Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1986-08-14
1988-03-15
Brust, Joseph Paul
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514343, 546281, 548537, A61K 3140, A61K 3144, C07D20709, C07D20718
Patent
active
047313765
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new chemical compounds, methods for making same and pharmaceutical media which contain these compounds.
Subject of the invention are compounds of the general formula I ##STR2## where A.sup.1 is a valence bond, a straight or branched alkylene group having 1 to 5 carbon atoms which can be substituted with a hydroxyl- or amino-carbonyl group, be substituted with one or more alkyl- or alkoxy group containing 1 to 4 carbon atoms or with halogen atoms, or an amino group or a diphenyl-methyl group, or a R.sup.4 --NH--CO group, in which advantageously a phenyl group,
In this description the significance of the substituents in the general formulae is also as follows: substituted with a hydroxyl group.
Since the above representations do not change, we refrain from repeating them.
The new compounds of the invention can be used as the basis for pharmaceutical media. They can also be used as intermediates in the chemical production of medically effective materials, especially for antiarrhythmics.
Our research upon different models has shown that the compounds of the general formula I and their salts have significant antiarrhythmic characteristics, so that the compounds under biological conditions function as heart rhythm disturbance amelioraters. The effectivity can be compared advantageously with pharmaceuticals acceptable in therapy (Chinidin, Lydocain, procainamide) and in many cases exceeds the effect of these pharmaceuticals.
A further advantage of the compounds according to the invention is that in the effective range of antiarrhythmic dosage, they do not generate arrhythmia of the heart chamber, do not produce bradycardia and do not reduce the blood pressure in animal subjects or only reduce the blood pressure in animal subjects to a minimum extent.
With parenteral and enteral administration, the compounds of the general formula I or their salts can be used advantageously against disturbances of heart rhythm as a prophylactic and as also a treatment.
Below, the pharmacological effect of the compounds of the general formula I is demonstrated on an aconitin arrhythmia model on rats (Zetler and Strubelt, Arzenim-Forsch. (Drug Res.) 30, 1497, 1980).
Wistar rats (200-220 g) are narcotized with urethane. The vena jugularis is connected with a polyethylene catheter. Using standard EKG-II leads, a control EKG is taken. The test substance and the physiological saline solution used as control are intravenously administered 5 minutes before the aconitin infusion. The aconitin solution is continuous administered at a dose of 5 mg/kg at a rate of 0.1 ml (100 g/minute) as an infusion into the vena jugularis. The progress is monitored by the EKG isoelectric line.
During the test the time to formation of the ventricular extrasystole, ventricular tachycardia and fibrillation were determined. Several results, each for a different type of compound, are collected in table II.
On the basis of the late occurrence of the ventricula extrasystole, ED.sub.125 and ED.sub.150 values were determined. The acute toxicities were determined on mice (CELP strain and the LD.sub.50 value was calculated after a week using the Litchfield-Wilcoxon method. The antiarrhythmically effective dosage or the LD.sub.50 value for several compounds of the various compound types are collected in Table III.
The compounds of the invention can be worked up with known methods for direct use as pharmaceuticals utilizing known methods of the pharmaceutical industry. Diluents, carriers and other auxiliary agents can be added. The pharmaceuticals can be put up in the form of tablets, dragees, capsules or like peroral formulations. The pharmaceutical can also be dispensed in parenteral form, mainly as i.v. injections. Body tissue is not attacked by the active ingredient.
The compounds of formula I can advantageously be used in the form of physiologically neutral or advantageous salts. For this purpose it is advantageous to use the hydrogen chloride, sulfuric acid or sulfonic acid salts or salts formed with hydrogen bromide.
From a biological vie
REFERENCES:
patent: 3020288 (1962-02-01), Wragg et al.
patent: 3334103 (1967-08-01), Feldman et al.
patent: 4111901 (1978-09-01), Hechenbleikner
Bodi Ilona
Csak Jozsef
Frank Laszlo
Hankovszky Olga H.
Hideg Kalman
Alkaloida Vegyeszeti Gyar
Brust Joseph Paul
Dubno Herbert
Myers Jonathan
Ross Karl F.
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