Patent ID: 6071908
Filing Date: 2000-06-06
Classification: A61K,A61P,C07C,C07D

Abstract:
A method of treating neoplastic disease which comprises the steps of:(a) administering to a patient in need of such treatment an effective amount of a radiation-activated cytotoxin prodrug (RACP) which has low toxicity, which is reducible by reducing agents generated by the radiolysis of water and which, upon reduction, releases a sufficient amount of a cytotoxic effector of sufficient cytotoxic potency to kill tumor cells, wherein the RACP is a compound of formula I ##STR32## wherein R.sup.1 represents H or C.sub.1 -C.sub.4 alkyl unsubstituted or substituted with hydroxyl, ether, amino, methylamino or dimethylamino groups;n is 0, 1 or 2, and each M is independently selected from NO.sub.2, 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;wherein arom is a single benzene ring or a 5- or 6-membered aromatic heterocycle containing one or two heteroatoms independently selected from O, S and N;L- is a pharmacologically acceptable counterion;K is H or Me;and wherein R.sup.2 is represented by:(i) a radical of formula II ##STR33## where X is halogen or OSO.sub.2 R.sup.1 (where R.sup.1 is as defined above);A and B are each H or collectively represent an unsubstituted or substituted fused benzene or pyrrole ring;W is selected from SO.sub.2 R.sup.1 (where R.sup.1 is as defined above) and the structures IIa and IIb, where:D is CH or N;E is NH or O;each Q is independently selected from OR.sup.1 and NR.sup.1 R.sup.1 wherein R.sup.1 is as defined above;n is 0, 1, 2 or 3; andHET represents a 5- or 6-membered carbocycle or heterocycle containing one or two heteroatoms independently selected from O, S, and N;(ii) a radical of formula III ##STR34## where X, A, B, Q and n are as defined above; and each D is independently CH or N; andeach E is independently NH or O;(iii) a radical of formula IV ##STR35## where Z is H or NHR.sup.1 (where R.sup.1 is as defined above); n is 0, 1 2, or 3; andeach Y is independently selected from Me and OMe; or(iv) a radical of formula V ##STR36## where each J is independently H or OH; and T is NMe.sub.2, or a moiety of the formula ##STR37## wherein n, M, arom, K and R.sup.1 are as defined for formula I above; and (b) irradiating said tumor cells with ionizing radiation to reduce the prodrug which is present at the locus of said tumor cells to release said cytotoxic effector.