`Bouchard et al.
`
`[54]
`
`[75]
`
`TAXOIDS, THEIR PREPARATION AND
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING THEM
`
`Inventors: Hervé Bouchard, Ivry-sur-Seine;
`J ean-Dominique Bourzat, Vincennes;
`Alain Commergon, Vitry-sur-Seine, all
`of France
`
`Assignee: Rhone-Poulenc Rorer, S.A., Antony
`CedeX, France
`
`Appl. No.:
`
`Filed:
`
`622,011
`Mar. 26, 1996
`
`Related US. Application Data
`
`Provisional application No. 60/010,144, Jan. 17, 1996.
`Foreign Application Priority Data
`
`[60]
`[30]
`Mar. 27, 1995 [FR]
`Dec. 22, 1995 [FR]
`
`US005847170A
`Patent Number:
`Date of Patent:
`
`[11]
`[45]
`
`5,847,170
`Dec. 8, 1998
`
`OTHER PUBLICATIONS
`Greene et al, “Protective Groups in Organic Synthesis”, pp.
`10—14, 2”“ edition, 1991.
`M.L. Shelanski et al., “Microtubule Assembly in the
`Absence of Added Nucleotides”, Proc. Natl. Acad. Sci. vol.
`70, No. 3,pp. 765—768 (1973).
`G. Chauviere et al., “Analyse structurable et etude bio
`chimique de produits isoles de l’if: TaXus baccata L. (Tax
`aces)”, CR. Acad. Sc. Paris, t.293, pp. 501—503 (1981).
`J. Kant et al., “A Chemoselective Approach to FunctionaliZe
`the C—10 Position of 10—Deacetylbaccatin III. Synthesis and
`Biological Properties of Novel C—10 TaXol Analogues”,
`Tetrahedron Letters, vol. 35, No. 31, pp. 5543—5546, 1994.
`Primary Examiner—Ba K. Trinh
`Attorney, Agent, or Firm—Finnegan, Henderson, FaraboW,
`Garrett & Dunner, L.L.P.
`[57]
`ABSTRACT
`
`NeW taXoids of general formula (I):
`
`France ................................. .. 95 03545
`France ................................. .. 95 15381
`
`R4
`
`0
`
`(I)
`
`[51] Int. Cl.6 ................................................. .. C07D 305/14
`[52] US. Cl. ................ ..
`549/510; 549/511
`[58] Field of Search
`.......... .. 549/510, 511
`
`[56]
`
`References Cited
`
`US. PATENT DOCUMENTS
`
`5,229,526
`5,319,112
`5,486,601
`5,739,362
`
`7/1993 Holton et al. ......................... .. 549/213
`6/1994 Kingston et al.
`549/510
`1/1996 Holton et al.
`514/337
`4/1998 Holton et al. ......................... .. 549/510
`
`FOREIGN PATENT DOCUMENTS
`
`0 336 841 10/1989 European Pat. Off. .
`604910 7/1994 European Pat. Off. .
`0 639 577 2/1995 European Pat. Off. .
`694539
`1/1996 European Pat. Off. .
`WO 92/09589
`6/1992 WIPO .
`WO 94/07878 4/1994 WIPO .
`WO 94/18164 8/1994 WIPO .
`WO96/00724 1/1996 WIPO .
`
`COCH3
`
`their preparation and pharmaceutical compositions contain
`ing them, and the neW products of general formula (I) in
`Which Z represents a radical of general formula (II):
`
`<11)
`
`OH
`display noteWorthy antitumour and antileukaemic proper
`ties.
`
`22 Claims, No Drawings
`
`MYLAN - EXHIBIT 1082
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`
`
`1
`TAXOIDS, THEIR PREPARATION AND
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING THEM
`
`5,847,170
`
`This application claims the priority of US. provisional
`application 60/010,144 ?led Jan. 17, 1996.
`The present invention relates to neW taXoids of general
`formula (I)
`
`(I)
`
`15
`
`in Which:
`Z represents a hydrogen atom or a radical of general
`formula (II):
`
`20
`
`RINH
`
`o
`
`R3
`
`(11)
`
`25
`
`in Which:
`R1 represents
`a benZoyl radical optionally substituted With one or more
`identical or different atoms or radicals selected from
`halogen atoms, alkyl radicals containing 1 to 4 carbon
`atoms, alkoXy radicals containing 1 to 4 carbon atoms
`and tri?uoromethyl radicals,
`a thenoyl or furoyl radical or
`a radical R2—O—CO— in Which R2 represents:
`an alkyl radical containing 1 to 8 carbon atoms,
`an alkenyl radical containing 2 to 8 carbon atoms,
`an alkynyl radical containing 3 to 8 carbon atoms,
`a cycloalkyl radical containing 3 to 6 carbon atoms,
`a cycloalkenyl radical containing 4 to 6 carbon atoms
`or
`a bicycloalkyl radical containing 7 to 10 carbon atoms,
`these radicals being optionally substituted With one or
`more substituents selected from halogen atoms,
`hydroXyl radicals, alkoXy radicals containing 1 to 4
`carbon atoms, dialkylamino radicals in Which each
`alkyl portion contains 1 to 4 carbon atoms, piperi
`dino radicals, morpholino radicals, 1-piperaZinyl
`radicals, said piperaZinyl radicals being optionally
`substituted at position 4 With an alkyl radical con
`taining 1 to 4 carbon atoms or With a phenylalkyl
`radical in Which the alkyl portion contains 1 to 4
`carbon atoms, cycloalkyl radicals containing 3 to 6
`carbon atoms, cycloalkenyl radicals containing 4 to
`6 carbon atoms, phenyl radicals, said phenyl radicals
`being optionally substituted With one or more atoms
`or radicals selected from halogen atoms, alkyl radi
`cals containing 1 to 4 carbon atoms, and alkoXy
`radicals containing 1 to 4 carbon atoms, cyano
`radicals, carboXyl radicals and alkoXycarbonyl radi
`cals in Which the alkyl portion contains 1 to 4 carbon
`atoms,
`a phenyl or ot- or [3-naphthyl radical optionally substi
`tuted With one or more atoms or radicals selected
`from halogen atoms, alkyl radicals containing 1 to 4
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`2
`carbon atoms, and alkoXy radicals containing 1 to 4
`carbon atoms,
`a S-membered aromatic heterocyclic radical preferably
`selected from furyl and thienyl radicals,
`or a saturated heterocyclic radical containing 4 to 6
`carbon atoms, optionally substituted With one or
`more alkyl radicals containing 1 to 4 carbon atoms,
`R3 represents
`an unbranched or branched alkyl radical containing 1 to 8
`carbon atoms,
`an unbranched or branched alkenyl radical containing 2 to
`8 carbon atoms,
`an unbranched or branched alkynyl radical containing 2 to
`8 carbon atoms,
`a cycloalkyl radical containing 3 to 6 carbon atoms,
`a phenyl or ot- or [3-naphthyl radical optionally substituted
`With one or more atoms or radicals selected from
`halogen atoms, alkyl, alkenyl, alkynyl, aryl, aralkyl,
`alkoXy, alkylthio, aryloXy, arylthio, hydroXyl,
`hydroXyalkyl, mercapto, formyl, acyl, acylamino,
`aroylamino, alkoXycarbonylamino, amino, alkylamino,
`dialkylamino, carboXyl, alkoXycarbonyl, carbamoyl,
`alkylcarbamoyl, dialkylcarbamoyl, cyano, nitro and
`tri?uoromethyl radicals,
`or a S-membered aromatic heterocycle containing one or
`more identical or different hetero atoms selected from
`nitrogen, oXygen and sulphur atoms and optionally
`substituted With one or more identical or different
`substituents selected from halogen atoms, alkyl, aryl,
`amino,
`alkylamino,
`dialkylamino,
`alkoXycarbonylamino, acyl, arylcarbonyl, cyano,
`carboXyl, carbamoyl, alkylcarbamoyl, dialkylcarbam
`oyl and alkoxycarbonyl radicals,
`With the understanding that, in the substituents of the
`phenyl, ot- or [3-naphthyl and aromatic heterocyclic
`radicals, the alkyl radicals and the alkyl portions of the
`other radicals contain 1 to 4 carbon atoms, the alkenyl
`and alkynyl radicals contain 2 to 8 carbon atoms, and
`the aryl radicals are phenyl or ot- or [3-naphthyl radicals,
`R4 represents
`an alkoXy radical containing 1 to 6 carbon atoms in an
`unbranched or branched chain,
`an alkenyloXy radical containing 3 to 6 carbon atoms in an
`unbranched or branched chain,
`an alkynyloXy radical containing 3 to 6 carbon atoms in
`an unbranched or branched chain,
`a cycloalkyloXy radical containing 3 to 6 carbon atoms or
`a cycloalkenyloXy radical containing 4 to 6 carbon atoms,
`these radicals being optionally substituted With one or
`more substituents selected from halogen atoms, an
`alkoXy radical containing 1 to 4 carbon atoms, an
`alkylthio radical containing 1 to 4 carbon atoms, a
`carboXyl radical, an alkyloXycarbonyl radical in Which
`the alkyl portion contains 1 to 4 carbon atoms, a cyano
`radical, a carbamoyl radical, an N-alkylcarbamoyl radi
`cal and a N,N-dialkylcarbamoyl radical in Which each
`alkyl portion contains 1 to 4 carbon atoms, or both alkyl
`portions, together With the nitrogen atom to Which they
`are linked, form a saturated 5- or 6-membered hetero
`cyclic radical optionally containing a second hetero
`atom selected from oxygen, sulphur and nitrogen
`atoms, said saturated 5- or 6-membered heterocyclic
`radical optionally being substituted With a substituent
`selected from an alkyl radical containing 1 to 4 carbon
`atoms, a phenyl radical, and a phenylalkyl radical in
`Which the alkyl portion contains 1 to 4 carbon atoms,
`
`
`
`5,847,170
`
`3
`
`R5 represents
`an alkoXy radical containing 1 to 6 carbon atoms in an
`unbranched or branched chain,
`an alkenyloXy radical containing 3 to 6 carbon atoms,
`an alkynyloXy radical containing 3 to 6 carbon atoms,
`a cycloalkyloXy radical containing 3 to 6 carbon atoms or
`a cycloalkenyloXy radical containing 3 to 6 carbon atoms,
`these radicals being optionally substituted With at least
`one substituent selected from halogen atoms, an alkoXy
`radical containing 1 to 4 carbon atoms, an alkylthio
`radical containing 2 to 4 carbon atoms, a carboXyl
`radical, an alkyloXycarbonyl radical in Which the alkyl
`portion contains 1 to 4 carbon atoms, a cyano radical,
`a carbamoyl radical, an N-alkylcarbamoyl radical, and
`a N,N-dialkylcarbamoyl radical in Which each alkyl
`portion contains 1 to 4 carbon atoms or, With the
`nitrogen atom to Which it is linked, forms a saturated 5
`or 6-membered heterocyclic radical optionally contain
`ing a second hetero atom selected from oxygen, sulphur
`and nitrogen atoms, optionally substituted With a sub
`stituent selected from an alkyl radical containing 1 to 4
`carbon atoms, a phenyl radical and a phenylalkyl
`radical in Which the alkyl portion contains 1 to 4 carbon
`atoms.
`Preferably, the aryl radicals Which can be represented by
`R3 are phenyl or ot- or [3-naphthyl radicals optionally sub
`stituted With one or more atoms or radicals selected from
`halogen atoms (?uorine, chlorine, bromine, iodine) alkyl,
`alkenyl, alkynyl, aryl, arylalkyl, alkoXy, alkylthio, aryloXy,
`arylthio, hydroXyl, hydroXyalkyl, mercapto, formyl, acyl,
`acylamino, aroylamino, alkoXycarbonylamino, amino,
`alkylamino, dialkylamino, carboXyl, alkoxycarbonyl,
`carbamoyl, dialkylcarbamoyl, cyano, nitro and tri?uorom
`ethyl radicals, on the understanding 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
`ot- or [3-naphthyl radicals.
`Preferably, the heterocyclic radicals Which can be repre
`sented by R3 are S-membered aromatic heterocyclic radicals
`containing one or more identical or different atoms selected
`from nitrogen, oXygen and sulphur atoms, optionally sub
`stituted With one or more identical or different substituents
`selected from halogen atoms (?uorine, chlorine, bromine,
`iodine), alkyl radicals containing 1 to 4 carbon atoms, aryl
`radicals containing 6 or 10 carbon atoms, alkoXy radicals
`containing 1 to 4 carbon atoms, aryloXy radicals containing
`6 or 10 carbon atoms, amino radicals, alkylamino radicals
`containing 1 to 4 carbon atoms, dialkylamino radicals in
`Which each alkyl portion contains 1 to 4 carbon atoms,
`acylamino radicals in Which the acyl portion contains 1 to 4
`carbon atoms, alkoXycarbonylamino radicals containing 1 to
`4 carbon atoms, acyl radicals containing 1 to 4 carbon atoms,
`arylcarbonyl radicals in Which the aryl portion contains 6 or
`10 carbon atoms, cyano radicals, carboXyl radicals, carbam
`oyl radicals, alkylcarbamoyl radicals in Which the alkyl
`portion contains 1 to 4 carbon atoms, dialkylcarbamoyl
`radicals in Which each alkyl portion contains 1 to 4 carbon
`atoms, and alkoXycarbonyl radicals in Which the alkoXy
`portion contains 1 to 4 carbon atoms.
`Preferably, the radicals R4 and R5, Which may be identical
`or different, represent unbranched or branched alkoXy radi
`cals containing 1 to 6 carbon atoms, optionally substituted
`With a methoXy, ethoXy, ethylthio, carboXyl,
`methoXycarbonyl, ethoXycarbonyl, cyano, carbamoyl,
`N-methylcarbamoyl, N-ethylcarbamoyl, N,N
`
`15
`
`25
`
`35
`
`45
`
`55
`
`4
`dimethylcarbamoyl, N,N-diethylcarbamoyl,
`N-pyrrolidinocarbonyl or N-piperidinocarbonyl radical.
`More particularly, the present invention relates to the
`products of general formula (I) in Which Z represents a
`hydrogen atom or a radical of general formula (II) in Which
`R1 represents a benZoyl radical or a radical R2—O—CO—
`in Which R2 represents a tert-butyl radical and R3 represents
`an alkyl radical containing 1 to 6 carbon atoms, an alkenyl
`radical containing 2 to 6 carbon atoms, a cycloalkyl radical
`containing 3 to 6 carbon atoms, a phenyl radical optionally
`substituted With one or more identical or different atoms or
`radicals selected from from halogen atoms (?uorine,
`chlorine), alkyl (methyl), alkoXy (methoXy), dialkylamino
`(dimethylamino), acylamino (acetylamino), alkoXycarbony
`lamino (tert-butoXycarbonylamino), tri?uoromethyl, a
`2-furyl radical, a 3-furyl radical, a 2-thienyl radical, a
`3-thienyl radical, a 2-thiaZolyl radical, a 4-thiaZolyl radical,
`and a 5-thiaZolyl radical, and R4 and R5, Which may be
`identical or different, each represent an unbranched or
`branched alkoXy radical containing 1 to 6 carbon atoms.
`Still more particularly, the present invention relates to the
`products of general formula (I) in Which Z represents a
`hydrogen atom or a radical of general formula (II) in Which
`R1 represents a benZoyl radical or a radical R2—O—CO—
`in Which R2 represents a tert-butyl radical and R3 represents
`an isobutyl, isobutenyl, butenyl, cycloheXyl, phenyl, 2-furyl,
`3-furyl, 2-thienyl, 3-thienyl, 2-thiaZolyl, 4-thiaZolyl or
`5-thiaZolyl radical, and R4 and R5, Which may be identical
`or different, each represent a methoXy, ethoXy or propoXy
`radical.
`The products of general formula (I) in Which Z represents
`a radical of general formula (II) display noteWorthy antitu
`mour and antileukaemic properties.
`According to the present invention, the neW products of
`general formula (I) in Which Z represents a radical of general
`formula (II) may be obtained by esteri?cation of a product
`of general formula (III):
`
`(III)
`
`in Which R4 and R5 are de?ned as above, by means of an
`acid of general formula (IV):
`
`(IV)
`
`in Which R1 and R3 are de?ned as above, and either R6
`represents a hydrogen atom and R7 represents a group
`protecting the hydroXyl function, or R6 and R7 together form
`a saturated 5- or 6-membered heterocycle, or by means of a
`derivative of this acid, to obtain an ester of general formula
`(V) :
`
`65
`
`
`
`5,847,170
`
`(V)
`
`in Which R1, R3, R4, R5, R6 and R7 are de?ned as above,
`followed by replacement of the protective groups repre
`sented by R7 and/or R6 and R7 by hydrogen atoms.
`The esteri?cation by means of an acid of general formula
`(IV) may be performed in the presence of a condensing
`agent (carbodiimide, reactive carbonate) and an activating
`agent (aminopyridines) in an organic solvent (ether, ester,
`ketones, nitriles, aliphatic hydrocarbons, halogenated ali
`phatic hydrocarbons, aromatic hydrocarbons) at a tempera
`ture from —10° to 90° C.
`The esteri?cation may also be carried out using the acid
`of general formula (IV) in the form of the symmetrical
`anhydride, Working in the presence of an activating agent
`(aminopyridines) in an organic solvent (ethers, esters,
`ketones, nitrites, aliphatic hydrocarbons, halogenated ali
`phatic hydrocarbons, aromatic hydrocarbons) at a tempera
`ture of from 0° to 90° C.
`The esteri?cation may also be carried out using the acid
`of general formula (IV) in halide form or in the form of a
`miXed anhydride With an aliphatic or aromatic acid, option
`ally prepared in situ, in the presence of a base (tertiary
`aliphatic amine), Working in an organic solvent (ethers,
`esters, ketones, nitriles, aliphatic hydrocarbons, halogenated
`aliphatic hydrocarbons, aromatic hydrocarbons) at a tem
`perature of from 0° to 80° C.
`Preferably, R6 represents a hydrogen atom and R7 repre
`sents a group protecting the hydroXyl function, or alterna
`tively R6 and R7 together form a saturated 5- or 6-membered
`heterocycle.
`When R6 represents a hydrogen atom, R7 preferably
`represents a methoXymethyl, 1-ethoXyethyl,
`benZyloXymethyl, trimethylsilyl, triethylsilyl,
`[3-trimethylsilylethoXymethyl, benZyloXycarbonyl or tet
`rahydropyranyl radical.
`When R6 and R7 together form a heterocycle, the latter is
`preferably an oXaZolidine ring optionally monosubstituted
`or gem-disubstituted at position 2.
`Replacement of the protective groups R7 and/or R6 and R7
`by hydrogen atoms may be performed, depending on their
`nature, in the folloWing manner:
`1) When R8 represents a hydrogen atom and R7 represents
`a group protecting the hydroXyl function, replacement
`of the protective groups by hydrogen atoms is per
`formed by means of an inorganic acid (hydrochloric
`acid, sulphuric acid, hydro?uoric acid) or organic acid
`(acetic acid, methanesulphonic acid, tri?uoromethane
`sulphonic acid, p-toluenesulphonic acid) used alone or
`miXed, Working in an organic solvent chosen from
`alcohols, ethers, esters, aliphatic hydrocarbons, halo
`genated aliphatic hydrocarbons, aromatic hydrocarbons
`or nitriles at a temperature of from —10° to 60° C., or
`by means of a source of ?uoride ions such as a
`hydro?uorine acid/triethylamine complex, or by cata
`lytic hydrogenation,
`2) When R6 and R7 together form a saturated 5- or
`6-membered heterocycle, and more especially an
`oXaZolidine ring of general formula (VI):
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`in Which R1 is de?ned as above and R6 and R9, Which may
`be identical or different, represent a hydrogen atom or an
`alkyl radical containing 1 to 4 carbon atoms, or an aralkyl
`radical in Which the alkyl portion contains 1 to 4 carbon
`atoms and the aryl portion preferably represents a phenyl
`radical optionally substituted With one or more alkoXy
`radicals containing 1 to 4 carbon atoms, or an aryl radical
`preferably representing a phenyl radical optionally substi
`tuted With one or more alkoXy radicals containing 1 to 4
`carbon atoms, or alternatively R8 represents an alkoXy
`radical containing 1 to 4 carbon atoms or a trihalomethyl
`radical such as trichloromethyl or a phenyl radical substi
`tuted With a trihalomethyl radical such as trichloromethyl
`and R9 represents a hydrogen atom, or alternatively R8 and
`R9, together With the carbon atom to Which they are linked,
`form a 4- to 7-membered ring, replacement of the protective
`group formed by R6 and R7 by hydrogen atoms may be
`performed, depending on the meanings of R1, R8 and R9, in
`the folloWing manner:
`a) When R1 represents a tert-butoXycarbonyl radical and
`R8 and R9, Which may be identical or different, repre
`sent an alkyl radical or an aralkyl (benZyl) or aryl
`(phenyl) radical, or alternatively R8 represents a triha
`lomethyl radical or a phenyl radical substituted With a
`trihalomethyl radical and R9 represents a hydrogen
`atom, or alternatively R8 and R9 together form a 4- to
`7-membered ring, treatment of the ester of general
`formula (V) With an inorganic or organic acid, Where
`appropriate in an organic solvent such as an alcohol,
`yields the product of general formula (VII):
`
`(v11)
`
`in Which R3, R4 and R5 are de?ned as above, Which is
`acylated by means of benZoyl chloride in Which the phenyl
`ring is optionally substituted or by means of thenoyl
`chloride, of furoyl chloride or of a product of general
`formula:
`
`in Which R2 is de?ned as above and X represents a halogen
`atom (?uorine, chlorine) or a residue —O—R2 or
`—O—CO—O—R2, to obtain a product of general formula
`(I) in Which Z represents a radical of general formula (II).
`Preferably, the product of general formula (V) is treated
`With formic acid at a temperature in the region of 20° C. to
`yield the product of general formula (VII).
`Preferably, the acylation of the product of general formula
`(VII) by means of a benZoyl chloride in Which the phenyl
`radical is optionally substituted or by means of thenoyl
`chloride, of furoyl chloride or of a product of general
`formula (VIII) is performed in an inert organic solvent
`
`
`
`5,847,170
`
`8
`ester residue such as a sulphuric or sulphonic ester residue
`or a halogen atom, to obtain a product of general formula
`(XIII):
`
`(XIII)
`
`ococ?ns
`in Which R and R4 are de?ned as above, the silyl protective
`groups of Which are replaced by hydrogen atoms to obtain
`a product of general formula (XIV):
`
`R4
`
`0
`
`(XIV)
`
`7
`chosen from esters such as ethyl acetate, isopropyl acetate or
`n-butyl acetate and halogenated aliphatic hydrocarbons such
`as dichloromethane or 1,2-dichloroethane, in the presence of
`an inorganic base such as sodium bicarbonate or an organic
`base such as triethylamine. The reaction is performed at a
`temperature of from 0° to 50° C., and preferably at about 20°
`C.
`b) When R1 represents an optionally substituted benZoyl
`radical, a thenoyl or furoyl radical or a radical R2O—CO—
`in Which R2 is de?ned as above, R8 represents a hydrogen
`atom or an alkoXy radical containing 1 to 4 carbon atoms or
`a phenyl radical substituted With one or more alkoXy radicals
`containing 1 to 4 carbon atoms and R9 represents a hydrogen
`atom, replacement of the protective group formed by R6 and
`R7 by hydrogen atoms is performed in the presence of an
`inorganic acid (hydrochloric acid, sulphuric acid) or organic
`acid (acetic acid, methanesulphonic acid, tri?uoromethane
`sulphonic acid, p-toluenesulphonic acid) used alone or
`miXed in a stoichiometric or catalytic amount, Working in an
`organic solvent chosen from alcohols, ethers, esters, ali
`phatic hydrocarbons, halogenated aliphatic hydrocarbons
`and aromatic hydrocarbons at a temperature of from —10° to
`60° C., and preferably from 15° to 30° C.
`According to the invention, the products of general for
`mula (III), that is to say the products of general formula (I)
`in Which Z represents a hydrogen atom and R4 and R5 are
`de?ned as above, may be obtained from 10-deacetylbaccatin
`III of formula (IX):
`
`10
`
`20
`
`25
`
`(IX)
`
`30
`
`in Which R4 is de?ned as above, Which is etheri?ed selec
`tively at position 7 by the action of a product of general
`formula:
`
`35
`
`It can be especially advantageous to protect the hydroXyl
`functions at the positions 7 and 13 selectively, for eXample
`in the form of a silyl diether Which may be obtained by the
`action of a silyl halide of general formula:
`
`in Which the symbols R, Which may be identical or different,
`represent an alkyl radical containing 1 to 6 carbon atoms,
`optionally substituted With a phenyl radical, or a cycloalkyl
`radical containing 3 to 6 carbon atoms or a phenyl radical,
`on 10-deacetylbaccatin III, to obtain a product of general
`formula (XI):
`
`45
`
`(XI)
`
`55
`
`60
`
`65
`
`in Which R is de?ned as above, folloWed by the action of a
`product of general formula:
`(XII)
`R'4—X1
`in Which R‘4 represents a radical such that R‘4—O is
`identical to R4 de?ned as above and X1 represents a reactive
`
`(XV)
`R'5—X2
`in Which R‘5 represents a radical such that R‘5—O is
`identical to R5 de?ned as above and X2 represents a halogen
`atom or a reactive ester residue such as a sulphuric or
`sulphonic ester residue, to give the product of general
`formula (III).
`Generally, the action of a silyl derivative of general
`formula
`on 10-deacetylbaccatin III is performed in
`pyridine or triethylamine, Where appropriate in the presence
`of an organic solvent such as an aromatic hydrocarbon, for
`instance benZene, toluene or Xylenes, at a temperature
`betWeen 0° C. and the re?uxing temperature of the reaction
`mixture.
`Generally, the action of a product of general formula (XII)
`on a product of general formula (XI) is performed, after
`metalation of the hydroXyl function at position 10 by means
`of an alkali metal hydride, such as sodium hydride, an alkali
`metal amide, such as lithium amide, or an alkali metal
`alkylide, such as butyllithium, Working in an organic
`solvent, such as dimethylformamide or tetrahydrofuran, at a
`temperature of from 0° to 50° C.
`Generally, the replacement of the silyl protective groups
`of the product of general formula (XIII) by hydrogen atoms
`is performed by means of an acid such as hydro?uoric acid
`or tri?uoroacetic acid in the presence of a base such as
`triethylamine or pyridine optionally substituted With one or
`more alkyl radicals containing 1 to 4 carbon atoms, the base
`optionally being combined With an inert organic solvent
`such as a nitrile, for instance acetonitrile, or a halogenated
`aliphatic hydrocarbon, such as dichloromethane, at a tem
`perature of from 0° to 80° C.
`Generally, the action of a product of general formula (XV)
`on a product of general formula (XIV) is performed under
`the conditions described above for the action of a product of
`general formula (XII) on a product of general formula
`
`
`
`9
`According to the invention, the products of general for
`mula (I) in Which Z represents a radical of general formula
`(II), R4 is de?ned as above and R5 is de?ned as above may
`be obtained from a product of general formula (XVI):
`
`HO
`
`O
`
`(XVI)
`
`5,847,170
`
`10
`The products of general formula (XVI) may be obtained
`under the conditions described in European Patent EP 0,336,
`841 and international Applications PCT WO 92/09589 and
`WO 94/07878, the disclosures of Which are hereby incor
`porated by reference in their entirety, or from the products of
`general formula
`
`(XX)
`
`in Which R1, R3, R6 and R7 are de?ned as above, by
`silylation at position 7 by means of a product of general
`formula (X), to obtain a product of general formula (XVII):
`
`HO
`
`O
`
`(XVII)
`
`o — Si(R)3
`
`in Which R1 and R3 are de?ned as above, according to
`knoWn methods for protecting the hydroXyl function of the
`side chain Without affecting the remainder of the molecule.
`
`COCH3
`
`in Which R, R1, R3, R6 and R7 are de?ned as above, Which
`is functionaliZed at position 10 by means of a product of
`general formula (XII) to give a product of general formula
`(XVIII):
`
`(XVIII)
`
`25
`
`According to the invention, the products of general for
`mula (I) in Which Z represents a hydrogen atom or a radical
`of general formula (II) may be obtained by the action of
`activated Raney nickel, in the presence of an aliphatic
`alcohol containing 1 to 3 carbon atoms or an ether such as
`tetrahydrofuran or dioXane, on a product of general formula
`(XXI):
`
`R’
`
`(XXI)
`
`ococ?ns
`in Which R, R1, R3, R4, R6 and R7 are de?ned as above, the
`silyl protective group of Which is replaced by a hydrogen
`atom to give a product of general formula (XIX):
`
`45
`
`R4
`
`0
`
`(XIX)
`
`Which, by the action of a product of general formula (XV),
`yields the product of general formula (V), the protective
`groups of Which are replaced by hydrogen atoms to give a
`product of general formula (I) in Which Z represents a
`radical of general formula (II).
`The reactions used for silylation, functionaliZation and
`replacement of the protective groups by hydrogen atoms are
`performed under conditions similar to those described
`above.
`
`55
`
`65
`
`in Which R4 is de?ned as above and R‘ and R“, Which may
`be identical or different, represent a hydrogen atom or an
`alkyl radical containing 1 to 6 carbon atoms, an alkenyl
`radical containing 2 to 6 carbon atoms, an alkynyl radical
`containing 2 to 6 carbon atoms, a cycloalkyl radical con
`taining 3 to 6 carbon atoms or a cycloalkenyl radical
`containing 3 to 6 carbon atoms, optionally substituted, or
`alternatively R‘ and R“, together With the carbon atom to
`Which they are linked, form a cycloalkyl radical containing
`3 to 6 carbon atoms or a cycloalkenyl radical containing 4
`to 6 carbon atoms, and Z1 represents a hydrogen atom or a
`radical of general formula (XXII):
`
`on
`
`in Which R1, R3, R6 and R7 are de?ned as above, and, to
`obtain a product of general formula (XXIII):
`
`
`
`11
`
`5,847,170
`
`(XXIII)
`
`12
`cell line selected for its resistance to doxorubicin (DOX)
`Which expresses mdr 1.
`The examples Which folloW illustrate the present inven
`tion.
`
`followed, When Z1 represents a radical of general formula
`(XXII), that is to say When the product of general formula
`(XXIII) is identical to the product of general formula (V), by
`replacement of the protective groups represented by R6
`and/or R6 and R7 by hydrogen atoms under the conditions
`described above.
`Generally, the action of activated Raney nickel in the
`presence of an aliphatic alcohol or an ether is performed at
`a temperature of from —10° to 60° C.
`According to the invention, the product of general for
`mula (XXI) in Which Z1 and R4 are de?ned as above may be
`obtained by the action of a sulphoxide of general formula
`(XXIV):
`
`10
`
`15
`
`20
`
`25
`
`(XXIV)
`
`in Which R‘ and R“ are de?ned as above, on a product of
`general formula
`Generally, the reaction of the sulphoxide of general for
`mula (XXIV), preferably dimethyl sulphoxide, With the
`product of general formula (XIX) is performed in the
`presence of a mixture of acetic acid and acetic anhydride or
`a derivative of acetic acid such as a haloacetic acid at a
`temperature of from 0° to 50° C., and preferably at about 25°
`C.
`The neW products of general formula (I) obtained by
`carrying out the processes according to the invention may be
`puri?ed according to knoWn methods such as crystalliZation
`or chromatography.
`The products of general formula (I) in Which Z represents
`a radical of general formula (II) display noteWorthy biologi
`cal properties.
`In vitro, measurement of the biological activity is per
`formed on tubulin extracted from pig’s brain by the method
`of M. L. Shelanski et al., Proc. Natl. Acad. Sci. USA, 70,
`765—768 (1973). Study of the depolymeriZation of micro
`tubules to tubulin is performed according to the method of
`G. Chauviere et al., CR. Acad. Sci., 293, series II, 501—503
`(1981). In this study, the products of general formula (I) in
`Which Z represents a radical of general formula (II) Were
`shoWn to be at least as active as taxol and Taxotere.
`In vivo, the products of general formula (I) in Which Z
`represents a radical of general formula (II) Were shoWn to be
`active in mice grafted With B16 melanoma at doses of from
`1 to 30 mg/kg administered intraperitoneally, as Well as on
`other liquid or solid tumours.
`The neW products have antitumour properties, and more
`especially activity against tumours Which are resistant to
`Taxol® or to Taxotere®. Such tumours comprise colon
`tumours Which have a high expression of the mdr 1 gene
`(multiple drug resistance gene). Multiple drug resistance is
`a customary term relating to the resistance of a tumour to
`different products having different structures and mecha
`nisms of action. Taxoids are generally knoWn to be strongly
`recogniZed by experimental tumours such as P388/DOX, a
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`EXAMPLE 1
`126 mg of dicyclohexylcarbodiimide and then 14 mg of
`4-(N,N-dimethylamino)pyridine Were added successively at
`a temperature in the region of 20° C. to a suspension
`containing 217.8 mg of 4ot-acetoxy-2ot-benZoyloxy-5[3,20
`epoxy-1[3,13ot-dihydroxy-7[3,10[3-dimethoxy-9-oxo-11
`taxene, 200 mg of (2R,4S,5R)-3-tert-butoxycarbonyl-2-(4
`methoxyphenyl)-4-phenyl-1,3-oxaZolidine-5-carboxylic
`acid and 50 mg of poWdered 4 A molecular sieve in 2 cm3
`of ethyl acetate. The suspension obtained Was stirred at a
`temperature in the region of 20° C. under an argon atmo
`sphere for 16 hours, and then concentrated to dryness under
`reduced pressure (0.27 kPa) at a temperature in the region of
`40° C. The residue obtained Was puri?ed by chromatography
`at atmospheric pressure on 50 g of silica (0.063—0.2 mm)
`contained in a column 2 cm in diameter (elution gradient:
`ethyl acetateldichloromethane from 10:90 to 40:60 by
`volume), collecting 10-cm3 fractions. Fractions containing
`only the desired product Were pooled and concentrated to
`dryness under reduced pressure (0.27 kPa) at 40° C. for 2
`hours. 271.8 mg of 40t-acetoxy-2ot-benZoyloxy-5[3,20
`epoxy- 1[3-hydroxy-7[3,10B-dimethoxy-9-oxo-11-taxen
`13ot-yl(2R,4S,5R)-3-tert-butoxycarbonyl-2-(4
`methoxyphenyl)-4-phenyl-1,3-oxaZolidine-5-carboxylate
`Were thereby obtained in the form of a White solid, the
`characteristics of Which Were as folloWs:
`1H NMR spectrum (400 MHZ; CDCl3 With a feW drops of
`CD3OD-d4; chemical shifts 6 in ppm; coupling constants J
`in HZ): 1.02 (s, 9H: C(CH3)3); 1.10 (s, 3H: CH3); 1.17 (s,
`3H: CH3); 1.63 (s, 3H: CH3); from 1.65 to 1.85 and 2.60 (2
`mts, 1H each; CH2 at position 6); 1.78 (unres. comp., 3H:
`CH3); 2.02 and 2.15 (2 dd, J=14 and 9, 1H each: CH2 at
`position 14); 2.14 (s, 3H: CH3); 3.22 and 3.35 (2 s, 3H each:
`OCH3); 3.64 (d, J=7, 1H: H at position 3); 3.73 (mt, 1H: H
`at position 7); 3.76 (s, 3H: ArOCH3); 4.06 and 4.16 (2 d,
`J=8.5, 1H each; CH2 at position 20); 4.53