Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-03-16
1998-05-12
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
548119, C07F 9141
Patent
active
057507104
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to cyclic nitrone derivatives which are usable as free-radical scavengers.
2. Description of the Related Art
A number of cyclic nitrones capable of scavenging free radicals are known at the present time: 5,5-dimethylpyrroline N-oxide (DMPO) is marketed in Europe by various companies such as Aldrich, Fluka and Sigma. This compound, a free-radical trapping agent, is used only in electron paramagnetic resonance experiments. Its application in the pharmaceutical and cosmetics fields is limited on account of its instability and its low solubility in biological media, as well as the instability of its scavenging adducts.
M. J. Turner and G. M. Rosen describe, moreover, in their paper published in J.Med. Chem. 29 (12), 2439-2444 (1986), three cyclic nitrones which proved to be more effective free-radical scavengers than DMPO, namely 5-butyl-5-methyl-1-pyrroline 1-oxide (BMPO), 5,5-di-propyl-1-pyrroline 1-oxide (DPPO) and 2-aza-2-cyclo-pentenespirocyclopentane 2-oxide (CPPO). However, the solubility of these compounds in biological media is insufficient as the result of their lipophilic properties, which are greatly superior to those of DMPO.
SUMMARY OF THE INVENTION
New cyclic nitrones displaying great stability and better solubility in biological media, and which lead to the formation of comparatively more stable scavenging adducts, have now been discovered.
The subject of the invention is cyclic nitrones of general formula I: ##STR1## in which:
R.sub.1 represents a phenyl or alternatively a (C.sub.1 -C.sub.18) alkyl,
R.sub.2 represents a hydrogen or deuterium atom, a phenyl or (C.sub.1 -C.sub.18) alkyl group or a radical Z of formula ##STR2## in which:
A is a single bond, a methylene group or an oxamethylene group (in which the oxygen atom is linked to the phosphorus atom of the radical Z), Y represents an oxygen atom and R represents a hydrogen atom, a (C.sub.1 -C.sub.18) alkyl or a (C.sub.6 -C.sub.18) aryl, or alternatively Y represents a methylene group and R represents a hydrogen atom, a (C.sub.1 -C.sub.17) alkyl or a (C.sub.6 -C.sub.18) aryl,
R.sub.3, R.sub.4 and R.sub.5 represent, independently of one another, a hydrogen or deuterium atom or a phenyl or (C.sub.1 -C.sub.18) alkyl group, and
R.sub.6 represents a hydrogen or deuterium atom, a phenyl or (C.sub.1 -C.sub.18) alkyl group or a radical ##STR3##
A representing a single bond and Y and R being as defined above,
R.sub.7 represents a hydrogen or deuterium atom or a methyl group,
with the proviso that one and only one of the groups R.sub.2 and R.sub.6 represents the radical Z of formula ##STR4##
A representing a single bond, a methylene group or an oxamethylene group (in which the oxygen atom is linked to the phosphorus atom of the radical Z), and R and Y being as defined above,
as well as their corresponding physiologically acceptable salts obtained by the action of an inorganic or organic base.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
A preferred group of compounds of formula I consists of the compounds of the following formula II: ##STR5## in which:
R represents a hydrogen atom, a (C.sub.1 -C.sub.18) alkyl or a (C.sub.6 -C.sub.18) aryl,
R.sub.1 represents a phenyl or alternatively a (C.sub.1 -C.sub.18) alkyl, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 represent, independently of one another, a hydrogen or deuterium atom, a phenyl group or a (C.sub.1 -C.sub.18) alkyl, and
R.sub.7 represents a hydrogen or deuterium atom or a methyl group,
Advantageously, R.sub.1 represents a methyl group and R.sub.7 is a hydrogen or deuterium atom.
Among these preferred compounds, the following may be mentioned 5-diethoxyphosphoryl-5-methyl-1-pyrroline 1-oxide (DEPMPO), 5-phosphono-5-methyl-1-pyrroline 1-oxide, and 5-diethoxyphosphoryl-5-methyl-(2,3,3-.sup.2 H.sub.3)-1-pyrroline 1-oxide (DEPMPO.sub.D).
(C.sub.1 -C.sub.17) alkyl and (C.sub.1 -C.sub.18) alkyl groups are understood to mean groups having a linear or branched chain possessing from 1 to 17 carbon atoms or from 1 to
REFERENCES:
patent: 4099918 (1978-07-01), Keana
Mercier A., B-Phosphonylated Five membered ring nitroxide. . . , Tetrahedron Letters, (32)19, pp. 2125-2128, (1991).
Alberti A. et al, Spin Trapping of Radicals . . . , Gazzetta Chimica Italiana, (113) pp. 869-871, (1983).
Barbe Frejaville Claudine Marie Clemence
Culcasi Marcel
Karoui Hakim
Le Moigne Francois
Pietri Sylvia
Centre National de la Recherche Scientifique (C.N.R.S.)
Ford John M.
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