Prodrugs of glutamine analogs

Patent metadata

Field	Value
Publication number	US-10738066-B2
Application number	US-201916454880-A
Country	US
Kind code	B2
Filing date	Jun 27, 2019
Priority date	Jul 31, 2015
Publication date	Aug 11, 2020
Grant date	Aug 11, 2020

Abstract

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.

First claim

That which is claimed:

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.

Assignees

• Univ Johns Hopkins
• Ústav Organické Chemi A Biochemie Av {Hacek Over (C)}R Vvi
• Ústav Organické Chemie A Biochemie Av {Hacek Over (C)}R Vvi

Inventors

• Slusher Barbara
• Rais Rana
• Tenora Lukas
• Majer Pavel
• Jancarik Andrej

Classifications

• C07C281/20 Primary

  the two nitrogen atoms of the functional groups being doubly-bound to each other, e.g. azoformamide · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/0808

  the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu · CPC title

• C07K5/06156

  and Trp-amino acid; Derivatives thereof · CPC title