DK144916B - Fremgangsmaade til fremstilling af vlb-3-spiro-5"-oxazolidin-2",4"-dion eller ikke-toxiske syreadditionssalte heraf - Google Patents
Fremgangsmaade til fremstilling af vlb-3-spiro-5"-oxazolidin-2",4"-dion eller ikke-toxiske syreadditionssalte heraf Download PDFInfo
- Publication number
- DK144916B DK144916B DK541177AA DK541177A DK144916B DK 144916 B DK144916 B DK 144916B DK 541177A A DK541177A A DK 541177AA DK 541177 A DK541177 A DK 541177A DK 144916 B DK144916 B DK 144916B
- Authority
- DK
- Denmark
- Prior art keywords
- vlb
- spiro
- acid addition
- addition salts
- oxazolidin
- Prior art date
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- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 229950003670 vinrosidine Drugs 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D519/04—Dimeric indole alkaloids, e.g. vincaleucoblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
(19) DANMARK
|j| i«) FREMLÆGGELSESSKRIFT on 144916B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENET
(21) Ansøgning nr. 5*Μ 1/77 (51) IntCI.3 C 07 D 519/0A
(22) Indleveringsdag 5- dec. 1977 (24) Løbedag 5- dec. 1977 (41) Aim. tilgængelig 7· jun. 1978 (44) Fremlagt 5 · jul. 1982 (86) International ansøgning nr. -(86) International indleveringsdag (85) Videreførelsesdag -(62) Stamansøgning nr. **
(30) Prioritet 6. dec. 1976, 747575, US
(71) Ansøger ELI LILLY AND COMPANY, Indianapolis, US.
(72) Opfinder Jean Corinne Miller, US: Gerald Edward Gutowski, US.
(74) Fuldmægtig Ingeniørfirmaet Hofman-Bang & Bout ard.
(54) Fremgangsmåde til fremstilling af VLB-3-epiro-5 " -oxazolidin-2", 4 " -dlon eller ikke-toxiske syread= ditIonssalte heraf.
Den foreliggende opfindelse angår en særlig fremgangsmåde til fremstilling af VLB-3-spiro-5"-oxazolidin-2",4"-dion, og fremgangsmåden ifølge opfindelsen er ejendommelig ved, at man i nærværelse af natriumhydrid omsætter vindesin med dimethylcarbonat, hvorefter man om ønsket omdanner den opnåede forbindelse til et salt.
Den omhandlede forbindelse og dens salte er terapeutisk anvende- ® lige imcd tumorer.
CO
07 Adskillige naturligt forekommende alkaloider udvundne af vinca _d" rosea er konstateret virksomme i behandlingen af eksperimentelt frem-kaldte maligne tilstande hos dyr. Blandt disse er leurosin (U.S.A.-^ patentskrift nr. 3 370 057)» vincaleukoblastin (vinblastin), som her- Q efter vil blive betegnet med forkortelsen VLB (U.S.A.-patentskrift 2 1449 16 nr. 3 097 137), leuroformin (belgisk patentskrift nr. 811 110), leurosidin (vinrosidin) og leurocristin (vineristin) (begge i U.S.A.-patentskrift nr. 3 205 220); deoxy-VLB "A" og "B", Tetrahedron Letters, 783 (1958); 4-desacetoxyvinblastin (U.S.A.-patentskrift nr. 3 954 773); 4-desacetoxy-3t-hydroxyvinblastin (U.S.A.-patentskrift nr. 3 944 554); leurocolombin (U.S.A.-patentskrift nr.
3 890 325) og vincadiolin (U.S.A.-patentskrift nr. 3 887 565). To af disse alkaloider, VLB og vineristin, bliver nu markedsført som medikament til behandling af maligne tilstande, specielt leukæmier og beslægtede sygdomme hos mennesker. Vineristin er det mest aktive og nyttige af de to medikamenter ved behandling af leukæmi, men er samtidig det mindst udbredte af de nævnte anti-neoplasma-Vinca rosea-alkaloider. Disse alkaloider indgives normalt intravenøst.
Kemisk modifikation af vinca-alkaloiderne er kun lykkedes i begrænset omfang. For det første er de pågældende molekylstrukturer yderst komplicerede, og kemiske reaktioner, som berører en specifik, funktionel gruppe i molekylet uden at omdanne andre grupper, er vanskelige at udforme. For det andet har man udvundet eller produceret alkaloider uden ønskelig kemoterapeutisk effekt ud fra vinca rosea-fraktioner eller -alkaloider, og fastlæggelsen af disses strukturformler har ført til den slutning, at disse forbindelser er nært beslægtede med de aktive alkaloider. Anti-neoplasma-effekter synes at være begrænset til helt specielle strukturformler, og mulighederne for at opnå mere effektive medikamenter ved at modificere disse strukturer synes at være beskedne. Blandt de mere heldige modifikationer af fysiologisk aktive alkaloider har været fremstillingen af dihydro-VLB (U.S.A.-patentskrift nr. 3 352 868) og udskiftningen af acetylgruppen ved C-4 (carbonatom nr. 4 i vinca-alkaloidringsystemet, se den nummererede strukturformel i indledningen til krav 1) med en højere alkanoylgruppe eller med ikke-beslægtede acylgrupper. (Se U.S.A.-patentskrift nr. 3 392 173). Adskillige af disse derivater er i stand til at forlænge levetiden hos mus indpodet med P 1534-leukæmi. Et af derivaterne, i hvilket en chloracetylgruppe erstatter acetylgruppen ved C-4-atomet i VLB, er ligeledes anvendeligt som mellemprodukt ved fremstillingen af strukturelt modificerede VLB-forbindelser, i hvilke en N,N-di-alkylglycylgruppe erstatter ac etylgrupp en ved C-4-atomet i VLB (se U.S.A.-patentskrift nr. 3 387 0Q1). C-3-carboxamid-derivater af VLB, vineristin, vincadiolin, m.fl. er ligeledes blevet frem- 3 1449 1 6 stillet og har vist sig at være effektive anti-tumor-medikamenter (belgisk patentskrift nr. 813 168). Disse forbindelser er særdeles interessante, fordi f.eks. 3-carboxamideme af VLB er mere effektive over for Ridgeways osteogeniske sarcom og Gardeners lym-phosarcom end VLB, hvoraf de er derivater. Visse af amidderivaterne nærmer sig faktisk vineristin i effektivitet overfor disse tumorer. Et af disse amider, 4-desacetyl-VLB-C-3-carboxamid (også kaldet vindesin) er for tiden under klinisk afprøvning på mennesker og er blevet fundet aktivt over for visse leukæmier. Anvendt på mennesker synes vindesin at være mindre neurotoxisk end vin-cristin.
Det har overraksende vist sig, at når vindesin omsattes med dimethyl carbonat i nærværelse af natriumhydrid, dannes der et 3-spiro-5"-oxazolidin-2",4"-dion-derivat af VLB, som har antitumorvirkning.
Ikke-toxiske syrer anvendelige til fremstilling af farmaceutisk acceptable syreadditionssalte af den omhandlede forbindelse omfatter salte afledt af uorganiske syrer, såsom saltsyre, salpetersyre, phosphorsyre, svovlsyre, hydrogenbromidsyre, hydrogeniodidsyre, salpetersyrling, phosphorsyrling og lignende, såvel som salte af ikke-toxiske organiske syrer omfattende alifatiske mono- og dicarboxylsy-rer, phenyl-substituerede alkanoater, hydroxyalkanoater og alkandioa-ter, aromatiske syrer, alifatiske og aromatiske sulfonsyrer, etc. Sådanne farmaceutisk acceptable salte omfatter således sulfat, pyrosul-fat, bisulfat, sulfit, bisulfit, nitrat, phosphat, monohydrogenphos-phat, dihydrogenphosphat, metaphosphat, pyrophosphat, chlorid, bromid, iodid, acetat, propionat, decanoat, caprylat, aerylat, formiat, isobutyrat, caprat, heptanoat, propiolat, oxalat, malonat, succinat, suberat, sebacat, fumarat, maleat, butyn-1,4-dioat, hexyn-l,6-dioat, benzoat, chlorbenzoat, methylbenzoat, dinitrobenzoat, hydroxybenzoat, methoxybenzoat, phthalat, terephthalat, benzensulfonat, toluensulfo-nat, chlorbenzensulfonat, xylensulfonat, phenylacetat, phenylpropio-nat, phenylbutyrat, citrat, lactat, 2-hydroxy-butyrat, glycolat, malat, tartrat, methansulfonat, propansulfonat, naphthalen-l-sul-fonat, naphthalen-2-sulfonat og lignende salte.
Ved gennemførelsen af omsætningen ved fremgangsmåden ifølge opfindelsen suspenderer man natriumhydrid i et inert organisk opløsningsmiddel såsom tetrahydrofuran, og vindesin sættes til 4 1449 16 suspensionen efterfulgt af dimethylcarbonat. Reaktionsblandingen omrores ved stuetemperatur, indtil oxazolidindiondannelsen i det store og hele er fuldstændig. Fjernelse af opløsningsmidlet fører til produktet i form af en inddampningsrest, som yderligere kan renses ved chromatografering. Andre inerte opløsningsmidler, som kan anvendes i ovennævnte omsætning, er f. eks. methylen-chlorid og chloroform.
Farmakologisk acceptable syreadditionssalte af den omhandlede forbindelse fremstilles ved at blande en opløsning af forbindelsen på fri baseform med 1 mol af den ønskede ikke-toxiske syre i et inert opløsningsmiddel. Hvis saltet er opløseligt, genvindes det ved afdampning af opløsningsmidlet under vakuum. Hvis saltet er uopløseligt i reaktionsmediet, vil det bundfældes og kan isoleres ved filtrering. Visse af de uorganiske salte fremstilles på en noget afvigende måde. For eksempel fremstilles sulfatsaltet ved at opløse den frie baseform i den mindst mulige mængde polært opløsningsmiddel, såsom ethanol, og derpå justere denne opløsenings pH til ca. 4,0 ved dråbe for dråbe at tilsætte en 2 % vandig svovlsyre i ethanol. Sulfatsaltet indvindes ved fordampning af opløsningsmidlerne til tørhed. Hydrochloridet kan fremstilles på lignende måde ved at sætte en alkoholisk opløsning af HC1 til en alkoholisk opløsning af den frie base. De som ovenfor beskrevet fremstillede syreadditionssalte kan renses ved velkendte metoder såsom chromatografi eller omkrystallisation.
Fremgangsmåden ifølge opfindelsen illustreres nærmere ved følgende specifikke eksempler: EKSEMPEL 1
Fremstilling af VLB-5-spiro-5"-oxazolidin-211,4"-dion I 20 ml tetrahydrofuran blev fremstillet en suspension af 208,0 mg natriumhydrid (i form af en 50% oliedispersion). Hertil blev sat 200,9 mg vindesin (VLB-C-3-carboxamid). Efter at opløsningen var blevet omrørt ved stuetemperatur i 25 minutter, blev 4,0 ml dimethylcarbonat tilsat. Reaktionsblandingen blev derpå omrørt ved stuetemperatur i 4,5 timer, hvorefter de flygtige bestanddele blev fjernet ved fordampning. Vand blev tilsat, og den vandige opløsning gjort sur ved fortyndet saltsyre. Den sure fase blev ekstraheret tre 5 144916 gange med methylenchlorid og methylenchloridekstrakterne borthældt.
Den vandige fase blev derpå gjort basisk med 109é vandig natriumhydroxid. VLB-3-spiro-5”-oxazolidin-2",4"-dion, som er uopløselig i det basiske lag, udskiltes og blev ekstraheret med 4 portioner methylenchlorid. Methylenchlorid-ekstrakterne blev forenet, og opløsningsmidlet fjernet ved fordampning. Inddampnings-resten på 98,4 mg blev behandlet ved præparativ tlc på silica-gel under anvendelse af et l:l-ethylacetat-methanol-opløsnings-middelsystem. Man iagttog 4 bånd, idet det fjerde bånd indeholdt 4-desacetyl VLB-3-spiro-5"-oxazolidon-2",4"-dion. Båndet blev mekanisk fraskilt og elueret fra silicagelen. Bortdampning af elue-ringsmidlet førte til en inddampningsrest på 10,9 mg med følgende fysiske kendetal: NMR i deuterochloroform: i ved 0,90, 2,87, 3,57, 3,65, 3,84, 3,95, 5,5-6,0, 6,08, 8,5.
IR-spektrum: maxima ved: 5680, 3470, 1810, 1735, 1620, 1505, 1460, 1435, 1335, 1010 og 910 cm"1.
Molekylar-spektrum: ioner ved: 807, 793, 763, 749, 718, 706, 692, 690, 634, 434, 422, 408, 355, 351, 325, 323, 297, 295, 269, 268, 187, 167, 154, 149 og 135.
Feltdesorption: molekylære ioner: 779, 753, 735.
Oxazolidindioner, som mangler en substituent ved ring-nitrogenatornet, kan eksistere i tautomere former, i hvilke hydrogenet ved ring-nitrogenatomet kan enolisere hver af de i ringen tilstedeværende carbonylgrupper til dannelse af en hydroxy-oxazolinon. Særligt kan en oxazolidin-2,4-dion tautomerisere til enten en 2-hydroxy-3-oxazo-lin-4-on eller en 4-hydroxy-3-oxalin-2-on. Man mener, at den ifølge ovenstående eksempel fremstillede forbindelse indeholder mindst to, hvis ikke alle tre sådanne tautomere former.
EKSEMPEL 2
Fremstilling af salte.
Salte af den omhandlede forbindelse fremstilles som følger:
Den frie base opløses i den mindst mulige mængde ethanol. pH sænkes til 4,0-0,2 ved dråbevis tilføring af 2 % svovlsyre i ethanol. pH bestemmes ved at udtage en delmængde svarende til 2 dråber, fortynde til 1 ml med vand og derpå bestemme pH med et pH-meter. Den sure 6 144916 ethanoliske opløsning Inddampes til tørhed. Inddampningsresten indeholdende sulfatsaltet kan om ønsket omkrystalliseres fra methanol eller ethanol.
De omhandlede forbindelser er blevet påvist som værende effektive over for i mus transplanterede tumorer in vivo, samt i stand til at fremkalde metafasestandsning i ovarieceller (Kinesisk hamster) dyrket i vævskultur. Ved påvisningen af de omhandlede forbindelsers effektivitet over for i mus transplanterede tumorer blev anvendt en procedure, hvorved forbindelsen blev indgivet - oftest intraperi-todelt - i et fastlagt dosisniveau i 7 til 10 dage efter indpodningen med tumoren.
Den omhandlede forbindelse giver ved intraperitoneal indgivelse i doser på 0,2-0,8 mg/kg forlængelse af overlevelsestiden på 62-92% hos mus transplanteret med tumoren B16 (en melanom). Der var 0-3 langtidsoverlevende, der overlevede i 60 dage, indtil forsøget blev afsluttet.
Ved anvendelsen af den omhandlede forbindelse som antitumormiddel på pattedyr kan man indgive den enten parenteralt eller peroralt.
Ved peroral dosering blandes en passende mængde af et farmaceutisk acceptabelt salt af forbindelsen, dannet med en ikke-toxisk syre, med stivelse eller en anden excipiens, og blandingen fyldes på teleskopiske gelatinekapsler hver indeholdende mellem 7,5 og 50 mg af forbindelsen. Tilsvarende kan et farmaceutisk acceptabelt salt blandes med stivelse, et bindemiddel og et smøremiddel, og blandingen kan slås til tabletter med delekærv, dersom mindre doser eller opdelte doser skal anvendes. Ved parenteral brug foretrækkes intravenøs indgift, omend man ved mindre pattedyr såsom mus anvender intraperitoneal indgift. Ved patenteral indgift anvendes iso-toniske opløsninger, der rummer 1-10 mg/ml af et salt af den omhandlede forbindelse. Forbindelsen gives i et omfang svarende til fra 0,01 til 1 mg/kg, fortrinsvis fra 0,1‘til 1 mg/kg, dyrelegems-vægt en eller to gange om ugen eller hveranden uge. En alternativ metode til fastlæggelse af den terapeutiske dosering baseres på le-gemsoverfladen og består i dosering af mellem 0,1 og 10 mg/m dy-relegemsoverflade hver 7. eller 14. dag.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US74757576 | 1976-12-06 | ||
| US05/747,575 US4096148A (en) | 1976-12-06 | 1976-12-06 | Oxazolidinedione derivatives of Vinca alkaloids |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK541177A DK541177A (da) | 1978-06-07 |
| DK144916B true DK144916B (da) | 1982-07-05 |
| DK144916C DK144916C (da) | 1982-12-06 |
Family
ID=25005690
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK541177A DK144916C (da) | 1976-12-06 | 1977-12-05 | Fremgangsmaade til fremstilling af vlb-3-spiro-5"-oxazolidin-2",4"-dion eller ikke-toxiske syreadditionssalte heraf |
| DK541077A DK145001C (da) | 1976-12-06 | 1977-12-05 | Fremgangsmaade til fremstilling af derivater af vinca-alkaloider |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK541077A DK145001C (da) | 1976-12-06 | 1977-12-05 | Fremgangsmaade til fremstilling af derivater af vinca-alkaloider |
Country Status (31)
| Country | Link |
|---|---|
| US (1) | US4096148A (da) |
| JP (1) | JPS5371100A (da) |
| AR (1) | AR218467A1 (da) |
| AT (2) | AT353987B (da) |
| AU (1) | AU513936B2 (da) |
| BE (1) | BE861417A (da) |
| BG (2) | BG33436A3 (da) |
| CA (2) | CA1103664A (da) |
| CH (2) | CH634076A5 (da) |
| CS (2) | CS195344B2 (da) |
| DD (2) | DD134228A5 (da) |
| DE (1) | DE2753791A1 (da) |
| DK (2) | DK144916C (da) |
| ES (2) | ES464764A1 (da) |
| FR (1) | FR2372839A1 (da) |
| GB (1) | GB1590649A (da) |
| GR (2) | GR67244B (da) |
| HK (1) | HK57281A (da) |
| HU (2) | HU180724B (da) |
| IE (1) | IE46105B1 (da) |
| IL (1) | IL53506A (da) |
| MX (1) | MX4326E (da) |
| MY (1) | MY8200176A (da) |
| NL (1) | NL7713336A (da) |
| NZ (1) | NZ185818A (da) |
| PL (2) | PL106522B1 (da) |
| PT (2) | PT67342B (da) |
| RO (2) | RO75391A (da) |
| SE (2) | SE436036B (da) |
| SU (2) | SU843753A3 (da) |
| ZA (1) | ZA777237B (da) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU181874B (en) * | 1977-08-08 | 1983-11-28 | Lilly Co Eli | Process for preparing amides of deacetyl-leurosine and deacetyl-leuroformine |
| US4357334A (en) * | 1980-03-20 | 1982-11-02 | Eli Lilly And Company | Use of VLB 3-(2-chloroethyl) carboxamide in treating neoplasms |
| US4362664A (en) * | 1980-12-29 | 1982-12-07 | Eli Lilly And Company | Vinblastine oxazolidinedione disulfides and related compounds |
| GR81790B (da) * | 1983-04-29 | 1984-12-12 | Omnichem Sa | |
| HUT76925A (hu) * | 1995-04-04 | 1998-01-28 | MTA Enzimológiai Intézet | Bisz-indol-származékok, eljárás előállításukra és az azokat tartalmazó gyógyszerkészítmények |
| HK1049787B (en) | 1999-10-01 | 2014-07-25 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT649883A (da) * | 1960-05-24 | |||
| HU165986B (da) * | 1973-02-16 | 1974-12-28 | ||
| AR204004A1 (es) * | 1973-04-02 | 1975-11-12 | Lilly Co Eli | Procedimientos para preparar derivados de vinblastina leurosidina y leurocristina |
| US4012390A (en) * | 1974-10-16 | 1977-03-15 | Eli Lilly And Company | Vinblastinoic acid |
-
1976
- 1976-12-06 US US05/747,575 patent/US4096148A/en not_active Expired - Lifetime
-
1977
- 1977-11-30 PT PT67342A patent/PT67342B/pt unknown
- 1977-11-30 SE SE7713586A patent/SE436036B/sv not_active IP Right Cessation
- 1977-11-30 CS CS777940A patent/CS195344B2/cs unknown
- 1977-11-30 RO RO7792261A patent/RO75391A/ro unknown
- 1977-11-30 CA CA292,072A patent/CA1103664A/en not_active Expired
- 1977-11-30 SE SE7713587A patent/SE435930B/sv not_active IP Right Cessation
- 1977-11-30 RO RO7792262A patent/RO74137A/ro unknown
- 1977-11-30 GR GR54898A patent/GR67244B/el unknown
- 1977-11-30 CA CA292,101A patent/CA1082180A/en not_active Expired
- 1977-11-30 GR GR54897A patent/GR67243B/el unknown
- 1977-11-30 PT PT67343A patent/PT67343B/pt unknown
- 1977-11-30 NZ NZ185818A patent/NZ185818A/xx unknown
- 1977-11-30 CS CS777939A patent/CS195343B2/cs unknown
- 1977-11-30 GB GB49906/77A patent/GB1590649A/en not_active Expired
- 1977-12-01 NL NL7713336A patent/NL7713336A/xx not_active Application Discontinuation
- 1977-12-01 IL IL53506A patent/IL53506A/xx unknown
- 1977-12-02 JP JP14561377A patent/JPS5371100A/ja active Granted
- 1977-12-02 DE DE19772753791 patent/DE2753791A1/de active Granted
- 1977-12-02 BE BE1008557A patent/BE861417A/xx not_active IP Right Cessation
- 1977-12-02 BG BG037936A patent/BG33436A3/xx unknown
- 1977-12-02 FR FR7736437A patent/FR2372839A1/fr active Granted
- 1977-12-02 BG BG037937A patent/BG33437A3/bg unknown
- 1977-12-05 HU HU77EI771A patent/HU180724B/hu not_active IP Right Cessation
- 1977-12-05 ZA ZA00777237A patent/ZA777237B/xx unknown
- 1977-12-05 PL PL1977202660A patent/PL106522B1/pl unknown
- 1977-12-05 DK DK541177A patent/DK144916C/da not_active IP Right Cessation
- 1977-12-05 ES ES464764A patent/ES464764A1/es not_active Expired
- 1977-12-05 AT AT868877A patent/AT353987B/de not_active IP Right Cessation
- 1977-12-05 SU SU772549952A patent/SU843753A3/ru active
- 1977-12-05 PL PL1977202659A patent/PL110671B1/pl unknown
- 1977-12-05 HU HU77EI7723A patent/HU180725B/hu not_active IP Right Cessation
- 1977-12-05 AU AU31230/77A patent/AU513936B2/en not_active Expired
- 1977-12-05 MX MX776608U patent/MX4326E/es unknown
- 1977-12-05 ES ES464765A patent/ES464765A1/es not_active Expired
- 1977-12-05 SU SU772549000A patent/SU865127A3/ru active
- 1977-12-05 CH CH1486177A patent/CH634076A5/de not_active IP Right Cessation
- 1977-12-05 IE IE2469/77A patent/IE46105B1/en unknown
- 1977-12-05 DK DK541077A patent/DK145001C/da not_active IP Right Cessation
- 1977-12-05 CH CH1486277A patent/CH632516A5/de not_active IP Right Cessation
- 1977-12-05 AT AT868777A patent/AT361638B/de not_active IP Right Cessation
- 1977-12-06 AR AR270267A patent/AR218467A1/es active
- 1977-12-06 DD DD77202424A patent/DD134228A5/xx unknown
- 1977-12-06 DD DD77202423A patent/DD134227A5/xx unknown
-
1981
- 1981-11-19 HK HK572/81A patent/HK57281A/xx unknown
-
1982
- 1982-12-30 MY MY176/82A patent/MY8200176A/xx unknown
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| Date | Code | Title | Description |
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| PBP | Patent lapsed |