Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-01-22
1995-01-03
Fan, Jane T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546321, C07D21186, A61K 31455
Patent
active
053787188
DESCRIPTION:
BRIEF SUMMARY
The invention relates to novel 4-(substituted phenyl)-1,4-dihydropyridine derivatives containing one or more nitrate ester functions in at least one of the substituents on the phenyl ring, and to their salts. These novel compounds have the formula 1 (cf. enclosed formulae sheet), wherein --CH.sub.2 --NH.sub.2, (bi)(cyclo)alkyl group, alkyl group, a lower, optionally branched alkoxy group, CN, NO.sub.2, F, Cl or Br, that of the formula [(CH.sub.2).sub.2 O].sub.q (CH.sub.2).sub.2, wherein q is 1 or 2,
It has been found that these novel 1,4-dihydropyridine derivatives have valuable properties for use as medicaments. They can be used, optionally symptomatically, in the treatment of pathological processes in mammals, especially man, where it is necessary, for example,
a. to increase the availability of oxygen to the tissues;
b. to protect the mucosa, for example the gastrointestinal mucous membrane;
c. to intervene in the reproduction mechanisms of viruses; or
d. to reduce resistance to oncolytic agents and thus to maintain the oncolytic activity.
By virtue of their pharmacological characteristics, the novel 1,4-dihydropyridine derivatives are, for example, suitable for use as medicaments, for example in the treatment and/or prevention of
a) ischemic heart diseases (such as angina pectoris and latent ischemia)
b) cardiac decompensation, myocardial infarction or raised blood pressure (especially portal hypertension)
c) cerebral thrombosis and atherosclerosis
d) vessel spasms and arrhythmia etc.
e) disorders of the gastrointestinal tract, such as achalasia and irritable bowel syndrome
f) tardive dyskinesia.
The invention thus also relates to a medicament for the treatment of the abovementioned disorders which contains, as active substance, a 1,4-dihydropyridine derivative of the formula 1 described above and/or a pharmacologically compatible salt thereof.
1,4-Dihydropyridine derivatives are described in many patents, for example in British Patents 1,173,862 and 1,455,502 and U.S. Pat. No. 4,472,411. The compounds described in these literature references are known to have a calcium influx-modulating action which is used in particular in the therapy of ischemic heart diseases, hypertension and cerebral circulatory disturbances.
These known 1,4-dihydropyridine derivatives generally have in common that they have a 4-(nitrophenyl)2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid ester structure. It is also known that organic nitrate esters can be used in ischemic heart diseases and cardiac decompensation. Organic nitrate esters such as glyceryl trinitrate and isosorbide dinitrate have already been used medicinally for more than 100 years and 50 years respectively.
With regard to the manner in which vasodilation is effected by nitrate esters it is postulated that this is caused, inter alia, by nitric oxide NO. It is known that endogenous NO can be liberated from endothelial cells of an intact vessel wall by specific mediators, such as acetylcholine, bradykinin, serotonin, histamine and the like. This endogenous NO, which is also termed Endothelium Derived Relaxing Factor (EDRF), is alleged, in turn, to stimulate the enzyme guanylate cyclase in the adjacent smooth muscle cells. As a result, inter alia, of the increased concentrations of cyclic GMP, the existing balance in the vessel wall tension is disturbed, which, via a cascade of reactions, ultimately leads to relaxation of the smooth muscle cells in the vessel wall.
Organic nitrate esters can give rise to vasodilation even if the endothelial cell layer has been damaged or removed, which effect could be explained by direct formation of NO from these nitrate esters.
From the therapeutic standpoint it can be worthwhile to combine medicaments, such as Ca-antagonists and organic nitrate esters, in dosages at which possible side effects are prevented as far as possible and, nevertheless, a clinically optimum result is obtained. A chemical combination can be produced under certain circumstances, but it is then unpredictable as to what the pharmacological and clinical
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Appel Current Neurology vol. 6, p. 108 Year Book Medical Publishers, Inc. 1987.
Schramm et al. Nature vol. 303, pp. 535-537, Jun. 1983.
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Bron Jan
Sterk Geert J.
Timmerman Hendrik
Van Der Werf Jan F.
Cedona Pharmaceuticals B.V.
Fan Jane T.
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