EP1187615A2 - Effets immunosuppresseurs des derives de pteridine - Google Patents

Effets immunosuppresseurs des derives de pteridine

Info

Publication number
EP1187615A2
EP1187615A2 EP00902660A EP00902660A EP1187615A2 EP 1187615 A2 EP1187615 A2 EP 1187615A2 EP 00902660 A EP00902660 A EP 00902660A EP 00902660 A EP00902660 A EP 00902660A EP 1187615 A2 EP1187615 A2 EP 1187615A2
Authority
EP
European Patent Office
Prior art keywords
dimethyl
dimethyllumazine
lumazine
pharmaceutical composition
carbon atoms
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Withdrawn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
EP00902660A
Other languages
German (de)
English (en)
Inventor
Mark Jozef Albert Waer
Piet André Maurits Maria HERDEWIJN
Wolfgang Eugen Pfleiderer
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.)
4 AZA IP NV
Original Assignee
Katholieke Universiteit Leuven
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 Katholieke Universiteit Leuven filed Critical Katholieke Universiteit Leuven
Publication of EP1187615A2 publication Critical patent/EP1187615A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the invention relates to a pharmaceutical composition for the treatment of autoimmuno disorders and/or the treatment or prevention of transplant- rejections comprising pteridine derivatives.
  • the invention further relates to combined pharmaceutical preparations comprising one or more pteridine derivates and one or more known immunosuppressan , and to a group of novel pteridine derivates as such. Further the invention is also related to a method for the treatment of autoimmuno disorders and/or of transplant-rejections.
  • pteridine derivates are known in nature and used in the preparation of medicines, for example as described in EP-A-108 890.
  • Other medical uses of derivatives of pteridine are described in WO 95-31987 as NO-synthase inhibitors, for example for the treatment of diseases caused by a high nitrogen monoxide level .
  • WO-95-32203 describes also the use of tetrahydropteridine derivatives as NO-synthase inhibitors .
  • a first object of the invention is to provide a pharmaceutical composition having high immunosuppressive activity.
  • Another object of the invention is to provide a combined immunosuppressive preparation which causes a superadditive effect, comprising a pteridine derivative of the invention and other known immunosuppressants .
  • Another further object of the invention is to provide immunosuppressive compounds, which are active in a minor dose, in order to decrease the considerable treatment costs.
  • Known immunosuppressive compounds are for example cyclosporine A, subsituted xanthines, tacrolimus (FK 506) , rapamycine (RPM) , leflunomide, mofetil, adrenocortical steroids, cytotoxic drugs and antibody preparations .
  • CyA cyclosporine A
  • Methylxanthines for example pentoxifylline (PTX) , are known having immunosuppressive effects in vitro.
  • PTX pentoxifylline
  • the present invention relates in particular to the application of a group pteridine derivatives and their pharmaceutical salts, possessing unexpectedly desirable pharmaceutical properties, i.e. are highly active immunosuppressive agents .
  • the invention demonstrates the immunosuppressive effects of pharmaceutical composition for the treatment of autoimmuno disorders and/or for the treatment or prevention of transplant-rejections comprising a pteridine derivative of general formula:
  • R and R are independently hydrogen,- aliphatic saturated or unsaturated; straight or branched carbon chain with 1 to 7 carbon atoms; substituted or unsubstituted aryl or alkylaryl substituents, whereby the carbon atoms may be oxidized represented by alcohol or carbonyl function or carboxylic acids and their esters;
  • R 3 and R 4 are independently hydrogen, hydroxyl, halogen, alkyl, haloalkyl, alkoxy, wherein alkyl and the alkyl group may be branched or straight and contains one or four carbon atoms, formyl and derivatives such as hydroxylamino conjugates and acetals, cyano, carboxylic acids and carboxyl acid derivatives such as esters and amides, sulfhydryl, amino, al ylamino, cycloalkylamino, alkenylamino, alkynylamino, benzyla ino, hydroxylalkylamino, morfolinoalkylamino, fenyl ydrazino, morfoline, piperidine, mercaptobenzyl, mercaptoalkyl, cysteinyl ester, styryl, substituted or unsubstituted aromatic ring,- aromatic or heterocyclic substituent substituted with an aliphatic spacer between the
  • X and Y are independently oxygen or sulfur or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier.
  • Preferred pteridine derivatives comprising compositions are given in claims 2-9. Particularly preferred are the compositions according to claim 10.
