Title of Invention

C7 ESTER SUBSTITUTED TAXANES AS ANTITUMOR AGENTS

Abstract The present invention relates to a taxane the formula R<SUB>2</SUB> is acyloxy; R7 is R<SUB>7a</SUB>COO-; R<SUB>7a</SUB> 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<SUB>7a</SUB> is a substituent; R<SUB>9</SUB> is keto, hydroxy, or acyloxy; R<SUB>10</SUB> is hydroxy; R<SUB>14</SUB> is hydrido or hydroxy; X<SUB>3</SUB> is substituted or unsubstituted alkyl, alkenyl, alkynyl, or heterocyclo; X<SUB>5</SUB> is -COXlo, -COOXlo, or -CONHX\o; X<SUB>10</SUB> is hydrocarbyl, substituted hydrocarbyl, or heterocyclo; and Ac is acetyl.
Full Text

C7 ESTER SUBSTITUTED TAXANES AS ANTITUMOR AGEHTS
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 baccatin 111 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 types of cancers and toxicity to subjects when administered at various doses.

SUMMARY OF THE (NVENTtON
Among the objecis 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 substltuent other than formate, acetate and heterosubstituted acetate at C-7, a hydroxy substituent at C-10 and a range of C-3' subatituents.
Briefly, therefore, the present invention is directed to the taxane composition, per se, to pharmaceutical compositions comprising the taxane and a pharmaceutlcaily 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.
DETAILED DES'DRIPTION OF THE PREFERRED EMBODIMENTS
In one embodiment of the present invention, the taxanes of the present invention con-espond to stnjcture (1):

wherein
R2 is acyfoxy;
Rj is R^aCOO-;
Rya is hydrocarbyl, substituted hydrocarbyi, or heterocyclo wherein said hydrocarbyl or substituted hydrocarbyl contains carbon atoms in the alpha and beta positions relative to the carbon of which R-^g is a substituent;
Rs is keto, hydroxy, or acyloxy;
R,o is hydroxy;
R.. is hvdrido or hydroxy;

Ac is acetyl; and
RT, Rg, and R,Q independently have the alpha or beta stereochemical configuration.
In one embodiment, Rj is an ester (R2aC{0)0-), a carbamate (R2aR2bNC(0)0-), a carbonate (R230C(0)0-), or a thiocarbamate (R23SC(0)0-) wherein R23 and R;;, are independently hydrogen, hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferred embodiment, Rj is an ester {R23C(0)0-), wherein Rj^ is aryi or heteroaromatic. In another preferred embodiment, R^ is an ester (R23G(0)Q-), wherein Rs^ is substituted or unsubstituted phenyl, furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R; is benzoyloxy.
In one embodiment, R7 is R^aCOO- wherein R^g is (i) substituted or unsubstituted C^ to Cg alkyl (straight, branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted or unsubstituted Cs to Cg alkenyl (straight, branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C; to Cg alkynyl (straight or branched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyi; (iv) substituted or unsubstituted phenyl; or (v) substituted or unsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. The substituents may be hydrocarbyl or any of the heteroatom containing substituents identified elsewhere herein for substituted hydrocarbyl. In a preferred embodiment, Ry^ is ethyl, straight, branched or cyclic propyl, straight, branched or cyclic butyl, straight, branched or cyclic pentyl, straight, branched or cyclic hexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. In another embodiment, R^^ is substituted ethyl, substituted propyl (straight, branched or cyclic), substituted propenyl (straight or branched), substituted isobutenyl, substituted furyl or substituted thienyl wherein the substituent(s) is/are selected from the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
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

Rgg 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 (RggC{0)0-), wherein Rg^ is substituted or unsubstituted phenyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, or substituted or unsubstituted pyridyl. in one embodiment Rg is (R9aC(0)0-) 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 R^, is substituted methyl, substituted ethyl, substituted propyl (straight, branched or cyclic), substituted butyl (straight, branched or cyclic), substituted pentyl, (straight, branched or cyclic), or substituted hexyl (straight, branched or cyclic) wherein the substituent(s) Is/are selected from the group consisting of heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amide, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
Exemplary X3 substituents include substituted or unsubstituted C2 to Cg alkyl, substituted or unsubstituted Cj to C3 alkenyl. substituted or unsubstituted C2 to C3 alkynyl, substituted or unsubstituted heteroaromatics containing 5 or 6 ring atoms, and substituted or unsubstituted phenyl. Exemplary preferred X3 substituents include substituted or unsubstituted ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.
Exemplary Xg substituents include -COX,o, -COOX,o or -CONHX,o wherein X,o is substituted or unsubstituted alkyl, alkenyl, phenyl or heteroaromatic. Exemplary preferred X5 substituents include -COX,o, -COOX1Q or -CONHXIQ wherein X,o is (i) substituted or unsubstituted C, to C3 alkyl such as substituted or unsubstituted methyl, ethyl, propyl (straight, branched or cyclic), butyl (straight, branched or cyclic), pentyl (straight, branched or cyclic), or hexyl (straight, branched or cyclic); (ii) substituted or unsubstituted C; to Cg alkenyl such as substituted or unsubstituted ethenyl, propenyl (straight, branched or cyclic}, butenyl (straight, branched or cyclic), pentenyl (straight, branched or cyclic) or hexenyl (straight, branched or cyclic); (iii) substituted or unsubstituted Cj to Cg
allcvn\/l CI ir-h ac ci ihctiti ttoj-f nr t inei ihctiti rtciH cith\/n\/! nmrw/ni/l /e+rainht nr

heterocycio, alkoxy, aikenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal, acetal, ester and ether moieties, but not phosphorous containing moieties.
in one preferred embodiment, the taxanes of the present invention correspond to the following structural formula (2):
wherein
Rj is R^aCOO-;
RiQ is hydroxy;
X3 is substituted or unsubstituted aikyi, alkenyl, alkynyl, or heterocycio;
Xg is -COX,o, -COOX,o, or -CONHX,o;
X,Q is hydrocarbyi, substituted hydrocarbyl, or heterocycio;
Rja is hydrocarbyi, substituted hydrocarbyl, or heterocycio wherein said hydrocarbyi or substituted hydrocarbyl contains carbon atoms in the alpha and beta positions relative to the carbon of which R3 is a substituent;
Bz is benzoyl-, and
Ac is acetyl. For example, in this preferred embodiment in which the taxane corresponds to structure (2), R73 may be substituted or unsubstituted ethyl, propyl or butyl, more preferably substituted or unsubstituted ethyl or propyl, still more preferably substituted or unsubstituted ethyl, and still more preferably unsubstituted ethyl. While Rya is selected from among these, in one embodiment X3 is selected from substituted or unsubstituted alkyl, alkenyl, phenyl or heterocycio, more preferably substituted or unsubstituted alkenyl, phenyl or heterocycio, still rnore preferably substituted or unsubstituted nhenvl or heterocvnio. and still more nreferablv

wherein X,o is phenyl, alky! or heterocyclo, more preferably phenyl, or X5 Is -COOX,Q wherein X,o is alkyl, preferably t-butyl. Among the more preferred embodiments, therefore, are taxanes corresponding to structure 2 in which (i) Xg is -COOX15 wherein X,o is tert-butyl or X5 is -COX,^ wherein X^o is phenyl, (ii) X3 is substituted or unsubstituted cycloalkyi, alkenyl, phenyl or heterocyclo, more preferably substituted or unsubstituted isobutenyt, phenyl, furyl, thienyl, or pyridyl, still more preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and (iii) R7a is unsubstituted ethyl or propyl, more preferably ethyl.
Among the prefen'ed embodiments, therefore, are taxanes corresponding to structure 1 or 2 wherein R^ is RjaCOO- wherein R^a is ethyl. 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 or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, aikoxycartjonyl, 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; X5 Is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, R^ is keto and R^^ is hydrido. In another altemative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and Ri4 is hydroxy. In another altemative of this embodiment, X3 is heterocyclo; X5 is benzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is hydroxy and R,4 is hydroxy. In another 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; R; is benzoyl, Rg is hydroxy and R,. is hydrido. In another altemative of this embodiment, X3 is

heterocyciocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is acyioxy and R14 is hydrido. In each of the alternatives of this embodiment when the taxane has structure 1, R7 and R^Q may each have the beta stereochemical configuration, R^ and R,o may each have the alpha stereochennical configuration, Rj may have the alpha stereochemical configuration while R,o has the beta stereochemical configuration or R7 may have the beta stereochemical configuration while R^^ has the alpha stereochemical configuration.
Also among the preferred embodiments are taxanes corresponding to stnjcture 1 or 2 wherein R^ is R^gCOO- wherein R^^ is propyl. In this embodiment, X3 is preferably cycloalkyi, isobutenyl, phenyl, substituted phenyl such as p-nitrophenyl, or heterocycio, more preferably heterocyclo, still more preferably furyl, thienyl or pyridyl; and X5 is preferably benzoyl, alkoxycarbonyl, or heterocyciocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyciocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R^ is benzoyl, Rg is keto and R^ is hydrido. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyciocarbonyl, 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; Xg is benzoyl, alkoxycarbonyl. or heterocyciocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; Rj is benzoyl, Rg is keto and R,4 is hydroxy. In another alternative of this embodiment, X3 is heterocyclo; Xg is benzoyl, alkoxycarbonyl, or heterocyciocarbonyl, more preferably benzoyl, t-butoxycarbonyl or t-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 heterocyciocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R^ is benzoyl, Rg is hydroxy and R,4 is hydrido. \n another alternative of this embodiment, X3 is

heterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyi ort-amyioxycarbonyl, stili more preferably t-butoxycarbonyl; R^ is benzoyl, R^ is acyloxy and R,4 Is hydrldo. in each of the alternatives of this embodiment when the taxane has structure 1, R7 and R^Q may each have the beta stereochemical configuration, R^ and R,o may each have the alpha stereochemical configuration, Rf may have the alpha stereochemical configuration v^fhiie R,Q has the beta stereochemical configuration or R^ may have the beta stereochemical configuration while R^Q has the alpha stereochemical configuration.
Taxanes having the general formula 1 may be obtained by treatment of a (3-iactam with an alkoxide having the taxane tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a [3-amido ester substituent at C-13 (as described more fully In Holton U.S. Patent 5,466,834), followed by removal of the hydroxy protecting groups. The p-lactam has the following stnjctural formula (3):

wherein M is a metai or ammonium, ?,□ is a hydroxy protecting group and Rj, Rg,

embodiment of the present invention, the C(10) hydroxyl group of 10-deacetylbaccatin III is selectively protected with a silyl group using, for example, a siiylamide or bissilyamide as a silylating agent. Preferred silylating agents include tri{hydrocarbyl)silyl-trifluoromethylacetamides and bis tn(hydrocarbyl)-silyltrifluoromethylacetamides (with the hydrocarbyl moiety being substituted or unsubstituted alkyl oraryl) such as N,0-bis-(trimethylsiiyl) thfluoroacetamlde, N,0-bis-{triethylsilyl)trifIuoroacetamlde, N-methyl-N-tnethylsily!trifluoroacetamide, and N,0-bis(t-butyldimethylsiiyl)trifluoroacetamide. The silylating agents maybe used either alone or in combination with a catalytic amount of a base such as an alkali metal base. Alkali metal amides, such as lithium amide catalysts, in general, and lithium hexamethyldisilazide, in particular, are preferred. The solvent for the selective siiylation reaction is preferably an ethereal solvent such as tetrahydrofuran. Alternatively, however, other solvents such as ether or dimethoxyethane maybe used. The temperature at which the C( 10) selective siiylation is carried out is not narrowly critical. In general, however, it is carried out at 0 °C or greater.
Selective esterification of the C(7) hydroxyl group of a C(10) protected taxane can be achieved using any of a variety of common acylating agents including, but not limited to, substituted and unsubstituted carboxylic acid derivatives, e.g., carboxylic acid halides, anhydrides, dicarbonates, isocyanates and haloformates. For example, the C(7) hydroxyl group of the 10-protected-10-deacteyl baccatin III can be selectively acylated with dibenzyl dicarbonate, dialiyi dicarbonate, 2,2,2-trichloroethyl chloroformate, benzyl chlcroformate or another common acyiating agent. In general, acyiation of the C{7) hydroxy group of a C(10) protected taxane are more efRcient and more selective than are C(7) acylations of a 7,10-dihydroxy taxane such as 10-DAB; stated another way, once the C{10) hydroxyl group has been protected, there is a significant difference in the reactivity of the remaining C(7), C(13), and C(1) hydroxyl groups. These acyiation reactions may optionally be carried out in the presence or absence of an amine base.
Derivatives of 10-deacetylbaccatin III having alternative substituents at
Cf2^. CC91 and CM41 and orocafi.'^fis fnr their nrpnarafrnn arp known in th^ art

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-deacetyibaccatin III.
Processes for the preparation and resolution of the p-lactam starting material are generally well known. For example, the p-lactam may be prepared as described in Holton, U.S. Patent No. 5.430,160 and the resulting enatiomeric mixtures of P-lactams may be resolved by a stereoselective hydrolysis using a lipase or enzyme as described, for example, in Patel, U.S. Patent No. 5,879,929 Pate! U.S. Patent No. 5,567,614 or a liver homogenate as described, for example, in PCT Patent Application No. 00/41204. In a preferred embodiment in which the P-lactam is fury! substituted at the C(4) position, the p-lactam can be prepared as illustrated in the following reaction scheme:


wherein Ac is acetyl, NEtj is triethylamine, CAN is eerie ammonium nitrate, and p-TsOH is p-toluenesulfonic acid. The beef liver resolution may be carried out, for example, by combining the enatiomerie ^lactam mixture with a beef liver suspension (prepared, for example, by adding 20 g of frozen beef liver to a blender and then adding a pH 8 buffer to make a total volume of 1 L).
Compounds of fonnula 1 of the instant Invention are useful for inhibiting tumor growth in mammals including humans and are preferably administered in the form of a pharmaceutical composition comprising an effective antitumor amount of a compound of the instant invention in combination with at least one phannaeeutically orphannacologieally acceptable earner. The carrier, also known in the art as an exeipient, vehicle, auxiliary, adjuvant, or diluent, is any substance which is pharmaceutically inert, confers a suitable consistency or form to the composition, and does not diminish the therapeutic efficacy of the antitumor compounds. The carrier is "pharmaceutically or pharmacologically acceptable" if it does not produce an adverse, allergic or other untoward reaction when administered to a mammal or human, as appropriate.
The pharmaceutical compositions containing the antitumor compounds of the present invention may be formulated in any conventional manner. Proper formulation is dependent upon the route of administration chosen. The compositions of the invention can be formulated for any route of administration so long as the target tissue is available via that route. Suitable routes of administration include, but are not limited to, oral, parenteral (e.g., intravenous, intraarterial, subcutaneous, rectai, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intraperitoneal, or intrastemal), topical (nasal, transdermal, intraocular), intravesical, intrathecal, enteral, pulmonary, intralymphatic, intracavital, vaginal, transurethral, intradermal, aural, intramammary, buccal, orthotopic, intratracheal, intralesional, percutaneous, endoseopical, transmucosal, sublingual and intestinal administration.
Phannaeeutically 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

Easton, Pa., (1985), pp. 1492-1517, the contents of which are incorporated herein by reference).
The compositions are preferably formulated as tablets, dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes, granules, solutions, suspensions, emulsions, synjps, elixirs, troches, dragees, lozenges, or any other dosage form which can be administered orally. Techniques and compositions for making oral dosage forms useful in the present invention are described in the following references: 7 Modern Pharmaceutics. Chapters 9 and 10 (Banker & Rhodes, Editors, 1979); Lieberman et al.. Pharmaceutical Dosage Forms: Tablets (1981); and Ansel. Introduction to Phannaceutical Dosage Forms 2nd Edition (1976).
The compositions of the invention for oral administration comprise an effective antitumor amount of a compound of the invention in a pharmaceutically acceptable carrier. Suitable carriers for solid dosage forms include sugars, starches, and other conventional substances including lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar, mannitol, sorbitol, calcium phosphate, calcium carbonate, sodium carbonate, kaolin, alginic acid, acacia, corn starch, potato starch, sodium saccharin, magnesium carbonate, tragacanth, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, and stearic acid. Further, such solid dosage forms may be uncoated or may be coated by known techniques; e.g., to delay disintegration and absorption.
The antitumor compounds of the present invention are also preferably fomnulated for parenteral administration, e.g., formulated for injection via intravenous, intraarterial, subcutaneous, rectal, subcutaneous, intramuscular, intraorbital. Intracapsular, intraspinal, intraperitoneal, or intrasternal routes. The compositions of the invention for parenteral administration comprise an effective antitumor amount of the antitumor compound in a pharmaceutically acceptable canier. 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.

DW5), electrolyte solutions, or any other aqueous, pharmaceutlcally acceptable liquid.
Suitable nonaqueous, pharmaceutically-acceptable polar solvents include, but are not limited to, alcohols (e.g., a-g!ycerol formal, p-glycerol fomnal, 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, tetrahydrofurfury! alcohol, lauryl alcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fatty alcohols such as polyalkylene glycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan, sucrose and cholesterol); amides {e.g., dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide, N-(p-hydroxyethyt)-lactamide, N, N-dimethylacetamide.amides, 2-pyrrolidinone, 1-methyl-2-pyrrolldlnone, or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidlnone, acetate esters such as monoacetin, diacetin, and triacetin, aliphatic or aromatic esters such as ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan, fatty acid derived PEG esters, glyceryl monostearate, glyceride esters such as mono, di, ortri-glycerides, fatty acid esters such as isopropyl myristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pym^lidinone, pluronic 60, polyoxyethyiene sorbitol oleic polyesters such as poly(ethoxyiated)3o.£o sorbitol poly(oieate)2^^ poly{oxyethylene)i5.;omonooieate, poly(oxyethylene) 15.20 mono 12-hydroxystearate, and poly(oxyethyiene)i5.2o mono ricinoleate, polyoxyethyiene sorbitan esters such as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitan monopalmitate, polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas, Wilmington, DE, polyvinylpyrrolidone, alkyleneoxy modified fatty acid esters such as poiyoxyl 40 hydrcgenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution), saccharide fatty acid esters (i.e., the condensation product of a

acid, myristic acid, palmitic acid and stearic acid, and unsaturated fatty acids such as palmitoleic acid, oleic acid, elaidic acid, erucic acid and linoleic acid}), or steroidal esters); alkyl, aryl, or cyclic ethers having 2-30 carbon atoms {e.g., diethyl ether, tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethyt ether); glycofuro! (tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone); aliphatic, cycloaiiphatic or aromatic hydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon, tetramethyienesulfoxide, toluene, dimethylsulfoxide (DMSO), or tetramethyienesuifoxide); oils of mineral, vegetable, animal, essential or synthetic origin (e.g., mineral oils such as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic based hydrocarbons, and refined paraffin oil, vegetable oils such as linseed, tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed, coconut, palm, olive, com, com germ, sesame, persic and peanut oil and glycerides such as mono-, di- or Mglycerides, animal oils such as fish, marine, spemi, cod-liver, haliver. squalene, squalane, and shark liver oil, oleic oils, and polyoxyethytated castor oil); alkyl or aryl halides having 1-30 carbon atoms and optionally more than one halogen substituent; methylene chloride; monoethanolamine; petroleum benzrn; trolamine; omega-3 polyunsaturated fatty acids (e.g., aipha-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 pharmaceutically acceptable solvents for use in the invention are well known to those of ordinary skill in the art, and are identified in The Chemotheraov Source Book (Williams & Wilkens Publishing), The Handbook of Pharmaceutical Excioients. (American Pharmaceutical Association, Washington, D.C., and The Pharmaceutical Society of Great Britain, London, England, 1968), Modem Phamiaceutics. fG. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, New York, 1995), The Pharmacolooical Basis of Therapeutics. (Goodman &

(National Publishing, Philadelphia, PA, 2000), A.J. Spiegel et a!., 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, saffloweroJI, soybean oil or mixtures thereof, and alkyleneoxy modified fatty acid esters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution). Commercially available triglycerides include Intralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm, Sweden), Nutralipid ® emulsion (McGaw, Irvine, California), Liposyn® II 20% emulsion (a 20% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), Liposyn® III 2% emulsion (a 2% fat emulsion solution containing 100 mg safflower oil, 100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml of solution; Abbott Laboratories, Chicago, Illinois), natural or synthetic glycerol derivatives containing the 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 Travemulsion®. Ethane! is a preferred solvent for use in dissolving the antitumor compound to form solutions, emulsions, and the like.
Additional minor components can be included in the compositions of the invention for a variety of purposes well known in the pharmaceutical industry. These components will for the most part impart properties which enhance retention of the antitumor compound at the site of administration, protect the stability of the composition, control the pH, facilitate processing of the antitumor compound into pharmaceutical formulations, and the like. Preferably, each of these components is individually present in less than about 15 weight % of the total composition, more preferably less than about 5 weight %, and most preferably less than about 0.5 weight % of the total composition. Some components, such as fillers or diluents, can constitute up to 90 wt.% of the total

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, hydroxypropylcelluiose, tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes, flow aids, non-volatile silicones (e.g., cyclomethicone), days (e.g., bentonites}, adhesives, bulking agents, flavorings, sweeteners, adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannltol, or sorbitol, cellulose, or calcium phosphate), diluents (e.g., water, saline, electrolyte solutions), binders {e.g., starches such as maize starch, wheat starch, rice starch, or potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers, acacia), disintegrating agents (e.g., starches such as maize starch, wheat starch, rice starch, potato starch, or carboxymethyl starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate, croscarmellose sodium or crospovidone), lubricants (e.g., silica, talc, stearic acid or salts thereof such as magnesium stearate, or polyethylene glycol), coating agents (e.g., concentrated sugar solutions including gum arable, 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, phanmaceutically acceptable solvent and an antitumor compound having a solubility in ethanol of at least about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not being bound to a particular theory. It is believed that the ethanol solubility of the antitumor compound may be directly related to its efficacy. The antitumor compound can also be capable of being crystallized from a solution. In other words, a crystalline antitumor compound, such as compound 1393, can be dissolved in a solvent to form a solution and then recrystailized upon evaporation of the solvent without the formation of any amorphous antitumor compound. It is also preferred that the antitumor compound have an ID50 vaiue (i.e, the drug concentration producing 50% inhibition of

whether the purpose of the administration is therapeutic or prophylactic, and other factors known to and assessable by a skilled practitioner.
Dosage and regimens for the administration of the pharmaceutical compositions of the invention can be readily determined by those with ordinary skill In treating cancer. It is understood that the dosage of the antitumor compounds will be dependent upon the age, sex. health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. For any mode of administration, the actual amount of antitumor compound delivered, as well as the dosing schedule necessary to achieve the advantageous effects described herein, will also depend, in part, on such factors as the bioavailability of the antitumor compound, the disorder being treated, the desired therapeutic dose, and other factors that will be apparent to those of skill in the art. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect the desired therapeutic response in the animal over a reasonable period of time. Preferably, an effective amount of the antitumor compound, whether administered orally or by another route, is any amount which would result in a desired therapeutic response when administered by that route. Preferably, the compositions for oral administration are prepared in such a way that a single dose in one or more oral preparations contains at least 20 mg of the antitumor compound per 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 mg of the antitumor compound per m^of patient body surface area. Preferably, a single

therapeutic effect. It should be noted that the ranges of effective doses provided herein are not intended to limit ^e invention and represent preferred dose ranges. The most preferred dosage will be tailored to the individual subject, as is understood and determinable by one of ordinary skill in the art without undue experimentation.
The concentration of the antitumor compound in a liquid phamiaceutical composition is preferably between about 0.01 mg and about 10 mg per ml of the composition, more preferably between about 0.1 mg and about 7 mg per mi, even more preferably between about 0.5 mg and about 5 mg per ml, and most preferably between about 1.5 mg and about 4 mg per ml. Relatively low concentrations are generally preferred because the antitumor compound is most soluble in the solution at low concentrations. The concentration of the antitumor compound in a solid pharmaceutical composition for oral administration is preferably between about 5 weight % and about 50 weight %, based on the total weight of the composition, more preferably between about 8 weight % and about 40 weight %, and most preferably between about 10 weight % and about 30 weight %.
In one embodiment, solutions for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound {e.g., ethanol or methylene chloride) to form a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® EL solution, is added to the solution while stimng to fonm a pharmaceutically acceptable solution for oral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol. which is known in the art to cause adverse physiological effects when administered at certain concentrations in oral formulations.
In another embodiment, powders or tablets for oral administration are prepared by dissolving an antitumor compound in any pharmaceutically acceptable solvent capable of dissolving the compound (e.g..ethanol or methylene chloride) to form a solution. The solvent can optionally be capable of evaporating when the solution is dried under vacuum. An additional carrier can

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 phaimaceutically acceptable solvent capable of dissolving the compound (e.g., ethanol or methylene chioride) to fonn a solution. An appropriate volume of a carrier which is an emulsion, such as Liposyn® II or Liposyn® III emulsion, is added to the solution while stirring to form a pharmaceutically acceptable emulsion for parenteral administration to a patient. If desired, such emulsions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, w/hich are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
Solutions for parenteral administration can be prepared by dissolving an antitumor compound in any phamiaceutically acceptable solvent capable of dissolving the compound {e.g., ethanol or methylene chloride) to fonn a solution. An appropriate volume of a carrier which is a solution, such as Cremophor® solution, is added to the solution while stirring to form a pharmaceutically acceptable solution for parenteral administration to a patient. If desired, such solutions can be formulated to contain a minimal amount of, or to be free of, ethanol or Cremophor® solution, which are known in the art to cause adverse physiological effects when administered at certain concentrations in parenteral formulations.
If desired, the emulsions or solutions described above for oral or parenteral administration can be packaged in IV bags, vials or other conventionai containers in concentrated fomi and diluted with any pharmaceutically acceptable liquid, such as saline, to form an acceptable taxane concentration prior to use as is known in the art.
Definitions
The terms "hydrocarbon" and "hydrocarbyl" as used herein describe organic compounds or radicals consisting exdusiveiy of the elements carbon and

The "substituted hydrocarbyl" moieties described herein are hydrocarbyl moieties which are substituted with at least one atom other than carbon, inciuding 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, heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyl. acyloxy, nitro, amino, amido, nitro, cyano, thiol, ketals. acetals, esters and ethers.
The tenri "heteroatom" shall mean atoms other than carbon and hydrogen.
The "heterosubstituted methyl" moieties described herein are methyl groups in which the carbon atom is covalently bonded to at least one heteroatom and optionally with hydrogen, the heteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatom may, in turn, be substituted with other atoms to form a 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 form a heterocycio, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ether moiety.
Unless othenA^ise indicated, the alkyl groups described herein are preferably lower alkyl containing from one to eight carbon atoms in the principal chain and up to 20 carbon atoms. They may be straight or branched chain or cyclic and Include methyl, ethyl, propyl, Isopropyl, butyl, hexyl and the like.
Unless 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, butenyi, isobutenyl, hexenyi, and the like.

The terms "aryl" or "ar" as used herein alone or as part of another group denote optionally substituted homocyclic aromatic groups, preferably monocyclic or bicyclic groups containing from 6 to 12 carbons in the ring portion, such as phenyl, biphenyl, naphthyl, substituted phenyl, substituted biphenyl or substituted naphthyl. Phenyl and substituted phenyl are the more preferred aryl.
The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, and iodine.
The terms "heterocycio" or "heterocyclic" as used herein alone or as part of another group denote optionally substituted, fully saturated or unsaturated, monocyclic or bicyclic, aromatic or nonaromatlc groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heterocycio group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms In the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heterocycio include heteroaromatics such as furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoqulnojinyl 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, nitre, cyano, thiol, ketals, acetals, esters and ethers.
The term "heteroaromatic" as used herein alone or as part of another group denote optionally substituted aromatic groups having at least one heteroatom in at least one ring, and preferably 5 or 6 atoms in each ring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may be bonded to the remainder of the molecule through a carbon or heteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinoiinyl 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 tenn "acyl," as used herein alone or as part of another group, denotes

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 othenAfise indicated, the carbamoyloxy moieties described herein are derivatives of carbamic acid in which one or both of the amine hydrogens is optionally replaced by a hydrocarbyl, substituted hydrocarbyl or heterocycio moiety.
Thetenns "hydroxyl protecting group" and "hydroxy protecting group" as used herein denote a group capable of protecting a free hydroxyl group {"protected hydroxyl") which, subsequent to the reaction for which protection is employed, may be removed without disturbing the remainder of the molecule. A variety of protecting groups for the hydroxyl group and the synthesis thereof may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981, or Fieser & Fieser. Exemplary hydroxyl protecting groups include methoxymethyi, 1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethy!silylethoxy)methy!,tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl,t-butyl(diphenyI)silyl,trialkyIsiiyl, trichtoromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.
As used herein, "Ac" means acetyl; "Bz" means benzoyl; "Et" means ethyl; "Me" means methyl; "Ph" means phenyl; "Pr" means propyl; "Bu" means butyl; "Am" means amyl; "cpro" means cyclopropyl; "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-trichloroethyicarbamate or tertbutylcarbamate; "protected hydroxy" means -OP wherein P is a hydroxy protecting group; "PhCO" means phenyicarbonyl; "tSuOCO" and "Boc" mean tert-butoxycarbonyl; "tAmOCO" means tert-amyloxycarbonyl; "2-FuCO" means 2-fury!carbonyl; "2-ThCO" means 2-

isobutylcarbonyl; "iBuOCO" means isobutoxycarbonyl; "tPrOCO" means isopropyloxycarbonyl; "nPrOCO" means n-propyloxycarbonyl; "nPrCO" means n-propylcarbonyl; "ibue" means isobutenyl; THF" means tetrahydrofuran; "DMAP" means 4-dimethyiamino pyridine; "LHMDS" means Lithium HexamethylDiSiiazanide.

