Antiparasitic agents

Abstract

The present invention relates to compounds of the formula (I) and pharmaceutically acceptable salts thereof, compositions containing such compounds and the uses of such compounds as antiparasitic agents.

1 . A compound of the formula 
     
       
         
         
             
             
         
       
       or a tautomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, tautomer or prodrug, wherein: 
       X is O or S; 
       R 1 , R 2 , R 3  and R 4  are each independently selected from H, halo, CN, (C 1 -C 4 )alkyl optionally substituted by R A , (C 3 -C 6 )cycloalkyl optionally substituted by R A , (C 1 -C 4 )haloalkyl, Ar, Het A , Het B , CHO, C(O)—(C 1 -C 4 )alkyl, C(O)—(C 1 -C 4 )haloalkyl, C(O)Ar, C(O)Het A ; C(O)OR B , C(O)NR C R D , OR B , O—CHO, OC(O)—(C 1 -C 4 )alkyl, OC(O)—(C 1 -C 4 )haloalkyl, OC(O)Ar, OC(O)Het A ; OC(O)OR E , OC(O)NR C R D , NR C R D , NH—CHO, NH—C(O)—(C 1 -C 4 )alkyl, NH—C(O)—(C 1 -C 4 )haloalkyl, NH—C(O)Ar, NH—C(O)Het A ; NH—C(O)OR E , NH—C(O)NR C R D , NH—S(O) 2 R E , NH—S(O) 2 NR C R D , S(O) n R E  and S(O) 2 NR C R D , 
       R 5 , R 6 , R 7 , R 8  and R 9  are each independently selected from H, halo, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )haloalkyl, O—(C 1 -C 4 )alkyl, O—(C 3 -C 6 )cycloalkyl, O—(C 1 -C 4 )haloalkyl, SF 5 , S(O) m —(C 1 -C 4 )alkyl, S(O) m —(C 3 -C 6 )cycloalkyl and S(O) m —(C 1 -C 4 )haloalkyl; 
       R 10  is H or (C 1 -C 4 )alkyl; 
       R 11  is H or (C 1 -C 4 )alkyl; 
       R A  is selected from CN, (C 3 -C 6 )cycloalkyl, OR B , NR C R D , S(O)NR E , C(O)OR B , C(O)NR C R D , Ar, Het A  and Het B ; 
       R B  is selected from H and R E ; 
       R C  and R D  are each independently selected from H and R E , or R C  and R D  together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, piperazine or morpholine ring; 
       R E  is selected from Ar, Het A , (C 3 -C 6 )cycloalkyl, (C 1 -C 4 )haloalkyl and (C 1 -C 4 )alkyl optionally substituted by (C 3 -C 6 )cycloalkyl, Ar or Het A ; 
       Ar is phenyl optionally substituted with up to three groups independently selected from halo, (C 1 -C 4 )alkyl, OH and O—(C 1 -C 4 )alkyl; 
       Het A  is a 5- or 6-membered aromatic ring with one heteroatom selected from N, O and S, and optionally one or two further nitrogen atoms, which ring may optionally be substituted with up to three groups independently selected from halo, (C 1 -C 4 )alkyl and O—(C 1 -C 4 )alkyl; 
       Het B  is a 3-, 4-. 5-, 6- or 7-membered saturated ring with one or two heteroatoms selected from N, O and S, which ring may optionally be substituted with up to three (C 1 -C 4 )alkyl groups; 
       m is 0, 1 or 2; and 
       n is 0, 1 or 2. 
     
   
   
       2 . A compound according to  claim 1  wherein R 1 , R 2 , R 3  and R 4  are each independently selected from H, F, Cl, Br, CN, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl and OR B ; and R B  is (C 1 -C 4 )alkyl or (C 1 -C 4 )haloalkyl. 
   
   
       3 . A compound according to  claim 2  wherein at least one of R 1 , R 2 , R 3  and R 4  is CN and at least two of R 1 , R 2 , R 3  and R 4  are H. 
   
   
       4 . A compound according to  claim 3  wherein one of R 1  and R 4  is H and the other is selected from H, F, Cl, Br and CF 3 , and one of R 2  and R 3  is H and the other is CN. 
   
   
       5 . A compound according to  claim 1  wherein one of R 5 , R 6 , R 7,  R 8 and R 9  is selected from halo, (C 1 -C 4 )haloalkyl, O—(C 1 -C 4 )haloalkyl, SF 5  and S(O) m —(C 1 -C 4 )haloalkyl and the others are H. 
   
   
       6 . A compound according to  claim 5  wherein one of R 6  and R 7  is CF 3 , OCF 3 , SF 5 , SCF 3  or S(O) 2 CF 3 , and the other is H. 
   
   
       7 . A compound according to  claim 6  wherein R 7  is CF 3 , OCF 3 , SF 5 , SCF 3  or S(O) 2 CF 3  and R 7 , R 8 , R 10  and R 11  are H. 
   
   
       8 . A compound according to  claim 1  wherein R 10  is (C 1 -C 4 )alkyl. 
   
   
       9 . A compound according to  claim 10  wherein R 10  is methyl. 
   
   
       10 . A compound according to  claim 1  wherein R 11  is H 
   
   
       11 . A compound according to  claim 10  wherein X is O. 
   
   
       12 . A compound of the formula 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein: 
       X is O or S; 
       R 1  and R 4  are each independently selected from H, halo, CN, (C 1 -C 4 )alkyl optionally substituted by R A , (C 1 -C 4 )haloalkyl and OR B ; 
       one of R 2  and R 3  is CN and the other is selected from H and CN; 
       one of R 7  and R 8  is CF 3 , OCF 3 , SF 5 , SCF 3  or S(O) 2 CF 3  and the other is H; 
       R A  is selected from CN and OR B ; 
       R B  is selected from H and R E ; and 
       R E  is selected from (C 1 -C 4 )haloalkyl and (C 1 -C 4 )alkyl. 
     
