Aromatic amino acid derivative and positron emission topography (PET) probe using the same

Patent metadata

Field	Value
Publication number	US-9839701-B2
Application number	US-201414766826-A
Country	US
Kind code	B2
Filing date	Feb 10, 2014
Priority date	Feb 12, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

Abstract

A compound having a structure represented by the general formula (I):

(wherein n is 0 or 1;

R 1 represents a hydrogen atom (only if n=0), a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, an optionally substituted amino group, an optionally substituted phenyl group, a C1-C6 alkylthio group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group or a C7-C12 aralkyloxy group;

R 2 represents —(CH 2 ) p —[O(CH 2 ) q ] r —X (wherein X is a halogen atom, p is an integer of 1 to 6, q is an integer of 1 to 4, and r is an integer of 0 to 4);

R 3 represents a hydrogen atom, a C1-C6 alkyl group, a C7-C16 aralkyl group or a C6-C14 aryl group; and

R 4 represents a hydrogen atom or a C1-C6 alkyl group), or a pharmaceutically acceptable salt thereof excels FAMT in terms of the tendency to accumulate intensively in cancer, the affinity for LAT1 and the selectivity for cancer, and can be labeled using an automated synthesizer in clinical settings, and therefore is useful as a highly versatile PET imaging agent.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein n is 0 or 1;
R 1 is a nonradioactive halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, an optionally substituted phenyl group, a C1-C6 alkylthio group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group or a C7-C12 aralkyloxy group;
R 2 is —(CH 2 ) p —[O(CH 2 ) q ] r —X (wherein X is a fluorine atom, p is an integer of 1 to 6, q is an integer of 1 to 4, and r is an integer of 0 to 4);
—OR 2 is at the 4 or 5 position of the benzene ring;
R 3 is a hydrogen atom; and
R 4 is a hydrogen atom or a C1-C6 alkyl group, or
a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has an activity to specifically accumulate in cancer cells.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2-amino-3-(5-(2-fluoroethoxy)-2-iodophenyl)propanoic acid and
2-amino-3-(2-cyclopropyl-5-(2-fluoroethoxy)phenyl)propanoic acid.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
2-amino-3-(2-bromo-5-(2-fluoroethoxy)phenyl)propanoic acid,
2-amino-3-(5-(4-fluorobutoxy)-2-iodophenyl)propanoic acid and
2-amino-3-(5-(2-(2-fluoroethoxy)ethoxy)-2-iodophenyl)propanoic acid.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a radioactive fluorine atom.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is an optically active compound or a mixture of optically active compounds.

7. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. An optically active compound of formula (II):

wherein n is 0 or 1;
R 1 is a nonradioactive halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, an optionally substituted phenyl group, a C1-C6 alkylthio group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group or a C7-C12 aralkyloxy group;
R 2 is —(CH 2 ) p —[O(CH 2 ) q ] r —Y (wherein Y is a leaving group, p is an integer of 1 to 6, q is an integer of 1 to 4, and r is an integer of 0 to 4);
—OR 2 is at the 4 or 5 position of the benzene ring;
R 4 is a hydrogen atom or a C1-C6 alkyl group;
R 5 is a hydrogen atom or a protecting group for a carboxyl group; and
R 6 is a hydrogen atom or a protecting group for an amino group,
or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 1.

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein n is 1, and R 1 is a nonradioactive halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, an optionally substituted phenyl group, a C1-C6 alkylthio group, a C2-C6 alkoxy group, a C1-C6 haloalkoxy group or a C7-C12 aralkyloxy group.

11. A positron emission tomography diagnostic imaging method comprising administering, to a mammal, an effective amount of the compound according to claim 5 or a pharmaceutically acceptable salt thereof, and imaging the mammal with positron emission tomography.

12. A method for detecting a cancer tissue, comprising administering, to a mammal, an effective amount of the compound according to claim 5 or a pharmaceutically acceptable salt thereof, and detecting a cancer tissue.

13. A method for evaluating the malignancy of a cancer, comprising administering, to a mammal, an effective amount of the compound according to claim 5 or a pharmaceutically acceptable salt thereof, and evaluating the malignancy of a cancer.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein X is a radioactive fluorine atom.

Assignees

• Univ Osaka
• Nard Institute Ltd

Inventors

• Nagamori Shushi
• Kanai Yoshikatsu
• Nakao Hidekazu
• Ogata Tokutaro

Classifications

• C07D295/096

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

• C07C229/36

  with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C2601/04

  with a four-membered ring · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title