WO1999035126A1 - Synthese d'acides hydroxamiques sur support solide - Google Patents
Synthese d'acides hydroxamiques sur support solide Download PDFInfo
- Publication number
- WO1999035126A1 WO1999035126A1 PCT/IB1998/002117 IB9802117W WO9935126A1 WO 1999035126 A1 WO1999035126 A1 WO 1999035126A1 IB 9802117 W IB9802117 W IB 9802117W WO 9935126 A1 WO9935126 A1 WO 9935126A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- resin
- acid compound
- side chain
- hydroxamic acid
- moiety
- Prior art date
Links
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 230000015572 biosynthetic process Effects 0.000 title description 7
- 239000007787 solid Substances 0.000 title description 6
- 238000003786 synthesis reaction Methods 0.000 title description 6
- 229920005989 resin Polymers 0.000 claims abstract description 54
- 239000011347 resin Substances 0.000 claims abstract description 54
- 239000002253 acid Substances 0.000 claims abstract description 39
- 238000000034 method Methods 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- -1 carboxylic acid compound Chemical class 0.000 claims abstract description 13
- 150000002923 oximes Chemical group 0.000 claims abstract description 11
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 9
- SSUCKKNRCOFUPT-UHFFFAOYSA-N o-[tert-butyl(dimethyl)silyl]hydroxylamine Chemical compound CC(C)(C)[Si](C)(C)ON SSUCKKNRCOFUPT-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000006482 condensation reaction Methods 0.000 claims abstract description 4
- 125000005647 linker group Chemical group 0.000 claims abstract description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 239000000463 material Substances 0.000 abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 230000004048 modification Effects 0.000 description 7
- 238000012986 modification Methods 0.000 description 7
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- 229960004592 isopropanol Drugs 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 description 3
- LNOLJFCCYQZFBQ-BUHFOSPRSA-N (ne)-n-[(4-nitrophenyl)-phenylmethylidene]hydroxylamine Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C(=N/O)/C1=CC=CC=C1 LNOLJFCCYQZFBQ-BUHFOSPRSA-N 0.000 description 3
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 3
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- SMNDYUVBFMFKNZ-UHFFFAOYSA-N 2-furoic acid Chemical compound OC(=O)C1=CC=CO1 SMNDYUVBFMFKNZ-UHFFFAOYSA-N 0.000 description 2
- LCFNTCQYRMTQOA-NSHDSACASA-N C1=CC(C)=CC=C1S(=O)(=O)N(O)C(=O)[C@H]1NCCC1 Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N(O)C(=O)[C@H]1NCCC1 LCFNTCQYRMTQOA-NSHDSACASA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000007306 functionalization reaction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical compound O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229920006009 resin backbone Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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
- C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/10—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
- C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/11—Compounds covalently bound to a solid support
-
- C—CHEMISTRY; METALLURGY
- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
- C40B40/00—Libraries per se, e.g. arrays, mixtures
Definitions
- the subject invention relates to methods for synthesizing hydroxamic acid compounds using a solid-support resin to facilitate purification of intermediates.
- Hydroxamic acids are an important class of organic molecules playing a key role in many biologically relevant interactions.
- MMPs matrix metalloproteinases
- FIG. 732 Rockwell, A.; Melden, M.; Copeland, R. A.; Hardman, K.; Decicco, C. P.; DeGrado, W. F.; J. Am. Chem. Soc., vol. 118 (1996), p.
- R can be virtually any organic radical. It is limited only by stability and solubility factors during processing and as part of the final product.
- the subject invention processes use a solid-support resin having an oxime moiety as the linking moiety of the resin.
- a preferred resin is an oxime (Kaiser) resin available commercially from Novabiochem, San Diego, California, having the structure:
- the first step of the subject invention processes involves treating the resin with a carboxylic acid compound:
- R can be virtually any organic radical that provides a stable and soluble compound (3), and will not react preferentially (to the acid moiety) with the oxime moiety of the resin. R can be the same or different from R.
- the carboxylic acid becomes attached to the resin by a simple condensation reaction between the carboxyl moiety of the carboxylic acid and the oxime moiety of the resin. Preferably the reaction is carried out with the resin suspended in dichloromethane (DCM) in the presence of one equivalent of 1,3- diisopropylcarbodiimide (DIC) and a catalytic amount of 4-dimethylaminopyridine (DMAP).
