Note: Descriptions are shown in the official language in which they were submitted.
so
- 1 - 231~9-5554
The present invention relates to the use of dodder-
pardons to counter atherosclerotic vascular changes in the form
of fibromusculoelastic plaques, anti arteriosclerotic agents con-
tenon them and their preparation. Some of the compounds to be
used according to the invention and their vasodilator, hypotensive
and coronary activity are known from DEMOS (German Published
specification) 2,117,571; DEMOS (German Published Specification)
1,670,827; DEMOS (German Published Specification) 2,117,573;
DYES (German Published Specification) 2,549,568 and DEMOS (German
Published Specification) 2,841,667.
It has likewise been disclosed that the compound knifed-
pine (compare DEMOS (German Published Specification) 1,67~,827)
and other calcium antagonists inhibit entry ox Cay into smooth
muscle cells. In addition, it has since been disclosed for
nifedipine -that it can suppress infiltration of cholesterol into
the vessel wall of rabbits fed with cholesterol (compare Do
Henry and Bentley, KIWI.: J. Olin. Invest. 68, 1366-9, 1981).
The use of the ~ihydropyridines according to the invent
lion as anti arteriosclerotic agents which inhibit the formation,
caused by damage -to vessel walls, of fibromusculoelastic plaques
produced by a proliferating intima has not hitherto been disclosed.
Cardiovascular diseases, which are diagnosed as the
cause of more than 50~ of the cases of death in the mortality
statistics in industrialized countries, very frequently have their
cause in arteriosclerotic changes in the arterial part ox the
vascular system. Intimal proliferation its rewarded as a important
early stage in the etiology of atheroc3enesls. Arteriosclerotic
changes of this type, which can lead to partial or complete occlu-
soon of the vessel, cause damage to tissue and can load to
local tissue necrosis, infarction, for example in the heart or
brain.
The present invention relates to 1,4-dihydropyridines of
the general formula (I)
\~'~
R OX COO (I)
11
3 H SHEA
in which
Al and R2 are identical or different and each represent
alkyd or alkoxyalkyl having up to 12 C atoms, the alkyd radical
optionally being substituted by fluorine or chlorine, and
R3 represents one or -two identical or different
substituents from the group comprising vitro, trifluoromethyl,
halogen or ennui,
err use to counter arteriosclerosis.
'rho invention therefore provides pharmaceutical
compositions yin dosage unit form suitable for oral a~lininixtrcl-tion
to a mammal ire countering the formation of fibromusculo elclstic
plaques produced by intimal proliferation in mammals, whelk
compositions comprise a compound of general formula (I) dew Ed
avow, in admixture with a suitable pharmaceutically acceptable
I error or cliluent.
In anther aspect the inventiorl provides a process for
35~
preparing a therapeutic agent for countering the formation of
fibromusculo elastic plaques produced by intimal proliferation in
a mammal, in ready-to-use drug form, characterized in that the
therapeutic agent includes as active ingredient a compound of
formula (I) as defined above.
Those compounds of the general formula (I) are portico
laxly suitable, in which
Al and R2 are identical or different and each represent
alkyd having 1 -to 4 C atoms or alkoxyal~yl having up to 6 carbon
atoms, and
R3 represents one or two subs-tituents in the ortho or
mote position from the group comprising vitro, chlorine or
trifluoromethyl.
Compounds of the general formula (I) which may be very
particularly emphasized are those in which
Al and R2 represent alkyd having 1 to 4 carbon atoms and
R represents vitro.
prom a knowledge of the state of the art, it could not
be expected that the compounds usable according to the invention
have such an advantageous anti arteriosclerotic effect.
Arteriosclerosis is a complex disease, the original
- pa -
US
-- 3 --
lion of which can frequently be affected or caused by the
following processes:
a) Damage to a vessel wall with subsequent proliferation
of smooth muscle cells and production of a fibromusco-
elastic lesion Infiltration of lipids into this lesion and
c) Formation of a mural thrombus and its incorporation into the
vessel wall.
The following examples illustrate,
the advantageous specific inhibitory effect on
proliferation of the compounds to be used according to the
invention.
Test method
Proliferation of the intima is induced on rats by
vascular lesion. By subjecting the carotid artery to
hypotherm;a(-10C, Z minutes), partial or complete
removal of the endothelium in a localized region is produced.
Proliferation of the intima occurs after a short period
of about 10 days and this largely corresponds to the
early stages of arteriosclerotic plaques in humans. The
zones of proliferation are excised and weighed. The jet
weight is about 200 to 300 in the chilled segment
of 1 cm. The animals also receive a heft diet (3 I
of cholesterol).
The incorporated lipids are stained Vito the fat-
soluble distaff Sudan IV and can be determined as an
additional parameter compare F. Setter et Allah Export-
mentally induced thromboatherosclerosis. Folio annul-
Gina 28, as ~1980)).
