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NO792020L - Fremgangsmaate for fremstilling av farmakologisk aktive fenylpiperaziner - Google Patents

Fremgangsmaate for fremstilling av farmakologisk aktive fenylpiperaziner

Info

Publication number
NO792020L
NO792020L NO792020A NO792020A NO792020L NO 792020 L NO792020 L NO 792020L NO 792020 A NO792020 A NO 792020A NO 792020 A NO792020 A NO 792020A NO 792020 L NO792020 L NO 792020L
Authority
NO
Norway
Prior art keywords
alkyl
compound
reacted
preparation
stands
Prior art date
Application number
NO792020A
Other languages
English (en)
Inventor
Henry Najer
Philippe Manoury
Jean-Pierre Kaplan
Original Assignee
Synthelabo
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from FR7818352A external-priority patent/FR2429216A1/fr
Priority claimed from FR7818351A external-priority patent/FR2429212A1/fr
Application filed by Synthelabo filed Critical Synthelabo
Publication of NO792020L publication Critical patent/NO792020L/no

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—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
    • C07D213/02—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
    • 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • 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
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C07D233/36—One oxygen atom with hydrocarbon radicals, substituted by nitrogen atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—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
    • C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/10—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/14—Radicals substituted by nitrogen atoms not forming part of a nitro radical

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Foreliggende oppfinnelse vedrører en fremgangsmåte for fremstilling av terapeutisk aktive fenylpiperazinderivater med den generelle formel (I)
hvori
n er 1, 2 eller 3, og
R står for enten
- et radikal
hvori
og R2hver betyr et hydrogenatom eller R^og R2sammen betyr gruppen X er tio-oksy, imino, alkylimino eller metylen, og m er 0 eller 1, eller står for - et radikal eller står for
- 2-tetrahydrofuryl, CH2~SH, Cl^-S-alkyl, CH2-0-alkyl, eller Cl^-S-CO-alkyl, hvori alkylgruppene har 1 - ,8
karbonatomer,
samt deres addisjonssalter med farmasøytisk tålbare syrer, og det særegne ved fremgangsmåten i henhold til oppfinnelsen er at enten
a) omsettes m-trifluormetyltio-fenyl-piperazin (II) med formel
med en forbindelse (III)
R-(CH0) -Y (III)
2. n
hvori R og n har den ovennevnte betydning og Y står for et anion av et aktivert alkoholderivat som halogenid, mesylat, tosylat, halogen-metansulfonat, eller
b) for fremstilling av en forbindelse (I) hvori R er CI^SH omsettes fenylpiperazinet (II) med etylensulfid, eller c) for fremstilling av forbindelse (I) hvori R er CH„0-alkyl eller CH„S-alkyl, omsettes en forbindelse
med en forbindelse
hvori R og n har den ovennevnte betydning og Hal står for et halogenatom, og om ønsket, for fremstilling av en forbindelse (I) hvori R er CH2~S-alkyl eller CH2-S-CO-alkyl, omsettes en erholdt forbindelse
hvori n har den ovennevnte betydning, med et tilsvarende alkyl-halogenid eller acylhalogenid.
Disse trekk ved fremgangsmåten i henhold til oppfinnelsen frem-går av patentkravet.
Reaksjonen under a) gjennomføres fordelaktig ved en temperatur fra 20 - 150°C i et eventuelt polart løsningsmiddel som f.eks. et benzenhydrokarbon, et hydroksyholdig løsningsmiddel eller ketonisk løsningsmiddel, dimetylformamid (DMF) eller heksametyl-fosfortriamid (HMPT).
Forbindelsene III er tidligere beskrevet i litteraturen.
De følgende eksempler illustrerer fremgangsmåten og analyser og spektra IR og RMN bekrefter strukturen av forbindelsene.
EKSEMPEL 1.
1- {2- [4-(3-trif luormetyltio-f enyl) -l-piperazinyl]-etylj -2-pyridon og dets hydroklorid.
Under nitrogen bringes en blanding av 18,36 g (0,07 mol) 4-(3-trifluormetyltio-fenyl)-piperazin, videre 11,8 g (0,075 mol) av N-l-(3-klor-etyl)-2-pyridon, 58,8 ml toluen, 17,25 g (0,1248 mol) pulverisert kaliumkarbonat og 0,35 g kaliumjodid til tilbakeløps-temperaturen. Blandingen opptas i eter og ekstraheres med 10% saltsyre. Den vandige fase gjøres alkalisk til pH 9 - 10 ved hjelp av NaOH-løsning.
Produktet ekstraheres med eter og vaskes med vann til pH 7 - 8.
Produktet tørkes, filtreres og inndampes. Det oppnås 24 g olje som kromatograferes over 600 g silika (elueringsmiddel MeOH 0,5/CHCl^9,5). Det gjenvinnes 18,8 g av en brun olje som opp-løses i eter og tilsettes 10,86 ml (0,0489 mol) saltsur eter 4,5 N. Det filtreres, vaskes med eter og omkrystalliseres fra isopropanol. Det oppnås et hvitt pulver. Basen frigis ved hjelp av konsentrert NH^OH hvorfra man oppnår hydrokloridet ved hjelp av saltsur eter 4,18 N. Man filtrerer, vasker med eter og tørker i oppvarmet ekcikator i nærvær av kalium.
Det oppnådde produkt smelter ved 217 - 218°C.
EKSEMPEL 2.
1- ^2- [4-(3-trifluormetyltio-fenyl)-1-piperazinyl]-etylj-3-metyl-2- benzimidazolidinon.
Under nitrogen bringes følgende blanding: 10,5 g (0,04 mol) 4-(3-trifluormetyltio-fenyl)-piperazin, 12,16 g (0,088 mol) pulverisert K2C03, 40 ml toluen, 9,48 g (0,045 mol) 1-(3-klor-etyl)-3-metyl-2-benzimidazolidinon og 0,3 g kaliumjodid til til-bakeløpstemperaturen. Etter omtrent 16 timer er reaksjonen omtrent opphørt og man filtrerer og inndamper filtratet. Det krystalliserte produkt opptas i eter og filtreres og man oppnår basen.
Smp. = 125 - 127°C.
Basen oppløses i 400 ml aceton og 50 ml CE^C^. Det innføres
7 ml (0,0293 mol) saltsur eter 4,18 N. Hydrokloridet utfelles sakte. Det omrøres i 1 time hvoretter det filtreres og tørkes i oppvarmet ekcikator ved 60°C i 8 timer. Det oppnås et hvitt pulver.
Smp. = 260 - 263°C (spaltning).
EKSEMPEL 3.
1-(m-trifluorometyltio-fenyl)-4-(2-tetrahydrofuryl-metyl)-piperazin og dets hydroklorid.
Til 120°C oppvarmes i 2 timer en blanding av 13,5 g (0,05 mol) m-trifluormetyltio-piperazin, 13,5 g (0,0 54 mol) av 2-tetrahydrofuryl-metyltosylat og 13,5 ml HMPT. Det avkjøles til 10°C og tilsettes 100 ml vann. Vannet separeres fra oljen hvoretter oljen vaskes tre ganger med vann for å fjerne HMPT. Oljen opp tas i kloroform, spor av vann fjernes og kloroformløsningen tørkes over magnesiumsulfat. Det tilsettes saltsur eter og løsningsmidlet avdampes. Resten behandles for avdampning med eter og bunnfallet avsuges på filter. Det gjøres alkalisk med 2N NaOH og ekstraheres med kloroform. Kloroform avdampes og hydrokloridet fremstilles ved å gå ut fra oljen som er tilbake fra inndampingen. Forbindelsen omkrystalliseres fra en blanding isopropanol/eter.
Smp. = 210°C.
EKSEMPEL 4.
1-(m-trifluormetyltio-fenyl)-4-(2-merkapto-etyl)-piperazin og dets hvdroklorid.
I en erlenmeyerkolbe tilsettes dråpevis ved 20 C 3,84 g (0,064 mol) etylensulfid til en oppløsning av 15 g (0,0557 mol) m-trifluormetyltio-fenylpiperazin og 2 ml metanol.
Det oppvarmes gradvis til 55°C og denne temperatur opprettholdes i 1 time og 3 0 minutter. Løsningsmidlet avdampes og det rektifi-seres med kulekjøler.
Kokepunkt = 2 00°C under 0,1 mm Hg.
Hydrokloridet fremstilles ved tilsetning av saltsur eter til en oppløsning av basen i etylacetat. Smp. = 141°C.
EKSEMPEL 5.
1-(m-trifluormetyltio-fenyl)-4-(2-metyltio-etyl)-piperazin og dets hydroklorid.
Til en oppløsning avkjølt til +5°C av 4,8 g (0,015 mol) 1-(m-tri- luormetyltio-fenyl)-4-(2-merkapto-etyl)-piperazin i 40 mlDMF, tilsettes porsjonsvis 0,84 g (0,0175 mol) natriumhydrid 50%. Etter at utviklingen av hydrogen er opphørt tilsettes dråpevis 2,16 g (0,0152 mol) metyljodid i oppløsning i 20 ml DMF. Blandingen setter bort over natten, helles ut over is og ekstraheres 2 ganger med eter. Eterløsningen tørkes over magnesiumsulfat og inndampes. Hydrokloridet fremstilles fra etylacetat ved tilsetning av den teoretiske mengde etanolisk saltsyre.
Smp. = 13 5°C.
I den etterfølgende tabell I er angitt eksempelvise forbindelser fremstilt i henhold til oppfinnelsen. De nye forbindelser fremviser terapeutisk aktivitet på det sentrale nervesystem påvist ved den såkalte fireplaters test (Aron C. Thése de Médecine - Paris 1970); Biossier J.R.,
Simon P. et Aron C. - Une nouvelle méthode de détermination des tranquillisants chez la souris. Eur. J. Pharmacol. 1968,
4, 145 - 151).
Forbindelsene tilføres i flere doser (1,3 og 10 mg/kg) ved oral tilførsel 60 minutter før testen. Man måler den prosentvise stimulering av musene.
Ved dosering 1 mg/kg varierer den prosentvise økning fra 35 til 70 og ved dosering 3 mg/kg varierer den fra 80 til 150 og ved dosering 10 mg/kg varierer den fra 120 til 300.
I de samme doser vil prosentandelen øke sterkere når aktiviteten av forbindelsen er stor.
Akutt giftighet (LD50) bestemmes i mus ved intraterritoneal til-førsel etter 48 timer, eller ved oral tilførsel i 7 døgn (LD50) ved intraterritoneal tilførsel varierer mellom 75 og 230 mg/kg og LD50 ved oral tilførsel varierer mellom 250 og 1000 mg/kg.
Forbindelsene har psykotrope egenskaper som tillater at de kan anvendes for behandling av forskjellige tilstander med angst og depresjon.
De kan tilføres oralt eller parenteralt med alle passende til-setningsmidler, i enhver passende tilførselsform som geler,
tabletter, kapseler, dragéer, injiserbare oppløsninger, etc.
Total dose er fra 5 til 200 mg.

