DK146541B - Analogifremgangsmaade til fremstilling af 4'-epi-daunomycin eller de individuelle alfa- eller beta-anomere deraf - Google Patents
Analogifremgangsmaade til fremstilling af 4'-epi-daunomycin eller de individuelle alfa- eller beta-anomere deraf Download PDFInfo
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- DK146541B DK146541B DK109275AA DK109275A DK146541B DK 146541 B DK146541 B DK 146541B DK 109275A A DK109275A A DK 109275AA DK 109275 A DK109275 A DK 109275A DK 146541 B DK146541 B DK 146541B
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- DK
- Denmark
- Prior art keywords
- epi
- daunomycine
- alfa
- analogue
- individual
- Prior art date
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- 238000000034 method Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 2
- 229960000975 daunorubicin Drugs 0.000 title 1
- 150000001875 compounds Chemical class 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- YOFDHOWPGULAQF-MQJDWESPSA-N (7s,9s)-9-acetyl-6,7,9,11-tetrahydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound C1[C@@](O)(C(C)=O)C[C@H](O)C2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O YOFDHOWPGULAQF-MQJDWESPSA-N 0.000 description 6
- YOFDHOWPGULAQF-UHFFFAOYSA-N Daunomycin-Aglycone Natural products C1C(O)(C(C)=O)CC(O)C2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O YOFDHOWPGULAQF-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002402 hexoses Chemical class 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- STQGQHZAVUOBTE-HQXHJQOISA-N (7s,9s)-9-acetyl-7-[(2r,4r,5s,6r)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@@H](N)[C@H](O)[C@@H](C)O1 STQGQHZAVUOBTE-HQXHJQOISA-N 0.000 description 4
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 4
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 229940101209 mercuric oxide Drugs 0.000 description 2
- 230000000394 mitotic effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- WPJRFCZKZXBUNI-ZLUOBGJFSA-N (3s,4r,5s)-3-amino-4,5-dihydroxyhexanal Chemical compound C[C@H](O)[C@H](O)[C@@H](N)CC=O WPJRFCZKZXBUNI-ZLUOBGJFSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000006994 Koenigs-Knorr glycosidation reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 1
- 208000006268 Sarcoma 180 Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 231100000457 cardiotoxic Toxicity 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
U6541
Opfindelsen angår en analogifremgangsmåde til fremstilling af 4'-epi-daunomycin eller de individuel le oC- eller ^-anomere deraf. Daunomycin og daunomycinon er beskrevet i britisk patent nr. 1 o33 383.
Det fuldstændige kemiske navn på 41 -epi-daunomycin-oC-anomer er 7-0-(3'-amino-2',31,61-tridesoxy-o(-L-arabino-hexopyranosyl)-daunomycinon med formlen I:
0 OH
C0CH3
I I x 0H
H3C0 o OH o K\ nh2
Det fuldstændige kemiske navn på 4'-epi-daunomycin-/3-anomer er 7-0-(31-amino-21,3',61-tridesoxy-^-L-arabino-hexopyranosyl ) -daunomycinon med formlen II:
0 OH
^^000H3 H3CO 0 OH ! (II) nh2 H0\l f/ U6541 2
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte og omfatter kondensation af daunomycinon med formlen III:
0 OH
COCH3 | | '''OH (III) H,C0 0 OH i ύ i
OH
med et derivat af 4'-epi-daunosamin (3-amino-2,3,6-tri-desoxy-L-arabino-hexose) med formlen IV: HO a—0 tøCH3 Vv OH (IV) nh2 til fremstilling af de farmakologiske aktive glycosider med formlen (I) og (II). I praksis må hexosen IV beskyttes og omdannes til et 1-derivat som f. eks. et halogenid, der er egnet til kondensation med daunomycinon. Efter kondensationen fjernes de beskyttende grupper.
3-aminogruppen i hexosen IV skal beskyttes med grupper, der kan fjernes uden yderligere nedbrydning af produkterne, som indeholder forskellige kemisk følsomme grupper. N-trifluoracetylgruppen kan på tilfredsstillende måde fjernes ved svag alkalisk behandling.
Η 6541 3
Indføringen af trifluoracetylgrupper er beskrevet i Med.
Chem., 1974, 17, 659.
Hexosen IV skal omdannes til derivater, der er i besiddelse af tilstrækkelig stabilitet til at kunne anvendes i syntesen. Instabiliteten af 1-halogen derivater af 2-desoxy-kulhydrater er veldokumenteret (W. W. Zorbach et al., Advances in Carbonhydrate Chemistry, 1966, 21, 273).
Tri-trifluoracetylderivaterne af hexosen IV omsættes på sædvanlig måde med tørt hydrogenchlorid; herved fremkommer de tilsvarende 1-chlorhexoser. Disse er faste stoffer, som kan opbevares adskillige døgn under vandfri betingelser.
Med hensyn til egnede reaktionsbetingelser for syntesen af glycosidbindingen angiver den velkendte Koenigs-Knorr reaktion (J. Conchi, G. A. Lewy and C. A. Marsh, Advances in Carbonhydrate Chemistry, 1957, J_2, 157) en række forskellige betingelser, som omfatter modifikationer af opløsningsmiddel, temperatur, katalysator samt hydrogenchlorid- eller hydrogenbromidacceptor. Modifikationernes betydning er således, at for opnåelse af en rimelig reaktionshastighed er en række optimale betingelser nødvendige.
Omsætningen af daunomycinon med hexoser er kendt fra J.
Med. Chem., 1974, Γ7, 659-660.
Fremgangsmåden ifølge opfindelsen omfatter en mild behandling af daunomycinon (III) med I-chIor-N,0-di-tri-fluoracetylderivat af hexosen IV i et organisk opløsningsmiddel som f. eks. chloroform eller dichlormethan i nærværelse af en katalysator bestående af et mercuri-halogenid (f. eks. mercuribromid) og en hydrogenchlorid- 146541 4 acceptor (f. eks. mercurioxid), og ved fjernelse af N-trifluoracetyl med fortyndet alkali opnås det omhandlede 4'-epi-daunomycin.
Fremgangsmåden ifølge opfindelsen illustreres ved det følgende eksempel, hvor temperaturerne angives i °C.
Eksempel 1 g 2,3,6-tridesoxy-3-trifluoracetamido-L-arabinohexose opslemmes i 20 ml vandfrit diethylether og behandles ved 0°C med trifluoreddikesyreanhydrid. Efter henstand i to timer ved 0°C og en time ved stuetemperatur fjernes opløsningsmidlet ved reduceret tryk, og remanensen omkrystalliseres fra dichlormethan. Det opnåede produkt behandles i vandfrit diethylether ved 0°C med vandfrit gasformigt hydrogenchlorid. Efter henstand ved +5°C natten over fjernes opløsningsmidlet i vacuum, hvorved man opnår et kvantitativt udbytte af 2,3,6-tridesoxy-N,0-di-trifluoracetyl -L-arabinohexopyranosylchlorid.
NMR (CDC1 g): 1,30 6 (d, J = 6,0 Hz, 3H, CHg) 2,25-2,806 (m, 2H, C(2)H2) 4,20-4,656 (m, IH, C(5)H) 4,65-5,156 (m, 2H, C(3)H og C(4)H) 6,256 (m, WH = 6,0 Hz, IH, C(l)H) 6,456 (bred s, IH, NH)
En opløsning af 0,5 g daunomycinon i vandfrit chloroform behandles med 1,0 g mercurioxid, 0,25 g mercuribromid, 10 g molecularsi (3 Å, Merck) og 0,5 g 2,3,6-tridesoxy-N,0-di-trifluoracetyl-L-arabinohexopyranosylchlorid. Blandingen omrøres i 24 timer, befries for faste stoffer ved filtrering og inddampes under vacuum. Remanensen opløses i methanol, koges med tilbageløbskøling i 15 minutter, 146541 5 inddampes til tørhed og kromatograferes på en kiselsyre-søjle med en blanding af chloroform:benzen:methanol 10:20:3 som elueringsmiddel. Hovedproduktet udgør en blanding i forholdet 70:30 af <A- og /3-7-0-(N-trifluor-acetyl-4'-epi-daunosaminyl)-daunomycinon (udbytte efter omkrystallisation fra chloroform 0,3 g).
Dette materiale omdannes ved behandling med 0,1 N natriumhydroxid som beskrevet ovenfor kvantitativt til en blanding af de korresponderende <x- og/<3-glycosider som fri baser.
Produktet adskilles i <x- og/3-anomere ved silicagelkroma-tografi ved anvendelse af et chloroform:methanol:vand opløsningssystem 135:20:2 (volumenforhold) som elueringsmiddel. Man f år <*-anomer (4'-epi-daunomycin, I), [oc]^ + 320° (c = 0,o45, methanol), smp. 199-201 °C, ud bytte 0,16 g og /3-anomer (II), smp. 182-184°C, udbytte 0,06 g.
Biologisk aktivitet af forbindelserne I (41-epi-daunomy-cin, c<-anomer) og II (41-epi-daunomycin,/3 -anomer)
Forbindelserne I og II udviser fremragende biologiske egenskaber som kraftige inhibitorer for cellemitose og proliferativ aktivitet i dyrkede celler in vitro. De har også vist væsentlig aktivitet på celletransformationer induceret af oncogene virus. De har antitumoraktivitet hos mus som vist af en forøgelse i middeloverlevelsestiden ved ikke-toksiske doser hos dyr, der har et antal eksperimentelle tumorer (tabellerne 1-4).
Den cardiotoksiske "in vitro"-aktivitet af forbindelse I er meget lav (lavere end for daunomycin), som det fremgår af følgende forsøg.
6 146541
Metoden består i dyrkning af enkelte cardiaceller isoleret ved tripsinisering fra hjertet af nyfødte mus. Efter 3-4 dage kan kulturerne, som viser klynger af pulserende celler, studeres både med hensyn til frekvens og rytme (A. Necco, T. Dasdia, IRCS, 2, 1293, 1974).
Tabel 1
Virkning af forbindelserne I og II på mitotisk index og proliferativ aktivitet af dyrkede HeLa-celler ved forskellige eksponeringstider.
Resultaterne er udtrykt som % af ubehandlede kontrolprøver.
Forbindelse Dosis Mitotisk index Koloniantal (jig/ml) 2 t 4 t 8 t 2 t 4 t 24 t 0,025 226* 100 117 113 88 48 I 0,05 I89* 103 122 115 56 23 0,1 79 140 O 77 23 3 DI50 0,16 0,056 0,027 0,25 137 103 85 108 86 70 jr 0,5 95 67 88 101 37 18 1 52 40 O 98 17 6
Die« >1 0,47 °>33 __J?0__
Daunomycin DI^ 0,098 0j036 0>021 *Metafasisk blokering 146541 7
Tabel 2
Virkning af forbindelserne I og II på foci-dannelse og på celleproliferation i dyrkede musefibroblaster, inficeret med Moloney Sarcoma virus (3 døgns behandling).
Forbindelse Dosis Fooi - dannelse Celle proliferation B/A
__(^/ml) kW- Lnt,ol»r. ’’tø™_ 0,0062 51 75 j 0,025 O 0,006 23 0,013 0,1 O 14 0,4 o 1 0,0062 48 87 n 0,025 44 80 0,1 5 °’01 28 °>064 6·4 0,4 O 14
Daunomycin 0,006 0,0086 1,4
Tabel 3
Virkning af forbindelserne I og II på middeloverlevelsestiden og på antallet af overlevende hunmus (Swiss CDI) intraperitonealt inoculeret med Sarcoma 180 ascites (1 x 10** celler/mus).
Forbindelserne blev anvendt dagen efter transplantationen af tumoren.
8 146541
Forbindelse Dosis Middeloverlevelsestid Antal overlevende (mg/kg) % af kontrolprøver på 60. dag 0,22 111,1 1/10 τ 1,1 120,8 1/10 5.7 174,5 0/10 0,26 96,6 0/10 II 1,3 114,8 1/10 6.7 118,6 1/10
Tabel 4
Virkning af forbindelserne I og II på Gross-transplanter-bar leukæmi. Middeloverlevelsestid for C^H hunmus intravenøst inoculeret med en suspension af leukæmiske lymfe-
C
kirtler og milt (2,5 x 10 celler/mus). Forbindelserne blev anvendt én gang daglig i fem dage, første gang dagen efter transplantationen af tumoren.
Forbindelse Daglig dosis Middeloverlevelsestid (mg/kg) <f0 af kontrolprøver 1.5 115 I 2,25 143 3 162 3,75 122 4.5 120 1.5 106 II 2,25 102 3 121
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1225474 | 1974-03-20 | ||
| GB1225474A GB1457559A (en) | 1974-03-20 | 1974-03-20 | Daunomycins |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK109275A DK109275A (da) | 1975-09-21 |
| DK146541B true DK146541B (da) | 1983-10-31 |
| DK146541C DK146541C (da) | 1984-04-09 |
Family
ID=10001195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK109275A DK146541C (da) | 1974-03-20 | 1975-03-18 | Analogifremgangsmaade til fremstilling af 4'-epi-daunomycin eller de individuelle alfa- eller beta-anomere deraf |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5833880B2 (da) |
| AT (1) | AT338419B (da) |
| BE (1) | BE826848A (da) |
| CA (1) | CA1046508A (da) |
| CH (1) | CH615198A5 (da) |
| DE (1) | DE2510926C3 (da) |
| DK (1) | DK146541C (da) |
| FR (1) | FR2264554B1 (da) |
| GB (1) | GB1457559A (da) |
| NL (1) | NL176636C (da) |
| SE (1) | SE434843B (da) |
| SU (1) | SU589926A3 (da) |
| ZA (1) | ZA751687B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5977082A (en) * | 1985-08-02 | 1999-11-02 | Pharmacia & Upjohn Company | Injectable ready-to-use solutions containing an antitumor anthracycline glycoside |
| US5124317A (en) | 1985-08-02 | 1992-06-23 | Farmitalia Carlo Erba S.P.A. | Injectable ready-to-use solutions containing an antitumor anthracycline glycoside |
| FR2678274A1 (fr) * | 1991-06-25 | 1992-12-31 | Medgenix Group Sa | N-leucyl epirubicine application a titre de medicament antitumoral et procede de preparation. |
-
1974
- 1974-03-20 GB GB1225474A patent/GB1457559A/en not_active Expired
-
1975
- 1975-03-13 DE DE2510926A patent/DE2510926C3/de not_active Expired
- 1975-03-14 NL NLAANVRAGE7503079,A patent/NL176636C/xx not_active IP Right Cessation
- 1975-03-17 AT AT202875A patent/AT338419B/de not_active IP Right Cessation
- 1975-03-18 ZA ZA00751687A patent/ZA751687B/xx unknown
- 1975-03-18 DK DK109275A patent/DK146541C/da not_active IP Right Cessation
- 1975-03-18 SE SE7503084A patent/SE434843B/xx not_active IP Right Cessation
- 1975-03-18 SU SU752129602A patent/SU589926A3/ru active
- 1975-03-19 FR FR7508547A patent/FR2264554B1/fr not_active Expired
- 1975-03-19 BE BE154470A patent/BE826848A/xx not_active IP Right Cessation
- 1975-03-19 CH CH352975A patent/CH615198A5/de not_active IP Right Cessation
- 1975-03-19 JP JP50033493A patent/JPS5833880B2/ja not_active Expired
- 1975-03-20 CA CA222,610A patent/CA1046508A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AT338419B (de) | 1977-08-25 |
| ZA751687B (en) | 1976-02-25 |
| DE2510926A1 (de) | 1975-09-25 |
| CH615198A5 (en) | 1980-01-15 |
| NL7503079A (nl) | 1975-09-23 |
| JPS50126657A (da) | 1975-10-04 |
| FR2264554A1 (da) | 1975-10-17 |
| GB1457559A (en) | 1976-12-08 |
| ATA202875A (de) | 1976-12-15 |
| SE7503084L (da) | 1975-09-22 |
| SE434843B (sv) | 1984-08-20 |
| SU589926A3 (ru) | 1978-01-25 |
| JPS5833880B2 (ja) | 1983-07-22 |
| AU7919775A (en) | 1976-09-23 |
| NL176636C (nl) | 1985-05-17 |
| DE2510926C3 (de) | 1980-03-13 |
| FR2264554B1 (da) | 1978-07-28 |
| DK109275A (da) | 1975-09-21 |
| CA1046508A (en) | 1979-01-16 |
| DE2510926B2 (de) | 1979-07-19 |
| BE826848A (fr) | 1975-09-19 |
| NL176636B (nl) | 1984-12-17 |
| DK146541C (da) | 1984-04-09 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |