PT88924B - PROCESS FOR THE PREPARATION OF GINKGOLIDOS DERIVATIVES - Google Patents

PROCESS FOR THE PREPARATION OF GINKGOLIDOS DERIVATIVES Download PDF

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Publication number
PT88924B
PT88924B PT88924A PT8892488A PT88924B PT 88924 B PT88924 B PT 88924B PT 88924 A PT88924 A PT 88924A PT 8892488 A PT8892488 A PT 8892488A PT 88924 B PT88924 B PT 88924B
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ginkgolide
alkoxy
derivatives
preparation
ethoxy
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PT88924A
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Portuguese (pt)
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PT88924A (en
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Pierre Braquet
Andre Esanu
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Scras
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Publication of PT88924B publication Critical patent/PT88924B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/22—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains four or more hetero rings
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Steroid Compounds (AREA)

Abstract

The reaction of an excess of a diazoalkane with Ginkgolide A, B, C, J or M in a solvent gives a mixture of the 1-alkoxy and 10-alkoxy derivatives of that Ginkgolide. The mixture can be separated to give the individual derivatives, which are of interest in the treatment of PAF-Acether induced maladies. Methoxy and ethoxy derivatives are preferred. Pharmaceutical compositions containing the alkoxy-Ginkgolide derivatives are also disclosed.

Description

A presente invenção refere-se a um processo para a preparação de derivados de Ginkgolidos.The present invention relates to a process for the preparation of Ginkgolid derivatives.

A presente invenção proporciona derivados 1-alcoxi e 10-alcoxi dos Ginkgolidos A, B, C, J e M. Os grupos alcoxi preferidos são os grupos metoxi e etoxi.The present invention provides 1-alkoxy and 10-alkoxy derivatives of Ginkgolides A, B, C, J and M. The preferred alkoxy groups are methoxy and ethoxy groups.

A invenção proporciona um método para a preparação de derivados 1-alcoxi e 10-alcoxi de GinkgolidosThe invention provides a method for the preparation of 1-alkoxy and 10-alkoxy derivatives of Ginkgolides

A, B, C, J e M, consistindo o método em fazer reagir os Ginkgolidos A, B, C, J ou M em solução num solvente não polar com um excesso de diazo-alcano e em fazer a separação da mistura resultante de 1-alcoxi-Ginkgolido e 10-alcoxi-Ginkgolido, .M.A, B, C, J and M, the method consisting of reacting the Ginkgolides A, B, C, J or M in solution in a non-polar solvent with an excess of diazoalkane and separating the resulting mixture of 1 -alkoxy-Ginkgolide and 10-alkoxy-Ginkgolide, .M.

De acordo com um procedimento preferencial dissolve-se em dioxano o Ginkgolido escolhido, adequadamen• te numa concentração de 1 g por 100 ml, e dissolve-se o diazo-According to a preferred procedure, the chosen Ginkgolide is dissolved in dioxane, suitably at a concentration of 1 g per 100 ml, and the diazone is dissolved

-alcano escolhido em éter dietílico. Adiciona-se lentamente a solução que contém o diazo-alcano à solução que contém o Ginkgolido, na proporção de 10 equivalentes de diazo-alcano por equivalente de Ginkgolido. Deixa-se a solução mista em repouso à temperatura ambiente durante 3 a 8 horas, proporcionando uma mistura de 1-alcoxi-Ginkgolido e de 10-alcoxiGinkgolido. Po de efectuar-se adequadamente a separação dos dois produtos a partir do Ginkgolido remanescente que não reagiu fazendo a evaporação dos solventes e eluindo o resíduo através de uma coluna de gel de silica utilizando como eluente acetato de etilo/hexano 1:1. Evapora-se a solução resultante e trata-se com clorofér mio o qual dissolve o derivado 10-alcoxi. Recupera-se o referido derivado 10-alcoxi a partir desta solução em clorofórmio e trata-se depois a solução remanescente com éter dietílico para proporcionar o derivado 1-alcoxi.-alkane chosen in diethyl ether. The solution containing the diazo-alkane is slowly added to the solution containing the Ginkgolide, in the proportion of 10 equivalents of diazo-alkane per equivalent of Ginkgolide. The mixed solution is left to stand at room temperature for 3 to 8 hours, providing a mixture of 1-alkoxy-Ginkgolide and 10-alkoxy-Ginkgolide. The two products could be properly separated from the remaining unreacted Ginkgolide by evaporating the solvents and eluting the residue through a column of silica gel using ethyl acetate / hexane 1: 1 as eluent. The resulting solution is evaporated and treated with chloroform which dissolves the 10-alkoxy derivative. Said 10-alkoxy derivative is recovered from this solution in chloroform and the remaining solution is then treated with diethyl ether to provide the 1-alkoxy derivative.

Os alcoxi-Ginkgolidos de acordo com a pre sente invenção possuem interesse para o tratamento de doenças induzidas pelo éter PAF-Ac, pelo que a invenção proporciona também uma composição farmacêutica constituída por um derivado 1-alcoxi de Ginkgolido” A, B, C, J ou M ou por um derivado 10-alcoxi de um dos referidos Ginkgolidos ou por uma mistura de dois ou vários dos referidos derivados 1-alcoxi e/ou 10-alcoxi, em mistura com um diluente ou veículo farmaceuticamente aceitável.The alkoxy-Ginkgolides according to the present invention are of interest for the treatment of diseases induced by PAF-Ac ether, so the invention also provides a pharmaceutical composition consisting of a 1-alkoxy derivative of Ginkgolide ”A, B, C, J or M or by a 10-alkoxy derivative of one of said Ginkgolides or by a mixture of two or more of said 1-alkoxy and / or 10-alkoxy derivatives, in admixture with a pharmaceutically acceptable diluent or carrier.

Ilustra-se a invenção com os exemplos seguintes:The invention is illustrated with the following examples:

Exemplo 1Example 1

1-metoxi-Ginkgolido B e 10-metoxi-Ginkgolido B1-methoxy-Ginkgolide B and 10-methoxy-Ginkgolide B

A uma solução de Ginkgolido B em dioxano (10 g/l) adicionou-se lentamente 10 equivalentes de uma solução de diazo-metano em éter dietílico. Agitou-se a mistura à temperatura ambiente durante 2 horas e depois separou-se de acordo com o procedimento preferencial de separação anteriormente descrito. Obteve-se 1-metoxi-Ginkgolido B cuja estrutura se confir mou por HPLC, com um rendimento de 66,1% e obteve-se o 10-meto2To a solution of Ginkgolide B in dioxane (10 g / l) was added slowly 10 equivalents of a solution of diazo-methane in diethyl ether. The mixture was stirred at room temperature for 2 hours and then separated according to the preferred separation procedure described above. 1-Methoxy-Ginkgolid B was obtained, the structure of which was confirmed by HPLC, with a yield of 66.1% and 10-metho2 was obtained

xi-Ginkgolido B com um rendimento de 24,4$.xi-Ginkgolide B with a yield of 24.4%.

Procedendo como anteriormente, mas utilizando os Ginkgolidos” A e C obtiveram-se os seguintes rendimentos:Proceeding as before, but using Ginkgolides ”A and C, the following yields were obtained:

1-metoxi 1-methoxy 10 - metóxi 10 - methoxy Ginkgolido A Ginkgolide A 56,3 $ $ 56.3 13,2 $ $ 13.2 Ginkgolido C Ginkgolide C U9,l $ U9, l $ 16,7 $ $ 16.7

Exemplo 2Example 2

1-etoxi-Ginkgolido B e 10-etoxi-Ginkgolido B1-ethoxy-Ginkgolide B and 10-ethoxy-Ginkgolide B

De acordo com o procedimento descrito no Exemplo 1 mas utilizando diazo-etano em vez de diazo-metano (duração: 6 horas) obteve-se 1-etoxi-Ginkgolido B com um rendimento de 63,2$ e obteve-se 10-etoxi-Ginkgolido B com um rendimento de 25,7$.According to the procedure described in Example 1 but using diazo-ethane instead of diazo-methane (duration: 6 hours), 1-ethoxy-Ginkgolide B was obtained in a yield of 63.2% and 10-ethoxy was obtained -Ginkgolide B with a yield of 25.7 $.

