Endoparasitic depsipeptides

Patent metadata

Field	Value
Publication number	US-11331369-B2
Application number	US-201816652136-A
Country	US
Kind code	B2
Filing date	Nov 28, 2018
Priority date	Nov 29, 2017
Publication date	May 17, 2022
Grant date	May 17, 2022

Abstract

The present invention provides cyclic depsipeptides of Formula (1), stereoisomers thereof, and veterinary acceptable salts thereofwherein each of R1, R2, R3, R4, L1, and L2, 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)

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, 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, and C 2 -C 6 alkynl optionally substituted with cyclopropyl or phenyl;
stereoisomers thereof, and veterinary acceptable salts thereof.

2. A compound of claim 1 wherein each pyrazole is independently and separately optionally substituted with at least one to three substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, sec-butyl, cyano, bromo, fluoro, chloro, iodo, —CH 2 F, —CHF 2 , —CF 3 ; cyclopropyl, cylobutyl, cyclopentyl, each optionally substituted with at least substituent selected from fluoro, chloro, methyl and methoxy; methoxy, ethoxy, isopropoxy, isobutoxy; phenyl optionally substituted with at least one substituent selected from halo and methoxy; C 2 -C 6 alkynl optionally substituted with cyclopropyl or phenyl; stereoisomers thereof, and veterinary acceptable salts thereof.

3. A compound of claim 1 that is selected from the group consisting of:
1-(4-(((2R,5S,8R,11 S,14R,17S,20R,23S)-14-(4-((4-bromo-3-cyano-1H-pyrazol-1-yl)methyl)benzyl)-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-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile;
1-(4-(((2R,5S,8R,11 S,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-14-(4-((5-phenyl-1H-pyrazol-1-yl)methyl)benzyl)-1,7,13,19-tetraoxa-4,10,16,22-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile;
1-(4-(((2R,5S,8R,11 S,14R,17S,20R,23S)-14-(4-((3,5-dicyclopropyl-1H-pyrazol-1-yl)methyl)benzyl)-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-tetraazacyclotetracosan-2-yl)methyl)benzyl)-1H-pyrazole-3,5-dicarbonitrile;
(3S,6R,9S,12R,15S,18R,21 S,24R)-6-(4-((4-iodo-1H-pyrazol-1-yl)methyl)benzyl)-3,9,15,21-tetraisobutyl-4,10,12,16,22,24-hexamethyl-18-(4-((4-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,21 S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12-(4-((3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)benzyl)-24-(4-((5-(trifluoromethyl)-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,21 S,24R)-6-(4-((3-bromo-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-bromo-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; and
(3S,6R,9S,12R,15S,18R,21 S,24R)-6-(4-((3-cyclopentyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((5-cyclopentyl-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;
or a Table 1 b compound selected from the group consisting of:
(3S,6R,9S,12R,15S,18R,21 S,24R)-6,18-bis({4-[(3,5-dicyclopropyl-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,21 S,24R)-6,18-bis(4-((4-chloro-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,21 S,24R)-6,18-bis(4-((4-iodo-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,21 S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((3-(trifluoromethyl)-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,21 S,24R)-6,18-bis(4-((3,5-bis(difluoromethyl)-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,21 S,24R)-6,18-bis(4-((3-chloro-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,21 S,24R)-6,18-bis(4-((5-cyclopropyl-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,21 S,24R)-6,18-bis(4-((4-(cyclopropylethynyl)-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,21 S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-isopropyl-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,21 S,24R)-6,18-bis(4-((5-(tert-butyl)-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,21 S,24R)-3,9,15,21-tetraisobutyl-4,6,10,16,18,22-hexamethyl-12,24-bis(4-((5-phenyl-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,21 S,24R)-6,18-bis(4-((5-cyclobutyl-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,21 S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-(4-methoxyphenyl)-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,21 S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((3-isopropoxy-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,21 S,24R)-6,18-bis(4-(2-(4-ethoxy-1H-pyrazol-1-yl)propan-2-yl)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,21 S,24R)-6,18-bis(4-((4-isobutoxy-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,21 S,24R)-6-(4-((5-ethyl-3-methyl-1H-pyrazol-1-yl)methyl)benzyl)-18-(4-((3-ethyl-5-methyl-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,21 S,24R)-6,18-bis(4-((5-(cyclopropylmethyl)-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,21 S,24R)-3,9,15,21-tetraisobutyl-6,18-bis(4-((5-isobutyl-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,

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 Christoper S
• Vairagoundar Rajendran

Classifications

• A01N37/46

  N-acyl derivatives · CPC title

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D498/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title