Patent IE-910334-A1 (IE)
Title: Glycosyl prodrugs of anthracyclines, a process for the¹preparation thereof and the use thereof in combination with¹functionalized tumor-specific enzyme conjugates
IPC: A61K47/48
Filed: 1991-01-31
Abstract: The present invention relates to glycosyl-anthracycline prodrugs, to processes for their preparation and to their use in combination with functionalised tumour-specific enzyme conjugates for the treatment of cancers, and it specifically relates to 14-O-glycosyl-anthracyclines as prodrugs which can be cleaved by the action of tumour-specific enzyme conjugates to cytotoxic agents, the liberated agent being suitable, by reason of its cytostatic activity, for the treatment of cancers. The invention relates to 14-O-glycosyl-anthracyclines of the formula I and to salts thereof with an inorganic or organic acid  in which R<1>, R<2> and R<3> are, independently of one another, hydrogen, hydroxyl, methoxy, R<4>, R<5> and R<6> are, independently of one another, hydrogen, hydroxyl, halogen, aliphatic acyloxy (C1-C8), benzoyloxy or substituted benzoyloxy such as para-nitrobenzoyloxy, alkyloxy (C1-C8), allyloxy, benzyloxy or substituted benzyloxy, tetrahydropyranyloxy, amino, NH-acyl (C1-C8), NH-(9-fluorenylmethoxycarbonyl), morpholino or substituted morpholino, preferably 3-O-methylmorpholino or 2-cyanomorpholino, R<7> is a carbohydrate of the general formula II  in which R<8> is methyl, hydroxymethyl, acyloxymethyl (C1-C8), alkyloxymethyl (C1-C8), benzyloxymethyl, allyloxymethyl, carboxyl, carboxymethyl or carboxyallyl, R<9>, R<10> and R<11> are, independently of one another, hydrogen, hydroxyl, acyloxy (C1-C8), benzoyloxy or substituted benzoyloxy such as para-nitrobenzoyloxy, alkyloxy (C1-C8), allyloxy, benzyloxy or substituted benzyloxy, amino, NH-acyl (C1-C8) or NH-(9-fluorenylmethoxycarbonyl). Excepted are compounds in which R<4> = R<5> = R<9> = R<10> = O-acetyl and R<6> = R<11> = H in the alpha-L-deoxyfucose conformation. A functionalised tumour-specific enzyme means within the scope of the invention an enzyme of the formula III A-Sp-E III in which A is an antibody or one of its fragments, which have specificity for a tumour-associated antigen, or a biomolecule which accumulates in a tumour, such as EGF (epidermal growth factor), TGF- alpha (transforming growth factor alpha ), PDGF (platelet derived growth factor), IGF I+II (insulin-like growth factor I+II) or a+b FGF (acidic + basic fibroblast growth factor), E is a glycosidase which has little or no immunogenicity, preferably a mammalian glycosidase such as alpha - or beta -glucosidase, alpha -galactosidase, alpha - or beta -mannosidase, alpha -fucosidase, N-acetyl- alpha -galactosaminidase, N-acetyl- beta -N-acetyl- alpha -glucosaminidase or beta -glucuronidase, and Sp (spacer) is a bifunctional sulphide or disulphide containing group of the formula IV X(S)nY IV or (S)n in which X or Y is -CO-R<12>-(N-succinimido)- or -C(=R<13>)-CH2-CH2- where R<12> is -CH2-CH2-, 1,4-cyclohexylidene, 1,3- or 1,4-phenylene or methoxycarbonyl- or 1,4-chlorophenylene and R<14> is O or NH, Y is -C(=R<13>)-CH2-CH2- where R<13> has the stated meaning, and n is 1 or 2, or a polypeptide spacer.