Europaisches Patentamt
`
`European Patent Office
`Office européen des brevets
`
`@ Publication number:
`
`0 604 910 A1
`
`EUROPEAN PATENT APPLICATION
`
`2 ®
`
`@ Application number: 93120801.1
`
`@ Date of filing: 23.12.93
`
`@ Int. Cl.5: C07F 9/655, A61K 31/675,
`C07F 9/6558, C07D 305/14,
`C07D 407/12, C07F 7/18
`
`A request for correction of the description has
`been filed pursuant to Rule 88 EPC. A decision
`on the request will be taken during the
`proceedings before the Examining Division
`(Guidelines for Examination in the EPO, A—V,
`2.2).
`
`Priority: 24.12.92 us 996455
`17.08.93 us 108015
`24.11.93 us 154840
`
`Date of publication of application:
`06.07.94 Bulletin 94/27
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IE IT LI LU MC
`NL PT SE
`
`@ Applicant: Bristol-Myers Squibb Company
`345 Park Avenue
`
`New York, N.Y. 1o154(us)
`
`® Inventor: Golik, Jerzy
`48 South End Road
`
`Southington, CT 06489(US)
`Inventor: Vyas, Dolatrai
`19 Thames Way
`Madison, CT 06443(US)
`
`Inventor: Wrigth, John J. (Kim)
`609 Lake Drive
`
`Guilford, CT 06437(US)
`Inventor: Wong, Henry
`98 Black Walnut Drive
`
`Durham, CT 06422(US)
`Inventor: Kadow, John F.
`9 Quarry Run
`Wallingford, CT 06492(US)
`Inventor: Thotathil, John K.
`31 Ellsworth Drive
`
`Robbinsville, NJ 08691(US)
`Inventor: Li, Wen-Sen
`3 Holly Hill Road
`Marlboro, NJ 07746(US)
`Inventor: Kaplan, Murray A.
`1026 Glencove Road
`
`Syracuse, NY 13206(US)
`Inventor: Perrone, Robert K.
`7353 Tomwood Drive
`
`Liverpool, NY 13090(US)
`
`Representative: Kinzebach, Werner, Dr. et al
`Patentanwalte
`
`Reitstotter, Kinzebach und Partner
`Postfach 86 06 49
`
`D-81633 Miinchen (DE)
`
`@ Phosphonooxymethyl ethers of taxane derivatives.
`
`@ The present invention concerns novel water-soluble phosphonooxymethyl ethers of taxane derivatives, their
`use as antitumor agents, and pharmaceutical compositions containing the novel compounds.
`
`EP0604910A1
`
`Rank Xerox (UK) Business Services
`(3.10/3.09/3.3.4I
`
`AVENTIS EXHIBIT 2003
`Mylan v. Aventis
`IPR2016-00627
`
`

`
`EP 0 604 910 A1
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`
`The present invention concerns antitumor compounds. More particularly, the invention provides novel
`taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.
`
`2. Background Art
`
`Taxol® (paclitaxel) is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia.
`
`It
`
`has been shown to have excellent antitumor activity in i_n E animal models, and recent studies have
`elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of
`mitosis.
`It
`is currently undergoing clinical
`trials against ovarian, breast and other types of cancer in the
`United States and France and preliminary results have confirmed it as a most promising chemotherapeutic
`agent. The results of paclitaxel clinical studies are reviewed in Rowinsky and Donehower, "The Clinical
`Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics" Pharmac. Ther., 52:35-84,
`1991.
`
`Recently, a semi-synthetic analog of paclitaxel named Taxotere® has also been found to have good
`antitumor activity in animal models. Taxotere® is also currently undergoing clinical trials in Europe and the
`United States. The structures of paclitaxel and Taxotere® are shown below; the conventional numbering
`system of the paclitaxel molecule is provided.
`
`PhC(O)C:)
`
`R = Ph; R‘ = acetyl
`Taxol®:
`R = t-butoxy; R‘ = hydrogen
`Taxotere®:
`to be formulated in
`One drawback of paclitaxel
`is
`its very limited water solubility requiring it
`nonaqueous pharmaceutical vehicles. One commonly used carrier is Cremophor EL which may itself have
`undesirable side effects in man. Accordingly, a number of research teams have prepared water-soluble
`derivatives of paclitaxel which are disclosed in the following references:
`(a) Haugwitz et al, U.S. Patent No. 4,942,184;
`b) Kingston et al, U.S. Patent No. 5,059,699;
`c) Stella et al, U.S. Patent No. 4,960,790;
`d) European Patent Application 0,558,959 A1 published September 8, 1993.
`e) Vyas et al, Bioorganic & Medicinal Chemistry Letters, 1993, 3:1357-1360.
