N-alkoxyamide conjugates as imaging agents

Patent metadata

Field	Value
Publication number	US-9732047-B2
Application number	US-201514977249-A
Country	US
Kind code	B2
Filing date	Dec 21, 2015
Priority date	Jan 8, 2008
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

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 compound of Formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
X is N, O, S, or P;
R 1 is selected from the group consisting of hydrogen, alkyl, alkenyl, arylalkyl, alkylarylalkyl, alkoxyalkyl, heteroalkyl, and heterocyclylalkyl;
R 2 and R 3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, and carbonyl;
or wherein at least one of R 2 or R 3 comprises the following structure:

wherein n is 0-6, R z is alkyl, aryl, cycloalkenyl, cycloalkyl, heteroaryl, or heterocyclyl, and the other of R 2 and R 3 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, and carbonyl;
R 4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, 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, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, —NR 19 R 20 , —SH, —S(Pg), —OH, —PR 19 R 20 , —P(O)R 21 R 22 , —CO 2 H, ═O, halo, trifluoromethyl, 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;
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, 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 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, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, and carbonyl;
Pg is a thiol protecting group; and
n′ is an integer from 1-3,
wherein the compound of Formula (I) comprises at least one chelator moiety, at least one of R 1 , R 2 , R 3 , or R 4 is substituted with the at least one chelator moiety, and the at least one chelator moiety is of the formula:

wherein X′ is nitrogen, one of D 1 and D 2 is a hydrogen and the other of D 1 and D 2 is selected from the group consisting of:

wherein o, p, q, r, s, t, and u are each independently 1-6, and v, w, x, and y are each independently 1-3.

2. The compound of claim 1 , wherein at least one R 1 is H.

3. The compound of claim 1 , wherein X is N.

4. The compound of claim 1 , wherein X is O, S, or P.

5. The compound of claim 1 , wherein:
X is N;
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 each R 1 , R 2 , R 3 , and R 4 is independently unsubstituted or substituted with one or more of the following: alkyl, alkenyl, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, —NR 19 R 20 , —SH, —S(Pg), —OH, —PR 19 R 20 , —P(O)R 21 R 22 , —CO 2 H, ═O, halo, trifluoromethyl, 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;
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, 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 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, cycloalkyl, alkylaryl, alkylcarbonyl, aryl, arylalkyl, alkylarylalkyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, heteroalkyl, heterocyclyl, heterocyclylalkyl, and carbonyl;
Pg is a thiol protecting group; an

Assignees

• Lantheus Medical Imaging Inc

Inventors

• Cesati Richard R
• Harris Thomas D
• Looby Richard J
• Cheesman Edward H
• Casebier David S

Classifications

• C07D257/02 Primary

  not condensed with other rings · CPC title

• C07D213/56

  Amides · CPC title

• C07D209/20

  substituted additionally by nitrogen atoms, e.g. tryptophane · CPC title

• C07C271/22

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

• C07C259/14

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