Antineoplastic polyethylene conjugates of cytostatic compounds and pharmaceuticals comprising same

摘要

The following are claimed; (1) conjugate addition derivatives (A) of transferrin and albumin are new. The conjugates comprise a thiolated transferrin or albumin and a cytostatic (doxorubicin, daunorubicin, epirubicin, idarubicin, chlorambucil, melphalan, 5-fluorouracil, 5'-deoxy-5-fluorouridine, or cisplatin analogue of formula (I)) derivatised with a maleimide compound of formula of formula (IV). The coupling bond between the maleimide and the cytostatic is an amide, ester, imine, hydrazone, acyl, benzoylhydrazone, oxycarbonyl, acetal or ketal. R' = (CH2)nX, p = 0 and R" = H; or R' = H, p = 0 or 1; R" = (CH2)nX; n = 0-6; X = NH2, OH, OCO(CH2)nCOCR'; R' = H, phenyl or 1-6C alkyl; R = 1-6C aliphatic and Y = Y1; or R = benzyl or optionally substituted phenylene and Y = Y2; Y1 = Y2 or CONHNH2; Y2 = OH, COOH, COCl, COO(CH2)nOH, COO(CH2)nNH2, COO(CH2)nNHNH2, SO3H, SO3Cl, SO2NHNH2, OCOCl, CHO or COR'. (2) bismaleimide derivatives of formula (V). Z = CONH(CH2)mNHCO, COO(CH2)mOCO, C=NH(CH2)mNH=C, C=NNH(CH2)mNHN=C, C=NNHCO(CH2)mCONHN=C; and m = 2-12. (3) chemoimmunoconjugates comprising albumin loaded with 5-30 equivalents of a cytostatic compound as in (1) conjugated to a protein, such as transferrin or a monoclonal antibody against a tumour-associated antigen, especially transferrin, via (V) or an aliphatic or aromatic bismaleimide compound.