Mixtures of optically active nitrodihydropyridines active on the circulatory system

Pure enantiomers of 5-nitrodihydropyridine of the formula ##STR1## are mixed, wherein one of the enantiomers has a high vasodilative action and a low negative inotropic activity on heart muscle, the other enantiomer has a low vasoconstrictive action and a high positive inotropic activity on heart muscle, the mixture being high in vasodilative activity and in positive inotropic activity on heart muscle.

The present invention relates to (+)- and (-)-enantiomers of 
5-nitrodihydropyridines of the general formula I 
##STR2## 
in which R represents heteroaryl, or represents aryl (6 or 10 C atoms) 
which is optionally monosubstituted or polysubstituted, identically or 
differently, by halogen, nitro, cyano, carboxyl, hydroxyl, alkoxycarbonyl 
(up to 4 C atoms), amino, monoalkylamino or dialkylamino (in each case up 
to 3 C atoms), sulphonamido or --SO.sub.2 --alkyl (up to 4 C atoms), by 
optionally halogen-substituted alkyl or alkoxy (in each case up to 6 C 
atoms), or by the group 
##STR3## 
wherein X represents oxygen, sulphur or NR.sup.7, 
R.sup.7 represents hydrogen, alkyl (up to 3 C atoms) or phenyl and 
R.sup.5 and R.sup.6 are identical or different and represent hydrogen, 
nitro, cyano or alkyl, alkoxy, alkylthio, halogenoalkyl, halogenoalkoxy or 
halogenoalkylthio (alkyl in each case up to 6 C atoms), 
R.sup.1 represents hydrogen or the group CO.sub.2 R.sup.8 
wherein 
R.sup.8 represents hydrogen or linear or branched alkyl (up to 10 C atoms) 
which can be interrupted by one or two oxygen and/or sulphur atoms in the 
chain and which is optionally substituted by phenyl, nitro, halogen, 
hydroxyl, cyano, sulphonamido, --SO.sub.2 -alkyl (up to 4 C atoms), 
carboxyl, alkoxycarbonyl (up to 4 C atoms), pyridyl or by an amino group, 
it being possible for this amino group to be substituted by one or two 
substituents from the series alkyl (up to 4 C atoms), aryl (6 or 10 C 
atoms) or aralkyl (7-14 C atoms), 
R.sup.2 and R.sup.4 can be identical or different and represent cyano or 
linear or branched alkyl (up to 6 C atoms) which is optionally substituted 
by hydroxyl, cyano, halogen, aryl (6 or 10 C atoms), carboxyl or 
alkoxycarbonyl (up to 6 C atoms) and 
R.sup.3 represents hydrogen or linear or branched alkyl (up to 6 C atoms), 
and to salts thereof. 
Preferred (+)- and (-)-enantiomers of the general formula I are those in 
which R represents pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, 
oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, 
pyrazinyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, quinazolyl or 
quinoxalyl, or represents phenyl which is optionally monosubstituted or 
disubstituted, identically or differently, by fluorine, chlorine, bromine, 
nitro, cyano, carboxyl, alkoxycarbonyl (up to 2 C atoms), --SO.sub.2 
-alkyl (up to 2 C atoms) or by optionally halogen-substituted alkyl or 
alkoxy (up to 5 C atoms), or represents the group 
##STR4## 
wherein X represents oxygen or sulphur and 
R.sup.5 and R.sup.6 are identical or different and represent hydrogen, 
nitro, cyano or alkyl, alkoxy, alkylthio, halogenoalkyl or halogenoalkoxy 
(in each case up to 4 C atoms), 
R.sup.1 represents hydrogen or the group CO.sub.2 R.sup.8 
wherein 
R.sup.8 represents hydrogen or linear or branched alkyl (up to 8 C atoms) 
which can be interrupted by one or two oxygen and/or sulphur atoms in the 
chain and which is optionally substituted by phenyl, nitro, one or more 
fluorine, chlorine, bromine, hydroxyl, cyano, --SO.sub.2 -alkyl (up to 2 C 
atoms), alkoxycarbonyl (up to 2 C atoms) or pyridyl groups or by an amino 
group, it being possible for this amino group to be substituted by one or 
two substituents from the series alkyl (up to 3 C atoms), phenyl or 
benzyl, 
R.sup.2 and R.sup.4 represent cyano or linear or branched alkyl (up to 4 C 
atoms) which is optionally substituted by hydroxyl, fluorine, chlorine, 
phenyl or alkoxycarbonyl (up to 4 C atoms) and 
R.sup.3 represents hydrogen or linear or branched alkyl (up to 4 C atoms), 
and salts thereof. 
