TIGLIEN-3-ONE DERIVATIVES
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 - 24 . (canceled)
25 . 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, —OC(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)cycloalkyl, —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)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 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 , —OR 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 sugars, starches, cellulose and its derivatives, malt, gelatine, talc, calcium sulphate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffered solutions, emulsifiers or isotonic saline.
26 . A pharmaceutical composition according to claim 25 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.
27 . The pharmaceutical composition of claim 25 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.
28 . A pharmaceutical composition according to claim 25 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.
29 . A pharmaceutical composition according to claim 25 wherein R 4 and R 5 form a double bond or R 4 and R 5 are hydrogen or together are —O—.
30 . A pharmaceutical composition according to claim 25 wherein R 8 is hydrogen or —C 1 -C 3 alkyl.
31 . A pharmaceutical composition according to claim 25 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.
32 . A pharmaceutical composition according to claim 25 wherein R 13 and R 14 are independently selected from the group consisting of hydrogen and —C 1 -C 3 alkyl.
33 . A pharmaceutical composition according to claim 25 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.
34 . A pharmaceutical composition according to claim 25 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.
35 . A pharmaceutical composition according to claim 25 wherein R 23 and R 24 are each hydroxyl.
36 . A pharmaceutical composition according to claim 25 wherein the compound is selected from:
(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.
37 . A pharmaceutical composition according to claim 25 wherein the pharmaceutically, agriculturally or pesticidally acceptable carrier is a polyol.
38 . A pharmaceutical composition according to claim 25 formulated for oral, intra-dermal, subcutaneous, transdermal or topical administration.