JPH068294B2 - Novel 1,4-dihydropyridine derivative and salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides a compound represented by the general formula (I): "In the formula, R ¹ and R ⁵ are the same or different and each is a lower alkyl group; R ² is a pyridyl or an imidazolyl group;
R ³ is a phenyl group which may be substituted with one or more substituents selected from halogen atom, trihalo lower alkyl group and nitro group; R ⁴ is an esterified carboxyl group; R ⁶ is Hydrogen atom, lower alkyl group, aryl group or aralkyl group; A is alkylene,
An alkyleneoxyalkylene or alkylenethioalkylene group; B is an alkylene or alkenylene group or a bond; Y is a vinylene group; Z is an oxygen or sulfur atom or an alkylene group. ] The novel 1,4-dihydropyridine derivative represented by these and its salt.

[Conventional technology]

Conventionally, 2,6-dimethyl-4- (2-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
Dimethyl ester (generic name: nifedipine, US Patent No.
3,644,627) and 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-
1,4-Dihydropyridine derivative such as dicarboxylic acid-3- [2- (N-benzyl-N-methylamino) ethyl] ester-5-methyl ester / hydrochloride (generic name: nicardipine, JP-B-55-45075) Is known to be useful as a therapeutic agent for cerebral circulatory disorders and cardiac circulatory disorders.

[Problems to be solved by the invention]

However, all of them have strong vasodilatory effects, but their effects on the thrombus, which is one of the causes of cerebral and cardiac circulatory disorders, are not sufficient.

Therefore, it has been desired to develop a compound having not only a vasodilatory action but also a platelet aggregation inhibitory action.

[Means for solving problems]

Under such circumstances, the inventors of the present invention have conducted diligent research, and as a result, the carboxyl group of the conventionally known 1,4-dihydropyridine derivative has the general formula [Wherein R ¹ , R ⁶ , A, B, Y and Z have the same meanings as described above], that is, a compound having a group represented by the general formula (I) The 4-dihydropyridine derivative and its salt have not only a vasodilatory action but also an excellent platelet aggregation action, and are extremely useful as vasodilators, antihypertensive agents, antithrombotic agents, therapeutic agents for cerebral and cardiac circulatory disorders. The present invention has been completed and the present invention has been completed.

Hereinafter, the compound of the present invention will be described in detail.

In the present specification, the lower alkyl group means a C _1-4 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; the lower alkoxy group means methoxy. , Ethoxy, n
A C _1-4 alkoxy group of -propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy; an aryl group is, for example, phenyl,
A group such as naphthyl; an aralkyl group is, for example,
A substituted or unsubstituted aryl-lower alkyl group such as benzyl, phenethyl, methylbenzyl, chlorobenzyl and methoxybenzyl; an alkylene group is, for example, methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1 - a C _{1 to 6} alkylene groups such as methyl trimethylene; is alkylene oxyalkylene group, for example, methyleneoxy, ethylene oxyethylene, _{Cl to 6} alkyleneoxy C ₁ having an oxygen atom in the chain, such as propylene polyoxyethylene _{~ 6} alkylene group; alkylenethioalkylene group is, for example, methylenethioethylene, ethylenethioethylene, propylenethioethylene and the like having a sulfur atom in the chain C
_1-6 alkylenethio C _1-6 alkylene group; and an alkenylene group, for example, a C _2-4 alkenylene group such as propenylene, methylpropenylene; a halogen atom,
For example, it means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Examples of the trihalo lower alkyl group as the substituent of the optionally substituted phenyl group of R ³ include trifluoromethyl.

Examples of the ester-forming group in the esterified carboxyl group of R ⁴ include ester-forming groups generally known in the art. Examples of the ester-forming group include a lower alkyl group; methoxyethyl, methoxypropyl, Lower alkoxy-lower alkyl groups such as ethoxyethyl, propoxyethyl, butoxyethyl; lower alkylthio-lower alkyl groups such as methylthioethyl, ethylthioethyl, propylthioethyl, butylthioethyl; N, N-dimethylaminoethyl, N, N, N-di (lower alkyl) amino-lower alkyl groups such as N-diethylaminoethyl, N, N-dipropylaminoethyl and the like;
N-aralkyl-N-lower alkylamino-lower alkyl groups such as N-benzyl-N-methylaminoethyl, N- (4-chlorobenzyl) -N-methylaminoethyl, N-benzyl-N-methylaminopropyl N-aryl-N such as N-phenyl-N-methylaminoethyl
-Lower alkylamino-lower alkyl group; groups such as N, N-dialkylalkylamino-lower alkyl group such as N, N-dibenzylaminoethyl and the like can be mentioned.

Y is an oxygen or sulfur atom or a vinylene group. The salt of the 1,4-dihydropyridine derivative of the general formula (I) may be a pharmaceutically acceptable salt, and examples thereof include hydrochloric acid and hydrobromic acid. , Salts with mineral acids such as sulfuric acid, phosphoric acid; salts with organic carboxylic acids such as formic acid, acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid; methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid , And salts with inorganic acids and organic acids such as salts with sulfonic acids such as hydroxybenzene sulfonic acid, dihydroxybenzene sulfonic acid and naphthalene sulfonic acid.

The compound of the present invention includes optical isomers, geometric isomers and tautomers, and further includes all hydrates and crystal forms.

The 1,4-dihydropyridine derivative of the general formula (I) or a salt thereof can be produced by a method known per se, for example, the method shown below.

[In the formula, R ⁷ represents a halogen atom, an alkanesulfonyloxy group or an arenesulfonyloxy group, D represents an alkylene group or an alkenylene group, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and A , B, Y and Z have the same meaning as described above. Process 1 The compounds of general formula (I) are obtained by reacting the compounds of general formulas (II), (III) and (IV) in the presence or absence of a solvent. The solvent used may be any one that does not adversely affect the reaction, for example, alcohols such as methanol, ethanol, 2-propanol, butanol, ethylene glycol and methyl cellosolve; aromatic hydrocarbons such as benzene and toluene. Halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane; Ethers such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane; Esters such as ethyl acetate and butyl acetate; Nitriles such as acetonitrile Carboxylic acids such as acetic acid, propionic acid and dichloroacetic acid; amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and water, and these solvents may be used in combination of two or more. Good.

In this reaction, the amount of the compounds of general formulas (II) and (III) used is 0.5 to 2.0, respectively, with respect to the compound of general formula (IV).
A double mole is preferable. In addition, this reaction is at 30 to 150 ° C,
It may be carried out for 1 to 24 hours.

Process 2 The compound of general formula (I) is obtained by reacting the compound of general formula (V) with the compound of general formula (VI) or a salt thereof in the presence or absence of a deoxidizing agent and a solvent. As the deoxidizing agent used, for example, amines such as triethylamine, diisopropylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, etc., and as a solvent, those not adversely affecting the reaction may be used. For example, the same solvents as those described in the production method 1 may be mentioned. Examples of the salt of the compound of the general formula (VI) include salts with mineral acids such as hydrochloric acid and hydrobromic acid.

In this reaction, the amount of the compound of the general formula (VI) used is preferably 0.5 to 1.0 times the mol of the compound of the general formula (V),
Further, the amount of the deoxidizing agent used may be equimolar or more to the compound of the general formula (VI), but it can also serve as a solvent by using an excessive amount. In addition, this reaction is 30
It may be carried out at ~ 120 ° C for 10 minutes to 20 hours.

Production Method 3 Among the compounds of the general formula (I), R ⁶ is a hydrogen atom (the compound of the general formula (X)), and the compound of the general formula (VII) and the compound of the general formula (VIII) are subjected to dehydration condensation reaction. It can also be obtained by subjecting the compound of general formula (IX) obtained by subjecting it to a reduction reaction.

The dehydration condensation reaction is carried out, for example, in a solvent such as aromatic hydrocarbons such as benzene and toluene; alcohols such as ethanol and 2-propanol; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane, if necessary. For example, it is carried out in the presence of an acid catalyst such as p-toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid and / or a dehydrating agent such as molecular sieves. In this reaction,
The amount of the compound of the general formula (VIII) used is preferably 1.0 to 1.5 times the mol of the compound of the general formula (VII). Moreover, this reaction may be carried out at 30 to 120 ° C. for 1 to 12 hours. The compound of formula (IX) thus obtained may be subjected to the next reaction without isolation.

The reduction reaction is carried out by allowing a reducing agent such as sodium borohydride or sodium cyanoborohydride to act in a solvent such as methanol or ethanol. In this reaction, the amount of the reducing agent used is preferably 0.25 to 1.0 times the mol of the compound of the general formula (IX). The reaction may be carried out at 0 to 30 ° C for 0.5 to 5 hours.

In addition, a general formula which is a raw material for producing the compound of the present invention
The compounds represented by (III), (IV), (VI) and (VIII) can be produced, for example, by combining the following methods or methods known per se.

1) Method for producing compound of general formula (III) [Wherein R ⁴ and R ⁵ have the same meanings as described above] Examples of the compound of the general formula (III) include, for example, Journal of the American Chemical Society (J. Am. Chem. S).
oc.), 67 , 1019 (1945) and the like, it can be produced by reacting the compound of general formula (XI) with ammonia.

2) Compounds of general formula (IV), compounds of general formula (VI) or salts thereof, and processes for producing compounds of general formula (VIII) [In the formula, R ¹ , R ² , R ⁶ , R ⁷ , A, B, D, Y and Z
Has the same meaning as described above, R ⁸ represents a hydrogen atom or an alkoxy group, and B ¹ represents an alkylene or alkenylene group. The compound of the general formula (VI) or a salt thereof is obtained by adding a halogenating agent such as thionyl chloride, thionyl bromide or phosphorus tribromide to a compound of the general formula (XII) or an alkanesulfonyl halide such as mesyl chloride or ethanesulfonyl chloride or It is obtained by reacting arenesulfonyl halide such as benzenesulfonyl chloride and tosyl chloride. This product can be used in the next reaction without isolation.

The compound of general formula (VIII) can be obtained by reacting the compound of general formula (XII) with an oxidizing agent such as nickel peroxide and manganese dioxide.

The compound of the general formula (IV) is a compound of the general formula (XIV) obtained by reacting the compound of the general formula (VI) or a salt thereof with the compound of the general formula (XIII), for example, Journal of the Journal・ American Chemical Society (J.Am.Chem.So
c.), 97 , 1978 (1910) and Journal of the J.
American Chemical Society (J.Am.Chem.So
c.), 75 , 5400 (1953) and the like, and can be produced by reacting a diketene, a diketene = acetone adduct or the like.

The compound of general formula (XII) can be produced by subjecting the compound of general formula (XV) to a conventional reduction reaction with a reducing agent such as lithium aluminum hydride or sodium borohydride.

The compounds of the general formula (IV) and the compounds of the general formula (XIV) are novel compounds, which are useful intermediates.

The compound of formula (I) thus obtained can be isolated and purified by a usual method such as extraction, crystallization, column chromatography and the like. Further, the salt of the compound of the general formula (I) can be obtained by a method known per se.

〔The invention's effect〕

Next, the pharmacological action of the representative compound of the present invention will be described.

Test substance: 1.2,6-dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethyl] ester-5-isopropyl ester 2.2,6 -Dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-Methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethyl] ester-5-methyl ester 3.2,6 -Dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethyl] ester-5- (2-methoxy)
Ethyl ester 4.2,6-dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-Methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethyl] ester-5-ethyl ester 5.2,6 -Dimethyl-4- (2,3-dichlorophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- [2- [N-methyl-N-[(E) -3- [4
-(Pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethyl] ester-5-isopropyl ester 6.2,6-dimethyl-4- (2-trifluoromethylphenyl) -1,4-dihydropyridine- 3,5-dicarboxylic acid-3- [2- [N-methyl-N-[(E) -3-
[4- (pyridin-3-ylmethyl) phenyl] -2-
Methylallyl] amino] ethyl] ester-5-isopropyl ester 7.2,6-dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] allyl] amino]
Ethyl] ester-5-isopropyl ester 8.2,6-dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-[(E) -3- [4- (pyridyl-3-
Ilmethyl) phenyl "-2-methylallyl] amino]
Ethyl] ester-5-isopropyl ester 9.2,6-dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-Methyl-N- [3- [4- (imidazol-1-ylmethyl) phenyl] allyl] amino] ethyl] ester-5-isopropyl ester 10.2,6-dimethyl-4- (3 -Nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2- [N-Methyl-N-[(E) -3- [4- (pyridin-3-yloxy) phenyl] -2-methylallyl] amino] ethyl] ester-5-ethyl ester Nicardipine: 2,6 -Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- [2- (N-benzyl-N-methylamino) ethyl] ester-5-methyl ester / hydrochloric acid Salt OKY-1581: (E) -3- [4- (3-pyridylmethyl)
Phenyl] -2-methylpropenoate sodium The test substance of the present invention was used as a hydrochloride.

1. Effect of increasing vertebral artery blood flow The vertebral artery blood flow of dogs (mongrel, 12-22 kg, group 2-3) anesthetized with sodium pentobarbital (30 mg / kg, iv) was measured by an electromagnetic blood flow meter (Nihon Kohden, MFV). -210
It was measured in 0). A test substance was prepared with distilled water to a concentration of 1 mg / m, and a solution diluted with physiological saline to a target concentration was intravenously administered. The dose of the test substance showing the same activity as 1 mg / kg (iv) of papaverine hydrochloride was determined, and the ratio with the dose of papaverine hydrochloride (1 mg / kg) was calculated and expressed as the efficacy ratio.

The results are shown in Table-1.

2. Thromboxane synthase inhibitory action Rats fasted overnight (Wistar strain, male, 300-3)
Oral administration of the test substance aqueous solution to 50 g, 4 animals per group)
After a lapse of time, citrate blood is collected from the abdominal aorta. 1 x 10 ⁹
/ M Platelet-rich plasma (PRP) 2m is preincubated for 2 minutes at 37 ° C. Then, 0.1 mM of 10 mM sodium arachidonic acid is added and reacted for 6 minutes, and then indomethacin is added to stop the reaction. The reaction solution is deproteinized, reacted with a TBA (thiobarbituric acid) reagent, and then extracted with 3 m of n-butanol. Colorimetric determination (λ = 532 nm) of this extract was performed to determine malondialdehyde (M
DA) production is measured. Platelet-poor plasma obtained from the same individual
Also for (PPP), the MDA production amount is measured in the same manner, and the difference is defined as the MDA value. MDA of control group
The MDA production inhibition rate (%) by the test substance was determined by comparing with the value.

The results are shown in Table-2.

3. Antithrombotic effect (effect on mouse pulmonary infarction model) G. Diminno and MJ Si
Method of L.B. (M.J.Silver) [Journal of Pharmacology Experime
General Therapy (J.Pharmacol.Exp.Therap.),225
(1) 57-60 (1983)]. That is,
Oral injection of the test substance aqueous solution into a mouse (ICR system, male, 4 weeks old)
1 hour later, collagen (150 μg / m),
0.15m of mixed solution of pinephrine (100μM) intravenously
Then, the paralysis time was measured. Paralysis time of control group
Compare and calculate the paralysis time reduction rate (%) due to the test substance
It was In the case of death, the paralysis time was calculated as 15 minutes.

The results are shown in Table-3.

4. Acute toxicity The LD ₅₀ value of the test substances 2, 7, 8, 9 and 10 in mice (ICR strain, male, 4 weeks old, 5 mice per group) by intravenous administration was 30 mg / kg or more.

From the above results, it can be easily understood that the compound of the present invention has excellent vasodilatory action and thromboxane synthase inhibitory action, ie, platelet aggregation inhibitory action, that is, antithrombotic action, and low toxicity.

Therefore, the compounds of the present invention are useful as vasodilators, antihypertensive agents, antithrombotic agents, therapeutic agents for cerebral and cardiac circulatory disorders, and the like.

When the compound of the present invention is used as a medicine, it may be used in the form of tablets, capsules, granules, powders, injections, etc. by appropriately mixing itself or pharmaceutically acceptable excipients, carriers, diluents and other additives. It can be administered orally or parenterally. In the case of oral administration, the dose is usually 10 to 600 mg per adult per day.
Depending on the degree, this is administered in one or several divided doses,
It is appropriately selected according to age, weight and symptoms.

〔Example〕

Hereinafter, in order to explain the present invention in more detail, reference examples,
Examples and formulation examples are given, but the present invention is not limited thereto.

Reference Example 1 (E) -3- [4- (Pyridin-3-ylmethyl) phenyl] acrylic acid ethyl ester (24.0 g) was dissolved in anhydrous diethyl ether (200 m), and lithium aluminum hydride (2.4 g) was added thereto under ice cooling. Add it little by little over time. After reacting for 1 hour under ice-cooling and further for 1 hour at room temperature, water-containing tetrahydrofuran (water content: 10
(v / v%) 91m is added little by little. The insoluble matter is filtered off, and the solvent is distilled off under reduced pressure. The obtained oily substance is dissolved in 200 m of chloroform, 40 m of water is added thereto, and the pH is adjusted to 7.0 with 2N hydrochloric acid. Separate the organic layer,
After washing successively with 50 m of water and 50 m of saturated saline and drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [Wako silica gel C-200, eluting solvent; benzene. : Ethyl acetate (volume ratio 1: 1)] to give a colorless oil (E)
-3- [4- (pyridin-3-ylmethyl) phenyl]
10.5 g (yield 52.0%) of allyl alcohol is obtained. Crystallization of this with a mixed solvent of chloroform and diethyl ether gives colorless needle crystals having a melting point of 81 to 82 ° C.

IR (KBr) cm ^-1 : 3240 NMR (CDC ₃ ) δ value: 3.85 (2H, s), 4.23 (1H, s), 4.27 (2H, d, J = 4.5Hz), 6.28 (1H,
dt, J = 16Hz, 4.5Hz), 6.50 (1H, d, J = 16Hz), 6.85-7.55 (6
H, m), 8.20 to 8.51 (2H, m) Similarly, the following compound is obtained.

○ (E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl alcohol (colorless oil) IR (film) cm ⁻¹ : 3350 to 3230 NMR (CDC ₃ ) δ value: 1.92 ( 3H, bs), 3.98 (2H, s), 4.25 (3H, bs), 6.63 (1H, bs), 6.9
0 to 7.68 (6H, m), 8.40 to 8.70 (2H, m) ○ (E) -3- [4- (pyridin-3-yloxy) phenyl] -2-methylallyl alcohol (colorless oil) IR (film) cm ⁻¹ : 3500 to 3100,1600 NMR (CDC ₃ ) δ value: 1.89 (3H, s), 3.50 (1H, bs), 4.16 (2H, s), 6.46 (1H, s), 6.82
~ 7.36 (6H, m), 8.20 ~ 8.42 (2H, m) Reference Example 2 1.6 g of anhydrous aluminum chloride was added to anhydrous diethyl ether 3
It is dissolved in 6 m and 1.3 g of lithium aluminum hydride is added thereto little by little over 10 minutes under ice cooling. After stirring at room temperature for 30 minutes, (E) -3- [4
-(Imidazol-1-ylmethyl) phenyl] alkulic acid ethyl ester 5.9 g anhydrous tetrahydrofuran 4
The 8m solution is added dropwise under ice cooling over 30 minutes, and the mixture is reacted at room temperature for 1 hour. Then, 50 m of water-containing tetrahydrofuran (water content: 10 v / v%) is added under ice cooling, the insoluble matter is filtered off, and the mixture is washed 5 times with 20 m of each methanol. The washing solution and the filtrate are combined, the solvent is distilled off under reduced pressure, and 100 m of chloroform and 50 m of water are added to the obtained oily substance to dissolve it. The organic layer is separated, washed successively with 50 m of water and 50 m of saturated saline, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [Wako Silica Gel C-
200, elution solvent; chloroform: ethanol (volume ratio 20: 1)] to give colorless oil (E) -3-
4.0 g (yield 81.3%) of [4- (imidazol-1-ylmethyl) phenyl] allyl alcohol are obtained. Crystallization of this with a mixed solvent of methylene chloride and diisopropyl ether gives colorless needle crystals having a melting point of 97 to 99 ° C.

IR (KBr) cm ^-1 : 3170 NMR (CDC ₃ ) δ value: 4.29 (2H, d, J = 4.5Hz), 4.50 (1H, s), 5.01 (2H, s), 6.08 ~ 7.
46 (9H, m) Reference Example 3 3- [4- (pyridin-3-ylmethyl) phenyl] allyl alcohol (0.50 g) was dissolved in ethanol (10 m), and 5% palladium-carbon (0.10 g) was added thereto under a hydrogen atmosphere. Stir at room temperature for 2.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 0.50 g of colorless oily 3- [4- (pyridin-3-ylmethyl) phenyl] propanol.
(Yield 99.1%) is obtained.

IR (film) cm ^-1 : 3300 NMR (CDC ₃ ) δ value: 1.62 to 2.14 (2H, m), 2.51 to 2.84 (2H, m), 3.50 to 3.97 (4H,
m), 5.51 (1H, bs), 6.82 to 7.55 (6H, m), 8.16 to 8.60 (2H, m) Reference Example 4 (1) (E) -3- [4- (pyridin-3-ylmethyl)
Phenyl] -2-methylallyl alcohol 1.85 g is dissolved in methylene chloride 9.25 m and thionyl chloride 2.
After dropping 80 m, the mixture is reacted for 30 minutes under heating under reflux. The solvent and excess thionyl chloride are distilled off under reduced pressure to obtain an oily hydrochloride of (E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl chloride. Then it is dissolved in 9.25 m of methylene chloride.

(2) The methylene chloride solution obtained in (1) was added dropwise to a mixed solution of 2-methylaminoethanol 1.86 m and methylene chloride 9.25 m under ice-cooling, and the mixture was reacted overnight at room temperature. Then, the reaction solution was washed 3 times with 10 m of water each time, and then washed with water 1
Add 8 m and adjust to pH 1.5 with 2N hydrochloric acid. The aqueous layer was separated and washed 4 times with 9 m each of chloroform, 18 m of ethyl acetate was added, and the pH was adjusted to 8.0 with sodium hydrogen carbonate.
Adjust to. After separating the organic layer and washing with 9 m of water,
Dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako Silica Gel C-200, eluting solvent: chloroform: ethanol (volume ratio 20: 1)] to give colorless oil 2- [ 1.36 g (yield 59.4%) of N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethanol are obtained.

IR (liquid film) cm ⁻¹ : ν _OH 3400 NMR (CDC ₃ ) δ value: Reference Example 5 (1) 2.04 g of 3- [4- (pyridin-3-ylmethyl) phenyl] propanol was dissolved in 10 m of methylene chloride, and 3.26 m of thionyl chloride was added dropwise under ice cooling, and then heated under reflux for 1 hour. React. The solvent and excess thionyl chloride are distilled off under reduced pressure to obtain oily hydrochloride of 3- [4- (pyridin-3-ylmethyl) phenyl] propyl chloride.

(2) 2-Methylaminoethanol (7 m) is added to the hydrochloride obtained in (1), and the mixture is reacted at 100 ° C for 30 minutes. Excessive 2-methylaminoethanol is distilled off under reduced pressure, methylene chloride (30 m) and water (20 m) are added to the obtained residue, and the mixture is stirred at room temperature for 30 minutes, and then the organic layer is separated. Then, the organic layer is washed successively with 20 m of water and 10 m of saturated saline and then dried over anhydrous magnesium sulfate.
When the solvent was distilled off under reduced pressure, 2.44 g of colorless oily 2- [N-methyl-N- [3- [4- (pyridin-3-ylmethyl) phenyl] propyl] amino] ethanol (yield 9
5.7%).

IR (liquid film) cm ⁻¹ : ν _OH 3350 NMR (CDC ₃ ) δ value: Reference Example 6 (1) 3- [4- (imidazol-1-ylmethyl) phenyl] allyl alcohol 2.11 g was added to methylene chloride 11 m.
The resulting solution is dissolved in water and thionyl chloride (3.57 m) is added dropwise under ice cooling, and the mixture is reacted under heating under reflux for 1 hour. When the solvent and excess thionyl chloride are distilled off under reduced pressure, oily 3- [4-
(Imidazol-1-ylmethyl) phenyl] allyl chloride hydrochloride is obtained. This is dissolved in 8 m of methylene chloride.

(2) The methylene chloride solution obtained in (1) was added dropwise to a mixed solution of 2.94 m of 2-methylaminoethanol and 6 m of methylene chloride under ice cooling, and the mixture was reacted overnight at room temperature. The reaction solution is washed twice with 20 m each of water and successively with 10 m of saturated saline, and then dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography [Wako Silica Gel C-200, eluting solvent;
Chloroform: Ethanol (volume ratio 20: 1 to 10:
1)], colorless oily 2- [N-methyl-N
1.7 g of [[3- [4- (imidazol-1-ylmethyl) phenyl] allyl] amino] ethanol (yield 63.7
%).

IR (liquid film) cm ⁻¹ : ν _OH 3200 NMR (d ₆ -DMSO) δ value: 2.23 (3H, s), 2.48 (2H, t, J = 6Hz), 3.14 (2H, d, J = 6Hz) , 3.5
4 (2H, t, J = 6Hz), 4.15 (1H, s), 5.16 (2H, s), 6.21 (1H, dt, J
= 16Hz, 6Hz), 6.56 (1H, d, J = 16Hz), 6.84 to 7.81 (7H, m) In the same manner, the following compound was obtained.

O 2- [N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] allyl] amino] ethanol (colorless oil) NMR (CDC ₃ ) δ value: 2.30 (3H, s), 2.58 (2H, t, J = 6Hz), 3.20 (2H, d, J = 6Hz), 3.6
8 (2H, t, J = 6Hz), 3.92 (3H, s), 6.18 (1H, d, J = 16Hz, 6Hz),
6.52 (1H, d, J = 16Hz), 6.80 ~ 7.60 (6H, m), 8.28 ~ 8.68 (2H,
m) ○ 2- [N-benzyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethanol (colorless oil) NMR (CDC ₃ ) δ value : Reference Example 7 3- [4- (pyridin-3-ylmethyl) phenyl]-
Dissolve 0.5 g of 2-methylallyl alcohol in 5 m of benzene and add 1.4 g of nickel peroxide to
React at 12 ° C for 12 hours. Then, the insoluble matter is filtered off and washed with 10 m of benzene. The filtrate and washings are combined, the solvent is distilled off under reduced pressure, and the obtained residue is purified by column chromatography [Wako Silica Gel C-200, elution solvent; benzene: ethyl acetate (volume ratio 5: 1)]. For example, 0.48 g of 3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylacrylaldehyde as a pale yellow oil (yield
96.0%).

IR (liquid film) cm ⁻¹ : ν _{c = o} 1665 NMR (CDC ₃ ) δ value: 2.01 (3H, d, J = 2Hz), 3.96 (2H, s), 6.86 to 7.56 (7H, m), 8.20
~ 8.50 (2H, m), 9.45 (1H, s) Example 1 (1) 2- [N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2 1.26 g of methylallyl] amino] ethanol are dissolved in 5 m of ethyl acetate. A mixed solution of 0.36 m of diketene and 1 m of ethyl acetate was added dropwise to this solution under reflux with heating for 1 hour, and further reacted at the same temperature for 30 minutes. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako Silica Gel C-200, eluting solvent: benzene: ethyl acetate (volume ratio 1: 1)] to give a colorless oil. Acetoacetic acid-2- [N-methyl-N-[(E)
-3- [4- (pyridin-3-ylmethyl) phenyl]
-2-Methylallyl] amino] ethyl ester 1.06 g
(Yield 65.8%) is obtained.

IR (liquid film) cm ⁻¹ : ν _{c = o} 1740,1720 NMR (CDC ₃ ) δ value: 1.99 (3H, bs), 2.22 (3H, s), 2.65 (2H, t, J = 6Hz), 2.66 (3H,
s), 3.05 (2H, s), 3.45 (2H, s), 3.95 (2H, s), 4.26 (2H, t, J = 6
Hz), 6.39 (1H, bs), 6.92 to 7.68 (6H, m), 8.25 to 8.65 (2H, m) Similarly, the following compound is obtained.

Acetoacetic acid-2- [N-methyl-N-[(E) -3-
[4- (Pyridin-3-ylmethyl) phenyl] allyl] amino] ethyl ester (colorless oil) IR (liquid film) cm ⁻¹ : ν _{c = o} 1740,1720 NMR (CDC ₃ ) δ value: 2.21 (3H, s), 2.30 (3H, s), 2.65 (2H, t, J = 6Hz), 3.16 (2H, d,
J = 6Hz), 3.44 (2H, s), 3.90 (2H, s), 4.22 (2H, t, J = 6Hz), 6.
10 (1H, dt, J = 16Hz, 6Hz), 6.50 (1H, d, J = 16Hz), 6.84〜7.6
0 (6H, m), 8.22-8.62 (2H, m) ○ acetoacetic acid-2- [N-benzyl-N-[(E) -3
-[4- (Pyridin-3-ylmethyl) phenyl] -2
-Methylallyl] amino] ethyl ester (colorless oil) IR (liquid film) cm ^-1 : ν _{c = o} 1740,1720 NMR (CDC ₃ ) δ value: 1.90 (3H, bs), 2.20 (3H, s), 2.74 (2H, t, J = 5Hz), 3.14 (2H,
s), 3.38 (2H, s), 3.62 (2H, s), 3.92 (2H, s), 4.21 (3H, t, J = 5
Hz), 6.42 (1H, bs), 6.90 to 7.65 (11H, m), 8.32 to 8.70 (2H, m) Acetoacetic acid-2- [N-methyl-N- [3- [4-
(Pyridin-3-ylmethyl) phenyl] propyl] amino] ethyl ester (colorless oil) IR (liquid film) cm ⁻¹ : ν _{c = o} 1740,1710 acetoacetic acid-2- [N-methyl-N- [3 -[4-
(Imidazol-1-ylmethyl) phenyl] allyl]
Amino] ethyl ester (colorless oil) IR (liquid film) cm ⁻¹ : ν _{c = o} 1735,1710 (2) acetoacetic acid-2- [N-methyl-N-[(E) -3
-[4- (Pyridin-3-ylmethyl) phenyl] -2
-Methylallyl] amino] ethyl ester 1.01 g, 3-
Aminocrotonic acid isopropyl ester 0.38 g and 3
-Nitrobenzaldehyde 0.40g in 2-propanol 4
It is dissolved in m and reacted under heating under reflux for 3 hours. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako Silica Gel C-200, elution solvent; benzene: ethyl acetate (volume ratio 1: 1)] to give a yellow oil. 2,6-Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- [2- [N-methyl-N-[(E) -3
-[4- (Pyridin-3-ylmethyl) phenyl] -2
1.28 g (yield 71.5%) of -methylallyl] amino] ethyl] ester-5-isopropyl ester are obtained.

IR (liquid film) cm ⁻¹ : ν _NH 3320, ν _{c = o} 1680 NMR (CDC ₃ ) δ value: Similarly, the compounds of Table-4 and Table-5 are obtained.

Example 2 (1) (E) -3- [4- (pyridin-3-yloxy)
Phenyl] -2-methylallyl alcohol hydrochloride 0.35
g was suspended in 5 m of methylene chloride, 0.18 m of thionyl chloride was added thereto under ice cooling, and the mixture was reacted for 30 minutes under heating under reflux. The solvent and excess thionyl chloride are distilled off under reduced pressure to obtain oily hydrochloride of (E) -3- [4- (pyridin-3-yloxy) phenyl] -2-methylallyl chloride. This is dissolved in 2 m of methylene chloride.

(2) 2,6-Dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
0.76 g of-(2-methylaminoethyl) ester-5-ethyl ester was dissolved in 3 m of methylene chloride, 0.35 m of triethylamine and the methylene chloride solution obtained in (1) were added thereto under ice cooling, and the mixture was heated under reflux. React for 10 hours. The reaction solution is washed twice with 2 m of water each time and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Wako Silica Gel C-200, eluting solvent; benzene: ethyl acetate (volume ratio 2: 1)] to give 2 as a yellow powder. ，
6-dimethyl-4- (3-nitrophenyl) -1,4-
Dihydropyridine-3,5-dicarboxylic acid-3- [2-
[N-methyl-N-[(E) -3- [4- (pyridine-
0.48 g (yield 60.8%) of 3-yloxy) phenyl] -2-methylallyl] amino] ethyl] ester-5-ethyl ester is obtained.

IR (KBr) cm ⁻¹ : ν _NH 3330, ν _{c = o} 1690 NMR (CDC ₃ ) δ value: 1.17 (3H, t, J = 8Hz), 1.84 (3H, bs), 2.22 (3H, s), 2.34 (6H,
s), 2.60 (2H, t, J = 6Hz), 2.98 (2H, s), 3.87-4.25 (4H, m),
5.10 (1H, s), 6.36 (2H, bs), 6.84〜8.41 (12H, m) (3) (2) 0.40g of yellow powder obtained in 4m of chloroform
Dissolved in 7 N-hydrochloric acid (ethanol solution) under ice cooling.
Add 2m. After stirring at the same temperature for 5 minutes, the solvent was distilled off under reduced pressure to give 2,6-dimethyl-4 as a yellow powder.
-(3-Nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- [2- [N-methyl-N
-[(E) -3- [4- (pyridin-3-yloxy)
0.44 g of the hydrochloride of phenyl] -2-methylallyl] amino] ethyl] ester-5-ethyl ester is obtained.

IR (KBr) cm ^-1 : ν _{c = o} 1680 Example 3 (1) 2,6-Dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
1.0 g of-(2-aminoethyl) ester-5-isopropyl ester was dissolved in 10 m of methylene chloride, and (E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylacrylaldehyde 0.59 was dissolved therein. g and molecular sieves 4A (1.0 g) were added, and the mixture was heated under reflux to 3
React for hours. After removing the molecular sieves by filtration, the solvent was distilled off under reduced pressure to obtain a pale yellow oily 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid- 3- [2- [N-
[(E) -3- [4- (Pyridin-3-ylmethyl) phenyl] -2-methylallylidene] amino] ethyl] ester-5-isopropyl ester is obtained. This is dissolved in 8 m of ethanol.

(2) 0.10 g of sodium borohydride is added portionwise to the ethanol solution obtained in (1) under ice cooling, and then the mixture is reacted for 30 minutes under ice cooling. Next, 0.15 m of acetic acid was added, the solvent was distilled off under reduced pressure, and 20 m of methylene chloride was added to the obtained residue.
And 20 m of water are added and dissolved. The organic layer is separated, washed successively with 20 m of water and 10 m of saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography [Wako Silica Gel C-200, eluting solvent: chloroform: ethanol (volume ratio 20: 1)] to give 2,6 as a yellow oil. -Dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid-3- [2- [N-[(E) -3- [4- (pyridin-3-ylmethyl) Phenyl] -2-methylallyl] amino] ethyl] ester-5-isopropyl ester 1.
33 g (yield 85.8%) are obtained.

IR (liquid film) cm ⁻¹ : ν _NH 3330, ν _{c = o} 1685 NMR (CDC ₃ ) δ value: Example 4 The following compound is obtained by reacting in the same manner as in Example 2- (3).

○ 2,6-Dimethyl-4- (3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
Hydrochloride of [-[2- [N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethyl] ester-5-isopropyl ester (yellow Powdery) IR (KBr) cm ^-1 : ν _{c = o} 1690 Formulation example 2,6-dimethyl-4- (3-nitrophenyl) -1,
4-dihydropyridine-3,5-dicarboxylic acid-3-
25 mg of [2- [N-methyl-N-[(E) -3- [4- (pyridin-3-ylmethyl) phenyl] -2-methylallyl] amino] ethyl] ester-5-isopropylester hydrochloride was obtained. The containing tablet is prepared by a method known per se using the following additives. About 10000 tablets: The above compound 250g Cellulose 700g Lactose 780g Corn starch 700g Magnesium stearate 20g Water Suitable amount

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/44 ACB 9360-4C (72) Inventor Katsuyuki Nagumo 9-1 Matsuwakacho, Toyama City, Toyama Prefecture ( 72) Inventor Hiroki Takagi 119 Nishiosawa, Osawano-cho, Kamishinkawa-gun, Toyama Prefecture

Claims (1)

[Claims] 1. A general formula "In the formula, R ¹ and R ⁵ are the same or different and each is a lower alkyl group; R ² is a pyridyl or an imidazolyl group;
R ³ is a phenyl group which may be substituted with one or more substituents selected from halogen atom, trihalo lower alkyl group and nitro group; R ⁴ is an esterified carboxyl group; R ⁶ is Hydrogen atom, lower alkyl group, aryl group or aralkyl group; A is alkylene,
An alkyleneoxyalkylene or alkylenethioalkylene group; B is an alkylene or alkenylene group or a bond; Y is a vinylene group; Z is an oxygen or sulfur atom or an alkylene group. ] The 1,4-dihydro pyridine derivative represented by these, and its salt.