially in the same manner as in Production Method 2, and therefore the reaction method and reaction conditions of this production method, such as base, solvent, reaction temperature, etc., are similar to Production Method 2.
Please refer to the explanation. Production method 8 The target compound [m] and its salt can be produced by aminating compound [l] or its salt. This reaction is carried out in substantially the same manner as Production Method 4, and therefore, the description of Production Method 4 can be referred to for the reaction method and reaction conditions of this production method, such as aminating agent, solvent, reaction temperature, etc. . Among the raw material compounds [ ], the new compound can be obtained by a method known in the art for producing compounds structurally similar to these. Target compound [] and raw material compound [],
[], [], [] and [] respectively,
It may contain one or more stereoisomers based on the asymmetric carbon atoms in the molecule, and the compounds [][],
All such isomers of [], [], [] and [] are intended to be encompassed within the scope of this invention. The novel pyrimidine derivatives [ ] of this invention and their pharmaceutically acceptable salts have cardiotonic effects, platelet aggregation inhibitory effects, cerebral vasodilator effects, and antihypertensive effects, such as cardiac diseases such as heart failure, thrombosis, cerebrovascular diseases, etc. Useful in treating hypertension. In order to demonstrate the pharmacological activity of the pyrimidine derivative [], the results of a cardiotonic effect test, a platelet aggregation inhibitory effect test, a cerebral vasodilatory effect test, and a hypotensive effect test are explained below. Test method A (cardiotonic effect test) Male and female mongrel dogs were treated with pentobarbital sodium.
Anesthetized by intraperitoneal injection of 35 mg/Kg. The left carotid artery was dissected, and a catheter (USCI, #8F) filled with heparin-saline was inserted and placed in the left ventricle. The catheter was connected to a pressure transducer (Nihon Kohdensha, MPU-0.5A), the left ventricular pressure was measured, and dp/dt Max. was determined. A catheter was inserted into the right femoral vein for test compound administration. Left ventricular pressure and dp/dt Max. were recorded on a polygraph (Nihon Kohdensha, RJG-4008). Test compounds were added to distilled water (dose volume 0.2 ml/Kg) or dimethyl sulfoxide (dose volume 0.04 ml/Kg).
Kg) and administered intravenously. Parameters after administration were compared with those before administration. The test results were expressed as the rate of change in dp/dt Max. (dp/dt MC) calculated using the following formula. dp/dt MC (%) = (post-administration dp/dt Max./pre-administration dp/dt Max.-1) x 10
0 Test results A

[Table] Known compounds used in this case.
Test method B (platelet aggregation inhibitory effect test) Platelet-rich plasma (PRP) containing 6.5 to 7.5×10 ⁸ platelets/ml was prepared from rabbit blood. PRP200μ contains 5μ of calcium chloride aqueous solution (1mM), sodium chloride (120mM), and test compound.
Tris-acetate solution (5mM) 50μ of PH7.4
were added sequentially, and then stirred at 37°C for 2 minutes. Add 5μ of adenosine diphosphate (ADP) (2.5μM) to this solution.
Alternatively, 5μ of collagen (2.5μg/ml) was added as an aggregation inducer. Aggregation was measured using an aggregometer (NKKHEMA Tracer 1). ID ₅₀ Shown in Table 2. Test result B

[Table] Test Method C (Cerebral Vasodilation Test) Male and female mongrel dogs were treated with pentobarbital sodium.
Anesthetized by intraperitoneal injection of 35 mg/Kg. After ligating the external carotid artery, a flowmeter probe was attached to the common carotid artery. A polyethylene cannula was inserted into the femoral artery for blood pressure measurement and into the saphenous vein for drug infusion. Blood pressure was measured with a pressure transducer and the arterial pulse was used to activate the heart monitor. Blood pressure, heart rate and cerebral blood flow (CBF) were recorded on a polygraph. Test compounds were dissolved in an equimolar solution of hydrochloric acid, diluted with water (dose volume 0.2 ml/Kg) and injected intravenously. Post-administration parameters were compared with pre-administration parameters. Table 3 shows the average increase rate of CBF. Test result C

[Table] Test method D (antihypertensive effect test) One kidney was removed from a 5-week-old Wistar male rat under anesthesia. Deoxycorticosterone acetate (DOCA) suspended in peanut oil (30mg/Kg)
was injected subcutaneously twice a week, and 1% saline was given as drinking water. 5-7 weeks after surgery, average blood pressure 150-200
mmHg animals were used in the experiments. Test compounds were administered orally. Blood pressure was measured from the femoral artery and the mean blood pressure was recorded. Table 4 shows the average value of the maximum blood pressure reduction rate. Test result D

[Table] As is clear from the above test results, the object compound of the present invention [] is useful as a cardiotonic agent, an antihypertensive agent, a cerebral vasodilator, and a platelet aggregation inhibitor. For therapeutic use, the subject compounds of this invention [ ] or pharmaceutically acceptable salts thereof may be prepared in conventional pharmaceutically acceptable forms such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or external administration. It can be used in the form of conventional pharmaceutical preparations by mixing with carriers such as Pharmaceutical formulations may be compositions in solid form, such as capsules, tablets, dragees, or suppositories, or liquid compositions, such as solutions, suspensions, or emulsions. If necessary, the above formulation may contain auxiliary agents, stabilizers, wetting agents or emulsifiers, buffers and other commonly used additives. Active ingredients are usually in unit dosages of 0.01mg/Kg to 500
mg/Kg can be administered 1 to 4 times per day. However, the above dosage may be increased or decreased depending on the age, weight, condition or administration method of the patient. The present invention will be explained in more detail with reference to Reference Examples and Examples below. Reference example 1 Ethyl veratroyl acetate (10g) and N,
To a mixture of N'-dimethylurea (3.84 g) are added concentrated hydrochloric acid (1 drop) and ethanol (1 ml). The mixture is heated to 120° C. for 3.5 hours under reduced pressure. Further concentrated hydrochloric acid (2 drops) is added to the residue and the mixture is heated again under reduced pressure to 120° C. for 4 hours. Add water to the reaction mixture and extract with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated in a mixture of isopropyl ether and ethyl acetate to give 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2,4-(1H,
3H)-pyrimidinedione (7.60 g) is obtained. Melting point 118-120°C IR (Nujiol): 1700, 1660cm ^-1 NMR (DMSO-d ₆ , δ): 7.24 (1H, s), 7.20
(2H, s), 5.72 (1H, s), 3.90 (3H, s),
3.88 (3H, s), 3.28 (3H, s), 3.20 (3H, s) Example 1 In substantially the same manner as in Reference Example 1, ethyl 2-(4-methoxy-3-methylbenzoyl)acetate (5.0 g) and N,N'-dimethylurea (2.05g)
, 1,3-dimethyl-6-(4-methoxy-
2-methylphenyl)-2,4-(1H,3H)-pyrimidinedione (4.8 g) is obtained. IR (film): 1700, 1660, 1615 cm ^-1 NMR (CDCl ₃ , δ): 6.7−7.2 (3H, m), 5.62
(1H, s), 3.82 (3H, s), 3.40 (3H, s),
3.06 (3H, s), 2.20 (3H, s) Example 2 In substantially the same manner as Reference Example 1, 2-(3,4
-dichlorobenzoyl)ethyl acetate (10.0 g) and N,N'-dimethylurea (3.71 g), 6-
(3,4-dichlorophenyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (5.27
g) is obtained. Melting point 172-175°C IR (Nujiol): 1695, 1660, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 7.83 (1H, d, J = 2
Hz), 7.80 (1H, d, J=8Hz), 7.50 (1H, dd,
J = 2Hz, 8Hz), 5.68 (1H, s), 3.23 (3H,
s), 3.10 (3H, s) Example 3 In substantially the same manner as Reference Example 1, 2-(3,4
-dimethoxyphenyl)-2-formylacetate (1.2 g) and urea (0.3 g)
4-dimethoxyphenyl)-2,4-(1H,3H)
- Obtain pyrimidinedione (0.52 g). Melting point 180-185°C NMR (DMSO-d ₆ , δ): 3.73 (3H, s), 3.80
(3H, s), 4.40 (1H, br s), 4.48 (1H, br s)
s), 6.60−7.15 (3H, m), 8.17 (1H, d, J
= 4 Hz) Example 4 In substantially the same manner as Reference Example 1, 2-(3,4
-dimethoxyphenyl)-2-formylacetate (1.2 g) and N,N'-dimethylurea (0.49
g) from 5-(3,4-dimethoxyphenyl)-
1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (0.78 g) is obtained. Melting point 146-148°C IR (Nujiol): 1685, 1650cm ^-1 NMR (DMSO-d ₆ , δ): 3.23 (3H, s), 3.37
(3H, s), 3.78 (6H, s), 6.85−7.20 (3H,
m), 7.90 (1H, s) Example 5 Ethyl nicotinoyl acetate (2.30 g) and N,
To a mixture of N'-dimethylurea (1.05 g) are added concentrated hydrochloric acid (a few drops) and ethanol (1 ml) and the mixture is stirred at 110-115° C. under reduced pressure (30 mm Hg) for 4 hours. After cooling to room temperature, the solution was adjusted to pH 7.0 with an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off to give 6-(3-pyridyl)-1,3-dimethyl-2,4(1H,3H).
- Obtain pyrimidinedione (0.91 g). Melting point 120-122°C IR (Nujiol): 1705, 1660cm ^-1 NMR (DMSO-d ₆ , δ): 8.68 (2H, m), 7.95
(1H, m), 7.53 (1H, dd, J=4.5Hz, 7Hz),
5.70 (1H, s), 3.23 (3H, s), 3.10 (3H, s) Example 6 6-(3,4-dimethoxyphenyl)-2,4
(1H,3H)-pyrimidinedione (8.0g) N,
In a solution of N'-dimethylformamide (50 ml), add 50
% oily sodium hydride (3.40 g) is added and the mixture is heated under stirring at 60° C. for 30 minutes. After cooling this mixture to room temperature, methyl iodide (40 ml) was added.
This mixture is stirred at the same temperature for 90 minutes. Water is added to the reaction mixture and subjected to vacuum distillation. Add the residue to water (300ml)
and extract with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is subjected to column chromatography on silica gel, eluting with a mixture of chloroform and methanol. Fractions containing the target compound were combined and concentrated under reduced pressure to give 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2,4
(1H,3H)-pyrimidinedione (1.94 g) is obtained. Melting point 118-120°C IR (Nujiol): 1700, 1660cm ^-1 NMR (DMSO-d ₆ , δ): 7.24 (1H, s), 7.20
(2H, s), 5.72 (1H, s), 3.90 (3H, s),
3.88 (3H, s), 3.28 (3H, s), 3.20 (3H, s) Example 7 6-(3,4-dimethoxyphenyl)-2,4
To a suspension of (1H,3H)-pyrimidinedione (1.0 g) in a mixture of water (5 ml) and methanol (5 ml) was added potassium hydroxide (0.57 g), and to the almost dissolved mixture was added methyl iodide (5 ml). Add. The mixture is stirred at ambient temperature for 18 hours. The resulting precipitate was filtered and washed sequentially with water, ethanol and diisopropyl ether to give 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (0.13 g). get. Melting point 262-263°C Example 8 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.0
g) N,N'-dimethylformamide (30ml)
Add 60% oily sodium hydride (0.5 g) to the solution. The mixture was heated to 60°C for 20 minutes under stirring;
Cool to 0°C. N-propyl iodide (15 ml) was added to this mixture with stirring, and the mixture was stirred at 0°C for 2 hours and at room temperature for 3 hours. After adding water, the reaction mixture is extracted with ethyl acetate. Wash the extracted organic layer with water,
Dry over magnesium sulfate and remove the solvent under reduced pressure. The residue was triturated in diisopropyl ether and the precipitate was collected by filtration to give 6-(3,4-dimethoxyphenyl)-3-methyl-2-propoxy-4
(3H)-pyrimidinone (1.15 g) is obtained as a by-product. The crystals obtained by distilling off the solvent of the filtrate are collected by filtration, and 6
-(3,4-dimethoxyphenyl)-3-methyl-
1-propyl-2,4(1H,3H)-pyrimidinedione (0.94 g) is obtained. (a) 6-(3,4-dimethoxyphenyl)-3-methyl-2-propoxy-4(3H)-pyrimidinone Melting point 131-133°C IR (Nudiol): 1670, 1600 cm ^-1 NMR (CDCl ₃ , δ ): 7.57 (1H, dd, J=2Hz,
J=8Hz), 7.50 (1H, d, J=2Hz), 6.90
(1H, d, J=8Hz), 6.50 (1H, s), 4.48
(2H, t, J=7Hz), 3.92 (6H, s), 3.43
(3H, s), 1.91 (2H, tq, J=7Hz, 7Hz),
1.06 (3H, t, J = 7Hz) (b) 6-(3,4-dimethoxyphenyl)-3-methyl-1-propyl-2,4(1H,3H)-pyrimidinedione Melting point 103-105℃ IR (nujiol): 1705, 1660 cm ^-1 NMR (CDCl ₃ , δ): 6.75−7.0 (3H, m), 5.64
(1H, s), 3.93 (6H, s), 3.5−3.9 (2H,
m), 3.37 (3H, s), 1.20−1.90 (2H, m),
0.74 (3H, t, J = 7Hz) Example 9 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (1.0
g) N,N'-dimethylformamide (10ml)
Add 60% oily sodium hydride (0.17 g) to the solution. The mixture is stirred at 60° C. for 20 minutes and cooled to room temperature. Ethyl iodide (5 ml) was added to the mixture with stirring, and the mixture was stirred at room temperature for 3.5 hours. Add water to the reaction mixture and extract with ethyl acetate. The extracted organic layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated in a mixture of ethyl acetate and diisopropyl ether, and the precipitate was filtered to give 6-(3,4-dimethoxyphenyl).
-2-Ethoxy-3-methyl-4(3H)-pyrimidinone (0.18 g) is obtained as a by-product. Melting point 137-139°C IR (Nujiol): 1675, 1600cm ^-1 NMR (DMSO-d ₆ , δ): 7.65 (1H, d, J = 8
Hz), 7.58 (1H, s), 7.03 (1H, d, J=8
Hz), 6.62 (1H, s), 4.55 (2H, q, J=7
Hz), 3.82 (6H, s), 3.27 (3H, s), 1.41 (3H,
t, J = 7 Hz) The filtrate was evaporated to dryness and the residue was cooled to −10° C. and triturated in a mixture of ethyl acetate and diisopropyl ether to give 6-(3,4-dimethoxyphenyl)-1- Ethyl-3-methyl-2,4 (1H,
3H)-pyrimidinedione (0.8 g) is obtained. melting point
110-120℃. The compound thus obtained is recrystallized from a mixture of ethyl acetate and diisopropyl ether to obtain the desired compound as crystals. Melting point 111-114°C IR (Nujiol): 1695, 1655 cm ^-1 NMR (DMSO-d ₆ , δ): 7.06 (3H, s), 5.56
(1H, s), 3.82 (6H, s), 3.69 (2H, q, J
= 6.5Hz), 3.21 (3H, s), 1.05 (3H, t, J =
6.5Hz) Example 10 In substantially the same manner as in Example 9, 6-(3,4
-dimethoxyphenyl)-3-methyl-2,4
6-(3,4-dimethoxyphenyl)-1-(2, 3-epoxypropyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (4.02 g) is obtained. Melting point: 98-103°C [Recrystallized from a mixture of ethyl acetate and diisopropyl ether (1:1 v/v)] IR (Nudyol): 1700, 1660 cm ^-1 NMR (CDCl ₃ , δ): 6.93 (3H, s), 5.68 (1H,
s), 3.93 (6H, s), 3.7−4.1 (2H, m), 3.4
(3H, s), 3.1−3.6 (1H, m), 2.77 (1H, t,
J=4.5Hz), 2.40 (1H, dd, J=4.5Hz, J=3
Hz) Example 11 In substantially the same manner as in Example 9, 6-(3,4
-dimethoxyphenyl)-3-methyl-2,4
From (1H,3H)-pyrimidinedione (3.0 g), 50% oily sodium hydride (0.6 g) and allyl bromide (4.9 ml), 1-allyl-6-(3,4-dimethoxyphenyl)-3 -Methyl-2,4(1H,
3H)-pyrimidinedione (2.66 g) is obtained. Melting point 88-92℃ IR (Nujiol): 1700, 1660, 1620, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 3.24 (3H, s), 3.77
(3H, s), 3.81 (3H, s), 4.27 (2H, m),
5.11 (2H, m), 5.50−6.14 (1H, m), 5.61
(1H, s), 7.02 (3H, s) Example 12 In substantially the same manner as in Example 9, 6-(3,4
-dimethoxyphenyl)-3-methyl-2,4
1-benzyl-6-(3,4-
dimethoxyphenyl)-3-methyl-2,4(1H,
3H)-pyrimidinedione (3.4 g) is obtained. Melting point 87-95℃ IR (Nujiol): 1700, 1660, 1615, 1685 cm ^-1 NMR (DMSO-d ₆ , δ): 3.27 (3H, s), 3.48
(3H, s), 3.76 (3H, s), 4.92 (2H, s),
5.67 (1H, s), 6.74-7.70 (8H, m) Example 13 In substantially the same manner as in Example 9, 6-(4-methoxyphenyl)-3-methyl-2,4 (1H,
3H)-pyrimidinedione (5.0 g), 50% oily sodium hydride (1.1 g) and methyl iodide (6.7
ml) to obtain 1,3-dimethyl-6-(4-methoxyphenyl)-2,4(1H,3H)-pyrimidinedione (3.1 g). Melting point 76-79℃ IR (Nujiol): 1690, 1655, 1610 cm ^-1 NMR (DMSO-d ₆ , δ): 3.17 (3H, s), 3.26
(3H, s), 3.87 (3H, s), 5.62 (1H, s),
7.07 (2H, d, J = 9.0Hz), 7.50 (2H, d, J
=9.0Hz) Example 14 6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (3.0
g) N,N'-dimethylformamide (30ml)
Add 60% oily sodium hydride (0.50 g) to the solution. The mixture was heated to 60°C for 20 minutes under stirring;
Cool to room temperature. Isopropyl bromide (15
ml) under stirring, and stirred at room temperature for 5 hours and at 50°C for 25 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The extracted organic layer is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated in diisopropyl ether to give 6
-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4(3H)-pyrimidinone (2.73 g) is obtained. Melting point 124-126°C IR (Nujiol): 1680, 1670, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 7.5-7.8 (2H, m),
7.01 (1H, d, J = 8Hz), 5.4 (1H, sep, J =
6Hz), 3.83 (6H, s), 3.27 (3H, s), 1.42
(6H, d, J=6Hz) Example 15 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-(2,4,6-trimethylphenylimino)-2 (1H)-pyrimidinone (14.2 g) in N,N'-dimethylformamide (142
ml), potassium hydroxide (5.5 g) and ethyl iodide (6.0 ml) were added, and the mixture was stirred at room temperature.
Stir for 2.5 hours. Further potassium tert-butoxide (5.0 g) and ethyl iodide (3.0 ml) are added to the reaction mixture, and the mixture is stirred at room temperature for 2 hours. Pour the mixture into ice water (1500ml). The resulting precipitate was collected by filtration, air-dried, and subjected to column chromatography using silica gel, eluting with a mixture of dichloromethane and methanol to obtain 3,4-dihydro-6-(3,4-dimethoxyphenyl). -2-ethoxy-3-methyl-4-(2,4,6-trimethylphenylimino)pyrimidine (0.135 g) is obtained. Melting point 116-119°C IR (Nujiol): 1640, 1650, 1590 cm ^-1 NMR (CDCl ₃ , δ): 7.15-7.55 (2H, m), 6.7-
7.0 (3H, m), 5.83 (1H, s), 4.56 (2H, q,
J=7Hz), 3.85 (6H, s), 3.56 (3H, s),
2.25 (3H, s), 2.04 (6H, s), 1.13 (3H, t,
J=7 Hz) The other fractions are combined and the solvent is distilled off under reduced pressure.
The residue was recrystallized from a mixture of ethanol and water (4:1) to give 3,4-dihydro-6-(3,4-
dimethoxyphenyl)-1-ethyl-3-methyl-4-(2,4,6-trimethylphenylimino)
-2(1H)-pyrimidinone (8.9 g) is obtained. Melting point 116-118℃ IR (Nujiol): 1685, 1660, 1600cm ^-1 NMR (CDCl ₃ , δ): 6.6-6.9 (5H, m), 5.07
(1H, s), 3.85 (3H, s), 3.83 (3H, s),
3.80 (2H, q, J=7Hz), 3.57 (3H, s),
2.20 (3H, s), 2.02 (3H, s), 2.02 (6H, s),
1.12 (3H, t, J = 7Hz) Example 16 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-ethoxy-3-methyl-4 was prepared substantially in the same manner as in Example 15. -(2,4,6-trimethylphenylimino)pyrimidinone (0.47 g) is obtained. mp139−140℃. IR (nujiol): 1640 cm ^-1 NMR (CDCl ₃ , δ): 7.42 (1H, d, J = 2Hz),
7.27 (1H, dd, J=2Hz, J=9Hz), 6.84
(2H, s) 6.79 (1H, d, J=9Hz), 5.84
(1H, s), 4.10 (3H, s), 3.87 (3H, s),
3.86 (3H, s), 3.56 (3H, s), 2.26 (3H, s),
2.03 (6H, s) Example 17 6-(3,4-dimethoxyphenyl)-1-(2,
3-epoxypropyl)-3-methyl-2,4
A solution of (1H,3H)-pyrimidinedione (0.6 g) in ethanol (20 ml) was
ml). The mixture is refluxed for 2.5 hours and the solvent is removed under reduced pressure. The residual syrup was triturated in a mixture of diethyl ether and diisopropyl ether to give 1-(3-tert-butylamino-2-hydroxy-1-propyl)-6-(3,4
-dimethoxyphenyl)-3-methyl-2,4
(1H,3H)-pyrimidinedione (0.66 g) is obtained. Melting point 123-125°C IR (Nujiol): 1700, 1655 cm ^-1 NMR (CDCl ₃ , δ): 6.93 (3H, br, s), 5.68
(1H, s), 3.92 (3H, s), 3.88 (3H, s),
3.77 (2H, br, s), 3.7−4.0 (1H, m), 3.37
(3H, s), 2.1−2.8 (2H, m), 2.0 (2H, br,
s), 1.00 (9H, s) Reference example 2 6-(3,4-dimethoxyphenyl)-1,3-
A mixture of dimethyl-2,4(1H,3H)-pyrimidinedione (1.57 g) and phosphorous pentasulfide (3.3 g) in pyridine (33 ml) is refluxed with stirring for 15 hours. The solvent of the reaction mixture is distilled off under reduced pressure. 1N residue
Wash with hydrochloric acid and extract with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is triturated in diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.58 g). . Melting point 146-148°C IR (Nujiol): 1685, 1615 cm ^-1 NMR (CDCl ₃ , δ): 6.95 (2H, s), 6.86 (1H,
s), 6.60 (1H, s), 3.93 (3H, s), 3.90 (3H,
s), 3.84 (3H, s), 3.30 (3H, s) Example 18 In substantially the same manner as in Reference Example 2, 1,3-dimethyl-6-phenyl-2,4(1H,3H)-pyrimidine From dione (4.0 g) and phosphorus pentasulfide (4.7 g), 3,4-dihydro-1,3-dimethyl-6-
Phenyl-4-thioxo-2(1H)-pyrimidinone (3.0 g) is obtained. Melting point 101-103°C IR (Nujiol): 1680, 1615 cm ^-1 NMR (DMSO-d ₆ , δ): 7.53 (5H, s), 6.44
(1H, s), 3.68 (3H, s), 3.15 (3H, s) Example 19 In substantially the same manner as in Reference Example 2, 1,3-dimethyl-6-(3-pyridyl)-2,4 (1H, 3H)−
From pyrimidinedione (0.78 g) and phosphorus pentasulfide (0.92 g), 3,4-dihydro-1,3-dimethyl-6-(3-pyridyl)-4-thioxo-2
(1H)-pyrimidinone (0.69 g) is obtained. Melting point 136-139°C IR (Nujiol): 1680, 1650, 1615 cm ^-1 NMR (DMSO-d ₆ , δ): 8.87 (2H, m), 8.03
(1H, m), 7.58 (1H, dd, J=4.5Hz, 7Hz),
6.54 (1H, s), 3.71 (3H, s), 3.18 (3H, s) Example 20 In substantially the same manner as in Reference Example 2, 1,3-dimethyl-6-(4-methoxy-2-methylphenyl )
-2,4(1H,3H)-pyrimidinedione (4.80
g) and phosphorus pentasulfide (8.17 g), 3,4-dihydro-1,3-dimethyl-6-(4-methoxy-2-methylphenyl)-4-thioxo-2 (1H)
- Obtain pyrimidinone (3.51 g). Melting point: 117-119℃ IR (Nujiol): 1690, 1610cm ^-1 NMR (CDCl ₃ , δ): 6.6-7.3 (3H, m), 6.55
(1H, s), 3.84 (6H, s), 3.12 (3H, s),
2.22 (3H, s) Example 21 In substantially the same manner as Reference Example 2, 6-(3,4
-dichlorophenyl)-1,3-dimethyl-2,
From 4(1H,3H)-pyrimidinedione (5.20g) and phosphorus pentasulfide (10.0g), 3,4-dihydro-
6-(3,4-dichlorophenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (4.57 g) is obtained. Melting point 126-127°C IR (Nujiol): 1690, 1620, 1100 cm ^-1 NMR (DMSO-d ₆ , δ): 7.85 (1H, d, J = 2
Hz), 7.80 (1H, d, J=8Hz), 7.52 (1H, dd,
J=2Hz, 8Hz), 6.50 (1H, s), 3.68 (3H,
s), 3.14 (3H, s) Example 22 In substantially the same manner as Reference Example 2, 1-allyl-
6-(3,4-dimethoxyphenyl)-3-methyl-2,4(1H,3H)-pyrimidinedione (2.5g)
and phosphorus pentasulfide (5.5 g), 1-allyl-3,
4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2(1H)-pyrimidinone (2.0 g) is obtained. Melting point 103-107°C IR (Nujiol): 1680, 1615, 1600, 1580 cm ^-1 NMR (DMSO-d ₆ , δ): 3.67 (3H, s), 3.75
(3H, s), 3.80 (3H, s), 4.29 (2H, m),
5.14 (2H, m), 5.52-6.26 (1H, m), 6.44
(1H, s), 7.03 (3H, s) Example 23 In substantially the same manner as in Reference Example 2, 1-benzyl-6-(3,4-dimethoxyphenyl)-3-methyl-2,4( 1H, 3H)-pyrimidinedione (3.2
g) and phosphorus pentasulfide (6.1 g), 1-benzyl-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2
(1H)-pyrimidinone (2.9 g) is obtained. Melting point 134-139°C IR (Nujiol): 1700, 1605, 1575 cm ^-1 NMR (DMSO-d ₆ , δ): 3.48 (3H, s), 3.70
(3H, s), 3.76 (3H, s), 4.94 (2H, s),
6.49 ((1H, s), 6.79-7.46 (8H, m) Example 24 In substantially the same manner as Reference Example 2, 5-(3,4
-dimethoxyphenyl)-1,3-dimethyl-2,
From 4(1H,3H)-pyrimidinedione (3.0g) and phosphorus pentasulfide (2.78g), 3,4-dihydro-
5-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo-2(1H)-pyrimidinone (2.45 g) is obtained. Melting point 164-165°C IR (Nujiol): 1700, 1620 cm ^-1 NMR (DMSO-d ₆ , δ): 3.38 (3H, s), 3.68
(3H, s), 3.72 (3H, s), 3.78 (3H, s),
6.90-7.10 (3H, m) 7.78 (1H, s) Example 25 6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4(3H)-pyrimidinone (2.5 g) and A mixture of phosphorus sulfide (3.5 g) in pyridine (50 ml) is refluxed under stirring for 13 hours. The solvent of the reaction mixture is distilled off under reduced pressure. 1N residue
Wash with hydrochloric acid and extract with chloroform. The extract is washed with water, dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was triturated in ethanol and the precipitate was triturated again in chloroform and filtered to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2.
(1H)-pyrimidinone (0.27 g) is obtained. The solvent of the filtrate is distilled off under reduced pressure. The residue is triturated in diisopropyl ether to give 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4-thioxopyrimidine (0.88 g). (a) 3,4-dihydro-6-(3,4-dimethoxyphenyl)-2-isopropoxy-3-methyl-4-thioxopyrimidine Melting point 128-131°C IR (Nudiyol): 1600, 1580 cm ^-1 NMR ( _CDCl3 , δ): 7.64 (1H, dd, J=2Hz,
J=9Hz), 7.57 (1H, s), 7.48 (1H, d,
J=2Hz), 6.91 (1H, d, J=9Hz), 5.48
(1H, sep, J=6Hz), 3.90 (6H, s), 3.86
(3H, s), 1.46 (6H, d, J=6Hz) (b) 3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2
(1H)-pyrimidinone Melting point 245-248℃ IR (Nudiyol): 1685, 1610 cm ^-1 Reference example 3 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-thioxo −
To a solution of 2(1H)-pyrimidinone (1.51 g) in tetrahydrofuran (150 ml) was added methyl iodide (30 ml).
and reflux the mixture for 90 minutes. Precipitate 2,4,
Add 6-trimethylaniline (6 g) and heat the mixture to 110-120° C. for 3 hours. The reaction mixture is washed with a mixture of hexane and diisopropyl ether to remove excess 2,4,6-trimethylaniline. The resulting precipitate is collected by filtration and then dissolved in chloroform. After washing the solution with an aqueous sodium carbonate solution and drying over magnesium sulfate, chloroform was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain 3,4
-dihydro-6-(3,4-dimethoxyphenyl)
-1,3-dimethyl-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone (1.44 g) is obtained. Melting point 68-70℃. The compound thus obtained is recrystallized from a mixture of methanol and water (5:1) to obtain the target compound as crystals. Melting point: 96-98℃ IR (nujiol): 1680, 1640, 1590 cm ^-1 NMR (CDCl ₃ , δ): 6.8 (4H, s), 6.7 (4H,
s), 6.7 (1H, s), 5.13 (1H, s), 3.87 (3H,
s), 3.85 (3H, s), 3.57 (3H, s), 3.14 (3H,
s), 2.20 (3H, s), 2.00 (6H, s) Example 26 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
3-dimethyl-4-thioxo-2(1H)-pyrimidinone (0.2 g), methyl iodide (4 ml) and 4-
From chloro-2-methylaniline (0.4 g), 4
-(4-chloro-2-methylphenylimino)-
3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2(1H)-pyrimidinone (0.17 g) is obtained. Melting point 61-66℃ IR (Nujiol): 1685, 1640, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 7.3-6.6 (6H, m),
5.13 (1H, s), 3.75 (6H, s), 3.22 (3H, s),
3.09 (3H, s), 2.05 (3H, s) Example 27 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and 3-
From aminopyridine (4.0 g), 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3
-dimethyl-4-(3-pyridylimino)-2
(1H)-pyrimidinone (1.1 g) is obtained. The resulting compound is dissolved in ethyl acetate. A mixture of hydrochloric acid and ethyl acetate is added to this solution. The precipitate was collected by filtration and washed with diisopropyl ether.
Vacuum drying to give 3,4-dihydro-6-(3,4
-dimethoxyphenyl)-1,3-dimethyl-4
-(3-pyridylimino)-2(1H)-pyrimidinone dihydrochloride (1.30 g) is obtained. Melting point 145-148℃ IR (Nujiol): 1710, 1610, 1580 cm ^-1 NMR (D ₂ O, δ): 9.2-8.6 (3H, m), 8.30 (1H,
dd, J=5.5, 8Hz), 7.15 (3H, s), 6.23
(1H, s), 3.93 (3H, s), 3.90 (6H, s),
3.53 (3H, s) Example 28 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
From 3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and tert-butylamine (10 ml), 4-(tert-butylimino)-3,4-dihydro- 6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2(1H)
- Obtain pyrimidinone (0.57 g). Melting point 153-155°C IR (nujiol): 1680, 1650, 1605, 1595 cm ^-1 NMR (DMSO-d ₆ , δ): 7.04 (3H, s), 5.66
(1H, s), 3.85 (6H, s), 3.20 (3H, s),
3.04 (3H, s), 1.25 (9H, s) Example 29 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
4-Cyclohexylimino-3,4-dihydro-1,3-dimethyl from 3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and cyclohexylamine (4.0 g) -6-(3,4-dimethoxyphenyl)-2
(1H)-pyrimidinone (0.98 g) is obtained. Melting point 116-118°C IR (Nujiol): 1680, 1650, 1600 cm ^-1 NMR (DMSO-d ₆ , δ): 7.02 (3H, s), 5.83
(1H, s), 3.80 (6H, s), 3.2 (3H, s), 3.1
−3.2 (1H, br), 3.03 (3H, s), 1.0−2.0
(10H, m) Example 30 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and 3,
From 4-dimethoxybenzylamine (3.0g),
3,4-dihydro-4-(3,4-dimethoxybenzylimino)-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-2(1H)-pyrimidinone (1.08 g) is obtained. Melting point 144-144℃ IR (Nujiol): 1660, 1640, 1590 cm ^-1 NMR (CDCl ₃ , δ): 6.7-7.1 (6H, m), 5.7 (1H,
s), 4.28 (2H, s), 3.9 (3H, s), 3.87 (3H,
s), 3.85 (3H, s), 3.83 (3H, s), 3.47 (3H,
s), 3.15 (3H, s) Example 31 In substantially the same manner as in Reference Example 3, 3,4-dihydro-1,3-dimethyl-6-phenyl-4-thioxo-2(1H)-pyrimidinone ( 1.0 g), methyl iodide (22.7 ml) and 2,4,6-trimethylaniline (3.6 g),
3-dimethyl-6-phenyl-4-(2,4,6
-trimethylphenylimino)-2(1H)-pyrimidinone (0.81 g) is obtained. Melting point: 136-139℃ IR (Nujiol): 1680, 1650cm ^-1 NMR (DMSO-d ₆ , δ): 7.40 (5H, m), 6.10
(2H, s), 4.76 (1H, s), 3.46 (3H, s),
3.04 (3H, s), 2.13 (3H, s), 1.93 (6H, s) Example 32 3,4-dihydro-6-(3,4-dimethoxyphenyl) )-1,
From 3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and aniline (3.0 g), 3,4-dihydro-6-
(3,4-dimethoxyphenyl)-1,3-dimethyl-4-phenylimino-2(1H)-pyrimidinone (0.64 g) is obtained. Melting point 60-64℃ IR (nujiol): 1670, 1655, 1590 cm ^-1 NMR (CDCl ₃ , δ): 6.6-7.5 (8H, m), 5.50
(1H, s), 3.86 (3H, s), 3.83 (3H, s),
3.53 (3H, s), 3.16 (3H, s) Example 33 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
3-dimethyl-2(1H)-pyrimidinone (1.0g),
From methyl iodide (20 ml) and 3,4,5-trimethoxyaniline (3.0 g), 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-
Dimethyl-4-(3,4,5-trimethoxyphenylimino)-2(1H)-pyrimidinone (0.63g)
get. Melting point 185-188°C IR (Nujiol): 1680, 1675, 1650 cm ^-1 NMR (CDCl ₃ , δ): 6.7-6.95 (3H, m), 6.10
(2H, s), 5.60 (1H, s), 3.90 (3H, s),
3.87 (3H, s), 3.80 (9H, s), 3.52 (3H, s),
3.18 (3H, s) Example 34 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and 2,
From 4,6-trimethoxyaniline (3.20g),
3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(2,4,6-
Trimethoxyphenylimino)-2(1H)-pyrimidinone (1.19 g) is obtained. Melting point 173-177°C IR (Nujiol): 1680, 1640, 1590 cm ^-1 NMR (CDCl ₃ , δ): 6.6-7.0 (3H, m), 6.18
(2H, s), 5.26 (1H, s), 3.89 (3H, s),
3.85 (3H, s), 3.77 (9H, s), 3.62 (3H, s),
3.15 (3H, s) Example 35 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
3-dimethyl-4-thioxo-2(1H)-pyrimidinone (3.0 g), methyl iodide (60 ml) and 4-
From hydroxyaniline (4.5 g), 3,4-dihydro-6-(3,4-dimethoxyphenyl)-
1,3-dimethyl-4-(4-hydroxyphenylimino)-2(1H)-pyrimidinone (3.05 g) is obtained. Melting point: 104-108℃ IR (Nujiol): 1660, 1640cm ^-1 NMR (CDCl ₃ , δ): 6.82 (3H, s), 6.70 (4H,
s), 3.87 (3H, s), 3.84 (3H, s), 3.50 (3H,
s), 3.16 (3H, s) Example 36 In substantially the same manner as in Reference Example 3, 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,
3-dimethyl-4-thioxo-2(1H)-pyrimidinone (1.0 g), methyl iodide (20 ml) and 2-
From amino-5-methyl-1,3,4-thiadiazole (3.0 g), 3,4-dihydro-6-(3,
4-dimethoxyphenyl)-1,3-dimethyl-
4-(5-Methyl-1,3,4-thiadiazol-2-ylimino)-2(1H)-pyrimidinone (0.06 g) is obtained. Melting point 206-209°C IR (Nujiol): 1680, 1620cm ^-1 NMR (DMSO-d ₆ , δ): 7.05 (3H, br, s),
6.50 (1H, s), 3.80 (3H, s), 3.77 (3H, s),
3.43 (3H, s), 3.25 (3H, s), 2.50 (3H, s) Example 37 3,4-dihydro-1,3-dimethyl-6-(4 -Methoxy-
2-methylphenyl)-4-thioxo-2(1H)-
From pyrimidinone (1.5 g), methyl iodide (25 ml) and 2,4,6-trimethylaniline (4.0 g), 3,4-dihydro-1,3-dimethyl-6-
(4-methoxy-2-methylphenyl)-4-(2,
4,6-trimethylphenylimino)-2(1H)-
Obtain pyrimidinone (1.67 g). Melting point 57-60℃ IR (nujiol): 1690, 1650, 1610, 1590 cm ^-1 NMR (CDCl ₃ , δ): 7.1-6.6 (5H, m), 5.08
(1H, s), 3.80 (3H, s), 3.61 (3H, s),
3.01 (3H, s), 2.22 (3H, s), 2.19 (3H, s),
2.03 (3H, s), 2.01 (3H, s) Example 38 In substantially the same manner as in Reference Example 3, 1-allyl-
3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl-4-thioxo-2(1H)-
Pyrimidinone (1.8g), methyl iodide (30.6ml) and 2,4,6-trimethylaniline (6.4ml)
, 1-allyl-3,4-dihydro-6-(3,
4-dimethoxyphenyl)-3-methyl-4-
(2,4,6-trimethylphenylimino)-2
(1H)-pyrimidinone (1.48 g) is obtained. Melting point 63-67℃ IR (Nujiol): 1685, 1640, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 2.01 (6H, s), 2.19
(3H, s), 3.53 (3H, s), 3.78 (3H, s),
3.80 (3H, s), 4.23 (2H, m), 4.81−5.02
(2H, m), 4.91 (1H, s), 5.60−6.08 (1H,
m), 6.75-7.04 (5H, m) Example 39 In substantially the same manner as in Reference Example 3, 1-benzyl-3,4-dihydro-6-(3,4-dimethoxyphenyl)-3-methyl -4-thioxo-2(1H)
-pyrimidinone (2.8g), methyl iodide (41.2ml)
and 2,4,6-trimethylaniline (8.5ml)
, 1-benzyl-3,4-dihydro-6-
(3,4-dimethoxyphenyl)-3-methyl-4
-(2,4,6-trimethylphenylimino)-2
(1H)-pyrimidinone (0.9 g) is obtained. Melting point 144-146°C IR (nujiol): 1695, 1640, 1600, 1590 cm ^-1 NMR (DMSO-d ₆ , δ): 2.02 (6H, s), 2.16
(3H, s), 3.44 (3H, s), 3.52 (3H, s),
3.73 (3H, s), 4.85 (2H, s), 4.95 (1H, s),
6.61-7.40 (10H, m) Example 40 3,4-dihydro-6-(3,4-dichlorophenyl)-1,3-dimethyl-4-thioxo-2
(1H)-pyrimidinone (1.0g) in toluene (100g)
ml) solution was added methyl iodide (20 ml) and the mixture was refluxed for 3 hours. To this was added further methyl iodide (20 ml) and the mixture was refluxed for another 5 hours. After cooling, the solvent of the mixture is distilled off under reduced pressure. Add 2,4,6-trimethylaniline (3.0g) to the residual oil.
is added and the mixture is stirred at 120°C for 4 hours. The oil is dissolved in ethyl acetate and washed successively with aqueous sodium bicarbonate and water. After drying over magnesium sulfate, the solvent is distilled off under reduced pressure. The residue was subjected to column chromatography using silica gel and eluted with chloroform to give 3,4-dihydro-6-(3,4-dichlorophenyl)-1,3-dimethyl-4-(2,4 , 6-trimethylphenylimino)-2(1H)-pyrimidinone (0.59 g) is obtained. Melting point 194-198°C IR (Nujiol): 1700, 1645, 1600 cm ^-1 NMR (CDCl ₃ , δ): 7.42 (1H, d, J = 8Hz),
7.28 (1H, d, J = 2Hz), 7.02 (1H, dd, J =
8Hz, 2Hz), 6.80 (2H, br, s), 5.10 (1H,
s), 3.57 (3H, s), 3.10 (3H, s), 2.20 (3H,
s), 2.02 (6H, s) Example 41 3,4-dihydro-1,3-dimethyl-6-
(3-Pyridyl)4-thioxo-2(1H)-pyrimidinone (1.2g) in tetrahydrofuran (12ml)
Add a mixture of hydrochloric acid and ethyl acetate to the solution.
The precipitate was collected by filtration, washed with ethyl acetate and dissolved in N,N-dimethylformamide (25 ml). Add methyl iodide (10 ml) to this solution and stir at 60°C for 40 minutes. The solution is evaporated to dryness under reduced pressure. Add the residue to 2,4,6-trimethylaniline (10 ml). After heating to 120°C for 2 hours, the mixture is cooled to room temperature. The precipitate was collected by filtration and 3,4-dihydro-
1,3-dimethyl-6-(1-methyl-3-pyridinio)-4-(2,4,6-trimethylphenylimino)-2(1H)-pyrimidinone iodide (1.75
g) is obtained. IR (Nujiyor): 1680, 1645, 1630, 1080, 860
cm ^-1 NMR (DMSO-d ₆ , δ): 1.93-2.30 (9H, m),
3.05 (3H, s), 3.45 (3H, s), 4.33 (3H, s),
6.66 (1H, s), 6.78 (2H, s), 8.20 (1H, m),
8.67 (1H, m), 9.10 (2H, m) Example 42 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-(4-hydroxyphenylimino) A solution of -2(1H)-pyrimidinone (1.5 g) in acetone (30 ml) was added with potassium carbonate (0.56 g) and epichlorohydrin (0.32 g).
ml). After the mixture has been refluxed for 7 hours, further epichlorohydrin (1.6 ml) is added to it and the mixture is refluxed for a further 38 hours. The solvent of this mixture was distilled off, the mixture was subjected to chromatography using silica gel, and the crude product obtained by eluting with chloroform was recrystallized from diethyl ether. phenyl)-1,3-
Dimethyl-4-[4-(2,3-epoxypropoxy)phenylimino]-2(1H)-pyrimidinone (1.17 g) is obtained. Melting point 155-157°C IR (Nujiol): 1680, 1640, 1590 cm ^-1 NMR (CDCl ₃ , δ): 6.6-7.0 (7H, m), 5.51
(1H, s), 3.9−4.3 (2H, m), 3.87 (3H, s),
3.84 (3H, s), 3.50 (3H, s), 3.2−3.4 (1H,
s), 3.16 (3H, s), 2.6-3.0 (2H, m) Example 43 3,4-dihydro-6-(3,4-dimethoxyphenyl)-1,3-dimethyl-4-[4- (2,
3-epoxypropoxy)phenylimino]-2
(1H)-pyrimidinone (1.0g) in ethanol (30
ml) solution, add isopropylamine (2.0 ml). The mixture is refluxed for 2 hours. After cooling, the mixture was evaporated and powdered in diisopropyl ether to give 3,4-dihydro-6-(3,4
-dimethoxyphenyl)-1,3-dimethyl-4
-[4-(3-isopropylamino-2-hydroxypropoxy)phenylimino]-2(1H)-pyrimidinone (1.13 g) is obtained. Melting point 129-132°C IR (Nujiol): 1685, 1645, 1605 cm ^-1 NMR (CDCl ₃ , δ): 6.6-7.1 (7H, m), 5.53
(1H, s), 3.9-4.1 (3H, m), 3.90 (3H, s),
3.87 (3H, s), 3.53 (3H, s), 3.17 (3H, s),
2.6−3.0 (3H, m), 2.4 (2H, br, s), 1.08
(6H, d, J=6Hz)

Claims (1)

[Claims] 1. General formula {wherein Z is [formula] [formula] and [formula] [wherein R ¹ and R ² are each hydrogen; alkenyl group; al (lower) alkyl group; or epoxy group, hydroxyl group, amino group and / or a lower alkyl group which may be substituted with a lower alkylamino group; R ⁵ means a lower alkyl group], R ³ is hydrogen; a lower alkyl group, a lower alkoxy group and/or a halogen atom an aryl group which may be substituted with; or a pyridyl group which may be substituted with a lower alkyl group; R ⁴ is hydrogen; a lower alkyl group; or a phenyl group which may be substituted with a lower alkoxy group; Y is = O, =S or =N-R ⁶ [In the formula, R ⁶ is a lower alkyl group; a cyclo(lower) alkyl group; an a(lower) alkyl group optionally substituted with a lower alkoxy group; substituted with a lower alkyl group or an aryl group which may be substituted with a hydroxyl group, a lower alkyl group, a halogen atom, and/or a lower alkoxy group, and the lower alkoxy substituent is an epoxy group. , which may be substituted with a hydroxyl group, an amino group and/or a lower alkylamino group] respectively. However, when R ³ is hydrogen, R ⁴ means a lower alkyl group or a phenyl group optionally substituted with a lower alkoxy group, R ¹ and R ² are each hydrogen or a lower alkyl group, and When R ³ is a phenyl group,
Y means =S or =N- ^R6 , ^R1 and ^R2
are each hydrogen or a lower alkyl group, R ³ is an aryl group substituted with a lower alkoxy group, and
When R ⁶ is an aryl group substituted with a lower alkyl group, R ⁴ means a lower alkyl group or a phenyl group optionally substituted with a lower alkoxy group. } Pyrimidine derivatives and pharmaceutically acceptable salts thereof.