Tiglien-3-one derivatives

Abstract

The present invention relates to tiglien-3-one compounds and their use in methods of treating or preventing protozoal infections, bacterial infections, parasitic infections and cell proliferative disorders. The tiglien-3-one compounds are also used in methods of controlling pests in humans, animals, plants and the environment

1 - 20 . (canceled) 
     
     
         21 . A pharmaceutical composition comprising a compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein:
 X is —O—; 
 R 1  and R 2  are each independently hydrogen, —OH, —OC 1 -C 10  alkyl, —OC 2 -C 10  alkenyl, —OC 2 -C 10  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 10  alkyl, —OC(O)C 2 -C 10  alkenyl, —OC(O)C 2 -C 10  alkynyl, —OC(O)cycloalkyl, —OC(O)NHC 1 -C 10  alkyl or —OC(O)NHC 2 -C 10  alkenyl, —OC(O)NHC 2 -C 10  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 10  alkyl, —OC(S)NHC 2 -C 10  alkenyl, (S)NHC 2 -C 10  alkynyl, —OC(S)NHcycloalkyl or —OC(S)NHaryl, or R 1  and R 2  taken together are ═O, ═S, ═NH or ═N(C 1 -C 6  alkyl); 
 R 3  is hydrogen, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl or —C 2 -C 10  alkynyl; 
 R 4  and R 5  are each independently hydrogen, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl, —C 2 -C 10  alkynyl, —OH, —OC 1 -C 10  alkyl, —OC 2 -C 10  alkenyl, —OC 2 -C 10  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 10  alkyl, —OC(O)C 2 -C 10  alkenyl, —OC(O)C 2 -C 10  alkynyl, —OC(O)cycl ° alkyl, —OC(O)aryl, —OC(O)NHC 1 -C 10  alkyl, —OC(O)NHC 2 -C 10  alkenyl, —OC(O)NHC 2 -C 10  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 10  alkyl, —OC(S)NHC 2 -C 10  alkenyl, —OC(S)NHC 2 -C 10  alkynyl, —OC(S)NHcycloalkyl, —OC(S)NHaryl, F, Cl, Br, I, —CN, —NO 2  or N(R 25 ) 2 , or R 4  and R 5  taken together form a double bond or are —O—, —S—, —NR 25 — or —CR 26 R 27 —; 
 R 6  is selected from the group consisting of hydrogen, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl and —C 2 -C 10  alkynyl; 
 R 8  is selected from the group consisting of hydrogen, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl and —C 2 -C 10  alkynyl; 
 R 10  is selected from the group consisting of hydrogen, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl and —C 2 -C 10  alkynyl; 
 R 11  is —OH, —OC 1 -C 20  alkyl, —OC 2 -C 20  alkenyl, —OC 2 -C 20  alkynyl, —Ocycloalkyl, —OC(O)C 2 -C 20  alkyl, —OC(O)C 2 -C 20  alkenyl, —OC(O)C 2 -C 20  alkynyl, —OC(O)cycloalkyl, —OC(O)aryl, —OC(O)NHC 1 -C 20  alkyl, —OC(O)NHC 2 -C 20  alkenyl, —OC(O)NHC 2 -C 20  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 20  alkyl, —OC(S)NHC 2 -C 20  alkenyl, —OC(S)NHC 2 -C 20  alkynyl, —OC(S)NHcycloalkyl or —OC(S)NHaryl, or R 10  and R 11  taken together form a carbonyl group (═O); 
 R 12  is —OH, —OC 1 -C 20  alkyl, —OC 2 -C 20  alkenyl, —OC 2 -C 20  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 20  alkyl, —OC(O)C 2 -C 20  alkenyl, —OC(O)C 2 -C 20  alkynyl, —OC(O)cycloalkyl, —OC(O)aryl, —OC(O)NHC 1 -C 20  alkyl, —OC(O)NHC 2 -C 20  alkenyl, —OC(O)NHC 2 -C 20  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 20  alkyl, —OC(S)NHC 2 -C 20  alkenyl, —OC(S)NHC 2 -C 20  alkynyl, —OC(S)NHcycloalkyl or —OC(S)NHaryl; 
 R 13  and R 14  are each independently hydrogen or —C 1 -C 10  alkyl; 
