Prodrugs of glutamine analogs
The disclosure provides compounds having formula (I): and the pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 2 ′, and X are as defined as set forth in the specification. Compounds having formula (I) are prodrugs that release glutamine analogs, e.g., 6-diazo-5-oxo-L-norleucine (DON). The disclosure also provides compounds having formula (I) for use in treating cancer.
1. A compound having formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X is —CH 2 —;
R 1 is selected from the group consisting of H, methyl, ethyl, isopropyl, C 3 -C 10 cycloalkyl, substituted C 3 -C 10 cycloalkyl, C 2 -C 6 alkenyl and substituted C 2 -C 6 alkenyl;
R 2 is —C(═O)—Y—(CR 3 R 4 ) m —NR 5 R 6 ;
Y is a bond;
m is 1 or 2;
each R 3 and R 4 is independently H, C 1 -C 6 alkyl, aryl or substituted aryl, —(CR 3 R 4 ) m —NR 5 R 6 , or
each R 5 and R 6 is independently H, alkyl, —C(═O)—(CR 3 R 4 ) m H, —C(═O)—(NR 5 R 6 ), or —C(═O)—(CR 3 R 4 ) m —NR 5 R 6 ;
R 2 ′ is selected from the group consisting of H, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl.
2. The compound of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, isopropyl, cyclopentyl, and cyclohexyl.
3. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.
4. The compound of claim 2 , wherein R 1 is selected from the group consisting of methyl, ethyl, and isopropyl.
5. The compound of claim 1 , wherein:
each R 3 is independently H or C 1 -C 6 alkyl;
each R 4 is H; and
each R 5 and R 6 is independently H, alkyl, —C(═O)—(CR 3 R 4 ) m H, —C(═O)—(NR 5 R 6 ), or —C(═O)—(CR 3 R 4 ) m —NR 5 R 6 .
6. The compound of claim 5 , wherein:
R 5 and R 6 are each H.
7. The compound of claim 1 , wherein:
R 5 is H;
R 6 is —C(═O)—(CR 3 R 4 ) m H.
8. The compound of claim 1 , wherein:
R 5 is H;
R 6 is —C(═O)—(CR 3 R 4 ) m —NR 5 R 6 .
9. A compound of formula (IIA):
wherein:
R 1 is selected from the group consisting of H and C 1-6 alkyl;
R 11 is:
R 12 is selected from the group consisting of H, C 1-4 alkyl, and —C(═O)R 13 ; and
R 13 is C 1-4 alkyl.
10. A compound of formula (IIB):
wherein:
R 1 is selected from the group consisting of H and C 1-6 alkyl;
R 11 is:
R 12 is selected from the group consisting of H, C 1-4 alkyl, and —C(═O)R 13 ; and
R 13 is C 1-4 alkyl.
11. The compound of claim 9 , wherein R 1 is selected from the group consisting of methyl, ethyl, and isopropyl.
12. The compound of claim 10 , wherein R 1 is selected from the group consisting of methyl, ethyl, and isopropyl.
13. The compound of claim 9 , wherein R 12 is —C(═O)R 13 .
14. The compound of claim 10 , wherein R 12 is —C(═O)R 13 .
15. The compound of claim 13 , wherein R 13 is methyl.
16. The compound of claim 1 selected from the group consisting of:
17. The compound of claim 9 selected from the group consisting of
18. A pharmaceutical composition comprising:
and an aqueous solution.