JPH07188168A - Dihydropyridine compound and its production - Google Patents

Abstract

PURPOSE:To obtain the subject new compound, having strong and persistent vasodilator and antihypertensive activities and useful in therapeutic treatment for cardiovascular disorder and hypertension, e.g. coronary arterial insufficiency or angina pectoris. CONSTITUTION:This dihydropyridine compound is expressed by formula I {R<1> and R<2> are each an (lower)alkyl; W is cyano, a halo(lower)alkyl or an (lower) alkyl; A is a 1-10C alkylene; B is direct bond, oxa, a (substituted)imino, a (substituted)amide, etc.; X and Y are each H, a (lower)alkyl, a halo(lower)alkyl, etc.; M is a group expressed by either of formulas II and III [Ar<1> is a (substituted)aryl; Ar<2> is a bivalent phenylene; R<3> is H or an amino-protecting group; R<4> is a (lower)alkyl]} or its acid addition salt, e.g. a compound expressed by formula IV. Furthermore, the compound expressed by formula I is obtained by reacting, e.g. a dihydropyridine derivative expressed by formula V (Z is an eliminative group) with an amine expressed by formula VI.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel dihydropyridine derivative, and more particularly to a novel dihydropyridine derivative having an antihypertensive property or an acid addition salt thereof, a process for producing the derivative, a drug containing the derivative, the derivative, etc. To a method for treating hypertension in humans or animals using the derivative or the like.

[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. A typical example of such a derivative is nifedipine, which is dimethyl-1,4-dihydro-2,6-dimethyl-
It is 4-o-nitrophenylpyridine-3,5-dicarboxylate. Nilvadipine, another class of 1,4-dihydropyridine derivatives, 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, many 1-aryloxy-3-amino-propan-2-ol derivatives are known to have an adrenergic β-receptor blocking property and also have an antihypertensive effect. For example, propranolonol and atenolol, ie 1-each
(Naphth-1-yloxy) -3-isopropylaminopropan-2-ol and 1-p-carbamoylmethylphenoxy-3-isopropylaminopropan-2-
Oar is the most widely used example.

These two chemical structures, namely 2,6
-Dialkyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylate and 1-aryloxy-
Attempts to combine 3-aminopropan-2-ol have been previously described and can be found in various literature and patents. For example, a report by an employee of Merck (J. Med. Chem., 24,628-631,1981) describes 4-aryl-1,4-dihydropyridine derivatives as 4- An example in which a 3-amino-2-hydroxypropoxy substituent is introduced into the aryl substituent is described. U.S. Pat.No. 4,500,527 also describes a similar compound in which a 4-amino substituent is bonded to a 3-amino-2-hydroxypropoxy substituent by a -CH = N- group, which compound is It is claimed to have hypertensive properties and adrenergic β-receptor blocking properties. More recently, 4-aryl-1,4
-In the 4-aryl substituent of the dihydropyridine derivative, 1-
Structurally similar compounds having an aryloxy-3-aminopropan-2-ol moiety introduced therein are disclosed in European Patent No. 194,751, JP 61-12662, and JP 62-149659.
JP-A-62-228060, JP-A-1-9936, and JP-A-1-151554.

[0004]

However, all the compounds described in these patent documents have (lower) an ester residue at the 3 or 5 position of the 1,4-dihydropyridine moiety.
They share the structural characteristics of having an alkyl group, an alkenyl group, or an alkoxyalkyl group.

[0005]

We have now found that a group of new classes of compounds have antihypertensive effects. This group of compounds is a compound characterized by having a side chain containing an amide or urethane or urea bond at the 2-position of the dihydropyridine ring. That is, the present invention has the following general formula (I)

[0006]

[Chemical 7]

The present invention provides a dihydropyridine represented by: or an acid addition salt thereof. Here, R ¹ and R ² represent a (lower) alkyl group, W represents a cyano group, a halo (lower) alkyl group or a (lower) alkyl group, and A represents a carbon which may be optionally interrupted by an oxa group. Number 1 to 1
Represents an alkylene group of 0, B is a direct bond, an oxa group, an imino group, a substituted imino group, an amide group, a substituted amide group, a cycloalkylene group having 4 to 8 carbon atoms, a heterocyclic group, a lower alkylene group or a bond thereof. Or oxa group, imino group, substituted imino group, amide group, substituted amide group, carbon number 4
To 8 represent a (lower) alkylene group which may be optionally interrupted by a cycloalkylene group or a divalent heterocyclic group, wherein X and Y are each independently a hydrogen atom, a (lower) alkyl group, or a halo (lower) alkyl group. Represents a group, a halogen or a nitro group, M is the following formula (1) or (2)

[0008]

[Chemical 8]

[In the formula, Ar ¹ represents an optionally substituted aryl group, Ar ² represents a phenylene group, R ³ represents a hydrogen atom or an amino protecting group, and R ⁴ represents a (lower) alkyl group. Represent ) Represents a group represented by any formula.

As used herein, the term (lower) alkyl group means a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. The term alkylene group having 1 to 10 carbon atoms, which may be optionally interrupted by an oxa group, is
It means a divalent linear or branched paraffinic hydrocarbon residue having 1 to 10 carbon atoms, which may have an -O- group in the carbon chain. The term cycloalkylene group having 4 to 8 carbon atoms refers to 2 to 4 carbon atoms.
Means a valent alicyclic hydrocarbon residue. The term alkylene group having 1 to 6 carbon atoms, which may be optionally interrupted by a divalent heterocyclic group, is a divalent linear or branched paraffin hydrocarbon residue having 1 to 6 carbon atoms. And the heterocyclic group may be interrupted in the carbon chain.

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, a lower alkoxy group and a halogen. , Lower alkyl group, cyano group, 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)

[0013]

[Chemical 9]

(Wherein R ¹ , R ² , W, A, X and Y have the same meaning as described above, and Z means a suitable leaving group (reactive functional group)) Dihydropyridine derivative and the following general formula (III)

[0015]

[Chemical 10]

Reacting with an amine represented by the formula (wherein B, Ar ¹ and R ³ have the same meanings as described above), or the following general formula (IV)

[0017]

[Chemical 11]

(Wherein R ¹ , R ² , W, A, B, Ar ² , X and Y
Has the same meaning as above) or the following general formula (V)

[0019]

[Chemical 12]

(Wherein R ¹ , R ² , W, A, B, Ar ² , X and Y
Has the same meaning as described above, and L represents a suitable leaving group (reactive functional group), and a compound represented by the following general formula (VI) R ⁵ R ³ NH (VI) (formula Wherein R ³ and R ⁵ have the same meanings as described above).

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 a suitable solvent, chromatography, precipitation, It can be performed by recrystallization or the like.

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 compound of the present invention is shown by W, R ¹ , R
² , R ³ , R ⁴ , A, B, M, Ar ¹ , Ar ² , X, Y, and the substitution pattern by the 6-position substituent of the dihydropyridine nucleus. . More specifically, W can be preferably selected from the group consisting of cyano, trifluoromethyl, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl and isohexyl, and more preferably cyano and triethyl. It is selected from fluoromethyl and methyl. R ¹ , R ² and R ⁴ are methyl, ethyl, propyl,
It can be selected from the group consisting of isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl and isohexyl, preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl.

A can be preferably selected from the group consisting of methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, propylene and 2-oxabutylene, and more preferably 2 -Oxabutylene. Preferred examples of the imino group represented by B include a cycloalkyleneimino group having 4 to 8 carbon atoms. The substituted imino moiety represented by B may be, for example, an alkylimino having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. A substituted imino moiety, which may optionally interrupt the alkylene group, may be, for example, an alkylimino having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The substituted amide moiety represented by B may be, for example, an alkylamide having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Preferred examples of the bond represented by B represented by oxa group, imino group, substituted imino group, amide group, substituted amide group, cycloalkylene group having 4 to 8 carbon atoms, heterocyclic group and lower alkylene group include:
_{O- (CH 2) n -,} - NH- (CH 2) n - equal (n is 2
The group represented by the formula 4) can be mentioned.

Substituted amide moieties which may optionally interrupt the alkylene group may be, for example, alkyl amides having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The heterocyclic group moiety which may be optionally interrupted to the alkylene group is also a saturated or unsaturated monocyclic or polycyclic heterocyclic ring containing at least one hetero atom such as oxygen, sulfur or nitrogen atom. Good.

The heterocyclic group moiety is preferably 3-8.
A membered ring, more preferably a 5- or 6-membered ring, 1 to 4
A saturated or unsaturated mono-heterocycle having a nitrogen atom and optionally 1 or 2 oxygen atoms. Examples of the heterocyclic group include pyrrolediyl, pyrrolinediyl, imidazoldiyl, imidazolinediyl (for example, 2-imidazolinediyl), pyrazolediyl, pyrazolinediyl, pyridinediyl, pyridinediyl N-oxide, pyridinediylio, dihydropyridinediyl, tetrahydropyridine. Diyl (for example, 1,2,3,6-tetrahydropyridindiyl etc.), pyrimidinediyl, pyrimidinediylo, pyrazinediyl, pyrazinediylo, pyridazinediyl, pyridazinediylio, triazinediyl (for example, 1,3,5-triazinediyl, 1,2,4-triazinediyl and 1,2,3-triazinediyl), tetrahydrotriazinediyl (for example, 1,2,5,6-tetrahydro-1,2,4-
Triazinediyl, 1,4,5,6-tetrahydro-1,2,4-triazinediyl), triazolediylio, triazolediyl (for example, 1H-1,2,4-triazolediyl, 1H-1,2, 3-triazolediyl, 2H-1,2,3-triazolediyl, etc.), tetrazindiyl, tetrazolediyl (e.g., 1H-tetrazolediyl, 2H-tetrazolediyl), tetrazolediylo, pyrrolidinediyl, imidazolidinediyl, pyrazo Examples include lysine diyl, piperidine diyl, piperazine diyl and morpholine diyl. Most preferably, said heterocyclic group moiety is pyrrolidinediyl, piperidinediyl or piperazinediyl.