(+)- and (-)-enantiomers of the general formula I which are particularly 
preferred are those in which R represents furyl, thienyl, pyridyl or 
pyrimidyl, or represents phenyl which is optionally mono-substituted or 
disubstituted, identically or differently, by fluorine, chlorine, nitro or 
cyano or by alkyl or alkoxy (in each case up to 4 C atoms) which is 
optionally substituted by one or more fluorine atoms, or by the group 
##STR5## 
wherein X represents oxygen or sulphur and 
R.sup.5 and R.sup.6 are identical or different and represent hydrogen, 
nitro, cyano or alkyl, alkoxy, alkylthio, halogenoalkyl or halogenoalkoxy 
(in each case up to 2 C atoms), and halogen preferably represents one or 
more fluorine atoms, 
R.sup.1 represents hydrogen or the group CO.sub.2 R.sup.8 
wherein 
R.sup.8 represents hydrogen or linear or branched alkyl (up to 6 C atoms) 
which can be interrupted by an oxygen and/or sulphur atom in the chain and 
which is optionally substituted by phenyl, nitro or one or more fluorine, 
chlorine, cyano, benzylmethylamino or pyridyl groups, 
R.sup.2 and R.sup.4 represent methyl or ethyl which is optionally 
substituted by hydroxyl or one or more fluorine, phenyl or alkoxycarbonyl 
(up to 2 C atoms) groups and 
R.sup.3 represents hydrogen or methyl or ethyl, 
and salts thereof. 
The substances according to the invention can be in the form of their 
salts. These are, in general, salts with inorganic or organic acids. The 
physiologically acceptable salts of the substances according to the 
invention with organic or inorganic acids are preferred. Examples which 
may be mentioned are hydrochlorides, hydrobromides, bisulphates, 
sulphates, hydrogenphosphates, acetates, maleates, fumarates, citrates, 
tartrates or benzoates. 
The (-)-enantiomers of the general formule (I) are very particularly 
preferred. 
The (+)- and (-)-enantiomers, according to the invention, of the general 
formula (I) are prepared by reacting the optically active aminocrotonic 
acid esters of the general formula (II) 
##STR6## 
in which R.sup.2 and R.sup.3 have the meaning indicated above and 
*R.sup.9 represents a chirally uniform 2-methoxy-2-phenylethyl radical, 
with ylidene compounds of the general formula (III) 
##STR7## 
if appropriate in the presence of water or inert organic solvents, then 
separating by customary methods the diastereomers obtained in this 
reaction, because of the two possible different configurations at the 
C.sub.4 atom of the dihydropyridine ring, and either transesterifying the 
resulting 1,4-dihydropyridines having a chiral ester grouping of the 
general formula IV 
##STR8## 
in which R, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and *R.sup.9 have the 
meaning indicated above, in accordance with customary methods by replacing 
the chiral radical *R.sup.9 by a non-chiral radical R.sup.8 (.noteq. 
hydrogen), or hydrolyzing the resulting 1,4-dihydropyridines having a 
chiral ester grouping of the general formula IV to give compounds in which 
R.sup.8 =hydrogen and then, if appropriate, re-esterifying the latter or 
decarboxylating them to give compounds in which R.sup.1 =H, (+)- and 
(-)-enantiomers of the general formula I being obtained in each case. 
The starting materials of the formula (II) and (III) are known or can be 
prepared by known methods (see A. Dornow, W. Sassenberg, Liebigs Ann. 
