EP0991626A2 - Derives de pyrimidine-2,4,6-trione, leur procede de production et medicaments contenant ces composes - Google Patents

Derives de pyrimidine-2,4,6-trione, leur procede de production et medicaments contenant ces composes

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Publication number
EP0991626A2
EP0991626A2 EP98937509A EP98937509A EP0991626A2 EP 0991626 A2 EP0991626 A2 EP 0991626A2 EP 98937509 A EP98937509 A EP 98937509A EP 98937509 A EP98937509 A EP 98937509A EP 0991626 A2 EP0991626 A2 EP 0991626A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
aryl
aralkyl
heteroaryl
amino
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Withdrawn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
EP98937509A
Other languages
German (de)
English (en)
Inventor
Frank Grams
Gerd Zimmermann
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.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
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 Roche Diagnostics GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0991626A2 publication Critical patent/EP0991626A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/60—Three or more oxygen or sulfur atoms
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to new Py ⁇ m ⁇ dm-2,4,6-t ⁇ on-De ⁇ vate. their preparation and medicaments containing them. These compounds inhibit metalloproteases, in particular the proteases of the M2, M3 families. Astacin subfamily of M12 and Ml 3 These protease families are in N D Rawlmgs and A J Barret. Methods Enzym (1995) 248, 183-277
  • protease group Ml 2 particular preference is given to BMP-1 as an inhibition target of the compounds of the invention. Further preferred are ECE and NEP from the M13 family and ACE (peptidyl dipeptidase A) from subgroup M2
  • ACE angiotension converting enzyme
  • NEP neutral endopeptidase
  • the endothelin converting enzyme cleaves the endogenous, inactive big endothelin to the effective vasoconstructor endothelin-1, a peptide consisting of 21 amino acids
  • ECE endothelin converting enzyme
  • BMP-1 bone morphogenic protein 1
  • BMP-1 has been recognized as a metalloprotease, which plays a role in the conversion of procollagen into fibular collagen inhibitors of this enzyme are for the treatment of fibrosis and skierotic suitable processes and can also cause scarring during Favorably influence wound healing.
  • Metalloproteases such as NEP, ECE have hitherto been known to have no clinically usable active ingredients which are free from undesirable side effects and are available orally.
  • Rl and R2 can independently be H, alkenyl or alkyl
  • R3 represents a group WV in which W represents a bond or a linear or branched alkyl or alkenyl group which can optionally be interrupted by oxygen, sulfur or nitrogen, with hydroxyl, amino, mercapto, alkoxy, oxo, carboxy, Acyl, alkyl, aralkyl, aryl or heteroaryl groups can be substituted and N stands for H, a monocyclic or bicyclic, saturated or unsaturated ring which may optionally contain 1 to 4 nitrogen, oxygen or sulfur atoms and which may be substituted by hydroxy , Amino, mercapto, alkoxy, oxo, carboxy, acyl, acylamido, alkyl aralkyl, aryl or heteroaryl groups can be substituted,
  • R4 is a radical - ⁇ (R13) -C (O) -R5, -N (R13) -C (O) -OR5, -N (R13) -SO2-R5, -N (R13) - C (S) - R5, -N (R13) -C (S) -OR5, -N (R13) -C (O) -CR14R15 (-CR16R17) n -C (O) -R5, or -N (R13) -CR14R15 (- Can be CR16R17) n -C (O) -R18, which is in each case bound to the central pyrimidine ring via the nitrogen atom, n is 0 or 1
  • R13 has the meaning given above for R3 or optionally forms a 4 to 7-membered heterocycle with R14 or R16 and
  • R5 represents an alkyl, cycloalkyl, aralkyl, aryl or heteroaryl radical, which radicals can be substituted by hydroxyl, amino groups or halogen.
  • R14, R15, R16 and R17 independently of one another represent hydrogen, the C ⁇ residue of a proteinogenic amino acid, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; R14 and R15 or alternatively R16 and R17 together can form a 3 to 7-membered carbocycle.
  • R 1 denotes 8 OH or N (R6R7), where
  • R6 can be H, alkyl, cycloalkyl, aralkyl, aryl or heteroaryl and R7 stands for a group which together with the N atom represents a proteinogenic or non-proteinogenic ⁇ - or ⁇ -amino acid or amino acid amide and also R6 and R7 together form one Can form a 4 to 7-membered ring which may contain heteroatoms such as oxygen, sulfur or nitrogen, and may optionally be substituted by alkyl, aralkyl, aryl or heteroaryl.
  • R1 and R2 are, independently of one another, preferably H or methyl, particularly preferably H
  • R3 preferably represents H, alkyl, cycloalkyl or aryl, heteroaryl, aralkyl or heteroaralkyl. H or Ci-C ⁇ -alkyl is particularly preferred
  • R4 is preferably the residue of a proteinogenic or non-proteinogenic ⁇ - or ⁇ -amino acid which is linked via the nitrogen atom to the central pyrimidine ring and whose carboxyl group is either free or is connected to Rx or a group -NH-CO-CHR14-CO- Rx, where Rx is hydroxy, alkoxy or the above-described group -N (R6, R7)
  • R13 is preferably H or alkyl
  • R14 and R16 are, independently of one another, preferably alkyl or cycloalkyl, or the C ⁇ residue of a proteinogenic amino acid.
  • R15 and R17 is preferably hydrogen
  • n is preferably 0.
  • alkyl should be a straight-chain or branched Ci-Cio, preferably C ⁇ -C 6 ,
  • Alkyl chain such as Methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, pentyl or
  • alkenyl group means unsaturated residues with 3-6 C atoms, e.g. Allyl, but-2-enyl, hexa-2,4-dienyl.
  • Cycloalkyl stands for a 3-7 membered ring in which a CH2 group through O or
  • NH can be replaced as u. a. the cyclopropyl, cyclobutyl, cyclopentyl,
  • Cyclohexyl or the cycloheptyl ring preferably the cyclopentyl and the
  • Alkoxy groups mean a combination of an alkyl group according to the above
  • Aryl groups denote a carbon-aromatic radical, preferably one having 6-10 carbon atoms, in particular the phenyl or naphthyl group, which can in each case be linked to hydroxy and amino, which can optionally be substituted by alkyl groups, and alkyl and alkoxy groups.
  • Heteroaryl groups are aromatic radicals which are made up of unsaturated carbon atoms and heteroatoms such as nitrogen, oxygen and sulfur, where the sum of the ring atoms can be between 5 and 10. Examples of this are the
  • Aralkyl groups mean radicals in which an alkyl group defined above is linked to a previously characterized aryl radical, the benzyl radical being preferred.
  • a heteroaralkyl radical stands for the combination of an alkyl group defined above with an aryl radical described above. Pyridylmethyl is preferred
  • cycloalkyl, aryl and heteroaryl radicals are 1- to 3-fold independently of one another with alkyl, hydroxy, alkoxy, amino, alkylamino,
  • Dialkylamino, mercapto or thioalkyl substituted are straight-chain or branched C 2 -C 20 carbonyl alkyls, and preference is given to C 2 -C 6 acyl radicals
  • R6 and R7 together with the nitrogen atom to which they are attached form a ring, they are 5-7 rings, preferably a six-membered ring. Particularly preferred are the piperidine, piperazine, tetrahydroquinoline and tetrahydroisoquinoline, bicylo ( 9 4 0) pentadecyl and 1 2.3.4 - tetrahydrobenzo (g) isoquinoline ring.
  • the monocycle listed under V is understood to mean saturated or unsaturated ring systems with 3 to 8, preferably 5 to 7 carbon atoms, which can optionally be interrupted one or more times by heteroatoms such as nitrogen, oxygen or sulfur, in particular cyclopentyl, cyclohexyl, cycloheptyl -, morpholinyl, thiamorpholinyl, piperidinyl, piperazinyl, tetrahydro
  • tetrahydro tetrahydropyranyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, furyl, thiophenyl, imidazolyl, thiazolyl, oxaz Isothiazolyl, isoxazolyl, 1,2,3-triazolyl or 1,2,4-triazolyl radical.
  • Lower alkyl, alkoxy and halogen are particularly suitable as substituents.
  • the bicycles listed under V are preferably radicals such as naphthyl, tetrahydronaphthyl, decalinyl, quinolinyl, isoquinolin-yl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, indazolyl, benzindolyl, oxindolyl, oxindolyl, oxindolyl -, Benzothiophenyl-, Benzthiazoiyl, Benzoxazolyl- or the Purinylrest, but especially around the Naphthyl-, Quinolinyl-, Isoquinolinyl-, Tetrahydrochinolinyl-, Indolyl-, or Benzimidazolylrest
  • non-proteinogenic amino acids 2-amino-2-methylbutane carboxylic acid, 2-fluoro-ß-alanine, ß-alanine, 2,3-
  • Hydroxynorvaline ß-methylaspartic acid, homocysteine, O-methylserine, penicillamine, propargylglycine, vinylglycine, H-4,5-dehydro-Leu-OH, H- ⁇ -Me-Val-OH, H- propargyl-Gly-OH, H- Allo-Ile-OH, H-Pra-OH, H-Trans-4,5-dehydro-Lys-OH, 3-hydroxyaspartic acid, 6-hydroxynorleucine, allo-isoleucine, allyl glycine, ⁇ -amino-N-butyric acid, ⁇ -Methylleucine, ⁇ , ß-diaminosuccinic acid, O-carbamoyl-serine, S-methyl-cysteine, citrulline, cyclohexylalanine,, y-diaminobutyric acid, leaned-diaminopropionic acid, me
  • R1, R2 and R3 have the meanings given above and T represents a leaving group such as shark or OSO2R8, where shark is chlorine, bromine or iodine and R8 is an aryl or the methyl radical, with a compound of the general formula III
  • Groups can be protected by conventional protective groups, reacted and, if necessary, converted into pharmacologically acceptable salts,
  • R1 represents an optionally substituted alkyl, cycloalkyl, aryl or heteroaryl radical
  • D C (O), O-C (O), SO2 or a valence line
  • halogen chlorine, bromine or iodine and A represent oxygen or sulfur
  • Amines of the general formula III are commercially available or are generally known from the literature.
  • Carboxylic acid chlorides of the general formula VII are known or can be prepared from the corresponding carboxylic acids by generally known methods.
  • the reaction usually takes place with thionyl chloride, or phosphorus tri- or pentabromide or chloride in inert solvents such as dichloromethane, diethyl ether, dioxane or tetrahydrofuran at temperatures from 0 ° C. to 50 ° C., preferably between 20 ° C. and 40 ° C. .
  • Chloroformic acid esters of the general formula VII are known from the literature or can be obtained from the corresponding alcohols by reaction with phosgene or diphosgene by generally known methods.
  • the reaction runs in inert solvents such as. As diethyl ether, dichloromethane, dioxane, tetrahydrofuran or toluene at temperatures between -20 ° C and 20 ° C.
  • inert solvents such as. As diethyl ether, dichloromethane, dioxane, tetrahydrofuran or toluene at temperatures between -20 ° C and 20 ° C.
  • bases usually tertiary amines such as. B. triethylamine or pyridine.
  • Sulfonic acid chlorides of the general formula VII are known or can be prepared analogously to the methods described from the corresponding sulfonic acids by reaction with phosphorus pentachloride or thionyl chloride.
  • the reaction is in usually carried out in inert solvents such as dimethylformamide or without solvents at temperatures of 20 ° C to 180 ° C, preferably at 50 ° C to 100 ° C.
  • Isocyanates of the general formula VTII are known or can be prepared by methods known from the literature. B reacting corresponding alkyl halides of the general formula R1-Hal with potassium cyanate analogously to Synthesis 1978, 760. Further methods involve the reactions of an acid amide of the general formula R1-CONH2 with oxalyl chloride, the thermal decomposition of an acid azide of the general formula R1-CON3 or the reactions of an amine of the general formula R1-NH2 with phosgene (analogous to Ann Chem 562, 110)
  • reaction of carboxylic acid halides, sulfonic acid halides or chloroformic acid esters of the general formula VII with amines of the general formula VI is generally carried out in a solvent such as dichloromethane,
  • Dimethylformamide or pyridine with the addition of an auxiliary base such as triethylamine or 4-dimethylaminopyridine at a temperature between -10 ° C and 50 ° C, preferably at room temperature
  • an auxiliary base such as triethylamine or 4-dimethylaminopyridine
  • Racemic or in optically active form can contain one or more chiral centers and can then be present in racemic or in optically active form.
  • the racemates can be separated into the enantiomers by methods known per se.
  • the racemic mixtures are preferably reacted with an optically active acid such as eg D- or L-tartaric acid, almond acid, malic acid, lactic acid or camphorsulfonic acid or an optically active amine such as eg D- or L-phenylethylamine, ephedrine, quinidine or cinchonidine, diastereomeric salts which can be separated by crystallization
  • an optically active acid such as eg D- or L-tartaric acid, almond acid, malic acid, lactic acid or camphorsulfonic acid
  • an optically active amine such as eg D- or L-phenylethylamine, ephedrine, quinidine or cinchonidine
  • the pharmacological contractual salts used are primarily alkali metal salts, ammonium salts, acetates or hydrochlorides, which are obtained in a conventional manner, for example by titration of the compounds with inorganic or organic bases or inorganic acids such as. As sodium hydroxide, potassium hydroxide, aqueous ammonia, amines such as. B. triethylamine or hydrochloric acid.
  • the salts are usually cleaned by falling over from water / acetone.
  • the new substances of the formula I according to the invention and their salts can be administered enterally or parenterally in liquid or solid form. All the usual forms of application are possible here, for example tablets, capsules, dragées, syrups, solutions, suspensions, etc.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizers, solubilizers and buffers.
  • Such additives are e.g. B. tartrate and citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts), high molecular weight polymers (such as liquid polyethylene oxide) for viscosity control.
  • Liquid carriers for injection solutions must be sterile and are preferably filled into ampoules.
  • Solid carriers are e.g. b.
  • Preparations suitable for oral administration can optionally contain flavorings and sweeteners.
  • the dosage can depend on various factors, such as the mode of administration, species, age and / or individual condition.
  • the daily doses to be administered are about 10-1000 mg / person, preferably 100-500 mg / person and can be taken in one or more times distributed.
  • Example 1 160 mg of the compound obtained in Example 1 are added to 7 ml of saturated methanolic methylamine solution. After a short time, the
  • Example 1 If in Example 1 the monomethyl malonate chloride is replaced by monoethyl t-butylmalonic acid chloride, the title compound is obtained in a yield of 94%.
  • Example 3 1 g of the product obtained in Example 3 is dissolved in ethanol and 0.5 g of potassium hydroxide in 1 ml of water is added. After 2 days at room temperature, the reaction mixture is evaporated, the residue is mixed with ice water and ethyl acetate and acidified to pH 3 with 2N HCl. The ethyl acetate phase is dried and evaporated. 0.7 g (75%) of the title compound are obtained.
  • Enzyme Angiotensin-converting-enzyme from rabbit lung (EC. 3.4.15.1),
  • Substrate stock solution 0.4 nM in assay buffer
  • Enzyme stock solution 50 ⁇ l / ml
  • Inhibitor stock solution imm in DMSO dil.
  • Measuring tubes 50 ⁇ l substrate (results in 20 ⁇ M) 100 ⁇ l enzyme
  • the substrate, inhibitor and buffer are combined in a temperature-controlled measuring cell, and the enzyme reaction is started by adding enzyme.
  • the increase in fluorescence over time (200 s) is followed in a time.scan.
  • the respective initial speed is determined from the gradient.
  • the ICso value can be determined as follows:

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des substances de formule générale (I), des sels et esters pharmacologiquement tolérables de formule générale (I), ainsi que l'utilisation de ces composés pour la production de médicaments. Dans la formule générale (I), R1 et R2 représentent indépendamment l'un de l'autre H, alcényle ou alkyle; R3 représente un groupe W-V, dans lequel W représente une liaison ou un groupe alkyle ou alcényle linéaire ou ramifié, éventuellement interrompu par oxygène, soufre ou azote et pouvant être substitué par des groupes hydroxy, amino, mercapto, alcoxy, oxo, carboxy, acyle, alkyle, aralkyle, aryle ou hétéroaryle, et dans lequel V représente H, un cycle monocyclique ou bicyclique, saturé ou insaturé, pouvant éventuellement contenir 1 à 4 atomes d'azote, d'oxygène ou de soufre et pouvant éventuellement être substitué par des groupes hydroxy, amino, mercapto, alcoxy, oxo, carboxy, acyle, acylamido, alkyle, aralkyle, aryle ou hétéroaryle; R4 représente un reste -N(R13)-C(O)-R5, -N(R13)-C(O)-OR5, -N(R13)-SO2-R5, -N(R13)-C(S)-R5, -N(R13)-C(S)-OR5, -N(R13)-C(O)-CR14R15(-CR16R17)n-C(O)-R5 ou -N(R13)-CR14R15(-CR16R17)n-C(O)-R18 relié au cycle pyrimidine central par l'atome d'azote; n vaut 0 ou 1; R13 a la signification indiquée plus haut pour R3 ou forme éventuellement, avec R14 ou R16, un hétérocycle de 4 à 7 chaînons; et R5 représente un reste alkyle, cycloalkyle, aralkyle, aryle ou hétéroaryle, ces restes pouvant être substitués par des groupes hydroxy, des groupes amino ou halogène. R14, R15, R16 et R17 représentent, indépendamment l'un de l'autre, hydrogène, le reste C alpha d'un acide aminé protéinogène, alkyle, cycloalkyle, aryle, hétéroaryle, aralkyle ou hétéroaralkyle. R14 et R15 ou bien R16 et R17 peuvent former ensemble un noyau carbocyclique de 3 à 7 chaînons. R18 représente OH ou N(R6R7), où R6 peut représenter H, alkyle, cycloalkyle, aralkyle, aryle ou hétéroaryle, où R7 est un groupe représentant, avec l'atome N, un acide aminé ou amide d'acide aminé alpha ou beta protéinogène ou non protéinogène, et où R6 et R7 peuvent, en outre, former ensemble un cycle de 4 à 7 chaînons contenant éventuellement des hétéroatomes tels que oxygène, soufre ou azote et pouvant éventuellement être substitué par alkyle, aralkyle, aryle ou hétéroaryle.
EP98937509A 1997-06-23 1998-06-19 Derives de pyrimidine-2,4,6-trione, leur procede de production et medicaments contenant ces composes Withdrawn EP0991626A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19726427A DE19726427A1 (de) 1997-06-23 1997-06-23 Pyrimidin-2,4,6-trion-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel
DE19726427 1997-06-23
PCT/EP1998/003740 WO1998058915A2 (fr) 1997-06-23 1998-06-19 Derives de pyrimidine-2,4,6-trione et son utilisation comme inhibiteurs de metalloprotease

Publications (1)

Publication Number Publication Date
EP0991626A2 true EP0991626A2 (fr) 2000-04-12

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EP98937509A Withdrawn EP0991626A2 (fr) 1997-06-23 1998-06-19 Derives de pyrimidine-2,4,6-trione, leur procede de production et medicaments contenant ces composes

Country Status (13)

Country Link
US (1) US6242455B1 (fr)
EP (1) EP0991626A2 (fr)
JP (1) JP2002504917A (fr)
KR (1) KR20010014152A (fr)
CN (1) CN1268126A (fr)
AR (1) AR013119A1 (fr)
AU (1) AU8627898A (fr)
BR (1) BR9810286A (fr)
CA (1) CA2294113A1 (fr)
DE (1) DE19726427A1 (fr)
TR (1) TR199903213T2 (fr)
WO (1) WO1998058915A2 (fr)
ZA (1) ZA985406B (fr)

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KR101155335B1 (ko) * 2005-01-07 2012-06-11 엘지전자 주식회사 이동통신 단말기의 멀티미디어 메시지 동작방법
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BR9810286A (pt) 2000-09-12
US6242455B1 (en) 2001-06-05
CA2294113A1 (fr) 1998-12-30
AU8627898A (en) 1999-01-04
KR20010014152A (ko) 2001-02-26
AR013119A1 (es) 2000-12-13
ZA985406B (en) 1999-12-22
CN1268126A (zh) 2000-09-27
WO1998058915A2 (fr) 1998-12-30
DE19726427A1 (de) 1998-12-24
WO1998058915A3 (fr) 1999-05-14
JP2002504917A (ja) 2002-02-12
TR199903213T2 (xx) 2000-06-21

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