Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1993-10-12
1995-10-24
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514641, 564270, 564299, C07C29104, A61K 3113
Patent
active
054610788
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/00646 filed Apr. 4, 1992.
This invention relates to novel anthracenes which are of particular value in the treatment of cancer.
Certain aminoalkylamino anthracenes have been described for use as chemotherapeutic agents for the treatment of cancer. However, in common with other cytotoxic chemotherapeutic agents these anthracenes have the disadvantage that their activity is not confined to neoplastic cells and they therefore exhibit various undesirable side effects.
It is an object of the present invention to provide a group of anthracene pro-drugs which are of lesser cytotoxicity than the drug itself, preferably being substantially non-cytotoxic, the pro-drugs being converted in vivo under the anaerobic conditions within neoplastic tissue to the cytotoxic drug thereby mitigating the side effects of administering that drug directly.
Accordingly the present invention comprises a compound of formula (I) ##STR2## in which R.sub.1 is CH.dbd.CHR, CH.dbd.NNHR, CH.dbd.N--A--N(O)R'R" or CH.sub.2 --NH--A--N(O)R'R" and R.sub.2 is separately selected from hydrogen, CH.dbd.CHR, CH.dbd.NNHR, CH.dbd.N--A--(O)R'R" and CH.sub.2 --NH--A--N(O)R'R", wherein A is a C.sub.2-4 alkylene group with a chain length between N or NH and N(O)R'R" of at least 2 carbon atoms, R is a thiazolyl or imidazolyl group in which the tertiary nitrogen atom is in N-oxide form, and R' and R" are each separately selected from C.sub.1-4 alkyl groups and C.sub.2-4 hydroxyalkyl and C.sub.3-4 dihydroxyalkyl groups in which the carbon atom attached to the nitrogen atom does not carry a hydroxy group and no carbon atom is substituted by two hydroxy groups, or R' and R" together are a C.sub.2-6 alkylene group which with the nitrogen atom to which R' and R" are attached forms a heterocyclic group having 3 to 7 atoms in the ring, and R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are each separately selected from hydrogen, hydroxy, halogeno, amino, C.sub.1-4 alkoxy and C.sub.2-8 alkanoyloxy, the compound optionally being in the form of a physiologically acceptable salt.
The compounds of formula (I) contain at least one tertiary nitrogen atom in N-oxide form. Anti-cancer drugs containing a group of this type are not unknown. However, although anthracene drugs have been described for various uses, we are not aware of any previous disclosure of anthracene anti-cancer drugs which contain a tertiary nitrogen atom in N-oxide form. Moreover, the N-oxide compounds of the present invention have the particualr value that they are pro-drugs of lower cytotoxicity which generate a toxic drug in vivo. Thus, it is believed that the N-oxides of the present invention are bioreductively activated within neoplastic tissue to form the cytotoxic compound containing the tertiary nitrogen atom without the oxide atom, thereby providing the desired anti-cancer activity of this compound but with mitigation of its undesired side effects.
A similar approach to that of the present invention is described for aminoalkylamino anthraquinones in UK Patent Application No. GB 2237283 and PCT Application No. GB 90/01574.
As regards groups R.sub.1 and R.sub.2 of the type CH.dbd.CHR and CH.dbd.NNHR, R is preferably a 1,3-thiazolyl N-oxide group or more especially an imidazolyl N-oxide group and is preferably attached to CH.dbd.CH-- or CH.dbd.NNH-- at the 2-position of the ring system. Of the two types of group, CH.dbd.NNHR groups are particularly preferred, especially the group ##STR3##
Although such groups CH.dbd.CHR and CH.dbd.NNHR are of some interest, groups R.sub.1 and R.sub.2 of the type CH.dbd.N--A--N(O)R'R" and especially CH.sub.2 --NH--A--N(O)R'R" are particularly preferred. The group A present in such groups (which may differ among the groups R.sub.1 and R.sub.2) may be branched or more conveniently a straight chain alkylene group, i.e. tetramethylene, especially trimethylene, or particularly ethylene.
R' and R" (which again may differ among the groups R.sub.1 and R.sub.2) may also have a branched carbon chain but are conveniently straight chain whether they
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British Technology Group Limited
Gerstl Robert
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