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

• US 9,839,701 B2
• Filed: 02/10/2014
• Issued: 12/12/2017
• Est. Priority Date: 02/12/2013
• Status: Active Grant

• Current Assignee: NARD Institute Ltd., Osaka University
• Original Assignee: NARD Institute Ltd., Osaka University
• Inventors: Nagamori, Shushi, Kanai, Yoshikatsu, Nakao, Hidekazu, Ogata, Tokutaro
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): Donohue, Sean R
• Application Number:
  US14/766,826
• Publication Number:
  US 20160038620A1
• Time in Patent Office: 1,401 Days
• Field of Search: 424 189
• CPC Class Codes: A61K 51/0402 carboxylic acid carriers, fatty acids amino acids A61K51/0406
• CPC Class Codes: C07B 2200/05 Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 309/73 to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 323/63 the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Abstract

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

(wherein n is 0 or 1;
R¹ 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;
R² represents —(CH₂)_p—[O(CH₂)_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);
R³ represents a hydrogen atom, a C1-C6 alkyl group, a C7-C16 aralkyl group or a C6-C14 aryl group; and
R⁴ 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.

Claims

1. A compound of formula (I):

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.

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

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.

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

10. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein n is 1, and R¹ 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.