CN116751240A - 2’-去氧-2’,2’-二氟胞苷碳酸酯酰肼的制备及其应用 - Google Patents
2’-去氧-2’,2’-二氟胞苷碳酸酯酰肼的制备及其应用 Download PDFInfo
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- CN116751240A CN116751240A CN202310471808.7A CN202310471808A CN116751240A CN 116751240 A CN116751240 A CN 116751240A CN 202310471808 A CN202310471808 A CN 202310471808A CN 116751240 A CN116751240 A CN 116751240A
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- Prior art keywords
- deoxy
- butoxycarbonyl
- compound
- tert
- carbonate
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Abstract
本发明涉及一系列2’‑去氧‑2’,2’‑二氟胞苷(2',2'‑difluoro 2'‑deoxycytidine,dFdC,gemcitabine)碳酸酰肼酯的衍生物及其药学上可接受的盐的制备方法和在治疗领域中的应用。进一步地,本发明提供一系列结构新颖、制备简单、抗肿瘤活性高的2’‑去氧‑2’,2’‑二氟胞苷5’‑碳酸酰肼酯衍生物(式I)和2’‑去氧‑2’,2’‑二氟胞苷3’‑碳酸酰肼酯衍生物(式II)。其结构主要在2’‑去氧‑2’,2’‑二氟胞苷结构中5’‑位或3’‑位的羟基上进行碳酸酰肼酯衍生。这些化合物容易制备,溶解度好,血液循环稳定,在体外没有活性或活性很弱,在体内将原药释放出来发挥治疗效果。他们可以单药、组合药、抗体偶联药物组分应用于肿瘤疾病的治疗。
Description
技术领域
本发明涉及医药领域。具体地说,本发明提供一系列新型的2’-去氧-2’,2’-二氟胞苷碳酸酯酰肼的制备和应用。
背景技术
2’-去氧-2’,2’-二氟胞苷是一种胞嘧啶核苷衍生物,被广泛应用多种肿瘤的治疗。
然而,2’-去氧-2’,2’-二氟胞苷使用过程中常出现严重的抗药性,如核苷转运体(NTs)的缺乏导致药物不能进入肿瘤组织细胞,脱氧胞嘧啶激酶(dCK)的缺乏使得药物不能形成关键的dFdCMP,脱氧胞苷脱氨酶(dCDA)作用导致药物脱氨形成无效的dFdU。
因此,急需开发一种高抗肿瘤活性的2’-去氧-2’,2’-二氟胞苷衍生物。
发明内容
本发明根据肼结构在肿瘤细胞容易氧化断裂的特性,在2’-去氧-2’,2’-二氟胞苷的3’或5’-OH上进行碳酸酰肼酯化,形成一系列2’-去氧-2’,2’-二氟胞苷-3’或5’-酰肼酯衍生物,这些化合物能够避开脱氧胞嘧啶激酶抗药性和逃避脱氧胞苷脱氨酶的作用,而在肿瘤细胞内进行肼基氧化释放出活性药物分子发挥抗肿瘤作用。鉴于这些衍生物的高抗肿瘤活性和低毒性,他们可以作为单药或组合药物应用于肿瘤的治疗。
在本发明的第一方面,提供了一种2’-去氧-2’,2’-二氟胞苷碳酸酯酰肼衍生化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,所述的化合物具有如式I或式II所示的结构:
其中,
R1选自下组:H、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6酰基、羧基C1-C6烷基、C3-C8饱和或部分不饱和碳环基、5-12元饱和或部分不饱和杂基、6-10元芳基、5-12元杂芳基、其中,R3、R4选自下组:H、C1-C3烷基;n=0、1、2、3或4;
R2选自下组:H、C1-C6酰基;
其中,R1、R2、R3、R4各自独立地被一个或多个选自下组的取代基取代:卤素、氰基、羟基、氨基、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6酰基、羧基C1-C6烷基、C1-C6烷胺基、C3-C8饱和或部分不饱和碳环基、5-12元饱和或部分不饱和杂基、6-10元芳基、5-12元杂芳基;
并且,所述的立体异构体包括几何异构体和光学异构体。
在部分实施方式中,R1选自下组:H、C1-C6烷基、C3-C8饱和或部分不饱和碳环基、5-12元饱和或部分不饱和杂基、6-10元芳基、5-12元杂芳基、
其中,R3、R4、n的定义如前所述。
在部分实施方式中,R2选自下组:H、C1-C6酰基。
在另一优选例中,R2为H。
在部分实施方式中,R1选自下组:H、苯基、
在部分实施方式中,R3、R4为H。
在部分实施方式中,所述的化合物选自下组:
在本发明的第二方面,提供了一种如本发明第一方面所述的化合物的制备方法,其特征在于,包括步骤:
1).将2’-去氧-2’,2’-二氟胞苷和Boc-酸酐反应,得到相应的3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷;
2).将3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷和N,N'-羰基二咪唑CDI反应,再和相应的肼反应得到相应的3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-5-碳酸酯酰肼衍生物;
3).将3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰肼和三氟乙酰反应,得到2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰肼衍生物;
4).将2’-去氧-2’,2’-二氟胞苷和Boc-酸酐反应,得到相应的4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷;
5).将4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷和TBDMS-Cl反应,得到相应产物5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷;
6).5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷和CDI反应,再和相应取代的肼化合物反应得到相应的5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼衍生物;
7).将5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼和TBAF反应,得到4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼;
8).将4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼和三氟乙酰反应,得到2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼衍生物。
在部分实施方式中,步骤1)中所述的Boc-酸酐用量,相对于2’-去氧-2’,2’-二氟胞苷,为2.1-2.4摩尔当量。
在另一优选例中,步骤2)中所述的CDI的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1-2摩尔当量。
在另一优选例中,步骤2)中所述的CDI的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1.2-1.5摩尔当量。
在另一优选例中,步骤2)中所述的肼基化合物的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1-2摩尔当量。
在另一优选例中,步骤2)中所述的肼基化合物的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1.2-1.5摩尔当量。
在另一优选例中,步骤3)中所述的三氟乙酸为1-30%的DCM溶液。
在另一优选例中,步骤3)中所述的三氟乙酸为5-10%的DCM溶液。
在另一优选例中,步骤4)中所述的Boc-酸酐的用量,相对于2’-去氧-2’,2’-二氟胞苷,为1-1.1摩尔当量。
在另一优选例中,步骤5)中所述的TBDMS-Cl的用量,相对于4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1-1.2摩尔当量。
在另一优选例中,步骤6)中所述的TBAF的用量,相对于5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1.2-1.5摩尔当量。
在另一优选例中,步骤7)中所述的三氟乙酸的为1-30%的DCM溶液。
在另一优选例中,步骤7)中所述的三氟乙酸的为5-10%的DCM溶液。
在本发明的第三方面,提供了一种药物组合物,其特征在于,所述的药物组合物包括:如本发明第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐,或者它们的混合物中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
在本发明的第三方面,提供了一种如本发明第一方面所述的化合物、其立体异构体、前药或其药学上可接受的盐,或者如本发明第三方面所述的药物组合物的用途,其特征在于,用于治疗肿瘤疾病。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
具体实施方式
发明人经过广泛而深入的研究,出乎意料地发现一系列2’-去氧-2’,2’-二氟胞苷的磷酸酯酰胺衍生物,对其进行了生物活性测试,发现其具有高抗肿瘤活性,且毒副作用低。在此基础上完成了本发明。
定义
