Derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine and uses thereof
View Patent ↗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.
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 CH 2 , O, CO, and C═NOR A and wherein when n=2, X═CH 2 ,
Y is O, S, NOR A , or NR A ,
wherein U and V are each O═S═O,
wherein R A is selected from H, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, —C(═O)RB, —C(═O)OR B , —C(═O)NR B R C , —C(═NR B )RC, —NR B R C , heterocycloalkyl, aryl or polyaromatic, heteroaryl, arylalkyl and alkylaryl,
wherein each of said R B and R C is independently H, alkyl, or heteroalkyl,
R 1 , R 2 , R 3 , and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said NR 1 R 2 and NR 3 R 4 can independently combine to form a heterocycloalkyl,
R 5 and R 6 are each independently selected from H, OH, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COOR D ,
CONR D R E , NR D R E , NR D COR E , NR D SO 2 R E , and NR F CONR D R E ;
wherein R D , R E and R F 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
NR 1 R 2 and NR 3 R 4 are not identical then R 1 and R 3 are each independently selected from H and lower alkyl, and wherein R 2 and R 4 are each independently selected from lower alkoxy(loweralkyl), di(lower)alkylamino(lower)alkyl, halobenzyl, morpholino(lower)alkyl, or NR 1 R 2 and NR 3 R 4 are independently piperidino, morpholino, piperazino, N-phenylpiperazino, ethylamino, or substituted glycine,
and wherein if X is (CH 2 ) 2 , and Y is O or NOH, then none of R 1 , R 2 , R 3 , and R 4 is methyl,
and wherein if X is CO and Y is O, then NR 1 R 2 and NR 3 R 4 are not identical, and wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from methyl, ethyl, hydroxy-C 1 -C 3 -alkyl, SH, RO, COOH, SO, NH 2 , and phenyl or wherein one or both of non-identical NR 1 R 2 and NR 3 R 4 is unsubstituted piperidino, N-methylpiperazino or N-methyl homopiperazino, wherein said unsubstituted piperidino, N-methylpiperazino or N-methylhomopiperazino NR 1 R 2 and NR 3 R 4 moieties are not identical,
and wherein when X is C═O or C═NOH, Y is O or NOH, and one of R 1 or R 2 and one of R 3 or R 4 is phenyl then the other of R1 or R 2 and R 3 or R 4 is not H or alkyl,
or a pharmaceutically acceptable salt, ester, amide, stereoisomer or geometric isomer thereof.
2. The method of claim 1 , wherein X is CH 2 and n=1 or 2 and Y is O or S.
3. The method of claim 1 , wherein X is CH 2 and n=1 or 2 and Y is NOR A , or NR A .
4. The method of claim 1 , wherein X is O, and Y is O or S.
5. The method of claim 1 , wherein X is O, and Y is NOR A , or NR A .
6. The method of claim 1 , wherein X is CO and Y═O.
7. The method of claim 1 , wherein the compound has formula II
wherein R 7 and R 8 are independently selected from H and SO 2 NR 3 R 4 and one of R 7 or R 8 is hydrogen and the other substituents have the meanings as defined in claim 1 .
8. The method of claim 7 , wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from H, alkyl, cycloalkyl, alkenyl, and alkynyl.
9. The method of claim 7 , wherein NR 1 R 2 and NR 3 R 4 are each independently a 6- to 15-membered heterocycloalkyl.
10. The method of claim 1 , wherein X is CO and Y is NOR A or NR A .
11. The method of claim 1 , wherein X is C═NOR A and Y is O.
12. The method of claim 1 , wherein X is C═NORA and Y is NORA.
13. The method of claim 1 , wherein said compound has Formula III
wherein R 7 and R 8 are independently selected from H and SO 2 NR 3 R 4 , wherein one of R 7 and R 8 is hydrogen and the other substituents have the meanings as defined in claim 1 .
14. The method of claim 13 , wherein R 1 , R 2 , R 3 , and R 4 are each independently selected from H, alkyl, cycloalkyl, alkenyl, or alkynyl.
15. The method of claim 1 , wherein said compound has the following formula: