Ligands for nematode nuclear receptors and uses thereof

Abstract

An effective anti-nematode methodology entails contacting nematodes with a biologically effective amount of at least one compound according to formula I: where Q, Q′, R 1 , R 2 , and n are defined herein, or with a stereoisomer, solvate, or pharmaceutically acceptable salt of such compound.

1 . A method for controlling the growth of a nematode, comprising contacting the nematode with a biologically effective amount of at least one compound according to formula I or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 each instance of   independently is a single bond or a double bond; wherein one of   is optionally absent so that one of rings A, B, C or D is no longer a cyclic ring or part of a cyclic ring, and wherein when   is absent, the two resultant terminal carbon atoms are substituted with one or more hydrogen atoms to satisfy the carbon atom valencies, 
 one of Q or Q′ is OH or SH and the other of Q or Q′ is hydrogen, or Q and Q′ together with the carbon atom to which they are attached form a carbonyl or thiocarbonyl group; 
 R 1  is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein each instance of   independently is a single bond, a double bond, or a triple bond; and 
             wherein R 1  is optionally substituted with 1 to 8 substituents, each of which is independently selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, NRR′, OR, and SR; 
           
           R 2  is a substituent on one or more carbon atoms in rings A, B, C, and D and, in each instance, is independently selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, NRR′, oxo, thione, OR, and SR; 
           R and R′ are independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )fluoroalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl; and 
           n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. 
         
       
     
     
         2 . The method according to  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         3 . The method according to  claim 1 , wherein the nematode is a parasitic nematode. 
     
     
         4 . The method according to  claim 3 , wherein the parasitic nematode is a member of an order selected from the group consisting of the Strongylida, Rhabditida, Ascaridida, Spirurida, Oxyurida, Enoplida, Tylenchida, and Dorylaimida nematode orders. 
     
     
         5 . The method according to  claim 3 , wherein the parasitic nematode is a member of a genus selected from the group consisting of  Haemonchus, Oestertagia, Trichostrongylus, Cooperia, Dictyocaulus, Strongylus, Oesophagostomum, Syngamus, Nematodirus, Heligmosomoides, Nippostrongylus, Metastrongylus, Angiostrongylus, Acyclostoma, Necator, Uncinaria, Bunostomum, Strongyloides, Steinernema, Ascaris, Parascaris, Toxocara, Toxascaris, Baylisascaris, Anisakis, Pseudoterranova, Heterakis, Wuchereria, Brugia, Onchocerca, Dirofilaria, Loa, Thelazia, Dracunculus, Gnathostoma, Enterobius, Oxyuris, Syphacia, Trichinella, Trichuris, Capillaria, Globodera, Heterodera, Meloidogyne, Anguina, Ditylenchus, Hirschmanniella, Naccobus, Pratylenchus, Radopholus, Criconema, Tylenchulus, Paratylenchus, Aphelenchus, Bursaphelenchus, Longidorus, Xiphinema, Trichodorus , and  Paratrichodorus  nematode genera. 
     
     
         6 . A method of preventing or reducing nematode infestation of a plant that is infested or susceptible to infestation by a nematode population, comprising administering to the plant a biologically effective amount of at least one compound according to formula I or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 each instance of   independently is a single bond or a double bond; wherein one of   is optionally absent so that one of rings A, B, C or D is no longer a cyclic ring or part of a cyclic ring, and wherein when   is absent, the two resultant terminal carbon atoms are substituted with one or more hydrogen atoms to satisfy the carbon atom valencies, 
 one of Q or Q′ is OH or SH and the other of Q or Q′ is hydrogen, or Q and Q′ together with the carbon atom to which they are attached form a carbonyl or thiocarbonyl group; 
 R 1  is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein each instance of   independently is a single bond, a double bond, or a triple bond; and 
             wherein R 1  is optionally substituted with 1 to 8 substituents, each of which is independently selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, NRR′, OR, and SR; 
           
           R 2  is a substituent on one or more carbon atoms in rings A, B, C, and D and, in each instance, is independently selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, NRR′, oxo, thione, OR, and SR; 
           R and R′ are independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )fluoroalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl; and 
           n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. 
         
       
     
     
         7 . The method according to  claim 6 , wherein the administering comprises treating with the compound soil in which the plant is grown. 
     
     
         8 . The method according to  claim 6 , wherein the administering comprises treating with the compound a seed from which the plant is to be grown. 
     
     
         9 . A method of preventing or reducing a nematode infestation in a mammal, comprising administering to the mammal a therapeutically effective amount of at least one compound according to formula I or a stereoisomer, solvate, or pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein
 each instance of   independently is a single bond or a double bond; wherein one of   is optionally absent so that one of rings A, B, C or D is no longer a cyclic ring or part of a cyclic ring, and wherein when   is absent, the two resultant terminal carbon atoms are substituted with one or more hydrogen atoms to satisfy the carbon atom valencies, 
 one of Q or Q′ is OH or SH and the other of Q or Q′ is hydrogen, or Q and Q′ together with the carbon atom to which they are attached form a carbonyl or thiocarbonyl group; 
 R 1  is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein each instance of   independently is a single bond, a double bond, or a triple bond; and 
             wherein R 1  is optionally substituted with 1 to 8 substituents, each of which is independently selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, NRR′, OR, and SR; 
           
           R 2  is a substituent on one or more carbon atoms in rings A, B, C, and D and, in each instance, is independently selected from the group consisting of halo, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkyl, NRR′, oxo, thione, OR, and SR; 
           R and R′ are independently selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, (C 1 -C 8 )fluoroalkyl, (C 1 -C 8 )hydroxyalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )heterocycloalkyl, heteroaryl, aryl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 3 -C 8 )heterocycloalkyl(C 1 -C 6 )alkyl, heteroaryl(C 1 -C 6 )alkyl and aryl(C 1 -C 6 )alkyl; and 
           n is selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.