`Bouchard et al.
`
`US006331635B1
`US 6,331,635 B1
`*Dec. 18, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) TAXOIDS, THEIR PREPARATION AND
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING THEM
`
`(75) Inventors: Hervé Bouchard, Ivry-sur-Seine;
`J ean-Dominique Bourzat, Vincennes;
`Alain Commergon, Vitry-sur-Seine, all
`of (FR)
`
`(73) Assignee: Aventis Pharma S.A., Antony (FR)
`
`(*) Notice:
`
`This patent issued on a continued pros
`ecution application ?led under 37 CFR
`1.53(d), and is subject to the tWenty year
`patent term provisions of 35 U.S.C.
`154(a)(2).
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis
`claimer.
`
`(21) Appl. N0.: 09/066,929
`(22) Filed:
`Apr. 28, 1998
`
`Related US. Application Data
`
`(63) Continuation of application No. 08/622,011, ?led on Mar.
`26, 1996, now Pat. NO. 5,847,170.
`Foreign Application Priority Data
`
`(30)
`
`Mar. 27, 1995
`Dec. 22, 1995
`
`(FR) ................................................ .. 95 03545
`(FR) ........................................ .. 95 15381
`
`.. C07D 263/06; C07D 305/14
`(51) Int. Cl.7 ..
`(52) US. Cl. .......................... .. 548/215; 549/60; 549/472;
`549/473; 549/510; 549/511
`(58) Field of Search ................................... .. 549/510, 511,
`549/60, 472, 473; 548/215
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,229,526
`5,319,112
`5,489,601
`5,739,362
`
`549/213
`7/1993 Holton ............ ..
`549/510
`6/1994 Kingston et al. .
`514/337
`2/1996 Holton et al.
`4/1998 Holton et al. ...................... .. 549/510
`
`FOREIGN PATENT DOCUMENTS
`
`0 336 841
`0 604 910
`0 639 577
`0 694 539
`WO 92/09589
`WO 94/07878
`W0 94/18164
`W0 96/00724
`
`10/1989 (EP) .
`7/1994 (EP) .
`2/1995 (EP) .
`1/1996 (EP) .
`6/1992 (W0).
`4/1994 (W0).
`8/1994 (W0).
`1/1996 (WO).
`
`OTHER PUBLICATIONS
`
`Michael L. Shelanski et al., “Microtubule Assembly in the
`Absence of Added Nucleotides”, vol. 70, No. 3, pp. 765—768
`(Mar. 1973).
`de Gerard Chauviére et al., “Comptes Rendus Des Seances
`de L’Académie des Sciences”, pp. 501—503 (Oct. 1981).
`Joydeep Kant et al., “A Chemoselective Approach to Func
`tionaliZe the C—10 Position of 10—Deacetylbaccatin III Syn
`thesis and Biological Properties of Novel C—10 TaXol®
`Analogues”, Bristol Myers Squibb Pharmaceutical Research
`Institute, vol. 35, No. 31, pp. 5543—5546 (Jun. 1994).
`Theodora W. Greene, “Protective Groups in Organic Syn
`thesis”, Wiley—lnterscience Publication, pp. 50—62 (1981).
`Shu—Hui Chen et al., “PaclitaXel Structure—Activity Rela
`tionships and Core Skeletal Rearrangements”, Central
`Chemistry, Bristol—Myers Squibb, Chapter 18, pp. 247—261
`(Oct. 1994).
`D.G.I. Kingston et al., “Progress in the Chemistry of
`Organic Natural Products”, Springer—Verlag, pp. 62—81
`(1993).
`Primary Examiner—Ba K. Trinh
`(74) Attorney, Agent, or Firm—Finnegan, Henderson,
`FaraboW, Garrett & Dunner, L.L.P.
`(57)
`ABSTRACT
`
`NeW taXoids of general formula (I):
`
`their preparation and pharmaceutical compositions contain
`ing them.
`
`The neW products of general formula (I) in Which Z repre
`sents a radical of general formula (II):
`
`RlljH
`
`0
`
`(II)
`
`display noteWorthy antitumour and antileukaemic proper
`ties.
`
`25 Claims, No Drawings
`
`MYLAN - EXHIBIT 1083
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`
`
`US 6,331,635 B1
`
`1
`TAXOIDS, THEIR PREPARATION AND
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING THEM
`
`This is a continuation of application Ser. No. 08/622,011,
`?led Mar. 26, 1996 now US. Pat. No. 5,847,170.
`The present invention relates to neW taXoids of general
`formula (I)
`
`R4
`
`0
`
`HO
`
`OCOCH3
`5
`OCOC6H5
`
`(1)
`
`10
`
`15
`
`20
`
`in Which:
`Z represents a hydrogen atom or a radical of general
`formula (II):
`
`RlljH
`
`0
`
`Olllln E
`
`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, piperidino
`radicals, morpholino radicals, 1-piperaZinyl radicals,
`said piperaZinyl radicals being optionally substituted at
`position 4 With an alkyl radical containing 1 to 4 carbon
`atoms or With a phenylalkyl radical in Which the alkyl
`portion contains 1 to 4 carbon atoms, cycloalkyl radi
`cals containing 3 to 6 carbon atoms, cycyloalkenyl
`radicals containing 4 to 6 carbon atoms, phenyl
`radicals, said phenyl radicals being optionally substi
`tuted With one or more atoms or radicals selected from
`halogen atoms, alkyl radicals containing 1 to 4 carbon
`atoms, and alkoXy radicals containing 1 to 4 carbon
`atoms, cyano radicals, carboXyl radicals and alkoXy
`carbonyl radicals in Which the alkyl portion contains 1
`to 4 carbon atoms,
`
`25
`
`(II)
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`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
`carbon atoms, and alkoXy radicals containing 1 to 4
`carbon atoms,
`a 5-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 5-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
`
`
`
`US 6,331,635 B1
`
`3
`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,
`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 selected With a substitu
`ent 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 5 -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 to 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
`
`4
`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
`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
`R3 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)
`
`15
`
`25
`
`35
`
`45
`
`55
`
`in Which R4 and R5 are de?ned as above, by means of an
`acid of general formula (IV):
`
`(IV)
`
`R3
`
`Ollm
`
`OH
`
`65
`
`in Which R1
`represents a
`
`and R3 are de?ned as above, and either R6
`hydrogen atom and R7 represents a group
`
`
`
`US 6,331,635 B1
`
`5
`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)
`
`6
`or nitriles at a temperature of from —10 to 60° C., or by
`means of a source of ?uroide ions such as a hydrof
`luorine acid/triethylamine complex, or by catalytic
`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):
`
`(VI)
`
`Elihu
`
`HO
`
`6COCH3
`
`15
`
`in Which R1, R3, R4, R5, R6 and R7 are de?ned 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, nitriles, 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 presence of a base (tertiary aliphatic
`amine), Working in an organic solvent (ethers, ester, ketones,
`nitriles, aliphatic hydrocarbons, halogenated aliphatic
`hydrocarbons, aromatic hydrocarbons) at a temperature 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
`
`in Which R1 is de?ned as above and R8 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 R9, Which may be identical or different, represent an alkyl
`radical or an aralkyl (benZyl) or aryl (phenyl) radical, or
`alternatively R6 represents a trihalomethyl 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,
`yield the product of general formula (VII):
`
`(VII)
`
`0""...
`
`HO
`
`Elihu
`
`25
`
`35
`
`45
`
`55
`
`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, or furoyl chloride or of a product of general
`formula:
`
`65
`
`(VIII)
`R2—O—CO—X
`in Which R2 is de?ned as above and X represents a halogen
`atom (?uorine, chloride) or a residue —O—R2 or
`
`
`
`US 6,331,635 B1
`
`7
`—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
`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) Wherein R1 represents an optionally substituted ben
`Zoyl 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, methanesul
`phonic acid, tri?uoromethanesulphonic acid,
`p-toluenesulphonic acid) used alone or miXed in a stoichio
`metric or catalytic amount, Working in an organic solvent
`chosen from alcohols, ethers, esters, aliphatic hydrocarbons,
`halogenated aliphatic hydrocarbons and aromatic hydrocar
`bons 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
`
`15
`
`25
`
`35
`
`HO
`
`6cocH3
`
`in Which R is de?ned as above, folloWed by the action of a
`product of general formula:
`
`R'4—X1
`
`(XII)
`
`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
`ester residue such as a sulphuric or sulphonic ester residue
`or a halogen atom, to obtain a product of general formula
`(XIII):
`
`(XIII)
`
`Elihu
`
`6COCH3
`
`HO
`
`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)
`
`Elm..
`
`(_)COCH3
`
`HO
`
`(IX)
`
`45
`
`HO
`
`O
`
`Elihu
`
`6cocH3
`
`HO
`
`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 R4 is de?ned as above, Which is etheri?ed selec
`tively at position 7 by the action of a product of general
`formula:
`
`55
`
`(R)3—Si—Hal in Which the symbols R1 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):
`
`65
`
`R'5—X2
`
`(XV)
`
`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
`
`
`
`US 6,331,635 B1
`
`9
`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
`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):
`
`(XVI)
`
`35
`
`HO
`
`O
`
`15/
`
`O
`
`R3/\z)ko In I...
`g
`O—R7
`
`HO
`
`o
`
`5
`:
`6COCH3
`6COC6H5
`
`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):
`
`45
`
`55
`
`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):
`
`65
`
`1O
`
`HO
`
`(_)COCH3
`
`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):
`
`(XIX)
`
`R4
`
`0
`
`25
`
`R3
`
`Olllw
`
`HO
`
`(_)COCH3
`
`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.
`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)
`
`HO
`
`O
`
`R3/\)komm.
`
`Elm..
`
`(_)COCH3
`
`HO
`
`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.
`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
`
`
`
`635 B1
`US 6,331,
`
`11
`tetrahydrofuran or dioXane, on a product of general formula
`(XXI):
`
`(XXI)
`
`12
`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):
`
`R'
`
`R' m,
`
`SO
`
`(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., C. R. 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
`cell line selected for its resistance to doXorubicin (DOX)
`Which eXpresses mdr 1.
`The eXamples Which folloW illustrate the present inven
`tion.
`
`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
`
`15
`
`20
`
`25
`
`45
`
`50
`
`55
`
`60
`
`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):
`
`in Which R1, R3, R6 and R7 are de?ned as above, and, to
`obtain a product of general formula (XXIII):
`
`R4
`
`0
`
`(XXIII)
`
`Z1
`
`OI In..
`
`0
`
`HO
`
`6COCH3
`6COC6H5
`
`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.
`
`
`
`US 6,331,635 B1
`
`13
`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 acetate/dichlorom