Intermediates for the synthesis of epothilones and methods...

Details Intermediates for the synthesis of epothilones and methods... Intermediates for the synthesis of epothilones and methods...

2000-11-17

2002-02-26

Lambkin, Deborah C. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S203000, C548S204000, C549S476000

Reexamination Certificate

active

06350878

ABSTRACT:

SUMMARY OF THE INVENTION
The invention relates to a new method of synthesis of an intermediate useful for the synthesis of epothilone B and desoxyepothilone B and derivatives thereof, as well as to certain new partial reaction sequences for the production of key intermediates.
BACKGROUND OF THE INVENTION
Among cytotoxic agents for the treatment of tumors, Taxol® (Paclitaxel), a microtubule stabilizing agent, has become a very important compound with a remarkable economic success (see McGuire, W. P., et al., Ann. Int. Med. 111, 273-9 (1989)).
Taxol® has a number of disadvantages. Especially its extremely low solubility in water represents a severe problem. It has become necessary to administer Taxol in a formulation with Cremophor EL® (polyoxyethylated castor oil; BASF, Ludwigshafen, Germany) which has severe side effects, causing inter alia allergic reactions that in one case even were reported to have led to the death of a patient. More severely, certain tumor types are known to be refractory against treatment with Taxol®.
Taxol® treatment is associated with a number of significant side effects and some major classes of solid tumors, namely colon and prostate, are poorly responsive to this compound (see Rowinsky E. K., loc. cit.).
The epothilones A and B are a new class of microtubule stabilizing cytotoxic agents (see Gerth, K. et al., J. Antibiot. 49, 560-3 (1966); Hoefle et al., DE 41 38 042) of the formulae:
wherein Z is hydrogen (epothilone A) or methyl (epothilone B).
These compounds have the following advantages:
(i) they show better water solubility than Taxol and are thus more appropriate for formulation; and
(ii) they have been reported to be active also against the proliferation of cells that, due to the activity of the P-glycoprotein efflux pump which renders them multidrug resistant, show resistance to the treatment with other chemotherapeutics, e.g. Taxol (see Bollag, D. M., et al., “Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action”, Cancer Research 55, 2325-33 (1995); and Bollag D. M., Exp. Opin. Invest. Drugs 6, 867-73 (1997); and
(iii) despite apparently sharing the same, or at least a largely overlapping binding site on the microtubule, the epothilones have been shown to be active against a Taxot®-resistant ovarian carcinoma cell line with an altered &bgr;-tubulin (see Kowalski, R. J., et al., J. Biol. Chem. 272(4), 2534-2541 (1997)).
Due to their impressive biological profile, multiple initial efforts towards the synthesis of epothilones appeared almost simultaneously in the literature. Three groups described total syntheses of epothilone A, and two total syntheses of epothilone B appeared concurrently as well. In addition, a flood of papers appeared which presented partial solutions towards the synthesis of epothilones. Since these studies, many derivatives have been synthesized and their biological profiles have been tested.
Especially epothilone B provides important biological properties that are exemplary for other epothilones:
Epothilone B is appropriate preferably in the treatment of proliferative diseases, such as of gastrointestinal tumors, more preferably (1) a tumor of the colon AND/OR the rectum (colorectal tumor), especially if it is refractory to a (meaning at least one) representative of the taxane class of anti-cancer agents, in particular paclitaxel, AND/OR at least one standard treatment with an other chemotherapeutic, especially 5-fluorouracil; (2) a tumor of the genitourinary tract, more preferably a tumor of the prostate, including primary and metastatic tumors, especially if refractory to hormone treatment (“hormone refractory prostate cancer”) and/or treatment with other standard chemotherapeutics; (3) an epidermoid tumor, more preferably an epidermoid head and neck tumor, most preferably a mouth tumor; (4) a lung tumor, more preferably a non-small cell lung tumor, especially any of these tumors that is refractory to treatment with one or more other chemotherapeutics (especially due to multidrug resistance), especially to treatment with a member of the taxane class of anti-cancer agents, in particular TAXOL®; or (5) a breast tumor, more preferably one that is multidrug resistant, especially refractory to treatment with a member of the taxane class of anti-cancer agents, in particular TAXOL®; relating especially also to the treatment of a multidrug resistant lung tumor (preferably a non-small cell lung tumor), a multidrug resistant breast tumor, or a multidrug resistant epidermoid tumor, or in a broader sense of the invention to a treatment schedule for the treatment of an aforementioned or (in a broader sense of the invention) any other tumor.
Epothilone B is preferably used weekly or three-weekly; preferably for weekly treatment the dose is between about 0.1 and about 6, preferably about 0.1 and about 5 mg/m
2
, more preferably about 0.1 and about 3 mg/m
2
, even more preferably 0.1 and 1.7 mg/m
2
, most preferably about 0.3 and about 1 mg/m
2
; for three-weekly treatment (treatment every three weeks or every third week) the dose is between about 0.3 and about 18 mg/m
2
, preferably about 0.3 and about 15 mg/m
2
, more preferably about 0.3 and about 12 mg/m
2
, even more preferably about 0.3 and about 7.5 mg/m
2
, still more preferably about 0.3 and about 5 mg/M
2
, most preferably about 1.0 and about 3.0 mg/m
2
. This dose is preferably administered to the human by intravenous (i.v.) administration during 2 to 180 min, preferably 2 to 120 min, more preferably during about 5 to about 30 min, most preferably during about 10 to about 30 min, e.g. during about 30 min.
Preferably, especially in the case of weekly treatment, rest periods of more than one week, more preferably of two to ten weeks, more preferably three to six weeks after the preceding treatment may be necessary after for example 3, 4, 6, 8, or more treatment cycles, depending on patient condition, to allow for sufficient recovery from the preceding treatment.
The pharmaceutical compositions comprise from about 0.00002 to about 95%, especially (e.g. in the case of infusion dilutions that are ready for use) of 0.0001 to 0.02%, or (for example in case of infusion concentrates) from about 0.1% to about 95%, preferably from about 20% to about 90%, active ingredient (weight by weight, in each case). Pharmaceutical compositions according to the invention may be, for example, in unit dose form, such as in the form of ampoules, vials, suppositories, dragees, tablets or capsules.
Preferred is an infusion formulation comprising epothilone B and a pharmaceutically acceptable organic solvent. The pharmaceutically acceptable organic solvent used in a formulation according to the invention may be chosen from any such organic solvent known in the art. Preferably the solvent is selected from alcohol, e.g. absolute ethanol or ethanol/water mixtures, more preferably 70% ethanol, polyethylene glycol 300, polyethylene glycol 400, polypropylene glycol or N-methylpyrrolidone, most preferably polypropylene glycol or 70% ethanol or especially polyethylene glycol 300.
Epothilone B may preferably be present in the formulation in a concentration of about 0.1 to about 100 mg/ml, more preferably about 1 to about 100 mg/ml, still more preferably about 1 to about 10 mg/ml (especially in infusion concentrates).
It is a goal of the present invention to provide novel routes to manufacture an intermediate for the synthesis of epothilone B and its predecessor, desoxyepothilone B.
In contrast to a published synthesis by Nicolaou et al. (see J. Am. Chem. Soc. 119, 7974-91 (1997)) for the synthesis of epothilone B, the new route is more convergent, that is, it is based on three rather than two key fragments that have to be assembled to the final product. The disadvantage of the prior art two-fragment strategy consists in the fact that many more steps are required to prepare the individual fragment. Therefore the new synthesis offers large advantages.
DETAILED DESCRIPTION OF THE INVENTION
The invention relates to a formal total synthesis route via an intermediate ap

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