Chem. 602, 14 (1957); or S. A. Glickmann, A. C. Cope, J. Am. Chem. Soc., 
67, 1017 (1945)). 
The substances of the formula (IV) are new and can be prepared in the 
manner indicated. 
Suitable diluents are water or any inert organic solvent. These preferably 
include alcohols, such as methanol, ethanol, propanol or isopropanol, 
ethers, such as diethyl ether, dioxane, tetrahydrofuran or glycol 
monoethyl ether, glacial acetic acid, pyridine, dimethylformamide, 
acetonitrile, dimethyl sulphoxide or hexamethylphosphoric acid triamide. 
The reaction temperatures can be varied within a fairly wide range. In 
general, the reaction is carried out within a range from 10.degree. C. to 
200.degree. C., preferably from 20.degree. C. to 150.degree. C. 
The reaction can be carried out under normal pressure but also under 
elevated pressure. In general, the reaction is carried out under normal 
pressure. 
The compounds of the formula (IV) formed in accordance with the process 
indicated above differ, as diastereomers, in their physical and chemical 
properties and can, therefore, be separated from one another by means of 
known methods. The following may be mentioned as preferable methods of 
separation: recrystallization from inert solvents or thin layer, column or 
high pressure liquid chromatography. 
The necessary hydrolysis or transesterification of the chirally uniform 
compounds IV is preferably effected via alkaline hydrolysis or 
alcoholysis, if appropriate in the presence of an inert solvent, using as 
the reagent R.sup.8 O.sup.-, wherein R.sup.8 has the meaning indicated 
above. 
Solvents suitable for this hydrolysis or transesterification are water or 
any inert organic solvent or mixtures thereof. These preferably include 
alcohols, such as methanol, ethanol. propanol or isopropanol, ethers such 
as dioxane, tetrahydrofuran, glycol monoethyl ether of glycol dimethyl 
ether, or dimethylformamide, dimethyl sulphoxide, acetonitrile, pyridine 
or hexamethylphosphoric acid triamide. 
The reaction temperatures can be varied within a fairly wide range. In 
general, the reaction is carried out between 20.degree. and 150.degree. 
C., preferably at approximately 50.degree. to 100.degree. C. 
The hydrolysis or transesterification can be carried out under normal 
pressure, but also under elevated pressure. In general, the reaction is 
carried out under normal pressure. 
Suitable alcoholysis or hydrolysis reagents R.sup.8 O.sup.- are the 
customary bases. It is preferable to employ alkali or alkaline earth metal 
hydroxides, such as, for example, sodium hydroxide, potassium hydroxide, 
calcium hydroxide or barium hydroxide, or alkali metal alcoholates, such 
as, for example, sodium methylate or ethylate or potassium methylate or 
ethylate. It is also possible to use a mixture of bases. In carrying out 
the hydrolysis or alcoholysis, the bases are in each case employed in 
molar amounts or in a slight excess. 
The decarboxylation of the compounds in which R.sup.1 =COOH to give 
compounds in which R.sup.1 =H is effected in a customary manner. It is 
preferable to carry out thermal decarboxylation, if appropriate in the 
absence of an acid catalyst, by heating the approprite carboxylic acid 
with or without a solvent. 
Suitable solvents for the decarboxylation are water and inert organic 
solvents or mixtures. These preferably include water, alcohols, such as, 
for example, methanol, ethanol, propanol, glycol or diglycol, ethers, such 
as dioxane, tetrahydrofuran, glycol monoethyl ether, glycol dimethyl ether 
or diethylene glycol dimethyl ether, or dimethylformamide, dimethyl 
sulphoxide, acetonitrile, glacial acetic acid, hexamethylphosphoric acid 
triamide, toluene or xylene. 
The reaction temperatures can be varied within a fairly wide range. In 
general, the reaction is carried out between 40.degree. and 200.degree. 
C., preferably between 60.degree. and 150.degree. C. 
The decarboxylation can be carried out under normal pressure, under 
elevated pressure or under reduced pressure. In general, it is carried out 
under normal pressure. The customary inorganic or organic acids can be 
used as catalysts. These preferably include hydrogen halide acids, such as 
HCl or HBr, sulphuric acid, phosphoric acid or organic acids, such as 
acetic acid, formic acid, toluenesulphonic acid or methanesulphonic acid. 
The re-esterification of the carboxylic acids according to the invention 
(R.sup.8 =H) is effected by known methods, if appropriate via a reactive 
acid derivative such as, for example, activated esters, hydroxysuccinimide 
esters, acid imidazolides or mixed anhydrides, or by reaction with 
dicyclohexylcarbodiimide. 
The customary organic solvents are suitable for this purpose. These 
preferably include hydrocarbons, such as methylene dichloride, chloroform, 
carbon tetrachloride or 1,2-dichloroethane, ethers, such as diethyl ether, 
dioxane, tetrahydrofuran or 1,2-dimethoxyethane, aromatic hydrocarbons, 
such as toluene or xylene, acetonitrile, nitromethane, dimethylformamide, 
hexamethylphosphoric acid triamide, pyridine or ethyl acetate. 
The reaction temperatures in this case can be varied within a fairly wide 
range. In general, the reaction is carried out within a range from 
-70.degree. C. to +60.degree. C., preferably from -50.degree. C. to 
+40.degree. C. 
The re-esterification can be carried out under normal pressure, but also 
under elevated pressure. In general, it is carried out under normal 
pressure. 
In carrying out the reaction, the ratio of the reactants is immaterial. 
However, it has proved expedient to employ the corresponding alcohol in an 
excess of up to 20 times molar, preferably up to 10 times molar. 
The enantiomers of the general formula (I) are also obtained if the 
corresponding racemates are separated into the (+)- and (-)-enantiomers of 
the general formula (I) by means of suitable methods of separation, if 
desired using optically active materials, by means of, for example, thin 
layer, column or high pressure liquid chromatography. 
It is known that racemic nitrodihydropyridines intensify the contractile 
force-boosting positively inotropic action on heart muscle. Moreover, it 
is known that the pharmacological activity of the isolated enantiomers 
differs from that of the racemate. 
Thus, one of the isomers often has a stronger action, and the other a 
weaker action, than the racemate. It was not foreseeable that the 
enantiomers according to the invention would differ completely in their 
action. Surprisingly, one enantiomer in each case, whose absolute 
configuration is that of formula V 
##STR9## 
has a vasodilative action and is negatively inotropic on heart muscle, 
while the other enantiomer, whose absolute configuration is that of 
formula VI 
##STR10## 
is vasoconstrictive and positively inotropic on heart muscle. 
The (-)-enantiomers of all the preparative examples are in accordance with 
the absolute configuration of formula VI but the optical rotation of other 
(-)-enantiomers according to the invention have the configuration of 
formula V. 
In detail, the following principal actions were demonstrated for the 
vasodilative enantiomers in an animal experiment: 
1. On parenteral, oral and perlingual administration the compounds produce 
a distinct and long-lasting dilation of the coronary vessels. They 
influence or modify the heart metabolism in the sense of an energy saving. 
2. The excitability of the nervous impulse generation and stimulus 
conduction system within the heart is reduced, so that an 
anti-fibrillation action demonstrable in therapeutic doses. 
3. The tonus of the smooth muscle of the vessels is greatly reduced under 
the action of the compounds. This vascular-spasmolytic action can occur in 
the entire vascular system or can manifest itself more or less isolatedly 
in circumscribed vascular zones (such as, for example, the central nervous 
system). Accordingly, the compounds are also suitable for use as cerebral 
therapeutic agents. 
4. The compounds lower the blood pressure of normal tonic and hypertonic 
animals and can accordingly be used as anti-hypertensive agents. 
5. Compounds have powerful muscular-spasmolytic actions which manifest 
themselves on the smooth muscle of the stomach, intestinal tract, 
urogenital tract and respiratory system. 
Because of these properties, these enantiomers according to the invention 
are particularly suitable for the prophylaxis and therapy of acute or 
chronic ischaemic heart disorders and for the treatment of cerebral and 
peripheral circulatory disturbances. 
The optical antipodes to these enantiomers have a positive inotropic action 
and accordingly exhibit an unforeseeable and valuable pharmacological 
spectrum of action. They can serve as cardiotonics to improve the heart 
contractivity. In addition, they can be employed as anti-hypotonics, to 
reduce the blood sugar level, to detumesce mucous membranes and to 
influence the salt balance and fluid balance. 
The invention moreover relates to a new active compound combination 
containing (-)-enantiomers of the formula (I) (component X) and 
(+)-enantiomers of the formula (I) (component Y). 
At suitable ratios of the components X and Y, the combination shows a 
completely surprising action profile: they are positively inotropic and 
vasodilative, especially coronary-dilative. 
Per part by weight of component X, 0.01-1,000 parts by weight, preferably 
0.1-50 parts by weight, of component Y can be employed. 
In case of a 1:1 mixture not the racemate of compound X and Y is meant, 
which occurs if no optically active starting material in the preparation 
is used. In case of a 1:1 mixture a combination of different enantiomers 
is meant. 
The combinations may be prepared by dissolving the individual components in 
inert solvents which dissolve them, and subsequently mixing the solutions. 
As examples of inert solvents, alcohols such as ethanol or glycols such as 
polyethylene glycol, or dimethylsulphonide may be mentioned. 
The active compound combination according to the invention can be used to 
combat illnesses, in particular circulatory disorders. 
The cardiac and vascular actions of the enantiomers according to the 
invention and of the combination were found on the isolated perfused heart 
of the guinea pig (modified according to Opie, L., J. Physiol. 180 (1965) 
529-541). For this purpose, the hearts of albino guinea pigs weighing 250 
to 350 g are used. The animals are killed by a blow to the head, the 
thorax is opened, a metal cannula is tied into the exposed aorta and the 
left auricle is opened. The heart is removed together with the lungs from 
the thorax and is connected via the aorta cannula to the perfusion 
apparatus, while the perfusion is running. The lungs are severed off at 
the lung roots. The perfusion medium used is Krebs-Henseleit solution 
(118.5 mmol of NaCl/liter, 4.75 mmol of KCl/liter, 1.19 mmol of KH.sub.2 
PO.sub.4 /liter, 119 mmol of MgSO.sub.4 /liter, 25 mmol of NaHCO.sub.3 
/liter, and 0.013 mmol of NaEDTA/liter), the CaCl.sub.2 concentration of 
which is varied according to requirements but is as a rule 1.2 
mmol/liter. 10 mmol of glucose/liter are added as an energy-supplying 
substrate. Before perfusion, the solution is filtered to remove any 
particles. The solution is gassed with carbogen (95% of O.sub.2, 5% of 
CO.sub.2 to maintain the pH value of 7.4). The hearts are perfused at 
constant flux (10 ml/min) at 32.degree. C., by means of a peristaltic 
pump. 
To measure the heart function, a liquid-filled latex balloon which is 
connected via a liquid column to a pressure sensor is introduced through 
the left auricle into the left ventricle and the isovolumetric 
contractions are recorded on a high-speed pen recorder. 
The perfusion pressure is recorded by means of a pressure sensor which is 
connected to the perfusion system upstream of the heart. Under these 
conditions, a reduction in perfusion pressure indicates a coronary 
dilation and an increase in the left ventricular pressure amplitude 
indicates an increase in heart contractility. The enantiomers according to 
the invention, or their combinations, in suitable dilutions are infused 
into the perfusion system a short way upstream of the isolated heart. 
Table 1 shows the action of some stereoisomers on the contractility and 
coronary resistance of the isolated heart of the guinea pig. 
Isomer 1: (+)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
Isomer 2: (-)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
Isomer 3: (+)-[Methyl 
4(2-benzylthiophenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxyla 
te] 
Isomer 4: (-)-[Methyl 
4(2-benzylthiophenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxyla 
te] 
TABLE 1 
______________________________________ 
Isomer 
Concentration Change in CA 
Change in PP 
No. (g/mol) (%) (%) 
______________________________________ 
1 3 .multidot. 10.sup.-8 
-21 -12 
1 3 .multidot. 10.sup.-7 
-76 -18 
2 3 .multidot. 10.sup.-9 
+47 +8 
2 3 .multidot. 10.sup.-8 
+86 +20 
3 10.sup.-7 0 -15 
3 10.sup.-6 -26 -31 
4 .sup. 10.sup.-10 
+2 +22 
4 10.sup.-9 +106 +20 
______________________________________ 
CA = contraction amplitude 
PP = perfusion pressure 
Table 2 shows, by way of example, the contractility-boosting and 
coronary-dilating action of combinations on the isolated perfused heart of 
the guinea pig. 
Combination 1: consisting of 
(-)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] and 
(+)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
in the ratio of 1:10. 
Combination 2: consisting of 
(-)-[methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] and 
(+) [methyl 
4-(2-benzylthiophenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxyl 
ate] 
in the ratio of 1:30. 
______________________________________ 
Combination 
Concentrations CA PP 
______________________________________ 
1 10.sup.-9 /10.sup.-8 g/ml 
+29% -8% 
10.sup.-8 /10.sup.-7 g/ml 
+48% -17% 
2 3 .times. 10.sup.-9 /9 .times. 10.sup.-8 g/ml 
+68% -21% 
10.sup.-8 /3 .times. 10.sup.-7 g/ml 
+75% -27% 
______________________________________ 
CA = contraction amplitude 
PP = perfusion pressure 
Both individual active substances and the active substance combination can 
be converted, in a known manner, to the customary formulations, such as 
tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, 
suspensions and solutions, using inert, non-toxic, phamaceutically 
suitable carriers or solvents. The therapeutically active compounds or 
combinations should in each case be present in a concentration of about 
0.5 to 90% by weight of the total mixture, i.e. in amounts which suffice 
to achieve the stated dosage range. 
These formulations are prepared, for example, by extending the active 
substance combination or individual active substances with solvents and/or 
dispersants and, for example when using water as a diluent, organic 
solvents can, where appropriate, be used as auxiliary solvents. 
As auxiliary substances there may be mentioned, for example: 
Water, non-toxic organic solvents, such as paraffins (for example petroleum 
fractions), vegetable oils (for example ground nut oil/sesame oil), 
alcohols (for example ethyl alcohol and glycerol), glycols (for example 
propylene glycol and polyethylene glycol), solid carriers, such as, for 
example, natural rock powders (for example kaolins, aluminas, talc and 
chalk), synthetic rock powders (for example highly disperse silica and 
silicates), sugars (for example sucrose, lactose and glucose), emulsifiers 
(for example polyoxyethylene fatty acid esters, polyoxyethylene fatty 
alcohol ethers, alkylsulphonates and arylsulphonates), dispersants (for 
example lignin, sulphite waste liquors, methylcellulose, starch and 
polyvinylpyrrolidone) and lubricants (for example magnesium stearate, 
talc, stearic acid and sodium lauryl sulphate). 
Administration takes place in the usual manner, preferably orally or 
parenterally, especially perlingually or intravenously. In the case of 
oral use, tablets can of course also contain, in addition to the stated 
carriers, additives such as sodium citrate, calcium carbonate and 
dicalcium phosphate together with various adjuvants, such as starch, 
preferably potato starch, gelatin and the like. Furthermore, lubricants, 
such as magnesium stearate, sodium lauryl-sulphate and talc can 
additionally be used to tablet-making. In the case of aqueous suspensions 
and/or elixiers, which are intended for oral use, the active substances or 
combinations can be mixed, not only with the abovementioned auxiliaries, 
but also with various flavour improvers or colorants. 
For parenteral application, solutions of the active substance combination 
or of individual active substances can be employed, using suitable liquid 
vehicles.

PREATION EXAMPLES 
Example 1 
(a) (+)-[(S)-2-Methoxy-2-phenylethyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
2.35 g (10 mmol) of (+)-[(S)-2-methoxy-2-phenylethyl 3-aminocrotonate] are 
heated to reflux temperature in 20 ml of i-propanol with 2.59 g (10 mmol) 
of 2-nitro-1-(2-trifluoromethylphenyl)-but-1-en-3-one. On rubbing, the 
product crystallises out from the hot solution, and is then recrystallised 
from hot isopropanol and filtered off while hot. 
Yield: 2.1 g (44% of theory). 
Melting point: 209.degree. C. (decomp.). 
Optical rotation [.alpha.].sub.D.sup.20 =+144.47.degree. (dioxane). 
(b) (+)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
1.19 g (2.5 mmol) of (+)-[(S)-2-methoxy-2-phenylethyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)pyridine-3-car 
boxylate] in 100 ml of methanol are heated at 50.degree. C. for 50 hours 
with 270 mg of sodium methylate. The pH is then adjusted to 3 with 
methanolic HCl, the mixture is evaporated, and the residue is 
chromatographed over silica gel with 3% chloroform/methanol. 
Yield: 480 mg (54% of theory). 
Melting point: 177.degree. C. 
Optical rotation [.alpha.].sub.D.sup.20 =+46.8.degree. (dioxane). 
Example 2 
(a) (-)-[(R)-2-Methoxy-2-phenylethyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
2.35 g (10 mmol) of (-)[-(R)-2-methoxy-2-phenylethyl 3-aminocrotonate] are 
heated at reflux temperature in 20 ml of i-propanol with 2.59 g (10 mmol) 
of 2-nitro-1-(2-trifluoromethylphenyl)-but-1-en-3-one. After rubbing, the 
product crystallises from the hot solution; it is isolated from the hot 
solution. 
Yield: 2.3 g (48% of theory). 
Melting point: 208.degree. (decomp.). 
Optical rotation [.alpha.].sub.D.sup.20 =-142.47.degree. (dioxane). 
(b) (-)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
1.19 g (2.5 mmol) of (-)-[(R)-2-methoxy-2-phenylethyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] in 100 ml of methanol are heated at 50.degree. C. for 3 hours 
with 270 mg of sodium methylate. The pH is adjusted to 3 with methanolic 
HCl, the mixture is evaporated and the residue is chromatographed over 
silica gel with chloroform +3% of methanol. 
Yield: 510 mg (57% of theory). 
Melting point: 176.degree. C. 
Optical rotation [.alpha.].sub.D.sup.20 =-56.7.degree. (dioxane). 
The following were prepared analogously to Examples 1 and 2. 
Example 3 
(+)-[Methyl 
4-(2-benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxyla 
te] 
Optical rotation [.alpha.].sub.D.sup.20 =+83.5.degree. (dioxane). 
Example 4 
(-)-[Methyl 
4-(2-benzyloxyphenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxyla 
te] 
Optical rotation [.alpha.].sub.D.sup.20 =-92.3.degree. (dioxane). 
Example 5 
(+)-[Methyl 
4-(2-difluoromethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-car 
boxylate] 
Optical rotation [.alpha.].sub.D.sup.20 =+14.7.degree.. 
Example 6 
(-)-[Methyl 
4-(2-difluoromethoxyphenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-car 
boxylate] 
Optical rotation [.alpha.].sub.D.sup.20 =-16.1.degree.. 
Example 7 
(+)-[Methyl 
4-[2-(3-nitro)-benzylthio-phenyl]-1,4-dihydro-2,6-dimethyl-5-nitropyridine 
-3-carboxylate] 
Optical rotation [.alpha.].sub.D.sup.20 =+35.2.degree. (dioxane). 
Example 8 
(-)-[Methyl 
4-[2-(3-nitro)-benzylthio-phenyl]-1,4-dihydro-2,6-dimethyl-5-nitropyridine 
-3-carboxylate] 
Optical rotation [.alpha.].sub.D.sup.20 =-42.7.degree. (dioxane). 
Example 9 
(+)-[Methyl 
4-(2-benzylthiophenyl)-1,4-dihydro-2,6-dimethyl-5-nitropyridine-3-carboxyl 
ate] 
Optical rotation [.alpha.].sub.D.sup.20 =+56.1.degree. (dioxane). 
Example 10 
(-)-[Methyl 
4-(2-benzylthiophenyl)-1,4-dihydro-2,6-dimethyl-5-nitro-pyridine-3-carboxy 
late] 
Optical rotation [.alpha.].sub.D.sup.20 =-58.4.degree.. 
Example 11 
(+)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(5-pyrimidyl)-pyridine-3-carboxylate] 
Optical rotation [.alpha.].sub.546.sup.20 =+37.7.degree. (acetone). 
Example 12 
(-)-[Methyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(5-pyrimidyl)-pyridine-3-carboxylate] 
Optical rotation [.alpha.].sub.546.sup.20 =-39.1.degree. (acetone). 
Example 13 
(-)-1,4-Dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3 
-carboxylic acid 
1.19 g (2.5 mmol) of (+)-[(S)-2-methoxy-2-phenylethyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)pyridine-3-car 
boxylate] in 100 ml of methanol are heated at 40.degree. C. for 15 hours 
with 300 mg of sodium hydroxide. The mixture is then evaporated, and the 
residue is taken up in chloroform and washed with twice 20 ml of water. 
The pH of the aqueous phase is adjusted slowly to 3 with dilute HCl; the 
product crystallises out and is filtered off with suction. 
Yield: 320 mg (37% of theory). 
Melting point: 218.degree. C. (decomp.). 
Optical rotation: [.alpha.].sub.546.sup.20 =-10.6.degree. (acetone). 
Example 14 
(+)-1,4-Dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3 
-carboxylic acid 
1.19 g (2.5 mmol) of (-)-[(R)-2-methoxy-2-phenylethyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)pyridine-3-car 
boxylate] in 100 ml of methanol are heated at 40.degree. C. for 15 hours 
with 300 mg of sodium hydroxide. The mixture is then evaporated, and the 
residue is taken up in chloroform and washed with twice 20 ml of water. 
The pH of the aqueous phase is adjusted slowly to 3 with dilute HCl; the 
product crystallises out and is filtered off with suction. 
Yield: 345 mg (40% of theory). 
Melting point: 217.degree. C. (decomp.). 
Optical rotation: [.alpha.].sub.546.sup.20 =+11.5.degree. C. (acetone). 
Example 15 
(-)-1,4-Dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine 
171 mg (0.5 mmol) of 
(-)-1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine- 
3-carboxylic acid in 10 ml of methanol are heated to the reflux temperature 
for 7 hours with 100 mg of concentrated sulphuric acid. The mixture is 
then diluted with 50 ml of H.sub.2 O. The precipitated product is filtered 
off with suction and recrystallised from i-propanol. 
Yield: 122 mg (82% of theory). 
Melting point: 210.degree. C. 
Optical rotation: [.alpha.].sub.D.sup.20 =-583.degree. (acetone). 
Example 16 
(+)-1,4-Dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine 
171 mg (0.5 mmol) of 
(+)-1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine- 
3-carboxylic acid in 10 ml of methanol are heated to the reflux temperature 
for 7 hours with 100 mg of concentrated sulphuric acid. The mixture is 
then diluted with 50 ml of H.sub.2 O. The precipitated product is filtered 
off with suction and recrystallised from i-propanol. 
Yield: 114 mg (76% of theory). 
Melting point: 211.degree. C. 
Optical rotation: [.alpha.].sup.20 =-587.degree. (acetone). 
Example 17 
(-)-[3-Bromopropyl 
1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine-3-ca 
rboxylate] 
700 mg (5 mmol) of 3-bromopropanol and 123 mg (0.6 mmol) of 
dicyclohexylcarbodiimide are added at room temperature to 171 mg (0.5 
mmol) of 
(+)-1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-trifluoromethylphenyl)-pyridine- 
3-carboxylic acid in 15 ml of tetrahydrofuran. After the solvent has been 
removed by evaporation, the residue is chromatographed over silica gel, 
using chloroform. 
Yield: 104 mg (45% of theory). 
Optical rotation: [.alpha.].sup.20 =42.46 (dioxane).