AU3481001A

AU3481001A - Taxane formulations having improved solubility

Info

Publication number: AU3481001A
Application number: AU34810/01A
Authority: AU
Inventors: Robert A. Holton
Original assignee: Florida State University Research Foundation Inc
Current assignee: Florida State University Research Foundation Inc
Priority date: 2000-02-02
Filing date: 2001-02-02
Publication date: 2001-08-14
Also published as: IL145635A0; HUP0200995A3; WO2001057013A1; EP1175414A1; NO20014752D0; BR0104358A; KR20010111580A; NZ514073A; HUP0200995A2; NO20014752L

Description

WO 01/57013 PCT/USO1/03624 TAXANE FORMULATIONS HAVING IMPROVED SOLUBILITY BACKGROUND OF THE INVENTION The present invention is directed to various formulations of taxane derivatives having improved solubility as compared to paclitaxel, particularly 5 formulations of such taxane derivatives for parenteral administration to a patient. Paclitaxel has shown remarkable antineoplastic effect in a wide range of human cancers. Initially approved in 1992 for the treatment of refractory ovarian cancer, paclitaxel is now the first-line therapy for metastatic breast cancer and advanced ovarian cancer. Paclitaxel's effectiveness has also been demonstrated 10 against non-small cell lung cancer, head and neck cancers, melanoma, colon cancer and Kaposi's sarcoma. In addition to its cytotoxic effects, paclitaxel has also been shown to be a potent inhibitor of angiogenesis. Despite its broad clinical utility, there has been difficulty formulating paclitaxel because of its insolubility in water. The aqueous solubility of paclitaxel is only 0.25 g per ml. 15 Paclitaxel is also insoluble in most pharmaceutically-acceptable solvents, and lacks a suitable chemical functionality for formation of a more soluble salt. Consequently, special formulations are required for parenteral administration of paclitaxel. Paclitaxel is very poorly absorbed when administered orally (less than 1 %). No oral formulation of paclitaxel has obtained regulatory approval for 20 administration to patients. Paclitaxel is currently formulated as Taxol@, which is a concentrated nonaqueous solution containing 6 mg paclitaxel per ml in a vehicle composed of 527 mg of polyoxyethylated castor oil (Cremophor@ EL) and 49.7% (v/v) dehydrated ethyl alcohol, USP, per milliliter (available from Bristol-Myers Squibb 25 Co., Princeton, N.J.). Cremophor@ EL improves the physical stability of the solution, and ethyl alcohol solubilizes paclitaxel. The solution is stored under refrigeration and diluted just before use in 5% dextrose or 0.9% saline. Intravenous infusions of paclitaxel are generally prepared for patient administration within the concentration range of 0.3 tol.2 mg/mI. In addition to 30 paclitaxel, the diluted solution for administration consists of up to 10% ethanol, up to 10% Cremophor@ EL and up to 80% aqueous solution. However, dilution to certain concentrations may produce a supersaturated solution that could precipitate. An inline 0.22 rmicron filter is used during Taxol@ administration to guard against the potentially life-threatening infusion of particulates.

WO 01/57013 PCT/US01/03624 2 Several toxic side effects have resulted from the administration of paclitaxel in a Cremophor@/ethanol-based formulation including anaphylactic reactions, hypotension, angioedema, urticaria, peripheral neuropathy, arthralgia, mucositis, nausea, vomiting, alopecia, alcohol poisoning, respiratory distress such 5 as dyspnea, cardiovascular irregularities, flu-like symptoms such as myalgia, gastrointestinal distress, hematologic complications such as neutropenia, genitourinary effects, and skin rashes. Some of these undesirable adverse effects were encountered in clinical trials, and in at least one case, the reaction was fatal. To reduce the incidence and severity of these reactions, patients are 10 premedicated with corticosteroids, diphenhydramine, H2 -antagonists, antihistamines, or granulocyte colony-stimulating factor (G-CSF), and the duration of the infusion has been prolonged. Although such premedication has reduced the incidence of serious hypersensitivity reactions to less than 5%, milder reactions are still reported in approximately 30% of patients. 15 There is an additional drawback to the Cremophor@-based formulation. Cremophor@ EL can leach phthalate plasticizers from polyvinyl chloride infusion bags and intravenous administration set tubing. This has led to the use of glass bottles or polyolefin containers for storing Taxol@ solution and polyethylene-lined administration tubing or tubing made with tris (2-ethylhexyl) trimellitate plasticizer 20 for Taxol@ administration. The physiological problems associated with paclitaxel administration have limited the dosage of paclitaxel that a patient can receive and prolonged the time of administration. Paclitaxel is typically given in a dose ranging from about 110 mg/m 2 to 300 mg/m 2 over a 3-24 hour period every 21 days or more, often with 25 premedication. At dosages above 300 mg/m 2 , peripheral neuropathy has been observed. Infusion times do not generally exceed 24 hours because the paclitaxel is physically stable for only 27 hours. In instances where a patient receives a multi-day continuous infusion, the patient must have a new bag of Taxol@ solution each day. In addition to the 30 inconvenience for patients and staff and increased therapy cost, the bag exchange increases the risk of intravenous catheter microbial colonization. It would be advantageous to have a taxane product that remains stable for the entire period of the multi-day administration. There is a strong need for reformulating taxane compositions using a safer 35 and better-tolerated vehicle than Cremophor@. Alternative formulations of paclitaxel that avoid the use of Cremophor@ have been proposed. One approach WO 01/57013 PCT/USO1/03624 3 is incorporation of the drug into a liposomal formulation. However, it has been reported that there is difficulty in achieving a quantitative incorporation of the drug into the liposomal compartment, and that low loading capability and nonspecific uptake by the reticuloendothelial system have limited the clinical usefulness of 5 such liposomes. This formulation is also not storage stable and must be freeze dried and reconstituted before use. Another approach is to formulate paclitaxel as a lipid emulsion. Most of the efforts to create a paclitaxel formulation as a stable lipid emulsion have been unsuccessful. It has been widely reported in the literature that paclitaxel is 10 insoluble in lipid emulsions containing soybean oil, such as Intralipid@, or lipid emulsions that are a mixture of soybean and safflower oils, such as Liposyn@. See, for example, L.C. Collins-Gold et al., "Parenteral Emulsions for Drug Delivery," Advanced Drug Delivery Reviews, 5, 189-208 (1990); B.D. Tarr, "A New Parenteral Emulsion for the Administration of Taxol," Pharmaceutical 15 Research, 4(2), 163 (1987); Dolatrai M. Vyas, Paclitaxel (Taxol) Formulation And Prodrugs, The Chemistry and Pharmacology of Taxol and its Derivatives, Elsevier Science B.V., 107 (1995); J.M. Meerum Terwogt et al., "Alternative Formulations of Paclitaxel" Cancer Treatment Reviews, 23, 89 (1997). Paclitaxel's solubility in soybean oil is only 0.3 mg/ml. Vyas, supra. Physical methods for solubilizing 20 paclitaxel in either soybean oil or safflower oil, such as heating or heating with sonication do not solubilize appreciable amounts of paclitaxel. Thus, the lipid emulsion formulations have significant drawbacks in that additives are still needed to solubilize paclitaxel and to prevent it from precipitating out of solution. Tarr et al., supra, developed a parenteral triacetin emulsion formulation of 25 paclitaxel. The emulsion contained 50% triacetin, 2.0% ethyl oleate, 1.5% Pluronic@ F68, 1.5% purified soybean oil and 10 mg paclitaxel. Glycerol was added up to 10% to prevent creaming. This emulsion was reported to be adequately stable for parenteral administration. However, triacetin (glyceryl triacetate) itself proved to be toxic to mice when administered intravenously in 30 concentrations required to deliver therapeutic doses of paclitaxel. Furthermore, no antitumor activity was observed with this formulation. Andersson, U.S. Patent No. 5,877,205, discloses a pharmaceutical composition for parenteral administration containing a taxane analog, dimethylacetamide, polyethylene glycol and an aqueous lipid emulsion. The 35 aqueous lipid emulsion is preferably a soybean oil emulsion. Andersson solubilizes paclitaxel by dissolving it in an organic solvent of dimethylacetamide WO 01/57013 PCT/USO1/03624 4 as the primary vehicle and adding a secondary polyethylene glycol solvent to stabilize the drug in solution for subsequent final dilution in an aqueous solvent, such as an aqueous lipid emulsion (e.g., emulsified soybean oil (Intralipid@), Liposyn@, Soyacal@, and Travemulsion@). 5 Kaufman et al., U.S. Patent No. 5,616,330 report a composition of a taxine in a stable oil-in-water emulsion for intravenous administration. The taxine is dissolved in an alcohol and then mixed with an oil such as safflower or sunflower oil to form a solution. The alcohol is then removed from the solution by evaporation. The solution is added to an aqueous surfactant dispersion and 10 stirred at high speed to form an emulsion. The emulsion is then refined through a homogenizer. Although Taxol@ and Taxotere@ are useful chemotherapeutic formulations, there are limitations on their effectiveness, including limited efficacy against certain types of cancers and toxicity to subjects when administered at various 15 doses. Accordingly, a need remains for additional formulations of chemotherapeutic agents with improved efficacy and less toxicity. SUMMARY OF THE INVENTION Among the various aspects of the present invention, therefore, is the provision of taxane-containing pharmaceutical compositions which compare 20 favorably to Taxol@ and Taxotere@ formulations with respect to efficacy as anti tumor agents and with respect to toxicity and stability. Accordingly, it is an aspect of the invention to provide pharmaceutical compositions for oral or parenteral administration which comprise a taxane and at least one nonaqueous, pharmaceutically acceptable solvent. In one embodiment 25 of the invention, the taxane has a solubility in ethanol of at least 100 mg/mI. In another aspect of the present invention, the taxane has a solubility in ethanol of at least 100 mg/ml and is capable of being crystallized from a solution. In yet another aspect, the pharmaceutical compositions comprise a taxane which has a solubility in ethanol of at least 60 mg/mI and an ID 5 0 value determined relative to 30 the HCT1 16 cell line that is at least 4 times less than that of paclitaxel. A further aspect of the present invention is the provision of pharmaceutical compositions for oral or parenteral administration which comprise a taxane of the invention and a pharmaceutically acceptable carrier.

WO 01/57013 PCT/US01/03624 5 Other objects and features of this invention will be in part apparent and in part pointed out hereinafter. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention provides compositions and methods for the 5 solubilization of taxane antitumor compounds in pharmaceutically acceptable carriers. The taxanes of the invention are more soluble in the carriers and exhibit greater cytotoxic activity as compared to paclitaxel. Therefore, taxane compositions can be formulated to include significantly less ethanol and Cremophor@ EL solution as compared to Taxol@ solution, or can be formulated to 10 be free of ethanol and/or Cremophor@ solution. The taxanes remain physically and chemically stable in the compositions for an extended period of time, allowing for multi-day continuous infusion without replacement of the composition and for administration without the use of an inline filter. The taxane compositions can be administered systemically or locally without undue toxicity caused by the carrier or 15 by precipitation or recrystallization of the taxane. The risk of anaphylactic reactions or other adverse side effects is minimized with the compositions of the invention. The compositions of the invention allow for a broad range of administration protocols including oral administration. Oral administration has been found to 20 decrease toxic side effects as compared with conventional intraveneous therapy. Rather than producing a sudden high taxane concentration in blood levels as is usually the case with an intravenous infusion, absorption of the taxane through the gut wall provides a more gradual appearance of taxane in the blood levels and enables a stable, steady-state maintenance of desired levels for a long 25 period of time. The compositions can also be administered parenterally in less than 1, 2 or 3 hours so that patients can be treated on an out-patient basis while still providing an anti-neoplastic effective dosage without exceeding dose-limiting toxicities. The compositions are also effective in minimizing or eliminating premedication to reduce patient discomfort and the expense and duration of 30 treatment. In instances where parenteral administration cannot be shortened in duration, the compositions contain lower taxane concentrations as compared to conventional paclitaxel compositions and result in minimal or no adverse side effects. In one embodiment of the present invention, the taxanes of the present 35 invention correspond to structure (1): WO 01/57013 PCT/US01/03624 6

X

5 NH 0 Rg X3 .: O. OH

R

14 HO 4a O 2 Ac (1) 5 wherein one of R 7 and Rio is hydroxy and the other is acyloxy;

X

3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;

X

5 is -COX 1 O, -C00X 10 , or -CONHX1 0 ; 10 X 1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

R

2 is acyloxy; R. is keto, hydroxy, or acyloxy;

R

1 4 is hydrido or hydroxy; and Ac is acetyl. 15 R 7 , R., and R 1 independently have the alpha or beta stereochemical configuration. In one embodiment, R 2 is an ester (R 2 aC(O)O-), a carbamate

(R

2 aR 2 bNC(O)0-), a carbonate (R 2 aOC(O)0-), or a thiocarbamate (R 2 aSC(O)O-) wherein R 2 a and R 2 b are independently hydrogen, hydrocarbyl, substituted 20 hydrocarbyl or heterocyclo. In a preferred embodiment, R 2 is an ester

(R

2 aC(O)O-), wherein R 2 a is aryI or heteroaromatic. In another preferred embodiment, R 2 is an ester (R 2 aC(O)O-), wherein R 2 a is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R 2 is benzoyloxy. 25 While R. is keto in one embodiment of the present invention, in other embodiments R 9 may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, a- or p-hydroxy or a- or p-acyloxy. For example, when R. is acyloxy, it may be an ester (R 9 aC(O)0-), a carbamate (ReaRgbNC(0)0-), a carbonate (ReaOC(0)O-), or a 30 thiocarbamate (ReaSC(O)0-) wherein Rga and Rgb are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R. is an ester (ReaC(O)O-), WO 01/57013 PCT/USO1/03624 7 R.a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic. Still more preferably, R. is an ester (RgaC(0)O-), wherein Rga is substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or 5 unsubstituted thienyl, or substituted or unsubstituted pyridyl. In one embodiment R. is (RaC(O)0-) wherein Rga is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl, (straight, branched or cyclic), or hexyl (straight, branched or cyclic). In another embodiment R 9 is (ReaC(O)0-) wherein R 9 a is substituted methyl, substituted ethyl, substituted propyl (straight, 10 branched or cyclic), substituted butyl (straight, branched or cyclic), substituted pentyl, (straight, branched or cyclic), or substituted hexyl (straight, branched or cyclic) wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, 15 but not phosphorous containing moieties. Exemplary X 3 substituents include substituted or unsubstituted C2 to C8 alkyl, substituted or unsubstituted C2 to C alkenyl, substituted or unsubstituted C2 to C8 alkynyl, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X 3 20 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl. Exemplary X, substituents include -COX 10 , -C00X 1 0 or -CONHX 1 0 wherein

X

1 0 is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred X, substituents include -COX 1 0 , -COOX 0 or -CONHX 1 0 25 wherein X 1 0 is (i) substituted or unsubstituted C1 to C8 alkyl such as substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (straight, branched or cyclic), or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C2 to C alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight, branched or cyclic), 30 butenyl (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched or cyclic); (iii) substituted or unsubstituted C2 to C8 alkynyl such as substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or hexynyl (straight or branched); (iv) substituted or unsubstituted phenyl, or (v) 35 substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, wherein the substituent(s) is/are selected from the group consisting of WO 01/57013 PCT/USO1/03624 8 heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties. C10 Carbonates 5 In one embodiment, R 1 is RI 0 aOCOO- wherein R1 0 a is (i) substituted or unsubstituted C1 to C8 alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl (straight or branched) 10 such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heterocyclo such as furyl, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred embodiment, R10a is methyl, ethyl, straight, branched or cyclic propyl, 15 straight, branched or cyclic butyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. In another embodiment, R10a is substituted ethyl, substituted propyl (straight, branched or cyclic), substituted propenyl (straight or branched), substituted isobutenyl, substituted furyl or substituted thienyl wherein the substituent(s) is/are selected from the group 20 consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties. In one of the preferred embodiments, the taxanes of the present invention correspond to structure (2):

X

5 NH O R10 0 _ 0 X3 tR7 OH HO BzOc O Aco 0 25 (2) wherein

R

7 is hydroxy;

R

1 0 is carbonate; WO 01/57013 PCT/US01/03624 9

X

3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X. is -COX 1 O, -C00X 10 , or -CONHX 1 ; and

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. 5 For example, in this preferred embodiment in which the taxane corresponds to structure (2), R 1 may be RIO0OCOO- wherein R10a is substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl or hexyl, more preferably substituted or unsubstituted methyl, ethyl or propyi, still more preferably substituted or unsubstituted methyl, ethyl, and still more preferably unsubstituted methyl or 10 ethyl. While R 7 a is selected from among these, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While RI 0 , and X 3 are 15 selected from among these, in one embodiment X 5 is selected from -COX 10 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R1Oa and X 3 are selected from among these, in one embodiment X 5 is selected from -COXI 0 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X. is -COOXIO wherein X 1 0 is alkyl, preferably t-butyl. Among the more 20 preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X. is -C00X 10 wherein X 1 0 is tert-butyl or X. is -COX 1 wherein X 1 0 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or 25 pyridyl, and (iii) R 10 a is unsubstituted methyl, ethyl or propyl, more preferably methyl or ethyl. Among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R 1 is R 10 0C00- wherein R10a is methyl. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, or heterocyclo, more preferably heterocyclo, still 30 more preferably furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t 35 butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R 14 is hydrido. In another alternative of this embodiment, WO 01/57013 PCT/US01/03624 10

X

3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or 5 heterocyclocarbony, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 10 benzoyl, R. is hydroxy and R1 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbony; R 2 is benzoyl, R. is hydroxy and R 14 is hydrido. In another alternative of this embodiment, X 3 is 15 heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 20 amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 may each have the beta stereochemical configuration, R 7 and R 1 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 has the beta 25 stereochemical configuration or R 7 may have the beta stereochemical configuration while R 1 has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure I or 2 wherein R 1 is RI 0 a0COO- wherein R1 0 a is ethyl. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl 30 such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X, is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t 35 butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, WO 01/57013 PCT/USO1/03624 11

X

3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or 5 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo;

X

5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 10 benzoyl, R. is hydroxy and R 14 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R 14 is hydrido. In another alternative of this embodiment, X 3 is 15 heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 20 amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R 14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 0 may each have the beta stereochemical configuration, R 7 and R 1 , may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while Rio has the beta 25 stereochemical configuration or R 7 may have the beta stereochemical configuration while R 1 0 has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R 1 0 is R 0 0COO- wherein R1 0 a is propyl. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl 30 such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t 35 butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, WO 01/57013 PCT/US01/03624 12

X

3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or 5 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 10 benzoyl, R 9 is hydroxy and R, 4 is hydroxy. In another alternative of this embodiment, X. is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is hydroxy and R 14 is hydrido. In another alternative of this embodiment, X 3 is 15 heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is acyloxy and R 14 is hydroxy. In another alternative of this embodiment, X. is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 20 amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 0 has the beta 25 stereochemical configuration or R 7 may have the beta stereochemical configuration while R 1 has the alpha stereochemical configuration. CI Esters In one embodiment, R 10 is R1OaCOO- wherein R 10 2 is (i) substituted or unsubstituted C2 to C alkyl (straight, branched or cyclic), such as ethyl, propyl, 30 butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C. alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or 35 pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing WO 01/57013 PCT/USO1/03624 13 substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred embodiment, R10a is ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic pentyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. In another 5 embodiment, R10a is substituted ethyl, substituted propyl (straight, branched or cyclic), substituted propenyl (straight or branched), substituted isobutenyl, substituted furyl or substituted thienyl wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, 10 ester and ether moieties, but not phosphorous containing moieties. In one of the preferred embodiments, the taxanes of the present invention correspond to structure (2):

X

5 NH 0

R

10 0 X3'11 0 t OR OH HO . BzO~c AcO5 (2) wherein 15 R 7 is hydroxy;

R

1 , is R1OaCOO-;

X

3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X. is -COX 10 , -C00X 10 , or -CONHX 1 O; and 20 X1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and

R

10 a is hydrocarbyl, substituted hydrocarbyl, or heterocyclo wherein said hydrocarbyl or substituted hydrocarbyl contains carbon atoms in the alpha and beta positions relative to the carbon of which R1 0 a is a substituent; Bz is benzoyl; and 25 Ac is acetyl. For example, in this preferred embodiment in which the taxane corresponds to the above structure (2), R1 0 a may be substituted or unsubstituted ethyl, propyl or butyl, more preferably substituted or unsubstituted ethyl or propyl, still more preferably substituted or unsubstituted ethyl, and still more preferably WO 01/57013 PCT/US01/03624 14 unsubstituted ethyl. While R 1 , is selected from among these, in one embodiment

X

3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or 5 heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R1Oa and X 3 are selected from among these, in one embodiment X. is selected from -COX 1 0 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R10a and X 3 are selected from among these, in one embodiment X 5 is selected from -COX 10 wherein X 1 0 is phenyl, alkyl or 10 heterocyclo, more preferably phenyl, or X. is -C00X 10 wherein X 1 0 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X. is -COOX 1 0 wherein X 1 0 is tert-butyi or X 5 is -COX 1 wherein X 1 0 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably 15 substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R 7 a is unsubstituted ethyl or propyl, more preferably ethyl. Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R 1 is R1OaCOO- wherein R1Oa is ethyl. In this 20 embodiment, X 3 is preferably cycloalkyl, isobutenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X. is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or 25 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; Y- in han7nvI allenvxnrhnrA nr hotornemnorhnurnnre nrafarnhilu hn,~i + WO 01/57013 PCT/USO1/03624 15 hydroxy and R 14 is hydroxy. In another alternative of this embodiment, X is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is hydroxy and R, 4 is hydrido. In another 5 alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more 10 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and Rio may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration, R 7 may have the alpha stereochemical 15 configuration while R 1 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R,, has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R,, is R1OaCOO- wherein ROa is propyl. In this 20 embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X, is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is 25 benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R 14 is hydrido. In another alternative of this embodiment,

X

3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t 30 butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R 14 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; 35 X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is WO 01/57013 PCT/USO1/03624 16 benzoyl, R. is hydroxy and R1 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is 5 hydroxy and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or 10 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbony; R 2 is benzoyl, R. is acyloxy and R 14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R1 0 may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration, 15 R 7 may have the alpha stereochemical configuration while R 1 0 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 1 0 has the alpha stereochemical configuration. C10 Carbarmates In one embodiment, R 1 0 is RlOaRlObNCOO- wherein R1Oa and R1b are 20 independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. Exemplary preferred R10 substituents include RIOaRIObNCOO- wherein (a) R1Oa and RIb are each hydrogen, (b) one of R1Oa and RiOb is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted 25 C2 to C alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, or (c) Roa and R1Ob are 30 independently (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or 35 hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or WO 01/57013 PCT/USO1/03624 17 unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R 1 substituents include RlOaRlObNCOO- wherein one of R1a and RiOb is hydrogen and the other is methyl, ethyl, or straight, branched or 5 cyclic propyl. In one of the preferred embodiments, the taxanes of the present invention correspond to structure (2):

X

5 NH 0 R1O 0 0 X3 -. 0 O, , R OH HO J 0 AcO (2) 10 wherein

R

7 is hydroxy;

R

1 is carbamoyloxy;

X

3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; 15 X. is -COX 10 , -C00X 10 , or -CONHX 10 ; and

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R 1 0 may be R1OaRiObNCOO- wherein one of R1 0 a and R1Ob is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl 20 such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substituted phenyl such as nitro, 25 alkoxy or halosubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R 1 0 substituents include RIOaRIObNCOO- wherein one of R10a and ROb is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted 30 methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, WO 01/57013 PCT/US01/03624 18 preferred R 1 0 substituents include R1OaRlObNCOO- wherein one of R1 0 a and R1ob is hydrogen and the other is substituted or unsubstituted phenyl or heterocyclo. While Rio and RiOb are selected from among these, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, 5 more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R10a, Riob, and X 3 are selected from among these, in one embodiment X, is selected from -COX 1 0 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, 10 while RiOa, Rjob, and X 3 are selected from among these, in one embodiment X. is selected from -COX 1 0 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -C00X 10 wherein X 1 0 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X 5 is -COOX 1 0 wherein X 1 0 is tert-butyl or X, is -COX 1 0 wherein X 1 0 is 15 phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R 1 0 is R1OaRiObNCOO-, one of R1Oa and R1Ob is hydrogen and the other is substituted or unsubstituted substituted or unsubstituted C1 to C. alkyl, 20 phenyl or heterocyclo. Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R 1 0 is R1OaRIObNCOO- wherein RIOa is methyl and ROb is hydrido. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably 25 heterocyclo, still more preferably furyl, thienyl or pyridyl; and X, is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t 30 butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; 35 X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyi, still more preferably t-butoxycarbony; R 2 is WO 01/57013 PCT/USO1/03624 19 benzoyl, R. is keto and R, 4 is hydroxy. In another alternative of this embodiment,

X

3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is hydroxy and R 14 is hydroxy. In another 5 alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more 10 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is acyloxy and RM is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbony, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is 15 acyloxy and R 14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R,, may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 0 has the beta stereochemical configuration or R 7 may have the beta stereochemical 20 configuration while R 1 0 has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R 1 0 is R1OaRIObNCOO- wherein R1Oa is ethyl and ROb is hydrido. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably 25 heterocyclo, still more preferably furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t 30 butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R, is keto and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; 35 X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbony; R 2 is WO 01/57013 PCT/USO1/03624 20 benzoyl, R. is keto and R 14 is hydroxy. In another alternative of this embodiment,

X

3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R, 4 is hydroxy. In another 5 alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbony; R 2 is benzoyl, R. is hydroxy and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more 10 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X. is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is 15 acyloxy and R 14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 0 may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 , has the beta stereochemical configuration or R 7 may have the beta stereochemical 20 configuration while R 1 has the alpha stereochemical configuration. C10 Heterosubstituted Acetates In one embodiment, R 1 is R 10 aC(O)O- wherein Ri0a is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R1 0 a is a substituent. The 25 heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, 30 thiol, ketals, acetals, esters or ether moiety. Exemplary R1 0 substituents include R1OaCOO- wherein RiOa is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl. In one of the preferred embodiments, the taxane corresponds to structure 1, X 5 is -COX 10 wherein X 1 0 is phenyl or -COOX 1 0 wherein X 1 0 is t-butoxycarbonyl, 35 and R 1 is R10aC(O)0- wherein Rjea is alkoxymethyl, preferably methoxymethyl or WO 01/57013 PCT/US01/03624 21 ethoxymethyl. In another embodiment of the present invention the taxane corresponds to structure 1, X. is -COX,, wherein X 1 0 is phenyl or -COOX,o wherein X 1 0 is t-butoxycarbonyl, and R 1 0 is R1OaC(O)O- wherein RIO, is acyloxymethyl, preferably acetoxymethyl. 5 In another embodiment of the present invention, the taxane corresponds to structure 1, X 5 is -COX 1 wherein X 1 0 is phenyl or -C00X 10 wherein X 1 0 is t butoxycarbonyl, R 1 is R1 0 aC(O)O- wherein Ria is alkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl, and X 3 is heterocyclo. In another embodiment of the present invention the taxane 10 corresponds to structure 1, X. is -COX 1 0 wherein X 1 0 is phenyl or -C00X 10 wherein X 1 0 is t-butoxycarbonyl, and RIO is R1OaC(O)O- wherein Rjoa is acyloxymethyl, preferably acetoxymethyl, and X. is heterocyclo. In another embodiment, the taxanes correspond to structure (2):

X

5 NH 0 R 10 0 X3__O I OR7 OH HO BzOAc 0 (2) 15 wherein

R

7 is hydroxy; RIO is heterosubstituted acetate;

X

3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; 20 X. is -COX 10 , -COOX 10 , or -CONHX 1 ; and

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R 1 is R10aCOO- wherein R10a is heterosubstituted methyl, more preferably heterosubstituted methyl wherein the heterosubsituents are selected 25 from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atoms, still more preferably heterosubstituted methyl wherein the heterosubstituent is alkoxy or acyloxy. While R 10 a is selected from among these, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, WO 01/57013 PCT/USO1/03624 22 phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While RiOa and X. are selected from among these, in one embodiment X, is selected from -COX 1 0 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably 5 phenyl. Alternatively, while RI 0 and X 3 are selected from among these, in one embodiment X, is selected from -COX 1 wherein Xic is phenyl, alkyl or heterocyclo, more preferably phenyl, or X, is -COOXI 0 wherein X 1 0 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X. is -C00X 10 wherein X 1 O is 10 tert-butyl or X 5 is -COXI 0 wherein X 1 0 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R 1 is alkoxyacetyl aryloxyacetyl, or acyloxyacetyl. 15 C7 Carbonates In one embodiment, R 7 is R 7 aOCOO- wherein R 7 a is (i) substituted or unsubstituted C1 to C alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or 20 hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heterocyclo such as furyl, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing substituents identified elsewhere herein for substituted hydrocarbyl. In 25 a preferred embodiment, R 7 a is methyl, ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. In another embodiment, R 7 a is substituted ethyl, substituted propyl (straight, branched or cyclic), substituted propenyl (straight or branched), substituted isobutenyl, substituted furyl or 30 substituted thienyl wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties. In one of the preferred embodiments, the taxanes of the present invention 35 correspond to structure (2): WO 01/57013 PCT/USO1/03624 23

X

5 NH O R1o _ 0 OH Oil. HO BzO0 AcO (2) wherein

R

7 is carbonate;

R

1 0 is hydroxy; 5 X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X. is -COX 1 0 , -C00X 10 , or -CONHXI 0 ; and

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to 10 structure (2), R 7 may be R 7 aOCOO- wherein R 7 , is substituted or unsubstituted methyl, ethyl, propyl, butyl, pentyl or hexyl, more preferably substituted or unsubstituted methyl, ethyl or propyl, still more preferably substituted or unsubstituted methyl, ethyl, and still more preferably unsubstituted methyl or ethyl. While R 7 , is selected from among these, in one embodiment X 3 is selected 15 from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R 7 , and X 3 are selected from among these, in one embodiment X 5 is selected from -COX 1 0 20 wherein X1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R7. andX are selected from among these, in one embodiment X, is selected from -COX 1 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X. is -COOX 1 0 wherein X 1 0 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in 25 which (i) X 5 is -COOX1 0 wherein X 1 0 is tert-butyl or X. is -COX 1 0 wherein X 1 0 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R 7 a is unsubstituted methyl, ethyl or propyl, more preferably 30 methyl or ethyl.

WO 01/57013 PCT/US01/03624 24 Among the preferred embodiments, therefore, are taxanes corresponding to structure I or 2 wherein R 7 is R 7 ,OCOO- wherein R 7 a is methyl. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more 5 preferably furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 10 benzoyl, R. is keto and R 14 is hydrido. In another alternative of this embodiment,

X

3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or 15 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo;

X

5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 20 benzoyl, R. is hydroxy and R 14 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R, 4 is hydrido. In another alternative of this embodiment, X 3 is 25 heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 30 amyloxycarbonyl, still more preferably t-butoxycarbony; R 2 is benzoyl, R. is acyloxy and R, 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and RIO may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 has the beta 35 stereochemical configuration or R 7 may have the beta stereochemical configuration while R 1 0 has the alpha stereochemical configuration.

WO 01/57013 PCT/US01/03624 25 Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R 7 is R 7 .OCOO- wherein R 7 a is ethyl. In this embodiment,

X

3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably 5 furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 10 benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment,

X

3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or 15 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R 14 is hydroxy. In another alternative of this embodiment, X. is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 20 benzoyl, R. is hydroxy and R 14 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R, 4 is hydrido. In another alternative of this embodiment, X 3 is 25 heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 30 amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R 1 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 0 may each have the beta stereochemical configuration, R 7 and RIO may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 0 has the beta 35 stereochemical configuration or R 7 may have the beta stereochemical configuration while R,, has the alpha stereochemical configuration.

WO 01/57013 PCT/USO1/03624 26 Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R 7 is R 7 aOCOO- wherein R 7 , is propyl. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more 5 preferably furyl, thienyl or pyridyl; and X. is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbony; R 2 is 10 benzoyl, R. is keto and R 14 is hydrido. In another alternative of this embodiment,

X

3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or 15 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R 14 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo;

X

5 is benzoyl, alkoxycarbonyl, or heterocyclocarbony, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 20 benzoyl, R 9 is hydroxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R, 4 is hydrido. In another alternative of this embodiment, X 3 is 25 heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is acyloxy and R 14 is hydroxy. In another alternative of this embodiment, X. is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 30 amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R1 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R- and R 1 0 may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 0 has the beta 35 stereochemical configuration or R 7 may have the beta stereochemical configuration while Rio has the alpha stereochemical configuration.

WO 01/57013 PCT/USO1/03624 27 C7 Ester In one embodiment, R 7 is R 7 ,COO- wherein R 7 , is (i) substituted or unsubstituted C2 to C alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl (straight, 5 branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing 10 substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred embodiment, R 7 a is ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic pentyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. In another embodiment, R 7 , is substituted ethyl, substituted propyl (straight, branched or 15 cyclic), substituted propenyl (straight or branched), substituted isobutenyl, substituted furyl or substituted thienyl wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties. 20 In one of the preferred embodiments, the taxanes of the present invention correspond to the following structural formula (2):

X

5 NH O R 10 0 X3 :oil, OH /' HO . AcO (2) wherein

R

7 is R 7 .COO-; 25 R 1 is hydroxy;

X

3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo; X, is -COX 1 O, -C00X 10 , or -CONHX 1 0 ;

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; WO 01/57013 PCT/USO1/03624 28

R

7 a is hydrocarbyl, substituted hydrocarbyl, or heterocyclo wherein said hydrocarbyl or substituted hydrocarbyl contains carbon atoms in the alpha and beta positions relative to the carbon of which R, is a substituent; Bz is benzoyl; and 5 Ac is acetyl. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R 7 a may be substituted or unsubstituted ethyl, propyl or butyl, more preferably substituted or unsubstituted ethyl or propyl, still more preferably substituted or unsubstituted ethyl, and still more preferably unsubstituted ethyl. 10 While R 7 a is selected from among these, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While R 7 a and X 3 are selected from 15 among these, in one embodiment X 5 is selected from -COX 10 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R 7 a and

X

3 are selected from among these, in one embodiment X 5 is selected from -COX 10 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X, is -C00X 1 0 wherein X 10 is alkyl, preferably t-butyl. Among the more preferred 20 embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X 5 is -COOX 10 wherein X 1 0 is tert-butyl or X. is -COX 1 0 wherein X 1 0 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and 25 (iii) R 7 a is unsubstituted ethyl or propyl, more preferably ethyl. Among the preferred embodiments, therefore, are taxanes corresponding to structure I or 2 wherein R 7 is R 7 aCOO- wherein R 7 a is ethyl. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more 30 preferably furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 35 benzoyl, R 9 is keto and R 14 is hydrido. In another alternative of this embodiment,

X

3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more WO 01/57013 PCT/US01/03624 29 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X. is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 5 amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R1 4 is hydroxy. In another alternative of this embodiment, X. is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R 14 is hydroxy. In another alternative of this 10 embodiment, X. is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and RU is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more 15 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is 20 acyloxy and R, 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 0 may each have the beta stereochemical configuration, R 7 and R 1 0 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 has the beta stereochemical configuration or R 7 may have the beta stereochemical 25 configuration while R 1 has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R 7 is R 7 aCOO- wherein R 7 a is propyl. In this embodiment,

X

3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably 30 furyl, thienyl or pyridyl; and X 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl. In one alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is 35 benzoyl, R. is keto and RU is hydrido. In another alternative of this embodiment,

X

3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more WO 01/57013 PCT/US01/03624 30 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is keto and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t 5 amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R 14 is hydroxy. In another alternative of this 10 embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more 15 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is 20 acyloxy and R 14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 10 may each have the beta stereochemical configuration, R 7 and R 1 may each have the alpha stereochemical configuration,

R

7 may have the alpha stereochemical configuration while R 1 0 has the beta stereochemical configuration or R 7 may have the beta stereochemical 25 configuration while R 1 has the alpha stereochemical configuration. C7 Carbamates In one embodiment, R 7 is R 7

,R

7 bNCOO- wherein R 7 a and R 7 b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. Exemplary preferred R 7 substituents include R 7 aR 7 bNCOO- wherein (a) R 7 a and 30 R 7 b are each hydrogen, (b) one of R 7 a and R 7 b is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as 35 ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; WO 01/57013 PCT/USO1/03624 31 (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, or (c) Rya and Ryb are independently (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or 5 unsubstituted C2 to C alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents 10 may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R 7 substituents include R 7 aR 7 bNCOO- wherein one of R 7 a and R 7 b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl. In one of the preferred embodiments, the taxanes of the present invention 15 correspond to structure (2):

X

5 NH 0 R1o 0 X3 g O OH HO B zOAc5 O Aco (2) wherein

R

7 is carbamoyloxy; R1 0 is hydroxy; 20 X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo; X, is -COX 1 0 , -COOX 10 , or -CONHXIO; and

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R 7 may be R 7

,R

7 bNCOO- wherein one of R 7 a and R 7 b is hydrogen 25 and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 WO 01/57013 PCT/US01/03624 32 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substituted phenyl such as nitro, alkoxy or halosubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted 5 hydrocarbyl. In one embodiment, preferred R 7 substituents include R 7

,R

7

NCOO

wherein one of R 7 , and R 7 b is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R 7 substituents include

R

7

,R

7 bNCOO- wherein one of R 7 , and R 7 b is hydrogen and the other is substituted 10 or unsubstituted phenyl or heterocyclo. While R 7 and R 7 b are selected from among these, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or heterocyclo, and still more preferably heterocyclo such as furyl, thienyl 15 or pyridyl. While R 7 a, Ryb, and X 3 are selected from among these, in one embodiment X, is selected from -COX 1 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R 7 ., R 7 b, and X 3 are selected from among these, in one embodiment X 5 is selected from -COX 1 0 wherein X1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X. is 20 -COOX 10 wherein X 1 0 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X 5 is -COOX 10 wherein X 1 0 is tert-butyl or X. is -COX 10 wherein X 1 0 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, 25 still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R 7 is

R

7 aR 7 bNCOO-, one of R 7 a and R 7 b is hydrogen and the other is substituted or unsubstituted C 1 to C8 alkyl, phenyl or heterocyclo. Among the preferred embodiments, therefore, are taxanes corresponding to structure I or 2 wherein R 7 is R 7 aR 7 bNCOO- wherein R 7 a is methyl and R 7 b is 30 hydrido. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X. is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X 3 is 35 heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- WO 01/57013 PCT/US01/03624 33 butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R 1 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto 5 and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo;

X

5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R 9 is keto and R 1 is hydroxy. In another alternative of this embodiment,

X

3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more 10 preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R 1 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is 15 hydroxy and R1 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X, is benzoyl, alkoxycarbonyl, or 20 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R 1 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 0 may each have the beta stereochemical configuration, R 7 and R 1 may each have the alpha stereochemical configuration, 25 R 7 may have the alpha stereochemical configuration while R 1 0 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 1 has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R 7 is R 7 aR 7 bNCOO- wherein R 7 a is ethyl and Ryb is 30 hydrido. In this embodiment, X 3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X. is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X 3 is 35 heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- WO 01/57013 PCT/US01/03624 34 butoxycarbonyl; R 2 is benzoyl, R. is keto and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto 5 and R, 4 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo;

X

5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is keto and R 14 is hydroxy. In another alternative of this embodiment,

X

3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more 10 preferably benzoyl, t-butoxycarbony or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R. is hydroxy and R 14 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is 15 hydroxy and R 14 is hydrido. In another alternative of this embodiment, X 3 is heterocyclo; X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t butoxycarbonyl; R 2 is benzoyl, R 9 is acyloxy and R 14 is hydroxy. In another alternative of this embodiment, X 3 is heterocyclo; X. is benzoyl, alkoxycarbonyl, or 20 heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t amyloxycarbonyl, still more preferably t-butoxycarbonyl; R 2 is benzoyl, R. is acyloxy and R, 4 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R 7 and R 1 0 may each have the beta stereochemical configuration, R 7 and R 1 may each have the alpha stereochemical configuration, 25 R 7 may have the alpha stereochemical configuration while R 1 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration. C7 Heterosubstituted Acetates In one embodiment, R 7 is R 7 C(O)O- wherein R 7 a is heterosubstituted 30 methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R 7 a is a substituent. The heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in 35 turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, WO 01/57013 PCT/US01/03624 35 alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R 7 substituents include

R

7 aCOO- wherein R 7 a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, or methylthiomethyl. 5 In one of the preferred embodiments, the taxane corresponds to structure 1, X 5 is -COX 1 wherein X 1 0 is phenyl or -C00X 1 0 wherein X 1 0 is t-butoxycarbonyl, and R 7 is R 7 aC(O)O- wherein R 7 a is alkoxymethyl, preferably methoxymethyl or ethoxymethyl. In another embodiment of the present invention the taxane corresponds to structure 1, X 5 is -COX1 0 wherein X 1 0 is phenyl or -C00X 1 0 10 wherein X1 0 is t-butoxycarbonyl, and R 7 is R 7 aC(O)O- wherein R 7 a is acyloxymethyl, preferably acetoxymethyl. In another embodiment of the present invention, the taxane corresponds to structure 1, X 5 is -COX 1 0 wherein X 1 0 is phenyl or -C00X 1 0 wherein X 1 0 is t butoxycarbonyl, R 7 is R 7 aC(0)O- wherein R 7 a is alkoxymethyl such as 15 methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl, and X 3 is heterocyclo. In another embodiment of the present invention the taxane corresponds to structure 1, X, is -COX 10 wherein X 1 0 is phenyl or -C00X 1 0 wherein X 1 0 is t-butoxycarbonyl, and R 7 is R 7 aC(0)O- wherein R 7 a is acyloxymethyl, preferably acetoxymethyl, and X 3 is heterocyclo. 20 In one preferred embodiment, the taxanes of the present invention correspond to structure (2):

X

5 NH 0 RIO 0 X3'11 0 I OR , OH '/ HO 0 Aco (2) wherein

R

7 is heterosubstituted acetate; 25 R 1 0 is hydroxy;

X

3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;

X

5 is -COX 1 0 , -C00X 1 0 , or -CONHX 1 ; and

X

1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

WO 01/57013 PCT/USO1/03624 36 For example, in this preferred embodiment in which the taxane corresponds to structure (2), R 7 may be R 7 aCOO- wherein R 7 a is heterosubstituted methyl, more preferably heterosubstituted methyl wherein the heterosubsituents are selected from the group consisting of nitrogen, oxygen, silicon, phosphorous, boron, sulfur, 5 or halogen atoms, still more preferably heterosubstituted methyl wherein the heterosubstituent is alkoxy or acyloxy. While R 7 a is selected from among these, in one embodiment X 3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted alkenyl, phenyl or heterocyclo, still more preferably substituted or unsubstituted phenyl or 10 heterocyclo, and still more preferably heterocyclo such as furyl, thienyl or pyridyl. While Rya and X3 are selected from among these, in one embodiment X. is selected from -COX 10 wherein X 1 0 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R 7 a and X 3 are selected from among these, in one embodiment X. is selected from -COX,, wherein X 1 0 is phenyl, alkyl or 15 heterocyclo, more preferably phenyl, or X, is -COOX 10 wherein X 1 0 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X. is -C00X 10 wherein X 1 0 is tert-butyl or X 5 is -COX1 0 wherein X 1 0 is phenyl, (ii) X 3 is substituted or unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, more preferably 20 substituted or unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R 7 is alkoxyacetyl or acyloxyacetyl. Taxanes having the general formula I may be obtained by treatment of a p-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 25 metallic oxide substituent to form compounds having a p-amido ester substituent at C(13), as described more fully in Holton U.S. Patent 5,466,834, followed by removal of the hydroxy protecting groups. Taxanes having C(10) carbonates may be prepared from 10 deacetylbaccatin IlIl by selective formation of a carbonate of the C-10 hydroxyl 30 group and then protection of the C-7 hydroxyl group (as described more fully in Holton et al., PCT Patent Application WO 99/09021, followed by treatment with a metallic amide. Acylating agents which may be used for the selective acylation of the C(10) hydroxyl group of a taxane include dimethyldicarbonate, diethyldicarbonate, di-t-butyldicarbonate, dibenzyldicarbonate and the like. While 35 the acylation of the C(10) hydroxy group of the taxane will proceed at an adequate rate for many acylating agents, it has been discovered that the reaction WO 01/57013 PCT/USO1/03624 37 rate may be increased by including a Lewis acid in the reaction mixture. Preferred Lewis acids include zinc chloride, stannic chloride, cerium trichloride, cuprous chloride, lanthanum trichloride, dysprosium trichloride, and ytterbium trichloride. Zinc chloride or cerium trichloride is particularly preferred when the 5 acylating agent is a dicarbonate. Taxanes having C(10) esters may be prepared from 10-deacetylbaccatin Ill (or a derivative thereof) by selective protection of the C(7) hydroxyl group and then esterification of the C(10) hydroxyl group followed by treatment with a metallic amide. The C(7) hydroxyl group of 10-deacetylbaccatin Ill, for example, 10 may be selectively protected with a silyl group as described, for example, by Denis, et. al. (J. Am. Chem. Soc., 1988, 110, 5917). In general, the silylating agents may be used either alone or in combination with a catalytic amount of a base such as an alkali metal base. Taxanes having C(10) carbamates may be prepared from 10 15 deacetylbaccatin Ill by protecting the C-7 and C-10 hydroxyl groups of a taxane (as described more fully in Holton et al., PCT Patent Application WO 99/09021), coupling the protected alkoxide with the p-lactam, selectively removing the C(7) and C(10) hydroxy protecting groups, and treating this product with an isocyanate in the presence of a Lewis acid. 20 Taxanes having C(7) carbonates may be prepared from 10 deacetylbaccatin Ill (or a derivative thereof) by selective protection of the C-10 hydroxyl group and then acylation of the C-7 hydroxyl group followed by treatment with a metallic amide. The C(10) hydroxyl group of 1 0-deacetylbaccatin Ill is then selectively protected with a silyl group using, for example, a silylamide 25 or bissilyamide as a silylating agent. Selective acylation of the C(7) hydroxyl group of a C(10) protected taxane to form a C(7) carbonate can be achieved using any of a variety of common acylating agents such as a haloformates. Taxanes having C(7) carbamates may be obtained by treatment of a 0 lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic 30 oxide substituent to form compounds having a 1-amido ester substituent at C(13), as described more fully in Holton U.S. Patent 5,466,834, followed by reaction with an isocyanate or a carbamoyl chloride, and removal of the hydroxy protecting groups. Taxanes having C(7) esters may be prepared from I 0-deacetylbaccatin Ill 35 (or a derivative thereof) by selective protection of the C-10 hydroxyl group and then esterification of the C-7 hydroxyl group followed by treatment with a metallic WO 01/57013 PCT/USO1/03624 38 amide. The C(10) hydroxyl group of 10-deacetylbaccatin III may be selectively protected with a silyl group using, for example, a silylamide or bissilyamide as a silylating agent. Selective esterification of the C(7) hydroxyl group of a C(10) protected taxane can be achieved using any of a variety of common acylating 5 agents including, but not limited to, substituted and unsubstituted carboxylic acid derivatives, e.g., carboxylic acid halides, anhydrides, dicarbonates, isocyanates and haloformates. Derivatives of 10-deacetylbaccatin IlIl having alternative substituents at C(2), C(9) and C(14) and processes for their preparation are known in the art. 10 Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Patent No. 5,728,725 or Kingston et al., U.S. Patent No. 6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Patent No. 6,011,056 or Gunawardana et al., U.S. 15 Patent No. 5,352,806. Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin Ill. Processes for the preparation and resolution of the P-lactam starting material are generally well known. For example, the p-lactam may be prepared as described in Holton, U.S. Patent No. 5,430,160 and the resulting enatiomeric 20 mixtures of P-lactams may be resolved by a stereoselective hydrolysis using a lipase or enzyme as described, for example, in Patel, U.S. Patent No. 5,879,929 Patel U.S. Patent No. 5,567,614 or a liver homogenate as described, for example, in PCT Patent Application No. 00/41204. Compounds of formula 1 of the instant invention are useful for inhibiting 25 tumor growth in mammals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the instant invention in combination with at least one pharmaceutically or pharmacologically acceptable carrier. The carrier, also known in the art as an excipient, vehicle, auxiliary, adjuvant, or diluent, is any 30 substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the antitumor compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate. 35 The pharmaceutical compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper WO 01/57013 PCT/USO1/03624 39 formulation is dependent upon the route of administration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, 5 intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, 10 endoscopical, transmucosal, sublingual and intestinal administration. Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, 15 disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable carriers are readily determined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack Publishing Co., Easton, Pa., (1985), pp. 1492-1517, the contents of which are incorporated herein 20 by reference). The compositions are preferably formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, syrups, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally. Techniques and compositions for 25 making oral dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976). 30 The compositions of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, 35 calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, WO 01/57013 PCT/USO1/03624 40 microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption. 5 The antitumor compounds of the present invention are also preferably formulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal routes. The compositions of the invention for parenteral administration comprise an effective 10 antitumor amount of the antitumor compound in a pharmaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art. 15 Suitable carriers used in formulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptable polar solvents such as oils, alcohols, amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, as well as water, saline solutions, dextrose solutions (e.g., DW5), electrolyte solutions, or any other aqueous, pharmaceutically acceptable 20 liquid. Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol formal, P-glycerol formal, 1, 3 butyleneglycol, aliphatic or aromatic alcohols having 2-30 carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol, t-butanol, hexanol, octanol, 25 amylene hydrate, benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(p 30 hydroxyethyl)-lactamide, N, N-dimethylacetamide-amides, 2-pyrrolidinone, 1 -methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., I -methyl-2 pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of 35 glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, WO 01/57013 PCT/USO1/03624 41 fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, or tri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N methyl pyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesters such 5 as poly(ethoxylated) 3060 sorbitol poly(oleate) 24 , poly(oxyethylene) 1 5

-

2 0 monooleate, poly(oxyethylene) 1 5

-

2 0 mono 1 2-hyd roxystearate, and poly(oxyethylene) 1

.

2 0 mono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate@ 20, 40, 10 60 or 80 from IC Americas, Wilmington, DE, polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor@ EL solution or Cremophor@ RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a monosaccharide (e.g., pentoses such as ribose, ribulose, arabinose, xylose, 15 lyxose and xylulose, hexoses such as glucose, fructose, galactose, mannose and sorbose, trioses, tetroses, heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose) or oligosaccharide or mixture thereof with a C4_ C22 fatty acid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such 20 as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyl ether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobuty 25 ketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral, vegetable, animal, essential or synthetic 30 origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil; vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil and glycerides such as mono-, di- or triglycerides, animal 35 oils such as fish, marine, sperm, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1- WO 01/57013 PCT/USO1/03624 42 30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 5 12-hydroxystearic acid and polyethylene glycol (Solutol@ HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate. Other pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The 10 Chemotherapy Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excipients, (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modern Pharmaceutics, (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basis of Therapeutics, (Goodman & 15 Gilman, McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds., )(Marcel Dekker, Inc., New York, New York, 1980), Remington's Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, PA, 1995), The United States Pharmacopeia 24, The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), A.J. Spiegel et al., and Use of 20 Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963). Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified fatty acid esters such as 25 polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor@ EL solution or Cremophor@ RH 40 solution). Commercially available triglycerides include Intralipid@ emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid @ emulsion (McGaw, Irvine, California), Liposyn@ 1120% emulsion (a 20% fat emulsion solution containing 100 mg 30 safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), Liposyn@ 1I1 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), natural or synthetic glycerol derivatives 35 containing the docosahexaenoyl group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco@ (from Martek Biosciences WO 01/57013 PCT/USO1/03624 43 Corp., Columbia, MD), DHA Maguro@ (from Daito Enterprises, Los Angeles, CA), Soyacal@, and Travemulsion@. Ethanol is a preferred solvent for use in dissolving the antitumor compound to form solutions, emulsions, and the like. Additional minor components can be included in the compositions of the 5 invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of 10 these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total composition, as is well known in the formulation art. Such additives include 15 cryoprotective agents for preventing reprecipitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents 20 (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g., bentonites), adhesives, 25 bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, or sorbitol, cellulose, or calcium phosphate), diluents (e.g., water, saline, electrolyte solutions), binders (e.g., starches such as maize starch, wheat starch, rice starch, or potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, 30 polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g., starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or salts thereof such as magnesium 35 stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, WO 01/57013 PCT/USO1/03624 44 polyethylene glycol, or titanium dioxide), and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, and thiophenols). In a preferred embodiment, a pharmaceutical composition of the invention 5 comprises at least one nonaqueous, pharmaceutically acceptable solvent and an antitumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being bound to a particular theory, it is believed that the ethanol solubility of the antitumor compound may be directly related to its efficacy. The antitumor compound can also be capable of being 10 crystallized from a solution. In other words, a crystalline antitumor compound, such as compound 1393, can be dissolved in a solvent to form a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound. It is also preferred that the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% 15 inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measured according to the protocol set forth in the working examples. Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, 20 whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner. Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill in treating cancer. It is understood that the dosage of the antitumor 25 compounds will be dependent upon the age, sex, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of antitumor compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on 30 such factors as the bioavailability of the antitumor compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time. 35 Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired WO 01/57013 PCT/US01/03624 45 therapeutic response when administered by that route. Preferably, the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m 2 of patient body surface area, or at least 50, 100, 150, 200, 300, 5 400, or 500 mg of the antitumor compound per m 2 Of patient body surface area, wherein the average body surface area for a human is 1.8 M 2 . Preferably, a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m 2 of patient body surface area, more preferably from about 25 to about 400 mg/m 2 , even more preferably, from 10 about 40 to about 300 mg/m 2 , and even more preferably from about 50 to about 200 mg/m 2 . Preferably, the compositions for parenteral administration are prepared in such a way that a single dose contains at least 20 mg of the antitumor compound per m 2 of patient body surface area, or at least 40, 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m 2 of patient body 15 surface area. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m 2 Of patient body surface area, more preferably from about 40 to about 400 mg/m 2 , and even more preferably, from about 60 to about 350 mg/m 2 . However, the dosage may vary depending on the dosing schedule which can be adjusted as 20 necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose ranges. The most preferred dosage will be tailored to the individual subject, as is understood and determinable by one of ordinary skill in the art without undue experimentation. 25 The concentration of the antitumor compound in a liquid pharmaceutical composition is preferably between about 0.01 mg and about 10 mg per ml of the composition, more preferably between about 0.1 mg and about 7 mg per ml, even more preferably between about 0.5 mg and about 5 mg per ml, and most preferably between about 1.5 mg and about 4 mg per ml. Relatively low 30 concentrations are generally preferred because the antitumor compound is most soluble in the solution at low concentrations. The concentration of the antitumor compound in a solid pharmaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total weight of the composition, more preferably between about 8 weight % and about 35 40 weight %, and most preferably between about 10 weight % and about 30 weight %.

WO 01/57013 PCT/USO1/03624 46 In one embodiment, solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as 5 Cremophor@ EL solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol, which is known in the art to cause adverse physiological effects when administered at certain concentrations in oral formulations. 10 In another embodiment, powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g.,ethanol or methylene chloride) to form a solution. The solvent can optionally be capable of 15 evaporating when the solution is dried under vacuum. An additional carrier can be added to the solution prior to drying, such as Cremophor@ EL solution. The resulting solution is dried under vacuum to form a glass. The glass is then mixed with a binder to form a powder. The powder can be mixed with fillers or other conventional tabletting agents and processed to form a tablet for oral 20 administration to a patient. The powder can also be added to any liquid carrier as described above to form a solution, emulsion, suspension or the like for oral administration. Emulsions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of 25 dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is an emulsion, such as Liposyn@ II or Liposyn@ IllI emulsion, is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient. If desired, such emulsions can be formulated to contain a minimal amount of, or 30 to be free of, ethanol or Cremophor@ solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations. Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of 35 dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor@ WO 01/57013 PCT/USO1/03624 47 solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor@ solution, which are known in the art to cause adverse 5 physiological effects when administered at certain concentrations in parenteral formulations. If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any pharmaceutically acceptable liquid, 10 such as saline, to form an acceptable taxane concentration prior to use as is known in the art. Definitions The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and 15 hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms. 20 The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, 25 hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "heteroatom" shall mean atoms other than carbon and hydrogen. The "heterosubstituted methyl" moieties described herein are methyl groups in which the carbon atom is covalently bonded to at least one heteroatom 30 and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.

WO 01/57013 PCT/USO1/03624 48 The "heterosubstituted acetate" moieties described herein are acetate groups in which the carbon of the methyl group is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The 5 heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Unless otherwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal 10 chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl and the like. Unless otherwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or 15 cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like. Unless otherwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and 20 include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like. The terms "aryl" or "ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted 25 naphthyl. Phenyl and substituted phenyl are the more preferred aryl. The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine. The terms "heterocyclo" or "heterocyclic" as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, 30 monocyclic or bicyclic, aromatic or nonaromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygen atoms, I or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocyclo include 35 heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or WO 01/57013 PCT/USO1/03624 49 more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "heteroaromatic" as used herein alone or as part of another 5 group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics 10 include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinoliny, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. 15 The term "acyl," as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group --COOH of an organic carboxylic acid, e.g., RC(O)-, wherein R is R 1 , R 1 0-, R 1

R

2 N-, or R'S-, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl. 20 The term "acyloxy," as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (--0--), e.g., RC(O)O- wherein R is as defined in connection with the term "acyl." Unless otherwise indicated, the alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted 25 hydrocarbon moieties. Unless otherwise indicated, the carbamoyloxy moieties described herein are derivatives of carbamic acid in which one or both of the amine hydrogens is optionally replaced by a hydrocarbyl, substituted hydrocarbyl or heterocyclo moiety. 30 The terms "hydroxyl protecting group" and "hydroxy protecting group" as used herein denote a group capable of protecting a free hydroxyl group ("protected hydroxyl") which, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule. A variety of protecting groups for the hydroxyl group and the synthesis thereof may 35 be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser. Exemplary hydroxyl protecting groups WO 01/57013 PCT/USO1/03624 50 include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl. 5 As used herein, "Ac" means acetyl; "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "Pr" means propyl; "iPr" means isopropyl; "Bu" means butyl; "Am" means amyl; "Cpro" means cyclopropyl; "tBu" and "t-Bu" means tert-butyl; "R" means lower alkyl unless otherwise defined; "Py" means pyridine or pyridyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "LAH" 10 means lithium aluminum hydride; "10-DAB" means 10-desacetylbaccatin Ill"; "amine protecting group" includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; "protected hydroxy" means OP wherein P is a hydroxy protecting group; "PhCO" means phenylcarbonyl; "tBuOCO" and "Boc" mean tert-butoxycarbonyl; "tAmOCO" means tert 15 amyloxycarbonyl; "2-FuCO" means 2-furylcarbonyl; "2-ThCO" means 2 thienylcarbonyl; "2-PyCO" means 2-pyridylcarbonyl; "3-PyCO" means 3 pyridylcarbonyl; "4-PyCO" means 4-pyridylcarbonyl; "C 4 HCO" means butenylcarbonyl; "tC 3 HCO" means trans-propenylcarbonyl; "EtOCO" means ethoxycarbonyl; "ibueCO" means isobutenylcarbonyl; "iBuCO" means 20 isobutylcarbonyl; "iBuOCO" means isobutoxycarbonyl; "iPrOCO" means isopropyloxycarbonyl; "nPrOCO" means n-propyloxycarbonyl; "nPrCO" means n propylcarbonyl; "ibue" means isobutenyl; "THF" means tetrahydrofuran; "DMAP" means 4-dimethylamino pyridine; "LHMDS" means Lithium HexamethylDiSilazanide. 25 The term "storage stable composition" as used herein is a composition which, after storage at room temperature for one year and dilution prior to use, is suitable for administration to a patient and is cytotoxically active. The following examples illustrate the invention.

WO 01/57013 PCT/USO1/03624 51 Example 1: Preparation of Taxane having C-7 Ester and C-10 Hydroxy Substituents HO O OTES TESO OH NTES - OH HO'" N, HO"~ LHMDS BzOAc 0 BzO c o 10-Triethylsilyl-10-deacetyl baccatin Ill. To a solution of 1.0 g (1.84 mmol) of 5 10-deacetyl baccatin Ill in 50 mL of THF at -10 0C under a nitrogen atmosphere was added 0.857 mL (2.76 mmol, 1.5 mol equiv) of NO-(bis)-TES trifluoroacetamide over a period of 3 min. This was followed by the addition of 0.062 mL of a 0.89 M THF solution of lithium bis(trimethylsilyl)amide (0.055 mmol, 0.03 mol equiv). After 10 min 0.038 mL (0.92 mmol, 0.5 mol equiv) of methanol 10 was added, and after an additional 5 min 4 mL (0.055 mmol, 0.03 mol equiv) of acetic acid was added. The solution was diluted with 300 mL of ethyl acetate and washed two times with 100 mL of saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with 100 mL of ethyl acetate and the combined organic layers were washed with brine, dried over 15 sodium sulfate, and concentrated under reduced pressure. To the residue was added 100 mL of hexane and the solid (1.23 g, 101%) was collected by filtration. Recrystallization of the solid by dissolving in boiling ethyl acetate (20 mL, 17 mL/g) and cooling to room temperature gave 1.132 g (94%) of a white solid. m.p. 242 0C; [a]D 25 -60.4 (c 0.7, CHCl 3 ); 'H NMR (CDC 3 , 400MHz) 5 (p.p.m): 8.10 (2H, 20 d, Jm = 7.5Hz, Bzo), 7.60 (1H, t, Jm = 7.5Hz, Bzp), 7.47 (2H, t, Jo = 7.5Hz, Bzm), 5.64 (1H, d, J3 = 6.9Hz, H2), 5.26 (1H, s, H10), 4.97 (1H, dd, J6p = 2.2Hz, J6a =9.9Hz, H5), 4.85 (1H, dd, J14a =8.9Hz, J14p = 8.9Hz, H13), 4.30 (1H, d, J20P =8.5Hz, H20a), 4.23 (1H, ddd, J70H = 4.5Hz, J6a = 6.6Hz, J6p = 11.0Hz, H7), 4.15 (1H, d, J20oa =8.5Hz, H20P), 4.00 (1H, d, J2 = 6.9Hz, H3), 2.58 (1H, 25 ddd, J7 = 6.6Hz, J5 = 9.9Hz, J6P = 14.5Hz, H6a), 2.28-2.25 (5H, m, 4Ac, H14a, H14p1), 2.02 (3H, s, 18Me), 1.97 (1H, d, J7 = 4.5Hz, H70H), 1.78 (1H, ddd, J7 = 11.0Hz, J5 = 2.2Hz, J6a = 14.5Hz, H6P), 1.68 (3H, s, 19Me), 1.56 (1H, s, OH1), 1.32 (1H, d, J13 = 8.8Hz, OH13 ), 1.18 (3H, s, 17Me), 1.06 (3H, s, 16Me), 0.98 (9H, t, JCH 2 (TES) = 7.3Hz, CH 3 (TES)), 0.65 (6H, dq, JCH 3 (TES) = 30 7.3Hz, CH 2

(TES)).

WO 01/57013 PCT/USO1/03624 52 TESO O TESO -- OH CH 3

CH

2 COCI H H & BzAcO BzOAc 0 10-Triethylsilyl-10-deacetyl-7-propionyl baccatin Ill. To a solution of 1.0 g (1.517 mmol) of 10-triethylsilyl-10-deacetyl baccatin Ill and 37.0 mg (0.303 mmol) of DMAP in 20 mL of dichloromethane at room temperature under a nitrogen atmosphere was added 0.920 mL (11.381 mmol) of pyridine and 0.329 mL (3.794 5 mmol, 2.5 mol equiv) of propionyl chloride in that order. The mixture was stirred at room temperature for 6 h, diluted with 350 mL of ethyl acetate and extracted with 50 mL of 10% aqueous copper sulfate solution. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution, 50 mL of brine, dried over sodium sulfate and concentrated under reduced pressure. The 10 crude product was dissolved in 75 mL of ethyl acetate, 100 mg of Norit A was added, the mixture was filtered through celite and concentrated under reduced pressure to give 1.13 g of material. Recrystallization from ethyl acetate/hexanes (dissolved in 6.5 mL of refluxing ethyl acetate, then 24 mL of hexanes added, allowed to cool to room temperature, and left to stand for 17 h) afforded 787 mg 15 (72.5%) of a white crystalline solid. A second recrystallization (ca 340 mg material dissolved in 2 mL of refluxing ethyl acetate, then 10 mL of hexanes added, allowed to cool to room temperature, and allowed to stand for 17 h) afforded 181 mg (16.7 %) of a white crystalline solid. The combined yield after recrystallization was 89.2%. m.p. 129 "C; [a]D 25 -47.9 (c 1.0, CHC 3 ); NMR 'H (CDCI 3 , 300MHz) 6 20 (ppm): 8.10 (2H, d, Jm = 7.4Hz, Bzo), 7.60 (1H, t, Jm = 7.4Hz, Bzp), 7.48 (2H, dd, Jo = 7.4Hz, Jp = 7.4Hz, Bzm), 5.64 (1H, d, J3 = 7.4Hz, H2), 5.47 (1H, dd, J6a = 7.4Hz, J6P = 10.1Hz, H7), 5.28 (1H, s, H10), 4.94 (1H, d, J6a = 9.4Hz, H5), 4.80 - 4.90 (1H, m, H13), 4.31 (1H, d, J200 = 8.1Hz, H20a), 4.16 (1H, d, J20a = 8.1Hz, H20P), 4.06 (1H, d, J2 = 7.4Hz, H3), 2.55 (1H, ddd, J7 = 7.4Hz, J5 25 = 9.4Hz, J60 = 14.8Hz, H6a), 2.28 (3H, s, 4Ac), 2.23 - 2.32 (4H, m, 7CH2, H14a, H14p), 2.07 (3H, s, 18Me), 2.02 (1H, d, J13 = 4.7Hz, OH13), 1.76 - 1.87 (4H, m, H6P, 19Me), 1.60 (1H, s, OH1), 1.17 (3H, s, 17Me), 1.09 (3H, t, J7CH 2 =7.4Hz, 7CH 3 ), 1.04 (3H, s, 16Me), 0.96 (9H, t, JCH 2 (TES) = 8.0Hz, CH 3 (TES)), 0.52 0.62 (6H, m, CH 2

(TES)).

WO 01/57013 PCT/USO1/03624 53 Boo, 0 TESO Bocs TESO N.H O 0 OMOPOM H LHMDS HO 4 BzOAc O BzOZ 0 2'-O-MOP-3'-desphenyl-3'-(2-furyl)-10-triethylsilyl-7-propionyl taxotere. To a solution of 493 mg (0.690 mmol) of 1 0-triethylsilyl-1 0-deacetyl-7-propionyl baccatin IIl in 4 mL of anhydrous THF under a nitrogen atmosphere at -45 0C was added 0.72 mL (0.72 mmol) of a 1 M solution of LiHMDS in THF. After 0.5 h a 5 solution of 263 mg (0.814 mmol) of the b-Lactam (predried as described above) in 2 mL of anhydrous THF was added. The mixture was warmed to 0 'C, and after 2 h 0.5 mL of saturated aqueous sodium bicarbonate solution was added. The mixture was diluted with 50 ml of ethyl acetate and washed two times with 5 mL of brine..The organic phase was dried over sodium sulfate and concentrated 10 under reduced pressure to give 742 mg (104%) of a slightly yellow solid. The solid was recrystallized by dissolving it in 12 mL of a 1:5 mixture of ethyl acetate and hexane at reflux and then cooling to room temperature to give 627 mg (88%) of a white crystalline solid. Evaporation of the mother liquor gave 96 mg of material which was recrystallized as above from 2 mL of a 1:5 mixture of ethyl 15 acetate and hexane to give an additional 46 mg (6%) of white crystalline solid. The total yield from recrystallization was 94%. Evaporation of the mother liquor gave 46 mg of material which was purified by column chromatography on silica gel to give an additional 20 mg (3%) of product. m.p. 207-209 *C; [a]D 25 -30.0 (c 5.0, methanol); 1 H NMR (CDC 3 , 400MHz) d (ppm): 8.09-8.11 (m, 2H), 7.58-7.61 20 (m, 1H), 7.47-7.51(m, 2H), 7.39 (d, J =,0.8 Hz, 1H), 6.34 (dd, J = 3.2, 1.6 Hz, 1H), 6.26 (d, J = 3.2 Hz), 6.14 (dd, J = 8.8, 8.8 Hz, 1H), 5.71 (d, J = 6.8 Hz, 1H), 5.47 (dd, J = 10.0, 7.2 Hz, 1H), 5.30-5.36 (m, 2H), 5.28 (s, 1H), 4.95 (d, J = 7.6 Hz, 1H), 4.76 (s, IH), 4.33 (d, J= 8.0 Hz, IH), 4,19 (d, J = 8.4 Hz, 1H), 4.03 (d, J = 6.8 Hz, 1H), 2.83 (s, 3H), 2.55 (ddd, J = 17.2, 9.6, 7.6, 1H), 2.50 (s, 3H), 2.20-2.40 25 (m, 2H), 2.28 (q, J = 7.6 Hz, 2H), 1.95 (s, 3H), 1.84 (ddd, J = 14.8,10.8, 2 Hz), 1.80 (s, 3H), 1.67 (s, 1H), 1.39 (s, 9H), 1.32 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H), 1.74 (s, 3H), 1.09 (t, J = 7.6 Hz, 3H), 0.93-0.99 (m, 9H), 0.50-0.65 (m, 6H).

WO 01/57013 PCT/USO1/03624 54 BoGs TESO O BoG 0 HO O 0 .1N'L~/'~'~_HF O \ HFOOP OH H .H , BzOAc O BzO 3'-Desphenyl-3'-(2-furyl)-7-propionyl taxotere. (1393) To a solution of 206 mg (0.199 mmol) of 2'-O-MOP-3'-desphenyl-3'-(2-furyl)-10-triethylsilyl-7-propiony taxotere in 1.7 mL of pyridine and 5.4 mL of acetonitrile at 0 0C was added 0.80 mL (2.0 mmol) of an aqueous solution containing 49% HF. The mixture was 5 warmed to room temperature for 14 h and was then diluted with 20 mL of ethyl acetate and washed three times with 2 mL of saturated aqueous sodium bicarbonate and then with 8 mL of brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 170 mg (100%) of a white solid. The crude product was crystallized with 2 mL of solvent 10 (CH2CI2:hexane=1:1.7) to give 155 mg (90.5%) of white crystals. Concentration of the mother liquor under reduced pressure gave 15 mg of material which was recrystallized using 0.2 mL of a 1:1.7 mixture of methylene chloride and hexane to give an additional 11 mg (7.5%) of white crystals. The total yield from recrystallization was 98%. m.p. 150-152 0C; [a]D 2 1 -27.0 (c 5.0, methanol); Anal. 15 Calcd for C44H55NO16e0.5H20: C, 61.18; H, 6.48. Found: C, 61.40; H, 6.65. 'H NMR (CDCl 3 , 500 MHz) d (ppm): 8.11 (d, J = 7.5 Hz, 2H), 7.61 (dd, J = 7.5, 7.5 Hz, 1 H), 7.50 (dd, J = 8.0, 7.5 Hz 2H), 7.41 (d, J = 1.0 Hz, I H), 6.38 (dd, J = 3.0, 2.0 Hz, 1H), 6.33 (d, J = 3.5 Hz), 6.22 (dd, J = 9.5, 9.5 Hz, 1H), 5.69 (d, J = 7.0 Hz, 1 H), 5.49 (dd, J = 11.0, 7.5 Hz, I H), 5.35 (d, J = 9.5 Hz, I H), 5.33 (d, J = 1.5 20 Hz, IH), 5.25 (d, J = 9.5 Hz, 1H), 4.94 (d, J 8.5 Hz, 1H), 4.71 (dd, J = 5.5, 2.0 Hz, I H), 4.33 (d, J= 8.5 Hz, 1 H), 4,21 (d, J = 8.5 Hz, 1 H), 4.01 (d, J = 6.5 Hz, 1 H), 3.97 (d, J = 1.5 Hz, 1H), 3.30 (d, J = 5.5 Hz, 1H), 2.54 (ddd, J = 16.5, 9.5, 7.0, 1H), 2.41 (s, 3H), 2.37 (dd, J = 15.0, 9.0 Hz, 1H), 2.30 (dd, J = 17.5, 9.5 Hz, 1H), 2.25 (q, J = 7.5 Hz, 2H), 1.96 (s, 3H), 1.93 (ddd, J = 14.5, 11.0, 2.5 Hz), 1.85 (s, 25 3H), 1.64 (s, IH), 1.36 (s, 9H), 1.23 (s, 3H), 1.10 (t, J = 7.5 Hz, 3H).

WO 01/57013 PCT/USO1/03624 55 Example 2: Additional Taxanes having C-7 Ester and C-10 Hydroxy Substituents The procedures described in Example 1 were repeated, but other suitably protected p-lactams were substituted for the P-lactam of Example 1 to prepare the series of compounds having structural formula (3) and the combinations of 5 substituents identified in the following table.

X

5 NH 0 HO O ."/ R7 OH HO -. BzO~c O Aco (3) Compound X. X3 R7 1351 tBuOCO- ibue EtCOO 10 1364 tBuOCO- 2-pyridyl EtCOO 1372 tBuOCO- 3-pyridyl EtCOO 1386 tBuOCO- 4-pyridyl EtCOO 1393 tBuOCO- 2-furyl EtCOO 1401 tBuOCO- 3-furyl EtCOO 15 1418 tBuOCO- 2-thienyl EtCOO 1424 tBuOCO- 3-thienyl EtCOO 1434 tBuOCO- isopropyl EtCOO 1447 tBuOCO- cyclobutyl EtCOO 1458 tBuOCO- phenyl EtCOO 20 3069 2-FuCO- 2-thienyl EtCOO 3082 iPrOCO- 2-thienyl EtCOO 3171 nPrCO- 2-furyl EtCOO 3196 iBuOCO- 2-furyl EtCOO 3232 iBuOCO- 2-thienyl EtCOO 25 3327 nPrCO- 2-thienyl EtCOO- WO 01/57013 PCT/USO1/03624 56 3388 PhCO- 3-thienyl EtCOO 3444 iPrOCO- 2-furyl EtCOO 3479 2-ThCO- 2-thienyl EtCOO 3555 C 4

H

7 CO- 2-thienyl EtCOO 5 3560 tC 3

H

5 CO- 2-thienyl EtCOO 3611 EtOCO- 2-furyl EtCOO 3629 2-FuCO- 2-furyl EtCOO 3632 2-ThCO- 2-furyl EtCOO 3708 tC 3

H

5 CO- 2-furyl EtCOO 10 3713 C 4

H

7 CO- 2-furyl EtCOO 4017 PhCO- 2-furyl EtCOO 4044 EtOCO- 2-thienyl EtCOO 4106 3-PyCO- 2-thienyl EtCOO 4135 iPrOCO- 2-thienyl PrCOO 15 4175 PhCO- 2-thienyl PrCOO 4219 2-FuCO- 2-thienyl PrCOO 4256 tBuOCO- 2-thienyl PrCOO 4283 ibueCO- 2-thienyl PrCOO 4290 ibuOCO- 2-thienyl PrCOO 20 4312 ibueCO- 2-thienyl PrCOO 4388 2-ThCO- 2-thienyl PrCOO 4394 tBuOCO- 3-furyl PrCOO 4406 tBuOCO- isobutenyl PrCOO 4446 tBuOCO- 3-thienyl PrCOO 25 4499 tBuOCO- 2-furyl PrCOO 4544 iBuOCO- 3-thienyl EtCOO 4600 iBuOCO- 3-thienyl PrCOO 4616 iBuOCO- 2-furyl PrCOO 4737 tC 3 HCO- 2-furyl PrCOO 30 4757 tC 3

H

5 CO- 2-thienyl PrCOO 6171 ibueOCO- 2-furyl EtCOO- WO 01/57013 PCT/USO1/03624 57 6131 ibueOCO- 2-furyl iBuCOO 5989 ibueOCO- 2-furyl iPrCOO 6141 ibueOCO- 2-furyl nBuCOO 6181 ibueOCO- 2-furyl nPrCOO 5 6040 ibuOCO- 2-furyl ibueCOO 6121 iPrCO- 2-furyl iPrCOO 6424 tAmOCO- 2-furyl EtCOO 6212 tAmOCO- 2-furyl EtCOO 6282 tAmOCO- 2-furyl iBuCOO 10 6252 tAmOCO- 2-furyl iPrCOO 6343 tAmOCO- 2-furyl nBuCOO 6272 tAmOCO- 2-furyl nPrCOO 6202 tC 3

H

5 CO- 2-furyl iPrCOO 4454 2-ThCO- 2-thienyl nPrCOO 15 4414 PhCO- 2-thienyl nPrCOO 6333 tBuOCO- 2-thienyl iPrCOO 6686 tBuOCO- 2-thienyl tC 3

H

5

COO

6363 tBuOCO- 2-thiazo EtCOO 4787 iBuOCO- 3-furyl EtCOO 20 4828 iBuOCO- 3-furyl nPrCOO 4898 tC 3

H

5 CO- 3-furyl EtCOO 4939 tC 3

H

5 CO- 3-furyl nPrCOO 5020 tC 3

H

5 CO- 3-thienyl EtCOO 5030 tC 3 HgCO- 3-thienyl nPrCOO 25 5191 iBuOCO- cpro EtCOO 5202 iBuOCO- cpro nPrCOO 5070 tButOCO- cpro EtCOO 5080 tBuOCO- cpro nPrCOO 5121 iBuOCO- ibue EtCOO 30 5131 iBuOCO- ibue nPrCOO- WO 01/57013 PCT/USO1/03624 58 Example 3: Additional Taxanes having C-7 Ester and C-10 Hydroxy Substituents Following the processes described in Example I and elsewhere herein, the following specific taxanes having structural formula (4) may be prepared, wherein

R

7 is as previously defined, including wherein R 7 is RaCOO- and Ra s 5 (i) substituted or unsubstituted C2 to C8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or 10 unsubstituted phenyl; or (v) substituted or unsubstituted heterocyclo such as furyl, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous 15 containing moieties.

WO 01/57013 PCT/USO1/03624 59

X

5 NH 0 HO O 0 X3 tR 7 OH '. HO . AcO (4) X5 X3

R

7 tBuOCO- 2 -furyl RaCOO tBuOCO- 3-furyl RaCOO 5 tBuOCO- 2-thienyl RaCOO tBuOCO- 3-thienyl RaCOO tBuOCO- 2-pyridyl RaCOO tBuOCO- 3-pyridyl RaCOO tBuOCO- 4-pyridyl RaCOO 10 tBuOCO- isobutenyl RaCOO tBuOCO- isopropyl RaCOO tBuOCO- cyclopropyl RaCOO tBuOCO- cyclobutyl RaCOO tBuOCO- cyclopentyl RaCOO 15 tBuOCO- phenyl RaCOO benzoyl 2-furyl RaCOO benzoyl 3-furyl RaCOO benzoyl 2-thienyl RaCOO benzoyl 3-thienyl RaCOO 20 benzoyl 2-pyridyl RaCOO benzoyl 3-pyridyl RaCOO benzoyl 4-pyridyl RaCOO benzoyl isobutenyl RaCOO benzoyl isopropyl RaCOO- WO 01/57013 PCT/USO1/03624 60 benzoyl cyclopropyl RaCOO benzoyl cyclobutyl RaCOO benzoyl cyclopentyl RaCOO benzoyl phenyl RaCOO 5 2-FuCO- 2-furyl RaCOO 2-FuCO- 3-furyl RaCOO 2-FuCO- 2-thienyl RaCOO 2-FuCO- 3-thienyl RaCOO 2-FuCO- 2-pyridyl RaCOO 10 2-FuCO- 3-pyridyl RaCOO 2-FuCO- 4-pyridyl RaCOO 2-FuCO- isobutenyl RaCOO 2-FuCO- isopropyl RaCOO 2-FuCO- cyclopropyl RaCOO 15 2-FuCO- cyclobutyl RaCOO 2-FuCO- cyclopentyl RaCOO 2-FuCO- phenyl RaCOO 2-ThCO- 2-furyl RaCOO 2-ThCO- 3-furyl RaCOO 20 2-ThCO- 2-thienyl RaCOO 2-ThCO- 3-thienyl RaCOO 2-ThCO- 2-pyridyl RaCOO 2-ThCO- 3-pyridyl RaCOO 2-ThCO- 4-pyridyl RaCOO 25 2-ThCO- isobutenyl RCOO 2-ThCO- isopropyl RaCOO 2-ThCO- cyclopropyl RaCOO 2-ThCO- cyclobutyl RaCOO 2-ThCO- cyclopentyl RaCOO 30 2-ThCO- phenyl RaCOO 2-PyCO- 2-furyl RCOO- WO 01/57013 PCT/USO1/03624 61 2-PyCO- 3-furyl RaCOO 2-PyCO- 2-thienyl RaCOO 2-PyCO- 3-thienyl RaCOO 2-PyCO- 2-pyridyl RCOO 5 2-PyCO- 3-pyridyl RaCOO 2-PyCO- 4-pyridyl RaCOO 2-PyCO- isobutenyl RaCOO 2-PyCO- isopropyl RaCOO 2-PyCO- cyclopropyl RaCOO 10 2-PyCO- cyclobutyl RaCOO 2-PyCO- cyclopentyl RaCOO 2-PyCO- phenyl RaCOO 3PyCO- 2-furyl RaCOO 3-PyCO- 3-furyl RaCOO 15 3-PyCO- 2-thienyl RaCOO 3-PyCO- 3-thienyl RaCOO 3-PyCO- 2-pyridyl RaCOO 3-PyCO- 3-pyridyl RaCOO 3-PyCO- 4-pyridyl RaCOO 20 3-PyCO- isobutenyl RaCOO 3-PyCO- isopropyl RaCOO 3-PyCO- cyclopropyl RaCOO 3-PyCO- cyclobutyl RaCOO 3-PyCO- cyclopentyl RaCOO 25 3-PyCO- phenyl RCOO 4-PyCO- 2-furyl RaCOO 4-PyCO- 3-furyl RaCOO 4-PyCO- 2-thienyl RaCOO 4-PyCO- 3-thienyl RaCOO 30 4-PyCO- 2-pyridyl RaCOO 4-PyCO- 3-pyridyl RaCOO- WO 01/57013 PCT/USO1/03624 62 4-PyCO- 4-pyridyl RaCOO 4-PyCO- isobutenyl RaCOO 4-PyCO- isopropyl RaCOO 4-PyCO- cyclopropyl RCOO 5 4-PyCO- cyclobutyl RaCOO 4-PyCO- cyclopentyl RaCOO 4-PyCO- phenyl RaCOO

C

4

H

7 CO- 2-furyl RaCOO

C

4

H

7 CO- 3-furyl RaCOO 10 C 4

H

7 CO- 2-thienyl RaCOO

C

4

H

7 CO- 3-thienyl RaCOO

C

4

H

7 CO- 2-pyridyl RaCOO

C

4

H

7 CO- 3-pyridyl RaCOO

C

4

H

7 CO- 4-pyridyl RaCOO 15 C 4

H

7 CO- isobutenyl RaCOO

C

4

H

7 CO- isopropyl RaCOO

C

4

H

7 CO- cyclopropyl RaCOO

C

4

H

7 CO- cyclobutyl RaCOO

C

4

H

7 CO- cyclopentyl RaCOO 20 C 4

H

7 CO- phenyl RaCOO EtOCO- 2-furyl RaCOO EtOCO- 3-furyl RaCOO EtOCO- 2-thienyl RaCOO EtOCO- 3-thienyl RaCOO 25 EtOCO- 2-pyridyl RaCOO EtOCO- 3-pyridyl RaCOO EtOCO- 4-pyridyl RaCOO EtOCO- isobutenyl RaCOO EtOCO- isopropyl RaCOO 30 EtOCO- cyclopropyl RaCOO EtOCO- cyclobutyl RaCOO- WO 01/57013 PCT/USO1/03624 63 EtOCO- cyclopentyl RaCOO EtOCO- phenyl RaCOO ibueCO- 2-furyl RaCOO ibueCO- 3-furyl RaCOO 5 ibueCO- 2-thienyl RaCOO ibueCO- 3-thienyl RaCOO ibueCO- 2-pyridyl RaCOO ibueCO- 3-pyridyl RaCOO ibueCO- 4-pyridyl RaCOO 10 ibueCO- isobutenyl RaCOO ibueCO- isopropyl RaCOO ibueCO- cyclopropyl RaCOO ibueCO- cyclobutyl RaCOO ibueCO- cyclopentyl RaCOO 15 ibueCO- phenyl RaCOO iBuCO- 2-furyl RaCOO iBuCO- 3-furyl RCOO iBuCO- 2-thienyl RaCOO iBuCO- 3-thienyl RaCOO 20 iBuCO- 2-pyridyl RaCOO iBuCO- 3-pyridyl RaCOO iBuCO- 4-pyridyl RaCOO iBuCO- isobutenyl RaCOO iBuCO- isopropyl RaCOO 25 iBuCO- cyclopropyl RaCOO iBuCO- cyclobutyl RaCOO iBuCO- cyclopentyl RaCOO iBuCO- phenyl RaCOO iBuOCO- 2-furyl RaCOO 30 iBuOCO- 3-furyl RaCOO iBuOCO- 2-thienyl RaCOO- WO 01/57013 PCT/USO1/03624 64 iBuOCO- 3-thienyl RaCOO iBuOCO- 2-pyridyl RaCOO iBuOCO- 3-pyridyl RaCOO iBuOCO- 4-pyridyl RaCOO 5 iBuOCO- isobutenyl RaCOO iBuOCO- isopropyl RaCOO iBuOCO- cyclopropyl RaCOO iBuOCO- cyclobutyl RaCOO iBuOCO- cyclopentyl RaCOO 10 iBuOCO- phenyl RaCOO iPrOCO- 2-furyl RaCOO iPrOCO- 3-furyl RaCOO iPrOCO- 2-thienyl RaCOO iPrOCO- 3-thienyl RaCOO 15 iPrOCO- 2-pyridyl RaCOO iPrOCO- 3-pyridyl RaCOO iPrOCO- 4-pyridyl RaCOO iPrOCO- isobutenyl RaCOO iPrOCO- isopropyl RaCOO 20 iPrOCO- cyclopropyl RaCOO iPrOCO- cyclobutyl RaCOO iPrOCO- cyclopentyl RaCOO iPrOCO- phenyl RaCOO nPrOCO- 2-furyl RaCOO 25 nPrOCO- 3-furyl RaCOO nPrOCO- 2-thienyl RaCOO nPrOCO- 3-thienyl RaCOO nPrOCO- 2-pyridyl RaCOO nPrOCO- 3-pyridyl RaCOO 30 nPrOCO- 4-pyridyl RaCOO nPrOCO- isobutenyl RaCOO- WO 01/57013 PCT/USO1/03624 65 nPrOCO- isopropyl RaCOO nPrOCO- cyclopropyl RaCOO nPrOCO- cyclobutyl RaCOO nPrOCO- cyclopentyl RaCOO 5 nPrOCO- phenyl RaCOO nPrCO- 2-furyl RaCOO nPrCO- 3-furyl RaCOO nPrCO- 2-thienyl RaCOO nPrCO- 3-thienyl RaCOO 10 nPrCO- 2-pyridyl RaCOO nPrCO- 3-pyridyl RaCOO nPrCO- 4-pyridyl RaCOO nPrCO- isobutenyl RaCOO nPrCO- isopropyl RaCOO 15 nPrCO- cyclopropyl RaCOO nPrCO- cyclobutyl RaCOO nPrCO- cyclopentyl RaCOO nPrCO- phenyl RaCOO tBuOCO- cyclopentyl EtCOO 20 benzoyl 3-furyl EtCOO benzoyl 2-thienyl EtCOO benzoyl 2-pyridyl EtCOO benzoyl 3-pyridyl EtCOO benzoyl 4-pyridyl EtCOO 25 benzoyl isobutenyl EtCOO benzoyl isopropyl EtCOO benzoyl cyclopropyl EtCOO benzoyl cyclobutyl EtCOO benzoyl cyclopentyl EtCOO 30 benzoyl phenyl EtCOO 2-FuCO- 3-furyl EtCOO- WO 01/57013 PCT/USO1/03624 66 2-FuCO- 3-thienyl EtCOO 2-FuCO- 2-pyridyl EtCOO 2-FuCO- 3-pyridyl EtCOO 2-FuCO- 4-pyridyl EtCOO 5 2-FuCO- isobutenyl EtCOO 2-FuCO- isopropyl EtCOO 2-FuCO- cyclopropyl EtCOO 2-FuCO- cyclobutyl EtCOO 2-FuCO- cyclopentyl EtCOO 10 2-FuCO- phenyl EtCOO 2-ThCO- 3-furyl EtCOO 2-ThCO- 3-thienyl EtCOO 2-ThCO- 2-pyridyl EtCOO 2-ThCO- 3-pyridyl EtCOO 15 2-ThCO- 4-pyridyl EtCOO 2-ThCO- isobutenyl EtCOO 2-ThCO- isopropyl EtCOO 2-ThCO- cyclopropyl EtCOO 2-ThCO- cyclobutyl EtCOO 20 2-ThCO- cyclopentyl EtCOO 2-ThCO- phenyl EtCOO 2-PyCO- 2-furyl EtCOO 2-PyCO- 3-furyl EtCOO 2-PyCO- 2-thienyl EtCOO 25 2-PyCO- 3-thienyl EtCOO 2-PyCO- 2-pyridyl EtCOO 2-PyCO- 3-pyridyl EtCOO 2-PyCO- 4-pyridyl EtCOO 2-PyCO- isobutenyl EtCOO 30 2-PyCO- isopropyl EtCOO 2-PyCO- cyclopropyl EtCOO- WO 01/57013 PCT/USO1/03624 67 2-PyCO- cyclobutyl EtCOO 2-PyCO- cyclopentyl EtCOO 2-PyCO- phenyl EtCOO 3PyCO- 2-furyl EtCOO 5 3-PyCO- 3-furyl EtCOO 3-PyCO- 3-thienyl EtCOO 3-PyCO- 2-pyridyl EtCOO 3-PyCO- 3-pyridyl EtCOO 3-PyCO- 4-pyridyl EtCOO 10 3-PyCO- isobutenyl EtCOO 3-PyCO- isopropyl EtCOO 3-PyCO- cyclopropyl EtCOO 3-PyCO- cyclobutyl EtCOO 3-PyCO- cyclopentyl EtCOO 15 3-PyCO- phenyl EtCOO 4-PyCO- 2-furyl EtCOO 4-PyCO- 3-furyl EtCOO 4-PyCO- 2-thienyl EtCOO 4-PyCO- 3-thienyl EtCOO 20 4-PyCO- 2-pyridyl EtCOO 4-PyCO- 3-pyridyl EtCOO 4-PyCO- 4-pyridyl EtCOO 4-PyCO- isobutenyl EtCOO 4-PyCO- isopropyl EtCOO 25 4-PyCO- cyclopropyl EtCOO 4-PyCO- cyclobutyl EtCOO 4-PyCO- cyclopentyl EtCOO 4-PyCO- phenyl EtCOO

C

4

H

7 CO- 3-furyl EtCOO 30 C 4

H

7 CO- 3-thienyl EtCOO

C

4

H

7 CO- 2-pyridyl EtCOO- WO 01/57013 PCT/USO1/03624 68

C

4

H

7 CO- 3-pyridyl EtCOO

C

4

H

7 CO- 4-pyridyl EtCOO

C

4

H

7 CO- isobutenyl EtCOO

C

4

H

7 CO- isopropyl EtCOO 5 C 4

H

7 CO- cyclopropyl EtCOO

C

4

H

7 CO- cyclobutyl EtCOO

C

4

H

7 CO- cyclopentyl EtCOO

C

4

H

7 CO- phenyl EtCOO EtOCO- 3-furyl EtCOO 10 EtOCO- 3-thienyl EtCOO EtOCO- 2-pyridyl EtCOO EtOCO- 3-pyridyl EtCOO EtOCO- 4-pyridyl EtCOO EtOCO- isobutenyl EtCOO 15 EtOCO- isopropyl EtCOO EtOCO- cyclopropyl EtCOO EtOCO- cyclobutyl EtCOO EtOCO- cyclopentyl EtCOO EtOCO- phenyl EtCOO 20 ibueCO- 2-furyl EtCOO ibueCO- 3-furyl EtCOO ibueCO- 2-thienyl EtCOO ibueCO- 3-thienyl EtCOO ibueCO- 2-pyridyl EtCOO 25 ibueCO- 3-pyridyl EtCOO ibueCO- 4-pyridyl EtCOO ibueCO- isobutenyl EtCOO ibueCO- isopropyl EtCOO ibueCO- cyclopropyl EtCOO 30 ibueCO- cyclobutyl EtCOO ibueCO- cyclopentyl EtCOO- WO 01/57013 PCT/USO1/03624 69 ibueCO- phenyl EtCOO iBuCO- 2-furyl EtCOO iBuCO- 3-furyl EtCOO iBuCO- 2-thienyl EtCOO 5 iBuCO- 3-thienyl EtCOO iBuCO- 2-pyridyl EtCOO iBuCO- 3-pyridyl EtCOO iBuCO- 4-pyridyl EtCOO iBuCO- isobutenyl EtCOO 10 iBuCO- isopropyl EtCOO iBuCO- cyclopropyl EtCOO iBuCO- cyclobutyl EtCOO iBuCO- cyclopentyl EtCOO iBuCO- phenyl EtCOO 15 iBuOCO- 2-pyridyl EtCOO iBuOCO- 3-pyridyl EtCOO iBuOCO- 4-pyridyl EtCOO iBuOCO- isobutenyl EtCOO iBuOCO- isopropyl EtCOO 20 iBuOCO- cyclobutyl EtCOO iBuOCO- cyclopentyl EtCOO iBuOCO- phenyl EtCOO iPrOCO- 3-furyl EtCOO iPrOCO- 3-thienyl EtCOO 25 iPrOCO- 2-pyridyl EtCOO iPrOCO- 3-pyridyl EtCOO iPrOCO- 4-pyridyl EtCOO iPrOCO- isobutenyl EtCOO iPrOCO- isopropyl EtCOO 30 iPrOCO- cyclopropyl EtCOO iPrOCO- cyclobutyl EtCOO- WO 01/57013 PCT/USO1/03624 70 iPrOCO- cyclopentyl EtCOO iPrOCO- phenyl EtCOO nPrOCO- 2-furyl EtCOO nPrOCO- 3-furyl EtCOO 5 nPrOCO- 2-thienyl EtCOO nPrOCO- 3-thienyl EtCOO nPrOCO- 2-pyridyl EtCOO nPrOCO- 3-pyridyl EtCOO nPrOCO- 4-pyridyl EtCOO 10 nPrOCO- isobutenyl EtCOO nPrOCO- isopropyl EtCOO nPrOCO- cyclopropyl EtCOO nPrOCO- cyclobutyl EtCOO nPrOCO- cyclopentyl EtCOO 15 nPrOCO- phenyl EtCOO nPrCO- 3-furyl EtCOO nPrCO- 3-thienyl EtCOO nPrCO- 2-pyridyl EtCOO nPrCO- 3-pyridyl EtCOO 20 nPrCO- 4-pyridyl EtCOO nPrCO- isobutenyl EtCOO nPrCO- isopropyl EtCOO nPrCO- cyclopropyl EtCOO nPrCO- cyclobutyl EtCOO 25 nPrCO- cyclopentyl EtCOO nPrCO- phenyl EtCOO- WO 01/57013 PCT/US01/03624 71 Example 4: Additional Taxanes having C-7 Ester and C-10 Hydroxy Substituents Following the processes described in Example I and elsewhere herein, the following specific taxanes having structural formula (5) may be prepared, wherein

R

1 is hydroxy and R 7 in each of the series (that is, each of series "A" through "K") 5 is as previously defined, including wherein R 7 is R 7 aCOO- and R 7 a is (i) substituted or unsubstituted, preferably unsubstituted, C2 to C alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, C2 to C alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or 10 unsubstituted, preferably unsubstituted, C2 to C alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted, preferably unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl. 15 In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 and R 1 0 each have the beta stereochemical configuration. In the "B" series of compounds, X 1 0 and R 2 a are as otherwise as defined 20 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and Ry and R 1 0 each have the beta stereochemical configuration. 25 In the "C" series of compounds, X 1 0 and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rga is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 0 each 30 have the beta stereochemical configuration. In the "D" and "E" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R 9 (series D only) and R 1 0 35 each have the beta stereochemical configuration. In the "F" series of compounds, X 1 O, R 2 a and R 9 a are as otherwise as WO 01/57013 PCT/US01/03624 72 defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 , is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 0 each 5 have the beta stereochemical configuration. In the "G" series of compounds, X 1 , and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or 10 unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 0 each have the beta stereochemical configuration. In the "H" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, 15 or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical configuration. In the "I" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 20 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R and R 1 0 each have the beta stereochemical configuration. In the "J" series of compounds, X 1 0 and R 2 a are as otherwise as defined 25 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 each have the beta stereochemical configuration. 30 In the "K" series of compounds, X 1 0 , R 2 a and Rea are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 0 each 35 have the beta stereochemical configuration. Any substituents of each X 3 , X 5 , R 2 , R 7 , and R. may be hydrocarbyl or any WO 01/57013 PCT/USO1/03624 73 of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

X

5 NH O R 5 ~~X3 0 . R OH

R

14 HO .

R

2 0 OAc (5) Series X 5 X3 R7 R2 R R14 Al -C00X 1 0 heterocyclo R 7 aCOO- C 6

H

5 COO- 0 H 10 A2 -COX 1 0 heterocyclo R 7 aCOO- C 6 HCOO- 0 H A3 -CONHX 1 heterocyclo R 7 aCOO- C 6

H

5 COO- 0 H A4 -COOX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A5 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A6 -CONHX 1 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl 15 A7 -COOX 1 0 optionally R 7 COO- C 6

H

5 COO- 0 H substituted C2 to C8 alkenyl A8 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkenyl A9 -CONHX 1 optionally R 7 aCOO- CH 5 COO- 0 H substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 74 A10 -C00X 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkynyl Al I -COX 1 0 optionally RaCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkynyl A12 -CONHX 1 0 optionally RaCOO- CH 5 COO- 0 H substituted C2 to C8 alkynyl B1 -C00X 10 heterocyclo R 7 aCOO- R 2 aCOO- 0 H 5 B2 -CoX 1 heterocyclo R 7 aCOO- R 2 aCOO- 0 H B3 -CONHX 0 heterocyclo RyaCOO- R 2 aCOO- 0 H B4 -C00X 10 optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl B5 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl B6 -CONHX 1 0 optionally RaCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl 10 B7 -COOX 1 0 optionally RaCOO- R 2 aCOO- 0 H substituted C2 to C8 alkenyl B8 -COX 1 0 optionally RaCOO- R 2 COO- 0 H substituted C2 to C8 alkenyl B9 -CONHX 1 optionally RaCOO- R 2 aCOO- 0 H substituted C2 to C8 alkenyl B10 -C00X 1 0 optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 75 B11 -COX 1 0 optionally RaCOO- R 2 aCOO- 0 H substituted C2 to C8 alkynyl B12 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C 8 alkynyl C1 -C00X 1 0 heterocyclo R 7 aCOO- CH 5 COO- RgaCOO- H C2 -COX 1 0 heterocyclo R 7 aCOO- C 6

H

5 COO- ReaCOO- H 5 C3 -CONHX 1 heterocyclo R 7 aCOO- CH 5 COO- ReaCOO- H C4 -C00X 10 optionally R 7 aCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C alkyl C5 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- ReCOO- H substituted C2 to C alkyl C6 -CONHX 10 optionally R 7 0,COO- CH 5 COO- R 9 aCOO- H substituted C2 to C8 alkyl C7 -C00X 10 optionally R 7 aCOO- C 6

H

5 COO- ReaCOO- H substituted C2 to C8 alkenyl 10 C8 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C8 alkenyl C9 -CONHX 1 0 optionally R 7 aCOO- C 6

H

5 COO- R 9 COO- H substituted C2 to C8 alkenyl C10 -C00X 1 0 optionally R 7 COO- C 6

H

5 COO- RgaCOO- H substituted C2 to C8 alkynyl C11 -COX 1 0 optionally R 7 aCOO- CH 5 COO- RgaCOO- H substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 76 C12 -CONHXO optionally R 7 COO- C 6

H

5 COO- RgCOO- H substituted C2 to C8 alkynyl D1 -COOX 1 0 heterocyclo R 7 aCOO- C 6

H

5 COO- OH H D2 -COX 1 heterocyclo R 7 ,COO- C 6

H

5 COO- OH H D3 -CONHXO heterocyclo R 7 aCOO- C 6

H

5 COO- OH H 5 D4 -COOX 1 0 optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C alkyl D5 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkyl D6 -CONHXO optionally R 7 aCOO- CH 5 COO- OH H substituted C2 to C alkyl D7 -COOXIO optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkenyl D8 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkenyl 10 D9 -CONHXO optionally R 7 aCOO- CH 5 COO- OH H substituted C2 to C8 alkenyl D10 -C00X 10 optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkynyl D11 -COX 10 optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkynyl D12 -CONHXIO optionally R 7 aCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkynyl El -C00X 10 heterocyclo R 7 aCOO- C 6

H

5 COO- 0 OH 15 E2 -COX 1 0 heterocyclo R 7 aCOO- CH 5 COO- 0 OH WO 01/57013 PCT/USO1/03624 77 E3 -CONHXO heterocyclo R 7 aCOO- C 6

H

5 COO- 0 OH E4 -C00X 10 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl E5 -COX 10 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkyl E6 -CONHXO optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl 5 E7 -COOX 10 optionally R 7 aCOO- C 6 HCOO- 0 OH substituted C2 to C8 alkenyl E8 -COXIO optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkenyl E9 -CONHXO optionally RaCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkenyl E10 -COOXIO optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkynyl Eli -COX 1 0 optionally R 7 aCOO- CH 5 COO- 0 OH substituted

C

2 to C8 alkynyl 10 E12 -CONHX 1 0 optionally RaCOO- CH 5 COO- 0 OH substituted C2 to C8 alkynyl Fl -COOX 10 heterocyclo RaCOO- R 2 aCOO- RqCOO- H F2 -COX 1 0 heterocyclo RaCOO- R 2 aCOO- ReCOO- H F3 -CONHXIO heterocyclo RaCOO- R 2 aCOO- RgaCOO- H F4 -COOX 10 optionally R 7 aCOO- R 2 aCOO- RqCOO- H substituted C2 to C alkyl WO 01/57013 PCT/USO1/03624 78 F5 -COX 10 optionally R 7 aCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkyl F6 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkyl F7 -COOX 0 optionally RaCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkenyl F8 -COXO optionally RaCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkenyl 5 F9 -CONHXjO optionally RaCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkenyl F10 -C00X 10 optionally RaCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkynyl F11 -COX 10 optionally R 7 aCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkynyl F12 -CONHXO optionally R 7 aCOO- R 2 aCOO- ReaCOO- H substituted C2 to C8 alkynyl G1 -COOXo heterocyclo RaCOO- R 2 aCOO- OH H 10 G2 -COX 10 heterocyclo RaCOO- R 2 aCOO- OH H G3 -CONHXIO heterocyclo R 7 aCOO- R 2 aCOO- OH H G4 -COOX 1 0 optionally RaCOO- R 2 aCOO- OH H substituted C2 to C alkyl G5 -COX 10 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl G6 -CONHX,, optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl WO 01/57013 PCT/USO1/03624 79 G7 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C8 alkenyl G8 -COX 10 optionally RaCOO- R 2 aCOO- OH H substituted C2 to C8 alkenyl G9 -CONHX,, optionally RaCOO- R 2 aCOO- OH H substituted C2 to C8 alkenyl G10 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl 5 G11 -COX1 0 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl G12 -CONHXO optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl H1 -COOXO heterocyclo R 7 aCOO- C 6

H

5 COO- OH OH H2 -COXO heterocyclo RaCOO- C 6

H

5 COO- OH OH H3 -CONHX, heterocyclo RaCOO- CH 5 COO- OH OH 10 H4 -COOX 1 0 optionally RaCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H5 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H6 -CONHXI 0 optionally RyaCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H7 -COOX1 0 optionally R 7 aCOO- CHCOO- OH OH substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 80 H8 -COXIO optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkenyl H9 -CONHX 10 optionally R 7 aCOO- CH 5 COO- OH OH substituted C2 to C8 alkenyl HIO -C00X1 0 optionally R 7 aCOO- CH 5 COO- OH OH substituted C2 to C8 alkynyl H11 -COX 10 optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkynyl 5 H12 -CONHX 10 optionally RaCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkynyl 11 -COOX 1 0 heterocyclo R 7 aCOO- R 2 aCOO- 0 OH 12 -COX 1 0 heterocyclo R 7 aCOO- R 2 aCOO- 0 OH 13 -CONHX 10 heterocyclo RaCOO- R 2 aCOO- 0 OH 14 -COOX 1 0 optionally RaCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 10 15 -COX 1 0 optionally RaCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 16 -CONHX 1 0 optionally RaCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 17 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkenyl 18 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 81 19 -CONHX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkenyl 110 -COOX 1 0 optionally R 7 aCOO- R 2 COO- 0 OH substituted C2 to C8 alkynyl 111 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkynyl 112 -CONHX 1 optionally RaCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkynyl 5 J1 -C00X 1 0 heterocyclo R 7 aCOO- R 2 aCOO- OH OH J2 -COX 1 0 heterocyclo RaCOO- R 2 aCOO- OH OH J3 -CONHX 1 0 heterocyclo R 7 aCOO- R 2 aCOO- OH OH J4 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C8 alkyl J5 -COX 10 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C8 alkyl 10 J6 -CONHX 1 optionally RaCOO- R 2 aCOO- OH OH substituted C2 to C8 alkyl J7 -C00X 10 optionally RaCOO- R 2 aCOO- OH OH substituted C2 to C8 alkenyl J8 -COX 1 0 optionally RaCOO- R 2 aCOO- OH OH substituted C2 to C8 alkenyl J9 -CONHX 1 0 optionally RaCOO- R 2 aCOO- OH OH substituted C2 to C8 alkenyl

J

WO 01/57013 PCT/USO1/03624 82 J10 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C8 alkynyl Ji1 -COX 1 0 optionally R 7 COO- R 2 ,COO- OH OH substituted C2 to C8 alkynyl J12 -CONHX 1 optionally R 7 ,COO- R 2 ,COO- OH OH substituted C2 to C8 alkynyl K1 -C00X 10 heterocyclo R 7 aCOO- R 2 COO- RCOO- OH 5 K2 -COX 1 0 heterocyclo R 7 ,COO- R 2 aCOO- RgaCOO- OH K3 -CONHX 1 heterocyclo R 7 aCOO- R 2 aCOO- RgaCOO- OH K4 -C00X 1 0 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkyl K5 -COX 1 0 optionally R 7 COO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkyl K6 -CONHX 10 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkyl 10 K7 -C00X 10 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C8 alkenyl K8 -COX 10 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C8 alkenyl K9 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C8 alkenyl KI0 -C00X 10 optionally R 7 aCOO- R 2 aCOO- ReaCOO- OH substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 83 K11 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C8 alkynyl K12 -CONHX 1 0 optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C8 alkynyl Example 5: In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCT1 16) were plated in 60 mm Petri dishes containing 5 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 0C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was 10 added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony 15 counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound. Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 20 docetaxel 0.6 1351 <1 1364 <10 1372 26.1 1386 <1 25 1393 <1 WO 01/57013 PCT/USO1/03624 84 1401 <1 1418 <1 1424 <1 1434 <10 5 1447 <10 1458 <10 3069 <1 3082 <1 3171 <1 10 3196 <10 3232 <1 3327 <10 3388 <10 3444 <1 15 3479 <1 3555 <10 3560 <1 3611 <1 3629 <1 20 3632 <1 3708 <1 3713 <10 4017 <10 4044 <1 25 4106 <10 4135 <1 4175 <10 4219 29.0 4256 <1 30 4283 <1 4290 <10 WO 01/57013 PCT/USO1/03624 85 4312 <1 4388 <1 4394 <1 4406 <1 5 4446 <1 4499 <1 4544 <10 4600 <10 4616 <1 10 4737 <1 4757 <1 6171 <10 6131 <1 5989 <10 15 6141 <1 6181 <1 6040 <10 6121 <10 6424 21.7 20 6212 <1 6282 <10 6252 <1 6343 <10 6272 <1 25 6202 <1 4454 <1 4414 <1 6333 <1 6686 <1 30 6363 <10 4787 <10 WO 01/57013 PCT/USO1/03624 86 4828 <10 4898 <1 4939 <1 5020 <1 5 5030 <1 5191 <10 5202 <10 5070 <10 5080 <1 10 5121 21.1 5131 <10 Example 6: Preparation of Taxane having C-10 Ester and C-7 Hydroxy Substituents 0 HO N O HO O HO'". .)- HO'. H q-. He1 OAcO AcO 10-Propionyl-10-deacetyl baccatin Ill. To a mixture of 0.2 g (0.367 mmol) of 15 10-deacetyl baccatin Ill and 0.272 g (1.10 mmol) of CeCl. in 10 mL of THF at 25 0C was added 2.35 mL (18.36 mmol) of propionic anhydride. After 30 min the reaction mixture was diluted with 200 mL of EtOAc, then washed three times with 50 mL of saturated aqueous NaHCO 3 solution and brine. The organic extract was dried over Na 2

SO

4 and concentrated in vacuo. The crude solid was purified by 20 flash column chromatography on silica gel using 70% EtOAc/hexane as eluent to give 0.199 g (90%) of 10-propionyl-10-deacetyl baccatin Ill as a solid.

