CN1054381C - 具有抗癌活性的红豆杉烷，其制法及药物组合物 - Google Patents
具有抗癌活性的红豆杉烷，其制法及药物组合物 Download PDFInfo
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Abstract
本发明涉及结构式(1)的新红豆杉烷，它可从紫杉属类植物的根皮分离。化合物(1)抗癌活性比红豆杉醇的抗癌活性高，前者不象后者，对耐阿霉素细胞也有活性，并且作为抗白血病药。
Description
本发明涉及一种含有抗癌活性的红豆杉烷(taxane)核的新双萜。从光谱分析得到结构式(1)的新化合物，相当于在5β，20-环氧-1，2a，4，7β，10β，13α-六羟基红豆杉-11-烯-9-酮-4，10-二乙酸酯-2-苯甲酸酯的13位与(2R，3S)-N-己酰基-3-苯基异丝氨酸形成的酯。
式(1)化合物从紫杉属类根皮分离出来，产率为0.02％到0.06％。
化合物(1)从其中萃取的植物材料优选由紫杉属栽培品种的根皮组成，例如Taxus media cv Hicksii的根皮。该栽培品种通常用于花园装饰并供观赏。该事实避免不加选择地收获自生紫杉属树根，其生长极为缓慢，及它们随后快速的死灭。
通过只用氯化的溶剂例如氯代烃(如二氯甲烷)或其与醇如甲醇或乙醇的混合物来萃取化合物(1)，也可通过只用酮如丙酮或水混合使用来萃取植物材料。
根皮萃取物除含化合物(1)外，还含有一系列其它众所周知的红豆杉烷类如红豆杉醇(2)，cephalomanine(3)及它们各自的10-脱乙酰基衍生物(4)和(5)。从上面红豆杉烷中分离化合物(1)要求用柱色谱纯化。层析通过蒸发溶剂得到的干燥萃取物。2R′＝C6H5；R″＝COCH33R′＝-C(CH3)＝CHCH3；R″为乙酰基4R′＝C6H5；R″＝H5R′＝-C(CH3)＝CHCH3；R″＝H
为此目的，硅胶优选用作固定相。由脂肪烃如正己烷，环己烷或正庚烷，或芳香烃如甲苯，和较高极性溶剂如乙酸乙酯或丙酮组成的溶剂混合物用作洗脱剂。
一旦化合物(1)从含有它的色谱馏分中回收，它在从丙酮或异丙醚或其与正己烷或正庚烷的混合物中结晶后得到分离。
新化合物(1)显示出与抗癌药红豆杉醇(2)显著的结构相似性，其中在红豆杉烷核13位上结合的侧链类型不同。因此，除从植物材料萃取外，化合物(1)可通过类似于生产红豆杉醇(2)的方法(I.Ojima等，Tetrahedron 48，6985，1992)半合成。
由于化合物(1)和红豆杉醇(2)的之间的结构相似性，可以预料前者的类似抗癌活性。
确实，在体外化合物(1)对几种癌菌种如与乳腺、肺、结肠和卵巢癌有关的菌种拮抗活性可与红豆杉醇的拮抗活性相媲美，如表1所报告。然而，对于耐阿霉素(ADR)癌细胞及对白血病细胞来说新红豆杉烷(1)出人意料地表现出比红豆杉醇更高的活性。
因此，本发明还涉及一种具有抗癌活性的药物组合物，其中以化合物(1)作为活性成分。
利用Michael C.Alley等人在癌症研究(Cancer Research)1988年2月所述的方法进行了药效试验。
表1-红豆杉烷(1)和红豆杉醇(2)对不同癌菌种抑制生长活性的比较(IC50，nM)癌细胞 红豆杉烷(1) 红豆杉醇(2)L1210(鼠白血病) 3.6±0.3 57.0±3.0A121(人卵巢) 8.6±0.4 6.3±0.3A549(人NSCLC) 3.9±0.3 5.4±0.5HT-29(人结肠) 5.4±0.5 6.0±0.6MCF7(人乳腺) 2.2±0.1 4.3±0.5MCF7-ADR(耐ADR) 430±22 ＞1000
在体内研究中，化合物(1)，以含CremophorR水溶液给药，CremophorR是一种聚乙烯蓖麻油衍生物的商品名，由BASF公司生产。证明对植入裸鼠的癌是有效的。因此，预想红豆杉烷用作治疗液体癌和耐药癌如耐阿霉素癌的抗癌药。
根据在动物上的活性剂量，化合物(1)对人的剂量为150到250mg/m2之间，2或3周为一个周期，直到转移消失。
下面实施例举例说明本发明化合物的制备。实施例1
在5β，20-环氧-1，2α，4，7β，10β，13a-六羟基红豆杉-11-烯-9-酮-4，10-二乙酸酯-2-苯甲酸酯的13位与(2R，3S)-N-己酰基-3-苯基异丝氨酸形成的酯(式1)
50kg Taxus media cv Hicksii粉状皮在室温下用130升9∶1二氯甲烷/甲醇混合物萃取，随后用80升9∶1二氯甲烷/甲醇混合物萃取3次，每次萃取进行24小时。
收集的萃取液真空浓缩，残余物(4300g)溶于23升9∶1甲苯/丙酮混合物。过滤不溶物后，通过用27kg硅胶，同样溶剂混合物作为洗脱剂的柱色谱纯化。收集含产品(1)的馏分，减压蒸干。残余物从80ml 1∶1正己烷/丙酮混合物中结晶，得到17.5g化合物(1)，熔点：209℃，〔α〕D-42°(C＝0.3，甲醇)，M+am/z847。
化合物(1)的光谱测量数据如下：IR(nujol)：3500-3300，1710，1640cm-1 UV(MeOH)：222(13900)，232(16250)，274(1130)，282(990)nmCIMS(NH3)，
m/z865(40％，M+NH4)，848(10，MH)，586(30，M+NH4-279)1H-NMR(300 MHz，CDCl3，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，J2＝2,0；H-5)，2,54(ddd，J1＝15,5，J2＝9,4，J3＝6,6；H-6α)，1,84(ddd，J1＝15,5，J2＝10,9；J3＝2,0；H-6β)，4,39(ddd，J1＝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-20β)，4,65(dd，J1＝4,9，J2＝2,5；H-2′)，5,56(dd，J1＝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′-PhH-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，CDCl3)：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(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(COCH3)，166,95(Ph
CO)。C46H57NO14：实验值％C＝65,11；H＝6,86；N＝1,60
