Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-06-09
2000-07-25
Kight, John
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 51, 5442332, 544269, A61K 31435, C07D47122
Patent
active
060937203
DESCRIPTION:
BRIEF SUMMARY
This invention relates to novel racemic and optically active trans apovincaminic acid ester derivatives of formula ##STR2## wherein R is hydrogen or a ##STR3## group, wherein Z is C.sub.1-4 alkyl, optionally substituted aryl, aralkyl, heteroaryl or 14-eburnameninyl group; and compositions containing these compounds. Furthermore, the invention relates to a process for the preparation of the above compounds and compositions.
The compounds according to the invention are new and possess valuable biological activity. Under in vitro conditions they show a significant antioxidant (lipid peroxidation inhibitory) effect. Under in vivo conditions, they exert a remarkable antiischemic and antiamnesic action.
Accordingly, the invention relates also to a method of treatment, which comprises administering a therapeutically active amount of a compound of formula (I) or a therapeutically acceptable salt thereof to a patient to be treated. In the formula (I):
In the meaning of R: Z a C.sub.1-4 alkyl group is a straight or branched chain saturated or unsaturated group such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, vinyl, propenyl group and the like; as aryl group Z may be e.g. phenyl group; as aralkyl group, it may be a benzyl, diphenylmethyl group or the like; as heteroaryl group it may be a five-, six- or seven-membered cyclic group containing identical or different heteroatoms, e.g. nitrogen, oxygen or sulfur atom, such as e.g. pyrryl, furyl, thienyl, pyridyl, pyranyl, pyrazolyl, imidazolyl, pyrimidinyl, morpholinyl groups or the like.
Substituents of the above aryl, aralkyl and heteroaryl groups may be: halogens such as fluorine, chlorine or bromine; C.sub.1-4 alkyl or C.sub.1-4 alkoxy groups; as well as hydroxyl, nitro, amino, cyano, trifluoromethyl groups or the like.
The therapeutically acceptable salts of compounds of formula (I) of the invention may be acid addition salts or quaternary salts.
Apovincaminic acid derivatives of formula (II) used as starting substances can be prepared by the acidic treatment of an appropriate hydroxyimino octahydroindolo[2,3-a]quinolizine derivative as described in the British patent specification No. GB 2,124,214.
There are compounds known from the literature which are structurally related to the compounds of the formula (I). Esters of trans apovincaminic acid with antiinflammatory, anticonvulsive, antiparkinsonian and antiatherosclerotic effects are described in the Hungarian patent specification No. 186,891. Antihypoxic or vasodilatory apovincaminic acid derivatives bearing various side chains are disclosed in the Hungarian patent specification No. 187,733.
Contrary to the above substances known from the literature, the new trans apovincaminic acid ester derivatives possess significant antioxidant, antiamnesic and antiischemic effects.
The continuous preservation of blood circulation is required for a normal functioning of the central nervous system (CNS) since this ensures a suitable supply of the extreme glucose and oxygen demand of brain tissue.
Due to ischemia and reperfusion, cognitive functions are injured: both reversible and irreversible damage may occur depending on the severity and duration of the ischemia. The injuries of structure and function of the neuronal cell membranes can lead to death of the neuron.
Several pathologic processes such as formation of free radicals may occur as a consequence of the ischemia. The formation of free radicals leads to the oxidation of unsaturated fatty acids (lipid peroxidation), which are important components of the membranes. This is a less specific cell-destroying process altering or damaging the biomolecules. Thus, functions of various levels of cells, organs or the whole organism may be injured.
Free radical reactions likely play a causal role in the pathogenesis of several ischemia-induced injuries such as ischemic intestinal diseases, myocardial ischemia, haemorrhagic shock, cerebrovascular function disturbances accompanied by ischemia, ischemic liver injury, renal ischemia and the li
REFERENCES:
patent: 4486437 (1984-12-01), De Vincentiis
patent: 4614824 (1986-09-01), Kreidl et al.
Fitos, I. et al.: Binding of vinca alkaloid analogues to human serum albumin and to alpha-1-acid glycoprotein. Biochem. Pharm. vol. 41, pp. 377-383, 1991.
Auth Ferenc
Czibula Laszlo
Deutsch Nee Juhasz Ida
Farkas Sandor
Farkas Nee Kiriak Maria
Aulakh Charanjit S.
Dubno Herbert
Kight John
Myers Jonathan
Richter Gedeon Vegyeszeti GmbH
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