DK148595B - Analogifremgangsmaade til fremstilling af s,s'-bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)carbonodithioat eller pharmaceutiskacceptable salte deraf - Google Patents

Analogifremgangsmaade til fremstilling af s,s'-bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)carbonodithioat eller pharmaceutiskacceptable salte deraf Download PDF

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DK148595B
DK148595B DK303274AA DK303274A DK148595B DK 148595 B DK148595 B DK 148595B DK 303274A A DK303274A A DK 303274AA DK 303274 A DK303274 A DK 303274A DK 148595 B DK148595 B DK 148595B
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hydroxy
bis
methyl
hydroxymethyl
pyridylmethyl
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DK148595C (da
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Tsung-Ying Shen
Howard Jones
Dennis Michael Mulvey
Conrad Peter Dorn
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Merck & Co Inc
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
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    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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Description

i 148595
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af det hidtil ukendte S,S'-bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)carbonodithioat eller pharmaceutisk acceptable salte deraf, hvilken frem-5 gangsmåde er ejendommelig ved det i kravets kendetegnende del anførte. De omhandlede forbindelser egner sig som lægemidler, især til behandling af rheumatisk arthritis.
Den ved fremgangsmåden ifølge opfindelsen fremstillede 10 forbindelse har den i kravet angivne almene formel I.
Opfindelsen angår som nævnt også fremstilling af pharmaceutisk acceptable salte, nemlig additionssalte af mineralsyrer og organiske syrer af sædvanlig art, såsom saltsyre, hydrogenbromidsyre, svovlsyre, salpetersyre, malein-15 syre, fumarsyre, vinsyre og ravsyre.
Til trods for en intensiv forskning i de sidste 20 år i forbindelse med antiinflammatoriske midler er der stadig et stort behov for et effektivt og uskadeligt middel til behandling af rheumatisk arthritis. Konventionelle ikke-20 steroide, antiinflammatorisk, analgetisk og antipyretisk aktive midler, såsom aspirin og mange eksperimentelt nye lægemidler under klinisk bedømmelse, er effektive til fjernelse af symptomer på det akutte syndrom, men er ude af stand til at indvirke på selve sygdommens forløb. Som føl-25 ge heraf har den antirheumatiske virkning af to gamle mid ler, nemlig guld og D-penicillamin, til trods for deres potentielle sidevirkninger, opnået fornyet interesse i de sidste få år. Den kliniske effektivitet af begge lægemidler er atter blevet bekræftet af godt kontrollerede undersøgelser på en række klinikker. Mange gigtforskere har ud-30 trykt den opfattelse, at en D-penicillamin-lignende for bindelse med forbedrede egenskaber ville være et værdifuldt bidrag til medicinen på dette vigtige felt. Det må derfor betragtes som en vigtig opdagelse, at den hidtil ukendte 148595 2 mercaptomethylpyridin, der omfattes af den foreliggende opfindelse, har en betydelig grad af antirheumatisk arthri-tis-aktivitet.
De omhandlede forbindelser kan indgives oralt, topisk, pa-5 renteralt, ved inhalering af spray eller rektalt i enheds-doser indeholdende konventionelle, ikke-giftige, pharmaceu-tisk acceptable bæremedier, tilsætningsmidler og fyldstoffer.
Sædvanligvis er en effektiv dosis på 5-50 mg pr. kg legems-10 vægt pr. dag.
Forbindelsen I fremstilles ifølge opfindelsen ved (å) behandling af 2-methyl-3-hydroxy-4-hydroxymethyl-5-mercapto-methylpyridin med p-nitrophenylchlorformiat eller phosgen i et aprotisk opløsningsmiddel, såsom 15 THF, ether, glyme eller diglyme, ved 0-1 °C i 1-3 ti mer efterfulgt af opvarmning til 20-50 °C.
(b) hydrolyse af en forbindelse med formlen: r.1och2 r17 cii2or1 I c„ ς 1 os'!9 L y XX 11 S^CH3 med fortyndet base eller med fortyndet mineralsyre ved 19 ?n 20-50 °C i 1-5 timer, hvor R·1 og er ens eller for- skellige og repræsenterer hydrogen, en syrelabil be- 3 148595 = 19
skyttende gruppe, såsom tetrahydropyranyl, eller R
20 og R repræsenterer tilsammen en gruppe med formlen:
/G
4 s hvor R og R er ens eller forskellige og er hydrogen, 17 l o C, ,-alkyl eller phenyl, og R er =0 eller =N-R , t g hvor R er hydrogen, phenyl eller C, ,-alkyl, idet, 17 19 20 når R er =0, må R og R ikke begge være hydrogen; (c) oxidation af en forbindelse med formlen:
^2°11 S C-HOII
II I
HO £Η,— S~ C — S —CH? JL OH III
n ti CBj'® CHj eller ch3 chYY S "lTCH3 1111 3 CH7-S-C-S-CH2-|r^^f vi,, med et oxidationsmiddel, såsom kaliumpermanganat, salpetersyre eller mercurioxid, ved stuetemperatur i 1-3 timer, om nødvendigt efterfulgt af hydrolyse af dioxin-gruppen; (d) syrehydrolyse af en forbindelse med formlen: 148595 4 CH2OR20
IV
CH3 N' med mineralsyre og langsom opvarmning til 80-100 °C, 19 20 hvor R og R* har den ovenfor angivne betydning.
EKSEMPEL 1 S,S *-bis(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylme-
Trin Ai Præparation af S,S'-bis(2,2,8-trimethyl-4H-l,3- dioxino-[4,5-c]pyridin-5-yl-methyl)-carbonodithioat
Til en isafkølet opløsning af 4,5 g 5-mercaptomethyl-2,2,8-trimethyl-l,3-dioxino[4,5-c]pyridin i 50 ml tør pyridin 10 dryppedes 10 ml af en 12,5¾ opløsning af phosgen i benzen.
Reaktionsblandingen bragtes op på stuetemperatur og omrør-tes i tre timer, hvorefter den blev inddampet i vakuum.
Remanensen ekstraheredes mellem benzen og mættet natrium-carbonatopløsning. Benzenlaget fraskiltes, vaskedes med 15 vand, tørredes over natriumsulfat og inddampedes i vakuum.
Remanensen kromatograferedes på 250 g silicagel. Ued elu-ering med ether dannedes 3,59 gS,S'-bis(2,2,8-trimethyl-4H-l,3-dioxino[4,5-c]pyridin-5-yl-methyl)-carbonodithioat, smp.: 88-9Q °C.
5 148595
Trin B; Præparation af S,S'-bis(3-hydroxy-4-hydroxymethyl- 2-methyl-5-pyridyl-methyl)carbonodithioat-dihydro-chlorid-monohydrat__
En opløsning af 0,2 g S,S'-bis(2,2,8-trimethyl-4H-l,3-dio-5 xino-[4,5-c]pyridin-5-yl-methyl-carbonodithioat i 0,9 ml iskold koncentreret saltsyre omrørtes i kulden i 5 minutter, hvorefter den fortyndedes til 2,5 ml med methanol.
Ved afkøling i is/acetone dannedes et krystallinsk bundfald, som frafiltreredes til dannelse af 0,120 g S,S'-bis(3-hy-10 droxy-4-hydroxymethyl-2-methyl-5-pyridy1-methyl)carbonodio- thioat-dihydrochlorid-monohydrat, smp.: 125-130 °C.
EKSEMPEL 2
Bis [2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methylthio]- carbonat 15 En opløsning af 5-mercaptopyridoxin (0,1 mol) i tør tetra- hydrofuran (100 ml) omrøres ved 0-5 °C, medens 1-nitrophe-nylchlorformiat (0,1 mol) i tør tetrahydrofuran (10 ml) ledes ind i løbet af 1 time. Efter endnu 1 time inddampes opløsningen ved 10 °C til 10 ml. Om nødvendigt kan mellem-20 produktet p-nitrophenylmonothiocarbonat af 5-mercaptopyri- doxin isoleres ved filtrering på dette trin.
I stedet kan yderligere 0,1 mol 5-mercaptopyridoxin tilsættes forud for inddampning, og tetrahydrofuranopløsningen opvarmes til 40 °C. Efter inddampning ekstraheres dithio-25 carbonatet med ethylacetat (3 x 100 ml) fra mættet vandig natriumbicarbonat, og derefter tørres det organiske lag o-ver magnesiumsulfat. Det organiske lag filtreres og inddampes til tørhed. Det urene produkt kromatograferes på en kolonne af silicagel på 5 x 60 cm under anvendelse af op-30 løsninger af methylenchlorid-methanol som eluent, hvorved fås bis[2-methyl-3-hydroxy-4-hydroxymethyl]pyridyl-5-methyl-thio]carbonat i et udbytte på 7,3?ό og med et smeltepunkt på 175-181 °C.
6 148598 EKSEMPEL 3
Bis[2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methylthio ]-carbonat
Til 0,05 mol ammoniumdithiocarbamat i 300 ml 75K ethanol 5 sættes 0,1 mol 5-chlormethyl-2,2,8-trimethyl-4H-M-dioxino- [4,5-e]pyridin (behandlet med HC1 + NaHCOj). Reaktionsblandingen koges under tilbagesvaling i 2 timer, afkøles til stuetemperatur, pg blandingen, som indeholder bis[2,2,8-trimethyl-4H-M-diox\no[4,5-c]pyridyl-5-methylthio]carbamat, 10 gøres sur med saltsyre. Efter tre timer ved stuetemperatur inddampes reaktionsblandingen, og remanensen optages med ether/benzen og overskud af mættet natriumbicarbonat. Det organiske lag fraskilles, vaskes grundigt med vand, tørres og inddampes til dannelse af bis[2-methyl-3-hydroxy-4-hy-15 drox‘ymethylpyridyl-5-methylthio]carbonat.
EKSEMPEL 4
Bis [2-methyl-3-hydroxy-4-hydroxymethylpyridy1-5-methylthio]-carbonat __ _ _ _______________________
Til 0,2 mol natriQmhydrid i tørt dimethylformamid under 20 nitrogen sættes under afkøling 0,2 mol 5-mercaptomethyl- 2,2,8-trimethyl-4H-M-dioxino[4,5-c]pyridin i dimethylformamid. Blandingen.omrøres i 15 minutter, efter at udviklin--gen af hydrogen er ophørt. Derpå tilsættes 0,1 mol phenyl-.isonitrildichlorid. Reaktionsblandingen omrøres ved stue-25 temperatur i 18 timer og inddampes derefter i vakuum. Remanensen, som indeholder bis[2,2,8-trimethyl-4H-M-dioxino-[4,5-c]pyridyl-5-methylthio]-N-phenylcarbamat, omrøres i 3 timer ved stuetemperatur i fortyndet saltsyre, l/ed behandling med mættet natriumbicarbonat fås derefter bis[2-30 methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methylthio]car- bonat i et'udbytte på 83¾ og med et smeltepunkt på 174-176°C.
7 148595 EKSEMPEL 5
Bis [2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methylthio]-carbonat
Til 0,1 mol natriummethoxid i 150 ml ethanol sættes 0,1 5 mol 5-mercaptomethyl-2,2,8-trimethyl-4H-M-dioxino[4,5-c]- pyridin. Efter 15 minutter fjernes ethanolen ved inddamp-ning i vakuum. Til det dannede natriummercaptid sættes 0,05 mol diphenylcarbonat, og den dannede masse opvarmes på dampbad i 1 time, hvorved der dannes bis[2,2,8-trimethyl-10 4H-M-dioxino[4,5-c]pyridyl-5-methylthio]carbonat. Efter afkøling til stuetemperatur tilsættes en blanding af benzen/ether og fortyndet natriumhydroxid. Det organiske lag fraskilles, vaskes grundigt med vand, tørres og inddampes, hvorved fås bis[2-methyl-3-hydroxy-4-hydroxymethylpyridyl-15 5-methylthiojcarbonat i et udbytte på 65?ό og med et smeltepunkt på 173-175 °C.
EKSEMPEL 6
Bis[2-methyl-3-hydroxy-4-hydroxymethylpyridy1-5-methylthio]-carbonat 1 2 3 4 5 6 7 8 9 10 11
Til 0,4 mol rødt mercurioxid, som suspenderes under kraf 2 tig omrøring i 200 ml vand, sættes 0,22 mol bis(2,2,8-tri- 3 methyl-4H-M-dioxino[4,5-c]pyridyl-5-methylthio)thiocarbo- 4 nat i 100 ml eddikesyreanhydrid. Reaktionsblandingen omrø 5 res ved stuetemperatur i 1 time og ekstraheres derefter 6 med ether/benzen (1:1). Det organiske lag fraskilles, vas 7 kes med mættet natriumbicarbonat-opløsning, vand og tørres 8 over natriumsulfat til dannelse af bis(2,2,8-trimethyl-4H- 9 M-dioxino[4,5-c]pyridyl-5-methylthio)-carbonat. Syrehydro 10 lyse under de sædvanlige betingelser giver bis[2-methyl-3- 11 hydroxy-4-hydroxymethylpyridyl-5-methylthio)carbonat i et udbytte på 20,2?ό og med et smeltepunkt på 1.7.4-176 °C.
148595 8 I stedet kan isopropylidengruppen hydrolyseres først efterfulgt af oxidation af thiocarbonatgruppen til carbo-natet til opnåelse af samme resultat.
EKSEMPEL 7 5 Bis[2-methyl-3-hydroxy-4-hydroxymethylpyridyl-5-methylthio]- carbonat
En blanding af 0,1 mol 2,2,8-trimethyl-4H-M-dioxino[4,5-c]~ pyridyl-5-methylthiocyanat og 5 ml svovlsyre opvarmes langsomt på dampbad. En kraftig udvikling af carbondioxid fin-10 der sted. Efter at gasudviklingen er ophørt, hældes reaktionsblandingen på is, og der omrøres i 3 timer ved stuetemperatur. Den dannede blanding hældes derefter i en blanding af ether/benzen og overskud af natriumbicarbonatopløs-ning. Det organiske lag fraskilles, vaskes grundigt med 15 vand, tørres og inddampes til dannelse af bis[2-methyl-3- hydroxy-4-hydroxymethylpyridyl-5-methylthiol]carbonat.
Pharmakoloqisk rapport
Oral toxicitet.
Toxiciteten blev bestemt på mus ved oral indgift i for-20 skellige doser og forskellige hjælpemidler, og LD^g blev bestemt eller skønnet. De opnåede resultater fremgår af følgende tabel.
Prøveforbindelse: S,S’-bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)carbonodithioat.
25 Hjælpemiddel: 1% vandig methylcellulose.
LD5Q > 6850 mg/kg, skønnet.
9 148595
Dosis Kone. Antal Antal Bemærkninger mg/kg % dyr døde 400 5 5 0 Ingen 600 5 5 0 900 5 5 0 1350 550 2025 550 3040 20 5 0 4560 20 5 0 6850 20 5 0
Prøveforbindelse: S, S ' -bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethy1)-carbonodithioat-dihydrochlorid.
Hjælpemiddel: vand.
LD^0 6910 (6080-7860) mg/kg, skønnet.
Dosis Kone. Antal Antal Bemærkninger mg/kg % dyr døde 5460 20 5 0 Efter omkring 10 minutters 7inn „n s , forløb blev der for alle koncentrationer iagttaget 9240 20 5 5 ataksi, bradypnea og klonisk ι?ηηη ?n c c konvulsion. Anden dag - ataksi, bradypnea og nedsat aktivitet. Død på 20 min, til 4 timer. En senere død på '5 til 6 dage.
Prøve forbindelse: S,S'-bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)-carbonodithioat-sulfat-|iemihydrat.
Hjælpemiddel: l?i vandig methylcellulose.
LD5q 8870 (7540-10400 mg/kg), skønnet,.
148595 ίο
Dosis Kone. Antal Antal Bemærkninger mg/kg % dyr døde 4450 20 5 0 Alle koncentrationer: bradypnea 4Λ7Π ?n S n °9 nedsat aktivitet. 10000 mg/kg: ataksi, skælven og klo- 5 10000 20 5 4 niske konvulsioner. Overlevende synes normale dagen efter lægemiddeladministrering. Død på 40 min. til 1,5 timer.
Prøveforbindelse: 5-mercaptopyridoxin-hydrochlorid.
Hjælpemiddel: vand ved pH 2,5.
Koncentration: 8SS.
LD^g: 1250 mg/kg; 95/i's fiducialgrænser 1060-1480 mg/kg.
Aktivitet for mercaptoalkylpyridinderivater i lymphokin-10 induceret inflammation i marsvin._
Grupper på fire marsvin blev doseret p.o. med en forbindelse på tidspunktet nul i en koncentration på 30 mg/kg eller 90 mg/kg. Hvert dyr modtog en anden dosis lægemiddel 17 timer senere. En time efter den anden dosis lægemiddel blev 15 hvert dyr intradermalt udsat for lymphokin, og størrelsen af erythema på injektionsstedet blev målt til tidspunktet 22 timer.
Resultater: Både sulfatet af S,S'-bis(3-hydroxy-4-hydroxy-methyl-2-methyl-5-pyridylmethyl)carbonothioat og dihydro-20 chloridet deraf udviste aktivitet sammenlignelig med akti viteten af 5-mercaptopyridoxin, men i en dosis på en tredjedel .

Claims (1)

148595 Dosis Erythema- Inhibering Aktivitet Behandling mg/kg diameter, % mm Saltvand - 11,1 5-mercaptopyridoxin 90 7,6 32 aktiv S,S'-bis(3-hydroxy-4-hydroxy- 30 7.2 36 aktiv carbonodithioat-dihydrochlo- rid S,S'-bis(3-hydroxy-4-hydroxymethyl-2-methyl- 5-pyridylmethyl)carbono- 30 7,5 34* aktiv dithioat-sulfat-hemihy- drat * statistisk signifikans P 0,05 Patentkrav : Analogifremgangsmåde til fremstilling af S,S'-bis-(3-hy-droxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)carbonodi-thioat med formlen: ch2oh O CH-OH I il I HOyyB2"s_ c_ s_ch2y\/oh τ CH^^N ' ^ N CH3 eller pharmaceutisk acceptable salte deraf, 148595 kendetegnet ved, a) at 5-mercaptopyridoxin behandles med p-nitrophenylchlor-formiat eller phosgen, eller b) at en forbindelse med formlen: ?H20r2° r17 CH2OR20 R19°- J^nK19 X iT ij ck3 N S»-^ch3_ 19 20 hydrolyseres, idet R og R er ens eller forskellige og er hydrogen eller en syrelabil beskyttende gruppe, 19 20 eller R og R tilsammen repræsenterer en gruppe med formlen: R4 4 5 hvor R og R er ens eller forskellige og repræsenterer hydrogen, C, ,alkyl eller phenyl, og R^ repræsenterer j 8 28 =0 eller =N-R , hvor R er hydrogen, phenyl eller C, , 17 o 19 20 alkyl, idet, hvis R er =0, sa er R og R ikke begge hydrogen, eller
DK303274A 1973-06-15 1974-06-06 Analogifremgangsmaade til fremstilling af s,s'-bis-(3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridylmethyl)carbonodithioat eller pharmaceutiskacceptable salte deraf DK148595C (da)

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US36877473A 1973-06-15 1973-06-15
US36877473 1973-06-15
US47023174 1974-05-16
US05/470,231 US3971797A (en) 1973-06-15 1974-05-16 S,S'-bis(pyridylmethyl)-carbonodithioates

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US4061759A (en) * 1975-05-19 1977-12-06 Merck & Co., Inc. Ethenyl and ethynyl mercaptoalkyl pyridines
CH655110A5 (de) * 1982-09-03 1986-03-27 Otsuka Pharma Co Ltd Carbostyrilderivate, verfahren zu deren herstellung und arzneimittel, welche diese enthalten.
US5595995A (en) * 1992-05-15 1997-01-21 British Technology Group Limited Pyridyl-propan-2-yl esters of 1-adamantane carboxylates
GB2266887B (en) * 1992-05-15 1996-04-17 British Tech Group Substituted pyridines,their preparation and pharmaceutical use
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FI58775C (fi) 1981-04-10
GB1466295A (en) 1977-03-02
FR2233056A1 (da) 1975-01-10
DK303274A (da) 1975-02-10
DE2428409B2 (de) 1978-11-30
LU70342A1 (da) 1975-03-27
US3971797A (en) 1976-07-27
FR2233057A1 (da) 1975-01-10
NL7407618A (da) 1974-12-17
SE411346B (sv) 1979-12-17
CA1037956A (en) 1978-09-05
DK148595C (da) 1986-01-27
JPS5032181A (da) 1975-03-28
PH10366A (en) 1977-01-18
JPS5032180A (da) 1975-03-28
NL185841B (nl) 1990-03-01
RO71434A (ro) 1981-08-17
SE7407296L (da) 1974-12-16
CH613951A5 (da) 1979-10-31
AU7004174A (en) 1975-12-18
NL7407616A (da) 1974-12-17
RO70852A (ro) 1981-08-17
CH634302A5 (de) 1983-01-31
IE39467B1 (en) 1978-10-11
CH610305A5 (da) 1979-04-12
JPS5387363A (en) 1978-08-01
IL44998A (en) 1977-10-31
NL185841C (nl) 1990-08-01
NO144149B (no) 1981-03-23
DE2428409A1 (de) 1975-01-09
DD113001A5 (da) 1975-05-12
BG24408A3 (bg) 1978-02-10
DE2428409C3 (de) 1979-08-09
CH618428A5 (da) 1980-07-31
AR203749A1 (es) 1975-10-15
IL44998A0 (en) 1974-09-10
JPS5747189B2 (da) 1982-10-07
NO742042L (da) 1975-05-05
NO144149C (no) 1981-07-01
DE2428294A1 (de) 1975-01-09
IE39467L (en) 1974-12-15
FI168574A7 (da) 1974-12-16
FI58775B (fi) 1980-12-31
GB1466386A (en) 1977-03-09
FR2233057B1 (da) 1978-03-24
ES427277A1 (es) 1976-09-16
FR2233056B1 (da) 1977-10-28

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