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,术语“烷基”包括直链或支链的烷基。例如C1-C6烷基表示具有1-6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用,术语“烯基”包括直链或支链的烯基。例如C2-C6烯基指具有2-6个碳原子的直链或支链的烯基,例如乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、或类似基团。
如本文所用,术语“炔基”包括直链或支链的炔基。例如C2-C6炔基是指具有2-6个碳原子的直链或支链的炔基,例如乙炔基、丙炔基、丁炔基、或类似基团。
如本文所用,术语“环烷基”是指具有特定碳原子数目的环状饱和脂肪烃基。例如C3-C10烯基指具有3-10个碳原子的环状饱和脂肪烃基。其可以是单环,例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式,例如桥环或螺环形式。
如本文所用,术语“烷胺基”是指被烷基所取代的胺基。例如,“C1-C6烷胺基”是指被C1-C6烷基所取代的胺基,可以是单取代或双取代的;例如,甲胺基、乙胺基、丙胺基、异丙胺基、丁胺基、异丁胺基、叔丁胺基、二甲胺基、二乙胺基、二丙胺基、二异丙胺基、二丁胺基、二异丁胺基、二叔丁胺基等。
如本文所用,术语“烷氧基”是指具有烷基-氧基结构的基团。例如,“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链的烷氧基,包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用,术语“卤代烷基”代表其中有一个或多个氢原子被卤素取代的烷基基团,其中烷基的定义如上所述。
如本文所用,术语“卤代烷氧基”代表有一个或多个氢原子被卤素取代的烷氧基基团,其中烷氧基的定义如上所述。
如本文所用,术语“杂环基”或者“杂环烷基”是指具有特定的环原子数(如3-10个环原子)的,且其中1-3个原子为选自N、S和O的杂原子的饱和或部分饱和的环状基团。其可以是单环,也可以是双环或多环形式,例如桥环或螺环形式。具体的实例可以为氧杂环丁烷基、氮杂环丁烷基、四氢-2H-吡喃基、哌啶基、四氢呋喃基、吗啉基和吡咯烷基等。
如本文所用,术语“C6-C10芳基”是指具有6-10个碳原子的芳基,例如,苯基或萘基等类似基团。
如本文所用,术语“5-12元杂芳基”指具有5-12个原子,且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环,也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”,否则本发明的基团均可被选自下组的取代基所取代:卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用,“卤素”或“卤原子”指F、Cl、Br、和I。更佳地,卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明,本发明所描述的结构式意在包括所有的同分异构形式(如对映异构,非对映异构和几何异构体(或构象异构体)):例如含有不对称中心的R、S构型,双键的(Z)、(E)异构体等。因此,本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用,术语“互变异构体”表示具有不同能量的结构同分异构体可以越过低能垒,从而互相转化。比如,质子互变异构体(即质子移变)包括通过质子迁移进行互变,如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用,术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用,术语“水合物”是指本发明化合物与水进行配位形成的配合物。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
活性成分
在本发明中,提供了一种具有高抗肿瘤活性的活性成分,即式(I)或式(II)化合物,可用于治疗肿瘤疾病。
试验表明,本发明的活性成分可有效地抑制肿瘤生长,从而治疗肿瘤疾病。
应理解,本发明的活性成分包括式(I)或式(II)所示的化合物、或其药学上可接受的盐、或其前药。应理解,本发明的活性成分还包括式(I)或式(II)化合物的晶型、无定形化合物、以及氘代化合物等形式。
药物组合物和施用方法
由于本发明化合物具有优异的抗肿瘤活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗肿瘤疾病。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-200mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如 )、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药,或者与其他药学上可接受的治疗剂联合给药。
联合给药时,所述药物组合物还包括与一种或多种(2种,3种,4种,或更多种)其他药学上可接受的治疗剂。该其他药学上可接受的治疗剂中的一种或多种(2种,3种,4种,或更多种)可与本发明的化合物同时、分开或顺序地用于治疗肿瘤疾病。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选20~500mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
本发明的主要优点包括:
(1)本发明的化合物均具有良好的抗肿瘤活性。
(2)本发明的晶型制备方法简单。
(3)本发明的化合物药代动力学性质好,成药性好。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
中间体4-BocG和3’,4-dBocG的制备
4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷(4-BocG)和3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷(3’,4-dBocG)按照文献(J.Org.Chem.1999,64(22),8319-8322)制备:将2’-去氧-2’,2’-二氟胞苷(2.0g,7.6mmol)加入到装有DMF(12mL)的反应瓶中,搅拌下加入叔丁氧碳酸酐(2.5g,11.4mmol),加热至50℃搅拌24小时,冷却,倒入水中,过滤固体,乙酸乙酯重结晶得到白色固产物4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷(2.1g,产率77%)。
将上述4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷(2.5g,7.0mmol),Na2CO3(0.4g,35mmol)in dioxane,water(5:1,40mL)和叔丁氧碳酸酐(1.53g,7.0mmol),反应液在室温下下搅拌24小时,浓缩溶剂,石油醚/乙酸乙酯重结晶得到固体产物3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷(2.9g,产率92%)。
实施例1
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰肼(1)的合成
将3’,4-dBocG(3.0g,6.4mmol),三乙胺(1.8mL,12.9mmol),CDI(2.1g,12.9mmol)加入到装有DCM(30mL)的反应瓶中,室温下搅拌4小时,加入水合肼(0.5g,85%,12.9mmol),室温下搅拌过夜,减压除去溶剂,硅胶柱层析纯化得到化合物3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰肼(2.1g,产率65%);
将三氟乙酸(4mL)加入到3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰肼(2.1g,4.1mmol)的DCM(16mL)溶液中,室温下搅拌过夜,减压除去溶剂,硅胶柱层析纯化得到白色固体化合物1(1.0g,产率76%,HPLC:96%);1H NMR(500MHz,DMSO-d6)δ8.38(s,1H),7.55-7.34(m,3H),6.46(s,1H),6.18(t,J=8.6Hz,1H),5.84(d,J=7.9Hz,1H),4.36(d,J=12.4Hz,1H),4.27-4.05(m,4H),3.96(t,J=6.9Hz,1H);13C NMR(126MHz,DMSO)δ166.13,158.34,155.12,141.55,123.24,95.62,77.97,70.13,69.95,62.57;LCMS:(M+H)+:322.01(计算值:321.09)。
实施例2
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-羟乙酰基)肼(2)的合成
将化合物1(200mg,0.3mmol),羟基乙酸(30mg,0.3mmol)加入到装有DCM(4mL)的反应瓶中,向反应瓶中分别加入三乙胺(0.1mL,0.7mmol),DCC(157mg,0.7mmol)以及HOBt(103mg,0.7mmol),反应液室温下搅拌过夜,过滤掉固体,滤液用水洗涤,无水硫酸钠干燥,硅胶柱层析纯化得到白色固体化合物3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-羟乙酰基)肼(100mg,产率45%)。
将三氟乙酸(0.5mL)加入到3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-羟乙酰基)肼(85mg,0.14mmol)的DCM(4mL)溶液中,室温下搅拌过夜,减压除去溶剂,硅胶柱层析纯化得到白色固体化合物2(45mg,产率81%);1H NMR(600MHz,DMSO-d6)δ9.76(d,J=52.8Hz,2H),9.29(d,J=31.8Hz,2H),7.86(d,J=7.8Hz,1H),6.30-6.10(m,2H),5.03-4.58(m,1H),4.54-4.40(m,1H),4.37-4.01(m,4H),3.94(s,1H),1.11(d,J=4.5Hz,1H);13C NMR(151MHz,DMSO)δ172.03,160.12,159.18,156.00,147.44,115.17,95.98,88.41,84.28,78.85,69.70,61.30;LCMS:(M+H)+:379.98(计算值:379.09)。
实施例3
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-对羧基苯基)肼(3)的合成
将3’,4-dBocG(6.0g,12.9mmol),三乙胺(3.6mL,25.9mmol),CDI(4.2g,25.9mmol)加入到装有THF(45mL)的反应瓶中,室温下搅拌4小时,加入4-肼基苯甲酸(1.96g,12.9mmol)和DMF(15mL),室温下继续搅拌过夜,减压除去THF,倒入水中,过滤析出固体,溶解于DCM,用硅胶柱层析纯化得到化合物3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-对羧基苯基)肼(2.2g,产率27%)。
取3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-对羧基苯基)肼(100mg,0.15mmol)溶解于DCM(5mL),加入三氟乙酸(0.5mL),搅拌过夜,减压除去溶剂,硅胶柱层析纯化得到固体化合物3(53mg,产率77%);1H NMR(500MHz,DMSO-d6)δ9.54(d,J=24.1Hz,2H),9.24-8.98(m,1H),8.48(s,1H),7.97-7.86(m,1H),7.81(d,J=8.5Hz,2H),6.76(dd,J=8.6,1.5Hz,2H),6.32-6.17(m,2H),4.55-4.38(m,3H),4.22(dt,J=32.9,9.0Hz,3H);13C NMR(126MHz,DMSO)δ167.75,160.68,159.46,156.74,153.43,143.82,131.49,120.64,117.81,111.07,95.86,84.05,78.88,70.10,63.19;LCMS:(M+H)+:442.32(计算值:441.11)。
实施例4
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-3-羧基-6-吡啶基)肼(4)的合成
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-3-羧基-6-吡啶基)肼按照合成化合物4的方法得到(737mg,产率52%,HPLC:96%);LCMS:(M+H)+:443.02(计算值:442.34)。
实施例5
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰-N’-(氨乙基胺甲酰-4-苯基)肼(5)的合成
将上述合成的3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-对羧基苯基)肼(2.06g,3.2mmol)溶解于DCM(30mL),加入单Boc乙二胺(0.6g,3.8mmol),三乙胺(0.9mL,6.4mmol),DCC(1.3g,6.4mmol)以及HOBt(0.86g,6.4mmol),反应液在室温下搅拌15小时,过滤掉固体,滤液用水洗涤3次,无水硫酸钠干燥,浓缩后硅胶柱层析纯化,得到淡黄色固体化合物3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-Boc-乙二胺甲酰-4-苯基)肼(2.1g,产率84%,HPLC:96%)。
将上述3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-Boc-乙二胺甲酰-4-苯基)肼(2.1g,2.7mmol)溶解于DCM(15mL),加入三氟乙酸(4mL),室温下搅拌过夜,减压浓缩溶剂,硅胶柱层析纯化得到2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰-N’-(氨乙基胺甲酰-4-苯基)肼(400mg,产率31%,HPLC:98%);1H NMR(500MHz,DMSO-d6)δ9.42(s,1H),8.35(t,J=5.6Hz,1H),8.25(s,1H),7.92(s,3H),7.71(d,J=8.3Hz,2H),7.55(d,J=7.1Hz,2H),7.45(s,1H),6.70(d,J=8.3Hz,2H),6.54(d,J=6.5Hz,1H),6.23(t,J=8.6Hz,1H),5.85(d,J=7.5Hz,1H),4.44(d,J=12.4Hz,1H),4.31(dd,J=12.4,5.4Hz,1H),4.18(t,J=12.1Hz,1H),4.02(t,J=7.1Hz,1H),3.48(t,J=6.0Hz,2H),2.98(t,J=6.2Hz,2H);13C NMR(126MHz,DMSO)δ167.25,166.05,156.86,155.05,152.37,141.65,128.69,124.16,118.87,111.01,95.65,84.09,78.02,70.33,63.19,39.32,37.50;LCMS:(M+H)+:484.10(计算值:483.17)。