`
`an
`
`( ( ( (d (
`
`f) Nicolaou et al, Nature, 1993, 364:464—466
`taxane derivatives and
`Compounds of
`the present
`invention are phosphonooxymethyl ethers of
`pharmaceutically acceptable salts thereof. The water solubility of
`the salts facilitates preparation of
`pharmaceutical formulations.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to taxane derivatives having the formula (A):
`
`T-— OCH2(OCH2)mOP(O)(OH)2 n
`
`

`
`EP 0 604 910 A1
`
`wherein T is a taxane moiety bearing on the C13 carbon atom a substituted 3-amino-2-hydrox-
`ypropanoyloxy group; n is 1, 2 or 3; m is 0 or an integer from 1
`to 6 inclusive; or a pharmaceutically
`acceptable salt thereof.
`Another aspect of the present invention provides taxane derivatives having the formula (B):
`
`(B)
`
`T‘ T
`
`is T in which non-reacting hydroxy groups have been blocked, m and n are as defined under
`
`wherein T‘
`formula (A).
`Yet another aspect of the present invention provides intermediates having the formula (C):
`
`1' —[ OCH2(OCH2)mOP(O)(ORy)J
`
`I’)
`
`(C,
`
`wherein T‘, m and n are as defined under formula (A), and RV is a phosphono protecting group.
`Another aspect of the present invention provides compounds of the formula (D):
`
`13—OH~lxn— [OCH2(OCH2)mSCH3]
`
`I1
`
`(D)
`
`wherein m and n are as defined above; and txn is a taxane moiety; or a C13 metal alkoxide thereof.
`Another aspect of the present invention provides a method for inhibiting tumor in a mammalian host
`which comprises administering to said mammalian host an antitumor effective amount of a compound of
`formula (A).
`Yet another aspect of the present invention provides a pharmaceutical composition which comprises an
`antitumor effective amount of a compound of formula (A) and a pharmaceutically acceptable carrier.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`the following definitions apply.
`In the application, unless otherwise specified explicitly or in context,
`"Alkyl" means a straight or branched saturated carbon chain having from one to six carbon atoms;
`examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, sec-pentyl,
`isopentyl, and n-hexyl. "Alkenyl" means a straight or branched carbon chain having at least one carbon-
`carbon double bond, and having from two to six carbon atoms; examples include ethenyl, propenyl,
`isopropenyl, butenyl,
`isobutenyl, pentenyl, and hexenyl. "Alkynyl" means a straight or branched carbon
`chain having at least one carbon-carbon triple bond, and from two to six carbon atoms; examples include
`ethynyl, propynyl, butynyl, and hexynyl.
`"Aryl" means aromatic hydrocarbon having from six to ten carbon atoms; examples include phenyl and
`naphthyl. "Substituted aryl" means aryl substituted with at least one group selected from C1—s alkanoyloxy,
`hydroxy, halogen, C1—s alkyl, trifluoromethyl, 01-5 alkoxy, aryl, C2—s alkenyl, C1—s alkanoyl, nitro, amino,
`and amido. "Halogen" means fluorine, chlorine, bromine, and iodine.
`"Phosphono-" means the group -P(O)(OH)2 and "phosphonooxymethoxy" or "phosphonooxymethyl
`ether" means generically the group -OCH2(OCH2)mOP(O)(OH)2. "(Methylthio)thiocarbonyl" means the group
`-C(S)SCH3. "Methylthiomethyl" (also abbreviated as MTM) generically refers to the group -CH2SCH3.
`"Taxane moiety" (also abbreviated as txn) denotes moieties containing the twenty carbon taxane core
`framework represented by the structural formula shown below with the absolute configuration.
`
`

`
`EP 0 604 910 A1
`
`The numbering system shown above is one used in conventional taxane nomenclature, and is followed
`throughout the application. For example, the notation C1 refers to the carbon atom labelled as "1 "; C5-C20
`oxetane refers to an oxetane ring formed by the carbon atoms labelled as 4, 5 and 20 with an oxygen atom;
`and C9 oxy refers to an oxygen atom attached to the carbon atom labelled as
`said oxygen atom may
`be an oxo group, a- or /3-hydroxy, or a- or is-acyloxy.
`"Substituted 3-amino-2-hydroxypropanoyloxy" denotes a residue represented by the formula
`
`X--NH 0
`
`OX‘
`
`is hydrogen or a non-hydrogen group.) The stereochemistry of this
`(X is a nonhydrogen group and X‘
`residue is the same as the paclitaxel sidechain. This group is sometimes referred to in the application as
`the "C13 sidechain."
`
`"Taxane derivative" (abbreviated as T) refers to a compound having a taxane moiety bearing a C13
`sidechain.
`
`"Heteroaryl" means a five- or six-membered aromatic ring containing at least one and up to four non-
`carbon atoms selected from oxygen, sulfur and nitrogen. Examples of heteroaryl
`include thienyl, furyl,
`pyrrolyl,
`imidazolyl, pyrazolyl, thiazolyl,
`isothiazolyl, oxazolyl,
`isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl,
`tetrazolyl,
`thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
`triazinyl,
`tetrazinyl, and like
`rings.
`the
`"Phosphono protecting groups" means moieties which can be employed to block or protect
`phosphono functional group; preferably such protecting groups are those that can be removed by methods
`that do not appreciably affect the rest of the molecule. Suitable phosphonooxy protecting groups are well
`known to those skilled in the art and include for example benzyl and allyl groups.
`"Hydroxy protecting groups" include, but is not limited to, ethers such as methyl, t-butyl, benzyl, p-
`methoxybenzyl,
`p-nitrobenzyl,
`allyl,
`trityl, methoxymethyl, methoxyethoxymethyl,
`ethoxyethyl,
`tetrahydropyranyl,
`tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether and t-butyl-
`dimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono—, di—, and trihaloacetyl such
`as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates such as methyl, ethyl, 2,2,2-
`trichloroethyl, allyl, benzyl, and p-nitrophenyl.
`Additional examples of hydroxy and phosphono protecting groups may be found in standard reference
`works such as Greene and Wuts, Protective Groups in Organic Synthesis, 2d Ed., 1991, John Wiley &
`Sons, and McOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press. Methods for introducing
`and removing protecting groups are also found in such textbooks.
`"Pharmaceutical|y acceptable salt" means a metal or an amine salt of the acidic phosphono group in
`which the cation does not contribute significantly to the toxicity or biological activity of the active compound.
`Suitable metal salts include lithium, sodium, potassium, calcium, barium, magnesium, zinc, and aluminum
`salts. Preferred metal salts are sodium and potassium salts. Suitable amine salts are for example, ammonia,
`tromethamine
`(TRIS),
`triethylamine,
`procaine,
`benzathine,
`dibenzylamine,
`chloroprocaine,
`choline,
`diethanolamine,
`triethanolamine,
`ethylenediamine,
`glucamine, N-methylglucamine,
`lysine,
`arginine,
`
`

`
`EP 0 604 910 A1
`
`ethanolamine, to name but a few. Preferred amine salts are lysine, arginine and N-methylglucamine salts.
`In the specification and in the claims, the term —OCH2(OCH2)mOP(O)(OH)2 is intended to emcompass
`both the free acid and its pharmaceutically acceptable salts, unless the context indicates specifically that
`the free acid is meant.
`
`One aspect of the present invention provides taxane derivatives of the formula (A)
`
`T— OCH2(OCH2)mOP(O)(OH)2
`
`(A)
`
`I1
`
`wherein T is a taxane moiety bearing on the C13 carbon atom a substituted 3-amino-2-hydrox-
`ypropanoyloxy group; n is an 1, 2 or 3; m is 0, or an integer from 1
`to 6 inclusive, or a pharmaceutically
`acceptable salt thereof.
`In one embodiment the taxane moiety contains at least the following functionalities: C1-hydroxy, C2-
`benzoyloxy, C4-acetyloxy, C5-C20 oxetane, C9-oxy, and C11-C12 double bond.
`In a preferred embodiment the taxane moiety is derived from a residue having the formula
`
`wherein R29 is hydrogen and R29 is hydrogen, hydroxy, - OC(O)R", or -OC(O)OR"; or R29 is hydrogen and
`R23‘
`is fluoro; R39 is hydrogen, hydroxy,
`-OC(O)R", C1—galky|oxy, or -OC(O)OR"; one of R59 or R79 is
`hydrogen and the other is hydroxy or -OC(O)R"; or R“ and R79 together form an oxo group; RX is as
`defined below.
`
`In another embodiment, the C13 sidechain is derived from a residue having the formula
`
`R‘(o)pcor;iH o
`5?
`
`R
`
`o
`
`OR1 e
`
`wherein R” is hydrogen or -C(O)R", -C(O)OR"; R4 and R5 are independently C1—e alkyl, C2—s alkenyl, C2 —g
`alkynyl, or -Z-R5; Z is a direct bond. C1—s alkyl or C2—s alkenyl; R5 is aryl, substituted aryl, C3 -6 cycloalkyl,
`or heteroaryl; and R’‘ is C1—5 alkyl optionally substituted with one to six same or different halogen atoms,
`C3—6 cycloalkyl, C2—5 alkenyl, or a radical of the formula
`
`

`
`EP 0 604 910 A1
`
`Ra
`
`Rb
`
`RC
`
`\13
`
`wherein D is a bond or C1 -5 alkyl; and R5‘, Rb and R“ are independently hydrogen, amino, C1 -5 alkylamino,
`di-C1—salkylamino, halogen, C1 -5 alkyl, or C1 -5 alkoxy; p is 0 or 1.
`In a preferred embodiment, R4 is C1 -5 alkyl and p is 1, or R4 is or -Z-R5 and p is 0. More preferably,
`R"(O),, is t-butoxy, phenyl, isopropyloxy, n-propyloxy, or n-butoxy.
`In another preferred embodiment R5 is C2—salkenyl or -Z-R5 and Z and R5 are as previously defined.
`More preferably, R5 is phenyl, 2-furyl, 2-thienyl, isobutenyl, 2-propenyl, or C3—ecycloalkyI.
`In another embodiment, compound of formula (A) may be more specifically represented by the formula
`
`(I)
`
`R“(O)pCOl;IH
`
`0
`
`is hydroxy, -OCH2(OCH2),,,OP(O)(OH)2, -OC(O)R" or -OC(O)OR"; R” is hydrogen, and R2 is
`wherein R‘
`hydrogen, hydroxy, -OCHg(OCH2),,,OP(O)(OH)2 or -OC(O)OR"; or R2‘
`is fluoro, and R2 is hydrogen; R3 is
`hydrogen, hydroxy, acetoxy, -OCH2(0CH2),,,OP(O)(OH)2 or -OC(O)OR"; one of R5 or R7 is hydrogen and
`the other is hydroxy, C1 -5 alkanoyloxy, or -OCH2(OCH2),,,OP(0)(OH)2; or R5 and R7 together form an oxo
`group; with the proviso that at least one of R‘, R2, R3, R5 or R7 is -OCH2(OCH2),,,OP(O)(OH)2; R4, R5, R‘, m
`and p are as previously defined; or a pharmaceutically acceptable salt thereof.
`In compounds of formula (I), examples of RX include methyl, ethyl, n—propyl, isopropyl, n—butyl, isobutyl,
`chloromethyl, 2,2,2-trichloroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, 2-propenyl,
`phenyl, benzyl, bromophenyl, 4-aminophenyl, 4-methylaminophenyl, 4-methylphenyl, 4-methoxyphenyl and
`the like. Examples of R4 and R5
`include 2-propenyl,
`isobutenyl, 3-furanyl
`(3-furyl), 3-thienyl, phenyl,
`naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, methyl, ethyl, n-pro-
`pyl,
`isopropyl, n-butyl,
`isobutyl, t-butyl, ethenyl, 2-propenyl, 2-propynyl, benzyl, phenethyl, phenylethenyl,
`3,4-dimethoxyphenyl,
`2-furanyl
`(2-furyl),
`2-thienyl,
`2-(2-furanyl)ethenyl,
`2-methylpropyl,
`cyclopropyl,
`cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl and the like.
`in which R5 is
`In one preferred embodiment, the present invention provides compounds of formula (I)
`C2—salkenyl or -Z-R5 and Z and R5 are as previously defined. More preferably, R5 is phenyl, 3—furyl, 3-
`thienyl, 2-propenyl, isobutenyl, 2-furyl, 2-thienyl, or C3—gcycloalkyl.
`in which case p is 1; or
`is C1 —galkyl
`In another preferred embodiment R4 of compounds of formula (I)
`R4 is -Z-R5 and Z and R5 are as previously defined, and in which case p is 0. More preferably R4(O),,- is t-
`butoxy, phenyl, isopropyloxy, n-propyloxy, n-butoxy.
`In another preferred embodiment, the present invention provides compounds of formula (I) in which R‘
`is -OCH2(OCH2),,,OP(O)(OH)2 In a more preferred embodiment, R2 is hydroxy, -OCH2(OCH2),,,OP(O)(OH)2,
`or -OC(O)R", and R“ is preferably C1 -5 alkyl.
`In another more preferred embodiment, R3 is hydroxy or
`acetoxy.
`In another preferred embodiment, the present invention provides compound of formula (I) in which R2 is
`-OCH2(0CH2),,,OP(O)(OH)2; R‘
`is hydroxy or -OC(O)OR"; and R3 is hydrogen, hydroxy, acetoxy, -OCH2-
`(OCH2)mOP(0)(OH)2 or -OC(O)OR"; and R" is as previously defined. In a more preferred embodiment R‘
`is
`hydroxy or -OC(O)OR" and RX is preferably C1 -5 alkyl; and R3 is hydroxy or acetoxy.
`
`

`
`EP 0 604 910 A1
`
`In another preferred embodiment, the present invention provides compound of formula (I) in which R3 is
`—OCH2(0CH2)mOP(O)(OH)2; R‘
`is hydroxy or -OC(O)OR"; R2' is hydrogen, and R2 is hydrogen, hydroxy or
`-OC(O)OR"; or R2'
`is fluoro and R2 is hydrogen; and RX is as previously defined.
`In a more preferred
`embodiment, R‘
`is hydroxy or -OC(O)OR", and RX is preferably C1—s alkyl.
`In another more preferred
`embodiment, R2 is hydroxy.
`In another preferred embodiment, m is 0 or 1 when the phosphonooxymethoxy group is present on the
`C7 of the taxane moiety.
`The preferred pharmaceutically acceptable salts of a compound of formula (A) are alkali metal salts
`including lithium, sodium and potassium salts; and amine salts including triethylamine,
`triethanolamine,
`ethanolamine, arginine, lysine and N-methylglucamine salts. Even more preferred salts are arginine, lysine
`and N-methylglucamine salts.
`The most preferred embodiments of taxane derivatives of formula (A) include the following compounds:
`
`(3)
`(2) 2'-Q-(ethyloxycarbonyl)-7-Q-phosphonooxymethylpaclitaxel;
`(1) 7-Q-phosphonooxymethylpaclitaxel,
`2'-Q-phosphonooxymethylpaclitaxel;
`(4) 2',7-bis-Q-(phosphonooxymethyl)paclitaxel;
`(5) 3'-N-debenzoyl-3'-
`desphenyl-3'-N-(t-butyloxycarbonyl)-3'-(2-furyl)-2'-Q-ethyloxycarbonyI-7-Q-phosphonooxymethylpaclitaxel;
`(6)
`3'-N-debenzoyl-3'-desphenyl-3*N-(t-butyloxycarbonyl)-3'-(2-thienyI)-2'-Q-ethyloxycarbonyl-7-9
`phosphonooxymethylpaclitaxel;
`(7)
`10-desacetyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl)-10-9-
`(phosphonooxymethyl)paclitaxel; (8) 2'-9-phosphonooxymethoxymethylpaclitaxel and their respective phar-
`maceutically acceptable salts, particularly the sodium, potassium, arginine,
`lysine, N-methylglucamine,
`ethanolamine, triethylamine and triethanolamine salts.
`Compounds of formula (A) may be prepared from a taxane derivative starting material T-[OH],, wherein
`T and n are as previously defined. The identity of T-[OH],,
`is not particularly limited so long as there is at
`least one reactive hydroxy group present on either the taxane moiety or the C13 side chain to allow the
`formation of phosphonooxymethyl ether linkage.
`It is to be understood that the reactive hydroxy group may
`be directly attached to the C13 propanoyloxy backbone (e.g. the 2'-hydroxy group of paclitaxel) or to the
`taxane core framework (e.g. the 7-hydroxy group of paclitaxel); or it may be present on a substituent on the
`C13 sidechain, or on a substituent on the taxane core. The reaction sequence shown in Scheme I may be
`used to prepare compounds of formula (A)
`
`Scheme I
`
`T‘-[OH]" ———> T‘-[OCH2(OCH2)mSCH3ln
`(A3)
`(5)
`
`T‘—[OCH2(0CH2)m OP(O)(ORY)2]n
`(C)
`
`(A)
`
`is a taxane derivative in which non-reacting hydroxy groups have been blocked; RV is a
`In Scheme I T'
`phosphono protecting group; n and m are as previously defined. Thus an appropriately protected T‘ having
`one or more reactive hydroxy groups is first converted to a corresponding methylthiomethyl ether of
`formula (B). Using paclitaxel as an example, T’ may be paclitaxel itself (to effect 2',7-bismethylthiomethyla-
`
`tion), 7-Q-triethylsilylpaclitaxel, or 2'-Q-ethoxycarbonylpaclitaxel. A compound of formula (B) where m is 0
`may be prepared by treating T‘-[OH] with dimethylsulfoxide/acetic anhydride, or with dimethylsulfide and
`an organic peroxide. These reactions are discussed more fully in a subsequent section.
`The MTM ether having one intervening methyleneoxy unit (i.e. compounds of formula (B) where m = 1)
`may be prepared by several possible routes.
`In one a compound of formula (B) where m = 0 is reacted
`with N-iodosuccinimide (NIS) and methylthiomethanol to extend the chain by one methyleneoxy unit.
`
`

`
`EP 0 604 910 A1
`
`T‘—[OCH2SCH3]n
`
`+
`
`n cH3scH,—oH
`
`“'5
`
`T'—[OCH2OCH2SCH3]n
`
`The compound of methylthiomethanol and its preparation is reported in Syn. Comm., 1986, 16 (13): 1607-
`1610.
`
`In an alternative method, the T-alkoxide (Ad) generated by treating a compound of formula (Aa) with a
`base such as n-butyl
`lithium,
`lithium diisopropylamide or
`lithium hexamethyldisilazide,
`is reacted with
`chloromethyl methylthiomethyl ether to provide a compound of formula (B) in which m = 1.
`
`T'—[o~],,
`
`+
`
`n CH3SCH§—OCH2C| j» T'—[OCH2OCH2SCH3]n
`
`(Ad)
`
`(Ae)
`
`is prepared by reacting methylthiomethoxide (obtained from methythiomethanol by
`Compound (Ae)
`treatment with a base such as n-butyl lithium, lithium diisopropylamide or lithium hexamethyldisilazide) with
`chloroiodomethane. Compound (Ae) may also be prepared by treating 1,1'-dichlorodimethylether
`(ClCH2OCH2C|) with a stoichiometric amount or less (e.g. about 0.8 equivalent) of sodium iodide followed
`by sodium thiomethoxide. 1,1‘-Dichlorodimethyl ether is reported in Ind. J. Chem., 1989, 28B, pp. 454-456.
`In another method, a compound of formula (Aa) is reacted with bis(MTM)ether, CH3SCH2OCH2SCH3,
`and NIS to give a compound of formula (B) in which m = 1.
`
`T'-[OH]n 4'
`
`fl CH3SCH2OCH2SCH3 —’ T'-[OCH2OCH2SCH3]n
`
`Bis(MTM)ether is prepared by reacting 1,1‘-dichlorodimethyl ether with sodium iodide followed by sodium
`thiomethoxide.
`
`The procedure described above using methylthiomethanol and NIS may be applied to any reagent
`having an MTM group to extend the chain by one methyleneoxy unit at a time. For example, a compound
`of formula (B) wherein m = 1 can be reacted with methythiomethanol and NIS to provide a compound of
`formula (B) wherein m = 2. The process may be repeated to provide compounds of formula (B) in which m
`is 3, 4, 5 or 6.
`
`In the second step shown in Scheme I, the methylthiomethyl ether is converted to the corresponding
`protected phosphonooxymethyl ether. This is accomplished by treating the MTM ether with NIS and
`protected phosphate H0P(O)(ORV)2.
`In the third step, the phosphono protecting group and any hydroxy
`protecting group(s) are removed to provide a compound of formula (A). For example, a suitable phosphono
`protecting group is benzyl which may be removed by catalytic hydrogenolysis; hydroxy protecting groups
`such as trialkysilyl may be removed by fluoride ion,
`trichloroethoxycarbonyl may be removed by zinc.
`Removal of protecting groups are taught
`in textbooks such as Green and Wuts, Protective Groups in
`Organic Synthesis, John Wiley & Sons, 1991; and McOmie, Protective in Organic Chemistry, Plenum Press,
`1973. Both steps are discussed in detail in a later section in the specification.
`A variation of the reaction sequence shown in Scheme I is provided in Scheme II.
`
`Scheme II
`
`T'—[OH]n +
`
`n CH3SCH2(OCH2)m0P(O)(ORY)2
`
`(Aa)
`
`(Ca)
`
`(0)
`
`In Scheme II, a compound of formula (Aa) is reacted with a compound of formula (Ca) and NIS to give
`a compound of formula (C), which is then deblocked to give a compound of formula (A). Compounds of
`formula (Ca) in which m is 0 may be prepared by first treating methylthiomethanol with a base such as Na,
`
`

`
`EP 0 604 910 A1
`
`Li or K hexamethyldisilazide to give methylthiomethoxide; the methoxide is then reacted with a protected
`chlorophosphate such as dibenzyl chlorophosphate to provide the desired compound. Compounds of
`formula (Ca) in which m is 1 may be prepared by treating CH3SCH2OCH2 Cl with a diprotected phosphate
`salt, e.g. sodium, potassium, tetra(n-butyl)ammonium salts of dibenzyl phosphate; or CHsSCH20CH2Cl may
`be first converted to the corresponding iodo compound using sodium iodide prior to reacting with the
`phosphate salt. Alternatively, compounds of formula (Ca) in which m is 1 may be prepared by treating
`ClCH2OCH2CI with sodium iodide followed by sodium thiomethoxide to provide CH3SCH2OCH2SCH3; this
`compound is then treated with NIS and a diprotected phosphate such as dibenzyl phosphate to give the
`desired product. Any of the previously mentioned reagents having a MTM group may be extended one
`methyleneoxy unit at a time by reacting said reagent with methylthiomethanol and NIS.
`In another method for preparing a compound of formula (A), T-alkoxide (Ad)
`iodophosphate as shown in Scheme Ill.
`
`is reacted with an
`
`Scheme III
`
`T-_[o1n
`
`+
`
`lCH2(OCH2)mOP(O)(ORY)2
`
`(Ad)
`
`(C)
`
`In Scheme III, the iodophosphate compound is obtained by reacting ClCH2(OCH2)mCI with a diprotected
`phosphate salt to give CICH2(0CH2),,,OP(O)(OR‘/)2 which is then treated with sodium iodide to give the
`desired product.
`Yet another method suitable for preparing a subset of compounds of formula (A) in which at least one of
`the phosphonooxymethoxy groups is linked to the taxane moiety is shown in Scheme IV.
`
`Scheme IV
`
`+
`
`13-OH—txn -—-[OCH2(OCH2)mSCH3]n ——— (38)
`
`(D)
`
`In Scheme IV, m and n are as previously defined; X is a non-hydrogen group, P is a hydroxy protecting
`group; txn is a taxane moiety. Compounds of formula (D) are taxanes having a 13a-hydroxy group and one
`or more methylthiomethyl ether linked directly or indirectly to the taxane core; also included are C13 metal
`
`alkoxides of formula (D). An example of a compound of formula (D) is 7-Q-methyIthiomethylbaccatin III:
`
`OH Ac
`Phc(o)c5
`
`The coupling of the taxane (D) with the azetidinone is analogous to the one shown in Scheme Vl, infra; thus
`the procedure described there for the preparation of a compound of formula (Id) is also applicable to the
`preparation of a compound of formula (Ba) [i.e. a compound of formula (B) in which at least one of the MTM
`
`

`
`EP 0 604 910 A1
`
`if a compound of formula (D) is used in place of
`group is linked directly or indirectly to the taxane moiety],
`a compound of formula (II)
`in Scheme VI. The taxane (D)
`is preferably first converted to a C13 metal
`alkoxide such as sodium, potassium or lithium alkoxide;
`lithium alkoxide is preferred. The azetidinone
`serves as the precursor of
`the C13 sidechain. After the coupling reaction with a taxane.
`the hydroxy
`protecting group P is removed, and if desired, the free hydroxy group on the sidechain may be converted
`to the MTM ether or derivatized to an ester or a carbonate as herein described.
`
`The azetidinone may be prepared by methods described later which are also methods generally known
`in the art. Compounds of formula (D) may be prepared by the general procedure described above for the
`preparation of compounds of formula (B) using a suitably protected taxane. However, more conveniently,
`they can be obtained from a compound of formula (Ba) by cleaving the 13-sidechain using a borohydride
`
`is treated with
`
`such as sodium or tetrabutylammonium borohydride; for example, 7-Q-MTM of paclitaxel
`tetrabutylammonium borohydride to give 7-O-MTM baccatin III.
`The general process of Scheme I for the preparation of a compound of formula (A) is more particularly
`exemplified in Scheme V which illustrates the preparation of a compound of formula (I') (i.e. a compound of
`formula (I) in which m is 0). The procedure employed in this synthetic sequence is generally applicable to
`other taxane derivatives not specifically encompassed by formula (I). Furthermore, the procedure in Scheme
`(V) may be modified in accordance with teachings contained herein by one skilled in the art to arrive at
`taxane derivatives of formula (A) in which m is 1 or 2.
`It
`is to be understood that in Scheme V as well as elsewhere in the specification, the term "hydroxy
`protecting group" may encompass carbonates (-OC(O)OR");thus, when a carbonate is used as a hydroxy
`protecting group, it is intended to be removed in a later step to generate the free hydroxy group, otherwise,
`the carbonate moiety remains as part of the final product.
`
`

`
`EP 0 604 910 A1
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`Scheme V
`
`R4(o)pconH
`
`0
`
`R 0au-....
`
`(la) SMe2/(PhCO0)2
`
`or
`
`(lb) Aczo/DMSO
`
`R4(o)pco§H
`
`0
`
`removal of phosphono protecting
`(3)
`group and,
`if present, hydroxy protecting
`
`R4(o)pcoNH
`
`R5/\é/“\o.......
`
`is hydrogen, and R23
`In Scheme V, R13 is hydroxy, protected hydroxy, -OC(O)R" or -OC(O)OR"; R2'
`ishydrogen, hydroxy, protected hydroxy, or
`-OC(O)OR"; or R3 is fluoro, and R23 is hydrogen; R33 is
`hydrogen, hydroxy, protected hydroxy, acetoxy, or -OC(O)OR"; one of R63 or R73 is hydrogen and the other
`is hydroxy, protected hydroxy or C1—s alkanoyloxy; or R63 and R73 together form an oxo group; with the
`proviso that at least one of R‘3, R23 or R33, R63 or R73 is hydroxy. R“° is hydroxy, protected hydroxy,
`-OCH2SCH3, -OC(O)R" or -OC(O)OR"; R2'
`is hydrogen, and R2“ is hydrogen, hydroxy, protected hydroxy,
`-OCH2SCH3 or -OC(O)OR"; or R2'
`is fluoro, and R2” is hydrogen; R3“ is hydrogen, hydroxy, protected
`hydroxy, acetoxy, -OCH2SCH3 or -0C(O)OR"; one of R5“ or R7” is hydrogen and the other is hydroxy,
`
`11
`
`

`
`EP 0 604 910 A1
`
`protected hydroxy, C1—5 alkanoyloxy or -OCH2SCH3; or R6'‘’ and R7b together form an oxo group; with the
`proviso that at least one of R1“, Rab, Rab, R5'° or R7'° is -OCH2SCH3. R” is hydroxy, protected hydroxy,
`-OCH2OP(O)(OR‘/)2,
`- OC(O)R" or -OC(O)OR"; R2'
`is hydrogen, and R2“ ishydrogen, hydroxy, protected
`hydroxy, -OCH2OP(O)(ORV)2 or -OC(O)OR"; or R’ is fluoro, and R2“ is hydrogen; R3“ is hydrogen, hydroxy.
`protected hydroxy, acetoxy, -OCH2OP(O)(ORV)2 or -OC(O)0R"; one of R6“ or R7“ is hydrogen and the other
`is hydroxy, protected hydroxy, C1—5 alkanoyloxy or -OCH2OP(O)(ORV)2; with the proviso that at least one of
`R”, R2“, R3“, R6“ or R7“ is -OCH2OP(O)(OR‘/)2. R"is hydroxy, -OCH2OP(0)(OH)2, - OC(O)R" or -0C(O)OR";
`R2” is hydrogen, and R2" is hydrogen, hydroxy, -OCH2OP(O)(OH)2 or -OC(O)0R"; or R2" is fluoro, and R2"
`is hydrogen; R3'
`is hydrogen, hydroxy, acetoxy, -OCH2OP(O)(OH)2 or -OC(O)OR"; one of R"' or R7'
`is
`hydrogen and the other is hydroxy, Cl —galkanoyloxy or -OCH2 P(O)(OH)2; with the proviso that at least one
`of R", R2", R3', R6' or R7‘
`is -OCH2OP(O)(OH)2.R4, R5 and R’‘ are as defined previously, and RV is a
`phosphono protecting group.
`In the first step, the free hydroxy group of a compound of formula (la) is converted to the corresponding
`methylthiomethyl ether (-OCH2SCH3) group. This conversion may be accomplished by either one of the two
`procedures (1a - the dimethylsulfide method) and (1b - the dimethylsulfoxide method). The dimethylsulfide
`method for converting alcohols to methylthiomethyl ethers is reported in Medina et al, Tet. Lett., 1988, pp.
`3773-3776,
`the relevant portions thereof are hereby incorporated by reference. The dimethylsulfoxide
`method is the well-known reaction commonly known as the Pummerer reaction.
`It should be noted that the reactivity of a hydroxy group differs depending on its location on the taxane
`derivative starting material of formula (la). Although in general the 2'-hydroxy group is more reactive in
`acylation reactions than the 7-hydroxy group which in turn is more reactive than the 10-hydroxy group,
`it
`has been found that, surprisingly, the 7-hydroxy is more readily converted into the methylthiomethyl ether
`than the 2'-hydroxy group. The tertiary hydroxy group at C-1 is usually the least reactive. The difference in
`hydroxy reactivity may be exploited in controlling the site and degree of methylthiomethylation.
`Thus with a compound of formula (la) wherein R” and R23 are both hydroxy,
`the predominant
`methylthiomethylation product
`is
`the corresponding 7-Q-methylthiomethyl ether.
`In order to obtain a
`compound of formula (lb) wherein R”° is methylthiomethoxy, without also converting the 7-hydroxy group, if
`present,
`into a methylthiomethyl ether,
`the 7-hydroxy group is blocked with a conventional hydroxy
`protecting group such as triethylsilyl. Similarly, 10-methylthiomethyl ether may be obtained without also
`converting the 7- and/or 2'-hydroxy groups,
`if present, when the latter groups are blocked by the same of
`different hydroxy protecting groups. Even though the 7-hydroxy is the preferential methylthiomethylation
`site,
`it is still preferable to protect the 2'-hydroxy group if the 7-monomethylthiomethyl ether is the desired
`product.
`the reaction conditions may be manipulated to favor the formation of bis- or tris-methyl-
`Moreover,
`thiomethyl ether taxane derivatives. For example, in the case of paclitaxel, increasing reaction time or using
`a
`larger excess
`of
`the methylthiomethylating reagents can result
`in a higher
`ratio of 2',7-bis-
`(methylthiomethyl) ether paclitaxel in the product mixture.
`Returning now to Scheme V,
`in procedure (1 a) a compound of formula (la) is treated with dimethylsul-
`fide and an organic peroxide such as benzoyl peroxide. The reaction is carried out
`in an inert organic
`solvent such as acetonitrile, methylene chloride and the like at a temperature conducive to product
`formation; typically the reaction is carried at a temperature range of from about -40°C to about ambient
`temperature. Dimethylsulfide and benzoyl peroxide are used in excess relative to the taxane derivative
`starting material (la), and dimethylsulfide is used in excess relative to benzoyl peroxide.
`The relative amounts of starting materials used will depend on the degree of methylthiomethylation to
`be achieved. Thus when one free hydroxy group of the taxane deriva