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Details for Patent: 7,169,774

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Details for Patent: 7,169,774

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 (Le Mans, FR), Blanchard; Julie (Le Mans, FR), Chauviat; Ludovic (Le Mans, FR), Dhal; Robert (Pruille le Chetif, FR), Marie; Jean-Pierre (Sevres, FR), Radosevic; Nina (Trange, FR)
Assignee: Stragen Pharma S.A. (Geneva, CH)
Filing Date:Jun 25, 2004
Application Number:10/877,067
Claims:1. A process of purification of natural, synthetic or semi-synthetic crude harringtonines for the preparation of pure harringtonines of the following formula: ##STR00155## wherein n=2 or n=3 in which the total content of impurities 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%, comprising performing one or more chromatographic purification(s), and performing one or more crystallization(s) in which the solvent is water or lower C.sub.1-4 alkanol or an aqueous solvent mixture comprising one or more organic solvents.

2. The process of claim 1 in which the solvent is water.

3. The process of claim 1 in which the solvent is water or an aqueous solvent mixture containing one or more organic solvents.

4. The process of claim 1 in which the organic solvent mixture includes one or more lower C.sub.1-4 alkanol.

5. The process of claim 4 in which the lower alkanol is methanol.

6. The process of purification of claim 1 in which the chromatographic purification is in reverse phase, the solvent is an aqueous solvent containing a lower C.sub.1-4 alkanol, a solvent mixture of equivalent selectivity and a buffer.

7. The process of claim 1, in which the harringtonine is homoharringtonine.

8. The process of claim 1, in which the harringtonine is harringtonine.

9. The process of claim 6, wherein said buffer is based on phosphoric acid and is a salt.

10. A method for treatment of leukemia comprising administering to a patient in need of such therapy an effective amount of a purified and/or solid harringtonine as defined by the following formula: ##STR00156## wherein n=2 or n=3 in which the total content of impurities 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% for treatment of said leukemia, wherein said harringtonine is administered by an implant.

11. The process of claim 1, wherein the pure harringtonine is such that n=3 and the total content of impurities is lower than 1%, and/or the content of the major impurity is lower than 0.9%, and/or the chromatographic assay exhibits a homoharringtonine content higher than 97.5%.

12. The process of claim 1, wherein the pure harringtonine is such that n=2 and the total content of impurities is lower than 1%, and/or the content of the major impurity is lower than 0.9%, and/or the chromatographic assay exhibits a harringtonine content higher than 97.5%.

13. The process of claim 1, wherein the pure harringtonine is a crystalline natural, synthetic or semi-synthetic homoharringtonine having substantially the same DSC curve as set out in FIG. 1.

14. The process of claim 1, wherein the pure harringtonine is a crystalline natural, synthetic or semi-synthetic homoharringtonine 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.

15. The process of claim 1, wherein the pure harringtonine is a crystalline natural, synthetic or semi-synthetic homoharringtonine 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.

16. The process of claim 1, wherein the pure harringtonine is a crystalline natural, synthetic or semi-synthetic harringtonine having substantially the same DSC curve as set out in FIG. 4.

17. The process of claim 1, wherein the pure harringtonine is a crystalline natural, synthetic or semi-synthetic harringtonine having substantially the same IR spectrum, in KBr as set out in FIG. 5.

18. The process of claim 1, wherein the pure harringtonine is a crystalline natural, synthetic or semi-synthetic harringtonine 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.
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