Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-05-07
2000-06-06
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514290, 514399, 514400, 514414, 514424, 514501, 514643, 544126, 546 6, 546102, 546104, 5483271, 548455, 548512, 552301, 564282, 564284, 556146, A61K 3114, A61K 3140, A61K 31435, C07D21904, C07D20942, C07C22534
Patent
active
060719087
DESCRIPTION:
BRIEF SUMMARY
This invention relates to cancer therapy. More particularly, it relates to the use of ionising radiation to activate drugs to form cytotoxic species in hypoxic microenvironments, to methods of treating neoplastic disease, to a new class of compounds for use in such treatments and to methods for preparing these compounds.
BACKGROUND TO THE INVENTION
Ionising radiation is widely used to treat neoplastic disease, but its effectiveness appears often to be limited by the presence of radioresistant hypoxic cells in tumours. At present there is no generally-useful method for eliminating these hypoxic tumour cells. One approach, being evaluated clinically at present, is the use of compounds which are selectively toxic to cells under hypoxic conditions. The most important compounds of this type are known as bioreductive drugs (BD) because they are activated metabolically by enzymatic reduction to form cytotoxic products under hypoxic conditions. In general, the selectivity of these compound, to hypoxic cells is a consequence of reoxidation of the initial one-electron reduction product by dioxygen, resulting in futile redox cycling and suppression of net reduction in oxygenated tissue.
The mechanism of activation of most BD is as follows: ##STR1##
BD are however likely to have two main limitations in clinical use.
The first of these is that enzymatic activation of BD is not restricted exclusively to hypoxic environments in tumours, and these drugs will therefore have some toxic effect against normal, well-oxygenated tissues. In particular, reductive activation by oxygen-insensitive pathways (obligate 2-electron reduction, which bypasses the O.sub.2 -sensitive intermediate) may sometimes be a limitation.
A second limitation of BD is that, to be effective, enzymes capable of activating the bioreductive drug must be expressed at a high level in the tumour. This is not a condition which will be met by all tumours.
An alternative approach involving activation of a prodrug was reported by Nishimoto et al in J. Med. Chem 35:2712-2715 (1992). In this approach, radiolytic activation of a 5-fluorouracil (5-FU) dimer was suggested as a radiosensitisation strategy in mice. However, it is apparent that radiolytic activation of the reported 5-FU dimer would not be clinically effective as the yield of cytotoxin was too low (a theoretical maximum yield in the order of 2 .mu.mol/kg at the radiation dose used (20Gy)).
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a method of effectively treating neoplastic disease which is not subject to the limitations of BD therapy, or at least to provide the public with a useful choice.
Accordingly in a first aspect, the invention provides a method of treating neoplastic disease which comprises the steps of: amount of a radiation-activated cytotoxin prodrug (RACP) which has low toxicity, which can be reduced by reducing agents generated by the radiolysis of water (the aquated electron and/or the hydrogen radical) and which, upon reduction, releases a sufficient amount of an effector of sufficient cytotoxic potency to kill tumour cells; and the locus of said tumour cells to release said cytotoxic effector.
The RACP can be of formula I ##STR2## wherein R.sup.1 represents H or C.sub.1 -C.sub.4 alkyl optionally substituted with hydroxyl, ether, amino, methylamino or dimethylamino groups; CF.sub.3, CH.sub.2 OR.sup.1, COR.sup.1, CONHR.sup.1, OR.sup.1, NR.sup.1 R.sup.1 and SO.sub.2 R.sup.1 wherein R.sup.1 is as defined above; heterocycle containing one or two heteroatoms independently selected from O, S and N; ##STR3## where X is halogen or OSO.sub.2 R.sup.1 (where R.sup.1 is as defined above); fused benzene or pyrrole ring system; the structures IIa and IIb, where: R.sup.1 is as defined above; or two heteroatoms independently selected from O, S and N; ##STR4## where X, A, B, Q and n are as defined above; and each D is independently CH or N; and ##STR5## where Z is H or NHR.sup.1 (where R.sup.1 is as defined above); n is 0, 1, 2 or 3; and ##STR6## where each J is in
REFERENCES:
Journal of the American Chemical Society, vol. 112, No. 24, Nov. 21, 1990, DC US, pp. 8961-8971, XP002019527 Dale L. Boger et al: "Duocarmycin-pyrindamycin DNA alkylation properies an identification, systhesis, and evaluation of agents incorporating the pharmacophore of the duocarmyci-pyrindamycin alkylation subnit." See the whole document.
Journal of Medicinal Chemistry, vol. 35, No. 14, Jul. 10, 1992, Washington US, pp. 2711-2712, XP002019528 Sei-Ichi Nishimoto et al: "1-(5"-flourouracil, a novel N(1)-C(5)-linked dimer that releases 5-flourouracil by radiation activation under hypoxix conditions" cited in the application see whole document.
Journal of Medicinal Chemistry, vol. 36, No. 17, Aug. 20, 1993, Washington US, pp. 2578-2579, XP002019529 Moana Tercel et al: "Nitrobenzyl mustard quarternary salts: a new class of hypoxia-selective cytotoxins showing very high in vitro selectivity" cited in the application see whole document.
Journal of Medicinal Chemistry, vol. 36, No. 13, Jun. 25, 1993, Washington US, pp. 1839-1846, XP002019530 David C> Ware et al: "Hypoxia-selective antitumar agents. 7. Metal complexes of aliphatic mustards as a new class of hypoxia-selective cytotixins. Synthesis and evaluation of cobalt(III) complexes of bidentate mustards" cited in the application see the whole document.
Denny William A.
Tercel Moena
Wilson William R.
Auckland UniServices Limited
Higel Floyd D.
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