WO 01/57013 PCT/USO1/03624 87 O 0 OH Me 2 PhSiCI DMPS H HO, BzOAc O BzO c 0 7-Dimethylphenylsily-10-propionyl-10-deacetyl baccatin 1ll. To a solution of 0.200 g (0.333 mmol) of 10-propionyl-10-deacetyl baccatin IlIl in 12 mL of THF at 10 0C under a nitrogen atmosphere was added dropwise 0.668 mL (4.00 mmol) of chlorodimethyl-phenylsilane and 2.48 mL (30.64 mmol) of pyridine. After 90 min 5 the mixture was diluted with 100 mL of a 1:1 mixture of ethyl acetate and hexane. The mixture was washed with 20 mL of saturated aqueous sodium bicarbonate solution and the organic layer separated. The aqueous layer was extracted with 30 mL of a 1:1 mixture of ethyl acetate and hexane, and the combined organic extracts were washed with brine, dried over Na 2

SO

4 , and concentrated in vacuo. 10 The crude solid was purified by flash column chromatography on silica gel using 50% EtOAc/hexane as eluent to give 0.242 g (99%) of 7-dimethylphenylsilyl-1 0 propionyl-10-deacetyl baccatin IlI as a solid. 0 0 Bz, 0

N

zBz, 0 0 N.HO 0 ODMPS 'OTES ~ - DMPS Cl s S NOTES ' H i . LHMDS HO BzOA 0 BzO zAc 0 BOAc O 7-DimethylphenylsilyI-2'-0-triethylsilyl-3'-desphenyl-3'-(2-thienyl)-1 0 propionyl-10-deacetyl taxol. To a solution of 0.400 g (0.544 mmol) of 7 15 dimethylphenylsilyl-10-propionyl-10-deacetyl baccatin IlIl in 5.5 mL of THF at -45 0C under a nitrogen atmosphere was added 0.681 mL (0.681 mmol) of a 1 M solution of LHMDS in THF. After I h, a solution of 0.317 g (0.818 mmol) of cis-N benzoyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in 3 mL of THF was added slowly. The mixture was warmed to 0 0C and after 3 h 10 mL of saturated 20 aqueous sodium bicarbonate solution was added and the mixture was extracted three times with 50 mL of ethyl acetate. The combined organic extracts were WO 01/57013 PCT/USO1/03624 88 washed with brine, dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 40% EtOAc/hexane as eluent to give 0.531 g (87%) of 7-dimethylphenylsilyl-2'-O triethylsilyl-3'-desphenyl-3'-(2-thienyl)-10-propionyl-10-deacetyI taxol as a solid. Bz , O BzN O N.H O N.H O ODM S H- O S bTES S OH H H B BzO 0 zOAcO O OAcO 5 3'-Desphenyl-3'-(2-thienyl)-10-propionyl-10-deacetyl taxol. To a solution of 0.521 g (0.464 mmol) of 7-dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3'-(2 thienyl)-10-propionyl-10-deacetyl taxol in 2 mL of CH3CN and 2 mL of pyridine at 0 'C was added 0.5 mL of a solution of 30% HF in H 2 0. After 3 h 20 mL of a saturated aqueous sodium bicarbonate solution was added and the mixture was 10 extracted three times with 50 mL of ethyl acetate. The combined organic extracts were washed with brine, dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 70% EtOAc/hexane as eluent to give 0.405 g (100%) of 3'-desphenyl-3'-(2 thienyl)-10-propionyl-10-deacety taxol as a solid. m.p. 154-155 *C; [a]D 25 = -45.0 15 (c 0.1 in CHCl3); Anal. Calcd. for C 46

H,,NO

4 S: C, 63.22; H, 5.88; Found: C, 62.94; H, 5.97. 3'-Desphenyl-3'-(2-thienyl)-10-propionyl-10-deacetyl taxol 1 H NMR data (CDCl 3 ) Proton ppm pattern J (Hz) 20 2' 4.78 dd H3'(2.1), 2'OH(4.1) 2'OH 3.51 d H2'(4.1) 3' 6.07 dd NH(8.6), H2'(2.1) 5' 7.04 dd (3.5), (5.0) 10H 1.68 s 25 2 5.69 d H3(7.0) 3 3.85 d H2(7.0) WO 01/57013 PCT/USO1/03624 89 4Ac 2.42 s 5 4.96 app d 6a 2.45- app m 2.60 6b 1.89 ddd H7(10.9), H5(2.5), H6a(14.5) 5 7 4.42 ddd 70H(4.2), H6a(6.8), H6b(10.8) 70H 2.45- app m 2.60 10 6.32 s 13 6.27 app t H14a,b(9.0) 14a 2.40- app m 2.43 10 14b 2.34 dd H14a(15.5), H13(9.0) Me 16 1.16 s Me 17 1.25 app m Mel8 1.84 s Me19 1.70 s 15 20a 4.31 d H20b(8.5) 20b 4.22 d H20a(8.5) o-benzoate 8.14- m 8.16 o-benzamide 7.72- m 7.73 NH 6.88 d H3'(8.6) 20 CH3CH2 1.24 t CH3CH2(7.0) CH3CH2 2.45- app m 2.60 Example 7: Additional Taxanes having C-10 Ester and C-7 Hydroxy Substituents The procedures described in Example 6 were repeated, but other suitably protected P-lactams were substituted for the p-lactam of Example 6 to prepare the 25 series of compounds having structural formula (6) and the combinations of substituents identified in the following table.

WO 01/57013 PCT/USO1/03624 90

X

5 NH 0

R

10 0 - OH X3 z le . OH HO BZO -~ 0 Aco (6) Compound X 5 X3 R 0499 tBuOCO- isobutenyl EtCOO 0503 tBuOCO- 2-pyridyl EtCOO 5 0517 tBuOCO- 3-pyridyl EtCOO 0521 tBuOCO- 4-pyridyl EtCOO 0536 tBuOCO- 2-furyl EtCOO 0549 tBuOCO- 3-furyl EtCOO 0550 tBuOCO- 2-thienyl EtCOO 10 0562 tBuOCO- 3-thienyl EtCOO 0578 tBuOCO- cyclopropyl EtCOO 0583 tBuOCO- isopropyl EtCOO 0596 tBuOCO- cyclobutyl EtCOO 0602 tBuOCO- p-nitrophenyl EtCOO 15 0611 tBuOCO- phenyl EtCOO 0625 PhCO- isobutenyl EtCOO 0634 PhCO- 2-pyridyl EtCOO 0647 PhCO- 3-pyridyl EtCOO 0659 PhCO- 4-pyridyl EtCOO 20 0663 PhCO- 2-furyl EtCOO 0670 PhCO- 3-furyl EtCOO 0687 PhCO- 2-thienyl EtCOO 0691 PhCO- 3-thienyl EtCOO 0706 PhCO- cyclopropyl EtCOO 25 0719 PhCO- isopropyl EtCOO- WO 01/57013 PCT/USO1/03624 91 0720 PhCO- cyclobutyl EtCOO 0732 PhCO- p-nitrophenyl EtCOO 0748 PhCO- phenyl EtCOO 0838 tBuOCO- isobutenyl cproCOO 5 0843 tBuOCO- 2-furyl cproCOO 0854 tBuOCO- 2-thienyl cproCOO 0860 tBuOCO- cyclopropyl cproCOO 0879 tBuOCO- p-nitrophenyl cproCOO 0882 tBuOCO- phenyl cproCOO 10 0890 PhCO- isobutenyl cproCOO 0908 PhCO- 2-furyl cproCOO 0919 PhCO- 2-thienyl cproCOO 0923 PhCO- cyclopropyl cproCOO 0937 PhCO- phenyl cproCOO 15 0947 tBuOCO- isobutenyl PrCOO 0951 tBuOCO- 2-pyridyl PrCOO 0966 tBuOCO- 3-pyridyl PrCOO 0978 tBuOCO- 4-pyridy PrCOO 0983 tBuOCO- 2-furyl PrCOO 20 0999 tBuOCO- 3-furyl PrCOO 1003 tBuOCO- 2-thienyl PrCOO 1011 tBuOCO- 3-thienyl PrCOO 1020 tBuOCO- cyclopropyl PrCOO 1031 tBuOCO- isopropyl PrCOO 25 1044 tBuOCO- cyclobutyl PrCOO 1060 tBuOCO- phenyl PrCOO 1879 tBuOCO- isobutenyl 2-ThCOO 1883 tBuOCO- 2-pyridyl 2-ThCOO 1892 tBuOCO- 2-furyl 2-ThCOO 30 1900 tBuOCO- 2-thienyl 2-ThCOO 1911 tBuOCO- p-nitrophenyl 2-ThCOO- WO 01/57013 PCT/USO1/03624 92 1923 tBuOCO- 3-furyl 2-ThCOO 1939 tBuOCO- 3-thienyl 2-ThCOO 1948 tBuOCO- 3-pyridyl 2-ThCOO 1954 tBuOCO- 4-pyridyl 2-ThCOO 5 1964 tBuOCO- isopropyl 2-ThCOO 1970 tBuOCO- cyclobutyl 2-ThCOO 1988 tBuOCO- phenyl 2-ThCOO 2101 tBuOCO- isobutenyl 2-FuCOO 2111 tBuOCO- 2-pyridyl 2-FuCOO 10 2124 tBuOCO- 3-pyridyl 2-FuCOO 2132 tBuOCO- 4-pyridyl 2-FuCOO 2142 tBuOCO- 2-furyl 2-FuCOO 2159 tBuOCO- 3-furyl 2-FuCOO 2164 tBuOCO- 2-thienyl 2-FuCOO 15 2173 tBuOCO- 3-thienyl 2-FuCOO 2181 tBuOCO- isopropyl 2-FuCOO 2199 tBuOCO- cyclobutyl 2-FuCOO 2202 tBuOCO- p-nitrophenyl 2-FuCOO 2212 tBuOCO- phenyl 2-FuCOO 20 2226 tBuOCO- isobutenyl iPrCOO 2238 tBuOCO- 2-pyridyl iPrCOO 2242 tBuOCO- 3-pyridyl iPrCOO 2255 tBuOCO- 4-pyridyl iPrCOO 2269 tBuOCO- 2-furyl iPrCOO 25 2273 tBuOCO- 3-furyl iPrCOO 2287 tBuOCO- 2-thienyl iPrCOO 2291 tBuOCO- 3-thienyl iPrCOO 2306 tBuOCO- isopropyl iPrCOO 2319 tBuOCO- cyclobutyl iPrCOO 30 2320 tBuOCO- p-nitrophenyl iprCOO 2332 tBuOCO- isobutenyl tC 3

H

5

COO-

WO 01/57013 PCT/USO1/03624 93 2348 tBuOCO- 2-pyridyl tC 3

H

5

COO

2353 tBuOCO- 3-pyridyl tC 3

H

5

COO

2366 tBuOCO- 4-pyridyl tC 3

H

5

COO

2379 tBuOCO- 2-furyl tC 3

H

5

COO

5 2380 tBuOCO- 3-furyl tC 3

H

5

COO

2392 tBuOCO- 2-thienyl tC 3

H

5

COO

2408 tBuOCO- 3-thienyl tC 3

H

5

COO

2413 tBuOCO- isopropyl tC 3

H

5

COO

2424 tBuOCO- cyclobutyl tC 3

H

5

COO

10 2439 tBuOCO- p-nitrophenyl tC 3

H

5

COO

2442 tBuOCO- phenyl tC 3

HCOO

2455 tBuOCO- isobutenyl ibueCOO 2464 tBuOCO- 2-pyridyl ibueCOO 2472 tBuOCO- 4-pyridyl ibueCOO 15 2488 tBuOCO- 2-furyl ibueCOO 2499 tBuOCO- 3-furyl ibueCOO 2503 tBuOCO- 2-thienyl ibueCOO 2511 tBuOCO- 3-thienyl ibueCOO 2520 tBuOCO- phenyl ibueCOO 20 2781 tBuOCO- 3-furyl cproCOO 2794 tBuOCO- 3-thienyl cproCOO 2802 tBuOCO- 2-pyridyl cproCOO 2813 tBuOCO- 4-pyridyl cproCOO 2826 PhCO- 3-furyl cproCOO 25 2838 PhCO- 3-thienyl cproCOO 2844 PhCO- 2-pyridyl cproCOO 2855 PhCO- 4-pyridyl cproCOO 2869 PhCO- p-nitrophenyl cproCOO 3053 2-FuCO- 2-thienyl EtCOO 30 3071 iPrOCO- 2-thienyl cproCOO 3096 EtOCO- 2-thienyl PrCOO- WO 01/57013 PCT/USO1/03624 94 3102 iBuOCO- 2-furyl cproCOO 3110 iBuOCO- 2-furyl PrCOO 3129 iBuOCO- 2-thienyl cproCOO 3132 nPrCO- 2-thienyl cproCOO 5 3148 nPrCO- 2-thienyl PrCOO 3163 iBuOCO- 2-thienyl EtCOO 3204 PhCO- 2-furyl PrCOO 3219 nPrCO- 2-furyl EtCOO 3222 nPrCO- 2-furyl PrCOO 10 3258 PhCO- 2-thienyl PrCOO 3265 iBuOCO- 2-thienyl PrCOO 3297 2-FuCO- 2-thienyl cproCOO 3314 nPrCO- 2-thienyl PrCOO 3352 2-FuCO- 2-thienyl PrCOO 15 3361 iPrOCO- 2-thienyl EtCOO 3370 EtOCO- 2-thienyl EtCOO 3408 2-ThCO- 2-thienyl PrCOO 3417 iPrOCO- 2-furyl PrCOO 3425 2-ThCO- 2-thienyl EtCOO 20 3453 2-ThCO- 2-thienyl cproCOO 3482 PhCO- cyclopropyl PrCOO 3494 tC 3

H

5 CO- 2-thienyl EtCOO 3513 tC 3

H

5 CO- 2-thienyl cproCOO 3522 iPrOCO- 2-furyl EtCOO 25 3535 EtOCO- 2-furyl EtCOO 3543 C 4

H

7 CO- 2-thienyl cproCOO 3588 C 4

H

7 CO- 2-thienyl EtCOO 3595 tC 3

H

5 CO- 2-thienyl PrCOO 3603 C 4

H

7 CO- 2-thienyl PrCOO 30 3644 2-ThCO- 2-furyl EtCOO 3656 2-ThCO- 2-furyl PrCOO- WO 01/57013 PCT/USO1/03624 95 3663 2-ThCO- 2-furyl cproCOO 3677 EtOCO- 2-furyl cproCOO 3686 2-FuCO- 2-furyl PrCOO 3693 EtOCO- 2-furyl PrCOO 5 3800 C 4

H

7 CO- 2-furyl PrCOO 3818 2-FuCO- 2-furyl EtCOO 3853 iPrOCO- 2-furyl cproCOO 3866 2-FuCO- 2-furyl cproCOO 3909 iPrOCO- 2-thienyl PrCOO 10 3938 C 4

H

7 CO- 2-furyl cproCOO 3945 C 4

H

7 CO- 2-furyl EtCOO 3957 iBuOCO- 2-furyl PrCOO 3971 tC 3

H

5 CO- 2-furyl cproCOO 3982 tC 3

H

5 CO- 2-furyl EtCOO 15 3994 tC 3

H

5 CO- 2-furyl PrCOO 4051 EtOCO- 2-thienyl cproCOO 4062 nPrCO- 2-furyl cproCOO 4112 3-PyCO- 2-thienyl cproCOO 4121 3-PyCO- 2-thienyl EtCOO 20 4190 3-PyCO- 2-thienyl PrCOO 4207 4-PyCO- 2-thienyl EtCOO 4329 ibueCO- 2-thienyl cproCOO 4335 ibueCO- 2-thienyl EtCOO 4344 ibueCO- 2-thienyl PrCOO 25 4665 iBuOCO- 3-furyl cproCOO 4704 iBuOCO- 3-furyl PrCOO 4711 iBuOCO- 3-thienyl EtCOO 4720 iBuOCO- isobutenyl cproCOO 4799 iBuOCO- cyclopropyl EtCOO 30 4808 iBuOCO- cyclopropyl nPrCOO 4834 iBuOCO- 3-thienyl nPrCOO- WO 01/57013 PCT/USO1/03624 96 4888 tC 3

H

5 CO- 3-furyl EtCOO 4919 tC 3

H

5 CO- 3-furyl nPrCOO 4944 tC 3

H

5 CO- 3-furyl cproCOO 5011 iBuOCO- 3-thienyl cproCOO 5 5040 tC 3 HCO- 3-thienyl cproCOO 5065 iBuOCO- isobutenyl EtCOO 5144 iBuOCO- isobutenyl nPrCOO 5232 iBuOCO- cyclopropyl cproCOO 5495 tBuOCO- 3-furyl EtCOO 10 6522 tAmOCO- 2-furyl EtCOO Example 8: Additional Taxanes having C-10 Ester and C-7 Hydroxy Substituents Following the processes described in Example 6 and elsewhere herein, the following specific taxanes having structural formula (7) may be prepared wherein Rio is as previously defined, including wherein R 1 . is RaCOO- and Ra is 15 (i) substituted or unsubstituted C2 to C8 alkyl such as ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or, 20 unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, R 1 0 may be R1 0 aCOO wherein R1Oa is ethyl, straight, branched or cyclic propyl, straight or branched propenyl, isobutenyl, furyl or thienyl.

X

5 NH 0 RIO 0 OH X3 = O OH HO . BzO~c Aco 25 (7) WO 01/57013 PCT/USO1/03624 97 X5 X3 Rio tBuOCO- 2-furyl RaCOO tBuOCO- 3-furyl RaCOO tBuOCO- 2-thienyl RaCOO 5 tBuOCO- 3-thienyl RaCOO tBuOCO- 2-pyridyl RaCOO tBuOCO- 3-pyridyl RaCOO tBuOCO- 4-pyridyl RCOO tBuOCO- isobutenyl RCOO 10 tBuOCO- isopropyl RaCOO tBuOCO- cyclopropyl RaCOO tBuOCO- cyclobutyl RaCOO tBuOCO- cyclopentyl RaCOO tBuOCO- phenyl RaCOO 15 benzoyl 2-furyl RaCOO benzoyl 3-furyl RaCOO benzoyl 2-thienyl RaCOO benzoyl 3-thienyl RaCOO benzoyl 2-pyridyl RaCOO 20 benzoyl 3-pyridyl RaCOO benzoyl 4-pyridyl RaCOO benzoyl isobutenyl RaCOO benzoyl isopropyl RaCOO benzoyl cyclopropyl RaCOO 25 benzoyl cyclobutyl RaCOO benzoyl cyclopentyl RCOO benzoyl phenyl RaCOO 2-FuCO- 2-furyl RaCOO 2-FuCO- 3-furyl RaCOO 30 2-FuCO- 2-thienyl RaCOO 2-FuCO- 3-thienyl RaCOO- WO 01/57013 PCT/USO1/03624 98 2-FuCO- 2-pyridyl RaCOO 2-FuCO- 3-pyridyl RaCOO 2-FuCO- 4-pyridyl RaCOO 2-FuCO- isobutenyl RaCOO 5 2-FuCO- isopropyl RaCOO 2-FuCO- cyclopropyl RaCOO 2-FuCO- cyclobutyl RaCOO 2-FuCO- cyclopentyl RaCOO 2-FuCO- phenyl RaCOO 10 2-ThCO- 2-furyl RaCOO 2-ThCO- 3-furyl RaCOO 2-ThCO- 2-thienyl RaCOO 2-ThCO- 3-thienyl RaCOO 2-ThCO- 2-pyridyl RaCOO 15 2-ThCO- 3-pyridyl RaCOO 2-ThCO- 4-pyridyl RaCOO 2-ThCO- isobutenyl RaCOO 2-ThCO- isopropyl RaCOO 2-ThCO- cyclopropyl RaCOO 20 2-ThCO- cyclobutyl RaCOO 2-ThCO- cyclopentyl RaCOO 2-ThCO- phenyl RaCOO 2-PyCO- 2-furyl RaCOO 2-PyCO- 3-furyl RaCOO 25 2-PyCO- 2-thienyl RaCOO 2-PyCO- 3-thienyl RaCOO 2-PyCO- 2-pyridyl RaCOO 2-PyCO- 3-pyridyl RaCOO 2-PyCO- 4-pyridyl RaCOO 30 2-PyCO- isobutenyl RaCOO 2-PyCO- isopropyI RaCOO- WO 01/57013 PCT/USO1/03624 99 2-PyCO- cyclopropyl RaCOO 2-PyCO- cyclobutyl RaCOO 2-PyCO- cyclopentyl RaCOO 2-PyCO- phenyl RaCOO 5 3-PyCO- 2-furyl RaCOO 3-PyCO- 3-furyl RaCOO 3-PyCO- 2-thienyl RCOO 3-PyCO- 3-thienyl RaCOO 3-PyCO- 2-pyridyl RaCOO 10 3-PyCO- 3-pyridyl RaCOO 3-PyCO- 4-pyridyl RaCOO 3-PyCO- isobutenyl RaCOO 3-PyCO- isopropyl RaCOO 3-PyCO- cyclopropyl RaCOO 15 3-PyCO- cyclobutyl RaCOO 3-PyCO- cyclopentyl RaCOO 3-PyCO- phenyl RaCOO 4-PyCO- 2-furyl RaCOO 4-PyCO- 3-furyl RaCOO 20 4-PyCO- 2-thienyl RaCOO 4-PyCO- 3-thienyl RaCOO 4-PyCO- 2-pyridyl RaCOO 4-PyCO- 3-pyridyl RaCOO 4-PyCO- 4-pyridyl RaCOO 25 4-PyCO- isobutenyl RaCOO 4-PyCO- isopropyl RaCOO 4-PyCO- cyclopropyl RaCOO 4-PyCO- cyclobutyl RaCOO 4-PyCO- cyclopentyl RaCOO 30 4-PyCO- phenyl RaCOO

C

4

H

7 CO- 2-furyl RaCOO- WO 01/57013 PCT/USO1/03624 100

C

4

H

7 CO- 3-furyl RaCOO

C

4

H

7 CO- 2-thienyl RaCOO

C

4

H

7 CO- 3-thienyl RaCOO

C

4

H

7 CO- 2-pyridyl RaCOO 5 C 4

H

7 CO- 3-pyridyl RaCOO

C

4

H

7 CO- 4-pyridyl RaCOO

C

4

H

7 CO- isobutenyl RaCOO

C

4

H

7 CO- isopropyl RaCOO

C

4

H

7 CO- cyclopropyl RaCOO 10 C 4

H

7 CO- cyclobutyl RaCOO

C

4

H

7 CO- cyclopentyl RaCOO

C

4

H

7 CO- phenyl RaCOO EtOCO- 2-furyl RaCOO EtOCO- 3-furyl RaCOO 15 EtOCO- 2-thienyl RaCOO EtOCO- 3-thienyl RaCOO EtOCO- 2-pyridyl RaCOO EtOCO- 3-pyridyl RaCOO EtOCO- 4-pyridyl RaCOO 20 EtOCO- isobutenyl RaCOO EtOCO- isopropyl RaCOO EtOCO- cyclopropyl RaCOO EtOCO- cyclobutyl RaCOO EtOCO- cyclopentyl RaCOO 25 EtOCO- phenyl RaCOO ibueCO- 2-furyl RaCOO ibueCO- 3-furyl RaCOO ibueCO- 2-thienyl RaCOO ibueCO- 3-thienyl RaCOO 30 ibueCO- 2-pyridyl RaCOO ibueCO- 3-pyridyl RCOO- WO 01/57013 PCT/USO1/03624 101 ibueCO- 4-pyridyl RaCOO ibueCO- isobutenyl RaCOO ibueCO- isopropyl RaCOO ibueCO- cyclopropyl RaCOO 5 ibueCO- cyclobutyl RaCOO ibueCO- cyclopentyl RaCOO ibueCO- phenyl RaCOO iBuCO- 2-furyl RaCOO iBuCO- 3-furyl RaCOO 10 iBuCO- 2-thienyl RaCOO iBuCO- 3-thienyl RaCOO iBuCO- 2-pyridyl RaCOO iBuCO- 3-pyridyl RaCOO iBuCO- 4-pyridyl RaCOO 15 iBuCO- isobutenyl RaCOO iBuCO- isopropyl RaCOO iBuCO- cyclopropyl RaCOO iBuCO- cyclobutyl RaCOO iBuCO- cyclopentyl RaCOO 20 iBuCO- phenyl RaCOO iBuOCO- 2-furyl RaCOO iBuOCO- 3-furyl RaCOO iBuOCO- 2-thienyl RaCOO iBuOCO- 3-thienyl RaCOO 25 iBuOCO- 2-pyridyl RaCOO iBuOCO- 3-pyridyl RaCOO iBuOCO- 4-pyridyl RaCOO iBuOCO- isobutenyl RaCOO iBuOCO- isopropyl RaCOO 30 iBuOCO- cyclopropyl RaCOO iBuOCO- cyclobutyl RaCOO- WO 01/57013 PCT/USO1/03624 102 iBuOCO- cyclopentyl RaCOO iBuCO- phenyl RaCOO iPrOCO- 2-furyl RaCOO iPrOCO- 3-furyl RaCOO 5 iPrOCO- 2-thienyl RaCOO iPrOCO- 3-thienyl RaCOO iPrOCO- 2-pyridyl RaCOO iPrOCO- 3-pyridyl RaCOO iPrOCO- 4-pyridyl RaCOO 10 iPrOCO- isobutenyl RaCOO iPrOCO- isopropyl RaCOO iPrOCO- cyclopropyl RaCOO iPrOCO- cyclobutyl RaCOO iPrOCO- cyclopentyl RaCOO 15 iPrOCO- phenyl RaCOO nPrOCO- 2-furyl RaCOO nPrOCO- 3-furyl RaCOO nPrOCO- 2-thienyl RaCOO nPrOCO- 3-thienyl RaCOO 20 nPrOCO- 2-pyridyl RaCOO nPrOCO- 3-pyridyl RCOO nPrOCO- 4-pyridyl RaCOO nPrOCO- isobutenyl RaCOO nPrOCO- isopropyl RaCOO 25 nPrOCO- cyclopropyl RaCOO nPrOCO- cyclobutyl RaCOO nPrOCO- cyclopentyl RaCOO nPrOCO- phenyl RaCOO nPrCO- 2-furyl RaCOO 30 nPrCO- 3-furyl RaCOO nPrCO- 2-thienyl RaCOO- WO 01/57013 PCT/USO1/03624 103 nPrCO- 3-thienyl RaCOO nPrCO- 2-pyridyl RaCOO nPrCO- 3-pyridyl RaCOO nPrCO- 4-pyridyl RaCOO 5 nPrCO- isobutenyl RaCOO nPrCO- isopropyl RaCOO nPrCO- cyclopropyl RaCOO nPrCO- cyclobutyl RaCOO nPrCO- cyclopentyl RaCOO 10 nPrOCO- phenyl RaCOO tBuOCO- cyclopentyl EtCOO benzoyl cyclopentyl EtCOO 2-FuCO- 3-furyl EtCOO 2-FuCO- 3-thienyl EtCOO 15 2-FuCO- 2-pyridyl EtCOO 2-FuCO- 3-pyridyl EtCOO 2-FuCO- 4-pyridyl EtCOO 2-FuCO- isobutenyl EtCOO 2-FuCO- isopropyl EtCOO 20 2-FuCO- cyclopropyl EtCOO 2-FuCO- cyclobutyl EtCOO 2-FuCO- cyclopentyl EtCOO 2-FuCO- phenyl EtCOO 2-ThCO- 3-furyl EtCOO 25 2-ThCO- 3-thienyl EtCOO 2-ThCO- 2-pyridyl EtCOO 2-ThCO- 3-pyridyl EtCOO 2-ThCO- 4-pyridyl EtCOO 2-ThCO- isobutenyl EtCOO 30 2-ThCO- isopropyl EtCOO 2-ThCO- cyclopropyl EtCOO- WO 01/57013 PCT/USO1/03624 104 2-ThCO- cyclobutyl EtCOO 2-ThCO- cyclopentyl EtCOO 2-ThCO- phenyl EtCOO 2-PyCO- 2-furyl EtCOO 5 2-PyCO- 3-furyl EtCOO 2-PyCO- 2-thienyl EtCOO 2-PyCO- 3-thienyl EtCOO 2-PyCO- 2-pyridyl EtCOO 2-PyCO- 3-pyridyl EtCOO 10 2-PyCO- 4-pyridyl EtCOO 2-PyCO- isobutenyl EtCOO 2-PyCO- isopropyl EtCOO 2-PyCO- cyclopropyl EtCOO 2-PyCO- cyclobutyl EtCOO 15 2-PyCO- cyclopentyl EtCOO 2-PyCO- phenyl EtCOO 3-PyCO- 2-furyl EtCOO 3-PyCO- 3-furyl EtCOO 3-PyCO- 3-thienyl EtCOO 20 3-PyCO- 2-pyridyl EtCOO 3-PyCO- 3-pyridyl EtCOO 3-PyCO- 4-pyridyl EtCOO 3-PyCO- isobutenyl EtCOO 3-PyCO- isopropyl EtCOO 25 3-PyCO- cyclopropyl EtCOO 3-PyCO- cyclobutyl EtCOO 3-PyCO- cyclopentyl EtCOO 3-PyCO- phenyl EtCOO 4-PyCO- 2-furyl EtCOO 30 4-PyCO- 3-furyl EtCOO 4-PyCO- 3-thienyl EtCOO- WO 01/57013 PCT/USO1/03624 105 4-PyCO- 2-pyridyl EtCOO 4-PyCO- 3-pyridyl EtCOO 4-PyCO- 4-pyridyl EtCOO 4-PyCO- isobutenyl EtCOO 5 4-PyCO- isopropyl EtCOO 4-PyCO- cyclopropyl EtCOO 4-PyCO- cyclobutyl EtCOO 4-PyCO- cyclopentyl EtCOO 4-PyCO- phenyl EtCOO 10 C 4

H

7 CO- 3-furyl EtCOO

C

4

H

7 CO- 3-thienyl EtCOO

C

4

H

7 CO- 2-pyridyl EtCOO

C

4

H

7 CO- 3-pyridyl EtCOO

C

4

H

7 CO- 4-pyridyl EtCOO 15 C 4

H

7 CO- isobutenyl EtCOO

C

4

H

7 CO- isopropyl EtCOO

C

4

H

7 CO- cyclopropyl EtCOO

C

4

H

7 CO- cyclobutyl EtCOO

C

4

H

7 CO- cyclopentyl EtCOO 20 C 4

H

7 CO- phenyl EtCOO EtOCO- 3-furyl EtCOO EtOCO- 3-thienyl EtCOO EtOCO- 2-pyridyl EtCOO EtOCO- 3-pyridyl EtCOO 25 EtOCO- 4-pyridyl EtCOO EtOCO- isobutenyl EtCOO EtOCO- isopropyl EtCOO EtOCO- cyclopropyl EtCOO EtOCO- cyclobutyl EtCOO 30 EtOCO- cyclopentyl EtCOO EtOCO- phenyl EtCOO- WO 01/57013 PCT/USO1/03624 106 ibueCO- 2-furyl EtCOO ibueCO- 3-furyl EtCOO ibueCO- 3-thienyl EtCOO ibueCO- 2-pyridyl EtCOO 5 ibueCO- 3-pyridyl EtCOO ibueCO- 4-pyridyl EtCOO ibueCO- isobutenyl EtCOO ibueCO- isopropyl EtCOO ibueCO- cyclopropyl EtCOO 10 ibueCO- cyclobutyl EtCOO ibueCO- cyclopentyl EtCOO ibueCO- phenyl EtCOO iBuCO- 2-furyl EtCOO iBuCO- 3-furyl EtCOO 15 iBuCO- 2-thienyl EtCOO iBuCO- 3-thienyl EtCOO iBuCO- 2-pyridyl EtCOO iBuCO- 3-pyridyl EtCOO iBuCO- 4-pyridyl EtCOO 20 iBuCO- isobutenyl EtCOO iBuCO- isopropyl EtCOO iBuCO- cyclopropyl EtCOO iBuCO- cyclobutyl EtCOO iBuCO- cyclopentyl EtCOO 25 iBuCO- phenyl EtCOO iBuOCO- 2-furyl EtCOO iBuOCO- 2-pyridyl EtCOO iBuOCO- 3-pyridyl EtCOO iBuOCO- 4-pyridyi EtCOO 30 iBuOCO- isopropyl EtCOO iBuOCO- cyclobutyl EtCOO- WO 01/57013 PCT/USO1/03624 107 iBuOCO- cyclopentyl EtCOO iBuCO- phenyl EtCOO iPrOCO- 3-furyl EtCOO iPrOCO- 3-thienyl EtCOO 5 iPrOCO- 2-pyridyl EtCOO iPrOCO- 3-pyridyl EtCOO iPrOCO- 4-pyridyl EtCOO iPrOCO- isobutenyl EtCOO iPrOCO- isopropyl EtCOO 10 iPrOCO- cyclopropyl EtCOO iPrOCO- cyclobutyl EtCOO iPrOCO- cyclopentyl EtCOO iPrOCO- phenyl EtCOO nPrOCO- 2-furyl EtCOO 15 nPrOCO- 3-furyl EtCOO nPrOCO- 2-thienyl EtCOO nPrOCO- 3-thienyl EtCOO nPrOCO- 2-pyridyl EtCOO nPrOCO- 3-pyridyl EtCOO 20 nPrOCO- 4-pyridyl EtCOO nPrOCO- isobutenyl EtCOO nPrOCO- isopropyl EtCOO nPrOCO- cyclopropyl EtCOO nPrOCO- cyclobutyl EtCOO 25 nPrOCO- cyclopentyl EtCOO nPrOCO- phenyl EtCOO nPrCO- 3-furyl EtCOO nPrCO- 3-thienyl EtCOO nPrCO- 2-pyridyl EtCOO 30 nPrCO- 3-pyridyl EtCOO nPrCO- 4-pyridyl EtCOO- WO 01/57013 PCT/US01/03624 108 nPrCO- isobutenyl EtCOO nPrCO- isopropyl EtCOO nPrCO- cyclopropyl EtCOO nPrCO- cyclobutyl EtCOO 5 nPrCO- cyclopentyl EtCOO nPrOCO- phenyl EtCOO Example 9: Additional Taxanes having C-1 0 Ester and C-7 Hydroxy Substituents Following the processes described in Example 6 and elsewhere herein, the following specific taxanes having structural formula (8) may be prepared, wherein 10 R 7 is hydroxy and RIO in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein RIO is RIOaCOO- and R1oa s (i) substituted or unsubstituted, preferably unsubstituted, C2 to C alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, C2 to C, alkenyl (straight, branched or 15 cyclic), such as ethenyi, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C2 to C alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted, preferably unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or 20 pyridyl. In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 and RIO each have the beta stereochemical configuration. 25 In the "B" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each 30 have the beta stereochemical configuration. In the "C" series of compounds, X 1 0 and R 9 8 are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Roa is preferably substituted or WO 01/57013 PCT/US01/03624 109 unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "D" and "E" series of compounds, X,, is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 5 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R. (series D only) and RIO each have the beta stereochemical configuration. In the "F" series of compounds, X1 0 , R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued 10 furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and RIO each have the beta stereochemical configuration. In the "G" series of compounds, X 1 0 and R 2 a are as otherwise as defined 15 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and RIO each have the beta stereochemical configuration. 20 In the "H" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 , is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 each have the beta 25 stereochemical configuration. In the "I" series of compounds, XIO and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued fury], thienyl, or pyridyl, X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or 30 unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and RIO each have the beta stereochemical configuration. In the "J" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, 35 pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or WO 01/57013 PCT/USO1/03624 110 unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 0 each have the beta stereochemical configuration. In the "K" series of compounds, X 1 ., R 2 , and R., are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued 5 furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R10 each have the beta stereochemical configuration. Any substituents of each X 3 , X 5 , R 2 , R 9 , R 1 . may be hydrocarbyl or any of 10 the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

X

5 NH O R10 R9 15 OH '

R

14 HO O . O2 Ac (8) Series X 5 X3 R10 R2 R9 R1 Al -COOX 1 0 heterocyclo R10COO- C 6 HCOO- 0 H 20 A2 -COX 1 0 heterocyclo R1oCOO- C 6

H

5 COO- 0 H A3 -CONHX 1 0 heterocyclo R10COO- C 6

H

5 COO- 0 H A4 -COOX 10 optionally RIOaCOO- C 6

H

5 COO- 0 H substituted

C

2 to C 8 alkyl A5 -COXO optionally RioCOO- C 6

H

5 COO- 0 H substituted C2 to C. alkyl A6 -CONHX 1 0 optionally R 1 oCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkyl WO 01/57013 PCT/USO1/03624 111 A7 -COOX 1 0 optionally R1oaCOO- C 6

H

5 COO- 0 H substituted C2 to C. alkenyl A8 -COX 1 0 optionally RjOCOO- C 6

H

5 COO- 0 H substituted C2 to C alkenyl A9 -CONHX, optionally RjoaCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkenyl A10 -COOX 1 0 optionally RjOaCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkynyl 5 All -COX 10 optionally RjoaCOO- C 6

H

5 COO- 0 H substituted C2 to C, alkynyl A12 -CONHX 1 optionally R~aCOO- CcH 5 COO- 0 H substituted C2 to C8 alkynyl B1 -COOXIO heterocyclo RioaCOO- R 2 ,C00- 0 H B2 -COX 1 0 heterocyclo RioaCOO- R 2 aCOO- 0 H B3 -CONHX,, heterocyclo R1 0 aCOO- R 2 aCOO- 0 H 10 B4 -COOX 10 optionally RjoCOO- R 2 aCOO- O H substituted C2 to C8 alkyl B5 -COX 1 0 optionally RioeCOO- R 2 aCOO- O H substituted C2 to C8 alkyl B6 -CONHX 1 optionally RloCOO- R 2 COO- 0 H substituted C2 to C alkyl B7 -COOX 10 optionally RioCOO- R 2 aCOO- 0 H substituted C2 to C. alkenyl B8 -COX 1 0 optionally RloCOO- R 2 COO- O H substituted C2 to C alkenyl 15 B9 -CONHXO optionally RoCOO- R 2 aCOO- 0 H substituted C2 to C alkenyl B10 -COOXIO optionally R,0,COO- R 2 ,COO- O H substituted C2 to C alkynyl WO 01/57013 PCT/US01/03624 112 B11 -COX 1 0 optionally R 10 C00- R 2 aCOO- 0 H substituted C2 to C. alkynyl B12 -CONHX 1 optionally RioaCOO- R 2 ,C00- 0 H substituted C2 to C alkynyl C1 -COOX 1 0 heterocyclo ROaC00- CH5COO- R 9 C00- H C2 -COX 10 heterocyclo R 1 oCOO- CHCOO- RgaCOO- H 5 C3 -CONHXo heterocyclo RjoaCOO- CH 5 COO- RgaCOO- H C4 -COOX 1 0 optionally R1Oa0OO- C 6 HCOO- R 9 aCOO- H substituted C2 to C8 alkyl C5 -COX 1 0 optionally RoaC0OO- C 6 HCOO- RqaCOO- H substituted C2 to C8 alkyl C6 -CONHX,, optionally ROaC0OO- CHCOO- R 9 ,C00- H substituted C2 to C. alkyl C7 -COOXlo optionally RioaCOO- C 8 HCOO- ReaCOO- H substituted C2 to C alkenyl 10 C8 -COX 1 0 optionally ROaC00- C 6 HCOO- R 9 aCOO- H substituted C2 to C alkenyl C9 -CONHX 1 0 optionally R1OaCOO- CH 5 COO- RgaCOO- H substituted C2 to C alkenyl C10 -COOX 1 0 optionally R1Oa0OO- CHCOO- RgaCOO- H substituted C2 to C alkynyl C11 -COX 1 0 optionally R 1 oCOO- CH 5 COO- RgCOO- H substituted C2 to C8 alkynyl C12 -CONHX,, optionally R 102 ,C00- CH 5 COO- R 9 aCOO- H substituted C2 to C alkynyl 15 D1 -COOXo heterocyclo R1oaCOO- C 8 HCOO- OH H D2 -COX 1 0 heterocyclo RjoaCOO- CHCOO- OH H D3 -CONHX 1 heterocyclo RjoaCOO C 6

H

5 COO- OH H WO 01/57013 PCT/USO1/03624 113 D4 -COOX 1 0 optionally R1OaCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkyl D5 -COXO optionally ROC00- C 6

H

5 COO- OH H substituted C2 to C alkyl D6 -CONHX,, optionally RIoaCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkyl D7 -COOX 1 0 optionally RiOCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkenyl 5 D8 -COX 1 0 optionally R1 0 aCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkenyl D9 -CONHX 1 optionally RiOaCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkenyl D10 -COOXIO optionally R 10 COO- C 6

H

5 COO- OH H substituted C2 to C alkynyl D11 -COX 1 0 optionally R1a0COO- C 6

H

5 COO- OH H substituted C2 to C8 alkynyl D12 -CONHX 1 0 optionally R 10 COO- C 6

H

5 COO- OH H substituted C2 to C alkynyl 10 El -COOX 1 0 heterocyclo R1OaCOO- C 6

H

5 COO- 0 OH E2 -COX 10 heterocyclo RioaCOO- C 6

H

5 COO- 0 OH E3 -CONHXO heterocyclo R 1 OCOO- C 6

H

5 COO- 0 OH E4 -COOXIO optionally R1 0 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkyl E5 -COX 10 optionally RioaCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl 15 E6 -CONHX 1 0 optionally RoaC0OO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl E7 -COOXO optionally RjOaCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 114 E8 -COX 1 optionally RioCOO- C6H 5 COO- 0 OH substituted C2 to C alkenyl E9 -CONHX 1 optionally RIOaCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkenyl E1o -COOX 1 0 optionally R10aCOO- C 6

H

5 COO- 0 OH substituted

C

2 to C alkynyl El1 -COX 10 optionally RjoaCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl 5 E12 -CONHX 1 0 optionally R1OaCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl Fl -COOX 1 0 heterocyclo R 10 COO- R 2 COO- R 9 aCOO- H F2 -COXIO heterocyclo R 1 OCOO- R 2 ,COO- ReaCOO- H F3 -CONHXO heterocyclo RlOCOO- R 2 ,COO- RgaCOO- H F4 -COOX 1 0 optionally RioCOO- R 2 aCOO- RgaCOO- H substituted C2 to C alkyl 10 F5 -COXO optionally RioaCOO- R 2 aCOO- Rg.COO- H substituted C2 to C. alkyl F6 -CONHXO optionally RioaCOO- R 2 aCOO- RgzCOO- H substituted C2 to C8 alkyl F7 -COOX 1 0 optionally R1OaCOO- R 2 aCOO- R 9 COO- H substituted C2 to C alkenyl F8 -COX 10 optionally R1OaCOO- R 2 aCOO- Rq.COO- H substituted C2 to C alkenyl F9 -CONHX 1 optionally R 1 OCOO- R 2 aCOO- ReaCOO- H substituted C2 to C8 alkenyl 15 FIO -COOX 10 optionally R1OaCOO- R 2 COO- R 9 aCOO- H substituted C2 to C alkynyl Fl1 -COX 0 o optionally R1OaCOO- R 2 aCOO- R0,COO- H substituted C2 to C alkynyl WO 01/57013 PCT/USO1/03624 115 F12 -CONHX 1 optionally R 1 OCOO- R 2 C00- R0,COO- H substituted C2 to C8 alkynyl G1 -COOX 1 0 heterocyclo RIOCOO- R 2 aCOO- OH H G2 -COX 1 e heterocyclo R 102 ,C00- R 2 aCOO- OH H G3 -CONHX 1 heterocyclo R 1 OCOO- R 2 aCOO- OH H 5 G4 -COOXO optionally RloCOO- R 2 C00- OH H substituted C2 to C alkyl G5 -COXIO optionally RoCOO- R 2 aCOO- OH H substituted C2 to C alkyl G6 -CONHXO optionally RioCOO- R 2 aCOO- OH H substituted

C

2 to C. alkyl G7 -COOXO optionally R1OaCOO- R 2 ,COO- OH H substituted C2 to C. alkenyl G8 -COX 1 0 optionally RioaCOO- R 2 aCOO- OH H substituted C2 to C. alkenyl 10 G9 -CONHX 1 optionally RjoaCOO- R 2 aCOO- OH H substituted C2 to C8 alkenyl GIO -COOX 1 0 optionally RioaCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl G11 -COX 1 0 optionally R 1 oCOO- R 2 COO- OH H substituted C2 to C alkynyl G12 -CONHX 1 e optionally R 1 OCOO- R 2 aCOO- OH H substituted C2 to C, alkynyl HI -COOXIO heterocyclo R1OaCOO- C 6

H

5 COO- OH OH 15 H2 -COX 10 heterocyclo RjoaCOO- C 6

H

5 COO- OH OH H3 -CONHX 1 heterocyclo RIOCOO- C 6

H

5 COO- OH OH H4 -COOX 1 0 optionally RjoCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl WO 01/57013 PCT/USO1/03624 116 H5 -COXO optionally R,0,COO- C6H 5 COO- OH OH substituted

C

2 to C alkyl H6 -CONHXO optionally R 1 o,COO- CHCOO- OH OH substituted C2 to C alkyl H7 -COOX 1 0 optionally R 1 OCOO- CH COO- OH OH substituted C2 to C alkenyl H8 -COXIO optionally RjOaCOO- CH 5 COO- OH OH substituted C2 to C alkenyl 5 H9 -CONHXIO optionally RiOaCOO- CHCOO- OH OH substituted C2 to C alkenyl HIO -COOX 1 0 optionally R 1 OCOO- CH 5 COO- OH OH substituted C2 to C, alkynyl HII -COX 1 0 optionally R 102 ,C00- C 6

H

5 COO- OH OH substituted C2 to C. alkynyl H12 -CONHXO optionally RioaCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl 11 -COOX 1 heterocyclo R1 0 aCOO- R 2 aCOO- 0 OH 10 12 -COX 1 0 heterocyclo R1oCOO- R 2 aCOO- 0 OH 13 -CONHXO heterocyclo R1oCOO- R 2 aCOO- 0 OH 14 -COOXO optionally R10COO- R 2 aCOO- O OH substituted C2 to C alkyl 15 -COXO optionally R 10 COO- R 2 ,COO- 0 OH substituted C2 to C alkyl 16 -CONHXO optionally R 1 oCOO- R 2 ,COO- 0 OH substituted C2 to C alkyl 15 17 -COOXO optionally R 1 OCOO- R 2 ,COO- 0 OH substituted C2 to C alkenyl 18 -COX 1 optionally R 1 OCOO- R 2 ,COO- 0 OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 117 19 -CONHX 1 optionally RjoaCOO- R 2 aCOO- 0 OH substituted C2 to C, alkenyl 110 -COOX 10 optionally R1OaCOO- R 2 aCOO- 0 OH substituted C2 to C alkynyl il1 -COX 1 0 optionally RIoCOO- R 2 aCOO- 0 OH substituted C2 to C. alkynyl 112 -CONHX 1 optionally RIoCOO- R 2 aCOO- 0 OH substituted C2 to C, alkynyl 5 J1 -COOX 1 0 heterocyclo RioaCOO- R 2 ,COO- OH OH J2 -COX 10 heterocyclo RioaCOO- R 2 ,COO- OH OH J3 -CONHXIO heterocyclo R 1 oeCOO- R 2 ,COO- OH OH J4 -COOXIO optionally RioaCOO- R 2 ,COO- OH OH substituted C2 to C8 alkyl J5 -COXIO optionally RioaCOO- R 2 aCOO- OH OH substituted C2 to C. alkyl 10 J6 -CONHX 1 optionally RioaCOO- R 2 aCOO- OH OH substituted C2 to C. alkyl J7 -COOXIO optionally RioaCOO- R 2 ,COO- OH OH substituted C2 to C alkenyl J8 -COX 1 0 optionally RloCOO- R 2 aCOO- OH OH substituted C2 to C. alkenyl J9 -CONHX 1 e optionally ROCOO- R 2 ,COO- OH OH substituted C2 to C8 alkenyl J10 -COOX 1 0 optionally RioCOO- R 2 COO- OH OH substituted C2 to C8 alkynyl 15 Ji1 -COX 1 e optionally RiO.COO- R 2 aCOO- OH OH substituted C2 to C. alkynyl J12 -CONHX 1 optionally RjoaCOO- R 2 aCOO- OH OH substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 118 K1 -COOX 1 0 heterocyclo R1oaCOO- R 2 aCOO- R,COO- OH K2 -COX 1 0 heterocyclo RioaCOO- R 2 aCOO- R 92 ,COO- OH K3 -CONHX 1 0 heterocyclo R 1 oCOO- R 2 aCOO- R 9 ,COO- OH K4 -COOXIO optionally RjoCOO- R 2 ,COO- R 9 ,COO- OH substituted C2 to C8 alkyl 5 K5 -COX 10 optionally RjoaCOO- R 2 aCOO- RgCOO- OH substituted C2 to C alkyl K6 -CONHX 1 optionally R1OaCOO- R 2 aCOO- R 9 COO- OH substituted C2 to C alkyl K7 -C00X 1 0 optionally RioaCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C. alkenyl K8 -COX 1 0 optionally RjoaCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C alkenyl K9 -CONHX 1 0 optionally RioaCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C alkenyl 10 K10 -COOX 1 0 optionally RioaCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C, alkynyl K11 -COX 10 optionally RIoCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C. alkynyl K12 -CONHX,, optionally R1OaCOO- R 2 ,COO- R 9 aCOO- OH substituted C2 to C alkynyl Example 10: In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCTI 16) were plated in 60 mm Petri dishes containing 15 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 0C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 7 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was 20 added to the 2.7 mL of medium in the dish. The cells were then incubated with WO 01/57013 PCT/USO1/03624 119 drugs for 72 h at 37 0 C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony 5 counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound. Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 10 docetaxel 0.6 0499 <1 0503 <1 0517 <10 0521 <1 15 0536 <1 0549 <10 0550 <10 0562 <1 0578 <1 20 0583 <10 0596 <10 0602 <1 0611 <10 0625 <1 25 0634 <10 0647 12.0 0659 <1 0663 <1 0670 <1 WO 01/57013 PCT/USO1/03624 120 0687 <1 0691 <1 0706 <1 0719 <10 5 0720 <10 0732 <10 0748 <10 0838 <1 0843 <1 10 0854 <1 0860 <1 0879 <1 0882 <1 0890 <1 15 0908 <1 0919 <1 0923 <1 0937 <10 0947 <1 20 0951 <1 0966 <10 0978 <1 0983 <1 0999 <1 25 1003 <1 1011 <1 1020 <1 1031 <10 1044 <1 30 1060 <1 1879 <10 WO 01/57013 PCT/USO1/03624 121 1883 <10 1892 <1 1900 <1 1911 <10 5 1923 <1 1939 <1 1948 <10 1954 <1 1964 <10 10 1970 <10 1988 <10 2101 <1 2111 <1 2124 <10 15 2132 <1 2142 <1 2159 <1 2164 <1 2173 <1 20 2181 <10 2199 <10 2202 <1 2212 <10 2226 <1 25 2238 <1 2242 <10 2255 <1 2269 <1 2273 <1 30 2287 <1 2291 <1 WO 01/57013 PCT/USO1/03624 122 2306 <10 2319 <10 2320 <1 2332 <1 5 2348 <1 2353 <10 2366 <1 2379 <1 2380 <1 10 2392 <1 2408 <1 2413 <10 2424 <10 2439 <10 15 2442 <1 2455 <10 2464 <1 2472 <1 2488 <1 20 2499 <1 2503 <1 2511 <1 2520 <10 2781 <1 25 2794 <1 2802 <1 2813 <1 2826 <1 2838 <1 30 2844 <10 2855 <1 WO 01/57013 PCT/USO1/03624 123 2869 <10 3053 <1 3071 <1 3096 <1 5 3102 <1 3110 <1 3129 <10 3132 <1 3148 <1 10 3163 <1 3204 <1 3219 <1 3222 <1 3258 <1 15 3265 <10 3297 <1 3314 <1 3352 <1 3361 <1 20 3370 <1 3408 <1 3417 <1 3425 <1 3453 <1 25 3482 <1 3494 <1 3513 <1 3522 <1 3535 <1 30 3543 <10 3588 <10 WO 01/57013 PCT/USO1/03624 124 3595 <1 3603 <10 3644 <1 3656 <1 5 3663 <1 3677 <1 3686 <1 3693 <1 3800 <1 10 3818 <1 3853 <1 3866 <1 3909 <1 3938 <10 15 3945 <1 3957 <10 3971 <1 3982 <1 3994 <1 20 4051 <1 4062 <1 4112 <10 4121 <10 4190 <10 25 4207 <10 4329 <1 4335 <1 4344 <1 4665 <10 30 4704 <10 4711 <10 WO 01/57013 PCT/USO1/03624 125 4720 <10 4799 <1 4808 <10 4834 <10 5 4888 <1 4919 <1 4944 <1 5011 <10 5040 <1 10 5065 <10 5144 <10 5232 <10 5495 <1 6522 <1 15 Example 11: Preparation of Taxane having C-7 Substituted Acetate and C-10 Hydroxy N-Debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl) 10-deacetyl-7-methoxyacetyl taxol (6226) To a solution of N-debenzoyl-N-tert amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyl)-7 20 benzyloxycarbonyl-1 0-deacetyl-1 0-trimethylsilyl taxol (2.50 g, 2.292 mmol) in 50 mL of ethyl acetate was added 10% Pd-C (500 mg) and the mixture stirred at ambient temperature under a H 2 atmosphere (latex balloons) for 45 minutes. TLC of the reaction (silica gel, 1:1 ethyl acetate:hexane) showed the presence of only the product. The mixture was then filtered through a celite bed (5 g) and the celite 25 washed with 25 mL of ethyl acetate. The combined ethyl acetate fraction was concentrated under reduced pressure to give, the N-debenzoy-N-tert amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyl)-1 0-deacetyl 1 0-trimethylsilyl taxol as a white solid 2.10 g (96%) which was directly used in the next step. 30 To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2 methoxy-2-propyl)-1 0-deacetyl-1 0-trimethylsilyl taxol (400 mg, 0.418 mmol) in 4 mL WO 01/57013 PCT/USO1/03624 126 anhydrous pyridine at 0 OC was added DMAP (20 mg, 0.16 mmol) under a nitrogen atmosphere. To this mixture was added drop wise methoxyacetyl chloride (96 mL, 1.045 mmol). TLC (silica gel, 2:3 ethyl acetate:hexane) after 3 h showed no starting material. The reaction was cooled to 0 OC (ice-water bath) and quenched by adding 5 80 mL of water. To the reaction at 0 *C (ice-water bath) was added 4 mL of acetonitrile and 2 mL of 48% aqueous hydrofluoric acid and the cooling bath was removed. The reaction was stirred at room temperature for 8.0 h and then diluted with 60 mL of ethyl acetate and washed with 2x1 0 mL of saturated aqueous NaHCO 3 followed by 15 mL of saturated 10 aqueous NaCl. The organic layer was dried over Na 2

SO

4 and concentrated under reduced pressure to give 365 mg of a yellow solid which was purified by flash chromatography (silica gel, 1:1 ethyl acetate:hexane) to give 325 mg (88%) of N debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-1 0-deacetyl-7 methoxyacetyl taxol: mp 166-167 *C; 1 H NMR (CDCla) 8.12 (m, 2H), 7.62(m, IH), 15 7.46-7.51(m, 2H), 7.40 (m, IH), 6.39(dd, J=3.1, 1.5 Hz, 1H), 6.25 (d, J=3.1 Hz, 1H), 6.21 (dd, J=8.8, 8.7 Hz, 1 H), 5.67(1 H), 5.58 (m, I H), 5.26-5.38(m, 3H), 4.98(m, I H), 4.76(m, 1 H), 4.36 (d, J=9.3 Hz, 1 H), 4.21 (d, J=9.3 Hz, 1 H), 4.09(d, J=7.6 Hz, 1 H), 3.99 (m, 3H), 3.42 (s, 3H), 3.30 (d, J= 5.5 Hz, IH), 2.55-2.60(m, IH), 2.43 (s, 3H), 2.20-2.38(m,2H), 1.98 (s, 3H), 1.96-1.98 (m, 1 H), 1.84 (bs, 3H), 1.62-1.68(m, 2H), 20 1.36(s, 3H), 1.34(s, 3H), 1.23(s, 3H), 1.10(s, 3H), 0.81(t, J=8.2Hz, 3H); Anal. Calcd. for C 4

,H

57

NO

1 7 : C, 61.15; H, 6.50. Found: C, 61.01; H, 6.57. Example 12: Taxanes having C-7 Substituted Acetate and C-10 Hydroxy Substituents The procedures described in Example 11 were repeated, but other suitably 25 protected P-lactams were substituted for the p-lactam of Example 1 to prepare the series of compounds having structural formula (9) and the combinations of substituents identified in the following table: WO 01/57013 PCT/USO1/03624 127 HO

X

5 NH O 0 X3 Ola - R7 OH HO BzOAco 0 (9) Compound X 5 X3

R

7 5544 ibueCO- 2-furyl AcOAcO 5474 ibueCO- 2-furyl MeOAcO 5 5555 ibueCO- 2-furyl PhOAcO 5999 ibueCO- 2-furyl MeOAcO 6353 tAmOCO- 2-furyl AcOAcO 6226 tAmOCO- 2-furyl MeOAcO 5622 tBuOCO- 2-furyl AcOAcO 10 5515 tBuOCO- 2-furyl EtOAcO 5445 tBuOCO- 2-furyl MeOAcO 5600 tBuOCO- 2-furyl MeSAcO 5616 tBuOCO- 2-furyl PhOAcO 5835 tC 3

H

5 CO- 2-furyl MeOAcO 15 5811 tC 3

H

5 CO- 2-furyl PhOAcO 5919 C 3

H

5 CO- 2-furyl PhOAcO 6326 tBuOCO- 2-furyl MeOAcO Example 13: Taxanes having C7 Substituted Acetate and C-10 Hydroxy Substituents 20 Following the processes described elsewhere herein, the following specific taxanes having structural formula (10) may be prepared, wherein R 7 is as previously defined, including wherein R 7 is R 7 COO- and R 7 a is heterosubstituted methyl. In one embodiment, R 7 a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, or methylthiomethyl.

