Note: Descriptions are shown in the official language in which they were submitted.
~17028~
~ T ~ 5
The present invention relates to the use of N-alkylated
1,4-dihydropyri~;ne~;carboxylic acid esters, some of
which are known, as anti-atherosclerotic medicaments, in
particular to their use $or the prophylaxis of restenoses
following angioplasties and vascular surgery.
It is already known that 4-nitrophenyl-substituted 1,4-
dihydropyridines also bring about inhibition of the
formation of fibromuscular plaques [cf. DE 32 22 367l.
It has now been found that N-alkylated 1,4-dihydropyri-
dinedicarboxylic acid esters of the general formula (I)
R1
~R
Rso2C ~ CO2R4 (I)
H3C N CH3
R6
in which
R1 represents hydrogen, nitro, cyano, trifluoromethyl,
trifluoromethoxy, halogen or methyl,
R2 represents hydrogen, halogen, nitro, hydroxyl,
trifluoromethyl or methyl,
Le A 29 900 - 1 -
~1702&~
R3 represents hydrogen or cyano,
or
R2 and R3 together form a fused-on benzo ring,
R~ and R5 are identical or different and represent
straight-chain or br~nche~ alkyl having up to 8
carbon atoms, which is optionally substituted by
alkoxy having up to 4 carbon atoms,
R6 represents straight-chain or br~nch~ alkyl having
up to 6 carbon atoms,
or
represents cycloalkyl having 3 to 7 carbon atoms,
surprisingly po~sess, in addition to their haemorheologi-
cal effect, a strong inhibitory effect on the prolifera-
tion of smooth muscle cell~ and are consequently suitable
for use in controlling atherosclerosi~, in particular for
the prophylaxis of restenoses following angioplasties and
va~cular surgery.
Dimethyl 1,2,6-trimethyl-4-(4-trifluoromethylphenyl)-1,4-
dihydropyridine-3,5-dicarboxylate and dimethyl 4-(4-
chloro-3-trifluoromethylphenyl)-1-cyclopropyl-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylate are
particularly preferred in the control of atherosclerosis,
in particular for the prophylaxis of restenoses following
angioplasties and ~a~cular surgery.
Le A 29 900 - 2 -
2170285
The compounds according to the invention thus exhibit a
valuable spectrum of pharmacological activity which was
not to be foreseen.
The compounds according to the invention inhibit the
proliferation of smooth muscle cells. Injuries to the
vessel wall lead to neoint;m~l cell growth and
consequently to constriction of the free vessel lumen.
This process is the principal cause of restenosis prob-
lems following vessel-opening procedures, such as
percutaneous angioplasties, endarterectomies or bypass
operations.
They can therefore be employed in medicaments for the
treatment and prophylaxis of restenosis, e.g. following
angioplasties and vascular surgery. In addition to this,
the compounds according to the invention can also be
ployed for treating atherosclerosis.
Some of the compounds according to the invention are
known [cf. DOS 40 11 695].
In order to ascertain the antiproliferative effect of the
compounds according to the invention, balloon catheters
are inserted into the carotid arteries of rats, and these
catheters are then inflated and the inner side of the
blood vessel i~ damaged by moving the catheter
[Clowes A.W, et al., Lab. Invest. Vol. 49, No. 3, p. 327,
1983]. This damage brings about neointimal proliferation
of the smooth muscle, causing stenoses. The extent of
Le A 29 900 - 3 -
217028~
vessel constriction in the animals is determined after
about 2 weeks by histological processi~g of the blood
vessels, involving measurement of the area of prolifera-
ted tissue in vessel cross sections. Surprisingly, the
compounds according to the invention significantly
inhibit the vessel constrictions, as i8 evident from the
following table.
Example Proliferated tissue in ~m2 x 1000 (%)
No. Control 10 mg/kg p.o.
1 129 (100%) 76 (59%)
2 125 (100%) 56 (45%)
The novel active compounds can be converted, in a known
~anner, into the customary formulations, such as tablets,
coated tablets, pills, granules, aerosols, syrups,
emulsions, suspensions and solutions, using inert, non-
toxic, pharmaceutically suitable, excipients or solvents.
In this connection, the therapeutically active compound
should in each case be present at a concentration of
about 0.5 to 90% by weight of the total mixture, i.e. in
quantities which are sufficient to achieve the given
dosage scope.
The formulations are prepared, for example, by ext~n~ing
the active compounds with solvents and/or excipients,
optionally using emulsifiers and/or dispersants, it being
possible, where appropriate, for example when u~ing water
as a diluent, to use organic solvents as auxiliary 801-
vents.
Le A 29 900 - 4 -
~170285
Administration is effected in a customary manner, prefer-
ably orally or parenterally, in particular perlingually
or intravenously.
In the case of parenteral use, solutions of the active
compound can be employed using suitable liquid carrier
materials.
In general, it has proved ad~antageous to A~;n;ster
quantities of about 0.001 to 1 mg/kg, preferably about
0.01 to 0.5 mg/kg, of body weight in order to achieve
effective results in the case of intravenous a~inistra-
tion, and the dosage is about 0.01 to 20 mg/kg, prefer-
ably 0.1 to 10 mg/kg, of body weight in the case of oral
administration.
Despite this, it can, where appropriate, be necessary to
diverge from the said quantities, specifically dep~n~;ng
on the body weight and the nature of the route of admini-
stration, on the individual response to the medicament,
on the nature of its formulation, and on the time or
interval at which administration is effected. Thus, it
can, in some cases, be sufficient to make do with less
than the aforesaid lowesk quantity, while, in other
cases, the said upper limit must be exceeded. When larger
quantities are being administered, it can be advisable to
divide these into several smaller doses which are given
over the day.
Le A 29 900 . - 5 -
~1702~5
Example 1
Dimethyl 1,2,6-trimethyl-4-(4-trifluoromethylphenyl)-1,4-
dihydropyridine-3,5-dic~nhoYylate
(~ '
H3CO2C ~ CO2CH3
H3C N CH3
CH3
A mixture consisting of 5.22 g (0.03 mol) of 4-trifluoro-
methylbenzaldehyde, 7.04 g (0.06 mol) of methyl aceto-
acetate and 2.07 g (0.03 mol) of methyl~_; ne
hydrochloride in 20 ml of pyridine iR stirred under
reflux for 5 hours. After the pyridine has been distilled
off, partitioning takes place between water and methylene
chloride, and the organic phase is then w~h~A with
water, dried over sodium sulphate and e~aporated. The
re~idue is recrystallized from methanol.
M.p.: 154-155C
Yield: 7.88 g (68.5% of theory)
Example 2
Dimethyl 4-(4-chloro-3-trifluoromethylphenyl)-1-cyclopro-
pyl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Le A 29 900 - 6 -
2170285
~ CF~
H3CO2C ~1, CO2CH3
J~ ~
H3C N CH3
A
Process A
A solution of 23.3 g (0.15 mol) of methyl 3-cyclopropyl-
aminocrotonate, 46.0 g (0.15 mol) of methyl (4-chloro-3-
trifluoromethylbenzylidene)acetoacetate and 17.7 g
(0.15 mol) of pyridine hydrochloride in 100 ml of
pyridine is stirred under reflux for 7.5 h. Following
evaporation in vacuo, the residue is partitioned between
120 ml of methylene chloride and 150 ml of water. After
having been evaporated down, the organic phase yields a
resinous crude product which is recrystallized from 100
ml of cyclohexane.
M.p.: 131-135C
Yield: 35.0 g (52.6% of theory)
Process B
A solution of 4.17 g (0.02 mol) of 4-chloro-3-trifluoro-
methylbenzaldehyde, 4.65 g (0.04 mol) of methyl aceto-
acetate and 1.96 g (0.021 mol) of cyclopropylamine
Le A 29 900 - 7 -
21702~
hydrochloride in 20 ml of pyridine i8 stirred under
refluY. for 4 h. Following evaporation, the residue is
partitioned between 40 ml of methylene chloride and 50 ml
of water. Evaporation of the organic phase yields an oily
crude product which is crystallized using cycloh~Y~ne and
n-pentane.
M.p.: 131-134C
Yield: 3.33 g (37.5% of theory)
Le A 29 900 - 8 -
