JPH0155269B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention relates to 1,4-dihydropyridine-3,5
- A method for producing a dicarboxylic acid diester derivative or an acid addition salt thereof. More specifically, the present invention provides novel 1, which has excellent pharmacological effects such as hypotensive action and vasodilatory action, and has a long duration of action.
The present invention relates to a method for producing a 4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof. Prior Art Conventionally, as a compound having pharmacological effects such as hypotensive effect and vasodilatory effect, the formula 4-(0-nitrophenyl)-2,6 represented by
-dimethyl-1,4-dihydropyridine-3,5
-Dicarboxylic acid dimethyl ester (hereinafter abbreviated as nifedipine) is known. Nifedipine is a compound that has excellent pharmacological effects such as hypotensive action, but it has the disadvantage that its duration is short. Many nifedipine derivatives have been studied with the aim of obtaining compounds that have pharmacological effects such as long-lasting blood pressure lowering effects. For example, Tokkosho
Publication No. 56-6417 describes the 3rd or 5th position of nifedipine.
4- position converted to aminoalkyl ester
(m-nitrophenyl)-2,6-dimethyl-1,
4-dihydropyridine-3,5-dicarboxylic acid-
3-Methyl ester-5-β-(N-benzyl-
N-methylamino)ethyl ester hydrochloride (hereinafter abbreviated as nicardipine) has been reported. Also, in Japanese Patent Application Laid-open No. 55-9083, the fourth place of nifedipin is listed.
Nifedipine derivatives in which the 2'-nitrophenyl group is converted to a 2',3'-dihalogen-substituted phenyl group have been reported. However, although these compounds have excellent pharmacological effects, their sustained action is not fully satisfactory. Furthermore, the document Arzneim.−Forsch.− 29 , 226
(1979), the 2'-nitrophenyl group at the 4-position of nifedipine was converted to a di-substituted phenyl group such as 2'-nitro-4'-methoxyphenyl group or 2'-nitro-4'-chlorophenyl group. Nifedipine derivatives have been described, and it has been reported that these nifedipine derivatives have the same or reduced coronary vasodilatory effect as compared to nifedipine. OBJECT OF THE INVENTION The present inventors have discovered that nifedipine derivatives 1,
As a result of detailed studies on the structure and activity of 4-dihydropyridine-3,5-dicarboxylic acid diester derivatives, we found that the phenyl group at the 4-position of nifedipine was
A 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative that has been converted into a 2',3'-disubstituted phenyl group and the ethyl ester group at the 3- or 5-position has been converted into an aminoalkyl group has a strong ability to lower blood pressure. The present invention was achieved by discovering that the drug has pharmacological effects such as action, and that the duration of the pharmacological effect is extremely long. Therefore, the object of the present invention is to produce a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof that has excellent pharmacological effects such as hypotensive effect and has a long duration. It is about providing law. Structure and Effects of the Invention The novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative provided by the present invention has the following formula [] [In the formula, R ¹ is a methyl group, R ² is an unsubstituted benzyl group, R ³ is a methyl group, and A is an ethylene group or 2,2
-dimethyltrimethylene group, X and Y are the same or different and represent a halogen atom or a nitro group. ] It is expressed as . The 1,4-dihydropyridine-
The 3,5-dicarboxylic acid diester derivative has a 2',3'-disubstituted phenyl group at the 4-position and an aminoalkyl ester group at the 5-position, and has been specifically described in the literature. This is a new, undisclosed compound that has pharmacological effects such as long-lasting blood pressure lowering effects. In the above formula [], X and Y are the same or different and are a halogen atom or a nitro group. The halogen atom is preferably a fluorine atom or a chlorine atom. 1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives may be acid addition salts, such as inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; acetic acid, propionic acid, citric acid, succinic acid, maleic acid, etc. organic carboxylic acids; examples include organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. 1,4-dihydropyridine-3,5- of the present invention
Preferred examples of dicarboxylic acid diester derivatives are as follows. 2,6-dimethyl-4-(2',3'-dichlorophenyl)-1,4-dihydropyridine-3,5-
Dicarboxylic acid-3-methyl ester-5-[2-
(N-benzyl-N-methylamino)ethyl] ester, 2,6-dimethyl-4-(2'-chloro-3'-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5-
[2-(N-benzyl-N-methylamino)ethyl] ester, 2,6-dimethyl-4-(2'-bromo-3'-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5-
[2-(N-benzyl-N-methylamino)ethyl]ester, 2,6-dimethyl-4-(2'-fluoro-3'-
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-5
-[2-(N-benzyl-N-methylamino)ethyl] ester, 2,6-dimethyl-4-(3'-chloro-2'-fluorophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-5
-[2-(N-benzyl-N-methylamino)ethyl]ester, 2,6-dimethyl-4-(3'-chloro-2'-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5-
[2-(N-benzyl-N-methylamino)ethyl] ester, 2,6-dimethyl-4-(2'-chloro-3'-fluorophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-5
