# US 2014/0194345 A1 · Novel depsipeptide and uses thereof

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- Number: US 2014/0194345 A1
- Document ID: US20140194345A1
- Status: Published application
- Kind: A1
- Application number: 14/095,415
- Filed: 2013-12-03
- Published: 2014-07-10
- Earliest claimed: 2012-12-03
- Assignees: NovoBiotic Pharmaceuticals, LLC
- Inventors: Aaron J. Peoples; Dallas Hughes; Losee Lucy Ling; William Millett; Anthony Nitti; Amy Spoering; Victoria Alexandra Steadman; Jean-Yves Christophe Chiva; Linos Lazarides; Michael Kenyon Jones; Karine Gaelle Poullenec; Kim Lewis
- Web page: https://patentgrep.com/patent/US20140194345A1

## CPC

- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- A61K 38/15: Depsipeptides; Derivatives thereof
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/04: Amoebicides
- A61P 33/06: Antimalarials
- A61P 33/10: Anthelmintics
- A61P 33/12: Schistosomicides
- C07K 11/02: cyclic, e.g. valinomycins {; Derivatives thereof}
- C12N 1/205: Bacterial isolates
- C12P 17/14: Nitrogen or oxygen as hetero atom and at least one other diverse hetero ring atom in the same ring
- C12P 21/02: having a known sequence of two or more amino acids, e.g. glutathione
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C12R 2001/01: Bacteria or Actinomycetales {; using bacteria or Actinomycetales}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}
- C12R: INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates generally to novel depsipeptides, to methods for the preparation of these novel depsipeptides, to pharmaceutical compositions comprising the novel depsipeptides; and to methods of using the novel depsipeptides to treat or inhibit various disorders.

## Claims

### Claim 1

An isolated compound of Formula (I):
or an enantiomer, diastereomer, tautomer, or pharmaceutically-acceptable salt thereof, wherein each stereocenter (indicated with an “*”) can be either the R or S configuration.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is a natural product of bacterial isolate ISO1862.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is producible from bacterial isolate ISO1862.

### Claim 4

An isolated compound of Formula (II):
or tautomer or pharmaceutically-acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is characterized by at least ten 13C nuclear magnetic resonance peaks at chemical shifts in DMSO-d6 selected from 36.3 ppm, 36.5 ppm, 36.9 ppm, 37.4 ppm, 52.1 ppm, 52.2 ppm, 52.7 ppm, 53.5 ppm, 55.7 ppm, 56.1 ppm, 56.4 ppm, 56.7 ppm, 57.3 ppm, 57.8 ppm, 57.9 ppm, 61.8 ppm, and 71.1 ppm.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is characterized by 13C nuclear magnetic resonance peaks at chemical shifts in DMSO-d6 of 36.3 ppm, 36.5 ppm, 36.9 ppm, 37.4 ppm, 52.1 ppm, 52.2 ppm, 52.7 ppm, 53.5 ppm, 55.7 ppm, 56.1 ppm, 56.4 ppm, 56.7 ppm, 57.3 ppm, 57.8 ppm, 57.9 ppm, 61.8 ppm, and 71.1 ppm.

### Claim 7 (depends on 1)

A compound of claim 1, wherein the compound is characterized by at least one of:
(a) a molecular weight of about 1242.47 g/mol;
(b) a proton nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 1;
(c) a carbon 13 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 2;
(d) a COSY nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 3;
(e) a DEPT-135 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 4;
(f) a HSQC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 5; and
(e) a HMBC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 6.

### Claim 8 (depends on 1)

A compound of claim 1, wherein the compound is characterized by:
(a) a molecular weight of about 1242.47 g/mol;
(b) a proton nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 1;
(c) a carbon 13 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 2;
(d) a COSY nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 3;
(e) a DEPT-135 nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 4;
(f) a HSQC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 5; and
(e) a HMBC nuclear magnetic resonance spectrum substantially the same as that shown in FIG. 6.

### Claim 9

(canceled)

### Claim 10

An isolated compound of Formula (III):
or a tautomer or pharmaceutically-acceptable salt thereof; wherein each R1-R6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, C(═O)Ra and S(═O)2Rb; each Ra is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl; and each Rb is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl.

### Claim 11

An isolated compound of Formula (IV):
wherein X is NH, O or S; or a tautomer or pharmaceutically-acceptable salt thereof.

### Claim 12 (depends on 4)

A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically-acceptable excipient, carrier, or diluent.

### Claim 13

(canceled)

### Claim 14 (depends on 1)

A method for producing a compound of Formula (I) of claim 1,
the method comprising:
cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;
thereby producing a compound of Formula (I).

### Claim 15 (depends on 4)

A method for producing a compound of Formula (II) of claim 4,
the method comprising:
cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;
thereby producing a compound of Formula (II).

### Claim 16 (depends on 10)

A method for producing a compound of Formula (III) of claim 10
the method comprising:
cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;
thereby producing a compound of Formula (III).

### Claim 17 (depends on 11)

A method for producing a compound of Formula (IV) of claim 11,
the method comprising:
cultivating a bacterial isolate ISO18629 in a culture medium, the culture medium comprising assimilable sources of carbon, nitrogen, and inorganic salts under aerobic conditions;
thereby producing a compound of Formula (IV).

### Claim 18

(canceled)

### Claim 19

(canceled)

### Claim 20 (depends on 1)

A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (I) of claim 1
thereby treating the disorder in said subject.

### Claim 21 (depends on 4)

A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (II) of claim 4,
thereby treating the disorder in said subject.

### Claim 22 (depends on 10)

A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (III) of claim 10,
thereby treating the disorder in said subject.

### Claim 23 (depends on 11)

A method of treating a disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (IV) of claim 11,
thereby treating the disorder in said subject.

### Claim 24

(canceled)

### Claim 25 (depends on 21)

The method of claim 21, wherein the disorder is caused by a pathogen selected from the group consisting of a bacterium, a fungus, a virus, a protozoan, a helminth, a parasite, and combinations thereof.

### Claim 26 (depends on 25)

The method of claim 25, wherein the pathogen is a bacterium.

### Claim 27 (depends on 26)

The method of claim 26, wherein the bacterium is a Gram-positive bacterium.

### Claim 28 (depends on 27)

The method of claim 27, wherein the Gram-positive bacterium is selected from the group consisting of Streptococcus, Staphylococcus, Enterococcus, Corynebacteria, Listeria, Bacillus, Erysipelothrix, Mycobacterium, Clostridium, and Actinomycetales.

### Claim 29 (depends on 27)

The method of claim 27, wherein the Gram-positive bacterium is selected from the group consisting of methicillin-susceptible and methicillin-resistant staphylococci (including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus, and coagulase-negative staphylococci), glycopeptide intermediate-susceptible Staphylococcus aureus (GISA), penicillin-susceptible and penicillin-resistant streptococci (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sangius, Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus and Streptococci Group C, Streptococci Group G and Viridans streptococci), enterococci (including vancomycin-susceptible and vancomycin-resistant strains such as Enterococcus faecalis and Enterococcus faecium), Clostridium difficile, Clostridium clostridiiforme, Clostridium innocuum, Clostridium perfringens, Clostridium tetani, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansaii, Mycobacterium gordonae, Mycobacteria sporozoites, Listeria monocytogenes, Bacillus subtilis, Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Corynebacterium sporozoites, Erysipelothrix rhusiopathiae, and Actinomyces israelli.

### Claim 30 (depends on 25)

The method of claim 25, wherein the disorder is caused by infection with Bacillus anthracis.

### Claim 31 (depends on 26)

The method of claim 26, wherein the bacterium is a Gram-negative bacterium.

### Claim 32 (depends on 31)

The method of claim 31, wherein the Gram-negative bacterium is selected from the group consisting of Helicobacter pylori, Legionella pneumophilia, Neisseria gonorrhoeae, Neisseria meningitidis, pathogenic Campylobacter sporozoites, Haemophilus influenzae, Pseudomonas aeruginosa, Enterobacter aerogenes, Enterobacter cloacae, Klebsiella pneumoniae, Klebsiella oxytoca, Pasteurella multocida, Bacteroides sporozoites, Bacteroides fragilis, Bacteroides thetaiotaomicron Bacteroides uniformis, Bacteroides vulgatus Fusobacterium nucleatum, Streptobacillus moniliformis, Leptospira, Escherichia coli, Salmonella enterica, Salmonella salamae, Salmonella arizonae, Salmonella diarizonae, Salmonella houtenae, Salmonella bongori, Salmonella indica, Salmonella Enteritidis, Salmonella typhi, and Citrobacter freundii.

### Claim 33 (depends on 25)

The method of claim 25, wherein the pathogen is a virus.

### Claim 34

(canceled)

### Claim 35

(canceled)

### Claim 36 (depends on 25)

The method of claim 25, wherein the pathogen is a protozoan.

### Claim 37

(canceled)

### Claim 38 (depends on 25)

The method of claim 25, wherein the pathogen is a helminth.

### Claim 39

(canceled)

### Claim 40 (depends on 25)

The method of claim 25, wherein the pathogen is a parasite.

### Claim 41

(canceled)

### Claim 42

(canceled)

### Claim 43 (depends on 25)

The method of claim 25, wherein the pathogen is a fungus.

### Claim 44

(canceled)

### Claim 45

An isolated culture comprising a bacterial species, having the identifying characteristics of a ISO18629 isolate.

### Claim 46 (depends on 1)

A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (I) of claim 1
thereby inhibiting the growth of the infectious agent.

### Claim 47

(canceled)

### Claim 48 (depends on 4)

A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (II) of claim 4
thereby inhibiting the growth of the infectious agent.

### Claim 49

(canceled)

### Claim 50 (depends on 10)

A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (III) of claim 10,
thereby inhibiting the growth of the infectious agent.

### Claim 51

(canceled)

### Claim 52 (depends on 11)

A method of inhibiting the growth of an infectious agent, the method comprising contacting the agent with a compound of Formula (IV) of claim 11
thereby inhibiting the growth of the infectious agent.

### Claim 53

(canceled)