EP1133507A2 - Benzyllactobionamide als inhibitoren der proliferation von glatten muskelzellen - Google Patents
Benzyllactobionamide als inhibitoren der proliferation von glatten muskelzellenInfo
- Publication number
- EP1133507A2 EP1133507A2 EP99944107A EP99944107A EP1133507A2 EP 1133507 A2 EP1133507 A2 EP 1133507A2 EP 99944107 A EP99944107 A EP 99944107A EP 99944107 A EP99944107 A EP 99944107A EP 1133507 A2 EP1133507 A2 EP 1133507A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- carbon atoms
- alkyl
- hydrogen
- acyl
- pharmaceutically acceptable
- 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- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Definitions
- This invention relates to the use of substituted benzyllactobionamides as smooth muscle cell proliferation inhibitors and as therapeutic compositions for treating diseases and conditions which are characterized by excessive smooth muscle proliferation such as restenosis.
- glycosaminoglycans heparin and heparan sulfate are endogenous inhibitors of SMC proliferation, yet are able to promote endothelial cell growth (Castellot, J.J. Jr.; Wright, T. C; Karnovsky, M.J. Seminars in Thrombosis and Hemostasis 1987, 13, 489).
- heparin, heparin fragments, chemically modified heparin, low molecular weight heparins, and other heparin mimicking anionic polysaccharides may be compromised due to other pharmacological liabilities (excessive bleeding arising from anticoagulation effects, in particular) coupled with heterogeneity of the various preparations (Borman, S. Chemical and Engineering News, 1993, June 28, 27).
- US 5,296,588, US 5,336,765, and EP 550106A1 describe an improved process of preparing N-substituted aldonamides.
- US 5,310,542 and EP 551675-A1 also describe glycosides (specifically aldobionamides) being used in oral hygiene compositions to act as antimicrobial agents and inhibit formation and/or growth of bacteria responsible for dental plaque.
- US 2,752,334 describes a process of preparing N-substituted lactobionamides and their use as emulsifying agents (specially for cheese) and antimycotic agents.
- the compounds of the present invention differ in that the compounds of this invention (a) are acetylated or sulfated benzyllactobionamides, (b) have substituents on the aromatic core that are different, and (c) are being used as smooth muscle cell antiproliferatives.
- EP 312086 A2 and EP 312087 A2 describe polysulfate ester(s) of bis-aldonic acid amide derivatives as antiinflammatory and antithrombotic agents.
- the compounds of the present invention differ in that the compounds (a) are being used as smooth muscle cell antiproliferatives, (b) are not dimeric in nature, and (c) contain no more than two contiguous sugar residues (disaccharide).
- the compounds of the present invention differ in that the compounds (a) have substituents on the aromatic core that are different, (b) are not substituted at the benzylic position, (c) are being used as smooth muscle cell antiproliferatives, and (d) are not used as precursors to pyrazoles.
- US 5,498,775, WO 96/14324, and US 5,464,827 describe polyanionic benzylglycosides or cylcodextrins as smooth muscle cell proliferation inhibitors for treating diseases and conditions that are characterized by excessive smooth muscle proliferation.
- ⁇ -Cyclodextrin tetradecasulfate has been described as a smooth muscle cell proliferation inhibitor and as an effective inhibitor of restenosis (Reilly, C F.; Fujita, T.; McFall, R. C; Stabilito, 1. 1.; Wai-si E.; Johnson, R. G. Drug Development Research 1993, 29, 137).
- US 5019562 discloses anionic derivatives of cyclodextrins for treating pathological conditions associated with undesirable cell or tissue growth.
- WO 93/09790 discloses antiproliferative polyanionic derivatives of cyclodextrins bearing at least 2 anionic residues per carbohydrate residues.
- Wetsberger (EP 312087 A2 and EP 312086 A2) describes the antithrombotic and anticoagulant properties of sulfated bis-aldonic acid amides.
- US 4431637 discloses polysulfated phenolic glycosides as modulators of the complement system.
- the compounds of the present invention differ from all of the prior art in that the compounds (a) are benzyllactobionamides which bear no structural resemblance to heparin or sulfated cyclodextrins, (b) are compounds which are not dimeric in nature, (c) contain no more than two contiguous sugar residues (disaccharide), and (d) are of defined structure.
