PL178363B1 - Taksan o działaniu przeciwnowotworowym - Google Patents
Taksan o działaniu przeciwnowotworowymInfo
- Publication number
- PL178363B1 PL178363B1 PL94307089A PL30708994A PL178363B1 PL 178363 B1 PL178363 B1 PL 178363B1 PL 94307089 A PL94307089 A PL 94307089A PL 30708994 A PL30708994 A PL 30708994A PL 178363 B1 PL178363 B1 PL 178363B1
- Authority
- PL
- Poland
- Prior art keywords
- formula
- compound
- mixture
- fact
- acetone
- Prior art date
Links
- 229940123237 Taxane Drugs 0.000 title description 8
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 title description 6
- 230000003217 anti-cancerogenic effect Effects 0.000 title 1
- 230000001747 exhibiting effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 5
- 241000196324 Embryophyta Species 0.000 claims description 4
- 241001116500 Taxus Species 0.000 claims description 3
- 241001674343 Taxus x media Species 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 230000001093 anti-cancer Effects 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims 2
- 229930195733 hydrocarbon Natural products 0.000 claims 2
- 150000002430 hydrocarbons Chemical class 0.000 claims 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- ZKPUPHSBFMNFHO-UHFFFAOYSA-N [ClH]1C=CC=C1 Chemical compound [ClH]1C=CC=C1 ZKPUPHSBFMNFHO-UHFFFAOYSA-N 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 229930012538 Paclitaxel Natural products 0.000 description 8
- 229960001592 paclitaxel Drugs 0.000 description 8
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 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 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- -1 acetone Chemical class 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 1
- 101150065749 Churc1 gene Proteins 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 102100038239 Protein Churchill Human genes 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229960004543 anhydrous citric acid Drugs 0.000 description 1
- 230000002634 anti-blastic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 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
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
1. Zestryfikowany w pozycji 13 (2R,3S)-N-heksanoilo-3-fenyloizoseryna2-benzoe- san 4 , 10-dwuoctanu 5ß,20-epoksy-1,2a,4,7ß,10ß,13a-heksahydroksytaks-11-en-9-onu o wzorze 1 Wzór 1 PL PL PL PL PL PL
Description
Zwiqzek o wzorze 1 wyodr?bniono z kory korzeni z rodzaju Taxus, z wydajnosciq w granicach od 0.02 do 0.06%.
Material roslinny, z którego ekstrahuje si? zwiqzek o wzorze 1 korzystnie sklada si? z korzeni odmiany cisu, np. z kory Taxus media cv Hicksii. Odmian? t? stosuje si? obecnie w celach ozdobnych do ozdabiania ogrodów. Fakt ten pozwala uniknqc masowego zbierania korzeni drzew rosnqcych spontanicznie, których wzrost jest powszechnie znany jako wolny, i w konsekwencji ich wytrzebienia.
Zwiqzek o wzorze 1 ekstrahuje si? za pomocq chlorowanych rozpuszczalników, np. dwuchlorometanu, czystych lub w mieszaninie z alkoholami, np. z alkoholem metylowym i etylowym. Ekstrahowanie materialu roslinnego mozna takze prowadzic przy uzyciu ketonów, np. acetonu, czystego lub w mieszaninie z wodq.
Ekstrakt z kory korzeni zawiera, oprócz zwiqzku o wzorze 1, szereg innych dobrze znanych taksanów, takich jak taksol (zwiqzek o wzorze 2, w którym R' oznacza grup? C6H5; a R oznacza grup? COCH3), cefalomanina (zwiqzek o wzorze 2, w którym R' oznacza grup? -C(CH3)=CHCH3; a R oznacza H), i ich odpowiednie dezacetylowe pochodne (zwiqzek o wzorze 2, w którym R' oznacza grup? C6H5; a R oznacza H i zwiqzek o wzorze 2, w którym R' oznacza grup? -C(CH3)=CHCH3; a R oznacza H). Oddzielanie zwiqzku o wzorze 1 od wymienionych wyzej taksanów wymaga oczyszczania metodq chromatografii kolumnowej.
R7
wzór 2
178 363
W tym celu jako faz? stacjonarnq stosuje si? korzystnie zel krzemionkowy. Jako eluenty stosuje si? mieszaniny rozpuszczalników', skladajqce si? z w?glowodoru alifatycznego, np. n-heksanu, cykloheksanu lub n-heptanu, lub z w?glowodoru aromatycznego, np. toluenu, razem z rozpuszczalnikiem o wyzszej polamosci, takim jak octan etylu lub aceton.
Zwiqzek o wzorze 1, raz odzyskany z zawierajqcych go frakcji chromatograficznych, wyodr?bnia si? po krystalizacji bqdz z acetonu lub eteru izopropylowego lub z ich mieszanin z n-heksanem lub n-heptanem.
Nowy zwiqzek o wzorze 1 wykazuje znaczne powinowactwo strukturalne z przeciwnowotworowym lekiem, taksolem o wzorze 2, w którym R' oznacza grup? C()H5; a R oznacza grup? COCH3, od którego rózni si? rodzajem lahcucha bocznego, przytqczonego w pozycji 13 pierscienia taksanu. Dlatego, zwiqzek o wzorze 1 moze byc dost?pny, oprócz ekstrakcji z materialu roslinnego, poprzez pólsyntez? w procesach podobnych do tych, które stosuje si? do wytwarzania taksolu (zwiqzek o wzorze 2, w którym R' oznacza grup? C6H5; a R oznacza grup? COCH3) (I Ojima i wsp., Tetrahedron 48, 6985, 1992).
Ze wzgl?du na powinowactwo strukturalne pomi?dzy zwiqzkiem o wzorze 1 a taksolem (zwiqzek o wzorze 2, w którym R' oznacza grup? C6H5; a R oznacza grup? COCH3), mozna bylo oczekiwac od tego pierwszego podobnego dzialania przeciwnow'otw'orow'ego.
Rzeczywiscie, jak podano w tabeli 1, aktywnosc zwiqzku o wzorze 1 in vitro wobec szeregu nowotworowych linii komórkowych, np. zwiqzanych z rakiem piersi, pluc, okr?znicy i jajników, jest porównywalna z aktywnosciq taksolu. Nowy taksan o wzorze 1 nieoczekiwanie wykazujejednak aktywnosc wyzszq od aktywnosci taksolu w odniesieniu do komórek nowotworowych opornych na adriamycyn? (ADR) i w odniesieniu do komórek bialaczkowych.
Tabela 1
Porównanie pomi?dzy aktywnosciq antyblastyczna taksanu o wzorze 1 i taksolu wobec róznych linii komórek nowotworowych (1C50, nm)
| Komórki nowotworowe | Taksan o wzorze 1 | Taksol |
| L1210 (bialaczka myszy) | 3,6±0,3 | 57,0±3,0 |
| A121 (jajniki ludzkie) | 8,6±0,4 | 6,3±0,3 |
| A549 (NSCLC ludzkie) | 3,9±0,3 | 5,4±0,5 |
| HT-29 (okr?znica ludzka) | 5,4±0,5 | 6,0±0,6 |
| MCF7 (piers ludzka) | 2,2±0,1 | 4,3±0,5 |
| MCF7-ADR (oporne na ADR) | 430±22 | >1000 |
W badaniach in vivo, zwiqzek o wzorze 1, podawany w wodnym roztworze, zawierajqcym Cremophor(R), okaza! si? byc skuteczny wobec nowotworów implantowanych nagim myszom. W zwiqzku z tym oczekiwano, ze taksan o wzorze 1 b?dzie stosowany jako lekprzeciwnowotworowy do leczenia nowotworów cieklych i nowotworów opornych na leki, takich jak nowotwory oporne na adriamycyn?.
Na podstawie aktywnych dawek okreslonych dla zwierzqt stwierdzono, ze dawka zwiqzku o wzorze 1 dla ludzi powinna wynosic od 150 do 250 mg/m2 i byc podawana w cyklach powtarzajqcych si? w odst?pach dwóch lub trzech tygodni, az do znikni?cia przerzutów.
Nast?pujqcy przyklad ilustruje wytwarzanie zwiqzku wedlug wynalazku.
Przyklad I. Zestryfikowany w pozycji 13 (2R,3S)-N-heksanoilo-3-fenyloizoserynq 2-benzoesan 4,10-dwuoctanu 5P,20-epoksy-1,2a,4,7p,10p,13a-heksahydroksytaks-11-en-9-onu.
W temperaturze pokojowej 50 kg sproszkowanej kory Taxus media cv Hicksii ekstrahowano 130 litrami, a nast?pnie trzykrotnie, 80 litrami mieszaniny 9:1 chlorku metylenu z metanolem, przy czym kazdq ekstrakcj? prowadzono w ciqgu 24 godzin.
Zebrane ekstrakty zat?zano pod zmniejszonym cisnieniem, a pozostalosc (4300 g) roztworzono w 23 litrach mieszaniny 9:1 toluenu z acetonem. Po odsqczeniu substancji nierozpuszczal178 363 nych, roztwór oczyszczano metodq chromatografii kolumnowej, przepuszczajqc go przez 27 kg zelu krzemionkowego z eluowaniem takq samq mieszaninq rozpuszczalników··. Zebrano frakcje zawierajqce produkt o wzorze 1 i odparowano je do sucha pod zmniejszonym cisnieniem. Pozostalosc krystalizowano z 80 ml mieszaniny 1:1 n-heksanu z acetonem, otrzymujqc 17,5 g zwiqzku o wzorze 1, o temperaturze topnienia 209°C, [a]D -42° (c = 0,3, MeOH), M+ m/z 847.
Dane spektrometryczne zwiqzku o wzorze 1 sq nast?pujqce:
IR (nujol): 3500-3300, 1710, 1640 cm’1
UV (MeOH): 222 (13900), 232 (16250), 274 (1130), 282 (990) nm
CIMS (NH3), m/z 865 (40%, M+NH4), 848 (10, MH), 586 (30, M+NH4 -279) 'H-NMR (300 MHz, CDCty ppm, J w HZ), 5,66 (d, J=7,0; H-2), 3,78 (d, J=7,0; H-3), 4,93 (dd, J,=9,4, J2=2,0; H-5), 2,54 (ddd, J1=15,5, J2=9,4, J3=6,6; H-6a), 1,84 (ddd, J1=15,5, J2=10,9, J3=2,0; H-6p), 4,39 (ddd, J=10,9, J2=6,6, J3=4,1; H-7), 6,28 (s, H-10), 6,23 (t, J=6,23; H-13), 2,24-2,32 (2H, m; H-14), 1,26 (s, H-16), 1,14 (s, H-17), 1,81 (d, J= 1,2; H-18), 1,67 (s, H-19), 4,17 (d, J=8,6; H-20a), 4,28 (d, J=8,6; H-20P), 4,65 (dd, Jj=4,9, J2=2,5; H-2'), 5,56 (dd, J,=8,9, 12=2,5; H-3'), 2,18 (t, J=7,3; H-2), 1,56 (m; H-3), 1,28-1,20 (m; H-4 e H-5), 0,83 (t, J=6,7; H-6), 8,10 (d, J=7,8; PhCO H-2 e 6), 7,5 (t, J=7,8; PhCO H-3 e 5), 7,61 (t, J=7,8; PhCO H-4), 7,38 (m; 3'-Ph, H-2,3,4,5,6), 2,34 (s, COCH3), 2,24 (s, COCH3), 6,25 (d, J=8,9; NH), 2,49 (d, J=4,1 ; 7-OH), 1,84 (s, 1-OH), 3,55 (d, J=4,9; 2'-OH).
13C-NMR (75,43 Hz, CDO3): 78,99 (C-1), 74,93 (C-2), 45,57 (C-3), 81,07 (C-4), 84,37 (C-5), 35,59 (C-6), 72,15 (C-7), 58,56 (C-8), 203,63 (C-9), 75,55 (C-10), 138,06 (C-11), 142,05 (C-12), 72,29 (C-13), 35,59 (C-14), 43,18 (C-15), 26,79 (C-16), 21,86 (C-17), 14,81 (C-18), 9,54 (C-19), 76,46 (C-20), 172,78 (C-1'), 73,16 (C-2'), 54,53 (C-3'), 172,90 (C-1), 36,55 (C-2), 25,34 (C-3), 31,29 (C-4), 22,28 (C-5), 13,83 (C-6), 129,09 (PhCO C-1), 130,19 (PhCO C-2 e C-6), 128,68 (PhCO C-3 e C-5), 133,68 (PhCO C-4), 133,11 (Ph C-1), 126,94 4PhC-2e C-6), 118,92! (Ph C-3 e C-5), 128,23 (Ph C-4), 22,58 (COCH3), 20,84 (COCH3), 171,23 (COCH3), 170,23 (COCH3), 166,95 (PhCO).
Dla C46H57NOj4:
znaleziono % C = 65,11; H = 6,86; N = 1,60 obliczono % C = 65,15; H - 6,78; N = 1,65.
Przyklad II. Kompozycja farmaceutyczna.
Skladnik:
Zwiqzek o wzorze 1 wedlug zastrz. 1 Polisorbat 80
Bezwodny kwas cytrynowy Bezwodny alkohol mg
0,5 mi
0,005 mi w uzupeniieniu do 1 mi
178 363
Departament Wydawnictw UP RP. Naklad 70 egz Cena 2,00 zl.
Claims (7)
1. ZestryZikowany w pozycji 13 (2R,3S)-N-heksanoilo-3-ieoyloienserynq2-benzoesnn 4,10-dwuoctanu 5 P,2()yepoksy-1.2a,4,7[3, 1Op,l3a-hek-ahydroksyaìkyi1 lspn-9-onu c woozec 1
2. Sposób wotwarzania zwiqzlu o wzorze 1, znamienno tym, ze material roshnno odmiay ny cisu slstraau(e si? chlorowanomi w?glowodorami lub ich mieszaninami z nizszomi aieo-olay mi, wosuszono slstralt, otrzomano przez odparowanie oozpuszczalpiea, poddaje si? caoomatogoaaii, stosujqc (alo eluento mieszanino aliaatycznoca lub aromatycznoca w?glowodoy rów z oozpuszczalnikami o wozszej polamosci, i zwiqzee o wzorze 1, raz odzoseano z zawiei rajqcoca go araecji, oczoszcza si? przez lrostalizac(?.
3. Sposób wedlug zastrz. 2, znamienno tom, ze stosu(s si? material roslinno, stanowiqco lor? lorzeni Taxus media cv Hicesii.
4. Sposób wedlug zastrz. 2, znamienno tom, ze elstralc(? prowadzi si? mieszanipami chlorlu mstylenu z metapolsm.
5. Sposób wedlug zastrz. 2, znamienno tom, ze do rozdzielania c-romatograficznego (alo faz? stacjonamq stosuje si? zel erzemioneowv, a (alo eluent stosuje si? mieszanino toluenu z acetonem.
6. Sposób wedlug zastrz. 2, zpamisnno tom, ze do lo3stalizac(i stosu(s si? aceton, eter izopropolowo lub ich mieszapipo z plasloanem lub p-heptanem.
7. Kompozocja aanmaceutyczna o dzialaniu pozeciwpowotworowom, znamienna tom, ze zawiera zwiqzel o wzorze 1 wedlug zastrz. 1, (alo substapc(? czoniiq oraz aarmaceutocznie dopuszczalpo posnil.
Przedmiotem wopalazlu (est powo dwuterpsp z pierScisniem talsanu, o dzialaniu pneciwnowotworowom. Na prdstawis wopìIów analizo speltoometryczne(, temu powemu zwiqzlowi prz3pisapo wzór ogólno 1, odpowiada(qco zestrofϊlowapemu w pozoc(i 13 (2R,3S)lNlheksanollo-3-aenylolzoseryna2lbepzrssaIloyΊ 4.10-dwuoctanu 5β,20leprlsy-1,23, 4,7β, 1 Οβ, 133laelsaaodools3talsl 11 -epiO-onu.
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| ITRM930334A IT1261667B (it) | 1993-05-20 | 1993-05-20 | Tassano ad attivita' antitumorale. |
| PCT/EP1994/001405 WO1994027984A1 (en) | 1993-05-20 | 1994-05-03 | Taxane having antitumor activity |
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| PL307089A1 PL307089A1 (en) | 1995-05-02 |
| PL178363B1 true PL178363B1 (pl) | 2000-04-28 |
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| PL94307089A PL178363B1 (pl) | 1993-05-20 | 1994-05-03 | Taksan o działaniu przeciwnowotworowym |
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| KR (1) | KR100315495B1 (pl) |
| CN (1) | CN1054381C (pl) |
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| IT (1) | IT1261667B (pl) |
| NO (1) | NO310510B1 (pl) |
| PL (1) | PL178363B1 (pl) |
| RU (1) | RU2129551C1 (pl) |
| SK (1) | SK280873B6 (pl) |
| WO (1) | WO1994027984A1 (pl) |
Families Citing this family (32)
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| DE4139993A1 (de) * | 1991-12-04 | 1993-06-09 | Merck Patent Gmbh, 6100 Darmstadt, De | Pigmentzubereitung |
| IT1275936B1 (it) * | 1995-03-17 | 1997-10-24 | Indena Spa | Derivati della 10-deacetilbaccatina iii e della 10-deacetil-14b- idrossibaccatina iii loro metodo di preparazione e formulazioni |
| US5756536A (en) * | 1995-11-03 | 1998-05-26 | Purdue Research Foundation | Microbial transformation of taxol and cephalomannine |
| US5965752A (en) * | 1996-08-23 | 1999-10-12 | Institut National De La Recherche Scientifique | Preparative scale isolation and purification of taxanes |
| CA2188190A1 (en) | 1996-10-18 | 1998-04-18 | Sarala Balachandran | The semi-synthesis of a protected bacatin iii compound |
| WO1998017656A1 (en) * | 1996-10-24 | 1998-04-30 | Institute Armand-Frappier | A family of canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof |
| EP1229934B1 (en) | 1999-10-01 | 2014-03-05 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| BR0104779A (pt) * | 2000-02-02 | 2001-12-26 | Univ Florida State Res Found | Taxanos substituìdos com carbonato c10 comoagentes antitumor |
| US7064980B2 (en) * | 2003-09-17 | 2006-06-20 | Sandisk Corporation | Non-volatile memory and method with bit line coupled compensation |
| PE20050693A1 (es) * | 2004-02-13 | 2005-09-27 | Univ Florida State Res Found | Taxanos sustituidos con esteres de ciclopentilo en c10 |
| US7169307B2 (en) * | 2004-09-02 | 2007-01-30 | Jian Liu | Process for the extraction of paclitaxel and 9-dihydro-13-acetylbaccatin III from Taxus |
| US20060189679A1 (en) * | 2005-02-14 | 2006-08-24 | Florida State University Research Foundation, Inc. | C10 cyclopropyl ester substituted taxane compositions |
| CA2607940C (en) | 2005-05-18 | 2009-12-15 | Aegera Therapeutics Inc. | Bir domain binding compounds |
| DK2007744T3 (en) | 2006-04-03 | 2017-08-28 | Pharmatherm Chemicals Inc | THERMAL EXTRACTION PROCEDURE FOR PREPARING A TAXAN EXTRACT |
| BRPI0711591A2 (pt) | 2006-05-16 | 2011-11-16 | Aegera Therapeutics Inc | composto de ligação de domìnio bir da iap |
| US7905990B2 (en) | 2007-11-20 | 2011-03-15 | Ensyn Renewables, Inc. | Rapid thermal conversion of biomass |
| DK2080764T3 (da) | 2008-01-18 | 2012-09-24 | Indena Spa | Faste former af ortataxel |
| EP2276755A4 (en) * | 2008-03-31 | 2011-05-04 | Univ Florida State Res Found | C (10) -ETHYESTER- AND C (10) -CYCLOPROPYLESTER-SUBSTITUTED TAXANES |
| BR112012020113A2 (pt) | 2010-02-12 | 2016-06-07 | Pharmascience Inc | compostos de ligação ao domínio iap bir |
| US20110284359A1 (en) | 2010-05-20 | 2011-11-24 | Uop Llc | Processes for controlling afterburn in a reheater and for controlling loss of entrained solid particles in combustion product flue gas |
| US8499702B2 (en) | 2010-07-15 | 2013-08-06 | Ensyn Renewables, Inc. | Char-handling processes in a pyrolysis system |
| US9441887B2 (en) | 2011-02-22 | 2016-09-13 | Ensyn Renewables, Inc. | Heat removal and recovery in biomass pyrolysis |
| US9347005B2 (en) | 2011-09-13 | 2016-05-24 | Ensyn Renewables, Inc. | Methods and apparatuses for rapid thermal processing of carbonaceous material |
| US10400175B2 (en) | 2011-09-22 | 2019-09-03 | Ensyn Renewables, Inc. | Apparatuses and methods for controlling heat for rapid thermal processing of carbonaceous material |
| US10041667B2 (en) | 2011-09-22 | 2018-08-07 | Ensyn Renewables, Inc. | Apparatuses for controlling heat for rapid thermal processing of carbonaceous material and methods for the same |
| US9044727B2 (en) | 2011-09-22 | 2015-06-02 | Ensyn Renewables, Inc. | Apparatuses and methods for controlling heat for rapid thermal processing of carbonaceous material |
| US9109177B2 (en) | 2011-12-12 | 2015-08-18 | Ensyn Renewables, Inc. | Systems and methods for renewable fuel |
| US9670413B2 (en) | 2012-06-28 | 2017-06-06 | Ensyn Renewables, Inc. | Methods and apparatuses for thermally converting biomass |
| TWI645026B (zh) | 2013-06-26 | 2018-12-21 | 安信再生公司 | 可再生燃料之系統及方法 |
| CA2995845A1 (en) | 2015-08-21 | 2017-03-02 | Ensyn Renewables, Inc. | Liquid biomass heating system |
| MY193949A (en) | 2016-12-29 | 2022-11-02 | Ensyn Renewables Inc | Demetallization Of Liquid Biomass |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4206221A (en) * | 1979-01-03 | 1980-06-03 | The United States Of America As Represented By The Secretary Of Agriculture | Cephalomannine and its use in treating leukemic tumors |
| US5157049A (en) * | 1988-03-07 | 1992-10-20 | The United States Of America As Represented By The Department Of Health & Human Services | Method of treating cancers sensitive to treatment with water soluble derivatives of taxol |
| US4942184A (en) * | 1988-03-07 | 1990-07-17 | The United States Of America As Represented By The Department Of Health And Human Services | Water soluble, antineoplastic derivatives of taxol |
| FR2662441B1 (fr) * | 1990-05-22 | 1992-10-23 | Rhone Poulenc Sante | Procede de preparation enantioselective de derives de la phenylisoserine. |
| US5229526A (en) * | 1991-09-23 | 1993-07-20 | Florida State University | Metal alkoxides |
| US5250683A (en) * | 1991-09-23 | 1993-10-05 | Florida State University | Certain substituted taxanes and pharmaceutical compositions containing them |
| US5227400A (en) * | 1991-09-23 | 1993-07-13 | Florida State University | Furyl and thienyl substituted taxanes and pharmaceutical compositions containing them |
| US5243045A (en) * | 1991-09-23 | 1993-09-07 | Florida State University | Certain alkoxy substituted taxanes and pharmaceutical compositions containing them |
| IT1254515B (it) * | 1992-03-06 | 1995-09-25 | Indena Spa | Tassani di interesse oncologico, loro metodo di preparazione ed uso |
| US5200534A (en) * | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
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1993
- 1993-05-20 IT ITRM930334A patent/IT1261667B/it active IP Right Grant
- 1993-07-07 US US08/088,319 patent/US5407674A/en not_active Expired - Fee Related
- 1993-07-15 EP EP93111366A patent/EP0625517B1/en not_active Expired - Lifetime
- 1993-07-15 ES ES93111366T patent/ES2068166T3/es not_active Expired - Lifetime
- 1993-07-15 DE DE0625517T patent/DE625517T1/de active Pending
- 1993-07-15 AT AT93111366T patent/ATE174595T1/de not_active IP Right Cessation
- 1993-07-15 DE DE69322619T patent/DE69322619T2/de not_active Expired - Fee Related
- 1993-07-15 DK DK93111366T patent/DK0625517T3/da active
-
1994
- 1994-05-03 CN CN94190306A patent/CN1054381C/zh not_active Expired - Fee Related
- 1994-05-03 SK SK60-95A patent/SK280873B6/sk unknown
- 1994-05-03 HU HU9500152A patent/HU221503B/hu not_active IP Right Cessation
- 1994-05-03 CZ CZ1995122A patent/CZ286959B6/cs not_active IP Right Cessation
- 1994-05-03 PL PL94307089A patent/PL178363B1/pl unknown
- 1994-05-03 WO PCT/EP1994/001405 patent/WO1994027984A1/en active IP Right Grant
- 1994-05-03 RU RU95105981A patent/RU2129551C1/ru active
- 1994-05-03 JP JP7500149A patent/JPH07509259A/ja not_active Withdrawn
- 1994-05-03 KR KR1019950700197A patent/KR100315495B1/ko not_active IP Right Cessation
- 1994-05-03 AU AU67951/94A patent/AU6795194A/en not_active Abandoned
- 1994-05-03 CA CA002140519A patent/CA2140519A1/en not_active Abandoned
-
1995
- 1995-01-18 NO NO19950184A patent/NO310510B1/no not_active IP Right Cessation
- 1995-01-18 FI FI950207A patent/FI950207A0/fi unknown
- 1995-03-31 GR GR950300009T patent/GR950300009T1/el unknown
-
1998
- 1998-12-17 HK HK98113937A patent/HK1012628A1/xx not_active IP Right Cessation
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