JPS5948828B2 - 1.4↓-dihydropyridine compound and its manufacturing method - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 1,4-dihydropyridine derivatives that have vasodilatory and blood pressure lowering effects and are useful as pharmaceuticals.

Conventionally, the following compounds have been known as 1,4-dihydropyridine compounds, but as a result of intensive research, the inventor discovered 1,4-dihydropyridine which has stronger pharmacological action and is better as a medicine than this compound. He succeeded in synthesizing the compound and completed this invention.

The 1,4-dihydropyridine compound of this invention is represented by the following general formula (1).

(In the formula, R1 is a cyano group, a lower alkoxycarbonyl group, a lower alkanesulfamoyl group, or a 2- or 3-
-nitro group, R2 and R3 are both lower alkoxycarbonyl group, halogen-substituted lower alkoxycarbonyl group, lower alkoxy-substituted lower alkoxycarbonyl group,
N-lower alkyl-N-aryl-substituted lower alkylamino lower alkoxycarbonyl group, aryl-substituted lower alkoxy-substituted lower alkoxycarbonyl group or aryloxy-substituted lower alkoxycarbonyl group, and R
One of 4 and R5 is a lower alkyl group, and the other is a cyano group, lower alkanoyl group, hydroxy-substituted lower alkyl group, hydroxyiminomethyl group, diem (Gem)-
di-lower alkoxy-substituted lower alkyl group or diem (G
em) a mono-lower alkylenedioxy-substituted lower alkyl group, provided that when R1 is a 2-nitro group, R2 is a methoxycarbonyl group, ethoxycarbonyl group or isopropoxycarbonyl group, and R3 is a methoxycarbonyl group. , R4 represents a methyl group, and R5 represents a dimethoxymethyl group, formyl group, hydroxyiminomethyl group, cyano group, or hydroxymethyl group, or R2 represents a 2-benzyloxyethoxycarbonyl group, and R3 represents an ethoxy group. carbonyl group, R4
represents a methyl group, and R5 represents a hydroxymethyl group; Gem)-di-lower alkoxy-substituted lower alkyl group or diem (Gem)-di-lower alkylenedioxy-substituted lower alkyl group, with the proviso that
When R1 is a 2-nitro group, R2 is a methoxycarbonyl group, hydroxycarbonyl group or isopropoxycarbonyl group, R3 is a methoxycarbonyl group, R2 is a methyl group, and R Meng is a dimethoxymethyl group. and when R1 is a 3-nitro group,
R2 and R3 both represent a methoxycarbonyl group, R2 represents a methyl group, and R8 represents a dimethoxymethyl group, or when R2 represents 2-benzyloxyethoxy and R1 represents a 3-nitro group, R2 and R3 both represent a methoxycarbonyl group, R4 represents a methyl group, and R5 represents a dimethoxymethyl group, formyl group, hydroxyiminomethyl group, cyano group, or hydroxymethyl group, or R2 represents 2-benzyloxy ethoxycarbonyl group, R3 means ethoxycarbonyl group, R4 means methyl group, and R5 means diethoxymethyl group, formyl group, hydroxyiminomethyl group, cyano group or hydroxymethyl group) of this invention. In the 1,4-dihydropyridine compound (1), due to the presence of an asymmetric carbon in the molecule, 1
Alternatively, it may have two or more optical isomers, and such isomers are also included within the scope of the present invention.

The 1,4-dihydropyridine compound (1) of this invention is produced by the following various methods. Formation of 11,4-dihydropyridine ring (Process 1) Conversion reaction of functional group in 2 groups R4 or R5 (Process 2-5) (1
) Process 1 A carbonyl group, R3 means an ethoxycarbonyl group, R2 means a methyl group, and Ru means a diethoxymethyl group, respectively.

) (2) Process 2 (wherein R1, R2 and R3 have the same meanings as above, one of R87 and R0 is a lower alkyl group and the other is a 1,1-dialkoxy-substituted lower alkyl group or 1,1-lower alkylenedioxy-substituted lower alkyl group, and one of Kaji and R9 is a lower alkyl group and the other is a lower alkanoyl group, provided that when R1 is a 2-nitro group, R2 represents a methoxycarbonyl group, an ethoxycarbonyl group or an isopropoxycarbonyl group, R8/ and R both represent a methyl group, RH′ represents a dimethoxymethyl group, and RC
respectively mean a formyl group, and when R1 is a 3-nitro group, both R2 and R3 are a methoxycarbonyl group, R2 and R2 are both a methyl group, R is a dimethoxymethyl group, and respectively mean a formyl group, or R2 is a 2-benzyloxyethoxycarbonyl group, R3 is an ethoxycarbonyl group, R and R9 are both a methyl group, R is a diethoxymethyl group, and Kaji is (3) Process 3: (In the formula, R1, R2 and R3 each have the same meaning as above, one of Ry and RL' is a lower alkyl group, and the other is a formyl group) , R, and R are a lower alkyl group and the other is a hydroxyiminomethyl group, provided that when R1 is a 2-nitro group, R2 is a methoxycarbonyl group, an ethoxycarbonyl group, or an isopropoxycarbonyl group. group, R3 means a methoxycarbonyl group, Kaji and Kaji both mean a methyl group, R means a formyl group, and Ru means a hydroxyiminomethyl group, and when R1 is a 3-nitro group, R2 and R3 is both a methoxycarbonyl group, Rt and R5
Both have a methyl group, and Kaji has a formyl group. each represents a hydroxyiminomethyl group, or R
2 is a 2-benzyloxyethoxycarbonyl group, R3
has an ethoxycarbonyl group, and both Kaji and Kaji have a methyl group. shall mean a formyl group, and R5 shall mean a hydroxyiminomethyl group, respectively) 1) Process 4: (In the formula, R1, R2 and R3 have the same meanings as above, and among R and R, One is a lower alkyl group, the other is a hydroxyiminomethyl group, and one of Ra and RJ is a lower alkyl group and the other is a cyano group, provided that R1 is 2
- When it is a nitro group, R2 is a methoxycarbonyl group, ethoxycarbonyl group or isopropoxycarbonyl group, R3 is a methoxycarbonyl group, Kaji and Rj are both a methyl group, RS is a hydroxyiminomethyl group,
and RJ each mean a cyano group, and when R1 is a 3-nitro group, R2 and R3 are both a methoxycarbonyl group, R♂ and R are both a methyl group, and ? represents a hydroxyiminomethyl group, and the shield represents a cyano group, or R2 represents a 2-benzyloxyethoxycarbonyl group, R3 represents an ethoxycarbonyl group, R2 and R♂ both represent a methyl group, RS (5) Process 5: Each has the same meaning as above, one of which is a lower alkyl group and the other is a lower alkyl group. Each means a hydroxy-substituted lower alkyl group, provided that when R1 is a 2-nitro group, R2 is a methoxycarbonyl group, ethoxycarbonyl group or isopropoxycarbonyl group, R3 is a methoxycarbonyl group, and both R9 and R5 are methyl group, RC is formyl group, and ? represents a hydroxymethyl group, or R2 represents a 2-benzyloxyethoxycarbonyl group, R3 represents an ethoxycarbonyl group, Kaji and Ru both represent a methyl group, Kaji represents a formyl group, and R; represents a hydroxymethyl group. and when R1 is a 3-nitro group, R2 and R3 both represent a methoxycarbonyl group, Kaji and ? Both have methyl groups, ? represents a formyl group, and 4 represents a hydroxymethyl group, respectively, or R2 represents 2
-benzyloxyethoxycarbonyl group, R3 is an ethoxycarbonyl group, both present and 4 are methyl groups,
(Kaji means a formyl group, and R means a hydroxymethyl group.) Detailed explanations of the definitions in each of the above formulas are as follows.

In this invention, a "lower alkyl group" or a "lower alkyl" moiety means a linear or branched alkyl group having 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms. .

The lower alkoxycarbonyl group in R1 has the formula -CO
) lower alkyl, and the lower alkyl part in the formula is a monovalent group derived from a linear or branched lower alkane, and the lower alkoxycarbonyl group defined in this way is preferable. Examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, etc. The lower alkanesulfamoyl group in R1 is substituted with a lower alkanesulfonyl group. The lower alkane moiety is a monovalent group derived from a linear or branched lower alkane group, and a preferable example of a lower alkane sulfamoyl group defined in this way is Examples of the group include methanesulfamoyl, ethanesulfamoyl, propanesulfamoyl, isopropanesulfamoyl, butanesulfamoyl, pentanesulfamoyl, etc.As the lower alkoxycarbonyl group for R2 and R3, for example, , the lower alkoxycarbonyl group mentioned in the definition of R1 above may be mentioned as is, and in addition, 2-bromoethoxycarbonyl, 2-chloroethoxycarbonyl, 2- or 3
-Halogen-substituted lower alkoxycarbonyl groups such as chloropropoxycarbonyl, 2- or 3-promopropoxycarbonyl, 2,2-dichloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxy lower alkoxy-substituted lower alkoxycarbonyl groups such as carbonyl, 2- or 3-methoxy (or ethoxy) propoxycarbonyl, N-lower alkyl-N-aryl substituted lower alkylamino lower alkoxy such as N-methyl-N-benzylaminoethoxycarbonyl; Carbonyl group, aryl-substituted lower alkoxy-substituted lower alkoxycarbonyl group such as 2-benzyloxyethoxycarbonyl, 2- or 3-benzyloxypropoxycarbonyl, 2-phenoxyethoxycarbonyl, 2- or 3-phenoxypropoxycarbonyl and aryloxy-substituted lower alkoxycarbonyl groups.

R4, RAlR Mukaji, Kaji, R6, R Muru, Kaji, R5, R
Meng, R8′. Ru, B! , (R) The lower alkyl groups in Ru and 4 include linear and branched lower alkyl groups, and preferable examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
Examples include butyl, pentyl, neopentyl, hexyl, heptyl, octyl, etc., more preferred examples include alkyl groups having 1 to 4 carbon atoms, and even more preferred examples include methyl.

Preferred examples of the lower alkanoyl group in R4, R9, R5 and the base include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and the like; among these, formyl is the most preferred example.

Preferred examples of the hydroxy-substituted lower alkyl group include 1
-, 2- or 3-hydroxy substituted lower alkyl groups, and preferred examples of such groups include, for example:
Hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxybutyl, 1-hydroxy-2-methylpropyl, 1-hydroxypentyl, 1-
Hydroxy-3-methylbutyl, 1-hydroxy-2,
Examples include 2-dimethylpropyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, etc. A more preferred example is a 1-hydroxy-substituted lower alkyl group, and an even more preferred example is hydroxymethyl.

Preferred examples of the diem-di-lower alkoxy-substituted lower alkyl group include dimethoxymethyl, 1
, 1-dimethoxyethyl, diethoxymethyl, dipropoxymethyl, 2,2-diethoxyethyl, 2,2-diethoxypropyl, 3,3-dimethoxypropyl, etc., and more preferred examples include 1,1- Diem (Ge
m)-di-lower alkoxy-substituted lower alkyl group. The lower alkylene moiety of the Gem mono-lower alkylene dioxy-substituted lower alkyl group includes linear and branched alkylene, and preferable examples include, for example,
1,3-dioxolan-2-yl,2-methyl-1,3
-Dioxolan-2-yl, 4-methyl-1,3-dioxolan-2-yl, 4,5k-dimethyl-1,3-dioxolan-2-yl, 1,3-dioxolan-2-ylmethyl, 2-methyl -1,3-dioxolan-2-ylmethyl, 3-(1,3-dioxolan-2-yl)propyl, 1,3-dioxan-2-yl, 2-methyl-
Examples include 1,3-dioxan-2-yl, and a particularly preferred example is 1,3-dioxan-2-yl.

