Platinum-acridine compounds and methods of treating cancers

A method of preparing a compound represented by Formula I-A,

• wherein,
• each L independently represents monodentate NH3 or an amine ligand wherein the nitrogen coordinates to Pt, further wherein the two amine ligands optionally link up to form a diamine ligand (chelate);
• X represents nitrate or halide;
• each Y independently represents
• hydroxide, acetate, or
• wherein q is an integer from 1 to 6 inclusive, Ra represents OH, SH, NH2, COOH, amino acids, CN, an alkyne-containing group, N3, (OCH2CH2)rOC1-4alkyl or (NHCH2CH2)rNHC1-4alkyl, wherein r is an integer from 1 to 4 inclusive;
• o is 0, 1, 2 or 3;
• p is 1 or 2;
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• R1, R2 and R3 each independently represents a C1-10 alkyl, wherein one or more carbons of the C1-10 alkyl is optionally
• (a) replaced with a moiety selected from the group consisting of amino, oxygen, sulfur, amide, ester, carbamate, sulfonamide, sulfonyl, carbonate, ketone, and disulfide;
• or
• (b) substituted with a moiety selected from the group consisting of hydroxy, imino, oxo, cyano, C1-10alkoxy, C1-10 alkylthio, C1_6 alkylsulfonyl, and di-C1-10 alkylamine;
• Wherein optionally,
• (i) R1 and R3 link up to form a 4 to 8 membered ring;
• or
• (ii) R2 and R3link up to form a 5 to 8 membered ring;
• Each R4 is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, or (mono-, di-, or trihalogeno)methyl;
• R5 represents an optional substituent of L and is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, (mono-, di-, or trihalogeno)methyl, or C1-10 alkoxy;
• D represents an optional aromatic ring;
• comprising treating a compound of Formula I-C with an oxidizing agent selected from the group consisting of H2O2, ROOH, and ROOR wherein R is C1-4alkyl, wherein the substituents of Formula I-C are the same as those of I-A except lacking ligand Y.

A method of preparing a compound of Formula I-B,

• wherein,
• each L independently represents monodentate NH3 or an amine ligand wherein the nitrogen coordinates to Pt, further wherein the two amine ligands optionally link up to form a diamine ligand (chelate);
• X represents nitrate or halide;
• Each Y represents a halide;
• o is 0, 1, 2 or 3;
• p is 1 or 2;
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• R1, R2 and R3 each independently represents a C1-10 alkyl, wherein one or more carbons of the C1-10 alkyl is optionally
• (a) replaced with a moiety selected from the group consisting of amino, oxygen, sulfur, amide, ester, carbamate, sulfonamide, sulfonyl, carbonate, ketone, and disulfide;
• or
• (b) substituted with a moiety selected from the group consisting of hydroxy, imino, oxo, cyano, C1-10 alkoxy, C1-10 alkylthio, C1-6 alkylsulfonyl, and di-C1-10 alkylamine;
• Wherein optionally,
• (i) R1 and R3 link up to form a 4 to 8 membered ring;
• or
• (ii) R2 and R3 link up to form a 5 to 8 membered ring;
• R4 is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, or (mono-, di-, or trihalogeno)methyl;
• R5 represents an optional substituent of L and is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, (mono-, di-, or trihalogeno)methyl, or C1-10 alkoxy;
• comprising reacting the compound of Formula I-C with PhIC12 in a non-aqueous solvent at a temperature less than −20° C.

A method of treating a cancer in a subject, comprising:

• (a) determine expression of MATE1 in cancer tissue from the subject;
• (b) administer to the subject of a therapeutically effective amount of a compound of Formula I′, wherein,
• each L independently represents monodentate NH3 or an amine ligand wherein the nitrogen coordinates to Pt, further wherein the two amine ligands optionally link up to form a diamine ligand (chelate);
• X represents nitrate or halide;
• Each Y independently represents a ligand selected from the group consisting of halide,
• hydroxide, pseudohalide, acetate, and
• wherein q is an integer from 1 to 6 inclusive, Ra represents OH, SH, NH2, COOH, amino acids, CN, an alkyne-containing group, N3, (OCH2CH2)rOC1-4alkyl or (NHCH2CH2)rNHC1-4alkyl, wherein r is an integer from 1 to 4 inclusive;
• o is 0, 1, 2, or 3;
• p is 1 or 2;
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• D is an optional aromatic ring;
• R1, R2 and R3 each independently represents a C1-10 alkyl, wherein one or more carbons of the C1-10 alkyl is optionally
• (a) replaced with a moiety selected from the group consisting of amino, oxygen, sulfur, amide, ester, carbamate, sulfonamide, sulfonyl, carbonate, ketone, and disulfide;
• or
• (b) substituted with a moiety selected from the group consisting of hydroxy, imino, oxo, cyano, C1-10 alkoxy, C1-10 alkylthio, C1-6 alkylsulfonyl, and di-C1-10 alkylamine;
• Each R4 is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, or (mono-, di-, or trihalogeno)methyl;
• R5 represents an optional substituent of L and is selected from the group consisting of halogen, cyano, nitro, C1-10 alkylthio, C2-10 alkenyl, C2-10 alkynyl, C1-10 alkoxy, C1-10 dialkylamino, C1-10 alkyl, (mono-, di-, or trihalogeno)methyl, or C1-10 alkoxy.