Details for Patent: 7,842,687
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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 (Nyon, CH), Blanchard; Julie (Rouillon, FR), Marie; Jean-Pierre (Sevres, FR), Radosevic; Nina (Nyon, CH) |
Assignee: | Chemgenex Pharmaceuticals, Inc. (Geelong, Victoria, AU) |
Filing Date: | May 25, 2006 |
Application Number: | 11/440,648 |
Claims: | 1. A purified compound of the following formula: ##STR00157## wherein n=2 or n=3, 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%, and the chromatographic assay of the purified compound exhibits a content of the purified compound higher than 97.5%. 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: ##STR00158## 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: ##STR00159## 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. 6. A purified crystalline compound of the formula: ##STR00160## 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. 7. A purified crystalline compound of the formula: ##STR00161## wherein n=2 or n=3, having substantially the same DSC curve as set out in FIG. 4. 8. A purified crystalline compound of the formula: ##STR00162## 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: ##STR00163## 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 one or more pharmaceutically acceptable inactive component. 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 treatment of leukemia comprising administering to a patient in need of such therapy an effective amount of a purified compound as defined in claim 1 for treatment of said leukemia. 22. The method according to claim 21, wherein said leukemia is selected from the group consisting of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative disorders. 23. The method according to claim 22, wherein said myeloproliferative disorder is chronic myelogenous leukemia. 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, wherein said purified compound 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. |