JPH07165716A - 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 cyano or a haloalkyl; R, R<1> and R<2> are each an alkyl; X and Y are each H, an alkyl, a haloalkyl, a halogen or nitro; Ar and Ar<1> are each an aryl; B is an alkyelne; A is an alkylene) or its acid addition salt, such as 2-[4-[2-[4-(2-hydroxy-3- sopropylaminopropoxy)phenylamino]-ethoxy]phenyl]ethyl-1,4-dihydro-3- methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-trifluoromethylpyridine-5 -carboxylate dihydrochloride. The compound of formula I is obtained by reacting a dihydropyridine derivative of formula II (Z is an eliminable group) with an amine 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. 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. 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, many 1-aryloxy-3-amino-propan-2-ol derivatives are known which have an adrenergic β-receptor blocking property and also have an antihypertensive effect. For example propranolonol and atenolol, ie 1- (naphth-1-yloxy), respectively
-3-Isopropylaminopropan-2-ol and 1-p-carbamoylmethylphenoxy-3-isopropylaminopropan-2-ol are the most widely used examples.

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 (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. 4,500,527 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-
A structurally similar compound in which a 3-alkylamino-2-hydroxypropoxyphenyl moiety is introduced from the phenyl group side to the ester substituent at the 3-position or 5-position of the dihydropyridine derivative is disclosed in Japanese Patent Publication No. 62-501004, JP 61-1916
No. 84, JP-A-61-23368 and W093 / 03014.

[0007]

However, among these patent documents, the compounds described in JP-A-62-501004, JP-A-61-191684, and JP-A-61-23368 are all disclosed. , 1,4
-Having a lower alkyl group at the 2- and 6-positions of the dihydropyridine moiety, 2,6-dialkyl-4-aryl-
It shares some of the structural features of 1,4-dihydropyridine-3,5-dicarboxylate. Also,
The compounds described in JP-A-62-501004, JP-A-61-191684 and W093 / 03014 have a 3-alkylamino-2-hydroxypropoxyphenyl moiety at the 3- or 5-position ester substituent. It is introduced from the phenyl group side without further interposing another phenylene group.

[0008]

We have now found that a group of new classes of compounds have antihypertensive effects. This group of compounds has a cyano group or a halo (lower) alkyl group at the 2-position of the 1,4-dihydropyridine moiety, and has -B-Ar ¹ -OA-NH-Ar-O in the general formula (I). -CH ₂ -CH
As shown by OH-CH ₂ -NHR, 3-
It is a compound having a structural feature that an alkylamino-2-hydroxypropoxyphenyl moiety is introduced from the phenyl group side through another phenylene group.

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

[0010]

[Chemical 4]

The present invention provides a dihydropyridine represented by: or an acid addition salt thereof. Here, W represents a cyano group or a halo (lower) alkyl group, and R, R ¹ and R
² each independently represents a (lower) alkyl group, X and
Y independently represents a hydrogen atom, a (lower) alkyl group, a halo (lower) alkyl group, a halogen or a nitro group, Ar and Ar ¹ represent an optionally substituted aryl group, and B represents 1 to 10 Represents an alkylene group having a carbon atom, and A represents an alkylene group having 2 to 10 carbon atoms.

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. R ¹ , R ² ,
A methyl group is preferable as the alkyl group represented by X and / or Y. The alkyl group represented by R is preferably an isopropyl group.

The term "halo" as used herein means fluorine, bromine, chlorine or iodine, preferably fluorine, bromine or chlorine. In addition, halo (lower) alkyl means mono-, di- or trihaloalkyl having 1 to 6 carbon atoms, preferably trifluoromethyl. The term alkylene group having 1 to 10 carbon atoms means a divalent straight chain or branched paraffinic hydrocarbon residue having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms. The term alkylene group having 2 to 10 carbon atoms means a divalent straight chain or branched paraffinic hydrocarbon residue having 2 to 10 carbon atoms, preferably 2 to 4 carbon atoms.

The term optionally substituted aryl group represented by Ar and Ar ¹ is an optionally substituted C
_It means a _6- C ₁₀ aryl group, preferably phenyl, tolyl, xylyl, cumenyl, naphthyl and the like, most preferably a phenyl group.

Examples of the acid addition salt of the dihydropyridine derivative of the present invention include salts derived from inorganic acids such as hydrochlorides or sulfates, or salts derived from organic acids such as oxalates, lactates and succinates. 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)

[0017]

[Chemical 5]

(Wherein W, R ¹ , R ² , B, Ar ¹ , A, X and Y
Has the meaning defined in claim 1, Z represents a suitable leaving group (reactive functional group), and a dihydropyridine derivative represented by the following general formula (III)

[0019]

[Chemical 6]

A step of reacting with an amine represented by the formula (wherein R and Ar have the meanings defined in claim 1).

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.

Since the dihydropyridine of the present invention has an asymmetric carbon atom at the 4-position of the 1,4-dihydropyridine nucleus and an asymmetric carbon atom in the 3-amino-2-hydroxypropoxy moiety, it has at least two optical groups. There are isomers, and therefore the dihydropyridines of the present invention may exist as their respective optical isomers or as a mixture thereof. 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 compound of the present invention is due to the group of W, R, R ¹ , R ² , A, B, X, Y and the substituent of the phenyl ring at the 4-position of the dihydropyridine nucleus. It is considered to be structurally characterized by the substitution pattern by and the substitution pattern of Ar and Ar ¹ . More specifically, the group of W is preferably cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-
It can be selected from the group consisting of trifluoroethyl, trichloromethyl, dichloromethyl, monochloromethyl, 2,2,2-trichloroethyl, more preferably cyano or trifluoromethyl. R, R ¹ and R ² are each independently methyl, ethyl, propyl, isopropyl,
Butyl, isobutyl, amyl, isoamyl, hexyl,
It can be selected from the group consisting of isohexyl, preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl. A can be preferably selected from the group consisting of ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene, more preferably ethylene or tetramethylene. B is preferably methylene, ethylene, propylene, trimethylene,
It can be selected from the group consisting of tetramethylene, pentamethylene, hexamethylene, heptamethylene and octamethylene, more preferably ethylene.

X and Y are preferably independently selected from a hydrogen atom or a nitro group. A preferred substitution pattern by the substituent on the 4-position benzene ring of the dihydropyridine nucleus is 1,2,3-, 1,2,4-, 1,2,5-, 1,2,6-, 1,3 ,Four
-, 1,3,5-, 1,2-, 1,3-, and 1,4-.
Ar ¹ is 1,2-phenylene, 1,3-phenylene, 1,4
-Selected from phenylene. Phenyl is preferred as Ar.

For the purpose of treatment, 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) Test method for blood pressure lowering effect Three Wistar rats were used per group. Each animal was placed in a physically sized cage after catheterization of the femoral artery and vein under ether anesthesia. The blood pressure in the femoral artery was measured using a pressure transducer and recorded as the electrical integration value of the mean arterial blood pressure. Heart rate was counted periodically from the instantaneous pulse of arterial blood pressure by moving the recording paper at a higher speed. The test compound was intravenously administered through a catheter inserted into the femoral vein 2 hours or more after the operation.

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

[0030]

[Table 1]

2) 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. Frozen tissue was thawed in a buffer solution (0.25M sucrose, 10mM MOPS, pH7.4) and polytron (Kinematica (K
inematica)) was homogenized. After filtering the homogenate with gauze, the filtered homogenate was homogenized using a Teflon glass homogenizer.
Next, the homogenate was centrifuged (1,000 g × 10 minutes), and the supernatant was further centrifuged twice (10,000 g × 10 minutes).
Next, the supernatant was centrifuged again (100,000 g x 60 minutes) to obtain a pellet, which was again re-buffered (50 mM Tris-HCl, pH
7.4), and this suspension was referred to as a crude microsome 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 filtered on a Whatman GF / C glass filter with suction. 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, pack
ard) scintillation counter (Packard TRI-CAR
Radioactivity was counted in B4530).

Test Compound Dihydropyridine A Test Results

[0034]

[Table 2]

3) Test method for binding to β receptor (a) Preparation of crude heart microsomal 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 x 60 minutes) to obtain a pellet, and this pellet was resuspended in a buffer solution (50 mM Tris-HCl, pH 7.4). It was called fractionation. 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

[0038]

[Table 3]

[0039]

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 2-<< 4- [2- {4- (2
-Hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 1,4-
Dihydro-3-methoxycarbonyl-6-methyl-4-
Process for producing (3-nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate dihydrochloride

[0041]

[Chemical 7]

2- {4- (2-Bromoethoxy) phenyl} ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5- Carboxylate (0.
A solution of 88 g) and 4- (2-hydroxy-3-isopropylaminopropoxy) phenylamine (1.21 g) in acetonitrile (15 ml) was stirred under reflux for 6 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 4/1 (v / v), and then concentrated to give 2
-<< 4- [2- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitro Phenyl) -2
-Trifluoromethylpyridine-5-carboxylate (0.41g) was obtained as a yellow oil.

Next, this 2-<< 4- [2- {4- (2-
Hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4-
(3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (0.34 g) in methanol (5
ml) solution, add 1N methanolic hydrogen chloride (2 ml),
Stir for 30 minutes. Then, the methanol was distilled off under reduced pressure,
2-<< 4- [2- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy]
Phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2
-Trifluoromethylpyridine-5-carboxylate dihydrochloride (0.44g) was obtained as a yellow firm foam.

IR (KBr) 3390,2952,1704,1614,153
0,1512,1435,1386,1350,1280,1230,1180,1099,829cm
^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ 8.07-7.98 (m, 2H), 7.
49 (d, 1H), 7.37 (dd, 1H), 7.03 (d, 2H), 6.79 (d, 2H), 6.78 (d,
2H), 6.61 (d, 2H), 6.30 (s, 1H), 5.11 (s, 1H), 4.56-4.48 (m, 1
H), 4.27 (t, 2H), 4.11 (t, 2H), 4.06-3.84 (m, 2H), 3.71 (s, 3
H), 3.54-3.33 (m, 3H), 3.31-3.04 (m, 2H), 2.90-2.78 (m, 2
H), 2.37 (s, 3H), 1.45 (d, 3H), 1.44 (d, 3H); mass spectrometry, m / e (FD) 757 (M ⁺⁺ 1). (Example 2) 2-<< 3- [2- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 1,4-dihydro-
3-Methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-
Method for producing carboxylate dihydrochloride

[0045]

[Chemical 8]

2- {3- (2-Bromoethoxy) phenyl} ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5- Carboxylate (1.
A solution of 03 g) and 4- (2-hydroxy-3-isopropylaminopropoxy) phenylamine (1.51 g) in acetonitrile (30 ml) was stirred under reflux for 6 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 4/1 (v / v), and then concentrated to give 2
-<< 3- [2- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitro Phenyl) -2
-Trifluoromethylpyridine-5-carboxylate (0.29g) was obtained as a yellow oil.

Next, this 2-<< 3- [2- {4- (2-
Hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4-
(3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (0.29 g) in methanol (5
ml) solution, add 1N methanolic hydrogen chloride (2 ml),
Stir for 30 minutes. Then, the methanol was distilled off under reduced pressure,
2-<< 3- [2- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy]
Phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2
-Trifluoromethylpyridine-5-carboxylate dihydrochloride (0.32g) was obtained as a yellow firm foam.

IR (KBr) 3378, 2955, 1702, 1624, 152
9,1514,1386,1350,1280,1231,1158,1098,827,780,754,7
00 cm ^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ8.08-7.92 (m, 2H), 7.
46 (d, 1H), 7.35 (dd, 1H), 7.17 (t, 1H), 6.83-6.67 (m, 3H), 6.
78 (d, 2H), 6.60 (d, 2H), 6.34 (s, 1H), 5.10 (s, 1H), 4.62-4.5
3 (m, 1H), 4.37-4.27 (m, 2H), 4.10 (t, 2H), 4.02 (dd, 1H), 3.9
3 (dd, 1H), 3.70 (s, 3H), 3.50-3.33 (m, 4H), 3.18-3.08 (m, 1
H), 2.37 (s, 3H), 1.481 (d, 3H), 1.478 (d, 3H); mass spectrometry, m / e (FD) 757 (M ⁺⁺ 1). (Example 3) 2-<< 4- [2- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 2-cyano-1,4
-Dihydro-3-methoxycarbonyl-6-methyl-4
Method for producing-(3-nitrophenyl) pyridine-5-carboxylate dihydrochloride

[0049]

[Chemical 9]

2- {4- (2-bromoethoxy) phenyl} ethyl 2-cyano-1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) pyridine-5-carboxylate (1.00 g) and 4- (2-hydroxy-3-isopropylaminopropoxy) phenylamine (2.07 g) in acetonitrile (50 m
l) After stirring the solution under reflux for 6 hours, the reaction mixture was concentrated under reduced pressure. Then, the residue was subjected to silica gel column chromatography, and chloroform / methanol 4 /
After elution at 1 (v / v) and concentration, 2-<< 4- [2
-{4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 2-cyano-1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) Pyridine-5-carboxylate (0.42g) was obtained as a yellow oil.

Next, this 2-<< 4- [2- {4- (2-
Hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >> ethyl 2-cyano-1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) pyridine-5-carboxylate ( 0.42g) in methanol (5ml) solution to 1
N methanolic hydrogen chloride (2 ml) was added, and the mixture was stirred for 30 minutes. Next, methanol was distilled off under reduced pressure, and 2-<< 4-
[2- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} ethoxy] phenyl >>
Ethyl 2-cyano-1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl)
Pyridine-5-carboxylate dihydrochloride (0.47 g) was obtained as a yellow firm foam.

IR (KBr) 3320,3172,2951,2237,170
6,1616,1528,1514,1436,1386,1349,1245,1218,1179,109
8,827,754 cm ^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ9.65 (s, 1H), 9.47 (br
s, 1H), 8.72 (br s, 1H), 8.06-7.96 (m, 2H), 7.51 (d, 1H), 7.
39 (dd, 1H), 7.12 (d, 2H), 7.02 (d, 2H), 6.82 (d, 2H), 6.80 (d,
2H), 5.12 (s, 1H), 4.54-4.42 (m, 1H), 4.02-3.78 (m, 2H), 3.7
5 (s, 3H), 3.68-3.52 (m, 2H), 3.47-3.35 (m, 1H), 3.30-3.20
(m, 1H), 3.10-3.07 (m, 1H), 2.91-2.74 (m, 2H), 2.32 (s, 3H),
1.46 (d, 2H), 1.44 (d, 3H); mass spectrometry, m / e (FD) 714 (M ⁺⁺ 1). (Example 4) 2-<< 4- [4- {4- (2-hydroxy) -3-Isopropylaminopropoxy) phenylamino} butoxy] phenyl >> ethyl 1,4-dihydro-
3-Methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5-
Method for producing carboxylate dihydrochloride

[0053]

[Chemical 10]

2- {4- (4-Bromobutoxy) phenyl} ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2-trifluoromethylpyridine-5- Carboxylate (1.
A solution of 59 g) and 4- (2-hydroxy-3-isopropylaminopropoxy) phenylamine (2.30 g) in acetonitrile (20 ml) was stirred under reflux for 6 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 6/1 (v / v), and then concentrated to give 2
-<< 4- [4- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} butoxy] phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitro Phenyl) -2
-Trifluoromethylpyridine-5-carboxylate (0.49g) was obtained as a yellow oil.

Next, this 2-<< 4- [4- {4- (2-
Hydroxy-3-isopropylaminopropoxy) phenylamino} butoxy] phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4-
(3-Nitrophenyl) -2-trifluoromethylpyridine-5-carboxylate (0.49 g) in methanol (5
2N methanolic hydrogen chloride (2 ml),
Stir for 30 minutes. Then, the methanol was distilled off under reduced pressure,
2-<< 4- [4- {4- (2-hydroxy-3-isopropylaminopropoxy) phenylamino} butoxy]
Phenyl >> ethyl 1,4-dihydro-3-methoxycarbonyl-6-methyl-4- (3-nitrophenyl) -2
-Trifluoromethylpyridine-5-carboxylate dihydrochloride (0.54g) was obtained as a yellow firm foam.

IR (KBr) 3368,2952,1702,1624,153
0,1513,1438,1387,1349,1280,1229,1178,1084,827,755
cm ^-1 ; ¹ H NMR (CDCl ₃ -TMS) δ8.06-8.02 (m, 2H), 7.
51 (d, 1H), 7.43-7.33 (m, 1H), 7.16-6.94 (m, 4H), 6.85-6.65
(m, 4H), 6.43 (s, 1H), 5.11 (s, 1H), 4.52-4.38 (m, 1H), 4.27
(t, 2H), 4.43-3.74 (m, 4H), 3.71 (s, 3H), 3.51-2.96 (m, 5H),
2.90-2.78 (m, 2H), 2.34 (s, 3H), 2.04-1.81 (m, 4H), 1.50 (d,
3H), 1.48 (d, 3H); mass spec, m / e (FD) 785 (M ⁺ +1).

[0057]

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): (In the formula, W represents a cyano group or a halo (lower) alkyl group, R, R ¹ and R ² each independently represent a (lower) alkyl group, and X and Y each independently represent a hydrogen atom, a (lower) alkyl group. Represents a group, a halo (lower) alkyl group, a halogen or a nitro group, Ar and Ar ¹ represent an optionally substituted aryl group, B represents an alkylene group having 1 to 10 carbon atoms, and A represents Represents an alkylene group having 2 to 10 carbon atoms), or an acid addition salt thereof. 2. The acid addition salt of a dihydropyridine compound according to claim 1, wherein the acid addition salt is a hydrochloride or a sulfate. 3. 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. 4. The following general formula (II): (Wherein W, R ¹ , R ² , B, Ar ¹ , A, X and Y have the meanings defined in claim 1, and Z means 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, comprising reacting with an amine represented by the formula (wherein R and Ar have the meanings defined in claim 1). 5. The leaving group (reactive functional group) is methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, m-nitrobenzenesulfonyloxy group, p-nitrobenzenesulfonyloxy group, chloro group, It is a bromo group or an iodo group, The manufacturing method of Claim 4 characterized by the above-mentioned. 6. The dihydropyridine compound or its acid addition salt according to claim 1, wherein W is a cyano group or a trifluoromethyl 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.