-[2-(N-benzyl-N-methylamino)ethyl]ester, 2,6-dimethyl-4-(3'-chloro-2'-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5-
[(2,2-dimethyl-3-(N-benzyl-N-
methylamino)ethyl] ester, 2,6-dimethyl-4-(2'-chloro-3'-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5-
[(2,2-dimethyl-3-(N-benzyl-N-
methylamino)propyl] ester, 2,6-dimethyl-4-(2'-fluoro-3'-
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl-5-[(2,
2-dimethyl-3-(N-benzyl-N-methylamino)propyl] ester, 1,4-dihydropyridine-3,5- of the invention
The dicarboxylic acid diester derivative has the following formula [] [In the formula, X and Y are the same as defined above. ] and the following formula [] [In the formula, A, R ² and R ³ are the same as defined above. ] Acetoacetate compound represented by and the following formula [] [In the formula, R ¹ is the same as defined above. ] It is produced by reacting with a 3-aminocrotonic acid ester compound represented by the following, and subjecting it to a salt-forming reaction if necessary. To obtain the aldehyde compound of the above formula [], the following formula [] [In the formula, X and Y are the same as defined above, R ⁴ is methyl,
Represents hydroxymethyl. ] can be easily produced by oxidizing it in the presence of a known oxidizing agent. As an oxidizing agent, chromium,
Examples include oxidizing agents containing elements such as silver and selenium. The acetoacetic acid ester compound of the above formula [] and the 3-aminocrotonic acid ester compound of the above formula [] can be easily produced by known methods [M. Iwanami et al., chem.pharm.Bull. vol. 27, 1426
(1979)]. When reacting the above aldehyde compounds, acetoacetate compounds, and 3-aminocrotonic acid ester compounds, they can be used, for example, without a solvent or with lower alcohols such as ethanol, propanol, isopropanol, n-butanol, and t-butanol; In an organic solvent such as a halogenated hydrocarbon such as chloroform, dichloroethane, or toluchloroethane; or an aromatic compound such as benzene or pyridine, at 30 to 180°C, preferably 50 to 150°C.
The heating reaction is usually carried out for 2 to 24 hours. The aldehyde compound, acetoacetate compound, and 2-aminocrotonic acid ester compound can be used in amounts of 0.8 to 1.5 and 0.8 to 1.5 equivalents, respectively, per equivalent of the aldehyde compound. 1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives have pharmacological effects such as excellent blood pressure lowering effects and long-lasting effects, such as improving angina pectoris, cerebral blood flow, and circulation disorders.
It is effective as a therapeutic agent for cardiovascular diseases such as hypertension and ischemic heart disease. Furthermore, since the compound of the present invention is easily soluble in water, it can be used as an injection; on the other hand, when administered orally, it tends to be gradually absorbed through the intestinal mucosa. 1,4-dihydropyridine-3,5- of the present invention
Dicarboxylic acid diester derivatives are administered orally or parenterally, such as subcutaneously, intramuscularly, intravenously, transdermally, or rectally. The dosage form for oral administration is
Examples include tablets, pills, granules, powders, solutions, suspensions, capsules, and the like. To form tablets, excipients such as lactose, starch, and crystalline cellulose; binders such as carboxymethylcellulose, methylcellulose, and polyvinylpyrrolidone; and disintegrants such as sodium alginate, sodium bicarbonate, and sodium lauryl sulfate are used. It can be molded by a conventional method. Pills, powders, and granules can also be formed using the above-mentioned excipients and the like in a conventional manner. Solutions and suspensions are formed by conventional methods using, for example, glycerin esters such as tricaprylin and triacetin, and alcohols such as ethanol. Capsules are formed by filling granules, powders, liquids, etc. into capsules made of gelatin or the like. Dosage forms for subcutaneous, intramuscular, and intravenous administration include injections in the form of aqueous or nonaqueous solutions, suspensions, and the like. As the non-aqueous solutions and suspensions, propylene glycol, polyethylene glycol, olive oil, ethyl oleate, etc. are used, and preservatives, stabilizers, etc. are added to these as necessary. Injectables are sterilized by appropriate treatments such as filtration through a bacteria retention filter and addition of a sterilizing agent. Examples of dosage forms for transdermal administration include ointments and creams; ointments use fatty oils such as castor oil and olive oil; vaseline and the like; creams use fatty oils; diethylene glycol and sorbitan monofatty acid ester. It is molded by a conventional method using an emulsifier such as. For rectal administration, conventional suppositories such as gelatin soft capsules are used. 1,4-dihydropyridine-3,5- of the present invention
The dosage of the dicarboxylic acid diester derivative varies depending on the patient's age, sex, degree of disease, dosage form, etc., but is usually 0.01 to 10/mg/Kg/day, preferably
It is 0.05-5/mg/Kg/day. The present invention will be explained in more detail below with reference to Examples. Reference Example 1 3.0 g of 2-fluoro-3-nitro-toluene was added to 20 ml of ice-cooled acetic anhydride, and 4 ml of concentrated sulfuric acid was added dropwise. Acetic anhydride 20°C while keeping the temperature below 10°C.
