DK144821B - Analogifremgangsmaade til fremstilling af 4-heptamethylenimino-1-butyl-xanthen-9-carboxylat eller syreadditionssalte deraf - Google Patents

Analogifremgangsmaade til fremstilling af 4-heptamethylenimino-1-butyl-xanthen-9-carboxylat eller syreadditionssalte deraf Download PDF

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DK144821B
DK144821B DK434872AA DK434872A DK144821B DK 144821 B DK144821 B DK 144821B DK 434872A A DK434872A A DK 434872AA DK 434872 A DK434872 A DK 434872A DK 144821 B DK144821 B DK 144821B
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formula
heptamethylenimino
butyl
acid
carboxylate
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DK434872AA
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DK144821C (da
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E Karpati
K Felfoeldi
M Bartok
A Molnar
L Szporny
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Richter Gedeon Vegyeszet
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—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 no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • 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
    • C07D211/70—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to 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
    • C07D295/12—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 or doubly bound nitrogen 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
    • C07D295/14—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—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 carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
    • C07D311/82—Xanthenes
    • C07D311/84—Xanthenes 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 9
    • 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
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Plural Heterocyclic Compounds (AREA)

Description

o 1 144821
Denne opfindelse angår en analogifremcrancrsinåde til fremstilling af farmakologisk aktivt 4-heptamethylenimino-l-butyl--xanthen-9-carboxylat eller syreadditionssalte deraf.
Denne hidtil ukendte forbindelse har formlen 5
CHo-CH0-CHo y? V
/ \ >=< CH„ N- (CH2) - 0 - C - / jp (I) \ / 4 >=< 10 >CH2-CH2-CH2 ° >>
Den omhandlede forbindelse med formel I har værdi-15 fulde farmakologiske virkninger og kan først og fremmest anvendes som vasodilatoriske (anticholinerge) midler.
Coronaria-vasodllator-virkningen af 4-heptamethylen-imino-l-butyl-xanthen-9-carboxylat-hydrochlorid undersøgtes på isolerede rottehjerter ifølge metoden beskrevet af 20 Langendorff (E. van Remoortere et al.: Arch. int. Pharmacodyn.
95, 466, 1953). Resultaterne er angivet i tabel I. Procentforøgelsen af coronarstrømningen er karakteristisk for størrelsen af den vasodilatoriske virkning. Virkningen af den hidtil .¾ ukendte forbindelse sammenlignes med virkningen af "Persantin" ' ' 25 et i vid udstrækning anvendt coronar-vasodilatorisk middel inden for terapien.
Tabel I
30 Aktivt middel Dosis Forøgelse af jag coronarstrømmen, % "Persantin"® 5 11,8 15 17,6 50 32,4 35 4-Heptamethylenimino-l- 15 37,9 -butyl-xanthen-9-carboxy-lat-HCl 2 144821 o
Den her omhandlede analogifremgangsmåde er kendetegnet ved, at a) 4-halogenbutanol med den almene formel 5 Hal - (CH2)4 - OH (II) hvor Hal betyder et halogenatom, omsættes med heptamethylen-imin med formlen 10 / 2 2 2 CH, NH (III) O^-O^-OL, 15 hvorefter den fremkomne aminoalkohol med formlen ^ce2-ch2-ch2 CEn XN - (CH0), - OH (IV) ^2 / 2 4 CH2-CH2-CH2 20 omsættes med et reaktivt derivat af xanthencarboxylsyre med formlen 25 ^ ^ - COOH (V) eller b) et 4-heptamethylenimino-l-butylhalogenid med 30 den almene formel CHo-CH0-CH~ / 'i CH2 - (CH2)4 - Hal (VI) ^O^-O^-O^ hvor Hal har den ovenfor angivne betydning, omsættes med 35 o 3 144821 xanthencarboxylsyre med den almene formel (V), hvorefter den dannede forbindelse med formel (I) om ønsket overføres i et syreadditionssalt eller frigøres fra et sådant salt.
Fortrinsvis fremstilles syreadditionssalte med 5 saltsyre, hydrogenbromidsyre, svovlsyre, phosphorsyre, eddikesyre, citronsyre, maleinsyre, vinsyre eller fumarsyre.
Ved egnet valg af reaktionsbetingelser opstår produktet umiddelbart i form af et syreadditionssalt.
Fremgangsmådevariant a) kan gengives ved følgende 10 formelskema: CH,-CH0-CH9 / \
Cl-(CH2)4-OH + CH2 nh --^ 15 NvCH2-CH2-CH^/ -HCl J2H2-CH2~CH2 CH, \ - (CBU.-OH + Cl-C-ζ Np ->> 20 \ / >-< ch9-ch--ch0 o /\
.CH -CH--CH-J
/ 2 < /—V
25 CH2 N - (CH2)4-0-C-/ y , HCl ch2-ch2-ch2 o 30 Fremgangsmådevariant b) kan gengives ved følgende formelskema: ^ch2-ch2-ch2 <ςΐ3> 35 CH2 SN-(CH2)4-C1 + HO-C- S) -
Sxch2-ch2-ch^ O
4 144821 0 CH2-CH2-CH2 y· W \-(CH9) -0-C- < % , HC1