WO 01/57013 PCT/USO1/03624 128

X

5 NH 0 HO 0 OR7 OH / HO . BzAd (10) tBuOCO- 2-fury R 7 aCOO tBuOCO- 3-fu ryl R 7 aCOO 5 tBuOCO- 2-thienyl R 7 1COO tBuOCO- 3-thienyl. R 7 1COO tBuOCO- 2-pyridyl R 7 aOOO tBuOCO- 3-pyridyl R 7 aCOO tBuOCO- 4-pyridyl R 7 aCOO 10 tBuOOO- isobutenyl R 7 zCOO tBuOCO- isopropyl R 7

,COO

tBuOCO- cyclopropyl R-,aCOO tBuOCO- cyclobutyl R 7 8 C00 tBuOCO- cyclopentyl R 7 aCOO 15 tBuOCO- phenyl R 7 000 benzoyl 2-furyl R 7 aCOO benzoyl 3-fu ryl R 7 aCOO benzoyl 2-thienyl R 7 aCOO benzoyl 3-thienyl R 7 aCOO 20 benzoyl 2-pyridyl R 7

,COO

benzoyl 3-pyridyl R 7 aCOO benzoyl 4-pyridyl R 7 aCOO benzoyl isobutenyl R 7 aCOO benzoyl isopropyl R 7

,COO

25 benzoyl cyclopropyl R 7 1COO- WO 01/57013 PCT/USO1/03624 129 benzoyl cyclobutyl

R

7 aCOO benzoyl cyclopentyl

R

7 aCOO benzoyl phenyl

R

7 aCOO 2-FuCO- 2-furyl

R

7 aCOO 5 2-FuCO- 3-furyl

R

7 aCOO 2-FuCO- 2-thienyl

R

7 aCOO 2-FuCO- 3-thienyl

R

7 aCOO 2-FuCO- 2-pyridyl

R

7 aCOO 2-FuCO- 3-pyridyl

R

7 aCOO 10 2-FuCO- 4-pyridyl

R

7 aCOO 2-FuCO- isobutenyl

R

7 aCOO 2-FuCO- isopropyl

R

7 aCOO 2-FuCO- cyclopropyl

R

7 aCOO 2-FuCO- cyclobutyl

R

7 aCOO 15 2-FuCO- cyclopentyl

R

7 aCOO 2-FuCO- phenyl

R

7 aCOO 2-ThCO- 2-furyl

R

7 aCOO 2-ThCO- 3-furyl

R

7 aCOO 2-ThCO- 2-thienyl

R

7 aCOO 20 2-ThCO- 3-thienyl

R

7 aCOO 2-ThCO- 2-pyridyl

R

7 aCOO 2-ThCO- 3-pyridyl

R

7 aCOO 2-ThCO- 4-pyridyl

R

7 aCOO 2-ThCO- isobutenyl

R

7 aCOO 25 2-ThCO- isopropyl R 7 aCOO 2-ThCO- cyclopropyl

R

7 aCOO 2-ThCO- cyclobutyl

R

7 aCOO 2-ThCO- cyclopentyl R 7 aCOO 2-ThCO- phenyl

R

7 aCOO 30 2-PyCO- 2-furyl

R

7 aCOO 2-PyCO- 3-furyl

R

7 aCOO- WO 01/57013 PCT/USO1/03624 130 2-PyCO- 2-thienyl

R

7 aCOO 2-PyCO- 3-thienyl

R

7 aCOO 2-PyCO- 2-pyridyl R 7 aCOO 2-PyCO- 3-pyridyl

R

7 aCOO 5 2-PyCO- 4-pyridyl

R

7 aCOO 2-PyCO- isobutenyl

R

7 aCOO 2-PyCO- isopropyl

R

7 aCOO 2-PyCO- cyclopropyl

R

7 aCOO 2-PyCO- cyclobutyl

R

7 aCOO 10 2-PyCO- cyclopentyl

R

7 aCOO 2-PyCO- phenyl R 7 aCOO 3-PyCO- 2-furyl

R

7 aCOO 3-PyCO- 3-furyl R 7 aCOO 3-PyCO- 2-thienyl

R

7 aCOO 15 3-PyCO- 3-thienyl

R

7 aCOO 3-PyCO- 2-pyridyl

R

7 aCOO 3-PyCO- 3-pyridyl

R

7 aCOO 3-PyCO- 4-pyridyl

R

7 aCOO 3-PyCO- isobutenyl R 7 aCOO 20 3-PyCO- isopropyl

R

7 aCOO 3-PyCO- cyclopropyl

R

7 aCOO 3-PyCO- cyclobutyl

R

7 aCOO 3-PyCO- cyclopentyl

R

7 aCOO 3-PyCO- phenyl

R

7 aCOO 25 4-PyCO- 2-furyl

R

7 aCOO 4-PyCO- 3-furyl R 7 aCOO 4-PyCO- 2-thienyl

R

7 aCOO 4-PyCO- 3-thienyl R 7 aCOO 4-PyCO- 2-pyridyl

R

7 aCOO 30 4-PyCO- 3-pyridyl

R

7 aCOO 4-PyCO- 4-pyridyl R 7 aCOO- WO 01/57013 PCT/USO1/03624 131 4-PyCO- isobutenyl

R

7

COO

4-PyCO- isopropyl

R

7 aCOO 4-PyCO- cyclopropyl

R

7

COO

4-PyCO- cyclobutyl

R

7

,COO

5 4-PyCO- cyclopentyl R 7 aCOO 4-PyCO- phenyl

R

7

,COO

C

4

H

7 CO- 2-furyl R 7 aCOO

C

4

H

7 CO- 3-furyl

R

7

,COO

C

4

H

7 CO- 2-thienyl

R

7 aCOO 10 C 4

H

7 CO- 3-thienyl R 7 aCOO

C

4

H

7 CO- 2-pyridy R, 7 aCOO

C

4

H

7 CO- 3-pyridyl

R

7 aCOO

C

4

H

7 CO- 4-pyridyl

R

7 aCOO

C

4

H

7 CO- isobutenyl

R

7 aCOO 15 C 4

H

7 CO- isopropyl

R

7 aCOO

C

4

H

7 CO- cyclopropyl

R

7 aCOO

C

4

H

7 CO- cyclobutyl

R

7 aCOO

C

4

H

7 CO- cyclopentyl R 7

,COO

4-PyCO- phenyl

R

7 aCOO 20 EtOCO- 2-furyl

R

7 aCOO EtOCO- 3-furyl

R

7 aCOO EtOCO- 2-thienyl

R

7 aCOO EtOCO- 3-thienyl

R

7 aCOO EtOCO- 2-pyridyl

R

7 aCOO 25 EtOCO- 3-pyridyl

R

7 aCOO EtOCO- 4-pyridyl

R

7 aCOO EtOCO- isobutenyl

R

7 aCOO EtOCO- isopropyl

R

7 aCOO EtOCO- cyclopropyl

R

7 aCOO 30 EtOCO- cyclobutyl

R

7 aCOO EtOCO- cyclopentyl

R

7 aCOO- WO 01/57013 PCT/USO1/03624 132 EtOCO- phenyl

R

7 aCOO ibueCO- 2-furyl

R

7 1COO ibueCO- 3-furyl

R

7 aCOO ibueCO- 2-thienyl

R

7 aCOO 5 ibueCO- 3-thienyl

R

7 eCOO ibueCO- 2-pyridyl RaCOO ibueCO- 3-pyridyl

R

7 aCOO ibueCO- 4-pyridyl

R

7

,COO

ibueCO- isobutenyl

R

7

,COO

10 ibueCO- isopropyl R 7

COO

ibueCO- cyclopropyl R 7

.COO

ibueCO- cyclobutyl

R

7

.COO

ibueCO- cyclopentyl

R

7

,COO

ibueCO- phenyl

R

7

COO

15 iBuCO- 2-furyl R 7

,COO

iBuCO- 3-furyl

R

7 aCOO iBuCO- 2-thienyl

R

7

COO

iBuCO- 3-thienyl

R

7

COO

iBuCO- 2-pyridyl

R

7 yCOO 20 iBuCO- 3-pyridyl

R

7 aCOO iBuCO- 4-pyridyl

R

7

COO

iBuCO- isobutenyl

R

7

,COO

iBuCO- isopropyl

R

7 aCOO iBuCO- cyclopropyl R.aCOO 25 iBuCO- cyclobutyl

R

7

,COO

iBuCO- cyclopentyl

R

7

,COO

iBuCO- phenyl

R

7

,COO

iBuOCO- 2-furyl

R

7

,COO

iBuOCO- 3-furyl

R

7 aCOO 30 iBuOCO- 2-thienyl

R

7

.COO

iBuOCO- 3-thienyl

R

7

,COO-

WO 01/57013 PCT/USO1/03624 133 iBuOCO- 2-pyridyl

R

7 aCOO iBuOCO- 3-pyridyl

R

7

,COO

iBuOCO- 4-pyridyl

R

7 aCOO iBuOCO- isobutenyl R 7 aCOO 5 iBuOCO- isopropyl R 7 aCOO iBuOCO- cyclopropyl R 7 aCOO iBuOCO- cyclobutyl R 7 aCOO iBuOCO- cyclopentyl R 7 aCOO iBuOCO- phenyl

R

7 aCOO 10 iPrOCO- 2-furyl

R

7 aCOO iPrOCO- 3-furyl

R

7 aCOO iPrOCO- 2-thienyl

R

7 aCOO iPrOCO- 3-thienyl

R

7 aCOO iPrOCO- 2-pyridyl

R

7 aCOO 15 iPrOCO- 3-pyridyl

R

7 aCOO iPrOCO- 4-pyridyl

R

7 aCOO iPrOCO- isobutenyl

R

7 aCOO iPrOCO- isopropyl

R

7 aCOO iPrOCO- cyclopropyl R 7 aCOO 20 iPrOCO- cyclobutyl

R

7 aCOO iPrOCO- cyclopentyl

R

7 aCOO iPrOCO- phenyl

R

7 aCOO nPrOCO- 2-furyl RyaCOO nPrOCO- 3-furyl R 7 aCOO 25 nPrOCO- 2-thienyl

R_COO

nPrOCO- 3-thienyl R 7 aCOO nPrOCO- 2-pyridyl

R

7 aCOO nPrOCO- 3-pyridyl

R

7 aCOO nPrOCO- 4-pyridyl

R

7 aCOO 30 nPrOCO- isobutenyl

R

7 aCOO nPrOCO- isopropyl

R

7 aCOO- WO 01/57013 PCT/USO1/03624 134 nPrOCO- cyclopropyl

R

7

.COO

nPrOCO- cyclobutyl R 7

COO

nPrOCO- cyclopentyl

R

7

,COO

nPrOCO- phenyl R 7

,COO

5 nPrCO- 2-furyl R 7 aCOO nPrCO- 3-furyl R 7 aCOO nPrCO- 2-thienyl R 7 aCOO nPrCO- 3-thienyl

R

7 aCOO nPrCO- 2-pyridyl

R

7 aCOO 10 nPrCO- 3-pyridyl

R

7 aCOO nPrCO- 4-pyridyl R 7 aCOO nPrCO- isobutenyl

R

7 aCOO nPrCO- isopropyl R 7 aCOO nPrCO- cyclopropyl

R

7

COO

15 nPrCO- cyclobutyl

R

7 aCOO nPrCO- cyclopentyl

R

7 aCOO nPrCO- phenyl

R

7 aCOO Example 14: Taxanes having C-7 Substituted Acetate and C-10 Hydroxy Substituents 20 Following the processes described in Example 11 and elsewhere herein, the following specific taxanes having structural formula (11) may be prepared, wherein Rio is hydroxy and R 7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R 7 is R 7 aCOO- wherein R 7 a is a heterosubstituted methyl moiety lacking a carbon atom which is in the beta position 25 relative to the carbon atom of which R 7 a is a substituent. The heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected 30 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R 7 substituents include R 7 aCOO- wherein R 7 a is hydrogen, WO 01/57013 PCT/US01/03624 135 methyl, chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl. In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyi, or pyridyl, X 1 is 5 substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert butyl), and R 7 and R 1 0 each have the beta stereochemical configuration. In the "B" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, 10 phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 each have the beta stereochemical configuration. In the "C" series of compounds, X 1 0 and R 9 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 15 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rga is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 0 each have the beta stereochemical configuration. In the "D" and "E" series of compounds, X 10 is as otherwise as defined herein. 20 Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R. (series D only) and R 1 each have the beta stereochemical configuration. In the "F" series of compounds, X 10 , R 2 , and R.a are as otherwise as defined 25 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. 30 In the "G" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 . is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta 35 stereochemical configuration. In the "H" series of compounds, X 1 0 is as otherwise as defined herein.

WO 01/57013 PCT/US01/03624 136 Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and RIO each have the beta stereochemical 5 configuration. In the "I" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, 10 pyridyl, phenyl, or lower alkyl, and R 7 and RIO each have the beta stereochemical configuration. In the "J" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, 15 phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "K" series of compounds, X 1 0 , R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 20 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. Any substituents of each X 3 , X 5 , R 2 , R 7 , and R. may be hydrocarbyl or any of 25 the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

WO 01/57013 PCT/USO1/03624 137

X

5 NH O

R

10 R9 X3 00- . R OH

R

14 HO R 2 0 OAc (11) Series X, X3 R7 R2 R R1 Al -COOX 1 0 heterocyclo R 7 .C00- C 6

H

5 COO- 0 H 5 A2 -COX 1 0 heterocyclo R 7 aCOO- C 6

H

5 C00- 0 H A3 -CONHX 10 heterocyclo R 7 aCO0- C 6

H

5 COO- 0 H A4 -COOX 10 optionally RyCOO- C 6 HCOO- 0 H substituted C2 to C alkyl A5 -COX 1 0 optionally RyaCOO- C 6 HC00- 0 H substituted C2 to C alkyl A6 -CONHX 1 0 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl 10 A7 -COOXo optionally RyaCOO- CHCOO- 0 H substituted C2 to C8 alkenyl A8 -COX 10 optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C alkenyl A9 -CONHXo optionally R 7 aCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkenyl A10 -C00X 10 optionally R 7 COO- C 6

H

5 OO- 0 H substituted C2 to C alkynyl WO 01/57013 PCT/USO1/03624 138 All -COX 1 0 optionally R 7 aCOO- C 8

H

5 COO- 0 H substituted C2 to C. alkynyl A12 -CONHX 1 optionally R 7 ,COO- CH 5 COO- 0 H substituted C2 to C. alkynyl BI -COOX 1 0 heterocyclo R 7 ,COO- R 2 aCOO- 0 H B2 -COXO heterocyclo R 7 aCOO- R 2 aCOO- 0 H 5 B3 -CONHX 1 0 heterocyclo R 7 aCOO- R 2 aCOO- 0 H B4 -COOX 10 optionally R 7 ,COO- R 2 C00- 0 H substituted C2 to C alkyl B5 -COX 1 0 optionally RiaCOO- R 2 aCOO- 0 H substituted

C

2 to C alkyl B6 -CONHX 1 optionally RyCOO- R 2 aCOO- 0 H substituted C2 to C alkyl B7 -COOX, optionally R 7 COO- R 2 aC00- 0 H substituted C2 to C alkenyl 10 B8 -COXIO optionally R 7 aCOO- R 2 COO- 0 H substituted C2 to C alkenyl B9 -CONHXO optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C. alkenyl B1O -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 H substituted C2 to C alkynyl B11 -COX 1 0 optionally R 7 COO- R 2 aCOO- 0 H substituted C2 to C. alkynyl WO 01/57013 PCT/USO1/03624 139 B12 -CONHX,, optionally RyaCOO- R 2 COO- 0 H substituted C2 to C. alkynyl C1 -COOX 1 0 heterocyclo RiCOO- C 6

H

5 COO- RgaCOO- H C2 -COX 1 e heterocyclo R 7 ,COO- C 6

H

5 COO- RgaCOO- H C3 -CONHX 1 heterocyclo R 7 aCOO- C 6

H

5 COO- RgaCOO- H 5 C4 -COOX 1 0 optionally R 7 ,COO- C 6

H

5 COO- R 9 aCOO- H substituted C2 to C8 alkyl C5 -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C, alkyl C6 -CONHX 1 optionally R 7 ,COO- C 6

H

5 COO- RgaCOO- H substituted C2 to C8 alkyl C7 -COOXIO optionally R7,COO- C 6

H

5 COO- RgaCOO- H substituted C2 to C alkenyl C8 -COX 1 e optionally R 7 aCOO- C 6

H

5 COO- R 9 aCOO- H substituted C2 to C alkenyl 10 C9 -CONHX,, optionally R 7 aCOO- C 6

H

5 COO- ReaCOO- H substituted C2 to C, alkenyl C10 -COOX 1 0 optionally R 7 ,COO- C 6

H

5 COO- R 9 aCOO- H substituted C2 to C, alkynyl CI -COX 1 0 optionally R 7 aCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C. alkynyl C12 -CONHX 1 optionally R 7 COO- C 6

H

5 COO- R 9 aCOO- H substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 140 D1 -COOX 1 0 heterocyclo R 7 aCOO- C 6

H

5 COO- OH H D2 -COX 1 0 heterocyclo R 7 yCOO- C6H 5 COO- OH H D3 -CONHX 1 heterocyclo RCOO- C6HCOO- OH H D4 -COOX 10 optionally R 7 ,COO- CHCOO- OH H substituted C2 to C8 alkyl 5 D5 -COX 10 optionally R 7 aCOO- CHCOO- OH H substituted

C

2 to C alkyl D6 -CONHXO optionally R 7 aCOO- CHCOO- OH H substituted C2 to C8 alkyl D7 -COOXO optionally R 7 COO- CHCOO- OH H substituted C2 to C alkenyl D8 -COXIO optionally R 7 aCOO- C6HCOO- OH H substituted C2 to C. alkenyl D9 -CONHX 1 0 optionally R 7 aCOO- CH 5 COO- OH H substituted C2 to C alkenyl 10 D10 -COOX 1 0 optionally R 7 zCOO- CH 5 COO- OH H substituted C2 to C8 alkynyl D11 -COX 1 0 optionally R 7 yCOO- C 6

H

5 COO- OH H substituted C2 to C alkynyl D12 -CONHX 1 optionally R 7 aCOO- C 6 HCOO- OH H substituted C2 to C alkynyl El -COOX 1 0 heterocyclo R 7 ,C00- CHCOO- 0 OH E2 -COX 1 0 heterocyclo R 7 aCOO- C 6

H

5 COO- 0 OH 15 E3 -CONHX 1 heterocyclo R 7 aCOO- C 6 HCOO- 0 OH WO 01/57013 PCT/USO1/03624 141 E4 -COOX 1 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkyl E5 -COXIO optionally R 7 COO- CH 5 COO- 0 OH substituted

C

2 to C 8 alkyl E6 -CONHX 1 optionally R 7 ,COO- CHCOO- 0 OH substituted C2 to C alkyl E7 -COOX 10 optionally R 7 aCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkenyl 5 E8 -COX 10 optionally R 7 aCOO- C 6 HCOO- 0 OH substituted C2 to C alkenyl E9 -CONHXO optionally R 7 COO- C6H 5 COO- 0 OH substituted C2 to C. alkenyl E10 -COOX,, optionally RyCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl El1 -COX 1 0 optionally RyaCOO- CH 5 COO- 0 OH substituted C2 to C alkynyl E12 -CONHX 1 optionally R 7 aCOO- CH 5 COO- 0 OH substituted C2 to C alkynyl 10 F1 -COOX 1 0 heterocyclo RaCOO- R 2 aCOO- RgaCOO- H F2 -COXO heterocyclo R 7 ,COO- R 2 aCOO- RgaCOO- H F3 -CONHX 1 heterocyclo RaCOO- R 2 aCOO- RgaCOO- H F4 -COOXO optionally RyCOO- R 2 aC00- RgCOO- H substituted C2 to C alkyl WO 01/57013 PCT/USO1/03624 142 F5 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C alkyl F6 -CONHXIO optionally R 7 aCOO- R 2 aCOO- RgaCOO- H substituted C2 to C. alkyl F7 -COOXO optionally R 7 COO- R 2 aCOO- R 92 ,COO- H substituted C2 to C alkenyl F8 -COXO optionally R 7 aCOO- R 2 aCOO- RgCOO- H substituted C2 to C alkenyl 5 F9 -CONHX 10 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C. alkenyl FIO -COOX 10 optionally R 7 aCOO- R 2 ,COO- R 9 aCOO- H substituted C2 to C. alkynyl F11 -COXO optionally RyCOO- R 2 COO- R 0,COO- H substituted C2 to C alkynyl F12 -CONHXIO optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C alkynyl G1 -COOXIO heterocyclo R 7 ,COO- R 2 ,COO- OH H 10 G2 -COX 10 heterocyclo R 7 aCOO- R 2 aCOO- OH H G3 -CONHX 1 heterocyclo R 7 aCOO- R 2 aCOO- OH H G4 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C alkyl G5 -COXO optionally R 7 ,COO- R 2 aCOO- OH H substituted C2 to C alkyl WO 01/57013 PCT/USO1/03624 143 G6 -CONHX 1 e optionally R 7 ,COO- R 2 ,COO- OH H substituted

C

2 to C alkyl G7 -COOX 1 0 optionally R 7 ,COO- R 2 aCOO- OH H substituted C2 to C. alkenyl G8 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to Ca alkenyl G9 -CONHX 1 optionally R 7 yCOO- R 2 ,COO- OH H substituted C2 to C alkenyl 5 GI -COOX 1 optionally R 7 COO- R 2 aCOO- OH H substituted C2 to C, alkynyl G11 -COX 10 optionally R 7 zCOO- R 2 aCOO- OH H substituted C2 to C alkynyl G12 -CONHX 1 e optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C alkynyl H1 -COOX,O heterocyclo R 7 COO- C 6

H

5 COO- OH OH H2 -COX 10 heterocyclo R 7 aCOO- CH 5 COO- OH OH 10 H3 -CONHX 1 e heterocyclo R 7 aCOO- C 6

H

5 COO- OH OH H4 -COOX 1 0 optionally RyaCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H5 -COXIO optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H6 -CONHX 1 optionally R 7 aCOO- CHCOO- OH OH substituted C2 to C alkyl WO 01/57013 PCT/USO1/03624 144 H7 -COOXIO optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C. alkenyl H8 -COXO optionally R 7 aCOO- CH 5 COO- OH OH substituted C2 to C alkenyl H9 -CONHX,, optionally R 7 COO- CH 5 COO- OH OH substituted C2 to C alkenyl H10 -COOX 10 optionally RaCOO- C 6

H

5 COO- OH OH substituted C2 to C. alkynyl 5 H11 -COX 1 0 optionally RaCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl H12 -CONHXIO optionally R 7 aCOO- C 6

H

5 COO- OH OH substituted C2 to C, alkynyl 11 -COOXIO heterocyclo RaCOO- R 2 aCOO- 0 OH 12 -COX 1 0 heterocyclo R 7 aCOO- R 2 aCOO- 0 OH 13 -CONHX, heterocyclo R 7 COO- R 2 ECOO- 0 OH 10 14 -COOX10 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C 8 alkyl 15 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C. alkyl 16 -CONHXO optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C. alkyl 17 -COOXIO optionally RyaCOO- R 2 aCOO- 0 OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 145 18 -COXIO optionally R 7 COO- R 2 aCOO- 0 OH substituted C2 to C. alkenyl 19 -CONHX 1 optionally RaCOO- R 2 aCOO- 0 OH substituted

C

2 to C alkenyl 110 -COOX 10 optionally R 7 yCOO- R 2 COO- 0 OH substituted C2 to C alkynyl ill -COX 1 e optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C alkynyl 5 112 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- 0 OH substituted C2 to C. alkynyl J1 -COOXIO heterocyclo R 7 aCOO- R 2 aCOO- OH OH J2 -COX 1 0 heterocyclo RaCOO- R 2 aCOO- OH OH J3 -CONHXO heterocyclo R 7 aCOO- R 2 aCOO- OH OH J4 -COOXO optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C alkyl 10 J5 -COX 1 0 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C alkyl J6 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C alkyl J7 -COOX 1 0 optionally R 7 COO- R 2 aCOO- OH OH substituted C2 to C alkenyl J8 -COX 1 0 optionally R 7 ;COO- R 2 aCOO- OH OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 146 J9 -CONHX 1 optionally R 7 aCOO- R 2 ,COO- OH OH substituted C2 to C alkenyl JIo -COOX 1 0 optionally R 72 COO- R 2 aCOO- OH OH substituted C2 to C alkynyl Ji1 -COXIO optionally R 7 COO- R 2 aCOO- OH OH substituted C2 to C, alkynyl J12 -CONHX 1 optionally R 7 aCOO- R 2 aCOO- OH OH substituted C2 to C alkynyl 5 K1 -COOX 10 heterocyclo R 7 aCOO- R 2 ,COO- RgaCOO- OH K2 -COXIO heterocyclo R 7 aCOO- R 2 aCOO- RgaCOO- OH K3 -CONHX 1 heterocyclo R 7 COO- R 2 aCOO- R 9 COO- OH K4 -COOX 1 e optionally R 7 aCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C8 alkyl K5 -COXO optionally R 7 COO- R 2 aCOO- RgaCOO- OH substituted C2 to C. alkyl 10 K6 -CONHXO optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C alkyl K7 -COOX 10 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C. alkenyl K8 -COXIO optionally R 7 aCOO- R 2 COO- RgeCOO- OH substituted C2 to C alkenyl K9 -CONHX,, optionally R 7 aCOO- R 2 COO- R 9 aCOO- OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 147 K10 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C 8 alkynyl K11 -COX 1 0 optionally R 7 yCOO- R 2 COO- R 9 aCOO- OH substituted C2 to C alkynyl K12 -CONHX 1 0 optionally R 7 aCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C. alkynyl Example 15: In Vitro cytotoxicity measured by the cell colony formation assay 5 Four hundred cells (HCT1 16) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 0C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the 10 final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 0 C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell 15 colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound. Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 20 docetaxel 0.6 5544 <1 5474 <1 5555 <1 5999 <1 WO 01/57013 PCT/USO1/03624 148 6353 <1 6226 <1 5622 <1 5515 <1 5 5445 <1 5600 <1 5616 <1 5835 <1 5811 <1 10 5919 <1 6326 <1 Example 16: Preparation of Taxane having C-10 Substituted Acetate and C-7 Hydroxy N-Debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-1 0 15 methoxyacetyl taxol (6515) To a solution of N-debenzoyl-N-tert-amyloxycarbonyl 3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyl)-7-benzyloxycarbonyl-1 0-deacetyl 10-trimethylsilyl taxol (3.50 g) in 40 mL of 1:1 acetonitrile-pyridine at 0 0C (ice-water bath) was added dropwise over 10 minutes, 10 mL of 48% aqueous hydrofluoric acid. The cooling bath was then removed and the reaction stirred at ambient 20 temperature for 8 h, diluted with 200 mL of ethyl acetate and washed with 25 mL of water, 2 x 20 mL of saturated aqueous NaHCO 3 and 25 mL of saturated aqueous NaCl. The organic layerwas then dried over sodium sulfate and concentrated under reduced pressure to give N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2 furyl)-7-benzyloxycarbonyl-1 0-deacetyl taxol as a white solid which was dried under 25 high vacuum (0.1 mmHg, 12 h) and used directly in the next step. To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-7 benzyloxycarbonyl-10-deacetyl taxol (2.17 g, 2.293 mmol) in anhydrous methylene chloride (6 mL) was added with stirring triethylamine (1.60 mL, 11.46 mmol) followed by the dropwise addition of 0.46 mL of triethylsilyl chloride. TLC of the mixture (silica 30 gel, 2:3 ethyl acetate:hexane) after 2 h, showed the formation of only one product. Saturated aqueous NaHCO 3 , 2 mL was added to the reaction which was then diluted with 70 mL of ethyl acetate, washed with 10 mL of saturated aqueous NaHCO 3 and WO 01/57013 PCT/USO1/03624 149 15 mL of saturated aqueous NaCl. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give pure N-debenzoyl-N-telf amyloxycarbonyl-3'-desphenyl-3'-(2-fu ryl)-2'-triethylsilyl-7-benzyloxycarbonyl-1 0 deacetyl taxol as a white solid (2.21 g, 91%) 5 To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2' triethylsilyl-7-benzyloxycarbonyl-10-deacety taxol (660 mg, 0.622 mmol) in 4 mL anhydrous pyridine at 0 0C was added DMAP (20 mg, 0.16 mmol) under a nitrogen atmosphere. To this mixture was added drop wise methoxyacetyl chloride (220 mL, 2.489 mmol). TLC (silica gel, 2:3 ethyl acetate:hexane) after 2 h showed no starting 10 material. The reaction was cooled to 0 *C (ice-water bath) and quenched by adding 80 mL of water. To the reaction at 0 0C (ice-water bath) was added 4 mL of acetonitrile and 2 mL of 48% aqueous hydrofluoric acid and the cooling bath was removed. The reaction was stirred at room temperature for 8.0 h, diluted with 60 mL of ethyl acetate and washed 15 with 10 mL of saturated aqueous NaHCO 3 and 15 mL of saturated aqueous NaCl. The organic layer was dried over Na 2

SO

4 and concentrated under reduce pressure to give 602 mg of a yellow solid which was purified by flash-chromatography (silica gel, 1:1 ethyl acetate:hexane) to give 538 mg (85%) of pure N-debenzoyl-N-tert amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-7-benzyloxycarbonyl-1 0-deacetyl-1 0 20 methoxyacetyl taxol (TL-650): mp 145-146 0C; Anal. Calcd. for C 53

H

63

NO

1 9 : C, 62.53; H, 6.24. Found: C, 62.26; H, 6.20. To a solution of N-debenzoyl-N-tert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-7 benzyloxycarbonyl-10-deacetyl-10-methoxyacety taxol (TL-650, 350 mg, 0.343 mmol) in 15 mL ethyl acetate was added 10% Pd-C (100 mg). The mixture was 25 stirred under a H 2 atmosphere (using latex balloons) for 1 h, when TLC (silica gel, 1:1 ethyl acetate:hexane) showed no starting material. The reaction was then filtered through celite (3 g) and the celite pad washed with 25 mL of ethyl acetate. The combined organic extract was concentrated under reduced pressure to give 315 mg of a white solid which was purified by flash-chromatography (silica gel, 55:45 ethyl 30 acetate:hexane) to give 283mg (93%) of pure N-debenzoyl-N-tert-amyloxycarbonyl 3'-desphenyl-3'-(2-furyl)- -10-deacetyl-10-methoxyacetyl taxol: mp 164-166 0C; 'H NMR (CDCl 3 ) 8.13 (m, 2H), 7.62(m, IH), 7.46-7.51(m, 2H), 7.41 (m, 1H), 6.41 (bs, I H), 6.39(dd, J=3.1, 1.5 Hz, I H), 6.25 (d, J=3.1 Hz, I H), 6.22(dd, J=8.8, 8.7 Hz, 1 H), WO 01/57013 PCT/US01/03624 150 5.67(1 H), 5.22-5.38(m, 2H), 4.98(m, 1 H), 4.76(m, 1 H), 4.42(m, 2H), 4.36 (d, J=9.3 Hz, 1 H), 4.28(m, I H), 4.21 (d, J=9.3 Hz, I H), 3.82 (m, I H), 3.42 (s, 3H), 3.41 (d, J= 5.5 Hz, IH), 2.55-2.60(m, IH), 2.41 (s, 3H), 2.20-2.38(m, 2H), 1.92 (s, 3H), 1.91 1.94 (m, I H), 1.68 (bs, 3H), 1.62-1.68(m, 2H), 1.62(S, 3H), 1.36(s, 3H), 1.34(s, 3H), 5 1.23(s, 3H), 1.16(s, 3H), 0.80(t, J=8.2Hz, 3H); Anal. Calcd. for C 45

H

57

NO

17 .1/2H 2 0: C, 60.47; H, 6.49. Found: C, 60.64; H, 6.45. Example 17: Additional Taxanes having C-10 Acetate and C-7 Hydroxy Substituents The procedures described in Example 16 were repeated, but other suitably protected P-lactams were substituted for the P-lactam of Example 16 to prepare the 10 series of compounds having structural formula (12) and the combinations of substituents identified in the following table:

X

5 NH 0 R10 OH OH ' HO . AcOz (12) Compound X 5 X3 R1 15 6577 tAmOCO 2-furyl AcOAcO 6515 tAmOCO 2-furyl MeOAcO 6066 tC 3

H

5 CO 2-furyl MeOAcO 6111 tC 3

H

5 CO 2-furyl PhOAcO Example 18: Taxanes having C-10 Substituted Acetate and C-7 Hydroxy 20 Substituents Following the processes described in Example 16 and elsewhere herein, the following specific taxanes having structural formula (13 ) may be prepared, wherein

R

1 0 is R1OaCOO- and R1oa is heterosubstituted methyl. In one embodiment, R1 0 a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, 25 acetoxymethyl, acyloxymethyl, or methylthiomethyl.

WO 01/57013 PCT/USO1/03624 151 X5NH 0 Rj 1 0 X3 OH OH O Aco (13) X5 X3Rj 0 tBuOCO- 2fu yl RIOaCOO 5 tBuOO 3-furyI RioaCOO tBuOCO- 2-thienyl R, 02 000O tBuOCO- 3-thienyl RioaCOO tBuOCO- 2-pyridyl RjoCOO tBuOCO- 3-pyridyl RjoaCOO 10 tBuOCO- 4-pyridyl RiOaCOO tBuOCO- isobutenyl RjoaCOO tBuOCO- isopropyl RIOCOO tBuOCO- cyclopropyl Rji ,COO tBuOCO- cyclobutyl Rl 08 000 15 tBuOCO- cyclopentyl RjoaCOO tBuOCO- phenyl RIOCOO benzoyl 2-fu ryl RioaCOO benzoyl 3-fu ryl RjiaaCOO benzoyl 2-thienyl RIOaCOO 20 benzoyl 3-thienyl RioaCOO benzoyl 2-pyridyl RioaCOO benzoyl 3-pyridyl RiaaCOO benzoyl 4-pyridyl RjoaCOO Sbenzoyl isobutenyl R,02aCOO- WO 01/57013 PCT/USO1/03624 152 benzoyl isopropyl RIO.CO0 benzoyl cyclopropyl RjoCOO benzoyl cyclobutyl RIO.CO0 benzoyl cyclopentyl Rj 0 aCO0 5 benzoyl phenyl RjoC00 2-FuCO- 2-fu ryl RiO.COO 2-FuCO- 3-furyl RjoaCOO 2-FuCO- 2-thienyl RiOC0OO 2-FuCO- 3-thienyl RjoaCOO 10 2-FuCO- 2-pyridyl RIO.C00 2-FuCO- 3-pyridyl RjOaCOO 2-FuCO- 4-pyridyl RloaCOO 2-FuCO- isobutenyl RjoaCOO 2-FuCO- isopropyl RIOaCOO 15 2-FuCO- cyclopropyl RioaCOO 2-FuCO- cyclobutyl RjOaCOO 2-FuCO- cyclopentyl RjoaC0OO 2-FuCO- phenyl RjoaCO0 2-ThCO- 2-furyl RioaC00 20 2-ThO- 3-furyl Rjoa COO 2-ThCO- 2-thienyl RjoaCOO 2-ThO- 3-thienyl RioaCOO 2-ThCO- 2-pyridyl RioaCOO 2-Th 00- 3-pyridyl RjoaCOO 25 2-ThCO- 4-pyridyl RjoaC00 2-ThCO- isobutenyl RjoC00 2-ThCO- isopropyl RioeaC00 2-ThCO- cyclopropyl RjoaCOO 2-ThCO- cyclobutyl Ri~aC00 30 2-ThCO- cyclopentyl RjoaCOO 2-ThCO- phenyl RiOa C00 WO 01/57013 PCT/USO1/03624 153 2-PyCO- 2-furyl R1oaCOO 2-PyCO- 3-furyl R1 0 aCOO 2-PyCO- 2-thienyl R1oaCOO 2-PyCO- 3-thienyl R1oaCOO 5 2-PyCO- 2-pyridyl R1 0 aCOO 2-PyCO- 3-pyridyl R1 0 aCOO 2-PyCO- 4-pyridyl R1oaCOO 2-PyCO- isobutenyl R1oaCOO 2-PyCO- isopropyl Ri0COO 10 2-PyCO- cyclopropyl R1oaCOO 2-PyCO- cyclobutyl R1oaCOO 2-PyCO- cyclopentyl RI 0

.COO

2-PyCO- phenyl R1 0 aCOO 3-PyCO- 2-furyl R 10

COO

15 3-PyCO- 3-furyl R1oaCOO 3-PyCO- 2-thienyl R1oCOO 3-PyCO- 3-thienyl R1 0 aCOO 3-PyCO- 2-pyridyl R1oCOO 3-PyCO- 3-pyridyl R1 0 aCOO 20 3-PyCO- 4-pyridyl RioCOO 3-PyCO- isobutenyl R1 0 aCOO 3-PyCO- isopropyl R1 0 aCOO 3-PyCO- cyclopropyl R1oCOO 3-PyCO- cyclobutyl Ri.COO 25 3-PyCO- cyclopentyl R1oaCOO 3-PyCO- phenyl R1oaCOO 4-PyCO- 2-furyl R1 0

.COO

4-PyCO- 3-furyl R1oaCOO 4-PyCO- 2-thienyl R 10

COO

30 4-PyCO- 3-thienyl R1 0 aCOO 4-PyCO- 2-pyridyl RjoaCOO- WO 01/57013 PCT/USO1/03624 154 4-PyCO- 3-pyridyl RI 0 aCOO 4-PyCO- 4-pyridyl RIOaCOO 4-PyCO- isobutenyl RIOaCOO 4-PyCO- isopropyl R1 0 aCOO 5 4-PyCO- cyclopropyl R1 0 aCOO 4-PyCO- cyclobutyl R1oaCOO 4-PyCO- cyclopentyl R 10

COO

4-PyCO- phenyl RjeaCOO

C

4

H

7 CO- 2-furyl

RIOCOO

10 C 4

H

7 CO- 3-furyl

RIOCOO

C

4

H

7 CO- 2-thienyl R1 0 aCOO

C

4

H

7 CO- 3-thienyl R1 0 aCOO

C

4

H

7 CO- 2-pyridyl

RIOCOO

C

4

H

7 CO- 3-pyridyl RjoaCOO 15 C 4

H

7 CO- 4-pyridyl R 10

COO

C

4

H

7 CO- isobutenyl RioaCOO

C

4

H

7 CO- isopropyl RIOaCOO

C

4

H

7 CO- cyclopropyl R1OaCOO

C

4

H

7 CO- cyclobutyl R1 0 aCOO 20 C 4

H

7 CO- cyclopentyl RiOaCOO

C

4

H

7 CO- phenyl R1oaCOO EtOCO- 2-furyl R,0aCOO EtOCO- 3-furyl RI 0 aCOO EtOCO- 2-thienyl RioaCOO 25 EtOCO- 3-thienyl R,0aCOO EtOCO- 2-pyridyi R1 0 aCOO EtOCO- 3-pyridyl R1oaCOO EtOCO- 4-pyridyl R1oaCOO EtOCO- isobutenyl RieaCOO 30 EtOCO- isopropyl RIOaCOO EtOCO- cyclopropyl RjoaCOO- WO 01/57013 PCT/USO1/03624 155 EtOCO- cyclobutyl R1 0 aCOO EtOCO- cyclopentyl R1 0 aCOO EtOCO- phenyl R 10

CO

8

O

ibueCO- 2-furyl R1 0 aCOO 5 ibueCO- 3-furyl R1oaCOO ibueCO- 2-thienyl R1 0 aCOO ibueCO- 3-thienyl R1oaCOO ibueCO- 2-pyridyl R1OaCOO ibueCO- 3-pyridyl

RI

0 aCOO 10 ibueCO- 4-pyridyl RioCOO ibueCO- isobutenyl RioaCOO ibueCO- isopropyl R102COO ibueCO- cyclopropyl R1 0 aCOO ibueCO- cyclobutyl R1oaCOO 15 ibueCO- cyclopentyl R1 0

.COO

ibueCO- phenyl R1oaCOO iBuCO- 2-furyl R1oaCOO iBuCO- 3-furyl RioaCOO iBuCO- 2-thienyl RjoaCOO 20 iBuCO- 3-thienyl RjoaCOO iBuCO- 2-pyridyl R1OaCOO iBuCO- 3-pyridyl RioaCOO iBuCO- 4-pyridyl RjoaCOO iBuCO- isobutenyl R1oaCOO 25 iBuCO- isopropyl R1oaCOO iBuCO- cyclopropyl RjoaCOO iBuCO- cyclobutyl RjOaCOO iBuCO- cyclopentyl R1oaCOO iBuCO- phenyl RjoCOO 30 iBuOCO- 2-furyl R1iaCOO iBuOCO- 3-furyl R 1 OaCOO- WO 01/57013 PCT/USO1/03624 156 iBuOCO- 2-thienyl R1 0 aCOO iBuOCO- 3-thienyl R1OaCOO iBuOCO- 2-pyridyl R1 0 aCOO iBuOCO- 3-pyridyl R1OaCOO 5 iBuOCO- 4-pyridyl R1oaCOO iBuOCO- isobutenyl R1 0 aCOO iBuOCO- isopropyl R1 0 aCOO iBuOCO- cyclopropyl R1oaCOO iBuOCO- cyclobutyl RioaCOO 10 iBuOCO- cyclopentyl RioaCOO iBuOCO- phenyl R1 0 aCOO iPrOCO- 2-furyl R1oaCOO iPrOCO- 3-furyl R1 0 aCOO iPrOCO- 2-thienyl R1 0 aCOO 15 iPrOCO- 3-thienyl R1 0 aCOO iPrOCO- 2-pyridyl R1oaCOO iPrOCO- 3-pyridyl

RI

0 aCOO iPrOCO- 4-pyridyl R1oaCOO iPrOCO- isobutenyl R1oaCOO 20 iPrOCO- isopropyl R1 0 aCOO iPrOCO- cyclopropyl R1 0 aCOO iPrOCO- cyclobutyl RIOaCOO iPrOCO- cyclopentyl RjOaCOO iPrOCO- phenyl R1 0 aCOO 25 nPrOCO- 2-furyl RioCOO nPrOCO- 3-furyl R1oaCOO nPrOCO- 2-thienyl R1 0 aCOO nPrOCO- 3-thienyl R1oaCOO nPrOCO- 2-pyridyl R1 0 aCOO 30 nPrOCO- 3-pyridyl RioCOO nPrOCO- 4-pyridyl

R

1 oaCOO- WO 01/57013 PCT/USO1/03624 157 nPrOCO- isobutenyl R1oaCOO nPrOCO- isopropyl RIoaCOO nPrOCO- cyclopropyl RIOaCOO nPrOCO- cyclobutyl RiOaCOO 5 nPrOCO- cyclopentyl RI 0 aCOO nPrOCO- phenyl RioaCOO nPrCO- 2-furyl R1aCOO nPrCO- 3-furyl R1 0 aCOO nPrCO- 2-thienyl RiOaCOO 10 nPrCO- 3-thienyl R1 0 aCOO nPrCO- 2-pyridyl R1 0 aCOO nPrCO- 3-pyridyl RIOaCOO nPrCO- 4-pyridyl R1oaCOO nPrCO- isobutenyl R1OaCOO 15 nPrCO- isopropyl R1OaCOO nPrCO- cyclopropyl RioaCOO nPrCO- cyclobutyl R1OaCOO nPrCO- cyclopentyl R1 0 aCOO nPrCO- phenyl R1OaCOO 20 Example 19: Taxanes having C-10 Substituted Acetate and C-7 Hydroxy Substituents Following the processes described in Example 16 and elsewhere herein, the following specific taxanes having structural formula (14) may be prepared, wherein

R

7 is hydroxy and R 1 0 in each of the series (that is, each of series "A" through "K") is 25 as previously defined, including wherein R 1 is R1 0 aCOO- wherein R1oa is a heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R10a is a substituent. The heterosubstituted methyl is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, 30 sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected WO 01/57013 PCT/US01/03624 158 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R 10 substituents include R1 0 aCOO- wherein RIa is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl. 5 In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert butyl), and R 7 and R 1 0 each have the beta stereochemical configuration. In the "B" series of compounds, X 1 0 and R 2 , are as otherwise as defined 10 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 . is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical configuration. 15 In the "C" series of compounds, X 1 0 and Rea are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rga is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and RIO each have the beta 20 stereochemical configuration. In the "D" and "E" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 . is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R. (series D only) and R 1 0 each have the beta 25 stereochemical configuration. In the "F" series of compounds, X1 0 , R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued 30 furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 each have the beta stereochemical configuration. In the "G" series of compounds, X 1 0 and R 2 , are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, 35 phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued WO 01/57013 PCT/USO1/03624 159 furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 0 each have the beta stereochemical configuration. In the "H" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or 5 pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical configuration. In the "I" series of compounds, X1 0 and R 2 a are as otherwise as defined herein. 10 Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical configuration. 15 In the "J" series of compounds, X 1 0 and R 2 , are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 0 each have the beta 20 stereochemical configuration. In the "K" series of compounds, X 1 ., R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued 25 furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and Rio each have the beta stereochemical configuration. Any substituents of each X 3 , X., R 2 , R 7 , and R. may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, 30 acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

WO 01/57013 PCT/USO1/03624 160

X

5 NH O R10 Rg X3 0. R O H

-

'

R

14 HO = . R2 0 OAc (14) Series X 5 X3 RIO R 2 R R 5 Al -COOX 1 0 heterocyclo RjoCOO- C 6

H

5 COO- 0 H A2 -COX 10 heterocyclo R10,COO- C 6

H

5 COO- 0 H A3 -CONHXO heterocyclo R 1 OCOO- C 6

H

5 COO- 0 H A4 -COOX 10 optionally RIOCOO- C 6 HCOO- 0 H substituted C2 to C. alkyl A5 -COX 1 optionally RioaCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl 10 A6 -CONHX 10 optionally R1OaCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A7 -COOX 10 optionally R 10 .COO- CH 5 COO- 0 H substituted C2 to C alkenyl A8 -COX 10 optionally R1OaCOO- C 6 HCOO- 0 H substituted C2 to C alkenyl A9 -CONHX 1 optionally RioaCOO- C 6

H

5 COO- 0 H substituted C2 to C, alkenyl A10 -COOX 1 0 optionally R 1 OCOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl 15 Al1 -COX 1 0 optionally RjoaCOO- CH 5 COO- 0 H substituted C2 to C, alkynyl WO 01/57013 PCT/USO1/03624 161 A12 -CONHX 1 optionally RjOCOO- C 6 H5COO- 0 H substituted

C

2 to C alkynyl B1 -COOX 10 heterocyclo RjOaCOO- R 2 ,COO- 0 H B2 -COX 10 heterocyclo RioaCOO- R 2 aCOO- 0 H B3 -CONHX 10 heterocyclo R 1 oCOO- R 2 COO- 0 H 5 B4 -COOX 10 optionally RloaCOO- R 2 aCOO- 0 H substituted C2 to C. alkyl B5 -COX 1 0 optionally R1OaCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl . B6 -CONHXO optionally RIOCOO- R 2 aCOO- 0 H substituted C2 to C. alkyl B7 -COOX 1 0 optionally R1OaCOO- R 2 ,COO- 0 H substituted C2 to C. alkenyl B8 -COX 1 0 optionally R 1 OCOO- R 2 COO- 0 H substituted C2 to C8 alkenyl 10 B9 -CONHX 10 optionally R1O0COO- R 2 ,COO- 0 H substituted C2 to C alkenyl B10 -COOXO optionally RioaCOO- R 2 aCOO- 0 H substituted C2 to C alkynyl B11 -COX 10 optionally R 1 OCOO- R 2 COO- 0 H substituted C2 to C alkynyl B12 -CONHX 1 optionally R1OaCOO- R 2 ,COO- 0 H substituted C2 to C alkynyl C1 -COOX 10 heterocyclo R10.COO- C 6

H

5 COO- R 9 aCOO- H 15 C2 -COX 1 0 heterocyclo R1OaCOO- CHCOO- RgaCOO- H C3 -CONHX 10 heterocyclo R1OaCOO- C 6

H

5 COO- RaCOO- H C4 -COX 1 0 optionally R 1 OCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C8 alkyl WO 01/57013 PCT/USO1/03624 162 C5 -COX 1 0 optionally R1OaCOO- C6H 5 COO- R 9 aCOO- H substituted C2 to C alkyl C6 -CONHX 1 optionally R 1 OCOO- CH 5 COO- R 9 aCOO- H substituted C2 to C alkyl C7 -COOX 10 optionally R1OaCOO- CH 5 COO- ReCOO- H substituted C2 to C alkenyl C8 -COX 1 0 optionally R 1 OCOO- CH 5 COO- R 2 COO- H substituted C2 to C alkenyl 5 C9 -CONHX 0 optionally R1OaCOO- CH 5 COO- R 9 aCOO- H substituted C2 to C alkenyl C10 -COOX 1 0 optionally R1iaCOO- CH 5 COO- R 9 aCOO- H substituted C2 to C alkynyl C11 -COX 10 optionally R10.COO- CH 5 COO- R 9 aCOO- H substituted C2 to C, alkynyl C12 -CONHX 1 optionally RjOCOO- C 6 HCOO- R 0,COO- H substituted C2 to C alkynyl D1 -COX 1 0 heterocyclo RjOaCOO- CHCOO- OH H 10 D2 -COX 1 0 heterocyclo R1OC00- CHCOO- OH H D3 -CONHX 1 heterocyclo RjoaCOO- CHCOO- OH H D4 -COOX 10 optionally R1OaCOO- CHCOO- OH H substituted C2 to C8 alkyl D5 -COX 1 0 optionally R 1 oCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkyl D6 -CONHX 1 optionally R1OaCOO- CH 5 COO- OH H substituted C2 to C8 alkyl 15 D7 -COOXIO optionally R1 0 aCOO- CHCOO- OH H substituted C2 to C8 alkenyl D8 -COX 1 0 optionally R1OaCOO- CH 5 COO- OH H substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 163 D9 -CONHX 1 optionally R1 0 .COO- C 6

H

5 COO- OH H substituted C2 to C alkenyl D10 -COOX 1 0 optionally RloCOO- C 6

H

5 COO- OH H substituted C2 to C alkynyl DII -COX 1 0 optionally RioaCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkynyl D12 -CONHXO optionally R 1 o,COO- C 6

H

5 COO- OH H substituted C2 to C alkynyl 5 El -COOX 1 0 heterocyclo R 1 OCOO- C 6

H

5 COO- 0 OH E2 -COXO heterocyclo R 1 OCOO- C 6 HCOO- 0 OH E3 -CONHX 1 heterocyclo RioaCOO- C 6

H

5 COO- 0 OH E4 -COOX 1 0 optionally R 10 COO- C 6

H

5 COO- 0 OH substituted C2 to C, alkyl E5 -COX 1 0 optionally R1OaCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl 10 E6 -CONHXO optionally R 1 OCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl E7 -COOXIO optionally RIoaCOO- C 6

H

5 COO- 0 OH substituted C2 to C. alkenyl E8 -COX 1 0 optionally RioaCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkenyl E9 -CONHX 1 optionally R1OaCOO- C 6

H

5 COO- 0 OH substituted C2 to C, alkenyl ElO -COOX 1 0 optionally RlOaCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl 15 El1 -COX 1 0 optionally RjoaCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkynyl E12 -CONHXO optionally R 1 OC00- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl WO 01/57013 PCT/USO1/03624 164 F1 -COOX 1 0 heterocyclo RjoaCOO- R 2 ,COO- RgaCOO- H F2 -COX 1 0 heterocyclo RioaCOO- R 2 aCOO- R 9 aCOO- H F3 -CONHX 1 heterocyclo R 1 OCOO- R 2 aCOO- R 9 aCOO- H F4 -COOX 1 0 optionally RloCOO- R 2 aCOO- RgaCOO- H substituted C2 to C alkyl 5 F5 -COX 1 0 optionally R1OaCOO- R 2 aCOO- RgaCOO- H substituted C2 to C alkyl F6 -CONHX 1 optionally RjoaCOO- R 2 COO- RgaCOO- H substituted C2 to C alkyl F7 -COOX 1 0 optionally R 10 COO- R 2 aCOO- R 9 aCOO- H substituted C2 to C alkenyl F8 -COX 1 0 optionally RioaCOO- R 2 ,COO- RgCOO- H substituted C2 to C8 alkenyl F9 -CONHX 1 optionally RjoaCOO- R 2 aCOO- RgCOO- H substituted C2 to C alkenyl 10 F10 -COOX 1 0 optionally RioaCOO- R 2 aCOO- ReCOO- H substituted C2 to C alkynyl F11 -COX 10 optionally RjoaCOO- R 2 aCOO- RgeCOO- H substituted C2 to C alkynyl F12 -CONHXO optionally R1OaCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C8 alkynyl G1 -COOX 1 0 heterocyclo R 1 oCOO- R 2 aCOO- OH H G2 -COX 10 heterocyclo RoaCOO- R 2 aCOO- OH H 15 G3 -CONHXO heterocyclo R1OaCOO- R 2 aCOO- OH H G4 -COOXO optionally R1OaCOO- R 2 ,COO- OH H substituted C2 to C alkyl G5 -COXO optionally R 1 oCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl WO 01/57013 PCT/USO1/03624 165 G6 -CONHXO optionally RloCOO- R 2 aCOO- OH H substituted C2 to C, alkyl G7 -COOX 1 0 optionally R 10 ,COO- R 2 aCOO- OH H substituted C2 to C alkenyl G8 -COX 1 0 optionally RoaCOO- R 2 aCOO- OH H substituted

C

2 to C, alkenyl G9 -CONHXO optionally R 1 OCOO- R 2 aCOO- OH H substituted C2 to C alkenyl 5 G10 -COOX 1 0 optionally RioaCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl G11 -COXIO optionally RjoaCOO- R 2 aCOO- OH H substituted C2 to C alkynyl G12 -CONHXo optionally RjoaCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl H1 -COOXO heterocyclo R 1 OCOO- C 6

H

5 COO- OH OH H2 -COX 1 0 heterocyclo RjoaCOO- C 6

H

5 COO- OH OH 10 H3 -CONHX 1 heterocyclo RioaCOO- C 6

H

5 COO- OH OH H4 -COOX 1 0 optionally R1OaCOO- CH 5 COO- OH OH substituted C2 to C alkyl H5 -COX 10 optionally R 1 OCOO- CH 5 COO- OH OH substituted C2 to C alkyl H6 -CONHX 10 optionally RioaCOO- CH 5 COO- OH OH substituted C2 to C alkyl H7 -COOX 10 optionally R 1 oCOO- CH 5 COO- OH OH substituted C2 to C alkenyl 15 H8 -COX 1 0 optionally RioaCOO- C 6

H

5 COO- OH- OH substituted C2 to C8 alkenyl H9 -CONHX 1 e optionally R1a0COO- C6H 5 COO- OH OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 166 H10 -COOX 10 optionally R1OaCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl H11 -COX 1 0 optionally RloCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl H12 -CONHX 1 optionally Ro,COO- C 6

H

5 COO- OH OH substituted C2 to C8 alkynyl 11 -COOX 1 0 heterocyclo R1oaCOO- R 2 aCOO- 0 OH 5 12 -COX 1 0 heterocyclo R 102 ,C00- R 2 ,COO- 0 OH 13 -CONHXO heterocyclo RioaCOO- R 2 aCOO- 0 OH 14 -COOX 10 optionally RjoaCOO- R 2 aCOO- 0 OH substituted C2 to C alkyl 15 -COX 1 0 optionally RioaCOO- R 2 aCOO- 0 OH substituted C2 to C. alkyl 16 -CONHX 1 optionally R 1 OCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 10 17 -COOX 10 optionally RiOaCOO- R 2 aCOO- 0 OH substituted C2 to C alkenyl 18 -COX 10 optionally R1OaCOO- R 2 aCOO- 0 OH substituted C2 to C, alkenyl 19 -CONHX 1 optionally RioaCOO- R 2 ,COO- 0 OH substituted C2 to C8 alkenyl 110 -COOX 1 0 optionally R 102 COO- R 2 ,COO- 0 OH substituted C2 to C alkynyl Il1 -COX 1 0 optionally RioaCOO- R 2 aCOO- 0 OH substituted C2 to C. alkynyl 15 112 -CONHX 1 optionally R1 0 aCOO- R 2 aCOO- 0 OH substituted C2 to C alkynyl J1 -COOX 1 0 heterocyclo R 1 OCOO- R 2 ,COO- OH OH J2 -COXO heterocyclo RoaCOO- R 2 aCOO- OH OH WO 01/57013 PCT/USO1/03624 167 J3 -CONHXo heterocyclo RoaCOO- R 2 C00- OH OH J4 -COOX 1 0 optionally RIOaCOO- R 2 aCOO- OH OH substituted C2 to C. alkyl J5 -COX 1 0 optionally R 1 OCOO- R 2 ,COO- OH OH substituted C2 to C alkyl J6 -CONHX 1 optionally RiOaCOO- R 2 ,COO- OH OH substituted C2 to C alkyl 5 J7 -COOX 1 0 optionally R 10 COO- R 2 aCOO- OH OH substituted C2 to C alkenyl J8 -COX 1 0 optionally RIoC00- R 2 ,COO- OH OH substituted C2 to C alkenyl J9 -CONHXO optionally RioaCOO- R 2 aCOO- OH OH substituted C2 to C alkenyl JIO -COOX 1 0 optionally R 1 OCOO- R 2 aCOO- OH OH substituted C2 to C alkynyl Ji1 -COX 1 0 optionally R1OaCOO- R 2 ,COO- OH OH substituted C2 to C alkynyl 10 J12 -CONHX 1 optionally RioaCOO- R 2 C00- OH OH substituted C2 to C alkynyl K1 -COOX 1 0 heterocyclo R1OaCOO- R 2 aCOO- R 9 aCOO- OH K2 -COX 10 heterocyclo RioaCOO- R 2 aCOO- R0,COO- OH K3 -CONHX 1 heterocyclo RioaCOO- R 2 ,COO- RgCOO- OH K4 -COOX 1 0 optionally R1OaCOO- R 2 ,COO- R 9 aCOO- OH substituted C2 to C alkyl 15 K5 -COX 1 0 optionally RjOCOO- R 2 aCOO- R0,COO- OH substituted C2 to C alkyl K6 -CONHXO optionally RoaCOO- R 2 ,COO- R 9 aCOO- OH substituted C2 to C alkyl WO 01/57013 PCT/USO1/03624 168 K7 -COOX 1 0 optionally RIoaCOO- R 2 aCOO- RgCOO- OH substituted C2 to C alkenyl K8 -COX 1 0 optionally RioaCOO- R 2 aCOO- RgCOO- OH substituted C2 to C. alkenyl K9 -CONHX 1 0 optionally R1OaCOO- R 2 COO- RgCOO- OH substituted C2 to C alkenyl K10 -COOX 1 0 optionally R1OaCOO- R 2 aCOO- RgCOO- OH substituted C2 to C alkynyl 5 K11 -COX 1 0 optionally R 1 oCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C alkynyl K12 -CONHX 1 0 optionally R1OaCOO- R 2 COO- R 9 aCOO- OH substituted C2 to C alkynyl Example 20: In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCT1 16) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum 10 and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 *C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 0 C. 15 At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 20 50% inhibition of colony formation) were determined for each tested compound.

WO 01/57013 PCT/US01/03624 169 Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 6577 <1 5 6515 <1 6066 <1 6111 <1 Example 21: Preparation of Taxane having C-7 Carbonate and C-10 Hydroxy HO O OTES TESO FOH HO" OH NTES H LHMDS BzOAc O BzAcO 10 1 0-Triethylsilyl-1 0-deacetyl baccatin 111. To a solution of 1.0 g (1.84 mmol) of 10 deacetyl baccatin 111 in 50 mL of THF at -10 0C under a nitrogen atmosphere was added 0.857 mL (2.76 mmol, 1.5 mol equiv) of N, O-(bis)-TES-trifluoroacetamide over a period of 3 min. This was followed by the addition of 0.062 mL of a 0.89 M THF solution of lithium bis(trimethylsilyl)amide (0.055 mmol, 0.03 mol equiv). After 10 min 15 0.038 mL (0.92 mmol, 0.5 mol equiv) of methanol was added, and after an additional 5 min 4 mL (0.055 mmol, 0.03 mol equiv) of acetic acid was added. The solution was diluted with 300 mL of ethyl acetate and washed two times with 100 mL of saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with 100 mL of ethyl acetate and the combined organic layers were washed with 20 brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue was added 100 mL of hexane and the solid (1.23 g, 101%) was collected by filtration. Recrystallization of the solid by dissolving in boiling ethyl acetate (20 mL, 17 mL/g) and cooling to room temperature gave 1.132 g (94%) of a white solid. m.p. 242 0C; [a]D 25 -60.4 (c 0.7, CHC 3 ); 'H NMR (CDC 3 , 400MHz) 6 (p.p.m): 8.10 (2H, 25 d, Jm = 7.5Hz, Bzo), 7.60 (1 H, t, Jm = 7.5Hz, Bzp), 7.47 (2H, t, Jo = 7.5Hz, Bzm), 5.64 (1H, d, J3 = 6.9Hz, H2), 5.26 (1H, s, H10), 4.97 (1H, dd, J6P = 2.2Hz, J6a = WO 01/57013 PCT/USO1/03624 170 9.9Hz, H5), 4.85 (1H, dd, J14a = 8.9Hz, J14p = 8.9Hz, H13), 4.30 (1H, d, J20p = 8.5Hz, H20a), 4.23 (1 H, ddd, J70H = 4.5Hz, J6a = 6.6Hz, J6P = 11.0Hz, H7), 4.15 (1H, d, J20a = 8.5Hz, H20P), 4.00 (1H, d, J2 = 6.9Hz, H3), 2.58 (1H, ddd, J7 = 6.6Hz, J5 = 9.9Hz, J6P = 14.5Hz, H6a), 2.28-2.25 (5H, m, 4Ac, H14a, H14P), 2.02 5 (3H, s, 18Me), 1.97 (1H, d, J7 = 4.5Hz, H70H), 1.78 (1H, ddd, J7 = 11.0Hz, J5 = 2.2Hz, J6a = 14.5Hz, H61P), 1.68 (3H, s, 19Me), 1.56 (1 H, s, OH1), 1.32 (1 H, d, J13 = 8.8Hz, OH13 ), 1.18 (3H, s, 17Me), 1.06 (3H, s, 16Me), 0.98 (9H, t, JCH 2 (TES) = 7.3Hz, CH 3 (TES)), 0.65 (6H, dq, JCH 3 (TES) = 7.3Hz, CH 2 (TES)). TESO TESO 0I~ 0 OH CH 3 0COCI -0-- H 4,H W. BzOAc O BzAc 0 10-Triethylsilyl-I 0-deacetyl-7-methoxycarbonyl baccatin IlIl. To a solution of 9.3 10 g (14.1 mmol) of 10-triethylsilyl-10-deacetyl baccatin 111 and 10.35 g (84.6 mmol) of DMAP in 500 mL of dichloromethane at 0 0C under a nitrogen atmosphere was added 2.15 mL (22.7 mmol, 1.5 mol equiv) of methyl chloroformate. The mixture was stirred at 0 *C for 4 h, diluted with 300 mL of saturated aqueous ammonium chloride solution and extracted twice with 200 mL of ethyl acetate. The organic layer 15 was washed with 500 mL of 10% aqueous copper sulfate solution, 500 mL of saturated aqueous sodium bicarbonate solution, 100 mL of brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate to give 8.92 g (88%) of 10-triethylsilyl-10-deacetyl-7 methoxycarbonyl baccatin Ill. m.p. 260-262 *C; [a]b 2 -54.3 (c 0.89, CHC1 3 ); 1 H NMR 20 (CDC 3 , 500MHz) 6 (ppm): 8.10 (2H, d, Jm = 8.5Hz, Bzo), 7.60 (1H, t, Jm = 8.5Hz, Bzp), 7.47 (2H, t, Jo = 8.5Hz, Bzm), 5.64 (1 H, d, J3 = 7.0 Hz, H2), 5.31 (1 H, dd, J6a = 7.0Hz, J6p = 10.0 Hz, H7), 5.28 (1H, s, H10), 4.96 (1H, d, J6a = 8.5 Hz, H5), 4.86 (1H, t, J14a = 14.0 Hz, J140 = 7.0 Hz, H13), 4.31 (1H, d, J20p = 8.0 Hz, H20a), 4.16 (1H, d, J20a = 8.0Hz, H20P), 4.06 (1H, d, J2 = 7.0 Hz, H3), 3.77 (3H, 25 s, OMe) 2.65 (1H, ddd, J7 = 7.0 Hz, J5 = 8.5 Hz, J6 = 10.0 Hz, H6a), 2.29-2.26 (5H, m, 4Ac, HI4a, H14P ), 2.08 (3H, s, 18Me), 2.01 (1H, d, 130H), 1.92 (3H, ddd, J7 = 10.0 Hz, J5 = 2.3 Hz, J6a = 10.0 Hz, H61P), 1.80 (3H, s, 19Me), 1.18 (3H, s, 17Me), 1.05 (3H, s, 16Me), 0.97 (9H, t, JCH 2 (TES) = 8.0 Hz, CH 3 (TES)), 0.59 (6H, dq, JCH 3 (TES) = 8.0Hz, CH 2

(TES)).

WO 01/57013 PCT/USO1/03624 171 Boo 0 TESO O Bock TESO N.H 0 0 s OMO HAO C., O..- 'MOP H H zAcO LHMDS BzA O AcO BzAcO 2'-O-MOP-3'-desphenyl-3'-(2-thienyl)-10-triethylsilyl-7-methoxycarbonyl taxotere. To a solution of 495 mg (0.690 mmol) of I 0-triethylsilyl-1 0-deacetyl-7 methoxycarbonyl baccatin III in 4 mL of anhydrous THF under a nitrogen atmosphere at -45 C was added 0.72 mL (0.72 mmol) of a 1M solution of LiHMDS in THF. 5 After 0.5 h a solution of 278 mg (0.814 mmol) of the b-Lactam in 2 mL of anhydrous THF was added. The mixture was warmed to 0 0C, and after 2 h 0.5 mL of saturated aqueous sodium bicarbonate solution was added. The mixture was diluted with 50 ml of ethyl acetate and washed two times with 5 mL of brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give a slightly 10 yellow solid. The solid was recrystallized by dissolving it in 12 mL of a 1:5 mixture of ethyl acetate and hexane at reflux and then cooling to room temperature to give 679 mg (93%) of a white crystalline solid which was used directly in the next reaction. Boos... TESO O Bos. 0 HO o N.H O O N.H 0 O HF 0 O** \ MOPP OHI~ BzO' 0 BzO 0 zOAc OAcO 3'-Desphenyl-3'-(2-thienyl)-7-methoxycarbony taxotere. To a solution of 211 mg 15 (0.199 mmol) of 2'-O-MOP-3'-desphenyl-3'-(2-thienyl)-10-triethylsilyl-7 methoxycarbonyl taxotere in 1.7 mL of pyridine and 5.4 mL of acetonitrile at 0 0C was added 0.80 mL (2.0 mmol) of an aqueous solution containing 49% HF. The mixture was warmed to room temperature for 14 h and was then diluted with 20 mL of ethyl acetate and washed three times with 2 mL of saturated aqueous sodium 20 bicarbonate and then with 8 mL of brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 174 mg (100%) of a white solid. The crude product was crystallized with 2 mL of solvent WO 01/57013 PCT/USO1/03624 172 (CH2Cl2:hexane=1:1.7) to give 168 mg (97%) of white crystals. m.p. 142.5-143 C; [a]D 25 -25.1 (c 0.53, CHCl 3 ); Anal. Calcd for C43H53NO16S: C, 59.23; H, 6.13. Found: C, 58.99; H, 6.25. 1 H NMR (500 MHz, CDCl 3 ): Proton d (ppm) Pattern J (Hz) 5 2 5.69 d H3(6.5) o-benzoate 8.12 d m-benzoate(7.5) m-benzoate 7.51 t o-benzoate(7.5),p-benzoate(7.5) p-benzoate 7.62 t m-benzoate(7.5) 3 4.01 d H2(6.5) 10 4Ac 2.39 s 5 4.93 d H6a(8.0) 6a 2.53 ddd H7(7.5), H5(9.5), H6b(15.0) 6b 2.00 ddd H7(11.0), H5(2.5), H6a(1 5.0) 15 7 5.29 dd H6a(7.5), H6b(1 1.0) OMe 3.76 s 10 5.39 s 10-OH 4.06 br s 13 6.23 t H14a(9.0), H14b(9.0) 20 14a+14b 2.34 m 16Me 1.11 s 17Me 1.23 s 18Me 1.93 s 19Me 1.86 s 25 20a 4.33 d H20b(8.5) 20b 4.21 d H20a(8.5) 2' 4.64 br 2'OH 3.43 br 3' 5.51 br 30 3" 7.10 d H4"(3.5) 4" 7.01 dd H5"(5.0), H3"(3.5) 5" 7.28 d H4"(5.0) NH 5.34 d H3'(9.5) (CH3)3C 1.35 s WO 01/57013 PCT/USO1/03624 173 Example 22: Additional Taxanes having C-7 Carbonate and C-10 Hydroxy Substituents The procedures described in Example 21 were repeated, but other suitably protected P-lactams were substituted for the p-lactam of Example 21 to prepare the 5 series of compounds having structural formula (15) and the combinations of substituents identified in the following table.

X

5 NH O HO 0 -0 R7 X3 = Ol, OH HO BzOAcO 0 (15) Compound X5 X3

R

7 4144 iPrOCO- 2-thienyl MeOCOO 10 4151 iPrOCO- 2-thienyl EtOCOO 4164 ibueCO- 2-thienyl EtOCOO 4188 PhCO- 2-thienyl EtOCOO 4222 2-FuCO- 2-thienyl MeOCOO 4234 tBuOCO- 2-thienyl EtOCOO 15 4244 ibueCO- 2-thienyl MeOCOO 4262 tBuOCO- 2-thienyl MeOCOO 4304 2-FuCO- 2-thienyl EtOCOO 4355 iBuOCO- 2-thienyl MeOCOO 4363 iBuOCO- 2-thienyl EtOCOO 20 4411 PhCO- 2-thienyl MeOCOO 4424 2-ThCO 2-thienyl MeOCOO 4434 tBuOCO- 3-furyl MeOCOO 4455 2-ThCO 2-thienyl EtOCOO 4474 tBuOCO- 3-thienyl MeOCOO 25 4484 tBuOCO- isobutenyl MeOCOO- WO 01/57013 PCT/USO1/03624 174 4500 tBuOCO- 3-thienyl EtOCOO 4515 iBuOCO- 3-thienyl AcO 4524 tBuOCO- isobutenyl EtOCOO 4533 tBuOCO- 2-furyl MeOCOO 5 4555 tBuOCO- cyclopropyl AcO 4584 iBuOCO- 3-furyl MeOCOO 4566 tBuOCO- cyclopropyl MeOCOO 4575 tBuOCO- 2-furyl MeOCOO 4624 iBuOCO- 3-furyl EtOCOO 10 4644 iBuOCO- isobutenyl MeOCOO 4656 iBuOCO- 2-furyl MeOCOO 4674 iBuOCO- 3-thienyl MeOCOO 4688 iBuOCO- isobutenyl EtOCOO 4696 iBuOCO- 2-furyl EtOCOO 15 4744 tC 3

H

5 CO- 2-furyl MeOCOO 4766 tC 3 HCO- 2-thienyl MeOCOO 5466 ibueCO- 2-furyl BnOCOO 6151 ibueCO- 2-furyl EtOCOO 6246 tAmOCO- 2-furyl BnOCOO 20 5433 tBuOCO- 2-furyl BnOCOO 4818 tC 3

H

5 CO- 2-furyl EtOCOO 6566 tC 3

H

5 CO- 2-thienyl BnOCOO 4855 tC 3

H

5 CO- 2-thienyl EtOCOO 4464 tBuOCO- 3-furyl EtOCOO 25 4904 tC 3

H

5 CO- 3-furyl EtOCOO 4877 tC 3

H

5 CO- 3-furyl MeOCOO 4979 iBuOCO- 3-thienyl EtOCOO 4444 tBuOCO- 3-thienyl MeOCOO 4999 tC 3

H

5 CO- 3-thienyl EtOCOO 30 4969 tC 3

H

5 CO- 3-thienyl MeOCOO 5225 iBuOCO- cpro EtOCOO- WO 01/57013 PCT/USO1/03624 175 5211 iBuOCO- cpro MeOCOO 5165 tBuOCO- cpro EtOCOO Example 23: Additional Taxanes having C-7 Carbonate and C-10 Hydroxy Substituents 5 Following the processes described in Example 21 and elsewhere herein, the following specific taxanes having structural formula (16) may be prepared, wherein

R

7 is as previously defined, including wherein R 7 is RaOCOO- and Ra is (i) substituted or unsubstituted C, to C8 alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl 10 (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heterocyclo such as furyl, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing 15 substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

X

5 NH 0 HO O X3 =1- 0 OI , "/t OH o' HO AcO O 20 (16) X5 X3 R7 tBuOCO- 2-furyl RaOCOO tBuOCO- 3-furyl RaOCOO 25 tBuOCO- 2-thienyl RaOCOO tBuOCO- 3-thienyl RaOCOO- WO 01/57013 PCT/USO1/03624 176 tBuOCO- 2-pyridyl RaOCOO tBuOCO- 3-pyridyl RaOCOO tBuOCO- 4-pyridyl ROCOO tBuOCO- isobutenyl RaOCOO 5 tBuOCO- isopropyl RaOCOO tBuOCO- cyclopropyl RaOCOO tBuOCO- cyclobutyl ROCOO tBuOCO- cyclopentyl RaOCOO tBuOCO- phenyl RaOCOO 10 benzoyl 2-furyl RaOCOO benzoyl 3-furyl RaOCOO benzoyl 2-thienyl RaOCOO benzoyl 3-thienyl RaOCOO benzoyl 2-pyridyl RaOCOO 15 benzoyl 3-pyridyl ROCOO benzoyl 4-pyridyl RaOCOO benzoyl isobutenyl RaOCOO benzoyl isopropyl RaOCOO benzoyl cyclopropyl RaOCOO 20 benzoyl cyclobutyl RaOCOO benzoyl cyclopentyl RaOCOO benzoyl phenyl ROCOO 2-FuCO- 2-furyl RaOCOO 2-FuCO- 3-furyl RaOCOO 25 2-FuCO- 2-thienyl RaOCOO 2-FuCO- 3-thienyl RaOCOO 2-FuCO- 2-pyridyl RaOCOO 2-FuCO- 3-pyridyl RaOCOO 2-FuCO- 4-pyridyl RaOCOO 30 2-FuCO- isobutenyl RaOCOO 2-FuCO- isopropyl RaOCOO- WO 01/57013 PCT/USO1/03624 177 2-FuCO- cyclopropyl RaOCOO 2-FuCO- cyclobutyl RaOCOO 2-FuCO- cyclopentyl RaOCOO 2-FuCO- phenyl RaOCOO 5 2-ThCO- 2-furyl RaOCOO 2-ThCO- 3-furyl RaOCOO 2-ThCO- 2-thienyl RaOCOO 2-ThCO- 3-thienyl RaOCOO 2-ThCO- 2-pyridyl RaOCOO 10 2-ThCO- 3-pyridyl RaOCOO 2-ThCO- 4-pyridyl RaOCOO 2-ThCO- isobutenyl RaOCOO 2-ThCO- isopropyl RaOCOO 2-ThCO- cyclopropyl RaOCOO 15 2-ThCO- cyclobutyl RaOCOO 2-ThCO- cyclopentyl RaOCOO 2-ThCO- phenyl RaOCOO 2-PyCO- 2-furyl RaOCOO 2-PyCO- 3-furyl RaOCOO 20 2-PyCO- 2-thienyl RaOCOO 2-PyCO- 3-thienyl ROCOO 2-PyCO- 2-pyridyl RaOCOO 2-PyCO- 3-pyridyl RaOCOO 2-PyCO- 4-pyridyl RaOCOO 25 2-PyCO- isobutenyl RaOCOO 2-PyCO- isopropyl RaOCOO 2-PyCO- cyclopropyl RaOCOO 2-PyCO- cyclobutyl RaOCOO 2-PyCO- cyclopentyl RaOCOO 30 2-PyCO- phenyl ROCOO 3-PyCO- 2-furyl RaOCOO- WO 01/57013 PCT/USO1/03624 178 3-PyCO- 3-furyl RaOCOO 3-PyCO- 2-thienyl RaOCOO 3-PyCO- 3-thienyl RaOCOO 3-PyCO- 2-pyridyl RaOCOO 5 3-PyCO- 3-pyridyl RaOCOO 3-PyCO- 4-pyridyl RaOCOO 3-PyCO- isobutenyl RaOCOO 3-PyCO- isopropyl RaOCOO 3-PyCO- cyclopropyl RaOCOO 10 3-PyCO- cyclobutyl RaOCOO 3-PyCO- cyclopentyl RaOCOO 3-PyCO- phenyl RaOCOO 4-PyCO- 2-furyl RaOCOO 4-PyCO- 3-furyl RaOCOO 15 4-PyCO- 2-thienyl RaOCOO 4-PyCO- 3-thienyl RaOCOO 4-PyCO- 2-pyridyl RaOCOO 4-PyCO- 3-pyridyl RaOCOO 4-PyCO- 4-pyridyl RaOCOO 20 4-PyCO- isobutenyl RaOCOO 4-PyCO- isopropyl RaOCOO 4-PyCO- cyclopropyl RaOCOO 4-PyCO- cyclobutyl RaOCOO 4-PyCO- cyclopentyl RaOCOO 25 4-PyCO- phenyl RaOCOO

C

4

H

7 CO- 2-furyl RaOCOO

C

4

H

7 CO- 3-furyl RaOCOO

C

4

H

7 CO- 2-thienyl RaOCOO

C

4

H

7 CO- 3-thienyl RaOCOO 30 C 4

H

7 CO- 2-pyridyl RaOCOO

C

4

H

7 CO- 3-pyridyl RaOCOO- WO 01/57013 PCT/USO1/03624 179

C

4

H

7 CO- 4-pyridyl RaOCOO

C

4

H

7 CO- isobutenyl RaOCOO

C

4

H

7 CO- isopropyl RaOCOO

C

4

H

7 CO- cyclopropyl RaOCOO 5 C 4

H

7 CO- cyclobutyl RaOCOO

C

4

H

7 CO- cyclopentyl RaOCOO

C

4

H

7 CO- phenyl RaOCOO EtOCO- 2-furyl RaOCOO EtOCO- 3-furyl RaOCOO 10 EtOCO- 2-thienyl RaOCOO EtOCO- 3-thienyl RaOCOO EtOCO- 2-pyridyl RaOCOO EtOCO- 3-pyridyl RaOCOO EtOCO- 4-pyridyl RaOCOO 15 EtOCO- isobutenyl RaOCOO EtOCO- isopropyl RaOCOO EtOCO- cyclopropyl RaOCOO EtOCO- cyclobutyl RaOCOO EtOCO- cyclopentyl RaOCOO 20 EtOCO- phenyl ROCOO ibueCO- 2-furyl RaOCOO ibueCO- 3-furyl RaOCOO ibueCO- 2-thienyl RaOCOO ibueCO- 3-thienyl RaOCOO 25 ibueCO- 2-pyridyl RaOCOO ibueCO- 3-pyridyl RaOCOO ibueCO- 4-pyridyl RaOCOO ibueCO- isobutenyl RaOCOO ibueCO- isopropyl RaOCOO 30 ibueCO- cyclopropyl RaOCOO ibueCO- cyclobutyl RaOCOO- WO 01/57013 PCT/USO1/03624 180 ibueCO- cyclopentyl RaOCOO ibueCO- phenyl RaOCOO iBuCO- 2-furyl RaOCOO iBuCO- 3-furyl RaOCOO 5 iBuCO- 2-thienyl RaOCOO iBuCO- 3-thienyl RaOCOO iBuCO- 2-pyridyl RaOCOO iBuCO- 3-pyridyl RaOCOO iBuCO- 4-pyridyl RaOCOO 10 iBuCO- isobutenyl RaOCOO iBuCO- isopropyl RaOCOO iBuCO- cyclopropyl RaOCOO iBuCO- cyclobutyl RaOCOO iBuCO- cyclopentyl RaOCOO 15 iBuCO- phenyl RaOCOO iBuOCO- 2-furyl RaOCOO iBuOCO- 3-furyl RaOCOO iBuOCO- 2-thienyl RaOCOO iBuOCO- 3-thienyl RaOCOO 20 iBuOCO- 2-pyridyl RaOCOO iBuOCO- 3-pyridyl RaOCOO iBuOCO- 4-pyridyl RaOCOO iBuOCO- isobutenyl ROCOO iBuOCO- isopropyl RaOCOO 25 iBuOCO- cyclopropyl RaOCOO iBuOCO- cyclobutyl ROCOO iBuOCO- cyclopentyl RaOCOO iBuOCO- phenyl RaOCOO iPrOCO- 2-furyl RaOCOO 30 iPrOCO- 3-furyl RaOCOO iPrOCO- 2-thienyl RaOCOO- WO 01/57013 PCT/USO1/03624 181 iPrOCO- 3-thienyl RaOCOO iPrOCO- 2-pyridyl RaOCOO iPrOCO- 3-pyridyl RaOCOO iPrOCO- 4-pyridyl RaOCOO 5 iPrOCO- isobutenyl RaOCOO iPrOCO- isopropyl RaOCOO iPrOCO- cyclopropyl RaOCOO iPrOCO- cyclobutyl RaOCOO iPrOCO- cyclopentyl RaOCOO 10 iPrOCO- phenyl RaOCOO nPrOCO- 2-furyl RaOCOO nPrOCO- 3-furyl RaOCOO nPrOCO- 2-thienyl RaOCOO nPrOCO- 3-thienyl RaOCOO 15 nPrOCO- 2-pyridyl RaOCOO nPrOCO- 3-pyridyl RaOCOO nPrOCO- 4-pyridyl RaOCOO nPrOCO- isobutenyl RaOCOO nPrOCO- isopropyl RaOCOO 20 nPrOCO- cyclopropyl RaOCOO nPrOCO- cyclobutyl RaOCOO nPrOCO- cyclopentyl ROCOO nPrOCO- phenyl RaOCOO nPrCO- 2-furyl RaOCOO 25 nPrCO- 3-furyl RaOCOO nPrCO- 2-thienyl RaOCOO nPrCO- 3-thienyl RaOCOO nPrCO- 2-pyridyl RaOCOO nPrCO- 3-pyridyl RaOCOO 30 nPrCO- 4-pyridyl RaOCOO nPrCO- isobutenyl RaOCOO- WO 01/57013 PCT/USO1/03624 182 nPrCO- isopropyl RaOCOO nPrCO- cyclopropyl RaOCOO nPrCO- cyclobutyl RaOCOO nPrCO- cyclopentyl RaOCOO 5 nPrCO- phenyl RaOCOO tBuOCO- 2-furyl EtOCOO tBuOCO- 2-pyridyl EtOCOO tBuOCO- 3-pyridyl EtOCOO tBuOCO- 4-pyridyl EtOCOO 10 tBuOCO- isopropyl EtOCOO tBuOCO- cyclopropyl EtOCOO tBuOCO- cyclobutyl EtOCOO tBuOCO- cyclopentyl EtOCOO tBuOCO- phenyl EtOCOO 15 benzoyl 2-furyl EtOCOO benzoyl 3-furyl EtOCOO benzoyl 3-thienyl EtOCOO benzoyl 2-pyridyl EtOCOO benzoyl 3-pyridyl EtOCOO 20 benzoyl 4-pyridyl EtOCOO benzoyl isobutenyl EtOCOO benzoyl isopropyl EtOCOO benzoyl cyclopropyl EtOCOO benzoyl cyclobutyl EtOCOO 25 benzoyl cyclopentyl EtOCOO benzoyl phenyl EtOCOO 2-FuCO- 2-furyl EtOCOO 2-FuCO- 3-furyl EtOCOO 2-FuCO- 3-thienyl EtOCOO 30 2-FuCO- 2-pyridyl EtOCOO 2-FuCO- 3-pyridyl EtOCOO- WO 01/57013 PCT/USO1/03624 183 2-FuCO- 4-pyridyl EtOCOO 2-FuCO- isobutenyl EtOCOO 2-FuCO- isopropyl EtOCOO 2-FuCO- cyclopropyl EtOCOO 5 2-FuCO- cyclobutyl EtOCOO 2-FuCO- cyclopentyl EtOCOO 2-FuCO- phenyl EtOCOO 2-ThCO- 2-furyl EtOCOO 2-ThCO- 3-furyl EtOCOO 10 2-ThCO- 3-thienyl EtOCOO 2-ThCO- 2-pyridyl EtOCOO 2-ThCO- 3-pyridyl EtOCOO 2-ThCO- 4-pyridyl EtOCOO 2-ThCO- isobutenyl EtOCOO 15 2-ThCO- isopropyl EtOCOO 2-ThCO- cyclopropyl EtOCOO 2-ThCO- cyclobutyl EtOCOO 2-ThCO- cyclopentyl EtOCOO 2-ThCO- phenyl EtOCOO 20 2-PyCO- 2-furyl EtOCOO 2-PyCO- 3-furyl EtOCOO 2-PyCO- 2-thienyl EtOCOO 2-PyCO- 3-thienyl EtOCOO 2-PyCO- 2-pyridyl EtOCOO 25 2-PyCO- 3-pyridyl EtOCOO 2-PyCO- 4-pyridyl EtOCOO 2-PyCO- isobutenyl EtOCOO 2-PyCO- isopropyl EtOCOO 2-PyCO- cyclopropyl EtOCOO 30 2-PyCO- cyclobutyl EtOCOO 2-PyCO- cyclopentyl EtOCOO- WO 01/57013 PCT/USO1/03624 184 2-PyCO- phenyl EtOCOO 3-PyCO- 2-furyl EtOCOO 3-PyCO- 3-furyl EtOCOO 3-PyCO- 2-thienyl EtOCOO 5 3-PyCO- 3-thienyl EtOCOO 3-PyCO- 2-pyridyl EtOCOO 3-PyCO- 3-pyridyl EtOCOO 3-PyCO- 4-pyridyl EtOCOO 3-PyCO- isobutenyl EtOCOO 10 3-PyCO- isopropyl EtOCOO 3-PyCO- cyclopropyl EtOCOO 3-PyCO- cyclobutyl EtOCOO 3-PyCO- cyclopentyl EtOCOO 3-PyCO- phenyl EtOCOO 15 4-PyCO- 2-furyl EtOCOO 4-PyCO- 3-furyl EtOCOO 4-PyCO- 2-thienyl EtOCOO 4-PyCO- 3-thienyl EtOCOO 4-PyCO- 2-pyridyl EtOCOO 20 4-PyCO- 3-pyridyl EtOCOO 4-PyCO- 4-pyridyl EtOCOO 4-PyCO- isobutenyl EtOCOO 4-PyCO- isopropyl EtOCOO 4-PyCO- cyclopropyl EtOCOO 25 4-PyCO- cyclobutyl EtOCOO 4-PyCO- cyclopentyl EtOCOO 4-PyCO- phenyl EtOCOO

C

4

H

7 CO- 2-furyl EtOCOO

C

4

H

7 CO- 3-furyl EtOCOO 30 C 4

H

7 CO- 2-thienyl EtOCOO

C

4

H

7 CO- 3-thienyl EtOCOO- WO 01/57013 PCT/USO1/03624 185

C

4

H

7 CO- 2-pyridyl EtOCOO

C

4

H

7 CO- 3-pyridyl EtOCOO

C

4

H

7 CO- 4-pyridyl EtOCOO

C

4

H

7 CO- isobutenyl EtOCOO 5 C 4

H

7 CO- isopropyl EtOCOO

C

4

H

7 CO- cyclopropyl EtOCOO

C

4

H

7 CO- cyclobutyl EtOCOO

C

4

H

7 CO- cyclopentyl EtOCOO

C

4

H

7 CO- phenyl EtOCOO 10 EtOCO- 2-furyl EtOCOO EtOCO- 3-furyl EtOCOO EtOCO- 2-thienyl EtOCOO EtOCO- 3-thienyl EtOCOO EtOCO- 2-pyridyl EtOCOO 15 EtOCO- 3-pyridyl EtOCOO EtOCO- 4-pyridyl EtOCOO EtOCO- isobutenyl EtOCOO EtOCO- isopropyl EtOCOO EtOCO- cyclopropyl EtOCOO 20 EtOCO- cyclobutyl EtOCOO EtOCO- cyclopentyl EtOCOO EtOCO- phenyl EtOCOO ibueCO- 3-furyl EtOCOO ibueCO- 3-thienyl EtOC00 25 ibueCO- 2-pyridyl EtOCOO ibueCO- 3-pyridyl EtOCOO ibueCO- 4-pyridyl EtOCOO ibueCO- isobutenyl EtOCOO ibueCO- isopropyl EtOCOO 30 ibueCO- cyclopropyl EtOCOO ibueCO- cyclobutyl EtOCOO- WO 01/57013 PCT/USO1/03624 186 ibueCO- cyclopentyl EtOCOO ibueCO- phenyl EtOCOO iBuCO- 2-furyl EtOCOO iBuCO- 3-furyl EtOCOO 5 iBuCO- 2-thienyl EtOCOO iBuCO- 3-thienyl EtOCOO iBuCO- 2-pyridyl EtOCOO iBuCO- 3-pyridyl EtOCOO iBuCO- 4-pyridyl EtOCOO 10 iBuCO- isobutenyl EtOCOO iBuCO- isopropyl EtOCOO iBuCO- cyclopropyl EtOCOO iBuCO- cyclobutyl EtOCOO iBuCO- cyclopentyl EtOCOO 15 iBuCO- phenyl EtOCOO iBuOCO- 3-furyl EtOCOO iBuOCO- 2-pyridyl EtOCOO iBuOCO- 3-pyridyl EtOCOO iBuOCO- 4-pyridyl EtOCOO 20 iBuOCO- isopropyl EtOCOO iBuOCO- cyclopropyl EtOCOO iBuOCO- cyclobutyl EtOCOO iBuOCO- cyclopentyl EtOCOO iBuOCO- phenyl EtOCOO 25 iPrOCO- 2-furyl EtOCOO iPrOCO- 3-furyl EtOCOO iPrOCO- 3-thienyl EtOCOO iPrOCO- 2-pyridyl EtOCOO iPrOCO- 3-pyridyl EtOCOO 30 iPrOCO- 4-pyridyl EtOCOO iPrOCO- isobutenyl EtOCOO- WO 01/57013 PCT/USO1/03624 187 iPrOCO- isopropyl EtOCOO iPrOCO- cyclopropyl EtOCOO iPrOCO- cyclobutyl EtOCOO iPrOCO- cyclopentyl EtOCOO 5 iPrOCO- phenyl EtOCOO nPrOCO- 2-furyl EtOCOO nPrOCO- 3-furyl EtOCOO nPrOCO- 2-thienyl EtOCOO nPrOCO- 3-thienyl EtOCOO 10 nPrOCO- 2-pyridyl EtOCOO nPrOCO- 3-pyridyl EtOCOO nPrOCO- 4-pyridyl EtOCOO nPrOCO- isobutenyl EtOCOO nPrOCO- isopropyl EtOCOO 15 nPrOCO- cyclopropyl EtOCOO nPrOCO- cyclobutyl EtOCOO nPrOCO- cyclopentyl EtOCOO nPrOCO- phenyl EtOCOO nPrCO- 2-furyl EtOCOO 20 nPrCO- 3-furyl EtOCOO nPrCO- 2-thienyl EtOCOO nPrCO- 3-thienyl EtOCOO nPrCO- 2-pyridyl EtOCOO nPrCO- 3-pyridyl EtOCOO 25 nPrCO- 4-pyridyl EtOCOO nPrCO- isobutenyl EtOCOO nPrCO- isopropyl EtOCOO nPrCO- cyclopropyl EtOCOO nPrCO- cyclobutyl EtOCOO 30 nPrCO- cyclopentyl EtOCOO nPrCO- phenyl EtOCOO- WO 01/57013 PCT/USO1/03624 188 tBuOCO- 2-pyridyl MeOCOO tBuOCO- 3-pyridyl MeOCOO tBuOCO- 4-pyridyl MeOCOO tBuOCO- isopropyl MeOCOO 5 tBuOCO- cyclobutyl MeOCOO tBuOCO- cyclopentyl MeOCOO tBuOCO- phenyl MeOCOO benzoyl 2-furyl MeOCOO benzoyl 3-furyl MeOCOO 10 benzoyl 3-thienyl MeOCOO benzoyl 2-pyridyl MeOCOO benzoyl 3-pyridyl MeOCOO benzoyl 4-pyridyl MeOCOO benzoyl isobutenyl MeOCOO 15 benzoyl isopropyl MeOCOO benzoyl cyclopropyl MeOCOO benzoyl cyclobutyl MeOCOO benzoyl cyclopentyl MeOCOO benzoyl phenyl MeOCOO 20 2-FuCO- 2-furyl MeOCOO 2-FuCO- 3-furyl MeOCOO 2-FuCO- 3-thienyl MeOCOO 2-FuCO- 2-pyridyl MeOCOO 2-FuCO- 3-pyridyl MeOCOO 25 2-FuCO- 4-pyridyl MeOCOO 2-FuCO- isobutenyl MeOCOO 2-FuCO- isopropyl MeOCOO 2-FuCO- cyclopropyl MeOCOO 2-FuCO- cyclobutyl MeOCOO 30 2-FuCO- cyclopentyl MeOCOO 2-FuCO- phenyl MeOCOO- WO 01/57013 PCT/USO1/03624 189 2-ThCO- 2-furyl MeOCOO 2-ThCO- 3-furyl MeOCOO 2-ThCO- 3-thienyl MeOCOO 2-ThCO- 2-pyridyl MeOCOO 5 2-ThCO- 3-pyridyl MeOCOO 2-ThCO- 4-pyridyl MeOCOO 2-ThCO- isobutenyl MeOCOO 2-ThCO- isopropyl MeOCOO 2-ThCO- cyclopropyl MeOCOO 10 2-ThCO- cyclobutyl MeOCOO 2-ThCO- cyclopentyl MeOCOO 2-ThCO- phenyl MeOCOO 2-PyCO- 2-furyl MeOCOO 2-PyCO- 3-furyl MeOCOO 15 2-PyCO- 2-thienyl MeOCOO 2-PyCO- 3-thienyl MeOCOO 2-PyCO- 2-pyridyl MeOCOO 2-PyCO- 3-pyridyl MeOCOO 2-PyCO- 4-pyridyl MeOCOO 20 2-PyCO- isobutenyl MeOCOO 2-PyCO- isopropyl MeOCOO 2-PyCO- cyclopropyi MeOCOO 2-PyCO- cyclobutyl MeOCOO 2-PyCO- cyclopentyl MeOCOO 25 2-PyCO- phenyl MeOCOO 3-PyCO- 2-furyl MeOCOO 3-PyCO- 3-furyl MeOCOO 3-PyCO- 2-thienyl MeOCOO 3-PyCO- 3-thienyl MeOCOO 30 3-PyCO- 2-pyridyl MeOCOO 3-PyCO- 3-pyridyl MeOCOO- WO 01/57013 PCT/USO1/03624 190 3-PyCO- 4-pyridyl MeOCOO 3-PyCO- isobutenyl MeOCOO 3-PyCO- isopropyl MeOCOO 3-PyCO- cyclopropyl MeOCOO 5 3-PyCO- cyclobutyl MeOCOO 3-PyCO- cyclopentyl MeOCOO 3-PyCO- phenyl MeOCOO 4-PyCO- 2-furyl MeOCOO 4-PyCO- 3-furyl MeOCOO 10 4-PyCO- 2-thienyl MeOCOO 4-PyCO- 3-thienyl MeOCOO 4-PyCO- 2-pyridyl MeOCOO 4-PyCO- 3-pyridyl MeOCOO 4-PyCO- 4-pyridy MeOCOO 15 4-PyCO- isobutenyl MeOCOO 4-PyCO- isopropyl MeOCOO 4-PyCO- cyclopropyl MeOCOO 4-PyCO- cyclobutyl MeOCOO 4-PyCO- cyclopentyl MeOCOO 20 4-PyCO- phenyl MeOCOO

C

4

H

7 CO- 2-furyl MeOCOO

C

4

H

7 CO- 3-furyl MeOCOO

C

4

H

7 CO- 2-thienyl MeOCOO

C

4

H

7 CO- 3-thienyl MeOCOO 25 C 4

H

7 CO- 2-pyridyl MeOCOO

C

4

H

7 CO- 3-pyridyl MeOCOO

C

4

H

7 CO- 4-pyridyl MeOCOO

C

4

H

7 CO- isobutenyl MeOCOO

C

4 H7CO- isopropyl MeOCOO 30 C 4

H

7 CO- cyclopropyl MeOCOO

C

4

H

7 CO- cyclobutyl MeOCOO- WO 01/57013 PCT/USO1/03624 191

C

4

H

7 CO- cyclopentyl MeOCOO

C

4

H

7 CO- phenyl MeOCOO EtOCO- 2-furyl MeOCOO EtOCO- 3-furyl MeOCOO 5 EtOCO- 2-thienyl MeOCOO EtOCO- 3-thienyl MeOCOO EtOCO- 2-pyridyl MeOCOO EtOCO- 3-pyridyl MeOCOO EtOCO- 4-pyridyl MeOCOO 10 EtOCO- isobutenyl MeOCOO EtOCO- isopropyl MeOCOO EtOCO- cyclopropyl MeOCOO EtOCO- cyclobutyl MeOCOO EtOCO- cyclopentyl MeOCOO 15 EtOCO- phenyl MeOCOO ibueCO- 2-furyl MeOCOO ibueCO- 3-furyl MeOCOO ibueCO- 3-thienyl MeOCOO ibueCO- 2-pyridyl MeOCOO 20 ibueCO- 3-pyridyl MeOCOO ibueCO- 4-pyridyl MeOCOO ibueCO- isobutenyl MeOCOO ibueCO- isopropyl MeOCOO ibueCO- cyclopropyl MeOCOO 25 ibueCO- cyclobutyl MeOCOO ibueCO- cyclopentyl MeOCOO ibueCO- phenyl MeOCOO iBuCO- 2-furyl MeOCOO iBuCO- 3-furyl MeOCOO 30 iBuCO- 2-thienyl MeOCOO iBuCO- 3-thienyl MeOCOO- WO 01/57013 PCT/USO1/03624 192 iBuCO- 2-pyridyl MeOCOO IBuCO- 3-pyridyl MeOCOO iBuCO- 4-pyridyl MeOCOO iBuCO- isobutenyl MeOCOO 5 iBuCO- isopropyl MeOCOO iBuCO- cyclopropyl MeOCOO iBuCO- cyclobutyl MeOCOO iBuCO- cyclopentyl MeOCOO iBuCO- phenyl MeOCOO 10 iBuOCO- 2-pyridyl MeOCOO iBuOCO- 3-pyridyl MeOCOO iBuOCO- 4-pyridyl MeOCOO iBuOCO- isopropyl MeOCOO iBuOCO- cyclopropyl MeOCOO 15 iBuOCO- cyclobutyl MeOCOO iBuOCO- cyclopentyl MeOCOO iBuOCO- phenyl MeOCOO iPrOCO- 2-furyl MeOCOO iPrOCO- 3-furyl MeOCOO 20 iPrOCO- 3-thienyl MeOCOO iPrOCO- 2-pyridyl MeOCOO iPrOCO- 3-pyridyl MeOCOO iPrOCO- 4-pyridyl MeOCOO iPrOCO- isobutenyl MeOCOO 25 iPrOCO- isopropyl MeOCOO iPrOCO- cyclopropyl MeOCOO iPrOCO- cyclobutyl MeOCOO iPrOCO- cyclopentyl MeOCOO iPrOCO- phenyl MeOCOO 30 nPrOCO- 2-furyl MeOCOO nPrOCO- 3-furyl MeOCOO- WO 01/57013 PCT/USO1/03624 193 nPrOCO- 2-thienyl MeOCOO nPrOCO- 3-thienyl MeOCOO nPrOCO- 2-pyridyl MeOCOO nPrOCO- 3-pyridyl MeOCOO 5 nPrOCO- 4-pyridyl MeOCOO nPrOCO- isobutenyl MeOCOO nPrOCO- isopropyl MeOCOO nPrOCO- cyclopropyl MeOCOO nPrOCO- cyclobutyl MeOCOO 10 nPrOCO- cyclopentyl MeOCOO nPrOCO- phenyl MeOCOO nPrCO- 2-furyl MeOCOO nPrCO- 3-furyl MeOCOO nPrCO- 2-thienyl MeOCOO 15 nPrCO- 3-thienyl MeOCOO nPrCO- 2-pyridyl MeOCOO nPrCO- 3-pyridyl MeOCOO nPrCO- 4-pyridyl MeOCOO nPrCO- isobutenyl MeOCOO 20 nPrCO- isopropyl MeOCOO nPrCO- cyclopropyl MeOCOO nPrCO- cyclobutyl MeOCOO nPrCO- cyclopentyl MeOCOO nPrCO- phenyl MeOCOO 25 Example 24: Taxanes Having C-7 Carbonate and C-10 Hydroxy Substituents Following the processes described in Example 21 and elsewhere herein, the following specific taxanes having structural formula (17) may be prepared, wherein

R

1 0 is hydroxy and R 7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R 7 is R 7 aOCOO- and R 7 a is (i) substituted 30 or unsubstituted, preferably unsubstituted, C2 to C. alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, WO 01/57013 PCT/US01/03624 194 preferably unsubstituted, C2 to C8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C2 to C8 alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted, preferably 5 unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl. In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 . is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert 10 butyl), and R 7 and R 1 each have the beta stereochemical configuration. In the "B" series of compounds, X 1 0 and R 2 , are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued 15 furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 10 each have the beta stereochemical configuration. In the "C" series of compounds, X 1 0 and Ra are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, 20 phenyl, or lower alkyl (e.g., tert-butyl), R 9 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "D" and "E" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or 25 pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R. (series D only) and R 1 each have the beta stereochemical configuration. In the "F" series of compounds, X 10 , R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 30 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 each have the beta stereochemical configuration. In the "G" series of compounds, X 1 and R 2 a are as otherwise as defined 35 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, WO 01/57013 PCT/US01/03624 195 phenyl, or lower alkyl (e.g., tert-butyl), R 2 . is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "H" series of compounds, X 1 0 is as otherwise as defined herein. 5 Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 , is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and RIO each have the beta stereochemical configuration. 10 In the "I" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical 15 configuration. In the "J" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued 20 furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "K" series of compounds, X 1 0 , R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, 25 phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and RIO each have the beta stereochemical configuration. Any substituents of each X 3 , X 5 , R 2 , R 7 , and R. may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of 30 heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

WO 01/57013 PCT/US01/03624 196

X

5 NH O

R

9 X3 R7 OH

R

14 HO . R2 0 OAc 5 (17) Series X 5 X3 R7 R2 R 9 R14 Al -COOX 1 0 heterocyclo R 7 2 C00- C 6

H

5 C00- 0 H A2 -COX 10 heterocyclo R 7 .OCOO- C 6

H

5 COO- 0 H A3 -CONHX 1 heterocyclo R 7 a0COO- C 6

H

5 COO- 0 H 10 A4 -COOX 10 optionally R 7 aOCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A5 -COX 1 0 optionally R 7 aOCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A6 -CONHX 1 0 optionally Ry,00- C 6 HCOO- 0 H substituted C2 to C alkyl A7 -C00X 10 optionally R 7 aOCOO- C 6

H

5 C00- 0 H substituted C2 to C8 alkenyl A8 -COX 1 0 optionally R 7 aOCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkenyl 15 A9 -CONHX 1 optionally R 7 .OCOO- C 6

H

5 C00- 0 H substituted C2 to C alkenyl A10 -C00X 10 optionally R 7 aOCOO- C 6

H

5 C00- 0 H substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 197 All -COX 1 0 optionally Ry.OCOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl A12 -CONHX 1 optionally RiaOCOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl -B1 -C00X 1 0 heterocyclo R 7 aOCOO- R 2 ,COO- 0 H B2 -COXIO heterocyclo R 7 a0COO- R 2 aCOO- 0 H 5 B3 -CONHX 1 heterocyclo R 7 OCOO- R 2 aCOO- 0 H B4 -COOXIO optionally RyOCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl B5 -COX 10 optionally R 7 aOCOO- R 2 ,COO- 0 H substituted C2 to C8 alkyl B6 -CONHXO optionally R 7 0COO- R 2 aCOO- 0 H substituted C2 to C alkyl B7 -COOX 1 0 optionally R 7 0COO- R 2 aCOO- 0 H substituted C2 to C8 alkenyl 10 B8 -COX 1 0 optionally R 7 aOCOO- R 2 aCOO- 0 H substituted C2 to C. alkenyl B9 -CONHX 1 optionally R 7 aOCOO- R 2 aCOO- 0 H substituted C2 to C8 alkenyl B10 -COOX 10 optionally R 7 aOCOO- R 2 aCOO- 0 H substituted C2 to C alkynyl B11 -COX 1 0 optionally R 7 0COO- R 2 ,COO- 0 H substituted C2 to C.8 alkynyl WO 01/57013 PCT/USO1/03624 198 B12 -CONHX,, optionally R 7 a0COO- R 2 ,COO- 0 H substituted C2 to C alkynyl C1 -COOX 1 0 heterocyclo R 7 .OCOO- CHCOO- RaCOO- H C2 -COX 1 0 heterocyclo R 7 0COO- CHCOO- R 92 ,COO- H C3 -CONHXo heterocyclo R 7 aOCOO- CH 5 COO- RgaCOO- H 5 C4 -C00X 1 0 optionally R 7 0COO- CH 5 COO- RgaCOO- H substituted C2 to C alkyl C5 -COX 10 optionally R 7 OCOO- C 6 HCOO- R0,COO- H substituted C2 to C. alkyl C6 -CONHXO optionally R 7 a0COO- C 6

H

5 COO- RgCOO- H substituted C2 to C alkyl C7 -COOXIo optionally R 7 aOCOO- CHCOO- R 9 COO- H substituted C2 to C alkenyl C8 -COXO optionally R 7 a0COO- CH 5 COO- RgaCOO- H substituted C2 to C8 alkenyl 10 C9 -CONHXO optionally R 7 0COO- C 6 HCOO- RgaCOO- H substituted C2 to C alkenyl C10 -COOXIO optionally R 7 OCOO- CHCOO- R 9 aCOO- H substituted C2 to C. alkynyl C11 -COX 10 optionally R 7 aOCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C alkynyl C12 -CONHX 1 optionally R 7 aOCOO- CHCOO- RgaCOO- H substituted C2 to C alkynyl WO 01/57013 PCT/USO1/03624 199 D1 -COOX 1 0 heterocyclo R 7 OCOO- C 6

H

5 COO- OH H D2 -COXIO heterocyclo R 7 .OCOO- C 6

H

5 COO- OH H D3 -CONHX 1 heterocyclo R 7 OCOO- C 6

H

5 COO- OH H D4 -COOXO optionally RaOCOO- C 6

H

5 COO- OH H substituted C2 to C alkyl 5 D5 -COX 1 0 optionally R 7 .OCOO- C 6

H

5 COO- OH H substituted C2 to C alkyl D6 -CONHX 1 optionally R 7 aOCOO- C 6

H

5 COO- OH H substituted C2 to C alkyl D7 -COOX 1 0 optionally R 7 0COO- C 6

H

5 COO- OH H substituted C2 to C. alkenyl D8 -COXO optionally R 7 OCOO- C 6

H

5 COO- OH H substituted C2 to C alkenyl D9 -CONHX 1 optionally R 7 OCOO- C 6

H

5 COO- OH H substituted C2 to C alkenyl 10 D10 -COOX 1 0 optionally RiaOCOO- C 6

H

5 COO- OH H substituted C2 to C'alkynyl D11 -COX 10 optionally R 7 aOCOO- C 6

H

5 COO- OH H substituted C2 to C. alkynyl D12 -CONHX,, optionally R 7 aOCOO- CH 5 COO- OH H substituted C2 to C. alkynyl El -COOX 10 heterocyclo R 7 aOCOO- C 6

H

5 COO- 0 OH E2 -COX 1 0 heterocyclo R 7 OCOO- C 6

H

5 COO- 0 OH 15 E3 -CONHXO heterocyclo R 7 0COO- C 6

H

5 COO- 0 OH WO 01/57013 PCT/USO1/03624 200 E4 -COOXO optionally R 7 a0COO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl E5 -COX 1 0 optionally R 7 OCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl E6 -CONHX 1 optionally R 7 aOCOO- C 6

H

5 COO- 0 OH substituted C2 to C 8 alkyl E7 -COOX 10 optionally R 7 aOCOO- C 6 HCOO- 0 OH substituted C2 to C alkenyl 5 E8 -COX 1 0 optionally R 7 aOCOO- CH 5 COO- 0 OH substituted C2 to C8 alkenyl E9 -CONHXIO optionally R 7 aOCOO- CH 5 COO- 0 OH substituted C2 to C8 alkenyl E10 -COOX 1 0 optionally RiaOCOO- C 6 HCOO- 0 OH substituted C2 to C alkynyl Eli -COX 1 0 optionally R 7 .OCOO- CH 5 COO- 0 OH substituted C2 to C8 alkynyl E12 -CONHX 1 optionally R 7 yOCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl 10 Fl -COOXI 0 heterocyclo R 7 aOCOO- R 2 COO- R 9 aCOO- H F2 -COX 1 0 heterocyclo R 7 aOCOO- R 2 COO- R 9 aCOO- H F3 -CONHXO heterocyclo R 7 a0COO- R 2 aCOO- RgaCOO- H F4 -COOX 1 0 optionally R 7 aOCOO- R 2 aCOO- RgaCOO- H substituted C2 to C alkyl WO 01/57013 PCT/USO1/03624 201 F5 -COX 1 0 optionally R 7 a0COO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkyl F6 -CONHX 1 0 optionally R 7 aOCOO- R 2 ,COO- R 9 aCOO- H substituted C2 to C alkyl F7 -COOX 1 0 optionally R 7 C00- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkenyl F8 -COX 1 0 optionally R 7 yOCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkenyl 5 F9 -CONHX 10 optionally RyaOCOO- R 2 ,COO- RqaCOO- H substituted C2 to C alkenyl F10 -COOX 10 optionally R 7 a0COO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkynyl F11 -COX 1 0 optionally R 7 a0COO- R 2 ,COO- RCOO- H substituted C2 t o C 8 a lk y n y l C O O F12 -CONHX 1 0 optionally Ry,0COO- R 2 CO- RgeCOO- H substituted C2 to C8 alkynyl G1 -COOX 1 0 heterocyclo RyOCOO- R 2 aCOO- OH H 10 G2 -COXO heterocyclo R 7 yOCOO- R 2 aCOO- OH H G3 -CONHX 1 0 heterocyclo R 7 OCOO- R 2 aCOO- OH H G4 -COOX 1 0 optionally R 7 aCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl G5 -COX 1 optionally R 7 zOCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl WO 01/57013 PCT/USO1/03624 202 G6 -CONHXjO optionally RyaOCOO- R 2 ,COO- OH H substituted C2 to C alkyl G7 -COOX 1 0 optionally R 7 aOCOO- R 2 aCOO- OH H substituted C2 to C alkenyl G8 -COX 1 0 optionally R 7 aOCOO- R 2 aCOO- OH H substituted C2 to C alkenyl G9 -CONHX 1 optionally R 7 0COO- R 2 ,COO- OH H substituted C2 to C alkenyl 5 G10 -C00X 1 0 optionally R 7 OCOO- R 2 ,COO- OH H substituted C2 to C alkynyl G11 -COXIO optionally R 7 aOCOO- R 2 aCOO- OH H substituted C2 to C alkynyl G12 -CONHXIO optionally R 7 OCOO- R 2 aCOO- OH H substituted C2 to C alkynyl H1 -C00X 1 0 heterocyclo R 7 aOCOO- CH 5 COO- OH OH H2 -COX 10 heterocyclo R 7 OCOO- CH 5 COO- OH OH 10 H3 -CONHX 1 heterocyclo R 7 ,OCOO- CHCOO- OH OH H4 -COOX 10 optionally R 7 a0COO- CH 5 COO- OH OH substituted C2 to C alkyl H5 -COX 1 0 optionally R 7 yOCOO- CHCOO- OH OH substituted C2 to C alkyl H6 -CONHXO optionally R 7 aOCOO- C 6 HCOO- OH OH substituted C2 to C. alkyl WO 01/57013 PCT/USO1/03624 203 H7 -COOX 1 0 optionally R 7 aOCOO- C 6

H

5 COO- OH OH substituted C2 to C. alkenyl H8 -COX 1 0 optionally R 7 aOCOO- C 6

H

5 COO- OH OH substituted C2 to C. alkenyl H9 -CONHX 10 optionally R 7 aOCOO- C 6

H

5 COO- OH OH substituted C2 to C alkenyl H10 -COOXIO optionally R 7 @0COO- C 6

H

5 COO- OH OH substituted C2 to C, alkynyl 5 H11 -COX 1 0 optionally RiaOCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkynyl H12 -CONHX 1 optionally R 7 y0COO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl 11 -COOX 1 0 heterocyclo R 7 aOCOO- R 2 aCOO- 0 OH 12 -COX 10 heterocyclo R 7 aOCOO- R 2 aCOO- 0 OH 13 -CONHX 1 heterocyclo RyaOCOO- R 2 aCOO- 0 OH 10 14 -C00X 1 0 optionally R 7 a0COO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 15 -COX 1 0 optionally R 7 aOCOO- R 2 aCOO- 0 OH substituted C2 to C alkyl 16 -CONHX 1 optionally R 7 aOCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 17 -COOX 1 0 optionally R 7 ,0COO- R 2 COO- 0 OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 204 18 -COXIO optionally RyOCOO- R 2 COO- 0 OH substituted C2 to C. alkenyl 19 -CONHXO optionally R 7 0COO- R 2 ,COO- 0 OH substituted C2 to C alkenyl 110 -COOX 1 0 optionally RyaOCOO- R 2 ,COO- 0 OH substituted C2 to C alkynyl 111 -COX 1 0 optionally R 7 aOCOO- R 2 aCOO- 0 OH substituted C2 to C alkynyl 5 112 -CONHX 1 optionally R 7 aOCOO- R 2 COO- 0 OH substituted C2 to C alkynyl Ji -COOX 1 heterocyclo R 7 aOCOO- R 2 COO- OH OH J2 -COX 1 0 heterocyclo RyaOCOO- R 2 ,COO- OH OH J3 -CONHX 1 heterocyclo R 7 aOCOO- R 2 ,COO- OH OH J4 -COOX 1 0 optionally R,OCOO- R 2 ,COO- OH OH substituted C2 to C alkyl 10 J5 -COX 1 0 optionally R 7 0COO- R 2 COO- OH OH substituted C2 to C alkyl J6 -CONHX 10 optionally R 7 aOCOO- R 2 aCOO- OH OH substituted C2 to 0C alkyl J7 -COOX 1 0 optionally R 7 aOCOO- R 2 ,COO- OH OH substituted C2 to C alkenyl J8 -COX 10 optionally R 7 a0COO- R 2 ,COO- OH OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 205 J9 -CONHX 1 0 optionally R 7 aOCOO- R 2 aCOO- OH OH substituted C2 to C alkenyl J10 -COOX 10 optionally R 7 OCOO- R 2 aCOO- OH OH substituted C2 to C alkynyl Ji1 -COXIO optionally R 7 2 0COO- R 2 aCOO- OH OH substituted C2 to C, alkynyl J12 -CONHX 1 optionally R 7 aCOO- R 2 ,COO- OH OH substituted C2 to C alkynyl 5 K1 -COOX 1 0 heterocyclo R 7 a0COO- R 2 aCOO- R 0,COO- OH K2 -COXO heterocyclo R 7 OCOO- R 2 COO- ReaCOO- OH K3 -CONHX,, heterocyclo R 7 ,OCOO- R 2 aCOO- RgaCOO- OH K4 -C00X 10 optionally R 7 0COO- R 2 ,COO- RgaCOO- OH substituted C2 to C alkyl K5 -COXO optionally R 7 aOCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C alkyl 10 K6 -CONHXO optionally R 7 aOCOO- R 2 COO- R0,COO- OH substituted C2 to C alkyl K7 -COOX 1 0 optionally R 7 0COO- R 2 ,COO- RgaCOO- OH substituted C2 to C alkenyl K8 -COX 1 0 optionally R 7 aOCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkenyl K9 -CONHX 1 optionally R 7 aOCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 206 K10 -COOX 1 0 optionally R 7 aOCOO- R 2 aCOO- ReaCOO- OH substituted

C

2 to Cs alkynyl K11 -COX 1 0 optionally R 7 aOCOO- R 2 C00- RgaCOO- OH substituted

C

2 to C alkynyl K12 -CONHX,, optionally R 7 aOCOO- R 2 aCOO- R 9 aCOO- OH substituted

C

2 to C alkynyl Example 25: In Vitro cytotoxicity measured by the cell colony formation assay 5 Four hundred cells (HCTI 16) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 OC for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 22 were made up fresh in medium at ten times the 10 final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 0 C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell 15 colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound. Compound IN VITRO ID 50 (nm) HCT116 20 taxol 2.1 docetaxel 0.6 4144 <1 4151 <1 4164 <1 25 4188 <10 WO 01/57013 PCT/USO1/03624 207 4222 <1 4234 <1 4244 <1 4262 <1 5 4304 <10 4355 <1 4363 <10 4411 <1 4424 <1 10 4434 <1 4455 <1 4474 <1 4484 <1 4500 <1 15 4515 <10 4524 <1 4533 <1 4555 <1 4584 <10 20 4566 <1 4575 <1 4624 <10 4644 <10 4656 <1 25 4674 <1 4688 <10 4696 <1 4744 <1 4766 <1 30 5466 <1 6151 <1 WO 01/57013 PCT/USO1/03624 208 6246 <1 5433 <1 4818 <1 6566 <10 5 4855 <1 4464 <1 4904 <10 4877 <1 4979 <10 10 4444 <1 4999 <1 4969 <1 5225 <10 5211 <10 15 5165 <1 Example 26: Preparation of Taxanes having C-10 Carbonate and C-7 Hydroxy 0 HO EtOk 0 H (EtO 2

C)

2 0 -H H0" ' . ., H- H |- H .HC BzOAcO 0 BzA O 1 O-Ethoxycarbonyl-1 0-deacetyl baccatin IlIl. To a mixture of 0.941 g (1.73 mmol) of 10-deacetyl baccatin Ill and 0.043g (0.17 mmol) of CeCl 3 in 40 mL of THF at25 'C was added 0.64 mL (4.32 mmol) of diethyl pyrocarbonate. After 3 h the reaction 20 mixture was diluted with 200 mL of EtOAc, then washed three times with 50 mL of saturated aqueous NaHCO 3 solution and brine. The organic extract was dried over Na 2

SO

4 and concentrated in vacuo. The crude solid was purified by flash column chromatography on silica gel using 40% EtOAc/hexane as eluent to give 0.960 g (90%) of 10-ethoxycarbonyl-10-deacetyl baccatin Ill as a solid.

WO 01/57013 PCT/USO1/03624 209 0 0 EtO 0 EtO-0 0 0 OH Me 2 PhSiC - DMPS HGs,-- HO,--.. H 6 H Bzc O Bzbc 7-Dimethylphenylsilyl-1 O-ethoxycarbonyl-1 0-deacetyl baccatin 1ll. To a solution of 1.02 g (1.65 mmol) of 10-ethoxycarbonyl-10-deacetyl baccatin Ill in 30 mL of THF at -10 0C under a nitrogen atmosphere was added dropwise 0.668 mL (4.00 mmol) 5 of chlorodimethylphenylsilane and 2.48 mL (30.64 mmol) of pyridine. After 90 min the mixture was diluted with 200 mL of a 1:1 mixture of ethyl acetate and hexane. The mixture was washed with 30 mL of saturated aqueous sodium bicarbonate solution and the organic layer separated. The aqueous layer was extracted with 50 mL of a 1:1 mixture of ethyl acetate and hexane, and the combined organic extracts 10 were washed with brine, dried over Na 2

SO

4 , and concentrated in vacuo. The crude solid was purified by flash column chromatography on silica gel using 30% EtOAc/hexane as eluent to give 1.16 g (94%) of 7-dimethylphenylsilyl-10 ethoxycarbonyl-10-deacetyl baccatin Ill as a solid. 1 HNMR (400 MHz, CDC1 3 ): d 8.09 (dm, J= 7.64 Hz, 2 H, benzoate, o), 7.59 (tt, J= 7.54, 1.43 Hz, I H, benzoate, 15 p), 7.57 (m, 2 H, phenyl, o), 7.46 (t, J= 7.54 Hz, 2 H, benzoate, m), 7.37-7.33 (m, 3 H, phenyl, m,p), 6.21 (s, I H, H10), 5.63 (d, J= 7.05 Hz, 1 H, H2), 4.87-4.80 (m, 2 H, H5 and H13), 4.44 (dd, J= 6.84, 10.37 Hz, 1 H, H7), 4.27 (d, J= 8.27 Hz, 1 H, H20a), 4.16 (qm, J= 7.00 Hz, 2 H, CH 3

-CH

2 -), 4.13 (d, J= 8.27 Hz, I H, H20b), 3.83 (d, J= 7.05 Hz, 1 H, H3), 2.34 (ddd, J= 6.84, 9.63,14.66 Hz, I H, H6a), 2.26 (d, J= 7.65 Hz, 20 2 H, H14a,b), 2.25 (s, 3 H, Ac4), 2.03 (s, 3 H, Mel8), 1.98 (d, J= 5.29, 1 H, C130H), 1.77 (ddd, J= 2.12, 10.37, 14.66 Hz, I H, H6b), 1.73 (s, 1 H, Mel9), 1.59 (s, 1 H, C10H), 1.32 (t, J= 7.00 Hz, 3 H, CH 3

-CH

2 -), 1.19 (s, 3 H, Mel7), 1.07 (s, 3 H, Mel6), 0.45 (s, 3 H, PhMe 2 Si-), 0.35 (s, 3 H, PhMe 2 Si-).

WO 01/57013 PCT/USO1/03624 210 0 0 O.Boc 0 00 Boc., EtOA 0 - ODMPS OTES ODMPS H S OTES HO , LHMDS HO BzO Ac 6 0 BzOA 7-Dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3'-(2-thienyl)-1 0 ethoxycarbonyl-10-deacetyl taxotere. To a solution of 0.409 g (0.544 mmol) of 7 dimethylphenylsilyl-10-ethoxycarbonyl-10-deacety baccatin III in 5.5 mL of THF at -45 'C under a nitrogen atmosphere was added 0.681 mL (0.681 mmol) of a IM 5 solution of LHMDS in THE. After 1 h, a solution of 0.317 g (0.818 mmol) of cis-N benzoyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in 3 mL of THF was added slowly. The mixture was warmed to 0 0 C and after 3 h 10 mL of saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with 50 mL of ethyl acetate. The combined organic extracts were washed with brine, 10 dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 40% EtOAc/hexane as eluent to give 0.574 g (93%) of 7-dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3'-(2 thienyl)-10-ethoxycarbonyl-1 0-deacetyl taxotere as a solid. 0 0 BoG, EtO' 0 BoGo, EtCA 0 NH 0 O N.H 0 O

-

ODMPS HF -HOH 'TES s CCI H A--, H 40 , BAcO BzAc 0 3'-Desphenyl-3'-(2-thienyl)-10-ethoxycarbonyl-10-deacetyI taxotere. To a 15 solution of 0.527 g (0.464 mmol) of 7-dimethylphenylsilyl-2'-O-triethylsilyl-3' desphenyl-3'-(2-thienyl)-10-ethoxycarbonyl-1 0-deacetyl taxotere in 2 mL of CH 3 CN and 2 mL of pyridine at 0 'C was added 0.5 mL of a solution of 30% HF in H 2 0. After 3 h 20 mL of a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with 50 mL of ethyl acetate. The combined 20 organic extracts were washed with brine, dried over Na 2

SO

4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel WO 01/57013 PCT/USO1/03624 211 using 70% EtOAc/hexane as eluent to give 0.411 g (100%) of 3'-desphenyl-3'-(2 thienyl)-10-ethoxycarbonyl-1 0-deacetyl taxotere as a solid. m.p. 160-161 0C; [a]D 2 1 = -59.1 (c 1.0 in CH 2 Cl 2 ); Anal. Calcd. for C 44

H

55

NO

16 S: C, 59.65; H, 6.26; Found: C, 59.39; H, 6.34. 5 3'-Desphenyl-3'-(2-thienyl)-10-ethoxycarbonyl-10-deacetyI taxotere 'H NMR data (500 MHz, CDCl 3 ) Proton d (ppm) Pattern J (Hz) 10H 1.68 s 2 5.68 d H3(7.0) 10 3 3.80 d H3(7.0) 4Ac 2.38 s 5 4.95 dd H6b(2.0), H6b(9.8) 6a 2.56 ddd H7(6.6), H5(9.8), H6b(14.65) 6b 1.89 ddd H5(2.0), H7(10.9), H6a(14.65) 15 7 4.40 ddd C70H(4.2), H6a(6.6), H6b(10.9) 70H 2.50 d H7(4.2) 10 6.12 s 13 6.25 t H14a(9.1), H14b(9.1) 14a 2.35 dd H13(9.1), H14b(14.2) 20 14b 2.34 dd H13(9.1), H14a(14.2) 16Me 1.17 s 17Me 1.26 s 18Me 1.90 s 19Me 1.70 s 25 20a 4.31 d H20b(8.6) 20b 4.19 d H20a(8.6) 2' 4.64 dd C2'OH(5.5), H3'(2.0) 2'OH 3.38 d H3'(5.5) 3' 5.51 br d NH(9.5) 30 NH 5.28 d H3'(9.5) 3'(2-thienyl), H3" 7.29 dd 3'(2-thienyl), H5"(1.1), 3'(2-thienyl), H3"(5.1) 3'(2-thienyl), H4" 7.02 dd 3'(2-thienyl), H5"(3.6), 3'(2-thienyl), H3"(5.1) 3'(2-thienyl), H5" 7.09 d 3'(2-thienyl), H4"(3.6) Boc 1.34 s 35 benzoate, m 7.51 t benzoate, o(7.8), benzoate, p(7.8) benzoate, o 8.12 d benzoate, m(7.8) benzoate, p 7.61 t benzoate, m(7.8)

CH

3

-CH

2 -OCO 1.37 t CH 3

-CH

2 -OCO(7.1)

CH

3

-CH

2 -OCO 4.28 m WO 01/57013 PCT/USO1/03624 212 Example 27: Additional Taxanes having C-10 Carbonate and C-7 Hydroxy Substituents The procedures described in Example 26 were repeated, but other suitably protected P-lactams were substituted for the P-lactam of Example 26 to prepare 5 the series of compounds having structural formula (18) and the combinations of substituents identified in the following table.

X

5 NH 0

R

10 0 OH OH ' HO . AcO (18) Compound X 5 X3 RI 1755 tBuOCO- 2-thienyl EtOCOO 10 1767 tBuOCO- isopropyl EtOCOO 1781 tBuOCO- isobutenyl EtOCOO 1799 tBuOCO- 2-pyridyl EtOCOO 1808 tBuOCO- 3-pyridyl EtOCOO 1811 tBuOCO- 4-pyridyl EtOCOO 15 1822 tBuOCO- 2-furyl EtOCOO 1838 tBuOCO- 3-furyl EtOCOO 1841 tBuOCO- 3-thienyl EtOCOO 1855 tBuOCO- cyclobutyl EtOC00 1999 tBuOCO- isobutenyl MeOCOO 20 2002 tBuOCO- 2-pyridyl MeOCOO 2011 tBuOCO- 3-pyridyl MeOCOO 2020 tBuOCO- 4-pyridyl MeOCOO 2032 tBuOCO- 3-furyl MeOCOO 2044 tBuOCO- 2-thienyl MeOCOO 25 2050 tBuOCO- 3-thienyl MeOCOO- WO 01/57013 PCT/USO1/03624 213 2062 tBuOCO- isopropyl MeOCOO 2077 tBuOCO- cyclobutyl MeOCOO 2666 tBuOCO- 2-furyl MeOCOO 2972 PhCO- 2-thienyl EtOCOO 5 2988 EtOCO- 2-thienyl EtOCOO 2999 iPrOCO- 2-thienyl EtOCOO 3003 iBuOCO- 2-thienyl EtOCOO 3011 2-FuCO- 2-thienyl EtOCOO 3020 2-ThCO- 2-thienyl EtOCOO 10 3033 C 4

H

7 CO- 2-thienyl EtOCOO 3155 nPrCO- 2-thienyl EtOCOO 3181 iBuOCO- 2-furyl EtOCOO 3243 tC 3

H

5 CO- 2-thienyl EtOCOO 3300 3-PyCO- 2-thienyl EtOCOO 15 3393 4-PyCO- 2-thienyl EtOCOO 3433 2-PyCO- 2-thienyl EtOCOO 3911 2-FuCO- 2-furyl EtOCOO 3929 nPrCO- 2-furyl EtOCOO 3963 iPrOCO- 2-furyl EtOCOO 20 4000 tC 3

H

5 CO- 2-furyl EtOCOO 4020 EtOCO- 2-furyl EtOCOO 4074 C 4

H

7 CO- 2-furyl EtOCOO 4088 2-ThCO- 2-furyl EtOCOO 4090 PhCO- 2-furyl EtOCOO 25 4374 ibueCO- 2-thienyl EtOCOO 4636 iBuOCO- 3-furyl EtOCOO 6466 iPrCO- 2-furyl EtOCOO 4959 tC 3

H

5 CO- 3-furyl EtOCOO 4924 iBuOCO- 3-thienyl EtOCOO 30 4844 iBuOCO- cpro EtOCOO 5171 tBuOCO- cpro EtOCOO- WO 01/57013 PCT/USO1/03624 214 5155 iBuOCO- isobutenyl EtOCOO 1788 tBuOCO- isobutenyl EtOCOO 1767 tBuOCO- isopropyl EtOCOO 1771 tBuOCO- phenyl EtOCOO 5 1866 tBuOCO- p-nitrophenyl EtOCOO 2060 tBuOCO- isopropyl MeOCOO 2092 tBuOCO- phenyl MeOCOO 2088 tBuOCO- p-nitrophenyl MeOCOO Example 28: Additional Taxanes having C-10 Carbonate and C-7 Hydroxy 10 Substituents Following the processes described in Example 26 and elsewhere herein, the following specific taxanes having structural formula (19) may be prepared, wherein R 1 is as previously defined including wherein R 1 0 is ROCOO- and Ra s (i) substituted or unsubstituted C1 to C alkyl such as methyl, ethyl, or straight, 15 branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C3 to C8 alkenyl such as propenyl or straight, branched or cyclic butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C to C8 alkynyl such as propynyl or straight or branched butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as pyridyl. The 20 substituents may be those identified elsewhere herein for substituted hydrocarbyl. For example, R 1 may be R1 0 aOCOO- wherein R10a is methyl, ethyl, or straight, branched or cyclic propyl.

X

5 NH 0

R

1 0 OH X3 a Ol0 ., OH HO . 25 BzO .Z O Aco (19) WO 01/57013 PCT/USO1/03624 215 X5 X3 Rjo tBuOCO 2-furyl RioOCOO tBuOCO 3-furyl R1 0 aOCOO tBuOCO 2-thienyl R1O0,COO 5 tBuOCO 3-thienyl R1oOCOO tBuOCO 2-pyridyl R1 0

,OCOO

tBuOCO 3-pyridyl R1oOCOO tBuOCO 4-pyridyl R10,0COO tBuOCO isobutenyl R1oOCOO 10 tBuOCO isopropyl R1oa0COO tBuOCO cyclopropyl R 10

,OCOO

tBuOCO cyclobutyl R1oaOCOO tBuOCO cyclopentyl R1oOCOO tBuOCO phenyl R1oOCOO 15 benzoyl 2-furyl R 10

,OCOO

benzoyl 3-furyl Ri,OCOO benzoyl 2-thienyl R1oOCOO benzoyl 3-thienyl R1oOCOO benzoyl 2-pyridyl R1 0 aOCOO 20 benzoyl 3-pyridyl R1oaOCOO benzoyl 4-pyridyl RIOOCOO benzoyl isobutenyl R1oOCOO benzoyl isopropyl RI 0 aOCOO benzoyl cyclopropyl R1oOCOO 25 benzoyl cyclobutyl R1oaOCOO benzoyl cyclopentyl R 1 oOCOO benzoyl phenyl R1oOCOO 2-FuCO- 2-furyl R1oaOCOO 2-FuCO- 3-furyl R1OOCOO 30 2-FuCO- 2-thienyl R1 0 aOCOO 2-FuCO- 3-thienyl RIOaOCOO- WO 01/57013 PCT/USO1/03624 216 2-FuCO- 2-pyridyl R1oaOCOO 2-FuCO- 3-pyridyl R1 0 ,0COO 2-FuCO- 4-pyridyl R10,OCOO 2-FuCO- isobutenyl R10iOCOO 5 2-FuCO- isopropyl RIOOCOO 2-FuCO- cyclopropyl R10,OCOO 2-FuCO- cyclobutyl RI 0

,OCOO

2-FuCO- cyclopentyl R 10

OCOO

2-FuCO- phenyl R1 0 aOCOO 10 2-ThCO- 2-furyl R1oOCOO 2-ThCO- 3-furyl R1oOCOO 2-ThCO- 2-thienyl R1OaOCOO 2-ThCO- 3-thienyl R1oaOCOO 2-ThCO- 2-pyridyl R1 0 aOCOO 15 2-ThCO- 3-pyridyl R1 0

,OCOO

2-ThCO- 4-pyridyl R1oaOCOO 2-ThCO- isobutenyl R1oaOCOO 2-ThCO- isopropyl R 10 0COO 2-ThCO- cyclopropyl R1 0 aOCOO 20 2-ThCO- cyclobutyl R1 0 aOCOO 2-ThCO- cyclopentyl R1aOCOO 2-ThCO- phenyl R1oaOCOO 2-PyCO- 2-furyl R1 0 aOCOO 2-PyCO- 3-furyl R1 0 aOCOO 25 2-PyCO- 2-thienyl Roa00COO 2-PyCO- 3-thienyl R1OaOCOO 2-PyCO- 2-pyridyl R1oaOCOO 2-PyCO- 3-pyridyl R1oaOCOO 2-PyCO- 4-pyridyl R1 0 aOCOO 30 2-PyCO- isobutenyl R1 0 aOCOO 2-PyCO- isopropyl R1oaOCOO- WO 01/57013 PCT/USO1/03624 217 2-PyCO- cyclopropyl R1 0 aOCOO 2-PyCO- cyclobutyl R1oaOCOO 2-PyCO- cyclopentyl R1 0 O0COO 2-PyCO- phenyl RioOCOO 5 3PyCO- 2-furyl RI 0 O0COO 3-PyCO- 3-furyl R10iOCOO 3-PyCO- 2-thienyl R1 0 aOCOO 3-PyCO- 3-thienyl R10,OCOO 3-PyCO- 2-pyridyl RIOOCOO 10 3-PyCO- 3-pyridyl RIOOCOO 3-PyCO- 4-pyridyl R1oOCOO 3-PyCO- isobutenyl R1 0

,OCOO

3-PyCO- isopropyl R1oOCOO 3-PyCO- cyclopropyl R1o ,OCOO 15 3-PyCO- cyclobutyl R1 0 aOCOO 3-PyCO- cyclopentyl R1,OCOO 3-PyCO- phenyl R1 0 aOCOO 4-PyCO- 2-furyl R1oOCOO 4-PyCO- 3-furyl RIOOCOO 20 4-PyCO- 2-thienyl R1O0,0COO 4-PyCO- 3-thienyl RIO.,COO 4-PyCO- 2-pyridyl R1oOCOO 4-PyCO- 3-pyridyl R 10 O0COO 4-PyCO- 4-pyridyl R 1 oOCOO 25 4-PyCO- isobutenyl R102OCOO 4-PyCO- isopropyl R1 0

,OCOO

4-PyCO- cyclopropyl R 10 0COO 4-PyCO- cyclobutyl RI 0 O0COO 4-PyCO- cyclopentyl R1 0

OCOO

30 4-PyCO- phenyl R1 0 a0COO

C

4

H

7 CO- 2-furyl R 10 aOCOO- WO 01/57013 PCT/USO1/03624 218

C

4 HyCO- 3-furyl R1oOCOO

C

4

H

7 CO- 2-thienyl R1oaOCOO

C

4

H

7 CO- 3-thienyl RIOaOCOO

C

4

H

7 CO- 2-pyridyl R1 0

,OCOO

5 C 4

H

7 CO- 3-pyridyl R10,0COO

C

4

H

7 CO- 4-pyridyl R1 0

,OCOO

C

4

H

7 CO- isobutenyl R1oOCOO

C

4

H

7 CO- isopropyl R1oOCOO

C

4

H

7 CO- cyclopropyl

R

1 0a0COO 10 C 4

H

7 CO- cyclobutyl R1oaOCOO

C

4

H

7 CO- cyclopentyl R1oaOCOO

C

4

H

7 CO- phenyl R1oaOCOO EtOCO- 2-furyl R1oaOCOO EtOCO- 3-furyl R1oaOCOO 15 EtOCO- 2-thienyl R1oaOCOO EtOCO- 3-thienyl R1 0 aOCOO EtOCO- 2-pyridyl Ro,0COO EtOCO- 3-pyridyl RjoaOCOO EtOCO- 4-pyridyl RI 0 aOCOO 20 EtOCO- isobutenyl R1oaOCOO EtOCO- isopropyl RIOaOCOO EtOCO- cyclopropyl R1aaOCOO EtOCO- cyclobutyl R1 0 aOCOO EtOCO- cyclopentyl R 10 0COO 25 EtOCO- phenyl RIOaOCOO ibueCO- 2-furyl R1oOCOO ibueCO- 3-furyl R1 0

,OCOO

ibueCO- 2-thienyl R1aaOCOO ibueCO- 3-thienyl RIOaOCOO 30 ibueCO- 2-pyridyl R1 0 aOCOO ibueCO- 3-pyridyl R 1 oaOCOO- WO 01/57013 PCT/USO1/03624 219 ibueCO- 4-pyridyl R1 0 aOCOO ibueCO- isobutenyl R1oaOCOO ibueCO- isopropyl R1 0 aOCOO ibueCO- cyclopropyl RioaOCOO 5 ibueCO- cyclobutyl R1 0

,OCOO

ibueCO- cyclopentyl R1 0 aOCOO ibueCO- phenyl R1oaOCOO iBuCO- 2-furyl R1oOCOO iBuCO- 3-furyl R1oaOCOO 10 iBuCO- 2-thienyl R1aOCOO iBuCO- 3-thienyl R1aoCOO iBuCO- 2-pyridyl R1oaOCOO iBuCO- 3-pyridyl R1oaOCOO iBuCO- 4-pyridyl R1 0 aOCOO 15 iBuCO- isobutenyl R1oaOCOO iBuCO- isopropyl R1oaOCOO iBuCO- cyclopropyl R 10 0COO iBuCO- cyclobutyl R1 0 aOCOO iBuCO- cyclopentyl R1oaOCOO 20 iBuCO- phenyl R1 0 aOCOO iBuOCO- 2-furyl R1oaOCOO iBuOCO- 3-furyl R1 0 aOCOO iBuOCO- 2-thienyl R1oaOCOO iBuOCO- 3-thienyl R1oaOCOO 25 iBuOCO- 2-pyridyl RjoaOCOO iBuOCO- 3-pyridyl R1oaOCOO iBuOCO- 4-pyridyl R1oaOCOO iBuOCO- isobutenyl R1oaOCOO iBuOCO- isopropyl R1 0 aOCOO 30 iBuOCO- cyclopropyl R1oaOCOO iBuOCO- cyclobutyl R1oaOCOO- WO 01/57013 PCT/USO1/03624 220 iBuOCO- cyclopentyl RioaOCOO iBuOCO- phenyl R1 0

OCOO

PrOCO- 2-furyl R10iOCOO iPrOCO- 3-furyl R1oOCOO 5 iPrOCO- 2-thienyl R102OCOO iPrOCO- 3-thienyl R1 0 aOCOO iPrOCO- 2-pyridyl R1 0 aOCOO iPrOCO- 3-pyridyl R1 0

,OCOO

iPrOCO- 4-pyridyl RIOOCOO 10 iPrOCO- isobutenyl RioaOCOO iPrOCO- isopropyl RIOOCOO iPrOCO- cyclopropyl R1oaOCOO iPrOCO- cyclobutyl R1oOCOO iPrOCO- cyclopentyl RI 0

,OCOO

15 iPrOCO- phenyl R1 0 aOCOO nPrOCO- 2-furyl R 1 0 ,0COO nPrOCO- 3-furyl R1oOCOO nPrOCO- 2-thienyl R1 0 aOCOO nPrOCO- 3-thienyl R1oaOCOO 20 nPrOCO- 2-pyridyl R1oaOCOO nPrOCO- 3-pyridyl R1oOCOO nPrOCO- 4-pyridyl R1 0

,OCOO

nPrOCO- isobutenyl R1 0

,OCOO

nPrOCO- isopropyl R 10 20COO 25 nPrOCO- cyclopropyl R102OCOO nPrOCO- cyclobutyl R1oaOCOO nPrOCO- cyclopentyl RIOaOCOO nPrOCO- phenyl RI 0 0COO nPrCO- 2-furyl R1 0

,OCOO

30 nPrCO- 3-furyl R1 0

,OCOO

nPrCO- 2-thienyl R1oaOCOO- WO 01/57013 PCT/USO1/03624 221 nPrCO- 3-thienyl R1 0 aOCOO nPrCO- 2-pyridyl RIOaOCOO nPrCO- 3-pyridyl RIaaOCOO nPrCO- 4-pyridyl R1oaOCOO 5 nPrCO- isobutenyl R1 0 aOCOO nPrCO- isopropyl R1oaOCOO nPrCO- cyclopropyl R10aOCOO nPrCO- cyclobutyl R1 0 aOCOO nPrCO- cyclopentyl R1 0 aOCOO 10 nPrCO- phenyl R1 0 aOCOO tBuOCO cyclopentyl EtOCOO benzoyl 3-furyl EtOCOO benzoyl 3-thienyl EtOCOO benzoyl 2-pyridyl EtOCOO 15 benzoyl 3-pyridyl EtOCOO benzoyl 4-pyridyl EtOCOO benzoyl isobutenyl EtOCOO benzoyl isopropyl EtOCOO benzoyl cyclopropyl EtOCOO 20 benzoyl cyclobutyl EtOCOO benzoyl cyclopentyl EtOCOO benzoyl phenyl EtOCOO 2-FuCO- 3-furyl EtOCOO 2-FuCO- 3-thienyl EtOCOO 25 2-FuCO- 2-pyridyl EtOCOO 2-FuCO- 3-pyridyl EtOCOO 2-FuCO- 4-pyridyl EtOCOO 2-FuCO- isobutenyl EtOCOO 2-FuCO- isopropyl EtOCOO 30 2-FuCO- cyclopropyl EtOCOO 2-FuCO- cyclobutyl EtOCOO- WO 01/57013 PCT/USO1/03624 222 2-FuCO- cyclopentyl EtOCOO 2-FuCO- phenyl EtOCOO 2-ThCO- 3-furyl EtOCOO 2-ThCO- 3-thienyl EtOCOO 5 2-ThCO- 2-pyridyl EtOCOO 2-ThCO- 3-pyridyl EtOCOO 2-ThCO- 4-pyridyl EtOCOO 2-ThCO- isobutenyl EtOCOO 2-ThCO- isopropyl EtOCOO 10 2-ThCO- cyclopropyl EtOCOO 2-ThCO- cyclobutyl EtOCOO 2-ThCO- cyclopentyl EtOCOO 2-ThCO- phenyl EtOCOO 2-PyCO- 2-furyl EtOCOO 15 2-PyCO- 3-furyl EtOCOO 2-PyCO- 3-thienyl EtOCOO 2-PyCO- 2-pyridyl EtOCOO 2-PyCO- 3-pyridyl EtOCOO 2-PyCO- 4-pyridyl EtOCOO 20 2-PyCO- isobutenyl EtOCOO 2-PyCO- isopropyl EtOCOO 2-PyCO- cyclopropyl EtOCOO 2-PyCO- cyclobutyl EtOCOO 2-PyCO- cyclopentyl EtOCOO 25 2-PyCO- phenyl EtOCOO 3PyCO- 2-furyl EtOCOO 3-PyCO- 3-furyl EtOCOO 3-PyCO- 3-thienyl EtOCOO 3-PyCO- 2-pyridyl EtOCOO 30 3-PyCO- 3-pyridyl EtOCOO 3-PyCO- 4-pyridyl EtOCOO- WO 01/57013 PCT/USO1/03624 223 3-PyCO- isobutenyl EtOCOO 3-PyCO- isopropyl EtOCOO 3-PyCO- cyclopropyl EtOCOO 3-PyCO- cyclobutyl EtOCOO 5 3-PyCO- cyclopentyl EtOCOO 3-PyCO- phenyl EtOCOO 4-PyCO- 2-furyl EtOCOO 4-PyCO- 3-furyl EtOCOO 4-PyCO- 3-thienyl EtOCOO 10 4-PyCO- 2-pyridyl EtOCOO 4-PyCO- 3-pyridyl EtOCOO 4-PyCO- 4-pyridyl EtOCOO 4-PyCO- isobutenyl EtOCOO 4-PyCO- isopropyl EtOCOO 15 4-PyCO- cyclopropyl EtOCOO 4-PyCO- cyclobutyl EtOCOO 4-PyCO- cyclopentyl EtOCOO 4-PyCO- phenyl EtOCOO

C

4

H

7 CO- 3-furyl EtOCOO 20 C 4

H

7 CO- 3-thienyl EtOCOO

C

4

H

7 CO- 2-pyridyl EtOCOO

C

4

H

7 CO- 3-pyridyl EtOCOO

C

4

H

7 CO- 4-pyridyl EtOCOO

C

4

H

7 CO- isobutenyl EtOCOO 25 C 4

H

7 CO- isopropyl EtOCOO

C

4

H

7 CO- cyclopropyl EtOCOO

C

4

H

7 CO- cyclobutyl EtOCOO

C

4

H

7 CO- cyclopentyl EtOCOO

C

4

H

7 CO- phenyl EtOCOO 30 EtOCO- 3-furyl EtOCOO EtOCO- 3-thienyl EtOCOO- WO 01/57013 PCT/USO1/03624 224 EtOCO- 2-pyridyl EtOCOO EtOCO- 3-pyridyl EtOCOO EtOCO- 4-pyridyl EtOCOO EtOCO- isobutenyl EtOCOO 5 EtOCO- isopropyl EtOCOO EtOCO- cyclopropyl EtOCOO EtOCO- cyclobutyl EtOCOO EtOCO- cyclopentyl EtOCOO EtOCO- phenyl EtOCOO 10 ibueCO- 2-furyl EtOCOO ibueCO- 3-furyl EtOCOO ibueCO- 2-thienyl EtOCOO ibueCO- 3-thienyl EtOCOO ibueCO- 2-pyridyl EtOCOO 15 ibueCO- 3-pyridyl EtOCOO ibueCO- 4-pyridyl EtOCOO ibueCO- isobutenyl EtOCOO ibueCO- isopropyl EtOCOO ibueCO- cyclopropyl EtOCOO 20 ibueCO- cyclobutyl EtOCOO ibueCO- cyclopentyl EtOCOO ibueCO- phenyl EtOCOO iBuCO- 2-furyl EtOCOO iBuCO- 3-furyl EtOCOO 25 iBuCO- 2-thienyl EtOCOO iBuCO- 3-thienyl EtOCOO iBuCO- 2-pyridyl EtOCOO iBuCO- 3-pyridyl EtOCOO iBuCO- 4-pyridyl EtOCOO 30 iBuCO- isobutenyl EtOCOO iBuCO- isopropyl EtOCOO- WO 01/57013 PCT/USO1/03624 225 iBuCO- cyclopropyl EtOCOO iBuCO- cyclobutyl EtOCOO iBuCO- cyclopentyl EtOCOO iBuCO- phenyl EtOCOO 5 iBuOCO- 2-pyridyl EtOCOO iBuOCO- 3-pyridyl EtOCOO iBuOCO- 4-pyridyl EtOCOO iBuOCO- isopropyl EtOCOO iBuOCO- cyclobutyl EtOCOO 10 iBuOCO- cyclopentyl EtOCOO iBuOCO- phenyl EtOCOO iPrOCO- 3-furyl EtOCOO iPrOCO- 3-thienyl EtOCOO iPrOCO- 2-pyridyl EtOCOO 15 iPrOCO- 3-pyridyl EtOCOO iPrOCO- 4-pyridyl EtOCOO iPrOCO- isobutenyl EtOCOO iPrOCO- isopropyl EtOCOO iPrOCO- cyclopropyl EtOCOO 20 iPrOCO- cyclobutyl EtOCOO iPrOCO- cyclopentyl EtOCOO iPrOCO- phenyl EtOCOO nPrOCO- 2-furyl EtOCOO nPrOCO- 3-furyl EtOCOO 25 nPrOCO- 2-thienyl EtOCOO nPrOCO- 3-thienyl EtOCOO nPrOCO- 2-pyridyl EtOCOO nPrOCO- 3-pyridyl EtOCOO nPrOCO- 4-pyridyl EtOCOO 30 nPrOCO- isobutenyl EtOCOO nPrOCO- isopropyl EtOCOO- WO 01/57013 PCT/USO1/03624 226 nPrOCO- cyclopropyl EtOCOO nPrOCO- cyclobutyl EtOCOO nPrOCO- cyclopentyl EtOCOO nPrOCO- phenyl EtOCOO 5 nPrCO- 3-furyl EtOCOO nPrCO- 3-thienyl EtOCOO nPrCO- 2-pyridyl EtOCOO nPrCO- 3-pyridyl EtOCOO nPrCO- 4-pyridyl EtOCOO 10 nPrCO- isobutenyl EtOCOO nPrCO- isopropyl EtOCOO nPrCO- cyclopropyl EtOCOO nPrCO- cyclobutyl EtOCOO nPrCO- cyclopentyl EtOCOO 15 nPrCO- phenyl EtOCOO tBuOCO cyclopropyl MeOCOO tBuOCO cyclopentyl MeOCOO benzoyl 2-furyl MeOCOO benzoyl 3-furyl MeOCOO 20 benzoyl 2-thienyl MeOCOO benzoyl 3-thienyl MeOCOO benzoyl 2-pyridyl MeOCOO benzoyl 3-pyridyl MeOCOO benzoyl 4-pyridyl MeOCOO 25 benzoyl isobutenyl MeOCOO benzoyl isopropyl MeOCOO benzoyl cyclopropyl MeOCOO benzoyl cyclobutyl MeOCOO benzoyl cyclopentyl MeOCOO 30 benzoyl phenyl MeOCOO 2-FuCO- 2-furyl MeOCOO- WO 01/57013 PCT/USO1/03624 227 2-FuCO- 3-furyl MeOCOO 2-FuCO- 2-thienyl MeOCOO 2-FuCO- 3-thienyl MeOCOO 2-FuCO- 2-pyridyl MeOCOO 5 2-FuCO- 3-pyridyl MeOCOO 2-FuCO- 4-pyridyl MeOCOO 2-FuCO- isobutenyl MeOCOO 2-FuCO- isopropyl MeOCOO 2-FuCO- cyclopropyl MeOCOO 10 2-FuCO- cyclobutyl MeOCOO 2-FuCO- cyclopentyl MeOCOO 2-FuCO- phenyl MeOCOO 2-ThCO- 2-furyl MeOCOO 2-ThCO- 3-furyl MeOCOO 15 2-ThCO- 2-thienyl MeOCOO 2-ThCO- 3-thienyl MeOCOO 2-ThCO- 2-pyridyl MeOCOO 2-ThCO- 3-pyridyl MeOCOO 2-ThCO- 4-pyridyl MeOCOO 20 2-ThCO- isobutenyl MeOCOO 2-ThCO- isopropyl MeOCOO 2-ThCO- cyclopropyl MeOCOO 2-ThCO- cyclobutyl MeOCOO 2-ThCO- cyclopentyl MeOCOO 25 2-ThCO- phenyl MeOCOO 2-PyCO- 2-furyl MeOCOO 2-PyCO- 3-furyl MeOCOO 2-PyCO- 2-thienyl MeOCOO 2-PyCO- 3-thienyl MeOCOO 30 2-PyCO- 2-pyridyl MeOCOO 2-PyCO- 3-pyridyl MeOCOO- WO 01/57013 PCT/USO1/03624 228 2-PyCO- 4-pyridyl MeOCOO 2-PyCO- isobutenyl MeOCOO 2-PyCO- isopropyl MeOCOO 2-PyCO- cyclopropyl MeOCOO 5 2-PyCO- cyclobutyl MeOCOO 2-PyCO- cyclopentyl MeOCOO 2-PyCO- phenyl MeOCOO 3PyCO- 2-furyl MeOCOO 3-PyCO- 3-furyl MeOCOO 10 3-PyCO- 2-thienyl MeOCOO 3-PyCO- 3-thienyl MeOCOO 3-PyCO- 2-pyridyl MeOCOO 3-PyCO- 3-pyridyl MeOCOO 3-PyCO- 4-pyridyl MeOCOO 15 3-PyCO- isobutenyl MeOCOO 3-PyCO- isopropyl MeOCOO 3-PyCO- cyclopropyl MeOCOO 3-PyCO- cyclobutyl MeOCOO 3-PyCO- cyclopentyl MeOCOO 20 3-PyCO- phenyl MeOCOO 4-PyCO- 2-furyl MeOCOO 4-PyCO- 3-furyl MeOCOO 4-PyCO- 2-thienyl MeOCOO 4-PyCO- 3-thienyl MeOCOO 25 4-PyCO- 2-pyridyl MeOCOO 4-PyCO- 3-pyridyl MeOCOO 4-PyCO- 4-pyridyl MeOCOO 4-PyCO- isobutenyl MeOCOO 4-PyCO- isopropyl MeOCOO 30 4-PyCO- cyclopropyl MeOCOO 4-PyCO- cyclobutyl MeOCOO- WO 01/57013 PCT/USO1/03624 229 4-PyCO- cyclopentyl MeOCOO 4-PyCO- phenyl MeOCOO

C

4

H

7 CO- 2-furyl MeOCOO

C

4

H

7 CO- 3-furyl MeOCOO 5 C 4

H

7 CO- 2-thienyl MeOCOO

C

4

H

7 CO- 3-thienyl MeOCOO

C

4

H

7 CO- 2-pyridyl MeOCOO

C

4

H

7 CO- 3-pyridyl MeOCOO

C

4

H

7 CO- 4-pyridyl MeOCOO 10 C 4

H

7 CO- isobutenyl MeOCOO

C

4

H

7 CO- isopropyl MeOCOO

C

4

H

7 CO- cyclopropyl MeOCOO

C

4

H

7 CO- cyclobutyl MeOCOO

C

4

H

7 CO- cyclopentyl MeOCOO 15 C 4

H

7 CO- phenyl MeOCOO EtOCO- 2-furyl MeOCOO EtOCO- 3-furyl MeOCOO EtOCO- 2-thienyl MeOCOO EtOCO- 3-thienyl MeOCOO 20 EtOCO- 2-pyridyl MeOCOO EtOCO- 3-pyridyl MeOCOO EtOCO- 4-pyridyl MeOCOO EtOCO- isobutenyl MeOCOO EtOCO- isopropyl MeOCOO 25 EtOCO- cyclopropyl MeOCOO EtOCO- cyclobutyl MeOCOO EtOCO- cyclopentyl MeOCOO EtOCO- phenyl MeOCOO ibueCO- 2-furyl MeOCOO 30 ibueCO- 3-furyl MeOCOO ibueCO- 2-thienyl MeOCOO- WO 01/57013 PCT/USO1/03624 230 ibueCO- 3-thienyl MeOCOO ibueCO- 2-pyridyl MeOCOO ibueCO- 3-pyridyl MeOCOO ibueCO- 4-pyridyl MeOCOO 5 ibueCO- isobutenyl MeOCOO ibueCO- isopropyl MeOCOO ibueCO- cyclopropyl MeOCOO ibueCO- cyclobutyl MeOCOO ibueCO- cyclopentyl MeOCOO 10 ibueCO- phenyl MeOCOO iBuCO- 2-furyl MeOCOO iBuCO- 3-furyl MeOCOO iBuCO- 2-thienyl MeOCOO iBuCO- 3-thienyl MeOCOO 15 iBuCO- 2-pyridyl MeOCOO iBuCO- 3-pyridyl MeOCOO iBuCO- 4-pyridyl MeOCOO iBuCO- isobutenyl MeOCOO iBuCO- isopropyl MeOCOO 20 iBuCO- cyclopropyl MeOCOO iBuCO- cyclobutyl MeOCOO iBuCO- cyclopentyl MeOCOO iBuCO- phenyl MeOCOO iBuOCO- 2-furyl MeOCOO 25 iBuOCO- 3-furyl MeOCOO iBuOCO- 2-thienyl MeOCOO iBuOCO- 3-thienyl MeOCOO iBuOCO- 2-pyridyl MeOCOO iBuOCO- 3-pyridyl MeOCOO 30 iBuOCO- 4-pyridyl MeOCOO iBuOCO- isobutenyl MeOCOO- WO 01/57013 PCT/USO1/03624 231 iBuOCO- isopropyl MeOCOO iBuOCO- cyclopropyl MeOCOO iBuOCO- cyclobutyl MeOCOO iBuOCO- cyclopentyl MeOCOO 5 iBuOCO- phenyl MeOCOO iPrOCO- 2-furyl MeOCOO iPrOCO- 3-furyl MeOCOO iPrOCO- 2-thienyl MeOCOO iPrOCO- 3-thienyl MeOCOO 10 iPrOCO- 2-pyridyl MeOCOO iPrOCO- 3-pyridyl MeOCOO iPrOCO- 4-pyridyl MeOCOO iPrOCO- isobutenyl MeOCOO iPrOCO- isopropyl MeOCOO 15 iPrOCO- cyclopropyl MeOCOO iPrOCO- cyclobutyl MeOCOO iPrOCO- cyclopentyl MeOCOO iPrOCO- phenyl MeOCOO nPrOCO- 2-furyl MeOCOO 20 nPrOCO- 3-furyl MeOCOO nPrOCO- 2-thienyl MeOCOO nPrOCO- 3-thienyl MeOCOO nPrOCO- 2-pyridyl MeOCOO nPrOCO- 3-pyridyl MeOCOO 25 nPrOCO- 4-pyridyl MeOCOO nPrOCO- isobutenyl MeOCOO nPrOCO- isopropyl MeOCOO nPrOCO- cyclopropyl MeOCOO nPrOCO- cyclobutyl MeOCOO 30 nPrOCO- cyclopentyl MeOCOO nPrOCO- phenyl MeOCOO- WO 01/57013 PCT/US01/03624 232 nPrCO- 2-furyl MeOCOO nPrCO- 3-furyl MeOCOO nPrCO- 2-thienyl MeOCOO nPrCO- 3-thienyl MeOCOO 5 nPrCO- 2-pyridyl MeOCOO nPrCO- 3-pyridyl MeOCOO nPrCO- 4-pyridyl MeOCOO nPrCO- isobutenyl MeOCOO nPrCO- isopropyl MeOCOO 10 nPrCO- cyclopropyl MeOCOO nPrCO- cyclobutyl MeOCOO nPrCO- cyclopentyl MeOCOO nPrCO- phenyl MeOCOO Example 29: Additional Taxanes having C-10 Carbonate and C-7 Hydroxy 15 Substituents Following the processes described in Example 26 and elsewhere herein, the following specific taxanes having structural formula (20) may be prepared, wherein in each of the series (that is, each of series "A" through "K") R 7 is hydroxy and R 1 is as previously defined, including wherein RIO is R10aOCOO- and RiOa is 20 (i) substituted or unsubstituted, preferably unsubstituted, C2 to C8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, C2 to C alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C2 to C alkynyl (straight or branched) 25 such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted, preferably unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl. In the "A" series of compounds, X 1 0 is as otherwise as defined herein. 30 Preferably, heterocyclo is substituted.or unsubstitued furyl, thienyl, or pyridyl, XIO is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 and RIO each have the beta stereochemical configuration.

WO 01/57013 PCT/US01/03624 233 In the "B" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or 5 unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical configuration. In the "C" series of compounds, X 1 0 and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, 10 pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rea is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "D" and "E" series of compounds, XO is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 15 thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R. (series D only) and R 1 each have the beta stereochemical configuration. In the "F" series of compounds, X 1 0 , R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued 20 furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "G" series of compounds, X1 0 and R 2 a are as otherwise as defined 25 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 0 each have the beta stereochemical configuration. 30 In the "H" series of compounds, X 1 6 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta 35 stereochemical configuration.

WO 01/57013 PCT/US01/03624 234 In the "I" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or 5 unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and Ry and R 1 0 each have the beta stereochemical configuration. In the "J" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, 10 pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 0 each have the beta stereochemical configuration. In the "K" series of compounds, X 10 , R 2 a and R 9 8 are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued 15 furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. Any substituents of each of X 3 , X 5 , R 2 , R. and R 1 may be hydrocarbyl or 20 any of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

X

5 NH O

R

10

R

9 25 X3 0-, Ry OH R14 HO A--. R2 0 OAc (20) Series X, 5 X R 1 R2 R 9 R1 Al -COOX 1 0 heterocyclo RjoaOCOO- C 6

H

5 COO- 0 H A2 -C0X 1 heterocyclo RjoaOCOO- C 6

H

5 C00- 0 H 30 A3 -CONHX 1 e heterocyclo Rj 0 aOCOO- C 6

H

5 C00- 0 H WO 01/57013 PCT/USO1/03624 235 A4 -COOX 10 optionally RjOOCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A5 -COX 1 0 optionally R1 0 OCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A6 -CONHX 1 optionally R 1 OOCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A7 -COOX 1 0 optionally R1o00COO- C 6

H

5 COO- 0 H substituted C2 to C alkenyl 5 A8 -COX 1 0 optionally R 10 OCOO- C 6

H

5 COO- 0 H substituted C2 to C alkenyl A9 -CONHXo optionally R1OaOCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkenyl A10 -COOXO optionally R 10 OCOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl Al1 -COX 1 0 optionally R 10 OCOO- C 6

H

5 COO- 0 H substituted C2 to C8 alkynyl A12 -CONHX 1 optionally R10aOOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl 10 B1 -COOX, heterocyclo Ro,0COO- R 2 COO- 0 H B2 -COXIo heterocyclo RoaOCOO- R 2 aCOO- 0 H B3 -CONHX 1 heterocyclo R1,OCOO- R 2 aCOO- 0 H B4 -COOX 1 0 optionally R1OaOCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl B5 -COX 1 0 optionally RjoaOCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl 15 B6 -CONHX 1 optionally R 10 OCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl B7 -COOX 10 optionally RioaOCOO- R 2 ,COO- 0 H substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 236 B8 -COX 10 optionally RIoaOCOO- R 2 aCOO- 0 H substituted C2 to C alkenyl B9 -CONHX 1 optionally R10iOCOO- R 2 COO- 0 H substituted C2 to C alkenyl B10 -COOXIO optionally R 10 ,OCOO- R 2 ,COO- 0 H substituted C2 to C alkynyl B11 -COX 1 0 optionally Rjoa0COO- R 2 aCOO- 0 H substituted C2 to C alkynyl 5 B12 -CONHX 1 optionally R 10 OCOO- R 2 COO- 0 H substituted C2 to C alkynyl C1 -COOX 1 0 heterocyclo R1O00COO- CHCOO- RgaCOO- H C2 -COX 1 0 heterocyclo R 10 0COO- CHCOO- RgaCOO- H C3 -CONHX,, heterocyclo Ro, 0 OCOO- CHCOO- R 9 aCOO- H C4 -COOX 10 optionally R1OaOCOO- C 6 HCOO- R 9 COO- H substituted C2 to C alkyl 10 C5 -COX 1 0 optionally R 10 OCOO- CH 5 COO- RgaCOO- H substituted C2 to C alkyl C6 -CONHX 1 optionally RioaOCOO- CH 5 COO- R 9 COO- H substituted C2 to C8 alkyl C7 -COOX,( optionally RIOOO- CHCOO- Rg,COO- H substituted C2 to C alkenyl C8 -COXO optionally RoaOCOO- CH 5 COO- R 9 aCOO- H substituted C2 to C alkenyl C9 -CONHXjO optionally R1OaOCOO- C 6 HCOO- R 9 aCOO- H substituted C2 to C. alkenyl 15 C10 -COOX 1 0 optionally RaOCOO- C 6 HCOO- R 9 aCOO- H substituted C2 to C8 alkynyl C11 -COX 1 0 optionally R 10 ,0COO- CHCOO- R 9 aCOO- H substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 237 C12 -CONHX 1 optionally R1 0 aOCOO- C 6 HCOO- R 92 ,C00- H substituted C2 to C alkynyl D1 -COOX 1 0 heterocyclo R1OaOCOO- CH 5 COO- OH H D2 -COX 1 heterocyclo R1O.OCOO- CH 5 COO- OH H D3 -CONHX 1 heterocyclo R1iOCOO- CH 5 COO- OH H 5 D4 -COOXIO optionally R 10 0COO- C 6

H

5 COO- OH H substituted C2 to C alkyl D5 -COX 10 optionally R1OaOCOO- C 8

H

5 COO- OH H substituted C2 to C alkyl D6 -CONHX 1 optionally R1OaOCOO- C6H 5 COO- OH H substituted C2 to C alkyl D7 -COOX 1 0 optionally R1OaOCOO- CH 5 COO- OH H substituted C2 to C alkenyl D8 -COX 1 0 optionally R1OaOCOO- CH 5 COO- OH H substituted C2 to C alkenyl 10 D9 -CONHX 10 optionally R1OaCOO- CHCOO- OH H substituted C2 to C alkenyl D10 -COOX 1 0 optionally R1OaOCOO- CH 5 COO- OH H substituted C2 to C alkynyl D11 -COX 1 0 optionally R 10 0COO- CH 5 COO- OH H substituted C2 to C alkynyl D12 -CONHXO optionally R1OaOCOO- CHCOO- OH H substituted C2 to C alkynyl El -C00X 1 0 heterocyclo R1OaOCOO- CH 5 COO- 0 OH 15 E2 -COX 10 heterocyclo R 10 OCOO- CH 5 COO- 0 OH E3 -CONHX 1 0 heterocyclo RI 0 ,O0OO- CH 5 COO- 0 OH E4 -COOX 10 optionally R 10 0COO- CH 5 COO- 0 OH substituted C2 to C alkyl I I II WO 01/57013 PCT/USO1/03624 238 E5 -COX 1 0 optionally R1 0 aOCOO- C 6 HCOO- 0 OH substituted C2 to C alkyl E6 -CONHXO optionally R 10 ,OCOO- C6HCOO- 0 OH substituted C2 to C alkyl E7 -COOXIO optionally R1OaOCOO- CHCOO- 0 OH substituted C2 to C alkenyl E8 -COX 1 e optionally RjOOCOO- CHCOO- 0 OH substituted C2 to C alkenyl 5 E9 -CONHX 1 optionally R1OaOCOO- CHCOO- 0 OH substituted C2 to C alkenyl E10 -COOX 1 0 optionally RI 02 COO- CH 5 COO- 0 OH substituted C2 to C alkynyl El1 -COX 1 0 optionally R1OaOCOO- CH 5 COO- 0 OH substituted C2 to C alkynyl E12 -CONHXO optionally R 1 oOCOO- CHCOO- 0 OH substituted C2 to C alkynyl Fl -COOX 1 0 heterocyclo R1OaOCOO- R 2 ,COO- RgCOO- H 10 F2 -COX 1 0 heterocyclo R1OaOCOO- R 2 ,COO- R0,COO- H F3 -CONHX 1 heterocyclo R1OaOCOO- R 2 ,COO- R0,COO- H F4 -COOX 10 optionally R1OaOCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkyl F5 -COX 1 0 optionally R 1 02 COO- R 2 aCOO- R0,COO- H substituted C2 to C alkyl F6 -CONHX 10 optionally R1OaOCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C8 alkyl 15 F7 -COOX 1 0 optionally R 1 OOCOO- R 2 aCOO- RaCOO- H substituted C2 to C alkenyl F8 -COX 10 optionally R1 0 aO0OO- R 2 aCOO- R0,COO- H substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 239 F9 -CONHX 1 optionally RiOaOCOO- R 2 aCOO- RgaCOO- H substituted C2 to C alkenyl F10 -COOX 1 e optionally RlOaOCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkynyl F11 -COX 1 0 optionally R 1 OCOO- R 2 aCOO- RaCOO- H substituted C2 to C8 alkynyl F12 -CONHX 10 optionally RjOaOCOO- R 2 aCOO- RgaCOO- H substituted C2 to C. alkynyl 5 G1 -COOX 1 0 heterocyclo R OaOCOO- R 2 aCOO- OH H G2 -COX 10 heterocyclo R 10 OCOO- R 2 aCOO- OH H G3 -CONHX 1 heterocyclo RiOaOCOO- R 2 aCOO- OH H G4 -COOX 1 0 optionally RiOaOCOO- R 2 COO- OH H substituted C2 to C alkyl G5 -COX 1 optionally RIoaOCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl 10 G6 -CONHX 1 optionally RiOaOCOO- R 2 aCOO- OH H substituted C2 to C8 alkyl G7 -COOX 1 0 optionally RjOaOCOO- R 2 COO- OH H substituted C2 to C alkenyl G8 -COX 1 0 optionally R OaOCOO- R 2 aCOO- OH H substituted C2 to C alkenyl G9 -CONHX 1 e optionally RiOaOCOO- R 2 aCOO- OH H substituted C2 to C alkenyl G10 -COOX 1 0 optionally RjeaOCOO- R 2 aCOO- OH H substituted C2 to C alkynyl 15 G11 -COX 1 0 optionally RiOaOCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl G12 -CONHX 1 optionally RjeaOCOO- R 2 aCOO- OH H substituted C2 to C. alkynyl WO 01/57013 PCT/USO1/03624 240 H1 -COOXIO heterocyclo R10,OCOO- C 6

H

5 COO- OH OH H2 -COXIO heterocyclo R 10 0COO- C 6

H

5 COO- OH OH H3 -CONHXO heterocyclo RIoaOCOO- C 6

H

5 COO- OH OH H4 -COOX 1 0 optionally R 10 ,OCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkyl 5 H5 -COX 1 0 optionally R 10 0COO- C 6

H

5 COO- OH OH substituted C2 to C8 alkyl H6 -CONHX 1 optionally R1OaOCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H7 -COOX 1 0 optionally R1OaOCOO- C 6

H

5 COO- OH OH substituted C2 to C. alkenyl H8 -COX 1 0 optionally R1OaOCOO- C 6

H

5 COO- OH OH substituted C2 to C alkenyl H9 -CONHX 1 optionally RIoaOCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkenyl 10 H10 -COOX 1 0 optionally R 10 ,OCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkynyl H11 -COX 1 0 optionally R 10 OCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl H12 -CONHXO optionally R 10 0COO- C 6

H

5 COO- OH OH substituted C2 to C. alkynyl 11 -COOX 10 heterocyclo R1OaOCOO- R 2 aCOO- 0 OH 12 -COX 10 heterocyclo R 10 0COO- R 2 aCOO- 0 OH 15 13 -CONHX 1 heterocyclo RioaOCOO- R 2 aCOO- 0 OH 14 -COOXIO optionally R1OaOCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 15 -COX 1 0 optionally RioaOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl WO 01/57013 PCT/USO1/03624 241 16 -CONHX 1 optionally R1OzCOO- R 2 aCOO- 0 OH substituted C2 to C alkyl 17 -COOX 1 0 optionally RloaOCOO- R 2 ,COO- 0 OH substituted C2 to C alkenyl 18 -COXIO optionally R 10 OCOO- R 2 aCOO- 0 OH substituted C2 to C alkenyl 19 -CONHXIO optionally R 10 OCOO- R 2 aCOO- 0 OH substituted C2 to C alkenyl 5 110 -COOX 10 optionally R 10 ,OCOO- R 2 aCOO- 0 OH substituted C2 to C, alkynyl 11 -COX 1 0 optionally R1 0 aOCOO- R 2 aCOO- 0 OH substituted C2 to C alkynyl 112 -CONHXO optionally RioaOCOO- R 2 aCOO- 0 OH substituted C2 to C alkynyl J1 -COOX 10 heterocyclo R1OaOCOO- R 2 ,COO- OH OH J2 -COX 1 0 heterocyclo R1OaOCOO- R 2 ,COO OH OH 10 J3 -CONHXo heterocyclo R1OaOCOO- R 2 aCOO- OH OH J4 -COOX 1 0 optionally RioaOCOO- R 2 aCOO- OH OH substituted C2 to C alkyl J5 -COX 10 optionally ROaOC0OO- R 2 aCOO- OH OH substituted C2 to C alkyl J6 -CONHXO optionally RjOaOCOO- R 2 ,COO- OH OH substituted C2 to C alkyl J7 -C00X 10 optionally RoaOCOO- R 2 ,COO- OH OH substituted C2 to C alkenyl 15 J8 -COX 1 0 optionally RioaOCOO- R 2 aCOO- OH OH substituted C2 to C alkenyl J9 -CONHX 1 optionally R 10 0COO- R 2 .COO- OH OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 242 JIo -COOX 1 e optionally R1,OOCOO- R 2 aCOO- OH OH substituted C2 to Cs alkynyl Ji1 -COX 1 e optionally R1OaOCOO- R 2 aCOO- OH OH substituted C2 to C. alkynyl J12 -CONHX 1 optionally Ri 0 aO0OO- R 2 ,COO- OH OH substituted C2 to C alkynyl K1 -COOX 10 heterocyclo RI0,OCOO- R 2 aCOO- ReCOO- OH 5 K2 -COX 1 0 heterocyclo R1OaOCOO- R 2 aCOO- R 9 aCOO- OH K3 -CONHX 1 heterocyclo R1OaOCOO- R 2 aCOO- R 9 aCOO- OH K4 -COOX 1 0 optionally R1OaOCOO- R 2 aCOO- ReCOO- OH substituted C2 to C alkyl K5 -COX 1 0 optionally RiOOCOO- R 2 ,COO- RgaCOO- OH substituted C2 to C. alkyl K6 -CONHX 1 optionally R1OaOCOO- R 2 aCOO- R 9 COO- OH substituted C2 to C alkyl 10 K7 -COOX 1 0 optionally R1OaOCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkenyl K8 -COX 1 0 optionally R, 02 COO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkenyl K9 -CONHX 10 optionally R1OaOCOO- R 2 ,COO- RgCOO- OH substituted C2 to C alkenyl K10 -COOX 1 0 optionally R1OaOCOO- R 2 aCOO- R 9 COO- OH substituted C2 to C8 alkynyl K 11 -COX 1 0 optionally R 10 OCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkynyl _ 15 K12 -CONHX 1 optionally R1OaOCOO- R 2 ,COO- R 9 COO- OH substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 243 Example 30: In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCT1 16) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were 5 incubated in a C02 incubator at 37 0C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 27 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 * C. At the end of incubation the drug-containing media were 10 decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were 15 determined for each tested compound. Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 1755 <1 20 1767 <10 1781 <1 1799 <1 1808 <10 1811 <1 25 1822 <1 1838 <1 1841 <1 1855 <10 1867 <1 30 1999 <1 WO 01/57013 PCT/USO1/03624 244 2002 <1 2011 <10 2020 <1 2032 <1 5 2044 <1 2050 <1 2062 <10 2077 <10 2086 <1 10 2097 <1 2666 <1 2972 <10 2988 <1 2999 <1 15 3003 <10 3011 <1 3020 <1 3033 <10 3155 <1 20 3181 <1 3243 <1 3300 <10 3393 >50 3433 22.3 25 3911 <1 3929 <1 3963 <1 4000 <1 4020 <1 30 4074 <1 4088 <10 WO 01/57013 PCT/USO1/03624 245 4090 <1 4374 <1 4636 <10 6466 <10 5 4959 <1 4924 <10 4844 <1 5171 <1 5155 <10 10 1788 <1 1767 <10 1771 <10 1866 <1 2060 <10 15 2092 <1 2088 <1 Example 31: Preparation of Taxane Having C-7 Carbamoyloxy and C-10 Hydroxy N-Debenzoyl-N-isobutenyl-3'-desphenyl-3'-(2-furyl)-7-phenylcarbamoyl taxol 20 (5535) To a solution of N-debenzoyl-N-isobutenyl-3'-desphenyl-3'-(2-furyl)-2'-(2 methoxy-2-propyl)-10-triethylsily taxol (400 mg, 0.413 mmol) in 4 mL anhydrous pyridine was added 4-dimethylaminopyridine (10 mg, 0.08 mmol) under a nitrogen atmosphere. To this mixture was added dropwise phenyl isocyanate (112 L, 1.034 mmol). TLC (silica gel, 2:3 ethyl acetate:hexane) after 3 h showed no 25 starting material. The reaction mixture was cooled to 0* C (ice-water bath) and quenched by adding 50 L of water. To the reaction at 00 C (ice-water bath) was added 4 mL of acetonitrile and 2 mL of 48% aqueous hyderofluoric acid and the cooling bath removed. The reaction was stirred at room temperature for 12.5 h and then diluted with 60 mL of 30 ethyl acetate and washed with 10 mL of saturated aqueous NaHCO 3 followed by 15 mL of saturated aqueous NaCl. The organic layer was dried over Na 2 SO4 and WO 01/57013 PCT/USO1/03624 246 concentrated under reduce pressure to give 390 mg of an off-white solid which was purified by flash-chromatography (silica gel, 1:1 ethyl acetate:hexane) to give 320 mg (86%) of N-debenzoyl-N-isobutenyl-3'-desphenyl-3'-(2-furyl)-7 phenylcarbamoyl taxol: mp 188-89C; 1 H NMR (CDCl 3 ) 8.11 (m, 2H), 7.60(m, IH), 5 7.46-7.51(m, 2H), 7.26-7.40(m, 6H), 6.34(dd, J=3.1, 1.5 Hz, 1H), 6.25 (d, J=3.1 Hz, 1H), 6.21 (dd, J=8.8, 8.7 Hz, 1H), 5.67(2H), 5.47(2H), 4.98-5.01(m, 3H), 4.76(m, 1H), 4.32(d, J=8.0 Hz, IH), 4.21(d, J=8.0 Hz, 1H), 4.09(d, J=7.6 Hz, 1H), 3.99 (m, 1H), 3.30 (d, J= 5.5 Hz, 1H), 2.60-2.68(m, 1H), 2.43 (s, 3H), 2.37 (m, 1H), 2.08( m, 1H), 1.98 (s, 3H), 1.91 (bs, 3H), 1.84 (bs, 3H), 1.80 (s, 3H), 1.23(s, 10 3H), 1.10(s, 3H); Anal. Calcd. for C 4 8

H

54

N

2 0 15 : C, 64.13; H, 6.05. Found: C, 63.78; H, 6.20. Example 32: Taxanes having C7-Carbamoyloxy and C-10 Hydroxy Substituents The procedures described in Example 31 were repeated, but other suitably protected p-lactams and acylating agents were substituted for the p-lactam and 15 acylating agent of Example 31 to prepare the series of compounds having structural formula (21) and the combination of substituents identified in the following table.

X

5 NH O HO 0 X3__ R7 OH HO i . BzOAc5 0 (21) Compound X, X3 R7 20 5522 ibueCO- 2-furyl 3,4-diFPhNHCOO 6404 tAmOCO- 2-furyl 3,4-diFPhNHCOO 5415 tBuOCO- 2-furyl 3,4-diFPhNHCOO 5800 tC 3

H

5 CO- 2-furyl 3,4-diFPhNHCOO 5575 ibueCO- 2-furyl C 3

H

5

NHCOO

25 5385 tbuOCO- 2-furyl C 3

H

5

NHCOO

5844 tC 3

H

5 CO- 2-furyl C 3

HNHCOO-

WO 01/57013 PCT/USO1/03624 247 5373 tBuOCO- 2-furyl chexNHCOO 5895 tC 3

H

5 CO- 2-furyl chexNHCOO 5588 ibueCO- 2-furyl EtNHCOO 5393 tBuOCO- 2-furyl EtNHCOO 5 6696 tBuOCO- 2-furyl EtNHCOO 5822 tC 3

H

5 CO- 2-furyl EtNHCOO 5565 ibueCO- 2-furyl mnipNHCOO 6476 tAmOCO- 2-furyl mnipNHCOO 5400 tBuOCO- 2-furyl mnipNHCOO 10 5747 tC 3

H

5 CO- 2-furyl mnipNHCOO 5535 ibueCO- 2-furyl PhNHCOO 6399 tAmOCO- 2-furyl PhNHCOO 5757 tC 3

H

5 CO- 2-furyl PhNHCOO 5665 tBuOCO- 2-furyl PrNHCOO 15 5454 tBuOCO- 2-furyl tBuNHCOO Example 33: Taxanes having C7-Carbamoyloxy and C-10 Hydroxy Substituents Following the processes described in Example 31 and elsewhere herein, the following specific taxanes having structural formula (22) and the combinations of substituents identified in the following table may be prepared, wherein R 7 is as 20 previously defined, including wherein R 7 is R 7 aR 7 bNCOO- and (a) R 7 a and R 7 . are each hydrogen, (b) one of R 7 a and R 7 b is hydrogen and the other is (i) substituted or unsubstituted C1 to C8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C3 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl 25 or hexenyl; (iii) substituted or unsubstituted C3 to C alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, or (c) R 7 a and R 7 b are independently (i) substituted or unsubstituted C, to C alkyl such as methyl, ethyl, or straight, branched or cyclic 30 propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or WO 01/57013 PCT/USO1/03624 248 hexenyl; (iii) substituted or unsubstituted C2 to C alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere 5 herein for substituted hydrocarbyl. For example, R 7 may be R 7

,R

7 bNCOO wherein one of R 7 , and R 7 b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.

X

5 NH 0 HO X3 tR7 OH HO . BzO A 0 Aco (22) X5 X3 R 7 10 tBuOCO- 2-furyl R 7

,R

7 bNCOO tBuOCO- 3-furyl R 7 aR 7 bNCOO tBuOCO- 2-thienyl R 7 aR 7 bNCOO tBuOCO- 3-thienyl R 7

R

7 bNCOO tBuOCO- 2-pyridyl R 7

,R

7 bNCOO 15 tBuOCO- 3-pyridyl R 7

R

7 bNCOO tBuOCO- 4-pyridyl R 7

,R

7 bNCOO tBuOCO- isobutenyl R 7 aR 7 bNCOO tBuOCO- isopropyl R 7

,R

7 bNCOO tBuOCO- cyclopropyl R 7

,R

7 bNCOO 20 tBuOCO- cyclobutyl R 7 aRybNCOO tBuOCO- cyclopentyl R 7 yR 7 bNCOO tBuOCO- phenyl R 7

,R

7 bNCOO benzoyl 2-furyl R 7

,R

7 bNCOO benzoyl 3-furyl R 7 aR 7 bNCOO 25 benzoyl 2-thienyl R 7 aR 7 bNCOO- WO 01/57013 PCT/USO1/03624 249 benzoyl 3-thienyl R 7 aR 7 bNCOO benzoyl 2-pyridyl R 7

,R

7 bNCOO benzoyl 3-pyridyl R 7 zR 7 bNCOO benzoyl 4-pyridyl R 7

,R

7 bNCOO 5 benzoyl isobutenyl R 7 aR 7 bNCOO benzoyl isopropyl R 7

.R

7 bNCOO benzoyl cyclopropyl R 7 aRybNCOO benzoyl cyclobutyl R 7 aR 7 bNCOO benzoyl cyclopentyl R 7 aRybNCOO 10 benzoyl phenyl R 7 aR 7 bNCOO 2-FuCO- 2-furyl R 7 aR 7 bNCOO 2-FuCO- 3-furyl R 7 aRybNCOO 2-FuCO- 2-thienyl R 7 aR 7 bNCOO 2-FuCO- 3-thienyl R 7 aR 7 bNCOO 15 2-FuCO- 2-pyridyl R 7 aR 7 bNCOO 2-FuCO- 3-pyridyl R 7 aR 7 bNCOO 2-FuCO- 4-pyridy R 7 aR 7 bNCOO 2-FuCO- isobutenyl R 7 a R 7 bNCOO 2-FuCO- isopropyl R 7 aR 7 bNCOO 20 2-FuCO- cyclopropyl R 7 aR 7 bNCOO 2-FuCO- cyclobutyl R 7 aR 7 bNCOO 2-FuCO- cyclopentyl R 7 aRmbNCOO 2-FuCO- phenyl R 7 aR 7 bNCOO 2-ThCO- 2-furyl R 7 aR 7 bNCOO 25 2-ThCO- 3-furyl R 7 aR 7 bNCOO 2-ThCO- 2-thienyl R 7 aR 7 bNCOO 2-ThCO- 3-thienyl R 7 aR 7 bNCOO 2-ThCO- 2-pyridyl R 7 aR 7 bNCOO 2-ThCO- 3-pyridyl R 7 aR 7 bNCOO 30 2-ThCO- 4-pyridyl R 7 aR 7 bNCOO 2-ThCO- isobutenyl R 7 aR 7 bNCOO- WO 01/57013 PCT/USO1/03624 250 2-ThCO- isopropyl R 7

,R

7 bNCOO 2-ThCO- cyclopropyl R 7

,R

7 bNCOO 2-ThCO- cyclobutyl R 7 aR 7 bNCOO 2-ThCO- cyclopentyl R 7 aR 7 bNCOO 5 2-ThCO- phenyl R 7 aR 7 bNCOO 2-PyCO- 2-furyl R 7

R

7 bNCOO 2-PyCO- 3-furyl R 7 aR 7 bNCOO 2-PyCO- 2-thienyl R 7

,R

7 bNCOO 2-PyCO- 3-thienyl R 7 aR 7 bNCOO 10 2-PyCO- 2-pyridyl R 7 aR 7 bNCOO 2-PyCO- 3-pyridyl R 7

R

7

NCOO

2-PyCO- 4-pyridyl R 7 aR 7 bNCOO 2-PyCO- isobutenyl R 7

,R

7 bNCOO 2-PyCO- isopropyl R 7 yR 7 bNCOO 15 2-PyCO- cyclopropyl R 7 aR 7 bNCOO 2-PyCO- cyclobutyl R 7 aR 7 bNCOO 2-PyCO- cyclopentyl R 7 aR 7 bNCOO 2-PyCO- phenyl R 7 aR 7 bNCOO 3-PyCO- 2-furyl R 7 aR 7 bNCOO 20 3-PyCO- 3-furyl R 7 aR 7 bNCOO 3-PyCO- 2-thienyl R 7 aR 7 bNCOO 3-PyCO- 3-thienyl R 7 aR 7 bNCOO 3-PyCO- 2-pyridyl R 7 aR 7 bNCOO 3-PyCO- 3-pyridyl R 7 aR 7 bNCOO 25 3-PyCO- 4-pyridyl R 7 aR 7 bNCOO 3-PyCO- isobutenyl R 7 aR 7 bNCOO 3-PyCO- isopropyl R 7 aR 7 bNCOO 3-PyCO- cyclopropyl R 7 aR 7 bNCOO 3-PyCO- cyclobutyl R 7 aR 7 bNCOO 30 3-PyCO- cyclopentyl R 7 aR 7 bNCOO 3-PyCO- phenyl R 7 aR 7 bNCOO- WO 01/57013 PCT/USO1/03624 251 4-PyCO- 2-furyl R 7 zaROlCOO 4-PyCO- 3-furyl R 7 aR 7 bNCOO 4-PyCO- 2-thienyl R 7 aRObCOO 4-PyCO- 3-thienyl R 7 aR~bNCOO 5 4-PyCO- 2-pyridyl R 7

,R

7 bNCOO 4-PyCO- 3-pyridyl R 7 aR 7 bNCOO 4-PyCO- 4-pyridyl R 7

,R

7 bNCOO 4-PyCO- isobutenyl R 7 aR 7 bNCOO 4-PyCO- isopropyl R 7 aR 7 bNCOO 10 4-PyCO- cyclopropyl R 7 aR 7 bNCOO 4-PyCO- cyclobutyl R 7 ,R~bNCOO 4-PyCO- cyclopentyl R 7 aR~bNCOO 4-PyCO- phenyl R 7

,R

7 bNCOO

C

4

H

7 C0- 2-furyI R 7 aR 7 bNCOO 15 C 4

H

7 CO- 3-fu ryl R 7 aRObCOO

C

4

H

7 00- 2-thienyl R 7

,R

7 bNCOO

C

4

H

7 CO- 3-thienyl R 7 aR 7 bNCOO

C

4

H

7 00- 2-pyridyl R 7 2,R 7 bNCOO

C

4

H

7 CO- 3-pyridyl R 7 ,aRybNCOO 20 -C 4

H

7 00- 4-pyridyl R 7 2,R 7 bNCOO

C

4

H

7 00- isobutenyl R 7 aRObCOO

C

4

H

7 00- isopropyl R 7

,R

7 bNCOO

C

4

H

7 CO- cyclopropyl R 7 aR 7 bNCOO

C

4

H

7 00- cyclobutyl R 7 aR 7 bNCOO 25 C 4

H

7 00- cyclopentyl R 7 aR 7 bNCOO

C

4

H

7 00- phenyl R 7 zaRObCOO EtOCO- 2-furyl R 7

,R

7 bNCOO EtOCO- 3-fu ryl R 7 aR 7 bNCOO EtOCO- 2-thienyl R 72 R-,bCOO 30 EtOCO- 3-thienyl R 7 aR 7 bNCOO EtOCO- 2-pyridyl R 7 aRObCOO- WO 01/57013 PCT/USO1/03624 252 EtOCO- 3-pyridyl R 7 aR 7 bNCOO EtOCO- 4-pyridyl R 7 aRybNCOO EtOCO- isobutenyl R 7 aR 7 bNCOO EtOCO- isopropyl R 7 aR 7 bNCOO 5 EtOCO- cyclopropyl R 7 aRyNCOO EtOCO- cyclobutyl R 7

R

7 bNCOO EtOCO- cyclopentyl R 7 aR 7 bNCOO EtOCO- phenyl R 7 aR 7 bNCOO ibueCO- 2-furyl R 7 aR 7 bNCOO 10 ibueCO- 3-furyl R 7 aR 7 bNCOO ibueCO- 2-thienyl R 7 aR 7 bNCOO ibueCO- 3-thienyl R 7 aR 7 bNCOO ibueCO- 2-pyridyl R 7 aR 7 bNCOO ibueCO- 3-pyridyl R 7 aR 7 bNCOO 15 ibueCO- 4-pyridyl R 7 aR 7 bNCOO ibueCO- isobutenyl R 7 aR 7 bNCOO ibueCO- isopropyl R 7 aR 7 bNCOO ibueCO- cyclopropyl R 7 aR 7 bNCOO ibueCO- cyclobutyl R 7 aR 7 bNCOO 20 ibueCO- cyclopentyl R 7 aR 7 bNCOO ibueCO- phenyl R 7 aR 7 bNCOO iBuCO- 2-furyl R 7 aR 7 bNCOO iBuCO- 3-furyl R 7 aR 7 bNCOO iBuCO- 2-thienyl R 7 aR 7 bNCOO 25 iBuCO- 3-thienyl R 7 aR 7 bNCOO iBuCO- 2-pyridyl R 7 aR 7 bNCOO iBuCO- 3-pyridyl R 7 aR 7 bNCOO iBuCO- 4-pyridyl R 7 aR 7 bNCOO iBuCO- isobutenyl R 7 aR 7 bNCOO 30 iBuCO- isopropyl R 7 aR 7 bNCOO iBuCO- cyclopropyl R 7 aR 7 bNCOO- WO 01/57013 PCT/USO1/03624 253 iBuCO- cyclobutyl R 7

,R

7 bNCOO iBuCO- cyclopentyl R 7 aR 7 bNCOO iBuCO- phenyl R 7

,R

7 bNCOO iBuOCO- 2-furyl R 7 aR 7

NCOO

5 iBuOCO- 3-furyl R 7

,R

7 bNCOO iBuOCO- 2-thienyl R 7

,R

7 bNCOO iBuOCO- 3-thienyl R 7 ,RyNCOO iBuOCO- 2-pyridyl R 7 aR 7 bNCOO iBuOCO- 3-pyridyl R 7 RybNCOO 10 iBuOCO- 4-pyridyl R 7

,R

7 bNCOO iBuOCO- isobutenyl R 7 yRyNCOO iBuOCO- isopropyl R 7

,R

7

NCOO

iBuOCO- cyclopropyl R 7

,R

7 bNCOO iBuOCO- cyclobutyl R 7

,R

7 bNCOO 15 iBuOCO- cyclopentyl R 7 aRyNCOO iBuOCO- phenyl R 7 aRybNCOO iPrOCO- 2-furyl R 7

,R

7 bNCOO iPrOCO- 3-furyl R 7

,R

7 bNCOO iPrOCO- 2-thienyl R 7

,R

7 bNCOO 20 iPrOCO- 3-thienyl R 7

,R

7 bNCOO iPrOCO- 2-pyridyl R 7

,R

7 bNCOO iPrOCO- 3-pyridyl R 7

,R

7 bNCOO iPrOCO- 4-pyridyl R 7 RyNCOO iPrOCO- isobutenyl R 7

,R

7 bNCOO 25 iPrOCO- isopropyl R 7 aRybNCOO iPrOCO- cyclopropyl R 7 RybNCOO iPrOCO- cyclobutyl R 7

,R

7 bNCOO iPrOCO- cyclopentyl R 7 aR 7 bNCOO iPrOCO- phenyl R 7 aRybNCOO 30 nPrOCO- 2-furyl R 7

,R

7 bNCOO nPrOCO- 3-furyl R 7 yR 7 bNCOO- WO 01/57013 PCT/US01/03624 254 nPrOCO- 2-thienyl R 78

R

7 bNCOO nPrOCO- 3-thienyl R 7

,R

7 bNCOO nPrOCO- 2-pyridyl R 7

,R

7 bNCOO nPrOCO- 3-pyridyl R 7

,R

7 bNCOO 5 nPrOCO- 4-pyridyl R 7

,R

7 bNCOO nPrOCO- isobutenyl R 7

,R

7 bNCOO nPrOCO- isopropyl R 7 zR 7 bNCOO nPrOCO- cyclopropyl R 7

,R

7 bNCOO nPrOCO- cyclobutyl R 7

,R

7 bNCOO 10 nPrOCO- cyclopentyl R 7

,R

7 bNCOO nPrOCO- phenyl R 7

,R

7 bNCOO nPrCO- 2-furyl R 7 aR 7 bNCOO nPrCO- 3-furyl R 7 aR 7 bNCOO nPrCO- 2-thienyl R 7

,R

7 bNCOO 15 nPrCO- 3-thienyl R 7

,R

7 bNCOO nPrCO- 2-pyridyl R 7

,R

7 bNCOO nPrCO- 3-pyridyl R 7

,R

7 bNCOO nPrCO- 4-pyridyl R 7 zR 7 bNCOO nPrCO- isobutenyl R 7

,R

7 bNCOO 20 nPrCO- isopropyl R 7 aR 7 bNCOO nPrCO- cyclopropyl R 7 zR 7 bNCOO nPrCO- cyclobutyl R 7 aRybNCOO nPrCO- cyclopentyl R 7 aR 7 bNCOO nPrCO- phenyl R 7

,R

7 bNCOO 25 Example 34: Taxanes having C7-Carbamoyloxy and C-10 Hydroxy Substituents Following the processes described in Example 31 and elsewhere herein, the following specific taxanes having structural formula (23) may be prepared, wherein RIO is hydroxy and R 7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R 7 is R 7 aR 7 bNCOO- and 30 one of R 7 a and R 7 b is hydrogen and the other is (i) substituted or unsubstituted C, to C. alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, WO 01/57013 PCT/US01/03624 255 pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substituted phenyl 5 such as nitro, alkoxy or halosubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R 7 substituents include R 7 aR 7 bNCOO- wherein one of R 7 a and R 7 b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl. In 10 another embodiment, preferred R 7 substituents include R 7 aR 7 bNCOO- wherein one of R 7 a and R 7 b is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl. In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 15 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 and RIO each have the beta stereochemical configuration. In the "B" series of compounds, X 10 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, 20 pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 0 each have the beta stereochemical configuration. In the "C" series of compounds, X 10 and R 9 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, 25 thienyl, or pyridyl, X 1 . is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rga is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and RIO each have the beta stereochemical configuration. In the "D" and "E" series of compounds, X 1 0 is as otherwise as defined 30 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R. (series D only) and R 1 each have the beta stereochemical configuration. In the "F" series of compounds, X 10 , R 2 a and Rga are as otherwise as 35 defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, WO 01/57013 PCT/US01/03624 256 pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 0 each have the beta stereochemical configuration. In the "G" series of compounds, X 1 0 and R 2 a are as otherwise as defined 5 herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and RIO each have the beta stereochemical configuration. 10 In the "H" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X,, is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and RIO each have the beta 15 stereochemical configuration. In the "I" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, XIO is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or 20 unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and RIO each have the beta stereochemical configuration. In the "J" series of compounds, XjO and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued fury!, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, 25 pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and RIO each have the beta stereochemical configuration. In the "K" series of compounds, X 10 , R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued 30 furyl, thienyl, or pyridyl, X,, is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R 9 and R 1 each have the beta stereochemical configuration. Any substituents of each X 3 , X 5 , R 2 , R 7 , and R 9 may be hydrocarbyl or any 35 of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, WO 01/57013 PCT/USO1/03624 257 keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

X

5 NH O R 10

R

9 X3 00 , R7 OH O'

R

14 HO . R2 0 OAc 5 (23) Series X6 X3 R7 R2 R 9 R1 Al -COOX 10 heterocyclo R 7

R

7 bNCOO- CH 5 COO- 0 H A2 -COX 1 heterocyclo R 7

,R

7 bNCOO- C 6

H

5 COO- 0 H A3 -CONHXO heterocyclo R 7

R

7 bNCOO- C 6 HCOO- 0 H 10 A4 -COOXIO optionally R 7

,R

7 bNCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A5 -COXO optionally R 7 aR 7 bNCOO- CH 5 COO- 0 H substituted C2 to C alkyl A6 -CONHXO optionally R 7 aR 7 bNCOO- C6H 5 COO- 0 H substituted C2 to C alkyl A7 -COOX 1 0 optionally R 7 RybNCOO- C 8 HCOO- 0 H substituted C2 to C alkenyl A8 -COX 1 0 optionally R 7 aR 7 bNCOO- CH 5 COO- 0 H substituted C2 to C alkenyl 15 A9 -CONHXO optionally R 7 aRybNCOO- C 6

H

5 COO- 0 H substituted C2 to C alkenyl A10 -COOX 1 0 optionally R 7 aR 7 bNCOO- CH 5 COO- 0 H substituted C2 to C alkynyl WO 01/57013 PCT/USO1/03624 258 Al1 -COX 1 0 optionally R 7 RybNCOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl A12 -CONHXO optionally R 7 RyNOCOO- C 6

H

5 COO- 0 H substituted C2 to C. alkynyl B1 -COOXO heterocyclo R 7 ARyNCOO- R 2 ,COO- 0 H B2 -COX 1 0 heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- 0 H 5 B3 -CONHX 10 heterocyclo R7aR 7 bNCOO- R 2 aCOO- 0 H B4 -COOX 10 optionally R 7 aR 7 bNCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl B5 -COX 10 optionally R 7 aR 7 bNCOO- R 2 aCOO- 0 H substituted C2 to C alkyl B6 -CONHX 1 0 optionally R 7 aRybNCOO- R 2 ,COO- 0 H substituted C2 to C alkyl B7 -COOX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- 0 H substituted C2 to C alkenyl 10 B8 -COX 10 optionally R 7

R

7 bNCOO- R 2 aCOO- 0 H substituted C2 to C8 alkenyl B9 -CONHXO optionally RyaR 7 bNCOO- R 2 ,COO- 0 H substituted C2 to C alkenyl B10 -COOXIO optionally RR 7 bNCOO- R2,COO- 0 H substituted C2 to C alkynyl B11 -COX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- 0 H substituted C2 to C. alkynyl B12 -CONHX 10 optionally R 7 yR 7 bNCOO- R 2 COO- 0 H substituted C2 to C8 alkynyl 15 C1 -C00X 10 heterocyclo R 7 aR 7 bNCOO- C 6

H

5 COO- RgaCOO- H C2 -COX 1 o heterocyclo R 7 aRybNCOO- C 6

H

5 COO- R 9 COO- H C3 -CONHX 10 heterocyclo R 7 aR 7 bNCOO- C 6

H

5 COO- RgaCOO- H WO 01/57013 PCT/USO1/03624 259 C4 -COOX 1 0 optionally R 7

R

7 bNCOO- C 6

H

5 COO- R 9 ,COO- H substituted C2 to C alkyl C5 -COX 1 0 optionally R 7 aR 7 bNCOO- C6H 5 COO- R0,COO- H substituted C2 to C alkyl C6 -CONHX 1 optionally R 7 aR 7 bNCOO- C 6

H

5 COO- RgaCOO- H substituted C2 to C alkyl C7 -COOX 1 0 optionally R 7 yR 7 bNCOO- C 6

H

5 COO- RgCOO- H substituted C2 to C alkenyl 5 C8 -COX 10 optionally R 7 yR 7 bNCOO- CH 5 COO- RCOO- H substituted C2 to C alkenyl C9 -CONHX 1 0 optionally R 7 yR 7 bNCOO- CH 5 COO- R,COO- H substituted C2 to C8 alkenyl C10 -COOX 1 0 optionally R 7 yR 7 bNCOO- CHCOO- RgaCOO- H substituted C2 to C8 alkynyl C11 -COX 10 optionally R 7

R

7 bNCOO- CH 5 COO- R 9 aCOO- H substituted C2 to C8 alkynyl C12 -CONHXO optionally RlR 7 bNCOO- CH 5 COO- R 9 aCOO- H substituted C2 to C alkynyl 10 D1 -COOX 1 0 heterocyclo R 7 aR 7 bNCOO- C 6 HCOO- OH H D2 -COX 10 heterocyclo RyR 7 bNCOO- CHCOO- OH H D3 -CONHX 1 heterocyclo R 7 aR 7 bNCOO- CHCOO- OH H D4 -COOX 1 0 optionally R 7 aR 7 bNCOO- C 6 HCOO- OH H substituted C2 to C alkyl D5 -COX 1 0 optionally R 7 aRybNCOO- C 6

H

5 COO- OH H substituted C2 to C alkyl 15 D6 -CONHX 1 optionally R 7 aR 7 bNCOO- CH 5 COO- OH H substituted C2 to C8 alkyl D7 -COOX 1 optionally R 7 aR 7 bNCOO- CH 5 COO- OH H substituted C2 to C, alkenyl WO 01/57013 PCT/USO1/03624 260 D8 -COX 1 0 optionally R 7

,R

7 bNCOO- C 6 HCOO- OH H substituted C2 to C alkenyl D9 -CONHXO optionally R 7 aR 7 bNCOO- C 6 H5COO- OH H substituted C2 to C. alkenyl DIO -COOXIO optionally R 7 aR 7 bNCOO- C 6 HCOO- OH H substituted C2 to C alkynyl D11 -COX 1 0 optionally R 7 yR 7 bNCOO- C 6

H

5 COO- OH H substituted C2 to C alkynyl 5 D12 -CONHXO optionally R 7

R

7 bNCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkynyl El -COOXI 0 heterocyclo R 7 aR 7 bNCOO- CH, 5 COO- 0 OH E2 -COX 10 heterocyclo R 7 aRyNOCOO- C 6

H

5 COO- 0 OH E3 -CONHXO heterocyclo R 7 aR 7 bNCOO- C 6

H

5 COO- 0 OH E4 -COOXO optionally R 7 yRybNCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl 10 E5 -COX 10 optionally R 7 RbN COO- C 6

H

5 COO- 0 OH substituted C2 to C alkyl E6 -CONHXIO optionally R 7 aR 7 bNCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkyl E7 -C00X 10 optionally R 7 aR 7 bNCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkenyl E8 -COXIO optionally R 7 aR 7 bNCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkenyl E9 -CONHX 1 optionally R 7

,R

7 bNCOO- C 6

H

5 COO- 0 OH substituted C2 to C alkenyl 15 E10 -COOXIO optionally RyRybNOO- C 6

H

5 COO- 0 OH substituted C2 to C alkynyl El1 -COX 1 0 optionally R 7 aRybNCOO- C 6

H

5 COO- 0 OH substituted C2 to C8 alkynyl I I I I_ I WO 01/57013 PCT/USO1/03624 261 E12 -CONHXO optionally R 7

,R

7 bNCOO- C6HCOO- 0 OH substituted C2 to C alkynyl F1 -COOX 1 0 heterocyclo R 7

R

7 bNCOO- R 2 aCOO- R0,COO- H F2 -COX 1 0 heterocyclo R 7 ,RybNCOO- R 2 ,COO- R 9 aCOO- H F3 -CONHX 1 heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- RgCOO- H 5 F4 -COOX 10 optionally R 7 aR 7 bNCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C alkyl F5 -COX 1 optionally RlaR 7 bNCOO- R 2 ,COO- RgaCOO- H substituted C2 to C8 alkyl F6 -CONHX 1 optionally R 7 aRybNCOO- R 2 aCOO- RgzCOO- H substituted C2 to C8 alkyl F7 -COOX 1 0 optionally RyaR 7 bNCOO- R 2 ,COO- RgaCOO- H substituted C2 to C. alkenyl F8 -COX 1 0 optionally R 7 aRyNCOO- R 2 COO- R 9 COO- H substituted C2 to C8 alkenyl 10 F9 -CONHX 1 optionally R 7 aR 7 bNCOO- R 2 ,COO- RgCOO- H substituted C2 to C8 alkenyl F10 -COOX 1 0 optionally R 7 aR 7 bNCOO- R 2 ,COO- R 9 aCOO- H substituted C2 to C. alkynyl F11 -COXIO optionally R 7

,R

7 bNCOO- R 2 ,COO- RgCOO- H substituted C2 to C alkynyl F12 -CONHX 1 optionally R 7 aR 7 bNCOO- R 2 aCOO- R 9 aCOO- H substituted C2. to C alkynyl G1 -COOX 1 0 heterocyclo RaR 7 bNCOO- R 2 aCOO- OH H 15 G2 -COX 10 heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- OH H G3 -CONHX 1 heterocyclo R 7

R

7 bNCOO- R 2 aCOO- OH H G4 -COOX 1 optionally R 7 ,RybNCOO- R 2 aCOO- OH H substituted C2 to C. alkyl WO 01/57013 PCT/USO1/03624 262 G5 -COX 1 0 optionally R 7

,R

7 bNCOO- R 2 COO- OH H substituted C2 to C 8 alkyl G6 -CONHX 1 optionally R 7

,R

7 bNCOO- R 2 ,COO- OH H substituted C2 to C alkyl G7 -COOX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- OH H substituted C2 to C alkenyl G8 -COX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- OH H substituted C2 to C alkenyl 5 G9 -CONHX 1 optionally R 7 aR 7 bNCOO- R 2 aCOO- OH H substituted

C

2 to C alkenyl G10 -COOXIO optionally R 7 aR 7 bNCOO- R 2 aCOO- OH H substituted C2 to C alkynyl G11 -COX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- OH H substituted C2 to C alkynyl G12 -CONHX 1 optionally R 7

,R

7 bNCOO- R 2 COO- OH H substituted C2 to C alkynyl HI -COOX 10 heterocyclo R 7 ,RyNOCOO- CH5COO- OH OH 10 H2 -COXO heterocyclo R~aR 7 bNCOO- C 6

H

5 COO- OH OH H3 -CONHXO heterocyclo R 7 aR 7 bNCOO- C 6

H

5 COO- OH OH H4 -COOX 1 0 optionally R 7 aR 7 bNCOO- C 6

H

5 COO- OH OH substituted C2 to C8 alkyl H5 -COX 1 0 optionally R 7 aR 7 bNCOO- CH 5 COO- OH OH substituted C2 to C alkyl H6 -CONHX 1 0 optionally RlaR 7 bNCOO- CHCOO- OH OH substituted C2 to C8 alkyl 15 H7 -COOX 1 0 optionally R 7 aR 7 bNCOO- CH 5 COO- OH OH substituted C2 to C, alkenyl H8 -COX 1 0 optionally R 7 aR 7 bNCOO- C 6

H

5 COO- OH OH substituted C2 to C alkenyl WO 01/57013 PCT/USO1/03624 263 H9 -CONHX, optionally R 7 ,RybNCOO- CHCOO- OH OH substituted C2 to C alkenyl H1O -COOXO optionally R 7 ,RybNCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl H11 -COXIO optionally R 7 aRybNCOO- C 6

H

5 COO- OH OH substituted

C

2 to C. alkynyl H12 -CONHX 1 optionally RaR 7 bNCOO- C 6

H

5 COO- OH OH substituted C2 to C alkynyl 5 11 -COOX 1 0 heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- 0 OH 12 -COX 10 heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- 0 OH 13 -CONHXO heterocyclo RyaR 7 bNCOO- R 2 aCOO- 0 OH 14 -COOX 10 optionally RyaR 7 bNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 15 -COXIO optionally R 7 aR 7 bNCOO- R 2 ,COO- 0 OH substituted C2 to C. alkyl 10 16 -CONHX 1 optionally R 7 aR 7 bNCOO- R 2 aCOO- 0 OH substituted C2 to C. alkyl 17 -COOXO optionally R 7 aR 7 bNCOO- R 2 .COO- 0 OH substituted C2 to C. alkenyl 18 -COXO optionally RlR 7 bNCOO- R 2 ,COO- 0 OH substituted C2 to C alkenyl 19 -CONHXO optionally R 7

R

7 bNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkenyl 110 -COOX 1 0 optionally R 7 aR 7 bNCOO- R 2 ,COO- 0 OH substituted C2 to C. alkynyl 15 Il1 -CoX,( optionally R 7 aR 7 bNCOO- R 2 ,COO- 0 OH substituted C2 to C8 alkynyl 112 -CONHX 1 optionally RiR 7 bNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 264 JI -COOX 10 heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- OH OH J2 -COX 1 0 heterocyclo R 7 R-bNCOO- R 2 aCOO- OH OH J3 -CONHX 1 heterocyclo R 7 yR 7 bNCOO- R 2 aCOO- OH OH J4 -COOX 10 optionally R 7 aRybNCOO- R 2 aCOO- OH OH substituted C2 to C8 alkyl 5 J5 -COX 1 0 optionally R 7 aR 7 bNCOO- R 2 aC00- OH OH substituted C2 to C alkyl J6 -CONHX 1 optionally R 7 aR 7 bNCOO- R 2 aCOO- OH OH substituted

C

2 to C alkyl J7 -COOX 10 optionally R 7 aR 7 bNCOO- R 2 COO- OH OH substituted C2 to C alkenyl J8 -COXIO optionally R 7 aR 7 bNCOO- R 2 aCOO- OH OH substituted C2 to C alkenyl J9 -CONHXO optionally RyaR 7 bNCOO- R 2 aCOO- OH OH substituted

C

2 to C alkenyl 10 J10 -COOXO optionally R 7 aR 7 bNCOO- R 2 aCOO- OH OH substituted C2 to C alkynyl Ji1 -COX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- OH OH substituted C2 to C alkynyl J12 -CONHX,, optionally R 7 aR 7 bNCOO- R 2 aCOO- OH OH substituted C2 to C. alkynyl K1 -C00X 10 heterocyclo RlaR 7 bNCOO- R 2 aCOO- R 9 aCOO- OH K2 -COX 10 heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- RqaCOO- OH 15 K3 -CONHX,, heterocyclo R 7 aR 7 bNCOO- R 2 aCOO- RgaCOO- OH K4 -COOX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- R0aCOO- OH substituted C2 to C, alkyl K5 -COX 1 e optionally R 7 aR 7 bNCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C. alkyl WO 01/57013 PCT/USO1/03624 265 K6 -CONHXO optionally R 7 RybNCOO- R 2 COO- RgCOO- OH substituted C2 to C alkyl K7 -COOX, optionally R 7 aR 7 bNCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkenyl K8 -COX 1 0 optionally R 7

,R

7 bNCOO- R 2 ,COO- R 9 aCOO- OH substituted C2 to C. alkenyl K9 -CONHX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkenyl 5 KIO -COOX 1 0 optionally R 7 aRybNCOO- R 2 COO- R,COO- OH substituted C2 to C alkynyl K11 -COX 1 0 optionally Ry 2 RyNOCOO- R 2 ,COO- RgaCOO- OH substituted C2 to C alkynyl K12 -CONHX 1 0 optionally R 7 aR 7 bNCOO- R 2 aCOO- RgCOO- OH substituted C2 to C alkynyl Example 35 : In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCT1 16) were plated in 60 mm Petri dishes containing 10 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 0C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 32 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was 15 added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 0 C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony 20 counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound.

WO 01/57013 PCT/US01/03624 266 Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 5522 <1 5 6404 <10 5415 <1 5800 <10 5575 <1 5385 <1 10 5844 <10 5373 <10 5895 <1 5588 <1 5393 <1 15 6696 <1 5822 <10 5565 <1 6476 <10 5400 <1 20 5747 <10 5535 <1 6399 <10 5757 <10 5665 >50 25 5454 <10 WO 01/57013 PCT/USO1/03624 267 Example 36: Preparation of Taxane having C-10 Carbamoyloxy and C-7 Hydroxy Substituents HO 0 CbzO O H ,- OH CbzCl H01- - OCbz DMAP HO .

HO BzOA O BzU Ac 0 7,1 0-(bis)-carbobenzyloxy-1 0-deacetyl baccatin Ill. To a solution of 10-DAB (1.14 g, 2.11 mmol) in 20 mL of methylene chloride was added DMAP (6.20 g, 5 50.6 mmol) and benzyl chloroformate (1.8 mL, 12.7 mmol) slowly under a nitrogen atmosphere. The mixture was heated to 40-45 oC, kept at this temperature for 2 h, and an additional 1.8 mL (12.7 mmol) of benzyl chloroformate was added. Heating at 40-45 oC was continued for an additional 6 h, the mixture was diluted with 200 mL of CH2Cl2 and washed three times first 10 with 1N HCI and then with saturated sodium bicarbonate solution. The combined washings were extracted three times with 30 mL of CH2CI2, the organic layers were combined, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Chromatography of the residue on silica gel eluting with CH2C2/EtOAc gave 1.48 g (86%) of 7,10-(bis)-carbobenzyloxy-10-deacetyI 15 baccatin Ill. Bocs 0 CbzO O N Boc NH O CbzO - OCbz -' ""OTES - OCbz s"' CI\ S OTES HO LHMDS HO 0BzO 0 BzO Aco AcO O 7,1 0-(bis)-carbobenzyloxy-3'-desphenyl-3'-(2-thienyl)-2'-0-triethylsilyl docetaxel. To a solution of 425 mg (0.523 mmol) of 7,1 0-(bis)-carbobenzyloxy 10-deacetyl baccatin Ill in THF (4.5 mL) at -45 oC under a nitrogen atmosphere was added 0.80 mL of a solution of LHMDS (0.98 M) in THF dropwise. The 20 mixture was kept at -45 oC for I h prior to addition of a solution of 341 mg (0.889 mmol) of cis-N-tbutoxycarbonyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in 2 mL of THF. The mixture was allowed to warm to 0 0C, and after 2 h was poured WO 01/57013 PCT/USO1/03624 268 into 20 mL of saturated ammonium chloride solution. The aqueous layer was extracted three times with 50 mL of EtOAc/Hexanes (1:1) and the organic layers were combined, washed with brine, dried over Na2SO4 and concentrated. Chromatography of the residue on silica gel eluting with EtOAc/Hexanes gave 5 576 mg (92%) of 7,10-(bis)-carbobenzyloxy-3'-desphenyl-3'-(2-thienyl)-2'-O triethylsilyl docetaxel. Bocs CbzO Bocs HO NH 0 O NH 0 O \ sO ., O c bz s O T S - O H HO HO BzOAOO BzOAO 3'-Desphenyl-3'-(2-thienyl)-2'-O-triethylsilyl docetaxel. A suspension of 550 mg of 7,10-(bis)-carbobenzyloxy-3'-desphenyl-3'-(2-thienyl)-2'-O-triethylsilyl docetaxel and 50 mg of 10% Pd/C in 30 mL of EtOH and 10 mL of EtOAc was 10 stirred under a hydrogen atmosphere for 2 h at room temperature. The slurry was filtered through a pad of celite 545 which was then washed with EtOAc. The washings were concentrated and the residue was purified by column chromatography on silica gel using EtOAc/Hexanes as eluent to give 405 mg (95%) of 3'-desphenyl-3'-(2-thienyl)-2'-O-triethylsily docetaxel. BocN HO BocN EtHNCOO NH 0 O NH 0 0 \ O OH EtNCO -- OH O~~~~s\ O6 6TES HO . HO BzA O BzOA6 O 15 3'-Desphenyl-3'-(2-thienyl)-2'-O-triethylsilyl-10-N-ethylcarbamoyl docetaxel. To a slurry of 3'-desphenyl-3'-(2-thienyl)-2'-O-triethylsilyl docetaxel (201 mg, 0.217 mmol) and CuCl (43.0 mg, 0.434 mmol) in THF (3.5 mL) at -15 oC under a nitrogen atmosphere was added a solution of 51.5 mL (0.651 mmol) of ethyl isocynate in 1.9 mL of THF. The mixture was warmed'to 0 oC and after 1.4 h 5mL 20 of saturated aqueous sodium bicarbonate solution and 20 mL of ethyl acetate were added. The water layer was extracted three times with 50 mL of EtOAc/Hexanes (1:1). The organic layers were combined, dried over Na2SO4 and WO 01/57013 PCT/USO1/03624 269 evaporated to give 218 mg of a residue which was used directly without purification. BocN EtHNCOO Boc. EtHNCOO NH 0 0 NH 0 0 , OH O -, OH \ s 6T E S HO\Os OH HO HO .HO . BzOAcO BzOAcOO 3'-Despheny-3'-(2-thienyl)-1 O-N-ethylcarbamoyl docetaxel (2722). To a 5 solution of the 218 mg of 3'-desphenyl-3'-(2-thienyl)-2'-O-triethylsilyl-10-N ethylcarbamoyl docetaxel obtained above in 6 mL of pyridine and 12 mL of CH3CN at 0 oC was added 1.0 mL of 49% aqueous HF. The mixture was warmed to room temperature and after 2.5 h 50 mL of EtOAc was added. The mixture was washed with saturated aqueous sodium bicarbonate solution and brine, dried 10 over sodium sulfate, and concentrated under reduced pressure. Chromatography of the residue on silica gel using CH2CI2/MeOH as eluent gave 169 mg (88% for 2 steps) of 3'-desphenyl-3'-(2-thienyl)-10-N-ethylcarbamoyl docetaxel. Example 37: Taxanes having C-10 Carbamoyloxy and C-7 Hydroxy Substituents The procedures described in Example 36 were repeated, but other suitably 15 protected P-lactams were substituted for the cis-N-tbutoxycarbonyl-3 triethylsilyloxy-4-(2-thienyl) azetidin-2-one of Example 36 to prepare the series of compounds having structural formula (24) and the combinations of substituents identified in the following table. The following table also includes characterization data for certain of these compounds, along with characterization data for the 20 compound (2722) prepared in Example 36. Boc" OCONHEt NH 0 0 X 0OH OH '/ HO . Bzd5 ' Ac O (24) WO 01/57013 PCT/USO1/03624 270 No. X3 m.p. ( 0 C) [a]D(CHCI 3 ) Elemental Analysis 2600 2-pyridyl 173-175 -71.4 (c 0.22) Found: C, 60.70; H, 6.69 (Calcd. for C4 5

H

57 NO,,.0.5H 2 0: C, 60.79; H, 6.58) 2616 3-pyridyl 183-185 -61.0 (c 0.20) Found: C, 58.96; H, 6.51 (Calcd. for C4 5

H

57

NO

1 .2H 2 0: C, 59.00; H, 6.69) 2622 3-thienyl 173-175 -68.1 (c 0.19) Found: C, 58.40; H, 6.42 (Calcd. for C 44

H,,N

2 0,,S.H 2 0: C, 58.47; H, 6.47) 2633 i-propyl 170-172 -75.7 (c 0.22) Found: C, 60.10; H, 7.15 (Calcd. for C 43

H

6

N

2 0j,.H 2 0: C, 59.84; H, 7.24) 2686 i-butenyl 167-169 -106.7 (c 0.17) Found: C, 61.12; H, 7.10 (Calcd, for C 44

HON

2 0 1 .0.5H 2 0: C, 61.02; H, 7.10) 2692 4-pyridyl 203-205 -69.7 (c 0.18) Found: C, 60.19; H, 6.61 (Calcd. for C 4

,H

5 7

N

3 0 15

.H

2 0: C, 60.13; H, 6.62) 2700 2-furyl 169-171 -73.6 (c 0.22) Found: C, 60.59; H, 6.58 (Calcd. for C 4 4

H,,N

2 0,,: C, 60.82; H, 6.50) 2717 3-furyl 165-167 -53.8 (c 0.23) Found: C, 60.07; H, 6.48 (Calcd. for C 44

H,,N

2 0 1 .0.5H 2 0: C, 60.14; H, 6.54) 2722 2-thienyl 166-168 -52.2 (c 0.25) Found: C, 58.28; H, 6.32 (Calcd. for C 44

H

5

,N

2 0 1 5

S.H

2 0: C, 58.47; H, 6.47) 2733 cyclobutyl 168-170 -73.9 (c 0.23) Found: C, 60.96; H, 7.02 (Calcd. for C 44

H

6

ON

2 0 15 .0.5H 2 0: C, 61.02; H, 7.10) 2757 cyclopropyl 168-170 -91.7 (c 0.23) Found: C, 60.07; H, 6.86 (Calcd. for C 43

H,

8

N

2 0 15

.H

2 0: C, 59.98; H, 7.02) Example 38: Taxanes Having C-10 Carbomoyloxy and C-7 Hydroxy Substituents The procedures described in Example 36 were repeated, but other suitably protected p-lactams were substituted for the P-lactam of Example 36 to prepare the series of compounds having structural formula (25) and the combinations of substituents identified in the following table.

WO 01/57013 PCT/US01/03624 271

X

5 NH 0

R

10 0 OH X3- 0 : O , OH 5HH HO . AcO (25) Compound X, X3 RIO 2640 tBuOCO- phenyl EtNHCOO 2743 tBuOCO- p-nitrophenyl EtNHCOO 6015 tC 3

H

5 CO- 2-furyl 3,4diFPhNHCOO 6024 tC 3

H

5 CO- 2-furyl PhNHCOO 6072 tC 3

H

5 CO- 2-furyl EtNHCOO Example 39: Additional Taxanes having C-10 Carbamoyloxy and C-7 Hydroxy Substituents Following the processes described in Example 36 and elsewhere herein, the following specific taxanes having structural formula (26) may be prepared, wherein R 7 is as previously defined including wherein R 1 0 is RaRbNCOO- and (a) Ra and Rb are each hydrogen, (b) one of Ra and Rb is hydrogen and the other is (i) substituted or unsubstituted C1 to C alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C3 to C alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C3 to C alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, or (c) Ra and Rb are independently (i) substituted or unsubstituted C, to C alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. For example, R,, may be R RNCOO- wherein one of R, and Rb is hydrogen and the other is WO 01/57013 PCT/USO1/03624 272 methyl, ethyl, or straight, branched or cyclic propyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl.

X

5 NHO R1 X 3 Ole ., O H OOH OH "', HO . o AcO (26) X5 X3 Rio tBuOCO 2-furyl RaRbNCOO tBuOCO 3-furyl RaRbNCOO tBuOCO 2-thienyl RaRbNCOO tBuOCO 3-thienyl RaRbNCOO tBuOCO 2-pyridyl RaRbNCOO tBuOCO. 3-pyridyl RaRbNCOO tBuOCO 4-pyridyl RaRbNCOO tBuOCO isobutenyl RaRbNCOO tBuOCO isopropyl RaRbNCOO tBuOCO cyclopropyl RaRbNCOO tBuOCO cyclobutyl RaRbNCOO tBuOCO cyclopentyl RaRbNCOO tBuOCO phenyl RaRbNCOO benzoyl 2-furyl RaRbNCOO benzoyl 3-furyl RaRbNCOO benzoyl 2-thienyl RaRbNCOO benzoyl 3-thienyl RaRbNCOO benzoyl 2-pyridyl RaRbNCOO benzoyl 3-pyridyl RaRbNCOO benzoyl 4-pyridyl RaRbNCOO benzoyl isobutenyl RaRbNCOO benzoyl isopropyl RaRbNCOO- WO 01/57013 PCT/USO1/03624 273 benzoyl cyclopropyl RaRbNCOO benzoyl cyclobutyl RaRbNCOO benzoyl cyclopentyl RaRbNCOO benzoyl phenyl RaRbNCOO 2-FuCO- 2-furyl RaRbNCOO 2-FuCO- 3-furyl RaRbNCOO 2-FuCO- 2-thienyl RaRbNCOO 2-FuCO- 3-thienyl RaRbNCOO 2-FuCO- 2-pyridyl RaRbNCOO 2-FuCO- 3-pyridyl RaRbNCOO 2-FuCO- 4-pyridyl RaRbNCOO 2-FuCO- isobutenyl RaRbNCOO 2-FuCO- isopropyl RaRbNCOO 2-FuCO- cyclopropyl RaRbNCOO 2-FuCO- cyclobutyl RaRbNCOO 2-FuCO- cyclopentyl RaRbNCOO 2-FuCO- phenyl RaRbNCOO 2-ThCO- 2-furyl RaRbNCOO 2-ThCO- 3-furyl RaRbNCOO 2-ThCO- 2-thienyl RaRbNCOO 2-ThCO- 3-thienyl RaRbNCOO 2-ThCO- 2-pyridyl RaRbNCOO 2-ThCO- 3-pyridyl RaRbNCOO 2-ThCO- 4-pyridyl RaRbNCOO 2-ThCO- isobutenyl RaRbNCOO 2-ThCO- isopropyl RaRbNCOO 2-ThCO- cyclopropyl RaRbNCOO 2-ThCO- cyclobutyl RaRbNCOO 2-ThCO- cyclopentyl RaRbNCOO 2-ThCO- phenyl RaRbNCOO 2-PyCO- 2-furyl RaRbNCOO 2-PyCO- 3-furyl RaRbNCOO- WO 01/57013 PCT/USO1/03624 274 2-PyCO- 2-thienyl RaRbNCOO 2-PyCO- 3-thienyl RaRbNCOO 2-PyCO- 2-pyridyl RaRbNCOO 2-PyCO- 3-pyridyl RaRbNCOO 2-PyCO- 4-pyridyl RaRbNCOO 2-PyCO- isobutenyl RaRbNCOO 2-PyCO- isopropyl RaRbNCOO 2-PyCO- cyclopropyl RaRbNCOO 2-PyCO- cyclobutyl RaRbNCOO 2-PyCO- cyclopentyl RaRbNCOO 2-PyCO- phenyl R 2 RbNCOO 3-PyCO- 2-furyl R.RbNCOO 3-PyCO- 3-furyl RaRbNCOO 3-PyCO- 2-thienyl RaRbNCOO 3-PyCO- 3-thienyl RaRbNCOO 3-PyCO- 2-pyridyl RaRbNCOO 3-PyCO- 3-pyridyl RaRbNCOO 3-PyCO- 4-pyridyl RaRbNCOO 3-PyCO- isobutenyl RaRbNCOO 3-PyCO- isopropyl RaRbNCOO 3-PyCO- cyclopropyl RaRbNCOO 3-PyCO- cyclobutyl RaRbNCOO 3-PyCO- cyclopentyl RaRbNCOO 3-PyCO- phenyl RaRbNCOO 4-PyCO- 2-furyl RaRbNCOO 4-PyCO- 3-furyl RaRbNCOO 4-PyCO- 2-thienyl RaRbNCOO 4-PyCO- 3-thienyl RaRbNCOO 4-PyCO- 2-pyridyl RaRbNCOO 4-PyCO- 3-pyridyl RaRbNCOO 4-PyCO- 4-pyridyl RaRbNCOO 4-PyCO- isobutenyl RaRbNCOO- WO 01/57013 PCT/USO1/03624 275 4-PyCO- isopropyl RaRbNCOO 4-PyCO- cyclopropyl RaRbNCOO 4-PyCO- cyclobutyl RaRbNCOO 4-PyCO- cyclopentyl RaRbNCOO 4-PyCO- phenyl RaRbNCOO

C

4

H

7 CO- 2-furyl RaRbNCOO

C

4

H

7 CO- 3-furyl RaRbNCOO

C

4

H

7 CO- 2-thienyl RaRbNCOO

C

4

H

7 CO- 3-thienyl RaRbNCOO

C

4

H

7 CO- 2-pyridyl RaRbNCOO

C

4

H

7 CO- 3-pyridyl RaRbNCOO

C

4

H

7 CO- 4-pyridyl RaRbNCOO

C

4

H

7 CO- isobutenyl RaRbNCOO

C

4

H

7 CO- isopropyl RaRbNCOO

C

4

H

7 CO- cyclopropyl RaRbNCOO

C

4

H

7 CO- cyclobutyl RaRbNCOO

C

4

H

7 CO- cyclopentyl RaRbNCOO

C

4

H

7 CO- phenyl RaRbNCOO EtOCO- 2-furyl RaRbNCOO EtOCO- 3-furyl RaRbNCOO EtOCO- 2-thienyl RaRbNCOO EtOCO- 3-thienyl RaRbNCOO EtOCO- 2-pyridyl RaRbNCOO EtOCO- 3-pyridyl RaRbNCOO EtOCO- 4-pyridyl RaRbNCOO EtOCO- isobutenyl RaRbNCOO EtOCO- isopropyl RaRbNCOO EtOCO- cyclopropyl RaRbNCOO EtOCO- cyclobutyl RaRbNCOO EtOCO- cyclopentyl RaRbNCOO EtOCO- phenyl RARbNCOO ibueCO- 2-furyl RaRbNCOO- WO 01/57013 PCT/USO1/03624 276 ibueCO- 3-furyl RaRbNCOO ibueCO- 2-thienyl RaRbNCOO ibueCO- 3-thienyl RaRbNCOO ibueCO- 2-pyridyl RaRbNCOO ibueCO- 3-pyridyl RaRbNCOO ibueCO- 4-pyridyl RaRbNCOO ibueCO- isobutenyl RaRbNCOO ibueCO- isopropyl RaRbNCOO ibueCO- cyclopropyl RaRbNCOO ibueCO- cyclobutyl RaRbNCOO ibueCO- cyclopentyl RaRbNCOO ibueCO- phenyl RaRbNCOO iBuCO- 2-furyl RaRbNCOO iBuCO- 3-furyl RaRbNCOO iBuCO- 2-thienyl RaRbNCOO iBuCO- 3-thienyl RaRbNCOO iBuCO- 2-pyridyl RaRbNCOO iBuCO- 3-pyridyl RaRbNCOO iBuCO- 4-pyridyl RaRbNCOO iBuCO- isobutenyl RaRbNCOO iBuCO- isopropyl RaRbNCOO iBuCO- cyclopropyl RaRbNCOO iBuCO- cyclobutyl RaRbNCOO iBuCO- cyclopentyl RaRbNCOO iBuCO- phenyl RaRbNCOO iBuOCO- 2-furyl RaRbNCOO iBuOCO- 3-furyl RaRbNCOO iBuOCO- 2-thienyl RaRbNCOO iBuOCO- 3-thienyl RaRbNCOO iBuOCO- 2-pyridyl RaRbNCOO iBuOCO- 3-pyridyl RaRbNCOO iBuOCO- 4-pyridyl RaRbNCOO- WO 01/57013 PCT/USO1/03624 277 iBuOCO- isobutenyl RaRbNCOO iBuOCO- isopropyl RaRbNCOO iBuOCO- cyclopropyl RaRbNCOO iBuOCO- cyclobutyl RaRbNCOO iBuOCO- cyclopentyl RaRbNCOO iBuOCO- phenyl RaRbNCOO iPrOCO- 2-furyl RaRbNCOO iPrOCO- 3-furyl RaRbNCOO iPrOCO- 2-thienyl RaRbNCOO iPrOCO- 3-thienyl RaRbNCOO iPrOCO- 2-pyridyl RaRbNCOO iPrOCO- 3-pyridyl RaRbNCOO iPrOCO- 4-pyridyl RaRbNCOO iPrOCO- isobutenyl RaRbNCOO iPrOCO- isopropyI RaRbNCOO iPrOCO- cyclopropyl RaRbNCOO iPrOCO- cyclobutyl RaRbNCOO iPrOCO- cyclopentyl RaRbNCOO iPrOCO- phenyl RaRbNCOO nPrOCO- 2-furyl RaRbNCOO nPrOCO- 3-furyl RaRbNCOO nPrOCO- 2-thienyl RaRbNCOO nPrOCO- 3-thienyl RaRbNCOO nPrOCO- 2-pyridyl RaRbNCOO nPrOCO- 3-pyridyl RaRbNCOO nPrOCO- 4-pyridyl RaRbNCOO nPrOCO- isobutenyl RaRbNCOO nPrOCO- isopropyl RaRbNCOO nPrOCO- cyclopropyl RaRbNCOO nPrOCO- cyclobutyl RaRbNCOO nPrOCO- cyclopentyl RaRbNCOO nPrOCO- phenyl RaRbNCOO- WO 01/57013 PCT/US01/03624 278 nPrCO- 2-furyl RaRbNCOO nPrCO- 3-furyl RaRbNCOO nPrCO- 2-thienyl RaRbNCOO nPrCO- 3-thienyl RaRbNCOO nPrCO- 2-pyridyl RaRbNCOO nPrCO- 3-pyridyl RaRbNCOO nPrCO- 4-pyridyl RaRbNCOO nPrCO- isobutenyl RaRbNCOO nPrCO- isopropyl RaRbNCOO nPrCO- cyclopropyl RaRbNCOO nPrCO- cyclobutyl RaRbNCOO nPrCO- cyclopentyl RaRbNCOO nPrCO- phenyl RaRbNCOO Example 40: Additional Taxanes having C-10 Carbamoyloxy and C-7 Hydroxy Substituents Following the processes described in Example 36 and elsewhere herein, the following specific taxanes having structural formula (27) may be prepared, wherein R 7 is hydroxy and R 1 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R 1 0 is R1OaRjObNCOO- and one of R1 0 a and R1Ob is hydrogen and the other is (i) substituted or unsubstituted C1 to C alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C2 to C alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C2 to C8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substituted phenyl such as nitro, alkoxy or halosubstituted phenyl, or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl. In one embodiment, preferred R 1 substituents include R1OaRObNC00- wherein one of R1Oa and ROb is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R 1 0 substituents include R1OaRlObNCOO- wherein one of R 10 2 and RiOb is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl.

WO 01/57013 PCT/US01/03624 279 In the "A" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyi, or pyridyl, X 1 0 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 and R 1 0 each have the beta stereochemical configuration. In the "B" series of compounds, X 1 0 and R 2 , are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 , is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and R 1 each have the beta stereochemical configuration. In the "C" series of compounds, X,, and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rga is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. In the "D" and "E" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R 7 , R 9 (series D only) and R 1 each have the beta stereochemical configuration. In the "F" series of compounds, X1 0 , R 2 a and Ra are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R, and R 1 0 each have the beta stereochemical configuration. In the "G" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 0 each have the beta stereochemical configuration. In the "H" series of compounds, X 1 0 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, WO 01/57013 PCT/US01/03624 280 thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and RIO each have the beta stereochemical configuration. In the "I" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 and Rio each have the beta stereochemical configuration. In the "J" series of compounds, X 1 0 and R 2 a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and RIO each have the beta stereochemical configuration. In the "K" series of compounds, XIO, R 2 a and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X 1 0 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R 2 a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R 7 , R. and R 1 each have the beta stereochemical configuration. Any substituents of each of X 3 , X 5 , R 2 , R 7 , and R 9 may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.

X

5 NH O

R

10 X3 Om 0 .7 OH

R

14 HO . R2 0 OAc (27) Series X. X Rio R 2

R

9 RU Al -C00X 0 heterocyclo R10,RjebNCOO- C 6

H

5 COO- O H A2 -COX 1 0 heterocyclo RjOaRlObNCOO- C 6

H

5 C00O- 0 H WO 01/57013 PCT/USO1/03624 281 A3 -CONHX, heterocyclo RIOR1ObNCOO- CH 5 COO- 0 H A4 -COOXIO optionally RIoaRObNCOO- C 6

H

5 COO- 0 H substituted C2 to C alkyl A5 -COX 1 0 optionally R1OaRIObNCOO- CHCOO- 0 H substituted C2 to C alkyl A6 -CONHXIO optionally R1OaRIObNCOO- C 6

H

5 COO- 0 H substituted C2 to C. alkyl A7 -COOX 1 0 optionally RIOaRjObNCOO- CH 5 COO- 0 H substituted C2 to C8 alkenyl A8 -COXIO optionally RlOaR1ObNCOO- CH 5 COO- 0 H substituted C2 to C8 alkenyl A9 -CONHXIO optionally R1OaRlObNCOO- CH 5 COO- 0 H substituted C2 to C8 alkenyl Al0 -COOX 10 optionally RlOaRlObNCOO- CHCOO- 0 H substituted C2 to C alkynyl All -COX 10 optionally RlOaRlObNCOO- CH 5 COO- 0 H substituted C2 to C alkynyl A12 -CONHX 10 optionally R1OaRlObNCOO- C 6

H

5 COO- 0 H substituted C2 to C alkynyl B1 -C00X 1 0 heterocyclo R1OaRlObNCOO- R 2 aCOO- 0 H B2 -COX 10 heterocyclo RIOaRlObNCOO- R 2 aCOO- 0 H B3 -CONHXIO heterocyclo RIOaRlObNCOO- R 2 aCOO- 0 H B4 -COOXO optionally RIOaRlObNCOO- R 2 ,C00- 0 H substituted C2 to C alkyl B5 -COX 1 e optionally R1OaRIObNCOO- R 2 aCOO- 0 H substituted C2 to C8 alkyl WO 01/57013 PCT/USO1/03624 282 B6 -CONHX 1 optionally R1OaR1ObNCOO- R 2 aCOO- 0 H substituted

C

2 to C alkyl B7 -COOXO optionally RlOaRlObNCOO- R 2 aCOO- 0 H substituted C2 to C8 alkenyl B8 -COXIO optionally RIOaRObNCOO- R 2 aCOO- 0 H substituted C2 to C8 alkenyl B9 -CONHX 1 optionally R1OaRlObNCOO- R 2 COO- 0 H substituted C2 to C alkenyl B10 -COOX 1 0 optionally RIOaRIObNCOO- R 2 aCOO- 0 H substituted C2 to C8 alkynyl B11 -COX 10 optionally R1OaR10NCOO- R 2 aCOO- 0 H substituted C2 to C alkynyl B12 -CONHX,, optionally R1oR1obNCOO- R 2 aCOO- 0 H substituted C2 to C alkynyl C1 -COOX 10 heterocyclo R1OaRjObNCOO- C6H 5 COO- RgaCOO- H C2 -COX 1 0 heterocyclo R10,R10NCO- C 6

H

5 COO- R 9 aCOO- H C3 -CONHX, heterocyclo R1OaR1ObNCOO- CH 5 COO- R 9 aCOO- H C4 -COOXO optionally RIOaRIObNCOO- C6H 5 COO- RgaCOO- H substituted C2 to C alkyl C5 -COX 1 e optionally RIoaRlObNCOO- CHCOO- R 9 aCOO- H substituted C2 to C alkyl C6 -CONHXI 0 optionally RlOR1ObNCOO- C 6

H

5 COO- R 9 aCOO- H substituted C2 to C alkyl C7 -COOX 1 0 optionally R1OaRlObNCOO- C 6

H

5 COO- R 9 aCOO- H substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 283 C8 -COX1 0 optionally RlOaRlObNCOO- C 6 HCOO- R 0,COO- H substituted C2 to C 8 alkenyl C9 -CONHX 10 optionally R1OaRIObNCOO- C 6 HCOO- RgCOO- H substituted C2 to C alkenyl C10 -COOX 1 0 optionally RIOeRlObNCOO- CH 5 COO- RgaCOO- H substituted C2 to C8 alkynyl C11 -COXO optionally ROaRObNCOO- CH 5 COO- RgaCOO- H substituted C2 to C8 alkynyl C12 -CONHX, optionally R1OaRIObNCOO- C 6 HCOO- RgaCOO- H substituted C2 to C8 alkynyl D1 -COOX 1 0 heterocyclo RlOaR,ObNCOO- C6HCOO- OH H D2 -COX 1 0 heterocyclo RIOaRIObNCOO- CHCOO- OH H D3 -CONHX 1 heterocyclo RIOaRlObNCOO- CHCOO- OH H D4 -COOX 1 0 optionally RIOaRIObNCOO- C 6

H

5 COO- OH H substituted C2 to C alkyl D5 -COX 1 0 optionally RIOaRlObNCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkyl D6 -CONHXO optionally RIOaRIObNCOO- CHCOO- OH H substituted C2 to C8 alkyl D7 -COOX 10 optionally R1ORl0bNCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkenyl D8 -COX 1 0 optionally R1OaRIObNCOO- C 6 H5COO- OH H substituted C2 to C8 alkenyl D9 -CONHX 1 optionally RoaRIObNCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkenyl WO 01/57013 PCT/USO1/03624 284 D10 -COOX 1 0 optionally RioRlObNCOO- CH 5 COO- OH H substituted C2 to C8 alkynyl Dl -COX 1 optionally R1oaR1ObNCOO- C 6

H

5 COO- OH H substituted C2 to C8 alkynyl D12 -CONHX 1 e optionally R1OaRIObNCOO- CH 5 COO- OH H substituted C2 to C, alkynyl El -COOXO heterocyclo R1OaRIObNCOO- CH 5 COO- 0 OH E2 -COX 1 0 heterocyclo R1OaRIObNCOO- CH 5 COO- 0 OH E3 -CONHX 1 heterocyclo R1OaRlObNCOO- C 6

H

5 COO- 0 OH E4 -COOX 1 0 optionally R1OaR10bNCOO- CH 5 COO- 0 OH substituted C2 to C alkyl E5 -COX 1 0 optionally RIOaR1ObNCOO- C 6

H

5 COO- 0 OH substituted C2 to C 8 alkyl E6 -CONHX 1 e optionally R1OaR10bNCOO- C6H 5 COO- 0 OH substituted C2 to C alkyl E7 -COOX 10 optionally RlOR1ObNCOO- CH 5 COO- 0 OH substituted C2 to C8 alkenyl E8 -COX 1 0 optionally R1ORIObNCOO0- CH 5 COO- 0 OH substituted C2 to C8 alkenyl E9 -CONHX,, optionally R1,eRIObNCOO- C 8 HCOO- 0 OH substituted C2 to C8 alkenyl E10 -C00X 10 optionally R1OaR1ObNCOO- CH 5 COO- 0 OH substituted C2 to C8 alkynyl El1 -COX 1 0 optionally ROaRlObNC0OO- CH 5 COO- 0 OH substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 285 E12 -CONHX, optionally R1OaRlObNCOO- CH 5 COO- 0 OH substituted C2 to C8 alkynyl F1 -COOX 1 0 heterocyclo R1OaRIObNCOO- R 2 aCOO- RaCOO- H F2 -COXIO heterocyclo R1OaRIObNCOO- R 2 COO- RgCOO- H F3 -CONHXIO heterocyclo R1O.RIObNCOO- R 2 aCOO- RgzCOO- H F4 -COOX 0 optionally R1ORIObNCOO- R 2 COO- R 9 aCOO- H substituted C2 to C alkyl F5 -COX 1 0 optionally RIOaRlObNCOO- R 2 aCOO- RgCOO- H substituted C2 to C. alkyl F6 -CONHXIO optionally R1OaRlObNCOO- R 2 aCOO- R 9 COO- H substituted C2 to C, alkyl F7 -COOX 10 optionally RIOaR1ObNCOO- R 2 aCOO- RgaCOO- H substituted C2 to C8 alkenyl F8 -COXIO optionally RIOR1ObNCOO- R 2 COO- R 9 aCOO- H substituted C2 to C8 alkenyl F9 -CONHX 1 optionally R1OaR1ObNCOO- R 2 aCOO- R 9 aCOO- H substituted C2 to C8 alkenyl F10 -COOXIO optionally R1OaR1obNCOO- R 2 aCOO- RaCOO- H substituted C2 to C alkynyl F11 -COX 1 0 optionally ROaR1ObNCOO- R 2 aCOO- RgCOO- H substituted C2 to C8 alkynyl F12 -CONHX 1 optionally R1OaR1ObNCOO- R 2 aCOO- RgzCOO- H substituted C2 to C8 alkynyl G1 -COOX 1 0 heterocyclo R1OaRjObNCOO- R 2 aCOO- OH H G2 -COX 1 e heterocyclo R1OaRlObNCOO- R 2 aCOO- OH H G3 -CONHX 1 , heterocyclo R1OaR10bNCOO- R 2 aCOO- OH H WO 01/57013 PCT/USO1/03624 286 G4 -COOXIO optionally RIOaRObNCOO- R 2 ,COO- OH H substituted C2 to C alkyl G5 -COXIO optionally R1oRIObNCOO- R 2 aCOO- OH H substituted C2 to C 8 alkyl G6 -CONHXO optionally RlOaRlObNCOO- R 2 aCOO- OH H substituted C2 to C alkyl G7 -COOX 1 0 optionally RIOaRlObNCOO- R 2 aCOO- OH H substituted C2 to C8 alkenyl G8 -COX 1 e optionally RiOaRlObNCOO- R 2 aCOO- OH H substituted C2 to C8 alkenyl G9 -CONHXIO optionally ROaRIObNCOO- R 2 aCOO- OH H substituted C2 to C8 alkenyl G10 -COOX 1 optionally R1OaRjobNCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl G11 -COXIO optionally RlOaRIObNCOO- R 2 aCOO- OH H substituted C2 to C8 alkynyl G12 -CONHX 1 optionally RIOaRlObNCOO- R 2 C00- OH H substituted C2 to C1 alkynyl H1 -COOXO heterocyclo R1OaRIObNCOO- C 6

H

5 COO- OH OH H2 -COX 10 heterocyclo R1OaRjObNCOO- C 6

H

5 COO- OH OH H3 -CONHX 10 heterocyclo R1OaRlObNCOO- C 6

H

5 COO- OH OH H4 -COOXO optionally RjOaRjObNCOO- C 6

H

5 COO- OH OH substituted C2 to C alkyl H5 -COXIO optionally R1OaRjObNCOO- C 6 HCOO- OH OH substituted C2 to C alkyl H6 -CONHX 1 optionally RIOaRjObNCOO- C 6

H

5 COO- OH OH substituted C2 to C. alkyl __ WO 01/57013 PCT/USO1/03624 287 H7 -COOX 1 0 optionally RioRlObNCOO- C6H 5 COO- OH OH substituted C2 to C8 alkenyl H8 -COXO optionally R1OaRIObNCOO- CH 5 COO- OH OH substituted C2 to C8 alkenyl H9 -CONHXO optionally R1OaRjObNCOO- C6H 5 COO- OH OH substituted C2 to C alkenyl HIO -COOX 1 0 optionally R1OaRIObNCOO- CH 5 COO- OH OH substituted C2 to C8 alkynyl H11 -COXIO optionally RloR,ObNCOO- CHCOO- OH OH substituted C2 to C8 alkynyl H12 -CONHX 1 optionally R1OaRIObNCOO- C 6 HCOO- OH OH substituted C2 to C alkynyl 11 -COOX 1 0 heterocyclo R1OaRIObNCOO- R 2 aCOO~ 0 OH 12 -COXIO heterocyclo ROaRIObNCOO- R 2 aCOO- 0 OH 13 -CONHX,, heterocyclo R1O.R,ObNCOO- R 2 COO- 0 OH 14 -COOX 1 0 optionally RIOaRObNCOO- R 2 aCOO- 0 OH substituted C2 to C, alkyl 15 -COX 1 0 optionally RIOaRIObNCOO- R 2 aCOO- 0 OH substituted C2 to C alkyl 16 -CONHX 1 optionally RloR1obNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkyl 17 -COOX 1 0 optionally R1OaRIObNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkenyl 18 -COXO optionally R1OaRlObNCOO- R 2 COO- 0 OH substituted C2 to C3 alkenyl WO 01/57013 PCT/USO1/03624 288 19 -CONHX, optionally RIOaRlObNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkenyl 110 -COOXIo optionally RIO 2 RIObNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkynyl ill -COXIO optionally RjOaRlObNCOO- R 2 COO- 0 OH substituted C2 to C8 alkynyl 112 -CONHX 1 optionally RloaRlObNCOO- R 2 aCOO- 0 OH substituted C2 to C8 alkynyl J1 -COOX 10 heterocyclo RlOaRIObNCOO- R 2 aCOO- OH OH J2 -COX 1 0 heterocyclo R1OaRIObNCOO- R 2 aCOO- OH OH J3 -CONHX 1 heterocyclo RiOaRlebNCOO- R 2 aCOO- OH OH J4 -COOXO optionally RIGOR1ObNCOO- R 2 aCOO- OH OH substituted C2 to C alkyl J5 -COX 1 0 optionally RIOaRIObNCOO- R 2 aCOO- OH OH substituted C2 to C alkyl J6 -CONHX 1 optionally RlOaRlObNCOO- R 2 aCOO- OH OH substituted C2 to C, alkyl J7 -COOX 10 optionally RlOaRlObNCOO- R 2 aCOO- OH OH substituted C2 to C8 alkenyl J8 -COX 10 optionally RIOaRlObNCOO- R 2 aCOO- OH OH substituted C2 to C8 alkenyl J9 -CONHXO optionally RIOaRlObNCOO- R 2 aCOO- OH OH substituted C2 to C8 alkenyl J10 -COOXIO optionally RIO 6 RIObNCOO- R 2 aCOO- OH OH substituted C2 to c L _ alkynyl WO 01/57013 PCT/USO1/03624 289 Ji1 -COXID optionally RlOaR,ObNCOO- R 2 ,COO- OH OH substituted C2 to C 8 alkynyl J12 -CONHX 10 optionally R1OaR1ObNCOO- R 2 aCOO- OH OH substituted C2 to C8 alkynyl K1 -COOX 1 0 heterocyclo RIOaRlObNCOO- R 2 aCOO- ReaCOO- OH K2 -COXIO heterocyclo R1OaRIObNCOO- R 2 aCOO- RgaCOO- OH K3 -CONHX, heterocyclo RIoRIObNCOO- R 2 ,COO- R 0,COO- OH K4 -C00X 10 optionally RlOaRlObNCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C alkyl K5 -COX 10 optionally R1O.RIObNCOO- R 2 aCOO- RgCOO- OH substituted C2 to C alkyl K6 -CONHX 1 optionally R1OaRlObNCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C alkyl K7 -COOX 10 optionally R1OaRlObNCOO- R 2 aCOO- R 9 aCOO- OH substituted C2 to C8 alkenyl K8 -COX 10 optionally RlO 2 R,obNCOO- R 2 aCOO- ReCOO- OH substituted C2 to C8 alkenyl K9 -CONHXIO optionally RIOaRlObNCOO- R 2 aCOO- ReCOO- OH substituted C2 to C8 alkenyl K10 -COOX 10 optionally RIOaRIObNCOO- R 2 ,COO- R 9 COO- OH substituted C2 to C alkynyl K11 -COX 1 0 optionally R1OaR1ObNCOO- R 2 aCOO- RgaCOO- OH substituted C2 to C8 alkynyl K12 -CONHX 10 optionally R1oRoNCOO~ R 2 COO- RgCOO- OH substituted C2 to C8 alkynyl WO 01/57013 PCT/USO1/03624 290 Example 41: In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCTI 16) were plated in 60 mm Petri dishes containing 2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a C02 incubator at 37 0C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 37 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 * C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony counter after incubation for 7 days. Cell survival was calculated and the values of ID50 (the drug concentration producing 50% inhibition of colony formation) were determined for each tested compound. Compound IN VITRO ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 2600 <1 2616 27 2622 <1 2633 <10 2686 <1 2692 <1 2700 <1 2717 <1 2722 <1 2733 <10 2757 <1 2640 <1 2743 <1 6015 <10 WO 01/57013 PCT/USO1/03624 291 6024 <1 6072 <1 Example 42: Preparation of Solutions for Oral Administration Solution 1: Antitumor compound 1393 was dissolved in ethanol to form a solution containing 140 mg of the compound per ml of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 70 mg of compound 1393 per ml. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 2: Antitumor compound 1458 was dissolved in ethanol to form a solution containing 310 mg of the compound per mi of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 155 mg of compound 1458 per ml. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 3: Antitumor compound 1351 was dissolved in ethanol to form a solution containing 145 mg of the compound per mi of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 72.5 mg of compound 1351 per ml. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 4: Antitumor compound 4017 was dissolved in ethanol to form a solution containing 214 mg of the compound per mi of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 107 mg of compound 4017 per ml. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 5: Antitumor compound 1393 was dissolved in 100% ethanol then mixed with an equal volume of Cremophor@ EL solution to form a solution containing 70 mg of compound 1393 per ml. This solution was diluted using 9 parts by weight of D%W (an aqueous solution containing 5 % weight by volume of dextrose) or WO 01/57013 PCT/USO1/03624 292 0.9% saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 6: Antitumor compound 1771 was dissolved in ethanol to form a solution containing 145 mg of the compound per ml of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 72.5 mg of compound 1771 per ml of solution. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 7: Antitumor compound 1781 was dissolved in ethanol to form a solution containing 98 mg of the compound per ml of solution. An equal volume of Cremophor@ EL was added to the solution while stirring to form an solution containing 49 mg of compound 1781 per ml of solution. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 8: Antitumor compound 0499 was dissolved in ethanol to form a solution containing 106 mg of the compound per ml of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 53 mg of compound 0499 per ml of solution. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 9: Antitumor compound 0550 was dissolved in ethanol to form a solution containing 140 mg of the compound per ml of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 70 mg of compound 0550 per ml of solution. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Solution 10: Antitumor compound 0611 was dissolved in ethanol to form a solution containing 150 mg of the compound per ml of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 75 mg of compound 0611 per ml of solution. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient.

WO 01/57013 PCT/USO1/03624 293 Solution 11: Antitumor compound 0748 was dissolved in ethanol to form a solution containing 266 mg of the compound per ml of solution. An equal volume of Cremophor@ EL solution was added to the solution while stirring to form a solution containing 133 mg of compound 0748 per ml of solution. This solution was diluted using 9 parts by weight of saline to form a pharmaceutically acceptable solution for administration to a patient. Example 43: Preparation of a Suspension Containing Compound 1393 for Oral Administration An oral composition of antitumor compound 1393 was prepared by suspending 25 mg of compound 1393 as a fine powder in one ml of carrier containing 1% carboxymethylcellulose (CMC) in deionized water. Example 44: Preparation of a Tablet Containing Compound 1393 for Oral Administration Antitumor compound 1393 (100 mg) was dissolved in methylene chloride (2 ml) and Cremophor@ EL solution (1 00mg) was added. The methylene chloride was evaporated under vacuum to form a glass. Microcrystalline cellulose (600 mg) was added to the glass and mixed to form a powder which can be processed to form a tablet. Example 45: Preparation of Emulsions Containing Compound 1393 for Parenteral Administration Emulsion 1: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 40 mg of compound 1393 per ml of the solution. The solution was then diluted with 19 parts by weight of Liposyn@ 11(20%) with stirring to form an emulsion containing 2 mg of compound 1393 per ml for parenteral administration. Emulsion 2: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 40 mg of compound 1393 per ml of the solution. The solution was then diluted with 19 parts by weight of Liposyn@ II (2%) with stirring to form an emulsion containing 2 mg of compound 1393 per ml for parenteral administration. Emulsion 3: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing mg of compound 1393 per ml of the solution. The solution WO 01/57013 PCT/USO1/03624 294 was then diluted with 9 parts by weight of Liposyn@ 111 (2%) with stirring to form an emulsion containing 4 mg of compound 1393 per ml for parenteral administration. Example 46: Preparation of Solutions Containing Compound 1393 for Parenteral Administration Solution 1: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 140 mg of compound 1393 per ml. The solution was then diluted with an equal volume of Cremophor@ EL solution with stirring and was then diluted with 9 parts by weight of normal saline to form a solution containing 7 mg of compound 1393 per ml of solution for parenteral administration. Solution 2: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 140 mg of compound 1393 per ml of the solution. The solution was then diluted with an equal volume of Cremophor@ EL solution with stirring and was then diluted with 4 parts by weight of normal saline to form a solution containing 11.7 mg of compound 1393 per ml of solution for parenteral administration. Solution 3: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 140 mg of compound 1393 per ml of the solution. The solution was then diluted with an equal volume of Cremophor@ EL solution with stirring and was then diluted with 2.33 parts by weight of normal saline to form a solution containing 16.2 mg of compound 1393 per ml of solution for parenteral administration.

Claims

1. A pharmaceutical composition comprising a taxane and at least one nonaqueous, pharmaceutically acceptable solvent, wherein the taxane has a solubility in ethanol at room temperature of at least 100 mg/mI.

2. The composition of claim 1 wherein the taxane concentration is between 0.01 mg and about 10 mg per ml of the composition.

3. The composition of claim I wherein the taxane dosage is at least 20 mg/m 2 .

4. The composition of claim 3 wherein the taxane dosage is between 20 mg/m 2 and about 600 mg/m 2 .

5. The composition of claim 4 wherein the taxane dosage is between about 25 mg/m 2 and about 400 mg/m 2 .

6. The composition of claim 5 wherein the taxane dosage is between about 40 mg/m 2 and about 300 mg/m 2 .

7. The composition of claim 6 wherein the taxane dosage is between about 50 mg/m 2 and about 200 mg/m 2 .

8. The composition of claim 1 wherein the taxane has the formula: X 5 NH ORI R 9 X3 . R7 6H R 14 HO . R2 OAc wherein one of R 7 and R, 0 is hydroxy and the other is acyloxy; X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo; X. is -COX,(, -COOX 10 , or -CONHX 1 0 ; X 1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; WO 01/57013 PCT/USO1/03624 296 R 2 is acyloxy; R 9 is keto, hydroxy, or acyloxy; R, 4 is hydrido or hydroxy; and Ac is acetyl.

9. The composition of claim 8 wherein the composition is for parenteral administration.

10. The composition of claim 8 wherein the composition is for oral administration.

11. The composition of claim 8 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C alkenyl, or C2 C alkynyl.

12. The composition of claim 8 wherein X, is -COX 10 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C, - C alkyl, C2 - C alkenyl, or C2 - C alkynyl or X 5 is -COOXO and X 1 0 is substituted or unsubstituted C1 - C alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

13. The composition of claim 8 wherein R 4 is hydrido and R 2 is benzoyloxy.

14. The composition of claim 8 wherein R 7 is hydroxy and R10 is RIoaC(O)O-, R10aRleNC(0)O-, ROaOC(0)0 or RlOaSC(O)O- wherein R10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and Rob is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

15. The composition of claim 14 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C alkenyl, or C2 C alkynyl.

16. The composition of claim 14 wherein X, is -COX 1 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C8 alkenyl, or C2 - C alkynyl or X, is -C00X 10 and X 1 . is substituted or unsubstituted C, - C alkyl, C2 - C8 alkenyl, or C2 - C alkynyl. WO 01/57013 PCT/USO1/03624 297

17. The composition of claim 14 wherein R 14 is hydrido and R 2 is benzoyloxy.

18. The composition of claim 14 wherein R, 4 is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl; X 5 is -COX,, and X 1 0 is phenyl, or X. is -C00X 1 0 and X 1 0 is t-butyl.

19. The composition of claim 18 wherein X 3 is furyl or thienyl.

20. The composition of claim 19 wherein X. is -COOXO and X 1 0 is t-butyl.

21. The composition of claim 8 wherein R 1 0 is hydroxy and R 7 is R 7 aC(O)O-, R 7 aR 7 bNC(O)0-, R 7 aOC(0)O- or R 7 aSC(O)O- wherein R 7 , is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R 7 b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

22. The composition of claim 21 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 C alkynyi.

23. The composition of claim 21 wherein X 5 is -COX 1 0 and X,, is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C8 alkenyl, or C2 - C alkynyl or X. is -COOXO and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

24. The composition of claim 21 wherein R, 4 is hydrido and R 2 is benzoyloxy.

25. The composition of claim 21 wherein RU is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl; X. is -COX1 0 and X 1 0 is phenyl, or X 5 is -C00X 10 and X 1 0 is t-butyl.

26. The composition of claim 25 wherein X 3 is fury or thienyl.

27. The composition of claim 26 wherein X. is -COOX 1 0 and X 1 0 is t-butyl. WO 01/57013 PCT/USO1/03624 298

28. A pharmaceutical composition comprising a taxane and at least one nonaqueous, pharmaceutically acceptable solvent, wherein the taxane has a solubility in ethanol at room temperature of at least 100 mg/ml and is capable of being crystallized from a solution.

29. The composition of claim 28 wherein the taxane concentration is between 0.01 mg and 10 mg per ml of the composition.

30. The composition of claim 28 wherein the taxane dosage is at least 20 mg/m 2 .

31. The composition of claim 30 wherein the taxane dosage is between 20 mg/m 2 and about 600 mg/m 2 .

32. The composition of claim 31 wherein the taxane dosage is between about 25 mg/m 2 and about 400 mg/m 2 .

33. The composition of claim 32 wherein the taxane dosage is between about 40 mg/m 2 and about 300 mg/m 2 .

34. The composition of claim 33 wherein the taxane dosage is between about 50 mg/m 2 and about 200 mg/m 2 .

35. The composition of claim 28 wherein the taxane has the formula: X 5 NH O R 9 X3 O : O k , OH ' R 14 HO Z - = 0 R2 OAc wherein one of R 7 and R,, is hydroxy and the other is acyloxy; X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo; X, is -COXIO, -COOX 10 , or -CONHX 1 0 ; X,, is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; R 2 is acyloxy; WO 01/57013 PCT/USO1/03624 299 R. is keto, hydroxy, or acyloxy; R, 4 is hydrido or hydroxy; and Ac is acetyl.

36. The composition of claim 35 wherein the composition is for parenteral administration.

37. The composition of claim 35 wherein the composition is for oral administration.

38. The composition of claim 35 wherein X. is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 C alkynyl.

39. The composition of claim 35 wherein X, is -COX 1 0 and X 1 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X 5 is -COOX 10 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

40. The composition of claim 35 wherein R 1 4 is hydrido and R 2 is benzoyloxy.

41. The composition of claim 35 wherein R 7 is hydroxy and R 1 , is R10aC(O)O-, R10aRIeNC(0)O-, R10aOC(O)0 or R1 0 aSC(O)O- wherein R1 0 a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R10b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

42. The composition of claim 41 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 C8 alkynyl.

43. The composition of claim 41 wherein X. is -COX 1 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl or X. is -C00X 1 0 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl. WO 01/57013 PCT/USO1/03624 300

44. The composition of claim 41 wherein R 1 4 is hydrido and R 2 is benzoyloxy.

45. The composition of claim 41 wherein R 1 4 is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alky], C2 - C8 alkenyl, or C2 - C alkynyl; X. is -COX 10 and X 1 0 is phenyl, or X, is -COOX 1 0 and X 1 0 is t-butyl.

46. The composition of claim 45 wherein X 3 is furyl or thienyl.

47. The composition of claim 46 wherein X. is -C00X 10 and X,, is t-butyl.

48. The composition of claim 35 wherein R 1 , is hydroxy and R 7 is R 7 OC(0)0, R 7 ,R 7 bNC(0)0-, R 7 yOC(O)O- or R 7 SC(O)O- wherein R 7 , is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R 7 b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

49. The composition of claim 48 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - Ca alkenyl, or C2 C alkynyl.

50. The composition of claim 48 wherein X 5 is -COX 1 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C. alkyl, C2 - C alkenyl, or C2 - C alkynyl or X 5 is -C00X 1 0 and X 1 0 is substituted or unsubstituted C1 - C alkyl, C2 - C8 alkenyl, or C2 - C. alkynyl.

51. The composition of claim 48 wherein R 14 is hydrido and R 2 is benzoyloxy.

52. The composition of claim 48 wherein R, is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 - C3 alkynyl; X, is -COX 1 0 and X 1 0 is phenyl, or X 5 is -COOX 1 0 and X 1 0 is t-butyl.

53. The composition of claim 52 wherein X. is furyl or thienyl.

54. The composition of claim 53 wherein X, is -C00X 1 0 and X 1 0 is t-butyl. WO 01/57013 PCT/USO1/03624 301

55. A pharmaceutical composition comprising a taxane and at least one nonaqueous, pharmaceutically acceptable solvent, wherein the taxane has a solubility in ethanol at room temperature of at least 60 mg/ml and an ID 5 0 value determined relative to the HCTI 16 cell line that is at least 4 times less than that of paclitaxel.

56. The composition of claim 55 wherein the ID 5 0 value of the taxane is at least 5 times less than that of paclitaxel.

57. The composition of claim 56 wherein the ID 5 . value of the taxane is at least 6 times less than that of paclitaxel

58. The composition of claim57 wherein the ID 50 value of the taxane is at least 7 times less than that of paclitaxel

59. The composition of claim 58 wherein the ID 5 0 value of the taxane is at least 8 times less than that of paclitaxel.

60. The composition of claim 59 wherein the ID 5 0 value of the taxane is at least 9 times less than that of paclitaxel.

61. The composition of claim 60 wherein the ID 5 . value of the taxane is at least 10 times less than that of paclitaxel.

62. The composition of claim 55 wherein the taxane concentration is between 0.01 mg and 10 mg per ml of the composition.

63. The composition of claim 55 wherein the taxane dosage is at least 20 mg/m 2 .

64. The composition of claim 63 wherein the taxane dosage is between 20 mg/m 2 and about 600 mg/m 2 .

65. The composition of claim 64 wherein the taxane dosage is between about 25 mg/m 2 and about 400 mg/m 2 .

66. The composition of claim 65 wherein the taxane dosage is between about 40 mg/m 2 and about 300 mg/m 2 . WO 01/57013 PCT/USO1/03624 302

67. The composition of claim 66 wherein the taxane dosage is between about 50 mg/m 2 and about 200 mg/m 2 .

68. The composition of claim 55 wherein the taxane has the formula: X 5 NH 0 R 9 OH R 14 HO - 0 R2 OAc wherein one of R 7 and R 1 is hydroxy and the other is acyloxy; X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo; X 5 is -COX 1 0 , -C00X 10 , or -CONHX 10 ; X1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; R 2 is acyloxy; R 9 is keto, hydroxy, or acyloxy; R 14 is hydrido or hydroxy; and Ac is acetyl.

69. The composition of claim- 68 wherein the composition is for parenteral administration.

70. The composition of claim 68 wherein the composition is for oral administration.

71. The composition of claim 68 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C. alkyl, C2 - C alkenyl, or C2 C8 alkynyl.

72. The composition of claim 68 wherein X. is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X. is WO 01/57013 PCT/USO1/03624 303 -COOX 10 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

73. The composition of claim 68 wherein R, 4 is hydrido and R 2 is benzoyloxy.

74. The composition of claim 68 wherein R 7 is hydroxy and R 1 0 is R1 0 ,C(O)O-, R10aRIeNC(O)O-, R1oOC(0)0- or RioSC(0)- wherein Rioa is hydrocarbyl, substituted hydrocarbyl or heterocyclo and Rob is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

75. The composition of claim 74 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C alkenyl, or C2 C alkynyl.

76. The composition of claim 74 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C alkenyl, or C2 - C alkynyl or X. is -COOX 10 and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

77. The composition of claim 74 wherein R 14 is hydrido and R 2 is benzoyloxy.

78. The composition of claim 74 wherein R, 4 is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 - C8 alkenyl, or C2 - C. alkynyl; X. is -COX 10 and X,( is phenyl, or X 5 is -C00X 10 and X 10 is t-butyl.

79. The composition of claim 78 wherein X 3 is furyl or thienyl.

80. The composition of claim 79 wherein X. is -COOX 10 and X 1 , is t-butyl.

81. The composition of claim 68 wherein R 1 is hydroxy and R 7 is R 7 aC(O)0-, R 7 aR 7 bNC(0)0-, R 7 ,OC(0)0- or R 7 aSC(O)O- wherein R 7 a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and RMb is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. WO 01/57013 PCT/USO1/03624 304

82. The composition of claim 81 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C alkenyl, or C2 C8 alkynyl.

83. The composition of claim 81 wherein X. is -COX 1 0 and Xl, is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C alkyl, C2 - C8 alkenyl, or C2 - C. alkynyl or X. is -COOX 1 0 and X 1 , is substituted or unsubstituted C1 - C alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

84. The composition of claim 81 wherein R 14 is hydrido and R 2 is benzoyloxy.

85. The composition of claim 81 wherein R, 4 is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl; X. is -COX 1 0 and X 1 0 is phenyl, or X 5 is -COOX 1 0 and X 1 0 is t-butyl.

86. The composition of claim 85 wherein X 3 is furyl or thienyl.

87. The composition of claim 86 wherein X. is -C00X 10 and X,, is t-butyl.

88. A pharmaceutical composition for parenteral administration comprising a taxane having the formula: X 5 NH OR 0 R 9 X3 OR OH 7 R 14 HO R2 0 OAc wherein one of R 7 and Rio is hydroxy and the other is acyloxy; X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo; X 5 is -COX 10 , -C00X 10 , or -CONHX 10 ; X 1 0 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; R 2 is acyloxy; R. is keto, hydroxy, or acyloxy; R 1 is hydrido or hydroxy; and WO 01/57013 PCT/US01/03624 305 Ac is acetyl; and a pharmaceutically acceptable carrier.

89. The composition of claim 88 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyi, 4-pyridyl, C2 - C8 alkyl, C2 - C alkenyl, or C2 C8 alkynyl.

90. The composition of claim 88 wherein X. is -COXIO and X 1 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C, - C. alkyl, C2 - C alkenyl, or C2 - C alkynyl or X 5 is -C00X 10 and XIO is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

91. The composition of claim 88 wherein R 14 is hydrido and R 2 is benzoyloxy.

92. The composition of claim 88 wherein R 7 is hydroxy and R 1 0 is R 10 ,C(O)O-, RIO.RIObNC(O)0-, RioaOC(O)- or R1 0 aSC(O)O- wherein RIO, is hydrocarbyl, substituted hydrocarbyl or heterocyclo and ROb is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

93. The composition of claim 92 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C alkenyl, or C2 C8 alkynyl.

94. The composition of claim 92 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X. is -C00X 1 O and X 1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

95. The composition of claim 92 wherein R 14 is hydrido and R 2 is benzoyloxy.

96. The composition of claim 92 wherein R, 4 is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl; X. is -COX 1 0 and X 1 0 is phenyl, or X. is -COOX 1 0 and X 1 0 is t-butyl.

97. The composition of claim 96 wherein X 3 is furyl or thienyl. WO 01/57013 PCT/USO1/03624 306

98. The composition of claim 97 wherein X 5 is -COOX 10 and X,( is t-butyl.

99. The composition of claim 88 wherein Rio is hydroxy and R 7 is R 7 ,C(O)O-, R 7 aR 7 bNC(O)0-, R 7 aOC(O)O- or R 7 aSC(0)0- wherein R 7 a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R 7 b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

100. The composition of claim 99 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 - C alkenyl, or C2 C8 alkynyl.

101. The composition of claim 99 wherein X, is -COX,, and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C, - C alkyl, C2 - C8 alkenyl, or C2 - C alkynyl or X 5 is -COOX 1 0 and X 1 is substituted or unsubstituted C, - C alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

102. The composition of claim 99 wherein R, 4 is hydrido and R 2 is benzoyloxy.

103. The composition of claim 99 wherein R, 4 is hydroxy; X 3 is phenyl, 2-furyl, 3 furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl; X. is -COX 10 and X 1 0 is phenyl, or X, is -C00X 1 0 and X 1 0 is t-butyl.

104. The composition of claim 103 wherein X 3 is furyl or thienyl.

105. The composition of claim 104 wherein X 5 is -COOXO and X 1 0 is t-butyl.

106. A pharmaceutical composition for oral administration comprising a taxane having the formula: X 5 NH O R9 X3 OH Ryl OH R 14 HO R2 OAc WO 01/57013 PCT/USO1/03624 307 wherein one of R 7 and R 1 , is hydroxy and the other is acyloxy; X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo; X 5 is -COX 1 0 , -C00X 1 0 , or -CONHX 1 0 ; X 1 , is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; R 2 is acyloxy; R. is keto, hydroxy, or acyloxy; RU is hydrido or hydroxy; and Ac is acetyl; and a pharmaceutically acceptable carrier.

107. The composition of claim 106 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2 thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

108. The composition of claim 106 wherein X 5 is -COX 1 0 and X 1 0 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl or X 5 is -COOX 1 0 and X1 0 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

109. The composition of claim 106 wherein R 14 is hydrido and R 2 is benzoyloxy.

110. The composition of claim 106 wherein R 7 is hydroxy and R 1 0 is R10aC(O)O-, R10R1ObNC(0)0-, R10OC(O)O- or R10aSC(O)O- wherein R10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and ROb is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

111. The composition of claim 110 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2 thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

112. The composition of claim 110 wherein X, is -COX 1 and X 1 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X. is -C00X 10 and X 1 0 is substituted or unsubstituted C1 - C alkyl, C2 - C8 alkenyl, or C2 - C. alkynyl. WO 01/57013 PCT/US01/03624 308

113. The composition of claim 110 wherein R, 4 is hydrido and R 2 is benzoyloxy.

114. The composition of claim 110 wherein R1 4 is hydroxy; X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 C8 alkenyl, or C2 - C8 alkynyl; X, is -COXIO and X 1 0 is phenyl, or X, is -COOXO and X 1 0 is t-butyl.

115. The composition of claim 114 wherein X 3 is furyl or thienyl.

116. The composition of claim 115 wherein X 5 is -C00X 10 and X 1 0 is t-butyl.

117. The composition of claim 106 wherein R 1 is hydroxy and R 7 is R 7 ,C(0)O-, R 7 ,R 7 bNC(0)0-, R 7 aOC(0)O- or R 7 ,SC(0)O- wherein R 7 . is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R 7 b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.

118. The composition of claim 117 wherein X 3 is phenyl, 2-furyl, 3-furyl, 2 thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.

119. The composition of claim 117 wherein X. is -COX,( and X,, is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3 pyridyl, 4-pyridyl, C1 - C8 alkyl, C2 - C alkenyl, or C2 - C alkynyl or X. is -COOX 1 0 and X 1 0 is substituted or unsubstituted C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C alkynyl.

120. The composition of claim 117 wherein R 14 is hydrido and R 2 is benzoyloxy.

121. The composition of claim 117 wherein R 14 is hydroxy; X 3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 C8 alkenyl, or C2 - C8 alkynyl; X 5 is -COX 10 and XO is phenyl, or X. is -COOX,, and X 1 0 is t-butyl.

122. The composition of claim 121 wherein X 3 is furyl or thienyl.

123. The composition of claim 122 wherein X 5 is -C00X 10 and X 1 0 is t-butyl.