DK147974B - Analogifremgangsmaade til fremstilling af 4'-deoxy-4'-ioddoxorubicin - Google Patents
Analogifremgangsmaade til fremstilling af 4'-deoxy-4'-ioddoxorubicin Download PDFInfo
- Publication number
- DK147974B DK147974B DK400283A DK400283A DK147974B DK 147974 B DK147974 B DK 147974B DK 400283 A DK400283 A DK 400283A DK 400283 A DK400283 A DK 400283A DK 147974 B DK147974 B DK 147974B
- Authority
- DK
- Denmark
- Prior art keywords
- deoxy
- preparation
- doxorubicin
- ioddoxorubicin
- analogue
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims 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 claims description 2
- 229960000975 daunorubicin Drugs 0.000 claims description 2
- 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 claims description 2
- PDQGEKGUTOTUNV-TZSSRYMLSA-N 4'-deoxy-4'-iododoxorubicin 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](I)[C@H](C)O1 PDQGEKGUTOTUNV-TZSSRYMLSA-N 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 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 229960004679 doxorubicin Drugs 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010003445 Ascites Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 239000004280 Sodium formate Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 2
- 235000019254 sodium formate Nutrition 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- RIXHOXYAFWQBGU-UHFFFAOYSA-N 7-(4-amino-5-iodo-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(=O)CO)CC1OC1CC(N)C(I)C(C)O1 RIXHOXYAFWQBGU-UHFFFAOYSA-N 0.000 description 1
- 101100005766 Caenorhabditis elegans cdf-1 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- CEALXSHFPPCRNM-UHFFFAOYSA-L disodium;carboxylato carbonate Chemical compound [Na+].[Na+].[O-]C(=O)OC([O-])=O CEALXSHFPPCRNM-UHFFFAOYSA-L 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000434 field desorption mass spectrometry Methods 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
i 147974
Den foreliggende opfindelse angår en analogifremgangs-måde til fremstilling af et hidtil ukendt anthracyc-linglycosid-antibioticum med formlen 1 6 oh 9 il JL >>c-ch2oh OCH3 0 OH i.
i CH37~°Jv nh2 i 1
Det omhandlede glycosid dvs. 4'-deoxy-41-ioddoxorubi-5 cin har vist sig at have udmærket antitumoral virkning.
Udgangsmaterialet til fremstilling af den omhandlede forbindelse er 4'-deoxy-4'-ioddaunorubicin, en forbindelse, der allerede er beskrevet i dansk patentansøgning nr.
1733/82. Denne forbindelse omdannes, når den omsættes 10 med brom, til 14-bromderivatet heraf, der herefter underkastes hydrolyse med vandig natriumformiat til opnåelse af det omhandlede 4'-deoxy-41-ioddoxorubicin.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i kravets kendetegnende del anførte.
15 Den omhandlede forbindelse udviser bemærkelsesværdig virkning på eksperimentelle tumorer hos mus.
147974 2
Fremgangsmåden ifølge opfindelsen beskrives nærmere i det følgende eksempel.
Eksempel 41-Deoxy-4'-ioddoxorubicin (I;) (X00 - 0163) 5 Til 1,26 g (1,87 mMol) 41-deoxy-4'-ioddaunorubicin-hydrochlorid opløst i methanol (14 ml) og dioxan (38 ml) sattes 1 ml ethylorthoformiat. Opløsningen behandledes ved 10 °C med 1,96 mMol brom i 3 ml chloroform og 1,17 ml hydrogenchlorid i methanol.
10 Efter 1 times forløb udhældtes opløsningen i en blanding af petroleumsether (100 ml) og diethylether (200 ml).
Det dannede bundfald filtreredes, opløstés i dioxan (150 ml) og 0,25 N hydrogenbromid (150 ml) og henstod natten over ved 25 °C. Til opløsningen sattes 11 g 15 natriumformiat i vand (110 ml). Efter 24 timers forløb inddampedes opløsningen i vacuum, og remanensen opløstes i en blanding af 200 ml chloroform-methanol (13:6 v/v). Den organiske fase vaskedes med 5?ί vandig natriumdicarbonat og med vand. Efter afdampning af op-20 løsningsmidlet behandledes remanensen med et ækvivalent hydrogenchlorid i methanol, hvorved opnåedes 0,65 g 4'-deoxy-4'-ioddoxorubicinhydrochlorid. Smeltepunkt 230 °C (dekomponering); FD-MS: 653 (M+) TLC på kiesel-gelplader F2^ (Merck) under anvendelse af CHCl^: 25 Me0H:H20:Ac0H (80:20:7:3 v/v) Rf = 0,5.
