US20050267141A1 - Process to prepare camptothecin derivatives - Google Patents

Process to prepare camptothecin derivatives Download PDF

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US20050267141A1
US20050267141A1 US10/857,170 US85717004A US2005267141A1 US 20050267141 A1 US20050267141 A1 US 20050267141A1 US 85717004 A US85717004 A US 85717004A US 2005267141 A1 US2005267141 A1 US 2005267141A1
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formula
compound
phosgene
amine
solution
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Ragina Naidu
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Innovational Holdings LLC
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Phytogen Life Sciences Inc
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Assigned to PHYTOGEN LIFE SCIENCES INC. reassignment PHYTOGEN LIFE SCIENCES INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NAIDU, RAGINA
Priority to CNA200580017283XA priority patent/CN101022805A/zh
Priority to EP05756335A priority patent/EP1791539B2/en
Priority to DE602005016282T priority patent/DE602005016282D1/de
Priority to PCT/US2005/018793 priority patent/WO2005117879A1/en
Priority to AT05756335T priority patent/ATE440605T1/de
Priority to CA002568523A priority patent/CA2568523A1/en
Priority to TW094117529A priority patent/TW200607810A/zh
Priority to US11/628,055 priority patent/US8592588B2/en
Publication of US20050267141A1 publication Critical patent/US20050267141A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to improved processes to prepare camptothecin derivatives, such as irinotecan, in a one-pot operation.
  • Camptothecin 1 (shown in FIG. 1A ) is a pentacyclic alkaloid that was isolated by Wall et al. in the early 1960s from the Chinese tree, Camptotheca acuminate (Nyssaceae).
  • the compound raised immediate interest as a potential cancer chemotherapeutic agent due to its impressive activity against a variety of tumors.
  • camptothecin as an anti-cancer agent was its poor solubility in water.
  • the sodium salt was synthesized by hydrolysis of the lactone ring. The sodium salt forms an equilibrium with the ring-closed lactone form. As its sodium salt, camptothecin was moved to clinical trials and promising activity was initially observed. However severe side effects and drug-related toxicities finally led to discontinuation of the clinical program.
  • Second-generation camptothecin derivatives have been optimized for improved water solubility to facilitate intravenous drug administration. Highlights resulting from various programs at different companies and institutions are irinotecan 2 and topotecan 3, two compounds which are successfully used in clinical practice, and SN-38 4, exatecan 5, liposomal lurtotecan 6 (OSI-211) and CKD-602 7, which are in advanced stages of clinical development. The chemical structures of these compounds are shown in FIGS. 1A and 1B .
  • SN-38 is a camptothecin derivative that contains a hydroxyl group at the C10 position and an ethyl group at the C7 position.
  • Irinotecan is a camptothecin derivative (it may also be viewed as a derivative of SN-38) that contains a sidechain at the C10 position and an ethyl group at the C7 position.
  • Irinotecan was discovered at Yakult Honsha and was first approved in Japan in 1994 (Camptotesin®) for lung, cervical and ovarian cancer. Today it is marketed in the U.S. by Pharmacia (Camptosar®) and by Aventis in Europe (Campto®).
  • Irinotecan is a prodrug which is cleaved in vivo by carboxylic esterases, particularly by hCE-2, to release the active metabolite SN-38.
  • irinotecan has been described in the chemical literature and in patents.
  • a common approach to the synthesis of irinotecan is to form SN-38 and then add a sidechain to the C10 position of SN-38, to thereby form irinotecan.
  • U.S. Pat. No. 4,604,463 is one example of a patent that describes this approach, wherein either an activated form of the sidechain is separately formed and then reacted with SN-38, or the C10 hydroxyl group is activated and then in a separate reaction the sidechain is added.
  • the present invention is related to improved processes to prepare camptothecin derivatives, such as irinotecan, in a one-pot operation.
  • a process for adding a sidechain to a starting material comprising reacting together: (i) a compound of formula I: wherein each of the ring atoms may be carbon, or any one, two or three of the ring atoms may be nitrogen, and R a , R b and R c are the same or different and independently represent one or more optional non-hydrogen substituents on each of rings A, B and C; (ii) an amine of formula R 1 R 2 NH wherein R 1 and R 2 are the same or different and independently represent organic groups; and (iii) phosgene or a reactive equivalent thereof, to provide a solution comprising a compound of formula III:
  • the phosgene or reactive equivalent thereof and the amine of formula R 1 R 2 NH are combined to provide an intermediate solution, and the compound of formula I is added to the intermediate solution.
  • the process further comprises adding pyridine or a tertiary amine to the intermediate solution along with the compound of formula I.
  • the process further comprises a step wherein the solution comprising a compound of formula III is filtered and then freed from solvent to provide a residue.
  • the residue is purified by column chromatography, filtration, precipitation or crystallization.
  • the compound of formula I is SN-38
  • the amine of formula R 1 R 2 NH is piperidinopiperidine
  • the compound of formula III is irinotecan
  • the process is a one-pot operation.
  • the phosgene or reactive equivalent thereof is phosgene trihydrate
  • the phosgene trihydrate and piperidinopiperidine are combined in a solvent and allowed to react together to form an intermediate solution
  • the SN-38 and an organic base are added to the intermediate solution to form the solution comprising irinotecan.
  • the phosgene trihydrate is dissolved in a chlorinated solvent and then cooled to a temperature in the range of ⁇ 40° C. to 25° C. followed by addition of piperidinopiperidine to the cooled solution. More particularly, the phosgene trihydrate is cooled to a temperature in the range of ⁇ 10° C. to 0° C.
  • the present invention provides a composition comprising a solvent and the reaction product of: (i) a compound of formula I: wherein each of the ring atoms may be carbon, or any one, two or three of the ring atoms may be nitrogen, and R a , R b and R c are the same or different and independently represent one or more optional non-hydrogen substituents on each of rings A, B and C, (ii) an amine of formula R 1 R 2 NH wherein R 1 and R 2 are the same or different and independently represent organic groups, and (iii) phosgene or a reactive equivalent thereof.
  • FIGS. 1A and 1B show the chemical structures of camptothecin 1 and various analogs and derivatives of camptothecin, specifically, irinotecan 2, topotecan 3, SN-38 4, exatecan 5, lurtotecan 6 and CKD-602 7.
  • Alkyl refers to a hydrocarbon structure having from 1 to 14 carbon atoms, wherein the carbons are arranged in a linear, branched, or cyclic manner, including combinations thereof.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl and the like.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 14 carbon atoms.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, norbornyl, adamantyl and the like.
  • alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; propyl includes n-propyl and isopropyl.
  • Alkenyl refers to an alkyl group having at least one site of unsaturation, i.e., at least one double bond.
  • Alkynyl refers to an alkyl group having at least one triple bond between adjacent carbon atoms.
  • Alkoxy and “alkoxyl” both refer to moieties of the formula —O-alkyl. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to six carbons.
  • aryloxy refers to moieties of the formula —O-aryl.
  • Alkanediyl means a divalent alkyl from which two hydrogen atoms are taken from the same, or different, carbon atoms, such as —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH(CH 3 )CH 2 —, and the like.
  • “Acyl” refers to moieties of the formula —C( ⁇ O)-alkyl. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to six carbons.
  • Aryl refers to an aromatic carbocyclic moiety such as phenyl or naphthyl.
  • Heteroalkyl is a monovalent, saturated or unsaturated, straight or branched, chain containing carbon and at least one heteroatom.
  • the heteroalkyl group may, in various embodiments, have one heteroatom, or 1-2 heteroatoms, or 1-3 heteroatoms, or 1-4 heteroatoms.
  • Heteroalkyl chains may contain from 1 to 14 (i.e., 1-14) member atoms (carbon and heteroatoms) in the chain, and in various embodiments contain 1-12, or 1-6, or 1-4 member atoms.
  • the heteroalkyl group has zero branches (i.e., is a straight chain), one branch, two branches, or more than two branches.
  • the heteroalkyl group is saturated.
  • the heteroalkyl group is unsaturated.
  • the unsaturated heteroalkyl may have one double bond, two double bonds, more than two double bonds, and/or one triple bond, two triple bonds, or more than two triple bonds.
  • Heteroaryl refers to a 5- or 6-membered heteroaromatic ring containing 1-3 heteroatoms selected from O, N, or S; a bicyclic 9- or 10-membered heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S; or a tricyclic 13- or 14-membered heteroaromatic ring system containing 0-3 heteroatoms selected from O, N, or S.
  • Exemplary aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Heterocycle means a 5- to 7-membered monocyclic, or 7- to 10-membered bicyclic, heterocyclic ring which is either saturated, unsaturated, or aromatic, and which contains from 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized, including bicyclic rings in which any of the above heterocycles are fused to a benzene ring.
  • the heterocycle may be attached via any heteroatom or carbon atom.
  • Heterocycles include heteroaryls as defined above.
  • heterocycles also include morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydroprimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.
  • substituted means any of the above groups (e.g., alkyl, alkoxy, acyl, aryl, heteroalkyl, heteroaryl and heterocycle) wherein at least one hydrogen atom is replaced with a substituent.
  • substituents e.g., alkyl, alkoxy, acyl, aryl, heteroalkyl, heteroaryl and heterocycle
  • ⁇ O oxo substituent
  • Substituents include halogen, hydroxy, oxo, alkyl, substituted alkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, —NR a R b , —NR a C( ⁇ O)R b , —NR c C( ⁇ O)NR a R b , —NR a C( ⁇ O)OR b , —NR a SO 2 R b , —OR a , —C( ⁇ O)R a , C( ⁇ O)OR a , —C( ⁇ O)NR a R b , —OC( ⁇ O)R a , —OC( ⁇ O)OR a , —OC( ⁇ O)NR a R b , —NR a SO 2 R b , or a radical of the formula —Y-Z-R a where Y is
  • Forml refers to the moiety —C( ⁇ O)H.
  • Halogen refers to fluoro, chloro, bromo or iodo.
  • the present invention provides synthetic methods and compounds produced by, or using, the synthetic methods.
  • the compounds are useful as synthetic intermediates in the preparation of derivatives and analogs of irinotecan, where the synthetic intermediates may also have desirable biological activity.
  • the present invention provides a process for adding a sidechain to a starting material, comprising reacting together:
  • each of the ring atoms may be carbon, as shown, or any one, two or three of the ring atoms may be nitrogen, and R a , R b and R c are the same or different and independently represent one or more optional non-hydrogen substituents on each of rings A, B and C, respectively,
  • each of the ring atoms is shown as carbon. However, this depiction is for purposes of illustration only, and is intended to encompass compounds which, in addition to being carbocyclic may have, with one exception, any one, two or three of the ring atoms replaced with nitrogen. The one exception is that the ring atom at the C10 position must be carbon.
  • one of the ring carbon atoms is replaced with nitrogen and representative compounds of formula I have the following structures:
  • three of the ring carbon atoms may be replaced with nitrogen.
  • any three carbon atoms except the carbon atom at the C10 position may be replaced with nitrogen.
  • formula I only the ring atom at the C10 position is specifically shown to be substituted with a non-hydrogen substituent.
  • formula I is defined herein to encompass compounds wherein any one or more of the A, B and C rings may be substituted with one or more optional non-hydrogen substituents. This feature of the compounds of formula I is shown by the designations R a , R b and R c , where R a represents one or more optional non-hydrogen substituents on the A ring, and R b and R c have analogous definitions for the B and C rings, respectively.
  • formula I is defined herein to encompass compounds wherein two R a substituents, two R b substituents and/or two R c substitutents, together with the ring atoms to which they are attached, may optionally be joined together to form a carbocyclic or heterocyclic ring.
  • R a , R b and R c have, in total, no more than 30 carbon atoms and no more than 5 oxygen atoms.
  • R a , R b and R c groups include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, substituted acyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, formyl and halogen.
  • R a substituents are present, i.e., the A ring has no substitutions beyond the hydroxy group at the C10 position.
  • R b represents an alkyl group at the C7 position as the only optional substituent on the B ring.
  • R c represents two optional substituents on the C ring which are joined together, in particular, R c represents the well-known D and E rings of SN-38, i.e., the compound of formula I is substituted with D and E rings as shown below:
  • the starting material used in the process of the present invention has the formula II, as follows: wherein R 3 is hydrogen or an alkyl group, and each of the ring atoms is carbon or nitrogen as shown. In one aspect, R 3 is ethyl. In another aspect, R 3 is hydrogen. In another aspect, R 3 is a C 1 -C 6 alkyl group.
  • the compounds of formula II are particularly similar to SN-38, and thus are a typical starting material. However, the process of the present invention is more generally applicable to compounds of formula I. Amine of Formula R 1 R 2 NH
  • a second reactant in the process of the present invention is an amine of the formula R 1 R 2 NH.
  • groups R 1 and R 2 represent organic groups, where in various embodiments of the invention, R 1 and R 2 have, in total, less than 20 non-hydrogen atoms, or less than 15 non-hydrogen atoms.
  • R 1 and R 2 groups include alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, substituted acyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle.
  • the R 1 and R 2 groups may be separate from one another, e.g., as in the structures: or the R 1 and R 2 groups may be joined together, e.g., as in the structures:
  • heterocyclic ring that is thereby formed may optionally be substituted, e.g., as in the structures:
  • An amine of the structure is a typical compound of formula R 1 R 2 NH according to the present invention because this amine duplicates the sidechain present in irinotecan. Phosgene or a Reactive Equivalent Thereof
  • the third reactant that is employed in the process of the invention is phosgene or a reactive equivalent thereof.
  • reactive equivalents of phosgene include phosgene dimer (also known as trichloromethyl chloroformate or diphosgene), phosgene trimer (also known as triphosgene or bistrichloromethyl carbonate), carbonyldiimidazole and a combination of di-tert-butyl carbonate (DIBOC) with 4-(N,N-dimethylamino)pyridine (DMAP).
  • Phosgene and the reactive equivalents thereof may be in solid (e.g., phosgene trihydrate), liquid or gaseous form.
  • a compound of formula I a compound of formula R 1 R 2 NH, and phosgene or a reactive equivalent thereof are reacted. These three reactants are combined in a single reaction vessel.
  • the order of addition is not critical.
  • the phosgene compound is added to the vessel, followed by addition of the R 1 R 2 NH compound, followed by addition of the formula I compound.
  • other orders of combination may also be employed.
  • a solvent will also typically be present in the reaction vessel.
  • exemplary solvents include halogenated solvents (e.g., dichloromethane and chloroform), ethereal solvents (e.g., diethyl ether and tetrahydrofuran), and glymes.
  • a base is also typically present.
  • the base is thought to act by activating the hydroxy group at the C10 position of the compound of formula I so that it is more reactive and will convert to the desired sidechain moiety.
  • the base is a nitrogen-containing compound, e.g., pyridine, DABCO, tertiary amines and the like.
  • a catalytic amount of a condensing agent can also be added, such as DMAP or DCC and the like.
  • the reaction temperature is typically between about ⁇ 25° C. and +25° C., however other temperatures may be employed.
  • the temperature primarily affects the rate of reaction, and may be adjusted to achieve a reaction rate that is convenient for the operator.
  • the reaction may be conducted under an inert atmosphere, e.g., nitrogen or argon.
  • the reaction vessel contents are typically stirred or otherwise agitated.
  • the compound of formula 1 and the amine of formula R 1 R 2 NH are, respectively, SN-38, having the following structure: piperidinopiperidine, having the structure:
  • the product mixture obtained by combining a compound of formula I, a compound of formula R 1 R 2 NH, and phosgene or reactive equivalent thereof may be subjected to a purification scheme to obtain a compound of formula III in relatively pure form.
  • the product mixture may be filtered and the supernatant subjected to a solvent removal process (e.g., rotary evaporation).
  • the residue may then be further purified by column chromatography, precipitation or crystallization.
  • the residue may be dissolved in a solvent, e.g., dichloromethane, and applied to a silica gel column. Elution with a gradient or mixture of dichloromethane and methanol affords a purified compound of formula III.
  • the process of the present invention wherein a sidechain is added to a compound of formula I is very efficient.
  • This one-pot procedure may yield a final product of formula III in greater than 50% molar yield, based on the moles of compound of formula I employed.
  • the molar yield is greater than 75% based on the moles of compound of formula I used in the process.
  • the molar yield is greater than 90% based on the moles of compound of formula I used in the process.
  • the molar yield is 94% based on the moles of compound of formula I used in the process.
  • a further embodiment of the present invention provides a purification process for the product wherein the product is converted into a salt form.
  • a purification process includes combining a product mixture comprising a nitrogen-containing compound (e.g., irinotecan) with a chlorinated solvent (e.g., dichloromethane (DCM)) or an aqueous solvent (e.g., water) and cooling this mixture to about 0° C.
  • a chlorinated solvent e.g., dichloromethane (DCM)
  • aqueous solvent e.g., water
  • the solvent is evaporated to leave a solid residue which is dissolved in an alcoholic solvent (e.g., ethanol or methanol) and precipitated by addition of an ether solvent (e.g., diethyl ether). The precipitate is washed with the ether solvent to afford the pure salt.
  • an alcoholic solvent e.g., ethanol or methanol
  • an ether solvent e.g., diethyl ether
  • Phosgene trihydrate was dissolved in a chlorinated solvent, such as DCM under an argon atmosphere and cooled down to a low temperature in the range of ⁇ 10 to 0° C.
  • a chlorinated solvent such as DCM
  • To this solution was added sequentially, piperidinopiperidine in DCM drop wise, followed by the addition of N,N-diisopropylethylamine (Hünig's base) or TEA drop wise.
  • the reaction mixture was stirred at this temperature for one hour and slowly warmed to around room temperature and kept at this temperature for 2 hours.
  • the reaction was filtered and concentrated under vacuum to get the crude product.
  • the crude product was dissolved in DCM and washed with water, dried over anhydrous Na 2 SO 4 or MgSO 4 and evaporated.
  • This material was purified either by column chromatography using silica gel and eluted with mixture of DCM/MeOH or precipitation or crystallization to obtain the pure product, namely, irinotecan (i.e., the compound of formula III-A).
  • the yield of the desired product is 94%.
  • Example 2 The product from Example 1 was dissolved in DCM and cooled down to 0° C. 12N HCl was added drop wise to this solution and stirred for 2-3 hours. The solvent was evaporated to get a solid which was dissolved in methanol and precipitated by addition of diethyl ether. The precipitate is washed by ether 3 times to afford the pure product, namely, the salt form of irinotecan (i.e., the compound of formula III-A). The yield of the desired product is quantitative.
  • Example 1 the product from Example 1 is dissolved in water and 12N HCl is added drop wise to the solution. The product precipitates out and is obtained by filtration. The yield is 95%.

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US10/857,170 US20050267141A1 (en) 2004-05-28 2004-05-28 Process to prepare camptothecin derivatives
US11/628,055 US8592588B2 (en) 2004-05-28 2005-05-27 Process to prepare camptothecin derivatives
TW094117529A TW200607810A (en) 2004-05-28 2005-05-27 Process to prepare camptothecin derivatives
AT05756335T ATE440605T1 (de) 2004-05-28 2005-05-27 Verfahren zur herstellung von camptothecin- derivaten
EP05756335A EP1791539B2 (en) 2004-05-28 2005-05-27 Process to prepare camptothecin derivatives
DE602005016282T DE602005016282D1 (de) 2004-05-28 2005-05-27 Verfahren zur herstellung von camptothecin-derivaten
PCT/US2005/018793 WO2005117879A1 (en) 2004-05-28 2005-05-27 Process to prepare camptothecin derivatives
CNA200580017283XA CN101022805A (zh) 2004-05-28 2005-05-27 制备喜树碱衍生物的方法
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US20050267141A1 (en) 2004-05-28 2005-12-01 Phytogen Life Sciences Inc. Process to prepare camptothecin derivatives
US20050272757A1 (en) * 2004-06-04 2005-12-08 Phytogen Life Sciences Inc. Process to prepare camptothecin derivatives and novel intermediate and compounds thereof
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EP1791539B1 (en) 2009-08-26
CA2568523A1 (en) 2005-12-15
EP1791539A1 (en) 2007-06-06
US20080280935A1 (en) 2008-11-13
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WO2005117879A1 (en) 2005-12-15
CN101022805A (zh) 2007-08-22

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