1,4-DIHYDROPYRIDINE COMPOUNDS LINKED IN THE C-3 POSITION, THEIR PRODUCTION AND THEIR MEDICINAL USE

COMPOSES DE 1,4-DIHYDROPYRIDINE LIES EN POSITION 3, PROCEDE DE PRODUCTION ET USAGE EN MEDECINE

English Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to dimeri- 1,4-dihydropyridine compounds of
formula X
<IMG> I
Compounds of the invention include, for example, henanediyl 1,6-bis-[2,6-
dimethyl-5-methocycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-4-carboxylate]
and bexanediyl 1,6-bis-[2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)-1,4-
dihydropyridine-4-carboxylate]. The compounds display valuable circulation
influencing effects and can be used as antihypertensive agents, as vasodilators,
as cerebral therapeutic agents and as coronary therapeutic agents.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing 1,4-dihydropyridines which are linked in the
C-3 position, of the general formula
<IMG>
and pharmaceutically acceptable salts thereof, in which R and R' are identical
or different and each represents a phenyl or naphthyl radical or a heterocyclic
radical selected from thienyl, furyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl,
isoxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, quinolyl,
isoquinolyl, indolyl, benzimidazolyl, quinazolyl, or quinoxalyl radical, the
aryl or heterocyclic radical optionally carrying 1 or 2 identical or different
substituents selected from phenyl, alkyl with 1 to 8 carbon atoms, cycloalkyl
with 3 to 7 carbon atoms, alkenyl or alkinyl with in each case 2 to 6 carbon
atoms, alkoxy, alkenoxy or alkinoxy with in each case up to 4 carbon atoms, an
alkylene chain with 3 to 6 carbon atoms, dioxyalkylene with 1 or 2 carbon
atoms, halogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoro-
ethoxy, nitro, cyano, azido, hydroxyl, amino, mono- or di-alkylamino with in
each case 1 to 4 carbon atoms per alkyl group, carboxyl, carbalkoxy with 2 to
4 carbon atoms, carboxamido, sulphonamido and sulphonylalkyl or alkylmercapto
with in each case 1 to 4 carbon atoms per alkyl radical; R1 and R1' are identi-
cal or different and each represent a straight-chain, branched or cyclic,
saturated hydrocarbon radical which has up to 8 carbon atoms and is optionally
interrupted in the chain by 1 or 2 oxygen atoms and is optionally substituted
- 33 -

by fluorine, chlorine, hydroxyl, phenyl, phenoxy, phenylthio or phenylsulphonyl,
the phenyl radicals in turn optionally being substituted by 1 or 2 identical or
different substituents selected from nitro, trifluoromethyl, cyano, fluorine,
chlorine and alkyl and dialkylamino with in each case 1 to 4 carbon atoms in
the alkyl radicals; R2, R2' , R4 and R4' are identical or different and each
represent a hydrogen atom or a straight-chain, branched or cyclic, saturated
or unsaturated hydrocarbon radical which has up to 8 carbon atoms and is in
turn optionally substituted by fluorine, chlorine, hydroxyl, phenyl, amino,
alkylamino or cycloalkyl with up to 6 carbon atoms; R3 and R3' are identical
or different and each represent a hydrogen atom or a straight-chain or branched
alkyl radical which has up to 8 carbon atoms and optionally is interrupted in
the chain by an oxygen atom or is substituted by hydroxyl or halogen, or
represent optionally substituted phenyl, benzyl or phenethyl radical; Y and Y'
are in each case identical or different and each denote -COO-, -CONH-, -CO-,
-COS- or -SO2- and X represents a bridge member which has at least one CH2
group which is not bonded to the rings and at most 9 adjacent CH2 as chain
members, it being possible for the bridge member additionally to contain, in
any desired sequence, 1 to 4 identical or different chain members selected from
O, S, SO2, CO, CS, NR5 , C(R6)2 , CR6 =CR6 , C?C, CH=N, phenylene, naphthylene,
pyridylene and cycloalkylene or cycloalkenylene with in each case 3 to 7 carbon
atoms, piperazinylene, piperidinylene, pyrrolidinylene and morpholinylene,
wherein R5 represents a hydrogen atom, a benzyl radical or an alkyl radical
with 1 to 4 carbon atoms and R6 represents a hydrogen atom, a benzyl or phenyl
radical, a fluorine or chlorine atom, an alkyl radical with 1 to 4 carbon atoms,
a hydroxyl, trifluoromethyl, cyano, carboxyl or amino radical, an alkylamino
radical with 1 to 4 carbon atoms in the alkyl radical or a carbalkoxy radical
with 1 to 4 carbon atoms in the alkoxy radical, which process comprises:
(a) reacting a hydroxy-1,4-dihydropyridine derivative of the general
- 34 -

formula
<IMG> II
in which R, R1, R2, R3, R4, Y and X have the definitions given above, with an
equivalent amount of a dihydropyridine-3-carboxylic acid derivative of the
general formula
<IMG> III
in which R', R1', R2', R3', R4' and Y' have the definitions given above, but Y'
does not represent a carbonyl group, in an inert organic solvent in the
presence of water-binding agents at a temperature between 0°C and 180°C, water
being split off, or
b) reacting a 1,4-dihydropyridinecarboxylic acid of the general
formula
<IMG> IV
- 35 -

in which R, R1, R2, R3 and R4 have the definitions given above, is reacted with
a bifunctional compound of the general formula
Z-X-Z' V
in which X has the definition given above and Z and Z' are in each case identi-
cal or different and represent a hydroxyl, mercapto or NHR5 radical, wherein R5
has the definition given above, in a molar ratio of about 2:1 in the presence
of an inert organic solvent at a temperature between 0°C and 180°C, only a
compound of the general formula I in which Y and Y' do not represent a carbonyl
group being obtained by this variant, or
(c) reacting an ylidene-.beta.-keto ester of the general formula
<IMG> VI
R, R1 and R2 have the definitions given above, with an enaminocarboxylic acid
ester of the general formula
<IMG>
VII
in which R3, R3', R4 , R4' , Y and Y' have the same meanings as defined above, in
a molar ratio of about 2:1 in the presence of an inert organic solvent at a
temperature between 0°C and 180°C, and, if required, converting a compound of
formula I into a pharmaceutically acceptable salt thereof.
2. A process according to claim 1, in which R and R' are identical or
different and each represent a phenyl radical or a thienyl, furyl, naphthyl,
or pyridyl radical, the phenyl radical optionally being substituted by one or
two identical or different substituents selected from nitro, cyano, azido,
halogen, trifluoromethyl, hydroxyl, amino and alkyl, alkoxy, alkylamino and
alkylmercapto with in each case 1 or 2 carbon atoms in the alkyl groups; R1 and
R1' are identical or different and each represent a straight-chain or branched
- 36 -

hydrocarbon radical which has up to 6 carbon atoms and is optionally interrupted
in the chain by an oxygen and is optionally substituted by fluorine, chlorine,
hydroxyl, phenyl or phenoxy; R2, R2', R4 and R4' are identical or different and
each represent a hydrogen atom or a straight-chain or branched alkyl radical
which has up to 4 carbon atoms and is optionally substituted by fluorine,
chlorine, hydroxyl, phenyl or amino; R3 and R3' are identical or different and
each represents a hydrogen atom, an alkyl radical with 1 to 4 carbon atoms or a
phenyl, benzyl or phenethyl radical which is optionally substituted by hydroxyl,
fluorine or chlorine; Y and Y' are in each case identical or different and
denote -COO-, -CONH-, -CO- or -SO2- and X represents a bridge member which has
at least one CH2 group which is not bonded to the rings and at most 9 adjacent
CH2 groups as chain members, it being possible for the bridge member addition-
ally to contain, in any desired sequence, 1 to 3 identical or different chain
members selected from O, S, CO, CS, NR5 , C(R6)2, CH=N, phenylene, naphthylene,
pyridylene, cycloalkylene with 5 to 7 carbon atoms, piperazinylene, piperidinyl-
ene, pyrrolidinylene and morpholinylene, wherein R5 represents a hydrogen atom,
a benzyl radical or an alkyl radical with 1 to 4 carbon atoms, and R6 repre-
sents a hydrogen atom, a benzyl or phenyl radical, a fluorine or chlorine atom,
or an alkyl radical with 1 to 4 carbon atoms or a hydroxyl, trifluoromethyl,
cyano, carboxyl or amino radical.
3. A process according to claim 1 wherein R3 and R3' are hydrogen, R2,
R4, R2' and R4' are methyl, R and R' are selected from 3-nitrophenyl, 2-chloro-
phenyl, 2-nitrophenyl, 2-trifluororomethylphenyl, 2-cyanophenyl, 2-chloro-5-
nitrophenyl and .alpha.-naphthyl; R1 and R1' are selected from methyl, ethyl, iso-
propyl, methoxyethyl and acetyl; Y and Y' are selected from -COO- and -CONH-,
and X is selected from (CH2)n, wherein n is an integer from 3 to 8,
-(CH2CH2O)2-CH2CH2-, <IMG> , -(CH2CH2O)3-CH2CH2-(CH2)2-
- 37 -

<IMG>, -(CH2)2-S-(CH2)2-, <IMG>,
-(CH2)2-NHCONH(CH2)2- and -(CH2)2-S-S-(CH2)2-.
4. A process according to claim 3 wherein Y and Y' are both -COO- and R
and R' are the same and R1 and R1' are the same.
5. A process according to claim 1(b), in which the reaction is carried
out in the presence of a water-binding agent.
6. A process according to claim 1(c), in which the reaction is carried
out in an aprotic organic solvent or in an alcohol.
7. A process according to claim 1(a), 1(b) or 5, in which the reaction
is carried out in an aprotic organic solvent.
8. A process according to claim 1, 5 or 6, in which the reaction is
carried out at a temperature between 20° and 120°C.
9. A compound of formula I as defined in claim 1 or a pharmaceutically
acceptable salt thereof, when prepared by a process according to claim 1 or an
obvious chemical equivalent thereof.
10. A process according to claim 2 wherein R and R' are both 3-nitro-
phenyl, R1 and R1' are both methyl, R2, R4, R2' and R4' are all methyl, R3 and
R3' are both hydrogen, Y and Y' are both <IMG> and X is -(CH2)6-.
11. A process for preparing hexanediyl 1,6-bis-[2,6-dimethyl-5-methoxy-
carbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] which comprises
reacting 2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-
3-carboxylic acid with hexane-1,6-diol, in a molar ratio of about 2:1 and in
dimethylformamide.
- 38 -

12. The compound hexanediyl 1,6-bis-[2,6-dimethyl-5-methoxycarbonyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] when prepared by a process
according to claim 11 or an obvious chemical equivalent thereof.
13. A process according to claim 1 wherein R and R' are both 2-nitro-
phenyl, R1 and R1' are both methyl, R2, R4, R2' and R4' are all methyl, R3 and
R3' are both hydrogen, Y and Y' are both <IMG> and X is -(CH2)6-.
14. A process for preparing hexanediyl 1,6-bis-[2,6-dimethyl-5-methoxy-
carbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] which comprises
reacting hexanediyl 1,6-bis-(3-aminocrotonate) with 2-nitrobenzylideneaceto-
acetic acid methyl ester, in a molar ratio of about 1:2 in absolute ethanol
under nitrogen.
15. The compound hexanediyl 1,6-bis-[2,6-dimethyl-5-methoxycarbonyl-4-
(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] when prepared by a process
according to claim 14 or an obvious chemical equivalent thereof.
16. A process according to claim 1 wherein R and R' are both 3-nitro-
phenyl, R1 and R1' are both 2-methoxyethyl, R2, R4,R2' and R4' are all methyl,
R3 and R3' are both hydrogen, Y and Y' are both <IMG> and X is -(CH2)6-.
17. A process for preparing hexanediyl 1,6-bis-[2,6-dimethy]-5-(2-methoxy)-
ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] which com-
prises reacting hexanediyl 1,6-bis-(3-aminocrotonate) with 3-nitrobenzylidene-
acetoacetic acid 2-methoxy ethyl ester in a molar ratio of about 1:2 in absolute
alcohol under nitrogen.
18. The compound hexanediyl 1,6-bis-[2,6-dimethyl-5-(2-methoxy)-ethoxy-
carbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate] when prepared by
- 39 -

a process according to claim 17 or an obvious chemical equivalent thereof.
19. A process according to claim 1 wherein R and R' are both 2-chloro-
phenyl, R1 and R1' are both methyl, R2, R4, R2' and R4' are all methyl, R3 and
R3' are both hydrogen, Y and Y' are both <IMG> and X is -(CH2)8-.
20. A process for preparing octanediyl 1,8-bis-[2,6-dimethyl-5-methoxy-
carbonyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylate] which comprises
reacting hexanediyl 1,6-bis-(3-aminocrotonate) with 2-chlorobenzylideneaceto-
acetic acid methyl ester in a molar ratio of about 1:2 in absolute ethanol
under nitrogen.
21. The compound octanediyl 1,8-bis-[2,6-dimethyl-5-methoxycarbonyl-4-
(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylate] when prepared by a process
according to claim 20 or an obvious chemical equivalent thereof.
22. A process according to claim 1 wherein R and R' are both 3-trifluoro-
methylphenyl, R1 and R1' are both ethyl, R2, R4, R2' and R4' are all methyl, R3
and R3' are both hydrogen, Y and Y' are both <IMG> and X is -(CH2)2-S-(CH2)2-.
23. A process for preparing bis-(2-hydroxyethyl)-sulphide bis-[2,6-
dimethyl-5-ethoxycarbonyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3-
carboxylate] which comprises reacting bis-(2-hydroxyethyl)-sulphide bis-(3-
aminocrotonate) with 2-trifluoromethylbenzylideneacetoacetic acid ethyl ester
in a molar ratio of 2:1 in absolute ethanol under nitrogen.
- 40 -

24. The compound bis-(2-hydroxyethyl)-sulphide bis-[2,6-dimethyl-5-
ethoxycarbonyl-4-(2-trifluoromethylphenyl)-1,4-dihydropyridine-3-carboxylate]
when prepared by a process according to claim 23 or an obvious chemical
equivalent thereof.
- 41 -

Description

1179~34~
The present invention relates to certain new dimeric 1,4-dihydro-
pyridine compounds which are linked to one another in the 3-position, to se~eral
processes for their preparation and to their use in medicaments having an
influence on the circulation.
It is already known that certain 1,4-dihydropyridine derivatives have
interesting pharmacological properties ~see F. Bossert et al., Naturwissen-
schaften 58, 578 (1971) and DT-OS (German Published Speci~ication? 2,117,571).
Accordin~ to the present inventiOn we provide compounds whlch are
1,4-dihydropyri.dines linked in the C-3 position, of the general formula
R R'
~ R OOC ¦ Y-X-Y' ¦ COOR
: ~ 10
R N R R4 N R2
;~ ~ R3~ R3'
or a salt thereof, in which R and R' are identical or different and each
; represent a phenyl~or naphthyl radical or a he-terocyclic radical selected from
thienyl, furyl, pyrryl,~pyrazolyl, lmidazolyl, oxazolyl, isoxazolyl, thlazolyl,
pyridyl, pyridazinyl, pyri-midyl, pyrazinyl, quinolyl, isoquinolyl, indolylj
: : :
benzimidazolyl, quinazoly~l, or quinoxalyl radical, the aryl or heterocyclic:
radical optionally carrying 1 or 2 identical or different subst1tuents selected
:Erom phenyl, alkyl w1th 1 to 8 carbon atoms, cycloalkyl With 3 to 7 càrbon
atoms, alkenyl or alkinyl with in each case 2 to 6 carbon atoms, alkoxy,
alkenoxy or alkinoxy with in each case up to ~ carbon atoms, an alkylene chain
with 3 to 6 carbon atoms, dioxyalkylene wlth 1 or 2 carbon atoms, halogen,
triEluoromethyl, tri~luoromethoxy, difluoromethoxy, tetrafluoroethoxy, nitro,
cyano, azido, hydroxyl, amino, mono- or di-alkylamino with in each case 1 to 4
carbon atoms per alkyl group, carboxyl, carbalkoxy with 2 to 4 carbon atoms,
,
~; -' . . '' :'
' ' ' ' ' ' ,~' `
' ~

~1'7~3~2
carboxamido, sulphonamido and sulphonylalkyl or alkylmercapto with in each case
1 to 4 carbon atoms per alkyl radical; R and R are identical or different and
each represent a straight-chain, branched or cyclic, saturated or unsaturated
hydrocarbon radical which has up to 8 carbon atoms and is optionally interrupted
in the chain by 1 or 2 oxygen atoms and is optionally substituted by fluorine,
chlorine, hydroxyl, phenyl, phenoxy, phenylthio or phenylsulphonyl, the phenyl
radicals in turn optionally being substituted by 1 or 2 identical or different
substituents selected from nitro, trifluoromethyl, cyano, fluorine, chlorine and
alkyl and dialkylamino with in each case 1 to 4 carbon atoms in the alkyl radi-
cals; R , R , R and R are identical or different and each represent a hydro-
gen atom or a straight-chain, branched or cyclic, saturated or unsaturated
hydrocarbon radical which has up to 8 carbon atoms and is in turn optionally
substituted by fluorine, chlorine, hydroxyl, phenyl, amino, alkylamino or~cyclo-
. ~: alkyl with up to 6 carbon~atoms; R and R are identical or different and each
represent a hydrogen atom~or a straight-chain or branched alkyl radlcal which
has up to 8 carbon atoms~and optionally is interrupted in the chain by an oxygen
atom or is substituted by;hydroxyl or halogen, or represent optionally subst1-
tuted phenyl, benzyl or pbenethyl radical; Y and Y' are in each case identical
? ~ :: or different and each denote -C00-, -CONH-, -C0-, -COS- or -52- and X repre-
~ 20 sents a bridge member whlch has at least one CH2 group which 15 not bonded to
;~ ~ the rings and at most~9 adjacent CH2 as chain members, it being possible for
the bridge member additlonally to contaln, in any desired sequence,:l to
iden-tical or different chain~members selected fro~ 0, S, S02, C0, CS, NR ,
C(R )2~ CR =CR , C C, CFl=N, phenylene, naphthylene, pyridylene and cycloalkylene
or cycloalkenylene with in each case 3 to 7 carbon atoms, piperazinylene,
j~ S
piperidinylene, pyrrolidinylene and morpholinylene, wherein R represents a
hydrogen atom, a benzyl radlaal or an alkyl radical with 1 to 4 carbon atoms and
` R represents a hydrogen atom, a benæyl or phenyl radical, a fluorine or
- 2 -
':'
:,
: :~

3~;~
chlorine atom, an alkyl radical with 1 to 4 carbon atoms, a hydroxyl, trifluoro-
methyl, cyano, carboxyl or amino radical, an alkylamino radical with 1 to 4
carbon atoms in the alkyl radical or a carbalkoxy radical with 1 to 4 carbon
atoms in the alkoxy radical, which process comprises:
(a) reacting a hydroxy-1,4-dihydropyridine derivative of the general
formula
R
R OOC ~ Y- X- OH
~I~ I I
2 / N R4
in which R, R , R , R , R, Y and x have the definitions given above, with an
equivalent amount of a dihydropyridine-3-carboxylic acid derivative of the
general formula
R'
HY' COOR
R T R
R3
in which R', R , R , R , R and Y' have the definitions given above, but Y'
docs not represent a carbonyl group, in an inert organic solvent in the presence
o.E water-bindirlg agents at a temperature between 0 C and :L~30 C, water being
split oEE, or
(b) reac-tiny a 1,4-dihydropyridirlecarboxylic acid of the general
:Eormula
~ ~ .
-- 3 --

3~
R OOC ~ COOH
~ IV
R2 ~ N ~ R4
R3
in which R, Rl, R , R3 and R4 have the definitions given above, is reacted with
a bifunctional compound of the gen~ral formula
z--X--~ ' V
in which X has the definition given above and z and z' are in each case identi-
cal or different and represent a hydroxyl, mercapto or NHR radical, wherein R
has the definition given above, in a molar ratio of about. 2:1 in the presence of
an inert organic solvent at a temperature between 0 C and 180 C, only a compound
of the general for.~ula I in which Y and Y' do no-t represent a carbonyl group
being obtained by this variant, or
(c) reacting an ylidene-~-keto ester of the genexal formula
coR2
R-CH=C / VI
\ COOR
R, R and R have the definitions given above, with an enaminocarboxylic acid
ester of the general Eormula
R4-C=CH-Y-C-Y'-CH=C,-R
R3~ 3' VII
in which R , R , R , R , Y and Y' have the same mean:ings as def:ined above, in
a molar ratio of abou-t 2:1 in the presence o:E an inert organlc so:Lvent at a
temperature between 0 C and 180 C, and, i.f xequiredl converting a compound oE
formula I into a pharmaceutically acceptable salt thereof.
According to -the present invention we further provide a process for
` - 3a -

3~2
the production of a compound of the invention, in which
(a) a hydroxy-1,4-dihydropyridine derivative of the general formula
R
R OOC ~ Y-X-OH
R2 ~ N ~ R4
- 3b -

3~
-- 4 --
in which
R, Rl~ R2, R3, R4, Y and X have the above-
n~entioned meanings,
is reacted with an equlvalent amount of dihydropyridine-
3-carboxylic ~cid derivative of the gereral formula
: R'
HY ~ COOR1 (III) :
~ 2
: R4' ~ N' R
in which
p", Rl , R , R3 , R4 and Y' have the above~
. mentioned meanings~ but Y' does not~represent : :
a carbonyl group,
in an inert organic solvent in::the presence of a water-
binding agent at a~temperature between 0C and 180C,:~
water bein~ split of;f, or
b) a 1,4-dihydropyridinecarboxylic ac~ld of the general
formula ~ ~ R
`~Y~G ~` R OOC 1 COOH
S ~ R2 ~ R4 ~ ~ ~
in which
R, Rl~, R2, R3 and R4 have the abovementioned
: meaning,~
2~ is reacted with ~a bifunctional compound of the ~eneraI
ormula
:Z-X-Z' : : (V),~
: in which
~`~ X has the~:abovementioned meaning and
Z and Z~ are ~in each ca~e identical or different
and represent hydroxyl, mercapto or a NHR5 radical
wherein
R5 has the abovementioned meaning, :
in a molar rati~o :of~abo.ut 2~l in the presence of an inert
: ~e A 20 6~8
. ~ . :
::
:
; '
;~
:

.~'f ~2
organic solvent and, if appropriate, in the presence of
a water-binding agent, at a temperature between 0C
and 180C, only compounds of the ~eneral formula (I) ir.
which Y and Y' do not represent a carbonyl group being
obtained by this variant, or
c) an ylidene-~-keto ester of the general formula
cox2
R-C~=C (VI)
COOR
in which
R, Rl and R2 have the abovementioned meanings 3
is reacted with an en~ninocarboxylic acid ester of the
general formula
R4-C=CH-Y-X-Y'-CH=C-R (VII)
R3NH HNR3
in which
R3, R3 , R4, R4 , Y and y1 have the abovementioned
meanings,
in a molar ratio of about 2:1 in the presence of an inert
organic solvent at a temperature between 0C and 180C.
Preferably symmetric compounds, that is to say
compounds in which in each case Y and Y', R3 and R~ and
R4 and R4 are identical, are prepared by this process
variant c). Syr~metric compounds of the general formula
(I) in which Y denotes a carbonyl group can also be
prepared by this process variant c).
The ~ihydropyridines of the general forrnula (I)
according to the invention have valuable pharmacological
properties. By virtue Or their circulation
in~luencing action, they can be used as antihypertensive
agents, as vasodilators, as cerebral therapeutic agents and
as coronary therapeutic agents. Surprisingly, they
3 exhibit particularly long-lasting actions and are thus to
Le A 20 638

~l7~
be regarded as an enrichment of pharmacy.
Compounds of the general formula I according to the invention which
are of particular interest are those in which R and R' are identical or differ-
ent and each represent a phenyl radical or a thienyl, furyl, naphthyl, or
pyridyl radical, the phenyl radical optionally being substituted by one or two
identical or different substituents selected from nitro, cyano, azido, halogen,
trifluoromethyl, hydroxyl, amino and alkyl, alkoxy, alkylamino and alkyl-
mercapto with in each case 1 or 2 carbon atoms in the alkyl groups; R and R
are identical or different and each represent a straight-cnain or branched
hydrocarbon radical which has up to 6 carbon atoms and is optionally interrupted
in the chain by an oxygen and is optionally substi-tuted by fluorine, chlorine,
hydroxyl, phenyl or phenoxy; R , R , R and R are identical or different and
each represent a hydrogen atom or a straight-chain, or branched alkyl radical
which has up to 4 carbon atoms and is optionally sub.sti-tuted by fluorine,
: chlorine, hydroxyl, phenyl or amino; R and R are identical or different and
each represents a hydrogen a-tom, an alkyl radical with 1 to 4 carbon atoms or a
phenyl, benzyl or phenethyl radical which is optionally substi-tuted by hydroxyl,
fluorine or chlorine,
~ - 6 -

'~ 1
Y and Y' are in each case identical or different
and denote -COO-, -CONH-, -CO- or -S02-, and
X represents a bridge member which has at least
one CH group whic~l is not bonded to the rings
and at most 9 adjacent CH2 groups as chain rr.embers,
it being possible for the bridge member additionally
to contain, in any desired sequence, 1 to 3 ident-
ical or different chain members selected from
0, S, CO, CS, NR5, C(R6)2,
C~ , phenylene, naphthylene, pyridylene,
cycloalkylene with 5 to 7 carbon atoms, piper-
azinylene, piperidir.ylene, pyrrolidinylene and
morpholinylene~
wherein
R5 represents a hydrogen atom a benzyl radical or
an alkyl radical with 1 to 4 carbon atoms, and
R6 represents a hydrogen atom, a benzyl or phenyl
radical, a fluorine or chlorine atom, an alkyl
radical with 1 to 4 carbon atoms or a hydroxyl,
trifluoromethyl, cyano~ carboxyl or amino radical.
Using the particular starting substances shown,
the synthesis of the compounds of the general formula (I)
according to the invention by the individual process
variants is illustrated by the following equations:
Process variant (a)
~ CF3 ~ N02
CH300C ~ COO-(CH2-CH2 0)3-H HOOC ~
C~3 ~ N ~ CH3 ~ -H20 C~3 a ca3
Le A 20 63~

g
~CF3 $~02
CH300C ~[ COO- (CH2-CH2-0) 3-OC ~ COOC2H5
3 H CH3 3~CH3
Process variant (b )
~ 2
2x ~J
H5C200C~ COOH ~HO (CH2) 8 OH
3 H CH3 ~-2H20
~,N02 ~ N02
5 2 ~ COO (CH2) 3-oCf~x 2
Process variant (c )
_ .
,~ N02
2 x ~5 0 CEI2 CH2 <}<~ CH2-CH2-0-C
H5C200C ~ H ~CH3 ~1
CH ~02 I Ethanol ~ H3C H2
3 ~ H20
Le A 20 6 38

~7~
. ,~. . j ,~
2 ~ N02
C2ooC ~ 2 2 ~ 22 ~ COOC2H5
CH3 ~ N CH3 C~3 H 3
The hydroxy-1,4-dihydropyridine derivatives of
the formula (II) used as starting substances and the
dihydropyridine-3-carboxylic acid derivatives of the
formula tIII) are known, or they can be prepared by known
methods (see DT-OS (German Published Specification)
2,117,571).
The 1,4-dihydropyridinecarboxylic acids of the
general formula (IV) are known, or they can be prepared
by known methods (compare European Published Speci
fication) 11,706).
The bifunctional compounds of the general formula
(V) are likewise known, or they can be prepared by known
methods (see Beilstein, Volume I, 464 to 502).
The ylidene-~-keto esters of the general formula
- (VI) are known, or they can be prepared by processes
which are known from the literature (see G. Jones, The
'IKnoevenagel-Condensation", in Organic Reactions, Volume
XV, 204 et seq. (1967)).
The enaminocarboxylic acid esters of the general
formula t~II) used as starting substances are known, or
they can likewise be prepared by methods which are known
~rom the literature (see A.C. Cope, J. Am. Chem. Soc.
67, 1017 ~1945)).
Possible diluents ~or use in process variants (a)
and (b) are any of the aprotic organic solvents. These
include, preferably, ethers (such as dioxane, diethyl ether,
.
Le A 20 638

3~
~o
tetrahydrofuran and glycol dimethyl ether), hydrocarbons
(such as benzene, toluene or xylene) and dimethylformamide,
dimeti~ylsulphoxide, acetonitrile, pyridine or hexarnethyl-
phosphoric acid triamide.
In the case of process variant (c)~ alcohols (for
example met~lanol, ethanol or isopropanol) can also
advantageously be employed as diluents.
~ater-binding agents (for process variants (a) and
(b))which can be used are any of the reagents customary for
this, and the use of dicyclohexylcarbodiimide and the
addition of a catalyst, such as 4-dimethylaminopyridine,
are particularly advantageous.
The reaction temperature can be varied within the
substantial range of between O and 180C, preferably between
20 and 120C.
The reactions can be carried out under normal
pressure or under increased pressure. In general, they
are carried out under normal pressure.
The compounds of the present invention exhibit
interesting biological actions. They have a broad and
diverse pharmacological action spectrum and are
distinguished, in particular, by their long-lasting action.
The following main actions may be mentioned specifically:
1. On parenteral~ oral and perlingual administration,
the compounds produce a distinct and long-lasting dilation
of the coronary vessels. This action on the coronary
vessels is intensi~ied by a simultaneous nitrite-like
effect of reducing the load on the heart.
They influence or modify the heart metabolism in
3 the sense of an energy saving.
2. The excitability of the stimulus formation and
excitation conduction system within the heart is lowered,
so that an antifibrillation action demonstrable at
therapeutic doses results.
3. The tone of the smooth muscle of the vessels is
. .
Le A 20 638
.

greatly reduced under the action of the compounds. This
vaseular-spasmolytic action can take place in the entire
vascular system or can manifest itself as more or less
isolated in circumseribed vaseular regions (sueh as, for
example, the eentral nervous system).
4. The eompounds lower the blood pressure of
normotonie and hypertonic animals and can thus be used as
antihypertensive agents.
5. The eompounds have strongly muscular-spasmolytic
actions which manifest themselves on the smooth muscle of
the stomaeh, the intestinal tract, the urogenital tract and
the respiratory system.
As stated above, the invention also relates
to the use in human and veterinary medicine of the com-
pounds of the invention.
The present invention provides a pharmaceutîcal
composition containing as active ingredient a eompound
of 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 aetive agent.
The invention further provides a pharmaceutical
composition containing as active ingredient a eompound
of the invention in the form of a sterile and/or physio-
logically isotonie aqueous solution.
The invention also provides a medieament in
dosage unit form eomprising a eompound of the invention.
The invention also provides a medicament in
3 the form of tablets (including lozenges and granules),
dragees, capsules, pills, ampoules or suppositories
comprising a compound of the invention.
"Medieament" as used in this Specifieation means
physieally dlserete eoherent portions suitable for medieal
administration. "Medieament in dosage unit form'' as
Le A 20 638

~.~3.t7't3~
used in this Specification means physically discrete
coherent units suitable for ~edical administration each
containing a daily dose or a multiple (up to four times)
or submultiple (down to a fortieth) o~ a daily dose
of the compound of the invention in association with
a carrier and/or enclosed within an envelope. Whether
the medicarnent contains a daily dose or, for example,
a half, a third or a quarter of a daily dose will depend
on ~hether the medicament is to be administered once
o~, for example, twice, three times or ~our times a
day respectively.
The pharmaceutical composition according to
the invention may, for example, take the form o~ sprays
(including aerosols), suspensions, solutions and emulsions
of the active ingredient in aqueous or non-aqueous diluents,
syrups, granulates or powders.
The diluents to be used in pharmaceutical com-
positions (e.g. granulates) adapted to be formed into
tablets, dragees, capsules and pills include the ~ollowing:
(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 accelerators, e.g. quaternary ammonium
compounds; ~g) sur~ace active agents, e.g. cetyl alcohol,
glycerol rnonostearate; (h) adsorptive carriers, e.g.
~aolin and bentonite; (i) lubricants, e.g. talc, calcium
and magnes.ium stearate and solid polyethyl glycols.
The tablets, dragees, capsules and pills formed
from the pharmaceutical compositions of the invention
can have the customary coatin~s, envelopes and protective
matrices, which may contain opacifiers. They can be
.. . . ..
Le A 20 638

so constituted that they release the active in~redient
only or preferably in a particular part of the intestinal
tract, possibly over a period of time. ~he coatings,
envelopes and protective matrices may be made, for example,
of polymeric substances or waxes.
The ingredient can also be made up in micro-
encapsulated form together with one or several of the
above-mentioned diluents.
The diluents to be used in pharmaceutical com-
positions adapted to be ~ormed into supp~sitories can,for example, be the usual water-soluble diluents, such
as polyethylene glycols and fats (e.g. cocoa oil and
high esters (e.g. ClL~-alcohol with C16-fatty acid))
or mixtures of these diluents.
The pharmaceutical compositions which are powders
and sprays can, for example, contain the usual diluents9
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. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions
and emulsions can, for example, contain the customary
diluents (~lith, of course, the above-mentioned exclusion
of solvents having a molecular weight below 200 except
in the presence of a surface-active 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
Le A 20 638

~:~ 7~
~ '
glycol, dimethylformamide, oils (for example ground
nut oil), glycerol~ tetrahydrofurfuryl alcohol, poly-
ethylene glycols and fatty acid esters of sorbitol or
mixtures thereof.
For parenteral administration, solutions and
emulsions should be sterile, and, if appropriate, blood~
isotonic.
The pha~maceutical compositions which are sus-
pensions can contain the usual diluents, such as liquid
diluents, e.g. water, ethyl alcohol, propylene glycol,
surface-active a~ents (e.g. ethoxylated isostearyl
alcohols, polyoxyethylene sorbite and sorbitane esters),
microcrystalline cellulose, aluminium metahydroxide,
bentonite, agar-agar and tragacanth or mixtures thereof.
All the pharmaceutical compositions according to
the invention can also contain colouring agents and
preservatives 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 0.5 to 90% 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
invention may be any of those mentioned above in relation
to the pharmaceutical compositions of the present lnvention.
Such medicaments may include solvents of molecular weight
les~ 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
Le_A 20 638

7~a3'~
medical adnlinistration and may be, for e~ample~ any
of the following: tablets (including lozenges and
granulates), pills, dragees, capsules, suppositories
and arnpoules. Some of these forns may be made up for
delayed release of the active ingredient. Some~ such
as capsules, include a protective envelope which renders
the portions of the medica~ent physically discrete
and coherent.
The preferred daily dose ~`or intravenous
]o administration of the medicaments Or the invention is
2~5 mg to 250 mg of active ingredient, and ~or oral
administration o~ medicaments of the invention is 25 to
250 mg of active ingredient.
The production of the above-mentioned pharma-
ceutical compositions and medicaments is carried outby any method known in the art, for example, by mixing
the active ingredient(s) with the diluent(s) to form
a pharmaceutical composition (e.g. a granulate) and
then forming the composition into the medicament (e.g.
tablets).
This invention further provides a method of
combating (including prevention, relief and cure o~)
the above-mentioned 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 ~orm of a medicament according to
the invention.
It is envisaged that these active compounds
will be administered perorally, parenterally (for example
3o intramuscularly~ intraperitoneally, subcutaneously and
intravenously), or rectally, pre~erably orally or
parenterally, in particular perlin~ually or intravenously.
Preferred pharmaceutical compositions and medicaments
are there~ore those adapted for administration such
as oral or parenkeral administration. Adn.inistration
Le A 20 63~_
p ~_

~'7~3
J~
in the method of the invention is preferably oral or
parenteral administration.
In general it has proved advantageous to administer
intravenously amounts of from 0.01 mg to 10 mg/kg, prefer-
ably 0.05 mg to 5 mg~kg, of body weight per day or toadminister orally from 0.05 mg to 20 mg/kg, preferably
0.5 mg to 5 mg/kg, of body weight per day, to achieve
effective results. Nevertheless, it can at times
be necessary to deviate from those dosage rates, and
1~ in particular to do so as a function of the nature and
body weight of the human or animal subiect to be treated,
the individual reaction of this subject to the treatment,
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
administrations over the course of the day.
Processes for the production of compounds according
to the present invention are illustrated by the following
ExampleS~
Example 1
Butanediyl l-C2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitro-
phenyl)-1,4-dihydropyridine-3-carboxylate ~ 4- L2,6-dimethYl-
5-methoxycarbonyl-4-(2-chlorophenyl)-1,4-dihydropyridine-
3-carboxylate~
Le A 20 638
.

~ NO2 ~ Cl
H5C2OOC ~ COO-(CH2)4-OOc ~ COOCH3
3 H CH3 3 ~ CH3
(Process variant ta))
25 mmoles of 2,6-dimethyl-5-(4-hydroxybutoxy)-carbonyl-4-(3-nitro-
phenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester were dissolved in 50
ml of anhydrous dimethylformamide together with 25 mmoles of dicyclohexylcarbo-
diimide and 25 mmoles of 2,6-dimethyl-5-methoxycarbonyl-4-(2-chlorophenyl)-1,4-
dihydropyridine-3-carboxylic acid and the solution was heated -to 100 C ~or 4
hours, with the addition of 0.2 g of 4-dimethylaminopyridine. The mixture was
then filtered and the filtrate was diluted with methylene chloride, extracted
by shaking with aqueous NaOH and with HCl~ dried~ and concentrated in a rotary
evaporator.
The residue was then chromatographed on silica gel using ether.
Yield: 25~, amorphous foam.
H-NMR: ~ = 1.2 (t,3H), 1.4-1.8 (m, 4H), 2.4 (s,12H), 3.6 (S,3H), 3.~-4~4 (m,6H),
5.2 (s,lH), 5.4 (s,lH), 5.8 (s,NH), 6.3 (s,NH) and 6.9-8.3 (m,8H).
Example 2
Hexancdiyl 1,6~bis-[2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylate~

~2 ~2~o2
OEl 300C ~ COO- ( CH 2 ) 6-OOC `,b~ COOCH 3
C~l N CH 3 3 H CH 3
(Process variant

g
50 mmoles of 2,6-dimethyl-5-methoxycarbonyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid
were dissolved in 50 ml of anhydrous dimethylformamide
together with 50 mmoles of dicyclohexylcarbodiimide and
25 mmoles of hexane-1,6-diol and the solution was stirred
at 100C for 4 hours, with the addition of 0.2 g of
4-dimethylaminopyridine. The mixture was then filtered,
the filtrate was diluted with methylene chloride,
extracted by shaking with aqueous NaOH and with HCl, dried,
and concentrated in a rotary evaporator, and the residue
was recrystallised from methanol.
Melting point: 177-179C, yield: 37%.
xample 3
Propanediyl 1,3-bis-L2,6-dimethyl-5-methoxycarbonyl-4-
(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylate]
C~ ~Cl
CH300C ~ (CH2)3 OOC ~ CoocH3
3 H CH3 3 H CH3
~rocess variant (c))
25 mmoles of propanediyl 1,3-bis-(3-aminocrotonate)
and 50 mmoles of 2-chlorobenzylideneacetoacetic acid
methyl ester in 100 ml of absolute ethanol were boiled
under reflux and under N2 for 14 hours.
After the mixture had cooled, the solvent was
distilled off in vacuo and the residue was taken up in
50% strength aqueous ethanol. The semi-solid residue
was re~rystallised from methanol.
Melting point: 200 to 203C; yield: 50%.
Example 4
~OX4C~ rhon~
Triethylene glycol bis-L2,6-dimethyl-5-~e~h~ c~
4-(3-nitrophenyl)~1,4-dihydropyridine-3-carboxylate~
Le A 20 638
....

3~
` - t
~ ~ I
[~N~2 ~, N02
H5C200C ~ COO-(cH2-CH2-o)3~oc ~ COOC2~5
3 H 3 3 H CH3
Analogously to Example 2, 100 mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-194-dihydro-
pyridine-3-carboxylic acid were reacted with 50 mmoles o~
triethylene glycol and the mixture was worked up.
Melting point: 113 to 120C; yield: 32%.
Example 5
Decanediyl 1,10-bis-l2,6-dimethyl-5-ethoxycarbonyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate~
~,NO 2 ~,NO 2
H5C2C ~ COO-(CH2)10 _ OOC ~ COOC2H5
3 H CH3 CH3 H
100 mmoles of 2,6-dimethyl-5~ethoxycarbonyl-4-
(3-nitrophenyl )-13 4-dihydropyridine-3-carboxylic acid were
reacted with 50 mmoles of l,10-decanediol analogously
to Example 2.
Melting point: 121 to 125C; yield: 35%.
Exam ~
Octanediyl 1,8-bis- [2,6-dimethyl-5-ethoxycarbonyl-4-(3-
nitrophenyl-1,4-dihydropyridirle-3-carboxylate~
Le A 20 638
_ _
~ /q~

z
~o
~, N02 ~, N02
H5c2ooc~ COO- (CH2 ) 8 -C2C ~ COOC2H5
3 H 3 3 H CH3
Analogously to Example 2, 100 mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylic acid were reacted with 50 mmoles of
1,8-octanediol.
Melting point: 170 to 184C; yield: 47%.
Example_7
Pentanediyl 1~5-bis-~2,6-dimethyl-5-ethoxycarbonyl.-4-
(3-nitrophenyl-1,4-dihydropyridine-3-carboxylate~
~_ N02 ~N02
5C20OC ~ ( 2)5 02C ~ COOC2H5
CH3 H CH3 CH3 H CH3
Analogously to Example 2, 100 mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylic acid were reacted with 50 mmoles of
1,5-pentanediol.
Melting point: 145C; yield: 11%.
Exa ~ 8
1~,4-bis-(2-hydroxyethoxy)-benzene bis-[2,6-dimethyl-5-
ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-
carboxylate]
Le A 20 638

~:l7~3~2
-, I
~1
~ 2 ~ NO2
H5c2ooc ~ C00-(CH2)2-o ~ -O-(C~2)2-ooC ~ COX2H5
H3 H 3 CH3 H CH3
Analogously to Example 2, 100 mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylic acid were reacted with 50 m~oles of
1,4-bis-(2-hydroxyethoxy)-benzene.
Melting point: 160 to 190C (decomposition); yield: 49%.
Exam~le 9
Tetraethylene glycol bis-r2,6-dimethyl-5-ethoxycarbonyl-
4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylat~
~ NO2 ~ 2
5 2 ~ Coo-(cH2-cH2-o)4-oc ~ C03C2H5
Analogously to Example 2, 100 mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylic acid were reacted with 50 mmoles o~
tetraethylene glycol and the mixture was worked up.
Melting point: 93 to 98C yield: 16%.
Example 10
Hexanediyl 1,6-bls-L2,6-dimethyl-5-isopropoxycarbonyl-4-
(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate]
Le A 20 638
-

