Synthesis of epothilones, intermediates thereto, analogues...

Details Synthesis of epothilones, intermediates thereto, analogues... Synthesis of epothilones, intermediates thereto, analogues...

2001-03-14

2003-12-02

Solola, Taofiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S204000, C548S510000, C549S271000

Reexamination Certificate

active

06656961

ABSTRACT:

FIELD OF THE INVENTION
The present invention is in the field of epothilone macrolides. In particular, the present invention relates to processes for the preparation of epothilones A and B, desoxyepothilones A and B, and analogues thereof which are useful as highly specific, non-toxic anticancer therapeutics. In addition, the invention provides methods of inhibiting multidrug resistant cells. The present invention also provides novel compositions of matter which serve as intermediates for preparing the epothilones.
Throughout this application, various publications are referred to, each of which is hereby incorporated by reference in its entirety into this application to more fully describe the state of the art to which the invention pertains.
BACKGROUND OF THE INVENTION
Epothilones A and B are highly active anticancer compounds isolated from the Myxobacteria of the genus Sorangium. The full structures of these compounds, arising from an x-ray crystallographic analysis were determined by Höfle. G. Höfle et al.,
Angew. Chem. Int. Ed. Engl
., 1996, 35, 1567. The total synthesis of the epothilones is an important goal for several reasons. Taxol is already a useful resource in chemotherapy against ovarian and breast cancer and its range of clinical applicability is expanding. G. I. Georg et al.,
Taxane Anticancer Agents
; American Cancer Society: San Diego, 1995. The mechanism of the cytotoxic action of taxol, at least at the in vitro level, involves stabilization of microtubule assemblies. P. B. Schiff et al.,
Nature
(London), 1979, 277, 665. A series of complementary in vitro investigations with the epothilones indicated that they share the mechanistic theme of the taxoids, possibly down to the binding sites to their protein target. D. M. Bollag et al.,
Cancer Res
., 1995, 55, 2325. Moreover, the epothilones surpass taxol in terms of cytotoxicity and far surpass it in terms of in vitro efficacy against drug resistant cells. Since multiple drug resistance (MDR) is one of the serious limitations of taxol (L. M. Landino and T. L. MacDonald in
The Chemistry and Pharmacology of Taxol and its Derivatives
, V. Farin, Ed., Elsevier: New York, 1995, ch. 7, p. 301), any agent which promises relief from this problem merits serious attention. Furthermore, formulating the epothilones for clinical use is more straightforward than taxol.
Accordingly, the present inventors undertook the total synthesis of the epothilones, and as a result, have developed efficient processes for synthesizing epothilones A and B, the corresponding desoxyepothilones, as well as analogues thereof. The present invention also provides novel intermediates useful in the synthesis of epothilones A and B and analogues thereof, compositions derived from such epothilones and analogues, purified compounds of epothilones A and B, and desoxyepothilones A and B, in addition to methods of use of the epothilone analogues in the treatment of cancer. Unexpectedly, certain epothilones have been found to be effective not only in reversing multi-drug resistance in cancer cells, both in vitro and in vivo, but have been determined to be active as collateral sensitive agents, which are more cytotoxic towards MDR cells than normal cells, and as synergistic agents, which are more active in combination with other cytotoxic agents, such as vinblastin, than the individual drugs would be alone at the same concentrations.
Remarkably, the desoxyepothilones of the invention have exceptionally high specificity as tumor cytotoxic agents in vivo, more effective and less toxic to normal cells than the principal chemotherapeutics currently in use, including taxol, vinblastin, adriamycin and camptothecin.
SUMMARY OF THE INVENTION
One object of the present invention is to provide processes for the preparation of epothilones A and B, and desoxyepothilones A and B, and related compounds useful as anticancer therapeutics. Another object of the present invention is to provide various compounds useful as intermediates in the preparation of epothilones A and B as well as analogues thereof.
A further object of the present invention is to provide synthetic methods for preparing such intermediates. An additional object of the invention is to provide compositions useful in the treatment of subjects suffering from cancer comprising any of the analogues of the epothilones available through the preparative methods of the invention optionally in combination with pharmaceutical carriers.
A further object of the invention is to provide methods of treating subjects suffering from cancer using any of the analogues of the epothilones available through the preparative methods of the invention optionally in combination with pharmaceutical carriers.


REFERENCES:
patent: 5021430 (1991-06-01), Ksander et al.
patent: 5917084 (1999-06-01), Jiang et al.
patent: 5969145 (1999-10-01), Schinzer et al.
patent: 6043372 (2000-03-01), Schinzer et al.
patent: 6156905 (2000-12-01), Schinzer et al.
patent: 19542986.9 (1995-11-01), None
patent: 19639456.2 (1996-09-01), None
patent: 19542986 (1997-05-01), None
patent: 19636343 (1997-10-01), None
patent: 19639456 (1998-03-01), None
patent: 19645361 (1998-04-01), None
patent: 19645362 (1998-04-01), None
patent: WO97/19086 (1997-05-01), None
patent: WO98/08849 (1998-05-01), None
patent: WO98/25929 (1998-06-01), None
patent: WO99/02514 (1999-01-01), None
Bijoy, P. et al., “Synthetic Studies Directed Towards Epothilone A: . . . ”,Tetrahedron Letters39:209-212 (1998).
U.S. patent application Ser. No. 08/856,533, filed May 14, 1997.
U.S. patent application Ser. No. 08/923,869, filed Sep. 4, 1997.
U.S. provisional application Ser. No. 60/032,864, filed Dec. 13, 1996.
Bollag, Daniel M., “Epothilones, a New Class of MT-stabilizing Agents . . . ”,Cancer Research55:2325-2333 (1995).
Chakraborty, T.K. et al., “Radical-induced Opening of Trisubstituted Epothilones”,Tetrahedron Letters39:101-104 (1998).
Clause, E, et al., “Synthesis of the C1-C9 Segment of Epothilones”,Tetrahedron Letters38:8:1359-1362 (1997).
Gabriel, T., “The Chromium-Reformatsky Reaction: . . .”,Tetrahedron Letters38:8 1363-1366 (1997).
Gerth, K. et al., “Epothilone A and B: Antifungal and Cytotoxic Compounds . . . ”,Liebigs Ann. Chem.74 & 75, 49-53 (1996).
Giannakakou, P. et al., “Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant &bgr;-Tubulins . . . ”,J. Bio. Chem.272:27 17118-17125 (1997).
Höfle, G. et al. “Epothilone A and B-Novel 16-Membered Microlides with Cytotoxic . . . ”,,Chem Int. Ed. Engl.35:13 14, 1567-1569 (1996).
Kowalski, R.J. et al., “Activities of the Microtubule-stabilizing Agents Epothilones A and B . . . ”,J. of Bio. Chem.272:4 2534-2541 (1997).
Liu, Z.Y. et al., “Chiral Synthesis of the C3-13Segment of Epothilone A”Synlett Letters1383-84 (1997).
March, Advanced Organic Chemistry, 2nd Ed., McGraw-Hill (1977); p. 940, section 7-21.
Meng et al. “Studies toward a Synthesis of Epothilone A: Use of Hydropyran Templates for the Management of Acyclic Stereochemical Relationships”J. Org. Chem.61:23 7998-8001 (1996).
Moasser et al., “Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol . . . ”Proc. Natl. Acad. Sci. USA, 95:1369-1374 (1998).
Muhlradt et al., “Epothilone B Stabilizes Microtubuli of Macrophages Like Taxol. . . ”,Cancer Res.57, 3344-46 (1997).
Mulzer, J. et al., “Synthesis of the C(1)-C(9) Segment of the Cytotoxic Macrolides Epothilon A and B”,Terahedron Letters37:51, 9179-9182 (1996).
Nicolaou, K.C. et al., “Total Synthesis of 26-hydroxyepothilone B and related analogues”, Chem. Commun. 2343-2344 (1997).
Nicolaou, K.C. et al., “Total Synthesis of Epothilone A: The Macrolactonization Approach”,Agnew Chem. Int. Ed. Engl., (1997).
Nicolaou, K.C. et al. “Total Synthesis of Epothilone A and B via a Macrolactonization-Based Strategy”,J. Am. Chem.Soc.119, 7974-7991 (1997).
Nicolaou, K.C. et al., “Total Synthesis of Oxazole-and Cyclopropane-Containing Epothilone A Analogues. . . ”,Chem. Eur. J.3:12 1957-1970 (1997).
Nicolaou, K.C. et al., “Total Synthesis of Oxazole-and Cyclopropane-Containing Epothilone B Analogues. . . ”,Chem. Eu

Affiliated with

Also associated with

Rating

Synthesis of epothilones, intermediates thereto, analogues... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Synthesis of epothilones, intermediates thereto, analogues..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Synthesis of epothilones, intermediates thereto, analogues... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3132792