DK157860B - Analogifremgangsmaade til fremstilling af benzylimidazolderivater samt farmaceutisk acceptable syreadditionssalte deraf - Google Patents

Analogifremgangsmaade til fremstilling af benzylimidazolderivater samt farmaceutisk acceptable syreadditionssalte deraf Download PDF

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DK157860B
DK157860B DK239980A DK239980A DK157860B DK 157860 B DK157860 B DK 157860B DK 239980 A DK239980 A DK 239980A DK 239980 A DK239980 A DK 239980A DK 157860 B DK157860 B DK 157860B
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compound
acid addition
acceptable acid
preparation
formula
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DK239980A
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DK157860C (da
DK239980A (da
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Masaru Ogata
Katsuya Tawara
Yoshihachi Watanabe
Hiroshi Matsumoto
Toshio Takahashi
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Shionogi & Co
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Priority claimed from JP54071953A external-priority patent/JPS6011904B2/ja
Priority claimed from JP11546579A external-priority patent/JPS5639073A/ja
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/08—Acetic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/06—Oxalic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
    • C07C55/02—Dicarboxylic acids
    • C07C55/10—Succinic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/03—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring
    • C07C65/05—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups monocyclic and having all hydroxy or O-metal groups bound to the ring o-Hydroxy carboxylic acids
    • C07C65/10—Salicylic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

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Description

i
DK 157860B
Den foreliggende opfindelse angår en anal ogi fremgangsmåde til fremstilling af hidtil ukendte benzyl imidazolderivater eller farmaceutisk acceptable syreadditionssalte deraf, der er nyttige som antimykotiske lægemidler. Forbindelser af denne art er fx. omhandlet i offentliggjort 5 japansk patentansøgning nr. 50-148357 og i European Journal of Medicinal Chemistry 14, nr. 3, pp. 227-230, 231-237, 243-245 (1979). Fra dansk fremlæggelsesskrift nr. 139.909 kendes beslægtede forbindelser med anti-mykotisk virkning, som adskiller sig fra forbindelserne med formlen (I) ved ikke at have en dobbeltbundet methylengruppe. Det har imidlertid 10 overraskende vist sig, at de ifølge opfindelsen fremstillede forbindelser har en signifikant kraftigere virkning.
Ifølge den foreliggende opfindelse er der således tilvejebragt en anal ogifremgangsmåde til fremstilling af hidtil ukendte benzyl imidazol-derivater med den almene formel (I) 15
Gr*2* vnc=ch hvori R betegner phenyl, der eventuelt er substitueret med en eller to grupper eller atomer udvalgt blandt Cj_5-alkyl eller halogen, eller betegner 25 thienyl, der eventuelt er substitueret med halogen, eller farmaceutisk acceptable syreadditionssalte deraf.
I ovenstående almene formel betyder halogen chlor, brom, fluor eller iod, fortrinsvis chlor. C15-alkyl betyder methyl, ethyl, propyl, isopropyl, butyl, sek-butyl, pentyl, isopentyl eller lignende.
30 Forbindelserne med formel (I) kan let omdannes til de tilsvarende syreadditionssalte. Repræsentative syrer, som kan danne farmaceutisk acceptable salte, er organiske syrer såsom eddikesyre, citronsyre, vinsyre, methansulfonsyre, æblesyre, ravsyre, oxalsyre, salicylsyre eller lignende og uorganiske syrer såsom saltsyre, hydrogenbromidsyre, svovl-35 syre, salpetersyre, phosphorsyre eller lignende.
Anal ogi fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte og kan belyses ved følgende reaktionsskemaer.
DK 157860B
2
Reaktionsvariant al
5 fh'^N f^r°-CH2-R
^^C?=.CH2 å CH2 R (111) W^C=CH
- 6 ~~~ ά1
” 1=). M
Reaktionsvariant b) 15 ...
r^pO-M : rfi^o-CHj-R
M-C-e, A-CH2R (III), ^Ac-CH.
S 3 i-"—* 8 * 20 (V)' ™
^pO-CH2-R
^>^C=CH0 1 2 25 O (la)
Imidazoldanne!se -* N,Ν'-thionyldiimidazol eller N,N'-carbonyldimidazol 30 hvori M betegner hydrogen eller alkalimetal, A betegner halogen eller en esterrest, 35 og hvori R har den ovenfor anførte betydning.
3
DK 157860 B
Reaktionsvariant al
Denne variant kan udføres ved, at man omsætter forbindelsen med formlen (II) med forbindelsen med formlen (III) i nærværelse af en base i et inert opløsningsmiddel ved stuetemperatur eller under opvarmning.
5 Repræsentative baser er natriumhydroxid, kaliumhydroxid, natriumhydrid, natriumamid, kaliumamid, natriumethoxid, kaliumcarbonat o.l. Repræsentative inerte opløsningsmidler er dimethyl formamid, benzen, methanol, chloroform, dioxan, tetrahydrofuran, acetone o.l.
Udgangsforbindelsen med formlen (II) er tilgængelig fx. ved behand-10 ling af keton (V) med Ν,Ν'-thionyldiimidazol eller Ν,Ν'-carbonyldiimida-zol til imidazol-dannelse. Omsætningen udføres i et inert opløsningsmiddel såsom methylenchlorid, chloroform, tetrahydrofuran, dioxan, benzen, acetonitril eller 1,2-dichlorethan ved stuetemperatur eller under afkøling.
15
Reaktionsvariant bl
Omsætningen af udgangsforbindelsen med formlen (V) med forbindelsen med formlen (III) kan udføres på samme måde som i variant a). Dernæst underkastes mellemproduktet med formlen (VI) imidazoldannelse på samme 20 måde som ved ovennævnte fremstilling af udgangsforbindelsen med formlen (II).
De ifølge opfindelsen fremstillede forbindelser med formlen (I) og farmaceutisk acceptable syreadditionssalte deraf udviser fremragende anti my kot i ske virkninger og er værdifulde som antimykotiske lægemidler for 25 mennesker og dyr.
Den minimale inhibitoriske koncentration (MIC, jti/ml) in vitro for nogle typiske forbindelser med formlen (I) er vist i efterfølgende tabel I. Forbindelsernes numre henviser i hvert tilfælde til slutprodukterne i de tilsvarende nummererede eksempler.
30 4
DK 157860 B
Tabel I
Minimal vækstinhibitorisk koncentration og akut koncentration ^ K KIC (μ.g/ml) Akut tox.
^ * Kemisk Struktur I Candida Trichophyton (LD50 fumigates albicans H-9 asteroides p.O. ddy ______mus__! 1 *1 3,1 6'2 ^ 0,1 1000 *3 -HCl 10S0.4 m 7 - * 4 1.6 6.2 < 0.1 1150 ·'[ -Kl 1140.1 *3
Kl 10 3,1 3,1 < 0,1 1023·2 *3 m 14 . . 1-6 6-2 < o.l
Bi __ ;
totrol V0a 6 2 25 < Q1 373.8.....1*S
Å -Kl
Bf i
Kontrol 50 50 °-3 292.1 l*b B -BO.
JZL
Kontrol 50 50 0.8 601.4 I»" ocalste j.
Kontrol 25 25 0.4 337.6 l*5 jj
Bi
Kontrol 25 50 0.2 -
Bi 5
DK 157860 B
Note: *1 IM: 1-imidazolyl *2 LD50 på DS mus (p.o.), *3 oxalat *4 croconazol,HC1 [Prop. INN, supplement til WHO chronicle, 5 1986, vol. 40, nr. 1 (april), side 5] *5 fri base *6 forbindelse ifølge DK-fremlæggel sesskrift nr. 139.909.
10
Forbindelserne med formlen (I) eller farmaceutisk acceptable syreadditionssalte deraf kan anvendes på en lang række orale eller parente-rale dosisformer alene eller i blanding med additiver såsom fortyndingsmidler, bærere, dispergeringsmidler o.l. Farmaceutiske præparater inde-15 holdende forbindelser med formlen (I) kan være i form af opløsninger, suspensioner, pulvere, granulater, tabletter, injektioner, salver, tinkturer o.l. Præparaterne kan administreres på konventionel måde. Fx. kan forbindelser med formlen (I) administreres i en dosis på 100 til 2000 mg per dag til enteral anvendelse.
20 Fremstillingen af forbindelser med formlen (I) belyses nærmere i de følgende eksempler.
Eksempel 1 25
OH λ OH
OC OU
Q fjl - 30 U-N v ' trin 3 LJ1 λ<ττ —--> y? 2
NaH i
BrCH2-^-Cl LI ’HC1 (3) 6
DK 157860 B
Trin A
Til en opløsning af 60 g imidazol i 300 ml tør methylenchlorid sattes 26,2 g thionylchlorid, og blandingen omrørtes ved stuetemperatur i 10 minutter, blandedes med 20 g forbindelse (1) og omrørtes ved stuetem-5 peratur i 1,5 timer. Reaktionsblandingen blandedes med isvand og ekstra-heredes med methylenchlorid. Det organiske lag vaskedes med vand, tørredes over Glaubersalt og koncentreredes. Remanensen opløstes i en blanding af 5% methanol og methylenchlorid og kromatograferedes på en si 1 i -kagel-kolonne. Eluatet koncentreredes, og remanensen vaskedes med en 10 blanding af ethyl acetat og isopropylether til dannelse af 25,8 g forbindelse (2), smp. 150-151°C.
IR: i/Nujo1 3300 - 2100, 2570, 1630 cm-1, max
15 Trin B
Til en opløsning af natriumsaltet af forbindelse (2) fremstillet ud fra 500 mg forbindelse (2), 164 mg 60% natriumhydrid og 5 ml tør dime-thylformamid sattes 828 mg p-chlorbenzylbromid, og blandingen omrørtes ved stuetemperatur i 15 minutter. Reaktionsblandingen blandedes med is-20 vand og ekstraheredes med methylenchlorid. Det organiske lag vaskedes med vand, tørredes over Glaubersalt og koncentreredes. Remanensen kromatograferedes på en si li kagel-kolonne, som elueredes med en blanding af 2% methanol og methylenchlorid. Eluatet opsamledes og blandedes med en blanding af saltsyre og ethanol, og blandingen koncentreredes. Remanen-25 sen krystalliseredes fra en blanding af ethylacetat og ether og omkrystal -li seredes fra en blanding af methanol og ethylacetat til dannelse af 345 mg forbindelse (3) som hydrochlorid, smp. 180,5 ~ 181°C (dekompo-nering).
IR: i/Nujo1 2600, 2300, 1649 cm"1.
30 max
Eksempel 2 ,^s-ch2-^C>- C1 .S-CH0—<^q">-- Cl 35 ^coch3 s + soci2 . BC1 (4) " iLi (5)'
DK 157860B
7 ΤΠ en opløsning af Ν,Ν'-thionyldiimidazol fremstillet ud fra 2,95 g imidazol og 1,29 g thionylchlorid i 15 ml tør methylenchlorid sattes 2,0 g af forbindelse (4), og blandingen ekstraheredes med methylenchlo-rid. Det organiske lag vaskedes med vand, tørredes over Glaubersalt og 5 koncentreredes. Remanensen kromatograferedes på en sil i kagel-kolonne og elueredes med methylenchlorid til genvinding af 750 mg uomsat forbindelse (4). Eluatet fra 1% methanol-methylenchlorid til 2% methanol-methy-1enchlorid opsamledes og koncentreredes, og den resulterende remanens krystalliseredes fra ethanol isk saltsyre og omkrystalliseredes fra me-10 thanol-ethylacetat-ether til dannelse af 310 mg forbindelse (5), smp.
153-163°C.
Eksempel 3 ^YCH2 NaH~ -> ·. fy
(2) N (6) li—S
20
Til en opløsning af 1 g forbindelse (2) i 5 ml dimethylformamid sattes 322 mg 60% opløsning af natriumhydrid i mineralolie under isafkøling, og blandingen omrørtes i 5 minutter, blandedes med 1,14 g methyl-25 iodid og omrørtes ved stuetemperatur i 10 minutter. Reaktionsblandingen fortyndedes med isvand og ekstraheredes med ether. Det organiske lag vaskedes med vand, tørredes over Glaubersalt og koncentreredes. Remanensen kromatograferedes på en sil i kagel-kolonne og elueredes med 37% methanol-methyl enchl orid. Eluatet koncentreredes, og remanensen krystalli-30 seredes fra saltsyre-methanol og omkrystalli seredes fra methanol-eddikesyre til dannelse af 520 mg forbindelse (6), smp. 190-195°C.
Grundstofanalyse (for C^H^O^HCl)
Beregnet (%): C, 60,89; H, 5,54; N, 11,84; Cl, 14,98
Fundet (%): C, 60,78; H, 5,52; N, 11,73; Cl, 15,02 35
Eksempel 4 til 14
De følgende forbindelser fremstilledes på samme måde som beskrevet i de ovenfor anførte eksempler.
8
DK 157860 B
. .oai0R
C3T
^T®2
Or
Eks.
nr. -CHgR Salt Snip. (0°C) eller IR
4 -CH2Ph HC1 154 - 156 5 -CH2-<E>-C1 - 85-86 6 " HC1 180,5 - 181 7 -CK2<0>zC1 " 148,5 - 149
Cl 8 -CH " 161 - 163
Cl 9 -CH ζ<&~ C1 " 172 - 174 10 -CH2-<E>-CH3 HC1 180 - 183 11 -CH2~<i>-C2H5 " 138 - 147 12 -CHo-^Syi-Pr - Olieagtigt produkt 2 i/ film 1639 cm'1 13 -CH2-qqp HC1 139 - 142 14 "CH2TCP " 165 -172
cr"~S
Ph = phenyl, i-Pr = isopropyl
DK 157860B
9
De antimykotiske præparater kan fremstilles som følger:
Præparation 1
Creme: Forbindelsen fremstillet i eksempel 7 10 g 5 Bi voks 100 g
Cetyl al kohol 50 g 2-octyldodecanol 50 g
Prolylenglycol 300 g
Blanding (1:1 v/v) af sorbitanmonostearat og 50 g 10 polyoxyethylensorbitanmonostearat
Blanding (1,9:0,2 v/v) af butylparaben og 2 g methyl paraben
Blanding (0,06:1,25:9 v/v/v) af phosphorsyre 10 g natriumhydroxid og mononatriumphosphatdihydrat 15 Destilleret vand 428 g 1000 g 20 Præparation 2
Gel: Nitrat af forbindelsen fremstillet i eksempel 7 10 g
Carbopol 940 (carboxyvinylpolymer) 15 g
Ethanol 100 g
Prolylenglycol 650 g 25 Triisopropanolamin 10 g
Destilleret vand 215 g 1000 g 30

Claims (1)

1. Anal ogi fremgangsmåde til fremstilling af et benzyl imidazol-derivat med den almene formel (I) 5 ocr ” Ol <> hvori 15. betegner phenyl, som eventuelt er substitueret med en eller to grupper eller atomer udvalgt blandt Cjg-alkyl eller halogen, eller betegner thienyl, som eventuelt er substitueret med halogen, eller et farmaceutisk acceptabelt syreadditionssalt deraf, KENDETEGNET ved, at man a) omsætter en forbindelse med den almene formel (II) 20 ος Λ N (I) 25 hvor M betegner hydrogen eller al kalimetal, med en forbindelse med den almene formel (III) 30 A-CH2-R (III) hvor 35. er halogen eller en esterrest, og R har den ovenfor anførte betydning, i et inert opløsningsmiddel ved stuetemperatur eller under opvarmning, eller DK 157860 B π b) omsætter en forbindelse med den almene formel (IV) ^VjvO-Ql2"R 5 vy313 o at) hvor R har den ovenfor anførte betydning, 10 med Ν,Ν'-thionyldiimidazol eller N,N'-carbonyldi imidazol i et inert opløsningsmiddel ved stuetemperatur eller under afkøling eller opvarmning, hvorefter man om ønsket omdanner den fremstillede forbindelse med formel (I) til et farmaceutisk acceptabelt syreadditionssalt deraf. 15 20 25 30 35
DK239980A 1979-06-07 1980-06-03 Analogifremgangsmaade til fremstilling af benzylimidazolderivater samt farmaceutisk acceptable syreadditionssalte deraf DK157860C (da)

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Application Number Priority Date Filing Date Title
JP7195379 1979-06-07
JP54071953A JPS6011904B2 (ja) 1979-06-07 1979-06-07 １−ベンジルイミダゾ−ル誘導体
JP11546579A JPS5639073A (en) 1979-09-07 1979-09-07 1- alpha-styryl imidazole
JP11546579 1979-09-07

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DK239980A DK239980A (da) 1980-12-08
DK157860B true DK157860B (da) 1990-02-26
DK157860C DK157860C (da) 1990-07-30

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CA (1) CA1141388A (da)
CH (1) CH646693A5 (da)
DE (1) DE3021467A1 (da)
DK (1) DK157860C (da)
FR (1) FR2458545B1 (da)
GB (2) GB2054560B (da)
HU (1) HU188607B (da)
IE (1) IE49604B1 (da)
IL (1) IL60252A (da)
IT (1) IT1129813B (da)
MX (1) MX5880E (da)
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US5216007A (en) * 1980-10-01 1993-06-01 Rohm And Haas Company Substituted ethylene imidazole and triazoles
JPS6036427B2 (ja) * 1980-12-05 1985-08-20 塩野義製薬株式会社 １−ベンジルイミダゾ−ル誘導体
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IL60252A0 (en) 1980-09-16
SE8004194L (sv) 1980-12-08
GB2118549A (en) 1983-11-02
US4328348A (en) 1982-05-04
GB2054560A (en) 1981-02-18
FR2458545A1 (fr) 1981-01-02
DK157860C (da) 1990-07-30
NL184003C (nl) 1989-03-16
GB2054560B (en) 1983-09-01
US4483866A (en) 1984-11-20
DE3021467A1 (de) 1980-12-18
FR2458545B1 (fr) 1986-04-18
IE801159L (en) 1980-12-07
DK239980A (da) 1980-12-08
SE453991B (sv) 1988-03-21
HU188607B (en) 1986-04-28
MX5880E (es) 1984-08-16
GB2118549B (en) 1984-04-11
CH646693A5 (de) 1984-12-14
NL184003B (nl) 1988-10-17
IT1129813B (it) 1986-06-11
US4463011A (en) 1984-07-31
IL60252A (en) 1987-02-27
DE3021467C2 (da) 1989-11-02
CA1141388A (en) 1983-02-15
AR226847A1 (es) 1982-08-31
AR230184A1 (es) 1984-03-01
NL8003310A (nl) 1980-12-09
IE49604B1 (en) 1985-10-30
IT8067889A0 (it) 1980-06-06

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