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. A method of reducing scar tissue in a subject comprising administering to the scar tissue a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (II) has the following structure:
wherein:
X is —O—;
R 1 and R 2 are independently selected from 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, 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 and 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 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 2 -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 hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl and —C 2 -C 10 alkynyl;
R 8 is selected from hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl and —C 2 -C 10 alkynyl;
R 10 is selected from hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl and —C 2 -C 10 alkynyl;
R 11 is selected from 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 10 and R 11 taken together form a carbonyl group (═O);
R 12 is selected from 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;
R 13 and R 14 are independently selected from hydrogen and —C 1 -C 10 alkyl;
R 18 is selected from 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 and OC(S)NHaryl;
R 19 and R 20 are independently selected from 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 and —OC(O)aryl or R 19 and R 20 taken together form a carbonyl or thiocarbonyl group;
R 21 is selected from hydrogen, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl and —C 2 -C 10 alkynyl;
R 22 is selected from 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)NHcycloalky and, OC(S)NHaryl, or R 21 and R 22 taken together form a carbonyl group;
R 23 is selected from 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 and OC(S)NHaryl;
R 24 is selected from 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 and OC(S)NHaryl;
R 25 is selected from hydrogen and —C 1 -C 10 alkyl;
R 26 and R 27 are independently selected from hydrogen, —C 1 -C 10 alkyl, —OH, —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 8 cycloalkyl, —C 6 -C 14 aryl, arylalkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 dihaloalkyl or —C 1 -C 6 trihaloalkyl;
or a geometric isomer or stereoisomer thereof or a pharmaceutically acceptable salt thereof.
2. A method according to claim 1 wherein the compound of formula (II) 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″ 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 a geometric isomer or stereoisomer or a pharmaceutically acceptable salt thereof.
3. The method according to claim 1 wherein the compound of formula (II) 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, 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 ;
or a geometric isomer or stereoisomer thereof or a pharmaceutically acceptable salt thereof.
4. The method according to claim 1 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.
5. The method according to claim 1 wherein R 4 and R 5 form a double bond or R 4 and R 5 are hydrogen or together are —O—.
6. The method according to claim 1 wherein R 8 is hydrogen or —C 1 -C 3 alkyl.
7. The method according to claim 1 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.
8. The method according to claim 1 wherein R 13 and R 14 are independently selected from the group consisting of hydrogen and -C 1 -C 3 alkyl.
9. The method according to claim 1 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.
10. The method according to claim 1 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.
11. The method according to claim 1 wherein R 23 and R 24 are each hydroxyl.
12. The method according to claim 1 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;
or a pharmaceutically acceptable salt thereof.
13. The method according to claim 1 wherein the scar tissue is a keloid.
14. The method according to claim 1 wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered to the scar tissue topically.
15. The method according to claim 1 wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered to the scar tissue intra-lesionally.
16. The method according to claim 13 wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered to the keloid topically.
17. The method according to claim 13 wherein the compound of formula (II) or a pharmaceutically acceptable salt thereof is administered to the keloid intra-lesionally.
18. The method according to claim 13 wherein the compound of formula (II) is 12-tigloyl-13-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3-one.
19. The method according to claim 16 wherein the compound of formula (II) is 12-tigloyl-13-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3-one.
20. The method according to claim 17 wherein the compound of formula (II) is 12-tigloyl-13-(2-methylbutanoyl)-6,7-epoxy-4,5,9,12,13,20-hexahydroxy-1-tigliaen-3-one.