Indomethacin analogs for the treatment of castrate-resistant prostate cancer

A method for producing an indomethacin derivative that substantially lacks cyclooxygenase inhibitory activity but that has aldo-keto reductase family 1, member C3 (AKR1C3) inhibitory activity, the method comprising modifying indomethacin, or a derivative or salt thereof, to produce a compound with one of the following structures:

• wherein:
• R1 is selected from the group consisting of OH, OCH3, OCH2CH3 and HNSO2X;
• R2 is hydrogen or R— or S—C1-C6 alkyl;
• R3 is hydrogen or R— or S—C1-C6 alkyl;
• R4 is C1 to C6 alkyl;
• R5 is hydrogen, C1 to C6 alkoxy or halogen;
• R6 is C1 to C6 alkyl or C1 to C6 alkylcarboxylic acid or C1 to C6 alkyl-C(O)OR12 or C1 to C6 alkyl-C(O)N(H)SO2X;
• R7 is hydrogen or C2 to C6 alkyl or C2 to C6 alkylcarboxylic acid or C2 to C6 alkyl-C(O)OR12 or C2 to C6 alkyl- C(O)N(H)SO2X;
• R8 is hydrogen, R- or S-carboxylic acid or C(O)OR12 or C(O)N(H)SO2X;
• R9 is hydrogen, R- or S-carboxylic acid or C(O)OR12 or C(O)N(H)SO2X;
• the ring to which R8 or R9 are bound is cyclopentyl or cyclohexyl;
• R10 is present in two, three, four, or five positions in the phenyl ring and each instance is independently selected from the group consisting of hydrogen, halogen, nitro, C1 to C6 alkyl, singly or multiply halogen substituted C1 to C6 alkyl, C1 to C6 alkoxy, amino, and hydroxy;
• X is methyl or singly or multiply halogen substituted methyl;
• phenyl, optionally singly or multiply substituted phenyl or thiophenyl, wherein the single or multiple substitutions of the phenyl or thiophenyl are each independently selected from the group consisting of halogen, nitro, C1 to C6 alkyl, singly or multiply halogen substituted C1 to C6 alkyl, trifluoromethyl, acetyl, isopropyl, C1 to C6 alkoxy, trifluoromethyloxy, phenoxy, cyano, hydroxy, and amino;
• Y and Z are each individually CH or N;
• m and n are each individually 0 or 1.