- WO 9614325 discloses acylated benzylglycosides as smooth muscle cell proliferation inhibitors.
- the compounds of the present invention differ in that (a) the saccharide backbone is different, (b) the open chain core has preparation advantages over the cyclic array, and (c) the substituents on the carbohydrate backbone are different.
- This invention provides benzyllactobionamides of formula I
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each, independently, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 3- 7 carbon atoms, trifluoromethylacyl of 3-8 carbon atoms, benzoyl, or -SO 3 H;
- R 9 is hydrogen, CN, NO 2 , halo, CF 3 , alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms;
- R 10 is hydrogen.
- Z is O or S
- R 11 is an ⁇ -amino acid in which the ⁇ carboxyl group forms an amide with the nitrogen of R 10 , wherein if said amino acid is glutamic acid or aspartic acid, the non- ⁇ carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms;
- R 12 is hydrogen. CN. NO,, halo, CF 3 , alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or benzoyl;
- R 13 is hydrogen, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 3-7 carbon atoms, trifluoromethylacyl of 3- 8 carbon atoms, or benzoyl; or a pharmaceutically acceptable salt thereof.
- Alkyl includes both straight chain as well as branched moieties. Halogen means bromine, chlorine, fluorine, and iodine.
- R 11 is an ⁇ -amino acid
- the carboxyl moiety exists as an amide with the amide nitrogen being bonded to the phenyl ring of the compound of formula I.
- the following exemplifies the resulting structure when R 11 is alanine:
- the amino acid contains a second carboxyl moiety
- the moiety is an alkyl ester of the free acid.
- the following example shows aspartic acid methyl ester.
- Preferred amino acids include alanine, arginine, aspartic acid, cystine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
- the amino acids defined by R 11 include both the D and L amino acids.
- salts can be formed from organic and inorganic acids, for example, acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.
- Salts may also be formed from organic and inorganic bases, preferably alkali metal salts, for example, sodium, lithium, or potassium.
- Acid addition salts can be prepared when a compound of this invention contains a basic nitrogen, and base addition salts can typically be prepared when the compound of formula I contains a -SO 3 H moiety.
- the compounds of this invention may contain an asymmetric carbon atom or sulfoxide moiety and some of the compounds of this invention may contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers. While shown without respect to stereochemistry in Formula I, the present invention includes such optical isomers and diastereomers; as well as the racemic and resolved, enantiomerically pure R and S stereoisomers; as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof.
- Preferred compounds of this invention are benzyllactobionamides of formula I
- R 1 , R 2 , R 3 , R 4 , R 5 , R ⁇ , R 7 , and R 8 are each, independently, acyl of 2-7 carbon atoms or -SO 3 H;
- R 9 is hydrogen, CN, NO 2 , halo, CF 3 , alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms;
- R 10 is hydrogen, -NO 2 , -NHR 11 , -NHR 13 , -N(R 13 ) 2 , -NCH 3 R 13 , -NHCO 2 alkyl, wherein the alkyl moiety contains 1-6 carbon atoms, alkylsulfonamide of 1 to 4 carbon atoms,
- Z is O
- R 11 is an ⁇ -amino acid in which the ⁇ carboxyl group forms an amide with the nitrogen of R 10 , wherein if said amino acid is glutamic acid or aspartic acid, the non- ⁇ carboxylic acid is an alkyl ester in which the alkyl moiety contains from 1-6 carbon atoms;
- R 12 is hydrogen, CN, NO 2 , halo, CF 3 , alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, acyl of 2-7 carbon atoms, or benzoyl;
- R 13 is hydrogen, acyl of 2-7 carbon atoms, haloacyl of 2-7 carbon atoms, nitroacyl of 2-7 carbon atoms, cyanoacyl of 3-7 carbon atoms, trifluoromethylacyl of 3-
- More preferred compounds of this invention are benzyllactobionamides of formula I
- R ( 1 , r R»2 , ⁇ R-,3 , T R-, 4 , r R,5 , ⁇ R,6 , ⁇ R7 , and R are each, independently, acetyl or -SO 3 H;
- R 9 is hydrogen, CN, NO 2 , halo, CF 3 , alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms;
- R 10 is hydrogen, -NO 2 , -NHR 13 , -N(R 13 ) 2 ,
- R 13 is hydrogen, or acyl of 2-7 carbon atoms; or a pharmaceutically acceptable salt thereof.
- Specifically preferred compounds of this invention are:
- the compounds of this invention were prepared according to the following scheme from commercially available starting materials or starting materials which can be prepared using literature procedures. This scheme shows the preparation of representative compounds of this invention.
- Lactobiono-l,5-lactone (1, *H. S. Isbell; H. L. Frush. Methods Carbohyd. Chem. 1963, 2, 16-18.) is coupled with a benzyl amine 2 (in the presence of sodium carbonate when using amine salt) in a protic solvent such as methanol at temperatures ranging from 0 to 60 °C to yield glycoside 3 (Scheme 1).
- Reduction of the nitro group of 3 can be accomplished with a reducing agent such as stannous chloride in a polar aprotic solvent such as ethyl acetate at ambient temperature to reflux to afford an anilino compound 4.
- Coupling of 4 with an acid chloride can be completed in the presence of an amine base such as triethylamine or diisopropylethylamine or using a stronger base such as sodium hydride (for sterically hindered systems) in an aprotic solvent such as dichloromethane or tetrahydrofuran at temperatures ranging from 0°C to ambient temperature to yield the target compound 5.
- the peracetylated compound 5 can be converted to its octahydroxy intermediate with catalytic sodium methoxide in methanol or aqueous sodium hydroxide in methanol at temperatures ranging from ambient temperature to reflux.
- This intermediate can be further converted to the octasulfo compound 6 with sulfur trioxide trimethylamine complex in a polar solvent such as N,N-dimethylformamide at reflux.
- a polar solvent such as N,N-dimethylformamide at reflux.
- Many salts of the sulfate group can be prepared by using different ion exchange columns such as Dowex ⁇ a + or K + .
- the compounds of this invention are useful as antiproliferative agents.
- the following procedures show the evaluation of representative compounds of this invention in standard pharmacological test procedure which measured ability of the evaluated compound to inhibit smooth muscle cell proliferation
- the compounds of this invention are useful in treating or inhibiting diseases which are characterized by excessive smooth muscle cell proliferation (smooth muscle cell hyperproliferation).
- the compounds are particularly useful in treating hyperproliferative vascular diseases which are characterized by smooth muscle cell hyperproliferation, such as restenosis, which most frequently arises from vascular reconstructive surgery and transplantation, for example, balloon angioplasty, vascular graft surgery, coronary artery bypass surgery, and heart transplantation.
- Other disease states in which there is unwanted "cellular" vascular proliferation include hypertension, asthma, and congestive heart failure.
- the compounds of this invention are also useful as inhibitors of angiogenesis.
- Angiogenesis neovascularization
- the compounds of this invention are therefore useful as antineoplastic agents.
- the compounds of this invention can be formulated neat or with a pharmaceutical carrier for administration, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmacological practice.
- the pharmaceutical carrier may be solid or liquid.
- a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
- the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, lethicins, and oils (e.g. fractionated coconut oil and arachis oil).
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
- the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
- the compounds of this invention can also be administered orally either in liquid or solid composition form.
- the compounds of this invention may be administered rectally or vaginally in the form of a conventional suppository.
- the compounds of this invention may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.
- the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
- the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
- the creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type.
- Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
- a variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature.
- the dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Based on the results obtained in the standard pharmacological test procedures, projected daily dosages of active compound would be 0.1 to 10 mg/kg administered parenterally (intravenous preferred), with projected daily oral dosage being approximately ten-fold higher. Anticipated intravenous administration would last for approximately 5-30 days following acute vascular injury (i.e., balloon angioplasty or transplantation) and for a longer duration for the treatment of chronic disorders. Treatment will generally be initiated with small dosages less than the optimum dose of the compound.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, pre filled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- step 2 To a stirred solution of N-benzyl-lactobionamide (0.150 g, 0.335 mmol) and triethylamine (0.822 mL, 5.90 mmol) in DMF (3.4 mL) at rt was added dropwise acetic anhydride (0.278 mL, 2.95 mmol) followed by a catalytic amount of DMAP (0.0327 g, 0.268 mmol). After 18 h, the mixture was concentrated, and the resulting residue was diluted with EtOAc (100 mL). This layer was washed with 1 ⁇ HC1 (10 mL), sat. aq.
- N-(4-Amino-benzyl)-octa-6>-acetyl-lactobionamide A solution containing N-(4-nitro-benzyl)-octa-O-acetyl-lactobionamide (6.97 g, 8.41 mmol) and tin (II) chloride dihydrate (13.3 g, 58.9 mmol) in EtOAc (167 mL) was refluxed for 4 h. The reaction was cooled to rt, carefully quenched with sat. aq. ⁇ aHCO 3 (until basic), diluted with EtOAc (163 mL), stirred for 0.5 h and filtered.
- N-r3-(Acetylamino)-benzyll-octa-O-sulfo-lactobionamide octasodium salt step 1 A solution containing N-[3-(acetylamino)-benzyl]-octa-O-acetyl- lactobionamide (2.09 g, 2.49 mmol) and 25 weight % ⁇ aOMe in MeOH (42.6 ⁇ L, 0.746 mmol) in MeOH (62.7 ml) was refluxed for 2 h.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Neurology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Vascular Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Saccharide Compounds (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US19898298A | 1998-11-24 | 1998-11-24 | |
US198982 | 1998-11-24 | ||
PCT/US1999/027774 WO2000031092A2 (en) | 1998-11-24 | 1999-11-23 | Benzyllactobionamides as inhibitors of smooth muscle cell proliferation |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1133507A2 true EP1133507A2 (de) | 2001-09-19 |
Family
ID=22735720
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99944107A Withdrawn EP1133507A2 (de) | 1998-11-24 | 1999-11-23 | Benzyllactobionamide als inhibitoren der proliferation von glatten muskelzellen |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1133507A2 (de) |
JP (1) | JP2002530417A (de) |
CN (1) | CN1333779A (de) |
AU (1) | AU5706699A (de) |
BR (1) | BR9915641A (de) |
CA (1) | CA2351061A1 (de) |
WO (1) | WO2000031092A2 (de) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE397006T1 (de) * | 2004-08-05 | 2008-06-15 | Ivax Drug Res Inst Ltd | Polysulfatierte glykoside und salze davon |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3734815A1 (de) * | 1987-10-14 | 1989-04-27 | Luitpold Werk Chem Pharm | Polyschwefelsaeureester von bis-aldonsaeureamiden und deren derivaten, verfahren zu ihrer herstellung und arzneimittel |
IL115745A (en) * | 1994-11-07 | 2000-11-21 | American Home Prod | Acylated benzylglycosides and pharmaceutical compositions containing them |
-
1999
- 1999-02-04 AU AU57066/99A patent/AU5706699A/en not_active Abandoned
- 1999-11-23 WO PCT/US1999/027774 patent/WO2000031092A2/en not_active Application Discontinuation
- 1999-11-23 BR BR9915641-5A patent/BR9915641A/pt not_active Application Discontinuation
- 1999-11-23 CA CA002351061A patent/CA2351061A1/en not_active Abandoned
- 1999-11-23 JP JP2000583920A patent/JP2002530417A/ja active Pending
- 1999-11-23 CN CN99813573A patent/CN1333779A/zh active Pending
- 1999-11-23 EP EP99944107A patent/EP1133507A2/de not_active Withdrawn
Non-Patent Citations (1)
Title |
---|
See references of WO0031092A2 * |
Also Published As
Publication number | Publication date |
---|---|
BR9915641A (pt) | 2001-08-07 |
AU5706699A (en) | 2000-06-13 |
WO2000031092A2 (en) | 2000-06-02 |
JP2002530417A (ja) | 2002-09-17 |
CA2351061A1 (en) | 2000-06-02 |
CN1333779A (zh) | 2002-01-30 |
WO2000031092A3 (en) | 2001-01-18 |
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