EP0000649B1 - 1,2-Dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carbonitriles substitués en position 5 et procédé pour leur conversion en 1-acides carboxyliques correspondants - Google Patents

1,2-Dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carbonitriles substitués en position 5 et procédé pour leur conversion en 1-acides carboxyliques correspondants Download PDF

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Publication number
EP0000649B1
EP0000649B1 EP78300174A EP78300174A EP0000649B1 EP 0000649 B1 EP0000649 B1 EP 0000649B1 EP 78300174 A EP78300174 A EP 78300174A EP 78300174 A EP78300174 A EP 78300174A EP 0000649 B1 EP0000649 B1 EP 0000649B1
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Prior art keywords
pyrrole
pyrrolo
dihydro
nitrile
thenoyl
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EP78300174A
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German (de)
English (en)
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EP0000649A1 (fr
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Albert R. Van Horn
Pasquale G. Gallegra
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Syntex USA LLC
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Syntex USA LLC
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    • 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
    • C07D207/30—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
    • C07D207/33—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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D207/30—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
    • C07D207/33—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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to 5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a]-pyrrole derivatives useful as intermediates in the preparation of pharmaceutically active compounds, and to such preparative processes.
  • the present invention provides novel 5-substituted-1,2-dihydro-3H-pyrrolo [1,2-a]-pyrrole-1-nitriles of the formula :
  • the compounds of Formula (II) can, in accordance with the process hereof, be converted hydrolyticallyto the corresponding 5-substituted-1,2-dihydro-3H-pyrrolo-[1,2-a] pyrrole-1-carboxylic acids of the formula : wherein Y is defined as above.
  • the product compounds hereof of Formula (I) are useful as antiinflammatory agents, analgetic agents, and as smooth muscle relaxants. They can be used both prophylactically and therapeutically. See for example Netherlands Specifications Nos. 7707651, 7707652 and 7803378.
  • the present invention provides an alternative route for the preparation of the compounds of Formula I.
  • the new process hereof that is, the hydrolysis conversion of the compounds of Formula (II) to the compounds of Formula (I) can be carried out under a variety of acidic or basic conditions, generally those conditions employed by those skilled in the art for the conversion of nitriles to carboxylic acids.
  • hydrolysis conversion is carried out under acidic conditions it is generally preferred that it be done with a strong mineral acid, e.g., phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid. and the like, in the presence of water, with or without the presence of an organic acid, e.g., acetic acid, formic acid, propionic acid, and the like. If desired other organic solvents miscible with the mineral acid (and the water and the organic acid, if the latter is used) can be used.
  • a strong mineral acid e.g., phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid. and the like
  • an organic acid e.g., acetic acid, formic acid, propionic acid, and the like.
  • other organic solvents miscible with the mineral acid (and the water and the organic acid, if the latter is used) can be used.
  • Suitable organic solvents are methanol, ethanol, ethylene glycol, dimethylsulfoxide, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether (glyme), diethylene glycol dimethyl ether (diglyme), and the like.
  • the reaction is preferably carried out under an inert atmosphere, e.g., nitrogen, argon, and the like, with nitrogen being the most preferred.
  • the reaction times and temperatures are not critical and depend, as will be apparent to those skilled in the art, on the reactants (and other ingredients of the reaction mixture) employed. Thus, the reaction time can be from about one minute to about 10 hours with about five minutes to about three hours being preferred ; and the reaction temperature from about 60 °C to about 200 °C, with about 80 °C to about 120 °C being preferred.
  • hydrolysis conversion is carried out under basic conditions, it is generally preferred that it be done with a strong base, preferably a mineral base, e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, and the like, in the presence of water.
  • a strong base preferably a mineral base, e.g., potassium hydroxide, sodium hydroxide, lithium hydroxide, and the like
  • water miscible organic solvents e.g., 2-methoxyethanol, methanol, ethanol, ethylene glycol, dimethylsulfoxide, and the like are used to facilitate solution of the reactants.
  • the reaction is preferably carried out under an inert atmosphere, e.g., nitrogen, argon, and the like, with nitrogen being the most preferred.
  • reaction times and temperatures are not critical and depend, as will be apparent to those skilled in the art, on the reactants (and other ingredients of the reaction mixture) employed.
  • reaction time can be from about 5 minutes to about 2 hours, with about 30 minutes to about 1 hour being preferred ; and the reaction temperature from about 60 °C to reflux temperature with about 70 °C to reflux temperature being preferred.
  • Isolation, separation, and purification of the desired compound of Formula (I) from the reaction mixture containing it can be effected by any suitable separation or purification procedure, such as, for example, extractions, filtration, evaporation, distillation, crystallization, thin-layer chromatography, or column chromatography, high pressure liquid chromatography, and the like, or a combination of these procedures. Illustrations of suitable isolation, separation and purification procedures can be had by reference to the Examples (and Preparations) hereinbelow. However, other isolation, separation and purification procedures, could of course, also be used.
  • temperatures are room or ambient temperature (about 20 °C to about 30 °C).
  • the temperature is permitted to drop to room temperature and the reaction mixture is agitated to room temperature for 15 hours, followed by the addition of 16 ml of 25 % aqueous sodium hydroxide solution, agitation for 5 minutes, and the addition of 19 ml of methylene chloride and 20 ml of water.
  • the organic layer is separated and the aqueous layer is extracted with 19 ml of methylene chloride.
  • the organic portions are combined and washed with a mixture of 11 ml of saturated aqueous sodium chloride solution and 8 ml of water.
  • reaction mixture is then added to a hot (about 90 °C) solution of 12.6 g of sodium cyanide in 27 ml of water, the addition being at such a rate, while at the same time distilling the solvent off, that the internal reaction flask temperature is kept at about 90 °-95 °C.
  • the addition is complete, the mixture is brought to reflux and heated under reflux for 15 minutes.
  • the mixture is cooled to 25 °C, followed by the addition of 40 ml of water and 60 ml of methylene chloride.
  • the organic layer is separated, washed wifh 30 ml of a mixture of 50 : 50 saturated aqueous sodium chloride : water, the water layer is extracted twice with 30 ml of methylene chloride, and the combined organic layers are dried over anhydrous sodium sulfate and the solvent removed under vacuum to yield 21 g of a brown oil which upon purification on a silica gel chromatography column (using 50 : 50-ethyl acetate : hexane as solvent) yielded 13 g of 1-hydroxyethylpyrrole-2-acetonitrile having the following analysis :
  • the thus-obtained mixture is heated to 77 °C for one hour, cooled to 25°C, and 15 ml of methylene chloride is added thereto.
  • the organic salts are filtered off and washed with methylene chloride.
  • the solvent is removed from the filtrate under vacuum, leaving a residue which is taken up in a mixture of 30 ml of dilute aqueous sodium chloride solution.
  • the volume is then adjusted to about 2 ml by the addition of ethyl acetate, followed by cooling to 0°C and filtration to yield 0.2 g (50 %) 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having a melting point of 147°-148 °C.
  • the melting point remained the same following a second crystallization from ethyl acetate and high pressure liquid chromatography indicated a purity of 79.8 %.
  • 0.45 g of the crude product is taken up in 5 ml of hot ethyl acetate, cooled to 0 °C agitated for five minutes, and following filtration, washing with 2 ml of a 2 : 1 ethyl acetate-hexane mixture and vacuum drying at 45 °C there is obtained 0.32 g (71 % w/w) of 5-(2-thenoyl)-1,2-dihydro-3H-pyrrolo [1,2-a] pyrrole-1-carboxylic acid having a melting point of 157 °C-159 °C. Additional quantities of the product can be obtained by standard crystallization work-up procedures.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Claims (11)

