Certain 1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylates, composition containing same and method of use

The invention relates to 1,4-dihydropyridines which carry an arylalkyl or aryloxyalkyl radical in the 4-position. Also included in the invention are methods for the preparation of said compounds. The invention further relates to compositions containing said 1,4-dihydropyridines and the use of said compounds and compositions for their circulation influencing effects.

The present invention relates to certain new 1,4-dihydropyridine compounds, 
to processes for their production and to their use as medicaments for 
influencing the circulation. 
It is already known that 1,4-dihydropyridine derivatives have 
circulation-influencing properties. Thus for example, 
2,6-dimethyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 
dimethyl ester, a compound known under the Trade Mark "Nifedipin", (see 
German Patent Specification No. 1,607,827) is known as a compound which 
has a coronary-vasodilating action. 
According to the present invention there are provided compounds which are 
1,4-dihydropyridines of the formula 
##STR1## 
or a salt thereof, in which R.sup.1 and R.sup.2 are identical or different 
and denote a straight-chain or branched alkyl radical with 1 to 4 carbon 
atoms, 
R.sup.3 denotes a hydrogen atom, a methyl group or a phenyl radical and 
R.sup.4 represents a phenyl or phenoxy radical, which optionally carry 1 or 
more substituents selected from nitro, halogen, methyl and methoxy. 
1,4-Dihydropyridines which carry an arylalkyl or aryloxyalkyl radical in 
the 4-position have not previously been described. 
The compounds of the present invention possess circulation-influencing 
properties, and in particular dilate the coronary vessels and lower the 
blood pressure. 
According to the present invention there is further provided a process for 
the production of compounds of the invention in which 
(a) an aldehyde of the formula 
##STR2## 
in which R.sup.3 and R.sup.4 have the abovementioned meaning, is reacted 
with ammonia and an acetoacetic acid ester of the formula 
##STR3## 
in which R.sup.1 has the abovementioned meaning, in an organic solvent, 
(b) an aldehyde of formula (II), as defined above, is reacted with an 
enamino-ester of the formula 
##STR4## 
in which R.sup.1 has the abovementioned meaning, in an organic solvent, or 
(c) an ylidene compound of the formula 
##STR5## 
in which R.sup.2, R.sup.3 and R.sup.4 have the abovementioned meanings, is 
reacted with an enamino-ester of the formula (IV), as defined above, in an 
organic solvent. 
The organic solvent used can be an alcohol (especially an alkanol having 1 
to 4 carbonatous, particularly methanol, ethanol and isopropanol), 
dioxane, glacial acetic acid, ethyl acetate, dimethylformamide or 
acetonitrile. The reaction temperatures can be varied over a wide range, 
preferably between 20.degree. C. and 150.degree. C. More preferably, the 
reaction is carried out at the boiling point of the solvent. 
The starting materials which can be used are mostly known compounds, or can 
be prepared in accordance with known processes. 
As examples of aldehydes of the formula (II) there can be mentioned: 
2-(3-methoxyphenyl)-propionaldehyde, 2-(4'-methoxyphenyl)-propionaldehyde, 
2-(3',4'-dimethoxyphenyl)-propionaldehyde, 
3,4-dimethoxyphenylacetaldehyde, 2-(4'-chlorophenyl)-propionaldehyde, 
2-(2'-chlorophenyl)propionaldehyde, 2-chlorophenylacetaldehyde, 
4-chlorophenylacetaldehyde, 2-(3-nitrophenyl)-propionaldehyde, 
diphenylacetaldehyde, 2,6-dimethoxyphenoxyacetaldehyde and 
2,6-dichlorophenoxyacetaldehyde. 
Examples of acetoacetic acid esters of formula (III) suitable for use in 
reaction variant (a) are methyl acetoacetate, ethyl acetoacetate, propyl 
acetoacetate, isopropyl acetoacetate, butyl acetoacetate, sec.-butyl 
acetoacetate and isobutyl acetoacetate. 
The enamino esters of the formula (IV), suitable for use in reaction 
variant (b), are obtained from the corresponding acetoacetic acid esters 
of the formula (III) by reaction with ammonia. 
As stated above, the invention also relates to the use in medicine as 
circulation-influencing agents of the compounds of the invention. 
The present invention provides pharmaceutical compositions containing as 
active ingredient a compound of the invention in admixture with an inert 
pharmaceutical carrier, e.g. 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. 
The invention further provides a pharmaceutical composition containing as 
active ingredient a compound of the invention in the form of a sterile 
and/or physiologically isotonic aqueous solution. 
The invention also provides a medicament in dosage unit form comprising a 
compound of the invention. 
The invention also provides a medicament in the form 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 physically 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 submultiple (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 half, a third or a quarter of a 
daily dose will depend on whether the medicament is to be administered 
once or, for example, twice, three times or four times a day respectively. 
The pharmaceutical composition according to the invention may, for example, 
take the form of 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 compositions (e.g. granulates) 
adapted to be formed into tablets, dragees, 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 accelerators, 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 polyethyl 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. They 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 of time. 
The coatings, envelopes and protective matrices may be made, for 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. 
The diluents to be used in pharmaceutical compositions adapted to be formed 
into suppositories can, for example, be the usual water-soluble diluents, 
such as polyethylene glycols and fats (e.g. cocoa oil and high esters 
(e.g. C.sub.14 -alcohol with C.sub.16 -fatty acid)) or mixtures of these 
diluents. 
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, isopropyl alcohol, ethyl carbonate, ethyl acetate, 
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, 
dimethylformamide, oils (for example ground nut oil), glycerol, 
tetrahydrofurfuryl alcohol, polyethylene 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 pharmaceutical compositions which are suspensions can contain the usual 
diluents, such as liquid diluents, e.g. water, ethyl alcohol, propylene 
glycol, surface-active agents (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 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 invention may be any of those 
mentioned above in relation to the pharmaceutical 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 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 medicament 
physically discrete and coherent. 
The 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 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 the above-mentioned 
diseases in warm-blooded 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 intramuscularly, intraperitoneally, 
subcutaneously and intravenously), rectally or locally. 
Administration according to the invention is preferably peroral or 
intravenous. In general it has proved advantageous in the case of 
intraveneous administration, to administer about 0.01 to 10 mg/kg, 
preferably 0.1 to 5 mg/kg bodyweight per day, and, in the case of peroral 
administration to administer about 0.05 to 20 mg/kg, preferably 0.5 to 50 
mg/kg bodyweight per day to achieve effective results.

The following Examples illustrate processes for the production of compounds 
according to the present invention. 
EXAMPLE 1 
2,6-Dimethyl-4-[1-(3-methoxyphenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarbox 
ylic acid dimethyl ester. 
##STR6## 
16.4 g of 2-(3-methoxyphenyl)-propionaldehyde, 23.2 g of methyl 
acetoacetate and 2.1 ml of NH.sub.3 (33% strength) in 50 cm.sup.3 of 
ethanol were heated under reflux for 4 hours. After the mixture had 
cooled, the product crystallised out. It was purified by recrystallisation 
from ethanol. 
Yield: 26.7 g (75%). 
Melting point: 145.degree. to 147.degree. C. 
The following compounds of the present invention were obtained analogously: 
2,6-dimethyl-4-[1-(3-methoxyphenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarbo 
xylic acid diisopropyl ester, 
2,6-dimethyl-4-[1-(3-methoxyphenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarbo 
xylic acid dibutyl ester, 
2,6-dimethyl-4-[1-(2-chlorophenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarbox 
ylic acid diethyl ester, 
2,6-dimethyl-4-[1-(2-chlorophenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarbox 
ylic acid dipropyl ester and 
2,6-dimethyl-4-[1-(3-nitrophenyl)-ethyl]-1,4-dihydropyridine-3,5-dicarboxy 
lic acid dimethyl ester. 
