Classifications

• • 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.

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