JPH07165715A - Dihydropyridine compound and its production - Google Patents

Abstract

PURPOSE:To obtain a new dihydropyridine compound useful for treating cardiovascular disorder such as coronary insufficiency, angina pectoris, arteriosclerosis and hypertension, having strong and durable vasodilating activity and antihypertensive activity. CONSTITUTION:A dihydropyridine compound of formula I [W is a dialkoxymethyl, an alkoxycarbonylmethyl or an alkylenedioxymethuyl; R<1> to R<3> each is an alkyl; X and Y are each H, an alkyl, a haloalkyl, a halogen or nitro; Ar is an aryl; A is an alkylene; M is imino or 1,4-piperazinediyl) or its acid addition salt, such as 3,5-dimethyl-1,4-dihydro-4-[2-[4-(2-hydroxy-3- phenoxypropylamino)butoxy]-5-nitrophenyl]-2-dimethoxymethyl-6- methylpyridine-3,5-dicarboxylate. The compound of formula I is obtained by reacting a dihydropyridine derivative of formula II (Z is an eliminable group) with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to novel dihydropyridine derivatives having antihypertensive properties.

[0002]

2. Description of the Prior Art 2,6-Dialkyl-4-aryl-1,
4-Dihydropyridine-3,5-dicarboxylate derivatives are described in the literature as calcium ion channel blockers. Many of these derivatives are known to produce an antihypertensive effect in the cardiovascular system of warm-blooded animals. One representative of such derivatives is nifedipine, which is dimethyl-1,4-dihydro-2,6-dimethyl-4-o-nitrophenylpyridine-3,5-dicarboxylate. A further class of 1,4-dihydropyridine derivatives, nilvadipine, is also known and is characterized by having a cyano group at the 2-position of 1,4-dihydropyridine instead of an alkyl group.

On the other hand, 1-aryloxy-3-amino-
Many propan-2-ol derivatives are known which have an adrenergic β-receptor blocking property and also show an antihypertensive effect. For example, propranolonol and atenolol, the 1- (naphth-1-yloxy) -3-isopropylaminopropan-2-ol and 1-p-carbamoylmethylphenoxy-3-isopropylaminopropan-2-ol, respectively, are the most widely It is an example that is used.

These two chemical structures, namely 2,
Attempts to combine 6-dialkyl-4-aryl-1,4-dihydropyridin-3,5-dicarboxylates and 1-aryloxy-3-aminopropan-2-ols have been previously described, and Can be found in the literature and patents.

For example, a report by an employee of Merck (Journal of Medicinal Chemistry)
(J. Med. Chem.), 24,628-631,1981), an example in which a 3-amino-2-hydroxypropoxy substituent is introduced into the 4-aryl substituent of a 4-aryl-1,4-dihydropyridine derivative. Is listed. U.S. Pat.No. 4,500,52
No. 7 also has a 3-CH = N- group, which leads to 3-
Similar compounds have been described with attached amino-2-hydroxypropoxy substituents, which are claimed to have antihypertensive and adrenergic beta-receptor blocking properties. More recently, the 4-aryl substituent of the 4-aryl-1,4-dihydropyridine derivative has been replaced by 1-aryloxy-3-aminopropane-
Structurally similar compounds having a 2-ol moiety introduced therein are disclosed in European Patent No. 194,751, JP-A-61-2662,
JP-A-62-149659, JP-A-62-228060, JP-A-1-9
No. 936 and Japanese Patent Laid-Open No. 151554/1989.

[0006]

However, all of the compounds described in these patent documents are said to have a lower alkyl group at the 2-position of the 1,4-dihydropyridine moiety, that is, 2,6-dialkyl-4-. It shares some of the structural features of aryl-1,4-dihydropyridine-3,5-dicarboxylates.

[0007]

We have now found that a group of new classes of compounds have antihypertensive effects. In this group of compounds, a di (lower) alkoxymethyl group, a (lower) alkoxycarbonylmethyl group or a (lower) alkylenedioxymethyl group is introduced at the 2-position of the 1,4-dihydropyridine moiety to give 3-aryloxy-2 -Hydroxypropylamino group or 4- (3-
An aryloxy-2-hydroxypropyl) -piperazin-1-yl group is a compound attached to the 4-aryl-1,4-dihydropyridine moiety via a 4-aryl substituent via an alkylene chain.

That is, the present invention provides the following general formula (I)

[0009]

[Chemical 4]

The present invention provides dihydropyridine represented by: or an acid addition salt thereof.

Here, W represents a di (lower) alkoxymethyl group, a (lower) alkoxycarbonylmethyl group or a (lower) alkylenedioxymethyl group, and R ¹ , R ² and
R ³ each independently represents a (lower) alkyl group, X and Y are each independently a hydrogen atom, a (lower) alkyl group,
Represents a halo (lower) alkyl group, a halogen or a nitro group, Ar represents an optionally substituted aryl group, A
Represents an alkylene group having 1 to 10 carbon atoms,
M represents an imino group or a 1,4-piperazinediyl group.

The term "(lower) alkyl group" as used herein means
It means a saturated hydrocarbon group which is straight-chain or branched and has 1 to 6, preferably 1 to 4 carbon atoms. A methyl group is preferable as the alkyl group represented by X and / or Y. The term alkylene group having 1 to 10 carbon atoms means 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms,
It means a divalent linear or branched paraffinic hydrocarbon residue.

The preferred (lower) alkoxy moiety in the di (lower) alkoxymethyl group means a straight-chain or branched alkoxy having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. As methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy and the like can be mentioned, with methoxy being most preferable. A preferred example of the di (lower) alkoxymethyl group thus defined is a dimethoxymethyl group.

The preferred (lower) alkoxy moiety in the (lower) alkoxycarbonylmethyl group means a straight-chain or branched alkoxy having 1 to 6, preferably 1 to 4 carbon atoms. An example is methoxy,
Ethoxy, propoxy, butoxy, isobutoxy, pentoxy, hexyloxy and the like can be mentioned, and more preferable ones are methoxy and ethoxy. Particularly preferred examples of the (lower) alkoxycarbonylmethyl group thus defined include a methoxycarbonylmethyl group and an ethoxycarbonylmethyl group.

A suitable alkylenedioxy moiety in the (lower) alkylenedioxymethyl group is a straight-chain or branched alkylenedioxy moiety having 1 to 6, preferably 1 to 4 carbon atoms. Examples thereof include methylenedioxy, ethylenedioxy, methylmethylenedioxy, trimethylenedioxy, tetramethylenedioxy, pentamethylenedioxy, hexamethylenedioxy and the like.

The term "halo" as used herein means fluorine, bromine, chlorine or iodine, preferably fluorine, bromine or chlorine. The optionally substituted aryl group as used herein preferably means an optionally substituted phenyl group or naphthyl group, and suitable substituents include a hydroxy group and a (lower) alkoxy group. , Halogen, (lower) alkyl group, cyano group,
Means a nitro group and the like. Examples of the acid addition salt of the dihydropyridine derivative of the present invention include, for example, a salt derived from an inorganic acid, for example, a hydrochloride or a sulfate, or a salt derived from an organic acid such as an oxalate, a lactate, a succinate, a tartrate, Maleate, fumarate, acetate, salicylate, citrate, benzoate, β-naphthoate, adipate, methanesulfonate, benzenesulfonate or p-toluenesulfonate, etc. Can be mentioned.

The dihydropyridine derivative of the present invention can be prepared by using any chemical method known to be useful for preparing a chemically similar compound. One of the preferred methods for producing the dihydropyridine compound of the present invention is the following general formula (II)

[0018]

[Chemical 5]

Where W, R ¹ , R ² , R ³ , A, X, and Y have the meanings given above, and Z is a suitable leaving group (reactive functional group), such as methanesulfonyloxy. , Benzenesulfonyloxy, p-toluenesulfonyloxy, m-nitrobenzenesulfonyloxy, p-nitrobenzenesulfonyloxy, chloro, bromo, or iodo groups) and the following general formula (III):

[0020]

[Chemical 6]

A step of reacting with an amine represented by the formula (M and Ar in the formula have the above-mentioned meanings).

