NO179747B - Fremgangsmåte for fremstilling av alkylerte azaglycinderivater - Google Patents
Fremgangsmåte for fremstilling av alkylerte azaglycinderivater Download PDFInfo
- Publication number
- NO179747B NO179747B NO920312A NO920312A NO179747B NO 179747 B NO179747 B NO 179747B NO 920312 A NO920312 A NO 920312A NO 920312 A NO920312 A NO 920312A NO 179747 B NO179747 B NO 179747B
- Authority
- NO
- Norway
- Prior art keywords
- alkanoyl
- aryl
- tri
- fmoc
- mmol
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 7
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical class NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 title claims abstract description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 36
- 125000006239 protecting group Chemical group 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 12
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims abstract description 9
- 125000001841 imino group Chemical group [H]N=* 0.000 claims abstract description 6
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- 125000000075 primary alcohol group Chemical group 0.000 claims abstract description 3
- 150000003333 secondary alcohols Chemical class 0.000 claims abstract description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 35
- -1 p-dimethyl-aminophenyl-diphenylphosphine pyridyl-diphenylphosphine Chemical compound 0.000 claims description 25
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- 229920000642 polymer Polymers 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
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- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 abstract 1
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- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 14
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
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- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- MFGWMAAZYZSWMY-UHFFFAOYSA-N (2-naphthyl)methanol Chemical compound C1=CC=CC2=CC(CO)=CC=C21 MFGWMAAZYZSWMY-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical class Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
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- 230000002378 acidificating effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
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- SJVFAHZPLIXNDH-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-phenylpropanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=CC=C1 SJVFAHZPLIXNDH-QFIPXVFZSA-N 0.000 description 1
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 1
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- VVQIIIAZJXTLRE-QMMMGPOBSA-N (2s)-2-amino-6-[(2-methylpropan-2-yl)oxycarbonylamino]hexanoic acid Chemical compound CC(C)(C)OC(=O)NCCCC[C@H](N)C(O)=O VVQIIIAZJXTLRE-QMMMGPOBSA-N 0.000 description 1
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 1
- OIOAKXPMBIZAHL-LURJTMIESA-N (2s)-2-azaniumyl-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoate Chemical compound CC(C)(C)OC(=O)CC[C@H](N)C(O)=O OIOAKXPMBIZAHL-LURJTMIESA-N 0.000 description 1
- MCRMUCXATQAAMN-HNNXBMFYSA-N (2s)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)C1=CC=C(O)C=C1 MCRMUCXATQAAMN-HNNXBMFYSA-N 0.000 description 1
- ONOURAAVVKGJNM-SCZZXKLOSA-N (2s,3r)-2-azaniumyl-3-phenylmethoxybutanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])[C@@H](C)OCC1=CC=CC=C1 ONOURAAVVKGJNM-SCZZXKLOSA-N 0.000 description 1
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 1
- OQHKEWIEKYQINX-UHFFFAOYSA-N 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[b]pyrrol-1-ium-2-carboxylate Chemical compound C1CCC2NC(C(=O)O)CC21 OQHKEWIEKYQINX-UHFFFAOYSA-N 0.000 description 1
- NSENYWQRQUNUGD-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinolin-2-ium-3-carboxylate Chemical compound C1CCCC2CNC(C(=O)O)CC21 NSENYWQRQUNUGD-UHFFFAOYSA-N 0.000 description 1
- DIWCUPFNJXAUAE-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinolin-1-ium-2-carboxylate Chemical compound C1CCCC2NC(C(=O)O)CCC21 DIWCUPFNJXAUAE-UHFFFAOYSA-N 0.000 description 1
- BWKMGYQJPOAASG-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CNC(C(=O)O)CC2=C1 BWKMGYQJPOAASG-UHFFFAOYSA-N 0.000 description 1
- DQJOCEQKMJIKLJ-UHFFFAOYSA-N 1,2-oxazolidine-3-carboxylic acid Chemical compound OC(=O)C1CCON1 DQJOCEQKMJIKLJ-UHFFFAOYSA-N 0.000 description 1
- KYWXRBNOYGGPIZ-UHFFFAOYSA-N 1-morpholin-4-ylethanone Chemical compound CC(=O)N1CCOCC1 KYWXRBNOYGGPIZ-UHFFFAOYSA-N 0.000 description 1
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- SRXRBNCPSVMKIE-UHFFFAOYSA-N 2-azaspiro[4.4]nonane-3-carboxylic acid Chemical compound C1NC(C(=O)O)CC11CCCC1 SRXRBNCPSVMKIE-UHFFFAOYSA-N 0.000 description 1
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- GOEGBJDTWXTPHP-UHFFFAOYSA-N 4-diphenylphosphanyl-n,n-dimethylaniline Chemical compound C1=CC(N(C)C)=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 GOEGBJDTWXTPHP-UHFFFAOYSA-N 0.000 description 1
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N Glutamine Chemical compound OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 101001039684 Homo sapiens mRNA cap guanine-N7 methyltransferase Proteins 0.000 description 1
- VGALFAWDSNRXJK-VIFPVBQESA-N L-aspartic acid beta-benzyl ester Chemical compound OC(=O)[C@@H](N)CC(=O)OCC1=CC=CC=C1 VGALFAWDSNRXJK-VIFPVBQESA-N 0.000 description 1
- QEFRNWWLZKMPFJ-YGVKFDHGSA-N L-methionine S-oxide Chemical compound CS(=O)CC[C@H](N)C(O)=O QEFRNWWLZKMPFJ-YGVKFDHGSA-N 0.000 description 1
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- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 235000005311 Pandanus odoratissimus Nutrition 0.000 description 1
- 240000002390 Pandanus odoratissimus Species 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
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- 235000011399 aloe vera Nutrition 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- 230000008025 crystallization Effects 0.000 description 1
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
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Description
Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av alkylerte azaglycinderivater. Redox kondensa-sjonssystemer dietylazodikarboksylsyre (DEAD) -trifenylfosfin (TPP), bedre kjent som Mitsunobu-systemet, er en meget anvendt metode for alkyleringsreaksjoner (eksempelvis på imider, heterocykliske strukturer osv.) (0. Mitsunobu, Synthesis 1981, 1). Primære og sekundære amider kan derimot ikke bli alkylert ved hjelp av dette systemet (S. Bittner et al., J. Org. Chem. 1985, 50, 1712).
Det ble overraskende oppdaget at acylerte azaglycinderivater kun blir alkylert ved hjelp av Mitsunobu-reaksjonen.
Gjenstand for oppfinnelsen er dermed en fremgangsmåte for fremstilling av alkylerte azaglycinderivater med generell formel I,
hvori
X betyr en aminobeskyttelsesgruppe, valgt blant Fmoc,
Boe eller benzyloksykarbonyl, C^-Cg-alkanoyl, C5-C14-arylkarbonyl eller C5-C14-<a>ryl-C1-C4-alkanoyl,
A betyr eventuelt i tredjefunksjonen beskyttet
aminosyre- eller iminosyrerester,
n 0-10, der X betyr C^-Cg-alkanoyl, Cfc-C-^-arylkarbonyl
eller <C>6-Ci4-aryl-Ci-C4-alkanoyl, dersom n = 0, og
R betyr C-^-Cg-alkyl, C^-C14-aryl-C1-C4-alkanyl eller
pyridyl-<C>1-C4-alkanyl,
kjennetegnet ved at man omsetter en generell forbindelse med formel II,
der X, A og n har ovennevnte betydning, med en primær eller sekundær alkohol og DEAD i overskudd samt et tri-C^-C^,-alkylfosfin, tri-C^-C^-arylfosfin eller pyridyl-di-C^-<C>^4-arylfosfin, der aryldelen eventuelt kan være substituert med di-C^-C4-alkylamino, i en eter ved 0°C til 30°C og eventuelt avspalter aminobeskyttelsesgruppen X, forutsatt at ved anvendelsen av tri-n-butylfosfin betyr X ikke Fmoc.
Under fosfinderivater anvendes fortrinnsvis trifenylfosfin, tri-n-butyl-fosfin, p-dimetyl-aminpfenyl-difenylfosfin (M. von Itzstein et al., Synth. Comm. 1990, 20, 2049), pyridyl-difenylfosfin (Ibid) og polymerbundet trifenylfosfin (R.A. Amos, J. Org. Chem. 1983, 48, 3598), spesielt trifenylfosfin.
Alkoholer anvendt for alkyleringen utgjør fortrinnsvis primær og sekundær C^-C^g-alkylalkanol, som f.eks. metanol, etanol, C£,-C^4-aryl-C^-C4-alkanol, som f.eks. benzylalkohol, naftyl-C^-C4~alkanol eller C5-Cy-heteroarylalkoholer, som f.eks. pyridyl-C^-C4-alkanol, idet aryl- og heteroarylalkoholene kan være substituert i den aromatiske ringen også med halogen, som fluor, klor, brom eller jod, C^-C^-alkyl eller C^-C^-alkoksy.
En aminosyre som nevnt ovenfor, utgjør alle naturlige eller unaturlige aminosyrer som, dersom de er chirale, foreligger i D- eller L-form. a-aminosyrene er foretrukket. Eksempelvis kan følgende nevnes: Aad, Abu, TAbu, ABz, 2ABz, cAca, Ach, Acp, Adpd, Ahb, Aib, pAib, Ala, 3Ala, AAla, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2« Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gin, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hile, hLeu, hLys, hMet, hPro, hPhe, hSer, hThr, hTTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, I va, Kyn, Lant, Len, Leu, Lsg, Lys, pLys, ALys, Met, Mim, Min, nArg, Nie, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, APro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, eThi, Thr, Thy, Thx, Tly, Tia, Tie, Trp, Trta, Tyr, Val, Nal, Tbg, Npg, Chg, Cha, Thia (jfr. f.eks. Houben-Weyl, Methoden der organischen Chemie, Band XV/l og 2, Stuttgart 1974).
Under en iminosyre forstås generelt naturlige eller unaturlige aminosyrer, der aminogruppene er enkeltsubstituerte. Spesielt kan i denne sammenhengen nevnes forbindelser som C^-Cg-alkyl, som eventuelt er enkel eller dobbelt umettet, og som kan være substituert med opptil tre like eller for-skjellige rester fra rekken merkapto; hydroksy; C1-C7-alkoksy; karabamoyl; C^-Cg-alkanoyl; karboksy; C^-Cy-alkoksykarbonyl: F; Cl; Br: I; amino; amidino, som eventuelt kan være substituert med en, to eller tre C^-C^-alkylrester; guanidino, som eventuelt kan være substituert med en eller to benzyloksykarbonylrester eller med en, to, tre eller fire C^-Cg-alkylrester; C^-Cy-alkylamino; di-Ci-Cy-alkylamino, C-^-C^-alkoksykarbonylamino; Cy-C^-aralkoksykarbonyl; c7_ci5<_ >aralkoksykarbonylamino; fenyl-C^-C4-alkoksy; 9-fluorenyl-metoksykarbonylamino; C^-C^-alkylsulfonyl; C^-C^-alkylsulfin-yl; C^-C^-alkyltio; hydroksamino; hydroksimino; sulfamoyl; sulfo; karboksamido; formyl; hydrazono eller iminosubstitu-ert. Videre kommer heterocykler fra følgende gruppe i betraktning: Pyrrolidin-2-karboksylsyre, piperidin-2-karboksylsyre, 1,2,3,4-tetrahydroisochinolin-3-karboksylsyre, dekahydroiso-chinolin-3-karboksylsyre, oktahydroindol-2-karboksylsyre, dekahydrochinolin-2-karboksylsyre, oktahydrocyklopenta[b]-pyrrol-2-karboksylsyre, 2-aza-bicyklo[2.2.2.]oktan-3-karboksylsyre, 2-azabicyklo[2.2.l]heptan-3-karboksylsyre, 2-azabicyklo[3.1.0]heksan-3-karboksylsyre, 2-azaspiro[4.4]-nonan-3-karboksylsyre, 2-azaspiro[4.5]dekan-3-karboksylsyre, spiro[(bicyklo[2.2.1]neptan)-2,3-pyrrol idin-5-karboksylsyre], spiro[ (bicyklo[2.2.2]oktan)-2,3-pyrrol idin-5-karboksylsyre], 2-azatricyklo[4.3.0.1^»^]dekan-3-karboksylsyre, dekahydrocy-klohepta[b]pyrrol-2-karboksylsyre, dekahydrocyklookta[b]-pyrrol--2-karboksylsyre, oktahydroisoindol-l-karboksylsyre, 2 , 3 , 3a , 4 , 6a-heksahydrocyklopenta[b] pyrrol-2-karboksylsyre , 2,3,3a,4,5,7a-heksahydroindol-2-karboksylsyre, tetrahydrotia-zol-4-karboksylsyre, isoksazolidin-3-karboksylsyre, pyrazoli-din-3-karboksylsyre, hydroksyprolin-2-karboksylsyre, som alle eventuelt kan være substituerte.
Heterocyklene som ligger til grunn for de ovennevnte restene, kommer eksempelvis fra
US-A 4.344.949, US-A 4.374.847, US-A 4.350.704, EP-A 29.488, EP-A 31.741, EP-A 46.953, EP-A 49.605, EP-A 49.658, EP-A 50.800, EP-A 51.020, EP-A 52.870, EP-A 79.022, EP-A 84.164, EP-A 89.637, EP-A 90.341, EP-A 90.362, EP-A 105.102, EP-A 109.020, EP.A 111.873, EP-A 113.880, EP-A 271.865 og EP-A 344.682.
Under en aminobeskyttelsesgruppe forstås alle innen peptid-kjemien vanlige aminobeskyttelsesgrupper, som f.eks. acetamidometyl (Acm), 1-adamantyloksykarbonyl (Adoc), 1-(1-adamantyl)-l-metyl-etoksykarbonyl (Adpoc), allyloksykarbonyl (Aloe), tert.-butyloksykarbonyl (Boe), 1-(4-bifenylyl)-l-metyletoksykarbonyl (Bpoc), a,a-dimetyl-3,5-dimetoksyben-zyloksykarbonyl (Ddz), 4-dihydroksaborylbenzyloksykarbonyl (Dobz), 9-fluorenylmetyloksykarbonyl (Fmoc), Isobornyloksy-karbonyl (Iboc), 1-metyl-cyklobutyloksykarbonyl (Mboc), 4-metoksybenzyloksykarbonyl (Moe), metylsulfonyletoksykarbonyl (Msc), 2-fosfonioetoksykarbonyl (Peoc), fenylsulfonyletoksy-karbonyl (Pse), 4-pyridylmetoksykarbonyl (Pyoc), 2,2,2-trikloro-tert.-butyloksykarbonyl (Tcboc), toluolsulfonyletok-sykarbonyl (Tse), benzyloksykarbonyl (Z), halogensubstituert benzyloksykarbonyl (Z(Haln)), 4-nitro-benzyloksykarbonyl (Z(N02)) (se også f.eks. T.W. Greene, "Protective Groups in Organic Chemistry", New York, John Wiley & Sons, 1981; A. Hubbuch, Kontakte Merck 1979, nr. 3, side 14-23). Foretrukket er Fmoc, Boe og Z. Den tredje funksjonen til amino- hhv. iminosyrer kan bli beskyttet med egnede beskyttelsesgrupper, som f.eks. beskrevet i E.E.Bullesbach, Kontakte Merck 1980, nr. 1, side 23-35, eller være glykosylerte (se f.eks. EP-A 263.521 (HOE 86/F 253)). Følgende kan spesielt nevnes: Arg(Tos), Arg(Mts), Arg(Mtr), ARg(Pmc), Asp(OBzl), Asp(OtBu), Cys(4-MeBzl), Cys(Acm), Cys(StBu), Glu(OBzl), Glu(OtBu), His(Tos), His(Fmoc), His(Dnp), His(Trt), Lys(Cl-2), Lys(Boc), Met(O), Ser(Bzl), Ser(tBu), Thr(Bzl), Thr(tBu).
^6-C14_arv^ er eksempelvis fenyl, naftyl, bifenylyl eller fluorenyl; foretrukket er fenyl eller naftyl. Under C5-C12-beteroaryl forstås mono-, bi- eller tricykliske hetero-aromater, som ikke inneholder sure -NH-grupper. Som eksmepel kan følgende nevnes: pyrrolyl, furyl, tienyl, imidazolyl, pyrazolyl, oksazolyl, isoksazolyl, tiazolyl, isotiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, isoindolyl, indazolyl, ftalazinyl, chinolyl, isochinolyl, chinoksalinyl, chinazolinyl, kinnolinyl eller e-karbolinyl.
De alkylerte peptidene kan bli renset ved krystallisasjon eller ved kieselgelkromatografi. Ved anvendelse av trifenylfosfin er det ved reaksjonen oppståtte trifenylfosfinoksid, ofte vanskelig å separere. Dette problemet oppstår ikke med vannoppløselige triarylfosfiner, som f.eks. p-dimetyl-aminofenyl-difenylfosfin. Det her oppståtte fosfinoksidderi-vatet lar seg meget lett separere fra lipofile forbindelser, f.eks. beksyttede alkylerte peptider, på grunn av at det er godt oppløselig i surt, vandig miljø (M. von Itzstein et al., Synth. Comm. 1990, 20, 2049). Trifenylfosfinoksid kan derimot også bli separert, idet man avspalter aminobeskyttelsesgruppen og deretter separerer de vannoppløselige saltene til de tilsvarende peptidene fra de lipofile trifenylfosfinoksid-ene lett ved fordeling mellom vann og eddikester eller eter. Anvender man polymerbundet trifenylfosfin, kan det dannete trifenylfosfinoksid-derivatet bli separert ved filtrering. Ved anvendelse av tri-n-butylfosfin (PBU3) ble det fastslått at dette reagenset ikke er kompatibelt med Fmoc-beskyttelsesgruppen. Den nevnte amino-beskyttelsesgruppen blir i løpet av reaksjonen delvis avspaltet, slik at i dette tilfellet skal en basestabil beskyttelsesgruppe (som f.eks. Boc-gruppen) anvendes.
Utgangsprodukter:
a) Fmoc-Phe-azagly-NH2(C25<H>24N404, MG 444).
Til en oppløsning av 15 g (38,76 mmol) Fmoc-Phe-OH i 70 ml DMF tilsetter man 5,43 g (1 ekv.) HOBt, 4,32 g (1 ekv.) HC1-semikarbacid og 4,90 ml (1 ekv.) NAM. Man avkjøler til 0°C og tilsetter under omrøring 8,14 g (1 ekv.) DCC. Dette omrøres i en time ved 0°C, og oppløsningen blir latt stå overnatt. Deretter blir oppløsningen filtrert og rotert. Resten blir fordelt mellom AcOEt/vann. Ved ristingen faller peptidet ut. Resten blir suget av og vasket med rikelig vann, og til slutt med eter og tørket i høyvakuum. Man oppnår 13,10 g (29,50 mmol) peptid.
Den opprinnelige væsken (AcOEt-fasen) blir behandlet som vanlig (vasket med mettet NaHCC^-oppløsning (2 ganger), vann, KHS04-oppløsning, vann, tørket over natriumsulfat). Den organiske fasen blir rotert, resten behandlet med eter og avfUtrert. Til slutt blir dette trøket i høyvakuum. Man oppnår ytterligere 0,92 g (2 mmol) peptid.
Utbytte: 14,02 g (31,57 mmol) = 8196
Sm.p.: 193°C
[A]g<3>: - 16,2° (c = 1 i AcOH)
b) Boc-Phe-azagly-NH2 (C15H22<N>404, MG 322)
Til en oppløsning bestående av 30 g (113,2 mmol) Boc-Phe-OH i
100 ml DMF, tilsetter man 15,85 g (1 ekv.) HOBt, 12,61 g (1 ekv.) HCl-semikarbacid og 14,33 ml (1 ekv.) NAM. Dette avkjøles ved 0°C, og man tilsetter under omrøring 23,77 g (1 ekv.) DCC. Dette omrøres i 1 time og blir latt stå over weekenden. Deretter blir oppløsningen filtrert og rotert. Resten blir fordelt mellom AcOEt og vann, den organiske fasen blir etter hverandre vasket med mettet NaHCOø-oppløsning (3 ganger), vann, KHS04-oppløsning (2 ganger) og vann. Etter tørkingen blir oppløsningen rotert, resten behandlet med eter, filtrert og tørket i høyvakuum.
Utbytte: 20,31 g (63 mmol) = 57$
[a]<g3>: + 2,2° (c = 1 i AcOH)
EKSEMPEL 1
a) Fmoc-Phe-N(Me)-NH-CONH2 (<C>26<H>26<N>404, MG 45S)
Til 50 ml absolutt THF ved 0°C, tilsetter' man 2,5 g (5,36
mmol) Fmoc-Phe-azagly-NH2 som suspensjon, 1,83 ml (8 ekv.) MeOH, 2,96 g (2 ekv.) trifenylfosfin (PPh3), porsjonsvis 1,773 ml (2 ekv.) dietylazodikarboksylsyre (DEAD) og etter 15 minutters omrøring ytterligere 738 mg (0,5 ekv.) PPh3 og 0,443 ml (0,5 ekv.) DEAD. PPh3 og DEAD blir etter 15 minutter tilsatt en gang til i samme mengde. Deretter innstiller man denne suspensjonen på RT og rører i 4 timer (ikke noe mer utgangsmateriale! ). Denne suspensjonen blir filtrert, resten vasket med eter og tørket i høyvakuum. Man oppnår 930 mg (2,03 mmol) rent N-Me derivat (36%). Deretter blir den opprinnelige væsken rotert og behandlet med eter og suget av. Dette bunnfallet inneholder den ønskede forbindelsen og trifenylfosfinoksid (P0Ph3).
Sm.p.: 173-174°C.
[a]g<3> = + 27° (c = 1 i AcOH)
b) HCI-Phe-N(Me)-NH-C0NH2 (C11<H>16<N>402, MG 236)
900 mg (1,96 mmol) rent Fmoc-Phe-N(Me)-NH-C0NH2 blir løst opp
i 15 ml DMF. Deretter tilsetter man 2,16 ml (10 ekv.) Et2NH. Dette omrøres i 15 minutter, og oppløsningen roteres inn. Resten blir behandlet med eter og filtrert. Til slutt blir forbindelsen løst opp i MeOH, med IN HC1 bragt til pH 6,40, og oppløsningen blir rotert. Resten blir behandlet med eter, filtrert og tørket i høyvakuum.
Utbytte: 430 mg (1,58 mmol) = 80%
Sm.p.: 98-105° C
[a]<g3> = + 23° ( c = 1 i AcOH)
EKSEMPEL 2
a) Fmoc-Phe-N(Et)-NH-C0NH2 (C27<H>28<N>404, MG 472)
Til 50 ml absolutt THF tilsetter man 4 g (9 mmol) Fmoc-Phe-azagly-NH2 som suspensjon, 4,23 ml (8 ekv.) EtOH, 4,72 g (2 ekv.) PPh3 og 2,834 ml (2 ekv.) DEAD. I løpet av 15 minutter tilsettes ytterligere to ganger 0,5 ekv. PPh3 (1,18 g) og DEAD (0,708 ml). Etter den andre tilsetningen, lar man suspensjonen bli omrørt i 4 timer. Deretter blir oppløsningen rotert, og forbindelsen renset gjennom kieselgel-kromatografi (løpemiddel: CE2Cl2/AcOEt = 9/1 og
CH2Cl2/MeOH = 9,5/0,5). Fraksjonene (med P0Ph3 forurens-ninger) blir rotert, og resten behandlet med petroleter (PE), filtrert og tørket i høyvakuum.
b) HCl-Phe-N(Et )-NH-C0NH2 (C12H18N402, MG 250 )
9 mmol av ovenfor isolerte peptid (med P0Ph3; regnet som 100%
utbytte) blir løst opp i 20 ml DMF. Etter tilsetning av 9,90 ml (10 ekv.) Et2NH, lar man dette røre i 30 minutter, og roterer oppløsningen. Resten blir behandlet to ganger med PE, til slutt suspenderert i en blanding AcOEt/vann og under omrøring med IN EC1 bragt til pH 6,40. Deretter blir denne blandingen ristet, vannfasen vasket 3 ganger med eter, rotert (rest eter og AcOEt destillert ut), filtrert og frysetørket.
Utbytte: 1,42 g (5,68 mmol) = 56%
Sm.p.: 91-94°C
[a]<g3> = + 62,5° (c = 1 i AcOH).
EKSEMPEL 3
a) Fmoc-Phe-N(iPr )-NH-C0NH2 (<C>28<H>30<N>404, MG 486)
Tittelforbindelsen blir fremstilt analogt eksempel 2a.
Reagenser:
- Fmoc-Phe-azagly-NH2: 4 g, 9 mmol
- iPrOH: 5,50 ml (8 ekv. )
- PPh3: 4,72 g (2 ekv. )
- DEAD; 2,834 ml (2 ekv.)
- to ganger 1,18 g PPh3 (0,5 ekv.) og 0,708 ml DEAD (0,5 ekv. )
Etter 4 timer blir oppløsningen rotert, og peptidet renset gjennom kieselgel-kromatograf i (løsemiddel: CH2Cl2/AcOEt = 9/1 og CH2Cl2/MeOH - 9/1). Fraksjonene (peptider med P0Ph3) blir rotert, resten behandlet med PE, avfiltrert og tørket i høyvakuum.
b) HCI-Phe-N(iPr)-NH-C0NH2 (C13<H>20<N>402, MG 264)
Blanding på 9 mmol; analogt eksempel 2b.
Utbytte; 1,48 g (5,60 mmol) = 55%
Sm.p.: lOS-HO^C
EKSEMPEL 4
a) Boc-Phe-N(CH2-(2-pyridyl))-NH-C0NH2 (C21<E>27<N>504, MG 413)
Til 50 ml absolutt THF ved 0°C tilsettes 4 g (12,42 mmol)
Boc-Phe-azagly-NH2 4,80 ml (2 ekv.) 2-pyridyl-metanol, 6,51 g (2 ekv.) PPh3, 3,911 ml (2 ekv.) DEAD og i løpet av 15 minutter ytterligere to ganger 1,63 g (0,5 ekv.) PPh3 og 0,978 ml (0,5 ekv.) DEAD. Oppløsningen blir rørt i to timer ved 0°C og to timer ved RT. Deretter blir oppløsningen rotert, resten fordelt mellom eter og vann og hurtig avdekantert. Den organiske fasen blir stående ved 30 minutter ved 0°C. Deretter blir bunnfallet filtrert ut, vasket med kald eter og tørket i høyvakuum. Man oppnår 1,41 g (3,41 mmol) ren forbindelse. Den opprinnelige væsken blir rotert og omsatt med vann til man oppnår en fast forbindelse. Deretter blir dette bunnfallet tatt opp i CH2CI2, tørket og rotert. Denne fraksjonen blir renset gjennom kieselgel-kromatografi (løpemiddel CH2Cl2/MeOH = 9/0,4, deretter CH2Cl2/MeOH = 9/1). Man oppnår 370 mg (0,89 mmol) ren forbindelse.
Utbytte: 1,78 g = 35%
[a]<g3>: + 8,9° (c = 1 i AcOH)
b) 2 HCl-Phe-N(CH2-(2-p<y>ridyl))-NH-C0NH2 (C16HigN502, MG 313)
1,69 g (4,09 mmol) ren Boc-Phe-N(CH2-(2-pyridyl)-NH-C0NH2
blir suspendert i 20 ml dioksan. Ved 0"C tilsetter man 20 ml mettet HCl-dioksanoppløsning og omrører dette i en time ved 0°C. Oppløsningen blir deretter rotert, resten fordelt mellom AcOEt og vann og vannfasen ytterligere vasket to ganger med AcOEt. Deretter blir vannfasen rotert, filtrert og frysetør-ket.
Utbytte: 1,29 g (3,34 mmol) = 84%.
EKSEMPEL 5
a) Boc-Phe-N(CH2-(2-naftyl))-NH-C0NH2 (<C>26<H>30N404, MG 462)
Til 50 ml absolutt THF ved 0°C tilsettes 4 g (12,42 mmol)
Boc-Phe-azagly-NH2, 2,17 g (1,1 ekv.) 2-naftalenmetanol, 6,19 ml (2 ekv.) PBu3 og 3,911 ml (2 ev.) DEAD. Denne oppløsningen røres i 2 timer ved 0°C og ytterligere 2 timer ved RT. Til slutt blir oppløsningen rotert, resten omsatt med 100 ml PE, og denne blandingen blir rørt ved 0°C i 5 minutter 10 til 20 ml eter tilsettes og et hvitt bunnfall oppnås, og dette blir filtrert. Det blir tørket i høyvakuum. Man oppnår 3,14 g peptid-derivat (forurenset med P0Bu3). Den opprinnelige væsken blir rotert og latt stå i PE over weekenden i kjølerom. Deretter blir bunnfallet suget av, vasket med kald PE og tørket i høyvakuum. Man oppnår ytterligere 1,40 g råpeptid (peptid med P0Bu3). Denne andre fraksjonen blir til slutt renset ved kieselgel-kromatografi (løpemiddel; CH2Cl2/MeOH = 9/0,5). Fraksjonene blir sentrifugert, resten behandlet med PE, avfUtrert og tørket i høyvakuum,
Utbytte: 520 mg
[a]<g3> = + 40,1° (c = 1 i AcOH)
b) HCl-Phe-N(CH2(2-naftyl))-NH-C0NH2 (C21<H>22<N>402, MG 362)
500 mg (1,08 mmol) ren Boc-Phe-N(CH2(2-naftyl)-NH-C0NH2 blir
oppløst i 10 ml dioksan. Ved 0°C tilsetter man under omrøring 10 ml av en mettet HCl-dioksanoppløsning og rører dette i 1 time ved 0°C. Deretter blir oppløsningen sentrifugert, resten omsatt med eter, filtrert og tørket i høyvakuum.
Utbytte: 360 mg (0,90 mmol) = 90%
EKSEMPEL 6
a) Z-Tyr(OiPr)-Pro-N(iPr)-NH-C0NH2(<C>2<gN>39<N>506, MG 553)
Tittelforbindelsen blir fremstilt analogt eksempel 2a.
Reagenser:
- Z-Tyr-Pro-azagly-NH2: 5 g (10 mmol)
- iPrOH: 5,80 ml (7,5 ekv.)
- PPh3: 5,25 g (2 ekv. )
- DEAD; 3,15 ml (2 ekv. )
- to ganger 1,31 g (0,5 ekv.) PPh3 og 0,80 ml (0,5 ekv.) DEAD
Etter 4 timer blir oppløsningen sentrifugert og resten renset ved kieselgel-kromatografi (løpemiddel: 1) CH2Cl2/aceton = 9/1 og 2)
CH2Cl2/MeOH = 9,5/0,5). Fraksjonene blir sentrifugert, bunnfallet behandlet med PE, avfiltrert og tørket i høy-vakuum .
Utbytte: 4,46 (8,06 mmol) = 80%
[a]<g3>: - 23,5° (c = 1 i AcOH)
Fortegnelse av anvendte forkortelser: Cha cykloheksylalanin
Chg cykloheksylglycin
DCC dicykloheksylkarbodi imid DMF dimetylformamid Nal 3-(2-naftyl)alanin NAM N-acetyl-morfolin
Npg neopentylglycin
PE petroleter
Tbg tert.-butylglycin
Thia 2-tienylalanin
Claims (2)
1.
Fremgangsmåte for fremstilling av alkylerte azaglycinderivater med generell formel
hvori
X betyr en aminobeskyttelsesgruppe, valgt blant Fmoc,
Boe eller benzyloksykarbonyl, C^-Cg-alkanoyl, C5-C^-arylkarbonyl eller C^-C^-aryl-Ci-C^alkanoyl,
A betyr eventuelt i tredjefunksjonen beskyttet
aminosyre- eller iminosyrerester,
n 0-10, der X betyr C^-Cg-alkanoyl, C^-C-^-arylkarbonyl
eller C^-C-^-aryl-C-L-C^alkanoyl, dersom n = 0, og R betyr C^-Cg-alkyl, C6-<C>14-aryl-C1-C4-alkanyl eller
pyridyl-<C>^-C4-alkanyl,
karakterisert ved at man omsetter en generell forbindelse med formel II,
der X, A og n har ovennevnte betydning, med en primær eller sekundær alkohol og DEAD i overskudd samt et tri-C^-C^,-alkylfosfin, tri-C^-C-^-arylfosf in eller pyr idyl-di-C£,-C14-arylfosfin, der aryldelen eventuelt kan være substituert med di-C^-C4~alkylamino, i en eter ved 0°C til 30°C og eventuelt avspalter aminobeskyttelsesgruppen X, forutsatt at ved anvendelsen av tri-n-butylfosfin betyr X ikke Fmoc.
2.
Fremgangsmåte ifølge krav 1, karakterisert ved at man anvender trifenylfosfin, tri-n-butyl-fosfin, p-dimetyl-aminofenyl-difenylfosfin pyridyl-difenylfosf in eller polymerbundet trifenylfosfin.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4102015 | 1991-01-24 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO920312D0 NO920312D0 (no) | 1992-01-23 |
| NO920312L NO920312L (no) | 1992-07-27 |
| NO179747B true NO179747B (no) | 1996-09-02 |
| NO179747C NO179747C (no) | 1996-12-11 |
Family
ID=6423602
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO920312A NO179747C (no) | 1991-01-24 | 1992-01-23 | Fremgangsmåte for fremstilling av alkylerte azaglycinderivater |
Country Status (13)
| Country | Link |
|---|---|
| US (1) | US5326875A (no) |
| EP (1) | EP0496393B1 (no) |
| JP (1) | JP3018264B2 (no) |
| AT (1) | ATE117673T1 (no) |
| CA (1) | CA2059909C (no) |
| DE (1) | DE59201241D1 (no) |
| DK (1) | DK0496393T3 (no) |
| ES (1) | ES2069322T3 (no) |
| FI (1) | FI920270A (no) |
| GR (1) | GR3015103T3 (no) |
| IE (1) | IE66328B1 (no) |
| MX (1) | MX9200289A (no) |
| NO (1) | NO179747C (no) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7387779B2 (en) * | 1998-06-17 | 2008-06-17 | Beth Israel Deaconess Medical Center | Anti-angiogenic proteins and fragments and methods of use thereof |
| DK1633702T3 (da) * | 2003-05-30 | 2008-11-10 | Prozymex As | Proteaseinhibitorer |
| CA2570800A1 (en) * | 2004-06-18 | 2006-01-26 | Wyeth | Processes for preparing 6-alkyl-5-arylsulfonyl- dihydrophenanthridines |
| US7178756B2 (en) | 2005-03-18 | 2007-02-20 | Eastman Kodak Company | Automatic perforated web splicing system |
-
1992
- 1992-01-21 US US07/822,929 patent/US5326875A/en not_active Expired - Fee Related
- 1992-01-22 FI FI920270A patent/FI920270A/fi unknown
- 1992-01-23 DE DE59201241T patent/DE59201241D1/de not_active Expired - Fee Related
- 1992-01-23 NO NO920312A patent/NO179747C/no not_active IP Right Cessation
- 1992-01-23 AT AT92101078T patent/ATE117673T1/de not_active IP Right Cessation
- 1992-01-23 CA CA002059909A patent/CA2059909C/en not_active Expired - Fee Related
- 1992-01-23 ES ES92101078T patent/ES2069322T3/es not_active Expired - Lifetime
- 1992-01-23 IE IE920201A patent/IE66328B1/en not_active IP Right Cessation
- 1992-01-23 EP EP92101078A patent/EP0496393B1/de not_active Expired - Lifetime
- 1992-01-23 MX MX9200289A patent/MX9200289A/es unknown
- 1992-01-23 DK DK92101078.1T patent/DK0496393T3/da active
- 1992-01-23 JP JP4009826A patent/JP3018264B2/ja not_active Expired - Fee Related
-
1995
- 1995-02-17 GR GR950400321T patent/GR3015103T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO920312L (no) | 1992-07-27 |
| JPH04334360A (ja) | 1992-11-20 |
| ATE117673T1 (de) | 1995-02-15 |
| FI920270A0 (fi) | 1992-01-22 |
| FI920270A (fi) | 1992-07-25 |
| ES2069322T3 (es) | 1995-05-01 |
| DE59201241D1 (de) | 1995-03-09 |
| US5326875A (en) | 1994-07-05 |
| MX9200289A (es) | 1992-07-01 |
| EP0496393B1 (de) | 1995-01-25 |
| CA2059909A1 (en) | 1992-07-25 |
| DK0496393T3 (da) | 1995-06-26 |
| IE66328B1 (en) | 1995-12-27 |
| JP3018264B2 (ja) | 2000-03-13 |
| GR3015103T3 (en) | 1995-05-31 |
| CA2059909C (en) | 2002-05-21 |
| NO920312D0 (no) | 1992-01-23 |
| EP0496393A1 (de) | 1992-07-29 |
| IE920201A1 (en) | 1992-07-29 |
| NO179747C (no) | 1996-12-11 |
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