WO1992013839A1

WO1992013839A1 - Dihydropyridine compounds, and process for their preparation

Info

Publication number: WO1992013839A1
Application number: PCT/JP1992/000076
Authority: WO
Inventors: Kiyotaka Ito; Hidekazu Akamatsu; Keizo Inoue; Osamu Onomura; Takeshi Hamatani; Yoichiro Ueda; Kimio Esumi
Original assignee: Fujisawa Pharmaceutical Co., Ltd.; Daicel Chemical Industries, Ltd.
Priority date: 1991-01-30
Filing date: 1992-01-28
Publication date: 1992-08-20
Also published as: EP0522176A1; KR960001201B1; GB9102031D0; CA2078338A1; JPH06500336A; KR930700444A

Abstract

The invention relates to dihydropyridines of formula (I) wherein W represents a cyano or halo alkyl group in which the alkyl group has 1 to 6 carbon atoms; R1 represents an alkyl group having 1 to 6 carbon atoms; R?2 and R3¿, which may be the same or different, each represents an alkyl group having 1 to 6 carbon atoms; X and Y, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom or a nitro group; Ar represents an optionally substituted aryl group and A represents an alkylene group having 1 to 10 carbon atoms; or an acid addition salt thereof. The invention also includes methods of producing the said dihydropyridines.

Description

DESCRIPTION

DIHYDROPYRIDINE COMPOUNDS, AND PROCESS FOR THEIR

PREPARATION

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

In 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 1,4-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 cyano group at the 2-position in 1,4-dihydropyridine in place of alkyl group.

Also known are many l-aryloxy-3-amino-propan-2-ol derivatives which have beta-adrenergic receptor blocking properties, and which also exhibit an antihypertensive effect. Propranolol and atenolol, which are l-(naphth-l-yloxy)-3-isopropylaminopropan-2- ol and l-p-carbamoylmethylphenoxy-3-isopropylamino- propan-2-ol, respectively, are most widely used examples. 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-amino-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-l,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-1,4-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.

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

wherein W represents a cyano or halo alkyl group in which the alkyl group has 1 to 6 carbon atoms; R represents an alkyl group having 1 to 6 carbon atoms? R and R , whxch may be the same or dxfferent, each represents an alkyl group having 1 to 6 carbon atoms; X and Y, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a halogen atom or a nitro group; Ar represents an optionally substituted aryl group and A represents an alkylene group having 1 to 10 carbon atoms; or an acid addition salt thereof. The aryl group Ar is preferably an optionally substituted phenyl or naphthyl group. Preferably the substituents are in the ortho and/or para position to the oxy of the aryloxy group ArO-. Suitable substituents are for example alkoxy radicals having 1 to 6 preferably 1 to 4 carbon atoms, a halogen atom such as fluorine, chlorine or bromine and an alkyl group having 1 to 6 preferably 1 to 4 carbon atoms.

Most preferably such substituents are methyl, methoxy or chloro radicals. Preferably Ar is a substituted phenyl group. These specific examples of ArO- where

Ar is substituted phenyl are 2-methoxyphenoxy, 4- methoxyphenoxy, 2-chloro-phenoxy, 4-chlorophenoxy 2- methylphenoxy, 2,4,6-trimethylphenoxy 4-bromophenoxy groups and 4-(N-methylsulphonyl)aminophenoxy.

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. Suitable halogen atom associated with X and/or Y is, for example fluorine, chlorine or bromine and the preferred alkyl group associated with X and for Y is methyl. The term alkylene group of 1 to 10 carbon atoms means straight or branched bivalent paraffinic hydrocarbon residue of

1 to 10 preferably 1 to 6 carbon atoms. 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 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 fo.rmula:

1 ft wherexn W, R , R" , R , A, X, and Y have the meanings stated above , with an epoxide or an alcohol derivative of the formula :

° l>^^ ΛOA_Λr or _L^ O^H _QAr wherein Ar stands for an optionally substituted aryl group, and stands for a suitable leaving group

(reactive functional group) , for example, a methanesulphonyloxy, benzenesulphonyloxy, p- toluenesulphonyloxy, m-nitrobenzenesulphonyloxy, p- nitrobenzenesulphonyloxy, chloro, bromo 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:

1 n wherexn W, R , R , R , A, X, and Y have the meanxngs stated above, and wherein Z represents a suitable leaving group (reactive functional group) , for example, a methanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bromo or iodo group, with an a ine of the formula:

OH ^H2N_^Λ_^0Ar wherein Ar stands for phenyl or naphthyl group as stated above.

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

wherein R denotes the remainder of the molecule of the compounds of this invention as hereinbefore defined, Ar being phenyl or naphthyl, 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:

_Acc ue-*^'

H

wherein R¹ 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 or such purposes for instance, extraction with a suitable solvent, chromatography precipitation, recrystallization etc.

The dihydropyridines of this invention include at least 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 and thus can exist as each optical isomer or a mixture thereof. A racemic mixture of the optical isomers may be resolved into each optical isomer by a conventional method for racemic resolution, such as a chemical resolution of the salts of the diastereomer with a conventional optically active acid (e.g. tartaric acid or camphor sulfonic acid, etc.).

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 myocardinal infarction, and hypertension.

The favourable pharmacological activites of the compound according to this invention are believed to be structurally characterized by the radicals W, R ,

R 2, R3, A, X, Y and the substitution pattern of the substituents of the phenyl ring at the fourth position of the dihydropyridine nucleus. More specifically, the radical W may be selected from the group consisting of cyano, trifluoromethyl, difluoromethyl, monofluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, dichloromethyl, monochloromethyl,

2,2,2-trichloroethyl and preferably is selected from cyano and trifluoromethyl; may be selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, isohexyl and preferably is methyl, ethyl, propyl, isopropyl, butyl ft "3 or xsobutyl; the radxcals R^Λ and R^J may be independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, isoamyl, hexyl, isohexyl and preferably are each selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl; the radical A may be selected from the group consisting of methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octa ethylene, and preferably is tetramethylene; the radicals X and Y are independently and preferably selected from the group consisting of hydrogen, nitro, chloro and fluoro. The preferred substitution pattern of the substituents on the phenyl ring at the fourth position on the dihydropyridine nucleus is selcted from 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 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 comprise, as an active ingredient, the dihydropyridine compound 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, lemonade, 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 monostearate, 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) 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 periodically.

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 1, 2) Test results

(2) Ca channel binding assay Test methods

(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°C. The frozen tissue was thawed in a buffer (0.25M sucrose, lOmM MOPS, pH7.4) and homogenized in the same buffer by polytoron (Kinematica) . After filtration of the homogenate through gauzes, the filtrated homogenate was homogenized using a teflon glass homogenizer. The homogenate was centrifuged (l,000g x 10 min). 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 at -80°C until use. (b) F H]PN200-110 binding to preparative membrane

Frozen crude microsomal fractions were thawed. , -13-

[^■iH]PN200-110 (O.lnM) was incubated with 50 μl of the membrane preparation at 37°C for 90 minutes in a final volume of 200 pi. At the end of the incubation period, 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 (50mM Tris-HCl, pH7.4). The radioactivity was counted in 6 ml of Clear-sol I in Packard scintillation counter (Packard TRI-CARB 4530).

Test compound

Dihydropyridine A

Test result

(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

SUBSTITUTE SHEET -14- (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 at

-80°C until use.

(b) ³H-Dihydroalprenolol fDHA) binding to preparative membrane

Frozen crude microsomal membrane fractions were thawed. [³H] DHA (InM) was incubated with 50 ul 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

Test compound K, ( )

-7

Dihydropyridine A 7.46X10

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

SUBSTITUTE SHEET Example 1.

To a mixture of 5-isopropyl 3-methyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-2-cyano-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate (3.5 g) and 2- hydroxy-3-phenoxy propylamine (3.7 g) in acetonitrile

(65 ml) was added pyridine (0.5 ml). The mixture was heated to reflux and stirred for 4 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 eluent to afford a solid residue

(3.6 g) upon evaporation of the solvents. The solid residue was purified by recrystallization from ethanol to give 5-isopropyl 3-methyl 2-cyano-4-[2-{4-(2- hydroxy-3-phenoxypropylamino)butoxy}-5-nitropheny1]

-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate (2.3 g) as yellow crystals: mp142-151 O;

IR (KBr)2234.1699.1589.1514.1468.1384.1373.1340.1274.1184.1098,755, 691 cm-';

'HNMR (CDCl,-TMS) δ10.25 (brs, 1H), 8.19and 8.18(2d, 1H), 8.10and 8.09(2dd, 1H), 7.30 (dd, 2H),

6.98 (dd, 1H), 6.91 (d, 2H), 6.87 and 6.86 (2d, 1H), 5.22(s 1H).4.90 and 4.90 (2dd, 1H), 4.34-4_.23 (m.

1H),3.91 - 4.10(m,4H), 3.69 (s,3H), 2.55-2.98 (m,4H), 2.32and2.29 (2s,3H).2.10-1.60 (m,4H), 2.10-

1.60 (br, 2H), 1.27, 1.26, 1.01 and1.00(4d,6H); mass spectrum, m/β (FD) 623 (M^*+H).

Example 2_,

To a solution of 5-isopropyl 3-methyl 4- [ 2- ( 4- aminobutoxy) -5-nitrophenyl ] -2-cyano-6-methyl-l , 4- dihydropyridine-3 , 5-dicarboxylate ( 699 mg) in

SUBSTITUTE SHEET -16- methaπol (40 ml) was added l,2-epoxy-3-phenoxypropane

(247 mg) . The mixture was heated to reflux and stirred for 40 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 eluent to afford a solid residue (210 mg) . The residue was purified by recrystallization form ethanol to give 5- isαpropyl 3-methyl 2-cyano-4-[2-{4-(2-hydroxy-3- phenOaXypropylamino)butoxy}-5-nitrophenyl]-6-methyl

-l,4-dihydropyridine-3,5-dicarboxylate (190 mg) as yellow crystals, which was spectroscopically identical with the product from Example 1.

Example 3.

Under the similar conditions to Example 1 starting from 5-isopropyl 3-methyl 4-{2-(4- bromobutoxy)-3,5-dichlorophenyl}-2-cyano-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate(317mg) and

2-hydroxy-3-phenoxypropylamine (390mg) , 5-isopropyl 3-. methyl 2-cyano-4-[2-{4-(2-hydroxy-3-phenoxypropyi- amino)butoxy}-3,5-dichlorophenyl]-6-methyl- \,4- dihydropyridine-3,5-dicarboxylate (190 mg) was obtaine_d as a yellow stiff foam. mp 52-60 ^βC;

1R (KBr) 2236, 1703, 1588, 1511 , 1454, 1385. 1274, 1174, 1095. 755, 692 cm^'1; 'HNMR (CDCt_j-TMS) £7.30-7.24 (m, 2H). 7.17 and 7.16 (2s. 1H). 6.97 (dd, 1H), 6.91-6.89 (m, 2H), 6.71 (s, 1H). 5.903 and 5.088 (2s, 1H), 4.93 ( pt, 1H), 4.32-4.23 (m, 1H), 3.86 -4.08 (m, 4H), 3.71 (s, 3H). 3.05-2.78 (m, 4H), 2.33 and 2.32 (2s.3H), 2.60-1.72 (m, 4H), 2.60-1.72 (br s, 2H). 1.066, 1.072, 1.079 and 1.084 (4d, 6H); mass s-pectrum, m β (FD) 646 (M^*+H).

EET Example 4.

Under similar conditions to Example 1 starting from 3,5-dimethyl 4-{2-(4-bromobutoxy)-5-nitrophenyl>-

2-cyano-6-methyl-1,4-dihydropyridine- 3,5- dicarboxylate (400 mg) and 2-hydroxy-3-phenoxy propyla ine (474mg), 3,5-dimethyl-2-cyano-4-[2-{4-(2- hydroxy-3-phenoxypropylamino)butoxy}-5-nitrophenyl]

-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate

(301mg) was obtained as yellow crystals.

mp 142-153 'C;

IR (KBr) 2236. 1704. 1589. 1513. 1466. 1385. 1339. 1272. 1187. 1099. 754. 692 cnT'; 'H NMR (CDCIj-TMS) δ 10.70-9.90 (br, 1H), 8.19 (d, 1H), 8.10 and 8.09 (2dd, 1H). 7.30 (dd. 2H), 6.99 (dd, 1H), 6.91 (d. 2H), 6.87 and 6.86 (2d, 1H). 5.25 (s 1H). 4.31-4.22 (m, 1H).4.10 - 3.91 (m, 4H). 3.69 (s. 3H), 3.60 and 3.59 (2s, 3H), 2.97-2.78 (m, 4H), 2.33 and 2.29 (2s, 3H), 2.05-1.55 (m, 4H), 2.05-1.55 (br, 2H); mass spectrum, m β (FD) 595 (M^*-+H).

Example 5_

Under the similar conditions to Example 2 starting from 5-isopropyl 3-methyl 4-{2-(4- aminobutoxy)-5-nitrophenyl>-2-cyano-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate (400 mg) and 1,2- epoxy-3-(naphth-l-yloxy) ropane (170mg) 5-isopropyl 3- methyl 2-cyano-4-[2-[4-{2-hydroxy-3-(naphth-l- yloxy)propyla ino}butoxy]-5-nitrophenyl]-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate (138 mg) was obtained as a yellow stiff foam. -18- To a solution of 5-isopropyl 3-methyl 2-cyano-4- [2-[4-{2-hydroxy-3-(naphth-1-yloxy) ropylamino} butoxy]-5-nitrophenyl]-6-methyl-l,4-dihydropyridine- 3,5-dicarboxylate (123mg) in ethanol (ImL) was added maleic acid (21mg) . The mixture was stirred for 30 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform and the resulting solution was washed with water. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was evaporated under reduced pressure to give a maleate salt of 2- σyano-4-[2-[4-{2-hydroxy-3-(naphth-l-yloxy) ropyl amino>butoxy]-5-nitrophenyl]-6-methyl-l,4- dihydropyridine-3,5-dicarboxylic acid 5-isopropyl 3- methyl ester (130mg) as pale yellow crystals.

mp 94.5-105.0 *C;

IR (KBf) 3408. 3086. 2980. 2237. 1702. 1623. 1581. 1512. 1467. 1386. 1341. 1302, 1270, 1241 , 1216, 1100 cm ';

Η NMR (CDCIj-TMS) δ 9.08 (br s, 1H). 8.18 (br d, J-β.OHz, 1H). 8.12 (d, J-2.8Hz, 1H). 8.03 (dd. J-9.0 and 2.8Hz, 1H). 7.76 (d. J-7.6Hz. 1H). 7.47-7.38 (m, 3H).7.35-7.23 (m, 1H). 6.72(d. J-8.4Hz, 1H), 6.68 (d, J-7.5HZ.1 H). 6.31 (s, 2H).5.17 (s 1H), 4.87 (hpt. 1H), 4.64 (br s, 1H).4.19-4.10 (m.2H).3.92 (br s. 1H). 3.61 and 3.60 (2s, 3H). 3.43-3.-25 (m. 4H), 2.293 and 2.290 (2s, 3H), 2.26-1.50 (m, 8H), 1.25 (d, J-6.2HZ, 3H). 0.98 (d. J«6.2Hz, 3H); mass spectrum, πVe (FD) 673 (M^*+1).

Ex-ample 6,

Preparation of dimethyl 2-trifluoromethyl-4- [2- {4- (2-hydroxy-3-phenoxyproylamino) butoxy}-5- nitr opheny 1 ] - 6 -methyl- 1 ,4 -dihydropyridine- 3 , 5 - dicarboxylate .

SUBSTITUTE SHEET -19- A mixture of dimethyl 4-{2-(4-bromobutoxy)-5- nitrophenyl}-2-trifluoromethyl-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate (0.20g, 0.36 mmol) and 2-hydroxy-3-phenoxypropylamine (0.30g, 1.80 mmol) in acetonitrile (5ml) was refluxed for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (5ml 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 silica gel column (chloroform/methanol=10/l) . Dimethyl 2-trifluoro- methyl-4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy} -5-nitrophenyl]-6-methyl-l,4-dihydropyridine-3,5- dicarboxylate was obtained as a yellow stiff foam (0.20g) .

IR (KBr)3350,2950,1700, 1515, 1497,1341,753,693cm^"1;

ΗNMR(CDO_j-TMS) δ 8.09(dd, 1H).8.07-8.09(m, 1H),7.29(t.2H),6.97(t.1H),6.90(d, 1H).6.88(d, 1H), 5.37(s.1H),4.14-4.12(m, 1H).4.08-4.06(m.2H),4.00-3.96(m.2H).3.63(S, 3H).3.59(s.3H), 2.90- 2.79(m,4H).2.40(S,3H), 1.90-1.71(m,4H); mass spectrum, m/e (FD) 638 (M^*+H).

Example 7.

Preparation of 5-isopropyl 3-methyl 2 -trif luoro¬ methyl^-^- {4- (2-hydroxy-3-phenoxypropylamino) butoxy} -5-nitrophenyl ] -6-methyl-l , 4 -dihydropyridine- 3 , 5- dicarboxylate .

SUBSTITUTE SHEET 38

-20- The procedure described in Example 6 was followed using 5-isopropyl 3-methyl 4-[2-(4-bromobutoxy)- 5-nitrophenyl]-2-trifluoromethyl-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate (0.65g, 1.lOm ol) and 2-hydroxy-3-phenoxypropylamine (0.93g, 5.60mmol) as starting materials. 5-isopropyl 3-methyl 2- trifluoromethyl-4-[2-{4-(2-hydroxy-3-phenoxy- propyl-amino)butoxy}-5-nitrophenyl]-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam (0.63g).

IR (KBr) 3350. 2980.2949. 1728. 1699. 1589. 1514. 1497. 1340. 1269. 1228. 1177. 1145. 1082. 754. 692 cm^"'; ¹H NMR (CDCl,-TMS) δ 8.17-8.08(m. 2H), 7.29(t. 2H). 6.97(t, 1H). 6.91(d, 2H), 6.87(d, 1H), 5.32(s. 1H), 4.91-4.86(m. 1H), 4.13-4.08(m. 1H), 4.08-4.02(m. 2H), 4.00-3.95(m. 2H).3.62(s. 3H). 2.89- 2.75(m.4H). 2.38(S.3H). 1 1-1.86(m. 2H). 1.72-1.68(m. 2H), 1.23(d.3H), 0.97(d, 3H); mass spectrum, m/e (FD) 666 (M^*+H).

Example 8_,

Preparation of 5-Isopropyl 3-Ethyl 2- Trifluoromethyl-4-[2-{4-(2-hydroxy-3-phenoxy- propylamino)butoxy}-5-nitropheπyl]-6-methyl-l,4- dihydropyridine-3,5-dicarboxylate monohydrochloride.

A mixture of 5-isopropyl 3-ethyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-2-trifluoromethyl-6- methyl-1,4-dihydropyridine-3,5-dicarboxyla e (0.30g, 0.50 mmol) and 2-hydroxy-3-phenoxypropylamine (0.42g, 2.50mmol) in acetonitrile (5 ml) was refluxed for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (5ml x 3). The combined extracts were

SUBSTITUTESHEET washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was chromatographed on a silica gel column (chloroform/methanol = 10/1). 5-Isopropyl 3-ethyl 2- trifluoromethyl-4-[2-{4-(2-hydroxy-3-phenoxypropyl- amino)butoxy}-5-nitrophenyl]-6-methyl-l,4-dihydro- pyridine-3,5-dicarboxylate was obtained as a yellow oil (0.28g).

To a solution of 5-isopropyl 3-ethyl 2-trifluoro- methyl-4-[2-{4-(2-hydroxy-3-phenoxypropylanu.no)butoxy} -5-nitrophenyl]-6-methyl-l,4-dihydropyridine-3,5- dicarboxylate (0.25g, 0.36 mmol) in methanol (3ml) was added 2N 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. 5-Isopropyl 3-ethyl 2-trifluoro- methy1-4-[2-{4-(2-hydroxy-3-phenoxypropylamino) butoxy}-5-nitrophenyl]-6-methyl-l,4-dihydropyridine- 3,5-dicarboxylate monohydrochloride was obtained as a yellow stiff foam (0.26g).

IR (KBr) 3354.2981.1700.1590, 1514, 1498, 1341, 1274, 1234, 1201, 1177, 1146, 1080, 754, 693 cm^'';

1H NMR (CDCIj-TMS) δ 8.06-8.03(m, 2H), 7.23-7.21(m, 2H), 6.94(t, 1H), 6.85(d, 2H), 6.81(d, 1H), 5.33(s, 1H), 4.88(p, 1H), 4.61(bs, 1H), 4.09-3.96(m, 6H), 3.37-3.23(m.4H). 2.41(s, 3H), 2.20-1.95(m, 4H), 1.19(d,3H), 1.11(t,3H),0.98(d.3H); mass -spectrum, πVe (FD) 680 (M^*+H).

T Example 9

Preparation of dim ethyl 4-[3,5-dichloro-2-{4-(2-hydroxy-3- p enoxypropylamino)butoxy}pheπyI]-6-met yl-2-trifiuoromethyl-1,4-di ydropyridine- 3,5-dicarboxyIate

The procedure described in Example 6 was followed using dimethyl 4-[3,5-dichloro- 2-(4-bromobutoxy)phenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3_I5- dicarboxyiate (0.74g) and 2-hydroxy-3-phenoxypropylamiπe (1.08g) as starting materials. Dimethyl 4-[2-{4-(2-hydroxy-3-phenoxypropylammo)butoxy}-5-πitrophenyl]- S-methyl^-trifluoromethyl-l^-dihydropyridine-S.S-dicaitoxylate was obtained as a yellow stiff foam(0.43g).

IR (KBr) 3338, 2951, 1709, 1563, 1451, 1435, 1286, 1043, 899, 802, 667 cm-1 ;

'H NMR (CDCI3-TMS) S 7.26(t, 2H), 7.23(d, 1H), 6.99(bs, 1H), 6.95(t, 1H), 6.88(d, 2H), 5.24(s, 1H), 4.37(br.s, 1H), 4.02-3.99(m, 4H), 3.67(s, 3H), 3.61 (s, 3H), 3.16- 3.02(m, 4H), 2.43(s, 3H), 2.00-1.90(m, 4H); mass spectrum, m/e (FD) 661 (M^*+1).

Example 10

Preparation of 3-ethyl 5-methyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5- nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate

The procedure described in Example 6 was followed using 3-ethyl 5-methyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5- dicarboxylate (0.50g) and 2-hydroxy-3-phenoxypropylamiπe (0.45g) as starting materials. 3-Ethyl 5-methyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5- nitrophenyl]-6-methyI-2-trifluoromethyl-1,4Hdihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.43g).

IR (KBr) 3332, 2948. 1722, 1708, 1589, 1514, 1496, 1341, 1017, 753, 692 cm-1 ;

Η NMR (CDCI3-TMS) δ 8.09(dd, 1H), 8.08(s, 1H), 7.28(t, 2H), 6.96(t, 1H), 6.90(d, 2H), 6.87(d, 1H), 5.36(s, 1H), 4.13-3.95(m, 7H), 3.57(s, 3H), 2.88(ddd, 1H), 2.81 (dd, 1H), 2.77(t, 2H), 2.38(s, 3H), 1.89-1.68(m, 4H), 1.16(t, 3H); mass spectrum, m/e (FD) 652 (M^*+1 ).

Example 11

Under similar conditions to Example 1 starting from 5-ethyl 3-methyl 4-{2-(2- bromoethoxy)-5-nitrophenyl}-2-cyano-6-methyl-1,4-dihydropyridine-3,5- dicarboxylate(405mg) and 2-hydroxy-3-phenoxypropylamine (548mg) was obtained 5- ethyl 3-methyl 2-cyano-4-[2-{2-(2-hydroxy-3-phenoxypropylamino)ethoxy}-5- nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (86mg) as yellow crystals. mp 191-193 'C (from CH2CI2);

SUBSTITUTE SHEET IR (KBr) 2226, 1697, 1644, 1624, 1599, 1588, 1506, 1344, 1275, 1045, 826, 755 cm-1 ;

1H NMR (CDCI3-TMS) δ 8.30 (br s, 1 H), 8.175 (d, J=2.7Hz, 1 H), 8.106 (dd, J=9.0 and 2.9Hz, 1 H), 7.30 (br t, J=7.3Hz, 2H), 6.99 (br t, J=1.4Hz, 1 H), 6.94-6.90 (m, 3H), 5.34 and 5.29 (2s, 1H), 4.40-4.16 (m, 3H), 4.09 -3.93 (m, 4H), 3.70 (s, 3H), 3.26-2.87 (m, 4H), 2.35 and 2.34 (2s, 3H), 1.201 and 1.198 (2t, J=8.0 and 8.0Hz, 3H); mass spectrum, m/e (FD) 580 (M++H).

Example 12

Under similar conditions to Example 1 starting frcm 3,5-dimethyl | 4-^_2-(2- bromoethoxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylatθ(423mg) and 2-hydroxy-3-phenoxypropylamine (440mg) was obtained

3,5-dimethyl 2-cyano-4- [ 2- 2- ( 2-hydroxy-3-phenoxypropyla ino ) ethoxy}-5- nitrophenyl]-6-methyl-1 ,4-dihydropyridine-3,5--dicarboxylate (96mg) as yellow crystals. mp 160-163 'C (from CH2CI2);

IR (KBr) 2238, 1705, 1652, 1632, 1598, 1587, 1509, 1491 , 1432, 1344, 1301 , 1275, 1217, 1120, 825, 763 cm-1 ;

1 H NMR (CDCI3-TMS) δ 8.17 (t, J=3.0Hz, 1 H), 8.10 (dd, J=9.0 and 2.7Hz, 1 H), 7.33-7.23 (m, 2H), 7.02- 6.90 (m, 4H), 5.35 and 5.34 (2s, 1 H), 4.42-3.94 (m, 5H), 3.71 and 3.61 (2s, 3H), 3.25-2.88 (m, 4H), 2.35 and 2.34 (2s, 3H); mass spectrum, m/e (FD) 567 (M++1 ).

Example 13

Preparation of 5-ethyl 3-methyl 4-[2-{4-(2-hydroxy-3-pheπoxypropylamino)butoxy}-5- nitropheπyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxyiatθ The procedure described in Example 6 was followed using 5-ethyl 3-methyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxylate (0.25g) and 2-hydroxy-3-phenoxypropylamine (0.22g) as starting materials. 5-Ethyl 3-methyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5- nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyndine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.25g).

IR (KBr) 3328, 2950, 1700, 1514, 1496. 1340, 1268, 1175, 1082, 753, 692 cm-1 ;

1 H NMR (CDCI3-TMS) o 8.09(dd, 1 H), 8.08(s, 1H). 7.29(t, 2H), 6.97(t. 1 H), 6.91 (d, 2H), 6.88(d, 1 H), 5.36(s, 1 H), 4.l 3-3.95(m. 7H), 3.63(s, 3H), 2.89(dd . 1 H), 2.82(dd, 1 H), 2.78(t. 2H), 2.39(s, 3H), 1.90-1.67(m, 4H), 1.15(t, 3H); mass spectrum, m/e (FD) 652 (M₊-1 _..

SUBSTITUTE SHEET Exampie 14

_Preparation of 3-ethyl 5-isopropyl 4- [ 5- {4- ( 2-hy roxy-3- phenoxypropytamino)butoxy}-2-πitropheπyl]-6-methyl-2-trifiuoromethyl-l ,4- dihyαropyridiπe-3,5-dicarDoxylate

The procedure described in Example 6 was followed using 3-ethyl 5-isopropyl 4-[5- (4-bromobutoxy)-2-nitropheπyI]-6-methyl-2-trifluoromethyI-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.40g) and 2-hydroxy-3-phenoxypropylamine (0.45g) as starting materials. 3-Ethyl 5-isopropyl 4-[5-{4-(2-hydroxy-3-phenoxypropylamiπo)butoxy}-2- nitrophenyl]-6-methy!-2-trifiuoromethyl-l ,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.39g).

IR (KBr) 3341, 2981 , 2939, 1728, 1702, 1600, 1518, 1345, 1283, 1079, 754,

691 cm-1 ;

1H NMR (CDCI3-TMS) δ 7.91 (d, 1H), 7.27(t, 2H), 6.98(d, 1H), 6.96(t, 1H), 6.91 (d, 2H), 6.75(dd, 1 H), 6.37(s, 1 H), 5.92(s, 1H), 4.88(p, 1 H), 4.18-3.95(m, 7H), 2.89-2.68(m, 4H), 2.40(s, 3H), 1_88-1.66(m, 4H), 1.20(t, 3H), 1.14(d, 3H), 0.88(d, 3H); mass spectrum, m e (FD) 680 (M++1).

Example 15

Preparation of 3-ethyl 5-isopropyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)ethoxy}- 5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylate The procedure described in Example 6 was followed using 3-ethyl 5-isopropyl 4-[2-

(4-bromoethoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxylate (0.30g) and 2-hydroxy-3-phenoxypropylamine (0.35g) as starting materials. 3-Ethyl 5-isopropyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)ethoxy}-

5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.20g).

IR (KBr) 3328, 2981 , 2937, 1702, 1589, 1514, 1497, 1340, 1269, 1228, 1082, 753,

692 cm-1 ;

1H NMR (CDCI3-TMS) δ 8.11 (s, 1 H), 8.10(dd, 1 H), 7.27(t, 2H), 6.96(t, 1H), 6.92(d, 2H), 6.90-6.88(m, 1H), 6.67(s, 1 H), 5.43(s, 1H), 4.89(p, 1 H), 4.2C-3.88(m, 7H), 3.21 - 2.85(m, 4H), 2.40(s, 3H), 1.20(d, 3H), 1.14(t, 3H), 0.98(d_r 3H); mass spectrum, m/e (FD) 652 (M-r₊1).

ExamDie 16

Under similar conditions to Example 1 starting frαn 3 ,5-dimethyl 4-^2-( 6- bromohexyioxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylate(425mg) and 2-hyaroxv-3-phenoxypropylamine (463mg) was obtained 3 ,5-dimethyl 2-cyano-4- [ 2- 6- ( 2-hydroxy-3-phenoxypropylamino ) hexyloxy^-5- πitrophenyl]-6-methyi-1 ,4-dihydropyridiπe-3,5--αicarboxylatθ (350mg) as a yellow stiff foam.

IR (KBr) 2236, 1708, 1682.1644, 1624, 1588, 1514, 1341, 1270, 1245, 1217, 754 cm-1;

1H NMR (CDCI3-TMS) δ 8.16-8.14 (m, 1H), 8.08 (dd, J-9.1 and 2.8Hz, 1H), 7.32- 7.22 (m, 2H), 6.99-6.82 (m, 4H), 5..29 (s, 1H), 4.22-3.90 (m, 5H), 3.68 (s, 3H), 3.58 (s, 3H), 2.97-2.68 (m, 4H), 2.34 and 2.33 (2s.3H), 1.93-1.45 (m, 8H); mass spectrum, m/e (FD) 622 (M+).

Example 17

Preparation of diethyl 4-[ 2-{4-( 2-hydroxy-3-phenoxypropylamino)butoxyj--5- nitrophenyl]-6-methyl-2-trifluoromethyl-l ,4-dihydropyridine-3,5-dicarboxylate

The procedure described in Example 6 was followed using diethyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxylate (0.50g) and 2-hydroxy-3-pheπoxypropylamine (0.43g) as starting materials. Diethyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5- nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.45g).

IR (KBr) 3343, 2981 , 2937, 170., 1589, 1514, 1497, 1340, 1274, 753, 691 cm-1 ;

1 H NMR (CDCI3-TMS) δ 8.12-8.08(m, 2H), 7.29(t, 2H), 6.97(t, 1 H), 6.91 (d, 2H), 6.87(d, 1 H), 5.35(s, 1 H), 4.11-3.95(m, 9H), 2.88(ddd, 1 H), 2.82(ddd, 1 H), 2.77(t, 2H), 2.38(s, 3H), 1.88-1.69(m, 4H), 1.15(t, 6H); ma^ spectrum, m/e (FD) 680(M++1 ).

Example 18

Under the similar conditions to Example 1 starting from 3,5-dimethyl 4-{2-(4- bromobutoxy)-5-nitrophenyl}-2-cyano-6-ethyl-1 ,4-dihydropyridine-3,5- dicarboxylate(367mg) and 2-hydroxy-3-phenoxypropylamiπe (302mg) was obtained

3 , 5-dimethyl 2-cyano-6-ethyl-4- [ 2-( - ( 2-hydroxy-3-phenoxypropylamino ) butoxy) -5- nitrophenyi]-1 ,4-dihydropyridine-3,5-dicarboxyiate (240mg) as a yellow crystals. mp 158 - 162 'C (from ethanol);

IR (KBr) 2236, 1704, 1586, 1510, 1432, 1335, 1268, 1214, 1180, 1096, 750, 691 cm-1 ;

1 H NMR (CDCI3-TMS) δ 8.19 and 8.18 (d, J=2.7Hz, 1 H), 8.08 (dd, J=9.1 and 2.7Hz, 1 H), 7.28 (t, J=7.5Hz, 2H), 6.97 ( , J=7.3Hz, 1 H), 6.90 (d, J=8.0Hz, 2H), 6.86 (d, J=9.2Hz, 1 H), 5.26 (s, 1 H), 4.33-4.25 ( , 1 H), 4.08 - 3.92 (m, 4H), 3.68 (s, 3H), 3.61 and 3.60 (2s. 3H), 3.15 and 3.06 (2dd, J=7.5, 13.1 and 7.4, 13.0Hz, 1 H), 2.97-2.77 (m, 4H), 2.36 and 2.25 (2dd, J-7.4, 12.9 and 7.4, 13.1 Hz, 1 H), 1.97-1.68 (m, 4H), 1.25 and 1.19 (2t, J=7.0 and 7.4Hz, 3H); mass spectrum, m/e (FD. 609 (M—1 ). Examole 9

Under similar conditions _to Example i starting frαn 5-isopropyl 3-methyl 4-^2-

(4-bromoDutoxy)-5-nitrophenyl}-2-cyano-6-methyl-1.4-dihydropyridine-3,5- dicarboxylate(5l 4mg) and 2-hydroxy-3-(2-methoxypnenoxy)propyiamine (567mg) was ob_tained 5-isopropyl 3-methyl 2-cyano-4-[2-[4-(2-hydroxy-3-⁽2- methoxyphenoxy)propylamino}butoxy]-5-nitropnenyl]-6-methyl-1 ,4-dihydropyriσine-

3,5~dicarboxyfate (371 mg) as yellow crystals. mp 73-79 ^*C (from ethanol-water);

1R (KBr) 2234, 1700, 11590, 1471 , 1386, 1372, 1341 , 1273, 1180, 1096 cm-1 ;

1H NMR (CDCI3-TMS) δ 8.20-8.07 (m, 2H), 7.20-6.80 (m, 5H), 5.22 (s, 1 H), 4.90 and 4.89 (2hept, J=6.2 and 6.2Hz, 1H), 4.31-4.24 (m, 1 H), 4.13 - 3.72 (m, 4H), 3.86 (s, 3H), 3.68 (s, 3H), 2.97-2.79 (m, 4H), 2.33 and 2.30 (2s, 3H), 1.97-1.70 (m, 4H), 1.28, 1.27, 1.01 and 1.00 (4d, J=6.3, 6.3, 6.2 and 6.3Hz, 6H); mass spectrum, m e (FD) 653 (M++1 ).

Example 20

Preparation of 3-ethyl 5-isopropyl 4-[2-{4-(2-hydroxy-3-⁽2- methoxyphenoxy)propylamino)butoxy}-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-. dihydropyridine-3,5-dicarboxylate

The procedure described in Example 6 was followed using 3-ethyl 5-isopropyl 4-[2- (4-bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.30g) and 2-hydroxy-3-(2-methoxyphenoxy)propylamine (0.29g) as starting materials. 3-Ethyl 5-isopropyl 4-[2-{4-(2-hydraxy-3-(2- methoxyphenoxy)propyiamino)butoxy}-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4- dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.29g).

IR (KBr) 3342, 2980, 2939, 1698, 1590, 1506, 1340, 1274, 1223, 1178, 1078, 1023, 748 cm-1 ;

1H NMR (CDC13-TMS) δ 8.10-8.07(m, 2H), 7.16(bs, 1 H), 7.00-6.86(m,5H), 5.32(s, 1 H), 4.88(p, 1H), 4.29(br.s, 1 H), 4.11-4.00(m, 6H), 3.84(s, 3H), 3.84-2.92(m, 4H), 2.39(s, 3H), 1.99-1.84(m, 4H), 1.22(d, 3H), 1.13(t, 3H), 0.97(d, 3H); mass spectrum, m/e (FD) 710 (M+-r1 ).

ExamDle 21

Under similar conditions to Example 1 starting frαn 5-isopropyl 3-methyl 4--_2-⁽ 5- bromopenty.oxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarDoxylate(350mg) and 2-hydroxy-3-pheπoxypropyiamiπe (350mg) was obtained 5- isopropyl 3-methyi 2-cyaπo-4-[2-{5-(2-hyαroxy-3-pheπoxypropylamiπo)peπtyloxy}-5- πitropheπyl]-6-methyl-1 ,4-dihydrcpyridine-3,5--dicarboxylate (350mg) as a yellow stiff foam. IR (KBr) 2236, 170C, 1652, 1645, 1634 1589. 1515, 1496, 1340, 1302, 127C, 1215, 1096, 755 cm-1 ;

1 H NMR (CDC13-TMS) δ 8.18 (d, J=2.8Hz, 1 H), 8.09 (dd. J=9.0 and 2.9Hz, 1 H), 7.32-7.23 (m, 2H). 7.02-6.87 (m, 4H), 5.22 (s, 1 H), 4.95-4.87 (m, 1 H), 4.34-4.25 (m, 1 H), 4.10 - 4.03 (m, 2H), 3.99 (d, J=5.6Hz, 1 H), 3.89 (t, J=7.1 Hz, 1 H), 3.70 and 3.68 (2s. 3H), 3.11-2.68 (m, 4H), 2.37 and 2.31 (2s, 3H), 1.98-1.58 (m, 6H), 1.28, 1.27, 1.03 and 1.00 (4d, J=5.8, 5.8, 6.2 and 6.2Hz, 6H); mass spectrum, m/e (FD) 637 (M++1 ).

Example 22

Under similar conditions to Example 1 starting frcm 5-isopropyl 3-methyl 4-^2- (4-bromobutoxy)-5-chlorophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarθoxylate(429mg) and 2-hydroxy-3-phenoxypropylamine (341 mg) was obtained 5- isopropyl 3-methyl 2-cyano-4-[ 5-chloro-2-{4-(2-hydroxy-3- phenoxypropylamino)butoxy}phenyl]-6-methyl-1 ,4-dihydropyridine-3,5--dicarboxyiate (280mg) as a yellow powder.

IR (KBr) 2236, 1698, 1682, 1520, 1496, 1464, 1243, 1213, 1100, 1095, 801 , 755 cm-1 ;

1H NMR (CDCI3-TMS) δ 7.30 (br t, J=7.7Hz, 2H), 7.22 (t, J=2.5Hz, 1H), 7.11 and 7.09 (2t, J=2.5 and 2.5Hz, 1 H), 7.00-6.90 (m, 2H), 6.70 (br d, J=8.5Hz,1 H), 5.04 (s, 1 H), 4.93-4.89 (m, 1 H), 4.31-4.24 (m, 1H), 4.07 - 3.85 (m, 4H), 3.70 (s, 3H), 3.00-2.75 (m, 4H), 2.31 and 2.27 (2s, 3H), 1.86-1.75 (m, 4H), 1.27, 1.26, 1.09 and 1.08 (4d, J-6.1 , 6.2, 6.6 and 6.5Hz, 6H); mass spectrum, m/e (FD) 612 (M÷+1).

Example 23

Under similar conditions to Example 2 starting frcm 5-isopropyl 3-methyl 4- 2- (4-aminobutoxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylate (1.80g) and 3-(2-chloropheπoxy)-1 ,2-epoxypropane (0.49g) was obtained 5-isopropyl 3-methyl 4- [5-[ 4-^_ 3- ( 2-chlorophenoxy ) -2- hydroxypropylamino}butoxy]-5-nitroDhenyl]-2-cyano-6-methyl-1 ,4-dihydropyridiπe-3,5- dicarooxyiate (0.38g) as a yellow stiff foam.

IR (KBr) 2236.1699.1644, 1599, 1516, 1514.1488, 1340, 1272, 121 , 1096, 752 cm-1 ;

1H NMR (CDC.3-TMS) S 8.19-3.16 ( . 1H), 8.12-8.07 (m, 1H), 7.37-7.34 (m. 1H., 7.22 (t, J=7.8Hz, 1H), 6.96-6.84 (m.3H), 5.22 (S, 1H), 4.93-4.87 ( , 1H).4.38-4.32 (m, 1H), 4.16 - 3.96 (m, 4H), 3.684 and 3.673 (2s, 3H), 3.07-2.82 (m, 4H), 2.32 and 2.29 (2s, 3H), 1.95-1.74 (m.2H), 1.23.1.27.1.02 and 1.00 (4d. J-6.2.6.2. S.2 and 6.2Kz. 6H); -2b-

mass spectrum, m/e (FD) 657 (M— rl).

Example 24

Preparation of 3-ethyi 5-isobutyl 4-[2-{4-(2-hydroxy-3-phenoxypropyiamino)butoxy}- 5-nitrophenyl]-6-methyI-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylate

The procedure described in Example 6 was followed using 3-ethyl 5-isobutyl 4-[2-(4- bromobutoxy)-5-πitropheπyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.47g) and 2-hydroxy-3-phenoxypropylamine (0.42g) as starting materials. 3-EthyI 5-isobutyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5- nitrophenyI]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3, 5-dicarboxylate was obtained as a yellow stiff foam(0.44g).

IR (KBr) 3352, 2960, 1727, 1703, 1589, 1514, 1498, 1341 , 1273, 1228, 1175, 1080, 1015, 753, 692 cm-1 ;

1 H NMR (CDCI3-TMS) δ 8.08(dd, 1 H), 8.05(dd, 1 H), 7.26(t, 2H), 6.96(t, 1 H), 6.88(d, 2H), 6.85(d, 1 H), 6.70(s, 1 H), 5.38(s, 1 H), 4.39(bs, 1 H), 4.11-3.99(m, 6H), 3.12-3.02(m, 2H). 2.43(s, 3H), 1.96-1.90(m, 4H), 1.84-1.81 (m, 1 H), 1. 6(t, 3H), 0.84(d, 3H), 0.78(d, 3H); mass spectrum, m/e (FD) 694 (M++1 ).

Example 25

Preparation of 3-ethyl 5-propyl 4-[2-{4-(2-hydroxy-3-phenoxypropyiamino)butoxy}-5- nitrophθnylj-e-methyl^-trifluoromethyl-l^-dihydropyridine-S.δ-dicarboxylate

The procedure described in Example 6 was followed using 3-ethyl 5-propyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5- dicarboxyiate (0.35g) and 2-hydroxy-3-phβnoxypropylamine (0.38g) as starting materials. 3-Ethyl 5-propyl 4-[2-{4-(2-hydroxy-3-pheπoxypropylamiπo)butoxy}-5- πitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.30g}.

IR (KBr) 3342, 2940, 1724, 1703,1514, 1497, 1340, 1274, 1228, 1176, 1081 , 753 cm-1 ;

1 H NMR (CDCI3-TMS) δ 8.10-8.06(m, 2H), 7.27(t, 2H), 6.97(t, 1 H), 6.89(d, 2H). 6.86(d, 1 H), 6.74(s, 1 H), 5.37(s, 1 H), 4.34(br.s, 1 H), 4.10-3.91 (m, 8H), 3.10-2.97(m, 4H). 2.41 (s, 3H), 1.97-1.84(m, 4H), 1.58-1.50(m, 2H), 1.15(t, 3H), 0.81 (t, 3H); mass spectrum, m/e (FD) 680 (M+÷1).

Example 26

Under similar conditions to Example 2 starting frcm 5-isopropyl 3-methyl 4-/2- (4-amtnobutoxy)-5-nitrophenyI}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarooxylate (1 ,250mg) and 1 ,2-epoxy-3-(2-methytphenoxy)propane (304mg) was obtain ed 5 -iso p ropy l 3-m ethyl 2-cyan o -4-[2-[4-{2 -hyd ro xy-3-(2- methylphenoxy)propylamiπo}butoxy]-5-nitrophenyl]-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylate (230 mg) as a yellow stiff foam.

IR (KBr) 2236, 1701 , 1644, 1590, 1514, 1496, 1339, 1271 , 1215, 1097, 7532 cm-1 ;

^■ NMR (CDCI3-TMS) δ 8.20-8.18 (m, 1H), 8.12-8.07 (m, 1H), 7.17-7.13 (m, 2H), 6.92 and 6.79 (m, 3H), 5.22 (s, 1 H), 4.94-4.86 (m, 1 H), 4.36-4.29 (m, 1 H), 4.09 - 3.93 (m, 4H), 3.69 and 3.68 (2s, 3H), 3.04-2.80 (m, 4H), 2.33 and 2.30 (2s, 3H), 2.25-2.23 (2s, 3H), 1.95-1.73 (m, 4H), 1.28, 1.27, 1.02 and 1.01 (4d, J=6.2, 6.1 , 6.1 and 6.2Hz, 6H); mass spectrum, m/e (FD) 637 (M^*+1).

Example 27

Under similar conditions to Example 2 starting from 5-isopropyl 3-methyl 4-{2- (4-aminobutoxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylate (1.25g) and 1 ,2-epoxy-3-(2,4,6-trimethylphenoxy)propane (356mg) was obtained 5-isopropyl 3-methyl 2-cyano-4-[2-[4-{2-hydroxy-3-(2,4,6- trimethylphenoxy)propylamino}butoxy]-5-.nitrophenyl]-6-methyl-1 ,4-dihydropyridine- 3,5-dicarboxylate (160 mg) as a yellow stiff foam

IR (KBr) 2236, 1700, 1646, 1636, 1590, 1518, 1340, 1270, 1214, 1095, 735 cm-1 ;

¹H NMR (CDCI3-TMS) δ 10.30 (brs, 1H), 8.18 (d, J=2.9Hz, 1H), 8.08 (dd, J= 9.2 and 2.9Hz, 1 H), 6.87-6.80 (m, 3H), 5.22 (s, 1H), 4.95-4.86 (m, 1 H), 4.38-4.29 (m, 1 H), 4.10 - 3.98 (m, 2H), 3.85-3.63 (m, 2H), 3.68 and 3.67 (2s, 3H), 3.09-2.87 (m, 4H), 2.36 and 2.33 (2s, 3H), 2.25-2.18 (m, 9H), 1.98-1.78 (m, 4H), 1.28, 1.27, 1.01 and 1.00 (4d, J=6.2, 6.2, 6.2 and 6.2Hz, 6H); mass spectrum, m/e (FD) 665 (M^*+1 ).

Example 28

Under similar conditions to Example 1 starting from 5-isopropyl 3-methyl 4-{2-(4- bromobutoxy)-5-methyl-3-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- ^• dicarboxylate (2.28g) and 2-hydroxy-3-phenoxypropylamine (2.50g) was obtained 5- isopropyl 3-methyl 2-cyano-4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5- methyl-3-nitrophenyl]-6-methyl-1 ,4-dihydropyridine-3,5--dicarboxylate (930mg) as a yellow stiff foam.

IR (KBr) 2236, 1699, 1600, 1530, 1526, 1498, 1222, 1095, 755 cm-1 ;

¹H NMR (CDCI3-TMS) δ 7.47 (d, J=1.4Hz, 1 H), 7.32-7.25(m, 3H), 6.96 (br t, J= 7.2Hz, 1 H), 6.90 (br d, J=7.9Hz, 2H), 5.203 and 5.195 (2s, 1 H), 4.93 (hept. J=6.2Hz, 1 H), 4.33-4.24 (m, 1 H), 4.06 - 3.95 (m, 2H), 3.80-3.74 (m, 2H), 3.709 and 3.706 (2s, 3H), 3.06-2.77 (m, 4H), 2.32 (s, 3H), 2.31 and 2.17 (2s, 3H), 1.98-1.68 (m, 4H), 1.23 (br d, J=6.3Hz, 3H), 1.062 and 1.060 (2d, J=6.3 and 6.3Hz, 3H); mass spectrum, m/e (FD) 637 (M~1 ).

Example 29

Under similar conditions to Example 1 starting frcm 5-isoproyl 3-methyl 4-.J2-

(3-bromcpropoxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydrαpyridiπe-3,5- dicaraoxylate(280mg) and 2-hydroxy-3-phenoxypropyiamine (224mg) was obtained 5- isopropyf 3-methyl 2-cyano-4-[2-{3-(2-hydroxy-3-phenoxypropylamiπo)propoxy}-5- nitropheπyl]-6-methyI-1 ,4-dihydropyridine-3,5-dicarboxyIate (120mg) as a yellow stiff foam.

IR (KBr) 3466, 3232, 3089, 2981 , 2929, 2240, 1735, 1713, 1702, 1520, 1508, 1342, 1274, 1213, 1099, 825, 756, 692cm-1 ;

1HNMR(CDCI3-TMS) 58.15 and 8.14(2d,1 H), 8.08 and 8.06(2dd,1 H), 7.27 and 7.25 (2dd_r2H), 6.97-6.83(m,4H),5.20(s,1 H),4.87-4.83(m,1 H),4.34-4.32(m,1 H),4.04-

3.93(m,4H),3.68 and 3.67(2s,3H), 3.0-2.7(m,4H), 2.26 and 2.21 (2S,3H),2.18- 2.00(m,3H),1.23,1.22,0.97 and 0.94(4d,6H); mass spectrum, m/e (FD) 609 (M++1).

Example 30

Under similar conditions to Example 1 starting frcm 5-isopropyl 3-methyl 4- 2-

(4-bromαbutoxy)-4,6-dichiorophenyl}-2-cyaπo-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylate(0.38g) and 2-hydroxy-3-phenoxypropylamine (0.34g) was obtained 5- isopropyl 3-methyl 2-cyano-4-[4,6-dichloro-2-(4-(2-hydroxy-3- phenoxypropylamino)butoxy}phenyl]-6-methyl-1 ,4-dihydropyridine-3,5--dicarboxylate (0.20g) as a yellow stiff foam.

IR (KBr) 2235, 1696, 1578, 1522, 1454, 1302, 1246, 1213, 1096, 755 cm-1 ;

1 H NMR (CDCI3-TMS) δ 7.31-7.23 (m, 2H), 6.99-6.86 (m, 4H), 6.72 (dd, J=8.1 and 1.8Hz,1H), 5.70 and 5.69 (2s, 1H), 5.03-4.95 (m, 1 H), 4.33-4.22 (m, 1H), 4.05 - 3.82 (m, 4H), 3.680 and 3.676 (2s, 3H), 2.93-2.72 (m, 4H), 2.24 and 2.23 (2s, 3H), 1.90-1.68 (m, 4H), 1.24, 1.23, 1.03 and 1.01 (4d, J=6.2, 6.2 6.3 and 6.3Hz, 6H); mass spectrum, m/e (FD) 645 (M+).

Example 31

Under similar conditions to Example 1 starting frcm 5-isopropyl 3-methyl 4-{_2- (4-bromobutoxy)-5-πitropnenyl}-2-cyaπo-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylate(400mg) and 2-hydroxy-3-(4-methoxyphenoxy)propyiamine (441 mg) was obtained 5-isopropyl 3-methyl 2-cyano-4- [ 2- [ 4-^2-hydroxy-3- ( 4- methoxyphenoxy)propylamiπo}butoxy]-5-nitrophenyl]-6-methyl-1,4-dihydropyridine- 3,5--dicarboxylate (183 mg) as a yeilow powder, p 81-84 ^*C; IR (KBr) 2235, 1699, 1590, 1510, 1341 , 1302, 1273, 1216, 1097, 824 cm-1 ;

1 H NMR (CDC13-TMS) 5 10.02 (br s, 1 H), 8.18 (d, J=2.7Hz, 1 H), 8.09 (br d, J=9.1 Hz, 1 H), 6.88-6.79 (m, 5H), 5.22 (s, 1 H), 4.94-4.86 (m, 1 H), 4.34-4.27 (m, 1 H), 4.07 - 3.87 (m, 4H), 3.76 (s, 3H), 3.68 and 3.57 (2s, 3H), 3.03-2.84 (m, 4H), 2.34 and 2.31 (2s, 3H), 1.95-1.75 (m, 4H), 1.28, 1.27, 1.01 and 1.00 (4d. J=6.0, 6.0, 6.0 and 6.0Hz, 6H); mass spectrum, m/e (FD) 653 (M+-f-l ).

Example 32

Under similar conditions to Example 1 starting frcm 5-isopropyl 3-methyl 4-{2-

(4-bromobutoxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- dicarboxylate(490mg) and 3-(4-chloroρhenoxy)-2-hydroxypropylamine (553mg) was obtained 5-isopropyl 3-methyl 4-[2-[4-{.3-(4-chlorophenoxy)-2- hydroxypropylamino}butoxy]-5-nitropheπyl]-2-cyano-6-methyl-1 ,4-dihydropyridine-3,5- -dicarboxylate (388 mg) as a yellow powder. mp 96-99 'C;

IR (KBr) 2234, 1693, 1516, 1514, 1493, 1338, 1301 , 1275, 1213, 1099, 824 cm-1 ;

1 H NMR (CDCI3-TMS) δ 8.19-8.16 (m, 1H), 8.12-8.08 (m, 1H), 7.26-7.22 (m, 2H), 6.88-6.82 (m, 3H), 5.22 (s, 1 H), 4.93-4.87 (m, 1 H), 4.33-4.27 (m, 1 H), 4.07 - 3.88 (m, 4H), 3.69 and 3.68 (2s, 3H), 3.01-2.80 (m, 4H), 2.32 and 2.30 (2s, 3H), 1.95-1.74 (m, 4H), 1.28, 1.27, 1.02 and 1.01 (4d, J-6.1 , 6.2, 6.1 and 6.2Hz, 6H); mass spectrum, m/e (FD) 657 (M++1).

Example 33

Preparation of diethyl 4- [ 2- /4- ( 2-hydroxy-3- ( 2- methoxyphenoxy)propyiamino)butoxy}-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4- dihydropyridine-3,5-dicarboxylate

The procedure described in Example 6 was followed using diethyl 4-[2-(4- bromobutoxy)-5-nitrophenyl]-6-methyl-2-trifiuoromethyl-1 ,4-dihydropyridine-3,5- dicarboxylate (0.50g) and 2-hydroxy-3-(2-methoxypheπoxy)propylamiπe (0.51 g) as starting materials. Diethyl 4-[2-{4-( 2-hydroxy-3-(2- metnoxyphenoxy)propylamino)butoxy}-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1 ,4- dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.46g).

IR (KBr) 3315^, 2939, 1702, 1629, 1591 , 1506, 1455, 1368, 1340, 1278, 1095, 744 cm-1 ;

1 H NMR (CDCI3-TMS) δ 8.10(s, 1H), 8.07(dd, 1 H), 6.99-6.86(m, 5H), 5.33(s, 1 H), 4.19-4.18(m^, 1 H), 4.08-3.97(m, 8H), 3.85(s, 3H), 2.93-2.81 (m. 4H), 2.38(s, 3H), 1.19- 1.86(m, 2H), 1.75-1.72(m. 2H), 1.16-1.13(m, 6H); mass spectrum, m/e (FD) 695 (M₊-r1 ). Example 34

Under similar conditions to Example 1 starting from (*)-5-isopropyl 3-methyl 4-

{2-(4-bromobutoxy)-5-nitropheπyl}-2-cyaπo-6-methyl-l ,4-dihyoroρyridine-3,5- dicarocxyiate(l3.99g) anc (-)-2-hydroxy-3-pnenoxypropyIamine (13.03g) was obtained [ ■>■ ) -5-isopropyl 3-methyl 2-cyano-4- [ 2- - 4- ( 2-hydroxy-3- pheπoxypropylamino)butoxy}-5-nitrcpheπyl]-6-methyl-1 ,4-dihydropyrιdine-3,5- dicarfioxylate (7.40g) as yellow crystals. mp 105-107 ^*C (from acetonitrile-diisopropyl ether) ;

[a]25O +118' (c θ.8, methanol);

IR (KBr) 2245, 1698, 1589, 1472, 1384, 1341 , 1275, 1096, 756, 691 cm-1 ;

1 H NMR (CDCI3-TMS) δ 10.03 (brs, 1 H), 8.18 (d, J=2.7Hz, 1 H), 8.09 (dd, J-9.1 and 2.7HZ.1H), 7.29 (t, J=7.9Hz, 2H), 6.98 (t, J=7.2Hz, 1H), 6.91 (d, J=8.3Hz, 2H), 6.86 (d, J=9.3Hz, 1H), 5.22(s 1H), 4.90 (hept, J=6.2Hz, 1 H), 4.37-4.27 (m, 1H), 4.10 - 3.91 (m, 4H), 3.68 (s, 3H), 3.06-2.84 (m, 4H), 2.34 (s, 3H), 1.99-1.72 (m, 4H), 1.27 and 1.01 (2d, J=6.1 and 6.2Hz, 6H).

Example 35

Under similar conditions to Example 2 starting frcm (+)-5-isopropyl 3-methyl 4-

{2-(4-amiπobutoxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridiπθ-3,5- dicarboxyiate (8.65g) and (+)-1 ,2-epoxy-3-phenoxypropane (1.65g) was obtained (+)- 5-isopropyl 3-methyi 2-cyaπo-4-[2-{4-(2-hydroxy-3-phβnoxypropyiamino)butoxy}-5- nitropheπyi]-6-mβthyl-1 ,4-dihydropyridine-3,5-dicarboxyiate (2.73g) as yellow crystals. mp 103-105 ^*C (from ethanol-hexane);

[a]25O +123' (c θ.8, methanol).

Example 36

Under the similar conditions to Example 1 starting from 5-ethyl 3-methyl 4{2-(4-bromobutyoxy)-5-nitro- phenyl}-2-cyano-6-methyl-l , 4 -dihydropyridine- 3 , 5-dicarboxylate (776mg) and 2-hydroxy-3-phenoxypropyl-amine (635mg) was obtained 5-ethyl 3-methyl 2-cyano-4-[2-<4-(2-hydroxy-3- phenoxypropylamino ) butoxy} -5-nitrophenyl 1 -6-methyl-l , 4- dihydropyridine-3, 5-dicarboxylate (540mg) as yellow powders: mp 136-1.38 "C; IR (KBr) 2236.1698.1589.1465.1385.1338.1273.1099.753.690 cm'-

mass spectrum, m/β (FD) 609 (M*+1).

SUBSTITUTE SHEET O 92/13839 - 34 -

Example 37

Under similar conditions to Example 6 starting from 3,5-diethyl 4-{2-(4- bromobutoxyJ-S-nitrophenylJ-e-methyl^-trifluoromethyl-l ^-dihydropyridine-S.S- dicarboxylate(750m g) and 2-hydroxy-3-{4-(N-m et ylsulphoπyl-N- tetrahydropyran-2-yl ) aminophenox } propylamine ( 1340mg ) was obtained 3 , 5-diethyl 4- [ 2- [ 4- [ 2-hydroxy-3-{ 4- ( N-methylsulphonyl-N- tetrahydropyranyl)aminophenoxy}propylamino]butoxy]-5-nitrophenyl]-6-methyl-2- trifluoromethyI-1 ,4-dihydropyridine-3,5-dicarboxylate (870mg) as a yellow stiff foam. A mixture of the foam (870mg) and p-TsOH ^■ H₂O (700mg) in methanol (20ml) was refluxed for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (15ml X 3). The combined extracts were washed with brine and dried over anhydrous sodium sulphate. After evaporation of the solvent the residue was chromatographed using a silica gel column (chloroform/methanol=10/1 vv) to afford 3,5-diethyl 4-[2-[4-[2-hydroxy-3-{4-(/V- methylsulphoπyl)aminophenoxy}propylamino]butoxy]-5-nitrophenyl]-6-methyl-2- trifluoromethyl-1,4-dihydropyridine-3,5-dica oxyIatθ (540mg) as a yellow stif f foam:

IR (KBr)2983, 2934, 1702, 1628, 1609, 1590, 1510, 1468, 1368, 1340, 1275, 1152, 1098, 752 cm^"1;

'H NMR (CDCI₃-TMS) δ 8.10-8.07 (m, 2H), 7.16 (d, 2H), 6.92-6.75 (m, 4H), 5.35 (s, 1H), 4.24-4.15 (m, 1H), 4.10 - 3.93 (m, 8H), 3.02-2.85 (m, 4H), 2.95 (s, 3H), 2.39 (s, 3H), 1.95-1.73 (m, 4H). 1.15 (t, 6H); mass spectrum, m/e (FD) 759 (M^*+1).

Example 38

Under similar conditions to Example 37 starting from 5-isopropyl 3-methyl 4- {2-(4-bromobutoxy)-5-πitrophenyl}-2-cyano-6-methyf-1,4-dihydropyridiπe-3,5- dicarboxylate(820mg) and 2-hydroxy-3-{4-(Λ/-methylsulphonyl-/V- tetrahydropyran-2-yl)aminophenoxy} propylamine (1440mg) was obtained 5-isopropyl 3-methyl 4-[2-[4-[2-hydroxy-3- {4-(N- methylsulphonyI)aminophenoxy}propylamino]butoxy]-5-nitrophenyl]-2-cyano-6-methyl-

1,4-dihydropyridine-3,5-dicarboxylate (710mg) as a yellow stiff foam:

IR (KBr) 2236, 1699, 1590, 1512, 1340, 1268, 1152,1096 cm^"1;

¹H NMR (CDCI₃-TMS) δ 8.20-8.07 (m, 2H), 7.22-7.14 (m, 2H), 6.92-6.80 (m, 3H),5.22 (s, 1H), 4.33-4.27 (m, 1H), 4.11 - 3.88 (m, 4H), 3.68 and 3.67 (2s, 3H), 3.02-2.76 (m, H), 2.33 and 2.31 (2s, 3H), 1.97-1.66 (m, 4H), 1.29-0.97 ( , 6H); mass spectrum, m/e (FD)716 (M⁺+1 ).

Claims

1. A dihydropyrindine compound of the formula:

wherein represents a cyano or halo alkyl group in which the alkyl group has 1 to 6 carbon atoms; R¹ represents an alkyl group having 1 to 6 carbon atoms; "- .

R^ώ and R , which may be the same or different, each represents an alkyl group having 1 to 6 carbon atoms;

X and Y, which may be the same or different, each represents a hydrogen atom, an alkyl group having 1 to

6 carbon atoms, a halogen atom or a nitro group; Ar represents an optionally substituted aryl group and A represents an alkylene group having 1 to 10 carbon atoms; or an acid addition salt thereof.

2. A dihydropyridine compound as claimed in claim 1 characterised in that when X and/or Y is a halogen atom, the halogen atom is fluorine, chlorine or bromine.

3. A dihydropyridine compound as claimed in claim 1 or 2 characterised in that the acid addition salt is a hydrochloride or sulphate.

4. A dihydropyridine compound as claimed in claim 1 or 2 characterised in that the acid additional salt is an oxalate, lactate, succinate, tartrate, maleate, fumarate, acetate, salicylate, citrate, benzoate, beta-naphthoate, adipate, methanesulphonate, benzenesulphonate or p-toluenesulphonate.

5. A process for preparing a dihydropyridine compound claimed in claim 1 characterised by the reaction of an a ine of the formula:

wherein , R 1 , R , R "~, A, X, and Y have the meanings defined in claim 1, with an epoxide or an alcohol derivative of the formula:-

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

6. A process for producing a dihydropyridine compound claimed in claim 1 characterised by the reaction of a dihydropyridine derivative of the formula:

wherein , R , R , R , A, X, and Y have the meanings defined in claim 1, and wherein Z represents a suitable leaving group (reactive functional group), with an amine of the formula:

OH H_{2 ^}A^0Ar

wherein Ar has the meaning defined in claim 1.

7. A method as claimed in claim 5 or 6 characterised in that the leaving group (reactive functional group) is a methanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, m- nitrobenzenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bromo or iodo group.

8. A dihydropyridine compound as claimed in any of the preceding claims characterised in that when is a haloalkyl group the haloalkyl group is trifluoromethyl.