实施例6
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰-N’-(4-氨基丁氨基甲酰-4-苯基)肼(7)的合成
向反应瓶中加入三乙胺(0.013μL,0.93mmol),1-N-Boc-丁二胺(105.64mg,0.56mmol),二氯甲烷(6mL),3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-对羧基苯基)肼(0.3g,0.467mmol,实施例3),DCC(192.9mg,0.93mmol)和HOBT(143.2mg,0.93mmol),反应物在室温下搅拌12h,减压除去溶剂,硅胶柱层析纯化(DCM/MeOH=10:1)得到Boc-保护产物(0.18g,产率48%)。
将上述Boc-保护产物溶解于DCM(4mL),加入TFA(1mL),室温搅拌2小时,减压除去溶剂,加入甲基叔丁基醚,过滤析出固体,干燥得到产物7(70mg,产率62%);1H NMR(500MHz,DMSO-d6)δ9.51(s,1H),9.33(d,J=5.5Hz,1H),8.12(d,J=5.7Hz,1H),7.83-7.64(m,4H),7.60(d,J=8.1Hz,2H),6.60(d,J=8.3Hz,2H),6.17-5.99(m,2H),4.35(d,J=12.5Hz,1H),4.26(dd,J=12.4,5.6Hz,2H),4.12(h,J=7.1Hz,2H),4.03(t,J=6.6Hz,1H),3.16(q,J=6.0Hz,2H),2.73(q,J=6.3Hz,2H),1.47(d,J=5.4Hz,4H);13C NMR(126MHz,DMSO)δ166.53,161.05,159.29,156.82,152.06,143.76,128.95,124.87,118.08,115.73,111.06,95.88,84.28,78.87,70.13,63.14,39.14,38.73,26.77,25.04;LCMS:(M+H)+:512.17(计算值:511.20)。
实施例7
2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰-N’-(肼基甲酰-4-苯基)肼(8)的合成
将上述合成的3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-对羧基苯基)肼(2.4g,3.7mmol)溶解于DCM(30mL),加入单Boc-肼(0.59g,4.5mmol),三乙胺(1.0mL,7.4mmol),DCC(1.5g,7.4mmol)以及HOBt(1.0g,7.4mmol),反应液在室温下搅拌过夜,过滤掉固体,滤液用水洗涤3次,无水硫酸钠干燥,浓缩后硅胶柱层析纯化,得到淡黄色固体化合物3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-Boc-肼基甲酰-4-苯基)肼(2.4g,产率87%,HPLC:98%)。
将三氟乙酸(5mL)加入到装有3’,4-二(叔丁氧羰酰)-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-Boc-肼基甲酰-4-苯基)肼(.4g,3.1mmol)的DCM(20mL)的溶液中,室温下搅拌12小时,减压除去溶剂,硅胶柱层析纯化得到2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰(N’-肼基甲酰-4-苯基)肼(800mg,产率56%,HPLC 98%);1H NMR(500MHz,DMSO-d6)δ9.41(d,J=23.3Hz,2H),8.18(s,1H),7.66(d,J=8.3Hz,2H),7.57-7.40(m,3H),6.67(d,J=8.3Hz,2H),6.49(d,J=6.5Hz,1H),6.23(s,1H),5.84(d,J=7.4Hz,1H),4.49-4.26(m,4H),4.17(t,J=14.8Hz,1H),4.02(s,1H);13C NMR(126MHz,DMSO)δ166.62,166.13,156.87,155.10,152.05,141.57,128.74,123.54,123.21,111.12,95.62,77.96,70.31,70.13,63.14;LCMS:(M+H)+:456.39(计算值:455.14)。
实施例8
2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼(11)的合成
向盛有中间体4-BocG(5g,13.7mmol),咪唑(1.87g,27.5mmol)和DMF(40mL)的反应瓶中加入TBDMS-Cl(2.27g,15.1mmol),室温下搅拌过夜,倒入到水中,用甲基叔丁基醚萃取2次,无水硫酸钠干燥,硅胶柱层析纯化得到4-Boc-5-TBDMS-gemcitabine(4.8g,产率74%)。
