Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1984-09-20
1987-10-27
Hollrah, Glennon H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514259, 514343, 514422, 514428, 544287, 546281, 548465, 548526, 548565, A61K 3140, C07D40312
Patent
active
047030569
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATIONS
This application is a National Phase application corresponding to PCT/HU84/00005 filed Jan. 23, 1984 and based, in turn, on Hungarian applications 191/83 of Jan. 21, 1983 and Hungarian applications 384/83, 385/83 and 386/83, all filed Feb. 4, 1983 under under the International Convention. The present invention relates to alkyl diamine derivatives, a process for the preparation thereof and pharmaceutical compositions containing same.
In the patent specification hereinafter in the formulae the substituents are defined as follows:
R stands for ##STR2## wherein A stands for C.sub.1-5 alkylene which can be substituted by hydroxyl, halogen, C.sub.1-4 alkoxy or acylamino, optionally substituted by hydroxyl or thioalkylene or oxyalkylene, can be substituted by one or more hydroxyl, C.sub.1-4 alkyl and/or C.sub.1-4 alkoxy and/or halogen or methylenedioxy, and the alkyl group can be unsaturated as well ##STR3## salts thereof as well as pharmaceutical compositions containing the compounds of the formula I.
The compounds have not been disclosed so far in the prior art. The biological activity of the new compounds can be advantageously compared with the generally accepted antiarrhythmic agents such as quinidine, and procaine amide. In fact in some cases the activity is several times higher than the activity of said known anti-arrhythmic agents and the toxicity thereof is less than one tenth of the therapeutic dose.
The amines and salts of the formula I prepared according to the invention can be formulated to pharmaceutical compositions by admixing the active ingredients with the conventionally used excipients, such as carriers, lubricating agents and diluents. The pharmaceutical compositions can be administered in the form of parenteral, enteral and peroral compositions.
The antiarrhythmic activity of the compounds of the formula I was compared in a preventive aconitine arrhythmia test on rats as follows: Male and female rats of Wistar strain weighing 200 to 250 g. were narcotized i.p. with 1.25 g./kg. of urethane and their ECG was registered by a Hellige equipment by II standard limb lead.
Arrhythmia was induced by an i.v. infusion of 30 .mu.ug./kg. aconitine nitrate whereafter the ECG was continuously monitored for 30 minutes.
The test substances were always administered to the animals 2 minutes before giving the aconitine infusion, i.v., at i.v. LD.sub.50/10 dosis measured in mice.
Those cases were considered positive, where within 30 minutes after the aconitine infusion not a single phase of the arrhythmia occurred.
In control animals pretreated i.v. with a 0.9% sodium chloride solution (0.1 ml./100 g.) (n=20) the arrhythmogenic activity of the aconitine nitrate appeared after 2.88.+-.0.32 minutes.
In cases of compounds having outstanding antiarrhythmic activity ED.sub.125 and ED.sub.150 values were calculated in arrhythmia test carried out in rats according to Zetler and Strubelt (Arzneim.-Forsch.) Drug. Res. 1980. 30, 1947).
The acute intravenous (i.v.) toxicity values of the test-compounds was determined by the method of Litchfield and Wilcoxon and as test-animals white mice of both sexes were used (J. of Pharmacol. 1949, 96, 99.).
Biological test results obtained for some new diamines according to the invention are summarized in Table II. Percent values of the positive cases, average time of the appearance of the arrhythmia---when the induced arrhythmia appeared within 30 minutes--and toxicity values are shown.
The test results obtained in various arrhythmia tests show the apart from the significant antiarrhythmic activity of the compound they are also effective from a physiological point of view in ceasing heart arrhythmia.
The antiarrhythmic effectivity sometimes surpasses the activity of the referential substances: quinidine and procainamide several times and at the same time when examined the negative inotrop and negative chronotrop activity of these compounds in vitro on isolated artium compositions, said activities do not achieve the heart frequency decreasing or c
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
Dubno Herbert
Hollrah Glennon H.
Myers Jonathan
Ross Karl F.
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