DK172891B1 - Fremgangsmåde til fremstilling af nitrilotrieddikesyrederivater - Google Patents
Fremgangsmåde til fremstilling af nitrilotrieddikesyrederivater Download PDFInfo
- Publication number
- DK172891B1 DK172891B1 DK199701493A DK149397A DK172891B1 DK 172891 B1 DK172891 B1 DK 172891B1 DK 199701493 A DK199701493 A DK 199701493A DK 149397 A DK149397 A DK 149397A DK 172891 B1 DK172891 B1 DK 172891B1
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- Prior art keywords
- acid
- preparation
- nitrilotriacetic acid
- amino
- acid derivatives
- Prior art date
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- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical class OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- WBJINCZRORDGAQ-UHFFFAOYSA-N ethyl formate Chemical compound CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- NBZBKCUXIYYUSX-UHFFFAOYSA-N iminodiacetic acid Chemical compound OC(=O)CNCC(O)=O NBZBKCUXIYYUSX-UHFFFAOYSA-N 0.000 claims description 4
- BQDYDULZSDRWMI-UHFFFAOYSA-N 4-amino-2-[bis(carboxymethyl)amino]butanoic acid Chemical compound NCCC(C(O)=O)N(CC(O)=O)CC(O)=O BQDYDULZSDRWMI-UHFFFAOYSA-N 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims 3
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 239000013522 chelant Substances 0.000 abstract description 12
- 239000011347 resin Substances 0.000 abstract description 10
- 229920005989 resin Polymers 0.000 abstract description 10
- 229910052751 metal Inorganic materials 0.000 abstract description 8
- 239000002184 metal Substances 0.000 abstract description 8
- 235000018102 proteins Nutrition 0.000 abstract description 7
- 102000004169 proteins and genes Human genes 0.000 abstract description 7
- 108090000623 proteins and genes Proteins 0.000 abstract description 7
- 239000011159 matrix material Substances 0.000 abstract description 4
- 125000006850 spacer group Chemical group 0.000 abstract description 4
- 235000014304 histidine Nutrition 0.000 abstract description 3
- 238000004587 chromatography analysis Methods 0.000 abstract description 2
- 150000002411 histidines Chemical class 0.000 abstract description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229910021645 metal ion Inorganic materials 0.000 description 8
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 6
- 229920001222 biopolymer Polymers 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 229910006148 NiII Inorganic materials 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- SYFQYGMJENQVQT-UHFFFAOYSA-N 6-amino-2-[bis(carboxymethyl)amino]hexanoic acid Chemical compound NCCCCC(C(O)=O)N(CC(O)=O)CC(O)=O SYFQYGMJENQVQT-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YMVDHFYGOMPPIT-UHFFFAOYSA-N 2-[bis(carboxymethyl)amino]-4-(phenylmethoxycarbonylamino)butanoic acid Chemical compound OC(=O)CN(CC(O)=O)C(C(O)=O)CCNC(=O)OCC1=CC=CC=C1 YMVDHFYGOMPPIT-UHFFFAOYSA-N 0.000 description 1
- RKSASMXBVVMAAS-UHFFFAOYSA-N 2-[bis(carboxymethyl)amino]-6-(phenylmethoxycarbonylamino)hexanoic acid Chemical compound OC(=O)CN(CC(O)=O)C(C(O)=O)CCCCNC(=O)OCC1=CC=CC=C1 RKSASMXBVVMAAS-UHFFFAOYSA-N 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 229910002476 CuII Inorganic materials 0.000 description 1
- -1 CuII ions Chemical class 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000004873 anchoring Methods 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- KDPAWGWELVVRCH-UHFFFAOYSA-N bromoacetic acid Chemical compound OC(=O)CBr KDPAWGWELVVRCH-UHFFFAOYSA-N 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002668 lysine derivatives Chemical class 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 150000002815 nickel Chemical class 0.000 description 1
- 238000001742 protein purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Chemical compound NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
- C07K1/22—Affinity chromatography or related techniques based upon selective absorption processes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
- B01D15/08—Selective adsorption, e.g. chromatography
- B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
- B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
- B01D15/3804—Affinity chromatography
- B01D15/3828—Ligand exchange chromatography, e.g. complexation, chelation or metal interaction chromatography
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
- B01J20/30—Processes for preparing, regenerating, or reactivating
- B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
- B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
- B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
- B01J20/3244—Non-macromolecular compounds
- B01J20/3265—Non-macromolecular compounds with an organic functional group containing a metal, e.g. a metal affinity ligand
Landscapes
- Chemical & Material Sciences (AREA)
- Analytical Chemistry (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Treatment Of Liquids With Adsorbents In General (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Treatment Of Water By Ion Exchange (AREA)
- Developing Agents For Electrophotography (AREA)
- Peptides Or Proteins (AREA)
- Enzymes And Modification Thereof (AREA)
- Manufacture And Refinement Of Metals (AREA)
- Polymerisation Methods In General (AREA)
Description
i DK 172891 B1 , Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af nitrilotrieddikesyrederivater.
I 1975 udviklede Porath et al., (Nature 258. 1975, s. 598-599) metalchelataffinitetschromatografien, som var en ny 5 oprensningsmetode til proteiner. Denne nye teknik blev i mellemtiden med held anvendt mange steder og er allerede afhandlet i oversigtsartikler (B. Ldnnerdal og C.L. Keen, J.
AppI, Biochem. i, 1982, s. 203-208; E. Sulkowski, Trends in Biotechnology. 3., 1985, s. 1-7). Metalchelataffinitetsch-10 romatografi er baseret på den erkendelse, at metalioner såsom Cu og Zn , der er bundet (immobiliseret) til en chromato-grafigel ved chelatbinding, kan indgå i reversibel vekselvirkning med elektrondonorgrupper, som befinder sig på overfladen af proteiner, især imidazolsidekæden i histidin. Ved 15 en pH-værdi, ved hvilken elektrondonorgruppen i det mindste delvis foreligger i ikke-protoniseret form, bindes proteinet til chromatografigelen (fx agarose) og kan derefter elueres, fx ved hjælp af en puffer med en lavere pH-værdi, ved hvilken elektrondonorgruppen protoniseres. Som chelatdanner har fx 20 iminodieddikesyre, som bindes til harpiksens bærematrix via en såkaldt spacer, vist sig egnet.
En ideel chelatharpiks til oprensning af biopolymerer skal altså på den ene side kraftigt complexere metalionerne og på den anden side tillade reversible vekselvirkninger mellem 25 metalioner og proteiner. Immobiliseret iminodieddikesyre opfylder i vidt omfang disse betingelser for Cu^-ioner, men kun i begrænset omfang for NiII-ioner, da disse kun er svagt bundne og allerede ved påføring af proteinblandingen ofte udvaskes. På den anden side er NiII-chelatharpikser særlig 30 interessante til oprensning af biologisk materiale, da Ni^+ har et højere koordinationstal: NiII-ioner complexerer seks ligander og CuII-ioner fortrinsvis fire. I nikkelcomplexer står fire valenser til rådighed til forankring af metalionerne i harpiksen, og til vekselvirkningerne mellem metalioner 35 og biopolymerer er der to valenser til rådighed.
y DK 172891 B1 2
Det har hidtil ikke skortet på forsøg på at fremstille che-latharpikser med den højst mulige affinitet over for en metalion. Som complexdannende komponenter er der fx anvendt Ν,Ν,Ν'-ethylen-diamintrieddikesyre (M. Haner et al., Anal.
5 Biochem.. 138. 1984, s. 229-234) og 1,3-diaminopropan- Ν,Ν,Ν',N'-tetraeddikesyre (E.M. Moyers og J.S. Fritz, Anal.
Chem.. 49. 1977, s. 418-423). Disse harpikser har dog den ulempe, at vekselvirkningerne mellem metalioner og biopolymerer ikke er optimale.
10 Nitrilotrieddikesyre er en tetradentat chelatdanner. Immobi-liseret nitrilotrieddikesyre kunne være en egnet chelathar-piks for metalioner med koordinationstallet 6, da to valenser står til rådighed til reversibel binding af biopolymeren. En sådan metalchelatharpiks ville egne sig særligt til binding 15 af proteiner med to nabostillede histidiner på dens overflade .
Nitrilotrieddikesyre kan dog ikke analogt med iminodieddike-syre bindes til en bærer, uden at dens evner til chelatdan-nelse nedsættes betydeligt. Dette problem kan løses ved 20 fremstilling af hidtil ukendte nitrilotrieddikesyrederivater med den almene formel I
NH2-(CH2)x-CH(COOH) -N(CH2COOH)2 I
hvor x er 2, 3 eller 4, og deres immobilisering til en bærematrix via en spacer.
25 Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af nitrilotrieddikesyrederivater med den almene formel I og salte deraf. Særligt foretrukne nitrilotrieddikesyrederivater er N- [3-amino-1-carboxypropy1]iminodieddikesyre og N-[5-amino-l-carboxypentyl]iminodieddikesyre. Forbindel-30 serne kan immobiliseres til en bærematrix via en spacer.
Nitrilotrieddikesyrederivater med den almene formel I kan anvendes til fremstilling af metalchelatharpikser, der som DK 172891 B1 3 følge af deres metalchelatgrupper egner sig til oprensning af proteiner, som indeholder nabostillede histidinrester.
Metalchelatharpikserne er defineret ved den almene formel b*rematrix-spacer-NH-(CH2)x~CH(COOH)-N(CH2COO~)2Ni2+, hvor x 5 er 2, 3 eller 4.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved omsætning af en N-terminalbeskyttet forbindelse med den almene formel R-HN- (CH2)X~CH(NH2)-COOH, hvor R betegner en aminobe-skyttelsesgruppe, og x er 2, 3 eller 4, med mindst 2 ækviva-10 lenter bromeddikesyre efterfulgt af fraspaltning af beskyttelsesgruppen. En foretrukken aminobeskyttelsesgruppe er ben-zyloxycarbonylgruppen (Z), der igen kan fjernes ved katalytisk hydrogenering, fortrinsvis med palladium-på-kul. Herved kan N7-Z-L-2,4-diaminosmørsyre og Ne-Z-L-lysin omdannes til 15 de ovenstående særligt foretrukne nitrilotrieddikesyrederivater.
De følgende eksempler viser fremgangsmåden ifølge opfindelsen.
EKSEMPEL 1 20 41,7 g bromeddikesyre blev opløst i 150 ml 2N natriumhydro xidopløsning og afkølet til 0°C. Derefter blev der under omrøring langsomt tildryppet en opløsning af 42 g Ne-benzyl oxycarbonyl-L-lysin i 225 ml 2N natriumhydroxidopløsning ved 0°C. Efter 2 timer blev afkølingen indstillet, og der 25 omrørtes natten over. Derefter blev reaktionsblandingen i 2 timer holdt ved 50°C, hvorefter der tilsattes 450 ml IN saltsyre. Efter at blandingen var afkølet, blev de udskilte krystaller frafiltreret. Produktet blev opløst i IN natriumhydroxidopløsning og på ny udfældet med den samme mængde IN 30 saltsyre og frafiltreret. Herved vandtes 40 g N-[5-benzyloxy-carbonylamino-l-carboxypentyl]iminodieddikesyre i form af hvide krystaller, smeltepunkt 172-174°C (sønderdeling).
DK 172891 B1 4 [a]D = +9,9° (c » 1, O,IN NaOH).
7.9 g af det vundne lysinderivat blev opløst i 49 ml IN natriumhydroxidopløsning og hydrogeneret ved stuetemperatur og normalt tryk efter tilsætning af en spatelspids 5% Pd/C.
5 Katalysatoren blev frafiltreret, og filtratet inddampet.
Herved vandtes 6,2 g N-[5-amino-l- carboxypentyl]iminodieddi-kesyre, hvis struktur NH2~(CH2)4~CH(COOH)-N(CH2COOH)2 blev bekræftet ved NMR-spektroskopi.
EKSEMPEL 2 10 6,5 g bromeddikesyre blev opløst i 8,1 ml 4N natriumhydroxid opløsning og afkølet til 0°C. Derefter blev der under omrøring tildryppet en opløsning af 4,1 g Νγ-benzyloxycarbonyl-L-2,4-diaminosmørsyre i 24,4 ml 2N natriumhydroxidopløsning.
Efter 2 timer blev afkølingen indstillet, og der omrørtes 15 natten over. Derefter blev reaktionsblandingen holdt ved 50°C i 2 timer, hvorefter der tilsattes 12,2 ml 4N saltsyre. Efter at blandingen var afkølet, blev de udskilte krystaller frafiltreret. Produktet blev opløst i 2N natriumhydroxidopløsning og på ny fældet med 6,1 ml 4N saltsyre og frafiltreret.
20 Der vandtes 5 g N-[3-benzyloxycarbonylamino-l carboxypro- pyl]iminodieddikesyre i form af hvide krystaller, smeltepunkt 136-138°C (sønderdeling).
2.9 g af det vundne smørsyrederivat blev opløst i 16 ml IN natriumhydroxidopløsning og hydrogeneret ved stuetemperatur 25 og normalt tryk efter tilsætning af en spatelspids 5% Pd/C. Katalysatoren blev frafiltreret, og filtratet inddampet.
Herved vandtes 2,2 g N-[3-amino-l-carboxypropyl]iminodieddikesyre, hvis struktur, NH2~(CH2)2-CH(COOH)-N(CH2COOH)2, blev bekræftet ved NMR-spektroskopi.
