Compounds and anti-tumor NQO1 substrates

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 or a bridging group, wherein the bridging group is —O—, —S—, —NH—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, or a linker of the formula —W-A-W—, wherein

each W is independently —N(R′)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O) 2 —, —N(R′)—, —C(═O)—, —(CH 2 ) n — where n is 1-10, or a direct bond, wherein each R′ is independently H, (C1-C6)alkyl, or a nitrogen protecting group; and

each A is independently (C 1 -C 20 )alkyl, (C 2 -C 16 )alkenyl, (C 2 -C 16 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, —(OCH 2 —CH 2 ) n — where n is 1 to about 20, —C(O)NH(CH 2 ) n — wherein n is 1 to about 6, —OP(O)(OH)O—, —OP(O)(OH)O(CH 2 ) n — wherein n is 1 to about 6, or (C 1 -C 20 )alkyl, (C 2 -C 16 )alkenyl, (C 2 -C 16 )alkynyl, or —(OCH 2 —CH 2 ) n — interrupted between two carbons, or between a carbon and an oxygen, with a cycloalkyl, heterocycle, or aryl group;

each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (cycloalkyl)heteroalkyl, (heterocycloalkyl)heteroalkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, hydrogen, hydroxy, hydroxyalkyl, alkoxy, (alkoxy)alkyl, alkenyloxy, alkynyloxy, (cycloalkyl)alkoxy, heterocycloalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COR x , —COOR x , —CONHR x , —NHCOR x , —NHCOOR x , —NHCONHR x , —N 3 , —CN, —NC, —NCO, —NO 2 , —SH, -halo, alkoxycarbonyl, alkylaminocarbonyl, sulfonate, sulfonic acid, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, R x S(O)R y —, R x S(O) 2 R y —, R x C(O)N(R x )R y —, R x SO 2 N(R x )R y —, R x N(R x )C(O)R y —, R x N(R x )SO 2 R y —, R x N(R x )C(O)N(R x )R y —, carboxaldehyde, acyl, acyloxy, —OPO 3 H 2 , —OPO 3 Z 2 where Z is an inorganic cation, or saccharide; where each R x is independently H, OH, alkyl or aryl, and each R y is independently a group W;

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;

provided that when R 1 , R 2 , and R 4 are methyl, R 3 is not H or methyl.

2. The compound of claim 1 wherein R 4 is a (C 1-20 )alkyl group.

3. The compound of claim 1 wherein R 1 is a branched (C 1-20 )alkyl group.

4. The compound of claim 1 wherein R 2 is a (C 1-20 )alkyl group.

5. The compound of claim 1 wherein R 1 is a straight chain (C 1-20 )alkyl group.

6. The compound of claim 1 wherein R 4 is a (C 1-20 )alkyl group.

7. The compound of claim 1 wherein R 1 is methyl.

8. The compound of claim 1 wherein R 2 is methyl.

9. The compound of claim 1 wherein R 1 and R 2 are both methyl.

10. The compound of claim 1 wherein R 4 is methyl.

11. A compound of Formula (I):

wherein

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is 2-methyl-propane;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is butyl;

R 1 and R 4 are methyl and R 3 is hydrogen; and R 2 is ethyl;

R 1 and R 2 are methyl and R 3 is hydrogen; and R 4 is ethyl;

R 1 is methyl; R 3 is hydrogen; R 2 is propyl; and R 4 is butyl;

R 1 and R 4 are methyl; R 2 is propyl and R 3 is hydrogen;

R 1 is propyl; R 2 and R 4 are methyl and R 3 is hydrogen;

R 1 and R 2 are ethyl; R 3 is hydrogen; and R 4 is methyl;

R 1 is propyl; R 2 is methyl; R 3 is hydrogen; and R 4 is butyl;

R 1 and R 2 are propyl; R 3 is hydrogen; and R 4 is butyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is C 12 alkyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is tert-butyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is hydroxypropyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is 3,3-dimethylbutyl [—CH 2 CH 2 C(CH 3 ) 2 CH 3 ];

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is 3-methybutyl [—CH 2 CH 2 CH(CH 3 )CH 3 ];

R 2 and R 4 are methyl; R 3 is hydrogen; and R 1 is ethyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is propyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is n-pentyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is n-hexyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is isopropyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is cyclooctyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is cyclopropyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is methylcyclopropyl;

R 1 and R 2 are methyl; R 3 is hydrogen; and R 4 is ethylcyclopropyl;

R 2 and R 4 are methyl; R 3 is hydrogen; and R 1 is C 12 alkyl;

R 1 and R 4 are methyl; R 3 is hydrogen; and R 2 is C 12 alkyl;

R 2 is —CH 2 OPO 3 Na 2 ; R 1 and R 4 are methyl; and R 3 is hydrogen;

R 2 and R 4 are methyl; R 1 is —CH 2 OPO 3 Na 2 ; and R 3 is hydrogen;

R 1 and R 2 are methyl; R 4 is —CH 2 OPO 3 Na 2 ; and R 3 is hydrogen;

R 1 and R 2 are methyl; R 4 is —CH 2 CH 2 OPO 3 Na 2 ; and R 3 is hydrogen;

R 2 is —CH 2 OH; R 1 and R 4 are methyl; and R 3 is hydrogen;

R 2 and R 4 are methyl; R 1 is —CH 2 OH; and R 3 is hydrogen;

R 1 and R 2 are methyl; R 4 is —CH 2 OH; and R 3 is hydrogen; or

R 1 and R 2 are methyl; R 4 is —CH 2 CH 2 OH; and R 3 is hydrogen.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

13. A composition comprising a compound of claim 1 and hydroxypropyl-β-cyclodextrin (HPβCD).

14. A method of treating cancer characterized by tumor cells with elevated NQO 1 levels comprising:

administering to a patient affected by such cancer a therapeutically effective amount of a compound of Formula (I):

R 1 , R 2 , R 3 , and R 4 are each independently —H or —X—R;

each X is independently a direct bond or a bridging group, wherein the bridging group is —O—, —S—, —NH—, —C(═O)—, —O—C(═O)—, —C(═O)—O—, —O—C(═O)—O—, or a linker of the formula —W-A-W—, wherein

each W is independently —N(R′)C(═O)—, —C(═O)N(R′)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O) 2 —, —N(R′)—, —C(═O)—, —(CH 2 ) n — where n is 1-10, or a direct bond, wherein each R′ is independently H, (C1-C6)alkyl, or a nitrogen protecting group; and

each A is independently (C 1 -C 20 )alkyl, (C 2 -C 16 )alkenyl, (C 2 -C 16 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, —(OCH 2 —CH 2 ) n — where n is 1 to about 20, —C(O)NH(CH 2 ) n — wherein n is 1 to about 6,

—OP(O)(OH)O—, —OP(O)(OH)O(CH 2 ) n — wherein n is 1 to about 6, or (C 1 -C 20 )alkyl, (C 2 -C 16 )alkenyl, (C 2 -C 16 )alkynyl, or —(OCH 2 —CH 2 ) n — interrupted between two carbons, or between a carbon and an oxygen, with a cycloalkyl, heterocycle, or aryl group;

each R is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (cycloalkyl)heteroalkyl, (heterocycloalkyl)heteroalkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, hydrogen, hydroxy, hydroxyalkyl, alkoxy, (alkoxy)alkyl, alkenyloxy, alkynyloxy, (cycloalkyl)alkoxy, heterocycloalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COR x , —COOR x ,

—CONHR x , —NHCOR x , —NHCOOR x , —NHCONHR x , —N 3 , —CN, —NC, —NCO, —NO 2 , —SH, -halo, alkoxycarbonyl, alkylaminocarbonyl, sulfonate, sulfonic acid, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, R x S(O)R 3 —, R x S(O) 2 R y —, R x C(O)N(R x )R y —, R x SO 2 N(R x )R y —, R x N(R x )C(O)R y —, R x N(R x )SO 2 R y —, R x N(R x )C(O)N(R x )R y —, carboxaldehyde, acyl, acyloxy, —OPO 3 H 2 , —OPO 3 Z 2 where Z is an inorganic cation, or saccharide; where each R x is independently H, OH, alkyl or aryl, and each R y is independently a group W;

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;

provided that when R 1 , R 2 , and R 3 are methyl, R 4 is not H or methyl;

wherein the cancer cells are treated, killed, or inhibited from growing.

15. The method of claim 14 wherein the cancer cells are malignant.

16. The method of claim 15 wherein the malignant cancer cells are Non-Small-Cell Lung Carcinoma.

17. A method of treating a cancer cell having an elevated NQO1 level comprising:

exposing the cancer cell to a therapeutically effective amount of a compound of claim 1 , wherein the cancer cell is treated, killed, or inhibited from growing.

18. The method of claim 14 wherein the cancer cells are in the form of a solid tumor.

19. A compound of the Formula (I):

wherein

R 4 is —X—R;

X is a bridging group, wherein the bridging group is —C(═O)—, —C(═O)—O—, or a linker of the formula —W-A-W—, wherein

each W is independently —N(R′)C(═O)—, —C(═O)N(R′)—, —C(═O)O—, —S(O)—, —S(O) 2 —, —N(R′)—, —C(═O)—, —(CH 2 ) n — where n is 1-10, or a direct bond, wherein each R′ is independently H, (C 1 -C 6 )alkyl, or a nitrogen protecting group; and

A is (C 1 -C 20 )alkyl, (C 2 -C 16 )alkenyl, (C 2 -C 16 )alkynyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, —(OCH 2 —CH 2 ) n — where n is 1 to about 20, —C(O)NH(CH 2 ) n — wherein n is 1 to about 6, —OP(O)(OH)O—, —OP(O)(OH)O(CH 2 ) n — wherein n is 1 to about 6, or (C 1 -C 20 )alkyl, (C 2 -C 16 )alkenyl, (C 2 -C 16 )alkynyl, or —(OCH 2 —CH 2 ) n — interrupted between two carbons, or between a carbon and an oxygen, with a cycloalkyl, heterocycle, or aryl group;

R is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, (cycloalkyl)alkyl, (heterocycloalkyl)alkyl, (cycloalkyl)heteroalkyl, (heterocycloalkyl)heteroalkyl, aryl, heteroaryl, (aryl)alkyl, (heteroaryl)alkyl, hydrogen, hydroxy, hydroxyalkyl, alkoxy, (alkoxy)alkyl, alkenyloxy, alkynyloxy, (cycloalkyl)alkoxy, heterocycloalkyloxy, amino, alkylamino, aminoalkyl, acylamino, arylamino, sulfonylamino, sulfinylamino, —COR x , —COOR x , —CONHR x , —NHCOR x , —NHCOOR x , —NHCONHR x , —N 3 , —CN, —NC, —NCO, —NO 2 , —SH, -halo, alkoxycarbonyl, alkylaminocarbonyl, sulfonate, sulfonic acid, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aminosulfonyl, R x S(O)R y —, R x S(O) 2 R y —, R x C(O)N(R x )R y —, R x SO 2 N(R x )R y —, R x N(R x )C(O)R y —, R x N(R x )SO 2 R y —, R x N(R x )C(O)N(R x )R y —, carboxaldehyde, acyl, acyloxy, —OPO 3 H 2 , —OPO 3 Z 2 where Z is an inorganic cation, or saccharide; where each R x is independently H, OH, alkyl or aryl, and each R y is independently a group W;

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.

20. The compound of claim 19 wherein the compound is:

or a salt or solvate thereof.