CN1204886C - 硫代秋水仙素和浆果赤霉素的缩合衍生物及其组合物 - Google Patents
硫代秋水仙素和浆果赤霉素的缩合衍生物及其组合物 Download PDFInfo
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- CN1204886C CN1204886C CNB018064434A CN01806443A CN1204886C CN 1204886 C CN1204886 C CN 1204886C CN B018064434 A CNB018064434 A CN B018064434A CN 01806443 A CN01806443 A CN 01806443A CN 1204886 C CN1204886 C CN 1204886C
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- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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Abstract
本发明涉及式(I)的N-脱乙酰基硫代秋水仙素和10-脱乙酰基浆果赤霉素III衍生物,其中R和n具有本申请说明书中限定的含义。本发明还涉及含有这些化合物的药物组合物。
Description
本发明涉及式(I)的N-脱乙酰硫代秋水仙素和10-脱乙酰浆果赤霉素III衍生物
其中:-n是0至8的整数;-R是式a)、b)、c)、d)或e)的残基:
其中:-R1和R2可以相同或不同,是氢或下式的基团:
n优选是1至7的整数,更优选是1。
秋水仙素和硫代秋水仙素是已知的抑菌化合物,能够通过与微管蛋白的相互作用使微管去稳定。
秋水仙素目前被用于治疗痛风和相关的炎症疾病,但由于其高度的胃肠道毒性,其用途被限制在急性期。
鉴于许多秋水仙素或硫代秋水仙素衍生物可能用作抗肿瘤药物,对它们已进行了研究,但由于这些化合物的通常极为有限的治疗指数,研究者的努力目前尚未成功。
仅一种秋水仙素衍生物,脱羰秋水仙素,在过去被用来临床治疗白血病,但极不成功。
同样,紫杉烷(taxane)衍生物(帕尼特西(paclitaxel)和衍生物)的抗增殖活性与其不可逆结合微管中α和β形式微管蛋白的能力是相关的。异丝氨酸侧链上的Oxethane和苯基已证明对于活性是必需的;实际上,缺少异丝氨酸侧链的浆果赤霉素实质上没有抗增殖活性,这与帕尼特西和异丝氨酸的其它C13酯是不同的,它们可以和微管的两个不同位置形成键而防止解聚并因此抑制有丝分裂纺锤体的活性。
令人惊奇的是,现已发现式(I)化合物虽然在微管的组装和去组装步骤中均对微管蛋白缺乏亲和性,但具有抗增殖活性。
因此,式(I)化合物的活性是由一种未意料到的作用机制造成的,该机制从抗微管蛋白药物领域的现有知识还不能被证明。
本发明的化合物具有有力的抗有丝分裂活性,并且其特征在于有利的治疗指数使得它们适合于治疗各种形式的肿瘤以及变性类风湿性关节炎(一种以白细胞过度增殖和异常迁移为特征的疾病)。
化合物(I)具有类似于最有效的抗肿瘤药物的细胞毒性,然而具有明显较宽的作用谱,尤其是可作用于那些对已知药物具有抗性的细胞。
化合物(I)是通过N-脱乙酰硫代秋水仙素和二羧酸活性衍生物在无水溶剂中在以下条件下反应制备的,所述条件使得可以获得N-单乙酰化产物,该产物随后在适当缩合剂如二环己基碳二亚胺存在下,与根据所需要的化合物任选地在7、13或10位被保护的浆果赤霉素III衍生物反应。除去任选存在的所有保护性基团,和/或选择性地酰化浆果赤霉素III残基上的羟基以直接地产生化合物(I)。
当化合物(I)中R是式c)的基团时,由于异丝氨酸链中羟基的反应性,该反应可以在不预先保护紫杉烷化合物上存在的其它羟基的情况下进行。
适合的二羧酸反应性衍生物的例子包括酰基卤、酰基氯、活性酐或酯。
或者,还可以用二羧酸酰化紫杉烷衍生物,然后使所获产物和N-脱乙酰硫代秋水仙素缩合。
本发明化合物在治疗增生性疾病、尤其是各种起因的肿瘤、类风湿性关节炎或其中表现出需要抗增殖和抗炎症作用的其它变性病方面是有用的。
为了此目的,式(I)化合物以适合口服、肠胃外、表皮或经皮给药的药物组合物形式施用。式(I)化合物的剂量根据给药途径从1至100mg/m2身体面积变化。这些化合物优选通过口服给药。
组合物的例子包括胶囊、片剂、瓶、乳膏、溶液、颗粒。
以下实施例更详细地描述了本发明。
实施例1
a)将100mg脱乙酰硫代秋水仙素(0.268mmol,M.W.373g/mol)溶解在5ml无水二噁烷中,然后加入27mg琥珀酸酐(0.268mmol,M.W.100g/mol),并60℃加热反应混合物5小时。TLC监控:AcOEt/MeOH4∶1。通过蒸发除去二噁烷,产物不经纯化用于随后的反应。获得130mg产物。
b)将126mg步骤a)产物(0.268mmol,M.W.473g/mol)溶解在8ml无水甲苯中。加入187mg 7-Tes浆果赤霉素(0.268mmol,M.W.700g/mol)、66mg DCC(0.321mmol,M.W.206g/mol)和13mg DMAP(0.1mmol,M.W.122g/mol)。混合物在室温下搅拌约12小时直到起始产物消失。TLC监控:AcOEt/MeOH4∶1。混合物通过Celite过滤并蒸发至干。粗产物在柱(硅胶)上使用AcOEt/己烷9∶1作为洗脱液进行纯化,得到120mg被保护的缩合产物和80mg已经7位去保护的该产物。
c)将120mg步骤b)产物(0.103mmol,M.W.1155g/mol)溶解在5mlMeOH/AcCl(5ml甲醇和35μl AcCl)中。反应在15分钟内完成。向混合物中加入碳酸氢盐并用AcOEt抽提,得到100mg式(I)的产物,其中n是1且R是式a)的残基。
实施例2
a)将100mg 10-O-琥珀酰基-7-Tes浆果赤霉素III(M.W.699g/mol,0.14mmol)和54mg N-脱乙酰硫代秋水仙素(M.W.373g/ml,0.14mmol)溶解在5ml无水甲醇中,加入2ml二氯甲烷。室温下加入31mg DCC(M.W.206g/mol,0.15mmol)和8.5mg DMAP(M.W.122g/mol,0.07mmol)。一天后,通过Celite过滤反应物,用甲苯洗涤并蒸发至干。在快速柱(硅胶,洗脱液CH2Cl2∶MeOH=25∶1)上纯化,产生70mg产物。
b)将步骤a)产物200mg(0.213mmol)溶解在14ml无水甲苯中。加入183mg下式的噁唑烷衍生物(以下称作SHA-9)(0.426mmol):
以及88mg DCC(0.426mmol)和26mg DMAP(0.213mmol),室温下搅拌混合物。TLC监控:CH2Cl2∶MeOH=25∶1。4小时后通过Celite过滤反应混合物并通过柱层析纯化,获得240mg产物。
c) 将160mg步骤b)产物(0.12mmol M.W.1338)溶解在3.2ml通过将70μl AcCl溶解在10ml MeOH中获得的溶液中。半小时后,向反应混合物中加入5%NaHCO3,用CH2Cl2抽提,干燥并蒸发除去溶剂。通过快速层析纯化,产生97mg式(I)化合物,其中n是1且R是式b)的残基。
实施例3
将70mg帕尼特西(0.038mmol,M.W.1824)溶解在5ml无水二噁烷中。加入DCC(1.5当量)、DMAP(5%摩尔)和实施例1a的产物。110℃搅拌混合物2小时,然后再加入10mg实施例1a的产物和11mg DCC。之后,将反应置于室温48小时,然后110℃再加热24小时。蒸发除去溶剂并通过快速层析纯化残余物(AcOEt∶MeOH=99∶1),获得化合物(I)21mg,其中n是1且R是式c)的残基。
实施例4
a)0℃下向7-琥珀酰基-10,13-二Tes-浆果赤霉素III(390mg,0.479mmol,M.W.814)的10ml THF溶液加入TBAF(THF中1M,0.96mmol)溶液。混合物置于0℃下1小时30分钟,然后置于室温2小时。之后,加入1当量TBAF,并继续反应直到完全去除保护性基团。向反应混合物中加入水并用AcOEt抽提;水相用1N HCl酸化并用AcOEt抽提,获得350mg产物。
b)使步骤a)化合物(0.479mmol)与TIO-NH2(0.479mmol)、DCC(1.5当量)和DMAP(50%摩尔)在甲苯-THF中反应1小时。反应混合物通过Celite过滤并通过CC(CH2Cl2∶MeOH=25∶1)纯化,获得式(I)化合物,其中n是1且R是式d)的残基。
实施例5
将200mg实施例4化合物(0.206mmol)溶解在14ml甲苯-无水THF中。向混合物中加入177mg SHA9(2当量)、84mg DCC(2当量)和26mg DMAP(0.206mmol),室温下对其进行搅拌。TLC监控:CH2Cl2∶MeOH=25∶1。4小时后,反应混合物通过Celite过滤并在层析柱上纯化。所获产物溶解在4.8ml 70μl AcCl在10ml MeOH中的溶液中。半小时后,向反应物加入5%NaHCO3,并用CH2Cl2抽提。干燥抽提物并蒸发除去溶剂。通过快速层析纯化残余物,获得110mg化合物(I),其中n是1,R是式e)的残基,其中R1和R2是下式的基团:
Claims (4)
1.式(I)的化合物
其中:
-n是0至8的整数;
-R是式a)、b)、c)、d)或e)的残基:
其中:
-R1和R2可以相同或不同,是氢或下式的基团:
2.权利要求1的化合物,其中n是1至7的整数。
3.权利要求2的化合物,其中n是1。
4.药物组合物,该组合物含有权利要求1-3中任一项的化合物与适当的载体。
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IT2000MI000553A IT1319168B1 (it) | 2000-03-17 | 2000-03-17 | Derivati di condensazione ad attivita' antitumorale, loro metodo dipreparazione e formulazioni che li contengono. |
ITMI2000A000553 | 2000-03-17 |
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CN1416342A CN1416342A (zh) | 2003-05-07 |
CN1204886C true CN1204886C (zh) | 2005-06-08 |
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CNB018064434A Expired - Fee Related CN1204886C (zh) | 2000-03-17 | 2001-03-12 | 硫代秋水仙素和浆果赤霉素的缩合衍生物及其组合物 |
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US (1) | US6683109B2 (zh) |
EP (1) | EP1263431B1 (zh) |
JP (1) | JP2003526665A (zh) |
KR (1) | KR100766161B1 (zh) |
CN (1) | CN1204886C (zh) |
AU (2) | AU2001250377B2 (zh) |
CA (1) | CA2403168C (zh) |
CZ (1) | CZ301626B6 (zh) |
DK (1) | DK1263431T3 (zh) |
ES (1) | ES2305067T3 (zh) |
HK (1) | HK1051973A1 (zh) |
HU (1) | HU229257B1 (zh) |
IL (1) | IL151714A0 (zh) |
IT (1) | IT1319168B1 (zh) |
NO (1) | NO329422B1 (zh) |
PL (1) | PL357376A1 (zh) |
PT (1) | PT1263431E (zh) |
RU (1) | RU2264393C2 (zh) |
SI (1) | SI1263431T1 (zh) |
SK (1) | SK286849B6 (zh) |
WO (1) | WO2001068089A1 (zh) |
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CO5280224A1 (es) | 2000-02-02 | 2003-05-30 | Univ Florida State Res Found | Taxanos sustituidos con ester en c7, utiles como agentes antitumorales y composiciones farmaceuticas que los contienen |
US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
CA2354471A1 (en) * | 2001-07-31 | 2003-01-31 | Florida State University Research Foundation, Inc. | C10 ester substituted taxanes |
US6825236B2 (en) * | 2003-04-14 | 2004-11-30 | California Pacific Medical Center | Colchicine derivatives |
PE20050693A1 (es) | 2004-02-13 | 2005-09-27 | Univ Florida State Res Found | Taxanos sustituidos con esteres de ciclopentilo en c10 |
JP2007527432A (ja) | 2004-03-05 | 2007-09-27 | 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 | C7ラクチルオキシ置換タキサン |
US8242166B2 (en) | 2008-03-31 | 2012-08-14 | Florida State University Research Foundation, Inc. | C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes |
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FR2678930B1 (fr) * | 1991-07-10 | 1995-01-13 | Rhone Poulenc Rorer Sa | Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii. |
WO1993002105A1 (en) * | 1991-07-19 | 1993-02-04 | Hybritech Incorporated | Trifunctional compounds having specificity for multi-drug resistant cells |
CA2124329C (en) * | 1991-11-27 | 2008-11-18 | Gregory A. Kopia | Compounds, compositions and methods for binding bio-affecting substances to surface membranes of bio-particles |
US5426224A (en) * | 1993-03-18 | 1995-06-20 | The University Of North Carolina At Chapel Hill | Mammalian DNA topoisomerase II inhibitor and method |
WO1997024459A1 (en) * | 1995-12-29 | 1997-07-10 | Phanos Technologoes, Inc. | Method for reducing unwanted cellular adhesions |
CA2251703A1 (en) * | 1996-05-08 | 1997-11-13 | Peter G.M. Wuts | Process to prepare taxol |
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