FI90081B - FRAMEWORK FOR ACTIVATION OF THERAPEUTIC ACTIVATED GINKGOLIDDERIVAT - Google Patents
FRAMEWORK FOR ACTIVATION OF THERAPEUTIC ACTIVATED GINKGOLIDDERIVAT Download PDFInfo
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- FI90081B FI90081B FI885046A FI885046A FI90081B FI 90081 B FI90081 B FI 90081B FI 885046 A FI885046 A FI 885046A FI 885046 A FI885046 A FI 885046A FI 90081 B FI90081 B FI 90081B
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- ginkgolide
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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
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- 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
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- 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
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- 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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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
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Description
1 900811 90081
Terapeuttisesti aktiivisten ginkgolidien johdannaisten valmistusmenetelmä - Förfarande för framställning av terapeutiskt aktiva ginkgolidderivat 5 Keksintö koskee erilaisten ginkgolidien johdannaisten valmistusmenetelmää.The invention relates to a process for the preparation of various ginkgolide derivatives. The invention relates to a process for the preparation of various ginkgolide derivatives.
Keksintö koskee menetelmää ginkgolidien λ, B, C, J ja MThe invention relates to a process for ginkgolides λ, B, C, J and M
l-Cj^alkoksi- ja lO-C^^alkoksijohdannaisten valmistami-10 seksi. Edulliset alkoksiryhmät ovat metoksi- ja etoksiryh-mät.for the preparation of 1-C 1-4 alkoxy and 10-C 1-4 alkoxy derivatives. Preferred alkoxy groups are methoxy and ethoxy.
Keksintö tarjoaa menetelmän ginkgolidien A, B, C, J ja MThe invention provides a process for ginkgolides A, B, C, J and M
1-alkoksi- ja 10-alkoksijohdannaisten valmistamiseksi 15 menetelmän käsittäessä ginkgolidin A, B, C, J tai M saattamisen reagoimaan - johonkin ei-polaariseen liuottimeen liuotettuna - ylimäärän diatsoalkaania kanssa sekä saadun 1-alkoksiginkgolidin ja 10-alkoksiginkgolidin seoksen erottamisen.A process for the preparation of 1-alkoxy and 10-alkoxy derivatives comprises reacting ginkgolide A, B, C, J or M - dissolved in a non-polar solvent - with an excess of diazoalkane and separating the resulting mixture of 1-alkoxygincgolide and 10-alkoxygincgolide.
2020
Edullisessa menettelyssä valittu ginkgoli liuotetaan diok-saaniin, jolloin sopiva pitoisuus on 1 g/100 ml, ja valittu diatsoalkaani liuotetaan dietyylieetteriin. Diatsoalkaania sisältävä liuos lisätään hitaasti ginkgolidin sisältävään 25 liuokseen, jolloin määrinä käytetään 10 ekvivalenttia diatsoalkaania yhtä ginkgolidi-ekvivalenttia kohden. Sekoitettuna liuosta pidetään ympäristön lämpötilassa 3-8 tunnin ajan, jolloin saadaan 1-alkoksiginkgolidin ja 10-alkoksiginkgolidin seos. Saadun kahden tuotteen erottaminen jäl-30 jelle jäävästä ei-reagoineesta ginkgolidista voidaan sopivasti suorittaa poistamalla liuottimet haihduttamalla ja eluoimalla jäännöstä silikageelikolonnissa etyyliasetaat-ti/heksaani-seosta tilavuussuhteessa 1:1 eluenttina käyttäen. Saatu liuos haihdutetaan kuiviin, minkä jälkeen jään-35 nöstä käsitellään kloroformilla, joka liuottaa 10-alkoksi-johdannaisen. Sanottu 10-alkoksijohdannainen otetaan talteen tästä kloroformiliuoksesta, minkä jälkeen jäljelle 2 90081 jäänyttä liuosta käsitellään dietyylieetteri11ä, mikä tuottaa 1-alkoksijohdannaisen.In a preferred procedure, the selected ginkgol is dissolved in dioxane to a suitable concentration of 1 g / 100 ml, and the selected diazoalkane is dissolved in diethyl ether. The solution containing diazoalkane is slowly added to the solution containing ginkgolide in amounts of 10 equivalents of diazoalkane per equivalent of ginkgolide. The stirred solution is kept at ambient temperature for 3-8 hours to give a mixture of 1-alkoxygincgolide and 10-alkoxygincgolide. Separation of the two products obtained from the remaining unreacted ginkgolide can be conveniently carried out by removing the solvents by evaporating the residue and eluting the residue on a silica gel column using a 1: 1 by volume mixture of ethyl acetate and hexane as eluent. The resulting solution is evaporated to dryness, after which the residue is treated with chloroform, which dissolves the 10-alkoxy derivative. Said 10-alkoxy derivative is recovered from this chloroform solution, after which the remaining 2,900,81 solution is treated with diethyl ether to give the 1-alkoxy derivative.
Keksinnön mukaisilla aikoksiginkgolidei11 a on merkitystä 5 PAF-asteri-indusoitujen sairauksien hoidossa ja täten keksintö tarjoaa niinikään farmaseuttisen kokoonpanon, joka käsittää ginkgolidin A, B, C, J tai M 1-alkoksijohdannaisen tai jonkin sanotuista ginkgolideista 10-alkoksijohdannaisen tai kahden tai useamman sanotuista 1-alkoksi- ja/tai sano-10 tuista 10-alkoksijohdannaisista seoksen yhdistettynä seokseksi johonkin farmaseuttisesti hyväksyttävään laimentimeen tai kantajaan.The alkoxygincgolides 11a of the invention are important in the treatment of PAF-aster-induced diseases and thus the invention also provides a pharmaceutical composition comprising an A, B, C, J or M1 alkoxy derivative of ginkgolide or a 10-alkoxy derivative of two or more of said ginkgolides. -alkoxy and / or said 10-alkoxy derivatives in admixture as a mixture with a pharmaceutically acceptable diluent or carrier.
MYRKYLLISYYSTOXICITY
1515
Keksinnön mukaisten yhdisteiden myrkyllisyys määritettiin antamalla niitä hiirille suun kautta.The toxicity of the compounds of the invention was determined by oral administration to mice.
Kuolemia ei esiintynyt hiirille annetulla maksimiannoksel-20 la.No deaths occurred at the maximum dose given to mice-20 la.
FARMAKOLOGIAPHARMACOLOGY
Todiste keksinnön mukaisten yhdisteiden farmaseuttisesta 25 kiinnostavuudesta todettiin seuraavien farmaseuttisten kokeiden avulla.Evidence of the pharmaceutical interest of the compounds of the invention was established by the following pharmaceutical experiments.
1) Verihiutaleaggreaaation esto Uuden-Seelannin kaneissa ‘ 30 Kokeet suoritettiin Uuden-Seelannin kaneista saadusta plasmasta peräisin olevilla verihiutaleilla. Verinäytteet otettiin korvavaltimosta ja sijoitettiin sitraattipuskuriin (3,8-prosenttinen; pH 7,4), minkä jälkeen verta sentrifu-goitiin 15 minuutin ajan 1200 kierr./min kierrosnopeudella. 35 Tutkittava näyte valmistettiin DMSO:hon, minkä jälkeen se kaadettiin verihiutalepitoiseen plasmaan, jolloin 1 minuutin kuluttua lisättiin annos 2,5 nMN PAF-liuosta. Määritys 3 90081 suoritettiin valmistajan Cronolog Coultronics-1 aitteella, joka määrittää hajaantumista edeltävää maksimipiikkikor-keutta vastaavan transmissio-%:n.1) Inhibition of platelet aggregation in New Zealand rabbits ‘30 The experiments were performed on platelets derived from plasma obtained from New Zealand rabbits. Blood samples were taken from the ear artery and placed in citrate buffer (3.8%; pH 7.4), after which the blood was centrifuged for 15 minutes at 1200 rpm. The test sample was prepared in DMSO and then poured into platelet-containing plasma, after which a dose of 2.5 nMN PAF solution was added after 1 minute. Assay 3 90081 was performed on a Cronolog Coultronics-1 instrument that determines the% transmission corresponding to the maximum peak height before scattering.
a 5 Lasketaan estovaikutusvaihtelu-% suhteessa transmis- sio-%:iin (kontrol1i:puhdas DMSO). Tätä menetelmää kuvataan yksityiskohtaisesti artikkelissa: Laboratory Investigations 41:3 (1979) 275, Jean-Pierre Cazenave, Dr.Med., Jacques Benveniste; Dr.Med., ja J.Fraser Mustard, M.D., 10 'Aggregation of Rabbits Platelets by Platelet-Actibating Factor is indepedent of the Release Reaction and the Arachidonate Pathway and inhibited by Membrane-Active Drugs' ('Verihiutaleita aktivoivan tekijän aiheuttama kaniinin verihiutaleiden aggregaatio ei ole riippuvainen 15 liittyvästä vapautumisreaktiosta tai arakidoni happosyklis-tä ja sitä inhiboivat membraania aktivoivat lääkeaineet').a 5 Calculate the% inhibitory effect variation in relation to the% transmission (control: pure DMSO). This method is described in detail in: Laboratory Investigations 41: 3 (1979) 275, Jean-Pierre Cazenave, Dr.Med., Jacques Benveniste; Dr.Med., And J.Fraser Mustard, MD, 10 ‘Aggregation of Rabbits Platelets by Platelet-Actibating Factor is Indepedent of the Release Reaction and the Arachidonate Pathway and Inhibited by Membrane-Active Drugs’ (‘Platelet-activating factor-induced rabbit platelet aggregation is not dependent on the associated release reaction or arachidone acid cycle and is inhibited by membrane activating drugs').
Tulokset osoittavat, että yhdisteet estävät 2,5 nM PAF-liuoksen indusoimaa aggregaatiota. Suorittamiemme 5 kokeen 20 5 eri kanin avulla pystyimme laskemaan eri yhdisteiden IC5o~arvot lineaarisen regressioanalyysin avulla.The results show that the compounds inhibit aggregation induced by 2.5 nM PAF solution. Using 20 experiments in 5 different rabbits, we were able to calculate the IC50 values of the different compounds by linear regression analysis.
Totesimme IC5Q-arvot verihiutaleiden suhteen seuraaviksi: ·· 25We found the IC5Q values for platelets as follows: ·· 25
Ginkgo1idi tyyppi ia substituutioasema_-OCH3_-QCoHg___ B 1 - 6,6 10-7 1,1 10"6 B 10 - 2,9 10"7 7,2 10"6 • 30 C 1 - 4,2 10-6 8,5 10-6 c 10 - 3,0 10~6 9,3 10-6 A 1 - 4,6 10~6 8,7 10"6 ' A 10 - 1,3 10~5 6,2 10“4 4 90081Ginkgo1idi type and substitution position_-OCH3_-QCoHg ___ B 1 - 6.6 10-7 1.1 10 "6 B 10 - 2.9 10" 7 7.2 10 "6 • 30 C 1 - 4.2 10-6 8 .5 10-6 c 10 - 3.0 10 ~ 6 9.3 10-6 A 1 - 4.6 10 ~ 6 8.7 10 "6 'A 10 - 1.3 10 ~ 5 6.2 10" 4 4 90081
Vastaavat arvot 1ähtöaine-ginkgolidiini11 e samoissa olosuhteissa : 5 ginkgolidi A 8,32 x 10-6 ginkgolidi B 1,88 x 10-6 ginkgolidi C 1,53 x 10-5 ginkgolidi M 1,22 x 10-4 10 Tuloksista ilmenee, että substituointi on parantanut yhdisteiden farmakologisia ominaisuuksia.Equivalent values 1Ginkgolidine11 e under the same conditions: 5 Ginkgolide A 8.32 x 10-6 Ginkgolide B 1.88 x 10-6 Ginkgolide C 1.53 x 10-5 Ginkgolide M 1.22 x 10-4 10 The results show that that the substitution has improved the pharmacological properties of the compounds.
2) Yliherkkyyden tuottama keuhkoputkenkouristus passiivisesti herkistetyssä marsussa 152) Hypersensitivity bronchospasm in passively sensitized guinea pigs 15
Passiivinen vieras 1 aji-herkistäminenPassive guest 1 driving sensitization
Urospuolisia Hartely-marsuja (400 - 500 g) herkistettiin ruiskuttamalla laskimonsisäisesti (i.v.) kaniinin ovalbu-20 miinivastaista immuuniseerumia (Cooper Biomedical, USA). Tyydyttävän yliherkkyysvasteen saamiseksi asetettiin 24 tunnin kuluttua seuraavat olosuhteet: laimennetun seerumin (puoleen alkuperäisestä pitoisuudesta: 0,05 ml/100 g) ruiskutus penikseen.Male Hartely guinea pigs (400-500 g) were sensitized by intravenous (i.v.) injection of rabbit ovalbu-20 anti-mine immune serum (Cooper Biomedical, USA). To obtain a satisfactory hypersensitivity response, the following conditions were set after 24 hours: injection of diluted serum (half of the initial concentration: 0.05 ml / 100 g) into the penis.
2525
Keuhkoputkenkouristuksen mittausMeasurement of bronchospasm
Marsut nukutettiin uretaanilla (2 g/kg, i.p.), minkä jälkeen niiden henkitorvi avattiin ja hengitystä ylläpidettiin 30 keinotekoisesti hengityspumpun avulla (UGO BASILE): iskuti-lavuus 1 ml/100 g, 60 iskua/min.The guinea pigs were anesthetized with urethane (2 g / kg, i.p.), after which their trachea was opened and breathing was maintained artificially by means of a breathing pump (UGO BASILE): stroke volume 1 ml / 100 g, 60 strokes / min.
Spontaanin hengityksen estämiseksi tuotettiin ilmarinta. Lähtövastus pidettiin vakiona, 10 cm:n vesipaineena 35 Konzettin ja Rösslerin menetelmän mukaan ja ilmatila- vuusylimäärä mitattiin keuhkoputkenkouristus-transduktorin (UGO BASILE) avulla, joka oli yhdistetty UGO BASILE-rekis- 5 90081 teröimislaitteeseen 'Gemini'. Kaulaiaskimoon asetettiin katetri 1askimonsisäisiä ruiskeita varten. Yliherkkyysshok-ki indusoitiin ruiskuttamalla laskimonsisäisesti 0,75 mg/kg * ovalbumiinin passiivista vieras lajiherkistettä. Yhdisteet 5 annettiin suun kautta tuntia ennen antigeeniherkistettä kumimaisena vesisuspensiona annoksen ollessa 25 mg/kg.An air breast was produced to prevent spontaneous respiration. The output resistance was kept constant at a water pressure of 10 cm according to the method of Konzett and Rössler and the excess air volume was measured by means of a bronchospasm transducer (UGO BASILE) connected to a UGO BASILE recorder 'Gemini'. A catheter for intravenous injection was placed in the jugular vein. Hypersensitivity shock was induced by intravenous injection of 0.75 mg / kg * passive foreign species sensitizer of ovalbumin. Compounds 5 were administered orally one hour before the antigenic sensitiser as a gummy aqueous suspension at a dose of 25 mg / kg.
Tulokset 10 Ovalbumiinin indusoima keuhkoputkenkouristus ilmaistiin prosentteina maksimikeuhkoputkenkouristuksesta, joka oli saatu puristamalla henkitorvi kokonaan kiinni. Tulokset on esitetty seuraavassa taulukossa.Results 10 Ovalbumin-induced bronchospasm was expressed as a percentage of the maximum bronchospasm obtained by compressing the trachea completely. The results are shown in the following table.
15 Ginkgolidityyppi ja substituutioasema -OCH^ -OC2H5 B 1 - - 49,7*** - 38,3** B 10 - - 54,9*** - 36,2** C 1 - - 40,1** - 39,8** 20 C 10 - - 30,6* - 23,1*15 Ginkgolide type and substitution position -OCH 2 -OC 2 H 5 B 1 - - 49.7 *** - 38.3 ** B 10 - - 54.9 *** - 36.2 ** C 1 - - 40.1 ** - 39.8 ** 20 C 10 - - 30.6 * - 23.1 *
A 1 - - 32,0* - 15,1 NSA 1 - - 32.0 * - 15.1 NS
A 10 - - 25,2* - 12,2 NSA 10 - - 25.2 * - 12.2 NS
NS : ei merkitsevä 25 * : merkitsevä ** : huomattavan merkitsevä *** : erittäin merkitseväNS: not significant 25 *: significant **: significantly significant ***: very significant
ANNOSTUSDOSAGE
3030
Ihmisiä hoidettaessa tavanomaisesti annettavat annokset ovat 0,5 - 1 g päivässä tabletteina tai gelatiinikapseleina yhden kuukauden ajan.For human treatment, the usual doses are 0.5 to 1 g per day in tablets or gelatin capsules for one month.
35 Käytettäessä i.v. -annostelua suositellaan kolmea 0,5 - 0,2 g:n viikottaista ruisketta isotonisessa liuoksessa yhden kuukauden ajan.35 When using i.v. dosing is recommended three weekly injections of 0.5 to 0.2 g in isotonic solution for one month.
6 Ui 0816 Ui 081
Keksintöä havainnollistavat seuraavat esimerkit:The following examples illustrate the invention:
Esimerkki 1Example 1
5 l-Metoksiginkgolidi-B ia 10-metoksiginkoolidi-B5-Methoxygin glycol-B and 10-methoxygin glycol-B
Liuokseen, jossa oli ginkgolidi-B:tä dioksaanissa (10 g/litra), lisättiin hitaasti 10 ekvivalenttia diatsome-taaniliuosta dietyylieetterissä. Seosta pidetään ympäristön 10 lämpötilassa 4 tunnin ajan, minkä jälkeen se erotettiin käyttäen edellä kuvattua edullista erotusmenettelyä. 1-me-toksi-ginkgolidi-B:tä, jonka rakenne varmistettiin HPLC-ajon avulla, saatiin 66,1 %:n saanto ja 10-metoksiginkgoli-di-B:tä saatiin 24 %:n saanto.To a solution of ginkgolide-B in dioxane (10 g / liter) was slowly added 10 equivalents of a solution of diazomethane in diethyl ether. The mixture is maintained at ambient temperature for 4 hours, after which it was separated using the preferred separation procedure described above. 1-Methoxy-ginkgolide-B, the structure of which was confirmed by HPLC, was obtained in 66.1% yield and 10-methoxygincgol-di-B was obtained in 24% yield.
1515
Samalla ylläkuvatulla menetelmällä, mutta käyttämällä ginkgolidi-A:ta, C:tä, J:tä ja M:ä saatiin seuraavat saannot .By the same method described above, but using ginkgolide A, C, J and M, the following yields were obtained.
20 1-metoksi 10-metoksi ginkgolidi-A 56,3 % 13,2 % ginkgolidi-C 49,1 % 16,7 % ginkgolidi-J 46,2 % 41,3 % ginkgolidi-H 37,5 % 62,0 % 2520 1-methoxy 10-methoxy ginkgolide-A 56.3% 13.2% ginkgolide-C 49.1% 16.7% ginkgolide-J 46.2% 41.3% ginkgolide-H 37.5% 62.0 % 25
Esimerkki 2Example 2
1-etoksiginkgolidi-B ja 10-etoksiginkgolidi-B1-ethoxygin glycol-B and 10-ethoxygin glycolide-B
30 Esimerkeissä 1 kuvattua menettelyä käyttäen mutta korvaten diatsometaani diatsoetaanilla saatiin (6 tunnissa) 1-etoksiginkgolidi-B:tä 63,2 %:n saanto ja 10-etoksiginkgo-lidi-B:tä 25,7 %:n saanto.Using the procedure described in Examples 1 but replacing diazomethane with diazoethane, 1-ethoxygincgolide-B was obtained (in 6 hours) in 63.2% yield and 10-ethoxygincogolide-B in 25.7% yield.
35 Menetellen kuten edellä ginkgolideja A, C, ja M lähtöaineina käyttäen saatiin seuraavat saannot: 1 90081 1-etoksi 10-etoksi ginkgolidi-A 72,8 % 20,1 % ginkgolidi-C 59,2 % 30,4 % 5 ginkgolidi-J 66,6 % 15,3 % ginkgolidi-M 58,3 % 30,5 %35 Proceeding as above using ginkgolides A, C, and M as starting materials, the following yields were obtained: 1 90081 1-ethoxy 10-ethoxy ginkgolide-A 72.8% 20.1% ginkgolide-C 59.2% 30.4% 5 ginkgolide J 66.6% 15.3% ginkgolide-M 58.3% 30.5%
Tuotteiden sulamispisteet ovat: 10 Johdannaisten sulamispisteet (°C) Lähtö- ginkgolidi l-metoksi 10-metoksi 1-etoksi 10-etoksi A 240 212 271 207 B 252 224 282 220 15 C 263 205 259 195 J 293 239 288 237 M 244 258 273 248The melting points of the products are: 10 Melting points of derivatives (° C) Starting ginkgolide 1-methoxy 10-methoxy 1-ethoxy 10-ethoxy A 240 212 271 207 B 252 224 282 220 15 C 263 205 259 195 J 293 239 288 237 M 244 258 273 248
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB878725871A GB8725871D0 (en) | 1987-11-04 | 1987-11-04 | Ginkgolide derivatives |
GB8725871 | 1987-11-04 |
Publications (4)
Publication Number | Publication Date |
---|---|
FI885046A0 FI885046A0 (en) | 1988-11-02 |
FI885046A FI885046A (en) | 1989-05-05 |
FI90081B true FI90081B (en) | 1993-09-15 |
FI90081C FI90081C (en) | 1993-12-27 |
Family
ID=10626449
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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FI885046A FI90081C (en) | 1987-11-04 | 1988-11-02 | Process for the preparation of therapeutically active ginkgolide derivatives |
Country Status (28)
Country | Link |
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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)
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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1987
- 1987-11-04 GB GB878725871A patent/GB8725871D0/en active Pending
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1988
- 1988-10-24 GB GB8824859A patent/GB2211841B/en not_active Expired - Fee Related
- 1988-10-26 IN IN928DE1988 patent/IN173404B/en unknown
- 1988-10-26 GR GR880100726A patent/GR1000264B/en unknown
- 1988-10-26 NL NL8802635A patent/NL8802635A/en not_active Application Discontinuation
- 1988-10-27 NZ NZ226738A patent/NZ226738A/en unknown
- 1988-10-28 MY MYPI88001236A patent/MY103446A/en unknown
- 1988-10-28 BE BE8801244A patent/BE1003455A3/en not_active IP Right Cessation
- 1988-10-31 SE SE8803931A patent/SE8803931L/en not_active Application Discontinuation
- 1988-11-01 ZA ZA888184A patent/ZA888184B/en unknown
- 1988-11-01 MA MA21665A patent/MA21423A1/en unknown
- 1988-11-02 ES ES8803334A patent/ES2009364A6/en not_active Expired
- 1988-11-02 AT AT0269688A patent/AT397097B/en not_active IP Right Cessation
- 1988-11-02 FI FI885046A patent/FI90081C/en not_active IP Right Cessation
- 1988-11-03 TN TNTNSN88118A patent/TNSN88118A1/en unknown
- 1988-11-03 AU AU24644/88A patent/AU616367B2/en not_active Ceased
- 1988-11-03 NO NO884900A patent/NO167739C/en unknown
- 1988-11-03 PT PT88924A patent/PT88924B/en not_active IP Right Cessation
- 1988-11-03 IE IE331588A patent/IE61541B1/en not_active IP Right Cessation
- 1988-11-03 KR KR1019880014439A patent/KR970005536B1/en active IP Right Grant
- 1988-11-03 DK DK612788A patent/DK612788A/en not_active Application Discontinuation
- 1988-11-03 CH CH4081/88A patent/CH675583A5/fr not_active IP Right Cessation
- 1988-11-03 CA CA000582165A patent/CA1303619C/en not_active Expired - Fee Related
- 1988-11-04 FR FR888814392A patent/FR2622584B1/en not_active Expired - Fee Related
- 1988-11-04 FR FR888814393A patent/FR2622448B1/en not_active Expired - Fee Related
- 1988-11-04 DE DE3837550A patent/DE3837550A1/en active Granted
- 1988-11-04 JP JP63277522A patent/JPH0686455B2/en not_active Expired - Lifetime
- 1988-11-04 IT IT8822493A patent/IT1227456B/en active
-
1992
- 1992-04-29 SG SG48292A patent/SG48292G/en unknown
- 1992-07-23 HK HK539/92A patent/HK53992A/en not_active IP Right Cessation
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Legal Events
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BB | Publication of examined application | ||
MM | Patent lapsed | ||
MM | Patent lapsed |
Owner name: SOCIETE DE CONSEILS DE RECHERCHES ET D APPLICATION |