Metabolism probes for therapy and diagnosis

Patent metadata

Field	Value
Publication number	US-10189805-B2
Application number	US-201515510217-A
Country	US
Kind code	B2
Filing date	Sep 9, 2015
Priority date	Sep 9, 2014
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

Novel 2-substituted glutamylanides useful as modulators of ASCT2 inhibitors. Compounds of the present invention can be used to treat patients suffering from diseases caused or influenced by abnormal ASCT2 transporter dysfunction.

First claim

The invention claimed is:

1. A compound of the following formula:

wherein:
R 1 is a bond, optionally substituted C 1 -C 6 alkyl, or optionally substituted —(C 1 -C 6 alkyl)—SO 2 —R 2 ;
R 2 is optionally substituted and chosen from morpholino, pyrrolidine, pyrrole, piperidine, pyridine, benzoimidazole, benzothiazole, piperazine, methyl-piperazine;
R 3 is H or optionally substituted C 1 -C 6 alkyl; and
R 4 is NH 2 or NHBoc;

or pharmaceutically acceptable salts thereof.

2. A compound of claim 1 , wherein R 1 is a bond, —CH 2 —, or —CH 2 —CH 2 —.

3. A compound of claim 1 , wherein R 2 is chosen from:

4. A compound of claim 1 , wherein R 3 is —H or

5. A compound of claim 1 , of the following formula:

or a pharmaceutically acceptable salt thereof.

6. A method of modulating ASCT2 function in a patient in need thereof, comprising administering to the patient an effective ASCT2 function modulating amount of a compound of claim 1 .

7. A method of modulating angiogenesis, tumor progression, and/or metastasis comprising the step of administering a compound of claim 1 to a tissue or a subject associated with a disease condition in a therapeutically effective amount to inhibit cellular glutamine uptake via ASCT2.

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

9. A compound comprising:
a compound of claim 1 and an imaging agent coupled thereto.

10. A compound of claim 9 , wherein the imaging agent is a radionuclide.

11. A method of ameliorating a cancer influenced by abnormal ASCT2 transporter dysfunction, comprising administering to a subject in need thereof an effective ASCT2 function inhibiting amount of a compound of the following formula:

wherein:
R 1 is a bond, optionally substituted C 1 -C 6 alkyl, or optionally substituted —(C 1 -C 6 alkyl)—SO 2 —R 2 ;
R 2 is optionally substituted and chosen from morpholino, pyrrolidine, pyrrole, piperidine, pyridine, benzoimidazole, benzothiazole, piperazine, methyl-piperazine;
R 3 is H or optionally substituted C 1 -C 6 alkyl; and
R 4 is NH 2 or NHBoc;

or pharmaceutically acceptable salts thereof; to thereby treat cancer.

12. The method of claim 11 , wherein the cancer is lung, colon, or pancreas cancer.

13. The method of claim 11 , wherein the compound is of the following formula:

or a pharmaceutically acceptable salt thereof.

Assignees

• Univ Vanderbilt

Inventors

• Manning H Charles
• Schulte Michael

Classifications

• C07D235/18

  with aryl radicals directly attached in position 2 · CPC title

• C07D295/135

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07D213/40

  Acylated substituent nitrogen atom · CPC title

• C07C237/04

  the carbon skeleton being acyclic and saturated · CPC title

• C07D295/26 Primary

  Sulfur atoms · CPC title