™2 y' 2 4 X, X
xch2-ch2-ch2 0 ^ 5
Det første trin ved fremgangsmådevariant a) udføres i nærværelse af et opløsningsmiddel. Som opløsningsmiddel kan der f.eks. anvendes alkoholer, chlorerede aliphatiske carbonhydrider eller aromatiske carbonhydrider. Især er det 10 fordelagtigt at udføre det første trin i ethanol i nærværelse af et syrebindende middel. Som syrebindende middel kan der f.eks. anvendes alkalimetalhydroxider, alkalimetalcarbonater eller alkalimetalhydrogencarbonater eller et overskud af aminreagenset. Aminobutanolen med formel (IV) , der fås ved 15 det første trin, renses på passende måde, f.eks. ved destillation eller omkrystallisation, og omsættes med et reaktivt derivat af xanthencarboxylsyre med formel (V) i nærværelse af et indifferent opløsningsmiddel.
Som reaktivt derivat af syren anvendes fortrinsvis 20 det tilsvarende anhydrid eller halogenid, især chloridet, i et lille overskud, og reaktionen udføres i en chloreret aliphatisk carbonhydrid, en aromatisk carbonhydrid eller en lavere keton, fortrinsvis i chloroform, benzen eller acetone, ved tilbagesvaling af blandingen i én eller to timer. Reak-25 tionsblandingen afkøles, filtreres, og det krystallinske produkt omkrystalliseres fra et passende opløsningsmiddel eller opløsningsmiddelblanding fortrinsvis fra acetone, ethanol eller vand.
Fremgangsmådevariant b) udføres i et opløsningsmiddel 30 under opvarmning. Som opløsningsmidler kan der anvendes alkoholer eller aromatiske carbonhydrider med højere kogepunkt.
Det foretrækkes at anvende et chlorid eller bromid med den almene formel (VI) som udgangsforbindelse, og reaktionen udføres i isopropanol eller toluen ved kogepunktet for opløs-35 ningsmidlet.
c 144821 5
O
Den farmakologisk aktive forbindelse med formel (I) anvendes i form af farmaceutiske produkter. De farmaceutiske produkter til enteral, parenteral eller topisk anvendelse indeholder forbindelserne sammen med farmaceutisk acceptable 5 organiske eller mineralske, faste eller flydende bærestoffer. Bærestofferne må ikke indgå i reaktionen med den aktive ingrediens. Som bærestoffer kan f.eks. anvendes vand, alkohol, gelatine, propylenglycol, vegetabilske olier, cholesterol, stivelse, lactose, talkum, gummi, magnesiumstearat eller 10 andre kendte farmaceutiske bærestoffer. De farmaceutiske produkter kan om ønsket steriliseres.
De farmaceutiske produkter kan også indeholde hjælpestoffer, f.eks. præserveringsmidler, stabiliseringsmidler, befugtningsmidler, emulgeringsmidler, midler til at fremme 15 opløsningen, salte til indstilling af det osmotiske tryk eller puffere. I nogle tilfælde kan andre terapeutisk værdifulde stoffer også sættes til de farmaceutiske kompositioner. De farmaceutiske produkter kan fremstilles efter i og for sig kendt måde. De injicerbare præparater kan f.eks. fremstilles 20 som følger: Et syreadditionssalt eller et kvaternært salt af den aktive forbindelse opløses i pyrogenfrit fysiologisk saltvand eller to gange destilleret vand. Opløsningen steriliseres om nødvendigt og fyldes derpå i ampuller under sterile betingelser.
25 Opfindelsen skal forklares nærmere ved hjælp af de følgende eksempler.
Eksempel 1
Heptamethylenimino-l-butyl-xanthen-9-carboxylat--hydrochlorid.
Trin A: 4-Heptamethylenimino-butanol-l.
En opløsning af 17,0 g af heptamethylenimin og 14,5 g l-chlor-butanol-4 i 150 ml vandfrit ethanol blandes med 30 g vandfrit kaliumcarbonat, og blandingen omrøres og tilbagesvales i 24 timer. Reaktionsblandingen afkøles og fil-
OO
treres, og filtratet inddampes. Remanensen opløses i 30 ml o 6 144821 acetone, og opløsningen fortyndes med 300 ml vandfri ether.
De udskilte krystaller fraskilles ved filtrering.
Trin B: 4-Heptamethylenimino-l-butyl-xanthen-9--carboxylat-hydrochlorid.
5 En opløsning af 3,3 g 4-heptanmethylenimino-butanol-l i 50 ml benzen sættes dråbevis til en opløsning af 4,0 g xanthen-9-carboxylsyrechlorid i 20 ml benzen, og opløsningen tilbagesvales i 2 timer. Blandingen afkøles, og de udskilte krystaller samles ved filtrering og omkrystalliseres to gange 10 fra en 5:l-blanding af acetone og ethanol. Der fås 5,0 g 4-heptamethylenimino-l-butyl-xanthen-9-carboxylat-hydrochlorid, smp. 137-139°C.
Eksempel 2 15 4-Heptamethylenimino-l-butyl-xanthen-9-carboxylat- -hydrochlorid.
En opløsning af 4 g 4-heptamethyleniminobutylchlorid og 4,6 g xanthen-9-carboxylsyre i 20 ml isopropanol tilbagesvales i 15 timer. Opløsningen afkøles og fortyndes med 30 ml 20 acetone og opbevares i et køleskab i 1 dag. De udskilte krystaller samles ved filtrering og omkrystalliseres fra 5:l-blan-ding af acetone og ethanol. Der fås 6,0 g af den ovennævnte forbindelse med et smeltepunkt på 137-139°C.

Claims (2)

1. Analogifremgangsmåde til fremstilling af farmaceutisk aktivt 4-heptamethylenimino-l-butyl-xanthen-9-carboxy-lat med formlen 5 ^ch2-ch2-ch2 N=< ch2 ^n- (ch2)4 - o - c - /y (I) 10 '^CHj-CHj-Csf' ό eller syreadditionssalte deraf, kendetegnet ved, at 15 a) 4-halogenbutanol med den almene formel Hal - (CH2)4 - OH (II) hvor Hal betyder halogen, omsættes med heptamethylenimin med 20 formlen CH„-CH0-CH0 / 2
2 CH2 NH (III) \ch2-ch2-ch^ 25 hvorefter den dannede aminoalkohol med formlen CH0-CH0-CH0 / 2 2 sj CH~ N - (CH9) , - OH (IV) \ / CH2“CH2-CH2 30 omsættes med et reaktivt derivat af xanthencarboxylsyre med formlen 35 /""v i y - cooh (v) O
DK434872A 1971-09-03 1972-09-01 Analogifremgangsmaade til fremstilling af 4-heptamethylenimino-1-butyl-xanthen-9-carboxylat eller syreadditionssalte deraf DK144821C (da)

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DK212380A DK143559C (da) 1971-09-03 1980-05-14 Analogifremgangsmaade til fremstilling af 5'-heptamethylenimino-pentyl-xanthen-9-carboxylat eller syreadditionssalte deraf

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HURI000444 1971-09-03
HURI444A HU163608B (da) 1971-09-03 1971-09-03

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BE (1) BE788289A (da)
CA (1) CA1008075A (da)
CH (1) CH577957A5 (da)
CS (1) CS168004B2 (da)
DD (1) DD102142A5 (da)
DE (2) DE2265580C2 (da)
DK (1) DK144821C (da)
ES (1) ES406345A1 (da)
FI (1) FI56007C (da)
GB (1) GB1407456A (da)
HU (1) HU163608B (da)
IL (1) IL40169A (da)
NL (1) NL179205C (da)
PL (1) PL90702B1 (da)
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DE1445551A1 (de) 1964-12-10 1969-05-22 Boheringer Mannheim Gmbh Verfahren zur Herstellung neuer,basisch substituierter Xanthen-9-o1-9-carbonsaeureester und deren Salzen
US3523950A (en) * 1967-12-13 1970-08-11 Robins Co Inc A H Certain 4 - phenyl - 1,2,3,6 - tetrahydropyridyl-n-lower alkylene-ureas and derivatives

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YU221172A (en) 1980-10-31
AU4622172A (en) 1974-03-07
AT323741B (de) 1975-07-25
PL90702B1 (en) 1977-01-31
DE2265580C2 (de) 1982-11-18
YU35762B (en) 1981-06-30
DK144821C (da) 1982-11-01
CH577957A5 (da) 1976-07-30
NL179205C (nl) 1986-08-01
DE2243143B2 (de) 1980-10-09
GB1407456A (en) 1975-09-24
DE2243143A1 (de) 1973-04-12
CS168004B2 (en) 1976-05-28
NL179205B (nl) 1986-03-03
ES406345A1 (es) 1976-01-16
IL40169A0 (en) 1972-10-29
IL40169A (en) 1976-04-30
SU631068A3 (ru) 1978-10-30
CA1008075A (en) 1977-04-05
HU163608B (da) 1973-09-27
FI56007B (fi) 1979-07-31
FI56007C (fi) 1979-11-12
NL7211966A (da) 1973-03-06
BE788289A (fr) 1973-01-02
DD102142A5 (da) 1973-12-05
DE2243143C3 (de) 1982-01-21

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