JPH0674268B2 - Novel 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative - Google Patents

Description

The present invention relates to a novel 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative, more specifically, the following general formula (I): [Wherein R is an imidazolyl group or a pyridyl group, R ₁ is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, R ₂ is a lower alkyl group, A is a lower alkylene group, (B is a lower alkylene group or an O-lower alkylene group), (R ₄ is a hydrogen atom or a lower alkyl group) or a vinylene group, m is an integer of 4 to 12 and n is 1 or 2], and a 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative .

[Conventional technology and its problems]

Heretofore, 1,4-dihydropyridine-3,5-dicarboxylic acid derivatives have been known to have pharmacological actions such as vasodilator action, and various compounds have been synthesized so far, and their pharmacological actions have been investigated. It is being appreciated. For example, Nifedipin [Batale, W. (Vater, W. et al), Arzneim. Forsch, 22 , 1
(1972)], Nicardipine [Takenaka, Te. Etc. (Take
naka, T. et al), Arzneim. Forsch, 26 , 2172 (1976)], etc. are already on the market.

In addition, studies have been conducted to add compounds having various pharmacological effects to these dihydropyridines to add a pharmacological effect other than vasodilatory effect. For example, a compound having an inhibitory effect on platelet aggregation combined with an imidazole derivative. Have been reported (Japanese Patent Laid-Open Nos. 56-140989 and 60-2156).
No. 84).

However, these are not always satisfactory, and it has been desired to develop a derivative having a further excellent drug effect.

[Means for solving problems]

Under such circumstances, the present inventor has conducted earnest research and found that the novel 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative represented by the general formula (I) has excellent drug efficacy.

That is, the compound (I) of the present invention has a vasodilatory action, a blood flow increasing action, a platelet aggregation inhibiting action, a thromboxane A ₂ production inhibiting action, etc. It is a compound useful as a medicine such as a curing agent.
In particular, since the compound (I) of the present invention has both a coronary blood flow increasing action and a thromboxane A ₂ production inhibiting action, it is particularly advantageous as a therapeutic agent for arteriosclerosis. Further, the compound (I) of the present invention is compared with the above-mentioned nifedipine and nicardipine.
Has a long duration of increasing action on coronary artery and vertebral artery blood flow, and has a weak heart rate increasing action.

The compound (I) of the present invention can be produced, for example, by any of the following methods A to D.

Method A: Hantzsch Pyridine Synthesi
s, a. The compound (I) of the present invention is produced according to the following reaction formula by applying Hansyu (A. Hantzsch), Annalen der Chemie 215,1,72 (1882)] or a modification thereof. The symbols in the formula have the same meanings as described above.

A-1; A-2; A-3; A-4; A-5; (VII) + (V) → (I) A-6; A-7; (VIII) + (VI) → (I) Among the production methods of A-1 to A-7 above, A-1 is a Hansiu pyridine synthesis method, and A-2 to A-7 are variations thereof. Is the law.

The reaction of A-1 to A-7 is carried out in a solvent or without a solvent in the range of 30 to 30.
It is carried out by heating at 180 ° C, preferably 50 to 130 ° C for 2 to 24 hours. As the solvent, lower alcohols such as ethanol, propanol, isopropanol and n-butanol, halogenated hydrocarbons such as chloroform, dichloroethane and trichloroethane, benzene and pyridine can be used.

Method B: The compound (I) of the present invention is produced by reacting the compound (IX) with the compound (X). This reaction is carried out, for example, by reacting compound (IX) with N, N′-carbonyldiimidazole and then reacting compound (X) in an insoluble solvent. At this time, 1,8-
It is also possible to use diazabicyclo [5.4.0] -7-undecene (hereinafter referred to as DBU), sodium alcoholate, imidazole / alkali metal salt and the like. As the insoluble solvent, tetrahydrofuran, dioxane, chloroform, methylene chloride, N, N-dimethylformamide,
Dimethyl sulfoxide or the like is used. The reaction proceeds by stirring at room temperature or under heating for 1 to 24 hours to give compound (I).

Compound (I) can also be obtained by introducing compound (IX) into an acid halide according to a conventional method and reacting it with compound (X).

