CA1303619C - Alkoxy derivatives of ginkgolides, their preparation and therapeutic compositions containing the same - Google Patents
Alkoxy derivatives of ginkgolides, their preparation and therapeutic compositions containing the sameInfo
- Publication number
- CA1303619C CA1303619C CA000582165A CA582165A CA1303619C CA 1303619 C CA1303619 C CA 1303619C CA 000582165 A CA000582165 A CA 000582165A CA 582165 A CA582165 A CA 582165A CA 1303619 C CA1303619 C CA 1303619C
- Authority
- CA
- Canada
- Prior art keywords
- ginkgolides
- same
- alkoxy
- compositions containing
- therapeutic compositions
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
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)
Abstract
ABSTRACT
This invention relates to 1-alkoxy or 10-alkoxy substituted Ginkgolides or mixtures of the same, to a preparation process of these compounds consisting in reacting a dioxan solution of the selected Ginkgolide on a diethyl ether solution of diazoalkane in excess, at room temperature for 1 to 10 hours and to therapeutic compositions containing the same.
This invention relates to 1-alkoxy or 10-alkoxy substituted Ginkgolides or mixtures of the same, to a preparation process of these compounds consisting in reacting a dioxan solution of the selected Ginkgolide on a diethyl ether solution of diazoalkane in excess, at room temperature for 1 to 10 hours and to therapeutic compositions containing the same.
Description
13~?3~19 RS CAS_147 ~ he invontlon relata~ to GinX~olid~ d~rivAtlv ~, to met~o~ for their prep~r~tlon, and to phAr~ceu~l~al ~ompo~ltion~ oontalnlng t~em.
The lnvention provldes l-~lkoxy derivatlve~ of Glnkgollde~ A,~,C,J and M and further provl~-s 10-~lkoxy aerl~Atives o~ the ~ald GinXgol~des. Th~ pre~errod al~oxy groups are ~e~hoxy and othoxy groups.
rhe ln~entlon al~o provid~ a ~ethod ~or the preparation o~ l-alXoxy derlvative~ of Gin~olld-~ A,B,C,J
lo and M and o~ 10-alkoxy derivativoe o~ the ~ald Glnkgollds~, the method co~prl-ing reactlng, ln ~olution, Glnkgolide A,B,C, J or M w~tb an exc~ss o~ d$~zoalkAne ~nd -parating the re~ultant ~lYtur- o~ l-alkoxy-Glnkgol~de and 10-alkoxy-Glnkgolla~.
In a pre~err-a proceduro, the ~oloet-d ~lnXgollde i6 dl~solved ln dloxan, ~uita~ly at ~ concontratlon Or lg per 100 ml, an~ the sel-ote~ dlazo~lkan~ 1~ di-~ol~ed in die~hyl other. ~he olutlon ~ontalnlng th~ al~oalkAn~ iB
slowly a~d-d to that contalnlng the Glnkgolld~, allowing ten sgu~val~nto o~ ala~oal~an~ per ~qul~ nt of Glnkqolld~. Iho ~lxed olution i8 toad at a~b~ont t-mperA~ur~ ~or ~ro~ 3 to B ~ours, yl~lding ~ mlxture o~
l-alkoxy-GlnXgollde and 10~ oxy-Glnkgolldo. The ~opara-tlon o~ thQ two proaucts ~rom the r~lnlng non-r-~ct-d Glnkgollde ~ay u~t~bly be achle~ed by ~porAtlng o~ the ~olvent~ and ~lut~ng the rocldue e~rou~ a ~llioa g~l column u~ing thyl acet~te : hex~ne 1:1 hy volu~e ~
elu-nt.~he resultlng oolutlon 1~ ovapor~t~d o~ and tronted .
RS CAS 1~7 13~3 ~y ohloro~orm which di-~olve~ lO-alkoxy d-r~v~tlv-. The ~aid lO-al~oxy ~oriv~t~ve i~ r-cov-r-d ~om thl0 chlororor~lo olutlon and the r-malnln~ ~olutlon 1O the~
treateid wlth dlethyl ether w~lch glvo~ the l-alkoxy dorlv~tlve.
~ he ~lkoxy-Glnk~oll~o~ o~ th- lnvontlon ar- o~
~ntere~t ln th~ treat~ont ? PAF-Aooth-r lnduced ~ladie~, and the lnvent~on accordln~ly al80 provlde- a phaxmaaeutlaal composlt~on comprl~ln~ a l-~lkoxy dcrlvAtlv~
of Ginkgolldo A,B,C,J or M or lO-~lkoxy dorl~atlv- o~ one of the ald Glnkgolld-- or ~ ~lxturo o~ two o~ ~ore o~ ~ld l-Alkoxy ~nd/or ~d lO-alkoxy derlvatlve- ln admlxture wit~ a phar~acoutlcally ~oceptable dllu-nt or c~rrior.
ThB lnvent~on i~ lllu~trate~ by the ~ollowin~
15 exa~ple~ :
Exam~le 1 l-MethoxY-G~n~soll~e B and lO-M t~oxY-Glnkaolld- B
~ o ~ olution of Glnkgollde a ln dloxan ~lOg~l) WAB
slowly add-d lO oqul~al-nt- of a olutlon of diazo~ thane ln di-thyl eth-r. I~ ~lxtur wa- tood at a~bi-nt to~poraturo for ~ hour~, and t~ n -parAt d followlng the preferr~d -paration procedux4 d -crlb~d ~bove.
l-methoxy-aln~g~lldo ~, t~o otructur o~ whlch W~E
conflrmed by HPLC, wa- obtain d in 66.1 % yiel~ and 2S lo-~Qthoxy-Gin~gollae B wa- obteinoa ln Z4.4 % yl-ld.
r~
RS CAS 1~7 ~ 3~3~
Example 2 l-E~hoxy-Gink~ollde B ~nd 10-E~hoxY-Cln~qolld- ~
~ollDw~n~ the proc~dure de~crlb~d ln Ex~pl~ 1, but using dlazo4thane ln pl~ce Or ~l~zon than~
(duration ~ houx~), l--t~oxy-Gln~golld- ~ wa- Dbtaln~d ln 63 2 % yleld and ~o-othoxy-alnkgolid~ ~ wa~ obtaine~ ln 25,7 ~ ylel~
Proceedlng a~ ~bov~, but wlth Glnkgollde~ A ~md c, th~ ~ollowlng yi-ld~ w-re obt~ln-~:
=~
¦ Ginbgolld ~ ¦ 72 - ~ ¦ 20 1 ¦ Ginbqol~de C 59 2 % 30 4 %
TW~ICI~f The toxlcity of th~ compounds of tho lnventlon has b--n lS ~sured on ~1¢- by oral rout~
No death W~B not~ce~ ~t ma~lmu~ ad~ niotrat~on do~ to mlc~
PNM~CO~aY
-A proof of the ph~r~aooutlcal lnt-r--t of th~
2 0 compounds of tho lnv-ntion ha~ been o-tabll-hod by tho following pbarma¢-utlcal experl~ont~tlon~
~3tJ~
1) - Inhibition of the platelets aqqreqation on N w 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 Drugs".
The results demonstrate that the compounds inhibit the aggregation induced by 2.5 nN 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 ICso on platelets have been found as follows :
13~
Ginkgolide type and substitution - OCHJ - OC2H5 position , ~
B 1- 6.6 10-7 1.1 1o~6 B 10- 2.9 10-7 7.2 1o~6 C 1- 4.2 1o~6 8.5 1o~6 C 10- 3 0 10-6 9.~ 10-6 A 1- 4.6 10-6 8.7 1o~6 A 10- 1.3 10-5 6.2 10-4 2) - AnaPhYlactic bronchoconstriction of a Passively ~ sensitized nuinea-piq Passive heterolog sensitizing ________________ ___________ Male Hartley guinea-pigs (400-500g) were sensitized by an intravenous injection (IV) of an antiovalbumin immune-serum rabbit (Cooper Biomédical, U.S.A.). To obtain a satisfactory anaphylactic response, 24 hours later, the following conditions of use were fixed : injection into the penis of a diluted serum (to half concentration 0.05 ml/100 g).
Bronchoconstriction measure Guinea-pigs were anesthetized with urethan (2 g/kg IP), then tracheotomized and ventilated by mean of a respiratory pump (UG0 BASILE) : stroke volume 1 ml/100 g, 60 strokes/mn.
~, ~ , . . .
