1,4-Dihydropiridines and their use as antithrombotic drugs

The present invention refers to new 1,4-dihydropyridines, to their obtention processes and to their use as antithrombotic drugs. Said new 1,4-dihdyropyridines have the following general formula (I) ##STR1## wherein R represents hydrogen or a saturated or unsaturated alkyl group, with a linear or branched chain of 1 to 8 carbon atoms, PA0 R.sup.1 represents an alkyl radical with a linear, branched or cyclic, saturated or unsaturated chain of 1 to 12 carbon atoms, which may be interrupted by an oxygen or by a 2-(N-salicylamido)ethyl group, PA0 n is a number equal to 1 or 2. These new 1,4-dihydropyridines are obtained by processes based on the Hantzch reaction or on modifications thereof.

FIELD OF THE INVENTION 
Nowadays, there is no doubt about the role of platelets in arterial 
thrombosis (J. M. Sullivan in "Blood platelet function and medicinal 
chemistry", page 1, Elsevier Biomedical, New York (1984)) and that their 
main activation processes: adhesion, aggregation and releasing reaction, 
are fundamental factors in the pathogenesis of thromboembolic disorders, 
which are one of the most important causes of death in the western world. 
The build-up of a platelet aggregate at a damaged area of a blood vessel 
wall is a primary event in the development of a thrombus. Circulating 
thromboemboli may appear when these thrombi become emboli or when 
platelets find aggregating agents in the stream. 
A drug capable of directly or indirectly inhibiting these processes would 
have an obvious interest in the therapeutic control of those pathologic 
situations wherein platelets are involved and the use thereof would be 
very useful in the prophylaxis and treatment of arterial thrombosis. 
DETAILED DESCRIPTION OF THE INVENTION 
A class of 1,4-dihydropyridines has surprisingly shown to exhibit an 
exceptional activity as platelet activation inhibitors, at the same time 
as they lack any activity on heart and vascular smooth muscle, this being 
a characteristic of 1,4-dihydropyridines with calcium-antagonistic 
activity (A. Lasslo and R. P. Quintana in "Blood platelet function and 
medicinal chemistry", page 229, Elsevier Biomedical, New York (1984)). 
New 1,4-dihydropyridines according to the present invention have the 
following general formula (I) 
##STR2## 
wherein R represents hydrogen or a saturated or unsaturated alkyl group 
with a linear or branched chain of 1 to 8 carbon atoms, 
R.sup.1 may represent an alkyl radical with a linear, branched or cyclic 
chain, either saturated or unsaturated, or 1 to 12 carbon atoms, which may 
be interrupted by an oxygen atom; or a 2-(N-salicylamido)ethyl group. 
n is a number equal to 1 or 2. 
The new compounds may be obtained according to methods based on the Hantzch 
reaction or on modifications thereof, such as indicated hereinafter: 
(a) A compound of formula (II) 
##STR3## 
wherein R and n are as previously defined, is made to react with a 
compound of formula (III) 
##STR4## 
wherein R.sup.1 has been previously defined, so as to yield a compound of 
formula (I); or 
(b) A compound of formula (IV) 
##STR5## 
wherein n has been previously defined, is made to react with a compound of 
formula (V) 
##STR6## 
wherein R and R.sup.1 have been previously defined, so as to yield a 
compound of formula I, or 
(c) A compound of formula (VI) 
##STR7## 
wherein R.sup.1 has been previously defined, is made to react with a 
compound of formula (IV), wherein n has been previously defined and a 
compound of formula (VII) 
EQU R--CHO (VII) 
wherein R has been previously defined, so as to yield a compound of formula 
(I), or 
(d) A compound of formula (VIII) 
##STR8## 
wherein n has been previously defined, is made to react with a compound of 
formula (III), wherein R.sup.1 has been previously defined, and a compound 
of formula (VII), wherein R has been previously defined, so as to yield a 
compound of formula (I), or 
(e) A compound of formula (VI), wherein R.sup.1 has been previously 
defined, is made to react with a compound of formula (VIII), wherein n has 
been previously defined, and a compound of formula (VII), wherein R has 
been previously defined, and with NH.sub.3, so as to yield a compound of 
formula (I). 
The present invention also includes the formation of stable salts of 
compounds of formula I with organic or inorganic, pharmacologically 
suitable acids. 
The reaction conditions used in (a) and (e) variants are as follows: 
Water is considered as solvent, as well as all inert organic solvents such 
as alcohols, e.g. methanol, ethanol, isopropanol and n-butanol; ethers, 
such as inferior dialkyl ethers, e.g. diethyl ether, ter-buthylmethyl 
ether or cyclic ethers such as tetrahydrofurane and dioxane; inferior 
aliphatic carboxylic acids such as acetic and propionic acids; inferior 
dialkylformamides such as dimethylformamide; inferior alkylnitriles such 
as acetonitrile; dimethylsulfoxide; liquid heteroaromatic bases, such as 
pyridine. Solvent mixtures, water included, may also be used. If 
necessary, the reagents may be made to react without solvents. 
The reaction temperature may vary between 20.degree. and 150.degree. C., 
preferably between 50.degree. and 100.degree. C. The reaction is usually 
carried out at the boiling temperature of the solvent used. 
The reaction may be conducted at the normal pressure, but also under high 
pressure. It is usually conducted at the normal pressure. 
The time of the reaction ranges from 45 minutes to 10 hours. 
According to the invention, the separation and isolation of the product 
yielded along the reaction are carried out by techniques usually used for 
this purpose, the product being able to be submitted to a conventional 
purification such as recrystallization, distillation or chromatography. 
The present invention is illustrated by the following non-limitative 
examples: