PL154006B1 - Method for manufacturing pharmacologically active catechin derivatives - Google Patents

Method for manufacturing pharmacologically active catechin derivatives

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Publication number
PL154006B1
PL154006B1 PL1987283185A PL28318587A PL154006B1 PL 154006 B1 PL154006 B1 PL 154006B1 PL 1987283185 A PL1987283185 A PL 1987283185A PL 28318587 A PL28318587 A PL 28318587A PL 154006 B1 PL154006 B1 PL 154006B1
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PL
Poland
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formula
sup
defined above
group
pharmacologically active
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PL1987283185A
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English (en)
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    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/24—[b,e]-condensed with two six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Description

POCHODNYCH KATECHINY
Niniejszy wynalazek dotyczy sposobu wtwarzania nowych, farmakologicznie czynnyoh pochodnych katechiny o wzorze 1, w którym R i Rg oznaczają woodr, niższy acyl, aroil albo niższy alkiookarbamoil i X oznacza podstawnik elektroujemny taki, jak chlorowiec, grupa nitrowa, cyjanowa albo tróίΡΙ^^ιτΕyyoowa w pozycji 5 i Rg oznacza grupę o wzorze 2, w którym Rg i Rg niezależnie oznaczają wodór albo jedną z następujących grup: alkil, alkenyl, alkinyl, cykloalkil, aralkil, które są ewentualnie podstawione przez grupę hydroksylową, albo aryl, albo razem wzięte tworzą grupę piperydylową, która jest ewentualnie podstawiona przez arylokarbonyl alho cykloalkilokarbonyl, oraz farmaceutycznie dopuszczalnych soli tych związków.
Określenie alkil zastosowane tutaj samo albo jako część innej grupy obejmuje zarówno rodniki o łańcuchu prostjm, jak i rozgałęzoonym, zawierające do 18 atomów węgla, korzystnie o 1-8 atomach węgla, najkorzystniej 1-4 atomach węgla. Określenie niższy alkil, zastosowane tutaj samo albo jako część innej grupy, obejmuje zarówno rodniki o łańcuchu prostym i rozgałęzonnym o 1-7, korzystnie 1-4, najkorzystniej 1 albo 2 atomach węgla. Szczególnie przykłady rodników alkilwych i niższych rodników alkilwwych, stanowią odpowiednio meyl, etyl, propyl, izopropyl, butyl, III-rz.-butyl, pentyl, heksyl, oktyl, decyl i dodecyl, włącznie z ich różnymi izomerami o łańcuchach rozgałęzionych.
Okkeślenia alkenyl i alkinyl oznaczają rodnik węglowodorowy, jak podano wyżej w odniesieniu do określenia alkil, zawierający odpowiednio przynajmniej jedno podwójne wiązanie węgla z węglem i wiązanie potrójne węgla z węglem. Rodniki alkenylowy i alkinylowy mogą zawierać do 12, korzystnie 1t8, najkorzystniej 1-4 atomów węgla.
Okkeślenie acyl, zaslolwiane tutaj samo albo jako część innej grupy, odnosi się do grupy alkilokarbonylooeU albo alkjnnlokaΓbonnllwej, przy czym grupy alkHowa i alksnyoowa są zdefiniowane w/ń^żj.
154 006
154 006
Określanie aroil, zastosowane tutaj samo albo jako część innej grupy, odnosi się do grupy arylokarbonylowejj grupa jest monnoykliczną albo bicykliczną grupą, zawierającą 6-10-atomów węgla w części pierścieniowej. Szczególne przykłady grup arylowych stanowią feny]., naftyl itp.
Określenie niższa grupa alkildeenowa odnosi się do łańcucha, zawierającego 2-8, korzystnie 2-4 atomów węgla. Podobnie określenie grupa cykłoalkilidenowa odnosi się do cyklicznej grupy węglowodorowej, zawierającej 3-5, korzystnie 5-7 atomów węgla.
Okkeslenie alkoksy, zastosowane samo albo jako część innej grupy, obejmuje rodnik alkilowy, jak zdjfinnowaeo wyżej, połączony z atomem tlenu.
Określenie cykloalkil obejmuje nasycone cykliczne grupy węglowodorowe, zawierające 3-8, korzystnie 5-7 atomów węgla. Szczególne przykłady stanowią grupy cyklopentylowa, cykloheksylowa, cykloheptylowa i adamntylowa.
Okreslenie aralkil zastosowane tutaj odnosi się do grup alkilewych, jak zdefiniowano wyżżj, zawierających podstawnik arylowy. Szczególny przykład stanowi grupa benzylowa .
Określenie chlorowiec zastosowane tutaj odnosi się do chloru, bromu, fluoru albo jodu, korzystny jest chlor i brom.
Sposób według wynalazku polega na tym, że związki o wzorze 3, w którym R^ i X mją wyżej podane znaczenie i Ϊ oznacza chlorowiec, poddaje się reakcji z aminą o wzorze 4, w którym Rg i Rg mją wyżej podane znaczenie, z utworzeniem związku o wzorze 1a, w którym R^, R2, X, Rg i Rg mją wyżej podane znaczenie.
Nowe związki otrzymane sposobem według wynalazku łączy się również w kompozycje z lewodopa /lewodeuhySrolsyfθeylooαaneną/. Mogą one zawierać również peryferyjne inhibitory dopa-dekarboksylazy /DDC/ takie, jak karbidopa albo benserazydek, lecz ich obecność jest nie zawsze potrzebne.
Katechino-O-πietySlOransfr raza /COM?/ katalizuje przenoszenie grupy mtylowej z S-adeno2ylo-L-e.etioeiny do grupy związków o strukturach katechinowych. Ten enzym jest ważny w pozaneuronowej dezaktywsaji katechinoamin i leków o strukturach katechinowych. COMT jest jednym z najważniejszych enzymów objętych metabolizmni katechinoamin. Jest on obecny w większości- tkanek, zarówno w obwodowym jak i ośrodkwwym układzie nerwowym, Najwyższe aktywności znaleziono w wątrobie, jelicie i nerce. COMT przypuszczalnie jest obecna w postaciach rozpuszczalnych i związanych w błonie. Dokładny charakter tych dwóch postaci nie został ustalony.
W chorobie Parkinson a neurony dopaminergiczee, początkowo neurony nigrostriatalne, są uszkodzone, powodując niedobór dopaminy w mózgowych zwojach podstawowych. Ten niedobór może tyć wyrównany przez lewodopa, który jest przekształcony w dopai^-inę w układzie nerwowym ośrodkowym pod wpływem DDC.
Obecneeljczjeie lewodopa jest prawie niezmiennie uzupełniane inhibitorem obwodowym DDC w celu powstrzymania zbyt wczesnego tworzenia dopaminy i tym samym zwiększenia mózgowego stężenia lewldlpa i zmneij3zenia obwodowych efektów ubocznych 0opamiey. W dodatku do DDC, COM mesabi^lizuje lewodopa, przekształcając ją w 3-0-mtylodopa /3-CKD/, 3-OMD z łatwością przenika barierę krwi-mózgu via aktywny system przenoszenia. Sam jest on terapeutycznie eijjfekZeuey i szkodliwy, jeśli współzawodniczy z ljwo0opa. 3-OMD jest gromadzony w tkankach z powodu długości jego okresu półtrwania /około 15 h/ w porównaniu z lewodopa /około 1 h/. Wysoka aktywność COMT wyraźnie koreluje z ubogą skutecznością lewodopa plniml obecności obwodowego inhibitora DDC. W dodatku do oksydazy monoαmies /MAC/, COMT jest głównym enzymm, uczeatnictącym w mjεtoliźmie aminowym. Przez hamcwwnie mmtabolimu amin endogennych /dopamna, noradrenalina, adrenalina/ w mózgu inhibitory CCMT zmnnejszają rozkład tych związków. Tak więc mogą one być przydatne w leczeniu depresji.
Frzez skuteczne ha-noeenie obwodowego COŁTT, inhibitory C0L7? kierują drogę mjabolicznt lewodopa w stronę dekarboksylacja, tworząc tym samym więcej dopasiny, która jest ważna w leczeniu nadciśnienia i niewydolności serca, eijocir'kiwaeie zaobse wjowano, że związki według niniejszego wy^lszku są eadzwysss;jnie jfekSywnsmi inhibitorami CCI.JT. Otwierają
154 006 one nowe, przedtem nieznane możliwości w leczeniu choroby Parlinson 'a. V dodatku nowe związki mogą być przydatne również w leczeniu depresji i niewydolności serca, jak również nadciśnienia.
Jako inhibitory COMT znane są w stanie techniki n-butylogalusan /Bricson, A.D.J.
