Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-03-16
2004-12-14
Balasubramanian, Venkataraman (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S484000, C540S596000, C514S214010
Reexamination Certificate
active
06831180
ABSTRACT:
The present invention relates to a process for preparing cephalotaxane derivatives bearing a side chain.
The term “cephalotaxanes” refers to compounds or salts thereof which have a basic skeleton of formula
where p is equal to 1 or 2 (it being possible for the two units to be identical or different and linked via a single bond or an oxygen atom), which can contain various oxygenated substituents (aliphatic or aromatic ethers, free or esterified alcohols, substituted or free enols and/or phenols, bridged ethers, and more generally any substituent usually encountered in the natural state on compounds of this type).
Harringtonines are alkaloids which are of high interest in anticancer chemotherapy, in particular on certain haematosarcomas which are multi-resistant to the existing therapies. The selectivity of harringtonines, which is based on a novel mechanism of action relating to protein synthesis, is such that this series is favoured with a great future in anticancer therapy.
Several literature compilations give a seemingly exhaustive review of all of the knowledge relating to cephalotaxanes, these compilations being, chronologically: [C. R. Smith, Jr, R. G. Powell and K. L. Mikolajczack,
Cancer Treat. Rep
., Vol. 60, 1157 (1976); C. R. Smith, Jr, L. Kenneth, K. L. Mikolajczack and R. G. Powell in “Anticancer Agent Based on Natural Product Model”, 391 (1980); Liang Huang and Zhi Xue in “The Alkaloids”, Vol. XXIII (A. Brossi Ed.), 157 (1984); M. Suffness and G. A. Cordell in “The Alkaloids, Chemistry and Pharmacology” (A. Brossi Ed.), Vol. 25, 57-69, 295-298 (1'987); P. J. O'Dwyer, S. A. King, D. F. Hoth, M. Suffness and B. Leyland-Jones,
Journal of Clinical Oncology
, 1563 (1986); T. Hudlicky, L. D. Kwart and J. W. Reed, in “Alkaloid: Chemical and Biological Perspectives” (S. W. Pelletier Ed.), Vol. 5, 639 (1987); M. A. Miah, T. Hudlicky and J. Reed in “The Alkaloids”, Vol. 51, 199 (1998)].
Antiparasitic activities, in particular on the haematozoon of malaria, have also been recognized [J. M. Whaun and N. D. Brown,
Ann Trop. Med. Par
., Vol. 84, 229 (1990)].
Homo-harringtonine (HHT), the most active member of the series, is active at and above daily doses of 2.5 mg/m
2
of body area per 24 hours, i.e., as a guide, at doses twenty times lower than that for Taxol. HHT has already undergone fourteen phase I and II clinical trials and it is the only known product capable of a 70% reinduction of full haematological remissions in patients suffering from chronic myeloid leukaemias that have become resistant to alpha-interferon [S. O'Brien, H. Kantarjian, M. Keating, M. Beran, C. Koler, L. E. Robertson, J. Hester, M. Rios, M. Andreeff and M. Talpaz,
Blood
, 332 (1995);
Leukemia Insights
, Vol. 3, No. 1 (1998)].
Harringtonines were extracted over 35 years ago from an exclusively Asiatic cephalotaxacea known as
Cephalotaxus harringtonia
, following the programme of research into novel anticancer agents in the plant kingdom developed by the National Cancer Institute. In fact, the
Cephalotaxus
alkaloids consist essentially (at least 50%) of cephalotaxine, a biosynthetic precursor of the harringtonines, the latter individually representing only a few percent of the total alkaloids.
Besides their low concentration in the natural state in plant starting material, harringtonines are mixed with many congeners which have very similar chemical structures. Thus, in a high resolution high performance liquid chromatography (HPLC) chromatogram of a semi-purified alkaloid extract, no less than several tens of cephalotaxine esters are counted.
If we consider that:
on the one hand, harringtonines are generally relatively non-crystallogenic, as is suggested by the flexibility of their side chains, which are generally branched and aliphatic,
on the other hand, these esters, in particular harringtonine and homo-harringtonine, are contaminated with congeners which are themselves biologically active and very difficult to separate out, even by high resolution analytical HPLC,
the current state of the art does not allow these compounds to be produced viably on the industrial scale as regards the purity required for pharmaceutical active principles.
Although biosynthetically similar to the alkaloids of the genus
Erythrina
, cephalotaxanes are alkaloids which have a unique structure in nature, encountered only in the genus
Cephalotaxus
, which is the only genus of the Cephalotaxacea family. On the other hand, the side chains of the various harringtonine congeners are all derived from the methyl hemiester of the primary carboxyl of (2R) citramalic acid 3a (see Scheme 1 attached) by substitution of the tertiary methyl using alkyl or aralkyl radicals which may themselves be unsubstituted or substituted with tertiary hydroxyls, it then being possible for the latter to form a cyclic ether with a tertiary alcohol (anhydro derivatives).
The attached Scheme 1 shows the main examples of harringtonine congeners, which all have significant cytostatic activity to different degrees. None of the artificial analogous cephalotaxine esters synthesized hitherto in the literature has at least the sub-structure 3b (see Scheme 1) and lack significant cytostatic activity.
It is worthwhile pointing out that, although botanically very similar to the Cephalotaxaceas, Taxaceas contain triterpene alkaloids (taxines), accompanied by non-alkaloid triterpenes, taxanes, which are also of unique structure in nature. Although they are completely different from taxanes in terms of chemical structures and anticancer mechanism of activity, the harringtonines have analogy with taxanes in more than one respect:
they have cytostatic properties,
they consist of a polycyclic skeleton, an inactive biosynthetic precursor of the complete structure, onto which is grafted a side chain containing a similar combination of hydrophilic and hydrophobic substituents,
the polycyclic part of the taxanes (baccatins in the broad sense) and of the harringtonines (cephalotaxines) is relatively abundant in renewable parts of the plant, whereas the active molecules (harringtonines and taxanes) are ten to one hundred times less abundant therein,
the plum yew (
Cephalotaxus
) is a rare tree, even rarer than the yew (Taxus), and is much less ubiquitous than the latter.
It results from the above facts that, following the manner of the semi-synthesis of taxanes by adding a synthetic chain to a 10-deacetylbaccatin III of extracted origin, the asymmetric semi-synthesis of harringtonines by esterification of a cephalotaxine of natural origin is of considerable medical and economic value. Furthermore, the current population of
Cephalotaxus
is relatively reduced even in their original habitat. Thus, during its importation into Europe for ornamental purposes last century,
Cephalotaxus harringtonia
was already no longer present in spontaneous form in eastern China and in northern Japan. The use of a precursor present in a renewable part of the tree (the leaf) in order to prepare homo-harringtonine semi-synthetically is thus of considerable environmental interest, all the more so since the total synthesis of optically active cephalotaxine has not been achieved hitherto, despite the extensive synthetic studies carried out in this respect (a certain number of laborious syntheses of racemic cephalotaxine containing 10 to 15 steps have, however, been carried out: see bibliographic review above).
Consider that several hundred tonnes per year of this rare and very slow-growing tree (even slower growing than Taxus sp.) need to be extracted to satisfy the current market needs for homo-harringtonine (several kilograms per year), whereas the semi-synthesis would consume only a few tonnes of renewable parts of the tree (leaves). Furthermore, homo-harringtonine (HHT) of natural origin currently available on the active principles market is contaminated with its congeners, which, on account of their structural similarity, are very difficult to separate, even by “preparative” high performance liquid chromatography.
First of all, it shoul
Blanchard Julie
Cavoleau Sylvie
Charbonnel Sandra
Chauviat Ludovic
Dhal Robert
Burns Doane Swecker & Mathis L.L.P.
Stragen Pharma SA.
LandOfFree
Cephalotaxane derivatives and process for their preparation does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cephalotaxane derivatives and process for their preparation, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cephalotaxane derivatives and process for their preparation will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3301957