Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1992-11-17
1994-05-24
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544267, A61K 3152, C07D47308
Patent
active
053148908
DESCRIPTION:
BRIEF SUMMARY
This invention relates to 1-7 disubstituted xanthine derivatives having antiasthmatic activity, as well as to their physiologically acceptable salts, to their pharmaceutical compositions and to the process for preparation therof.
It has been known for long time that substituted xanthines have bronchodilatory activity.
Indeed, theophylline (1,3-dimethyl-xanthine) is successfully employed since a long time for the treatment of bronchial asthma, though its efficacy is limited by side effects on the cardiovascular system and on the central nervous system (Goodman and Gilman's "The Pharmacological Basis of Therapeutics", MacMillan Publishing Company, 1985).
In more recent times, accurate investigations have been carried out for finding xanthine derivatives endowed with a higher activity and/or with a more selective action than theophylline. Accordingly many alkyl- or hydroxyalkyl-substituted derivatives in the 1, 3, 7 and 8 positions of the xanthine structure have been synthesized.
In all compounds which showed to be the most interesting as bronchodilatory compounds the position 3 always is alkyl-substituted (for instance, enprofylline; bamifylline; doxofylline; the Merck Index, 11th Edition, 1989) and in addition in a structure-activity study presented by Carl G. A. Persson (Carl G. A. Persson, Trends Pharmacol. Sci., 1982, 312-313) it is set forth that the N.sub.3 -alkyl substitution is essential for giving the xanthine structure its bronchodilatory activity.
Just few examples of N.sub.3 -unsubstituted xanthine derivatives exist in the scientific literature, and, on the other side, paraxanthine itself (1,7-dimethyl-xanthine) has been very little investigated as regards its pharmacological effects up to the present time (Aznan Lelo et al., J. Pharm. and Exp. Therapeutics 1989, 248, 315-319; M. J. Arnaud, C. Welsch in "Theophylline and other Methylxanthine" (The Proceedings of an International Symposium, Frankfurt/Main, May 29-30, 1981) Vieweg and Sohn Braunschweig R.F.T.), though it is the most important caffeine (1,3,7-trimethyl-xanthine) metabolite in man.
The properties and the synthesis of 1,7-dialkyl-xanthines have been disclosed in the literature by Frederick G. Mann et al. (Frederick G. Mann et al., J. Chem. Soc. 1945, 751-60), but the authors just limit themselves to report that such compounds have a remarkable anti-thyroid activity.
As regards their synthesis, the 1,7-dialkyl-substituted derivatives cannot be prepared through the well known Traube's procedure (W. Traube; Chem. Ber. 1900, 3035-3056) as modified by Papesch (V. Papesch and E. F. Schroeder; J. Org. Chem. 1951, 16, 1879-1890) starting from a monoalkyl-substituted urea, because 3-alkyl-xanthines are always obtained by means of such procedure, from which compounds the 3,7-dialkyl-xanthines are easily prepared through further alkylation.
The preparation through alkylation of 1-alkyl-xanthines gives, on the other side, a number of problems, because 1-alkyl-xanthines are difficult to synthesize (Mah. T. Schamin et al. J. Med. Chem. 1989, 32, 1231-1237) on the one hand, and on the other hand they would give through alkylation a mixture of 1,3- and 1,7-dialkyl-xanthines which cannot be easily separated.
In the article by Frederick G. Mann mentioned above some alternative synthesis are reported which are however very complicated and give very low yields.
Accordingly, it is possible to think reasonably that the limited development of 1,7-dialkyl-substituted xanthine derivatives is due both to the remarkable difficulties involved in synthesizing them and to the fact that the N.sub.3 -substituted derivatives have been considered up to the present time better compounds as regards their antibronchospastic activity.
The paraxanthine mentioned above also has never been deeply investigated as far as its pharmacological activity is concerned (Aznon Lelo et al., of the bibliographic references quoted herein). However, in laboratory tests carried out by the Applicant itself it was found that paraxanthine does not show any significant antibronchospastic activ
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Mann, F. G., and J. W. G. Porter, "The Synthesis and Properties of 1:7-Dialkyl Xanthines", Journal of the Chemical Society (1945), pp. 751-760.
Mann et al., Jour. Chemical Soc. pp. 751-760.
Agostini Orenzo
Bacciarelli Carla
Bonacchi Graziano
Fedi Mauro
Manzini Stefano
Malesci Istituto Farmacobiologico S.p.A.
Shah Mukund J.
Sripada P. K.
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