` ~3~36~3 A pneumothorax wa- don- to abollsh spontaneous r-splratlon Th- initlal reslstanc- was kept constant at 10 c~ watsr pressur- accordlng to the method o~ Konzett and Ro~lcr and th- cxcess o~ alr volume wa~ measur-d with a bronchospa~
tranduc~r ~UG0 BASI~E) connected to a UC0 ~ASI~ r-cord-r "Gemlnin~ Th- ~ugular veln was cathet-rlzed for lntravenous ln~ections Th- anaphylactlc shock was lnduced by an intravenou- ln~ection of 0 7S mg/kg ot heterolog pa~slve of ovalbu~ine Products wer- given by oral rout-, 1 hour before the antiqenlc stimulation ln the fora of a qu~my water suspenslon, at th- dose of 25 mq/kg ~e~ult~
_______ Th- bronchoconstriction induced by ovalbumin was xpressed ln p-rcentag- of maxlual bronchoconstriction lS given by clamping of the trachea Tbe results are reported in th- following table Glnkgollde type and sub~t~tutlon - OSH, - OC,H, po~itlon _ .
B 1- - 49 7 - 38 3 ~*
C 1- - 40 1 ~ - 39 8 *~
C 10- - 30 6 * - 23 1 *
NS Non Significative Slqnificative ~ *~ Very Slgnificativs 114~ **~ ~ighly Signi~lcative . .
.
.
~ .
.
~3~3~1~
POSOLOGY
In human therapy, usual doses for per as administration are 0.5 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.
~,
The lnvention provldes l-~lkoxy derivatlve~ of Glnkgollde~ A,~,C,J and M and further provl~-s 10-~lkoxy aerl~Atives o~ the ~ald GinXgol~des. Th~ pre~errod al~oxy groups are ~e~hoxy and othoxy groups.
rhe ln~entlon al~o provid~ a ~ethod ~or the preparation o~ l-alXoxy derlvative~ of Gin~olld-~ A,B,C,J
lo and M and o~ 10-alkoxy derivativoe o~ the ~ald Glnkgollds~, the method co~prl-ing reactlng, ln ~olution, Glnkgolide A,B,C, J or M w~tb an exc~ss o~ d$~zoalkAne ~nd -parating the re~ultant ~lYtur- o~ l-alkoxy-Glnkgol~de and 10-alkoxy-Glnkgolla~.
In a pre~err-a proceduro, the ~oloet-d ~lnXgollde i6 dl~solved ln dloxan, ~uita~ly at ~ concontratlon Or lg per 100 ml, an~ the sel-ote~ dlazo~lkan~ 1~ di-~ol~ed in die~hyl other. ~he olutlon ~ontalnlng th~ al~oalkAn~ iB
slowly a~d-d to that contalnlng the Glnkgolld~, allowing ten sgu~val~nto o~ ala~oal~an~ per ~qul~ nt of Glnkqolld~. Iho ~lxed olution i8 toad at a~b~ont t-mperA~ur~ ~or ~ro~ 3 to B ~ours, yl~lding ~ mlxture o~
l-alkoxy-GlnXgollde and 10~ oxy-Glnkgolldo. The ~opara-tlon o~ thQ two proaucts ~rom the r~lnlng non-r-~ct-d Glnkgollde ~ay u~t~bly be achle~ed by ~porAtlng o~ the ~olvent~ and ~lut~ng the rocldue e~rou~ a ~llioa g~l column u~ing thyl acet~te : hex~ne 1:1 hy volu~e ~
elu-nt.~he resultlng oolutlon 1~ ovapor~t~d o~ and tronted .
RS CAS 1~7 13~3 ~y ohloro~orm which di-~olve~ lO-alkoxy d-r~v~tlv-. The ~aid lO-al~oxy ~oriv~t~ve i~ r-cov-r-d ~om thl0 chlororor~lo olutlon and the r-malnln~ ~olutlon 1O the~
treateid wlth dlethyl ether w~lch glvo~ the l-alkoxy dorlv~tlve.
~ he ~lkoxy-Glnk~oll~o~ o~ th- lnvontlon ar- o~
~ntere~t ln th~ treat~ont ? PAF-Aooth-r lnduced ~ladie~, and the lnvent~on accordln~ly al80 provlde- a phaxmaaeutlaal composlt~on comprl~ln~ a l-~lkoxy dcrlvAtlv~
of Ginkgolldo A,B,C,J or M or lO-~lkoxy dorl~atlv- o~ one of the ald Glnkgolld-- or ~ ~lxturo o~ two o~ ~ore o~ ~ld l-Alkoxy ~nd/or ~d lO-alkoxy derlvatlve- ln admlxture wit~ a phar~acoutlcally ~oceptable dllu-nt or c~rrior.
ThB lnvent~on i~ lllu~trate~ by the ~ollowin~
15 exa~ple~ :
Exam~le 1 l-MethoxY-G~n~soll~e B and lO-M t~oxY-Glnkaolld- B
~ o ~ olution of Glnkgollde a ln dloxan ~lOg~l) WAB
slowly add-d lO oqul~al-nt- of a olutlon of diazo~ thane ln di-thyl eth-r. I~ ~lxtur wa- tood at a~bi-nt to~poraturo for ~ hour~, and t~ n -parAt d followlng the preferr~d -paration procedux4 d -crlb~d ~bove.
l-methoxy-aln~g~lldo ~, t~o otructur o~ whlch W~E
conflrmed by HPLC, wa- obtain d in 66.1 % yiel~ and 2S lo-~Qthoxy-Gin~gollae B wa- obteinoa ln Z4.4 % yl-ld.
r~
RS CAS 1~7 ~ 3~3~
Example 2 l-E~hoxy-Gink~ollde B ~nd 10-E~hoxY-Cln~qolld- ~
~ollDw~n~ the proc~dure de~crlb~d ln Ex~pl~ 1, but using dlazo4thane ln pl~ce Or ~l~zon than~
(duration ~ houx~), l--t~oxy-Gln~golld- ~ wa- Dbtaln~d ln 63 2 % yleld and ~o-othoxy-alnkgolid~ ~ wa~ obtaine~ ln 25,7 ~ ylel~
Proceedlng a~ ~bov~, but wlth Glnkgollde~ A ~md c, th~ ~ollowlng yi-ld~ w-re obt~ln-~:
=~
¦ Ginbgolld ~ ¦ 72 - ~ ¦ 20 1 ¦ Ginbqol~de C 59 2 % 30 4 %
TW~ICI~f The toxlcity of th~ compounds of tho lnventlon has b--n lS ~sured on ~1¢- by oral rout~
No death W~B not~ce~ ~t ma~lmu~ ad~ niotrat~on do~ to mlc~
PNM~CO~aY
-A proof of the ph~r~aooutlcal lnt-r--t of th~
2 0 compounds of tho lnv-ntion ha~ been o-tabll-hod by tho following pbarma¢-utlcal experl~ont~tlon~
~3tJ~
1) - Inhibition of the platelets aqqreqation on N w 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 Drugs".
The results demonstrate that the compounds inhibit the aggregation induced by 2.5 nN 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 ICso on platelets have been found as follows :
13~
Ginkgolide type and substitution - OCHJ - OC2H5 position , ~
B 1- 6.6 10-7 1.1 1o~6 B 10- 2.9 10-7 7.2 1o~6 C 1- 4.2 1o~6 8.5 1o~6 C 10- 3 0 10-6 9.~ 10-6 A 1- 4.6 10-6 8.7 1o~6 A 10- 1.3 10-5 6.2 10-4 2) - AnaPhYlactic bronchoconstriction of a Passively ~ sensitized nuinea-piq Passive heterolog sensitizing ________________ ___________ Male Hartley guinea-pigs (400-500g) were sensitized by an intravenous injection (IV) of an antiovalbumin immune-serum rabbit (Cooper Biomédical, U.S.A.). To obtain a satisfactory anaphylactic response, 24 hours later, the following conditions of use were fixed : injection into the penis of a diluted serum (to half concentration 0.05 ml/100 g).
Bronchoconstriction measure Guinea-pigs were anesthetized with urethan (2 g/kg IP), then tracheotomized and ventilated by mean of a respiratory pump (UG0 BASILE) : stroke volume 1 ml/100 g, 60 strokes/mn.
~, ~ , . . .
