JPH0160464B2 - - 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 dicarboxylic acid diester derivative or an acid addition salt thereof, a method for producing the same, and a drug containing the same as an active ingredient. More specifically, the present invention provides a blood pressure lowering effect,
A novel 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative or its acid addition salt having excellent pharmacological effects such as vasodilating effect and long duration of action, a method for producing the same, and its effective use Concerning drugs as ingredients. Prior Art Conventionally, as a compound having pharmacological effects such as hypotensive effect and vasodilatory effect, the formula 4-(0-nitrophenyl)-2, represented by
6-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. Furthermore, among these nifedipine derivatives, felodipine (4-(2',
3'-dichlorophenyl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-ethyl ester)
is known (References, Stig-Lennart
Bostrom et al., Nature 292, 777, 1981). 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 is a 2′-nitro-5′-methoxyphenyl group,
Nifedipine derivatives converted to di-substituted phenyl groups such as 3′-nitro-6′-chlorphenyl groups have been described, and these nifedipine derivatives have the same or weaker coronary vasodilatory effect than nifedipine. It has been reported that. JP-A-57-171968 reports a nifedipine derivative in which the 3rd or 5th position is substituted with N-benzyl-3-piperidyl ester, etc. and the 4th position is substituted with a nitrophenyl group, as a related compound of nicardipine. ing. 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
The methyl ester group at the 3- or 5-position is converted into a 2',3'-disubstituted phenyl group, and the methyl ester group at the 3- or 5-position is converted into an N-benzyl-3-
1,4-dihydropyridine-3,5-dicarboxylic acid diester derivatives converted to piperidyl ester groups have pharmacological effects such as strong hypotensive effects,
The present invention was achieved by discovering that the duration of its pharmacological action is extremely long. Therefore, an object of the present invention is to provide a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof, which has excellent pharmacological effects such as hypotensive effect and has a long duration. It's about doing. A further object of the present invention is to provide a method for producing a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof. A further object of the present invention is to provide a drug containing a novel 1,4-dihydropyridine-3,5-dicarboxylic acid diester derivative or an acid addition salt thereof as an active ingredient. 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 [] [R ₁ is a substituted or unsubstituted benzyl group, R ₂
represents a lower alkyl group. ] 1,4-dihydropyridine-3,5 represented by
-Represented by a dicarboxylic acid diester derivative or its acid addition salt. The 1,4-dihydropyridine-
The 3,5-dicarboxylic acid diester derivative has a 2',3'-disubstituted phenyl group at the 4th position and an N-benzyl-3-piperidyl ester group at the 5th position. , is a new compound not disclosed in the literature and has pharmacological effects such as a long-lasting blood pressure lowering effect. In the above formula [], R ₁ is an unsubstituted or substituted benzyl group. Examples of substituents for the benzyl group include halogen atoms such as fluorine atoms and chlorine atoms; lower alkoxy groups such as methoxy, ethoxy, and propoxy groups;
Lower alkyl groups such as methyl, ethyl, and propyl; halogenated lower alkyl groups such as trifluoromethyl and trichloromethyl; and the like. R ₂ is a lower alkyl group, such as methyl,
Examples include ethyl, propyl, iso-propyl, and butyl groups. Among these, R ₂ is preferably a methyl group. A is a bond or a linear or branched alkylene group, such as methylene, ethylene,
Examples include linear alkylene groups such as propylene, butylene, and pentalene; and branched alkylene groups such as 2,2-dimethylpropylene. 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, tartaric acid, maleic acid, etc. Organic carboxylic acids such as acids; methanesulfonic acid,
Examples include organic sulfonic acids such as 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. (100) 2,6-dimethyl-4-(2',3'-dichlorophenyl)-1,4-dihydropyridine-
3,5-dicarboxylic acid-3-methyl ester-
5-(N-benzyl-3-piperidyl) ester, (102) 2,6-dimethyl-4-(2'-chloro-
3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(N-benzyl-3-piperidyl)
Ester, (104) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(N-benzyl- 3-piperidyl) ester, (106) 2,6-dimethyl-4-(3'-chloro-
2′-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(N-benzyl-3-piperidyl) ester, (108) 2,6-dimethyl-4- (3′-chloro-
2′-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(N-benzyl-3-piperidyl)
Ester, (110) 2,6-dimethyl-4-(2'-chloro-
(122) 4-(2′-chloro- 3′-nitrophenyl)
-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-ethyl ester-5-(N-benzyl-3-piperidyl) ester, (124) 2,6-dimethyl-4-( 2'-Fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-propyl ester-5-(N-benzyl-3-piperidyl) ester, (126) 4-(2' -Chloro-3′-nitrophenyl)
-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(N-4-methoxyphenylmethyl-
3-piperidyl) ester, (128) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-( N-Fluorophenylmethyl-
3-piperidyl) ester, (130) 4-(3'-chloro-2'-nitrophenyl)
-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[N-(4-trifluoromethylphenyl)methyl-3-piperidyl] ester, (132) 2,6-dimethyl-4-(2'-fluoro-3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-[N-(2',6'- dichlorophenylmethyl)-3-piperidyl] ester, 1,4-dihydropyridine-3,5- of the present invention
The dicarboxylic acid diester derivative has the following formula [] [In the formula, R ₁ is the same as defined above. ] Acetoacetate compound represented by and the following formula [] [In the formula, X and Y are the same as defined above. ] Aldehyde compounds represented by and the following formula [] In the formula, R ₂ is 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, and R ³ represents methyl or 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 acetoacetate compound of the above formula [] and the 3-aminocrotonic acid ester compound of the above formula [] can be easily produced by a known method [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 may be reacted without a solvent or with lower alcohols such as ethanol, propanol, isopropanol, n-butanol, and t-butanol. ; 30 to 180°C, preferably 50 to 150°C in an organic solvent such as a halogenated hydrocarbon such as chloroform, dichloroethane, or toluchloroethane; or an aromatic compound such as benzene or pyridine.