The alkylene group which may be optionally interrupted by an oxa group, an imino group, an imino group or a heterocyclic group is
Preferably, oxaalkylene having 2 to 6 carbon atoms, azaalkylene having 2 to 6 carbon atoms, 2 to 6
N- (alkyl having 1 to 6 carbon atoms) azaalkylene having 2 to 6 carbon atoms, or 2 to 6 carbon atom alkylene interrupted by pyrrolidinediyl, piperidinediyl or piperazinediyl. X and Y are preferably independently selected from a hydrogen atom, a lower alkyl group, a halo lower alkyl group, a halogen or a nitro group. Specifically, the lower alkyl group is preferably selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl and isohexyl, and the halo lower alkyl group is trifluoromethyl or difluoromethyl. Methyl, monofluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl,
It is preferably selected from the group consisting of dichloromethyl, monochloromethyl and 2,2,2-trichloroethyl, and halogen is preferably fluorine, bromine or chlorine. Preferred substitution patterns by the substituents on the phenyl ring at the 4-position 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 can 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 microsomal 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 preparations.
The cryofrozen crude microsome membrane fraction was thawed. [ ³ H] P
N200-110 (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). In 6 ml of Clear-sol I, Packard's scintillation counter (Packard TRI-CARB4530)
Radioactivity was counted at.

Test Compounds Dihydropyridine A (Compounds of Examples 2-5) Test Results

[0032]

[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

[0036]

[Table 2]

[0037]

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 1-1) 2- [2- {4- [Nt-butoxycarbonyl-N- (2-hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -3 -Ethoxycarbonyl-5-
Process for producing methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine

[0038]

[Chemical 13]

3-ethoxycarbonyl-2- [2-
[(1-Imidazolyl) carbonylamino] ethoxymethyl] -5-methoxycarbonyl-6-methyl-4-
A solution of (3-nitrophenyl) -1,4-dihydropyridine (0.85 g) in acetonitrile (20 ml) was added with N- (t
-Butoxycarbonyl) -N-hydroxybutyl-2-
Hydroxy-3-phenoxypropylamine (0.81g)
And reflux for 1 day. The reaction mixture was subjected to silica gel chromatography, chloroform-methanol (10
Elute at 0: 0 to 98: 2, V / V) to give 2- [2- {4- [N
-T-butoxycarbonyl-N- (2-hydroxy-3
-Phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-
(3-Nitrophenyl) -1,4-dihydropyridine (0.39 g) was obtained as a syrup.

¹ H NMR (CDCl ₃ ) δ1.22 (t, J = 7H
z, 3H), 1.47 (s, 9H), 1.62 (br s, 4H), 2.43 (s, 3H), 3.3-3.6
(m, 8H), 3.63 (s, 3H), 3.8-4.2 (m, 5H), 4.68and4.75 (ABq, J =
16Hz, 2H), 5.07 (br s, 1H), 5.09 (s, 1H), 6.8-7.0 (m, 3H), 7.
2-7.4 (m, 3H), 7.42 (br s, 1H), 7.62 (d, J = 8Hz, 1H), 8.00 (d
d, J = 2and8Hz, 1H), 8.11 (d, J = 2Hz, 1H) By the same method as in Example 1-1, the following Example 1-2
-The compound shown in Example 1-8 was obtained.

Example 1-2 2- [2- {2- [N-
t-butoxycarbonyl-N- (2-hydroxy-3-
Phenoxypropan-1-yl) amino] ethoxycarbonylamino} ethoxymethyl] -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4- (3
-Nitrophenyl) -1,4-dihydropyridine

[0042]

[Chemical 14]

[0043] ^{· IR (Neat) 1710,1690cm -1 ·} 1 H NMR (CDCl 3) δ1.22 (t, J = 7Hz, 3H), 1.47
(s, 9H), 2.42 (s, 3H), 3.4-3.7 (m, 8H), 3.64 (s, 3H), 3.9-4.3
(m, 7H), 4.62and4.73 (ABq, J = 16Hz, 2H), 5.09 (s, 1H), 5.12
(br s, 1H), 6.8-7.0 (m, 3H), 7.2-7.5 (m, 3H), 7.62 (d, J = 8H
z, 1H), 8.00 (d, J = 8Hz, 1H), 8.11 (s, 1H) (Example 1-3) 2- [2- {4- [Nt-butoxycarbonyl-N- (2- Hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -4- (2-chlorophenyl)-
3-ethoxycarbonyl-5-methoxycarbonyl-6
-Methyl-1,4-dihydropyridine

[0044]

[Chemical 15]

[0045] ^{· IR (Neat) 1710,1690cm -1 ·} 1 H NMR (CDCl 3) δ1.18 (t, J = 7Hz, 3H), 1.47
(s, 9H), 1.62 (br s, 4H), 2.36 (s, 3H), 3.2-3.8 (m, 8H), 3.61
(s, 3H), 3.8-4.2 (m, 7H), 4.68and4.74 (ABq, J = 16Hz, 2H), 5.
40 (s, 1H), 6.8-7.4 (m, 9H) (Example 1-4) 3,5-bis (methoxycarbonyl)
-2- [2- {4- [Nt-butoxycarbonyl-N
-(2-Hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -4- (3-nitrophenyl) -6-methyl-1,
Process for producing 4-dihydropyridine

