You’re using a public version of DrugPatentWatch with 5 free searches available | Register to unlock more free searches. CREATE FREE ACCOUNT

Last Updated: March 29, 2024

Claims for Patent: RE45128


✉ Email this page to a colleague

« Back to Dashboard


Summary 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.

Make Better Decisions: Try a trial or see plans & pricing

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.