Preferred examples of the diem (Gem) lower alkoxy-substituted lower alkyl group and the diem (Gem) mono-lower alkylenedioxy-substituted lower alkyl group in R2 and Rs, and the hydroxy-substituted lower alkyl group in N and RS include the above-mentioned R4 and Specific examples of groups corresponding to each of the groups mentioned in R5 can be listed as they are.

Diem (Gem)-dilower alkoxy-substituted lower alkyl group and diem (Gem) in R:′ and R:′
The mono-lower alkylenedioxy-substituted lower alkyl group is the same as the corresponding groups described above for R4 and R5, and specific examples thereof can also be cited as they are.

The starting materials of this invention include known and novel compounds, and the novel compounds can be produced, for example, by the following reactants) and (b).

(b) Starting materials used in process 1 (1X or 4
Aldehydes (B) are added to monosubstituted acetoacetic esters (A).
).

(In the formula, R1, R3 and RR each have the same meaning as above) (b) Starting material (self) used in the above process 1
is produced by the action of ammonia or its salts on the acetylene compound (IlA) or by the action of ammonia or its salts on the 4-monosubstituted acetoacetate compound (B).

(In the formula, R2 and Rs each have the same meaning as above) (
(wherein R2 and R2 each have the same meaning as defined above) The process for producing the 1,4-dihydropyridine compound (1) of the present invention will be described in detail below.

(1) Regarding process 1: This process involves reacting the oxo compound (4) with the amino compound (1), and then reacting the compound (1) with the amino compound (1).
-1)

The starting materials for this process are compounds () and (11
may have cis and trans geometric isomers due to the presence of double bonds in their molecules, but such isomers are equivalent with respect to the production of the target compound (-1) of this process. , therefore individual isomers or mixtures thereof can be used as starting materials () and (Ie).

This reaction is usually carried out at room temperature, at or under heating,
Further, although a solvent is not particularly required, it can be carried out in the presence of a solvent, such as benzene, toluene, xylene, chloroform, carbon tetrachloride, methylene chloride, ethylene chloride, methanol, ethanol, propanol, Examples include butanol, water, organic solvents that do not adversely affect this reaction, or mixed solvents thereof.

Further, this reaction is usually promoted by the presence of an acid, a base, or a conventional buffer; examples of such acids include acetic acid, and examples of bases include pyridine, picoline, and the like.

When the acid or base used as a reaction accelerator is liquid as described above, a solvent can also be used. This reaction is also promoted by heating. Conditions for this reaction are appropriately selected depending on the type of reactants used. Furthermore, this process is also carried out, for example, by reacting mixtures of 4-monosubstituted acetoacetic esters (A), aldehydes (IB) and amino compounds (11), and also acetylene compounds (A).
) or 4-monosubstituted acetoacetate compound (NO3
) is previously reacted with ammonia or its salts,
This reaction can also be carried out by subsequently reacting with compound (4), and such a reaction mode is also included within the scope of this process.

Examples of ammonia salts include inorganic ammonium salts such as ammonium chloride and ammonium sulfate, and organic ammonium salts such as ammonium acetate.

x χ

The starting material for this process, compound (1-1), can be prepared by the reaction of Process 1 above.

In this process, the compounds (1-1 Rr or B: '1) diem(Gem)-di-lower alkoxy, diem(Gem)-lower alkylidenedioxy and diem(Gem)-di-lower alkanoyloxy are hydrolyzed with heoxo Generate a group.

This hydrolysis reaction is carried out by a conventional method, whereby an acetal, ketal or acyral is cleaved,
The corresponding carbonyl group is generated.

The hydrolysis carried out in particular on Gem-di-lower alkoxy and Gem-mono-lower alkylenedioxy is preferably carried out under acidic conditions, i.e. hydrochloric acid,
Inorganic acids such as sulfuric acid, formic acid, acetic acid, trifluoroacetic acid, P-
The hydrolysis carried out in the presence of an organic acid such as toluenesulfonic acid and on the diem-di-lower alkanoyloxy group is preferably carried out under basic conditions, i.e., in addition to the above-mentioned acidic conditions. Inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methylate, sodium ethylate,
potassium methylate, potassium ethylate, pyridine,
It is carried out in the presence of an organic base such as picoline. Such hydrolysis reactions are usually carried out in a solvent, such as water, acetone, methyl ethyl ketone,
Examples include dioxane, methanol, ethanol, N,N-dimethylformamide, N-methylmorpholine, dimethyl sulfoxide, a mixed solvent thereof, or a normal buffer solution.

Although the reaction temperature is not particularly limited, it is usually carried out under conditions of cooling or heating.

}) Regarding Process 3: This process relates to a method for producing an oxime compound (1-3) by reacting oxo compound (1-2) with hydroxylamine or a salt thereof.

Oxo compound (1-2), which is the starting material for this process
can be manufactured by Process 2 above.

Through this reaction, the starting material Oki 1 compound 5 compound (1
-2) The oxo group in Kaji or Ru is converted to a hydroxyimino group.

Examples of hydroxylamine salts used in this reaction include salts with inorganic acids such as hydrochloric acid and sulfuric acid, acetic acid, and P-
Examples include salts with organic acids such as toluenesulfonic acid.

This reaction is carried out in a conventional manner.

That is, inorganic or organic acids such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, P-toluenesulfonic acid,
Under basic conditions, such as in the presence of an acid catalyst such as a Lewis acid such as boron trifluoride, silicon tetrachloride, titanium tetrachloride, etc., or by using free hydroxylamine,
Alternatively, it is often carried out in an ordinary acidic or basic buffer. Further, this reaction is usually carried out in a solvent. Examples of the solvent include water, dioxane, methanol, ethanol, N,N-dimethylformamide, or a mixed solvent thereof. Although the reaction temperature is not particularly limited, it is usually carried out under conditions of 25°C under cooling to around 25°C under heating.

(4) Regarding process 4: This process relates to a method for producing compound (1-4) by applying a dehydrating agent to oxime compound (1-3).

30 The starting material for this process, oxime compound (1-3'), can be prepared by Process 3 above. As the dehydrating agent used in this reaction, a conventional dehydrating agent capable of converting a hydroxyiminomethyl group into a cyano group can be used. Preferred examples of such dehydrating agents include sulfuric acid, phosphoric acid, polyphosphoric acid, and phosphoric acid. Acid, inorganic or organic acid such as acetic acid, ethanesulfonic acid, P-toluenesulfonic acid; acid anhydride such as acetic anhydride, benzoic anhydride, phthalic anhydride: acetic acid chloride, benzoic acid chloride, trichloroacetic acid chloride, mesyl Acid halides such as chloride, tosyl chloride, ethyl chlorocarbonate, phenyl chlorocarbonate; inorganic halogenated compounds such as thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide, tin chloride, titanium tetrachloride; N, N'
-Carbodiimide compounds such as dicyclohexylcarbodiimide and N-cyclohexyl-N'-morpholinoethylcarbodiimide;N,N'-carbonyldiimidazole, pentamethylene ketene-N-cyclohexylimine ethoxyacetylene; Lithium salt; examples include phosphoric acid compounds other than those mentioned above, such as phosphorus pentoxide, ethyl polyphosphate, ethyl phosphate, and phenyl phosphate.

In addition, when an acid is used as a dehydrating agent in this reaction, it can also be carried out in the presence of a salt of the acid with a metal such as sodium or potassium.

This dehydration reaction is carried out in the presence of a solvent such as diethyl ether, dimethylformamide, pyridine, acetic acid, formic acid, benzene, carbon tetrachloride, chloroform, methylene chloride, tetrahydrofuran, dioxane, or the like. Although the reaction temperature is not particularly limited, the reaction is usually carried out at room temperature, with heating, or under heating. Compound (1-4) can also be obtained from the reaction mixture obtained in the reaction of Process 3 above.
-3') can also be produced by directly subjecting the reaction mixture to a dehydration reaction without isolating it.

]) Process 5: This process relates to a method for reducing oxo compound (1-2) to produce compound (1-5).

Oxo compound (1-2), which is the starting material for this process
can be manufactured by Process 2 above.

The reducing agent used in this process may be a conventional reducing agent used to convert the oxo group of an aldehyde or ketone compound into a hydroxyl group. Examples of reduction methods using such a reducing agent include: Examples include reduction using a reducing agent such as an alkali metal borohydride such as lithium borohydride, sodium borohydride, potassium borohydride, sodium cyanoborohydride, or catalytic reduction.

As the catalyst used for the catalytic reduction, palladium on carbon, palladium chloride, rhodium on carbon, etc., as well as catalysts normally used for the 1y catalytic reduction can be used.

This reaction is usually carried out in a solvent, and any solvent that does not adversely affect this reaction can be used as the anti-solvent, such as water, methanol, ethanol, isopropyl alcohol, dimethylformamide, or a mixed solvent thereof.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating in a room. The reduction method can be appropriately selected depending on the type of oxo compound (1-2) that is the starting material. The target compounds produced in each of the above processes are isolated and collected by conventional methods such as extraction, chromatography, recrystallization, etc.

The compound () provided by this invention has optical isomers derived from the non-sacrificial carbon at the 4-position of its 1,4-dihydropyridine ring, and some of the compounds () have optical isomers derived from the non-sacrificial carbon at the 4-position of the 1,4-dihydropyridine ring. Some of the substituents at the 2, 3, 5 and 6 positions further have one or more non-sacrificial carbon atoms.

In such a case, compound (1) can exist as each optical isomer or racemate, as well as as a diastereomer or a mixture thereof. A mixture of diastereomers can be separated into racemic forms by conventional methods such as chromatography or fractional recrystallization, if necessary, and furthermore, for example, mixtures of diastereomers can be separated into their respective racemic forms by conventional methods such as chromatography or fractional recrystallization. Compounds are converted into salts with acids such as tartaric acid and gamfersulfonic acid or bases such as efuedrine and strychnine, which have optical activity, respectively, and separated by fractional recrystallization. can be resolved into its optical isomers.
Compound (1) of the present invention has vasodilatory and blood pressure lowering effects, and is effective against cardiovascular diseases such as hypertension, heart failure, angina pectoris, and myocardial infarction.

Especially the 1,4-dihydropyridine compound (1) of this invention
R4 or R5 is a cyano group, a lower alkanoyl group,
or a lower alkyl group substituted with at least one group selected from ω-cyano, hydroxy, and lower alkanoyl, it is more effective as a medicine for the above-mentioned diseases, and R4 or R5 is a lower alkanoyl group. or a lower alkyl group substituted with at least one group selected from lower alkoxy, lower alkylenedioxy and lower alkanoyloxy, as an intermediate for producing the compound as defined above, where R4 or R5 is is also useful.

Among the compounds (1) provided by this invention, the results of pharmacological tests comparing compounds 8 to K listed below with known compounds are shown below.

1) Test compound (A!l: dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-3,5-dicarboxylate IO: dimethyl 2-methyl-4-(2-cyanophenyl)-6
-Cyano-3,5-dicarboxylate 0: dimethyl
2-Methyl-4-(2-nitrophenyl)-6-hydroxymethyl-3,5-dicarboxylate l) 1:dimethyl 2-methyl-4-(3←nitrophenyl)-6-
Cyano-3,5-dicarboxylate 0: diethyl 2
-Methyl-4-(2-methoxycarbonylphenyl)-
6-hydroxymethyl-1,4-dihydropyridine-3
,5-dicarboxylate 0:diethyl 2-methyl-
4-(2-Methoxycarbonylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate CG: Isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6- Hydroxymethyl-1,4-dihydropyridine-3-carboxylate 0: Isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-cyano-
1,4-dihydropyridine-3-carboxylate Cr
l: 2-benzyloxyethoxycarbonyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-cyano-1,4-dihydropyridine-13-carboxylate Mark: 2-benzyloxyethoxycarbonyl 2-methyl -4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate IO: 2-benzyloxyethoxycarbonyl 2-methyl-4-(2-nitrophenyl)-5 -Ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate 2) Test Results The amount of increase in coronary blood flow using dogs is as shown above.