[0046]

[Chemical 16]

[0047] ^{· IR (Neat) 1710,1690cm -1 ·} 1 H NMR (CDCl 3) δ1.47 (s, 9H), 1.62 (br s, 4
H), 2.37 (s, 3H), 3.2-3.7 (m, 8H), 3.63 (s, 3H), 3.64 (s, 3H),
3.8-4.2 (m, 5H), 4.68and4.74 (ABq, J = 16Hz, 2H), 5.05 (br
s, 1H), 5.10 (s, 1H), 6.8-7.0 (m, 3H), 7.2-7.5 (m, 3H), 7.62
(d, J = 8Hz, 1H), 7.99 (d, J = 8Hz, 1H), 8.09 (s, 1H) (Example 1-5) 3-ethoxycarbonyl-2- [2-
{4-[(2-hydroxy-3-phenoxypropane-
1-yl) amino] butylaminocarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine

[0048]

[Chemical 17]

[0049] ^{· IR (EtOH) 1690,1680cm -1 ·} 1 H NMR (CDCl 3) δ1.20 (t, J = 7Hz, 3H), 1.5-1.
9 (m, 4H), 2.45 (s, 3H), 3.0-4.1 (m, 14H), 3.61 (s, 3H), 4.41
(br s, 1H), 4.68and4.70 (ABq, J = 16Hz, 2H), 5.07 (s, 1H), 5.
98 (br s, 1H), 6.8-7.0 (m, 3H), 7.1-7.4 (m, 3H), 7.62 (d, J = 8
Hz, 1H), 7.78 (s, 1H), 7.96 (d, J = 8Hz, 1H), 8.09 (s, 1H) (Example 1-6) 2- [2- {4- [Nt-butoxy Carbonyl-N- (2-hydroxy-3- (2-methoxyphenoxy) propan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-
(3-Nitrophenyl) -1,4-dihydropyridine

[0050]

[Chemical 18]

[0051] ^{· IR (EtOH) 1690,1670cm -1 ·} 1 H NMR (CDCl 3) δ1.22 (t, J = 7Hz, 3H), 1.46
(s, 9H), 1.62 (br s, 4H), 2.42 (s, 3H), 3.2-3.5 (m, 6H), 3.63
(s, 3H), 3.85 (s, 3H), 3.9-4.2 (m, 7H), 4.67and4.74 (ABq, J =
16Hz, 2H), 5.09 (s, 1H), 6.9-7.0 (m, 4H), 7.38 (t, J = 8Hz, 1
H), 7.43 (br s, 1H), 7.62 (d, J = 8Hz, 1H), 8.00 (d, J = 8Hz, 1
H), 8.11 (s, 1H) (Example 1-7) Trans-2- [2- {4- [N-t
-Butoxycarbonyl-N- (2-hydroxy-3-phenoxypropan-1-yl) amino] cyclohexyloxycarbonylamino} ethoxymethyl] -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4- (3- Nitrophenyl) -1,4-dihydropyridine

[0052]

[Chemical 19]

¹ H NMR (CDCl ₃ ) δ1.22 (t, J = 7H
z, 3H), 1.49 (s, 9H), 1.5-2.1 (m, 8H), 2.43 (s, 3H), 3.3-4.2
(m, 12H), 3.63 (s, 3H), 4.39 (br s, 1H), 4.68and4.76 (ABq, J
= 8Hz, 2H), 4.99 (br s, 1H), 5.09 (s, 1H), 6.7-7.0 (m, 2H), 7.
1-7.5 (m, 4H), 7.62 (d, J = 8Hz, 1H), 8.01 (d, J = 8Hz, 1H), 8.11
(s, 1H) (Example 1-8) 3-ethoxycarbonyl-2- [2-
{4-[(2-hydroxy-3-phenoxypropane-
1-yl) amino] piperidinocarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-
4- (3-nitrophenyl) -1,4-dihydropyridine

[0054]

[Chemical 20]

[0055] ^{· IR (Nujol) 1690cm -1 ·} 1 H NMR (CDCl 3) δ1.22 (t, J = 7Hz, 3H), 1.2-1.
5 (m, 2H), 1.9-2.0 (m, 2H), 2.44 (s, 3H), 2.6-3.1 (m, 6H), 3.5
-3.8 (m, 5H), 3.63 (s, 3H), 3.9-4.2 (m, 5H), 4.69and4.73 (AB
q, J = 16Hz, 2H), 4.98 (br s, 1H), 5.09 (s, 1H), 6.8-7.1 (m, 3
H), 7.2-7.5 (m, 3H), 7.6-7.7 (m, 2H), 7.99 (d, J = 7Hz, 1H), 8.
11 (s, 1H) -mass spectrometry, m / e 696 (M + 1 ⁺ ) .- mp 65-68 ° C (recrystallized with isopropyl ether) (Example 2-1) 3-ethoxycarbonyl-2- [ 2-
{4-[(2-hydroxy-3-phenoxypropane-
1-yl) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-4
Process for producing-(3-nitrophenyl) -1,4-dihydropyridine