1. Un composé de formule :
Figure imgb0011
dans laquelle Y représente
Figure imgb0012
où R est un atome d'hydrogène, un groupe méthyle, un radical chloro ou bromo, le substituant R occupant l'une des positions 3, 4 et 5 du noyau de thiophène,
R1 est un atome d'hydrogène, un groupe alkyle inférieur ayant 1 à 4 atomes de carbone, un groupe alkoxy inférieur ayant 1 à 4 atomes de carbone, un radical chloro, fluoro ou bromo, le substituant R1 étant en position ortho, méta ou para du groupe aroyle, et
R2 est un atome d'hydrogène ou un groupe alkyle inférieur ayant 1 à 4 atomes de carbone.
2. Le 5-(2-thénoyl)-1,2-dihydro-3H-pyrrolo-(1,2-a)-pyrrole-1-nitrile suivant la revendication 1.
3. Le 5-benzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)-pyrrole-1-nitrile suivant la revendication 1.
4. Le 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo-(1,2-a)-pyrrole-1-nitrile suivant la revendication 1.
5. Procédé de production d'un composé de formule :
Figure imgb0013
dans laquelle Y (et R, R1 et R2) ont les définitions données dans la revendication 1, caractérisé en ce qu'il consiste à hydrolyser le groupe nitrile d'un composé suivant la revendication 1.
6. Procédé suivant la revendication 5, caractérisé en ce que l'hydrolyse est conduite dans des conditions acides.
7. Procédé suivant la revendication 5, caractérisé en ce que l'hydrolyse est conduite dans des conditions basiques.
8. Procédé suivant les revendications 5, 6 ou 7 pour la production de l'acide 5-(2-thénoyl)-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1 -carboxylique.
9. Procédé suivant les revendications 5, 6 ou 7 pour la production de l'acide 5-benzoyl-1,2-dihydro- ' 3H-pyrrolo-[1,2-a]-pyrrole-1-carboxylique.
10. Procédé suivant les revendications 5, 6 ou 7 pour la production de l'acide 5-m-chlorobenzoyl-1,2-dihydro-3H-pyrrolo-[1,2-a]-pyrrole-1 -carboxylique.
EP78300174A 1977-07-25 1978-07-20 1,2-Dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carbonitriles substitués en position 5 et procédé pour leur conversion en 1-acides carboxyliques correspondants Expired EP0000649B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US81837777A 1977-07-25 1977-07-25
US818377 1977-07-25

Publications (2)

Publication Number Publication Date
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EP0000649B1 true EP0000649B1 (fr) 1981-03-25

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EP78300174A Expired EP0000649B1 (fr) 1977-07-25 1978-07-20 1,2-Dihydro-3H-pyrrolo(1,2-a)pyrrole-1-carbonitriles substitués en position 5 et procédé pour leur conversion en 1-acides carboxyliques correspondants

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US (1) US4140698A (fr)
EP (1) EP0000649B1 (fr)
JP (1) JPS5424889A (fr)
AT (1) AT364843B (fr)
AU (1) AU515352B2 (fr)
CA (1) CA1111431A (fr)
CS (1) CS201015B2 (fr)
DD (1) DD137229A5 (fr)
DE (1) DE2860560D1 (fr)
DK (1) DK146720C (fr)
ES (1) ES472002A1 (fr)
FI (1) FI64597C (fr)
GR (1) GR63733B (fr)
HK (1) HK17186A (fr)
HU (1) HU178354B (fr)
IE (1) IE47138B1 (fr)
IL (1) IL55181A (fr)
IT (1) IT1160443B (fr)
MY (1) MY8800142A (fr)
NO (2) NO166863C (fr)
NZ (1) NZ187924A (fr)
PL (1) PL111419B1 (fr)
PT (1) PT68328A (fr)
SG (1) SG31884G (fr)
SU (1) SU1138029A3 (fr)
YU (1) YU40717B (fr)
ZA (1) ZA784216B (fr)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4232038A (en) * 1979-08-31 1980-11-04 Syntex (U.S.A.) Inc. 5-Alkylsulfinylbenzoyl- and 5-alkylsulfonylbenzoyl-1,2-dihydro-3H-pyrrolo[1,]pyrrole-1-carboxylic acids
EP0034481B1 (fr) * 1980-02-14 1984-05-30 Grigg, Ronald Ernest Dérivés de méthyl-2-thiazole-5-méthylamine et carboxamides correspondantes
US4344943A (en) * 1980-06-09 1982-08-17 Syntex (U.S.A.) Inc. 6-Chloro- or 6-bromo-1,2-dihydro-3H-pyrrolo[1,2-a]-pyrrole-1-carboxylic acids and derivatives thereof
US4353829A (en) * 1980-11-21 1982-10-12 Syntex (U.S.A.) Inc. Process for 5-aroylation of 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic esters
WO1983001382A1 (fr) * 1981-10-13 1983-04-28 Mroszczak, Edward Promedicaments de thioesters menageant le systeme gastrointestinal
US4397862A (en) * 1981-10-13 1983-08-09 Syntex (U.S.A.) Inc. Gastrointestinal sparing thioester drugs
US4454151A (en) * 1982-03-22 1984-06-12 Syntex (U.S.A.) Inc. Use of pyrrolo pyrroles in treatment of ophthalmic diseases
US4457941A (en) * 1982-03-22 1984-07-03 Syntex (U.S.A.) Inc. Use of pyrrolo-pyrrole in treating microvascular diseases associated with diabetes
EP0117675B1 (fr) * 1983-02-19 1986-07-23 Beecham Group Plc Dérivés d'acide benzofuranne- et benzothiophène carboxylique
US4874871A (en) * 1987-03-25 1989-10-17 Syntex (U.S.A.) Inc. Process for preparing (+)-2,3-Dihydro-1H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid and related compounds
JP2649168B2 (ja) * 1988-02-25 1997-09-03 久光製薬株式会社 新規な５，６−ジフェニル−１，２−ジヒドロ−３Ｈ−ピロロ［１，２−ａ］ピロール−１−カルボン酸誘導体
WO1995001767A1 (fr) * 1993-07-08 1995-01-19 Cygnus Therapeutic Systems Systeme d'apports transdermique par matrice monolithe
US5621115A (en) * 1996-02-21 1997-04-15 Ohmeda Pharmaceutical Products Division Inc. Methods for preparing 5-aroyl-1,2-dihydro-3H-pyrrolo-[1,2-A]pyrrole-1-carboxylic acids
US6191285B1 (en) 1997-07-03 2001-02-20 Abbott Laboratories Process for the preparation of ketorolac tromethamine
EP1097152B1 (fr) * 1998-07-10 2006-04-19 Mallinckrodt Inc. Synthese de composes utiles dans la production du ketorolac

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS539789A (en) * 1976-07-14 1978-01-28 Syntex Inc Production of 55*22floyl** * 55*22thenoyl** * 55*33 floyl** and 55*33thenoyl** 1*22dihydroo3hhpyroro * 1*22a*pyrolee11carboxylic acid derivative
JPS539788A (en) * 1976-07-14 1978-01-28 Syntex Inc 55aloyll1*22dihydroo3hh pyroro *1*22a* pyroll11 carboxylic acid derivative
US4087539A (en) * 1976-07-14 1978-05-02 Syntex (U.S.A.) Inc. 5-(2-Furoyl)-, 5-(2-thenoyl)-, 5-(3-furoyl)- and 5-(3-thenoyl)-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid derivatives and process for the production thereof
US4089969A (en) * 1976-07-14 1978-05-16 Syntex (U.S.A.) Inc. 5-Aroyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylic acid derivatives and process for the production thereof
US4097579A (en) * 1977-03-31 1978-06-27 Syntex (U.S.A.) Inc. 5-(2-Pyrroyl)-1,2-dihydro-3H-pyrrolo 1,2-a!pyrrole-1-carboxylic acid derivatives and process for the production thereof

Also Published As

Publication number Publication date
IE47138B1 (en) 1983-12-28
YU174178A (en) 1983-01-21
IL55181A0 (en) 1978-09-29
US4140698A (en) 1979-02-20
FI64597C (fi) 1983-12-12
IE781473L (en) 1979-01-25
ES472002A1 (es) 1984-07-16
EP0000649A1 (fr) 1979-02-07
DK146720C (da) 1984-08-20
NO155244C (no) 1987-03-04
AU515352B2 (en) 1981-04-02
NO155244B (no) 1986-11-24
HU178354B (en) 1982-04-28
CS201015B2 (en) 1980-10-31
IT7868765A0 (it) 1978-07-24
ATA528978A (de) 1981-04-15
JPS5424889A (en) 1979-02-24
FI64597B (fi) 1983-08-31
GR63733B (en) 1979-12-04
NO851935L (no) 1979-01-26
PL208576A1 (pl) 1979-05-07
SG31884G (en) 1985-09-13
CA1111431A (fr) 1981-10-27
MY8800142A (en) 1988-12-31
SU1138029A3 (ru) 1985-01-30
IT1160443B (it) 1987-03-11
PL111419B1 (en) 1980-08-30
HK17186A (en) 1986-03-21
NO166863B (no) 1991-06-03
NO782545L (no) 1979-01-26
DK325078A (da) 1979-01-26
NZ187924A (en) 1980-03-05
JPS6337793B2 (fr) 1988-07-27
NO166863C (no) 1991-09-11
AT364843B (de) 1981-11-25
YU40717B (en) 1986-04-30
DD137229A5 (de) 1979-08-22
AU3826978A (en) 1980-01-31
DE2860560D1 (en) 1981-04-16
FI782307A (fi) 1979-01-26
ZA784216B (en) 1980-02-27
DK146720B (da) 1983-12-12
PT68328A (en) 1978-08-01
IL55181A (en) 1981-12-31

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