JPH0257066B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention relates to 1,4-dihydropyridine-3,5-
The present invention relates to 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-(o-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 long-lasting pharmacological effects such as hypotensive action. 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. Furthermore, JP-A-57-171968, JP-A-57-
62257, etc., by branching the ethylene residue of the 5-position ester side chain of nicardipine, that is, N-benzyl-2-biperidinyl methyl ester group or 2-(N-benzyl-N-methyl It has been reported that persistence can be extended by converting to amino)-1-phenylethyl ester group or the like. However, since these compounds contain two or more asymmetric carbon atoms, they theoretically contain four types or two of them.
Contains multiple optical isomers. These optical isomers are usually obtained as a mixture, but since the mixing ratio changes depending on the crystallization conditions, it is difficult to obtain a constant mixing ratio or a single substance. These 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivatives have significant differences in biological activity depending on their optical isomers, so a great deal of effort is required to maintain a certain level of quality in order to supply them as pharmaceuticals. It is necessary and the economic efficiency is low. OBJECT OF THE INVENTION The object of the present invention is to provide a novel compound that has excellent pharmacological effects such as blood pressure lowering effect and has a long duration, and which optically contains only one asymmetric carbon. , 4-dihydropyridine-3,5-dicarboxylic acid diester derivative or its oxidized salt. 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 represents a methyl group, R ² represents an unsubstituted benzyl group, R ³ represents a methyl group, and n and m represent 1. ] It is expressed as . The 1,4-dihydropyridine-
The 3,5-dicarboxylic acid diester derivative has a branched aminoalkyl ester group containing no asymmetric carbon atom at the 5-position, and is a novel compound that has not been specifically disclosed in the literature. Therefore, it has long-lasting and strong pharmacological effects such as blood pressure lowering effect. The novel compound provided by the present invention optically has 1
It is a 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative containing only one asymmetric carbon, and theoretically, optical isomers cannot be separated by conventional methods. That is, it is a racemate, exhibits a certain quality and a certain pharmacological activity, and is also highly economically efficient. 1,4-dihydropyridine- of the above formula []
In the 3,5-dicarboxylic acid diester derivative, the NO ₂ group of the phenyl group is preferably bonded to the 2' or 3' position. 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-(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'-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[2,2-dimethyl-3-(N-benzyl-N-methylamino)
propyl] ester. 1,4-dihydropyridine-3,5- of the present invention
The dicarboxylic acid diester derivative has the following formula The aldehyde compound represented by and the following formula [] [In the formula, n, m, 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. The acetoacetate compound of the above formula [] and the 2-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-mentioned aldehyde compounds, acetoacetate compounds, and 3-aminocrotonic acid ester compounds, they may be used without 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 at 50 to 150°C.
The heating reaction is usually carried out for 2 to 24 hours. The aldehyde compound, acetoacetate compound, and 3-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 ester derivatives have pharmacological effects such as excellent blood pressure lowering effects and have a long duration. It is effective as a therapeutic agent for organ diseases. 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 ester derivatives are administered orally or parenterally, such as subcutaneously, intramuscularly, intravenously, transdermally, or rectally. Examples of dosage forms for oral administration include tablets, pills,
Examples include granules, powders, liquids, suspensions, and capsules. To form tablets, excipients such as lactose, starch, and crystalline cellulose; binders such as carboxymethyl cellulose, methyl cellulose, 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 be similarly molded using the above-mentioned excipients and the like by conventional methods. 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 wedge-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 passing them through a bacteria-retaining filter, adding sterilizing agents, and other appropriate treatments. Examples of dosage forms for transdermal administration include ointments and creams; ointments are made with fatty oils such as castor oil and olive oil; petrolatum is used, and creams are made with fatty oils; diethylene glycol and sorbitan monofatty acid esters. 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 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), 3.95
(S, 2H), 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 1 152 mg of 2-nitrobenzaldehyde, 118 mg of methyl 3-aminocrotonate, and acetoacetic acid, 2,2
292 mg of -dimethyl-3-(N-benzyl-N-methylamino)-propyl ester was dissolved in 1 ml 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.
Target 2,6-dimethyl-4-(2'-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 IR (CHCl ₃ ) Vcm ⁺¹ max: 3440, 2940, 1690,
1528, 1466, 1350, 1204, 1112, 1094 NMR ( _CDCl3 ) δppm: 7.7-7.2 (m, 9H), 5.87 (brS, 1H), 5.24 (s, 1H), 3.91 (s, 2H), 3.54 ( s, 3H), 3.39 (s, 2H), 2.25 (s, 6H), 2.23 (s, 2H) 2.02 (s, 3H), 0.80 (s, 6H). Hydrochloride IR (KBr) Vcm ⁺¹ max: 1690, 1530, 1492,
1356, 1212, 1112, 1092 Example 2 152 mg of 3-nitrobenzaldehyde, 118 mg of methyl 3-amino-crotonate, and 2,2 acetoacetic acid
-dimethyl-3-(N-benzol-N-methyl)
229 mg of amino-propyl ester was 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 2,6-dimethyl-4-(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 property value IR (CHCl ₃ ) Vcm ⁺¹ max; 3438, 2952, 1692,
1528, 1468, 1351, 1121, 1101 NMR ( _CDCl3 ) δppm: 8.1-7.2 (m, 9H), 6.18 (brS, 1H), 5.13 (s, 1H), 3.90 (s, 2H), 3.62 (s, 3H), 3.40 (s, 2H), 2.38 (s, 3H), 2.26 (s, 3H), 2.18 (s, 2H), 2.02 (s, 3H), 0.83 (s, 3H), 0.80 (s, 3H) ) Hydrochloride IR (KBr) Vcm ⁺¹ max: 1684, 1526, 1484,
1344, 1208, 1112, 1088 Example 3 Measurement of blood pressure lowering effect Male Wistar rats weighing approximately 250 g were anesthetized with α-chloralose mixed with urethane ip, and heart rate was measured from carotid artery pressure and pulse wave. did. 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 = mean blood pressure value before compound administration - mean blood pressure value after compound administration / mean blood pressure value before compound administration × 10
0 (%) Activity display Antihypertensive activity: 5% or less: ± 5-10%: + 10-15%: ++ The results are shown in Table 1.

[Table] Example 5 Tablets were manufactured according to the following formulation. Compound of Example 1 (main drug) 20g polypynylpyrrolidone (molecular weight 40,000-50,000)
300g Ethanol 1.5 Dissolve and spray dry powder Carboxymethyl cellulose calcium
190 g Magnesium stearate 10 g After mixing and stirring, the mixture was tableted to produce tablets containing 20 mg of the active ingredient per tablet. Example 6 Capsules were manufactured according to the following formulation. Compound of Example 2 (principal 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.

Claims (1)

[Claims] 1. The following formula [] The aldehyde compound represented by and the following formula [] [In the formula, R ² represents an unsubstituted benzyl group, R ³ represents a methyl group, and n and m represent 1. ] 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 and optionally subjecting to a salt-forming reaction. [In the formula, R ¹ , R ² , R ³ , n, and m are the same as defined above. ] A method for producing a 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof. 2. 1,4-dihydropyridine-3,5-dicarboxylic acid according to claim 1, wherein in the above formulas [] and [], a nitro group is substituted at the 2'-position or 3'-position of the phenyl group. A method for producing an acid diester derivative or an acid addition salt thereof.