5 g of chromium trioxide dissolved in 1 ml was added in about 1 hour. After stirring for 2 hours, the mixture was poured into 150 ml of ice, the formed precipitate was filtered off, and the resulting solid was washed with 2% aqueous sodium bicarbonate. To the obtained solid were added 10 ml of dioxane, 4 ml of water, and 0.4 ml of concentrated sulfuric acid, and the mixture was heated under reflux for 30 minutes. After removing the solvent and concentrating, it was extracted with CH ₂ Cl ₂ ,
The organic layer was separated, washed with water, and dried. When the solvent was removed, 3.0 g of the desired 2-fluoro-3-nitrobenzaldehyde was obtained. mp46−47゜ IR (KBr) υ ^cm-1 _nax : 1690, 1610 NMR (CDCl ₃ ) δppm: 10.54 (s, 1H) 8.56-8.14 (m, 2H) 7.69-7.34 (m, 1H) Similarly, other A 2,3-disubstituted benzaldehyde compound is also obtained. Reference example 2 2,2-dimethyl-3-(N-benzyl-N-
2.07 g of methyl)-amino-propyl alcohol was dissolved in 1 ml of benzene and heated to 70°C. 1.0 g of diketene was slowly added dropwise to this mixed solution. After stirring for 1.5 hours, the solvent was distilled off, the residue was subjected to silica gel chromatography, and the hexane-ethyl acetate elution fraction was concentrated to obtain the desired acetoacetic acid-[2,2-
2.8 g of dimethyl-3-(N-benzyl-N-methyl)-amino-propyl] ester (oil) were obtained. Physical properties NMR (CDCl ₃ ) δppm: 7.35 (s, 5H), 3.57 (s, 2H), 3.38 (s, 2H), 2.28 (s, 2H), 2.18 (s, 3H), 2.15 (s, 3H) , 0.89 (s, 6H) Other acetoacetate compounds can also be obtained in the same manner. Example 1 After dissolving 350 mg of 2,3-dichlorobenzaldehyde, 510 mg of acetoacetic acid 2-(N-benzyl-N-methyl)-amino-ethyl ester and 250 mg of methyl 3-aminocrotonate in 2 ml of isopropanol, 12 The mixture was heated to reflux for an hour. After distilling off the solvent, silica gel chromatography was performed, and the desired 2,6-dimethyl-4-(2',3'-dichloro-phenyl)-1, was extracted from the fraction eluted with a chloroform-ethyl acetate mixture. 4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-5
600 mg of -[2-(N-benzyl-N-methylamino)ethyl]ester was obtained. The physical and chemical properties are as follows: IR (CHCl ₃ )υ ^cm-1 _nax : 1690, 1614 NMR (CDCl ₃ ) δppm: 7.38−6.98 (m, 8H), 6.01 (brs, 1H), 5.45 (s, 1H), 415 (t, 2H, J = 6Hz), 3.56 (s, 3H), 3.45 (s, 2H), 2.58 (t, 2H, J = 6Hz), 2.23 (s, 6H), 2.13 (s, 3H) By adding hydrogen chloride ether solution to the above target product, the corresponding hydrochloride [IR (KBr) υmax, cm
^-1 : 3430, 2620, 1690.] was obtained. Example 2 2-chloro-3-nitro-benzaldehyde
370 mg, methyl 3-aminocrotonate 252 mg, acetoacetic acid 2-(N-benzyl-N-methyl)-amino-ethyl ester 506 mg in isopropanol 2 ml
After heating under reflux for 12 hours, the solvent was distilled off.
The residue was chromatographed on silica gel and the fractions eluted with a mixture of chloroform and ethyl acetate were used to obtain the desired product, 2,6-dimethyl-4-(2'-chloro-3'-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5-
[2-(N-benzyl-N-methylamino)ethyl]ester was collected. IR (CHCl ₃ )υ ^cm-1 _nax : 1692, 1616, 1466 NMR (CDCl ₃ ) δppm: 7.73−7.20 (m, 8H), 6.07 (brs, 1H), 5.52 (s, 1H), 4.16 (t, Hydrochloride IR (KBr )υ ^cm-1 _nax : 3425, 2625, 1692, 1532, 1488 Example 3 2-Fluoro-3-nitrobenzaldehyde
330 mg, methyl 3-aminocrotonate 252 mg, acetoacetic acid 2-(N-benzyl-N-methyl)-amino-ethyl ester 506 mg in isopropanol 2 ml
After heating under reflux for 12 hours, the solvent was distilled off. The residue was subjected to silica gel chromatography to obtain the desired 2,6-dimethyl-4-(2'-fluoro-
3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2-(N-benzyl-N-methylamino)
ethyl] ester was obtained. Physical property values IR (CHCl ₃ )υ ^cm-1 _nax : 1692, 1614, 1462 NMR (CDCl ₃ ) δppm: 7.94−7.55 (m, 2H), 7.27 (s, 5H), 7.06 (m, 1H), 5.83 ( brs, 1H, ), 5.31 (s, 1H), 4.13 (t, 2H, J = 6Hz), 3.59 (s, 3H), 3.48 (s, 2H), 2.60 (t, 2H, J = 6Hz), 2.30 (s, 6H), 2.15 (s, 3H) MSm/e: 497 (M ⁺ ), 480, 466 Hydrochloride IR (KBr) υ ^cm-1 _nax : 3425, 2600, 1692, 1530, 1490 Example 4 3 -chloro-2-fluorobenzaldehyde
320 mg, methyl 3-aminocrotonate 252 mg, acetoacetic acid 2-(N-benzyl-N-methyl)-amino-ethyl ester 510 mg in isopropanol 2 ml
The mixture was then heated under reflux for 6 hours. The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain the desired 2,6-dimethyl-4-(3'-chloro-2'-fluorophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl ester-5-
500 mg of [2-(N-benzyl-N-methylamino)ethyl]ester was obtained. Physical property values IR (CHCl ₃ )υ ^cm-1 _nax : 1688, 1616, 1452 NMR (CDCl ₃ ) δppm: 7.27−6.85 (m, 8H), 5.99 (brs, 1H,), 5.24 (s, 1H), 4.13 (t, 2H, J = 6Hz), 3.58 (s, 3H), 3.47 (s, 2H), 2.60 (t, 2H, J = 6Hz), 2.26 (s, 6H), 2.15 (s, 3H) MSm/ e: 486 (M ⁺ ), 455, 338 Hydrochloride mp109−112゜ IR (KBr) υ ^cm-1 _nax : 3425, 2600, 1688, 1490 Example 5 3-chloro-2-nitrobenzaldehyde 556
mg and 362 mg of methyl 3-aminocrotonate and 2-(N-benzyl-N-methyl)-amino-acetoacetate.
