Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1984-07-20
1987-04-07
Jiles, Henry H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514356, 546283, 546321, A61K 31455, C07D21190, C07D40512
Patent
active
046561811
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new 1,4-dihydropyridines, to processes for their preparation and to medicaments containing the same, such medicaments being preferably used for their action on the blood vessels, and in particular as agents against coronary diseases or as anti-atheromatic agents. The applicant has discovered the important influence that have on the coronary vessels the new esters of 1,4-dihydropyridines (I) and their salts of the general formula: ##STR2## in which: R stands for a hydrogen atom, for a saturated or an unsaturated hydrocarbon radical or an alkylmorpholinic group, hydrogen atom, an alkyl group or an alkoxalkyl group, nitro, cyano, azido, alkyl, alkoxy, hydroxy, acyloxy, carbaloxy, amino, acylamino, alkylamino, S(O).sub.m -alkyl where m equals 0, 1 or 2, phenyl, trifluoromethyl or halo, with these substituents being identical or different, a benzyl, styryl, cycloalkyl, cycloalkenyl group, or a naphthyl, quinolyl, isoquinolyl, pyridyl, pyrimidyl, diphenyl, furyl, pyrryl or thiophenyl radical which can be substituted by an alkyl, alkoxy, dialkylamino, nitro or halo group, saturated, unsaturated or cyclic; it can also be interrupted by one or two atoms of oxygen or sulfur and can be substituted by one or two hydroxyl groups; R.sub.1 can also designate the ##STR3## the two substituents Y can be identical or different and have the following structures: 4-hydroxybenzoic acids or N-substituted piperazines of the following formula ##STR4## where R.sub.5 is an alkyl, acyl, or an arylsulfonyl radical. Y can also designate another group of products having for formula --OOC--R.sub.6 and --O--R.sub.6, where R.sub.6 is a hydrocarbon radical which can be saturated or cyclic, branched or not, heterocyclic or aromatic, and which can be substituted with one or two nitro, halo, hydroxy, acetyl, alkoxy, trifluoromethyl or acylamino groups. Y can also designate a 2-tetrahydrofuryl or a N-(4-benzoyl-piperidinyl) group.
These products (I) can be prepared by using the following processes: formula (III) ##STR5## (where R, R.sub.1 and R.sub.2 are defined as above) which are eventually isolated and thereafter reacted with an ylidenic derivative of the formula (V) ##STR6## (where X, R.sub.3, R.sub.4, n an Y are defined as above) which are obtained by reacting aldehydes of the formula (VI) of the formula (VII): ##STR7## (where R.sub.3, R.sub.4, n and Y are defined as above); or (b) By reacting .beta.-ketocarboxylic acids of the formula (VII) with amines of the formula (III) for obtaining enamines of the formula ##STR8## (where R, R.sub.3, R.sub.4, n and Y are defined as above) which are eventually isolated and thereafter reacted with ylidenic derivatives of the formula (IX) ##STR9## (where X, R.sub.1 and R.sub.2 are defined as above) which are obtained by reacting aldehydes of the formula (V) with esters of .beta.-ketocarboxylic acids of the formula (II); or with enamines of the formula (VIII) and aldehydes of the formula (VI); or with enamines of the formula (IV) and aldehydes of the formula (VI); or (VII) with one mole of amine of the formula (III) and one mole of aldehyde of the formula (VI); or oxygen or nitrogen, the compound (I) can also be obtained by reacting the 1,4-dihydropyridine of the formula (X) ##STR10## (where X, R, R.sub.1, R.sub.2 R.sub.3, R.sub.4 and n are defined as above and Hal stands for a halogen atom) with a compound of the formula (XI) When desired, salts of the products prepared according to the processes (a) to (f) can be prepared by using an acid. In formula (I), the saturated or unsaturated hydrocarbon radical R is preferably a straight or a branched C.sub.1 to C.sub.4 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl, or a straight or a branched C.sub.2 to C.sub.4 alkenyl such as ethenyl, 1-propenyl, 2-propenyl and butenyl. R can also be an alkylmorpholinic radical such as ethylmorpholinyl and propylmorpholinyl.
In the formula (I), the saturated or unsaturated hydrocarbon R.sub.1 is preferably a straight or a branched C.sub.1 to C.sub.4 alkyl, such as me
REFERENCES:
patent: 3574843 (1971-04-01), Bossert et al.
patent: 4258042 (1981-03-01), Loev et al.
patent: 4532248 (1985-07-01), Franckowiaki et al.
Bossert, F. et al., "4-Aryldihydropyridines", Angew. Chem. Int. Ed. Engl. 20, (1981) pp. 762-769.
Schramm, M. et at., "Novel Dihdropyridines with Positive Inotropic Action", Nature, vol. 303 (Jun. 9, 1983) pp. 535-537.
Fau de Casa-Juana Miguel
Statkow Peter R.
Straumann Danielle
Sunkel Carlos E.
Bjorkman Dale A.
Cermol S.A.
Jiles Henry H.
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