Claims for Patent: 7,763,615

Summary for Patent: 7,763,615

Title:	Ecteinascidin analogs for use as antitumour agents
Abstract:	Derivatives of ecteinascidin 736 of general formula (I) wherein the groups R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently selected from the group consisting of H, OH, OR', SH, SR', SOR', SO.sub.2R', C(.dbd.O)R', C(.dbd.O)OR', NO.sub.2, NH.sub.2, NHR', N(R').sub.2, NHC(O)R', CN, halogen, .dbd.O, substituted or unsubstituted C.sub.1-C.sub.25 alkyl, substituted or unsubstituted C.sub.2-C.sub.18 alkenyl, substituted or unsubstituted C.sub.2-C.sub.18 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic; wherein X is independently selected of OR', CN, (.dbd.O), or H; wherein each of the R' groups is independently selected from the group consisting of H, OH, NO.sub.2, NH.sub.2, SH, CN, halogen, .dbd.O, C(.dbd.O)H, C(.dbd.O)CH.sub.3, CO.sub.2H, substituted or unsubstituted C.sub.1-C.sub.25 alkyl, substituted or unsubstituted C.sub.2-C.sub.18 alkenyl, substituted or unsubstituted C.sub.2-C.sub.18 alkynyl, substituted or unsubstituted aryl; wherein m is 0, 1 or 2; and wherein n is 0, 1, 2, 3, or 4, and their use as antitumoral agent. ##STR00001##
Inventor(s):	Gallego; Pilar (Madrid, ES), Cuevas; Carmen (Madrid, ES), Munt; Simon (Madrid, ES), Manzanares; Ignacio (Madrid, ES), Martinez; Valentin (Madrid, ES)
Assignee:	Pharma Mar, S.A. (Madrid, ES)
Application Number:	10/485,536
Patent Claims:	1. A compound of the general formula I: ##STR00069## wherein R.sub.1 is OH, OR', SH, SR', SOR', SO.sub.2R', NO.sub.2, NH.sub.2, NHR', N(R').sub.2, NHC(.dbd.O)R', CN, halogen, substituted or unsubstituted C.sub.1-C.sub.25 alkyl, substituted or unsubstituted C.sub.2-C.sub.18 alkenyl, substituted or unsubstituted C.sub.2-C.sub.18 alkynyl, substituted or unsubstituted carbocyclic aryl selected from phenyl, naphthyl, biphenyl, phenanthryl and anthracyl, substituted or unsubstituted heterocyclic selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrrolidinyl; R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are each independently selected from H, OH, OR', SH, SR', SOR', SO.sub.2R', C(.dbd.O)R', C(.dbd.O)OR', NO.sub.2, NH.sub.2, NHR', N(R').sub.2, NHC(.dbd.O)R', CN, halogen, substituted or unsubstituted C.sub.1-C.sub.25 alkyl, substituted or unsubstituted C.sub.2-C.sub.18 alkenyl, substituted or unsubstituted C.sub.2-C.sub.18 alkynyl, substituted or unsubstituted carbocyclic aryl selected from phenyl, naphthyl, biphenyl, phenanthryl and anthracyl, and substituted or unsubstituted heterocyclic selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrrolidinyl; wherein X is independently selected from OR', CN, (.dbd.O), and H; wherein each of the R' groups is independently selected from the group consisting of H, OH, NO.sub.2, NH.sub.2, SH, CN, halogen, .dbd.O, C(.dbd.O)H, C(.dbd.O)CH.sub.3, CO.sub.2H, substituted or unsubstituted C.sub.1-C.sub.25 alkyl, substituted or unsubstituted C.sub.2-C.sub.18 alkenyl, substituted or unsubstituted C.sub.2-C.sub.18 alkynyl, and substituted or unsubstituted carbocyclic aryl selected from phenyl, naphthyl, biphenyl, phenanthryl and anthracyl; wherein m is 0, 1 or 2; and wherein n is 1, 2, 3 or 4. 2. A compound according to claim 1, wherein: R.sub.1 is hydroxy, halogen, alkyl, alkoxy or aralkyl; R.sub.2 and R.sub.3 are each independently selected from hydrogen, C(.dbd.O)R', COOR', and optionally substituted alkyl and optionally substituted alkenyl, wherein R' is optionally substituted alkyl or optionally substituted alkenyl and wherein the optional substituents being chosen from halo, amino, amino derived from amino acid, carbocyclic aryl selected from phenyl, naphthyl, biphenyl, phenanthryl and anthracyl, or heterocyclic selected from coumarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, benzothiazolyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, morpholinyl and pyrrolindinyl; R.sub.4 is hydrogen, alkyl, alkenyl or C(.dbd.O)OR', where R' is alkenyl; R.sub.5 is hydrogen or alkyl; X is hydrogen, hydroxy, cyano or (.dbd.O); m is 0 or 1; and n is 1. 3. A compound according to claim 1, wherein R.sub.1 is hydroxy, fluorine, methyl, methoxy or benzyloxy, and n is 1. 4. A compound according to claim 1, wherein R.sub.2 is hydrogen, acetyl, trifluoromethylcarbonyl, heptafluorobutyryl, 3-chloropropionyl, cinnamoyl, t-butyl-O--CO--, allyl-O--CO-- or vinyl-O--CO. 5. A compound according to claim 1 wherein R.sub.3 is hydrogen, allyl, CH.sub.3--(CH.sub.2).sub.n--CO-- where n is 1, 2, 4, 6, 12, 14 or 16; t-butyl-O--CO--, allyl-O--CO-- or vinyl-O--CO. 6. A compound according to claim 1 wherein R.sub.4 is hydrogen, C.sub.1 to C.sub.3 alkyl, allyl, or vinyl-O--CO. 7. A compound according to claim 1 wherein R.sub.5 is hydrogen or methyl and m is 1. 8. A compound according to claim 1, wherein X is hydroxy. 9. A compound according to claim 1 wherein R.sub.2 is not acetyl. 10. A compound according to claim 1 wherein R.sub.3 is not hydrogen. 11. A compound according to claim 1 wherein R.sub.5 is not hydrogen. 12. A pharmaceutical composition which comprises a compound according to claim 1 together with a pharmaceutically acceptable diluent. 13. A method for the treatment of lung cancer, colon cancer, kidney cancer, prostate cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, leukaemia or melanoma in a mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound of general formula according to claim 1. 14. A compound according to claim 2, wherein R.sub.1 is hydroxy, fluorine, methyl, methoxy or benzyloxy, and n is 1. 15. A compound according to claim 2 wherein R.sub.2 is hydrogen, acetyl, trifluoromethylcarbonyl, heptafluorobutyryl, 3-chloropropionyl, cinnamoyl, t-butyl-O--CO--, allyl-O--CO-- or vinyl-O--CO. 16. A compound according to claim 2 wherein R.sub.3 is hydrogen, allyl, CH.sub.3--(CH.sub.2).sub.n--CO-- where n is 1, 2, 4, 6, 12, 14 or 16, t-butyl-O--CO--, allyl-O--CO-- or vinyl-O--CO--. 17. A compound according to claim 2 wherein R.sub.4 is hydrogen, C.sub.1 to C.sub.3 alkyl, allyl or vinyl-O--CO--. 18. A compound according to claim 2 wherein R.sub.5 is hydrogen or methyl and m is 1. 19. A compound according to claim 2 wherein X is hydroxy. 20. A compound according to claim 2 wherein X is cyano. 21. A compound according to claim 1 wherein X is cyano. 22. A compound according to claim 1 of formula: ##STR00070## 23. A compound according to claim 1 of formula: ##STR00071## 24. A compound according to claim 1 of formula: ##STR00072## 25. A compound according to claim 1 of formula: ##STR00073## 26. A compound according to claim 1 of formula: ##STR00074## 27. A compound according to claim 1 of formula: ##STR00075## 28. A compound according to claim 1 of formula: ##STR00076## 29. A compound according to claim 1 of formula: ##STR00077## 30. A compound according to claim 1 of formula: ##STR00078## 31. A pharmaceutical composition which comprises a compound according to claim 2 together with a pharmaceutically acceptable diluent. 32. A method for the treatment of lung cancer, colon cancer, kidney cancer, prostate cancer, cervical cancer, ovarian cancer, breast cancer, pancreatic cancer, leukaemia or melanoma in a mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound of general formula according to claim 2.