Surprisingly, the compounds shown as examples in
the following table also have anti arteriosclerotic astute
after oral administration, the proliferation of the intima
being significantly inhibited
lo A Z1 534
2~1S~
Table
Substance Dose Proliferation Redllction
~mg/kg, day)* go I%)
-
Control - 309
substance pro. 159 49
example 310 pro. 270 13
substance pro. 73 44
example 130 pro. lo 16
Control - 130
* divided into two doses
Apart from cytostatic agents having alkylating effects and
glucocorticoids, which inhibit cell proliferation non-specifically, only
heparin has hitherto been effective in this model after parenteral administration.
Lipid-lowering substances, such as cholestyramine, neomycin and nicotinic
acid were ineffective. The dose-dependent effect of heparin, which serves
as a reference standard in the present case, is already knoll (compare R. Slit
et at., Suppression by heparin of intima proliferation in the injured carotid
artery (rat)., Arch. Pharmacol., Supply 311, Abstr. 1~8~ 198Q).
Ileparin has the significant disadvantage of parcnteral administration.
Virtually no effect occurs after oral administration. The oral effectiveness
Ox tile compo-mds according to the invention is surprising and could not be
~xpoctod from knowledge of the state of the art.
on suitable dose is usually in the range of from I to 150 my,
profor.lbly lo to lo my. A preferred form of composition is a tablet.
ration
I)IIP derivatives as anti atherosclerotic agents
2'-îYitrophenyl~-2,6-dimethyl-3,5-dicarbomethoxy-11,4-di,hydropyridiale
SLY
-- 5
I` No
SHEA 2 C~¢~CO2 C~3
SHEA H CX3
45 g of Z-nitrobenzaldehyde, 80 ml of methyl
acetoacetate, 75 ml of methanol and 32 Al of ammonia are
heated under reflex for several hours filtered, cooled
S and, after filtering off with suction, 75 9 of yellow
crystals of melting point 172 to 174C are obtained.
4-~3'-Nitrophenyl)-2,6-dimethyL-3,5-di-(carboxylicc acid
2 propcxyethyl ester)-1,4-dihydropyridjne
NO
I/
SHEA KIWI, SHEA OCHl SHEA 2 C KIWI Cal Cal OOZE, C~2 SUE
lo IL
C~3 CX3
7u5 9 of 3-nitrobenza~dehydef 19 9 of 7--propoxy-
ethyl acetoacetate and 5.5 ml of ammonia on 40 ml of
alcohol are heated under reflex for 6 to 8 hours and,
after cooling down, 21 9 of yellow crystals are obtained,
which are recrystallized from ligroin with addition of a
little Bunsen. Melting point 83 to 86C.
3-Methyl 5-ethyl 2,6-dimethyl-4-(3' nitrophenyl~-1,4-di-
hydropyr;dine-3,5-dicarboxylate
NO
of
EKE, C~¢~CO2C~
lo A 21 534
us
-- 6
After boiling a solution of 13.4 9 of ethyl 3'-
nitrobenzylideneacetoacetate and 5.8 9 of methyl Amman-
crotonate on 50 ml of ethanol for 10 hours, the 3-methyl
5-ethyl 2,6-dimsthyl-4-(3'-nitrophenyl)~1,4-dihydropyri-
Dunn dicarboxylate, of melting point 158C (ethanols obtained. Yield: 67~ of theory.
Example 4
Decal ethyl dodders dimethyl-4-(2-nitrophenyl~-
pyridine-3,5-dicarboxylate
I 2
H~C2O~C CO2-(C~2)9-CX
N
I C~3
A solution of 263 9 (1 molt of ethyl 2-(3-n;tro-
benzyl;dene)-acetoacetate end 241 9 (1 molt of decal I-
am;nocrotonate in 2~4 liters of absolute ethanol was
heated to bullying under nitrogen for 18 hours. It was
then filtered hot and evaporated to about one half of the
volume in vacua. The concentrated solution was cooled in
ice, whereupon a thick mass of crystals precipitated out.
This was filtered off with suction, recrystallized from
ethanol and, after washing with 0.5 lithe of Nixon,
Z0 dried in a vacuum oven at 60C~ Melting point 1û6 to
108C, yield: 337 9 (69.5~).
Example 5
Isobutyl2,6-d;methyl-3-methoxycarbonyl-4-~Z'~nitroph~nyl~--
1,4-d;hydropyr;d;ne-5~carboxylate
H, C
HO - H C -COO I,,, ~,~ C I C I,
I HO N CEIL
lo A Z1 53~_
Jo 2~35~
- 7
14.6 9 (50 Melissa) of isobutyl 2'-nitrobenzylidene-
acetoacetate, together with 5.8 g (50 Melissa) of methyl I-
aminocrotonate, were heated in 80 ml of ethanol under
reflex for 20 hours. After cooling the reaction mixture,
the solvent was distilled off in vacua and the oily nest-
due was thoroughly mixed with a little ethanol. The pro-
duct crystallized completely after a short time, and was
filtered off with suction and recrystallized from ethanol.
Melting point 151 to 152C, yield: 15.2 9 ~78X).
lo A 21 534
