NO310510B1 - Taxan med antitumoraktivitet - Google Patents
Taxan med antitumoraktivitet Download PDFInfo
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- NO310510B1 NO310510B1 NO19950184A NO950184A NO310510B1 NO 310510 B1 NO310510 B1 NO 310510B1 NO 19950184 A NO19950184 A NO 19950184A NO 950184 A NO950184 A NO 950184A NO 310510 B1 NO310510 B1 NO 310510B1
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- Prior art keywords
- mixtures
- compound
- acetone
- vegetable material
- crystallization
- Prior art date
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- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- 241001116500 Taxus Species 0.000 claims abstract description 4
- 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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000005418 vegetable material Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000000284 extract Substances 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- HKXCCCPZQFXXGM-UONOGXRCSA-N (2r,3s)-3-(hexanoylamino)-2-hydroxy-3-phenylpropanoic acid Chemical compound CCCCCC(=O)N[C@H]([C@@H](O)C(O)=O)C1=CC=CC=C1 HKXCCCPZQFXXGM-UONOGXRCSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000005526 G1 to G0 transition Effects 0.000 claims description 2
- 241001674343 Taxus x media Species 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims 1
- 238000013375 chromatographic separation Methods 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 238000002360 preparation method Methods 0.000 claims 1
- 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 abstract description 17
- 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 abstract description 8
- 229930012538 Paclitaxel Natural products 0.000 abstract description 7
- 229940123237 Taxane Drugs 0.000 abstract description 7
- 229960001592 paclitaxel Drugs 0.000 abstract description 7
- 241000196324 Embryophyta Species 0.000 abstract description 2
- 239000000063 antileukemic agent Substances 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- YWLXLRUDGLRYDR-LUPIKGFISA-N 7-epi-10-deacetylbaccatin iii Chemical group O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-LUPIKGFISA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 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
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241001116498 Taxus baccata Species 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 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
- 230000009401 metastasis Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002371 ultraviolet--visible spectrum 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)
Description
Foreliggende oppfinnelse vedrører et nytt diterpen med taxankjerne og antitumoraktivitet, en fremgangsmåte ved fremstilling av forbindelser og farmasøytiske formuleringer derav. Fra spektrometriske analyser ble den nye forbindelse gitt den strukturelle formel (1), tilsvarende esteren i 13-stillingen av 5p,20-epoksy-l,2a,4, 7p, 10p, 13a-heksahydrok-sytax-ll-en-9-on-4,10-diacetat-2-benzoat med (2R,3S)-N-heksanoyl - 3 - f enylisoserin.
Forbindelse med formel (1) er blitt isolert fra rotbarken
av genusen Taxus med utbytter varierende fra 0,02-0,06%.
Det vegetabilske materiale som forbindelse (1) er ekstra-
hert fra, består fortrinnsvis av røttene av barlind-cultivar, f.eks. barken av Taxus media cv Hicksii. Dette culti-
var anvendes ofte som prydvekst i haver. Dette faktum gjør det mulig å unngå den vilkårlige utnyttelse av røttene på vilde barlindtrær, hvis vekst er notorisk langsom, og der-
med deres medfølgende hurtige utryddelse.
Forbindelsen (1) ekstraheres ved hjelp av klorerte løs-ningsmidler, f.eks. diklormetan, alene eller i blanding med alkoholer, f.eks. metyl- og etylalkohol. Ekstraksjonen av det vegetabilske materiale kan også utføres med ketoner,
f.eks. aceton, alene eller i blanding med vann.
Rotbarkekstraktet inneholder, i tillegg til forbindelsen (1), en serie andre velkjente taxaner, såsom taxol (2), cefaloamin (3), og deres respektive 10-deacetylderivater
(4) og (5). Separasjonen av (1) fra ovennevnte taxaner kre-ver rensing ved kolonnekromatografi.
For dette formål anvendes fortrinnsvis kiselgel som stasjonær fase. Løsningsmiddelblandinger bestående av et ali-fatisk hydrokarbon, f.eks. n-héksan, cykloheksan eller n-heptan, eller et aromatisk hydrokarbon, f.eks. toluen, sam-men med et løsningsmiddel av høyere polaritet, såsom etyl-acetat eller aceton, anvendes som eluenter.
Forbindelsen (1) isoleres, når den er utvunnet fra de kromatografiske fraksjoner som inneholder den, etter krystallisasjon fra enten aceton eller diisopropyleter eller blandinger derav med n-heksan eller n-heptan.
Den nye forbindelse (1) viser bemerkelsesverdige affiniteter med antitumor-drogen taxol (2), som den adskiller seg fra på grunn av sidekjeden som er bundet i 13-stillingen på taxankjeden. Derfor kan forbindelsen (1) være tilgjengelig, foruten ved ekstraksjon fra vegetabilsk materiale, ved semisyntese ved hjelp av prosesser som ligner prosessene som anvendes for produksjon av taxol (2) (I. Ojima et al. Tetrahedron 48, 6985,1992).
På grunn av de strukturelle affiniteter mellom forbindelsen (1) og taxol (2) , kunne en lignende antitumoraktivitet for-ventes av førstnevnte.
I virkeligheten er det også slik at in vitro-aktivitet av (1) mot flere tumorlinjer, f.eks. linjen som vedrører bryst-, lunge-, colon- og ovarialkreft, kan sammenlignes med taxolens aktivitet, som angitt i tabell 1. Imidlertid viser det nye taxan (1) overraskende høyere aktivitet enn taxol med hensyn til adriamicin-resistente (ADR) tumor-celler og leukemiceller.
I in vivo-studier viste seg at forbindelsen (1) , admini-strert i vandig løsning inneholdende Cremophor®, var effektiv mot tumorer implantert i nakne mus. Følgelig er det forventet at taxan (1) kan anvendes som ant i tumor-droge for behandling av flytende tumorer og droge-resistente tumorer, såsom adriamicin-resistente tumorer.
I henhold til de aktive doser som man har funnet for dyr, skulle dosen av forbindelse (1) for mennesker omfatte mellom 150 og 250 mg/m<a> med cykluser gjentatt ved et to- eller tre-ukers intervall inntill metastasen er forsvunnet.
Eksempel 1
Ester i 13- stilling av 5]3, 20- epoksy- l, 2a, 4, 7|3, 100, 13a-heksahydroksytax- ll- en- 9- on- 4, 10- diacetat- 2- benzoat med ( 2R, 3S)- N- heksanoyl- 3- fenylisoserin ( formel 1) 50 kg pulverisert bark fra Taxus media cv Hicksii ble ekstrahert ved værelsestemperatur med 13 0 liter og deretter tre ganger med 80 liter av en 9:1 metyl enklor id/metanol-blanding, og hver ekstraksjon foregikk i 24 timer.
De sammenslåtte ekstrakter ble vakuumkonsentrert, og resi-duet (4300 g) ble tatt opp med 23 liter av en 9:1 toluen/- acetonblanding. Etter bortfiltrering av uløselig stoff ble løsningen renset ved kolonnekromatorgrafi gjennom 27 kg kiselgel, idet man eluerte med den samme løsningsmiddel-blanding. Fraksjonene somm inneholdt produktet (1) , ble oppsamlet og inndampet til tørrhet under vakuum. Residuet ble krystallisert fra 80 ml av en 1:1 n-heksan/aceton-blanding, og 17,5 g (l) , smp.209°, [a]D - 42° (c = 0,3, MeoH), M+ a m/z 847, ble erholdt. De spektrofotometriske data for forbindelsen (1) er følgende: IB (nujol): 3500-3300, 1710, 1640 cm"<1>
UV (MeOH): 222 (13900), 232 (16250), 274 (1130), 282
(990) nm
CIMS (N<H>3), mZz. 865 (40%, M+NH^), 848 (10, MH), 586
(30, M+NH4 -279)
^H-NMR (300 MHz, CDCI3, ppm, J in Hz) 5,66 (d, J = 7,0;
H-2), 3,78 (d, J = 7,0; H-3), 4,93 (dd, J1 = 9,4, <J>2<=>
2,0; H-5), 2,54 (ddd, J1 = 15,5, J2 = 9,4, <J>3<=> 6,6;
H-6a), 1,84 (ddd, Jx = 15,5, J2 = 10,9; J3 = 2,0;
H-60), 4,39 (ddd, Jj_ = 10,9, <J>2<=> 6,6, J3 = 4,1; H-7),
6,28 (6, 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-20Q), 4,65 (dd, Jx = 4,9,
J2 = 2,5; H-2'), 5,56 (dd, Jj- = 8,9, J2 = 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), 7,50 (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). 13 C- NMR (75,43 Hz, CDCI3): 78,99 (C-l), 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-ll), 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-l<1>), 73,16
(C-2'), 54,53 (C-3<«>)/ 172,90 (C-l"), 36,55 (C-2"),
25,34 (C-3"), 31,29 (C-4"), 22,28 (C-5"), 13,83 (C-6"),
129,09 (PhCO C-l), 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-l),
126,94 (Ph C-2 e C-6), 128,93 (Ph C-3 e C-5), 128,23
(Ph C-4), 22,58 (COCH3), 20,84 (COCH3), 171,23 (COCH3),
170,23 (CJ2CH3), 166,95 (Ph£0_).
<C>46<H>57<N0>14: Funnet % C = 65,11; H - 6,86; N = l/60
Beregnet % c = 65,15; H = 6,78; N = i/65.
Claims (7)
1. Esteren i 13-stillingen av 5p,20-epoksy-l,2a,4,7p,-lop,13a-heksahydroksytax-ll-en-9-on-4,10-diacetat-2-benzoat med (2R,3S)-N-heksanoyl-3-fenylisoserin som har formel (1)
hvor Ac er -COCH3.
2. Fremgangsmåte ved fremstilling av forbindelsen (1) ifølge krav 1,
karakterisert ved at det vegetabilske materiale av barlind-cultivar ekstraheres med klorerte hydrokarboner eller med blandinger derav med lavere alko-holder, at det tørkede ekstrakt, erholdt ved inndamping av løsningsmiddelet, kromatograferes med blandinger av alifa-tiske eller aromatiske hydrokarboner med løsningsmidler med høyere polaritet som elueringsmiddel, og at forbindelsen (1), når den er utvunnet fra fraksjonene som inneholder den, renses ved krystallisasjon.
3. Fremgangsmåte ifølge krav 2, karakterisert ved at det vegetabilske materiale består av rotbarken av Taxus media cv Hicksii.
4. Fremgangsmåte ifølge krav 2-3, karakterisert ved at ekstraksjonen utføres med metylenklorid/metanolblandinger.
5. Fremgangsmåte ifølge krav 2-4, karakterisert ved at kiselgel anvendes som stasjonær fase, og toluen/acetonblandinger anvendes for den kromatografiske separasjon.
6. Fremgangsmåte ifølge krav 2-5, karakterisert ved at aceton, diisopropyleter eller blandinger derav med n-heksan eller n-heptan anvendes for krystallisasjonen.
7. Farmasøytiske formuleringer med antitumoraktivitet karakterisert ved at den inneholder forbindelsen (1) ifølge krav 1 som aktiv ingrediens.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO950184D0 NO950184D0 (no) | 1995-01-18 |
| NO950184L NO950184L (no) | 1995-01-18 |
| NO310510B1 true NO310510B1 (no) | 2001-07-16 |
Family
ID=11401772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19950184A NO310510B1 (no) | 1993-05-20 | 1995-01-18 | Taxan med antitumoraktivitet |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5407674A (no) |
| EP (1) | EP0625517B1 (no) |
| JP (1) | JPH07509259A (no) |
| KR (1) | KR100315495B1 (no) |
| CN (1) | CN1054381C (no) |
| AT (1) | ATE174595T1 (no) |
| AU (1) | AU6795194A (no) |
| CA (1) | CA2140519A1 (no) |
| CZ (1) | CZ286959B6 (no) |
| DE (2) | DE69322619T2 (no) |
| DK (1) | DK0625517T3 (no) |
| ES (1) | ES2068166T3 (no) |
| FI (1) | FI950207A0 (no) |
| GR (1) | GR950300009T1 (no) |
| HK (1) | HK1012628A1 (no) |
| HU (1) | HU221503B (no) |
| IT (1) | IT1261667B (no) |
| NO (1) | NO310510B1 (no) |
| PL (1) | PL178363B1 (no) |
| RU (1) | RU2129551C1 (no) |
| SK (1) | SK280873B6 (no) |
| WO (1) | WO1994027984A1 (no) |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| US6410756B1 (en) | 1996-10-24 | 2002-06-25 | Institut National De La Recherche Scientifique | Family of Canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof |
| EP2266607A3 (en) | 1999-10-01 | 2011-04-20 | Immunogen, Inc. | Immunoconjugates for treating cancer |
| US6649632B2 (en) * | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| PL350028A1 (en) * | 2000-02-02 | 2002-10-21 | Univ Florida State Res Found | C10 carbonate substituted taxanes as antitumor agents |
| 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 |
| EP1883627B1 (en) | 2005-05-18 | 2018-04-18 | Pharmascience Inc. | Bir domain binding compounds |
| CA2647564C (en) * | 2006-04-03 | 2016-08-30 | Pharmatherm Chemicals Inc. | Thermal extraction method and product |
| CN101535300B (zh) | 2006-05-16 | 2014-05-28 | 埃格拉医疗公司 | Iap bir域结合化合物 |
| US7905990B2 (en) | 2007-11-20 | 2011-03-15 | Ensyn Renewables, Inc. | Rapid thermal conversion of biomass |
| ES2389518T3 (es) | 2008-01-18 | 2012-10-26 | Indena S.P.A. | Formas sólidas de ortataxel |
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| 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. |
| US5243045A (en) * | 1991-09-23 | 1993-09-07 | Florida State University | Certain alkoxy 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 |
| 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 |
| 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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