JPH04159266A - Pyrimidinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> is lower alkyl; R<2> is H or lower alkyl; R<3> is aryl having a substituent group selected from OH, lower alkoxy, ar(lower)alkoxy and lower alkanesulfonyloxy; R<4> is aryl which may have a substituent group selected from hydroxy(lower)alkyl, acyloxy(lower) alkyl and acyl] and its salt. EXAMPLE:4-(4-Carboxy-2,6-dimethylphenylimino)-6-(3,4-dimethoxyphenyl) -1-ethyl-3- methyl-1,2,3,4-tetrahydropyrimidin-2-one. USE:A cardiotonic agent useful for treating cardiopathy such as cardiac insufficiency. PREPARATION:A compound expressed by formula II is reacted with a compound expressed by the formula R<4>-NH in the presence of a reagent (e.g. a phosphorus halide or phosgene) capable of activating oxo group in the compound expressed by formula II to afford the objective compound expressed by formula I.

Description

[Detailed description of the invention] This invention relates to novel pyrimidinone derivatives.

More specifically, the present invention relates to novel pyrimidinone derivatives and salts thereof having pharmacological activity. More specifically,
The present invention relates to novel and useful pyrimidinone derivatives and salts thereof having cardiotonic effects, methods for producing them, and pharmaceutical compositions containing them.

The pyrimidinone derivative of the present invention is novel and has the following general formula (1) (wherein R1 is a lower alkyl group, R1 is hydrogen or a lower alkyl group, R3 is a hydroxy group, a lower alkoxy group,
an aryl group having a substituent selected from the group consisting of an al(lower) alkoxy group and a lower alkanesulfonyloxy group; R4 is selected from the group consisting of a hydroxy(lower) alkyl group, an acyloxy(lower) alkyl group and an acyl group; Aryl Jλ which may be substituted with a substituent such as -C is represented by the following formula.

The object compound (1) of this invention and its salt can be produced by the production method described in F.

(II) (1) or a salt thereof or a ring formation method thereof 2 (la) (lb) or a salt thereof or a ring formation thereof 2θ, 3 or a salt thereof or a ring formation method thereof 4 (Ie) (II) or Its salt or its ring formation 5 (Ig) (Ih) or its salt or its ring formation 6 (Ii) (Ij) or its salt or its ring Salt or its salt (in the formula,
R', R'', R'' and R4 each have the same meaning as before, R1 is a lower alkyl group, and the amount of R is a hydroxy group, a lower alkoxy group, or an Al (lower) group.
a protected hydroquine-substituted aryl group optionally substituted with a substituent selected from the group consisting of an alkoxy group and a lower alkanesulfonyloxy group, R- is a lower alkoxy group, an ar(lower) alkoxy group and a lower alkanesulfonyloxy group; Hydroquine-substituted aryl group optionally substituted with a substituent selected from the group consisting of 7 groups, R1 may be substituted with a substituent selected from the group consisting of a lower alkoxy group and an alkoxy group (lower) A good lower alkanesulfonyluokine-substituted aryl group, R2 is a lower alkyl-substituted phenyl group or a hydroxymethyl-substituted aryl group, Re is an aryl group substituted with an acyl group, and R is a lower alkyl optionally substituted with an acyl group. W-substituted phenyl group, R2 is a lower alkanoyloxy (lower) alkyl-substituted phenyl group optionally substituted with a substituent selected from the group consisting of an acyl group and a lower alkyl group, R2 is substituted with an acyl group; Ashiluoki / (
lower) alkyl-substituted aryl group, R? means a hydroquine (lower) alkyl-substituted aryl group which may be substituted with an anru group. ) In the foregoing and following descriptions of this specification, various suitable examples and explanations falling within the scope of this invention are set forth in detail below.

"Lower" shall mean groups having 1 to 6 carbon atoms, unless otherwise specified.

Examples of "lower alkyl groups" include straight or branched chain alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc., the most Preferred are methyl and ethyl groups.

"Examples of the lower alkanesulfonyloxy group J include methanesulfonyloxy, ethanesulfonyloxy, and the most preferred among them is the methanesulfonyloxy group.

[Examples of lower alkoxy groups J include straight chain or branched chain alkoxy groups such as methoxy, ethoquine, propoxy, impropoxy, butoquino, tertiary butoquine, benchluoquine, hequinluoquine, etc., among which the most preferred It is the most meth group.

Examples of the "hydroxy (lower) alkyl group" include hydroquinemethyl, 1-hydroquinemethyl, 1-hydroxypropyl, etc., and the most preferred among them is the hydroquinemethyl group.

Preferred acyl moieties in the terms "acyl" and "acyloxy(lower)alkyl" include groups such as carboxy, esterified carboxy, carbamoyl, lower alkylcarbamoyl, lower alkanoyl, ar(lower)alkanoyl, aroyl, and the like. It can be. The esterified carboxy is substituted or unsubstituted lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2.2.2 -trichloroethoxycarbonyl, etc.), substituted or unsubstituted aryloquine carbonyl (e.g., phenoxycarbonyl, 4-nitrophenoquine carbonyl, 2-naphthyloxycarbonyl, etc.), substituted or unsubstituted al(lower)
It may be alkoxycarbonyl (eg, benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl, etc.).

The lower alkylcarbamoyl is methylcarbamoyl,
It may be ethylcarbamoyl, propylcarbamoyl, dimethylcarbamoyl 1, diethylcarbamoyl, and the like.

The lower alkanoyl and “lower alkanoyloxy (
Suitable lower alkanoyl moieties in the term "lower)alkyl-substituted phenyl" include formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl, invaleryl,
It may be pivaloyl, hexanoyl, etc., with formyl and acetyl being preferred.

The al(lower)alkanoyl may be substituted or unsubstituted, such as phenylacetyl, phenylpropionyl, naphthylacetyl, tolylacetyl, chlorophenylacetyl.

The aroyl includes benzoyl, naphthoyl, toluoyl,
It may be xyloyl or the like.

Suitable examples of aryl groups include phenyl group, naphthyl group, tolyl group, xylyl group, mesityl group, cumenyl group, etc., especially phenyl group and phenyl group substituted with lower alkyl group, such as tolyl group, xylyl group. is preferred.

Suitable examples of "al(lower)alkoxy group" include phenyl(lower)alkoxy groups such as benzyloxy group, phenethyloxy group, phenylpropyloxy group, benzhydryloxy group, and trityloxy group. , especially a benzyloxy group.

Suitable lower alkanoyloxy(lower)alkyl moieties in the term "lower alkanoyloxy(lower)alkyl-substituted phenyl group" include acetoxymethyl, 1-acetoxyethyl, 1-acetoxyethyl, l-acetoquinpropyl, Examples thereof include quinmethyl, 1-propionyl quinethyl, 1-propionyloxyprobyl, and the most preferred among them is acetoxymethyl.

Suitable protected hydroxy moieties in the term "F protected hydroxy-substituted aryl group" include, for example, lower alkoxy groups such as methoxy, ethoxy, substituted or unsubstituted alkoxy groups such as benzyloxy, nitrobenzyloxy, etc. (lower) alkoxy groups, such as formyloxy,
Lower alkanoyloxy groups such as acetyloxy, propionyloxy, butyryloxy, inbutyryloxy, valeryloxy, invaleryloxy, pivaloyloxy, hexanoyloxy, 3゜3-dimethylbutyryloxy, such as methoxycarbonyloxy, ethoxy carbonyloxy, propoxycarbonyloxy, impropoxycarbonyloxy, butoxycarbonyloxy,
Lower alkoxy/calonyloxy groups such as imbutoxycarginyloxy, tertiary butoxycarbonyloxy, pentyloxycarbonyloxy, hexyloxycaronyloxy, etc., sulfonyloxy groups such as me/luoquine, tongluoquine, pencenesulfonyloxy group, etc. groups, e.g. substituted or unsubstituted al(
Alkoxy groups such as (lower)alcoquinocarbonyloxy groups, tri(lower)alkylsilyloxy groups such as trimethylsilyloxy, and the like.

Suitable salts of the target compound (1) include pharmaceutically acceptable salts, especially customary non-toxic salts, such as alkali metal salts such as sodium salts, potassium salts, and calcium salts, magnanium salts, etc. metal salts such as alkaline earth metal salts such as ammonium salts, e.g. triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, organic base salts such as N,N'-dibenzylethylenediamine salts, e.g. hydrochloric acid. salts, inorganic acid salts such as hydrobromides, sulfates, phosphates, such as formates, acetates, trifluoroacetates, maleates, tartrates, methanesulfonates, benzenesulfonates, p, - Examples include organic acid salts such as toluenesulfonate, salts with amino acids such as arginine salt, aspartate, and glutamate.

Suitable salts of compound (Il) are the same as the salts exemplified in the explanation of compound (1).

Compounds (Ia) to (112) are included in the scope of compound (1), so for suitable salts of these compounds (Ia) to (Il), refer to those exemplified in the explanation of compound (1). I can do it.

The method for producing the target compound (1) and its salt will be explained in detail below.

Production method 1 Compound (1) or a salt thereof is prepared by combining compound (II) or a salt thereof and compound (I[I) or a salt thereof into the compound (II) or a salt thereof.
) in the presence of a reagent that activates the oxo group.

Suitable salts for compound (III) include those exemplified for compound (1).

Suitable examples of reagents that activate the oxo group attached to compound (II) include phosphorus trichloride, phosphorus oxychloride (e.g., phosphoryl chloride, etc.), phosphorus oxybromide, phosphorus pentachloride, and other halogenated phosphorus. , phosphorus pentoxide, thionyl chloride, oxaluryl chloride, phoscene, and the like.

This reaction is usually carried out in conventional solvents such as benzene, toluene, xylene, tetrahydrofuran, dioxane, carbon tetrachloride, chloroform, methylene chloride, but any solvent that does not adversely affect the reaction may be used. The reaction can be carried out in any solvent or in a mixture thereof.

In this reaction, compound (It) may be reacted with a reagent that activates the oxo group exemplified above, and then compound (DI) may be reacted, or compounds (II) and (nl ) and the reagents may be reacted together.

The reaction temperature is not particularly limited, and the reaction is usually carried out with or without heating.

Manufacturing method? Compound (1b) or a salt thereof can be produced by subjecting compound (1a) or a salt thereof to an alkylation reaction.

The alkylating agents used in this alkylation reaction include di(lower) alkyl sulfates (e.g., dimethyl sulfate, diethyl sulfate, etc.), diazo(lower) alkanes (e.g., diazomethane, diazoethane, etc.), lower alkyl halides ( For example, methyl iodide, ethyl iodide, etc.), lower alkyl arenesulfonates (eg, p-toluenesulfone imitation methyl, etc.), and the like.

Di(lower)alkyl sulfate or lower alkylno＼o)f
Reactions using compounds or lower alkyl arenesulfonates are usually carried out using water, acetone, ethanol, ether,
It is carried out in a solvent such as dimethylformamide or other solvents that do not adversely affect the reaction. This reaction is preferably carried out in the presence of a base such as the above-mentioned inorganic bases or organic bases. The reaction temperature is not particularly limited, and the reaction is usually carried out with cooling or heating to about the boiling point of the solvent.

Reactions using diazo (lower) alkanes are usually carried out in a solvent such as ether or tetrahydrofuran. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature.

Compound (1d) or a salt thereof can be produced by subjecting compound (Ie) or a salt thereof to a hydroxy protecting group elimination reaction.

This reaction is carried out according to conventional methods such as hydrolysis, reduction, and conventional methods used in removing the protecting groups of phenols.

Hydrolysis is preferably carried out in the presence of a base or an acid, including a Lewis acid.

Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or hydrogen carbonates of these metals, hydrazine, trimethylamine, triethylamine, etc. Alkylamine, bifrin, 2゜6-lutidine, I,5-diazabicyclo[
4,30] non-5-ene, 1,4-diazabicyclo[
2,22]octane, 1,8-diazabicyclo[5,4
, O] Inorganic bases and organic bases such as undec-7-ene and the like.

Suitable acids include, for example, formic acid, acetic acid, propionic acid,
Organic acids such as trichloroacetic acid, trifluoroacetic acid, Lewis acids such as boron trihalides such as boron tribromide, boron trichloride, boron trifluoride, etc., and Lewis acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, chloride, etc. Examples include inorganic acids such as hydrogen, hydrogen bromide, and hydrogen fluoride.

In this reaction, when removing a lower alkyl group,
Preferably, a combination of 2,6-lutidine and lithium iodide is used.

The reaction is usually carried out using water, alcohols such as methanol and ethanol, methylene chloride, chloroform, carbon tetrachloride,
The reaction is carried out in a solvent such as tetrahydrofuran, or a mixture thereof, but the reaction can be carried out in any other solvent that does not adversely affect the reaction. Liquid bases or acids can also be used as solvents.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Reduction methods that can be applied to the elimination reaction include chemical reduction and catalytic reduction.

Suitable reducing agents used for chemical reduction include, for example, tin,
Metals such as zinc, iron, or metal compounds such as chromium chloride, chromium acetate, and organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, p)/l/enesulfonic acid, hydrochloric acid, hydrobromic acid, or It is a combination with an inorganic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plates, for example palladium black 1. f. Commonly used palladium catalysts such as radium-carbon and the like.

The reduction is usually carried out in conventional solvents or mixtures thereof that do not adversely affect the reaction, such as water, methanol, ethanol, propatool, N,N-dimethylformamide. Furthermore, if the acids used in the chemical reduction are liquids, they can also be used as solvents. Additionally, suitable solvents used for catalytic reduction include the above-mentioned solvents and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, acetic acid, etc.
or a mixture thereof.

The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling or heating.

Compound (If) or a salt thereof can be produced by reacting compound (Ie) or a salt thereof with a lower alkanesulfonylating agent.

Suitable lower alkanesulfonylating agents include lower alkanesulfonic acids and their reactive derivatives at the sulfo group.

Suitable examples of "lower alkanesulfonic acids" include straight-chain or branched-chain lower alkanesulfonic acids having 1 to 6 carbon atoms, such as methanesulfonic acid, ethanesulfonic acid, and propanesulfonic acid. The most preferred one is methanosulfonoic acid.

” Suitable reactive derivatives at the di-sulfo group include acid halides (e.g., acid chlorides, acid bromides, etc.);
Examples include acid anhydrides, activated esters, activated amides, and the like.

The reaction is usually carried out using water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N.

It is carried out in conventional solvents such as N-dimethylformamide, pyridine or other organic solvents that do not adversely affect the reaction. Among these solvents, hydrophilic solvents may be used in combination with water.

When lower alkanesulfonic acids are used in the reaction in the form of free acids, the reaction proceeds with N,N--dicyclohexylpolodiimide; phosphorus oxychloride, phosphorus trichloride; phosphorus pentachloride; thionyl chloride; oxalyl chloride, ■-( p-10robenzenesulfonyloxy)-6=chloro-IH-benzotriazole; For example, dimethylammonium chloride (chloromethylene) produced by reacting dimethylformamide with thionyl chloride or phosgene or reacting dimethylformamide with oxine phosphorus chloride It is preferable to carry out the reaction in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent, such as a compound prepared by the method.

The reaction may be carried out in the presence of an inorganic or organic base as exemplified above.

The reaction temperature is not particularly limited, and the reaction is carried out under cooling, at room temperature, or under heating.

Production method 5 Compound (Ih) or a salt thereof can be produced by reacting compound (Ig) or a salt thereof with an oxidizing agent.

Examples of suitable oxidizing agents include Jones' reagent, potassium permanganate, activated manganese dioxide, and the like.

This reaction is typically carried out using conventional solvents such as water, acetic acid, sulfuric acid, methylene chloride, carbon tetrachloride, acetone, ethyl acetate,
It is carried out in chloroform, other organic solvents that do not adversely affect the reaction, or in mixtures thereof.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

Production method” Compound (Ij) or a salt thereof can be produced by reacting compound (11) or a salt thereof with an alkali metal persulfate salt and a cupric lower fatty acid.

Examples of suitable alkali metal persulfates include sodium persulfate, potassium persulfate, and the like, the most preferred of which is potassium persulfate.

Examples of suitable cupric lower fatty acids include cupric acetate, cupric propionate, and the like, and the most preferred among them is cupric acetate.

This reaction is preferably carried out in the presence of an alkali metal salt of a lower fatty acid.

Suitable examples of alkali metal salts of lower fatty acids include sodium acetate, potassium acetate, sodium propionate,
Examples include potassium propionate, and the most preferred among them is sodium acetate.

This reaction is carried out in a solvent such as lower fatty acids (eg, acetic acid, propionic acid, etc.).

The reaction temperature is not particularly limited, and the reaction is usually carried out at or under heating.

Production method 7 Compound (+12) or a salt thereof can be produced by subjecting compound (Ik) or a salt thereof to a deacylation reaction.

This elimination reaction is carried out in substantially the same manner as the hydrolysis and reduction described in Preparation Method 3, and therefore the reaction method and reaction conditions for this reaction, such as solvent and reaction temperature, are as described in Preparation Method 3. Reference may be made to the description of hydrolysis and reduction.

The novel pyrimidinone derivative (1) and its salts have cardiotonic effects and are useful, for example, in the treatment of heart diseases such as heart failure.

In order to demonstrate the pharmacological activity of pyrimidinone derivative (1), the results of inotropic action tests of representative compounds of pyrimidinone derivative (1) are shown below.

(1) Cardiotropic effect (1) Test method: Male and female mongrel dogs were treated with bentoparbital sodium (35
/kg intraperitoneal administration). Animals were allowed to breathe spontaneously. The left carotid artery was dissected and a heparinized saline-filled catheter (USC+) was placed.

#8F) was inserted and advanced into the left ventricle. The catheter is a pressure cadence juicer (Nihon Kohden, MPLI-0,5A)
to measure the left ventricular pressure, and from this left ventricular pressure dp/
dt max was derived by analogobe calculation. A cannula was inserted into the left femoral artery for systemic blood pressure measurement. Arterial pulses were used to activate the heart rate monitor. Another catheter was placed in the vena cava via the right vena cava and the drug was injected.

Systemic blood pressure, left heart basin pressure, dp/dt max, and heart rate were simultaneously recorded on a polygraph (Nihon Kohden, RJG-4008).

Test compounds and control compounds were mixed with distilled water (0,2at!/
kg) or dimethyl sulfoxide (0.04 ml/
kg) and injected into the femoral vein. Post-administration parameters were compared with pre-administration parameters.

The result is dp/dL may change (d
Expressed as p/dLM, C,) rate.

(ii) 1) Test compound 4-(4-carboxine-2,6-dimethylphenylimino')-6-('3,4-dimethoxyphenyl)-1-
Ethyl-3-methyl-1,2,3,4-tetrahydropyrimidin-2-one 2) Control compound: 3-amino-5-(4-pyridyl)-2(IH)-viridinone, actually used as a cardiotonic drug Amrinone is a known compound.

(iii) Test Results - As is clear from the test results in Section F, Compound (1) of the present invention is useful as a cardiotonic agent.

For therapeutic use, the object compound (1) of this invention or a pharmaceutically acceptable salt thereof may be prepared in conventional pharmaceutically acceptable forms such as organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical administration. It can be mixed with a suitable carrier and used in the form of a conventional pharmaceutical preparation. Pharmaceutical formulations may be solid compositions such as capsules, tablets, dragees or suppositories, or liquid compositions such as solutions, suspensions or emulsions. If necessary, auxiliary agents, stabilizers, wetting agents or emulsifiers,
Buffers and other commonly used additives may also be included.

The active ingredient usually has a unit dosage of 0.01■/kg to 500
■/kg can be administered 1 to 4 times per day.

However, the above dosage may be increased or decreased depending on the patient's age, weight, condition or administration method.

The present invention will be explained in more detail below with reference to production examples and examples.

Production Example 1 Acetovanillon (77, 86g) and acetone (780g)
-') Potassium carbonate (67.99 g) and benzyl bromide (58.5+all) are added to the solution and refluxed for 2 hours. After cooling, the precipitate was filtered off, the solvent of the filtrate was distilled off under reduced pressure, and the mixture was triturated with diisopropyl ether to obtain 4'-benzyloxy-3-1methoxyacetophenone (115.25 g).

IR (Medi3-L): 1580, 1665cm
-'NMR (CDCl2.δ): 2.54 (30
,s), 3.93(3H,s).

5, 22 (2H, s), 6.88 (IH, 'd, J
=8Hz)'+7.2-7.6(7H.

m) Production Example 2 To a solution of tertiary butoxypotassium (126.1 g) in tetrahydrofuran (750111!) was added 4-benzyloxy-3'-methoxyacetophenone (115.2 g).
) and diethyl carbonate (2187 g) in tetrahydrofuran (400 d) are added dropwise. The mixture is refluxed for 2 hours and cooled. The resulting precipitate is filtered and dissolved in water. The solution is adjusted to p) 16 with concentrated hydrochloric acid. and extract with chloroform. The extract is washed with water and brine and dried over sodium sulfate. The solvent was distilled off and the residual oil was crystallized with diisopropyl ether to obtain ethyl (4-benzyloquino-3-methquinbenzoyl)acetate (97.58 g).

IR (Men 1-R): 1720.1670.1
585cm ”NMR (CDC13, δ)・1.25(
3B, L, J・7Hz), 3.93(5H,
s).

