Patent ID: 8778914
Filing Date: 2014-07-15
Classification: A61K,A61P

Abstract:
1. A prodrug, comprising general formula (I): wherein unit (a) represents a pharmaceutically and/or diagnostically active compound, said pharmaceutically and/or diagnostically active compound is a cytostatic agent selected from the group consisting of N-nitrosoureas, the anthracyclines doxorubicin, 2-pyrollinoanthracycline, morpholinoanthracycline, diacetatoxyalkylanthracycline, daunorubicin, epirubicin, idarubicin, mitoxantrone and ametantrone; the alkylating agents chlorambucil, bendamustine, melphalan, and oxazaphosphorines; the antimetabolites 5-fluorouracil, 2′-deoxy-5-fluorouridine, cytarabine, cladribine, fludarabine, pentostatine, gemcitabine, 6-thioguanine and 6-mercaptopurine; the folic acid antagonists methotrexate, raltitrexed, pemetrexed and plevitrexed; the camptothecins topotecan, irinotecan, SN-38, 10-hydroxycamptothecin, GG211, lurtotecan, 9-aminocamptothecin and camptothecin; the Vinca alkaloids vinblastine, vincristine, vindesine and vinorelbine; calicheamicins; maytansinoids; auristatins; epothilones; duocarmycins; bleomycin, dactinomycin, plicamycin, mitomycin C and cis-configured platinum(II) complexes; unit (b) represents a cleavable linker which is directly bound to the pharmaceutically and/or diagnostically active compound, said cleavable linker selected from the group consisting of: wherein the pharmaceutically and/or diagnostically active compound (a) is bound to the Z-terminus of the self-immolative group, wherein L and Z are independently selected from O, S and NH, and R represents one or more substituents at the phenyl ring which are independently selected from the group consisting of F, Cl, Br, I, NO wherein the pharmaceutically and/or diagnostically active compound (a) is bound to the Z-terminus of the self-immolative group, wherein L and Z are independently selected from O, S and NH, and R represents one or more substituents at the phenyl ring which are independently selected from the group consisting of F, Cl, Br, I, NO unit (c) represents a spacer group which is directly bound to the cleavable linker, the spacer group selected from the group consisting of a maleinimide—obtained unit, a halogenacetamide—obtained unit, a halogenacetate—obtained unit, a pyridylthio—obtained unit, a vinyl carbonyl—obtained unit, an aziridin—obtained unit, a disulfide—obtained unit, and a substituted or unsubstituted acetylene—obtained unit; and unit (d) represents one or more bisphosphonate groups which are directly bound to the spacer group, the one or more bisphosphonate groups are independently selected from the group consisting of etidronate, clodronate, tiludronate, pamidronate, 1-amino-1,1-diphosphonate methane, risedronate, ibandronate, 1-hydroxy ethylidene-1,1-diphosphonic acid, alendronate and zoledronate, or wherein the one of more bisphosphonate groups (d) are independently one of the following structures (IIa) to (Va), (IIb) to (Vb), (VIa) to (VIIIa) or (VIb) to (VIIIb): wherein o is an integer independently selected from 0 to 12, p is an integer independently selected from 0 to 2, q is an integer independently selected from 0 to 2, r is an integer independently selected from 1 or 2, s is an integer independently selected from 0 to 12, t is an integer independently selected from 0 to 2, u is an integer independently selected from 0 or 1, v is an integer independently selected from 0 to 2, each of X and Y are independently selected from the group consisting of F, Cl, Br, I, NO R E represents O, NH, a carbon-carbon single bond, a carbon-carbon double bond or a carbon-carbon triple bond, and