Claims (1)

  1. Fremgangsmåte for fremstilling av terapeutisk aktive fenyl- piperazinderiva.ter med den generelle formel (I)
    hvori n er 1, 2 eller 3, og R står for enten- et radikal hvori R., og R^ hver betyr et hydrogenatom eller R^ og R« sammen betyr gruppen
    X er tio-oksy, imino, alkylimino eller metylen, og m er 0 eller 1, eller står for - et radikal eller står for
    - 2-tetrahydrofuryl, CH2 -SH, CH2 -S-alkyl, CH2 -0-alkyl, eller CH2 -S-CO-alkyl, hvori alkylgruppene har 1-8 karbonatomer, samt deres addisjonssalter med farmasøytisk tålbare syrer, karakterisert ved at entena) omsettes m-trifluormetyltio-fenyl-piperazin (II) med formel med en forbindelse (III)
    hvori R og n har den ovennevnte betydning og Y står for et anion av et aktivert alkoholderivat som halogenid, mesylat, tosylat, halogen-metansulfonat, eller b) for fremstilling av en forbindelse (I) hvori R er CH2 SH omsettes fenylpiperazinet (II) med etylensulfid, eller c) for fremstilling av forbindelser (I) hvori R er CH2 0-alkyl eller CH„S-alkyl, omsettes en forbindelse
    med en forbindelse (V)
    hvori R og n har den ovennevnte betydning og Hal står for et halogenatom, og om ønsket, for fremstilling av en forbindelse (I) hvori R er CH2 -S-alkyl eller CH2~ S-CO-alkyl, omsettes en erholdt forbindelse (I)
    hvori n har den ovennevnte betydning, med et tilsvarende alkyl-halogenid eller acylhalogenid.
NO792020A 1978-06-20 1979-06-18 Fremgangsmaate for fremstilling av farmakologisk aktive fenylpiperaziner NO792020L (no)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR7818352A FR2429216A1 (fr) 1978-06-20 1978-06-20 Derives de phenylpiperazine, leur preparation et leur application en therapeutique
FR7818351A FR2429212A1 (fr) 1978-06-20 1978-06-20 Derives de phenylpiperazine et leur application en therapeutique

Publications (1)

Publication Number Publication Date
NO792020L true NO792020L (no) 1979-12-21

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NO792020A NO792020L (no) 1978-06-20 1979-06-18 Fremgangsmaate for fremstilling av farmakologisk aktive fenylpiperaziner

Country Status (15)

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AU (1) AU521110B2 (no)
DE (1) DE2924681A1 (no)
DK (1) DK251079A (no)
ES (1) ES481632A1 (no)
FI (1) FI791926A7 (no)
GB (1) GB2023594B (no)
GR (1) GR67646B (no)
IL (1) IL57569A0 (no)
IT (1) IT1121588B (no)
LU (1) LU81396A1 (no)
NL (1) NL7904755A (no)
NO (1) NO792020L (no)
NZ (1) NZ190758A (no)
PT (1) PT69775A (no)
SE (1) SE7905402L (no)

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IL57569A0 (en) 1979-10-31
NZ190758A (en) 1980-10-24
LU81396A1 (fr) 1981-02-03
GB2023594A (en) 1980-01-03
FI791926A7 (fi) 1979-12-21
ES481632A1 (es) 1980-02-16
IT1121588B (it) 1986-04-02
PT69775A (fr) 1979-07-01
SE7905402L (sv) 1979-12-21
IT7923695A0 (it) 1979-06-18
AU4811279A (en) 1980-02-07
DE2924681A1 (de) 1980-01-10
NL7904755A (nl) 1979-12-27
AU521110B2 (en) 1982-03-18
GR67646B (no) 1981-09-01
GB2023594B (en) 1982-10-13
DK251079A (da) 1979-12-21

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