DIHYDROPYRIDINE COMPOUNDS, THEIR PRODUCTION AND THEIR MEDICINAL USE

COMPOSES DE DIHYDROPYRIDINE, PRODUCTION ET USAGE MEDICAL

English Abstract

Abstract of the Disclosure
The invention includes novel 1,4-dihydropyridines
useful for the treatment of circulatory disorders; they
can be used, inter alia, as antihypertensive agents, vasodilators
or coronary agents. Also included in the invention are
methods for the manufacture of said 1,4-dihydropyridines,
compositions containing said 1,4-dihydropyridines and methods
for the use of said compounds and compositions.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIYE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a 1,4-dihydropyridine of the
formula I or its pharmaceutically acceptable acid addition salts:
<IMG> (I)
in which R is pyridyl or phenyl unsubstituted or substituted by 1 to 3
identical or different substituents each of which is lower alkyl, lower
alkoxy, halogen, trifluoromethyl, nitro or cyano, R1 and R3 are identical
or different and each is hydrogen or straight-chain or branched lower alkyl,
R2 is hydrogen or straight-chain or branched lower alkyl, Y is lower alkylene
or lower alkylene substituted by lower alkyl, Z is a straight-chain, branched
or cyclic saturated or unsaturated aliphatic hydrocarbon radical with up to
6 carbon atoms or such an aliphatic hydrocarbon radical which is interrupted
in the chain by one oxygen atom or which is substituted by phenyl, and X
represents a group -COR4 or -COOR5, wherein R4 is lower alkyl or phenyl and
R5 is a straight-chain, branched or cyclic alkyl having up to 6 carbon atoms
or such an alkyl interrupted by one oxygen atom, or such an alkyl substituted
by phenyl, phenoxy, a pyridine ring or an amino group which amino group is
substituted by two same or different substituents selected from lower alkyl,
phenyl or benzyl, or is alkenyl having up to 4 carbon atoms, or X is a group
-COO-Y'-S-Z' which is identical with or different from the group -COO-Y-S-Z
and wherein Y' and Z' are as defined for Y and Z respectively; characterized
in that
A) an ylidene compound of the general formula II
(II)
<IMG>
42

in which R, R1 and X have the same meaning as defined hereinbefore in formula
I, is reacted with an enaminocarboxylic acid ester of the general formula III
<IMG> (III)
in which R2, R3, Y and Z have the same meaning as defined hereinbefore in
formula I; or
B) an ylidene compound of the general formula II,
<IMG>
(II)
in which R, R1 and X have the same meaning as defined hereinbefore in formula
I, is reacted with an amine of the general formula IV and a .beta.-ketocarboxylic
acid ester of the general formula V
R2-NH2 R3-CO-CH2-COO-Y-S-Z
(IV) (V)
in which R2, R3, Y and Z have the same meaning as defined hereinbefore in
formula I; or
C) an ylidene-.beta.-dicarbonyl compound of the general formula VI
<IMG> (VI)
in which R, R3, Y and Z have the same meaning as defined hereinbefore in
formula I, is reacted with an enamino compound of the general formula VII
43

<IMG> (VII)
in which R1, R2 and X have the same meaning as defined hereinbefore in
formula I; or
D) an ylidene-.beta.-dicarbonyl compound of the general formula VI
<IMG> (VI)
in which R, R3, Y and Z have the same meaning as defined hereinbefore in
formula I, is reacted with an amine of the general formula IV and a keto
derivative of the formula VIII
R2-NH2 R1-CO-CH2-X
(IV) (VIII)
in which R2, R1 and X have the same meaning as defined hereinbefore in
formula I; or
E) an aldehyde of the general formula IX
<IMG> (IX)
in which R has the same meaning as defined hereinbefore in formula I, is
reacted with an enamino compound of the general formula VII
44

<IMG> (VII)
in which R1, R2 and X have the same meaning as defined hereinbefore in
formula I, and a .beta.-ketocarboxylic acid ester of the general formula V
R -CO-CH2-COO-Y-S-Z (V)
in which R3, Y and Z have the same meaning as defined hereinbefore in formula
I; or
F) an aldehyde of the general formula IX
<IMG> (IX)
in which R has the same meaning as defined hereinbefore in formula I, is
reacted with an enaminocarboxylic acid ester of the general formula III
(III)
<IMG>
in which R2, R3, Y and Z have the same meaning as defined hereinbefore in
formula I, and a keto derivative of the general formula VIII
R1-CO-CH2-X (VIII)
in which R1 and X have the same meaning as defined hereinbefore in formula I;
and where required converting the compound obtained into a corresponding
pharmaceutically acceptable salt or into the free form.

2. A process according to claim 1 in which the reaction is carried
out at from 20 to 150°C.
3. A process according to claim 1 or 2 wherein in the starting
materials R is phenyl unsubstituted or substituted by a nitro, chloro, tri-
fluoromethyl or methoxy group, or is a pyridyl group; R1 and R3 are lower
alkyl; R2 is hydrogen, Y is lower alkylene; Z is alkyl of up to 6 carbon
atoms or benzyl; and X is lower alkanoyl or a group -COOR5 wherein R5 is
alkyl or cycloalkyl of up to 6 carbon atoms or such an alkyl interrupted by
an oxygen atom, or such an alkyl substituted by phenyl, a pyridine ring or
an amino group which amino group is substituted by two lower alkyl groups.
4. A process according to claim 1 or 2 wherein in the starting
materials R is phenyl optionally substituted by halogen, nitro, cyano, tri-
fluoromethyl, trifluoromethoxy, or alkyl or alkoxy having 1 or 2 carbon
atoms in each case, or is pyridyl, R1 and R3 are identical or different and
each is alkyl having 1 or 2 carbon atoms, phenyl or benzyl, R2 is hydrogen,
alkyl having from 1 to 4 carbon atoms, Y is alkylene having from 1 to 4
carbon atoms, Z is alkyl having from 1 to 4 carbon atoms which is optionally
interrupted in the chain by an oxygen atom, or is benzyl and X is a group
-COR4 or -COOR5, wherein R4 is alkyl having from 1 to 4 carbon atoms, and
wherein R is straight-chain, branched or cyclic alkyl having up to 6 carbon
atoms and optionally interrupted by oxygen, or a N-alkyl group having 1 or 2
carbon atoms in each alkyl moiety, or is alkenyl having up to 4 carbon atoms,
or is alkyl having from 1 to 4,carbon atoms, which is substituted by phenyl
or pyridyl, or X is a group -COO-Y'-S-Z' which is identical with or different
from the group -COO-Y-S-Z and wherein Y' and Z' are as defined for Y and Z
respectively.
5. A process according to claim 1 or 2 wherein in the starting
materials R is nitrophenyl; R1 and R3 are methyl; R2 is hydrogen; Y is
ethylene; Z is methyl, ethyl or benzyl; and X is lower alkanoyl or a group
-COOR5 wherein R5 is alkyl or cycloalkyl of up to 6 carbon atoms or such an
46

alkyl interrupted by an oxygen atom, or such an alkyl substituted by phenyl,
a pyridine ring or an amino group which amino group is substituted by two
lower alkyl groups.
6. A process according to claim 1 or 2 wherein in the starting
materials R is nitrophenyl; R1 and R3 are methyl; R2 is hydrogen; Y is
ethylene; Z is methyl, ethyl or benzyl; and X is acetyl, methoxycarbonyl,
isopropoxycarbonyl, cyclopentyloxycarbonyl, 2-methoxyethoxycarbonyl,
allyloxycarbonyl, 2-ethylthioethoxycarbonyl, 2-dimethylaminoethoxycarbonyl,
benzyloxycarbonyl or pyrid-3-ylmethoxycarbonyl.
7. A process according to claim 1 or 2 wherein in the starting
materials R is phenyl unsubstituted or substituted by a nitro, chloro, tri-
fluoromethyl or methoxy group, or is a pyridyl group; R1 and R3 are methyl;
R2 is hydrogen, Y is ethylene; Z is ethyl; and X is methoxycarbonyl.
8. A process according to claim 1 or 2 wherein in the starting
materials R is m-nitrophenyl, o-chlorophenyl, o-trifluoromethylphenyl, o-
methoxyphenyl, pyrid-2-yl, pyrid-3-yl or phenyl; R1 and R3 are methyl; R2
is hydrogen; Y is ethylene; Z is ethyl; and X is methoxycarbonyl.
9. A process according to claim 1 or 2 wherein in the starting
materials R is 3'-nitrophenyl, R1, R3 and Z are each methyl, R2 is hydrogen,
Y is a -(CH2)2- group and X is methoxycarbonyl.
10. A process of preparing 1,4-dihydro-2,6-dimethyl-4-(3'-nitro-
phenyl)-pyridine-3,5-dicarboxylic acid methyl 2-methylthioethyl ester wherein
3'-nitrobenzylideneacetoacetic acid methyl ester is reacted with .beta.-amino-
crotonic acid 2-methylthioethyl ester.
11. A process according to claim 1 or 2 wherein in the starting
materials R is 3'-nitrophenyl, R1, R3 and Z are each methyl, R2 is hydrogen,
X is isopropoxycarbonyl and Y is a -(CH2)2- group.
12. A process of preparing 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-
pyridine-3,5-dicarboxylic acid isopropyl 2-methylthioethyl ester wherein
47

3'-nitrobenzylideneacetoacetic acid isopropyl ester is reacted with
.beta.-aminocrotonic acid 2-methylthioethyl ester.
13. A process according to claim 1 or 2 wherein in the starting
materials R is 3'-nitrophenyl, R1 and R3 are each methyl, R2 is hydrogen,
X is isopropoxycarbonyl, Y is a -(CH2)2-group and Z is benzyl.
14. A process of preparing 1,4-dihydro-2,6-dimethyl-4-(3'-nitro-
phenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-benzylthioethyl ester
wherein 3'-nitrobenzylideneacetoacetic acid isopropyl ester is reacted with
.beta.-aminocrotonic acid 2-benzylthioethyl ester.
15. A process according to claim 1 or 2 wherein in the starting
materials R is 3'-nitrophenyl, R1 and R3 are each methyl, R2 is hydrogen,
X is benzyloxycarbonyl, Y is a -(CH2)2- group and Z is ethyl.
16. A process of preparing 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-
pyridine-3,5-dicarboxylic acid benzyl 2-ethylthioethyl ester wherein 3'-
nitrobenzylideneacetoacetic acid benzyl ester is reacted with .beta.-aminocrotonic
acid 2-ethylthioethyl ester.
17. A process according to claim 1 or 2 wherein in the starting
materials R is 2'trifluoromethylphenyl, R1 and R3 are each methyl, R2 is
hydrogen, X is methoxycarbonyl, Y is a -(CH2)2- group and Z is ethyl.
18. A process of preparing 1,4-dihydro-2,6-dimethyl-4-(2'-trifluoro-
methylphenyl)-pyridine-3,5-dicarboxylic acid methyl 2-ethylthioethyl ester
wherein 2'-trifluoromethylbenzylideneacetoacetic acid methyl ester is reacted
with .beta.-aminocrotonic acid 2-ethylthioethyl ester.
19. 1,4 dihydropyridines of the general formula I as defined in claim
1 and their pharmaceutically acceptable salts, when prepared by the process
of claim 1 or 2 or by an obvious chemical equivalent thereof.
20. 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-dicarbox-
ylic acid methyl 2-methylthioethyl ester when prepared by the process of
48

claim 10 or by an obvious chemical equivalent thereof.
21. 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-di-
carboxylic acid isopropyl 2-methylthioethyl ester when prepared by the
process of claim 12 or by an obvious chemical equivalent thereof.
22. 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-di-
carboxylic acid isopropyl 2-benzylthioethyl ester when prepared by the
process of claim 14 or by an obvious chemical equivalent thereof.
23. 1,4-dihydro-2,6-dimethyl-4-(3'-nitrophenyl)-pyridine-3,5-di-
carboxylic acid benzyl 2-ethylthioethyl ester when prepared by the process
of claim 16 or by an obvious chemical equivalent thereof.
24. 1,4-dihydro-2,6-dimethyl-4-(2'-trifluoromethylphenyl)-pyridine-3,5-
dicarboxylic acid methyl 2-ethylthioethyl ester when prepared by the process
of claim 18 or by an obvious chemical equivalent thereof.
49

Description

~lQ1~6:~L5
The present invention relates to certain new 1,4-dihydro-
propyridine compounds with sulphur-containing ester groups, to
several processes for their production and to their use as medica- ,
ments, in particular as active compounds having an influence on
the circulat~on.
It has already been disclosed that 1,4-dihydro-2,6-
dimethyl-4-phenyl-pyridine~3,5-dicarboxyllc acid diethyl ester is
obtained when benzylideneacetoacetic acid ethyl ester is reacted
with ~-amino-crotonic acid ethyl ester or ethyl aceto-acetate and
10ammonia (Knoevenagel, Ber. dtsch. chem. Ges. 31, 743 (1898)).
Furthermore, it is known that certain 1,4-dihydropyri-
dines have interesting pharmacological porperties (F, Bossert and
W. Vater, Naturwissenschaften 58, 578 (1971)).
The present invention relates to compounds which are ~¦
1,4-dihydropyridines, of the following general formula (I) or
their salts or their pharmaceutically acceptable bioprecursors:
X\~ COO - Y - S - Z
R ~ I \ R3
in which R is pyridyl or phenyl unsubstituted or substituted by
1 to 3 identical or different substituents each of which is lower
alkyl, lower alkoxy, halogen, trifluoromethyl, nitro or cyano,
and R are identical or different and each is hydrogen or
straight-chain or branched lower alkyl, R2 is hydrogen or
straight-chain or branched lower alkyl, Y is lower alkylene or
lower alkylene substituted by lower alkyl, Z is a straight-chain,
branched or cyclic saturated or unsaturated aliphatic hydrocarbon
B~ ~ :
:
. .

radical with up to 6 carbon atoms or such an aliphatic hydrocar-
bon radical which is interrupted in the chain by one oxygen atom
or which is substituted by phenyl, and X represents a group
-CoR4 or -CooR5, w-herein R4 is lower alkyl or phenyl and R5 is a
straight-chain, branched or cyclic alkyl having up to 6 carbon
atoms or such an alkyl interrupted by one oxygen atom, or such
an alkyl substituted by phenyl, phenoxy, a pyridine ring or an
amino group which amino group is substituted by two same or
different substituents selected from lower alkyl, phenyl or
benzyl, or is alkenyl having up to 4 carbon atoms, or X is a group
-C00-Y~-S-Z' which is ident~cal with or different from the group
-CO0-Y-S~Z and wherein Y' and Z~ are as defined for Y and Z
respectively.
There is also provided a process for the production of
a 1,4-dihydropyridine compound of the invention in which
~ A~ an ylidene compound of the general formula II
CO - Rl
R - CH = C / (II)
in which R, Rl and X have the same meaning as defined herein-
before in formula I, is reacted with enaminocarboxylic acid
ester of the general formula III
R - C = CH - C00 - Y S - Z
R21H (III)
in which R2, R3, Y and Z have the same meaning as defined herein-
before in formula I, optionally in the presence of an inert or-
ganic solvent, or
- 3 =
: .

3~ f`'~ 5
(B) an ylidene compound of the general formula II
CO - Rl
R - CH = C / ~II)
X
in which R, R and X have the same meaning as defined herein-
before in formula I J iS reacted with an amine of the general
formula IV and a ~-ketocarboxylic acid ester of the general
formula V
R - NH2 R3 - C0 - CH2 - C00 - Y - S - Z
~IV) (V)
in which R2, R3, Y and Z have the same meaning as defined here-
inbefore in formula I, optionally in the presence of an inert
organic solvent, or
(C) an ylidene-~-dicarbonyl compound of the general
formula VI
f 0 - R3
R - CH = C ~VI)
\COO - Y - S - Z
in which R, R3, Y and Z have the same meaning as defined herein-
before in formula I is reacted with an enamino compound of the
general formula VII
R - C = CH - X
2 1 ~VII)
R - NH
in which Rl, R2 and X have the same meaning as defined herein-
before in formula I, optionally in the presence of an inert or-
ganic solvent, or
- 4 -
æ~

36~5
(D) an ylidene-~-dicarbonyl compound of the general
formula VI
/ C0 - R3
R - CH = C \ (VI)
C 00 - Y - S - Z ,: :
in which R, R3, Y and Z have the same meaning as defined herein-
before in formula I is reacted with an amine of the general
formula IV and a keto derivative of the formula VIII
R2 _ NH2 Rl - CO - CH2 - X
(IV~ ~VIII)
in which R2, Rl and X have the same meaning as defined herein-
before in formula I, optionally in the presence of an inert
organic solvent, or
~E) an aldehyde of the general formula IX
R - C / (IX)
~0
in which R has the same meaning as defined hereinbefore in
formula I is reacted with an enamino compound of the general
formula VII
R1 C = CH X
R2 IH (VII)
in which Rl, R2 and X have the same meaning as defined herein-
before in formula I, and a ~-ketocarboxylic acid ester of the
general formula V
R3 - C0 - CH2 - C00 - Y - S - Z (V)
- 5 -
.;'~`'~'`''

s
in which R , Y and Z have the same meaning as defined herein-
before in formula I, optional~y in the presence of an inert
organic solvent, or
(F) an aldehyde of the general formula IX
R - C 6 (IX)
in which R has the same meaning as defined hereinbefore in
formula I, is reacted w~th an enaminocarboxylic acid ester of
the general formula III
R - C = CH ~ C00 - Y - S - Z
¦ (III)
R2NH
lQ in which R2, R3, Y and Z have the same meaning as defined here-
inbefore in formula I, and a keto derivative of the general
~o~ula ~
R - C0 CH2 ~ X (VIII)
in which R and X have the same meaning as defined hereinbefore
in formula I, optionally in the presence of an inert organic sol-
vent, at a temperature of from 20C to 150C.
The 1,4-dihydropyridine compounds according to the in- .;
vention have valuable pharmacological properties. Because of
their action in influencing the circulation, they can be used as
antihypertensive agents, as vasodilators and as coronary thera-
peutic agents, and are thus to be regarded as an enrichment of
pharmacy,

.S '~
The synthesis of the compounds of the invention by the
processes of the invention is illustrated by the following re-
action equations, depending on the nature of the starting mat-
erials, 1,4-dihydro-2,6-dlmethyl-4-(3'-nitrophenyl)-pyridine-
3,5-dicarboxylic acid methyl 2-ethylthioethyl ester and 1,4-
dihydro-2,6-dimethyl-4-~2'-trifluoromethylphenyl)-pyridine-3,5-
dicarboxylic acid 2-benzylthioethyl isopropyl ester being used
as examples:
.
~- ~ 7
r i

8~ S
~- NO2
H3CO~ ~ H H~C02-(CH2 )2-SC2H5
H3 C ~ H2 N CH3 -H2 o
~ NO2
H3 CO2 C~ CO2 -CH2 -CH2 -SC2 H5
H3 C ~ N CH3
;
~3 ~e A 18 128 -~9'-

1086~
~V C~~ ov .~~ o ~
0=0 V ~ ~
o V V V ~=~
t t ~ I
t
V~
-~ ~ 0~ r~
: BI IR A 18 128 -~_
' .
.. . . . . . . . . , . . .. .. . ... . ... , _ .. . .. . . . . . . . ... .. ...

11~86~5
F) ~ NO2
O H
H3 CO ICH2 H COOCH2 CH2 SC2 H5
H3 C ~ ~O~ H2 N ~ ~ CH3 -2H~ O
~, NO2
H3 COOC ~COOCH2 CH2 SC2 H5
H
.
, .
~''
~J ~o
,,. ~e A 18 1?8 -~-
. .

Process variant A
The ylidene compounds of the formula II used as start-
ing materials are known from the literature or can be prepared
by methods which are known from the literature (compare, for
example, G. Jones "The Knoevenagel Condensation" in Org. React-
ions, Volume XV, 204 et seq. ~1967) and G. Beck and D. Gunther,
Chem. Ber. 106, 2758 (1973?),
Examples which may be mentioned are: benzylidene-
acetylacetone, 2'-nitrobenzylideneacetylacetone, 2'-nitrobenzyl-
ideneacetonacetlc acid methyl ester, 3'-nitrobenzylideneaceto-
acetic acid ethyl ester, 2'-trifluoromethylbenzylideneacetoacetic
acid n-butyl ester, 2'-cyanobenzylideneacetoacetic acid isopropyl
ester, 3'-cyanobenzylideneacetoacetic acid cyclopentyl ester,
2'-methylbenzylideneacetoacetic acid alkyl esters, 2'-chloro-
benzylideneacetoacetic acid 2-methoxyethyl ester, 2'-chloro-
benzylideneacetoacetic acid 2-methylthioethyl ester, 3'-chloro-
benzylideneacetoacetic acid 2-dimethylaminoethyl ester, 2'-
fluorobenzylideneacetoacetic acid 2~(N-benzyl-N-methylamino)-
ethyl ester, 2'-nitrobenzylideneacetoacetic acid isobutyl ester,
3'-chloro-4'-nitrobenzylideneacetoacetic acid benzyl ester, 3'-
cyanobenzylideneacetoacetic acid 2-phenoxyethyl ester, 2'-nitro- .
benzylideneacetoacetic acid 2-(pyrid-2-yl?-ethyl ester, 2'-
nitrobenzylidenepropionylacetic acid methyl ester, 2'-cyano-
benzylidenepropionylacetic acid ethyl ester and ~-acetyl-~-
(pyrid-3-yl~-acrylic acid methyl ester.
The enaminocarboxylic acid esters of the formula III
used as starting materials can be prepared by methods which are
known from the literature (compare A,C. Cope, J, Amer. chem.
Soc. 67, 1017 (1945)).
Examples which may be mentioned are ~amino~crotonic
acid 2-methylthioethy~l ester, ~-methylamino-crotonic acid 2-
- 11 -

s
methylthioethyl ester, ~-n-butylamino-crotonic acid 2-methyl-
thioethyl ester, ~-iso-butylamino-crotonic acid 2-ethylthioethyl
ester, ~-amino~-propyl-acrylic acid 2-n-butylthioethyl ester,
~-amino-crotonic acid 2-cyclohexylthioethyl ester, ~-amino-
crotonic acid 2-(2-methoxyethylthio)-ethyl ester, ~-amino-
crotonic acid 2-benzylthioethyl ester, ~-amino~crotonic acid
2(2-benzyl-ethylthio)-ethyl ester, ~-amino-crotonic acid 2-~2-
phenoxyethylthio)-ethyl ester, ~-amino-crotonic acid 2-(4-methyl-
benzylthio)-ethyl ester, ~-amino-crotonic acid 2-(3-methylbenzyl-
thio)-ethyl ester and ~-amino-crotonic acid 2-~4-methoxybenzyl-
thio)-ethyl ester,
Possible diluents are all the inert organic solvents.
These include, preferably, alcohols, such as ethanol, methanol
and isopropanol, ethers, such as dioxane, diethyl ether, tetra-
hydrofurane, glycol monomethyl ether and glycol dimethyl ether,
or glacial acetic acid dimethylformamide, dimethylsulphoxide, -~
acetonitrile, pyridine and hexamethylphosphoric acid triamide.
; The reaction temperatures can be varied within a
relatively wide range. In general, the reaction is carried out
~ 20 at from 20C to 150C, preferably from 20C to 100C and in
:~ particular at the boiling point of the particular solvent used.
The reaction can be carried out under ambient pressure,
but also under superatmospheric pressure, In general, it is
carried out under ambient pressure.
In carrying out the above process according to the in-
vention, one mol of the ylidene compound of the formula II is
preferably reacted with about one mol of enaminocarboxylic acid
ester of the formula III in a suitable solvent. The isolation
and purificat~on of the compounds according to the invention are
preferably carried out by distilling off the solvent in vacuo
and recrystallising the residue, which in some cases is obtained
- 12 _
c? ~ -:

in the crystalline form only after cooling with ice, from a
suita~le solvent.
Process variant B
Examples of the ylidene compounds of the formula II
used as starting substances are already listed under process
variant A.
The amines of the formula IV which can be used accord-
ing to the invention are already known.
Examples which may be mentioned are: ammonia, methyl-
amine, n-propylamine, isopropylamine, n-butylamine and isobutyl-
amine.
The ~ketocarboxylic acid esters of the formula V used
as starting materials can Be prepared by methods which are known
from the literature (for example D. Borrmann, "Umsetzung von
Diketen mlt Alkoholen, Phenolen und Mercaptanen" ~Reaction of
Dike~ene with Alcohols, Phenols and Mercaptans"), in Houben-
Weyl, Methoden der Organischen Chemie (Methods of Organic Chem-
istry) Volume VII/4, 230 et seq. (1~68)).
; Examples which may be mentioned are: acetoacetic acid
20 2-methylthioethyl ester, propionylacetic acid 2-methylthioethyl
ester, acetoacetic acid 2-n-butylthioethyl ester, acetoacetic
acid 2-iso-butylthioethyl ester, acetoacetic acid 2-cyclohexyl-
thioethyl ester, acetoacetic acid 2-(2-methoxyethylthio)-ethyl
ester, acetoacetic acid 2-(benzylthio)-ethyl ester, acetoacetic
acid 2-(benzylethylthio)-ethyl ester, acetoacetic acid 2-(2-
phenoxyethylthio)-ethyl ester, acetoacetic acid 2-(4-methyl-
benzylthio~-ethyl ester and acetoacetic acid 2-(4-methoxybenzyl-
thio)-ethyl ester
Possible diluents are all the inert organic solvents.
These include~ preferably, alcohols, such as ethanol, methanol
and isopropanol, ethers, such as dioxane, diethyl ether~ tetra-
- 13 -

~8~S
hydrofurane, glycol monomethyl ether and glycol dimethyl ether,or glacial acetic acid, dimethylformamide, dimethylsulphoxide,
acetonitrile, pyridine and hexamethylphosphoric acid triamide.
The reaction temperature can be varied within a relat-
ively wide range. In general, the reaction is carried out at
from 20C to 150C, but preferably at the boiling point of the
particular solvent used.
The reaction can be carried out under ambient pressure,
but also under superatmospheric pressure. In general, it is
carried Ollt under ambient pressure.
In carrying out the a6Ove process according to the in-
vention, the materials of the formula II, IV and V participating
in the reaction are each generally employed in approximately
molar amounts. The amine used is appropriately added in an ex-
cess of from 1 to 2 mols, The compounds according to the in
vention can ~e easily purified by recrystallisation from a suit-
able solvent,
Proce`ss vari`ant`C
The ylidene-~-dicarbonyl compounds of the formula VI
used as starting materials can be prepared by methods which are
known from the literature ~compare~ for example, G. Jones, "The
; Knoevenagel Condensation" in Org. Reactions, Volume XV, 204 et
seq. (1967)).
Examples which may be mentioned are: 2'-nitrobenzyl-
ideneacetoacetic acid 2-methylthioethyl ester, 3'-nitrobenzyl-
idenepropionylacetic acid 2-methylthioethyl ester, 2'-methoxy-
benzylidenebenzoylacetic acid 2-ethylthioethyl ester, 3'-methyl-
benzylideneacetoacetic acid 2-n-butylthioethyl ester, 2'-chloro-
benzylideneacetoacetic acid 2-iso-butylthioethyl ester, 3'-cyano-
benzylideneacetoacetic acid 2-cyclopentylthioethyl ester, 2~-
trifluoromethylaenzylideneacetoacetic acid 2-~2-methoxyethyl-
thio)-ethyl ester, 3'-trifluoromethylBenzylideneacetoacetic
- 14 -
~1 . .

acld 2-benzylthioethyl ester and 2-acetyl-3-(pyrid-3-yl)-
acrylic acid 2-ethylthioethyl ester.
The enamino compounds of the formula VII used as start-
ing materials are known from the literature or can be prepared
by methods which are known from the literature ~compare A.C.
Cope, J. Amer. chem. Soc. 67, 1017 ~1945) and N, Guruswamy et al,
Indian J. Chem. 11, 882 ~1973)).
Examples Nhich may be mentioned are: 4-amino-3-penten-
2-one, ~-amlnocrotonlc acid methyl ester, ~ methylaminocrotonic
10 acid n-butyl ester, ~-n-butylaminocrotonic acid isopropyl ester,
~-amino-~-ethylacrylic acid 2-methoxyethyl ester, ~-aminocrotonic
acid benzyl ester, ~-aminocrotonic acid 2-phenylethyl ester, ~-
aminocrotonic acid 2 -phenoxyethyl ester, ~-aminocrotonic acid
2-methylthioethyl ester, ~-aminocrotonic acid 2-ettlylthioethyl
ester, ~-aminocrotonic acid 4-methoxybenzyl ester, ~-amino-
,i crotonic acid 4-methylbenzyl ester, ~-aminocrotonic acid pyridyl-
`~ 2-methyl ester, ~-amlnocrotonic acid 2-dlmethylaminoethyl ester
j and ~-amlnocrotonic acld 2-~N~benzyl-N~methylamino~-ethyl ester,
, Posslb-le diluents are all the inert or~anic solvents.
2~ These include, preferably, alcohols, such as ethanol, methanol
, and isopropanol, ethersJ such as dioxane, diethyl ether, tetra-
; hydrofurane, glycol monomethyl ether and glycol dimethyl ether,
or glacial acetic acid, dimethylformamide, dimethylsulphoxide,
acetonitrile, pyridine and hexamethylphosphoric acid triamide.
~! The reaction temperature can be varied within a rela-
'I
tively w-ide range. In general, the reaction is carried out at
from 20C to 150C, but preferably at the boiling point of the
particular solvent used.
The reaction can be carried out under ambient pressure,
30 but also under superatmospheric pressure, In general, it is
carried out under ambient pressure,
- 15 ~

In carrying out the above process according to the
invention, one mol of the ylidene-~-dicarbonyl compound of the
formula VI is generally reacted with approximately one mol of
the enamino compound of the formula VII in a suitable solvent.
Process variant D
Examples of the ylidene~-dicarbonyl compounds of the
formula VI used as starting compounds are already listed in con-
nection with process variant C.
The amines of the formula IV which can be used accord-
ing to the invention have already aeen described in connectionwith process variant B above.
The keto derivatives of the formula VIII employed as
starting substances are known from the literature or can be
prepared by methods which are known from the literature (compare,
for example, D, Borrmann, "Umsetzung von Diketen mit Alkohlen,
Phenolen und Mercaptanen" ("Reaction of Diketene with Alcohols,
Phenols and Mercaptans"), in Houben-Weyl, Methoden der Organ-
ischen Chemie (Methods of Organic Chemistry), Volume VII/4, 230
et seq. (1968); and H.O. House and J.K. Larson, J. Org. Chem.
33, 61 (1968)).
Examples which may be mentioned are: acetylacetone,
formylacetic acid ethyl ester, acetoacetic acid methyl ester,
n-propionylacetic acid ethyl ester, acetoacetic acid isopropyl
ester, acetoacetic acid cyclopentyl ester, acetoacetic acid
allyl ester, acetoacetic acid 2-methoxyethyl ester, acetoacetic
acid 2-propoxyethyl ester, acetoacetic acid benzyl ester, aceto-
acetic acid 2-phenylethyl ester, acetoacetic acid 2-phenoxyethyl
ester, acetoacetic acid 2-methylthioethyl ester, acetoacetic
acid 2-benzylthioethyl ester, acetoacetic acid pyrid-2-yl-methyl
ester~ acetoacetic acid 2-dimethylaminoethyl ester and aceto-
acetic acid 2-(N-benzyl-N-methylamino)~ethyl ester.
- 16 -

s
Possible diluents are all the inert organic solvents.
These include, preferably, alcohols, such as ethanol, methanol
and isopropanol, ethers, such as dioxane, diethyl ether, tetra-
hydrofurane, glycol monomethyl ether and glycol dimethyl ether,
or glacial acetic acid, dimethylformamide, dimethylsulphoxide,
acetonitrile, pyridine and hexamethylphosphoric acid triamide.
The reaction temperatures can be varied w-ithin a rela-
tively wide range. In general, the reaction is carried out at
~ from 20C to 150C, but preferably at the boiling point of the: 10 particular solvent used.
The reaction can be carried out under ambient pressure,
but also under superatmospheric pressure. In general, it is
carried out under ambient pressure.
In carrying out the above process according to the in-
vention, the substances of the formula VI, IV and VIII partici-
pating in the reaction are generally each employed in approx-
' imately molar amounts, The amine used is appropriately added in
an excess of from 1 to 2 mols,
''P'roc'e'ss''variant E
i 20 The aldehydes of the formula IX used as starting mat-
erials are known from the literature or can be prepared by
methods which are known from the literature (compare, for ex-
ample, E, Mosettig, Org. Reactions VIII, 218 et seq, (1954)).
Examples which may be mentioned are: benzaldehyde,
2-, 3~ or 4-methylbenzaldehyde, 2- or 4-n-butylbenzaldehyde, 2~,
3- or 4-isopropylbenzaldehyde, 2,3-tetramethylene-benzaldehyde,
~; 3,4-dioxymethylenebenzaldehyde, 2-, 3- or 4-methoxybenzaldehyde,
2-, 3~ or 4-chloro-, -bromo- or -fluoro-benzaldehyde, 2-, 3^ or
4-trifluoromethylbenzaldehyde, 2-, 3- or 4-nitTobenzaldehyde,
2-, 3- or 4-cyanobenzaldehyde, 3,4,5-trimethoxybenzaldehyde,
2,4- or 2,6-dichlorobenzaldehyde, 2,4~dimethylbenzaldehyde, 2,4-
- 17 -
~1

s
or 2,6-dinitrobenzaldehyde~ 2-chloro-6-nitrobenzaldehyde, 4-
chloro-2-nitrobenzaldehyde, 2-nitro-4-methoxybenzaldehyde, 2-
nitro-4-cyanobenzaldehyde, 2-chloro-4-cyanobenzaldehyde, 4-cyano-
2-methylbenzaldehyde, 3-methyl-4-trifluoromethylbenzaldehyde
and 3-chloro-4-trifluoromethylbenzaldehyde, pyridine-2-aldehyde,
pyridine-3-aldehyde, pyridine-4-aldehyde, 4-methyl-pyridine-2-
aldehyde and 6-methylpyridine-2-aldehyde.
The enamino compounds of the formula VII which can be
used according to the invention have already been indicated
hereinbefore in connection with process variant C and the ~-
ketocarboxylic acid esters of the formula V employed according
to the invention have been indicated in connection with process
variant B.
Possible diluents are all the inert organic solvents,
These include, preferably, alcohols, such as ethanol, methanol
and isopropanol, ethers, such as dioxane, dimethyl ether, tetra-
hydrofurane, glycol monomethyl ether and glycol dimethyl ether,
or glacial acetic acid, dimethylformamide, dimethylsulphoxide,
acetonitrile, pyridine and hexamethylphosphoric acid triamide.
The reaction temperature can be varied within a relat-
ively wide range. Tn general, the reaction is carried out at
from 20C to 150C, but preferably at the boiling point of the
particular solvent used.
The reaction can be carried out under ambient pressure,
but also under superatmospheric pressure, In general, it is
carried out under ambient pressure.
In carrying out the above process according to the in-
vention, the substances of the formula IX, VII and V participat-
ing in the above reaction are generally each employed in approx-
imately molar amounts.
- 18 -

Process variant F
The aldehydes of the formula IX used as starting sub-
stances are listed under process variant E, the enaminocarbox-
ylic acid esters of the formula III are listed under process
variant A and the keto derivatives of the formula VIII are list-
ed under process variant D.
Possible diluents are all the inert organic solvents.
These include, preferably, alcohols, such as ethanol, methanol
and isopropanol, ethers, such as dioxane, diethyl ether, tetra-
hydrofurane, glycol monomethyl ether and glycol
Bl
- ~ . . ~ . i

s
dimethyl ether, or glacial acetic acid, dimethylformamide,
dimethylsulphoxide, acetonitrile, pyridine and hexamethyl-
phosphoric acid triamide. _
The reaction temperatures can be varied within a
relatively wide range. In general, the reaction is carried
out between 20C and 150C, but preferably at the boiling
point of the particular solvent.
The reaction can be carried out under normal pressure,
but also under increased pressure. In general, it is carried
out under normal pressure.
In carrying out the process according to the invention,
the substances of the formula IX, IIIand VIII participating
in the reaction are each employed in approximately molar
amounts.
The above preparation processes are only given for
illustration, and the preparation of the compounds of the
formula I is not limited to these processes, but any modification
of these processes is applicable in the same manner to the pre-
paration of the compounds according to the invention.
Depending on the choice of starting substances, the
compounds according to the invention can exist in stereoi-
someric forms which either behave as mirror images (enantiomers)
or do not behave as mirror images (diastereomers). The present
invention relates to both the antipodes arld the racemic forms as
well as the diastereomer mixtures. The racemic forms can be
separated into the stereoisomerically single constituents in a
known manner, as can the diastereomers (compare, for example,
E.L. Eliol, Stereochemistry of Carbon Compounds, McGraw Hill,
1962).
~ - 20 -

s
In addition to the preparation examples listed below,
the following active compounds according to the invention may be
mentioned: 1,4-dihydro-2,6-dimethyl-4-~2'~nitrophenyl)-pyridine-
3,5-dicarboxylic acid methyl 2-methylthioethyl ester, 1~4-di-
hydro-2,6-dimethyl-4-(2'-nitrophenyl)-pyridine-3,5-dicarboxylic
acid n-butyl 2-methylthioethyl ester, 1,4-dihydro-2,6-dimethyl-
4-~2'-nitrophenyl)~pyridine~3,5~dicarboxylic acid isopropyl 2-
methylthioethyl ester, 1,4-dihydro-2,6-dimethyl-4-~2'-nitro-
phenyl~-pyridine-3,5-dicarboxylic ac~d cyclopentyl 2-methylthio~
ethyl ester, 1,4-dihydro-2,6~dimethyl-4~(2'-nitrophenyl)-pyrid-
ine-3,5-dicarboxylic acid 2-methoxyethyl 2-ethylthioethyl ester,
1,4-dihydro-2,6-dimethy1-4-(3'-nitrophenyl)~pyridine-3,5-di-
carboxylic acid methyl 2-benzylthioethyl ester, 1,4-dihydro-2,6
dimethyl-4-~2'~trifluoromethylphenyl)-pyridine-3,5-dicarboxylic
, acid ethyl 2-ethylthioethyl ester, 1l4-dihydro~2,6-dimethyl~4-
(2'-trifluoromethylphenyl)-pyridine-3,5~dicarb.oxylic acid iso-
butyl 2-methylthioethyl ester, 1,4-dihydro-2,6-dimethyl~4-(2'-
trifluoromethylphenyl)-pyridine-3,5-dicarboxylic acid di-(2-
methylthioethyl~ ester, 1,4-dihydro-2,6-dimethyl-4-t2l-cyano-
phenyl~-pyridine-3,5-dicarboxylic acid methyl 2-methylthioethyl
ester, l,4-dihydro~2,6-dimethyl-4-(2'-chlorophenyl)-pyridine~
3,5-dicarboxylic acid ethyl 2-methylthioethyl ester, 1,4-di-
hydro-2,6-dimethy-1-4-(3'-methoxyphenyl)-pyridine-3,5~dicarboxylic
acid isopropyl 2-cyclohexylthioethyl ester and 1,4--dihydro=2,6-
dimethyl~4-(pyrid-2-yl~-pyridine-3,5-dicarboxylic acid methyl 2-
methylthioethyl ester.
The new compounds have a broad and diverse spectrum of
pharmacological action,
In detail, the following main actions could be demon-
3Q strated in animal experiments
i~,~ ", i
a~r~ ~ ,

(1) On parenteral, oral and perlingual administrationthe compounds produce a distinct and long-lasting dilation of the
- coronary vessels. This action on the coronary vessels is inten-
sified by a simultaneous nitrite-like effect of reducing the load
on the heart. They influence or modify the heart metabolism in
the sense of an energy saving.
~ 2) The excitability of the stimulus for~ation and
excitation conduction system within the heart is lowered, so
that an antifibrillation action which can be demonstrated at
therapeutic doses results.
(3) The tone of the smooth muscle of the vessels is
greatly reduced under the action of the compounds. This vascu-
lar-spasmolytic action can take place in the entire vascular
system or can manifest itself more or less isolated in circum-
scribed vascular regions (such as, for example, the
~31

central nervous system).
4) The compounds lower the blood pressure of normal tonic
and hypertonic animals and can thus be used as antihyper-
tensive agents.
5) ~he compounds have strongly muscular-spasmolytic actions
which manifest themselves on the smooth muscle of the
stomach, the intestinal tract, the urogenital tract and the
respiratory system.
~or the purpose o~ this speci~ication the term "pharma-
ceutically acceptable bioprecursor" of an active compound
of the invention means a compound having a structural formula
different from the active compound but which nonetheless
upon administration to an animal or human being, is conver-
ted in the patient's body to the active compound.
Among the salts of the invention, those salts that
are pharmaceutically acceptable are particularly important
and are preferred.
The free compounds of the general formula I and their
salts can be interconverted in any suitable manner; methods
for such interconversion are known in the art.
As stated above, the invention also relates to the use
in human and veterinary medicine of the compounds of the
invention.
The present invention provides a pharmaceutical composi-
tion containing as active ingredient a compound o~ the
invention in admixture with a solid or liquefied gaseous
- diluent, or in admixture with a liquid diluent other than a
solvent of a molecular weight less than 200 (preferably
less than 350) except in the presence of a surface active
agent.
~ e A 18 128

08~S
~he invention further provides a pharmaceutical
composition containing as active ingredient a compound o~
the invention in the form o~ a sterile and/or physiologically
isotonic aqueous solution.
The invention also provides a medicament in dosage unit
~orm comprising a compound of the invention.
The invention also provides a medicament in the ~orm
of tablets (including lozenges and granules), dragees,
capsules, pills, ampoules or suppositories comprising a
compound of the invention.
"Medicament" as used in this specification means physi-
cally discrete coherent portions suitable for medical
administration. "Medicament in dosage unit form" as used in
this specification means physically discrete coherent units
suitable for medical administration each containing a daily
dose or a multiple (up to four times) or sub-multiple (down
to a fortieth) of a daily dose of the compound of the
invention in association with a carrier and/or enclosed
within an envelope. Whether the medicament contains a daily
dose or, for example, a hal~, a third, or a quarter of a
daily dose will depend on whether the medioament is to be
administered once or, ~or example, twice, three times or
four times a day respectively.
The pharmaceutical compositions according to the inven-
tion may, for example, take the ~orm o~ ointments, gels,
pastes, creams, sprays (including aerosols), lotions,
suspensions, solutions and emulsions o~ the active ingred-
ient in aqueous or non-aqueous diluents, syrups, granulates
or powders.
The diluents to be used in pharmaceutical compositions
Le A 18 128 -~
,, ..,, ~ ~

S
(e.g. granulates) adapted to be formed into tablets, dragee~,
capsules and pills include the following:
(a) fillers and extenders, e.g. starch, sugars, mannitol,
and silicic acid; (b) binding agents, e.g. carboxymethyl
cellulose and other cellulose derivatives, alginates,
gelatine and polyvinyl pyrrolidone; (c) moisturizing agents,
e.g. glycerol; (d) disintegrating agents, e.g. agar-agar,
calcium carbonate and sodium bicarbonate; (e) agents for
retarding dissolution e.g. paraffin; (f) resorption
acceleratore, e.g. quaternary ammonium compounds; (g) surface
active agents, e.g. cetyl alcohol, glycerol monostearate;
(h) adsorptive carriers, e.g. kaolin and bentonite;
(i) lubricants, e.g. talc, calcium and magnesium stearate
and solid polyethylene glycols.
The tablets, dragees, capsules and pills formed from
the pharmaceutical compositions of the invention can have
the customary coatings, envelopes and protective matrices,
which may contain opacifiers. ~hey can be so constituted
that they release the active ingredient only or preferably
in a particular part of the intestinal tract, possibly over
a period o~ time. The coatings, envelopes and protective
matrices may be made, ~or example, of polymeric substances
or waxes.
The ingredient can also be made up in microencapsulated
form together with one or several of the above mentioned
diluents.
~he diluents to be used in pharmaceutical compositions
adapted to be formed into suppositories can, ~or example,
be the u~ual water-soluble or water-insoluble diluents, such
as polyethylene glycols and fats (e.g. cocoa oil and high
~S
B~ Le A 18 128 _ ~

esters fe.g. C14-alcohol with C16-fatty aci ~ ) or mi~tures
of these diluents.
The pharmaceutical compositions which are ointments,
pastes, creams and gels can, for example, contain the usual
diluents, e.g. animal and vegetable fats, wa~es, paraffins,
starch, tragacanth, cellulose derivatives, polyethylene
glycols, silicones, bentonites, silicic acid, talc and zinc
oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and
sprays can, for example, contain the usual diluents,
e.g. lactose, talc, silicic acid, aluminium hydroxide,
calcium silicate, and polyamide powder or mixtures of these
substances. Aerosol sprays can, for example, contain the
usual propellants, e.g. chloro~luorohydrocarbons.
The pharmaceutical compositions which are solutions
and emulsions can, for example, contain the customary dil-
uents (with, of course, the above mentioned e~clusion of
solvents having a molecular weight below 200 except in the
presence of a surface-acti~e agent), such as solvents,
dissolving agents and emulsifiers; specific examples of such
diluents are water, ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide,
oils ffor example ground nut oil~, glycerol, tetrahydro-
furfuryl alcohol, polyethylene glycols and fatty acid esters
o~ sorbitol or mixtures thereof.
For parenteral administration, solutions and emulsions
should be sterile, and, if appropriate, blood-isotonic.
The pharmaceutical compositions which are suspensions
cancontain the usual diluents, such as liquid diluents, e.g.
~G
~ l ~e ~ 18 128 -~
,
.

water, ethyl alcohol, propylene glycol, surface-active
agents (e.g. ethoxylated isostearyl alcohols, polyoxyethy-
lene sorbite and sorbitane esters), microcrystalline cellu-
lose, aluminium metahydro~ide, bentonite, agar-agar and
tragacanth or mixtures thereof.
All the pharmaceutical compositions according to the
invention can also contain colouring agents and preservativee
as well as perfumes and flavouring additions (e.g.
peppermint oil and eucalyptus oil) and sweetening agents
(e.g. saccharin).
The pharmaceutical compositions according to the
invention generally contain from 0.1 to 99.5, usually from
0.5 to 95% of the active ingredient by weight of the
total composition.
In addition to a compound of the invention, the
pharmaceutical compositions and medicaments according to the
invention can also contain other pharmaceutically active
compounds, They may also contain a plurality of compounds
of the invention.
Any diluent in the medicaments of the present inventio~
may be any of those mentioned above in relation to the pharm-
aceutical compositions of the present invention. Such
medicaments may include solvents of molecular weight less
than 200 as sole diluent.
The discrete coherent portions constituting the
medicament according to the invention will generally be
adapted, by virtue of their shape or packaging, for medical
administration and may be, for example, any of the following:
tablets, (including lozenges and granulates), pills, dragees,
capsules, suppositories and ampoules. Some of these forms
~7
~ 1 ~e A 18 128 - f~ -

may be made up ~or delayed release of the active ingredient.
Some, such as capsules, include a protective envelope which
renders the portions o~ the medicament physically discrete
and coherent.
The preferred daily dose for administration of the
medicaments of the invention ie from 0.5 to 500 mg intra-
venously and from 2.5 to 1000 mg orally of active ingredient.
~he production of the above mentioned pharmaceutical
compositions and medicaments is carried out by any method
known in the art, for example, by mixing the active ingred-
ient(s) with the diluent(s) to form a pharmaceutical compo-
sition (e.g. a granulate) and then ~orming the composition
into the medicament (e.g. tablets).
This invention further provides a method of combating
(including prevention, relief and cure of) the above men-
tioned diseases in human and non-human animals, which
comprises administering to the animals a compound of the
invention alone or in admixture with a diluent or in the
form of a medicament according to the invention.
It is envisaged that these active compounds will be
administered perorally, parenterally (for example intra-
muscularly, intraperitoneally or intravenously), rectally
or locally, preferably intravenously or orally. Pre~erred
pharmaceutical compositions and medicaments are there~ore
tho~e adapted for intravenous or oral administration, such
as injection solutions and suspensions and ampoules thereof,
or tablets, pills, dragees and capsules, respectively.
Administration in the method of the invention is preferably
intravenously or orally.
In general it has proved advantageous to administer
~?~
~ ~e_A 18 128 -~

