Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-12-08
1996-04-23
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544295, 544 60, 544125, 514252, 5142332, 5142282, 540575, 540467, 540488, C07D40114, C07D40314, A61K 3155, A61K 31505
Patent
active
055103456
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This is the National Stage of PCT/HU92/00036, filed Jun. 8, 1993.
The invention relates to novel biologically active eburnamenine derivatives of the formula ##STR2## wherein R.sup.1 and R.sup.2 as well as R.sup.3 and R.sup.4, independently from each other, stand for hydrogen, C.sub.2-6 alkyl group, C.sub.2-6 -alkenyl group; or a C.sub.3-10 alicyclic group containing 1 to 3 rings, and this latter group may be substituted by a C.sub.1-6 alkyl or C.sub.2-6 alkenyl group; or nitrogen atom and optionally with an additional oxygen or nitrogen atom, form a 4- to 6-membered, saturated or unsaturated cyclic group which may be substituted by a C.sub.1-6 alkyl or C.sub.2-6 alkenyl group; group; .alpha./.alpha.-, .alpha.-/.beta.- or .beta.-/.alpha.-steric position, as well as their acid additions salts, solvates and pharmaceutical compositions containing these compounds. Furthermore, the invention relates to a process for the preparation of the above compounds and to a method for inhibiting the peroxidation of lipids in mammals.
In the forthcoming formulae the eburnamenin-14-yl group will hereinafter be abbreviated "EBU"; thus any reference to the meaning of the wavy line relates to said line being present in the partial formula "EBU". ##STR3##
BACKGROUND OF THE INVENTION
The compounds of the formula (I) according to the invention are new and possess a significant antioxidant (lipid peroxidation-inhibiting) effect. Thus, they are therapeutically useful.
There are a high number of pathologic processes known in the case of which extremely reactive free oxygen radicals (O.sub.2.sup.-2) are accumulated. The formation of these free radicals leads to the oxidation of unsaturated fatty acids (lipid peroxidation) which are important components of the cell membranes. This is a less specific, cell-destroying process, altering or damaging the biomolecules. In this process, functions of various levels of cells, organs or the whole organism may suffer injuries.
Free radical reactions likely play a causal role in the pathogenesis of ischaemia-induced injuries such as ischaemic intestinal diseases, myocardial ischaemia, haemorrhagic shock, cerebrovascular function disturbances accompanied by ischaemia and renal ischaemia R. J. Korthuis et al.: "Physiology of Oxygen Radicals", Chapter 17, pages 217-249 (1986)!.
Due to their lipid peroxidation-inhibiting effect, antioxidative compounds assure protection against injuries induced by free radicals under ischaemic, hypoxic conditions. Thus, antioxidants as antiischaemic and antihypoxic compounds can be used for the treatment of such clinical pictures.
It can be considered to be proven that free radical reactions play a partial role in the development of symptoms of diseases of the connective tissues and a primary aetiological role in rheumatoid arthritis J. Lunec et al.: "Cellular Antioxidant Defense Mechanisms", Chapter 33, pages 143-159 (1988) (CRC Press Inc., Boca Raton, Fla., 1988)!.
There are several hepatotoxic substances known, the liver-damaging effect of which is presumably a consequence of pathologic free radical reactions. Thus, antioxidative compounds may provide protection against acute and chronic diseases of the liver J. Feher and A. Vereckei: "The Importance of Free Radical Reactions in Medicine" (in Hungarian), pages 99-104 (Editory Medicina, Budapest, 1985)!.
It has essentially been proven that free radical reactions play a role in several haematologic clinical pictures such as sickle-cell anaemia and beta-thalassaemia (Mediterranean anaemia).
Due to the diminished defense ability, O.sub.2 therapy or phototherapy, respectively, may further increase the risk of oxidative injuries in the cases of newburn or premature infants. The use of some antioxidants proved to be favorable in the treatment of such clinical pictures.
Lipid peroxidation occurring as a consequence of injuries is a secondary process. Some cells are immediately destroyed by the injury, which then extends also to the surrounding cells in the next following hours. This is also cause
REFERENCES:
patent: 4547505 (1985-10-01), Cepen et al..
patent: 5099019 (1992-03-01), McCall et al.
Fessenden et al., Organic Chemistry, 2nd ed., 1982, pp. 616-617.
Balogh Gabor
Baloghne Kardos Zsuzsa
Gazdag Maria
Gere Aniko
Incze Maria
Dubno Herbert
Grumbling Matthew V.
Myers Jonathan
Richter Gedeon Vegyeszeti Gyar Rt.
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