Endoparasitic depsipeptides

Patent metadata

Field	Value
Publication number	US-11786575-B2
Application number	US-202217696955-A
Country	US
Kind code	B2
Filing date	Mar 17, 2022
Priority date	Nov 29, 2017
Publication date	Oct 17, 2023
Grant date	Oct 17, 2023

Abstract

The present invention provides cyclic depsipeptides of Formula (1), stereoisomers thereof, and veterinary acceptable salts thereof

wherein each of R 1 , R 2 , R 3 , R 4 , L 1 , and L 2 , are as defined herein. The present invention also contemplates compositions and methods of treatment as an endoparasiticide with a Formula (1) compound.

First claim

We claim:

1. A compound of Formula (1A1-1)

stereoisomers thereof, and veterinary acceptable salts thereof;
wherein each pyrazole is independently and separately optionally substituted with at least one to three substituents selected from the group consisting of C 1 -C 6 alkyl, halo, cyano, hydroxy, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl optionally substituted with at least one substituent selected from fluoro, chloro, methyl and methoxy; C 1 -C 6 alkoxy; phenyl optionally substituted with at least one substituent selected from halo and methoxy; —C 1 -cyclopropyl; pyrimidinyl; pyrazinyl; pyridinyl optionally substituted with F and methyl; —CH 2 OCH 3 ; —CH 2 OCH 2 CH 3 ; —OCH 2 -cyclopropyl; and C 2 -C 6 alkynl optionally substituted with cyclopropyl or phenyl; selected from the group consisting of:
(3S,6R,9S,12R,15S,18R,21S,24R)-6-(4-((3-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6-(4-((3-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(4-hydroxy-3,5-dimethyl-1H-pyrazol-1-yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-fluoro-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-hydroxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis[[4-(pyrazol-1-ylmethyl)phenyl]methyl]-1,7,13,19-tetraoxa-4,10,16,22-tetrazacyclotetracosane-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis({4-[(4-ethynyl-1H-pyrazol-1 yl)methyl]phenyl}methyl)-4,10,12,16,22,24-hexamethyl-3,9,15,21-tetrakis(2-methylpropyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(1H-pyrazole-3,5-dicarbonitrile);
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((4-(pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((3-ethoxy-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxy-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((4-(cyclopropylmethoxy)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(methoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-methoxy-5-methyl-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(pyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(ethoxymethyl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(6-methylpyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
(3S,6R,9S,12R,15S,18R,21S,24R)-6,18-bis(4-((5-(5-fluoropyridin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone;
1,1′-(((((2R,5S,8R,11S,14R,17S,20R,23S)-5,11,17,23-tetraisobutyl-4,8,10,16,20,22-hexamethyl-3,6,9,12,15,18,21,24-octaoxo-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosane-2,14-diyl)bis(methylene))bis(4,1-phenylene))bis(methylene))bis(5-methyl-1H-pyrazole-3-carbonitrile);
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-(pyrazin-2-yl)-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone; and
(3S,6R,9S,12R,15S,18R,21S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(1-methoxyethyl)-1H-pyrazol-1-yl)methyl)benzyl)-4,10,12,16,22,24-hexamethyl-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2,5,8,11,14,17,20,23-octaone.

2. A composition comprising a compound of claim 1 , stereoisomer thereof, or a veterinary acceptable salt thereof, and further comprising a veterinary acceptable excipient.

3. The composition of claim 2 , further comprising at least one additional antiparasitic agent.

4. A method of treating a parasitic infection in an animal in need thereof by administering an effective amount of a compound of claim 2 stereoisomer thereof, and veterinary acceptable salt thereof, to said animal.

5. The method of claim 4 wherein the effective amount of the compound is administered to the animal in need thereof by oral, injectable, or topical administration.

6. The method of claim 4 wherein the parasitic infection is an endoparasitic infection.

7. The method of claim 6 wherein the endoparasitic infection is caused by a filarial parasite.

8. The method of claim 7 wherein the filarial parasite is a Dirofilaria parasite and the animal is a companion animal.

9. The composition of claim 3 , wherein the at least one additional antiparasitic agent is selected from the group consisting of moxidectin, doramectin, selamectin, abamectin, milbemycin, milbemycin oxime, pyrantel, praziquantel, and levamisole.

10. The method of claim 8 , wherein the companion animal is canine.

Assignees

• Zoetis Services Llc

Inventors

• Curtis Michael P
• Sheehan Susan M
• Kyne Graham M
• Bedore Matthew W
• Ewin Richard A
• Johnson Paul D
• Mctier Tom L
• Knauer Christopher S
• Vairagoundar Rajendran

Classifications

• A61K38/15 Primary

  Depsipeptides; Derivatives thereof · CPC title

• A61K31/35

  having six-membered rings with one oxygen as the only ring hetero atom · CPC title

• A61K31/4188

  condensed with other heterocyclic ring systems, e.g. biotin, sorbinil · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title