Title of Invention	C10 ESTER SUBSTITUTED TAXANES
Abstract	This invention relates to a taxane having the formula R2 is acyloxy; R7 is hydroxy; R9 is keto, hydroxy, or acyloxy; RIo is R10aCOO-; R1Oa 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 atom of which R\oa is a substituent; R14 is hydrido or hydroxy; X3 is heterocyclo; X5 is -COX1O, -COOX10, or -CONHXlo; X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and Ac is acetyl.

Title of Invention

C10 ESTER SUBSTITUTED TAXANES

Abstract

This invention relates to a taxane having the formula R2 is acyloxy; R7 is hydroxy; R9 is keto, hydroxy, or acyloxy; RIo is R10aCOO-; R1Oa 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 atom of which R\oa is a substituent; R14 is hydrido or hydroxy; X3 is heterocyclo; X5 is -COX1O, -COOX10, or -CONHXlo; X10 is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and Ac is acetyl.

Full Text	C10 ESTER SUBSTITUTED TAXANES BACKGROUND OF THE INVENTION The present invention is directed to novel taxanes which have exceptional utility as antitumor agents. The taxane family of terpenes, of which baccatln HI and taxol are members, has been the subject of considerable interest in both the biological and chemical arts. Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2"R. 3"S configuration and the following structural formula: Although taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain SUMMARY OF THE INVENTION Among the objects of the present invention, therefore, is the provision of taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity. In general, these taxanes possess an ester substituent other than formate, acetate and heterosubstituted acetate at C-10, a hydroxy substituent at C-7 and a range of C-3" substituents. Briefly, therefore, the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a phannaceutically acceptable carrier, and to methods of administration. Other objects and features of this invention will be in part apparent and in part pointed out hereinafter. ■tiJons relative to the carbon of which Ri^a is a substituent; ^ is hydrido or hydroxy; Ac is acetyl; and Ry, Rg, and R,o independently have the alpha or beta stereochemical configuration. In one embodiment, R2 is an ester (R2aC(0)0-), a carbamate (R2aR2bNC(O)0-). a carbonate (R2aOC(0)0-), or a thiocarbamate (R2aSC(0)0-) wherein R^a and Rjj, are independently hydrogen, hydrocarby!, substituted hydrocarbyl or heterocyclo. in a preferred embodiment, Rj is an ester (R2aC(0)0-), wherein Rgg is aryl or heteroaromatic. In another preferred embodiment, R2 is an ester (R2aC{0)0-), wherein Rja is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly prefen^ed embodiment, Rj is benzoyloxy. While Rg is keto in one embodiment of the present invention, in other embodiments Rg may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, a- or p-hydroxy or a- or p-acyloxy. For example, when Rg is acyloxy, it may be an ester (R9aC(0)0-), a carbamate (RflaR9bNC(0)0-), a carbonate (R9gOC{0)0-), or a thiocarbamate (R^SC(0)O-) wherein Rgg and Rg^ are independently hydrogen, hydrocart)yl, substituted hydrocarby! or heterocyclo. If Rg is an ester (RgaC{0)0-), Rga is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic. Still more preferably, Rg is an ester (R9aC(0)0-), wherein Rg^ is substituted or unsubstituted pheny}, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyridyl. In one embodiment Rg is (RggC(O)O-) wherein Rg^ is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl, (straight, branched or cyclic), or hexyl (straight, branched or cyclic). In another embodiment Rg is (R9aC(0)0-) wherein Rgg 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) js/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, htit nnt nhnsnhorous containina moieties. (iii) substituted or unsubstituted Cj to Cg alkynyi (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic such as furyf, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred ennbodiment, R,oa is ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic pentyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. in another embodiment, Ri^g 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 heterocycio, alkoxy, aikenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nltro, amino, annido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties. Exemplary X3 substituents include substituted or unsubstituted Cj to Cg alkyl, substituted or unsubstituted Cj to Cg alkenyl, substituted or unsubstituted Cj to Cg alkynyi, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X3 substituents Include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl. Exemplary Xj substituents include -COX,o, -COOX,o or -CONHX,o wherein XiQ is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred Xg substituents include -COX10, -COOXig or -CONHXIQ wherein X^^ is (i) substituted or unsubstituted C, to Cg 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 Cj to Cg alkenyl such as substituted or unsubstituted ethenyl, propenyl {straight, branched or cyclic), butenyi (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched or cyclic); (ill) substituted or unsubstituted Cj to Cg alkynyi such as substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or wherein Xio is phenyl, alkyl or heterocyclo, more preferably phenyl, or Xg is -COOXio wherein X^o is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to stnjcture 2 in which (i) Xg is -COOX10 wherein X^g is tert-butyl or X5 is -COX10 wherein X^Q is phenyl, (ii) X3 is substituted or unsubstituted cycloalkyi, alkenyl, phenyl or heterocyclo, more preferabJy substituted or unsubstituted isobuteny), phenyl, fury}, thienyl, orpyfidyi, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R^a is unsubstituted ethyl or propyl, more preferably ethyl. Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R10 is RiQaCOO- wherein R^^a Is ethyl, in this embodiment, X3 is preferably cycloalkyi, isobutenyl, or heterocyclo, more preferably heterocycfo, still more preferably furyf, thienyl or pyridyl; and Xg Is preferably benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and R,^ is hydride. In another altemative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyi; Rj is benzoyl, Rg is keto and R,4 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R^ Is benzoyl, Rg is keto and R,^ is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; Xs is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R^ is hydroxy. In another alternative of this embodiment, X3 Is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg Is hydroxy and R^ is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or 1 J. L.,.1—„ ,—,[.,„„, ,r ^,- + preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R^ is benzoyl, Rg is acyloxy and R„ is hydride. In each of the alternatives of this embodiment when the taxane has stnjcture 1, R^ and R^^ may each have the beta stereochemical configuration, Ry and RIQ may each have the alpha stereochemical configuration, Ry may have the alpha stereochemical configuration while Rio has the beta stereochemical configuration or R^ may have the beta stereochemical configuration while Rn, has the alpha stereochemical configuration. Also among the preferred embodiments are taxanes corresponding to stnjcture 1 or 2 wherein Rn, is RiogCOO- wherein R^^a i® propyl. In this embodiment, X3 is preferably cycloalkyi, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; Xj is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and R^^ is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and R^ is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xs is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and Ri4 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and Ri^ is hydrido. In another alternative of this embodiment, X3 is heterocydocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyi, still more preferably t-butoxycarbonyl; Rg is benzoyl, Rg is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, Ry and R^Q may each have the beta stereochemical configuration, Ry and R^o may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while Rio has the beta stereochemical configuration or Rj may have the beta stereochemical configuration while R,o has the alpha stereochemical configuration. Taxanes having the general formula 1 may be obtained by treatment of a p-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a P-amido ester substituent at C-13 (as described more fully in Helton U.S. Patent 5,466,834), followed by removal of the hydroxy protecting groups. The p-iactam has the following structural formula (3): wherein M is a metal or ammonium, P, is a hydroxy protecting group and R^^ is as previously defined. Alkoxide 4 may be prepared from 10-deacetylbaccatin III (or a derivative thereof) by selective protection of the C(7) hydroxy! group and then esterification of the C(10)hydroxyl group followed by treatment with a metallic amide. In one embodiment of the present invention, the C{7) hydroxy! group of 10-deacetylbaccatin III is selectively protected with a silyl group as described, for example, by Denis, et. al, (J.Am. Chem. Soc, 1988,110, 5917). In general, the silylating agents may be used either alone or in combination with a catalytic amount of a base such as an alkali metal base. Alternatively, the C(10) hydroxyl group of a taxane can be selectively acylated in the absence of a base, as described, for example in Holton et al., PCT Patent Application WO 99/09021. Acylating agents which may be used for the selective acylation of the C(1 D) hydroxyl group of a taxane include substituted or unsubstituted alkyl oraryl anhydrides. While the acylation of the C(10) hydroxy group of the taxane will proceed at an adequate rate for many acylating agents, it has been discovered that the reaction rate may be increased by including a Lewis acid in the reaction mixture. Preferred Lewis acids include zinc chloride, stannic chloride, cerium trichloride, cuprous chloride, lanthanum trichloride, dysprosium trichloride, and ytterbium trichloride. Zinc chloride or cerium trichloride is particulariy prefen^ed when the acylating agent is an anhydride. Derivatives of lO-deacetylbaccatin III having alternative substituents at C{2), C{9) and C(14) and processes for their preparation are known in the art. Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Patent No. 5,728,725 or Kingston et al., U.S. Patent No. 6,002.023. Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Patent No. 6,011,056 or Gunawardana et al., U.S. Patent No. 5,352,806. Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin 111. Processes for the preparation and resolution of the p-lactam starting material are generally well known. For example, the [J-!actam may be prepared a in PCT Patent Application No. 00/41204. In a preferred embodiment in whicti the p-lactam is fury! substituted at the C(4) position, the p-lactam can be prepared as illustrated in the following reaction scheme: substance which Is phannaceuticaliy inert, confers a suitable consistency or form to the composition, and does not diminish 1he therapeutic efficacy of the antitumor compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate. The phannaceutical compositions containing the antitumor compounds of the present invention n^ay be formulated in any conventional manner. Proper fomiulation is dependent upon the route of administration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral {e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal), topical {nasal, transdennal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradennai, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration. Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable earners are readily detennined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington"s Pharmaceutical Science (A. Gennaro, ed.). Mack Publishing Co., Easton, Pa., {1985), pp. 1492-1517, the contents of which are incorporated herein by reference). The compositions are preferably fonnulated 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 folinwlnn rf>fprpnppc- 7 ft^nHom Pharmar-anti^e r*h««+-^.-r. n -,«^ nn ro — i,^, o The compositions of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms inciude 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, croscannellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage fonns 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 intrastemal routes. The compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a phamiaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art. Suitable carriers used in fonnulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptabie 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, phannaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol fomial, p-giycerol fonnal, 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, i _ J. T- - hydroxyetliy\|}-lactamide, N, N-dimetlnylacetamide_amides, 2-pyrrolidinone, 1-methyl-2-pyrroIidinone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprytate or octanoate, alkyl oieate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, ortri-glyceryj citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oieate, fatty acid esters of sorbltan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, ortri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone, piuronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxyIated)3(j^(3 sorbitol poiy(oleate)2^, poly(oxyethylene)i5.2Q monooleate, poly(oxyethy)ene)i5.2o mono 12-hydroxystearate, and poly(oxyethy)ene)is.2o niono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethyiene-sorbitan monooleate, polyoxyethyiene-sorbitan monopalmitate, polyoxyethyiene-sorbitan monolaurate, polyoxyethyiene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, DE, polyvinylpyrrolidone, all atoms ^P! n honTOno /«^/^lnh£lv•5r^a ,J;,NUI>. ——--ii J»_..- 1 origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn genn, sesame, persic and peanut oil and giycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, spemi, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanoiamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate. Other phamiaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wllkens Publishing), The Handbook of Pharmaceutical Excipients. (American Phamiaceutical Association, Washington, D.C., andThePharmaceuticalSocietyof Great Britain, London, England, 1968), Modern Phamiaceutics. (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basisof Therapeutics. (Goodman & Gilman, McGraw Hill Publishing), Phamiaceutical Dosage Forms. (H. Lieberman et aL, eds., )(Marcel Dekker, Inc., New York, New York, 1980), Remington"s Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(MaGk Publishing, Easton, PA, 1995), The United States Pharmacopeia 24. The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), A.J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963). Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified faity acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., safflower oi!, 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 docosahexaenoyi group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® {from Martek Biosciences Corp., Columbia, MD), DHA Maguro® (from Daito Enterprises, Los Angeles, CA), Soyacal®, and Travemulslon®. Ethanol is a prefen-ed solvent for use in dissolving the antitumor compound to form solutions, emulsions, and the like. Additional minor components can be included in the compositions of the invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part Impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH. facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 vrt.% of the total composition, as is well known in the formulation art. Such additives include cryoprotective agents for preventing repreclpitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ). presen/atives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethlcone), clays (e.g., bentonites), adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g.. starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or salts thereof such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide), and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, and thiophenols). In a preferred embodiment, a pharmaceutical composition of the invention comprises at least one nonaqueous, phannaceutically 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 fonn a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound. It is also preferred that the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% Inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paciitaxel when measured according to the protocol set forth in the working examples. Dosage form administration by these routes may be continuous or intenmittent, 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 concun"ent treatment, if any, frequency of treatment, and the treated, the desired therapeutic dose, and other factors that will be apparent to those of skill In the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route. Preferably, the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m^ of patient body surface area, or at least 50,100,150, 200, 300, 400, or 500 mg of the antitumor compound per m^ of patient body surface area, wherein the average body surface area for a human is 1.8 m^ Preferably, a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m^of patient body surface area, more preferably from about 25 to about 400 mg/m^" even more preferably, from about 40 to about 300 mg/m^ and even more preferably from about 50 to about 200 mg/m^. Preferably, the compositions for parenteral administration are prepared in such a way that a single dose contains at least 20 mg of the antitumor compound per m^ of patient body surface area, or at least 40, 50,100, 150, 200, 300, 400, or 500 mgofthe antitumor compound per m^of patient body surface area. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m^ of patient body surface area, more preferably from about 40 to about 400 mg/m^" and even more preferably, from about 60 to about 350 mg/m^. However, the dosage may vary depending on the dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose I ranges. The most prefen^ed 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 ^nmni-ieitinn mnro r\rofcirahK/ hohn/aan ahni it fl 1 mn anr\ ahni if 7 mn nar ml o\/cin soluble in the solution at low concentrations. The concentration of the antitumor compound in a solid phannaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %. In one embodiment, solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanoi or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophoi® EL solution, is added to the solution while stirring to fonn a pharmaceutically acceptable solution for oral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanoi, which is known in the art to cause adverse physiological effects when administered at certain concentrations in oral formulations. In another embodiment, powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g..ethanoi 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 Cremophoits) 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., ethanoi or methylene chloride) to form a solution. An appropriate volume of a carrier which is an emulsion, such as Liposyn® 11 or adverse physiological effects when administered at certain concentrations in parenteral formulations. Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® solution, is added to the solution while stirring to fomi a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations. If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any phannaceutically acceptable liquid, such as saline, to fomi an acceptable taxane concentration prior to use as is known in the art. Definitions The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms. The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, fhini kfatnlc arotalc octArc nnH othorc 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 heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. The "heterosubstituted acetate" moieties described herein are acetate groups in which the carbon of the methyl group Is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to fonn a heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety. Unless othenwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexy! and the like. Unless othenwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl. isobutenyl, hexenyl, and the like. Unless othenwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and , include ethynyl, propynyl, butynyl, isobutynyl. hexynyl, and the like. The terms "ary!" or "ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl. The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine. heterocycio group preteraDly has l or ^ 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 heterocycio include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl. quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "heteroaromatic" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfijr 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, pyn-olyl, indolyl, quinolinyl, or Isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers. The term "acyl," as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group -COOH of an organic carboxylic acid, e.g., RC(0)-, wherein R is R\ R^O-, R^R^N-, or R^S-, R^ is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocycio and R^ is hydrogen, hydrocarbyl or substituted hydrocarbyl. The term "acyloxy," as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (-0-), e.g., RC{0)0- wherein R is as defined in connection with the term "acyl." Unless otherwise indicated, the alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted hydrocarbon moieties. Unless otherwise indicated, the carbamoyloxy moieties described herein are derivatives of carbamic acid in which one or both of the amine hydrogens Is nntlAnallv/ ronlanarf hx/ a h\/Hrnr"ai+t\/l ci rhctifi itnH h\/Wmr»arh\/! r\r hpfprnnuHfi ("protected hydroxy!") which, subsequent to the reaction for which protection is empioyed, may be removed without disturbing the remainder of the molecule. A \/anety of protecting groups for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981, orFieser & Fieser, Exemplary hydroxyl protecting groups include methoxymethy!, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsllyiethoxy)methyl,tetrahydropyranyl, 2,2,2-trich!oroethoxycarbonyl,t-butyl(diphenyl)silyl,trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl. As used herein, "Ac" means acetyl; "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "iPr" means isopropyl; "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; "tSuOCO" and "BOG" mean tert-butoxycarbonyl; "tAmOCO" means tert-amyloxycarbonyl; "PhCO means phenylcarbonyl"; "2-FuCO" means 2-furylcarbonyl; "2-ThCO" means 2-thienylcarbonyl; "2-PyCO" means 2rpyridylcarbonyl; "3-PyCO" means 3-pyridylcarbonyl; "4-PyCO" means 4-pyridylcarbonyi; "CjH^CO" means butenylcarbonyl; "EtOCO" means ethoxycarbonyl; "ibueCO" means isobutenylcarbonyl; "IBuCO" means isobutylcarbonyl; "iBuOCO" means isobutoxycarbonyl; "iPrOCO" means isopropyloxycarbonyl; "nPrOCO" means n-propyloxycarbonyl; "nPrCO" means n-propylcarbonyl; "tCaHgCO" means trans-propenyl carbonyl"; "Ibue" means isobutenyl; "THF" means tetrahydrofuran; "DMAP" means 4-dimethylamino pyridine; "LHMDS" means Lithium HexamethylDiSilazanide. The following examples illustrate the invention. 7-Dimethylphenylsilyl-10-propionyl-10-deacetyl baccatin ill. To a solution of 0.200 g (0.333 mmol) of 10-propionyl-10-deacetyl baccatin III in 12 mL of THF at -10 "C under a nitrogen atmosphere was added dropwise 0.668 mL (4.00 mmo)} oi chlorodimethyl-phenylsilane and 2.48 mL (30.64 mmol) of pyridine. After 90 min the mixture was diluted with 100 mL of a 1:1 mixture of ethyl acetate and hexane. The mixture was washed with 20 mL of saturated aqueous sodium bicarbonate solution and the organic layer separated. The aqueous layer was extracted with 30 mL of a 1:1 mixture of ethyl acetate and hexane, and the combined organic ovtra(~tc lA/oro wachoH with hrinft riripH nvpr Nfl.J^n. and concentrated in vacuO. 3"-Despheny!-3"-(2-thienyl)-10-propionyl-10-deac6tyl taxol. To a solution of 0.521 g (0.464 mmol)of7-dimethylphenyisilyl-2"-0-triethylsilyl-3"-despheny\|-3"-(2-thienyl)-10-propionyl-10-deacetyi taxol in 2 mL of CH3CN and 2 mL of pyridine at 0 °C was added 0.5 mL of a solution of 30% HF in HjO. After 3 h 20 mL of a 70% EtOAc/hexane as eluent to give 0.405 g (100%) of 3"-despheny!-3"-(2-thienyl)-10-propionyl-10-deacetyi taxol as a solid. m,p. 154-155 "C; [a];^^ = -45.0 (c 0.1 in CHC13); Anal. Calcd. for C^gHsiNO^S: C, 63.22; H, 5.88; Found: C, 62.94; H, 5.97. In the "A" series of compounds, XIQ is as othenwise as defined herein. Preferably, heterocycio is substituted or unsubstitued furyl, thienyl, or pyridyl, X^Q is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl {e.g., terf-butyl), and Ry and R^Q each have the beta stereochemical configuration. In the "B" series of compounds, X^o and R^^ are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^Q is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rj^ is preferably substituted or unsubstitued fury!, thienyl, pyridyl, phenyl, or lower alkyl, and R^ and Rio each have the beta stereochemical configuration. In the "C" series of compounds, X^Q and Rgg are as otherwise as defined herein. Preferably, heterocycio Is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^, Is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R^^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^, Rg and R^o each have the beta stereochemical configuration. In the "D" and "E" series of compounds, X^Q is as othenwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and Ry. Rg (series D only) and R^ each have the beta stereochemical configuration. In the "F" series of compounds, XIQ, Rjg and Rgg are as othenwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, Xio is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridy), phenyl, or lower alkyl, and R7, Rg and R^Q each have the beta stereochemical configuration. In the "G" series of compounds, X^Q and R2a are as othenrt^lse as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, XIQ IS preferably substituted or unsubstitued furyl, thienyi, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R^^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyi, and R7, Rg and Rio each or lower alkyl (e.g., tert-butyi), Rja is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and Ry and Rio each have the beta stereochemical configuration. In the "I" series of compounds, X^Q and Rja are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued fury!, thienyl, or pyridyl, Xio is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rj^ Is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R^ each have the beta stereochemical configuration. In the "J" series of compounds, X^j and Rja are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^o is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rja is preferably substituted or unsubstitued iury\, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration. In the "K" series of compounds, X^Q, R2a and Rg^ are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^Q is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^, Rg and R^Q each have the beta stereochemical configuration. Any substituents of each X3, Xg, Rj, Rg, Rio may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetai, ester and ether moieties, but not phosphorous containing moieties. Example 6 Preparation of Solutions for Oral Administration Solution 1: 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 Cremoplior® EL solution was added to the solution while stimng 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 2: 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 3: Antitumor compound 0611 was dissolved in ethanol to fonn 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 4: 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 fonn a pharmaceutically acceptable solution for administration to a patient. WE CLAIM: 1. A laxane having the formula 14. The taxane as claimed in claim 2 wherein R2 is benzoyloxy and Rg is keto. 24, The taxane as claimed in claim 23 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyi, 2-pyridyl, 3-pyridyl, or4-pyridyl. 25. The taxane as claimed in claim 23 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl. 3-furyl, 2-thienyl, 3-thienyl. 2-pyridyl, 3-pyridyl, 4~ pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl, or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Cs alkyl, C2 - Cs alkenyl, or C2 - Ce alkynyl. 26. The taxane as claimed in claim 23 wherein Ru is hydrogen. 27. The taxane as claimed in claim 26 wherein X3 is 2-furyl, 3-furyl, 2-thieny\|, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl. 28. The taxane as claimed in claim 26 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyrldyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ce alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Ca alkynyl. 29. The taxane as claimed in claim 23 wherein R2 is benzoyloxy. 30. The taxane as claimed in claim 29 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyi, or 4-pyridyl. 31. The taxane as claimed in claim 29 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyrJdyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ce alkynyl. 32. The taxane as claimed in claim 23 wherein Ru is hydrogen and R9 is keto. 33. The taxane as claimed in claim 32 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 34. The taxane as claimed in claim 32 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Ce alkenyl, or C2 - Ce alkynyl. 35. The taxane as claimed in claim 23 wherein R2 is benzoyloxy and Rg is keto. 36. The taxane as claimed in claim 35 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 37. The taxane as claimed in claim 35 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyhdyl, 3-pyridyl, 4-pyridyl, Ci - Cg alkyl, C2 - Cs alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or Ca - Ca alkynyl. 38. The taxane as claimed in claim 23 wherein Ru is hydrogen and Rz is benzoyloxy. 39. The taxane of claim 38 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyndyl. 40. The taxane as claimed in claim 38 wherein X5 is -COXio and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Cs alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Ca alkynyl. 41. The taxane as claimed in claim 23 wherein R14 is hydrogen, Rg Is keto, and R2 is benzoyloxy. 42. The taxane as claimed in claim 41 wherein X3 is 2-furyl, 3-furyl, 2-thlenyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 43. The taxane as claimed in claim 41 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thtenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Cs alkyl, C2 - Ca alkenyl, or Ca - Cs alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Cs alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl. 44. The taxane as claimed in claim 1 wherein Rioa is ethyl, 45. The taxane as claimed in claim 44 wherein X3 is 2-furyl, 3-furyi, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl. 46. The taxane as claimed in claim 44 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyt, 3-thienyl, 2-pyridyl, 3-pyndyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ce alkenyl, or C2 - Cg alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Cg alkyl, C2 - CB alkenyl, or C2 - Ce alkynyl. 47. The taxane as claimed in claim 44 wherein Ru is hydrogen. 48. The taxane as claimed in claim 47 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyndyl, 3-pyridyl, or4-pyridyI. 49. The taxane as claimed in claim 47 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thtenyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl. 50. The taxane as claimed in claim 44 wherein R2 is benzoyloxy. 51. The taxane as claimed in claim 50 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 52. The taxane as claimed in claim 50 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thlenyl, 2-pyndyl, 3-pyridyl, 4-pyridyl, Ci - Cg alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Cg alkenyl, or C2 - Ca alkynyl. 53. The taxane as claimed in claim 44 wherein Ru is hydrogen and R9 is keto. 54. The taxane as claimed in claim 53 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyr)dyl, 3-pyridyl, or 4-pyridyl. 55. The taxane as claimed in claim 53 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thlenyl, 2-pyridyl, 3-pyridyl, 4- pyridyl, Ci - Cs alkyl, C2 - Cs alkenyl, or C2 - Ce alkynyl or X5 is -COOX10 and X10 is substituted or unsubstltuted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Ce alkynyl. 56. The taxane as claimed in claim 44 wherein Rg is benzoyloxy and Rg is keto. 57. The taxane as claimed in claim 56 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 58. The taxane as claimed in claim 56 wherein X5 is -COXio and X10 is substituted or unsubstltuted phenyl, 2-furyl, 3-furyl, 2-thlenyl, 3-thienyl, 2-pyhdyl, 3-pyridyi, 4-pyridyl, Ci - Cg alkyl, C2 - Cs alkenyl, or Ca - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstltuted Ci - Ce alkyl, C2 - Ca alkenyl, or C2 - Ce alkynyl. 59. The taxane as claimed in claim 44 wherein Ru is hydrogen and R2 is benzoyloxy. 60. The taxane as claimed in claim 59 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 61. The taxane as claimed in claim 59 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ce alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ce alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl. 62. The taxane as claimed in claim 44 wherein Ru is hydrogen, Rg is keto, and R2 is benzoyloxy. 63. The taxane as claimed in claim 62 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyrldyl. 64. The taxane as claimed in claim 62 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ce alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ce alkyl, C2 - Ca alkenyl, or G2 - Ca alkynyl. 85. The taxane as claimed in claim 62 wherein X5 is -COOX10 and X10 is t-butyl. 73. The taxane as claimed in claim 70 wherein X3 is furyl or thienyl. 74. The taxane as claimed in claim 73 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl. 75. The taxane as claimed in claim 70 wherein Rioa is ethyl or propyl. 76. The taxane as claimed in claim 75 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 77. The taxane as claimed in claim 76 wherein X5 is -COXio and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyt, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl. 78. The taxane as claimed in claim 75 wherein X3 is furyl or thienyl. 79. The taxane as claimed in claim 78 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyt, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alky!, C2 - Ca alkenyl, or C2 - Ca alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl. 80. The taxane as claimed in claim 70 wherein X3 is furyl or thienyl, Rioa is ethyl, and X5 is -COXio and Xio is phenyl, or X5 is -COOX10 and Xio is t-butyl. 81. The taxane as claimed in claim 70 wherein X3 is substituted or unsubstituted furyl, Rioa is ethyl, and X5 is -COXio and Xio is phenyl, or X5 is -COOXio and Xio is t-butyl. 82. The taxane as claimed in claim 70 wherein X3 is substituted or unsubstituted thienyl, Rioa is ethyl, and X5 is -COXio and Xio is phenyl, or X5 is -COOXio and Xio is t-butyl. 83. The taxane as claimed in claim 70 wherein X3 is 2-furyl or 2-thienyl, Rioa is ethyl, X5 is -COOX10 and Xjo is t-butyl. 84. The taxane as claimed in claim 70 wherein X3 is 2-furyl, Rioa is ethyl, X5 is -COOX10 and X10 is t-butyl. 85. The taxane as claimed in claim 70 wherein X3 is 2-thienyl, Rioa is ethyl, X5 is -COOX10 and X10 is t-butyl. 86. A pharmaceutical composition comprising the taxane as claimed in claim 1 and at least one pharmaceutically acceptable carrier. 87. The pharmaceutical composition as claimed in claim 86 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl. 88. The pharmaceutical composition as claimed in claim 87 wherein Xg is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, S-thienyl, 2-pyridyl, 3-pyridy!, 4-pyridyl, Cj - Cs alkyl, C2 - Ce alkenyl, or C2 - Ce alkynyl, or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Cs alkynyl. 89. The phamiaceutical composition as claimed in claim 87 wherein Rioa is ethyl or propyl. 90. The pharrnaceuticai composition as claimed in claim 89 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyt. 91. The pharmaceutical composition as claimed in claim 90 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl, or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Cs alkyl, C2 - Cs alkenyl, or C2 - Cs alkynyl. 92. The pharmaceutical composition as claimed in claim 87 wherein X3 is furyl or thienyl, Rioa is ethyl, and X5 is -COX10 and X10 is phenyl, or X5 is -COOXio and X10 is t-butyl. 93. The pharmaceutical composition as claimed in claim 87 wherein X3 is substituted or unsubstituted furyl, Rioa is ethyl, and X5 is -COX10 and X10 is phenyl, or X5 is -COOXjo and X10 is t-butyl. 94. The phanmaceuticai composition as claimed in claim 87 wherein X3 is substituted or unsubstituted thienyl, Rioa is ethyl, and X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl. 95. The pharmaceutical composition as claimed in claim 87 wherein X3 is 2-furyl or 2-thienyl, Rioa is ethyl, X5 is -COOXio and X10 is t-butyl. 96. The phannaceutical composition as claimed in claim 87 wherein X3 is 2-furyl, Rioa is ethyl, X5 is -COOXio and X10 is t-butyl. 97. The pharmaceutical composition as claimed in claim 87 wherein X3 is 2-thienyl, Rioa is ethyl, X5 is -COOXio and Xio is t-butyl. 98. A pharmaceutical composition comprising the taxane as claimed in claim 70 and at least one pham^aceutically acceptable carrier. 99. A pharmaceutical composition comprising the taxane as claimed in claim 73 and at least one pharmaceutically acceptable carrier. 100. A composition for oral administration comprising the taxane as claimed in claim 1 and at least one pharmaceutically acceptable carrier. 101. The composition as claimed in claim 100 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl. 102. The composition as claimed in claim 101 wherein Rioa is ethyl or propyl. 103. The composition as claimed in claim 102 wherein R„ is hydrogen R^ is benzoyloxy, and X5 is -COX,o wherein X,„ is phenyl, or Xs is -COOX,„ wherein Xio is t-butyl. 104. The composition as claimed in claim 103 wherein X3 is furyl or thienyl; R,oa is ethyl; and X5 is -COOX10 and Xio is t-butyl. 105. The composition as claimed in claim 104 wherein X3 is furyl. 106. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is t-butyl, Rio^ is ethyl, propyl, isopropyl, or trans-propenyl, and X3 is 2-furyl or 3-furyl. 107. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is t-butyl, Rioa is ethyl, propyl, isopropyl, or trans-propenyl, and X3 is 2-thienyl or 3-thienyl. 108. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is t-butyl, Rioa is 2-thienyl or 2-furyl, and X3 is 2-furyl, 3-furyl, 2-thienyl, or 3-thienyl. 109. The taxane as claimed in claim 1 wherein X5 is -COXio and Xio is phenyl, Rioa is ethyl, and X3 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, or 3-thienyl. 110. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is ethyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-thienyl or 2-furyl. 111. The taxane as claimed in claim 1 wherein X5 is -COX10 and Xio is 2-furyl or 2-thienyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-thienyl. 112. The taxane as claimed in claim 1 wherein X5 is -COOXio and Xio is t-butyl, Rioa is cyclopropyl, and X3 is 2-furyl, 3-furyl, 2-thienyl, or 3-thienyl. 13. The taxane as claimed in claim 1 wherein X5 is -COOXio and Xio is isobutyl, Rioa is cyclopropyl or propyl, and X3 is 2-furyl or 3-furyt. 114. The taxane as claimed in claim 1 wherein X5 is -COOX10 and X10 is isobutyl, Rioa is cyclopropyl, propyl, or ethyl, and X3 is 2-thienyl. 115. The taxane as claimed in claim 1 wherein X5 is -COX10 and X^o is trans-propenyl, isobutenyl, or butenyl, Rioa is propyl, cyclopropyl, or ethyl, and X3 is 2-thienyl. 116. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is butenyl or trans-propenyl, Rioa is propyl, cyclopropyl, or ethyl, and X3 is 2-furyl. 117. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is trans-propenyl, Rioa is n-propyl, cyclopropyl, or ethyl, and X3 is 3-furyl. 118. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is phenyl, Rioa is cyclopropyl, and X3 is 2-furyl, 3-furyI, 2-thienyl, or 3-thienyl. 119. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is n-propyl, Rioa is cyclopropyl, ethyl, or propyl, and X3 is 2-furyl. 120. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is n-propyl, Rioa is cyclopropyl or propyl, and X3 is 2-thienyl. 121. The taxane as claimed in claim 1 wherein X5 is -COOX10 and X10 is isobutyl, Rioa is propyl, and X3 is 2-furyl. 122. The taxane as claimed in claim 1 wherein X5 is -COOXio and X10 is isobutyl, Rioa is n-propyl, cyclopropyl, or ethyl, and X3 is 3-thienyl. 123. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is isopropyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-thienyl or 2-furyl. 124. The taxane as claimed In claim 1 wherein X5 is -COOXio and X10 is t-butyl, Rioa is isobutenyl, and X3 is 2-furyI, 3-furyl, 2-thienyl, or 3-thienyl. 125. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is 2-furyl or 2- thienyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-furyl. 126. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is trans- propenyl, Rioa is cyclopropyl, and X3 is 3-thlenyl. 127. The taxane as claimed in claim 1 wherein X5 is -COXIQ and Xio is phenyl, Rioa is propyl, and X3 is 2-furyl or 2-thienyl. 128. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is tert-amyl, Rioa is ethyl, and X3 is 2-furyl.

Full Text

C10 ESTER SUBSTITUTED TAXANES
BACKGROUND OF THE INVENTION
The present invention is directed to novel taxanes which have exceptional utility as antitumor agents.
The taxane family of terpenes, of which baccatln HI and taxol are members, has been the subject of considerable interest in both the biological and chemical arts. Taxol itself is employed as a cancer chemotherapeutic agent and possesses a broad range of tumor-inhibiting activity. Taxol has a 2"R. 3"S configuration and the following structural formula:

Although taxol and docetaxel are useful chemotherapeutic agents, there are limitations on their effectiveness, including limited efficacy against certain

SUMMARY OF THE INVENTION
Among the objects of the present invention, therefore, is the provision of taxanes which compare favorably to taxol and docetaxel with respect to efficacy as anti-tumor agents and with respect to toxicity. In general, these taxanes possess an ester substituent other than formate, acetate and heterosubstituted acetate at C-10, a hydroxy substituent at C-7 and a range of C-3" substituents.
Briefly, therefore, the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a phannaceutically acceptable carrier, and to methods of administration.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.

■tiJons relative to the carbon of which Ri^a is a substituent; ^ is hydrido or hydroxy;

Ac is acetyl; and
Ry, Rg, and R,o independently have the alpha or beta stereochemical configuration.
In one embodiment, R2 is an ester (R2aC(0)0-), a carbamate (R2aR2bNC(O)0-). a carbonate (R2aOC(0)0-), or a thiocarbamate (R2aSC(0)0-) wherein R^a and Rjj, are independently hydrogen, hydrocarby!, substituted hydrocarbyl or heterocyclo. in a preferred embodiment, Rj is an ester (R2aC(0)0-), wherein Rgg is aryl or heteroaromatic. In another preferred embodiment, R2 is an ester (R2aC{0)0-), wherein Rja is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly prefen^ed embodiment, Rj is benzoyloxy.
While Rg is keto in one embodiment of the present invention, in other embodiments Rg may have the alpha or beta stereochemical configuration, preferably the beta stereochemical configuration, and may be, for example, a- or p-hydroxy or a- or p-acyloxy. For example, when Rg is acyloxy, it may be an ester (R9aC(0)0-), a carbamate (RflaR9bNC(0)0-), a carbonate (R9gOC{0)0-), or a thiocarbamate (R^SC(0)O-) wherein Rgg and Rg^ are independently hydrogen, hydrocart)yl, substituted hydrocarby! or heterocyclo. If Rg is an ester (RgaC{0)0-), Rga is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaromatic. Still more preferably, Rg is an ester (R9aC(0)0-), wherein Rg^ is substituted or unsubstituted pheny}, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyridyl. In one embodiment Rg is (RggC(O)O-) wherein Rg^ is methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl, (straight, branched or cyclic), or hexyl (straight, branched or cyclic). In another embodiment Rg is (R9aC(0)0-) wherein Rgg 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) js/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, htit nnt nhnsnhorous containina moieties.

(iii) substituted or unsubstituted Cj to Cg alkynyi (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic such as furyf, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred ennbodiment, R,oa is ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic pentyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. in another embodiment, Ri^g 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 heterocycio, alkoxy, aikenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nltro, amino, annido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
Exemplary X3 substituents include substituted or unsubstituted Cj to Cg alkyl, substituted or unsubstituted Cj to Cg alkenyl, substituted or unsubstituted Cj to Cg alkynyi, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X3 substituents Include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.
Exemplary Xj substituents include -COX,o, -COOX,o or -CONHX,o wherein XiQ is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred Xg substituents include -COX10, -COOXig or -CONHXIQ wherein X^^ is (i) substituted or unsubstituted C, to Cg 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 Cj to Cg alkenyl such as substituted or unsubstituted ethenyl, propenyl {straight, branched or cyclic), butenyi (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched or cyclic); (ill) substituted or unsubstituted Cj to Cg alkynyi such as substituted or unsubstituted ethynyl, propynyl (straight or branched), butynyl (straight or branched), pentynyl (straight or branched), or

wherein Xio is phenyl, alkyl or heterocyclo, more preferably phenyl, or Xg is -COOXio wherein X^o is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to stnjcture 2 in which (i) Xg is -COOX10 wherein X^g is tert-butyl or X5 is -COX10 wherein X^Q is phenyl, (ii) X3 is substituted or unsubstituted cycloalkyi, alkenyl, phenyl or heterocyclo, more preferabJy substituted or unsubstituted isobuteny), phenyl, fury}, thienyl, orpyfidyi, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R^a is unsubstituted ethyl or propyl, more preferably ethyl.
Among the preferred embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R10 is RiQaCOO- wherein R^^a Is ethyl, in this embodiment, X3 is preferably cycloalkyi, isobutenyl, or heterocyclo, more preferably heterocycfo, still more preferably furyf, thienyl or pyridyl; and Xg Is preferably benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and R,^ is hydride. In another altemative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyi; Rj is benzoyl, Rg is keto and R,4 is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R^ Is benzoyl, Rg is keto and R,^ is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; Xs is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and R^ is hydroxy. In another alternative of this embodiment, X3 Is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg Is hydroxy and R^ is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyi, or
1 J. L.,.1—„ ,—,[.,„„, ,r ^,- +

preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R^ is benzoyl, Rg is acyloxy and R„ is hydride. In each of the alternatives of this embodiment when the taxane has stnjcture 1, R^ and R^^ may each have the beta stereochemical configuration, Ry and RIQ may each have the alpha stereochemical configuration, Ry may have the alpha stereochemical configuration while Rio has the beta stereochemical configuration or R^ may have the beta stereochemical configuration while Rn, has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to stnjcture 1 or 2 wherein Rn, is RiogCOO- wherein R^^a i® propyl. In this embodiment, X3 is preferably cycloalkyi, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocyclo, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; Xj is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and R^^ is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and R^ is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xs is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is keto and Ri4 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is hydroxy and R14 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R2 is benzoyl, Rg is hydroxy and Ri^ is hydrido. In another alternative of this embodiment, X3 is

heterocydocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyi, still more preferably t-butoxycarbonyl; Rg is benzoyl, Rg is acyloxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, Ry and R^Q may each have the beta stereochemical configuration, Ry and R^o may each have the alpha stereochemical configuration, R7 may have the alpha stereochemical configuration while Rio has the beta stereochemical configuration or Rj may have the beta stereochemical configuration while R,o has the alpha stereochemical configuration.
Taxanes having the general formula 1 may be obtained by treatment of a p-lactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a P-amido ester substituent at C-13 (as described more fully in Helton U.S. Patent 5,466,834), followed by removal of the hydroxy protecting groups. The p-iactam has the following structural formula (3):

wherein M is a metal or ammonium, P, is a hydroxy protecting group and R^^ is as previously defined.
Alkoxide 4 may be prepared from 10-deacetylbaccatin III (or a derivative thereof) by selective protection of the C(7) hydroxy! group and then esterification of the C(10)hydroxyl group followed by treatment with a metallic amide. In one embodiment of the present invention, the C{7) hydroxy! group of 10-deacetylbaccatin III is selectively protected with a silyl group as described, for example, by Denis, et. al, (J.Am. Chem. Soc, 1988,110, 5917). In general, the silylating agents may be used either alone or in combination with a catalytic amount of a base such as an alkali metal base.
Alternatively, the C(10) hydroxyl group of a taxane can be selectively acylated in the absence of a base, as described, for example in Holton et al., PCT Patent Application WO 99/09021. Acylating agents which may be used for the selective acylation of the C(1 D) hydroxyl group of a taxane include substituted or unsubstituted alkyl oraryl anhydrides. While the acylation of the C(10) hydroxy group of the taxane will proceed at an adequate rate for many acylating agents, it has been discovered that the reaction rate may be increased by including a Lewis acid in the reaction mixture. Preferred Lewis acids include zinc chloride, stannic chloride, cerium trichloride, cuprous chloride, lanthanum trichloride, dysprosium trichloride, and ytterbium trichloride. Zinc chloride or cerium trichloride is particulariy prefen^ed when the acylating agent is an anhydride.
Derivatives of lO-deacetylbaccatin III having alternative substituents at C{2), C{9) and C(14) and processes for their preparation are known in the art. Taxane derivatives having acyloxy substituents other than benzoyloxy at C(2) may be prepared, for example, as described in Holton et al., U.S. Patent No. 5,728,725 or Kingston et al., U.S. Patent No. 6,002.023. Taxanes having acyloxy or hydroxy substituents at C(9) in place of keto may be prepared, for example as described in Holton et al., U.S. Patent No. 6,011,056 or Gunawardana et al., U.S. Patent No. 5,352,806. Taxanes having a beta hydroxy substituent at C(14) may be prepared from naturally occurring 14-hydroxy-10-deacetylbaccatin 111.
Processes for the preparation and resolution of the p-lactam starting material are generally well known. For example, the [J-!actam may be prepared
a
in PCT Patent Application No. 00/41204. In a preferred embodiment in whicti the p-lactam is fury! substituted at the C(4) position, the p-lactam can be prepared as illustrated in the following reaction scheme:

substance which Is phannaceuticaliy inert, confers a suitable consistency or form to the composition, and does not diminish 1he therapeutic efficacy of the antitumor compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate.
The phannaceutical compositions containing the antitumor compounds of the present invention n^ay be formulated in any conventional manner. Proper fomiulation is dependent upon the route of administration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral {e.g., intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal), topical {nasal, transdennal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradennai, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoscopical, transmucosal, sublingual and intestinal administration.
Pharmaceutically acceptable carriers for use in the compositions of the present invention are well known to those of ordinary skill in the art and are selected based upon a number of factors: the particular antitumor compound used, and its concentration, stability and intended bioavailability; the disease, disorder or condition being treated with the composition; the subject, its age, size and general condition; and the route of administration. Suitable earners are readily detennined by one of ordinary skill in the art (see, for example, J. G. Nairn, in: Remington"s Pharmaceutical Science (A. Gennaro, ed.). Mack Publishing Co., Easton, Pa., {1985), pp. 1492-1517, the contents of which are incorporated herein by reference).
The compositions are preferably fonnulated 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
folinwlnn rf>fprpnppc- 7 ft^nHom Pharmar-anti^e r*h««+-^.-r. n -,«^ nn ro — i,^, o

The compositions of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms inciude 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, croscannellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage fonns 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 intrastemal routes. The compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a phamiaceutically acceptable carrier. Dosage forms suitable for parenteral administration include solutions, suspensions, dispersions, emulsions or any other dosage form which can be administered parenterally. Techniques and compositions for making parenteral dosage forms are known in the art.
Suitable carriers used in fonnulating liquid dosage forms for oral or parenteral administration include nonaqueous, pharmaceutically-acceptabie 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, phannaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-glycerol fomial, p-giycerol fonnal, 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,
i _ J. T- -

hydroxyetliy|}-lactamide, N, N-dimetlnylacetamide_amides, 2-pyrrolidinone, 1-methyl-2-pyrroIidinone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprytate or octanoate, alkyl oieate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, ortri-glyceryj citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oieate, fatty acid esters of sorbltan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, ortri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone, piuronic 60, polyoxyethylene sorbitol oleic polyesters such as poly(ethoxyIated)3(j^(3 sorbitol poiy(oleate)2^, poly(oxyethylene)i5.2Q monooleate, poly(oxyethy)ene)i5.2o mono 12-hydroxystearate, and poly(oxyethy)ene)is.2o niono ricinoleate, polyoxyethylene sorbitan esters such as polyoxyethyiene-sorbitan monooleate, polyoxyethyiene-sorbitan monopalmitate, polyoxyethyiene-sorbitan monolaurate, polyoxyethyiene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, DE, polyvinylpyrrolidone, all atoms ^P! n honTOno /«^/^lnh£lv•5r^a ,J;,NUI>. ——--ii
J»_..- 1

origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn genn, sesame, persic and peanut oil and giycerides such as mono-, di- or triglycerides, animal oils such as fish, marine, spemi, cod-liver, haliver, squalene, squalane, and shark liver oil, oleic oils, and polyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanoiamine; petroleum benzin; trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid); polyglycol ester of 12-hydroxystearic acid and polyethylene glycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitan monooleate.
Other phamiaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The Chemotherapy Source Book (Williams & Wllkens Publishing), The Handbook of Pharmaceutical Excipients. (American Phamiaceutical Association, Washington, D.C., andThePharmaceuticalSocietyof Great Britain, London, England, 1968), Modern Phamiaceutics. (G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacological Basisof Therapeutics. (Goodman & Gilman, McGraw Hill Publishing), Phamiaceutical Dosage Forms. (H. Lieberman et aL, eds., )(Marcel Dekker, Inc., New York, New York, 1980), Remington"s Pharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(MaGk Publishing, Easton, PA, 1995), The United States Pharmacopeia 24. The National Formulary 19, (National Publishing, Philadelphia, PA, 2000), A.J. Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963).
Preferred solvents include those known to stabilize the antitumor compounds, such as oils rich in triglycerides, for example, safflower oil, soybean oil or mixtures thereof, and alkyleneoxy modified faity acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g.,

safflower oi!, 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 docosahexaenoyi group at levels between 25% and 100% by weight based on the total fatty acid content (Dhasco® {from Martek Biosciences Corp., Columbia, MD), DHA Maguro® (from Daito Enterprises, Los Angeles, CA), Soyacal®, and Travemulslon®. Ethanol is a prefen-ed solvent for use in dissolving the antitumor compound to form solutions, emulsions, and the like.
Additional minor components can be included in the compositions of the invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part Impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH. facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 vrt.% of the total composition, as is well known in the formulation art. Such additives include cryoprotective agents for preventing repreclpitation of the taxane, surface active, wetting or emulsifying agents (e.g., lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylene stearate ). presen/atives (e.g., ethyl-p-hydroxybenzoate), microbial preservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol, sorbic acid, thimerosal and paraben), agents for adjusting pH or buffering agents (e.g., acids, bases, sodium acetate, sorbitan monolaurate), agents for adjusting osmolarity (e.g., glycerin), thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol, stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethlcone), clays (e.g., bentonites), adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as

polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g.. starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or salts thereof such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide), and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodium sulfite, dextrose, phenols, and thiophenols).
In a preferred embodiment, a pharmaceutical composition of the invention comprises at least one nonaqueous, phannaceutically 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 fonn a solution and then recrystallized upon evaporation of the solvent without the formation of any amorphous antitumor compound. It is also preferred that the antitumor compound have an ID50 value (i.e, the drug concentration producing 50% Inhibition of colony formation) of at least 4, 5, 6, 7, 8, 9, or 10 times less that of paciitaxel when measured according to the protocol set forth in the working examples.
Dosage form administration by these routes may be continuous or intenmittent, 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 concun"ent treatment, if any, frequency of treatment, and the

treated, the desired therapeutic dose, and other factors that will be apparent to those of skill In the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route. Preferably, the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per m^ of patient body surface area, or at least 50,100,150, 200, 300, 400, or 500 mg of the antitumor compound per m^ of patient body surface area, wherein the average body surface area for a human is 1.8 m^ Preferably, a single dose of a composition for oral administration contains from about 20 to about 600 mg of the antitumor compound per m^of patient body surface area, more preferably from about 25 to about 400 mg/m^" even more preferably, from about 40 to about 300 mg/m^ and even more preferably from about 50 to about 200 mg/m^. Preferably, the compositions for parenteral administration are prepared in such a way that a single dose contains at least 20 mg of the antitumor compound per m^ of patient body surface area, or at least 40, 50,100, 150, 200, 300, 400, or 500 mgofthe antitumor compound per m^of patient body surface area. Preferably, a single dose in one or more parenteral preparations contains from about 20 to about 500 mg of the antitumor compound per m^ of patient body surface area, more preferably from about 40 to about 400 mg/m^" and even more preferably, from about 60 to about 350 mg/m^. However, the dosage may vary depending on the dosing schedule which can be adjusted as necessary to achieve the desired therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit the invention and represent preferred dose
I
ranges. The most prefen^ed 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
^nmni-ieitinn mnro r\rofcirahK/ hohn/aan ahni it fl 1 mn anr\ ahni if 7 mn nar ml o\/cin

soluble in the solution at low concentrations. The concentration of the antitumor compound in a solid phannaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %.
In one embodiment, solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanoi or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophoi® EL solution, is added to the solution while stirring to fonn a pharmaceutically acceptable solution for oral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanoi, which is known in the art to cause adverse physiological effects when administered at certain concentrations in oral formulations.
In another embodiment, powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g..ethanoi 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 Cremophoits) 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., ethanoi or methylene chloride) to form a solution. An appropriate volume of a carrier which is an emulsion, such as Liposyn® 11 or

adverse physiological effects when administered at certain concentrations in parenteral formulations.
Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® solution, is added to the solution while stirring to fomi a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventional containers in concentrated form and diluted with any phannaceutically acceptable liquid, such as saline, to fomi an acceptable taxane concentration prior to use as is known in the art.
Definitions
The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exclusively of the elements carbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, and aryl moieties. These moieties also include alkyl, alkenyl, alkynyl, and aryl moieties substituted with other aliphatic or cyclic hydrocarbon groups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwise indicated, these moieties preferably comprise 1 to 20 carbon atoms.
The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, including moieties in which a carbon chain atom is substituted with a hetero atom such as nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or a halogen atom. These substituents include halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano,
fhini kfatnlc arotalc octArc nnH othorc

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 heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.
The "heterosubstituted acetate" moieties described herein are acetate groups in which the carbon of the methyl group Is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to fonn a heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.
Unless othenwise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexy! and the like.
Unless othenwise indicated, the alkenyl groups described herein are preferably lower alkenyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and include ethenyl, propenyl, isopropenyl, butenyl. isobutenyl, hexenyl, and the like.
Unless othenwise indicated, the alkynyl groups described herein are preferably lower alkynyl containing from two to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain and , include ethynyl, propynyl, butynyl, isobutynyl. hexynyl, and the like.
The terms "ary!" or "ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.

heterocycio group preteraDly has l or ^ 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 heterocycio include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl. quinolinyl, or isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
The term "heteroaromatic" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfijr 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, pyn-olyl, indolyl, quinolinyl, or Isoquinolinyl and the like. Exemplary substituents include one or more of the following groups: hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.
The term "acyl," as used herein alone or as part of another group, denotes the moiety formed by removal of the hydroxyl group from the group -COOH of an organic carboxylic acid, e.g., RC(0)-, wherein R is R\ R^O-, R^R^N-, or R^S-, R^ is hydrocarbyl, heterosubstituted hydrocarbyl, or heterocycio and R^ is hydrogen, hydrocarbyl or substituted hydrocarbyl.
The term "acyloxy," as used herein alone or as part of another group, denotes an acyl group as described above bonded through an oxygen linkage (-0-), e.g., RC{0)0- wherein R is as defined in connection with the term "acyl."
Unless otherwise indicated, the alkoxycarbonyloxy moieties described herein comprise lower hydrocarbon or substituted hydrocarbon or substituted hydrocarbon moieties.
Unless otherwise indicated, the carbamoyloxy moieties described herein are derivatives of carbamic acid in which one or both of the amine hydrogens Is
nntlAnallv/ ronlanarf hx/ a h\/Hrnr"ai+t\/l ci rhctifi itnH h\/Wmr»arh\/! r\r hpfprnnuHfi

("protected hydroxy!") which, subsequent to the reaction for which protection is empioyed, may be removed without disturbing the remainder of the molecule. A \/anety of protecting groups for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981, orFieser & Fieser, Exemplary hydroxyl protecting groups include methoxymethy!, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsllyiethoxy)methyl,tetrahydropyranyl, 2,2,2-trich!oroethoxycarbonyl,t-butyl(diphenyl)silyl,trialkylsilyl, trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
As used herein, "Ac" means acetyl; "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "iPr" means isopropyl; "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; "tSuOCO" and "BOG" mean tert-butoxycarbonyl; "tAmOCO" means tert-amyloxycarbonyl; "PhCO means phenylcarbonyl"; "2-FuCO" means 2-furylcarbonyl; "2-ThCO" means 2-thienylcarbonyl; "2-PyCO" means 2rpyridylcarbonyl; "3-PyCO" means 3-pyridylcarbonyl; "4-PyCO" means 4-pyridylcarbonyi; "CjH^CO" means butenylcarbonyl; "EtOCO" means ethoxycarbonyl; "ibueCO" means isobutenylcarbonyl; "IBuCO" means isobutylcarbonyl; "iBuOCO" means isobutoxycarbonyl; "iPrOCO" means isopropyloxycarbonyl; "nPrOCO" means n-propyloxycarbonyl; "nPrCO" means n-propylcarbonyl; "tCaHgCO" means trans-propenyl carbonyl"; "Ibue" means isobutenyl; "THF" means tetrahydrofuran; "DMAP" means 4-dimethylamino pyridine; "LHMDS" means Lithium HexamethylDiSilazanide.
The following examples illustrate the invention.

7-Dimethylphenylsilyl-10-propionyl-10-deacetyl baccatin ill. To a solution of 0.200 g (0.333 mmol) of 10-propionyl-10-deacetyl baccatin III in 12 mL of THF at -10 "C under a nitrogen atmosphere was added dropwise 0.668 mL (4.00 mmo)} oi chlorodimethyl-phenylsilane and 2.48 mL (30.64 mmol) of pyridine. After 90 min the mixture was diluted with 100 mL of a 1:1 mixture of ethyl acetate and hexane. The mixture was washed with 20 mL of saturated aqueous sodium bicarbonate solution and the organic layer separated. The aqueous layer was extracted with 30 mL of a 1:1 mixture of ethyl acetate and hexane, and the combined organic
ovtra(~tc lA/oro wachoH with hrinft riripH nvpr Nfl.J^n. and concentrated in vacuO.

3"-Despheny!-3"-(2-thienyl)-10-propionyl-10-deac6tyl taxol. To a solution of 0.521 g (0.464 mmol)of7-dimethylphenyisilyl-2"-0-triethylsilyl-3"-despheny|-3"-(2-thienyl)-10-propionyl-10-deacetyi taxol in 2 mL of CH3CN and 2 mL of pyridine at 0 °C was added 0.5 mL of a solution of 30% HF in HjO. After 3 h 20 mL of a

70% EtOAc/hexane as eluent to give 0.405 g (100%) of 3"-despheny!-3"-(2-thienyl)-10-propionyl-10-deacetyi taxol as a solid. m,p. 154-155 "C; [a];^^ = -45.0 (c 0.1 in CHC13); Anal. Calcd. for C^gHsiNO^S: C, 63.22; H, 5.88; Found: C, 62.94; H, 5.97.

In the "A" series of compounds, XIQ is as othenwise as defined herein. Preferably, heterocycio is substituted or unsubstitued furyl, thienyl, or pyridyl, X^Q is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl {e.g., terf-butyl), and Ry and R^Q each have the beta stereochemical configuration.
In the "B" series of compounds, X^o and R^^ are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^Q is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rj^ is preferably substituted or unsubstitued fury!, thienyl, pyridyl, phenyl, or lower alkyl, and R^ and Rio each have the beta stereochemical configuration.
In the "C" series of compounds, X^Q and Rgg are as otherwise as defined herein. Preferably, heterocycio Is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^, Is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R^^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^, Rg and R^o each have the beta stereochemical configuration.
In the "D" and "E" series of compounds, X^Q is as othenwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and Ry. Rg (series D only) and R^ each have the beta stereochemical configuration.
In the "F" series of compounds, XIQ, Rjg and Rgg are as othenwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, Xio is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridy), phenyl, or lower alkyl, and R7, Rg and R^Q each have the beta stereochemical configuration.
In the "G" series of compounds, X^Q and R2a are as othenrt^lse as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, XIQ IS preferably substituted or unsubstitued furyl, thienyi, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R^^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyi, and R7, Rg and Rio each

or lower alkyl (e.g., tert-butyi), Rja is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and Ry and Rio each have the beta stereochemical configuration.
In the "I" series of compounds, X^Q and Rja are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued fury!, thienyl, or pyridyl, Xio is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rj^ Is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R7 and R^ each have the beta stereochemical configuration.
In the "J" series of compounds, X^j and Rja are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^o is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), Rja is preferably substituted or unsubstitued iury\, thienyl, pyridyl, phenyl, or lower alkyl, and R7, Rg and R10 each have the beta stereochemical configuration.
In the "K" series of compounds, X^Q, R2a and Rg^ are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^Q is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), R2a is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^, Rg and R^Q each have the beta stereochemical configuration.
Any substituents of each X3, Xg, Rj, Rg, Rio may be hydrocarbyl or any of the heteroatom containing substituents selected from the group consisting of heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetai, ester and ether moieties, but not phosphorous containing moieties.

Example 6 Preparation of Solutions for Oral Administration
Solution 1: 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 Cremoplior® EL solution was added to the solution while stimng 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 2: 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 3: Antitumor compound 0611 was dissolved in ethanol to fonn 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 4: 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 fonn a pharmaceutically acceptable solution for administration to a patient.

WE CLAIM:
1. A laxane having the formula

14. The taxane as claimed in claim 2 wherein R2 is benzoyloxy and Rg is keto.

24, The taxane as claimed in claim 23 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyi, 2-pyridyl, 3-pyridyl, or4-pyridyl.

25. The taxane as claimed in claim 23 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl. 3-furyl, 2-thienyl, 3-thienyl. 2-pyridyl, 3-pyridyl, 4~ pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl, or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Cs alkyl, C2 - Cs alkenyl, or C2 - Ce alkynyl.
26. The taxane as claimed in claim 23 wherein Ru is hydrogen.
27. The taxane as claimed in claim 26 wherein X3 is 2-furyl, 3-furyl, 2-thieny|, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl.
28. The taxane as claimed in claim 26 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyrldyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ce alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Ca alkynyl.
29. The taxane as claimed in claim 23 wherein R2 is benzoyloxy.
30. The taxane as claimed in claim 29 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyi, or 4-pyridyl.
31. The taxane as claimed in claim 29 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyrJdyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ce alkynyl.
32. The taxane as claimed in claim 23 wherein Ru is hydrogen and R9 is keto.
33. The taxane as claimed in claim 32 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
34. The taxane as claimed in claim 32 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Ce alkenyl, or C2 - Ce alkynyl.

35. The taxane as claimed in claim 23 wherein R2 is benzoyloxy and Rg is keto.
36. The taxane as claimed in claim 35 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
37. The taxane as claimed in claim 35 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyhdyl, 3-pyridyl, 4-pyridyl, Ci - Cg alkyl, C2 - Cs alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or Ca - Ca alkynyl.
38. The taxane as claimed in claim 23 wherein Ru is hydrogen and Rz is benzoyloxy.
39. The taxane of claim 38 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyndyl.
40. The taxane as claimed in claim 38 wherein X5 is -COXio and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Cs alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Ca alkynyl.
41. The taxane as claimed in claim 23 wherein R14 is hydrogen, Rg Is keto, and R2 is benzoyloxy.
42. The taxane as claimed in claim 41 wherein X3 is 2-furyl, 3-furyl, 2-thlenyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
43. The taxane as claimed in claim 41 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thtenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Cs alkyl, C2 - Ca alkenyl, or Ca - Cs alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Cs alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl.
44. The taxane as claimed in claim 1 wherein Rioa is ethyl,

45. The taxane as claimed in claim 44 wherein X3 is 2-furyl, 3-furyi, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl.
46. The taxane as claimed in claim 44 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyt, 3-thienyl, 2-pyridyl, 3-pyndyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ce alkenyl, or C2 - Cg alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Cg alkyl, C2 - CB alkenyl, or C2 - Ce alkynyl.
47. The taxane as claimed in claim 44 wherein Ru is hydrogen.
48. The taxane as claimed in claim 47 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyndyl, 3-pyridyl, or4-pyridyI.
49. The taxane as claimed in claim 47 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thtenyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl.
50. The taxane as claimed in claim 44 wherein R2 is benzoyloxy.
51. The taxane as claimed in claim 50 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
52. The taxane as claimed in claim 50 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thlenyl, 2-pyndyl, 3-pyridyl, 4-pyridyl, Ci - Cg alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Cg alkenyl, or C2 - Ca alkynyl.
53. The taxane as claimed in claim 44 wherein Ru is hydrogen and R9 is keto.
54. The taxane as claimed in claim 53 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyr)dyl, 3-pyridyl, or 4-pyridyl.
55. The taxane as claimed in claim 53 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thlenyl, 2-pyridyl, 3-pyridyl, 4-

pyridyl, Ci - Cs alkyl, C2 - Cs alkenyl, or C2 - Ce alkynyl or X5 is -COOX10 and X10 is substituted or unsubstltuted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Ce alkynyl.
56. The taxane as claimed in claim 44 wherein Rg is benzoyloxy and Rg is keto.
57. The taxane as claimed in claim 56 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
58. The taxane as claimed in claim 56 wherein X5 is -COXio and X10 is substituted or unsubstltuted phenyl, 2-furyl, 3-furyl, 2-thlenyl, 3-thienyl, 2-pyhdyl, 3-pyridyi, 4-pyridyl, Ci - Cg alkyl, C2 - Cs alkenyl, or Ca - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstltuted Ci - Ce alkyl, C2 - Ca alkenyl, or C2 - Ce alkynyl.
59. The taxane as claimed in claim 44 wherein Ru is hydrogen and R2 is benzoyloxy.
60. The taxane as claimed in claim 59 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
61. The taxane as claimed in claim 59 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ce alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ce alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl.
62. The taxane as claimed in claim 44 wherein Ru is hydrogen, Rg is keto, and R2 is benzoyloxy.
63. The taxane as claimed in claim 62 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyrldyl.
64. The taxane as claimed in claim 62 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ce alkenyl, or C2 - Ca alkynyl or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ce alkyl, C2 - Ca alkenyl, or G2 - Ca alkynyl.
85. The taxane as claimed in claim 62 wherein X5 is -COOX10 and X10 is t-butyl.

73. The taxane as claimed in claim 70 wherein X3 is furyl or thienyl.
74. The taxane as claimed in claim 73 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ce alkyl, C2 - Ca alkenyl, or C2 - Cs alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl.
75. The taxane as claimed in claim 70 wherein Rioa is ethyl or propyl.
76. The taxane as claimed in claim 75 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
77. The taxane as claimed in claim 76 wherein X5 is -COXio and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyt, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl.
78. The taxane as claimed in claim 75 wherein X3 is furyl or thienyl.
79. The taxane as claimed in claim 78 wherein X5 is -COXio and Xio is substituted or unsubstituted phenyl, 2-furyl, 3-furyt, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alky!, C2 - Ca alkenyl, or C2 - Ca alkynyl, or X5 is -COOX10 and Xio is substituted or unsubstituted Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl.
80. The taxane as claimed in claim 70 wherein X3 is furyl or thienyl, Rioa is ethyl, and X5 is -COXio and Xio is phenyl, or X5 is -COOX10 and Xio is t-butyl.
81. The taxane as claimed in claim 70 wherein X3 is substituted or unsubstituted furyl, Rioa is ethyl, and X5 is -COXio and Xio is phenyl, or X5 is -COOXio and Xio is t-butyl.
82. The taxane as claimed in claim 70 wherein X3 is substituted or unsubstituted thienyl, Rioa is ethyl, and X5 is -COXio and Xio is phenyl, or X5 is -COOXio and Xio is t-butyl.

83. The taxane as claimed in claim 70 wherein X3 is 2-furyl or 2-thienyl, Rioa is ethyl, X5 is -COOX10 and Xjo is t-butyl.
84. The taxane as claimed in claim 70 wherein X3 is 2-furyl, Rioa is ethyl, X5 is -COOX10 and X10 is t-butyl.
85. The taxane as claimed in claim 70 wherein X3 is 2-thienyl, Rioa is ethyl, X5 is -COOX10 and X10 is t-butyl.
86. A pharmaceutical composition comprising the taxane as claimed in claim 1 and at least one pharmaceutically acceptable carrier.
87. The pharmaceutical composition as claimed in claim 86 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyl.
88. The pharmaceutical composition as claimed in claim 87 wherein Xg is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, S-thienyl, 2-pyridyl, 3-pyridy!, 4-pyridyl, Cj - Cs alkyl, C2 - Ce alkenyl, or C2 - Ce alkynyl, or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Ca alkyl, C2 - Cs alkenyl, or C2 - Cs alkynyl.
89. The phamiaceutical composition as claimed in claim 87 wherein Rioa is ethyl or propyl.
90. The pharrnaceuticai composition as claimed in claim 89 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or4-pyridyt.
91. The pharmaceutical composition as claimed in claim 90 wherein X5 is -COX10 and X10 is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, Ci - Ca alkyl, C2 - Ca alkenyl, or C2 - Ca alkynyl, or X5 is -COOX10 and X10 is substituted or unsubstituted Ci - Cs alkyl, C2 - Cs alkenyl, or C2 - Cs alkynyl.

92. The pharmaceutical composition as claimed in claim 87 wherein X3 is furyl or thienyl, Rioa is ethyl, and X5 is -COX10 and X10 is phenyl, or X5 is -COOXio and X10 is t-butyl.
93. The pharmaceutical composition as claimed in claim 87 wherein X3 is substituted or unsubstituted furyl, Rioa is ethyl, and X5 is -COX10 and X10 is phenyl, or X5 is -COOXjo and X10 is t-butyl.
94. The phanmaceuticai composition as claimed in claim 87 wherein X3 is substituted or unsubstituted thienyl, Rioa is ethyl, and X5 is -COX10 and X10 is phenyl, or X5 is -COOX10 and X10 is t-butyl.
95. The pharmaceutical composition as claimed in claim 87 wherein X3 is 2-furyl or 2-thienyl, Rioa is ethyl, X5 is -COOXio and X10 is t-butyl.
96. The phannaceutical composition as claimed in claim 87 wherein X3 is 2-furyl, Rioa is ethyl, X5 is -COOXio and X10 is t-butyl.
97. The pharmaceutical composition as claimed in claim 87 wherein X3 is 2-thienyl, Rioa is ethyl, X5 is -COOXio and Xio is t-butyl.
98. A pharmaceutical composition comprising the taxane as claimed in claim 70 and at least one pham^aceutically acceptable carrier.
99. A pharmaceutical composition comprising the taxane as claimed in claim 73 and at least one pharmaceutically acceptable carrier.
100. A composition for oral administration comprising the taxane as claimed in claim 1 and at least one pharmaceutically acceptable carrier.
101. The composition as claimed in claim 100 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
102. The composition as claimed in claim 101 wherein Rioa is ethyl or propyl.

103. The composition as claimed in claim 102 wherein R„ is hydrogen R^ is benzoyloxy, and X5 is -COX,o wherein X,„ is phenyl, or Xs is -COOX,„ wherein Xio is t-butyl.
104. The composition as claimed in claim 103 wherein X3 is furyl or thienyl; R,oa is ethyl; and X5 is -COOX10 and Xio is t-butyl.
105. The composition as claimed in claim 104 wherein X3 is furyl.
106. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is t-butyl, Rio^ is ethyl, propyl, isopropyl, or trans-propenyl, and X3 is 2-furyl or 3-furyl.
107. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is t-butyl, Rioa is ethyl, propyl, isopropyl, or trans-propenyl, and X3 is 2-thienyl or 3-thienyl.
108. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is t-butyl, Rioa is 2-thienyl or 2-furyl, and X3 is 2-furyl, 3-furyl, 2-thienyl, or 3-thienyl.
109. The taxane as claimed in claim 1 wherein X5 is -COXio and Xio is phenyl, Rioa is ethyl, and X3 is 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 2-thienyl, or 3-thienyl.
110. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is ethyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-thienyl or 2-furyl.

111. The taxane as claimed in claim 1 wherein X5 is -COX10 and Xio is 2-furyl or 2-thienyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-thienyl.
112. The taxane as claimed in claim 1 wherein X5 is -COOXio and Xio is t-butyl, Rioa is cyclopropyl, and X3 is 2-furyl, 3-furyl, 2-thienyl, or 3-thienyl.
13. The taxane as claimed in claim 1 wherein X5 is -COOXio and Xio is isobutyl, Rioa is cyclopropyl or propyl, and X3 is 2-furyl or 3-furyt.

114. The taxane as claimed in claim 1 wherein X5 is -COOX10 and X10 is isobutyl, Rioa is cyclopropyl, propyl, or ethyl, and X3 is 2-thienyl.
115. The taxane as claimed in claim 1 wherein X5 is -COX10 and X^o is trans-propenyl, isobutenyl, or butenyl, Rioa is propyl, cyclopropyl, or ethyl, and X3 is 2-thienyl.
116. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is butenyl or trans-propenyl, Rioa is propyl, cyclopropyl, or ethyl, and X3 is 2-furyl.
117. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is trans-propenyl, Rioa is n-propyl, cyclopropyl, or ethyl, and X3 is 3-furyl.
118. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is phenyl, Rioa is cyclopropyl, and X3 is 2-furyl, 3-furyI, 2-thienyl, or 3-thienyl.
119. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is n-propyl, Rioa is cyclopropyl, ethyl, or propyl, and X3 is 2-furyl.
120. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is n-propyl, Rioa is cyclopropyl or propyl, and X3 is 2-thienyl.
121. The taxane as claimed in claim 1 wherein X5 is -COOX10 and X10 is isobutyl, Rioa is propyl, and X3 is 2-furyl.
122. The taxane as claimed in claim 1 wherein X5 is -COOXio and X10 is isobutyl, Rioa is n-propyl, cyclopropyl, or ethyl, and X3 is 3-thienyl.
123. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is isopropyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-thienyl or 2-furyl.
124. The taxane as claimed In claim 1 wherein X5 is -COOXio and X10 is t-butyl, Rioa is isobutenyl, and X3 is 2-furyI, 3-furyl, 2-thienyl, or 3-thienyl.

125. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is 2-furyl or 2-
thienyl, Rioa is ethyl, cyclopropyl, or propyl, and X3 is 2-furyl.
126. The taxane as claimed in claim 1 wherein X5 is -COX10 and X10 is trans-
propenyl, Rioa is cyclopropyl, and X3 is 3-thlenyl.
127. The taxane as claimed in claim 1 wherein X5 is -COXIQ and Xio is phenyl, Rioa is
propyl, and X3 is 2-furyl or 2-thienyl.
128. The taxane as claimed in claim 1 wherein X5 is -COOX10 and Xio is tert-amyl,
Rioa is ethyl, and X3 is 2-furyl.

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in-pct-2001-1335-che claims.pdf

in-pct-2001-1335-che correspondence-others.pdf

in-pct-2001-1335-che correspondence-po.pdf

in-pct-2001-1335-che description(complete).pdf

in-pct-2001-1335-che form-1.pdf

in-pct-2001-1335-che form-13.pdf

in-pct-2001-1335-che form-18.pdf

in-pct-2001-1335-che form-26.pdf

in-pct-2001-1335-che form-3.pdf

in-pct-2001-1335-che form-5.pdf

in-pct-2001-1335-che others.pdf

in-pct-2001-1335-che pct.pdf

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Patent Number

212780

Indian Patent Application Number

IN/PCT/2001/1335/CHE

PG Journal Number

07/2008

Publication Date

15-Feb-2008

Grant Date

17-Dec-2007

Date of Filing

27-Sep-2001

Name of Patentee

FLORIDA STATE UNIVERSITY RESEARCH FOUNDATION, INC

Applicant Address

100 SLIGER BUILDING, MC 2763,TALLAHASSEE, FL-32306-2763

Inventors:

#	Inventor's Name	Inventor's Address
1	HOLTON, Robert, A	Florida State University Research Foundation, Inc. 100 Sliger Building, MC 2763 Tallahassee, FL 32306-2763

PCT International Classification Number

C07D 409/12

PCT International Application Number

PCT/US01/03623

PCT International Filing date

2001-02-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/179,782	2000-02-02	U.S.A.