` ~3~36~3 A pneumothorax wa- don- to abollsh spontaneous r-splratlon Th- initlal reslstanc- was kept constant at 10 c~ watsr pressur- accordlng to the method o~ Konzett and Ro~lcr and th- cxcess o~ alr volume wa~ measur-d with a bronchospa~
tranduc~r ~UG0 BASI~E) connected to a UC0 ~ASI~ r-cord-r "Gemlnin~ Th- ~ugular veln was cathet-rlzed for lntravenous ln~ections Th- anaphylactlc shock was lnduced by an intravenou- ln~ection of 0 7S mg/kg ot heterolog pa~slve of ovalbu~ine Products wer- given by oral rout-, 1 hour before the antiqenlc stimulation ln the fora of a qu~my water suspenslon, at th- dose of 25 mq/kg ~e~ult~
_______ Th- bronchoconstriction induced by ovalbumin was xpressed ln p-rcentag- of maxlual bronchoconstriction lS given by clamping of the trachea Tbe results are reported in th- following table Glnkgollde type and sub~t~tutlon - OSH, - OC,H, po~itlon _ .
B 1- - 49 7 - 38 3 ~*
C 1- - 40 1 ~ - 39 8 *~
C 10- - 30 6 * - 23 1 *
NS Non Significative Slqnificative ~ *~ Very Slgnificativs 114~ **~ ~ighly Signi~lcative . .
.
.
~ .
.
~3~3~1~
POSOLOGY
In human therapy, usual doses for per as administration are 0.5 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 (3)
1) 1-alkoxy or 10-alkoxy substituted Ginkgolides or mixtures of the same.
2) A preparation process of the Ginkgolides derivatives according to claim 1 consisting in reacting a dioxan solution of the selected Ginkgolide on a diethyl ether solution of diazoalkane in excess, at room temperature for 1 to 10 hours.
3) A therapeutic composition of matter for the treatment of PAF-Acether induced maladies comprising, as an essential ingredient therein, a sufficient amount of a compound according to claim 1, together with an appropriate diluent or carrier.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8725871 | 1987-11-04 | ||
| GB878725871A GB8725871D0 (en) | 1987-11-04 | 1987-11-04 | Ginkgolide derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1303619C true CA1303619C (en) | 1992-06-16 |
Family
ID=10626449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000582165A Expired - Fee Related CA1303619C (en) | 1987-11-04 | 1988-11-03 | 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 |
| EP0540767B9 (en) * | 1991-11-04 | 2004-12-22 | Korth, Ruth-Maria, Dr. med | Treatment and prevention of mental diseases mediated by elevated lyso paf levels with paf antagonists |
| DE69132379T2 (en) * | 1990-06-06 | 2001-03-01 | Ruth-Maria Korth | Treatment of diseases with Paf antagonists and method for determining their effectiveness |
| 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 |
| US10875874B2 (en) | 2015-12-18 | 2020-12-29 | 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 BE BE8801244A patent/BE1003455A3/en not_active IP Right Cessation
- 1988-10-28 MY MYPI88001236A patent/MY103446A/en unknown
- 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 AT AT0269688A patent/AT397097B/en not_active IP Right Cessation
- 1988-11-02 FI FI885046A patent/FI90081C/en not_active IP Right Cessation
- 1988-11-02 ES ES8803334A patent/ES2009364A6/en not_active Expired
- 1988-11-03 PT PT88924A patent/PT88924B/en not_active IP Right Cessation
- 1988-11-03 AU AU24644/88A patent/AU616367B2/en not_active Ceased
- 1988-11-03 CH CH4081/88A patent/CH675583A5/fr not_active IP Right Cessation
- 1988-11-03 NO NO884900A patent/NO167739C/en unknown
- 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 TN TNTNSN88118A patent/TNSN88118A1/en unknown
- 1988-11-03 CA CA000582165A patent/CA1303619C/en not_active Expired - Fee Related
- 1988-11-04 FR FR888814393A patent/FR2622448B1/en not_active Expired - Fee Related
- 1988-11-04 JP JP63277522A patent/JPH0686455B2/en not_active Expired - Lifetime
- 1988-11-04 FR FR888814392A patent/FR2622584B1/en not_active Expired - Fee Related
- 1988-11-04 DE DE3837550A patent/DE3837550A1/en active Granted
- 1988-11-04 IT IT8822493A patent/IT1227456B/en active
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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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