CN1130356C - 具有抗肿瘤活性的半合成断紫杉烷 - Google Patents
具有抗肿瘤活性的半合成断紫杉烷 Download PDFInfo
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- CN1130356C CN1130356C CN00129055A CN00129055A CN1130356C CN 1130356 C CN1130356 C CN 1130356C CN 00129055 A CN00129055 A CN 00129055A CN 00129055 A CN00129055 A CN 00129055A CN 1130356 C CN1130356 C CN 1130356C
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- 230000000118 anti-neoplastic effect Effects 0.000 title 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical group NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 7
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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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
本发明涉及新的衍生物，它通过氧化和立体选择性还原10-脱乙酰基浆果赤霉素III，然后用不同取代的异丝氨酸链酯化制备紫杉醇类似物而得到。本发明的产物具有细胞毒性和抗肿瘤活性，且在适当配制时可通过注射和/或口服给药。
Description
本申请是申请日为1995年7月21日的中国专利申请95194333.2的分案申请，原案的发明名称为“具有抗肿瘤活性的半合成紫杉烷”。
发明领域
本发明涉及新的半合成紫杉烷衍生物，含有该衍生物的药物组合物及其制备治疗癌症药物的用途。
发明背景
具有紫杉烷(taxane)骨架的双萜，特别是紫杉醇，已知对人类许多肿瘤有抗肿瘤活性。但是，在使用这些药物时，特别是紫杉醇，由于产生不希望的副作用而导致使用上的缺点，而且由于这些抗肿瘤疗法很快引起耐受性，因此，开发新的能减少这类临床问题的分子是人们研究的热点。WO93/02067(Nippon Steel，1993年2月4日)公开了例如10-α-乙酰基紫杉醇，它从紫杉属的白蛋白组织培养物中提取出来，具有显著的细胞毒性。
发明内容
本发明涉及半合成得到的新的紫杉烷骨架的衍生物，它们具有很强的抗肿瘤活性。本发明的衍生物具有通式(I)：
它们可分成两个系列：a)在11，12位之间含有烯属双键和在10α-位为羟基或酰氧基的紫
(1a)(R3＝H；R4＝OH或酰氧基)b)在11和12位的碳原子之间含有单键，在12位的甲基为α-取向的，且在10β位为羟基或酰氧基的紫杉烷衍生物(式1b的紫杉烷)。
(1b)(R3＝OH或酰氧基；R4＝H)
在通式(1)的紫杉烷中，R1和R2可相同或不同，可以是C1-C8基，C2-C8链烯基，芳基(优选苯基)或杂芳基。R2也可以是叔丁氧基。
在通式(1a)化合物中，R3是氢，R4是羟基或C2-C8酰氧基。
在通式(1b)化合物中，R3是羟基或C2-C8酰氧基，且R4是氢。
通式(1)的紫杉烷可通过使用适当活化的异丝氨酸链作为酰化试剂在通式(2)的新合成子(syntones)的13-位酯化而制备，制备可按照半合成紫杉醇及其类似物的文献中描述的方法进行(参见，例如，EP-A-400971，1992，Fr.Dem.86，10400；E.Didier等，TetrahedronLetters 35，2349，1994；E.Didier等，ibid.35，3063，1994)。
在通式(2)中其中：
当11，12位之间存在烯属双键时，R3是氢原子，R4和R5是羟基，C2-C8酰氧基，烷基甲硅烷氧基或2，2，2-三氯乙氧羰氧基；
当11，12位之间不存在烯属双键时，12-位的甲基是α-取向的，R4是氢原子，R3和R5是羟基，C2-C8酰氧基，烷基甲硅烷氧基或2，2，2-三氯乙氧羰氧基。
具体地讲，通式(2a)的合成子用于合成通式(1a)的新的紫杉烷。另一方面，通式(2b)的合成子用于合成通式(1b)的新的紫杉烷。
在合成子(2a)中，在11和12位之间有烯属双键，在10α-位有C2-C8酰氧基或任意被保护的羟基。因此，在合成子(2a)中，R3是氢，R4和R5是羟基，酰氧基，烷基甲硅烷氧基(如三乙基甲硅烷氧基，O-TES)或2，2，2-三氯乙氧羰基氧基(O-CO-O-CH2CCl3，O-TROC)。
在合成子(2b)中，11-位和12-位的碳原子以单键相连，12-位的甲基是α-取向的，且在10α位有酰氧基或任意保护的羟基。因此，在合成子(2b)中，R4是氢，R3和R5是羟基，酰氧基，烷基甲硅烷氧基(如三乙基甲硅烷氧基，O-TES)或2，2，2-三氯乙氧羰基氧基(O-CO-O-CH2CCl3，O-TROC)。
在合成子(2)的13-位用异丝氨酸链酯化后，使用本领域的常规方法除去保护基，从而得到式(1)的新的紫杉烷。
10-脱乙酰基浆果赤霉素III(3)，可从浆果紫杉的叶子中分离得到(G.Chauvière et coll.，C.R.Acad.Sc.Ser.III，293；591[1981])，是用于制备合成子(2a)和(2b)的唯一起始物。
文献中未知的合成子(2a)可通过(反应流程1)从(3)得到，它是通过用乙酸铜(II)氧化(3)的10-位，得到二酮(4)，然后在铈(III)盐存在下用硼氢化钠还原得到。
所得产物(2a，R3＝H，R4＝R5＝OH)，它是(3)的10-位的差向异构体，在7-位和10-位适当进行保护，并用于合成紫杉烷(1a)。
反应流程1
在反应流程1中得到的副产物是新的断紫杉烷(secotaxane)(5)。
断紫杉烷(5)可用于合成具有潜在抗肿瘤活性的其他紫杉烷。
本发明还涉及半合成制备的新的断紫杉烷骨架的衍生物，它具有强的抗肿瘤活性。所述衍生物具有通式(5a)。
其中：
R1和R2，可以相同或不同，可以是C1-C20烷基，C2-C8链烯基，芳基(优选苯基)或杂芳基。R2也可以是叔丁氧基。
通式(5a)的紫杉烷可通过使用适当活化的异丝氨酸链作为酰化试剂在通式(5)化合物的13-位酯化而制备，如在半合成紫杉醇及其类似物的文献中报道的(参见，例如EP-A-400，971；E.Didier等，Tetrahedron Letters 35，2349，1994；E.Didier等，ibid.35，3063，1994)。可按传统方法，用合适的保护基将通式(5)化合物的羟基任意性地保护起来。
在化合物(5)的13-位用异丝氨酸链酯化后，使用文献中的常规方法除去保护基，就可得到通式(5a)的断紫杉烷。
合成子(2b)，在文献中是未知的，也可从10-脱乙酰基浆果赤霉素III(3)(反应流程2)得到。已发现可通过用间氯过苯甲酸(MCPBA)氧化(3)，得到相应的13-酮衍生物(6)。用三乙基甲硅烷基氯(TESCl)保护7-位羟基后，在铈(III)盐存在下用硼氢化钠还原，由(6)得到合成子(2b)(R3＝OH，R4＝H，R5＝O-TES)，它可用于合成式(1b)的紫杉烷。在合成子(2b)中，12-位α-取向的甲基可通过使用核磁共振的研究推断出来。
反应流程2
根据本发明的产物对不同肿瘤细胞系的细胞毒性效果进行筛选，其作用与紫杉醇相比较。表1显示了IC50数据的比较，即对化合物13-[(2R，3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-10-表-10-脱乙酰基浆果赤霉素III(1a，R1＝Ph，R2＝tBuO，R3＝H，R4＝OH)，13-[(2R，3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-10-脱乙酰基-11，12-二氢浆果赤霉素III(1b，R1＝Ph，R2＝tBu0，R3＝OH，R4＝H)，13-[(2R，3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素III(5a，R1＝Ph，R2＝tBuO)和13-[(2R，3S)-3-异丁基-2-羟基-3-己酰基氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素III(5a，R1＝异丁基，R2＝戊基)的数据与紫杉醇中得到的数据进行比较。
表1-紫杉烷1a(R1＝Ph，R2＝tBuO，R3＝H，R4＝OH)，1b(R1＝Ph，R2＝tBuO，R3＝OH，R4＝H)和紫杉醇对6种细胞系的IC50。
暴露时间 紫杉醇 1a 1b
(h) (R1＝Ph，R2＝tBuO，(R1＝Ph，R2＝tBuO，
R3＝H，R4＝OH) R3＝OH，R4＝H)L1210(鼠白血病) 48 57.0±3.0 46.0±2.1 32.0±0.1A121(人卵巢) 72 3.7±0.3 2.8±0.3 1.6±0.2A549(人NSCLC) 72 5.4±0.5 6.9±0.3 2.1±0.3HT-29(人结肠) 72 6.0±0.6 3.4±0.1 3.6±0.4HCF7(人乳房) 72 4.3±0.1 2.2±0.2 0.8±0.2HCF7-ADR(抗药性的) 72 395.0±8.7 130.0±2.2 128.0±6.2标准条件：培养基RPMI1640+20mM HEPES+2mM L-谷氨酰胺。
表1-续紫杉烷5a(R1＝Ph，R2＝tBuO)，5a(R1＝异丁基，R2＝戊基)和紫杉醇对6种细胞系的IC50。
暴露时间 紫杉醇 5a 5a
(h) (R1＝Ph， (R1＝异丁基，
R2＝tBuO) R2＝戊基)L1210(鼠白血病) 48 57.0±3.0 35±1.2 26±1.3A121(人卵巢) 72 3.7±0.3 1.9±0.2 1.3±0.1A549(人NSCLC) 72 5.4±0.5 3.3±0.4 2.6±0.3HT-29(人结肠) 72 6.0±0.6 3.2±0.3 2.7±0.2HCF7(人乳房) 72 4.3±0.1 1.5±0.2 1.1±0.2HCF7-ADR(抗药性的) 72 395.0±8.7 31.3±4.2 25.4±3.7标准条件：培养基RPMI1640+20mM HEPES+2mM L-谷氨酰胺
在异丝氨酸链上有不同取代基的化合物作用相似。这些化合物对于对其它抗肿瘤物质如阿霉素和顺铂(cis-platinum)有抗药性的细胞系的作用比紫杉醇具有惊人的优越性。在体内模型中这些化合物与紫杉醇的不同更为明显，如种植了人肿瘤细胞的无胸腺裸鼠。另外，我们还惊奇的发现，本发明的R2为烷基或链烯基的化合物完全无心脏毒性，不象紫杉醇和其已知的衍生物，因此，它们可有效地用于不能用紫杉醇和其已知衍生物治疗的心脏病患者。
本发明的化合物适于与适当的药用制剂结合用于非肠道和口服给药。对于静脉内给药而言，主要使用聚乙氧基化蓖麻油和乙醇的混合物，或用天然磷脂酰胆碱制成的脂质体制剂或天然磷脂与胆固醇的混合物。
具体实施方式
下面的实施例将进一步详述本发明。实施例1 10-脱氢-10-脱乙酰基浆果赤霉素III(4)的制备。
将10g10-脱乙酰基浆果赤霉素III(3)悬浮于350ml甲醇中，向其中加入Cu(OAc)265g。将悬浮液在室温连续搅拌120小时。滤除盐，溶液用100g硅胶色谱纯化，用6∶4己烷/乙酸乙酯混合物洗脱。用里格罗因(ligroin)结晶，得到9.5g(4)化合物。M+为m/z 542。实施例2制备10-脱乙酰基-10-表浆果赤霉素III(2a，R3＝H，R4＝R5＝OH)和C-断-10-脱乙酰基浆果赤霉素III(5)。
向300mg(4)的5ml甲醇溶液中加入一当量CeCl3·3H2O，室温搅拌5分钟，然后加入80mg NaBH4。溶液用NH4Cl溶液处理，用乙酸乙酯萃取，并用硅胶色谱纯化，用3∶7己烷/乙酸乙酯混合物洗脱。得到98mg(2a)(M+在m/z 544)和120mg(5)(M+在m/z 546)。10-脱乙酰基-10-表浆果赤霉素III具有1H-NMR(CDCl3)如下：H2，d 5.68 J 6.8；H3，d 4.26J 6.8；H5，d 5.03 J 7.1；H7/13，m 4.76；H10，br s 5.20；10 OH，br s3.44；H16，s 1.14；H17，s 1.68；H18，s 2.22；H19，s 1.13；H20a，d4.33；H20b，d 4.18；Ac，s 2.31；Bnz，br 8.12 J 8，br t 7.60 J 8，br t17.49 J 8.实施例3制备10-脱乙酰基-13-脱氢浆果赤霉素III(6)。
向1g10-脱乙酰基浆果赤霉素III(3)在100mlCH2Cl2中的悬浮液中加入3g间氯过苯甲酸和1g乙酸钠。将此悬浮液在室温连续搅拌120小时，然后用5％Na2CO3水溶液稀释。有机相用5％Na2CO3洗涤并蒸发至于，剩余物用硅胶色谱纯化，用3∶7己烷/乙酸乙酯混合物洗脱。得到789mg(6)，M+在m/z 542。实施例4制备10-脱乙酰基-11，12-二氢-7-三乙基甲硅烷基-浆果赤霉素III(2b，R3＝OH，R4＝H，R5＝O-TES)。
将1.6g(6)溶于二氯甲烷中并加入370mg4-二甲基氨基吡啶和2.5ml三乙基甲硅烷基氯。室温保持2小时后，将反应混合物用二氯甲烷稀释并用水洗涤。有机相浓缩至干。得到1.72g剩余物，用150ml95％乙醇溶解，并用9gNaBH4处理。3小时后混合物用NH4Cl溶液稀释，产物用乙酸乙酯萃取。用硅胶色谱纯化，使用7∶3己烷/乙酸乙酯洗脱，得到800mg(2b)(R3＝OH，R4＝H，R5＝O-TES)。实施例5制备11，12-二氢-7-TES-浆果赤霉素III(2b，R3＝OH，R4＝H，R5＝O-TES)和11，12-二氢浆果赤霉素III(2b，R3＝OAc，R4＝H，R5＝OH)
将500mg10-脱乙酰基-11，12-二氢-7-三乙基甲硅烷基浆果赤霉素III(2b，R3＝OH，R4＝H，R5＝O-TES)与3当量的乙酰氯在无水吡啶中在0℃反应6小时。反应混合物用水稀释并用二氯甲烷萃取。蒸发溶剂后，剩余物用丙酮/己烷结晶。得到510mg11，12-二氢-7-TES浆果赤霉素III，M+为m/z 702 III。将产物溶于甲醇并用稀HCl处理至完全脱甲硅基化。反应混合物用水稀释，用乙酸乙酯萃取，并用含水甲醇结晶。得到400mg11，12-二氢浆果赤霉素III，M+为m/z 588。实施例6制备13-[(2R，3S)-3-苯基-2-羟基-3叔丁氧羰基氨基-丙酰基]-11，12-二氢浆果赤霉素III(1b，R2＝Ph，R2＝tBuO，R3＝OAc，R4＝H)。
将500mg11，12-二氢浆果赤霉素III(2b，R3＝OAc，R4＝H，R5＝O-TES)溶于20ml甲苯中，与0.45g(4S，5R)-N-叔丁氧羰基-2，2-二甲基-苯基-5-噁唑烷羧酸，二环己基碳化二亚胺(1.03eq)和N，N-二甲基氨基吡啶(0.2eq)在80℃反应2小时。反应混合物用水洗涤直至除去过量的反应试剂，然后浓缩至干。剩余物用含1％甲酸的甲醇在室温处理4小时。甲醇溶液用水稀释，中和，并用乙酸乙酯萃取。有机相浓缩至干，剩余物用含1.5eq碳酸二叔丁基酯和碳酸氢钠在15ml四氢呋喃中的溶液处理。反应混合物用水稀释，用乙酸乙酯萃取，将复合乙酸相(heteroacetic phase)浓缩至于。剩余物用盐酸酸化的甲醇溶解以完成脱甲硅基化。溶液用水稀释，用乙酸乙酯萃取。蒸发复合乙酸相得到的剩余物用硅胶色谱纯化，1∶1丙酮/己烷混合物洗脱以除去反应杂质。得到580mg产物，M+为m/z 851。实施例7制备13-[(2R，3S)-3-苯甲酰氨基-3-苯基-2-羟基丙酰基]-11，12-二氢浆果赤霉素III(1b，R1＝R2＝Ph，R3＝OAc，R4＝H)。
将500mg11，12-二氢-7-TES-浆果赤霉素(2b，R3＝OAc，R4＝H，R5＝O-TES)溶于20ml甲苯，并与1.5g(4S，5R)-N-苯甲酰基-2，2-二甲基-4-苯基-5-噁唑烷羧酸，二环己基碳化二亚胺(1.03eq)和N，N-二甲基氨基吡啶(0.2eq)在80℃反应2小时.反应混合物用水洗条直至除去过量的反应试剂，然后浓缩至干。剩余物用含1％甲酸的甲醇在室温处理4小时。甲醇溶液用水稀释，中和，并用乙酸乙酯萃取。有机相浓缩至干，剩余物用盐酸酸化的甲醇溶解以完成脱甲硅基化。溶液用水稀释并用乙酸乙酯萃取。蒸发复合乙酸相得到的剩余物用硅胶色谱纯化，1∶1丙酮/己烷混合物洗脱以除去反应杂质。得到530mg产物，M+为m/z 855。实施例8制备13-[(2R，3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-10-表-10-脱乙酰基浆果赤霉素III(1a，R2＝Ph，R2＝tBuO，R3＝H，R4＝OH)。
将500mg10-脱乙酰基-10-表浆果赤霉素III(2a，R3＝H，R4＝R5＝OH)溶于15ml无水吡啶，并用三当量三氯乙氧羰基氯(TROC-Cl)在80℃处理5分钟，然后冷却到室温。加入1ml甲醇分解过量的TROC-Cl。溶液用冰水稀释并用氯仿萃取，用稀盐酸溶液洗涤有机相。有机相蒸发至干，剩余物用含三当量(4S，5R)-N-叔丁氧羰基-2，2-二甲基-4-苯基-5-噁唑烷羰酸，3当量二环己基碳化二亚胺和0.2当量N，N-二甲基氨基吡啶的甲苯溶液在室温处理24小时。反应混合物用水洗涤，有机相在真空下蒸发至干，剩余物溶于甲醇，并用一当量对甲苯磺酸处理48小时，之后用水稀释，并用乙酸乙酯萃取。有机相在真空下蒸发，剩余物溶于1∶1的乙酸/乙酸乙酯混合物200ml中，并用11当量锌粉在30℃处理3小时。滤除固体物质，溶液用水稀释，周乙酸乙酯萃取并用硅胶色谱纯化，用1∶4乙酸乙酯/己烷混合物洗脱。得到512mg产物(1a)，M+为m/z 807。实施例9制备7，9-二(三乙基甲硅烷基)-C-断-10-脱乙酰基浆果赤霉素III
向(5)(200mg，0.37mmol)在无水二甲基甲酰胺(DMF)(5ml)中的溶液中加入咪唑(75mg，1.11mmol，3eq.mol)和三乙基甲硅烷基氯(TES)(186ml，167.3mg，1.11mmol，3eq.mol)，反应混合物在室温搅拌10分钟。用TLC检测反应(3∶7己烷-乙酸乙酯，起始物的Rf为0.10，产物的Rf为0.80)。加入水和CeliteR终止反应，过滤沉淀并用水洗涤以除去DMF，然后用CHCl3洗涤以取出产物。用柱色谱(9∶1己烷/乙酸乙酯洗脱硅烷醇，6∶4己烷/乙酸乙酯洗脱出产物)纯化，得到146mg标题化合物(51％)。实施例10制备13-[(2R，3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素III(5a，R1＝Ph，R2＝tBuO)。
向实施例9的产物(126mg，0.16mmol)在无水甲苯(5ml)中的溶液中加入67.5mg二环己基碳化二亚胺(0.327mmol，2mol.eq.)，105mg(4S，5R)-N-Boc-2-(2，4-二甲氧苯基)-4-苯基-5-噁唑烷羧酸(0.327mmol，2mol.eq.)和5mg4-二甲基氨基吡啶。混合物在60℃加热24小时，然后用饱和NaHCO3水溶液和乙酸乙酯稀释。剩余物用柱色谱纯化(8∶2己烷-乙酸乙酯)得到175mg 13-酯(95％)。剩余物用50ml甲醇/HCl(0.01％)溶解，且反应混合物在室温保留1小时。溶液碱化至pH5，并在真空下浓缩至干。剩余物用硅胶柱色谱纯化，98∶2二氯甲烷-甲醇混合物洗脱。用乙酸乙酯结晶后，得到85mg标题化合物。实施例11制备13-[(2R，3S)-3-异丁基-2-羟基-3-己酰氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素III(5a，R1＝异丁基，R2＝戊基)。
向实施例9的产物(126mg，0.16mmol)在无水甲苯(5ml)中的溶液中加入67.5mg二环己基碳化二亚胺(0.327mmol，2mol.eq.)，140mg(4S，5R)-N-己酰基-2-(2，4-二甲氧苯基)-4-异丁基-5-噁唑烷羧酸(0.327mmol，2mol.eq)和5mg4-二甲基氨基吡啶。混合物在60℃加热24小时，然后用饱和NaHCO3水溶液和乙酸乙酯稀释。剩余物用柱色谱纯化(8∶2己烷-乙酸乙酯)得到175mg 13-酯(95％)。剩余物用50ml甲醇/HCl(0.01％)溶解，且反应混合物在室温保留1小时。溶液碱化至pH5，并在真空下浓缩至干。剩余物用硅胶柱色谱纯化，用98∶2二氯甲烷-甲醇混合物洗脱，用乙酸乙酯结晶后，得到88mg标题化合物。
Claims (6)
1.一种通式5a的半合成断紫杉烷其中：
R1和R2可相同或不同，它们是C1-C5烷基或苯基，R2也可以是叔丁氧基。
2.权利要求1的化合物，为13-[(2R，3S)-3-苯基-2-羟基-3-叔丁氧羰基氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素III，具有通式5a，
其中R1＝苯基，R2＝叔丁氧基。
3.权利要求1的化合物，为13-[(2R，3S)-3-异丁基-2-羟基-3-己酰氨基-丙酰基]-C-断-10-脱乙酰基浆果赤霉素III，具有通式5a，其中R1＝异丁基，R2＝戊基。
4.一种制备权利要求1的化合物的方法，其中将通式5化合物用在异丝氨酸链上适当活化的和/或保护的衍生物按常规方法进行酯化，从而在13位引入酰基，其中R1和R2定义如权利要求1，和然后按照常规方法除去保护基。
5.含有权利要求1中的紫杉烷的药物组合物。
6.权利要求1中的紫杉烷用于制备治疗癌症的药物。
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI94A001592 | 1994-07-26 | ||
| ITMI941592A IT1274356B (it) | 1994-07-26 | 1994-07-26 | Tassani semisintetici odtati di attivita' antitumorale |
| IT95RM000413A IT1278108B1 (it) | 1995-06-19 | 1995-06-19 | Secotassani dotati di attivita' antitumorale. |
| ITRM95A000413 | 1995-06-19 |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95194333A Division CN1073105C (zh) | 1994-07-26 | 1995-07-21 | 具有抗肿瘤活性的半合成紫杉烷 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1308073A CN1308073A (zh) | 2001-08-15 |
| CN1130356C true CN1130356C (zh) | 2003-12-10 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN95194333A Expired - Fee Related CN1073105C (zh) | 1994-07-26 | 1995-07-21 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129054A Expired - Fee Related CN1120161C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129056A Expired - Fee Related CN1128795C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129055A Expired - Fee Related CN1130356C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成断紫杉烷 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN95194333A Expired - Fee Related CN1073105C (zh) | 1994-07-26 | 1995-07-21 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129054A Expired - Fee Related CN1120161C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
| CN00129056A Expired - Fee Related CN1128795C (zh) | 1994-07-26 | 2000-09-29 | 具有抗肿瘤活性的半合成紫杉烷 |
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|---|---|
| US (1) | US5756776A (zh) |
| EP (1) | EP0773938B1 (zh) |
| JP (1) | JP2986550B2 (zh) |
| KR (1) | KR100220490B1 (zh) |
| CN (4) | CN1073105C (zh) |
| AT (1) | ATE176464T1 (zh) |
| AU (1) | AU684218B2 (zh) |
| BG (1) | BG62851B1 (zh) |
| CA (1) | CA2195844C (zh) |
| CZ (1) | CZ293076B6 (zh) |
| DE (1) | DE69507702T2 (zh) |
| DK (1) | DK0773938T3 (zh) |
| ES (1) | ES2126919T3 (zh) |
| FI (1) | FI120398B (zh) |
| GR (1) | GR3029309T3 (zh) |
| HK (1) | HK1011687A1 (zh) |
| HU (1) | HU222496B1 (zh) |
| NO (1) | NO315116B1 (zh) |
| PL (1) | PL187579B1 (zh) |
| RO (2) | RO115875B1 (zh) |
| RU (1) | RU2134688C1 (zh) |
| SI (1) | SI9520078B (zh) |
| SK (1) | SK281526B6 (zh) |
| WO (1) | WO1996003394A1 (zh) |
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| US6107332A (en) | 1995-09-12 | 2000-08-22 | The Liposome Company, Inc. | Hydrolysis-promoting hydrophobic taxane derivatives |
| US6395770B1 (en) * | 1995-10-26 | 2002-05-28 | Baker Norton Pharmaceuticals, Inc. | Method and compositions for administering taxanes orally to human patients |
| FR2745814B1 (fr) * | 1996-03-06 | 1998-04-03 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
| EP0868422A1 (de) * | 1996-09-24 | 1998-10-07 | Marigen S.A. | Ultramikroemulsionen aus spontan dispergierbaren konzentraten mit antitumoral und antiviral wirksamen estern von baccatin-iii-verbindungen |
| US5773464A (en) * | 1996-09-30 | 1998-06-30 | Bristol-Myers Squibb Company | C-10 epoxy taxanes |
| US5977386A (en) * | 1996-12-24 | 1999-11-02 | Bristol-Myers Squibb Company | 6-thio-substituted paclitaxels |
| US5902822A (en) * | 1997-02-28 | 1999-05-11 | Bristol-Myers Squibb Company | 7-methylthiooxomethyl and 7-methylthiodioxomethyl paclitaxels |
| US5912264A (en) * | 1997-03-03 | 1999-06-15 | Bristol-Myers Squibb Company | 6-halo-or nitrate-substituted paclitaxels |
| US6017935A (en) * | 1997-04-24 | 2000-01-25 | Bristol-Myers Squibb Company | 7-sulfur substituted paclitaxels |
| PL337064A1 (en) * | 1997-05-27 | 2000-07-31 | Baker Norton Pharma | Method of and compositions for orally administering taxanes to human beings |
| IT1308636B1 (it) * | 1999-03-02 | 2002-01-09 | Indena Spa | Procedimento per la preparazione di tassani da 10-desacetilbaccatinaiii. |
| CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| IT1317731B1 (it) * | 2000-01-18 | 2003-07-15 | Indena Spa | Tassani semisintetici con attivita' antitumorale ed antiangiogenetica. |
| US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
| EP1129991A1 (de) * | 2000-03-02 | 2001-09-05 | Degussa AG | Verfahren zur Herstellung eines titanhaltigen Zeolithen |
| US7064980B2 (en) * | 2003-09-17 | 2006-06-20 | Sandisk Corporation | Non-volatile memory and method with bit line coupled compensation |
| SV2006002010A (es) * | 2004-02-13 | 2006-08-23 | Univ Florida State Res Found | Taxanos sustituidos con esteres de ciclopentilo en c10 |
| JP2008530122A (ja) * | 2005-02-14 | 2008-08-07 | フロリダ・ステイト・ユニバーシティ・リサーチ・ファウンデイション・インコーポレイテッド | Ｃ１０シクロプロピルエステル置換タキサン組成物 |
| ITMI20050415A1 (it) * | 2005-03-15 | 2006-09-16 | Indena Spa | Derivati tassanici semi-sintetici ad attivita' antitumorale |
| ITMI20062479A1 (it) * | 2006-12-21 | 2008-06-22 | Indena Spa | Processo per la preparazione di secotassani |
| WO2009023967A1 (en) * | 2007-08-22 | 2009-02-26 | 6570763 Canada Inc. | Process for converting 9-dihydro-13-acetylbaccatin iii into docetaxel or paclitaxel |
| EP2276755A4 (en) * | 2008-03-31 | 2011-05-04 | Univ Florida State Res Found | C (10) -ETHYESTER- AND C (10) -CYCLOPROPYLESTER-SUBSTITUTED TAXANES |
| KR101671537B1 (ko) | 2008-08-11 | 2016-11-01 | 넥타르 테라퓨틱스 | 다분지형 중합체 알카노에이트 컨쥬게이트 |
| WO2012088391A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Non-ring hydroxy substituted taxanes and methods for synthesizing the same |
| WO2012088422A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
| WO2012088445A1 (en) | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
| WO2012088433A1 (en) * | 2010-12-22 | 2012-06-28 | Nektar Therapeutics | Deuterated and/or fluorinated taxane derivatives |
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| US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
| CA2092705C (en) * | 1991-07-17 | 1995-11-07 | Koji Saito | Compound having antitumor activity, nsc-lsc1, and process for producing the same |
| US5399726A (en) * | 1993-01-29 | 1995-03-21 | Florida State University | Process for the preparation of baccatin III analogs bearing new C2 and C4 functional groups |
| FR2688499B1 (fr) * | 1992-03-10 | 1994-05-06 | Rhone Poulenc Rorer Sa | Procede de preparation de la beta-phenylisoserine et de ses analogues. |
| US5200534A (en) * | 1992-03-13 | 1993-04-06 | University Of Florida | Process for the preparation of taxol and 10-deacetyltaxol |
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