CN102241727A - 环杷明类似物及其使用方法 - Google Patents
环杷明类似物及其使用方法 Download PDFInfo
- Publication number
- CN102241727A CN102241727A CN2011100943914A CN201110094391A CN102241727A CN 102241727 A CN102241727 A CN 102241727A CN 2011100943914 A CN2011100943914 A CN 2011100943914A CN 201110094391 A CN201110094391 A CN 201110094391A CN 102241727 A CN102241727 A CN 102241727A
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- Prior art keywords
- alkyl
- aryl
- amino
- aralkyl
- thiazolinyl
- Prior art date
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Abstract
本发明提供用于调节平滑(蛋白)依赖性途径激活的组合物与方法。本发明提供可用于抵消Hedgehog途径有害激活的表型作用(例如Hedgehog获得功能、Ptc丧失功能或平滑蛋白获得功能的突变所致)的环杷明类似物。本发明的化合物特别可用于治疗癌症。
Description
本发明专利申请是国际申请日为2005年8月26日、国际申请号为PCT/US2005/030406、进入中国国家阶段的申请号为200580035365.7、发明名称为“环杷明类似物及其使用方法”的发明专利申请的分案申请。
相关申请
本申请涉及以下美国申请:2004年8月27日提交的系列号60/605,020,2004年10月8日提交的系列号60/617,170,2004年11月5日提交的系列号60/625,676,2005年5月19日提交的系列号60/683,169,这些文献,每篇全文纳入本文作为参考。
发明背景
hedgehog信号转导途径对于胚胎发育期间的许多过程非常必要。分泌型蛋白的hedgehog家族成员控制细胞增殖、分化和组织图式形成(patterning)。虽然该途径首先在果蝇中破译,但已证明其在无脊椎动物与脊椎动物,包括人中高度保守。胚胎形成后,hedgehog信号转导途径的总活性在大多数细胞中降低,但在某些成人细胞类型中仍维持活性。最近,有研究显示hedgehog途径的不受控激活导致某些类型的癌症,如下所述。
Hedgehog多肽是分泌型蛋白质,其在hedgehog途径中起到信号转导配体的功能。示范性hedgehog基因与蛋白质见PCT公布的WO 95/18856与WO 96/17924所述。在人中发现了hedgehog蛋白的三种不同形式:Sonic hedgehog(Shh)、Deserthedgehog(Dhh)与Indian hedgehog(Ihh)。Sonic hedgehog是哺乳动物中最普遍的hedgehog成员,也是家族hedgehog中得到最充分鉴定的配体。分泌前,Shh经过分子内切割与脂质修饰反应。脂质修饰的肽负责所有信号转导活性。
两种跨膜蛋白:12-跨膜修补受体(Patched receptor)(Ptc)和7-跨膜平滑蛋白(Smoothened protein)(Smo)参与hedgehog途径中的信号转导。
本领域的发现提示,Hedgehog通过与Ptc结合起作用,从而解除(realease)Ptc对Smo的抑制作用。由于Ptc和Smo均是跨膜蛋白,有人提出它们物理结合以形成受体复合物的设想,虽然间接作用机理也是可能的。Smo从Ptc的抑制中去阻遏最可能涉及Smo构象改变。然而,Ptc对Smo的活性不是至关重要的,因为在完全没有修补蛋白时Smo变为组成型激活(Alcedo等,同上;Quirk等,(1997),Cold Spring Harbor Symp.Quant.Biol.,62:217-226)。一旦Smo去阻遏,其快速且高度磷酸化并转导能通过Gli转录因子(果蝇Ci蛋白的同源物)激活转录的信号(Alexandre等,(1996),Genes Dev.,10:2003-13))。Gli1转录因子上调参与生长与发育的许多基因(Alexandre等,同上)。Hedgehog信号转导在发育的许多阶段,特别是在左右对称性形成中至关重要。hedgehog信号转导丧失或降低导致多种发育缺陷和畸形,最明显的一种情况是独眼(Belloni等,(1996),Nature Genetics,14:353-6)。
最近,有报道说散发基底细胞癌(Xie等,(1998),Nature,391:90-2)和中枢神经***中的原发性神经外胚层瘤(Reifenberger等,(1998),Cancer Res,58:1798-803)中发生活化性(activating)hedgehog途径突变。许多类型的癌症也显示hedgehog途径的不受控激活,例如胃肠道癌症,包括胰腺癌、食道癌、胃癌(Berman等,(2003),Nature,425:846-51;Thayer等,(2003),Nature,425:851-56);肺癌(Watkins等,(2003),Nature,422:313-317);***癌(Karhadkar等,(2004),Nature,431:707-12;Sheng等,(2004),Molecular Cancer,3:29-42;Fan等,(2004),Endocrinology,145:3961-70);乳腺癌(Kubo等,(2004),Cancer Research,64:6071-74;Lewis等,(2004),Journal of Mammary Gland Biology and Neoplasia,2:165-181)与肝细胞癌(Sicklick等,(2005),“ASCO大会”(ASCO conference);Mohini等,(2005),“AACR大会”(AACR conference))。
在he此ehog途径不受控激活的许多不同癌症类型中,已证明hedgehog途径的小分子抑制导致细胞死亡(参见,例如Berman等,2003,Nature,425:846-51)。
目前,正在通过抑制Hedgehog途径活性的一个或多个方面能获得病症或疾病的治疗性作用的许多临床病症中研究Hedgehog途径拮抗剂。虽然主要的焦点集中于癌症,研究人员发现hedgehog途径的小分子抑制显示能缓解银屑病的症状(Tas等,2004,Dermatology,209:126-131,公布的美国专利申请20040072913(纳入本文作为参考))。银屑病是极其常见的慢性皮肤病,其典型特征是通常含有具银色鳞片的斑块和红斑丘疹的皮肤损伤,虽然皮肤和身体的其它部分都会有差异。目前认为银屑病是自身免疫疾病,但是其病原学仍不了解。
吸引许多兴趣的hedgehog途径抑制剂是天然产物环杷明。发现放牧的绵羊的后代生来具有严重的出生畸形后,在1966年从百合加州藜芦(Veratrumcalifornicum)中首次分离出环杷明。为鉴定导致出生畸形的物质,FDA研究了四基因(tetragens)可能的来源并鉴定了类固醇生物碱的蒜藜芦碱家族,包括化合物环杷明,因为四基因导致出生畸形。
多年以后,发现环杷明的作用机理是抑制hedgehog途径活性(Cooper等,(1998),Science,280:1603-7;Chen等,(2002),Genes and Development,16:2743-8)。环杷明与相关化合物显示能对hedgehog途径起作用而具有抗癌症活性。虽然开始时很有希望,但此家族的化合物或其类似物中无一成功地开发为抗癌症药物。本发明实现了这种需要并具有其它优点。
发明概述
本发明提供环杷明家族的类固醇生物碱类似物,所述类似物可用于抑制细胞增殖和/或促进细胞凋亡,例如用于治疗增殖性疾病,如癌症。本发明的hedgehog途径拮抗剂可用于在例如具有以下表型的患者中抑制细胞或组织增殖(或其它生物学结果):Ptc丧失功能、Smo获得功能或He此ehog获得功能。
在某些应用中,可利用本发明抵消Hedgehog途径有害激活的表型作用,例如Hedgehog获得功能、Ptc丧失功能或Smo获得功能的突变所致的Hedgehog途径有害激活。例如,本方法可包括使细胞(体外或体内)与含量足以拮抗Smo依赖性途径激活的本发明hedgehog途径拮抗剂(下文定义)接触。这种拮抗剂可终止或减缓有害的细胞增殖并可导致细胞死亡。
在某些实施方案中,本发明的方法与化合物可用于在体外和/或体内调节细胞增殖和/或细胞死亡,例如用于治疗头、颈、鼻腔、鼻窦、鼻咽、口腔、口咽、喉、舌、唾液腺、神经节细胞瘤、胰腺、胃、皮肤、食道、肝脏和胆道***(biliarytree)、骨、小肠、结肠、直肠、卵巢、***、肺、乳腺、淋巴***、血液、骨髓、中枢神经***或脑的恶性疾病。
在某些实施方案中,本发明的方法与化合物可用于治疗对象的银屑病症状。本发明化合物可作为单一药物或与一种或多种抗银屑病药物联用来治疗银屑病。在具体的实施方案中,本发明化合物局部给予需要的对象。
本发明化合物还可配制为含有药学上可接受的赋形剂的药物制品以给予患者作为癌症治疗方法。可将本发明的hedgehog途径拮抗剂和/或含有它们的制品给予患者来治疗涉及有害细胞增殖的疾病,例如头、颈、鼻腔、鼻窦、鼻咽、口腔、口咽、喉、舌、唾液腺、神经节细胞瘤、胰腺、胃、皮肤、食道、肝脏和胆管(biliary tree)、骨、小肠、结肠、直肠、卵巢、***、肺、乳腺、淋巴***、血液、骨髓、中枢神经***或脑的癌症和/或肿瘤。在某些实施方案中,可全身性(例如胃肠外)和/或部分性(locally)(如局部(topically))给予这种化合物或制品。
发明详述
定义
本文所用术语的定义应结合各术语在化学和药学领域公认的该领域目前状态的定义。在适当之处给出了范例。除非局限于具体实例,这些定义适用于整个说明书中所用的术语,无论是单独使用还是作为较大基团的一部分。
术语“杂原子”是本领域公认的,指除碳或氢以外的任何元素。示范性杂原子包括硼、氮、氧、磷、硫和硒。
术语“烷基”是本领域公认的,包括饱和的脂族基团,包括直链烷基、支链烷基、环烷基(脂环族)、烷基取代的环烷基与环烷基取代的烷基。在某些实施方案中,直链或支链烷基在其骨架具有约30个或更少的碳原子(例如,C1-C30的直链、C3-C30的支链),或者约20个或更少的碳原子。类似地,环烷基在其环结构具有约3-约10个碳原子,或者在环结构中具有约5、6或7个碳。除非另有说明,可任选用合适的取代基取代烷基。取代基的数目通常受限于烷基上可用的化合价的数目;因此,可通过替换存在于未取代基团上的一个或多个氢原子来取代烷基。烷基的合适取代基包括卤素、=O、=N-CN、=N-OR’、=NR’、OR’、NR’2、SR’、SO2R’、SO2NR’2、NR’SO2R’、NR’CONR’2、NR’COOR’、NR’COR’、CN、COOR’、CONR’2、OOCR’、COR’与NO2,其中R’各自独立为H、C1-C6烷基、C2-C6杂烷基、C1-C6酰基、C2-C6杂酰基、C6-C10芳基、C5-C10杂芳基、C7-C12芳基烷基或C6-C12杂芳基烷基,每个R’任选为一个或多个选自卤素、C1-C4烷基、C1-C4杂烷基、C1-C6酰基、C1-C6杂酰基、羟基、氨基和=O的基团取代;并且其中同一取代基上或毗邻原子上的两个R’可相连以形成任选最多含有3个选自N、O和S的杂原子的3-7元环。
除非碳原子数目另有说明,“低级烷基”指如上定义但在其骨架中具有1-约10个碳原子,或者1-约6个碳原子的烷基。类似地,“低级烯基”和“低级炔基”具有相似的链长。
术语“芳烷基”是本领域公认的,指用芳基(例如,芳族或杂芳族基团)取代的烷基。
术语“烯基”和“炔基”是本领域公认的,指不饱和脂族基团,其长度类似和可能的取代与上述烷基相似,但分别含有至少一个双键或三键,也可含有双键和三键混合物。除非另有说明,也可任选用上述烷基的相同取代基取代烯基和炔基。
“杂烷基”、“杂烯基”和“杂炔基”等与相应的烃基(烷基、烯基和炔基)类似定义,但“杂”术语指在骨架残基中含有1-3个O、S或N杂原子或其组合的基团;因此相应烷基、烯基或炔基的至少一个碳原子为所述杂原子之一所取代从而形成杂烷基、杂烯基或杂炔基。烷基、烯基和炔基的杂合形式(heteroform)的典型与优选的大小通常与相应的烃基相同,杂合形式中可能存在的取代基与上述烃基的相同。除非另有说明,也出于化学稳定性的原因,应知道这种基团不包含两个以上连续的杂原子,除了N或S上的氧代基团,例如磺酰基。
术语“芳基”是本领域公认的,指含有0-4个杂原子的5、6和7元单环芳族基团,例如苯、萘、蒽、芘、吡咯、呋喃、噻吩、咪唑、唑、噻唑、***、吡唑、吡啶、吡嗪、哒嗪和嘧啶等。在环结构中具有杂原子的那些芳基也称为“芳基杂环”或“杂芳族”。芳环可在一个或多个环位置用上述取代基取代,例如卤素、叠氮化物、烷基、芳烷基、烯基、炔基、环烷基、羟基、烷氧基、氨基、硝基、巯基、亚氨基、酰氨基、膦酸酯、次膦酸酯(phosphinate)、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、亚磺酰氨基(sulfonamido)、酮、醛、酯、杂环基(heterocyclyl)、芳族或杂芳族部分、-CF3、-CN等。术语“芳基”也包括具有两个或多个环的多环***,其中两毗邻环共用两个或多个碳(所述环是“稠合环”),其中至少一个环是芳族,例如另一环可以是环烷基、环烯基、环炔基、芳基和/或杂环基。
术语“邻”、“间”和“对”是本领域公认的,分别指1,2-、1,3-和1,4-二取代的苯。例如,名称1,2-,二甲基苯与邻二甲基苯是同义的。
术语“杂环基”、“杂芳基”或“杂环基团”是本领域公认的,指其环结构中包含1-4个杂原子的3-约10元环结构,或者3-约7元环。杂环也可以是多元环。杂环基团包括,例如噻吩、噻蒽、呋喃、吡喃、异苯并呋喃(isobenzofuran)、色烯(chromene)、呫吨、吩呫吨(phenoxanthene)、吡咯、咪唑、吡唑、异噻唑、异唑、吡啶、吡嗪、嘧啶、哒嗪、中氮茚、异吲哚、吲哚、吲唑、嘌呤、喹嗪、异喹啉、喹啉、2,3-二氮杂萘、1,5-二氮杂萘、喹喔啉、喹唑啉、噌啉、蝶啶、咔唑、咔啉、菲啶、吖啶、嘧啶、菲咯啉、吩嗪、吩吡嗪、吩噻嗪、呋咱(furazan)、吩嗪、吡咯烷、四氢呋喃(oxolane)、四氢噻吩(thiolane)、唑、哌啶、哌嗪、吗啉、内酯、内酰胺(如β-丙内酰胺和吡咯烷酮(pyrrolidinone))、磺内酰胺、磺内酯等。杂环可在一个或多个位置用上述取代基取代,例如卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、氨基、硝基、巯基、亚氨基、酰氨基、膦酸酯、次膦酸酯、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、酮、醛、酯、杂环基、芳族或杂芳族部分、-CF3、-CN等。
术语“多环基”或“多环基团”是本领域公认的,指两个或多个环(例如,环烷基、环烯基、环炔基、芳基和/或杂环基),其中两毗邻环共用两个或多个碳,例如所述环是“稠合环”。经非毗邻原子连接的环称为“桥”环。多环的各环可用上述取代基取代,例如卤素、烷基、芳烷基、烯基、炔基、环烷基、羟基、氨基、硝基、巯基、亚氨基、酰氨基、膦酸酯、次膦酸酯、羰基、羧基、甲硅烷基、醚、烷硫基、磺酰基、酮、醛、酯、杂环基、芳族或杂芳族部分、-CF3、-CN等。
术语“碳环”是本领域公认的,指其中各环原子是碳的芳族或非芳族环。
术语“硝基”是本领域公认的,指-NO2;术语“卤素”是本领域公认的,指-F、-Cl、-Br或-I;术语“巯基”是本领域公认的,指-SH;术语“羟基”指-OH;术语“磺酰基”是本领域公认的,指-SO2 -。“卤化物”指定为卤素相应的阴离子,“拟卤化物”具有Cotton和Wilkinson的《高级有机化学》(Advanced InorganicChemistry),第560页给出的定义。
术语“胺”、“氨基”和“铵”是本领域公认的,指未取代和取代的胺,例如以下通式所表示的部分:
其中R50、R51和R52各自独立表示氢、烷基、烯基、-(CH2)m-R61,或者R50和R51与和它们相连的N原子结合形成在环结构中具有4-8个原子的杂环;R61表示芳基、环烷基、环烯基、杂环或多环;m是0或1-8的整数。在其它实施方案中,R50和R51(与任选的R52)各自独立表示氢、烷基、烯基或-(CH2)m-R61。因此,术语“烷基胺”包括连接有取代或未取代的烷基的上述胺基团,即R50和R51中至少一个是烷基。
术语“酰基氨基”是本领域公认的,指以下通式所表示的部分:
其中R50如上定义,R54表示氢、烷基、烯基或-(CH2)m-R61,其中m与R61如上定义。
术语“酰氨基”是本领域公认的氨基取代的羰基,包括以下通式所表示的部分:
其中R50与R51如上定义。本发明中酰胺的某些实施方案不包括可能不稳定的酰亚胺(imide)。
术语“烷硫基”指具有与其相连的硫基的上述烷基。在某些实施方案中,“烷硫基”部分表示为-S-烷基、-S-烯基、-S-炔基和-S-(CH2)m-R61之一,其中m和R61如上定义。代表性烷硫基包括甲硫基、乙硫基等。
术语“羧基”是本领域公认的,包括以下通式所表示的部分:
其中X50是键或表示氧或硫;R55和R56表示氢、烷基、烯基、-(CH2)m-R61或药学上可接受的盐;R56表示氢、烷基、烯基或-(CH2)m-R61,其中m和R61如上定义。当X50是氧,R55或R56不是氢时,该通式表示“酯”。当X50是氧,而R55如上定义,该部分在本文称为羧基,特别是当R55是氢时,该通式表示“羧酸”。当X50是氧,R56是氢时,该通式表示“甲酸酯”。总体上,当上式的氧原子被硫取代时,该式表示“硫代羰基”。当X50是硫,R55或R56不是氢时,该式表示“硫羟酸酯(thiolester)”。当X50是硫,R55是氢,该式表示“硫羟羧酸(thiolcarboxylic acid)”。当X50是硫,R56是氢,该式表示“硫羟甲酸酯”(thiolformate)。在另一方面,当X50是键,R55不是氢时,上式表示“酮”基团。当X50是键,R55是氢时,上式表示“醛”基团。
术语“氨基甲酰基”指-O(C=O)NRR′,其中R和R′独立是H、脂族基团、酰基或杂芳基。
术语“氧代”指羰基氧(=O)。
术语“烷氧基(alkoxyl)”或“烷氧基(alkoxy)”是本领域公认的,指连接有氧基团的上述烷基。代表性是烷氧基包括甲氧基、乙氧基、丙氧基、叔丁氧基等。“醚”是通过氧共价连接的两个烃。因此,使其成为醚的烷基的取代基是或类似于烷氧基,例如可表示为-O-烷基、-O-烯基、-O-炔基、-O--(CH2)m-R61之一,其中m和R61如上所述。
术语“磺酸酯”是本领域公认的,指以下通式所表示的部分:
其中R57是电子对、氢、烷基、环烷基或芳基。
术语“硫酸酯”是本领域公认的,包括以下通式所表示的部分:
其中R57如上定义。
术语“亚磺酰氨基”是本领域公认的,包括以下通式所表示的部分:
其中R50和R56如上定义。
术语“氨磺酰基”是本领域公认的,指以下通式所表示的部分:
其中R50和R51如上定义。
术语“磺酰基”是本领域公认的,指以下通式所表示的部分:
其中R58是氢、烷基、烯基、炔基、环烷基、杂环基、芳基或杂芳基之一。
术语“亚砜基”是本领域公认的,指以下通式所表示的部分:
其中R58如上定义。
术语“磷酰基”是本领域公认的,可用以下通式表示:
其中Q50表示S或O,R59表示氢、低级烷基或芳基。当用于取代,例如烷基时,可用以下通式表示磷酰基烷基中的磷酰基:
其中Q50和R59各自独立如上定义,Q51表示O、S或N。当Q50是S时,磷酰基部分是“硫代磷酸酯”。
术语“亚磷酰胺(phosphoramidite)”是本领域公认的,可用以下通式表示:
其中Q51、R50、R51和R59如上定义。
术语“亚膦酰胺(phosphonamidite)”是本领域公认的,可用以下通式表示:
其中Q51、R50、R51和R59如上定义,R60表示低级烷基或芳基。
可对烯基和炔基作类似的取代从而产生,例如氨基烯基、氨基炔基、酰氨基烯基、酰氨基炔基、亚氨基烯基、亚氨基炔基、硫代烯基(thioalkenyl)、硫代炔基(thioalkynyl)、羰基取代的烯基或炔基。当各种表达,例如烷基、m、n等在任何结构中多次出现时,应独立于其在同一结构中其它地方的定义。
术语“硒烷基”是本领域公认的,指连接有取代的硒基的烷基。可在烷基上取代的示范性“硒醚”选自-Se-烷基、-Se-烯基、-Se-炔基和-Se-(CH2)m-R61,m和R61如上定义。
术语三氟甲磺酰基(triflyl)、甲苯磺酰基(tosyl)、甲磺酰基(mesyl)和九氟丁磺酰基(nonaflyl)是本领域公认的,分别指三氟甲磺酰基、对-甲苯磺酰基、甲磺酰基和九氟丁磺酰基。术语三氟甲磺酸酯(triflate)、甲苯磺酸酯(tosylate)、甲磺酸酯(mesylate)与九氟丁基磺酸酯(nonaflate)是本领域公认的,分别指三氟甲甲磺酸酯、对-甲苯磺酸酯、甲磺酸酯与九氟丁基磺酸酯官能团与分别含有所述基团的分子。
缩写Me、Et、Ph、Tf、Nf、Ts和Ms分别表示甲基、乙基、苯基、三氟甲磺酰基、九氟丁磺酰基、对-甲苯磺酰基与甲磺酰基。具有本领域普通技术的有机化学家所用的缩写的更全面清单见各卷“有机化学杂志”(Joumal of Organic Chemistry)的第一期;此清单通常见名为“缩写标准清单(Standard List of Abbreviations)”的表格。
本发明组合物中含有的某些化合物可存在具体的几何或立体异构形式。本发明考虑了所有这种化合物,包括顺式和反式异构体、R-和S-对映体、非对映体、(d)-异构体、(l)-异构体、它们的外消旋混合物与其它混合物,所有这些都落在本发明的范围内。取代基,例如烷基中可存在其它不对称碳原子。所有这种异构体及其混合物属于本发明。
例如,如果需要本发明化合物的特定对映体,可通过不对称合成或利用手性助剂衍生来制备,然后分离所得的非对映异构体混合物,切去助剂以提供纯的所需对映体。或者,当分子中含有碱性官能团,例如氨基或含有酸性官能团,例如羧基时,利用合适的光学活性酸或碱形成非对映体盐,然后通过本领域熟知的分部结晶或层析方法拆分如此获得的非对映体,再回收纯的对映体。类似地,可通过本领域已知的手性层析方法将外消旋混合物中的特定对映体与其对映体分离。
应该知道“取代”或“用...取代”包括的隐含条件是这种取代符合被取代原子和取代基所允许的化合价,并且取代得到稳定的化合物,例如不会通过重排、环化、消除或其它反应而自动转化的化合物。
也考虑术语“取代的”应包括有机化合物所有容许的取代基。在广义上,容许的取代基包括有机化合物的非环状和环状、直链和支链、碳环和杂环、芳族和非芳族取代基。示范性取代基,包括例如本文所述的那些取代基。就合适的有机化合物而言,容许的取代基可以是一个或多个并且可以相同或不同。为本发明的目的,杂原子,例如氮可具有能满足杂原子化合价的本文所述有机化合物的氢取代基和/或任何容许的取代基。本发明不以任何方式受有机化合物的容许取代基的限制。
本文所用的短语“保护基团”表示保护可能的反应性官能团发生不希望的化学转化的临时取代基。这种保护基团的实例分别包括羧酸酯、醇类的甲硅烷醚,以及醛和酮的乙缩醛和缩酮。有人总结了保护基团化学的领域(Greene,T.W.;Wuts,P.G.M,《有机合成的保护基团》(Protective Groups in Organic Synthesis),第二版;Wiley:纽约,1991)。本发明化合物的受保护形式属于本发明的范围。
为本发明的目的,按照《化学与物理手册》(Handbook of Chemistry andPhysics),第67版,1986-87,CAS版,封里的元素周期表鉴定化学元素。
基因的“异常修饰或突变”指诸如基因的核苷酸缺失、取代或添加以及基因的总染色体重排和/或基因异常甲基化的遗传损伤。类似地,基因的错表达指(与相似条件下的正常细胞的水平相比)基因转录的异常水平以及从该基因转录的mRNA的非野生型剪接。
“基底细胞癌”存在各种临床和组织学形式,例如结节-溃疡性、浅表性、着色性、硬皮样(morphealike)、纤维上皮瘤和痣样综合征。基底细胞癌是人中最常见的皮肤瘤。非黑色素瘤皮肤癌症的大多数新病例属于此范畴。
术语“癌”指由上皮细胞构成的新的恶性生长,所述细胞易渗入周围组织并发生转移。示范性癌包括:“基底细胞癌”,其是具有局部侵入和破坏可能,但很少转移的皮肤上皮肿瘤;“鳞状细胞癌”,指从鳞状上皮产生并具有柱状细胞(cuboid cell)的癌;“癌肉瘤”,包括癌性和肉瘤样组织构成的恶性肿瘤;“囊性腺样癌”是发生在乳腺、唾液腺和呼吸道的粘膜腺中的癌,其特征为由小上皮细胞的簇(nest)或束所分离或围绕的筒状或带状的透明或黏液基质;“表皮样癌”指易于以和表皮相同的途径分化的细胞,即它们易于形成棘细胞并经历角化;“鼻咽癌”,指发生在鼻后空间上皮层的恶性肿瘤;与“肾细胞癌”,其属于由各种排列的管状细胞构成的肾实质癌。
其它癌性上皮生长是“***瘤”,指源自上皮细胞并以***瘤病毒作为致病因子的良性肿瘤;与“表皮样瘤”,指在神经沟闭合时将外胚层元素(ectodermalelement)包含在内而形成的脑或脑膜肿瘤。
术语“ED50”指产生其50%最大应答反应或作用的药物剂量。
就本发明方法而言,所述化合物的“有效量”指将制品中的拮抗剂含量作为所需剂量方案的一部分施加时,根据待治疗疾病的临床可接受标准,能导致例如细胞增殖率和/或细胞存活率的变化的含量。
术语“上皮细胞或上皮(epithelia)”、“上皮的(epithelial)”指内部和外部身体表面的细胞覆盖物(皮肤的、粘膜的与浆液的),包括腺体与从其衍生的其它结构,例如角膜、食道(esophogeal)、表皮和发囊上皮细胞。其它示范性上皮组织包括:嗅上皮,其是鼻腔嗅觉区域的假复层上皮层并含有嗅觉受体;腺上皮,其指分泌型细胞构成的上皮;鳞状上皮,其指扁平盘状细胞构成的上皮。术语上皮也可指变移上皮,如特别在因收缩与延展而经受强大机械改变的中空器官里层(例如代表复层鳞状和柱状上皮间过渡的组织)发现的上皮。
细胞的“生长状态”指细胞的增殖速率和/或细胞的分化状态。“改变的生长状态”是特征为增殖速率异常的生长状态,例如与正常细胞相比,显示增殖速率增加或降低的细胞。
术语“hedgehog途径拮抗剂”指抑制hedgehog途径功能的药物,例如,阻遏靶基因转录(Gli1和Ptc基因),在正常细胞中这些基因通过细胞与hedgehog(蛋白)接触而诱导。除了改变平滑(蛋白)依赖性途径,在某些实施方案中,本发明的hedgehog途径拮抗剂可用于克服Ptc功能丧失、平滑(蛋白)功能获得和/或hedgehog功能获得。术语“功能丧失”与“功能获得”可适当地指(例如)Ptc基因、hedgehog基因或平滑基因的异常修饰或突变,或者指这种基因的表达水平降低或增加,从而导致,例如类似于细胞与hedgehog蛋白接触(如hedgehog途径的异常激活)或类似于Smo功能丧失的表型。突变可包括Ptc或Smo基因产物丧失调节Gli/Ci蛋白,例如Gli1、Gli2和Gli3的活性水平的能力。
本文所用的“无限增殖细胞”指通过化学和/或重组方法改变细胞从而使所述细胞在培养中能经无限次***而存活。
术语“LD50”指在50%测试对象中致死的药物剂量。
待用本方法治疗的“患者”或“对象”可以指人或非人动物。
本文利用短语“药学上可接受的”指在合理的医学判断范围内,适用于和人与动物组织接触而无过多毒性、刺激、过敏反应或其它问题或并发症并与合理的益处/风险比率相符的那些化合物、物质、组合物和/或剂型。
本文所用的短语“药学上可接受的运载体”指参与将所述化合物从一个器官或身体一部分携带或转运至另一器官或身体一部分的药学上可接受的物质、组合物或载体,例如液体或固体填充剂、稀释剂、赋形剂、生产辅料(如,润滑剂、滑石粉、硬脂酸镁、钙或锌或硬脂酸)或溶剂包裹材料。就与制剂的其它成分相容且不伤害患者的意义而言,各种载体必须是“可接受的”。可用作药学上可接受的载体的材料的一些例子包括:(1)糖,例如乳糖、葡萄糖和蔗糖;(2)淀粉,例如玉米淀粉和马铃薯淀粉;(3)纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;(4)粉状黄蓍胶;(5)麦芽;(6)明胶;(7)滑石粉;(8)赋形剂,例如可可油与栓剂蜡;(9)油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油与大豆油;(10)糖醇,例如丙二醇;(11)多元醇,例如甘油、山梨醇、甘露糖醇与聚乙二醇;(12)酯,例如油酸乙酯与月桂酸乙酯;(13)糖;(14)缓冲剂,例如氢氧化镁与氢氧化铝;(15)海藻酸;(16)无热源的水;(17)等渗盐水;(18)林格液;(19)乙醇;(20)pH缓冲溶液;(21)聚酯,聚碳酸酯和/或聚酐;与(22)药物制剂中使用的其它无毒相容物质。
术语“药物前体”应包括能在生理条件下转化为本发明治疗活性药物的化合物。制备药物前体的常规方法是包括能在生理条件下水解从而释放所需分子的选择部分。在其它实施方案中,宿主动物的酶促活性(或其它生理活性)转化所述药物前体。
本文所用的“增殖的”与“增殖”指经历有丝***的细胞。
在本说明书中,术语“增殖性皮肤疾病”指特征为皮肤组织的有害或异常增殖的任何皮肤疾病。这些病症的典型特征在于表皮细胞增殖或不完全的细胞分化,包括X-连锁鳞癣、银屑病、特应性皮炎、过敏性接触性皮炎、表皮松懈性角化过度与脂溢性皮炎。例如,表皮发育不良是表皮错误发育的一种形式。另一例子是“表皮松懈”,其指自发或在外伤部位发生的表皮松弛状态并伴有水泡形成。
