Prodrugs of glutamine analogs

Patent metadata

Field	Value
Publication number	US-11926640-B2
Application number	US-202117207388-A
Country	US
Kind code	B2
Filing date	Mar 19, 2021
Priority date	Jul 31, 2015
Publication date	Mar 12, 2024
Grant date	Mar 12, 2024

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 ) n —, wherein n is 1;
R 1 is selected from the group consisting of H, C 1-6 alkyl, and substituted C 1-6 alkyl;
R 2 is —C(═O)—O—(CR 3 R 4 ) m —O—C(═O)—R 10 ;
R 2 ′ is selected from the group consisting of H, C 1 -C 6 alkyl, and substituted C 1 -C 6 alkyl;
each R 3 and R 4 are independently H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl,

substituted aryl or
m is 1; and
R 10 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, monosaccharide, acylated monosaccharide, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of methyl, ethyl, and isopropyl.

3. The compound of claim 1 having formula (III):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of H and C 1-6 alkyl;
R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, aryl, and substituted aryl; and
R 10 is C 1-6 alkyl.

4. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

5. The compound of claim 4 selected from the group consisting of:

6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

7. A method of treating cancer in a subject, the method comprising administering to the subject in need thereof a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is hepatocellular cancer, brain cancer, lung cancer, breast cancer, head and neck cancer, pancreatic cancer, prostate cancer, melanoma, colorectal cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, or chronic myelocytic leukemia.

8. The method of claim 7 , wherein the cancer is colorectal cancer.

9. The method of claim 7 , wherein the cancer is breast cancer.

10. The method of claim 7 , wherein the cancer is brain cancer.

11. The method of claim 7 , wherein the cancer is pancreatic cancer.

12. The method of claim 7 , wherein the cancer is prostate cancer.

13. The compound of claim 1 , wherein
R 3 is H; and
R 4 is methyl, iPr, or aryl.

14. The compound of claim 1 , wherein
R 3 and R 4 are each H.

15. The compound of claim 1 , wherein
R 3 and R 4 are each methyl.

16. The compound of claim 3 , wherein R 10 is selected from the group consisting of isopropyl and tert-butyl.

Assignees

• Univ Johns Hopkins
• Ustav Organicke Chemie A Biochemie Av Hacek Over C R V V I

Inventors

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

Classifications

• C07F9/2458 Primary

  of aliphatic amines · CPC title

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07C227/14

  from compounds containing already amino and carboxyl groups or derivatives thereof · CPC title

• C07C245/18

  the carbon skeleton being further substituted by carboxyl groups · CPC title