Design, Synthesis, and Biological Activity of Platinum-benz[c]acridine Hybrid Agents and Methods Associated Therewith

摘要

The present invention relates to the compounds of formula I, pharmaceutically acceptable salts, and solvates thereof:;;wherein the various substituents are as defined herein. The compounds, solvates and salts thereof of Formula I are effective as anti-cancer compounds.

主权项

1. A compound of Formula I, and pharmaceutically acceptable salts and solvates thereof: wherein X is halo, OC(O)R9, nitrate or sulfate; R1 and R2 are amino groups or together with the platinum atom to which they are attached, R1 and R2 form the ring —NH2—(CH2)v—NH2— wherein v is 1, 2, 3, or 4 or R1 and R2 together can be any of the following groups a-h; wherein A is H, —CH3, —OCH3, CF3 or NO2; R3 is —N(R26)—; wherein R26 is hydrogen or C1-C6alkyl; R4 is hydrogen, C1-6 alkyl, or CH2—R12; R6 is independently an amino, a nitro, —NHC(O)(R10), —NHC(O)O(R10), —C(O)NHR10, —OC(O)NHR10, or halo; R10 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, or adamantyl; q is 0, 1, or 2; R5 is a direct bond, —NH— or C1-C6alkylene; or R5 and X together with the atoms to which they are attached form a 6- or 7-membered ring, wherein said 6- or 7-membered ring contains a linking group —C(O)O— or —OC(O)—; R7 is hydrogen, methyl, —CH(R17)(R18), —C(O)O—R18, or —OC(O)—R18; wherein R17 is hydrogen or C1-6 alkyl; R18 is hydrogen, C1-6 alkyl, —CH(R19)(R20), phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide; R19 is hydrogen or C1-6 alkyl; R20 is hydrogen, C1-6 alkyl; R8 is —H or —C1-6alkyl; R9 is hydrogen, C1-6 alkyl, phenyl, naphthyl, C3-6 cycloalkyl, norbornyl, adamantyl, a natural or unnatural amino acid or a peptide; R11 and R12 are independently hydrogen, hydroxyl, C1-6 alkyl, —OCH3, —CF3, NO2, —N3, —COOH, —CONH2, —CH═CH2, —C≡CH, —(CH2)1-6—OH, —(CH2)1-6—N3, —(CH2)1-6—COOH, —(CH2)1-6—CH═CH2, —(CH2)1-6—C≡CH, —(CH2)0-1(—OCH2CH2)—OH, —(CH2)0-1(—OCH2CH2)1-6—N3, or —(CH2)0-1(—OCH2CH2)1-6—COOH or either or both of R11 and R12 contain a reactive group on to which a linker and/or one or more of compound W can be added; E is C1-C6alkylene; G and G1 are independently N or CR16; R16 is hydrogen or methyl; compound W is one or more amino acids, one or more sugars, polymeric ethers, C1-6 alkylene-phenyl-NH—C(O)—R15, folic acid, αvβ3 integrin RGD binding peptide, tamoxifen, endoxifen, EGFR (epidermal growth factor receptor) antibody conjugates, kinase inhibitors, diazoles, triazoles, oxazoles, erlotinib, and mixtures thereof; and Z is independently one or more halo or nitro, or one or more counterions sufficient to balance the charge of the compound; wherein R15 is a peptide; and the benzene ring which is T is optionally present.