N-alkoxyamide conjugates as imaging agents
View Patent ↗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.
1. A compound of Formula (I),
or a pharmaceutically acceptable salt thereof,
wherein:
X is a heteroatom N, S, O, 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)R 24 , —OR 24 , —OC(═O)N(R 24 ) 2 , —NR 24 C(═O)R 24 , —NR 24 CO(═O)R 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 R 24 R 24 , —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)R 24 , —OR 24 , —OC(═O)N(R 24 ) 2 , —NR 24 C(═O)R 24 , —NR 24 CO(═O)R 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 compound comprises at least one chelator moiety, and 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. A compound as in claim 1 , wherein X is nitrogen.
3. A compound as in claim 1 , wherein X is oxygen.
4. A compound as in claim 1 , wherein X is sulfur.
5. A compound as in claim 1 , wherein X is phosphorus.
6. A compound 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. A compound as in claim 1 , wherein the chelator moiety comprises the structure,
8. A compound as in claim 1 , wherein the compound has the structure,
9. A diagnostic agent, comprising:
a compound as in claim 1 ; and
an imaging agent bound to the at least one chelator moiety.
10. A diagnostic agent of claim 9 , wherein the diagnostic agent has the structure,
11. A compound 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.
12. A compound as in claim 1 , wherein R 1 is substituted with the at least one chelator moiety, or R 1 has the structure:
13. A compound 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:
14. A compound as in claim 1 , wherein R 4 is substituted with the at least one chelator moiety or R 4 has the structure:
15. A compound 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 x is selected from the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, and heterocyclyl.
16. A compound as in claim 15 , wherein R 4 has the structure:
17. A compound as in claim 15 , wherein R 4 has the structure: