Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-10-07
2000-10-03
Huang, Evelyn Mei
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514183, 540478, 546 52, 546199, A61K 31475, C07D51904, A61P 3790
Patent
active
061273775
DESCRIPTION:
BRIEF SUMMARY
The dimeric alkaloids of Catharanthus roseus and their derivatives, commonly referred to as Vinca alkaloids, have been widely used in anticancer chemotherapy for about thirty years. They are represented by four products: vinorelbine, synthesized from the monomeric alkaloid precursors, catharanthine and vindoline. ##STR2##
STRUCTURES OF THE VINCA ALKALOIDS USED IN CHEMOTHERAPY
In the context of our research studies directed toward obtaining novel derivatives of this family which might lead to novel applications in anticancer chemotherapy, we have adopted an original approach which consists in using the exceptional reactivity of superacid media, which is capable of inducing profound changes in these highly functionalized molecules.
We have thus already prepared a series of compounds difluorinated in position 20', which have hitherto been inaccessible by standard synthetic methods (patent FR 2,707,988 of Jul. 21, 1993, WO 95/03312), and whose pharmacological properties are particularly advantageous. ##STR3##
GENERAL FORMULA OF THE COMPOUNDS DESCRIBED IN PATENT FR 2,707,988
The application of this uncommon chemistry to complex molecules of this type has enabled us to prepare a novel family of halogenated compounds, which are also inaccessible by standard chemistry.
The subject of the present invention, carried out at the Pierre Fabre Research Center, is novel derivatives of Vinca alkaloids, a method for their preparation and their therapeutic application.
The compounds of the invention have the general formula 1, represented schematically below: ##STR4## in which: n=1 or 2,
The invention also relates to the salts of the compounds of general formula 1 with pharmaceutically acceptable inorganic or organic acids. The acid used may be, by way of non-limiting example, sulfuric acid or tartaric acid.
The invention relates both to the isomers corresponding to the R and S configurations of the 4' and 20' carbons of the compounds of general formula 1, and their mixtures in any proportion.
The derivatives of the invention are prepared by reaction of a compound of general formula 2 in superacid medium, obtained by mixing a strong Bronsted acid such as hydrofluoric acid, and a strong Lewis acid such as antimony pentafluoride, in the presence of a reagent which generates species of superelectrophilic type, according to the terminology proposed by G. Olah (Ang. Chem. Int. Ed. Engl., 32, 767-88, 1993). This reagent can consist of a chloro derivative such as methylene chloride, chloroform, carbon tetrachloride, 2,2-dichloropropane or a mixture of these derivatives in all proportions.
The structure of the compounds of formula 2 is described below: ##STR5## in which: R.sub.3 represents a hydroxyl group and R.sub.4 represents a hydrogen atom, in which case compound 2 corresponds to vinblastine, formula 2 corresponds to 3',4'-anhydrovinblastine.
The reactions in superacid medium are carried out in hydrofluoric acid-resistant containers such as Teflon.RTM. or a steel of suitable composition. The derivative of formula 2, in which R.sub.3 and R.sub.4 are defined as above, is dissolved in hydrofluoric acid or, in a chloro derivative defined as above acting as solvent, and added to the superacid mixture, which may optionally already contain a fraction of chloro derivative. This addition is carried out while maintaining the temperature of the medium at a chosen value, of between -80 and -30.degree. C.
At low temperature and in the presence of methylene chloride or carbon tetrachloride, the compounds of formula 1 in which n=2, R.sub.1 =H and R.sub.2 =Cl are predominantly isolated. The compounds of formula 1 in which n=2, R.sub.1 =F and R.sub.2 =Cl are isolated from the same reaction medium in lower proportion. This is summarized in the scheme below: ##STR6##
The derivatives of general formula 1, in which n=1, R.sub.1 and R.sub.2 being defined as above, are prepared by contracting ring C' (n=2.fwdarw.n=1) of the compounds of general formula 1 in which n=2, according to the methods described in the literature (Eur. J. Med. Chem., 18
REFERENCES:
Fahy, J., JACS 119, No. 36, pp. 8576-8577 (Sep. 10, 1997).
Barret Jean-Marc
Duflos Alain
Fahy Jacques
Hill Bridget
Thillaye du Boullay Valerie
Adir et Compagnie
Huang Evelyn Mei
LandOfFree
Vinca alkaloid antimitotic halogenated derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Vinca alkaloid antimitotic halogenated derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Vinca alkaloid antimitotic halogenated derivatives will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-195930