N-alkoxyamide conjugates as imaging agents

Patent metadata

Field	Value
Publication number	US-9393329-B2
Application number	US-201414492896-A
Country	US
Kind code	B2
Filing date	Sep 22, 2014
Priority date	Jul 8, 2009
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

The present disclosure is directed to compounds, diagnostic agents, and related methods. In some cases, methods for treating patients are provided. More specifically, the disclosure provides compounds, diagnostic agents, and kits for detecting and/or imaging and/or monitoring elastin rich tissues. In addition, the disclosure provides methods of detecting and/or imaging and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurism, vasculitis, other diseases of the arterial wall, and/or damage or structural changes in ligaments, uterus, lungs or skin, as indicated by changes in total vessel wall area, internal lumen size, and exterior arterial perimeter.

First claim

What is claimed is:

1. A method of detecting, imaging, and/or monitoring a patient comprising the steps of:
administering to the patient a chelated imaging agent; and
acquiring an image of a site of concentration of the chelated imaging agent in the patient by a diagnostic imaging technique;
wherein the chelated imaging agent comprises a compound comprising at least one chelator moiety, and an imaging agent bound to the at least one chelator moiety;
wherein the compound is of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
X is N, 0 , S, or P;
R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, alkylarylalkyl, alkoxyalkyl, heteroalkyl, and heterocyclylalkyl;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, and carbonyl; and
R 4 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, and heterocyclylalkyl;
wherein each R 1 , R 2 , R 3 , and R 4 is independently unsubstituted or substituted with one or more of the following: alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, —NR 19 R 20 , —SH, —OH, —PR 19 R 20 , —P(O)R 21 R 22 , —CO 2 H, ═O, halo, trifluoromethyl, —CF 2 H, —CH 2 F, cyano, —CO 2 R 24 , —C(═O)R 24 , —C(═O)N(R 24 ) 2 , —CHO, —CH 2 OR 24 , —OC(═O)R 24 , —OC(═O)OR 24 , —OR 24 , —OC(═O)N(R 24 ) 2 , —NR 24 C(═O)R 24 , —NR 24 C(═O)OR 24 , —NR 24 C(═O)N(R 24 ) 2 , —NR 24 SO 2 N(R 24 ) 2 , —NR 24 SO 2 R 24 , —SO 3 H, —SO 2 R 24 , —SR 24 , —S(═O)R 24 , —SO 2 N(R 24 ) 2 , —N(R 24 ) 2 , —NHC(═S)NHR 24 , ═NOR 24 , —NO 2 , —C(═O)NHOR 24 , —C(═O)NHN(R 24 ) 2 , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, or a chelator moiety;
or wherein at least one of R 1 , R 2 , R 3 , and R 4 comprises the structure:

wherein n is 0 or greater, m is 0 or greater, and R c is a chelator moiety;
R 19 and R 20 are each independently selected from the group consisting of hydrogen, C 1-10 alkyl substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , C 3-10 cycloalkyl substituted with 0-3 R 23 , heterocyclyl-C 1-10 alkyl substituted with 0-3 R 23 , C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 23 , and heterocyclyl substituted with 0-3 R 23 ;
R 21 and R 22 are each independently selected from the group consisting of —OH, C 1-10 alkyl substituted with 0-3 R 23 , aryl substituted with 0-3 R 23 , C 3-10 cycloalkyl substituted with 0-3 R 23 , heterocyclyl-C 1-10 alkyl substituted with 0-3 R 23 , C 6-10 aryl-C 1-10 alkyl substituted with 0-3 R 23 , and heterocyclyl substituted with 0-3 R 23 ;
each R 23 is independently selected from the group consisting of ═O, halo, trifluoromethyl, —CF 2 H, —CH 2 F, cyano, —CO 2 R 24 , —C(═O)R 24 , —C(═O)N(R 24 ) 2 , —CHO, —CH 2 OR 24 , —OC(═O)R 24 , —OC(═O)OR 24 , —OR 24 , —OC(═O)N(R 24 ) 2 , —NR 24 C(═O)R 24 , —NR 24 C(═O)OR 24 , —NR 24 C(═O)N(R 24 ) 2 , —NR 24 SO 2 N(R 24 ) 2 , —NR 24 SO 2 R 24 , —SO 3 H, —SO 2 R 24 , —SR 24 , —S(═O)R 24 , —SO 2 N(R 24 ) 2 , —N(R 24 ) 2 , —NHC(═S)NHR 24 , ═NOR 24 , —NO 2 , —C(═O)NHOR 24 , —C(═O)NHN(R 24 ) 2 , —OCH 2 CO 2 H, 2-(1-morpholino)ethoxy, C 1-5 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkylmethyl, C 2-6 alkoxyalkyl, aryl substituted with 0-2 R 24 , and heterocyclyl;
each R 24 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, carbonyl, and a protecting group; and
n′ is an integer from 1-3;

wherein the chelator moiety comprises the structure:

wherein:
each R′ is a group capable of coordinating a metal ion; and
R″ is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, or substituted derivatives thereof.

2. The method as in claim 1 , wherein X is nitrogen.

3. The method as in claim 1 , wherein X is oxygen.

4. The method as in claim 1 , wherein X is sulfur.

5. The method as in claim 1 , wherein X is phosphorus.

6. The method as in claim 1 , wherein:
X is nitrogen;
R 1 is selected from the group consisting of hydrogen, alkyl, arylalkyl, and alkylarylalkyl;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkylaryl, aryl, arylalkyl, alkylarylalkyl, and heterocyclylalkyl;
R 4 is selected from the group consisting of alkyl, alkylaryl, aryl, arylalkyl, and alkylarylalkyl;
wherein at least one of R 1 , R 2 , R 3 , and R 4 is substituted with a chelator moiety.

7. The method as in claim 1 , wherein the chelator moiety comprises the structure,

8. The method as in claim 1 , wherein the compound has the structure,

9. The method of claim 1 , wherein the imaging agent is an echogenic substance, an optical reporter, a boron neutron acceptor, a paramagnetic metal ion, a ferromagnetic metal, a gamma-emitting radioisotope, a positron-emitting radioisotope, or an x-ray absorber.

10. The method of claim 1 , wherein the imaging agent is a gamma-emitting radioisotope or positron-emitting radioisotope selected from the group consisting of 111 In, 62 Cu, 64 Cu, 67 Ga, 68 Ga, and 153 Gd.

11. The method of claim 1 , wherein the chelated imaging agent has the structure,

12. The method as in claim 1 , comprising detecting, imaging, and/or monitoring elastin-rich tissues in the patient.

13. The method as in claim 1 , comprising detecting, imaging, and/or monitoring the presence of coronary plaque, carotid plaque, iliac/femoral plaque, aortic plaque, renal artery plaque, plaque of any arterial vessel, aneurism, vasculitis, other diseases of the arterial wall, and/or damage or structural changes in ligaments, uterus, lungs or skin in the patient.

14. The method as in claim 1 , wherein at least one of R 2 or R 3 comprises the following structure,

wherein:
n″ is 0-6; and
R z is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl.

15. The method as in claim 1 , wherein R 1 is substituted with the at least one chelator moiety, or R 1 has the structure:

Assignees

• Lantheus Medical Imaging Inc

Inventors

• Cesati Richard R
• Harris Thomas D
• Robinson Simon P
• Looby Richard J
• Cheesman Edward H
• Yalamanchili Padmaja
• Casebier David S

Classifications

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07C259/06

  having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• C07D257/02

  not condensed with other rings · CPC title

• A61K51/0406

  Amines, polyamines, e.g. spermine, spermidine, amino acids, (bis)guanidines · CPC title

• A61K49/10 Primary

  Organic compounds · CPC title