Granted Patent B2

US 9,393,329 · App. 14/492,896 · Granted Jul 19, 2016

Abstract

Claims (58)

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:

16. The method as in claim 1 , wherein R 2 or R 3 is substituted with the at least one chelator moiety, or R 2 or R 3 has the structure:

17. The method as in claim 1 , wherein R 4 is substituted with the at least one chelator moiety or R 4 has the structure:

18. The method as in claim 1 , wherein the compound has a structure as in Formula (II),

or a pharmaceutically acceptable salt thereof;

wherein:

n″ is 0-6;

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, substituted with the at least one chelator moiety; or

R 4 has the structure:

wherein n is 0 or greater, m is 0 or greater, and R c is a chelator moiety;

R y is selected from the group consisting of hydrogen, alkenyl, alkynyl, and alkyl; and

R z is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl.

19. The method as in claim 18 , wherein R 4 has the structure:

20. The method as in claim 18 , wherein R 4 has the structure:

Assignments (9)