EXAMPLE 2 
2,6-Dimethyl-4-(2'-chlorophenylmethyl)-1,4-dihydropyridine-3,5-dicarboxylic 
acid dimethyl ester 
##STR7## 
15.4 g of 2-chlorophenylacetaldehyde and 23 g of methyl 
.beta.-aminocrotonate in 50 ml of ethanol were heated under reflux for 4 
hours. After the mixture had cooled, the product precipitated. It was 
recrystallized from methanol. 
Yield: 21 g (60%). 
Melting point: 178.degree. C. to 179.degree. C. 
The following compounds of the present invention were obtained analogously: 
2,6-dimethyl-4-(2'-chlorophenyl)-methyl-1,4-dihydropyridine-3,5-dicarboxyl 
ic acid diisopropyl ester, 
2,6-dimethyl-4-(3',4'-dimethoxyphenyl)-methyl-1,4-dihydropyridine-3,5-dica 
rboxylic acid dimethyl ester and 
2,6-dimethyl-4-(3',4'-dimethoxyphenyl)-methyl-1,4-dihydropyridine-3,5-dica 
rboxylic acid dipropyl ester. 
EXAMPLE 3 
2,6-Dimethyl-4-(4'-methoxyphenylmethyl)-1,4-dihydropyridine-3,5-dicarboxyli 
c acid 3-methyl ester 5-isopropyl ester. 
##STR8## 
24.8 g of 2-(4'-methoxyphenyl)-ethylideneacetoacetic acid methyl ester and 
14.3 g of isopropyl .beta.-aminocrotonate in 100 cm.sup.3 of ethanol were 
heated under reflux for 4 hours. When the mixture had cooled, the product 
was filtered off and recrystallised from ethanol. 
Yield: 18.6 g (50%). 
Melting point: 163.degree. C. to 165.degree. C. 
The following compound of the present invention was obtained analogously: 
2,6-dimethyl-4-(3',4'-dimethoxyphenylmethyl)-1,4-dihydropyridine-3,5-dicar 
boxylic acid 3-ethyl ester 5-isopropyl ester. 
EXAMPLE 4 
2,6-Dimethyl-4-diphenylmethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 
diethyl ester 
##STR9## 
9.6 g of diphenylacetaldehyde and 26 g of ethyl .beta.-aminocrotonate in 50 
cm.sup.3 of ethanol were heated under reflux for 8 hours. After the 
mixture had cooled, the product precipitated. It was washed with ether and 
recrystallised from ethanol. 
Yield: 10.4 g (25%). 
Melting point: 140.degree. C. 
EXAMPLE 5 
2,6-Dimethyl-4-(2',6'-dimethylphenoxymethyl)-1,4-dihydropyridine-3,5-dicarb 
oxylic acid diethyl ester 
##STR10## 
16.4 g of 2,6-dimethylphenoxyacetaldehyde and 26 g of ethyl 
.beta.-aminocrotonate in 50 cm.sup.3 of ethanol were heated under reflux 
for 4 hours. After the mixture had cooled, the product precipitated, and 
was recrystallised from ethanol. 
Yield: 31.3% (55%). 
Melting point: 106.degree. C. to 107.degree. C. 
The following compound of the present invention was obtained analogously: 
2,6-dimethyl-4-(2',6'-dichlorophenoxymethyl)-1,4-dihydropyridine-3,5-dicar 
boxylic acid dimethyl ester. 
Among the new 1,4-dihydropyridine salts of the invention, those salts 
(especially acid-addition salts) that are pharmaceutically acceptable are 
particularly important and are preferred. 
The new free 1,4-dihydropyridines of the general formula (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 pharmaceutically 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 a warm-blooded animal is 
converted in the patient's body to the active compound.