# US 10,945,996 B2 · Inhibiting germination of clostridium perfringens spores to reduce necrotic enteritis

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- Number: US 10,945,996 B2
- Document ID: US10945996B2
- Status: Granted
- Kind: B2
- Application number: 16/236,919
- Filed: 2018-12-31
- Published: 2019-07-11
- Granted: 2021-03-16
- Earliest claimed: 2015-02-06
- Assignees: The Board of Regents of the Nevada System of Higher Education On Behalf of the University of Nevada, Las Vegas
- Applicants: The Board of Regents of the Nevada System of Higher Education on Behalf of the University of Nevada
- Inventors: Ernesto Abel-Santos; Norma Ramirez; Marc Liggins
- Web page: https://patentgrep.com/patent/US10945996B2

## CPC

- A61K 31/428: condensed with carbocyclic rings
- A23K 20/195: Antibiotics
- A61K 9/0056: {Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals}
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/04: Antibacterial agents
- A61K 9/1611: {Inorganic compounds}
- 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)
- A23K: FODDER
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are materials and methods useful for reducing, preventing, and/or inhibiting germination of C. perfringens spores, including methods for inhibiting C. perfringens germination to reduce necrotizing enteritis (NE, also referred to as necrotic enteritis) in animals. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

## Claims

### Claim 1

A method for preventing a disease caused by infection by Clostridium perfringens in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:
wherein Q is O and S;
wherein Z is selected from O, S, and NR4;
wherein R4, when present, is selected from hydrogen and C1-C8 alkyl;
wherein R1 is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, —CR5aR5b(C═O)NHN═CR6Ar1, Cy1, and Ar2;
wherein each of R5a and R5b, when present, is independently selected from hydrogen and C1-C4 alkyl;
wherein R6, when present, is selected from hydrogen and C1-C4 alkyl;
wherein Cy1 is selected from C3-C7 cycloalkyl and C2-C7 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein Ar1 is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein Ar2 is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and
wherein each of R2a, R2b, R2c, and R2d is independently selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino,
provided that when Q is S, then the compound is
thereby preventing the disease caused by infection by Clostridium perfringens in a subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, Cy1, and Ar2.

### Claim 3 (depends on 1)

The method of claim 1, wherein R1 is C1-C4 alkyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein each of R2a, R2b, R2c, and Red is hydrogen.

### Claim 5 (depends on 1)

The method of claim 1, wherein Z is selected from O and NR4;
wherein R1 is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl;
wherein each of R2a, R2b, R2c, and R2d is independently selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylamino, and (C1-C3)(C1-C3) dialkylamino; and
wherein R4, when present, is selected from hydrogen and C1-C3 alkyl.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound is:

### Claim 7 (depends on 1)

The method of claim 1, wherein the disease is necrotizing enteritis.

### Claim 8 (depends on 1)

The method of claim 1, wherein the subject is a farm animal.

### Claim 9 (depends on 8)

The method of claim 8, wherein the farm animal is selected from a chicken, a turkey, a goose, a duck, a cow, a sheep, a horse, and a pig.

### Claim 10

A method for inhibiting germination of at least one Clostridium perfringens spore, the method comprising contacting the spore with a compound having a structure represented by a formula:
wherein Q is O and S;
wherein Z is selected from O, S, and NR4;
wherein R4, when present, is selected from hydrogen and C1-C8 alkyl;
wherein R1 is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, —CR5aR5b(C═O)NHN═CR6Ar1, Cy1, and Ar2;
wherein each of R5a and R5b, when present, is independently selected from hydrogen and C1-C4 alkyl;
wherein R6, when present, is selected from hydrogen and C1-C4 alkyl;
wherein Cy1 is selected from C3-C7 cycloalkyl and C2-C7 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein Ar1 is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein Ar2 is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and
wherein each of R2a, R2b, R2c, and R2d is independently selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino,
provided that when Q is S, then the compound is
thereby inhibiting germination of at least one Clostridium perfringens spore.

### Claim 11 (depends on 10)

The method of claim 10, wherein the spore is in the gut of an animal.

### Claim 12 (depends on 10)

The method of claim 10, wherein Z is selected from O and NR4;
wherein R1 is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl;
wherein each of R2a, R2b, R2c, and R2d is independently selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 alkylamino, and (C1-C3)(C1-C3) dialkylamino; and
wherein R4, when present, is selected from hydrogen and C1-C3 alkyl.

### Claim 13 (depends on 10)

The method of claim 10, wherein the compound is:

### Claim 14

A feed composition comprising a feed component and a compound having a structure represented by a formula:
wherein Q is O and S;
wherein Z is selected from O, S, and NR4;
wherein R4, when present, is selected from hydrogen and C1-C8 alkyl;
wherein R1 is selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, —CR5aR5b (C═O)NHN═CR6Ar1, Cy1, and Ar2;
wherein each of R5a and R5b, when present, is independently selected from hydrogen and C1-C4 alkyl;
wherein R6, when present, is selected from hydrogen and C1-C4 alkyl;
wherein Cy1 is selected from C3-C7 cycloalkyl and C2-C7 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein Ar1 is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein Ar2 is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and
wherein each of R2a, R2b, R2c, and R2d is independently selected from hydrogen, halogen, —OH, —CN, —NO2, —NH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino,
provided that when Q is S, then the compound is

### Claim 15 (depends on 14)

The composition of claim 14, wherein the feed component is selected from a vegetable protein, a fat-soluble vitamin, a water soluble vitamin, a trace mineral, and a macro mineral.

### Claim 16 (depends on 14)

The composition of claim 14, wherein the composition is a granule.

### Claim 17 (depends on 14)

The composition of claim 14, wherein the composition is a pellet.

### Claim 18 (depends on 14)

The composition of claim 14, wherein the composition further comprises one or more of an antibiotic, an arsenical, an antioxidant, an antifungal, a probiotic, a flavoring agent, a binder, a pigment, a preservative, an emulsifier, and a sweetener.

### Claim 19 (depends on 14)

The composition of claim 14, wherein the compound is: