Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
1~85~i
The present invention relates to the new isobutyl methyl
1,4-dihydro-2.6-dimethyl-4-(2-nitrophenyl)-~.5-pyridine-
dicarboxylate several processes for its
preparation and its use as a coronary therapeutic agent.
It has already been disclosed that diethyl-1,4-~ihydro-
2.6-dimethyl-4-phenyl-3.5-pyridinedicarboxylate
is obtained when benæylideneacetoacetic acid ethyl
ester is reacted with ~-aminocro~onic acid ethyl ester or
acetoacetic acid ethyl ester and ammonia (Knoevenagel, ~er.
dtsch. chem. Ges. 31, 743 (1898)). Further, it is known
that certain 1,4-dihydropyridines exhibit interesting
pharmacological properties (F. Bo~sert and W. Vater,
Naturwissenschaften 58, 578 (1971)).
~urther, it has been disclosed, in the applicant 1 9
earlier German Of~enlegungsschriften (German Published
Specifications) 2,117,571 and 2,117,573 that similar dihydro-
pyridine~ can be used as coronary agents.
According to the present invention, we now provide
~sobutyl-methyl 1.4-dihydro-2.6-dimethyl-4-(2-nitrophenyl)-
3.5-pyridine dicarboxylate of the formula (I).
H3C~ ~ N02
H cH,C-H2C-ooC ~ COOCH3 (I
H3C N CH3
The compound of the invention exhibits a very powerful and
long-lasting coronary action.
Further, the new active compound of the formula (1) is
obtained when
A) 2'-nitrobenzylideneacetoacetic acid isobutyl ester
(formula (II))
Le A 16 774 - 2 -
.
: ~ ,
1085~
HC-HzC ~ , C ~ 5 r NO
H~C O
is reacted with R-aminocrotonic acid methyl ester (forr~ula
III))
H \ COOCH3
C
~ C (III)
H2N CH3
if appropriate in the presence of water or inert organic
solvents, or
B) 2'-nitrobenzylideneacetoacetic acid isobutyl ester
(formula (II)) is reacted with acetoacetic acid methyl ester
(:~`or~ula (IV))
O
C-C (IV)
CH2-COOCH3
and ammonia, if appropriate in the presence of water or inert
organic solvents, or ! ~ '
C) 2'-nitrobenzylideneacetoacetic acid methyl ester ~ :.
(formula (V)) ~
~ NOg
H ~ ~COOCH3 (V)
~ C
O CH~
is reacted with ~-aminocrotonic acid isobutyl ester (formula
(VI))
Le A 16 774 - 3 -
.
1085~V6
H3 \
HC - H2C-OOC\ / H
H3~ C (VI)
/ C\
H3C NH2
if appropriate in the presence of water or inert ~olvents,
or
D) 2'-nitrobenzylideneacetoacetic acid methyl e~ter
(formula (V)) is reacted with acetoacetic acid isobutyl
ester (formula (VII))
o
H3C-C /H3
CH2-C00-CH2-CH (VII)
and ammonia, if appropriate in the pre~ence of water or
inert organic ~olvents, or
E) ~-aminocrotonic acid i~obutyl ester (Formula (VI))
is reacted with 2-nitrobenzaldehyde (formula (VIII))
N02 (VIII)
~ C ~
and acetoacetic acid methyl ester (formula (IV)), if appropri-
ate in the pre~ence of water or inert organic solvent~, or
F) ~-aminocrotonic acid methyl ester (formula (III)) is
reacted with 2-nitrobenzaldehyde (formula (VIII)) and aceto-
acetic acid isobutyl ester (formula (VII)) a~ ~uch or in
water or in inert organic solvent~.
Surprisingly, the ~ubstance accordin g to the invention,
of the formula (I), has a particularly str ~ coronary action.
Amongst the series of the similar 1,4-dihydropyridine
~e A 16 774 _ 4 _
.:
1~85~6
derivatives known from the state of the art, such a strong
and long-lasting coronary action, especially after enteral
administration, has hitherto not been demon~trated. In
addition, the compound according to the invention i~ less
un~table to light than corresponding dihydropyridine~ which
are known from the state of the art. It thus represents
in respect of these specia~ properties, an enrichment of
pharmacy.
The compound according to the invention is chiral
and can exist in stereoisomeric forms which have an image/
relationsip to each other (enantiomers, antipodes). These
can, in turn again occur in different conformations. Both
the racemic form and the antipodes are included within the
present invention.
Depending on the nature of the starting materials
used, the synthesis of the compound according to the
invention can be represented by the ~llowing equation~:
~e A 16 774 _ 5 _
1~)85406
C~
o o o ~ ~ o
D ~ ~:Z; ~C ~5
O ~ ~) V V V
v 8 ~ 8 ~
~ V ~,
C) ~ V ~ 5
~ ~ t ~ ~ v c~ .
5~ t~o o
o ~ o~\ /
V ~ ~ ,
O + ~ H ~ ) O _~
g 5' 0 ~ o
V ~ o ~
~ H ~ H ~ H
V ~ V V ~ V V
~q V
Le A 16 774 - 6 -
10854V6
o~ o ~ Z ~,
V ~)
o o ,~
V ~ C~
_~ ~ ~ ` ~ ~ .
H
~ ,.'
~ t~ Yu ~
~
+ ~ ~ ~o
~ "o
V ~, oo ~ , ~V~
æ ~ ~ O
V H ~_ ~
V
~e A 16 774 - 7 -
1~85~6
The substances of the formulae (II) - ~VIII) used as
starting materials are known ~rom the l~terature or can be
prepared in accordance with methode known from the literature
~literature: Org. Reactions XV, 204 et seq. (1967); A.C.COPE,
J. Amer. chem. 30c. 67, 1,017 (1945); and Houben-Weyl,
Methoden der Organ, Chemie (Method3 of Organic Chemi~try)
VII/4, 230 et seq. (1968)).
In carrying out processes A-F accordin,s to the
invention the compounds particlpating in the reaction are in
each ca~e employed approximately in equimolar~amount~. The
a~onia ueed is advantageouely added ln exce~s.
Dlluents which can be used are water and all lnert
organi¢ eolvent~. These prefersntlally inolude alcohole
3uch ae athanol and methanol, ethers such ae dic~xane or dl-
ethyl ether, or glacial acetic acid, pyridine, dimethyl-
formamide, dimethylsulphoxide or acetonitrile.
~he reaction temperatures can be varied within a
~ubstantial range. In general, the reaction is carried out
at a temperature o~ rom 20 to 200C, preferably at 50 to
120C and e~pecially at the boiling point of the solvent.
The reaction can be carried out under normal preesure
but also under elevated pressure. In general, norm;~l
pressure is used.
The preceding processes of preparation are gi~ren solely
for clarification and the preparation of the compound (I)
is not re~tricted to these processes; in~tead, any mod-
ification of these proces~es can be used in the same manner
for the preparation of the compound (I).
The compound according to the invention is a substance
~0 which can be used a~ a medicament. When used enterally or
parenterally it produce~ a powerful and long-lasting increase
~e A 16 774 - 8 -
. . .
1085406
in myocardial perfusion and can therefore be employed for
the prophylaxis and treatment of ischaemic heart disease~,
especially if they are combined with hyperten~ion.
~he present inventlon provide~ a pharmaceuti¢al
compo~ition containing as actlve ingredient the compound
of the invention in admixture with a solid or liquefied
gaseou~ diluent, or in admixture with a liquid diluent other
than a solvent of a molecular weight less than 200 (preferably
le~s than 350) except in the presence of a surface active
agent.
The invention further provides a pharmaceutical
composition containing as active ingredient ths compound o~
the invention in the form of a sterile or ieotonic aqueous
~olution.
The invention also provides a medi¢ament in dosage
unit form comprisine the compound of the invention.
The i~vention al~o provides a medicament in the form
of tablets (including lozenges and granules), dragees, cap-
sules, pills, ampoule~ or suppositories comprising the
compound of the invention. I
"Medicament" as used in thi~ Specif~cation means
physically discrete ooherent portions suitable for medical
administration. "Medicament in dosage unit form" as used
in this Specification means physioally discrete coherent
units suitable for medical administration each ¢ontaining
a daily dose or a multiple (up to four times) or sub-
multiple (down to a fortieth) of a daily dose of the compou~d
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 half, a third, or a quarter of
a daily dose will depend on whether the medicament is to be
~e A 16 774 _ 9 _
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administered once or, for example, twice, three times or
four times a day respectively.
The pharmaceutical compositions according to the
invention may, for example, take the form of ointments,
gels pastes, crea~s, sprays (including aerosols), lotions,
~uspensions, solutions and emul~ions of the aotive ingredlent
in aqueous or non-aqueous diluents, syrups, granules or
powders.
The diluents to be used in pharmaceutical oompo~itions
(e.g. granulates) adapted to be formed into tablets, dragees,
capsules and pill~ include the following:
(a) ~iller~ and extenders, e.g. ~tarch, sugars,m~nnitol,
and ~ilicic acid; (b) binding ~gents, e.g. carboxymethyl
cellulose and other cellulose derivative~, alginates,
gelatine and polyvinyl pyrrolidone; (c) moisturizing agent~,
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
aGcelerator~, e.g. quaternary ammonium compound~; (g) sur-
face active agents, e.g. cetyl alcohol, glycerol monostearate;
(h) adsorptive carriers, e.g. kaolin and bentonite; (i) lubri-
cant3, e.g. talc, calcium and magne~ium stearate and solid
polyethylene glycols.
The tablets, dragees, capsules and pills formed from
the pharmaceutical composition6 of the invention can have
the cu~tomary coatings, envelopes and protec~ive matrice~,
which may contain opacifiers. They can be 80 conQtituted that
they release the active ingredient only or preferably in a
particular part of the intestinal tract, poQsibly over a
period of time. The 0atings, envelopes and protective
matrices may be made, for example, of polymeric substances
~e A 16 774 _ 10 _
. .
:108540t;
waxe~.
The ingredient can also be made up in microencap-
sulated ~orm together with one or ~everal of the above-
mentioned diluent 8 .
The diluents to be u~ed in pharmaceutical compo~itions
adapted to be formed into suppositories can, for example,
be the u~ual water-soluble or water-insoluble diluent~,
such as poly~hylene glycols and ~ats (e.g. cocoa oil and
high esters [e.g. C14-alcohol with C16-fatty acid]) or
mi~ture 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, waxes, parafYins,
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
~prays can, for example, contain the usual diluents, e.g.
lactose, talc, silicic acid, aluminium hydroxide, calcium
silicate, and polyamide powder or mixtures of these sub-
stances. ~erosol 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
diluents (with, 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, isoprnpyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl bensoate,
propylene glycol, 1,~-butylene glycol, dimethylformamide,
oils ~for example ground nut oil], glycerol, tetrahydrofur-
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,, .~ , . ,
1085~
furyl alcohol, polyethylene glycols and fatty acid e~ters
of sorbitol or mixtures thereof.
For parenteral administration, the solutions and
emulsions should be sterile, and, if appropriate, blood-
isotonic.
The pharmaceutical composition~ which are ~uspensions
can contain the usual diluents, such as liquid diluents,
e.g. water, ethyl alcohol, propylene glycol, ~ur~ace-active
agents (e.g. ethoxylated isostearyl alcohols, polyoxyethylene
sorbite and sorbitane esters), microcrystalline cellulose,
aluminium metahydroxide, bentonite, agar-agar and tragacanth
or mixtures thereo~.
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 in general contain from 0. 1 to 99.5, more usually
from 0.5 to 95% o~ the active ingredient by weight o~ 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 .
Any diluent in the medicaments o~ the present invention
may be any of those mentioned above in relation to the
pharmaceutical compo~itions of the present invention. Such
medicaments may include solvents oi molecular weight less
than 200 as sole diluent.
The discrete coherent portios constituting the medica
ment according to the invention will generally be adapted,
~e A 16 774 - 12 -
10854~6
by virtue of their shape or packaging, for medical ad-
ministration, and may be, for example, any of the following:
tablet~,(including lozenges and granules), pilla, dragees,
capsules, ~uppositories and ampoules. ~ome of these forms
may be made up for delayed release of the active ingredient.
~ome, such as capsules, include a protective envelope which
rendere the portions of the medicament physically discrste
and coherent.
r~he preferred daily dose for administration of the
medicaments of the inven~ion ia 0.005 mg to 1 g of active
ingredient.
The production of the above-mentioned pharmaceutical
composition~ and medicaments is carried out by 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 ~orming the compo3-
ition into the medicament (e.g. tablets).
This invention further provides a method of combating
(including prevention, relief and cure of) 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 form
of a medicament according to the invention.
It is envisaged that these active compounds will be
administered perorally, enterally, parenterally (~or
example intramuscularly, intraperitoneally or intravenously),
rectally or locally, preferably enterally or parenterally,
especially perlingually or intravenously. Preferred
pharmaceutical compositions and medicaments are therefore
those adapted for enteral or parenteral administr~tion.
In general it has proved advantageous, in the case of
~e ~ 16 774 - 13 -
1085406
lntravenou~ administration, to admini~ter amount~ o~ about
O.OOOl to l mg/kg, preferably about 0.0005 to 0.01 mg/kg
of body weight daily to achie~e effeotive results, whil~t
in the ca~e of enteral admini~tration the do~age is about
0.0005 to lO mg/kg, preferably 0.001 to O.l mg/kg of bod~
weight daily.
Neverthele~s it can at tlmes be necessary to deviate
from the amounts mentioned and in particular to do 90 as
a function of the body weight of the test animals or of the
nature of the administration route, but also because of the
specie~ of animal and its individual behaviour towards the
medicine or interval at which it is administered. Thus it
may suffice, in some cases, to manage with less than the
above-mentioned minimum amount whilst in other cases the
upper limit mentioned must be exceeded. Where ma~or amounts
are administered it can be advisable to divide these into
several individual administrations over the course of the
day. The same dosage range is envisaged for administration
in human medicine. Here, again, the general sense of the
above comments applies.
~o demonstrate the perfusion-assisting actio~ in heart
muscle, the substance was administered to dogs and the myo-
cardial perfusion was measured with the aid of an electro-
magnetic flow meter.
The substance increases the perfusion of the heart,
after intravenous and enteral administration. A particular
advantage is its rapid and complete resorption after
perlingual administration, 80 that the substance ha~ a
strong and long-lasting action even when used in this way,
in very low do~es.
~he results of the investigations on dogs after sub-
~e A 16 774 - 14 -
i(~854~6
lingual administration are shown in the table which
~ollows.
Do~e, mg/k~, Increase in heart~owering
administered perfusion of blood
sublingually by jO half-life ofpre~ure
the durationin %
of action,
in minutes
0.003 23 100
0.01 46 133 5
0,1 142 184 1~
It can be seen that the compound according to the
invention increases the perfusion of the heart muscle, as
a ~uncti3n of the dose, and, surprisingly, the effective
doses are very low. The action of the substance start~
a few minutes after sublingual administration and lasts,
depending on the dose, for 2 to 6 hours (in the table, the
half-life of the action is given as a more accurate yard-
stick of the duration of action). At the same time, it
cau~es a slight and equally long-lasting lowering of the
blood pressure, which as a rule represents an additional
advantage in the therapy of coronary illnesses.
The compound according to the invention is therefore
suitable for the prophylaxis and therapy of acute and chronic
ischaemic heart diseases in the broadest senseO The sub-
stance can be u~ed as an agent for the prophylaxis and
therapy of angina pectoris complaints and attacks, and for
the therapy of conditions after a heart infarct. It is
particularly suitable for the therapy of cases in which one
of the abovementioned heart diseases is combined with
hypertension.
The following Examples i~ustrate the alternative methods
~e A 16 774 _ 15 ~
~ ~ 8 5'~C~6
of preparation of isobutyl methyl 1.4-dihydro-2.6-dl-
methyl-4-(2-nitrophenyl)-3.5-pyridine dicarboxylate
in accordance with the invention.
H~C\ (~ NO2
HC-H2C-OOC ~ COOCH~
H,C' N CH~
Exam~le 1 (Process A)
14.6 g (50 mmol5 ) of 2'-nitrobenzylideneacetoacetic
acid isobutyl e~ter together with 5.8 g (50 mmol~) of ~-
aminocrotonic acid methyl ester, in 80 ml of ethanol, ~rere
heated for 20 hours under reflux. After the reaction
mixture had cooled, the solvent was disti1led off in vacuo
and the oily residue was mixed with a little ethanol. The
product cry~tallised completely after a short time and was
filtered off and recrystallised from ethanol. Melting point:
151-152C yield: 15.2 g (78%).
ExamPle 2 (Process B)
14.6 g (50 mmol~) of 2'-nitrobenzylideneacetoacetic
acid isobutyl ester together with 5.8 g (50 mmols) of
acetoacet acid methyl ester and 6 ml (88 mmols) of a 25 per
cent strength aqueous ammonia solution, in 80 ml of methanol,
were heated for 24 hours under reflux. The solvent was
then distilled off in vacuo and the oily residue wa~ mixed
with a little ~hanol. The product crystallised completely
after a short time and was filtered off and recrystallised
from ethanol.
Melting point:150-152 C, yield: 11.9 g (61%).
xamPle 3 (Process C)
12.5 g (50 mmols) of 2'-nitrobenzylideneacetoacetic
a~id methyl ester together with 7.85 g (50 mmols) of ~-
~e .~ 6 ,74 - 16 -
.
1085~06
aminocrotonic acid isobutyl ester in 80 ml of ethanol
were heated for 20 hours under reflux. After the reaction
mixture had cooled, the solvent wa~ distilled off in ~acuo
and the solid residue was triturated with ether, filtered
off and recrystallised from ethanol.
Melting point: 150-152C, yield: 14.5 g (74%).
Exam~le 4 (P;~o¢e~ D)
12.5 g (50 mmols) of 2'-nitrobenzylideneacetoacetic
acid methyl ester together with 7.85 g (50 mmol~) o~ aceto-
acetic acid isobutyl e~ter and 6 ml (88 mmols) oi a 25 per
cent ~trength aqueous ammonia solutlon, in 80 ml of isobutan-
ol, were heated for 15 hour~ under reflux. After the
reaotlon mi~ture had ¢ooled, the solvent wa~ di~tllled off
in vacuo. The oily re~ldue crystallised completely over-
night and was triturated with ether, filtered off and
recrystallised from ethanol.
Melting point: 150-152C, yield: 10.9 g (56%).
Exam~le 5 (Process ~)
7.85 g (50 mmols) of ~-aminocrotonic acid isobutyl
ester together with 7.6 g (50 mmols) of 2-nitrobenzaldehyde
and 5.8 g (50 mmols) of acetoacetic acid methyl ester in
80 ml of ethanol were heated ~or 24 hours under reflux.
After the reaction mixture had cooled, the solvent was con-
centrated in vacuo and the solid residue was triturated
with ether, filtered off and recrystallised from ethanol.
Melting point: 151-152C, yield: 14.5 g (75%).
E~am~le 6(Process Fl
5.8 g (50 mmols) of ~-aminocrotonic acid methyl ester
together with 7.6 g (50 mmols) of 2-nitroben~aldehyde and
7.85 g (50 mmols) of acetoacetic acid isobutyl ester, in
80 ml of ethanol, were heated to the boil for 24 hours. The
~e A 16 774 _ 17 _
.. . . , .. .. . _ .. .. .. . . . . . ... . .
'
'.
io85,4~6
solvent was then di~ti~led off in vacuo and the solid
residue was recrystall.ised from ethanol.
Melting point: 151-152C,yield: 13.6 g (70~o).
Le A 16 774 - 18 -
