Anthracene-9, 10-dione dioxime compound prodrugs and their uses
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, 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 compound having a structure represented by a formula (I)
or a geometric isomer, a stereoisomer, an enantiomer, a diastereomer, an ester, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein
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 6- to 15-membered heterocycloalkyl;
R 5 is selected from the group consisting of H, —P(O)(OH) 2 , —CHR 7 —O—P(O)(OH) 2 , —C(O)—R 8 , and —CHR 7 —O—C(O)—R 8 ,
R 6 is selected from the group consisting of —P(O)(OH) 2 ; CHR 7 —O—P(O)(OH) 2 , —C(O)—R 8 , and —CHR 7 —O—C(O)—R 8 ,
R 7 is H or an optionally substituted lower alkyl;
R 8 is a lower alkyl, -aryl, heteroaryl or heterocycloalkyl, wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with —NR 9 R 10 and/or OR 12 ;
R 9 and R 10 are independently selected from the group consisting of H, —P(O)(OH) 2 , and optionally substituted lower alkyl;
R 11 is independently selected from the group consisting of lower alkyl, aryl, heteroaryl and heterocycloalkyl wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with —NR 9 R 10 and/or —OH; and
R 12 is H or —P(O)(OH) 2 .
2. The compound of claim 1 , wherein NR 1 R 2 and NR 3 R 4 are selected from.
3. The compound of claim 1 , wherein R 5 is H.
4. The compound of claim 1 , wherein R 6 is —P(O)(OH) 2 .
5. The compound of claim 1 , wherein R 5 is selected from the group consisting of H, —P(O)(OH) 2 , and —CHR 7 —O—P(O)(OH) 2 ; and R 6 is selected from the group consisting of —P(O)(OH) 2 , and —CHR 7 —O—P(O)(OH) 2 .
6. The compound of claim 1 , wherein R 5 is selected from the group consisting of H, —C(O)—R 8 , and —CHR 7 —O—C(O)—R 8 ; and R 6 is selected from the group consisting of —C(O)—R 8 , and —CHR 7 —O—C(O)—R 8 .
7. A compound selected from the group consisting of
a geometric isomer, a stereoisomer, an enantiomer, a diastereomer, an ester, a tautomer, or a pharmaceutically acceptable salt thereof,
wherein AAE is an Amino Acid Ester selected from both natural and unnatural aminoacids.
8. The compound of claim 7 ,
wherein AAE is selected from the group consisting of Glycine, L-Alanine, L-Valine, D-Valine, L-Serine, L-Cysteine, L-Leucine, L-Isoleucine, L-Lysine, L-Phenylalanine, L-Proline, L-Tyrosine and L-Serine.
9. The compound of claim 7 , wherein said compound is selected from the group consisting of
wherein R is selected from the group consisting of H, methyl, isopropyl, t-butyl, —CH 2 OH, —CH 2 CH(Me) 2 , —CH(Me)CH 2 CH 3 , and
10. A compound selected from the group consisting of
a geometric isomer, a stereoisomer, an enantiomer, a diastereomer, an ester, a tautomer, or a pharmaceutically acceptable salt thereof.
11. A compound selected from the group consisting of
or a geometric isomer, a stereoisomer, an enantiomer, a diastereomer, an ester, a tautomer, or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 , wherein said compound is selected from the group consisting of
13. The compound of claim 10 , wherein said compound is selected from the group consisting of
14. The compound of claim 7 , wherein said compound is selected from the group consisting of
15. A compound selected from the group consisting of
wherein R is selected from the group consisting of H, methyl, i-propyl, t-butyl, —CH 2 OH, —CH 2 CH(Me) 2 , —CH(Me)CH 2 CH 3 , and
or a geometric isomer, a stereoisomer, an enantiomer, a diastereomer, an ester, a tautomer, or a pharmaceutically acceptable salt thereof.
16. A compound selected from the group consisting of
wherein R is CH 3 or ethyl, or R and R together form cyclopropyl, cyclopentyl, or pyran, or a geometric isomer, a stereoisomer, an enantiomer, a diastereomer, an ester, a tautomer, or a pharmaceutically acceptable salt thereof.
17. The compound of claim 1 , wherein said compound has the following structure:
18. A compound having a structure represented by a formula (I)
or a geometric isomer, a stereoisomer, an enantiomer, a diastereomer, an ester, a tautomer, or a pharmaceutically acceptable salt thereof:
wherein
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 6- to 15-membered heterocycloalkyl;
R 5 is selected from the group consisting of —P(O)(OH) 2 , —CHR 7 —O—P(O)(OH) 2 , —C(O)—R 8 , and —CHR 7 —O—C(O)—R 8 ,
R 6 is selected from the group consisting of H, —P(O)(OH) 2 ; CHR 7 —O—P(O)(OH) 2 , —C(O)—R 8 , and —CHR 7 —O—C(O)—R 8 ,
R 7 is H or an optionally substituted lower alkyl;
R 8 is a lower alkyl, —OR 11 , -aryl, heteroaryl or heterocycloalkyl, wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with —NR 9 R 10 and/or OR 12 ;
R 9 and R 10 are independently selected from the group consisting of H, —P(O)(OH) 2 , and optionally substituted lower alkyl;
R 11 is independently selected from the group consisting of lower alkyl, aryl, heteroaryl and heterocycloalkyl wherein said lower alkyl, aryl, heteroaryl or heterocycloalkyl is optionally substituted with —NR 9 R 10 and/or —OH; and
R 12 is H or —P(O)(OH) 2 .
19. A method for treating cancer comprising administering to a subject in need thereof a combination of: 1) a pharmaceutically effective amount of a compound of claim 1 , 7 , 10 , 11 , 15 , 16 or 18 ; and 2) a pharmaceutically effective amount of at least one additional anti-cancer agent.
20. The method of claim 19 , wherein the additional anti-cancer agent is selected from the group consisting of antimitotic agents, antimetabolite agents, HDAC inhibitors, proteosome inhibitors, immunotherapeutic agents, FLT-3 kinase inhibitors, and WNT pathway inhibitors.
21. A method of treating or ameliorating cancer or tumor metastasis in a mammal in need thereof comprising administering to said mammal an effective amount of a compound of claim 1 , 7 , 10 , 11 , 15 , 16 or 18 .