Patent CA-2101104-C (CA)
Title: Amino acid linked nitrogen mustard derivatives and their use as prodrugs in the treatment of tumors
Inventor: BURKE PHILIP JOHN
IPC: C07D213/56
Filed: 1993-07-22
Granted: 2007-01-23
Abstract: Prodrugs, of generic formula I, are disclosed for use in antibody directed enzyme prodrug therapy (ADEPT). The prodrugs are substrates for carboxypeptidase G2 (CPG2) and yield more active cytotoxic drugs than known products of CPG2 catalysed reactions. Formula I is as follows:   (see formula I) wherein R1 and R2 each independently represents chlorine, bromine, iodine, OSO2Me, or OSO2phenyl (wherein phenyl is optionally substituted with 1,2,3,4 or 5 substituents independently selected from C1-4alkyl, halogen, -CN or -NO2);      R1a and R2a each independently represents hydrogen, C1-4alkyl or C1-4haloalkyl;  R3 and R4 each independently represents hydrogen, C1-4 alkyl or C1-4 haloalkyl;      R5a, R5b, R5c and R5d each independently represents hydrogen, C1-4 alkyl optionally containing one double bond or one triple bond, C1-4 alkoxy, halogen, cyano, -NH2, -CONR7R8 (wherein R7 and R8 are as defined below), -NH(C1-4-alkyl), -N(C1-4-alkyl)2 and C2-5alkanoyl; or R5a and R5b together represent a) C4 alkylene optionally having one double bond; b) C3 alkylene ;or c) -CH=CH-CH=CH-, -CH=CH-CH2- or -CH2-CH=CH- each optionally substituted with 1, 2, 3 or 4 substituents said substituents each independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen, cyano, nitro, C2-5alkanoyl and -CONR7R8 (wherein R7 and R8 are as defined below);      X represents O, NH or -CH2-;      Y represents O; 2 represents -V-W where V is -CH2-T- in which T is -CH2-, -O-, -S-, -(SO)- or -(SO2)- (provided that when V has sulphur or oxygen as its second atom, W is other than -COON) and said group V optionally further carrying one or two substituents Q1 and/or Q2 on carbon; wherein Q1 and Q2 each independently represents C1-4 alkyl or halogen; or, when Q1 and Q2 are bonded to adjacent carbon atoms, Q1 and Q2 together may additionally represent a C3-C4alkylene radical optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C1-4alkyl and halogen; and W represents (1) COON, (2) -(C=O)-O-R6 wherein R6 represents a C1-6alkyl, C3-6cycloalkyl or aryl (as defined in 3 below) group; (3) -(C=O)-NR7R8 wherein R7 and R8 each independently represent hydrogen or a C1-6alkyl, C3-6cycloalkyl, aryl, heteroaryl linked to N via carbon or C7-9aralkyl group wherein aryl is phenyl; heteroaryl is a 5 or 6 membered ring containing 1 to 3 heteroatoms selected from the group consisting of nitrogen and sulphur; the aryl moiety per se, the heteroaryl moiety and the aryl moiety of the aralkyl group may be substituted on carbon with 1-4 substituents selected from the group consisting of -COOH, -OH, -NH2, -CH2-NH2, -(CH2)1-4-COOH, tetrazol-5-yl and -SO3H and the alkyl moiety may optionally carry a methyl group; (4) -SO2NHR9 wherein R9 is as defined for R7 but may additionally represent -CF3, -CH2CF3 or aryl as defined above; (S) SO3R10 in which R10 represents H, C1-6alkyl or C3-6cycloalkyl, (6) PO3R10R10 (wherein the R10 radicals, which may be the same or different, are as herein defined) (7) a tetrazol-5-yl group; (8) -CONH-SO2R11 in which R11 represents (a) C3-7cycloalkyl; (b) C1-6-alkyl optionally substituted with substituents selected from the group consisting of aryl as defined below, C1-4-alkyl, CF3 or halogen; and (c) perfluoro-C1-6alkyl; wherein aryl is phenyl or phenyl having 1-5 substituents wherein the substituents are selected from the group consisting of halogen, -NO2, -CF3, C1-4alkyl, C1-4alkoxy, -NH2, -NHCOCH3, -CONH2, -OCH2COOH, -NH(C1-4-alkyl), -N(C1-4-alkyl)2, -NHCOOC1-4alkyl, -OH, -COOH, -CN and -COOC1-4alkyl; and (9)-M-Het wherein b represents S, SO or SO2 and Het represents a.5: or 6 membered heterocyclic aromatic ring linked to M via a carbon atom of the aromatic ring, said aromatic.ring containing 1, 2, 3 or 4-heteroatoms selected from the group consisting of O, N and S said aromatic ring optionally being substituted on carbon atoms of the ring with 1, 2, 3 or 4 substituents selected from the group consisting of -OH, -SH, -CN, -CF3, NH2 and halogen.