~1~8~S
amounts of from 0.01 to 10 mg, preferably from 0.05 to 5 mg,
intravenously or from 0.05 to 20 mg, preferably from 0.05 to
5 mg orally, per kg of body weight per day to achieve effective
results. Nevertheless, it can at times be necessary to deviate
from those dosage rates, and in particular to do so as a function
of the nature and body weight of the human or animal subject to
be treated, the individual reaction of this su6ject to the treat-
ment, the type of formulation in which the active ingredient is
administered and the mode in which the administration is carried
out, and the point in the progress of the disease or interval at
which it is to be administered. Thus it may in some case suffice
to use less than the above mentioned minimum dosage rate, whilst
other cases the upper limit mentioned must be exceeded to achieve
the desired results. Where larger amounts are administered it
can be advisable to divide these into several individual admin-
istrations over the course of the day.
Compounds of the general formula ~I~ in which
R is phenyl optionally substituted by halogen, nitro,
cyano, trifluoromethyl, trifluoromethoxy, or alkyl or
alkoxy having 1 or 2 carbon atoms in each case, or is
pyridyl,
Rl and R3 are identical or different and each is alkyl having i
or 2 carbon atoms, phenyl or benzyl,
R2 is hydrogen, alkyl having from 1 to 4 carbon atoms, in
particular methyl or benzyl,
Y is alkylene having from 1 to 4 carbon atoms, in part-
icular ethylene,
Z is alkyl having from 1 to 4 carbon atoms which is
optionally interrupted in the chain by an oxygen atom,
or is benzyl and
_ 29_
'v~ ,.................................................. .
...
. .

: : ~
X is a group -CoR4 or -CooR5,
wherein
R4 is alkyl having from 1 to 4 carbon atoms, in particular
methyl,
and wherein
R5 is straight-chain, branched or cyclic alkyl having up ':
to 6 carbon atoms and optionally interrupted by oxygen,
or a N-alkyl group having 1 or 2 carbon atoms in each
alkyl moiety, or is alkenyl having up to 4, in partic-
ular 3, carbon atoms, or is alkyl having from 1 to 4,
in particular 1 or 2, carbon atoms, which is substituted
by phenyl or pyridyl, or are of particular interest.
Preparat'ion E'xamples :
Whilst the compounds of Examples 7 and 16 to 22 are -
outside the scope of the present claims, these examples are set '-
forth to illustrate processes applicable to the preparation of ~
compounds within the scope of the present claims, :'
` Exa'mple 1
3-Acetyl-1,4-dihydro-2,6-dimethyl-4-~3'-nitrophenyl)-
20 pyridine-5-carboxylic acid 2-ethylt'hioethyl ester
NO
1l ~ 2
H3C ~ CO0 - CH2 ~ CH2 ~ S C2 5
H3C N 3 ~.
r
~3j ~ 30 ~
. .

s
Process variant A
17.5 g (75 mmols) of 3'-nitrobenzylideneacetylacetone
were heated under reflux together with 14.2 g (75 mmols) of ~-
aminocrotonic acid 2-ethylthioethyl ester in 80 ml of ethanol
for 24 hours. After cooling the reaction mixture, the solvent
was distilled off In vacuo and the solid residue was recrystal-
lised from ethanol.
Melting point: 130 C; yield: 21.3 g (70%).
Example _
~ N2
l~ i
H3COOC ~ COO - CH2 - CH2 - S - CH3
~1 11
~ N ~
H3C H CH3
Analogously to Example 1, 1,4-dihydro-2,6-dimethyl-4-
~3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid methyl 2-methyl-
thioethyl ester of melting point: 126C (ethanol) was obtained
by reacting 3'-nitrobenzylideneacetoacetic acid methyl ester and
~-aminocrotonic acid 2-methylthioethyl ester in ethanol.
Yield: 80~ of theory.
_ 31
. i .

I Example 3 1~8~5
~, N2
H3C\ ~
HC-OOC ~ ~ COO-CH.,-CH2-S-CH3
Analogously to Example 1. 1.4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3.5-dicarboxylic acid isopropyl 2-
methylthioethyl ester of melting point: 154C (ethanol) was
obtained by reacting 3'-nitrobenzylideneacetoacetic acid iso-
propyl ester and ~-aminocrotonic acid 2-methylthioethyl ester
in ethanol.
Yield: 84% of theory.
ExamPle 4
~ N2
HC-OOC ~ ~ COO-CH2-CH2-S~c2Hs
H3C H3C ' N CH3
Analogously to Example 1. 1,4-dihydro-2,6-dimethyl-4-
(3l-nitrophenyl)-pyridine-3~5-dicarboxylic acid isopropyl 2-
ethylthioethyl ester of melting point: 95C (ethanol) was ~s
obtained by reacting 3'-nitrobenzylideneacetoacetic acid iso-
propyl ester and ~-aminocrotonic acid 2-ethylthioethyl ester
in ethanol.
Yield: 70% of theory.
B~ Le A 18 128 - ~ -

ExamPle 5 ~ 5
H3C H,C ~ ~0 -CH2-CH2-S-cH2 ~
A solution of 20.8 g (75 mmols) of 3'-nitrobenzylidene-
acetoacetic acid isopropyl ester and 18.8 g (75 mmols) of ~-
aminocrotonic acid 2-benzylthioethyl ester in lQ0 ml of ethanol
was heated to the boil for 24 hours. After cooling the
reaction mixture, the solvent was distilled off in vacuo and
the oily residue was purified by column chromatography over
silica gel using chl.oroform as the running agent. An oil
was obtained (16.3 g = 43%), which on the basis of the spectro-
scopic data was clearly identified as 1.4-dihydro-2.6-dimethyl-
4-(3 7 -nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl
2-benzylthioethyl ester.
Example 6
~ NO2
OOC ~ C00-CH2-CH2-S-C2H5
H~C H CH,
Analogously to Example 1. 1.4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3.5-dicarboxylic acid cyclopentyl 2-
ethylthioethyl ester of melting point: 93C (ethanol) was
obtained by reacting 3'-nitrobenzylideneacetoacetic acid cyclo-
pentyl ester and ~-aminocrotonic acid 2-ethylthioethyl cster
in ethanol.
Yield: 68% of theory. 3
Le A 18 128 - ~

- ExamPle 7 ~ 5
~, NO2
H2C-HC-H2C-OOC ~ _ C00-CHz~CH2~S~c2Hs
~3 C ~ HN 1 CH3
Analogously to Example 5. 1,4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid allyl 2-ethyl-
thioethyl ester (oil) was obtained by reacting 3'-nitrobenzyli-
deneacetoacetic acid allyl ester and ~-aminocrotonic acid 2-
ethylthioethyl ester in ethanol.
Yield: 80% of theory.
ExamPle 8
~, NO2
H3C0-H2C-H2C-OOC ~ C00-CH2-CH2-S-C2Hs
H
Analogously to Example 1. 1,4-dihydro-2,6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid 2-methoxy- ;;,r
ethyl 2-ethylthioethyl ester o~ melting point: 90C (ethanol)
was obtained by reacting 3'-nitrobenzylideneacetoacetic acid
2-methoxyethyl ester and ~-aminocrotonic acid 2-ethylthioethyl
ester in ethanol.
Yield: 79% of theory.
~; Le A 18 128 - l~r-
.

ExamPle g ~ 3$~5
,~,, N2
H5C2S-H2C-H2C-OOC ~ C00-CH2-CH2-SC2H5
H~C' N CH3
Analogously to Example 1. 1.4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid di-(2-ethyl-
thioethyl) ester of melting point: 118C (ethanol) was obtained
by reacting 3'-nitrobenzylideneacetoacetic acid 2-ethylthio-
ethyl ester and ~-aminocrotonic acid 2-ethylthioethyl ester in
ethanol.
Yield: 60% of theory.
Exam~le 10
~ NO2
H3C~ ~
N-H C i C COC ~ C00-CH2-CH2~S~c2Hs
H3C ~ N CH3
Analogously to Example 5. 1.4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid 2-dimethyl-
aminoethyl 2-ethylthioethyl ester (oil, eluting agent chloro-
form:acetone = 20:1) was obtained by reacting 3'-nitrobenzyli-
deneacetoacetic acid 2-dimethylaminoethyl ester and ~-amino-
crotonic acid 2-ethylthioethyl ester in ethanol.
Yield: 48% of theory.
Le A 18 128 - ~ -

Example 11
`` l~$B6~5
k~' N2
H2C-OOC ~ COO-CH2-CHz~sc2Hs
H C- N C~3
Analogously ~ Example 1. 1.4-dihydro-2,6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid benzyl 2-ethyl-
thloethyl ester of melting point: 132C (ethanol) was obtainedby reacting 3'-nitrobenzylideneacetoacetic acid benzyl ester and
~-aminocrotonic acid 2-ethylthioethyl ester in ethanol.
Yield: 69% of theory.
hxamPle 12
,~ NO2
~ ~2C-OOC ~ COO-CH2-CH2-SC2H5
H3C ' HN CH3 `~
Analogously to Example 1. 1,4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid pyrid-3-yl-
methyl 2-ethylthioethyl ester of melting point: 144C (ethanol)
was obtained by reacting 3'-nitrobenzylideneacetoacetic acid
pyrid-3-yl-methyl ester and ~-aminocrotonic acid 2-ethylthio-
ethyl ester in ethanol.
Yield: 65% of theory.
n~ 3 ~
~-J ~ Le A 18 128 -_4gr-

Example 13 ~ 5
H3COOC ~ COO-CHz-CHz-S-C2H5
H3C -" N CH3
Analogously to Example 1, 1,4-dihydro-2,6-dimethyl-4-
(2'-chlorophenyl)-pyridine-~5-dicarboxylic acid methyl 2-
ethylthioethyl ester of melting point: 92C (petroleum ether/ether) was obtained by reacting 2'-chlorobenzylideneaceto-
acetic acid methyl ester and ~-aminocrotonic acid 2-ethylthio-
ethyl ester in ethanol.
Yield: 71% of theory.
ExamPle 14
~ CF3
H3COOC ~ ~ COO-CH2-CH2-S-C2H5
H3C- N CH3
Analogously to Example 5, 1,4-dihydro-2,6-dimethyl-4-
(2'-trifluoromethylphenyl)-pyridine-~,5-dicarboxylic acid
methyl 2-ethylthioethyl ester (oil) was obtàined by reacting
2'-trifluoromethylbenzylideneacetoacetic acid methyl ester
and ~-aminocrotonic acid 2-ethylthioethyl ester in ethanol.
Yield: 65% of theory.
Exam~le 15
~ OCH3
H~COOC I COO-CH2-CH2-S-C2Hs
H3C ~ CH3
Le A 18 128 _
. .

$1~ 5
Analogously to Example 1. 1.4-dihydro-2.6-dimethyl-4-
(2'-methoxyphenyl)-pyridine-3,5-dicarboxylic acid methyl 2-
ethylthioethyl ester of melting point: 121C (ethanol) was
obtained by reacting 2'-methoxybenzylideneacetoacetic acid
methyl ester and ~-aminocrotonic acid 2-ethylthioethyl ester
in ethanol.
Yield: 83% of theory.
ExamPle 16
~ N
H3COOC ~ C00-CH2-CH2-S-C2H5
H
Analogously to Example 1. 1,4-dihydro-2,6-dimethyl-4-
(pyrid-2-yl)-pyridine-3.5-dicarboxylic acid methyl 2-ethylthio-
ethyl ester of melting point: 137C (ethanol) was obtained by
reacting 2-acetyl-3-(pyrid-2-yl)-acr~ic acid methyl ester and
~-aminocrotonic acid 2-ethylthioethyl ester in ethanol.
Yield: 63% of theory.
Exam~le 17
~ N
H3COOC ~ C00-CH2 CH2-SC2H5
H~C ~ N CH~
Analogously to Example 1. 1.4-dihydro-2.6-dimethyl-4-
(pyrid-3-yl)-pyridine-3,5-dicarboxylic acid methyl 2-ethylthio-
ethyl ester of melting point:l51C (ethanol) was obtained by
reacting 2-acetyl-3-(pyrid-3-yl)-acrylic acid methyl ester and
~-aminocrotonic acid 2-ethylthioethyl ester in ethanol.
Le A 18 128 -~r~

Yield: 72% of theory. ~1~8615
Example 18
~ NO2
2
H3c,S ~ ~ COO-CH2-CH2-S-C2H5
H3C ' N CH3
Analogously to Example 1, 1.4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-3-methylsulphonyl-pyridine-5-carboxylic acid
2-ethylthioethyl ester of melting point: 136C was obtained by
reacting 3-methylsulphonyl-4-(3'-nitrophenyl)-3-butenone-2
and ~-aminocrotonic acid 2-ethylthioethyl ester in ethanol.
Yield: 63% of theory.
10 ExamPle 19
'..
2 ~ COO-CH2-CH2-SC2H5
H3C N CH3
Analogously to Example 1, 1,4-dihydro-2.6-dimethyl-4-
phenyl-3-phenylsulphonyl-pyridine-5-carboxylic acid 2-ethylthio-
ethyl ester of melting poin~ 129C (ethanol) was obtained by
reacting 3-phenylsulphonyl-4-phenyl-3-buten-2-one and ~-amino-
crotonic acid 2-ethylthioethyl esterin ethanol.
Yield: 72% of theory.
39
D ~, Le A 18 128 - ~

Example 20 ~1~8~15
~, NO2
~ S2 ~ COO-CH2-CH2-Sc2Hs
Analogously to Example 1, 1.4-dihydro-2,6-dimethyl-4-
(3'-nitrophenyl)-3-phenylsulphonyl-pyridine-5-carboxylic acid
2-ethylthioethyl ester of melting point: 130C (ethanol) was
obtained by reacting 3-phenylsulphonyl-4-(3'-nitrophenyl)-3-
buten-2-one and ~-aminocrotonic acid 2-ethylthioethyl ester in
ethanol.
Yield: 70% of theory.
ExamPle 21
~ NO2
~J
H3COOC ~ COO-CH2-CH2-S-CH3
H3C ' N CH3
Analogously to Example 1. 1.4-dihydro-2.6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3.5-dicarboxylic acid methyl 2-methyl-
sulphonylethyl ester of melting point: 74C (ethanol) was
obtained by reacting 3'-nitrobenzylideneacetoacetic acid methyl
ester and ~-aminocrotonic acid 2-methylsulphonylethyl ester in
ethanol.
Yield: 68% of theory.
Bl Le A 18 128

ExamPle 22
~ NO2
H~C~ X 2
H(C 00(' ~ 3' COO-CH2-CH2-S-CH3
3 ~3C ' N ~ CH3
Analogously to Example 1. 1.4-dihydro-2,6-dimethyl-4-
(3'-nitrophenyl)-pyridine-3,5-dicarboxylic acid isopropyl 2-
methylsulphonylethyl ester of melting point: 153C (ethanol)
was obtained by reacting 3'-nitrobenzylideneacetoacetic acid iso-
propyl ester and ~-aminocrotonic acid 2-methylsulphonylethyl
ester in ethanol.
Yield: 62% of theory.
Le A 18 128 - ~ -
.
,: ,