Compounds for use as iron(III) MRI contrast agents

Patent metadata

Field	Value
Publication number	US-11261208-B2
Application number	US-201816615024-A
Country	US
Kind code	B2
Filing date	May 21, 2018
Priority date	May 19, 2017
Publication date	Mar 1, 2022
Grant date	Mar 1, 2022

Abstract

Provided are macrocyclic compounds and compounds with two or more macrocyclic groups, iron coordinated macrocyclic compounds, and iron coordinated compounds with two or more macrocyclic groups. The iron is high-spin iron(III). The iron coordinated compounds may exhibit a negative redox potential (e.g., relative to a normal hydrogen electrode at a biologically relevant pH, for example, a pH of 6.5-7.5). The compounds can be used as MRI contrast agents.

First claim

The invention claimed is:

1. A macrocyclic complex comprising: a macrocyclic core, wherein the macrocyclic core is a TACN group, an S-substituted TACN, an O-substituted TACN, or a cyclam group having the following structure:

and Z 1 , Z 2 , Z 3 , and Z 4 are each independently H or one or more of the following pendant groups:

or a deprotonated analog thereof or a stereoisomer thereof, wherein R is methyl, R 1 , R 2 , and R 3 are each independently a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted alkyl group, and R 1 , R 2 , and R 3 are not pendant donors; Q 1 and Q 2 are each independently H, OCH 3 , CO 2 H, or CH 2 CO 2 G 4 , G 4 is H, C 1 to C 12 substituted or unsubstituted alkyl groups of linear or branched structure or a (—CH 2 CH 2 O—) n group, wherein n is 1-2, Q 3 is H, C 1 to C 12 substituted or unsubstituted alkyl groups of linear or branched structure or a (—CH 2 CH 2 O—) n group, wherein n is 1-12, Q 4 and Q 5 are each independently H, OCH 3 , CO 2 H, or substituted or unsubstituted alkyl groups of linear or branched structures, A is a substituted or unsubstituted alkyl group of linear or branched structure with C 1 to C 12 or is a substituted or unsubstituted aryl group or an amino acid, and
a high-spin Fe(III) cation complexed to the macrocyclic core and at least one pendant group, or a salt, a partial salt, a hydrate, a polymorph, or a stereoisomer thereof,
wherein the macrocyclic complex exhibits a redox potential of less than 0 vs. normal hydrogen electrode (NHE) in an aqueous medium at a pH of 6.5-7.5,
wherein the macrocyclic core has structure I, Z 1 is H and Z 2 and Z 3 are each independently a pendant group;
wherein the macrocyclic core has structure II, III, or XV, Z 1 and Z 2 are each independently a pendant group;
wherein the macrocyclic core has structure XVI, Z 1 is a pendant group;
wherein the macrocyclic core has structure XII, Z 4 is a pendant group and Z 1 , Z 2 and Z 3 are each independently H or a pendant group, provided that at most two of Z 1 , Z 2 , and Z 3 are H;
wherein the macrocyclic core has structure XIII, Z 1 and Z 3 are each independently a pendant group and Z 2 is H or a pendant group;
wherein for all structures I, II, III, XII, XIII, XIV, XV, and XVI, each of Z 1 , Z 2 , Z 3 and Z 4 , as applicable, are selected independently of each other.

2. The macrocyclic complex of claim 1 , wherein at least one or more pendant groups is covalently bound to a N on the macrocyclic core.

3. The macrocyclic complex of claim 1 , wherein the macrocyclic complex has at least one open coordination site.

4. The macrocyclic complex of claim 1 , wherein the macrocyclic complex has at least one water or at least one hydroxide complexed to the high-spin Fe(III) cation.

5. The macrocyclic complex of claim 1 , wherein at least one of the pendant groups is substituted at a benzylic position or any carbon the alkyl group leading to the heteroatom of the pendant group.

6. The macrocyclic complex of claim 1 , wherein the macrocyclic complex comprises a TACN moiety and at least one anionic pendant groups.

7. The macrocyclic complex of claim 6 , wherein the anionic pendants are individually chosen from carboxylate pendants, imidazolate pendants, pyrazolate pendants, alkoxide pendants, and phenoxide pendants.

8. The macrocyclic complex of claim 7 , wherein the macrocyclic complex further comprises a coordinating pendant group or a non-coordinating pendant group.

9. The macrocyclic complex of claim 1 , wherein the macrocyclic core has one of the following structures:

10. The macrocyclic complex of claim 1 , wherein the macrocyclic core has the following structure:

11. The macrocyclic complex of claim 1 , wherein the macrocyclic complex has one of the following structures:

12. A composition comprising one or more macrocyclic complexes of claim 1 and a pharmaceutically acceptable carrier.

13. The composition of claim 12 , wherein the composition further comprises human serum albumin and/or meglumine.

14. A method to obtain an image of at least a portion of a cell, organ, vasculature, or tissue comprising:
contacting the cell, organ, vasculature, or tissue with one or more macrocyclic complexes of claim 1 , and
imaging at least a portion of the cell, organ, vasculature, or tissue to obtain an image of the portion of a cell, organ, vasculature, or tissue,

wherein the image is obtained by using magnetic resonance.

15. The method of claim 14 , wherein the cell, organ, vasculature, or tissue is part of an individual.

16. The method of claim 14 , wherein the image is obtained using magnetic resonance imaging (MM).

17. The method of claim 14 , wherein the macrocyclic complexes T 1 agents.

Assignees

• Univ New York State Res Found

Inventors

• Morrow Janet R
• Snyder Eric M
• Asik Didar

Classifications

• C07D403/14

  containing three or more hetero rings · CPC title

• C07F15/025 Primary

  without a metal-carbon linkage · CPC title

• A61K49/085

  conjugated systems · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D255/02 Primary

  not condensed with other rings · CPC title