Acetylsalicylic acid nitrates

Details Acetylsalicylic acid nitrates Acetylsalicylic acid nitrates

1997-10-24

1999-01-12

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

558488, 560 64, 564169, A61K 3121, C07C20300, C07C 6976, C07C23300

Patent

active

058590536

DESCRIPTION:

BRIEF SUMMARY
The invention relates to new derivatives of acetylsalicylic acid (called ASA in the following), which contain an NO.sub.3 structure. They are therapeutically active either as the intact active compound molecule or after cleavage (NO release). The invention also relates to processes for their preparation and their use as medicaments, in particular for the alleviation of pain, inhibition of platelet aggregation, lowering of fever and for the prevention of cardiovascular disorders and oncoses.
The valuable therapeutic effects of ASA have been known for a long time. Thus ASA is employed for the alleviation of pain, in thromboembolic disorders such as, for example, primary and secondary prevention of cardiovascular disorders, cerebrovascular disorders and peripheral vascular occlusions and also in the prevention of oncoses. In particular in the preventive indications, combinations with vitamins or other active compounds such as, for example, phytopharmaceuticals such as Ginkgo or calcium antagonists such as nifedipine, nimodipine or amlodipine are frequently employed advantageously.
Besides the valuable therapeutic effects, however, the undesired side effects of ASA, in particular on chronic administration and in high doses, have also been known for a long time. It has been attempted again and again to avoid or to decrease these undesired properties, in particular the gastrointestinal side effects, by derivatization or by means of enteric-coated administration forms. The success of these experiments to improve the tolerability of ASA, however, has until now only been seen to a small extent. One reason for this is that the lesions of the gastrointestinal mucous membrane are caused not only by the active compound directly released in this area, but also as a result of the principle of action of ASA. One cause of these undesired side effects is the inhibition of prostaglandin synthesis by ASA. There has therefore been the need for a long time to decrease the undesired side effects of ASA whilst if possible retaining the desired therapeutic effects.
It has been found that nitrates of ASA (in the following called NO-ASA) have at least the same therapeutic effects as ASA, but are virtually free of the mentioned undesired gastrointestinal side effects.
The invention relates to new NO-ASA compounds of the general formula ##STR1## in which A represents O or NH, two of the substituents Z represent ONO.sub.2 or else ONO.sub.2 in combination with OH.
The compounds of the formula (I) can contain one or more chiral carbon atoms and exist as optically pure compounds or as enantiomer mixtures or diastereomer mixtures.
The compounds of the general formula (I) can be prepared by reacting derivatives of ASA of the general formula (I), in which other inorganic or organic acids, the individual hydroxyl groups being either exhaustively or partially esterified.
The reaction of alcohols with nitric acid to give nitrate esters is known. Methods for the preparation of nitric acid esters of di- or polyhydric alcohols are likewise known and described, for example, in "Methoden der
The compounds of the general formula (I) in which acid halides or mixed anhydrides of the general formula (II) ##STR2## in which R represents halogen, alkoxycarbonyloxy or optionally substituted aryloxycarbonyloxy, ##STR3## in which A represents O or NH, liberation of the hydroxyl function.
Suitable protective groups T are those which can be removed selectively in the presence of other carboxylic acid ester groups or carboxamide groups. Examples of such protective groups are known (P. J. Kocienski: Protecting Groups, Thieme, Stuttgart, 1994), e.g. ester groups such as 2,2,2-trichloroacetyl or ethers such as allyl, benzyl or p-methoxybenzyl or acetals such as methoxymethyl or isopropylidene, cyclohexylidene or benzylidene.
A suitable acid halide is, for example, 2-acetoxybenzoyl chloride, whose preparation is known (Riegel and Wittcoff, J. Amer. Chem. Soc., 64 (1942) 1486). Mixed anhydrides of ASA are formed in the reaction of ASA with alkoxycarbonyl halides in t

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