IE61541B1 - New alkoxy derivatives of ginkgolides, their preparation and therapeutic compositions containing the same - Google Patents
New alkoxy derivatives of ginkgolides, their preparation and therapeutic compositions containing the sameInfo
- Publication number
- IE61541B1 IE61541B1 IE331588A IE331588A IE61541B1 IE 61541 B1 IE61541 B1 IE 61541B1 IE 331588 A IE331588 A IE 331588A IE 331588 A IE331588 A IE 331588A IE 61541 B1 IE61541 B1 IE 61541B1
- Authority
- IE
- Ireland
- Prior art keywords
- ginkgolide
- alkoxy
- mixture
- ginkgolides
- derivatives
- Prior art date
Links
- 229930184727 ginkgolide Natural products 0.000 title claims abstract description 33
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 5
- 125000003545 alkoxy group Chemical group 0.000 title claims description 3
- 230000001225 therapeutic effect Effects 0.000 title 1
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 239000002904 solvent Substances 0.000 claims abstract description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 238000001704 evaporation Methods 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- -1 ethyl - Chemical class 0.000 claims description 2
- 239000011369 resultant mixture Substances 0.000 claims description 2
- 239000000741 silica gel Substances 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 claims 1
- 239000012454 non-polar solvent Substances 0.000 claims 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 abstract description 6
- FPUXKXIZEIDQKW-MFJLLLFKSA-N ginkgolide A Natural products O=C1[C@H](C)[C@@]2(O)[C@@H](O1)C[C@]13[C@@H]4OC(=O)[C@]21O[C@@H]1OC(=O)[C@H](O)[C@]31[C@@H](C(C)(C)C)C4 FPUXKXIZEIDQKW-MFJLLLFKSA-N 0.000 abstract description 4
- 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 abstract description 3
- 108010003541 Platelet Activating Factor Proteins 0.000 abstract description 3
- 238000006243 chemical reaction Methods 0.000 abstract description 2
- FPUXKXIZEIDQKW-VKMVSBOZSA-N ginkgolide-a 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@@]13C[C@@H]1OC(=O)[C@@H](C)[C@]21O FPUXKXIZEIDQKW-VKMVSBOZSA-N 0.000 abstract description 2
- 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 abstract description 2
- LMEHVEUFNRJAAV-HOSIAMDISA-N ginkgolide J Natural products O=C1[C@H](C)[C@@]2(O)[C@H](O1)C[C@@]13[C@H]4[C@@H](O)[C@@H](C(C)(C)C)[C@@]51[C@@H](O)C(=O)O[C@@H]5O[C@@]23C(=O)O4 LMEHVEUFNRJAAV-HOSIAMDISA-N 0.000 abstract 2
- AMOGMTLMADGEOQ-FNZROXQESA-N Ginkgolide C Chemical compound O([C@H]1O2)C(=O)[C@H](O)C31[C@]14[C@@H](O)[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@@H](O)[C@H]3C(C)(C)C AMOGMTLMADGEOQ-FNZROXQESA-N 0.000 abstract 1
- CBAUUWCEZZNYTD-OOWJTCQTSA-N Ginkgolide M Natural products O=C1[C@@H](C)[C@@H]2[C@@H]([C@@H](O)[C@@]34[C@H]5[C@@H](O)[C@@H](CC(C)C)[C@@]63[C@@H](O)C(=O)O[C@@H]6O[C@@]24C(=O)O5)O1 CBAUUWCEZZNYTD-OOWJTCQTSA-N 0.000 abstract 1
- KDKROYXEHCYLJQ-DYXVGVPESA-N Ginkgolide M Chemical compound C[C@H]1[C@H]2[C@H]([C@@H](C34[C@]25C(=O)O[C@@H]3[C@@H]([C@H](C46[C@H](C(=O)O[C@H]6O5)O)C(C)(C)C)O)O)OC1=O KDKROYXEHCYLJQ-DYXVGVPESA-N 0.000 abstract 1
- AMOGMTLMADGEOQ-DPFZUGDXSA-N ginkgolide C Natural products O=C1[C@@H](C)[C@]2(O)[C@H]([C@H](O)[C@@]34[C@H]5[C@H](O)[C@@H](C(C)(C)C)[C@]63[C@H](O)C(=O)O[C@H]6O[C@@]24C(=O)O5)O1 AMOGMTLMADGEOQ-DPFZUGDXSA-N 0.000 abstract 1
- LMEHVEUFNRJAAV-UKWFQYJJSA-N ginkgolide-j Chemical compound O([C@H]1O2)C(=O)[C@H](O)[C@@]31[C@]14C[C@@H]5OC(=O)[C@@H](C)[C@]5(O)[C@@]12C(=O)O[C@@H]4[C@H](O)[C@H]3C(C)(C)C LMEHVEUFNRJAAV-UKWFQYJJSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 206010006482 Bronchospasm Diseases 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000004220 aggregation Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 241000283977 Oryctolagus Species 0.000 description 2
- 208000009144 Pure autonomic failure Diseases 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 230000007885 bronchoconstriction Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 208000033399 Anaphylactic responses 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
- 241000219198 Brassica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 108010058846 Ovalbumin Proteins 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000007503 antigenic stimulation Effects 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
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 101150058626 gcH3 gene Proteins 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 238000011597 hartley guinea pig Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 210000004731 jugular vein Anatomy 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 229940092253 ovalbumin Drugs 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 201000003144 pneumothorax Diseases 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 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
Landscapes
- 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
The invention relates to Ginkgolide derivatives, to methods for their preparation, and to pharmaceutical compositions containing them.
The invention provides 1-alkoxy and 10-alkoxy derivatives,· separatelv or in admixture, of any one of the Ginkgolides A,B,C,J ..and M. The preferred alkoxy groups are methoxy and ethoxy groups.
The invention also provides a method for the preparation of ι-alkoxy derivatives of Ginkgolides A.B.C.J and M and of 10-alkoxy derivatives of the said Ginkgolides,. the method comprising reacting, in solution. Ginkgolide A.B.C.J or M with an excess of diazoalkane and separating the resultant mixture of l-alkoxy-Ginkgolide and 10-alkoxy-Ginkgolide.
In a preferred procedure, the selected Ginkgolide is dissolved in dioxan, suitably at a concentration of Ig per J.00 ml, and the selected diazoalkane is dissolved in diethyl ether. The solution containing the diazoalkane is slowly added to that containing the Ginkgolide, allowing ten equivalents of diazoalkane per equivalent of Ginkgolide. The mixed solution is stood at ambient temperature oro from 3 to 8 hours, yielding a mixture of !-alkoxy~Ginkgolide and 10-alkoxy-Ginkgolide. The separation of the two products from the remaining non-reacted Ginkgolide may suitably be achieved by evaporating off the solvents and eluting the residue through a silica gel column using ethyl acetate: hexane i:i by volume as eluent. The resulting solution is evaporated off and treated with chloroform which dissolves Ζ the ίΟ-alkoxy derivative. The said 10-alkoxy derivative is recovered from this chloroformic solution and the remaining solution is then treated with diethyl ether which gives the 1-alkoxy derivative.
The alkoxy-Ginkgolides of the invention are of interest in. the treatment of PAF-Acether induced maladies, and the invention accordingly also provides a pharmaceutical composition comprising a 1-alkoxy or 10-alkoxy derivative of one of the Ginkgolides A,B,C,J and M or a mixture of the 1-alkoxy and 10-alkoxy derivatives of one of the said Ginkgolides in admixture with a pharmaceutically acceptable diluent or carrier.
The invention is illustrated by the following examples: Example 1 1-Hethoxy-Ginkqolid_e B and IQ-Methoxy-Ginkgolide B To a solution of Ginkgolide B in dioxan (lOg/1) was slowly added 10 equivalents of a solution of diazomethane in diethyl ether. The mixture was stood at ambient temperature for 4 hours, and then separated following the preferred separation procedure described above. 1-methoxy-Ginkgolide B, the structure of which was confirmed by HPLC, was obtained in 65.1% yield and 10-methoxy-Ginkgolide B was obtained in 24.4% yield. 1 - methoxy 10 - methoxy Ginkgolide A 56.3 % 13.2 % Ginkoolide c 49.1 % 16.7 % .. . .. .......
Example 2 a-Bthoxy-Ginkgolide 3 and 3.0-Bfchoxy-Ginkqolide B Following the procedure described in Example l. but using diasEoefchane in place of diasomethane, and allowing the reactants to stand for six hours. l~ethoxy-Ginkgolide B was obtained in ¢3.2% yield and 10-ethoxy-Ginkgolide B was obtained in 25.7% yield.
