Compositions comprising macrocycle derivatives incorporating bridged macrocycles and methods of producing and using same

Patent metadata

Field	Value
Publication number	US-12139481-B2
Application number	US-202017075167-A
Country	US
Kind code	B2
Filing date	Oct 20, 2020
Priority date	Aug 17, 2015
Publication date	Nov 12, 2024
Grant date	Nov 12, 2024

Abstract

Compositions are disclosed herein that include macrocycle derivatives incorporating bridged macrocycles. Also disclosed are methods of producing and using the compositions.

First claim

What is claimed is:

1. A method of inhibiting the growth and/or activity of at least one microbe selected from at least one bacteria, at least one fungus, and at least one parasite, the method comprising the step of:
contacting the at least one microbe with a composition containing at least one macrocyclic ligand, the composition comprising a compound of Formula (II):
A 1 -J-A 2   (II)

wherein each “A” is a macrocyclic ligand that is independently selected from the group consisting of Formulas (a)-(e), with the proviso that at least one “A” must come from Formulas (a)-(d):
(a) a tetradentate ethylene cross-bridged macropolycyclic rigid ligand with ring size 12-14 and having the structure:

(b) a tetradentate ethylene side-bridged macropolycyclic rigid ligand with ring size 12-15 and having the structure:

(c) a tetradentate propylene cross-bridged macropolycyclic rigid ligand with ring size 12-14 and having the structure:

(d) a pentadentate ethylene cross-bridged macropolycyclic rigid ligand having the structure:

and
(e) a tetradentate or pentadentate-macrocyclic ligand having the structure:

wherein, in Formulas (a)-(e):
each “R” is independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, and heteroalkylaryl groups;
each “n” is an integer independently selected from 0, 1, and 2, completing the valence of the atoms to which the “R” moieties are covalently bonded;
each “z” is an integer independently selected from 0 and 1; and
each “t” is an integer independently selected from 1 and 2; and

and wherein “J” in Formula (II) is a linking m-, o-, or p-xylyl group.

2. The method of claim 1 , wherein the composition further comprises a metal with which the compound is complexed, wherein the metal is selected from the group consisting of a transition metal, a main group metal, a lanthanide, an actinide, and mixtures thereof.

3. The method of claim 2 , wherein the transition metal is selected from the group consisting of cobalt, copper, iron, manganese, nickel, zinc, and mixtures thereof.

4. The method of claim 2 , wherein in Formulas (a)-(e), each nitrogen atom coordinates to a metal ion.

5. The method of claim 1 , wherein in Formulas (a)-(e) of the compound, at least one “R” is a benzyl group.

6. The method of claim 1 , wherein the at least one microbe comprises a fungus selected from the group consisting of Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, Candida albicans, Candida glabrata, Candida krusei, Aspergillus fumigatus , and combinations thereof.

7. The method of claim 1 , wherein the at least one microbe comprises a bacteria selected from the group consisting of Staphylococcus aureus , Methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa, Mycobacterium intracellulare , and combinations thereof.

8. The method of claim 1 , wherein the at least one microbe comprises a parasite selected from the group consisting of Leishmania donovani, Leishmania major, Leishmania tropica, Leishmania braziliensis, Leishmania Mexicana, Plasmodium falciparum, Schistosoma mansoni , and combinations thereof.

9. A method of treating, reducing the occurrence of, and/or reducing the severity of an infection in a subject, wherein the infection is selected from at least one of a bacterial infection, a fungal infection, and a parasitic infection, the method comprising the step of:
administering an effective amount of a pharmaceutical composition containing at least one macrocyclic ligand to the subject, wherein the pharmaceutical composition comprises at least one pharmaceutically acceptable carrier and at least one compound of Formula (II):
A 1 -J-A 2   (II)

wherein each “A” is a macrocyclic ligand that is independently selected from the group consisting of Formulas (a)-(e), with the proviso that at least one “A” must come from Formulas (a)-(d):
(a) a tetradentate ethylene cross-bridged macropolycyclic rigid ligand with ring size 12-14 and having the structure:

(b) a tetradentate ethylene side-bridged macropolycyclic rigid ligand with ring size 12-15 and having the structure:

(c) a tetradentate propylene cross-bridged macropolycyclic rigid ligand with ring size 12-14 and having the structure:

(d) a pentadentate ethylene cross-bridged macropolycyclic rigid ligand having the structure:

and
(e) a tetradentate or pentadentate-macrocyclic ligand having the structure:

wherein, in Formulas (a)-(e):
each “R” is independently selected from the group consisting of H, alkyl, heteroalkyl, aryl, heteroaryl, alkylaryl, and heteroalkylaryl groups;
each “n” is an integer independently selected from 0, 1, and 2, completing the valence of the atoms to which the “R” moieties are covalently bonded;
each “z” is an integer independently selected from 0 and 1; and
each “t” is an integer independently selected from 1 and 2; and

and wherein “J” in Formula (II) is a linking m-, o-, or p-xylyl group.

10. The method of claim 9 , wherein the pharmaceutical composition further comprises a metal with which the compound of Formula (II) is complexed, wherein the metal is selected from the group consisting of a transition metal, a main group metal, a lanthanide, an actinide, and mixtures thereof.

11. The method of claim 10 , wherein the transition metal is selected from the group consisting of cobalt, copper, iron, manganese, nickel, zinc, and mixtures thereof.

12. The method of claim 10 , wherein in Formulas (a)-(e), each nitrogen atom coordinates to a metal ion.

13. The method of claim 9 , wherein in Formulas (a)-(e) of the compound, at least one “R” is a benzyl group.

14. The method of claim 9 , wherein the infection is further defined as an opportunistic infection.

15. The method of claim 9 , wherein the infection is a fungal infection caused by at least one of Cryptococcus neoformans, Cryptococcus laurentii, Cryptococcus albidus, Candida albicans, Candida glabrata, Candida krusei , and Aspergillus fumigatus.

16. The method of claim 9 , wherein the infection is a bacterial infection caused by at least one of Staphylococcus aureus , Methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, Pseudomonas aeruginosa , and Mycobacterium intracellulare.

17. The method of claim 9 , wherein the infection is a parasitic infection caused by at least one of Leishmania donovani, Leishmania major, Leishmania tropica, Leishmania braziliensis, Leishmania Mexic

Assignees

• Southwestern Oklahoma State Univ
• Univ Mississippi

Inventors

• Hubin Timothy J
• Khan M O Faruk
• Archibald Stephen James
• Tekwani Babu Lal

Classifications

• G01N2800/26

  Infectious diseases, e.g. generalised sepsis · CPC title

• G01N33/60

  involving radioactive labelled substances · CPC title

• G01N33/582

  with fluorescent label · CPC title

• C07D273/00

  Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00 · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title