CA2190651A1 - New taxoids, preparation thereof and pharmaceutical compositions containing them - Google Patents

Abstract

New taxoids having general formula (I), (II) preparation thereof and pharmaceutical compositions containing them. In general formula (I): R¿a? is hydrogen, hydroxy, alkoxy, acyloxy, alkoxyacetoxy, and R¿b? is hydrogen or R¿a? and R¿b? form together with the carbon atom to which they are linked a ketone function, Z is a hydrogen atom or a radical having general formula (II) wherein R¿1? is an optionally substituted benzoyl radical, a thenyl or furoyl radical or a radical R¿2?-O-CO- wherein R¿2? is an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted phenyl or heterocyclyl radical; R¿3? is an alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, naphtyl or heterocyclic aromatic radical, and R¿4? and R¿5?, similar or different, represent an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, aryl or heterocyclyl radical, with the condition that R¿5? does not represent a methyl radical. The new products having general formula (I) wherein Z is a radical having general formula (II) have remarkable antitumoral and antileukaemic properties.

Description

21 90~5l wo 95133736 P~llr~
I
NEW TAXOIT)E~. LFUR PRF.PARATrON _T I F.~ COMPOSITION.
PHARMACEUTIOUES YES rF~ CONTIFNNF.~T
This in ~ ention relates to new taxoids of general formula:
~ .
zo,~ <~ (I) HO OCORs 5 in which:
Ra represents tm atom of ~ .LUs ~,... or a hydroxy or alkoxy radical containing 1 to 4 cat-bone atoms, acyloxy containing 1 to 4 carbon atoms or al ~ .u ~ y whose alkyl part contains 1 to 4 carbon atoms and Rb represents an atom of; ~ y ~ hu ~ or else Ra and Rb form together with the atom of 10 carbon to which they are linked a ketone function, Z represents an atom of hr ~ u ~ c or a radical of general formula:
NHR O
~(11) OH
in which:
R1 represents a berr ~ oyl radical C .. "substituted by one or 15 several atoms or radicals, identical or different, chosen from the atoms halogen and alkyl radicals containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms or i ^ u~lC~le, thenoyl or furoyl, or a radicar R2-O-COdams where R2 represents:
- um alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 20 carbon atoms, arcynyl containing 3 to 8 carbon atoms, ~lual~vyle containing 3 to 6 carbon atoms, ~.,lu~ r'r, containing 4 to 6 carbon atoms, b; ~, '', yl ~, contenamt 7 to 10 carbon atoms, these radicals being éV ~ t ~ ~ pntsubstituted by one or more 'chosen from halogen atoms and hydroxy, alkoxy radicals containing 1 to 4 carbon atoms, ~; uy; ~ ul ~ v including 25 each alkyl part c, contains 1 to 4 carbon atoms, piperidino ""~
piperazinyl-1 (;.. . ~...11. --- ..; substituted at -4 by an alkyl radical containing 1 to 4

2 1 9065 1 WO 95133736~r~

carbon atoms or by a ra ~ lical phenylalkyl whose alkyl part contains 1 to 4 carbon atoms), ~, ~ containing 3 to 6 carbon atoms, ey~ the containing 4 to 6 carbon atoms, phenyl (;. 'I substituted by one or several atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms), cyano, carboxy or -' y1~1~...~r1~, of which the alkyl part contains 1 to 4 carbon atoms, - a phenyl radical or a- or ~ naphthyl;. ~I substituted by one or more~s atoms or radicals selected from halogen atoms and alkyl radicals 10 containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms or um radical }. ~, t ~ ~ 5-membered aromatic preferably chosen from furyl and thienyl radicals, - Or a saturated llé ~ é ~ lyl radical containing 4 to 6 carbon atoms;. ~ l ~ t ~. ~ tsubstituted by one or more alkyl radicals containing 1 to 4 carbon atoms, R3 represents a straight or branched alkyl radical containing 1 to 8 carbon atoms.
carbon, straight alkenyl or rummy containing 2 to 8 carbon atoms, straight alkynyl or branched chain containing 2 to 8 carbon atoms, ~ k ' , ~ containing 3 to 6 carbon atoms, phenyl or a- or ~naphthyl ~ substituted by one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, '.yl~" mercapto, forrnyl, acyl, acylamino, ~' ~ 'y~l~.~l-amino, amino"',y' , ~ J' 1, carboxy, rl~.,~l~..~1~" ~ILb~lllVyl~., y ~ l ~ b ~ yle ~ cyano, nitro and l,; ll ~,.~ Ih.~ or a ~ t.. ~ .; the aromatic having 5 members and containing one or more ~
25 identical or different, chosen from nitrogen, oxygen or sulfur atoms and ~"'1--- substituted by one or more identical or different ', chosen from the atoms of ~ lalogène and the radicals alkyls, aryls, amino, ',~' ~, ~''~' , I'~.,~1~.~' , acyl, ~I~I,u..;l~" cyano, carboxy, ~ '' yle ~ Lale ~ l ~ Jyle or r ~ y ~, ~ l ~ l; l ~ " being 30 understood that, in the 'of the phenyl radicals, a- or ~ naphthyl and l ~ t; ~ Ies alkyl radicals and alkyl portions of other radicals, 1 to 4 carbon atoms and that alkenyl radicals and alkynyls with 2 to 8 carbon atoms and that aryl radicals are phenyl or a- or ~naphthyl radicals, and R4 and Rs, identical or different, I~,~JI~'' 2 1 9r365 1 WO 9a/33736 P~. . /her - tln straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl straight or branched containing 2 to 8 carbon atoms, straight or branched alkyl containing 2 to 8 carbon atoms ~, ~.y~, lual~, vyl~ containing 3 to 6 carbon atoms, ~, lual ~;. Ayl ~ contenaltt 4 to 6 carbon atoms or L ~, y., loal ~; ~, y ~, containing 7 to 11 carbon atoms, these radicals being e .. 'I substituted by tm or many chosen from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, ~''y' , each part of which is alooyl contains 1 to 4 carbon atoms, piperidino, ...ul~l.uli.to, piperazinyl-l (evPnt-.Pll substituted at -4 by an alkyl radical containing 1 to 4 atoms of 10 carbon or by a phenylalkyl radicsl whose p ~ trtie alkyl contains 1 to 4 atoms carbon), ~; y ~, lu ~ lcuylt containing 3 to 6 carbon atoms, ~; y, ''' Jle containing 4 to 6 carbon atoms, phenyl .,.. ~lP~pnt substituted, cyano, carboxy or a! ~ yl ~ J ~ .yl ~ l.. bullylc whose alkyl pattie oontient 1 to 4 atoms of carbon, 15 - or an aryl radical i, .. 'lPr ~ pnt substituted by one or more atoms or radicals selected from among halogen atoms and alkyl, alkenyl, alcyttyl radicals, aryls, aralkyls, alco~y, alkylthio, aryloxy, aryltio, hydroxy, }~J~itU~y '~y~"
mercapto, formyl, ac~le, acylamino, ~uuy', 'y~ullyl-amino~amino, y~, ~y', carboxy, r~y~lyl~
20 dialcuy''~I~., cyalto, nitro, azido, i~U...~ Or ln . ~y, or a radical I u~,y~,lyl~, saturated or unsaturated containing 4 to 6 chatnons and '..' substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that Rs cannot represent a methyl radical, 25 it being understood that the radicals ~; y ~, luilc ~ ''' jl ~ or b; ~ y ~ l ~ JalC ~ Jy can be ~,. '1- substituted by one or more alkyl radicals containing 1 to 4 carbon atoms.
Preferably the aryl radicals which can be represented by R3, R4 andlor Rs are phenyl or a- or ,~naphthyl, .. " radicals substituted with a 30 or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and the radicals alkyls, alkenyls, alc ~ nyls, aryls, ~ y ''". ~ " alkoxy, alkylthio, atyloxy, atylthio, hydroxy, IIJ~U~ .YI~" mercapto, fotmyl, acyl, acylamino, ~uuy' ), -'y.,~l,u..y' . amino, ~',y' ), ~"' y- .
carboxy, :' Y~ULbVIIJ~ J1C~ " ~ ,J'' ~YIt, c~ano, nitro, azido, 35 i "''yl ~, and i ~ irlu.u ~ v ~ t.61 ~ Ay, Étautt understood that the alcvyles radicals and the 21 90~1 wo 95/33736 r--llr~ a alkyl portions of other radicdux ~ 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals, 2 to 8 carbon atoms and that the aryl radicals are phenyl or a- or ~naphthyl radicals, and that the radical Rs cannot represent a methyl radical.
Preferably the radicals II~L~, L~u~ can be .C~I' by R3, R4 and/or Rs are radica~xh~f,.u~,L~dtiqu~ having 5 cha~ons and containing one or more atoms, identical or different, chosen from the atoms nitrogen, oxygen or sulfur, c.. " substituted by one or more identical or different, chosen from halogen atoms (fluorine, 10 chlorine, bromine, iodine) and ra ~ ical alkyls containing 1 to 4 carbon atoms, aryls containing 6 to 10 carbon atoms, alkoxy containing 1 to 4 carbon atoms, aryloxy containing 6 to 10 carbon atoms, amino, ~o containing 1 to 4 carbon atoms, d;AI~YI~IV each alkyl part of which contains 1 to 4 carbon atoms carbon, acylamino whose dcyl part contains 1 to 4 carbon atoms, 15 -' ~ w, l ~ .. ~ containing 1 to 4 carbon atoms, æyle containing 1 to 4 carbon atoms, ~uyl~lvllyl~ whose aryl part contains 6 to 10 carbon atoms carbon, cyano, carboxy, ~, A bA llvyl ~ JI ~, A. Ir~ , the alkyl part of which contains 1 to 4 carbon atoms, ~ ~b~IU~1C of which each alkyl part contains 1 to 4 carbon atoms or 'y~ , the alkoxy part of which contains 1 to 4 carbon atoms 20 carbon.
More ~ ~ lt, the present invention relates to products of formula general a) in which Ra represents a hydroxy, alkoxy radical containing 1 to 4 carbon atoms, æyloxy containing 1 to 4 carbon atoms or r ~ t., ~
whose alkyl part contains 1 to 4 carbon atoms and Rb represents an atom 25 of llydluO ~ .le, Z represents an atom of l ~ o- ~ or a radical of general formula (II) in which R1 represents a benzoyl radical or an R2-O-CO-daiAs radical which R2 represents a tert-butyl radical and R3 repri ~ feels an alkyl radical containing 1 to 6 carbon atoms, alkenyl containing 2 to 6 carbon atoms, ~. '' yl ~, containing 3 to 6 carbon atoms, phenyl c ~ rA- ~ nt substituted with 30 one or more identical or different atoms or radicals chosen from the atoms halogen (fluorine, chlorine) and alkyl radicals (methyl), alkoxy (methoxy), LI.f, l} lr- 3, æylamino (a ~, fl ~ -), r ~ bullyldl ~ 0 (tert-) or l~ill "~,.. ':hyl~ Or a furyl-2 or -3, thienyl-2 or

-3 or thiazolyl-2, -4 or -5 and R4 represents a phenyl radical C .. 'I ~ rA ~ nt 35 substituted by one or more atoms or radicals, identical or different, chosen W09503736 2 1 '?~511 r~l/r~-l ~Ja among halogen atoms and alkyl, alkoxy, amino, '~I~.~v radicals, d; dl ~ vy ', æylamint, ' r ~ l, ul.y' azido, ~ VlVII._t ~ ylt and trifluoro-methoxy, or a thienyl-2 or -3 or furyl-2 or -3 radical and Rs represents a radical substituted alkyl ~_.. " containing 1 to 4 carbon atoms, it being understood 5 that Rs cannot represent a methyl radical.
Even more ~ `, the present invention relates to the products of general formula (I) in which Ra represents an atom of lly ~ ut_l.t or a radical hydrvxy or acetyloxy or Illclllu ~ fcl ~,., you ~ y and Rb represents an atom of ~ ue, ~ .." Z
represents an atom of l- ~ d ~ u ~ or a radical of general formula (II) in which 10 Rl represents a radical l ~ enzoyle or a radical R2-O-CO- in which R2 represents a tert-butyl radical and R3 represents an isobutyl radical, i ~ vl).,.Llrlt, butenyl, CIVI.~AYIC~ phenyl, furyl-2, fu~yl-3, thienyl-2, thienyl-3, thiazolyl-2, ~ u ~ vl ~, 1 or thiazolyl-5 and R4 represents a phenyl radical C .. 'l substituted by an halogen atom and Rs represents an alkyl radical containing 2 to 4 15 carbon atoms.
The products of general formula (I) in which Z represents a radical of general formula (II) have properties ,...1 ~....,.~,.1. and udl~lf~.
According to the present invention, the products of general formula (I) in which 20 Ra represents an atom ~, rhJ ~ u ~, _.l ~, or an alkoxy, acyloxy or alw ~ c ~ y radical, Rb represents an atom ~rl~yl-ut_..~" R4, Rs and Z are defined as 1 can be obtained by the action of an alkali metal halide (sodium chloride, sodium iodide, potassium fluoride) or an alkali metal azide (sodium azide sodium) or a quaternary salt or an alkali metal phosphate on 25 a product of general formula:
~=b ~2-CF3 <~
HO OCORs where Z, R4 and Rs are defined as 1~ f ~ S:. Ra represents an atom ~ ydlu ~,;..~, OR an alkoxy, acyloxy radical, ~, u~ y ~ clu ~ or a hy ~ roxy radical WO9 ~ D3736 2 1 9 0 ~ ~ 1 P ~ llr. r,~~

protected, and Rb represents an atom (1 }l~dlVL~ followed, if necessary, by the du 6l~, protector carried by Ra by an atom of llydl~
1 ~ ~ t, the reaction is carried out in a chosen organic solvent parnu ethers (~ally~ dii~~ .ylel~lel, methyl tert-butyl ether) and 5 nitriles ~ 7 ~) alone or as a mixture has a ~ el ~ ule between 20C and the . 'Boiling the mél7Jnge.
The product of general formula III) in which Z represents a radical of general formula (II) can be obtained by ~ ~.~. r~ .. of a product of formula general:
~ 10-SO2-CF3 HO~

in which R4, Rs are defined as 1~1, 't, and Ra represents an atom dll ~ J6 ~ or an alkoxy, acyloxy, ', ~ éL ~ y or a protected hydroxy radical, and Rb represents an atom dll ~ Jr ~ lle, by means of an acid of formula general:
#6 R~OH
GOLD~~
wherein R1 and R3 are defined as ~ 't, or R6 represents a atom of ll.~L~J~_.. , and R7 represents a v . function protector hydroxy, and either R6 and R7 together form a 5 or 6 saturated heterocycle cha3 ^ nons, or a derivative of this acid ~ our obtain an ester of general formula:
not R~\.R6~O2-CF3 R/JIO~ ~ (VI) R~ HO - OCORs 2 1 ~06~ ~
WO 95133736 1 ~ J ~

where Ra~ Rb, Rl, R3, R4, Rs, R6 and R7 are defined as ~ t, followed by ., "~ 1 of the c seen ~.~ L protectors represented by R7 and/or R6 and R7 by dQ atomQs of l~yu~uc_. ~ and i,~. ..1,.. 11 ., ..1 Ra~ when it represents a radical acyloxy, 31 ~ a., é ~ y or a hydroxy radical protected by a hydroxy radical.
L ~;.; r ~ by means of an acid of general formula (V) can be carried out in the presence of an agent of .Y ~ n ~ (., al ~ liiu..lde, reactive carbonate) and an activating agent ~ .iliinQ) in an organic solvent (ether, Qter, ketonQs, nitriles, Il. ~ Lu ~, al'~ Q it, ~ 1U., O1I / UIW ~ 1 I --. halogenated, l ~ dluuall ~ O ~ `to a ~ 'between -10 and 90C.
The ~ ~ -, r;, ~;. ", can also be made using the acid of formula general (V) in the form ~ y ~ Lide by operating in the presence of an agent of ~ ulivali, an (àl ~ iu ~ u ~ lidil ~.,) in an organic solvent (ethers, Qters, ketones, nitriles, Lu~ ;IJ -~ ~I . Ily~Lu~,alb, w ~ halogenated, ;I.yJlul,alb uu....,Liqu~) to ume i . d between 0 and 90C.
The ~ , ;r,. ~ can also be made using the acid of formula general (V) in the form of"'o,, , or in the form cl'',~idd with an acid aliphatic or aromatic, éVPnt--Pll prepared in situ, in the presence of a base (tertiary aliphatic amine) by operating in an organic solvent (ethers, esters, ketones, nitriles, II~Lu~,~bul~ -'.',;Iy~u~bu~; halogenated, ~u~bu-~s ~uulllaii~ ) to a . 'between 0 and 80C
When Ra represents a c~. hydroxy function protector. Ra is preferably a radi ~ al trichloro-2,2,2 i: au ~, ~ bull ~ lu ~ y.
Preferably, R6 represents an atom of h.r~uc`~._ and R7 represents a c uu ~ -l ~ protector of the hydroxy function or else R6 and R7 together form a l~ luu~ule saturated with 5 or 6 members.
When R6 represents an atom of l .. ~ uc ~, R7 preferably represents a radical -.Ca-u ~ al ~ the, ethoxy-1 ethyl, l ~. ~ lu,. ~ ' ~ 11 "hi. ~ .sll-yl ~ he ~ the ~
hi~llyl~ilylc, ~hi~ hybilyL~ yl..~al.rl~, l~,~lu~ ~ubu...~ or tetrahydro-pyranyl.
When R6 and Rj together form an 11~: elected.,y.,ll" this is preferably an oxazolidine ring C,. ~ mono-substituted or gem-disubstituted in position -2.
The l~ . ~ 1 R7 e ~ lou R6 and R7 protectors by atoms of h.r~uc~l~ and C.." of Ra by a hydroxy radical can be 35 carried out, according to their nature in the following way:

wo 95/~3736 2 1 9 0 6 1 P~ ~/r~ a 1) when R6 represents a dl atom, ~ Lv ~ èi. ~ and R7 represents a ~ r protector of the hydroxy function, Ra represents an alkoxy, acyloxy or alcv~a~ vi~y~ the . '- des " . IJIvLcl,~.ua by atoms y ~ J ~ `JL ~ is carried out with the mo ~ in a mineral acid (acid '' J ~ ',, acid 5 sulfuric acid nuvll.J ~ i ~ uc) or organic (acetic acid, methane-sulphonic, ~inu~ acid, pl~ fvniq~ acid) utiliæ æul or in mixture by operating in an organic solvent chosen from alcohols, ethers, esters, hJ ~ v ~ L ~ '. the lly~Lv~,al~uL~
halogenated, the llydlv ~ l / ~, s ~ u, . or nitriles to a ~ lawlc: included 10 between -10 and 60C, 2) when R6 represents an atom of l ~ y ~ v ~ and R7 represents a ~;.. -.1 ~ .. l protector of the hydroxy function, Ra represents a 2,2,2-trichloro radical ~L~Iv/~y~auLIvllylv~y, the 1~ of ~VU~ protector R7 is performed in the conditions described above under 1) and that of Ra by treatment with the ~ inc, 15 C.." associated with copper, in the presence of acetic acid at a between 30 and 60C or by means of a mineral or organic acid such as hydrochloric acid or acetic acid in solution in an aliphatic alcohol containing 1 to 3 carbon atoms (methanol, ethanol, propanol, iaV~ . I) or in an aliphatic ester (ethyl acetate, iav ~ lv ~ yl acetate, n-butyl acetate) in presence of zinc ~.. ~.. It.. ~ associated with copper, 3) when R6 and R7 together form a saturated heterocycle with 5 or 6 members and more particularly a cycle, '' of general formula:
R~-N><O (VII) R~ R9 in which Rl is defined as ~nl 't, R8 and Rg, identical or different, 25 I ~ l, .. an atom of ~ ~ v ~ or 'an aleoyl radical containing 1 to 4 atoms of carbon, or an aralkyl radical in which the alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical C.. 'I ~ rn ~ nt substituted by one or more alkoxy radicals eontenant 1 to 4 atoms of carbon, or a radieal ar ~ the . . t, preferably a phenyl radical 30 C.. 'Ir ~ m nt substituted by one or more aleoxy radicals containing 1 to 4 atoms carbon, or else R8 represents an alkoxy radieal containing 1 to 4 carbon atoms.

2 1 q~6~ 1 wo ss~33736 P~ rA,S.. /a~

carbon or a radical trh ~ m ~ thyle such as ~; hlu ~ u ~ yl or a phenyl radical substituted by a radical trl ~ lr) mpthyle such as ~ l.lu.u ... éLllyle and Rg represents a - atom of the ~ ylllu ~, or else R8 and Rg form together with the carbon atom to which they are linked a ring having 4 to 7 members, and Ra represents an acyloxy radical 5 or ~ l ~, v ~ a ~ you ~ y or 2,2,2-trichloro ~ u ~ y ~ bullylu ~ y, the, ."~ 1 of ~, , protector formed by Ro and R7 by atoms I'I.~Lu~ , and of Ra by a hydroxy radical can be made, according to the ~ i ~ 'of Ra ~ Rl, R8 and Rg, of the following way:
a) when Rl represents a tert-buLu radical,.y.,~ul,ullyL,, R8 and Rg, 10 identical or different, I ~ l; ~ .lt ~ an alkyl radical or an aralkyl radical ~ Benzyl) or aryl (phenyl), or R8 represents a radical i '''yl ~. or one phenyl radical substituted by a ~lillalu~ -yl radical, and Rg represents an atom of llyJIut ~, or R8 and Rg together form a cycle having 4 to 7 ch ~ ûnons, the treatment of residue of general formula (VI) with a mineral or organic acid 15 C. " in an organic solvent such as an alcohol leads to the product of general formula:
3~b a~O O-SO2-CF3 OH~O (VIII) HO OCORs wherein Ra~ Rb, R3, R4 and Rs are defined as oornme ~ - - which is acylated by means of ch ~ benzoyl oride in which the phenyl ring is;. "
20 substituted, thenoyl chloride, furoyl chloride or a product of formula general:
R2-O-CO-X(IX) in which R2 is c~ defined as ~., ' and X represents an atom of halogen (fluorine, chlorine) or a residue -O-R2 or -O-CO-O-R2, to obtain a product 25 of general formula:

WO 9S / 33736 2 1 9 0 6 5 1 P ~ T / FR95100735 Rb a~O~O-SO2-CF3 R,-NH O ~/~
R3 ~O ~ ,~o (X) HO. ~ OCORs in which Ra~ Rb, Rl, R3, R4 and Rs are defined as ~.lf~ fl.,... ~ whose i ~, protector Ra ~ Ic ~ 3 that it represents a prvtégé hydrvxy radical ~ is replaced, if necessary, by p;3r a hydroxy radical.
Preferably, the product of general formula (VI) is treated with acid formic at a ~ la ~ uG Yoisine of 20C.
Preferably, the acylativn of the product of general formula (VIII ~ by means a benzoyl chloride d ~ 3ns in which the phenyl radical is c .. "substituted, of thenoyl chloride or of furvyl chloride or of a product of general formula 10 (IX) is carried out in an inert organic sol-~ ant chosen from esters such as ethyl acetate, acetate ~ vi ~ ivpylG or n.butyl acetate and lly ~ vl, iuiJuuGI ~
~ I - i halogenated such as ~-''"' or dich'ioro-1,2 ethane in presence of a mineral base such as sodium or organic base such as that the liiGlh ~ '- The reaction is carried out at a ~ Gil ~ iUG cvmprise between 0 and 1550C, preferably close to 20C.
Preferably, the, 'of the g ~ v ~ prvtector of Ra ~ when it represents a 2,2,2-trichloro radical. r~ bvl~.~lvi~y, is carried out within the conditions described pll '' under 2), b) when Rl represents a substituted benzoyl radicali ~ mP ~ lt, thenoyl or furoyl or a ri3dical R2O-CO- wherein R2 is defined as ,.é 't, R8 represents ~ n atom ~ li'llyd ~ vi ~ i .., or a radica'i a! icoxy contenamt 1 to 4 carbon atoms or a phenyl radical substituted by one or more radicals alkoxy containing 1 to 4 carbon atoms and Rg represents an atom ~ v "`.l ~, Ie .' ~ VU ~ G..I ~ .lL protector formed by R6 and R7 by atoms 25 ~ li'llyd ~ v ~, is carried out in the presence of a mineral acid (acid ch'ivllly ~ Liq ~, acid sulfuric acid) or organic (acetic acid, scide ll.6LIii~i~ 3 rv~i;q~ scide i ~ inuvl ~ 'C ~ ic, acid r ~. ) used alone or mixed in quantity '~' . or catalytic, operating in an organic solvent 2~9~
WO 95133736 r~, l/r~ a chosen from alcohols, ethers, esters, l ~ u ~ 'GS ~ U ~, llylLu~ubuuGs~ and halogenated ]I.~'d~Ul,allJUlGa uulllaiiqu~ to a t ~ GlaLl..G between erltre -10 and 60C, preferably between 15 and 30C and the ""~ du ~-, protector of Râ~ when he represents a radieal 5 trichloro-2,2,2; h ~ l ~ wbu ~ ylu ~ y by an atom cll ~ y ~ ub ~ ic, is carried out under the conditions described pl ~ '' under 2).

4) when Ra represents an alkoxyacetyl radical and R6 and R7 are defined as in point 1) above, we first perform the ~ ~ IUUp ~ .l .., .l; R7 protector by an atom of llyLue, ~ ilc by operating under the acid conditions described in point 1) 10 above, then replaces evl ~ ntllpllpmpnt Ra with a hydroxy radical by treatment in alkaline medium or by the action of a zinc halide under conditions which do not not affect the rest of the molecule. GPnP~lt, alkaline treatment is carried out by the action of ammonia in a hydro-alcoholic medium at a ~ GllI ~ .al ~ G close to 20C. é 't, treatment with a zinc halide, preferably iodide 15 zinc is made in methanol to a ~ a ~ uue close to 20C.

5) when Ra represents a radical al ~ u ~ Lya., é.v, -y and R6 and R7 are defined as in point 2-a) above, one carries out the l ~ --r ~ ' of the radical Ra by a radical hydroxy by treatment in an alkaline medium or by treatment with a zinc halide under the conditions described in point 3) above, then treats the product of formula 20 general (VI) obtained under the conditions of délJlu. ~ iull and acylation described in point 2-a) above.

6) when Ra represents ~a radical ~I.,v~ tv~y and R6 and R7 are defined as in point 2-b) above, we perform the. ~ -. l of the radical Ra by a radical hydroxy by treatment in. alkaline medium or by treatment with a zinc halide 25 under the conditions described in point 3) above, then treats the product obtained in the conditions described in point 2-b) above.
According to the invention, the products of general formula (III) in which R4 and Rs are defined as t, Ra represents dll.~uo~ atom or a radical alkoxy, acyloxy or -' ~, v, .y, and Rb represents an atom of h. ~ uL ~ "or 30 although Ra and Rb form together with the carbon atom to which they are bonded, a ketone function and Z represents an atom of hyll ~ can be obtained by actiond'un derivative of linuul acid ~. 'fonic such as anhydride or N-phenyl '.''''~' on a product of general formula:

wos~l33736 2 1 ~ 0 6 5 1 P_~/r~ /~a =b ~/ ~
HO OCORs where Ra~ Rb, R4 and Rs are defined as ~,.~, .1., . ,....I
C. ~ 1 t, the reaction is carried out in an inert organic solvent (Il,ydl~ubulca~éVf~t..~ ' halogenated, l~ydlu~,a buul,D alullldti~ucD) in 5 presence of an organic base such as an aliphatic tertiary amine (ui ~, ~ lallull ~) or pyridine to a t ~ a ~. between -50 and +20C.
The products of general formula (Xl) in which R4 and Rs are defined comrne ~ CA '' t, Ra represents a hydrogen atom or an alkoxy radical, dCylOXy or al~u~a~tu~ or a protected hydroxy radical, Rb represents an atom 10 of ~ u ~ e, can be obtelllus by action of acid lluu ~ d ~ ~ or acid hinuul~', in a basic organic solvent, such as pyridine .." substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, or the ~ ' - c~.-.h.. It. .~ 1 in combination with a solvent inert organic such as methylene chloride or '~ or 15 t; ~ dlyJIl 'to a ~ .ll ~ .a ~ ulc compriæ between 20 and 80C on a product of general formula:
b G-O~
HO OCORs OCOR,, where R4 and Rs are defined as ~.....",l Ra represents an atom of h ~ u ~ , or an alkoxy radical, acyloxv or dl ~, u ~ au ~ u ~ or a hydroxy radical 20 protected, Rb represents an atom of}.r ~ Lut_.l ~, and the symbols Gl, which are identical l ~ JII a triacoylsilyl radical.
-21 90~5~
WO 951337361 P~, I /r 1 The product of general formula (XII) can be obtained by the action of a product of general formula:
- RY (XIII) in which R represents an alkyl, alkanoyl or -' y ~ yl radical or a . UU~~ L protector ~ e the hydroxy function and Y represents a halogen atom on a product of general formula:
G-Oll" ~ (XIV) HO OCORs in which R4, Rs and Gl are scrolled like l"~
When R represents an alkyl radical or al ~ u ~ y ~ yl ~ it is 10 particularly advantageous to operate in a basic organic solvent such as pyridine or in an inert organic solvent such as methylene chloride, ~ LIulu ~ u .., or 1,2-dichloroethane in the presence of a year ~ ine tertiary such as hi ~ or pyridine to i, ~ close to 0C.
When R represents an alkyl radical, it is advantageous to metaUer I '' the hydruxy function at -10 by means of an alkali hydride (sodium hydride) seen from a metal alkylide (I,uly''').
The product of general fvrmule (XIV) and év~nn~ the product of general formula (XII) can be obtained by the action of a derivative ~; r ... ~ iq ~ -of general formula:
R4-M (XV) where R4 is defined as 1~'' and M represents an atom metal, preferably a lithiur atom.. or O 'on a product of general formula:

W095/33736 2 1 9 5 ' ~ 1 P~.lrh ,~
Rb ~O Cl G-~ (XVI) O OCORs o~o where Ra~ Rb, Rs and Gl are defined as I
~ '- t, the reaction is carried out d3ns an organic solvent such as a ether (t ~ ti ~ l ` at an Ic ... ~ i less than -503C, preferably close 5de-78C.
The product of general formula (XVI) can be obtained by ~ a product of general formula:
Rb Gl-O ""~~. ; XVII) OOH
in which Ra~ Rb and Gl are defirlis like ~ Lé~' t, by means of an acid 10general formula:
Rs-COOH (XVIII) d3ns in which Rs is defined as I '' t, or a derivative of this acid such a halide or anhyd ~ ide in the presence of an agent, 'or a mineral or organic base.
The product of general formula (XVII) can be obtained by the action of a product of general formula (Xm) on a product of general formula:

2190G5~
wo 95133736 r~ rl _ I /.5a ~Gl G-O~ (XIX) oh. OH
~_~
in which Gl is clefini cornme ~ 1 in the cc ~ nditic ~ s described ~11'' . for the action of a product of general formula (XIII) on a product of general formula (XIV).
The product of general formula (XIX) can be prepared by the action of phosgene or one of its derivatives such as ki ~ on a product of for ~ nulegenerale:
Gl-O ~ (XX) OH OH
OH
in which Gl is defined cornne ~ Jll 'in C \ operating in a solvent basic organic material such as pyricline at an i ~ lower than -50C, from preferably close to -78C.
The product of fc)r general formula (XX) can be prepared by action of ur h~ g~n~ ''y'' on a product of general formula:
HoWO O^GI
~ I
HO~ (XXI) OH OH
OH
15in which Gl is clefni as 1.ll''' by operating in a solvent basic organic.
The product of formula-general (XXI) can be prepared under the conditions described by DGI Kings ~ on et al., Jourr ~ al of Nat. Prod., ~, 884 (1993).

w095/33736 r~l,r~ a The products of general formula n) in which Ra and Rb LCIUlt: s ~ llt ~
each a cl'l-yLu~ atom can be obtained by C~ vly~ u~ teduction of a product of general formula (I) in which Ra represents a hydroxy radical or a acyloxy radical or 'ya ~ y or under the conditions described in the application 5' - PCTWO 93/06093.
The products of general formula (I) in which Ra and Rb together form with the carbon atom to which they are attached a ketone function can be obtained by oxidation of a product of general formula ~I) in which Ra represents a hydroxy radical and Rb represents a dl~y~v~l~ atom, by means, for example, of 10 chl~u~.l, of ~ of py~idinium dichromate, of dichromate of potassium dichromate or dioxide m ~ ,,, pn ~ 3eP
The new products of general formula (I) obtained by placing implementation of the processes according to the invention can be purified according to the methods known as criet ~ ion or ~, 1 .., ,, , ' -The products of general formula (I) in which Z represents a radical of general formula (II) have properties l ~, nlng;. ~ a ~ 4udblcs.
In vitro, the biological activity is measured on tubulin extracted from porcine brain by the method of ML Shelans ~ ci et al., Pro ~ Natl.
Acad. Science. USA, 70. 765-768 (1973). The study of the d~pvly~ a~ microtu-20 bubbles in tubulin is carried out according to the method of G. Chauvière et al., CR Acad.Sci., ~2~. series n, 501-503 (1981). In this study the products of general formula (I) in which Z represents a radical of general formula (II) have been shown at less as active as taxol and taxotere.
In vivo, the products of general formula (I) in which Z represents a 25 radicals of general formula (I10 have been shown to be active in mice grafted with the melanoma B16 at doses between 1 and 10 mg/lcg per route as well as other liquid or solid tumors.
New products have anti-tumor properties and more "`~ activity on rumors that are resistant to Taxol~D or 30 Taxotere (E9. Such tumors ~. colon tumors that have a high expression of the mdr 1 gene (multi-drug resistance gene). The multi-drug resistance is a common term æ referring to the resistance of a tumor to different products of different structures and of ' action. The taxoids are g ~ '' known to be strongly recognized by tumors c, 21 9G~Sl wo ssl33736 l~I/r. /~a such as P388 / DOX, an oellular line s ~ for its resistance to dv~v~ ' (DOX) which expresses mdr 1.
The following examples illustrate the present invention.
FXFMPIi.F. 1 SA a solution of 0.193 g of tert-bulv~y.,~l,v.lyhu..~o-3 hydrvxy-2 phenyl-4 ~ .~ l (2R,4S) of benzoyloxy-2a epoxy-5 ~,20 hydroxy-l ~ methoxy-acetoxy-10~ oxo-9 In" ~ylv~y-4a i ''' ~ Jlv,.r-7~ taxene-ll yle-13a in 2.5 cm3 of acetonitrile and 0.250 cm3 of i 'ydlu ~ uu ~ r "is added ~uccc~ . 0.096 g of sieve '' _ 4A powder, 0.290 g of chloride of 10 sodium. The reaction medium is kept under stirring at a ~ .llpel.l ~ UlC: neighbor of 75C for 5 hours ptUS, at an i I ~ close to 20C, supplemented with 75 cm3 of di ~ u ~ v ~ e and 50 cm3 of a saturated aqueous solution of chloride of sodium. The organic phase is decanted, washed twice with 40 cm3 of a solution aqueous saturated with sodium chlomre then dried over sulphate ~. filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. 0.150 g of a product which is purified by ~ on 80 g of silica (0.063-0.2 mm) contained in a column 1 cm in diameter (eluent: di ~ lil .. lv ... ~ -methanol: 98/2 by volume) rec1ueillant fractions of 10 cm3. Fractions not containing that the product sought are combined and ~,., dry under reduced pressure (2.7kPa) at 40C. 0.080 g of tert- ~ y ~ l, v .. ~ '-3 hydrvxy-2 are obtained phenyl-3,~,.., (2R,4S) benzoyloxy-2a-epoxy-513,20 hydroxy-l~ metnoxy-acetoxy-10j3 methylene-7 ~, 8 nor-19 oxo-9 1 ~ '. ylw~y-4a taxene-ll yle-13a of which the, , are as follows:
- 1H NMR spectrum (400 MHz, CDC13, ~ in pprn): 1.24 (t, J = 7.5 Hz, 3H: CH3ethyl); 1.24 (s, 6H: CH3); 1.27 (s, 9H: C(CH3)3); 1.42 (mt, 1H: H 7); 1.68 and 2.24 (2 mts, 1H each: CH2 at 19); 1.86 (s, 1H OH in 1); 1.86 (s, 3H: CH3);
2.12 and 2.86 (I~ iVt~ d and dt, J=16 and J=16 and 5 Hz, lH each: CH2 at 6);
from 2.15 to 2.30 and 2.41 (I~ti~. mt and dd, J = 16 and 9 Hz, lH each: CH2 in 14); 2.64 (mt, 2H: CH2 ethyl); 3.26 (mt, 1H:OH at 2'); 3.52 (s, 3H:OCH3);
4.07 (d, J=7Hz, 1H:H at 3); 4.04 and 4.33 (2d, J=9Hz, 1H each: CH2 at 20);
4.22 (AB limit, J=16Hz, 2H: OCOCH30); 4.62 (mt, 1H:H at 2'); 4.70 (d, J=4Hz,1H:Hen5);5.28(md,2H:Hen3'andCONH~;5.67(d,J=7Hz,1H:Hen2);
6.26 (broad t, J=9Hz, 1H:H at 13); 6.42 (s, 1H:H in 10); from 7.25 to 7.45 (mt, 5H: H ~, , in 3'); 7.52 (t, J=7.5 Hz, 2H: OCOC6H5 H in meta); 7.62 (t, wo s5n3736 r~ a J = 7.5 Hz, lH: OCOC6H5 H in para); 8.16 (d, J = 7.5 Hz, 2H: OCOC6H5 H in ortho).
The tert- ~ r ~, albu ~ 3 hydroxy-2 phenyl4 ~, lur (2R, 4S) of benzoyloxy-2a-epoxy-513,20 hydroxy~.6,Llw~Lu~y-10fl oxo-91~yl~y-5 4a'-,'''~y-7~taxene-ll yl-13a can be prepared as next:
A solution of 0.760 g of tert-'y ~ ul ~.JI-3 (4-methoxyphenyl)-2 phenyl-4.~ 1,3 uall~ y- 5 (2R,4S,5R) of benzoyloxy-2a-epoxy-5~,20 hydroxy-1 ~ ll,; '~J~.u~r-10~oxo-91~. Yl~J~r4~ LLill..~.. ' .c

7 ~ taxene-ll yle 13a darls 6.6 cm3 of a 0.1N solution of ethanol rLlli ~ ue is kept stirring at a ~ .YI ~ IdLul ~ close to 0C for 22 hours. the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at 20C. The gross reaction is dissolved in 8al cm3 of ~ - and 80 cm3 of a solution aqueous saturated with;; c ~ L of sodium. The organic phase is separated by d~mt~ti. n then ext ~ aite by 2 times 50 cm3 of ~ '-' The phases organic materials are combined, washed with 50 cm3 of distilled water and then dried over sulphate of filtered and . ~., W dry under reduced pressure (2.7 kPa) at 20C. We oWent 0.9 g of a white meringue that ron purifies by ~ about 150 g of silica (0.063-0.2 mrn) contained in a column 3 cm in diameter (eluent: dL ~, lilul ~ '- ~': 95-5 by volume) by recueirlant fractions of 15 cm3.
The fractions containing only the desired product are combined and . ~,w dry under reduced pressure (2.7 kPa) at 20C. 0.456 g of tert-bu ~ u ~ r., ~ l) ullr -3 hydroxy-2 phényW 1 ~. (2R,4S) of l~vrl~,Ar-2a epoxy-513.20 hydroxy-l~.LlW~ Lu~r-10l3 oxo-9~LI ylu~r-4a trifluoro-~ - r ~ 1.,. ~ r-713 taxene-ll yl-13a and whose,. physical are the following:
- N.M.R. spectrum. lH (400 ~Hz, CDC13, o in ppm): 1.24 (s, 9H,: CH3 and CH3 ethyl); 1.34 (s, 9H: C(CH3)3); 1.74 (s, 1H:OH to 1); 1.88 (s, 3H: CH3); 2.05 (s broad, 3H: CH3); 2.24 and 2.86 (2 mts, 1H each: CH2 at 6); 2.33 (d, J = 9H~, 2H:
CHz at 14); 2.68 (mt, 2H: ClH2 ethyl); 3.30 (mt, 1H:OH at 2'); 3.52 (s, 3H:
OCH3); 3.93 (mt, 1H:H at 3); 4.19 (AB limit, J=16Hz, 2~: OCOCH2O); 4.20 and 4.36 (2d, J=9Hz, 1H each: CH2 at 20); 4.64 (d wide, J=5.5Hz, lH:H in 2');4.86(dlarge,J=1OHz,1H:Hen5);5.22(mt,1H:Hen3');5.30(d,J=10 Hz,lH:CONH);5.51(dd,J=lOet7.5Hz,lH:Hen7);5.75(d,J= 7Hz.lH:
Hen2);6.20(mt,1H:Hen13);6.71(s,1H:Hen10);7.30 to 7.45(mt,5H:H

~ woss~33736 2 ~ 9G~S ~ r~llr~ J~

Al~l...~l;ll.'~; in 3'); 7.52 (t, J = 7.5 Hz, 2H: OCOC6H5 H in meta); 7.64 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para); 8.13 (d, J = 7.5 Hz, 2H: OCOC6Hs H in ortho).
The tert-l, uLu ~ y ~ 1-3 (methoxy-4 phenyl) -2 phenyl4 ~ '' 1,3 ~ l ~ y '5 (2R, 4S, 5R) of benzoyloxy-2a epoxy-5 ~, 20 hydroxy-113 methoxy-5 acetoxy-1013 oxo-9 ~ lu~Ly4a ~ IYIU~Y-7~ taxene-11 yl-13a can be prepared as follows:
To a solution of ~ 0.590 g of benzoyloxy-2a-dihydroxy-1 ~, 13a-epoxy-513,20 Il._Lllu~a~y-1013 oXo-9 ~ . ylu~y4a L inhul ''' ~lu~y-7 taxene-11 in 10 cm3 of anhydrous ethyl acetate, add su ~ c ~ .,: ~, 0.463 g acid tert-butu ~ y ~ l-3 (methoxy4 phenyl) -2 phenyl4, '' - 1,3 ~ l ~ yL ~ ue ~ 5 (2R, 4S, 5R), 0.319 g of dil, y, '' yl ~ _.l ~ l---- ~; ~ l and 0.028 g of 44LIléLl.y '-py ~ idme The reaction mixture is stirred for 15 hours, under ~ LII-V ~ argon, at a t ~ laLuu ~ close to 20C, then added 75 cm3 of ''' , '' and 50 cm3 of a saturated aqueous solution of chloride ~'' -The organic phase is decanted, washed with 2 times 40 cm3 of an aqueous solution saturated with sodium chloride then dried over sulphate ~ 'filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We obtain 0.980 g which we purifies by '~~ the on 150 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent:! '- '' ull, ~ ul ~ -methanol: 95-5 by volume) by collecting fractions of 15 cm3. Fractions containing only the product sought are met and: ~ dry under reduced pressure (2.7kPa) at 40C. We obtains 0.740 g of tert-1,uh,~r~1,ullyl-3(methoxy~phenyl)-2-phenyl4,'' 1.3 ~ L ~ y' 5 (2R,4S"5R) of benzoyloxy-2a-epoxy-5 ~ 3,20 hydroxy-1 ~ methoxy-acetoxy-10~ oxo-9~,1,1,.~lu,.y4a ir''CVl~ U~y-7~ taxene-11 yle-13a in the form of a white meringue and whose. ~ . physical are the following:
- 1H NMR spectrum (400 MHz, CDCI3, o in ppm): 1.06 (s, 12H: CH3 and C(CH3)3); 1.20 (s, 3H1:CH3); 1.27 (t, J = 7.5 Hz, 3H: CH3 ethyl); 1.67 (s, 1H:OH
in 1); 1.71 (s, 3H: CH3); 1.83 (s, 3H: CH3); from 2.00 to 2.30 and 2.83 (2 mt, lH
chaclm: CH2 at 6); 2.00 to 2.30 (mt, ZH: CH2 ethyl); 2.08 and 2.22 (2 dd, J = 16 and 9 Hz, 1H chaclm: CH2 at 14); 3.52 (s, 3H:OCH3); 3.82 (s, 3H: ArOCH3); 3.82 (mt, 1H:H at 3); 4.12 and 4.29 (2d, J=9Hz, 1H chactm:CH2 at 20); 4.18 (AB
limit, J = 16 Hz, 2H: OCOCH2O); 4.51 (d, J=5-Iz, 1H:H at 2'); 4.80 (d wide, J = 10Hz, 1H: H 5); 5.35 to 5.45 (mt, 1H:H at 3'); 5.43 (dd, J = 10.5 and 7.5Hz, 1H:Hen7);5.68(d,J -7Hz,1H:Hen2);6.01(mt,1H:Hen13);6.38(mt, 21 qO651 wo 95l33736 r~l,r~7~c /~5 1H: H at 5'); 6.60 (s, 1H:H in 10); 6.92 (d, J = 8.5 Hz, 2H: H ~ --; in or~o of OCH3); 7.39 (d, J=8.5 Hz, 2H: H<uu...~.Li4~,, meta to OCH3); of 7.30 to 7.45 (mt, 5H: H~uV~, in 3'); 7.50 (t, J = 7.5 Hz, 2H: OCOC6H5 H in meta); 7.65 (t, J = 7.5 Hz, 1~: OCOC6Hs H in para); 8.03 (d, J=7.5Hz, 2H:
5 OCOC6Hs H in ortho).
The ~ e. ~ v ~ hJ. ~ y-2a dihydroxy-1 ~ 3,13a epoxy-5 ~, 20 ~, Lllu ~ tv ~ y-10 OXO-9 ~ lv ~ y-4a i " ~ '''' JIU ~ y-7 ~ taxene-ll can be prepared as follows:
To a solution of 0.660 g of benzoyloxy-2a-epoxy-5~,20 Il~,L~Iv~~tvAy 10,~ oxo-9 1~u~J~.v~lvi~y-4a trihydroxy-1~,713,13a taxene-ll in 6.6 cm3 of di ~, llvl ~ '' anhydrous and 0.338 cm3 of pyridine, mamtenue under ~ LIllu ~ h.,.e of argon, to an i . 'ev ~ dsdne of 0C, add 0.354 cm3 drop by drop of ' .Li~ll, L inw.. ''' . The orange solution obtained is stirred for 10 mdnutes to an i . e neighbor of 0C, 30 mdnutes to a t ~,.ll ~ élQL ~ the vodsdne of 20C, then -'' 3 cm3 of water and 50 cm3 of di ~ .llu.ur ~. The sentence organic is decanted, washed with 2 fods 40 cm3 of an aqueous solution, saturated with sodium chloride p ~ us dried over sulphate of m: lgn.oQ; ~ m filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We obtain 0.800 g which is purified by c;~v. on 100 g of silica (0.063-0.2 mm) contained in a column of ~
20 2 cm in diameter (eluent: dielllul~: 95-5 by volume) in collecting fractions of 15 cm3. Fractions containing only the desired product are combined and ~ - - ~ s dry under reduced pressure (2.7 kPa) at 40C. We obtain 0.591 g of l~vylu~y-2a dlihydroxy-1~,13a-epoxy-5~,20 I..,L~lu~y~y-10 OXO-9 ~ u~ 4a " ~ 'w~y-713 taxene-ll as a white meringue and whose ., ~; qu- - physical are as follows:
- 1H NMR spectrum (400 MHz, CDC13, o in ppm): 1.05 (s, 3H: CH3); 1.19 (s, 3H: CH3); 1.23 (t, J = 7.5 Hz, 3H: CH3 ethyl); 1.62 (s, 1H:OH at 11; 1.89 (s, 3H: CH3); 2.12 (d, J=5Hz, 1]H:OH at 13); 2.24 and 2.90 (2 mts, l]H chaclm: CH2 in 6); 2.25 (s, 3H: CH3); 2.30 (AB limit, 2H: CH2 at 14); 2.64 (mt, 2H: CH2 ethyl); 3.52 (s, 3H:OCH3); 4.02 (d, J 5 =7Hz, 1H:H at 3); 4.15 and 4.35 (2d, J = 9 Hz, 1H each: CH2 in 20); 4.20 (AB limit, J=16Hz, 2H: OCOCH2O); 4.85 (mt,1H:Hen13);4.91(dlarge,J=1OHz,1H:Hen5);5.57(dd,J=10et7Hz, 1H:Hen7);5.69(d,J=7Hz,1H:Hen2);6.73(s,1H:Hen10);7.50(t,J=
7.5 Hz, 2H: OCOC6H5 H in m~ta); 7.63 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para);

8.11 (d, J = 7.5 Hz, 2H: OCOC6Hs H in ortho).

~ wo ssa3736 1 9 0 ~ 5 1 P~l/~ L ,~
Benzoyloxy-2a epoxy-513.20 ~ u ~ ya ~ you ~ y-101 ~ oxo-9 ~. ylV~r-4a-trihydroxy-113,713,13a-taxene-ll can be prepared as follows:
To a solution of 1.21 g of benzoyloxy-2a''. ~ ily'u ~ y-713,13a epoxy-5~3,20 hydroxy-1~ I..6~lu~ya~,élv~y 10~oxo-9~,.",ylu~a-taxene-11 in 15 cm3 of rfirh1 "' ~, we add, to an i. ~: close to 20C, 23 cm3 of complex lli ~ y- ~ cide nuv ~ llyl-. The reaction mixture is stirred for 8 p.m. to one; . è close to 20C then we add 50 cm3 of "', 'and 100 cm3 of a saturated aqueous solution of ~ y ~ u ~ of sodium. The organic phase is decanted, washed with 2 times 50 cm3 of a solution aqueous solution saturated with sodium chloride then dried over v sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. 1.04 g of l ~. ~ ylu ~ y-2a epoxy-5 ~, 20 I ~ ya ~ yl-lOfl oxo-9 ~ u ~ lvylu, ~ y-4a trihydroxy-1 ~, 7 ~, 13a taxene-ll SOIlS form of a white meringue and whose, physical are as follows:
- 1H NMR spectrum (400 MHz, CDCl3, v in ppm): 1.11 (s, 6H: CH3); 1.25 (t, J = 7.5 Hz, 3H: CH3 ethyl); 1.65 (s, 1H: OH er~1); 1.70 (s, 3H: CH3); 1.88 and 2.60 (2 mts, 1H each: CH2 at 6); 2.08 (s, 3H: CH3); 2.30 (AB limit, 2H: CH2 at 14); 2.39 (d, J=4Hz, 1H:OH at 7); 2.63 (mt, 2H: ethyl CH2); 3.55 (s, 3H:OCH3); 3.90 (d, J=7Hz, 1H:H at 3); 4.17 and 4.32 (2d, J = 9 Hz, lH each: CH2 in 20); 4.25 (A13 limit, J=16Hz, 2H: OCOCH2O); 4.51 (mt, 1H:H at 7); 4.89 (mt, 1H:H at 13); 4.95 (d wide, J=10Hz, 1H:H in 5); 5.64 (d, J=7Hz, lH:H
in 2~; 6.43 (s, 1H:H in 10); 7.48 (t, J=8 Hz, 2H: OCOC6Hs H in meta); 7.61 (t, J = 8 Hz, lH: OCOC6Hs H in para); 8.13 (d, J=8 Hz, 2H: OCOC6H5 H in ortho).
Benzoyloxy-2a~"'ybilylu..y-7~,13a-epoxy-5~,20-hydroxy-113 ~ yl ~; e ~ yl-10 ~ oxo-9 ~ ylu ~ -r ~ a taxene-11 can be prepared from the following way:
To a solution of 0.900 g of 2a-benzoyloxy-113,10-dihydroxy (ili;; hybilrlu ~ r) -7 ~, 13a epoxy-5 ~, 20 oxo-9 ~ I ~. ,Jlu,.y~a taxene-11 in 15cm3 of pyridine, 0.520 cm3 of ya., ~, yl chloride is added to a ~ .I. ~ el ~ lule close to 0''C. The reaction mixture is stirred for 2 hours at a . 5. 't ~ close to 20C then add 100 cm3 of ~''' and 50 cm3 an aqueous .saturated solution of c-chloride; The organic phase is decanted, washed with 2 times 40 cm3 of an aqueous solution saturated with chloride of; then dried over sulfate of v filtered and concentrated to dryness under 35 reduced pressure (2.7 I ~ Pa) at 40C. We obtain 1.3 g which we purify with WO gs / 33736 P ~, l / r ~ _ 'L l ~ a v. on 150 g of silica (0.063-0.2 mm) contained in a column of 2.5 cm in diameter (eluent: ethyl acetate-cyclohexane: 25-75 by volume) in collecting fractions of 10 cm3. Fractions containing only the desired product are combined and ~, dry under reduced pressure (2.7 kPa) at 40C. We obtain 0.780 g of benzoyloxy-2a b;D(''''yl~ilylu~y)-713,13a-epoxy-5~,20 hydr~vxy-l~
v~a~ y-10~ oxo-9 ln, ~ ylu~y~a taxene-ll in the form of a meringue white and whose, ~ , physics are as follows:
- 1H NMR spectrum (400 ]\~Hz, CDCI3, ~ in ppm): from 0.50 to 0.70 (mt, 12 H:
CH2 ethyl); 0.92 (t, J=7.5]-z, 9H: CH3 ethyl); 1.00 (t, J = 7.5 Hz, 9H: CH3ethyl); 1.10 (s, 3H: CH3); 1.17 (s, 3H: CH3); 1.29 (t, J = 7.5 Hz, 3H: CHl ethyl in 4); 1.61 (s, 1H:OH to 1); 1.68 (s, 3H: CH3); 1.84 and 2.51 (2 mts, 1H each:CH2 at 6); 2.09 and 2.21 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 2.10 (s, 3H:
CH3); 2.60 (mt, 2H: ethyl CH2 at 4); 3.50 (s, 3H:OCH3); 3.78 (d, J=7Hz, 1H:H at 3); 4.12 and 4.30 (2d, J=9Hz, 1H each: CH2 at 20); 4.15 (AB limit, J = 16 Hz, 2H: OCOCH2O); 4.49 (dd,J=11 and 7Hz, 1H:H at 7); 4.90 (mt, 2H: H in 5 and H at 13); 5.62 (d, J=7Hz, 1H:H at 2); 6.52 (s, 1H H in 10); 7.45 (t, J = 7.5 Hz, 2H: OCOC6H5 H in meta); 7.58 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para); 8.09 (d, J = 7.5 Hz, 2H: OCOC6H5 H in ortho).
Benzoyloxy-2a-dihydroxy-1~,10~(dihi~lrb;lrlu~y)-713,13a-epoxy-513.20 oxo-9~,.u~Jal.vylu~,y-4a taxene-ll can be prepared as follows:
To a solution of 1.105 g of carbonate-113.2a 1 ybilrlu ~ r) -7l3 ~ l3a epoxy-513.20 ~ J~u~a~étu~yl 0~ oxo-9 ~ yk/~y-4a taxene-l 1 in 50 cm3 of t6h ~ ir ~ L ~) ru ~, anhyd ~ ide, add 1.8 cm3 of a lM solution of 1 ', ' in the t~hallr~urlllal~ to an i . c: close to -78C The reaction mixture is stirred for 15 minutes at a ~ IIl ~ the ~ close to -78C pL ~ iS is added 10 cm3 of a saturated aqueous solution of chloride ~ A t ~ _lYI ~
close to 20C, 20 cm3 of a saturated aqueous solution of chloride are added ~ 'and 50 cm3 of d; ~ Llulu ~; llall ~. The organic phase is decanted, washed by 2 times 10 cm3 of a saturated aqueous solution of sodium chloride then dried on sulphate ~ filtered and concentrated to dryness under reduced pressure (2.7 kPa) to 40C We oWent 1.3 g which is purified by, '~.' on 150 g of silica (0.063-0.2 mm) contained in a 5 cm diameter column (eluent: acetate of ethyl- ~ -r ~ ~: 10-90 erl volumes) by collecting fractions of 18 cm3 The fractions containing only the desired product are combined and I ~ s dry under reduced pressure (2.7 l ~ a) ~ 40C. We oWent 0.840 g of ~.~ vylu ~ y-2a dihydroxy-WO 95133 ~ 36 2 ~ 9 ~ 6 5 ~ r. ,~

~,10~ (IH~ybilyl~.y)-71f~,13~epoxy-51′~,20-oxo-9 IJlulJall~Jyl~y 4 taxene-ll in the form of a white meringue and whose ~ physif ~ ues are the - following:
- 1H NMR spectrum (400 MHz, CDC13, ~ in ppm): 0.53 (mt, 6 H: CH2 ethyl);
5 0.65 (mt, 6H: CH2 ethyl); 0.92 (t, J=7.5 Hz, 9H: CH3 ethyl); 1.00 (t, J = 7.5 Hz, 9H: CH3 ethyl); 1.07 (s, 3H: CH3); 1.14 (s, 3H: CH3); 1.26 (t, J = 7.5Hz, 3H: CH3 ethyl in 4); 1.40 (s, 1H:OH to 1); 1.71 (s, 3H: CH3); 1.88 and 2.45 (2 mts, 1H each: CH2 at 6); 2.00 (s, 3H: CH3); 2.06 and 2.18 (2 dd, J = 16 and 9 Hz, 1H each: CH2 at 14); 2.60 (q, J = 7.5 Hz, 2H: CH2 ethyl at 4); 3.84 (d, J=7Hz, 1H:H at 3); 4.14 and 4.30 (2d, J=8.5Hz, 1H each: CH2 at 20); 4.26 (d, J=
0.5Hz, 1H:OH at 10); 4.40 (dd,J=11 and 7Hz, 1H:H at 7); 4.90 (dwide,J=10Hz,1H:Hen5);4.94(twide,J=9Hz,1H:Hen13);5.12(d,J=0.5Hz,1H:H
en10);5.58(d,J=7H[z,1H:Hen2);7.45(t,J=7.5Hz,2H:OCOC6HsHen meta); 7.60 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.09 (d, J=7.5Hz, 2H:
OCOC6Hs H in ortho).
The carbonate-] 13,2a bi ~ bil. ~ y) -713,13a epoxy-51 '~, 20 methoxy-acetoxy-1013 oxo-9 1~ ylv..y 1a taxene-ll can be prepared as next:
To a solution of 2.0 g of carbonate-11'~,2f~1,.,~'ybilylo~y)-7~13 epoxy-51'i,20 hydroxy4~, I.é~ ~a~,~tu~y 10~3 oxo-9 taxene-ll in 90 cm3 of dil, lllu ~ 'we add 3.37 g of 4 ~ .r',,-' and 3.64 cm3 anhydride ~ IV ~; UII; ~,. The reaction medium is heated to an I, close to of 42C for 8 hours. 50 cm3 of a saturated aqueous solution of chloride of s ~ Jdium and 50 f m3 of ~ '''' The organic phase is decanted, washed with 2 times 40 cm3 of an aqueous solution saturated with sodium chloride then dried over sulphate of ~ filt ~ ed and concentrated to dryness under reduced pressure (2.7kPa) at 40C. We obtain 2.6 g which ron purifies by ~ hl ~. ' ~ on 100 g of silica (0.063-0.2 mm) contained in a column 3 cm in diameter (eluent:
ethyl acetate- ~, '': 5-95 by volume) by collecting fractions of I2 cm3. The fractions containing only the desired product are combined and I
dry under reduced pressure (2.7 kPa) at 40C. 1.97 g of carbonate-1~3,2 are obtained b ~ (~ ll.rbilyloxy) -7; '~, 13 epoxy-51' ~, 20 methoxyacetoxy 10 ~ oxo-9 propanoyl-oxy4 taxene-ll under ~ elm of a white meringue and whose physical are as follows:

wo ss/33736 Z 1 (~ O 6 5 1 . ~l~rh~ a - 1H NMR spectrum (400 MHz, CDCI3, ~ in ppm): from 0.50 to 0.75 (mt, 12H:
CH2 ethyl); 0.94 (t, J=7.5 Hz, 9H: CH3 ethyl); 1.03 (t, J=7.5Hz, 9H.CH3 ethyl);
1.21 (mt, 6H: CH3 and CH3 ethyl); 1.28 (s, 3H: CH3); 1.75 (s, 3H: CH3); 1.90 and 2.60 (2 mts, 1H each CH2 er 6); 2.13 (s, 3H: CH3); 2.15 and 2.38 (2 dd, J = 16 and

9 Hz, 1H each: CH2 at 14); 2.43 (mt, 2H: CH2 ethyl); 3.43 (d, J = 5.5 Hz, lH:
H in 3); 3.51 (s, 3H:OCH3); 4.18 (s, 2H: OCOCH2O); 4.46 (dd, J =11 and 7Hz, 1H: H at 7); 4.48 and 4.65 (2d, J=9Hz, 2H: CH2 at 20); 4.51 (d, J=5.5Hz, 1H:Hen2); 4.93(dlarge,J=1011z,1H:Hen5);5.02(t,J=9Hz,1H:Hen13);
6.51 (s, 1H:H in 10).
Cdrbonate-1~,2 bi,(li;~l~ lu~)-7~,13a-epoxy-5~,20-hyd~oxy-4a ;a~u~~-10~oxo-9 taxene-ll can be prepared as follows:
To a solution of 4.12 g of carbonate-1~,2a dihydroxy~a,l0 bD(li;;~ lu~)-713,13a-epoxy-5~,20-xo-9-taxene-ll in 80 cm3 of pyridine, is added, with stirring and at a t ~ dtul ~ close to 0C, 2 g of sieve '~ 'c 4A powder and 2.86 cm3 of chloride ~ au ~ a ~,. The mixture reaction is stirred for 15 minutes at a t ~, .ll ~ h, .a ~ close to 0C then let the i, 't, of the reaction maieu rise gently to a tc ~ ~ alu ~ e close to 20C. After 4 hours of agitdtion at a l ~ lllpéla ~ close to 20C, 50 cm3 of a saturated aqueous solution of chloride 'I and 100 cm3 of ~ 'The organic phase is decanted, washed with 2 times 40 cm3 of a saturated aqueous solution of chloride of 2 times 25 cm3 of a solution saturated aqueous solution of copper sulphate and 2 times 25 cm3 of a saturated aqueous solution of sodium chloride then dried over sulphate of v 'filtered and concentrated to dry under reduced pressure (2.7 kPa) at 40C. 5.3 g are obtained which are purified by ',, on 200 g of silica (0.063-0.2 mmj contained in a column of 4cm in diameter (eluent: ethyl acetate-~ - ': 25-75 by volume) in collecting fractions of 12 cm3. Fractions containing only the desired product are réurlies and ~ dry under reduced pressure (2.7 kPa) at 40C. We obtain 4.21 g of carbonate-1~,2a l,i;,(-~1u~)-7~,13a-epoxy-5~,20-hydroxy-4a ''. ~ a ~ -10 ~ oxo-9 taxene-ll in the form of a white meringue and whose physical are as follows:
- N.M.R. spectrum. 1H (400 ~ Hz, CDCI3, ~ in ppm): 0.59 (mt, 6H: CH2 ethyl);
0.73 (mt, 6H: CH2 ethyl); 0.91 (t, J = 7.5 Hz, 9H: CH3 ethy; 1.02 (t, J = 7.5 Hz, 9H: CH3 ethyl); 1.15 (s, 3H: CH3); 1.18 (s, 3H: CH3); 1.65 (s, 3H: CH3); 1.98 and 2.51 (2 mts, 1H each: CH[2 at 6); 2.15 (s, 3H: CH3); 2.54 and 2.72 (2 dd, 2 1 9~65 WO 95~33736 r ~ ~ Ir S

.~o"e~L~. J = 16 and 9 Hz and J = 16 and 3 Hz, lH each: CH2 at 14); 2.93 (s, 1H:OH at 4); 3.03 (d, J=5Hz, 1H:H at 3); 3.51 (s, 3H:OCH 3 ); 4.16 (mt, lH:
H in 7); 4.17 (AB,J=:18Hz, 2H: OCOCH2O); 4.37 (d, J=5Hz, 1H:H at 2);
4.54 (AB, J=9Hz, 2H:CH2 at 20); 4.76 (d wide, J=10Hz, 1H:H in 5); 4.81 (dd,J=9et3Hz,1H:Hen13);6.51 (s,1H:Hen10).
Carbonate-1~,2a-dihydroxy-4a,101A~ b~(kié11~ 1vAy)-7lA~,13a epoxy-51A~,20 oxo-9 taxene-l 1 can be prepared as follows:
At urle solution of 0.400 g of IJ;o (kiél;~.ybilyl~vAy)-7~l3a epoxy-51A~,20 oxo-9 '~ vAy-llA ~, 2a, 4a, 10 ~ taxene-ll in 10 cm3 of dL ~ l lv--', we add, under stirring and at an i . 6 close to -78C, 1 cm3 of pyridine and 0.560 g of l.il, l..,.v: ..r The reaction mixture is stirred for 2 hours at t ~, ..llJél ~
close to -78C then the reaction medium is allowed to rise gently to a . 't, close to 20C. 30 cm3 of a saturated aqueous solution of chloride .1'_ and 20 cm3 of dL ~ I ~ .. The gold phase ~ anique is 15 decanted, washed with 2 times 40 cm3 of a saturated aqueous solution of chloride of sodium then dried over lv sulfate, filtered and concentrated to dryness under pressure reduced (2.7 k~a) at 40C. 0.400 g of a yellow mixture is obtained which is purified by ~v. on 25 g of silica (0.063-0.2 mm) contained in a column of 2cm in diameter (eluent: ethyl acetate-~,'': 20-80 by volume) in 20 picking fractions dle 10 cm3. L~w fractions containing only the desired product are combined and, 6w dry under reduced Fession (2.7 k ~ Aa) at 40C. We obtain 0.330 g ae carbonate-llA~,2a dihydroxy-4a,10lA~ biO(IIi6,ilyb;1~1uAy)-7lA~,13a epoxy-513.20 oxo-9 taAene-ll in the form of a white merinvue and whose . - ... ~.. ;~I ,.l....
physical are as follows:
- 1H NMR spectrum (400 MHz, CDC13, ~ in ppm): 0.54 (mt, 6H: CH2 ethyl);
0.63 (mt, 6H: CH2 ethyl); 0.92 (t, J = 7.5 Hz, 9H: EthyV CH3; 1.03 (t, J = 7.5 Hz, 9H: CH3 ethyl); 1.11 (s, 3H: CH3); 1.19 (s, 3H: CH3); 1.72 (s, 3H: CH3); 1.98 and 2.46 (2 mts, 1H each: CH2 at 6); 2.06 (s, 3H: CH3); 2.55 and 2.66 (2 dd, .w~li~. J = 16 and 9 Hz and J = 16 and 3 Hz, lH each: CH2 at 14); 3.00 (s, lH:OHen4);3.13(d,J=5Hz,lH:Hen3);4.06(dd,J=llet7Hz,lH:Hen 7);4.20(d,J=2.5Hz,1H:OHen10);4.33(d,J=5Hz,1H:Hen2);4.55(AB, J=9Hz,2H:CH2en20);4.76(dlarge,J=1OHz,1H:Hen5);4.82(dd,J=9et 3Hz,1H:Hen13);5.19(d,J=2.5Hz,1H:Hen10).
Le 1~(~ ,Ay)-7~,13a epoxy-5~,20 oxo-9 i~ vAy-1~,2a,4a, 1013 taxene-ll can be prepared in the following way:

2~906J 1 wo 95~33736 P~llr~l .

To a solution of 3 ,, ~ 30 g of epoxy-5 ~, 20 oxo-9 1 'y ~ Lw ~ y-113,2a, 4a, 1013.13a ilic~ ilylu~y-7~ taxene-11 in 100 cm3 of dichlul~ '~, we add, under agitation and at an i , '~; close to 0C, 1.20 cm3 of pyridine and 2.48 cm3 of ~, LIuluhié ~ 'The reactiannel mixture is stirred for 3 hours at a 5 i . ~ close to 0C. 100 cm3 of a saturated aqueous solution of sodium chloride. The organic phase is decanted, washed with 2 times 100 cm3 of a saturated aqueous solution of sodium chloride then dried over sulphate of filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We obtain 5.34 g of an orange oil which is purified by .,} ~ on 300 g of silica (0.063-

10 0.2 nm) contained in a column 3 cm in diameter (eluent: ethyl acetate-~ yl '' ~: 25-75 by volume) collecting fractions of 40 cm3. Fractions containing only the ch.erché product are combined and ~.: Ul ~ c6.1 ~ 5 dry under pressure reduced (2.7 ~ Pa) at 40C. 4.18 g of 1~('yl~;lyl~y)-7~i,13a epoxy-5~.20 oxo-9 i '.~dlu~.yl~2a~4a~lo~ taxene-11 in the form of a meringue 15 white and whose . ,,~s~ physics are as follows:
- 1H NMR spectrum (400 r~Hz, CDCl3, o in ppm): 0.53 (mt, 6H: CH2 ethyl);
0.75 (mt, 6H: CH2 ethyl); 0.91 (t, J=7.5 Hz, 9H: CH3 ethyl); 1.01 (s, 3H: CH3);
1.03 (t, J=7.5 Hz, 9H: CH3 ethyl); 1.09 (s, 3H: CH3); 1.63 (s, 3H: CH3); 1.97 (s, 3H: CH3); from 1.95 to 2.10 and 2.40 (2 mts, 2H each: CH2 at 14 and CH2 at 6); 3.17(s,1H:OH);3.18(d,J=5.5Hz,1H:Hen3);3.43(d,J=1OHz,1H:OHer12);
3.76(dd,J=lOet5.5Hz,lH:Hen2);3.96(dd,J=llet6Hz,lH:Hen7);4.10 (s,1H:OH); 4.18 (d, J=3~z, 1H.OH in 10); 4.44 and 4.73 (2d, J=9Hz, lH
each: CH2 in 20); 4.64 (d wide, J=10Hz, lH:H in 5); 4.74 (mt, 1H:H at 13);
5.14(d,J=3Hz,1H:Hen10).
FXF.MPJ F 2 To a solution of ~0.5 mg of tert-l,u~y.,~l,ullylal~lu-3 hydroxy-2 pbenyl-3 ~ -r- (2R,3S) dlepoxy-5~3,20 hydroxy-1~ u~y~ u~.y-10~ oxo-9 ~ . ylu~y-4a (~l6r.uylu~y-2)-2a i-~l '' .~lu~y-7~ taxene-11 yle 13a in 0.2 cm3 of '~' and 0.025 cm3 of i 'y~, we add 45 mg of sodium chloride and a sieve spatula ~llul~uL8u~ activated 4A. the mixture obtained is port ~ at reflux, under. '` ~ i argon, for 2 hours. After l., r., 'to a,' ~ near 20C, the solvar ~ ts are evaporated under reduced pressure (0.27 ~ Pa) at lme i, ~ i close to 40C, the solid residue is taken up with 5 cm3 of ~'-'~'' ~, filtered through cotton and rinsed with 5 cm3 of a 2 1 9065 ~
~ W<~95/33736 P~,l/r~ .fa ethyl acetate-dichlol mixture. ' (50-50 in Yolumes). Organic phases are ~ .w under reduced pressure (0.27 kPa) at a t ~ e ~ ~ uu close to 40C.
- We thus oWent 17.1 mg of a yellow meringue that we could ~ ifie by ~ Iu, preparative on a thin layer [2 plates 1.6 ~ Merck, Kieselgel 60F254, thickness 0.25 mm, deposit in solution in the diclllu., 'éluint mixture methanol-dichloro-meth ~ ine (6-94 by volume)]. After elution of the zone Wll~ r '' to the main product by a methanol~ mixture (10-90 in volumw), filtration on sintered glass, then,./.~ulo.liull solvents under prwsion reduced (0.27 kPa) to an i . e close to ~ 0C, we obtain 10.0 mg of tert-butu ~ r ~ ull ~ 3 hydroxy-2 phenyl-3 ~ . (2R,3S) of epoY~y-5~,20 hydroxy-1~;h.~A~a~,é~u~y-10~ methylene-7,8~ oxo-9~.,, ylu~Ly4a 6.lvylu ~ y-2) -2a nor-19 taxene-ll yl-13a in the form of a white lake whose are as follows:
- 1H NMR spectrum (400 MHz, CDC13, o in ppm): 1.18 (t, J = 7.5 Hz, 3H: CH3 ethyl); 1.22 (s, 6H: C-13); 1.32 (s, 9H: C(CH3)3); 1.41 (mt, 1H:H at 7); 1.69 and 2.23 (2 mts, l~each: CH2 at 19); 1.81 (s, 1H:OH to 1); 1.85 (s, 3H: CH3);
2.12 and 2.50 (Iw~.,li~. d and dt, J = 16 and J = 16 and 4.5 Hz, lH each: CH2 in 6); 2.25 and 2.39 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 2.63 (mt, 2H: CH2ethyl); 3.23 (mt, 1H:OH at 2'); 3.52 (s, 3H: ()CH3); 4.03 (d, J=7Hz, lH:H
in 3); 4.12 and 4.44 (2d, J=9Hz, 1H each: CH2 at 20); 4.20 (AB limit, J = 16 Hz, 2H: OCOCH2O); 4.62 (mt, 1H:H at 2'); 4.70 (d, J=4Hz, 1H:H at 5); 5.22 (mt,1H:Hen3');5.28(d,J=1OHz,1H:CONH);5.58(d,J=7Hz,1H:Hen2);
6.23(tlarge,J=9Hz,1H:Hen13);6.41(s,1H:Hen10);7.18(dd,J=5and3.5 Hz, lH:H at 4 of thenoyl-2); from 7.30 to 7.50 (mt, 5H: H ~UVIII~ at 3'); 7.67 (d wide, J = 5 Hz, lH: ~ en 5 of thenoyl-2); 7.96 (d wide, J=3.5Hz, lH:H in 5 thenoyl-2).
The tert-l ye ~ l ~ ull ~ -3 hydroxy-2 phenyl-3 ~ I ~. -(2R,3S) epoxy-5~,20 hydroYy-113 lll~alu~,6tv~y-10~oxo-9~lv~OIlvylu~y4a (a1;..uylu,.y-2)-2a; " ~ ''' Jlu~y-7~ taxene-ll yl-13a can be 30 prepared as follows:
- A solution of 75 mg of tert-~uv~bvll~1-3 (4-methoxy-phenyl)-2 phenyl4 IY~7rlliriinr 1,3~,~ul u~y' 5 (2R,4S,5R) of epoYy-5~,20 hydroxy-l~
,lllv~ y-1013 OXO-9 ~ l ,ylu,-y-4a (al6LvyluAy-2)-2a (Hnuululllé
v~y-713 taxene-ll yle-13a in 0.77 cm3 of an acid solution ~LIvlll~ u~
35 0.1N in ethanol is stirred at one hour, .. ~ the ~ l ~ the neighbor of 5C for 2 heurw. the 21 9~65 1 wo 95/33736 . ~llr~

reaction mixture is then diluted with 10 cm3 of di ~; ~ lu ~ ull ~ 6a ~ -c, washed twice 1 cm3 of distilled water. After extraction of the aqueous phase with 1 c~n3 of dichl ~ .u, r, ~ a. ~ the, the organic phases are ". ~, ..1.1 ~., dried over sulphate of mrt~P~ m filtered on sintered glass and ws under reduced pressure (0.27 kPa) at S a ~ la ~ u ~:: close to 40C. 74.4 mg of a yellow lake are thus obtained which are purified by .1... ~ at Fession r ,'', on 8 g of silica (0.063-0.2mm) contained in a column 1.5 cm in diameter (g; ~ dient of elution:
ethyl acetate-~ l - '' from 5-95 to 20-80 by volume) by recueiaant fractions of 8 cm3. The fractions containing only the desired product are combined and ~ U .. ~ ~ dry under reduced pressure (0.27 kPa) at 40C for 2 hours. We oWent thus 56.3 mg of tert-' y~ u,"~' -,-3-hydroxy-2-phenyl-3-propionate-(2R,3S) epoxy-5~,20-hydroxy-113 IlI~,alUAy~ UAy-10~ oxo-9 propanoyloxy-4a ~ ..uyluAy-2)-2a i-~ l ''' y ~ uAy-7 ~ taxene-ll yle-13a in the form of a pale yellow meringue whose, are the following:
- 1H MN R spectrum (400]\~Hz, CDC13, o in ppm): 1.20 (s, 6H: CH3); 1.22 (t,J = 7.5 Hz, 3H: CH3 ethyl); 1.36 (s, 9H: C(CH3)3); 1.71 (s, 1H4:OH in 1); 1.89 (s, 3H: CH3); 2.05 (s, 3H: CH3); 2.25 and 2.86 (2 mts, 1H each: CH2 at 6);
2.33 (d, J=9Hz, 2H: CH2 at 14); 2.66 (mt, 2H: CH2 ethyl); 3.28 (d, J=5Hz,1H:OHen2');3.52(s,3H:OCH3);3.90(d,J=7Hz,1H:Hen3);4.20(AB
limit, J = 16 Hz, 2H: OCOCH2O); 4.27 and 4.50 (2d, J= 9 Hz, lH each: CH2 in 20); 4.61 (mt, 1H:H at 2'); 4.88 (d wide, J=10Hz, 1H:H in 5); 5.20 (d wide, J=lOHz,lH:Hen3');5.30(d,J=lOHz,lH:CONH);5.50(dd,J=lOet7Hz, 1H:Hen";5.65(d,J=7Hz,1H:Hen2);6.18(tlarge,J=9Hz,1H:Hen13);
6.70 (s, 1H:H in 10); 7.18 (dd, J=5 and 3.5 Hz, 1H:H at 4 of thenoyl-2); of 7.30 to 7.50 (mt, 5H: H -., in 3'); 7.69 (dd, J= 5 and 1.5 Hz, lH: H in 5 of the thenoyl-2); 7.92 (dd, J = 3.5 and 1.5 Hz, lH: ~ en 5 of thenoyl-2).
The tert-l. yu~bu~yl-3-(4-methoxy-phenyl)-2-phenyl-4~
~1~UAY' 5 (2R,4~i,5R) epoxy-5~,20 hydroxy-113 'y~ Ay-10~ oxo-9 ~, u~!~u-uyluAy-4a (~uylu.~y-2)-2a h;n~l~tl - ~r ylUAy-713 taxene-ll yl-13a can be prepared in the following way:
To a solution of 55.2 mg of epoxy^5~,20-dihydroxy-1~,13a Ill~aluAy~l~..,tuAy-10~ OXO-9 lJ~ yluAy-4a (thenoyloxy-2)-2a iHnuu.ul~a.~.c SUIIUII ~ IUAY-7 ~ taxene-ll in 0.1 cm3 of anhydrous toluene, is added to the ~: C6 ~ ~ '41 mg of tert-1 acid, uluAy., al u..yl-3 (methoxy4 phenyl) -2-phenyl-4, '' ~ 1,3 35 ~ L, UAYIi ~ U ~ 5 (2R, 4S, 5R), 26 mg of di ~ ul.., Ayl- _.l ~ l:.",:.i ~. and 3 mg of ~ W09Sf3373G 2 ~ 9065 ~ r--llr~ a N,N-di...c~.y' ~4 pyndine. The reaction mixture is stirred for 2 hours, UNDER I ~ `e of argon, at a t ~ Jél ~ f ~ ue close to 20C, then deposited on a column of ~,Iu~ ~ . 'to pressure~.. . ;.l (15 g of silica (0.063-0.2 mm) contained in a 1.5 cm diameter column (elution gradient: acetate ethyl ~ hluL. ' from 5-95 to 10-90 by volume) by collecting fractions of 10 cm3). The fractions containing only the desired product are combined and f ~, ~ dry under reduced ression ~ (0.27 kPa) at 40C for 2 hours. We thus obtains 75.3 mg of tert-bu~uAy~ bull,rl-3 (methoxy4 phenyl)-2 phenyl4 ,..-,.,1,.1.,. ~ 1,3 ~ o ~ bui ~ y- 5 (2R, 4S, 5R) epoxy-51 '~, 20 hydroxy-113 methoxy-acetoxy-101'~ oxo-9 ~1u~ lvylu~y4a (~vylu~y-2)-2a ,.inuu~
oxy-71'~ taxene-ll yle-13a in the form of a white meringue whose characteristics the following are:
- 1H NMR spectrum (400 MHz, CDC13, ~S in ppm): 1.04 (s, 9H: C(CH3)3);
1.04 (t, J = 7.5 Hz, 3H: CH3 ethyl); 1.14 (s, 3H: CH3); 1.16 (s, 3H: CH3); 1.61(s,1H:OH to 1); 1.68 (s, 3H: CH3); 1.81 (s, 3H: CH3); from 2.00 to 2.30 (mt, 4H:
CH2 ethyl and CH2 at 14); 2.03 and 2.80 (2 mts, 1H each: CH2 at 6); 3.50 (s, 3H:
OCH3); 3.77 (d, J=7Hz, 1H:H at 3); 3.81 (s, 3H: ArOCH3); 4.13 (AB limit, J=16Hz, 2H: OCOCH20); 4.18 and 4.39 (2d, J=9Hz, 1H each: CH2 at 20);
4.48(d,J=4Hz,lH:H[en2');4.78(dlarge,J=lOHz,lH:Hen5);from 5.35to 5SO(mt,2H:Hen3'etllen7);5.55(d,J=7Hz,lH:Hen2);5.96(tlarge,J=9 Hz,1H:Hen13);6.34(mt,1H:Hen15');6.56(s,1H:Hen10);6.88(d,J=8 Hz, 2H: H .u, , ortho to OCH3); 7.13 (dd, J=5 and 3.5 Hz, lH:H in 4 thenoyl-2); from 7.30 to 7.45 (mt, 5H: H ~u.~ i4u~,~ in 3'); 7.36 (d, J=8Hz, 2H:
H alulll ~.li4,, ~., in meta dtl OCH3); 7.62 (d wide, J=5 Hz, lH:H in 5 of thenoyl-2); 7.80 (broad d, J=3.5]Hz, 1H:H at 5 of thenoyl-2).
Epoxy-51~,20-dihydroxy-113,13f~,a~u~y~tv~y-lOlfi oxo-9~ylu~y-4a (11~vylu~.y-2)-2f~.rlu~y-71fi taxene-ll can be prepared from the following way:
To a solution of 50 mg of epoxy-5~,20~,tl~u~y~w~y-lOIf~oxo-9 I,.u~, Jylu,.y-4a (thenoyloxy-2)-2ft trihydroxy-11~,7l~,13a taxene-ll in 0.5 cm3 of di ~, llv ........... anhydrous and 0.0255 cm3 of py ~ idine, maintained under ~ v ~ .`.c ~
of argon, to an i . ~ close to 0C, add 0.0265 cm3 drop by drop arlhydride i.inuo .. I ~ r ..; ~ The orange solution obtained is stirred 10 minutes to a t~. ~ close to 0C, 45 minutes at a .c...l c. c near to 20C, p ~ us: "0.1 cm3 of a methanol / di ~ l.lu .. '(5/95 in Wo 95n3736 2 1 ~ 0 6 5 1 1~I/rl~

olumes). The solution is deposited on a column of ~: lu ~ ~, 'at pressure i ~ (10 g of 5ilica (3.063-0.2 nm) contained in a column of 1.5 cm in diameter (elution gradient: methanol-di., LIu.. ' from 2-g8 to 5-95 in Yolumes) by collecting fra ~ tions of 8 cm3). Fractions containing only the product sought are combined and ~ ~ _O dry under reduced pressure (0.27 kPa) to 40C for 2 hours. 55.2 mg of epoxy-513,20-dihydroxy-1~,13a are thus obtained ll._;llu~ ~Ay-10~ oxo-9 ~ IwLy~a (~ vylu~y-2)-2a sullull~lu~y-7i3 taxene-l 1 in the form of a white meringue.
Epoxy-513,20-trihydroxy-1~,7~,13a If.~ u~y~l~,Glu~y-10~oxo-9-propanoyl-oxy-4a (~i~_.luylu~y-2)-2a taxene-ll can be prepared as follows:
To a solution of 0.302 g of epoxy-513.20 hydroxy-l ~ ll.611lu ~, tuAy-10 oxo-9 ~,.,. ylu,.y-4a (thenoyloxy-2)-2a b;O(~;llyl~ lu~.y)-7~,13a taxene-ll in 5 cm3 of ~ '' u ~ l._; L ~, we add, at an i, ~ close to 20C, 6 cm3 of complex i '~' acid nuull ~ yl', (Et3N.3HF). The reaction mixture is stirred for 24 hours at a ~ Iuu ~ close to 20C then 50 cm3 are added of dichlulul .._; h ~ ul., and 100 crn3 of an aqueous solution satufée in hydrogeno-sodium carbonate. The organic phase is decanted, washed pa ~ f 2 times 40 cm3 of a Saturated aqueous solution of sodium chloride then dried over sulphate ~.
filtered and concentrated to dryness under reduced pressure (2.7 kPs) at 40C. We oWent ainOi 0.24 g of epoxy-5 ~, 20 trihydfoxy-113,713,13a Ir._ ~ lu ~ u ~ Ly-1013 oxo-9 propanoyl-oxy-4a (Ih_~.uyluAy-2)-2a tOxene-ll in the form of a white meringue whose ' , are the following:
- N.M.R. spectrum. 1H (400 MHz, CDCI3, o in ppm): 1.07 (s, 3H: CH3); 1.10 (s, 3H: CH3); 1.22 (t, J = 7.5 Hz, 3H: CH3 ethyl); 1.62 (s, 1H:OH to 1); 1.69 (s, 3H: CH3); 1.89 and 2.63 (2 mts, 1H each: CH2 at 6); 2.03 (d, J=5.5Hz, lH:
OHen13);2.07(s,3H:CH3);2.27(d,J=9Hz,2H:CH2en14);2.35(d,J=4.5 Hz, 1H:OH in 7); 2.59 (mt, 2H: CH2 ethyl); 3.52 (s, 3H:OCH3); 3.84 (d, J=7 Hz, 1H:H in 3); 4.23 and 4.43 (2d, J=9Hz, 1H each: CH2 at 20); 4.25 (AB
limit, J = 16 Hz, 2H: OCOCH2O); 4.49 (mt, 1H:H at 7); 4.87 (mt, lH:H in 13); 4.95 (d wide, J=10Hz, l]H:H in 5); 5.53 (d, J=7Hz, 1H:H at 2); 6.42 (s, lH:Hen1O);7.14(dd,J=4.5et3.5Hz,1H:Hen4duthenoyl-2);7.61 (dd,J=
4.5 and 1.5 Hz, 1H:H at 5 of thenoyl-2); 7.83 (dd, J = 3.5 and 1.5 Hz, lH:H in 3 of the thenoyl-2).

2 1 9~65 ~
w0 95~33736 r~~ I.sa Epoxy-513.20 llydroxy-l~u~y~.tv~y-10l3 oxo-9~ylu~y-4 (lrl.,r.vylu~y-2)-2 I i .(~bilylu~y)-713,13 taxene-l l can be prepared from the following way:
Has a solution, n of 0.5 g of epoxy-513,20 dihydroxy-1 ~, 10 ~ oxo-9 propanoyl-oxy4 (~ v.~lu.~y-2)-2a bi~ ybilrlu~.y)-7~,~3 taxene-11 in 10cm3 of py-ridine ~ 0.286 cm3 of chloride of l ~ 0; 1 ~ u ~ y ~ ylu is added to an i close to 0C. Melan ~ e reaction is stirred for 10 hours at a t ~
close to 20C then 100 cm3 of di ~, llu ~ and 50 cm3 of a solution are added aqueous saturated with hl chloride...~ "'.. The organic phase is decanted, washed with 2 times 40 cm3 of an aqueous solution saturated with chloride then dried over sulphate ~ 'filtered and concentrated to dryness under reduced pressure (2.7 kPa) to 40C. The residue obtained (0.6 g) is purified by ', ~,' on 50 g of silica (0.063-0.2 mm) contained in a cylinder 2 cm in diameter (eluent: acetate ethyl-~; y ~ '': 5-95 by volume) by collecting fractions of 10 cm3. The fractions containing only the product sought are combined and ,: ~,~ dry under reduced pressure (0.27kP~) at 40C. 0.320 g of epoxy-513.20 hydroxy-l ~ are obtained.
lllu~Lyl~;.,tv~y-1013 oxo-9 ~ylu~y-4 (~ylu.~y-2)-2 1~ ~ylu~y)-713.13 taxene-l 1 in the form of a white meringue whose ~, physical are as follows:
- 1400 MHz lH NMR spectrum, CDC13, ~ in ppm): from 0.50 to 0.70 (mt, 12 H,:
CH2 ethyl): 0.92 (t, J = 7.5 Hz, 9H: CH3 ethyl); 0.98 (t, J=7.5Hz, 9H: CH3 ethyl); 1.09 (s, 3H: CH3); 1.15 (s, 3H: CH3); 1.27 (t, J = 7.5 Hz, 3H: CH3 ethyl in 4); 1.59 (s, 1H:OH to 1); 1.65 (s, 3H: CH3); 1.85 and 2.52 (2 mts, 1H each:CH2 at 6); 2.07 and 2.18 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 2.08 (s, 3H:
CH3); 2.58 (mt, 2H: 4-CH2ethyl); 3.50 (s, 3H:OCH3); 3.73 (d, J=7Hz, lH:
H in 3): 4.13 (AB limit, J=16 Hz, 2H: OCOCH2O); 4.20 and 4.41 (2d, J=9Hz, lH each: CH2 in 20); 4.49 (dd, J=11 and 7Hz, 1H:H at 7); 4.89 (wide tee, J=9 Hz,1H:Hen13);4.91(dlarge,J=1OHz,1H:Hen5);5.53(d,J=7Hz,1H:H
in 2); 6.51 (s, 1H:H in 10); 7.12 (dd, J=4.5 and 3Hz, 1H:H at 4 of thienoyl-2);
7.61 (d, J=4.5 Hz, 1H:H at 5 of t13ienoyl-2); 7.83 (d, J=3Hz, lH:H in 3 - thienoyl-2).
Epoxy-5~,20-dihydroxy-113,10~oxo-9~JIu~lvylv~r 4c4(2-thenoyloxy)-2 Li ~ i.,; llyLlylu ~ y) -713,13 ~ taxene-ll can be prepLré as follows: A solution of 0.5 g of ~ bull. ~ ldiuAy-1 ~, 2 epoxy-5 ~, 20 methoxy-35 acetoxy-1013 oxo-9~l~I ylu~y-4 bb(l~ yb;lylv~y)-713,13 taxene-11 in 21 ~0051 wo sst33736 r- l~r 20 cm3 of t; t ~ y ~ Luf ~ ulc, under I ' ` ~ of argon, at ume ~ luue close to -78C, 1.5 cm3 of a lM solution of 2 ~ '' is added to the t; ~ dllt ~ Ur, The reaction mixture is stirred for 35 minutes at a ~: close to -78C p ~ us 1 cm3 of a saturated aqueous solution is added in 5 chloride cl' ~ At a t ~, .ll ~ alul ~: close to 20C, 10 crn3 of a saturated aqueous solution of i chloride and 50 cm3 of di ~, llvlulll ~ lc. The organic phase is decanted, washed with 2 times 10 cm3 of a saturated aqueous solution of sodium chloride then s ~ ched on sulphate of the filtered and conoentrée with dry under reduced pressure (2.7 kPa) at 40C. 0.65 g of a solid is obtained which is purifies by ~, u, ~ ur 90 g of silioe (0.063-0.2 mm) contained in a column of 1 cm in diameter ~ e (eluent: ethyl acetate- ~: y. '' ~: 10-90 in volumes) by collecting fractions of 10 cm3. Fractions containing only the product sought are combined ~ t ~ < w ~ dry under reduced pressure (0.27 kPa) to 40C. 0.511 g of el ~ oxy-5 ~, 20 &ydroxy-113,10 ~ oxo-9 ~, lu, ~, ~ u.oylu ~ y4a (~, .. vylu ~ y-2) -2a bb ( ~ bil ~ lu ~ y)-713,13a taxene-ll in the form of a meringue Wanche whose ~u,-- t'. ;~ u - physics are as follows:
- 1H NMR spectrum (600 I~Hz, CDCI3, o in ppm): 0.57 (mt, 6 H: ethyl CH2);
0.68 (mt, 6H: CH2 eb-yl); 1~.95 (t, J=7.5 Hz, 9H: CH3 ethyl); 1.01 (t, J = 7.5 Hz, 9H: CH3 ethyl); 1.07 (s, 3H: CH3); 1.17 (s, 3H: CH3); 1.27 (t, J = 7.5Hz, 3H: CH3 ethyl in 4); 1.73 (s, 3H: CH3); 1.90 and 2.47 (2 mbs, lH each: CH2 in 6); 2.02 (s, 3H: CH3); 2.09 and 2.18 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14);
2.60 (mt, 2H: CH2 eblyl at 4); 3.82 (d, J=7Hz, 1H:H at 3); 4.24 and 4.44 (2d, J = 9 Hz, lH each: CH2 in 20); 4.26 (d, J=0.5Hz, 1H:OH at 10); 4.42 (dd, J=llet7Hz,lH:Hen7);4.93(dlarge,J=lOHz,lH:Hen5);4.97(tlarge,J=
9Hz,1H:Hen13);5.13(d,J=0.5Hz,1H:Hen10);5.53(d,J=7Hz,1H:H
in 2); 7.15 (dd, J=4.5 and 3 Hz, 1H:H at 4 of b-ienoyl-2); 7.63 (d, J=4.5Hz, lH: H in 5 of theoyl-2); 7.85 (d, J = 3 Hz, 1H:H in 3 of thienoyl-2).
E~F.MPLF. 3 To a solution of 154 mg of tert-l~utv,.y1aLbu.lyl~ iu~0-3 hydroxy-2-phenyl-3 ~ (2R, 3S) of benz ~ yloxy-2a 1, ylu ~ -4a epoxy-513,20 hydroxy-l ~
J ~ y-1013 OXO-9 i 1 ~ 1u ~ y-713 taxene-ll yl-13a in 2 cm3 of; ''- and 200 ~e toh~ url . we add succ.~ . 96mg of sieve '' ~, 4A powder, 225 mg of sodium chloride. The mixture reaction is maintained under stirring at one. c close to 75C during 2lsa6sl WO 9S133736 r ~ r 5'~ ~Ja 5 hours p us, at a ~ <, Lu e close to 20C, added with 15 cm3 of d; ~, l-lu-- and 10 crl3 of a saturated aqueous solution of sodium chloride. The - organic phase is decanted, washed with 2 times 20 crn3 of a saturated aqueous solution of sodium chloride then dried over sulphate of ~ ~ ~ r ~. l, filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. 133 mg is obtained which is purified by u}~. ,, .' on 80 g of silica (0.063-0.2 mm) contained in a column of 1 cm in diameter by eluting with a di~~ mixture. '' methanol (98-2 in volumes) and collecting fractions of 10 cm3. Fractions containing only the product sought are combined and dry ~ ~ s under reduced pressure (2.7 kPa) to 40C. We obtain 63 mg of tert-bu ~ wy ~ ~ ul, u ~ .. ulo-3 hydroxy-2 phenyl-3 ~ul (2R,3S) of benzoyloxy-2a buLuluylu~y~a epoxy-51'i,20 hydroxy-ll'i ~ -0Ll ~ u ~ y ~ éLu ~ y-101'i methylene-71'i,8 nor-l9 oxo-9=taxene-11 yl-13a in the form of a white meringue elt whose f - - - ', physical are as follows:
- 1H NMR spectrum (~00 MHz; CDC13; o in ppm): 0.92 (t, J = 7.5 Hz, 3H: CH3 propyl); 1.26 (s, 6H: CH3); 1.31 (s, 9H: C(CH3)3); 1.42 (mt, 1H:H at 7);
1.71 and 2.26 ~2 mts, lH each: CH2 at 19); from 1.60 to 1.85 (mt, 2H: CH2 of propyl); 1.86 (s, 3H: CH3); 1.88 (s, 1H:OH to 1); 2.12 and 2.50 (Ica~.,Li~.d wide and mt, J = 16 Hz, lH each: CH2 at 6); 2.23 and 2.39 (le~Li~. mt and dd, J = 16 and 9 Hz, 2H: C~2 in 14); 2.49 and 2.65 (2 mts, lH each: OCOCH2 from propyl); 3.25 (mt, 1H: ~H at 2'); 3.51 (s, 3H:OCH3); 4.05 and 4.32 (2 d, J = 9 Hz, lHeach:CH2in20);4.10(d,J=7Hz,lH:Hen3);4.16and4.22(2d,J=16 Hz, 1H each: OCOCH2O); 4.62 (mt, 1H:H at 2'); 4.68 (d wide, J=4.5Hz, lH:
Hen5);5.25(dlarge,J=1OHz,1H:Hen3');5.30(d,J=1OHz,1H:CONH);
5.65(d,J=7Hz,1H:Hen2);6.23(tlarge,J=9Hz,1H:Hen13);6.42(s,1H:
H in 10); 7.25 to 7.45 (mt, 5H: H 1Uullldti4uw at 3'); 7.51 (t, J=7.5Hz, 2H:
OCOC6Hs H in meta); 7.62 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.16 (d, J=
7.5 Hz, 2H: OCOC6Hs H in ortho).
The tert-buLu ~.y~ bully -3 hydroxy-2-phenyl-3 ~ r (2R,3S) of ~.~ylu~y-2a 1 yl~y4a epoxy-51'i,20 hydro~y-ll'i lll~llu~dury-101fi oxo-9 30 L ~ inuu '' ~ furlu ~ y-7 ~ taxene-ll yle-13a can be prepared in the manner next:
A solution of 400 mg of tert-~y~bullyl-3 (4-methoxy-phenyl)-2 phenyl-4..~ ,1..1~ 1,3 ~ubu~.y' 5 (2R,4S,5R) key benzoyloxy-2a ~uuu~vylu~y4a epoxy-51'i,20 hydroxy-ll'i ~ .L ~ lu ~ ,.,.u ~ y-10 ~ oxo-9 L in ~ ylu ~ y-713 taxene-ll-yl-13a in 6.4 cm3 of a 0.1N solution of chlu.;.y, ethanol. is 2 1 9/~65 1 wo 95/33736 P~~
~ .

kept stirring at a le- ~ .aLul ~ Yoisine of 0 ~ C for 6 hours then auurle l ~, .ll ~. ~ -Lu-c close to 20C for 15 hours. The reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) at 20C. The crude product of the reaction is dissolved in 20 cm3 of di ~, Llo ~ 'and 10 cm3 of a saturated aqueous solution 5 of i' sodium. The aqueous phase is separated by ~ then extracted by 2 times 20 cm3 of di ~ Llu ~ u ~,. Orgalucous phases are combined, washed par30 cm3 of distilled water p us dried over sulphate ~ 'filtered and, ~ to dry under reduced pressure (2.7 I; Pa) at 20C. 410 mg of a product are obtained which are purifies by .,1... ~ .-- s~tr 60 g of silica (0.063-0.2 mm) contained in a 10 column 1 cm in diameter eluting with a mixture (d; ~, llu,, 'methanol 98.5-1.5 in volume) and collecting fractions of 10 cm3. The fractions containing only the foduit sought are combined and rt ~ dry under FeSSion reduced (2.7 kPa) at 20C. 307 mg of tert- ~ u.. yl.llllill ~ 3 are obtained 2-hydroxy-3-phenyl P~l (2R,3S) of benzoyloxy-2a '~lu~.y-4a epox,Y-5~,20 hydrox,Y-1~u~y-10~oxo-9 Lliiluul~''''.ylw~y-7 taxene-ll yle-13a in the form of a white meringue and whose. .
physical are as follows:
- 1H NMR spectrum (400 MHz; CDC13; ~ in ppm): 0.93 (t, J = 7.5 Hz, 3H: CH3 of the prcpyle); 1.22 (s, 3H: CH3); 1.24 (s, 3H: CH3); 1.35 (s, 9H: C(CH3)3); 1.65 at 1.85 (mt, 2H: CH2 of propyl); 1.74 (s, 1H:OH to 1); 1.88 (s, 3H: CH3); 2.04 (s, 3H: CH3); 2.25 and 2.86 (2 mts, 1H each: CH2 at 6); 2.33 (d, J=9Hz, 2H:
CH2 at 14); 2.52 and 2.66 (2 mts, J = 14.5 and 6.5 Hz, lH each: OCOCH2 du propyl); 3.33 (d, J=4Hz, 1H:OH at 2'); 3.52 (s, 3H:OCH3); 3.94 (d, J=7Hz, 1H:H in 3); 4.16 and 4.21 (2d, J=16Hz, 1H each: OCOCH2O); 4.19 and 4.35 (2 d, J = 9 Hz, lH each: CH2 at 20); 4.62 (mt, 1H:H at 2'); 4.86 (d wide, J=10 Hz,1H:Hen5);5.22(dlarge,J=1OHz,1H:Hen3');5.33(d,J=1OHz,1H:
CONH);5.50(dd,J=llet8Hz,1H:Hen7);5.73(d,J=7Hz,1H:Hen2);
6.16 (broad t, J=9Hz, 1H:H at 13); 6.71 (s, 1H:H in 10); from 7.25 to 7.45 (mt, 5H:
H ~ in 3'); 7.51 (t, J=7.5 Hz, 2H: OCOC6Hs H in meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para); 8.12 (d, J = 7.5 Hz, 2H: OCOC6Hs H in ortho).
The tert-'.r~lnJ~l.rl-3 (methoxy4 phenyl)-2 phenyl4 "~ 1,3 w~l~y'-5 (2R,4S,5R) of b~nzoyloxy-2a 1~.ylu~4c~epox~Y-5~,20 hydrox~Y-,Lh~ u~-10fl oxo-9 ~ Jlu,~r-713 taxene-ll yle-13a can be prepared in the following way:

~ woss~33736 2 1 9~ t ~ r~ ~ a To a solution of 400 mg of benzoyloxy-2c ~ l ylv ~ y4a dihydrvxy-1~,13c~ epoxy-5~,20 II~;;-V IYA~ V~Y-1O~ oxo-9 Llinuv~ vllYlvAr-7l3 - taxene-ll in 10 cm3 of anhydrous ethyl acetate, succ ~ .ll 247 mg is added of acid tert-b.. ~ Ay ~ lJvll. ~ l-3 (methoxy4 phenyl) -2 phenyl4 ~ r 1,3 5 ~; ~ ul ~ yLqu ~ 5 (2R, 4S, 5R ~, 186 mg of d; ~, '' yl ~; "' and 12.5 mg of 4 ~ 'The reaction mixture is stirred for 15 hours, under allllv ~ l, h ~ e of argon, at ulle t ~ ~., close to 20C, then concentrated to dryness under redlute pressure (2.7 l ~ a) at 40C. 1 g of um product is obtained, which is purified by ,- O ,- on 100 g of silica (0.063-0.2 mm) contained in a column of 3 cm of dl-amètre élllant with a mixture ~ - v ~ ll;. ~. ~ æ-methanol (95-5 volumes) and collectlamt fractions of 12 cm3. Fractions containing only the product sought are combined and ~ dry under reduced pressure (2.7 kPa) at 40C. 410 mg of tert-l,."v,~y.,A l~llyl-3 (4-methoxy-phenyl)-2-phenyl4 are obtained -1,3 ~, lbv ~ y -5 (2R,4S,5R) of benzoyloxy-2a ~ uL ~ ulvylv ~ .y4a epoxy-513.20 hydroxy-1~ u~y~ y-10~ oxo-9 L inuvl~ - - r ~IV~Y-7l3 taxene-ll yle-13a in the form of a white meringue and whose. A~
are as follows:
- 1H NMR spectrum (~00 MHz; CDCl3; o in ppm): 0.92 (t, J = 7.5 Hz, 3H: CH3 propyl); 1.07 (s, 9H: C(CH3)3); 1.17 (s, 6H: CH3); from 1.55 to 1.70 (mt, 3H:
CH2 of propyl and OH in 1); 1.64 (s, 3H: CH3); 1.84 (s, 3H: CH3); 2.08 and 2.15 at 2.30 (I~Li~. dd and mt, J = 16 and 9 Hz, lH each: CH2 at 14); from 2.15 to 2.30 and 2.82 ~2 mts, lH each: CH2 at 6); from 2.15 to 2.30 (mt, 2H: OCOCH2 of propyl); 3.51 (s, 3H:OCH3); 3.82 (s, 3H: ArOCH3); 3.83 (d, J=7Hz, lH:H in 3); 4.12 and 4.28 (2d, J=9Hz, 1H each: CH2 at 20); 4.14 and 4.22 (2d, J=16Hz, lH each: OCOCH2O); 4.52 (d wide, J=4.5Hz, 1H:H at 2'); 4.79 (d wide, J=10Hz,1H:Hen5);5.35to5.50(mt,1H:Hen3');5.44(dd,J=9and7Hz,1H:
Hen7);5.67(d,J=7Hz,lH:Hen2);5.99(tlarge,J=9Hz,lH:Henl3);6.40 (mf, 1H:H at 5'); 6.59 (s, 1H:H in 10); 6.92 (d, J = 8.5 Hz, 2H: H _~,IlI. Li~u.,,, in ortho of OCH3); from 7.25 to 7.45 (mt, 5H: H ~ v ~ lldti4u ~ in 3 '); 7.37 (d, J=8.5Hz, 2H:H~. . meta to OCH3); 7.48 (t, J=7.5Hz, 2H: OCOC6Hs H in meta); 7.63 (t, J = 7.5 -z, 1H: OCOC6Hs H in para); 8.11 (d, J=7.5Hz, 2H:
OCOC6Hs H in ortho).
Benzoylox ~ Y-2a 1 ylo ~ .y4a dihydroxy-1 ~, 13a epoxy-513,20 ~ Lllu~ Lv~y-loll3l OXO-9 i ~..~ '- r ~Iv~y-7~ taxene-ll can be 35 prepared in the following way:

WO95/33736 2l~a65~r~_'C

To a solution of 389 mg of benzoyloxy-2a bu ~ -uylu ~ y-4a epoxy-5~,20 1llclllw~ya~u~yl-l0l3 0~0-9 trihydroxy-1~,7j3,13a taxene-ll in 6 cm3 of "'' Ulll., '-lal ~ anhydrous and 390, ul of pyridine, maintained under a ~ lllu ~ h ~ i of argon, at an i .' ~ close to aloc, 410 111 anhydride is added drop by drop 5 hirl.lul. ''~ The orange solution obtained is stirred for 15 minutes at a ~ the ~ ul ~ close to 0C then -'" of 3 crn3 of water and 50 cm3 of Sun~,llulull~,hlall~. The organic phase is decanted, washed with 2 times 40 crn3 of a saturated aqueous solution of sodium chloride then dried over sulphate of filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We get 510 mg which ron purifies by ~,}.. , " . ' on 70 g of silioe (0.063-0.2 mm) contained dars a column 1 cm in diameter, eluting with a mixture of di~ lu~u~ thane-methanol (95-5 by volume) and collecting 10 crn3 fractions. Fractions do container that the expensive product ~ hey come together and, ~ dry under pressure reduced (2.7 kPa) at 40C. 410 mg of 1 ~. ~ uylu ~ y-2a ~ yluAy4a are obtained dihydroxy-113,13a-epoxy-5 ~, 20 IY ~ 6 ~ lu ~ aoetvr.y-10l3 oxo-9 h ~ u.
sulfonyloxy-7~ taxene-ll in the form of a white meringue and whose ~
'lu~physics are as follows:
- 1H NMR spectrum (400 MHz; CDC13; o in ppm): 1.06 (t, J = 7.5 Hz, 3H: CH3 propyl); 1.06 (s, 3H: CH3); 1.20 (s, 3H: CH3); 1.63 (s, 1H:OH to 1); 1.77 (mt, 2H: CH2 of propyl); 1.87 (s, 3H: CH3); 2.18 (d, J=5Hz, 1H:OH at 13);
2.15 to 2.40 (AB limit, 2H: CH2 14); from 2.15 to 2.40 and 2.89 (2 mts, lH each:
CH26); 2.25(s, 3H: CH3); 2.59 (AB lirnite, J = 16 and 7.5 Hz, 2H: OCOCH2 of propyl); 3.51 (s, 3H:OCH3); 4.03 (d, J=7Hz, 1H:H 3); 4.16 and 4.24 (2 d, J = 16 Hz, 1H each: OCOCH2O); 4.18 and 4.35 (2d, J=9Hz, 1H each: CH2 20); 4.85 (mt, 1H: H 13); 4.92 (d wide, J=10Hz, 1H:H5); 5.57 (dd, J = 10.5 and 7 Hz, lH:
H7);5.68(d,J=7Hz,1H:H2);6.73(s,1H:H10);7.51 (t,J=7.5Hz,2H:
OCOC6H5 H meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC6Hs H para); 8.10 (d, J=7.5Hz, 2H: OCOC6Hs H ortho).
The ~.~uyluA.~-2a 1,ylu~y-4a epoxy-5~,20 Ill.,illu~a~,c~u~y-10l3 oxo-9 trihydroxy-1~,713,13c~taxene-ll can be prepared as follows:
To a solution of 580 mg of benzoyloxy-2cI bulul~ylu~y 4a bii~(hical~lsilylu~y)-7;3,13a-epoxy-5~,20-hydroxy-l~ll.;;~lu~.~a.,.,tu~ y-10l3 oxo-9 taxene-ll in 5 crn3 of f"'"' ~, we add, to an ir'' t~ close to 20C, 5.5 cm3 of complex hi;; h ~ 'r ~ hiq ~ acid. The reaction mixture 35 is stirred for 23 hours at u ~ ei. ~ i close to 20C then we add 50 cm3 2 1 ~5t ~ WO 95133736 r~l~r~ J:~

of di, Ll ~,.~,.~.c, ll.dlle and 100 cm3 of a saturated aqueous solution cl'~y~LvO_..ou~L
sodium. The organic phase is decanted, washed with 2 times 20 cm3 of a solution aqueous solution saturated with sodium chloride then dried over sulphate of rr ~ Pei..m filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We obtain 520 mg which we - 5 purifies by ~1.. , O .' - on 70 g of silica (0.063-0.2 nm) contained in a column 2 cm in diameter, eluting with a methanol-~ mixture; L~ul~
(5-95 by volume) and collecting 10 cm3 fractions. Fractions not containing that the desired product are combined and ~ ~., dry under reduced pressure (2.7kPa) at 40C. 389 mg of benzoyloxy-2a L ~ ul u ~ vylv ~ y-4a epoxy-5 ~, 20 are obtained ~ .y~ tv ~ y-10 ~ oxo-9 trihydroxy-1 ~, 7 ~, 13a taxene-ll in the form of a white meringue and therefore the physical ~s are as follows:
- 1H NMR spectrum ~(400 MHz; CDCI3; ~3 in ppm): 1.05 (t, J = 7.5 Hz, 3H: CH3 propyl); 1.11 (s, 61 -: CH3); 1.67 (s, 3H: CH3); 1.71 (s, 1H OH to 1); 1.75 (mt, 2H: CH2 of propyl); 1.85 and 2.45 to 2.65 (2 mts, 1H each: CH2 at 6);
2.05 (s, 3H: CH3); 2.24 (d, J=5Hz, 1H:OH); 2.28 (AB limit, J = 16 and 9 Hz, 2H:
CH2 at 14); 2.40 (d, J=4Hz, 1H:OH); 2.56 (borderline AB, 2H: OCOCH2 of FPYIe);3.51 (s,3H:OCH3);3.88(d,J=7Hz,1H:Hen3);4.15and4.32(2d,J=
9 Hz, 1H each: CH2 in 20); 4.23 (AB Limit, J=16Hz, 2H: OCOCH2O); 4.48 (mt,1H:Hen7);4.86(mt,1H:Hen13);4.94(dlarge,J=1OHz,1H:Hen5);
5.62(d,J=7Hz,1H:Hen2);6.43(s,1H:Hen10);7.49(t,J=7.5Hz,2H:
OCOC6H5 H in meta); 7.62 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.12 (d, J=
7.5 Hz, 2H: OCOC6H5 ll in ortho).
Benzoyloxy-2a L~uku~oylu~y-4a L,~ lvi~y)-7~,13a epoxy-5~,20 hydroxy-1~."~u.~yl.~é~u~y-10~oxo-9-taxene-ll can be prepared as next:
To a solution of 906 mg of benzoyloxy-2a L~uku.~)ylo~y-4a dihydroxy-1~,10j3 Li~(lli0~1~ 1v.~y)-7~,13a epoxy-5~,20 oxo-9 taxene-ll in 18 cm3 of pyridine, 1.03 cm3 of chlorLlre ~ Iv ~ yl ~ was added to a. , ~ neighbor 0C The reaction mixture is stirred for 14 hours at a t ~ UI ~ close 20C then add 20 cm3 of ~, and 20 cm3 of an aqueous solution saturated with chloride The organic phase is decanted, washed 4 times 20 cm3 of a saturated aqueous solution of copper sulphate, 2 times 40 cm3 of a saturated aqueous solution of copper chloride then dried over copper sulphate filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We obtains 800 mg of a product which is purified by ~, Iu. O. - - on 100 g of silica w0 95133736 2 ~ 9 3 6 ~ 1 P~l/r~ 5 ~

(0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol-dichlu mixture. ~ .al ~ (2-98 by volume) and collecting fractions of 15 cm3. The fractions containing only the desired product are combined and Wl- ~ ~ dry under reduced pressure (2.7 kPa) at 40C. 580 mg of benzoyloxy-2a ~uk~yl~Ay4a 1,;~,b;lyloxy)-7'13,13a epoAy-5t3,20 hydroxy-lt3 lll6;1l~A~ra~vAy-1013 oxo-9 taxene-11 in the form of a white meringue and whose the physical ~s are as follows:
- 1H NMR spectrum (400 MHz; CDCI3 o in ppm): 0.60 and 0.68 (2 mts, 6H
each: ethyl CH2); 0.95 and 1.04 (2 t, J=7.5 Hz, 9H each: CH3 of ethyl);
1.09 (t, J=7.5 Hz, 3H: CH3 from propyl); 1.13 (s, 3H: CH3); 1.18 (s, 3H CH3); 1.64 (s, 1H: OH en1); 1.68 (s, 3H: CH3); 1.84 (mt, 2H: CH2 from propyl); 1.89 and 2.50 (2 mts, lH each: CH2 at 6); 2.11 and 2.23 (2 dd, J = 16 and 9 Hz, lH each:
CH2 at 14); 2.13 (s, 3H: CH3); 2.55 (mt, 2H: OCOCH2 from propyl); 3.53 (s, 3H:
OCH3); 3.82 (d,J=7Hz, 1H:H at 3); 4.13 and 4.31 (2 d, J = 9 Hz, lH each:
CH2 at 20); 4.16 (AB limit, .J = 16 Hz, 2H: OCOCH2Ol; 4.52 (dd, J = 11 and 7 Hz, lH:Hen7);4.91(mt,1H:lHenl3);4.93( dlarge,J=1OHz,1H:Hen5);5.64 (d, J = 7 Hz, lH: H in 2); 6.54 (s, 1H:H in 10); 7.47 (t, J=7.5Hz, 2H:
OCOC6H5 H in meta); 7.61 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para); 8.11 (d, J=
7.5 Hz, 2H: OCOC6Hs H in crtho).
Benzoyloxy-2a ~ yl, JAy-4a dihydroxy-113,1013 L- ''; I ~; IYIrJAY)-713.13a epo ~ y-513.20 oxo-9 ta ~ .ene-11 can be prepared as follows:
To a solution of 907 mg of buLarl~ylrJA~r~lCc carbonate-113,2a b~(Lr;6~b;l~,lvAy)-7t3~l3a epoAy-513.20 l~JA~a~,~t~lAy-1013 oxo-9 taxene-11 in 50 cn3 of ~ v ~ ,,.. ~ anhydrous, 2.34 cm3 of a lM solution of 25 ~,}i.,..~"' in the i '"J.~,r, at a ~ alr~ close to -78C The reaction mixture is stirred for 1 hour at an i, ~, close to -78C then 10 cm3 of a saturated aqueous solution of chloride, "At a ~ ll ~ laLur. ~ close to 20C, we a30ute 20 cm3 of a saturated aqueous solution dechloride rl'i 'and 50 cm3 of d; -, l ~ .. '' The organic phase is 30 decanted, washed with 2 times 10 cm3 of a saturated aqueous solution of chloride of sodium then dried over sulphate ~ filtered and concentrated to dryness under pressure reduced (2.7 kPa) at 40C 1.3 g is obtained which is purified by, ~, 'on 150 g of silica (0.063 0.2 mm) contained in a column 5 cm in diameter in eluting with a mixture of ethyl acetate-, ~ y, '' (10-90 by volume) and in 35 collecting fractions of 18 cm3. Fractions containing only the desired product 2 1 ~0~5 W095133736 r~ /J~

svnt combined and f- - ~ a dry under reduced pressure (2.7 kPa) at 40C. 906 mg of benzoyloxy-2a buLu.vylv ~ r-4a dihydroxy-l ~, lOfl 'rlbilrlv ~ - are obtained 713.13a epvxy-5~,20 oxo-9 taxene-ll in the form of a white meringue and whose .,~u~i , physics are as follows:
- 1H NMR spectrum (400 MHz; CDCI3; o in ppm): 0.56 and 0.67 (2 mts, 6H
each: ethyl CH2); 0.95 and 1.03 (2 t, J=7.5 Hz, 9H each: CH3 of ethyl);
1.08 (s, 3H: CH3); 1.10 (t, J = 7.5 Hz, 3H: CH3 from propyl); 1.18 ~s, 3H: CH3);
1.60 (s, 1H:OH to 1); 1.73 (s, 3H: CH3); 1.84 (mt, 2H: prvpyle CH2); 1.91 and 2.48 (2 mts, 1H each: CH2 at 6); 2.03 (s.3H: CH3); 2.11 and 2.22 (2 dd, J = 16 and 9 Hz, 1H each: CH2 at 14); 2.58 (mt, 2H: prvpyle OCOCH2); 3.87 (d, J=7 Hz,lH:Hen3);4.18and4.32(2d,J=9Hz,lHeach:CH2in20);4.28(d,J=2 Hz, 1H:OH in 10); 4.42 (dd, J=10.5 and 6.5 Hz, 1H:H at 7); 4.93 (d wide, J=10 Hz,1H:Hen5);4.98(1:~J=9Hz~1H:Hen13);5~17(d~J=2Hz~1H:Henlo);
5.62 (d, J=7Hz, 1H:H at 2); 7.49 (t, J=7.5 Hz, 2H: OCOC6H5 H in meta); 7.61 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.12 (d, J=7.5Hz, 2H: OCOC6H5 in ortho).
The buL~vrlvA~/-4a carbonate-1~3,2a b;a(~rlailylu~r)-7~,13a épvxy-5 ~, 20 I ~ lv ~ tv,.r-lO ~ oxo-9 taxene-ll can be prepared in the following way: A solution of 870 mg of carbonate-1j3,2a ~; a (hi6 ~ lrlailyloxy) - 7~,13a epoxy-513.20 hydrvxy~la~1lu~ tu~r-10~ oxo-9 taxene-ll in 15 cm3 of dichlO ~ u ~ tl ~ .,, 1.46 g of 4 ~ Ulv ~ r "and 3.90 cm3 are added of butyric anhydride. The reaction medium is heated to ume; , c: neighbor of 42C for 45 hours. Add 50 cm3 of a saturated aqueous solution of chloride of sodium and 50 cm3 of dichlu.ul ~. The organic phase is decanted, washed with 2 times 40 cm3 of a saturated aqueous solution of sodium chlorute then dried over v sulfate filtered and concentrated to dryness under reduced pressure (2.7 kPa) to 40C. We get 2.0 g which we putify with ~ O. 'on 170 g of silica (0.063-0.2 mm) contained in cme column of 3 cm in diameter by eluting with a mixture ethyl acetate-~.'' - (5-95 by volume) and collecting fractions of 15 cm3. The fractions containing only the desired product are combined and rr ~
dry under reduced pressure (2.7 kPa) at 40C. 1.00 g of 1,uLu.vrlu~r-4a are obtained carbonate-1~,2a dil~;61.~1~;1rlu~r-7~,13a ep~xy-513,20 ~u~lu~,tv~r-10j3 oxo-9 taxene-11 in the form of a white meringue and whose. ~ physical are the following:

2T ~a~l woss/33736 r~.,~ ,c /~a - 1H NMR spectrum (400 MHz; CDCI3: o in ppm): from 0.50 to 0.70 (mt, 12H:
ethyl CH2); from 0.90 to 1.10 (mt, 21H: CH3 of ethyl and CH3 of propyl); 1.18 (s, 3H: CH3); 1.28 (s, 3H: CH3); 1.73 (mt, 2H: CH2 from propyl); 1.75 (s, 3H:
CH3); 1.92 and 2.59 (2 mts, lH each: CHz at 6); 2.13 (s, 3H: CH3); 2.14 and 2.35 to 2.45 (~ lcll ~ dd and mt, J = 16 and 9 Hz, lH each: CH2 at 14); of 2.35-2.45 (mt, 2H: OCOCH2 from propyl); 3.42 (d, J=6.5Hz, 1H:H at 3); 3.51 (s,3H:OCH3); 4.18 (s, 2H: OCOCH2O); 4.46 (dd, J=10 and 6.5 Hz, 1H:H at 7);
4.50 and 4.63 (2d, J=9Hz, 1H[ each: CH2 at 20); 4.51 (d, J=6.5Hz, lH:H in 2); 4.93 (d wide, J=10Hz, IH:H in 5); 5.02 (broad t, J=9Hz, 1H:H at 13);
6.51 (s,1H:Hen10).
FX~ pLF 4 By operating as in example 3, and starting from tert-butu~yucu~u~.rl-3-anqino 2-hydroxy-3-phenyl ~UpiO~ , (2R,3S) of b~.~v~lu~y-2a ~h_.~.yL~c6.u~.y-4a 6poxy-5~,20 hydroxy~ 6;1lw~ vcLu~y-10~ oxo-9 Llln~.ul.~ r~ luAy-7 taxene-ll yl-13, we obtain tert-l y ~ olbullyl ~ llillu-3 hydroxy-2 ph6 ~ nyl-3 (2R,3S) of benzoyloxy-2a-epoxy-5j3,20-hydroxy-113...~LIIU~ LUJC~-1O~
m6~thylene-713.8 nor-19 oxo-9 1'~lll~Lu~y4a taxene-ll yle-13a including lw ". ~ are the following:
- 1H NMR spectrum (400 MHz; CDCI3; δ in ppm): 1.24 (s, 15H: CH3 - CH3 and C(CH3)3); 1.40 (mt, 1H:H at 7); 1.66 and 2.24 (2 dd, J = 6 and 5 Hz and J = 10 and 6 Hz, 1H each: CH2 at 19); 1.92 (s, 1H:OH to 1); 1.96 (s, 3H: CH3); 2.07 and 2.46 (.~,~,li~. d wide and dt, J = 16 Hz and J = 16 and 4.5 Hz, lH each: CH2 at 6);
2.32 and 2.54 (~. dd and dd wide, J = 16 and 9 Hz, lH each: CH2 at 14);
3.24 (mt, 1H:OH at 2'); 3.53 (s, 3H:OCH3); 3.90 and 4.14 (2 d, J = 15 Hz, lH
each: OCOCH2Ar); 4.00 and 4.16 (2d, J=9Hz, 1H each: CH2 at 20); 4.20 and 4.26 (2d, J=16Hz, 1H each: OCOCH2O); 4.23 (d, J=7Hz, 1H:H at 3); 4.55 (dlarge,J=4.5Hz,lH:Hen5);4.63(mt,1H:Hen2');5.31(ABlimit,2H:H
en3'etCONH);5.71(d,J=7Hz,lH:Hen2);6.34(tlarge,J=9Hz,lH:Hen 13); 6.44 (s, 1H:H in 10); from 7.10 to 7.45 (mt, 10H: H ~ u. . and H
~uulll~:l;quw in 3'); 7.51 (t, J=7.5 Hz, 2H: OCOC6Hs H in meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para); 8.16 (d, J = 7.5 Hz, 2H: OCOC6Hs H in ortho).
By operating under dw conditions analogous to those described in Example 3, prepares the tert-l ~ ubull ~ '-3 hydroxy-2 phenyl-3 ~ r- ' (2R,3S) of 21 ~0~5t ~WO 95133736 r~,l/r~ a ~. ~ uyl ~ y-2a epoxy-5 ~, 20 hydroxy-l ~ lu ~ yd ~ u ~ y-1013 oxo-9 ~ ,.lyl ~ tv ~ y-4a; .A ~ lu ~ y-7 ~ taxene-ll yle-13a whose ~ are the following:
- 1H NMR spectrum (400 MHz; CDCI3; ~ in ppm): 1.24 (s, 6H: CH3); 1.36 (s, 59H: C(CH3)3); 1.74 (s, 1H:OH to 1); 1.87 (s, 3H: CH3); 2.14 (s, 3H: CH3); 2.19 and 2.83 (2 mts, 1H each: CH2 at 6); 2.39 and 2.48 (2 dd wide, J = 16 and 9 Hz, lH
each: CH2 at 14); 3.38 (d, J=4.5Hz, 1H:OH at 2'); 3.53 (s, 3H:OCH3); 3.90 and 4.14 (2d, J=15Hz, 1H each: OCOCH2Ar); 4.01 (d, J=7Hz, 1H:H at 3);
4.11 and 4.20 (2d, J=9Hz, 1H each: CH2 at 20); 4.17 and 4.25 (2 d, J = 16 Hz, lH
each: OCOCH2O); 4.65 (mt, 1H:H at 2'); 4.68 (d wide, J=10Hz, lH:H in 5); 5.28 (d wide, J=10Hz, 1H:H at 3'); 5.35 (d, J=10Hz, 1H: CONH); 5.50 (dd, J = 10 and 7 Hz, 1H: ]~ at 7): 5.77 (d, J = 7 Hz, 1H: H at 2); 6.28 (wide tee, J=9 Hz, 1H:H at 13); 6.74 (s, 1H:H in 10); from 7.15 to 7.45 (mt, 10H: H ~ llUllld ~ u ~ and H < UUIna ~ iqU ~ in 3 ');'7.51 (t, J = 7.5 Hz, 2H: OCOC6Hs H in meta); 7.66 (t, J =
7.5 Hz, 1H: OCOC6H5 H in para); 8.08 (d, J=7.5 Hz, 2H: OCOC6H5 H in ortho).
By operating under conditions similar to those described in Example 3, the tert-l, utu ~ y ~ a ~ lJu ~ -3 (methoxy-4 phenyl) -2-phenyl-4 I ..,.,.l ~ 1,3ul ~ yld ~ -5 (2R, 4S, 5R) benzoyloxy-2a-epoxy-51A~,20-hydroxy-113-methoxy-acetoxy-1013 oxo-9 ~ 1~é~u~y4a l-illUu -~ lfonyloxy-7~ taxene-ll yle-13a whose, , are the following:
- 1H NMR spectrum (~00 MHz; CDCI3; a ~elll~ ld~UUC: of 333K, ~ in ppm):
1.06 (s, 9H: C(CH3)3); 1.12 (s, 3H: CH3); 1.24 (s, 3H: CH3); 1.66 (s, lH:OH in 1); 1.83 (s, 3H: CH3); 1.86 (s, 3H: CH3); 2.14 and 2.79 (2 mts, 1H each: CH2 to6); 2.24 and 2.30 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 3.45 and 3.58 (2 d, J =
15Hz, 1H each: OCOCH2Ar); 3.54 (s, 3H:OCH3); 3.85 (s, 3H: ArOCH3);
3.94(d,J=7Hz,1H:Hen3);4.08and 4.17(2d,J=9Hz,1Heach:CH2en20);
4.14 and 4.22 (2 d, J = 16 H[z, 1H each: OCOCH,O); 4.59 (d wide, J=10Hz, lH:
Hen5);4.63(d,J=5.5Hz,1H:Hen2');5.45(d,J=5.5Hz,1H:Hen3');5.47 (mt,lH:Hen7);5.72(d,J=7Hz,lH:Hen2);6.14(tlarge,J=9Hz,lH:Hen 13); 6.34 (s, 1H:H at '3'); 6.65 (s, 1H:H in 10); 6.94(d, J=8.5Hz, 2H:H
~uulllaliq~c~ in ortho of OCH3); from 7.20 to 7.45 (mt, 12H: H ~UUIllaiiqu~ and H
aLUl ~ ldti ~ lUe ~ i in meta OCH3 and H ~ U ~ I ~ IIa ~ i ~ UC ~ in 3 '); 7.48 (t, J=7.5Hz, 2H:
OCOC6H5 H in meta); 7.64 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 7.98 (d, J=
7.5 Hz, 2H: OCOC6H5 H ~in ortho) 21 9065 liters wo 95/33736~r~5 By operating under conditions similar to those described in Example 3, preparing the l ~. ~ uylu ~ y-2a dihydroxy-1 ~, 13a epoxy-5 ~, 20 ~ .01 ~ u ~ au; .uAy-10 OXO-9 ~h~ y-4a l~inuu~ lu~y-713 taxene-ll whose ,.. r~ are as follows:
- 1H NMR spectrum (400 ~1Hz; CDCI3; ~ in ppm): 1.07 (s, 3H: CH3); 1.21 (s, 3H: CH3); 1.64 (s, 1H:OH to 1); 1.87 (s, 3H: CH3); 2.18 (d, J=4.5 H12, 1H: OHen13); 2.20 and 2.88 (2 mts, 1H each: CH2 at 6); 2.30 (s, 3H: CH3); from 2.25 to 2.35 (mt, 2H: CH2 at 14); 3.52 (s, 3H:OCH3); 3.90 and 3.97 (2 d, J = 15 Hz, lH
each: OCOCH2Ar); 4.08 (d, J=7Hz, 1H:H at 3); 4.12 and 4.27 (2d, J=9Hz, lH each: CH2 in 20); 4.16 and 4.24 (2d, J=16Hz, 1H each: OCOCH2O); 4.80 (d wide, J=10Hz, lH:H in 5); 4.92 (mt, 1H:H at 13); 5.55 (dd, J = 10 and 6.5 Hz,1H:Hen7);5.71(d,J=7Hz,1H:Hen2);6.74(s,1H:Hen10);7.25to 7.45 (mt, 5H: H~uulllaliyuw); 7.48 (t, J=7.5 Hz, 2H: OCOC6H5 H in meta); 7.64 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.03 (d, J=7.5Hz, 2H: OCOC6H5 H in ortho).
By operating under conditions similar to those described in Example 3, preparing the ~ .. Luylo ~ y-2a epoxy-5 ~, 20 1l ~ 6l ~ lu ~ a ~ e ~ u ~ y-lol3 OXO-9 ~ / I ~ .,.., ~ I ~ .,. ~y-4a-trihydroxy-1~3,7~,13a-taxene-l 1 of which lew, I are the following:
- 1H NMR spectrum (400 MHz; CDCl3 o in ppm) 1.12 (s, 3H: CH3); 1.14 (s, 3H: CH3); 1.66 (s, 1H: OHI in 1); 1.67 (s, 3H: CH3); 1.84 and 2.56 (2 mts, lH
each: CH2 in 6); 2.11 (s, 3H: CH3); 2.20 to 2.45 (2 mts, 1H each: OH);
2.35 and 2.42 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 3.54 (s, 3H:OCH3);
3.94 (AB limit, J=15Hz, 2H: OCOCH2Ar); 3.94 (d, J=7Hz, 1H:H at 3); 4.12 and 4.25 (2d, J=9Hz, 1H each: CH2 at 20); 4.26 (AB limit, J=16Hz, 2H:
OCOCH2O); 4.50 (mt, 1H:H at 7); 4.87 (d wide, J=10Hz, 1H:H in 5); 4.96 (mt,1H:Hen13);5.66(d,J=7Hz,1H:Hen2);6.44(s,1H:Hen10);de7.25 at 7.45 (mt, 5H: H~uullla~iyUw); 7.47 (t, J=7.5 Hz, 2H: OCOC6H5 H in meta);
7.62 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.04 (d, J=7.5Hz, 2H: OCOC6H5H
in ortho) By operating under conditions similar to those described in Example 3, preparing benzoyloxy-2a l ~ i ~ ('yl ~ ilylu ~ y) -713,13a epoxy-513,20 hydroxy-l ~
Ill'~lu~a~y-10l3OXO-9~'ylac~y-4atataxene-lldontles, .. r;~ are the following:

21 ~065 1 WO 95133736 1 ._lrr~

- 1H NMR spectrum (400 MHz; CDCI3; iS in ppm): 0.60 and 0.72 (2 mts, 6H
each: ethyl CH2); 0.94 and 1.05 (2 t, J=7.5 Hz, 9H each: CH3 of ethyl~;
1.15 (s, 3H: CH3); 1.22 (s, 3H: CH3); 1.66 (s, 3H: CH3); 1.69 (s wide, lH:OH in 1); 1.84 and 2.51 (2 mts, 1H each: CH2 at 6); 2.20 (s, 3H: CH3); 2.24 and 2.36 (2 dd, J = 16 and 9 Hz, lH each: CH2 at 14); 3.54 (s, 3H:OCH3); 3.82 and 3.96 (2 d, J
= 15 Hz, 1H each: OCOCH2Ar); 3.89 (d, J=7Hz, 1H:H at 3); 4.06 and 4.16 (2 d, J = 9 Hz, lH each: CH2 at 20); 4.20 (AB limit, J=16Hz, 2H: OCOCH2O);
4.52(dd,J=lOet6Hz,lH:Hen7);4.79(dlarge,J=lOHz,lH:Hen5);4.96(t wide,J=9Hz,lH:Henl3);5.66(d,J=7Hz,lH:Hen2);6.58(s,1H:Hen 10); from 7.25 to 7.45 (mt, 7H: H al ". and OCOC6HsH in meta); 7.61 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.00 (d, J=7.5 Hz, 2H: OCOC6H5 H in ortho).
By operating under conditions similar to those described in Example 3, prepares 2-berlzoyloxy-1-dihydroxy, 1013 b;~(hi~ylsil~lu~y)-7l3,13a-5~,20-epoxy Ox[}9; '' yla~ vAy4a ~xène-l l whose ~ ~ ,.. t~ are as follows:
- 1H NMR spectrum (600 MHz; CDC13; ~ in ppm): 0.53 and 0.72 (2 mts, 6H
each: ethyl CH2); 0.94 and 1.05 (2 t, J = 7.5 Hz, 9H each: CH3 of ethyl);
1.10 (s, 3H: CH3); 1.20 (s, 3H: CH3); 1.64 (s, 1H:OH to 1); 1.70 (s, 3H: CH3);
1.86 and 2.45 (2 mts, 1H each: CH2 at 6); 2.10 (s, 3H: CH3); 2.20 and 2.32 (2 dd, J = 16 and 9 Hz, lH each: CH2 at 14); 3.80 and 3.96 (2 d, J = 16 Hz. lH each:
OCOCH2-r); 3.95 (d, J=7Hz, 1H:H at 3); 4.07 and 4.17 (2 d, J = 9 Hz, lH
each: CH2 in 20); 4.29 (s wide, 1H:OH at 10); 4.43 (dd, J=11 and 7Hz, lH:H
in 7); 4.79 (d wide, J=10Hz, 1H:H in 5); 5.03 (broad t, J=9Hz, 1H:H at 13);
5.19 (s wide, 1H:H at 111)); 5.63 (d, J=7Hz, 1H:H at 2); from 7.25 to 7.45 (mt, 7H:
H~; and OCOC6H5 H in meta); 7.60 (t, J = 7.5 Hz, lH: OCOC6H5 H in para); 8.00 (d, J=7.5 Hz, 2H: OCOC6H5 H in ortho).
By operating under conditions similar to those described in Example 3, the carbonate-113,2a b;~(hi~;lylo~y)-7~,13a-epoxy-5~,20 is prepared l~a~ y-1013oxo9~,}1~ la~ y-4atataxene-l1dontles~, are the following:
- 1H NMR spectrum ~(400 MHz; CDCI3; ~ in ppm): 0.61 and 0.74 (2 mts, 6H
each: ethyl CH2); 0.92 and 1.05 (2 t, J=7.5 Hz, 9H each: CH3 of ethyl);
1.20 (s, 3H: CH3); 1.30 ~s, 3H: CH3); 1.73 (s, 3H: CH3); 1.83 and 2.54 (2 mts, 1H each: CH2 at 6); 2.18 (s, 3H: CH3); 2.27 and 2.48 (2 dd, J = 16 and 9 Hz, lH
each: CH2 at 14); 3.50 (d, J=6.5Hz, 1H:H at 3); 3.53 (s, 3H:OCH3); 3.65 (AB limit, J = 14 Hz, 2H: OCOCH2Ar); 4.18 (AB limit, 2H: OCOCH2O); 4.45 and 21 qG65 l WO 9'iD3736 ~ /r 4.53 (2d, J=9Hz, 1H each: CHz at 20); 4.46 (mt, 1H:H at 7); 4.53 (d, J = 6.5 Hz,lH:Hen2);4.68(dlarge,J=lOHz,lH:Hen5);5.06(tlarge,J=9Hz,lH:
H at 13); 6.53 (s, 1H:H in 10); from 7.25 to 7.45 (mt, 5H:H, PXP.I\~IPI P. 5 By operating as in example 3, and without tert-l.utv~.,~
3-amino-2-hydroxy-3-phenyl ~.,. (2R,3S) of ~.~yhJ~-2a lli;~(ll._;ilu;~y-acetoxy)-4a,1013 epoxy-5~3,20 hydroxy-1~ oxo-9 I~inuvl~ - 'fvllrlw~-7 taxene-ll yle-13a, we pre ~ pare the teAt-l; utvAy.Aul, ~ o-3 hydroxy-2-phenyl-3 ~, I (2R, 3S) benzoyloxy-2a l,; ~ .v ~ v ~) -4a, 10 ~ epoxy-5 ~, 20 hydroxy-113 methylene-7Fi,8 nor-19 oxo-9 taxene-ll yl-13a whose l AA~
are the following:
- 1H NMR spectrum (400 MHz; CDCI3 ~ é. ~ uu ~ 333K, o in ppm): 1.26 (s, 3H: CH3); 1.29 (s, 3H: CH3); 1.35 (s, 9H: C(CH3)3); 1.42 (mt, 1H:H at 7);
1.71 and 2.29 (l~i~. dd and mt, J=6.5 and 5 Hz, 1H each: CH2 at 19); 1.81 (s, 1H: OH to 1); 1.91 (s, 3H: CH3); 2.15 and 2.54 (It:D~Li~. d wide and dt, J =
16 Hz and J = 16 and 4.5 Hz, lH each: CH2 at 6); 2.32 (AB li nite, 2H:CH2 at 14);
3.50 and 3.53 (2s, 3H each: OCH3); 3.60 (mf, 1H:OH at 2'); 4.11 and 4.56 (2d,J=16Hz, 1H each: OCOCH2O); 4.12 and 4.31 (2 d, J = 9 Hz, lH each: CH2 in 20); 4.17 (d, J=7Hz, 1H:H at 3); 4.19 and 4.24 (2 d, J = 16 Hz, lH each:
OCOCH2O); 4.67 (mt, 1H:H at 2'); 4.78 (d, J=4.5Hz, 1H:H at 5); 5.29 (d large,J=10~z,1H:Hen3');5.47(d,J=1OHz,1H:CONH);5.70(d,J=7Hz, 1H:Hen2);6.21(tlarge,J=9Hz,1H:Hen13);6.44(s,1H:Hen10);7.30(t, J = 7.5Hz, 1H. H in para of r~, i in 3'); 7.39 (t, J=7.5Hz, 2H:H in meta of the ul . in 3'); 7.45 (d, J = 7.5 Hz, 2H: H in ortho of r in 3~);
7.51 (t, J=7.5 Hz, 2H: OCOC6Hs H in meta); 7.61 (t, J = 7.5 Hz, lH: OCOC6Hs H
in para); 8.12 (d, J = 7.5 Hz, 2H: OCOC6H5 H in ortho).
By operating under conditions analogous to those described in Example 3, the tert-l, u.vAy ~ '-3 hydroxy-2-phenyl-3 ~ JII, '(2R, 3S) of ~.~ylo~ y-2a L~(l..6;h~_~tv~y)-4a,1013-epoxy-5~i,20-hydroxy-1~oxo-9 30 ; ~ r Jl,"y 7~ taxene-ll yle-13a whose A r ~ ; are the following:
- r, pectrum of R MN lH (400 MHz; CDCI3; t ~ Ult ~ of 333K, ~ in ppm): 1.22 (s, 3H: CH3); 1.27 (s, 3H: CH3); 1.38 (s, 9H: C(CH3)3); 1.64 (s, 1H:OH to 1);

2 1 90~ 1 ~ WO95133736 P~l/r~ /Ja 1.92 (s, 3H: CH3); 2.11 (s, 3H: CH3); Z.25 and 2.~2 (2 mts, 1H each: CH2 at 6); 2.26 and 2.36 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 3.47 and 3.52 (2s, 3H each: OCH3); 3.66 (s wide, 1H:OH at 2'); 3.99 (d, J=7Hz, 1H:H at 3); 4.15 and 4.57 (2d, J=16Hz, 1H each: OCOCHaO); 4.19 (AB limit, J=16Hz, 2H:
5OCOCH2O); 4.24 and 4.35 (2d, J=9Hz, 1H each: CH2 at 20); 4.70 (mt, lH:H
2'); 4.95 (d wide, J=10Hz, 1H:H in 5); 5.29 (d wide, J=10Hz, 1H:H at 3');
5.49 (d, J=10Hz, 1H: CONH); 5.53 (dd, J=11 and 8Hz, 1H:H at 7); 5.76 (d, J=
7Hz,1H:Hen2);6.1~(tlarge,J=9Hz,1H:Hen13);6.74(s,1H:Hen10);
7.30 (t, J = 7.5 Hz, lH: H in para of 1'~LVI~d~iqUe in 3'); 7.38(t, J=7.5Hz, 2H:H
in meta of the ~UUl~lad~ , in 3'); 7.45 (d, J = 7.5 Hz, 2H: H in ûrtho of the dLVlla, LiqU~
in 3'); 7.49 (t, J= 7.5 ~ Iz, 2H: OCOC6Hs H in meta); 7.63 (t, J = 7.5Hz, lH:
OCOC6H5 H in para); 8.09 (d, J = 7.5 Hz, 2H: OCOC6Hs H in ortho).
By operating under conditions similar to those described in Example 3, we prepare tert-L ~ bvllv1-3 (methoxy4 phenyl) -2 phenyl-4 v ~ a4vlidiu ~ c-1,3 ~, ~ uL ~ y '5 (2R, 4S, 5R) of benzoyloxy-2a bis (methv; ~ cl ~ v ~ y) 4a, 10l3 epoxy-5 ~, 20 hydroxy-113 oxo-9 L in ~ .J ~,. lfrlnyloxy-7l3 taxene-ll yl-13a whose are the following:
- N.M.R. spectrum. 1H (100 MHz; CDC13; ~,n~.~ of 333K, o in ppm): 1.10 (s, 9H: C(CH3)3); 1.18 (s, 3H: CH3); 1.20 (s, 3H: CH3); 1.64 (s, 1H: OH to 1);
1.75 (s, 3H: CH3); 1.86 (s, 3H: CH3); 2.12 and 2.26 (2 dd, J = 16 and 9 Hz, lH
each: CH2 at 14); 2.24 and 2.86 (2 mts, 1H each: CH2 at 6); 3.33 and 3.53 (2s, 3H:OCH3); 3.65 and 4.10 (2d, J=16Hz, 1H each: OCOCH2O); 3.83 (s, 3H:
ArOCH3); 3.86 (d, J=7Hz, 1H:H at 3); 4.14 and 4.20 (2 d, J = 16 Hz, lH each:
OCOCH2O); 4.19 and 4.32 (2d, J=9Hz, 1H each: CH2 at 20); 4.72 (dwide, J=4.5Hz,1H:Hen2');4.89(dwide,J=1OHz,1H:Hen5);5.46(mt,1H:Hen 3'); 5.45 (dd, J=11 and 8Hz, 1H:H at 7); 5.69 (d, J=7Hz, 1H:H at 2); 5.94 (t wide, J=9Hz,1H:Hen13);6.40(swide,1H:Hen15');6.63 (s,1H:Hen10);
6.93 (d, J=8.5 Hz, 2H: }I ILI . ortho to OCH3); from 7.30 to 7.45 (mt, 5H:
H aLVll ~ dtillU ~ in 3 '); 7.38 (d, J = 8.5 Hz, 2H: H uv~ lLiqu~ in meta to OCH3);
7.48 (t, J=7.5 Hz, 2H: OCOC6H5 H in meta); 7.63 (t, J=7.5Hz, lH: OCOC6H5H
in para); 8.08 (d, J = 7.5 Hz, 2H: OCOC6H5 H in ortho).
By operating under conditions similar to those described in Example 3, preparing benzoyloxy-2a 1 ~ dc ~, tv ~ y) 4a, 10 ~ dihydroxy-1 ~, 13a epoxy-wo s~/33736 2 1 9 0 6 5 1 ~ c _ lva ~

5 ~, 20 oxo-9 v ~ rlu ~ ul ~ lu ~ -713 taxene-ll including ~; are the following:
- 1H NMR spectrum (400 MHz; CDCl3; o in ppm) 1.06 (s, 3H: CH3); 1.20 (s, 3H:CH3);1.61(s,1H:OHen1);1.89(s,3H:CH3);2.23(d,J=5Hz,1H:OH
in 13); from 2.20 to 2.35 and 2.92 (2 mts, 1H each: CH2 at 6); 2.26 (s, 3H: CH3);
2.32 (d, J=9Hz, 2H: CH2 at 14); 3.52 and 3.58 (2s, 3H chaclm:OCH3); 4.04 (d,J=7Hz, 1H:H at 3); 4.19 and 4.32 (2 limit AB, J = 16 Hz, 2H each:
OCOCH2O); 4.20 and 4.38 (2d, J=9Hz, 1H each: CH2 at 20); 4.82 (mt, lH:H
enl3);4.99(dlarge,J=10]~z,lH:Hen5);5.55(dd,J=lOet7Hz,lH:Hen 7);5.69(d,J=7Hz,1H:Hen2);6.73(s,1H:Hen10);7.51(t,J=7.5Hz,2H:
OCOC6H5 H in meta); 7.64 (~, J=7.5 Hz, 1H: OCOC6Hs H in para); 8.13 ~d, J =
7.5 Hz, 2H: OCOC6Hs H in ortho).
By operating under conditions similar to those described in Example 3, benzoyloxy-2a Lv(~ y)-4a,10~ epoxy-5~,20 oxo-9 is prepared trihydroxy-lr3,7 ~, 13a taxene-ll whose. ~ are as follows:
- 1H NMR spectrum (400 MHz; CDCl3 o in ppm): 1.11 (s, 6H: CH3); 1.63 (s, 1H:OH in 1); 1.70 (s, 3H: CH3); 1.92 and 2.63 (2 mts, 1H each: CH2 at 6); 2.08(s, 3H: CH3); from 2.20 to 2.30 (mt, 3H: CH2 at 14 and OH); 2.40 (d, J = 4Hz, lH:
OH); 3.54 and 3.59 (2s, 3H each OCH3); 3.92 (d, J=7Hz, 1H:H at 3); 4.20 and 4.35 (2d, J=9Hz, 1H chaclm:CH2 at 20); 4.24 and 4.28 (2 AB limit, J = 16 Hz, 2H
each: OCOCH2O); 4.50 (mt, 1H:H at 7); 4.86 (mt, 1H:H at 13); 5.03 (d wide, J=1OHz,1H:Hen5);5.65(d,J=7Hz,1H:Hen2);6.44(s,1H:Hen10);
7.49 (t, J=7.5 Hz, 2H OCOC6H5 H in meta); 7.63 (t, J=7.5Hz, lH: OCOC6H5H
in para); 8.14 (d, J = 7.5 Hz, 2H: OCOC6Hs H in ortho).
By operating under conditions similar to those described in Example 3, preparing the hvenzoyloxy-2a L; v (..,; ~ .u ~ y) -4a,10 ~ L '''jlv'ylu ~) -713.13 epoxy-5 ~, 20 hydroxy-l ~ oxo-9 taxene-ll including ~ v ~ U ~ U ~ I ''. please the following:
- 1H NMR spectrum (40~ MHz; CDC13 ~ in ppm): 0.60 and 0.70 (2 mts, 6H
each: ethyl CH2); 0.94 and 1.02 (2 t, J=7.5 Hz, 9H each: CH3 of ethyl);
1.12 (s, 3H: CH3); 1.20 (s, 3H: CH3); 1.64 (s, 1H:OH to 1); 1.70 (s, 3H: CH3);
1.91 and 2.57 (2 mts, 1H each: CH2 at 6); 2.12 (s, 3H: CH3); 2.13 and 2.23 (2 dd,J = 16 and 9 Hz, 1H each CH2 at 14); 3.53 and 3.57 (2s, 3H each: OCH3); 3.83 (d, J=7Hz, 1H:H at 3); 4.15 and 4.40 (2d, J=16Hz, 2H: OCOCH2O); 4.19 (AB

~ WO95133736 1 ~ r. 1.55 limit, J = 16 Hz, 2H: OCOCH2O); 4.21 and 4.37 (2 d, J = 9 Hz, lH each: CH2 in 20); 4.51 (dd, J=11 and 7Hz, 1H:H at 7); 4.93 (t, J=9Hz, 1H:H at 13); 5.02 (d wide,J=lOHz,lH:~len5);5.64(d,J=7Hz,lH:Hen2);6.56(s,1H:Hen 10); 7.48 (t, J=7.5-z, 2H: OCOC6H5 H in meta); 7.63 (t, J = 7.5Hz, lH:
OCOC6HsH in para); 8.19 (d, J = 7.5 Hz, 2H: OCOC6HsH in ortho).
Erl operating under conditions similar to those described in example 3, benzoylcxy-2a &ydroxy-113,10~ 1 -('yl~ilyl~.y)-7~l3 epoxy- is prepared 5j3,20 ~ u~c~ y 4a oxo-9 taxene-ll whose ~ , are the following:
- 1H NMR spectrum (400 MHz; CDCI3; ~ in ppm): 0.57 and 0.69 (2 mts, 6H
each: ethyl CH2); 0.94 and 1.03 (2t, J=7.5Hz, 9H chaclm: ethyl CH3);
1.09 (s, 3H: CH3); 1,1,~ (s, 3H: CH3); 1.58 (s, 1H:OH to 1); 1.75 (s, 3H: CH3); 1.93 and 2.49 (2 mts, 1H each: CH2 at 6); 2.03 (s, 3H: CH3); 2.09 and 2.18 (2 dd, J = 16 and 9 Hz, lH each ~ n: CH2 at 14); 3.57 (s, 3H:OCH3); 3.88 (d, J=7Hz, lH:
H in 3); 4.16 and 4.40 (2d, J=16Hz, 1H each: OCOCH2O); 4.20 and 4.36 (2d, J = 9 Hz, lH each: CH2 in 20); 4.23 (s wide, 1H:OH in 10); 4.42 (mt, lH:H
en7);4.97(t,J=9Hz,1H:Hen13);5.01 (dlarge,J=1OHz,1H:Hen5);5.17 (slarge,1H:Hen10),5.62(d,J=7Hz,1H:Hen2);7.47(t,J=7.5Hz,2H:
OCOC6Hs H in meta); θ7.61 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para); 8.18 (d, J=
7.5 Hz, 2H: OCOC6Hs ~1 in ortho).
By operating under 3 conditions similar to those described in Example 3, preparing the b ~ (III;, ~ .y ~ y) -4a, 1013 carbonate-1 ~, 2a IJ; ~ L.Jl ~ ilylOxy) 7 ~ 3,13a epoxy-5 ~, 20 oxc ~ 9 taxene-ll whose. ~ are the following:
- 1H NMR spectrum (400 MHz; CDC13; o in ppm): 0.60 and 0.68 (2 mts, 6H
each: ethyl CH2); 0.92 and 1.01 (2 t, J=7.5 Hz, 9H each: CH3 of ethyl);
1.19 (s, 3H: CH3); 1.27 (s, 3H: CH3); 1.75 (s, 3H: CH3); 1.91 and 2.63 (2 mts, lH each: CH2 at 6); 2.0~ and 2.41 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 2.12 (s, 3H: CH3); 3.44 (d, J=6.5Hz, 1H:H at 3); 3.46 and 3.50 (2s, 3H each:
OCH3); 4.06 and 4.14 (~d, J=16 Hz, lH each: OCOCH2O); 4.16 (s, 2H:
OCOCH2O); 4.46 (dd, J=10 and 7Hz, 1H:H at 7); 4.50 and 4.66 (2d, J=9Hz, 1H each: CH2 at 20); 4.51 (d, J=6.5Hz, 1H:H at 2); 4.99 (mt, 1H:H at 13);
5.00(dlarge,J=1OHz,1H:Hen5);6.51(s,1H:Hen10).

O~' 1 woss/33736 21 9 ~) r~llr~ 5.

EXF.MPI.F. 6 By operating as in example 3, and starting from tert-b~u~w~ul.rl-3-amino-2-hydroxy-3-phenyl~, (2R,3S) of ~.~uyl~y-2a~;y~,luyl~ulvylu~y-4a epoxy-5 ~, 20 hydroxy-l ~ o: ~ o-9 I.l6 ~ u ~ ya ~ y-10 ~ llinuu ~, ''fo ~ .yloxy-7 ~ taxene-ll yl-13a, tert-hu ~ u, .y ~ allJullylLullulu-3 hydroxy-2-phenyl-3 is prepared (2R,3S) of benzoyloxy-2a ~, 1u ~ luparluylu ~ y-4a epoxy-5 ~, 20 hydroxy-1 ~ It .;; Illu ~. ~ a ~, ~; 'u ~ y-10 ~ methylene-7 ~, 8 nor-19 oxo-9 taxene-ll yle-13a whose . r. 1~1 . are the following:
- 1H NMR spectrum (400 MHz; CDC13; hr''~ close to 333K, o en ppm): 0.80 81.40 (mt, 4H: CH2CH2 du ~, lU~JlVU,y~); 1.30 (s, 6H: CH3); 1.35 (s, 9H: C(CH3)3); 1.30 to 1.40 (me~1H:H in 7); 1.70 and 2.23 (2 dd, ,,s~ . J = 6 and 5.5 Hz and J = 10 and 5.5 Hz, 1H chdcun: CH2 at 19); 1.80 (mt, lH: CH du ~,y~,lu~lu~l~.); 1.735 (s, 1H:OH to 1); 1.86 (s, 3H: CH3); 2.11 and 2.44 (l~li~. d wide and dt, J = 16 Hz and J = 16 and 4.5 Hz, lH each: CH2 at 6);
2.34 and 2.50 (2 dd, J=16 and 5 Hz, 1H each: CH2 at 14); 3.22 (d, J = 4Hz, lH:
OH at 2'); 3.52 (s, 3H: OC-13); 4.08 and 4.28 (2 d, J = 9 Hz, lH each: CH2 in 20); 4.13 (d, J=7Hz, 1H:H at 3); 4.16 and 4.24 (2 d, J= 16 Hz, lH each:
OCOCH2O); 4.62 (d, J=4.5Hz, 1H:H at 5); 4.70 (d la~e, J = 4 Hz, lH: H in 2'); 5.2-3 (limiting AB, 2H: H3' and CONH); 5.70 (d, J=7Hz, 1H:H at 2); 6.23 (tlarge, J=9Hz, 1H:H at 13); 6.42 (s, 1H:H in 10); from 7.20 to 7.45 (mt, 5H:H
auullldti ~ u ~, ~ in 3 '); 7.52 (t, J=7.5 Hz, 2H: OCOC6Hs H in meta); 7.61 (t, J = 7.5 Hz, 1H: OCOC6Hs H in para); 8.14 (d, J= 7.5 Hz, 2H: OCOC6Hs H in ortho).
By operating under conditions similar to those described in Example 3, tert- ~ y ~, allJul ~ 3 hydroxy-2-phenyl-3 1 "', (2R, 3S) of benzoyloxy-2a c ~ lu ~, l. . ,~loxy4a epoxy-513,20 hyd7~0xy-l~ n.;~lluA~a~ y-10~
oxo-9 1~ illuul~ lu~ y-7l3 taxèlle-l l yle-l3a do;lt les ~ - - sollt the following:
- 1H NMR spectrum (400 MHz; CDCI3; o in ppm): from 0.85 to 1.40 (mt, 4H:
CH2CH2 of ~, lu ~ llulJyl ~); 1.22 (s, 3H: CH3); 1.24(s, 3H: CH3); 1.39 (s, 9H:
C(CH3)3); 1.70 (s, 1H OH ell 1); 1.83 (mt, 1H: CH du~,lu~J~u~yl~); 1.88 (s, 3H:
CH3); 2.05 (s, 3H: CH3); 2.23 and 2.84 (2 mts, 1H each: CH2 at 6); 2.34 and 2.42 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 3.35 (d, J=5.5Hz, 1H:OH at 2');
3.52 (s, 3H:OCH3); 3.96 (d, J=7Hz, 1H:H at 3); 4.16 and 4.25 (2 d, J = 16 Hz, lH each: OCOCH2O); 4.17 and 4.28 (2d, J=9Hz, 1H each: CH2 at 20); 4.72 2~ q~5 1 ~ WO95133736 P~rA,~

(mt, 1H:H at 2'); 4.81 (d wide, J=10Hz, 1H:H in 5); 5.28 (d wide, J=10Hz, lH:Hen3');5.36(d,J=lOHz,lH:CONH);5.48(dd,J=10.5et7Hz,lH:Hen 7);5.72(d,J=7Hz,1H:Hen2);6.11(mt,1H:Hen13);6.71(s,1H:Hen10);
from 7.25 to 7.45 (mt, 5H: H cuUillo.Li4u - in 3'); 7.52 (t, J=7.5Hz, 2H: OCOC6H5H
in meta); 7.65 (t, J = 7.5 Hz, lH: OCOC6H5 H in para); 8.08 (d, J= 7.5 Hz, 2H:
OCOC6H5 H in ortho).
In opérarlt under conditions arlalogs has ceaes described in example 3, tert-l, u ~ u ~ y ~ culJullyl-3 (methoxy-4 phenyl) -2 phenyl4 is prepared., ~ -1,3 u ~ y '5 (2R, 4S, 5R) of benzoyloxy-2 ~: yclu ~ Jl ~ ollvyloxy4 epoxy-5 ~, 20 hydroxy~ilu~a~elui~y-10~oxo-9 IHnuu~.rlu~lcy-7l3 taxene-ll yle-13dontles. ", I~ I;, I..F; are as follows:
- 1H NMR spectrum (400 MHz; CDCI3: â in ppm): from 0.50 to 1.50 (mt, 5H: CH
and CH2 of cyclo ~ lu ~ yl); 1.04 (s, 9H: C(CH3)3); 1.17 (s, 3H: CH3); 1.19 (s, 3H:
CH3); 1.65 (s, 1H:OH to 1); 1.72 (s, 3H: CH3); 1.84 (s, 3H: CH3); 2.14 and 2.32 (2 dd, J = 16 and 9 Hz, lH each: CH2 at 14); 2.16 and 2.79 (2 mts, lH each: CHz in 6); 3.52 (s, 3H:OCH3); 3.82 (s, 3H: ArOCH3); 3.86 (d, J=7Hz, 1H:H at 3);
4.11 and 4.24 (2d,J=9Hz, 1H each: CH2 at 20); 4.15 and 4.22 (2 d, J = 16 Hz, lH
each: OCOCH2O); 4.60 (d, J=4.5Hz, 1H:H at 2'); 4.74 (d wide, J=10Hz, lH:Hen5);5.44(dd,J=10.5et8Hz,lH:Hen7);5.50(mt,1H:Hen3');5.67 (d, J = 7 Hz, lH: H in 2JI; 5.88 (mt, lH: H in 13); 6.41 (m~F, lH: H in 5'); 6.61 (s, 1H:H in 10); 6.92 (d, J=8.5Hz, 2H:H~1 ortho to OCH3); 7.38 (d, J = 8.5 Hz, 2H: H ~u.. Li.~ in meta of OOEli3); from 7.25 to 7.45 (mt, 5H:H
, . in 3'); 7.49 (t, J=7.5 Hz, 2H: OCOC6Hs H in meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.02 (d, J = 7.5 Hz, 2H: OCOC6Hs H in ortho).
By operating under conditions analogous to those described in Example 3, 2-benzoyloxy is prepared ~, IUIJII I ylu ~ y4-dihydroxy-1 ~, 13-epoxy-5 ~, 20 ~ucal~ ~t~y-10~ oxo-9 llinu~u, ~ ~1u~y-713 taxene-llwhose r~ t~F- ~ are as follows:
- 1H NMR spectrum (400 MHz; CDC13; i , ' ~, of 333K, ~ in ppm): from 0.90 to 1.40 (mt, 4H: Cll2CH2 du ~,y~,lu~JIu~.rld); 1.10 (s, 3H: CH3); 1.22 (s, 3H:
CH3); 1.61 (s, 1H:OH to 1); from 1.70 to 1.85 (mt, 2H: CH of cy ~ .lol) lu ~. and Oh in 13); 1.90 (s, 3H: CH3); 2.22 and 2.86 (2 mts, 1H each: CH2 at 6); 2.26 (s, 3H:
CH3); 2.36 (d, J=9Hz, 2H: CH2 at 14); 3.52 (s, 3H:OCH3); 4.05 (d, J=7Hz, 1H:H in 3); 4.14 and 4.22 (2d, J=16Hz, 1H each: OCOCH2O); 4.20 and 4.36 (2 wo ssn3736 2 1 ~ 3 6 5 l ~ ~l/r~7~ .sa ~

d, J = 9 Hz, lH each: CH2 at 20); 4.84 (mt, 1H:H at 13); 4.85 (d wide, J=10 Hz,lH:Hen5);5.54(dd,J=llet8Hz,lH:Hen7);5.72(d,J=7Hz,lH:H
in 2); 6.73 (s, 1H:H in 10); 7.51 (t, J=7.5 Hz, 2H: OCOC6H5 H in meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.12 (d, J=7.5Hz, 2H:OCOC6H5H in 5 ortho) By operating under conditions similar to those described in Example 3, preparing the Ih.k ~ ylu ~ y-2a ~, yl ~ y 4 dihydroxy-1 ~, 13a epoxy-5 ~, 20 ~ h~ y-1013 oxo-9 hinuu., '' ~lo,.y-7~ taxene-ll whose .,,u, , are as follows:
- 1H NMR spectrum (400 MHz; CDCI3; 1, ~, of 333K, δ in ppm): from 0.90 to 1.40 (mt, 4H: CH2CH2 du .;~lu~yl~); 1.10 (s, 3H: CH3); 1.22 (s, 3H:
CH3); 1.61 (s, 1H:OH to 1); from 1.70 to 1.85 (mt, 2H: CH du ~y~;lO~ Jyl~ and OH
in 13); 1.90 (s, 3H: CH3~; 2.22 and 2.86 (2 mts, lH each: CH2 in 6); 2.26 (s, 3H:
CH3); 2.36 (d, J=9Hz, 2H: CH2 at 14); 3.52 (s, 3H:OCH3); 4.05 (d, J=7Hz, 1H:H in 3); 4.14 and 4.22 (2~1, J=16Hz, 1H each: OCOCH2O); 4.20 and 4.36 (2d, J=9Hz, 1H each: CH2 at 20); 4.84 (mt, 1H:H at 13); 4.85 (d wide, J=10 Hz,lH:Hen5);5.54(dd,J=llet8Hz,lH:Hen7);5.72(d,J=7Hz,lH:H
in 2); 6.73 (s, 1H:H in 10); 7.51 (t, J=7.5 Hz, 2H: OCOC6H~H in meta); 7.63 (t, J = 7.5 Hz, 1H: OCOC6H5 H in para); 8.12 (d, J=7.5Hz, 2H:OCOC6H5H in ortho) By operating under conditions similar to those described in Example 3, we prepare the ~.~ y-2a ~.lvl, . ,.~lv~y~ IY~(hi;~h~lsiurlv~y)-7~13a epoxy-5 ~,20 hydroxy~ ~é.wy-10~ oxo-9 taxene-ll whose are the following:
- 1H NMR spectrum (400 MHz; CDC13 ~ in ppm): 0.60 and 0.68 (2 mts, 6H
each: ethyl CH2); from 0.90 to 1.35 (mt, 4H: CH2CH2 du .,~,.u~l~,); 0.94 and 1.03 (2t, J=7.5Hz, 9H each: CH3 of ethyl); 1.14 (s, 3H: CH3); 1.20 (s, 3H:
CH3); 1.64 (s, 1H:OH to 1); 1.71 (s, 3H: CH3); 1.73 (mt, lH CH du ~ ); 1.87 and 2.50 (.~li~ dd wide and mt, J = 14 and 11 Hz, lH
each: CH2 in 6); 2.11 and 2.29 (2 dd, J=16 and 9 Hz, 1H each: CH2 at 14); 2.15 (s, 3H: CH3); 3.53 (s, 3H: C-CH3); 3.86 (d, J=7Hz, 1H:H at 3); 4.14 and 4.26 (2 d, J = 9 Hz, lH each: CH2 at 20); 4.19 (AB limit, J=16Hz, 2H: OCOCH2O);
4.52(dd,J=llet7Hz,lH:Hen7);4.84(dlarge,J=lOHz,lH:Hen5);4.95(t wide,J=9Hz,lH:Henl3);5.65(d,J=7Hz,lH-Hen2);6.56(s,1H:Hen ~ wossl33736 21 ~165 ~ r~llr ~ ~a~

10); 7.50 (t, J=1.5 l-z, 2H: OCOC6Hs H in meta); 7.62 (t, J = 7.5 Hz, lH:
OCOC6Hs H in para); 8.09 (d, J=7.5 Hz, 2H: OCOC6H5 H in ortho).
E;n operating under conditions similar to those described in Example 3, benzoyloxy-2a ~, lv ~ uAr-4a-dihydroxy-113,1013 bis(triethyl-silyloxy) -713,13a-epoxy-513,20-oxo-9-taxene-ll which ~.~. are the following:
- N.M.R. spectrum. lH (400 MHz; CDCI3: S in ppm): 0.58 and 0.68 (2 mts, 6H
each: ethyl CH2); 0.90 to 1.35 (mt, 4H: CH2CH2 of l;.r., lv~ rle); 0.94 and 1.03 (2t, J=7.5Hz, 9H[ each: CH3 of ethyl); 1.12 (s, 3H: CH3); 1.22 (s, 3H:
CH3); 1.59 (s, 1H:OH to 1); 1.67 (mt, lH: CH du ~r~, lv~lu~yle); 1.73 (s, 3H:
CH3); 1.90 and 2.44 (2 mts, 1H each: CH2 at 6); 2.06 (s, 3H: CH3); 2.10 and 2.25 (2dd,J=16and9Hz,l~leach:CH2enl4);3.91(d,J=7Hz,lH:Hen3);4.16 and 4.26 (2d, J=9Hz, 1H each: CH2 at 20); 4.28 (d, J = 1.5 Hz, lH:OH en en 10);4.42(dd,J=llet6Hz,1H:Hen7);4.841(dlarge,J=1OHz,1H:Hen5);
5.00(t,J=9Hz,1H:E~len13);5.16(d,J=1.5Hz,1H:Hen10);5.62(d,J=7 Hz, 1H:H in 2); 7.50 (t, J=7.5 Hz, 2H: OCOC6H5 H in meta); 7.62 (t, J = 7.5Hz, 1H: OCOC6H5 H in para); 8.09 (d, J=7.5 Hz, 2H: OCOC6H5 H in ortho).
Carbonate-1~,2t~~.,lol,.v~ vylv~y-4a bi~(L i;, .ybil~ r)-7~,13 epoxy-5~,20 llléLll~ac~Lu~r-lofl oxo-9 taxene-ll can be prepared as follows:
To a solution of 100 mg of carbonate-1 ~, 2a L, i ~ (L i ~ llrl ~ ilyloxy) -7 ~, 13a epoxy-5 ~, 20 hydroxy4c ~; llw ~ y ~ C ~ LIJ ~ r-10 ~ o ~ o-9 taxene-ll in 7 cm3 of LI~l~Lurl . 345 μl of a lM solution of , ~ '' lithium in hexane, at a ~ a ~ close to -30C. the reaction mixture is stirred for 15 minutes at this t ~ cL ~ p us is added, dropwise, 39 ~ I of chloride ~ u ~ vyle. The reaction mixture is stirred for 30 minutes at a L.-~ L.--~ near 0C then hydrolyzed by addition of 1 cm3 of a solution ~: ion saturated with chloride of i and 50 cm3 of dichlu.. The organic phase is decanted, washed with 2 times 40 cm3 of a 30 p us saturated aqueous solution of sodium chloride dried over O 'sulfate filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We get 120 mg of a product purified by ~}.. ~ on 70 g of silica (0.063-0.2 mm) contained in a colum of 2 cm in diameter, eluting with an acetate mixture ethyl-~, '' (20-30 by volume) and collecting fractions of 10 cm3. The 2 l qo6~ l wo ss/33736 ~Is~

fractions containing only the desired product are combined and ~ ~,~ dry under reduced pressure (2.7 kPa) at 40C. 31 mg of carbonate-1~,2a are obtained u~a Ivylu~ 4a bia(L~ bilylu~)-7~13a epoxy-5~,20 ~ LlluA~a~,~tv~y-10 oxo-9 taxene-11 s^vus forms a white meringue whose, ^ ,..
physical are as follows:
- 1H NMR spectrum (400 MHz; CDC13: v in ppm): 0.60 and 0.66 (2 mts, 6H
each: ethyl CH2); 0.90 to 1.35 (mt, 4H: CH2CH2 du ~); 0.92 and 1.02 (2t, J=7.5Hz, 9H each one: ethyl CH3); 1.19 (s, 3H: CH3); 1.29 (s, 3H:
CH3); 1.60 (s, 1H:OH to 1); 1.62 (mt, 1H: CH du ~, lu ~ lu ~ ); 1.73 (s, 3H:
CH3); 1.88 and 2.57 (.~L;~. dd wide and mt, J = 15 and 10 Hz, lH each: CH2 in 6); 2.15 (s, 3H: CH3); 2.19 and 2.37 (2 dd, J - 16 and 9 Hz, lH each: CH2 in 14); 3.48 (d, J=7Hz, 1H:H at 3); 3.51 (s, 3H:OCH3); 4.16 (s, 2H:
OCOCH2O); 4.44 (mt, lH: H in n; 4.45 and 4.54 (2 d, J=9 Hz, lH each: CH2 in 20); 4.49 (d,J=7Hz, 1H:H at 2); 4.85 (d wide, J=10Hz, 1H:H in 5); 5.02 (t wide, J = 9 Hz, lH: H at 13); 6.52 (s, 1H:H in 10).
The new products of general formula (I) in which Z represents a radical of general formula (II) r '' an inhibitory activity s. ~ LricaLv ~ of the ; r; l ~ LLu ~ abnormal cell and have properties allowing ~
the treatment of patients with conditions ~ v. associated with a 20 ~ vl; r; laLu ~ abnormal cell. The conditions I - ' ~ i include the ~ulire~.sliu abnormal cells of malignant or non-malignant cells of various tissues and/or organs, . ~ t, in a non-limiting way, the tissues 'ca, bone or ~^~^,~j.^,n~ the skin, the brain, the lungs, the sexual organs, the systems 1 ~, '. or kidneys, the marmary or blood cells, the liver, the 25 digestive system, the pancreas and the thyroid or adrenal glands. These conditions '~ . may also include psoriasis, solid tumors, cancers ovary, breast, brain, prostate, colon, stomach, kidney or testicles, Kaposi's sarcoma, ^hr~ ,uwll~, Ie ~llu~;ul,al~.ulv~, ~I~,~ublaaAJl.~ Wilms tumor, Hodgkin's disease, the "les 30 multiple myeloma, the ~ c, emia 1. ~ I .y Ll ~ ~ i. the lymphomas acute or chronic granulocytic. The new products according to the invention are ' ` . useful for the treatment of ovarian cancer. The products according to the invention can be used to prevent or delay the onset or '~1'~';1;'''~ of the conditions I 'I~, l or to treat these conditions 35 1 ~ 1u ~, .

~ WO 9 ~ 1 ~ 3736 2 1 9 ~ 6 5 1 r ~ l ~ rl, ~

The products according to the invention can be administered to a patient according to different shapes adapted to the ~ route chosen which, preferably, is the channel 1 ~ The. 'parenterally includes the ~ "U; ~
.. - . I. - ' ~ or subcutaneous. More ~ iC.
- 5 preferred is the Arl ~ t.-~ or it ~ L ~
The present invention also includes ~ phatmaceu-ticks which, at least one product of general formula (I) in an amount sufficient suitable for remploi in ~ A;. ~ human or veterinary ~ ure. The e~p. ~ Can be prepared according to the usual methods using one or more adjuvants, suppotts or excipients ~,,. qr.-qpfqhl~
media wll~n~u~ include diluents, sterile aqueous media and miscellaneous non-toxic solvents. Preferably the r ~ are in the form of solutions or s ~ i ~ ..c;. ~ aqueous solutions, injectable solutions which may contain agents, ~ - ', dyes, ~ l ~ l vaLi ~ or - ~ tqhi ~ iCq-f- ~
The choice of adjuvants or excipients can be determined by the solubility and the chemical properties of the product, the particular mode of ' and the good practices ~l., , For the parenteral, we use solutions or! 1~ "`;"
sterile aqueous or not, ~ queuS-es. For the preparation of solutions or ~
20 non-aqueous can be used natural vegetable oils such as oil olive oil, sesame oil or paraffin oil or injectable organic esters such as than ethyl oleate. Sterile aqueous solutions may consist of a solution of a salt ~ aoceptable in solution in water. The aqueous solutions WIIV'' for l- ' i it. ~ ~ insofar as 25 the pII is w.... '' adjusted and where isotonicity is achieved, for example, by a sufficient amount of sodium chloride or glucose. The cfrrjlicq~rn can be carried out by heating or by any other means which n ~ does not alter the r, ~ ~ '1~ '';1;"' It is understood that all the products entering the ~ according to the invention must be pure and non-toxic for the amounts used.
The ~; l; .. nc may contain at least 0.01% of therapeutic product only active. The quantity of active product in a ~ is such that a dosage wnvenable p ~ isse be prescribed. Preferably, the ~.Y~ are prepared so that a unit dose contains from 0.01 to about 1000 mg of active product for the ' by way p--~ '-woss/33736 2 1 ~ Q 6 5 1 p~l/rlv~. ,~s~, Processing ~ can be performed ~:UII~.UI~ 'with other treatments i,, incl ~ ant of AA ~; .l.'U ~ CI; q. ~. antibodies therapies;~ OR .",1: ,l1,~ .; or "~answers~O . Mo~'r answers include, of 'im ~ uuère non-limiting, the 1 ~ ~ 'and the cytokines ter ~ es that the Uli ~ ''', the interferons (a, ~ or o) and TNF. Other Ahimiulll ~ u ~ agents useful in the treatment of disorders due to abnormal ~ nulir ~ _Lv ~ l include, of non-limiting manner, arkylating agents such as nitrogen mustards such as ll.~Llv~ the ~. ', ' . '' the melphalan and the . '1,. A ~ 1, sulfonates 10 arkyle such as busulfan, rUUU ~ such as, AAr ~ m ~ tjn ~ lomustine, semustine and the ~L~ ;.. . Ies triazenes like the ~- ' the hnlit~q such as analogs of folic acid such as III;; llv ~ analogs of pyrimidine like fluorouracil and cjAtarabine, purine analogs like He..,~. -1 ~ l ~ 'IJ; ~ and the tl O of natural products such as vinca alkaloids 15 such as vinWastine, vincristine and vendésirle, C~ vdv~}.rr~uluAu.~ like etoposide and teniposide, A..:: l.; .ll; .l ~ as the ~.LIIv ~, ulc. the ~ urv., ' the dUA ~ VlULl; ~ the l, l ~ o ". ~. the PI; ~ U ~ and the X y ~, UI ~ of the enzymes such as k., ,, , various agents such as complexes of platinum such as cisplatin, substituted ureas such as 20 rl-~ vA-.~...~, derivatives of Y-' r~ u* such as yllJr~
- . 1 u~,..~ _n~ . such as mitotane and ~minn~ ''ry' hormones and . - ~ -g....: .~ ~ like the a~l..,..~vl ~;~v~.~"v;des like the ~JI~ ' .
Ies ~ IVo_ ~ t; ll ~., such as caproate of ~ dIVA ~ JIVO ~ VII ~ acetate of ~ ,, . ~ and megestrol acetate, 1- vO ~. ~ S as the 25 diethylstilbestrol and I ~ L ~ lly ~ iol ~ the Aull; v ~ LvO_ .. ~ cotnme the t ~ moYif ~ n ~ the vO .._~ such as L~tU~ propionate.. and auvA~
The doses used to implement the methods according to the invention are cer ~ es that allow treatment ~, read ~ u ~ or maximum response li , Doses vary depending on the form of the particular product 30 selected and the . . specific to the subject to be treated. In general, the doses arecircles which are i' . . effective in the treatment of disorders due to uliri~ liul~ oerlulaire abnormal. The products according to the invention can be administered as often as necessary to obtain the desired effect III ~.
Some patients may respond quickly to '~_.I.~.'doses; strong or Weak 35 may need low or no maintenance doses. C~. 't of 21 9065 1 ~
WO95133736 1~5 low doses will be used at the start of treatment and, if necessary, higher doses stronger will be a' until an optimum effect is obtained. For other patients it may be necessary to '~,. maintenance doses 1 to 8 times a day, preferably 1 to 4 times, depending on the needs of the patient concerned. He is - 5 as possible that for some patients it is necessary to use only one or two In humans, the doses are g, . ..~. AI.~ t between 0.01 and 200mg/kg. Per route, the doses will generally be between 0.1 and 100 mg ~ g and, preferably between 0.5 and 50 mg / kg and, even more, ~, 10 between 1 and 10 mg/kg. By way i ~ o ~ the doses are L ~ .. "I ~ included between 0.1 and 50 mg ~ cg and preferably between 0.1 and 5 mg ~ cg and even more - between 1 el: 2 mg~g. It is understood that, in order to choose the dosage most appropriate, must be taken into account the way of ~, a;.~.., the weight of the patient, his general state of health, his age and all the factors which can influence the efflca ^
15 quoted from the treatment.
The following example illustrates a. ~ according to the invention.
F.XEl~Pr .F.
40 rrlg of the product obtained in Example 1 are dissolved in 1 cm3 of EIl ~ ul ~
EL 620 and 1 cm3 of ethanol then the solution is diluted by adding 18 cm3 of serum 20 ~ 'o~, The ~ li is administered by infusion for 1 hour by introduc-h~darlsdusolutepuydol~

Claims (7)

56 1- New taxoids of general formula:
(I) in which:
Ra represents a hydrogen atom or a hydroxy, alkoxy containing 1 to 4 carbon atoms, acyloxy containing 1 to 4 carbon atoms or alkoxyacetoxy radical whose alkyl part contains 1 to 4 carbon atoms and Rb represents an atom of hydrogen or else Ra and Rb form together with the carbon atom to which they are linked a ketone function, Z represents a hydrogen atom or a radical of general formula:
(II) in which:
R1 represents a benzoyl radical optionally substituted by one or several atoms or radicals, identical or different, chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms or trifluoromethyl, thenoyl or furoyl, or a radical R2-O-CO- in which R2 represents:
- an alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, bicycloalkyl containing 7 to 10 carbon atoms, these radicals optionally being substituted by one or more substituents chosen from halogen atoms and hydroxy, alkoxy radicals containing 1 to 4 carbon atoms, dialkylamino including each alkyl part contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl (optionally substituted by one or several atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy radicals containing 1 to 4 carbon atoms carbon), cyano, carboxy or alkoxycarbonyl in which the alkyl part contains 1 to 4 carbon atoms, - a phenyl or .alpha.- or .beta.-naphthyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms or a 5-membered aromatic heterocyclic radical preferably chosen from furyl and thienyl radicals, - or a saturated heterocyclyl radical containing 4 to 6 carbon atoms optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, -R3 represents a straight or branched alkyl radical containing 1 to 8 atoms of carbon, straight or branched alkenyl containing 2 to 8 carbon atoms, straight alkynyl or branched containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, carbon, phenyl or .alpha.- or .beta.-naphthyl optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryl, aralkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl-amino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and trifluoromethyl, or a 5-membered aromatic heterocycle containing one or more heteroatoms, identical or different, chosen from nitrogen, oxygen or sulfur atoms and optionally substituted by one or more substituents, identical or different, chosen from halogen atoms and alkyl, aryl, amino, alkylamino, dialkylamino, alkoxycarbonylamino, acyl, arylcarbonyl, cyano, carboxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl or alkoxycarbonyl, being understood that, in the substituents of the phenyl radicals, .alpha.- or .beta.-naphthyl and aromatic heterocyclyls, alkyl radicals and alkyl portions of other radicals contain 1 to 4 carbon atoms and that alkenyl radicals and alkynyls, 2 to 8 carbon atoms and that aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals, and R4 and R5, identical or different, represent - a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl straight or branched containing 2 to 8 carbon atoms, straight or branched alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents selected from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino each of which is alkyl contains 1 to 4 carbon atoms, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenylalkyl radical whose alkyl part contains 1 to 4 carbon atoms carbon), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl in which the alkyl part contains 1 to 4 atoms of carbon, -or an aryl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl, alkenyl, alkynyl, aryls, aralkyls, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonyl-amino, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethyl or trifluoromethoxy, being understood that R5 cannot represent a methyl radical or a radical saturated or unsaturated heterocyclyl containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, it being understood that R5 cannot represent a methyl radical, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals may optionally be substituted by one or more alkyl radicals containing 1 to 4 carbon atoms. 2 - New taxoids according to claim 1 for which Ra represents a hydroxy, alkoxy radical containing 1 to 4 carbon atoms, acyloxy radical containing 1 to 4 carbon atoms or alkoxyacetoxy in which the alkyl part contains 1 to 4 carbon atoms carbon and Rb represents a hydrogen atom, Z represents a hydrogen atom or a radical of general formula (II) in which R1 represents a benzoyl radical or a radical R2-O-CO- in which R2 represents a tert-butyl radical and R3 represents an alkyl radical containing 1 to 6 carbon atoms, alkenyl containing 2 with 6 carbon atoms, cycloalkyl, containing 3 to 6 carbon atoms, phenyl optionally substituted by one or more atoms or radicals, identical or different chosen from halogen atoms (fluorine, chlorine) and alkyl radicals, alkoxy, dialkylamino, acylamino, alkoxycarbonylamino or trifluoromethyl or a 2- or -3-furyl, 2- or -3-thienyl or 2-, -4- or -5-thiazolyl radical and R4 represents a phenyl radical optionally substituted by one or more identical or different atoms or radicals, chosen from halogen atoms and alkyl radicals, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino, azido, trifluoromethyl and trifluoromethoxy, or a thienyl-2 or -3 or furyl-2 or -3 radical and R5 represents an optionally substituted alkyl radical containing 1 to 4 atoms carbon, it being understood that R5 cannot represent a methyl radical. 3 - New taxoids according to claim 1 for which Ra represents a hydrogen atom or a hydroxy or acetyloxy or methoxyacetoxy radical and Rb represents a hydrogen atom, Z represents a hydrogen atom or a radical of general formula (II) in which R1 represents a benzoyl radical or a radical R2-O-CO- in which R2 represents a tert-butyl radical and R3 represents a radical isobutyl, isobutenyl, butenyl, cyclohexyl, phenyl, furyl-2, furyl-3, thienyl-2, thienyl-3, thiazolyl-2, thiazolyl-4 or thiazolyl-5 and R4 represents a radical phenyl optionally substituted by a halogen atom and R5 represents a radical alkyl containing 2 to 4 carbon atoms. 4 - Process for preparing a product according to one of claims 1 to 3 characterized in that one treats with an alkali metal halide or an azide of alkali metal or a quaternary ammonium salt or an alkali metal phosphate a product of general formula:
(III) in which Z, R4 and Rs are defined in one of claims 1 to 3, Ra represents a hydrogen atom or an alkoxy, acyloxy, alkoxyacetoxy radical or a protected hydroxy radical, and Rb represents a hydrogen atom, then replaces optionally the protective group represented by Ra by an atom of hydrogen. 5 - Process for preparing a product according to one of claims 1 to 3 wherein R4 and R5 are defined as in one of claims 1 to 3 and Ra and Rb each represent a hydrogen atom characterized in that one reduces by electrolytically a product according to one of claims 1 to 3 for which Ra represents a hydroxy, acyloxy or alkoxyacetoxy radical. 6 - Process for preparing a product according to one of claims 1 to 3 wherein R4 and R5 are defined as in one of claims 1 to 3, Ra and Rb form together with the carbon atom to which they are linked a function ketone characterized in that a product according to one of claims 1 to 3 for which Ra represents a hydroxy radical and Rb represents an atom of hydrogen. 7. Pharmaceutical composition in that it contains at least a product according to one of claims 1 to 3 for which Z represents a radical of general formula (II) in combination with one or more products pharmaceutically acceptable whether they are inert or pharmacologically active.