DK148098B - Analogifremgangsmaade til fremstilling af daunomycinderivater - Google Patents
Analogifremgangsmaade til fremstilling af daunomycinderivater Download PDFInfo
- Publication number
- DK148098B DK148098B DK564777AA DK564777A DK148098B DK 148098 B DK148098 B DK 148098B DK 564777A A DK564777A A DK 564777AA DK 564777 A DK564777 A DK 564777A DK 148098 B DK148098 B DK 148098B
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- iii
- trideoxy
- trifluoroacetamido
- chloride
- Prior art date
Links
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical class 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 title description 6
- 238000000034 method Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229930182470 glycoside Natural products 0.000 description 4
- 150000002338 glycosides Chemical class 0.000 description 4
- 208000032839 leukemia Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 241001465754 Metazoa 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
- 230000009102 absorption Effects 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- KZMGYPLQYOPHEL-UHFFFAOYSA-N boron trifluoride etherate Substances FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 229940045799 anthracyclines and related substance Drugs 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- -1 halogen sugars Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 239000002244 precipitate 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
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 1
- SIHHLZPXQLFPMC-UHFFFAOYSA-N chloroform;methanol;hydrate Chemical compound O.OC.ClC(Cl)Cl SIHHLZPXQLFPMC-UHFFFAOYSA-N 0.000 description 1
- OAIVIYSBZFEOIU-UHFFFAOYSA-N chloroform;propan-2-one Chemical compound CC(C)=O.ClC(Cl)Cl OAIVIYSBZFEOIU-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- RSVJKZGXFDABAD-UHFFFAOYSA-N diazomethane;trifluoroborane Chemical compound C=[N+]=[N-].FB(F)F RSVJKZGXFDABAD-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006345 epimerization reaction Methods 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-UHFFFAOYSA-N hexopyranose Chemical compound OCC1OC(O)C(O)C(O)C1O WQZGKKKJIJFFOK-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 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
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/12—Acyclic radicals, not substituted by cyclic structures attached to a nitrogen atom of the saccharide radical
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
148098
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte antitumorglycosider, der tilhører anthracyclinrækken.
De omhandlede glycosider, der har den i kravets indledning angivne almene formel, er nærmere betegnet sådanne daunomycinderivater, hvori en 3-amino-2,3,6-trideoxy-4-0-methyl-L-lyxo- eller -oc-L-arabinohexopyranose er bundet glycosi-disk til daunomycinon med formlen: i? j® ,9^gh ^ r'oS 3 U) 0CH-. 0 OH ]
-3 OH
2 148098
Den omhandlede fremgangsmåde, der er ejendommelig ved det i kravets kendetegnende del anførte, beror på kondensation af daunomycinon med beskyttede 1-halogenderivater af aminodeoxysukkere, nemlig 2,3,6-trideoxy-3-trifluorace-tamido-4-Q-methyl-L-lyxo-hexopyranosylehlorid (II-E) og 2,3,6-trideoxy-3-tri-fluoracetamido-4-0-methyl-ot_L-arabinohexopyranosylchlorid (III-E)
Cl Cl
/W H,CQ E-.CD HH HH
3 I i
0=0 CO
• I
CF3 CF3 (II-E) (III-E) hvorved man opnår de "beskyttede glycosider (IV) og (Vi):
I I ''0H
OCH, 0 OH I J 0 s3 °r^j o H c{iir (ir s a* = -c-cf3) (T : E· = H) 0 OH g <°0gH3
0CH3 0 OH
o hGT^ / (VI : Η» = -C-CF,) 3 N (VII : E« » H) 3 148098 hvoraf man ved fjernelse af "beskyttelsesgruppen opnår slutprodukterne (?) og (lrIl).
Kondensationsreaktionen mellem daunomycinon (I) og de beskyttede halogensukkere (II-E) og (III-E), hvorunder glycosidbindinge'n dannes, gennemføres i et egnet organisk opløsningsmiddel, såsom chloroform eller methylenchlorid, under tilstedeværelse af et opløseligt sølvsalt som katalysator, såsom sølvtrifluormethansul-fonat (AgSO^CF^), °S molekylsigte · som dehydratiseringsmiddel, svarende til den i britisk patent nr. 1 500 200 beskrevne fremgangsmåde..
Forbindelserne methyl-2,3,6-trideoxy-3-trifluoracetamido-ød-L-lyxo-he-xopyranosid (II-A)· og methyl-2,3,6-trideoxy-3-trifluoracetamido-o£-L-arabino-he-xopyranosid (III-A) er beskrevet i "britisk patent nr. 1 457 559.
0CH OCH, h3cT~— o y E3°7^0 y Γμ£οΟΗ3Ρ, e0 eh-co-cf, RO 5 Δ (Il-At R = H) (III-A: R = H) (II—B: E = CH3) (III-B: R = CH3)
H3y^°4H H H,0H
r^^LoF h3C0 h3co m 00 CI3 3 m-co-cp3 (IIC) (IIIC) h3o yH’0R H3cy--.oy» or _ ' ra-co-op, -5 M-co-oP-, j 3 (II-D) (III-D) o || __.
hvori R = -C-Z^-EOg.
4 148098
Behandlingen af forbindelserne (II-A) og (III-A) med diazomethan-bortrifluoridetherat i methylendichlorid ( som beskrevet af J.O.Deferrari et al. i Methods in Carbohydrate Chemistry, bd. VI, p. 365, 1972, Academic Press,
Few York and London) giver de tilsvarende, hidtil ikke kendte 4-0-methylderivater (iI-B) og (III-B) i godt udbytte. Ved syrehydrolyse opnås de tilsvarende forbindelser ( II-C) og (III-C), som indeholder den frie OH-gruppe i stilling 1, hvilke forbindelser omsættes med p-nitrobenzoylchlorid i pyridinj derved opnås de tilsvarende 1-0-p-nitrobenzoylderivater (II-L) og (iII-D), som ved behandling med tørt hydrogenchlorid i vandfrit methylenchlorid giver de tilsvarende 1-chlor-derivater (II-E) og (III-B).
De nye forbindelser (V) og (VII) viser antimitotisk virkning og er.værdifulde terapeutiske midler til behandling af forsøgstumorer hos dyr.
Forbindelserne er prøvet på BDF^-mus (C57BL/6xD3A)^, hvori der i.p. var injiceret 10^ eeller/mus af L1210 ascitisk leukæmi, eller 10^ celler/mus af P388 ascitisk leukæmi. Behandlingen gennemførtes i.p. på 1. dag efter tumor-inoculationen; stofferne opløstes i destilleret vand som hydrochlorider. Daunomyoin og daunomycinderivater er prøvet på P388 leukæmi, som er meget følsom for anthracyclinemes antitumoraktivitet. De i tabel 1 opførte data viser at 4*-0-methyldaunomycin i en dosis på 4)4 mg/kg var mere aktivt end daunomycini 4,-epi-4,-0-methyldaunomycin viste et stort område for aktive doser (fra 4,4 til 20 mg/kg) og var mindre toksisk end daunomyc in. Ved de optimale ikke-toksiske doser viste daunomyoin (2,9 mg/kg) og 4'-epi-41-O-methyldauno-mycin (20 mg/kg) samme antitumoraktivitet. Epimerisering af 4’-substituenten forårsager en formindskelse af den generelle toksicitet, som vist hos mus med tumorer.
5 148098
Tabel 1 - Aktivitet mod P368-1eukæmi
Forbindelse Dosis T/C^ Antal toksiske (mg/kg) i dødsfald/total
Daunomycin 2,9 169 4.4 169 2/10 6,6 160 7/10 41 -O-methyldaunomycin.HC1 (V) 2,9 156 4.4 191 3/10 6,6 139 7/10 4'-epi-4'-0-methyldaunomycin 4,4 150 .HC1 (YII) 10,0 143 20,0 174 40,0 34 9/9 "* Middeloverlevelsestid for behandlede dyr divideret med middeloverlevelsestid for kontroldyr, x 100.
Fremstilling af udgangsforbindelsen 2,3,6-trideoxy-4-0-methyl-3-trifluoracetamido-L-lyxo-hexopyranosylchlorid (II-E)
En opløsning af 2,57 g (10mmol) methyl-2,3,6-trideoxy-3-trifluoracetamido-«-L-lyxo-hexopyranosid (II-A) i 45 ml tørt methylendichlorid behandledes ved 0°C med 0,1 ml bortrifluoridetherat. Mens temperaturen holdtes på 0°C tilsattes diazomethan i methylenchlorid, indtil der opstod en blivende matgul farve. Efter 90 minutter ved 0°C frafiltreredes et hvidt fast stof (polymethylen) og filtratet vaskedes med en 10$' s natriumbicarbonatopløsning og med vand og tørredes derefter over vandfrit magnesiumsulfat. Den ved inddampning opnåede remanens krystalliseredes fra ethylether-hexan, hvorved der opnåedes 2,3 g (85/) rent methyl-2,3,6-trideoxy-3-trifluoracetamido-4-0-methyl-tø-Ii-lyxo-hex:opyranosid (II-B), smp.l37-138°C,= - 150° (c = 1 i CHCl^); massespektrum m/e 271 (M+). MER-spektret (ODCl^) viser absorptioner ved 1,23 (d, GH^-C-5), 3,23 og 3,40 (to s, -OCH^) og 4,70<f(bred s, C-l-H).
6 148098
Til en .opløsning af 2,17 g (8mmol) af forbindelsen (II-B) i 40ml eddikesyre sattes l60 ml vand og blandingen opvarmedes i 1 time til 100°C. Ved krystallisation af den ved inddampning opnåede remanens fra acetone-hexan opnåedes 2g (97*?°) 2,3,6-trideoxy-3-trifluoracetamido-4-0-methyl-c&-L-lyxo-hexopyranose (II-C), smp. 193-194°G, M D = -130° (o = 0,97 i CHCl^), massespektrum m/e 257 (M+). Ulffi-spektret (CDCl^) viste absorptioner ved 1,23 (d, CH^-C-5)j 3,50 (s, GH^O) og 5s40é(bred s, C-l-H).
En opløsning af 1,68 g (6,53 mmol) af forbindelsen (iI-C) i 48 ml tørt pyridin behandledes ved 0°C under omrøring med 2,52 g p-nitrobenzoylohlorid.
Efter 14 timer ved stuetemperatur hældtes reaktionsblandingen i isvand og bundfaldet filtreredes fra og vaskedes med vand til neutralitet. 1-p-nitrobenzoatet (blanding afa- ogβ-anomer) opløstes i chloroform og tørredes over magnesium-sulfat. Den ved inddampning opnåede remanens gav 2,4 g 2,3,6-trideoxy-4-0-raethyl-l-0-p-nitrobenzoyl-3-trifluoracetainido-Ii-lyxQ-hexopyranose (II-D) (udbytte 92/), smp.l68-170°c,£(iQ) = “39°(o ** 0,45 i CHCl-j),massespektrum m/e240(M-00C-^"~y-ITOg).
En opløsning af 1,05 g (2,5 mmol) af forbindelsen (II-D) i tørt methylen-dichlorid mættedes ved 0°C med tørt hydrogenohlorid. p-liitrobenøoesyrebundfaldet frafiltreredes under vandfri betingelser og filtratet inddampedes til tørhed.
Det opnåede 2,3,6-trideoxy-4-0-methyl-3-trifluoracetamido-L-lyxo-hexopyranosyl- chlorid (II-E) (0,69 g) anvendtes uden yderligere rensning til koblingsreaktionen.
Fremstilling af udgangsforbindelsen 2,3,6-fcrideoxy-4-0-methyl-3-trifluoracetamido-of-L-arabino-hexopyranosylchlorid (III-E)
Ved behandling af 2,57 g (10 mmol) methyl-2,3,6-trideoxy-3-trifluoracetamido-α-L-arabinohexopyranosid (III-A) i methylenchlorid med diazomethan/bortrifluorid, ' som beskrevet .ovenfor, opnåedes 1,7 g (63 /) af det tilsvarende 4-0-methylderivat, smp. 185°C, [«ί jp = -101° (c = 1 i GHCl^), massespektrum m/e 271 (E+), ME-spek-trum (CDC13) : 1,31 (d, CH3~G-5), 3,30 og 3,43 (to s, 0CE3) og 4,70<f(hred s, 7 148098 C-l-H). Ved syrehydrolyse af 1,63 g (6 mmol) af forbindelsen (IIT-B) opnåedes 1,51 g (98 f°) 2,3,6-trideo3y-4-0-methyl-3-trifluoracetamido-L-arabino-hexopyran-ose (III-C), smp.201°C, [o*-] = -12,7° (c = 0,48 i CECl^), massespektrum m/e 257 (M+).
Behandling af 1,41 g (5,5 nmol) af forbindelsen (iII-iC) med p-nitrobenzoyl-chlorid i pyridin gav 1,78 g (80 fa) af det tilsvarende 1-0-pnitrobenzoylderivat (III-D), smp. 159-l60°C, jjp = -33,5° (0= 0,47 i CHCl^), massespektrum m/e 240 (m-oco-<Q>-ito2).
En opløsning af 1,6 g (4 mmol) af forbindelsen (III-B) i tørt methylendi-chlorid mættedes ved 0°C med tørt hydrogenchlorid. Efter frafiltrering af den udfældte p-nitrobenzoesyre inddampedes opløsningen til tørhed, hvorved der opnåedes 1,1 g 2,3,6-trideoxy-4-0-methyl-3-trifluoracetamido-OC-L-arabino-kexo-pyranosylchlorid (III-E), HMR-spektrum (CDCl^) s 1,34 (d, CH^-C-S), 3,44 (s, CH^O-C-H) og 6,176 (bred s,C-l-H).
De følgende eksempler skal nærmere belyse fremgangsmåden ifølge den foreliggende opfindelse.
Eksempel 1 : 4,-0-methyldaunomyoin (V) (TMT 69)
Til en opløsning af 1 g (2,5 mmol) daunomycinon i 100 ml tørt methylendi-chlorid sattes 0,69 g 2,3,6-trideoxy-4-0-methyl-3-trifluoracetamido-L-lyxohexo-pyranosylchlorid (ΙΙ-Ξ) og 7 g molekylsigte(4Å Merck), hvorefter der behandledes med 0,78 g AgSO^CF^i vandfri ethylether under kraftig omrøring. Efter 2 timer ved stuetemperatur neutraliseredes reaktionsblandingen med en mættet vandig HaHCO^-opløsning og den organiske fase skiltes fra og inddampedes i vakuum. Ved kromatografisk rensning af den rå remanens på en kiselsyre søjle under anvendelse af chloroform-acetone (99:l) som elueringsmiddel opnåedes 0,9 g 4’—0—methyl—H-trifluorace tyl daunomycinon (iv), smp. 151-152°C, = +250° (c = 0,06 i CHCl^).
ME-spektret (CBCl^) viste absorptioner ved 1,33 (d, CH^-C-5*), 2,40 (s, CH^-CO), 3,53 (s, C-4'-0-CH3), 4,03 (s, C-4-0-CH3), 5,20 (bred s, C-7-H), 5,50 (bred s, 8 148098 C-l'-H), 6,43 (ffl), 7,16-8,06 (m, aromatiske protoner), 16,26 og 17,74 <f (to s, phenoliske OH).
En opløsning af 0,5 g af forbindelsen (IV) i 30 ml acetone behandledes med 30 ml 0,111 vandig natriumhydroxidopløsning og omrørtes under nitrogen ved stuetemperatur. Efter 1 time indstilledes reaktionsblandingen med vandig IH saltsyre til en pH-værdi på. 3,5og ekstraheredes derefter med chloroform, for at fjerne tilstedeværende forureninger. Den til pH 8,5indstillede vandige fase ekstraheredes med chloroform (50 og 30 ml's portioner). Den over Ha^SO^ tørrede organiske ekstrakt inddampedes til et lille volumen og indstilledes til pH 4»5 med 0,5H methanolisk hydrogenchlorid. Ted tilsætning af overskydende diethylether opnåedes 0,4 g 4*-0-methyldaunomycin (T) som hydrochlorid, udbytte 90 smp. 173°C (dek.), [cc)D = +210° (c = 0,04 i CH^OH); tyndtlagskromatografi på Merck kiselgel *254“ plade, chlorofoim-methanol-vand (150:42:6) som opløsningsmiddel : Hf 0,40 (daunomycin Hf 0,25).
Eksempel 2 : 4' -epi-4' -O-meth.yldaunomycin (VII) (IMI 74)
Fremstillingen af den i titlen nævnte forbindelse,ud fra daunomycinon (i) og 2,3,6-trideoxy-4-0-methyl—3-trifluoracetamido-of-L-arabino-hexopyranosylchlorid (III-E), skete ved den i eksempel 1 beskrevne fremgangsmåde.
4,-epi-4'-0-methyldaunomycinon (Til) opnåedes som hydrochlorid i foim af orangerøde krystaller, smp. 192°C (dekomp. ),[<*] ^ = +270° (c = 0,047 i CH^OH).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK388683A DK150518C (da) | 1976-12-22 | 1983-08-25 | Analogifremgangsmaade til fremstilling af adriamycinderivater |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB53454/76A GB1550879A (en) | 1976-12-22 | 1976-12-22 | Antitumour glycosides |
| GB5345476 | 1976-12-22 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK564777A DK564777A (da) | 1978-06-23 |
| DK148098B true DK148098B (da) | 1985-03-04 |
| DK148098C DK148098C (da) | 1985-07-29 |
Family
ID=10467870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK564777A DK148098C (da) | 1976-12-22 | 1977-12-19 | Analogifremgangsmaade til fremstilling af daunomycinderivater |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4183919A (da) |
| JP (1) | JPS5379851A (da) |
| AT (1) | AT354629B (da) |
| AU (1) | AU518244B2 (da) |
| BE (1) | BE862102A (da) |
| CA (1) | CA1090788A (da) |
| CH (1) | CH632770A5 (da) |
| CS (1) | CS198280B2 (da) |
| DE (1) | DE2757102C2 (da) |
| DK (1) | DK148098C (da) |
| FI (1) | FI63419C (da) |
| FR (1) | FR2375252A1 (da) |
| GB (1) | GB1550879A (da) |
| GR (1) | GR70040B (da) |
| HU (1) | HU176957B (da) |
| IE (1) | IE45951B1 (da) |
| IL (1) | IL53635A (da) |
| NL (1) | NL7713850A (da) |
| NO (1) | NO145163C (da) |
| NZ (1) | NZ186047A (da) |
| SE (1) | SE437992B (da) |
| SU (1) | SU797583A3 (da) |
| YU (1) | YU301177A (da) |
| ZA (1) | ZA777555B (da) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4265885A (en) * | 1978-10-25 | 1981-05-05 | Farmitalia Carlo Erba S.P.A. | Anthracyclines containing branched-chain amino-deoxy sugars |
| US4254110A (en) * | 1979-02-02 | 1981-03-03 | Farmitalia Carlo Erba S.P.A. | Pentofuranosyl anthracyclines, intermediates in and method for their preparation and compositions and use thereof |
| NL8001417A (nl) * | 1979-03-17 | 1980-09-19 | Erba Farmitalia | Antitumorglycosiden. |
| BE883759A (fr) * | 1979-06-16 | 1980-10-01 | Erba Farmitalia | Glycosides d'anthracycline |
| DE3064485D1 (en) * | 1979-07-04 | 1983-09-08 | Erba Farmitalia | Anthracycline glycosides, process for their preparation and therapeutical composition containing them |
| DE3100968A1 (de) * | 1980-01-16 | 1982-01-14 | Farmitalia Carlo Erba S.p.A., 20159 Milano | Anthracyclinderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| CA1248944A (en) * | 1982-09-28 | 1989-01-17 | Gareth J. Thomas | Anthracycline glycosides |
| WO2007075094A1 (en) * | 2005-12-27 | 2007-07-05 | Instytut Biochemii I Biofizyki | New derivatives of epirubicin, their medicinal application and pharmaceuticaly acceptable forms of drugs |
| WO2007075092A1 (en) * | 2005-12-29 | 2007-07-05 | Instytut Biochemii I Biofizyki | New derivatives of epirubicin, their medicinal application and pharmaceuticals acceptable forms of drugs |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1506200A (en) * | 1975-04-30 | 1978-04-05 | Farmaceutici Italia | Glycosides |
| US3976667A (en) * | 1975-06-19 | 1976-08-24 | The Upjohn Company | Steffimycinone, 7-deoxysteffimycinone and derivatives |
| GB1511559A (en) * | 1975-09-26 | 1978-05-24 | Farmaceutici Italia | Anthracycline glycosides |
-
1976
- 1976-12-22 GB GB53454/76A patent/GB1550879A/en not_active Expired
-
1977
- 1977-12-14 US US05/860,447 patent/US4183919A/en not_active Expired - Lifetime
- 1977-12-14 NL NL7713850A patent/NL7713850A/xx not_active Application Discontinuation
- 1977-12-19 GR GR55011A patent/GR70040B/el unknown
- 1977-12-19 SE SE7714464A patent/SE437992B/sv not_active IP Right Cessation
- 1977-12-19 IL IL53635A patent/IL53635A/xx unknown
- 1977-12-19 FI FI773822A patent/FI63419C/fi not_active IP Right Cessation
- 1977-12-19 AU AU31748/77A patent/AU518244B2/en not_active Expired
- 1977-12-19 FR FR7738201A patent/FR2375252A1/fr active Granted
- 1977-12-19 NO NO774370A patent/NO145163C/no unknown
- 1977-12-19 YU YU03011/77A patent/YU301177A/xx unknown
- 1977-12-19 IE IE2579/77A patent/IE45951B1/en unknown
- 1977-12-19 DK DK564777A patent/DK148098C/da not_active IP Right Cessation
- 1977-12-19 AT AT907377A patent/AT354629B/de not_active IP Right Cessation
- 1977-12-20 NZ NZ186047A patent/NZ186047A/xx unknown
- 1977-12-20 CS CS778604A patent/CS198280B2/cs unknown
- 1977-12-20 ZA ZA00777555A patent/ZA777555B/xx unknown
- 1977-12-21 BE BE183664A patent/BE862102A/xx not_active IP Right Cessation
- 1977-12-21 CH CH1580877A patent/CH632770A5/de not_active IP Right Cessation
- 1977-12-21 DE DE2757102A patent/DE2757102C2/de not_active Expired
- 1977-12-21 JP JP15424677A patent/JPS5379851A/ja active Granted
- 1977-12-21 CA CA293,545A patent/CA1090788A/en not_active Expired
- 1977-12-22 HU HU77FA999A patent/HU176957B/hu unknown
-
1979
- 1979-06-18 SU SU792778651A patent/SU797583A3/ru active
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4067969A (en) | Anthracycline glycosides, their preparation and use | |
| US4020270A (en) | L-lyxohex-1-enopyranose derivative | |
| US4112076A (en) | Epi-daunomycin and epi-adriamycin compounds and method of use | |
| NO890567L (no) | Anthracyklin-derivater. | |
| DK148098B (da) | Analogifremgangsmaade til fremstilling af daunomycinderivater | |
| CS221274B2 (en) | Method of making the new 4-substituted derivatives of daunorubicine | |
| DK160616B (da) | Fremgangsmaade til fremstilling af anthracyclinderivater eller syreadditionssalte deraf | |
| US4325946A (en) | Anthracycline glycosides, their preparation, use and compositions thereof | |
| FI84075C (fi) | Foerfarande foer framstaellning av nya antracykliner. | |
| SU1017173A3 (ru) | Способ получени антрациклингликозидов | |
| US4199571A (en) | Substituted anthracyclines, their preparation and use | |
| US4254110A (en) | Pentofuranosyl anthracyclines, intermediates in and method for their preparation and compositions and use thereof | |
| US4265885A (en) | Anthracyclines containing branched-chain amino-deoxy sugars | |
| SU650507A3 (ru) | Способ получени гликозидных антибиотиков или их гидрохлоридов | |
| SU1378784A3 (ru) | Способ получени антрациклингликозидов | |
| HU196821B (en) | Process for producing 6-deoxy-antracyclin-glycoside derivatives | |
| CA2005932A1 (en) | Rhodomycins with a modified carbohydrate unit | |
| DK150606B (da) | Analogifremgangsmaade til fremstilling af 3',4'-diepi-4'-o-methyldaunorubicin eller 3',4'-diepi-4'-o-methyldoxorubicin, samt et beskyttet halogensukker til anvendelse ved fremgangsmaaden | |
| US4604381A (en) | 4-demethoxy-13-dihydrodaunorubicin and use thereof | |
| SU1227117A3 (ru) | Способ получени антрациклических гликозидов или их гидрохлоридов | |
| RU2024483C1 (ru) | 4-замещенные антрациклиноны и гликозид антрациклина | |
| DK147260B (da) | Analogifremgangsmaade til fremstilling af 4'-deoxyadriamycin | |
| CS235540B2 (cs) | Způsob výroby nových derivátů glykosidů anthracyklinu | |
| DK146721B (da) | Analogifremgangsmaade til fremstilling af 4'-epi-6'-hydroxyadriamycin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |