CA2078338A1 - Dihydropyridine compounds, and process for their preparation - Google Patents

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; R2 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

- 2~7~3~

DESCRIPTXON
DI~IYDROPYRIDINE COMPOUNDS, AND PROCESS FOR THEIR
PREPAR~ lrON
This invention relates to new dihydropyridine derivatives which possess antihypertensive properties.
In the literature many 2,6-dialkyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylate derivatives are known which are referred to as calcium ion cha~nel 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-~Lmethyl-4-o-nitrophenyl-pyridine-3,5-dicarboxylate. Yet another type ~f 1,4-dihydropyridine derivative is known, namely, nilvadipine, which is characterized by having cyano group at the 2-po~ition 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 1-(naphth-1-yloxy)-3-isopropylaminopropan-2-ol and 1-p-carbamoylmethylphenoxy-3-isopropylamino-propan-2-ol, respectively, are most widely used examples.

WO92/13839 ~ Q ~ ~ 3 ~ 8 PCT/JP92/00076 Previously described attempts at combining these two types of chemical structure, i.e. 2,6-dialkyl-4-aryl-1,4-dihydropyrindine-3,5-dicarboxylate and 1-aryloxy-3-amino-propan-2-ol, are found in the literature and patents.
A report by Merck wor-~ers (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 whi~h the 3-amino-2-hydroxypropoxy substituent is linked to the 4-aryl substitusnt by the group -C~=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-1,4-dihydropyridine derivativès, are disclosed in European Patent No. 194,751, Japan Xoukai No. 86-12662, Japan Koukai No.87-149659, Japan Xoukai No. 87-228060, ~apan Koukai No. 83-3936, and Japan Xoukai 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 lowex alkyl group at the 2-position in the 1,4-dihydropyridine moiety. We have now found that a W092/13839 PCT/JP9~/00076 ,, 2~7~3~8 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-1,4-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:
X /Y H OH

,--O-A--N ~,OAr ~302c~co2~2 wherein W represents a cyano or halo alkyl group in which the alkyl group has 1 to 6 carbon atoms; Rl represents an alkyl group having 1 to 6 carbon atoms;
R2 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 halogPn 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 ther~of.

~ ~4_ 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 AxO-. 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 spPcific examples of ArO- where AI 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.

2~7~

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 formula:
X Y

R302C~Co2R2 W--N'~Rl wherein W, Rl, R2, R3, A, X, and Y have the meanings stated above, with an epoxide or an alcohol derivative of the formula:

O~OAr or L ~OAr W092~13839 pCT/JP92/0~76 ~ 6-wherein Ar stands for an optionally substituted aryl group, and ~ stands for a suitable leaving group (reactive functiona`l 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:

X Y
~ O-A-Z

R~02C~ 02R2 H

wherein ~, Rl, R2, R3, A, X, and Y have the meanings stated above, and wherein Z represents a suitable leaving group (reactive functional group3, for example, a methanesulphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, p-nitrobenzenesulphonyloxy, chloro, bromo or iodo group, with an amine of the formula:

OH
H2N ~ OAr WO92/13839 PCT/JP92/~0076 _7_ ~7~3~,8 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:

H
p/, N ~J~OAr wherein R denotes the remainder of the molecule of the compounds of this invention as hereinbefore definèd, 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:

AcO~N ~r,R

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 mi.xture and purified by methods commonly used WO9~/13839 PCT/JPg2~00076 C~Q~n~3~ ` "~

for 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 l,4-dihydropyridine pucleus 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 rasemic 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, Rl, R2, R3, A, X, Y and the substitution pattern of the W~92/13S39 PCT/JP92/00076 29~3~
g 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; R1 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 or isobutyl; 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 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, octamethylene, and prefera~ly 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-, W092tl3839 PCT/JP92/0~6 .
~ -10- ~
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 mg, preferably 1 to 250 ~g.
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 mg., preferably about 0.1 mgO 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 ingr~dient 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 lik~. 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, gelatinj W092/13~39 PCT/JP~2/00076 2~7~33~

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 ths femoral artery and vein under ether anesthesia. ~lood 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 insta~t 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 com~ound Dihydrop~ridine 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, 10mM 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 (1,000g 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 (50nM Tris-HCl, pH7.4), which were referred to as crude microsomal membrane fractions. The obtained suspensions were stored at -80°C until use.
(b) [2H]PN200-110 binding to preparative membrane Frozen crude microsomal fractions were thawed.

W~92/13839 PCT~JP92/00076 - 2~7~3~8 [ ~]PN200-110 (O.lnM) was incubated with 50 ~l o~ the membrane preparation at 37C for 90 minutes in a final volume of 200 ~l. 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 ~uffer (50mM Tris-~Cl, p~7.4). The ratioactivity wa~
counted in 6 ml of Clear-~ol I in Packard scintillation counter (Packard TRI-CARB 4530).
TeYt compound Dihydropyridine A
Test result ¦ Testcompound I ~(M) ¦ l:ihydropyridineA ¦ 3.25X10 (3) ~ re~eptor binding Test methods (a) Crude ç3~a~ ~19~Q@9~L1 me~brane aE~2~3~19~
SD strain rats were sacrificed by decapitation.
The heart was removed and homogenized in buffer (0.25M
sucrose, lOmM MOPS, p~7.4) by using Polytoron (Kinematica). The homogenate was homogenized using a teflon glass homogenizer. The homogenate was centrifuged (l,OOOg x 10 min.) to remove tissue clumps and the supernatant was centrifuged (lO,OOOg x 10 min) twice. The supernatant was ag~in centrifuged SUBSTITUTE SHEET

WO 92/~3839 ~Q~ PCr/JP92/00076 (lOO,OOOg x 60 min.) to yield pellets. The pellets were resuspended in buffer (50~ Tris-~Cl, pH7.4), which were referred to as crude microsomal membrane fractions. The obtained suspensions were stored at -80C until use.
(b) 3H-Dihvdroalprenolol (D~A) bindinq to Preparative membrane Frozen crude microsomal mem~rane fractions were thawed. ~3~ D~A (lnM) was incuba~ed with 50 ul of the membrane preparation at 25C for 30 minutes in a final volume of 200ul. At the end o~ the incubation period, reaction mixture was quickly filtrated over a Whatman GF/C gla~s filter under aspiration. The filter~ were w~shed 5 times wi h 3ml of the buffer (50m~ Tri~-~Cl, p~7.4). The radioactivity wa~ cou~ted in 6ml of Clear-sol I in Packard scintilla~ion counter (Packard TRI-CARB 4530).
Test comPound Dihydropyridine A
Test result Testcompound I ~(M) ¦ DihydropyridineA ¦ 7.46X10 The invention is further illustrated but not limited by the following Examples:- _ SUBSTITU T ~; SHE:ET

W092/13839 PCT/JP92iooo76 2 ~ 7 ~ ~ ~ 8 ExamPle 1 To a mixture of 5-isopropyl 3-methyl 4-[2-(4-bromobutoxy)-5-nitrophenyl]-2-cyano-6-methyl-lr4 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 ~tirred for 4 hours. The reaction mixture wa~ ooncentrat~d under reduced pressure. The residue was chromatographed on a silica gel column using a 96~4(~/v) mixture of chloroform and methanol as an eluent to a~ord a ~olid re~idue (3.6 g) upon evaporation of the solvent The solid residue was purified by recrystallization from ethanol to give 5-isopropyl 3-methyl 2-cyAno-4-~2-{4-(2-hydroxy-3-phenoxypropylamlno)buto~y}-5-nitrophenyl~
-6-methyl-1, 4-dihydropyridi~e-3, 5-dicarboxylate t2.3 g) as yellow crystal~:
mp 142-151 C;
IR (K~r) 2234,1699,1589,1514,1468,1384,1373,1340,1274,1164,1098,755,691 cm ' 'H NMR (CDC~-TMS) ~ 10.25 (brs, lH),8.19 and 8.18 (2d,1H),8.10 and 8.09 (2dd, lH),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, 1 H),3.91 - 4.10 (m,4H),3.69 (s,3H),2.55-2.98 ~m,4H),2.32 and 2.29 (2s,3H),2.10-1.60 (m.4H),2.10-1.60 (br,2H),1.27,1.26,1.01 and 1.00 (4d,6H);
~ss spe~m, nV~ (FD) 623 (M-+~.

Exaunple 2 To a solution of 5-isopropyl 3-methyl 4-[2-(4-aminobutoxy)-5-nitrophenyl]~2-cyano-6-methyl-1,4-dihydropyridine-3~5-dlcarboxylate (699 mg) in SUE~STITUTE ~HEET

W092/l3839 ~ PCT/JP92/0007fi -'6-methanol (43 ml) was added 1,2-epoxy~3-phenoxypropane (247 mr~). The mixture was heated to -eflux and stirred for 40 hours; `The reac~ion mlxture was concentrated under reduced pressure. The residue was chromatoyra~hed on a silica gel column using a 96/4 (~/~) mixture o~ chloroform and methanol as an eluent to af~ord a solid residue (210 mg). The residue was purified by recrystallization form ethanol to give S-iqopropyi ~-methyl 2-cyano-4-[2-{4-(2-hydroxy-~-phenoxypropylamlno)butoxy}-5-nitrophenyl~-6-methyl -1,4 dihydropyridine-3,5-dicarboxylate (l90 mg) a~
yellow crystal~, which wa spectrosco~ically ide~tical with the product ~rom Example l.
Example 3 Under the imilar conditions to Example 1 ~tarting from 5-isopropyl 3-methyl 4-{2-(4-bromobutoxy)-3,5-dlchlorophenyl3-2-cyano 6-methyl-1,4-dihydropyridine-3~5-dicarboxylate(3l7mg) and 2-hydroxy-3-phenoxypropylamine (390mg), 5-isopropyl 3-.
methyl 2-cyano ~-~2-{4-(2-hydroxy-3-Dhenoxvpropyi amlno)butoxy}-3,5 -dir hloroDhenvl]-o-methyl-1.,4-dihydropyridi~e-3,5-dicarboxylate Q90 mg) was obt~ined as a yellow st-f~ foam.

mp 52-60 JC;
1~ ~Kar) 2236, 1703, 1588, 1511, 1454, 1385, 1Z74, 1174, 1095, 755, 692 cm':
'H~R (CDC~ AS) ~7.30-7.24 (m,2H),7.17 and 7.16 (2s, lH),6.97 ~dd,1H),6.91-6.89 (m,2H), 6.71 (s, lH),5.so3 and 5.088 (Zs, lH),4.93 (hpt, lH),4.32-4.23 (n~ 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),1.066,1.072,1.07s and 1.084 (4d,6H);
mass spcctnJm, n~ (FD) 646 (M;H) SUBSTi~UTE S~IEET

WO92/13B39 PCT/JP92/0~76 -17- 2~ ~3~
Exa~E~ 4 - Under similar conditions T O Example 1 starting from 3,5-dimethyl 4-{2-(4-bromobutoxy)-5-nitrophenyl}-2-cyano-6-methyl-1,4-dihydropy:ridine- 3,5-dicarboxylate (400 mg) and 2-hydroxy-3-phenoxy propylamine (474mg), 3,5-dimethyl-2-cyano 4-~2-{4-(2 hydroxy-~-phenoxypropylamino)butoxy}-5-nitrophenyl]
-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (30lmg) was obtained as yellow crystals.

mp 142-153 G;
IR (K3r) 2236, 1704, 1589, 1513, 1466, 1385, 1339, 1272, 1187, 1099, 754, 692 ur~';
'H~R ~COC~-TMS) ~10.70-9.90 (bt, 1H), 8.19 ~d, lH~, 3.1û and 8.û9 (2dd, lH), ~.30 ~dd, 2H), 6.99 ~dd, 1H), 6.9~ ~d, 2H), 6.R7 and 6.86 (2d, lH~, 525 (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, 3t~, 2.05-1.55 ~m, 4H), 2.05-1.55 (br, 2H);
- mass sp~ctrum, rn~ (FD) 595 (M-~.

Exam~le 5 Under the similar co~ditions to Example 2 tarting from 5-i~opropyl 3 methyl 4-{2-(4-amlnobutoxy)-5-nitrophenyl}-2-cyano-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (400 mg) and 1,2-epoxy-3-(naphth-l-yloxy)propane (170mg) 5-isopropyl 3-methyl 2-cyano-4-[2-[4-{2-hydroxy-3-(naphth-1-yloxy)propylamino~butoxy]-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (138 mg) was obtained as a yellow stiff foam.

SUEV ~ .J ~ s. ~IEET

WO92/13839 PCT/JP92/0~76 To a solution of 5-isopropyl 3-methyl 2-cyano-4-~2-~4-{2-hydroxy-3-(naphth-1-yloxy)propylamino~
butoxy]-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (123mg) in ethanol (lmL) was added maleic acid ~2lmg). The mixture was stirred for 30 min. The reaction mixture was ~onc~ntrated under reduced pressure. The residue wa~ dissolved in chloroform and the resulti~g solution was wa~hed with water. The organic layer was dried over anhydrous magne~ium sulfate and the filtrate was evaporated under reduced pre~ure to give a maleate ~alt of 2-cyano-4-[2-[4-{2-hydroxy-3-(naphth-l-yloxy)pro~yl amino}butoxy]-5-nitrophenyl]-S~methyl-l~4-dihydropyridine-3,5-dicarboxylic acid S~ opropyl 3-methyl e~ter (130mg) a pale yellow crystal~.
mps4.5-10s.0~;
IR~K8r~ 3408, 30B6, 2980, 22~7, 1702, 1623, 1581, 1512, 1467, 1386, 1341, 1302, 1270, 1241, 1216, 1~00cm';
'H NMR (CDCI,-~MS) ~ 9.08 (br s, 1H), 8.18 (k d, J~8.0Hz, 1H), 8.12 (d, J~2.8Hz, 1H), 8.0~ (dd, J-9.0 and 2.8H2, lH), 7.76 (d, J~7.6H2, 1H), 7A7-7.38 ~m, 3H), 7.35 7.23 (m, 1H), 6.72(d, J.8.4H~, lH), 6.68 (d, J~75H7, 1H), 6.S1 (s, 2H), ~.17 (s 1H), 4.87 ~hp~, 1H), 4.64 (br3, 1H), 4.19-4.10 (m, 211), 3.92 (br s, 1H), 3.61 arld 3.~0 (2s, 3H), 3.43-3.2S (m, 4H), 2.293 and 2.290 (2s, 3H), 22~1.50 (m, 8H), 1.25 (d, J~6.2Hz, ~H), 0.98 (d, J..6.2Hz, 3HJ;
mass spec~m, m~ (FD) 673 (M'+1).

Example 6 PreparatiOn of dlmethyl 2-trifluoromethyl-4-[2-{4-(2-hydroxy-3-phenoxyproylamino)butoxy}-5 nitrophenyl]-6-methy~ 4-dihydropyridine-3~5 dicarboxylate.

SlJBSTITUTE SHEET

P~T/JPg2/0~76 ,~
-19- 2~7~3~
A mixture of dlmethyl 4-~2-(4-bromobutoxy)-5-nitrophenyl}-2-trifluoromethyl-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (0~20g, 0.36 mmol) and 2-hydroxy-3-phenoxypropylamine (O.30g, 1.80 mmol) in a~tonitrile (Sml) was refluxed for 2 hours. The reaction mlxture was poured into saturated a~ueous sodium bicarbonate solution and extracted with chloroform (5ml x 3). The combi~ed extra~ts were waRhed with brine and dried over anhydrous sodium ~ulfate. After e~aporation of the ~olvent, the residue wa~ chromatographed using a 3ilica gel column ~chloro~orm/methanolalO/1). DLmethyl 2-tri~luoro-methyl-4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}
-5-nitrophenyl~-6-methyl-1,4-dihydropyridin~-3,5-dicarboxylate wa~ obtained as a yellow tiff foam (0~20g).

IF~ (K~r) 3350, 2950,1700, 1515, 1497, 1341, 753, 693 cm ';
'H Nh~R (COa, TIUS3 ~ 8.09 (dd, 1H), 8.07 8.09 ~m, 1H), 7.29 (t, 2H), 6.97 (t, 1H), 6.90(d, 1H), 6.8a(d~
1H), 5.37(s, 1~, 4.14-4.12(m, 11~, 4.08-4.06(m, 2H~, 4.00-3.96(m, 2H), 3.63(s, 3H), 3.59(s, 3H), 2.gO-2.79~m, 4H), 2.4ûls, 3H), 1.90-1.71(m, 4H);
rr~ass spealum, rn~ (FD) 638 ~M-~H).

EXamD1e 7 Preparation of 5-isopropyl 3-methyl 2-trifluoro-methyl-4-~2-{4-~2-hydroxy-3-phenoxypropylamino)butoxy}
5-nitrophenyl]-6-methyl-lr4-dihydropyridine-3~5 dicarboxylate.

SUIBSTITUTE SHEET

PCT/JP92~00076 The procedurP 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 (O.65g, l.lOmmol) and 2-hydroxy-3-phenoxypropylamine (O.93g, 5.60mmol) as starting materials. 5-isopropyl 3-methyl 2-trifluoromethyl-4-[2-{4-(2-hydroxy 3 phenoxy-propylamino)butoxy}-s-nitrophenyl~-6-methyl-l~4~
dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam (O.63g).
IR (K3r) 3350, 2980, 2949, 1728, 1699, 15~9, 1514, 1497, 1340, 1269, 1228, 1177, 1145, 1082, 754 692 cm '; 'H NMR (CDCI,-rMS) ~ 8.17-3.08(m, 2H), 7.29(~ ), 6.97(~, 1H), 6.91(d, 2~, ~.87(d, 1~
5.32(s, 1H), 4.91-4.86(m, lH), 4.13-4.08(m, 1~, 4.98-4.02(m, 2H), 4.00-3.9~(m, 2H~, 3.62(s, 3H), 2.99-2.75(m, 4H), 2.~9~s, 3H), 1.91-1.~6(m, 2H), 1.72-1.68(m, 2H), 1.23(d, 3H), 0.97(d, 3H);
rnass spearum, mlb (FD) 666 (M;H).
Example 8 Preparation of 5-IRopropyl 3-Ethyl 2-Tri~luoromethyl-4-[2-~4-(2-hydroxy-3-phenoxy-propylamino)butoxy}-5-nitrophenyl]-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate monohydrochloride.
A mixture of 5-isopropyl 3-ethyl 4-r2-(4-bromobutoxy)-5-nitrophenyl]-2-trifluoromethyl-6-methyl-l,4-dihydropyridine-3,5-dicarboxylate (0.30g, 0.50 mmol) and 2-hydroxy-3-phenoxypropylamine ~0.42g, 2.5Ommol) 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 SIJE18TITUTE~ SHEEr W092/l3839 PCT/JP92/0~76 -21- 2~7$3~8 washed with brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, tha residue was chromatographed on a silica gel column (chloroform/methanol = lO/l). 5-Isopropyl 3~ethyl 2-trifluoromethyl-4-~2-{4-~2-hydroxy-3-phenoxypr A~; no)bntoxy~-S-nitrophenyl~-6~methyl-1,4-dihydro-pyridine-3,5-dicarboxylate was obtained as a yellow oil (0.28g).
To a 301ution of 5-i~opropyl 3-ethyl 2-trifluoro-methyl-4-[2-~4-(2-hydroxy-3~phenoxypropyla~lno)butoxy}
5-nitrophenyl]-6-methyl-lt4-dihydropyridine-3~5-dicarboxylate (0025g, 0.36 mmol) in methanol (3ml) was added 2N methanol ~olutio~ of hydrogen chloride (2 ml~. The reaction mixture was stirred f or 1 hour at room temperature. T'he methanol waC~ evaporated under reduced pres~ure. S-Isopropyl 3-ethyl 2-trifluoro-methyl-4-E2-{4-(2-hydroxy-3-ph~noxypropylamino) butoxy}-5-nitrophenyl3-~-me~hyl-1,4-dihydropyridine-3, 5-dicarbox~rlate monohydrochloride was obtained a~ a ye 1 low sti:E f f oam t O . 2 6g ) .
IR(K~r)3354,2981,1700,1590,1514,14s8,1341,1274,1234,1201,1177,1146,1080,754,693 cm;
1H NMR (C~ MS) ~ 8.06~.03(m, 2H)~ 7.23-7.21(m, 2H), 6.94~t, lH), 6.85~d, 2H), 6.81~d, lH), 5.33~s, lH), 4.88(p, lH). 4.61(bs. lH), 4.09-3.96(m. 6~), 3.37-3.23(m, 4H), 2.41(s, 3H), 2.201.95(m.
4H), 1.19(d, 3H), 1.11(t, 3H), 0.98(d, 3H):
mass sps~tnJm, rn~ (F0) 680 (M;H).

SUBSTI; ~, ~ S~EET

Wo 92/13839 ~3~ PCr/JPs2/0007 Example g ?.,~¦
Preparation of dimethyl 4-[3,5-dichloro-2-~4-(2-hydroxy-3-phenoxypropylamino)butoxy~phenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5~icarbaxylate The procedurs described in Example 6 was followed using dimethyl 4-[3,5-dichloro-2-(4-bromobutoxy)phenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylat~ (0.749) and 2-hydroxy-3-phenoxypropylamine (1.089) as starting materials. Dimethyl 4-[2-i4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5-nitrophenyl]-6-methyl-2-trifluoromethyl-1,4-dihydropyridine-3,5-dicarooxylate was obtained as a yellow stiff foam(0.43g).
IR (K8r) 3338, 2951,1709,1563,1451,1435,1286, 1043, 899, ~02, 667 cm-1;
'H NMR (CDCI3-TMS) ~ 7.26(t, 2H), 7.23(d, 1H), 6.99(bs, lH), 6.95(t, 1H), 6.88(d, 2H), 5.24(s, 1H), 4.~7(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, rn/o ~FD) 661 (M-+1).
ExamPle 1 0 Preparation of 3~thyl 5-methyl 4-t2-~4-(2-hydroxy-3-phenoxypropylamino)butoxy~-5-nitrophanyl]-6-methyl-2-trinuoromethyl-1,4-dihydropyridina-3,5-dicarboxylato The procedure described in Exampla 6 was followed using 3-ethyl 5-m~thyl 4-[2-(4-bromobutoxy)-5-nitrophenyl]-6-mQthyl-2-trifluoromsthyl-1,4-dihydropyndinc-3,5-dicarboxylate (0.509) and 2-hydroxy-3-phenoxypropylamine (0.459) as starting matsrials. 3-Ethyl 5-methyl 4-[2-{4-(~-hydroxy-3-phanoxypropylamino)butoxy)-5-nitrophenyl]-6-methyl-2-trinuoromethyl-1,4-dihydropyridine-3.5 dicarboxylato wasobtained as a y8110w stiff foam(0.43g).
IR (I<Br) 3332, 2948,1722,1708,1589,1514,1496,1341,1017, 753, 892 Gm-1;
'H NMR (CDCI3-TMS) ~ 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), æ38(s,3H), 1.89-1.6&(m, J,H),1.16(t, 3~1);
mass spectnum, m/e (FD) 652 (M-+1).
Exarnple 11 Under similar conditions to Example 1 starting from s-ethyl 3-methyl 4-{2-~2-bromoethoxy)-5--nitroph~nyl}-2-cyano.6-methyl-1,4-dihydropyridine-3,5-dicarboxylate(40smg) and 2-hydroxy-3-phenoxypropylamine (548m9) was obtained 5-ethyl 3-methyl 2-cyano-4-[2-{2-(2-hydroxy-3-phenoxypropylamino)ethoxy}-5-nitrophenyl]-6-methyl-1,4-dihydropyridin~-3,5--dicarboxylate (86rn9) as y~llow crystals.
mp 191-193 C (from CH2CI2);

~vo 92/13x39 Pc~/Jps2iooo76 -23- 2~7~3~
IR (K~r) 2226. 1697, 1644, 1624, 1559, 1588, 1506, 1344, 1275, 1Od,5, 826, 75~cm-1;
1H NMR (CDCI3-TMS) ô 8.30 (br s, lH), 8.175 (d, J=2.7Hz, lH), 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, qH), 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 1.19~ (2t, J=8.0 and 8.0Hz. 3H);
mass spectrL m, Tlle (FD) 580 (M++H).

Example 12 Under simllar conditions to Example 1 start m g from 3,5-dimethyl ¦ 4-~2-(2-bromoethoxy)-5-nitrophenyl}-2-cyano-6-methyl-1 ,4-dihydropyridine-3.~-dic~rboxylatel423mg) and 2-hydroxy~3-ph~noxypropylamin~ (440mg) was obtained 3,5-dim~thyl 2-cyano-4-[2-~2-(2-hydroxy-3-phenoxypropylamino)etho ~ -S-nitrophenyl]-6-msthy~ 4-dihy~ropyridine-3~s--dicar~oxylat~ (96mg) as yellow crystals.
mp 180-163 C (from CH2CI2);
IR (KBr) 2238, 170~, 1652, 1632, 1598, 1587, 1509, 1491, 1432. 1344, 1301, 1275,1217, 1 120, 82~, 763 cm-1;
lH NMR (CDCI3-TMS) ~ 8.17 (t, J=3.0~z, 1H), 8.10 (dd, J=g.0 and ~.7Hz, lH), 7.33-7.23 (m, 2H), 7.02- 6.90 (m, 4H), 5.~5 and ~.34 (2s, 1 H), 4.42-3.94 (m, 5H), 3.71 and 3.61 (2s, 3H), 3.25-2.88 (m, ~H), 2.35 and 2.34 (2s, 3H);
m~cs spectnJm, m/e (FD) 567 (M++1).

Example 13 Preparation ot 5-ethyl 3Imothyl 4-[2-{4-(2-hydroxy-3-phenoxyprOpylaminO)bUtOxy~-5 nitrophenyl]-6-methyl-2-tnfluoromethyl-1 ,wihydropyridine-3~5-dicarboxylat~
Th~ procsdure dascrib~d in Exampl~ 6 was followed using ~-ethyl 3-m~thyl ~-[2-(4-bromobutoxy)-5-nitrophenyl]-6-methyl-2-tn~luoromethyl-1 ,4-dihydropyridine-3.5-dicarboxylate (0.2~9) and 2-hydroxy-3-phenoxypropylamine (0.229) as staning materials. 5~Ethyl 3-m~thyl 4-[2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5-nitrophenyl]-6-m ethyl-2-tnfluorom ethyl-1,4-dihydropy~idine-3.5-dicarboxylate was obtained as a yellow stiff foam(0.25g).
IR (KBr) 3328, 2950, 1700, 1514, 1496. 1340, 1268. 1 175, 1082, 753. 692 cm-1;
1 H NMR (CDC13-TMS) o 8.0s(dd,, H!~ 8.08(s. 1H), 7.29(t, 2H!, 6.97(t, 1 H), 6.91 (d, 2H), 6~aa(d~ IH), 5.36(s, 1H), 4.13-3.3s(m, 7H), 3.63(s, 3H), 2.89(ddd. lH), 2.82(dd.
1 H), 2.78(t. 2H), 2.39(s, 3H), 1.90-1 .6/(m, 4H), 1 .15(t, 3H~;
m s spectrum. mt~ (FD~ 652 (M+-1 !

SUBSTITUTE SHEET

W092/13839 ~1~3~ P(-r/JI9~/~0~76 Exam Dle 14 Preparation of 3-ethyl ~-isopropyl 4-~ 4-~2-nYoroxY-3-phenoxypropylamino)butoxy~-2-nitrophenyl]-ô-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicar~oxylate The pro~edure described in Example 6 was followed using 3-ethyl ~-isopropyl 4-[5-(4-bromobuloxy)-2-ni~rophenyl]-6-methyl-2-triiluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylate (0.409) and 2-hydroxy-3-ph~noxypropylamine (0.459) as star;ing materials. 3-Ethyl 5-isopropyl 4-[~-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-2nitrophenyl]-6-methyl-2-trifluoromothyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.39g).
IR (KBr) 3341, ~981, 2939, 1728, 170~, 1600, 1518, 1345, 1283, 1079, 754, 691 cm-1;
1H NMR (CDCI3~TMS) ~ 7.91(d, 1H), 7.27(t, 2H), 6.g8(d, 1H), 6.96(t, 1H), 6.91(d,2H), 6.7~(dd, 1 H), 6.37(s, 1 H), 5.s2(s, 1 H), 4.~8(p, 1 H), 4.1 8-3.95(m, 7H), 2.89-2.68(m, 4H3, 2.40(s, 3H~, 1.88-1.66(m, 4H~, 1.20(~, 3H), 1.14(d, 3H), 0.88(d, 3H);
mass spectrum, rrle (FD) 680 (M+~1).

Exampl~ 1 5 Preparation of 3-ethyl 5-isopropyl 4-[2-{4-(2-hydroxy-3-ph~noxypropylamino)~thoxy}
5-nitrophenyl]-6-m~thyl-2-trifluoromathyl-1 ,4-dihydropyridine-3~5-dicarboxylateThe procedure described in Example 6 was foilowed using 3-ethyl 5-isopropyl 4-[2-(4-bromoethoxy)-6-nitrophenyl]-6-m~thyl-2.trifluoromethyl-1 ,4-dihydropyridlne-3l5-dicarboxylat~ (0.30g) and 2-hydroxy-3-phanoxypropylamine (0.359) as starting materials. 3-Ethyl 5-isopropyl 4-E2-{4-(2-hydroxy-3-phenoxypropylamino)athoxy}-~-nitrophenyl]-6-methyl-2-tn~luoro methyl-1,4-dihydropyndine~3 5-dicarboxylate was obtained as a yollow -~tiff foam(0.209).
IR (K8r) 3328, 2981, 2937, 1702, 1~89, 1514. 14g7, 1340, 1269, 1228, 1082, 753, 6~2 cm-1;
1 H NMR (CDC13-TMS) ~ 8.1 1 (s, 1 H), 8.1 O(dd. 1 H), 7.27(t. 2H), 6.96(t, 1 H), 6.92(d, 2H), 6.90-6.88(m, 1H), 6.67(s, lH), 5.43(s, 1H), 4.89(p, 1H), 4.2'-3.88(m, 7H), 3.21-2.85(m, 4H), 2.40(s. 3H), 1.20(d, 3H), 1.14(t, 3H), 0.93(d, 3H) mass spectrum, m/e (FD) 652 (MT+1).
Exam~le 16 Under similar conditions to Example l s~arting rrom 3 ~-dim~thyl 4-~2-(6-bromohexyloxy)-5-nitrophenyl}-2-cyano-6-methyl-l ,4-dihyaropyridine-3,5-dicarboxylate(425m~) and ~-hyaroxv-3-DnenoxyProDylamins (46~mg) was obtained ~,5-dimethyl 2-cvano-4-[2-)6-(2-hydroxy-3-phenoxypropylamino)hexyloxy~
nltrophenyl]-6-mathy~ 4-dihydropyndine-3~s--aicarboxvlate (350mg) as a yellow stiff VV0 92/13839 ~ ~ 7~ P~r/JP~2/~0076 , foam.
IR (KBr) 2236~ 1708, 1682. 164~, 1624, 1588, 1514, 1341, 127C, 1245, 1217, 754 cm-1;
1H NMR (CDC;13-TMS) ~ 8~16-a~14 (m, lH), 8.08 (dd, J=9.1 and 2.8Hz, 1H), 7.32-7.22 (rn, 2H), 6.99-6.87 (m, 4H), 5..29 (s, lH), 4.22-3.90 (m, SH), 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 specln~m. m/e tFD) 622 (M+).

Exampie 17 Prep2ratlon of diethyl 4-[2-~4-(2-hydroxy-3-phenoxypropylamino)buto ~ -;-nitrophanyl]-6-methyl-2-trifluorom~thyl-1 ,4-dihydropyridin~-3,5-dicarbOxylate The procedure descnb~d in Example 6 was followed using diethyl 4-t~-(4-brom~butoxy)-5-nitrophenyl]-6-mathyl-2-tnfluoromethyl-1 ,4-dihydropyridin~-3,~-dicarboxylate (0.509) and 2-hydroxy-3-phenoxypropylamine (0.439) as starting matenals. Diethyl 4-[2-{4-(2-hydroxy-3-ph~noxypropylamino)butoxy~-5-nitrophanyl]-6-ml3thyl-2-tritlu~rom~thyl-1 ,4 dihydropyridine- ~,~;-dicarboxyl:~tg wa5 ob~a~ned as a yellow stiff foam(0.45g).
IR (K8r) 3343, 2981, 2937, 170., 1589, 1514, 1497, 1340, 1274, 753, 691 cm-1;
lH NMR (CDCI3-TMS) ~ 8.12-8.08(m, 2H), 7.29(t, 2H), 6.97(t, 1H), 6.91(d, 2H~, 6.87(d, 1H), 5.35(s, 1H), 4.11-3.g5(m, gH), 2.88(ddd, lH), 2.82(ddd, 1H), 2.77(t, 2H), 2.38(s, 3H), 1.88-1.69(m, 4H), 1.15(t, 6H);
ma~s sp~rum, rn/e (FD) 6 O(M++1).

Example 18 Under the similar conditions to Exampl~ 1 star~ing from 3,5~imathyl 4-{2-(4 bromobutoxy)-~-nitroph~nyl~-2-cyano.6-~thyl-1 ,4-dihydropyridin~-3,5-dicarboxylate(367mg) and 2-hydroxy-3-phenoxypropylamina (302mg) was obtained 3,5-dimethyl 2-cyano-6-ethyl-4-[2- ~ -(2-hydroxy-3--phenoxypropylamino)buto ~ -5-nitrophenyl]-1 ,4-dihydropyridin~-~,5--dicarboxylate (240mg) as a yellow crystals.
mp 158 -162 C (fron ethanol);
!R (KBr) 2236, 1704, 15~6, 1510, 1432, 1335, 1268, 1214, 1180, 1096, 750, 691 cm-1;
1H N~R (CDC13-TMS) ~8.19 and 8.18 (d. J=2.7Hz. lH), 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.QHz, 2H), 6.86 (d, J=9.2Hz, 1H), 5.26 (s, 1H), 4.33-4.2, (m, 1H), 4.08 - 3.92 (m, 4H), 3.68 (s. 3H), 3.61 and 3.60 (2s, 3H), 3.15 and 3.06 (2~ =7.5,13.1 and 7.~, 13.0Hz. 1H), 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 7.4H~. 3H);
m ass sDec~num, m/e (F~) 609 (M -1).

W O 92/13839 ~3~ PC~r/JP92/00076 , _ Examole 19 Under similar conditlons to Exam~`lè.l startlng f~cm ;-isoprop~l 3-meth~l 4-~2-(4-bromobutoxy)-5-nitrophenyl~-2-cyano-6-msthyl-1,4-dihydropyridine-3,5-dicarboxylate(514mg) and 2-hydroxy-3-(2-methoxypnsnoxy)propylamine (o67ms) was obta1ned ~-iso~ropyl 3-methyl 2-cyano-4-[2-[4-~2-hydrox~-3-(2-methoxyphenoxy)propylamino}butoxy]-5 nitrophenyl]-6-methyl-1,4-dihyaropyridine-3,5--dicarDoxylate (371 mg) as yellow crystals.

mp 73-79 C (from ethanol-water);

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

lH NMR (CDCI3-TMS) ~ 8.20-8.07 (m, 2H), 7.20-6.80 (m, 5H), 5.22 (s, 1H), 4.90 and 4.89 (2hept, J=6.2 and 6.2Hz, 1H), 4.31-4.24 (m, 1 H), 4.13 - 3.72 (rn, 4H), 3.86 (s, 3H), 3.68 (s, 3H), 2.97-2.79 (m, 4Hi), 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/s (FD) 653 (M++1).

Exampie 20 Preparation of 3-ethyl 5-isopropyl 4-[2-~4-(2-hydroxy-3-(2-methoxyphenoxy~propylamino)butoxy}-5-nitroph~nyl]-6-mgthyl-2-trifluorom~thyl1,4-.
dihydropyridine-3,5-dicarboxylate The procedure d~scribad in Exampl~ ~ was followed using 3-~thyl ~-isopropyl 4-[2-(4-bromobutoxy)-5-nitrophenyl]~6~methyl~-trifluoromathyl-~ ,Wihydropyridirla-3,5-dicarboxylato (0.30g) and 2-hydroxy-3-(2-mathoxyphenoxy)propylamine ~0.299~ a.c starting materials. 3-Ethyl 5-isopropyl 4-~2-{4-(2-hydroxy-3-(2-methoxyphenoxy)propylamino)butoxy}-s-nitroph~nyl]-6-methyl-2-trifluoromothyl-1,4-dihydropyridine-3,5-dicarboxylate was obtain~d as a y~llow stiff foam(0.29g).
IR (K9r) 3342, 2980, 293g, ~ 698,1590, 1506,1340. 1274,12~3, 1178, 107B,1023, 748 cm-1;
1H NMR (CDC13-TMS) ~ 8.10-8.07(m, 2H), 7.16(bs, lH), 7.00-6.86(m,5H), 5.32(5, 1 H), 4.~8(p, 1 H), 4.29(br.s, 1 H), 4.11-~.OO(m, 6H), 3.84(s, 3Hi), 3.84-2.92(m, 4H), 2.39(s, 3H),1.9~-1.84(m, 4H),1.22(~,3H),1.13(t, 3H), 0.97(d,3H);
mass spectrum, m/~ (FD) 710 (MTT1 ).

ExamDIe 21 Under similar conditions to Example 1 starting from S-isopropyl 3-~eth~1 4-~2-(-~-bromopentyloxy)-5-nitrophenyl}-2-cyano-6-methyl-l ,4-dihydropyriciine-3.5-dicarboxylate(350mg) and 2-hyaroxy-3-phenoxypropylamine (350mg) was obtained 5-isopropyl 3-methyl 2-cyano-4-[2-~5-(2-hyarcxy-3-phenoxypropylamino)pentyioxy}-5-nitrophenyl';-6-methyl-1,4-dihycrOpyridine-3~s--dicarDoxylate (350ms) as a yellow stiff foam.

WO 92/13839 ~ ~ 7 ,~ 3 ~ 3 PCT/JPg2/00076 IR(Kar)2236.1700~16a2,1645,1634,1525,15l5,1496.134C~3o2~12lc~ 1215, 1096,75acm-1;
1H NMR (CDCI3-TMS) ~ 8.1a (d, J=2.aHz, lH), 8.09 (d~, J=9.0 and 2.9H-. 1H), 7.32-7.28 (m, 2H),7.02-6.87 (m, 4H),5.22(s,1 H), 4.95-4.87 (m, 1 H), 4.34-4.25 tm,1 H), - 4.10 - 4.03 (m, 2H), 3.99 (d, J=8.6Hz,1 H), q.89 (t,J=7.1 H-. 1 H), q.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=~.8, 5.8, 6.2 and 6.2Hz, 6H);
mass spectrum, rnle (FD)637(M+ 1) ExamDIa22 Under s ~ lar conditions to Exam~le 1 st ~ ~g from ~-isopropyl 3-methyl 4-~-(4-bromobutoxy~ chlorophenyl~-2-cyano-6.m~thyl-1,4-dihydropyridina-3,5 dicaraoxylate(429mg) and 2-hydraxy-3-ph~noxypropylamina (341 mg) was cbtain~d 5-isopropyl 3-methyl 2-cyan~-4-[,-chloro-~-~4-(2-hydroxv-3-phenoxypropylamino)butoxy~ph~nyl]-6~m~thyl~1,4~ihydropyridin~ 3,~--dicarboxylata(280mg) as a yellow powder.
IR (KBr) 22~6, 1698, i682, ~520~ 1496,1464,1243,1213, 1100, 1095, 801, 7~5 cm-1;
lH NMR (CDC13-TMS) ~ 7.30 (br t, ~=7.7Hz, 2H), 7.æ (t, J=2.5Hz, lH), 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.~9 (m, 1H), 4.31-4.24 (m, 1H), 4.07 3.~ (m, 4H), 3.70 (s, 3H), 3.00-2.7~ (m, 4H), 2.31 and 2.27 (2s, 3H), 1.86-1.7~ (m, 4H), 1.27, 1.~6, 1.09 and 1.08 (4d, J=.6.1, 6.2, 6.6 and 6.~Hz, 6H);
mass spsctrum, m/~ (FD) 612 (M ~ +1).

ExamDla 23 Under sImilar condition~ to E~le 2 st~ing rrcm 5-isoDro~yl 3-methyl 4-~2-(4-aminobutoxy)-~-nitrcphenyl}-2-cyano-6-methyl-1 ,4-dihydropyridin3-3.~-dicarboxylate (1.809) and 3-(2-chlorophenoxy)-1,2-epoxypropane (0.499) was obtained ~-iso~ropyl 3-methvl 4- [5-~4-~. 3-(2-c:hlorophenoxy)-2-hydroxypropylamino~butoxy]-5-nitrophenyl!-2~cyano-6-metnyl-1~4-dihydropyridine-3~5 dicarDoxyIate(0.385)asayeIIowstifffoam.
IR(K8r)2236~1699~1644~1sgg~1s16~ls14~l ~8a. 1340.~272,121",1096.
752cm-1;
1H NMR (CDCi3-TMS) ô 8~19-a 16 (m~ 1H), a.12-8 07 (m, 1H), ~.37-1.34 (~.. 1H~, 7.æ (t,J=7.8H-,1H), 6.96-ô.84(m,3H),5~æ (s~1H),4.93-4.87(m,1H),4.38-4.32(m.
1H),4.16-3.9O(m,4H),3.684 anc 3.678(2s.3H).3.07-2.82~m.4H).2.32 and 2.29 (2s,3H),1.95-1.74(m,2H),1.2a,1~ ,o2 an~ ~.00 (4a. J=ô.2.6.2.6.2 an~ 6.2H_.
6H);

W092~13839 ~ 3~ PCI/JP92tO0076 --'~c--mass spec:rum, m/e (rD) 657 (M~

ExamDle 24 Preparation of 3-ethyl ~-isobutyl 4-~2-{4-(2-hyaroxy-3-phenoxyproPylamino)butoxy}-5-nitrophenyl~-6-methyl-2-trifluoromethyl-1,4-dihydropyridina-3,5-dicarboxylate The procedure described in Example 6 was followed using 3-ethyl 5-isobutyl 4-[2-(4-bromobutoxy)-5-nitrophenyl]-6-methyl-2-tnfluoromethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.479) and 2-hydroxy-3-phenoxypropylamine (0.429) as starting materials. 3-Ethyl 5-isobutyl 4-~2-{4-(2-hydroxy-3-phenoxypropylamino)butoxy}-5-nitrophenyl]-6-methyl-2-tri~luoromethyl-1,4-dihydropyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.44g).
IR (KBr~ 3352, 2960,1727, 1703,1 ~89, 1514,1498, 1341,1273, 1228~ 1175, 1080, 1015,753, 692 cm-1;
lH NMR (CDCI3-TMS) ~ 8.08(dd,1H), 8.05(dd,1 H), 7.26(t, 2H), 6.96(t,1H), 6.88(d,2H), 6.85(d,1H), 6.70(s,1H), 5.38(s,1H), 4.39(bs,1H), 4.11-3.~9(m, 6H), 3.12-3.02(m, 2H), 2 43(s, 3H), 1.96-1.90(m, 4H), 1.84-~ .81 (m, 1 H), 1.16(t, 3H), 0.84(d, 3H), 0.78(d, 3H);
mass spectn~m, m/e (FD) 694 (M++1).

Example 25 Preparation ot 3-~thyl 5-propyl 4-[2-~4-(2-hydroxy-3-phenoxypropylamino)bUtOXy}-~-nitrophenyl]-6-methyl-2-trifluoromsthyl.1,4-dihydropyridine-3,5-dicarbOXylat~
The procedur0 d0scribed in Example ~ was folluwed using 3-ethyl ~-propyl 4-[2-(4-bromobutoxy)-5-nitrophenyl]-6-methyl-2-tnfluorom~thyl-1,4-dihydropyridine-~,5-dicarboxylate (0.359) and 2-hydroxy-3-phenoxypropy~amin~ (0.389) as star~ing mat~nals. 3-Ethyl 5-propyl 4-[2-{4-(~-hydroxy-3-phenoxypropylamint))butoxy}-~-nitrophenyl]-~-m ~thyl-2-tnfluoro m sthyl-1,~-dihydropyndin~-3,~-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;
1H NMR (CDC13-TMS) ~ 8.10-8.06(m, 2H), 7.27(t, 2H), 6.97(t, 1H), 6.89(d, 2H), 6.86(d, 1H), 6.74(s, 1H), 5.37(s, 1H), 4.34(br.s, 1H), 4.1o-3.s1(m~ 8H). 3.10-2.97(m, 4H). 2.41(s. 3H),1.97-1.84(m, 4H),1~s8-1.so(m~ 2H),1 1s(t~ 3H),0.81(t, 3H);
mass spec~.rL m, m/e (FD) 6~0 (M++1).

ExamDle 26 Under similar conditions to Example 2 starting from 5-isoproDyl 3-methyl 4-~2-(4-aminobutoxy)-5-nitrophenyl~-2-cyano-6-methyl-1,4-dihydropyridine-3,5-dicar~oxylato ( "250mg) ana 1~2-e~oxy-3-(2-methylphonoxy)pro~ane (304mg) was WO 92/13839 - 29 _ 2 ~ 7 ~ ~ ~ 8 PCI'/JP92/00076 obtained 5-isopropyl 3-methyl 2-cyano-4-[2-~4-{2-hydroxy-3-(2-methylphenoxy)propylamino}butoxy]-5-nitrophenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate t230 mg) as a yellow stiff foam.
IR (KBr~ 2236,1701,1644,1590,1514,1496,1339,1271,1215,1097, 7532 cm-1;
'H NMR (CDC13-TMS) ~ 8.20-8.18 (m, lH), 8.12-8.07 (rn, lH), 7.17-7.13 (m, 2H), 6.92 and 6.79 (m, 3H), 5.22 (s, lH), 4.94-4.86 (rn, 1H), 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 spectmm, rn/~ (FD) 637 (M~+1).

ExamDle 27 Under similar conditions to Example 2 starting from 5-isopropyl 3-m~thyl 4-~2-(4-aminobutoxy)-5-nitrophenyl}-2-cyano-6-m~thyl-1,4-dihydropyridine-3,5-dicarboxylat~ (1.25g) and 1,2-epoxy-3-(2,4,6-trim~thylphenoxy~propane ~356mg) was obtained 5-isopropyl 3-methyl 2-cyano-4-[2-[4-{2-hydroxy-3-(2,4,6-trimsthylphenoxy)propylarnino)bu~oxy]-5~nitrophenyl]-6 m~thyl-1,4~dihydropyndine-3,5-dicarboxylate (160 mg) as a yellow stiff foam IR (KBr) 2236,1700,1646,1636,1590,151~,1340, 1270,1214,1095, 735 cm-1;
'H NMR (CDCI3-TMS) 3 10.30 (brs, 1H), 8.18 (d, JY2.9HZ, 1H), 8.08 (dd, J= 9.2 and 2.9Hz, lH), 6.87-6.~0 (m, 3H), 5.22 (s, 1H), 4.9~4.8~ (m, lH), 4.38-4.29 (m,1H), ~.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/a (FD) 665 (M~+~ ).
ExamPle 28 Under similar conditions to Exampl~ 1 s~alting from 5-isopropyl 3-m~thyl 4-(2-(4:
bromobutoxy)-S-methyl-3-nitrophenyl}-2-cyano-~-methyl-1,4-dihydropyndine-3,5-dicarboxylat~ (2.289) and 2-hydroxy-3-phenoxypropylamin~ (2.509) was obtained 5-isopropyl 3-methyl 2-cyano-4-[2 {4-(2 hydroxy-3-phenoxypropylamino)butoxy}-5-methyl-3-nitrophanyl]-6-methyl-1,4-dihydropyridine-3,5--dicarboxylate (930mg) as a yellow stiff ~oam.
IR (K8r) 2236,1699,1600,1530,1526,1498,1222, 1095, 755 cm-1;
'H NMR (CDC13-TMS) ~ 7.47 (d, J=1.4Hz, 1H), 7.32-7.25(m, 3H), 6.96 (br t, J=

7.2Hz, 1H), 6.90 (br d, J=7.9Hz, 2H), 5.203 and ~.19~ (2s, 1H), 4.93 (hept, J=6.2Hz, 1H), 4.33-4.24 (m, 1H), 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 (rn, 4H),1.23 (br d, J=6.3Hz, 3H),1.062 and 1.060 (2d, J=6.3 and 6.3Hz, 3H);

SUESTITTuT~ S~' E~

W O 92/13~39 ~ PC~r/JP92/00076 !

mass s?ec.:~m, m/e (F~) 63~ (M~

Examr~le ~S
Under sLmilar conditions to Example 1 starting from a-isoproyl 3-methyl 4-~2-(3-bromopropoxy)-a-nitrophenyl}-2-cyano-6-mathyl-1 ,4-dihydropyridine-3,5-dicari~oxylat3(280mg) and 2-hydroxy-3-phenoxypropylamin9 (224mg) was obtained 5-isopropyl 3-m~thyl 2 cyano-4-~2-{3-(2-hydroxy-3-phenoxypropylamino)propoxy}-5-nitrophenyl]-6-methyl-1,4-dihydropyridins-3,5--dicarboxylate (120ms) as a yellow stiff foam.
IR (KRr) 3466, 3232, 3089, 2981, 2929, 2240, 1735, 1713, 1702, 1520, 1508, 1342,1274, 1213, 1099, 825, 756, 692cm-1;
1 HNMR(CDCI3-TMS) ~ 8.15 and 8.1 4(2d,1 H), 8.08 and 8.06(2dd,1 H), 7.77 and 7.25 (2dd,2H), 6.97-6.83(m,4H),a.~O(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),1.23,1.22Ø97 and 0.94(4d,6H);
mass spectrum, m/~ (FD) 60~ tM++1).

ExamDle 30 Under similar conditions to Example 1 start m g from 5-isopropyl 3-~ethyl 4-t2-(4-bromobutoxy)-4,6-dichlorophenyl~-2-cyano-6-m~thyl-1 ,4-dihydropyridina-3,!;-dicarboxyla~a(0.38g) an~ 2-hydroxy-3-phenoxypropylamine (0.349) was obtain~d 5-isopropyl 3-methyl 2-cyano-4-[4,6-dichloro-2 ~4-(2-hydroxy-3-phenoxypropylamino)butoxy~ph~nyl]-6-m~thyl.1,4-dihydropyndine-3~- dicarboxyla~e (0.209) ~ a y~llow stiff foam.
IR (K8r) 2235, 1 696, 1578, 1522, 1454, 1302, 1246, 1213, 1096, 75~ cmw1;
1 H NMR (CDC13-TMS) ~ 7.31-7.23 (m, 2H), 6.9~-6.86 ~m, 4H), 6.72 (dd, J=8.1 and 1.8Hz,1 H), 5.70 and 5.69 (2s, 1 H), 5.03-4.g5 (m, 1 H), 4.33-4.22 (m, 1 H), 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 ( 'd, J=6.2, 6.~ 6.3 and 6.3Hz, 6H);
mass sDectn~m, m/e (F:D) 645 (M+).

ExamDle 31 ~ nder similar conditions to Exam~le 1 starting from 5-isoprop~l 3-methyl ~-i2-(4-bromobutoxy)-5-nitropnenyl~-2-cyano-6-methyl-1 ,4-dihyaropyridine-3,5-dicarboxylate(40ûms) and 2-hydroxy-3-(4-methoxypnenoxy)propylamina (441 mg) was obtained ~-isopropyl 3-methyl 2-cyano-4-12-14~2-hydroxy-3-(4-methoxyphenoxy)propylamino~utoxy]-s-nitrophenyl]-6-methyl-1 ,4-dihydropyridine-3,5--dicarboxylate (183 ms) as a yellow powder.
mp 81-~4 C;

wO92/13839 ~ 3~ p~r/Jps2/ooo76 IR tKBr) 2235,16g9,1590,151Q,1341,1302, 1273,1216. 109,, 824 cm-1;
1H NMR (CDCI3-TMS) ~ 10.02 (brs,1H), 8.18 (d, J=2./Hz,1H), 8.09 (brd, J=3.1Hz, 1H), 6.88-ô.79 (m, 5tt), 5.22 (s, lH), 4.94-4.86 (m, 1H), ~.34-~.27 (m, 1H), 4.07 - 3.8, (m, 4H), 3.76 (s. 3H), 3.68 and 3.ô7 (2s, 3H), 3.03-2.84 (m, 4H), 2.34 and 2.31 (2s, 3H), 1.95-1.7~ (m, 4H), 1.28, 1.27, 1.01 and 1.00 (4d, J=6.0, 6.0, 6.0 and 6.0Hz. 6H);
mass spec2rum, m/a (FD) 653 (M

Example 32 Under sim~lar conditlons to Ex~ple 1 starting fran 5-isopropyl 3-rnethyl 4-J2-(4-bromobutoxy)-5-nitrophenyl~-2-cyano-6-methyl-1,4-dihydropyridine-3,5-dlc~arboxylate(490mg) and 3-(4-chlorophenoxy)-2-hydroxypropylamine (5~3mg) was obtalned 5-isopropyl 3-methyl 4- [ 2- [ 4-J 3 ( 4-chlorophenoxy ) -2-hydroxypropylamino}butoxy}-5-nitroph~nyl]-2-cyano-6~m~lhyl-1,4-dihydropyridin~-3,5-~icarboxylat~ (388 mg) as a yellow powd~r.
mp96-99 C;
IR (KBr) 2234, 1693,1516,1514,1493,1338, ~301, ~275, 1213,10g9, 824 cm-1;
1H NMR (CDCI3-TMS) ~ 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, 1H), 4.93-4.87 (m, lH), 4.33-4.27 (m, 1H), 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) 6~7 (M~+1).

Exampls 33 Preparation of diethyl 4-[2~~4-(2-hydroxy-3-(2-m~thoxypnenoxy)propylamino)busoxy}~5-nitroph~nyll-6-mathyl-~-trifluororTlathyl-1 ,4-dihydropyridine-3,5-dicarboxylats The procedure described in Example 6 was tollow~d using diethyl 4-~2-(4-brornobutoxy)-5-nitrophenyl]-6-methyl.2-trifluoromethyl-1,4-dihydropyridine-3,5-dicarbo.Yytate (0.509) and 2-hydroxy-3-(2-methoxyphenoxy)prOPYIamin~ (0.~19) as starting materials. Diethyl 4-!2-J4-(2-hydroxy-3-(2-metnoxyphenoxy)propylamino)butoxy}-5-nitrophenyl]-6-methyl-2-~rifluoromethyl-1l4dihydrspyridine-3,5-dicarboxylate was obtained as a yellow stiff foam(0.46g).
IR (KBr) 3315, 2939,1702.1629, ~591,1506,1455,1368,1340,1278,1095, 744 cm-1;
lH NhtR (CDCt3-TMS) o 8.10(s, 1H), 8.07(dd, lH), 6.99-6.86(m, 5H), 5.33(s, 1H), 4.19-4.18(m, lH), 4.08-3.97(m, 8H), 3.85(s, 3H), 2.s3-2.81(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, r~e (FD) 695 (M, -1).

w092/13839 Q'1~33~ Pcr/J~92/OUO76 ExamDla 34 Under similar conditions to Example 1 starting frc~.(})~ soDropyl 3-methyl 4-{2-(4-bromobu~oxy)-~-nitrcphenyl}-2-cyano-6-methyl- 1,4-dihyaropyridine-3,5-dicarDoxylate(13.99g) anc (-)-2-hydroxy-3-pnenoxypropylamine (13.039) was obtained (+)-~-isopropyl 3-methyl 2-cyano-4-12- 4-(2-hydr~xy~3-phenoxypropylarnino)butoxy}-5-nitrcphenyl]-6-methyl-1,4-dihydropyridine-3,5-dicarboxylaté (7.409) as yellow crystals.
mp 105-107 C (from acetonitrile-diisopropyl ether);
[~r]25D +118 (c0.8, methanol);
IR (KBr) 2245,16g8,1589, 1472,13~4,1341,127~,1096, 756, 691 cm~1;
1H NMR (CDCI3-TMS) ~ 10.03 (brs,1H), 8.18 (d, J=2.7Hz.1H), 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, lH), 5.22(s 1H), 4.90 (hept, J=6.2Hz, lH), 4.37-4.27 (m, 1Hj, 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 3~
Under similar conditions to Example 2 starting from (+)-5-isopropyl 3-methyl 4-t2-(4-aminobutoxy)-5-nitrophenyl}-2-cyano.6.methyl~1,4-dihydropyridin~-3,~-dicarboxylate (8.659) and (+)-1,2-epoxy-3-phenoxypropane (1.6~9) was obtained ( I )-5-isopropyl 3-methyl 2-cyano-4-[2-{4~(2-hydroxy-3-phenoxypropylamino)butoxy}-5 nitrophenyl]-6-mathyl-1,4-dihydropyridine.3,5.dicarboxylate (2.739) as y9110w crystals.
mp 103-105 C (from ethano1-hexane);
[ a ]25D f l 23 (C 0.8, methanol).

WO 92t13839 PCI/JPg2/0~076 ExamDle ~6 Under the si.mi.lar conditionS to Example 1 starting from 5-ethyl 3-methyl 4{2-(4-bromo~utyoxy)-5-nitro-phenyl}-2-cyano-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate (776mg) and 2-hydroxy-3-phenoxypropyl-anL~.ne (635mg) was obtained 5-ethyl 3-methyl 2-cyano-4-~2-{4-~2-hydroxy-3-phenoxypropylamino)butoxy} -5-nitrophenyl]-6-methyl-l,4-d.ihydropyridine-3,5-dicarboxylate (54Omg) as yellow powders:
mp136138 ~;
IR(K8r~2236,1698,1589,1465,1385,1338,1273,1099,753,690cm' 'H NMR (CDa,TMS) ~8.20 8.07(m,2H),7.31-7.27(m,2H),7.004.84(m,4H),5.25(s.lH),4.344.25 (m,1H~,4.15-3.91(m,6H),3.69 and3.68(2s,3H), 3.01~2.78(m,4H),2.33and 2.30~2s,3H),1.95 1.71 (m,4H), 1.23-1.17(m,3H);
masssp~ctrum, m~(FD)609(M

S~'BS . I 1 -~iT~; S~iEET

~ " PCr/~ /00076 WO92/13839 ~

Example 37 Under simitar conditions to E~ample 6 starting from 3,5-diethyl 4-{2-(4-bromobutoxy)-5-nitrophenyl}-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylate(750mg~ and 2-hydroxy-~-{4-(N-methylsulphonyl-N-tetrahydropyran-2-yl)aminOphenoxy } p:copylamine (1340mg) was ~btained 3,5-diethyl 4-[2-[4-[2-hydroxy-3-{4-~N-methylsulphonyl-N-tetrahydropyranyl3aminophenoxy~propylamino3butoxy~-5-nitroph~nyl]-6-methyl-2-trifluoromethyl-1 ,4-dihydropyridine-3,5-dicarboxylat~ (870mg) as a yellow stiff foam. A
mixture of the foam (870m~) and ~TsOH- H20 (700mg) in methanol (20ml) was refluxed for 2 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform (1 5ml X 3). The combined exlracts were washed with brine and dried ov0r anhydrous sodium sulphate. After evapora~ion of the solvant the residue was chromatographad using a silica gel column (chloroform/methanol=10/1 vh) to afford 3,5-di~thyl 4-12-~4-[2-hydroxy-3-(4-(N-methylsulphonyl)aminopherloxy3propyiamino]butoxy]-~-nitrophenyl]-6-methyl~2-trinuoromethyl-1,q-dihydropyridinc-3,5-dicarboxyla~ (540mg) as a yellow stiff foam:
IR (KBr)2983, 2934. 1702, 1628, 1609, 1590, 1510, 1468, 1368, 1340, 1275, 1 152,1098, 752 cm l;
'H NMR (CDCla-TMS) ~ 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~

Example 38 Under similar conditions to Exampl~ 37 starting from 5-isopropyl 3-methyl 4-~2-t4-bromobutoxy)-5-nitrophenyl}-2-cyano-6-m~thyl-1 ,4-dihydropyridine-3.5-dicarboxylate(820mg) and 2-hydroxy-3-{4-(N-methylsulphonyl-N-tetrahydropyran-2-yl)aminophenoxy} propylamine (1440mg) was obtained 5- isopropyl 3-methyl 4-[2-[4-[2-hydroxy-3- {4-(N-methylsulphonyl)aminophenoxyJpropylamino]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, 1 1h2,1096 cm ';
IH NMR (CDCI3-TMS) ~8.20-8.07 (m, 2H), 7.22-7.14 (m, 2H), 6.92-6.80 (m, 3H),~.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, 7H), 2.33 and 2.31 (2s, 3H), 1.97-1.66 (m, 4H), 1.29-0.97 (m, 6H);
mass spectrum, m/e (FD)716 (M~

SU~STITI~TE S~iEET

Claims (8)

1. A dihydropyrindine compound of the formula:

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;
R2 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.

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, benzanesulphonate or p-toluenesulphonate.

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

wherein W, R1, R2, R3, A, X, and Y have the meanings defined in claim 1, with an epoxide or an alcohol derivative of the formula:- or 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 W, R1, R2, R3, 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:

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 W
is a haloalkyl group the haloalkyl group is trifluoromethyl.