Sci. 1971, 14, 193/ i 3*, 4 '-dwuhydrożky-2-metyllżetylofe nyloke to n /U 0521/ /Giles, H.B.; Miler, J. W, J. Pharm col. Exp. Ther, 1967, 156, 201/.
N-butylogalusan jest słabym inhibioorem COMT i z powodu swej toksyczności nie nadaje się do aplikacji /Ericsson, AD., J. Sci. 1971, 14, 193/, 3*, 4 *-dwwhhdroksy-2mtyloetylofenyloketon był również tesoowany u pacjenta /Reches, A; Pahn, S. Adv.
Neurol. 1984, 40, 171/, lecz ten związek ma tę wadę, le hamuje również hydroksylazę tyrozyny, która jest ważna dla biosyntezy katecholoamin /Lloyd, T.; Boyd, B.; Walega, MA; Ebersole, B.J.; Weesz, J., J. Neurochem, 1982,' 38, 948/. Moc tego związku jest również bardzo niska, prawdopodobnie dlatego, że jest on dobrym substratem COIM. Zwwązki ujawnione w niniejszym zgłoszeniu są niezwykle swoistymi inhibitorami COtST z brakiem aktywności przeciw innym istotnym enzymom związarym z syntezą i TOtlbolioϊr^m katecholoamin i najbardziej aktywne związki są więcej niż 1000 razy silniejsze niż 3*,4''-^dwuhyd roksy-2-met ylo -e tylofe nyloke t o n.
Nowe inhibitory COŁtt, które powstrzymują tworzenie 3-OMD, mogą zmnnejszyć niepomyślne efekty długotrwałego stosowania lewodopa. Ponadto można zmnnejsznć dawki lewodopa. Wylcazano, że dawka lewodopa może być zimnejszona do połowy albo do jednej trzeciej dawki stosowanej bez inhibitora COIM. Ponieważ dozowanie lewodopa jest indywidualne, trudno jest podać jakieś absolutne dawkowanie, lecz dzienne dawki tak niskie, jak 25-50 mg brano pod uwagę jako wyytarczające na samym początku.
Wstępne próby na n-butylogalusanie, znanym inhibitorze COBM, wykazywały wyraźnie korzystne działanie n-butylogalusanu u pacjentów z chorobą Parkinson a. Badanie jednak przerwano z powodu zbyt wysokiej toksyczności n-butnlogllusanu.
Skuteczność hamującą COMT związków według wynalazku tesoowano stosując następujące doświadczalne sposoby postępowania.
Oznaczenie aktywności COMT in vitro.
Aktywność COMT in iitro oznaczano w preparatach enzymu, w^zlelonych z mózgu i wątroby żeńskich szczurów Han-Wist, ciężar około 100 g. Szczury uśmiercono za pomocą dwutlenku węgla, a tkanki usunięto i przechowywano w temperaturze -80°C aż do oznaczanie ektywności enzymu.
Preparat enzymu sporządzono przez homogenizowanie tkanek w 10 mŁI buforu fogfoltżooegż, pH 7,4 /1:10 wagowo g/ml/, który zawierał 0,5 mK dwojiożreilolu. Produkt homoognnizaji odwirowano przy 15 000 x G w ciągu 20 minut. Produkt unoszący się na powOtΓZjhni odwirowEno przy 100 000 x G w ciągu 60 minut. Wssyntkte procesy przeprowadzono w temperaturze +4°C. Produkt unoszący się na powierzchni z ostatniego odwirowania /100 000 x G/ użyto do oznaczenia aktywności rozpuszczalnego enzymu COIM.
Oznaczenie IC'' przeprowadzono przez pomiar aktywności COMT w kilku stęże niech leku w mieszaninie reakcyjnej, która zawierała preparat enzymu, 0,4 mM kwasu do^uhynroksybenzoesowego /substrat/, 5 mli chlorku mgnezu, 0,2 mM S-adenozy^-L-metioniny i inhibitora COMT w 0,1 M buforu fosforanowego, pH 7,4. Do próbki kontrolnej nie dodano inhibitora COMT. Miiszaninę poddano inkubacji w ciągu 30 M.nut w tempe^^rze 37°C, po czym reakcję przerwano za pomocą kwasu nadchlorowego i wytrącone proteiny usunięto przez odwirowanie /4000 x G/ w ciągu 10 minuu/. Aktywność enzymu zmorzono przez oznaczenie stężenia kwasu 3-me toktn-4-hnrroksybenzoesowego, utworzonego z substratu COMT /^was douhynroksytetzoesowy,/ za pomocą HPLC /chromfoggam cieczowej wyso^oprez^in-nj/ z zastosowaniem detektora tltktżocheotjzttgż. Clh:ΌIIOtożΓalię przjpΓowldzono przez wtryskiwanie 20/:1 próbki do kolumny 4,6 o x 150 mm Spherisorb ODS /wielkość cząstki 5/woO. Produkty reakcji eluowano z kolumny za pomocą 20¾ meeanolu, zawierającego 0,1 U fosforanu, 20 mM kwissu cytrynowego i 0,15 mi EDTA /kwasu TCrsenoMgo/, pH 3,2, prEy szybkości przepływu 1,5 ml/minutę. Detektor jlektżccheoijznn nastawiono na 0,9 V wobec elektrody Ag/AgCl. Stężenie produktu
154 006 reakcji, kwasu 3-metoksy^-hydroksybenzoesowego, porównano z próbkami kontrolnymi i próbkami zewierającymi inhibitor COI.TT. Wartość ΙΟ^θ stanowi stężenie, które powoduje 50% zmnnejszenie aktywności COOM.
7/ynnki. Najlepsze inhibitory C0?7T według wynalazku były więcej niż tysiąc razy bardziej skuteczne in vitro niż najbardziej skuteczny znany związek odniesienia U-0521 /patrz tabela/. Związek odniesienia U-0521 ponadto przenika barierę krwi-mózgu i powstrzymuje aktywność hydroksylazy tyrozyny, tym samym blokując biosyntezę witalnie ważnych katechi^min. Przeciwnie, związki są specyficzne dla COMT i nie przenikają istotnie bariery krwi-mózgu.
Wyynki in vitro
Tabela
Przykład I. N-/l-adamantnlo/-3,4-dwuacetoksy-5-nitrobenzamid. Roztwór, zawierający 0,85 g kwasu 3,4-dwuujetoksy-5-a.itrobanoeesowego i 0,32 g chlorku tionylu i katalityczną ilość Ν,Ν-diUπmiynoformamidu w 10 ml toluenu ogrzewano w ciągu 1 h w temperaturze 80°C. Rozpuszczalnik odparowano pod zmniejszonjm ciśnieniem, a pozostałość rozpuszczono w 5 ml dwuchlorometanu i dodano do msszaniny, zawierającej 0,56 g chlorowodorku 1-aminoadamintanu i 0,94 ml trójβnylaaminy w 10 ml dwuchloromtanu. Całość mieszano w cisgu 15 minut w temperaturze 20°C. Dodano wodę do mieszaniny reakcyjnej i fazę dwuchlorometanową oddzielono. Rozpuszczalnik odparowano pod zmniejszoiym ciśnieniem, uzyskując wydajność lepkiego oleju, wynoszącą 1,2 g /100%/.
Przykład II. N-/1-adamanaylo/-3,4-dwuhydroksyn5-nitrobinzamid. Roztwór zawierający 1,2 g produktu otrzymanego w przykładzie I i katalityczną ilość kwasu siarkowego w 10 ml meanolu ogrzewano pod chłodnicą zwrotną w ciągu 3 h. Dodano 20 ml wody i przez oziębianie wykrystalżoowano 0,85 g /89,5%/ żądanego produktu, temperatura topnienia 207-208°C.
Przykład III. 4-cnkloheksyloksrbonyno-1-/3,4-dwucαeioksyn---nirobenEzίlo/-piperydyna.
Powtórzono postępowanie, opisane w przykładzie I stosując 0,58 g cykloheksylokarboanloeeeerydnay i 0,38 ml P^-luyydyny zamiast odpowiednio chlorowodorku 1-aminoadamantanu i trójenyljεminn. 7^8jność 1,2 g /87%/, lepki żółty olej.
Przykład IV. 4-cykloheksylokaΓbonnnl-1-/3,4-dwuCydΓok3y-5-nitrobsiazilu/-piper^yna.
Powtórzono postępowanie, opisane w przykładzie II, stosując 1,2 g produktu otrzymanego w przykładzie III. wydaność 0,5 g /50%/, tem^piritura topnienia 155-165°C.
Przykład V. N-bsnzylo-3,4-dwuacetoksy-5-nitrobenzamid.
0,75 g kwasu 3,4-diUacetoksy-5-nitΓoiaioeesiwego przekształcono w oipowiidni chlorek kwasowy w sposób opisany w przykładzie I. Rozpuszczono go w 5 ml dwuchlorometanu i dodano do roztworu zawierającego 0,27 ml beaznloaminy i 9,5 ml 2,6-lunydynn w 7 ml dwuuhloromtanu, wy da ność 0,95 g /96%/, lepki olej.
Przykła d VI. N-benzylo-3,4-dwuhynroksy-5-nitrobiniamid.
Pow^rzono postępowanie, opisane w przykładzie II, stosując 0,95 g produktu, otrzymanego w przykładzie V. Wj^yd^ność 0,5 g /685/, timpeΓatura topnienia 185-139°C.
Przykład VII. N-/1-adamanaylo/-3,4-dwuacetok^n-5-chlorobenzamid.
0,7 g kwasu 3,4-dwuacetoksn-5-chloroeazzieoiWigo przekształcono w odpovw^dni chlorek kwasowy i powtórzono postępowanie, opisane w przykładzie I. 7/ynεjność 1,0 g /95%/, lepki ole j.
154 006 irzykła d VIII. N-/l-adamantylo-3,4-dwuhydroksy-5-chlorobensamid.
Produkt z przykładu VII odacatyOowano w sposób, opisany w przykładzie II. 'ydajność 0,6 g /7C%/, temperatura topnienia 244-247°C.
Preykła d IX. N-/1-adamantylo/-3,4adwuacetoksy-5-cyjanobenzamid.
0,6 g kwasu 3,4-dwuacetoksy-5-cyjanobenoeesowego prze kształć ono w odpowiedni chlorek kwasowy i powtórzono postępowanie, opisane w przykładzie I. Wyddjność 0,75 g /38%/, lepki olej.
Przykład X. ^I-/1-adamantylo/-3,4a0wuhyarnksy-5-cy;janobeazamid.
0,75 g powyższego produktu odacetynowann w sposób, opisany w przykładzie II. Y/yddjność 0,5 g /£39%/, temperatura topnienia 253-255°C.
Przykład XI. N-/3-hydroksyprnpyln/-3,4adiuhydróksy-5-aitrobenzamia.
Powtórzono postępowania opisane w przykładach I i II, stosując kwas 3,4^dwu^(^^toksy-5-nitnoeannoenowy i 3-aminopropan-1-01. 'YYddjność 85%, temppratura topnienia 16O-163°C.

Claims (1)

  1. Sposób wytwarzania nowych, farmakologicznie czynnych pochodnych katechiny o wzorze 1, w którym R·, i R? oznaczają wodór, niższy acyl, arnil albo niższy alkilokarbamoil i X oznacza podstawnik elektroujemny taki, jak chlornoien, grupa nitrowa, cyjanowa albo trój flucoometylowa w pozycji 5 i Rj oznacza grupę o wzorze 2, w którym Rg i Rg niezależnie oznaczają wodór albo jedną z następujących grup alkil, alkenyl, alkinyl, cykloalkil, aralkil, które są ewa^ua^^ podstawione przez grupę hydroksylową albo aryl, albo razem wzięte tworzą grupę piperydylową, która jest ewentualnie podstawiona przez ardlokarbnayl albo cykloalkilokarOnayl, znamienny tym, że związek o wzorze 3, w któiym R.|, Rg i X mają wyżej podane znaczenie i Y oznacza chlnrnwien, podda je się reakcji z aminą o wzorze 4, w którym Rg i Rg mją ^żej podane znaczenie, z utworzeniem związku o wzorze 1a, w którym R^, Rg, X, Rg i Rg mają wyżej podane znaczenie.
PL1987283185A 1986-11-28 1987-11-27 Method for manufacturing pharmacologically active catechin derivatives PL154006B1 (en)

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FI93350B (fi) 1994-12-15
SU1729291A3 (ru) 1992-04-23
FI875229A (fi) 1988-05-29
DD281375A5 (de) 1990-08-08
FI875229A0 (fi) 1987-11-27
FI93350C (fi) 1995-03-27
MX9524A (es) 1993-12-01
FI864875A0 (fi) 1986-11-28
HRP921250A2 (en) 1998-06-30
KR960004771B1 (en) 1996-04-13
NO1999010I1 (no) 1999-06-10
GB8712437D0 (en) 1987-07-01
ZA878953B (en) 1988-05-24
LT3770B (en) 1996-03-25
HRP921250B1 (en) 2000-06-30
KR880006170A (ko) 1988-07-21
LTIP915A (en) 1995-03-27
US5112861A (en) 1992-05-12

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