EP0948493A1 - Indenes inhibiteurs du cox-2 - Google Patents

Indenes inhibiteurs du cox-2

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Publication number
EP0948493A1
EP0948493A1 EP97945622A EP97945622A EP0948493A1 EP 0948493 A1 EP0948493 A1 EP 0948493A1 EP 97945622 A EP97945622 A EP 97945622A EP 97945622 A EP97945622 A EP 97945622A EP 0948493 A1 EP0948493 A1 EP 0948493A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
hydrogen
alkyl
halogen
fluoroalkoxy
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Withdrawn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
EP97945622A
Other languages
German (de)
English (en)
Inventor
Amedeo Arturo Failli
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.)
Wyeth LLC
Original Assignee
American Home Products Corp
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
Application filed by American Home Products Corp filed Critical American Home Products Corp
Publication of EP0948493A1 publication Critical patent/EP0948493A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention is in the fields of antiinflammatory and anticancer pharmaceutical agents and specifically relates to compounds, compositions and methods for treating inflammation and inflammation-associated disorders, such as arthritis and Alzheimer disease, and for the treatment and/or prevention of cycloxygenase-mediated disorders such as may occur in diabetic retinopathy and tumor angiogenesis. More particularly, they may prove useful in certain types of cancer growth, such as colorectal cancer and in the treatment of Alzheimer disease.
  • Prostaglandins have been known for some time to play a major role in the inflammation process, and have been shown to be involved in the pathophysiology of several chronic human diseases. They are involved as mediators of pain, edema and vascular permeability in arthritic diseases such as rheumatoid arthritis and osteoarthritis (Lewis and Kreft, Immunopharmacol. Immunotoxicol. 17, 607-663 (1995)).
  • prostaglandins have been postulated to be involved in the pathophysiology of colorectal cancer (Marcus, New Eng. I. Med. , 333, 656-657 (1995); Huang and Heimbrook, Exp.Opin. Invest. Drugs., 4 (3), 243-249 (1995)).
  • an agent that inhibits prostaglandin synthesis may be useful in treating these disorders.
  • prostaglandins were previously thought to be due to the action of a single cyclooxygenase enzyme on arachidonic acid to afford prostaglandin H 2 (Vane et al, Postgrad. Med. J. , 66 (Suppl 4), S2-S17 (1990); Lewis and Kreft, Immunopharmacol. Immunotoxicol. 17, 607-663 (1995)).
  • This intermediate is subsequently transformed into the various members of the prostaglandin family by more distal enzymes.
  • cyclooxygenase inhibitors often called NSAIDs; nonsteroidal antiinflammatory drugs
  • COX-1 tissue is termed COX-1 and the inducible cyclooxygenase enzyme (reported by Hla and Nielson, Proc. Ntl. Acad. Sci. USA, 89, 7384 (1992)) responsible for prostaglandin synthesis in inflamed tissue is termed COX-2.
  • COX-1 appears to have a physiological role being involved in maintenance of gastrointestinal integrity and renal blood flow, while COX-2 appears to be mainly responsible for the pathological effects of prostaglandins.
  • Indomethacin a relatively non-selective inhibitor of COX-1 and COX-2 has been shown to be useful in the treatment of Alzheimer's disease (Rogers et al., Neurology 43, 1609-1611 (1993)). These findings suggest that novel COX-2 inhibitors would be attractive targets for the treatment of Alzheimer disease and for antiarthritic therapy with reduced potential for gastrointestinal toxicity and renal side effects.
  • the COX-2 enzyme has been shown to be upregulated in colorectal cancer and a selective COX-2 inhibitor may also be of use in this disease (Sano et. al. Cancer Res.., 55 , 3785-3789 (1995); Huang and Heimbrook, Exp. Opin. Invest. Drugs 4 (3), 243-249, (1995)).
  • the above-cited patents disclose compounds that are structurally different from the compounds of the present invention.
  • the compounds of the present invention are cycloxygenase inhibitors, and unexpectedly exhibit marked selectivity for the inhibition of COX-2 over COX-1.
  • the compounds disclosed in each of the patents cited above unlike the compounds of the present invention do not act as preferential inhibitors of COX-2; thus, they are not expected to exhibit any of the advantages of the compounds of the present invention, i.e. they are not expected to produce a reduced amount of side effects.
  • COX-2 inhibitors which are useful as antiarthritic, anticancer and anti-Alzheimers agents of formula I:
  • R 1 is hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, fluoroalkoxy of 1-6 carbon atoms, trifluoromethyl, alkylthio of 1-3 carbon atoms, or SCF3
  • R 2 and R 3 are each independently, hydrogen or alkyl of 1-6 carbon atoms, or R 2 and R 3 may be taken together to form a saturated cycloalkyl ring of 3-7 carbon atoms
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-3 carbon atoms, alkylsulfinyl of 1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, halogen, fluoroalkoxy of 1-6 carbon atoms, CF3, or SCF3.
  • R 1 is preferably lower alkoxy of 1-6 carbon atoms or halogen;
  • R 2 and R 3 are preferably hydrogen;
  • R 4 , R 5 , R 6 , R 7 and R 8 are each independently, hydrogen, halogen, thioalkyl of 1-3 carbon atoms, alkylsulfinyl of 1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, CF3, or fluoroalkoxy of 1-6 carbon atoms; more preferably R 4 , R 5 , R 6 , R 7 and R 8 are each independently chlorine, hydrogen or thiomethyl.
  • Particular preferred embodiments are those wherein R ⁇ and R ⁇ are both hydrogen, more particularly embodiments wherein R 4 , R 6 and R 8 are chlorine or R 4 and R 8 are hydrogen and R 6 is thiomethyl.
  • Preferred compounds of this invention are those of formula 2:
  • R 1 is lower alkoxy of 1-6 carbon atoms or halogen; and R 4 , R 5 , R 6 , R 7 and R 8 are each independently, hydrogen, halogen, thioalkyl of 1-3 carbon atoms, alkylsulfinyl of 1-3 carbon atoms, alkylsulfonyl of 1-3 carbon atoms, CF3, or fluoroalkoxy of 1-6 carbon atoms.
  • More preferred compounds of this invention are those of formula 3:
  • R 4 , R 6 and R 8 are chlorine; or R 4 and R 8 are hydrogen and R 6 is thiomethyl.
  • Some of the compounds of this invention contain one or more asymmetric centers and may thus give rise to optical isomers and diastereomers.
  • 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.
  • the absolute configuration at the asymmetric center is not indicated, it is intended to embrace both R and S enantiomers as well as mixtures of the two.
  • Certain compounds within the scope of the present invention exist in the form of E and Z stereoisomers and the individual isomers can be differentiated by the prefixes E and Z, as assigned by the accepted sequence rule procedures. Accordingly, the present invention embraces the E, Z and mixed isomer forms of those final product compounds exhibiting this form of stereoisomerism.
  • alkyl includes both straight chain as well as branched moieties. This includes the alkyl portions of substituents such as alkoxy, thioalkyl, alkylsulfinyl, alkylsulfonyl, fluoroalkoxy, and the like. Examples of alkyl include methyl, ethyl, n- propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl and n-hexyl.
  • halo includes fluorine, chlorine, bromine, and iodine.
  • Fluoroalkoxy includes mono-, di-, tri-, and polyfluorinated alkoxy moieties such as -OCF3, -OCH2F, -OCHF2, -OCH 2 CF 3 , and the like.
  • the present invention also relates to the use of the compounds described above as a medicament and to their use in the preparation of a medicament for the treatment of arthritic disorders, colorectal cancer or Alzheimer's disease.
  • the invention further relates to a process for the preparation of the compounds which comprises reacting a substituted indene 3-acetic acid of Formula 4 with a tetronic acid, e.g. as described below.
  • tetronic acid derivatives of the present invention can be made by a variety of synthetic routes using conventional methods. According to one preparative scheme (Scheme I) an appropriately substituted indene 3-acetic acid of formula 4 is reacted with a tetronic acid to yield the desired final product of formula 1.
  • the substituted indene 3-acetic acids starting materials of formula 4 can be prepared as described in U.S. Patent 3,654,349.
  • a preferred route is shown in Scheme II. Condensation of an appropriately substituted aromatic aldehyde with an acid anhydride and the sodium salt of the same acid provides the corresponding cinnamic acid.
  • the intermediate cinnamic acid is hydrogenated in presence of a palladium catalyst to the corresponding hydrocinnamic acid.
  • the intermediate hydrocinnamic acid is cyclized in hot polyphosphoric acid and the resulting indanone is condensed with a cyano acetic acid to provide the substituted indene 3-acetic acid.
  • the intermediate indene 3-acetic acid is then condensed with an appropriately substituted aromatic aldehyde in the presence of an alkoxide to produce the intermediate indenyl acetic acid of formula 4.
  • REAGENTS (a) CJH SCOOCOC ⁇ HJ; , , C ⁇ COONa, heat; basify; acidify; (b) H 2 , 5% Pd-C, EtOH; (c) PPA, heat; (d) NC C(R 2 R 3 ) COOH, CH 3 COONH 4 AcOH, toluene, heat; basify, acidify; (e) MeONa, MeOH; acidify
  • the compounds of the present invention inhibit the COX-2 enzyme (Table 1) believed to be responsible for the production of high levels of prostaglandins in inflammation and certain types of cancer, such as colorectal cancer. It has been shown that preferential inhibition of the COX-2 enzyme relative to COX-1 inhibition leads to an anti inflammatory effect with substantially reduced G.I. toxicity (Chan et al, J. Pharmacol. Exp. Ther. 274, 1531-1537 (1995); Masferrer et al. Proc. Natl. Acad. Sci. USA , 91, 3228-3232 (1994); Seibert et al social Proc. Natl. Acad. Sci. USA, 91, 12013-12017 (1994)). Futaki et al. (Gen. Pharmac.
  • the compounds of this invention by virtue of their inhibition of cyclooxygenase-2 and/or their specificity for cyclooxygenase-2 over cyclooxygenase- 1, are for the treatment of inflammatory diseases such as rheumatoid arthritis and Alzheimer disease, and of certain types of cancer particularly in patients with peptic ulcers, gastric lesions and other gastric disorders because of their safer profile.
  • a representative compound of this invention was evaluated for inhibition of COX-2 and COX-1 enzymes as follows.
  • Human COX-1 and COX-2 cDNAs were cloned from human monocytes, untreated and LPS-treated respectively, by RT-PCR using oligonucleotide primers based on published hCOX-1 and hCOX-2 sequences (Jones et al., /. Biol. Chem., 268, 9049 (1993)).
  • the cDNAs were then transfected into either Sf9 or CHO cells and subsequently converted into a microsomal preparation as described by Glaser et al (Eur. I. Pharmacol. 281, 107-111 (1995)).
  • microsomal human recombinant enzymes were diluted with buffer (100 mM Tris, pH 7.8 at 37°C) containing 0.5 mM phenol (964 ⁇ l total volume).
  • the enzyme preparations were preincubated with vehicle (DMSO) or compounds in DMSO (1% DMSO in final assay) for 30 min at 37°C. Excess hematin was added 1 min prior to initiation of reaction (1.25 ⁇ M final hematin) with 30 ⁇ M arachidonic acid (sodium salt).
  • Final assay volume was 1.0 ml (100 mM Tris (pH 7.8), 0.5 mM phenol, 1.25 ⁇ M hematin and 30 ⁇ M arachidonic acid at 37°C).
  • the reaction was incubated for 35 sec (maximum level of PGH2 accumulation as determined from time course studies), and terminated by addition of 50-60 mL of SnCh (1 mg ml) in 0.1 N HC1.
  • PGH2 is quantitatively converted to PGF2 a by this reaction (50% efficiency of total conversion).
  • the pH of each tube is adjusted to pH 3.0-3.5 with IN-NaOH and extracted twice with 1.5 ml of ethyl acetate (75-90% efficiency per extraction). Combined ethyl acetate extracts were dried under N2(g) and redissolved in ELA buffer (2.0 ml), and PGF2 ⁇ was quantified by EIA.
  • the results in this standard pharmacological test procedures demonstrated high inhibition of the human COX-2 isozyme.
  • the compounds of this invention are useful for the treatment of arthritic disorders, Alzheimer disease and colorectal cancer.
  • the compounds of this invention are also expected to have a high selectivity for the inhibition of the human COX-2 isozyme and would be expected to have a greater margin of G.I. safety in the treatment of arthritic disorders, Alzheimer disease, and colorectal cancer.
  • the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or 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 may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient of this invention 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 fat.
  • 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 examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g.
  • cellulose derivatives preferably sodium carboxymethyl cellulose solution
  • alcohols including monohydric alcohols and polyhydric alcohols e.g. glycols
  • 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 used in sterile liquid form compositions for parenteral administration.
  • 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. Oral administration may be either liquid or solid composition form.
  • 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 packeted powders, vials, ampoules, prefilled 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.
  • the amount of therapeutically active compound that is administered and the dosage regimen for treating a specific arthritic disorder or colorectal cancer with the compound and/or compositions of this invention depends on a variety of factors, including the weight, age, sex, medical condition of the subject, the severity of the disease, the route and frequency of administration, and the specific compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain active ingredient in the range of 0.1 to 2000 mg, preferably in the range of 0.5 to 500 mg and most preferably between 1 and 100 mg. Projected daily dosages of active compound are 0.01 to 100 mg/kg body weight. The daily dose of can be administered in one to four doses per day.
  • Patent 3,654,349 which is hereby incorporated by reference
  • l-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride 0.607 g, 3.16 mmol.
  • the ice bath was removed and stirring continued overnight at room temperature.
  • Additional triethylamine (0.39 mL) and 4-dimethylamino pyridine (0.138 g) were added and the mixture was stirred for two more days.
  • the solvent was evaporated in vacuo and the residue diluted with water, and acidified to pH 4 with IN HC1. The precipitated product was collected and the filtrate evaporated to dryness.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Furan Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

La présente invention concerne des composés représentés par la structure (1) de la formule générale (I). Dans cette formule, R1 est hydrogène, halogène, alkyl, alcoxy, fluoroalcoxy, trifluorométhyl, alkylthio ou SCF¿3?; R?2 et R3¿ sont chacun indépendamment hydrogène ou alkyl, ou bien R2 et R3 peuvent, ensemble, former un cycle cycloalkyl saturé. Enfin, R?4, R5, R6, R7 et R8¿ sont chacun indépendamment hydrogène, alkyl, alcoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halogène, fluoroalcoxy, CF¿3? ou SCF3. Ces composés conviennent particulièrement au traitement de troubles arthritiques, du cancer colorectal et de la maladie d'Alzheimer.
EP97945622A 1996-11-12 1997-11-10 Indenes inhibiteurs du cox-2 Withdrawn EP0948493A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US74794896A 1996-11-12 1996-11-12
US747948 1996-11-12
PCT/US1997/020231 WO1998021195A1 (fr) 1996-11-12 1997-11-10 Indenes inhibiteurs du cox-2

Publications (1)

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EP0948493A1 true EP0948493A1 (fr) 1999-10-13

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EP (1) EP0948493A1 (fr)
JP (1) JP2001504118A (fr)
KR (1) KR20000053227A (fr)
CN (1) CN1237162A (fr)
AU (1) AU5105598A (fr)
BR (1) BR9713346A (fr)
CA (1) CA2269035A1 (fr)
HU (1) HUP9904696A2 (fr)
WO (1) WO1998021195A1 (fr)

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JP2003523958A (ja) 1999-12-23 2003-08-12 ニトロメド インコーポレーテッド ニトロソ化およびニトロシル化されたシクロオキシゲナーゼ−２の阻害剤、組成物ならびに使用法
PL1745791T3 (pl) 2003-05-07 2013-11-29 Osteologix As Leczenie chorób chrząstki/kości za pomocą rozpuszczalnych w wodzie soli strontu
AU2007205208B2 (en) 2006-01-04 2012-11-01 Southern Research Institute Derivatives of sulindac, use thereof and preparation thereof
CN104592091B (zh) * 2015-01-27 2017-07-04 冉瑞琼 一种含吲哚乙酸核心结构的化合物及其应用
CA3209491A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-ethanol-amine conjuguee a l'acide hyaluronique en combinaison avec des medicaments anti-inflammatoires non steroidiens (ains) pour traiter ou soulager des maladies inflammatoire
CN116635368A (zh) * 2021-10-15 2023-08-22 北京安健熹医药科技有限公司 2,3-二甲氧基-5-甲基-1,4-苯醌烷基醇衍生物及其应用

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US3647858A (en) * 1970-05-01 1972-03-07 Merck & Co Inc Process for preparing 1-benzylidene-3-indenyl acetic acids
MX9302419A (es) * 1992-04-28 1994-03-31 American Home Prod Derivados de acido tetronico, tiotetronico y tetramico.
GB9403857D0 (en) * 1994-03-01 1994-04-20 Scotia Holdings Plc Fatty acid derivatives

Non-Patent Citations (1)

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Title
See references of WO9821195A1 *

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Publication number Publication date
JP2001504118A (ja) 2001-03-27
WO1998021195A1 (fr) 1998-05-22
CN1237162A (zh) 1999-12-01
CA2269035A1 (fr) 1998-05-22
BR9713346A (pt) 2000-05-09
HUP9904696A2 (hu) 2000-05-28
KR20000053227A (ko) 2000-08-25
AU5105598A (en) 1998-06-03

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