The dihydropyridine compound of the present invention has the following general formula (IV)

[0023]

[Chemical 7]

(Wherein R represents the rest of the molecule of the compound of the invention as defined above, M and Ar having the meanings given above), a suitable reducing agent,
It can also be produced, for example, by reduction with an alcohol solution of sodium borohydride.

Separation and isolation of the dihydropyridine reaction product of the present invention from the reaction mixture, and purification are carried out by methods commonly used for this purpose, such as extraction with suitable solvents, chromatography, precipitation, It can be performed by recrystallization or the like.

The dihydropyridines of the present invention include 1,4-
Asymmetric carbon atom at 4-position of dihydropyridine nucleus and 3-aryloxy-2-hydroxypropylamino moiety or 4- (3-aryloxy-2-hydroxypropyl)
Due to the presence of the asymmetric carbon atom of the -piperazin-1-yl group, there are at least two sets of optical isomers, and therefore the dihydropyridines of the present invention can exist as either optical isomer or as a mixture thereof. It may exist. Resolution of a racemic mixture of optical isomers into each optical isomer can be achieved by a conventional method used for racemic resolution, for example, a diastereomeric salt can be converted into a conventional optically active acid (eg tartaric acid or camphor sulfonic acid). It can be carried out by a method such as chemically dividing with.

The compounds of the invention and their pharmaceutically acceptable salts possess potent and persistent vasodilatory and antihypertensive activity, cardiovascular disorders and hypertension, eg coronary insufficiency, Angina or myocardial infarction,
And is useful in the therapeutic treatment of hypertension.

Such excellent pharmacological activity of the compounds of the present invention is attributed to the W, R ¹ , R ² , R ³ , A, M, Ar, X, Y groups as well as the 4-position of the dihydropyridine nucleus. It is believed to be structurally characterized by the substitution pattern of the phenyl ring with the substituents. In more detail, the group W preferably _{-CH (OCH 3) 2, -CH} (OCH 2 CH 3)
_2, -CH ₂ COOCH ₃ or -CH ₂ COOCH ₂ CH ₃
Can be selected from the group consisting of: Also, R ¹ , R ² and
R ³ can be preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl and isohexyl, preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl, More preferably, R ¹ and R ³ are methyl and ethyl, and R ² is methyl, ethyl and isopropyl.

A can be preferably selected from the group consisting of methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene, more preferably ethylene or tetramethylene.

X and Y are each independently a hydrogen atom,
It is preferably selected from (lower) alkyl groups, halo (lower) alkyl groups, halogens or nitro groups. Preferred substitution patterns by the substituents on the 4-benzene ring of the dihydropyridine nucleus are 1,2,3,5-, 1,2,4,5-, 1,2,3-, 1,2,4
-, 1,2,5-, 1,2,6-, 1,3,4-, 1,3,5-, 1,2-, 1,3
-, And 1,4-.

For therapeutic purposes, the dihydropyridine derivative of the present invention may be administered at a daily dose of 0.1 to 500 mg, preferably 1 to 250 mg. The pharmaceutical composition of the present invention contains, as an active ingredient, a dihydropyridine compound or a pharmaceutically acceptable salt thereof in an amount of about 0.01 mg to about 500 mg, preferably about 0.1 mg to about 500 mg per dosage unit for oral and parenteral use. Contains 250 mg.

Those skilled in the art will appreciate that the amount of active ingredient in dosage unit form will be determined in view of the activity of the ingredient as well as the size of the human body to which it is administered.
The active ingredient is usually incorporated into solid forms such as tablets, granules, powders, capsules, troches, lozenges, or suppositories, or in the form of suspensions or solutions, such as syrups, injections, emulsions, limonades, etc. You can As the pharmaceutical carrier or diluent, solid or liquid non-toxic pharmaceutically acceptable substances are used. Examples of solid or liquid carriers or diluents are lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, acacia, peanut oil, olive oil, or sesame oil, cocoa butter, There are commonly used substances such as ethylene glycol. The carrier or diluent may also be a release-retarding substance, such as glyceryl monostearate, glyceryl distearate, or wax. For the purpose of showing the usefulness of the compounds of the present invention, the results of pharmacological tests of representative compounds are shown below.