Compound (IX), which is a starting material, is a known compound [Chem. And Pharmacy Bulletin (Chem.Pharm.Bull.), 27 , 1426 (197).
9)], and can be manufactured by various methods.

Method C: The compound (I) of the present invention is produced by reacting the compound (XI) with the compound (XII). This reaction is carried out, for example, in a dicyclohexylcarbodiimide (DC
It is carried out in the presence of a dehydrating agent such as C). At this time, 4-dimethylaminopyridine, 4-pyrrolidinopyridine, or the like can be used as the reaction accelerator. In addition, the compound (XI
The imidazolide derivative obtained by reacting I) with N, N′-carbonyldiimidazole can also be reacted with compound (XI). When this is done, the compound (I) is obtained in each case.

In addition, the starting compound (XI) of this method C is
Manufactured according to the method of 7 or the compound (IX) and the formula
HO- (CH ₂₎ a compound of mOH is connexion produced by the reacting in the same manner as the method C.

Method D: The compound (I) of the present invention is produced by reacting the compound (XIII) with imidazole or pyridine represented by the formula RH. Imidazole is preferably used as an alkali metal salt, and pyridine is used, for example, as pyridyllithium obtained by reacting brompyridine with n-butyllithium at -35 ° C. or similarly obtained pyridylalkyllithium. preferable. The reaction is carried out in an inert solvent such as ether or tetrahydrofuran at -80 to
It is advantageous to proceed at a temperature of −30 ° C. for a few minutes to 1 hour.

In addition, the starting compound (XIII) of this method D is
According to the method of A-7 or by adding compound (IX) to the formula By reacting the compound represented by
Alternatively, it is produced by reacting compound (XI) with a compound represented by the formula HOCO-A-Hal in the same manner as in Method C.

Further, in the above methods B to D, using the N-protected compound of compound (IX), compound (XI), or compound (XIII), the reaction is carried out, and then the protecting group is eliminated. Therefore, the compound (I) of the present invention can be obtained. Here, as the N-protecting group, for example, a methoxymethyl group,
An ethoxymethyl group or the like can be used, and these can be easily eliminated by hydrolysis after completion of the reaction.

The compound of formula (I) thus obtained is an inorganic or organic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, acetic acid, citric acid, maleic acid or tartaric acid according to a conventional method. Can lead to salt.

[Action]

The pharmacological effects of the representative compounds of the present invention are shown below.

(1) Thromboxane synthase inhibitory action [In vitro, malondialdehyde (MDA) production inhibitory action] (Measurement method) 500 μl of rabbit washed platelets, the substance solution of the present invention (dissolved in ethanol and diluted with physiological saline to a predetermined concentration) 20μ
1 and pre-incubate at 37 ° C for 5 minutes.
Then, 20 μl of 1.25 mM sodium arachidonic acid solution is added and incubated at 37 ° C. for 5 minutes, and then 2.5 ml of 20% trichloroacetic acid solution is added to stop the reaction. to this
Add 1 ml of 0.67% thiobarbituric acid solution and react at 100 ° C for 30 minutes. After cooling with water, extract with 2 ml of n-butyl alcohol and perform fluorescence analysis (excitation wavelength 515 nm, fluorescence wavelength 548 nm)
Calculate MDA production.

(Results) As shown in Table 1. The result is 30% inhibition concentration [IC
₃₀ (M)].

(2) Blood flow increasing action (measuring method) An adult dog anesthetized by intravenously administering pentobarbital 30 mg / Kg was used, and the substance of the present invention (dissolved in 0.1N hydrochloric acid) was intravenously administered for 30 seconds under artificial respiration. Then, the coronary blood flow was measured by attaching an electric blood flow meter probe to the left convolution technique. The dose was varied and a dose-dependent curve was applied to determine the 100% increase.

(Results) As shown in Table 2. The result is 100% increased dose [H
D ₁₀₀ ].

The compound of the present invention has an extremely strong thromboxane synthase inhibitory action. In addition, the compound of the present invention also has an effect of increasing blood flow in coronary arteries and vertebral arteries, and is characterized in that its action duration is long.

These actions of the compound of the present invention indicate that the compound of the present invention is useful not only as a vasodilator but also as a therapeutic agent for arteriosclerosis.

When the compound of the present invention is used as a pharmaceutical composition, a liquid or solid carrier or diluent may be used. Examples of these carriers include known excipients, binders, lubricants, emulsifiers and the like in the production of pharmaceutical compositions. Examples of carriers or diluents are starches such as potato starch, wheat starch, corn starch and rice starch; sugars such as lactose, sucrose, glucose, mannitol and sorbitol; crystalline cellulose, carboxycellulose calcium and hydroxy with a small amount of substitution. Propylcelluloses; Inorganic substances such as potassium phosphate, calcium sulfate, calcium carbonate and talc; Binders such as gelatin, gum arabic, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone and hydroxypropylcellulose; fatty acid monoglyceride, sorbitan fatty acid ester, sucrose and Polyhydric alcohol ester anion surfactants such as fatty acid esters; and polyoxyethylene anion field Active agents.

These pharmaceutical compositions can be in any pharmaceutically known dosage forms such as suppositories, powders, granules, tablets, sublingual tablets, solutions, injections and suspensions.

The pharmaceutical composition of the compound of the present invention may be administered orally or parenterally such as intravenously, sublingually or rectally. However, oral administration is preferred for long-term administration.

Although the dose may be changed as necessary, for example, the compound (I) of the present invention may be administered at about 1 to 500 mg / body / day, preferably 50 to 200 mg / body / day. The compound of the present invention has an acute toxicity value (LD ₅₀ ) of about 300 mg / orally when orally administered.
Kg (rat), 30 to 50 mg / Kg for intravenous administration
(Rat) and has extremely low toxicity.

〔Example〕

 Next, examples will be described.

Example 1 1,4-dihydro-3-methoxycarbonyl-1-methoxymethyl-2,6-dimethyl-4- (2,3-dichlorophenyl) -5-pyridinecarboxylic acid 219 mg anhydrous N, N-dimethylformamide solution To this, 159 mg of N, N'-carbonyldiimidazole was added, and the mixture was stirred at 35 ° C for 1 hour. Then,
4- [2- (1H-imidazol-1-yl) ethoxy]
Benzoic acid 4-hydroxybutyl ester 316 mg and 1,8-
0.05 ml of diazabicyclo [5.4.0] -7-undecene (abbreviated as DBU) was added, and the mixture was stirred at 80 ° C. for 6 hours. After the reaction
After adding a saturated ammonium chloride aqueous solution to the reaction mixture, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried, then the solvent was evaporated and the obtained residue was purified by silica gel column chromatography to give 1,4-dihydro-1-methoxy as a colorless oil. Methyl-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinecarboxylic acid 3-methyl ester 5- [4- [4- [4- [2- (1H-imidazol-1-yl) ethoxy] benzoyl Oxy] butyl] ester 36
0 mg (96% yield) was obtained.

NMR (CDCl ₃ ) δ: 1.60-1.90 (4H, m, -CH ₂ (CH ₂ ) ₂ (CH
₂₋ ), 2.42 and 2.48 (3H × 2, s × 2, −CH ₃ × 2), 3.36
(3H, s, −OCH ₃ ), 3.66 (3H, s, −COOCH ₃ ), 4.13 (2H, t, J
= 6.1Hz, 4.24 (2H, t, J = 6.2Hz, 4.27 (2H, t, J = 4.9Hz, 4.37 (2H, t, J = 4.9Hz, −OCH ₂ −), 4.80 (2H, s, NCH ₂ O
−), 5.50 (1H, s, C ₄ −H), 6.89 (2H, d, J = 8.8Hz, 7.03 (1H, t, J = 7.5Hz, 7.05 and 7.08 (1H × 2, s × 2, 7.15 (1H, dd, J = 7.5,1.8Hz, 7.22 (1H, dd, J = 7.5,1.8Hz, 7.60 (1H, s, 7.98 (2H, d, J = 8.8Hz, 0.30 ml of 6N hydrochloric acid was added to a tetrahydrofuran solution of the obtained imidazole compound (304 mg), and the mixture was stirred at room temperature for 1.5 hours.
A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture to make it alkaline, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried, then the solvent was evaporated and the obtained residue was purified by silica gel column chromatography to give 1,4-dihydro-2,6-dimethyl-
4- (2,3-dichlorophenyl) -3,5-pyridinecarboxylic acid 3-methyl ester 5- [4- [4- [2-
(1H-imidazol-1-yl) ethoxy] benzoyloxy] butyl] ester (Compound 1) 185 mg (yield 65
%) Was obtained.

Molecular formula C ₃₂ H ₃₃ Cl ₂ N ₃ O ₇ Colorless viscous oil NMR (CDCl ₃ ) δ: 1.85-1.55 (4H, m, -CH ₂ (CH ₂ ) ₂ (CH
₂₋ ), 2.31 (6H × 2, s, −CH ₃ × 2), 3.61 (3H, s, −COOCH
₃ ), 4.04 and 4.15 (1H, 2, dt × 2, J = 11.2,6.0Hz, 4.24 (2H, t, J = 6.2Hz, 4.28 (2H, t, J = 4.8Hz, -CH ₂ N), 4.38 (2H, t, J = 4.8H
z, −OCH ₂ −), 5.44 (1H, s, C ₄ −H), 5.99 (1H, broads,
NH), 6.88 (2H, d, J = 8.9Hz, 7.05 (1H, t, J = 7.8Hz, 7.05 and 7.09 (1H × 2, s × 2, 7.21 (1H, dd, J = 7.8,1.8Hz, 7.30 (1H, dd, J = 7.8,1.8Hz, 7.61 (1H, s, 7.97 (2H, d, J = 8.9Hz, Example 2 To a solution of 6-bromohexanoic acid (300 mg) in anhydrous N, N-dimethylformamide was added N, N'-carbonyldiimidazole 324.
mg was added, and the mixture was stirred at room temperature for 70 minutes. Then 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-
3,55-Pyridinecarboxylic acid 3-ethyl ester 5-
644 mg of (4-hydroxybutyl) ester was added.
Further, imidazole 220 mg was added to an anhydrous N, N-dimethylformamide suspension of 50% sodium hydride 148 mg, and a solution obtained by stirring at room temperature until hydrogen generation was completed was added, and then stirred at room temperature for 20 hours. . After the reaction, 60 ml of a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate solution and then saturated brine, and dried. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography to give 1,4-dihydro-2,6-dimethyl-4-
(3-Nitrophenyl) -3,5-pyridinecarboxylic acid 3
-Ethyl ester 5- [4- [6- (1H-imidazol-1-yl) hexanoyloxy] butyl] ester (Compound 2) 640 mg (yield 71%) was obtained.

Molecular formula C ₃₀ H ₃₈ N ₄ O ₈ Yellow viscous oil NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.1, .CH ₂ CH ₃ ), 1.2-1.
_{9 (10H, m, -CH 2} (CH 2) 2 (CH 2 -), and -CH ₂ (C
H ₂ ) ₃ CH ₂ −), 2.30 (2H, t, J = 7.3Hz, −CH ₂ COO−), 2.36
(6H, s, −CH ₃ × 2), 3.91−4.28 (8H, m, −COOCH ₂ − × 2,
-COOCH ₂ CH ₃ and _{-CH 2 N), 5.09 (1H} , s, C 4 -H), 6.
94 and 7.06 (1H x 2, s x 2, 7.37 (1H, t, J = 7.8Hz, 7.40 (1H, broads, NH), 7.50 (1H, s, 7.65 (1H, dt, J = 7.8,18Hz, 7.99 (1H, ddd, J = 7.8,2.0,1.8Hz, 8.14 (1H, s, Examples 3 to 13 The following compounds were obtained in the same manner as in Example 1 or 2.

Compound 3 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinecarboxylic acid 3-ethyl ester 5- [4- [4- [2- [1H-imidazole-1 −
YL) ethoxy] benzoyloxy] butyl] ester Molecular formula C ₃₂ H ₃₄ N ₄ O ₉ Yellow amorphous powder NMR (CDCl ₃ ) δ: 1.6-1.9 (4H, broad m, -CH ₂ (CH ₂ ) ₂
(CH ₂ −), 2.35 (6H, s, −CH ₃ × 2), 3.64 (3H, s, −COOC
_{H 3), 4.00-4.20 (2H,} m, 4.22-4.43 (6H, m, _{5.08 (1H, s, C 4} -H), 6.88 (2H, d, J = 9.0Hz, 7.08 (2H, s, 7.17 (1H, s, NH), 7.34 (1H, t, J = 8Hz, 7.63 (1H, s, 7.95 (2H, d, J = 9Hz, 8.11 (1H, broad t, J ＝ 2Hz, Compound 4 1,4-dihydro-2,6-dimethyl-4- (3-chlorophenyl) -3,5-pyridinecarboxylic acid 3-methyl ester 5- [4- [4- [2- [1 (H-imidazole-1 −
Ill) ethoxy] benzoyloxy] butyl] ester molecular formula C ₃₂ H ₃₄ ClN ₃ O ₇ colorless amorphous powder _{NMR (CDCl 3) δ: 1.85-1.55} (4H, m, -CH 2 - (CH 2) 2 -
(CH ₂ −), 2.30 and 2.31 (3H × 2, s × 2, −CH ₃ × 2),
3.61 (3H, s, −COOCH ₃ ), 4.06 and 4.14 (1H × 2, dt × 2,
J = 10.7,5.9Hz, 4.23 (2H, t, J = 5.4Hz, 4.27 (2H, t, J = 4.5Hz, -CH 2 -CH 2 -N), 4.38 (2H, t,
_{J = 4.5Hz, -O-CH 2} CH 2 -), 5.37 (1H, s, C 4 -H), 5.78
(1H, broad, NH), 6.88 (2H, d, J = 9.0Hz, 7.00 and 7.11 (1H × 2, dt × 2, J = 1.4, 7.5Hz, 7.05 and 7.08 (1H × 2, s × 2, 7.20 (1H, dd, J = 1.4,7.5Hz, 7.37 (1H, dd, J = 1.4,7.5Hz, 7.60 (1H, s, 7.97 (2H, d, J = 9.0Hz, Compound 5 1,4-dihydro-2,6-dimethyl-4- (2-fluorphenyl) -3,5-pyridinedicarboxylic acid 3-methyl ester 5- [4- [4- [2- [1H-imidazole −
1-yl) ethoxy] benzoyloxy] butyl] ester molecular formula C ₃₂ H ₃₄ FN ₃ O ₇ colorless amorphous powder _{NMR (CDCl 3) δ: 1.80-1.55} (4H, m, -CH 2 (CH 2) 2 CH
₂ −), 2.32 (6H, s, −CH ₃ × 2), 3.61 (3H, s, −COOC
H ₃ ), 4.12 and 4.02 (1H × 2, dt × 2, J = 10.5,6.9Hz, 4.25 (2H, t, J = 4.4Hz, 4.27 (2H, t, J = 4.6Hz, -CH ₂ N), 4.38 (2H, t, J = 4.6H
z, −OCH ₂ −), 5.23 (1H, s, C ₄ −H), 5.83 (1H, broad,
NH), 6.88 (2H, d, J = 9.0Hz, 7.05 and 7.08 (1H x 2s x 2, 7.61 (1H, s, 7.98 (2H, d, J = 9.0Hz, Compound 6 1,4-dihydro-2,6-dimethyl-4- (2-trifluoromethylphenyl) -3,5-pyridinedicarboxylic acid 3
- methyl ester 5- [4- [4- [2-(1H-imidazol-1-yl) ethoxy] benzoyloxy] butyl] ester molecular formula C ₃₃ H ₃₄ F ₃ O ₇ colorless amorphous powder _{NMR (CDCl 3) δ: 1.85-1.55} (4H, m, -CH 2 - (CH 2) 2 CH 2
−), 2.30 (6H, s, −CH ₃ × 2), 3.58 (3H, s, −COOCH ₃ ),
4.14 and 4.02 (1H × 2, dt × 2, J = 10.9, 5.8Hz, 4.22 (2H, t, J = 6.1Hz, 4.28 (2H, t, J = 4.8Hz, -CH ₂ N), 4.38 (2H, t, J = 4.8H
_{z, -O-CH 2 -)} , 5.54 (1H, s, C 4 -H), 5.98 (1H, broa
d, NH), 6.88 (2H, d, J = 8.9Hz, 7.05 and 7.08 (1H x 2, s, x 2, 7.20 (1H, t, J = 7.6Hz, 7.39 (1H, t, J = 7.6Hz, 7.45 (1H, d, J = 7.6Hz, 7.53 (1H, d, J = 7.6Hz, 7.61 (1H, s, 7.97 (2H, d, J = 8.9Hz, Compound 7 3,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-ethyl ester 5- [4- [4- (1H-imidazol-1-ylmethyl) Benzoyloxy] butyl] ester Molecular formula C ₃₂ H ₃₄ N ₄ O ₈ Light yellow amorphous powder _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.0Hz, -CH 2 - (CH 3),
1.62-1.90 (4H, m, −CH ₂ (CH ₂ ) ₂ CH ₂ −, 2.36 (6H, s, −C
H ₃ × 2), 4.04−4.44 (4H, m, −COOCH ₂ − × 2), 4.11 (2
H, q, J = 7.0Hz, -COOCH 2 CH 3), 5.12 (1H, s, C 4 -H), 5.2
2 (2H, s, -CH ₂ N), 6.44 (1H, s, NH), 6.95 and 7.1
5 (1H x 2, s x 2, 7.22 (2H, d, J = 8.0Hz, 8.03 (2H, d, J = 8.0Hz, 8.15 (1H, t, J = 1.5Hz, Compound 8 3,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid ethyl ester 5- [4- [4- [6- [1H-imidazol-1-yl ) Hexyloxy] benzoyloxy] butyl] ester Molecular formula C ₃₇ H ₄₄ N ₄ O ₉ Yellow viscous oil _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.2Hz, -CH 2 CH 3), 1.3
−1.9 (12H, m, −CH ₂ (CH ₂ ) ₄ CH ₂ − and −CH ₂ (CH ₂ ) ₂
CH-), 2.36 and 2.37 (3H x 2, s x 2, -CH ₃ x 2), 3.9
_{-4.3 (10H, -COOCH 2 - ×} 3, -O-CH 2 - and -CH ₂ N
), 5.09 (1H, s, C ₄ -H), 6.90 (1H, s, NH), 6.93 and 7.06 (1H × 2, s × 2, 7.34 (1H, td, J = 8.0,1.8Hz, 7.96 (1H, ddd, J = 8.0,2.0,1.8Hz, 8.13 (1H, t, J = 2.0Hz, Compound 9 3,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-dicarboxylic acid 3-ethyl ester 5-
[4- [3- (3-pyridyl) acryloyloxy] butyl] ester molecular formula C ₂₉ H ₃₁ N ₃ O ₈ pale yellow prisms Mp139-141 ° C. NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.5Hz, -CH ₂ CH ₃ ), 1.54
_{-1.89 (4H, m, -CH 2} (CH 2) 2 CH 2 -), 2.35 and 2.39
(3H x 2, s x 2, -CH ₃ x 2), 4.12 (2H, q, J = 7.5Hz, -CO
OCH ₂ CH ₃ ), 4.00−4.32 (4H, m, −COOCH ₂ − × 2), 5.15
(1H, s, C ₄ -H), 5.98 (1H, s, NH), 6.54 (1H, d, J = 1
7.0Hz, -CH = CH-COO-), 7.73 (1H, d, J = 17.0Hz, 8.63-8.90 (2H, m, Compound 10 3,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-dicarboxylic acid 3-ethyl ester 5-
[4- [2-Methyl-3- [4- (3-pyridylmethyl) phenyl] acryloyloxy] butyl] ester Molecular formula C ₃₇ H ₃₉ N ₃ O ₈ Light yellow viscous oil _{NMR (CDCl 3) δ: 1.22} (3H, t, J = 7.0Hz, -CH 2 CH 3), 1.55
−1.92 (4H, m, −CH ₂ (CH ₂ ) ₂ CH ₂ −), 2.11 (3H, s 2.37 (6H, s, −CH ₃ × 2), 3.94−4.56 (6H, m, −COOCH ₂ −
× 3), 4.02 (2H, s, 5.13 (1H, s, C ₄ -H), 6.11 (1H, s, NH), 8.04 (1H, d, J
= 8.0Hz, 8.18 (1H, s, 7.95-8.30 (1H, m, 8.48-8.62 (2H, m, Compound 11 3,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-methyl ester 5- [6- [4- [2- [1H-imidazole-1
- yl) ethoxy] benzoyloxy] hexyl] ester molecular formula C ₃₄ H ₃₈ N ₄ O ₉ yellow viscous oil NMR (CDCl ₃ ) δ: 1.2-1.8 (8H, m, -CH ₂ (CH ₂ ) ₄ CH
₂₋ ), 2.35 and 2.36 (3H × 2, s × 2, −CH ₃ × 2), 3.64
(3H, s, −COOCH ₃ ), 3.93−4.16 (2H, m, 4.22-4.43 (6H, m, -OCH ₂ - and _{CH 2 N), 5.08 (1H} , s, C 4 -H), 6.67 (1
H, s, NH), 6.88 (2H, d, J = 9.0Hz, 7.07 and 7.09 (1H × 2, s, × 2, 7.36 (1H, t, J = 7.8Hz, 7.60−7.67 (2H, broad m, and 7.97 (2H, d, J = 9.0Hz, 8.11 (1H, t, J = 2.0Hz, Compound 12 3,4-Dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-ethyl ester 5- [8- [4- [2- (1H-imidazole-1
-Yl) ethoxy] benzoyloxy] octyl] ester Molecular formula C ₃₇ H ₄₄ N ₄ O ₉ Light yellow viscous oil NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0Hz, −CH ₂ CH ₃ ), 1.20
_{-1.88 (12H, m, -CH 2} (CH 2) 4 CH 2 -), 2.39 (6H, s, -CH
₃ x 2), 4.08 (2H, t, J = 6.0Hz, 4.12 (2H, q, J = 7.0Hz, −COOCH ₂ CH ₃ ), 4.20−4.54 (6H,
m, And -OCH ₂ CH ₂ N), 5.15 (1H, s, C ₄ -H), 6.81 (1H,
s, NH), 6.93 (2H, d, J = 9.0Hz, 7.13 (2H, s, 7.40 (1H, t, J = 8.0Hz, 7.69 (1H, s, 7.72 (1H, d, J = 7.0Hz, 7.90-8.16 (1H, m, 8.04 (2H, d, J = 9.0Hz, 8.21 (1H, t, J = 1.5Hz, Compound 13 3,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-ethyl ester 5- [12- [3- [4- (1H-imidazole-1
-Ylmethyl) phenyl] acryloyloxy] dodecyl] ester Molecular formula C ₃₂ H ₅₂ N ₄ O ₈ Light yellow viscous oil _{NMR (CDCl 3) δ: 1.12-1.84} (23H, m, -CH 2 (CH 2) 10 CH 2
− And −CH ₂ CH ₃ ), 2.38 (6H, s, −CH ₃ × 2), 4.01 (2
H, t, J = 7.0Hz, 4.12 (2H, q, −COOCH ₂ CH ₃ ), 4.24 (2H, t, J = 7.0Hz, −CH
_{= CH-COOCH 2 -),} 5.14 (1H, s, C 4 -H), 5.18 (2H, s, -
CH ₂ N), 6.46 (1H, d, J = 16.0Hz, -CH = CH-COO-), 6.
97 and 7.15 (1H x 2, s x 2, 7.04 (1H, s, NH), 7.28 (2H, d, J = 8.0Hz, 7.39 (1H, t, J = 7.0Hz, 7.56 (2H, d, J = 8.0Hz, 7.62 (1H, s, 7.71 (1H, d, J = 16.0Hz, 7.73 (1H, d, J = 7.0Hz, 8.05 (1H, d, J = 7.0Hz, 8.19 (1H, t, J = 1.5Hz,

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical display area A61K 31/455 ACB AED 7431-4C C12N 9/99 (C07D 401/12 211: 00 9165-4C 213 : 00) 8217-4C (C07D 401/12 211: 00 9165-4C 233: 00) 9360-4C

Claims (1)

[Claims] 1. A general formula (I) [Wherein R is an imidazolyl group or a pyridyl group, R ₁ is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group, R ₂ is a lower alkyl group, A is a lower alkylene group, (B is a lower alkylene group or an O-lower alkylene group), (R ₄ is a hydrogen atom or a lower alkyl group) or a vinylene group, m is an integer of 4 to 12, and n is 1 or 2.] 1,4-dihydropyridine-3,5-dicarboxylic acid ester derivative .