CA2156908C - C9 taxane derivatives and pharmaceutical compositions containing them - Google Patents

C9 taxane derivatives and pharmaceutical compositions containing them Download PDF

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CA2156908C
CA2156908C CA002156908A CA2156908A CA2156908C CA 2156908 C CA2156908 C CA 2156908C CA 002156908 A CA002156908 A CA 002156908A CA 2156908 A CA2156908 A CA 2156908A CA 2156908 C CA2156908 C CA 2156908C
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hydrogen
hydroxy
alkyl
alkenyl
aryl
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CA2156908A1 (en
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Robert A. Holton
Ki-Byung Chai
Yukio Suzuki
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Florida State University
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Florida State University
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Abstract

Taxane derivatives, useful as anti-tumor and anti-leukenia agents, having alternative C9 substituents wherein the substituents are selected from a group consisting of hydrogen, hydroxy, protected hydroxy and acyloxy.

Description

CONTAINING THEM
BACKGROUND OF THE INVENTION
The present invention is directed to novel taxanes which have utility as antileukemia and antitumor agents.
The taxane family of terpenes, of which taxol* is a member, has attracted considerable interest in both the biological and chemical arts. Taxol* is a promising cancer chemotherapeutic agent with a broad spectrum of antileukemic and tumor-inhibiting activity. Taxol* has a 2'R, 3'S
configL,v ~ .on and the f~~llowing structural form»~
OAc ,e 0 s 0 'ri C6HSCONH 0 "

.~t ~,,,~1~ ,7 01111 13 15~ 16 8 7 C6H5 =_ ) CH Z ,~ , s/
0 H H \y 1 ~ -_ 0~~., c ~2 a' 0 ~~HSC00 (_ Wherein ac is acetyl. Because of this promising .~ctivicy, taxol* is currently undergoing clinical trials in both France and the and the United States.
Colin et al. reported in U.S. Patent No. 4,814,470 that taxol* derivative; having structural formula (2) below, have an activity sign~f:icantly greater than that of taxol* (1).
q o 0 oh co-o I
2 ~CH-Ga ~ .
I . _ ~0 r u~,,u_c~ . . nu , a ,''OCOCSHg *Trade-mar'.

R' represents hydrogen or acetyl and one of R " and R " ' represents hydroxy and t:he other represents tert-butoxy-carbonylamino and their stereoisomeric forms, and mixtures thereof. The compound of formula (2) :in which R' is hydrogen, R " is hydroxy, R " ' is tert-butoxy-carbonylamino having the 2'R, 3'S configuration is commonly referred to as taxotere.
Although taxo7_ and taxotere are promising chemotherapeutic agents, they are not universally effective.
Accordingly, a need remains for additional chemotherapeutic agents.
SUMMARY OF THE INVENTI01'd Among the objects of the present invention, therefore, is the provi~~ion of novel t<~xane derivatives which are valuable antileukem=_a and antitumor agents.
Briefly, therefore, the present invention is directed to C9 taxane derivative:;. In a preferred embodiment, the taxane derivative has a tricyclic or tetracyclic core and corresponds to the formula:

WO 94!20088 Fi~~a ,e R10/ R9 "~~ R9a R~
,z ,o /
g 19 X5\N~ 2 '.~OIIII ~~ " R7a ' ~ ~ ~" ' S~Rsa R~ R5a R2a R R5 R~4a 4e R2 Rq (3) wherein X1 i s -OX6 , -SX~ , or -N.~BXg ;
Xz is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
X3 and X4 are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
XS is -COXlo, -COOXlo, -COSXlo, -CONXBXlo, or -SOZXll ;
X6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, hydroxy protecting group, or a functional group which increases the water solubility of the taxane derivative;
X, is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl, alkynyl, aryl or heteroaryl;
X9 is an amino protecting group;
Xlo is alkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterosubstituted alkyl, alkenyl alkynyl, aryl or heteroaryl;
X11 is alkyl, alkenyl, alkynyl, aryl, heteroaryl , -OXio , or -NXaXl4 X14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;

WO 94/20088 ~ PCTIUS94102210 ~~,~6 .
RZ is hydrogen, hydroxy, -OCOR31, or together with RZa forms an oxo;
R2a is hydrogen or together with Rz forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with Rsa and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyano, hydroxy, -OCOR3o, or together with R4 forms an oxo, oxirane or methylene;
RS is hydrogen or together with Rsa forms an oxo, Rsa is hydrogen, hydroxy, protected hydroxy, acyloxy, together with RS forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;

R6 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroazyl, hydroxy, protected hydroxy or together with R6a forms an oxo;

R6a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;

R~ is hydrogen or together with Rya forms an oxo, Rya is hydrogen, halogen, protected hydroxy, -ORZB, or together with R, forms an oxo;
R9 is hydrogen;
R9a is hydrogen, hydroxy, protected hydroxy, or acyloxy;
Rlo is hydrogen or together with Rloa forms an oxo, Rloa is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with Rlo forms an oxo;
R14 is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;

WO 94/20088 ~ 21 ~ 6 9 Q ~ PCT/US94102210 Rl4a is hydrogen, alkyl, alkenyl, alkynyl, aryl, or heteroaryl;
. Rz8 is hydrogen, aryl, :hydroxy protecting group or a functional group which incrEsa::es the solubility of 5 the taxane derivative; and Rz9~ Rso and R31 are independently hydrogen, alkyl, alkenyl, alkynyl, monocyclic aryl or monocyclic heteroaryl.
Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
As used herein "Ar" means aryl; "Ph" means phenyl; "Ac" means acetyl; "Et" rneans ethyl; "R" means alkyl unless otherwise defined; "Bu" means butyl; "Pr"
means propyl; "TES" means triethylsilyl; "TMS" means trimethylsilyl; "TPAP" means tet~:apropylammonium perruthenate; "DMAP" means p-dimethylamino pyridine;
"DMF" means dimethylformamide; "LDA" means lithium diisopropylamide; "LHMDS" means Lithium hexamethyl-disilazide; "LAH" means lithium aluminum hydride; "Red-Al" means sodium bis(2-methoxyethoxy) aluminum hydride;
"AIBN" means azo-(bis)-isobutyronitrile; "10-DAB" means 10-desacetylbaccatin III; FAR means 2-chloro-1,1,2-trifluorotriethylamine; protected hydroxy means -OR
wherein R is a hydroxy protecting group; sulfhydryl protecting group" includes, but is not limited to, hemithioacetals such as 1-ethoxyethyl and methoxymethyl, thioesters, or thiocarbonates; "amine protecting group"
includes, but is not limited to, carbamates, for example, 2,2,2-trichloroethylcarbamate or tertbutylcarbamate; and "hydroxy protecting group" includes, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxy-benzyl, p-nitrobenzyl, allyl, tri:tyl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetra-WO 94/20088 ~ PCTIUS94102210 ~690~
.. ~,'~
hydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, form~~~,~ mono-, di-, and trihalo-acetyl such as chloroacetyl~, dichloroacetyl, trichloro-acetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloroethyl;
alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1_6 alkoxy, or nitro. Other hydroxyl, sulfhydryl and amine protecting groups may be found in "Protective Groups in Organic Synthesis" by T. W. Greene, John Wiley and Sons, 1981.
The alkyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkyl containing from one to six carbon atoms in the principal chain and up to 15 carbon atoms.
They may be substituted, straight, branched chain or cyclic and include methyl, ethyl, propyl, isopropyl, butyl, hexyl, cyclopropyl, cyclopentyl, cyclohexyl and the like.
The alkenyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkenyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched PCTlUS94/02210 chain and include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, hexenyl, and the like.
The alkynyl groups described herein, either alone or with the various substituents defined herein are preferably lower alkynyl containing from two to six carbon atoms in the principal chain and up to 15 carbon atoms. They may be substituted, straight or branched chain and include ethynyl, propy:nyl, butynyl, isobutynyl, hexynyl, and the like.
The aryl moieties described herein, either alone or with various substituents, contain from 6 to 15 carbon atoms and include phenyl. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, amido, etc. Phenyl is the more preferred aryl.
The heteroaryl moietiea described herein, either alone or with various subatituents, contain from 5 to 15 atoms and include, furyl, t:hienyl, pyridyl and the like. Substituents include alkanoxy, protected hydroxy, halogen, alkyl, aryl, alkenyl, acyl, acyloxy, nitro, amino, and amido.
The acyloxy groups described herein contain alkyl, alkenyl, alkynyl, aryl or heteroaryl groups.
The substituents of the substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl groups and moieties described herein, may be alkyl, alkenyl, alkynyl, aryl, heteroaryl and/or may contain nitrogen, oxygen, sulfur, halogens and inc7.ude, for example, lower alkoxy such as methoxy, ethoxy, butoxy, halogen such as chloro or fluoro, nitro, amino, and keto.
In accordance with the present invention, it has been discovered that compounds corresponding to structural formula 3 show remarkable properties, _in vitro, and are valuable antileuke~mia and antitumor agents. Their biological activity has been determined _in vitro, using tubulin assays according to the method of 8 ~ PCTIUS94102210 Parness et al., J. Cell Biolocty, 91: 479-487 (1981) and human cancer cell lines, and is comparable to that exhibited by taxol and taxotere.
In a preferred embodimerr~ cf the present invention, the taxane has a s~;ri~,eture corresponding to taxol or taxotere except fog=:the C9 substituents, R9, which is hydrogen and R9a, which is hydrogen, hydroxy, or acyloxy (such as acetoxy). That is, RZa is hydrogen, RZ
is benzoyloxy, R14 and Rl4a are hydrogen, Rlo is hydrogen, Rloa is hydroxy or acetoxy, R7 is hydrogen, Rya is hydroxy, RS is hydrogen, Rsa and R4 and the carbons to which they are attached form an oxetane ring, R4a is acetoxy, R1 is hydroxy, X1 is -OH, XZ is hydrogen, X3 is phenyl, X4 is hydrogen, XS is -COXlo, Xlo is phenyl or t-butoxy and the taxane has the 2'R, 3'S configuration.
In other embodiments of the present invention, the taxane has a structure which differs from that of taxol or taxotere with respect to the C9 substituent and at least one other substituent. For example, R2 may be hydroxy or -OCOR31 wherein R31 is hydrogen, alkyl or selected from the group comprising z z z z s o 0 0 . . ~Z , and and Z is alkyl, hydroxy, alkoxy, halogen, or trifluoro-methyl. RQa may be hydroxy or acyloxy (other than acetoxy) Rya may be hydrogen and R~ may be acetoxy or other acyloxy or halogen, Rloa and Rlo may each be hydrogen or together form an oxo; X3 may be selected from isobutenyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl, cyclohexyl, furyl, thienyl, pyridyl or the substituted derivatives thereof, XS may be -COXIo or -COOXlo and Xlo may be selected from furyl, thienyl, alkyl WO 94/20088 ~ PCTIUS94102210 substituted furyl or thienyl, pyridyl, tert-, iso- or n-butyl, ethyl, iso- or n-propyl, cyclopropyl, cyclohexyl, allyl, crotyl, ~1;3-diethoxy-2-propyl, 2-methoxyethyl, amyl, neopentyl, RYiCH20-, -NPh2, -NHnPr, -NHPh, and -NHEt .
Taxanes having the genesral formula 3 may be obtained by reacting a i3-lactam with alkoxides having the taxane tricyclic or tetracyclic nucleus and a C-13 metallic oxide substituent to form compounds having a i3-amido ester substituent at C-13. The i3-lactams have the following structural formula:;
X5\N ~0 ~ z ~ 3 wherein X1 - XS are as defined above.
The i3-lactams can be prepared from readily available materials, as is illustrated in schemes A and B
below:
Scheme A

0~ X4 /N / _ a CI
+ '' 0 X 4 iiii X OAc b 5\N /~ a 'N /~ cd \N
----X4 1 XQ -~C 1 X4 BOAC

WO 94!20088 PCTIUS94102210 Scheme B
0 X'1 OLi f 0 E t --r X ~.O~E t vN ~~

N-TMS
X3X4C0 ~ X3~~ X3 X2 IX~ a Xg 0 \N

reagents: (a) triethylamine, CHzCl2, 25oC, 18h; (b) 4 equiv ceric ammonium nitrate, CH3CN, -10~C, 10 min; (c) 5 KOH, THF, H20, O~C, 30 min, or pyrolidine, pyridine, 25 °C, 3h, (d) TESC1, pyridine, 25 °C, 30 min or 2-methoxypropene toluene sulfonic acid (cat.), THF, OaC, 2h; (e) n-butyllithium, THF, -78 °C, 30 min; and an acyl chloride or chloroformate (XS = -COXIO)., sulfonyl chloride 10 (XS = -COSXlo) or isocyanate (XS = -CONXaXlo) ; ( f ) lithium diisopropyl amide, THF -78aC to -50oC; (g) lithium hexa-methyldisilazide, THF -78oC to O~C; (h) THF, -78oC to 25~C, 12h.
The starting materials are readily available.
In scheme A, oc-acetoxy acetyl chloride is prepared from glycolic acid, and, in the presence of a tertiary amine, it cyclocondenses with imines prepared from aldehydes and p-methoxyaniline to give 1-p-methoxyphenyl-3-acyloxy-4-arylazetidin-2-ones. The p-methoxyphenyl group can be readily removed through oxidation with ceric ammonium nitrate, and the acyloxy group can be hydrolyzed under WO 94/20088 ~ 21 ~ 6 9 O g pCT/US94/02210 standard conditions familiar to those experienced in the art to provide 3-hydroxy-4-arylazetidin-2-ones. In Scheme B, ethyl-oc-triethylsilyloxyacetate is readily prepared from glycolic acid.
In Schemes A and B, X1 is preferably -OX6 and X6 is a hydroxy protecting group. Protecting groups such as 2-methoxypropyl ("MOP"), 1-ethoxyethyl ("EE") are preferred, but a variety of other standard protecting groups such as the triethylsilyl group or other trialkyl (or aryl) silyl groups may be used. As noted above, additional hydroxy protecting groups and the synthesis thereof may be found in "Protective groups in Organic Synthesis" by T.W. Greene, John Wiley & Sons, 1981.
The racemic i3-lactams :may be resolved into the pure enantiomers prior to protection by reczystallization of the corresponding 2-methoxy-2-(trifluoromethyl) phenylacetic esters. However, the reaction described hereinbelow in which the i3-amido ester side chain is attached has the advantage of being highly diastereo-selective, thus permitting the use of a racemic mixture of side chain precursor.
The alkoxides having t:he tricyclic or tetra-cyclic taxane nucleus and a C-13 metallic oxide or ammonium oxide substituent have the following structural formula:
R~~s ~e R~o~R9 Rsa R~
~z ~o s ~s MOIIIII ~~ '~ ~R~a R
s R 14 z 3 , ~s~R s a R~ ~, ~RSa Rpa ~R4a R5 R~4a Rz R4 WO 94120088 ~ PCTIUS94/02210 21569Q$
wherein R1 - RIQa are as previously defined and M
comprises ammonium or is a metal optionally selected from the group comprisir_g Group IA, Group IIA and transition metals, and prefer~biy, Li, Mg, Na, K or Ti. Most preferably, the alkoxide has the tetracyclic taxane nucleus and corresponds to the structural formula:
R ~ n a R "
p MOIIiII Rya ~r a wherein M, R2, R4a, R~, Rya, R9, R9a, R10, and Rloa are as previously defined.
The alkoxides can be prepared by reacting an alcohol having the taxane nucleus and a C-13 hydroxyl group with an organometallic compound in a suitable solvent. Most preferably, the alcohol is a protected baccatin III, in particular, 7-O-triethylsilyl baccatin III (which can be obtained as described by Greene, et al.
in JACS 110: 5917 (1988) or by other routes) or 7,10-bis-O-triethylsilyl baccatin III.
As reported in Greene et al., 10-deacetyl baccatin III is converted to 7-0-triethylsilyl-10-deacetyl baccatin III according to the following reaction scheme:

WO 94/20088 ~ PCTIUS94102210 21~s9o$
OH
~0 OH
CH3 10 ~H3 'CH3~
H . 0 OH ~ ' 1 . ~ C2H5] ,3S i C I , CSHSN
2. CH3COC1, CSHSN
OR
CH /~ 0S i ~ C2H5] 3 ~H3 _ CH3 .7 CH3~ ~a ~0 H
OH ~ OCOCH3 (4) a, R=:H
b, R=:COCH3 Under what is reported to be carefully optimized 5 conditions, 10-deacetyl baccatin III is reacted with 20 equivalents of (CZHS) 3SiC1 at 23oC under an argon atmosphere for 20 hours in the presence of 50 ml of pyridine/mmol of 10-deacetyl bac;catin III to provide 7-triethylsilyl-10-deacetyl bacc;atin III (4a) as a 10 reaction product in 84-86~ yield after purification. The reaction product may then optionally be acetylated with 5 equivalents of CH3COCl and 25 mL of pyridine/mmol of 4a at 0 oC under an argon atmosphere f:or 48 hours to provide 86o yield of 7-0-triethylsilyl baccatin III (4b).
Greene, et al. in JACS 110, 5917 at 5918 (1988).
The 7-protected baccat:in III (4b) is reacted with an organometallic compound such as LHNa7S in a solvent such as tetrahydrofuran (THF), to form the metal WO 94120088 ~ ~ ~ , PCTIUS94102210 alkoxide 13-O-lithium-7-O-triethylsilyl baccatin III as shown in the following reaction scheme:
OR
CH3 r .0 - C~~CH3 OS t ~ CZHS] 3 LHMDS + HO---13 ~~CH3 7 OH ' 1 H , THF
OR

1 CH ~CH3 OS t [ CzHS] 9 L i 0 --- 13 ~CH~~
OH ;
H , OCOCH., As shown in the following reaction scheme, 13-0-lithium-7-O-triethylsilyl baccatin III reacts with a i~-lactam in which X1 is preferably -OX6, (X6 being a hydroxy protecting group) and XZ - XS are as previously defined to provide an intermediate in which the C-7 and C-2' hydroxyl groups are protected. The protecting groups are then hydrolyzed under mild conditions so as not to disturb the ester linkage or the taxane substituents.

WO 94!20088 ~ - ~ PCTIUS94l02210 Ac0 - ' OTES
M OI I I I I ~// X 5\
N
HO _ PhC00 ACO 0 X3 X,4 XZ X1 ~1] THF
~2] HF, Pyridine, CH3CN
Ac0 ' 0 X5~ ~ - ~ OH
N OIIII~
//i/

HO
PhC00 Ac Both the conversion of the alcohol to the alkoxide and the ultimate synthesis of the taxane derivative can take place in the same reaction vessel.
5 Preferably, the i3-lactam is added to the reaction vessel after formation therein of the alkoxide.
Compounds of formula 3 of the instant invention are useful for inhibiting tumor growth in animals including humans and are preferably administered in the 10 form of a pharmaceutical composition comprising an effective antitumor amount of compound of the instant invention in combination with a pharmaceutically acceptable carrier or diluent.
Antitumor compositions herein may be made up in 15 any suitable form appropriate for desired use; e.g., oral, parenteral or topical administration. Examples of parenteral administration are in.tramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration.

WO 94!20088 2,~~ PCT/US94102210 The diluent or carrier ingredients should not be such as to diminish the the~~~~eutic effects of the antitumor compounds.
Suitable dosage forms for oral use include tablets, dispersible powders, granules, capsules, suspensions, syrups, and elixirs. Inert diluents and carriers for tablets include, for example, calcium carbonate, sodium carbonate, lactose and talc. Tablets may also contain granulating and disintegrating agents such as starch and alginic acid, binding agents such as starch, gelatin and acacia, and lubricating agents such as magnesium stearate, stearic acid and talc. Tablets may be uncoated or may be coated by unknown techniques;
e.g., to delay disintegration and absorption. Inert diluents and carriers which may be used in capsules include, for example, calcium carbonate, calcium phosphate and kaolin. Suspensions, syrups and elixirs may contain conventional excipients, for example, methyl cellulose, tragacanth, sodium alginate; wetting agents, such as lecithin and polyoxyethylene stearate; and preservatives, e.g., ethyl- p-hydroxybenzoate.
Dosage forms suitable for parenteral adminis-tration include solutions, suspensions, dispersions, emulsions and the like. They may also be manufactured in the form of sterile solid compositions which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain suspending or dispersing agents known in the art.
The water solubility of compounds of formula t3) may be improved by modification of the C2' and/or C7 substituents. For instance, water solubility may be increased if X1 is -OX6 and Rya is -ORze, and X6 and R28 are independently hydrogen or -COGCOR1 wherein:
G is ethylene, propylene, -CH=CH-, 1,2-cyclo-hexylene, or 1,2-phenylene;
Ri - OH base, NRZR3, OR3, SR3, OCH-,CONR4R', or OH;
Rz - hydrogen, methyl R3 - ( CHZ ) nNR6R.~ ~ ( CHz ) nN~R6R~R8Xo n = 1 to 3 R4 - hydrogen, lower alkyl containing 1 to 4 carbons RS - hydrogen, lower alkyl containing 1 to 4 carbons, benzy, hydroxyethyl, CHzCO2H, dimethylaminoethyl R6R' - lower a:Lkyl containing 1 or 2 carbons, benzyl or R6 and R' '~~Gether with the nitrogen atom c' NR6R' form the f v ~~ving rinds U C~
C~
C~
g N
"ri3 k~ - lower alkyl containing :L or 2 .~-Nuns, benzyl 1=, X° - halide base = NH3 , ( FiOC2H4 ) 3N , N ( CH3 ) 3 , CH3N ( CZH40H ) z , NHz (CHz) 6NHz, N-methylglucamine, NaOH, KOH.
The preparation of compounds in which X1 or Xz is -COGCOR is set forth in Haugwitz U.S. Patent 4,942,184.

17a Alternatively, solubility may be increased when X1 is -OX6 and X6 is a radical having the formula -COCX=CHX or -COX-CHX-CHX-S020-M wherein X is hydrogen, alkyl or aryl and M
is hydrogen, alkaline metal or an ammonio group as described in Kingston et al., U.S. Patent No. 5,059,699.
Taxanes having alternative C9 substituents may be prepared by selectively reducing the C9 keto PCTlUS94102210 substituent to yield the corresponding C9 (3-hydroxy derivative. The reducing agent is preferably a borohydride and, most preferably; tetrabutylammonium-borohydride (Bu4NBH4) or Lriac'etoxyborohydride.
As illustrated iri Reaction Scheme 1, the reaction of baccatin III with Bu4NBH4 in methylene chloride yields 9-desoxo-9(3-hydroxybaccatin III 5. After the C7 hydroxy group is protected with the triethylsilyl protecting group, for example, a suitable side chain may be attached to 7-protected-9i3-hydroxy derivative 6 as elsewhere described herein. Removal of the remaining protecting groups thus yields 9i3-hydroxy-desoxo taxol or other 9(3-hydroxytetracylic taxane having a C13 side chain.

WO 94/20088 ' .: PCT/US94/02210 OAc OAc OH - OH
HO~i~~ HOIi~~~
'~i 6u4N8H4 ~~i .; ' ' Ph~o c0~' '0 Ph~O c0~~'' 'O

TESCI

OAc OH
- OTES
HOW ~~
~i HO
Ph~ Ac0 0 \\0 Alternatively; the C13 hydroxy group of 7-protected-9(3-hydroxy derivative 6~ may be protected with trimethylsilyl or other protecting group which can be selectively removed relative to t:he C7 hydroxy protecting group as illustrated in Reaction Scheme 2, to enable further selective manipulation of: the various substituents of the taxane. For example, reaction of 7,13-protected-9(3-hydroxy derivative 7 with KH causes the acetate group to migrate from C1C) to C9 and the hydroxy group to migrate from C9 to C10, thereby yielding 10-desacetyl derivative 8. Protection of the C10 hydroxy group of 10-desacetyl derivative 8 with triethylsilyl yields derivative 9. Selective removal of the C13 WO 94/20088 ~ PCTIUS94102210 hydroxy protecting group from derivative 9 yields derivative 10 to which a suitable side chain may be attached as described abov:~:

_ 21~~690~3 OAC OAC
OH OH
- OTES - OTES
HOm~~ TMSO1~~
'~i '~i 1] TMSCI, Et3N
_ ~ _ _ /
0 ~~~ 0 ~~~~'-~~
PhH AcO~\~0 PhH Ac0~~~0 ~0 ~0 2] KH
OTES OH
OAC OAc - OTES - OTES
TMSOIi~~~ TMSOIi~~~
TESCI
O ~~~ E T N 0 .~~
phH ACO~\~0 3 PhH Ac0~~0 ~0 ~0 g 8 HF
pyridine OTES
OAC
/-\ - T I OTES
HOIi~
H
0 \~~~
P h A c 0 1--- 0 ~0 As shown in Reaction Scheme 3, 10-oxo derivative 11 can be provided by oxidation of 10-WO 94120088 2 ~,~ PCTIUS94I02210 desacetyl derivative 8. Thereafter, the C13 hydroxy protecting group can be se~~e~tively removed followed by attachment of a side chain as described above to yield 9-acetox_y-10-oxo-taxol or other 9-acetoxy-10-oxotetracylic taxanes having a C13 side chain. Alternatively, the C9 acetate group can be selectively removed by reduction of 10-oxo derivative 11 with a reducing agent such as samarium diiodide to yield 9-desoxo-10-oxo derivative 12 from which the C13 hydroxy protecting group can be selectively removed followed by attachment of a side chain as described above to yield 9-desoxo-10-oxo-taxol or other 9-desoxo-10-oxotetracylic taxanes having a C13 side chain.

OH
\ ~ OAc - OTES
TMS011~~~ - OTES
TPAP TMSOI~~~~
....~i H
H __ ph~ Ac0 0 ~0 p h---r( A c 0 0 ~~0 5mI2 TES
TMSOW ~~
HQ

Ph~ Ac0 ~~0 is Reaction Scheme 4 illustrates a reaction in which 10-DAB is reduced to yield pentaol 13. The C7 and WO 94/20088 ~ PCTlUS94102210 C10 hydroxyl groups of pentaol 13 can then be selectively protected with the triethylsilyl or another protecting group to produce triol 14 to which a C13 side chain can be attached as described above or, alternativ~:ly, after further modification of the tetracylic substituents.

OH OH
H
H /-\ ~~( ~ OH
HOIm~( ~ V / HCllm~
Bu4NBH4 W

p' ~~. p ph~ Ac0 0 Ph~ ACO
\\0 \\0 TESCI

OTES
\ 1 off HCIW ~~
-\ ~~( / OTES
Hd Ph~ ACO
'1 4 Taxanes having C9 and/or C10 acyloxy substituents other than acetate can be prepared using 10 DAB as a starting material as illustrated in Reaction Scheme 5. Reaction of 10-DAB with triethylsilyl chloride in pyridine yields 7-protected 10-DAB 15. The C10 hydroxy substituent of 7-protected 10-DAB 15 may then be readily acylated with any standard acylating agent to yield derivative 16 having a new C10 acyloxy substituent.
Selective reduction of the C9 ket.o substituent of WO 94/20088 ~ PCTIUS94102210 .~~~,9~8 derivative 16 yields 9i3-hydroxy derivative 17 to which a C13 side chain may be attac~laed. Alternatively, the C10 and C9 groups can be caused to migrate as set forth in Reaction Scheme 2, above.

OH OH
1 .0 \ ~ 0 - ' OH - ' OTES
HOIIII i TESC I HOIIII
pyrtdtne H 0 ~ H~ \\'~ H 0 ~ H~~\' 0 ~ 0 ph~ ACO 0 Ph~ ACO 0 \'0 '\0 Acylatlng agent ~H ~ ~ 0 - OTES - OTES
HOIIII , 1] HF HOIIII
2] BugNBH4 H 0 o H~~'\\~~ 3 ] T E S C 1 H 0 ~ H ''\\~
ph~ Ac0 0 Ph~ Ac0 0 \\0 \\0 'I 7 'i 6 Taxanes having alternative C2 and/or C4 esters can be prepared using baccatin III and 10-DAB as starting materials. The C2 and/or C4 esters of baccatin III and 10-DAB can be selectively reduced to the corresponding alcohol(s) using reducing agents such as LAH or Red-A1, and new esters can thereafter be substituted using standard acylating agents such as anhydrides and acid chlorides in combination with an amine such as pyridine, triethylamine, DMAP, or diisopropyl ethyl amine.
Alternatively, the C2 and/or C4 alcohols may be converted W0 94/20088 ~ ~ PCTIUS94I02210 to new C2 and/or C4 esters through formation of the corresponding alkoxide by treatment of the alcohol with a suitable base such as LDA followed by an acylating agent such as an acid chloride.
5 Baccatin III and 10-DAB analogs having different substituents at C2 and/or C4 can be prepared as set forth in Reaction Schemes 6-10. To simplify the description, 10-DAB is used as th.e starting material. It should be understood, however, that baccatin III
10 derivatives or analogs may be produced using the same series of reactions (except for the protection of the C10 hydroxy group) by simply replacing 10-DAB with baccatin III as the starting material. Derivatives of the baccatin III and 10-DAB analogs having different 15 substituents at C9 and at least one other position, for instance C1, C2, C4, C7, C10 and C13, can then be prepared by carrying out any of the other reactions described herein and any others which are within the level of skill in the art.
20 In Reaction Scheme 6, protected 10-DAB 3 is converted to the triol 18 with lithium aluminum hydride.
Triol 18 is then converted to the corresponding C4 ester using C12C0 in pyridine followed by a nucleophilic agent (e. g., Grignard reagents or alkyllithium reagents).

WO 94!20088 PCTIUS94102210 Scheme 6 OTES

OTES - ~ OTES
TMS01111 ii,~~ LAH TMSOIIIII
H 0 = Lj HO
Ph~ ACO~ 0 HO ~~ ' H 0 '0 8 'I 8 cizco pyrtdine OTES OTES

- ~ OTES - ~ OTES
TMS01111 , TMSOIIII
~~ii R3~Lt or HO __ ~ R31Mg8r 0 0 H v ~0 v ~ H0~\~0 HO 0 R 3 1 \' 2 0 'i g Deprotonation of trio! 18 with LDA followed by introduction of an acid chloride selectively gives the C4 ester. For example, when acetyl chloride was used, trio!
18 was converted to 1,2 diol 4 as set forth in Reaction Scheme 7.
Trio! 18 can also readily be converted to the 1,2 carbonate 19. Acetylation of carbonate 19 under vigorous standard conditions provides carbonate 21 as described in Reaction Scheme 8; addition of alkyllithiums or Grignard reagents to carbonate 19 provides the C2 ester having a free hydroxyl group at C4 as set forth in Reaction Scheme 6.

WO 94!20088 ~ PCTIUS94/02210 ~15690~8 Scheme 7 OTES
_ p OTES
- ~ OTES LDA 0 TMSOI1111 - ~ OTES
' i,~~ R3~COC I TMSOIIII , iii HO
H~ H'y HO s H
~~\~0 H 0 HO R3oC00~ ,0 '1 8 4 Scheme 8 OTES

OTES CI CO
TMSOIIIII 2 - ~ OTES
Pyridine TMS01111 iii i HO
H0 H~w~ 0 = H
HO 0 ~~ Ow 8 0~ H o~ o 'i 9 OMAP
OTES

OTES
TMSOIIII
i, 0 H w O/ AcO~ 0 2 'I
As set forth in Reaction Scheme 9, other C4 substituents can be provided by rE=acting carbonate 19 with an acid chloride and a tertiary amine to yield carbonate 22 which is then reacted with alkyllithiums or WO 94/20088 5 ~ ' PCTIUS94102210 Grignard reagents to provide 10-DAB derivatives having new substituents at C2.
Scheme ~a OTES OTES
v 1 ,,° \ . 0 - ~ OTES CIZCO - ~ ~ OTES
TMS011111 ,~~ pyr i d i ne TMSOIIII
~~~i~
H0 ~
H 0 H 0\~~~~0 0 H y\

pyridine DMAP
OTES OTES
i~ \ ~ 0 - i OTES - ~~ OTES
TMSOIIIII ~~~ R L t or TMS01111 ii 3 ~ iii r HO = H ' R3~MgBr 0 R3~C00 'w Q H
R C00 ~0 30 ~~oC00 Alternatively, baccatin III may be used as a starting material and reacted as shown in Reaction Scheme 10. After being protected at C7 and C13, baccatin III is reduced with LAH to produce 1,2,4,10 tetraol 24. Tetraol 24 is converted to carbonate 25 using C12C0 and pyridine, and carbonate 25 is acylated at C10 with an acid chloride and pyridine to produce carbonate 26 (as shown) or with acetic anhydride and pyridine (not shown). Acetylation of carbonate 26 under vigorous standard conditions provides carbonate 27 which is then reacted with alkyl lithiums to provide the baccatin III derivatives having new substituents at C2 and C10.

j ';. I
WO 94120088 ~ PCTIUS94102210 ~~.~69~~~

Scheme 10 OAc OAC
0 ' 0 _ ~ OH
OTES

1] TESCI, PY
HO = H ~~ 2] TMSCI, OMAP HO = _ ph~0AC0~''' 0 I m i dazo I e, OMF Ph ACO~''\ 0 ~0 LAH
OH

OTES
TMSOIIII _~ C I zC0 - ~ OTES
~~i, pyr t d i ne TMSOIItI
viiii ~ H''\~ HO _=
H0~ ~~0 HO H w 0 H 0~ 0 pyrtdtne ocoaz9 cc~a~a 1 0 \ 1 , OZ'ES
TMSOIIII i~~~\~~ pMAP TMSOIIIIC ~ _~~°TES
~ ~_.- ~ 0 _.. s -H'~ Hy 5 ~0 H0~ 0 ~~ ACO~\
° 27 ° 26 R3~Li 10 OCORzg o TMSOIIII
-\ _ ~Y I OTES
HO
° H W~~ -, 15 R3~'~ Ac0 10-desacetoxy derivatives of baccatin III and 10-desoxy derivatives oi= 10-DAB may be prepared by reacting baccatin III or 10-DAB (or their derivatives) with samarium 2C diiodide. Reaction between the tetracyclic taxane having C10 leaving group and samarium diiodide may be carried out at 0°C in a solvent such as tetralz:ydrofuran. Advantageously, the samarium diiodide selectively abstracts the C10 leaving group;
C13 side chains and oths=_r substituents on the tetracyclic 25 nucleus remain undisturbed. Thereafter, the C9 keto substituent may be reduced to provide the corresponding 9-desoxo-9(3-hydroxy-10-desacetyoxy or 10-desoxy derivatives as otherwise described herein.
C7 dihydro and other C7 substituted taxanes can be 30 prepared as set forth in Reaction Schemes 11, 12 and 12a.

WO 94/20088 ~ PCTIUS94102210 OAc OAc ~ ~ C

H01111 NaH HOIIII "SCH3 ~ ~

HO ~ H HO

~

0 ~ 0 H ~~~
Ph~ ~~ Ph~ Ac0 0 Ac0 ~~0 ~~0 nBu3SnH

AIBN at]
[c toluene (reflux]

OAC

a ~ _0 iii HO

Ph~ Ac0 '\0 WO 94J20088 ~ PCTIUS94J02210 ~1 OAc OAc - ~ OH - ~ F
HOIi~~~ HOI~~~~
FAR '~i H _ H
/0 ~~~ 0 Ph~ Ac0 0 Ph~ Ac0 0 \\0 \\0 OAc OAc - ~ OH - ~ CI
HOIi~~~ H01~~~~
MsC I
Et3N
H = Et3NHCl H
0 ~~~ 0 Ph~ Ac0 0 Ph~ AcO~
\\0 \\0 WO 94/20088 ~ _ 215 6 9 Q

REACTION SCHEME 12a a o OAC OAC
- OTES - OTES
TMSOIIIII //~/ HF, pY HOIIIII
HO = \~ HO
0 \~~~ 0 ph~ Ac0 0 Ph~ Ac0 0 1 1 \\0 LHMOS

OAC
OTES X5~
L i O I I I I I ,~~ N
ii HO
0 w X3 X4 X2 X1 Ph~ AcO~ 0 [ 1J THF
[2~ HF, Pyr id i ne, CH3CN
OH

X5~ I - ~ OAC
N ~ 01111 //
////

HO ~
PhC00 A C O ~~..--0 As shown in Reaction Scheme 12, Baccatin III
may be converted into 7-fluoro baccatin III by treatment with FAR at room temperature in THF solution. Other baccatin derivatives with a free C7 hydroxyl group behave similarly. Alternatively, 7-chloro baccatin III can be prepared by treatment of baccatin III with methane sulfonyl chloride and triethylamine in methylene chloride solution containing an excess of triethylamine hydro-chloride.

WO 94/20088 . PCTIUS94102210 Taxanes having C7 ac~loxy substituents can be prepared as set forth in F~-e'~ction Scheme 12a, 7,13-protected 1U-oxo-derivative 11 is converted to its corresponding C13 alkoxide by selectively removing the Cl3 protecting group and replacing it with a metal such as lithium. The alkoxide is then reacted with a ~i-lactam or other side chain precursor. Subsequent hydrolysis of the C7 protecting groups causes a migration of the C7 hydroxy substituent to C10, migration of the C10 oxo substituent to C9, and migration of the C9 acyloxy substituent to C7.
A wide variety of tricyclic taxanes are naturally occurring, and through manipulations analogous to those described herein, an appropriate side chain can be attached to the C13 oxygen of these substances.
Alternatively, as shown in Reaction Scheme 13, 7-O-triethylsilyl baccatin III can be converted to a tricyclic taxane through the action of trimethyloxonium tetrafluoroborate in methylene chloride solution. The product diol then reacts with lead tetraacetate to provide the corresponding C4 ketone.

WO 94/20088 . _ ~ I ~ ~ 9 0 g OAC OAc - ~ OTES - ~ OTES
HOl ,. ~~ Me308F4 HOl ,.
Hd _ ~ Hd __ Ph~ AcO~~', O ph~0 HO~'' /'~OAc ~~0 ~~0 H O
Pb[OAc~4 OAc \ ~ 0 -~ ~~ OTES
HOIi~~~ /
Hd __ 0 OAc \\0 Recently a hydroxylated taxane (14-hydroxy-10-deacetylbaccatin III) has been discovered in an extract 5 of yew needles (C&EN, p 36-37, April 12, 1993).
Derivatives of this hydroxylated taxane having the various C2, C4, etc. functional groups described above may also be prepared by using this hydroxylated taxane.
In addition, the C14 hydroxy group together with the C1 10 hydroxy group of 10-DAB can be converted to a 1,2-carbonate as described in C&EN or it may be converted to a variety of esters or other functional groups as otherwise described herein in connection with the C2, C4, C9 and C10 substituents.
15 The following examples are provided to more fully illustrate the invention.

WO 94120088 ~ PCT/LTS94102210 ~.~~ 69 a~

EXAMPLE:'-.2 OH
0 Ph 0 OH
OH
~~~~ 0 i ~ i i t B a 0 N _ i,~~
- i H OH
HO = H
OAcO~\~0 P h~
~~0 (67-3 ) Preparation of 10-deacetyl-9-desoxo-9(3-hydroxy-N-debenzoyl-N-(t-butoxycarbonyl) taxol.
To a solution of 7,10-(bis)triethylsilyl-10-deacetyl-9-desoxo-9~i-hydroxy baccatin III (95 mg, 0.123 mmol) in 1 mL of THF at -45 °C was added dropwise 0.250 mL
of a 0.98M solution of (TMS)2NLi in THF. After 1 h at -45 °C, a solution of cis-1-(t-butoxycarbonyl)-3-triethyl-silyloxy-4-phenylazetidin-2-one (137 mg, 0.37 mmol) in 1 mL of THF was added dropwise to the mixture. The solution was gradually warmed to 0 °C during 6h before 1 mL of aqueous solution was added. The mixture was partitioned between saturated aqueous NaHCO, and ethyl acetate. Evaporation of the organic layer gave a residue which was purified by flash chromatography to afford 127 mg of (2'R,3'S)-2',7,10-(tris)triethylsilyl-10-deacetyl-9-desoxo-9~3-hydroxy-N-debenzoyl-N-(t-butoxycarbonyl) taxol and 8 mg of the (2'S,3'R) isomer.
To a solution of 90 mg of the major compound obtained from the previous reaction in 1.5 mL of acetonitrile and 2 mL of pyridine at 0 °C was added 0.8 mL
of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 2S °C for 24 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl acetate solution gave 71 mg of ,, WO 94!20088 21 ~ ~ 9 0 ~ PCTIUS94102210 material which was purified by flash chromatography to give 58 mg (92~) of 10-deacetyl-9-desoxo-9(3-hydroxy-N-debenzoyl-N-(t-butoxycarbonyl) taxol, which was recrystallizeci rrom ethyl acetate/ether/hexane.
m.p. 160-161 °C; [a]"Na -18.75 ° (c 0.08 , CHC1,) .
1H NMR (CD,OD, 500 MHz) 8 8.10 (d, J = 7.0 Hz, 2H, benzoate ortho), 7.61 (m, 1H, benzoate, para), 7.50 (m, 2H, benzoate, meta), 7.41 (d, J = 8.0 Hz, 2H, phenyl, ortho), 7.36 (m, 2H, phenyl, meta), 7.28 (m, 1H, phenyl, para) , 6.18 (m, 1H, H13 ) ; 6 .18 (d, J = 5 . 5 Hz, 1H, H2 (3) , 5.18 (br s, 1H, H3'), 5.10 (d, J = 5.5 Hz, 1H, H10), 4.99 (d, J = 8.2 Hz, 1H, H5), 4.91 (d, J = 9.3 Hz, 1H, NH), 4.59 (br s, 1H, H2'), 4.51 (d, J = 5.5 Hz, 1H, H9), 4.22(d, J = 8.0 Hz, 1H, H2Oa), 4.16 (d, J = 8.0 Hz, 1H, H20~i), 3.86 (dd, J = 9.5, 7.5 Hz, 1H, H7), 3.13 (d, J =
5.5 Hz, 1H, H3), 2.48 (m, 1H, H6a), 2.29 (m, 1H, Hl4a), 2.28 (s, 3H, 4Ac), 2.19 (m , 1H, H14~), 1.85 (ddd, J =
15.1, 9.6, 1.4 Hz, 1H, H6(3), 1.79 (s, 3H, Mel6), 1.78 (s, 3H, MelB), 1.61 (s, 3H, Mel9H), 1.42 (s, 9H, t-Bu), 1.29 (s, 3H, Mel7).

~~ 6~

EXi'~PLE 2 off 0 p OH
_ OH
t8u0~N _ Otitt - ~~i H OH
OAcO

(70-2) Preparation of 3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9~3-hydroxy-10-desacetyl taxol.
To a solution of 7,10-(bis)-O-triethylsilyl-9-desoxo-9(3-hydroxy-10-deacetyl baccatin (III) (70.0 mg, 0.09 mmol) in 1.0 mL of THF at -45°C was added dropwise 0.10 mL of a 0.98 M solution of LiN(SiMe3)2 in hexane.
After 0.5 h at -45 °C, a solution of cis-1-t-butoxy-carbonyl-3-triethylsilyloxy-4-(2-thienyl)azetidin-2-one (103.8 mg, 0.27 mmol) in 1.0 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10o solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/
hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 97.4 mg of a mixture containing (2'R,3'S)-2',7,10-(tris)-0-triethylsilyl-3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-desacetyl taxol and a small amount of the (2'S,3'R) Isomer.
To a solution of 97.4 mg (0.084 mmol) of the mixture obtained from the previous reaction in 13.5 mL of acetonitrile and 0.57 mL of pyridine at 0 °C was added i;
~ms9os WO 94120088 ~ PCTlUS94l02210 1.92 mL of 48o aqueous FiF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acecate solution gave 69.4 mg of material which was purified by flash chromatography to give 63.1 mg (89~) of 3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9~3-hydroxy-10-desacetyl taxol, which was recrystallized from methanol/water.
m.p.146-148°C; [a]=SNa -54.2° (c 0.0026, CHC1,) .
1H NMR (MeOH, 300 MHz) 8 8.11(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.48(m, 2H, benzoate meta), 7.25(dd, J=5.4, 1.2 Hz, 1H, thienyl), 7.14(d, J=3.3 Hz, 1H, thienyl), 7.03(dd, J=5.4, 3.9 Hz, 1H, thienyl), 6.18(m, 1H, H13), 6.18(d, J=5.5 Hz, 1H, H2), 5.23(br s, 1H, H3'), 5.07(d, J=5.5 Hz, 1H, H10), 4.97(d, J=8.1 Hz, 1H, H5), 4.84(d, J=9.3 hz, 1H, NH), 4.52(br s, 1H, H2'), 4.50(d, J=5.5 Hz, 1H, H9), 4.23(d, J=8.1, 1H, H20a), 4.16(d, J=8.1 Hz, 1H, H20(3), 3.92(dd, J=9.4, 7.5 Hz, 1H, H7), 3.13(d, J=5.5 Hz, H3), 2.47(m, 1H, H6a), 2.26(m, 1H, Hl4a), 2.27(s, 3H, 4Ac), 2:16(m, 1H, H14(3), 1.84(ddd, J=15.1, 9.4, 1.2 Hz, H6~i), 1.79(s, 3H, Mel6), 1.76(s, 3H, Mel8), 1.62(s, 3H, Mel9) 1.39(s, 9H, 3Me t-butoxy), 1.27(s, 3H, Mel7).

WO 94/20088 ' PCTlUS94102210 EXAMPLE ~.'3 OH
tBuO N Oltil iii H OH
H0 ~ H
OACO\~0 Ph (70-3) Preparation of 3'-desphenyl-3'-(2-furyl)-N-desbenzoyl-5 N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-desacetyl taxol.
To a solution of 7,10-(bis)-O-triethylsilyl-9-desoxo-9~i-hydroxy-10-deacetyl baccatin (III) (70.0 mg, 0.09 mmol) in 1.0 mL of THF at -45 °C was added dropwise 10 0.10 mL of a 0.98 M solution of LiN(SiMe3)~ in hexane.
After 0.5 h at -45 °C, a solution of cis-1-t-butoxy-carbonyl-3-triethylsilyloxy-4-(2-furyl)azetidin-2-one (99.5 mg, 0.27 mmol) in 1.0 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept 15 at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/
hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to 20 give 94.3 mg of a mixture containing (2'R,3'S)-2',7,10-(tris)-0-triethylsilyl-3'-desphenyl-3'-(2-furyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-desacetyl taxol and a small amount of the (2'S,3'R) isomer.
25 To a solution of 94.3 mg (0.082 mmol) of the mixture obtained from the previous reaction in 13.5 mL of acetonitrile and 0.57 mL of pyridine at 0 °C was added PCTlUS94102210 WO 94!20088 1.92 mL of 48~ aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave 72.3 mg of material which was purified by flash chromatography to give 59.1 mg (89~) of 3'-desphenyl-3'-(2-furyl)-N-desbenzoyl-N-Et-butoxycarbonyl)-9-desoxo-9~3-hydroxy-10-desacetyl taxol, which was reczystallized from methanol/water.
m.p.144-146°C; [a]=SNa -54.0° (c 0.0028, CHC1,) .
1H NMR (MeOH, 300 MHz) 8 8.10(d, J=7.1 Hz, 2H, benzoate ortho), 7.60(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta) , 7 . 40 (m, 1H, fury! ) , 6 .37 (m, 1H, fury! ) , 6 . 34 (m, 1H, fury!), 6.17(m, 1H, H13), 6.16(d, J=5.4 Hz, 1H, H2), 5.24(br s., 1H, H3'), 5.11(d, J=5.5 Hz, 1H, H10), 4.86(d, J=8.1 Hz, 1H, H5), 4.83(d, J=9.3 hz, 1H, NH), 4.50(d, J=5.5 Hz, 1H, H9), 4.45(br s, 1H, H2'), 4.21(d, J=8.1, 1H, H20a), 4.13(d, J=8.1 Hz, 1H, H20(3), 3.92(dd, J=9.4, 7.5 Hz, 1H, H7), 3.11(d, J=5.5 Hz, H3), 2.46(m, 1H, H6oc) , 2 .24 (m, 1H, Hl4oc) , 2 .21 (s, 3H, 4Ac) , 2 .15 (m, 1H, H14(3) , 1.79 (ddd, J=15.1, 9.4, 1.2 Hz, H6(3) , 1.77 (s, 3H, Mel6), 1.73(s, 3H, Mel8), 1.61(s, 3H, Mel9), 1.37(s, 9H, 3Me t-buthoxy), 1.26(s, 3H, Mel7).

WO 94120088 ~ PCTIUS94102210 ~~~ ~90~

EXAMPLE.4 OH
p \ p OH
off taao i = o....
H OH _ (70-4) Preparation of 3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-desacetyl taxol.
To a solution of 7,10-(bis)-O-triethylsilyl-9-desoxo-9(3-hydroxy-10-deacetyl baccatin (III) (70.0 mg, 0.09 mmol) in 1.0 mL of THF at -45 °C was added dropwise 0.10 mL of a 0.98 M solution of LiN(SiMe3)z in hexane.
After 0.5 h at -45 °C, a solution of cis-1-(t-butoxy-carbonyl)-3-(2-methoxyisopropyloxy)-4-(isobutenyl)-azetidin-2-one (84.5 mg, 0.27 mmol) in 1.0 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10o solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 88.3 mg of a mixture containing (2'R,3'S)-2',7,10-(tris)-0-triethylsilyl-3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9~i-hydroxy-10-desacetyl taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 88.3 mg (0.080 mmol) of the.
mixture obtained from the previous reaction in 13.5 mL of acetonitrile and 0.55 mL of pyridine at 0 °C was added WO 94/20088 ~ PCTIUS94l02210 _216948 1.90 mL of 48o aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave . 5 67.2 mg of material which was purified by flash chromatography to give 52.7 mg (82%) of 3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-9(3-hydroxy-10-desacetyl taxol, which was recrystallized from methanol/water.
m.p.138-140°C; [a]=SNa -55.2° (c 0.0026, CHC1,) .
1H NMR (MeOH, 300 MHz) 8 8.11(d, J=7.1 Hz, 2H, benzoate ortho), 7.61(m, 1H, benzoate para), 7.48(m, 2H, benzoate meta), 6.13(m, 1H, H13), 6.12(m, 1H, H2), 5.21(br s., 1H, H3'), 5.02(d, J=5.3 Hz, 1H, H10), 4.93(d, J=8.1 Hz, 1H, H5), 4.85(d, J=9.1 hz, 1H, NH), 4.84(d, J=8.5 Hz, 1H, MezC=CH-), 4.50(br s, 1H, H2'), 4.50(d, J=5.5 Hz, 1H, H9), 4.22(d, J=8.1, 1H, H20a), 4.18(d, J=8.1 Hz, 1H, H20(3), 3.89(dd, J=9.4, 7.5 Hz, 1H, H7), 3.12(d, J=5.5 Hz, H3), 2.45(m, 1H, H6a), 2.31(m, 1H, Hl4a), 2.29(s, 3H, 4Ac), 2 .18 (m, 1H, H14(3), 1.85 (ddd, J=15.1, 9.4, 1.2 Hz, H6(3) , 1.81(s, 3H, Mel6), 1.76(s, 3H, Mel8), 1.72(s, 6H, 2Me from isobuthenyl), 1.61(s, 3H, Mel9), 1.39(s, 9H, 3Me t-buthoxy), 1.26(s, 3H, Mel7).

WO 94/20088 ~ PCTIUS94102210 EXANlP~E 5 Ph 0 - OH
t8u0 N OIIII
iiiii H OH
H0 __ H
Ph 0 ~ 0 0 Ac0 (74-3) Preparation of N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol.
To a solution of 7-0-triethylsilyl-9-desoxo-10-desacetoxy-10-keto baccatin (III) (30.0 mg, 0.047 mmol) in 0.5 mL of THF at -45 °C was added dropwise 0.05 mL of a 0.98 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45 °C, a solution of cis-1-t-butoxycarbonyl-3-triethyl-silyloxy-4-phenylazetidin-2-one (53.1 mg, 0.14 mmol) in 0.5 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane. Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 43.7mg of a mixture containing (2'R,3'S)-2',7-(bis)-O-triethylsilyl-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 43.7 mg (0.042 mmol) of the mixture obtained from the previous reaction in 4.0 mL of acetonitrile and 0.20 mL of pyridine at 0 °C was added 0.50 mL of 48% aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned WO 94J20088 ~ PCTIUS94102210 between saturated aqueous sodium bicarbonate and ethyl acetate. Evaporation of the ethyl acetate solution gave - 33.2 mg of material which was purified by flash chromatography to give 24.1 mg (73 0) of i~1-desbenzoyl-5 N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol, which was recrystallized from methanol/wate.r.
m.p.162-165°C; [oc]=5Na -58.7° (c 0.0025, CHC1,) .
1H NMR (CDC1" 300 MHz) 8 8.11(d, J=7.1 Hz, 2H, benzoate ortho), 7.63(m, 1H, benzoate para), 7.50(m, 2H, benzoate 10 meta), 7.40-7.29(m, 5H, benzoate, phenyl), 6.11(td, J=7.8, 1.0 Hz, 1H, H13), 5.94(d, J=6.4 Hz, 1H, H2), 5.52(d, J=9.8 Hz, 1H, H3'), 5.27(d, J=9.3 Hz, 1H, NH), 4.93(dd, J=8.8 Hz, 1H, H5), 4.64(br s, 1H, H2'), 4.32(d, J=8.3 Hz, 1H, H20oc), 4.18(d, J=8.3 Hz, 1H, H20(3), 3.88(br 15 s, 1H, 2'OH), 3.71(m, 1H, H7), 3.11(d, J=5.1 Hz, 1H, H3), 3 .10 (d, J=15:7 Hz, H9oc), 2 .88 (d, J=16.1, 1H, H9(3), 2 . 54 (m, 1H, H6oc) , 2 .44 (m, 1H, H14(3) , 2.29 (s, 3H, 4Ac) , 2.26 (m, 1H, Hl4oc), 2.02(br s, 1H, 7 OH), 1.88(s, 1H, 1 OH), 1.80(m, 1H, H6(3), 1.65( s, 3H, Mel8), 1.55(s, 3H, Mel6), 1.46(s, 20 3H, Mel9), 1.35(s, 9H, 3Me t-butoxy), 1.29(s, 3H, Mel7).(74-4) WO 94120088 ~ PCTIUS94102210 EXAMPLE 6.

0 \ 0 OH
tBuO~N _ 01111 H OH
HO

Ph~ _, 0 '1p ACO
(74-4) Preparation of 3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol.
To a solution of 7-O-triethylsilyl-9-desoxo-10-desacetoxy-10-keto baccatin (III) (30.0 mg, 0.047 mmol) in 0.5 rnL of THF at -45 °C was added dropwise 0.05 mL of a 0.98 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45 °C, a solution of cis-1-t-butoxycarbonyl-3-(2-methoxy-isopropyloxy)-4-(isobutenyl) azetidin-2-one (44.1 mg, 0.141 mmol) in 0.5 mL of THF was added dropwise to the mixture. The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH
in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.
Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 40.8 mg of a mixture containing (2'R,3'S)-2'-O-(2-methoxy-isopropyl)-7-O-triethylsilyl-3'-desphenyl-3'-(iso-butenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 40.8 mg (0.043 mmol) of the mixture obtained from the previous reaction in 4 mL of acetonitrile and 0.2 mL of pyridine at 0 °C was added 0.5 WO 94/20088 ' PCTlUS94l02210 mL of 48o aqueous HF. The mixture was stirred at 0 °C for 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
F~aaporation of the ethyl acetate solution gave 34.4 mg of material which was purified by flash chromatography to give 23.0 mg (700) of 3'-desphenyl-3'-(isobutenyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol, which was recrystallized from methanol/water.
m.p.149-153°C; [a]"Na -56.3° (c 0.0025, CHC1,) .
IH NMR (CDC1" 300 MHz) 8 8.12(d, J=7.2 Hz, 2H, benzoate ortho), 7.64(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 6.12(t, J=7.5 Hz, 1H, H13), 5.95(d, J=6.2 Hz, 1H, H2), 5.30(d, J=8.9 Hz, 1H, NH), 4.94(d, J=8.2 Hz, 1H, H5), 4.88(d, J=8.9 Hz, 1H, MezC=CH-), 4.79(td, J=8.9, 2.4 Hz, 1H, H3'), 4.34(d, J=8.2 Hz, 1H, H20a), 4.27(dd, J=5.5, 2.7 Hz, 1H, H2'), 4.19(d, J=8.2 Hz, 1H, H20(3) "
3.73(m, 1H, H7), 3.67(br s, 1H, 2'OH), 3.13(d, J=5.1 Hz, 1H, H3), 3.12(d, J=15.7 Hz, 1H, H9a), 2.90(d, J=15.7 Hz, 1H, H9~3) , 2 . 55 (m, 1H, H6a), 2.47(m, 1H, H14~3), 2 . 32 ( s, 3H, 4Ac), 2.28(m, 1H, Hl4a), 2.04(br s, 1H, 7 OH), 1.88(s, 1H, 1 OH), 1.82 (m, 1H, H6(3), 1.79 (s, 3H, Mel8) , 1.76 (s, 6H, 2Me from isobuthenyl), 1.57(s, 3H, Mel6), 1.47 (s, 3H, Mel9); 1.40(s, 9H, 3Me t-buthoxy) 1.30(s, 3H, Mel7).(75-1) WO 94/20088 ~ PCTIUS94I02210 ,~~69~~

off te~o i = o~~~~
H OH
Ph OACO~ VO

(75-1) Preparation of 3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol.
To a solution of 7-0-triethylsilyl-9-desoxo-10-desacetoxy-10-keto baccatin (III) (25.0 mg, 0.039 mmol) in 0.5 mL of THF at -45 °C was added dropwise 0.05 mL of a 0.98 M solution of LiN(SiMe3)2 in hexane. After 0.5 h at -45 °C, a solution of cis-1-t-butoxycarbonyl-3-triethyl-silyloxy-4-(2-thienyl)azetidin-2-one (45.0 mg, 0.117 mmol) in 0.5 mL of THF was added dropwise to the mixture.
The solution was warmed to 0 °C and kept at that temperature for 1 h before 1 mL of a 10% solution of AcOH
in THF was added. The mixture was partitioned between saturated aqueous NaHCO, and 60/40 ethyl acetate/hexane.
Evaporation of the organic layer gave a residue which was purified by filtration through silica gel to give 36.2 mg of a mixture containing (2'R,3'S)-2',7-(bis)-O-triethyl-silyl-3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol and a small amount of the (2'S,3'R) isomer.
To a solution of 36.2 mg (0.035 mmol) of the mixture obtained from the previous reaction in 3.0 mL of acetonitrile and 0.15 mL of pyridine at 0°C was added 0.45 mL of 48% aqueous HF. The mixture was stirred at 0 °C for WO 94120088 PCTlUS94102210 3 h, then at 25 °C for 13 h, and partitioned between saturated aqueous sodium bicarbonate and ethyl acetate.
Evaporation of the ethyl,acetate solution gave 29.4 mg of material which was purified by flash chromatography to give 24.3 mg (87~) of 3'-desphenyl-3'-(2-thienyl)-N-desbenzoyl-N-(t-butoxycarbonyl)-9-desoxo-10-desacetoxy-10-keto taxol, which was recrystallized from methanol/water.
m.p.163-169°C; [a]=SNa -54.2° (c 0.0023, CHCl,) .
1H NMR (CDC1" 300 MHz) 8 8.12(d, J=7.3 Hz, 2H, benzoate ortho), 7.64(m, 1H, benzoate para), 7.51(m, 2H, benzoate meta), 7.26(m, 1H, thienyl), 7.10(d, J=3.4 Hz, IH, thienyl), 6.99(dd, J=5.1, 3.4 Hz, 1H, thienyl), 6.12(td, J=6.1, 1.0 Hz, 1H, H13), 5.95(d, J=5.9 Hz, 1H, H2), 5.50(d, J=4.4 Hz, 1H, NH), 5.42(d, J=9.8 Hz, 1H, H3'), 4.94(d, J=8.3 Hz, 1H, H5), 4.64(dd, J=4.2, 2.0 Hz, 1H, 2'), 4.33(d, J=7.8 Hz, 1H, H20a), 4.18(d, J=7.8 Hz, 1H, H20(3), 3.90(br s, 1H, 2'OH), 3.73(m, 1H, H7), 3.11(d, J=15.8 Hz, H9a), 3.09(d, J=5.1 Hz, 1H, H3), 2.90(d, J=15 . 6 Hz, 1H, H9~i), 2 .54 (m, 1H, H6a) , 2 .45 (m, 1H, H14(3) , 2.31(s, 3H, 4Ac), 2.28(m, 1H, Hl4a)" 2.01(br s, 1H, 7 OH), 1.88(s, 1H, 1 OH), 1.83(m, 1H, H6(3), 1.69(s, 3H, Mel8), 1.56(s, 3H, Mel6), 1.46(s, 3H, Mel9), 1.40(s, 9H, 3Me t-buthoxy), 1.29(s, 3H, Mel7).

Taxanes 67-3, 70-2, 70-3, 70-4, 75-1, 74-4, and 74-3 of Examples 1-7 were evaluated in in vitro cytotoxicity activity against human colon carcinoma cells HCT-116. Cytotoxicity was assessed in HCT116 human colon carcinoma cells by XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenyl-amino)carbonyl]-2H-tetrazolium hydroxide) assay (Scudiero et al, "Evaluation of a soluble tetrazolium/ formazan assay for cell growth and drug sensitivity in culture:, using human and other tumor cell lines", Cancer Res,.~4°8':4827-4833, 1988). Cells were plated at 4000 cells/~well in 96 well microtiter plates 5 and 24 hours later drugs were added and serial diluted.
The cells were incubated at 37oC for 72 hours at which time the tetrazolium dye, XTT, was added. A dehydro-genase enzyme in live cells reduces the XTT to a form that absorbs light at 450 nm which can be quantitated 10 spectrophotometrically. The greater the absorbance the greater the number of live cells. The results are expressed as an ICSo which is the drug concentration required to inhibit cell proliferation (i.e. absorbance at 450 nm) to 50% of that of untreated control cells.
15 All compounds had an ICSO less than 0.1, indicating that they are all cytotoxically active.

Claims (22)

CLAIMS:
1. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14:
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo, R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C1-C15 heteroaryl , hydroxy, protected hydroxy or together with R6 forms an oxo;

R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and R29, R30 and R31 are independently hydrogen C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
2. The taxane derivative of claim 1 wherein R31 is selected from the group consisting of and Z is C1-C15 alkyl, hydroxy, alkoxy, halogen, or trifluoromethyl.
3. The taxane derivative of claim 2 wherein Z is methyl or methoxy.
4. The taxane derivative of claim 1 wherein R9a is hydrogen.
5. The taxane derivative of claim 1 wherein R9a is .beta.-hydroxy.
6. The taxane derivative of claim 1 wherein R9a is acetoxy.
7. The taxane derivative of claim 1 wherein R14 and R14a are hydrogen, R10 is hydrogen, R10a is hydroxy or acetoxy, R9a is hydrogen or .beta.-hydroxy, R7 is hydrogen, R7a is hydroxy, R5 is hydrogen, R5a and R4 and the carbons to which they are attached form an oxetane ring, R4a is acetoxy, R2a is hydrogen, R2 is benzoyloxy, R1 is hydroxy, X1 is -OH, X2 is hydrogen, X3 is phenyl, X4 is hydrogen, X5 is -COX10, X10 is phenyl or t-butoxy and the taxane has the 2'R, 3'S configuration.
8. The taxane derivative of claim 1 wherein R14 and R14a are hydrogen, R10 is hydrogen, R10a is hydroxy or acetoxy, R9a is hydrogen, .beta.-hydroxy or .beta.-acetoxy, R7 is hydrogen, R7a is hydroxy, R5 is hydrogen, R5a and R4 and the carbons to which they are attached form an oxetane ring, R4a is acetoxy, R1 is hydroxy, X1 is -OH, X2 is hydrogen, X3 is C1-C15 alkyl or C2-C15 alkenyl, X4 is hydrogen, X5 is -COX10, X10 is phenyl, tert-, iso-or n-butoxy, ethoxy, iso- or n-propoxy, cyclohexyloxy, allyloxy, crotyloxy, 1,3-diethoxy-2-propoxy, 2-methoxyethoxy, amyloxy, neopentyloxy, PhCH2O-, -NPh2, -NHnPr, -NHPh, and -NHEt.
9. A pharmaceutical composition which contains the taxane derivative of claim 1 and one or more pharmacologically acceptable, inert or physiologically active diluents or adjuvants.
10. A taxane derivative having the formula wherein X1 is -OX6, - SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl or substituted phenyl, substituted with an C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl group, provided, however that X3 is other than phenyl when X4 is hydrogen, and X4 is other than phenyl when X3 is hydrogen;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
alkenyl, X4 is hydrogen, X5 X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C1-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl , cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo, R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl, hydrogen, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and R29, R30 and R31 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
11. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
as is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X9 is an amino protecting group;

X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, or -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;

R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with. R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and R29, R30 and R31 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
12. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;

X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14:
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;

R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen. or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
R28 is hydrogen, aryl, or a hydroxy protecting group;
R29, R30 and R31 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl, provided, however, that R31 is not unsubstituted phenyl.
13. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl , C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 alkynyl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen or together with R4d forms an oxo;
oxirane or methylene;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo, R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, or together with R5 forms an oxo;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;

R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and R29, R30 and R31 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
14. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;

R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, o:r together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;

R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and R29, R30 and R31 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
15. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10, or -SO2X11;

X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, ar C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy, or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is acyl, or a hydroxy protecting group; and R29, R30 and R31 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
16. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NX8X9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently :hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX12, -COOX10, -COSX10, -CONX8X10 or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;

X9 is an amino protecting group;
X10 is C1-C15 alkyl, C1-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15, heteroaryl, or heterosubstituted C1-C15; alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl. C5-C15 heteroaryl, -OX10, or -NX8X14;
X12 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl, provided, however, that X12 is other than unsubstituted phenyl;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, -C6-15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo;
R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;

R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen or together with R7a forms an oxo;
R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, acyl, or a hydroxy protecting group;
and R29, R30 and R31 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
17. A taxane derivative having the formula wherein X1 is -OX6, -SX7, or -NXSX9;
X2 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X3 and X4 are independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
X5 is -COX10, -COOX10, -COSX10, -CONX8X10 or -SO2X11;
X6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or a hydroxy protecting group;
X7 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or sulfhydryl protecting group;
X8 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;
X9 is an amino protecting group;
X10 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, or heterosubstituted C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl or C5-C15 heteroaryl;

X11 is C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, -OX10, or -NX8X14;
X14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R1 is hydrogen, hydroxy, protected hydroxy or together with R14 forms a carbonate;
R2 is hydrogen, hydroxy, -OCOR31, or together with R2a forms an oxo;
R2a is hydrogen or together with R2 forms an oxo;
R4 is hydrogen, together with R4a forms an oxo, oxirane or methylene, or together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, C5-C15 heteroaryl, cyano, hydroxy, or -OCOR30, or together with R4 forms an oxo, oxirane or methylene;
R5 is hydrogen or together with R5a forms an oxo, R5a is hydrogen, hydroxy, protected hydroxy, acyloxy, together with R5 forms an oxo, or together with R4 and the carbon atoms to which they are attached form an oxetane ring;
R6 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6a forms an oxo;
R6a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R6 forms an oxo;
R7 is hydrogen. or together with R7a forms an oxo;

R7a is hydrogen, halogen, protected hydroxy, or -OR28, or together with R7 forms an oxo;
R9 is hydrogen;
R9a is hydrogen, .beta.-hydroxy, .beta.-protected hydroxy, or .beta.-acyloxy;
R10 is hydrogen or together with R10a forms an oxo;
R10a is hydrogen, -OCOR29, hydroxy, or protected hydroxy, or together with R10 forms an oxo;
R14 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl, hydroxy, protected hydroxy or together with R1 forms a carbonate;
R14a is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, C6-C15 aryl, or C5-C15 heteroaryl;
R28 is hydrogen, aryl, or a hydroxy protecting group;
R29 is hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl, provided, however, that R29 is other than methyl; and R30 and R31 area independently hydrogen, C1-C15 alkyl, C2-C15 alkenyl, C2-C15 alkynyl, monocyclic C6-C15 aryl or monocyclic C5-C15 heteroaryl.
18. The taxane derivative of claim 1 wherein R10a is other than hydroxy.
19. The taxane derivative of claim 1 wherein X5 is -COX10, -COSX10, -CONX8X10, or -SO2X11, with X8 and X11 as defined above and X10 being other than phenyl, or X5 is -COOX10 with X10 being other than butyl.
20. A taxane derivative having the formu a wherein X1, R1 and R7 are hydroxy;
X3 is furyl, thienyl, isobutenyl, or phenyl;
X5 is -COX10;
X10 is butoxy or phenyl;
R2 is benzoyloxy;
R4 together with R5a and the carbon atoms to which they are attached form an oxetane ring;
R4a is acetoxy;
R9a is hydrogen or .beta.-hydroxy;
R10 is hydrogen or together with R10 forms an oxo;
R10a is hydroxy or together with R10 forms an oxo; and X2, X4, R2a, R5, R7a, R9, R14 and R14a, are hydrogen.
21. The taxane derivative of claim 20 wherein X10 is t-butoxy, R9a is hydrogen, and R10 and R10a form an oxo.
22. The taxane derivative of claim 20 wherein X10 is t-butoxy, R9a is .beta.-hydroxy, R10 is hydrogen, and R10a is hydroxy.
CA002156908A 1993-03-05 1994-03-01 C9 taxane derivatives and pharmaceutical compositions containing them Expired - Fee Related CA2156908C (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US2697393A 1993-03-05 1993-03-05
US08/026,978 1993-03-05
US3485293A 1993-03-22 1993-03-22
US08/034,852 1993-03-22
US9508793A 1993-07-20 1993-07-20
US08/095,087 1993-07-20
PCT/US1994/002210 WO1994020088A1 (en) 1993-03-05 1994-03-01 C9 taxane derivatives and pharmaceutical compositions containing them

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