WO2001057013A1 - Taxane formulations having improved solubility - Google Patents

Taxane formulations having improved solubility Download PDF

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Publication number
WO2001057013A1
WO2001057013A1 PCT/US2001/003624 US0103624W WO0157013A1 WO 2001057013 A1 WO2001057013 A1 WO 2001057013A1 US 0103624 W US0103624 W US 0103624W WO 0157013 A1 WO0157013 A1 WO 0157013A1
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Prior art keywords
pyridyl
thienyl
substituted
composition
furyl
Prior art date
Application number
PCT/US2001/003624
Other languages
French (fr)
Inventor
Robert A. Holton
Original Assignee
Florida State University Research Foundation, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to NZ514073A priority Critical patent/NZ514073A/en
Application filed by Florida State University Research Foundation, Inc. filed Critical Florida State University Research Foundation, Inc.
Priority to AU34810/01A priority patent/AU3481001A/en
Priority to BR0104358-7A priority patent/BR0104358A/en
Priority to CA002367661A priority patent/CA2367661A1/en
Priority to EP01906972A priority patent/EP1175414A1/en
Priority to KR1020017012367A priority patent/KR20010111580A/en
Priority to PL01350075A priority patent/PL350075A1/en
Priority to MXPA01009900A priority patent/MXPA01009900A/en
Priority to JP2001556863A priority patent/JP2003521545A/en
Priority to IL14563501A priority patent/IL145635A0/en
Publication of WO2001057013A1 publication Critical patent/WO2001057013A1/en
Priority to NO20014752A priority patent/NO20014752L/en
Priority to HK03100165.6A priority patent/HK1047933A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to various formulations of taxane derivatives having improved solubility as compared to paclitaxel, particularly 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 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.
  • paclitaxel 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.
  • 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 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 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.
  • Taxol® 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
  • Intravenous infusions of paclitaxel are generally prepared for patient administration within the concentration range of 0.3 to1.2 mg/ml.
  • the diluted solution for administration consists of up to 10% ethanol, up to 10% Cremophor® EL and up to 80% aqueous solution.
  • dilution to certain concentrations may produce a supersaturated solution that could precipitate.
  • An inline 0.22 micron filter is used during Taxol® administration to guard against the potentially life-threatening infusion of particulates.
  • paclitaxel in a Cremophor®/ethanol-based formulation
  • anaphylactic reactions hypotension, angioedema, urticaria, peripheral neuropathy, arthralgia, mucositis, nausea, vomiting, alopecia, alcohol poisoning, respiratory distress such as dyspnea, cardiovascular irregularities, flu-like symptoms such as myalgia, gastrointestinal distress, hematologic complications such as neutropenia, genitourinary effects, and skin rashes.
  • 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 for Taxol® 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 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.
  • paclitaxel is 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.
  • lipid emulsion formulations have significant drawbacks in that additives are still needed to solubilize paclitaxel and to prevent it from precipitating out of solution.
  • 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 aqueous lipid emulsion is preferably a soybean oil emulsion.
  • Andersson solubilizes paclitaxel by dissolving it in an organic solvent of dimethylacetamide 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®).
  • an aqueous lipid emulsion e.g., emulsified soybean oil (Intralipid®), Liposyn®, Soyacal®, and Travemulsion®.
  • aqueous lipid emulsion e.g., emulsified soybean oil (Intralipid®), Liposyn®, Soyacal®, and Travemulsion®.
  • aqueous lipid emulsion e.g., emulsified soybean oil (Intralipid®), Liposyn®, Soy
  • 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 doses. Accordingly, a need remains for additional formulations of chemotherapeutic agents with improved efficacy and less toxicity.
  • taxane-containing pharmaceutical compositions which compare favorably to Taxol® and Taxotere® formulations with respect to efficacy as anti- tumor agents and with respect to toxicity and stability.
  • compositions for oral or parenteral administration which comprise a taxane and at least one nonaqueous, pharmaceutically acceptable solvent.
  • the taxane has a solubility in ethanol of at least 100 mg/ml.
  • the taxane has a solubility in ethanol of at least 100 mg/ml and is capable of being crystallized from a solution.
  • the pharmaceutical compositions comprise a taxane which has a solubility in ethanol of at least 60 mg/ml and an ID 50 value determined relative to the HCT116 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.
  • the present invention provides compositions and methods for the 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 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 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.
  • compositions of the invention allow for a broad range of administration protocols including oral administration.
  • Oral administration has been found to 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 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.
  • compositions are also effective in minimizing or eliminating premedication to reduce patient discomfort and the expense and duration of treatment.
  • 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.
  • the taxanes of the present invention correspond to structure (1):
  • R 7 and R 10 are hydroxy and the other is acyloxy;
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ;
  • X 10 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.
  • R 7 , R 9 , and R 10 independently have the alpha or beta stereochemical configuration.
  • R 2 is an ester (R 2a C(O)O-), a carbamate (R 2a R 2b NC(O)O-), a carbonate (R 2a OC(O)O-), or a thiocarbamate (R 2a SC(O)O-) wherein R 2a and R 2b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
  • R 2 is an ester (R 2a C(O)O-), wherein R 2a is aryl or heteroaromatic.
  • R 2 is an ester (R 2a C(O)O-), wherein R 2a is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl.
  • R 2 is benzoyloxy.
  • R g 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, ⁇ - or ⁇ -hydroxy or ⁇ - or ⁇ -acyloxy.
  • R 9 when R 9 is acyloxy, it may be an ester (R 9a C(O)O-), a carbamate (R 9a R 9b NC(O)O-), a carbonate (R 9a OC(O)O-), or a thiocarbamate (R 9a SC(O)O-) wherein R 9a and R 9b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R 9 is an ester (R 9a C(O)O-), R 9a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic.
  • R 9 is an ester (R 9a C(O)O-), wherein R 9a is substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyridyl.
  • R 9 is (R 9a C(O)O-) wherein R 9a is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl, (straight, branched or cyclic), or hexyl (straight, branched or cyclic).
  • R 9 is (R 9a C(O)O-) wherein R 9a is substituted methyl, substituted ethyl, substituted propyl (straight, 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, amidp, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
  • Exemplary X 3 substituents include substituted or unsubstituted C 2 to C 8 alkyl, substituted or unsubstituted C 2 to C 8 alkenyl, substituted or unsubstituted C 2 to C 8 alkynyl, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl.
  • Exemplary preferred X 3 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.
  • Exemplary X 5 substituents include -COX 10 , -COOX 10 or -CONHX 10 wherein X 10 is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic.
  • Exemplary preferred X 5 substituents include -COX 10 , -COOX 10 or -CONHX 10 wherein X 10 is (i) substituted or unsubstituted C 1 to C 8 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 C 2 to C 8 alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight,
  • R 10 is R 10a OCOO- wherein R 10a is (i) substituted or unsubstituted C, to C 8 alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heterocycl
  • R 10a 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.
  • R 10a 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, ester and ether moieties, but not phosphorous containing moieties.
  • taxanes of the present invention correspond to structure (2):
  • R 7 is hydroxy;
  • R 10 is carbonate;
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ; and
  • X 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • R 10 may be R 10a OCOO- wherein R 10a 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.
  • 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.
  • R 10a and X 3 are selected from among these
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • X 3 is preferably cycloalkyl, isobutenyl, 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, still more preferably t-butoxycarbonyl.
  • 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.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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.
  • 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.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 g is hydroxy and R 14 is hydrido.
  • 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
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • R 10 is R 10a COO- wherein R 10a is (i) substituted or unsubstituted C 2 to C 8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 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,
  • R 10a 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.
  • R 10a 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, ester and ether moieties, but not phosphorous containing moieties.
  • taxanes of the present invention correspond to structure (2):
  • R 7 is hydroxy
  • R 10 is R 10a COO-
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ; and X 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and
  • R 10a 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 10a is a substituent;
  • Bz is benzoyl; and Ac is acetyl.
  • R 10a 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.
  • 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.
  • R 10a and X 3 are selected from among these
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • X 3 is preferably cycloalkyl, isobutenyl, 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.
  • 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 g is keto and R 14 is hydrido.
  • X 3 is heterocyclo;
  • X_ i « ⁇ nr ⁇ for ⁇ hlx/ oKzoul t hydroxy and R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • X 3 is heterocyclo
  • X 5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort- amyloxycarbonyl, still more preferably t-butoxycarbonyl
  • R 2 is benzoyl
  • R 9 is acyloxy
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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 g is acyloxy
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • R 10 is R 10a R 10b NCOO- wherein R 10a and R 10b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • exemplary preferred R 10 substituents include R 10a R 10b NCOO- wherein (a) R 10a and R 10b are each hydrogen, (b) one of R 10a and R 10b is hydrogen and the other is (i) substituted or unsubstituted C, to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or
  • R 10 substituents may be those identified elsewhere herein for substituted hydrocarbyl.
  • preferred R 10 substituents include R 10a R 10b NCOO- wherein one of R 10a and R 10b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
  • taxanes of the present invention correspond to structure (2):
  • R 7 is hydroxy;
  • R 10 is carbamoyloxy;
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ;
  • R 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • R 10 may be R 10a R 10b NCOO- wherein one of R 10a and R 10b is hydrogen and the other is (i) substituted or unsubstituted C 1 to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or hex
  • substituents may be those identified elsewhere herein for substituted hydrocarbyl.
  • preferred R 10 substituents include R 10a R 10b NCOO- wherein one of R 10a and R 10b is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted methyl, ethyl, or straight, branched or cyclic propyl.
  • preferred R 10 substituents include R 10a R 10b NCOO- wherein one of R 10a and R 10b is hydrogen and the other is substituted or unsubstituted phenyl or heterocyclo.
  • 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 10a , R 10b , and X 3 are selected from among these, in one embodiment X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • X 5 is -COOX 10 wherein X 10 is tert-butyl or X 5 is -COX 10 wherein X 10 is phenyl
  • 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
  • R 10 is R 10a R 10b NCOO-, one of R 10a and R 10b is hydrogen and the other is substituted or unsubstituted substituted or unsubstituted C 1 to C 8 alkyl, phenyl or heterocyclo.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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 g is keto and R 14 is hydroxy.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl.
  • 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.
  • 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.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 g is hydroxy and R 14 is hydrido.
  • 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
  • R 14 is hydroxy.
  • 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 g is acyloxy
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration, R 7 and R 10 may each have the alpha stereochemical configuration, R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • R 10 is R 10a C(O)O- wherein R 10a is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R 10a 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 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.
  • R 10 substituents include R 10a COO- wherein R 10a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxy methyl, acyloxymethyl, or methylthiomethyl.
  • the taxane corresponds to structure 1 , X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t-butoxycarbonyl, and R 10 is R 10a C(O)O- wherein R 10a is alkoxymethyl, preferably methoxymethyl or ethoxymethyl.
  • the taxane corresponds to structure 1 , X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t-butoxycarbonyl, and R 10 is R 10a C(O)O- wherein R 10a is acyloxymethyl, preferably acetoxymethyl.
  • the taxane corresponds to structure 1
  • X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t- butoxycarbonyl
  • R 10 is R 10a C(O)O- wherein R 10a is alkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl
  • X 3 is heterocyclo.
  • the taxane corresponds to structure 1 , X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t-butoxycarbonyl, and R 10 is R 10a C(O)O- wherein R 10a is acyloxymethyl, preferably acetoxymethyl, and X 3 is heterocyclo.
  • taxanes correspond to structure (2):
  • R 7 is hydroxy
  • R 10 is heterosubstituted acetate
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ;
  • X 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • R 10 is R 10a COO- wherein R 10a is heterosubstituted methyl, more preferably heterosubstituted methyl wherein the heterosubsituents are selected 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.
  • 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.
  • R 10a and X 3 are selected from among these
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • R 7 is R 7a OCOO- wherein R 7a is (i) substituted or unsubstituted C 1 to C 8 alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 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 fu
  • R 7a 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.
  • R 7a 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, ester and ether moieties, but not phosphorous containing moieties.
  • taxanes of the present invention correspond to structure (2):
  • R 7 is carbonate;
  • R 10 is hydroxy;
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ; and
  • X 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • R 7 may be R 7a OCOO- wherein R 7a 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.
  • 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.
  • R 7a and X 3 are selected from among these
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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 g is acyloxy
  • R 14 is hydroxy.
  • 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 g is acyloxy
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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.
  • 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.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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
  • R 14 is hydroxy.
  • 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 g is acyloxy
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration, R 7 and R 10 may each have the alpha stereochemical configuration, R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • R 7 is R 7a COO- wherein R 7a is (i) substituted or unsubstituted C 2 to C 8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 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,
  • R 7a 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.
  • R 7a 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, ester and ether moieties, but not phosphorous containing moieties.
  • the taxanes of the present invention correspond to the following structural formula (2):
  • R 7 is R 7a COO-;
  • R 10 is hydroxy;
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ;
  • X 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo
  • R 7a 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 a is a substituent
  • Bz is benzoyl
  • Ac is acetyl.
  • R 7a 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.
  • 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.
