Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1994-10-20
1996-07-09
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
C07D25170
Patent
active
055346251
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00625, filed Mar. 26, 1993.
This invention relates to novel 2,4,6-triamino- 1,3,5-triazines, compositions containing them, processes for making them and their use in the treatment of carcinomas, particularly ovarian carcinomas.
Trimelamol [2,4,6-tris{(hydroxymethyl) (methyl) amino)-1,3,5-triazine] is clinically active, particularly against ovarian carcinomas, but its clinical development has been halted due to difficulties with formulation due to instability with respect to the formation of dimers during formulation. It has been established that the half-life of trimelamol activity in humans is short and that may limit its clinical efficacy (I. R. Judson, et al Cancer Res. 49, 5475-5479, 1989). We believe that this is, in part, due to the chemical instability of the N-hydroxymethyl functions resulting in the release of formaldehyde. We have investigated reducing the number of N-hydroxymethyl functions and stabilizing these functions using electron-withdrawing organic groups (defined in the present context as electron-withdrawing relative to methyl), with a view to lengthening the half-life and also improving amenability to formulation, for example in aqueous solutions.
Accordingly this invention provides novel 2,4,6-triamino-1,3,5-triazines having the following general formula: ##STR2## wherein each R.sup.1 which may be the same or different, is hydrogen, alkyl or an electron-withdrawing group and R.sup.2 is hydrogen, alkyl or an electron-withdrawing organic group. Preferably, all three groups R.sup.1 are not hydrogen. The alkyl group R.sup.1 and/or R.sup.2 is preferably a C.sub.1 -C.sub.4 alkyl group, particularly methyl and it is preferred that all three R.sup.1 groups, when alkyl, are all methyl.
BRIEF DESCRIPTION OF THE DRAWINGS
Preferred electron-withdrawing organic groups are --CH.sub.2 CF.sub.3 and --CH.sub.2 .tbd.CH. Because of the greater stability conferred on such compounds by the presence of such electron withdrawing substituents, which may constitute in lengthening the half-life and also in improving amenability to formulation, they may be prepared by allowing tris-hydroxymethyl compounds or precursors thereof to decompose in aqueous organic media and separating from the mixture of products (see FIG. 1) thus generated the appropriate compounds of the present invention, for example by chromatography on silica gel.
We have found that these new analogues of trimelamol have a similar level of activity against carcinomas, particularly ovarian carcinomas, as trimelamol, but are more stable and do not form dimers and polymers and thus are more amenable to formulation.
The compounds of the present invention are also prepared via novel intermediate compounds of the general formula: ##STR3## wherein R.sup.1 and R.sup.2 are as defined above for the formula I
The intermediates are prepared by reacting a cyanuric halide of general formula: ##STR4## wherein X is fluoro or chloro with an amine of the formula R.sup.1 --NH.sub.2 or R.sup.1 R.sup.2 NH.sub.2, wherein R.sup.1 and R.sup.2 are as defined in formula (I), optionally in the presence of caesium fluoride.
In the absence of caesium fluoride, less than three of the substituents on the 1,3,5-triazine ring may be displaced, which allows for the preparation of asymmetrical compounds.
Treatment of the intermediates II with aqueous formaldehyde, optionally in the presence of potassium carbonate, gives the compounds of formula (I). In order to provide compounds of the formula I in which R.sup.1 is methyl and R.sup.2 is hydrogen, starting from compounds of the formula II in which R.sup.1 and R.sup.2 are also methyl and hydrogen respectively, we prefer to use a concentration of formaldehyde of from about 2 to 5% (w/v), for example about 3% (w/v). This provides a final product which contains as the major product the compound of the formula I. A small amount of the corresponding trimelamol (i.e. R.sup.1 =methyl, R.sup.2 =CH.sub.2 OH) and `monomelamol` (i.e. three methyls but only one hydroxymethyl group) compounds will be pr
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Coley Helen M.
Jarman Michael
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