Proceeding as above, but with Ginkgolides A. and C, the following yields were obtained? 1 - ethoxy = - > -·-· - ~ io - ethoxy Ginkgolide A 72.8 % 20.1 % —— >- Ginkgolide c 59.2 % 30.4 % .- r - -- — ---- TOXICITY The toxicity of the compounds of the invention has been measured on mice by the oral route. No death was noticed at the maximum adminstration dose.
PHARMACOLOGY The pharmaceutical interest of the compounds of the invention is shown by the following pharmaceutical experiments. 1) - Inhibition of the platelets aggregation on New Zealand rabbits.
The experimentation was conducted on platelets with plasma of New Zealand rabbits.
Blood samples were taken from auricular artery and placed in a citrate buffer (3.8 % ? pH 7.4) ? blood was further centrifugated for 15 mn at 1200 RPM.
The tested sample was prepared in DMSO, then poured on platelets rich plasma for 1 mn, then a dose of 2.5 nM of PAF was added.
The determination is made on a Cronolog Coultronics apparatus which determines the transmission percentage corresponding to the maximum height of the peak before the desaggregation.
The percentage of variation of the inhibition with respect to the transmission percentage is calculated (control : pure DMSO).
This method was described in detail in LABORATORY INVESTIGATIONS, Vol. 41, No. 3, p. 275, 1979, JEAN-PIERRE CAZENAVE, 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 Drugs8'.
The results demonstrate that the compounds inhibit the aggregation induced fay 2.5 nM of PAF. Five tests made on 5 different rabbits allowed us to calculate the icso of the various compounds using the linear regression test.
The values for IC30 on platelets have been found as follows : Sinkgolide type and substitution position - gch3 - OCSIIB B 1- 6.6 io7 1.1 io"5 3 10- 2.9 10~7 7.2 10^ c 1- 4.2 10-« 8.5 ios c 10- 3.0 VO I o F-J 9.3 io"6 A 1- 4.6 I0~6 8.7 10"S A 10- 1.3 10~5 6.2 10-* 2) - Anaphylactic bronchocosasfcrlctiion og a passively sensitized guinea-pig 20 ?®§9iHS_5®£SESc99„iSS§i£iSiB9 Male Hartley guinea-pigs (400-500«) were sensitized by an intravenous injection (IV) of an antiovalbumin immune-serum rabbit (Cooper Biomedical, U.S.A.). To obtain a 25 satisfactory anaphylactic response, 24 hours later, the following conditions of use vets fixed : injection into the penis of a diluted serum (to half concentration 0..05 ml/100 g) „ BEonchoconstriction^geagure Guinea-pigs were anesthetized with urethan (2 g/kg IP), then tracheotomised and ventilated by mean of a respiratory pump (UGO BASILE) : stroke volume I ml/100 g, strokes/mn.
. A pneumothorax was done to abolish spontaneous respiration. The initial resistance was kept constant at 10 cm water pressure according to the method of Konzett and Bossier and the excess of air volume was measured with a bronchospasm tranducer (UGO BASILE) connected to a UGO BASILE recorder Gemini". The jugular vein was catheterised for intravenous injections. The anaphylactic shock was induced by an intravenous injection of 0.75 mg/kg of heterolog passive of ovalbumine. Products were given by oral route, 1 hour before the antigenic stimulation in the form of a gummy water suspension, at the dose of 25 mg/kg.
Results The bronchoconstriction induced by ovalbumin was expressed in percentage of maximal bronchoconstriction given by clamping of the trachea.. The results are reported in the following table : Ginkgolide type and substitution position - oca, - OC.HS B 1- *** - 49.7 ** - 38.3 0 10- ft** - 54.9 ft* - 36.2 C 1" & ά - 40.1 ft* - 39.8. c 10- -30.6 & ~ 23.1 A 1- * - 32.0 - 15.1 NS A 10- * - 25.2 - 12.2 NS NS : Non Significant * : Significant ft* : very Significant : Highly Significant *** posowcy In human therapy, usual doses for per as administration are 0.. S to 1 g per diem, in tablets or gelatine capsules for one month.
In I.V. administration, three weekly injections at 0.05 to 0.2 g in isotonic solution, for one month are recommended.
Claims (11)
1.claims 1 l. A 1-alkoxy or io-alkoxy derivative of one of the ? Ginkgolides A,B,C e J or M or a mixture of the i-alkoxy and 10-alkoxy derivatives of one of the said Ginkgolides.
2. A Ginkgolide derivative according to claim ϊ or mixture of Ginkgolide derivatives according to claim i in which the or each alkoxy group is a methoxy or ethoxy group.
3. A process for the preparation of a Ginkgolide derivative according to claim 1 or a mixture of Ginkgolide derivatives according to claim 1, the process comprising reacting, in solution in a non-polar solvent, one of the Ginkgolides 15 A, B, C, J, or M with an excess of diazoalkane, and optionally separating the resultant mixture of l-alkoxy-Ginkgolide and 10-alkoxy-Ginkgolide .
4. A process according to claim 3 in which the diazoalkane is diazoraethane or diazoethane.
5. A process according to claim 3 or claim 4 in which approximately 10 equivalents of the diazoalkane are employed per equivalent of Ginkgolide. 2 5 s.
6.A process according to any of claims 3 to 5 in which a diethyl ether solution of the diazoalkane Is mixed with a dioxan solution of the Ginkgolide and the mixture is allowed to react for from 3 to 8 hours at ambient ^30 temperature.
7. A process according to any of claims 3 to 6 In which the mixture is separated by evaporating off the solvent, eluting the residue through a silica gel column using ethyl - § acetate: hexane 1:1 by volume as eluent, evaporating off the solvent from the eluate,, taking up the residue in chloroform, recrystallising the 10-alkoxy-Ginkgolide from ‘ solution and adding diethyl ether £o the remaining solution
8. T© obtain the l-alkoxy-Ginkgolide8. A process for the preparation of a Ginkgolide derivative according to claim 1 or a mixture of Ginkgolide derivatives according to claim i, the process being
9. 10 substantially as described herein with reference to either of the Examples. S. A pharmaceutical composition comprising a 1-alkoxy or iQ-alkoxy derivative of one of the Ginkgolides A,B,C.J and 15 M or a mixture of the l-alkoxy and 10-alkoxy derivatives of one of the said Ginkgolides in admixture with a pharmaceutically acceptable diluent or carrier.
10. A Ginkgolide derivative according to claim 1 or a mixture of Ginkgolide derivatives according to claim 1 whenever prepared by a process as claimed in any of claims 3 to 8. 7
11. A Ginkgolide derivative according to claim 1 or a mixture of Ginkgolide derivatives according to claim 1 substantially as herein25 before described wi/th reference to either of the Examples.
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 |
|---|---|
| IE883315L IE883315L (en) | 1989-05-04 |
| IE61541B1 true IE61541B1 (en) | 1994-11-16 |
Family
ID=10626449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE331588A IE61541B1 (en) | 1987-11-04 | 1988-11-03 | New alkoxy derivatives of ginkgolides, their preparation and therapeutic compositions containing the same |
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) | FR2622448B1 (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 |
| EP0459432B1 (en) * | 1990-06-01 | 2000-08-23 | Korth, Ruth, Dr. med. | Treatment of diseases with paf-antagonists and procedure for determining their efficacy |
| ATE221779T1 (en) * | 1991-11-04 | 2002-08-15 | Ruth-Maria Korth | TREATMENT AND PREVENTION OF ELEVATED LYSO-PAF LEVELS-MEDIATED MENTAL DISEASES USING 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 |
| CN106892930B (en) | 2015-12-18 | 2020-02-18 | 成都百裕金阁莱药业有限公司 | Bilobalide B derivative and preparation method and application thereof |
| 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 |
| 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 |
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 NL NL8802635A patent/NL8802635A/en not_active Application Discontinuation
- 1988-10-26 GR GR880100726A patent/GR1000264B/en unknown
- 1988-10-26 IN IN928DE1988 patent/IN173404B/en unknown
- 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 FI FI885046A patent/FI90081C/en not_active IP Right Cessation
- 1988-11-02 AT AT0269688A patent/AT397097B/en not_active IP Right Cessation
- 1988-11-02 ES ES8803334A patent/ES2009364A6/en not_active Expired
- 1988-11-03 AU AU24644/88A patent/AU616367B2/en not_active Ceased
- 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 CA CA000582165A patent/CA1303619C/en not_active Expired - Fee Related
- 1988-11-03 CH CH4081/88A patent/CH675583A5/fr not_active IP Right Cessation
- 1988-11-03 DK DK612788A patent/DK612788A/en not_active Application Discontinuation
- 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 TN TNTNSN88118A patent/TNSN88118A1/en unknown
- 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 FR FR888814392A patent/FR2622584B1/en not_active Expired - Fee Related
- 1988-11-04 IT IT8822493A patent/IT1227456B/en active
- 1988-11-04 JP JP63277522A patent/JPH0686455B2/en not_active Expired - Lifetime
-
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
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |