NO167739B - ANOLOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE GINKOLIDE DERIVATIVES. - Google Patents
ANOLOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE GINKOLIDE DERIVATIVES. Download PDFInfo
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- NO167739B NO167739B NO884900A NO884900A NO167739B NO 167739 B NO167739 B NO 167739B NO 884900 A NO884900 A NO 884900A NO 884900 A NO884900 A NO 884900A NO 167739 B NO167739 B NO 167739B
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- derivatives
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- ginkolide
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- 238000000034 method Methods 0.000 title claims description 8
- 230000001225 therapeutic effect Effects 0.000 title 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 229930184727 ginkgolide Natural products 0.000 claims description 10
- 229960004132 diethyl ether Drugs 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 239000000243 solution Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 206010006482 Bronchospasm Diseases 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 230000007885 bronchoconstriction Effects 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229940092253 ovalbumin Drugs 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241000700198 Cavia Species 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- HVAUUPRFYPCOCA-AREMUKBSSA-N 2-O-acetyl-1-O-hexadecyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCOC[C@@H](OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C HVAUUPRFYPCOCA-AREMUKBSSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- 206010002199 Anaphylactic shock Diseases 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-M Arachidonate Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC([O-])=O YZXBAPSDXZZRGB-DOFZRALJSA-M 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 108010003541 Platelet Activating Factor Proteins 0.000 description 1
- 206010070834 Sensitisation Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229940114078 arachidonate Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- SQOJOAFXDQDRGF-WJHVHIKBSA-N ginkgolide B Natural products O=C1[C@@H](C)[C@@]2(O)[C@@H]([C@H](O)[C@]34[C@@H]5OC(=O)[C@]23O[C@H]2OC(=O)[C@H](O)[C@@]42[C@H](C(C)(C)C)C5)O1 SQOJOAFXDQDRGF-WJHVHIKBSA-N 0.000 description 1
- SQOJOAFXDQDRGF-MMQTXUMRSA-N ginkgolide-b Chemical compound O[C@H]([C@]12[C@H](C(C)(C)C)C[C@H]3OC4=O)C(=O)O[C@H]2O[C@]24[C@@]13[C@@H](O)[C@@H]1OC(=O)[C@@H](C)[C@]21O SQOJOAFXDQDRGF-MMQTXUMRSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 201000003144 pneumothorax Diseases 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 230000008313 sensitization Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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)
Description
Oppfinnelsen gjelder fremgangsmåte for fremstilling av ginkolid-derivater. The invention relates to a process for the production of ginkgolide derivatives.
Oppfinnelsen angår særlig fremstilling av l-C1-C4-alkoksy-og 10-C1-C4-alkoksy-derivater av ginkolidene A, B, C, J og M. The invention relates in particular to the production of 1-C1-C4-alkoxy- and 10-C1-C4-alkoxy derivatives of the ginkolides A, B, C, J and M.
De foretrukne alkoksy-grupper er metoksy- og etoksy-grupper. The preferred alkoxy groups are methoxy and ethoxy groups.
Oppfinnelsen angår nærmere bestemt en fremgangsmåte for fremstilling av l-Ci-C4-alkoksy- og 10-Ci-C4-alkoksy-derivater av ønskede ginkolider, særlig A, B, C, J og M, og den omfatter omsetning i en dioksanoppløsning av det valgte ginkolid med et overskudd av en dietyleter-oppløsning av diazoalkan og ad-skillelse av den resulterende blanding av l-C1-C4-alkoksy-ginkolid og 10—ci-C4-alkoksy-ginkolid. More precisely, the invention relates to a process for the production of 1-Ci-C4- alkoxy and 10-Ci-C4- alkoxy derivatives of desired ginkolides, in particular A, B, C, J and M, and it comprises reaction in a dioxane solution of ginkgolide was selected with an excess of a diethylether solution of the diazoalkane and separation of the resulting mixture of 1-C1-C4-Alkoxygincolide and 10-C1-C4-Alkoxygincolide.
I en foretrukken fremgangsmåte, løses det utvalgte In a preferred method, the selected is resolved
ginkolid opp i dioksan, hensiktsmessig i en konsentrasjon på lg pr. 100 ml og det utvalgte diazoalkan løses opp i dietyleter. Oppløsningen som inneholder diazoalkanet tilsettes sakte til den som inneholder ginkolidet, i en mengde på 10 ekvivalente diazoalkan pr. ekvivalent ginkolid. Den blandede oppløsning hensettes ved omgivelsenes temperatur i 3-8 timer, og gir en blanding av l-ci~C4-alkoksy-ginkolid og 10-C^-C4-alkoksy-ginkolid. Adskillelsen av de to produkter fra det gjenværende ikke-omsatte ginkolid, kan hensiktsmessig oppnås ved å dampe bort oppløsningsmidlene og vaske bort det gjenværende gjennom en silikagel-kolonne ved bruk av etylacetat: heksan 1:1 i volum som eluent. Den gjenværende oppløsning dampes inn og behandles med kloroform som løser opp10-C<1->C<4->alkoksy-derivatet. Det nevnte 10-C1-C4-alkoksy-derivat gjenvinnes fra denne kloroform-oppløsning og den gjenværende oppløsning behandles deretter med dietyleter som gir l-C1-C4-alkoksy-derivatet. ginkgolide in dioxane, suitably in a concentration of lg per 100 ml and the selected diazoalkane is dissolved in diethyl ether. The solution containing the diazoalkane is slowly added to that containing the ginkgolide, in an amount of 10 equivalents of diazoalkane per ginkgolide equivalent. The mixed solution is allowed to stand at ambient temperature for 3-8 hours, yielding a mixture of 1-C 1 -C 4 -Alkoxy ginkgolide and 10 -C 1 -C 4 -Alkoxy ginkgolide. The separation of the two products from the remaining unreacted ginkgolide can conveniently be achieved by evaporating the solvents and washing the residue through a silica gel column using ethyl acetate:hexane 1:1 by volume as eluent. The remaining solution is evaporated and treated with chloroform, which dissolves the 10-C<1->C<4->alkyl derivative. The aforementioned 10-C1-C4-Alkoxy derivative is recovered from this chloroform solution and the remaining solution is then treated with diethyl ether to give the 1-C1-C4-Alkoxy derivative.
Alkoksy-ginkolidene fremstilt ifølge oppfinnelsen er av interesse ved behandling av sykdommer bevirket av "PAF-Acheter". Alkoxygincolides produced according to the invention are of interest in the treatment of diseases caused by "PAF-Acheter".
Oppfinnelsen illustreres ved de følgende eksempler: The invention is illustrated by the following examples:
Eksempel 1 Example 1
1- metoksy- qinkolid B og 10- metoksv- ginkolid B 1- methoxy-gincolide B and 10- methoxy-gincolide B
Til en oppløsning av ginkolid B i dioksan (lOg/1) ble det sakte tilsatt 10 ekvivalenter av en oppløsning av diazometan i dietyleter. Blandingen fikk stå ved omgivelsenes temperatur i 4 timer og ble deretter adskilt ifølge den foretrukne adskil-lelsesmåte beskrevet ovenfor. 1-metoksy-ginkolid B, hvis struktur ble bekreftet ved HPLC, ble dannet med 66,1% utbytte og10-metoksy-ginkolid B ble dannet med 24,4% utbytte. To a solution of ginkgolide B in dioxane (10g/1) was slowly added 10 equivalents of a solution of diazomethane in diethyl ether. The mixture was allowed to stand at ambient temperature for 4 hours and was then separated according to the preferred separation method described above. 1-Methoxy-gincolide B, whose structure was confirmed by HPLC, was formed in 66.1% yield and 10-methoxy-gincolide B was formed in 24.4% yield.
Eksempel 2 Example 2
1- etoksv- qinkolid B oa 10- etoksy- qinkolid B 1-ethoxyquincolide B and 10-ethoxyquincolide B
Ved å følge fremgangsmåten beskrevet i Eksempel 1, men ved å anvende diazoetan istedenfor diazometan (varighet: 6 timer), ble1-etoksy-ginkolid B dannet med 63,2% utbytte og 10-etoksy-ginkolid B ble dannet ved 25,7% utbytte. By following the procedure described in Example 1, but using diazoethane instead of diazomethane (duration: 6 hours), 1-ethoxy-gincolide B was formed in 63.2% yield and 10-ethoxy-gincolide B was formed in 25.7% dividend.
Ved å gå frem som ovenfor, men med ginkolidene A og C, ble de følgende utbytter oppnådd: Proceeding as above, but with ginkolides A and C, the following yields were obtained:
Toksisitet Toxicity
Toksisiteten til forbindelsene fremstilt ifølge oppfinnelsen er målt på mus ad oral vei. The toxicity of the compounds produced according to the invention has been measured in mice ad orally.
Ingen dødsfall ble oppdaget ved administrering av maksimal dose til mus. No deaths were detected when the maximum dose was administered to mice.
Farmakologi Pharmacology
Et bevis på den farmasøytiske verdi av forbindelsene fremstilt ifølge oppfinnelsen er bragt tilveie ved de følgende farmasøytiske eksperimenter. 1) - Hemning av blodplate- aggreqasjonen hos New Zeland A proof of the pharmaceutical value of the compounds prepared according to the invention is provided by the following pharmaceutical experiments. 1) - Inhibition of platelet aggregation in New Zealand
kaniner. rabbits.
Eksperimentene ble gjennomført på blodplater med plasma The experiments were carried out on platelets with plasma
fra New Zealand-kaniner. from New Zealand rabbits.
Blodprøver ble tatt fra ørets arterier og plassert i citrat-buffer (3,8%; pH 7,4); blodet ble videre sentrifugert i 15 minutter ved 1200 RPM. Blood samples were taken from the arteries of the ear and placed in citrate buffer (3.8%; pH 7.4); the blood was further centrifuged for 15 minutes at 1200 RPM.
Testprøven ble tilberedt i DMSO, deretter helt i blodplaterikt plasma i 1 minutt, deretter ble en dose på 2,5 nM PAF tilsatt. Bestemmelsen gjøres med en "Cronolog Coultronics"-apparatur som bestemmer overføringsprosenten som tilsvarer maksimumshøyde på toppen før aggregasjonen avtar. The test sample was prepared in DMSO, then completely in platelet-rich plasma for 1 minute, then a dose of 2.5 nM PAF was added. The determination is made with a "Cronolog Coultronics" apparatus which determines the transfer percentage corresponding to the maximum height of the peak before the aggregation subsides.
Prosentvis variasjon av hemninger når det gjelder overfør-ingsprosenten beregnes (kontroll: ren DMSO). Percentage variation of inhibitions in terms of transfer percentage is calculated (control: pure DMSO).
Denne fremgangsmåte ble beskrevet i detalj i LABORATORY INVESTIGATIONS, Vol. 41, No.3,S.275, 1979, JEAN-PIERRE This procedure was described in detail in LABORATORY INVESTIGATIONS, Vol. 41, No.3, P.275, 1979, JEAN-PIERRE
CAZENAVE, Dr.MED. JAQUES BENVENISTE, Dr.MED., AND J.FRASER CAZENAVE, Dr. MED. JAQUES BENVENISTE, MD, AND J. FRASER
MUSTARD, M.D., "Aggregation of Rabbits Platelets by Platelet-Activating Factor is independent of the Release Reaction and 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". the Arachidonate Pathway and inhibited by Membrane-Active Drugs".
Resultatene viser at forbindelsene hemmer aggregasjonen forårsaket av 2,5 nM PAF. Fem prøver gjort med fem forskjellige kaniner tillot oss å beregne IC50for de forskjellige forbind-elser ved bruk av lineær regresjonstest. The results show that the compounds inhibit the aggregation caused by 2.5 nM PAF. Five tests done with five different rabbits allowed us to calculate the IC 50 for the different compounds using the linear regression test.
Verdiene for IC50på blodplater er funnet som følgende The values for IC50 on platelets have been found as follows
(i nM): (in nM):
Tilsvarende verdier for utgangsginkolidene under samme betingelser: Corresponding values for the starting gincolides under the same conditions:
Det vil sees at forbedring kan oppnås ved substituering, særlig av ginkolidene B og C. It will be seen that improvement can be achieved by substitution, especially of the ginkolides B and C.
2) - Anafylaktisk broncokonstriksion hos et passivt sensibilisert marsvin 2) - Anaphylactic bronchoconstriction in a passively sensitized guinea pig
Passiv heterolog sensibilisering Passive heterologous sensitization
Hartley hannmarsvin (400-500g) ble sensibilisert ved en intravenøs injeksjon (IV) av et anti-ovalbumin immunserum fra kanin (Cooper Biomédical, U.S.A.)- For å få en tilfredsstillende anafylaktisk reaksjon, ble det 24 timer senere alltid bruk følgende betingelser: injeksjon i penis med et fortynnet serum (til halve konsentrasjonen 0,05 ml/100g). Hartley male guinea pigs (400-500g) were sensitized by an intravenous injection (IV) of a rabbit anti-ovalbumin immune serum (Cooper Biomédical, U.S.A.) - To obtain a satisfactory anaphylactic reaction, 24 hours later the following conditions were always used: injection in the penis with a diluted serum (to half the concentration 0.05 ml/100g).
Måling av broncokonstriksjon Measurement of bronchoconstriction
Marsvin ble bedøvet med uretan (2 g(kg IP), deretter trakeotomisert og ventilert ved hjelp av en respirasjonspumpe (UGO BASILE): slagvolum 1 ml/100g, 60 slag pr. minutt. Guinea pigs were anesthetized with urethane (2 g(kg IP), then tracheotomized and ventilated using a respiratory pump (UGO BASILE): stroke volume 1 ml/100g, 60 strokes per minute.
En pneumoptorax ble gjennomført for å hindre spontan pusting. Begynnelsesmotstanden ble holdt konstant på 10 cm vanntrykk ifølge Konzett and Rosslers fremgangsmåte og overskudd av luftvolum ble målt med en broncospasmtransducer (UGO BASILE) forbundet med et UGO BASILE registreringsapparat "Gemini". Det ble satt inn kateter i halsvenen til intravenøse injeksjoner. Det anafylaktiske sjokk ble bevirket ved en intravenøs injeksjon av 0,75 mg/kg heterolog passiv av ovalbumin. Produktene ble gitt ad oral vei, én time før antigen-stimuleringen, i form av en gummiaktig vannsuspensjon i dose på 25 mg/kg. A pneumothorax was performed to prevent spontaneous breathing. The initial resistance was kept constant at 10 cm water pressure according to Konzett and Rossler's method and excess air volume was measured with a bronchospasm transducer (UGO BASILE) connected to a UGO BASILE recording device "Gemini". A catheter was inserted into the jugular vein for intravenous injections. The anaphylactic shock was induced by an intravenous injection of 0.75 mg/kg heterologous passive ovalbumin. The products were given orally, one hour before the antigen stimulation, in the form of a gummy water suspension in a dose of 25 mg/kg.
Resultater Results
Broncokonstriksjonen bevirket av ovalbumin ble uttrykt i prosent av maksimal broncokonstriksjon gitt ved å sette klemme på trakea. Resultatene er angitt i følgende tabell: The bronchoconstriction effected by ovalbumin was expressed as a percentage of the maximum bronchoconstriction given by clamping the trachea. The results are shown in the following table:
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878725871A GB8725871D0 (en) | 1987-11-04 | 1987-11-04 | Ginkgolide derivatives |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO884900D0 NO884900D0 (en) | 1988-11-03 |
| NO884900L NO884900L (en) | 1989-05-05 |
| NO167739B true NO167739B (en) | 1991-08-26 |
| NO167739C NO167739C (en) | 1991-12-04 |
Family
ID=10626449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO884900A NO167739C (en) | 1987-11-04 | 1988-11-03 | ANOLOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE GINKOLIDE DERIVATIVES. |
Country Status (28)
| Country | Link |
|---|---|
| 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
1987
- 1987-11-04 GB GB878725871A patent/GB8725871D0/en active Pending
-
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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