Procedendo conforme descrito anteriormente, mas utilizando os Ginkgolidos” A e C, obtêm-se os rendimentos seguintes:Proceeding as described above, but using Ginkgolides ”A and C, the following yields are obtained:

1- etoxi 1- ethoxy 10 - etoxi 10 - ethoxy Ginkgolido À Ginkgolido à 72,8 $ $ 72.8 20,1 $ $ 20.1 Ginkgolido C Ginkgolide C 59,2 $ $ 59.2 30,4 $ $ 30.4

= 3 == 3 =

TOXICIDADETOXICITY

Mediu-se a toxicidade dos compostos da presente invenção nos ratos, por via oral.The toxicity of the compounds of the present invention in rats was measured orally.

Não se observou mortalidade de ratos para a administração de dose máxima.No mortality from rats was observed for the administration of the maximum dose.

FARMACOLOGIAPHARMACOLOGY

Demonstrou-se o interesse farmacêutico dos com postos da presente invenção com as seguintes experiências farma cêuticas.The pharmaceutical interest of the compounds of the present invention has been demonstrated with the following pharmaceutical experiments.

1) - Inibição de agregação de plaquetas em coelhos da Nova Zelândia1) - Inhibition of platelet aggregation in New Zealand rabbits

Efectuou-se a experiência sobre as plaquetas em plasma de coelhos da Nova Zelandia.Plasma experiments were carried out on plasma from New Zealand rabbits.

Extrairam-se amostras de sangue da artéria auricular e colocaram-se em tampão citrato (3,8 $; pH 7,4); fez-se a centrifugação do sangue durante 15 minutos a 1200 RPM.Blood samples were taken from the auricular artery and placed in citrate buffer (3.8%; pH 7.4); blood was centrifuged for 15 minutes at 1200 RPM.

Preparou-se a amostra de ensaio em DMSO, seguidamente verteu-se sobre o plasma rico em plaquetas durante 1 minuto, e depois adicionou-se uma dose de 2,5 nM de PAF.The test sample was prepared in DMSO, then poured into the platelet-rich plasma for 1 minute, and then a 2.5 nM dose of PAF was added.

Efectuou-se a determinação com um aparelho Crç nolog Coultronics o qual determina a percentagem de transmissão correspondente à altura máxima de pico antes da desagregação.The determination was made with a Crologolog Coultronics device which determines the percentage of transmission corresponding to the maximum peak height before disaggregation.

Calcula-se a percentagem de variação da inibição relativamente à percentagem de transmissão (controlos DMSO puro).The percentage of variation of the inhibition relative to the percentage of transmission is calculated (pure DMSO controls).

Este método foi descrito pormenorizadamente em LABORATORY INVESTIGATIONS, Vol. 4l, No. 3, P· 275, 1979, JEAN-PIERRECCAZENAVE, Dr. MED., JACQUES BENVENISTE, Dr. MED., AND J. FRASER MUSTARD, M.D., Aggregation of Rabbits Platelets by Platelet-Activating Factor is independent of the Release Reaction and the Arachidonate Pathway and inhibited by Membrane-Active Drugs.This method has been described in detail in LABORATORY INVESTIGATIONS, Vol. 4l, No. 3, P · 275, 1979, JEAN-PIERRECCAZENAVE, Dr. MED., JACQUES BENVENISTE, Dr. MED., AND J. FRASER MUSTARD, MD, Aggregation of Rabbits Platelets by Platelet-Activating Factor is independent of the Release Reaction and the Arachidonate Pathway and inhibited by Membrane-Active Drugs.

Os resultados demonstram que os compostos ini-The results demonstrate that the compounds

bem a agregação induzida por 2,5 nM de PAF. Cinco testes feitos enc cinco coelhos diferentes permitiram calcular os valoreswell the aggregation induced by 2.5 nM PAF. Five tests carried out on five different rabbits made it possible to calculate the values

IC__ dos diversos compostos utilizando o ensaio de regressão li 50 near.IC__ of the various compounds using the li 50 near regression assay.

Encontraram-se os valores IC seguintes:The following IC values were found:

Tipo de Ginkgolido” e posição de subs- Ginkgolide type ” and position of subs- - och3 - och 3 - oc2h5 - oc 2 h 5 tituição titution B B 1- 1- 6,6 6.6 10“ 7 10 “ 7 1,1 1.1 io“6 io “ 6 B B 10- 10- 2,9 2.9 io-7 io-7 7,2 7.2 1o”6 1st ” 6 C Ç 1- 1- 4,2 4.2 10”6 -610 ” 6 -6 8,5 8.5 1o6 . -61st 6 . -6 C Ç 10- 10- 3,0 3.0 10 10 9,3 9.3 10 10 A THE 1- 1- 4,6 4.6 10” 6 10 ” 6 8,7 8.7 10 6 10 6 A THE 10- 10- 1,3 1.3 10” 5 10 ” 5 6,2 6.2 10”^ 10 ”^

2) - Broncoconstrição anafilática de um porco da índia sensibilizado passivamente2) - Anaphylactic bronchoconstriction in a passively sensitized guinea pig

Sensibilização heterologa passivaPassive heterologous sensitization

Fez-se a sensibilização de porcos da índia macho do tipo Hartley” (400-500 g) por injecção intravenosa (IV) de um soro de coelho imune à antiovalbumina (Cooper Biomedical, U.S.A.). Para se obter uma resposta anafilática satisfatória 24 horas mais tarde, estabelecerem-se as condições seguintes: injecção no pénis de um soro diluído (para metade da concentração 0,05 ml/100 g).Hartley-type male guinea pigs (400-500 g) were sensitized by intravenous (IV) injection of rabbit serum immune to antiovalbumin (Cooper Biomedical, U.S.A.). In order to obtain a satisfactory anaphylactic response 24 hours later, the following conditions are established: injection into the penis of a diluted serum (for half the concentration 0.05 ml / 100 g).

íí2ÉÉ222_É2_5£22222222Í£i2B2£ 22222222Í £ i2B2 íí2ÉÉ222_É2_5

Anestesiaram-se porcos da índia com uretano (2 g/kg, IP), depois fez-se uma traqueomia e ventilou-se por meio de uma bomba respiratória (UGO BASILE) : volume por ciclo 1 ml/ = 5 =Guinea pigs were anesthetized with urethane (2 g / kg, IP), then a tracheomy was performed and ventilated using a respiratory pump (UGO BASILE): volume per cycle 1 ml / = 5 =

/100 g, 6O ciclos/minuto./ 100 g, 60 cycles / minute.

Efectuou-se um pneumotórax para abolir a respiração espontânea. Manteve-se constante a resistência inicial à pressão de 10 cm de água, de acordo com o método de Konzett e Rossler e mediu-se o excesso de volume de ar com um transdutor de broncoespasmo (UGO BASILE) ligado a um registador UGO BASILE Gemini. Aplicou-se um catéter à veia jugular para injecções intravenosas. Induziu-se o choque anafilático com uma injecção intravenosa de 0,75 mg/kg de um composto passivo heterologo de ovalbumina. Os produtos foram administrados por via oral 1 hora antes da estimulação antigénica, na forma de uma suspensão gomosa em água, na dose de 25 mg/kg.A pneumothorax was performed to abolish spontaneous breathing. The initial pressure resistance of 10 cm of water was kept constant, according to the method of Konzett and Rossler and the excess air volume was measured with a bronchospasm transducer (UGO BASILE) connected to a UGO BASILE Gemini recorder . A catheter was applied to the jugular vein for intravenous injections. Anaphylactic shock was induced with an intravenous injection of 0.75 mg / kg of a passive heterologous compound of ovalbumin. The products were administered orally 1 hour before antigenic stimulation, in the form of a gummy suspension in water, at a dose of 25 mg / kg.

ResultadosResults

Exprime-se a broncoconstrição induzida por oval bumina em percentagem da broncoconstrição máxima proporcionada por aperto da traqueia. Os resultados apresentam-se na Tabela seguinte:Bronchoconstriction induced by oval bumina is expressed as a percentage of the maximum bronchoconstriction provided by tracheal tightening. The results are shown in the following table:

Tipo de Ginkgolido e posição de subs- Ginkgolide Type and position of subs- - och3 - och 3 ~ C02H5~ C0 2 H 5 tituição titution B B 1- 1- _ 49,7*** _ 49.7 *** - 38,3** - 38.3 ** B B 10- 10- - 54,9*** - 54.9 *** - 36,2** - 36.2 ** C Ç 1- 1- - 40,1** - 40.1 ** - 39,8** - 39.8 ** C Ç 10- 10- - 30,6 * - 30.6 * - 23,1* - 23.1 * A THE 1- 1- - 32,0 * - 32.0 * - 15,1 NS - 15.1 NS A THE 10- 10- - 25,2 * - 25.2 * - 12,2 NS - 12.2 NS

NS NS : Não significativo : Not significant X X : Significativo : Significant XX XX : Muito significativo : Very significant XXX XXX : Muitíssimo Significativo : Very Significant

= 6 == 6 =

Na terapia humana as doses habituais para admi nistração per os estão entre 0,5 e 1 g per diem em pastilhas ou cápsulas de gelatina para um mês.In human therapy, the usual doses for administration per os are between 0.5 and 1 g per diem in lozenges or gelatin capsules for one month.

Na administração I.V. recomenda-se 3 injecções semanalmente de 0,05 até 0,2 em solução isotónica.In the I.V. administration, 3 injections weekly from 0.05 to 0.2 in isotonic solution are recommended.

Claims (1)

- lê Processo para a preparação de derivados de 1-alcoxi ou 10-alcoxi ginkgolidos substituídos, caracterizado por fazer-se reagir uma solução de dioxano do ginkgolido seleccionado numa solução de éter dietílico de diazo-alcano em excesso à temperatura ambiente durante 1 a 10 horas.- reads Process for the preparation of substituted 1-alkoxy or 10-alkoxy ginkgolide derivatives, characterized by reacting a dioxane solution of the selected ginkgolide in an excess of diazo alkane diethyl ether in excess at room temperature for 1 to 10 hours. A requerente declara que o primeiro pedido desta patente foi apresentado na Prança em 4 de Novembro de 19θ7,The applicant declares that the first application for this patent was filed at Prança on 4 November 19θ7,
PT88924A 1987-11-04 1988-11-03 PROCESS FOR THE PREPARATION OF GINKGOLIDOS DERIVATIVES PT88924B (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB878725871A GB8725871D0 (en) 1987-11-04 1987-11-04 Ginkgolide derivatives

Publications (2)

Publication Number Publication Date
PT88924A PT88924A (en) 1988-12-01
PT88924B true PT88924B (en) 1993-01-29

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JP (1) JPH0686455B2 (en)
KR (1) KR970005536B1 (en)
AT (1) AT397097B (en)
AU (1) AU616367B2 (en)
BE (1) BE1003455A3 (en)
CA (1) CA1303619C (en)
CH (1) CH675583A5 (en)
DE (1) DE3837550A1 (en)
DK (1) DK612788A (en)
ES (1) ES2009364A6 (en)
FI (1) FI90081C (en)
FR (2) FR2622584B1 (en)
GB (2) GB8725871D0 (en)
GR (1) GR1000264B (en)
HK (1) HK53992A (en)
IE (1) IE61541B1 (en)
IN (1) IN173404B (en)
IT (1) IT1227456B (en)
MA (1) MA21423A1 (en)
MY (1) MY103446A (en)
NL (1) NL8802635A (en)
NO (1) NO167739C (en)
NZ (1) NZ226738A (en)
PT (1) PT88924B (en)
SE (1) SE8803931L (en)
SG (1) SG48292G (en)
TN (1) TNSN88118A1 (en)
ZA (1) ZA888184B (en)

Families Citing this family (8)

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Publication number Priority date Publication date Assignee Title
US5895785A (en) * 1987-10-20 1999-04-20 Ruth Korth Treatment and prevention of disorders mediated by LA-paf or endothelial cells
DE69132379T2 (en) * 1990-06-06 2001-03-01 Ruth-Maria Korth Treatment of diseases with Paf antagonists and method for determining their effectiveness
ES2181665T3 (en) * 1991-11-04 2003-03-01 Ruth-Maria Korth TREATMENT AND PREVENTION OF MENTAL DISEASES, ACCOMPANIED BY ELEVATED LEVELS OF LISO PAF, WITH PAF ANTAGONISTS.
FR2763592B1 (en) * 1997-05-20 1999-07-16 Sod Conseils Rech Applic NOVEL GLYCOSYL DERIVATIVES OF GINKGOLIDES, THEIR APPLICATION AS MEDICAMENTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
FR2777280B1 (en) * 1998-04-10 2001-04-20 Centre Nat Rech Scient GINKGOLIDE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
CA3008698C (en) 2015-12-18 2020-12-15 Chengdu Baiyu Ginkgolide Pharmaceuticals Co., Ltd. Ginkgolide b derivative and preparation method and use thereof
CN108373474B (en) * 2017-12-25 2020-06-09 上海信谊百路达药业有限公司 A bilobalide compound extracted from folium Ginkgo and its preparation method
CN108383852B (en) * 2017-12-25 2019-11-22 上海信谊百路达药业有限公司 A kind of Ginkgolid extracted from ginkgo leaf and its preparation

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GB8418424D0 (en) * 1984-07-19 1984-08-22 Scras Inhibition of platelets aggregation
DE3710921C2 (en) * 1986-10-21 1996-09-26 Korth Ruth Use of Gingkolide BN 52020, BN 52021 and BN 52063 for the treatment of arteriosclerosis
DE3735525C2 (en) * 1987-10-20 1997-02-20 Korth Ruth Maria Method for determining the efficacy of paf-acether receptor antagonists

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Publication number Publication date
FR2622584A1 (en) 1989-05-05
GB8824859D0 (en) 1988-11-30
ZA888184B (en) 1989-07-26
GR1000264B (en) 1992-05-12
FR2622584B1 (en) 1992-01-10
FR2622448A1 (en) 1989-05-05
NO884900L (en) 1989-05-05
SE8803931L (en) 1989-05-05
SE8803931D0 (en) 1988-10-31
IE883315L (en) 1989-05-04
KR970005536B1 (en) 1997-04-17
GB8725871D0 (en) 1987-12-09
ES2009364A6 (en) 1989-09-16
IE61541B1 (en) 1994-11-16
KR890008156A (en) 1989-07-10
NL8802635A (en) 1989-06-01
DE3837550C2 (en) 1991-12-12
FI90081B (en) 1993-09-15
NO167739B (en) 1991-08-26
NO884900D0 (en) 1988-11-03
FI885046A (en) 1989-05-05
AU2464488A (en) 1989-05-25
DE3837550A1 (en) 1989-05-18
BE1003455A3 (en) 1992-03-31
SG48292G (en) 1992-06-12
ATA269688A (en) 1993-06-15
FR2622448B1 (en) 1992-01-10
IT1227456B (en) 1991-04-11
MY103446A (en) 1993-06-30
NZ226738A (en) 1990-05-28
HK53992A (en) 1992-07-30
AU616367B2 (en) 1991-10-24
CH675583A5 (en) 1990-10-15
GB2211841A (en) 1989-07-12
FI90081C (en) 1993-12-27
TNSN88118A1 (en) 1990-07-10
JPH0686455B2 (en) 1994-11-02
JPH01151583A (en) 1989-06-14
GB2211841B (en) 1991-01-16
DK612788A (en) 1989-05-05
CA1303619C (en) 1992-06-16
NO167739C (en) 1991-12-04
FI885046A0 (en) 1988-11-02
DK612788D0 (en) 1988-11-03
PT88924A (en) 1988-12-01
MA21423A1 (en) 1989-07-01
IT8822493A0 (en) 1988-11-04
IN173404B (en) 1994-04-30
AT397097B (en) 1994-01-25

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