Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-12-05
1997-08-26
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 18, 530331, 558482, 558483, 930260, A61K 3805, A61K 3806, C07K 500
Patent
active
056611293
DESCRIPTION:
BRIEF SUMMARY
CROSS REFERENCE TO RELATED APPLICATION
This is a national application based on a PCT/DE94/00726 filed 24 Jun. 1994.
FIELD OF THE INVENTION
The invention relates to novel nitrates containing a disulphide group, and to processes for their preparation.
BACKGROUND OF THE INVENTION
Organic nitrates (esters of nitric acid) are proven medicinal substances for the treatment of heart diseases. They display their effect both by relieving the heart via a reduction in the preload and afterload and by improving the oxygen supply to the heart via coronary dilatation.
However, it has been found that the classical organic nitrates used in therapy, such as glycerol trinitrate, isosorbide dinitrate or isosorbide 5-mononitrate, display, on continuous intake of high doses, within a short time a distinct attenuation of the effect, nitrate tolerance. It has been possible to eliminate this deficiency using the compounds made available by EP 0 362 575 and EP 0 451 760.
According to EP 0 362 575 and EP 0 451 760, the effect of the nitro compounds is mediated by NO free radicals formed therefrom. Reaction of the nitrates with the thiol group of cysteine initially results in the formation of a reactive and short-lived intermediate product which is still hypothetical and is presumably the thiol ester of nitric acid or a thionitrate, which undergoes intramolecular rearrangement and subsequently decomposes to a pharmacologically active NO free radical and an unstable thio free radical which reacts with other thio free radicals to give the corresponding disulphide. The formation and release of the NO free radical requires a reduced thiol group-containing cysteine, which is converted into disulphides, so that the decrease in the effect of nitro compounds on continuing intake or administration of high doses is attributed to an exhaustion of the SH group pool. EP 0 362 575 and EP 0 451 760 claim compounds which contain sulphydryl groups and, on the basis of this general structural principle, prevent nitrate tolerance or diminish a nitrate tolerance which has already occurred.
SUMMARY OF THE INVENTION
It has now been found, surprisingly, that nitro compounds which, in place of a free thiol group, contain a disulphide group, are also effective and likewise display no nitrate tolerance on continuing intake. The present invention therefore relates to compounds of the general formula I ##STR1## in which R and R' denote groups of the general formulae ##STR2## in which R.sup.11 denotes hydrogen, alkyl having 1 to 6 carbon atoms, substituted lower alkyl in which the substituent is halogen, hydroxyl, lower alkoxy, aryloxy, amino, lower alkylamino, acylamino, acyloxy, arylamino, mercapto, lower alkylthio, arylthio, phenyl-lower-alkyl, methoxyphenyl-lower-alkyl, hydroxyphenyl-lower-alkyl, hydroxy-lower-alkyl, alkoxy-lower-alkyl, amino-lower-alkyl, acylamino-lower-alkyl, mercapto-lower-alkyl or lower alkylthio-lower-alkyl, di-lower-alkylamino-lower-alkoxy, acylamino-lower-alkoxy, acyloxy-lower-alkoxy, aryloxy, aryl-lower-alkoxy, substituted aryloxy or substituted aryl-lower-alkoxy, in which the substituent is methyl, halogen or methoxy; amino, lower alkylamino, di-lower-alkylamino, aryl-lower-alkylamino, hydroxy-lower-alkyl-amino, pyrrolidine, piperidine, morpholine, piperazine or amino-acid residues via peptide linkage, form an ester or amide, form an alkylene bridge having 2 to 4 carbon atoms, an alkylene bridge having 2 to 3 carbon atoms and a sulphur atom, an alkylene bridge having 3 to 4 carbon atoms, which contains a double bond or an alkylene bridge as above, substituted by hydroxyl, lower alkoxy, lower alkyl or di-lower-alkyl,
The present invention furthermore relates to compounds which have the following names: disulphide, disulphide, ylethyldisulphanyl]-3-methylbutyric acid.
These are asymmetric disulphides which generally contain sulphur-containing amino acids, especially glutathione or penicillamine.
The compounds according to the invention may also be in the form of their physiologically tolerated acid addition salts.
According
REFERENCES:
patent: 5284872 (1994-02-01), Sandrock et al.
patent: 5428061 (1995-06-01), Sandrock et al.
Bokens Hilmar
Feelisch Martin
Lehmann Jochen
Meese Claus
Sandrock Klaus
Celsa Bennett
Schwarz Pharma AG
Tsang Cecilia J.
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