# US 11,110,102 B2 · Antifungal agents used in combination

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- Number: US 11,110,102 B2
- Document ID: US11110102B2
- Status: Granted
- Kind: B2
- Application number: 15/945,428
- Filed: 2018-04-04
- Published: 2018-11-15
- Granted: 2021-09-07
- Earliest claimed: 2017-04-10
- Assignees: Scynexis, Inc.
- Applicants: Scynexis, Inc.
- Inventors: David A. Angulo Gonzalez
- Web page: https://patentgrep.com/patent/US11110102B2

## CPC

- A61K 31/58: containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin (digitoxin {A61K31/7048})
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/10: Antimycotics
- 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

The present invention relates to the use of enfumafungin derivative triterpenoid antifungal compounds in combination with other antifungal agents such azoles, polyenes, lipopeptides, and allylamides to treat fungal diseases. More particularly, the invention relates to antifungal combinations of enfumafungin derivative triterpenoids which are inhibitors of (1,3)-β-D-glucan synthesis, in combination with other antifungal agents such as mold-active agents that have activity against molds, including but not limited to voriconazole, isavuconazole, posaconazole, itraconazole and amphotericin B, for the treatment and/or prevention of infections caused by molds.

## Claims

### Claim 1

A method of treating an Aspergillus infection in a subject in need thereof, the method comprising administering to the subject:
(a) a first therapeutic agent that is a compound of Formula (II):
which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid,
or a pharmaceutically acceptable salt thereof; and
(b) a second therapeutic agent that is isavuconazole,
wherein the first therapeutic agent is administered orally at a dose of 50 mg to 1000 mg, and the second therapeutic agent is administered at a dose of 50 mg to 1000 mg, and
wherein the dose of the first therapeutic agent and the dose of the second therapeutic agent are each administered at least once or twice per day for at least one week.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the Aspergillus infection is invasive pulmonary aspergillosis.

### Claim 3

A method of treating an Aspergillus infection in a subject in need thereof, the method comprising administering to the subject:
(a) a first therapeutic agent that is a compound of Formula (IIa):
which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylicacid,
or a pharmaceutically acceptable salt thereof; and
(b) a second therapeutic agent that is isavuconazole,
wherein the first therapeutic agent is administered orally at a dose of 50 mg to 1000 mg, and the second therapeutic agent is administered at a dose of 50 mg to 1000 mg, and
wherein the dose of the first therapeutic agent and the dose of the second therapeutic agent are each administered at least once or twice per day for at least one week.

### Claim 4 (depends on 3)

The method according to claim 3, wherein the Aspergillus infection is invasive pulmonary aspergillosis.

### Claim 5 (depends on 3)

The method according to claim 3, wherein the first therapeutic agent is the citrate salt of the compound of Formula (IIa).

### Claim 6 (depends on 3)

The method according to claim 3, wherein the first therapeutic agent is administered sequentially with the second therapeutic agent.

### Claim 7 (depends on 3)

The method according to claim 3, wherein the first therapeutic agent is administered concurrently with the second therapeutic agent.

### Claim 8

A method of preventing pulmonary aspergillosis in a subject in need thereof, the method comprising administering to the subject:
(a) a first therapeutic agent that is a compound of Formula (IIa):
which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylic acid,
or a pharmaceutically acceptable salt thereof, and
(b) a second therapeutic agent that is isavuconazole,
wherein the first therapeutic agent is administered orally at a dose of 50 mg to 1000 mg, and the second therapeutic agent is administered at a dose of 50 mg to 1000 mg, and
wherein the dose of the first therapeutic agent and the dose of the second therapeutic agent are each administered at least once or twice per day for at least one week.

### Claim 9

A method of treating an Aspergillus infection in a subject in need thereof, the method comprising administering to the subject:
(a) a first therapeutic agent that is a compound of Formula (IIa):
which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylicacid,
or a pharmaceutically acceptable salt thereof; and
(b) a second therapeutic agent that is isavuconazole,
wherein the first therapeutic agent and the second therapeutic agent are each administered in an amount effective to increase survival compared to the survival resulting from the administration of the first therapeutic agent in the absence of the second therapeutic agent or the administration of the second therapeutic agent in the absence of the first therapeutic agent.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the Aspergillus infection is invasive pulmonary aspergillosis.

### Claim 11

A method of treating an Aspergillus infection in a subject in need thereof, the method comprising administering to the subject a pharmaceutical combination of:
(a) a first therapeutic agent that is a compound of Formula (IIa):
which is (1S,4aR,6aS,7R,8R,10aR,10bR,12aR,14R,15R)-15-[[2-amino-2,3,3-trimethylbutyl]oxy]-8-[(1R)-1,2-dimethylpropyl]-14-[5-(4-pyridinyl)-1H-1,2,4-triazol-1-yl]-1,6,6a,7,8,9,10,10a,10b,11,12,12a-dodecahydro-1,6a,8,10a-tetramethyl-4H-1,4a-propano-2H-phenanthro[1,2-c]pyran-7-carboxylicacid,
or a pharmaceutically acceptable salt thereof, and
(b) a second therapeutic agent that is isavuconazole,
wherein the pharmaceutical combination, when administered to a first population of subjects having an Aspergillus infection, results in a survival rate that is higher than the survival rate of a second population of subjects having an Aspergillus infection and receiving either (i) the first therapeutic agent or (ii) the second therapeutic agent.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the Aspergillus infection is invasive pulmonary aspergillosis.

### Claim 13 (depends on 11)

The method according to claim 11, wherein administering to the subject the pharmaceutical combination comprises administering the first therapeutic agent sequentially with the second therapeutic agent.

### Claim 14 (depends on 11)

The method according to claim 11, wherein administering to the subject the pharmaceutical combination comprises administering the first therapeutic agent concurrently with the second therapeutic agent.