The results are expressed as a percentage of the increase when no drug was administered [29.5±5.5 m1/min], with the control being 100. 3
) Test method The test compound was administered intravenously to a dog anesthetized with pentobarbital, and the coronary blood flow was measured according to a conventional method, and the maximum value (ml/min) of the coronary blood flow at each dose was determined. .

Compound (1) of this invention is administered in the form of a composition containing an effective and non-toxic amount thereof.

The composition is used in a dosage form suitable for oral or parenteral administration together with inorganic or organic, solid or liquid pharmaceutical carriers commonly used in pharmaceutical formulations.
Preferred dosage forms include tablets, granules, powders, powders, capsules, sublingual tablets, suppositories, solutions, syrups, and injections. Examples of solid or liquid pharmaceutical carriers include lactose, magnesium stearate, sucrose,
Examples include corn starch, talc, stearic acid, gelatin, agar, pectin, gum arabic, peanut oil, olive oil, sesame oil, and cocoa butter. Each of the above-mentioned various formulations can be manufactured by a well-known method.

When the compound (1) of this invention is used as a medicine, the daily dose for oral administration is 0.1 to 500 to
, preferably 1-50η, and for intravenous administration, the daily dose is 1/10 to 1/4 of the oral dose, divided into appropriate doses, but the dose depends on the dosage form, patient's gender, It is preferable to select the appropriate amount in consideration of age, weight, symptoms, etc.

Next, the present invention will be explained with reference to examples.

Production method of raw material Production example 1 Production of methyl 4,4-dimethoxyacetoacetate Dissolve sodium metal (80.59) in methanol (960m) and concentrate to prepare a methanol suspension of sodium methylate (470m0). do.

To this suspension, 2,2-dichloroacetate 1299) was gradually added dropwise at a rate that the solvent was refluxing, and then heated under reflux with stirring for 3.5 hours. To this reaction solution, a mixture of methanol (200 m0 and hydrogen chloride (100 g)) was added dropwise over 30 minutes at a temperature below 10°C, and the mixture was stirred at room temperature for 18 hours. 32
Neutralize with a methanol solution of sodium methylate prepared from 9) and methanol (4007n1), collect the precipitate, and wash with methanol. The washing liquid and the finished liquid are combined and concentrated to dryness under reduced pressure at 30° C. or below, and the residue is extracted once with benzene 200a and twice with 100ml. The extract was concentrated to dryness and the remaining oil was purified by distillation to obtain oily methyl 2,2-dimethoxyacetate (89.5
9) is obtained. Separately, metallic sodium (18.289) was dissolved in methanol (300 ml), and the methanol was distilled off under reduced pressure.

The resulting residue is suspended in anhydrous toluene (approximately 700 μm) and concentrated at normal pressure until the residual liquid becomes 200 μm to prepare a methanol-free toluene suspension of sodium methylate. The 2,2-dimethoxyacetic acid solution obtained above was added to this suspension. methyl (88.89) and methyl acetate (58.89
) was added dropwise over 50 minutes at 50 to 60°C, and the mixture was heated under reflux for 2 and a half hours. The reaction mixture was poured into a mixture of acetic acid and ice water and stirred for a short time. The organic layer is separated, washed with an aqueous sodium bicarbonate solution, and dried over magnesium sulfate.
This solution was concentrated to dryness and the resulting residue was distilled under reduced pressure to give methyl 4,4-dimethoxyacetoacetate (82.27
g) is obtained. Boiling point 88-91°C/511H9. Manufacturing example
2 Production of N-methyl O-formylbenzenesulfonamide N,N-dimethylamine hydrochloride (7.349) was added to a mixture of sodium hydroxide (6.629), water (25d) and acetone (10ml). After 0-nitoluenesulfonyl chloride (14.419) in acetone (10d
) The solution was added dropwise over 30 minutes while stirring at 0°C.
Stir for 15 minutes at ~4°C.

The reaction mixture was diluted with water (50 mt) and then diluted with ethyl acetate (7 mt).
Extract twice at 0d). This extract is washed successively with dilute hydrochloric acid, dihydrate and aqueous sodium chloride solution, and then dried over magnesium sulfate. This solution was concentrated to dryness under reduced pressure to form an oily N,Nl dimethyl O-toluenesulfonamide (1
4.99) is obtained. N, N- obtained as above
dimethyl O-toluenesulfonamide (20.09),
Acetic anhydride (16.39) and acetic acid (1707IL1)
Sulfuric acid (40.29) was added dropwise to the mixture at 5-8°C over 15 minutes, and chromium trioxide (28g) was added over 1 hour and 20 minutes.
After the addition took several minutes, the mixture was stirred at the same temperature for 1 hour.
Leave it overnight. The reaction mixture was poured into ice (11<g) and water (20
0ml) with stirring, neutralized with sodium bicarbonate, and extracted twice with ethyl acetate (400d). This extract was washed successively with an aqueous sodium bicarbonate solution, water, and an aqueous sodium chloride solution, and then dried over magnesium chloride. This solution was concentrated to dryness under reduced pressure, and the resulting oily residue was subjected to column chromatography using silica gel (5169). A mixture of benzene and ethyl acetate (
Fractions containing the target compound were collected at a volume ratio of 15:1 and concentrated to dryness under reduced pressure to yield N-methyl O-(1,1-diacetoxymethyl)benzenesulfonamide (8.36
9) is obtained. Then N-methyl O-(1,1-diacetoxymethyl)benzenesulfonamide (8.3f!),
Concentrated hydrochloric acid (33d), ethanol (11mt) and water (
The mixture consisting of 55d) is heated under reflux for 45 minutes.

The reaction mixture was diluted with water (100 d) and then diluted with ethyl acetate (1
00T! Add Ll) and stir briefly. The ethyl acetate layer was separated and the remaining aqueous layer was extracted with ethyl acetate (50ml).
The extracts are combined, washed successively with an aqueous sodium bicarbonate solution, water and an aqueous sodium chloride solution, and dried over magnesium sulfate. This solution was concentrated to dryness under reduced pressure, and the resulting oily residue (1.999) was crystallized from diethyl ether to give N-methyl O-formylbenzenesulfonamide (57
0wa) is obtained. Melting point: 110-112°C. Further, the mother liquor was concentrated and the resulting residue was subjected to column chromatography using silica gel (40 g). Fractions containing the target compound were collected by elution with a mixture of benzene and ethyl acetate (volume ratio 10:3), and then concentrated to dryness under reduced pressure to recover the target compound (1.19). Total yield 1.679. Manufacturing example
3 (1) Production of methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate 2-formylbenzonitrile 6.56 g, methyl 4,4-dimethoxyacetoacetate 7.939, acetic acid 0.18 f! , piperidine 0.17
A mixed solution consisting of f1 and benzene 40a is heated to reflux with stirring, and the resulting water is azeotropically distilled over a period of 5 hours and 20 minutes.

After cooling, benzene was added to the reaction mixture, which was washed twice with water and once with an aqueous sodium chloride solution, and then dried over magnesium sulfate.

Brown oil obtained by distilling off benzene under reduced pressure 13.7
5f! was subjected to column chromatography using silica gel 4209 and eluted with a mixed solvent of benzene and ethyl acetate (volume ratio 25:1).

Fractions containing the target product are collected and the solvent is distilled off under reduced pressure to obtain 2-
10.119 of methyl (2-cyanobenzylidene)-4,4-dimethoxyacetoacetate is obtained. Nuclear Magnetic Resonance Absorption Spectrum The following compound is obtained in the same manner as in Production Example 3-(1).

(2) 2-(2-methoxycarbonylbenzylidene-4,4-dimethoxyacetoacetic acid methyl nuclear magnetic resonance absorption spectrum) (3) 2-(2-cyanobenzylidene) acetoacetic acid 2
-Chloroethyl nuclear magnetic resonance absorption spectrum (4) 2-(2-cyanobenzylidene)acetoacetic acid 2
-Ethoxyethyl Nuclear Magnetic Resonance Absorption Spectrum Production method of target compound Example 1 1-1) 2-cyanobenzaldehyde (5.09),
Methyl 4,4-dimethoxyacetoacetate (7.39f1)
and acetic acid (0.4589) in benzene (15ml), piperidine (390η) was added to benzene (5ml).
m1) The solution was divided into three portions and added dropwise at intervals of 20 minutes.

The reaction mixture was heated under reflux for 2 hours, and water produced by the reaction was distilled off as an azeotrope during the course of the reaction. After the reaction, a mixture of cooled μbenzene (50 ml) and water (30 ml) was added and shaken. The organic layer was separated and washed successively with a dilute aqueous solution of sodium hydrogen carbonate and water. Washing liquid with benzene (
307! The benzene extract was combined with the organic layer and washed with water. This was dried over magnesium sulfate and evaporated to dryness under reduced pressure, and the oily residue (14.8 fl) was developed on a silica gel (2009) column chromatograph. Mixture of benzene and ethyl acetate (volume ratio 25:1)
When eluted with , oily 2-(2-cyanobenzylidene)
-4,4-dimethoxyacetoacetate methyl (6.901)
was gotten. Thin layer chromatography and NMR spectra of this product showed it to be a mixture of two stereoisomers. 8.0 and 8.15 (1H, s each) 1-11) Methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (6.8
A mixture of 9) and methyl 3-aminocrotonate (2.989) was heated at about 60°C for 2 hours with stirring.

Thereafter, the temperature of the reaction mixture was gradually raised to 10 for 10 hours.
The temperature was maintained at 0-103°C. During the course of the reaction, n-propyl alcohol (3d) was added to dissolve the crystalline material produced by the reaction. Next, the reaction mixture was dissolved in a mixture of diisopropyl ether (9d) and methanol (3 ml) and allowed to stand for some time to give light brown microcrystalline 2-methyl-4-(2
-cyanophenyl)-6-dimethoxymethyl-1,4-
Dimethyl dihydropyridine-3,5-dicarboxylate (6
．． 399) was obtained. This was fractionated and recrystallized with a mixed solution of diisopropyl ether and methanol (volume ratio 1:1) to obtain pure crystals with an Mpl of 33 to 134.5°C. 2-1) Methyl 2-formylbenzoate (4.92
259), ethyl 4,4-diethoxyacetoacetate (7.
2f! ) and acetic acid (0.369) to benzene (15d)
A solution of piperidine (306 w) in benzene (5d) was added dropwise to the mixture in three portions at intervals of 20 minutes.

The reaction mixture was heated under reflux for 3 hours, during which time the water produced was distilled off as an azeotrope. After the reaction was cooled, the reaction mixture was diluted with benzene (25 ml), washed three times with water, further washed successively with a dilute aqueous sodium hydrogen carbonate solution, water and 35 ml of a saturated aqueous solution of sodium chloride, and then diluted with magnesium sulfate. Dry. The solvent was distilled off under reduced pressure to obtain a red oily crude ethyl 2-(2-methoxycarbonylbenzylidene)-4,4-diethoxyacetoacetate (12.79), which was purified as follows without purification. It was used as raw chrysanthemum material in the process. 2-11) Ethyl 2-(2-methoxycarbonylbenzylidene)-4,4-diethoxyacetoacetate (12.79) and ethyl 3-aminocrotonate ZO
The mixture of (5.039) was stirred for 1.5 hours while heating to about 60-70°C.

Next, the reaction temperature was gradually increased, and was maintained at 90°C for 3 hours, and finally at 110°C, and the reaction was continued for 4.5 hours. After cooling, the reaction mixture was dissolved in ethyl acetate (50d),
After washing twice with water, dry with magnesium sulfate. Ethyl acetate was evaporated off under reduced pressure, leaving a reddish brown oily residue (
12.89) was obtained, which was treated with a mixture of diisopropyl ether and n-hexane (volume ratio 1:10) to give 2-methyl-4-(2-methoxycarbonylphenyl)-6-diethoxymethyl- Light brown crystalline powder of diethyl 1,4-dihydropyridine-3,5-dicarboxylate (
3.59) was obtained. Also, the same substance (0.3
39) was recovered, and the oily substance (8.0 g) that did not crystallize was developed on a silica gel (2409) column chromatograph and eluted with a mixture of benzene and ethyl acetate (volume ratio 15:1 and 10:1). One substance (1.69) was recovered from the total mother liquor (total yield: 5.43f!)
. Select 300η from the first recovered product (0.339) and recrystallize it with n-hexane (3d) to obtain 290~
A pure product was obtained in crystalline form. Mp94-95°C {) 2-
N-methylsulfamoylbenzaldehyde (1.75
9), methyl 4,4-dimethoxyacetoacetate (1.70
9) and acetic acid (0.19) in benzene (5d) solution,
A solution of piperidine (9.0TI9) in benzene (3d) was added and the reaction mixture was heated to reflux for 2 hours.

The water produced during the reaction was distilled off as an azeotrope. After the reaction was completed, the mixture was cooled and diluted with benzene (15d).
After washing twice with a dilute aqueous solution of sodium bicarbonate, water,
It was washed successively with a saturated aqueous solution of 1 cum sodium chloride and dried over magnesium sulfate. It was then evaporated to dryness under reduced pressure to give a reddish-yellow oil (3.469), which was dissolved in silica gel (
699) was developed on a packed column chromatograph. This was eluted with a mixture of benzene and ethyl acetate (volume ratio 3.5:1), and oily methyl 2-(2-N-methylsulfamoylbenzylidene)-4,4-dimethoxyacetoacetate (
1.121) was obtained. The oil thus obtained (1.09)
Add methyl 3-aminocrotonate (355~) to 60
Heated at ℃ for 3 hours. During the reaction, the temperature gradually increases, and 1.
The temperature reached 100°C in 5 hours, and the reaction was continued while maintaining the temperature at 100°C for an additional 5.5 hours. The reaction mixture was mixed with silica gel (33
9) Developed in a packed column chromatograph and eluted with a mixture of benzene and ethyl acetate (volume ratio 5:1) to form an oily 2-methyl-4-(2-N-methylsulfamoylphenyl)-6. -dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl (840W1f
7) was obtained. 4) Methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (15.19
) and methyl 3-aminocrotonate (6.509) was heated at 60-63°C for 6 hours, and further heated to 100-105
The mixture was heated at ℃ for 4 hours and 45 minutes.

The resulting crystalline solid was powdered with methanol and collected by filtration to give 2-methyl-4-(2-nitrophenyl)-6-
Dimethoxymethyl-1,4-dihydropyridine-3,5
-Dimethyl dicarboxylate (12.049) was obtained.
The crystals thus obtained (1.079) were mixed with methanol (5
When recrystallized with m1), a pure crystal (0.939) was obtained.

Mpl32-133 (CNMRδPPl(CDCl3) 2.36 (3H, s), 3.40 (3H, s), 3.4
4 (3H, s), 3.56 (3H, s), 3.66 (3
H, s), 5.76 (1H, s), 5.99 (1H, s
), 6.85 (1H, Prode s), 7.1-7.8 (
4H, m) 5) 2-nitrobenzaldehyde (6.80
099), methyl chrysanthemum 4,4-dimethoxyacetoacetate (8
．． A mixture of 72049), acetic acid (0.54059) and piperidine (0.45989) in benzene (30ml) was heated under reflux for 2 hours, and the water produced was successively distilled off as an azeotrope.

The reaction mixture was diluted by adding benzene (100 mO) and diluted with 2
After washing twice with water, it was washed successively with a dilute aqueous solution of sodium hydrogen carbonate and water, and dried over magnesium sulfate. The solvent was distilled off and dried under reduced pressure to obtain crude oily methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (
15.239) was obtained. This crude oil (15.2
39) and ethyl 3-aminocrotonate (6.68409
) was heated at about 65°C for 6 hours and further heated to 98-1
The temperature was raised to 000C and heated for 5 hours.

The resulting viscous brown oil was dissolved in ethyl acetate, washed with water three times, and then dried over magnesium sulfate. The solvent was distilled off and dried under reduced pressure to obtain a brown oil (19.40 g). Methanol (10ml) was added to the residual oil to give a yellow crystalline powder (12.779).

This product is 2-methyl-4-(2-nitrophenyl)-5-
Methoxycarbonyl-6-dimethoxymethyl-1,4-
It is ethyl dihydropyridine-3-carboxylate. Crystals (0.53f!) of the same substance were also obtained from the mother liquor.
When these were recrystallized with methanol, yellow granules were obtained. Mpl22-124℃ NMRδPlEl (CDC
l3) 1.15 (3H, t, J=7.5Hz), 2.3
8 (3H, s), 3.40 (3H, s), 3.45 (3
H, s), 3.60 (3H, s), 4.04 (2}1,
q, J2 7.5Hz), 4.08 (2H, q, J=7.
5Hz), 5.83 (1H, s), 5.98 (1H, s
), 6.77 (1H, Prode s), 7.1-7.85
(4H, m)6) 2-nitrobenzaldehyde (6.
809), methyl 4,4-dimethoxyacetoacetate (8.
729) and acetic acid (0,549) in benzene (30m0
Piperidine (0.469) was added to the solution in the same manner as in Examples 1-1) and 2-1), and the reaction mixture was refluxed for 2 hours.

The water produced during that time was gradually distilled off as an azeotrope as the reaction progressed. After the reaction mixture was cooled, it was diluted with benzene (100a), washed three times with water, successively washed with dilute aqueous sodium bicarbonate solution and water, and dried over magnesium sulfate. Evaporation of the solvent to dryness under reduced pressure gave methyl 2-(2-nitrobenzylidene)-4,4-dimethoxyacetoacetate (14.739) as an oil. A mixture of this oil (14.709) and isopropyl 3-aminocrotonate (7.099) was heated at 60-63°C for 2 hours and then at 85-90°C for about 10 hours, respectively.

The reaction mixture was treated with ethyl acetate to obtain yellow crystals, which were collected by filtration and washed with methanol. Further crystals were obtained by concentrating the mother liquor and adding methanol to the residue. These crystals were combined (11.109) and recrystallized from methanol to give 2-methyl-4-(2-nitrophenyl)-5-
Methoxycarbonyl-6-dimethoxymethyl-1,4-
Pure crystals of isopropyl dihydropyridine-3-carboxylate were obtained. Mpl43-145 C7) 3-Utrobenzaldehyde (7.569), methyl 4,4-dimethoxyacetoacetate (9.699) and acetic acid (600m
piperidine (f) in a mixture with benzene (25d)
A solution of 851TI19) in benzene (5a) was added dropwise in one-fifth portions at intervals of 20 minutes.

This mixture was heated under reflux for 4 hours, and the water produced was gradually distilled off as an azeotrope. After cooling, the reaction mixture was diluted with benzene (50 ml) and washed with a dilute aqueous solution of sodium bicarbonate, followed by successive washing with water and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the solvent was evaporated to dryness under reduced pressure to yield a reddish-brown crude oil (17.82 g) of methyl 2-(3-nitrobenzylidene)-4,4-dimethoxyacetoacetate. This product was used as it was in the next step reaction without purification. The oily substance (
17.829) and methyl 3-aminocrotonate (6.3
39) mixture at 60~65℃ for 4.5 hours and then at 100~105℃ for 8 hours.
Each was heated for 5 minutes.

The reaction mixture was developed on a column chromatograph packed with silica gel (4409) and eluted with a mixture of benzene and ethyl acetate (volume ratio 10:1) to obtain crystalline 2-methyl-4-(3-nitrophenyl)-6. Dimethyl -dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (10.46 f!) was obtained. This product (720m
Recrystallization of g) with diisopropyl ether (10d) gave a pure specimen (560η). Mp99~100
℃NMRδPPl(CDCl,)2.47(3H,s)
, 3.52 (3H, s), 3.57 (3H, s), 3.
77 (3H, s), 5.25 (1H, s), 6.1 (1
H, s), 6.98 (1H, Prode s), 7.38~
8.17 (4H, m) {) 3-Nitrobenzaldehyde (4.531), 2-benzyloxyethyl acetoacetate (7.79 g) and acetic acid (360 immediately) in benzene (15
d) A 5d solution of piperidine (360 mf) in benzene was added to the solution in the same manner as in Example 1-1.

The mixture was heated under reflux for 2.5 hours, and the water produced was distilled off as an azeotrope. After the reaction mixture was allowed to cool, it was diluted with benzene (50 ml) and washed successively with water, a dilute aqueous sodium bicarbonate solution, and water. After drying with magnesium sulfate, the solvent was evaporated to dryness under reduced pressure to obtain 2-benzyloxyethyl 2-(3-nitrobenzylidene)acetoacetate (12.58f1) as a brown oil. This oil (12.589) and ethyl 3-amino-4,4-diethoxycrotonate (8.479) were mixed at 100 to 102
It was heated at 110-115°C for 4 hours and then for 6.5 hours at 110-115°C.

After cooling, the reaction solution was dissolved in ethyl acetate and washed twice with water and once with a saturated aqueous solution of sodium chloride. After washing with magnesium sulfate, the solvent was evaporated to dryness under reduced pressure.
The remaining brown oil (19.04 g) was purified by silica gel (
5709) was developed on a packed column chromatograph and eluted with a mixture of benzene and ethyl acetate (volume ratio 13:1) to form an oily 2-methyl-4-(3-nitrophenyl)-
5-ethoxycarbonyl-6-diethoxymethyl-1,
2-benzyloxyethyl 4-dihydropyridine-3-carboxylate (9.64f1) was obtained. NMRδPF
l (CDCl3) 1.17 (6H, t, J27Hz), 1.23 (3H,
t, J=7z), 2.35 (3H, s), 3.43~4
．． 4 (10H, m), 4.5 (2H, s), 5.18 (
1H, s), 6.86 (1H, Prode s), 7.33
~8.13 (9H, m) Example 21) 2-Methyl-
4-(2-cyanophenyl)-6-dimethoxymethyl-
To a solution of dimethyl 1,4-dihydropyridine-3,5-dicarboxylate (6.09) in acetone (60d) was added 6N hydrochloric acid (6ml).

The resulting mixture was stirred at room temperature for 3 hours, diluted with water (30 mL, and then adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The acetone was distilled off under reduced pressure, and the remaining crystalline solid was washed with a glass rod. Grind it as finely as possible. Add water (1
00Tn1) was further added and washed, collected by filtration, thoroughly washed with water, and air-dried to obtain 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5- Crystalline powder of dimethyl dicarboxylate (5
．． 199) was obtained. NMRl)PF(CDCl3)
2.41 (3H, s), 3.65 (3H, s), 3.7
5 (3H, s), 5.5 (1H, s), 7.0 (1H,
s), 7.25-7.66 (4H, m), 10.53 (
1H,s)2) Diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (5.
039) in acetone (50d), add 6N hydrochloric acid (50d).
d) was added and the reaction mixture was stirred at room temperature for 2 hours.

After adding water (30 ml), the reaction mixture was neutralized by adding an aqueous sodium bicarbonate solution, and the acetone was distilled off under reduced pressure. The remaining oily precipitate was extracted with ethyl acetate, and the extract was washed successively with water and a saturated aqueous solution of sodium chloride, and then dried over magnesium sulfate. Evaporation of the solvent to dryness under reduced pressure gave the crude diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2
69) was obtained. This product was used as a raw material for the next process without any special shaping. NMRδPFl(CDCl
,) 1.1 (3H, t, J=7Hz), 1.8 (3H, t,
J = 7Hz), 2.37 (3H, s), 3.93 (3H
, s), 3.9-4.28 (4H, m), 6.2 (1H
, s), 6.98 (1H, s), 7.1-7.8 (4H
,m),10.2(1H,s)3)2-methyl-4-(
Dimethyl 2-N-methylsulfamoylphenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (6007r1f) was dissolved in acetone (6T
A mixture of 1L1) and 6N hydrochloric acid (0.6ml) was stirred at room temperature for 2.5 hours, and then adjusted to pH 7-8 with a dilute aqueous sodium hydrogen carbonate solution.

Next, the acetone was distilled off under reduced pressure, and water was added to the remaining oily precipitate to powder it, resulting in 2-methyl-4-(2-N
-methylsulfamoylphenyl)-6-formyl-1
A crystalline powder (380η) of dimethyl ,4-dihydropyridine-3,5-dicarboxylate was obtained. Dimethyl 02-methyl-4-(2-nitrophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (10.689) with acetone (110 ml)
The mixture in normal hydrochloric acid (10d) was stirred at 25°C for 3 hours.

This was neutralized by adding an aqueous sodium hydrogen carbonate solution, and the acetone was distilled off under reduced pressure. After solidifying the red-yellow oily precipitate, it was crushed and collected in a furnace. After washing with water and air drying overnight, 2-methyl-4-(2-nitrophenyl)-6-formyl-1
, 4-dihydropyridine-3,5-dicarboxylic acid crude crystals (9.339) were obtained. NMRI) P voice (CDCl,) 2.41 (3H, s), 3.58 (3H, s), 3.7
1 (3H, s), 5.88 (1H, s), 7.10 (1
H, Prode s), 7.2-7.9 (4H, m), 10
．． 43(1H,s)5) Isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylate (10.59) in acetone (105 ml )
6N hydrochloric acid (15.5d) was added to the solution.

5 After stirring this mixture at 25°C for 2 hours, acetone was distilled off, and water (50wL1) was added to the remaining liquid to dilute it.
This was made alkaline by adding a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the solvent was distilled off under reduced pressure. Red-yellow oily residue (11
．． When a mixture of diethyl ether and n-hexane is added to 089) and powdered, a yellowish crystalline powder (8.
94f1) was obtained. This product is 2-methyl-154-
(2-nitrophenyl)-5-methoxycarbonyl-6
-formyl-1,4-dihydropyridine-3-carboxylic acid isopropyl. NMRδPIm(CDCl3)
0.97 (3H, d, J2 6Hz), 1.21 (320
H, d, J=6Hz), 2.43 (3H, s), 3.7
0 (3H, s), 4.97 (1H, hept., J=6
z), 6.00 (1H, s), 6.95 (1H, Prode s), 7.2-7.9 (4H, m), 10.38 (1
H,s) 256) 2-methyl-4-
(3-nitrophenyl)-6-dimethoxymethyl-1,
4-dihydropyridine-3,5-dicarboxylic dimethyl acid (7.59) was added to acetone (75mt), and to this was further added 6N hydrochloric acid (7.5d).

The reaction mixture was stirred at room temperature for 6 hours and the precipitate that separated during the course of the reaction was filtered to give 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5- Yellow crystals of dimethyl dicarboxylate (2.269) were obtained. An aqueous solution of sodium 35 thorium bicarbonate was added to the mother liquor to adjust the pH to 7.5-8, and acetone was distilled off under reduced pressure to produce orange-yellow crystals of the same substance (3.849).
was gotten. Total yield 6.1g. A small amount of the first isolated compound was recrystallized from methanol to obtain the pure product. 40mp157-157.5℃NMRδPIm
(CDCl3) 2.48 (3H, s), 3.7 (3H, s), 3.81
(3H, s), 5.3 (1H, s), 7.13-8.1
7 (5H, m), 10.5 (1H, s) 1) 2-Methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl (6.0f
! ) in acetone (60w11) solution with 6N hydrochloric acid (6d
) was added and the mixture was stirred at room temperature for 2 hours.

Add sodium hydrogen carbonate aqueous solution to the reaction mixture to adjust the pH to 7.
．． After adjusting to 5 to 8, acetone was distilled off under reduced pressure.
The residue was diluted with water (150 ml) and the separated oil was extracted twice with ethyl acetate (100 wLI! and 50 ml). The organic layer was washed with water, dried over magnesium sulfate, and the solvent was evaporated to dryness under reduced pressure to form an oily 2-methyl-
2-benzyloxyethyl 4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (5.02 f!) was obtained. NMRδPPl (CDCl,) 1.25 (3H, t, J=7Hz), 2.41 (3H,
s), 4.5 (4H, s), 3,5 to 4.4 (6H, m
), 5.29 (1H, s), 7.3-8.15 (10H
, m), 10.45 (1H, s)'' (Example 3) Dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2. 4g), hydroxylamide heptahydrochloride (
539.37!9) and sodium acetate (752.3η
) in acetic acid (15d) was stirred at room temperature for 55 minutes to give 2-methyl-4-(2-cyanophenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,
Dimethyl 5-dicarboxylate is produced.

Acetic anhydride (2.3759) is added to the reaction mixture and the mixture is reacted for 4 hours at 110° C. with stirring. The reaction mixture is concentrated, water (30d) is added, and the resulting acidic liquid is adjusted to a PFI of 7.5 to 8 by adding an aqueous sodium bicarbonate solution, and then extracted twice with ethyl acetate. The organic layer was washed successively with water and saturated aqueous sodium chloride solution, and the solvent was evaporated to dryness under reduced pressure. The residue was left in the refrigerator overnight to crystallize, and the crystals were collected by filtration and washed with a small amount of cold methanol to give 2-methyl-4-(2-cyanophenyl)-
Crystals of dimethyl 6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.719) were obtained. The same substance (0.99) was also recovered from the mother liquor.

These crystals were combined (2.619) and recrystallized from methanol to obtain pure crystals (1.2 g). Mpl6
6-166.5℃2) Diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.69
) Hydroxylamine hydrochloride (495η) and vinegar 15
When a mixture of sodium chloride (691) and acetic acid (20d) was stirred at room temperature for 1 hour, 2-methyl-4-(
20 diethyl (2-methoxycarbonylphenyl)-6-hydroxyiminomethyl-1,4-dihydropyridine-3,5-dicarboxylate is produced.

Acetic anhydride (2.189) was added to the reaction mixture, and the mixture was reacted at 110° C. for 3.5 hours with stirring. Acetic acid was distilled off from the reaction mixture under reduced pressure, and the residue was adjusted to pH 8 by adding aqueous sodium hydrogen carbonate solution, and then extracted with ethyl acetate.
5ru. The ethyl acetate extract is washed successively with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and then the solvent is evaporated to dryness. The residual oil (2.889) was developed on a column chromatograph packed with silica gel (729), and a mixture of benzene, 30 and ethyl acetate (volume ratio 10:
Elution with 1) gave an oil (1.69). When diisopropyl ether (3 m0) was added to this and powdered, a crystalline powder (1.39) was obtained. A mixed solution of diisopropyl ether and ethanol (20 m11 volume ratio 15
:1), diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.03
9) was obtained.

Mpl26-127℃) Dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.6f!), Hydroxylamine hydrochloride (764~) and sodium acetate (1.069) to acetic acid (20 m),
After stirring for 45 minutes at room temperature, 2-methyl-4-(2-nitrophenyl)-6-hydroxyiminomethyl-1,4
Dimethyl -dihydropyridine-3,5-dicarboxylate is produced.

Acetic anhydride (3.379) was added to the reaction mixture and the mixture was heated at room temperature for 1
The mixture was stirred for 5 minutes and at 100° C. for 3 hours. After distilling off the acetic acid, an aqueous sodium hydrogen carbonate solution was added to the residue to adjust the pH to 7.
5 and extracted with ethyl acetate. The extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was evaporated to dryness under reduced pressure. The residual oil (3.809) was developed on a column chromatograph packed with silica gel (1109) and eluted with a mixture of benzene and ethyl acetate (volume ratio 9:1).
2.059) was obtained. Add this to ethyl acetate (12d)
and n-hexane (6 ml) to give yellow particles of 2-methyl-4-(2-nitrophenyl)-6-
Dimethyl cyano-1,4-dihydropyridine-3,5-dicarboxylate (1.199) was obtained. Mpl7O.
5-171.59C02-Methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1
, 4-dihydropyridine-3-carboxylic acid isopropyl (3.889), hydroxylamine hydrochloride (0.76
449) and sodium acetate (1.06649) were added to acetic acid (20m0) and this was stirred at room temperature for 1 hour.
Isopropyl -methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-carboxylate is produced.

After acetic anhydride (3.379) was distilled off, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract, water,
After washing with an aqueous sodium hydrogen carbonate solution and water in this order, and drying with magnesium sulfate, the solvent was evaporated to dryness under reduced pressure. The residual oil (3.69f) was purified with silica gel (100r
) packed column chromatography and eluted with a mixture of benzene and ethyl acetate (volume ratio 5:1), an oily 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-cyano- Isopropyl 1,4-dihydropyridine-3-carboxylate (2.0f) was obtained. This was left in the refrigerator for several days to crystallize, and when recrystallized with methanol, pure crystals were obtained. Mpl75.
5-176.5°C5) Dimethyl 2-methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.0r), hydroxylamine hydrochloride (424. 3W19) and sodium acetate (591.8~) were added to acetic acid (12ml) and stirred at room temperature for 80 minutes, resulting in 2-methyl-4-(3-nitrophenino(he)-6-hydroxyiminomethyl-1,4).
Dimethyl -dihydropyridine-3,5-dicarboxylate is produced.

To this reaction mixture was added acetic anhydride (1.87f) and
Stirred at 10°C for 3.5 hours. When the solvent was distilled off from the reaction mixture, a crystalline solid remained, which was neutralized with an aqueous sodium bicarbonate solution and then ground. This was collected by filtration and thoroughly washed with water to obtain crystals (1.92f).
Recrystallization from a mixture of methanol and ethyl acetate yields 2-methyl-4-(3-nitrophenyl)-6-cyano-1,
Dimethyl 4-dihydropyridine-3,5-dicarboxylate (1.04f) is obtained. Mp2O 207℃. The target substance (0.6r) was recovered from the recrystallization mother liquor. :)
2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (2.
44t), hydroxylamine hydrochloride (377W19)
2-methyl-4-(3-
Nitrophenyl)-5-ethoxycarbonyl-6-hydroxyiminomethyl-1,4-dihydropyridine-3-
2-benzyloxyethyl carboxylate is produced.

Acetic anhydride (1.66f) was added to the reaction mixture, and the mixture was heated at room temperature for 1.
The mixture was further stirred at 100° C. for 3 hours.

After distilling off the acetic acid, aqueous sodium hydrogen carbonate solution was added to adjust the pH to 7.5, and the mixture was extracted twice with ethyl acetate. This extract was washed twice with water and once with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then the solvent was evaporated to dryness under reduced pressure. The brown residual oil (2.6f) was developed on a column chromatograph packed with silica gel (78t),
Elution with a mixture of benzene and ethyl acetate (12:1 by volume) gave an oil (1.45f). This was powdered with a small amount of a mixture of diisopropyl ether and diethyl ether, and then recrystallized with a mixture of diisopropyl ether (9d) and ethanol (1 ml).
-(3-nitrophenyl)-5-ethoxycarbonyl-
Pure crystal of 2-benzyloxyethyl 6-cyano-1,4-dihydropyridine-3-carboxylate (8407f1
f) was obtained. Mpll 4-115°C. If the mother liquor is concentrated and the residue is left in the refrigerator, the same substance (560η
) were recovered. Major Example 4 1) 2-Methyl-4-(2-cyanophenyl)-6-
A solution of dimethyl formyl-1,4-dihydropyridine-3,5-dicarboxylate (2.3r) in methanol (46d) was cooled and added with sodium borohydride (140.7η) for 10 minutes at -5°C. Added.

During this time, the reaction temperature was maintained at -4 to -5°C and stirring was continued. The temperature of the reaction mixture was lowered to −6° C. and stirred for a further 15 minutes, then diluted with water (20 ml) and acidified with 50% acetic acid to a pH of about 5. This was then concentrated under reduced pressure to precipitate crystals. More water (30d)
After adding , the crystals were collected by filtration, thoroughly washed with water, and then dried. When the crystals thus obtained (2.05 t) were recrystallized from methanol (15 ml), dimethyl 2-methyl-4-(2-cyanophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained. A pure crystal (1.67 f) was obtained. Mpl7
7-178 (C2) diethyl 2-methyl-4-(2-methoxycarbonylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (in 1.2 t of ethanol (15 ml) solution, Sodium borohydride was added over 30 minutes.

During this time, the reaction temperature was kept at 0° C. and stirring was continued. Then 0℃
The mixture was stirred for an additional 20 minutes while maintaining the temperature. 5 to the reaction mixture
0% acetic acid was added to adjust the pH to 6, and ethanol was distilled off under reduced pressure. A mixture of water and ethyl acetate was added to the residue, and the mixture was shaken, and the organic layer was separated. The organic layer was washed successively with water, an aqueous sodium bicarbonate solution, and then water, dried over magnesium sulfate, and then the solvent was evaporated to dryness under reduced pressure. Residual oily substance (】.
Diethyl ether (2 ml) was added to 07) to powder it, and the crude crystals were recrystallized from various solvents, but all failed. Therefore, the recovered product (0.9 V) was developed on a column chromatograph packed with silica gel (277) and eluted with a mixture of benzene and ethyl acetate (volume ratio 7:1). diethyl -methoxycarbonylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (800
η) was obtained, and this was recrystallized from a mixture of diethyl ether and n-hexane to obtain pure crystals (5007r9). MplO6-108(C02-methyl-4-
Dimethyl (2-N-methylsulfamoylphenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (350 η) was added to methanol (7 ml) and this cold suspension was added to the hydrogenated Sodium boron (17.8
51T19) was added in one third portions over a period of 2 minutes.

Stirring was continued during this time, and for an additional 1 hour and 45 minutes, -5
Stirring was continued while maintaining the temperature at ~-4°C. During this continuous stirring, methanol (3 ml) was first added after 30 minutes, and then methanol (4 ml) was added after 1 hour to dilute the mixture.
25 minutes before the end of the reaction, add a small amount of sodium borohydride (
9~) was added. After the reaction was completed, water (30 d) was added, and when the mixture was allowed to cool for 1 hour, precipitation of crystals was observed. This crystal (260
) is collected by filtration and recrystallized from methanol (3d),
Dimethyl 2-methyl-4-(2-N-1methylsulfamoylphenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained. Mp
A solution of dimethyl 2-methyl-4-(2-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (3.60 t) in methanol (72 ml) was heated to 0°C. After cooling, sodium borohydride (0.22717) was added in small portions under cooling stirring.

After stirring at the same temperature for 15 minutes, 50% acetic acid was added to adjust the pH of the reaction mixture to 6, and methanol was distilled off under reduced pressure at a temperature below 30°C. The residual solution was diluted with water (100 ml) and extracted with ethyl acetate. The extract, water,
The mixture was washed successively with an aqueous sodium hydrogen carbonate solution and then with water, dried over magnesium sulfate, and then the solvent was evaporated to dryness. When diisopropyl ether was added to the residual oil (3.70r) and powdered, crude crystals (2.74r) were obtained. This product was first recrystallized from methanol (8d) and then from ethyl acetate, resulting in 2-methyl-4-(2-nitrophenyl-6-
Hydroxymethyl-1,4-dihydropyridine-3,5
-Pure crystals (770 w) of dimethyl dicarboxylate were obtained. Mpl64.5-165°C. All mother liquors from the above recrystallization were combined and concentrated, and the crystalline residue was collected by filtration and washed with methanol (5d), resulting in additional crystals of the same material (1.
72r) was obtained, which was recrystallized from ethyl acetate,
A pure product with the same melting point (840η) was recovered. Total yield1.
61t0NMRδPpm (CDCl3) 5) A methanol (70ml) solution of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate (3.88r) After cooling to below -3°C, sodium borohydride (0.2082f) was added little by little with stirring.

After stirring for an additional 30 minutes at -2°C, 50% acetic acid was added to make the mixture acidic, and methanol was distilled off under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extract was washed successively with water, aqueous sodium carbonate and water, dried over magnesium sulfate and the solvent was evaporated to dryness under reduced pressure to give a red viscous oil (4.37f). This was powdered with a mixture of diethyl ether and n-hexane to obtain a yellow crystalline powder (3.75 t). When this product was recrystallized from methanol (10ml!), yellow particles of isopropyl 2-methyl-4-(2-nitrophenyl)-5-methoxycarbonyl-6-hydroxymethyl-1,4-dihydrobiridine-13-carboxylate were obtained. (2.38f) was obtained. The melting point of this product is 135-137℃, and when it is further recrystallized with ethyl acetate (5Tn1), the pure product (】
．． 08r) was obtained. Mpl36.5~138℃02
-Methyl-4-(2-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylate 2-benzyloxyethyl (1.8r
) dissolved in ethanol (36w11) in a coolant,
Sodium borohydride (75.5~) was added below -3°C, and the resulting mixture was stirred at -3 to -5°C for 40 minutes.

After the reaction, the pH was adjusted to 5 to 6 with 50% acetic acid, and ethanol was evaporated to dryness under reduced pressure. Water (100 d) was added to the residue, and the liberated crystalline solid was crushed and collected by filtration. This product (1.57f) was recrystallized from a mixture of diethyl ether and n-hexane. Since the obtained crystals (910 mfi!) were impure and unsuitable for elemental analysis, they were combined with recrystallization mother liquor, filtered, and developed on a silica gel column chromatograph. Elution was performed with a mixture of benzene and ethyl acetate (volume ratio 10:1) to obtain an oil (1r). When this was recrystallized from a mixture of diisopropyl ether and ethanol, 2-methyl-4-(2-nitrophenyl)-5
-ethoxycarbonyl-6-hydroxymethyl-1,4
Pure crystals (530 mf) of 2-benzyloxyethyl -dihydropyridine-3-carboxylate were obtained. Mp9
6-97℃7) 2-Methyl-4-(3-nitrophenyl)-6-formyl-1,4-dihydropyridine-3,5
-dimethyl dicarboxylate (3.84t) in methanol (
To the cold suspension added to 76d), sodium borohydride (221.8 η) was added under stirring at −7° C. over 7 minutes.

Stirring was continued for an additional 5.5 hours, during which time additional sodium borohydride (40 η) was added. Water (5
0ml) was added to dilute it, and the pH was adjusted to 5-6 with 50% acetic acid. A small amount of insoluble matter was filtered off and the filtrate was evaporated to dryness.
The residual solids and oil were dissolved in diisopropyl ether (10
m1) to obtain a solid product (2.7 t). Mix this product with a mixture of methanol and diisopropyl ether (20ml)
) and then recrystallized with methanol (6m0) to give 2-methyl-4-(3-nitrophenyno(ha)-6-
Hydroxymethyl-1,4-dihydropyridine-3,5
-Pure crystals of dimethyl dicarboxylate (1.487) were obtained. Mpl45-146°C. When the initial recrystallization mother liquor was concentrated and powdered with methanol, a crystalline powder (330η) of the same substance was obtained. 8) 2-methyl-4-(3
-nitrophenyl)-5-ethoxycarbonyl-6-formyl-1,4-dihydropyridine-3-carboxylic acid 2
-benzyloxyethyl (2.07) to ethanol (4
Sodium borohydride (
84.1η) was added over 3 minutes at −5° C. with stirring.

After 35 minutes, sodium borohydride (8.4T1Z9)
was added, and the mixture was further stirred at -2°C for 10 minutes.

50% acetic acid was added to the reaction mixture to adjust the pH to 5 to 6, and ethanol was distilled off under reduced pressure. The residue was diluted with water (100 d) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and evaporated to dryness under reduced pressure. The residual oil was left in a refrigerator overnight to crystallize. The crystals were washed with n-hexane, and the obtained crystals (1.67) were recrystallized from a mixture of diisopropyl ether and ethanol (12ml, volume ratio 1:1), resulting in Mp
Pure crystals of 2-benzyloxyethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-hydroxymethyl-1,4-dihydropyridine-3-carboxylate at 4.5-115.5°C (860T19
)was gotten. The same substance (22
0~) were collected. Mpll2-1142C example
5 2-(2-methoxycarbonylbenzylidene)-4,4
-Methyl ethylenedioxyacetoacetate was treated with isopropyl 3-aminocrotonate in the same manner as in 2-Ii) of Example 1, and 2-methyl-4-(2-methoxycarbonylphenyl)-5-methoxycarbonyl-6-ethylene Isopropyl dioxymethyl-1,4-dihydropyridine-3-carboxylate is obtained.

Mpl29-129.5°C. Example 6 1) A mixture of 10.1 t of methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate and 5.517 t of isopropyl 3-aminocrotonate was prepared at 78°C by
Stir at 120 °C for 4 h 30 min, then 12 min.
React for 1 hour at 5°C without stirring.

The reaction mixture was allowed to cool and stand overnight, and then dissolved in ethyl acetate.
This solution is washed twice with water, dried, and concentrated to dryness under reduced pressure. The resulting residue was powdered with ethyl ether and removed to give crude 4-(2-cyanophenyl)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1.
, 8.96 t of 4-dihydropyridine-3-carboxylic acid isopropyl ester are obtained. Additionally, 0.77 f of a crude product of this compound was recovered from the solution. 0.5 y of this crude product is recrystallized with isopropyl ether to obtain 0.37 t of a purified product of the same compound.

Mpl7l-172.5 C The following compound is obtained in the same manner as in Example 6-1).

2) 4-(2-methoxycarbonylphenyl)-5-
Methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester.

Nuclear magnetic resonance absorption spectrum Example 7 1) 2-(2-cyanobenzylidene)acetoacetic acid 2-
A mixture of 4.72r of chloroethyl and 4.06f of ethyl 3-amino-4,4-diethoxycrotonate was added to 100
After heating and stirring at ~105°C for 3 hours, and cooling, the reaction mixture was dissolved in ethyl acetate, washed with an aqueous sodium chloride solution, and dried over magnesium sulfate.

The solvent was distilled off under reduced pressure, and the resulting oily residue (8.83 t) was subjected to column chromatography using silica gel and eluted with a mixed solvent of benzene and ethyl acetate (volume ratio 5:1). Fractions containing the target compound were collected and the solvent was distilled off under reduced pressure to yield 4-(2-cyanophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-2-methyl-1.
, 5.81 t of 4-dihydropyridine-3-carboxylic acid 2-chloroethyl ester are obtained. Nuclear Magnetic Resonance Absorption Spectrum The following compound is obtained in the same manner as in Example 7-1).

2) 5-ethoxycarbonyl-4-(2-cyanophenyl)-6-diethoxymethyl-2-methyl-1,4-
Dihydropyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)ethyl ester nuclear magnetic resonance absorption spectrum δPpm (CDCl3): 1.1~]. 5 (9H, m)
3) 5-ethoxycarbonyl-4-(2-cyanophenyl)-6-diethoxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester nuclear magnetic resonance absorption spectrum 4) 5-ethoxy Carbonyl-4-(2-cyanophenyl)-6-diethoxymethyl-2-methyl-1,4-
Dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester, Mp 94-95°C.

5) 5-ethoxycarbonyl-4-(2-cyanophenyl)-6-diethoxymethyl-2-methyl-1,4-dihydrobiridine-3-carboxylic acid 2-benzyloxyethyl ester, Mp97.5-98.5 ℃.

Example 8 1) 4-(2-cyanopheno(c)-5-methoxycarbonyl-6-dimethoxymethyl-2-methyl-1,
4-dihydropyridine-3-carboxylic acid isopropyl ester 9.32r16N hydrochloric acid 11ml and acetone 9
The mixture consisting of 5 ml is stirred at room temperature for 5 hours.

After neutralizing the reaction mixture with sodium hydrogen carbonate, acetone was distilled off, and water and ethyl acetate were added to the residue. The ethyl acetate layer is separated, washed with water and then with an aqueous sodium chloride solution, and then dried over magnesium sulfate. After distilling off the solvent and washing the remaining solid with a mixed solvent of ethyl ether and hexane, the crude 4-(2-cyanophenyl)-5-methoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine was collected. 7,65t of -3-carboxylic acid isopropyl ester is obtained. 0.5t of this crude product
The product is recrystallized from isopropyl ether to obtain a yellow-orange purified product of 0.347.

Mpl32-134 C0 Example 8-1? The following compound is obtained in the same manner. 2) 4-(2-methoxycarbonylphenyl)-5-methoxycarbonyl-6-formyl-
2-Methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester.

Nuclear magnetic resonance absorption spectrum 3) 2-(N-benzyl-N-methylamino)ethyl 5-ethoxycarbonyl-4-(2-cyanophenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylate Estenol nuclear magnetic resonance absorption spectrum 4) 5-ethoxycarbonyl-4-(2-cyanophenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester
Mpll5-116℃.

5) 5-ethoxycarbonyl-4-(2-cyanophenyl)-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester.

MplO4-105°C. 6) 5-ethoxycarbonyl-
4-(2-cyanophenyl)-6-formyl-2-methyl-1,4-dihydrobiridine-3-carboxylic acid 2-benzyloxyethyl ester nuclear magnetic resonance absorption spectrum Example 9 1) 4-(2-cyanophenyl) -5-methoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester 3.9
0.88 t of hydroxylamine hydrochloride and sodium acetate]. Add 30f and stir at room temperature for 1 hour.

After adding 3.79 f of acetic anhydride to this reaction solution,
and then stirred at 95-100°C for 4 hours. After cooling, acetic acid was distilled off from the reaction mixture under reduced pressure, the residue was diluted with water, and then neutralized with sodium hydrogen carbonate. This aqueous solution is extracted twice with ethyl acetate, and the extract is washed twice with water and then dried. The solvent was distilled off from this solution under reduced pressure, and the remaining oil was pulverized with ethyl ether, filtered, and washed with isopropyl ether to give 4-(2-cyanophenyl)-5-
Methoxycarbonyl-6-cyano-2-methyl-1,4
3.22 tons of yellow powder of -dihydropinodine-3-carboxylic acid isopropyl ester are obtained. Furthermore, when this powder is recrystallized with methanol, the purified product of the above compound has a voltage of 1.99V.
get.

Mpl98-2000C0 Example 9-1') I::. The following compound is obtained in the same manner.

2) 4-(2-methoxycarbonylphenyl)-5-
Methoxycarbonyl-6-cyano-2-methyl-1,4
-dihydropyridine-3-carboxylic acid isopropyl ester, Mpl2]. 5-1233) 6-cyano-5-
Ethoxycarbonyl-4-(2-cyanophenyl)-2
- Hydrochloride of methyl-1,4-dihydropyridine-3-carboxylic acid 2-(N-benzyl-N-methylamino)ethyl ester, Mp 230°C (decomposed).

4) 6-cyano-5-ethoxycarbonyl-4-(2
-cyanophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester,
Mpl35-136°C05) 6-cyano-5-ethoxycarbonyl-4-(2-cyanophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester, Mpl7O. 5-172℃.

6) 6-cyano-5-ethoxycarbonyl-4-(2
-cyanophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester, Mpl 32-133°C.

Example 10 1) 4-(2-cyanopheno(c)-5-methoxycarbonyl-6-formyl-2-methyl-1,4-dihydropyridine-13-carboxylic acid isopropyl ester 3)
．． Add 2r to a solution of 65) 7L of ethanol at 0°C.
While stirring, add 0.33r of sodium boron hydride to 1
The mixture was added over a period of 0 minutes and stirred at the same temperature for 1 hour.

The reaction mixture was adjusted to be slightly acidic with 50% acetic acid while cooling at 0°C, and then ethanol was distilled off under reduced pressure. Water was added to the residue, completely neutralized with sodium bicarbonate, and then extracted twice with ethyl acetate. The extracts are combined, washed twice with water and once with an aqueous sodium chloride solution, and then dried. The solvent was distilled off under reduced pressure, and the resulting yellow oil was powdered with a mixed solvent of ethyl ether and hexane to give 4-(2-cyanophenyl)-5-methoxycarbonyl-6-hydroxymethyl-
3.19 t of crude 2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester is obtained. Further, this crude product is recrystallized from isoprobyl ether containing a small amount of methanol to obtain purified product 1.97r of the present compound.Mpl35-137°C.The following compound is obtained in the same manner as Example 10-1y.

2) 4-(2-methoxycarbonylphenyl)-5-
Methoxycarbonyl-6-hydroxymethyl-2-methyl-1,4-dihydropyridine-3-carboxylic acid isopropyl ester, Mpl44-145℃03) 6-hydroxymethyl-5-ethoxycarbonyl-4-(2-cyanophenyl)-2 -Methyl-1,4-dihydropyridine-3-carboxylic acid 2-ethoxyethyl ester, Mp
l27.5-128.5℃04) 6-hydroxymethyl-5-ethoxycarbonyl-4(2-cyanopheno(
c)-2-Methyl-1,4-dihydropyridine-3-carboxylic acid 2-phenoxyethyl ester, Mpll6 - 117°C.

5) 6-hydroxymethyl-5-ethoxycarbonyl-
4-(2-cyanophenyl)-2-methyl-1,4-dihydropyridine-3-carboxylic acid 2-benzyloxyethyl ester, MplO9-110<0>C.

Example 11 2-cyanobenzaldehyde (30.97f), 4,4
- A benzene solution (120d) of methyl dimethoxyacetoacetate (46.14r), acetic acid (2.3t) and piperidine (2.4f) is heated under reflux for 8 hours.

After adding benzene (80d) to the reaction solution, it is washed with water and treated with activated carbon. The residue obtained by concentrating the P solution was immersed in silica gel (
500f) using column chromatography.
Elution with methylene chloride and concentration of the eluate to dryness yielded 2-
Methyl (2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (25.16V) is obtained. The above compound (1
1.121) and n-propyl 3-aminocucatonate (7.53f) at 67°C for 4 hours at 95.5°C.
Stir at 102° C. for 14 hours and then at 102° C. for 15 hours.

The reaction mixture (1].83f) was dissolved in an equivalent amount of diisopropyl ether, and then subjected to column chromatography using silica gel (300 t).

Elution with methylene chloride and concentration of the eluate to dryness yielded 6-
Dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihytopyridine-3-carboxylic acid n-propyl ester (1.45
t) is obtained. Mpl39-141℃o Example 122-
Methyl (2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (10.82y) and isobutyl 3-aminocrotonate (8.477) were treated in the same manner as in Example 11 to obtain 6-dimethoxymethyl-2-methyl- 4-(2
-cyanophenyl)-5-methoxycarbonyl-1,4
-dihydropyridine-3-carboxylic acid isobutyl ester (17.38t) is obtained.

Mpl26-128℃0IVV\VGoho 1st crystal ano Example 13 Methyl 2-(2-cyanobenzylidene)-4,4-dimethoxyacetoacetate (10.37t) and neopentyl 3-aminocrotonate (8.601 ) was treated in the same manner as in Example 11 to obtain 6-dimethoxymethyl-2-methyl-4
-(2-cyanophenyl)-5-methoxycarbonyl-
1,4-dihydropyridine-3-carboxylic acid neopentyl ester (8.53t) is obtained.

Mpl3O-131°C. Example 146-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-
Methoxycarbonyl-1,4-dihydropyridine-3-
6N hydrochloric acid (13.2TfL) was added to a solution of carboxylic acid n-propyl ester (13.28t) in acetone (132ml).
Add 1) and stir at 12.C for 5.5 hours.

After adjusting the reaction solution to pH 7 with an aqueous sodium hydrogen carbonate solution, acetone was distilled off. The precipitated crystals were collected, washed with an aqueous sodium chloride solution, water, and then petroleum ether, and then recrystallized from a mixed solvent of benzene and n-hexane.
Upon washing with diethyl ether, 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid n
-Propyl ester (3.37r) is obtained. Mpl37
．． 5-14]. O℃. Furthermore, the recrystallization mother liquor was concentrated and the residue was subjected to column chromatography using silica gel (240t).

Elution is performed with methylene chloride, and the eluate is concentrated to dryness to recover the target compound (3.83f). Total yield 7.2t
0 Example 15 6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid isobutyl ester (20
．． 377) and 6N hydrochloric acid (14ml) in the same manner as in Example 14 to obtain 6-formyl-2-methyl-4-(2
-cyanophenyl)-5-methoxycarbonyl-1,4
-dihydropyridine-3-carboxylic acid isobutyl ester (6.82t) is obtained.

Mpl52, 5-154.5°C. Example 16 6-dimethoxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid neopentyl ester (15.56
f) and 6N hydrochloric acid (14.2d) in the same manner as in Example 14 to give 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydrocapyridine-3- Carboxylic acid neopentyl ester (5.83t) is obtained.

Mpl4l. O-143.0°C. Example 17 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid n-propyl ester (4.297
), hydroxylamine hydrochloride (0.87t), sodium acetate (].13y) and acetic acid (26wL1) are stirred at room temperature for 5 hours.

Acetic anhydride (5f) is added to this reaction solution, and the mixture is stirred at room temperature for 80 minutes, at 85°C for 2.5 hours, and then at 93°C for 9.5 hours. After cooling, the solvent is distilled off from the reaction solution, and an aqueous sodium hydrogen carbonate solution and methylene chloride are added to the residue. The organic solvent layer is separated, washed with water, dried, and concentrated to dryness. The resulting residue was recrystallized twice from a mixed solvent of methanol and water and once from methylene chloride to give 6-cyano-2-methyl-4-(2-cyanophenyno(ha)-5-methoxycarbonyl-1,4). -dihydropyridine-3-carboxylic acid n-propyl ester (2.29r) is obtained.Mpl
5O. O-151.5°C. Example 18 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid isobutyl ester (3.39f)
, hydroxylamine hydrochloride (0.89y), sodium acetate (t). 12t), acetic acid (25mt) and acetic anhydride (6.24f) were treated in the same manner as in Example 17 to obtain 6.
-cyano-2-methyl-4-(2-cyanophenyl)-
5-methoxycarbonyl-1,4-dihydropyridine-
3-carboxylic acid isobutyl ester (1.81r) is obtained.

Mpl96. O-197.5°C. Example 19 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid neopentyl ester (3.78f
), hydroxylamine hydrochloride (0.97y), sodium acetate (1.19f), acetic acid (25ml) and acetic anhydride (6.4t) were treated in the same manner as in Example 17 to obtain 6-
Cyano-2-methyl-4-(2-cyanophenyl)-5
-methoxycarbonyl-1,4-dihydropyridine-3
-Carboxylic acid neopentyl ester (1.69r) is obtained.

Mpl73. O-174.0°C. Example 20 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid n-propyl ester (2.00t
Sodium borohydride (0.179) was added to the ethanol suspension (40-) of ) at -5 to -10°C over 5 minutes, and the mixture was stirred at the same temperature for 2 hours.

After adding 50% acetic acid (0.67! Ll) to the reaction solution, the solvent was distilled off. The resulting residue was dissolved in ethyl acetate, washed with an aqueous sodium chloride solution, and dried.

This solution was concentrated to dryness and the resulting crude crystals (2.04f
) is recrystallized from a mixed solvent of methanol and water,
6-hydroxymethyl-2-methyl 4-(2
-cyanophenyl)-5-methoxy/carbonyl-1,4
-dihydropyridine-3-carebonic acid n-propyl ester (1.34?) was obtained.5. mp149.0-15
2.5 C. N. M. R. appm (CDCl3): 0.77 (3H,
t, = 7Hz) ,1.61( 2H, sixtet
, J= 7Hz), 2.38 (3H, s), 3.63
( 3H, s), 3.99 ( 2H, t, J = 7Hz
)4.79(2H,s),5.31(IH,s),7
．． 32 (IH, m), 7.1-7.6 (4H, m)
Example 21 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dinitropyridine-3-canoleboic acid isobutynolester t
(2.001) and sodium borohydride (
0.18t) was treated in the same manner as in Example 20 to obtain 6-hydroxymethyl-2-methyl-4-(2-cynobuenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid. Isobutyl L still (
1.49t) is obtained.

Mpl34.5-137.00C. N. M. R. ijppm (CDCI,): 0.75 (
3H, d, = 7Hz), 0.81 ( 3H, d, J =
7Hz), ]. 97 (IH, m), 2.39 (3H,
s), 2.8 (IH, m), 3.64 (3H, s),
3.86 (2H, d, J = 7Hz), 4.81 (2
H, s), 5.35 (IH, s), 7.1-7.7 (
5H, m) Example 22 6-formyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydropyridine-3-carboxylic acid neopentyl ester (2.001) and hydrogenated hydrogen Sodium (0.1
6t) in the same manner as in Example 20 to obtain 6-hydroxymethyl-2-methyl-4-(2-cyanophenyl)-5-methoxycarbonyl-1,4-dihydrobiridine-13-carboxylic acid neopentyl ester ( ]
．． 541) is obtained.

Mpl78. O-179.5 (C. N. M. R. 6 ppm (CDCl3): 0.87 (9H
, s), 2.38 (3H, s), 3.63 (3H, s)
, 3.81 (2H, s), 4.78 (2H, s), 5.
33 (IH, s), 7.37 (IH, m), 7.1-
7.6 (4H, m)

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ , R^2 and R^3 are both lower alkoxycarbonyl group, halogen-substituted lower alkoxycarbonyl group, lower alkoxy-substituted lower alkoxycarbonyl group, N-lower alkyl-N-aryl substituted lower alkylamino lower alkoxycarbonyl group, aryl-substituted lower an alkoxy-substituted lower alkoxycarbonyl group or an aryloxy-substituted lower alkoxycarbonyl group, and one of R^4 and R^5 is a lower alkyl group and the other is a cyano group, lower alkanoyl group, hydroxy-substituted lower alkyl group, hydroxyimino A substituted methyl group, a diem-di-lower alkoxy-substituted lower alkyl group, or a diem-lower alkylenedioxy-substituted lower alkyl group, respectively, provided that R^1 is 2-
When it is a nitro group, R^2 is a methoxycarbonyl group, ethoxycarbonyl group, or isopropoxycarbonyl group, R^3 is a methoxycarbonyl group, R^4 is a methyl group, and R^5 is a dimethoxymethyl group. , means a formyl group, a hydroxyiminomethyl group, a cyano group or a hydroxymethyl group, respectively, or R^2
represents 2-benzyloxyethoxycarbonyl group, R^3
represents an ethoxycarbonyl group, R^4 represents a methyl group, and R^5 represents a hydroxymethyl group, and when R^1 is a 3-nitro group, R^2 and R^3 are both methoxycarbonyl group,
R^4 represents a methyl group, and R^5 represents a dimethoxymethyl group, formyl group, hydroxyiminomethyl group, cyano group or hydroxymethyl group, or R^2 represents a 2-benzyloxyethoxycarbonyl group. , R^3 is an ethoxycarbonyl group, R^4 is a methyl group, and R^5 is a diethoxymethyl group, a formyl group,
1 represented by hydroxyiminomethyl group, cyano group or hydroxymethyl group, respectively)
,4-dihydropyridine compound. 2 R^1 is a cyano group, lower alkoxycarbonyl group or lower alkanesulfamoyl group, R^2, R
^3, R^4 and R^5 each have the same meaning as defined in claim 1. Claim 1
Compounds described in Section. 3 Claim 2 in which R^2 and R^3 are lower alkoxycarbonyl groups, and R^1, R^4 and R^5 have the same meaning as defined in Claim 2.
Compounds described in Section. 4 R^4 is a lower alkyl group, R^5 is a cyano group, and R^1, R^2 and R^3 each have the same meaning as defined in claim 3. A compound according to scope item 3. 5 R^1 is a cyano group, R^2, R^3, R^4
and R^5 each have the same meaning as defined in claim 4. 6. The compound according to claim 5, wherein R^1 is a 2-cyano group, R^2 and R^3 are both a methoxycarbonyl group, R^4 is a methyl group, and R^5 is a cyano group. . 7 R^1 is a lower alkoxycarbonyl group, R^2, R
Claim 4, in which ^3, R^4 and R^5 each have the same meaning as defined in claim 4.
Compounds described in Section. 8. Claim 7, wherein R^1 is a 2-methoxycarbonyl group, R^2 and R^3 are both ethoxycarbonyl groups, R^4 is a methyl group, and R^5 is a cyano group. Compound. 9 A patent claim in which R^4 is a lower alkyl group, R^5 is a lower alkanoyl group, and R^1, R^2, and R^3 each have the same meaning as defined in claim 3. A compound according to item 3 of the scope. 10 R^1 is a cyano group, R^2, R^3, R^
9. A compound according to claim 9, wherein 4 and R^5 each have the same meaning as defined in claim 9. 11. The compound according to claim 10, wherein R^1 is a 2-cyano group, R^2 and R^3 are both a methoxycarbonyl group, R^4 is a methyl group, and R^5 is a formyl group. . 12 R^1 is a lower alkoxycarbonyl group, R
The compound according to claim 9, wherein ^2, R^3, R^4 and R^5 each have the same meaning as defined in claim 9. 13. Claim 12, wherein R^1 is a 2-methoxycarbonyl group, R^2 and R^3 are both an ethoxycarbonyl group, R^4 is a methyl group, and R^5 is a formyl group. Compound. 14 R^1 is a lower alkanesulfamoyl group,
The compound according to claim 9, wherein R^2, R^3, R^4 and R^5 each have the same meaning as defined in claim 9. 15 In claim 14, R^1 is a 2-methanesulfamoyl group, R^2 and R^3 are both a methoxycarbonyl group, R^4 is a methyl group, and R^5 is a formyl group. Compounds described. 16 R^4 is a lower alkyl group, R^5 is a 1-hydroxy-substituted lower alkyl group, and R^1, R^2 and R
A compound according to claim 3, wherein ^3 each has the same meaning as defined in claim 3. 17 R^1 is a cyano group, R^2, R^3, R^
16. The compound according to claim 16, wherein 4 and R^5 each have the same meaning as defined in claim 16. 18 R^1 is a 2-cyano group, R^2 and R^
3 is both a methoxycarbonyl group, R^4 is a methyl group,
and the compound according to claim 17, wherein R^3 is a hydroxymethyl group. 19 R^1 is a lower alkoxycarbonyl group and R^
16. The compound according to claim 16, wherein R^3, R^4 and R^5 each have the same meaning as defined in claim 16. 20 R^1 is a 2-methoxycarbonyl group, R^2 and R^3 are both ethoxycarbonyl groups, R^4 is a methyl group, and R^5 is a hydroxymethyl group, according to claim 19 compound. 21 R^1 is a lower alkanesulfamoyl group,
The compound according to claim 16, wherein R^2, R^3, R^4 and R^5 each have the same meaning as defined in claim 16. 22 Claim 21, wherein R^1 is a 2-methanesulfamoyl group, R^2 and R^3 are both a methoxycarbonyl group, R^4 is a methyl group, and R^5 is a hydroxymethyl group. Compounds described in. 23 R^1 is a 2-nitro group, R^2 is a methoxycarbonyl group, ethoxycarbonyl group, or isopropoxycarbonyl group, R^3 is a methoxycarbonyl group, R^4 is a methyl group, and R^5 is a dimethoxymethyl group , formyl group, hydroxyiminomethyl group, cyano group or hydroxymethyl group. 24 R^2 is a methoxycarbonyl group or isopropoxycarbonyl group, R^5 is a formyl group, R^1, R
The compound according to claim 23, wherein ^3 and R^4 each have the same meaning as defined in claim 23. 25 R^2 is a methoxycarbonyl group or isopropoxycarbonyl group, R^5 is a cyano group, R^1, R
The compound according to claim 23, wherein ^2, R^3 and R^4 each have the same meaning as defined in claim 23. 26 R^2 is a methoxycarbonyl group or isopropoxycarbonyl group, R^5 is a hydroxymethyl group,
The compound according to claim 23, wherein R^1, R^3 and R^4 each have the same meaning as defined in claim 23. 27 Claims in which R^1 is a 2-nitro group, R^2 is a 2-benzyloxyethoxycarbonyl group, R^3 is an ethoxycarbonyl group, R^4 is a methyl group, and R^5 is a hydroxymethyl group. A compound according to item 1. 28 R^1 is a 3-nitro group, R^2 and R^3 are both a methoxycarbonyl group, R^4 is a methyl group and R
The compound according to claim 1, wherein ^5 is a dimethoxymethyl group, a formyl group, a hydroxyiminomethyl group, a cyano group, or a hydroxymethyl group. 29 R^5 is a formyl group, R^1, R^2, R
A compound according to claim 28, wherein ^3 and R^4 each have the same meaning as defined in claim 28. 30 R^5 is a cyano group, R^1, R^2, R^
29. A compound according to claim 28, wherein 3 and R^4 each have the same meaning as defined in claim 28. 31 R^5 is a hydroxymethyl group, R^1, R
The compound according to claim 28, wherein ^2, R^3 and R^4 each have the same meaning as defined in claim 28. 32 R^1 is a 3-nitro group, R^2 is a 2-benzyloxycarbonyl group, R^3 is an ethoxycarbonyl group, R
The compound according to claim 1, wherein ^4 is a methyl group and R^5 is a diethoxymethyl group, a formyl group, a hydroxyimino group, a cyano group, or a hydroxymethyl group. 33 R^5 is a formyl group, R^1, R^2, R
A compound according to claim 32, wherein ^3 and R^4 each have the same meaning as defined in claim 32. 34 R^5 is a cyano group, R^1, R^2, R^
33. A compound according to claim 32, wherein 3 and R^4 each have the same meaning as defined in claim 32. 35 R^5 is a hydroxymethyl group, R^1, R
The compound according to claim 32, wherein ^2, R^3 and R^4 each have the same meaning as defined in claim 32.