在反应瓶中加入乙腈(5mL),三乙胺(0.26mL,1.86mmol),4-Boc-5-TBDMS-gemcitabine(0.3g,0.62mmol)和碳酸二(N-羟基丁二酰亚胺)酯(0.24g,0.93mmol),室温下搅拌过夜,减压除去溶剂后,乙酸乙酯萃取,饱和食盐水洗涤,除去溶剂后溶解于DCM(4mL),加入肼(35uL,0.7mmol),室温下搅拌10min,减压除去溶剂,硅胶柱层析纯化,得到4-Boc-5-TBDMS-gemcitabine-3-碳酸酯酰肼(0.1g,产率32%)。
将上述化合物4-Boc-5-TBDMS-gemcitabine-3-碳酸酯酰肼(0.1g,0.18mmol)溶解于甲醇(2mL),加入浓盐酸(0.1mL),室温下搅拌2h,减压出去溶剂,粗产物用硅胶柱层析纯化后得到产物11(0.04g,产率65%);1H NMR(500MHz,DMSO-d6)δ11.03(s,1H),10.31(s,1H),9.07(d,J=13.2Hz,1H),8.15(d,J=7.7Hz,1H),7.56-7.26(m,1H),6.34(d,J=7.8Hz,1H),6.22(q,J=9.5,8.7Hz,1H),5.38-5.32(m,1H),4.33-4.17(m,2H),3.77(td,J=12.6,3.0Hz,2H),3.65(d,J=13.0Hz,1H);13C NMR(126MHz,DMSO)δ160.06,154.42,147.25,144.46,121.75,102.87,95.51,79.74,71.22,59.37;LCMS:(M+H)+:322.21(计算值:321.09)。
测试例:抑制肿瘤细胞生长活性
将人食管癌细胞OE33(人乳腺腺癌细胞SK-BR-3,或人胃癌细胞NCI-N87)在含有10%胎牛血清(Cellmax)的RPMI1640(Cellmax)中培养。将处于指数增长期的肿瘤细胞用培养基稀释至1×105cells/mL,以每孔100μL加入到96孔细胞培养板中,放回37℃,5%CO2的培养箱中过夜培养。第二天,使用培养基将化合物稀释至10000nM、2000nM、400nM、80nM、16nM、3.2nM、0.64nM、0.13nM,并以每孔2μL将稀释后的化合物加入到96孔细胞培养板中,每个浓度设置3个复孔,未添加化合物的阴性对照和空白对照组每孔加入2μL的稀释液。加样完成后,放回37℃,5%CO2的培养箱中继续孵育72h。孵育完成后,取出细胞培养板,用移液器将培养板中的培养基吸弃,每孔加入100μL含有10%CCK-8的培养基,37℃孵育3h。孵育完成后,取出培养板,避光,置于酶标板中,选择630nm为参比波长,450nm为测定波长测定吸光度。根据吸光值,使用GraphPad中四参数回归计算IC50值(表2)。
表2.部分化合物抑制肿瘤细胞生长的IC50s(nM)值
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (22)
1.一种2’-去氧-2’,2’-二氟胞苷碳酸酯酰肼衍生化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,所述的化合物具有如式I或式II所示的结构:
其中,
R1选自下组:H、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6酰基、羧基C1-C6烷基、C3-C8饱和或部分不饱和碳环基、5-12元饱和或部分不饱和杂基、6-10元芳基、5-12元杂芳基、其中,R3、R4选自下组:H、C1-C3烷基;n=0、1、2、3或4;
R2选自下组:H、C1-C6酰基;
其中,R1、R2、R3、R4各自独立地被一个或多个选自下组的取代基取代:卤素、氰基、羟基、氨基、羧基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6酰基、羧基C1-C6烷基、C1-C6烷胺基、C3-C8饱和或部分不饱和碳环基、5-12元饱和或部分不饱和杂基、6-10元芳基、5-12元杂芳基;
并且,所述的立体异构体包括几何异构体和光学异构体。
2.如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,R1选自下组:H、C1-C6烷基、C3-C8饱和或部分不饱和碳环基、5-12元饱和或部分不饱和杂基、6-10元芳基、5-12元杂芳基、
其中,R3、R4、n的定义如权利要求1中所述。
3.如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,R2选自下组:H、C1-C6酰基。
4.如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,R2为H。
5.如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,R1选自下组:H、苯基、
6.如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,R3、R4为H。
7.如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,其特征在于,所述的化合物选自下组:
8.如权利要求1所述的化合物的制备方法,其特征在于,包括步骤:
1).将2’-去氧-2’,2’-二氟胞苷和Boc-酸酐反应,得到相应的3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷;
2).将3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷和N,N'-羰基二咪唑CDI反应,再和相应的肼反应得到相应的3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-5-碳酸酯酰肼衍生物;
3).将3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰肼和三氟乙酰反应,得到2’-去氧-2’,2’-二氟胞苷-5’-碳酸酯酰肼衍生物;
4).将2’-去氧-2’,2’-二氟胞苷和Boc-酸酐反应,得到相应的4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷;
5).将4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷和TBDMS-Cl反应,得到相应产物5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷;
6).5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷和CDI反应,再和相应取代的肼化合物反应得到相应的5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼衍生物;
7).将5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼和TBAF反应,得到4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼;
8).将4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼和三氟乙酰反应,得到2’-去氧-2’,2’-二氟胞苷-3’-碳酸酯酰肼衍生物。
9.如权利要求8所述的方法,其特征在于,步骤1)中所述的Boc-酸酐用量,相对于2’-去氧-2’,2’-二氟胞苷,为2.1-2.4摩尔当量。
10.如权利要求8所述的方法,其特征在于,步骤2)中所述的CDI的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1-2摩尔当量。
11.如权利要求8所述的方法,其特征在于,步骤2)中所述的CDI的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1.2-1.5摩尔当量。
12.如权利要求8所述的方法,其特征在于,步骤2)中所述的肼基化合物的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1-2摩尔当量。
13.如权利要求8所述的方法,其特征在于,步骤2)中所述的肼基化合物的用量,相对于3’,4-二叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1.2-1.5摩尔当量。
14.如权利要求8所述的方法,其特征在于,步骤3)中所述的三氟乙酸为1-30%的DCM溶液。
15.如权利要求8所述的方法,其特征在于,步骤3)中所述的三氟乙酸为5-10%的DCM溶液。
16.如权利要求8所述的方法,其特征在于,步骤4)中所述的Boc-酸酐的用量,相对于2’-去氧-2’,2’-二氟胞苷,为1-1.1摩尔当量。
17.如权利要求8所述的方法,其特征在于,步骤5)中所述的TBDMS-Cl的用量,相对于4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1-1.2摩尔当量。
18.如权利要求8所述的方法,其特征在于,步骤6)中所述的TBAF的用量,相对于5’-TBDMS-4-叔丁氧羰酰-2’-去氧-2’,2’-二氟胞苷,为1.2-1.5摩尔当量。
19.如权利要求8所述的方法,其特征在于,步骤7)中所述的三氟乙酸的为1-30%的DCM溶液。
20.如权利要求8所述的方法,其特征在于,步骤7)中所述的三氟乙酸的为5-10%的DCM溶液。
21.一种药物组合物,其特征在于,所述的药物组合物包括:如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,或者它们的混合物中的一种或多种,以及一种或多种可药用的载体、赋形剂、佐剂、辅料和/或稀释剂。
22.如权利要求1所述的化合物、其立体异构体、前药或其药学上可接受的盐,或者如权利要求21所述的药物组合物的用途,其特征在于,用于治疗肿瘤疾病。
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