(1) Ca channel binding test Test method (a) Preparation of crude blood vessel microsome membrane Porcine thoracic aorta was obtained from a slaughterhouse. The fat and connective tissue were removed and the vascular tissue was frozen at -80 ° C. Thaw frozen tissue in buffer (0.25 M sucrose, 10 mM MOPS, pH 7.4),
Homogenized with a polytoron (Kinematica) in the same buffer. After filtering the homogenate with gauze, the filtered homogenate was homogenized using a Teflon glass homogenizer. Next, centrifuge the homogenate (1,000 g × 10
, And the supernatant was centrifuged twice (10,000 g × 1).
0 minutes). Then centrifuge the supernatant again (100,000 g x 60
Min) pellets, which are re-buffered (50 mM Tris-
HCl, pH 7.4) and this suspension was designated as the crude microsomal membrane fraction. The resulting suspension was stored at -80 ° C until use.

(B) Binding of [ ³ H] PN200-110 to membrane preparation.
The cryofrozen crude microsome fraction was thawed. [ ³ H] PN2
00-110 (0.1 nM) was incubated with 50 μl of membrane preparation for a final volume of 200 μl at 37 ° C. for 90 minutes.
At the end of the incubation period, the reaction mixture was quickly suction filtered on a Whatman GF / C glass filter. The filters were then washed 5 times with 3 ml of buffer (50 mM Tris-HCl, pH 7.4). 6 ml of clear sol I
Radioactivity was counted in a (Packard) scintillation counter (Packard TRI-CARB4530) in (Clear-sol I).

Test Compound Dihydropyridine A ( Product of Example 1) Test Results

[0036]

[Table 1]

(2) Test method for binding to β receptor (a) Preparation of crude heart microsome membrane SD rats were killed by decapitation. Hearts were removed and homogenized using Polytron (Kinematica) in buffer (0.25 M sucrose, 10 mM MOPS, pH 7.4). The homogenate was homogenized using a Teflon glass homogenizer. Next, the homogenate was centrifuged (1,000 g × 10 minutes) to remove the tissue mass, and the supernatant was centrifuged twice (10,000 g × 10 minutes). Next, the supernatant was centrifuged again (100,000 g × 60 minutes) to obtain a pellet, and this pellet was suspended again in a buffer solution (50 mM Tris-HCl, pH 7.4),
This suspension was designated as the crude microsomal membrane fraction. The resulting suspension was stored at -80 ° C until use.

(B) ³ H-dihydroalprenol (DH
Binding of A) to membrane preparation Frozen crude microsomal membrane fractions were thawed. [ ³ H] D
HA (1 nM) was added to the final volume with 50 μl of membrane preparation.
200 μl was incubated for 30 minutes at 25 ° C. At the end of the incubation period, mix the reaction mixture with Whatman GF.
/ C glass filter was used for quick suction filtration. The filter was washed 5 times with 3 ml of buffer (50 mM Tris-HCl, pH 7.4). Radioactivity was counted in 6 ml of Clearsol I with a Packard scintillation counter (Packard TRI-CARB4530).

Test Compound Dihydropyridine A Test Results

[0040]

[Table 2]

[0041]

EXAMPLES The present invention will be explained in more detail by the following examples, but the present invention is not limited to these examples.

Example 1 3,5-Dimethyl 1,4-dihydro-4- [2- {4- (2-hydroxy-3-phenoxypropylamino) butoxy} -5-nitrophenyl] -2-dimethoxy Methyl-6-methylpyridine-
Method for producing 3,5-dicarboxylate

[0043]

[Chemical 8]

3,5-Dimethyl 4- {2- (4-bromobutoxy) -5-nitrophenyl} -1,4-dihydro-2-dimethoxymethyl-6-methylpyridine-3,
Pyridine (0.25 ml) was added to a solution of 5-dicarboxylate (1.70 g) and 2-hydroxy-3-phenoxypropylamine (2.31 g) in acetonitrile (30 ml), and the mixture was stirred under reflux for 4 hours, and then the reaction mixture was added. It was concentrated under reduced pressure. Next, the residue was subjected to silica gel column chromatography, and chloroform-methanol 15/1 (v /
After elution in v) and concentration, 3,5-dimethyl 1,4
-Dihydro-4- [2- {4- (2-hydroxy-3-
Phenoxypropylamino) butoxy} -5-nitrophenyl] -2-dimethoxymethyl-6-methylpyridine-3,5-dicarboxylate (1.43 g) was obtained as a yellow, firm foam.

IR (KBr) 3391, 2948, 2836, 1699, 160
0,1588,1512,1384,1339,1279,1187,1097,754,692c
m ⁻¹ ; ¹ H NMR (CDCl ₃ -TMS) δ8.132 and 8.126 (2
d, 1H), 8.03 (dd, 1H), 7.35-7.25 (m, 2H), 6.96 (dd, 1H), 6.91
(d, 2H), 6.83 (d, 1H), 5.97 and 5.96 (2s, 1H), 5.41 and 5.
40 (2s, 1H), 4.24-3.93 (m, 5H), 3.61 (s, 3H), 3.59 (s, 3H), 3.
470 and 3.461 (2s, 3H), 3.446 and 3.441 (2s, 3H), 3.02-
2.77 (m, 4H), 2.34 (s, 3H), 2.28-1.71 (m, 4H); mass spectrometry, m / e (FD) 644 (M ⁺⁺ 1). (Example 2) 5-isopropyl-3-methyl 1,4-
Dihydro-4- [2- (2- (2-hydroxy-3-phenoxypropylamino) ethoxy) -5-nitrophenyl] -2-dimethoxymethyl-6-methylpyridine-
Method for producing 3,5-dicarboxylate

[0046]

[Chemical 9]

5-isopropyl 3-methyl 4- {2
-(2-Bromoethoxy) -5-nitrophenyl}-
1,4-dihydro-2-dimethoxymethyl-6-methylpyridine-3,5-dicarboxylate (0.45 g) and 2-hydroxy-3-phenoxypropylamine (0.40
g) in acetonitrile (5 ml) solution in pyridine (65 μl)
Was added and the mixture was stirred under reflux for 8 hours, and then the reaction mixture was concentrated under reduced pressure. The residue is then subjected to silica gel column chromatography, chloroform-methanol 15 /
After elution with 1 (v / v) and concentration, 5-isopropyl 3-methyl-1,4-dihydro-4- [2- {2-
(2-Hydroxy-3-phenoxypropylamino) ethoxy} -5-nitrophenyl] -2-dimethoxymethyl-6-methylpyridine-3,5-dicarboxylate (0.35 g) was obtained as a yellow, firm foam. Was given.

IR (KBr) 3324,2988,2936,1695,158
8,1514,1491,1340,1274,1245,1216,1094,1038,754cm
^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ8.15 (d, 1H), 8.04 (d
d, 1H), 7.28 (t, 2H), 6.98-6.90 (m, 3H), 6.86 (d, 1H), 6.69 (b
rs, 1H), 5.91 and 5.89 (2s, 1H), 5.42 (s, 1H), 4.95-4.87
(m, 1H), 4.27-4.12 (m, 3H), 4.05-4.00 (m, 2H), 3.622 and
3.619 (2s, 3H), 3.47 (s, 3H), 3.45 and 3.43 (2s, 3H), 3.17-
2.96 (m, 3H), 2.90-2.82 (m, 1H), 2.355 and 2.349 (2s, 3H),
1.31 (d, 3H), 1.03 and 1.01 (2d, 3H); mass spectrometry, m / e (FD) 644 (M ⁺⁺ 1). (Example 3) 5-isopropyl 3-methyl 1,4-
Dihydro-4- [2- [2- {4- (2-hydroxy-
Process for producing 3-phenoxypropyl) piperazin-1-yl} ethoxy] -5-nitrophenyl] -2-dimethoxymethyl-6-methylpyridine-3,5-dicarboxylate

[0049]

[Chemical 10]

5-isopropyl 3-methyl 4- {2
-(2-Bromoethoxy) -5-nitrophenyl}-
Acetonitrile (4 ml) of 1,4-dihydro-2-dimethoxymethyl-6-methylpyridine-3,5-dicarboxylate (0.30 g) and 1- (2-hydroxy-3-phenoxypropyl) piperazine (0.38 g) Pyridine (44 μl) was added to the solution, the mixture was stirred under reflux for 3 hours, and then the reaction mixture was concentrated under reduced pressure. Next, the residue is subjected to silica gel column chromatography, eluted with chloroform-methanol 20/1 (v / v), and then concentrated to give 5
-Isopropyl 3-methyl 1,4-dihydro-4-
[2- {4- (2-hydroxy-3-phenoxypropylpiperazin-1-yl) ethoxy} -5-nitrophenyl] -2-dimethoxymethyl-6-methylpyridine-
3,5-Dicarboxylate (0.35 g) was obtained as a yellow firm foam.

