Glycosyl prodrugs of anthracyclines, a process for the...

C - Chemistry – Metallurgy – 07 – H

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167/129, 260/208

C07H 15/252 (2006.01) A61K 39/00 (2006.01) A61K 47/48 (2006.01)

Patent

CA 2035385

- 1 - HOE 90/8 001 Abstract of the disclosure: Glycosyl prodrugs of anthracyclines, a process for the preparation thereof and the use thereof in combination with functionalized tumor-specific enzyme conjugates The invention relates to glycosyl prodrugs of anthra- cyclines, a process for the preparation thereof and the use thereof in combination with functionalized tumor- specific enzyme conjugtes for treating cancers, and it specifically relates to 14-O-glycosylanthracyclines as prodrugs which can be cleaved by the action of tumor- specific enzyme conjugates to cytotoxic active substan- ces, where the liberated active substance is suitable because of its cytotoxic activity for the treatment of cancers. The invention relates to 14-O-glycosylanthracyclines of the formula I and the salts thereof with an inorganic or organic acid Image I in which R1, R2 and R3 are, independently of one another, hydrogen, hydroxyl, methoxy, R4, R5 and R6 are, independently of one another, hydrogen, hydroxyl, halogen, aliphatic acyloxy (C1-C8), benzoyloxy or substituted benzoyloxy such as para- nitrobenzoyloxy, alkyloxy (C1-C8), allyloxy, - 2 - benzyloxy or substituted benzyloxy, tetrahydro- pyranyloxy, amino, NH-acyl (C1-C8), NH-(9-fluorenyl- methoxycarbonyl), morpholino or substituted morpholino, preferably 3-O-methylmorpholino or 2- cyanomorpholino, R7 is a carbohydrate of the formula II Image II with R8 being methyl, hydroxymethyl, acyloxymethyl (C1-C8), alkyloxymethyl (C1-C8), benzyloxymethyl, allyloxy- methyl, carboxyl, carboxymethyl or carboxyallyl, R9, R10 and R11 are, independently of one another, hydro- gen, hydroxyl, acyloxy (C1-C8), benzoyloxy or substi- tuted benzoyloxy such as para-nitrobenzoyloxy, alkyloxy (C1-C8), allyloxy, benzyloxy or substituted benzyloxy, amino, NH-acyl (C1-C8) or NH-(9- fluorenylmethoxycarbonyl). Compounds in which R4=R5=R9=R10=O-acetyl and R5-R11=H in the alpha-L-deoxyfucose conformation are excepted. A functionalized tumor-specific enzyme is intended to mean 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 tumor-associatad antigen, or a biomolecule which accumulates in a tumor, such as - 3 - 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 of 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, .beta.- acetyl-.beta.-/N-acetyl-.alpha.-glucosaminidase or .beta.-glucuroni- dase, and Sp (spacer) is a bifunctional sulfide or disulfide- containing group of the formula IV X(S)nY IV or (S)n in which X or Y is -CO-R12(N-succinimido)- or -C(=R13)-CH2-CH2- with R12 being -CH2-CH2-, 1,4-cyclohexylidene, 1,3- or 1,4- phenylene or methoxycarbonyl- or chloro-1,4-phenyl- ene and R14 is O or NH, Y is -C(=R13)-CH2-CH2- where R13 has the stated meaning, and n is 1 or 2, or a polypeptide spacer.

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