CZ298027B6 - Zpusob prípravy epothilon-N-oxidu a N-oxidy epothilonu - Google Patents
Zpusob prípravy epothilon-N-oxidu a N-oxidy epothilonu Download PDFInfo
- Publication number
- CZ298027B6 CZ298027B6 CZ0286599A CZ286599A CZ298027B6 CZ 298027 B6 CZ298027 B6 CZ 298027B6 CZ 0286599 A CZ0286599 A CZ 0286599A CZ 286599 A CZ286599 A CZ 286599A CZ 298027 B6 CZ298027 B6 CZ 298027B6
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- CZ
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- Prior art keywords
- epothilone
- oxides
- oxide
- epothilones
- per
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- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title claims abstract description 6
- 229930013356 epothilone Natural products 0.000 title claims description 16
- 150000001204 N-oxides Chemical class 0.000 title claims description 3
- 238000004519 manufacturing process Methods 0.000 title 1
- -1 Epothilone N-oxide Chemical class 0.000 claims description 7
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 7
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 150000004965 peroxy acids Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 claims description 2
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Plural Heterocyclic Compounds (AREA)
- Polyesters Or Polycarbonates (AREA)
- Silicon Polymers (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
- Epoxy Compounds (AREA)
Abstract
Zpusob prípravy epothilon-N-oxidu, pri nemž se chránený nebo nechránený epothilon A nebo B prevede na N-oxid, zejména peroxykyselinou nebo dioxiranem. Epothilon A-N-oxid a epothilon B-N-oxid.
Description
Způsob přípravy epothilon-N-oxidů a N-oxidy epothilonů
Oblast techniky
Epothiolony A a B jsou známé; srovnej například DE 4 138 042, WO 93 10121 a WO 97 19086. Jmenovaný stav techniky je navrhuje jako terapeutické prostředky.
Dosavadní stav techniky
V PNAS USA 95 (1998) 1369 - 1374 jsou epothilony označovány jako užitečné terapeutické prostředky. V důsledku jejich terapeutických efektů se podle Angew. Chem. Int. Ed. 36 (1997) 2097 - 2103 bude dokonce opatřovat obsáhlá knihovna sloučenin tohoto druhu (extensive library of compounds).
Podstata vynálezu
Vynález se týká způsobu přípravy epothilon-N-oxidů, při němž se chráněný nebo nechráněný epothilon A nebo B o sobě známým způsobem převede na N-oxid.
Tento postup podle vynálezu je s výhodou charakterizován tím že se N-oxidace provádí peroxykyselinou nebo dioxiranem.
Předmětem vynálezu je rovněž epothilon-N-oxid (epothilon A-N-oxid) vzorce
r1, r2 = h, z = o; r = h
Dále je předmětem vynálezu epothilon-N-oxid (epothilon B-N-oxid) vzorce:
r1,r2 = h, z = o; r = ch3
-1 CZ 298027 B6
Příklady provedení vynálezu
Příklad 1
Epothilon A-N-oxid
Ke 100 mg epothilonu A v 1 ml dichlormetanu bylo přidáno 100 mg 70% kyseliny w-chlorperoxybenzoové v 0,5 ml dichlorethanu. Po 6 hodinách míchání při teplotě místnosti bylo zředěno dichlormethanem a postupně vytřepáváno roztokem siřičitanu sodného a roztokem bikarbonátu sodného k odstranění přebytečné peroxykyseliny. Rozpouštědlo bylo odpařeno ve vakuu a zbytek byl rozdělen preparativní HPLC na sloupci Nucleosilu RP-18 (250 x 20 mm, mobilní fáze methanol/voda 60:40). Výtěžek 60 mg bezbarvého oleje.
Rf= 0,60 (silikagel DC Alufolie, mobilní fáze dichlormethan/methanol 1:1);
ESI-MS (negativní ionty) m/z 510;
UV (methanol): Zmax = 240 nm;
13C-NMR (CDC13): C-l 70,5, C-2 39,9, C-3 70,8, C^l 55,1, C-5 221,4, C-6 40,9, C-7 72,9, C8 37,6, C-9 31,8, C-10 22,8, C-l 1 28,0, C-12 58,0, C-13 55,8, C-14 32,2, C-15 75,5, C-16 144,5, C-17 111,4, C-18 143, 4, C-19 110,3, C-20 145,6, C-21 13,5, C-22 15,4, C-23 23,3, C24 12,0, C-25 16,5, C-27 18,2 ppm.
Příklady syntéz
Epothilon A-N-oxid: R1, R2 = H, Z = O', R = H
Epothilon B-N-oxid: R1, R2 = H, Z = O', R = CH3
Claims (4)
1. Způsob přípravy epothilon-N-oxidů, vyznačený tím, že se 3,7-chráněný nebo nechráněný epothilon A nebo B o sobě známým způsobem převede na N-oxid.
2. Způsob podle nároku 1,vyznačený tím, že se N-oxidace provádí peroxykyselinou nebo dioxiranem.
3. Epothilon-N-oxid (epothilon A-N-oxid) vzorce:
kde R1, R2 = H, Z = O ; R = H
4. Epothilon-N-oxid (epothilon B-N-oxid) vzorce:
kde R1, R2 = H, Z = O“, R = CH3
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19707505 | 1997-02-25 | ||
| PCT/EP1998/001060 WO1998038192A1 (de) | 1997-02-25 | 1998-02-25 | Seitenkettenmodifizierte epothilone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CZ286599A3 CZ286599A3 (cs) | 2000-03-15 |
| CZ298027B6 true CZ298027B6 (cs) | 2007-05-30 |
Family
ID=7821415
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CZ0286599A CZ298027B6 (cs) | 1997-02-25 | 1998-02-25 | Zpusob prípravy epothilon-N-oxidu a N-oxidy epothilonu |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US6359140B1 (cs) |
| EP (2) | EP0975638B1 (cs) |
| JP (1) | JP2001513098A (cs) |
| KR (1) | KR100494179B1 (cs) |
| CN (2) | CN1544436A (cs) |
| AR (1) | AR011878A1 (cs) |
| AT (1) | ATE221888T1 (cs) |
| AU (1) | AU736062B2 (cs) |
| BR (1) | BR9807742B1 (cs) |
| CA (1) | CA2281105A1 (cs) |
| CZ (1) | CZ298027B6 (cs) |
| DE (2) | DE59805110D1 (cs) |
| DK (1) | DK0975638T3 (cs) |
| ES (1) | ES2183338T3 (cs) |
| HU (1) | HU228851B1 (cs) |
| IL (1) | IL131343A (cs) |
| NO (1) | NO327211B1 (cs) |
| NZ (1) | NZ337195A (cs) |
| PL (1) | PL190422B1 (cs) |
| PT (1) | PT975638E (cs) |
| RU (1) | RU2201932C2 (cs) |
| TW (1) | TW480263B (cs) |
| WO (1) | WO1998038192A1 (cs) |
| ZA (1) | ZA981575B (cs) |
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| US6441186B1 (en) | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
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| PT975638E (pt) * | 1997-02-25 | 2002-12-31 | Biotechnolog Forschung Mbh Gbf | Epothilons modificados nas cadeias laterais |
| US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US6320045B1 (en) | 1997-12-04 | 2001-11-20 | Bristol-Myers Squibb Company | Process for the reduction of oxiranyl epothilones to olefinic epothilones |
| US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993010121A1 (de) * | 1991-11-19 | 1993-05-27 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilone, deren herstellungsverfahren und ihre verwendung als arzneimittel und pflanzenschützende mittel |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6288237B1 (en) * | 1995-11-17 | 2001-09-11 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Epothilons C and D, preparation and compositions |
| US6441186B1 (en) * | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
| PT975638E (pt) * | 1997-02-25 | 2002-12-31 | Biotechnolog Forschung Mbh Gbf | Epothilons modificados nas cadeias laterais |
-
1998
- 1998-02-25 PT PT98912388T patent/PT975638E/pt unknown
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993010121A1 (de) * | 1991-11-19 | 1993-05-27 | GESELLSCHAFT FüR BIOTECHNOLOGISCHE FORSCHUNG MBH (GBF) | Epothilone, deren herstellungsverfahren und ihre verwendung als arzneimittel und pflanzenschützende mittel |
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