IR (KBr) 3404, 2940, 16
94, 1600, 1588, 1513, 1488, 13
40, 1276, 1246, 1215, 1093, 10
39,1011,754 cm ^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ8.14 (d, 1H), 8.04 (d
d, 1H), 7.31-7.23 (m, 2H), 6.96 (t, 1H), 6.93 (d, 2H), 6.87
(d, 1H), 6.69 (br s, 1H), 5.94 (s, 1H), 5.32 (s, 1H), 4.91 (qu
int., 1H), 4.17 (t, 2H), 4.11 (quint., 1H), 3.99 (d, 2H), 3.6
2 (s, 3H), 3.46 (s, 3H), 3.45 (s, 3H), 2.93-2.48 (m, 10H), 2.3
4 (s, 3H), 1.23 (d, 3H), 1.01 (d, 3H); mass spectrometry, m / e (FD) 712 (M ⁺ ) (Example 4) 3,5-dimethyl 1,4-dihydro -4-
[2- {4- (2-hydroxy-3-phenoxypropylamino) butoxy} -5-nitrophenyl] -2-methoxycarbonylmethyl-6-methylpyridine-3,5
-Method for producing dicarboxylate

[0052]

[Chemical 11]

3,5-Dimethyl 4- {2- (4-bromobutoxy) -5-nitrophenyl} -1,4-dihydro-2-methoxycarbonylmethyl-6-methylpyridine-3,5-dicarboxylate A solution of (0.30 g) and 2-hydroxy-3-phenoxypropylamine (0.27 g) in acetonitrile (5 ml) was stirred under reflux for 4 hours, and then the reaction mixture was concentrated under reduced pressure. Next, the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol 10/1 (v / v), and concentrated to give 3,5-dimethyl 1,4-dihydro-4- [2-.
{4- (2-Hydroxy-3-phenoxypropylamino) butoxy} -5-nitrophenyl] -2-methoxycarbonylmethyl-6-methylpyridine-3,5-dicarboxylate (0.15 g) was a yellow firm foam. Obtained as a substance.

IR (KBr) 3434,2951,1738,1694,168
2,1600,1588,1511,1496,1339,1268,1244,1100,755cm
^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ8.13 (d, 1H), 8.00 (d
d, 1H), 7.23 (t, 2H), 6.96-6.78 (m, 4H), 5.29 and 5.28 (2s,
1H), 4.40-3.78 (m, 7H), 3.70 (s, 3H), 3.57 (s, 3H), 3.56 and
3.55 (2s, 3H), 3.18-2.86 (m, 4H), 2.32 (s, 3H), 2.10-1.85
(m, 4H); mass spectrometry, m / e (FD) 642 (M ⁺⁺ 1). (Example 5) 5-ethyl 3-methyl 1,4-dihydro-4- [2- {4- (2- Hydroxy-3-phenoxypropylamino) butoxy} -5-nitrophenyl]
Method for producing 2-methoxycarbonylmethyl-6-methylpyridine-3,5-dicarboxylate

[0055]

[Chemical 12]

5-Ethyl 3-methyl 4- {2- (4
-Bromobutoxy) -5-nitrophenyl} -1,4-
Dihydro-2-methoxycarbonylmethyl-6-methylpyridine-3,5-dicarboxylate (0.30 g) and 2-hydroxy-3-phenoxypropylamine (0.22
A solution of g) in acetonitrile (5 ml) was stirred under reflux for 3 hours and then the reaction mixture was concentrated under reduced pressure. Next, the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol 10/1 (v / v), and then concentrated to give 5-ethyl 3-methyl 1,4-dihydro-4- [2-. (4- (2-hydroxy-3-phenoxypropylamino) butoxy) -5-nitrophenyl]-
2-methoxycarbonylmethyl-6-methylpyridine-
3,5-Dicarboxylate (0.15 g) was obtained as a yellow, firm foam.

IR (KBr) 3440, 2948, 1737, 1693, 167
8,1650,1644,1600,1589,1511,1494,1468,1340,1270,124
3,1120,1098,1049,755 cm ^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ8.18-8.16 (m, 1H), 8.
03 (dd, 1H), 7.30-7.23 (m, 2H), 6.97 (t, 1H), 6.89 (t, 2H), 6.
82 (d, 1H), 5.31 and 5.30 (2s, 1H), 4.35-3.95 (m, 9H), 3.71
(s, 3H), 3.56 and 3.55 (2s, 3H), 3.10-2.85 (m, 4H), 2.32
(s, 3H), 2.05-1.80 (m, 4H), 1.15 (t, 3H); mass spectrometry, m / e (FD) 656 (M ⁺⁺ 1).

[0058]

INDUSTRIAL APPLICABILITY The compound of the present invention and its pharmaceutically acceptable salt have potent and persistent vasodilatory activity and antihypertensive activity, and have cardiovascular disorders and hypertension such as coronary arteries. Insufficiency, angina or myocardial infarction,
And is useful in the therapeutic treatment of hypertension.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Osamu Onomura 14-14-101, Sengen, Tsukuba, Ibaraki Prefecture (72) Inventor Takeshi Hamaya 14-14-403, 1-1, Sengen, Tsukuba, Ibaraki (72) ) Inventor Yoichiro Ueda 2-13-28-402 Kawaguchi, Tsuchiura City, Ibaraki Prefecture (72) Inventor Kimio Esumi 1-5-11-305 Sumiyoshi Yamate, Higashinada-ku, Kobe City, Hyogo Prefecture

Claims (9)

[Claims] 1. The following general formula (I): (W in the formula is a di (lower) alkoxymethyl group, (lower)
Represents an alkoxycarbonylmethyl group or a (lower) alkylenedioxymethyl group, R ¹ , R ² and R ³ each independently represent a (lower) alkyl group, and X and Y each independently represent a hydrogen atom, (lower) alkyl Group, halo (lower) alkyl group, halogen or nitro group, Ar represents an optionally substituted aryl group, A represents an alkylene group having 1 to 10 carbon atoms, M represents an imino group or A dihydropyridine compound represented by 1,4-piperazinediyl group) or an acid addition salt thereof. 2. The dihydropyridine compound or its acid addition salt according to claim 1, wherein X and Y are any of fluorine, bromine and chlorine. 3. The acid addition salt of a dihydropyridine compound according to claim 1, wherein the acid addition salt is a hydrochloride or a sulfate. 4. The acid addition salt is oxalate, lactate, succinate, tartrate, maleate, fumarate, acetate, salicylate, citrate, benzoate, β-naphthoate, The acid addition salt of a dihydropyridine compound according to claim 1, which is an adipate, a methanesulfonate, a benzenesulfonate or a p-toluenesulfonate. 5. The following general formula (II): (W, R ¹ , R ² , R ³ , A, X and Y in the formula have the meanings defined in claim 1, and Z is a suitable leaving group (reactive functional group).
And a dihydropyridine derivative represented by the following general formula (III): The method for producing a dihydropyridine compound according to claim 1 or an acid addition salt thereof, which comprises reacting with a compound represented by the formula (M and Ar in the formula have the meanings defined in claim 1). 6. The leaving group (reactive functional group) is methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, m-nitrobenzenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, chloro group, The production method according to claim 5, which is a bromo group or an iodo group. 7. A drug containing the compound according to claim 1, which is an active ingredient, and / or an acid addition salt thereof, and a mixture containing a pharmaceutically acceptable carrier or excipient. 8. A method of using the compound according to claim 1 or an acid addition salt thereof for the manufacture of a medicament for treating hypertension. 9. A method for treating hypertension, which comprises administering the compound according to claim 1 and / or an acid addition salt thereof to a human or an animal.