DK153158B - Fremgangsmaade for fremstilling af en adriamycinon glycosid - Google Patents
Fremgangsmaade for fremstilling af en adriamycinon glycosid Download PDFInfo
- Publication number
- DK153158B DK153158B DK114475AA DK114475A DK153158B DK 153158 B DK153158 B DK 153158B DK 114475A A DK114475A A DK 114475AA DK 114475 A DK114475 A DK 114475A DK 153158 B DK153158 B DK 153158B
- Authority
- DK
- Denmark
- Prior art keywords
- adriamycin
- anomers
- epi
- anomer
- hours
- Prior art date
Links
- 229930182470 glycoside Natural products 0.000 title claims description 3
- 238000000034 method Methods 0.000 title description 5
- -1 ADRIAMYCINON GLYCOSIDE Chemical class 0.000 title 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 claims description 2
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 238000001640 fractional crystallisation Methods 0.000 claims description 2
- 150000002338 glycosides Chemical class 0.000 claims description 2
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 claims description 2
- 150000003840 hydrochlorides Chemical class 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims 2
- 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 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 125000000837 carbohydrate group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin 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(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 28
- 150000001875 compounds Chemical class 0.000 description 16
- 229940009456 adriamycin Drugs 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- 229960001904 epirubicin Drugs 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 208000032839 leukemia Diseases 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 241000713862 Moloney murine sarcoma virus Species 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000007774 longterm Effects 0.000 description 6
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- IBZGBXXTIGCACK-CWKPULSASA-N Adriamycinone Chemical compound C1[C@@](O)(C(=O)CO)C[C@H](O)C2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O IBZGBXXTIGCACK-CWKPULSASA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 208000006268 Sarcoma 180 Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000001451 cardiotoxic effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000013068 control sample Substances 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 239000012024 dehydrating agents Substances 0.000 description 2
- UKWHYYKOEPRTIC-UHFFFAOYSA-N mercury(ii) oxide Chemical compound [Hg]=O UKWHYYKOEPRTIC-UHFFFAOYSA-N 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100062772 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) dcl-2 gene Proteins 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 150000004862 dioxolanes Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 150000002402 hexoses Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940101209 mercuric oxide Drugs 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- 150000008136 β-glycosides Chemical class 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
DK 153158B
Den foreliggende opfindelse angår en analogifremgangs-måde til fremstilling af det hidtil ukendte 4'-epi-adriamycin (III), dvs. y-O-iS'-amino-Z',3'^'-trideoxi-oC-L-arabinohexopyranosy 1 )-adriamcynon :
0 OH
C0-CH20H
^ I ji '0H
CH30 0 OH I
tø
NH2 III
5 og dets hidtil ukendte /3-anomer (IV), dvs. 7-0-(31 -amino-2’,3',6'-trideoxi-/3-L-arabinohexopyranosyI)-adriamycinon:
0 OH
co-ch2oh CH30 o oh j m2_
NPlY
HO υ IV
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del angivne. Fremgangsmåden 10 gennemføres nærmere bestemt ved, at man lader adriamycinon reagere med dimetoxipropan i nærværelse af p-to- 2
DK 153158 B
luensylfonsyre, hvorved der dannes et dioxolanderivat V i godt udbytte: 0 OH OH 0CH3
i) I
CH-0 0 OH OH X
ch3 ch3
V
Forbindelsen V omsættes derefter med 1-chlor-2,3,6-trideoxi-3-tri-fluoracetamido-4-trifIuor-acetoxi-hexopyranosyl, som 5 har L-arabino-konfiguration ved en Kdnigs-Knorr-konden-sation i nærværelse af mecuridibromid og mecurioxid og af et dehydratiseringsmiddel (molecularsigte) under dannelse af de beskyttende glycosider VII, f .eks .
0 OH OH 0CH3 yVtV v ch3o o oh ; /\ I ch3 ch3 0
CH3/^-^0-X
F3CC0° \
H CO
CF3 vi Ib hvorved - efter fjernelse af Ο,Ν-trifluor-acetylgrupperne 10 med fortyndet alkali og hydrolysen af sidekædens cycliske ketal med fortyndet syre - opnås slutproduktet III (oC-ano-mer) sammen med dets /2-anomer IV.
3
DK 153158 B
Adskillelsen af dC- og/3-glycosider kan med lethed udføres, f.eks. ved fraktioneret krystallisation og/eller kromatografi. Forbindelserne med formlen VIII har biologisk aktivitet i form af antitumoraktivitet, der til 5 dels er af en anden art end den, der udvises af adria-mycin; jf. tabel 1-8.
Opfindelsen anskueliggøres nærmere ved hjælp af følgende eksempel:
Fremstilling af mellemprodukter V
10 Adriamycinon (1 g) i dioxan (10 ml) og chloroform (200 ml) behandles med dimethoxypropan (80 ml) og p-toluensulfonsyre (0,17 g). Blandingen henstår 24 timer ved stuetemperatur. Herefter tilsættes natriumbicarbo-nat (0,34 g), og blandingen omrøres i fem minutter.
15 Det organiske lag extraheres gentagne gange med vand til neutral reaktion, tørres over vandfrit natriumsulfat, filtreres og inddampes ved reduceret tryk. Remanensen placeres i en kiselsyresøjle og elueres med opløsningssystemet chloroform:acetone (volumenforhold 20 10:1). Hovedproduktet ved reaktionen, som identificeres ved tyndtlagskromatografi (Rf = 0,38 ved anvendelse af si 1 icagelplader og det ovenfor nævnte opløsningssystem), er 9-desacetyl-9-(21,2'-dimethyl-41-methoxy-41-dioxol-anyl)-dauno-mycinon (V), blanding af epimere.
25 Forbindelsen (V) karakteriseres ved NMR, IR og masse-Spektre.
MNR (CDC13): 1,48 e 1,65 (to s, geminal CH3) 3,47 (s, CH30 - C(13)) 4,0-4,6 (m, C(14)H2) 13,02 e 13,71 (to s, chelatiseret OH ved C-6 og C-ll) IR (KBr): carbonyl absorption, som er typisk for adriamycinon ved 1725 cm"1, mangler
DK 153158 B
4 MS (DIS): 486 m/e (M+) 454 _ . (m-32 = M-CH3OH) 450 - - (M-36 = M-2H20) 438 - - (M-58 = M-CH3C0CH3) 5 131 - - (substitueret dioxylanyl)
Eksempel 1
Opløsningen af V (0,7 g) i dichormethan (35 ml) behandles med mercurioxid (1,4 g), mercuribromid (0,350 g) og et overskud molecularsigte (3 Å, Merck) som dehydra-10 tiseringsmiddel.
Blandingen omrøres ved stuetemperatur, og to tilsætninger af substitueret hexose 2,3,6-trideoxi-3-tri-fI uoracetamido-4-0-1rif luoracetyl -oC-L-arabino-hexopyranosylchlorid (hver på 0,35 g) foreta-15 ges efter henholdsvis en og tre timer. Omrøringen fortsættes natten over. Chloroform (50 ml) tilsættes. Reaktionsblandingen filtreres, og den resulterende opløsning inddampes i vacuum, remanensen opløses i 0,1 N natriumhydroxid (50 ml) og acetone (10 ml). Efter 30 mi-20 nutters henstand ved stuetemperatur indstilles pH til 8,4 med fortyndet vandig hydrogenchlorid. Opløsningen extraheres gentagne gange med chloroform. De samlede extrakter tørres med vandfrit natriumsulfat, filtreres og inddampes i vacuum. Remanensen opløses i 0,1 N van-25 dig hydrogenchlorid (50 ml) og henstår ved stuetemperatur i 36 timer. Den sure opløsning vaskes med chloroform (for at eliminere spor af aglycon) og indstilles til pH 8,6 under omrøring og ved tilstedeværelse af chloroform (50 ml) ved langsom tilsætning af 0,1 N van-30 dig natriumhydroxid. Den organiske fase skilles fra, tørres med vandfrit natriumsulfat og koncentreres til 10 ml.
Ved forsigtig tilsætning af HCl/methanol opnås et rødt
DK 153158 B
5 precipitat, som opsamles, vaskes med diethylether og tørres. Produktet (220 mg) er 41-epi-adriamycin hydro-chlorid som en blanding af III (j^-anomer) og IV {p -anomer) i forholdet 70:30 [dCj jp° + 258° (c 0,05 i me-5 thanol indeholdende 20¾ 0,1 N vandig hydrogenchlorid).
De to anomerer adskilles ved kromatografi på kiselsyre.
4 1 -epi-adriamycinhydrochlorid (oC-anomer): smeltepunkt 168°C;[dCj22 = +328°C (c = 0,05 CH3OH); 41 -epi-adriamycinhydrochlorid (^-anomer): smeltepunkt 10 1740C ; [λ] 22 + 290°C (c = 0,01 CH3OH).
De følgende inhiberingszoner blev opnået på agar-B-sub-tilis plader ved papirskivemetoden . (diameter i mm angives; analyse viste at forbindelserne var hydrochlori-der): 15 /ty Adriamycin 4'-epi- 41-ep i - 4'-epi- adriamycin adriamycin adriamycin (blanding (a-anomer) (/9-anomer) af anomerer) 20 5 19 19 15 10 21 21 21 15,5 15 - 22 22 16 20 23 23 23 17
Biologisk aktivitet 25 Aktiviteten af 41-epi-adriamycin (en blanding af ct- og ^-anomer 70:30 el ler oC-anomeren) er blevet vurderet på adskillige transplanterede tumorer hos mus, og in vitro forsøg, til sammenligning med adriamycin. Resultaterne angives i de følgende tabeller.
6
DK 153158 B
Ascites Sarcoma 180
Forsøgene blev udført på grupper af 10 mus (Swiss CD
1) . De undersøgte forbindelser blev anvendt intraperi-tonealt hos dyrene dagen efter en intraperitoneal ino- /r culation af 1 x 10 tumorceller pr. dyr. Tabel 1 an-5 giver middeloverlevelsestid i procent af kontrolgrupperne (= 100) og antallet af langtidsoverlevende.
Tabel 1 f : Virkning pn Ascites Sarcoma ΙδΟ 1 Forbindelser Dosis middeloverlevelsestid Langtidsoverlevende ! mg/kg ia (efter 60 døgn) ’ Kontrolprøve - j 100 j 0/30 \ I ' r ! Adriamycin 1 169 ; 0/10 : 5 276 2/10
i 4*-epi~adriamycin 0,2 124 O/lO
j ( blanding af 1 247 7,/30 i (X-og/3-anomer) i 1,5 ; 342 12/20 : I 2,25 I 345 9/20 ; j 5 j 1?2 0/10______
i 4’-epi-adriamycin | 0,5 135 O/lO
( OL -anomer) ; 2 164 0/10 ;_________J_____iO_____________________ _______234_________ ___________..........1/8___________
Transplanteret Gross - leukemi
Indavlede C3H/He - mus blev intravenøst inoculeret med 2,5 x 10^ leukemiceller/mus og behandledes fra første 10 til femtedagen herefter intravenøst med de undersøgte forbindelser. Tabel 2 angiver middeloverlevelsestiden i 7
DK 153158B
procent af kontrolgrupperne (= 100) og antallet af langtidsoverlevende.
fabel 2
Virkning på transplanteret Gross - leukemi
Forbindelser Dosis Middeloverlevelsestid langtidsoverlevende mg/kg i io ( efter 60 døgn)
Forsøg. 1 Forsøg 2
Kontrolprøve - 0/30
Adriamycin 2 183 0/10 2,5 208 186 0/20 2,75 ' 208 0/10 3 186 0/10 3,6 200 0/10 A’-epi-adriamycin 2 133 0/10 (OC+Ø) 2,5 142 143 0/20 2,75 142 0/10 3 j 157 0/10 3>6 I _171 0/10 L|21 o " leukemi
Lndavlede BDF, - mus blev intraperitonealt inoculeret 5 o med 10 leukemiceller/mus . På første og anden dagen herefter blev de 5 gange (hver anden time) intraperitonealt behandlet med de undersøgte forbindelser. Tabel 3 angiver middeloverlevelsestid i procent af kontrolgrupperne (= 100) og antallet af langtidsoverlevende .
fabel 3 I Virkning på Ll210 - leukemi
Forbindelser Dosis Middeloverlevelsestid Langtidsoverlevende :____mg/kg i ( efter 60 døgn) i Adriamycin 0,75 160 i 1 155 I 1/10 : ! 1,25 175 ' I—" ' ' ...... 1 ”** — - — — Γ —«-·· ..i...™..- — 4"~epi-adriamycin j 0,75 140 ·, I ( α + fi> ) |i : 140 1 i_1____________1--------J_________________________i____________
DK 153158B
8
Fast Sarcoma 180
Swiss CD 1 - mus blev podet subcutant med et fragment af neoplastisk væv og intravenøst behandlet efter forskellige fremgangsmåder. Tumorvæksten blev vurderet ved tværsnitsmåling på tiendedagen efter tumor implantatio-5 nen . Tabel 4 viser inhibitorisk virkning på tumorvækst og middeloverlevelsestid i procent af kontrolgrupperne (= 100) .
Tabel 4
Virkning på Past Sarcoma 180 j Forbindelse Dosis Behandling ^inhibering Middelover- Toksiske mg/kg af tumor- levelsestid dødsfald på ! tilvækst i» 10. dagen i- ......—— ----—— --_--------— ----—— ; Adriamycin j 1,25 5 gange 69 112 0/10 ; ί 1,75 (hver anden 75 8? 1/10 [ : ί i 2,45 time) 32 6/10 I 4' -epi-adria- 1,25 °e 3* 31 105 0/10 ; mycin 1,75 dagen 47 100 0/10 I (oc +tS ) 2,45 gi 97 0/10
Adriamyoin 2,5 1 gang pr. 54 O/lO
3,5 dag 7/10 I 1.,2.,3.,4.
4'-epi-adria- 2,5 og 5<dagen 31 0/10 3-5 (intravenøst) 46 0/10 (oc + /S) I 4,5 43 o/io -1_____________
Adriamycin j 2 2 gange 70 100 1/10 I 2,5 pr. dag 71 100 2/10 S 3 l.,2. og 3. 57 6/10 ! !
! dagen I
4'-epi-adria- ·. 3 (mtraveneet) 45 j 133 0/9 mycin ! 4 57 | 106 0/10 ( * + β ) ! 5 59 j 84 1/10 -i-i----- I__ 9
DK 153158 B
Prøver in vitro på focidannelse af Moloney Sarcoma virus (MSV)
Forbindelserne blev forsøgsvis anvendt på museembryofi-broblast-kulturer inficeret eller ikke-inficeret med MSV. Efter behandling i 3 døgn, vurderes inhibitordosis 50 (ID5o) På celleproliferation i uinficerede kultu-5 rer (cytotoksisk virkning) og på MSV focidannelse i inficerede kulturer (antiviral virkning). Tabel 5 viser de opnåede resultater.
Tabei 5
Forbindelse Antiviral virkning Cytotoksisk virkning id50 γ/mi n>50 y/m 1
Adriamycin 0,005 0,01 4«-epi-.adriamycin under 0,006 0,01 i------------------
Aktivitet på MSV-produktion MSV inficerede kulturer blev behandlet i tre dage, og 10 virusudbyttet blev bestemt i celle - og supernatant medium ved focusforsøg i nærværelse af leukemivirus . Tabel 6 viser resultaterne.
Tabel 6 J Forbindelser Dosis ( Y/ml) FFLT /ml I g i Kontrolprøver ! 457 x 10 I----------h---------------------------- i 4'-epi-adriamycin ,0,05 ? I ' 4 x 10 I 0,0250 i
Prøve in vitro på kloneffektiviteten hos HeLa - celler
Efter behandling i 2, 8 eller 24 timer blev HeLa -15 celler udsået (200 celler pr. plade) og antallet af
DK 153158B
10 kolonier blev talt 8 dage senere. ID5Q er den dosis der giver 50% inhibering af kolonier. Tabellerne 7 og 8 angiver de opnåede resultater.
Tabel 7 I-]-j--1 j Forbindelser j Dosis j Gennemsnitlige antal kolonier efter behandling i j 2 timer 8 timer 24 timer _j
Kontrolprøver - 132 125 223_j
Adriajnycin 1 21 8 O ; 0,5 42 16 0 i 0,25 46 38 20 0,1 79 73 48 0,05 100 96 76 ID5q 0,17/^/ml IDj-q 0,14/ig/ml ID^ 0,016^/ml 4'-epi-adriamycin 1 57 36 29 (oc-anomer) 0,5 101 92 52 0,25 103 150 199 0,1 104 158 216 ID50 0,85yxg/ml ID^Q 0,7 yxg/ml ID^Q 0,36 ^g/ml Tabel 8
Forbindelser Dosis Gennemsnitlige antal kolonier efter behandling i 2 timer 8 timer 24 timer
Kontrolprøver - 156 189 136
Adriamycin 0,5 27 14 n.d.
