Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof

摘要

Chemical agents, such as disulfonamide derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine, and similar heterocyclic ring structures, including salts thereof, that act as anti-cancer and anti-tumor agents, especially where such agents modulate the activity of the Wnt/β-catenin signaling pathway, and serve to reduce β-catenin levels present in cells, such as cancer cells, or where the agents modulate levels of gene expression in cellular systems, including cancer cells, are disclosed, along with methods for preparing such agents, as well as pharmaceutical compositions containing such agents as active ingredients and methods of using these as therapeutic agents.

主权项

1. A method of decreasing beta-catenin levels in tumor cells in a mammal comprising administering to said mammal an effective amount of a compound having the structure of Formula I wherein n=1-2 and wherein when n=1, X is selected from CH2, O, CO, and C═NORA and wherein when n=2, X═CH2, Y is O, S, NORA, or NRA, wherein U and V are each O═S═O, wherein RA is selected from H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, —C(═O)RB, —C(═O)ORB, —C(═O)NRBRC, —C(═NRB)RC, —NRBRC, heterocycloalkyl, aryl or polyaromatic, heteroaryl, arylalkyl and alkylaryl, wherein each of said RB and RC is independently H, alkyl, or heteroalkyl, R1, R2, R3, and R4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NR1R2 and NR3R4 can independently combine to form a heterocycloalkyl, R5 and R6 are each independently selected from H, OH, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COORD, CONRDRE, NRDRE, NRDCORE, NRDSO2RE, and NRFCONRDRE;
wherein RD, RE and RF are independently H, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl; provided that is X is O, Y is O and U and V are both O═S═O, then NR1R2 and NR3R4 are not identical then R1 and R3 are each independently selected from H and lower alkyl, and wherein R2 and R4 are each independently selected from lower alkoxy(loweralkyl), di(lower)alkylamino(lower)alkyl, halobenzyl, morpholino(lower)alkyl, or NR1R2 and NR3R4 are independently piperidino, morpholino, piperazino, N-phenylpiperazino, ethylamino, or substituted glycine, and wherein if X is (CH2)2, and Y is O or NOH, then none of R1, R2, R3, and R4 is methyl, and wherein if X is CO and Y is O, then NR1R2 and NR3R4 are not identical, and wherein R1, R2, R3, and R4 are each independently selected from methyl, ethyl, hydroxy-C1-C3-alkyl, SH, RO, COOH, SO, NH2, and phenyl or wherein one or both of non-identical NR1R2 and NR3R4 is unsubstituted piperidino, N-methylpiperazino or N-methyl homopiperazino, wherein said unsubstituted piperidino, N-methylpiperazino or N-methylhomopiperazino NR1R2 and NR3R4 moieties are not identical, and wherein when X is C═O or C═NOH, Y is O or NOH, and one of R1 or R2 and one of R3 or R4 is phenyl then the other of R1 or R2 and R3 or R4 is not H or alkyl, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or geometric isomer thereof.