JPS615076A - Novel 1,4-dihydropyridine derivative and its salt - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> and R<5> are lower alkyl; R<2> is (substituted) nitrogen-containing heterocyclic group; R<3> is (substituted) aryl or aromatic heterocyclic group; R<4> is esterified carboxyl; A is alkylene, alkyleneoxyalkylene or alkylthioalkylene; X is O or S; n is 4-10] and its salt. EXAMPLE:2,6-Dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbo xylic acid 3-{2-[9-(imidazol-1-yl)nonyloxy]ethyl} ester 5-ethyl ester. USE:Vasodilator, hypotensor, antithrombotic agent, and remedy for cerebral and cardiac circulation disorder. PREPARATION:The compound of formula I can be prepared by reacting the aldehyde compound of formula II with the compound of formula III and the compound of formula IV in the presence or absence of an inert organic solvent or water, preferably at 30-150 deg.C for 1-24hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 1,4-dihydropyridine derivatives represented by the general formula and salts thereof.

[Purpose of the invention]

Its purpose is to have not only a vasodilatory effect but also a platelet aggregation inhibitory effect, a vasodilator, an antihypertensive agent,
The object of the present invention is to provide a novel compound useful as an antithrombotic agent and a therapeutic agent for Ic cerebral and cardiac circulation disorders [Prior art] Conventionally, 2,6-lenti/l/-4-(2-nitrophenyl)-1 , 4-dihydropyridine-3,5-dicarboxylic acid-dimethyl ester (generic name: nifedipine, U.S. Pat. No. 3,644,627) and 2,6-dimethyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-[2-(N-hensyl-
N-methylamino)ethyl ester-5-methyl ester hydrochloride (generic name: nicardipine, Japanese Patent Publication No. 1983-4
It has been known that 1,4-dihydropyridine derivatives such as No. 5075) are useful as therapeutic agents for cerebral circulation disorders and cardiac circulation disorders.

[Problem that the invention seeks to solve]

However, although all of these have strong vasodilatory effects, their effects on blood clots, which are a cause of cerebral and cardiac circulation disorders, have not been sufficient.

[Means for solving problems]

Under such circumstances, the present inventors developed a compound in which a group represented by the general formula %) was introduced into the carboxyl group of a conventionally known 1,4-dihydropyridine derivative, that is, a compound represented by the general formula (%).
It has been discovered that the novel 1,4-dihydropyridine derivative represented by I) and its salt have not only a vasodilatory effect but also an excellent platelet aggregation inhibiting effect, and can achieve the intended purpose, and the present invention I was able to complete it.

The compounds of the present invention will be explained below.

In addition, in this specification, lower alkyl group means, for example,
C1-4 alkyl groups such as methyl, ethyl, n-propyl, inflovir, n-butyl, isobutyl, 5ec-butyl, tert-butyl; lower alkoxy groups include, for example, methoxy, ethoxy, n-propoxy,
Impropoxy, n-butoxy, isobutoxy, 8ee
-01-4 alkoxy groups such as butoxy and tert-butoxy; Aryl groups include, for example, phenyl and naphthyl; Alkylene groups include, for example, methylene, ethylene, propylene, trimethylene, tetramethylene, hexamethylene. , hexamethylene, 1-methyltrimethylene, etc.; alkyleneoxyalkylene group refers to C1-6 alkylene groups having an oxygen atom in the chain, such as methyleneoxyethylene, ethyleneoxyethylene, propyleneoxyethylene, etc. Alkyleneoxy01-6 alkylene group; An alkylenethioalkylene group is, for example, a C□-6 alkylenethioC1-6 alkylene group having a busy sulfur atom in the chain, such as methylenethioethylene, ethylenethioethylene, fluorylenethiethylene, etc. The halogen atom means, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.

Examples of the nitrogen-containing heterocyclic group for R2 include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl,
5- or 6-membered or fused nitrogen-containing heterocycles such as pyrimidinyl, indolyl, indolinyl, isoindolyl, imidazolyl, quinolidinyl, quinolyl, isoquinolyl, purinyl, phthalazinyl, naphthyridinyl, benzimidazolyl, pyrrolopyridyl, imidazopyridyl, pyridazinyl, imidazopiperidyl, etc. Examples include formula groups. These nitrogen-containing heterocyclic groups may be substituted with a lower alkyl group.

Examples of the optionally substituted aryl or aromatic heterocyclic group for R3 include those commonly known in the art. Examples of aromatic heterocyclic groups include 5- or 6-membered groups such as chenyl, furyl, pyrrolyl, and pyridyl.
and membered heterocyclic groups. Examples of the substituent for the aryl or aromatic heterocyclic group of R3 include a halogen atom, a nitro group, a cyan group, an azide group, a lower alkyl group,
Lower alkoxy group; trihalo-lower alkyl group such as trifluoromethyl; lower alkylsulfonyl group such as mesyl, ethanesulfonyl, propanesulfonyl; aralkyl group such as benzyl, phenethyl; aryl group; benzyloxy, phenethyloxy, p-chlorobenzyl Aralkoxy groups such as oxy and p-methoxybenzyloxy; Aryloxy groups such as phenoxy, naphthoxy, and p-methylphenoxy; Lower alkylthio groups such as methylthio, ethylthio, propylthio, and butylthio; phenylthio, naphthylthio, p-methylphenylthio, etc. Arylthio group; benzylthio, 7enethylthio,
Groups such as aralkylthio groups such as p-chlorobenzylthio and p-methoxybenzylthio; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl are lauded, and the aryl or aromatic heterocyclic group of R3 is , may be substituted with one or more of these substituents.

Examples of the ester-forming group in the esterified carboxyl group of R4 include ester-forming groups commonly known in the art, such as lower alkyl groups; methoxy, ethyl, methoxypropyl, Lower alkoxy-lower alkyl groups such as ethoxyethyl, propoxyethyl, butoxyethyl, methylthioethyl, ethylthioethyl, /ropylthioethyl,
Lower alkylthio-lower alkyl groups such as butylthioethyl: N,N-dimethylaminoethyl, N,N-diethylaminoethyl, N,N-dipropylaminoethyl/L
'Nato (7) N, N-di(lower alkyl)amino-lower alkyl group; N-benzyl-N-methylaminoethyl,
N-(4-ri-tetralopenzyl) -N-methylaminoethyl, N-benzyl-N-methylaminopropyl, etc.
-Aralkyl-N-lower alkyl/l'7mi/-lower alkyl group iN-phenylene/l/N-methylaminoethyl and other N-aryl-N-lower alkylamino-lower alkyl group i N,N-di N such as benzylaminoethyl,
Examples include groups such as N-sialalkylamino-lower alkyl group.

The salt of the 1,4-dihydropyridine derivative of general formula (I) may be any pharmaceutically acceptable salt, such as a salt with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, or a salt with formic acid. , salts with organic carboxylic acids such as acetic acid, fumaric acid, maleic acid, malic acid, tartaric acid, aspartic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid, naphthalenesulfonic acid Examples include salts with inorganic acids and organic acids, such as salts with sulfonic acids.

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

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

R”-CHO + R5-C=CHR4H11 (n) (IIT) R”-COCHxCOOA
4, R'', A,
The compound of general formula (I) or a salt thereof can be obtained by reacting the compound of V) in the presence or absence of an organic solvent or water that does not adversely affect the reaction. Examples of organic solvents used here include methanol, ethanol, impropatol, butanol,
ethylene glycol.

Alcohols such as methyl cellosolve; Aromatic hydrocarbons such as benzene and toluene; Halogenated hydrocarbons such as 1,2-dichloroethane; Ethers such as tetrahydrofuran, dioxane, and 1,2-dimethoxyenne; Acetonitrile, etc. Nitriles i N,N-dimethylformamide, N,N-dimethylacetamide, and the like can be mentioned, and two or more of these organic solvents or water may be used in combination.

In this reaction, the amount of the compound of general formula (n) and Tsukuda) used is 0.5 to 2, respectively, relative to the compound of general formula (Ko).
．． 0 times mole is preferred. In addition, the reaction temperature is 30 to 150
C. The reaction time is preferably 1 to 24 hours. The starting material for the process of the present invention can be produced, for example, by the following method or a combination of methods known per se.

(i) Method for producing a compound of the general formula Tsukuda) The compound of the general formula Tsukuda) has the general formula R'C0CH! Ammonia is added to the compound R4 [wherein R4 and R5 have the meanings given above], for example, J, Am.

It can be obtained by reaction under the conditions described in Chem. Soc., 67.1019 (1945).

0I) Method for producing compound of general formula ([V) The compound of general formula ([V)] can be obtained, for example, by the method shown below.

R6-(CH,)n-R" + HO-A-XH-→H
O-A-X-(CH! Paste-R2(V) (VI)
(%IO↓ R1-C0CHeg C0O-A-X(CXiao-R3(EV)) The compound of general formula (4) is a compound of general formula (V) or a salt thereof and a compound of general formula (to), For example * 5yn
thetic Qrganic Chemistry
(John WLIey & 5ons) Chapter 6, pp.
, 226-229 (1961).

Examples of the salt of the compound of the general formula (1) include the same salts as those listed as the salt of the general formula (0), and this salt can be produced by a method known per se.

Adding diketene to the thus obtained compound of general formula (9),
For example, J, (:hem, Soc, +97 v
1978 (1910) etc., the compound of the general formula CIV) is produced.

The compound of general formula (I) thus obtained can be purified by conventional methods such as extraction, crystallization, and column chromatography. Obtained by method.

〔Effect of the invention〕

Next, the pharmacological effects of representative compounds of the present invention will be described.

Test substance 1, 2.6-lentiA/-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(2-C4-(imidazol-1-yl)phthyloxy [ethyl]ester-5-ethyl ester 2.2.6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-(2-1 nia-(imidazol-1-yl)hebutyloxy]ethyl]ester-5-ethyl ester 3, 2,6-dimethyl-4-(3-nidocylindrical phenyl)
=1,4-dihydropyridine-3,5-dicarboxylic acid-
3-[2-(9-(imidazol-1-yl)nonyloxy]ethyl]ester-5-ethyl ester 4.2.6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-(2-[9-(imidazol-1-yl)nonylthio]ethyl]ester-5-ethyl ester 5, 2,6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
3-(2-[6-(imidazo[1,5-111pyridin-5-yl)hexyloxy]ethyl]ester-5-
Ethyl ester 6.2.6-dimethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2-[6-(5,6,7,8-tetrahytotetraimidazo(1,5-a)pyridin-5-yl)hexyloxy]ethyl]ester-5-ethyl ester 7, 2,6-dimethyl- 4-(3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
3-(2-[2-[4-(imidazol-1-yl)butyloxy]ethyloxy]ethyl]ester-5-ethyl ester 8, 2.6-dimethyl-4-(3-nitrophenyl)
-1,4-dihydropyridine-3,5-dicarboxylic acid-
3-[2-[2-[5-(pyridin-3-yl)pentyloxy]ethyloxy]ethyl]ester-5-ethyl ester9.2.6-Simethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2-[9-(pyridin-3-yl)nonyloxy,
[Ethyl]ester-5-ethyl estercaldibin: 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-C2-(N-benzyl-N -methylamino)ethyl]ester-5-methylester Φ hydrochloride 0KY-1581: (E)-3-[4-(pyridine-
Sodium 3-ylmethyl)phenyl]-2-methylpropenoate 1, coronary vasodilator JW-E knit (Hartley series, male, 5oo~7
o.

f, the hearts of 3 animals per group were removed and placed in Langendor.
It was attached to a ff perfusion device. Krebs bicarbon to which approximately 0.596 defibrinated blood was added and a gas mixture consisting of 95% Os and 54 Cot was bubbled through.
ate solution is perfused, and the test substance is dimethyl sulfoxide and polyoxyethyl fatty acid glyceride [trade name:
10 each of Cremophor-EL s (manufactured by Sigma)
1 (volume) containing aqueous solution to a concentration of iq/IJ1,
It was diluted to the target concentration with physiological saline and administered at a volume of 0.1 d through a rubber tube retrogradely inserted into the aorta just before the cannula. The dilation effect is measured by measuring the amount of fluid that perfuses the coronary blood vessels from the aorta using a multi-drop needle (all-purpose drop needle: manufactured by Natsume Seisakusho), and the flow rate increases by 50 qb compared to before adding the test substance. Dose was determined as EDse value. Table 1 shows the results.
Shown below.

Table-1 2. Vertebral artery blood flow increasing effect bentoparbital sodium (30"P, kai, i, v
) anesthetized dogs (mongrel, 12-20#, 2-3 per group)
The vertebral artery blood flow in the head) was measured using an electromagnetic blood flow meter (Nihon Kohden, M
FV-2100). The test substance was prepared in the same manner as in 1 and administered intravenously. Pavaperine hydrochloride 1 ”f/#
The dose of the test substance exhibiting the same activity as (i, v,) was determined, and the ratio to the dose of papaperine hydrochloride (lq/#) was calculated and expressed as an efficacy ratio.

The results are shown in Table-2.

Table 2 3. Inhibitory effect on toxinboxane synthetase - overnight fasted rats (Wistar strain, male, 300-3
50? , 4 animals per group) was added to a test substance solution [an aqueous solution containing 101 (volume) each of dimethyl sulfoxide and cremophor at 5 W/Il! 7! (adjusted to the desired concentration and then diluted with water to the desired concentration)] is administered orally, and 1 hour later, citrate blood is collected from the abdominal aorta. Pre-incubate 2 ml of I x 10'/- platelet rich plasma (PRP) at 37°C for 2 minutes. Next, 0.1 d of 10 mM sodium arachidonate is added and the mixture is reacted for 6 minutes, and then indomethacin is added to stop the reaction. The reaction solution is subjected to protein removal treatment, reacted with a TBA (thiobarbic acid) reagent, and then extracted with n-butanol 3-. This extract is colorimetrically determined (λ=s32 nm) to measure the amount of malondialdehyde (MDA) produced. Platelet poor plasma (PPP) obtained from the same individual is similarly operated to measure the amount of MDA produced, and the difference is taken as the MDA value. The MDA production inhibition rate by the test substance was determined by comparing it with the MDA value of the control group.

The results are shown in Table-3.

Table 3 4. Antithrombotic effect (effect on mouse pulmonary infarction model) Method of G, DiMinno and M, J, 5ilver [J.

Pharmacol, Exp, Therap, 2
25(1) 57-60 (1983)).

That is, a test substance solution prepared in the same manner as in 3 was orally administered to mice (ICR strain, male, 4 weeks old), and 1 hour later collagen (150 μr/#+7) and epinephrine (100 μr/#+7) were administered.
A mixture of 0.1 μM) was administered intravenously, resulting in death and 10
We investigated the effect of preventing the appearance of cases of paralysis lasting more than 30 minutes.

The results are shown in Table 4.

Table 4 5. LI by intravenous administration of test substances 3.4.5 and 9 in acutely toxic mice (ICR strain, male, 4 weeks old, 5 mice per group)
The so value was 30 tny/ky or more.

From the above results, it can be easily understood that the compounds of the present invention have excellent vasodilatory effects and thromboxane synthase inhibitory effects, as well as platelet aggregation inhibitory effects, that is, antithrombotic effects, and have low toxicity.

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

When the compound of the present invention is used as a medicine, it can be prepared by itself or mixed with appropriate additives such as pharmaceutically acceptable excipients, carriers, and diluents in the form of a single tablet, capsule, granule, powder, or injection. It can be administered orally or parenterally. In the case of oral administration, the dosage is usually 10 to 6 ml per day for adults.
The dose is approximately 0.00 kg, which is administered once or divided into several doses, and is appropriately selected depending on the patient's age, body weight, and condition.

Reference Examples, Examples, and Formulation Examples will be given below to explain the present invention in more detail, but the present invention is not limited thereto.

Reference Example 1 9-(imidazol-1-yl)nonyl alcohol 0.
5Of is dissolved in 5 dK of methylene chloride, 0.52-thionyl chloride is added under water cooling, and the mixture is reacted under heating under reflux for 1 hour. The solvent and excess thionyl chloride were distilled off under reduced pressure,
The resulting residue was mixed with 20 ml of ethyl acetate and 201 nt of water.
Dissolve in a mixed solvent of and adjust pI (7.5) with saturated aqueous sodium hydrogen carbonate solution. Separate the organic layer and add 20 -
and 10 m of saturated saline solution, followed by anhydrous sulfuric acid)
After drying with IJum, if the solvent is distilled off under reduced pressure,
Crude 9-(imidazol-1-yl)nonyl chloride hydrochloride is obtained. This compound and 2-mercaptoethanol 0
．． 31m and 0.18f of sodium hydroxide are dissolved in 4d of ethanol and reacted at room temperature for 30 minutes and then at 50°C for 1 hour.

Then, the solvent is distilled off under reduced pressure, and the resulting residue is dissolved in a mixed solvent of 20 g of ethyl acetate and 20 g of water. Separate the organic layer and add 20 parts of water and 10 parts of saturated saline.
- and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is crystallized with a mixed solvent of ethanol and diethyl ether, ν, to form colorless needle-shaped 2-[9-(imidazo) crystals with a melting point of 48-50°C. -A/1-yl)nonylthio]ethanol 0.42t
(Yield, 70.0 cm) is obtained.

IR (KBr) cm-1' 315ONMR (CDC
Is) δ value: 1.05-2.00 (14H, m).

2.55 (2H, t, J=7I(z).

2.74 (2H, t, J-6, 5Hz).

3.78 (2H, t, J=6.5H2').

3.97 (2H, t, J=6.5Hz).

4.20 (IH, s).

7.00 (IH, bs).

7.12 (IH, bs).

7.57 (IH, bs) (1) Dissolve 0.28t of sodium metal in 5.01Rt of ethylene glycol, and dissolve 9-(pyridine-3-
A mixture of 0.69 F of nonyl tetralide hydrochloride and 2.2 m of dimethyl sulfoxide was added dropwise, and the mixture was heated to 110°C.
Let it react for 1 hour. Then, water 51)d was added under water cooling, the pl was adjusted to 7 with 2N-hydrochloric acid, and then toluene 20
- Extract. The extract was mixed with 30 parts of water and 20 parts of saturated saline.
Wash sequentially at 1Rt and dry over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by column chromatography [Japanese silica gel C-200° elution solvent: toluene: ethyl acetate (volume ratio 5:1)]. -[9-(pyridin-3-yl)nonyloxy]ethanol 0.46f (yield 60.5t)
get.

IR (film) cm-1 = aas.

NMR (CDo 1 m) δ value: 1.05-1.82 (14H, m).

2.60 (2H, t, J=7Hz).

3.35-3.86 (7H, m).

7.03-7.62 (2H, m).

8.26-8.63 (2H, m) Similarly, the following compound was obtained.

0 2-[9-(imidazol-1-yl]nonyloxy]ethanol (colorless oil) IR (film) cm-1: 3420-320O
NMR (CDCIi) δ value 1 0.75-2.10 (14H, m).

3.25-4.13 (8H, m).

4.22 (IH, s).

6.98 (IH, be).

7.09 (IH, bg).

7.53 (IH, fi) 0 2-(7-(imidazol-1-yl)hebutyloxy)ethanol (colorless oil) IR (film) cm-1 = 33750 2-C4
-Cimidazol-1-yl)butyloxy]ethanol (colorless oil) IR (film) cm-i + 3400-3300
0 2-C6-Cimidazo-[1,5-a]pyridine-
5-I/I/)hexyloxy]ethanol (light brown crystals) Melting point = 67°C I R (Kn r ) cm -12 315ONM
R(CDCls)δ value: 1.02-2.15 (8H, m).

2.55-3.05 (2H, m) = 3.15-3
．． 85 (7H, m).

6.15-6.85 (2H1m).

7, i 5-7.45 (2H, m).

8.05 (IH, 5) (2) Using trimethylene glycol (in place of ethylene glycol) or diethylene glycol (1)
) to obtain the following compound.

0 3-(9-(imidazol-1-yl)nonyloxy)propatool (colorless oil) IR (film) cm-
1= 3400-3290' 02-(2-(4-
(imidazol-1-yl)butyloxy]ethyloxy]ethanol (colorless oil) IR (film) scratch-123375 NMR (CDC!s) δ value: 1.23-2.22 (4H, m).

3.18-4.25 (12H, m).

4.53 (IH, g).

7.07 (IH, bg).

7.15 (IH, bs).

7.68 (IH, s) 0 2-[2-[5-(pyridin-3-yl)pentyloxy]ethyloxy]ethanol (colorless oil) IR (film) ci-1: 3350 Reference Example 3 2-(6 -(Imidazo[1,5-a]pyridin-5-yl)hexyloxila 0.442 ethanol was dissolved in a mixture of 20 - ethanol and 5 d of concentrated hydrochloric acid, and 0.7 t of 10% palladium carbon was added to this. is added and stirred for 8 hours at room temperature under a hydrogen atmosphere (5 atm).The reaction solution is filtered and the lachrymal fluid is concentrated under reduced pressure to obtain 2-[6-(5,6,
7,8-tetrahydroimidazo(1,5-a)pyridin-5-yl)hexyloxiraethanol hydrochloride
- [Colorless oil, IR (film) cm-1 = 34
00: Get l. This compound was mixed with chloroform 101n
ammonia gas is introduced for 20 minutes at room temperature.

The precipitated ammonium salt is removed and the solvent is distilled off under reduced pressure. The residue was dissolved in 5 gt of anhydrous tetrahydrofuran, 1 drop of triethylamine was added thereto, a mixture of 0.11 diketene and 1 d of anhydrous tetrahydrone was added dropwise under heating to reflux, and the mixture was reacted at the same temperature for 1 hour.

Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography [Wako silica gel C-200° elution solvent: chloroform:ethanol (volume ratio 30:1)
), acetoacetic acid-2-[6-(
5,6,7,8-tetrahydroimidazo[1,5-a]
pyridin-5-yl)hexyloxyphethyl ester 0.39f (45166, Section 5) is obtained.

IR (film) cm-1+ 1740.172ON
MR (CD C1s) δ value: 1.15 to 2.15 (14H, m) 12.24 (3H
, s) 2.55-2.90 (2H, m).

3.25-3.75 (6H, m)- 3,84-4.40 (3H, rn).

6.62 (IH, @).

7.38 (LH, 8) Example 1 +1) 0.56 f of 2-[9-(pyridin-3-yl)nonyloxy]ethanol is dissolved in 8 d of anhydrous sodium chloride and 1 drop of triethylamine is added.

A mixed solution of diketene 0120m and anhydrous tetrahydronerane 2- is added dropwise to this solution over 1 hour under heating and reflux, and the mixture is allowed to react at the same temperature for 1 hour. Then, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography [Wako silica gel C-200, elution solvent: toluene:ethyl acetate (volume ratio 5:1)] to obtain acetoacetic acid as a colorless oil. 2-[9-(pyridin-3-yl)nonyloxyphethyl ester A10.71t (yield: 95.9t) is obtained.

IR (film) cm””: 1745.172
ONMR (CC14) δ value: LO5-1.85 (14H, m).

2.22 (3H, s).

2.62 (2H, t, J=7Hz).

3.20-3.70 (6H, m).

4.10-4.35 (2H, m).

7.06-7.58 (2H, m).

8.25-8.53 ('2H, m) (2) Acetoacetic acid-2-[9-(pyridin-3-yl)nonyloxy]ethyl ester 0.71? .

0.34f of 3-aminocrotonic acid ethyl ester and 0.29f of 3-nitrobenzaldehyde were added to ethanol-71
%/8m/ and reacted under heating and reflux for 10 hours. Then, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to chromatography [Wako Silica Gel C-200].
, elution solvent: toluene:ethyl acetate (volume ratio 5:1))
2,6-dimethyl-4-(3
-nitrophenyl)-1,4-dihydropyridine-3,
5-dicarboxylic acid-3-[2-[9-(pyridine-3-
yl)nonyloxy]ethyl]ester-5-ethyl ester (0.911% (yield: 75.8%)).

I R (KB r ) cWL-1 = 3330.17
00.1530.1345NMR(CD01s)δ
Value: 1.05-1.85 (17H, m).

2.39 (6H, s).

2.65 (2H, t, J=7.5Hz).

3.28-3.73 (4H, rn).

3.85-4.37 (4H, m).

5.18 (IH, g).

7-. 10-8.30 (7H, m).

8.35-8.61 (2H, m) Similarly, the following compound is obtained.

02.6-cymethyl-4-(3-nitrophenyl) -
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2-[9-(imidazol-1-yl)nonyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (film) cm-'' 1710.16
75.1535.135 ONMR (CDCIs) δ value: 0.83-2.03 (17H, m).

2.37 (6H, s).

3.20-3-70 (4H, m).

3.78-4.34 (6H, m) 15.13 (I
H, 8).

6.92 (IH, bs).

7.05 (IH, bs).

7.14-8.28 (6H, m) Hydrochloride: Yellow crystals (recrystallization solvent; mixed solvent of ethanol and ethyl acetate) Melting point 143-144°C 02.6-dimethyl-4-(3-nitrophenyl) -
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[3-1:9-(imidazol-i-yl)nonyloxy]propyl]ester-.5-ethyl ester Cj
L color oil) IR (film) cm””: 169
0,1525,135ONMR(CDCIn)δ
value.

0.70-2.15 (19H, m).

2.45 (6H, s).

3.08-3.59 (4H, m).

3.70-4.60 (6H, m).

5.10 (IH9g) + 7.20-8.40 (8H, m) Hydrochloride: Yellow crystals (recrystallization solvent: mixed solvent of ethanol and ethyl acetate) Melting point 114-115°C 02.6-dimethyl-4-( 3-nitrophenyl)-1
,4-dihydropyridine-3,5-dicarboxylic acid-3-
[2-47-(imidazol-1-yl)hephthyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (film) crrL-1: 1705,167
5,1615,1530°35O NMR (CD01m) δ value: 0.96-2.04 (13H, m).

2.29 (3H, s).

2.39(3H,5)I 3.26-3.70 (4H, m).

3.77-4.34 (6H, m).

5.15 (iH,s).

6.98 (IH, bs).

7.11 (IH, bi).

7.24-8.29 (6H, rn).

Hydrochloride: Yellow crystals (recrystallization solvent; mixed solvent of ethanol and ethyl acetate) Melting point 140-145°C o 2,6-dimethyl-4-(3-nido-0-phenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-(2-[4-(imidazol-1-yl)butyloxy]ethyl]ester-5-ethyl ester yellow crystals (recrystallization solvent: acetonitrile) Melting point 152
~153℃ IR(KBr) cm-1= 1690.163
0.1350 NMR (CDCIg) δ value: 1.26 (3H,t, J=7Hz).

1.44-2.10 (4H, m).

2.42 (6H, 8).

3.39-3.80 (4H, m).

3.90-4.40 (6H, m).

5.22 (IH, s).

6.99-8.34 (8H, m) 02.6-cymethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[:2-(2-[5-(pyridin-3-yl)pentyloxy]ethyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (film) m-1: 3310,1690,
1520,1345 NMR (CDCIm) δ value: 1.05-1.85 (9H, m).

2.35 (6H, s).

2.68 (2H, t, J=7Hz).

3.30~3.82 (8H, m) = 3.88~4
．． 37 (4H, m).

5.16 (lH, s).

7.07-8.57 (9H, m) 02.6-cymethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-C2-C2-C4-Cimidazol-1-yl)butyloxy]ethyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (Fi #A) 3-1: 1690.152
5.135ONMR (CDCl2) δ value: 2.33 (3H, s).

2.42 (3H, s).

3.35-3.85 (8H, m).

3.90-4.39 (6H, rn).

5.18 (IH, s).

6.97-8.32 (8H, m) 02.6-cymethyl-4-(3-nitrophenyl)-
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-42-[9-(imidazol-1-yl)nonylthio]ethyl]ester-5-ethyl ester (yellow powder') -IR(KBr) cm-113320,169
0,1525,1345 NMR (CDCIn) δ value: 1.00-1.98 (17H, m).

3.80-4.40 (6H, m).

5.16 (IH, s).

6.90-8.30 (8H, m) Hydrochloride: Yellow crystals (recrystallization solvent; mixed solvent of ethanol and diethyl ether) Melting point 118-120°C 02.6-dimethyl-4-(3-nitrophenyl) -
1,4-dihydropyridine-3,5-dicarboxylic acid-3
-[2-[6-(imidazo[1,5-a]pyridine-5
-yl)hexyloxy]ethyl]ester-5-ethyl ester (yellow oil) IR (film) cm-1 = 1690.1640.
1620.1520.135ONMR(CDCIg)
δ value: 1.20 (3H, t, J='lHz).

1.2-2.05 (8H, m).

2.36 (6H, s).

2.65~3.05 (2H, m) 13.16~3
．． 70 (4H, m).

3.80-4.32 (4H, m).

5.10 (IH, s).

6.36 (IH, d, J=6Hz).

6.70 (IHlqlJ:=e9Hz16Hz)17.
0-8.15 (8H, m) 02.6-cymethyl-4-(3-nitrophenyl)-1
,4-dihydropyridine-3,5-dicarbo/acid-3-
C2-[6-(5,6,7,8-tetrahumantetraimidazo[1,5-alpyridin-5-yl)hexyloxy]
Ethyl]ester-5-ethyl ester (yellow oil) IR (film) crn-1: 1740.1690
．． 1630.1525.135ONMR(CDCl2)
δ value: 1.08-2.28 (17H, m).

2.38 (3H,,).

2.42 (3H, g).

2.60-3.0 (2H, m).

3.28-3.78 (4H, m).

3.80-4.40 (5H, m).

5.16 (IH,!+).

6.75 (IH, s).

7,10-8.30 (6H,m) Formulation example 2.6-dimethyl-4-(3-nitrophenyl)-1,
4-dihydropyridine-3,5-dicarboxylic acid-3-[
2-[9-(imidazol-1-yl)nonyloxy]
Tablets containing ethyl]ester-5-ethyl ester 25 are prepared in a manner known per se using the following additives.

About 1000 tablets 2 Above compounds 25f Cellulose 70f Lactose 78f Corn starch 70? Magnesium stearate 2 in water
Appropriate amount

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 and R^5 are the same or different and represent a lower alkyl group; R^2 is an optionally substituted group; A nitrogen heterocyclic group; R^3 is an optionally substituted aryl or aromatic heterocyclic group; R^4 is an esterified carboxyl group; A is alkylene, alkyleneoxyalkylene or alkylenethioalkylene group; X represents an oxygen or sulfur atom; and n represents an integer from 4 to 10, respectively. ] A 1,4-dihydropyridine derivative and a salt thereof.