- DCM dichloromethane
- DIC 1,3- diisopropylcarbodiimide
- DMAP 4-dimethylaminopyridine
- reaction and purification procedures can be used to modify the structure of the side chain R .
- This second step is optional since R and R may be the same moiety, or no modification of R may be desired at this stage of the process. However, this second step is preferably used, since the ease of modifying R during this step is one of the primary advantages of the subject processes.
- Linkage of the material undergoing modification to the solid-support resin provides the advantage of easy purification of intermediates by simply washing excess reagents and impurities from the resin-bound materials using appropriate solvents.
- An advantage of the subject invention process is that the linkage of the product to the oxime resin is typically both acid and base stable to a sufficient extent that a wide variety of reactions can be utilized in modifying the side chain of the product. This includes the use of both acid and base labile protecting groups during these reaction and purification steps.
- Resin:C NOC(O)R* (4) where R* is R or R or R .
- a product is cleaved from the resin in a third step by treating structure (4) with O-tert-butyldimethylsilylhydroxylamine:
- the O-TBS -protected product (5) may be useful in its own right, if further modifications of the material are desired to be made with the O-protecting group in place. If R* is R or R , it is modified in an optional fourth step through one or more reaction and purification procedures to produce side chain R of the target hydroxamic acid compound:
- This step is optional since it is not needed if R* is R.
- the corresponding unprotected hydroxamic acid compound is produced in a fifth step by treating structure (6) with acid, producing the target compound:
- This step is optional, because it may be desirable to retain the hydroxamic acid compound produced in its O-TBS -protected state.
- inorganic acids such as HC1 or HBr can be used in this fifth step to produce the hydroxamic acid
- a volatile organic acid such as trifluoroacetic acid (TFA)
- TFA trifluoroacetic acid
- Both TBSONH2 and an acid such as TFA are generally more volatile than the unprotected hydroxamic acid product, so that excess amounts of them are readily separated from the unprotected hydroxamic acid compound by evaporation.
- the subject invention processes provide easy purification of intermediates which are bonded to the resin, and easy purification of the final product due to the volatility of the reagents used. This makes the processes amenable to automation.
- a preferred exemplary synthetic route which is outlined in Scheme 1, utilizes oxime (Kaiser) resin (1) which is reacted with carboxylic acid to produce esters (2). After side chain modification, the product is cleaved as an O-protected hydroxamic acid (3), using O-tert-butyldimethylsilylhydroxylamine. (At this stage the crude product can be purified by silica gel chromatography.) Finally, the silyl group is removed with trifluoroacetic acid at room temperature to afford pure hydroxamic acid (4).
- N- tosyl-proline hydroxamic acid (8) is prepared according to Scheme 2 and the following described procedure:
- Reagents a) Boc-Pro-OH, DIC, DMAP, DCM; b) 25% TFA/DCM ; c) TsCl, DIPEA, DCM; d) TBSONH2, DCE; e) 95% TFA/H2O.
- Oxime resin (1.0 g, 1.17 mmol/g, 1.17 mmol; Novabiochem, product number 01-64-0022) is rinsed several times with DCM.
- Boc-proline (5eq, 1.28 g, 5.85 mmol) in DCM (12 mL) is added, followed by DIC (737 mg, 5.85 mmol) and a catalytic amount of DMAP (5 mg).
- the reaction mixture is shaken for 17 hours, and the resin is filtered and washed (DCM, 2-propanol, DMF).
- the reaction mixture is shaken for 6 h, then filtered, washed (DCM, 2-propanol and again DCM several times) and vacuum dried (room temperature, 48h).
- the resin is swelled in DCE (10 mL) and TBSONH2 (0.107 mg, 0.730 mmol 5 eq) is added, and the reaction mixture is refluxed for 20 h (ca. 90°C).
- the resin is filtered and washed (DCM); the filtrate is collected and evaporated.
- the oily residue is vacuum dried and co-evaporated with chloroform several times to give 55.2 mg of oily product (95% yield).
- the oily product is dissolved in TFA:water (95:5; v:v) and stirred for 16 h, then evaporated to yield a yellowish, waxy solid.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
Abstract
La présente invention concerne des processus permettant de fabriquer des composés d'acide hydroxamique au moyen d'une résine de support solide dans laquelle un fragment d'oxime constitue le fragment de liaison de cette résine. Les processus de cette invention consistent: a) à traiter ladite résine avec un composé d'acide carboxylique, de sorte que ce composé est lié à la résine par une réaction de condensation entre l'oxime et les fragments carboxyles; b) à modifier éventuellement la chaîne latérale; c) à dissocier un produit de la résine, grâce à un traitement à l'O-tert-butyldiméthylsilylhydroxylamine; d) à modifier éventuellement ladite chaîne latérale; et e) à traiter éventuellement la substance ainsi obtenue, protégée par O-TBS, à l'aide d'un acide, afin de produire un composé d'acide hydroxamique non protégé.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US09/582,975 US6291709B1 (en) | 1998-12-28 | 1998-12-28 | Solid supported synthesis of hydroxamic acids |
| AU15029/99A AU1502999A (en) | 1998-01-09 | 1998-12-28 | Solid supported synthesis of hydroxamic acids |
| EP98959113A EP1045831A1 (fr) | 1998-01-09 | 1998-12-28 | Synthese d'acides hydroxamiques sur support solide |
| CA002318487A CA2318487A1 (fr) | 1998-01-09 | 1998-12-28 | Synthese d'acides hydroxamiques sur support solide |
| IL13721798A IL137217A0 (en) | 1998-01-09 | 1998-12-28 | Solid supported synthesis of hydroxamic acids |
| JP2000527528A JP2002500216A (ja) | 1998-01-09 | 1998-12-28 | ヒドロキサム酸の固体支持合成 |
| NO20003541A NO20003541L (no) | 1998-01-09 | 2000-07-10 | FremgangsmÕte ved fremstilling av hydroksamsyrer pÕ en fast bærer |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7098098P | 1998-01-09 | 1998-01-09 | |
| US60/070,980 | 1998-01-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999035126A1 true WO1999035126A1 (fr) | 1999-07-15 |
Family
ID=22098530
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IB1998/002117 WO1999035126A1 (fr) | 1998-01-09 | 1998-12-28 | Synthese d'acides hydroxamiques sur support solide |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP1045831A1 (fr) |
| JP (1) | JP2002500216A (fr) |
| AU (1) | AU1502999A (fr) |
| CA (1) | CA2318487A1 (fr) |
| IL (1) | IL137217A0 (fr) |
| NO (1) | NO20003541L (fr) |
| WO (1) | WO1999035126A1 (fr) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996026223A1 (fr) * | 1995-02-24 | 1996-08-29 | British Biotech Pharmaceuticals Limited | Synthese de derives d'acide hydroxamique |
| WO1998018754A1 (fr) * | 1996-10-28 | 1998-05-07 | Versicor, Inc. | Procedes pour synthese de composes d'hydroxylamine et derives en phase solide et banques combinatoires correspondantes |
-
1998
- 1998-12-28 EP EP98959113A patent/EP1045831A1/fr not_active Withdrawn
- 1998-12-28 CA CA002318487A patent/CA2318487A1/fr not_active Abandoned
- 1998-12-28 WO PCT/IB1998/002117 patent/WO1999035126A1/fr not_active Application Discontinuation
- 1998-12-28 IL IL13721798A patent/IL137217A0/xx unknown
- 1998-12-28 JP JP2000527528A patent/JP2002500216A/ja not_active Withdrawn
- 1998-12-28 AU AU15029/99A patent/AU1502999A/en not_active Abandoned
-
2000
- 2000-07-10 NO NO20003541A patent/NO20003541L/no not_active Application Discontinuation
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996026223A1 (fr) * | 1995-02-24 | 1996-08-29 | British Biotech Pharmaceuticals Limited | Synthese de derives d'acide hydroxamique |
| WO1998018754A1 (fr) * | 1996-10-28 | 1998-05-07 | Versicor, Inc. | Procedes pour synthese de composes d'hydroxylamine et derives en phase solide et banques combinatoires correspondantes |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20003541L (no) | 2000-08-31 |
| IL137217A0 (en) | 2001-07-24 |
| AU1502999A (en) | 1999-07-26 |
| EP1045831A1 (fr) | 2000-10-25 |
| NO20003541D0 (no) | 2000-07-10 |
| JP2002500216A (ja) | 2002-01-08 |
| CA2318487A1 (fr) | 1999-07-15 |
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