# US 8,569,495 B2 · Anthelmintic agents and their use

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- Number: US 8,569,495 B2
- Document ID: US8569495B2
- Status: Granted
- Kind: B2
- Application number: 12/808,897
- Filed: 2008-12-16
- Published: 2011-01-27
- Granted: 2013-10-29
- Earliest claimed: 2007-12-17
- Assignees: Intervet International B.V.
- Applicants: Christophe Pierre Alain Chassaing; Jörg Schröder; Thomas Simon Ilg; Manfred Uphoff; Thorsten Meyer
- Inventors: Christophe Pierre Alain Chassaing; Jörg Schröder; Thomas Simon Ilg; Manfred Uphoff; Thorsten Meyer
- Web page: https://patentgrep.com/patent/US8569495B2

## CPC

- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/10: Anthelmintics
- C07D 211/26: with hydrocarbon radicals, substituted by nitrogen atoms
- C07D 295/108: to an acyclic saturated chain
- C07D 487/08: Bridged systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention is directed to compounds and salts that are generally useful as anthelmintic agents or as intermediates in processes for making anthelmintic agents. This invention also is directed to processes for making the compounds and salts, pharmaceutical compositions and kits comprising the compounds and salts, uses of the compounds and salts to make medicaments, and treatments comprising the administration of the compounds and salts to animals in need of the treatments.

## Claims

### Claim 1

A compound or salt thereof, wherein:
the compound corresponds in structure to:
each of R1, R2, R3, R4, and R5 is independently selected from the group consisting of hydrogen, halogen, cyano, alkyl, and alkoxy, wherein:
the alkyl, and alkoxy, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, alkylsulfanyl, and haloalkylsulfanyl;
X1 is selected from the group consisting of —O—, and —NH—, wherein:
the —NH— is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, and carbocyclylalkyl, wherein:
any such substituent is optionally substituted with one or more independently selected halogen;
X2 is selected from the group consisting of straight-chain C3-C5-alkyl, straight-chain C3-C5-alkenyl, straight-chain C3-C5-alkynyl, and C4-C6-carbocyclyl, wherein:
the straight-chain C3-C5-alkyl, straight-chain C3-C5-alkenyl, straight-chain C3-C5-alkynyl, and C4-C6-carbocyclyl are optionally substituted with one or more independently selected alkyl;
X3 is selected from the group consisting of —CH2—, —O—, —C(O)—, and —S—, wherein:
the —CH2— is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and carbocyclyl, and
wherein:
any such substituent is optionally substituted with one or more independently selected halogen;
Z1 is CH, wherein:
the CH is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, aminosulfonyl, alkyl, alkoxycarbonyl, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, aryl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl, wherein:
the alkyl, alkoxycarbonyl, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl, alkylsulfanyl, aryl, arylsulfanyl, arylsulfinyl, arylsulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen and alkyl, and
the aminosulfonyl is optionally substituted with up to two independently selected alkyl;
Z2 is CH, wherein:
the CH is optionally substituted with a substituent selected from the group consisting of cyano, halogen, nitro, alkyl, haloalkyl, and haloalkylsulfanyl; and
each of Z3, Z4, and Z5 is CH, wherein:
the CH is optionally substituted with a substituent selected from the group consisting of halogen, cyano, nitro, alkyl, alkylsulfanyl, haloalkyl, haloalkoxy, and haloalkylsulfanyl; and
A is O or S.

