Methods and compositions for wound healing
The present invention relates to epoxy-tigliane compounds and their use in promoting wound healing. In particular embodiments, the epoxy-tigliane compounds are epoxy-tigliaen-3-one compounds. Methods of inducing or promoting wound healing as well as methods of reducing scarring and improving cosmetic outcomes upon healing of a wound are described. Compounds and compositions for use in wound healing are also described.
1. A method of promoting wound healing in a subject comprising administering to a wound an epoxy-tigliane compound, wherein the wound is an acute wound, or is a chronic wound that has failed to heal at a normal rate, wherein the compound promotes wound healing by restoring tissue integrity of the wound, and wherein the epoxy-tigliane compound is a compound of formula (II) or a geometric isomer or stereoisomer or a pharmaceutically acceptable salt thereof:
wherein
R 3 is hydrogen or C 1-6 alkyl;
R 6 is hydrogen or C 1-6 alkyl;
R 7 is —OH or —OR 18 ;
R 8 is —OH or —OR 18 ;
provided that R 7 and R 8 are not both OH;
R 9 and R 10 are independently selected from hydrogen and C 1-6 alkyl;
R 11 and R 12 or R 12 and R 13 together form an epoxide and the remaining group of R 11 and R 13 is hydrogen, —OH or —OR 17 ;
R 15 is hydrogen or —R 17 ;
R 17 is hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C(O)C 1-6 alkyl, —C(O)C 2-6 alkenyl or —C(O)C 2-6 alkynyl;
R 18 is C 1-20 alkyl, —C 2-20 alkenyl, —C 2-20 alkynyl, —C(O)C 1-20 alkyl, —C(O)C 2-20 alkenyl, —C(O)C 2-20 alkynyl, —C(O)cycloalkyl, —C(O)C 1-10 alkylcycloalkyl; —C(O)C 2-10 alkenylcycloalkyl, —C(O)C 2-10 alkynylcycloalkyl, —C(O)aryl, —C(O)C 1-10 alkylaryl, —C(O)C 2-10 alkenylaryl, —C(O)C 2-10 alkynylaryl, —C(O)C 1-10 alkylC(O)R 19 , —C(O)C 2-10 alkenylC(O)R 19 , —C(O)C 2-10 alkynylC(O)R 19 , —C(O)C 1-10 alkylCH(OR 19 )(OR 19 ), —C(O)C 2-10 alkenylCH(OR 19 )(OR 19 ), —C(O)C 2-10 alkynylCH(OR 19 )(OR 19 ), —C(O)C 1-10 alkylSR 19 , —C(O)C 2-10 alkenylSR 19 , —C(O)C 2-10 alkynylSR 19 —C(O)C 1-10 alkylC(O)OR 19 , —C(O)C 2-10 alkenylC(O)OR 19 , —C(O)C 2-10 alkynylC(O)OR 19 , —C(O)C 1- alkylC(O)SR 19 , —C(O)C 2-10 alkenylC(O)SR 19 , —C(O)C 2-10 alkynylC(O)SR 19 ,
and
R 19 is hydrogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, cycloalkyl or aryl; and
wherein each alkyl, alkenyl, alkynyl, cycloalkyl or aryl group is optionally substituted.
2. The method according to claim 1 wherein the wound is an acute wound.
3. The method according to claim 1 wherein the wound is a chronic wound.
4. The method according to claim 1 wherein the epoxy-tigliane compound is in the form of a plant extract.
5. The method according to claim 4 wherein the plant extract is obtainable from a plant which is a Fontainea species or a Hylandia species.
6. The method according to claim 1 wherein the compound of formula (II) is a compound of formula (III) or a geometric isomer or stereoisomer or a pharmaceutically acceptable salt thereof:
wherein R 7 , R 8 , R 11 , R 12 , R 13 and R 15 are as defined for formula (II).
7. The method according to claim 1 wherein R 3 is hydrogen or —C 1-3 alkyl.
8. The method according to claim 1 wherein R 6 is hydrogen or —C 1-3 alkyl.
9. The method according to claim 1 wherein R 7 is —OH, —OC(O)C 1-15 alkyl, —OC(O)C 2-15 alkenyl, —OC(O)C 2-15 alkynyl, —OC(O)aryl wherein the aryl group is optionally substituted, —OC(O)C 1-15 alkylaryl, —OC(O)C 1-10 alkylC(O)H, —OC(O)C 2-10 alkenylC(O)H, —OC(O)C 1-10 alkylC(O)C 1-6 alkyl, —OC(O)C 2-10 alkenylC(O)C 1-6 alkyl, —OC(O)C 1-10 alkylCH(OC 1-3 alkyl)(OC 1-3 alkyl), —OC(O)C 2-10 alkenylCH(OC 1-3 alkyl)(OC 1-3 alkyl), —OC(O)C 1-10 alkylSC 1-6 alkyl, —OC(O)C 2-10 alkenylSC 1-6 alkyl, —OC(O)C 1-10 alkylC(O)OC 1-6 alkyl or —OC(O)C 2-10 alkylC(O)OC 1-6 alkyl.
10. The method according to claim 1 wherein R 8 is —OC(O)C 1-15 alkyl, —OC(O)C 2-15 alkenyl, —OC(O)C 2-15 alkynyl or —C(O)aryl where the aryl group is optionally substituted.
11. The method according to claim 1 wherein R 9 and R 10 are independently —C 1-3 alkyl.
12. The method according to claim 1 wherein R 11 and R 12 form an epoxide and R 13 is —OH, —OC(O)C 1-6 alkyl, —OC(O)C 2-6 alkenyl or —OC(O)C 2-6 alkynyl or wherein R 12 and R 13 form an epoxide and R 11 is —OH, —OC(O)C 1-6 alkyl, —OC(O)C 2-6 alkenyl or —OC(O)C 2-6 alkynyl.
13. The method according to claim 1 wherein R 15 is hydrogen, —C(O)C 1-6 alkyl, —C(O)C 2-6 alkenyl or —C(O)C 2-6 alkynyl.
14. A method of reducing excessive scarring of a healing wound comprising applying to the healing wound an epoxy-tigliane compound, wherein the wound is an acute wound, or is a chronic wound that has failed to heal at a normal rate, wherein the compound promotes wound healing by restoring tissue integrity of the wound, and wherein the epoxy-tigliane compound is a compound of formula (II) or a geometric isomer or stereoisomer or a pharmaceutically acceptable salt thereof:
wherein
R 3 is hydrogen or C 1-6 alkyl;
R 6 is hydrogen or C 1-6 alkyl;
R 7 is —OH or —OR 18 ;
R 8 is —OH or —OR 18 ;
provided that R 7 and R 8 are not both OH;
R 9 and R 10 are independently selected from hydrogen and C 1-6 alkyl;
R 11 and R 12 or R 12 and R 13 together form an epoxide and the remaining group of R 11 and R 13 is hydrogen, —OH or —OR 17 ,
R 15 is hydrogen or —R 17 ;
R 17 is hydrogen, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —C(O)C 1-6 alkyl, —C(O)C 2-6 alkenyl or —C(O)C 2-6 alkynyl;
R 18 is C 1-20 alkyl, —C 2-20 alkenyl, —C 2-20 alkynyl, —C(O)C 1-20 alkyl, —C(O)C 2-20 alkenyl, —C(O)C 2-20 alkynyl, —C(O)cycloalkyl, —C(O)C 1-10 alkylcycloalkyl; —C(O)C 2-10 alkenylcycloalkyl, —C(O)C 2-10 alkynylcycloalkyl; —C(O)aryl, —C(O)C 1-10 alkylaryl, —C(O)C 2-10 alkenylaryl, —C(O)C 2-10 alkynylaryl, —C(O)C 1-10 alkylC(O)R 19 , —C(O)C 2-10 alkenylC(O)R 19 , —C(O)C 2-10 alkynylC(O)R 19 , —C(O)C 1-10 alkylCH(OR 19 )(OR 19 ), —C(O)C 2-10 alkenylCH(OR 19 )(OR 19 ), —C(O)C 2-10 alkynylCH(OR 19 )(OR 19 ), —C(O)C 1-10 alkylSR 19 , —C(O)C 2-10 alkenylSR 19 , —C(O)C 2-10 alkynylSR 19 , —C(O)C 1-10 alkylC(O)OR 19 , —C(O)C 2-10 alkenylC(O)OR 19 , —C(O)C 2-10 alkynylC(O)OR 19 , —C(O)C 1-10 alkylC(O)SR 19 , —C(O)C 2-10 alkenylC(O)SR 19 , —C(O)C 2-10 alkynylC(O)SR 19 ,
and
R 19 is hydrogen, —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, cycloalkyl or aryl; and
wherein each alkyl, alkenyl, alkynyl, cycloalkyl or aryl group is optionally substituted.