Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-19
1997-04-15
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
540478, C07D51904, A61K 31475
Patent
active
056209851
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 U.S.C. 371 National Stage filing of PCT FR94/00898 published as WO95/03312 on Feb. 2, 1995.
Antimitotic alkaloids extracted from Catharanthus roseus, which have been used in anticancer chemotherapy for more than thirty years, are mainly represented by vinblastine (R.dbd.CH.sub.3) and vincristine (R.dbd.CHO). ##STR2##
A great number of semi-synthetic derivatives have since been studied both chemically and pharmacologically, and only a few have reached the stage of clinical studies [O. Van Tellingen, J. H. M. Sips, J. H. Beijnen, A. Bult and W. J. Nooijen, Anticancer Research, 12, 1699-1716 (1992)].
Only two additional products, obtained by semi-synthesis, have been marketed worldwide: vindesine by the E. Lilly Laboratories in 1983, and vinorelbine by the Pierre Fabre Laboratories in 1989. ##STR3##
Within the context of our program of research into novel antimitotic agents, we have discovered, surprisingly, that the binary alkaloids of the vinblastine and vinorelbine family react selectively in "superacid", type media, in order to lead to novel products, fluorinated on sites which are inaccessible by the standard chemical routes.
The subject of the present invention is novel chemical compounds derived from binary alkaloids from Catharanthus roseus, their preparation and their therapeutic application.
The compounds of the invention possess the general formula I: ##STR4## in which: n is equal to 1 or 2,
The invention also relates to the salts of the compounds of formula 1 with pharmaceutically acceptable inorganic or organic acids. The acid employed may be, by way of a non-limiting example, sulfuric acid or tartaric acid.
The invention equally relates to the mixtures of diastereoisomers corresponding to configurations of carbon 20' of the compounds of general formula 1, as well as to their mixture in all proportions.
The derivatives of the invention are prepared by reaction of a compound of general formula 2 in superacid medium, originating from the combination of a Bronsted acid such as hydrofluoric acid HF and a Lewis acid such as antimony pentafluoride SbF.sub.5, in the presence of a halogenating reagent such as bromine, a hypochlorite such as calcium hypochlorite or an N-halo imide such as N-chlorosuccinimide or N-bromosuccinimide.
The compounds of general formula 2 possess the structure described below: ##STR5## in which: n, R.sub.1, R.sub.2 and R.sub.3 are defined as above,
The reaction is carried out at a temperature between -60.degree. C. and -15.degree. C. in Teflon vessels according to the following scheme: ##STR6##
The compounds of general formula 1 where R.sub.3 .dbd.H may also be prepared by hydrolysis of the ester function of the compounds 1 where R.sub.3 .dbd.COCH.sub.3. This step is preferably carried out in methanol in the presence of sodium methoxide, according to the following scheme: ##STR7## where 3 corresponds to the compound 1 when R.sub.3 .dbd.COCH.sub.3, and 4 corresponds to the compound 1 when R.sub.3 .dbd.H.
The examples which follow illustrate the invention without, however, limiting the scope thereof.
The spectroscopic characteristics (IR, NMR, high resolution mass confirm the structure of the compounds obtained according to the invention.
The products are described using biogenetic numbering [J. Lemen and W. I. Taylor, Experientia, 21, 508 (1965)].
EXAMPLE 1
To a solution of 33.75 g (156 mmol) of antimony pentafluoride in 33.75 g (1690 mmol) of anhydrous hydrofluoric acid contained in a 125 ml Teflon flask and cooled to -50.degree. C. are added, with magnetic stirring, 2.69 g (2.5 mmol) of vinorelbine ditartrate 2 (n=1, R.sub.1 .dbd.CH.sub.3, R.sub.2 .dbd.OCH.sub.3, R.sub.3 .dbd.COCH.sub.3, R.sub.4 and R.sub.5 .dbd.double bond), followed by 0.48 g (2.7 mmol) of N-bromosuccinimide. The mixture is kept stirring at -50.degree. C. for 20 minutes.
The crude reaction mixture is then poured rapidly onto one liter of (water+ice) mixture to which is added 80 g of sodium carbonate so as to prevent the mixture from heating up. 15 ml of acetone are then added in or
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Berrier Christian
Bigg Dennis
Fahy Jacques
Jacquesy Jean-Claude
Jouannetaud Marie-Paule
Ivy C. Warren
Pierre Fabre Medicament
Smith Lyman H.
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