EP0741705A1

EP0741705A1 - 4-(2-(3-aryloxy-2-hydroxypropylamino alkyloxy)-5-nitrophenyl)-1,4-dihydropyridines as antihypertensive agents

Info

Publication number: EP0741705A1
Application number: EP95906531A
Authority: EP
Inventors: Kiyotaka Lions Mansion Akashihigashifutami 207 ITO; Hidekazu Akamatsu; Keizo Inoue; Osamu Onomura; Takeshi Hamatani; Yoichiro Ueda; Kimio Esumi
Original assignee: Fujisawa Pharmaceutical Co Ltd; Daicel Chemical Industries Ltd
Current assignee: Daicel Corp; Fujisawa Pharmaceutical Co Ltd
Priority date: 1994-01-29
Filing date: 1995-01-27
Publication date: 1996-11-13
Also published as: AU1467095A; JPH09510964A; WO1995020576A1

Abstract

A dihydropyridine compound of formula (I), wherein: (1) W represents a cyano or halo lower alkyl group; R1 represents a lower alkyl group; R?2 and R3¿, which may be the same or different, each represents a lower alkyl group; A represents an alkylene group having 1 to 10 carbon atoms; Ar represents an indolyl group, an oxotetrahydronaphthyl group, or a hydroxyl-, cyano-, nitro- or acetyl substituted phenyl group, or (2) W represents a cyano or trifluoromethyl group, R?1, R2 and R3¿ each represents a methyl group, A represents a tetramethylene group, and Ar represents a 2-tolyl or 2-chlorophenyl group, or (3) W represents a trifluoromethyl group, R?1 and R3¿ each represents a methyl group, R2 represents a methyl or ethyl group, A represents a hexamethylene group, and Ar represents a phenyl group, or (4) W represents a trifluoromethyl group, R?1 and R2¿ each represents a methyl group, R3 represents an isopropyl group, A represents a tetramethylene group, and Ar represents a phenyl group, or an acid addition salt thereof. The invention also provides the individual optical isomers of the compounds of formula (I). The invention further includes processes for the production of the above compounds, pharmaceutical compositions containing same and the use thereof.

Description

4-(2-(3-ARYL0XY-2-HYDR0XYPR0PYLAMIN0 ALKYL0XY)-5-NITR0PHENYL) -1,4-DIHYDROPYRIDINES AS ANTIHYPERTENSIVE AGENTS

This invention relates to new dihydropyridine derivatives which possess antihypertensive properties.

More particularly, it relates to new dihydropyridine derivatives and pharmaceutically acceptable salts thereof, which have antihypertensive properties, to processes for the preparation thereof, to a pharmaceutical composition comprising the same, to use of the same as a medicament and to a method for the treatment of hypertension in a human being or an animal.

I the literature many 2,6-dialkyl-4-aryl-l,4- dihydropyridine-3,5-dicarboxylate derivatives are known which are referred to as calcium ion channel blockers, and which produce an antihypertensive effect in the cardiovascular- system of warm-blooded animals. one typical type of these is nifedipine, which is dimethyl l,4-dihydro-2,6-dimethyl-4-o- nitrophenyl-pyridine-3,5-dicarboxylate. Yet another type of 1,4-dihydropyridine derivative is known, namely, nilvadipine, which is characterized by having a cyano group at the 2-position in 1,4-dihydropyridine in place of alkyl group.

Also known axe many l-aryloxy-3-amino-propan-2-ol derivatives which have beta-adrenergic receptor blocking properties, and which also exhibit an antihypertensive effect. Prcpranolol and atenolol, which aire l-(naphth-l-yloxy)-3- isopropylaminopropan-2-ol and l-p-caxbamoylmethylphenoxγ-3- isopropylamino-propan-2-ol, respectively, -ire most widely used exajnoles. Previously described attempts at combining these two types of chemical structure, i.e. 2,6-dialkyl-4- aryl-l,4-dihydropyrindine-3,5-dicarboxylate and 1- aryloxy-3-aιn.,no-propan-2-ol, are found in the literature and patents.

A report by Merck workers (J. Med. Chem. , 24 , 628-631, 1981) describes a case in which a 3-amino-2- hydroxypropoxy substituent was introduced into the 4- aryl substituent of a 4-aryl-1,4-dihydropyridine derivative. US Patent No. 4,500,527 describes similar compounds in which the 3-amino-2-hydroxypropoxy substituent is linked to the 4-aryl substituent by the group -CH=N-, and claims to have antihypertensive and beta-adrenergic receptor blocking properties.

More recently, structurally similar compounds, incorporating a l-aryloxy-3-amino-propan-2-ol moiety onto the 4-aryl substituent of 4-aryl-l,4- dihydropyridine derivatives, are disclosed in European Patent No. 194,751, Japan Koukai No. 86-12662, Japan Koukai No.87-149659, Japan Koukai No. 87-228060, Japan Koukai No. 89-9936, and Japan Koukai No. 89-151554. But all the compounds described in these patents invariably have partial structural features of 2,6- dialkyl-4-aryl-l,4-dihydropyridine-3,5-dicarboxylate having a lower alkyl group at the 2-position in the 1,4-dihydropyridine moiety. We have now found that a class of new type compounds possesses an antihypertensive effect, which incorporate cyano group or halo(lower)alkyl group at the 2-position in the

1,4-dihydropyridine moiety, and the 3-aryloxy-2- hydroxypropylamino substituent is linked to the

4-aryl-l,4-dihydropyridine moiety by way of 4-aryl substituent by the connecting alkylene group.

Reference should also be made to W092/13839 which discloses dihydropyridine compounds and processes for their production.

According to the present invention there is provided a dihydropyridine of the formula:

wherein ( 1 ) W represents a cyano or halo lower alkyl group ; R represents a lower alkyl group; R~ and R , which may be the same or different, each represents a lower alkyl group; A represents an alkylene group having 1 to 10 carbon atoms; Ar represents an indolyl group, an oxotetrahydronaphthyl group, or a hydroxyl-, cyano-, nitro- or acetyl substituted phenyl group, or

(2) W represents a cyano or trifluoromethyl group, R , and R^J each represents a methyl group,

A represents a tetramethylene group, and

Ar represents a 2-tolyl or 2-chlorophenyl group*, or

(3) W represents a trifluoromethyl group, R¹ and R each represents a methyl group, R^ represents a methyl or ethyl group

A represents a hexamethylene group, and Ar represents a phenyl group; or

(4) W represents a trifluoromethyl group,

1 _j

R and R^ each represents a methyl group, R represents an isopropyl group, A represents a tetramethylene group, and Ar represents a phenyl group )

or an acid addition salt thereof.

In this specification the term lower alkyl group means a saturated hydrocarbon grouping which is straight-chained or branched and which contains 1 to 6 preferably 1 to 4 carbon atoms. The term alkylene group having 1 to 10 carbon atoms means straight or branched bivalent paraffinic hydrocarbon residue of 1 to 10 preferably 1 to 6 carbon atoms.

Suitable halo alkyl groups associated with W are the above mentioned lower alkyl groups which further contain from 1 to 3 halogen atoms such as fluorine, chlorine or bromine.

The acid-addition salt of the dihydropyridine derivatives of the invention may be for example, a salt derived from an inorganic acid, for example a hydrochloride or sulphate, or a salt derived from an organic acid, for example an oxalate, lactate, succinate, tartrate, maleate, fumarate, acetate, salicylate, citrate, benzoate, beta-naphthoate, adipate, methanesulphonate, benzenesulphonate, camphor sulphonate or p-toluenesulphonate.

The dihydropyridine derivatives of the invention may be proposed by any chemical process known to be useful for manufacture of chemically analogous compounds. One preferred process for preparing the dihydropyridine compounds of this invention comprises the reaction of an amine of the formula:

₂

wherein W, R , R , R , and A, have the meanings stated above, with an epoxide or an alcohol derivative of the formula:

OH

W ^OAr or L^^-OAr

wherein Ar has the meaning as stated above, and L stands for a suitable leaving group (reactive functional group) , for example, a methanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, m- nitrobenzenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bro o or iodo group.

A second preferred process for manufacturing the dihydropyridine compounds of this invention comprises the reaction of a dihydropyridine derivative of the formula: wherein W, R , R , R , and A, have the meanings stated above, and wherein Z represents a suitable leaving group (reactive functional group) , for example, a methanesulphoπyloxy, benzenesulphonyloxy, p- toluenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bro o or iodo group, with an amine of the formula:

wherein Ar has the meaning as stated above.

The dihydropyridine compounds of this invention may also be prepared, by reduction of an aminoketone of the formula:

H y N U OAΓ wherein R denotes the remainder of the molecule of the compounds of this invention as hereinbefore defined, and Ar has the meaning as stated above, with an appropriate reducing agent such as sodium borohydride in alcohol.

When W is a cyano group, the dihydropyridines of this invention may be prepared by removal of acetic acid from an oxime acetate of the formula:

AcO-" ^c

H wherein R' represents the remainder of the molecule of the compounds of this invention as hereinbefore defined by means of heating, for example, in acetic anhydride.

The dihydropyridine reaction product of this invention can be separated and isolated from the reaction mixture and purified by methods commonly used for such purposes for instance, extraction with a suitable solvent, chromatography, precipitation, recrystallization etc.

Examples of the methods to prepare the staring materials of the reactions as stated above are shown in Schemes A, B and C. Scheme A

-NPht = phthalimide group

Scheme C

-NP t. = phthalimide group

The dihydropyridines of this invention include a least two pairs of optical isomers due to the presenc of an asymmetric carbon atom at the fourth position o the 1 , 4 -dihydropyridine nucleus and an asymmetri carbon atom in the 3 -aryloxy-2 -hydroxypropylamin moiety and thus can exist as each optical isomer or mixture thereof . A mixture of the optical isomers ma be resolved into each optical isomer by a conventiona method for racemic resolution, such as a chemica resolution of the salts of the diastereomer with conventional optically active acid (e.g. tartaric aci or camphor sulphonic acid, etc.) .

Another conventional method capable of directl producing single optical isomers is by reactin optically active starting materials (for example, se

Scheme D) . Thus, the 1, -dihydropyridine nucleus an the 3 -aryloxy-2 -hydroxypropylamine moiety (or the 3 aryloxy- 1 , 2 -epoxypropane or corresponding alcoho moiety) are both secured in an optically active for and an appropriate reaction combining them wit retention of the chirality of the asymmetric carbo atoms can theoretically result in a production of eac optical isomer of the dihydropyridines of thi invention in an optically active form.

Scheme D

The optical isomers of the 1 , 4 -dihyropyridine nucleus can be prepared, for instance, by the optical resolution of the race ic 1, 4-dihydropyridine nucleus as described above (see Schemes A, B and C) using chromatography (e.g. HPLC etc.) , chemical resolution of the salts of the enantiomers with the conventional optical active acid (e.g. tartaric acid or camphor sulphonic acid, etc.) or other conventional optical resolving method.

On the other hand, the optical isomers of the 3- aryloxy-2-hydroxypropylamine moiety and the 3-aryloxy- 1, 2-epoxypropane moiety (see Scheme D) can be prepared, for instance, by the method as shown in Scheme E.

Scheme E

( S )-isomer ( R )-isomer ( R )-isomer

( R )-isomer

The hydropy idine compound of the invention is useful for treating hypertension such as essential hypertension and renal hype tension. cardiopathy such as angina pectoris. arrhythmia and yocardial infarction and heart failure. - 1 D -

The compounds of this invention and their pharmaceutically acceptable salts possess strong and long lasting vasodilating and anti -hypertensive activities and are useful for therapeutical treatment in cardiovascular disorders and in hypertension such as coronary insufficiency, angina pectoris or myocardial infarction, and hypertension. The radical may be selected from the group consisting of cyano, trifluoromethyl, difluoromethyl , monofluoromethyl , 2, 2, 2-trifluoroethyl, tricholoromethyl, dichloromethyl, monochloromethyl, 2, 2, 2-trichloroethyl and preferably is selected from cyano and trifluoromethyl; R¹ may be selected from the group consisting of methyl, ethyl, propyl , isopropyl, butyl, isobutyl, amyl , isoamyl, hexyl, isohexyl and preferably is methyl; the radicals R² and R³ may be independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, isohexyl and preferably R² is methyl, ethyl or isopropyl and R³ is methyl, ethyl or isopropyl; the radical A may be selected from the group consisting of methylene, ethylene, propylene, tri ethylene, tetramethylene, pentamethylene, hexamethylene, hepta ethylene, octamethylene, and preferably is tetramethylene or hexamethylene .

For therapeutical purposes, the dihydropyridine compound of this invention may be administered in a daily dosage of from 0.1 to 500 g, preferably 1 to 250 mg.

The pharmaceutical compositions of this invention may co orise, as an active ingredient, the dihydropyridine com_ϋound or pharmaceutically acceptable salt thereof in an amount of about 0.01 mg. to about 500 g. , preferably about 0.1 mg. to about 250 mg. per dosage unit for oral and parenteral use.

One skilled in the art will recognize that the amount of the active ingredient in the dosage unit form may be determined by considering the activity of the ingredient as well as the size of the host human being. The active ingredient may usually be formulated in a solid form such as tablet, granule, powder, capsule, troche, lozenge or suppository, or a suspension or solution form such as syrup, injection,

emulsion, limonade, etc. and the like. A pharmaceutical carrier or diluent includes solid or liquid non-toxic pharmaceutically acceptable substances. 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, cacao butter, ethyleneglycol or the other conventional ones. Similarly, the carrier or diluent may include a time delay material such as glyceryl onostearate, glyceryl distearate, a wax and the like.

For the purpose of showing the utility of the compound of this invention, the pharmacological test results of a representative compound are shown as follows. (1) Ca channel binding assay Test method

(a) crude vascular microsomal membrane preparation

Porcine thoracic aorta was obtained from a slaughterhouse. The fat and connective tissues were removed and the vascular tissue was frozen at -80^l,c.

The frozen tissue was thawed in the buffer containing 0.25 M of sucrose and 10 mM of MOPS at a pH of 7.4 and homogenized in the same buffer by polytoron, named by Kinematica (tradename) . After filtration of the homogenate through gauzes, the filtrated homogenate was homogenized by a poly-fluo inated ethylene, Teflon (tradename) , glass homogenizer. The homogenate was centrifuged at 1.000 g for 10 minutes. The supernatant was centrifuged at 10,000 g for 10 minutes twice. The supernatant was centrifuged at 100,000g for 60 minutes to yield pellets. The pellets were resuspended in buffer containing 50 M of tris-HCl at a pH of 7.4, which were referred to as crude microsomal membrane fractions. The obtained suspensions were stored at -80°c until use.

(b) [ H1PN200-110 binding to preparative membrane

Frozen crude microsomal fractions were thawed. [³H]PN200-110 at 0. InM was incubated with 50 microliters of the membrane perparation at 37°c for 90 minutes in a final volume of 200 microliters. At the end of the incubation period, the reaction mixture was quickly filtrated over a Whatman GF/C glass filter under aspiration. The filters were then washed 5 times with 3 ml of the buffer containing 50 M of tris-HCl at a pH of 7.4. The radioactivity was counted in 6 ml of Clear-sol I in Packard scintillation counter, Packard TRI-CARB 4530 (tradename) . The test compound was dihydropyridine A. Test results are: test compound K . (M)

- _p dihydropyridine A 5.43 x 10

The dihydropyridine compound of the invention is useful to treat hypertension such as essential hypertension and renal hypertension, cardiopathy such as angina pectoris, arrhythmia and myocardial infarction, heart failure and the like.

{ -) Hypotensive effect Test method

Three Wistar rats were used per group. Each animal was placed in a cage sized to the body after cannulation of catheters into the femoral artery and vein under ether anesthesia. Blood pressure was measured in the femoral artery by means of a pressure, transducer and recorded as electrically integrated values of mean arterial pressure. Heart rate was counted from instant arterial pressure pulses by running the record paper at a faster speed

periodicall •

The test compound was administered intravenously through a catheter cannulated in the femoral vein more than 2 hours after the completion of the operation. Test compound

Dihydropyridine A (The product of Example 13) Test results

(^'3) β receptor binding

Test methods

(a) Crude cardiac microsomal membrane preparation

SD strain rats were sacrificed by decapitation. The heart was removed and homogenized in buffer (0.25M sucrose, lOmM MOPS, pH7.4) by using Polytoron (Kinematica) . The homogenate was homogenized using a teflon glass homogenizer. The homogenate was centrifuged (l,000g x 10 min.) to remove tissue clumps and the supernatant was centrifuged (10,000g x 10 min) twice. The supernatant was again centrifuged (100,000g x 60 min.) to yield pellets. The pellets were resuspended in buffer (50mM Tris-HCl, pH7.4) , which were referred to as crude microsomal membrane fractions. The obtained suspensions were stored ar -80°C until use .

(b) ³H-Dihvdroalprenolol fPHAD binding to preparative membrane

Frozen crude microsomal membrane fractions were thawed. [ H] DHA (InM) was incubated with 50 μl of the membrane preparation at 25°C for 30 minutes in a final volume of 200ul. At the end of the incubation period, reaction mixture was quickly filtrated over a Whatman GF/C glass filter under aspiration. The filters were washed 5 times with 3ml of the buffer (50mM Tris-HCl, pH7.4). The radioactivity was counted in 6ml of Clear- sol I in Packard scintillation counter (Packard TRI- CARB 4530) . Test compound

Dihydropyridine A Test result

The invention is further illustrated but not limited by the following Examples:-

Exampie l

Preparation of 5-isopropyl 3-methyi- 2-cyano-1 ,4-dihydro-4-[2-[4-{2- hydroxy-3-{4-indolyloxy)propyiamino}butoxy]-5-nitrophenyl]-6- methylpyridine-3,5-dicarboxylate

A mixture ' of 5-isopropyl 3-methyl 4-{2-(4-bromobutoxy)-5- πitropheπyl}-2-cyaπo-1 ,4-dihydro-6-methylpyridine-3,5-dicarboxylate (0.41 g) and 2-hydroxy-3-(4-iπdolyloxy)propylarnine (0.34 g) in acetoπitrile (5 ml) was heated to reflux and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using a 96 / 4(v/v) mixture of chloroform and methanol as an elueπt to afford a solid residue (0.34 g) upon evaporation of the solvents. The solid residue was purified bv recrystallization from chloroform to afford 5-isopropyl 3-methyl 2-cyano-l,4- dihydro-4-[2-[4-{2-hydroxy-3-(4-indoiyloxy)propylamiπo}butαxy]-5- nitrophenyQ-6-methyfpyridine-3,5-dicarboxyiate (0.32 g) as a yeiiow po der, mp 98.5-104 °C;

IR (KSr) 3296, 2953, 2868, 1728, 1640, 1526, 1208, 1167, 1110, 740 cm^'1;

¹H NMR (CDCI₃-T S) S 8.21-8.16 (m, 2H), 8.09 (dd, 1H), 7.15-7.04 ( , 3H), 6.85 (d, 1H), 6.67-6.62 (m, 1 H), 6.52 (d, 1 H), 5.22 (s 1 H), 4.94-4.85 (m, H), 4.43-4.38 (m, 1H), 4.23-4.00 (m, 4H), 3.689 and 3.684 (2s, 3H), 3.08-2.80 (m, 4H), 2.33 and 2.30 (2s, 3H), 1.28 and 1.27 (2d, 3H), 1.02 and 1.01(2d, 3H); mass spectrum, m/e (FD) 662 (M l).

Example 2

Preparation of 5-isopropyl 3-methyl 2-cyano-1 ,4-dihydro-4-[2-[4-{2- hydroxy-3-(3-hydroxyphenoxy)propyiamino}butoxy]-5-nitrophenyl]-6- methylpyridine-3,5-dicarboxylate monohydrochloride

A mixture of 5-isopropyl 3-methyl 4-{2-(4-bromobutoxy)-5- nrtrophenyt}-2-cyano-1 ,4-dihydro-6-methyipyridine-3,5-dicarboxylate (1.13 g), 2-hydroxy-3-(3-hydroxyphenoxy)propyiamine (1.16 g) and potassium carbonate (0.69 g) in acetonitriie (5 mi) was heated tc reflux and stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using a 96 / 4(v/v) mixture of chloroform and methanol as an eiueπt to afford a yellow oil (0.23 g) upon evaporation of the solvents. To a solution of the oil in methanol (3 ml) was added 1N methanol solution of hydrogen chloride (2 mi). The reaction mixture was stirred for 1 hour at room temperature. The methanol was evaporated under reduced pressure. 5-lsopropyl 3-methyl 2-cyano- 1,4-dihydro-4-[2-[4-{2-hydroxy-3-(3- hydroxyphenoxy)propylamino}butoxy]-5-nitrophenyl]-6-methylpyridine-3_:5- dicarboxyiate monohydrochloride was obtained as a stiff yeiiow foam (0.25

9)-

IR (KBr) 3196, 3084, 2980, 2238, 1698, 1594, 1510, 1341, 1302, 1273,

1216, 1097, 754 cm^"1;

¹H N R (Acetone-d^δ-TMS) S 8.15 (d, 1 H), 8.10 (dd, 1 H), 7.16 (d, 1 H), 7.07 (t, 1 H), 6.49-6.41 (m, 3H), 5.27 (s, 1 H), 4.86 (hept, 1 H), 4.63-4.57 (m, 1 H), 4.17 (t 2H), 4.10-4.01 (m, 2H), 3.637 and 3.635 (2s, 3H), 3.43-3.27 (m, 4H), 2.44 (s, 3H), 2.20-2.00 (m, 4H), 1.24 (d, 3H), 0.992 and 0.987 (2d, 3H); mass spectrum, m/e (FD) 639 (fvT+1).

Example 3

Preparation of 5-ethyI 3-methyl 4-[2-[4-{3-(2-cyanophenoxy)-2- hydroxypropylamiπo}butoxy3-5-nitropheπyl]-1 ,4-dihydro-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxyiate

A mixture of 5-ethyl 3-methyl 4-{2-{4-bromobutoxy)-5-πitrophenyi}- 1 ,4-dihydro-6-methyl-2-trifluoromethyipyridine-3,5-dicarboxyiate (0.68 g) and 3-(2-cyanophenoxy)-2-hydroxypropylamiπe (0.65 g) in acetonitriie (5 ml) was heated to reflux and stirred for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (10 ml X 3). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was chromatographed using a siiica gel column (ch!oroform/methanol=10/1 ). 5-Ethyl 3-methyl 4-[2-[4-{3-(2- cyanophenoxy)-2-hydroxypropyiamino}butoxy]-5-πitrophenyi]-1 ,4-dihydro- 6-methyl-2-trifiuoromethyipyridine-3,5-dicarboxyiate was obtained as a stiff pale yellow foam (0.62g).

IR (KBr) 3340, 2949, 2228, 1700, 1599, 1514, 1493, 1340, 1290, 1265, 1222, 1178, 1145, 1098, 753 cm^'1;

'H NMR (CDCIg-TMS) δ 8.11-8.08 (m, 2H), 7.58-7.52 (m, 2H), 7.04 (t, 1H), 7.03-6.98 (m, 1H), 6.89 (d, 1H), 5.34 (s, 1 H), 4.23^.06 (m, 5H), 4.02 (q, 2H), 3.63 (s, 3H), 3.05-2.80 (m, 4H), 2.400 and 2.396 (2s, 3H), 1.95-1.86 (m. 2H), 1.80-1.72 (m, 2H); mass spectrum, m/e (FD) 677 (MVl).

Example 4

Preparation of 5-isopropyl 3-methyl 2-cyaπo-4-[2-[4-{3-(2- cyanopheπoxy)-2-hydroxypropyiamino}butoxyj-5-nitrophenyl]-1 ,4-dihydro- 6-methyipyridine-3,5-dicarboxylate

A mixture of 5-isopropyi 3-methyl 4-{2-{4-bromobutoxy)-5-nitrophenyi}- 2-cyano-1 ,4-dihydro-6-methylpyridine-3,5-dicarboxylate (0.70 g) and 3-(2- cyanophenoxy)-2-hydroxypropyiamine (0.70 g) in acetonitriie (5 ml) was heated to reflux and stirred for 2 hours. Into the reaction mixture was poured water (20 ml) to afford a solid residue. The solid residue was washed with a mixture of toluene (15 ml) and π-hexane (15 ml). The resulting residue was purified by recrystallizatioπ from isopropanol to afford 5-isopropyl 3-methyl 2-cyano-4-[2-[4-{3-(2-cyanophenoxy)-2- hydroxypropylamino}butoxy]-5-πitrophenyf]-1 ,4-dihydro-6-methylpyridine-

3,5-dicarbθXyiate (0.40 g) as an orange powder. mp 102.5-104 °C;

IR (KBr) 2979, 2938, 2230, 1702, 1513, 1493, 1450, 1338, 1303, 1276, 1261 , 1211 , 1098, 760 cm^'1;

'H NMR (CDCI₃-T S) a 8.17 (t, 1 H), 8.09 (dd, 1 H), 7.60-7.53 (m, 2H), 7.08-7.03 (m, 1 H), 6.99 (d, 1 H), 6.87 (d, 2H), 5.22 (s, 1 H), 4.93-4.87 (m, 1 H), 4.40-4.35 (m, 1 H), 4.22-4.02 (m, 4H), 3.680 and 3.576 (2s, 3H), 3.11-2.90 ( , 4H), 2.331 and 2.325 (2s, 3H), 2.00-1.76 (m, 4H), 1.27 and 1.26 (2d, 3H), 1.02 and 1.01 (2d, 3H); mass spectrum, m/e (FD) 648 ( VI). Exa le5

Preparation of 5-isopropyl 3-methyl 2-cyano-l,4- dihydro-4-_[2-[4-_{2-hydroxy-3-(2-nitrophenoxy) propylamino}butox ]-5-nitropheny1]-6- methylpyridine -3,5-dicarboxylate.

A mixture of 5-isopropyl 3-methyl 4-{2-(4-bromobutoxy)-5- πitropheπyl}-2-cyano-1,4-dihydro-6-methylpyridine-3,5-dicarboxylate (0.62 g) and 2-hydroxy-3-(2-πitropheπoxy)propylarnine (0.62 g) in acetonitriie (5 ml) and-dimethylformamide (3 ml) was heated to reflux and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using a 96 / 4(v/v) mixture of chloroform and methanol as an elueπt to afford a yellow oil (0.29 g) upon evaporation of the solvents. To the oil was added ethyl acetate (2 ml) and π-hexaπe (1 ml). The resulting mixture was standing for 12 hours . at room temperature to afford 5-isopropyl 3-methyl 2-cyano-1 ,4-dihydro-4- [2-[4-{2-hydroxy-3-(2-πitrophenoxy)propylamino}butoxy]-5-nitrophenyl]-6- methyipyridiπe-3,5-dicarboxylate (0.16 g) as a yeiiow powder. mp 166-168.5 °C;

IR (KBr) 3446, 3290, 3189, 3088, 2981 , 2935, 2232, 1700, 1608, 1522, 1334, 1302, 1277, 1210, 1101 , 751 cm^'1;

'H MR (CDCI₃-TMS} δ 8.18 (d, 1 H), 8.09 (dd, 1 H). 7.91 (t, 1 H), 7.57

(t, 1H), 7.12-7.08 (m, 2H), 6.88 (d, 1H), 5.22 (s, 1 H), 4.90 (hept, 1H).

4.47-4.38 (m, 1 H), 4.30-4.03 (m, 4H), 3.674 and 3.665 (2s, 3H), 3.20-3.00

(m, 4H), 2.35 and 2.34 (2s, 3H), 2.02-1.70 (m, 4H), 1.27 (d, 3H), 1.01 (d, 3H); mass spectrum, m/e (FD) 668 (MVl).

Example 6

Preparation of 5-ethyl 3-methyl 1 ,4-dihydro-4-[2-[4-{2-hydroxy-3-(2- πitrophenoxy)propylamiπo}butoxy]-5-πitrophenyi]-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate monohydrochloride

A mixture of 5-ethyl 3-methyl 1 ,4-dihydro-4-{2-(4-bromobutoxy)-5- nf^trophenyi}-5-methyi-2-trifiuoromethylpyridine-3,5-dicarboxylate (0.62 g) and 2-hydroxy-3-(2-nitrophenoxy)propylamine (0.62 g) in acetonitriie (8 ml) and dimethylformamide (3 mi) was heated to reflux and stirred for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with -chloroform (10 mi X 3). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, to a solution of the resulting oil in methanol (3 ml) was added 1 N methanol solution of hydrogen chloride (2 ml). ^• The reaction mixture was stirred for 1 hour at room temperature. The methanol was evaporated under reduced pressure. To the residue was added ethyl acetate (2 ml) and n-hexane (1 ml). The resulting mixture was standing for 12 hours at room temperature to afford 5- ethyl 3-methyl 1 ,4-dihydro-4-[2-[4-{2-hydroxy-3-(2- nitropheπoxy)propylamino}butoxy]-5-nitropheny -6-methyi-2- trifluoromethylpyridiπe-3,5-dicarboxylate monohydrochloride (0.29 g) as a yellow powder . mp 105-107.5 °C;

IR (KBr) 3422, 2954,1702, 1624, 1609, 1518, 1347, 1172, 749 cm^*1;

*H NMR (CDCI₃-TMS) δ 9.60 (br s, 1H), 8.60 (br d, 1 H), 8.09 (dd, 1 H), 8.04 (dd, 1 H), 7.90 (d, 1 H), 7.56 (t, 1 H), 7.12-7.03 (m, 2H), 6.89 (d, 1 H), 5.34 (s, 1 H), 4.67 (br s, 1H), 4.31-4.23 (m, 1 H), 4.15-4.07 (m, 2H), 4.05-3.98 (m, 2H), 3.621 and 3.618 (2s, 3H), 3.55-3.25 (m, 4H), 2.447 and 2.437 (2s, 3H), 2.20-1.96 (m, 4H), 1. 6 (t, 3H); mass spectrum, m/e (FD) 697 (M⁺+1).

Example 7

Preparation of dimethyl 1 ,4-dihydro-4-[2-{6-(2-hydroxy-3- phenoxypropyiamino)hexyioxy}-5-nitropheπyl]-6-meihyl-2- trif!uoromethyipyridine-3,5-dicarboxylate

The procedure described in Example 3 was followed using dimethyl ^■ 4-{2-(6-^bromohex_yioxy)-5- ^•nitrophenyl}-1 ,4-dihydro-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate (0.60 g) and 2-hydroxy-3- phenoxypropyiamine (0.52 g) as starting materials. Dimethyl 1 ,4- dihydro-4-{2-{6-(2-hydroxy-3-phenoxypropyiamino)hexyioxy}-5- πitropheny0-6-methyl-2-trifiuoromethyipyridine-3,5-dicarboxylate was

Obtained s a ^"stiff yellow foam (0.52g). IR (KBr) 3341, 3112, 2947, 2858, 1706, 1628, 1599, 1590, 1514, 1497, 1464, 1465, 340, 1269, 1229, 1178, 1144, 1086, 1041, 753 cm^'1;

¹H NMR (CDCI₃-TMS) δ 8.09 (dd, 1H), 8.05 (d, 1H), 7.28 (dd, 2H), 6.96 (t, 1H), 6.91 (dd, 2H), 6.88 (d, 1H), 6.19 and 6.17 (2br s, 1H), 5.39 (s, 1H), 4.10-3.97 (m, 5H), 3.65 (s, 3H), 3.58 (s, 3H), 2.88 (dd, 1H), 2.79 (ddd, 1H), Z72-2.66 (m,2H), 2.40 (s, 3H), 1.85-1.81 (m, 2H), 1.58-1.44 (m,4H); mass spectrum, m/e (FD) 666 (M⁺+1).

Example 8

Preparation of 3-isopropyi 5-methy! 1 ,4-dihydro-4-[2-{4-(2-hydroxy-3- phenoxypropylamino)butoxy}-5-πitropheπyi]-5-methyl-2- trifluoromethyipyridine-3,5-dicarboxylate

The procedure described in Example 3 was followed using 3-isopropyl 5-methyl 4-{2-(4-bromobutoxy)-5-nitrophenyl}-1 ,4-dihydro-6-methyl-2- trifluoromethylpyridiπe-3,5-dicarboxylate (0.60 g) and 2-hydroxy-3- phenoxypropyiamiπe (0.52 g) as starting materials. 3-isopropyl 5-methyl 1 ,4-dihydro-4-[2-{4-(2-hydroxy-3-phenoxypropyiamiπo)butoxy}-5- nitropheny -6-methyl-2-trifluoromethylpyridine-3,5-dicarboxyiate was

Obtained as a stiff yellow foam ( 0. 57g ) .

IR (KBr) 3324,2982, 2945, 1706, 1628, 1600, 1570, 1516, 1514, 1497, 1340, 1268, 1232, 1176, 1145, 1094,753cm^"1;

¹H NMR (CDCI₃-TMS) δ 8.07(dd, 1H), 8.06 (s, 1H), 7.27(t, 2H),6.95(t, 1H), 6.89 (dd, 2H), 6.85 (d, 1H), 6.98 and6.81 (2brs, 1H), 5.31 (s, 1H), 4.91 (quint, 1H), 4.12-3.93 (m, 5H), 3.55 (s, 3H), 2.86 (dt, 1H), 2.79 (ddd, 1H), 2.75 (t, 2H), 2.35 (s, 3H), 1.90-1.83 (m, 2H), 1.73-1.64 (m, 2H), 1.09 (d, 6H); mass spectrum, m/e (FD) 666 (MVl).

Example 9

Preparation of 5-ethyl 3-methyl 1 ,4-dihydro-4-[2-{6-(2-hydroxy-3- pheπoxypropyiamino)hexyloxy}-5-πitrophenyi]-6-methyl-2- trifiuoromethyipyridine-3,5-dicarboxylate

The procedure described in Example 3 was followed using 5-ethyl 3- methyl 4-{2-(6-bromohexyioxy)-5-nitropheπyi}-1 ,4-dihydro-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate ^~ (0.60 g) and 2-hydroxy-3- pheπoxypropylamine (0.51 g) as starting materials. 5-Ethyl 3-methyl 1 ,4- dihydro-4-[2-{6-(2-hydroxy-3-pheπoxypropylamino)hexyloxy}-5- πitropheny -6-methyl-2-trifluoromethylpyridiπe-3,5-dicarboxyiate was

Obtained as stiff yellow foam ( 0. 58g ⁾ .

IR (KBr) 3346, 2935, 2859, 2732, 1701 , 1600, 1589, 1514, 1497, 1468, 1340, 1277, 1244, 1173, 1144, 1082, 1041 , 753, 692 cm^"1;

'H NMR (CDCI₃-TMS) δ 8.10 (dd, 1H), 8.07 (s, 1H), 7.28 (t, 2H), 6.96 (t, 1 H), 6.91 (dd, 2H), 6.88 (d, 1 H), 6.19 and 6.16 (2br s, 1 H), 5.37 (s, 1 H), 4.07- 3.97 (m, 7H), 3.64 (s, 3H), 2.87 (dd, 1 H), 2.79 (ddd, 1 H), 2.73-2.64 (m, 2H), 2.39 (s, 3H), 1.88-1.78 (m, 2H), 1.59-1.43 (m, 4H), 1.14 (t, 3H); mass spectrum, m/e (FD) 680 (M^*+1).

Example 10

Preparation of dimethyl 2-cyano-1 ,4-dihydro-4-[2-[4-{2-hydroxy-3- (2rmethylphenoxy)propylamino}butoxy]-5-nitropheπy -6-methylpyridine- 3,5-dicarboxyiate

A mixture of dimethyl 4-{2-(4-bromobutoxy)-5-nitrophenyl}-2- cyano-1 ,4-dihydro-6-methyipyridine-3,5-dicarboxylate (0.70 g) and 2- hydroxy-3-(2-methylpheπoxy)propylamine (0.75 g) in acetonitriie (5 mi) was heated to reflux and stirred for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (10 ml X 3). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was added methanol (4 ml) and diisopropyl ether (6 ml). The resulting mixture was standing for 2 hours at room temperature to afford dimethyl 2-cyano-1 ,4-dihydro-4-[2-[4-{2-hydroxy-3-(2- methyiphenoxy)propylamino}butoxy]-5-nitropheπyi]-6-methylpyridine-3,5- dicarboxylate (0.44 g) as a yeiiow powder. mp 165-170.5 °C;

IR (KBr) 3196, 3092, 2948, 2236, 1708, 1704, 169S, 589, 152C, 1515, 1514, 1503, 1497, 1338, 1305, 1282, 1208, 749 cm^' ; H NMR (CDCI₃-TMS) δ 8.19 (d, 1H), 8.10-8.07 (m, 1H), 7.15 (d, 2H), 6.92-6.79 (m, 3H), 5.25 (s, 1 H), 4.3 4.26 (m, 1H), 4.08-3.92 (m, 4H), 3.69 (s, 3H), 3.60 and 3.59 (2s, 3H), 3.00-2.76 (m, 4H), 2.32 and Z29 (2s, 3H), 2^46 and 2.237 (2s, 3H), 1.93-1.70 (m, 4H); mass spectrum, m/e (FD) 609 (MV1).

Example 11

Preparation of dimethyl 4-[2-[4-{3-(2-chloropheπoxy)-2- hydroxypropylamiπoJbutoxyJ-S-nitrophenylj^-cyano-l ^-dihydro-e- methylpyridine-3,5-dicarboxyiate

Under the similar conditions to Example 10 starting from dimethyl 4- 2-(4-bromobutoxy)-5-nitrophenyl}-2-cyano-1 _l4-dihydro-6- methylpyridine-3,5-dicarboxylate (0.64 g) and 3-(2-chloropheπoxy)-2- hydroxypropylamine (0.70 g) was obtained . dimethyl 4-[2-[4-{3-(2- chloropheπoxy)-2-hydroxypropylamiπo}butoxy]-5-nitropheπy -2-cyano- 1 ,4-dihydro-6-methylpyridine-3,5-dicarboxylate (0.22 g) as a yeiiow powder. mp 166-177.5 ^"C;

IR (KBr) 3300,3187, 3084, 2950, 2236, 1708, 1702, 1512, 1510, 1506, 1336, 1270, 1224, 1098,748cm^"1;

'H NMR (CDCI₃-TMS) δ 8.18 (d, 1H), 8.09 (dd, 1H), 7.37 (d, 1H), 7.22 (t, 1H), 6.94 (t,2H), 6.86 (d, 1H), 5.24 (s, 1H), 4.34-4.26 (m, H), 4.16-3.95 (πv4H), 3.69 (s, 3H), 3.599 and 3.585 (2s, 3H), 3.01-2.87 (m, 4H), 2.309 andZ289 (2s, 3H), 1.92-1.80 (m, 4H); massspectrum, m/e(FD) 629 (M^*+1).

Example 12

Preparation of dimethyl 1 ,4-dihydro-4-[2-[6-[3-{1-(7,8-dihydro-5- oxo-6H-naphtoxy)}-2-hydroxypropyiaminojhexyloxy]-5-nitropheπyl]-6- methyl-2-trifluoromethylpyridine-3,5-dicarboxylate

The procedure described in Example 3 was followed using dimethyl 4-{2-(6-bromohexyioxy)-5-nitrophenyl}-l ,4-dihydro 6-methyi-2- trifiuoromethylpyridine-3,5-dicarboxyiate (1.00 g) and 3-{1-(7,8-dihydro-5- oxo-6H-naphtoxy)}-2-hydroxypropylamine (1.20g) as starting materials. Dlmethyl 1 ,4-dihydro-4-[2-[6-[3-{1 -(7,8-dihydro-5-oxo-6H-naphtoxy)} 2-hydroxypropyiamino]hexyioxy]-5-nitrophenyl]-6-methyl-2- trifluoromethylpyridiπe-3,5-dicarboxyiate was obtained as a stiff yen ow foam (0.61 g).

IR (KBr) 3378, 2947, 2860, 1706, 1686, 1590, 1514, 1340, 1265, 1227, 1182, 1144, 1086, 1033, 1007, 751, 726cm^*1;

¹H NMR (CDCI_g-TMS) δ 8.09 (dd, 1H), 8.05 (d, 1H), 7.67 (d, 1H), 7.26 (t, 1H), 7.03 (d, 1H), 6.88 (d, 1H), 6.14 and 6.12 (2br s, 1H), 5.40 (s, 1H), 4.13-3.98 (m, 5H), 3.65 (s, 3H), 3.59 (s, 3H), 2.83 (ddd, 1H), 2.75-2.58 (m, 2H), 2.63 (t, 2H), 2.41 (s, 3H), 2.12 (quint, 2H), 1.88-1.78 (m, 2H), 1.62-1.43 (m,4H); mass spectrum, m/e (FD) 734 (M⁺+1).

Example 13

Preparation of dimethyl 1 ,4-dihydro-4-[2-[4-{2-hydroxy-3-(2- methylphenoxy)propyiamino}butoxy]-5-πitropheπy0-6-methyl-2- trifluoromethy!pyridine-3,5-dicarboxylate monohydrochloride

A mixture of dimethyl 1 ,4-dihydro-4-{2-(4-bromobutoxy)-5- nitrophenyl}-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate (0.79 g) and 2-hydroxy-3-(2-methylphenoxy)propylamine (0.73 g) in acetonitriie (10 mi) was heated to reflux and stirred for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (10 ml X 3). The combined extracts were washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, to a solution of the resulting oil in methanol (3 ml) was added 1N methanol solution of hydrogen chloride (2 ml). The reaction mixture was stirred for 1 hour at room temperature. The methanol was evaporated under reduced pressure. To the residue was added ethyl acetate (2 ml) and n-hexane (1 ml). The resulting mixture was standing for 12 hours at room temperature to afford dimethyl 1 ,4-dihydro-4-[2-[4-{2-hydroxy-3- (2-methylpheπoxy)propyiamino}butoxy]-5-nitropheπyi]-6-methyl-2- trifiuoromethylpyridine-3,5-dicarooxylate monohydrochloride (0.50 g) as a yellow powder. mp 175.5-182 'C;

IR (KBr) 3278, 2952, 1699, 1506, 1335, 1289, 1269, 1252, 1182, 1106, 1088, 747 cm^"1;

¹H NMR (CDCI₃-TMS) δ 8.06 (dd, 1H), 8.02 (t, 1H), 7.10 (t, 2H), 6.87 (t, 1 H), 6.81 (d, 1 H), 6.73 (d, 1 H), 5.38 (s, 1H), 4.70^.63 (m, 1 H), 4.10-3.83 (m, 4H), 3.63 (s, 3H), 3.58 (s, 3H), 3.40-3.24 (m, 4H), 2.416 and 2.412 (2s, 3H), 2.18 (s, 3H), 2.17-1.98 (m, 4H); mass spectrum, m/e (FD) 652 (M^*+1).

Example 14

_Preparation of •dimethyl 4-[2-[4-{3-(2-chlorophenoxy) -2- hydroxypropylamino}butoxy]-5- nitrophenyl]-l,4-dihydro-6- methyl-2-trifluoromethylpyridine-3,5- dicarboxylate monohydrochloride.

The procedure described in Example 13 was followed using dimethyl 4-[2-(4-bromobutoxy)-5- nitrophenyl]-l,4-dibydro-6- methyl-2-trifluomethylpyridine-3,5-dicarboxylate (0.80g) and 3- (2-chlorophenoxy)-2-hydroxypropyla-nine (l.OOg) as starting materials. Dimethyl 4-[2-[4-{3-(2-chlorophenoxy)-2- hydroxypropylamino}butoxy]-5-nitrophenyl] -1,4-dihydro -6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate monohydrochloride was obtained as a yellow powder (0.43 g) . mp107.5-110^*C;

-IR (KBr) 3296,2950, 1704, 1698, 1694, 1686, 1590, 1520, 1516, 1512, 1510, 1502, 1488, 1342, 1338, 1278, 1270, 1250, 1224, 1179, 1146, 1100, 752cm^*1;

Η NMR (CDCI3-TMS) δ 8.05 (dd, 1H), 8.03 (s, 1H), 7.32 (d, 1H), 7.17 (t, 1H), 6.91 (t, 1H), 6.87 (d, 1H), 6.83 (d, 1H), 5.36 (s, 1H), 4.65-4.58 (m, 1H), 4.15-3.99 (m, 4H), 3.62 (s, 3H), 3.58 (s, 3H), 3.42-3.22 (m, 4H), 2.416 and2.411 (2s, 3H), 2.13-1.95 (m, 4H); mass spectrum, m/e (FD) 672 (MV1).

Example 15

Preparation of 5-ethyl 3-methyl 4-[2-[4-{3-(2-acetyiphenoxy)-2- πydroxypropylamino}butoxy]-5-nitrophenyl]-1 ,4-dihydro-5-methyl-2- trifiuoromethylpyridine-3,5-dicarboxylate monohydrochloride

To a solution of 5-ethyl 3-methyi 4-{2-(4-aminobutoxy) -5- πitropheπyl}-1 ,4-dihydro-6-methyl-2-trffluoromethylpyridine-3,5- dicarboxylate (2.01 g) in methanol (10 ml) was added 3-(2-acetyiphenoxy)- 1 ,2-epoxypropane (0.77 g). The mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was chromatographed on a silica gel coiumπ using a 96/4(v /v) mixture of chloroform and methanol as an eluent to afford a yellow oil (0.23 g). To a solution of the oil in methanol (3 ml) was added 1 N methanol solution of hydrogen chloride (2 ml). The reaction mixture was stirred for 1hour at room temperature. The methanol was evaporated under reduced pressure. 5-Ethyl 3-methyl 4-[2-[4-{3-(2-acetylpheπoxy)-2- hydroxypropylaminoJbutoxyj-S-nitropheπylH -dihydro-δ-methyl^- trifluoromethylpyridine-3,5-dicarboxylate monohydrochloride was obtained aS a stiff yellow foam ( 0 .24g ) .

IR (KBr) 3308, 2953, 1699, 1674, 1514, 1340, 1258, 1236, 1178, 1085, 753 cm^*1;

¹H NMR (CDCI₃-TMS) δ 9.30 (br d, 1 H). 9.10 (br s, 1 H), 8.10-8.04 (m, 2H), 7.77 (d, 1 H), 7.66 (br d, 1 H), 7.51 (t, 1 H), 7.07 (t, 1 H), 6.97 (d, 1 H), 6.88 (d, 1H), 5.29 (s, 1H), 4.60 (br s, 1 H), 4.22-4.18 (m, 2H), 4.07 (br t, 2H), 3.98 (q, 2H), 3.65-3.20 (m, 4H), 3.597 and 3.585 (2s, 3H), 2.57 (s, 3H), 2.470 and 2.462 (2s, 3H), Z22-2.00 (m, 4H), 1.15 (t, 3H); mass spectrum, m/e (FD) 694 (M^*+1).

The compounds obtained as shown in Examples 1-15 include two pairs of optical isomers due to the presence of an asymmetric carbon atom at the fourth position of the 1 , 4 -dihydropyridine nucleus and an asymmetric carbon atom in the 3-aryloxy 2- hydroxypropylamino moiety. For example, dimethyl 1,4- dihydro-4 - [2- [4- {2-hydroxy-3 - (2- methylphenoxy) propylamino}butoxy] -5-nitrophenyl] -6- methyl-2- trif luoromethylpyridine-3 , 5-dicarboxylate monohydrochloride as shown in Example 13 exists as a mixture of four optical isomers (isomers A,B,C and D) . One of the methods to obtain each optical isomer

(isomer A,B,C and D) is shown in Examples 16-19.

In Examples 16, 17, 18 and 19, the starting compounds are identified by the following physical data.

(-) -dimethyl-1 , 4-dihydro-4- [2- (4-bromobutoxy ) -5- nitrophenyl ]-6-methyl-2-t if luoromethylpy idine-3,5- dicarboxylate used in Examples 16 and 17

[ -X ]_ -188.4 (C 0.10, methanol) melting point=166.5-169.0 c

(+) -dime thy 1-1, 4-dihydro-4- [2- (4-bromobutoxy ) -5- n it rophenyl]-6-methyl-2-tr if luoromethylpyridine-3, 5- dicarboxylate used in Examples 18 and 19

[ sY ] ^D +179.2 (C 0.10, methanol) melting point=167.0-169.2 c

(R) - (+)-2-hy roxy-3- (2-methylphenoxy ) propyl a ine used in Examples 16 and 18

[ (X 1 +12.4" (C 1.00, methanol) melting point from toluene =60.5-62. l"c

(S)- (-)-2-hydroxy-3- (2-methylphenoxy)propylamine used in Examples 17 and 19

I CX^' -_D -13.0 (C 1.02, methanol) melting point from toluene =64.0-65.5°c Example 16

Preparation of (-)-dimethyl 1, -dihydro-4- [2- [4- { (R) -2-hydroxy-3- ⁽2- methylphenoxy)propylamino}butoxy]-5-nitropheny!]-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate monohydrochloride (isomer A)

The procedure described in Example 13 was followed using (-)- dimethyl 1 ,4-dihydro-4-{2-(4-bromobutoxy)-5-nitropheπyl}-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate (0.50 g) and (R)-(÷)-2-hydroxy-3- (2-methylphenoxy)propylamine (0.50 g) as starting materials. (-)-Dimethyl _l,₄-dihydrό-₄- [₂- [₄-{ (R) -2-hydroxy-3- (2-methylphenoxy⁾propylamino}butoxy] -

5-nitrophenyl]-6-methyl-2-trifluoromethylpyridiπe-3,5-dicarboxylate mono ydroc loride (iSOmer A) was obtained as a yellow powder (0.32g).

[^]_D ²⁵-113.6^° (c1.06, methanol); mp 154.7-156.0 ^*C (from ethyl acetate — n-hexane);

IR (KBr) 3278, 2950, 1731, 1712, 1700, 1510, 1498, 1437, 1335, 1289, 1269, 1251 , 1182, 1150, 1106, 1087, 747 cm^"1 ;

¹H NMR (CDCI₃-TMS) δ 8.05 (dd, 1 H), 8.02 (d, 1 H), 7.10 (t, 2H), 6.92- 6.84 (m, 2H), 6.81 (d, 1H), 6.73 (d, 1H), 5.37 (s, 1H), 4.70-4.62 (m, 1H), 4.13-

3.94 (m, 4H), 3.62 (s, 3H), 3.57 (s, 3H), 3.42-3.24 (m, 4H), 2.41 (s, 3H), 2.23-

1.95 (m,4H), 2.18 (s,3H).

Example 17

_Preparation of ₍-₎ -dimethyl 1, 4-dihydro-4- [2- ^[4- { ^(S) -²-hydroxy-3- ⁽2- methylphenoxy)propylamino}butoxy]-5-nitrophenyl]-6-methyl-2- trifiuoromethylpyridine-3,5-dicarboxylate monohydrochloride (isomer B)

The procedure described in Example 13 was followed using (-)- dimethyl 1 ,4-dihydro-4-{2-(4-bromobutoxy)-5-nitrophenyl}-6-methyl-2- trifiuoromethylpyridine-3,5-dicarboxylate (1.68 g) and (S)-(-)-2-hydroxy-3- (2-methylphenoxy)ρroρylamine (1.68 g) as starting materials. (-)-DimethyT _l,4-_dihydro-₄-_[2-_[4-{_(S)-₂-hydroxy-₃-₍₂-me_thylphenoxy)propylamino}b toxy]-

5-r,itrophenyl]-6-methy!-2-trifiuoromethylpyridine-3,5-dicarboxylate mono ydrochloride (iSOmer B) was obtained as a yellow powder (1.32g). [a]_D ^2~- 147.6^° (C1.02. methanol); mp 171.2-172.6 ^°C (from ethyl acetate);

IR (KBr) 3275, 2953, 1730, 1712.1700.1510, 1497, 1437, 1340.1288, 1268, 1251 , 1180, 1145, 1087, 749 cm^"' ;

'H NMR (CDCI₃-TMS) δ 8.05 (dd, 1H), 8.02 (d, 1H), 7.13-7.06 (m, 2H), 6.90-6.83 (m, 2H), 6.81 (d, 1 H), 6.73 (d, 1 H), 5.37 (s, 1 H), 4.71 -4.61 (m, 1 H), 4.10-4.00 (m, 3H), 3.96 (dd, 1H), 3.62 (s, 3H), 3.58 (s, 3H), 3.38 (dd, 1H), 3.34-3.20 (m, 3H), 2.42 (s, 3H), 2.22-1.95 (m, 4H), 2.18 (s, 3H),.

Example 18

Preparation of (+) -dimethyl l,4-dihydro-4- [2- [4- { (R) ~2-hydroxy-3- (2- methylphenoxy)propylamino}butoxy]-5-πitrophenyI]-6-methyI-2- trifluoromethyIpyridine-3,5-dicarboxylate monohydrochloride (isomer C)

The procedure described in Example 13 was followed using (+)- dimethyl 1 ,4-dihydro-4-{2-(4-bromobutoxy)-5-nitropheπyl}-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate (0.50 g) and (R)-(+)-2-hydroxy-3- (2-methylphenoxy)propy!amine (0.50 g) as starting materials. (÷)-Dimethyl l,4-dihydro-4- [2- [4-{ (R) -2-hydroxy-3- (2-methylphenoxy)propylamino}butoxy] -

5-nitrophenyI]-6-methyI-2-trifluoromethylpyridiπe-3,5-dicarboxylate monohydrochloride (iSOmer C) was obtained as a yellow powder (0.40g).

[tf]_D ²⁵÷163.2^° (d.OO, methanol); mp 168.0-170.5 ^°C (from ethyl acetate — π-hexaπe);

IR (KBr) 3272, 2952, 1732, 1712, 1699.1589, 1512, 1510, 1506, 1497, 1437, 1336, 1288, 1268, 1252, 1207, 1181 , 1144, 1130, 1106, 1086, 747 cm^"1;

¹H NMR (CDCI₃-TMS) δ 8.05 (dd, 1H), 8.02 (d, 1H), 7.09 (t, 2H), 6.92- 6.85 (m, 2H), 6.80(d, 1H), 6.73 (d, 1H), 5.37 (s, 1H), 4.71-4.63 (m, 1H), 4.13- 3.94 (m, 4H), 3.62 (s, 3H), 3.57 (s.3H), 3.41-3.24 (m, 4H), 2.42 (s, 3H), 2.18 (s, 3H).2.18-1.98 (m,4H).

Example 19

Preparation of (->) -dimethyl l , 4-dxhydro-4- [2- [4- I (S) -2-hydroxy-3- ⁽2- methy!phenoxy)propylamino}butoxyj-5-niτrophenyl]-6-methyl-2- trifiuoromethylpyridine-3,5-α^'icarboxylate monohydrochloride (isomer D)

The procedure described in Example 13 was followed using (+)- dimethyl 1 ,4-dihydro-4-{2-(4-bromobutoxy)-5-πitrophenyI}-6-methyl-2- trifluoromethylpyridine-3,5-dicarboxylate (2.02 g) and (S)-(-)-2-hydroxy-3- (2-methylpheπoxy)propylamine (2.02 g) as starting materials. (÷)-Dimethyl

1 , 4-dihydro-4- [2- [4- { (S) -2-hydroxy-3 - (2-methylphenoxy) propylamino}butoxy] -

5-nitrophenyI]-6-methyl-2-trifluoromethylpyridine-3,5-dicarboxylate monohydrochloride (isomer D) was obtained as a yellow powder ( 0.77g) .

[_Q ]_D ²⁵ _÷147.7^β (c 1.01 , methanol); mp 161.0-162.6 ^βC (from ethanol);

IR (KBr) 3276, 2951 , 1731 , 1712, 1699, 1510, 1496, 1436, 1336, 1288, 1269, 1250, 1 182, 1149, 1087, 747 cm^" ;

¹H NMR (CDCI₃-TMS) S 8.05 (dd, 1 H), 8.02 (d, 1 H), 7.13-7.06 (m, 2H), 6.92 (s, 1 H), 6.87(t, 1 H), 6.80 (d, 1 H), 6.73 (d, 1 H), 5.36 (s, 1 H), 4.71-4.62 (m, 1 H), 4.1 1 -3.99 (m, 3H), 3.96 (dd, 1 H), 3.62 (s, 3H), 3.57 (s, 3H , 3.37 (dd, 1 H), 3.32-3.22 (m, 3H), 2.41 (s, 3H), 2.23-1.92 (m, 4H), 2.18 (s, 3H); mass spectrum, m/e (FD) 652 (M~÷1).

The optical isomer D of Example 19 has been found to be the most effective of isomers A to D, in terms of the pharmacological tests (1) and (2) described earlier in this specification.

The products prepared in the preceding Examples 1-19 have the following structural formulae:

Example 1 -

Example 2 -

Example 3 -

Example 4 -

Example 5 - CH

Example 6 -

Example 7 -

Example 8 -

Example 9

Example 1 0 - CH

Example 11 -

Exampie 12 -

EΞxampie 13 -

EΞxampie 14 -

EΞxampie 15 -

Example16 isomer A

Example17 isomer B

Example 9 isomer D

Optically active starting materials as shown in Example 16-19 were prepared by the method described below.

Namely, the optical resolution of (±) -dimethyl l,4-dihydro-4- {2- (4-bromobutoxy) -5-nitrophenyl } -6- methyl-2-trif luoromethylpyridine-3 , 5 -dicarboxylate by HPLC under the conditions stated below afforded each of (+) -dimethyl 1 , 4-dihydro-4- {2- (4-bromobutoxy) -5- nitrophenyl} -6-methyl-2-trif luoromethylpyridine-3 , 5- dicarboxylate and (-) -dimethyl 1, 4-dihydro-4- {2- (4- bromobutoxy ) - 5 -nitrophenyl } - 6 -methyl - 2 - trif luoromethylpyridine-3, 5 -dicarboxylate.

HPLC conditions

Column CHIRALCEL OD 10cm φ x 50cm Eluent n-hexane: 2 -propanol=90 :10 (v/v) Flow rate 190ml /min Wavelength UV-254nm Temp. 25°C

(±) -Dimethyl 1, 4-dihydro-4- {2- (4-bromobutoxy) -5- nitrophenyl} -6-methyl-2-trif luoromethylpyridine-3 , 5- dicarboxylate was prepared by the dehydration of (±) - dimethyl 4- {2- (4-bromobutoxy) -5-nitrophenyl} -2-hydroxy- 6 -methyl -1, 2 , 3 , 4-tetrahydro-2-trif luoromethylpyridine- 3 , 5-dicarboxylate which was synthesized from 2- (4- bromobutoxy ) - 5 -nitrobenzaldehyde , methyl 4,4,4- trif luoroacetoacetate and methyl 3-aminocrotonate .

On the other hand, ( S ) - (-) - 2 - hydroxy- 3 - ( 2 - methylphenoxy) propylamine was prepared by the addition of ammonia to (S) -1, 2 -epoxy-3- (2 -methylphenoxy) propane which was synthesized from (R) -epichlorohydrine and o -cresol. Similarly, ( R) - ( + ) - 2 -hydroxy- 3 - ( 2 - methylphenoxy) ropylamine was prepared from (S) - eoichlorohydrine .

Claims

CLAIMS :

1. A dihydropyridine compound of the formula:

wherein:

(1) W represents a cyano or halo lower alkyl group: R¹ represents a lower alkyl group; R² and R³, which may be the same or different, each represents a lower alkyl group; A represents an alkylene group having 1 to 10 carbon atoms; Ar represents an indolyl group, an oxotetrahydronaphthyl group, or a hydroxyl-, cyano-, nitro- or acetyl substituted phenyl group, or

(2) W represents a cyano or trifluoromethyl group, R¹, R² and R³ each represents a methyl group, A represents a tetramethylene group, and Ar represents a 2-tolyl or 2-chlorophenyl group, or

(3) W represents a trifluoromethyl group, R¹ and R³ each represents a methyl group, R² represents a methyl or ethyl group, A represents a hexamethylene group , and Ar represents a phenyl group, or

(4 ) W represents a trifluoromethyl group , R¹ and R² each reprsent s a methyl group , R³ repre sent s an isopropyl gorup , A represents a tetramethylene group , and Ar represents a phenyl group ,

or an acid additon salt thereof .

2 . A dihydropyridine compound of the formula : wherein W, R¹, R², R³, A and Ar are as defined in claim 1, or an acid addition salt thereof.

3. A dihydropyridine compound of the formula:

wherein W, R¹, R², R³, A and Ar are as defined in claim 1, or an acid addition salt thereof.

4. A dihydropyridine compound of the formula:

5. A dihydropyridine compound of the formula:

6. A dihydropyridine compound according to any preceding claim, the acid addition salt being a hydrochloride or sulphate.

7. A dihydropyridine compound according to any of claims 1 to 5, the acid addition salt being an oxalate, lactate, succinate, tartrate, maleate, fumarate, acetate, salicylate, citrate, benzoate, betanaphthoate, adipate, methanesulphonate, benzenesulphonate, camphor sulphonate or p-toluenesulphonate.

8. A dihydropyridine compound according to any preceding claim, in which W is a trifluoromethyl group.

9. A process for preparing a dihydropyridine compound according to claim 1, in which an amine of the formula:

wherein W, R¹, R², R³ and A are as defined in claim 1, reacts with an epoxide or an alcohol derivative of the formula:-

or

wherein Ar is as defined in claim 1, and L stands for a suitable leaving group (reactive functional group).

10. A process for producing a dihydropyridine compound according to claim 1, in which a dihydropyridine derivative of the formula:

wherein W, R¹, R², R³ and A are as defined claim 1 and Z represents a suitable leaving group (reactive functional group), reacts with an amine of the formula: wherein Ar is as defined in claim 1.

11. A process for producing a dihdyropyridine compound according to claim 1 , by reduction of a dihydropyridine aminoketone derivative of the formula :

wherein W, R¹, R², R³, A and Ar are as defined in claim 1.

12. A process according to claim 11, in which the reduction is effected by sodium borohydride.

13. A process for producing a dihydropyridine compound according to claim 1 and in which W is a cyano group, by removal of acetic acid by heating from an oxime acetate of the formula:

14. A process for preparing an optically active dihydropyridine compound according to claim 2, 3, 4 or 5, wherein the reaction of claim 9 is carried out between one optical isomer of an amine of the formula:

wherein W, R¹, R², R³ and A are as defined in claim 1, substantially in the absence of any other optical isomer thereof, and one optical isomer of an epoxide or an alcohol derivative of the formula:

or

wherein Ar and L are as defined in claim 9, substantially in the absence of any other optical isomer thereof.

15. A process for preparing an optically active dihydropyridine compound according to claim 2, 3, 4 or 5, wherein the reaction of claim 10 is carried out between one optical isomer of a dihydropyridine derivative of the formula: wherein W, R¹, R², R³, A and Z are as defined in claim 10, substantially in the absence of any other optical isomer thereof, and one optical isomer of an amine of the formula

wherein Ar is as defined in claim 1, substantially in the absence of any other optical isomer thereof.

16. A process according to any of claims 9, 10, 14 or 15, in which the leaving group (reactive functional group) is a methanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, m-nitrobenzenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bromo or iodo group.

17. A dihydropyridine derivative when obtained by a process according to any of claims 9 to 16.

18. A pharmaceutical composition comprising as an active ingredient a compound according to any of claims 1 to 8 and 17, and a pharmaceutically acceptable carrier or excipient.

19. A dihydropyridine derivative according to any of claims 1 to 8 and 17, for use in medicine.

20. Use for the manufacture of a medicament for the treatment of hypertension, of a compound according to any of claims 1 to 8 and 17.

21. Use of a compound according to any of claims 1 to 8 and 17 for the treatment of hypertension.

22. A method of treatment of hypertension in a human being or animal which comprises administering thereto an effective amount of a compound according to any of claims 1 to 8 and 17.