10-Triethylsilyl-10-deacetyIbaccatmin. To a solution of 1.0 g (1.84mmol)of 10-deacetyt baccatinUl in 50 mL of THF at-10 "C under a nitrogen atmosphere was added 0.857 mL (2.76 mmol. 1.5 mol equlv) of N, 0-(bis)-TES-trifluoroacetamlde over a period of 3 min. This was followed by the addition of 0.062 mL of a 0.89 M THF solution of lithium bis(trimethylsilyi)amide (0.055 mmol, 0.03 mol equlv). After 10 min 0.038 mL (0.92 mmol, 0.5 mol equiv) of methanol was added, and after an additional 5 min 4 mL (0.055 mmol, 0.03 mol equiv) of acetic acid was added. The solution was diluted with 300 mL of ethyl acetate and washed two times with 100 mL of saturated aqueous sodium bicarbonate solution. The combined aqueous layers were extracted with 100 mL of ethyl acetate and the combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. To the residue was added 100 mL of hexane and the solid (1.23g, 101%) was collected by filtration. Recrystallization of the solid by dissolving in boiling ethyl acetate (20 mL, 17 mL/g) and cooling to room temperature gave 1.132 g (94%) of a white solid. m-P-

H7), 4.15 (1H. d, J20a = 8.5Hz, H20P). 4.00 (1H, d, J2 = 6.9H2, H3), 2.58 (1H, ddd, J7 = 6.6H2, J5 = 9.9Hz, J63 = 14.5Hz, H6a), 2.28-2.25 (5H, m, 4Ac, H14a, H14I3). 2.02 (3H, s, 18Me). 1.97 {1H, d, J7 = 4.5Hz, H70H), 1.78 {1H, ddd, J7 = 11.0H2. J5 = 2.2Hz, J6a = 14.5Hz, H6P), 1.68 (3H, s. 19Me), 1.56 (1H, s, 0H1), 1.32 (1H,d,J13 = 8.8Hz, 0H13 }, 1.18 (3H, s, 17Me), 1.06 (3H, s, 16Me), 0.98 (9H, t, JCHj(TES) = 7.3Hz, CH3(TES)), 0.65 (6H, dq, JCHjCTES) = 7.3H2, CH2(TES)),

10-Triethylsilyl-10-deacety!-7-propionyl baccatin III. To a solution of 1.0 g (1.517 mmol) of 10-triethylsilyl-10-deacetyl baccatin 111 and 37.0 mg (0.303 mmol) of DMAP in 20 mL of dichloromethane at room temperature under a nitrogen atmosphere was added 0.920 mL (11.381 mmol) of pyridine and 0.329 mL (3.794 mmol, 2.5 mol equlv) of propionyl chloride in that order. The mixture was stirred at room temperature for 6 h, diluted with 350 mL of ethyl acetate and extracted with 50 mL of 10% aqueous copper sulfate solution. The organic layer was washed with 50 mL of saturated aqueous sodium bicarbonate solution, 50 mL of brine, dried over sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in 75 mL of ethyl acetate, 100 mg of Norit A was added, the mixture was filtered through celite and concentrated under reduced pressure to give 1.13 g of material. Recrystallization from ethyl acetate/hexanes (dissolved in 6.5 mL of refluxing ethyl acetate, then 24 mL of hexanes added, allowed to cool to room temperature, and left to stand for 17 h) afforded 787 mg (72.5%) of a white crystalline solid. A second recrystallization {ca 340 mg material dissolved in 2 mL of refluxing ethyl acetate, then 10 mL of hexanes added, allowed to cool to room temperature, and allowed to stand for 17 h) afforded 181 mq (16.7 %) of a white crvstalline solid. The combined yield after recrystallization


2'-O-MOP-3'-desphenyI-3'-{2-furyl)-10-triethylsilyI-7-propionyl taxotere. To a
solution of 493 mg (0.690 mmol) of 10-triethyisilyl-10-deacetyl-7-propionyl baccatin 111 in 4 mL of anhydrous THF under a nitrogen atmosphere at-45 °C was added 0.72 mL (0.72 mmol) of a 1iy solution of LIHMDS in THF. After 0.5 ha solution of 263 mg (0.814 mmol) of the b-Lactam (predried as described above) in 2 mL of anhydrous THF was added. The mixture was warmed to 0 "C, and after 2 h 0.5 mL of saturated aqueous sodium bicarbonate solution was added. The mixture was diluted with 50 ml of ethyl acetate and washed two times with 5 mL of brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 742 mg (104%) of a slightly yellow solid. The solid was recrystallized by dissolving it in 12 mL of a 1:5 mixture of ethyl acetate and hexane at reflux and then cooling to room temperature to give 627 mg (88%) of a white crystalline solid. Evaporation of the mother liquor gave 96 mg of material which was recrystallized as above from 2 mL of a 1:5 mixture of ethyl acetate and hexane to give an additional 46 mg (6%) of white crystalline solid. The total yieid from recrystallization was 94%. Evaporation of the mother liquor
nauA 4R mn nf matprial whinh was; nirrifipH hu rniiimn rhrnmatnnranhv nn silir.3

(dd, J = 10.0, 7.2 Hz. 1H), 5.30-5.36 (m, 2H), 5.28 (s, 1H}, 4.95 (d, J = 7.6 Hz, 1H}, 4.76 (s, 1H), 4.33 (d, J= 8.0 Hz, 1H), 4,19 (d, J = 8.4 Hz. 1H). 4.03 (d, J = 6.8 Hz, IN). 2.83 (s. 3H). 2.55 (ddd, J = 17.2, 9.6. 7.6, 1H), 2.50 (s, 3H). 2.20-2.40 (m, 2H}. 2.28 (q, J = 7.6 Hz, 2H). 1.95 (s, 3H), 1.84 (ddd, J = 14.8. 10.8, 2 Hz), 1.80 (s, 3H), 1.67 (s, 1H), 1.39 (s, 9H), 1.32 {s, 3H). 1.21 (s. 3H), 1.20 (s. 3H), 1.74 (s, 3H), 1.09 (t, J = 7.6 Hz, 3H), 0.93-0.99 (m, 9H), 0.50-0.65 (m, 6H).

3'-Despheny!-3'.(2-furyl)-7-propionyI taxotere. (1393) To a solution of 206 mg (0.199 mmol) of 2'-O-MOP-3*-desphenyl-3'-(2-furyl)-10-triethyisily!-7-propionyi taxotere in 1.7 mL of pyridine and 5.4 mL of acetonitrile at 0 "C was added 0.80 mL (2.0 mmol) of an aqueous solution containing 49% HF. The mixture was warmed to room temperature for 14 h and was then diluted witii 20 mL of ethyl acetate and washed three times with 2 mL of saturated aqueous sodium bicarbonate and then with 8 mL of brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure to give 170 mg (100%) of a white solid. The crude product was crystallized with 2 mL of solvent (CH2Cl2:hexane=1:1.7) to give 155 mg (90.5%) of white crystals. Concentration of the mother liquor under reduced pressure gave 15 mg of material which was recrystallized using 0.2 mL of a 1:1.7 mixture of methylene chloride and hexane to give an additional 11 mg (7.5%) of white crystals. The total yield from recrystallization was 98%. m.p. 150-152 °C; [a]a^^ -27.0 (c 5.0, methanol); Anal. CalcdforC44H55NOi6«0.5H2O: C, 61.18; H, 6.48. Found: C, 61.40; H, 6.65. 'H NMR (CDCI3. 500 MHz) d (ppm): 8.11 (d, J = 7.5 Hz. 2H), 7.61 (dd, J = 7.5, 7.5 Hz, 1H), 7.50 (dd, J = 8.0, 7.5 Hz 2H), 7.41 (d, J = 1.0 Hz, 1H). 6.38 (dd, J = 3.0, 2.0 Hz, 1H), 6.33 (d, J = 3.5 Hz). 6.22 (dd, J = 9.5, 9.5 Hz, 1H), 5.69 {d, J = 7.0

2.25 (q, J = 7.5 Hz. 2H), 1.96 (s, 3H), 1.93 (ddd, J = 14.5, 11.0, 2.5 Hz), 1.85 (s. 3H), 1.64 (s, 1H), 1.36 (s. 9H), 1.23 (s, 3H), 1.10 {t, J = 7.5 Hz, 3H).
Example 2
The procedures described in Example 1 were repeated, but other suitably protected p-lactams were substituted for the |3-lactam of Example 1 to prepare the series of compounds having stojctural formula (13) and the combinations of substituents identified In the following table.














I I "■' " ' t " !
















Example 4
Following the processes described in Example 1 and elsewhere herein, the following specific taxanes having structural formula 15 may be prepared, wherein R,o is hydroxy and R7 in each of the series (that is, each of series "A" through "K") is as previously defined, including wherein R^ is R^aCOO- and R7, is (i) substituted or unsubstituted, preferably unsubstituted, Cj to Cg alkyl (straight. branched or cyclic), such as ethyl, propyl, butyl, pentyl. or hexyl; (ii) substituted or unsubstituted, preferably unsubstituted, Cj to Cg alkenyl (straight, branched or cyclic), such as ethenyi, propenyl, butenyi, pentenyl orhexenyl; (iii) substituted or unsubstituted, preferably unsubstituted, C; to Cg aikynyl (straight or branched) such as ethynyl, propynyl, butynyi, pentynyl, or hexynyl; (iv) substituted or unsubstituted, preferably unsubstituted, phenyl; or (v) substituted or unsubstituted, preferably unsubstituted, heteroaromatic such as furyl, thienyl, or pyridyl.
In the "A" series of compounds, X^o is as othenwise as defined herein. Preferably, heterocycio is substituted or unsubstitued furyl, thienyl, or pyridyl, X,o is substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alky! (e.g., tert-butyl), and Rj and R,o each have the beta stereochemical configuration.
In the "B" series of compounds, Xio and Rj^ are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued fun/I,

In the "C" series of compounds, X^Q and R^^ are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^^ 'S preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl {e.g., tert-butyl), Rg^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^, Rg and R.Q each have the beta stereochemical configuration.
In the "D" and °E" series of compounds, X^Q is as otherwise 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), and R^, Rg (series D only) and Rio each have the beta stereochemical configuration.
in the "F" series of compounds, X,o, Rja and Rgg are as othenwise as defined herein. Preferably, heterocycio Is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, X^j 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 "G" series of compounds, X,o and Rjg are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued fury!, 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 furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^, Rg and R.Q each have the beta stereochemical configuration.
In the "H" series of compounds, X^ Is as othenwise 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), Rja is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^ and Ru, each have the beta stereochemical configuration.
In the T series of compounds, X^Q and Rja are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl,

unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R^ and R,o each have the beta stereochemical configuration.
In the "J" series of compounds, X^, and R^^ are as otherwise as defined herein. Preferably, heterocycio is preferably substituted or unsubstitued furyl, thienyl, or pyridyl, XIQ is preferably substituted or unsubstitued furyl. thienyl, pyridyl, phenyl, or lower alkyt (e.g., tert-butyl), R^^ is preferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl. and R^, Rg and R^^ each have the beta stereochemical configuration.
In the "K" series of compounds, Xia, Rja and Rgg 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), 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.






I wu I vwi 1, .*\jc I —f-—. -^ii^j J . -/a J —5- "3 — - f - j J





I i ! «" ; - ^" "" I I I ' '








Example 5 In Vitro cytotoxicity measured by the cell colony formation assay
Four hundred cells {HCT116) were plated in 60 mm Petri dishes containing 2.7 mL of medium {modified McCoy's 5a medium containing 10% fetal bovine semm and 100 units/mL penicillin and 100 g/mL streptomycin). The cells were incubated in a CO2 incubator at 37 "C for 5 h for attachment to the bottom of Petri dishes. The compounds identified in Example 2 were made up fresh in medium at ten times the final concentration, and then 0.3 mL of this stock solution was added to the 2.7 mL of medium in the dish. The cells were then incubated with drugs for 72 h at 37 " C. At the end of incubation the drug-containing media were decanted, the dishes were rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL of fresh medium was added, and the dishes were returned to the incubator for colony formation. The cell colonies were counted using a colony






Solution 1: Antitumor compound 1393 was dissolved in ethanol to form a

Solution 2: Antitumor compound 1458 was dissolved in ethanol to form a solution containing 310 mg of the compound per mi of solution. An equal volume of Cremophor® EL solution was added to the solution while stirring to form a solution containing 155 mg of compound 1458 per ml. This solution was diluted using 9 parts by weight of saline to form a pharmaceutlcally acceptable solution for administration to a patient.
Solution 3: Antitumor compound 1351 was dissolved in ethanol to form a solution containing 145 mg of the compound per ml of solution. An equal volume of Cremophor® EL solution was added to the solution while stirring to form a solution containing 72.5 mg of compound 1351 per ml. This solution was diluted using 9 parts by weight of saline to form a pharniaceutlcally acceptable solution for administration to a patient.
Solution 4: Antitumor compound 4017 was dissolved In ethanol to form a solution containing 214 mg of the compound per ml of solution. An equal volume of Cremophor® EL solution was added to the solution while stirring to form a solution containing 107 mg of compound 4017 per ml. This solution was diluted using 9 parts by weight of saline to form a pharmaceutlcally acceptable solution for administration to a patient.
Solution 5; Antitumor compound 1393 was dissolved in 100% ethanol then mixed with an equal volume of Cremophor® EL solution to form a solution containing 70 mg of compound 1393 per ml. This solution was diluted using 9 parts by weight of D%W (an aqueous solution containing 5 % weight by volume of dextrose) or 0.9% saline to form a pharmaceutlcally acceptable solution for administration to a patient.
Example 7 Preparation of a Suspension Containing Compound 1393 for Oral Administration

Example 8 Preparation of a Tablet Containing Compound 1393 for Oral Administration
Antitumor compound 1393 (100 mg) was dissolved in methylene chloride (2 ml) and Cremophor® EL solution (lOOmg) was added. The methylene chloride was evaporated under vacuum to form a glass, Microcrystalline cellulose {600 mg) was added to the glass and mixed to form a powder which can be processed to form a tablet.
Example 9 Preparation of Emulsions Containing Compound 1393 for Parenteral
Administration
Emulsion 1: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 40 mg of compound 1393 per ml of the solution. The solution was then diluted with 19 parts by weight of Liposyn® II (20%) with stining to form an emulsion containing 2 mg of compound 1393 per ml for parenteral administration.
Emulsion 2: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 40 mg of compound 1393 per ml of the solution. The solution was then diluted with 19 parts by weight of Liposyn® IH (2%) with stirring to fonn an emulsion containing 2 mg of compound 1393 per ml for parenteral administration.
Emulsion 3: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing mg of compound 1393 per ml of the solution. The solution was then diluted with 9 parts by weight of Liposyn® 111 (2%) with stirring to form an emulsion containing 4 mg of compound 1393 per ml for parenteral administration.

Example 10 Preparation of Solutions Containing Compound 1393 for Parenteral
Administration
Solution 1; Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 140 mg of compound 1393 per ml. The solution was then diluted with an equal volume of Cremophor® EL solution with stirring and was then diluted with 9 parts by weight of normal saline to form a soMton containing 7 mg of compound 1393 per ml of solution for parenteral administration.
Solution 2: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 140 mg of compound 1393 per ml of the solution. The solution was then diluted with an equal volume of Cremophor® EL solution with stirring and was then diluted with 4 parts by weight of normal saline to form a solution containing 11.7 mg of compound 1393 per ml of solution for parenteral administration.
Solution 3: Antitumor compound 1393 was dissolved in 100% ethanol to form a solution containing 140 mg of compound 1393 per ml of the solution. The solution was then diluted with an equal volume of Cremophor® EL solution with stirring and was then diluted with 2.33 parts by weight of normai saline to form a solution containing 16.2 mg of compound 1393 per ml of solution for parenteral administration.


WE CLAIM:
1. A taxane having the formula
said
hydrocarbyl or substituted hydrocarbyl contains carbon atoms in the alpha and beta positions relative to the carbon atom of which R20 is a substituent;


5. The taxane of claim 2 wherein X^ is -COXIQ and X,o is phenyl, or X5 is -COOX-o and X,o is t-butyl.
6. The taxane of claim 2 wherein R,^ is hydrido.
7. The taxane of claim 6 wherein X3 is 2-furyl, 3-furyl. 2-thienyl, 3-
thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C, - C3 alkyl, Cj - Cg alkenyl, or Cj - Cg
alkynyl.

14. The taxane of claim 2 wherein R,^ is hydrido and Rg is keto.

16. The taxane of claim 14 wherein X^ is -COX,(j and X,o is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thjenyl, 3-thienyl, 2-pyridyl, 3-pyridy!, 4-pyridyl, C, - Cg alkyl, Cj - Cg aikenyi. or Cj - Cg alkynyl or Xj is -COOX,o and X,o is substituted or unsubstituted C, - Cg alkyl, Cj - Cg alkenyl, or Cj - Cg alkynyl.
17. The taxane of claim 14 wherein Xg is -COX,^ and X^o Is phenyl, or Xj is -COOX,o and X,o is t-butyl.
18. The taxane of claim 2 wherein R; is benzoyloxy and Rg is keto.
19. The taxane of claim 18 wherein X3 is 2-fury(, 3-furyl, 2-thienyl, 3-thienyl. 2-pyridyl, 3-pyridyl, 4-pyridyi, C, - Cg alkyl, Cj - Cg alkenyl, or C; - Cg alkynyl.
20. The taxane of claim 18 wherein X5 is -COX^^ and X,o is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C, - Cg alkyl, Cj - Cg alkenyl, or C; - Cg alkynyl or X5 is -COOXio and X^o 's substituted or unsubstituted C, - Cg alkyl, Cj - Cg alkenyl, or C; - Cg alkynyl.
21. The taxane of claim 18 wherein X5 is -COX^Q and X^^ is phenyl, or X5 is -COOX,o and X,^ Is t-butyi.
22. The taxane of claim 2 wherein R,^ is hydrido and R; is benzoyloxy.
23. The taxane of claim 22 wherein Xg is 2-furyl, 3-furyl. 2-thi6nyl, 3-thienyl, 2-pyridyI, 3-pyridyl, 4-pyridyl, C, - Cg alkyl, C; - Cg alkenyl, or C^ - Cg alkynyl.
24. The taxane of claim 22 wherein X5 is -COXIQ and X,o is substituted or unsubstituted phenyl, 2-furyi, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-

26. The taxane of claim 2 wherein R,^ is hydrido, Rg is keto, and R^ is
benzoyloxy.
27. The taxane of claim 26 wherein X3 is 2-furyl, 3-furyl, 2-thieny!, 3-

34. The taxane of claim 30 wherein R,^ is hydrido.

36. The taxane of claim 34 wherein X5 is -COX^^ and X^Q 'S substituted or unsubstituted phenyl, 2-fury!. 3-furyI, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-


46. The taxane of claim 30 wherein R; is benzoyioxy and Rg is l 47. The taxane of claim 46 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-
thienyl. 2-pyridyl, 3-pyridyl, 4-pyridyl, C, - Cg alkyl, C2 - Cg alkenyl, or C; - C3
aikynyl.

54. The taxane of claim 30 wherein R,4 is hydrido, Rg is keto, and R^ is
benzoyioxy.
55. The taxane of claim 54 wherein X3 is 2-furyl, 3-furyi, 2-thienv!, 3-

56. The taxane of claim 54 wherein X5 is -COXIQ and X,,, is substituted or unsubstituted phenyl, 2-fiJryl, 3-fury(, 2-thienyi, 3-thienyl, 2-pyridyl, 3-pyndyi, 4-pyridyl. C, - C3 alkyl, Cj - Cg alkenyl, or C; - Cg alkynyl or X5 is -COOX,o and Xi^ is substituted or unsubstituted C, - Cg alkyi. ^2 - Cg alkenyf, or €3 - Cg alkynyl.
57. The taxane of claim 54 wherein X5 is -COXic and Xi^ is phenyl, orXj is -COOXjo and X(o is t-butyl.
58. The taxane of claim 1 wherein R^^ is ethyl.
59. The taxane of claim 58 wherein X3 is 2-furyl, 3-furyl, 2-thi6nyl, 3-
thienyl. 2-pyridyl, 3-pyridy!. 4-pyridy!, C, - Cg alkyl, C2 - Cg alkenyl, or Cj - Cg
alkynyl.
60. The taxane of claim 58 wherein X5 is -COX,Q and X,Q is substituted
or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, S-pyhdyl, 4-
pyridyl, C, - Cg alkyl. Cj - Cg alkenyl, or C^ - Cg alkynyl, or Xg is -COOX10 and X,o is
substituted or unsubstituted C, - C^ alkyl, Cj - Cg alkenyl, or C^ - Cg alkynyl.
61. The taxane of claim 58 wherein X5 is -COXIQ and XIQ is phenyl, orXj
is -COOX10 and X,o is t-butyl.
62. The taxane of claim 58 wherein R,4 is hydrido.


66. The taxane of claim 58 wherein R^ is benzoyloxy.
67. The taxane of claim 66 wherein Xj is 2-furyl, 3-furyl, 2-thienyi, 3-
thienyl, 2-pyridyl, 3-pyndyl, 4-pyridyi, C, - Cg alky!, Cj - Cg all alkynyi.
i


pyridyl, C, - Cg alkyl, C; - Cg alkenyl, or C^ - Cg alkynyl orXg is -COOXIQ and XIQ is substituted or unsubstituted C, - Cg alkyl, C2 - Cg alkenyl, or C^ - Cg aikynyl.
77. The taxane of claim 74 wherein X5 is -COX1Q and X,o is phenyl, or X5
is -COOXio and X,o is t-butyl.
78. The taxane of claim 58 wherein R,4 is hydrido and R^ is benzoyloxy.
79. The taxane of claim 78 wherein X3 is 2-furyl, 3-furyl, 2-thieny!, 3-
thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C, - Cg alkyl, Cj - Cg alkenyl, or C^ - Cg
alkynyi.


87. The taxane of claim 86 wherein X3 is 2-furyl, 3-furyl. 2-thienyi, 3-
thieny!, 2-pyridyl, 3-pyridyl, 4-pyridyi, C, - Cg alkyl, C^ - Cg alkenyl. or C; - Cg
aikyny!.
88. The taxane of claim 86 wherein X3 is fury! or thleny!.
89. The taxane of claim 86 wherein X3 is 2-furyl.
90. The taxane of claim 86 wherein X3 is 2- thienyl.
91. The taxane of claim 86 wherein X3 is cycloalkyl.
92. A taxane having the formula


94. The taxane of claim 93 wherein X5 is -COX,o and X^, is substituted
or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyi, 3-thienyl, 2-pyridyi, 3-pyridyl, 4-
pyridyl, C, - Cg alkyl, C^ - Cg alkenyl, or C^ - Cg alkynyl, or X5 is -COOXIQ and X^Q is
substituted or unsubstituted C, - Cg alkyl, C; - Cg alkenyl, or Cj - Cg alkynyl.
95. The taxane of claim 93 wherein X5 Is -COX,o and X^o is phenyl, or X5
is -COOX,o and X^j is t-butyl.
96. The taxane of claim 92 wherein X3 is furyl or thienyl.

102. The taxane of claim 93 wherein X3 is isobutenyl.
103. The taxane of claim 102 wherein Xg is -COX10 and X^ is substituted
r\r ) inei ihetiti itcii-* nhoi-n/l 0_fi in/l "^-ft \T\I\ 0-iWiain\i\ ^_f hion\/l O-nv/rrHv/l ^_n\/riH\/l A-

104. The taxane of claim 102 wherein Xg is -COXIQ and X,o is phenyl, or
Xg is -COOX^o and X^^ Is t-butyl.
105. The taxane of claim 92 wherein R7a is ethyl or propyl.
106. The taxane of claim 105 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyi, 4-pyridyi, C, - Cg alkyl, C^ - Cg alkenyl, or C; - Cg alkynyl.


115. The taxane of claim 105 wherein X3 is isobutenyl.


126. The taxane of claim 92 wherein X3 is isobutenyl, Xg is -COOX10 and X,Q is t-butyl.

132. The pharmaceutical composition of claim 128 wherein R^g is ethyl or
propyl.
133. The pharmaceutical composition of claim 132 wherein X3 is 2-furyl,
3-furyl, 2-thienyl, 3-thienyl. 2-pyridyl, 3-pyridyl, 4-pyridyl, C^ - Cg alkyl, Cj - Cg
alkenyl, or Cj - Cg alkynyl.
134. The phamiaceuticai composition of claim 133 wherein Xg is-COX10
and X,(j is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, C, - C3 alkyl, C^ - Cg alkenyl, or C^ - Cg alkynyl, or Xg

135. The pharmaceutical composition of claim 133 wherein Xg is -COXia
and X,o is phenyl, orXg is -COOXn, and X,o is t-butyl.
136. The pharmaceutical composition of claim 129 wherein X3 is furyl or
thienyl, R^, is ethyl, and X5 is -COX,o and X,o is phenyl, or Xg is -COOX,o and X.^
is t-butyl.

142. The pharmaceutical composition of claim 129 wherein X3 is 2-furyl.
R73 is ethyl, Xg is -COOX10 and X,o is t-butyi.
143. The phamiaceutical composition of claim 129 wherein X3 is 2-
thienyl, R^, is ethyl, X5 is -COOX,o and X^Q is t-butyl.
144. The Dhamnaceutical comoosition of claim 129 wherein X, is

146. A composition for oral administration comprising the taxane of claim 1 and at least one phamiaceutically acceptable earner.
147. The composition of claim 146 wherein X3 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C, - Cg alkyl, Cj - Cg aikenyl, or C; - Cg alkynyi.
148. The composition of claim 146 wherein X^ is-COX,o and XIQ is phenyl, or X5 is -COOX,o and XIQ is t-butyl.
149. The composition of claim 146 wherein R^^ is ethyl or propyl.
150. The composition of claim 149 wherein X3 is 2-furyl, 3-furyl, 2-thlenyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyi, C2 - Cg alkyl, C^ - Cg aikenyl, or C^ - C3 alkynyi.
151. The composition of claim 150 wherein X5 is-COX,□ and X,o is phenyl, orXj is -COOX^Q and X^Q is t-butyl.
152. The composition of claim 150 wherein Xjisfuryi, thienyl or isobutenyl, R^^ is ethyl, and X5 is -COXjo wherein X^Q is phenyl, or X5 Is -COOXjo wherein X,o is t-butyl.
153. The composition of claim 146 wherein X3 is alkyl, R^^ is ethyl, and Xg is -COX10 and X^^ is phenyl, orXg is -COOX,o and X^ is t-butyl.
154. The composition of claim 152 wherein X3 is 2-furyl or 2-thienyl, R^, is ethyl, Xs is -COQX^^ and Xio is t-butyi or X5 is -COXIQ and X,Q is phenyl.
155. The composition of claim 154 wherein X3 is 2-furyl, R^g is ethyl. X5 is -COX^o and X.Q is phenyl.

156. The composition of claim 152 wherein X3 is isobutenyl, R7a is ethyl, and X; is -COXio and Xio is phenyl, or X; is -COOXio and Xjo is t-butyl.
157. The composition of claim 157 wherein X3 is isobutenyl, R7a is ethyl, X5
is -COOXio and Xm is t-butyl.
159. The composition of claim 152 wherein X3 is phenyl, R7a is ethyl, X5 is -
COOXIO and X,o is t-butyl.
160. A pharmaceutical composition comprising the taxane of claim 92 and at
least one pharmaceutically acceptable carrier.
161. A pharmaceutical composition comprising the taxane of claim 96 and at
least one pharmaceutically acceptable carrier.


Documents:

abs-1337.jpg

in-pct-2001-1337-che abstract.pdf

in-pct-2001-1337-che claims.pdf

in-pct-2001-1337-che correspondence-others.pdf

in-pct-2001-1337-che correspondence-po.pdf

in-pct-2001-1337-che description(complete).pdf

in-pct-2001-1337-che form-1.pdf

in-pct-2001-1337-che form-13.pdf

in-pct-2001-1337-che form-18.pdf

in-pct-2001-1337-che form-26.pdf

in-pct-2001-1337-che form-3.pdf

in-pct-2001-1337-che form-4.pdf

in-pct-2001-1337-che form-5.pdf

in-pct-2001-1337-che pct.pdf

in-pct-2001-1337-che petition.pdf


Patent Number 243646
Indian Patent Application Number IN/PCT/2001/1337/CHE
PG Journal Number 45/2010
Publication Date 05-Nov-2010
Grant Date 28-Oct-2010
Date of Filing 27-Sep-2001
Name of Patentee FLORIDA STATE UNIVERSITY RESEARCH FOUNDATION
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 100 SLIGER BUILDING, MC 2763. TALLAHASSEE, FL 32306-2763.
PCT International Classification Number A61K31/00
PCT International Application Number PCT/US01/03385
PCT International Filing date 2001-02-02
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/179,794 2000-02-02 U.S.A.