820 mg of ethyl ester and 4 ml of isopropanol
The mixture was stirred and heated under reflux for 6 hours. After distilling off the solvent, the residue was subjected to silica gel chromatography to obtain the desired 2,6-dimethyl-4-(3'-chloro-2'-
Nitrophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-5
900 mg of -[2-(N-benzyl-N-methylamino)ethyl]ester was collected. Physical property values IR (CHCl ₃ )υ ^cm-1 _nax : 1692, 1614, 1465 NMR (CDCl ₃ ) δppm: 7.40−7.20 (brs, 8H), 5.85 (brs, 1H), 5.24 (s, 1H), 4.13 ( MSm/e: 515 (M ⁺ ), 513 (M ⁺ ) Hydrochloride IR (KBr) υ ^cm-1 _nax : 3420, 1692, 1532, 1488 Example 6 2-chloro-3-fluorobenzaldehyde
460 mg of methyl 3-amino-crotonate and 820 mg of 2-(N-benzyl-N-methyl)-amino-ethyl acetoacetate were dissolved in 4 ml of isopropanol and heated under reflux for 8 hours. The solvent was distilled off and the residue was subjected to silica gel chromatography to obtain the desired 2,6-dimethyl-4-(2'-chloro-3'-fluorophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-methyl-5-[2-(N-
Benzyl-N-methylamino)ethyl] ester was purified. Physical property values IR (CHCl ₃ )υ ^cm-1 _nax : 1688, 1616, 1452 NMR (CDCl ₃ ) δppm: 7.27−6.85 (m, 8H), 5.95 (brs, 1H), 5.28 (s, 1H), 4.20 ( t, 2H, J = 6Hz), 3.58 (s, 3H), 3.45 (s, 2H), 2.60 (t, 2H, J = 6Hz), 2.26 (s, 6H), 2.15 (s, 3H) Hydrochloride IR (KBr)υ ^cm-1 _nax : 3420, 2620, 1692, 1620, 1490 Example 7 3-chloro-2-nitrobenzaldehyde 185
mg and methyl 3-aminocrotonate 118 mg and 2,2-dimethyl-3-(N-benzyl-N-acetoacetate)
-Methylamino)-propyl ester (292 mg) was dissolved in 1 mg of isopropanol and heated under reflux in the dark for 12 hours. The solvent was distilled off, and the residue was subjected to silica gel chromatography to obtain the desired 2,6-dimethyl-4-
(3'-chloro-2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[(2,2-dimethyl-3-
(N-benzyl-N-methylamino)propyl]
The ester was collected. Physical property values NMR (CDCl ₃ ) δppm: 7.4-7.0 (brs, 8H), 6.15 (brs, 1H), 5.28 (s, 1H), 3.92 (s, 2H), 3.60 (s, 3H), 3.41 (s, 2H), 2.21 (s, 6H), 2.04 (s, 2H), 0.80 (s, 6H) Hydrochloride IR (KBr) υ ^cm-1 _nax : 3400, 1684, 1536, 1480 mp 124-127゜Example 8 2,3-dichlorobenzaldehyde 175mg and 3
126 mg of methyl -amino-crotonate and 2,2-dimethyl-3-(N-benzyl-N-methylamino)propyl acetoacetate were dissolved in 1 ml of isopropanol and heated under reflux for 8 hours. After distilling off the solvent, the residue was subjected to silica gel chromatography to obtain the desired 2,6-dimethyl-4(2',3'-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester. 5-[2,2
-dimethyl-3-N-benzyl-N-methylamino)propyl)] ester was collected. Physical properties NMR (CDCl ₃ ) δppm: 7.37-7.00 (m, 8H), 5.88 (brs, 1H), 5.47 (s, 1H), 3.91 (s, 2H), 3.58 (s, 3H), 3.44 (s, 2H), 2.23 (s, 8H), 2.05 (s, 3H), 0.84 (s, 6H) Hydrochloride mp 124−127゜ IR (KBr) υ ^cm-1 _nax : 3450, 1688, 1492, 1380 Example 9 2-chloro-3-nitrobenzaldehyde
128.7 mg of methyl 3-amino-crotonate and 2,2-dimethyl-3-(N-benzyl-N-methyl)amino-propyl acetoacetate were dissolved in 1 ml of isopropanol and heated under reflux for 8 hours. The solvent was distilled off and the residue was subjected to silica gel chromatography to obtain the desired 2,8-dimethyl-4-(2'-chloro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3. -Methyl ester-5-[2,2-dimethyl-3-(N-benzyl-N-methylamino)propyl] ester was collected. Physical properties NMR (CDCl ₃ ) δppm: 7.6-7.0 (m, 8H), 5.65 (brs, 1H,), 5.50 (s, 1H), 3.95 (s, 2H), 3.66 (s, 3H), 3.46 (s , 2H), 2.30 (s, 6H), 2.08 (s, 2H), 0.89 (s, 6H) Hydrochloride mp 128−132゜ IR (KBr) υ ^cm-1 _nax : 3400, 1686, 1532, 1490, 1428 Example 10 2-fluoro-3-nitrobenzaldehyde
169 mg and methyl aminocrotonate 116 mg and 2,2'-dimethyl-3-(N-benzyl-N-
291 mg of methyl)-amino-propyl ester were dissolved in 1 ml of isopropyl alcohol and heated under reflux for 8 hours. The solvent was distilled off and the residue was subjected to silica gel chromatography to obtain the desired 2,6-dimethyl-4-
(2'-fluoro-3'-nitrophenyl)-1,4-
Dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2,2-dimethyl-3-(N
-benzyl-N-methylamino)propyl] ester was collected. Physical properties NMR (CDCl ₃ ) δppm: 7.7-7.5 (m, 2H), 7.3-7.1 (m, 6H), 6.19 (brs, 1H,), 5.39 (s, 1H), 3.95 (s, 2H), 3.62 (s, 3H), 3.47 (s, 2H), 2.35 (s, 8H), 2.08 (s, 3H), 0.90 (s, 6H) Hydrochloride IR (KBr) υ ^cm-1 _nax : 3450, 1692, 1532 , 1492, 1352 Example 11 Measurement of blood pressure lowering effect Male Wistar rats weighing approximately 250 g were anesthetized by ip administration of α-chloralose with urethane, and carotid artery pressure and heart rate were measured from their pulse waves. The antihypertensive activity of the compound (test substance) was measured over time when the compound (test substance) was administered intravenously. The antihypertensive activity was calculated using the following formula and was expressed as follows. Antihypertensive activity = Average blood pressure value before compound administration - Average blood pressure value after compound administration / Average blood pressure value before compound administration × 100 (%) Activity display Antihypertensive activity: Less than 5%: ± 5 to less than 10%: + 10 to 15%: ++ The results are shown in Table 1.

[Table] Example 2 Measurement of vasodilatory effect using rat peripheral constant flow perfusion specimen SD male rats weighing 350 to 400 g were anesthetized by intraperitoneal administration of 60 mg/Kg of sodium pentobarbital and used in the experiment. After systemic heparinization by intravenous administration of 100 u/kg heparin, 6 to 7 ml/min of blood was introduced from the left common carotid artery to the lower part of the renal artery branch of the abdominal aorta using a perfusion pump, and constant flow perfusion was performed to the peripheral site. The test solution was injected into the perfused blood on the distal side of the perfusion pump, and changes in perfusion pressure were measured. The activity of the test compound was determined as the relative activity ratio to papaverine from the dose-response curves of the standard drug papaverine and the test compound. Table 2 shows the vasodilatory effects of the compounds of the present invention. Note that the control compound * had extremely low solubility in water. In contrast, the compounds of the present invention have high solubility in water.

[Table] Example 13 Tablets were manufactured according to the following formulation. Compound of Example 1 (main drug) 20g polyvinylpyrrolidone (molecular weight 40,000-50,000)
After dissolving 300 g of ethanol and spray-drying the powder, 190 g of carboxymethyl cellulose (calcium) and 10 g of magnesium stearate were mixed and stirred and then tableted to produce tablets containing 20 mg of the active ingredient per tablet. Example 14 Capsules were manufactured according to the following formulation. Compound of Example 3 (main drug) 10g Lactose 148g Avicel 100g Magnesium stearate 2g Mix and stir and fill into hard capsules by conventional method.
Capsules containing 10 mg of the main drug were manufactured. Example 15 Blood pressure lowering effect upon oral administration Male Wistar rats (weighing approximately 250 g) that had been fasted for 16 hours or more were fixed in a Bollman cage after a catheter was inserted into the femoral artery under ether anesthesia.
After more than 1 hour had passed since the animals became narcotized, the test compound was forcibly administered using an oral probe. The test compound was prepared by dissolving it in water. The femoral artery pressure was measured over time, and the values calculated using the following formula: change in mean blood pressure (mmHg) = mean blood pressure after administration (mmHg) - mean blood pressure before administration (mmHg) are shown in Table 3.

【table】

Claims (1)

[Claims] 1. The following formula [] [Wherein, X and Y are the same or different and represent a halogen atom or a nitro group. ] [In the formula, A represents an ethylene group or a 2,2-dimethyltrimethylene group, R ² represents an unsubstituted benzyl group, and R ³ represents a methyl group. ] Acetoacetate compound represented by and the following formula [] [In the formula, R ₁ represents a methyl group. ] The following formula [ ], which is characterized by reacting with a 3-aminocrotonic acid ester compound represented by [In the formula, R ¹ , R ² , R ³ , A, X, and Y are the same as defined above. ] 1,4-dihydropyridine-3,5 represented by
- A method for producing a dicarboxylic acid diester derivative or an acid addition salt thereof.