[0056]

[Chemical 21]

2- [2- {4- [Nt-butoxycarbonyl-N- (2-hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -3-ethoxycarbonyl- 5-Methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine (0.39 g) in 4N hydrochloric acid-
The dioxane (15 ml) solution is stirred at room temperature for 2.5 hours. The reaction mixture is poured into aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was dried over sodium sulfate and subjected to silica gel chromatography, eluting with chloroform-methanol (1: 0-9: 1, V / V) to give 3-
Ethoxycarbonyl-2- [2- {4-[(2-hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-4- (3- Nitrophenyl) -1,4-dihydropyridine (0.16 g) was obtained as a syrup.

¹ H NMR (CDCl ₃ ) δ1.22 (t, J = 7H
z, 3H), 1.73 (br s, 4H), 2.43 (s, 3H), 2.3-3.1 (m, 6H), 3.4-
3.6 (m, 4H), 3.63 (s, 3H), 3.9-4.1 (m, 5H), 4.68and4.74 (AB
q, J = 16Hz, 2H), 5.09 (s, 1H), 6.8-7.0 (m, 3H), 7.2-7.5 (m, 3
H), 7.62 (d, J = 8Hz, 1H), 8.01 (dd, J = 2Hz and J = 8Hz, 1H), 8.
11 (d, J = 2Hz, 1H) The following Example 2-2 is performed by the same method as that of the above Example 2-1.
-The compound shown in Example 2-6 was obtained.

Example 2-2 3-Ethoxycarbonyl-2- [2- {2-[(2-hydroxy-3-phenoxypropan-1-yl) amino] ethoxycarbonylamino} ethoxymethyl] -5- Methoxycarbonyl-6
-Methyl-4- (3-nitrophenyl) -1,4-dihydropyridine

[0060]

[Chemical formula 22]

[0061] ^{· IR (EtOH) 1690cm -1 ·} 1 H NMR (CDCl 3) δ1.22 (t, J = 7Hz, 3H), 2.43
(s, 3H), 2.7-3.0 (m, 4H), 3.4-3.8 (m, 4H), 3.63 (s, 3H), 3.9-
4.3 (m, 7H), 4.69and4.74 (ABq, J = 16Hz, 2H), 5.09 (s, 1H), 5.
26 (br s, 1H), 6.8-7.0 (m, 3H), 7.2-7.4 (m, 3H), 7.62 (d, J = 7
Hz, 1H), 7.99 (d, J = 7Hz, 1H), 8.11 (s, 1H) (Example 2-3) 4- (2-chlorophenyl) -3-ethoxycarbonyl-2- [2- {4- [(2-Hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-1,4-dihydropyridine

[0062]

[Chemical formula 23]

(Example 2-4) 3,5-bis (methoxycarbonyl) -2- [2- {4-[(2-hydroxy-
3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -6-methyl-4
-(3-Nitrophenyl) -1,4-dihydropyridine

[0064]

[Chemical formula 24]

[0065] ^{· IR (Neat) 1710,1690cm -1 ·} 1 H NMR (CDCl 3) δ1.69 (br s, 4H), 2.43 (s, 3
H), 2.6-3.1 (m, 4H), 3.2-3.7 (m, 4H), 3.63 (s, 3H), 3.64 (s, 3
H), 3.9-4.3 (m, 5H), 4.68and4.74 (ABq, J = 16Hz, 2H), 5.10
(s, 1H), 5.49 (br s, 1H), 6.8-7.0 (m, 3H), 7.2-7.5 (m, 3H),
7.5-7.7 (m, 2H), 7.98 (d, J = 8Hz, 1H), 8.09 (s, 1H) (Example 2-5) 3-ethoxycarbonyl-2- [2-
{4-[(2-Hydroxy-3- (2-methoxyphenoxy) propan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-
Dihydropyridine

[0066]

[Chemical 25]

[0067] ^{· IR (EtOH) 1685cm -1 ·} 1 H NMR (CDCl 3) δ1.22 (t, J = 7Hz, 3H), 1.67 (b
rs, 4H), 2.43 (s, 3H), 2.5-3.0 (m, 6H), 3.3-3.8 (m, 4H), 3.6
3 (s, 3H), 3.83 (s, 3H), 3.8-4.4 (m, 5H), 4.67and4.74 (ABq, J
= 16Hz, 2H), 5.09 (s, 1H), 5.61 (br s, 1H), 6.90 (s, 4H), 7.37
(t, J = 8Hz, 1H), 7.5-7.7 (m, 2H), 7.99 (d, J = 8Hz, 1H), 8.27
(s, 1H) -mass spectrometry, m / e 715 (M + 1 ⁺ ). (Example 2-6) 3-ethoxycarbonyl-2- [2-
{4-[(2-hydroxy-3-phenoxypropane-
1-yl) amino] cyclohexylcarbonylamino}
Ethoxymethyl] -5-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine

[0068]

[Chemical formula 26]

[0069] ^{· IR (Neat) 1705,1685cm -1 ·} 1 H NMR (CDCl 3) δ1.23 (t, J = 7Hz, 3H), 1.1-1.
5 (m, 4H), 1.9-2.1 (m, 4H), 2.42 (s, 3H), 2.5-2.8 (m, 4H), 2.7
7 (dd, J = 19Hz and J = 8Hz, 1H), 2.94 (dd, J = 19Hz and J = 4H
z, 1H), 3.4-3.8 (m, 5H), 3.63 (s, 3H), 3.9-4.2 (m, 6H), 4.6-
4.9 (m, 3H), 4.94 (t, J = 6Hz, 1H), 5.10 (s, 1H), 6.8-7.0 (m, 3
H), 7.2-7.5 (m, 4H), 7.62 (d, J = 8Hz, 1H), 8.00 (d, J = 8Hz, 1
H), 8.11 (s, 1H) (Example 3-1) 3-ethoxycarbonyl-2- [2-
{4-[(2-hydroxy-3-phenoxypropane-
1-yl) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-4
Process for producing-(3-nitrophenyl) -1,4-dihydropyridine hydrochloride

[0070]

[Chemical 27]

3-ethoxycarbonyl-2- [2- {4
-[(2-Hydroxy-3-phenoxypropane-1-
Il) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-4-
To a solution of (3-nitrophenyl) -1,4-dihydropyridine (0.16 g) in ethanol (20 ml), concentrated hydrochloric acid (0.023 m
l) was added and concentrated under reduced pressure to give 3-ethoxycarbonyl-2.
-[2- {4-[(2-Hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-
Methyl-4- (3-nitrophenyl) -1,4-dihydropyridine hydrochloride (118 mg) was obtained.

IR (Nujol) 1690,1675 cm ⁻¹ · ¹ H NMR (DMSO-d ₆ ) δ1.15 (t, J = 7 Hz, 3 H), 1.
63 (br s, 4H), 2.37 (s, 3H), 2.8-3.5 (m, 8H), 3.55 (s, 3H), 3.
9-4.2 (m, 7H), 4.58and4.65 (ABq, J = 14Hz, 2H), 5.00 (s, 1H),
6.9-7.0 (m, 3H), 7.2-7.4 (m, 3H), 7.5-7.6 (m, 2H), 7.9-8.1
(m, 2H), 8.6-9.0 (m, 2H) -mass spectrometry, m / e 685 (M + 1 ⁺ ) .- mp 48-51 ° C The following example was carried out in the same manner as in Example 3-1 above. 3-2
-The compound shown in Example 3-6 was obtained.

Example 3-2 3-Ethoxycarbonyl-2- [2- {2-[(2-hydroxy-3-phenoxypropan-1-yl) amino] ethoxycarbonylamino} ethoxymethyl] -5- Methoxycarbonyl-6
-Methyl-4- (3-nitrophenyl) -1,4-dihydropyridine hydrochloride

[0074]

[Chemical 28]

IR (EtOH) 1690,1710 cm ⁻¹ · ¹ H NMR (DMSO-d ₆ ) δ1.15 (t, J = 7 Hz, 3 H), 2.
39 (s, 3H), 3.0-3.6 (m, 8H), 3.56 (s, 3H), 3.9-4.2 (m, 4H), 4.
2-4.4 (m, 3H), 4.59and4.66 (ABq, J = 14Hz, 2H), 5.01 (s, 1H),
6.9-7.0 (m, 3H), 7.2-7.7 (m, 5H), 7.9-8.1 (m, 2H), 8.99 (br
s, 1H), 9.26 (br s, 1H) -mass spectrometry, m / e 657 (M + 1 ⁺ ). (Example 3-3) 4- (2-chlorophenyl) -3-ethoxycarbonyl-2- [2- {4-[(2-Hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-1,4-dihydropyridine hydrochloride

[0076]

[Chemical 29]

[0077] ^{· IR (EtOH) 1700,1690cm -1 ·} 1 H NMR (DMSO-d 6) δ1.10 (t, J = 7Hz, 3H), 1.
64 (br s, 4H), 2.31 (s, 3H), 2.8-3.7 (m, 8H), 3.50 (s, 3H), 3.
9-4.3 (m, 7H), 4.54and4.61 (ABq, J = 14Hz, 2H), 5.29 (s, 1H),
6.9-7.4 (m, 9H), 8.76 (br s, 1H), 8.94 (br s, 1H) -mass spectrometry, m / e 674 (M + 1 ⁺ ) .- mp 55-62 ° C (Example 3) -4) 3,5-bis (methoxycarbonyl)
-2- [2- {4-[(2-hydroxy-3-phenoxypropan-1-yl) amino] butoxycarbonylamino} ethoxymethyl] -6-methyl-4- (3-nitrophenyl) -1,4 -Dihydropyridine hydrochloride

[0078]