   
   
       13 . A compound according to  claim 12  wherein R 1  and R 4  are each independently selected from H, Cl, Br and CF 3 , R 7  is CF 3 , OCF 3 , SF 5 , SCF 3  or S(O) 2 CF 3 , and R 8  is H. 
   
   
       14 . A compound according to  claim 13  wherein X is O. 
   
   
       15 . A compound according to  claim 14  wherein R 1  is selected from H, Cl, Br and CF 3 , R 2  is H, R 3  is CN, and R 4  is H. 
   
   
       16 . A compound according to  claim 12  selected from:
 N-[1-cyano-1-(5-cyano-2,3-dihydro-1-benzofuran-2-yl)ethyl]-4-[(trifluoromethyl)thio]benzamide,   N-{(1R*)-1-cyano-1-[(2R*)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-[(trifluoromethyl)thio]benzamide,   N-{(1R)-1-cyano-1-[(2R)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-[(trifluoromethyl)thio]benzamide,   N-{(1S)-1-cyano-1-[(2S)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-[(trifluoromethyl)thio]benzamide,   N-{(1R*)-1-cyano-1-[(2S*)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-[(trifluoromethyl)thio]benzamide,   N-{(1R)-1-cyano-1-[(2S)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-[(trifluoromethyl)thio]benzamide,   N-{(1S)-1-cyano-1-[(2R)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-[(trifluoromethyl)thio]benzamide,   N-[1-cyano-1-(5-cyano-2,3-dihydro-1-benzofuran-2-yl)ethyl]-4-(trifluoromethoxy)benzamide,   N-{(1R*)-1-cyano-1-[(2R*)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-(trifluoromethoxy)benzamide,   N-{(1R)-1-cyano-1-[(2R)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-(trifluoromethoxy)benzamide,   N-{(1S)-1-cyano-1-[(2S)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-(trifluoromethoxy)benzamide   N-{(1R*)-1-cyano-1-[(2S*)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-(trifluoromethoxy)benzamide,   N-{(1R)-1-cyano-1-[(2S)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-(trifluoromethoxy)benzamide,   N-{(1S)-1-cyano-1-[(2R)-5-cyano-2,3-dihydro-1-benzofuran-2-yl]ethyl}-4-(trifluoromethoxy)benzamide,   N-[1-(7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl )-1-cyanoethyl]-4-(trifluoromethoxy)benzamide,   N-{(1R*)-1-[(2R*)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl )-1-cyanoethyl]-4-(trifluoromethoxy)benzamide,   N-{(1R)-1-[(2R)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl)-1-cyanoethyl]-4-(trifluoromethoxy)benzamide,   N-{(1S)-1-[(2S)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl )-1-cyanoethyl]-4-(trifluoromethoxy)benzamide,   N-{(1R*)-1-[(2S*)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl)-1-cyanoethyl]-4-(trifluoromethoxy)benzamide,   N-{(1R)-1-[(2S)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl)-1-cyanoethyl]-4-(trifluoromethoxy)benzamide,   N-{(1S)-1-[(2R)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl)-1-cyanoethyl]-4-(trifluoromethoxy)benzamide,   N-[1-(7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl)-1-cyanoethyl]-4-(pentafluorothio)benzamide,   N-{(1R*)-1-[(2R)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl]-1-cyanoethyl]-4-(pentafluorothio)benzamide,   N-{(1R)-1-[(2R)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl]-1-cyanoethyl]-4-pentafluorothiobenzamide,   N-{(1S)-1-[(2S)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl]-1-cyanoethyl]-4-(pentafluorothio)benzamide,   N-{(1R*)-1-[(2S)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl]-1-cyanoethyl]-4-(pentafluorothio)benzamide,   N-{(1R)-1-[(2S)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl]-1-cyanoethyl]-4-(pentafluorothio)benzamide, and   N-{(1S)-1-[(2R)-7-chloro-5-cyano-2,3-dihydro-1-benzofuran-2-yl]-1-cyanoethyl]-4-(pentafluorothio)benzamide,   or a pharmaceutically acceptable salt thereof.   
   
   
       17 . A method of treatment of a parasitic infestation in a host animal, comprising treating said host animal with an effective amount of a compound as defined in  claim 1  or a pharmaceutically acceptable salt thereof. 
   
   
       18 . The method according to  claim 17  wherein the host animal is a non-human animal. 
   
   
       19 . The method according to  claim 17  wherein the parasite is a nematode. 
   
   
       20 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
   
   
       21 . The pharmaceutical composition according to  claim 20  further comprising a second therapeutic agent. 
   
   
       22 . The pharmaceutical composition according to  claim 21  wherein the second therapeutic agent is selected from ivermectin, avermectin, abamectin, emamectin, eprinomectin, doramectin, selamectin, moxidectin, nemadectin and milbemycin oxime. 
   
   
       23 . The pharmaceutical composition according to  claim 21  wherein the second therapeutic agent is selected from albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, oxfendazole, oxibendazole and parbendazole. 
   
   
       24 . The pharmaceutical composition according to  claim 21  wherein the second therapeutic agent is selected from tetramisole, levamisole, pyrantel pamoate, oxantel and morantel. 
   
   
       25 . The pharmaceutical composition according to  claim 21  wherein the second therapeutic agent is selected from closantel, triclabendazole, clorsulon, rafoxanide, niclosamide, praziquantel and epsiprantel. 
   
   
       26 . The pharmaceutical composition according to  claim 21  wherein the second therapeutic agent is selected from fipronil, lufenuron, tebufenozide, spinosad and imidacloprid.