3~
..,.,.,
i, i
N0
/ ~ 2)6 OOC 00-CH
Analogously to Example 3, ?5 mmoles of hexanediyl
1,6-bis-(3-aminocrotonate) were reacted with 50 mmoles of
3-nitrobenzylldeneacetoacetic acid diisopropyl ester.
Melting point: 120 to 136C yield; 83%.
Example 11
Hexanediyl 1,6-bis-[?,6-dimethyl-5-methoxycarbonyl-4-
(2-nitrophenyl)-1,4-dihydropyridine-3-carboxylate~
~ 2 ~ N02
CH30OC ~ C-~CH2)6-C ~ COOCH3
Analogously to Example 3, 25 mmoles of hexanediyl
1,6-bis-(3-aminocrotonate) were reacted with 50 mmoles of
2-nitrobenzylideneacetoacetic acid methyl ester.
Melting point: 88 to 95C yield: 82%.
Example 12
15 Hexanediyl bis-[2,6-dimethyl-5-methoxycarbonyl-4-(2
chlorophenyl)-1,4-dihydropyridine-3-carboxylate~
~ C1 ~ C1
CH300C~,~CcOO- (CH2 ) 6-0Oc~OOCH3
CH3 H H3 C ~ H H3
Le A 20 638

~li 7~39~2
. 3 ~23
Analogously to Example 3, 25 mmoles of hexanediyl
bis-(3-aminocrotonate) were reacted with 50 mmoles of
2-c~lorobenzylideneacetoacetic acid methyl ester.
~ielting point: 152 to 158C. yield: 27%.
Example 13
N,N'-bis-(2-hydroxyethyl)-piperaxine bis-L2,6-dimethyl-
5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-
3-carbGxylate~
~,N02 ~N02
5C200C~COO'cH2-cH2-lcN-CH2-CH -OOC ~3C:2dS
~; 10 Analogously to Example 2, lOG mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dillydro-
pyridine-3-carboxylic acid were reacted with 50 mmoles o~
N,N'-bis-(2-hydroxyethyl)-piperazine.
Melting point: 203 to 208C yield: 18%.
Example 14
..
Bis-hydroxyethyl sulphide bis-r2,6-dimethyl-5-ethoxycar-
bonyl-~ ni~p~ yll-1,4-dihydropyridine 3-ca.~xylate]
SC200C ,1~ Coo-cH2_cH2_S_cH2_cH2_0oc~OOC2H5
CH3 ~ CH3 C~N H3
Analogous~y to Example 2, 100 mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(2-nitrophenyl)-1,4-dlhydro-
pyridine-3-carboxylic acid were reacted with 50 mmoles o~
bis-hydroxyethyl sulphide.
Yield: 70%.
Le A 20 638
,..

3l~'7~
Example 15
Hexanediyl 1,6-bis-~2,6-dimethyl-5-ethoxycarbonyl-4-(3-
nitropherlyl)-1,4-dihydropyridine-3-carboxylate~
~ CF3 ~ c~3
H5CzOOC ~ oO ~CH2)6 OOC ~ 03C2H,
Analogously to Example 3, 25 mmoles of hexanediyl
1,6-bis-(3-aminocrotonate) were reacted with 50 mmoles of
2-trifluoromethylbenzylideneacetoacetic acid ethyl ester.
Melting point: 129 to 139C yield 49%.
hxample 16
Hexanediyl 1,6-bis-~2,6-dimethyl-5-(2-methoxy)-ethoxy-
carbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxy-
late~
~ N02 [~N2
30-CH2 CH200C ~ ~CH2)6~x~ ~ ~X~2-CH2~}{~3
C~ 3 C~H3 N C~3
H H
Analogously to Example 3, 25 mmoles of hexanediyl
1,6-bis-(3-aminocrotonatej were reacted with 50 mmoles of
3-nitrobenzylideneacetoacetic acid 2-methoxy ethyl ester.
Melting point: 144 to 156C yield: 50~.
Exarnple 17
Hexanediyl 1,6-bis-~2,6-dimethyl-5 methylcarbonyl-4-
(2-chloro-5-nitrophenyl)-1,4-dihydropyridine-3-carboxy-
late~
Le A 20 638
. _

~7~
~5
~.
C ~ 2
3 C~02 (C 2) 6 ~COCH3
H 3 H
Analogously to ~xample ~, 25 mmoles of hexanediyl
1,6-bis-(3-aminocrotonate) were reacted with 50 mmoles of
2-chloro-5-nitro-benzylidene-2,4-butanedione.
Melting point: 147 to 153C yield: 46%.
Example 18
E-1,4-Bis(hydroxymethyl)cyclohexane bis-L2,6-dimethyl-5-
ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-
carboxylate~ O
~ 2 ~ 2
H5C200~C ~ COO-CH2~ C } ~ CH2-OOC ~ COOC2H5
H CH3 trans CH3 N H3
Anal.ogously to Example 2, 50 mmoles o~ 2,6-dimethyl-
5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-
carboxylic acid were reacted ~lith 25 mmoles of E-1,4-bis-
~ydroxymethyl)-cyclohexane.
Melting point: 172 to 188C yield: 15~.
Example 19
1,4-Bls-(hydroxymethyl)-benzene bis-~2,6-dimethyl-5-
ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-
3-carboxylate~
Le A 20 6~8
_ .

"` ~17
'~1
~ 2 ~ 2
H5C200C ~ oo-CH2 ~ CH2-oo-c ~ o3c2H5
3 H 3 H
Analogously to Example 2, 50 mmoles of 2,6-
dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylic acid were reacted with 25 mmoles of
1,4-bis-(hydroxymethyl)-benzene.
Melting point: 244 to 59C yield: 30~.
~xample 20
. .
Hexanediyl 1,6-bis-j2,6-dimethyl-5-ethoxycarbonyl-4-
(2-cyanophenyl)-1,4-dihydropyridine-3-carboxylate~
1 0 ~CN
H5C200C ~ 00-~CH2)6-OOCC ~ OOC2HS
Analogously to ~xample 3, 25 mmoles of hexanediyl
1,6-bis-[3-aminocrotonate) were reacted with 50 mmoles of
2-cyanobenzylideneacetoacetic acid ethyl ester.
Yield: 80%.
Example 21
Bis-~2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-
dihydropyridine-3-carboxylic acidJ 1,6-~exanediylamide
Le A ? 6 3 8
~ q ~

N02 [~' N02
~{3 ~ Co-NH-(cH2)6-NH-oc ~ 3
Analogously to Example 2, 25 mmoles of 2,6-dimethyl-
5-ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-
3-carboxylic acid were reacted with 12.5 mmoles of 1,6-
diaminohexane.
Yield: 27% (melting point: 147 to 152C).
Example 22
Octanediyl 1,8-bis-C2,6-dimethyl-5-methoxycarbonyl-4-
(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylate3
~ Cl ~ Cl
CH~OOC ~ COO-ICE2)g-OOC ~ CFOCH~
Analogously to Example 3, 25 mmoles of hexanediyl
1,6-bis-(3-aminocrotonate) were reacted with 5V mmoles of
2-chlorobenzylideneacetoacetic acid methyl ester.
Yield: 8Q% of amorphous substance.
lH-NMR (CDC13): ~ = 1.0-1.4 (m, 8H), 1.4-1.7 (m, 4H),
2.2 (2s, 12H), 3.6 (s, 6H), 4.0 (t, 4H), 5.4 (s, 2H),
5.9 (s, NH) and 6.9-7.5 (ml 8H).
Exam_le ?3
N,N'-Bishydroxyethylurea bis-[2,6-dimethyl-5-ethoxycarbonyl-
4-(3 nitrophenyl)-1,4-dihydropyridine-3-carboxylate~
Le A 20 638
. _

7~
;
~, NO 2 [~, NO 2
H5C200C ~ ~ COO-(CH2)2-NH-~-NH-(CH2)2-OO ~ COOC2H5
3 H 3 H
This compound was prepared analogously to Example
2 from N,N'-bishydroxyethylurea and 2,~-dimethyl-5-
ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-
carboxylic acid.
Yield: 32%, melting point: 178 to 187C.
Example 24
Bis-(2-hydroxyethyl)-sulphide bis-~2,6-dimethyl-5-
methoxycarbonyl-4-(2-nitrophenyl)-1,4-dihydropyridine-
3-carboxylate]
~ ~N02 ~ ~2
CH300C ~ COO-(CH2)2-S-(cH2)2-ooc ~ ~ COOCH3
CH3 N ~ CH3 3 H 3
This compound was prepared analogously to Example
3 from bis-(2-hydroxyethyl) sulphide bis-(3-aminocrotonate)
and 2-nitrobenzylideneacetoacetic acid methyl ester.
5 Yield: 80% of amorphous substance
H-NMR (CDCl ): ~ ~ 2.3 (2s, 12H), 2.4-2.8 (m, 4H), 3.6
_---- 3
(~, 6H), 3,9-4,3 (m, 4H), 5.8 (s, 2H), 6.3 (s~ NH) and
7 .1-7 . 8 (m, 8H) .
Example ? 5
Hexanediyl 1,6-bis-L2,6-dirnethyl-5-(2-methoxy)-ethoxy-
carbonyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3-
carboxylate~
Le A 20 638

''' ~ !
~ Cl ~ C1
CH30-(CH2)200C ~ ~ C-(CH2)6-C ~ ~ C~0 (CH2)2 OCH3
3 H 3 3 H 3
This compound was prepared analogously to Example
3 from 25 mmoles of hexanediyl 1,6-bis-(3-aminocrotonate)
and 50 mmoles of 2-chlorobenzylideneacetoacetic acid
2-methoxyethyl ester.
Yield: 67% (melting point: 135 to 143C)o
Example 26
Bis-(2-hydroxyethyl)-sulphide bis-~2,6-dimethyl-5-
ethoxycarbonyl-4 (2-trifluoromethylphenyl)-1,4-dihydro-
pyridine-3-carboxylate]
~ CF3 ~ CF3
~15C200C ~ ~ COO-(CH2)2-5--(CH2)2~ 5 ~ COOC2H5
CH3~ N' CH3 3 H CH3
This compound was prepared analogously to Example
3 from 25 mmoles of bis-(2-hydroxyethyl)-sulphide bis-
(3~aminocrotonate) and 2-trifluoromethylbenzylidene-
acetoacetic acid ethyl ester.
Yield: 79% of amorphous substance.
H-NMR (CDC13): ~ = 1.2 (t, 6H), 2.2 tsl 12H), 2.4-2.8
(m, 4H), 3.9-4.5 (m, 8H), 5.6 (s, 2H), 6.7 (s, NH) and
7.1-7.7 (m, 8H).
Example 27~
Bis-(2-hydroxyethyl)-disulphide bi~-[2,6-dimethyl-5-
ethoxycarbonyl-4-(3-nitrophenyl)-1,4-dihydropyridine
3-carboxylate~
I,e A 20 638

~ ~7~342
[~N2 ~N02
H5c2ooc ~ ~ COO-(CH2)2-S-S-~CH2)2 OOC ~ ¢ ~ COOC2H5
CH3 N CH3 CH ' CH
Analogously to Example 2, 12.5 mmoles o~ bis-
(2-hydroxyethy1)-disulphide were reacted with 25 mmoles
of 2,6-di~ethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)-1~4-
dihydropyridine-3-carboxylic acid.
Yield: 77% of amorphous substance.
H-NMR (CDCl ): ~ = 1.2 (t, 6H), 2.4 (s, 12H), 2.7-3.1
_ _ 3
(m, 4H), 3.9-4.5 (m, 8H), 5.1 (s, 2H), 6.4 (sl NH) and
7.2-8.2 (m, 8H).
10 Example ,, ?~,8
Octanediyl 1,8-bis-[2,6-dimethy1-5-(2-methoxyethoxycar-
bonyl)-4-(3-nitrophenyl)-lJ4-dihydropyridine-3-carboxyl-
ate~ ~ N2 ~ N02
CH30-(CH2)2-00C ~ COO-(CH2)8-~ ~ C00-(CH2)2-C~3
3 H 3 CH3~ ~ CH3
H
Analogously to Example 3, 25 mmoles of octanediyl
lJ8-bis-(3-aminocrotonate) were reacted together with
50 mmoles o~ 3-nitrobenzylideneacetoacetic acid 2-methoxy
ethyl ester.
Yield: 75% (melting point: 146 to 150C).
~
1,4-Bis-(hydroxymethyl)-benzene bis-[2,6-dimethyl-5-
(2-methoxyethoxycarbonyl)-4-(3-nitrophenyl)-1,4-dihydro-
pyridine-3-carboxylate~
Le A 20 638
.

~, N02 [~, N02
Ch30-(CH2)2-0 ~ COO-CH2- ~ -C~2-c ~ COO (CH2)2 OCH3
CH3 N CH3 CH~ ' N CH3
This compound was prepared analogously to Example
3 from 25 mmoles of 1,4-bis-(hydroxymethyl)-benzene bis-
(3-aminocrotonate) and 50 mmoles of 3-nitrobenzylidene-
acetoacetic acid 2-methoxyethyl ester.
Yield: 67% (melting point: 159 to 162C).
Example 30
Bis-(2 hydroxyethyl~-sulphide bis-~2,6-dimethyl 5-(2-
methoxyethoxycarbonyl)-4-(2-trifluoromethylphenyl)-1,4-
10 dihydropyridine-3-carboxylatei
CF3 ~ CF3
CH30-(cH2)2-Oo ~ 00-(CH2)2-S-(CH2)2-OOC ~ (CH2)2 OCH3
3 H 3 3 H 3
This compound was prepared analogously to Example 3.
: Yield: 28% (meltin~ point: 100 to 112C).
Example 31
Octanediyl 1,8-bis-[2,6-dimethyl-5-methoxycarbonyl-4-
(l-naphthyl)-1,4-dihydropyridine-3-carboxylate3
CH300C ~ C-(CH2)8-C ~ COOCH3
CH3 ~ NJ~ CH3 CH3~ CH3
H H
This compound was prepared analogously to Example 3.
Yield: 76% of amorphous substance.
. . ~ . . .
Le A 20 638

~.~'7~
~ NMr~ (CDC13): ~ = 0.8-1.5 (m~ 12H), 2~3 (2s, 12H),
3.5 (s, 6H), 3.6-4.1 (m, 4H), 5.8 (S9 2H), 6.1 (s, NH)
and 7.1-7.8 (m, 14H).
Among the new 1~4-dihydropyridine compound salts
of the invention, those salts that are pharmaceutically
acceptable are particularly important and are preferred.
The new free 1,4-dihydropyridine compounds of the
general ~ormula (I) and their salts can be interconverted
in any suitable manner; methods for such interconversion
are known in the art.
The present invention also comprises pharmaceutic-
ally acceptable bioprecursors of the active compounds of
the present invention.
For the purposes of this specification the term
'pharmaceutically 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 converted in the patient's body to the
active compound.
L,e A 20 638
_____