# US 11,028,113 B2 · Cyphomycin, compositions and uses thereof

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- Number: US 11,028,113 B2
- Document ID: US11028113B2
- Status: Granted
- Kind: B2
- Application number: 16/664,722
- Filed: 2019-10-25
- Published: 2020-04-30
- Granted: 2021-06-08
- Earliest claimed: 2018-10-26
- Assignees: Wisconsin Alumni Research Foundation
- Applicants: Wisconsin Alumni Research Foundation
- Inventors: Timothy S. Bugni; Monica Tallarico Pupo; David R. Andes; Cameron R. Currie; Humberto Enrique Ortega Dominguez
- Web page: https://patentgrep.com/patent/US11028113B2

## CPC

- C07H 17/04: Heterocyclic radicals containing only oxygen as ring hetero atoms
- C12N 1/20: Bacteria; Culture media therefor
- A61K 31/351: not condensed with another ring
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/513: having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K 31/7048: having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin {, digitoxin or digoxin}
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)

## Abstract

Cyphomycin, an isolated compound of Formula I or IA is provided. A compound isolated from insect Streptomyces and having a chemical formula of C77H122O26 is also provided. Compositions including Cyphomycin, such as pharmaceutical compositions including effective amounts of Cyphomycin for treating fungal infections such as Candida and Aspergillus, including drug-resistant strains thereof, are also disclosed. Methods of treating fungal infections with Cyphomycin and compositions thereof are disclosed.

## Claims

### Claim 1

A method of treating a fungal infection comprising administering to a mammal in need thereof an effective amount of a compound, or a pharmaceutical composition thereof, wherein:
the compound is a compound of Formula I,
or the compound is a compound of Formula IA,
or the compound has the formula, C77H122O26 and exhibits one or more of the following spectral features:
one or more 13C NMR peaks at or about the ppm chemical shifts in the table below;
one or more 1H NMR peaks at or about the ppm chemical shifts in the table below; or
one or more UV λmax at about 204, about 248, about 254, or about 334 nm;
δC
δH, mult. (J in Hz)
δC
δH, mult. (J in Hz)
168.7
—
38.5
2.00, m
122.1
5.86, br d (15.8)
80.5
3.88,m
153.5
7.06, dd (15.8, 6.8)
22.9
1.64, m
1.36, m
43.5
2.47, m
11.5
0.98, t (7.2)
74.2
3.78,m
14.1
1.09, d (6.7)
41.7
1.60, m
13.6
0.79, d (6.4)
1.54, m
71.8
3.78, m
17.3
1.03, d (6.5)
38.9
1.32-1.62, m
9.7
0.90, d (6.8)
23.0
1.45-1.68, m
5.0
0.90, d (6.8)
38.5
1.32-1.62, m
10.6
0.78, d (6.4)
72.9
3.51, m
96.4
5.01, br s
36.4
1.38-1.47, m
37.9
1.93, dd (3.70, 14.0)
1.53-1.63 m
1.55, d (14.0)
31.9
1.69,m
71.2
—
1.30, m
36.2
2.25, m
81.7
3.31, m
75.8
4.69, d (2.2)
64.7
4.44, m
210.6
—
17.3
1.21, d (6.6)
99.4
—
27.5
1.24, s
41.1
2.09,m
104.0
4.58, br d (7.6)
1.33, m
64.9
4.08, m
31.3
2.01, m
1.56, m
42.0
1.96, m
28.6
2.10, m
1.21,m
1.56,m
67.7
4.20, m
74.4
4.45, m
45.6
1.45-1.74, m
74.5
3.54, dq (6.1, 9.3)
65.4
4.08, m
18.5
1.19, d (6.1)
46.3
1.43-1.67, m
175.5
—
68.2
4.04, m
48.9
2.78, dq (8.5, 7.1)
46.0
1.40-1.76, m
76.4
4.86, d (8.5)
71.3
3.79, m
150.3
—
38.4
1.32-1.62, m
125.3
8.01, br s
22.7
1.51, m
133.5
—
38.4
1.32-1.62, m
186.2
—
72.4
3.94, m
136.5
6.88, br d (1.4)
135.2
5.53, dd (15.6, 4.5)
149.8
—
133.1
5.49, dd (15.6, 7.2)
186.3
—
40.4
2.54, m
132.9
—
77.3
5.14, br d (9.5)
127.6
8.07, d (8.0)
38.7
1.97, m
133.2
7.79, dd (8.0, 1.3)
78.5
3.39, br d (9.5)
14.3
0.94, d (7.1)
36.0
1.81, m
16.4
2.17, s
79.4
3.52, m.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mammal is human.

### Claim 3 (depends on 1)

The method of claim 1, wherein the fungal infection is caused by one or more of Candida or Aspergillus.

### Claim 4 (depends on 1)

The method of claim 1, wherein the fungal infection is caused by one or more of Candida albicans, Candida glabrata, Candida auris, Aspergillus fumigatus, and drug-resistant strains thereof.

### Claim 5 (depends on 1)

The method of claim 1, wherein a second antifungal other than the compound of Formula I is administered to the mammal in need thereof simultaneously, sequentially or separately with the compound of Formula I, or the pharmaceutical composition.

### Claim 6 (depends on 5)

The method of claim 5, wherein the second antifungal is a selected from the group consisting of amphotericin B, flucytosine, fluconazole, micafungin, and forazoline.

### Claim 7 (depends on 1)

The method of claim 1, wherein the effective amount of the compound is about 0.01 mg/kg/day to 100 mg/kg/day.

### Claim 8 (depends on 1)

The method of claim 1, wherein the effective amount of the compound is about 0.1 mg/kg/day to 5 mg/kg/day.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound is a compound of Formula I.

### Claim 10 (depends on 9)

The method of claim 9, wherein the mammal is human.

### Claim 11 (depends on 10)

The method of claim 10, wherein the fungal infection is caused by one or more of Candida or Aspergillus.

### Claim 12 (depends on 11)

The method of claim 11, wherein the effective amount of the compound is about 0.01 mg/kg/day to 100 mg/kg/day.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is a compound of Formula IA.

### Claim 14 (depends on 13)

The method of claim 13, wherein the mammal is human.

### Claim 15 (depends on 14)

The method of claim 14, wherein the fungal infection is caused by one or more of Candida or Aspergillus.

### Claim 16 (depends on 15)

The method of claim 15, wherein the effective amount of the compound is about 0.01 mg/kg/day to 100 mg/kg/day.

### Claim 17 (depends on 1)

The method of claim 1, wherein the compound the compound has the formula, C77H122O26and exhibits one or more of the following spectral features:
one or more 13C NMR peaks at or about the ppm chemical shifts in the table below;
one or more 1H NMR peaks at or about the ppm chemical shifts in the table below; or
one or more UV λmax at about 204, about 248, about 254, or about 334 nm;
TABLE 2
1H and 13C NMR (MeOH-d4,
500/125 MHz) cyphomycin data
No.
δC
δH, mult. (J in Hz)
1
168.7
—
2
122.1
5.86, br d (15.8)
3
153.5
7.06, dd (15.8, 6.8)
4
43.5
2.47, m
5
74.2
3.78, m
6
41.7
1.60, m
1.54, m
7
71.8
3.78, m
8
38.9
1.32-1.62, m
9
23.0
1.45-1.68, m
10
38.5
1.32-1.62, m
11
72.9
3.51, m
12
36.4
1.38-1.47, m
1.53-1.63 m
13
31.9
1.69, m
1.30, m
14
36.2
2.25, m
15
75.8
4.69, d (2.2)
16
210.6
—
17
99.4
—
18
41.1
2.09, m
1.33, m
19
64.9
4.08, m
20
42.0
1.96, m
1.21, m
21
67.7
4.20, m
22
45.6
1.45-1.74, m
23
65.4
4.08, m
24
46.3
1.43-1.67, m
25
68.2
4.04, m
26
46.0
1.40-1.76, m
27
71.3
3.79, m
28
38.4
1.32-1.62, m
29
22.7
1.51, m
30
38.4
1.32-1.62, m
31
72.4
3.94, m
32
135.2
5.53, dd (15.6, 4.5)
33
133.1
5.49, dd (15.6, 7.2)
34
40.4
2.54, m
35
77.3
5.14, br d (9.5)
36
38.7
1.97, m
37
78.5
3.39, br d (9.5)
38
36.0
1.81, m
39
79.4
3.52, m
40
38.5
2.00, m
41
80.5
3.88, m
42
22.9
1.64, m
1.36, m
43
11.5
0.98, t (7.2)
44
14.1
1.09, d (6.7)
45
13.6
0.79, d (6.4)
46
17.3
1.03, d (6.5)
47
9.7
0.90, d (6.8)
48
5.0
0.90, d (6.8)
49
10.6
0.78, d (6.4)
1′
96.4
5.01, br s
2′
37.9
1.93, dd (3.70, 14.0)
1.55, d (14.0)
3′
71.2
—
4′
81.7
3.31, m
5′
64.7
4.44, m
6′
17.3
1.21, d (6.6)
7′
27.5
1.24, s
1″
104.0
4.58, br d (7.6)
2″
31.3
2.01, m
1.56, m
3″
28.6
2.10, m
1.56, m
4″
74.4
4.45, m
5″
74.5
3.54, dq (6.1, 9.3)
6″
18.5
1.19, d (6.1)
50
175.5
—
51
48.9
2.78, dq (8.5, 7.1)
52
76.4
4.86, d (8.5)
53
150.3
—
54
125.3
8.01, br s
55
133.5
—
56
186.2
—
57
136.5
6.88, br d (1.4)
58
149.8
—
59
186.3
—
60
132.9
—
61
127.6
8.07, d (8.0)
62
133.2
7.79, dd (8.0, 1.3)
63
14.3
0.94, d (7.1)
64
16.4
2.17, s.

### Claim 18 (depends on 17)

The method of claim 17, wherein the mammal is human.

### Claim 19 (depends on 18)

The method of claim 18, wherein the fungal infection is caused by one or more of Candida or Aspergillus.

### Claim 20 (depends on 19)

The method of claim 19, wherein the compound exhibits 13C NMR peaks selected from those at about 210.6, about 168.7, about 122.1, about 153.5, about 135.2, about 133.1, about 175.5, about 150.3, about 186.2, and about 186.3 ppm, and/or 1H NMR peaks selected from those at about 8.07, about 8.01, about 7.79, about 7.06, about 6.88, about 5.86, about 5.53, about 5.49, about 5.14, about 4.69, and about 3.54 ppm.