Macrocycles, cobalt and iron complexes of same, and methods of making and using same

Patent metadata

Field	Value
Publication number	US-2016228581-A1
Application number	US-201415021626-A
Country	US
Kind code	A1
Filing date	Sep 12, 2014
Priority date	Sep 12, 2013
Publication date	Aug 11, 2016
Grant date	—

Abstract

Provided are macrocyclic compounds and iron or cobalt coordinated macrocyclic compounds. The compounds can be used as MRI contrast agents. Certain compounds are redox active and can be used to assess the biological redox status of a sample.

First claim

1 )- 9 ) (canceled)

10 ) A macrocyclic compound having a macrocyclic core comprising from 9 to 15 atoms, wherein at least one of the atoms in the macrocyclic core is a N atom, at least two carbon atoms separate a heteroatom selected from the group consisting of: N atom, O atom, or S atom, and one or more of the following pendant groups as substituents on the macrocyclic core:

wherein R 1 is H, C 1 to C 12 alkyl groups of linear or branched structure, PEG group, thioether group, or CH 2 CO 2 R′, wherein R′ is a C 1 to C 12 alkyl group of linear or branched structure,
R 2 is H, C 1 to C 12 alkyl groups of linear or branched structure, PEG group, thioether group, CH 2 CO 2 R, or OCH 3 ,
R 3 is H, C 1 to C 12 alkyl groups of linear or branched structure, PEG group, thioether group, or CH 2 CO 2 R′, wherein R′ is a C 1 to C 12 alkyl group of linear or branched structure, and
a Co(II) or Fe(II) cation is complexed to the macrocyclic core and/or at least one pendant group substituent of the macrocyclic compound, and
wherein the macrocyclic compound exhibits reversible oxidation to Co(III) or Fe(III), respectively.

11 ) The macrocyclic compound of claim 10 , wherein the macrocyclic compound has at least one exchangeable proton or associated water molecule.

12 ) The macrocyclic compound of claim 10 , wherein at least one of the one or more pendant groups is covalently bound to a N on the macrocyclic core.

13 ) The macrocyclic compound of claim 10 , 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.

14 ) The macrocyclic compound of claim 13 , wherein the pendant group is

15 ) The macrocyclic compound of claim 10 , wherein the macrocyclic core is a Cyclen moiety, Cyclam moiety, or TACN moiety.

16 ) The macrocyclic compound of claim 10 , wherein the macrocyclic compound has one of the following structures:

wherein, X 1 , X 2 , X 3 , X 4 , and X 5 are each independently nitrogen, sulfur or oxygen atoms,
X 6 or X 7 are each independently C or N,
and Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently a pendant group,
Y 6 and Y 7 are each independently a halide or amines or NO 2 group,
m 1 , m 2 , m 3 , m 4 and m 5 are each independently 0 or 1, and
and n 1 , n 2 , n 3 , n 4 and n 5 are each independently 1 or 2,

provided that if X is O or S, then m 1 is 0 and Y 1 is H.

17 ) The macrocyclic compound of claim 10 , wherein the macrocyclic core has one of the following structures:

wherein R 4 and R 5 are each independently a pendent group,
R 6 is an alkyl group, and
R 7 and R 8 are independently an amine group, a nitro group, or a halide.

18 ) The macrocyclic compound of claim 10 , wherein the macrocyclic compound is one of a plurality of the macrocyclic compounds tethered together via a polymer, dendrimer, protein, or peptide.

19 ) The macrocyclic compound of claim 10 , wherein the macrocyclic compound has one of the following structures:

20 ) A composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.

21 ) A method to obtain an image of at least a portion of a cell, organ, vasculature or tissue comprising the steps of:
contacting the cell, organ, vasculature, or tissue with a compound of claim 10 , 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.

22 ) The method of claim 21 , wherein the cell, organ, vasculature, or tissue is part of an individual.

23 ) The method of claim 21 , wherein the image is obtained using magnetic resonance imaging (MRI).

24 ) The method of claim 21 , wherein the image is obtained using chemical exchange saturation transfer (CEST).

25 ) The method of claim 21 , wherein the image is obtained using paramagnetic chemical exchange saturation transfer (paraCEST).

26 ) The method of claim 21 , wherein the image is obtained using magnetic resonance spectroscopy imaging (MRSI).

27 ) The method of claim 21 , wherein the cell, organ, vasculature, or tissue is contacted with the compound of claim 10 and the image is indicative of the redox status of the cell, organ, vasculature, or tissue.

Assignees

• Univ New York State Res Found
• Health Research Inc

Inventors

• Morrow Janet R
• Tsitovich Pavel B
• Dorazio Sarina J
• Olatunde Abiola O
• Spernyak Joseph A
• Burns Patrick
• Snyder Eric M
• Bond Christopher J

Classifications

• A61K49/106 Primary

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• C07D255/02

  not condensed with other rings · CPC title