4, 22 (2H, q, J=7Hz), 5.23 (
2t1. s), 6.90 (IH, d, J=8Hz
), 7.2-7.6 (7H, m) Production Example 3 (4-benzyloxy-3-methoxybenzoyl) To a solution of ethyl acetate (5.0 g) in methanol (15 ml),
Ethyl orthoformate (3,33 mff ”) and concentrated sulfuric acid (0, Im& ) are added. The mixture is refluxed for 1.5 hours and methylurea (3,38 g) is added. The mixture is refluxed again at 1
The mixture was refluxed for 5 hours and the solvent was distilled off. A solution of sodium hydroxide (1.22 g) in water (20-) is added to the residue.

The mixture is stirred at 60-70°C for 2 hours. After cooling, the mixture is neutralized with 6N hydrochloric acid and stirred for 1 hour while cooling with water. The precipitate was collected by filtration, washed with water, and 6-(4-benzyloxy-3
-methoxyphenyl)-3-methyl-1,2,3,4-
Tetrahydropyrimidine-2,4-dione (4,94g
).

m, p,: 254-259°C IR (nuji l-1): 1710.1630cm
-'NMR (CDCI3+MeOH-d, δ)
: 3.34 (3H, s), 3.96 (3H, s).

5, 22 (2B, s), 5.92 (IH, s),
7.00 (IH, d, J・97) 7, 1-7.6 (7
H, m) Example 1 6- (4-benzyloxy-3-methoxyphenyl)
-3-Methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (10,0 g) in dioxane (50 g)
d') Add phosphorus oxychloride (5,5all) to the suspension and reflux for 1 hour. The mixture was cooled to 90°C and then 2.4.6-)limethylaniline (6,22WIt
! '). The mixture is again refluxed for 1 hour. After cooling, the mixture is poured into water (70 d) and neutralized with 8N aqueous sodium hydroxide solution. The resulting precipitate was chromatographed on silica gel and eluted with a mixture of chloroform and methanol (0-5%, v/v) to give 6-(
4-hensyloxy-3-methoxyphenyl)-3-methyl-4-(2,4,6-drimethylphenylimino)
-1,2,3,4-tetrahydrobiwamidin-2-one (5,59 g) is obtained.

m, p,: 237-239°C II? (Neufcor): 16850640cm
-'NMR (CDCIs+MeOH-d-, δ):
2. (13 (6Ls), 2.26 (31Ls)
, 3.38(3)1. s), 3.92 (3H, s)
, 5.16 (2B, s).

5, 35 (IH, s), 6.8-7.5 (1011,
m) Example 2 6-(3,4-dimethoxyphenyl)-1-ethyl-3
-Methyl-4-(2,4,6-trimethylphenylimino)-1,2,3,4-tetrahydropyrimidine-2-
Add chromium trioxide (122,7 g) to a 10% sulfuric acid (2,51) solution of
0d) dropwise at 80° C. over 1.5 h and the mixture is stirred vigorously at 80° C. for 1 h.

The reaction mixture is cooled and extracted with chloroform.

The organic layer was washed with brine, dried over sodium sulfate, and
4-(
4-carboxine-2,6-dimethylphenylimino)-
6-(3,/l-dimethoxyphenyl)-1-ethyl-
3-Methyl-], 2,3°4-tetrahydropyrimidin-2-one (35,94 g) was obtained and recrystallized from ethanol.

m, p,: 201-202°C IR (streak 1-l): 1680, 1665.1
645.1585cm-'NMR(CDCl2.δ)
: 1.15 (3H, t, J=7Hz), 2.12
(611, s).

3,61(3H,s), 3.72(2H,q, J
=7Hz), 3.86(3H,s), 3.88(
3H,s), 4.98(IH,s), 6.70(I
H,d.

J・2nd period), 6.77 (I) I, dd J・27th, 8th period), 6.85 (II, d.

J=8Hz), 7.77(2H,s) Example 3 4-(4-carboxy-2,6-dimethylphenylinomi)-6-(3,4-dimethoxyphenyl)-1-ethyl- 1 in a solution of 3-methyl-1,2,3,4-tetrahydropyrimidin-2-one (1.0 g) in acetic acid (15d).
, sodium acetate (0,47 g).

Copper acetate (■) monohydrate (0.23 g) and potassium persulfate (0.62 g) are added. The mixture is refluxed for 4 hours, cooled, poured into water (+50+nf) and extracted with chloroform. The organic layer is washed twice with water and aqueous sodium bicarbonate solution and dried over sodium sulfate. The solvent was evaporated and the residue was chromatographed using a chloroform and methanol mixture (
0-5%, V/V), 4-(2-acetoxymethyl-4-carboxy-6-methylphenylimino)
-6-(3゜4-dimethoxyphenyl)-1-ethyl-
3-Methyl-1,2,3,4-tetrahydropyrimidin-2-one (0.42 g) is obtained as a syrup and used in the reaction of the next example without further purification.

Example 4 4-(2-acetoxymethyl-4-carboxine-6-methylphenylimino)-6-(3,4-dimethoxyphenyl)-1-ethyl-3-methyl-1,2,3,4-tetrahydro To a solution of pyrimidin-2-one (0.42 g) in methanol (10 aff) is added IN aqueous sodium hydroxide solution (1.7 d') and stirred at room temperature for 5 hours.

The reaction mixture was neutralized with IN hydrochloric acid and extracted with a mixture of chloroform and methanol (91, v/v). The organic layer was dried over sodium sulfate, the solvent was evaporated, and chromatographed using a soli gel, eluting with a mixture of chloroform and methanol (2-15%, V/V).
-(4-carboxylic acid 2-hydroxy/methyl-6-methylphenylimino') -6-(3゜4-dimethoxyphenyl)-]-ethyl-3-methyl-1,2,3,4-
Tetrahydropyrimidin-2-one (0.15 g) is obtained.

m, p,: 207-209°C IR (streak 3-l): 1700, 1645 cm-'
NMR(CDC1,-MeOl(-d4.δ): 1
．． 14(31(,t, J=7Hz), 211(3H,
s), 3.58 (3H, s), 3.70 (2H, q
, J=7Hz).

3, 88 (3H, s), 3.85 (3H, s), 4
．． 36 (IH, d, J13Hz) 4.64 (IH,
d, J13Hz), 5.00 (IH, s), 6.7
1 (IH, dJ = 2Hz), 6.77 (II (, dd
, J=2Hz, 8Hz), 6.87 (IH.

d, 8Hz), 7.81 (IH, s), 7.9
2(IH,s)Mass(m/e): 453(M”
) Example 5 6-(4-pendyloquino-3-methoxyphenyl)-
3-Methyl-4-(2,4,6-)limethylphenylimino')-1,2,3,4-tetrahydropyrimidine-
Potassium hydroxide (1.35 g) was added to a solution of 2-one (5.5 g) in N,N-dimethylformamide (44 ml).
) and stirred at 30-35°C for 2 hours. After cooling with water, ethyl iodide (2,4atff) was added and the solution was incubated at 0-5 °C for 4 h, at room temperature for 62 h and at 80-90 °C.
Stir for 2 hours. The mixture is poured into a mixture of water (200d) and ethyl acetate (200mf). The separated organic layer is washed with brine and dried over sodium sulfate. The solvent is evaporated and the residue is triturated with diisopropyl ether to remove insoluble starting material. Evaporate the diisopropyl ether and recrystallize from ethanol to give 6-(4-benzyloxy-3-methoxyphenyl)-1-ethyl-3
-Methyl-4-(2,4,6-drimethylphenylimino)-1,2,3,4-tetrahydropyrimidine-2-
On (5.02g) is obtained.

m, p,: 122-125℃ IR (line 1-l): 16g5.1630cm
-'NMR (CDCl2.δ): 1.11 (311
,t, J41(z), 2.02(6H,s)2.2
1 (3H, s), 3.57 (3H, s), 3.
65 (2H, Q, J=7Hz) 3.86 (3H, s)
, 5.07 (Ill, s), 5.15 (2H,
s), 6.6-7.0 (5H, a), 7.2-
7.6 (58, m) Example 6 6-(4-pendyluoquin-3-methquinphenyl)-
1-Ethyl-3-methyl-4-(2,4゜6-drimethylphenylimino)-1,2,3゜4-tetrahydropyrimidin-2-one (5.0g) in acetic acid (50m12
) solution with palladium-carbon (10%).

0.5 g) and ammonium formate (l, 96 g). The mixture is stirred at 50° C. for 1 hour. After cooling, the catalyst is filtered off, the solvent is evaporated and the residue is dissolved in chloroform, washed successively with aqueous sodium bicarbonate solution and water and dried over sodium sulfate.

The solvent was evaporated and the residue was chromatographed on silica gel, eluting with a mixture of chloroform and methanol (0-3%, v/v) to give 1-ethyl-6-(4
-Hydroxy/-3-methquinophenyl)-3-methyl-
4-(2,4,6-drimethylphenylimino)-]+
2.3. /I-tetrahydropyrimidin-2-one (3,77 g) is obtained. m, p, : 15g-1
60℃ IR (Sunyeol): 1680.164
0cm −' Mouth R (CDCl2.δ): 1.13 (3
H, t, J・7) 1z), 2.04 (6H, s).

2, 21 (3) 1. s), 3.62 (311, s)
, 3.68 (2Lq, JIHz).

3, 87 (3L s), 5.10 (IH, s), 6
．． 67 (IH, d, J=2Hz).

6, 71 (II, dd, J=2s, 8s), 6.
81 (2H, s).

6,89 (IH, d, J = 8 cells) Example 7 1-ethyl-6-(4-hydroquine-3-methoxyphenyl)-3-methyl-4-(2,4,6-drimethylphenyl imino)-], 2,3,4-tetrahydropyrimidin-2-one (4,03 g) in methylene chloride (80 d
) To the solution, add pyridine (3,1d) and methanesulfonyl chloride (2,4TnI''). The solution is refluxed for 9 hours and cooled. The solution is diluted with chloroform and
Wash sequentially with aqueous sodium bicarbonate solution, water and brine, and dry over sodium sulfate. The solvent was evaporated and the residue was chromatographed using 7-silica gel, eluting with chloroform to give 1-ethyl-6-(4-methylsulfonylox/-3-methoxyphenyl)-3-methyl-4. -(2,4,6-)limethylphenylimino')-
1,2,3,4-tetrahydropyrimidin-2-one (
4.42g) is obtained.

m, p,: 80-90℃ IR (Nuc 3-L): 1660, 1635cm
-'NMR (CDC1,, δ): 1.14 (3H, t,
J=77), 2.02 (6H, s).

2, 22 (311, s), 3.21 (3H, s),
3.58 (3B, s), 3.65 (2H.

q, J=7Hz), 3.88(3H,s), 5
．． 08 (IH, s), 6. '8-6.9 (4B, *
), 7.27 (IH, d, J=47) Example 8 ■-Ethyl-6-(4-methylsulfonyloxy-3-
methoxyphenyl)-3-methyl-4=(2,4,6-
Chromium trioxide (4.54 g) was added to a solution of 10% sulfuric acid (428 d) of 1゜2.3.4-tetrahydropyrimidin-2-one (4.28 g).
A 10% aqueous sulfuric acid solution (34 ml) was stirred vigorously at 80°C for 2.5 hours, and then added dropwise. After dropping, the reaction was heated to 80°C.
I poked it for 5 hours. Add methanol (5ff1g),
Dividing chromium (Vl) into chromium (III). The organic compounds were extracted from the blue solution with chloroform, dried over sodium sulfate, chromatographed using silica gel, and extracted with a mixture of chloroform and methanol (0-
5%, V/V), 4-(4-carboquine-2,
6-dimethylphenylimino)-1-ethyl-6-(4
-methylsulfonyloxy-3-methoxyphenyl)-
3-Methyl-1,2,3,4-tetrahydropyrimidin-2-one (0.22 g) is obtained.

m, p,: 195°C (minute IR): 1720, 1680.164
0 cm-'NMR (CDC1,, δ): 1.15 (3
)1. t, J・7s), 2.08(6H,s)+3,
20 (3H, s), 3.59 (3H, s), 3.6
7 (2B, q, J=7Hz).

3, 88 (3H, s), 4.97 (IH, s), 6
．． 8-6.9 (21 (, m), 7.32 (IH, d,
J = 8 cells), 7.72 (2H, s) Example 9 4-(/1~carboxylic/-2,6-methylphenylimino)-1-ethyl-6-(4-methylsulfonylox 3-methoxyphenyl)-3-methyl-1,2,3
,4-tetrahydropyrimidin-2-one (0,2g)
In a suspension of dioxane (2d) and water (1-), I
Add N aqueous sodium hydroxide solution (2.0 d). The mixture is stirred at room temperature for 21 hours and at 60° C. for 35 hours. After cooling, the mixture is neutralized with IN hydrochloric acid and the solvent is evaporated.

The residue is dissolved in a small amount of water and adjusted to pH 4 with IN hydrochloric acid.

The solution was chromatographed using HP-20 and mixed with water and isopropyl alcohol (0-40%,
v/v) and eluted with 4-(4-carboxy-2,6-dimethylphenylimino)-1-ethyl-6-(4-hydroxy-3-methoxyphenyl)-3-methyl-1, 2
,3,4-tetrahydropyrimidin-2-one (76■
).

m, p, : 136-140'C 11i (nu)! -le): 1685.1640c
m-'NMR (CDCI3, 6 houses 1.14 (311,
t+J4Hz), 2.11 (6H, s).

3,6i1(311,s), 3.70(211,q,
J=714z), 3.87(3+l,s).

4,96(1!I, s), 6゜66(III, d
, J=H&), 6.72(IH, dd, J・2
+17. ．． 8 G17. ), 6. 90(lt
l, d, J ・8Hz), 7. 76 (2
11,s)Mass(m/e): 423(M”
) Example 10 6-(3,4-dimethoxyphenyl)-1-ethyl-
3-Methyl-4-(2,4,6-drimethylphenylimino)-1,2,3,4-tetrahydropyrimidine-2
-one (10,0 g) of 2,6-lutidine (150 d
) Add lithium iodide (4.93 g) to the solution and reflux for 4 days. The mixture is dissolved in chloroform (450d), washed successively with water and brine, and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed using silica gel and chromatographed with chloroform and n
- Elute with a mixture of 1:1 to 10: 1.v/v with beef san and 1-ethyl to 6-(3-hydroxy-4-methoxyphenyl)-3-methyl-4-(2, 4°6-Dolimethylphenylimino)-1,2,3°4-tetrahydropyrimidin-2-one (1,22 g) is obtained.

m, p,: +72-173℃ IR (nunodol): 1670.1640cm
-'NMR(CDC1,,6 houses 1.10(3+1.t
, J・7Hz), 2.02 (6H,s).

2, 21 (31 (, s), 3.59 (3H, s),
3.68 (211,q, J=7Hz).

3, 89 (3H, s), 5.06 (IH, s), 5
．． 80 (IH, s), 6.67 (IH.

dd, J・2Hz, 8Hz), 6.7-6,
9(4H,m) Example ll 6-(3,4-dimethoxyphenyl)-1-ethyl-
3-Methyl-4-(2,4,6-1-limethylphenylimino)-1,2,3,4-tetrahydropyrimidine-
To a solution of 2-one (5.0 g) in acetic acid (75 ml), sodium acetate (2.52 g), copper acetate (■) monohydrate (1
, 22 g) and potassium persulfate (4.98 g). The mixture is refluxed for 4 hours and poured into water (375d). The organic compounds are extracted with chloroform, washed successively with water and aqueous sodium bicarbonate solution, and dried over sodium sulfate. After evaporation of the solvent, the residue was chromatographed on silica gel to give 4-(4-acetoxymethyl-2,6-dimethylphenylimino)-6-(
3,4-Dimethoxyphenyl)-1-ethyl-3-methyl-1,2,3,4-tetrahydropyrimidin-2-one (3,48 g) was obtained as an oil without further purification in the following example. used for.

NMR (CDCI, δ): 1.13 (311,
L, J=7Hz), 2.07 (9H, s).

3,59 (3■, s), 3.65 (2H, Q, J
□7Hz), 3.86 (3H, s).

3, 89 (3H, s), 4.98 (2H, s), 5
．． 06 (IH, s), 6.7-6, 8 (3H, m),
6.99(2H,s) Example 12 4-(4-acetoxymethyl-2,6-dimethylphenylimino") -6-(3,4-dimethoxyphenyl)
To a solution of -1-ethyl-3-methyl-1,213,4-tetrahydropyrimidin-2-one (3°34 g) in methanol (83.5 d) was added IN aqueous sodium hydroxide solution (14.3 d), and the mixture was heated at room temperature. Stir for 3 hours. After evaporating the solvent, the residue is dissolved in chloroform, washed with water and dried over sodium sulfate. 6-(3,4-dimethoxyphenyl)-4-(216-dimethyl-4-hydroxymethylphenylimi/)-1-ethyl-3-methyl-], 2,3. 4-tetrahydropyrimidin-2-one (1,64 g) is obtained.

a, p,: 65-75℃ IR (streak J-ru): 1680, 1640
c+a-'NMR (CDCIl, δ): 1.13 (3
H,t,J=7Hz), 2.06(6H,s).

3,59(3H,s), 3.67(2H,q, J=
7Hz), 3.86 (3H, s).

3, 88 (3) 1. s), 4.53(l)I, s
), 4.56 (IH,s), 5.05 (IH.

s), 6.70 (IH, d, J□2Hz), 6
．． 75 (IH, dd, J□2Hz.

8Hz), 6.84 (IH, d, J=8Hz)
, 6.99 (2H, s) Mass (i/e): 4
23 (M”) Example] 3 6-(3,4-dimethoxydiphenyl) -4-(2,6
-Simethyl-4-hydroxymethylphenylimino)-
1-ethyl-3-methyl-1,2,3゜4-tetrahydropyrimidin-2-one (1,0 g) in carbon tetrachloride (5
0d) Add manganese dioxide (■) to the solution and reflux for 70 minutes. After cooling, the reagents were filtered off and the solution was chromatographed on silica gel, eluting with chloroform to give 6-(3,4-dimethoxy/phenyl)i-(
2,6-7methyl-4-formylphenylimi/)-1
-ethyl-3-methyl-], 2,3.4-tetrahydropyrimidin-2-one (0.74 g).

m, p,: 65-75℃ IR (line 1-l): 1680, 1640cm
-'NMR (CDCI3.δ): 1.15 (3H,
t, J・7Hz), 2.13 (68,s).

3,60(3H,s), 3.70(2H,q, J・
7s), 3.86 (3H,s).

3, 88 (3H, s), 4.96 (IH, s), 6
．． 70 (IH, d, J = 2 ministers).

6, 77 (IH, dd, J=2 Arashi, 8Hz),
6.850H, d, J=8ce).

7, 54 (2H, s), 9.82 (IH, s) Mas
s(m/e): '421 (M'') Example 4 The following compound was obtained in the same manner as in Example 1.

4-(4-acetoxymethyl-2,6-dimethylphenylimino') -6-(4-benzyloxy-3-methoxyphenyl)-1-ethyl-3-methyl-1,2,
3,4-tetrahydropyrimidin-2-one.

IR (knee): 1730.1685.164
0cm-'NMR (CDCI, δ): 1.2
3 (3+1.t, J・IH2), 2.02 (611,
s).

2,07(311,s), 3.57(3H,s),
3.70 (211,q, J4Hz).

3, 86 (3) 1. s), 4.97 (IH, s),
5.15 (2tl, s), 6.6-7, 0 (5H
, i), 7.2-7.5 (5H, m) Example 15 In the same manner as in Example 12, the following compound is obtained.

6-(4-benzyloxy-3-methoxyphenyl)-
4-(2,6-dimethyl-4-hydroxymethylphenylimino)-1=ethyl-3-methyl-1,2,3,4
-tetrahydropyrimidin-2-one.

IR (streak 1-t): 1675, 1635C1
1-'NMR (CDC1s, δ): 1.12 (3B
, t, J=7Hz), 2.05(6H,s).

3,58(3H,s), 3.67(2H,q, J=
7Hz), 3.86<3H,s).

4, 53 (2B, s), 5.03 (1B, s),
5.15 (2H, s), 6.5-6.95 (3H,
+m), 6.97 (2H, s), 7.2-7.5 (SR
,-) Example 16 6-(4-benzyloxy-3-methoxyphenyl)-
4-(2,6-dimethyl-4-hydroxymethylphenylimino)-1-ethyl-3-methyl-1,2,3,4
-tetrahydropyrimidin-2-one (0.40 g) (
7) Flow IN hydrochloric acid solution at 3 o'clock Fin)Fl. After cooling, the solution is neutralized with aqueous sodium bicarbonate solution and extracted with chloroform. The organic layer was dried over sodium sulfate, the solvent was distilled off, and chromatographed using silica gel, followed by chromatography using a mixture of chloroform and methanol (0-3%
+ v/V) and eluted with 1-(2,6-cymethyl-4
-hydroxymethylphenylimino)-1-ethyl-6
-(4-hydroxy-3-methoxyphenyl)-3-methyl-1,2,3,4-tetrahydropyrimidine-2-
On (0:17g) is obtained.

m, p,: 85-95°C IR<1 sill) + 1675.1635cm
-'NMR (CDC1,, δ): 1.12 (3H,
L, J=7Hz), 2.06 (6B, s).

3,58(3H,s), 3.68(2H,q, J=
7Hz), 3.87 (3H, s).

4, 55 (2B, s), 5.04 (IH, s),
5.83 (IH, br, s).

Claims (1)

[Claims] 1. Formula; ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 is a lower alkyl group, R^2 is hydrogen or a lower alkyl group, R^3 is a hydroxy group, a lower an aryl group having a substituent selected from the group consisting of an alkoxy group, an alkoxy group, and a lower alkanesulfonyloxy group; ) and salts thereof.