The heating reaction is usually carried out for 6 to 13 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 diester derivatives can also be converted into corresponding acid addition salts by treatment with an acid by a reaction known per se. Although the compounds provided by the present invention contain two or more asymmetric carbon atoms, all optically active forms and mixtures thereof are included within the scope of the present invention. For example, when two asymmetric carbons are contained, theoretically four types of optical isomers are possible, and the present invention includes these four possible optical isomers and mixtures thereof within the scope of the invention. An optically pure single isomer can be obtained from these optical isomers by an optical selective or stereoselective synthesis method, or by a method using optical resolution from an optical mixture. These optical or stereoselective synthesis methods and optical resolution methods can be carried out by conventionally known methods. 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, and on the other hand, when administered orally, it is easily absorbed and has high bioavailability. 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 made 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. Example 1 2,3-dichlorobenzaldehyde 175mg
(1 mmol), 275 mg (1 mmol) of 3-N-benzylpiperidyl acetoacetate, and 120 mg (1.04 mmol) of methyl 3-aminocrotonate were heated under reflux in 1 ml of isopropanol overnight. The residue obtained by distilling off the reaction solvent was subjected to silica gel chromatography to obtain the desired 4-(2',3'-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3. , 5-dicarboxylic acid-3-methyl ester-5-(N-benzyl-3-piperidyl) ester is a mixture of diastereoisomers.
235 mg (yield 44%) was obtained. It was further separated into two distinct bands by thin layer chromatography. The physical properties of the isomer with high Rf (α-diastereoisomer) and the isomer with low Rf (β-diastereoisomer) are as follows (TLC development conditions: n-hexane: ethyl acetate = 7:3). α-diastereoisomer IR (CHCl ₃ ) ν: 1690, 1614, 1466, 1098 cm ¹ NMR (CDCl ₃ ) δ: 7.45-7.70 (m, 8H), 5.83
(brs, 1H), 5.44 (s, 1H), 4.9 (m, 1H),
3.63 (s, 3H), 3.43 (s, 2H), 2.28 (s, 3H),
2.26 (s, 3H), 2.8−1.3 (m, 8H) Hydrochloride IR (KBr) ν: 3430, 2525, 1692,
1492, 1206, 1114, 1092 cm ¹ β-diastereoisomer IR (CHCl ₃ ) ν: 1692, 1616, 1468, 1102 cm ¹ NMR (CDCl ₃ ) δ: 7.4-7.0 (m, 8H), 5.86
(brs, 1H), 5.44 (s, 1H), 4.8 (m, 1H),
3.62 (s, 3H), 3.48 (s, 2H), 2.28 (s, 6H),
2.7−1.2 (m, 8H) Hydrochloride IR (KBr) ν: 3425, 2525, 1690,
1490, 1206, 1112, 1092cm ¹ Example 2 2-fluoro-3-nitrobenzaldehyde
358 mg (2.12 mmol), acetoacetic acid 3-N-benzylpiperidyl ester 554 mg (2.01 mmol) and methyl 3-aminocrotonate 240 mg (2.09 mmol)
was dissolved in 2 ml of isopropanol and heated under reflux overnight. The residue obtained by distilling off the solvent was subjected to silica gel column chromatography (hexane:ethyl acetate=7:3) to obtain 309 mg of a yellow-orange liquid containing the target product as a main component. Further purification of this by thin layer chromatography yields the desired 4-(2-fluoro-3-nitrophenyl).
-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-
5-(N-benzyl-3-piperidyl) ester was obtained as two bands with different Rf values (the one with the larger Rf value is the α-diastereoisomer and the one with the smaller Rf value is the β-diastereoisomer). . The physical property values are as follows. α-diastereoisomer IR (CHCl ₃ ) ν: 3450, 2950, 1688, 1612,
1466, 1352, 1120, 1100cm ¹ NMR (CDCl ₃ ) δ: 7.7−6.8 (m, 3H), 7.13
(s, 5H), 6.00 (s, 1H), 5.16 (s, 1H), 4.7
(brs, 1H), 3.52 (s, 3H), 3.43 (s, 2H),
2.8−1.2 (m, 8H), 2.24 (s, 6H) Hydrochloride mp: 150−152° IR (KBr) ν: 1688, 1532, 1490, 1352,
1212, 1118, 1094cm ¹ β-diastereoisomer IR (CHCl ₃ ) ν: 3460, 2960, 1690, 1614,
1466, 1352, 1120, 1100cm ¹ NMR (CDCl ₃ ) δ: 7.7−6.8 (m, 3H), 7.09
(s, 5H), 5.88 (s, 1H), 5.16 (s, 1H), 4.7
(brs, 1H), 3.51 (s, 3H), 3.36 (s, 2H),
2.8-1.2 (m, 8H), 2.24 (s, 6H) Hydrochloride mp: 151-153゜ IR (KBr) ν: 1688, 1532, 1490, 1352,
1214, 1118, 1096cm ¹ Example 3 2-fluoro-3-chlorobenzaldehyde
622 mg (3.91 mmol), acetoacetic acid 3-N-benzylpiperidyl ester 1.07 g (3.90 mmol) and methyl 3-aminocrotonate 450 mg
(3.91 mmol) was dissolved in 3 ml of isopropanol and heated under reflux overnight. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography (chloroform: ethyl acetate = 2:1).
The desired 4-(3-chloro-2-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid-3-methyl ester-5-(N-benzyl-3- 605 mg (1.18 mmol, 30%) of a mixture of diastereoisomers of (piperidyl) ester was obtained as a pale yellow powder. The physical property values are as follows. IR (CHCl ₃ ) ν: 3460, 2960, 1690, 1618,
1458, 1124, 1104cm ¹ NMR (CDCl ₃ ) δ: 7.1−6.7 (m, 8H), 5.79
(s, 1H), 5.09 (s, 1H), 4.7 (brs, 1H),
3.52(s, 3H), 3,4(s, 2H), 2.7−1.5
(m, 8H), 2.23 (s, 6H) Example 4 Blood pressure lowering effect upon oral administration: - A catheter was inserted into the femoral artery of male Wistar rats (weighing approximately 250 g) that had fasted for 16 hours or more under ether anesthesia. Afterwards, they were fixed in Bollman cages. 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) = Post-administration mean blood pressure (mmg) - Pre-administration mean blood pressure (mmHg) are shown in Table 1.

[Table] Example 5 Blood pressure lowering effect upon intravenous administration Male Wistar rats weighing approximately 250 g were anesthetized by ip administration of α-chloralose with urethane, and carotid artery pressure was measured. 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 × 100 (
%) Activity display Antihypertensive activity: Less than 5%: ± 5 to less than 10%: + 10 to 15%: ++ The results are as shown in Table 2. As a result of an acute toxicity test of the test substance using male Wistar rats (body weight approximately 250 g), the LD ₅₀ was 150 mg/Kg when administered orally.

[Table] Example 6 Tablets were manufactured according to the following formulation. Compound of Example 1 (main drug) 20 g Polyvinylpyrrolidone 300 g (molecular weight 40,000-50,000) Ethanol 1.5 Calcium carboxymethylcellulose 190 g Magnesium stearate 10 g The above ingredients were mixed and stirred and then compressed to give tablets containing 20 mg of the main drug per tablet. Manufactured. Example 7 Capsules were manufactured according to the following formulation. Compound of Example 1 (main drug) 10 g Lactose 148 g Avicel 100 g Magnesium stearate 2 g The above ingredients were mixed and stirred and filled into hard capsules by a conventional method to produce capsules containing 10 mg of the main drug.

Claims (1)

[Claims] 1. The following formula [] [In the formula, X and Y are the same or different and represent a halogen atom or a nitro group, R ₁ represents a substituted or unsubstituted benzyl group, and R ₂ represents a lower alkyl group. ] 1,4-dihydropyridine-3,5 represented by
-Dicarboxylic acid diester derivatives or acid addition salts thereof. 2 The following formula [] [In the formula, R ₁ represents a substituted or unsubstituted benzyl group. ] Acetoacetate represented by and the following formula [] [In the formula, X and Y are the same or different and represent a halogen atom or a nitro group. ] Benzaldehyde compound represented by and the following formula [] [In the formula, R ₂ represents a lower alkyl group. ] The following formula [ ], which is characterized by reacting with 3-aminocrotonic acid ester represented by [ ] and then subjecting it to a salt-forming reaction as necessary. [In the formula, X, Y, R ₁ and R ₂ are the same as defined above. ] 1,4-dihydropyridine-3,5 represented by
-Production method of dicarboxylic acid ester derivatives or acid addition salts thereof. 3 The following formula [] [In the formula, X and Y are the same and represent a halogen atom, R ₁ represents a substituted or unsubstituted benzyl group, and R ₂ represents a lower alkyl group. ] 1,4-dihydropyridine-3,5 represented by
-An antihypertensive agent containing a dicarboxylic acid ester derivative or its acid addition salt as an active ingredient.