### Claim 2 (depends on 1)

A compound or salt of claim 1, wherein:
each of R1, R2, R3, R4, and R5 is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, and C1-C6-alkoxy, wherein:
the C1-C6-alkyl, and C1-C6-alkoxy, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, C1-C6-alkylsulfanyl, and halo-C1-C6-alkylsulfanyl;
X1 is selected from the group consisting of —O —, and —NH—, wherein:
the —NH— is optionally substituted with a substituent selected from the group consisting of C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1 -C6-alkoxy-C -C6-alkyl, C3-C6-carbocyclyl, and C3-C6-carbocyclyl-C1-C6-alkyl, wherein:
any such substituent is optionally substituted with one or more independently selected halogen;
X2 is selected from the group consisting of straight-chain C3-C4-alkyl, straight-chain C3-C4-alkenyl, straight-chain C3-C4-alkynyl, and C4-C6-carbocyclyl, wherein:
the straight-chain C3-C4-alkyl, straight-chain C3-C4-alkenyl, straight-chain C3-C4-alkynyl, and C3-C4-carbocyclyl are optionally substituted with one or more independently selected C1-C6-alkyl;
X3 is selected from the group consisting of —CH2—, —O—, —C(O)—, and —S—, wherein:
the —CH2— is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl and cyclopropyl,
wherein:
any such substituent is optionally substituted with one or more independently selected halogen;
Z1 is CH, wherein:
the CH is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, aminosulfonyl, C1-C6-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, phenyl, phenylsulfanyl, phenylsulfinyl, phenylsulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl, wherein:
the C1-C6-alkyl, C1-C6-alkoxycarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-alkylsulfanyl, phenyl, phenylsulfanyl, phenylsulfinyl, phenylsulfonyl, heteroaryl, heteroarylsulfanyl, heteroarylsulfinyl, and heteroarylsulfonyl are optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1-C6-alkyl, and
the aminosulfonyl is optionally substituted with up to two independently selected C1-C6-alkyl;
Z2 is CH, wherein:
the CH is optionally substituted with a substituent selected from the group consisting of cyano, halogen, nitro, C1-C6-alkyl, halo-C1-C6-alkyl, and halo-C1-C6-alkylsulfanyl;
each of Z3, Z4, and Z5 is independently CH, wherein:
the CH is optionally substituted with a substituent selected from the group consisting of halogen, cyano, nitro, C1-C6-alkyl, C1-C6-alkylsulfanyl, halo-C1-C6-alkyl, and halo-C1-C6-alkylsulfanyl; and
each heteroaryl is a 5- to 6-member heteroaryl.

### Claim 3

A compound or salt thereof, wherein: the compound corresponds in structure to:
each of R1, R2, R3, R4, and R5 is independently selected from the group consisting of hydrogen, halogen, cyano, C1-C6-alkyl, and C1-C6-alkoxy, wherein:
the C1-C6-alkyl, and C1-C6-alkoxy, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy;
X1 is selected from the group consisting of —O—, and —NH—, wherein:
the —NH— is optionally substituted with a substituent selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, and carbocyclylalkyl, wherein:
any such substituent is optionally substituted with one or more independently selected halogen;
X2 is C4-C6-carbocyclyl optionally substituted with one or more independently selected C1-C6-alkyl; and
X3 is selected from the group consisting of —CH2—, —O—, —C(O)—, and —S—, wherein:
the —CH2— is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and carbocyclyl, and
wherein:
any such substituent is optionally substituted with one or more independently selected halogen;
Z1 is CH, wherein:
the CH is substituted with a substituent selected from the group consisting of halogen, nitro, cyano, aminosulfonyl, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, phenylsulfonyl, and heteroaryl, wherein:
the C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylsulfanyl, C1-C6-alkylsulfinyl, C1-C6-alkylsulfonyl, C1-C6-alkylsulfanyl, phenylsulfonyl, and heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halogen and C1-C6-alkyl, and
the aminosulfonyl is optionally substituted with up to two independently selected C1-C6-alkyl;,
Z2 is CH, wherein:
the CH is optionally substituted with a substituent selected from the group consisting of cyano, halogen, nitro, alkyl, alkoxy, haloalkyl, and haloalkylsulfanyl; and
each of Z3, Z4, and Z5 is CH, wherein:
the CH is optionally substituted with a substituent selected from the group consisting of halogen, cyano, nitro, alkyl, alkoxy, alkylsulfanyl, haloalkyl, haloalkoxy, and haloalkylsulfanyl; and
A is O or S.

### Claim 4 (depends on 1)

A compound or salt thereof according to claim 1, wherein X6 is selected from the group of linkers consisting of:
wherein
any such group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, oxo, and thiocarbonyl.

### Claim 5 (depends on 1)

A compound or salt thereof according claim 1, wherein the compound is selected from the group consisting of:

### Claim 6 (depends on 1)

A compound or salt thereof according to claim 1, wherein the compound is selected from the group consisting of:

### Claim 7 (depends on 3)

A compound or salt thereof according to claim 3, wherein Z2 is CH substituted with a substituent selected from the group consisting of cyano, halogen, nitro, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, and halo-C1-C6-alkylsulfanyl.

### Claim 8 (depends on 1)

A compound or salt thereof according to claim 1, wherein R3 is independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, and C1-C6-alkoxy, wherein:
the C1-C6-alkyl, C1-C6-alkoxy, phenyl, phenoxy, and benzyloxy are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy; and
at least two of R1, R2, R4, and R5 are each hydrogen.

### Claim 9 (depends on 1)

A compound or salt thereof according to claim 1, wherein the compound corresponds in structure to a formula consisting of:

### Claim 10 (depends on 1)

A compound or salt thereof according to claim 1, wherein the compound corresponds in structure to a formula consisting of:

### Claim 11 (depends on 1)

A compound or salt thereof according to claim 1, wherein:
the compound corresponds in structure to a formula consisting of:
R3 is selected from the group consisting of halogen, cyano, C1-C6-alkyl, and C1-C6-alkoxy, wherein:
the C1-C6-alkyl, and C1-C6-alkoxy, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkyl, and halo-C1-C6-alkoxy; and
at least two of R1, R2, R4, and R5 are each hydrogen.

### Claim 12 (depends on 1)

A compound or salt thereof according to claim 1, wherein the compound is selected from the group consisting of:

### Claim 13 (depends on 1)

A compound or salt thereof according to claim 1, wherein the compound is selected from the group consisting of:

### Claim 14 (depends on 1)

A compound or salt of claim 1, wherein the compound or salt is active against Haemonchus contortus resistant to one or more anthelmintic agents selected from the group consisting of an avermectin, a benzimidazole derivative, levamisole, and pyrantel.

### Claim 15 (depends on 1)

A pharmaceutical composition, wherein the composition comprises:
at least one compound or salt of claim 1, and
at least one excipient.

### Claim 16 (depends on 1)

A method of treating a nematode infection in an animal, wherein the method comprises administering at least one compound or salt of claim 1 to the animal.

### Claim 17 (depends on 16)

A method of claim 16, wherein the nematode infection comprises an infection by at least one of Trichostrongylus axei , Trichostrongylus colubriformis, Haemonchus contortus, Ascaridia galli, and Oesophagostomum dentatum.

### Claim 18 (depends on 16)

A method of claim 16, wherein the animal is a sheep.

### Claim 19 (depends on 16)

A method of claim 16, wherein the animal is a bovine animal.

### Claim 20 (depends on 1)

A kit, wherein the kit comprises:
at least one compound or salt of claim 1, and
at least one other component selected from the group consisting of an excipient, an active ingredient, instructions for combining the compound or salt with an excipient or active ingredient, an apparatus for combining the compound or salt with an excipient or active ingredient, instructions for administering the compound or salt to an animal, an apparatus for administering the compound or salt to an animal, and a diagnostic tool.

### Claim 21

A compound of the formula

### Claim 22 (depends on 1)

A process for preparing a compound of claim 1, wherein the process utilizes an intermediate compound selected from the group consisting of:

### Claim 23 (depends on 1)

A compound or salt thereof according to claim 1, wherein the compound is

### Claim 24 (depends on 3)

A compound or salt thereof according claim 3, wherein the compound is selected from the group consisting of:

### Claim 25 (depends on 3)

A compound or salt of claim 3, wherein the compound or salt is active against Haemonchus contortus resistant to one or more anthelmintic agents selected from the group consisting of an avermectin, a benzimidazole derivative, levamisole, and pyrantel.

### Claim 26 (depends on 3)

A pharmaceutical composition, wherein the composition comprises at least one compound or salt of claim 3, and at least one excipient.

### Claim 27 (depends on 3)

A method of treating a nematode infection in an animal, wherein the method comprises administering at least one compound or salt of claim 3 to the animal.

### Claim 28 (depends on 27)

A method of claim 27, wherein the nematode infection comprises an infection by at least one of Trichostrongylus axei, Trichostrongylus colubriformis, Haemonchus contortus, Ascaridia galli, and Oesophagostomum dentatum.

### Claim 29 (depends on 27)

A method of claim 27, wherein the animal is a sheep or a bovine animal.

### Claim 30 (depends on 3)

A kit, wherein the kit comprises:
at least one compound or salt of claim 3, and
at least one other component selected from the group consisting of an excipient, an active ingredient, instructions for combining the compound or salt with an excipient or active ingredient, an apparatus for combining the compound or salt with an excipient or active ingredient, instructions for administering the compound or salt to an animal, an apparatus for administering the compound or salt to an animal, and a diagnostic tool.

### Claim 31 (depends on 3)

A process for preparing a compound of claim 3, wherein the process utilizes an intermediate compound selected from the group consisting of: