Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1987-03-16
1989-05-23
Daus, Donald G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544267, A61K 3152, C07D47304
Patent
active
048331465
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel xanthine derivatives with at least one tertiary hydroxyalkyl group in the 1- or 7-position, processes for their preparation and their use as active compounds in medicaments which are particularly suitable for the treatment of disturbances in peripheral and cerebral circulation.
1-Oxoalkyl-3,7-dialkyl- and 7-oxoalkyl-1,3-dialkylxanthines and 1-hydroxyalkyl-3,7-dialkyl- and 7-hydroxyalkyl-1,3-dialkylxanthines which have a secondary alcohol group and promote circulation are already known. Within this group of substances, the vasotherapeutic pentoxifylline, 3,7-dimethyl-1-(5-oxohexyl)-xanthine, has acquired considerable therapeutic importance for medicamentous treatment of disturbances both in peripheral and in cerebral circulation. As a vasoactive medicament of the more recent generation (Schweiz. med. Wschr. 111 (1981), pages 637-640), in many countries it now has, for example, a firm place amongst the medicaments used for therapy of peripheral arterial occlusive disease, whilst in some countries it is also used very successfully for deficient cerebral circulation.
The clinically well-established action of this product, however, is counteracted by the disadvantage that both the active compound per se and also its first metabolite, 1-(5-hydroxyhexyl)-3,7-dimethylxanthine, which is also pharmacologically active, are subject to rapid and complete biotransformation in animals and humans, this transformation proceeding almost exclusively via enzymatic oxidation of the oxo- or hydroxyhexyl side chain and being associated with a pronounced "liver first-pass" effect. This means that, especially on oral administration, after absorption from the gastrointestinal tract and transportation via the portal vein system to the liver, the most important filter organ for foreign substances, a considerable proportion of the dose administered is already metabolized by medicament-degrading enzymes in the course of the first passage through the liver, so that in spite of complete absorption, only a certain portion of the drug reaches the systemic, general blood circulation in unchanged form. The "first-pass" effect, also called presystemic elimination, thus leads to a reduction in systemic availability of unchanged active substance. However, the actual handicap of a pronounced "first-pass" effect derives less from the oral dose being reduced en route to the systemic circulation than from the fact that this process as a rule exhibits a wide intra- and interindividual variability (Schweiz. med. Wschr. 110 (1980) pages 354-362), which makes it difficult to draw up definitive dosage plans and thus may impair the therapeutic result.
This unsatisfactory state of affairs is the reason for the understandable desire of clinicians and the intensive search of pharmaceutical researchers for novel xanthine compounds which have a considerably greater metabolic stability, coupled with a similarly good or if possible even more potent pharmacological action and the same outstanding tolerance, and thus have a substantially smaller or even negligible "first-pass" effect and consequently decisively improve the reliability of the therapy in respect of the dosage problems described above. Such products could represent a true advance in medicamentous therapy of disturbances in peripheral and cerebral circulation, which are among the most frequent causes of illness and death in the industrialized countries.
Surprisingly, it has now been found that the hitherto uninvestigated alkyl branching of the secondary hydroxyalkyl radical on the carbon atom carrying the hydroxyl group leads, regardless of whether this radical is in the 1- and/or 7-position on the xanthine skeleton, to compounds in which the hydroxyalkyl side chain, now with a tertiary alcohol structure, is stable towards the polyfunctional microsomal oxidases of the liver and which at the same time also meet the other abovementioned therapeutic requirements.
The present invention thus relates to tertiary hydroxyalkylxanthines of the general formula I (see pate
REFERENCES:
patent: 2517410 (1950-08-01), Papesch
patent: 4108995 (1978-08-01), Mohler et al.
patent: 4575795 (1985-05-01), Hinze et al.
patent: 4576947 (1986-03-01), Hinze et al.
patent: 4713455 (1987-12-01), Furrer et al.
Fieser et al., "Advanced Organic Chemistry", Reinhold Publishing Co., New York, 1961, pp. 270-276.
PCT International Preliminary Examination Report, 6 pages.
Mahler, Schweiz. Med. Wschr., 111 (1981), 637-640.
Raaflaub, Schweiz. Med. Wschr., 110 (1980), 354-362.
Von K. Thiele et al., Arzneim-Forsch/Drug. Res., 34 (I), No. 1 (1984).
Gebert Ulrich
Okyayuz-Baklouti Ismahan
Thorwart Werner
Daus Donald G.
Hoechst Aktiengesellschaft
Rivers Diana G.
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