计算值％C＝65,15；H＝6,78；N＝1,65。
Claims (10)
1.在5β，20-环氧-1，2α，4，7β，10β，13α-六羟基红豆杉-11-烯-9-酮-4，10-二乙酸酯-2-苯甲酸酯的13位与(2R，3S)-N-己酰基-3-苯基异丝氨酸形成的式(I)酯
2.一种制备权利要求1的化合物(1)的方法，其特征在于用氯代烃或其与甲醇或乙醇的混合物萃取紫杉属栽培植物的植物材料，用脂肪烃或芳香烃与乙酸乙酯或丙酮的溶剂混合物作为洗脱剂，层析通过蒸发溶剂得到的干燥萃取物，以及一旦从含它的馏分中回收后通过结晶纯化化合物(1)。
3.按照权利要求2的方法，其特征在于植物材料由Taxusmedia cv Hicksii的根皮组成。
4.按照权利要求2或3的方法，其特征在于用二氯甲烷/甲醇混合物进行萃取。
5.按照权利要求2或3的方法，其特征在于作为固定相的硅胶和作为洗脱剂的甲苯/丙酮混合物用于色谱分离。
6.根据权利要求4的方法，其特征在于作为固定相的硅胶和作为洗脱剂的甲苯/丙酮混合物用于色谱分离。
7.按照权利要求2或3的方法，其特征在于丙酮，异丙醚或其与正己烷或正庚烷的混合物用于结晶。
8.按照权利要求4的方法，其特征在于丙酮，异丙醚或其与正己烷或正庚烷的混合物用于结晶。
9.按照权利要求5的方法，其特征在于丙酮，异丙醚或其与正己烷或正庚烷的混合物用于结晶。
10.一种具有抗癌活性的药物组合物，其特征在于含有权利要求1的化合物(1)作为活性成分。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITRM93A000334 | 1993-05-20 | ||
| ITRM93A00033 | 1993-05-20 | ||
| ITRM930334A IT1261667B (it) | 1993-05-20 | 1993-05-20 | Tassano ad attivita' antitumorale. |
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| Publication Number | Publication Date |
|---|---|
| CN1110055A CN1110055A (zh) | 1995-10-11 |
| CN1054381C true CN1054381C (zh) | 2000-07-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN94190306A Expired - Fee Related CN1054381C (zh) | 1993-05-20 | 1994-05-03 | 具有抗癌活性的红豆杉烷，其制法及药物组合物 |
Country Status (22)
| Country | Link |
|---|---|
| US (1) | US5407674A (zh) |
| EP (1) | EP0625517B1 (zh) |
| JP (1) | JPH07509259A (zh) |
| KR (1) | KR100315495B1 (zh) |
| CN (1) | CN1054381C (zh) |
| AT (1) | ATE174595T1 (zh) |
| AU (1) | AU6795194A (zh) |
| CA (1) | CA2140519A1 (zh) |
| CZ (1) | CZ286959B6 (zh) |
| DE (2) | DE69322619T2 (zh) |
| DK (1) | DK0625517T3 (zh) |
| ES (1) | ES2068166T3 (zh) |
| FI (1) | FI950207A (zh) |
| GR (1) | GR950300009T1 (zh) |
| HK (1) | HK1012628A1 (zh) |
| HU (1) | HU221503B (zh) |
| IT (1) | IT1261667B (zh) |
| NO (1) | NO310510B1 (zh) |
| PL (1) | PL178363B1 (zh) |
| RU (1) | RU2129551C1 (zh) |
| SK (1) | SK280873B6 (zh) |
| WO (1) | WO1994027984A1 (zh) |
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| 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 |
| AU4768797A (en) | 1996-10-24 | 1998-05-15 | Institute Armand-Frappier | A family of canadensol taxanes, the semi-synthetic preparation and therapeutic use thereof |
| AU775373B2 (en) | 1999-10-01 | 2004-07-29 | 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 |
| HUP0200759A3 (en) | 2000-02-02 | 2002-10-28 | Univ Florida State Res Found | C10 carbonate substituted taxanes as antitumor agents and pharmaceutical compositions containing them and their use |
| US7064980B2 (en) * | 2003-09-17 | 2006-06-20 | Sandisk Corporation | Non-volatile memory and method with bit line coupled compensation |
| HN2005000054A (es) * | 2004-02-13 | 2009-02-18 | Florida State University Foundation Inc | 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 |
| CA2597682A1 (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 |
| EP2007744B1 (en) | 2006-04-03 | 2017-05-17 | Pharmatherm Chemicals Inc. | Thermal extraction method for producing a taxane 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 |
| EP2080764B1 (en) | 2008-01-18 | 2012-08-22 | INDENA S.p.A. | Solid forms of ortataxel |
| EP2276755A4 (en) * | 2008-03-31 | 2011-05-04 | Univ Florida State Res Found | C (10) -ETHYESTER- AND C (10) -CYCLOPROPYLESTER-SUBSTITUTED TAXANES |
| SG182724A1 (en) | 2010-02-12 | 2012-08-30 | Pharmascience Inc | Iap bir domain binding compounds |
| 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 |
| US9044727B2 (en) | 2011-09-22 | 2015-06-02 | Ensyn Renewables, Inc. | Apparatuses and methods for controlling heat 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 |
| 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 |
| EP3013922A4 (en) | 2013-06-26 | 2017-02-08 | Ensyn Renewables, Inc. | Systems and methods for renewable fuel |
| WO2017034981A1 (en) | 2015-08-21 | 2017-03-02 | Ensyn Renewables, Inc. | Liquid biomass heating system |
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| 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 |
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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 DE DE69322619T patent/DE69322619T2/de not_active Expired - Fee Related
- 1993-07-15 DK DK93111366T patent/DK0625517T3/da active
- 1993-07-15 EP EP93111366A patent/EP0625517B1/en not_active Expired - Lifetime
- 1993-07-15 DE DE0625517T patent/DE625517T1/de active Pending
- 1993-07-15 ES ES93111366T patent/ES2068166T3/es not_active Expired - Lifetime
- 1993-07-15 AT AT93111366T patent/ATE174595T1/de not_active IP Right Cessation
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1994
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- 1994-05-03 PL PL94307089A patent/PL178363B1/pl unknown
- 1994-05-03 CZ CZ1995122A patent/CZ286959B6/cs not_active IP Right Cessation
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- 1994-05-03 CN CN94190306A patent/CN1054381C/zh not_active Expired - Fee Related
- 1994-05-03 CA CA002140519A patent/CA2140519A1/en not_active Abandoned
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- 1994-05-03 WO PCT/EP1994/001405 patent/WO1994027984A1/en active IP Right Grant
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1995
- 1995-01-18 FI FI950207A patent/FI950207A/fi unknown
- 1995-01-18 NO NO19950184A patent/NO310510B1/no not_active IP Right Cessation
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1998
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991017976A1 (fr) * | 1990-05-22 | 1991-11-28 | Rhone-Poulenc Rorer S.A. | Procede de preparation enantioselective de derives de la phenylisoserine |
| US5200534A (en) * | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
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