  • R 7a and X 3 are selected from among these
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, orX 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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 g is keto and R 14 is hydrido.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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 g is hydroxy
  • R 14 is hydroxy.
  • 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 g is hydroxy and R 14 is hydrido.
  • 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
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl.
  • 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.
  • 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.
  • 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.
  • 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 g is hydroxy
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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
  • R 14 is hydroxy.
  • 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 g is acyloxy
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration, R 7 and R 10 may each have the alpha stereochemical configuration, R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • R 7 is R 7a R 7b NCOO- wherein R 7a and R 7b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • exemplary preferred R 7 substituents include R 7a R 7b NCOO- wherein (a) R 7a and R 7b are each hydrogen, (b) one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C, to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or
  • R 7 substituents may be those identified elsewhere herein for substituted hydrocarbyl.
  • preferred R 7 substituents include R 7a R 7b NCOO- wherein one of R 7a and R 7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
  • taxanes of the present invention correspond to structure (2):
  • R 7 is carbamoyloxy;
  • R 10 is hydroxy;
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;
  • R 7 may be R 7a R 7b NCOO- wherein one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C, to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl
  • R 7 substituents include R 7a R 7b NCOO- wherein one of R 7a and R 7b is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted methyl, ethyl, or straight, branched or cyclic propyl.
  • preferred R 7 substituents include R 7a R 7b NCOO- wherein one of R 7a and R 7b is hydrogen and the other is substituted or unsubstituted phenyl or heterocyclo.
  • 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 7a , R 7b , and X 3 are selected from among these, in one embodiment X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • X 5 is -COOX 10 wherein X 10 is tert-butyl or X 5 is -COX 10 wherein X 10 is phenyl
  • 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
  • R 7 is R 7a R 7b NCOO-, one of R 7a and R 7b is hydrogen and the other is substituted or unsubstituted C, to C 8 alkyl, phenyl or heterocyclo.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl.
  • 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.
  • 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.
  • 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.
  • 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
  • R 14 is hydroxy.
  • 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 hydrido.
  • 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 g is acyloxy
  • R 14 is hydroxy.
  • 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 g is acyloxy
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration, R 7 and R 10 may each have the alpha stereochemical configuration, R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration or R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • 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 5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl.
  • 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 g is keto and R 14 is hydrido.
  • 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.
  • 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.
  • 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 g is hydroxy
  • R 14 is hydroxy.
  • 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 g is hydroxy and R 14 is hydrido.
  • 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
  • R 14 is hydroxy.
  • 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
  • R 14 is hydrido.
  • R 7 and R 10 may each have the beta stereochemical configuration
  • R 7 and R 10 may each have the alpha stereochemical configuration
  • R 7 may have the alpha stereochemical configuration while R 10 has the beta stereochemical configuration
  • R 7 may have the beta stereochemical configuration while R 10 has the alpha stereochemical configuration.
  • R 7 is R 7a C(O)O- wherein R 7a is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R 7a 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 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.
  • R 7 substituents include R 7a COO- wherein R 7a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, or methylthiomethyl.
  • the taxane corresponds to structure
  • X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t-butoxycarbonyl, and R 7 is R 7a C(O)O- wherein R 7a is alkoxymethyl, preferably methoxymethyl or ethoxymethyl.
  • the taxane corresponds to structure 1
  • X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t-butoxycarbonyl
  • R 7 is R 7a C(O)O- wherein R 7a is acyloxymethyl, preferably acetoxymethyl.
  • the taxane corresponds to structure 1
  • X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t- butoxycarbonyl
  • R 7 is R 7a C(O)O- wherein R 7a is alkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl
  • X 3 is heterocyclo.
  • the taxane corresponds to structure 1 , X 5 is -COX 10 wherein X 10 is phenyl or -COOX 10 wherein X 10 is t-butoxycarbonyl, and R 7 is R 7a C(O)O- wherein R 7a is acyloxymethyl, preferably acetoxymethyl, and X 3 is heterocyclo.
  • the taxanes of the present invention correspond to structure (2):
  • R 7 is heterosubstituted acetate
  • R 10 is hydroxy
  • X 3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;
  • X 5 is -COX 10 , -COOX 10 , or -CONHX 10 ;
  • X 10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.
  • R 7 may be R 7a COO- wherein R 7a is heterosubstituted methyl, more preferably heterosubstituted methyl wherein the heterosubsituents are selected 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.
  • 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.
  • R 7a and X 3 are selected from among these
  • X 5 is selected from -COX 10 wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl.
  • X 5 is selected from -COX o wherein X 10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X 5 is -COOX 10 wherein X 10 is alkyl, preferably t-butyl.
  • Taxanes having the general formula 1 may be obtained by treatment of a ⁇ -lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a ⁇ -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 III by selective formation of a carbonate of the C-10 hydroxyl 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.
  • 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 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 acylating agent is a dicarbonate.
  • Taxanes having C(10) esters may be prepared from 10-deacetylbaccatin III (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 III may be selectively protected with a silyl group as described, for example, by Denis, et. al. (J. Am. Chem. Soc, 1988, 110, 5917).
  • 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- deacetylbaccatin III 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 ⁇ -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.
  • Taxanes having C(7) carbonates may be prepared from 10- deacetylbaccatin III (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 10-deacetylbaccatin III is then selectively protected with a silyl group using, for example, a silylamide 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 ⁇ - lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a ⁇ -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 10-deacetylbaccatin III (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 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 agents including, but not limited to, substituted and unsubstituted carboxylic acid derivatives, e.g., carboxylic acid halides, anhydrides, dicarbonates, isocyanates and haloformates.
  • carboxylic acid derivatives e.g., carboxylic acid halides, anhydrides, dicarbonates, isocyanates and haloformates.
  • 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 Springfield 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. Patent No. 5,352,806.
  • Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy- 10-deacetylbaccatin III.
  • the ⁇ -lactam may be prepared as described in Holton, U.S. Patent No. 5,430,160 and the resulting enatiomeric mixtures of ⁇ -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 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 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.
  • compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper formulation is dependent upon the route of administration chosen.
  • 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, 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, endoscopical, transmucosal, sublingual and intestinal administration.
  • parenteral e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrasternal
  • topical nasal, transdermal, intraocular
  • intravesical, intrathecal enteral
  • 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, 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 by reference).
  • 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 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).
  • 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, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid.
  • Such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption.
  • 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 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.
  • 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 liquid.
  • 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 liquid.
  • Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., ⁇ -glycerol formal, ⁇ -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, 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),
  • 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 polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution).
  • oils rich in triglycerides for example, safflower oil, soybean oil or mixtures thereof
  • 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).
  • triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Sweden), Nutralipid ® emulsion (McGaw, Irvine, California), Liposyn® II 20% emulsion (a 20% 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), Liposyn® III 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 containing the docosahexaenoyl group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® (from Martek Biosciences Corp., Columbia, MD), DHA
  • 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 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.
  • each of 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.
  • cryoprotective agents for preventing reprecipitation of the taxane include 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 (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, sterol
  • a pharmaceutical composition of the invention 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 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.
  • the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% 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.
  • ID50 value i.e, the drug concentration producing 50% inhibition of colony formation
  • Dosage form administration by these routes may be continuous or intermittent, depending, for example, upon the patient's physiological condition, 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 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 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.
  • an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route.
  • 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, 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 .
  • 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 about 40 to about 300 mg/m 2 , and even more preferably from about 50 to about 200 mg/m 2 .
  • 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 surface area.
  • 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 .
  • the dosage may vary depending on the dosing schedule which can be adjusted as 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.
  • 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 concentrations are generally preferred because the antitumor cornpound 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 40 weight %, and most preferably between about 10 weight % and about 30 weight %.
  • 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 Cremophor® EL solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for oral administration to a patient.
  • 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.
  • 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 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 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 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® III emulsion, is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient.
  • emulsions 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 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 dissolving the compound (e.g., ethanol or methylene chloride) to form a solution.
  • a pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride)
  • An appropriate volume of a carrier which is a solution, such as Cremophor® solution is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient.
  • 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 physiological effects when administered at certain concentrations in parenteral formulations.
  • 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, such as saline, to form an acceptable taxane concentration prior to use as is known in the art.
  • hydrocarbon and “hydrocarbyl” as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and 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.
  • 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.
  • substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals, acetals, esters and ethers.
  • 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 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.
  • 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 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.
  • the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal 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.
  • 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 cyclic and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
  • 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 include ethynyl, propynyl, butynyl, isobutynyl, hexynyl, and the like.
  • 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 naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
  • halogen or halo as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
  • heterocyclo or “heterocyclic” as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, 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, 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.
  • heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
  • 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.
  • heteroaromatic as used herein alone or as part of another 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 include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.
  • 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.
  • acyl 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 O-, R 1 R 2 N-, or R 1 S-, R 1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R 2 is hydrogen, hydrocarbyl or substituted hydrocarbyl.
  • acyloxy denotes an acyl group as described above bonded through an oxygen linkage (-O-), e.g., RC(O)O- wherein R is as defined in connection with the term "acyl.”
  • alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted hydrocarbon moieties.
  • 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.
  • 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 be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John
  • hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
  • 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” means lithium aluminum hydride; “10-DAB” means 10-desacetylbaccatin III”; “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; “tBuOC
  • Example 1 Preparation of Taxane having C-7 Ester and C-10 Hydroxy Substituents
  • 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 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.
  • Example 2 Additional Taxanes having C-7 Ester and C-10 Hvdroxy Substituents The procedures described in Example 1 were repeated, but other suitably protected ⁇ -lactams were substituted for the ⁇ -lactam of Example 1 to prepare the series of compounds having structural formula (3) and the combinations of substituents identified in the following table.
  • Example 3 Additional Taxanes having C-7 Ester and C-10 Hydroxy Substituents Following the processes described in Example 1 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 R a COO- and R a is (i) substituted or unsubstituted C 2 to C 8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl (straight or branched) such as ethynyl, propynyl, butynyl,
  • 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 containing moieties.
  • Example 4 Additional Taxanes having C-7 Ester and C-10 Hvdroxy Substituents Following the processes described in Example 1 and elsewhere herein, the following specific taxanes having structural formula (5) may be prepared, wherein R 10 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 7a COO- and R 7a is
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 9a are as otherwise as defined herein.
  • 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 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R 9 (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • any substituents of each X 3 , X 5 , R 2 , R 7 , and R g 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.
  • Example 5 In Vitro cytotoxicitv measured by the cell colony formation assay
  • HCT116 Four hundred cells (HCT116) 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 CO2 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 ° C.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin
  • 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.
  • HBSS Hank's Balance Salt Solution
  • 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.
  • 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-10- propionyl-10-deacetyl baccatin III as a solid.
  • 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 ⁇ -lactams were substituted for the ⁇ -lactam of Example 6 to prepare the series of compounds having structural formula (6) and the combinations of substituents identified in the following table.
  • 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 R 10 is as previously defined, including wherein R 10 is R a COO- and R a is (i) substituted or unsubstituted C 2 to C 8 alkyl such as ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or straight or branched propynyl, butynyl, pentynyl, or
  • R 10 may be R 10a COO- wherein R 10a is ethyl, straight, branched or cyclic propyl, straight or branched propenyl, isobutenyl, furyl or thienyl.
  • R 7 is hydroxy and R 10 in each of the series (that is, each of series "A” through “K”) is as previously defined, including wherein R 10 is R 10a COO- and R 10a is (i) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alkyn
  • X 10 is as otherwise as defined herein.
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 9a are as otherwise as defined herein.
  • 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 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R 9 (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • any substituents of each X 3 , X 5 , R 2 , R 9 , R 10 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.
  • Example 10 In Vitro cytotoxicitv measured by the cell colony formation assay Four hundred cells (HCT116) 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 CO2 incubator at 37 C C 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 added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 ° C.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin
  • 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.
  • HBSS Hank's Balance Salt Solution
  • N-Debenzoyl-N-fert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)- 10-deacetyl-7-methoxyacetyl taxol (6226)
  • N-debenzoyl-N-te/T- amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyl)-7- benzyloxycarbonyl-10-deacetyl-10-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.
  • Example 12 Taxanes having C-7 Substituted Acetate and C-10 Hydroxy Substituents
  • Example 11 The procedures described in Example 11 were repeated, but other suitably protected ⁇ -lactams were substituted for the ⁇ -lactam of Example 1 to prepare the series of compounds having structural formula (9) and the combinations of substituents identified in the following table:
  • Example 13 Taxanes having C7 Substituted Acetate and C-10 Hydroxy Substituents 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 7a COO-and R 7a is heterosubstituted methyl. In one embodiment, R 7a is chloromethyl, hydroxy methyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, or methylthiomethyl.
  • Example 14 Taxanes having C-7 Substituted Acetate and C-10 Hydroxy Substituents Following the processes described in Example 11 and elsewhere herein, the following specific taxanes having structural formula (11) may be prepared, wherein R 10 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 7a COO- wherein R 7a is a heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R 7a 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 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.
  • R 7 substituents include R 7a COO- wherein R 7a is hydrogen, methyl, chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.
  • X 10 is as otherwise as defined herein.
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert- butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 9a are as otherwise as defined herein.
  • 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 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R g (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R g and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R g and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 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 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.
  • Example 15 In Vitro cvtotoxicitv measured by the cell colony formation assay Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing
  • the drug-containing media were decanted, the dishes were rinsed with 4 L 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.
  • HBSS Hank's Balance Salt Solution
  • 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.
  • N-Debenzoyl-N-ferf-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-10- methoxyacetyl taxol (6515)
  • N-debenzoyl-N-ferf-amyloxycarbonyl- 3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyI)-7-benzyloxycarbonyl-10-deacetyl- 10-trimethylsilyl taxol (3.50 g) in 40 mL of 1 :1 acetonitrile-pyridine at 0 °C (ice-water bath) was added dropwise over 10 minutes, 10 mL of 48% aqueous hydrofluoric acid.
  • Example 16 The procedures described in Example 16 were repeated, but other suitably protected ⁇ -lactams were substituted for the ⁇ -lactam of Example 16 to prepare the series of compounds having structural formula (12) and the combinations of substituents identified in the following table:
  • Example 18 Taxanes having C-10 Substituted Acetate and C-7 Hvdroxy Substituents
  • R 10 is R 10a COO- and R 10a is heterosubstituted methyl.
  • R 10a is chloromethyl, hydroxy methyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.
  • R 7 is hydroxy and R 10 in each of the series (that is, each of series "A” through “K”) is as previously defined, including wherein R 10 is R 10a COO- wherein R 10a is a heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R 10a 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 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.
  • R 10 substituents include R 10a COO- wherein R 10a is chloromethyl, hydroxy methyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.
  • X 10 is as otherwise as defined herein.
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert- butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 9a are as otherwise as defined herein.
  • 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 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R 9 (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R g and R 10 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 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.
  • Example 20 In Vitro cvtotoxicity measured by the cell colony formation assay
  • HCT116 Four hundred cells (HCT116) 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 CO2 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 ° C.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin
  • 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.
  • HBSS Hank's Balance Salt Solution
  • 10-Triethylsllyl-10-deacetyl-7-methoxycarbonyl baccatin III To a solution of 9.3 g (14.1 mmol) of 10-triethyIsilyI-10-deacetyl baccatin III and 10.35 g (84.6 mmol) of DMAP in 500 mL of dichloromethane at 0 °C 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 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 under reduced pressure to give 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 679 mg (93%) of a white crystalline solid which was used directly in the next reaction.
  • Example 21 The procedures described in Example 21 were repeated, but other suitably protected ⁇ -lactams were substituted for the ⁇ -lactam of Example 21 to prepare the series of compounds having structural formula (15) and the combinations of substituents identified in the following table.
  • Example 23 Additional 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 (16) may be prepared, wherein R 7 is as previously defined, including wherein R 7 is R a OCOO- and R a is (i) substituted or unsubstituted C 1 to C 8 alkyl (straight, branched or cyclic), such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl (straight or branched) such as ethynyl, propynyl, buty
  • 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 containing moieties.
  • R 10 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 7a OCOO- and R 7a is (i) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alky
  • X 10 is as otherwise as defined herein.
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert- butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 9a are as otherwise as defined herein.
  • 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 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R g and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R g (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R g and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 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 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.
  • Example 25 In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing
  • 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.
  • HBSS Hank's Balance Salt Solution
  • 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 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 III as a solid.
  • Example 26 The procedures described in Example 26 were repeated, but other suitably protected ⁇ -lactams were substituted for the ⁇ -lactam of Example 26 to prepare the series of compounds having structural formula (18) and the combinations of substituents identified in the following table.
  • R 10 is as previously defined including wherein R 10 is R a OCOO- and R a is (i) substituted or unsubstituted C, to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 3 to C 8 alkenyl such as propenyl or straight, branched or cyclic butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 3 to C 8 alkynyl such as propynyl or straight or branched butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted phenyl, or (v) substituted or unsubstituted phenyl, or
  • R 7 is hydroxy and R 10 is as previously defined, including wherein R 10 is R 10a OCOO- and R 10a is (i) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C 2 to C 8 alky
  • X 10 is as otherwise as defined herein.
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R ga are as otherwise as defined herein.
  • 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 ga is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R 9 (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • any substituents of each of X 3 , X 5 , R 2 , R 9 and R 10 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.
  • Example 30 In Vitro cytotoxicity measured by the cell colony formation assay
  • HCT116 Four hundred cells (HCT116) 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 CO2 incubator at 37 °C 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.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin
  • 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.
  • HBSS Hank's Balance Salt Solution
  • 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 (5535) To a solution of N-debenzoyl-N-isobutenyl-3'-desphenyl-3'-(2-furyl)-2'-(2- methoxy-2-propyl)-10-triethylsilyI taxol (400 mg, 0.413 mmol) in 4 mL anhydrous pyridine was added 4-dimethylaminopyridine (10 mg, 0.08 mmol) under a nitrogen atmosphere.
  • Example 31 The procedures described in Example 31 were repeated, but other suitably protected ⁇ -lactams and acylating agents were substituted for the ⁇ -lactam and 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.
  • 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 previously defined, including wherein R 7 is R 7a R 7b NCOO- and (a) R 7a and R 7b are each hydrogen, (b) one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C 1 to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 3 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or
  • R 7 may be R 7a R 7b NCOO- wherein one of R 7a and R 7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
  • 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 R 10 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 7a R 7b NCOO- and one of R 7a and R 7b is hydrogen and the other is (i) substituted or unsubstituted C to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstitute
  • substituents may be those identified elsewhere herein for substituted hydrocarbyl.
  • preferred R 7 substituents include R 7a R 7b NCOO- wherein one of R 7a and R 7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
  • preferred R 7 substituents include R 7a R 7b NCOO- wherein one of R 7a and R 7b is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl.
  • X 10 is as otherwise as defined herein.
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or Unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 9a are as otherwise as defined herein.
  • 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 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R 9 (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 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 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.
  • Example 35 In Vitro cytotoxicitv measured by the cell colony formation assay Four hundred cells (HCT116) 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 CO2 incubator at 37 °C 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 added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 ° C.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin
  • 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. 10
  • HBSS Hank's Balance Salt Solution
  • 3'-Desphenyl-3'-(2-thienyl)-2'-O-triethylsilyl docetaxel A suspension of 550 mg of 7,10-( )/s)-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 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.
  • 3'-Desphenyl-3'-(2-thienyl)-10-N-ethylcarbamoyl docetaxel (2722).
  • Example 37 Taxanes having C-10 Carbamoyloxy and C-7 Hydroxy Substituents The procedures described in Example 36 were repeated, but other suitably protected ⁇ -lactams were substituted for the c/s-N-fbutoxycarbonyl-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 compound (2722) prepared in Example 36.
  • Example 38 Taxanes Having C-10 Carbomoyloxy and C-7 Hydroxy Substituents The procedures described in Example 36 were repeated, but other suitably protected ⁇ -lactams were substituted for the ⁇ -lactam of Example 36 to prepare the series of compounds having structural formula (25) and the combinations of substituents identified in the following table.
  • R 7 is as previously defined including wherein R 10 is R a R b NCOO- and (a) R a and R b are each hydrogen, (b) one of R a and R b is hydrogen and the other is (i) substituted or unsubstituted C 1 to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 3 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 3 to C 8 alkynyl such as ethynyl or straight or branched propynyl, butyny
  • R 10 may be R a R b NCOO- wherein one of R a and R b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
  • the substituents may be those identified elsewhere herein for substituted hydrocarbyl.
  • R 7 is hydroxy and R 10 in each of the series (that is, each of series "A” through “K”) is as previously defined, including wherein R 10 is R 10a R 10b NCOO- and one of R 10a and R 10b is hydrogen and the other is (i) substituted or unsubstituted C, to C 8 alkyl such as methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C 2 to C 8 alkenyl such as ethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C 2 to C 8 alkynyl such as ethynyl or straight or branched prop
  • substituents may be those identified elsewhere herein for substituted hydrocarbyl.
  • preferred R 10 substituents include R 10a R 10b NCOO- wherein one of R 10a and R 10b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
  • preferred R 10 substituents include R 10a R 10b NCOO- wherein one of R 10a and R 10b is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl.
  • X 10 is as otherwise as defined herein.
  • heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl
  • X 10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl)
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 9a are as otherwise as defined herein.
  • 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 9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 7 , R 9 (series D only) and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R g and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 is as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 and R 10 each have the beta stereochemical configuration.
  • X 10 and R 2a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 each have the beta stereochemical configuration.
  • X 10 , R 2a and R 9a are as otherwise as defined herein.
  • 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 2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl
  • R 7 , R 9 and R 10 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.
  • Example 41 In Vitro cytotoxicity measured by the cell colony formation assay
  • HCT116 Four hundred cells (HCT116) 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 CO2 incubator at 37 °C 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.
  • medium modified McCoy's 5a medium containing 10% fetal bovine serum and 100 units/mL penicillin and 100 g/mL streptomycin
  • 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.
  • HBSS Hank's Balance Salt Solution
  • 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 ml 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 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 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 ml 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.
  • 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 0.9% saline to form a pharmaceutically acceptable solution for administration to a patient.
  • D%W an aqueous solution containing 5 % weight by volume of dextrose
  • 0.9% saline 0.9% saline
  • 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.
  • 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.
  • CMC carboxymethylcellulose
  • 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 (100mg) 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® II (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® III (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 was then diluted with 9 parts by weight of Liposyn® III (2%) with stirring to form an emulsion containing 4 mg of compound 1393 per ml 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.

Abstract

The present invention is directed to various formulations of taxanes having improved solubility as compared to paclitaxel, particularly formulations of such taxane derivatives for oral or parenteral administration to a patient.

Description

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 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 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. 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 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 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 to1.2 mg/ml. In addition to 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 micron filter is used during Taxol® administration to guard against the potentially life-threatening infusion of particulates. 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 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 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. 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 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/m2 to 300 mg/m2 over a 3-24 hour period every 21 days or more, often with premedication. At dosages above 300 mg/m2, 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 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 and better-tolerated vehicle than Cremophor®. Alternative formulations of paclitaxel that avoid the use of Cremophor® have been proposed. One approach 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 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 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 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 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 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 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 aqueous lipid emulsion is preferably a soybean oil emulsion. Andersson solubilizes paclitaxel by dissolving it in an organic solvent of dimethylacetamide 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®). 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 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 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 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 of the invention, the taxane has a solubility in ethanol of at least 100 mg/ml. 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/ml and an ID50 value determined relative to the HCT116 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. 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 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 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 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 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 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 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 invention correspond to structure (1):
Figure imgf000007_0001
(1) wherein one of R7 and R10 is hydroxy and the other is acyloxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10; X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
R2 is acyloxy;
R9 is keto, hydroxy, or acyloxy; R14 is hydrido or hydroxy; and Ac is acetyl. R7, R9, and R10 independently have the alpha or beta stereochemical configuration.
In one embodiment, R2 is an ester (R2aC(O)O-), a carbamate (R2aR2bNC(O)O-), a carbonate (R2aOC(O)O-), or a thiocarbamate (R2aSC(O)O-) wherein R2a and R2b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, R2 is an ester (R2aC(O)O-), wherein R2a is aryl or heteroaromatic. In another preferred embodiment, R2 is an ester (R2aC(O)O-), wherein R2a is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R2 is benzoyloxy. While Rg is keto in one embodiment of the present invention, in other embodiments R9 may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, α- or β-hydroxy or α- or β-acyloxy. For example, when R9 is acyloxy, it may be an ester (R9aC(O)O-), a carbamate (R9aR9bNC(O)O-), a carbonate (R9aOC(O)O-), or a thiocarbamate (R9aSC(O)O-) wherein R9a and R9b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R9 is an ester (R9aC(O)O-), R9a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic. Still more preferably, R9 is an ester (R9aC(O)O-), wherein R9a is substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyridyl. In one embodiment R9 is (R9aC(O)O-) wherein R9a 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 R9 is (R9aC(O)O-) wherein R9a is substituted methyl, substituted ethyl, substituted propyl (straight, 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, amidp, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
Exemplary X3 substituents include substituted or unsubstituted C2 to C8 alkyl, substituted or unsubstituted C2 to C8 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 X3 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.
Exemplary X5 substituents include -COX10, -COOX10 or -CONHX10 wherein X10 is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred X5 substituents include -COX10, -COOX10 or -CONHX10 wherein X10 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 C8 alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight, branched or cyclic), 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) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl, 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.
C10 Carbonates In one embodiment, R10 is R10aOCOO- wherein R10a 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 (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 substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred embodiment, R10a 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, 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, 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):
Figure imgf000009_0001
(2) wherein
R7 is hydroxy; R10 is carbonate; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X5 is -COX10, -COOX10, or -CONHX10; and X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R10 may be R10aOCOO- wherein R10a 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 R7a is selected from among these, in one embodiment X3 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 R10a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R10a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R10a is unsubstituted methyl, ethyl or propyl, more preferably methyl or ethyl.
Among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R10 is R10aOCOO- wherein R10a is methyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 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, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R10 is R10aOCOO- wherein R10a is ethyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R10 is R10aOCOO- wherein R10a is propyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
C10 Esters
In one embodiment, R10 is R10aCOO- wherein R10a is (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 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 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 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, 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):
Figure imgf000014_0001
(2)
wherein R7 is hydroxy;
R10 is R10aCOO-;
X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;
X5 is -COX10, -COOX10, or -CONHX10; and X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and
R10a 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 R10a is a substituent;
Bz is benzoyl; and Ac is acetyl.
For example, in this preferred embodiment in which the taxane corresponds to the above structure (2), R10a 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. While R10a is selected from among these, in one embodiment X3 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 R10a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R10a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R7a is unsubstituted ethyl or propyl, more preferably ethyl.
Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R10 is R10aCOO- wherein R10a is ethyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo;
X_ i«ϊ
Figure imgf000015_0001
nrαforαhlx/ oKzoul t hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl,. alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R10 is R10aCOO- wherein R10a is propyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
C10 Carbamates
In one embodiment, R10 is R10aR10bNCOO- wherein R10a and R10b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. Exemplary preferred R10 substituents include R10aR10bNCOO- wherein (a) R10a and R10b are each hydrogen, (b) one of R10a and R10b is hydrogen and the other is (i) substituted or unsubstituted C, 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 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) R10a and R10b are independently (i) substituted or unsubstituted C, 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 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 herein for substituted hydrocarbyl. In one embodiment, preferred R10 substituents include R10aR10bNCOO- wherein one of R10a and R10b 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 correspond to structure (2):
Figure imgf000018_0001
wherein
R7 is hydroxy; R10 is carbamoyloxy;
X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X5 is -COX10, -COOX10, or -CONHX10; and
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R10 may be R10aR10bNCOO- wherein one of R10a and R10b 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 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 R10 substituents include R10aR10bNCOO- wherein one of R10a and R10b is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R10 substituents include R10aR10bNCOO- wherein one of R10a and R10b is hydrogen and the other is substituted or unsubstituted phenyl or heterocyclo. While R10a and R10b are selected from among these, in one embodiment X3 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 R10a, R10b, and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R10a, R10b, and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R10 is R10aR10bNCOO-, one of R10a and R10b is hydrogen and the other is substituted or unsubstituted substituted or unsubstituted C1 to C8 alkyl, phenyl or heterocyclo.
Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R10 is R10aR10bNCOO- wherein R10a is methyl and R10b is hydrido. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R10 is R10aR10bNCOO- wherein R10a is ethyl and R10b is hydrido. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
C10 Heterosubstituted Acetates
In one embodiment, R10 is R10aC(O)O- wherein R10a is heterosubstituted methyl, said 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, 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. Exemplary R10 substituents include R10aCOO- wherein R10a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, acetoxy methyl, acyloxymethyl, or methylthiomethyl.
In one of the preferred embodiments, the taxane corresponds to structure 1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t-butoxycarbonyl, and R10 is R10aC(O)O- wherein R10a is alkoxymethyl, preferably methoxymethyl or ethoxymethyl. In another embodiment of the present invention the taxane corresponds to structure 1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t-butoxycarbonyl, and R10 is R10aC(O)O- wherein R10a is acyloxymethyl, preferably acetoxymethyl.
In another embodiment of the present invention, the taxane corresponds to structure 1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t- butoxycarbonyl, R10 is R10aC(O)O- wherein R10a is alkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl, and X3 is heterocyclo. In another embodiment of the present invention the taxane corresponds to structure 1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t-butoxycarbonyl, and R10 is R10aC(O)O- wherein R10a is acyloxymethyl, preferably acetoxymethyl, and X3 is heterocyclo.
In another embodiment, the taxanes correspond to structure (2):
Figure imgf000022_0001
(2)
wherein
R7 is hydroxy;
R10 is heterosubstituted acetate;
X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms;
X5 is -COX10, -COOX10, or -CONHX10; and
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R10 is R10aCOO- wherein R10a is heterosubstituted methyl, more preferably heterosubstituted methyl wherein the heterosubsituents are selected 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 R10a is selected from among these, in one embodiment X3 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 R10a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R10a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R10 is alkoxyacetyl aryloxyacetyl, or acyloxyacetyl.
C7 Carbonates
In one embodiment, R7 is R7aOCOO- wherein R7a 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) 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, R7a 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, R7a 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, 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):
Figure imgf000024_0001
(2) wherein
R7 is carbonate; R10 is hydroxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X5 is -COX10, -COOX10, or -CONHX10; and X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R7 may be R7aOCOO- wherein R7a 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 R7a is selected from among these, in one embodiment X3 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 R7a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R7a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R7a is unsubstituted methyl, ethyl or propyl, more preferably methyl or ethyl. Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R7 is R7aOCOO- wherein R7a is methyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R7 is R7aOCOO- wherein R7a is ethyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p- nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R7 is R7aOCOO- wherein R7a is propyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration. C7 Ester
In one embodiment, R7 is R7aCOO- wherein R7a is (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 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 substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred embodiment, R7a 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, R7a 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, ester and ether moieties, but not phosphorous containing moieties. In one of the preferred embodiments, the taxanes of the present invention correspond to the following structural formula (2):
Figure imgf000028_0001
(2) wherein
R7 is R7aCOO-; R10 is hydroxy;
X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10;
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; R7a 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 Ra is a substituent; Bz is benzoyl; and Ac is acetyl.
For example, in this preferred embodiment in which the taxane corresponds to structure (2), R7a 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. While R7a is selected from among these, in one embodiment X3 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 R7a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R7a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, orX5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R7a is unsubstituted ethyl or propyl, more preferably ethyl.
Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R7 is R7aCOO- wherein R7a is ethyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R7 is R7aCOO- wherein R7a is propyl. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p- nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
C7 Carbamates
In one embodiment, R7 is R7aR7bNCOO- wherein R7a and R7b are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo. Exemplary preferred R7 substituents include R7aR7bNCOO- wherein (a) R7a and R7b are each hydrogen, (b) one of R7a and R7b is hydrogen and the other is (i) substituted or unsubstituted C, 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 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) R7a and R7b 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 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 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, preferred R7 substituents include R7aR7bNCOO- wherein one of R7a and R7b 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 correspond to structure (2):
Figure imgf000032_0001
(2) wherein
R7 is carbamoyloxy; R10 is hydroxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10; and X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R7 may be R7aR7bNCOO- wherein one of R7a and R7b is hydrogen and the other is (i) substituted or unsubstituted C, 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 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 R7 substituents include R7aR7bNCOO- wherein one of R7a and R7b is hydrogen and the other is substituted or unsubstituted, preferably unsubstituted methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R7 substituents include R7aR7bNCOO- wherein one of R7a and R7b is hydrogen and the other is substituted or unsubstituted phenyl or heterocyclo. While R7a and R7b are selected from among these, in one embodiment X3 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 R7a, R7b, and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R7a, R7b, and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R7 is R7aR7bNCOO-, one of R7a and R7b is hydrogen and the other is substituted or unsubstituted C, to C8 alkyl, phenyl or heterocyclo.
Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R7 is R7aR7bNCOO- wherein R7a is methyl and R7b is hydrido. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to structure 1 or 2 wherein R7 is R7aR7bNCOO- wherein R7a is ethyl and R7b is hydrido. In this embodiment, X3 is preferably cycloalkyl, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t- butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is keto and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R14 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t- butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t- amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, R9 is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1 , R7 and R10 may each have the beta stereochemical configuration, R7 and R10 may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while R10 has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R10 has the alpha stereochemical configuration.
C7 Heterosubstituted Acetates
In one embodiment, R7 is R7aC(O)O- wherein R7a is heterosubstituted methyl, said heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R7a 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 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R7 substituents include R7aCOO- wherein R7a is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, or methylthiomethyl. In one of the preferred embodiments, the taxane corresponds to structure
1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t-butoxycarbonyl, and R7 is R7aC(O)O- wherein R7a is alkoxymethyl, preferably methoxymethyl or ethoxymethyl. In another embodiment of the present invention the taxane corresponds to structure 1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t-butoxycarbonyl, and R7 is R7aC(O)O- wherein R7a is acyloxymethyl, preferably acetoxymethyl.
In another embodiment of the present invention, the taxane corresponds to structure 1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t- butoxycarbonyl, R7 is R7aC(O)O- wherein R7a is alkoxymethyl such as methoxymethyl or ethoxymethyl, or aryloxymethyl such as phenoxymethyl, and X3 is heterocyclo. In another embodiment of the present invention the taxane corresponds to structure 1 , X5 is -COX10 wherein X10 is phenyl or -COOX10 wherein X10 is t-butoxycarbonyl, and R7 is R7aC(O)O- wherein R7a is acyloxymethyl, preferably acetoxymethyl, and X3 is heterocyclo. In one preferred embodiment, the taxanes of the present invention correspond to structure (2):
Figure imgf000036_0001
(2) wherein
R7 is heterosubstituted acetate; R10 is hydroxy;
X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10; and
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R7 may be R7aCOO- wherein R7a is heterosubstituted methyl, more preferably heterosubstituted methyl wherein the heterosubsituents are selected 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 R7a is selected from among these, in one embodiment X3 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 R7a and X3 are selected from among these, in one embodiment X5 is selected from -COX10 wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl. Alternatively, while R7a and X3 are selected from among these, in one embodiment X5 is selected from -COX o wherein X10 is phenyl, alkyl or heterocyclo, more preferably phenyl, or X5 is -COOX10 wherein X10 is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure (2) in which (i) X5 is -COOX10 wherein X10 is tert-butyl or X5 is -COX10 wherein X10 is phenyl, (ii) X3 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) R7 is alkoxyacetyl or acyloxyacetyl.
Taxanes having the general formula 1 may be obtained by treatment of a β-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a β-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 III by selective formation of a carbonate of the C-10 hydroxyl 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 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 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 acylating agent is a dicarbonate.
Taxanes having C(10) esters may be prepared from 10-deacetylbaccatin III (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 III, for example, 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- deacetylbaccatin III 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 β-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. Taxanes having C(7) carbonates may be prepared from 10- deacetylbaccatin III (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 10-deacetylbaccatin III is then selectively protected with a silyl group using, for example, a silylamide 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 β- lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a β-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 10-deacetylbaccatin III (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 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 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 III having alternative substituents at C(2), C(9) and C(14) and processes for their preparation are known in the art. 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. Patent No. 5,352,806. Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy- 10-deacetylbaccatin III.
Processes for the preparation and resolution of the β-lactam starting material are generally well known. For example, the β-lactam may be prepared as described in Holton, U.S. Patent No. 5,430,160 and the resulting enatiomeric mixtures of β-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 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 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. The pharmaceutical compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper 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, 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, 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, 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 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 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). 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, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, 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. 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 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. 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 liquid.
Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., α-glycerol formal, β-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, 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-(β- hydroxyethyl)-lactamide, N, N-dimethylacetamide_amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g., 1-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 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, 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 as poly(ethoxylated)30.60 sorbitol poly(oleate)2.4 poly(oxyethylene)15.20 monooleate, poly(oxyethylene)15.20 mono 12-hydroxystearate, and poly(oxyethylene)15.20 mono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI 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, 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 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 isobutyl 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 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 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- 30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-Iinolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 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 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 & 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 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 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® II 20% emulsion (a 20% 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), Liposyn® III 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 containing the docosahexaenoyl group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® (from Martek Biosciences 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 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 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 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 (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, 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, 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 stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, 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 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 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% 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, 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 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 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. Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired 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 m2of patient body surface area, or at least 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m2of patient body surface area, wherein the average body surface area for a human is 1.8 m2. Preferably, a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m2of patient body surface area, more preferably from about 25 to about 400 mg/m2' even more preferably, from about 40 to about 300 mg/m2, and even more preferably from about 50 to about 200 mg/m2. 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 m2of patient body surface area, or at least 40, 50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m2of patient body 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 m2of patient body surface area, more preferably from about 40 to about 400 mg/m2' and even more preferably, from about 60 to about 350 mg/m2. However, the dosage may vary depending on the dosing schedule which can be adjusted as 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. 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 concentrations are generally preferred because the antitumor cornpound 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 40 weight %, and most preferably between about 10 weight % and about 30 weight %. 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 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.
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 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 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 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® III 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 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 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® 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 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, 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 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. 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, 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 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. 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 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 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 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 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 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, 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, 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 heterocyclo include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, 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.
The term "heteroaromatic" as used herein alone or as part of another 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 include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, 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. 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 R1, R1O-, R1R2N-, or R1S-, R1 is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocyclo and R2 is hydrogen, hydrocarbyl or substituted hydrocarbyl. 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 (-O-), 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 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. 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 be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John
Wiley and Sons, 1981 , or Fieser & Fieser. Exemplary hydroxyl protecting groups include methoxymethyl, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl. 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" means lithium aluminum hydride; "10-DAB" means 10-desacetylbaccatin III"; "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- 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; "C4H7CO" means butenylcarbonyl; "tC3H5CO" means ans-propenylcarbonyl; "EtOCO" means ethoxycarbonyl; "ibueCO" means isobutenylcarbonyl; "iBuCO" means 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. 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. Example 1 : Preparation of Taxane having C-7 Ester and C-10 Hydroxy Substituents
Figure imgf000052_0001
10-Triethylsϊlyl-10-deacetyl baccatin III. To a solution of 1.0 g (1.84 mmol) of 10-deacetyl baccatin III in 50 mL of THF at -10 °C under a nitrogen atmosphere was added 0.857 mL (2.76 mmol, 1.5 moi equiv) of Λ/,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 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 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 °C; [ ]D 25 -60.4 (c 0.7, CHCI3); 1H NMR (CDCI3, 400MHz) δ (p.p.m): 8.10 (2H, d, Jm = 7.5Hz, Bzo), 7.60 (1 H, t, Jm = 7.5Hz, Bzp), 7.47 (2H, t, Jo = 7.5Hz,
Bzm), 5.64 (1 H, d, J3 = 6.9Hz, H2), 5.26 (1 H, s, H10), 4.97 (1 H, dd, J6β = 2.2Hz, J6α = 9.9Hz, H5), 4.85 (1 H, dd, J14α = 8.9Hz, J14β = 8.9Hz, H13), 4.30 (1 H, d, J20β = 8.5Hz, H20α), 4.23 (1 H, ddd, J7OH = 4.5Hz, J6α = 6.6Hz, J6β = 11.0Hz, H7), 4.15 (1 H, d, J20α = 8.5Hz, H20β), 4.00 (1 H, d, J2 = 6.9Hz, H3), 2.58 (1 H, ddd, J7 = 6.6Hz, J5 = 9.9Hz, J6β = 14.5Hz, H6α), 2.28-2.25 (5H, m, 4Ac,
H14α, H14β ), 2.02 (3H, s, 18Me), 1.97 (1 H, d, J7 = 4.5Hz, H7OH), 1.78 (1 H, ddd, J7 = 11.0Hz, J5 = 2.2Hz, J6α = 14.5Hz, H6β), 1.68 (3H, s, 19Me), 1.56 (1H, 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, JCH2(TES) = 7.3Hz, CH3(TES)), 0.65 (6H, dq, JCH3(TES) = 7.3Hz, CH2(TES)).
Figure imgf000053_0001
10-Trlethylsilyl-10-deacetyl-7 -propionyl baccatin III. To a solution of 1.0 g
(1.517 mmol) of 10-triethylsilyl-10-deacetyl baccatin III 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 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 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 (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; [α]D 25 -47.9 (c 1.0, CHCI3); NMR 1H (CDCI3, 300MHz) δ (ppm): 8.10 (2H, d, Jm = 7.4Hz, Bzo), 7.60 (1 H, t, Jm = 7.4Hz, Bzp), 7.48 (2H, dd, Jo = 7.4Hz, Jp = 7.4Hz, Bzm), 5.64 (1 H, d, J3 = 7.4Hz, H2), 5.47 (1 H, dd, J6 = 7.4Hz, J6β = 10.1 Hz, H7), 5.28 (1 H, s, H10), 4.94 (1 H, d, J6 = 9.4Hz, H5), 4.80 - 4.90 (1 H, m, H13), 4.31 (1 H, d, J20β = 8.1 Hz, H20α), 4.16 (1H, d, J20α = 8.1 Hz, H20β), 4.06 (1 H, d, J2 = 7.4Hz, H3), 2.55 (1 H, ddd, J7 = 7.4Hz, J5 = 9.4Hz, J6β = 14.8Hz, H6α), 2.28 (3H, s, 4Ac), 2.23 - 2.32 (4H, m, 7CH2, H14 , H14β), 2.07 (3H, s, 18Me), 2.02 (1H, d, J13 = 4.7Hz, OH13), 1.76 - 1.87 (4H, m, H6β, 19Me), 1.60 (1 H, s, OH1 ), 1.17 (3H, s, 17Me), 1.09 (3H, t, J 7CH2 = 7.4Hz, 7CH3), 1.04 (3H, s, 16Me), 0.96 (9H, t, JCH2(TES) = 8.0Hz, CH3(TES)), 0.52 - 0.62 (6H, m, CH2(TES)).
Figure imgf000054_0001
2'-O-MOP-3'-desphenyl-3'-(2-furyl)-10-triethylsilyl-7-propionyl taxotere. To a solution of 493 mg (0.690 mmol) of 10-triethylsilyl-10-deacetyl-7-propionyl 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 1 M solution of LiHMDS in THF. After 0.5 h a 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 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 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); 1H NMR (CDCI3, 400MHz) d (ppm): 8.09-8.11 (m, 2H), 7.58-7.61 (m, 1 H), 7.47-7.51 (m, 2H), 7.39 (d, J = 0.8 Hz, 1 H), 6.34 (dd, J = 3.2, 1.6 Hz, 1 H), 6.26 (d, J = 3.2 Hz), 6.14 (dd, J = 8.8, 8.8 Hz, 1 H), 5.71 (d, J = 6.8 Hz, 1 H), 5.47 (dd, J = 10.0, 7.2 Hz, 1 H), 5.30-5.36 (m, 2H), 5.28 (s, 1 H), 4.95 (d, J = 7.6 Hz, 1 H), 4.76 (s, 1 H), 4.33 (d, J= 8.0 Hz, 1 H), 4,19 (d, J = 8.4 Hz, 1 H), 4.03 (d, J = 6.8 Hz, 1 H), 2.83 (s, 3H), 2.55 (ddd, J = 17.2, 9.6, 7.6, 1 H), 2.50 (s, 3H), 2.20-2.40 (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).
Figure imgf000055_0001
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-propionyl taxotere in 1.7 mL of pyridine and 5.4 mL of acetonitrile at 0 °C 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 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 (CH2Cl2: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 °C; [a]D 25 -27.0 (c 5.0, methanol); Anal. Calcd for C44H55NOi6*0.5H2O: C, 61.18; H, 6.48. Found: C, 61.40; H, 6.65. 1H NMR (CDCI3, 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, 1 H), 6.38 (dd, J = 3.0, 2.0 Hz, 1 H), 6.33 (d, J = 3.5 Hz), 6.22 (dd, J = 9.5, 9.5 Hz, 1 H), 5.69 (d, J = 7.0 Hz, 1 H), 5.49 (dd, J = 11.0, 7.5 Hz, 1 H), 5.35 (d, J = 9.5 Hz, 1 H), 5.33 (d, J = 1.5 Hz, 1 H), 5.25 (d, J = 9.5 Hz, 1 H), 4.94 (d, J = 8.5 Hz, 1 H), 4.71 (dd, J = 5.5, 2.0 Hz, 1 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, 1 H), 3.30 (d, J = 5.5 Hz, 1 H), 2.54 (ddd, J = 16.5, 9.5, 7.0, 1 H), 2.41 (s, 3H), 2.37 (dd, J = 15.0, 9.0 Hz, 1 H), 2.30 (dd, J = 17.5, 9.5 Hz, 1 H), 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, 3H), 1.64 (s, 1 H), 1.36 (s, 9H), 1.23 (s, 3H), 1.10 (t, J = 7.5 Hz, 3H). Example 2: Additional Taxanes having C-7 Ester and C-10 Hvdroxy Substituents The procedures described in Example 1 were repeated, but other suitably protected β-lactams were substituted for the β-lactam of Example 1 to prepare the series of compounds having structural formula (3) and the combinations of substituents identified in the following table.
Figure imgf000056_0001
(3)
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000058_0001
Example 3: Additional Taxanes having C-7 Ester and C-10 Hydroxy Substituents Following the processes described in Example 1 and elsewhere herein, the following specific taxanes having structural formula (4) may be prepared, wherein R7 is as previously defined, including wherein R7 is RaCOO- and Ra is (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 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 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.
Figure imgf000060_0001
(4)
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Example 4: Additional Taxanes having C-7 Ester and C-10 Hvdroxy Substituents Following the processes described in Example 1 and elsewhere herein, the following specific taxanes having structural formula (5) may be prepared, wherein R10 is hydroxy and R7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R7 is R7aCOO- and R7a is
(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 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 unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl. In the "A" series of compounds, X10 is as otherwise as defined herein.
Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7 and R10 each have the beta stereochemical configuration. In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration. In the "C" series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, R9 (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "H" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "I" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration. In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
Any substituents of each X3, X5, R2, R7, and Rg 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.
Figure imgf000074_0001
(5)
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Example 5: In Vitro cytotoxicitv measured by the cell colony formation assay
Four hundred cells (HCT116) 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 CO2 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 ° 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.
Figure imgf000084_0002
10
15
20
25
30
Figure imgf000085_0001
10
15
20
25
30
Figure imgf000086_0001
Figure imgf000087_0002
Example 6: Preparation of Taxane having C-10 Ester and C-7 Hydroxy Substituents
Figure imgf000087_0001
10-Propionyl-10-deacetyl baccatin III. To a mixture of 0.2 g (0.367 mmol) of 10-deacetyl baccatin III and 0.272 g (1.10 mmol) of CeCI3 in 10 mL of THF at 25 °C 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 NaHCO3 solution and brine. The organic extract was dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by flash column chromatography on silica gel using 70% EtOAc/hexane as eluent to give 0.199 g (90%) of 10-propionyl-10-deacetyl baccatin III as a solid. Me2PhSiCI
Figure imgf000088_0002
Figure imgf000088_0001
7-Dimethylphenylsilyl-10-propionyl-10-deacetyl baccatin III. To a solution of 0.200 g (0.333 mmol) of 10-propionyl-10-deacetyl baccatin III in 12 mL of THF at - 10 °C 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 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 Na2SO4, and concentrated in vacuo. 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-10- propionyl-10-deacetyl baccatin III as a solid.
Figure imgf000088_0003
7-Dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3'-(2-thienyl)-10- propionyl-10-deacetyl taxol. To a solution of 0.400 g (0.544 mmol) of 7- dimethylphenylsilyl-10-propionyl-10-deacetyl 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 1 M solution of LHMDS in THF. After 1 h, a solution of 0.317 g (0.818 mmol) of cis- - benzoyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in 3 mL of THF was added slowly. The mixture was warmed to 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, dried over Na2SO4, 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-deacetyl taxol as a solid.
Figure imgf000089_0001
3'-Desphenyl-3'-(2-thienyl)-10-propionyl-10-deacetyl taxol. To a solution of 0.521 g (0.464 mmol) of 7-dimethylphenyIsilyl-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 H2O. 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 organic extracts were washed with brine, dried over Na2SO4, 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-deacetyl taxol as a solid, m.p. 154-155 °C; [a]D 25 = -45.0 (c 0.1 in CHCI3); Anal. Calcd. for C46H51NO14S: C, 63.22; H, 5.88; Found: C, 62.94; H, 5.97.
3'-Desphenyl-3'-(2-thienyl)-10-propionyl-10-deacetyl taxol 1H NMR data
(CDCI3)
Figure imgf000089_0002
Figure imgf000090_0001
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 β-lactams were substituted for the β-lactam of Example 6 to prepare the series of compounds having structural formula (6) and the combinations of substituents identified in the following table.
Figure imgf000091_0001
(6)
Figure imgf000091_0002
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0002
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 R10 is as previously defined, including wherein R10 is RaCOO- and Ra is (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 OP 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, R10 may be R10aCOO- wherein R10a is ethyl, straight, branched or cyclic propyl, straight or branched propenyl, isobutenyl, furyl or thienyl.
Figure imgf000097_0001
(7)
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Example 9: 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 (8) may be prepared, wherein R7 is hydroxy and R10 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R10 is R10aCOO- and R10a is (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 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 unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl.
In the "A" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7 and R10 each have the beta stereochemical configuration. In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "C" series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, R9 (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration. In the "H" series of compounds, X10 is as otherwise as defined herein.
Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "I" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
Any substituents of each X3, X5, R2, R9, R10 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.
Figure imgf000111_0001
(8)
Figure imgf000111_0002
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Example 10: In Vitro cytotoxicitv measured by the cell colony formation assay Four hundred cells (HCT116) 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 CO2 incubator at 37 CC 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 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.
Figure imgf000120_0001
10
15
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30
Figure imgf000121_0001
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Figure imgf000122_0001
10
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Figure imgf000123_0001
10
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Figure imgf000124_0001
10
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Figure imgf000125_0001
Figure imgf000126_0001
Example 11 : Preparation of Taxane having C-7 Substituted Acetate and C-10 Hydroxy
N-Debenzoyl-N-fert-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)- 10-deacetyl-7-methoxyacetyl taxol (6226) To a solution of N-debenzoyl-N-te/T- amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyl)-7- benzyloxycarbonyl-10-deacetyl-10-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 H2 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 washed with 25 mL of ethyl acetate. The combined ethyl acetate fraction was concentrated under reduced pressure to give, the N-debenzoyl-N-tetτf- amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyl)-10-deacetyl- 10-trimethylsilyl taxol as a white solid 2.10 g (96%) which was directly used in the next step.
To a solution of N-debenzoyl-N-te/τ-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-(2- methoxy-2-propyl)-10-deacetyl-10-trimethylsilyl taxol (400 mg, 0.418 mmol) in 4 mL anhydrous pyridine at 0 °C 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 °C (ice-water bath) and quenched by adding 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 2x10 mL of saturated aqueous NaHCO3 followed by 15 mL of saturated aqueous NaCI. The organic layer was dried over Na2SO4 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-fe/τ-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-10-deacetyl-7- methoxyacetyl taxol: mp 166-167 °C; 1H NMR (CDCI3) 8.12 (m, 2H), 7.62(m, 1H), 7.46-7.51 (m, 2H), 7.40 (m, 1 H), 6.39(dd, J=3.1 , 1.5 Hz, 1 H), 6.25 (d, J=3.1 Hz, W), 6.21 (dd, J=8.8, 8.7 Hz, 1 H), 5.67(1 H), 5.58 (m, 1 H), 5.26-5.38(m, 3H), 4.98(m, 1 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, 1 H), 2.55-2.60(m, 1H), 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), 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 C45H57NO17: 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 protected β-lactams were substituted for the β-lactam of Example 1 to prepare the series of compounds having structural formula (9) and the combinations of substituents identified in the following table:
Figure imgf000128_0001
0)
Figure imgf000128_0002
Example 13: Taxanes having C7 Substituted Acetate and C-10 Hydroxy Substituents Following the processes described elsewhere herein, the following specific taxanes having structural formula (10) may be prepared, wherein R7 is as previously defined, including wherein R7 is R7aCOO-and R7a is heterosubstituted methyl. In one embodiment, R7a is chloromethyl, hydroxy methyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, or methylthiomethyl.
Figure imgf000129_0001
Figure imgf000129_0002
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Example 14: Taxanes having C-7 Substituted Acetate and C-10 Hydroxy Substituents Following the processes described in Example 11 and elsewhere herein, the following specific taxanes having structural formula (11) may be prepared, wherein R10 is hydroxy and R7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R7 is R7aCOO- wherein R7a is a heterosubstituted methyl moiety lacking a carbon atom which is in the beta position relative to the carbon atom of which R7a 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 hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Exemplary R7 substituents include R7aCOO- wherein R7a is hydrogen, methyl, chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.
In the "A" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert- butyl), and R7 and R10 each have the beta stereochemical configuration.
In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "C" series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, Rg (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration. In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "H" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "I" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
Any substituents of each X3, X5, R2, R7, and R9 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.
Figure imgf000138_0001
(11)
Figure imgf000138_0002
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Example 15: In Vitro cvtotoxicitv measured by the cell colony formation assay Four hundred cells (HCT116) 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 CO2 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 ° C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 L 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.
Figure imgf000148_0002
Figure imgf000149_0001
Example 16: Preparation of Taxane having C-10 Substituted Acetate and C-7
Hydroxy
N-Debenzoyl-N-ferf-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-10- methoxyacetyl taxol (6515) To a solution of N-debenzoyl-N-ferf-amyloxycarbonyl- 3'-desphenyl-3'-(2-furyl)-2'-(2-methoxy-2-propyI)-7-benzyloxycarbonyl-10-deacetyl- 10-trimethylsilyl taxol (3.50 g) in 40 mL of 1 :1 acetonitrile-pyridine at 0 °C (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 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 NaHCO3 and 25 mL of saturated aqueous NaCI. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure to give N-debenzoyl-N-fetτ-amyloxycarbonyl-3'-desphenyl-3'-(2- furyl)-7-benzyloxycarbonyl-10-deacetyl taxol as a white solid which was dried under high vacuum (0.1 mmHg, 12 h) and used directly in the next step.
To a solution of N-debenzoyl-N-fetf-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 gel, 2:3 ethyl acetate:hexane) after 2 h, showed the formation of only one product. Saturated aqueous NaHCO3, 2 mL was added to the reaction which was then diluted with 70 mL of ethyl acetate, washed with 10 mL of saturated aqueous NaHCO3 and 15 mL of saturated aqueous NaCI. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give pure N-debenzoyl-N-te/ - amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'-triethylsilyl-7-benzyloxycarbonyl-10- deacetyl taxol as a white solid (2.21 g, 91%)
To a solution of N-debenzoyl-N-tetτ-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-2'- triethylsilyl-7-benzyloxycarbonyI-10-deacetyl taxol (660 mg, 0.622 mmol) in 4 mL anhydrous pyridine at 0 °C 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 material. The reaction was cooled to 0 °C (ice-water bath) and quenched by adding 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, diluted with 60 mL of ethyl acetate and washed with 10 mL of saturated aqueous NaHCO3 and 15 mL of saturated aqueous NaCI. The organic layer was dried over Na2SO4 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-fe/T- amyloxycarbonyI-3'-desphenyl-3'-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl-10- methoxyacetyl taxol (TL-650): mp 145-146 °C; Anal. Calcd. for C53H63NO19: C, 62.53; H, 6.24. Found: C, 62.26; H, 6.20.
To a solution of N-debenzoyl-N-fe/7-amyloxycarbonyl-3'-desphenyl-3'-(2-furyl)-7- benzyloxycarbonyl-10-deacetyl-10-methoxyacetyl taxol (TL-650, 350 mg, 0.343 mmol) in 15 mL ethyl acetate was added 10% Pd-C (100 mg). The mixture was stirred under a H2 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 acetate:hexane) to give 283mg (93%) of pure N-debenzoyl-N-tetf-amyloxycarbonyl- 3'-desphenyl-3'-(2-furyl)- -10-deacetyl-10-methoxyacetyl taxol: mp 164-166 °C; 1H NMR (CDC 8.13 (m, 2H), 7.62(m, 1 H), 7.46-7.51 (m, 2H), 7.41 (m, 1 H), 6.41 (bs, 1 H), 6.39(dd, J=3.1 , 1.5 Hz, 1 H), 6.25 (d, J=3.1 Hz, 1 H), 6.22(dd, J=8.8, 8.7 Hz, 1 H), 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, 1 H), 4.21 (d, J=9.3 Hz, 1 H), 3.82 (m, 1 H), 3.42 (s, 3H), 3.41 (d, J= 5.5 Hz, 1 H), 2.55-2.60(m, 1 H), 2.41 (s, 3H), 2.20-2.38(m, 2H), 1.92 (s, 3H), 1.91- 1.94 (m, 1 H), 1.68 (bs, 3H), 1.62-1.68(m, 2H), 1.62(S, 3H), 1.36(s, 3H), 1.34(s, 3H), 1.23(s, 3H), 1.16(s, 3H), 0.80(t, J=8.2Hz, 3H); Anal. Calcd. for C45H57NO17.1/2H2O: 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 β-lactams were substituted for the β-lactam of Example 16 to prepare the series of compounds having structural formula (12) and the combinations of substituents identified in the following table:
Figure imgf000151_0001
(12)
Figure imgf000151_0002
Example 18: Taxanes having C-10 Substituted Acetate and C-7 Hvdroxy Substituents
Following the processes described in Example 16 and elsewhere herein, the following specific taxanes having structural formula (13 ) may be prepared, wherein R10 is R10aCOO- and R10a is heterosubstituted methyl. In one embodiment, R10a is chloromethyl, hydroxy methyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.
Figure imgf000152_0001
(13)
Figure imgf000152_0002
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
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 R7 is hydroxy and R10 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R10 is R10aCOO- wherein R10a 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, 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. Exemplary R10 substituents include R10aCOO- wherein R10a is chloromethyl, hydroxy methyl, methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl. In the "A" series of compounds, X10 is as otherwise as defined herein.
Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert- butyl), and R7 and R10 each have the beta stereochemical configuration.
In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration. In the "C" series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, R9 (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "H" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "I" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration. In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration.
Any substituents of each X3, X5, R2, R7, and R9 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.
Figure imgf000161_0001
(14)
Figure imgf000161_0002
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Example 20: In Vitro cvtotoxicity measured by the cell colony formation assay
Four hundred cells (HCT116) 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 CO2 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 ° 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.
Figure imgf000170_0002
Example 21 : Preparation of Taxane having C-7 Carbonate and C-10 Hydroxy
Figure imgf000170_0001
10-Triethylsilyl-10-deacetyl baccatin III. To a solution of 1.0 g (1.84 mmol) of 10- deacetyl baccatin III in 50 mL of THF at -10 °C under a nitrogen atmosphere was added 0.857 mL (2.76 mmol, 1.5 mol equiv) of Λ/,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(trimethylsilyi)amide (0.055 mmol, 0.03 mol equiv). After 10 min 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 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 °C; [α]D 25 -60.4 (c 0.7, CHCI3); 1H NMR (CDCI3, 400MHz) δ (p.p.m): 8.10 (2H, d, Jm = 7.5Hz, Bzo), 7.60 (1 H, t, Jm = 7.5Hz, Bzp), 7.47 (2H, t, Jo = 7.5Hz, Bzm), 5.64 (1 H, d, J3 = 6.9Hz, H2), 5.26 (1 H, s, H10), 4.97 (1 H, dd, J6β = 2.2Hz, J6α = 9.9Hz, H5), 4.85 (1 H, dd, J14α = 8.9Hz, J14β = 8.9Hz, H13), 4.30 (1 H, d, J20β = 8.5Hz, H20α), 4.23 (1 H, ddd, J7OH = 4.5Hz, J6 = 6.6Hz, J6β = 11.0Hz, H7), 4.15 (1 H, d, J20α = 8.5Hz, H20β), 4.00 (1 H, d, J2 = 6.9Hz, H3), 2.58 (1 H, ddd, J7 = 6.6Hz, J5 = 9.9Hz, J6β = 14.5Hz, H6α), 2.28-2.25 (5H, m, 4Ac, H14α, H14β ), 2.02 (3H, s, 18Me), 1.97 (1 H, d, Jl = 4.5Hz, H7OH), 1.78 (1 H, ddd, Jl = 11.OHz, J5 = 2.2Hz, J6α = 14.5Hz, H6β), 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, JCH2(TES) = 7.3Hz, CH3(TES)), 0.65 (6H, dq, JCH3(TES) = 7.3Hz, CH2(TES)).
Figure imgf000171_0001
10-Triethylsllyl-10-deacetyl-7-methoxycarbonyl baccatin III. To a solution of 9.3 g (14.1 mmol) of 10-triethyIsilyI-10-deacetyl baccatin III and 10.35 g (84.6 mmol) of DMAP in 500 mL of dichloromethane at 0 °C 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 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 III. m.p.260-262 °C; [α]D 25-54.3 (c0.89, CHCI3); 1H NMR (CDCI3, 500MHz) δ (ppm): 8.10 (2H, d, Jm = 8.5Hz, Bzo), 7.60 (1 H, 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, J6α = 7.0Hz, J6β = 10.0 Hz, H7), 5.28 (1 H, s, H10), 4.96 (1H, d, J6α = 8.5 Hz, H5), 4.86 (1 H, t, J14α = 14.0 Hz, J14β = 7.0 Hz, H13), 4.31 (1 H, d, J20β = 8.0 Hz, H20 ), 4.16 (1 H, d, J20α = 8.0Hz, H20β), 4.06 (1 H, d, J2 = 7.0 Hz, H3), 3.77 (3H, s, OMe) 2.65 (1 H, ddd, Jl = 7.0 Hz, J5 = 8.5 Hz, J6β = 10.0 Hz, H6α), 2.29-2.26 (5H, m, 4Ac, H14α, H14β ), 2.08 (3H, s, 18Me), 2.01 (1 H, d, 13OH), 1.92 (3H, ddd, Jl = 10.0 Hz, J5 = 2.3 Hz, J6α = 10.0 Hz, H6β), 1.80 (3H, s, 19Me), 1.18 (3H, s, 17Me), 1.05 (3H, s, 16Me), 0.97 (9H, t, JCH2(TES) = 8.0 Hz, CH3(TES)), 0.59 (6H, dq, JCH3(TES) = 8.0Hz, CH2(TES)).
Figure imgf000172_0001
2'-O-MOP-3'-desphenyl-3'-(2-thienyl)-10-triethylsilyl-7-methoxycarbonyl taxotere. To a solution of 495 mg (0.690 mmol) of 10-triethylsilyl-10-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 1 M solution of LiHMDS in THF. 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 °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 under reduced pressure to give 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 679 mg (93%) of a white crystalline solid which was used directly in the next reaction.
Figure imgf000172_0002
3'-Desphenyl-3'-(2-thienyl)-7-methoxycarbonyl taxotere. To a solution of 211 mg (0.199 mmol) of 2'-O-MOP-3'-desphenyl-3'-(2-thienyl)-10-triethylsiIyl-7- methoxycarbonyl taxotere in 1.7 mL of pyridine and 5.4 mL of acetonitrile at 0 °C 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 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 (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, CHCI3); Anal. Calcd forC43H53NOιeS: C, 59.23; H, 6.13. Found: C, 58.99; H, 6.25. 1H NMR (500 MHz, CDCl3):
Proton d (ppm) Pattern J (Hz)
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 /77-benzoate(7.5)
3 4.01 d H2(6.5)
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(15.0)
7 5.29 dd H6a(7.5), H6b(11.0)
OMe 3.76 s
10 5.39 s
10-OH 4.06 br s
13 6.23 t H14a(9.0), H14b(9.0)
14a+14b 2.34 m
16Me 1.11 s
17Me 1.23 s
18Me 1.93 s
19Me 1.86 s
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
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 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 β-lactams were substituted for the β-lactam of Example 21 to prepare the series of compounds having structural formula (15) and the combinations of substituents identified in the following table.
Figure imgf000174_0001
(15)
Figure imgf000174_0002
Figure imgf000175_0001
Figure imgf000176_0002
Example 23: Additional 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 (16) may be prepared, wherein R7 is as previously defined, including wherein R7 is RaOCOO- and Ra 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) 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 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.
Figure imgf000176_0001
(16)
Figure imgf000176_0003
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
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 R10 is hydroxy and R7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R7 is R7aOCOO- and R7a is (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 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 unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl.
In the "A" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert- butyl), and R7 and R10 each have the beta stereochemical configuration.
In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "C" series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, Rg (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration.
In the "H" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration. In the "I" series of compounds, X10 and R2a are as otherwise as defined herein.
Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
Any substituents of each X3, X5, R2, R7, and R9 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.
Figure imgf000197_0001
(17)
Figure imgf000197_0002
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Example 25: In Vitro cytotoxicity measured by the cell colony formation assay Four hundred cells (HCT116) 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 CO2 incubator at 37 °C 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 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.
Figure imgf000207_0002
10
15
20
25
30
Figure imgf000208_0001
Figure imgf000209_0002
Example 26: Preparation of Taxanes having C-10 Carbonate and C-7 Hvdroxy
Figure imgf000209_0001
10-Ethoxycarbonyl-10-deacetyl baccatin III. To a mixture of 0.941 g (1.73 mmol) of 10-deacetyl baccatin III and 0.043g (0.17 mmol) of CeCI3 in 40 mL of THF at 25 °C was added 0.64 mL (4.32 mmol) of diethyl pyrocarbonate. After 3 h the reaction mixture was diluted with 200 mL of EtOAc, then washed three times with 50 mL of saturated aqueous NaHCO3 solution and brine. The organic extract was dried over Na2SO4 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 III as a solid.
Figure imgf000210_0001
7-Dimethylphenylsilyl-10-ethoxycarbonyl-10-deacetyl baccatin III. To a solution of 1.02 g (1.65 mmol) of 10-ethoxycarbonyl-10-deacetyl baccatin III in 30 mL of THF at -10 °C under a nitrogen atmosphere was added dropwise 0.668 mL (4.00 mmol) 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 were washed with brine, dried over Na2SO4, 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 III as a solid. 1HNMR (400 MHz, CDCI3): d 8.09 (dm, J= 7.64 Hz, 2 H, benzoate, o), 7.59 (tt, J= 7.54, 1.43 Hz, 1 H, benzoate, 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, 1 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, CH3-CH2-), 4.13 (d, J= 8.27 Hz, 1 H, H20b), 3.83 (d, J= 7.05 Hz, 1 H, H3), 2.34 (ddd, J= 6.84, 9.63, 14.66 Hz, 1 H, H6a), 2.26 (d, J= 7.65 Hz, 2 H, H14a,b), 2.25 (s, 3 H, Ac4), 2.03 (s, 3 H, Me18), 1.98 (d, J= 5.29, 1 H, C13OH), 1.77 (ddd, J= 2.12, 10.37, 14.66 Hz, 1 H, H6b), 1.73 (s, 1 H, Me19), 1.59 (s, 1 H, C1 OH), 1.32 (t, J= 7.00 Hz, 3 H, CH3-CH2-), 1.19 (s, 3 H, Me17), 1.07 (s, 3 H, Me16), 0.45 (s, 3 H, PhMe2Si-), 0.35 (s, 3 H, PhMe2Si-).
Figure imgf000211_0001
7-Dimethylphenylsilyl-2'-O-triethylsilyl-3'-desphenyl-3'-(2-thienyl)-10- ethoxycarbonyl-10-deacetyl taxotere. To a solution of 0.409 g (0.544 mmol) of 7- dimethylphenylsilyl-10-ethoxycarbonyl-10-deacetyl 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 1M solution of LHMDS in THF. After 1 h, a solution of 0.317 g (0.818 mmol) of c/s-N- benzoyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in 3 mL of THF was added slowly. The mixture was warmed to 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, dried over Na2SO4, 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-10-deacetyl taxotere as a solid.
Figure imgf000211_0002
3'-Desphenyl-3'-(2-thienyl)-10-ethoxycarbonyl-10-deacetyl taxotere. To a solution of 0.527 g (0.464 mmol) of 7-dimethylphenylsilyl-2'-O-triethylsilyl-3'- desphenyl-3'-(2-thienyl)-10-ethoxycarbonyl-10-deacetyl taxotere 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 H2O. 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 organic extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel using 70% EtOAc/hexane as eluent to give 0.411 g (100%) of 3'-desphenyI-3'-(2- thienyl)-10-ethoxycarbonyl-10-deacetyl taxotere as a solid, m.p. 160-161 °C; [a]D 25 = -59.1 (c 1.0 in CH2CI2); Anal. Calcd. for C44H55NO16S: C, 59.65; H, 6.26; Found: C, 59.39; H, 6.34.
3'-Desphenyl-3'-(2-thienyl)-10-ethoxycarbonyl-10-deacetyl taxotere 1H NMR data (500 MHz, CDCI3)
Proton d (ppm) Pattern J (Hz)
1OH 1.68 s
2 5.68 d H3(7.0)
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)
7 4.40 ddd C7OH(4.2), H6a(6.6), H6b(10.9)
7OH 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)
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
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)
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 benzoate, m 7.51 t benzoate, o(7.8), benzoate, p(7.8) benzoate, 0 8.12 d benzoate, m(7.8) benzoate, P 7.61 t benzoate, m(7.8)
CH3-CH2-OCO 1.37 t CH3-CH2-OCO(7.1)
CH3-CH2-OCO 4.28 m 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 β-lactams were substituted for the β-lactam of Example 26 to prepare the series of compounds having structural formula (18) and the combinations of substituents identified in the following table.
Figure imgf000213_0001
(18)
Figure imgf000213_0002
Figure imgf000214_0001
Figure imgf000215_0002
Example 28: Additional Taxanes having C-10 Carbonate and C-7 Hydroxy Substituents
Following the processes described in Example 26 and elsewhere herein, the following specific taxanes having structural formula (19) may be prepared, wherein R10 is as previously defined including wherein R10 is RaOCOO- and Ra is (i) substituted or unsubstituted C, 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 propenyl or straight, branched or cyclic butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C3 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 substituents may be those identified elsewhere herein for substituted hydrocarbyl. For example, R10 may be R10aOCOO- wherein R10a is methyl, ethyl, or straight, branched or cyclic propyl.
Figure imgf000215_0001
(19)
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Example 29: Additional Taxanes having C-10 Carbonate and C-7 Hvdroxy 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") R7 is hydroxy and R10 is as previously defined, including wherein R10 is R10aOCOO- and R10a is (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 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 unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl.
In the "A" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7 and R10 each have the beta stereochemical configuration. In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "C" series of compounds, X10 and Rga are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 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 R7, R9 and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, R9 (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration. In the "H" series of compounds, X10 is as otherwise as defined herein.
Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration. In the "I" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
Any substituents of each of X3, X5, R2, R9 and R10 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.
Figure imgf000235_0001
(20)
Figure imgf000235_0002
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Example 30: In Vitro cytotoxicity measured by the cell colony formation assay
Four hundred cells (HCT116) 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 CO2 incubator at 37 °C 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 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.
Figure imgf000244_0001
10
15
20
25
30
Figure imgf000245_0001
Figure imgf000246_0001
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 (5535) To a solution of N-debenzoyl-N-isobutenyl-3'-desphenyl-3'-(2-furyl)-2'-(2- methoxy-2-propyl)-10-triethylsilyI 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 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 0° 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 ethyl acetate and washed with 10 mL of saturated aqueous NaHCO3 followed by 15 mL of saturated aqueous NaCI. The organic layer was dried over Na2SO4 and 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; H NMR (CDCI3) 8.11 (m, 2H), 7.60(m, 1 H), 7.46-7.51 (m, 2H), 7.26-7.40(m, 6H), 6.34(dd, J=3.1 , 1.5 Hz, 1 H), 6.25 (d, J=3.1 Hz, 1 H), 6.21 (dd, J=8.8, 8.7 Hz, 1 H), 5.67(2H), 5.47(2H), 4.98-5.01 (m, 3H), 4.76(m, 1 H), 4.32(d, J=8.0 Hz, 1 H), 4.21 (d, J=8.0 Hz, 1 H), 4.09(d, J=7.6 Hz, 1 H), 3.99 (m, 1 H), 3.30 (d, J= 5.5 Hz, 1 H), 2.60-2.68(m, 1 H), 2.43 (s, 3H), 2.37 (m, 1 H), 2.08( m, 1 H), 1.98 (s, 3H), 1.91 (bs, 3H), 1.84 (bs, 3H), 1.80 (s, 3H), 1.23(s, 3H), 1.10(s, 3H); Anal. Calcd. for C4sH54N2Oi 5: 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 β-lactams and acylating agents were substituted for the β-lactam and 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.
Figure imgf000247_0001
(21)
Figure imgf000247_0002
Figure imgf000248_0001
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 R7 is as previously defined, including wherein R7 is R7aR7bNCOO- and (a) R7a and R7b are each hydrogen, (b) one of R7a and R7b 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 or hexenyl; (iii) substituted or unsubstituted C3 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) R7a and R7b 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 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 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. For example, R7 may be R7aR7bNCOO- wherein one of R7a and R7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl.
Figure imgf000249_0001
(22)
Figure imgf000249_0002
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
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 R10 is hydroxy and R7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R7 is R7aR7bNCOO- and one of R7a and R7b is hydrogen and the other is (i) substituted or unsubstituted C 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 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 R7 substituents include R7aR7bNCOO- wherein one of R7a and R7b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R7 substituents include R7aR7bNCOO- wherein one of R7a and R7b is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl.
In the "A" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or Unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7 and R10 each have the beta stereochemical configuration.
In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "C" series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, R9 (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration. In the "H" series of compounds, X10 is as otherwise as defined herein.
Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "I" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
Any substituents of each X3, X5, R2, R7, and R9 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.
Figure imgf000258_0001
(23)
Figure imgf000258_0002
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Example 35 : In Vitro cytotoxicitv measured by the cell colony formation assay Four hundred cells (HCT116) 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 CO2 incubator at 37 °C 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 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. 10
15
20
25
Figure imgf000267_0001
Example 36: Preparation of Taxane having C-10 Carbamoyloxy and C-7 Hydroxy Substituents
Figure imgf000268_0001
7, 10-( ws)-carbobenzyloxy-10-deacetyl baccatin III. To a solution of 10-DAB (1.14 g, 2.11 mmol) in 20 mL of methylene chloride was added DMAP (6.20 g, 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 CH2CI2 and washed three times first with 1 N 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 CH2Cl2/EtOAc gave 1.48 g (86%) of 7,10-(£/s)-carbobenzyloxy- 0-deacetyl baccatin III.
Figure imgf000268_0002
7,10-(b/s)-carbobenzyloxy-3'-desphenyl-3'-(2-thienyl)-2'-O-triet ylsilyl docetaxel. To a solution of 425 mg (0.523 mmol) of 7,10-(jb/s)-carbobenzyloxy- 10-deacetyl baccatin III 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 mixture was kept at -45 oC for 1 h prior to addition of a solution of 341 mg (0.889 mmol) of c/s-N-fbutoxycarbonyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in 2 mL of THF. The mixture was allowed to warm to 0 °C, and after 2 h was poured 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 576 mg (92%) of 7,10-(b/s)-carbobenzyloxy-3'-desphenyl-3'-(2-thienyl)-2'-O- triethylsilyl docetaxel.
Figure imgf000269_0001
3'-Desphenyl-3'-(2-thienyl)-2'-O-triethylsilyl docetaxel. A suspension of 550 mg of 7,10-( )/s)-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 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-triethylsilyl docetaxel.
Figure imgf000269_0002
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 CuCI (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 °C and after 1.4 h 5mL 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 evaporated to give 218 mg of a residue which was used directly without purification.
Figure imgf000270_0001
3'-Desphenyl-3'-(2-thienyl)-10-N-ethylcarbamoyl docetaxel (2722). To a 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 °C 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 over sodium sulfate, and concentrated under reduced pressure. Chromatography of the residue on silica gel using CH2Cl2/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 protected β-lactams were substituted for the c/s-N-fbutoxycarbonyl-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 compound (2722) prepared in Example 36.
Figure imgf000270_0002
(24)
Figure imgf000271_0001
Example 38: Taxanes Having C-10 Carbomoyloxy and C-7 Hydroxy Substituents The procedures described in Example 36 were repeated, but other suitably protected β-lactams were substituted for the β-lactam of Example 36 to prepare the series of compounds having structural formula (25) and the combinations of substituents identified in the following table.
Figure imgf000272_0001
(25)
Figure imgf000272_0002
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 R7 is as previously defined including wherein R10 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 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 or hexenyl; (iii) substituted or unsubstituted C3 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) Ra and Rb are independently (i) substituted or unsubstituted C, 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 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, R10 may be RaRbNCOO- wherein one of Ra and Rb is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl. The substituents may be those identified elsewhere herein for substituted hydrocarbyl.
Figure imgf000273_0001
(26)
Figure imgf000273_0002
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
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 R7 is hydroxy and R10 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R10 is R10aR10bNCOO- and one of R10a and R10b is hydrogen and the other is (i) substituted or unsubstituted C, 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 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 R10 substituents include R10aR10bNCOO- wherein one of R10a and R10b is hydrogen and the other is methyl, ethyl, or straight, branched or cyclic propyl. In another embodiment, preferred R10 substituents include R10aR10bNCOO- wherein one of R10a and R10b is hydrogen and the other is substituted methyl, ethyl, or straight, branched or cyclic propyl. In the "A" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7 and R10 each have the beta stereochemical configuration.
In the "B" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "C" series of compounds, X10 and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R9a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R7, R9 (series D only) and R10 each have the beta stereochemical configuration.
In the "F" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration.
In the "G" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "H" series of compounds, X10 is as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "I" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R10 each have the beta stereochemical configuration.
In the "J" series of compounds, X10 and R2a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X10, R2a and R9a are as otherwise as defined herein. Preferably, heterocyclo is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X10 is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7, R9 and R10 each have the beta stereochemical configuration.
Any substituents of each of X3, X5, R2, R7, and R9 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.
Figure imgf000281_0001
(27)
Figure imgf000281_0002
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Example 41 : In Vitro cytotoxicity measured by the cell colony formation assay
Four hundred cells (HCT116) 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 CO2 incubator at 37 °C 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.
Figure imgf000291_0001
Figure imgf000292_0001
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 ml 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 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 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 ml 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 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. 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 (100mg) 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® II (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® III (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 was then diluted with 9 parts by weight of Liposyn® III (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

What is claimed is:
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/ml.
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 1 wherein the taxane dosage is at least 20 mg/m2.
4. The composition of claim 3 wherein the taxane dosage is between 20 mg/m2 and about 600 mg/m2.
5. The composition of claim 4 wherein the taxane dosage is between about 25 mg/m2 and about 400 mg/m2.
6. The composition of claim 5 wherein the taxane dosage is between about 40 mg/m2 and about 300 mg/m2.
7. The composition of claim 6 wherein the taxane dosage is between about 50 mg/m2 and about 200 mg/m2.
8. The composition of claim 1 wherein the taxane has the formula:
Figure imgf000296_0001
wherein one of R7 and R10 is hydroxy and the other is acyloxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10;
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; R2 is acyloxy;
Rg is keto, hydroxy, or acyloxy; R14 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 X3 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.
12. The composition of claim 8 wherein X5 is -COX10 and X10 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 X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
13. The composition of claim 8 wherein R14 is hydrido and R2 is benzoyloxy.
14. The composition of claim 8 wherein R7 is hydroxy and R10 is R10aC(O)O-, R10aR10bNC(O)O-, R10aOC(O)O- or R10aSC(O)O- wherein R10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R10b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
15. The composition of claim 14 wherein X3 is phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyi, 3-pyridyl, 4-pyridyl, C2 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
16. The composition of claim 14 wherein X5 is -COX10 and X10 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 X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
17. The composition of claim 14 wherein R14 is hydrido and R2 is benzoyloxy.
18. The composition of claim 14 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
19. The composition of claim 18 wherein X3 is furyl or thienyl.
20. The composition of claim 19 wherein X5 is -COOX10 and X10 is t-butyl.
21. The composition of claim 8 wherein R10 is hydroxy and R7 is R7aC(O)O-, R7aR7bNC(O)O-, R7aOC(O)O- or R7aSC(O)O- wherein R7a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R7b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
22. The composition of claim 21 wherein X3 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.
23. The composition of claim 21 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
24. The composition of claim 21 wherein R14 is hydrido and R2 is benzoyloxy.
25. The composition of claim 21 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
26. The composition of claim 25 wherein X3 is furyl or thienyl.
27. The composition of claim 26 wherein X5 is -COOX10 and X10 is t-butyl.
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/m2.
31. The composition of claim 30 wherein the taxane dosage is between 20 mg/m2 and about 600 mg/m2.
32. The composition of claim 31 wherein the taxane dosage is between about 25 mg/m2 and about 400 mg/m2.
33. The composition of claim 32 wherein the taxane dosage is between about 40 mg/m2 and about 300 mg/m2.
34. The composition of claim 33 wherein the taxane dosage is between about 50 mg/m2 and about 200 mg/m2.
35. The composition of claim 28 wherein the taxane has the formula:
Figure imgf000299_0001
wherein one of R7 and R10 is hydroxy and the other is acyloxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10;
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
R2 is acyloxy; Rg is keto, hydroxy, or acyloxy; R14 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 X3 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.
39. The composition of claim 35 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl orX5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
40. The composition of claim 35 wherein R14 is hydrido and R2 is benzoyloxy.
41. The composition of claim 35 wherein R7 is hydroxy and R10 is R10aC(O)O-, R10aR10bNC(O)O-, R10aOC(O)O- or R10aSC(O)O- wherein R10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R10b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
42. The composition of claim 41 wherein X3 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.
43. The composition of claim 41 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C^ - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
44. The composition of claim 41 wherein R14 is hydrido and R2 is benzoyloxy.
45. The composition of claim 41 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
46. The composition of claim 45 wherein X3 is furyl or thienyl.
47. The composition of claim 46 wherein X5 is -COOX10 and X10 is t-butyl.
48. The composition of claim 35 wherein R10 is hydroxy and R7 is R7aC(O)O-, R7aR7bNC(O)O-, R7aOC(O)O- or R7aSC(O)O- wherein R7a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R7b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
49. The composition of claim 48 wherein X3 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.
50. The composition of claim 48 wherein X5 is -COX10 and X10 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 X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
51. The composition of claim 48 wherein R14 is hydrido and R2 is benzoyloxy.
52. The composition of claim 48 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
53. The composition of claim 52 wherein X3 is furyl or thienyl.
54. The composition of claim 53 wherein X5 is -COOX10 and X10 is t-butyl.
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 ID50 value determined relative to the HCT116 cell line that is at least 4 times less than that of paclitaxel.
56. The composition of claim 55 wherein the ID50 value of the taxane is at least
5 times less than that of paclitaxel.
57. The composition of claim 56 wherein the ID50 value of the taxane is at least
6 times less than that of paclitaxel
58. The composition of claim57 wherein the IDS0 value of the taxane is at least
7 times less than that of paclitaxel
59. The composition of claim 58 wherein the ID50 value of the taxane is at least
8 times less than that of paclitaxel.
60. The composition of claim 59 wherein the ID50 value of the taxane is at least
9 times less than that of paclitaxel.
61. The composition of claim 60 wherein the ID50 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/m2.
64. The composition of claim 63 wherein the taxane dosage is between 20 mg/m2 and about 600 mg/m2.
65. The composition of claim 64 wherein the taxane dosage is between about 25 mg/m2 and about 400 mg/m2.
66. The composition of claim 65 wherein the taxane dosage is between about 40 mg/m2 and about 300 mg/m2.
67. The composition of claim 66 wherein the taxane dosage is between about 50 mg/m2 and about 200 mg/m2.
68. The composition of claim 55 wherein the taxane has the formula:
Figure imgf000303_0001
wherein one of R7 and R10 is hydroxy and the other is acyloxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10;
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
R2 is acyloxy;
R9 is keto, hydroxy, or acyloxy;
R14 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 X3 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.
72. The composition of claim 68 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C^ - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
73. The composition of claim 68 wherein R14 is hydrido and R2 is benzoyloxy.
74. The composition of claim 68 wherein R7 is hydroxy and R10 is R10aC(O)O-, R10aR10bNC(O)O-, R10aOC(O)O- or R10aSC(O)O- wherein R10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R10b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
75. The composition of claim 74 wherein X3 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.
76. The composition of claim 74 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C^ - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
77. The composition of claim 74 wherein R14 is hydrido and R2 is benzoyloxy.
78. The composition of claim 74 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
79. The composition of claim 78 wherein X3 is furyl or thienyl.
80. The composition of claim 79 wherein X5 is -COOX10 and X10 is t-butyl.
81. The composition of claim 68 wherein R10 is hydroxy and R7 is R7aC(O)O-, R7aR7bNC(O)O-, R7aOC(O)O- or R7aSC(O)O- wherein R7a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R7b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
82. The composition of claim 81 wherein X3 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.
83. The composition of claim 81 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
84. The composition of claim 81 wherein R14 is hydrido and R2 is benzoyloxy.
85. The composition of claim 81 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
86. The composition of claim 85 wherein X3 is furyl or thienyl.
87. The composition of claim 86 wherein X5 is -COOX10 and X10 is t-butyl.
88. A pharmaceutical composition for parenteral administration comprising a taxane having the formula:
Figure imgf000305_0001
wherein one of R7 and R10 is hydroxy and the other is acyloxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10;
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
R2 is acyloxy;
R9 is keto, hydroxy, or acyloxy;
R14 is hydrido or hydroxy; and Ac is acetyl; and a pharmaceutically acceptable carrier.
89. The composition of claim 88 wherein X3 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.
90. The composition of claim 88 wherein X5 is -COX10 and X10 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 X5 is -COOX10 and X10 is substituted or unsubstituted C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
91. The composition of claim 88 wherein R14 is hydrido and R2 is benzoyloxy.
92. The composition of claim 88 wherein R7 is hydroxy and R10 is R10aC(O)O~, R10aR10bNC(O)O-, R10aOC(O)O- or R10aSC(O)O- wherein R10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R10b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
93. The composition of claim 92 wherein X3 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.
94. The composition of claim 92 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
95. The composition of claim 92 wherein R14 is hydrido and R2 is benzoyloxy.
96. The composition of claim 92 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
97. The composition of claim 96 wherein X3 is furyl or thienyl.
98. The composition of claim 97 wherein X5 is -COOX10 and X10 is t-butyl.
99. The composition of claim 88 wherein R10 is hydroxy and R7 is R7aC(O)O-, R7aR7bNC(O)O-, R7aOC(O)O- or R7aSC(O)O- wherein R7a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R7b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
100. The composition of claim 99 wherein X3 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.
101. The composition of claim 99 wherein X5 is -COX10 and X10 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 X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
102. The composition of claim 99 wherein R14 is hydrido and R2 is benzoyloxy.
103. The composition of claim 99 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
104. The composition of claim 103 wherein X3 is furyl or thienyl.
105. The composition of claim 104 wherein X5 is -COOX10 and X10 is t-butyl.
106. A pharmaceutical composition for oral administration comprising a taxane having the formula:
Figure imgf000307_0001
wherein one of R7 and R10 is hydroxy and the other is acyloxy; X3 is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl or heterocyclo;
X5 is -COX10, -COOX10, or -CONHX10;
X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;
R2 is acyloxy;
Rg is keto, hydroxy, or acyloxy;
R14 is hydrido or hydroxy; and
Ac is acetyl; and a pharmaceutically acceptable carrier.
107. The composition of claim 106 wherein X3 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.
108. The composition of claim 106 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C1 r C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
109. The composition of claim 106 wherein R14 is hydrido and R2 is benzoyloxy.
110. The composition of claim 106 wherein R7 is hydroxy and R10 is R10aC(O)O-, R10aR10bNC(O)O-, R10aOC(O)O- or R10aSC(O)O- wherein R10a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R10b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
111. The composition of claim 110 wherein X3 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 X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3- pyridyl, 4-pyridyl, C, - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
113. The composition of claim 110 wherein R14 is hydrido and R2 is benzoyloxy.
114. The composition of claim 110 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
115. The composition of claim 114 wherein X3 is furyl or thienyl.
116. The composition of claim 115 wherein X5 is -COOX10 and X10 is t-butyl.
117. The composition of claim 106 wherein R10 is hydroxy and R7 is R7aC(O)O-, R7aR7bNC(O)O-, R7aOC(O)O- or R7aSC(O)O- wherein R7a is hydrocarbyl, substituted hydrocarbyl or heterocyclo and R7b is hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo.
118. The composition of claim 117 wherein X3 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 X5 is -COX10 and X10 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 X5 is -COOX10 and X10 is substituted or unsubstituted C1 - C8 alkyl, C2 - C8 alkenyl, or C2 - C8 alkynyl.
120. The composition of claim 117 wherein R14 is hydrido and R2 is benzoyloxy.
121. The composition of claim 117 wherein R14 is hydroxy; X3 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; X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
122. The composition of claim 121 wherein X3 is furyl or thienyl.
123. The composition of claim 122 wherein X5 is -COOX10 and X10 is t-butyl.
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