 R 18  is C 1 -C 20  alkyl, —C 2 -C 20  alkenyl, —C 2 -C 20  alkynyl, —OH, —OC 1 -C 20  alkyl, —OC 2 -C 20  alkenyl, —OC 2 -C 20  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 20  alkyl, —OC(O)C 2 -C 20  alkenyl, —OC(O)C 2 -C 20  alkynyl, —OC(O)cycloalkyl, —OC(O)aryl, —NHC 1 -C 20  alkyl, —NHC 2 -C 20  alkenyl, —NHC 2 -C 20  alkynyl, —NHcycloalkyl, —NHaryl, —OC(O)NHC 1 -C 20  alkyl, —OC(O)NHC 2 -C 20  alkenyl, —OC(O)NHC 2 -C 20  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 20  alkyl, —OC(S)NHC 2 -C 20  alkenyl, —OC(S)NHC 2 -C 20  alkynyl, —OC(S)NHcycloalkyl or —OC(S)NHaryl; 
 R 19  and R 20  are each independently hydrogen, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 20  alkynyl, —OH, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 6  alkyl, —OC(O)C 2 -C 6  alkenyl, —OC(O)C 2 -C 6  alkynyl, —OC(O)cycloalkyl or —OC(O)aryl, or R 19  and R 20  taken together form a carbonyl or thiocarbonyl group; 
 R 21  is hydrogen, —C 1 -C 10  alkyl, —C 2 -C 10  alkenyl or —C 2 -C 10  alkynyl; 
 R 22  is —OH, —OC 1 -C 20  alkyl, —OC 2 -C 20  alkenyl, —OC 2 -C 20  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 20  alkyl, —OC(O)C 2 -C 20  alkenyl, —OC(O)C 2 -C 20  alkynyl, —OC(O)cycloalkyl, —OC(O)aryl, —OC(O)NH C 1 -C 20  alkyl, —OC(O)NHC 2 -C 20  alkenyl, —OC(O)NHC 2 -C 20  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 20  alkyl, —OC(S)NHC 2 -C 20  alkenyl, —OC(S)NHC 2 -C 20  alkynyl, —OC(S)NHcycloalkyl and —OC(S)NHaryl, or R 21  and R 22  taken together form a carbonyl group; 
 R 23  is hydrogen, —OH, —OC 1 -C 20  alkyl, —OC 2 -C 20  alkenyl, —OC 2 -C 20  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 20  alkyl, —OC(O)C 2 -C 20  alkenyl, —OC(O)C 2 -C 20  alkynyl, —OC(O)cycloalkyl, —OC(O)aryl, —OC(O)NHC 1 -C 20  alkyl, —OC(O)NHC 2 -C 20  alkenyl, —OC(O)NHC 2 -C 20  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 20  alkyl, —OC(S)NHC 2 -C 20  alkenyl, —OC(S)NHC 2 -C 20  alkynyl, —OC(S)NHcycloalkyl or —OC(S)NHaryl; 
 R 24  is hydrogen, —OH, —OC 1 -C 20  alkyl, —OC 2 -C 20  alkenyl, —OC 2 -C 20  alkynyl, —Ocycloalkyl, —OC(O)C 1 -C 20  alkyl, —OC(O)C 2 -C 20  alkenyl, —OC(O)C 2 -C 20  alkynyl, —OC(O)cycloalkyl, —OC(O)aryl, —OC(O)NHC 1 -C 20  alkyl, —OC(O)NHC 2 -C 20  alkenyl, —OC(O)NHC 2 -C 20  alkynyl, —OC(O)NHcycloalkyl, —OC(O)NHaryl, —OC(S)NHC 1 -C 20  alkyl, —OC(S)NHC 2 -C 20  alkenyl, —OC(S)NHC 2 -C 20  alkynyl, —OC(S)NHcycloalkyl or —OC(S)NHaryl; 
 R 25  is hydrogen or —C 1 -C 10  alkyl; 
 R 26  and R 27  are each independently hydrogen, —C 1 -C 10  alkyl, —OH or —OC 1 -C 10  alkyl; 
 wherein each alkyl, alkenyl, alkynyl, cycloalkyl and aryl is optionally substituted with one or more optional substituents, wherein each optional substituent is independently —F, —Cl, —Br, —I, —CN, —CF 3 , —CO 2 R 28 , —COR 28 , —SR 28 , —N(R 28 ) 2 , —NO 2 , —NR 28 OR 28 , —ON(R 28 ) 2 , —SOR 28 , —SO 2 R 28 , —SO 3 R 28 , —SON(R 28 ) 2 , —SO 3 N(R 28 ) 2 , —P(R 28 ) 3 , —P(═O)(R 28 ) 3 , —OSi(R 28 ) 3 , —OB(R 28 ) 2  and wherein R 28  is hydrogen, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C 2 -C 6  alkynyl, —C 3 -C 8  cycloalkyl, —C 6 -C 14  aryl, arylalkyl, —C 1 -C 6  haloalkyl, —C 1 -C 6  dihaloalkyl or —C 1 -C 6  trihaloalkyl; 
 and geometric isomers or stereoisomers thereof and pharmaceutically, agriculturally or pesticidally acceptable salts thereof; and 
 a pharmaceutically, agriculturally or pesticidally acceptable carrier comprising at least one of cellulose derivatives, malt, gelatine, talc, calcium sulphate, vegetable oils, synthetic oils, alginic acid, phosphate buffered solutions, emulsifiers, isotonic saline, magnesium carbonate, magnesium stearate, lactose, pectin, tragacanth, cocoa butter, low melting wax, propylene glycol, polyethylene glycol, acetone, ethanol, acacia, sucrose, glycerin, cyclodextrin, benzyl alcohol, cremaphor and a propellant. 
 
       
     
     
         22 . A pharmaceutical composition according to  claim 21  wherein the compound is a compound of formula (III): 
       
         
           
           
               
               
           
         
         wherein:
 R 3  is hydrogen, —C 1 -C 6  alkyl or —C 2 -C 6  alkenyl; 
 R 4  and R 5  are each independently hydrogen, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —OH, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC(O)C 1 -C 6  alkyl, —OC(O)C 2 -C 6  alkenyl, —OC(O)aryl, F, Cl, Br or I, or R 4  and R 5  taken together form a double bond or are —O—; 
 R 6  is hydrogen, —C 1 -C 6  alkyl or —C 2 -C 6  alkenyl; 
 R 8  is hydrogen, —C 1 -C 6  alkyl or —C 2 -C 6  alkenyl; 
 R 13  and R 14  are each independently hydrogen or —C 1 -C 6  alkyl; 
 R a  is hydrogen, —C 1 -C 20  alkyl, —C 2 -C 20  alkenyl, —C 2 -C 20  alkynyl, —C(O)C 2 -C 20  alkyl, —C(O)C 2 -C 20  alkenyl, —C(O)C 2 -C 20  alkynyl, —C(O)cycloalkyl, —C(O)aryl, —C(O)NHC 1 -C 20  alkyl, —C(O)NHC 2 -C 20  alkenyl, —C(O)NHC 2 -C 20  alkynyl, —C(O)NHcycloalkyl, —C(O)NHaryl, —C(S)NHC 1 -C 20  alkyl, —C(S)NHC 2 -C 20  alkenyl, —C(S)NHC 2 -C 20  alkynyl, —C(S)NHcycloalkyl and —C(S)NHaryl; 
 R b , R c , R d , R e  and R f  are each independently selected from the group consisting of hydrogen, —C 1 -C 20  alkyl, —C 2 -C 20  alkenyl, —C 2 -C 20  alkynyl, —C(O)C 1 -C 20  alkyl, —C(O)C 2 -C 20  alkenyl, —C(O)C 2 -C 20  alkynyl, —C(O)cycloalkyl, —C(O)aryl, —C(O)NHC 1 -C 20  alkyl, —C(O)NHC 2 -C 20  alkenyl, —C(O)NHC 2 -C 20  alkynyl, —C(O)NHcycloalkyl, —C(O)NHaryl, —C(S)NHC 1 -C 20  alkyl, —C(S)NHC 2 -C 20  alkenyl, —C(S)NHC 2 -C 20  alkynyl, —C(S)NHcycloalkyl and —C(S)NHaryl; 
 wherein each alkyl, alkenyl and aryl group is optionally substituted with one or more optional substituents wherein each optional substituent is as defined in claim  1 ; 
 or geometric isomers or stereoisomers and pharmaceutically, agriculturally or pesticidally acceptable salts thereof. 
 
       
     
     
         23 . The pharmaceutical composition of  claim 21  wherein the compound is a compound of formula (IV): 
       
         
           
           
               
               
           
         
         wherein:
 R 3  is hydrogen, —C 1 -C 6  alkyl or —C 2 -C 6  alkenyl; 
 R 4  and R 5  are each independently hydrogen, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —OH, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC(O)C 1 -C 6  alkyl, —OC(O)C 2 -C 6  alkenyl, —OC(O)aryl, —OC(O)heterocyclyl, —OC(O)heteroaryl, F, Cl, Br or I, or R 4  and R 5  taken together form a double bond or are —O—; 
 R 6  is hydrogen, —C 1 -C 6  alkyl or —C 2 -C 6  alkenyl; 
 R 8  is hydrogen, —C 1 -C 6  alkyl or —C 2 -C 6  alkenyl; 
 R 10  is hydrogen; 
 R 11  is hydroxy, —OC 1 -C 20  alkyl, —OC 2 -C 20  alkenyl, —OC(O)C 2 -C 20  alkyl, —OC(O)C 2 -C 20  alkenyl or —OC(O)aryl; or R 10  and R 11  taken together form a carbonyl group; 
 R 12′  is hydrogen, —C 1 -C 20  alkyl, —C 2 -C 20  alkenyl, —C(O)C 1 -C 20  alkyl, —C(O)C 2 -C 20  alkenyl or —C(O)aryl; 
 R 13  and R 14  are each independently hydrogen or —C 1 -C 6  alkyl; 
 R 18′  is hydrogen, —C 1 -C 6  alkyl, —C 2 -C 6  alkenyl, —C(O)C 1 -C 6  alkyl, —C(O)C 2 -C 6  alkenyl or —C(O)aryl; 
 R 19  and R 20  are independently selected from the group consisting of hydrogen, —OH, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl or R 19  and R 20  taken together form a carbonyl group; 
 R 21  is hydrogen; 
 R 22  is hydroxy, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC(O)C 1 -C 6  alkyl, —OC(O)C 2 -C 6  alkenyl, —OC(O)aryl or R 21  and R 22  taken together form a carbonyl group; 
 wherein each alkyl, alkenyl and aryl is optionally substituted with one or more optional substituents, wherein each optional substituent is as defined in claim  1 ; 
 and geometric isomers or stereoisomers thereof and pharmaceutically, agriculturally or pesticidally acceptable salts thereof. 
 
       
     
     
         24 . A pharmaceutical composition according to  claim 21  wherein R 1  and R 2  are independently selected from the group consisting of hydrogen, hydroxy, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC(O)C 1 -C 6  alkyl or —OC(O)C 2 -C 6  alkenyl or R 1  and R 2  taken together form a carbonyl group. 
     
     
         25 . A pharmaceutical composition according to  claim 21  wherein R 4  and R 5  form a double bond or R 4  and R 5  are hydrogen or together are —O—. 
     
     
         26 . A pharmaceutical composition according to  claim 21  wherein R 8  is hydrogen or —C 1 -C 3  alkyl. 
     
     
         27 . A pharmaceutical composition according to  claim 21  wherein R 11  is selected from the group consisting of hydroxy, —C 1 -C 20  alkyloxy, —C 2 -C 20  alkenyloxy, —OC(O)C 2 -C 20  alkyl or —OC(O)C 2 -C 20  alkenyl and R 12  is selected from hydroxy, —C 1 -C 20  alkyloxy, —C 2 -C 20  alkenyloxy, —OC(O)C 1 -C 20  alkyl or —OC(O)C 2 -C 20  alkenyl. 
     
     
         28 . A pharmaceutical composition according to  claim 21  wherein R 13  and R 14  are independently selected from the group consisting of hydrogen and —C 1 -C 3  alkyl. 
     
     
         29 . A pharmaceutical composition according to  claim 21  wherein R 19  and R 20  are independently hydrogen, hydroxy, —OC 1 -C 3  alkyl and —OC 2 -C 3  alkenyl or R 19  and R 20  taken together form a carbonyl group and R 18  is selected from the group consisting of hydroxy, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC(O)C 1 -C 6  alkyl and —OC(O)C 2 -C 6  alkenyl. 
     
     
         30 . A pharmaceutical composition according to  claim 21  wherein R 22  is hydroxy, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC(O)C 1 -C 6  alkyl or —OC(O)C 2 -C 6  alkenyl. 
     
     
         31 . A pharmaceutical composition according to  claim 21  wherein R 23  and R 24  are each hydroxyl. 
     
     
         32 . A pharmaceutical composition according to  claim 21  wherein the compound is selected from the group consisting of:
 (12-tigloyl-13-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3-one); 
 (12,13-di-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-tigliaen-3-one); 
 12-(dodeca-2,4,6-trienoyl)-13-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3-one; 
 12-(deca-2,4-dienoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3-one; 
 12,13-di-(2-methylbutanoyl)-1,2-2H-1,2,6,7-diepoxy-6-carboxy-4,5,9,12,13-pentahydroxy-tigliaen-3-one; and 
 12,13-di-(2-methylbutanoyl)-5,20-di-acetoyl-4,5,9,12,13,20-hexahydroxy-tigliaen-3-one. 
 
     
     
         33 . A pharmaceutical composition according to  claim 21  formulated for oral, intra-dermal, subcutaneous, transdermal or topical administration.