2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same

The present invention relates to new compounds having antihypertensive effect, which compounds are of the formula I, ##STR1## wherein R.sup.1 is selected from the group consisting of --CH.sub.3, --C.sub.2 H.sub.5, --CH.sub.2 CH.sub.2 OCH.sub.3, and --CH.sub.2 CH.sub.2 OC.sub.2 H.sub.5, and R.sup.2 is selected from the group consisting of --C.sub.2 H.sub.5, --CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, --CH(CH.sub.3)CH.sub.2 OCH.sub.3, C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3, and --CH.sub.2 C(CH.sub.3).dbd.CH.sub.2, whereby R.sup.1 and R.sup.2 are not the same, R.sup.3 is selected from the group consisting of chloro, and R.sup.4 is selected from the group consisting of chloro, and methyl, a method for lowering the blood pressure in mammals including man using said compounds, and pharmaceutical preparations containing said compounds.

DESCRIPTION 
TECHNICAL FIELD 
The present invention relates to new compounds having valuable 
antihypertensive properties, process for their preparation, method for 
lowering blood pressure in mammals including man, and pharmaceutical 
preparations containing said compounds. 
The object of the present invention is to obtain new antihypertensive 
agents, which lower blood pressure in the peripheral vessels in lower 
doses than they lower blood pressure in the heart vessels, by selective 
dilation of peripheral blood vessels. 
BACKGROUND OF THE INVENTION 
Compounds of the formula 
##STR2## 
wherein R is nitro or trifluoromethyl in 2 or 3-position are known to 
possess cerebral vasodilating effect, effect against angina pectoris or 
blood pressure lowering effect. 
Agents which relax vascular smooth muscle may be used for treatment of 
arterial hypertension since such patients suffer from elevated peripheral 
resistance to blood flow. Compounds which interfere with vascular smooth 
muscle activity have been used clinically for several years. However, 
their usefulness has often been limited due to insufficient efficacy 
and/or due to adverse effects. Side effects (outside the cardiovascular 
system) have often been connected with properties of the agent not 
relevant to the smooth muscle relaxant effect. Sometimes the vasodilating 
agents have also exerted a negative effect on the contractility of the 
heart. 
It appears that the development of specific smooth muscle relaxants devoid 
of adverse effects, can offer a therapeutic advantage in arterial 
hypertension and for treatment of ischaemic heart disease and of the 
acutely failing heart. Further more, such agents can also be useful in 
treatment of other conditions with excessive activation of smooth muscle 
of the visceral type. 
DISCLOSURE OF THE INVENTION 
It has now surprisingly been shown that the compounds of the formula I 
##STR3## 
wherein R.sup.1 is selected from the group consisting of --CH.sub.3, 
--C.sub.2 H.sub.5, --CH.sub.2 CH.sub.2 OCH.sub.3 and --CH.sub.2 CH.sub.2 
OC.sub.2 H.sub.5 and R.sup.2 is selected from the group consisting of 
--C.sub.2 H.sub.5, --CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, 
--CH(CH.sub.3)CH.sub.2 OCH.sub.3, --C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3, 
and --CH.sub.2 C(CH.sub.3).dbd.CH.sub.2, whereby R.sup.1 and R.sup.2 are 
not the same, R.sup.3 is chloro, and R.sup.4 is selected from the group 
consisting of chloro, and methyl, possess a specific muscle relaxing 
effect related to the peripheral vascular system whereby the compounds are 
devoid of adverse effects. 
Specific preferred compounds of the invention are: 
(1) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-methylester-5-ethylester; 
(2) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-ethylester-5-(2-methoxyethylester) 
(3) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-methylester-5-isopropylester 
(4) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-methyl-5-tert.butylester 
(5) 2,6-dimethyl-4-(2,3-dichlorophenyl)1,4-dihydropyridine-3,5-dicarboxylic 
acid-3-methylester-5-(2-methoxy-1-methylethylester) 
(6) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-(2-methoxyethyl)ester-5-isopropylester 
(7) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-(2-ethoxyethyl)ester-5-ethylester 
(8) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-methylester-5-(2-methoxy-1,1-dimethylethyl)ester 
(9) 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic a 
cid-3-methylester-5-(2-methyl)-allylester 
(10) 
2,6-dimethyl-4-(2-chloro-3-methylphenyl)-1,4-dihydropyridine-3,5-dicarboxy 
lic acid-3-methylester-5-ethylester 
The substances are intended to be administered orally or parenterally for 
acute and chronic treatment of above mentioned cardiovascular disorders. 
The biological effects of the new compounds have been tested, and the 
different tests carried out will be shown and explained below. 
The new compounds are obtained according to methods known per se. 
Thus, 
(a.sup.1) a compound of formula IIa 
##STR4## 
wherein R.sup.1, R.sup.3 and R.sup.4 have the meanings given above is 
reacted with a compound of formula IIIa 
##STR5## 
(wherein R.sup.2 has the meaning given above to give a compound of formula 
I, or 
(a.sup.2) a compound of formula IIb 
##STR6## 
wherein R.sup.2, R.sup.3 and R.sup.4 have the meanings given above is 
reacted with a compound of formula IIIb 
##STR7## 
wherein R.sup.1 has the meaning given above, to the formation of a 
compound of formula I; or 
(b.sup.1) a compound of formula IV 
##STR8## 
wherein R.sup.3, and R.sup.4 have the meanings given above is reacted with 
the compounds of formulas Va and IIIa 
##STR9## 
wherein R.sup.1, and R.sup.2 have the meanings given above to the 
formation of a compound of formula I, or 
(b.sup.2) a compound of formula IV above wherein R.sup.3, and R.sup.4 have 
the meanings given above is reacted with the compounds of formulas Vb and 
VIb 
##STR10## 
wherein R.sup.1 and R.sup.2 have the meanings given above, to the 
formation of a compound of formula I; or 
(c.sup.1) a compound of formula IIa wherein R.sup.1, R.sup.3 and R.sup.4 
have the meanings given above is reacted with a compound of the formula 
VIa 
##STR11## 
wherein R.sup.2 has the meaning given above in the presence of ammonia, to 
the formation of a compound of the formula I, or 
(c.sup.2) a compound of formula IIb wherein R.sup.2, R.sup.3, and R.sup.4 
have the meanings given above is reacted with a compound of formula VIb 
##STR12## 
wherein R.sup.1 has the meaning given above, in the presence of ammonia, 
to the formation of a compound of the formula I; or 
(d) a compound of formula IV above, wherein R.sup.3, and R.sup.4 have the 
meanings given above, is reacted with the compounds of the formulas Va and 
Vb above, wherein R.sup.1 and R.sup.2 have the meanings given above, in 
the presence of ammonia, to the formation of a compound of the formula I. 
The invention also relates to any embodiment of the process of which one 
starts from any compound obtained as an intermediate in any process step 
and one carries out the lacking process step, or one breaks off the 
process at any step, or at which one forms a starting material under the 
reaction conditions, or at which a reaction component possibly in the form 
of its salt is present. 
The new compounds may, depending on the choice of starting materials and 
process, be present as optical antipodes or racemate, or, if they contain 
at least two asymmetric carbon atoms, be present as an isomer mixture 
(racemate mixture). 
The isomer mixtures (racemate mixtures) obtained may, depending on 
physical-chemical differences of the components, be separated into the two 
stereoisomeric (diastereomeric) pure racemates e.g. by means of 
chromatography and/or fractional crystallization. 
The racemates obtained can be separated according to known methods, e.g., 
by means of recrystallization from an optically active solvent, by means 
of microorganisms, or by a reaction with optically active acids forming 
salts of the compound, and separating the salts thus obtained, e.g. by 
means of the different solubility of the diastereomeric salts, from which 
the antipodes may be set free by the action of a suitable agent. Suitably 
usable optically active acids are e.g. the L- and D-forms of tartaric 
aicd, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic 
acid or quinic acid. Preferably the more active part of the two antipodes 
is isolated. 
Suitably such starting materials are used for carrying out the reactions of 
the invention, which material leads to groups of end products preferably 
desired and particularly to the specifically described and preferred end 
products. 
The starting materials are known or may, if they are novel, be obtained 
according to processes known per se. 
In clinical use the compounds of the invention are usually administered 
orally, or rectally in the form of a pharmaceutical preparation, which 
contains the active component as free base in combination with a 
pharmaceutically acceptable carrier. 
Thus the mentioning of the new compounds of the invention is here related 
to the free amine base even if the compounds are generally or specifically 
described, provided that the context in which such expressions are used, 
e.g., in the examples, with this broad meaning should not correspond. The 
carrier may be a solid, semisolid or liquid diluent or a capsule. These 
pharmaceutical preparations are a further object of the invention. Usually 
the amount of active compound is between 0.1 and 99% by weight of the 
preparation, suitably between 0.5 and 20% by weight in preparations for 
injection and between 2 and 50% by weight in preparations for oral 
administration. In the preparation of pharmaceutical preparations 
containing a compound of the present invention in the form of dosage units 
for oral administration the compound elected may be mixed with a solid, 
pulverulent carrier, as e.g., with lactose, saccharose, sorbitol, 
mannitol, starch, such as potatoe starch, corn starch, amylopectin, 
cellulose derivatives or gelatine, as well as with an antifriction agent 
such as magnesium stearate, calcium stearate, polyethyleneglycol waxes or 
the like, and be pressed into tablets. If coated tablets are wanted, the 
above prepared core may be coated with concentrated solution of sugar, 
which solution may contain, e.g., gum arabicum, gelatine, talc, 
titandioxide or the like. Furthermore, the tablets may be coated with a 
laquer dissolved in an easily volatile organic solvent or mixture of 
solvents. To this coating a dye may be added in order to easily 
distinguish between tablets with different active compounds or with 
different amounts of the active compound present. 
In the preparation of soft gelatine capsules (pearl-shaped, closed 
capsules), which consist of gelatine and, e.g., glycerine, or in the 
preparation of similar closed capsules, the active compound is mixed with 
a vegetable oil. Hard gelatine capsules may contain granules of the active 
compound in combination with a solid, pulverulent carrier as loactose, 
saccharose, sorbitol, mannitol, starch (as, e.g., potatoe starch, corn 
starch or amylopectin), cellulose derivatives or gelatine. 
Dosage units for rectal administration may be prepared in the form of 
suppositories, which contain the active substance in a mixture with a 
neutral fat base, or they may be prepared in the form of gelatine-rectal 
capsules which contain the active substance in a mixture with a vegetable 
oil or paraffin oil. Liquid preparations for oral administration may be 
present in the form of sirups or suspensions, e.g. solutions containing 
from about 0.2% by weight to about 20% by weight of the active substance 
described, glycerol and propylene glycol. If desired, such liquid 
preparations may contain colouring agents, flavouring agents, saccharine 
and carboxymethylcellulose as a thickening agent. 
The preparation of pharmaceutical tablets for peroral use is carried out in 
accordance with the following method: 
The solid substances included are ground or sieved to a certain particle 
size. The binding agent is homogenized and suspended in a certain amount 
of solvent. The therapeutic compound and necessary auxiliary agents are 
mixed with continuous and constant mixing with the binding agent solution 
and are moistened so that the solution is uniformly divided in the mass 
without overmoistening any parts. The amount of solvent is usually so 
adapted that the mass obtains a consistency reminiscent of wet snow. The 
moistening of the pulverulent mixture with the binding agent solution 
causes the particles to gather together slightly to aggregates and the 
real granulating process is carried out in such a way that the mass is 
pressed through a sieve in the form of a net of stainless steel having a 
mesh size of about 1 mm. The mass is then placed in thin layers on a tray 
to be dried in a drying cabinet. This drying takes place during 10 hours 
and has to be standardized carefully as the damp degree of the granulate 
is of outmost importance for the following process and for the feature of 
the tablets. Drying in a fluid bed may possibly be used. In this case the 
mass is not put on a tray but is poured into a container having a net 
bottom. After the drying step the granules are sieved so that the particle 
size wanted is obtained. Under certain circumstances powder has to be 
removed. 
To the so called final mixture, disintegrating, antifriction agents and 
antiadhesive agents are added. After this mixture the mass shall have its 
right composition for the tabletting step. 
The cleaned tablet punching machine is provided with a certain set of 
punches and dies, whereupon the suitable adjustment for the weight of the 
tablets and the degree of compression is tested out. The weight of the 
tablet is decisive for the size of the dose in each tablet and is 
calculated starting from the amount of therapeutic agent in the granules. 
The degree of compression affects the size of the tablet, its strength and 
its ability to disintegrate in water. Especially with regard to the two 
later properties the choice of compression pressure (0.5 to 5 ton) means 
something of a compromise. When the right adjustment is set, the 
preparation of tablets is started and is carried out with a rate of 20,000 
to 200,000 tablets per hour. The pressing of the tablets requires 
different times and depends on the size of the batch. 
The tablets are freed from adhering pulver in a specific apparatus and are 
then stored in closed packages until they are delivered. 
Many tablets, especially those which are rough or bitter, are coated with a 
coating. This means that they are coated with a layer of sugar or some 
other suitable coating. The tablets are usually packed by machines having 
an electronic counting device. The different types of packages consist of 
glass or plastic gallipots but also boxes, tubes and specific dosage 
adapted packages. 
The daily dose of the active substance varies and is dependent on the type 
of administration, but as a general rule it is 100 to 1000 mg/day of 
active substance at peroral administration.

BEST MODE OF CARRYING OUT THE INVENTION 
The following illustrates the principle and the adaption of invention, 
however, without being limited thereto. Temperature is given in degree 
Celsius. 
EXAMPLE 1 (method a.sup.1, a.sup.2) 
Preparation of 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic 
acid-3-methylester-5-ethylester 
2.87 g of 2,3-dichlorobenzylideneacetylacetic acid-methylester and 1.3 g of 
3-aminocrotonic acid ethylester were dissolved in 10 mls of t.-butanol. 
The reaction mixture was allowed to stand at ambient temperature for 4 
days, whereupon the t.-butanol was evaporated and the residue was 
dissolved and was stirred with a small amount of isopropylether, whereby 
the compound crystallized. After recrystallization from isopropylether 
pure 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxy 
lic acid-3-methylester-5-ethylester was obtained. M.p. 145.degree. C. Yield 
75%. 
EXAMPLE 2 (method b.sup.1, b.sup.2) 
Preparation of 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic 
acid-3-ethylester-5-(2-methoxyethyl)ester 
4.4 g of 2,3-dichlorobenzaldehyde, 3,2 g of 3-aminocrotonic acid 
ethylester, 4.0 g acetylacetic acid-2-methoxyethylester and 25 mls of 
ethanol were refluxed over night. The reaction mixture was poured out onto 
icewater, whereby the compound crystallized. After filtration 
recrystallization was carried out from ethanol, whereby pure 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5l -dicarboxylic 
acid-3-ethylester-5-(2-methoxyethyl)ester was obtained. M.p. 139.degree. 
C. Yield 36%. 
EXAMPLES 3-10 
The compounds of table 1 below were prepared in accordance with Examples 1 
and 2 above. 
TABLE 1 
__________________________________________________________________________ 
Prep 
acc 
to Mp Yield 
Ex No. 
R.sup.1 R.sup.2 R.sup.3 
R.sup.4 
Ex .degree.C. 
% 
__________________________________________________________________________ 
3 --CH.sub.3 --CH(CH.sub.3).sub.2 
Cl 
Cl 2 148 
47 
4 --CH.sub.3 --C(CH.sub.3).sub.3 
Cl 
Cl 1 156 
32 
5 --CH.sub.3 --CH(CH.sub.3)CH.sub.2 OCH.sub.3 
Cl 
Cl 2 160 
44 
6 --CH.sub.2 CH.sub.2 OCH.sub.3 
--CH(CH.sub.3).sub.2 
Cl 
Cl 1 132 
31 
7 --CH.sub.2 CH.sub.2 OCH.sub.2 CH.sub.3 
--CH.sub.2 CH.sub.3 
Cl 
Cl 1 118 
44 
8 --CH.sub.3 --C(CH.sub.3).sub.2 CH.sub.2 OCH.sub.3 
Cl 
Cl 1 120 
17 
9 --CH.sub.3 --CH.sub.2 C(CH.sub.3).dbd.CH.sub.2 
Cl 
Cl 1 152 
26 
10 --CH.sub.3 --C.sub.2 H.sub.5 
Cl 
--CH.sub.3 
150 
18 
__________________________________________________________________________ 
EXAMPLE 11 (method c.sup.1, c.sup.2) 
5.74 g of 2,3-dichlorobenzylideneacetylacetic acid methylester, 2.6 g of 
ethylacetoacetate and 2.8 mls of conc. NH.sub.3 were dissolved in 25 mls 
tert.-butanol. The reaction mixture was allowed to stand at ambient 
temperature for 5 days, whereupon the tert.-butanol was evaporated and the 
residue was dissolved in isopropylether. After cooling the compound 
crystallized and after recrystallization from isopropylether pure 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic 
acid-3-methylester-5-ethylester was obtained, M.p. 145.degree. C. Yield 
59%. 
EXAMPLE 12 (method d) 
10.7 g of 2-bromo-3-chlorobenzaldehyde, 6.3 g of ethylacetoacetate, 5.7 g 
of methylacetoacetate and 5 mls of conc. NH.sub.3 were dissolved in 25 mls 
of ethanol. The reaction mixture was refluxed over night, whereupon it was 
poured out onto ice-water. Thereby the compound crystallized and after 
recrystallization from ethanol pure 
2,6-dimethyl-4-(2-bromo-3-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxyl 
ic acid-3-methylester-5-ethylester was obtained. M.p. 159.degree. C. Yield 
48%. 
EXAMPLE 13 
A syrup containing 2% (weight per volume) of active substance was prepared 
from the following ingredients: 
______________________________________ 
2,6-dimethyl-4-(2,3-chlorophenyl)-1,4-dihydropyridine- 
3,5-dicarboxylic acid-3-methylester-5-ethylester 
2.0 g 
Saccharine 0.6 g 
Sugar 30.0 g 
Glycerine 5.0 g 
Flavouring agent 0.1 g 
Ethanol 96% 10.0 g 
Distilled water ad 100.0 ml 
______________________________________ 
Sugar, saccharine and the active substance were dissolved in 60 g of warm 
water. After cooling, glycerine and solution of flavouring agents 
dissolved in ethanol were added. To the mixture water was then added to 
100 ml. 
The above named active substance may be replaced by other therapeutically 
active substances of the invention. 
EXAMPLE 14 
Granules were prepared from 
2,6-dimethyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic 
acid-3-methylester-5-(1-methyl-2-methoxyethyl)ester (250 g), lactose 
(175.9 g) and an alcoholic solution of polyvinylpyrrolidone (25 g). After 
the drying step the granules were mixed with talc (25 g), potatoe starch 
(40 g) and magnesium stearate (2.50 g) and were pressed into 10.000 
tablets being biconvex. These tablets are coated with a 10% alcoholic 
solution of shellac and thereupon with an aqueous solution containing 
saccharose (45%), gum arabicum (5%), gelatine (4%) and dyestuff-(0.2%). 
After the first five coatings talc and powdered sugar were used for 
powdering. The priming coat was then coated with a 66% sugar syrup and 
polished with a 10% carnauba wax solution in carbon tetrachloride. 
BIOLOGICAL TESTS 
The antihypertensive effect of the compounds was tested in conscious, 
unrestrained spontaneously hypertensive rats (SHR) of the Okamoto strain. 
The animals had been prepared by prior implantation of indwelling 
catheters in the abdominal aorta via the femoral artery. Mean arterial 
blood pressure (MABP) and heart rate were continuously monitored. After a 
2 hour control period the compound under study was administered by oral 
intubation at 2 hour intervals, suspended in methocel solution (5 ml/kg 
bodyweight). The cumulated doses were 1, 5 and 25 .mu.moles/kg bodyweight. 
The antihypertensive response, i.e. the BP reduction to each dose, was 
expressed as a percentage of the initial control BP level and plotted 
against the dose on a logarithmic scale. The dose which would give 20 
percent BP reduction was then determined by interpolation. The results are 
shown in table 2. 
The specificity towards smooth muscle relaxation was examined as follows: 
The isolated portal vein preparation of Wistar rats was mounted in an 
organ bath together with a paced isolated papillary heart muscle 
preparation of the same animal. The integrated contractile activity of the 
portal vein smooth muscle and the peak force amplitude of the papillary, 
myocardial, preparation were recorded. The respective activities during a 
30 min control period were set as 100 percent and the ensuing activities 
under the influence of an agent under study were expressed as a percentage 
thereof. The agent was administered at 10 min intervals and the potency 
for vasodilatation(-log ED.sub.50 of portal vein) and that of myocardial 
depression (-log ED.sub.50 of papillary muscle) were determined by 
interpolation from the concentration-effect relationships determined in 
each experiment. A "separation" value was determined for each compound by 
averaging the differences of the -log ED.sub.50 values for vasodilatation 
and myocardial depression, respectively, obtained in the experiments. This 
logarithmic separation value was transformed into numeric format and 
entered into table 2. 
The compounds of the invention were compared with Nifedipin 
[2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic 
acid-3,5-dimethylester]. 
TABLE 2 
______________________________________ 
SHR Ratio 
Compound according to 
ED.sub.20 .mu.moles/kg 
heart 
Ex. bodyweight vasc. 
______________________________________ 
1 4 98 
2 15 78 
3 1 56 
5 7 124 
4 5 48 
9 2 44 
7 -- 28 
6 4 107 
Nifedipin 5 15 
8 8 118 
______________________________________