Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1998-01-09
1999-09-28
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514215, 540581, C07D49108, A01N 5700, A61K 3155
Patent
active
059589035
DESCRIPTION:
BRIEF SUMMARY
The present invention concerns novel galanthamine derivatives, a procedure for their preparation, pharmaceutical compositions comprising them and their use notably as cholinesterase inhibitors.
A certain number of cholinesterase inhibitors are used clinically as antagonists of neuromuscular blocking induced by nondepolarized muscular relaxants so as to palliate diverse anomalies linked to cholinergic transmission such as maintenance of muscle force in patients suffering from myasthenia gravis or in the treatment of glaucoma. For several years, pharmacological studies of cholinesterase inhibitors have been developed extensively, leading to the perfection for use of such medications as tacrine. This compound reduces the symptoms of Alzheimer's disease that results from a progressive neurodegenerative process characterized by short and long-term memory loss, cognitive functions and intellectual performances. Among these inhibitors, galanthamine of formula ##STR2## is well known. It is an alkaloid from the family of Amaryllidaceae that was isolated from snowdrop Galanthus Nivalis. This alkaloid is a reversible inhibitor of acetylcholinesterase and is generally used in the treatment of neurodegenerative diseases and, more recently, of the Alzheimer type senile dementias. Galanthamine bromohydrate is used clinically under the commercial name Nivaline.TM.
The invention has thus as its object products of the general formula Ia: ##STR3## in which comprising from 1 to 12 carbon atoms; R'R"R'" in which arylalkyl; arylalkenyl; alkylcarbonyl or arylcarbonyl, the alkyl, alkylenyl and aryl radicals potentially being substituted by one or more identical or different radicals chosen from among the halo, hydroxy, alkoxy, alkylthio, acyl, free carboxy, salified or estcrified, cyano, nitro, mercapto, or amino radicals, the amino radical potentially itself being substituted by one or more identical or different alkyl radicals; or R' and R" are bonded and, with the nitrogen atom to which they are attached, form a heterocycle; arylalkenyl, alkylcarbonyl, or arylcarbonyl, the alkyl, alkylenyl and aryl radicals potentially being substituted by one or more identical or different radicals chosen from among the halo, hydroxy, alkoxy, alkylthio, acyl, free carboxy, salified or esterified, cyano, nitro, mercapto or amino radicals, the amino radical potentially being itself substituted by one or more identical or different alkyl radicals; A and R have the significance indicated above; which R'.sub.9 represents a linear or branched alkyl radical or a linear and branched alkenyl radical, the alkyl and alkenyl radicals potentially being substituted by one or more identical or different radicals chosen from among the halo; hydroxy; alkoxy; alkylthio; acyl; free carboxy, salified or esterified; cyano; nitro; mercapto; amino of formula --NR'R" in which R' and R" are as defined above; cycloalkyl or aryl, the cycloalkyl and aryl radicals potentially themselves being substituted by one or more identical or different radicals chosen from among the halo, hydroxy, alkyl, alkenyl, haloalkyl, alkoxy, alkylthio, acyl, free carboxy, salified or esterified, cyano, nitro or amino radicals potentially being substituted by one or more identical or different alkyl radicals;
The pharmaceutically acceptable X.sup.- anion may be formed by organic or inorganic acids, such as hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, trifluoroacetic, citric, propionic, malonic, succinic, fumaric, tartaric, cinnamic, methanesulfonic and p-toluene-sulfonic acids.
At specific pH-values the product of formula Ia, as defined above is, in equilibrium with the product corresponding to formula Ib ##STR4## in which R, A, R.sub.6, and R.sub.9, have the significance indicated above, according to the following diagram: ##STR5##
The existence of this equilibrium according to the pH-value may be of interest in order to travers the biological barriers according to the method of administration used.
The invention has as object as well products of formula Ib, such as defined above
REFERENCES:
patent: 4663318 (1987-05-01), Davis
patent: 5428159 (1995-06-01), Shieh et al.
patent: 5589475 (1996-12-01), Snorrason
patent: 5633238 (1997-05-01), Snorrason
Chemical Abstracts, vol.115,No. 1, Jul. 8, 1991, C.Paul Bianchi Helvetica Chimica Acta vol. 77 (1-94) pp. 1611-1615.
Christen Yves
Guillou Catherine
Mary Aude
Potier Pierre
Renko Dolor
Ford John M.
Societe de Conseils de Recherches et D'Applications Scientifique
Sripada Pavanaram K
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