EP1425261A2 - Procede de production d'ethers 4-amino-1-naphtol - Google Patents

Procede de production d'ethers 4-amino-1-naphtol

Info

Publication number
EP1425261A2
EP1425261A2 EP02797591A EP02797591A EP1425261A2 EP 1425261 A2 EP1425261 A2 EP 1425261A2 EP 02797591 A EP02797591 A EP 02797591A EP 02797591 A EP02797591 A EP 02797591A EP 1425261 A2 EP1425261 A2 EP 1425261A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
general formula
unsubstituted
haloalkyl
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02797591A
Other languages
German (de)
English (en)
Inventor
Joachim Komoschinski
Herbert Diehl
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Saltigo GmbH
Original Assignee
Bayer Chemicals AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE2001142461 external-priority patent/DE10142461A1/de
Priority claimed from DE2001154076 external-priority patent/DE10154076A1/de
Application filed by Bayer Chemicals AG filed Critical Bayer Chemicals AG
Publication of EP1425261A2 publication Critical patent/EP1425261A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08

Definitions

  • the present invention relates to a ner process for the preparation of 4-amino-1-naphthol ethers and new intermediates.
  • 4-Amino-1-naphthol ethers are valuable intermediates in the production of active pharmaceutical ingredients (see, for example, WO 00/43384; B. Bachman, J. Wetzel, J. Org. Chem., 11, 1946, pp. 454-462; R. Herbst, P. Johnson, J. Org. Chem. 17, 1952, pp. 693-697).
  • the e.g. from WO 00/43384 known synthetic route starts from 4-amino-1-naphthol hydrochloride and includes the conversion of the amine into a protected derivative, the alkylation of the hydroxy group and then the elimination of the protective group.
  • step a) of the nerfalirene according to the invention preference is given to using substituted or unsubstituted 1- ⁇ -phthols of the general formula (I)
  • R represents hydrogen, halogen or Ci-C 4 alkyl
  • R represents hydrogen, halogen, Ci-C 4 alkyl or C 1 -C 4 alkoxy and
  • n zero, one, two, three or four
  • R 4 each independently of one another for halogen, nitro, cyano, protected formyl, -Cs-alkyl, C 7 -C 10 arylalkyl, CrCs-hydroxyalkyl, -Cs-haloalkyl or C 6 -C 10 aryl or substituents of the general Formula (II),
  • D is absent or represents a -Cs alkylene radical
  • E represents a carbonyl group or sulfonyl group
  • F represents R ⁇ , OR 6 , NH 2 , SR 6 , NHR 6 or NR 6 R 7 ,
  • R and R each independently represent substituted or unsubstituted d-Cs-alkyl, CrCg-Halpgenalkyl, C 7 -C 12 arylalkyl or C 6 - C 10 aryl or
  • NR 6 R 7 as a whole represents a 5- to 8-membered heterocycle.
  • alkyl or alkylene each independently denotes a straight-chain, cyclic, branched or unbranched alkyl or alkylene radical. The same applies to the alkyl part of an arylalkyl radical.
  • Examples of -CC alkyl radicals are methyl, ethyl, n-propyl, isopropyl or n-butyl, for d-Cs-alkyl radicals also n-pentyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl and iso-octyl.
  • d-Cg-alkylene radicals examples are methylene, 1,1-ethylene, 1,2-ethylene, 1,2-
  • C 7 -C 12 arylalkyl radicals are benzyl or p-methylbenzyl.
  • C 1 -C 4 alkoxy radicals are methoxy, ethoxy, n-propoxy, iso-propoxy or n-butoxy.
  • aryl stands for both carbocyclic and heteroaromatic radicals in which none, one, two or three carbon atoms per cycle, but in the rest of at least one carbon atom, is substituted by heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.
  • carbocyclic aromatic radicals or heteroaromatic radicals can be substituted with up to five identical or different substituents per cycle, selected from the group bromine, chlorine, fluorine, nitro, cyano, free or protected formyl, dC 8 alkyl, d-Cs- Hydroxyalkyl or radicals of the general formula (II) with the meaning given there.
  • Carbocyclic, aromatic radicals or heteroaromatic radicals can, for example, be substituted or unsubstituted phenyl, pyridyl, imidazolyl, or pyrazolyl.
  • Halogen means fluorine, chlorine, bromine or iodine in the contexts mentioned.
  • Haloalkyl in the abovementioned contexts means in each case independently straight-chain, cyclic, branched or unbranched alkyl radicals which can be substituted by one, more or completely selected from the group fluorine, chlorine or bromine independently of one another by halogen atoms.
  • C 1 -C 8 haloalkyl radicals are trifluoromethyl, pentafluoroethyl, 2,2,2-
  • Trifluoroethyl, trichloromethyl or 2-chloroethyl Trifluoroethyl, trichloromethyl or 2-chloroethyl.
  • hydroxyalkyl in each case means independently straight-chain, cyclic, branched or unbranched alkyl radicals which are substituted with one or more hydroxy groups in such a way that each carbon atom of the radical carries at most one oxygen, sulfur or nitrogen atom.
  • d-Cs-hydroxyalkyl radicals are hydroxymethyl or 2-hydroxyethyl.
  • Protected formyl means a formyl radical which is protected by conversion into an aminal, acetal or a mixed aminal acetal, the aminals,
  • Acetals and mixed amino acetals can be acyclic or cyclic.
  • 5- to 8-membered heterocycle stands for heterocycles which, in addition to nitrogen, can also contain up to 3 further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur.
  • heterocycles are unsubstituted or substituted pyrrolidines, piperidines or morpholines.
  • step a) of the process according to the invention as substituted or unsubstituted 1-naphthols are those of the general formula (I) used in the
  • n zero, one or two
  • R 4 each independently of one another for halogen, nitro, cyano, dC 8 alkyl, C ⁇ -
  • E represents a carbonyl group or sulfonyl group and F represents R 6 , OR ⁇ , NH 2 , NHR 6 or NR 6 R 7 and where
  • 1-Naphthol is very particularly preferably used for step a).
  • step a) the substituted or unsubstituted 1-naphthols are optionally added in the presence of a base with reactive alkyl compounds
  • Reactive alkyl compounds are, for example, those compounds of the general formula (purple) or (IIIb),
  • R 1 represents C 3 -C 12 alkyl, C 2 -C 8 haloalkyl, C 7 -C 13 arylalkyl or substituents of the general formula (IN),
  • B represents ⁇ R 6 R 7 , SR 6 or OR 6 in which
  • R and R each independently represent substituted or unsubstituted dC 8 -alkyl, Ci-C 8 -haloalkyl, C -C 12 arylalkyl or C 6 -do-aryl or
  • NR R as a whole represents a 5- to 8-membered heterocycle
  • Y represents chlorine, bromine, iodine, or a sulfonate.
  • R 1 represents substituents of the general formula (IV) in which
  • A represents C 2 -C 4 alkylene or C 2 -C 4 haloalkylene
  • R and R each independently represent substituted or unsubstituted C 1 -C 4 alkyl or
  • NR 6 R 7 as a whole represents a 5- or 6-membered heterocycle
  • Y represents chlorine, bromine, iodine, methanesulfonate, tosylate or trifluoromethanesulfonate.
  • Such compounds of the general formula (purple) are very particularly preferably used as activated alkyl compounds in the
  • R represents substituents of the general formula (IV) in which
  • B represents NR 6 R 7 or OR 6
  • R and R each independently represent substituted or unsubstituted C 1 -C 4 alkyl or
  • NR R as a whole represents pyrrolidinyl, piperidinyl or morpholinyl and
  • Y represents chlorine, bromine or trifluoromethanesulfonate.
  • N- (2-chloroethyl) morpholine N- (2-bromoethyl) morpholine, N- (2-methanesulfonylethyl) morpholine, with N- (2-chloroethyl) morpholine being even more preferred ,
  • N- (2-chloroethyl) morpholine can preferably be used in the form of the hydrochloride.
  • the compounds of the general formulas (purple) or (IIIb) can, for example, in a molar ratio of 0.8 to 2.0 based on the substituted one used or unsubstituted 1-naphthol, a ratio of 0.9 to 1.5 is preferred, a ratio of 1.0 to 1.4 is very particularly preferred.
  • the conversion of the substituted or unsubstituted 1-Na ⁇ hthole to the 1-Naphtholether can e.g. in the presence of base in a suitable solvent at a suitable temperature.
  • Suitable bases are, for example, hydroxides, alcoholates, hydrides, amides, carbonates or hydrogen carbonates of alkali metals or alkaline earth metals or amines.
  • hydroxides or carbonates of the alkali metals are preferred, and sodium or potassium hydroxide or carbonate are particularly preferred.
  • Sodium hydroxide is very particularly preferred.
  • Alkali metal hydroxides are preferably used in the form of an aqueous solution with a proportion of 30 to 70% by weight of base, and a solution of 30 to 70% by weight sodium hydroxide in water is particularly preferred.
  • the amount of base can be, for example, between 0.8 and 5.0 equivalents based on the substituted or unsubstituted 1-naphthol used, preferably 0.9 to 1.5 equivalents, very particularly preferably 0.9 to 1.2 equivalents.
  • Suitable solvents for step a) of the process according to the invention are aliphatic or aromatic hydrocarbons such as toluene, xylene, or hexane, chlorinated hydrocarbons such as chlorobenzene or methylene chloride, ethers such as tetrahydrofuran or diethyl ether, alcohols such as for example methanol, ethanol or isopropanol, esters such as ethyl acetate or polar aprotic solvents such as dimethylformamide or dimethyl sulfoxide or mixtures of such solvents.
  • aliphatic or aromatic hydrocarbons such as toluene, xylene, or hexane
  • chlorinated hydrocarbons such as chlorobenzene or methylene chloride
  • ethers such as tetrahydrofuran or diethyl ether
  • alcohols such as for example methanol, ethanol or isopropanol
  • esters such as ethy
  • the reaction is preferably carried out in an alcohol.
  • Ethanol is very particularly preferred as solvent for step a).
  • the temperature for step a) can be chosen, for example, from 0 to 120 ° C., preferably from 20 to 80 ° C., particularly preferably from 40 to 80 ° C.
  • the pressure during the reaction is not critical, preferably at ambient pressure.
  • step a) for example, the substituted or unsubstituted 1-naphthol and as reactive alkyl compound, for example N- (2-chloroethyl) morpholine hydrochloride are introduced in ethanol and the sodium hydroxide at 40 to 60 ° C. as 30-70- % aqueous solution added.
  • reactive alkyl compound for example N- (2-chloroethyl) morpholine hydrochloride
  • R, R, R, R and n have the meanings given above with the preferred ranges mentioned.
  • the acylamination of electron-rich aromatics such as. of 1-methoxy-naphthalene is known from T. Cablewski et al, 1 Org. Chem., 1994, 59, pp. 5814-5817, but the process described there is only slightly regio-selective.
  • step b) the conversion of the 1-naphthol ether into 4-acylamino-1-naphthol ether is carried out, for example,
  • 1-naphthol ethers are reacted with a hydroxylammonium salt and a carboxylic acid in the presence of polyphosphoric acid.
  • polyphosphoric acid is understood to mean, for example, those polyphosphoric acids which have a content of more than 100% based on orthophosphoric acid.
  • a content of 100% to 300% is preferred, particularly preferably 100% to 150%.
  • Commercially available polyphosphoric acid with a content of 116% based on orthophosphoric acid is very particularly preferred.
  • the amount of polyphosphoric acid used can be, for example, 5 to 12 times, preferably 5 to 8 times, based on the molar ratio of the unsubstituted or substituted 1-naphthol ether used.
  • the molar amount of polyphosphoric acid is given based on the content based on orthophosphoric acid.
  • Suitable hydroxylammonium salts can be, for example, hydroxylamine hydrochloride, hydrogen sulfate or dihydrogen phosphate.
  • Hydroxylamine hydrochloride is preferred.
  • Suitable carboxylic acids are, for example, those of the general formula (VI)
  • Acetic acid, trifluoroacetic acid, propionic acid and their anhydrides are preferred; acetic acid, propionic acid and trifluoroacetic acid are particularly preferred. Acetic acid is even more preferred.
  • the amount of the carboxylic acid of the general formula (VI) used can be, for example, 0.8 to 20 times based on the molar ratio to the unsubstituted or substituted 1-naphthol ether used, preferably 1.0 to 3.0 times, more preferably preferably 1.2 to 1.5 times.
  • the temperature during the reaction can be, for example, 50 to 130 ° C., 70 to 120 ° C. are preferred.
  • the total reaction time can be, for example, 1 to 48 hours, preferably 2 to 10 hours, particularly preferably 5 to 8 hours.
  • step b) carboxylic acid, hydroxylammonium salt and polyphosphoric acid are introduced, and the 1-naphthol ether at a temperature between 70 and 90 ° C. over a period of 0.5 to
  • the work-up can preferably be carried out in such a way that the reaction mixture is brought together with ice and, if appropriate after addition of water, the pH is adjusted to a value of 9 to 10 with a base, preferably sodium hydroxide.
  • the temperature is preferably kept below 40 ° C, particularly preferably at 25 ° C or less.
  • R represents C -C 12 alkyl, C 2 -C 8 haloalkyl, C -C 13 arylalkyl or substituents of the general formula (IV),
  • R and R each independently represent substituted or unsubstituted dC 8 -alkyl, d-Cs-haloalkyl, C -Ci 2 -arylalkyl or C 6 -do-aryl or
  • R 2 for hydrogen, halogen or .
  • R 3 represents hydrogen, halogen, -CC 4 alkyl or dC 4 alkoxy and
  • n zero, one, two, three or four
  • R 4 each independently of one another for halogen, nitro, cyano, protected formyl, dC 8 alkyl, C 7 -C 10 arylalkyl, C 1 -C 8 -hydroxyalkyl, C 1 -C 8 haloalkyl or C 6 -do-aryl or substituents of the general formula (II),
  • D is absent or represents a dC 8 alkylene radical
  • E represents a carbonyl group or sulfonyl group
  • R 6 and R 7 each independently of one another are substituted or unsubstituted Ci-Cg-alkyl, d-Cs-haloalkyl, C 7 -C 12 - arylalkyl or C 6 -
  • C 10 aryl or NR R as a whole represents a 5- to 8-membered heterocycle
  • R s is dC 6 alkyl or C 1 -C 4 haloalkyl.
  • Examples of individual compounds are 4- (2- [l] -naphthyloxy- [4] -acetamino-ethyl) -morpholine, 4- (2- [l] -naphthyloxy- [4] -propionylamino-ethyl) -mo holin and 4
  • the compounds of the general formula (VIIa) can either be stored or reacted further.
  • the compounds of the general formula (VIIIa) are to be stored and R 1 also contains amine nitrogen, the compounds can also be converted into their analogous ammonium compounds.
  • Preferred acids H-An are mineral acids such as e.g. Sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tetrafluoroboric acid, hydrogen halides such as e.g. Hydrogen chloride, hydrogen bromide, carboxylic acids such as those of the general
  • the anions An are derived accordingly from the acids H-An.
  • step c) the 4-acylamino-1-naphthol ethers can be converted into the corresponding 4-
  • Amino-1-naphthol ether are transferred.
  • This step can be carried out analogously to the literature (e.g. to B. Bachman, J. Wetzel, J. Org. Chem., 11, 1946, pp. 454-462), for example by acidic or alkaline acyl group elimination, saponification with an acid is preferred , where the 4-amino-1-naphthol ether in the form of their ammonium salts attack.
  • radicals R 1 which contain amine nitrogen
  • the 4-amino-1-naphthol ethers are obtained in the form of the diammonium salts.
  • suitable acids are those which have a pKa of 2 or less.
  • these are hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic sulfonic acids such as methanesulfonic acid or mixtures of such acids.
  • Hydrochloric acid and sulfuric acid are preferred, and concentrated hydrochloric acid is very particularly preferred.
  • X stands for an anion of an acid. If the radical R 1 has amine nitrogen, the formula (VIIIb) also includes its ammonium salts.
  • Vlla The compounds of the general formulas (Vlla), (VHb), (Villa) and (Vlllb) are particularly suitable for use in a process for the preparation of medicaments.
  • the process according to the invention is characterized in particular by the fact that it uses the inexpensive 1-naphthols as starting substances and leads selectively to the desired 4-amino-1-naphthol ethers or their ammonium salts in high yields in a few steps.
  • the salt formed is filtered off and washed with ethanol.
  • the combined filtrates are evaporated to dryness on a rotary evaporator in the bath and 10 mbar at 80 ° C.
  • the cooled residue is dissolved in 1200 ml of diethyl ether and first with 180 ml of water, then twice with 450 ml of 5% sodium hydroxide solution and finally twice The Etheiphase is dried with sodium sulfate and concentrated to dryness at 60 ° C and 10 mbar.
  • the filter cake is suspended in 10 liters of water and dissolved with heating to 90 ° C.
  • the solution is clarified with activated carbon.
  • 530 g of 50% sodium hydroxide solution are added with stirring in 1 h until a pH of 10 is reached.
  • Crystal suspension is filtered off at 50 ° C and the filter cake washed neutral with plenty of water. The filter cake is then dried in a vacuum drying cabinet.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé pour produire des éthers 4-amino-1-naphtol, selon lequel on produit d'abord des éthers de naphtol à partir de 1-naphtols, puis ces éthers de naphtol sont transformés en éthers 4-acétamino-1-naphtol correspondants, et ensuite, le groupe acyle est séparé. La présente invention porte également sur des éthers 4-acétamino-1-naphtol.
EP02797591A 2001-08-31 2002-08-19 Procede de production d'ethers 4-amino-1-naphtol Withdrawn EP1425261A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE10142461 2001-08-31
DE2001142461 DE10142461A1 (de) 2001-08-31 2001-08-31 Verfahren zur Herstellung von 4-Amino-1-naphtolethem
DE2001154076 DE10154076A1 (de) 2001-11-02 2001-11-02 Verfahren zur Herstellung von 4-Amino-1-naphtholethern
DE10154076 2001-11-02
PCT/EP2002/009242 WO2003020686A2 (fr) 2001-08-31 2002-08-19 Procede de production d'ethers 4-amino-1-naphtol

Publications (1)

Publication Number Publication Date
EP1425261A2 true EP1425261A2 (fr) 2004-06-09

Family

ID=26010026

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02797591A Withdrawn EP1425261A2 (fr) 2001-08-31 2002-08-19 Procede de production d'ethers 4-amino-1-naphtol

Country Status (5)

Country Link
US (2) US6964963B2 (fr)
EP (1) EP1425261A2 (fr)
CN (1) CN1315781C (fr)
AU (1) AU2002333464A1 (fr)
WO (1) WO2003020686A2 (fr)

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE827951C (de) * 1949-07-29 1952-01-14 Bayer Ag Verfahren zur Herstellung von Alkyloxy-amino-acylamino-naphthalinen
US3933913A (en) * 1971-06-01 1976-01-20 Smithkline Corporation N,N'-bis[3-substituted-4-hydroxypheyl)-2-hydroxyethyl)]-polymethylenediamines
DE2235597A1 (de) * 1972-07-20 1974-01-31 Boehringer Mannheim Gmbh 1-eckige klammer auf 3-(5,6,7,8tetrahydronaphth-1-yl-oxy) -propyl eckige klammer zu -piperazin-derivate und verfahren zu ihrer herstellung
FR2387971A1 (fr) * 1977-04-19 1978-11-17 Delalande Sa Nouvelles trimethoxy cinnamoyles piperazines, leur procede de preparation et leur application en therapeutique
WO1994001394A1 (fr) * 1992-07-02 1994-01-20 Commonwealth Scientific And Industrial Research Organisation Preparation d'amides n-aryle
JPH11180966A (ja) * 1997-09-09 1999-07-06 Sankyo Co Ltd アゾール誘導体
UA73492C2 (en) * 1999-01-19 2005-08-15 Aromatic heterocyclic compounds as antiinflammatory agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03020686A3 *

Also Published As

Publication number Publication date
CN1547568A (zh) 2004-11-17
US20030083525A1 (en) 2003-05-01
WO2003020686A2 (fr) 2003-03-13
US20050261498A1 (en) 2005-11-24
AU2002333464A1 (en) 2003-03-18
WO2003020686A3 (fr) 2003-12-04
US6964963B2 (en) 2005-11-15
CN1315781C (zh) 2007-05-16

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