Tiglien-3-one derivatives

1. A method of treating a cell proliferative disorder comprising administering to a subject a compound of formula (II):

wherein:

X is selected from —O—, —S— and —NR 25 —;

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 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 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, —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 6 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)NHcycloalkyl 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 substituents independently selected from —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 , —SON(R 28 ) 2 , —SO 3 N(R 28 ) 2 , —P(R 28 ) 3 , —P(═O)(R 28 ) 3 , —OSi(R 28 ) 3 and —OB(R 28 ) 2 , wherein each R 28 is independently selected from hydrogen, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, arylalkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 dihaloalkyl and —C 1 -C 6 trihaloalkyl;

and geometric isomers or stereoisomers thereof and a pharmaceutically acceptable salt thereof;

wherein the cell proliferative disorder is selected from a sarcoides, a leukemia and a solid tumor cancer selected from melanoma, prostate cancer, breast cancer, ovarian cancer, basal cell carcinoma, squamous cell carcinoma, fibrosarcoma, colon cancer and lung cancer.

2. The method according to claim 1 , 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 selected from 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, —OC(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 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 acceptable salt thereof.

3. The method according to claim 1 , 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, 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 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, aryl, heterocyclyl or heteroaryl 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 acceptable salt thereof.

4. The method according to claim 1 wherein R 1 and R 2 are independently selected from hydrogen, 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, 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 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 and —OC(O)C 2 -C 20 alkenyl.

8. The method according to claim 1 wherein R 13 and R 14 are independently selected from hydrogen and —C 1 -C 3 alkyl.

9. The method according to claim 1 wherein X is —O—.

10. The method according to claim 1 wherein R 19 and R 20 are hydrogen, hydroxy, —OC 1 -C 3 alkyl, —OC 2 -C 3 alkenyl or R 19 and R 20 taken together form a carbonyl group and R 18 is selected from 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 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.

12. The method according to claim 1 wherein R 23 and R 24 are each hydroxy.

13. The method according to claim 1 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);

(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.

14. A method according to claim 1 , wherein the cell proliferative disorder is sarcoides.

15. A method according to claim 14 , wherein the cell proliferative disorder is equine sarcoides.

16. A method according to claim 1 , further comprising administration of an anti-inflammatory agent.