Claims (4)
1. Fremgangsmåde til fremstilling af nitrilotrieddikesyre-derivater med den almene formel H2N-(ch2)x-ch(cooh)-n(ch2cooh)2 5 hvor x er 2, 3 eller 4, kendetegnet ved, at en N-terminal-beskyttet forbindelse med den almene formel R-NH-(CH2)x-CH(NH2) -COOH hvor R betegner en aminobeskyttelsesgruppe, og x er 2, 3 10 eller 4, omsættes med mindst 2 ækvivalenter bromeddikesyre, og beskyttelsesgruppen spaltes fra det resulterende reaktionsprodukt .
2. Fremgangsmåde ifølge krav 1, 15 kendetegnet ved, at beskyttelsesgruppen er ben-zyloxycarbonyl (Z), og at dens fraspaltning udføres ved hydrogenering i nærværelse af Pd/C.
3. Fremgangsmåde til fremstilling af N-[3-amino-l-carboxypro-pyl]iminodieddikesyre, 20 kendetegnet ved, at Ny-benzyloxycarbonyl-L-2,4-diaminosmørsyre omsættes med bromeddikesyre, og det resulterende reaktionsprodukt hydrogeneres i nærværelse af Pd/C.
4. Fremgangsmåde til fremstilling af N-[5-amino-l-carboxypen-tylj iminodieddikesyre, 25 kendetegnet ved, at Nt-benzyloxycarbonyl-L-lysin omsættes med bromeddikesyre, og det resulterende reaktionsprodukt hydrogeneres i nærværelse af Pd/C. j- \
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH278286 | 1986-07-10 | ||
| CH278286 | 1986-07-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DK149397A DK149397A (da) | 1997-12-19 |
| DK172891B1 true DK172891B1 (da) | 1999-09-13 |
Family
ID=4241469
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198702851A DK172602B1 (da) | 1986-07-10 | 1987-06-03 | Metalchelatharpikser, fremgangsmåde til fremstilling deraf, anvendelse deraf til metalchelat-chromatografi, nitrilotrieddik |
| DK199701493A DK172891B1 (da) | 1986-07-10 | 1997-12-19 | Fremgangsmåde til fremstilling af nitrilotrieddikesyrederivater |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198702851A DK172602B1 (da) | 1986-07-10 | 1987-06-03 | Metalchelatharpikser, fremgangsmåde til fremstilling deraf, anvendelse deraf til metalchelat-chromatografi, nitrilotrieddik |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US4877830A (da) |
| EP (1) | EP0253303B1 (da) |
| JP (2) | JPH0822382B2 (da) |
| AT (1) | ATE76866T1 (da) |
| AU (1) | AU596674B2 (da) |
| CA (1) | CA1304886C (da) |
| DE (1) | DE3779501D1 (da) |
| DK (2) | DK172602B1 (da) |
| IE (1) | IE60468B1 (da) |
| IL (1) | IL83079A (da) |
| NZ (1) | NZ220948A (da) |
| PH (1) | PH23746A (da) |
| ZA (1) | ZA874860B (da) |
Families Citing this family (75)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1304886C (en) * | 1986-07-10 | 1992-07-07 | Heinz Dobeli | Metal chelate resins |
| US5057302A (en) * | 1987-02-13 | 1991-10-15 | Abbott Laboratories | Bifunctional chelating agents |
| CA1340522C (en) * | 1987-03-10 | 1999-05-04 | Heinz Dobeli | Fusion proteins containing neighbouring histidines for improved purification |
| EP0309746A1 (de) * | 1987-09-08 | 1989-04-05 | F. Hoffmann-La Roche Ag | Antimalaria-Vakzine |
| US5225534A (en) * | 1987-09-08 | 1993-07-06 | Hoffmann-La Roche Inc. | Recombinant malarial polypeptides |
| US4952321A (en) * | 1988-10-07 | 1990-08-28 | Brigham Young University | Process of removing and concentrating desired ions from solutions |
| US5169936A (en) * | 1989-04-14 | 1992-12-08 | Biogen, Inc. | Protein purification on immobilized metal affinity resins effected by elution using a weak ligand |
| JP3124969B2 (ja) * | 1989-08-19 | 2001-01-15 | キアゲン・ゲーエムベーハー | 温度勾配ゲル電気泳動による混合物成分の分離・検出方法および装置 |
| US5266686A (en) * | 1992-09-25 | 1993-11-30 | Pierce Chemical Company | Method for isolation and purification of enzyme-antibody conjugates |
| CA2125467C (en) * | 1993-07-06 | 2001-02-06 | Heinz Dobeli | Process for producing hydrophobic polypeptides, proteins or peptides |
| SE9303822D0 (sv) * | 1993-11-18 | 1993-11-18 | Kabi Pharmacia Ab | Method for purification |
| DE4433980C2 (de) * | 1994-09-23 | 1996-08-22 | Boehringer Ingelheim Int | Verfahren und Biosensorhit zur Untersuchung der Wechselwirkung von Biomolekülen mittels Oberflächen-Plasma-Resonanz |
| US5620850A (en) | 1994-09-26 | 1997-04-15 | President And Fellows Of Harvard College | Molecular recognition at surfaces derivatized with self-assembled monolayers |
| US6472148B1 (en) | 1994-09-26 | 2002-10-29 | President And Fellows Of Harvard College | Molecular recognition at surfaces derivatized with self-assembled monolayers |
| TW442492B (en) * | 1995-07-26 | 2001-06-23 | Novartis Ag | Process for the enrichment of interferon |
| DE19531173A1 (de) * | 1995-08-24 | 1997-02-27 | Boehringer Mannheim Gmbh | Verfahren zum Stabilisieren des Gehalts glykierten Proteins einer Probe auf einem Matrixmaterial |
| DE69730551T2 (de) | 1996-04-15 | 2005-09-01 | Givaudan S.A. | Hydroxyperoxide Lyasen |
| US5858724A (en) * | 1996-07-16 | 1999-01-12 | Pel-Freez | Recombinant rabbit tissue factor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU426693B2 (en) * | 1968-07-18 | 1972-07-31 | Mobil Oil Corporation | Fuel additive |
| US4530963A (en) * | 1982-08-20 | 1985-07-23 | Devoe-Holbein International, N.V. | Insoluble chelating compositions |
| CA1304886C (en) * | 1986-07-10 | 1992-07-07 | Heinz Dobeli | Metal chelate resins |
-
1987
- 1987-06-02 CA CA000538559A patent/CA1304886C/en not_active Expired - Lifetime
- 1987-06-03 DK DK198702851A patent/DK172602B1/da not_active IP Right Cessation
- 1987-07-03 IL IL83079A patent/IL83079A/xx not_active IP Right Cessation
- 1987-07-03 NZ NZ220948A patent/NZ220948A/xx unknown
- 1987-07-03 ZA ZA874860A patent/ZA874860B/xx unknown
- 1987-07-06 AU AU75245/87A patent/AU596674B2/en not_active Expired
- 1987-07-07 PH PH35505A patent/PH23746A/en unknown
- 1987-07-08 AT AT87109892T patent/ATE76866T1/de not_active IP Right Cessation
- 1987-07-08 EP EP87109892A patent/EP0253303B1/de not_active Expired - Lifetime
- 1987-07-08 DE DE8787109892T patent/DE3779501D1/de not_active Expired - Lifetime
- 1987-07-09 IE IE184287A patent/IE60468B1/en not_active IP Right Cessation
- 1987-07-09 JP JP62169950A patent/JPH0822382B2/ja not_active Expired - Lifetime
- 1987-07-13 US US07/072,452 patent/US4877830A/en not_active Expired - Lifetime
-
1995
- 1995-06-23 JP JP7157981A patent/JP2562571B2/ja not_active Expired - Lifetime
-
1997
- 1997-12-19 DK DK199701493A patent/DK172891B1/da not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| IL83079A0 (en) | 1987-12-31 |
| PH23746A (en) | 1989-11-03 |
| EP0253303B1 (de) | 1992-06-03 |
| JPH0899944A (ja) | 1996-04-16 |
| DK285187A (da) | 1988-01-11 |
| IE871842L (en) | 1988-01-10 |
| NZ220948A (en) | 1990-07-26 |
| JP2562571B2 (ja) | 1996-12-11 |
| US4877830A (en) | 1989-10-31 |
| EP0253303A3 (en) | 1989-05-24 |
| DK172602B1 (da) | 1999-02-22 |
| DK149397A (da) | 1997-12-19 |
| IE60468B1 (en) | 1994-07-13 |
| AU7524587A (en) | 1988-01-14 |
| ATE76866T1 (de) | 1992-06-15 |
| JPH0822382B2 (ja) | 1996-03-06 |
| DK285187D0 (da) | 1987-06-03 |
| ZA874860B (en) | 1988-01-11 |
| IL83079A (en) | 1991-11-21 |
| EP0253303A2 (de) | 1988-01-20 |
| JPS6344947A (ja) | 1988-02-25 |
| AU596674B2 (en) | 1990-05-10 |
| CA1304886C (en) | 1992-07-07 |
| DE3779501D1 (de) | 1992-07-09 |
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