a
`
`Europaisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`
`
`Publication number:
`
`63
`
`0 604 910 A1
`
`®
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 93120301.1
`
`(23) Date of filing: 23.12.93
`
`GD
`
`Int. 01.5; CDTF 9f655, A61 K 31r675,
`COYF 9.6558, 007D 305i14,
`COTD 407r12. COYF 7MB
`
`A request for correction of the description has
`been filed pursuant to Rule 33 EPC. A decision
`on the request will be taken during the
`proceedings beiore the Examining Division
`(Guidelines for Examination in the EPO. A-V.
`22).
`
`® Priority: 24.12.92 US 996455
`17.03.93 US 108015
`24.11.93 US 154840
`
`@ Date of publication of application:
`06.07.94 Bulletin 9422?
`
`Designated Contracting States:
`AT BE CH DE DK ES FR GB GR IE IT LI LU MC
`NL PT SE
`
`ED Applicant: Bristol-Myers Squibb Company
`345 Park Avenue
`
`New York, N.Y. 10154(US}
`
`® Inventor: Golilr, .Ierzy
`48 South End Road
`
`Southington, CT UB489IUS)
`Inventor: Vyas, Dolatrai
`19 Thames Way
`Madison, CT DIEM-NUS)
`
`
`
`64) Phosphonooxymethyl ethers oi taxane derivatives.
`
`Inventor: Wriglh, John J. {Kim}
`609 Lake Drive
`
`Guiltord, 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: Thotathll, John K.
`31 Ellsworth Drive
`
`Hobbinsvllle, NJ BBSSHUS)
`Inventor: Li, Wen-Sen
`3 Holly Hill Road
`Marlboro, NJ 07746(US)
`Inventor: Kaplan, Murray A.
`1026 Glencove Road
`
`Syracuse, NY 13206tUS)
`Inventor: Perrone, Robert K.
`7353 Tomwood Drive
`
`Liverpool, NY 13090{US)
`
`Representative: Kinzebaoh, Werner, Dr. et al
`Patentanwalte
`Fteitstiitter, Kinzebach und Partner
`Postfach 36 06 49
`
`D-31633 MUnohen (DE)
`
`@ The present invention concerns novel water-soluble phosphonooxymethyl ethers oi taxane derivatives, their
`use as antitumor agents, and pharmaceutical compositions containing the novel compounds.
`
`EP0604910A1
`
`Rank Xerox {UK} Business Services
`I3.10}'3.09r’3.3.4]
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`NEPTUNE GENERICS EX. 1036 00001
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`EP 0 604 910 A1
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`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 vifl 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 previded.
`
`
`
`Fl = Ph; H‘ = acetyl
`Taxo|®:
`Ft = t-butoxy; Fl' = 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} Haugvvitz et al, U.S. Patent No. 4,942,184;
`{b} Kingston et al, US. Patent No. 5,059,699;
`to} Stella et al, US. Patent No. 4,960,790;
`(d) European Patent Application 0,558,959 A1 published September 8, 1993.
`
`(9) Was et al, Bioorganic & Medicinal Chemistry Letters, 1993, 3:1357-1360.
`and
`
`
`{f} Nicolaou et al, Nature. 1993. 364:464-466
`taxane derivatives and
`Compounds of
`the present
`invention are phesphonooxymethyl 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)z n
`
`(A)
`
`2 N
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`EP0604910A1
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`wherein T is a taxane moiety bearing on the 013 carbon atom a substituted 3-arnino-2-hydrox-
`ypropanoymxy 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' — oc Hzrocngmsw3 n
`
`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}:
`
`T' —— [ ocezrocr-imoproiroel’);
`
`n
`
`(c,
`
`wherein T'. m and n are as defined under formula (A), and Fttr is a phosphono protecting group.
`Another aspect of the present invention provides compounds of the formula (DJ:
`
`13—0H—txn— [OCH2(OCH2)mSCH3]n
`
`to)
`
`s
`
`re
`
`rs
`
`20
`
`25
`
`30 wherein m and n are as defined above; and txn is a taxane moiety; or a 013 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.
`
`35
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`In the application‘ unless otherwise specified explicitly or in context the following definitions apply.
`"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, isobutvl, 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,
`isobutenvl, 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
`ethvnyli propynvl. butvnvli and hexvnyl.
`"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 01 —s alkanoyloxy,
`hvdmxy, halogen. C1-5 alkyl. trifluoromethvl. 01-6 alkoxv, aryl. (32—5 alkenyl, 01—5 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)m0P(O)(0H)2. "tMethylthioithiocarbonyl" means the group
`-O[SiSCH3. "Methylthiomethyl" (also abbreviated as MTM] genericallyr refers to the group -CH280H3.
`"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.
`
`40
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`45
`
`so
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`3
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`EP 0 604 910 A1
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`
`
`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-C2D
`oxetane refers to an oxetane ring formed by the carbon atoms labelled as 4, 5 and 20 with an oxygen atom:
`and 09 oxy refers to an oxygen atom attached to the carbon atom labelled as "9", said oxygen atom may
`be an oxo group, or- or fi-hydroxy, or a- or s-aoyloxy.
`"Substituted 3-amino-2-hydroxypropanoyloxy" denotes a residue represented by the formula
`
`X-"NH O
`
`
`
`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 "013 sidechain."
`
`"Taxane derivative" (abbreviated as T} refers to a compound having a taxane moiety bearing a 013
`sidechain.
`
`T'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,
`lmidazolyl, pyrazolyl, thiazolyl,
`isothlazolyl, oxazolyl,
`isoxazolyl, triazolyl, thiadiazolyl, oxadlazolyl,
`letrazolyl,
`thialriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl,
`triazinyl,
`tetrazinyl. and like
`rings.
`
`the
`"Phosphono protecting groups‘1 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, others such as methyl, t-butyl, benzyl, p-
`methoxybenzyl,
`p-nilrobenzyl,
`allyl,
`trityl, melhoxymethyl, 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 8:
`
`Sons, and McOmie, Protective Groups in Organic Chemistry, 1975, Plenum Press. Methods for introducing
`and removing protecting groups are also found in such textbooks.
`"Pharmaceutically 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
`(THIS),
`triethylamine.
`procaine,
`benzathine,
`dibenzylamine,
`chloroprocaine,
`choline,
`diethanolamine.
`triefhanolamine.
`ethylenediamine.
`glucamine. N-methylglucamine,
`lysine,
`arginine.
`
`4 N
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`EP0604910A1
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`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{0}{0H}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.
`
`5
`
`One aspect of the present invention provides taxane derivatives of the formula (A)
`
`to
`
`rs
`
`2O
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`25
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`35'
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`35
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`40
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`45
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`so
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`T — [OCHAOCH2)mOP(O)(OH)2]
`
`n
`
`(A)
`
`wherein T is a taxane moiety bearing on the 013 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 iunctionalities: C1-hydroxy, C2-
`benzoyloxy. C4-acetyloxy, 05-020 oxetane‘ CQ-oxy, and 011-012 double bond.
`In a preferred embodiment the taxane moiety is derived from a residue having the formula
`
`
`
`HO
`
`AC
`__:'.
`booen
`
`is hydrogen hydroxy‘ - 00(0)er or -OO(O)OH"; or FF‘3 is hydrogen and
`wherein H” is hydrogen and FIEre
`R” is fluoro; R39 is hydrogen, hydroxy,
`-OC(O)R‘. Ci—aalkyloxy. or -OC{0IOR"; one of FF" 0r FF9 is
`hydrogen and the other is hydroxy or -OC{O}FI"; or Fifie and FiTe together form an oxo group; FI" is as
`defined below.
`
`In another embodiment, the 013 sidechain is derived from a residue having the formula
`
`R‘(0)pcogiH o
`5
`
`R
`
`o
`
`0R1 e
`
`wherein Ft"3 is hydrogen or -Ct0}Fi", -Ct0}OFI"; Fl”r and R5 are independently C1—5 alkyl. (32—; alkenyl, (32—5
`alkynyl, or -Z-Fl5; Z is a direct bond, 01 —g alkyl or 02—; alkenyl; F16 is aryl, substituted aryl, 03—5 cycloalkyl,
`0r heteroaryl: and Ft" is 01-5 alkyl optionally substituted with one to six same or different halogen atoms.
`(33-; cycloalkyl, 02-5 alkenyl, or a radical of the formula
`
`5
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`NEPTUNE GENERICS EX. 1036 00005
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`EP 0 604 910 A1
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`Ra
`
`Rb
`
`RC
`
`\D
`
`wherein [J is a bond or C1 -s alkyl: and Fla, Ftb and Ft0 are independently hydrogen. amino. C1 -5 alkylamino.
`di-C1—salkylamino, halogen, 01-6 alkyl, or 01-13 alkoxy; p is 0 or 1.
`In a preferred embodiment. Flt
`is C1 —5 alkyl and p is 1, or Ft" is or -Z-FtE and p is 0. More preferably,
`
`R‘t{0)p is t-butoxy, phenyl, isopropyI0xy, n-propyloxy. or n-but0xy.
`In another preferred embodiment H5 is 02 —salkeny| or -Z-Ft6 and Z and R5 are as previously defined.
`More preferably, R5 is phenyl, 2-furyl, 2-thienyl, isobutenyl, 2-propenyl. or C1; —acycloalkyl.
`In another embodiment, compound of formula (A) may be more specifically represented by the formula
`
`(ll
`
`R4rolpc
`
`( I )
`
`is hydroxy, -OCH2(OCH2)m0P(O)(OH}2, 00(0)th or -OC(O)0R"; Ft? is hydrogen. and Ft2 is
`wherein Ft‘
`hydrogen. hydroxy. -00H2(OCH2)mOP(OJ(OH)2 or -OC(O)0Fl"; or F? is fluoro. and F12 is hydrogen; F13 is
`hydrogen, hydroxy, aeetoxy, -OCH2{OCH2lmOP(O){OH}2 or -OC(O}OH“; one of R5 or Ft?
`is hydrogen and
`the other is hydroxy, C1 —5 alkanoyloxy, or -OCH2(OCH2)mOP{0)(OH)2; or H5 and Ft7 together form an oxo
`group; with the proviso that at least one of Ft‘, R2, R3, th 0r Ft? is -OCH2(OCH2),,,OP{0}(0HJ2; Ft‘t, R5, Ft“, m
`and p are as previously defined; or a pharmaceutically acceptable salt thereof.
`In compounds of formula (I), examples of Ft” include methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl.
`chloromethyl, 2,2,2-trichlomsthyl, Cyclopropyl, Cyclobutyl, cyclopentyl, Cyclohexyl. ethenyl, 2-propenyl,
`phenyl, benzyl, bromophenyl. 4-aminophenyl, 4-methylaminophenyl. 4-methylphenyl. 4-methoxyphenyl and
`the like. Examples of Ft" and Ft5
`include 2-propenyl,
`isobutenyl, 3-furanyl
`(3-furyl}, 3-thienyl, phenyl,
`naphthyl, thydroxyphenyl, 4wmethoxyphenyl, 4wtluorophenyl, +tritluoromethylphenyl, methyl. ethyl, n-pro-
`pyl, isopropyl. n-butyl,
`isobutyl, t-butyl, ethenyl, 2-propenyl, 2-propynyl, benzyl, phenethyl, phenyiethenyl,
`3,4-dimethoxyphenyl.
`2-turanyl
`(2-furyl),
`2-thienyl,
`2-(2-turanyl)ethenyl,
`2-methylpropyl,
`cyclopropyl,
`cyclobutyl, cyclopentyl, cyclohexyl. cyclohexylmethyl, cyclohexylethyl and the like,
`in which Ft5 is
`In one preferred embodiment, the present invention provides compounds of formula (I)
`C2-5alkenyl or -Z-F15 and Z and R5 are as previously defined. More preferably, F15
`is phenyl, 3-furyl, 3-
`thienyl, 2-propenyl, isobutenyl, 2-furyl, 2-thienyl, or Cs—acycloalkyl.
`in which case p is 1; or
`In another preferred embodiment Ft“ of compounds of formula {I} is C1—salkyl
`Flt is -Z-FtG and Z and Ft6 are as previously defined, and in which case p is 0. More preferably Ft‘t(0)p- is t-
`butoxy, phenyl. isopropyloxy. n-propyloxy, n-butoxy.
`In another preferred embodiment. the present invention provides compounds of formula (I) in which Ft1
`is -OCH2{00H2)MOP{0)(OH)2 In a more preferred embodiment, FF is hydroxy, -OCH2{OCH2}mOP{0}-{0H}2,
`or -OC(O)Ft". and Ft" is preferably 01-5 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 H2 is
`-OCH2(OCH2JmOP{O){OHJ2: R1 is hydroxy or -OC(O)OFt“: and R3 is hydrogen, hydroxy. acetoxy. -OCH2-
`(OCH2ImOP(O)(0H]2 or -OC(O)OFt"; and Ft* is as previously defined. In a more preferred embodiment Ft1 is
`hydroxy or -OC{O)OH" and Ft" is preferably 01-5 alkyl; and R3 is hydroxy or aoetoxy.
`
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`EPTUNE GENERICS EX. 1036 00006
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`EP0604910A1
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`In another preferred embodiment, the present invention provides compound of formula {I} in which R3 is
`-OGH2(OCH2)mOP{0}(OH)2; Ft1
`is hydroxy or -00(0}0Ft": Ft? is hydrogen, and Ft2 is hydrogen, hydroxy or
`-OC(0}OFt"; or RE is fluoro and H2 is hydrogen; and Fl" is as previously defined In a more preferred
`embodiment, Ft‘
`is hydroxy or -OC[O}OFt", and Pi"
`is preferably 01—6 alkyl.
`In another more preferred
`embodiment, H2 is hydroxy.
`In another preferred embodiment, m is D 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}-7-9-phosphonooxymethylpaclitaxel;
`(1] 7-9-phosphonooxymethylpaclitaxel,
`2‘-g-phosphon00xymethylpaclitaxel;
`(4} 2',7-bis-9-{phosphonooxymethy|}paclitaxel;
`(5} 3'-N-debenzoyI-3'-
`desphenyl-3'-N-{t-butyloxycarbonyl]-3'-{2-furyI]-2'-9-ethyloxycarbonyI-7-9-phosphonooxymethylpaclitaxel;
`(6}
`3'-N-debenzoyl-3'—desphenyl-3'-N-(t-butyloxycarbony|}-3'—(2-thienyl}-2‘-Q-ethy|oxycarbonyl-T—Q-
`phosphonooxymethylpaclitaxel;
`(7}
`10-desacetyl-3'-N-desbenzoyl-3'-N-(t-butyloxycarbonyl}-10-9-
`(phosphonooxymethyl}paclitaxel: (8} 2'-Q-phosphonooxymethoxymethylpacIitaxel 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-[OHln wherein
`T and n are as previously defined. The identity of T-[OH]n is not particularly limited so long as there is at
`least one reactive hydroxy group present on either the taxane moiety or the (313 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 G13 propanoyloxy backbone {eg the 2'-hydroxy group of paclitaxel} or to the
`taxane core framework (eg. the 7-hydroxy group of paciitaxel}: 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]... —I- T'u-[OCH2(OCH2}mSCH3]n
`
`(Aa)
`
`(B)
`
`T—[OCHzth2}mOP(O}(ORV}2]n
`(C)
`
`(A)
`
`In Scheme I T‘ is a taxane derivative in which non-reacting hydroxy groups have been blocked: FDr is a
`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'-[0H]n with dimethylsulfoxideracetic anhydride. or with dimethylsulfide and
`an organic peroxide. These reactions are discussed more fully in a subsequent sections
`The MTM ether having one intervening methyleneoxy unit {i.e. compounds of formula {3} where m = 1}
`may be prepared by several possible routes.
`In one a compound of formula {B} where rn = 0 is reacted
`with N-iodosuccinimide (NIS) and methylthiomethanol to extend the chain by one methyleneoxy unit
`
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`EP 0 604 910 A1
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`T—[ocrizscngn + n CHascHQ—OH
`
`
`"3
`
`T'—[0CH200H,sc1-i3]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 previde a compound of formula (B) in which m = 1.
`
`T'—[0']n
`
`+ nCHasCHrOCH2CI —- T‘—[OCH2OCHZSCH3]n
`
`(Ad)
`
`(AB)
`
`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
`(CICH200H2CI) with a stoichiometric am0unt or less (eg. about 0.8 equivalent} of sodium iodide followed
`by sodium thiomethoxide. 1,1'-Dichlorodimethyl ether is reported in Ind. J. Chem, 1989, 283, pp. 454456.
`In another method, a compound of formula (Aa) is reacted with bisiMTM1ether, CHascHzocHgsCHa.
`and NIS to give a compound of formula [B] in which in = 1.
`
`T'-[OH]" + n CH380H2 OCHQSCHg -" T"[00H2OCHQSCH3]n
`
`BistMTMlether is prepared by reacting 1,1‘-dichlorodimethy| 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 B.
`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 HOP(0}(OFIY}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 rem0ved 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 | is provided in Scheme II.
`
`Scheme II
`
`T'—[0H]n +
`
`n CH380H3{OCH2}mOP10}(ORY)2
`
`(Aa)
`
`(Ca)
`
`(C)
`
`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 methytthiomethanol with a base such as Na.
`
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`EP0604910A1
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`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 CH3$CH200H20I with a diprotected phosphate
`salt. eg. sodium. potassium, tetra(n-butyl)ammonium salts of dibenzyl phosphate; or CHaSGH20CHzC| 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 in is 1 may be prepared by treating
`ClCHzOCHgCI with sodium iodide followed by sodium thiomethoxide to provide CHaSCH20CH280Ha; this
`compound is then treated with NIS and a diprotected phosphate such as dibenzyl phosphate to give the
`desired products Any of the previously mentioned reagents having a MTM group may be extended one
`methyleneow 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 III.
`
`reacted with an
`
`is
`
`Scheme
`
`II
`
`T—[O'in
`
`+
`
`ICl-12{l£)(:H2)mOF’iOHOlFitli']2
`
`(Ad)
`
`(C)
`
`In Scheme III. the iodophosphate compound is obtained by reacting CICHziOCHzimCI with a diprotected
`phosphate salt to give GIGH2(OCH2)mOP{O){ORV}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.
`
`w
`
`p0,!
`
`~x
`
`l
`
`Ni
`
`0
`
`‘X
`
`+
`
`13-OH—txn —[OCH2(OCH2}mSCH3]n ——- (Ba)
`(D)
`
`In Scheme IV. m and n are as previously defined; X is a non-hydrogen group, P is a hydroxy protecting
`group; t><n 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 013 metal
`
`alkoxides of formula (D). An example of a compound of formula (D) is T-Q-methylthiomethylbaccatin lll:
`
`
`
`OH _.-"
`PhC(O)O-
`
`The coupling of the taxane (D) with the azetidinone is analogous to the one shown in Scheme VI, M1; 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) [Le a compound of formula (B) in which at least one of the MTM
`
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`group is linked directly or indirectly to the taxane moiety], if a compound of formula (D) is used in place of
`a compound of formula (II)
`in Scheme VI. The taxane {DJ
`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 comp0unds of fermula (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, Y-Q-MTM of paclitaxel
`tetrabutylammonium borohydride to give 7-0-MTM baccatin III.
`The general process of Scheme | 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‘} (Le. 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 (-0CtO}OFt");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.
`
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`figneme V
`
`R“ (oipcogn
`
`EP0604910A1
`
`o
`
`5'
`j AGO
`OCOPh
`
`H0
`
`ill
`a
`
`{la} SHEg/{Phcooiz
`or
`(lb) AchlDMSD
`
`(Ia)
`
`-
`
`{I13}
`
`Rab
`
`6b 1b
`13-.
`R
`
`R213
`
`
`
`R‘tinCONH o
`M
`
`R
`
`o'.....
`
`é
`= b
`R1
`
`
`:_
`1; A30
`H0
`OCOPh
`
`t2} HIS/HOMO) {ORY)2
`
`R‘ioipcogu
`
`“$0-----
`
`0
`
`RIC
`
`(Ic)
`
`i3i
`removal of phosphono protecting
`group and,
`if present, hydroxy protecting
`group
`
`R“ icipcowe
`
`o
`
`IRA/Lou“...
`
`In Scheme V, R13 is hydroxy. protected hydroxy, -OC(O)R" or -OC(O}OR"; Fig is hydrogen‘ and R23
`ishydrogen, hydr0xy, protected hydroxy. or
`-OC(O)0FP‘: or FF'
`is fluoro. and H23 is hydrogen:
`F138'
`is
`hydrogen. hydroxy, protected hydroxy, acetoxy. or -OC{O}OR"; one of F153 or Flm is hydrogen and the other
`is hydr0xy. protected hydroxy or 01-5 alkanoyloxy; or Fi°*a and Ft?" together form an oxo group; with the
`proviso that at least one of Ft”. Rea or R33, Ft"El or Fi”l
`is hydroxy. R“ is hydroxy. protected hydroxy,
`-OCH2SCH3. -OC(O)R" or -OC(O)OFP‘; Fig is hydrogen. and R2” is hydrogen hydroxy, protected hydroxy.
`-OCHgSCH3 or -OG(O)0H"; or R? is fluoro, and H2” is hydrogen; Fish is hydrogen, hydroxy, protected
`hydroxy, acetoxy, -OCH230H3 or -OC(OJOR"; one of R5” or R7” is hydrogen and the other is hydroxy.
`
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`EP 0 604 910 A1
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`protected hydroxy, 01—5 alkanoyloxy or -OCHzSCH3; or Heb and Ft?" together form an oxo group; with the
`proviso that at least one of Ft'“, Rab. R3“, RE" or Ft?” is -OCH230H3. Ft1C is hydroxy, protected hydroxy.
`-OCH20P(O](OH"']2,
`- OC(O]Ft" or -OC(O)0Ft"; Ft? is hydrogen, and R2“ ishydrogen, hydroxy, protected
`hydroxy, -OCH20P(O){ORV)2 or -OC(O)OFt"; or FF is fluoro, and R2” is hydrogen; F130 is hydrogen, hydroxy.
`protected hydroxy, acetoxy, -OCH20P{0)(OR"')2 or -OC(0)OR"; one of FI'S'c or FtFD is hydrogen and the other
`is hydroxy, protected hydroxy, Ci—a alkanoyloxy or -OCH2OP(O)(OH5‘}2; with the proviso that at least one of
`Ft“, R33, R3", Fifi" or Ft“ is -OCH20P(O)IORY)2. Ft‘is hydroxy, -OCH20P(O)(OH}2, - 00(01th or -OC(O)OFP‘;
`R2... is hydrogen, and H2" is hydrogen, hydroxy, -OCH20P(O){OH}2 or -OC(O}OR"; or H2... is fluoro, and R2"
`is hydrogen: R3'
`is hydrogen, hydroxy, acetoxy. -OCH20P(O)(OH)2 or -OC(0}OFP‘; one of R‘" or HT is
`hydrogen and the other is hydroxy. C1-Saikan0yioxy or -OCH2P[O){0H}2; with the proviso that at least one
`of Ft". R2", R3, F19 or FF“
`is -OCH20P[O)(OH}2.R‘, R5 and Fl" 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 (-OCH280H3} 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 1D-hydroxy group. it
`has been found that, surprisingly, the 7-hydroxy is more readily converted into the methylthiomethyl ether
`than the 2‘-hyclroxy group. The tertiary hydroxy group at (3-1 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 Ft'a and H23 are both hydroxy.
`the predominant
`methylthiomethylation product
`is the corresponding 7-g-methylthiomethyl ether.
`In order to obtain a
`compound of formula (lb) wherein Ft'b is methylthiomethoxy, without also converting the 7-hydroxy group, if
`present,
`into a methylthiomethyl ether,
`the T—hydroxy group is blocked with a conventional hydroxy
`protecting group such as triethylsilyl. Similarly, IO-methylthiomethyl ether may be obtained