CN1218474A - 从马比木分离的喜树碱骨架化合物及其作为新药物及治疗剂的合成子的用途 - Google Patents
从马比木分离的喜树碱骨架化合物及其作为新药物及治疗剂的合成子的用途 Download PDFInfo
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Abstract
本发明涉及式(1)新的生物碱的分离或半合成,该生物碱存在于马比木的各个部分,本发明还涉及使用所述生物碱的药物以及该生物碱作为制备具有抗肿瘤和抗病毒活性的化合物的新合成子的用途;所述物质是用于制备喜树碱和FoetidineⅠ和Ⅱ的新类似物的新的合成子。这些新化合物的水溶性具有非常重要的意义,因为无需进行衍生化即可进行胃肠外给药。
Description
本发明涉及从马比木分离的喜树碱骨架生物碱或通过半合成从所述生物碱制得的喜树碱骨架化合物。
马比木是一种生长在印度次大陆的植物,已知在其各个部分、尤其是种子中含有喜树碱、mappicine和foetidineⅠ和Ⅱ(EP-A-685481)。
本发明的生物碱具有如下结构通式:其中R是氢原子或甲氧基;R1是羟基、OM基团,其中的M是碱的阳离子,优选钠或钾、C1-C6烷氧基、选择性取代的苯氧基、氨基、C1-C6单烷基氨基或C2-C12二烷基氨基,其中的烷基部分可选择性地被氨基取代、芳基氨基;R2是C1-C6烷基或式COR3的基团,其中的R3是C1-C6烷基或选择性取代的苯基或苄基。
苯氧基、苯基或苄基可以被卤原子、C1-C6烷基、C1-C6烷氧基、硝基、氰基、C1-C3卤代烷基取代。
其中的R是氢或甲氧基,R1是羟基或OM基团(M=钠或钾),R2是乙酰基的化合物1可以从马比木分离得到:对在不超过50℃、优选35℃的温度下人工干燥的植物材料进行萃取,首先用脂族的酮或脂族的酯,然后用脂族醇萃取。在该操作条件下,可以以高的收率萃取到喜树碱的17-乙酰基衍生物和9-甲氧基-喜树碱酸(camptothecinic acid)。尽管将马比木作为喜树碱的选择性来源对其进行了广泛的研究,但并未鉴定出上述的生物碱,这可能是由于在用不适当溶剂萃取的过程中它们降解成了喜树碱。在脂族醇的存在下,这些生物碱即使是在萃取的中性pH下也很容易转变成喜树碱。
通过在碱性溶媒中选择性乙酰化喜树碱的C17羟基可得到同样的化合物。
所得到的化合物随后又可用作制备其中R2不是乙酰基和/或R1是以上定义的烷氧基、苯氧基或氨基的其它式1化合物或制备FoetidinesⅠ和Ⅱ的原料。为此,可使用制备酯或酰胺的常规方法,例如,将其中R1是OM基团的化合物1与烷基卤化物如溴乙酸乙酯或苄酯反应来制备酯,或将其中R1是OH的化合物1与胺和二环己基碳二亚胺反应来制备酰胺。
化合物1对肿瘤细胞系具有细胞毒性。例如,表1给出了对结肠癌系(HCT116)和对最常用的化疗剂具有抗药性的同种品系(HCT116/VM46)的细胞毒性。结果证实了本发明的化合物比喜树碱更为有效。
表1:17-乙酰基-喜树碱酸和喜树碱的细胞毒性
IC50(nMoles/ml)
HCT116品系 HCT116/VM46品系喜树碱 10.5 96.717-乙酰基-喜树碱酸 8.2 25.3
因此,可将化合物1用作抗肿瘤药物组合物的活性成分与适宜载体如可注射生理溶液混合。剂量可在宽的范围(5-500mg/天)内变动,但原则上为约10mg生物碱/天。
用以下实施例进一步说明本发明。实施例117-乙酰基-喜树碱酸和17-乙酰基-9-甲氧基喜树碱酸的分离
将3Kg马比木种子用无水丙酮在室温下萃取三次(3×31)。将合并的萃取液浓缩至于得到580g蜡状物质,其中含有喜树碱、9-甲氧基-喜树碱和少量的17-乙酰基-喜树碱酸。将用丙酮萃取后的植物材料用甲醇于10℃下再次反复萃取(3×31);将萃取液低温下浓缩后得到200g干燥残余物,将其悬浮于11水中,用500ml正丁醇萃取三次;将合并的丁醇萃取液于不超过30℃的温度下真空浓缩至干。得到28.9g富含17-乙酰基-喜树碱酸和9-甲氧基-17-乙酰基-喜树碱酸的混合物的生物碱馏份,将其用RP18柱进行反相色谱,用甲醇/水和甲醇洗脱得到分别由香豆酰胍基丁胺和喜树碱酸组成的三种馏份。将该馏份进一步通过硅胶纯化得到3.8g 17-乙酰基-喜树碱酸,其具有如下波谱学和物理化学特征:m.p.:258℃,αD=+63.4(c=0.05,H2O);1H-NMR(DMSO-d6)δ:0.85(t,3H,H-18),1.95(m+s,5H,H-19+COCH3),5.20(s,2H,H-17),5.40,60(q,JAB=10.6Hz,H-5),7.65-8.65(m,6H,arom).
9-甲氧基-17-乙酰基-喜树碱酸的量为17-乙酰基-喜树碱酸的五分之一,其具有如下波谱学和物理化学特征:m.p.208℃,αD=56.4(c=0.05H2O)。实施例2从喜树碱制备17-乙酰基-喜树碱酸
将1g喜树碱悬浮在30ml水中,加入340mg氢氧化钠并在40℃下搅拌2小时或直至完全溶解;真空蒸除水并将残余物加入20ml DMF中,反应剧烈;向溶液中逐渐加入600mg乙酸酐并将反应混合物搅拌约2小时。真空蒸除溶剂,残余物在氯仿/甲醇/水5∶6∶4混合物之间进行分配。将甲醇相浓缩至干并将残余物结晶得到具有与实施例1中报道的特征相同的17-乙酰基-喜树碱酸。实施例317-乙酰基喜树碱-21-甲酯
将17-乙酰基喜树碱(100mg,0.25mmol)溶于无水DMF(8ml),向其中加入无水碳酸钾(68mg,0.49mmol)和碘甲烷(69mg,0.49mmol),室温下搅拌20小时。将反应混合物过滤并用氯仿(5ml)洗涤。将滤液用氯仿(10ml)稀释并用水(5ml×3)洗涤。将有机相用无水硫酸钠干燥。过滤后,真空蒸除溶剂并将残余物(170mg)进行闪式色谱(氯仿∶甲醇=9∶1)。得到固体状标题化合物(45mg,收率45%)。1H NMR(CDCl3)δ:1.02(t,J=7Hz,3H,H-18),2.09(s,3H,OCOCH3),2.26-2.45(m,2H,H-19),3.82(s,3H,OCH3),5.38(s,2H,H-5),5.52(s,2H,H-17),7.51-8.42(m,6H,arom)MS(EI) M+ 422m.p.(分解):234-235℃.
按照相同的方法,但用溴乙酸乙酯或溴乙酸叔丁酯代替碘甲烷,得到相应的乙酯(a)或叔丁酯(b):(a)1H NMR(CDCl3)δ:1.10(t,J=7.5Hz,3H,H-18),1.30(t,J=7.5Hz,3H,CH3),2.10(s,3H,OCOCH3),2.30-2.55(m,2H,H-19),4.25(q,J=7.5Hz,2H,CH2),4.70(q,JAB=15Hz,2H,OCOCH2CO),5.32(s,2H,H-5),5.52(s,2H,H-17),7.6(m,5H,arom).(b)1H NMR(CDCl3)δ:1.10(t,J=7.5Hz,3H,H-18),1.46(s,9H,C(CH3)3),2.10(s,3H,OCOCH3),2.35-2.52(m,2H,H-19),4.60(q,JAB=15 Hz,2H, OCOCH2CO),5.30(s,2H,H-5),5.52(s,2H,H-17),7.58-8.38(m,6H,arom).实施例41-脱乙酰基-喜树碱酸,21-酯
将化合物b(60mg,0.11mmol)溶于无水氯仿(2ml)。于0℃及氮气氛下加入碘代三甲基硅烷(33mg,0.17mmol),0℃下搅拌1小时,然后室温搅拌1小时。将反应混合物倒入5%碳酸氢钠溶液(5ml)中。将水相反复用氯仿洗涤,直至氯仿相成为无色。将水相用2.5%盐酸于0℃下中和至pH7并用丁醇(5ml×6)萃取。合并丁醇相并真空蒸发得到残余物(51mg),将其进行闪式硅胶色谱,用氯仿-甲醇洗脱得到标题化合物(11mg)。1H NMR(DMSO-d6)δ:(ppm)0.82(t,J=7Hz,3H,H-18),2.12(s+m,5,H-19 and H-17),4.29(f,JAB=15Hz,2H,5.22(s,2H,H-5),6.62(s,1H,OH),7.50-8.62(m,6H,arom).13C NMR (DMSO-d6)δ:(ppm)7.7(t,C-19),13.7(t,C-17),30.01(f,C-18),50.2(f,C-5),63.9(f,C-5),77.5(s,C-20),99.1(d,C-14),125.9(s,C-16),127.3(d,C-10),127.8(s,C-8),128.6(d,C-9),128.9(d,C-12),129.7(s,C-6),130.3(d,C-11),131.4(d,C-7),141.3(s,C-3),148.0(s,C-13),150.7(s,C-15),153.9(s,C-2),160.8(s,16a),171.0(s,
172.8(s,C-21).
Claims (7)
2.根据权利要求1的化合物,其中R是氢或甲氧基,R1是羟基或OM基团(M=钠或钾),R2是乙酰基。
3.权利要求2的化合物作为中间体的用途。
4.权利要求2化合物的制备方法,包括将预先在低于50℃的温度下干燥的马比木植物材料用脂族的酮或脂族的酯萃取,然后用脂族醇萃取。
5.权利要求2化合物的制备方法,包括将喜树碱的C17羟基在碱性溶媒中选择性乙酰化。
6.权利要求1化合物的制备方法,包括将权利要求2的化合物用已知方法酯化或酰胺化。
7.含有权利要求1或2的化合物作为活性成分的药物组合物用于制备抗肿瘤细胞毒性药物。
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Application Number | Priority Date | Filing Date | Title |
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IT96MI000944A IT1283635B1 (it) | 1996-05-10 | 1996-05-10 | Composti a scheletro camptotecinico isolati da mappia foetida e loro uso come sintoni per farmaci o come principi attivi |
ITMI96A000944 | 1996-05-10 |
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CN1218474A true CN1218474A (zh) | 1999-06-02 |
CN1082509C CN1082509C (zh) | 2002-04-10 |
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CN97194492A Expired - Fee Related CN1082509C (zh) | 1996-05-10 | 1997-05-02 | 从马比木分离的喜树碱骨架化合物及其作为新药物及治疗剂的合成子的用途 |
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US (1) | US6121277A (zh) |
EP (1) | EP0912573B1 (zh) |
JP (1) | JP3483257B2 (zh) |
KR (1) | KR20000010893A (zh) |
CN (1) | CN1082509C (zh) |
AT (1) | ATE211140T1 (zh) |
AU (1) | AU715482B2 (zh) |
CA (1) | CA2253914C (zh) |
CZ (1) | CZ287901B6 (zh) |
DE (1) | DE69709357T2 (zh) |
DK (1) | DK0912573T3 (zh) |
ES (1) | ES2169389T3 (zh) |
HK (1) | HK1019600A1 (zh) |
IT (1) | IT1283635B1 (zh) |
NO (1) | NO311839B1 (zh) |
PL (1) | PL188228B1 (zh) |
PT (1) | PT912573E (zh) |
RU (1) | RU2169149C2 (zh) |
SK (1) | SK283050B6 (zh) |
WO (1) | WO1997043290A1 (zh) |
Families Citing this family (7)
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FR2792937B1 (fr) | 1999-04-27 | 2001-08-10 | Cemaf | NOUVEAUX DERIVES DE PYRROLO-(3,4-b) QUINOLEINE, LEUR PROCEDE DE PREPARATION ET LEUR UTILISATION A TITRE DE MEDICAMENT |
JP4776843B2 (ja) | 1999-10-01 | 2011-09-21 | イムノゲン インコーポレーティッド | 免疫複合体及び化学療法剤を用いる癌治療用組成物及び方法 |
JP2006528691A (ja) * | 2003-05-12 | 2006-12-21 | パーデュー・リサーチ・ファウンデーション | 細胞傷害性インデノおよびイソインドロイソキノロン |
ITMI20051348A1 (it) * | 2005-07-14 | 2007-01-15 | Indena Spa | Analoghi della camptotecina loro processo di ottenimento loro uso e formulazioni che li contengono |
CN100339377C (zh) * | 2005-09-05 | 2007-09-26 | 合肥中科大生物技术有限公司 | 喜树碱衍生物及其制备 |
CN1319971C (zh) * | 2005-09-09 | 2007-06-06 | 合肥中科大生物技术有限公司 | 喜树碱衍生物及其用途 |
US9888690B2 (en) * | 2011-06-22 | 2018-02-13 | Council Of Scientific & Industrial Research | Insecticidal compounds from Nothapodites foetida and process for the extraction thereof |
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IT1269862B (it) * | 1994-05-30 | 1997-04-15 | Indena Spa | Alcaloidi da mappia foetida, loro uso e formulazioni che li contengono |
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1996
- 1996-05-10 IT IT96MI000944A patent/IT1283635B1/it active IP Right Grant
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1997
- 1997-05-02 KR KR1019980709040A patent/KR20000010893A/ko not_active Application Discontinuation
- 1997-05-02 PL PL97329765A patent/PL188228B1/pl not_active IP Right Cessation
- 1997-05-02 EP EP97922937A patent/EP0912573B1/en not_active Expired - Lifetime
- 1997-05-02 CZ CZ19983620A patent/CZ287901B6/cs not_active IP Right Cessation
- 1997-05-02 CN CN97194492A patent/CN1082509C/zh not_active Expired - Fee Related
- 1997-05-02 US US09/155,960 patent/US6121277A/en not_active Expired - Fee Related
- 1997-05-02 AT AT97922937T patent/ATE211140T1/de not_active IP Right Cessation
- 1997-05-02 JP JP54044797A patent/JP3483257B2/ja not_active Expired - Fee Related
- 1997-05-02 PT PT97922937T patent/PT912573E/pt unknown
- 1997-05-02 ES ES97922937T patent/ES2169389T3/es not_active Expired - Lifetime
- 1997-05-02 AU AU28901/97A patent/AU715482B2/en not_active Ceased
- 1997-05-02 RU RU98122224/04A patent/RU2169149C2/ru not_active IP Right Cessation
- 1997-05-02 CA CA002253914A patent/CA2253914C/en not_active Expired - Fee Related
- 1997-05-02 DK DK97922937T patent/DK0912573T3/da active
- 1997-05-02 SK SK1540-98A patent/SK283050B6/sk not_active IP Right Cessation
- 1997-05-02 WO PCT/EP1997/002244 patent/WO1997043290A1/en not_active Application Discontinuation
- 1997-05-02 DE DE69709357T patent/DE69709357T2/de not_active Expired - Lifetime
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1998
- 1998-11-06 NO NO19985186A patent/NO311839B1/no not_active IP Right Cessation
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1999
- 1999-10-27 HK HK99104790A patent/HK1019600A1/xx not_active IP Right Cessation
Also Published As
Publication number | Publication date |
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DE69709357T2 (de) | 2002-08-22 |
CA2253914C (en) | 2002-10-22 |
DK0912573T3 (da) | 2002-04-15 |
ATE211140T1 (de) | 2002-01-15 |
IT1283635B1 (it) | 1998-04-23 |
PL329765A1 (en) | 1999-04-12 |
DE69709357D1 (de) | 2002-01-31 |
CZ362098A3 (cs) | 1999-06-16 |
RU2169149C2 (ru) | 2001-06-20 |
JP2000503666A (ja) | 2000-03-28 |
KR20000010893A (ko) | 2000-02-25 |
AU2890197A (en) | 1997-12-05 |
NO985186D0 (no) | 1998-11-06 |
PT912573E (pt) | 2002-06-28 |
SK283050B6 (sk) | 2003-02-04 |
ES2169389T3 (es) | 2002-07-01 |
EP0912573A1 (en) | 1999-05-06 |
NO985186L (no) | 1998-11-06 |
PL188228B1 (pl) | 2004-12-31 |
WO1997043290A1 (en) | 1997-11-20 |
HK1019600A1 (en) | 2000-02-18 |
ITMI960944A0 (zh) | 1996-05-10 |
JP3483257B2 (ja) | 2004-01-06 |
CZ287901B6 (cs) | 2001-03-14 |
AU715482B2 (en) | 2000-02-03 |
CN1082509C (zh) | 2002-04-10 |
EP0912573B1 (en) | 2001-12-19 |
NO311839B1 (no) | 2002-02-04 |
US6121277A (en) | 2000-09-19 |
ITMI960944A1 (it) | 1997-11-10 |
CA2253914A1 (en) | 1997-11-20 |
SK154098A3 (en) | 1999-04-13 |
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