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Claims for Patent: RE45128

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Claims for Patent: RE45128

Title:Cephalotaxane derivatives and their processes of preparation and purification
Abstract: The present invention concerns a new general process for asymmetric hemisynthesis of harringtonines and their analogs, that are alkaloids used in chemotherapy. This process comprises direct esterification of a natural cephalotaxine with an acylating compound constituted of a side chain precursor which backbone and functionalization are entirely preformed. The invention also concerns a natural, synthetic or semi-synthetic harringtonines including their tautomeric forms and their salts of the following formula: ##STR00001## wherein n=2 (i.e. harringtonine) or n=3 (i.e. homoharringtonine), in which the total content of impurities, possibly including enantiomeric forms, is lower than 1%, and/or the content of the major impurity is lower than 0.9%, and/or the chromatographic assay exhibits a harringtonines content higher than 97.5%.
Inventor(s): Robin; Jean-Pierre (Geneva, CH), Blanchard; Julie (Puyricard, FR), Marie; Jean-Pierre (Sevres, FR), Radosevic; Nina (Geneva, CH)
Assignee: IVAX International GmbH (Rapperswil, CH)
Application Number:13/661,677
Patent Claims: 1. .[.A purified compound of the following formula.]. .Iadd.Cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester).Iaddend.: ##STR00156## .[.wherein n=2 or n=3,.]. having a total content of impurities of lower than 1%.[., and/or.]. .Iadd.and .Iaddend.having a total content of impurities wherein the major impurity is lower than 0.9%.[.,.]. and the chromatographic assay of the .[.purified compound.]. .Iadd.cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) .Iaddend.exhibits a content of the .[.purified compound.]. .Iadd.cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) of .Iaddend.higher than 97.5%.Iadd., and/or a salt thereof.Iaddend..

.[.2. The purified compound of claim 1, wherein n=3..].

.[.3. The purified compound of claim 1, wherein n=2..].

.[.4. A purified crystalline compound of the formula: ##STR00157## wherein n=2 or n=3, having substantially the same DSC curve as set out in FIG. 1..].

5. .[.A purified crystalline compound of the formula.]. .Iadd.Crystalline cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester).Iaddend.: ##STR00158## .[.wherein n=2 or n=3, having substantially the same X-ray diffractogram as set out in FIG. 2, and substantially the same IR spectrum, in KBr, as set out in FIG. 3.]. .Iadd.characterized by an X-ray powder diffractogram pattern comprising at least one peak chosen from peaks at approximately 7.9, 9.2, and 10.9 degrees 2-theta and having a total content of impurities of lower than 1%.Iaddend..

6. .[.A purified crystalline compound of the formula.]. .Iadd.Crystalline cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester).Iaddend.: ##STR00159## .[.wherein n=2 or n=3, having substantially the same DSC curve as set out in FIG. 1, substantially the same X-ray diffractogram as set out in FIG. 2, and substantially the same IR spectrum, in KBr, as set out in FIG. 3.]. .Iadd.characterized by an X-ray powder diffractogram pattern comprising at least one peak chosen from peaks at approximately 7.9, 9.2, and 10.9 degrees 2-theta and having a total content of impurities of lower than 1% and having a total content of impurities wherein the major impurity is lower than 0.9%.Iaddend..

7. .[.A purified crystalline compound of the formula.]. .Iadd.Crystalline cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester).Iaddend.: ##STR00160## .[.wherein n=2 or n=3, having substantially the same DSC curve as set out in FIG. 4.]. .Iadd.according to claim 6 containing greater than 97.5% of cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) by analytical HPLC assay.Iaddend..

.[.8. A purified crystalline compound of the formula: ##STR00161## wherein n=2 or n=3, having substantially the same IR spectrum, in KBr, as set out in FIG. 5..].

.[.9. A purified crystalline compound of the formula: ##STR00162## wherein n=2 or n=3, having substantially the same DSC curve as set out in FIG. 4, and substantially the same IR spectrum, in KBr, as set out in FIG. 5..].

.[.10. The purified compound of claim 1, wherein said purified compound is present in tautomeric forms and salts thereof..].

.[.11. The purified compound of claim 1, wherein said purified compound is an enantiomer and the total content of impurities includes the other enantiomeric forms..].

12. A pharmaceutical composition comprising .[.an effective amount of one or more purified compounds according to claim 1, together with.]. .Iadd.cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester).Iaddend.: ##STR00163## .Iadd.having a total content of impurities of lower than 1% and having a total content of impurities wherein the major impurity is lower than 0.9% and containing greater than 97.5% of cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) by analytical HPLC assay and/or a pharmaceutically acceptable salt thereof, .Iaddend..[.together with .]. .Iadd.and at least .Iaddend.one .[.or more.]. pharmaceutically acceptable inactive component .Iadd.chosen from carriers, excipients, adjuvants, and diluents.Iaddend..

.[.13. The pharmaceutical composition of claim 12, wherein said pharmaceutically acceptable inactive component is selected from the group consisting of carriers, excipients, adjuvants and diluents..].

.[.14. A pharmaceutical composition comprising an effective amount of one or more purified compounds according to claim 2, together with one or more pharmaceutically acceptable inactive components..].

.[.15. A pharmaceutical composition comprising an effective amount of one or more purified compounds according to claim 3, together with one or more pharmaceutically acceptable inactive components..].

.[.16. A pharmaceutical composition comprising an effective amount of one or more purified crystalline compounds according to claim 5, together with one or more pharmaceutically acceptable inactive components..].

.[.17. A pharmaceutical composition comprising an effective amount of one or more purified crystalline compounds according to claim 6, together with one or more pharmaceutically acceptable inactive components..].

.[.18. A pharmaceutical composition comprising an effective amount of one or more purified crystalline compounds according to claim 9, together with one or more pharmaceutically acceptable inactive components..].

.[.19. A method for treatment of a mammalian parasitic disease comprising administering to a patient in need of such treatment an effective amount of a purified compound as defined in claim 1 for treatment of said parasitic disease..].

.[.20. A method for immunosuppressive therapy comprising administering to a patient in need of such therapy an effective amount of a purified compound as defined in claim 1 for said immunosuppressive therapy..].

21. A method for .Iadd.the .Iaddend.treatment of leukemia comprising administering to a patient in .Iadd.recognized .Iaddend.need of such therapy .[.an effective amount of a purified compound as defined in claim 1 for treatment of said leukemia.]. .Iadd.cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00164## having a total content of impurities of lower than 1% and having a total content of impurities wherein the major impurity is lower than 0.9% and containing greater than 97.5% of cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) by analytical HPLC assay, and/or a pharmaceutically acceptable salt thereof.Iaddend..

22. .[.The.]. .Iadd.A .Iaddend.method .[.according to claim 21, wherein said leukemia is selected from the group consisting of.]. .Iadd.for the treatment of .Iaddend.acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) .[.and.]..Iadd., and/or .Iaddend.myeloproliferative disorders .Iadd.comprising administering to a patient in recognized need of such treatment cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00165## having a total content of impurities of lower than 1% and having a total content of impurities wherein the major impurity is lower than 0.9% and containing greater than 97.5% of cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) by analytical HPLC assay, and/or a pharmaceutically acceptable salt thereof.Iaddend..

23. .[.The.]. .Iadd.A .Iaddend.method .[.according to claim 22, wherein said myeloproliferative disorder is.]. .Iadd.for the treatment of .Iaddend.chronic myelogenous leukemia .Iadd.comprising administering to a patient in recognized need of such treatment cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00166## having a total content of impurities of lower than 1% and having a total content of impurities wherein the major impurity is lower than 0.9% and containing greater than 97.5% of cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) by analytical HPLC assay, and/or a pharmaceutically acceptable salt thereof.Iaddend..

.[.24. The method according to claim 21, wherein said purified compound is administered as an adjuvent therapy of resistance to other chemotherapeutic agents..].

25. The method according to claim .[.21.]. .Iadd.23.Iaddend., wherein said .[.purified compound.]. .Iadd.cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester), and/or pharmaceutically acceptable salt thereof, .Iaddend.is administered by a parenteral mode of administration.

.[.26. The method according to claim 21, wherein said purified compound is administered by an oral mode of administration..].

.[.27. The method according to claim 21, wherein said purified compound is administered by an anal administration..].

.[.28. The method according to claim 21, wherein said purified compound is administered by a topical mode of administration..].

29. The method according to claim 26, wherein said parenteral mode of administration is subcutaneous.

.Iadd.30. The cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00167## and/or salt thereof according to claim 1 wherein said cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) and/or salt thereof is semi-synthetic or synthetic. .Iaddend.

.Iadd.31. A pharmaceutical composition comprising semi-synthetic and/or synthetic cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00168## having a total content of impurities wherein the major impurity is lower than 0.9%, and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive component selected from carriers, excipients, adjuvants, and diluents. .Iaddend.

.Iadd.32. The cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) according to claim 5 wherein said cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) is semi-synthetic. .Iaddend.

.Iadd.33. A salt of cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00169## comprising cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester) having a total content of impurities of lower than 1% and/or having a total content of impurities wherein the major impurity is lower than 0.9%. .Iaddend.

.Iadd.34. A pharmaceutical composition comprising semi-synthetic and/or synthetic cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00170## having a total content of impurities of lower than about 1%, and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive component selected from carriers, excipients, adjuvants, and diluents. .Iaddend.

.Iadd.35. A pharmaceutical composition comprising cephalotaxine, 4-methyl (2'R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl) butanedioate (ester): ##STR00171## having a total content of impurities of lower than 1% and having a total content of impurities wherein the major impurity is lower than 0.9%, and/or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable inactive component selected from carriers, excipients, adjuvants, and diluents. .Iaddend.
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