[Chemical 30]

[0079] ^{· IR (EtOH) 1690cm -1 ·} 1 H NMR (DMSO-d 6) δ1.63 (br s, 4H), 2.37
(s, 3H), 2.9-3.5 (m, 8H), 3.57 (s, 3H), 3.58 (s, 3H), 3.9-4.0
(m, 4H), 4.20 (br s, 1H), 4.58and4.65 (ABq, J = 14Hz, 2H), 5.
03 (s, 1H), 6.9-7.0 (m, 3H), 7.2-7.4 (m, 3H), 7.5-7.7 (m, 2
H), 7.96 (s, 1H), 8.02 (d, J = 8Hz, 1H), 8.6-9.0 (m, 3H) -mass spectrometry, m / e 671 (M + 1 ⁺ ). (Example 3-5) 3 -Ethoxycarbonyl-2- [2-
{4-[(2-hydroxy-3-phenoxypropane-
1-yl) amino] butylaminocarbonylamino} ethoxymethyl] -5-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine hydrochloride

[0080]

[Chemical 31]

IR (EtOH) 1690,1680 cm ⁻¹ · ¹ H NMR (DMSO-d ₆ ) δ1.15 (t, J = 7Hz, 3H), 1.
3-1.7 (m, 4H), 2.40 (s, 3H), 2.8-4.3 (m, 15H), 3.55 (s, 3H),
4.56and4.65 (ABq, J = 14Hz, 2H), 5.01 (s, 1H), 6.9-7.0 (m, 3
H), 7.2-7.4 (m, 2H), 7.5-7.7 (m, 2H), 7.9-8.1 (m, 2H), 8.6-
9.0 (m, 2H) -mass spectrometry, m / e 684 (M + 1 ⁺ ). (Example 3-6) 3-ethoxycarbonyl-2- [2-
{4-[(2-hydroxy-3-phenoxypropane-
1-yl) amino] cyclohexylcarbonylamino}
Ethoxymethyl] -5-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -1,4-dihydropyridine hydrochloride

[0082]

[Chemical 32]

IR (Nujol) 1710,1690 cm ⁻¹ · ¹ H NMR (CDCl ₃ ) δ1.22 (t, J = 7 Hz, 3 H), 1.2-2.
5 (m, 8H), 2.42 (s, 3H), 3.0-3.6 (m, 6H), 3.63 (s, 3H), 3.9-4.
4 (m, 5H), 4.5-5.0 (m, 4H), 5.09 (s, 1H), 6.8-7.0 (m, 3H), 7.2
-7.5 (m, 4H), 7.62 (d, J = 7Hz, 1H), 7.99 (d, J = 7Hz, 1H), 8.10
(s, 1H), 8.65 (br s, 1H), 9.60 (br s, 1H) -mass spectrometry, m / e 711 (M + 1 ⁺ ) .- mp 77-82 ° C (Example 4) 6- Cyano-3-ethoxycarbonyl-2
-[2- {4- (2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine hydrochloride

[0084]

[Chemical 33]

6-Cyano-3-ethoxycarbonyl-2
-[2- {4- (2,3-Epoxypropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine (0.53 g) and isopropylamine (2.0 m
A solution of l) in ethanol (25 ml) was stirred under reflux for 3 hours, and then the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, chloroform-
After eluting with methanol (10: 1, V / V) and concentrating, 6-
Cyano-3-ethoxycarbonyl-2- [2- {4-
(2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -1,
4-Dihydropyridine (0.31 g) was obtained as a yellow oil.

6-Cyano-3-ethoxycarbonyl-2
-[2- {4- (2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -1,4-dihydropyridine (0.31 g) in methanol 1N methanolic hydrogen chloride (1 ml) was added to the (4 ml) solution, and the mixture was stirred for 30 minutes. Methanol was distilled off under reduced pressure, 6
-Cyano-3-ethoxycarbonyl-2- [2- {4-
(2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -1,
4-Dihydropyridine hydrochloride (0.33 g) was obtained as a yellow firm foam.

IR (KBr) 3326, 2230, 1699, 1645, 16
13,1531,1512,1481,1436,1394,1350,1298,1245,1213,10
99,827,785,742,702 cm ^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ8.09 (s, 1H), 8.04
(d, J = 8Hz, 1H), 7.68-7.53 (m, 1H), 7.52-7.34 (m, 2H), 7.24-
6.92 (m, 2H), 5.18 (s, 1H), 4.90-2.65 (m, 16H), 3.74 (s, 3H),
1.53-0.80 (m, 9H); mass spectrometry, m / e (FD) 680 (M ⁺ +1) (Example 5) 3-ethoxycarbonyl-2- [2- {4
-(2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -6-
Process for producing trifluoromethyl-1,4-dihydropyridine hydrochloride

[0088]

[Chemical 34]

3-ethoxycarbonyl-2- [2- {4
-(2,3-Epoxypropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4-
(3-Nitrophenyl) -6-trifluoromethyl-
A solution of 1,4-dihydropyridine (0.53 g) and isopropylamine (2.5 ml) in methanol (15 ml) was refluxed.
After stirring for 2.5 hours, the reaction mixture was concentrated under reduced pressure.
The residue was subjected to silica gel column chromatography,
After eluting with chloroform-methanol (5: 1, V / V),
When concentrated, 3-ethoxycarbonyl-2- [2- {4-
(2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -6-
Trifluoromethyl-1,4-dihydropyridine (0.46
g) was obtained as a yellow oil.

3-ethoxycarbonyl-2- [2- {4
-(2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -6-
Trifluoromethyl-1,4-dihydropyridine (0.46
To a solution of g) in methanol (5 ml) was added 1N methanolic hydrogen chloride (1 ml) and the mixture was stirred for 30 minutes. Methanol was distilled off under reduced pressure, and 3-ethoxycarbonyl-2- [2- {4
-(2-Hydroxy-3-isopropylaminopropoxy) phenylacetamido} ethoxymethyl] -5-methoxycarbonyl-4- (3-nitrophenyl) -6-
Trifluoromethyl-1,4-dihydropyridine monohydrochloride (0.48g) was obtained as a yellow firm foam.

IR (KBr) 3395, 1732, 1698, 1654, 16
48,1613,1533,1514,1490,1437,1348,1300,1246,1220,11
80,1099,828,740,689 cm ^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ9.63 (br s, 1H), 8.
49 (br s, 1H), 8.10 (s, 1H), 8.08 (d, J = 8Hz, 1H), 7.74 (s, 1
H), 7.61 (d, J = 7Hz, 1H), 7.47 (dd, J = 8Hzand7Hz, 1H), 7.22-
7.07 (m, 2H), 6.93-6.78 (m, 2H), 5.92-5.78 (m, 1H), 5.18 (s,
1H), 4.77and4.69 (ABq, J = 16Hz, 2H), 4.66-4.55 (m, 1H), 4.2
1-3.88 (m, 4H), 3.80-3.23 (m, 8H), 3.72 (s, 3H), 3.22-3.05
(m, 1H), 1.51and1.48 (2d, J = 7and7Hz, 6H), 1.22 (t, J = 7Hz, 3
H);-mass spectrometry, m / e (FD) 723 (M ⁺ +1).

[0092]

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 1-14-14-101 Sengen, Tsukuba-shi, Ibaraki (72) Inventor Takeshi Hamaya 1-14-14-403 Sengen, Tsukuba-shi, Ibaraki (72) Invention Yoichiro Ueda 2-13-12-408 Hanabata, Tsukuba City, Ibaraki Prefecture (72) Inventor Kimio Esumi 1-5-11-305 Sumiyoshi Yamate, Higashinada Ward, Kobe City, Hyogo Prefecture

Claims (9)

[Claims] 1. The following general formula (I): [Wherein R ¹ and R ² represent a (lower) alkyl group, W represents a cyano group, a halo (lower) alkyl group or a (lower) alkyl group, and A may be optionally interrupted by an oxa group. Represents an alkylene group having 1 to 10 carbon atoms, B is a direct bond, an oxa group, an imino group, a substituted imino group, an amide group, a substituted amide group, a cycloalkylene group having 4 to 8 carbon atoms, a heterocyclic group, a lower alkylene group Alternatively, a bond thereof or an oxa group, an imino group, a substituted imino group, an amide group, a substituted amide group, a cycloalkylene group having 4 to 8 carbon atoms or a divalent heterocyclic group may be optionally interrupted (lower)
Represents an alkylene group, X and Y each independently represent a hydrogen atom, a (lower) alkyl group, a halo (lower) alkyl group, a halogen or a nitro group, and M represents the following formula (1) or
Formula (2) (In the formula, Ar ¹ represents an optionally substituted aryl group, Ar ² represents a divalent phenylene group, R ³ represents a hydrogen atom or an amino protecting group, and R ⁴ represents a (lower) alkyl group. Represents a group represented by any of the formulas]) 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): (Wherein R ¹ , R ² , W, A, X and Y have the same meanings as described above, and Z means a suitable leaving group (reactive functional group)) , The following general formula (II
I) [Chemical 4] (Wherein B, Ar ¹ and R ³ have the same meanings as described above), or reacting with an amine represented by the following general formula (IV) (Wherein R ¹ , R ² , W, A, B, Ar ² , X and Y have the same meanings as described above) or the following general formula (V): (Wherein R ¹ , R ² , W, A, B, Ar ² , X and Y have the same meanings as described above, and L represents a suitable leaving group (reactive functional group)) A compound represented by the following formula (VI) R ⁵ R ³ NH (VI) (wherein R ³ and R ⁵ have the same meanings as described above) is reacted. A method for producing the dihydropyridine compound according to claim 1, or an acid addition salt thereof. 6. A leaving group (reactive functional group) Z or L is a methanesulfonyloxy group, a benzenesulfonyloxy group, or p.
-Toluenesulfonyloxy group, m-nitrobenzenesulfonyloxy group, chloro group, bromo group, iodo group or 1-imidazolyl group.
The manufacturing method described. 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.