# US 2025/0375458 A1 · Compositions and methods to combat multidrug-resistant and persistent t-cell-mediated, oncological and infectious diseases

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- Number: US 2025/0375458 A1
- Document ID: US20250375458A1
- Status: Published application
- Kind: A1
- Application number: 18/734,622
- Filed: 2024-06-05
- Published: 2025-12-11
- Earliest claimed: 2024-06-05
- Assignees: Theralase Technologies, Inc.
- Applicants: Theralase Technologies, Inc.
- Inventors: Arkady Mandel; Roger Dumoulin-White
- Web page: https://patentgrep.com/patent/US20250375458A1

## CPC

- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 38/40: Transferrins, e.g. lactoferrins, ovotransferrins
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed is a method for treating a condition, which includes the steps of: selecting a patient for treatment who has the condition; administering to the patient at least one active pharmaceutical ingredient (API); and administering to the patient at least one metal complex represented by formula (I): including hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof. Also disclosed is a composition for conducting the method, which includes: at least one API selected from the group consisting of Cisplatin, Temozolomide, Vandetanib, Withaferin A, Vemurafenib, Amiodarone, Vinblastine, Metformin, Gemcitabine and Acyclovir; and at least one metal complex effective to potentiate an efficacy of the API to treat the condition, wherein the at least one metal complex is represented by formula (I), including hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof.

## Claims

### Claim 1

A method for treating a condition, said method comprising the steps of:
selecting a patient for treatment who has the condition;
administering to the patient at least one active pharmaceutical ingredient (API); and
administering to the patient at least one metal complex represented by formula (I):
including hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, wherein:
M is selected from the group consisting of manganese, molybdenum, rhenium, iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, platinum, and copper;
X is selected from the group consisting of Cl−, PF6−, Br−, BF4−, ClO4−, CF3SO3−, and SO4−2.
n=0, 1, 2, 3, 4, or 5;
y=1, 2, or 3;
z=0, 1, or 2;
Lig at each occurrence is independently selected from the group consisting of
R1 is selected from the group consisting of
u is an integer of 1 to 20;
R2a, R2b, R2c, R2d, R2e, and R2f at each occurrence are each independently selected from the group consisting of hydrogen, C1-6 optionally substituted alkyl, C1-6 optionally substituted branched alkyl, C3-7 optionally substituted cycloalkyl, C1-6 optionally substituted haloalkyl, C1-6 optionally substituted alkoxy, CO2R5, CONR62, NR72, sulfate, sulfonate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, and optionally substituted heterocycle;
R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h R3i, R3j, R3k, R3l, and R3m at each occurrence are each independently selected from the group consisting of hydrogen, C1-6 optionally substituted alkyl, C1-6 optionally substituted branched alkyl, C1-6 optionally substituted haloalkyl, C1-6 optionally substituted alkoxy, and CO2R8;
R4a, R4b, and R4c at each occurrence are each independently selected from the group consisting of hydrogen, C1-6 optionally substituted alkyl, C1-6 optionally substituted C1-6 optionally substituted alkoxy, CO2R5, CONR62, NR72, sulfate, sulfonate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, and optionally substituted heterocycle;
R4a and R4bat each occurrence on a thiophene ring are taken together with the atom to which they are bound to form an optionally substituted ring having from 6 ring atoms containing 2 oxygen atoms;
R5 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl;
R6 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl;
R7 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl; and
R8 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl,
wherein:
the administering to the patient of the at least one metal complex is conducted prior to, during and/or after the administering to the patient of the at least one API; and
the at least one API has a structure not represented by Formula (I).

### Claim 2 (depends on 1)

The method of claim 1, wherein the administering to the patient of the at least one metal complex causes an improvement in an efficacy of treating the condition relative to continued treatment of the condition with only the at least one API.

### Claim 3 (depends on 1)

The method of claim 1, wherein the at least one metal complex is administered to the patient only after the condition has developed a resistance to the at least one API, which continues to be administered to the patient along with the at least one metal complex.

### Claim 4 (depends on 1)

The method of claim 1, wherein the at least one metal complex is administered to the patient prior to or concurrently with the step of administering to the patient the at least one active pharmaceutical ingredient.

### Claim 5 (depends on 1)

The method of claim 1, wherein the condition is cancer, and the at least one API is at least one member selected from the group consisting of a chemotherapeutic agent, an immunotherapeutic agent and a targeted therapeutic agent.

### Claim 6 (depends on 1)

The method of claim 1, wherein the condition is an infectious disease and the at least one API is at least one member selected from the group consisting of an antibiotic agent, an antimicrobial agent, an antifungal agent and an antiviral agent.

### Claim 7 (depends on 1)

The method of claim 1, wherein the at least one API is selected from the group consisting of Cisplatin, Temozolomide, Vandetanib, Withaferin A, Vemurafenib, Amiodarone, Vinblastine, Metformin, Gemcitabine and Acyclovir.

### Claim 8 (depends on 1)

The method of claim 1, further comprising administering transferrin to the patient.

### Claim 9 (depends on 1)

The method of claim 1, further comprising administering to the patient radiation selected from the group consisting of infrared light, visible light, X-rays and gamma rays.

### Claim 10 (depends on 1)

The method of claim 1, wherein the at least one metal complex comprises at least one member selected from the group consisting of:
Ru(2,2′-bipyridine)2(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(2,2′-bipyridine)2(2-(2′,2″:5″,2″′;5″′,2″″-quaterthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2″′;5″′,2″″-quaterthiophene) -imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di-t-butyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di-t-butyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di-t-butyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethoxy-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(5,5′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(5,5′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(5,5′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(6,6′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(6,6′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(6,6′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di (methylcarboxy)-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene) -imidazo[4,5-f][1,10] phenanthroline);
Ru(2,2′-bipyrimidine)2(2-(2′,2″:5″,2″″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(2,2′-bipyrimidine)(4,4′-dimethyl-2,2′-bipyridine)(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(1,10-phenanthroline)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(1,10-phenanthroline)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(1,10-phenanthroline)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(1,10-phenanthroline)2(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(4,4′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline); and
pharmaceutically acceptable salts thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the at least one metal complex is Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline) or a pharmaceutically acceptable salt thereof.

### Claim 12

A composition for combination therapy effective to treat a condition in a patient, said composition comprising:
at least one active pharmaceutical ingredient (API) selected from the group consisting of Cisplatin, Temozolomide, Vandetanib, Withaferin A, Vemurafenib, Amiodarone, Vinblastine, Metformin, Gemcitabine and Acyclovir; and
at least one metal complex effective to potentiate an efficacy of the active pharmaceutical ingredient to treat the condition, wherein the at least one metal complex is represented by formula (I):
including hydrates, solvates, pharmaceutically acceptable salts and prodrugs thereof, wherein:
M is selected from the group consisting of manganese, molybdenum, rhenium, iron, ruthenium, osmium, cobalt, rhodium, iridium, nickel, platinum, and copper;
X is selected from the group consisting of Cl−, PF6−, Br−, BF4−, ClO4−, CF3SO3−, and SO4−2;
n=0, 1, 2, 3, 4, or 5;
y =1, 2, or 3;
z=0, 1, or 2;
Lig at each occurrence is independently selected from the group consisting of
R1 is selected from the group consisting of
u is an integer of 1 to 20;
R2a, R2b, R2c, R2d, R2e, and R2f at each occurrence are each independently selected from the group consisting of hydrogen, C1-6 optionally substituted alkyl, C1-6 optionally substituted branched alkyl, C3-7 optionally substituted cycloalkyl, C1-6 optionally substituted haloalkyl, C1-6 optionally substituted alkoxy, CO2R5, CONR62, NR72, sulfate, sulfonate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, and optionally substituted heterocycle;
R3a, R3b, R3c, R3d, R3e, R3f, R3g, R3h R3i, R3j, R3k, R3l, and R3m at each occurrence are each independently selected from the group consisting of hydrogen, C1-6 optionally substituted alkyl, C1-6 optionally substituted branched alkyl, C1-6 optionally substituted haloalkyl, C1-6 optionally substituted alkoxy, and CO2R8;
R4a, R4b, and R4c at each occurrence are each independently selected from the group consisting of hydrogen, C1-6 optionally substituted alkyl, C1-6 optionally substituted C1-6 optionally substituted alkoxy, CO2R5, CONR62, NR72, sulfate, sulfonate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, and optionally substituted heterocycle;
R4a and R4b at each occurrence on a thiophene ring are taken together with the atom to which they are bound to form an optionally substituted ring having from 6 ring atoms containing 2 oxygen atoms;
R5 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl;
R6 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl;
R7 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl; and
R8 at each occurrence is independently selected from the group consisting of hydrogen and optionally substituted alkyl.

### Claim 13 (depends on 12)

The composition of claim 12, wherein the condition is cancer.

### Claim 14 (depends on 12)

The composition of claim 12, wherein the condition is an infectious disease.

### Claim 15 (depends on 12)

The composition of claim 12, further comprising transferrin.

### Claim 16 (depends on 12)

The composition of claim 12, wherein the at least one metal complex comprises at least one member selected from the group consisting of:
Ru(2,2′-bipyridine)2(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(2,2′-bipyridine)2(2-(2′,2″:5″,2″′;5″′,2″″-quaterthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2″′;5′″,2″″-quaterthiophene) -imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di-t-butyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di-t-butyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di-t-butyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-dimethoxy-2,2′-bipyridine)2(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(5,5′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(5,5′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(5,5′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(6,6′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Ru(6,6′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(6,6′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(4,4′-di (methylcarboxy)-2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene) -imidazo[4,5-f][1,10] phenanthroline);
Ru(2,2′-bipyrimidine)2(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(2,2′-bipyrimidine)(4,4′-dimethyl-2,2′-bipyridine)(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Ru(1,10-phenanthroline)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(2,2′-bipyridine)2(2-(2′,2″:5″,2′″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(1,10-phenanthroline)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(1,10-phenanthroline)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(1,10-phenanthroline)2(2-(2′,2″:5″,2″′-terthiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(4,4′-dimethyl-2,2′-bipyridine)2(2-thiophenimidazo[4,5-f][1,10] phenanthroline);
Os(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″-bithiophene)-imidazo[4,5-f][1,10] phenanthroline);
Os(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline); and
pharmaceutically acceptable salts thereof.

### Claim 17 (depends on 12)

The composition of claim 12, wherein the at least one metal complex is
Ru(4,4′-dimethyl-2,2′-bipyridine)2(2-(2′,2″:5″,2″-terthiophene)-imidazo[4,5-f][1,10] phenanthroline); ) or a pharmaceutically acceptable salt thereof.