(12) United States Patent
`Bouchard et al.
`
`US006387946B1
`US 6,387,946 B1
`May 14, 2002
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) METHODS FOR TREATING
`PATHOLOGICAL CONDITIONS OF
`ABNORMAL CELL PROLIFERATION
`
`(75) Inventors: Hervé Bouchard, Ivry-sur-Seine;
`J ean-Dominique Bourzat, Vincennes;
`Alain Commercon, Vitry-sur-Seine, all
`of (FR)
`
`(73) Assignee: Aventis Pharma S.A., Antony (FR)
`
`* N'
`ot1ce:
`
`Sbj
`yd'l'
`h
`fh'
`u ect to an 1sc a1mer, t e term 0 t is
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/985,956
`(22) Filed:
`Sep. 25, 2001
`
`Related US. Application Data
`
`(63) Continuation of application No. 09/066,929, ?led on Apr.
`28, 1998, now Pat. No. 6,331,635, which is a continuation
`of application No. 08/622,011, ?led on Mar. 26, 1996, now
`Pat. No. 5,847,170.
`(60) Provisional application No. 60/010,144, ?led on Jan. 17,
`1996.
`Foreign Application Priority Data
`
`(30)
`
`Mar. 27, 1995
`Dec. 22, 1995
`
`(FR) .......................................... .. 95 03545
`(FR) .......................................... .. 95 15381
`
`(51) Int. Cl.7 ................... .. A61K 31/337; C07D 305/14
`(52) US. Cl. ...................... .. 514/449; 549/510; 549/511
`(58) Field of Search ........................ .. 514/449; 549/510,
`549/511
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5/1990 Colin et al. ............... .. 549/510
`4,924,012 A
`7/1993 Holton .............. ..
`549/213
`5,229,526 A
`6/1994 Kingston et al.
`549/510
`5,319,112 A
`2/1996 Holton et al. ............. .. 514/337
`5,489,601 A
`6/1997 Commercon et al. ..... .. 548/215
`5,637,723 A
`4/1998 Holton et al. ............. .. 549/510
`5,739,362 A
`5,962,705 A 10/1999 Didier et al.
`549/510
`
`6,013,626 A
`1/2000 Moore et al. . . . . . . . .
`. . . . .. 514/9
`6,160,135 A 12/2000 Bouchard et al. ......... .. 549/510
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`EP
`EP
`FR
`W0
`W0
`W0
`W0
`W0
`W0
`
`0 336 841
`0 604 910
`617 018 A1
`0 639 577
`0 694 539
`2771 092
`WO 92/09589
`WO 94/07878
`WO 94/18164
`WO 96/00724
`WO 96/30335
`WO 97/32869
`
`10/1989
`7/1994
`9/1994
`2/1995
`1/1996
`5/1999
`6/1992
`4/1994
`8/1994
`1/1996
`10/1996
`9/1997
`
`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 Gérard Chauviere 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 .
`
`Theo)dora W. Greene, “Protective Groups in Organic Syn
`thesis”, Wiley—Interscience 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).
`. ,” Proc.
`.
`Bank et al., “Protecting hematopoietic cells from .
`Annu. Meet. Am. Assoc. Cancer Res., 37:634 (1996),
`abstract only.
`Caubere, P., “Unimetal Super Bases,” Chem. Rev.,
`93:2317—2334 (1993).
`collateral
`and
`Parekh
`et
`al.,
`“Cross—resistance
`sensitivity .
`.
`. ,” Cancer Chemotherapy and Pharmacology,
`37(5):457—462 (1996), abstract only.
`Ringel, I., et al., Studies With RP 56976 (TaXotere): A
`Semisynthetic Analogue of TaXol, J. Nat. Cancer Inst.,
`83(4):288—291 (1991).
`Schlosser, M., Superbases as PoWerful Tools in Organic
`Syntheses, Mod. Synth. Methods, 6:227—271 (1992).
`English language DerWent Abstract of FR 2 771 092 (May
`21, 1999).
`Primary Examiner—Ba K. Trinh
`(74) Attorney, Agent, or Firm—Finnegan, Henderson,
`FaraboW, Garrett & Dunner LLP
`(57)
`ABSTRACT
`
`NeW taXoids of general formula (I):
`
`HO
`
`OCOCH3
`
`their preparation and pharmaceutical compositions contain
`ing them. The neW products of general formula (I) in Which
`Z represents a radical of general formula (II):
`
`(II)
`
`RlNH
`
`0
`
`Olln...
`
`display noteWorthy antitumour and antileukaemic proper
`ties.
`
`8 Claims, No Drawings
`
`MYLAN - EXHIBIT 1085
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`

`

`US 6,387,946 B1
`
`1
`METHODS FOR TREATING
`PATHOLOGICAL CONDITIONS OF
`ABNORMAL CELL PROLIFERATION
`
`This is a continuation of application Ser. No. 09/066,929,
`?led Apr. 28, 1998, now US. Pat. No. 6,331,685 Which is a
`continuation of 08/622,011, ?led Mar. 26, 1996, now US.
`Pat. No. 5,847,170 all of Which are incorporated herein by
`reference. The application also claims the priority bene?t of
`provisional application 60/010,144 dated Jan. 17, 1996.
`The present invention relates to neW taXoids of general
`formula (I)
`
`10
`
`(I)
`
`15
`
`20
`
`25
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`in Which,
`Z represents a hydrogen atom or a radical of general
`formula (II):
`
`(II)
`
`Rlrgn
`
`0
`
`Ohm 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 con
`taining 1 to 4 carbon atoms, alkoXy radicals con
`taining 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 con
`taining 1 to 4 carbon atoms, dialkylamino
`radicals in Which each alkyl portion contains 1
`to 4 carbon atoms, piperidino radicals, mor
`pholino radicals, 1-piperaZinyl radicals, said
`piperaZinyl radicals being optionally substi
`tuted at position 4 With an alkyl radical con
`taining 1 to 4 carbon atoms or With a pheny
`lalkyl radical in Which the alkyl portion
`
`2
`contains 1 to 4 carbon atoms, cycloalkyl radi
`cals containing 3 to 6 carbon atoms, cycloalk
`enyl 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
`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,
`a phenyl or ot- or [3-naphthyl radical optionally
`substituted With one or more atoms or radicals
`selected from halogen atoms, alkyl radicals con
`taining 1 to 4carbon atoms, and alkoXy radicals
`containing 1 to 4 carbon atoms,
`a 5 -membered aromatic heterocyclic radical pref
`erably 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 contain
`ing 1 to 8 carbon atoms,
`an unbranched or branched alkenyl radical con
`taining 2 to 8 carbon atoms,
`an unbranched or branched alkynyl radical con
`taining 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?uorom
`ethyl 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,
`dialkylcarbamoyl 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 radi
`cals contain 2 to 8 carbon atoms, and the aryl
`radicals are phenyl or (X- or [3-naphthyl
`radicals,
`R 4 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,
`
`

`

`US 6,387,946 B1
`
`3
`a cycloalkyloXy radical containing 3 to 6 carbon
`atoms or
`a cycloalkenyloXy radical containing 4 to 6 car
`bon 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 radical 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 heterocyclic radical optionally
`containing a second hetero atom selected from;
`oxygen, sulphur and nitrogen atoms, said satu
`rated 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 pheny
`lalkyl radical in Which the alkyl portion con
`tains 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 car
`bon atoms, these radicals being optionally sub
`stituted With at least one substituent selected
`from halogen atoms, an alkoXy radical con
`taining 1 to 4 carbon atoms, an alkylthio radi
`cal 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 containing a second hetero
`atom selected from oxygen, sulphur and nitro
`gen atoms, optionally substituted With a sub
`stituent selected from an alkyl radical contain
`ing 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
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`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
`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):
`
`

`

`US 6,387,946 B1
`
`(III)
`
`Houmn
`
`écocgg
`
`in Which R4 and R5 are de?ned as above, by means of an
`acid of general formula (IV):
`
`15
`
`(IV)
`
`Rn\ //Rs 0
`
`R3
`
`Ollm
`
`OH
`
`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):
`
`25
`
`(V)
`
`35
`
`6
`esters, ketones, nitrites, 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 R6 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 nitrites at a temperature of from —10 to 60° C., or by
`means of a source of ?uoride 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)
`
`écocgg
`
`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, nitrites, 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,
`
`45
`
`55
`
`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 radi
`cals containing 1 to 4 carbon atoms, or an aryl radical
`preferably representing a phenyl radical optionally
`substituted With one or more alkoXy radicals con
`taining 1 to 4 carbon atoms, or alternatively R8
`represents an alkoXy radical containing 1 to 4 carbon
`atoms or a trihalomethyl radical such as trichlorom
`ethyl or a phenyl radical substituted With a trihalom
`ethyl radical such as trichloromethyl and R9 repre
`sents 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 hydro
`gen atoms may be performed, depending on the
`meanings of R1, R8 and R9, in the folloWing manner:
`
`

`

`US 6,387,946 B1
`
`7
`a) When R1 represents a tert-butoXycarbonyl radical
`and R8 and 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 alterna
`tively 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 appro
`priate 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 substi
`tuted 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 repre
`sents 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
`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?uoromethanesulphonic acid,
`
`8
`p-toluenesulphonic acid) used alone or miXed in a
`stoichiometric or catalytic amount, Working in an
`organic solvent chosen from alcohols, ethers,
`esters, aliphatic hydrocarbons, halogenated ali
`phatic hydrocarbons and aromatic hydrocarbons at
`a temperature of from —10 to 60° C., and prefer
`ably 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):
`
`(IX)
`
`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):
`
`0
`
`HO
`
`O—Si(R)3
`
`(XI)
`
`HO
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`in Which R is de?ned as above, folloWed by the action of a
`product of general formula:
`
`65
`
`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):
`
`

`

`US 6,387,946 B1
`
`10
`the conditions described above for the action of a product of
`general formula (XII) on a product of general formula
`
`(XIII)
`
`5
`
`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
`
`6COCH3
`
`10
`
`(XVI)
`
`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):
`
`(XIV)
`
`Olllu
`
`HOlllw
`
`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:
`
`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 dimnethylformamide 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
`
`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):
`
`(XVII)
`
`Olllu
`
`HO
`
`6cocII3
`
`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)
`
`3O
`
`35
`
`50
`
`55
`
`Ollm.
`
`HO
`
`6cocII3
`
`65 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
`atoms to give a product of general formula (XIX):
`
`

`

`US 6,387,946 B1
`
`11
`
`12
`
`(XIX)
`
`(XXI)
`
`1O
`
`15
`
`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.
`
`25
`
`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 is products
`of general formula
`
`35
`
`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):
`
`(XXII)
`
`(XX)
`
`45
`
`in Which R1, R3, R6 and R7 are de?ned as above, and, to
`obtain a product of general formula (XXIII):
`
`(XXIII)
`
`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.
`
`55
`
`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):
`
`65
`
`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
`
`

`

`US 6,387,946 B1
`
`13
`obtained by the action of a sulphoxide of general formula
`(XXIV):
`
`R,
`
`R, I,”
`
`SO
`
`(xxrv)
`
`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., 29, 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 resist