  • the invention further relates to a combined preparation having synergetic effects containing 1) cyclosporine A, substituted xanthines, tacrolimus (FK506) , Rapa ycin (RPM) , Leflunomide, Mofetil, adrenocortical steriods, cytotoxic drugs and antibody compositions and 2) at least one pteridine derivative of formula (I) defined above, and optionally a pharmaceutical excipient, for simultaneous, separate or sequential use in (auto) immune disorders and/or in the treatment of transplant-rejections.
  • the invention further relates to a method for treating auto-immuno disorders or transplant-rejections in a subject by administering an effective amount of a pharmaceutical composition of claims 1-11, to the compounds as such as defined above, to the use of these compounds for the treatment of autoimmuno disorders and/or the treatment and/or prevention of transplant rejections, and to a method for selecting potent immunosuppressive agents based on the determination of the three parameters MLC, ACD 3 and ACD 28 .
  • 6- (1, 2-Dibromo-2- (methoxycarbonyl) ethyl) -1,3- dimethyllumazine (6) To a solution of 6- [ (E) -2-methoxycarbonylethenyl] lumazine (0.7 g, 2.53 mmoles) in CHC1 3 (20 ml) was added bromine (0.64 g, 4 mmoles) dissolved in CHC1 3 (5 ml) and then the mixture stirred at room temperature for 6 hours . It was evaporated to dryness and the residue treated with MeOH to give a colorless precipitate. The solid was collected, washed with MeOH and dried in a vacuum desiccator. Yield: 0.97 g (88%). M.p.
  • 6- (l-Methoxy-2-methoxycarbonyl) ethenyl) -1,3- dimethy1lumazine (10) A suspension of 6 (0.2 g, 0.46 mmoles) in dry MeOH (8 ml) was treated with a solution of sodium (0.046 g, 2 mmoles) in MeOH (2 ml) at room temperature with stirring for 15 min. Then NH 4 C1 (0.1 g) and H 2 0 (10 ml) were added and the mixture extracted with CHC1 3 (2 x 50 ml) . The organic layer was dried over Na 2 S0 4 , evaporated and the residue crystallized from CHCl 3 /n-hexane. Yield: 0.085 g (60%). M.p. 160°C. UV (MeOH): 204 (4.20); 245 (4.15); 288 (4.23) ; 350 (3.99) .
  • 1, 3 -Dimethyl-6-phenyl-7-mercaptolumazine (28) A mixture of 7-hydroxy-l, -dimethyl-6-phenyllumazine [5] (2.84 g, 0.01 mole) and P 4 S 10 (3.3 g) was heated in pyridine (75 ml) under reflux for 1 hour. After cooling was diluted with H 2 0 (50 ml) and after standing for several hours the yellow precipiptate (28-pyridinium salt, 3.3 g, 87%). The salt was dissolved in hot H 2 0 (100 ml) and acidified by HCl to pH 0. The resulting yellow crystals were collected, washed and dried in the oven.
  • 6-Benzoyl-l, 3-dimethyl-7- (4-methoxyphenyl) lumazine (31) A suspension of 6-benzoyl-7, 8-dihydro-l, 3-dimethyl-7- (4- methoxyphenyl) lumazine (31a) (0.3 g, 0.74 mmoles) in dioxane (40 ml) was treated at room temperature with 1%- KMn0 4 solution (10 ml) by dropwise addition with stirring. After 30 min the excess of KMn0 4 was reduced by NaHS0 3 , the Mn0 2 filtered off, washed with warm EtOH (3 x 20 ml) and then the united organic phases evaporated to dryness.
  • 6-Benzoyl-1, 3-dimethyl-7-phenyllumazine (32) Analogous to procedure 31 from ⁇ -benzoyl-7, 8-dihydro-l, 3- di ethyl- 7 -phenyllumazine (32a) (0.3 g, 0.78 mmoles). Yield: 0.18 g (62%). M.p. 185-187°C. UV (MeOH): 252 (4.39); [290 (4.08)]; 349 (4.16).
  • Various models may be used for testing an immunosuppressive effect.
  • different transplantation models are available. They are strongly influenced by different immunogenicities, depending on the donor and recipient species used and depending on the nature of the transplanted organ. The survival time of transplanted organs can thus be used to measure the suppression of the immune response.
  • lymphocyte activation tests There exist also various models. The most used are lymphocyte activation tests. Usually activation is measured via lymphocyte proliferation. Inhibition of proliferation thus always means immunosuppression under the experimental conditions applied.
  • - CD3 assay here there is an activation of the T- lymphocytes via an exogenously added antibody (OKT3) . This antibody reacts against the CD3 molecule located on the lymphocyte membrane. This molecule has a costimulatory function.
  • OKT3-CD3 results in T-cell activation which proceeds via the Ca 2 +/calmodulin/calcineurin system and can be inhibited by CyA.
  • CD28 assay here specific activation of the T- lymphocyte goes also via an exogenously added antibody against the CD28 molecule. This molecule is also located on the lymphocyte membrane, and delivers strong costimulatory signals. This activation is Ca 2 +-independent and thus cannot be inhibited by CyA.
  • PBMC Peripheral blood mononuclear cells
  • Allogeneic PBMC or EBV-transformed human B cells [RPMI1788 (ATCC name CCL156)] which strongly express B7-1 and B7-2 were used as stimulator cells after irradiation with 30 Gy.
  • MLR was performed in triplicate wells. After 5 days incubation at 37 °C, 1 ⁇ Ci [ 3 H] -thymidine was added to each cup. After a further 16 hours incubation, cells were harvested and counted in a ⁇ -counter.
  • T cells were purified by removing non-T cells. Briefly, monocytes were removed by cold agglutination. The resulting lymphoid cells were further purified by a cell enrichment immunocolumn [Cellect Human T (Biotex, Edmonton, Alberta, Canada)] by a process of negative selection. More than 95% of the B cells were removed with this procedure. After depletion, the resulting T cell preparation was highly purified explaining these cells could not be activated by PHA or rIL-2 alone at concentrations capable of stimulating RBMC prior to deletion.
  • T cell proliferations induced by anti-CD3 mAb + PMA or anti-CD28 mAb + PMA Highly purified T cells (10 6 /ml) were stimulated by immobilized anti-CD3 or anti-CD28 mAb in the presence of PMA.
  • Anti-CD3 mAb (CLB-CD3; CLB, Amsterdam, The Netherlands) were fixed on the 96-microwell plates by incubating the wells with 50 ⁇ l of mAb solution (1/800 dilution in culture medium) .
  • Anti-CD28 mAb (CLB-CD28; CLB, Amsterdam, The Netherlands) 50 ⁇ l (1/650 dilution in culture medium) was added directly to the wells. Further, 20 ⁇ l PMA (Sigma, St.
  • column II shows the IC50 values of the various substances in the MLR.
  • the IC50 value represents the lowest concentration of the substances that resulted in a 50% suppression of the MLR.
  • WBA is a lymphoprolif ⁇ ration assay performed in vitro but using lymphocytes present in whole blood, taken from animals that were previously given test substances in vivo. Hence it reflects the in vivo effect of substances as assessed with an in vitro read-out assay.
  • Rats inbred, male 6- to 8-weeks old R/A rats weighing ⁇ 200 g were used as recipients.
  • Drug administration Pteridine derivatives were dissolved in DMSO and further diluted with PBS. Products were given orally in different concentrations 2 times a day for 2 days. To perform the experiments, 6-8 hours after the last administration 1 ml of blood is taken by heart puncture after ether anesthesia and anticoagulated with 100 U/ml of preservative free heparine.
  • Heparinized whole blood was diluted (1:25) with complete RPMI medium and stimulated with 15 ⁇ g/ml of concanavalin A (Con A) in triplicate wells in 96-well microtiter plates at 37 °C and 5% C0 2 . After 96-h culture, proliferation was determined by measuring the incorporation (cpm) of [ 3 H] -thymidine.
  • MLR mixed lymphocyte reaction
  • autoimmune diseases including diabetes mellitus, multiple sclerosis, glomerulonephritis, rheumatoid arthritis, psoriasis systemic diseases such as vasculitis; scleroderma, polymyositis, autoimmune endocrine disorders (thyroiditis) , ocular diseases (uveitis) , inflammatory bowel diseases (Crohn's disease, colitis ulcerosa) , autoimmune liver diseases (autoimmune hepatitis, primary biliary cirrhosis) autoimmune pneumonitis and auto-immune carditis .
  • autoimmune diseases including diabetes mellitus, multiple sclerosis, glomerulonephritis, rheumatoid arthritis, psoriasis systemic diseases such as vasculitis; scleroderma, polymyositis, autoimmune endocrine disorders (thyroiditis) , ocular diseases (uveitis) , inflammatory bowel diseases (
  • cyclosporine A and FK506 are only active in the anti-CD3 + PMA test
  • the pteridine derivatives according to the invention were active, not only in the anti-CD3 + PMA but also in the anti-CD28 + PMA test. It has been shown that the latter is Ca-calmodulin resistant, and resistant to CsA and FK506.
  • the anti-CD28 + PMA pathway has also been called the cosignal pathway and is important to induce energy and even tolerance in T cells.
  • representative compounds have been found to be active in an whole blood assay.
  • organ in the description is understood all organs or parts of organs (even several) in mammals, in particular humans, for example kidney, heart, skin, liver, muscle, cornea, bone, bone marrow, lung, pancreas, intestine or stomach.
  • Rejection reactions mean all reactions of the recipient body or of the transplanted organ which in the end lead to cell or tissue death in the transplanted organ or adversely affect the functional ability and viability of the transplanted organ or adversely affect the functional ability and viability of the transplanted organ or the recipient. In particular, this means acute and chronic rejection reactions.
  • Auto-immune disorders include, inter alia, systemic lupus erythematosus , rheumatoid arthritis, psoriasis, pemphigus, atopic dermatitis, myositis, multiple sclerosis, nephrotic syndrome (in particular glomerulonephritis) , ulcerative colitis or juvenile diabetes.
  • the invention further relates to the use of cyclosporin A or FK506 or Rapamycine and at least one pteridine derivative according to the invention for the production of a pharmaceutical composition for inhibiting the replication of viruses such as picorna-, toga-, bunya-, orthomyxo-, paramyxo- , rhabdo-, retro-, arena-, hepatitis B-, hepatitis C-, hepatitis D-, adeno-, vaccinia-, papilloma- , herpes-, varicella-zoster-virus or human immunodeficiency virus (HIV) ; or for treating of cancer such as lung cancers, leukaemia, ovarian cancers, sarcoma, Kaposi's sarcoma, meningioma, colon cancers, lymp node tumors, glioblastoma multiforme, prostate cancers or skin carcinoses .
  • viruses such as picorn
  • the invention further relates to the use of cyclosporin A or FK506 or rapa ycin and at least one pteridine derivative of the general formula (I) for the production of a pharmaceutical composition for the treatment of human after organ transplantation or of (auto) immune disorders.
  • the advantage to associate pteridine with other immunosuppressants may be that, first, the therapeutic spectrum of action of the individual components is quantitatively and qualitatively broadened. Secondly that it allows, by means of a dose reduction without reduced efficacy but with increased safety, that the treatment of immune disorders which were hitherto no indication for immunosuppressive therapy as a result of side effects may be considered. At the same time, the therapy costs can be decreased to an appreciable extent .
  • known pteridine derivatives are submitted to the same test conditions as the pteridine derivatives of the invention. These compounds and the results thereof are given in table IV and show no particular immunosuppressive activity.
  • the preparation according to the invention may contain the pteridine compounds over a broad content range depending on the contemplated use of the preparation.
  • the content of the preparation is within the range of 0.01-50 wt.%, preferably within the range of 0.01-10 wt.%, more preferably within the range of 0.1-10 wt.%, and most preferably within the range of 0.1-5 wt.%. Accordingly, the preparation may be used in a dosing regime which is suitable for most contemplated pharmaceutical utilities .
  • the preparation according to the invention may be used as such or in combination with any acceptable carrier material, excipient or diluent.
  • the preparation according to the invention may be administared orally or in any other suitable fashion. Oral administration is preferred and the preparation may have the form of a tablet, aqueous dispersion, dispersable powder or granule, emulsion, hard or soft capsule, syrup-, elixir or gel.
  • the dosing forms may be prepared using any method known in the art for manufacturing these pharmaceutical compositions and may comprise as additives sweeteners, flavoring agents, coloring agents, preservatives and the like.
  • Carrier materials and excipients may include calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, binding agents and the like.
  • the preparation may be included in a gelatin capsule mixed with any inert solid diluent or carrier material, or has the form of a soft gelatin capsule, in which the ingredient is mixed with a water or oil medium.
  • Aqueous dispersions may comprise the preparation in combination with a suspending agent, dispersing agent or wetting agent.
  • Oil dispersions may comprise suspending agents such as a vegetable oil.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Transplantation (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour le traitement de troubles auto-immuns et/ou pour le traitement ou la prévention de rejets de greffes comprenant un dérivé de ptéridine de formule générale (I), particulièrement une lumazine, éventuellement combinée à un second agent actif.
EP00902660A 1999-02-02 2000-02-02 Effets immunosuppresseurs des derives de pteridine Withdrawn EP1187615A2 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US11828299P 1999-02-02 1999-02-02
US11829599P 1999-02-02 1999-02-02
US11823599P 1999-02-02 1999-02-02
US118282P 1999-02-02
US118235P 1999-02-02
US118295P 1999-02-02
PCT/EP2000/000938 WO2000045800A2 (fr) 1999-02-02 2000-02-02 Effets immunosuppresseurs des derives de pteridine

Publications (1)

Publication Number Publication Date
EP1187615A2 true EP1187615A2 (fr) 2002-03-20

Family

ID=27382128

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00902660A Withdrawn EP1187615A2 (fr) 1999-02-02 2000-02-02 Effets immunosuppresseurs des derives de pteridine

Country Status (5)

Country Link
EP (1) EP1187615A2 (fr)
JP (1) JP2002536320A (fr)
AU (1) AU780284B2 (fr)
CA (1) CA2361561A1 (fr)
WO (1) WO2000045800A2 (fr)

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AU780284B2 (en) 2005-03-10
CA2361561A1 (fr) 2000-08-10
WO2000045800A2 (fr) 2000-08-10
JP2002536320A (ja) 2002-10-29
AU2441800A (en) 2000-08-25
WO2000045800A3 (fr) 2002-01-10

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