术语“治疗指数”指定义为LD50/ED50的药物治疗指数。
术语“转化细胞”指自发转化为不受限制生长状态的细胞,即它们已获得了在培养中能经无限次***生长的能力。就其生长失控而言,可用例如瘤的、间变的和/或超常增生的等术语描述转化细胞的特征。
本文所用的术语“对象”指动物,通常是作为治疗、观察和/或实验目标的哺乳动物或人。当该术语与化合物或药物的给予联用时,则所述对象是治疗、观察和/或化合物或药物给予的目标。本文所用的短语“治疗有效量”指能在至少一种动物细胞亚群中,以适用于任何医学治疗的合理益处/风险比率产生一定所需治疗作用的化合物、物质或含有本发明化合物的组合物的用量。
本文所用的短语“胃肠外给药”与“胃肠外给予”指除小肠与局部给药以外的给药方式,通常是注射,包括但不限于:静脉内、肌肉内、动脉内、鞘内、囊内、眶内、心脏内、真皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内、胸骨内注射与输液。
本文所用的短语“全身性给药”、“全身性给予”、“外周给药”和“外周给予”指除直接给予至hedgehog途径介导疾病的部位以外来给予化合物、药物或其它物质,从而使之进入患者的***,因而能经历代谢与其它类似的过程,例如皮下给药。
本文所用的术语“糖”指天然或非天然单糖、二糖或含有一个或多个吡喃糖或呋喃糖环的寡糖。所述糖可通过醚键或烷基键与本发明的类固醇生物碱共价结合。在某些实施方案中,糖部分可以在糖环的端基异构中心(anomeric center)共价连接于本发明的类固醇生物碱。
术语“双基”指烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基与杂芳烷基的一系列二价基团中的任一种。例如,是烷基双基;也是烷基双基;是芳烷基双基;与是(烷基)杂芳烷基双基。典型的例子包括通用结构(CH2)x所示的亚烷基(其中X是1-6),与具有2-6个碳原子和一个或多个双键或三键的相应亚烯基(alkenylene)与亚炔基(alkynylene)连接基(linker);具有3-8个环成员的亚环烷基(cycloalkylene);与其中一个开放的化合价位于芳环,一个位于烷基部分的芳烷基,例如及其异构体。
本发明的化合物
本发明提供环杷明类似物及其分离和纯化的形式,包括合成与半合成类似物,以及含有这种类似物的药物组合物。在一个实施方案中,本发明提供下式1所示化合物或其药学上可接受的盐:
其中R1和R8各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基、卤化物、巯基、烷硫基(alkylthio)、芳硫基(arylthio)、芳烷硫基(aralkylthio)、羟基、烷氧基、芳氧基、酰氧基、氨基、烷基氨基、芳基氨基、酰基氨基(acylamino)、芳烷基氨基、硝基、酰硫基(acylthio)、羧酰胺(carboxamide)、磺酰胺、羧基、腈、硫酸酯、-OP(L)(OR20)2、-X-C(L)-R21或-X-C(L)-X-R21;
其中R1也可以是糖;
X是O或NR,其中R是H、烷基、烯基、炔基、芳基、环烷基或芳烷基;
L是O或S;
R2和R9独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、巯基、烷硫基、芳硫基、芳烷硫基、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
R5和R11各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、烷硒基(alkylseleno)、芳烷硒基(aralkylseleno)、芳硒基(arylseleno)、烷硫基、芳烷硫基、芳硫基、杂芳基或杂芳烷基;
R3、R4、R6、R7、R13和R14各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
或R1与R2和/或R8与R9和它们所结合的碳连接在一起形成-(C=O)-、-(C=S)-、-(C=N(OR20))-、-(C=N(R20))-、-(C=N(N(R20)(R20))),或形成任选取代的3-8元环;或者
R4与R5连接在一起和/或R5与R6连接在一起和/或R10与R11连接在一起形成双键或形成下式1b所表示的基团:
其中Z是NR21、O或C(R23)(R23);
R12是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、羟基、芳烷基、杂芳基、杂芳烷基、卤代烷基、烷氧基、-C(O)R21、-CO2R21、-SO2R21、-C(O)N(R21)(R21)、-[C(R21)2]q-R21、-[(W)-N(R21)C(O)]qR21、-[(W)-C(O)]qR21、-[(W)-C(O)O]qR21、-[(W)-OC(O)]qR21、-[(W)-SO2]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-N(R21)]qR21或-[(W)-S]qR21;
其中W是双基,q是1、2、3、4、5或6;
R15、R16和R17独立为H、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基;或者R15与R16和与它们结合的碳连接在一起形成-C(O)-或-C(S)-;
R18和R19独立为H、烷基、芳烷基、卤化物、酰氨基或酯;
R20是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基或杂芳烷基;或者同一取代基上的任何两个R20可结合在一起形成4-8元任选取代的环;
R21是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基或-[C(R20)2]p-R25,其中p是0-6;或者同一取代基上的任何两个R21可结合在一起形成4-8元任选取代的环;
R23是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基、卤化物、烷氧基、芳氧基、酰氧基、甲硅烷氧基、腈、-C(O)R21、-CO2R21、-SO2R21和-C(O)N(R21)2;
R25是羟基、酰基氨基、-N(R20)COR20、-N(R20)C(O)OR20、-N(R20)SO2(R20)、-COR20N(R20)2、-OC(O)R20N(R20)(R20)、-SO2N(R20)(R20)、-N(R20)(R20)、-COOR20、-C(O)N(OH)(R21)、-OS(O)2OR20、-S(O)2OR20、-OP(L)(OR20)(OR20)、-NP(O)(OR20)(OR20)或-P(O)(OR20)(OR20)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R13、R14、R15、R16和R17是氢。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基、糖、-OP(L)(OR20)2、-X-C(L)-R21或-X-C(L)-X-R21;或者R1和R2与和它们结合的碳相连形成-C(O)-。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R4和R5结合在一起形成双键。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1和R2与和它们结合的碳相连形成-C(O)-。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是氢。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是氢;R5和R6结合在一起形成双键;或者R5和R6结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R10和R11结合在一起形成双键;或者R10和R11结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R5和R6结合在一起形成双键并且R10和R11结合在一起形成双键。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1和R2与和它们结合的碳相连形成-C(O)-,R4和R5结合在一起形成双键;R10和R11结合在一起形成双键;或者R10和R11结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是H;R10和R11结合在一起形成双键;或者R10和R11结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R8和R9是H;或者R8和R9与和它们结合的碳相连形成-C(O)-。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R13、R14、R15、R16和R17是氢;R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R4和R5结合在一起形成双键;R1和R2与和它们结合的碳相连形成-C(O)-;R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是H;R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由下式所示化合物表示:
其中:
R12是H、烷基、芳基、环烷基、杂环烷基、羟基、芳烷基、杂芳基、杂芳烷基、卤代烷基、烷氧基、-C(O)R21、-CO2R21、-SO2R21、-C(O)N(R21)(R21)、-[C(R21)2]p-R21、-[(W)-N(R21)C(O)]qR21、-[(W)-C(O)]qR21、-[(W)-C(O)O]qR21、-[(W)-OC(O)]qR21、-[(W)-SO2]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-N(R21)]qR21或-[(W)-S]qR21;
q是1、2、3、4、5或6;
R20是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基或杂芳烷基;或者任何两个R20可结合在一起形成4-8元任选取代的环;
R21是H、烷基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基或-[C(R20)2]p-R25;或者任何两个R21可结合在一起形成4-8元任选取代的环;
R25是羟基、酰基氨基、-N(R20)COR20、-N(R20)C(O)OR20、-N(R20)SO2(R20)、-COR20N(R20)2、-OC(O)R20N(R20)(R20)、-SO2N(R20)(R20)、-N(R20)(R20)、-COOR20、-C(O)N(OH)(R21)、-OS(O)2OR19、-S(O)2OR20、-OP(L)(OR20)(OR20)、-NP(O)(OR20)(OR20)或-P(O)(OR20)(OR20)。
具体地说,本发明提供以下组化合物:
在某些实施方案中,本发明的化合物由任一上述化合物与附加的定义表示,其中所述化合物由下式表示:
在一个实施方案中,本发明提供式2所示化合物或其药学上可接受的盐:
其中R1和R8各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基、卤化物、巯基、烷硫基、芳硫基、芳烷硫基、羟基、烷氧基、芳氧基、酰氧基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、硝基、酰硫基、羧酰胺、磺酰胺、羧基、腈、硫酸酯、-OP(L)(OR20)2、-X-C(L)-R21或-X-C(L)-X-R21;
其中R1也可以是糖;
X是O或NR,其中R是H、烷基、烯基、炔基、芳基、环烷基或芳烷基;
L是O或S;
R2和R9独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、巯基、烷硫基、芳硫基、芳烷硫基、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
R5和R11各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、烷硒基、芳烷硒基、芳硒基、烷硫基、芳烷硫基、芳硫基、杂芳基或杂芳烷基;
R3、R4、R6、R7、R13和R14各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
其中R1与R2和/或R8与R9和它们所结合的碳连接在一起形成-(C=O)-、-(C=S)-、-(C=N(OR20))-、-(C=N(R20))-、-(C=N(N(R20)(R20))),或形成任选取代的3-8元环;或者
R4与R5连接在一起和/或R5与R6连接在一起和/或R10与R11连接在一起形成双键或形成下式1b所表示的基团:
其中Z是NR21、O或C(R23)(R23);
R12是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、羟基、芳烷基、杂芳基、杂芳烷基、卤代烷基、烷氧基、-C(O)R21、-CO2R21、-SO2R21、-C(O)N(R21)(R21)、-[C(R21)2]q-R21、-[(W)-N(R21)C(O)]qR21、-[(W)-C(O)]qR21、-[(W)-C(O)O]qR21、-[(W)-OC(O)]qR21、-[(W)-SO2]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-N(R21)]qR21或-[(W)-S]qR21;
其中W是双基,q是1、2、3、4、5或6;
R15、R16和R17独立为H、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基;或者R15与R16和与它们结合的碳连接在一起形成-C(O)-或-C(S)-;
R18和R19独立为H、烷基、芳烷基、卤化物、酰氨基或酯;
R20是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基或杂芳烷基;或者同一取代基上的任何两个R20可结合在一起形成4-8元任选取代的环;
R21是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基或-[C(R20)2]p-R25,其中p是0-6;或者同一取代基上的任何两个R21可结合在一起形成4-8元任选取代的环;
R23是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基、卤化物、烷氧基、芳氧基、酰氧基、甲硅烷氧基、腈、-C(O)R21、-CO2R21、-SO2R21和-C(O)N(R21)2;与
R25是羟基、酰基氨基、-N(R20)COR20、-N(R20)C(O)OR20、-N(R20)SO2(R20)、-COR20N(R20)2、-OC(O)R20N(R20)(R20)、-SO2N(R20)(R20)、-N(R20)(R20)、-COOR20、-C(O)N(OH)(R21)、-OS(O)2OR20、-S(O)2OR20、-OP(L)(OR20)(OR20)、-NP(O)(OR20)(OR20)或-P(O)(OR20)(OR20);
前提是在所述的式2化合物上至少有一个式1b所示的基团。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R13、R14、R15、R16和R17是氢。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基、糖、-OP(L)(OR20)2、-X-C(L)-R21或-X-C(L)-X-R21;或者R1和R2与和它们结合的碳相连形成-C(O)-。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R4和R5结合在一起形成双键。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1和R2与和它们结合的碳相连形成-C(O)-。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是氢。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是氢;R5和R6结合在一起形成双键;或者R5和R6结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R10和R11结合在一起形成双键;或者R10和R11结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R5和R6结合在一起形成双键并且R10和R11结合在一起形成双键。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1和R2与和它们结合的碳相连形成-C(O)-;R4和R5结合在一起形成双键;R10和R11结合在一起形成双键;或者R10和R11结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是H;R10和R11结合在一起形成双键;或者R10和R11结合在一起形成1b所示的基团:
其中:
Z是C(R23)(R23)。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R8和R9是H;或者R8和R9与和它们结合的碳相连形成-C(O)-。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R13、R14、R15、R16和R17是氢;R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R4和R5结合在一起形成双键;R1和R2与和它们结合的碳相连形成-C(O)-;R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由式1与附加的定义所表示,其中R1是羟基,R2是H;R12是H、烷基、环烷基、芳烷基、杂芳基、杂芳烷基、卤代烷基、羟基、烷氧基、-[(W)-N(R21)C(O)]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-C(O)]qR21或-[(W)-C(O)O]qR21。
在某些实施方案中,本发明的化合物由下式所示化合物表示:
其中:
R12是H、烷基、芳基、环烷基、杂环烷基、羟基、芳烷基、杂芳基、杂芳烷基、卤代烷基、烷氧基、-C(O)R21、-CO2R21、-SO2R21、-C(O)N(R21)(R21)、-[C(R21)2]p-R21、-[(W)-N(R21)C(O)]qR21、-[(W)-C(O)]qR21、-[(W)-C(O)O]qR21、-[(W)-OC(O)]qR21、-[(W)-SO2]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-N(R21)]qR21或-[(W)-S]qR21;
q是1、2、3、4、5或6;
R20是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基或杂芳烷基;或者任何两个R20可结合在一起形成4-8元任选取代的环;
R21是H、烷基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基或-[C(R20)2]p-R25;或者任何两个R21可结合在一起形成4-8元任选取代的环;
R25是羟基、酰基氨基、-N(R20)COR20、-N(R20)C(O)OR20、-N(R20)SO2(R20)、-COR20N(R20)2、-OC(O)R20N(R20)(R20)、-SO2N(R20)(R20)、-N(R20)(R20)、-COOR20、-C(O)N(OH)(R21)、-OS(O)2OR19、-S(O)2OR20、-OP(L)(OR20)(OR20)、-NP(O)(OR20)(OR20)或-P(O)(OR20)(OR20)。
具体地说,本发明提供以下细化合物:
在某些实施方案中,本发明的化合物由任一上述化合物与附加的定义表示,其中所述化合物由下式表示:
在某些实施方案中,本发明涉及含有上述任一种或多种化合物与药学上可接受的赋形剂的药物组合物。
合成类固醇生物碱化合物
可直接从作为天然产物分离的(或合成的)类固醇生物碱或这些化合物的N-保护形式制备本发明的环丙基类固醇生物碱衍生物。合适的氮保护基团包括但不限于:Fmoc、Alloc、Boc、Troc、三氟乙酸酯、Tosyl、Cbz、乙基氰与Bn。
可利用各种环丙基化(cyclopropanate)试剂环丙基化类固醇生物碱。包含称为卡宾体的反应性物质的1,1-卤代烷基金属络合物通常用于环丙基化烯烃。这些试剂通常利用二碘烷烃或重氮烷与金属或有机金属物质,例如Et2Zn、iBu3Al、钐、铜、铑或钯制成。在某些实施方案中,利用Et2Zn与二碘甲烷实现环丙基化。也可采用其它已知的环丙基化方法,例如利用硫内盐来与和羰基共轭的烯烃反应从而添加CH2或CH-烷基或CH-芳基的那些方法,与重氮烷基和α-重氮-羰基化合物(例如,重氮甲烷和重氮乙酸乙酯)的金属催化分解;这些方法不难获得具有烷基、芳基、烷氧基羰基(-COOR)或酰基取代基的环丙烷。例如,在含有金属催化剂,如铜或钯的有机溶剂中向烯烃化合物中加入重氮丙酸乙酯(EtO2C-C(N2)-Me)得到含有式1b所示基团的环丙烷,其中Z表示C(R23)2,其中一个R23是Me,另一个R23是COOEt。
通过小心地选择环丙基化试剂,可在具有不止一个烯烃的类固醇生物碱环丙基化中实现位点选择性。例如,如果在某些条件下利用二碘甲烷与Et2Zn环丙基化蒜藜芦碱,只有更富含电子的烯烃可以反应。
可采用多种方法控制环丙基化的非对映选择性。例如,降低环丙基化反应的温度可导致较高的非对映选择性。或者,可利用手性环丙基化试剂来区分类固醇生物碱的各非对映面(diastereo-face)。也可采用底物导向的反应(即,利用Et2Zn/CH2I2试剂的烯丙基醇环丙基化)来实现环丙基化中的面选择性(Facial selectivity)。
可在质子惰性溶剂中进行环丙基化反应,优选在其中反应成分基本上可溶的溶剂。合适的溶剂包括醚,例如***,1,2-二甲氧基乙烷,二甘醇二甲醚、叔丁基甲基醚、四氢呋喃等;卤化溶剂,例如氯仿,二氯甲烷,二氯乙烷等;脂族或芳族烃溶剂,例如苯、二甲苯、甲苯、己烷、戊烷等;酯与酮,例如乙酸乙酯,丙酮和2-丁酮;极性质子惰性溶剂,例如乙腈,二甲基亚砜,二甲基甲酰胺等;或者两种或多种溶剂的组合。在一优选的实施方案中,二氯甲烷是在使用二烷基锌和二碘甲烷时用于环丙基化的溶剂。
合成环丙基化的类固醇生物碱母核后,可采用本领域已知的各种官能化反应来衍生该化合物。代表性例子包括与烯基卤或芳基卤的钯偶联反应、氧化反应、还原反应、与亲核试剂反应、与亲电试剂反应、周环反应、加入保护基团、除去保护基团等。
在有路易斯或勃朗斯德酸存在下,本发明的环丙基环杷明类似物在此时进行未观察到的重排(unobserved rearrangement)与扩环从而得到新的环杷明类似物,其中D环增加了一个碳。环丙基环可以是取代或未取代的。在该环丙基环是取代的情况中,重排与扩环后与环丙烷的亚甲基相连的基团可以位于D环上。合适的酸包括但不限于:ZnI2、BF3、甲磺酸、二芳氧基磷酸(diaryloxyphosporic acid)与HCl。在本发明优选的实施方案中,所用的路易斯酸是BF3。可采用本领域已知的各种官能化反应进一步官能化这些同系的类似物(homologated analog)。代表性例子包括与烯基卤或芳基卤的钯偶联反应、氧化反应、还原反应、与亲核试剂反应、与亲电试剂反应、周环反应、加入保护基团、除去保护基团等。
本发明方法
本发明还提供治疗、缓解过度增殖性疾病,例如癌症以及其它hedgehog途径介导的疾病或病症的一种或多种症状,并降低其严重性的方法。
目前正在通过抑制Hedgehog途径活性的一个或多个方面能获得病症或疾病的治疗作用的大量临床病症中研究Hedgehog途径拮抗剂。虽然主要将注意力集中在癌症上,研究人员发现hedgehog的小分子抑制剂能缓解银屑病的症状(Tas等,2004,Dermatology,209:126-131,公布的美国专利号申请20040072913(纳入本文作为参考))。银屑病是极其常见的慢性皮肤病,其典型特征是通常含有具银色鳞片的斑块和红斑丘疹的皮肤损伤,虽然皮肤和身体的其它部分都会有差异。目前认为银屑病是自身免疫疾病,但是其病原学仍不了解。在一项研究中,将环杷明局部应用于银屑病的伤口导致该伤口完全或部分消退,同时炎性细胞减少(Tas等,同上)。
可利用本发明的hedgehog途径拮抗剂作为单一药物或与一种或多种其它抗银屑病药物联用来治疗或预防银屑病,所述其它抗银屑病药物包括但不限于:皮质类固醇、tar、卡泊三烯(calcipotriene)、他佐罗汀(tazarotene)、钙调磷酸酶抑制剂、紫外辐射、氨甲喋呤、类视黄醇、环孢菌素、免疫调节药物、依那西普(etanercept)、阿法西普(alefacept)、依法利组单抗(efalizumab)和英夫利昔单抗(infliximab)。
许多肿瘤和增殖性病症显示依赖于hedgehog途径。用本发明的化合物治疗可影响这种细胞的生长与存活。例如,Hedgehog途径的小分子抑制剂显示能抑制基底细胞癌(Williams等,2003,PNAS,100:4616-21)、成髓细胞瘤(Berman等,2002,Science,297:1559-61)、***癌(Berman等,2003,Nature,425:846-51)、胃肠癌症(Berman等,2003,Nature,425:846-51,公布的PCT申请WO 05/013800)、食道癌(Berman等,2003,Nature,425:846-51)、肺癌(Watkins等,2003.,Nature,422:313-7)与***癌(Karhadkar等,2004.,Nature,431:707-12)的生长。
此外,许多类型的癌症显示具有不受控的hedgehog途径激活,例如乳腺癌(Kubo等,2004.,Cancer Research,64:6071-4)、肝细胞癌症(Patil等,2005.,ACRR第96届年会(96th Annual AACR conference),摘要#2942;Sicklick等,2005.,ASCO年会(ASCO annual meeting),摘要#9610)、血液恶性肿瘤(Watkins和Matsui,未发表的结果)、基底癌(Bale和Yu,2001.,Human Molec.Genet.,10:757-762;Xie等,1998,Nature,391:90-92)、成髓细胞瘤(Pietsch等,1997.,Cancer Res.,57:2085-88)与胃癌(Ma等,2005,Carcinogenesis,2005年5月19日(Epub))。
可通过给予本发明的化合物与组合物治疗的癌性或瘤性疾病以及相关疾病包括但不限于:肾上腺皮质癌(Adrenal Cortical Cancer)、***癌、再生障碍性贫血、胆管癌、膀胱癌、骨癌、脑/CNS肿瘤、乳腺癌、***、非何杰金淋巴瘤、结肠癌、直肠癌、子宫内膜癌、食道癌、尤因家族肿瘤、眼癌、胆囊癌、胃肠道类癌瘤、胃肠道基质瘤(Gastrointestinal Stromal Tumor)、妊娠性滋养层细胞病、何杰金病、卡波西肉瘤、肾癌、喉与舌癌、急性淋巴细胞性白血病、急性髓细胞性白血病、儿童白血病(Children’s Leukemia)、慢性淋巴细胞性白血病、慢性髓细胞性白血病、肝癌、肺癌、肺类癌瘤、非何杰金型淋巴瘤、男性乳癌、恶性间皮瘤、多发性骨髓瘤、骨髓异常增生综合征、鼻腔与鼻旁癌(ParanasalCancer)、鼻咽癌、神经母细胞瘤、口腔癌、口咽癌、骨肉瘤、卵巢癌、胰腺癌、***癌、垂体癌、***癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、肉瘤、黑色素瘤皮肤癌、非黑色素瘤皮肤癌、胃癌、睾丸癌、胸腺癌、甲状腺癌、子宫肉瘤、***癌、阴门癌、瓦尔等斯特伦聚球蛋白血症与肾母细胞瘤。
本发明的方法与组合物可用于治疗人类癌症,例如基底细胞癌与上皮组织,例如皮肤的其它肿瘤。此外,可通过给予治疗有效量的至少一种本发明化合物作为单一药物或与另一种抗癌症药物联用将本发明化合物用作基底细胞癌、胰腺癌、***癌、肉瘤、淋巴瘤、白血病、胃肠道癌症、多发性骨髓瘤、小细胞肺癌、胶质瘤、乳腺癌、肝细胞或成髓细胞瘤的治疗方案的一部分。
本发明的方法与组合物可用于治疗致瘤性或超常增生转化,例如发生在中枢神经***中的。例如,本发明的化合物可用于使得这种转化细胞变为有丝***后或凋亡。因此,本发明方法可用作,例如恶性胶质瘤、脑膜肿瘤、成髓细胞瘤、神经外胚层肿瘤(neuroectodermal tumor)和室管膜瘤的治疗方案的一部分。
在一个实施方案中,本发明方法可用作,例如恶性成髓细胞瘤与其它原发性CNS恶性神经外胚层肿瘤的治疗方案的一部分。
在某些实施方案中,本发明涉及治疗癌症的方法,包括给予需要的对象治疗有效量的一种或多种上述化合物。
在某些实施方案中,本发明涉及治疗癌症的方法,包括给予需要的对象治疗有效量的一种或多种上述化合物,所述癌症位于对象的头、颈、鼻腔、鼻窦、鼻咽、口腔、口咽、喉、舌、唾液腺、神经节细胞瘤、胰腺、胃、皮肤、食道、肝脏和胆道***、骨、小肠、结肠、直肠、卵巢、***、肺、乳腺、淋巴***、血液、骨髓、中枢神经***或脑。
在某些实施方案中,本发明涉及治疗癌症的方法,包括给予需要的对象治疗有效量的一种或多种上述化合物,其中所述癌症是基底细胞癌、胰腺癌、***癌、肉瘤、淋巴瘤、白血病、胃癌、食道癌、胆癌(biliary cancer)、结肠癌、多发性骨髓瘤、小细胞肺癌、胶质瘤、乳腺癌、肝细胞或成髓细胞瘤。
在某些实施方案中,本发明涉及上述方法,其中所述化合物与放疗或另一抗癌症化疗药物联用。
在某些实施方案中,本发明涉及上述方法,其中所述化合物局部给予至肿瘤或全身性给予患者。
在某些实施方案中,本发明涉及上述方法,其中所述化合物的给药方式是吸入、口服、静脉内、舌下、眼部、透皮、直肠、***、局部、肌肉内、动脉内、鞘内、皮下、含服或鼻部给药。
在某些实施方案中,本发明涉及上述方法,其中所述给药方式是口服、静脉内或局部给药。
在某些实施方案中,本发明涉及拮抗细胞的hedgehog途径的方法,包括使表达平滑(蛋白)的细胞与有效量的一种或多种上述化合物接触。
在某些实施方案中,本发明涉及拮抗细胞的hedgehog途径的方法,包括使表达平滑(蛋白)的细胞与有效量的一种或多种上述化合物接触,其中所述表达平滑(蛋白)的细胞在体外与所述化合物接触。
在某些实施方案中,本发明涉及拮抗细胞的hedgehog途径的方法,包括使表达平滑(蛋白)的细胞与有效量的一种或多种上述化合物接触,其中所述表达平滑(蛋白)的细胞在体内与所述化合物接触。
在某些实施方案中,本发明涉及拮抗细胞的hedgehog途径的方法,包括使表达平滑(蛋白)的细胞与有效量的一种或多种上述化合物接触,其中所述表达Smo(蛋白)的细胞是在患者体内。
在某些实施方案中,本发明涉及治疗或预防对象的银屑病的方法,包括给予需要的对象治疗有效量的一种或多种上述化合物。
在某些实施方案中,本发明涉及治疗或预防的银屑病的上述方法,其中所述化合物的给药方式是局部给药。
在某些实施方案中,本发明的一种或多种化合物与一种或多种抗银屑病药物联用,所述一种或多种抗银屑病药物包括但不限于:皮质类固醇、tar、卡泊三烯(calcipotriene)、他佐罗汀(tazarotene)、钙调磷酸酶抑制剂、紫外辐射、氨甲喋呤、类视黄醇、环孢菌素、免疫调节药物、依那西普(etanercept)、阿法西普(alefacept)、依法利组单抗(efalizumab)和英夫利昔单抗(infliximab)。
联用放疗或化疗治疗癌症
在某些实施方案中,一种或多种本发明化合物与一种或多种抗癌症、化疗药物联用来治疗或预防癌症或致瘤性疾病,所述抗癌症、化疗药物包括但不限于:2,2-二氟脱氧胞嘧啶核苷(gemcitabine)、氨甲喋呤、紫杉醇、巯基嘌呤、硫代鸟嘌呤、羟脲、阿糖胞苷、环磷酰胺、异环磷酰胺、亚硝基脲、顺式铂氨、脱羧铂氨、丝裂霉素、甲氮咪胺、丙卡巴肼(procarbizine)、鬼臼亚乙苷、强的松龙、***、阿糖胞苷(cytarbine)、campathecins、博莱霉素、阿霉素、依达比星、柔红霉素、更生霉素、普卡霉素、二羟蒽酮、天冬酰胺酶、长春花碱、长春花新碱、脱水长春花碱、紫杉醇(paclitaxel)与紫杉萜(docetaxel)。在一优选的实施方案中,一种或多种本发明化合物与一种或多种化疗或其它抗癌症药物联用来治疗或预防癌症或致瘤性疾病,所述化疗或其它抗癌症药物包括但不限于:射线(例如γ-射线)、氮芥子(例如环磷酰胺、异环磷酰胺、氯乙环磷酰胺、苯丁酸氮芥、雌氮芥磷酸钠和美法仑)、亚硝基脲(例如亚硝基脲氮芥(BCNU)和洛莫司汀(CCNU))、烷基磺酸酯(例如白消安和二羟白消安)、三氮烯类(Triazenes)(例如甲氮咪胺和替莫唑胺(Temozolomide))、含铂的化合物(例如顺式铂氨、脱羧铂氨和奥利沙铂)、长春花生物碱(例如长春新碱、长春碱、脱乙酰长春花碱和脱水长春花碱)、紫杉烷(Taxoids)(例如紫杉醇和紫杉萜(Docetaxol))、Epipodophyllins(例如鬼臼亚乙苷、表鬼臼毒噻吩糖苷、抑拓扑酶素、9-氨基喜树碱、坎图利诺替康(Camptoirinotecan)、克立那托(Crisnatol)、丝裂霉素C和丝裂霉素C)、抗代谢物、DHFR抑制剂(例如氨甲喋呤和曲美沙特(Trimetrexate))、IMP脱氢酶抑制剂(例如霉酚酸、噻唑呋林(Tiazofurin)、利巴韦林和EICAR)、核糖核苷酸还原酶抑制剂(例如羟脲和去铁胺)、尿嘧啶类似物(例如氟尿嘧啶、5-氟脱氧尿苷、去氧氟尿苷、雷替曲塞(Ratitrexed)和卡培他滨(Capecitabine))、胞嘧啶类似物(例如阿糖胞苷(ara C)、胞嘧啶***糖苷和氟达拉滨)、嘌呤类似物(例如巯基嘌呤和硫代鸟嘌呤)、抗***(例如三苯氧胺、雷洛昔芬(Raloxifene)和甲地孕酮)、LHRH激动剂(例如戈舍瑞林(goscrclin)和醋酸亮丙瑞林)、抗雄激素(例如氟他胺和比卡鲁胺(Bicalutamide))、维生素D3类似物(例如EB 1089、CB 1093和KH 1060)、光动疗法(例如维替泊芬(vertoporfin)(BPD-MA)、酞菁、光敏剂Pc4和脱甲氧基-竹红菌甲素(2BA-2-DMHA))、细胞因子(例如干扰素α、干扰素γ和肿瘤坏死因子)、异戊二烯化抑制剂(例如洛伐他汀)、多巴胺能神经毒素(例如1-甲基-4-苯基吡啶离子)、细胞周期抑制剂(例如星形孢菌素)、放线菌素(例如放线菌素D和更生霉素)、博莱霉素类(例如博莱霉素A2、博莱霉素B2和丙胺博莱霉素)、蒽环素类(例如柔红霉素、阿霉素(亚得里亚霉素)、依达比星、表柔比星、吡柔比星、佐柔比星和二羟蒽酮)、MDR抑制剂(例如异搏定)、Ca2+ATP酶抑制剂(例如毒胡萝卜素(thapsigargin))、抗体(例如阿瓦斯汀(Avastin)、爱比妥昔(Erbitux)、利妥昔单抗(Rituxan)和托西莫单抗(Bexxar))、皮质类固醇(例如强的松龙(prednilone)、强的松(predisone)等)、伊马替尼(Imatinib)、沙立度胺、莱那立度胺(Lenalidomide)、硼替佐米(Bortezomib)、2,2-二氟脱氧胞嘧啶核苷(Gemcitabine)、埃罗替尼(Erlotinib)、吉非替尼(Gefitinib)、索拉非尼(Sorafenib)和苏替尼(Sutinib)。
可根据本领域熟知的治疗方案给予化疗药物和/或放疗。本领域技术人员应知道给予化疗药物和/或放疗可根据所治疗的疾病与化疗药物和/或放疗对该疾病的已知作用而不同。根据熟练的临床医师的知识,治疗方案(例如,剂量和给药次数)也可因观察到的所给予药物(即,抗致瘤性药物或射线)对患者的作用、疾病对所给予治疗性药物的应答反应与观察到的副作用而不同。
本发明的化合物与化疗药物通常也不必在同一药物组合物中给予,由于二者不同的理化性质,可能需经不同途径给予。例如,可静脉内给予本发明的化合物以产生和维持良好的血液水平,而化疗药物可口服给予。熟练的临床医师熟知(如何)确定给药方式与在同一药物组合物中给药(是否)明智(如果可能的话)。可根据本领域已知的确定方案进行最初给药,然后熟练的临床医师可根据观察到的作用修正剂量、给药方式与给药次数。
化疗药物或射线的具体选择取决于医师的诊断与他们对患者的状况以及合适治疗方案的判断。
可取决于增殖性疾病的性质、患者的状况、待与本发明化合物联合给予(即,在一个治疗方案内)的化疗药物和/或射线的实际选择来同时给予(例如,同时、基本上同时或在同一治疗方案内)或连续给予本发明的化合物、化疗药物和/或射线。
如果本发明的化合物与化疗药物和/或射线不同时给予或基本上不同时给予,则给予本发明化合物与化疗药物和/或射线的最佳顺序可因肿瘤不同而不同。因此,在某些情况中,可首先给予本发明化合物,然后给予化疗药物和/或射线,在其它情况中,可首先给予化疗药物和/或射线,再给予本发明化合物。在一个治疗方案内,可重复这种交替给药。对所治疗疾病与患者的状况进行评估后,熟练的医师可熟知(如何)确定给药顺序、各治疗性药物在治疗方案期间的重复给药次数。例如,可首先给予化疗药物和/或射线(特别是如果是细胞毒性药物),然后给予本发明化合物来继续治疗,再给予化疗药物和/或射线(确定有利时)等等,直至完成治疗方案。
因此,在治疗进行中,实施医师可根据经验和知识,按照每位患者的需要修正各治疗方案中治疗组分(治疗性药物,即,本发明化合物、化疗药物或射线)的给予。
药物组合物
在另一实施方案中,本发明提供药学上可接受的组合物,其含有治疗有效量的一种或多种上述化合物(式1和2),与一种或多种药学上可接受的载体(添加剂)和/或稀释剂配制在一起。本发明的药物组合物可专门配制为以固体或液体形式给药,包括适用于以下给药方式的:(1)口服给药,例如灌服剂(drench)(水性或非水性溶液或悬浮液)、片剂(如靶向面颊、舌下与全身吸收)、大丸剂(boluse)、粉末、粒剂、敷用于舌的糊剂;(2)胃肠外给药,例如以诸如无菌溶液或悬浮液或缓释制剂通过皮下、肌肉内、静脉内或硬膜外注射;(3)局部应用,例如以乳膏、软膏或控释贴剂或喷剂应用于皮肤;(4)***内或直肠内给药,例如作为***栓、乳膏或泡沫剂;(5)舌下给药;(6)眼部给药;(7)透皮给药;(8)肺部给药或(9)鼻部给药。如上所述,本发明化合物的某些具体形式可含有碱性官能团,例如氨基或烷基氨基,因而能与药学上可接受的酸形成药学上可接受的盐。在这点上,术语“药学上可接受的盐”指本发明化合物的相对无毒的、无机和有机酸加成盐。这些盐可以在给药载体或剂型制造过程中原位制备,或者通过使游离碱形式的本发明纯化合物单独与合适的有机或无机酸反应,然后在随后的纯化中分离如此得到的盐来制备。代表性盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、延胡索酸盐、琥珀酸盐、酒石酸盐、萘酸盐(napthylate)、甲磺酸盐、葡庚糖酸盐、乳糖酸盐与月桂基磺酸盐等。(参见,例如Berge等,(1977),“药物盐”(Pharmaceutical Salts),J.Pharm.Sci.,66:1-19)。
本发明化合物的药学上可接受的盐包括所述化合物的常规无毒盐或季铵盐,例如从无毒的有机或无机酸(制备)。例如,这种常规无毒盐包括衍生自无机酸,例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的那些盐;与从有机酸,例如乙酸、丙酸、琥珀酸、乙醇酸(glycolic)、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸(salicyclic)、对氨基苯磺酸、2-乙酰氧基苯甲酸、延胡索酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、异硫羰酸(isothionic)等制备的盐。
在其它情况中,本发明化合物可含有一个或多个酸性官能团,因此能与药学上可接受的碱形成药学上可接受的盐。在这些例子中,术语“药学上可接受的盐”指本发明化合物的相对无毒的、无机和有机碱加成盐。这些盐可以类似地在给予载体或剂型制造过程中原位制备,或者通过使游离酸形式的纯化合物单独与合适的碱,例如药学上可接受的金属阳离子的氢氧化物、碳酸盐或碳酸氢盐,与铵盐,或与药学上可接受的有机伯胺、仲胺或叔胺反应来制备。代表性的碱或碱土盐包括锂、钠、钾、钙、镁与铝盐等。用于形成碱加成盐的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等。(参见,例如Berge等,同上)
所述组合物中也可存在润湿剂、乳化剂与润滑剂(例如月桂基硫酸钠和硬脂酸镁)以及着色剂、释放剂(release agent)、包衣剂、甜味剂、调味剂、芳香剂、防腐剂和抗氧化剂。
药学上可接受的抗氧化剂的例子包括:(1)水溶性抗氧化剂,例如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等;(2)油溶性抗氧化剂,例如棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁基化羟基甲苯(BHT)、卵磷脂、棓酸丙酯、α-生育酚等;与(3)金属螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
制备这些制剂或组合物的方法包括使本发明化合物与载体和任选的一种或多种辅助成分结合的步骤。一般通过使本发明化合物与液体载体,或精细磨碎的固体载体或二者均匀且紧密地结合,然后(如果需要)使产品成形。
适合于胃肠外给药的本发明药物组合物包含一种或多种本发明化合物与一种或多种药学上可接受的无菌等渗的水性或非水性溶液、分散液、悬浮液或乳液,或在使用前重建为无菌可注射溶液或分散液的无菌粉末,它们可包含糖、醇、抗氧化剂、缓冲液、抑菌剂、使得制剂与预计受者的血液等渗的溶质或悬浮或增稠剂。
本发明药物组合物所用合适的水性与非水性载体的例子包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等)及其适当的混合物,植物油,例如橄榄油与可注射有机酯,例如油酸乙酯。可例如通过利用包衣材料,如卵磷脂,在分散体的情况中维持所需粒剂与利用表面活性剂来维持适当的流动性。
这些组合物也可包含佐剂,例如防腐剂、润湿剂、乳化剂与分散剂。可通过加入各种抗菌剂与抗真菌剂,例如对羟基苯甲酸酯、氯代丁醇、山梨酸苯酚(phenol sorbic acid)等来确保本发明化合物不受微生物的作用。也需要在组合物中加入等渗剂,例如糖、氯化钠等。此外,可通过加入能延缓吸收的物质,例如单硬脂酸铝和明胶以实现可注射的药物形式的长期吸收。
在一些情况中,为延长药物的作用,需要减缓药物从皮下或肌肉内注射(部位)的吸收。可通过利用水溶性不佳的晶体或无定形物质的液体悬浮液来实现此目的。因此,药物的吸收速率取决于其溶解速率,进而取决于晶体大小和晶型。或者,可通过将药物溶解或悬浮在油载体中以实现胃肠外给予的药物形式的延迟吸收。
可利用生物可降解的聚合物,例如聚交酯-聚乙醇酸交酯形成本发明化合物的微囊基质来制备可注射的长效剂型(depot form)。药物的释放速率可依照药物和聚合物之比与所用具体聚合物的性质得以控制。其它生物可降解聚合物的例子包括聚(原酸酯)和聚(酐)。也可通过将药物包裹在与身体组织相容的脂质体或微乳剂中来制备长效的可注射制剂。
适合于口服给药的本发明制剂可以是胶囊、扁囊剂、药丸、片剂、糖锭(利用调味基,通常是蔗糖与***胶或黄蓍胶)、粉末、粒剂形式或作为水性或非水性液体配制的溶液或悬浮液,或作为水包油或油包水液体乳剂,或作为酏剂或糖浆,或作为锭剂(利用惰性锭基,如明胶和甘油,或者蔗糖和***胶)和/或作为漱口剂等,上述制剂各含有预定量的本发明化合物作为活性成分。本发明化合物也可作为大丸剂、药糖剂或糊剂给予。
当将本发明化合物作为药物给予人和动物时,可以其本身或作为含有,例如0.1-99%(更优选10-30%)活性成分与药学上可接受的载体的药物组合物给予。
可通过任何合适的给药途径给予人和其它动物这些化合物来治疗,所述给予途径包括口服、鼻部(例如作为喷剂)、直肠、***内、胃肠外、脑池内、局部(例如作为粉末、乳膏或滴剂)给药,包括含服与舌下给药。
无论选择何种给药途径,可通过本领域技术人员已知的常规方法将本发明化合物(可以合适的水合形式使用)和/或本发明的药物组合物配制为药学上可接受的剂型。
本发明药物组合物中活性成分的实际剂量水平可不同,从而获得能有效实现具体患者所需的治疗应答的活性成分含量、组成与给药方式,而对患者无毒性。
选择的剂量水平取决于各种因素,包括所用本发明具体化合物或其酯、盐或酰胺的活性,给药途径,给药时间,所用具体化合物的排出或代谢速率,吸收的速率和程度,治疗的持续时间,可与所用具体化合物联用的其它药物、化合物和/或物质,所治疗患者的年龄、性别、体重、状况、总体健康情况与以前的病史等医学领域熟知的因素。
具有本领域普通技术的医师或兽医不难确定并开出有效量的所需药物组合物的处方。例如,医师或兽医开始给药时药物组合物中本发明化合物的剂量可以低于为达到所需治疗作用需要的剂量,然后逐渐增加剂量直至达到所需作用。
本发明化合物合适的每日剂量一般是能有效产生治疗作用的最低剂量的化合物用量。这种有效剂量通常取决于上述因素。对于患者,当用于所示镇痛作用时,本发明化合物的口服、静脉内、脑室内和皮下剂量一般为约0.0001-约100mg/公斤体重/天。
如果需要,活性化合物的有效每日剂量可任选以单位剂量形式,分为2、3、4、5、6或更多次亚剂量在白天以合适的间隔分别给予。优选的给药是每日一次给药。
虽然可能单独给予本发明化合物,优选作为药物制剂(组合物)给予该化合物。
接受该治疗的对象一般是需要治疗的任何动物,包括灵长类,特别是人与其它哺乳动物,例如马、牛、猪和绵羊;与家禽和宠物。
本发明化合物可如所述或与药学上可接受的载体混合给予,也可与抗菌剂,例如青霉素、头孢菌素、氨基糖苷类和糖肽类联合给予。因此,联合疗法包括以后续给药时,先给予的化合物的治疗作用不完全消失的方式连续、同时与分别给予活性化合物。
例证
现已总体描述了本发明,参考以下实施例更易于理解本发明,这些实施例只是为说明本发明的某些方面与实施方案,而非限制本发明。
实施例1
制备环杷明的衍生物:
A部分
在室温向环杷明2(250mg,0.6mmol,1当量)的DCM溶液(10mL)中加入Fmoc-OSu(205mg,0.6mmol,1当量),得到的混合物在室温搅拌过夜。将得到的粗制Fmoc-环杷明溶液冷却至0℃,用甲苯配制的15%二乙基锌(0.5mL,0.6mmol,1当量)处理并搅拌30分钟(烧瓶A)。
在0℃用甲苯配制的15%二乙基锌(3mL,3mmol,5当量)处理用DCM(20mL)配制的二碘甲烷(0.4mL,6mmol,10当量),得到的溶液搅拌5分钟(烧瓶B)。
将烧瓶B的内含物经套管转移至烧瓶A中,得到的悬浮液在室温搅拌5小时。用HCl(1M)猝灭反应,搅拌10分钟(直至所有白色固体再溶解),用DCM(5×)萃取。干燥(MgSO4)有机萃取物,经硅藻土(Celite)过滤,真空浓缩。快速层析(1∶1己烷/乙酸乙酯)纯化残留物。得到9∶1非对映体混合物的目标产物(target)11,12-单环丙烷与20%非对映体的双-环丙烷化产物(总回收率80%)。采用制备型SFC色谱分离此混合物。
B部分
在室温下用二乙胺(0.5mL,4.8mmol,32当量)处理在DCM(2mL)中的Fmoc-单环丙基环杷明3(100mg,0.15mmol,1当量)过夜,真空浓缩得到的溶液,将残留物吸附到硅胶上并经快速层析纯化(2∶1→1∶1己烷/乙酸乙酯,然后95∶5→90∶10→20∶80DCM/甲醇)。得到白色固体状的所需产物(95%产率)。MS(ESI(+))m/e 426.31(M+H)+。
实施例2
治疗环杷明的衍生物:
A部分
75℃在3分钟期间向氢化肉桂酸5(3.01g,20mmol,1当量)的无水氯仿(30mL)溶液中滴加亚硫酰氯(1.75mL,24.1mmol,1.2当量)。混合物回流3.5小时。蒸馏除去溶剂得到淡黄色粘稠液体状的粗制酰基氯。该粗产物无需进一步纯化即可使用。
B部分
25℃,向DCM(30mL)配制的7(3.16g,24.1mmol,1.2当量)与NaOH水溶液(2.0M,30mL,3当量)的双相混合物中加入酰基氯6(3.38g,20mmol,1当量)的DCM溶液(10mL),得到的混合物在25℃搅拌3小时。然后用HCl水溶液(2M,30mL)中和混合物。分离有机层,用DCM(3×50mL)萃取水层。用HCl(2.0M,25mL)、水(3×50mL)、饱和盐水(50mL)洗涤合并的有机层,硫酸镁干燥,减压蒸发除去溶剂。粗制品利用5%甲醇∶DCM作为洗脱剂进行硅胶层析,然后用10%甲醇∶DCM洗柱得到1.141g化合物8。
C部分
在0℃向酸8(264mg,1mmol,1当量)、EDCI(231mg,1.2mmol,1.2当量)与三乙胺(168μL,1.2mmol,1.2当量)的DCM(2mL)混合物中加入烯丙胺(90.3μL,1.2mmol,1.2当量),得到的混合物在0℃搅拌1小时,然后在2小时期间回暖至25℃。向反应混合物中加入水(50mL),用DCM(4×25mL)萃取,用1M HCl(2×25mL)、水(3×25mL)、饱和盐水(25mL)洗涤合并的有机层,硫酸镁干燥,减压蒸发除去溶剂得到287.5mg所需产物。该物质无需进一步纯化即可使用。
D部分
向烯丙基酰胺9(70mg,0.23mmol,1当量)的丙酮(1mL)与水(0.3mL)的溶液中加入四氧化锇溶液(0.35mL,0.035mmol,0.15当量,2.5w/w用叔丁醇配制)。加入OsO4溶液后立即将反应混合物在冰中冷却,得到的暗棕色溶液在0℃搅拌15分钟。将高碘酸钠(110mg,0.51mmol,2.2当量)分5份加入上述混合物,在0℃继续搅拌1小时,然后在2小时期间回暖至25℃。用DCM(3mL)稀释反应混合物,经硫酸镁的短柱(short plug)过滤,用DCM(4×3mL)洗涤滤饼。浓缩滤液,残留物(67.9mg)利用5%甲醇∶DCM经RP硅胶短柱过滤得到38.9mg所需产物。
E部分
向1(10mg,0.023mmol,1当量)的乙腈悬浮液(2mL)中加入醛10(17mg,0.056mmol,2.4当量)的乙腈溶液(0.3mL),然后加入三乙酰氧基硼氢化钠(6.5mg,0.031mmol,1.3当量),反应混合物在25℃搅拌16小时。然后减压蒸发除去溶剂,残留物利用3%甲醇∶DCM经硅胶(柱)层析(7cm×10mm)得到24.6mg粗制物质。此物质再次利用2%甲醇∶DCM进行柱层析,回收到18.2mg不纯的产物,该产物利用3%甲醇∶DCM作为展开溶液经制备型TLC纯化(进行2次)得到6.3mg所需产物。MS(ESI(+))m/e 714.4(M+H)+。
实施例3
制备环杷明的衍生物:
A部分
将环杷明2(20mg,0.049mmol,1当量)悬浮在干燥甲苯(0.6mL)与环己酮(150μL,1.47mmol,30当量)中,然后加入异丙醇铝(79mg,0.392mmol,8当量)。得到的混合物加热回流2小时,冷却至室温,用乙酸乙酯稀释,用罗谢尔盐溶液猝灭。将此双相混合物搅拌过夜,分层,用乙酸乙酯萃取水相,用(MgSO4)干燥合并的有机萃取物,过滤并真空浓缩。采用快速层析(DCM,DCM/甲醇98∶2与95∶5)纯化残留物。得到白色结晶固体状的目标产物(70%产率)。
B部分
在0℃用甲苯配制的15%二乙基锌(0.2mL,0.2mmol,10当量)处理用DCM(0.52mL)配制的二碘甲烷(40μL,0.5mmol,25当量),得到的溶液搅拌5分钟。加入DCM(0.35mL)配制的化合物12(10mg,0.02mmol,1当量),在室温(除去冰浴)搅拌得到的混合物3小时,用2N NaOH猝灭反应并搅拌10分钟,分层,用DCM(2×)萃取水层。干燥(MgSO4)有机萃取物,过滤并真空浓缩。残留物经快速层析(DCM/甲醇92∶8)纯化。得到白色固体状的环丙基化物质。MS(ESI(+))m/e 424.5(M+H)+。
实施例4
制备环杷明的衍生物:
A部分
在室温向环杷明2(250mg,0.6mmol,1当量)的DCM(10mL)溶液中加入Fmoc-OSu(205mg,0.6mmol,1当量),得到的混合物在室温搅拌过夜,真空浓缩。得到灰白色泡沫状的粗制Fmoc-环杷明。
B部分
将粗制Fmoc-环杷明3(15mg,0.024mmol,1当量)的DCM(0.5mL)溶液冷却至-78℃,用依次用碳酸氢钠(4mg,0.047mmol,1.96当量)与mCPBA(4mg,0.024mmol,1当量)处理。反应混合物在-78℃搅拌1小时,用H2O稀释,用DCM(3×)萃取。用10%NaHCO3和盐水洗涤有机萃取物,干燥(MgSO4),,过滤并真空浓缩。粗制物质经制备型TLC(己烷/乙酸乙酯1∶2)纯化得到白色泡沫状的环氧化物(70%产率)。
C部分
在室温用Et2NH(0.5mL,4.8mmol,282当量)处理化合物14(11mg,0.017mmol,1当量)的DCM(0.5mL)溶液,得到的溶液在室温搅拌过夜,然后真空浓缩。残留物经制备型TLC(DCM/甲醇9∶1)纯化。得到白色固体状的化合物13(90%产率)。MS(ESI(+))m/e 428.5(M+H)+。
实施例5
制备环杷明的衍生物:
A部分
称出(mass out)化合物2(1.30g,3.2mmol,1当量),加入反应容器。称出碳酸钾(0.91g,6.6mmol,2.1当量),加入反应容器,然后加入二氯乙烷(6.0mL,76mmol,23.8当量)和无水DMSO(5mL)。在氮气气氛中将反应体系加热至70℃,持续36小时。将反应体系冷却至室温,用DCM(15mL)稀释并用水(2×15mL)洗涤两次。硫酸钠干燥有机层,过滤(如果需要的话,进行DCM清洗),浓缩至干得到浅黄色固体。经快速层析(DCM/乙酸乙酯)得到白色结晶固体状目标物质。
B部分
将化合物16(0.111g,0.233mmol,1当量)转移入置于氮气气氛中的反应烧瓶中,无水DCM(2mL)溶解。加入氯碘甲烷(0.238mL,3.27mmol,14当量)。将溶液冷却至-15℃。在30分钟期间滴加二乙基锌(1M,庚烷配制,1.63mL,1.63mmol,6.5当量),小心控制放热。将反应维持于-10℃到-14℃数小时,直至TLC显示起始物质已被耗尽。然后小心加入THF(6mL),再加入水性柠檬酸盐缓冲液(pH 4.5,10mL)以猝灭反应。使各层回暖至室温。饱和硫酸钠(10mL)。充分混合各层,用过量的DCM将其转移至分液漏斗,收集有机层。用氢氧化钠水溶液(1N,10mL)与饱和的硫酸钠水溶液(10mL)洗涤有机层,硫酸钠干燥,然后浓缩至干。粗制物质经快速层析纯化得到55%产率的所需产物。
实施例6
制备环杷明的衍生物:
向化合物11(5mg,0.01mmol,1当量)和化合物10(10mg,0.04mmol,3当量)的无水DCM溶液(5mL)中加入固体三乙酰氧基硼氢化钠(8mg,0.04mmol,3当量),得到的悬浮液在25℃搅拌2小时。用碳酸氢钠猝灭反应混合物,用DCM(4×10mL)萃取,收集有机层并用饱和的盐水(1×20mL)洗涤,硫酸镁干燥,然后减压浓缩。粗品经PTLC(DCM/甲醇95∶5)纯化得到8mg的所需产物。
实施例7
制备环杷明的衍生物
A部分
将环杷明2(20mg,0.049mmol)悬浮在干燥甲苯(0.6mL)和环己酮(150μL,1.47mmol,30当量)中,然后加入异丙醇铝(79mg,0.392mmol,8当量)。得到的混合物加热至回流,持续2小时,冷却至室温,用乙酸乙酯稀释,然后用罗谢尔盐溶液猝灭。所述双相混合物搅拌过夜,分层,用乙酸乙酯萃取水相,干燥(MgSO4)合并的有机萃取物,过滤,然后真空浓缩。残留物经快速层析(DCM,DCM/甲醇98∶2和95∶5)纯化。得到白色结晶固体状的目标产物12(70%产率)。
B部分
在0℃用甲苯配制的15%二乙基锌(0.2mL,0.2mmol,1.0当量)处理用DCM(0.52mL)配制的二碘甲烷(40μL,0.5mmol,2.5当量),得到的溶液搅拌5分钟(观察到白色沉淀物)。加入DCM(0.35mL)配制的烯酮12(10mg,0.02mmol,1当量),得到的混合物在室温(除去冰浴)搅拌3小时,用NaOH(2N)猝灭反应并搅拌10分钟,分层,用DCM(两次)萃取水相。MgSO4干燥有机萃取物,过滤,并真空浓缩。残留物经快速层析(DCM/甲醇92∶8)纯化。得到白色固体状环丙基化物质11。
C部分
0℃,在氩气气氛中向环丙基烯酮11(10mg,24μmol,1当量)的DCM(0.5ml)溶液中加入BF3.Et2O(30μL,0.24mmol,10当量),得到的溶液在0℃搅拌1.5小时,用DCM稀释,用饱和的碳酸氢钠猝灭反应。用饱和的碳酸氢钠洗涤有机相,用DCM萃取合并的水层。用盐水洗涤合并的有机层,MgSO4干燥,过滤,减压浓缩。残留物经制备型TLC(DCM/甲醇9∶1)纯化。得到白色固体状的目标产物18(90%产率)。MS(ESI(+))m/e 424.62(M+H)+。
实施例8
制备环杷明的衍生物:
A部分
在室温向环杷明2(250mg,0.6mmol,1当量)的DCM溶液(10mL)中加入Fmoc-OSu(205mg,0.6mmol,1当量),得到的混合物在室温搅拌过夜。然后将得到的粗制Fmoc-环杷明溶液冷却至0℃,用甲苯配制的15%二乙基锌(0.5mL,0.6mmol,1当量)处理并搅拌30分钟(烧瓶A,淡黄色溶液)。
在0℃用甲苯配制的15%二乙基锌(3mL,3mmol,5当量)处理用DCM(20mL)配制的二碘甲烷(0.4mL,6mmol,10当量),得到的溶液搅拌5分钟(烧瓶B,白色沉淀物)。
将烧瓶B的内含物经套管转移至烧瓶A中,得到的悬浮液在室温搅拌5小时。用HCl(1N)猝灭反应,搅拌10分钟(直至所有白色固体再溶解),用DCM(5×)萃取。干燥(MgSO4)有机萃取物,经硅藻土过滤,真空浓缩。残留物经快速层析(己烷/乙酸乙酯1∶1)纯化。得到9∶1非对映体混合物的目标产物11,12-单环丙烷5与20%非对映体的双-环丙烷化产物(总回收率80%)。采用制备型SFC色谱分离此混合物。
B部分
将Fmoc-环丙基环杷明3(14mg,22μmol,1当量)溶解在DCM(0.5ml)中,冷却至0℃,用BF3·Et2O(27μL,0.22mmol,10当量)处理1小时,然后用饱和的碳酸氢钠猝灭反应,分层,用DCM萃取水相。MgSO4干燥合并的有机萃取物,过滤,真空浓缩。残留物经制备型薄板层析(己烷/乙酸乙酯2∶1)纯化。得到清澈的油状目标产物Fmoc-扩环的(expanded)环杷明。
用Et2NH(0.5mL,4.8mmol,154当量)处理粗制的Fmoc-扩环的环杷明(20mg,31μmol,1当量)的DCM(0.5m1)溶液过夜,真空浓缩,残留物经快速层析(DCM,DCM/甲醇98∶2和95∶5)纯化。得到油状的所需化合物,该化合物能在静置后结晶。MS(ESI(+))m/e 426.29(M+H)+。
实施例9
制备环杷明的衍生物:
A部分
将化合物6(23mg,54μmol,1当量)溶解于DCM(1mL),加入甲基碘(0.17mL,0.54mmol,10当量)。在氮气气氛中于室温将反应体系搅拌过夜。第二天清晨,TLC/LC-MS显示仍有一些SM。加入一勺(spatula)Na2CO3,混合物再搅拌1小时。将粗制物质加样于Biotage 25Si+M上,用DCM/乙酸乙酯/甲醇(82.5/10/7.5)洗脱。得到16mg无定形物质。MS(ESI(+))m/e 440.32(M+H)+。
实施例10
制备环杷明的衍生物:
A部分
将氢化肉桂酰氯22(1.13g,6.7mmol,1当量)与烯丙胺(0.77mL,10mmol,1.5当量)溶解于THF(20mL),在室温搅拌反应体系24小时。形成白色沉淀。过滤反应混合物。MgSO4干燥滤液,减压浓缩。分离到无色油状物,该物质随后转化为蜡状固体(1.1g)。
在0℃向烯丙酰胺(0.81mg,0.27mmol,1当量)的丙酮∶水(9mL;3∶1)混合物中加入OsO4(0.55mL,2.5w/w,叔丁醇配制)溶液,得到的浅褐色混合物搅拌10分钟。将高碘酸钠固体(0.13g,0.59mmol,2.2当量)分3份加入,混合物在0℃继续搅拌,然后在2小时期间回暖至25℃。用DCM(25mL)稀释灰白色(light offwhite)奶油状混合物,硫酸镁干燥,经硅藻土垫滤去固体,减压浓缩滤液。粗制品缓慢显出黄黑色。将粗制物质加样于Biotage 25+S上,用己烷/乙酸乙酯(1∶1-1∶2)纯化得到无色油状物(250mg),所述物质一旦干燥即固化。
B部分
向18(108mg,0.25mmol,1当量)与醛21(100mg,0.52mmol,2.1当量)的DCM(5mL)溶液中一次性加入三乙酰氧基硼氢化钠(100mg,0.47mmol,1.9当量),在室温搅拌浆料7小时。通过加入甲醇和经硅藻土过滤来猝灭反应。蒸发至干得到230mg油状物。所述物质经层析纯化(SiO2,柱3cm×4cm)用己烷/乙酸乙酯(4∶6-2∶8)洗脱得到38mg所需产物。MS(ESI(+))m/e 599.74(M+H)+。
实施例11
制备环杷明的衍生物:
A部分
将2-苯基乙磺酰氯25(1.13g,5.5mmol,1当量)与烯丙胺(0.56mL,7.3mmol,1.3当量)溶解于THF(20mL),在室温过夜反应24小时。形成白色沉淀。过滤反应混合物。MgSO4干燥滤液,过滤并真空浓缩。分离到淡黄色油状物(1.1g)。该粗制物质可直接用于下一步骤。
在0℃向烯丙基磺酰胺(0.15g,0.66mmol,1当量)的丙酮∶水(4mL,3∶1)溶液中加入OsO4溶液(0.13mL,2.5w/w,叔丁醇配制),得到的浅褐色混合物搅拌10分钟。将高碘酸钠(0.31g,1.46mmol,2.2当量)分3份加入,混合物在0℃继续搅拌,然后在2小时期间回暖至25℃。用DCM(25mL)稀释灰白色(light off white)奶油状混合物,硫酸镁干燥,经硅藻土垫滤去固体,减压浓缩滤液。粗制物以SiO2(柱2cm×12cm)纯化用己烷/乙酸乙酯(7∶3)洗脱得到所需物质(16mg)。
B部分
在室温向18(15mg,35.4mmol,1当量)与醛26(16mg,70μmol,2当量)的DCM(3mL)溶液中一次性加入三乙酰氧基硼氢化钠(20mg,94μmol,2.6当量)。24小时后,加入数滴甲醇猝灭反应,经硅藻土过滤。粗制品经制备型TLC 1mm(第一次洗脱:甲苯/丙酮(9∶1),第二次洗脱:甲苯/丙酮(4∶1))纯化得到4mg无色油状物。MS(ESI(+))m/e 635.43(M+H)+。
实施例12
制备环杷明的衍生物:
A部分
称出化合物2(1.30g,3.2mmol,1当量),加入反应容器。称出碳酸钾(0.91g,6.6mmol,2.1当量),加入反应容器,然后加入二氯乙烷(6.0mL,76mmol,23.8当量)和无水DMSO(5mL)。在氮气气氛中将反应体系加热至70℃,持续36小时。将反应体系冷却至室温,用DCM(15mL)稀释并用水(2×15mL)洗涤两次。硫酸钠干燥有机层,过滤(如果需要进行DCM清洗),浓缩至干得到浅黄色固体。经快速层析(DCM/乙酸乙酯)得到白色结晶固体状目标物质。
B部分
将化合物16(0.111g,0.233mmol,1当量)转移入置于氮气气氛中的反应烧瓶中,无水DCM(2mL)溶解。加入氯碘甲烷(0.238mL,3.27mmol,14当量)。将溶液冷却至-15℃。在30分钟期间滴加二乙基锌(1M,庚烷配制,1.63mL,1.63mmol,6.5当量),小心控制放热。将反应维持于-10℃到-14℃数小时,直至TLC显示起始物质已被耗尽。然后小心加入THF(6mL),再加入水性柠檬酸盐缓冲液(pH 4.5,10mL)以猝灭反应。使各层回暖至室温。饱和硫酸钠(10mL)。充分混合各层,用过量的DCM将其转移至分液漏斗,收集有机层。用氢氧化钠水溶液(1M,10mL)与饱和的硫酸钠水溶液(10mL)洗涤有机层,硫酸钠干燥,然后浓缩至干。粗制物质经快速层析纯化得到55%产率的所需产物。
C部分
在氮气气氛中将化合物15(1.25g,2.56mmol,1当量)溶解于DCM(22mL)中,溶液冷却至0.9℃内部温度。在数小时期间分批加入纯的BF3-OEt2(1.6mL,12.8mmol,5当量),同时采用LCMS监测反应。反应体系缓慢回暖至10℃直至完成。在0℃用甲醇(5mL)猝灭反应,用KOH(2M,30mL)稀释,室温搅拌2小时。分层,用水洗涤有机层,Na2SO4干燥、过滤并浓缩至干。用DCM/乙酸乙酯层析得到所需产物。
实施例13
制备环杷明的衍生物:
A部分
将化合物27(29mg,60μmol,1当量)置于5mL圆底烧瓶中。加入丁酮(2mL)和Al(OiPr)3(12.3mg,60μmol,1当量)。在氩气气氛中将圆底烧瓶中的内含物在回流温度加热7小时。然后在室温搅拌反应混合物10小时。用柠檬酸(500g)、NaOH(15.7g)和水(500mL)混合形成的溶液(2mL)猝灭反应混合物。得到的混合物快速搅拌直至乳浊液消失。然后用乙酸乙酯(3×10mL)萃取混合物。收集有机层,Na2SO4干燥并浓缩。粗制物质经柱层析纯化。MS(ESI(+))m/e 486.26(M+H)+。
实施例14
制备环杷明的衍生物:
A部分
将化合物28(25mg,0.051mmol,1当量)溶解于无水2-甲氧基乙醇(1mL,12.7mmol,234当量)。加入碳酸钾(7.1mg,0.051mmol,1当量),反应加热至120℃。通过TLC监测反应。当TLC显示反应停止时,将反应体系冷却至室温。然后用乙酸乙酯稀释反应体系,用水洗涤。硫酸钠干燥有机层,浓缩至干。用DCM/乙酸乙酯层析得到所需产物。MS(ESI(+))m/e 526.66(M+H)+。
实施例15
制备环杷明的衍生物:
A部分
75℃在3分钟期间向氢化肉桂酸5(3.01g,20mmol,1当量)的30mL无水氯仿溶液中滴加亚硫酰氯(1.75mL,24.1mmol,1.2当量)。混合物回流3.5小时。蒸馏除去溶剂得到淡黄色粘稠液体状的粗制酰基氯。粗制品无需进一步纯化即可使用。
B部分
在25℃向DCM(30mL)配制的7(3.16g,24.1mmol,1.2当量)与NaOH水溶液(2.0M,30mL,3当量)的双相混合物中加入酰基氯6(3.38g,20mmol,1当量)的DCM(10mL)溶液,得到的混合物在25℃搅拌3小时。然后用HCl水溶液(2M,30mL)中和该混合物。分出有机层,用DCM(3×50mL)萃取水层。用HCl(2.0M,25mL)、水(3×50mL)、饱和的盐水(50mL)洗涤合并的有机层,硫酸镁干燥,减压蒸发溶剂。粗制品利用5%甲醇∶DCM作为洗脱剂进行硅胶层析,然后用10%甲醇∶DCM洗柱得到1.141g化合物8。
C部分
在0℃向酸8(264mg,1mmol,1当量)、EDCI(231mg,1.2mmol,1.2当量)与三乙胺(168μL,1.2mmol,1.2当量)的DCM(2mL)混合物中加入烯丙胺(90.3μL,1.2mmol,1.2当量),得到的混合物在0℃搅拌1小时,然后在2小时期间使混合物回暖至25℃。向反应混合物中加入水(50mL),用DCM(4×25mL)萃取,用1M HCl(2×25mL)、水(3×25mL)、饱和盐水(25mL)洗涤合并的有机层,硫酸镁干燥,减压蒸发除去溶剂得到287.5mg所需产物。该物质无需进一步纯化即可使用。
D部分
向烯丙基酰胺9(70mg,0.23mmol,1当量)的1丙酮(mL)与水(0.3mL)的溶液中加入四氧化锇溶液(0.35mL,0.035mmol,2.5w/w,叔丁醇配制),加入OsO4溶液后立即将反应混合物在冰中冷却。得到的暗棕色溶液在0℃搅拌15分钟。将高碘酸钠(110mg,0.51mmol,2.2当量)分5份加入上述混合物,在0℃继续搅拌1小时,然后在2小时期间回暖至25℃。用DCM(3mL)稀释反应混合物,经硫酸镁的短柱(short plug)过滤,用DCM洗涤滤饼(数次)。浓缩滤液,残留物(67.9mg)以5%甲醇∶DCM作为洗脱剂经RP硅胶短柱过滤得到38.9mg所需产物。
E部分
在23℃向19(0.0242g,0.0569mmol,1当量)与醛10(0.0346g,0.114mmol)的3.0mL DCM溶液中一次性加入三乙酰氧基硼氢化钠(24.1mg,0.114mmol,2当量),得到的混合物搅拌16小时。LCMS和TLC检测到起始物质完全转化为所需产物后,用2.5mL甲醇溶解该混合物,通过反相制备型HPLC(乙腈-20mM碳酸铵缓冲液,基本(basic)方法)纯化。浓缩各馏分(fraction),用最少体积的乙腈溶解,冷冻并冻干溶液得到0.007g(0.0098mmol,17%)白色固体。MS(ESI(+))m/e 714.6(M+H)+。
实施例16
制备环杷明的衍生物:
A部分
向18(35mg,0.08mmol,1当量)和醛32(34mg,0.17mmol,2.0当量)的THF(2.0mL)溶液中一次性加入三乙酰氧基硼氢化钠(35mg,0.17mmol,2.0当量)。溶液在23℃搅拌12小时。然后浓缩混合物,经硅胶层析利用1∶1的己烷∶乙酸乙酯梯度,接着1∶2和1∶4的己烷∶乙酸乙酯梯度以及直接乙酸乙酯洗脱来纯化。一些物质仍旧流出,所以用9∶1的乙酸乙酯∶甲醇冲洗。所需产物与一些醛共同洗脱,所以采用制备型HPLC来纯化该物质。(基本方法50_100)冷冻并冻干所需各馏分得到油状残留物(12mg,0.02mmol,24%产率)。MS(ESI(+))m/e 614.44(M+H)+。
实施例17
制备环杷明的衍生物:
A部分
向18(8.0mg,0.02mmol,1当量)和醛34(6.0mg,0.04mmol,2.0当量)的CH2Cl2(1.0mL)溶液中一次性加入三乙酰氧基硼氢化钠(8.0mg,0.17mmol,2.0当量)。溶液在23℃搅拌12小时。然后浓缩混合物,利用1∶1己烷∶乙酸乙酯梯度、接着1∶2和1∶4的己烷∶乙酸乙酯梯度经硅胶层析纯化,以分离与一些醛共同洗脱的所需产物。然后采用制备型HPLC来纯化该物质。冷冻并冻干所需各馏分得到白色粉末(4.9mg,0.009mmol,46%产率)。MS(ESI(+))m/e570.41(M+H)+。
实施例18
制备环杷明的衍生物:
A部分
向18(6.0mg,0.01mmol,1当量)和苯甲醛36(3.0mg,0.02mmol,2.0当量)的CH2Cl2(0.5mL)溶液中一次性加入三乙酰氧基硼氢化钠(6.0mg,0.02mmol,2.0当量)。溶液在23℃搅拌12小时。然后浓缩混合物,利用4∶1、1∶1己烷∶乙酸乙酯梯度进行硅胶层析纯化,以分离与一些醛共同洗脱的所需产物。然后采用制备型HPLC来纯化该物质。冷冻并冻干所需各馏分得到白色粉末(0.6mg,0.001mmol,8%产率)。
实施例19
制备环杷明的衍生物:
A部分
向18(6.0mg,0.01mmol,1当量)和4-苯氧基苯甲醛38(6.0mg,0.02mmol,2.0当量)的CH2Cl2(0.5mL)溶液中一次性加入三乙酰氧基硼氢化钠(6.0mg,0.02mmol,2.0当量)。溶液在23℃搅拌12小时。然后浓缩混合物,利用4∶1、1∶1己烷∶乙酸乙酯梯度进行硅胶层析纯化,以分离与一些醛共同洗脱的所需产物。然后采用制备型HPLC来纯化该物质。冷冻并冻干所需各馏分得到白色粉末(1.8mg,0.003mmol,21%产率)。MS(ESI(+))m/e 606.4(M+H)+。
实施例20
制备环杷明的衍生物:
A部分
向18(40mg,0.09mmol,1当量)和碳酸氢钠(15mg,0.18mmol,2.0当量)的CH2Cl2(0.5mL)混合物中加入溴代乙醇40(33μL,0.47mmol,5.0当量)。溶液加热回流4小时。然后浓缩混合物,利用DCM,然后依次用38∶1∶1、36∶3∶1、17∶2∶1的二氯甲烷∶乙酸乙酯∶甲醇的梯度进行硅胶层析纯化,以分离油状的所需产物(12mg,0.026mmol,27%产率)。MS(ESI(+))m/e 468.24(M+H)+。
实施例21
制备环杷明的衍生物:
A部分
向18(100mg,0.24mmol,1当量)和醛42(42mg,0.35mmol,1.5当量)的CH2Cl2(2.5mL)溶液中一次性加入三乙酰氧基硼氢化钠(100mg,0.47mmol,2.0当量)。溶液在23℃搅拌12小时,LCMS显示只有50%转化。向混合物中再加入等当量的醛36(26mg,0.24mmol,1.0当量)与三乙酰氧基硼氢化钠(48mg,0.24mmol,1.0当量),搅拌2小时。然后浓缩混合物,利用1∶1、1∶2、1∶4己烷∶乙酸乙酯梯度进行硅胶层析纯化,以分离与一些醛共同洗脱的所需产物。然后采用制备型HPLC来纯化该物质。冷冻并冻干所需各馏分得到白色粉末(53mg,0.10mmol,43%产率)。MS(ESI(+))m/e 526.66(M+H)+。
实施例22
制备环杷明的衍生物:
A部分
向18(15mg,0.04mmol,1当量)和醛44(6.9mg,0.04mmol,1.0当量)的CH2Cl2(0.6mL)溶液中一次性加入三乙酰氧基硼氢化钠(15mg,0.07mmol,2.0当量)。溶液在23℃搅拌12小时,LCMS显示只有50%转化。向混合物中再加入等当量的醛44(6.9mg,0.04mmol,1.0当量)与三乙酰氧基硼氢化钠(7.5mg,0.04mmol,1.0当量),搅拌12小时。然后浓缩混合物,利用1∶1、1∶2、1∶4己烷∶乙酸乙酯梯度进行硅胶层析纯化,以分离油状的所需产物(12mg,0.19mmol,54%产率)。MS(ESI(+))m/e 635.43(M+H)+。
实施例23
制备环杷明的衍生物:
A部分
向18(12mg,0.03mmol,1当量)和碳酸钾(40mg,0.28mmol,10当量)的DMF(0.5mL)混合物中加入盐酸2-(二甲基氨基)乙基氯46(20mg,0.14mmol,5.0当量)。溶液在23℃搅拌2小时,无反应发生。然后将溶液在65℃加热12小时,用水(2mL)猝灭,然后用***(2×10mL)萃取。用盐水洗涤合并的有机溶液,MgSO4干燥。然后浓缩混合物,采用制备型HPLC纯化。冷冻并冻干所需的各馏分得到白色粉末(17,1.8mg,0.004mmol,13%产率)。MS(ESI(+))m/e 495.71(M+H)+。
实施例24
制备环杷明的衍生物:
A部分
向18(100mg,0.24mmol,1当量)和氯代乙酰胺48(250mg,1.2mmol,5.0当量)的CH2Cl2(1.0mL)溶液中加入三乙胺(160μL,1.2mmol,5.0当量)。将溶液加热至回流,并搅拌72小时。然后浓缩混合物,利用4∶1、2∶1、1∶1、1∶2己烷∶乙酸乙酯梯度进行硅胶层析纯化,以分离为两个斑点的混合物的所需产物。重复同样的柱条件,分离到油状的所需产物(17mg,0.14mmol,12%产率)。
实施例25
制备环杷明的衍生物:
将化合物18(103mg,0.24mmol,1当量)溶解于DCM(3.0mL),冷却至-78℃。向此溶液中加入mCPBA(77%重量,54mg,0.24mmol,1.0当量),然后在12小时期间将溶液回暖至22℃。反应转化了50%(LCMS)。用碳酸氢钠猝灭溶液,用DCM萃取。用硫酸镁干燥合并的有机相,过滤并浓缩。然后通过硅胶层析纯化该物质,利用95∶2.5∶2.5、92.5∶5.0∶2.5、85∶10∶5DCM∶乙酸乙酯∶甲醇梯度分离与少量其它物质共同洗脱的所需产物。浓缩合并的各馏分,通过制备型HPLC纯化得到3.4mg所需产物。MS(ESI(+))m/e 440.63(M+H)+。
实施例26
利用环杷明的类似物抑制细胞培养物的Hedgehog途径
可采用以下试验确定Hedgehog途径特异性的癌细胞杀伤作用。当C3H10T1/2细胞与sonic hedgehog肽(Shh-N)接触时,其分化为成骨细胞;分化后,这些成骨细胞产生可用酶试验检测的高水平碱性磷酸酶(AP)(Nakamura等,1997,BBRC,237:465)。因此可通过AP产量降低鉴定能阻断C3H10T1/2分化为成骨细胞(Shh依赖性事件)的化合物(van der Horst等,2003,Bone,33:899)。试验的细节描述于下文。下表1显示了分化试验的近似结果(抑制的EC50)。
试验方案
细胞培养
在37℃,5%CO2的空气气氛下,在补加了10%热灭活FBS(Hyclone)、50单位/ml青霉素和50ug/ml链霉素(Gibco/Invitrogen)的基本MEM培养基(Gibco/Invitrogen)中培养小鼠胚胎中胚层成纤维细胞C3H10T1/2(得自ATCC)。
碱性磷酸酶试验
将C3H10T1/2细胞以8×103细胞/孔的密度接种于96孔板。细胞生长至汇合(72小时)。sonic Hedgehog(250ng/ml)(R&D Systems)和/或化合物处理后,用110ul裂解缓冲液(50mM Tris,pH 7.4,0.1%TritonX100)裂解细胞,超声处理各板,裂解物经0.2um PVDF板(Corning)离心。在含有1mg/ml对硝基苯基磷酸酯的碱性缓冲溶液(Sigma)中测定40ul裂解物的AP活性。在37℃培育30分钟后,利用Envision板读数计读取各板在405nm的读数。利用Pierce的BCA蛋白质试验试剂盒,按照生产商的使用说明定量测定总蛋白。针对总蛋白标准化AP活性。注意,“A”表明IC50小于200nM,“B”表明IC50为200-500nM,“C”表明IC50>500nM。
表1-抑制的近似EC50
实施例27
制备型超临界流体层析(SFC)纯化方法
下文描述的是纯化本发明化合物的制备型超流体层析方法。
所用的硬件:
SFC:Berger制备型SFC***
紫外检测器(Ultra-Violet Detector):Knauer K-2501型
柱(Column):Berger 5微米二氧化硅,20mm,250mm
SFC条件:
流动相(Mobile phases):CO2-95%;甲醇-5%
流速(Flow rate):50.00mL/分钟
柱温(Column Temperature):35℃
在超临界CO2中以5%甲醇恒溶剂洗脱40分钟
注射体积(Injection volume):1000uL
样品通常以5.0mg/mL的浓度运行
样品制备:将样品溶解于20%DCM/80%甲醇
产品在25-40分钟之间洗脱
紫外检测器参数
波长(Wavelength)=210nm;分辨率(Resolution)=1.0nm
实施例28
液相层析质谱(LCMS)方法
下文描述的是本发明化合物的液相层析质谱方法。
[A]引入方法报告
[B]实验报告
[C]ZQ调谐参数
参考文献引用
本文引用的所有美国专利与公布的美国专利申请纳入本文作为参考。
等价方案
本领域技术人员只采用常规实验可以知道,或能确定本文所述本发明具体实施方案的许多等价方案。这种等价方案应包括在以下权利要求中。
Claims (11)
1.一种方法,该方法包括将式2所示第一化合物与环丙基化试剂接触以形成式2所示第二化合物,
式2所示第一化合物中:
R1和R8各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基、卤化物、巯基、烷硫基、芳硫基、芳烷硫基、羟基、烷氧基、芳氧基、酰氧基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、硝基、酰硫基、羧酰胺、磺酰胺、硫酸酯、-OP(L)(OR20)2、-X-C(L)-R21或-X-C(L)-X-R21;
R1也可以是糖;
各X独立为O或NR,其中R是H、烷基、烯基、炔基、芳基、环烷基或芳烷基;
L是O或S;
R2和R9独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、腈、芳烷基、烷氧基、芳氧基、酰氧基、羧基、卤化物、巯基、烷硫基、芳硫基、芳烷硫基、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
R5为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、烷硒基、芳烷硒基、芳硒基、烷硫基、芳烷硫基、芳硫基、杂芳基或杂芳烷基;
R3、R4、R6、R7、R13和R14各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
或R1与R2和/或R8与R9和它们所结合的碳连接在一起形成-(C=O)-、-(C=S)-、-(C=N(OR20))-、-(C=N(R20))-、-(C=N(N(R20)(R20))),或形成含有最多两个选自N、O或S的杂原子的任选取代的3-8元环;或者
R4与R5连接在一起和/或R5与R6连接在一起形成双键;
R10与R11连接在一起形成双键;
R12是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、羟基、芳烷基、杂芳基、杂芳烷基、卤代烷基、烷氧基、-C(O)R21、-CO2R21、-SO2R21、-C(O)N(R21)(R21)、-[C(R21)2]q-R21、-[(W)-N(R21)C(O)]qR21、-[(W)-C(O)]qR21、-[(W)-C(O)O]qR21、-[(W)-OC(O)]qR21、-[(W)-SO2]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-N(R21)]qR21或-[(W)-S]qR21;
其中各W独立为双基,q是1、2、3、4、5或6;
R15、R16和R17独立为H、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基;或者R15与R16和与它们结合的碳连接在一起形成-C(O)-或-C(S)-;
各R20独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基或杂芳烷基;或者同一取代基上的任何两个R20可结合在一起形成4-8元任选取代的环;
各R21独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基或-[C(R20)2]p-R25,其中p是0-6;或者同一取代基上的任何两个R21可结合在一起形成含有最多2个选自N、O、S或P的杂原子的4-8元任选取代的环;与
各R25独立为H、羟基、酰基氨基、-N(R20)COR20、-N(R20)C(O)OR20、-N(R20)SO2(R20)、-COR20N(R20)2、-OC(O)R20N(R20)(R20)、-SO2N(R20)(R20)、-N(R2 0)(R20)、-COOR20、-C(O)N(OH)(R21)、-OS(O)2OR20、-S(O)2OR20、-OP(L)(OR20)(OR20)、-NP(O)(OR20)(OR20)或-P(O)(OR20)(OR20);
式2所示第二化合物中R1、R2、R3、R4、R6、R7、R8、R9、R12、R13、R14R15、R16和R17如上所定义;和式2所示第二化合物中R10与R11连接在一起形成1b所表示的基团:
其中Z是C(R23)(R23);和各R23独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基、卤化物、烷氧基、芳氧基、酰氧基、甲硅烷氧基、腈、-C(O)R21、-CO2R21、-SO2R21和-C(O)N(R21)2。
2.如权利要求1所述的方法,其特征在于,还包括将式2所示第二化合物与酸接触以形成式1所示化合物或其药学上可接受的盐:
其中R1和R8各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基、卤化物、巯基、烷硫基、芳硫基、芳烷硫基、羟基、烷氧基、芳氧基、酰氧基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、硝基、酰硫基、羧酰胺、磺酰胺、硫酸酯、-OP(L)(OR20)2、-X-C(L)-R21或-X-C(L)-X-R21;
其中R1也可以是糖;
各X独立为O或NR,其中R是H、烷基、烯基、炔基、芳基、环烷基或芳烷基;
L是O或S;
R2和R9独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、腈、芳烷基、烷氧基、芳氧基、酰氧基、羧基、卤化物、巯基、烷硫基、芳硫基、芳烷硫基、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
R5为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、烷硒基、芳烷硒基、芳硒基、烷硫基、芳烷硫基、芳硫基、杂芳基或杂芳烷基;
R3、R4、R6、R7、R13和R14各自独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基、杂芳基或杂芳烷基;
或R1与R2和/或R8与R9和它们所结合的碳连接在一起形成-(C=O)-、-(C=S)-、-(C=N(OR20))-、-(C=N(R20))-、-(C=N(N(R20)(R20))),或形成含有最多两个选自N、O或S的杂原子的任选取代的3-8元环;或者
R4与R5连接在一起和/或R5与R6连接在一起形成双键;
R10与R11连接在一起形成双键;
R12是H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、羟基、芳烷基、杂芳基、杂芳烷基、卤代烷基、烷氧基、-C(O)R21、-CO2R21、-SO2R21、-C(O)N(R21)(R21)、-[C(R21)2]q-R21、-[(W)-N(R21)C(O)]qR21、-[(W)-C(O)]qR21、-[(W)-C(O)O]qR21、-[(W)-OC(O)]qR21、-[(W)-SO2]qR21、-[(W)-N(R21)SO2]qR21、-[(W)-C(O)N(R21)]qR21、-[(W)-O]qR21、-[(W)-N(R21)]qR21或-[(W)-S]qR21;
其中各W独立为双基,q是1、2、3、4、5或6;
R15、R16和R17独立为H、烷氧基、芳氧基、酰氧基、卤化物、羟基、氨基、烷基氨基、芳基氨基、酰基氨基、芳烷基氨基;或者R15与R16和与它们结合的碳连接在一起形成-C(O)-或-C(S)-;
R18和R19独立为H、烷基、芳烷基、卤化物、酰氨基或酯;
各R20独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基或杂芳烷基;或者同一取代基上的任何两个R20可结合在一起形成4-8元任选取代的环;
各R21独立为H、烷基、烯基、炔基、芳基、环烷基、杂环烷基、芳烷基、杂芳基、杂芳烷基或-[C(R20)2]p-R25,其中p是0-6;或者同一取代基上的任何两个R21可结合在一起形成含有选自N、O、S或P的0-3个杂原子的4-8元任选取代的环;和
各R25独立为H、羟基、酰基氨基、-N(R20)COR20、-N(R20)C(O)OR20、-N(R20)SO2(R20)、-COR20N(R20)2、-OC(O)R20N(R20)(R20)、-SO2N(R20)(R20)、-N(R20)(R20)、-COOR20、-C(O)N(OH)(R21)、-OS(O)2OR20、-S(O)2OR20、-OP(L)(OR20)(OR20)、-NP(O)(OR20)(OR20)或-P(O)(OR20)(OR20)。
3.如权利要求1所述的方法,其特征在于,R13、R14、R15、R16和R17是氢。
4.如权利要求1所述的方法,其特征在于,R1是羟基、糖、-OP(L)(OR20)2、-X-C(L)-R21或-X-C(L)-X-R21;或者R1和R2与和它们结合的碳连接在一起形成-C(O)-。
5.如权利要求1所述的方法,其特征在于,R4和R5连接在一起形成双键。
6.如权利要求5所述的方法,其特征在于,R1和R2与和它们结合的碳连接在一起形成-C(O)-。
7.如权利要求1所述的方法,其特征在于,R1是羟基,和R2是H。
8.如权利要求1所述的方法,其特征在于,R5和R6连接在一起形成双键。
10.如权利要求1所述的方法,其特征在于,所述环丙基化试剂是1,1-卤代烷基金属络合物。
11.如权利要求10所述的方法,其特征在于,所述1,1-卤代烷基金属络合物由二碘甲烷与Et2Zn形成。
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