Manganese-based chelate conjugates for molecular MR imaging

Patent metadata

Field	Value
Publication number	US-10835623-B2
Application number	US-201615751617-A
Country	US
Kind code	B2
Filing date	Aug 12, 2016
Priority date	Aug 13, 2015
Publication date	Nov 17, 2020
Grant date	Nov 17, 2020

Abstract

Provided herein are examples of metal chelating ligands that have high affinity for manganese. The resultant metal complexes can be used as MRI contrast agents, and can be functionalized with moieties that bind to or cause relaxivity change in the presence of biochemical targets.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of a C 2 -C 6 alkylene, a C 3 -C 10 cycloalkylene, 4-10 membered heterocycloalkylene, C 6 -C 10 arylene, 5-10 membered heteroarylene, (C 1 -C 6 )dialkyl)(C 6 -C 10 arylene), and (C 1 -C 6 )dialkyl(5-10 membered heteroarylene), wherein the alkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are each optionally substituted by 1, 2, 3, or 4 independently selected R X groups, and wherein R 1 is bound to the adjacent nitrogens via the 1,2 or 1,3 positions on R 1 ;
each R 2 and R 3 is independently selected from the group consisting of H, CO 2 H, (C 1 -C 6 alkyl)CO 2 H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 4 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 4 R 5 , CH 2 NHCOR 4 , C(O)N(OH)R 4 , C(O)NHSO 2 R 4 , CH 2 NHSO 2 R 4 , N(OH)C(O)R 4 , P(R 4 )O 2 R 5 , PO 3 R 4 R 5 , and [L]-[TBM];
each R 4 and R 5 is independently selected from the group consisting of H, C 1 -C 6 alkyl, and [L]-[TBM], wherein the alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R X groups;
DG is selected from the group consisting of:

or any constitutional isomers of Formulas IV and V, wherein
each Y is independently CH, CZ, N, O, S or NR 4 ;
Q is CH, CZ, N, O, S or NR 4 ;
each Z is independently selected from the group consisting of H, OH, OR 4 , CO 2 R 4 , —(C 1-6 alkyl)CO 2 H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 4 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 4 R 5 , CH 2 NHCOR 4 , C(O)N(OH)R 4 , C(O)NHSO 2 R 4 , CH 2 NHSO 2 R 4 , N(OH)C(O)R 4 , P(R 4 )O 2 R 5 , PO 3 R 4 R 5 , and -[L]-[TBM], wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R X groups;
L is a linker;
TBM is a target binding moiety; and
each R X is independently selected from the group consisting of OH, SH, CN, NO 2 , halo, pseudohalo, amino, thionyl, sulfinyl, sulfonyl, sulfo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, di(C 1 -C 4 alkyl)amino, C 1 -C 4 alkylamine, phosphinate, phosphinate ester, phosphonate, phosphonate ester, phosphodiester, C 1-4 alkylphosphodiester, C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, (C 1 -C 4 alkyl)phenyl, and -[L]-[TBM];
wherein if Q is CH or CCOOH and all Y are CH, then at least one of R 2 or R 3 is not H; and
wherein if all R 2 and R 3 are H and at least one Y of Formula IV is not CH, then R 1 is not C 2 alkylene.

2. A compound of Formula (XV):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of a C 2 -C 6 alkylene, a C 3 -C 10 cycloalkylene, 4-10 membered heterocycloalkylene, C 6 -C 10 arylene, 5-10 membered heteroarylene, (C 1 -C 6 )dialkyl)(C 6 -C 10 arylene), and (C 1 -C 6 )dialkyl(5-10 membered heteroarylene), wherein the alkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are each optionally substituted by 1, 2, 3, or 4 independently selected R X groups, and wherein R 1 is bound to the adjacent nitrogens via the 1,2 or 1,3 positions on R 1 ;
each R 2 , R 3 , and R 4 are independently selected from the group consisting of CO 2 H, (C(O)NR 5 R 6 , CH 2 NHCOR 5 , C(O)N(OH)R 5 , C(O)NHSO 2 R 5 , CH 2 NHSO 2 R 5 , N(OH)C(O)R 5 , P(R 5 )O 2 R 6 , and PO 3 R 5 R 6 , and compounds of formula:

wherein X is CZ, N, O, S, or NR 5 ;
each W is independently CH, CZ, N, O, S, or NR 5 ;
each Z is independently selected from H, OH, OR 4 , CO 2 H, —(C 1-6 alkyl)CO 2 H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 4 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 5 R 6 , CH 2 NHCOR 5 , C(O)N(OH)R 5 , C(O)NHSO 2 R 5 , CH 2 NHSO 2 R 5 , N(OH)C(O)R 5 , P(R 5 )O 2 R 6 , PO 3 R 5 R 6 , and -[L]-[TBM], wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently selected R X groups;
each R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 6 alkyl, and -[L]-[TBM], wherein the alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R X groups;
L is a linker;
TBM is a target binding moiety; and
each R X is independently selected from the group consisting of OH, SH, CN, NO 2 , halo, pseudohalo, amino, thionyl, sulfinyl, sulfonyl, sulfo, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl, C 1 -C 4 cyanoalkyl, C 1 -C 4 hydroxyalkyl, C 1 -C 4 alkoxy, C 1 -C 4 aminoalkyl, di(C 1 -C 4 alkyl)amino, C 1 -C 4 alkylamine, phosphinate, phosphinate ester, phosphonate, phosphonate ester, phosphodiester, C 1-4 alkylphosphodiester, C 3 -C 6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, (C 1 -C 4 alkyl)phenyl, and -[L]-[TBM].

3. A compound of Formula (XVII):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of a C 2 -C 6 alkylene, a C 3 -C 10 cycloalkylene, 4-10 membered heterocycloalkylene, C 6 -C 10 arylene, 5-10 membered heteroarylene, (C 1 -C 6 )dialkyl(C 6 -C 10 arylene), and (C 1 -C 6 )dialkyl(5-10 membered heteroarylene), wherein the alkylene, cycloalkylene, heterocycloalkylene, arylene, and heteroarylene are each optionally substituted by 1, 2, 3, or 4 independently selected R X groups, and wherein R 1 is bound to the adjacent nitrogens via the 1,2 or 1,3 positions on R 1 ;
each R 2 and R 3 are independently selected from the group consisting of H, CO 2 H, (C 1 -C 6 alkyl)CO 2 H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 4 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 4 R 5 , CH 2 NHCOR 4 , C(O)N(OH)R 4 , C(O)NHSO 2 R 4 , CH 2 NHSO 2 R 4 , N(OH)C(O)R 4 , P(R 4 )O 2 R 5 , PO 3 R 4 R 5 , and [L]-[TBM];
each R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 6 alkyl, and [L]-[TBM], wherein the alkyl is optionally substituted by 1, 2, 3, or 4 independently selected R X groups;
DG is selected from the group consisting of:

or any constitutional isomers of Formulas IV and V, wherein
each Y is independently CH, CZ, N, O, S, or NR 4 ;
Q is CH, CZ, N, O, S, or NR 4 ;
each Z is independently selected from the group consisting of H, OH, OR 4 , CO 2 H, —(C 1-6 alkyl)CO 2 H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 4 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl, C(O)NR 4 R 5 , CH 2 NHCOR 4 , C(O)N(OH)R 4 , C(O)NHSO 2 R 4 , CH 2 NHSO 2 R 4 , N(OH)C(O)R 4 , P(R 4 )O 2 R 5 , PO 3 R 4 R 5 , and -[L]-[TBM], wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted by 1, 2, 3, or 4 independently select

Assignees

• Massachusetts Gen Hospital

Inventors

• Gale Eric M
• Caravan Peter

Classifications

• G16H10/40

  for data related to laboratory analysis, e.g. patient specimen analysis · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07F13/005

  Compounds without a metal-carbon linkage · CPC title

• C07D235/14

  Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10) · CPC title