0,25 92 28 43 0,125 166 103 69 ID50 0,35/g/ml ID50 0,l8jug/ml ID^ 0,125^g/ml 4'-epi-adriamycin 1 105 27 17 j
( oc -anomer) 0,5 130 45 38 I
0,25 109 43 46 I
0,125 245 170 100 i j IDcq 5 /g/ml ID 0,2^g/ml ID50 0,2 jug/ml 1 11
DK 15315 8 B
Prøver in vitro på den cardiotoxiske aktivitet
Den cardiotoxiske aktivitet blev prøvet in vitro på my-ocardialceller fra SALB/c eller CD 1 nyfødte mus (Necco A., Dasdia T. IRCS, 2: 1293, 1974). Adriamycin forårsager 50¾ nedgang i slag på 2 timer ved en dosis på 0,5 5 g/ml. 41 -epi-adriamycin ( σι- og/?-anomer), op til en dosis på 5 g/ml, ændrede ikke slaghastigheden (F i g. i).
Claims (3)
- 0 OH C0CH20H OlXX^0" och3 0 OH i 0
- 1 VIII X hvor X er NH2 k«r)) NH2 eller dens hydrochlorid, 5 kendetegnet ved, at man først beskytter den primære hydroxylgruppe hos adriamycinonen ved omsætning af adriamycinonen med 2,2-dimetoxipropan i chloroformopløsning ved stuetemperatur i nærværelse af p-toluensulfonsyre som katalysator for fremstilling af 10 9-desacetyl-9-(21,21-dimetyl-41-metoxi-4'-dioxolanyl)- daunomycinon med formelen V:
- 0 OH OH 0CH3 ' 0CH3 0 0H H '°H C<\h3 V DK 15315 8 B søm derefter kondenseres, opløst i metylendichlorid, ved stuetemperatur, med 2,3,6-trideoxi-3-trifluoraceta-mido-4-0-trifluo racety 1- ct-L-arabino-hexopyranosy1chlo-rid, i nærværelse af mercuribromid som katalysator, 5 mercurioxid som hydrogenchloridacceptor og molecular-sigte som dehydratiseringsmiddel for fremstilling af N,0-trifluor-acetylbeskyttede glycosider, fra hvilke først fjernes ved svag alkalisk hydrolyse med 0,1 N natriumhydroxid de beskyttende N,0-trifluoracetylgrup-10 per på kulhydratresten og derefter ved sur behandling med 0,1 N saltsyre sidekæde-ketalgruppen på aglyconde-len, hvorved de fri glycosidiske baser fås som blanding af &- og /6-anomerer, hvorefter man separerer a-anome-rerne fra /3-anomererne ved fraktioneret krystallisation 15 eller kromatografi og isolerer de ønskede glycosider eventuelt i form af deres respektive hydrochlorider.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB1278374 | 1974-03-22 | ||
| GB1278374A GB1457632A (en) | 1974-03-22 | 1974-03-22 | Adriamycins |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK114475A DK114475A (da) | 1975-09-23 |
| DK153158B true DK153158B (da) | 1988-06-20 |
| DK153158C DK153158C (da) | 1989-01-16 |
Family
ID=10011048
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK114475A DK153158C (da) | 1974-03-22 | 1975-03-20 | Fremgangsmaade for fremstilling af en adriamycinon glycosid |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4058519A (da) |
| JP (1) | JPS5840555B2 (da) |
| AT (1) | AT338420B (da) |
| AU (1) | AU497500B2 (da) |
| BE (1) | BE826978A (da) |
| CA (1) | CA1046507A (da) |
| CH (1) | CH612947A5 (da) |
| DE (1) | DE2510866C3 (da) |
| DK (1) | DK153158C (da) |
| ES (1) | ES435833A1 (da) |
| FR (1) | FR2264555B1 (da) |
| GB (1) | GB1457632A (da) |
| HK (1) | HK882A (da) |
| MY (1) | MY103912A (da) |
| NL (1) | NL176635C (da) |
| SE (1) | SE434844B (da) |
| SU (1) | SU583763A3 (da) |
| ZA (1) | ZA751781B (da) |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4133877A (en) * | 1976-07-08 | 1979-01-09 | Societa Farmaceutici Italia S.P.A. | Anthracycline ethers and use therefor |
| US4201773A (en) * | 1978-07-26 | 1980-05-06 | The United States Of America As Represented By The Department Of Health, Education And Welfare | 7-O-(2,6-Dideoxy-α-L-lyxo-hexopyranosyl)-daunomycinone, desmethoxy daunomycinone, adriamycinone, and carminomycinone |
| US4345068A (en) * | 1979-11-22 | 1982-08-17 | Farmitalia Carlo Erba S.P.A. | Process for the preparation of 4'-epidaunorubicin, 3',4'-diepidaunorubicin, their doxorubicin analogs, and intermediates used in said process |
| DE51280T1 (de) * | 1980-11-01 | 1983-01-20 | Farmitalia Carlo Erba S.p.A., 20159 Milano | Anthracyclin-glycoside, verfahren zu ihrer herstellung, zwischenprodukte und ihre herstellung und arzneimittel. |
| JPS57106694A (en) * | 1980-11-01 | 1982-07-02 | Erba Carlo Spa | Anthracycline glycoside |
| US4562177A (en) * | 1982-08-17 | 1985-12-31 | The Ohio State University Research Foundation | 3'-Amino-2' halo-anthracycline antibiotics |
| US4537882A (en) * | 1984-05-10 | 1985-08-27 | Ohio State University | 4-Demethoxy-3'-desamino-2'-halo-anthracycline and pharmaceutical composition containing same |
| DE3500029A1 (de) * | 1985-01-02 | 1986-09-04 | Farmitalia Carlo Erba S.p.A., Mailand/Milano | Anthracyclinester |
| GB2169284A (en) * | 1985-01-05 | 1986-07-09 | Erba Farmitalia | 4'-Epidoxorubicin-14-esters |
| JPS61172891A (ja) * | 1985-01-24 | 1986-08-04 | フア−ミタリア・カルロ・エルバ・ソシエタ・ペル・アツイオ−ニ | アントラサイクリン類エステルの製法 |
| US5977082A (en) * | 1985-08-02 | 1999-11-02 | Pharmacia & Upjohn Company | Injectable ready-to-use solutions containing an antitumor anthracycline glycoside |
| US5124318A (en) * | 1985-08-02 | 1992-06-23 | Farmitalia Carlo Erba S.R.L. | Injectable ready-to-use solutions containing an antitumor anthracycline glycoside |
| GB8519452D0 (en) * | 1985-08-02 | 1985-09-11 | Erba Farmitalia | Injectable solutions |
| US5124317A (en) | 1985-08-02 | 1992-06-23 | Farmitalia Carlo Erba S.P.A. | Injectable ready-to-use solutions containing an antitumor anthracycline glycoside |
| DE69609845T2 (de) | 1996-12-16 | 2000-12-21 | Pharmachemie B.V., Haarlem | Verfahren zur Herstellung von Epirubicin oder Zusatzsalzen davon, von Daunorubicin |
| ATE284893T1 (de) | 1998-10-16 | 2005-01-15 | Mercian Corp | Kristallisation von doxorubicin-hydrochlorid |
| KR100785966B1 (ko) * | 2000-08-10 | 2007-12-14 | 동아제약주식회사 | 안트라싸이클린계 항암제인 에피루비신 및 약학적으로허용되는 그 염의 제조방법 |
| KR100850408B1 (ko) * | 2000-08-10 | 2008-08-04 | 동아제약주식회사 | 안트라싸이클린계 항암제인 에피루비신 및 약학적으로허용되는 그 염의 제조방법 |
| WO2005004805A2 (en) * | 2003-07-02 | 2005-01-20 | Solux Corporation | Thermally stable crystalline epirubicin hydrochloride and method of making the same |
| JP5475234B2 (ja) | 2005-01-21 | 2014-04-16 | アステックス・セラピューティクス・リミテッド | 医薬化合物 |
| PL375008A1 (pl) | 2005-05-12 | 2006-11-13 | Institut National De La Sante Et De La Recherche Medicale, Inserm | Nowe zastosowanie medyczne chlorowodorku epirubicyny |
| JP5528807B2 (ja) | 2006-10-12 | 2014-06-25 | アステックス、セラピューティックス、リミテッド | 複合薬剤 |
| WO2008044041A1 (en) | 2006-10-12 | 2008-04-17 | Astex Therapeutics Limited | Pharmaceutical combinations |
| US8173621B2 (en) | 2008-06-11 | 2012-05-08 | Gilead Pharmasset Llc | Nucleoside cyclicphosphates |
| SG194404A1 (en) | 2008-12-23 | 2013-11-29 | Gilead Pharmasset Llc | Synthesis of purine nucleosides |
| KR20110098849A (ko) | 2008-12-23 | 2011-09-01 | 파마셋 인코포레이티드 | 뉴클레오시드 유사체 |
| PT2376088T (pt) | 2008-12-23 | 2017-05-02 | Gilead Pharmasset Llc | Fosforamidatos de nucleósidos de 2-amino-purina 6-osubstituída |
| PT2609923T (pt) | 2010-03-31 | 2017-08-30 | Gilead Pharmasset Llc | Processo para a cristalização de 2-(((s)- (perfluorofenoxi)(fenoxi)fosforil)amino)propanoato de (s)-isopropilo |
| CN108473523B (zh) * | 2016-01-11 | 2022-03-15 | 浙江海正药业股份有限公司 | 一种盐酸表柔比星的制备方法及其中间体 |
| ES3057783T3 (en) | 2016-03-15 | 2026-03-04 | Oryzon Genomics Sa | Combinations of lsd1 inhibitors for use in the treatment of neoplastic diseases |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3629231A (en) * | 1968-05-23 | 1971-12-21 | Biorex Laboratories Ltd | Derivatives of glycyrrhetinic acid |
| FR2183710A1 (en) * | 1972-05-06 | 1973-12-21 | Farmaceutici Italia | Daunomycin (hydrochloride) prepn - by reaction of daunomycinone with daunosamines, useful as antitumour agent and anti-leucemic |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3356674A (en) * | 1961-07-07 | 1967-12-05 | Rikagaku Kenkyusho | 3-c-hydroxymethyl-3, 5-didesoxy-l-lyxofuranose and its derivatives, and a process for the production thereof |
| US3427300A (en) * | 1965-11-12 | 1969-02-11 | Merck & Co Inc | Anti-inflammatory steroid 2'-acetamido-2'-deoxy-glucoside compounds |
| YU33730B (en) * | 1967-04-18 | 1978-02-28 | Farmaceutici Italia | Process for preparing a novel antibiotic substance and salts thereof |
| US3803124A (en) * | 1968-04-12 | 1974-04-09 | Farmaceutici It Soc | Process for the preparation of adriamycin and adriamycinone and adriamycin derivatives |
| US3651090A (en) * | 1969-12-17 | 1972-03-21 | Cutter Lab | 1 3-dioxolan-4-yl-alkyl guanidines |
-
1974
- 1974-03-22 GB GB1278374A patent/GB1457632A/en not_active Expired
-
1975
- 1975-03-12 NL NLAANVRAGE7502934,A patent/NL176635C/xx not_active IP Right Cessation
- 1975-03-13 DE DE2510866A patent/DE2510866C3/de not_active Expired
- 1975-03-18 AT AT207475A patent/AT338420B/de not_active IP Right Cessation
- 1975-03-19 FR FR7508548A patent/FR2264555B1/fr not_active Expired
- 1975-03-19 AU AU79263/75A patent/AU497500B2/en not_active Expired
- 1975-03-19 US US05/560,104 patent/US4058519A/en not_active Expired - Lifetime
- 1975-03-20 SE SE7503215A patent/SE434844B/xx active Protection Beyond IP Right Term
- 1975-03-20 ZA ZA00751781A patent/ZA751781B/xx unknown
- 1975-03-20 DK DK114475A patent/DK153158C/da not_active IP Right Cessation
- 1975-03-20 JP JP50033095A patent/JPS5840555B2/ja not_active Expired
- 1975-03-20 CA CA222,609A patent/CA1046507A/en not_active Expired
- 1975-03-21 SU SU7502115054A patent/SU583763A3/ru active
- 1975-03-21 ES ES435833A patent/ES435833A1/es not_active Expired
- 1975-03-21 CH CH365975A patent/CH612947A5/xx not_active IP Right Cessation
- 1975-03-21 BE BE154581A patent/BE826978A/xx not_active IP Right Cessation
-
1982
- 1982-01-14 HK HK8/82A patent/HK882A/xx unknown
-
1988
- 1988-09-14 MY MYPI88001026A patent/MY103912A/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3629231A (en) * | 1968-05-23 | 1971-12-21 | Biorex Laboratories Ltd | Derivatives of glycyrrhetinic acid |
| FR2183710A1 (en) * | 1972-05-06 | 1973-12-21 | Farmaceutici Italia | Daunomycin (hydrochloride) prepn - by reaction of daunomycinone with daunosamines, useful as antitumour agent and anti-leucemic |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA751781B (en) | 1976-02-25 |
| SU583763A3 (ru) | 1977-12-05 |
| DE2510866A1 (de) | 1975-10-02 |
| FR2264555B1 (da) | 1980-01-11 |
| ATA207475A (de) | 1976-12-15 |
| JPS5840555B2 (ja) | 1983-09-06 |
| AU497500B2 (en) | 1978-12-14 |
| DE2510866B2 (de) | 1979-12-06 |
| NL7502934A (nl) | 1975-09-24 |
| SE7503215L (da) | 1975-09-23 |
| NL176635C (nl) | 1985-05-17 |
| FR2264555A1 (da) | 1975-10-17 |
| CH612947A5 (da) | 1979-08-31 |
| HK882A (en) | 1982-01-22 |
| DE2510866C3 (de) | 1980-08-14 |
| US4058519A (en) | 1977-11-15 |
| AT338420B (de) | 1977-08-25 |
| DK153158C (da) | 1989-01-16 |
| CA1046507A (en) | 1979-01-16 |
| DK114475A (da) | 1975-09-23 |
| MY103912A (en) | 1993-10-30 |
| ES435833A1 (es) | 1976-12-01 |
| AU7926375A (en) | 1976-09-23 |
| JPS50126656A (da) | 1975-10-04 |
| GB1457632A (en) | 1976-12-08 |
| NL176635B (nl) | 1984-12-17 |
| BE826978A (fr) | 1975-09-22 |
| SE434844B (sv) | 1984-08-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DK153158B (da) | Fremgangsmaade for fremstilling af en adriamycinon glycosid | |
| US4067969A (en) | Anthracycline glycosides, their preparation and use | |
| US4039663A (en) | Daunomycins, process for their uses and intermediates | |
| CA1041488A (en) | Process for the preparation of analogues of daunomycin | |
| UMEZAWA et al. | SYNTHESIS OF 4-DEMETHOXY-IIDEOXY-ANALOGS OF DAUNOMYCIN AND ADRIAMYCIN | |
| DK170752B1 (da) | Cytostatisk aktive anthracyclinderivater samt anvendelse deraf | |
| KR950004897B1 (ko) | 안트라사이클린 글리코사이드 유도체의 제조방법 | |
| US5034517A (en) | Process for producing 2,6-dideoxy-2-fluoro-L-talopyranose | |
| US4183919A (en) | Antitumor glycosides, process for their preparation including intermediates therefor and their use | |
| JPS61227589A (ja) | 新規アントラサイクリングリコシド類，それらの製造方法及びそれらを含む抗腫瘍剤 | |
| US3996205A (en) | Aminoglycoside antibiotics and intermediates | |
| US5081234A (en) | 4'-demethylepipodophyllotoxin glycosides | |
| EP0230013B1 (en) | New anthracycline derivatives, uses thereof as antitumor agent and production thereof | |
| US4965352A (en) | Anthracycline derivatives having cytostatic activity | |
| US5719130A (en) | Anthracycline derivative having a trifluoromethylated sugar | |
| US4997931A (en) | Epipodophyllotoxin glycosides | |
| HU198505B (en) | Process for producing antitumour anthracycline glycosides | |
| US4038478A (en) | O-glycoside ortho esters of neamine containing compounds | |
| Yoshino et al. | Facile synthesis of 2′-substituted lactoses | |
| CA2046645A1 (en) | 4'-epi-4'-amino anthracyclines | |
| US4098798A (en) | Adriamycins, process for their preparation and uses thereof | |
| US6075135A (en) | 3,4-di-O,N-Protected-4-amino-2,4,6-trideoxy-2-fluoro-L-manno-pyranosyl halide and a process for its preparation | |
| DK146541B (da) | Analogifremgangsmaade til fremstilling af 4'-epi-daunomycin eller de individuelle alfa- eller beta-anomere deraf | |
| JPH02504153A (ja) | 新規ｌ‐フコース類似体、その製造方法、これら類似体の新規グリカール類の製造に対する応用、これらのグリカール類を用いて得られるアンスラサイクリン類、および前記アンスラサイクリン類の医薬製品としての用途 | |
| SU1227117A3 (ru) | Способ получени антрациклических гликозидов или их гидрохлоридов |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUP | Patent expired |