(12) United States Patent
`Bouchard et al.
`
`US006372780B2
`US 6,372,780 B2
`Apr. 16, 2002
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) METHODS OF TREATING CELL LINES
`EXPRESSING MULTIDRUG RESISTANCE
`P-GLYCOPROTEIN
`
`(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 Cedex
`(FR)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/752,779
`(22) Filed:
`Jan. 3, 2001
`
`Related US. Application Data
`
`(63) Continuation of application No. 09/066,929, ?led on Apr.
`28, 1998, 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
`
`(52) US. Cl. ..................................................... .. 514/449
`(58) Field of Search ........................................ .. 514/449
`
`(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
`
`0 336 841 A1 10/1989
`0 604 910 A1
`7/1994
`
`(List continued on neXt page.)
`
`OTHER PUBLICATIONS
`
`English Language Abstract No. WPI Acc No. 89—294696/
`198941 for EP 0 336 841 A1, 1989.
`Michael L. Shelanski et al., “Microtubule Assembly in the
`Absence of Added Nucleotides,” Proc. Nat. Acad. Sci. USA,
`70(3):765—768 (Mar. 1973).
`Gérard Chauviere et al., “Analyse Structurale et Etude
`Biochimique De Produits Isolés d’lf: Taxus baccata L.
`(TaXacées),” CR. Acad. Sc. Paris, 293(7): 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,” Tetrahedron Letters, 35(31): 5543—5546 (Jun.
`1994).
`Theodora W. Greene, Protective Groups in Organic Synthe
`sis, pp. 50—62 (1981).
`Shu—Hui Chen et al., “Chapter 18: PaclitaXel Structure—Ac
`tivity Relationships and Core Skeletal Rearrangements,”
`TaxaneAnticancerAgents, vol. 583, Georg, G.I. et al., Eds.,
`pp. 247—261 (May 1995).
`D.G.I. Kingston et al., Progress in the Chemistry of Organic
`Natural Products, 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, 1999.
`
`Primary Examiner—Ba K. Trinh
`(74) Attorney, Agent, or Firm—Finnegan, Henderson,
`FaraboW, Garrett & Dunner LLP
`(57)
`ABSTRACT
`
`NoW 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):
`
`(11)
`
`display noteWorthy antitumor and antileukaemic properties.
`
`14 Claims, No Drawings
`
`MYLAN - EXHIBIT 1084
`Mylan Laboratories Limited v. Aventis Pharma S.A.
`IPR2016-00712
`
`

`

`US 6,372,780 B2
`Page 2
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`EP
`FR
`
`617 018 A1
`0 639 577 A1
`0 694 539 A1
`2 771 092
`
`9/1994
`2/1995
`1/1996
`5/1999
`
`W0
`W0
`W0
`W0
`W0
`W0
`
`WO 92/09589
`WO 94/07878
`WO 94/18164
`WO 96/00724
`WO 96/30335
`WO 97/32869
`
`6/1992
`4/1994
`8/1994
`1/1996
`10/1996
`9/1997
`
`

`

`US 6,372,780 B2
`
`1
`METHODS OF TREATING CELL LINES
`EXPRESSING MULTIDRUG RESISTANCE
`P-GLYCOPROTEIN
`
`This is a continuation of application Ser. No. 09/066,929,
`?led Apr. 28, 1998, allowed Which is a continuation of
`application Ser. No. 08/622,011, ?led Mar. 26, 1996, now
`US. Pat. No. 5,847,170, Which claims bene?t of provisional
`application No. 60/010,144, dated Jan. 17, 1996, all of
`Which are speci?cally incorporated herein by reference.
`The present invention relates to neW taXoids of general
`formula (I)
`
`10
`
`(I)
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`in Which
`Z represents a hydrogen atom or a radical of general
`formula (II).
`
`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 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
`
`2
`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
`substituted With one or more atoms or radicals
`selected from halogen atoms, alkyl radicals con
`taining 1 to 4 carbon atoms, and alkoXy radicals
`containing 1 to 4 carbon atoms,
`a 5-membered aromatic heterocyclic radical prefer
`ably 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, form yl, 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
`
`

`

`US 6,372,780 B2
`
`3
`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,
`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 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 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,
`
`10
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`4
`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 R 4 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
`a n 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 halogen atoms (?uorine, chlorine),
`alkyl (methyl), alkoXy (methoXy), dialkylamino
`(dimethylamino), acylamimo (acetylamino), alkoXycarbo
`nylamino (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
`mor 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)
`
`HON"..
`
`in Which R4 and R5 are de?ned as above, by means of an
`acid of general formula (IV):
`
`

`

`US 6,372,780 B2
`
`6
`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:
`
`(IV)
`
`R3
`
`Olln
`
`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):
`
`(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,
`benZoyloXymethyl, 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.
`
`5
`
`10
`
`15
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`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 performed by
`means of an inorganic acid (hydrochloric acid, sulphuric
`acid, hydro?uoric acid) or organic acid (acetic acid,
`methanesulphonic acid, tri?uoromethanesulphonic acid,
`p-toluenesulphonic acid) used alone or miXed, Working in
`an organic solvent chosen from alcohols, ethers, esters,
`aliphatic hydrocarbons, halogenated aliphatic
`hydrocarbons, aromatic hydrocarbons or nitrites at a tem
`perature 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 catalytic hydrogenation,
`2) When R6 and R7 together form a saturated 5- or
`6-membered heterocycle, and more especially an oXaZo
`lidine ring of general formula (VI):
`
`(VI)
`
`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 R6 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 R6 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).
`
`

`

`US 6,372,780 B2
`
`(vII)
`
`(IX)
`
`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.
`
`R2—O—CO—X
`
`(VIII)
`
`5
`
`10
`
`15
`
`HOlllw
`
`13
`
`(=)COC6H5
`
`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:
`
`20
`
`(R)3—Si—Hal
`
`(X)
`
`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):
`
`(XI)
`
`HO
`
`6COC6H5
`
`in Which R is de?ned as above, folloWed by the action of a
`product of general formula:
`
`25
`
`40
`
`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
`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
`45
`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 R1 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, aliphatic hydrocarbons, halogenated aliphatic
`hydrocarbons and aromatic hydrocarbons at a tempera
`ture 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):
`
`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
`50 (XIII).
`
`55
`
`60
`
`(XIII)
`
`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):
`
`

`

`US 6,372,780 B2
`
`(XIV)
`
`IIIZ
`
`10
`
`(XVI)
`
`HOlllw
`
`HO
`
`6COCH3
`
`1O
`
`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:
`
`15
`
`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)
`
`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).
`
`25
`
`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.
`
`35
`
`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.
`
`45
`
`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.
`
`55
`
`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):
`
`65
`
`HO
`
`6COCH3
`
`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):
`
`HO
`
`6COCH3
`
`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)
`
`Which, by the action of a product of general formula (XV),
`yields the product of general formula (V), the protective
`
`

`

`US 6,372,780 B2
`
`11
`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
`
`12
`
`(XXII)
`
`R
`R
`1\IE/ 6 O
`
`R3/\E)k
`
`(E)—R7
`
`10
`
`in Which R1, R3, R6 and R7 are de?ned as above, and, to
`obtain a product of general formula (XXIII):
`
`(XX)
`
`15
`
`R4
`
`0
`
`(XXIII)
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`55
`
`60
`
`65
`
`HO
`
`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 R8
`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):
`
`(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
`
`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
`tetrahydrofuran or dioXane, on a product of general formula
`(XXI):
`
`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):
`
`

`

`US 6,372,780 B2
`
`13
`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 ar