Compounds and anti-tumor NQO1 substrates
Compounds of Formula (I) can be selectively lethal toward a variety of different cancer cell types. The compounds are useful for the management, treatment, control, or adjunct treatment of diseases, where the selective lethality is beneficial in chemotherapeutic therapy.
1. A compound of the Formula (I):
wherein
R 1 is alkyl;
R 3 is H;
R 2 and R 4 are each independently —X—R;
each X is independently a direct bond, —C(═O)—, or (C 1 -C 20 )alkyl;
each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, (cycloalkyl)heteroalkyl, aryl, heteroaryl, alkoxy, (alkoxy)alkyl, or saccharide;
wherein any alkyl or aryl can be optionally substituted with one or more hydroxy, amino, cyano, nitro, or halo groups;
provided that R 1 , R 2 , and R 4 are not each methyl;
or a salt or solvate thereof
provided that when R 1 , R 2 , and R 3 are methyl, R 4 is not H or methyl; and provided that when R 1 , R 3 , and R 4 are methyl, the group —X—R of R 2 is not acyloxy.
2. The compound of claim 1 wherein R 1 is a straight chain or branched (C 1-20 )alkyl group.
3. The compound of claim 1 wherein R 2 or R 4 is a straight chain or branched (C 1-20 )alkyl group.
4. The compound of claim 1 wherein R 1 is methyl, R 2 is methyl, or R 1 and R 2 are both methyl.
5. The compound of claim 1 wherein R 4 is methyl.
6. The compound of claim 1 wherein:
R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is ethyl; propyl; isopropyl; n-butyl; tert-butyl; isobutyl; n-pentyl; n-hexyl; 3-methybutyl; 3,3-dimethylbutyl; C 8-12 alkyl; cyclooctyl; cyclopropyl; methylcyclopropyl; ethylcyclopropyl; —CH 2 OPO 3 Na 2 ; —CH 2 CH 2 OPO 3 Na 2 ; —CH 2 OH; —CH 2 CH 2 OH; or hydroxypropyl;
R 1 and R 2 are ethyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 and R 2 are propyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 is methyl; R 2 is propyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 is propyl; R 2 is methyl; R 3 is hydrogen; and R 4 is alkyl;
R 1 and R 4 are methyl; R 3 is hydrogen; and R 2 is ethyl, propyl; C 8-12 alkyl; —CH 2 OPO 3 Na 2 ; or —CH 2 OH; or
R 2 and R 4 are methyl, R 3 is hydrogen; and R 1 is ethyl, propyl, C 8-12 alkyl; —CH 2 OPO 3 Na 2 ; or —CH 2 OH.
7. The compound of claim 1 wherein the compound is a compound of Formula IA:
wherein
R 4 is —X—R;
X is a direct bond, —C(═O)—, or (C 1 -C 20 )alkyl;
each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, (cycloalkyl)heteroalkyl, aryl, heteroaryl, alkoxy, or saccharide;
wherein any alkyl or aryl can be optionally substituted with one or more hydroxy, amino, cyano, nitro, or halo groups;
or a salt or solvate thereof.
8. The compound of claim 1 wherein the compound is:
or a salt or solvate thereof.
9. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
10. The pharmaceutical composition of claim 9 wherein the composition comprises a cyclodextrin.
11. The pharmaceutical composition of claim 9 wherein the composition is a liquid for injection or infusion.
12. The pharmaceutical composition of claim 9 wherein the composition is a solid for oral administration.
13. The compound of claim 1 wherein R 1 is a straight chain or branched (C 1-20 )alkyl group and wherein R 2 or R 4 is a straight chain or branched (C 1-20 )alkyl group.
14. The compound of claim 1 wherein R 1 is a straight chain or branched (C 1-12 )alkyl group and wherein R 2 or R 4 is a straight chain or branched (C 1-12 )alkyl group.
15. The compound of claim 7 wherein X is a direct bond and R is (C 1 -C 20 )alkyl.
16. The compound of claim 7 wherein X is a direct bond and R is a substituted (C 1 -C 12 )alkyl.
17. The compound of claim 7 wherein X is a direct bond and R is an unsubstituted (C 1 -C 12 )alkyl.
18. The compound of claim 7 wherein the compound is:
19. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.
20. The pharmaceutical composition of claim 19 wherein the composition comprises a cyclodextrin.