Biologisk afprøvning af forbindelsen XQQ-0163
Forbindelsen afprøvedes i sammenligning med doxorubicin (DX) over for HeLa-celler in vitro. De i tabel 1 angivne resultater viser, at X00-0163 var mere cytotoxisk end 30 DX. Den antitumorale virkning undersøgtes in vivo hos 3 U7974 mus, der havde P388 ascites leukæmi. Resultaterne er angivet i tabel 2. Ved den optimale ikke-toxiske dosis på 15 mg/kg helbredte X00-163 mere end 50¾ af musene (6 ud af 10), og ved en dosis på 10 mg/kg 5 helbredtes 3 ud af 10 mus, og der opnåedes en bemær kelsesværdig høj forøgelse af levetiden sammenlignet med kontrollerne (205¾). Derfor er den antitumorale virkning af X00-0163 afgørende bedre end virkningen af DX, der ved optimal ikke-toxisk dosis på 10 mg/kg 10 kun af og til helbreder musene med tumor.
Tabel 1
Virkning gå HeLa-cellers kloningseffektivitet3
Dosis ID,-n
Forbindelse (ng/ml) % ^ /ml)
Doxorubicin 25 08 12,5 16 6,2 70 X00-0163 (4'-deoxy-4'-iod- 25 0 5,5 doxorubicin) 1^5 91 0,39 104 g
Behandling i 24 timer 4 147974
Tabel 2 \/irkning_o\/er_f°r P_388 ascites leukæmi3 , . Toxiske
Forbindelse Dosis0 T/Cc LTS° dødsfald (mg/kg) %
Doxorubicin 4,4 210 0/10 0/10 6,6 260 0,10 0/10 10 265 1/10 0/10 X00-0163 6,6 240 0/10 0/10 10 305 3/10 0/10 15 >620 6/10 0/10 22,5 390 3/10 1/10 aForsøgene udførtes i BDF 1 eller CDF 1 mus, der var podet med 10^ leukæmiceller intraperitonealt.
b 5 Behandling intraperitonealt på dag 1 efter tumorindpod ning.
ø
Middeloverleuelsestid af behandlede mus/middeloverlevel-sestid af kontroller, X100.
^Langtidsoverlevende (>60 dage).
ø e 10 Bedømt pa basis af autopsifund.
Claims (2)
147974 Patentkrav : Analogi fremgangsmåde til fremstilling af 4'-deoxy-4'-ioddoxorubicin med formlen P OH 1 ^ il L . ,C.CH2°H och3 o oh i CH3r-W nh2 i 1 kendetegnet ved, at man omsætter 4'-deoxy-5 41-ioddaunorubicin med brom til dannelse af 14-derivatet med formlen
0 OH 9 1 i^.e--cH2Br och3 o oh : <»37—o "y ζ NH2
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK400283A DK147974C (da) | 1982-04-19 | 1983-09-02 | Analogifremgangsmaade til fremstilling af 4'-deoxy-4'-ioddoxorubicin |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK173382A DK147262C (da) | 1982-04-19 | 1982-04-19 | Analogifremgangsmaade til fremstilling af 4'-deoxy-4'-ioddaunorubicin |
| DK173382 | 1982-04-19 | ||
| DK400283A DK147974C (da) | 1982-04-19 | 1983-09-02 | Analogifremgangsmaade til fremstilling af 4'-deoxy-4'-ioddoxorubicin |
| DK400283 | 1983-09-02 |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK400283D0 DK400283D0 (da) | 1983-09-02 |
| DK400283A DK400283A (da) | 1983-10-20 |
| DK147974B true DK147974B (da) | 1985-01-21 |
| DK147974C DK147974C (da) | 1985-08-19 |
Family
ID=26066070
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK400283A DK147974C (da) | 1982-04-19 | 1983-09-02 | Analogifremgangsmaade til fremstilling af 4'-deoxy-4'-ioddoxorubicin |
Country Status (1)
| Country | Link |
|---|---|
| DK (1) | DK147974C (da) |
-
1983
- 1983-09-02 DK DK400283A patent/DK147974C/da active
Also Published As
| Publication number | Publication date |
|---|---|
| DK147974C (da) | 1985-08-19 |
| DK400283A (da) | 1983-10-20 |
| DK400283D0 (da) | 1983-09-02 |
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