WO 92/13839 PCT/JP92/00076
- 2~7~3~
--1--
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
--2--
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
W N R1
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.
W092/13839 PCT/JP92/00076
~ ~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.
WO92/13839 PCT/JP92/00076
2~7~
--5--
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
O -A-NH2
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
W N R1
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)
WO 92/13839 PCT/JP92/0076
-12-
Test results
<IMG>
(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
3 -13-
[ ~]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
-14-
(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
-15-
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
-18-
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
WO92/13839
,~
-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
W092/13839
20-
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);
51VE3STITUTE SHEET
~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
-33-
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
