Nitrobenzyl derivatives of anti-cancer agents
Provided herein are compounds of formula I, wherein the variables are defined herein, processes of making them, and methods of treating cancer comprising administering such compounds.
1. A compound of formula (I):
or a pharmaceutically acceptable salt, or a solvate thereof, wherein
X 10 consists of O;
A is C 6 -C 10 aryl, 5-15 membered heteroaryl, or —N═CR 1 R 2 ;
each R 1 and R 2 independently is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR 13 R 14 , or —NR 13 COR 14 ;
each X, Y, and Z independently is hydrogen, CN, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR 13 R 14 , or —NR 13 COR 14 ;
each R independently is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR 13 R 14 , or —NR 13 COR 14 ;
each R 13 and R 14 independently is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether;
wherein L 1 and D are defined as follows:
(1) L 1 is selected from the group consisting of:
R 40 and R 41 are independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, or 5-15 membered heteroaryl;
R 42 is C 2 -C 3 alkylene or heteroalkylene optionally substituted with 1-3 C 1 -C 6 alkyl groups;
V(−) is any anion;
D is a moiety such that D-OH is an anti-cancer drug wherein OH is an aliphatic or a phenolic hydroxy group or is an OH moiety attached to a phosphorous atom; or
(2) L 1 is:
R 40 is defined as above, R 43 is hydrogen or together with D forms a heterocycle ring, and the phenylene moiety is optionally substituted, and
D is a moiety such that D-NR 43 H is an anti-cancer drug; or
(3) L 1 is a bond, —O—C(R 40 R 41 ) 2 —, —O—C(R 40 R 41 )—NR 40 R 41 (+)-C(R 40 R 41 )—, or
wherein R 40 , R 41 and V are defined as above, and
D is an anticancer drug containing a tertiary or a secondary nitrogen atom, wherein the tertiary or the secondary nitrogen atom is bonded to L 1 ; and
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, or ether groups are optionally substituted.
2. The compound of claim 1 , wherein the compound is formula (1A-2) or (1A-3):
wherein D is part of a cytotoxic agent, HO-D, containing at least one hydroxyl group, and the remaining variables are defined as in claim 1 .
3. The compound of claim 1 , wherein the compound is formula (1A-4), (1A-6), or (1A-6-i):
wherein
in formula (1A-4), D is part of a cytotoxic agent, HO-D, containing at least one hydroxyl group,
in formula (1A-6-i), DNR 40 R 41 is a drug,
in formula (1A-6), D is a drug containing a secondary nitrogen atom, where the secondary nitrogen atom is bonded to the methylene group as shown above, and the remaining variables are defined as in claim 1 .
4. The compound of claim 1 , wherein the compound is formula (1A-5) or (1A-7):
wherein
in formula (1A-5), DNR 40 R 41 is a drug,
in formula (1A-7), D is a drug containing a secondary nitrogen atom, where the secondary nitrogen atom is bonded to the methylene group as shown above, and the remaining variables are defined as in claim 1 .
5. The compound of claim 1 , wherein Z is hydrogen; X is hydrogen; and Y is hydrogen or halo.
6. The compound of claim 1 , wherein A is C 6 -C 10 aryl.
7. The compound of claim 6 , wherein A is phenyl.
8. The compound of claim 1 , wherein A is 5-15 membered heteroaryl.
9. The compound of claim 8 , wherein A is pyridyl.
10. The compound of claim 1 , wherein A is —N═CR 1 R 2 where R 1 and R 2 are defined as in claim 1 .
11. The compound of claim 1 , wherein each R is hydrogen.
12. The compound of claim 1 , wherein one of the R groups is hydrogen and the other R group is C 1 -C 6 alkyl, or wherein both the R groups are non-hydrogen substituents as defined in claim 1 .
13. The compound of claim 12 , wherein R is methyl.
14. The compound of claim 1 , wherein each of R 40 , R 41 , and R 43 is independently, hydrogen or methyl and R 42 is —CH 2 —CH 2 — or CH 2 —C(Me) 2 -.
15. A pharmaceutically acceptable composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient or carrier.
16. The compound of claim 1 , wherein the compound is