CA2175384A1 - Novel taxoids, their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Novel taxoids of general formula (I), their preparation and pharmaceutical compositions containing them. In general formula (I), Ar is an aryl, alkyl, alkenyl, cycloalkyl or cycloalkenyl radical; R is a hydrogen atom or an alkanoyl, alkyloxyacetyl or alkyl radical; R¿1? is a benzoyl radical or a radical of formula R¿2?-O-CO-, wherein R¿2? is an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, bicycloalkyl, phenyl, heterocyclyl radical and R¿3? is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, bicycloalkyl, optionally substituted aryl (excepting non-substituted phenyl) or heterocyclyl radical. The novel products of general formula (I) have remarkable antitumor activity.

Description

~ WO 9 ~ / 13271 2 1 7 5 3 8 4 PCTml94 / 01283 NEW TAXOID ~ S. THEIR FPARATlON AND L F. ~ COMPOSITIONS
PHARMACEUTIOUES YES T FS CONTAIN
The present invention relates to new taxoldes of general formula:
R1-N H o ~ ~
- OCOCH

5 their ~ llivll and ~. who them.
In the general formula (1), Ar represents an aryl, alkyl radical containing 1 to 4 carbon atoms, alkenyl containing 2 to 4 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms or ~: y ~ lo ~ L, é..yl ~ containing 3 to 6 carbon atoms, 10 R represents an atom of l. ~ U ~ or an alkanoyl radical, ah; v ~ .. ~ .yle or alkyl, R1 represents a benzoyl, thenoyl or furoyl radical or an R2-O-CO- radical in which R2 represents:
- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms Carbon, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms or bi ~, lv ~ l ~, vyl ~ containing 7 to 11 carbon atoms, these radicals being evpnt ~ pllpmp ~ substituted by ùn or more! '"'' choose among halogen atoms and hydroxy, alkoxy radicals containing 1 to 4 carbon atoms, didl ~; uyl ~ 0 of which each alkyl part contains 1 to 4 atoms of 20 carbon, piperidino, ~, l.olino, pipérazinyl-l (éVPntllPll substituted in -4 by a alkyl radical conterlant 1 to 4 carbon atoms or by a radical 1 ~ '.yl ~
whose alkyl part contains 1 to 4 carbon atoms), ~, y ~ .loaL, uyle containing 3 to 6 carbon atoms, ~ y ~ .lU ~ L ~ yl ~ containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or al ~, uyl ~ J ~ yw ~. the alkyl part of which contains 1 to 4 atoms of

2 ~ carbon, - or a phenyl radical, if necessary, substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 to 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, WO gS113271 PCTII ~ Rg4 / 01283 0 -- or a heterocyclyl radical sah ~ re or not sah ~ re containing 4 to 6 links and ev, nh ~ Pll ~ m ~ ^ nt substituted by one or more alkyl radicals containing 1 to 4 atoms carbon, and R3 represents 5 - a straight or branched alkyl radical containing 1 to 8 carbon atoms, slcényle containing 2 to 8 carbon atoms, alkynyl containing 2 to 8 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms, ~ '~''yl ~. containing 4 to 6 carbon atoms or l, i ~, ludlcvyle containing 7 to 11 carbon atoms, these radicals being C ~ "substituted by one or more. ^ ~. ~ h ~ l: l ..- .. l ~ selected 10 from halogen atoms and hydroxy, alkoxy radicals containing 1 to 4 carbon atoms, dialkoylamino, each alkyl part of which contains 1 to 4 atoms of carbon, piperidino, IIIU ~ 'pipérazinyl-l (L' ~. 'l ^ -n ^ nt substituted in -4 by a alkyl radical containing 1 to 4 carbon atoms or by a radical IJll6.l ~ 1dl ~, uyld whose alkyl part contains 1 to 4 carbon atoms), L, y, I ~ ~ yle containing 3 to 6 15 carbon atoms, ~ I ~ AIc ~ ..yle containing 4 to 6 carbon atoms, phenyl ev nt.l, ll, ^ m, ^ t substituted, cyano, carboxy or alkyl, .y ~, a ~ l.ollyle whose pattie alkyl contains 1 to 4 carbon atoms, - or an aryl radical ÉVrnf ~ lPm ~ nt substituted, it being understood that R3 cannot l an unsubstituted phenyl radical, 20 - or a radical l ~ L ~ Iu ~ yl, lyl ~ saturated or unsaturated containing 4 to 6 links and ev ~ nt. ~ PIlr-mPnt substituted by one or more alkyl radicals containing 1 to 4 atoms of carbon, it being understood that the radicals ~: yL; luàlcuylds, L, y ~ lodl., ~ lyl ~ or bicycloalcoyles can be ev ~ ~ lpllpmpnt substituted by um or more alkyl radicals 25 containing 1 to 4 carbon atoms.
Preferably the aryl radicals l ~ by Ar and R3 are radicals phenyls or - or ~ 3-naphthyls L '~ "r11" ~ 1 substituted by one or more atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals, alkenyls, alkynyls, aryls, aly ~ ~, alkoxy, alkylthio, aryloxy, 30 arylthio, hydroxy, llyLu ~ aluu ~ / lc ~ mercapto, formyle, acyl, acylamino, aluy ~ âhu ~ LyLa ~ ly '`~, amino, r ~ ylallllno ~ dialcoylamino, carboxy, al ~ u ~ yl, ~ ubullylc, ballluyl ~ "dialcoylcarbamoyle, cyano, nitro, azido, L iLluu ~ u ~ Lllu ~ y and LLi [1UUIUIII ~; IIYI ~ it being understood that the alkyl radicals and the alkyl portions of other radicals cnntipnnpnf 1 to 4 carbon atoms, than alkenyl radicals and 35 alkynyls ~: (... I, ~ .- ~ .t.ll 2 to 8 carbon atoms and that the aryl radicals are ~ WO95 / 13271 ~ 17 ~ 384 pCT ~ R94 / 01283 phenyl or cc- or ~ naphthyl rafts, and that the radical R3 cannot an unsubstituted phenyl radical.
Preferably the radicals l ~, by Ar and R3 are radicals II ~ Lélu ~ _y ~; l ;; L ~ .., having 5 strings and containing one or more ~ s 5 atoms, identical or different, ehoisis paumi the atoms of nitrogen, oxygen or sulfur, C. ~. "'substituted by one or more ider ~ ic or different, chosen among the halogen atoms (fluorine, chlorine, brosne, iodine) and the alkyl radicals containing 1 to 4 earbone stomes, a ~ yles containing 6 to 10 atoms of earbone, alkoxy containing 1 to 4 atoms of earbone, aryloxy containing 6 to 10 10 carbon atoms, amino, 'ylall "~ w containing 1 to 4 carbon atoms, "'~ .r; dl ~ U' each alkyl part of which contains 1 to 4 carbon atoms, acylamino of which the acyl part contains 1 to 4 carbon atoms, 'yl, all ull.rlalllilw containing 1 to 4 carbon atoms, acyl containing 1 to 4 carbon atoms, ~ yl ~ h ~ u ~ C of which the aryl part contains 6 to 10 carbon atoms, cyano, carboxy, wballlu ~
15 '~ yl ~ ballluyl ~ whose alkyl part contains 1 to 4 earbone atoms, diàll: uyluaLlJà ~ luyle of which each part alco ~ contains it 1 to 4 atoms of w-bone or al1uAyl.al, ullrle whose alkoxy part contains 1 to 4 carbon atoms, it being understood that the cycloalkyl, cycloalkenyl or bicycloalkyl radicals can be ev ~ nt ~ m ~ nf sub $ ituted by um or more alkyl radicals 20 containing 1 to 4 carbon atoms.
Plus ~ Lil ~ Ar represents a phenyl, thienyl-2 or -3 radical or fusyle-2 or -3 EV ~ nt ~ nn ~ nt sub $ ituted by one or more atoms or radicals, identical or different, chosen by hal halogen atoms and alkyl radicals, alkoxy, amino, 'y', dial ~ u, y- :), acylamino, ', ~, ~ bUIIJ' -I and 25 L ~ inuv ~ U ~ dalrl ~ and R3 represents a phenyl radical substituted by one or more identical or different atoms or radicals, selected from halogen atoms and alkyl radicals, alkoxy, amino, 'yl ~ l.illo, liàl ~ u, y'', acylamino, alkoxy-ylàll ~ v and Llinuulul ~ Lllyld.
Plus ~ ua ~ liculiè ~ lll ~ eneore, Ar represents a possible phenyl radical-30 Lement substituted by a chlorine or fluorine atom, or by an alkyl (methyl), alkoxy (methoxy), didlcuy; al ~ il ~ (dillléLllylaullillu), acylamino (acetyl-amino) or al ~ y ~ all ~ u., ylà, lliuw (tert-buLu ~ yuallJullylallliA ~) or thienyl-2 or -3 or furyl-2 or -3 and R3 represents a phenyl radical substituted by a halogen atom.
Of even more particular interest are the products of general formula (I) 35 in which Ar represents a phenyl radical and R1 represents a benzoyl radical or WOg5113271 PCTlFRg4 / 01283 0 tert.l, u ~ uAy ~, d.bu..yl ~ and R3 represents a phenyl rddical substituted by an atom halogen.
According to the invention the new t ~ txoids of general formula (I) can be obtained by ~ ctPrifir ~ t-'rn d'tm product of general formula:
OR ~ O (He) OH OCOa ~ 3 in which Ar and Rl are defined as ~. ~ l. ~, ..,., ~., ~ and, or else R4 represents an atom of llydLu5b ~ le and Rs represents a gluu ~ w ~ lel ~ t protective of the function hydroxy, or else R4 and Rs together form a 5- or 6-membered saturated heterocycle, Gl represents an alkanoyl (acetyl) radical, al ~, uAra ~ lyle (lll611l ~ JAra ~; etyl ~) or 10 alkyl (methyl) or a ~ uu ~, ~, .-- ~ t protective of the hydroAy function by means of a acid of general formula:
R3-CO-OH (III) in which R3 is defined as ~ f ~. or an activated derivative of this acid, to obtain a product of general formula:
R, ~ N, R ~ o ~ 0 in which Ar, Rl, R3, R4, Rs and Gl are defined as pL ~., the F.ll des ~; IUUp6111 ~ protectors Rs, when R4 represents an atom hydrogen, or R4 and Rs, when R4 and Rs together form a heterocycle saturated with 5 or 6 links, and évPnf ~ pllprnpnt Gl by atoms of l-y ~ ucbA ~, leads to 20 product of general formula (I) in passing éVpnh ~ pllf ~ mF ~ nt ~ according to the gign ~ fi ~ nc de R1, R4 and Rs, for a product of general formula:

"'~ (V) - OCOCH
CORa in which Ar and R are defined as ~ t, which is acylated by means of benzoyl, thenoyl or furoyl chloride or a product of general formula:
R2-O-CO-X (VI) 5 in which R2 is defined as 1 ~ 'and X represents a halogen atom (auor, chlorine) or a residue -O-R2 or -O-CO-O-R2 When R4 represents an atom of l ~ r ~ Lu ~., Rs preferably represents a radical ll.calu ~ y..l ~, ll.yle, ethoxy-l ethyl, benzyl ~ lld ~ lyld ~ .é ~ ilyld, triethylsilyl, (~ -t ~ yl ~; lyl_lllu ~ y) methyl or ~ ildlly ~ Lu} ~ yl ~.
When R4 and Rs together form a heterocycle, this is preferably a cycle, ~ - .1; .1 ;,). event ~ PII ~ n ~ Pnt mono-substituted or gem-disubstituted in position -2.
Preferably, Gl represents an acetyl or alkyl radical or a radical alkoxyacetyl.
The. ~,; R, ~ ;. ", of the product of general formula (II) can be carried out by reacting the acid of general formula (III) preferably in the form ~ "'~, c"
such as chloride, on the product of general formula (II) 1 '''' metallic. The mPt ~ llsfil ~ n is ~ n ~ r ~ lPmPnt made using an alkali metal alkyl such as butyllithium by operating in an inert organic solvent such as an ether 20 like the i '' yd ~ u ~, at ume t..ll ~ Ld ~ bC: less than -50C and, pr ~ preferably at neighborhood of -78C. The P ~ r ~ is gPnPrglPmPnt performed by operating at the same : in the same solvent.
According to the nature of the protective g. ~ of the product of general formula (IV), their In,., ~. .. - by atoms of l ~ ydlut ~ can be done in the way 25 next:
1) when R4 represents a hydrogen atom, Rs is defined as ~ P. ~
and Gl represents an alkanoyl (acetyl) radical, aL, u ~ d ~ yle (~ u ~ yle), alkyl (methyl), ,, .1; ~ by atoms WO95 / 13271 PCT / l; R94 / 01283 ~

-d'lly ~ Lu ~ .lF can be carried out by treating the product of general formula (IV ~ with a mineral acid (chlu.ll ~ ic acid, sulfuric acid, rluullly acid ~ Liquc) or organic (acetic acid, mrthAnpclllfonique acid ~ L inuulu acid ", 6G, ailF
sulfonic, acid r ~ r. . ~ used alone or in mixture while operating in a 5 organic solvent chosen from alcohols, ethers, esters,; ~ ydluu ~ lJ ~ t :: ~
A1, ~ .F ~, the l ~ y ~ u ~ w A1irhA-tir¦ ~ 1r ~ c halogenated, the; Iy ~ A cs ~ uu ~ L
or nitriles at an i, '~; between -10 and 60DC.
2) when R4 and Rs together form a ~. ~, T; .uu ~ saturated island with 5 or 6 chains ~ and more L ~, ul; ~ a cycle ~ 1 of general formula:
R1-N><O (VII) in which Rl is challengeAi includes ~ l, R6 and R7, identical or different, Ir, "lc ~ u ~ an atom of i ~ r ~ u ~, ~ or an alkyl radical containing l to 4 atoms of carbon, or an aralkyl radical in which the alkyl part contains l to 4 carbon atoms and the aryl part preferably represents a phenyl radical ~ n rntsubstituted by one or more alkoxy radicals containing l to 4 carbon atoms, or an aryl radical Ir ~, ~, L ~, preferably a phenyl radical év-ntl- ~ llr ~ m ~ nt substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or well R6 represents an alkoxy radical containing 1 to 4 carbon atoms or a radical trih? 11 ~ m ~ thyle such as ~, OR a phenyl radical substituted by a radical trih? lf ~ m ~ fhyl such that L i ~ Llv ~ u ~, G ~ rle and R7 represents an atom dl ~ .ylllu _.le, or well R6 and R7 form together with the carbon atom to which they are linked a cycle having 4 to 7 cha ~ nons, and Gl represents an alkanoyl (acetyl) radical, ~ cc ~ yle (.lléLl.u ~ l ~, cLyl ~) oualcoyle (methyl), le rI ~ r ~ I dest.vu ~ ~ -ul ~ - ~ s by atoms of ll ~ d ~ ug ~ can be carried out, according to the ci ~, ri ~ of Rl, R6 and R7, as follows:
a) when Rl represents a radical t.bu ~ w ~ y ~ LIv ~, R6 and R7, identical or different ~ I ~ l ~ .., ~, .. '~ .lL an alkyl radical or an aralkyl radical (benzyl) or aryl (phenyl), or else R6 represents a trih? l ~ m ~ thyle radical or a radical phenyl substituted by a radical tr h? l-lm ~ thyle and R7 represents an atom 30 d'lly ~ Lu, ~, or else R6 and R7 together form a ring having 4 to 7 links, the treatment of a product of general formula (IV) with a mineral or organic acid , -ev. ntl-Pll.-mPnt in an organic solvent such as an alcohol leads to a product of general formula (V) which is acylated by means of a product of general formula (VI).
~ e preferably, the product of general formula (IV) is treated with formic acid to a ~ cll-pd- ~ lLuuc close to 20C. Preferably, the acylation of the product of formula 5 general (V) by means of a product of general formula (VI) is carried out in a inert organic solvent chosen by ~ nor the esters such as ethyl acetate, acetate iDvl! lvlJylc OR butyl acetate and hJ ~ r ~ ir ~. halogenated such than ~ hl- ~ OR 1,2-dichloroethane in the presence of a mineral base such as sodium or organic l ~ such as L i ~, a ~. The 10 reaction is carried out at an ~ between 0 and 50C, preferably close to 20C.
b) when R1 represents a benzoyl radical or an R2-O-CO- radical in which R2 is defined as ~. - R6 represents a dhy ~ u ~ atom. or an alcoYy radical containing 1 to 4 carbon atoms or a substituted phenyl radical 15 by one or more alkoxy radicauY containing 1 to 4 carbon atoms and R7 represents an atom of ll ~ v ~, Ie ll .1 ~ des ~ UU ~ CIIIWIi. ~ ~ IVk: C ~ UID by l-y atoms ~ Lv ~ c is carried out in the presence of a mineral acid (acid chlvllly ~ hi ~ uc, sulfuric acid) or organic (acetic acid, methane acid-sulfonic acid L irluul ~. q P, acid r tr) l ~ npculfonique) utiliæ æul 20 or as a mixture, operating in an organic solvent chosen from alcohols, ethers, esters, lly ~ v ~ bulcD rl, l.1 -l; .l ...; the ll ~ dlV ~ 1b ~ .1CD Ill lr ~ ll;
halogenated and the IIY ~ VUOI1JUICD ~ vlll ~, iq ~ ._, to an ICIIIPCI4lUIC compriæ between -10 and 60C, preferably between 15 and 30C. The acid can be used in a catalytic amount OR ~ lv ~ l 1,; .-,., ~ 1,; .1 ~ 1 ~
3) when Gl represents an alcv ~ 4 radical. é; yle and R4 and Rs are defined as in point 1) above, we first perform the ~ du ~ vu ~ dlll ~ ll protector Rs by an atom of ~ IIYdIVg`.US operating under the acid conditions described in point 1) above, then replaces évf ~ nt ~ Pll le ~; lU ~ JCll ~ protector Gl by an atom dily ~ llv ~; cl ~ by treatment in an alkaline medium or by the action of a '' - ~, c of zinc 30 under conditions which do not affect the rest of the molecule. G. 't, le alkaline treatment is carried out by the action of ~ lr..llvll; ac in a hydro-alcoholic medium or hydrazine in an alcoholic medium at an LCIII ~ JW4LUUC close to 20C. General-The treatment with a zinc halide, preferably zinc iodide is carried out.
killed in methanol at an Lclll ~ J ~ LaLuud close to 20C.
.., ...... . ... . _ _ _ wo 95/13271 PCT ~ Rs4 / 012 $ 3 0 2 1 75 ~ 8 ~

4) when Gl i-e has an alkoxyacetyl radical and R4 and Rs are defined as in point 2-a) below, we perform i, ~ Pn ~ Pnt the IPI ~ of the i ~ uu ~
PI ^ otector by treatment in millet; eti alca'iin or by treatment with an I '~ e of zinc under the conditions described in point 3) above, then treats the product with 5 general form (V) obtained under the acylation conditions described in point 2-a) ei-above.
5) when Gl represents a radiea'i ~ i'i., V ~ ya ~,;. Yle and R4 and Rs are defined as in point 2-b) ei above, effeetue ~. '1PmPnt le ~ du i ~ vu ~. ~
protector Gl by treatment in mid-water or by treatment with a halide of 10 zinc under the conditions described in point 3) above, then processes the product obtained under the conditions described in point 2-b) above.
The products of general formula (II) can be obtained by reduction elect Livly Li iud of a generic product:
~ 0 (Vlll) oCOCH3 OCOCsHs 15 in which Ar, Rl and R4 are defined as the ic 'r ~ n ~ .l Rs is defined as p ~ PI ~ and may i ~ l additionally an atom ~ r ~ iiuc ~ ilc, G'l repi ~ present a atom ~ y (hv j ~ ..lc or an a1icanoyl radical (acetyl), ^ 'y ~ i ~, dlyld (lI.' IilV Ly ~ Lyl ~,) or a'icoyl (metityl) or a ~ j.VUlJCII .., .. ~ protector of the hydroxy function according to the following diagram:
~ 0 ~, do ~ nl ~ A ~ ~
it being understood that, when n is equal to 2, the cleavage product is 1 ~ 1 ~ llyilid and, when n is equal to 4, the p ~ cutoff is a ~ beitzyle icool, followed WO 95/13271 2 1 7 5 3 8 4 PCT ~ 94/01283 éyPntllpllpnApnf of the protection of the hydroxy functions defined by -OR5 and -OG 1 to obtain the product of general formula (II).
The electrolytic reduction from the product of general formula (VIII) is made in an el ~ hul ~ Lu containing a support cathAolyte in which is dissolved the product of general formula (VIII) at an r ~ of between 0.1 g / l and the saturation of the solution with product of general formula (VIII ~.
r ~, f ~ lPmPnt reduction takes place in an el ~ hul ~ at , h A jl ~ 1 ~
According to a mode of implementation of the process according to the ill ~. the reduction élechulyh ~ read is performed dj ~ ns an él ~, hul ~ u1 ~ pu1ku ~ a cathode, a eulnlJa ~ èl ~ rAAthrriirl-P, a dia ~ JIuà ~, separator, a ~) aLiull ~, .li anodic and an anode whose. A ~ AI ir ~ r ~ are as follows:
a) the cathode consists of a sheet of mercury, b) the cathode eu111 ~ d1 ~ contains the catholyte which consists of a solution of the product of general formula (VIII) in an organic medium, c) the rl; A ~ separator consists of a poreuAY material such as a plate, a sleeve or a candle of sintered Yerre or porcelain or by a membrane P ~ 'd ~ ions, preferably by an é membrane. l - .g. ~ cations, d) the ~ u111 ~ d1 li111e1 ~ anodic contains the anolyte preferably consisting of the same solvent or mixture of solvents and the same support electrolyte as that used in the; Ulllpal iilllC.- ~ ~ AAth ~ jiq ~ e, e) the anode consists of a material which produces electricity, the nature of which is not not essential for the implementation of the process, CPnprAlpmpnt ~ the anode is made of wlldul material, ie ~ of The electricity; ~ P under the conditions of the electrolysis such as for example the polished platinum, solid or on ~ 'support, graphite or glassy carhJone.
The support electrolyte consists of a salt .IA I ~ r` ~ e such that teh acetate ~; llylA ~ or biL ~ l ~ v1ul ~ u1ai. ~, from b ~ h ~ h ~ or their mixtures soluble in the solvent or the mixture of solvents.
CPnPrAlpmr ~ nt ~ we use solvents which easily cr`ililiAP.`t the products of general formula (II) and (VIII) and which are not very resistant such as alcohols as methanol, nittiles such as acetonitrile or amides such as dimethyl-formamide.

WO95 / 13271 PCT ~ 94/01283 0 2 ~ 7538 ~ lo The pH must be compatible with the stability of the substrate. The middle can be buffered by adding a weak acid such as acetic acid in c ~
equimolar with ~ 4Uf Lt acetate: lll ~ island :.
According to a preferred embodiment of the method, the anode, the cathode and 5 the f ~ separator are in parallel planes h ~ Ia cathode being consisting of a sheet of mercury.
La i, du bairl ~ I '., IU ~, L ~ ~ is g ~ ~~~' ~ between 0 and 30C.
The electrolysis is carried out at controlled potential which can be between -I, 90 and -2.10 volts compared to a saturated calomel reference electrode. It is necessary to deaerate the solution by bubbling an inert gas such as argon for about ten minutes before the start of electrolysis, I'i ~ i ''"
inert being maintained for the duration of the electrolysis The product of general formula (VIII) can be obtained:
1) by the action of an alkali metal halide (sodium chloride, fluoride potassium) or an alkali metal azide (sodium azide) or a salt of. ",.". ~ quaternary or of an alkali metal phosphate on a product of general formula:
~ 2-CF3 ~ o ~ IX) - oCOCH3 oCOc6H6 in which Ar, Rl, R4 and G'l are defined cor ~ lme ~ .., .. 1 and Rs is defined like ~ f 1 ~. , - - etpeutrepresenterenoutreunatomedl1y ~ u ~
Generally, the reaction is carried out in a selected organic solvent among ethers (~ llufuu ~ uulf ~ d; i ~ u ~ LI- ~ -, methyl t.butyl ether) and nitriles (PA ~ f ~ mitrilP) alone or mixed with ume ~ e-1. ~, ~ Lu. ~ between 20C and 25 ~. ~ P ~ 1f. ~ Boiling ule of the reaction mixture.
The product of general formula (IX) can be obtained by the action of a derivative Llifluol acid ~ '''u ~ hlue such as anhydride or N-phenyl trifluoro-m.oth ~ npsl ~ lfonimide on a taxoid of general formula:

wo 95113271 2 1 7 5 3 8 4 PCI'IF ~ 94/01283 O R5 ~
- oCOCH3 OCOCsHs in which Ar, R1, R4 and G'1 are defined as I 'and Rs is defined commel) ,. S, ~ P.lf .. ",. ~ 1 GPnp ~ pmpnf ~ the reaction is carried out in an inert organic solvent 5 (l ~ y ~ Loc ~ 1irhotiq ~ P ~ évPntnf ~ llPmPni halogenés, llydlu ~, al ~
in the presence of an organic base such as an aliphatic tertiary amm (L ~ ylalliille) OR pyridine at a ~ .IIl ~ é-d ~ eu between -50 and + 20C
The taxoid of general formula (X), in which G'1 represents an atom hr ~ Lug ~ lf or an acetyl radical, al ~: u ~ a., ~ yl ~, or alkyl, can be obtained from 10 of a product of general formula:
~ y ~ O (Xl) oCOCH3 OCOCsHs in which Ar, R1 e ~ R4 are defined as ~ l ~ cP.i ~ Rs is defined as f fl ~ and G 1 represents an acetyl radical, al ~ yl f ~ U alkyl or a protector of the hydroxy function and G'2 represents an "r- r 15 protector of the hydroxy function by nPmr ~ f ~ n-Pnt des ~, .u ~ I ~ u ~ G 2 and évPntl ~ PllPmPnt G'l by cl'lly atoms ~ u ~
The radicals G'1 and G'2, when one ~ u., ~ Protective of the hydroxy function, are preferably 2,2,2-trichloro radicals ;; llu ~ r ~; a bull ~
(2-trichloromethyl propoxy) -2 carbonyl or triaL ~ cylsilyl radicals, diaLIcyl-20 arylsilyles, alkyldiarylsilyles or triarylsilyles in which the alkyless parts ~ ntiPnnPnt 1 to 4 carbon atoms and the aryl parts are preferably phenyl radicals.
When G'l and G'2 ~, .It ~ L a 2,2,2,2-trichloro radical, Lllu ~ y ~ bul.
or (2-trichloromethyl propoxy) -2 carbonyl, the if ~ r ~ l des ~, r- r- -WO 95113271 PCT / FR94 / 01283 1 ~

-protectors by hydrogen atoms is made by zinc, éVPntllp ~ npnt associated with copper, in the presence of acetic aid to a Lel ~ p ~ la ~ uue compnse between 20 and 60C or by means of a mineral or organic acid such as chlu.ly acid ~ Liy ~ c or acetic acid in solution in an aliphatic alcohol containing 1 to 3 atoms of 5 carbon or an aliphatic ester such as ethyl acetate, acetate d ~ V ~ JIU ~ YI ~ or n.butyl acetate in the presence of zinc ~ associated with copper.
When G'2 represents a silylated radical and G'1 represents a radical alkanoyl (acetyl), al ~ u ~ yae .. ~ yle (~ u ~ yacé ~ yle) or alkyl (metltyle), the of the s.vu ~. ~ A protector G'2 by an atom of l-y-llv ~, ~ ._ can 10 be carried out by means, for example, of acid ~ llu ~ l ~ ydliy ~ e, gaseous in solutionk ~, G at a t ~ yéla ~ Uue close to 0C or by the action of an acid complex nuvlllydli ~ uè-LI; ~ Lll ~ a ~ e Or acid ~ luu ~ llydli ~ lu ~ pyridine in a solvent organic such as dicl-lvlvll-éLlla ~ - ~ ,, le ~ éLlall ~ l 't or l ~ rPtnnit ~ ilP à une ~ elnpela ~ uuc close to 20C, under conditions which have no effect on the rest of the 15 molecule.
When R4 and Rs together form a cycle .., ~ l; .i; .. r of formula general (VII) in which R6 represents an atom of l ~ y ~ Luke ~. ~ e and R7 represents trn substituted phenyl radical, treatment in an acid medium leads to a product of general formula (X) in which R4 and Rs are ~ CllL each an atom 20 dl ~ yd ~ u ~ èl. ~. It is then necessary to selectively protect the hydroxy function le ~ ..., .._ .. Lce by -O-Rs in the product of general formula (X), preferably under form of a silylated radical, before preparing the general formula product (LX).
The product of general formula (XI) in which G ~ I represents an atom 'I; l.rLU ~ Or an acetyl radical, ~ lcu ~ acO ~ yl or alkyl can be obtained in conditions described in European patents EP 0 336 840 and EP 0 336 841 and in the request; .. A; n lAlP PCT / WO 9209589 by ~; .. baccatin III or of 10-deacetyl baccatin III whose hydroxy functions in -7 and event ~ PIIP ~ Pr t -10 are prvtégées, it being understood that to obtain a product of general formula (XI) in which G'l represents a radical ~ lcv ~ yaeé ~ yL. or alkyl, it is necessary to 30 treat ~ Ia deacetyl-10 baccatin III protected at -7, preferably by a silylated radical, by an acid halide alCuAya., c ~ iquc or by a halide alkyl.
Generally the iu ~ L ~ vduc ~ iu ~ of a gv ~ c ... ~ alcuAya ~ c ~ yle is carried out in treating 10-deacetyl baccatin III pre-protected at -7 with an acid halide WO 95 / ~ 3271 2 1 7 5 3 8 4 PCTIFR94101283 -alcv ~ al ~ eLiqua by operating in a basic organic solvent such as pyridine at a k111pc ~ uThe Yoisine of 20C.
"1 .. ~ 1" ~ iU ~, Livl1 of an alkyl radical is carried out by treating the 10-deacetyl baccatin m protected in -7 and meta11 in -10, using for example5 an alkali hydride (sodium hydride) or a metal alkyl (butyllithium), by an alkyl halide.
2) by ~ "r ;. A; 1- ~ ~ of a product of general formula:
G ~
HO ~ I ~ (XII) ~
HO ~ -OCOC6Hs in which Gl is defined as ~ - -1, by means of an acid of formula 10 general:
R i ~, R4 Af ~ OH (Xlll) ~ Rs in which Ar, Rl, R4 and Rs are defined as IJLfA a ~. 11, OR a derivative of this acid.
The ~ ~. ; r ;. A ~ l by means of an acid of general formula (XIII) can be 15 carried out in the presence of an agent of .. ~ .1 ~ .1 ~ A1; (111 (. A l ,. ~ l ;; .. ~ la, reactive carbonate and an agent Ll '~ aiiv1 ~ (al11; 1lU ~ yLiLl; llc) in an organic solvent (ether, ester, ketones, nitriles, l1 ~ dLvua ~ bu ~ c ~ LvcalL cs Fl; ll l; q ~ halogenated, It ~ LLuL`albuues aLvlllaliq ~ s) to a tu ~ cla ~ uLe between -lO and 90C.
AetarifiAAti - n can also be carried out using racide of formula 20 general (XIII) in the form .1 '' ~ LLidè by operating in the presence of a delivery agent (a111iul ~ ylL; l; nc) in an organic solvent (ethers, esters, ketones, nitriles, hydrocar-bures A1; ~ 8 ~ LL ~ IuallJuuc ~ A1irh ~ tiq ~ ae halogenés, l1 ~ LL ~: aLI, uc ~ aroma-ticks) has a 1c111 ~ c1a ~ uuc between 0 and 90C.
The ~ "t ~ '.;R; ~ Al; l., ~ Can also be carried out using the acid of formula 25 general (XIII) in the form of halide or in .1 '' form dide with an acid WO95 / 13271 l ~ l / r ~ 4'012830 aliphatic or ~ uvllla ~ iq ~ éVo ~ t- ~ PIlPn ~ l ~ nt prepared in situ, in the presence of a base (tertiary aliphatic amine) by operating in an organic solvent (ethers, esters, ketones, nitriles, llydLUCaLb ~ liph ~ tl ~ i. IlydLUUaLl / Ult :: ~ A1irh ~ tiq ~ s halogenés, IIYdLVI ~ aLblLL ~ uullLdt ~) 8 a i Ij 'between O and 80C.
The product of general formula (XII) can be obtained by nction of a alkali metal halide (sodium chloride, potassium fluoride) or ur alkali metal azide (sodium azide) or url salt; ~ or of an alkali metal phosphate on a product of general formula:
G ~ 02 CF3 ~ / `S ~ O (XIV) OCOC ~ Hs 10 in which Gl is defined as ~
Cri ~ n ~ r ~ l ~ mrnt the reaction is carried out in a selected organic solvent among ethers (Lé ~ LallydLVrULd ~ nl ~, dii :: ~ ul ~ v ~) yll ~ Lllel, methyl t.butyl ether) and nitriles (~ f ~ t ~ nitril ~) alone or mixed with a ~ lul ~ between 20C and the Lll ~ ult ~ boiling mixture ~ f shot ~ nn ~
The product of formula (XIV) in which G1 represents an atom d'l-y ~ Lv6 ~ l ~ Or an alkanoyl radical (acetyl), alcvAya ~ é ~ yl ~, lLv ~ ya ~ yl ~) or alkyl (methyl) can be obtained by the action of an acid derivative l ~ uvlvll ~ e-sulfonic such as anhydride or N ~ yll ~ iLluvl ~ '''~ on the baccatin III or deacetylbaccatin III, which can be extracted according to 20 known methods from yew leaves (Taxus baccata), followed by evf ~ nt- ~ r ~ n1 ~ nt protection in position 10, it being understood that to obtain a product of formula general (XIV) in which Gl represents an al1v, ya ~ yl or alkyl radical, it is necessary to treat ~ desacetyl-10 baccatine III protected in -7, preferably by a silylated radical, by an acid halide al ~ v. ~ ya ~, éli ~ l ~ or by a 25 alkyl halide.
G ~ on ~ 5rAlf ~ m ~ nt the reaction of a derivative of LLilluull acid ~
takes place in an inert organic solvent (llydlu ~ dfl ~ u ~ lirh ~ tiq ~
év ~ nt ~ m.ont halogenés, llydlv ~ lJuu ~ ~ vllla ~ S) in the presence of a base WO95 / 13271 2 1 7 5 3 8 4 Pcr ~ FR94JO1283 organic such as an aliphatic tertiary amine (L ~ dal ~ lillc) or pyridine at a l ~ laiu t; between -50 and + 20C.
CPnPrr ~ ulu ~ iùl ~ of a ~ P- 1 alkoxyacetyl is carried out in treating 10-deacetyl baccatin m protected in -7 by an acid halide 5 alc. ~ Y ~. ~, É ~, operating in a basic organic solvent such as pyridine at a ~ LaL ~ e close to 20C.
GPn ~ l --- I "~ lu ~, liu ~ of an alkyl radical is carried out by treating the 10-deacetyl baccatin m protected at -7 and metallized at -I0, using for example an alkaline hydride (sodium hydride) or a metal alkyl (butyllithium), 10 with an alkyl halide.
According to the invention, the new products of general formula (I) can be obtained by ~ of a product of general formula:
Ar ~ O "~ (XV) 01 ~
in which Ar, Rl, R4, Rs and Gl are defined as ~, ~ f ~ and G2 15 represents a ~ u ~., .. l protector of the chosen hydroxy function, preferably among the radicals lli ~ yLlyl ~, d; dLl ~ Lybilyl ~, "yl liolyl ~ ilyl ~ or l ~; ~ yl ~;
in which the alkyl parts ~ 1 to 4 carbon atoms and the parts aryls are preferably phenyl radicals, using an acid of fc ~ rmulegénérale (Ill), to obtain a product of general formula:
R ,, N, R4 oj ~ 2 Ar ~~ J ~ O '' C \ ~ 1 (XVI) in which Ar, Rl, R3, R4, Rs, Gl and G2 are defined as ~ whose we replace ~ the ~; protector G2 by an atom ~ ylLu ~
to obtain a product of general formula:

Wo 95113271 PcT / ~ s4 / 01283 0 Ar ~ O ~ ~ (XVII) O-R5 ~ O
- OCOCH

in which Ar, Rl, R3, R4, Rs and Gl are defined as 1 ~ which, by action of a racide derivative; ~ 1 such as anhydride or N-phenyl,. ,. . r I ~ is transformed into a product of general formula:
Ar '~~ Jl ~ o ~ 2-CF3 O R6 ~ H ~ G

in which Ar, Rl, R3, R4, Rs and Gl are defined as IJ. ~ n ~ whose .n ~ u ~ S ~ Jl ~. ". L ~ by Rs or by R4 and Rs soffl replaced by hydrogen atoms to give a product of general formula:
Ar ~ o "~ (XIX ~

10 in which Ar, Rl, R3 and Gl are defined as ~. .. 1 which, by action of a alkali metal halide (sodium chloride, potassium fluoride, sodium chloride sodium) or an alkali metal azide (sodium azide) or a salt quaternary or of an alkali metal phosphate, leads to the product of general formula (I) in which R represents an acetyl, al., ~ Tyl ~, or alkyl radical which may be 15 transformed into product of general formula (I) in which R represents an atom hydrogen.
L ~ r .. - ~ '.... of a product of general formula (XV) using an acid of general formula (I11) is carried out under the conditions described l, ~ for WO95 / 13271 2 1 7 5 3 8 ~ Pcr ~ s4 / 0l283 I ~ r ~ 1r1; r ;. 1;. ~ .- d ~ a product of general formula (II) by means of an acid of formula general (III).
The ~ of ~ JU ~ .I. ~ Protector G2 by an atom of il ~ ydlU ~
takes place ~ onr ~ r ~ l 'by treating the product of general formula (XVI) with racide 5 nuu.l.yd.iq ~ or acid i 11 '. erl presence of an organic base such as pyridine or an aliphatic tertiary amine such as i ~ - by operating in an organic solvent such as an ether (~ llall, ~ d ~ ur ~,) or a nitrile (, - 't. -1 il-).
The ~., ..R ~ .... .... ~ of a product of general formula (XVII) into a product of general formula (XVIII) is carried out under the conditions described ~ 'for 10 prepare the product of general formula (IX) from the product of general formula (X).
Le ~ des t.uu ~ l .. ~ plul ~ t ~ "lla. ~ P., By Rs or by R4 and Rs is carried out in the ccnditions described ~ r ~ ..1 for the Ir ...
of 2;. ~ Jup ~ The protectors of the product of general formula (IV).
The l., 1, .cr .., .. ~;, .. of a product of general formula (XIX) into a product of general formula (1), in which R represents an alkanoyl radical, r1 ~ ya ~ Lyle or alkyl, is carried out under the conditions described ~ Ir ~ r ~ 1 FOR
l, r., ~ r ~., 111, .1;.,. ~ of a product of general formula (IX) into a product of general formula (VIII).
The. ~ 1. 'optional radical R of the product of general formula (I), in which R represents an alkanoyl radical, alcu ~ a ~ yl ~ or alkyl, by an atom d'l ~ y ~ Lu ~ can be performed under the conditions described ~ ._., 1 for the .r "~ r", r., 1 des, ~ 5.uupw, .., .. ~ plul ~ _kula of a product of general formula (IV) by atoms of l ~ Y ~ IIUc - l ~
The product of general formula (XV) can be obtained under the conditions described in the request; .. ~. - '; ~ PCT WO 94/20484.
The new products of general formula (I) obtained by the implementation processes according to the invention can be puri6és according to known methods t ~ lles that the rict ~ llic ~ tir ~ n or the .lu. ,., - ~ .l,; r The products of general formula (I) have hi ~ giql properties.
remarkable.
In vitro, the measurement of biological activity is carried out on tubulin extracted from pig brain by the method of ML Shelanski et al., Proc. Natl.
Acad. Sci. USA, 70, 765-768 (1973). The study of d ~ ol ~ ....,. ~ Liol, microtu-35 bules in tubulin is carried out according to the method of G. Chauvière et al., CR Acad.
..... _ _. ,. , .., .. ,, .. _ _. . ..,. . ,. . ,., ... .... ., .., ,,,,. ,,, _ _ _ _ _ _ _ _ _ _, WO 95/13271 P ~ .l / r ~ t! O12U ~
2 1 753v4 Sci., ~ 2 ~, series II, 501-503 (1981). In this study the products of general formula (I) have been shown to be at least as active as taxol and Taxotere.
In vivo, the products of general formula (I) have been shown to be active in mice grafted with melanoma B16 at doses between 1 and 10 mglkg par5 U ~ '' 1P route, as well as on other liquid or solid tumors.
The new products have activity on tumors that are resistant to Taxol ~) or Taxotere ~). Such tumors ~ ~ tumors colon who have high expression of the mdr 1 gene (multi-drug gene resistance). Multi-drug resistance is a common term related to resistance 10 of a tumor with different products of different structures and l.le. ~ action.
Taxoids are g ~ - '- ~' known to be highly recognized by C tumors such as P388 / DOX, a cell line ~ 'for its resistance to dw ~ ulubic; ll., (DOX) and which expresses mdr 1.
The following examples illustrate the present invention.
15 F: XF.l \ IPJ F 1 To a solution of 91.5 mg of 3-amino-2-hydroxy-3-phenyl IJII r- '- (2R, 3S) diacetoxy-4a, 10 ~ (fluoro4 ~. ~ uylo ~ y) -2a epoxy-5 ~, 20 hydroxy-1 ~ methylene-7 ~, 813 oxo-9 nor-19 taxene-11 yle-13a in 0.2 cm3 of dichlulul ~ a, ~. ~ "Maintained under ~ IL-llv ~~ argon, 12.5 mg of i, ydlut, ~. sodium carbonate are added, then 20 drop by drop, to a u, l ~ close to 20C, a solution of 32 mg of li ~, ~; of di-t.butyle in 0.1 cm3 of t1i ~ `hl '' The solution obtained is stirred for 22 hours at a ~. ~ é ~ close to 20C then: '"of mixture of 0.5 cm3 of dis ~ llée water and 5 cm3 of ~ hl ~ The aqueous phase is extracted by 0.5 cm3 from 1 '-''-' - The combined organic phases are 25 dried over m ~ n sulfate filtered then ~: ul ~ ~ dry under reduced pressure (2.7 kPa) at 40C. 99.2 mg of yellow ering meringue are thus obtained, which ron purifies by 1-. "" ,. 1 "~, 1" .o preparative on 6 thin-layer silica plates (Kieselgel60F254, Merck) 0.25 mm thick, eluting twice with a methanol mixture dichlu, ul., éa.dl ~ (2-98 by volume). After elution of the zone UUII ~ IJUllli ~ uli at 30 product sought by a mixture of methanol-di..l, lulu ... éal ~. ~ (10-90 by volume) p us Ul ~ l ~ iOll UNDER reduced pressure (0.27 kPa) at an il ~ el ~ UI1 close to 40C, we obtains 32.7 mg of t.buLu ~ y ~ allJullyldllllllllO-3 hydroxy-phenyl-3 lr '' (2R, 3S) diacetoxy-4a, 1013 ffluoro-4 l ~ cl.Lvylu. ~ y) -2a epoxy-5 ~, 20 hydroxy-~

Wo 95/13271 PCTI ~ R94 / 01283 2 ~ 75384 -methylene-7 ~, 81S ~ oxo-9 nor-19 taxene-ll yle-13 in the form of a white meringue - whose . ~ s; are the following:
- nuclear resonance spectrum ~ 1 f of the proton (400 MHz; CDC13;
~ Iripl- 'chemical in ppm): 1.28 (s, 3H: -C ~ I3 in 16 or 17); 1.30 s, 9H: -C (C ~ 3) 3]; 1.37 (mt, 1H: -s in 7); 1.58 (s, 3H: -CH3 in 16 or 17) 1.68 and 2.25 (tet m, 1H each: C ~ I2 from ~ l ~ r ~ ~; 1.87 (s, 3H: -C ~ 13 in 18); 2.12 and 2.47 (d and td, 1H each: -C_2 in 6); 2.22 (s, 3H: -COC ~ 3 in 10); 2.22 and 2.40 (m, 1H
each: -CH2 in 14); 2.38 (s, 3H: -COC ~ in 4); 3.26 (broad s, 1H: -O_ in 2 ');
4.05 and 4.30 (d, 1H each: -C ~ 2- in 20); 4.10 (d, 1H: -_ in 3); 4.64 (broad s, 1H:
- ~ in 2 '); 4.75 (d, 1H - ~ in 5); 5.30 (d, large, 1H: - ~ in 3 '); 5.31 (d, 1H:
-CON ~ -); 5.65 (d, 1h: -H in 2); 6.29 (broad t, 1H: -H at 13); 6.32 (s, 1H: -_ in 10); 7.20 [t, 2H: -OCOC6H4F (-H in 3 and -; t ~ in 5)]; from 7.30 to 7.45 (mt, 5H: C6Hs in 3 '); 8.19 [dd, 2H: -OCOC6H4F (- ~ in 2 and - ~ in 6).
3-amino-2-hydroxyphenyl-3 1 -s- - (2R, 3S) diacetoxy-4a, 10 (fluoro-4 L ~. ~ vyluAy) -2a epoxy-5 ~, 20 hydroxy-l ~ methylene-713.8 ~ oxo-9 nor-19 taxene-ll yle-13a can be prepared as follows:
A 130 mg solution of tIJU ~ V ~ YC ~ UIIYI 3 2,2-dimethyl-4-phenyl r ~ Ju ~ ylr ~ 5- (4R ~ 5s) of diacetoxy4a, 101S ~ (fluoro-4 1 ~ vylu ~ y) -2a epoxy-5 ~ 3.20 hydroxy-113 methylene-7 ~, 813 oxo-9 nor-19 tAxene-ll yle-13a daiA, s 1.3 cm3 of formic acid is stirred for 2 hours at a ~ c ~ u ~ c close to 20C then concentrated to dryness under reduced pressure (0.27 k ~ a) at 30C. Meringue white obtained is purified dh ~ by ~ - pressure Al,., ~ Î ~ llf; .lur ~ on 40g silica (0.063-0.2mm) contained in a column of 2.5Crn in diameter, eluting with a methanol-dichlu.u ... clllanf mixture (elution gradient 2.5-97.5 to 5-95 by volume). Fractions containing only the desired product are combined and ~ dry under reduced pressure (0.27 kPa) at 40C. We obtain thus 91.5 mg of amino-3 hydroxy-2 phenyl-3 propionate- (2R, 3S) of diacetoxy-4a, 10 (fluoro4 1 ~, ~ uylvAy) -2a epoxy-5, ~, 20 hydroxy-113 methylene -7 ~, 813 oxo-9 nor-19 taxene-l 1 yle-13a in the form of a white meringue.
T.bu ~ v ~ yc_ ~ lJullyl-3 dimethyl-2,2 phenyl-4 ~ ylA-t ~ - 5 (4R, 5S) of diacetox, Y-4a, 10 ~ (fluoro-4 I ~. ~ Vylv1Ly) -2a epoxy-5 ~, 20 hydroxy-113 methylene-7 ~, 813 oxo-9 nor-19 taxene-ll yle-13a can be prepared in the manner next:
To a solution of 190 mg of t.bu ~ u ~ ycA ~ bvllyl-3 dimethyl-2,2 phenyl-4 rYA7rl, ~ I; rr Ad) vacylate-5- (4R, 5S) of diacetoxy-4a, 10 ~ epoxy-5 ~, 20 dihydroxy-1 ~, 2a wo 95/13271 PCT / F ~ 94/01283 ~
2 ~ 7 ~ 384 -methylene-713.8 ~ oxo-9 nor-19 taxene-11 yle-13a in 4 cm3 of LéLIl ~ J ~ vrl a ~ hydra, maintained under: .'` of argon, we add Su ~ u ~ i ~ ellL, to a Lell ~ péld ~ ule close to -78C, 0.38 cm3 of a 1.3 M solution of nl ~ u ~ y '' in hexane then 0.0585 cm3 of fluoro4 benzoyl chloride. The solution is stirred5 for 45 minutes at 1 ~ .... ~ ,, close to -78C and then SU ~ A ~ I ._ ..;
at the same l ~ -. 0.38 cm3 of a 1.3 M solution of n Luly'- in hexane then 0.0585 cm3 of fluoro4 benzoyl chloride. The solution is stirred for 35 minutes to a ~ .llpela ~ ule close to -78C then 1 crn3 of a saturated solution of chloride is added; The reacti ~ nel mixture is brought to a 10 Lel ~ ule close to 20C in 15 minutes. After ~ 'the aqueous phase is extracted with 2 times I cm3 of ethyl acetate. The combined organic phases are dried on r.Aa ~ m sulfate filtered then cu .. ~, ellt ~, dry under reduced pressure (2.7 kPa) at 40C. 245 mg of a yellow oil are thus obtained which is purified by AII ~ pressure chromatography on 40 g of silica (0.063-0.2 mm) contained in a column 2.5 cm in diameter, eluting with a methanol-di._llvlulll., illàl ~ è (elution gradient from 0.5-99.5 to 2.5-97.5 in volumes). Fractions containing only the desired product are combined and, dry under pressure reduced (0.27 kPa) at 40C This gives 130 mg of t.butv ~ yeallJvllyl-3 dimethyl-2,2-phenyl-4 ~ ylaLe-5- (4R ~ 5s) of diacetoxy-4a, 10 ~ (fluorv-4 ~. ~ vyluAy) -2a epvxy-513.20 hydroxy-113 methylene-7 ~, 8 ~ oxo-9 nor-19 taxene-11 yle-13a in the form of a white meringue.
Le t. ~ U ~ uAy ~ bullyl-3-2,2-dimethylphenyl4 .. l; .l .. A. 18) ~ 5 (4R, 5S) of diacetoxy-4a, 10 ~ epoxy-513.20 dihydroxy-113,2a methylene-7 ~, 813 oxo-9nor-19 taxene-11 yle-13a could be prepared as follows:
We proceed to the reduction ~! ~ 11-. t bulv ~ eA l ~ vllyl-3 dimethyl-2,2 phenyl4 ~ yh ~ 5- (4R, 5S) of diacetox ~ v-4a, 1013 1 ~. ~ VyluA.y-2a epoxy-5 ~, 20 hydroxy-1 ~ methylene-7j3,8 ~ oxo-9 nor-19 taxene-11 yle-13a in a dléle ~ vly ~ e cell whose. A. ~ are as follows:
- the cell is a 100 cm3 glass vase divided into 2 c ~. by a membrane of cations, - the cathode is a sheet of mercury whose useful surface is approximately 4cm2, - the anode is a platinum grid, - the reference electrode is a saturated calomel electrode.

WO 9 ~ / 13271 PCrlPR941012g3 -In the f ~ f sfh ~ iq ~ F we introduce 10 cm3 of a solution containing:
- t.buLo ~ aLluullrl-3 dimethyl-2,2 phenyl-4 ~ y '5- (4R, 5S) diacetoxy-4a, 101 '~ benzoyloxy-2a epoxy-51' ~, 20 hydroxy ~ methylene-7fl, 8 '~ oxo-9 nor-l9 taxene-ll yle-13a 27.3 mg - t ~, LG ~ luulubul ,, ~ de toha ~: Lll. ~; '''''1 er 0.15 M / l - acetate of ~ Lil ~ qer 0 ~ 05 M / l - acetic acid qcr 0'05 M / l - methanol qc r- lo cm3 10 In the ~ l anode, we introduce 10 cm3 of an acid solution 0.1 ~ aqueous sulfuric.
After fif ~ Fr ~ tif ~ n of the solution for 10 minutes by bubbling um argon current which is maintained for the duration of r ~ l ~., L.ulysc, the potential of the cathode is set at -1.95 volts relative to the reference electrode.
The solution is electrolysed for 54 minutes, that is to say the time required the passage of 100 coulombs. After ~ dry under reduced pressure (0.27 kPa) at a ~ laluLt: close to 35 ~, the residue is taken up in 10 cm3 of acetate ethyl and 10 cm3 of distilled water. After extrsction and flPf sntstif) n the aqueous phase is extracted twice with 5 cm3 of ethyl acetate. The organic phases are combined, washed with 10 cm3 of 0.2 m aqueous phosphate buffer (pH = 7), dried over sulfate of m ~ nf- ~ m, filtered then., U ,. ~,.,. ILI ~ s at dec under reduced pressure. We thus obtain 24 mg of a pale yellow merngue which is purified by ~ l ~ aLa ~ ivt: out of 4 thin-layer silica sheets (Kieselgel 60F254, Merck; thickness 0.25 mm) in eluting with a methanol-acetonitrile-.li ~ llulul ~ lé1h ~ mixture, (5-5-90 by volume).
After identification under UV (254 rlm) and elution of the ~ one Wll- r '' to the product main by a mixture of methanol- ~ '''''(1-1 by volume) then e ~ lLion under reduced pressure (0.27 kPa) at a ~ .IIIJ ~ alL .. ~ close to 40C, we obtain 9.6 mg of t.bulu ~ y ~ albullyl-3 dimethyl-2,2 phenyl4. ~ F - ~ Y '5- (4R, 5S) of diacetoxy-4a, 10, ~ epoxy-5, i.20 dihydroxy-1 ~, 3,2a methylene-71 '~, 81' ~ oxo-9 nor-l9 30 taxene-ll yle-13a in the form of a white meringue.
The t.buL ~ yLall> ùllyl-3 dimethyl-2,2 phenyl4. ~. , .. 1; .I .. ~ F ~ r ~ 5 (4R, 5S) of diacetoxy-4a, 101 '~ 1 ~. ~ Vylwy-2a eroxy-51,3,20 hydroxy-ll'i methylene-71f ~, 81' ~ oxo-9 nor-l9 taxene-ll yle -13a can be prepared as follows:
To a solution of 1.8 g of tb. ~ Tu ~, aLbull ~ 1-3 2,2-dimethylphenyl4 ~ if ~ .l, o ~ '5- (4R, 5S) of diacetoxy-4a, 101' ~ ~ uyl ~ y-2a époxy-5, '~, 20 Wo 95/13271 PCI / FR94 / 0 1283 ~
2 ~ 75384 -hydroxy ~ oxo-9 Llillu ~ fonateA7l ~ taxene-ll yle-13fl in 20 cm3 anhydrous acetonitrile and 4 cm3 of ~ allydlu ~ uua ~ anhydrous, maintained under a ~ .f` n argon, 4 g of sodium chloride and 300 mg of sieve are added , .. olé., ul ~ ue 4A activated powder. The reaction mixture is heated for 2 hours 5 with stirring and under,; ' `argon, at an L ~ ... pf aLu ~ c: close to 80C, then refrvidi to an i ~. ., 1 ~. Al ~ '' n close to 20C and filt ~ é on sintered glass lined with celite. The the filtrate is concentrated to dryness under reduced pressure (2.7 l ~ a) at one i. see 40C. 4.9 g of an orange-brown residue are thus obtained, which is punctured by ~ .lu ~, pressure. 'i on 40 g of silica (0.063-0.2 rnm) contained 10 in a column 4.5 cm in diameter, eluting with an ethyl acetate mixture (elution gradient from 0-100 to 10-90 by volume). Fractions do containing that the desired product are combined and ~, .. L w ~ dry under reduced pressure (0.27 kPa) at 40C. We obtain aiiAIsi 1.35 g of t. ~ ULvA. ~ Bowl. ~ 1-3 dimethyl-2,2 phenyl4., - A ~ b ~ Y '' 5- (4R, 5S) of diacetoA ~ y-4fl, 101 '~ 1 ~. ~ ylu ~ y-2a epoxy-51 '~, 20 hydroxy-ll' ~ methylene-71 '~, 81'i oxo-9 nor-19 taxene-ll yle-13a under shaped like a white meringue.
Le t.bulu ~ yl, ~ bvllyl-3 dimethyl-2,2-phenyl-4 ~ '' L ~ -5-(41 '~, 5S) of diacetoxy-4a, 101' ~ benzoyloxy-2a epoxy-51 '~, 20 hydroxy-li' ~ oxo-9 trifluv .- ,, .. ~ lr ~, .l .. 71f ~ taxene-ll yle-13a can be prepared in this way 20 next:
To a solution of 3.85 g of t.burlJ ~ yu ~ ulJoll. ~ L-3 dimethyl-2,2 phenyl-4 , .. li.l; .lP. .l .., ~ laL ~ 5- (4R, 5S) of diacetoxy-4a, 101 '~ benzoyloxy-2a epoxy-5 ~, 20dihydroxy-11' ~, 7 ~ oxo-9 taxene-ll yle-13a daris 40 cm3 of anhydrous f '--'-', maintained under, L ... o ~ pl.; t: argon, 1.3 cm3 of pyridine and 100 mg of sieve are added 25 molecular 4A activated powder. The reaction mixture is cooled to a , é.aLu. ~ close to -30C. 1.2 cm3 of ydlidl triflluoro- is added slowly . "~ Il ..; ... ~ ..1 ~."". ~ Stirred at ~ ell ~ laLuu ~; close to 0C for 1 hour.
again cools to an L ~ - ~ .pé-aLuid close to -30C then 1.2 cm3 are added of anhydride Llifluvl. ~ - lr ~ JIli LU ~, stirred at an L ~ JelaL ~: close to 0C
30 for 1 hour and add 10 cm3 of distilled water. The reaction mixture is brought to an L ~ el, ~ Lu. ~ close to 20C, filtered through sintered glass lined with celite. Sintered glass is rinsed with 50 cm3 of an ethyl acetate-di ~ mixture, l.lu.u ... éLl. ~ u ~ f (1-1 en volumes). The aqueous phase is separated by flf ~ nt ~ tinn and then extracted with 10 cm3 of dichlv. ~, l.l0.Lalle ~ The combined organic phases are dried over 35 mslvnf ~ ei - m filtered then ~: or ~ t-é ~ dry under reduced pressure (2.7 kPa) at 40C On wo g5, l3271 ~ ~ 7 5 3 8 4 pct ~ g4 / 0l283 thus obtains 4.39 g of a yellow solid which is purified by ~ Iu ~ ,,. ", 1 .. ~ at pressure on 350 g of silica (0.063-0.2 mm) contained in a column of 4.5 cm in diameter, eluting with an ethyl acetate-dichlu mixture ~
(elution gradient from 0-100 to 5-95 by volume). Fractions containing only 5 sought product are reurlies and ~~ ~ ~~ c ~ dry under reduced pressure (0.27 kPa) at 40C. We thus oWent 4.07 g of t butu ~ .r ~, ~ l ~ lyl-3-dimethyl-2,2 phenyl4 oxazoli-d ~ l ~,., ~ L ~ y '5- (4R, 5S) of diacetoxy 4c ~, 10 ~ ~. ~ Vrl ~, .y-2a époxy-5 ~, 20 hydroxy-1j3 oxo-9 ~ '''' 7 ~ taxene-ll yle-13cc in the form of urLe white meringue.
Ld tbuL ~ J ~ Ly ~ yl-3 dimethyl-2,2 phenyl-4 (~ .. y '5 (4R, 5S) of diacetoxy-4a, 10 ~ beyloxy-2 epoxy-5 ~, 20 dihydroxy-113,7 ~ oxo-9 taxene-ll yle-13 can be prepared under the conditions described in the application, "~" ~ lr- PCT WO 9209589.

To a solution of 500 mg of tert-bu ~ y- ~ ul, o lyl-3 (4-methoxyphenyl) -2 phenyl-4 (. ~ -1.3 ~ ubu ~ liLud-5- (2R, 4S, 5R) acetoxy-4c ~ dihydroxy-1 ~, 2 epoxy-5 ~, 20 metll ~, A ~ y-10 ~ oxo-9 triethylsilyloxy-7 ~ taxene-ll yle-13 in 7 cm3 of ~ L ~ ydloruu ~ e maintained under stirring and under ~ bone ~ of argon, add ~ uc ~ -L, to a t ~ laLuu ~ isine of -78 ~ C, 0.9 cm3 of a solution 1.4 M of n-butyllithium in hexane and 279 mg of chloride of L ~ rlub ~ 6a ~ y-3 benzoyl. The solution is thus kept stirred for 45 minutes and then added 10 cm3 of a saturated aqueous chloride solution. "The medium is reduced to a ~ .Il ~ close to 20C in 1 hour. The solution obtained is poured into a mixture of 50 cm3 of ethyl acetate and 50 cm3 of an aqueous solution saturated with chloride ~ I't ~ The aqueous phase is separated by ~ nf ~ tjl ~ n then extracted with 2 times 50 cm3 of ethyl acetate. The organic phases are combined, washed with 50 cm3 of distilled water and then dried over .. ~ .... sulfate, filtered and are dry under reduced pressure (2.7 kPa) at 40C. 620 mg of a white meringue which is purified by., L "" ~ t k. ~ on 200 g of silica (0.063-30 0.2 mm) contained in a column 2 cm in diameter [eluent: ethyl acetate-cyclohexane (10-90 by volume)] by collecting fractions of 30 cm3. Fractions containing only the sought product are combined and ~ u ~ ..u ~ S dry under pressure reduced (2.7 kPa) to 40C. We obtain 244 mg of tert-buLu, ~ y ~; ~ ub ~ Jllyl-3 (methoxy-4 phenyl) -2 phenyl4 f-vL ~ 7-7lirlin ~ 1,3 ~ .ad ~ u ~ yli ~ ue-5 (2R, 4S, 5R) of acetoxy4a -époAy-5 ~, 20 hydroxy-1 ~ ca ~ uAya ~ uA ~ y-10¦3 oxo-9 L iéa ~ ybilylvAy-7fl (L inuvl ~ v ~ cLlloxy-3 1 ~. ~ VyluAy) -2a taxene-ll yle-13a in the form of a meringue white and whose. At Al ~ are the following:
- proton NMR spectrum (400 MHz; CDC13; ~ in ppm): 0.59 (q, J = 7.5 Hz, 6H: ethyl SiCH2); 0.94 (t, J = 7.5 Hz, 9H: ethyl CH3); 1.08 (s, 9H: (CH3) 3);
1.19 (s, 3H: CH3); 1.21 (s, 3H: CH3); 1.62 (s, 1H: OH in 1); 1.67 (s, 3H: CH3);
1.70 (s, 3H: CH3); 1.83 (s, 3H: COCH3); 1.85 and 2.50 (2 mts, 1H each: CH2 in 6); 2.08 and 2.19 (2 dd, J = 16 and 9 Hz, 1H each: CH2 at 14); 3.53 (s, 3H: OCH3);

3.73 (d, J = 7Hz, 1H: Hen3); 3.84 (s, 3H: ArOCH3); 4.07 and 4.22 (2d, J = 8.5 Hz, 1H each: CH2 at 20); 4.18 (AB limit, J = 16 Hz, 2H: OCOCH2O); 4.43 (dd, J = 11 and 6.5 Hz, 1H: H at 7); 4.58 (d, J = 5 Hz, 1H: H in 2 '); 4.87 (d wide, J =
10 Hz, 1H: H at 5); 5.43 (mt, 1H: H in 3 '); 5.62 (d, J = 7 Hz, 1H: H in 2); 6.07 (t large, J = 9Hz, 1H: Hen13); 6.40 (mt, 1H: Hen5 '); 6.46 (s, 1H: Hen10); 6.93 (d, J = 8 Hz, 2H: H at ~ .ah.read in gold ~ ho from OCH3); from 7.30 to 7.50 (mt, 7H: H
alulllali ~ ues and H alvlYIa ~ u ~ in meta of OCH3); 7.49 (d wide, J = 7.5 Hz, 1H: H
in 4 of the alullla ~ in 2); 7.53 (t, J = 7.5 Hz, 1H: H in 5 of 1 ', 2 in);
7.90 (broad s, 1H: H in 2 of ~ uullla ~ i Lu1 in 2); 7.99 (d, J = 7.5 Hz, 1H: H in 6 of alulllali4ue in 2).
To a solution of 240 mg of tert- ~ uLuAy-, a ~ l ~ alyl-3 (4-methoxyphenyl) -2 phenyl4 (~ ~ 1,3 ~ albuAyli ~ u ~ -5- (2R, 4S, 5R) of acetoxy ~ epoxy-513,20 hydroxy-1 ~ alVA ~ a., ~ LVAy-10 ~ oxo-9 L ica.yl ~ ilylu. ~ y-7l3 (L inuv.ul..ca.vAy-3 1 ~, ~ 4vylvAy) -2a taxene-ll yle-13a in 4 cm3 of di., Hlvlvl ~. ~ A ~ c, we add, to a L ~ .a ~ uc close to 20C, 3.3 cm3 of compleAe L ica .. ~ 'acid Lluv ~ l ~ ydl; q--.
The reaction mixture is stirred for 4 hours at a L.ll ~ the ~ close to 20C Then 10 cm3 of ii ~, l.lv., 'And 50 cm3 of a saturated aqueous solution are added of l ~ ydlu ~ sodium ocarbonate. The organic phase is decanted, washed twice 50 cm3 of a saturated aqueous solution of sodium chloride then dried over sulfate ~ filtered and concentrated to dryness under reduced pressure (2.7 kPa) at 40C. We obtains 205 mg of tert-bu ~ vAy., al) v. ~ yl-3 (4-methoxyphenyl) -2 phenyl4 1 '' 1,3 ~, alboAyli ~ u ~ 5- (2R, 4S, 5R) acetoxy-4a dihydroxy-1,3,7 ~ epoxy-5 ~, 20 methoxy-acetoxy-1013 oxo-9 (~ .inuu ~.,. c ~ l.uAy-3 1 ~ vylvAy) -2a taxene-ll yle-13a sous shape of a white meringue and including AA ~; are the following:
proton NMR spectrum (400 MHz, CDCl3, o in ppm): 1.06 (s, 9H: (CH3) 3);
1.24 (s, 3H: CH3); 1.28 (s, 3H: CH3); 1.56 (s, 3H: CH3); 1.65 (s, 3H: CH3);
1.85 (s, 3H: COCH3); 1.85 and 2.53 (2 mts, 1H each: CH2 in 6); 2.08 and 2.21 (2 ~ WOs ~ 13271 2 1 7 5 3 8 4 Pcr ~ Rs4Jol2s3 ~ 25 dd, J = 16 and 9 Hz, 1H each: CH2 at 14); 2.35 (mf, 1H: OH in 1); 3.53 (s, 3H:
OCH3); 3.72 (d, J = 7 Hz, 1H: H at 3); 3.83 (s, 3H: ArOCH3); 4.08 and 4.22 (2 d, J = 8.5 Hz, 1H each: CH2 at 20); 4.25 (limit AB, J = 16 Hz, 2H: OCOCH2O);

- 4.37 (dd, J = llet8Hz, 1H: Hen7); 4.58 (d, J = 5Hz, 1H: Hen2 '); 4.90 (dlarge,

5 J = 10Hz, 1H: Hen5); 5.43 (mt, 1H: Hen3 '); 5.62 (d, J = 7Hz, 1H: Hen2);

6.13 (broad t, J = 9 Hz, 1H: H at 13); 6.31 (s, 1H: H at 10); 6.39 (mt, 1H: H at 5 '); 6.93 (d, J = 8 Hz, 2H: H ~ ortho to OCH3); from 7.30 to 7.50 (mt, 7H: H ~ and H, in rr ~ eta of OCH3); 7.49 (d wide, J = 7.5 Hz, 1H: H in 4 of the ulullluii ~ l_., in 2); 7.54 (t, J = 7.5 Hz, 1H: H in 5 of rblv.l.uLi read in 2); 7.88 (broad s, 1H: H in 2 of r ~ ullluli ~ in 2); 7.98 (d, J = 7.5 Hz, 1H: H at 6 u vlllu ~ uè in 2).
To a solution of 200 mg of tert-bu ~ u ~ y ~ uLlJullyl-3 (4-methoxyphenyl) -2 phenyl-4 (~ ._, .. l; ~ l;. ~ r 1,3 uubwyle-5- (2R, 4S, 5R) acetoxy-4a dihydroxy-1 ~, 7époxy-5 ~, 20 ~ l ~ éLllu ~ u ~ é ~ u ~ y-lo ~ oxo-9 (hinuulull ~ 6il ~ v ~ y-3 1 ~. ~ vyluAy) -2a taxene-ll yle-13a in 3 cm3 of, "'u ~ ell. ~ e anhydrous and 0.120 cm3 of pyridine, kept under ~? . ~ argon, to an ~ elll ~ e ~ close to 0C, we add drip 0.125 cm3 ~ hide hinuv .. It. ~ fvl iq ~. The solution orange obtained is stirred for 20 minutes at a ~ .llpéLaLuue close to 0C and then additiomne 3 cm3 of water and 30 cm3 of di ~ lllv ~ u ~ éL ~ e ~ The organic phase is Decanted, washed twice with 20 cm 3 of a saturated aqueous solution of chloride sodium and then dried over .. ~ .. sulfate, filtered and concentrated to dryness under pressure reduced (2.7 kPa) to 40C. 233 mg is obtained which is purified by, - ,,, - on 200 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter [eluent: di ~ llv ~ u ~} ~ ~ methanol (98-2 by volume)] by collecting fractions of 25 10 cm3. The fractions containing only the sought product are combined and dry under reduced pressure (2.7 kPa) at 40C. We obtain 192 mg of tert-bULV ~ Y ~: U.IJU ... YI-3 (4-methoxyphenyl) -2 phenyl-4. . ~ ~ 1.3 ~ bv ~ L ~ _ ~, 5-(2R, 4S, 5R) acetoxy-4a epoxy-513.20 hydroxy-l ~ ~ l.6ill ~ A ~ u ~ v ~ y-10 ~ oxo-9 hiiluv ~ "~ r ~" ~ ylu ~ y-7l3 (ullléLllu-y-3 1 ~. ~ vylu ~ y) -2a taxène-ll yle-13a in the form of a white mermgue and whose. - ~. Ir ~ q ~ - are as follows:
- proton NMR spectrum (400 MHz, CDCl3, o in ppm): 1.07 (s, 9H: (CH3) 3);
1.18 (s, 3H: CH3); 1.20 (s, 3H: CH3); 1.65 (s, 1H: OH in 1); 1.72 (s, 3H: CH3);
1.84 (s, 3H: CH3); 1.92 (s, 3H: COCH3); 2.07 and 2.10 to 2.25 (le ~ euLi ~ dd ~: 1 = 16 and 9 Hz) and mt, 1H each: CH2 at 14); from 2.10 to 2.25 and 2.83 (2 mts, 1H
each: CH2 in 6); 3.52 (s, 3H: OCH3); 3.83 (s, 3H: ArOCH3); 3.85 (mt, 1H: H

wo 95113271 PCT ~ R94101283 ~

in 3); 4.08 and 4.26 (2 d, J = 8.5 Hz, 1H each: CH2 in 20); 4.14 and 4.22 (2 d, J =
16 Hz, 2H: OCOCH2O); 4.56 (d, J = 5 Hz, 1H: H in 2 '); 4.86 (d wide, J = 10 Hz, 1H: H in 5); 5.43 (dd, J = 11 and 8 Hz, 1H: H at 7); 5.46 (mt, 1H: H in 3 '); 5.66 (d, J = 7Hz, 1H: Hen2); 6.06 (tlarge, J = 9Hz, 1H: Hen13); 6.40 (mt, 1H: Hen 5 '); 6.63 (s, 1H: H at 10); 6.93 (d, J = 8 Hz, 2H: H ~; I in ortho of OCH3); from 7.30 to 7.50 (mt, 7H: H r '~ and H ~, in meta of OCH3); 7.50 (broad d, J = 7.5 Hz, 1H: H in 4 from 1'blvll to 4 ~ in 2); 7.56 (t, J = 7.5 Hz, 1H: H in 5 of ralvl ~ .a i4u ~, in 2); 7.89 (broad s, 1H: H in 2 of r. In 2); 7.99 (d, J = 7.5 Hz, 1H: H in 6 of ~ u,. In 2).
A solution of 190 mg of tert-l ~ u, v ~ y ~, ~ ubvl ~ yl-3 (methox, Y-4 phenyl) -2 phe-nyl-4. . ~,. .1i.1;,. ~ -1.3 ~ ubw ~ yli4ue-5- (2R ~ 4s ~ 5R) -dlacétoxy4a épox ~ Y-513,20 hydrQxy-1 ~ methox ~ Yacetoxy-10 ~ oxo-9 llin ~ "... ~ r ..., ~ lv ~ y-7 ~ (11inuulvlllelllv ~ y-3 I; ~ Lvylu ~ y) -2a taxene-ll yle-13a in 3.2 cm3 of a 0.1N solution of chlorine ethanol-water is kept stirring at a lelll ~ éla ~ ul ~; close to 20C for 20 15 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to 40C. The crude product obtained is dissolved in 50 cm3 of di ~, llvlvllléllla ~., And 50 cm3 of a saturated aqueous solution of sodium l. The organic phase is separated by ~ nt ~ tif) n then extracted twice with 50 cm3 of Lc ~ .llulvlllé ~. The organic phases are combined, laYées with 50 c ~ n3 of distilled water and then dried over 20 m ~ m sulphate, filtered and ~: ullcellLlées dry under reduced pressure (2.7 kPa) at 40C. 175 mg of a Wanche neringue are obtained which are purified by ~ '.. /. ~, .1.1.; ~
preparative on a 0.5 mm thick silica plate [eluent: di ~ hlvlvl ~ léll ~ aule-methanol (94-6 by volume)]. 66 mg of tert-ly are obtained ~ bvllylallLulo-3 hydroxy-2 phenyl-3 ~ n ~ i (2R, 3S) of acetoxy4a epoxy-5 ~, 20 hydroxy-l ~
25 I ~ ~ a ~: é ~ y-10 ~ oxo-9 I "n., ~"". ~ R ~ .., rlu ~ y-7 ~ nuululllélllv ~ y-3 I ~. ~ Vylv ~ y) -2a taxene-ll yle-13a in the form of a white meringue and whose lr ~ are as follows:
- Proton NMR spectrum (400 MHz, CDCl3, en in ppm): 1.22 (s, 3H: CH3);
1.26 (s, 3H: CH3); 1.37 (s, 9H: (CH3) 3); 1.72 (s, 1H: OH in 1); 1.91 (s, 3H:
CH3); 2.07 (s, 3H: CH3); 2.26 and 2.89 (2 mts, 1H each: CH2 in 6); 2.36 (mt, 2H: CH2 at 14); 2.37 (s, 3H: COCH3); 3.36 (d, J = 5 Hz, 1H: OH in 2 '); 3.54 (s, 3H: OCH3); 3.97 (d, J = 7.5Hz, 1H: Hen3); 4.16 and 4.26 (2d, J = 16Hz, 2H:
OCOCH2O); 4.17 and 4.34 (2 d, J = 8.5 Hz, 1 H each: CH2 in 20); 4.62 (d wide, J = 5Hz, 1H: Hen2 '); 4.94 (dlarge, J = 10Hz, 1H: Hen5); 5.24 (dlarge, J = 10 Hz, 1H: H in 3 '); 5.36 (d, J = 10 Hz, 1H: CONH); 5.49 (dd, J = 11 and 8 Hz, 1H: H

WO 95/13271 ~ ~ 7 ~ 3 8 4 r ~., R ~ 4 ~ 01283 .27 en7); 5.73 (d, J = 7Hz, 1H: Hen2); 6.17 (tlarge, J = 9Hz, 1H: Henl3); 6.73 (s, - 1H: H at 10); from 7.30 to 7.50 (mt, 5H: H alUIllciiU, U ~ :: I); 7.50 (wide d, J = 7.5 Hz, 1H: H in 4 of 1 '. in 2); 7.57 (t, J = 7.5 Hz, 1H: H in 5 of r ~ u, llc ~ iuue in 2); 7.99 (broad s, 1H: H in 2 of the cu ~ l ~ cLi ~ u ~, in 2); 8.07 (d, J = 7.5 Hz, 1H: H at 6 5 of the hlv.l, cii ~ Lua in 2).
Has a solutiorl of 66 mg of tert- ~ uLu. y., c l.vllyl ~ u ~ iu ~ v-3 hydroxy-2 phenyl-3 ~ - (2R, 3S) of acetoxy-4a hydroxy-ll '~ epoxy-51' ~, 20 ~; liv ~ .y ~ Ly-10 OXO-9 i ~ lu ~ y-71f ~ r-3 ~. ~ Vylu. ~ R) -2a taxene-ll yle-13a in 0.855 cm3 of acetonitrile and 0.085 cm3 of i '' r.llu ~, we add suc ~ iv ~ lll ~ lL 200 mg of sieve mf "'4A powder and 100 mg of chloride sodium The reaction mixture is kept under stirring at an L ~ cLuu ~ close to 75C for 5 hours then, at an L ~ l .., J ~ aLuu ~ close to 20C, added with 75 cm3 of flifhl 'and 50 cm3 of a saturated aqueous chloride solution of sodium The organic phase is decanted, washed with 2 times 40 cm3 of a solution 15 saturated aqueous sodium chloride and then dried over ~ filtered sulfate and concentrated to dryness under reduced pressure (2.7 l ~ a) at 40C. We get 110 mg that we purifies with ~ "l, l ~ .I ~ Li ~, on a 0.5 mm thick silica plate in eluting with a cyclohexane-ethyl acetate mixture (1-1 by volume). 30 mg of tert-l, uL ~ y ~ bu..yla l are obtained;; o-3-hydroxy-2-phenyl-4 ~, - (2R, 3S) acetoxy-4a hydroxy-ll ~ epoxy-5 ~ '~, 20 llléLlluAyc ~ éLoAy-101f ~ methylene-71 ~, 8 nor-l9 oxo-9 (ilinuulul ~ Lllu ~ y-3 1 ~. ~ urluAy) -2a taxene-ll yle-13a and whose characteristics are the following:
- Proton NMR spectrum (400 MHz, CDC13, ~ in ppm): 1.22 (s, 3H: CH3);
1.25 (s, 3H: CH3); 1.28 (s, 9H: (CH3) 3); 1.38 (mt, 1H: H at 7); 1.65 and 2.25 (2 mts, 1H each: CH2 in 19); 1.80 (s, 1H: OH in 1); 1.85 (s, 3H: CH3); 2.09 and 2.45 (le ~ euLiy ~ .lL d and dt, J = 16 Hz and J = 16 and 4 Hz, 1H each: CH2 in 6);
2.32 (mt, 2H: CH2 at 14); 2.32 (s, 3H: COCH3); 3.28 (mf, 1H: H in 2 '); 3.49 (s, 3H: OCH3); 4.00 and 4.27 (2 d, J = 8.5 Hz, 1H each: CH2 in 20); 4.08 (d, J = 7.5 Hz, 1H: H at 3); 4.13 (limit AB, J = 16 Hz, 2H: OCOCH2O); 4.57 (s broad, 1H:
Hen2 '); 4.72 (dlarge, J = 4Hz, 1H: Hen5); 5.21 (dlarge, J = 10Hz, 1H: Hen 3 '); 5.30 (d, J = 10, 1H: CONH); 5.62 (d, J = 7 Hz, 1H: H in 2); 6.19 (large t, J =
9 Hz, 1H: H at 13); 6.39 (s, 1H: H at 10); from 7.25 to 7.50 (mt, 5H: H aroma-ticks); 7.44 (broad d, J = 7.5 Hz, 1H: H in 4 of hlUIllaLi.l ~ in 2); 7.55 (t, J = 7.5 Hz, 1H: H at 5 of hollolllaLuu ~, at 2); 7.99 (s broad, 1H: H in 2 of the huul ~ laLi L ~ in 2); 8.08 (d, J = 7.5 Hz, 1H: H in 6 of aluminum, ~, aLique in 2).

WO 9S / 13271 PCT / E ~ 94/01283 0 21 7538 ~

-EXFMPI .F 3 A mixture of 300 mg of tert-1, uLu, ~ y., Gubu..ylGl ~ o-3 hydroxy-2 phenyl-3 (2R, 3S) acetoxy-4a (cllloro-3 brc.L ~ uylu..y) -2a epoxy-5 ~, 20 hydroxy-1 ~ calu; ~ yG ~ fcLu ~ Ly-10l3 OXO-9 IHnuu ~ r ~ ylu ~ y-7 ~ taxene-11 yle-13a, de 500 mg of sodium chloride and 100 mg of screen '' activated 4A, in 3 cm3 of acetonitrile and 0.6 cm3 of Li, ~ u ~ y ~ Lu ~ uuGul ~ is heated at reflux for 3 hours. After It r, ~ up to an i I Yoisine of 20C, the mixture is filtered on sintered glass garnished with celite. The filtrate was washed with 5 cm3 of water, then the phase organic is decanted, dried over ~ 'sulfate After filtration on glass sintered and. ~ under reduced pressure (0.27 kPa) at a ~ rJ ~ fc ~ G ~ uurc close to 40C, 410 mg of a pale yellow meringue is obtained which is purified by ~, luul ~ laiu lGlJlLe prepGrative on thin layer [12 Ulri plates ~ JGLGLiV ~ Co Merck, Kieselgel 60F254; 0.25 mm thick; deposit in solution in the di ~, hlulull ~ ca ~ G u ,;
eluent: methanol-dichlulul mixture,., ca.G. ~ (7-93 by volume)]. After elution of the 15 zone ~: UII ~ O ~ O ~ GIII to the main product by a methanol-dichlu.u ~, li. ~ U. ~, (10-90 by volume), filtration on friKé glass, then f ~ a ~ ulaLiùll of solvents under reduced pressure (0.27 kPa) at an Irclll ~ rcla ~ uuc close to 40C, we obtain 136.8 mg tert-l, uLu ~ y ~ a-bullylalll; llu-3 hydroxy-2 phenyl-3 ~ rlu ~ riullc ~ (2R, 3S) acetoxy-4a (chloro-3 1 ~. ~ uylu ~ y) -2a epoxy-5 ~, 20 hydroxy-1 ~ lcLllu ~ ya ~; riLu ~ y-10 ~ methylene-7,813 oxo-9 nor-19 taxene-11 yle-13a in the form of a white meringue whose " are the following :.
- Proton NMR spectrum (400 MHz; CDC13; o in ppm): 1.22 (s, 6H: CH3);
1.26 (s, 9H: (CH3) 3); 1.37 (mt, 1H: H at 7); 1.67 and 2.34 (2 mts, 1H each: CH2 in 19); 1.78 (s, 1H: OH in 1); 1.85 (s, 3H: CH3); 2.10 and 2.44 (Ir, o ~ Li ~ 'd and dt, J = 16 Hz and J = 16 and 4 Hz, 1H each: CH2 in 6); 2.23 (mt, 2H: CH2 in 14); 2.34 (s, 3H: COCH3); 3.26 (mt, 1H: OH in 2 '); 3.49 (s, 3H: OCH3); 3.98 and 4.27 (2d, J = 8.5Hz, 1H each: CH2en20); 4.07 (d, J = 7.5Hz, 1H: Hen3);
4.15 and 4.22 (2 d, J = 16 Hz, 2H: OCOCH2O); 4.57 (mt, 1H: H in 2 '); 4.73 (d large, J = 4Hz, 1H: Hen5); 5.22 (dlarge, J = 10Hz, 1H: Hen3 '); 5.30 (d, J = 10 Hz, 1H: COl ~ H); 5.60 (d, J = 7Hz, 1H: Hen2); 6.20 (tlarge, J = 9Hz, 1H: Hen 13); 6.40 (s, 1H: H 10); from 7.20 to 7.50 (mt, 5H: H alull.aLiq ~); 7.44 (t, J = 7.5 Hz, 1H: H in 5 of alul..a ~ ique in 2); 7.57 (large d, J = 7.5 Hz, 1H: H in 4 of the alul.l ~ liqu, c in 2); 8.02 (d, J = 7.5 Hz, 1H: H in 6 of ~ uulll ~ liir ~ u ~ in 2); 8.14 (s Iarge, 1H: H in 2 of ~ uulllaLi ~ u ~ c in 2).

WO95 / 13271 2 ~ 7 5 3 8 4 PCT11; ~ 94/01283 Tert-buLuAyualbu ~ lyla ~ llulo-3 h ~ droxy-2 phenyl-3 ~. (2R, 3S) acetoxy-4 (chloro-3 I ~ VYIUAY) -2 epoxy-5 ~, 20 hydroxy-1 ~ u ~ a ~ uAy-10 ~ oxo-9` i ~ '''''' ylUAy-713 taxene-ll yle-13 can be prepared from as follows:
A solutic ~ n of 770 mg of tert-l ~ uluAy ~ bullyl-3 (4-methoxyphenyl) -2 phenyl 1 ... ~; 1,3 ~, albv ~ y '-5- (2R, 4S, 5R) acetoxy-4a (chloro-3 b ~ l ~ vylu, ~ y) -2a epoxy-513.20 hydroxy-113 oxo-9 i ~. ,, 1v ~ y-7 taxene-11 yle-13a in 20 cm3 of a chlullly acid solution ~ 'l 0.1N in the ethanol is stirred at ~. ~ .a ~; close to 5C for 16 hours. The mixture reaction is then diluted with 50 cm3 of dichlulvllwlLa l ~, washed twice with 10 cm3 distilled water. After extraction of the aqueous phase with 10 cm3 of Lu; lv ~
Ies organic phases are ". ~.;, Dried on sulphate of ~ filtered on sintered glass and ~: u-- ~, e, l-é, aO under reduced pressure (0.27 kPa) at a t ~, .l. ~ lal ~ vvisine 40C. 7io mg of a yellow solid are thus obtained which is purified by cl ~. ,., .- .., ~, .. ll ~ at pressure ~ on 50 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter, eluting with an elution gradient:
ethyl acetate-ll; l ll .., .. ': l - .. from 10-90 to 20-80 by volume and collecting fractions of 10 cm3. The sections containing only the sought product are combined and ~: UI ~.,. ILl ~ O dry under reduced pressure (0, ~ 7 kPa) at 40C for 2 hours. This gives 594 mg of tert-l, u ~ u ~ y., All, u.lylc .. ulu-3 hydroxy-2 phenyl-3 ~
(2R, 3S) acetoxy-4 (chloro-3 ~. ~ Vylu ~ y) -2a epoxy-513.20 hyd ~ xy-113 methoxy-acetoxy-1013 oxo-9 i ~ uu ~ r ~ lVAy-7 ~ taxene-ll yle-13a in the form a pale yellow meringue whose ~ are as follows:
- proton NMR spectrum (400 MHz; CDC13; ~ in ppm): 1.23 (s, 3H: CH3);
1.24 (s, 3H: CH3); 1.38 (s, 9H: (CH3) 3); 1.68 (s, 1H: OH in 1); 1.90 (s, 3H:
CH3); 2.08 (s, 3H: CH3); 2.26 and 2.88 (2 mts, 1H each: CH2 in 6); 2.31 (mt, 2H: CH2 at 14); 2.41 (s, 3H: COCH3); 3.35 (mt, 1H: OH in 2 '); 3.54 (s, 3H:
OCH3); 3.95 (d, J = 7.5 Hz, 1H: H at 3); 4.15 and 4.35 (2 d, J = 8.5 Hz, 1H each:
CH2 in 20); 4.16 and 4.25 (2 d, J = 16 Hz, 2H: OCOCH2O); 4.64 (mt, 1H: H in 2 ');
4.95 (broad d, J = 10 Hz, 1H: H at 5); 5.26 (broad d, J = 10 Hz, 1H: H in 3 '); 5.37 (d, J = 10Hz, 1H: CONH); 5.48 (dd, J = 10.5 and 8Hz, 1H: Hen7); 5.70 (d, J = 7 Hz, 1H: Hen2); 6.19 ~ tlarge, J = 9Hz, 1H: Hen13); 6.73 (s, 1H: Hen10);

7.30 to 7.50 (mt, 5H: H alUllUlli ~ lU ~ o); 7.48 (t, J = 7.5 Hz, 1H: H in 5 of aromatic in 2); 7.62 (d wide, J - 7.5 Hz, 1H: H in 4 of ~ ullld ~ ._ in 2); 8.00 WO95 / 13271 PcrlFR94101283 1 ~
2 ~ 75384 -(d, J = 7.5 Hz, 1H: H in 6 of h .., ll.dtique in 2); 8.11 (s wide, 1H: H in 2 of rdl ~ dli ~ lU ~ in 2).
Tert-buLvAyu ~ l, -u.yl-3 (4-methoxyphenyl) -2 phenyl4 f ~ - 1.3 I, ~ lbuAy '-5- (2R, 4S, 5R) acetoxy-4a (chloro-3 1, w ~ rh, Ay) -2a epoxy-5 ~, 20 5 hydroxy-llfj oxo-9 L-in ,, ~ r ~ f ~ Ay-7lf ~ taxene-ll y ~ e-13a can be prepared as follows:
To a solution of 680 mg of tert-buh.Ar ~ ul ~ .yl-3 (4-methoxyphenyl) -2 phenyl-4 ~ "" ~ 1,3 ~, o.lbUAy- '5- (2R, 4S, SR) acetoxy-4a (3-chloro benzoyl-oxy) -2a epoxy-51f ~, 20 dihydroxy-llf ~, 71f ~ oxo-9 taxene-ll yle-13a in 7 cm3 of 10 ~ f and 0.43 cm3 of anhydrous pyridine, added to a t ~ Luue Yoisine of 20C from the sieve '' 4A powder. At the arnsi suspension obtained, we add, to a ~ d ~ uUe close to -30C, under d ~ lllU ~ C inert argon, 0.445 cm3 of triflic anhydride. After leaving the ~ t: llllJ ~ .l ~ UU ~: of the mixture reaction go back to VU ~, __. fj.,. l ~ 20C in about 1 hour, we add succ ~ ivt: "~ elll 5 cm3 of distilled water and 50 cm3 of tiifhl .., ..: l - f ~ then we filter the sieve on sintered glass garnished with celite. After rl ~; fn, the aqueous phase is extracted by 2 times 5 cm3 of ~ ll- f The organic phases are. ~ f ~
dried over m ~ ei- n sulfate, filtered through sintered glass, and ~ tlW ~ UNDER pressure reduced (0.2 ~ kPa) to an i, c ~ close to 40C. 1.13 g of a brown meringue which is purified by, ',,,' pressure, '~ - on 60 g of silica (0.063-0.2 mm) contained in a column 2 cm in diameter eluting with an ethyl acetate-fiirhl 'elution gradient from 0-100 to 10-90 .in volumes and collecting 10 cm3 fractions. Fractions containing only the desired product are combined and ~: or._ ~ .t ~ dry under reduced pressure (0.27 kPa) at 40C for 2 hours. 762 mg of tert- ~ are thus obtained. VAy ~ albull.yl-3 (methoxy4 phenyl) -2 phenyl4 I -, .l; l: ~ r ~ 1.3 u ~ ul ~ y '5- (2R, 4S, 5R) acetoxy-4a (chloro-3 lic. ~ yluAy) -2a epoxy-5 ~, 20 hydroxy-ll ~ oxo-9 ~ in ~,., yl, JAy-7, ~
taxene-l l yle-13a in the form of a yellow-orange meringue whose. ... Ir.; ~ 1; ~ 1 ....
are the following:
- proton NMR spectrum (400 MHz; CDC13; o in ppm): 1.08 (s, 9H:
(CH3) 3); 1.20 (s, 6H: CH3); 1.61 (s, 1H: OH in 1); 1.71 (s, 3H: CH3); 1.85 (s, 3H: CH3); 1.95 (s, 3H: COCH3); 2.08 and 2.10 to 2.30 (.. ~ e ~ ~ iv, dd (J = 16 and 9 Hz) and mt, 1H each: CH2 at 14); from 2.10 to 2.30 and 2.84 (2 mts, 1H each: CH2 in 6); 3.53 (s, 3H: OCH3); 3.85 (s, 3H: ArOCH3); 3.85 (mt, 1H: H at 3);
4.09 and 4.28 (2 d, J = 8.5 Hz, 1H each: CH2 in 20); 4.15 and 4.23 (2 d, J = 16 Hz, WO95113271 2 1 75384 I ~ l / r ~ Cl ~ os 2H: OCOCH2O); 4.58 (d, J = 5 Hz, 1H: H in 2 '); 4.87 (d wide, J = 10 Hz, 1H: H
en5); 5.42 (dd, J = 10ET7Hz, 1H: Hen7); 5.45 (mt, 1H: Hen3 '); 5.65 (d, J =
7 Hz, 1H: H in 2); 6.06 (wide t, J = 9 Hz, 1H: H at 13), 6.42 (mt, 1H: H at 5 ');
- 6.61 (s, 1H: H at 10); 6.94 (d, J = 8.5 Hz, 2H: H ~ uvlllaLi Luci ~ in ortho of OCH3);
from 7.30 to 7.50 (mt, 8H: H ~ and H h ~ in meta of OCH3); 7.45 (t, J = 7.5 Hz, 1H: H in 5 of r ~ uu.l. ~ Liilu ~ in 2); 7.62 (d wide, J = 7.5 Hz, lH: H in 4 of the alv ~ Li4 ~. ~ In 2); 7.92 (d, J = 7.5 Hz, 1H: H in 6 of r ~,, in 2); 8.01 (s large, 1H: H in 2 of 1 'in 2).
Tert-buLv ~ y ~ Jvll.yl-3 (4-methoxyphenyl) -2 phenyl4 ~ P 1 ~ 3 C ~ v ~ y '5- (2R, 4S, 5R) of acetoxy-4a ~ chloro-3 1 ~. ~ VylVAy) -2 ~ epoxy-5 ~, 20 dihydroxy-113,7 ~ oxo-g taxene-ll yle-13a can be prepared as follows:
To a solution of 800 mg of tert-b ~ u ~ y ~ vllyl-3 (4-methoxyphenyl) -2 phenyl-4 ~, 3 i; c ~ l ~ v ~ - -5- (2R, 4S, 5R) of acetoxy4a (3-chloro benzoyl-oxy) -2a epoxy-5 ~, 20 hydroxy-113 oxo-9 Lii ~ a ~ yl ~ ilylvAy-7 ~ taxene-ll yle-13a dans8cm3 of dichlu.vl, caloll ~, maintained under, .1 .. ~. 1, "~ * of argon, add drop to drop, at an i. .l. ~ él ~ u ~ c close to 0C, 8.5 cm3 of the lluvLllyiLiilu acid complex * -L i ~ a. ~ Ld li le (3HF.Et3N). The solution is stirred for 4 hours at 0C, then diluted per 20 cm3 of dichlvlv ... ca.l. ~, and poured onto 40 cm3 of a saturated aqueous solution in sodium hydrogen carbonate maintained at a tU ~ 'C close to 0C.
20 After ~ -IP ~ the aqueous phase is extracted with 3 times 30 cm3 of di ~ Llu ~ v ~ * Ll ~ dl ~. The organic phases.,. ~ Are dried over sulphate 1 .. ~, ~ .... 11 filtered on sintered glass, then i VII ~., LlLicc ~ under reduced pressure (0.27 kPa) to an Lc-l- ~ l ~ Luic close to 40C. 781 mg of a pale yellow meringue are thus obtained.
which are purified by ~, ll ~., .. ~ ~ U, ~ pressure ~ i-, on 100 g of silica (0.063-0.2 mm) contained in a column 3.5 cm in diameter, eluting with a mixture of ethyl acetate-dichlulv.l.cLlldlie (25-75 by volume) and collecting fractions of 15 cm3. The fractions containing only the sought product are combined and i, O. ~, .ltli ', C ~ dry under reduced pressure (0.27 kPa) at 40C for 2 hours. We thus obtains 686 mg of tert-1, uLuAyi; ~ ul, ullyl-3 (4-methoxyphenyl) -2 phenyl4 ~ .. P-1,3 c ~ ul ~ u ~ yld ~ c-5- (2R, 4S, 5R) acetoxy-4a (chloro-3 L ~ vylu ~ y) -2a epoxy-5 ~, 20 dihydroxy-1 ~, 7 ~ oxo-9 taxene-ll yle-13a in the form of ume meringue white whose car ~ r ~ ri ~ tiq ~ P ~ are the following:
- proton NMR spectrum (400 MHz; CDC13; o in ppm): 1.08 (s, 9H:
(CH3) 3); 1.12 (s, 3H: CH3); 1.25 (s, 3H: CH3); 1.58 (s, 3H: CH3); 1.64 (s, 1H:
OH in 1); 1.66 (s, 3H: CH3); 1.86 and 2.54 (2 mts, 1H each: CH2 in 6); 1.88 (s, WO95113271 2 1 7 5 ~ 8 4 PCT / FR94101283 0 3H: COCH3); 2.08 and 2.21 '~ 2 dd, J = 16 and 9 Hz, 1H each: CH2 14); 2.32 (d, J =
4Hz, 1H: OHen7); 3.54 (s, 3H: OCH3); 3.71 (d, J = 7Hz, 1H: H3); 3.83 (s, 3H: ArOCH3); 4.08 and 4.24 (2 d; J = 8.5 Hz, 1H each: CH2 in 20); 4.26 (AB
irnite, J = 16 Hz, 2H: OCOCH2O); 4.37 (mt, 1H: H at 7); 4.61 (d, J = 5 Hz, 1H:
5 Hen2 '); 4.91 (dlarge, J = 10Hz, 1H: Hen5); 5.43 (mt, 1H: Hen3'); 5.60 (d, J =
7Hz, 1H: Hen2); 6.14 (tlarge, J = 9Hz, 1H: Hen13); 6.30 (s, 1H: Hen10);
6.40 (mt, 1H: H in 5 '); 6.94 (d, J = 8.5 Hz, 2H: H ~ ortho to OCH3);
from 7.30 to 7.50 (mt, 8H: H uv, .. aLiq., w and H ~ er. meta of OCH3); 7.45 (t, J = 7.5 Hz, 1H: H 5 of rAromatic in 2); 7.61 (d wide, J = 7.5 Hz, lH: H in 4 a, vl.la ~ ua in 2); 7.92 (d, J = 7.5 Hz, 1H: H in 6 of the alvlllaii ~ u ~ in 2); 8.03 (s large, 1H: H in 2 of the alvllla ~ iu, u ~, in 2).
Tert-buLv ~ y ~ all) b ~ l-3 (4-methoxyphenyl) -2 phenyl-4 1 ~ ~ - 1.3 ~; clbv ~ ylaL ~ -5- (2R, 4S, 5R) acetoxy-4a (chloro-3 1 ~ .wylv ~ y) -2a epoxy-51 '~, 20 hydroxy-ll '~ oxo-9 L ~ iét ~ ilylu ~ .y-71' ~ taxene-ll yle-13a can be prepared from 15 as follows:
To a solution of 2.5 g of tert-1, uLu, y ~ bù..yl-3 ~ 4-methoxyphenyl) -2 phenyl-4 f) ~ 7f) liflinf ~ 1,3 ~ bv ~ y '5- (2R, 4S, 5R) acetoxy-4a dihydroxy-11' ~, 2a epoxy-51 '~, 20 lllelllw ~ ya ~ e ~ u ~ y-lo! 3 oXo-9 Llié ~' ~ y ~ ilylwy-71 ~ taxene-ll yle-13a in 25 cm3 of L ~ L al ~ y ~ vr ~ maintained with stirring and under ~ argon, we add ~ u ~ f ~ i ~, to an Lt, .np. ~ a ~ uuè Yoisine of -78C, 3.90 cm3 of a solution 1.6M of n-butyllithium in hexane and 0.8 cm3 of metachlu chloride, vbel., Vyle.
The solution is thus stirred at a ~ a ~ be Yoisine of -78C for 45 minutes then 10 cm3 of a saturated aqueous chloride solution are added, ~. ' The reaction mixture is brought to ume t ~ p6 ~ a ~ close to 20C in 1 hour and diluted with 20 cm3 of ethyl acetate. The aqueous phase is separated by f ~ then extracted with 2 times 10 cm3 of ethyl acetate. The organic phasw are united, washed with 10 cm3 of distilled water, dried over sodium sulfate, after filtration and fA ~ dry under reduced pressure (2.7. ~ 'a) at 40C, 3.47 g of a pale yellow meringue which is purified by A'iU- ~ SUr 250 g of silica (0.063-0.2 mm) contained in a column 5 cm in diameter, eluting with an ethyl acetate-flirh ~ f elution gradient from 3-97 to 10-90 in volumw and in collecting fractions of 15 cm3. The fractions contain only the product sought are combined and ~: u .. ~ are dry under reduced pressure (2.7. ~ Pa) at 40 ~ C. We obtain 1.41 g of tert -., ... v, .y., Al ~ v..yl-3 (4-methoxyphenyl) -2 phenyl4, '' -1,3 35 caulJv ~ y '5- (2R, 4S, 5R) acetoxy-4a (chloro-3 ~ .wylv ~ y) -2a epoxy-51' ~, 20 WO 9 ~ 113271 2 1 7 5 3 ~ 4 PCT / ~ 94 ~ 01283 -hyd ~ oxy ~ oxo-9 Llié1Lyl ~ ily ~ u ~ y-7lf ~ taxène-ll yle-13a in the form of a white meringue whose f ~ are as follows:
- proton NMR spectrum (400 MHz; CDCl3; S in ppm): 0.60 (q, J = 7.5 Hz, 6H: ethyl SiCH2); 0.95 (t, J = 7.5 Hz, 9H: ethyl CH3); 1.08 (s, 9H: (CH3) 3);
1.19 (s, 3H: CH3); 1.21 (s, 3H: CH3); 1.62 (s, 1H: OH in 1); 1.65 (s, 3H: CH3);
1.70 (s, 3H: CH3); 1.85 (s, 3H: COCH3); 1.85 and 2.51 (2 mts, 1H each: CH2 in 6); 2.08 and 2.19 (2 dd, J = 16 and 9 Hz, 1H each: CH2 at 14); 3.53 (s, 3H:
OCH3); 3.71 (d, J = 7.5 Hz, 1H: H at 3); 3.84 (s, 3H: ArOCH3); 4.07 and 4.24 (2 d, J = 8.5 Hz, 1H each: CH2 at 20); 4.15 and 4.22 (2 d, J = 16 Hz, 2H:
OCOCH2O); 4.42 (dd, J = 10 and 6 Hz, 1H: H at 7); 4.60 (d, J = 5 Hz, 1H: H in 2 ');
4.88 (dlarge, J = 10Hz, 1H: Hen5); 5.42 (mt, 1H: Hen3 '); 5.60 (d, J = 7.5Hz, 1H: Hen2); 6.08 (tlarge, J = 9Hz, 1H: Hen13); 6.40 (mt, 1H: Hen5 '); 6.45 (s, 1H: H at 10); 6.93 (d, J = 8.5 Hz, 2H: H alulllaLi ~ u ~ in ortho of OCH3); of 7.30 to 7.50 (mt, 8H: H dulaLi ~ ues and H au..aLiqu ~ in meta of OCH3 and H in 5 of I'alullla ~ i ~ uè in 2); 7.61 (broad d, J = 7.5 Hz, 1H: H in 4 of the ~ uulllaiillu ~. Erl 2); 7.94 (d, J = 7.5 Hz, 1H: H in 6 of au..aii4ua in 2); 8.03 (s broad, 1H: H in 2 of a-u -. ALi ~ ua in 2).
Tert-buLu ~ y ~ allJullyl-3 (4-methylphenyl) -2 phenyl-4, ~ -1.3 ~, albu ~ laLe-5 (2R, 4S, 5R) acetoxy-4a dihydroxy-1 ~, 2a epoxy-51 '~, 20 methoxy-acetoxy-101 '~ oxo-9 lliéLil.rl ~ ilylu ~ y-7lf ~ tdxene-ll yle-13a can be prepared in conditions described in application n ~ slP PCT WO 94/20484.
The new products of general formula (I) ~ - rr ~ an activity inhibitor s; ~ ricdLiv ~ of ~ r, ~ abnormal cell and have properties thf-r.orf- ~ tif ~ allow the treatment of patients with ceditions rothfllflgifl ~ lf- ~ associated with an abnormal y ~ ulirated ~ aLiull cell. The c ~ mditions r ~ th ~ llogj ~ include the abnormal cell malignant cell ivlirélaLivll or non-malignant of various tissues and / or organs, ~ UIIl ~ lal. ~, without limitation, the tissues Illu ~ uldile ~, bone or ronjfm ~ tifc the skin, the brain, the lungs, sex organs, Iy ~ llau ~ lue ~ or kidney systems, cells or - 30 blood cells, the faith, the digestive system, the pancreas and the thyroid glands or adrenal. These pathological conditions may also include psoriasis, solid tumors, ovarian, breast, brain, prostate, colon cancer, stomach, kidney or testes, Kaposi's sarcoma, .1. ~ uv "e, choriocarcinoma, le, leu ul, ~ LvlJle ~ WiLms tumor, Hodgkin's disease, 35 m ~ l ~ n ~ mps ~ multiple myelomas, lyllllJllv leuoemias ~, ~ Lau ~., 1. ~, .

Wo 95113271 Pcr ~ 94101283 ~
2 1 753 ~ 4 Acute or chronic granulocytic lymphomas. The new ælon products rinvention are palliuuli ~ A ,. useful for the treatment of ovarian cancer. The products according to the invention can be used to prevent or delay the onset or the 1éà ~ ali1iol- conditions r thn1n ~ C or to treat these conditiorls 5 r ^ ~ hnln ~ flllf c The products according to the invention can be ~ 'to a patient ælon different shapes adapted to the chosen path of ~ f ~ which, preferably, is the way pal ~ 1Lrl ~ llf. The 'by I' comprerld the admin-tions illi ~ a ~ --r ~ r Or subcutaneous. More particularly 10 strongly preferred is ~ r ~ - '~, 1, ~ ...; .. 1.,. 1 ~ 1; ~ - ",'., L. ~ Oumtla ~ lfu ~ e.
The present invention also includes the ~; .. f ~ c pharmaceu-ticks which ~ at least one product of general formula (I) in an amount sufficient suitable for use in 1 ~) e ~ human or veterinary. The comro-sitions can be prepared according to the usual methods using one or more adjuvants, supports or excipients ~ A ~ ff ~) lf ~ Les ~ lableo media include thinners, sterile aqueous media and miscellaneous non-toxic solvents. Preferably the ~ are in the form of aqueous solutions or ~, injectable solutions which may contain agents ~; r; - 1 ~, dyes, ~ l Va ~ irO OR Ct ~ tC
The choice of adjuvants or excipients can be determined by the solubility and the chemical properties of the product, the particular mode of ~ l,.; ~ '-, - 1; .. 1 and the good practices 1.1. - r ~ `r ~
For ls ~ l ~ l ~; ~ 1 ,,, 1;,. ,, ~ '', solutions or suspen-aqueous or non-aqueous sterile ions. For the ~ 1; pa aliO1l of non-aqueous solutions or de25 S ~ lr ~ can be used natural vegetable oils such as olive oil, sesame oil or paraffin oil or organic esters injectables such as ethyl oleate. Aqueous sterile solutions can be consisting of a solution of a salt ~ IA r ~ f ~ - ~ acceptable in solution in some water. Aqueous solutions ~ ". ~;.,., ..., .. ~ for 1 '' ~, in 30 the measurement where the pH is ~ 11 ~ adjusted and where risotonicity is achieved, by for example, with a sufficient amount of sodium chloride or glucose. The qtf ~ riliclltinn can be achieved by heating or by any other means q ~ u does not alter It is understood that all the products entering the. . according to 35 the invention must be pure and non-toxic for the amounts used.

WO 95/13271 PCT / F ~ 94/01283 The. ~ "~ May contain at least 0.1% of therapeutic product.
quement acti The quantity of active product in a ~; "" is such that a suitable dosage can be prescribed. Preferably, the ~ are - prepared in such a way that a unit dose contains from 0.10 to 1000 mg approximately 5 of active product for ~ Y ~ I r ~ 1 by way ~ GIC.IICL ~
Ih 'nl ~ t ~ treatment can be performed ~ ~ with others treatments 11 ~, npe ~ P ~ incluarlt of "" ~ ~ 1 5, antibodies r ~, therapies v. or ~ or '~ answers hi ~ girll.P ~ The m ~ iifir ^ ~ l ~ answers include, from 10 non-limiting manner, ly ~ lluhillci ~ and lcs cytokines teDes that Ies interferons (a, 13 or o) and INF. Other useful rh; mi ~ agents in the treatment of disorders due to abnormal luLuli ~ ld ~ iu l cells include, but not limited to, alkylating agents such as mustards with nitrogen such as. ~ P11 ~ c: y, ~, melphalan and rhl ~ lrPm ~ ril ~
15 alkyl sulfonates like busulfan, l iLIusuu cc ~ like la ~, la lomustine, semustine and SLL. ~ r, triazenes such as ~; r, the hlll, ~ like analogs of folic acid such as I ~ uLl ~ Gh ~
pyrimidine analogs like rluOIuuldcil and cytarabine, analogs of purines like la --c ~ r and l ~ g ~ ~ ~, 1, r ~ of natural products hls that les20 vinca alkaloids like vinblastine, vincristine and vendesine, desé ~ ipudùl, l, yllotoxins like etoposide and teniposide, des. ~ ~; 1,;, l1 .q P ~ as the dG ~ Li ~ u ~ y ~ e ~ la ~ 1-- ~. . 1 ;; lP, la dU ~ UIUbiL, In ~, la l ~ léu ... ~, la I ".rc _._ and la yuille ~ enzymes like ~ -'IJ ~ -. various agents including complexes of 1 ~;,. platinum hl as cisplatin, substituted ureas hl 25 that I ~ IIYdLU ~ UILSCI the derivatives of IllcLll ~ DlydLG ~ ul ~, such as ~ / IUL ~ I '', SUI ~ I) I'C ~ CUL: ~ aLILP ~ -U ~ r ~ as mitotane and rl "Igl ~ t ~ ', hormones and ..., l ~ gl ~ as a ~ iL, ~ locu, l; -, u ~ Lcluid ~ as the prednisone, the ~ JlUo _., Lilici, like the caproate Llll ~ LUAy ~ f ~, the acetah of lllcLllw ~ yluruoc ~ Lélull ~ and megestrol acetate, oc ~ Lluowl ~ s as 30 diethyistilbestrol and cL ~ l ~ llyD, _ .. ddiul, antioestrogens like Ld ~ l ~ u ~ if ~ "Ies androgens like the propionate of ~ ci ~ Lu ~ Lc ~ u ~ lc and the auu ~ y ... csLclu .. ~.
The doses used to implement the methods according to rinvcntion are those that allow ~ u, ul ~ ylacLi ~ uc treatment or maximum response r The doses vary according to the form of n ~, the particular product link selected and the specific GIs of the subject to be treated. In general, the doses wo 95113271 PCT ~ 94/01283 ~
2 ~ ~ 5384 are those which are ill. effective for the treatment of disorders due to an abnormal ulcer. Ælon rinvention products can be administered as often as necessary to achieve the desired ~ u ~ effect.
Some patients may respond .AI ~ n 1 to large doses 5 low then need low or no maintenance doses. Gf ~ - t, low doses will be used at the start of treatment and, if necessary, key doses stronger and stronger will be 'until obtaining an optimum effect. For other patients may need ~ 1 '' maintenance doses 1 to 8 times per day, preferably 1 to 4 times, as needed ~ Cv l of the patient 10 considered. It is also possible that for some patients it is necessary to use only one to two 'ILiuns j ~ "` ~ i.,.
In humans, the doses are v 'between 0.01 and 200 mg / kg. By way; ,, I ,,. I .. '.; I, .l ~ lr the doses will generally be between 0.1 and 100 mg / kg and, preferably between 0.5 and 50 mg / lcg and, even more ~ 1 ~ if;, l., .., ... ~
between 1 and 10 mg / kg. By illL ~, the doses are ePn5r ~ 1rnnPnf included between 0.1 and 50 mg ~ g and, preferably between 0.1 and 5 mg / kg and, even more SpéCifi-only between 1 and 2 mg / kg. It is understood that, to choose the most appropriate dosage appropriate, must take into account the way ~ the weight of the patient, general health, age and all factors that may affect efficiency 20 of the processing.
The following example illustrates an rflm3 ~ citir ~ n according to the invention.
.XF ~ PLE
40 mg of the product obtained in example 1 are dissolved in 1 cm 3 of "EL"
620 and 1 cm3 of ethanol then the solution is diluted by adding 18 cm3 of serum 25 physiological.
La ~ est ~ tlminiefT ~ c by infusion for 1 hour by infoduct-tiûn in physiological saline.

Claims (11)

37 1 - New taxoids of general formula:
(I) in which:
Ar represents an aryl, alkyl containing 1 to 4 carbon atoms, alkenyl radical containing 2 to 4 carbon atoms, cycloalkyl containing 3 to 6 carbon atoms or cycloalkenyl containing 3 to 6 carbon atoms, R represents a hydrogen atom or an alkanoyl, alkoxyacetyl or alkyl, R1 represents a benzoyl, thenoyl or furoyl radical or an R2-O-CO- radical in which R2 represents:
- a straight or branched alkyl radical containing 1 to 8 carbon atoms, alkenyl containing 2 to 8 carbon atoms, alkynyl containing 3 to 8 carbon atoms carbon, cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 with 6 carbon atoms or bicycloalkyl containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more selected substituents among halogen atoms and hydroxy radicals, alkyloxy containing 1 to 4 carbon atoms, dialkylamino of which each alkyl part contains 1 to 4 atoms carbon, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a radical phenylalkyl whose alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, phenyl, cyano, carboxy or alkyloxycarbonyl of which the alkyl part contains 1 to 4 carbon atoms, - or a phenyl radical optionally substituted by one or more atoms or radicals chosen from halogen atoms and alkyl radicals containing 1 with 4 carbon atoms, alkyloxy containing 1 to 4 carbon atoms, - or a saturated or unsaturated heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 carbon atoms, and R3 represents - a straight or branched 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 or bicycloalkyl, containing 7 to 11 carbon atoms, these radicals being optionally substituted by one or more substituents chosen from halogen atoms and hydroxy, alkyloxy radicals containing 1 to 4 carbon atoms, dialkylamino of which each alkyl part contains 1 to 4 atoms carbon, piperidino, morpholino, piperazinyl-1 (optionally substituted at -4 by an alkyl radical containing 1 to 4 carbon atoms or by a phenyl-alkyl whose alkyl part contains 1 to 4 carbon atoms), cycloalkyl containing 3 to 6 carbon atoms, cycloalkenyl containing 4 to 6 carbon atoms, optionally substituted phenyl, cyano, carboxy or alkyloxycarbonyl whose alkyl part contains 1 to 4 carbon atoms, - or an aryl radical optionally substituted by one or more atoms or radicals selected from halogen atoms and alkyl radicals containing 1 to 4 atoms carbon, alkyloxy containing 1 to 4 carbon atoms, it being understood that R3 cannot represent an unsubstituted phenyl radical, - or a saturated or unsaturated nitrogen heterocyclyl radical containing 4 to 6 members and optionally substituted by one or more alkyl radicals containing 1 to 4 atoms of carbon, and 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 R and R1 being defined as in claim 1, the aryl radicals represented by Ar and R3 are phenyl or .alpha.- or .beta.-naphthyl radicals optionally substituted by one or several atoms or radicals chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl, alkenyl, alkynyl, aryl, arlylalkyl, alkoxy, alkylthio, aryloxy, arylthio, hydroxy, hydroxyalkyl, mercapto, formyl, acyl, acylamino, aroylamino, alkoxycarbonylamino, amino, alkylamino, dialkyl-amino, carboxy, alkoxycarbonyl, carbamoyl, dialkylcarbamoyl, cyano, nitro, azido, trifluoromethoxy and trifluoromethyl, it being understood that the alkyl radicals and the alkyl portions of the other radicals contain 1 to 4 carbon atoms, that the alkenyl and alkynyl radicals contain 2 to 8 carbon atoms and that the aryl radicals are phenyl or .alpha.- or .beta.-naphthyl radicals, and that the radical R3 cannot represent an unsubstituted phenyl radical, and the radicals heterocyclics represented by Ar and R3 are heterocyclic radicals 5-membered aromatics containing one or more atoms; identical or different, chosen from nitrogen, oxygen or sulfur atoms, optionally substituted by one or more substituents, identical or different, chosen from halogen atoms (fluorine, chlorine, bromine, iodine) and alkyl radicals 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, alkylamino containing 1 to 4 carbon atoms, dialkylamino, each alkyl part of which contains 1 to 4 carbon atoms, acylamino whose acyl part contains 1 to 4 carbon atoms, alkoxycarbonyl-amino containing 1 to 4 carbon atoms, acyl containing 1 with 4 carbon atoms, arylcarbonyl whose aryl part contains 6 to 10 carbon atoms, carbon, cyano, carboxy, carbamoyl, alkylcarbamoyl of which the alkyl part contains 1 to 4 carbon atoms, dialkylcarbamoyl of which each alkyl part contains 1 to 4 carbon atoms or alkoxycarbonyl in which the alkoxy part contains 1 to 4 carbon atoms carbon. 3 - New taxoids according to claim 1 for which R and R1 being defined as in claim 1, Ar represents a phenyl, thienyl-2 or -3 or furyl-2 or -3 optionally substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and alkyl radicals, alkoxy, amino, alkylamino, dialkylamino, acylamino, alkoxycarbonylamino and trifluoromethyl and R3 represents a phenyl radical substituted by one or more atoms or radicals, identical or different, chosen from halogen atoms and the alkyl, alkoxy, amino, alkylamino, dialkylamino, acylamino radicals, alkoxycarbonylamino and trifluoromethyl. 4 - Process for the preparation of a new taxoid according to one of the claims cations 1, 2 or 3 characterized in that a product of general formula is esterified:

(II) in which Ar and R1 are defined as in one of claims 1, 2 or 3, or indeed R4 represents a hydrogen atom and R5 represents a protective group of the hydroxy function, or else R4 and R5 together form a saturated heterocycle at 5 or 6 membered, G1 represents an alkanoyl, alkoxyacetyl, alkyl radical or a protecting group of the hydroxy function, by means of an acid of formula general:
R3-CO-OH(III) wherein R3 is defined as in one of claims 1, 2 or 3, or a active derivative of this acid, to obtain a product of general formula:
(IV) in which Ar, R1, R3, R4, R5 and G1 are defined as above whose replacement of protective groups R5, when R4 represents an atom of hydrogen, or else R4 and R5, when R4 and R5 together form a heterocycle saturated with 5 or 6 members, and possibly G1 by led hydrogen atoms to the product of general formula (I) possibly passing according to the meanings of R1, R4 and R5, by a product of general formula:
(V) in which R is defined as above, which is acylated by means of chloride of benzoyl, thenoyl or furoyl or of a product of general formula:
R2-O-CO-X(VI) in which R2 is defined as above and X represents an atom of halogen or an -O-R2 or -O-CO-O-R2 residue. 5 - Process according to claim 4 characterized in that the esterification of product of general formula (II) is carried out by reacting the acid of formula general (III), preferably in halide form, on the product of general formula (II) previously metallized by means of an alkali metal alkylide in operating in an inert organic solvent such as an ether at a lower temperature at -50°C. 6 - Process according to claim 4 characterized in that the replacement protective groups of hydroxy functions by hydrogen atoms is carried out:
1) when R4 represents a hydrogen atom, R5 is defined as above and G1 represents an alkanoyl, alkoxyacetyl or alkyl radical, treating the product of general formula (IV) with a mineral acid chosen from hydrochloric acids, sulfuric and hydrofluoric or organic chosen from acetic acids, methanesulfonic, trifluoromethanesulfonic, p.toluenesulfonic used alone or as a mixture by operating in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, aliphatic hydrocarbons halogenated hydrocarbons, aromatic hydrocarbons or nitriles at a temperature between between -10 and 60°C, 2) when R4 and R5 together form a saturated heterocycle of general formula:
(VII) in which R1 is defined as in one of claims 1, 2 or 3, R6 and R7, identical or different, represent a hydrogen atom or an alkyl radical containing 1 to 4 carbon atoms, or an aralkyl radical whose alkyl part contains 1 to 4 carbon atoms and the aryl part preferably represents a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or an aryl radical representing, preferably a phenyl radical optionally substituted by one or more alkoxy radicals containing 1 to 4 carbon atoms, or else R6 represents an alkoxy radical containing 1 to 4 carbon atoms or a trihalomethyl radical or a radical phenyl substituted by a trihalomethyl radical and R7 represents an atom of hydrogen, or else R6 and R7 form together with the carbon atom to which they are attached a ring having 4 to 7 members, and G1 represents an acetyl radical or alkyl, is carried out, according to the meanings of R1, R6 and R7, in the manner next:
a) when R1 represents a t.butoxycarbonyl radical, R6 and R7, identical or different, represent an alkyl radical or an aralkyl or aryl radical, or although R6 represents a trihalomethyl radical or a phenyl radical substituted by a trihalomethyl radical and R7 represents a hydrogen atom, or else R6 and R7 together form a ring having from 4 to 7 members, by treating a product of formula general (IV) by a mineral or organic acid optionally in a solvent organic such as an alcohol to obtain a product of general formula (V) which is acylated by means of a product of general formula (VI).
b) when R1 represents a benzoyl radical or an R2-O-CO- radical in which R2 is defined as above, R6 represents a hydrogen atom or an alkoxy radical containing 1 to 4 carbon atoms or a substituted phenyl radical by one or more alkoxy radicals containing 1 to 4 carbon atoms and R7 represents a hydrogen atom, by treating a product of general formula (IV) by presence of a catalytic or stoichiometric amount of a selected mineral acid from hydrochloric and sulfuric or organic acids chosen from acids acetic, methanesulfonic, trifluoromethanesulfonic and p.toluenesulfonic used alone or as a mixture, in an organic solvent chosen from alcohols, ethers, esters, aliphatic hydrocarbons, aliphatic hydrocarbons halogenated and aromatic hydrocarbons at a temperature between -10 and 60°C.
3) when G1 represents an alkoxyacetyl radical and R4 and R5 are defined as in point 1) above, first replacing the protective group R5 with an atom of hydrogen by operating under the acid conditions described in point 1 above, then by replacing the protective group G1 with a hydrogen atom by treatment in an alkaline medium using ammonia or hydrazine or by treatment with a zinc halide under conditions that do not affect the rest of the molecule.
4) when G1 represents an alkoxyacetyl radical and R4 and R5 are defined as in point 2-a) above, possibly replacing the protective group G1 by treatment in an alkaline medium or by treatment with a zinc halide in the conditions described in point 3) above, then treating the product of formula general (V) obtained under the deprotection and acylation conditions described in point 2-a) above.
5) when G1 represents an alkoxyacetyl radical and R4 and R5 are defined as in point 2-b) above, possibly replacing the protective group G1 by treatment in an alkaline medium or by treatment with a zinc halide in the conditions described in point 3) above, then processes the product obtained in the conditions described in point 2-b) above. 7 - Process for preparing a product according to one of claims 1, 2 or 3 characterized in that a product of general formula is esterified:
(XV) in which Ar and R1 are defined as in one of claims 1, 2 or 3 and R4, R5 and G1 are defined as in claim 4 and G2 represents a protective group for the hydroxy function chosen from trialkylsilyl radicals, dialkylarylsilyls, alkyldiarysilyls or triarylsilyls in which the alkyl moieties contain 1 to 4 carbon atoms and the aryl parts are phenyl radicals, by means of an acid of general formula:

R3-CO-OH(III) wherein R3 is defined as in one of claims 1, 2 or 3 to obtain a product of general formula:

(XVI) in which Ar, R1, R3, R4, R5, G1 and G2 are defined as above, of which the protecting group G2 is selectively replaced by a hydrogen atom, to obtain a product of general formula:
(XVII) in which Ar, R1, R3, R4, R5 and G1 are defined as above, which, by the action of a derivative of trifluoromethanesulfonic acid chosen from the anhydride or the N-phenyl trifluoromethanesulfonimide, is transformed into product of general formula:
(XVIII) in which Ar, R1, R3, R4, R5 and G1 are defined as previously, of which we replaces the protective groups represented by R5 or by R4 and R5 by hydrogen atoms to give a product of general formula:
(XX) in which Ar, R1, R3 and G1 are defined as above, which is treated by an alkali metal halide, an alkali metal azide or a quaternary ammonium salt or an alkali metal phosphate, to obtain the product according to one of claims 1, 2 or 3 in which R represents an acetyl, alkoxyacetyl or alkyl which is optionally converted into a product according to one of the claims 1, 2 or 3 for which R represents a hydroxy radical. 8 - The product of general formula:
(II) in which Ar and R1 are defined as in one of claims 1, 2 or 3, and, or alternatively R4 represents a hydrogen atom and R5 represents a group protector of the hydroxy function, or else R4 and R5 together form a heterocycle saturated with 5 or 6 members, G1 represents an alkanoyl, alkoxyacetyl or alkyl radical or a protecting group of the hydroxy function. 9 - New product according to claim 8 characterized in that Ar and R1 being defined as in one of claims 1, 2 or 3, and, when R4 represents a hydrogen atom, R5 preferably represents a methoxy-methyl radical, 1-ethoxyethyl, benzyloxymethyl, trimethylsilyl, triethylsilyl, (.beta. trimethylsilyl-ethoxy) methyl or tetrahydropyranyl and, when R4 and R5 together form a heterocycle, this is an optionally mono-substituted or gem-disubstituted in position -2 and G1 represents an alkanoyl, alkoxyacetyl radical or alkyl or a protective group of the hydroxy function. 10 - Process for preparing a product according to one of claims 8 or 9 characterized in that an electrolytic reduction of a product of general formula:

(VIII) wherein Ar, R1 and R4 are defined as in one of claims 1, 2, 3 or 4, R5 is defined as in claim 4 and may additionally represent an atom hydrogen, G'1 represents a hydrogen atom, an alkanoyl radical, alkoxyacetyl or alkyl or a protecting group of the hydroxy function, in operating in an electrolyte consisting of a quaternary ammonium salt soluble in the organic solvent or in a hydro-organic mixture at a controlled potential. 11 - Pharmaceutical composition characterized in that it contains at least a product according to one of claims 1, 2 or 3 in combination with one or more pharmaceutically acceptable products whether inert or physiologically assets.