CN113939525A - 吉西他滨的口服活性前药 - Google Patents
吉西他滨的口服活性前药 Download PDFInfo
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- CN113939525A CN113939525A CN201980090197.3A CN201980090197A CN113939525A CN 113939525 A CN113939525 A CN 113939525A CN 201980090197 A CN201980090197 A CN 201980090197A CN 113939525 A CN113939525 A CN 113939525A
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
Landscapes
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- Engineering & Computer Science (AREA)
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Abstract
本公开包含式(I)化合物:其中R1、R2和R3在本文中定义。还公开了一种用于用这些化合物治疗赘生性疾病的方法。
Description
相关申请的交叉引用
本申请要求于2018年11月25日提交的美国临时专利申请第62/771,100号的提交日期的权益,所述美国临时专利申请的全部内容通过引用并入本文。
背景技术
如下所示,吉西他滨(gemcitabine)是表明对多种实体瘤类型具有活性的嘧啶核苷类似物。继1996年FDA批准后,吉西他滨已成为胰腺癌治疗的护理标准。最近,所述化合物还获批用于治疗非小细胞肺癌、卵巢癌、膀胱癌和乳腺癌。
吉西他滨的化学结构
目前,吉西他滨通过以下方式施用:每周一次经30分钟以大约1000mg/m2到1250mg/m2的剂量静脉输注,持续至多7周,然后停药一周。通过口服使用吉西他滨可能受限于由于首关代谢(first pass metabolism)引起的不良口服生物利用度。Shipley LA.等人,“吉西他滨和溶瘤脱氧胞苷类似物在小鼠、大鼠和狗中的代谢和处置(Metabolism anddisposition of gemcitabine,and oncolytic deoxycytidine analog,in mice,rats,and dogs)”.《药物代谢与处置(Drug Metabolism&Disposition)》.20(6):849-55,1992。此外,当通过口服给药时,吉西他滨会牵涉到引起不良的剂量限制性肠道损伤,在给予167mg/kg、333mg/kg或500mg/kg的单个口服(灌胃)吉西他滨剂量的小鼠中,所述不良的剂量限制性肠道损伤的特征在于肠道的整个长度上粘膜上皮的中度到明显损失(萎缩性肠病)。Horton ND等人,“单剂量口服吉西他滨在小鼠体内的毒性(Toxicity of single-doseoral gemcitabine in mice)”,美国癌症研究协会海报展示(American Association forCancer Research,Poster Presentation),佛罗里达州奥兰多(Orlando,FL),2004年3月27-31日。在先前的小鼠研究中通过静脉内给药实现的相当的暴露未导致死亡或胃肠道毒性。
本领域中报道了用于制备吉西他滨的口服活性前药的方法。2009年,Bender等人报告了吉西他滨的口服活性前药LY2334737,其由于在4-(N)位处存在丙戊酸键而明显不易被CDA降解。基于HCT-116人结肠异种移植物的体内数据,LY2334737已得到进一步开发并且已进入I期临床研究。然而,在2013年对日本患者进行的一项研究中观察到LY2334737QD具有意外的肝毒性之后,终止了研发。
总之,尽管LY2334737对本领域做出了重大贡献,但在此技术领域中,对吉西他滨的口服活性前药的搜寻从未停止。
发明内容
本发明涉及吉他滨口服的新一类活性前药。如上文在吉西他滨化学结构中所示,吉西他滨具有易于进行化学前药衍生化的三个官能团(即,-OH、-OH、-NH2)。因此,合理地设计了口服活性的三重前药(Triple-Prodrug),其中使用经典的前体部分(Pro-moiety)同时对吉西他滨的全部三个官能团(即,-OH、-OH、-NH2)进行衍生化。(在前药设计中,前体部分意指用于修饰母体药物的结构以改善物理化学性质、生物制药性质或药代动力学性质的化学官能团。前体部分通常不具生物活性但具有安全性。)因此,本发明中吉西他滨的口服活性三重前药可以用于治疗患有肿瘤的患者。
本发明提供了式(I)化合物或其N-氧化物或所述式(I)化合物或其N-氧化物的药学上可接受的盐、溶剂化物、多晶型物、互变异构体、立体异构体、同位素形式或前药:
其中
R1、R2和R3中的每一个独立地是其中R是烷基、螺烷基、烯基、炔基、环烷基、环烯基、杂环烷基、螺杂环烷基、杂环烯基、芳基、杂芳基、卤基、硝基、氧代基、氰基、ORa、SRa、烷基-Ra、NH(CH2)pRa、C(O)Ra、S(O)Ra、SO2Ra、C(O)ORa、OC(O)Ra、NRbRc、C(O)N(Rb)Rc、N(Rb)C(O)Rc、-P(O)RbRc、-烷基-P(O)RbRc、-S(O)(=N(Rb))Rc、-N=S(O)RbRc、=NRb、SO2N(Rb)Rc或N(Rb)SO2Rc,其中所述烷基、螺烷基、烯基、炔基、环烷基、环烯基、杂环烷基、螺杂环烷基、杂环烯基、芳基或杂芳基任选地被一个或多个Rd取代;
Ra、Rb、Rc和Rd独立地是H、D、烷基、螺烷基、烯基、炔基、卤基、氰基、胺、硝基、羟基、=O、-P(O)RbRc、-烷基-P(O)RbRc、-S(O)(=N(Rb))Rc、-N=S(O)RbRc、=NRb、C(O)NHOH、C(O)OH、C(O)NH2、烷氧基、烷氧基烷基、卤代烷基、羟烷基、氨烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷氨基、氧代基、卤代-烷氨基、环烷基、环烯基、杂环烷基、螺杂环烷基、杂环烯基、芳基或杂芳基,其中所述烷基、环烷基、环烯基、杂环烷基、杂环烯基、芳基、杂芳基任选地被一个或多个Re取代;
Re是H、D、烷基、螺烷基、烯基、炔基、卤基、氰基、胺、硝基、羟基、=O、C(O)NHOH、烷氧基、烷氧基烷基、卤代烷基、羟烷基、氨烷基、烷基羰基、烷氧基羰基、烷基羰基氨基、烷氨基、氧基、卤代-烷氨基、环烷基、环烯基、杂环烷基、螺杂环烷基、杂环烯基、芳基或杂芳基。
在优选实施例中,所述化合物由式(II)表示:
其中
本发明的化合物可以含有一个或多个不对称碳原子。因此,所述化合物可以以非对映异构体、对映异构体或其混合物的形式存在。不对称碳原子中的每个不对称碳原子均可以呈R或S构型,并且这两种构型均处于本发明的范围内。
还设想了此类化合物中的任何一种化合物的包含与未经修饰的化合物相比,药物溶解度、稳定性、生物利用度和/或治疗指数有所提高(例如,增强、更大)的修饰的经修饰化合物。示例性修饰包含(但不限于)适用的前药衍生物和富氘化合物。
应当认识到,本发明的化合物可以以盐或溶剂化物的形式存在并且任选地可以以盐或溶剂化物的形式施用。本发明涵盖以上所描述的化合物和其修饰中的任何一种的任何药学上可接受的盐和溶剂化物。
含有以上所描述的化合物、修饰和/或盐以及其组合物中的一种或多种的用于治疗肿瘤疾病的药物组合物、其治疗用途以及所述化合物在制备用于治疗疾病/病症的药物中的用途也处于本发明的范围内。
本发明还涉及通过向有需要的受试者施用有效量的以上所描述的化合物、修饰和/或盐以及其组合物中的一种或多种来治疗Pim过表达性肿瘤疾病的方法,所述Pim过表达性肿瘤疾病包含但不限于白血病、淋巴瘤、多发性骨髓瘤、前列腺癌、胰腺癌、胃癌、结肠癌或肝癌。
在以下描述中阐述了本发明的一个或多个实施例的细节。根据所述描述和权利要求书,本发明的其它特征、目的和优点将变得显而易见。应当理解,除非不适用或明确放弃,否则本文所描述的本发明的所有实施例/特征(化合物、药物组合物、制造/使用方法等),包含实例和原始权利要求书中所述的任何特定特征,可以彼此结合。
具体实施方式
本文所描述的示例性化合物包含但不限于以下:
异丁酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
缬氨酸((2R,3R,5R)-3-((L-缬氨酰基)氧基)-4,4-二氟-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
L-缬氨酸((2R,3R,5R)-4,4-二氟-3-(异丁酰氧基)-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸((2R,3R,5R)-4,4-二氟-3-(异丁酰氧基)-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
异丁酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸((2R,3R,5R)-3-((L-缬氨酰基)氧基)-4,4-二氟-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-5-(4-(((己氧基)羰基)氨基)-2-氧嘧啶-1(2H)-基)-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-5-(4-((丁氧基羰基)氨基)-2-氧嘧啶-1(2H)-基)-4,4-二氟-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)-2-((新戊酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-5-(4-(((己氧基)羰基)氨基)-2-氧嘧啶-1(2H)-基)-2-((新戊酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-5-(4-(环己烷甲酰胺基)-2-氧嘧啶-1(2H)-基)-4,4-二氟-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-5-(4-(环庚烷甲酰胺基)-2-氧嘧啶-1(2H)-基)-4,4-二氟-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-5-(4-(2,6-二甲基四氢-2H-吡喃-4-甲酰胺基)-2-氧嘧啶-1(2H)-基)-4,4-二氟-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(2-丙基己酰胺基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-5-(4-(2-乙基己酰胺基)-2-氧嘧啶-1(2H)-基)-4,4-二氟-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-新戊酰胺基嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-5-(4-(4-(叔丁基)苯甲酰胺基)-2-氧嘧啶-1(2H)-基)-4,4-二氟-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(4-辛酰胺基-2-氧嘧啶-1(2H)-基)四氢呋喃-3-基酯。
本发明的化合物可以含有一个或多个不对称碳原子。因此,所述化合物可以以非对映异构体、对映异构体或其混合物的形式存在。所述化合物的合成可以采用外消旋体、非对映异构体或对映异构体作为起始材料或作为中间体。可以通过色谱方法或结晶方法分离非对映异构化合物。类似地,可以使用相同的技术或本领域已知的其它技术分离对映异构混合物。不对称碳原子中的每个不对称碳原子均可以呈R或S构型,并且这两种构型均处于本发明的范围内。
还设想了此类化合物中的任何一种化合物的包含与未经修饰的化合物相比,药物溶解度、稳定性、生物利用度和/或治疗指数有所提高(例如,增强、更大)的修饰的经修饰化合物。修饰的实例包含但不限于前药衍生物和富氘化合物。例如:
·前药衍生物:在向受试者施用之后,前药将在体内转化成本发明的活性化合物[《自然评论:药物发现(Nature Reviews of Drug Discovery)》,2008,第7卷,第255页]。应当注意,在许多情况下,前药本身也落入根据本发明的化合物的范围内。本发明的化合物的前药可以通过标准的有机反应制备,例如通过与氨甲酰化剂(例如,1,1-酰氧基烷基氯甲酸酯、对硝基苯基碳酸酯等)或酰化剂反应来制备。在《生物有机和药物化学快报(Bioorganicand Medicinal Chemistry Letters)》,1994,第4卷,第1985页中描述了制备前药的方法和策略的另外实例。
·富氘化合物:氘(D或2H)是氢的一种稳定的非放射性同位素并且原子量为2.0144。氢以同位素XH(氢或氕)、D(2H或氘)和T(3H或氚)的混合物形式天然存在。氘的自然丰度是0.015%。本领域的普通技术人员认识到,在所有具有H原子的化合物中,H原子实际上表示H和D的混合物,其中约0.015%为D。因此,氘水平已经富集到大于其自然丰度0.015%的化合物应被认为是非天然的,并且因此与其非富集性对应物相比,是新颖的。
应当认识到,本发明的化合物可以以盐和溶剂化物的形式存在并且任选地可以以盐和溶剂化物的形式施用。例如,根据本领域公知的程序,将本发明的化合物转化成源自各种有机和无机酸和碱的其药学上可接受的盐以及以所述药学上可接受的盐的形式使用所述化合物处于本发明的范围内。
当本发明的化合物具有游离碱形式时,可以通过使化合物的游离碱形式与药学上可接受的无机或有机酸反应来将化合物制备为药学上可接受的酸加成盐,所述药学上可接受的无机或有机酸加成盐例如:氢卤化物,如氢氯化物、氢溴化物、氢碘化物;其它矿物酸,如硫酸盐、硝酸盐、磷酸盐等;和烷基和单芳基磺酸盐,如乙磺酸盐、甲苯磺酸盐和苯磺酸盐;以及其它有机酸和其对应的盐,如乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐和抗坏血酸盐。本发明的另外的酸加成盐包含但不限于:己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、环戊烷丙酸盐、二葡萄糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、富马酸盐、半乳糖酸盐(来自粘酸)、半乳糖醛酸盐、葡萄糖庚酸盐、葡萄糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、2-羟基乙磺酸盐、碘化物、羟乙磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、草酸盐、油酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、苯乙酸盐、3-苯基丙酸盐、膦酸盐和邻苯二甲酸盐。应当认识到,游离碱形式通常在物理性质,如极性溶剂中的溶解度,方面与其相应的盐形式有所不同,但是出于本发明的目的,所述盐在其它方面相当于其相应的游离碱形式。
当本发明的化合物具有游离酸形式时,可以通过使化合物的游离酸形式与药学上可接受的无机或有机碱反应来制备药学上可接受的碱加成盐。此类碱的实例是:碱金属氢氧化物,包含氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;以及各种有机碱,如氢氧化铵、哌啶、二乙醇胺和N-甲基谷氨酰胺。还包含本发明的化合物的铝盐。本发明的另外的碱盐包含但不限于:铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐和锌盐。有机碱盐包含但不限于伯胺、仲胺和叔胺的盐、经取代的胺(包含天然存在的经取代的胺)、环胺和碱性离子交换树脂,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因(chloroprocaine)、胆碱、N,N'-二苄基乙二胺(苄星青霉素(benzathine))、二环己胺、二乙醇胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡萄糖、组氨酸、海巴明(hydrabamine)、异丙胺、利多卡因(lidocaine)、赖氨酸、葡甲胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因(procaine)、嘌呤、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三-(羟甲基)-甲胺(氨丁三醇)。应当认识到,游离酸形式通常在物理性质,如极性溶剂中的溶解度,方面与其相应的盐形式有所不同,但是出于本发明的目的,这些盐在其它方面相当于其相应的游离酸形式。
在一方面,药学上可接受的盐是盐酸盐、氢溴酸盐、甲磺酸盐、甲苯磺酸盐、乙酸盐、富马酸盐、硫酸盐、硫酸氢盐、琥珀酸盐、柠檬酸盐、磷酸盐、马来酸盐、硝酸盐、酒石酸盐、苯甲酸盐、碳酸氢盐、碳酸盐、氢氧化钠盐、氢氧化钙盐、氢氧化钾盐、氨丁三醇盐或其混合物。
包括含叔氮基团的本发明的化合物可以用如以下等药剂进行季铵化:(C1-4)烷基卤化物,例如甲基、乙基、异丙基和叔丁基氯化物、溴化物和碘化物;硫酸二-(C1-4)烷基酯,例如硫酸二甲酯、硫酸二乙酯和硫酸二戊酯;烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;以及芳基(C1-4)烷基卤化物,例如苄基氯化物和苯乙基溴化物。此类盐允许制备本发明的水溶性和油溶性化合物。
具有叔氮原子的抗癌剂的氧化胺(也称为胺-N-氧化物和N-氧化物)已被开发为前药[《分子癌症疗法(Mol Cancer Therapy)》.2004年3月;3(3):233-44]。包括叔氮原子的本发明的化合物可以被如过氧化氢(H2O2)、卡罗酸(Caro's acid)或过酸(如间氯过氧苯甲酸(mCPBA))等药剂氧化以形成氧化胺。
本发明涵盖包括本发明的化合物和药物赋形剂以及其它常规药物非活性药剂的药物组合物。通常用作载体或稀释剂的任何惰性赋形剂可以用于本发明的组合物中,所述赋形剂如糖、多元醇、可溶性聚合物、盐和脂质。可以采用的糖和多元醇包含但不限于乳糖、蔗糖、甘露醇和山梨醇。可以采用的可溶性聚合物的实例是聚氧乙烯、泊洛沙姆、聚乙烯吡咯烷酮和葡聚糖。有用的盐包含但不限于氯化钠、氯化镁和氯化钙。可以采用的脂质包含但不限于脂肪酸、甘油脂肪酸酯、糖脂和磷脂。
另外,药物组合物可以进一步包括:粘合剂(例如,阿拉伯胶、玉米淀粉、明胶、卡波姆胶、乙基纤维素、瓜尔胶、羟丙基纤维素、羟丙基甲基纤维素、聚维酮);崩解剂(例如,玉米淀粉、马铃薯淀粉、藻酸、二氧化硅、交联羧甲基纤维素钠、交联维酮、瓜尔胶、羧基乙酸淀粉钠、初凝胶(Primogel));不同pH和离子强度的缓冲液(例如,tris-HCL、乙酸盐、磷酸盐);防止吸附到表面的添加剂(如白蛋白或明胶);洗涤剂(例如,Tween 20、Tween 80、PluronicF68、胆汁酸盐);蛋白酶抑制剂;表面活性剂(例如,十二烷基硫酸钠);渗透促进剂;增溶剂(例如,甘油、聚乙烯甘油、环糊精);助流剂(例如,二氧化硅胶体);抗氧化剂(例如,抗坏血酸、焦亚硫酸钠、丁基羟基茴香醚);稳定剂(例如,羟丙基纤维素、羟丙基甲基纤维素);增粘剂(例如,卡波姆胶、二氧化硅胶体、乙基纤维素、瓜尔胶);甜味剂(例如,蔗糖、阿斯巴甜、柠檬酸);调味剂(例如,薄荷、水杨酸甲酯或橙色调味剂);防腐剂(例如,硫柳汞、苯甲醇、对羟基苯甲酸酯);润滑剂(例如,硬脂酸、硬脂酸镁、聚乙二醇、十二烷基硫酸钠);助流剂(例如,二氧化硅胶体);增塑剂(例如,邻苯二甲酸二乙酯、柠檬酸三乙酯);乳化剂(例如,卡波姆胶、羟丙基纤维素、十二烷基硫酸钠、甲基纤维素、羟乙基纤维素、羧甲基纤维素钠);聚合物涂层(例如,泊洛沙姆或泊洛沙明);涂层和成膜剂(例如,乙基纤维素、丙烯酸酯、聚甲基丙烯酸酯);和/或佐剂。
在一个实施例中,药物组合物与将保护化合物免于从体内快速消除的载体一起制备,所述载体如控释调配物,包含植入物和微囊化的递送系统。可以使用可生物降解的生物相容的聚合物,如乙烯乙酸乙烯酯、聚酸酐、聚乙醇酸、胶原、聚原酸酯和聚乳酸。用于制备此类调配物的方法对本领域技术人员而言是显而易见的。所述材料还可以从Alza公司(Alza Corporation)和Nova制药公司(Nova Pharmaceuticals,Inc)商购获得。脂质体悬浮液(包含靶向受感染细胞的具有针对病毒抗原的单克隆抗体的脂质体)也可以用作药学上可接受的载体。可以根据本领域的技术人员已知的例如美国专利第4,522,811号中所述的方法来制备这些调配物。
此外,本发明涵盖包括本发明的化合物的任何固体或液体物理形式的药物组合物。例如,化合物可以呈结晶形式,呈无定形形式,并且可以具有任何粒径。颗粒可以是微粉化的,或者可以是附聚的颗粒、粉末、油、油性悬浮液或任何其它形式的固体或液体物理形式。
当根据本发明的化合物表现出溶解度不足时,可以使用用于使化合物增溶的方法。此类方法对于本领域的技术人员来说是已知的并且包含但不限于:pH调节和盐形成;使用共溶剂,如乙醇、丙二醇、聚乙二醇(PEG)300、PEG 400、DMA(10-30%)、DMSO(10-20%)、NMP(10-20%);使用表面活性剂,如聚山梨酯80、聚山梨酯20(1-10%)、cremophor EL、Cremophor RH40、Cremophor RH60(5-10%)、Pluronic F68/泊洛沙姆188(20-50%)、Solutol HS15(20-50%)、维生素E TPGS和d-α-生育酚PEG 1000琥珀酸盐(20-50%);使用络合,如HPβCD和SBEβCD(10-40%);以及使用先进的方法,如胶束、添加聚合物、纳米颗粒悬浮液和脂质体形成。
各种施用方法可以与本发明的化合物结合使用。本发明的化合物可以口服、肠胃外、腹腔内、静脉内、动脉内、经皮、舌下、肌内、经直肠、经颊、鼻内、经脂质体、通过吸入、经阴道、眼内、通过局部递送(例如通过导管或支架)、皮下、脂肪内、关节内或鞘内施用或联合施用。根据本发明的化合物还可以以缓释剂型施用或联合施用。化合物可以呈以适于要使用的施用途径的方式调配的气体、液体、半液体或固体形式。对于口服施用,合适的固体口服调配物包含片剂、胶囊、丸剂、颗粒剂、团粒、小袋和泡腾剂、粉剂等。合适的液体口服调配物包含溶液、悬浮液、混悬剂、乳剂、油等。对于肠胃外施用,通常使用冻干粉的重构。
如本文所用,“酰基”意指由式-C(O)-R表示的含羰基的取代基,其中R为H、烷基、碳环、杂环、碳环取代的烷基或杂环取代的烷基,其中所述烷基、烷氧基、碳环和杂环如本文所定义。酰基包含烷酰基(例如,乙酰基)、芳酰基(例如,苯甲酰基)和杂芳酰基。
“脂肪族”意指由组成碳原子的直链或支链布置表征的部分并且可以是饱和的或部分不饱和的,具有一个或多个双键或三键。
术语“烷基”是指含有1-20个碳原子(例如,C1-C10)的直链或支链烃。烷基的实例包含但不限于甲基、亚甲基、乙基、亚乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。优选地,烷基具有一到十个碳原子。更优选地,烷基具有一到四个碳原子。
术语“烯基”是指含有2-20个碳原子(例如,C2-C10)以及一个或多个双键的直链或支链烃。烯基的实例包含但不限于乙烯基、丙烯基和烯丙基。优选地,亚烷基具有两到十个碳原子。更优选地,亚烷基具有两到四个碳原子。
术语“炔基”是指含有2-20个碳原子(例如,C2-C10)以及一个或多个三键的直链或支链烃。炔基的实例包含但不限于乙炔基、1-丙炔基、1-丁炔基和2-丁炔基以及1-甲基-2-丁炔基。优选地,炔基具有两到十个碳原子。更优选地,炔基具有两到四个碳原子。
术语“烷氨基”是指–N(R)-烷基,其中R可以是H、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基。
“烷氧基”意指具有另外一个烷基取代基的氧部分。
“烷氧基羰基”意指与羰基连接的烷氧基。
“氧代烷基”意指进一步被羰基取代的烷基。羰基可以是醛、酮、酯、酰胺、酸或酰氯。
术语“环烷基”是指具有3到30个碳原子(例如,C3-C12、C3-C8或C3-C6)的饱和烃环系统。环烷基的实例包含但不限于环丙基、环丁基、环戊基、环己基、环庚基和环辛基。术语“环烯基”是指具有3到30个碳(例如,C3-C12)以及一个或多个双键的非芳香族烃环系统。实例包含环戊烯基、环己烯基和环庚烯基。
术语“杂环烷基”是指具有一个或多个杂原子(如O、N、S、P或Se)的非芳香族5-8元单环、8-12元双环或11-14元三环系统。杂环烷基的实例包含但不限于哌嗪基、吡咯烷基、二噁烷基、吗啉基和四氢呋喃基。
术语“杂环烯基”是指具有一个或多个杂原子(如O、N、S、P或Se)和一个或多个双键的非芳香族5-8元单环、8-12元双环或11-14元三环系统。
术语“芳基”是指6碳单环、10碳双环、14碳三环芳香族环系统。芳基的实例包含但不限于苯基、萘基和蒽基。术语“杂芳基”是指具有一个或多个杂原子(如O、N、S、P或Se)的芳香族5-8元单环、8-12元双环或11-14元三环系统。杂芳基的实例包含吡啶基、呋喃基、咪唑基、苯并咪唑基、嘧啶基、噻吩基、喹啉基、吲哚基和噻唑基。
以上提及的烷基、烯基、炔基、环烷基、杂环烷基、环烯基、杂环烯基、烷氨基、芳基和杂芳基包含经取代的部分和未经取代的部分两者。烷氨基、环烷基、杂环烷基、环烯基、杂环烯基、芳基和杂芳基上的可能的取代基包含但不限于以下:C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、C1-C10烷氨基、芳氨基、羟基、卤基、氧代基(O=)、硫氧基(S=)、硫基、甲硅烷基、C1-C10烷硫基、芳硫基、C1-C10烷基磺酰基、芳基磺酰基、酰氨基、氨酰基、氨基硫代酰基、脒基、巯基、酰胺基、硫脲基、氰硫基、磺酰胺基、胍、脲基(ureido)、氰基、硝基、酰基、硫代酰基、酰氧基、氨基甲酰胺基(carbamido)、氨甲酰基、羧基和羧酸酯。另一方面,烷基、烯基或炔基上的可能的取代基包含除C1-C10烷基以外的所有上述取代基。环烷基、环烯基、杂环烷基、杂环烯基、芳基和杂芳基也可以彼此稠合。
“氨基”意指具有两个另外的取代基的氮部分,其中每个取代基具有与氮α键合的氢或碳原子。除非另有指示,否则本发明的含有氨基部分的化合物可以包含其受保护的衍生物。氨基部分的合适的保护基包含乙酰基、叔丁氧羰基、苄氧羰基等。
“芳香族”意指组成原子构成不饱和环系统的部分,所述环系统中的所有原子都被sp2杂化并且π电子的总数等于4n+2。芳香环可以为使得环原子仅为碳原子或者可以包含碳原子和非碳原子(参见杂芳基)。
“氨基甲酰基”是指基团-OC(O)NRaRb,其中Ra和Rb各自独立地是两个另外的取代基,其中氢原子或碳原子与氮α键合。应当注意,氨基甲酰基部分可以包含其受保护的衍生物。氨基甲酰基部分的合适的保护基的实例包含乙酰基、叔丁氧羰基、苄氧羰基等。应当注意,未受保护的衍生物和受保护的衍生物均落入本发明的范围内。
“羰基”是指基团-C(O)-。应当注意,羰基可以进一步被各种取代基取代以形成不同的羰基,包含酸、酸性卤化物、酰胺、酯和酮。
“羧基”是指基团-C(O)O-。应当注意,含有羧基部分的本发明的化合物可以包含其受保护的衍生物,即,其中氧被保护基取代。羧基部分的合适的保护基包含苄基、叔丁基等。
“氰基”意指基团-CN。
“甲酰基”意指基团-CH=O。
“亚胺甲基”意指基团-HC=NH。
“卤基”意是指氟、氯、溴或碘。
作为独立基团或较大基团的一部分的“卤基取代的烷基”意指被一个或多个“卤”原子取代的“烷基”。卤基取代的烷基包含卤代烷基、二卤代烷基、三卤代烷基、全卤代烷基等。
“羟基”意指基团-OH。
“亚胺衍生物”意指包括-C(=NR)-部分的衍生物,其中R包括与氮α键合的氢原子或碳原子。
“异构体”意指具有相同分子式但其原子键合性质或顺序或其原子空间布置不同的任何化合物。原子空间布置不同的异构体被称为“立体异构体”。并非彼此的镜像的立体异构体称为“非对映异构体”,并且作为不可重叠的镜像的立体异构体称为“对映异构体”或有时称为“光学异构体”。与四个不相同取代基键合的碳原子称为“手性中心”。具有一个手性中心的化合物具有手性相反的两种对映异构形式。所述两种对映异构形式的混合物称为“外消旋混合物”。
“硝基”意指基团-NO2。
“受保护的衍生物”意指化合物的反应位点被保护基阻断的衍生物。受保护的衍生物可用于制备药物或本身可以具有抑制剂活性。合适的保护基团的综合列表可以在以下文献中找到:T.W.Greene,《有机合成中的保护基(Protecting Groups in OrganicSynthesis)》,第3版,约翰威利父子公司(Wiley&Sons),1999。
术语“经取代的”意味着原子或原子团已经替代氢作为与另一基团连接的取代基。对于芳基和杂芳基,术语“经取代的”是指任何程度的取代,即单取代、二取代、三取代、四取代或五取代,其中此类取代是允许的。取代基是独立选择的,并且取代可以在任何化学上可接近的位置处进行。术语“未经取代的”意指给定部分可以通过可用化合价而仅由氢取代基组成(未经取代的)。
如果官能团被描述为“任选取代的”,则所述官能团可以是(1)未经取代的或(2)经取代的。如果官能团的碳被描述为任选地被一系列取代基中的一个或多个取代基取代,则所述碳上的氢原子中的一个或多个氢原子(如果有的话)可以分别和/或一起被独立选择的任选取代基取代。
“硫化物”意指-S-R,其中R是H、烷基、碳环、杂环、碳环烷基或杂环烷基。具体的硫化物基团是巯基、烷基硫醚,例如甲基硫醚(-S-Me);芳基硫醚,例如,苯基硫醚;芳烷基硫醚,例如,苄基硫醚。
“亚磺酰基”意指基团-S(O)-。应当注意,亚磺酰基可以进一步被各种取代基取代以形成不同的亚磺酰基,包含亚磺酸、亚磺酰胺、亚磺酰基酯和亚砜。
“磺酰基”意指基团-S(O)(O)-。应当注意,磺酰基可以进一步被各种取代基取代以形成不同的磺酰基,包含磺酸、磺酰胺、磺酸酯和砜。
“硫代羰基”意指基团-C(S)-。应当注意,硫代羰基可以进一步被各种取代基取代以形成不同的硫代羰基,包含硫代酸、硫代酰胺、硫代酸酯和硫代酮。
“动物”包含人类、非人类哺乳动物(例如,非人类灵长类动物、啮齿动物、小鼠、大鼠、仓鼠、狗、猫、兔子、牛、马、绵羊、山羊、猪、鹿等)和非哺乳动物(例如,鸟等)。
如本文所用,“生物利用度”是药物或药物组合物的施用剂量的完整到达体循环的分数或百分比。通常,当静脉内施用药物时,其生物利用度为100%。然而,当通过其它途径(例如,口服)施用药物时,其生物利用度降低(例如,由于吸收不完全和首关代谢)。提高生物利用度的方法包含前药方法、盐合成、粒径减小、络合、改变物理形式、固体分散体、喷雾干燥和热熔挤出。
“疾病”具体地包含动物或其一部分的任何不健康状况,并且包含可能由应用于该动物的医学或兽医疗法引起或伴随而来的不健康状况,即此类疗法的“副作用”。
“药学上可接受的”意味着可用于制备通常是安全的、无毒的并且既不是生物学上也不是其它方面不合需要的药物组合物的物质并且包含对于兽医用途以及人类药物用途是可接受的物质。
“药学上可接受的盐”意指本发明的化合物的如上所定义的药学上可接受的并且具有期望的药理活性的有机或无机盐。此类盐包含与无机酸或有机酸形成的酸加成盐。药学上可接受的盐还包含碱加成盐,所述碱加成盐可以在当存在的酸性质子能够与无机或有机碱反应时形成。示例性盐包含但不限于硫酸盐、柠檬酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、硫酸氢盐、磷酸盐、酸性磷酸盐、异烟酸盐、乳酸盐、水杨酸盐、酸性柠檬酸盐、酒石酸盐、油酸盐、丹宁酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、琥珀酸盐、马来酸盐、龙胆酸盐、富马酸盐、葡萄糖酸盐、葡萄糖醛酸盐、蔗糖盐、甲酸盐、苯甲酸盐、谷氨酸盐、甲磺酸盐(methanesulfonate,mesylate)、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、双羟萘酸盐(即,1,1'-亚甲基-双-(2-羟基-3-萘甲酸盐))、碱金属(例如,钠和钾)盐、碱土金属(例如,镁)盐和铵盐。药学上可接受的盐可以涉及包含另一种分子,如乙酸根离子、琥珀酸根离子或其它抗衡离子。抗衡离子可以是使母体化合物上的电荷稳定的任何有机或无机部分。此外,药学上可接受的盐可以在其结构中具有多于一个的带电原子。多个带电原子是药学上可接受的盐的一部分的实例可以具有多个抗衡离子。因此,药学上可接受的盐可以具有一个或多个带电原子和/或一个或多个抗衡离子。
“药学上可接受的载体”意指与本发明的化合物混合以形成药物组合物,即,能够向患者施用的剂型,的无毒溶剂、分散剂、赋形剂、佐剂或其它材料。药学上可接受的载体的实例包含合适的聚乙二醇(例如,PEG400)、表面活性剂(例如,Cremophor)或环多糖(例如,羟丙基-β-环糊精或磺丁基醚β-环糊精)、聚合物、脂质体、胶束、纳米球等。
如国际纯粹化学和应用化学联合会(The International Union of Pure andApplied Chemistry)所定义,“药效团(pharmacophore)”是空间特征与电子特征的集合,所述集合对于确保与特定生物靶标的最佳超分子相互作用并且对于触发(或阻断)其生物反应来说是必需的。例如,喜树碱(camptothecin)是众所周知的药物拓扑替康(topotecan)和伊立替康(irinotecan)的药效团。二氯甲基二乙胺(mechlorethamine)是一系列广泛使用的氮芥类药物(例如,美法仑(Melphalan)、环磷酰胺(Cyclophosphamide)、苯达莫司汀(Bendamustine)等)的药效团。
“前药”意指在体内可代谢地转化为根据本发明的活性药物的化合物。例如,可以将包括羟基的抑制剂作为通过体内水解转化为羟基化合物的酯施用。
“稳定性”通常是指药物保持其性质而不丧失功效的时间长度。稳定性有时被称为保质期。除其它之外,影响药物稳定性的因素包含药物的化学结构、调配物中的杂质、pH、含水量以及环境因素,如温度、氧化、光和相对湿度。可以通过提供合适的化学和/或晶体修饰(例如,可以改变水合动力学的表面修饰;可以具有不同性质的不同晶体)、赋形剂(例如,剂型中除活性物质以外的任何物质)、包装条件、储存条件等来提高稳定性。
本文所描述的组合物的“治疗有效量”意指所述组合物的以适用于任何药物治疗的合理的受益/风险比对被治疗受试者赋予治疗效果的量。治疗效果可以是客观的(即,可通过某一测试或标志物测量)或主观的(即,受试者给出效果的指示或感受到效果)。上述组合物的有效量的范围可以为约0.1mg/kg到约500mg/kg,优选地约0.2mg/kg到约50mg/kg。有效剂量还将根据施用途径以及与其它药剂一起使用的可能性而不同。然而,应理解的是,本发明的组合物的总日用量将在合理的医学判断的范围内由主治医师决定。任何特定患者的具体治疗有效剂量水平将取决于多种因素,包含:所治疗的病症和病症的严重程度;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、总体健康状况、性别和饮食;所采用的具体化合物的施用时间、施用途径和排泄率;治疗的持续时间;与所采用的具体化合物组合或同时使用的药物;以及医学领域众所周知的类似因素。
如本文所用,术语“治疗”是指向患有肿瘤病症或免疫性病症或具有所述病症的症状或对所述病症有易感性的受试者施用化合物,以治疗、治愈、减轻、缓解、改变、补救、改善、改进或影响所述病症、所述病症的症状或对所述病症的易感性。术语“有效量”是指赋予受试者预期的治疗效果所需的活性剂的量。如本领域的技术人员所认识到的,有效量可以取决于施用途径、赋形剂的使用以及与其它药剂一起使用的可能性而变化。
“受试者”是指人类和非人类动物。非人类动物的实例包含所有脊椎动物,例如,哺乳动物,如非人类灵长类动物(尤其是高等灵长类动物)、狗、啮齿动物(例如,小鼠或大鼠)、豚鼠、猫;以及非哺乳动物,例如,鸟、两栖动物、爬行动物等。在一优选实施例中,受试者是人类。在另一个实施例中,受试者是实验动物或适合作为疾病模型的动物。
“组合疗法”包含将本发明的化合物与其它生物活性成分(如但不限于第二种不同的抗肿瘤药剂)和非药物疗法(如但不限于外科手术或放射治疗)进一步组合进行施用。例如,本发明的化合物可以与其它药物活性化合物或非药物疗法,优选地能够增强本发明的化合物的效果的化合物组合使用。本发明的化合物可以与其它疗法同时(作为单一制剂或单独制剂)或依次施用。通常,组合疗法设想在单个周期或疗程期间施用两种或更多种药物/治疗。
在一个实施例中,本发明的化合物与一种或多种传统化学治疗剂组合施用。传统化学治疗剂涵盖肿瘤学领域中的大量治疗性治疗。这些药剂在疾病的各个阶段施用以缩小肿瘤、破坏外科手术后留下的剩余癌细胞、诱导缓解、维持缓解和/或减轻与癌症或其治疗有关的症状。此类药剂的实例包含但不限于:烷化剂,如氮芥类(例如,苯达莫司汀、环磷酰胺、美法仑、瘤可宁(Chlorambucil)、异环磷酰胺(Isofosfamide))、亚硝基脲(Nitrosurea)(例如,卡莫司汀(Carmustine)、洛莫司丁(Lomustine)和链脲佐菌素(Streptozocin))、亚乙基亚胺(ethylenimine)(例如,噻替派(thiotepa)、六甲嘧胺(hexamethylmelanine))、烷基磺酸盐(例如,白消安(Busulfan))、肼类和三嗪类(例如,六甲蜜胺(Altretamine)、丙卡巴肼(Procarbazine)、达卡巴嗪(Dacarbazine)和替莫唑胺(Temozolomide))以及基于铂的药剂(例如,卡铂(Carboplatin)、顺铂(Cisplatin)和奥沙利铂(Oxaliplatin));植物生物碱,如鬼臼毒素(Podophyllotoxin)(例如,依托泊苷(Etoposide)和替尼泊苷(Tenisopide))、紫杉烷类(例如,紫杉醇(Paclitaxel)和多西他赛(Docetaxel))、长春花生物碱(例如,长春新碱(Vincristine)、长春花碱(Vinblastine)和长春瑞滨(Vinorelbine));抗肿瘤抗生素,如色霉素(Chromomycin)(例如,更生霉素(Dactinomycin)和普卡霉素(Plicamycin))、蒽环类(例如,多柔比星(Doxorubicin)、道诺霉素(Daunorubicin)、表柔比星(Epirubicin)、米托蒽醌(Mitoxantrone)和依达比星(Idarubicin))以及其它抗生素,如丝裂霉素(Mitomycin)和博来霉素(Bleomycin);抗代谢物,如叶酸拮抗剂(例如,甲氨蝶呤(Methotrexate))、嘧啶拮抗剂(例如,5-氟尿嘧啶(5-Fluorouracil)、氟尿苷(Foxuridine)、阿糖胞苷(Cytarabine)、卡培他滨(Capecitabine)和吉西他滨)、嘌呤拮抗剂(例如,6-巯基嘌呤(6-Mercaptopurine)和6-硫鸟嘌呤(6-Thioguanine))和腺苷脱氨酶抑制剂(例如,克拉屈滨(Cladribine)、氟达拉滨(Fludarabine)、奈拉滨(Nelarabine)和喷司他丁(Pentostatin));拓扑异构酶抑制剂,如拓扑异构酶I抑制剂(托扑替康、伊立替康)、拓扑异构酶II抑制剂(例如,安吖啶(Amsacrine)、依托泊苷、磷酸依托泊苷、替尼泊苷)以及其它抗肿瘤药物,如核糖核苷酸还原酶抑制剂(羟基脲(Hydroxyurea))、肾上腺皮质类固醇抑制剂(米托坦(Mitotane))、抗微管剂(雌莫司汀(Estramustine))和类视黄醇(蓓萨罗丁(Bexarotene)、异维甲酸(Isotretinoin)、维甲酸(ATRA)。
在本发明的一方面,可以将化合物与一种或多种靶向抗癌剂组合施用,所述靶向抗癌剂对参与各种疾病状态的蛋白激酶进行调节。此类激酶的实例可以包含但不限于ABL1、ABL2/ARG、ACK1、AKT1、AKT2、AKT3、ALK、ALK1/ACVRL1、ALK2/ACVR1、ALK4/ACVR1B、ALK5/TGFBR1、ALK6/BMPR1B、AMPK(A1/B1/G1)、AMPK(A1/B1/G2)、AMPK(A1/B1/G3)、AMPK(A1/B2/G1)、AMPK(A2/B1/G1)、AMPK(A2/B2/G1)、AMPK(A2/B2/G2)、ARAF、ARK5/NUAK1、ASK1/MAP3K5、ATM、Aurora A、Aurora B、Aurora C、AXL、BLK、BMPR2、BMX/ETK、BRAF、BRK、BRSK1、BRSK2、BTK、CAMK1a、CAMK1b、CAMK1d、CAMK1g、CAMKIIa、CAMKIIb、CAMKIId、CAMKIIg、CAMK4、CAMKK1、CAMKK2、CDC7-DBF4、CDK1-周期素A、CDK1-周期素B、CDK1-周期素E、CDK2-周期素A、CDK2-周期素A1、CDK2-周期素E、CDK3-周期素E、CDK4-周期素D1、CDK4-周期素D3、CDK5-p25、CDK5-p35、CDK6-周期素D1、CDK6-周期素D3、CDK7-周期素H、CDK9-周期素K、CDK9-周期素T1、CHK1、CHK2、CK1a1、CK1d、CK1ε、CK1g1、CK1g2、CK1g3、CK2a、CK2a2、c-KIT、CLK1、CLK2、CLK3、CLK4、c-MER、c-MET、COT1/MAP3K8、CSK、c-SRC、CTK/MATK、DAPK1、DAPK2、DCAMKL1、DCAMKL2、DDR1、DDR2、DLK/MAP3K12、DMPK、DMPK2/CDC42BPG、DNA-PK、DRAK1/STK17A、DYRK1/DYRK1A、DYRK1B、DYRK2、DYRK3、DYRK4、EEF2K、EGFR、EIF2AK1、EIF2AK2、EIF2AK3、EIF2AK4/GCN2、EPHA1、EPHA2、EPHA3、EPHA4、EPHA5、EPHA6、EPHA7、EPHA8、EPHB1、EPHB2、EPHB3、EPHB4、ERBB2/HER2、ERBB4/HER4、ERK1/MAPK3、ERK2/MAPK1、ERK5/MAPK7、FAK/PTK2、FER、FES/FPS、FGFR1、FGFR2、FGFR3、FGFR4、FGR、FLT1/VEGFR1、FLT3、FLT4/VEGFR3、FMS、FRK/PTK5、FYN、GCK/MAP4K2、GRK1、GRK2、GRK3、GRK4、GRK5、GRK6、GRK7、GSK3a、GSK3b、Haspin、HCK、HGK/MAP4K4、HIPK1、HIPK2、HIPK3、HIPK4、HPK1/MAP4K1、IGF1R、IKKa/CHUK、IKKb/IKBKB、IKKe/IKBKE、IR、IRAK1、IRAK4、IRR/INSRR、ITK、JAK1、JAK2、JAK3、JNK1、JNK2、JNK3、KDR/VEGFR2、KHS/MAP4K5、LATS1、LATS2、LCK、LCK2/ICK、LKB1、LIMK1、LOK/STK10、LRRK2、LYN、LYNB、MAPKAPK2、MAPKAPK3、MAPKAPK5/PRAK、MARK1、MARK2/PAR-1Ba、MARK3、MARK4、MEK1、MEK2、MEKK1、MEKK2、MEKK3、MELK、MINK/MINK1、MKK4、MKK6、MLCK/MYLK、MLCK2/MYLK2、MLK1/MAP3K9、MLK2/MAP3K10、MLK3/MAP3K11、MNK1、MNK2、MRCKa/、CDC42BPA、MRCKb/、CDC42BPB、MSK1/RPS6KA5、MSK2/RPS6KA4、MSSK1/STK23、MST1/STK4、MST2/STK3、MST3/STK24、MST4、mTOR/FRAP1、MUSK、MYLK3、MYO3b、NEK1、NEK2、NEK3、NEK4、NEK6、NEK7、NEK9、NEK11、NIK/MAP3K14、NLK、OSR1/OXSR1、P38a/MAPK14、P38b/MAPK11、P38d/MAPK13、P38g/MAPK12、P70S6K/RPS6KB1、p70S6Kb/、RPS6KB2、PAK1、PAK2、PAK3、PAK4、PAK5、PAK6、PASK、PBK/TOPK、PDGFRa、PDGFRb、PDK1/PDPK1、PDK1/PDHK1、PDK2/PDHK2、PDK3/PDHK3、PDK4/PDHK4、PHKg1、PHKg2、PI3Ka、(p110a/p85a)、PI3Kb、(p110b/p85a)、PI3Kd、(p110d/p85a)、PI3Kg(p120g)、PIM1、PIM2、PIM3、PKA、PKAcb、PKAcg、PKCa、PKCb1、PKCb2、PKCd、PKCε、PKCη、PKCg、PKCι、PKCmu/PRKD1、PKCnu/PRKD3、PKCθ、PKCζ、PKD2/PRKD2、PKG1a、PKG1b、PKG2/PRKG2、PKN1/PRK1、PKN2/PRK2、PKN3/PRK3、PLK1、PLK2、PLK3、PLK4/SAK、PRKX、PYK2、RAF1、RET、RIPK2、RIPK3、RIPK5、ROCK1、ROCK2、RON/MST1R、ROS/ROS1、RSK1、RSK2、RSK3、RSK4、SGK1、SGK2、SGK3/SGKL、SIK1、SIK2、SLK/STK2、SNARK/NUAK2、SRMS、SSTK/TSSK6、STK16、STK22D/TSSK1、STK25/YSK1、STK32b/YANK2、STK32c/YANK3、STK33、STK38/NDR1、STK38L/NDR2、STK39/STLK3、SRPK1、SRPK2、SYK、TAK1、TAOK1、TAOK2/TAO1、TAOK3/JIK、TBK1、TEC、TESK1、TGFBR2、TIE2/TEK、TLK1、TLK2、TNIK、TNK1、TRKA、TRKB、TRKC、TRPM7/CHAK1、TSSK2、TSSK3/STK22C、TTBK1、TTBK2、TTK、TXK、TYK1/LTK、TYK2、TYRO3/SKY、ULK1、ULK2、ULK3、VRK1、VRK2、WEE1、WNK1、WNK2、WNK3、YES/YES1、ZAK/MLTK、ZAP70、ZIPK/DAPK3、KINASE、MUTANTS、ABL1(E255K)、ABL1(F317I)、ABL1(G250E)、ABL1(H396P)、ABL1(M351T)、ABL1(Q252H)、ABL1(T315I)、ABL1(Y253F)、ALK(C1156Y)、ALK(L1196M)、ALK(F1174L)、ALK(R1275Q)、BRAF(V599E)、BTK(E41K)、CHK2(I157T)、c-Kit(A829P)、c-KIT(D816H)、c-KIT(D816V)、c-Kit(D820E)、c-Kit(N822K)、C-Kit(T670I)、c-Kit(V559D)、c-Kit(V559D/V654A)、c-Kit(V559D/T670I)、C-Kit(V560G)、c-KIT(V654A)、C-MET(D1228H)、C-MET(D1228N)、C-MET(F1200I)、c-MET(M1250T)、C-MET(Y1230A)、C-MET(Y1230C)、C-MET(Y1230D)、C-MET(Y1230H)、c-Src(T341M)、EGFR(G719C)、EGFR(G719S)、EGFR(L858R)、EGFR(L861Q)、EGFR(T790M)、EGFR、(L858R、T790M)、EGFR(d746-750/T790M)、EGFR(d746-750)、EGFR(d747-749/A750P)、EGFR(d747-752/P753S)、EGFR(d752-759)、FGFR1(V561M)、FGFR2(N549H)、FGFR3(G697C)、FGFR3(K650E)、FGFR3(K650M)、FGFR4(N535K)、FGFR4(V550E)、FGFR4(V550L)、FLT3(D835Y)、FLT3(ITD)、JAK2(V617F)、LRRK2(G2019S)、LRRK2(I2020T)、LRRK2(R1441C)、p38a(T106M)、PDGFRa(D842V)、PDGFRa(T674I)、PDGFRa(V561D)、RET(E762Q)、RET(G691S)、RET(M918T)、RET(R749T)、RET(R813Q)、RET(V804L)、RET(V804M)、RET(Y791F)、TIF2(R849W)、TIF2(Y897S)和TIF2(Y1108F)。
在本发明的另一方面,可以将本发明化合物与调节非激酶生物学靶标、途径或过程的一种或多种靶向抗癌剂组合施用。此类靶标、途径或过程包含但不限于热休克蛋白(例如,HSP90)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)、缺氧诱导因子(HIF)、蛋白酶体、Wnt/Hedgehog/Notch信号传导蛋白、TNF-α、基质金属蛋白酶、法呢基转移酶、凋亡途径(例如,Bcl-xL、Bcl-2、Bcl-w)、组蛋白去乙酰化酶(HDAC)、组蛋白乙酰基转移酶(HAT)和甲基转移酶(例如,组蛋白赖氨酸甲基转移酶、组蛋白精氨酸甲基转移酶、DNA甲基转移酶等)。
在本发明的另一方面,本发明的化合物与一种或多种其它抗癌剂组合施用,所述其它抗癌剂包含但不限于基因疗法、RNAi癌症疗法、化学保护药剂(例如,阿米福汀(amfostine)、美司钠(mesna)、右雷佐生(dexrazoxane))、抗体缀合物(例如,本妥昔单抗(brentuximab vedotin)、替伊莫单抗(ibritumomab tioxetan)、癌症免疫疗法(如白介素-2(Interleukin-2))、癌症疫苗(例如,西普鲁塞-T(sipuleucel-T))或单克隆抗体(例如,贝伐单抗(Bevacizumab)、阿仑单抗(Alemtuzumab)、利妥昔单抗(Rituximab)、曲妥珠单抗(Trastuzumab)等)。
在本发明的另一方面,本发明化合物与放射疗法或外科手术组合施用。放射线通常从采用光子(x射线或γ射线)或粒子放射线的机器内部(在癌症部位附近植入放射性物质)或外部递送。当组合疗法进一步包括放射治疗时,可在任何合适的时间进行放射治疗,只要从治疗剂与放射治疗的组合的共同作用中实现有益作用即可。例如,在适当的情况下,当从治疗剂的施用中暂时去除放射治疗时(也许是数天甚至数周),仍然实现有益作用。
在某些实施例中,本发明的化合物与放射疗法、外科手术或抗癌剂中的一种或多种组合施用,所述抗癌剂包含但不限于DNA损伤剂、抗代谢物、拓扑异构酶抑制剂、抗微管剂、激酶抑制剂、表观遗传剂、HSP90抑制剂、PARP抑制剂以及靶向VEGF、HER2、EGFR、CD50、CD20、CD30、CD33等的抗体。
在某些实施例中,本发明的化合物与以下中的一种或多种组合施用:阿巴瑞克(abarelix)、醋酸阿比特龙(abiraterone acetate)、阿地白介素(aldesleukin)、阿仑单抗、六甲蜜胺、阿那曲唑(anastrozole)、天冬酰胺酶(asparaginase)、苯达莫司汀、贝伐单抗、蓓萨罗丁、比卡鲁胺(bicalutamide)、博来霉素、硼替佐米(bortezombi)、本妥昔单抗、白消安、卡培他滨、卡铂、卡莫司汀、西妥昔单抗(cetuximab)、瘤可宁、顺铂、克拉屈滨、氯法拉滨(clofarabine)、氯米芬(clomifene)、克唑替尼(crizotinib)、环磷酰胺、达沙替尼(dasatinib)、道诺霉素脂质体(daunorubicin liposomal)、地西他滨(decitabine)、地加瑞克(degarelix)、地尼白介素(denileukin diftitox)、地尼白介素、地诺单抗(denosumab)、多西他赛、多柔比星、多柔比星脂质体(doxorubicin liposomal)、表柔比星、甲磺酸艾日布林(eribulin mesylate)、埃罗替尼(erlotinib)、雌莫司汀、磷酸依托泊苷(etoposide phosphate)、依维莫司(everolimus)、依西美坦(exemestane)、氟达拉滨、氟尿嘧啶、福莫司汀(fotemustine)、氟维司群(fulvestrant)、吉非替尼(gefitinib)、吉西他滨、吉妥珠单抗(gemtuzumab ozogamicin)、醋酸戈舍瑞林(goserelin acetate)、醋酸组氨瑞林(histrelin acetate)、羟基脲、替伊莫单抗、伊达比星、异环磷酰胺、甲磺酸伊马替尼(imatinib mesylate)、干扰素α2a(interferon alfa 2a)、伊匹单抗(ipilimumab)、伊沙匹隆(ixabepilone)、二甲苯磺酸拉帕替尼(lapatinib ditosylate)、来那度胺(lenalidomide)、来曲唑(letrozole)、亚叶酸(leucovorin)、醋酸亮丙瑞林(leuprolideacetate)、左旋咪唑(levamisole)、洛莫司丁(lomustine)、二氯甲基二乙胺、美法仑、甲氨蝶呤、丝裂霉素C(mitomycin C)、米托蒽醌、奈拉滨、尼罗替尼(nilotinib)、奥沙利铂、紫杉醇、紫杉醇蛋白结合颗粒(paclitaxel protein-bound particle)、帕米磷酸二钠(pamidronate)、帕尼单抗(panitumumab)、培门冬酶(pegaspargase)、聚乙二醇干扰素α2b(peginterferon alfa-2b)、培美曲塞二钠(pemetrexed disodium)、喷司他丁、雷洛昔芬(raloxifene)、利妥昔单抗(rituximab)、索拉非尼(sorafenib)、链脲佐菌素、马来酸舒尼替尼(sunitinib maleate)、它莫西芬(tamoxifen)、替西罗莫司(temsirolimus)、替尼泊苷、沙利度胺(thalidomide)、托瑞米芬(toremifene)、托西莫单抗(tositumomab)、曲妥珠单抗、维甲酸、乌拉莫司汀(uramustine)、凡德他尼(vandetanib)、维罗非尼(vemurafenib)、长春瑞滨、唑来磷酸(zoledronate)、放射疗法或外科手术。
本发明进一步提供了用于预防或治疗肿瘤疾病或自身免疫性疾病的方法。在一个实施例中,本发明涉及一种治疗需要治疗的受试者的肿瘤疾病或自身免疫疾病的方法,所述方法包括向所述受试者施用治疗有效量的本发明的化合物。在一个实施例中,本发明进一步提供了本发明的化合物在制备用于中止或减少肿瘤疾病或自身免疫性疾病的药物中的用途。
在某些实施例中,肿瘤疾病是肺癌、头颈癌、中枢神经系统癌、前列腺癌、睾丸癌、结肠直肠癌、胰腺癌、肝癌、胃癌、胆道癌、食道癌、胃肠道间质瘤、乳腺癌、宫颈癌、卵巢癌、子宫癌、白血病、淋巴瘤、多发性骨髓瘤、黑色素瘤、基底细胞癌、鳞状细胞癌、膀胱癌、肾癌、肉瘤、间皮瘤、胸腺瘤、骨髓增生异常综合征或骨髓增生性疾病。
可以使用根据本发明的化合物和组合物影响的自身免疫性疾病包含但不限于过敏症、阿尔茨海默氏病(Alzheimer's disease)、急性播散性脑脊髓炎、阿狄森氏病(Addison's disease)、强直性脊柱炎、抗磷脂抗体综合征、哮喘、动脉粥样硬化、自身免疫性溶血性贫血、自身免疫性溶血和血小板减少状态、自身免疫性肝炎、自身免疫性内耳疾病、大疱性类天疱疮、乳糜泻、查加斯病(chagas disease)、慢性阻塞性肺疾病、慢性特发性血小板减少性紫癜(ITP)、查格-施特劳斯综合征(churg-strauss syndrome)、克罗恩病(Crohn's disease)、皮肌炎、1型糖尿病、子宫内膜异位症、古德帕斯彻氏综合征(Goodpasture's syndrome)(和相关的肾小球肾炎和肺出血)、格雷夫斯病(graves'disease)、格林-巴利综合征(guillain-barrésyndrome)、桥本氏病(hashimoto'sdisease)、化脓性汗腺炎、特发性血小板减少性紫癜、间质性膀胱炎、肠易激综合征、红斑狼疮、硬斑病、多发性硬化症、重症肌无力、嗜睡症、神经性肌强直、帕金森氏病(Parkinson'sdisease)、寻常型天疱疮、恶性贫血、多肌炎、原发性胆汁性肝硬化、牛皮癣、银屑病关节炎、类风湿性关节炎、精神分裂症、败血性休克、硬皮病、舍格伦氏病(Sjogren's disease)、系统性红斑狼疮(和相关的肾小球肾炎)、颞动脉炎、移植器官的组织移植排斥和超急性排斥、血管炎(ANCA相关的血管炎和其它血管炎)、白癜风和韦格纳氏肉芽肿病(wegener'sgranulomatosis)。
应当理解,本发明不限于在本文中示出和描述的特定实施例,而是可以在不脱离由权利要求书限定的本发明的精神和范围的情况下进行各种改变和修改。
可以根据多种方案合成根据本发明的化合物。可以通过有机化学的标准程序获得必要的起始材料。结合以下代表性的合成方案和实例,将更好地理解本发明的化合物和方法,所述合成方案和实例仅用于说明而不限制本发明的范围。对公开的实施例的各种改变和修改对本领域的技术人员来说是显而易见的,并且在不脱离本发明的精神和所附权利要求书的范围的情况下,可以进行此类改变和修改,包含但不限于与本发明的化学结构、取代基、衍生物和/或方法有关的改变和修改。
方案A中描述了合成式(1)化合物的典型方法。一般方案A中的R1、R2和R3与上文的“发明内容”部分中所描述R1、R2和R3的相同。
方案A
在方案A中,起始材料吉西他滨可以与2-丙戊酸或合适的氯甲酸烷基酯(alkylcarbonochloridate)反应以产生中间体A-2,所述中间体可以与合适的酰氯或羧酸反应以形成中间体A-3。最后,A-3可以与合适的酰氯或羧酸反应以形成期望的具有式(I)的最终产物。
结合以下实例,将更好地理解本发明的化合物和方法,所述合成方案和实例仅用于说明而不限制本发明的范围。对公开的实施例的各种改变和修改对本领域的技术人员来说是显而易见的,并且在不脱离本发明的精神和所附权利要求书的范围的情况下,可以进行此类改变和修改,包含但不限于与本发明的化学结构、取代基、衍生物、调配物和/或方法有关的改变和修改。
在呈现NMR数据的情况下,1H图谱是在XL400(400MHz)上获得的并且以相对于Me4Si处于低场处的ppm值报告,其中在括号中指示质子数、多重性和以赫兹计的耦合常数。在呈现HPLC数据的情况下,分析是使用安捷伦1100系统(Agilent 1100system)进行的。在呈现LC/MS数据的情况下,分析是使用应用生物系统公司API-100质谱仪(Applied BiosystemsAPI-100mass spectrometer)和岛津公司SCL-10A LC柱(Shimadzu SCL-10A LC column)进行的。
实例1:2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯的合成
将2-丙戊酸(12g,83.21mmol,1.30当量)、HOBt(10.27g,76.01mmol,1.15当量)、NMM(7.67g,75.83mmol,1.15当量)和EDCI.HCl(18.87g,1.30当量)于N,N-二甲基甲酰胺(60mL)中的溶液放入用惰性氮气气氛吹扫和维持的500mL 3颈圆底烧瓶中。在室温下将含4-氨基-1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-1,2-二氢嘧啶-2-酮盐酸盐(20g,66.74mmol,1.00当量)的DMF(20mL)加入到上述溶液中。将所得溶液在油浴中在55℃下搅拌过夜。然后通过加入200mL盐水来淬灭反应。将所得溶液用3×50mL乙酸乙酯萃取并且将有机层合并。将所得混合物用1×50mL HCl水溶液和1×50mL盐水洗涤。将所得混合物干燥并在真空下浓缩。将残留物施加到使用乙酸乙酯/石油醚(1:3)的硅胶柱上。这产生17.5g(67%)呈灰白色固体的N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]-2-丙基戊酰胺。(ES,m/z):[M+H]+=390。1H-NMR:(300MHz,CDCl3,ppm):δ8.80(br,1H),8.21(d,J=7.8Hz,1H),7.57(d,J=7.8Hz,1H),6.26(t,J=6.7Hz,1H),5.20(br,1H),4.53(m,1H),4.15-3.90(m,4H),2.39(br,1H),1.69-1.21(m,8H),0.92(t,J=7.2Hz,6H)。
将N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]-2-丙基戊酰胺(500mg,1.28mmol,1.00当量)、2-甲基丙酰氯(272mg,2.55mmol,2.20当量)、4-二甲基氨基吡啶(16mg,0.13mmol,0.10当量)放入用惰性氮气气氛吹扫和维持的25mL圆底烧瓶中。随后在0℃下加入吡啶(5mL)并且将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩并且通过快速制备型HPLC(Flash-Prep-HPLC)纯化。这产生167mg(24%)呈浅棕色半固体的2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。LC-MS:(ES,m/z):[M+H]+=530。1H-NMR:(300MHz,d6-DMSO,ppm):δ11.11(s,1H),8.06(d,J=7.8Hz,1H),7.38(d,J=7.8Hz,1H),6.33(t,J=8.7Hz,H),5.45(q,J=6.0Hz,1H),4.52-4.36(m,3H),2.76-2.52(m,3H),1.61-1.03(m,20H),0.86(t,J=7.2Hz,3H)。
实例2:(2S)-2-氨基-3-甲基丁酸(2R,3R,5R)-4,4-二氟-2-[[(2-甲基丙酰基)氧基]甲基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-3-基酯的合成
将2-甲基丙酸(170mg,1.93mmol,1.50当量)、CDI(0.31g,1.93mmol,1.50当量)、四氢呋喃(30mL)放入50mL圆底烧瓶中。随后加入N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]-2-丙基戊酰胺(0.5g,1.29mmol,1.00当量)。将所得溶液在室温下搅拌2小时。将所得混合物在真空下浓缩。通过快速纯化粗产物,PE:EA=100/20在20分钟内增加到PE:EA=100/50。这产生0.45g(76%)呈白色油的2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。1H-NMR:(300MHz,d6-DMSO,ppm):δ11.12(s,1H),8.21(d,J=7.8Hz,1H),7.35(d,J=7.8Hz,1H),6.30(t,J=8.7Hz,1H),5.47-5.30(m,2H),4.27(m,1H),3.84-3.58(m,2H),2.66-2.55(m,2H),1.60-1.10(m,14H),0.88(t,J=7.1Hz,6H)。
将2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯(0.4g,0.87mmol,1.00当量)、(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(380mg,4.36mmol,2.00当量)、DCC(360mg,4.37mmol,2.00当量)、4-二甲基氨基吡啶(215mg,4.34mmol,2.00当量)、N,N-二甲基甲酰胺(15mL)放入50mL圆底烧瓶中。将所得溶液在室温下搅拌2小时。然后通过加入H2O来淬灭反应。将所得溶液用乙酸乙酯萃取并且将有机层合并且在真空下浓缩。通过快速纯化粗产物,PE:EA=100/20在30分钟内增加到PE:EA=100/60。这产生0.52g(91%)呈白色油的(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(2R,3R,5R)-4,4-二氟-2-[[(2-甲基丙酰基)氧基]甲基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-3-基酯。
将(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(2R,3R,5R)-4,4-二氟-2-[[(2-甲基丙酰基)氧基]甲基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-3-基酯(500mg,0.76mmol,1.00当量)、氯化氢/二噁烷(4M,30mL)放入50mL圆底烧瓶中。将所得溶液在室温下搅拌1小时。将所得混合物在真空下浓缩。通过制备型HPLC纯化粗产物。这产生312mg(46%)呈灰白色固体的(2S)-2-氨基-3-甲基丁酸(2R,3R,5R)-4,4-二氟-2-[[(2-甲基丙酰基)氧基]甲基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-3-基酯。LC-MS:(M+H)+=559.1H-NMR:(300MHz,d6-DMSO,ppm):δ11.12(s,1H),8.07(d,J=7.8Hz,1H),7.38(d,J=7.8Hz,1H),6.35(t,J=8.7Hz,1H),5.47(q,J=6.0Hz,1H),4.55-4.51(m,3H),3.86(d,J=6.0Hz,1H),2.76-2.71(m,2H),2.15(m,1H),1.59-1.03(m,14H),1.01-0.83(m,12H)。
实例3:(2S)-2-氨基-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯的合成
将(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(0.4g,1.84mmol,1.20当量)、CDI(300mg,1.85mmol,1.20当量)、四氢呋喃(25mL)放入100mL圆底烧瓶中。将所得混合物在室温下搅拌30分钟。向所得混合物加入N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]-2-丙基戊酰胺(0.6g,1.54mmol,1.00当量)并且将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。通过快速纯化粗产物,PE:EA=100/50。这产生0.72g(79%)呈白色油的(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。LC-MS:(ES,m/z):589[M+H]+。
将(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯(700mg,1.19mmol,1.00当量)、4-二甲基氨基吡啶(290mg,2.38mmol,2.00当量)、2-甲基丙酰氯(153mg,1.40mmol,1.20当量)、吡啶(14mL)放入50mL圆底烧瓶中。将所得溶液在室温下搅拌1小时。将所得混合物在真空下浓缩。通过制备型HPLC纯化粗产物。这产生210mg(27%)呈白色固体的(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。LC-MS:(ES,m/z):[M+H]+=659。1H-NMR:(300MHz,d6-DMSO,ppm):δ11.11(s,1H),8.09(d,J=7.8Hz,1H),7.38(d,J=7.8Hz,1H),6.35(t,J=8.7Hz,1H),5.50(br,1H),4.45-4.28(m,2H),3.93(m,1H),2.72-2.58(m,2H),2.05(m,1H),1.60-1.06(m,24H),0.95-0.84(m,12H)。
将(2R)-2-[[(叔丁氧基)羰基]氨基]丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯(200mg,0.32mmol,1.00当量)、氯化氢/二噁烷(2mL)放入用惰性氮气气氛吹扫和维持的50mL圆底烧瓶中。将所得溶液在室温下搅拌30分钟。将所得混合物在真空下浓缩。将残留物通过制备型HPLC纯化,然后施加到使用乙酸乙酯的硅胶柱上。这产生35.1mg(41%)呈无色油的(2S)-2-氨基-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。LC-MS:(ES,m/z):[M+H]+=559。1H-NMR:(300MHz,d6-DMSO,ppm):δ11.11(s,1H),8.07(d,J=7.8Hz,1H),7.38(d,J=7.8Hz,1H),6.35(t,J=8.7Hz,1H),5.50(q,J=6.0Hz,1H),4.52-4.37(m,3H),3.28(d,J=6.0Hz,1H)2.67-2.60(m,3H),1.99-1.87(m,2H),1.60-1.06(m,15H),0.95-0.84(m,12H)。
实例4:(2S)-2-氨基-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-氨基-3-甲基丁酰基]氧基]-4,4-二氟-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯的合成
将N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]-2-丙基戊酰胺(778mg,2.00mmol,1.00当量)于N,N-二甲基甲酰胺(20mL)中的溶液放入用惰性氮气气氛吹扫和维持的50mL圆底烧瓶中,并且然后向所述溶液中加入(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(1.73g,7.96mmol,4.00当量)、4-二甲基氨基吡啶(730mg,5.98mmol,3.00当量)、DCC(2.5g,12.12mmol、6.00当量)。将所得溶液在室温下搅拌3小时。然后通过加入50mL水来淬灭反应。将所得溶液用3×100mL乙酸乙酯萃取并且将有机层合并且在真空下浓缩。将残留物施加到使用乙酸乙酯/石油醚(1:1)的硅胶柱上。这产生700mg(44%)呈灰白色固体的(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酰基]氧基]-4,4-二氟-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。
将(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酰基]氧基]-4,4-二氟-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯(200mg,0.13mmol,1.00当量)、氯化氢/二噁烷(4M,5mL)放入25mL圆底烧瓶中。将所得溶液在室温下搅拌1小时。将所得混合物在真空下浓缩并用MeCN重结晶。这产生90mg(55%)呈白色固体的(2S)-2-氨基-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-氨基-3-甲基丁酰基]氧基]-4,4-二氟-5-[2-氧代-4-(2-丙基戊酰胺基)-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。LC-MS:(M+H)+=588.1H-NMR:(300MHz,d6-DMSO,ppm):δ11.13(s,1H),8.12(d,J=7.8Hz,1H),7.39(d,J=7.8Hz,1H),6.35(t,J=8.7Hz,1H),5.65(m,1H),4.68-4.61(m,3H),4.03-3.94(m,2H),2.69-2.60(m,1H),2.30-2.19(m,2H),1.60-1.10(m,8H),1.10-0.95(m,12H),0.84(t,J=7.1Hz,6H)。
实例5:2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯的合成
将4-氨基-1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-1,2-二氢嘧啶-2-酮(200mg,0.66mmol,1.00当量)于CH3CN(2mL)中的溶液、氯甲酸戊酯(126mg,0.84mmol,1.30当量)、NMM(153.6mg,1.52mmol,2.40当量)放入用惰性氮气气氛吹扫和维持的25mL圆底烧瓶中。将所得溶液在室温下搅拌2小时。将所得溶液用10mL水稀释。将所得溶液用2×10mL乙酸乙酯萃取并且将有机层合并且在真空下浓缩。将残留物施加到使用乙酸乙酯/石油醚(1:1)的硅胶柱上。这产生90mg(31%)呈灰白色固体的N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]氨基甲酸戊酯。LC-MS:(ES,m/z):[M+H]+=378。1H-NMR:(300MHz,d6-DMSO,ppm):δ10.81(br,1H),8.23(d,J=7.8Hz,1H),7.11(d,J=7.8Hz,1H),6.31(d,J=6.3Hz,1H),6.17(t,J=7.5Hz,1H),5.30(t,J=5.5Hz,1H),4.20(m,1H),3.93-3.60(m,3H),1.69-1.23(m,8H),0.90(m,3H)。
将戊基-N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]氨基甲酸酯(110mg,0.29mmol,1.00当量)于吡啶(1mL)中的溶液放入用惰性氮气气氛吹扫和维持的25mL圆底烧瓶中,并且然后向所述溶液中加入4-二甲基氨基吡啶(10mg,0.08mmol,0.10当量)、2-甲基丙酰氯(69mg,0.65mmol、2.20当量)。将所得溶液在室温下搅拌3小时。将所得混合物在真空下浓缩。将粗产物通过快速制备型HPLC纯化,并且产生90mg(60%)呈无色油的2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-[2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基]草脲胺-2-基]甲酯。LC-MS:(ES,m/z):[M+H]+=518。1H-NMR:(300MHz,d6-DMSO,ppm):δ10.89(br,1H),8.06(d,J=7.8Hz,1H),7.15(d,J=7.8Hz,1H),6.35(t,J=8.7Hz,1H),5.45(m,1H),4.49-4.37(m,3H),4.12(t,J=6.6Hz,2H),2.77-2.54(m,2H),1.66-1.58(m,2H),1.40-1.04(m,16H),0.90(m,3H)。
实例6:(2S)-2-氨基-3-甲基丁酸(2R,3R,5R)-5-[4-[(丁氧基羰基)氨基]-2-氧代-1,2-二氢嘧啶-1-基]-4,4-二氟-2-[[(2-甲基丙酰基)氧基]甲基]草脲胺-3-基酯的合成
将2-甲基丙酸(350mg,3.97mmol,1.50当量)于四氢呋喃(10mL)中的溶液放入用惰性氮气气氛吹扫和维持的25mL圆底烧瓶中。向溶液中加入CDI(680mg,4.19mmol,1.60当量)并且然后将混合物在室温下搅拌30分钟。向以上溶液中加入戊基-N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]氨基甲酸酯(1.0g,2.65mmol,1.00当量)。将所得溶液在室温下搅拌3小时。将所得混合物在真空下浓缩。将残留物施加到使用乙酸乙酯/石油醚(1:1)的硅胶柱上。这产生500mg(42%)呈白色固体的2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯。LC-MS:(ES,m/z):[M+H]+=448。1H-NMR:(300MHz,d6-DMSO,ppm):δ10.85(br,1H),8.18(d,J=7.8Hz,1H),7.14(d,J=7.8Hz,1H),6.30(t,J=8.7Hz,1H),5.45-5.30(m,2H),4.25(m,1H),3.85-3.60(m,2H),2.77-2.63(m,1H),1.70-1.58(br,2H),1.40-1.12(m,12H),0.86(m,3H)。
将2-甲基丙酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯(250mg,0.56mmol,1.00当量)于N,N-二甲基甲酰胺(3mL)中的溶液、(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(157.7mg,0.73mmol,1.30当量)、DCC(150mg,0.73mmol,1.30当量)、4-二甲基氨基吡啶(136mg,1.11mmol,2.00当量)放入用惰性氮气气氛吹扫和维持的25mL圆底烧瓶中。将所得溶液在室温下搅拌1.5小时。将固体滤出。将残留物浓缩并施加到使用乙酸乙酯/石油醚(1:1)的硅胶柱上。这产生320mg(91%)呈白色固体的(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(2R,3R,5R)-5-[4-[(丁氧基羰基)氨基]-2-氧代-1,2-二氢嘧啶-1-基]-4,4-二氟-2-[[(2-甲基丙酰基)氧基]甲基]草脲胺-3-基酯。LC-MS:(ES,m/z):[M+H]+=647。
将(2R,3R,5R)-5-[4-[(丁氧基羰基)氨基]-2-氧代-1,2-二氢嘧啶-1-基]-4,4-二氟-2-[[(2-甲基丙酰基)氧基]甲基]草脲胺-3-基-(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸酯(100mg,0.16mmol,1.00当量)于二噁烷(2mL)中的溶液、氯化氢/二噁烷(1mL)放入用惰性氮气气氛吹扫和维持的25mL圆底烧瓶中。将所得溶液在室温下搅拌1小时。将所得混合物在真空下浓缩并且通过制备型HPLC(TFA)纯化。这产生50mg(50%)呈灰白色固体的(2S)-2-氨基-3-甲基丁酸(2R,3R,5R)-5-[4-[(丁氧基羰基)氨基]-2-氧代-1,2-二氢嘧啶-1-基]-4,4-二氟-2-[[(2-甲基丙酰基甲基)氧基]甲基]草脲胺-3-基酯。LC-MS:(ES,m/z):[M+H]+=547。1H-NMR:(300MHz,d6-DMSO,ppm):δ10.92(br,1H),8.40(br,3H),8.05(d,J=7.8Hz,1H),7.16(d,J=7.8Hz,1H),6.35(t,J=8.7Hz,1H),5.50(m,1H),4.62-4.51(m,3H),4.13(t,J=6.6Hz,2H),4.03(s,1H),2.77-2.67(m,1H),2.21-2.16(m,1H)1.62(m,1H),1.34-1.30(m,4H),1.16(t,J=5.6Hz,1H),1.05-0.86(m,9H)。
实例7:(2R)-2-氨基-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯的合成
将(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(315mg,1.45mmol,1.10当量)、CDI(235mg,1.45mmol,1.10当量)放入100mL圆底烧瓶中。随后加入四氢呋喃(20mL)并在室温下搅拌30分钟。在搅拌下向此溶液中逐滴加入戊基-N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]氨基甲酸酯(0.5g,1.32mmol,1.00当量)。将所得溶液在室温下搅拌过夜。将所得混合物在真空下浓缩。通过快速制备型HPLC纯化粗产物,PE:EA=95:5在30分钟内增加到PE:EA=70:30。这产生0.6g(79%)呈灰白色固体的(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯。1H-NMR:(300MHz,d6-DMSO,ppm):δ10.86(br,1H),8.20(d,J=7.8Hz,1H),7.40(d,J=7.8Hz,1H),7.13(d,J=7.5Hz,1H),6.30(t,J=8.7Hz,1H),5.50-5.30(m,2H),4.22(m,1H),4.10(t,J=6.3Hz,2H),3.97-59(m,3H),2.05(m,1H),1.66(m,2H),1.35-1.25(m,13H),0.91(m,9H)。
将2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-羟基-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯(0.5g,0.86mmol,1.00当量)、2-甲基丙酰氯(110mg,1.03mmol,1.20当量)、4-二甲基氨基吡啶(212mg,1.74mmol,2.00当量)、吡啶(10mL)放入50mL圆底烧瓶中。将所得溶液在室温下搅拌2小时。将所得混合物在真空下浓缩。将所得溶液用甲醇萃取并且将有机层合并。通过制备型HPLC纯化粗产物。这产生300mg(53%)呈白色固体的2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯。1H-NMR:(300MHz,d6-DMSO,ppm):δ10.89(br,1H),8.06(d,J=7.8Hz,1H),7.42(d,J=7.8Hz,1H),7.15(d,J=7.5Hz,1H),6.35(t,J=8.7Hz,1H),5.55(m,1H),4.55-4.30(m,3H),4.10(t,J=6.3Hz,2H),3.92(m,1H),2.70-2.59(m,1H),2.10(m,1H),1.68-1.55(m,2H),1.45-1.27(m,13H),1.19-1.05(m,6H),0.91(m,9H)。
将(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯(100mg,0.08mmol,1.00当量)、氯化氢/二噁烷(5mL)放入25mL圆底烧瓶中。将所得溶液在室温下搅拌30分钟。将所得混合物在真空下浓缩。通过制备型HPLC纯化粗产物。这产生35.8mg(35%)呈白色固体的(2R)-2-氨基-3-甲基丁酸[(2R,3R,5R)-4,4-二氟-3-[(2-甲基丙酰基)氧基]-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯。LC-MS:(M+H)+=547.1H-NMR:(300MHz,CD3OD,ppm):δ8.01(d,J=7.8Hz,1H),7.40(d,J=7.8Hz,1H),6.40(t,J=8.7Hz,1H),5.65(m,1H),4.58-4.50(m,3H),4.23-4.19(m,3H),2.72-2.62(m,1H),2.44-2.38(m,1H),1.70(m,1H),1.42-1.35(m,4H),1.22-1.13(m,12H),0.96(m,3H)。
实例8:(2S)-2-氨基-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-氨基-3-甲基丁酰基]氧基]-4,4-二氟-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯的合成
将戊基-N-[1-[(2R,4R,5R)-3,3-二氟-4-羟基-5-(羟甲基)草脲胺-2-基]-2-氧代-1,2-二氢嘧啶-4-基]氨基甲酸酯(500mg,1.33mmol,1.00当量)、(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸(1.15g,5.29mmol,4.00当量)、DCC(1.64g,7.96mmol,6.00当量)、4-二甲基氨基吡啶(485mg,3.98mmol,3.00当量)、N,N-二甲基甲酰胺(30mL)放入100mL圆底烧瓶中。将所得溶液在室温下搅拌2小时。然后通过100ml水来淬灭反应。将所得溶液用100ml乙酸乙酯萃取并且将有机层合并。将所得混合物用2×100mL盐水洗涤。将混合物经无水硫酸钠干燥并在真空下浓缩。通过制备型HPLC纯化粗产物。这产生400mg(39%)呈白色固体的(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酰基]氧基]-4,4-二氟-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯。1H-NMR:(300MHz,d6-DMSO,ppm):δ10.87(br,1H),8.06(d,J=7.8Hz,1H),7.43(d,J=6.6Hz,1H),7.27(d,J=7.8Hz,1H),7.27(d,J=7.8Hz,1H),6.36(t,J=8.7Hz,1H),5.6-5.42(br,1H),4.51-4.28(m,3H),4.13(t,J=6.8Hz,2H),3.95(m,2H),2.05(m,2H),1.64(m,2H),1.45-1.29(m,22H),0.96(m,15H)。
将(2R)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-[[(叔丁氧基)羰基]氨基]-3-甲基丁酰基]氧基]-4,4-二氟-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯(100mg,0.13mmol,1.00当量)、氯化氢/二噁烷(8mL)放入25mL圆底烧瓶中。将所得溶液在室温下搅拌30分钟。将所得混合物在真空下浓缩。这产生54mg(65%)呈浅棕色固体的(2S)-2-氨基-3-甲基丁酸[(2R,3R,5R)-3-[[(2S)-2-氨基-3-甲基丁酰基]氧基]-4,4-二氟-5-(2-氧代-4-[[(戊氧基)羰基]氨基]-1,2-二氢嘧啶-1-基)草脲胺-2-基]甲酯。LC-MS:(M+H)+=576.1H-NMR:(300MHz,CD3OD,ppm):δ8.11(d,J=7.8Hz,1H),7.27(d,J=7.8Hz,1H),6.30(t,J=8.7Hz,1H),5.85(m,1H),4.85-4.65(m,3H),4.27-4.19(m,3H),4.10(m,1H),3.8-3.6(m,1H),2.50-2.32(m,2H),1.76-1.71(m,2H),1.44-1.32(m,4H),1.22-1.06(m,12H),0.96(m,3H)。
生物实例1:小鼠PK研究
通过静脉内施用和口服施用评估化合物在雄性CD1小鼠中的药代动力学。在颈静脉中通过缓慢推注施用iv剂量,并且通过灌胃施用口服剂量。调配物是2.5%DMSO、10%EtOH、20%Cremphor EL、67.5%D5W。PK时间点是给药后5分钟、15分钟、30分钟、1小时、2小时、4小时、6小时、8小时。将在每个时间点收集大约0.03mL血液。将血液保持在室温下,并且在15分钟内通过在4℃离心机中以4000g离心5分钟来收集血浆。将血浆样品储存在聚丙烯试管中。进行分析之前,将把血浆样品储存在-75±15℃的冰箱中。将使用LC-MS/MS方法分析血浆样品中化合物和活性代谢物吉西他滨的浓度。将使用WinNonlin(PhoenixTM,版本6.1)或其它类似软件来进行药代动力学计算。只要可能,将根据血浆浓度对时间数据来计算以下药代动力学参数:IV施用:C0、CL、Vd、T1/2、AUCinf、AUC最后、MRT、回归点数;PO施用:Cmax、Tmax、T1/2、AUCinf、AUC最后、F%、回归点数。将使用如平均值、标准偏差等描述性统计数据来描述药代动力学数据。可以在贡献科学家的判断下进行另外的药代动力学或统计分析,并且将把分析数据记录在数据汇总中。
如下表所示出的以10mg/kg口服给药的结果表明,相比LY2334737,新型实例2,即,三重前药,具有更好的活性代谢物吉西他滨的口服暴露量。另外,在针对此PK研究进行的调配期间,相比LY2334737,实例2显示出明显更高的水溶性。
下表示出了单个剂量的实例2之后小鼠体内的活性代谢物吉西他滨的浓度。结果示出了良好的PK线性度,并且在300mg/kg下吉西他滨Cmax高达20,165nM。
以上小鼠PK研究证实了实例2是吉西他滨的前药,具有极好的水溶性。
生物实例2:体内异种移植研究
选择实例2的化合物用于在卵巢癌A2780异种移植模型中进行体内研究。通常,从供应商处获得6-8周龄的胸腺裸鼠(CD-1nu/nu)或SCID小鼠并使其适应至少7天。然后将癌细胞植入裸鼠中。根据具体的肿瘤类型,通常在植入后约两周就可以检测到肿瘤。当肿瘤大小达到约100-200mm3时,将具有明显肿瘤大小和形状的动物随机分组(每组8只小鼠),包含一个媒剂对照组和多个治疗组。剂量根据通常为期约3-4周的每个研究的目的和时间长短而不同。通常每周三次测量肿瘤大小和体重。除了确定肿瘤大小变化之外,最后一次肿瘤测量还用于产生肿瘤大小变化率(T/C值),肿瘤大小变化率是由美国国家癌症研究所(National Cancer Institute)开发的用于异种移植肿瘤评估的标准度量。在大多数情况下,使用以下公式计算%T/C值:%T/C=100×ΔT/ΔC(如果ΔT>0)。然而,当发生肿瘤消退时(ΔT<0),使用以下公式:%T/T0=100×ΔT/T0。<42%的值被认为是显著的。
卵巢癌是女性中第5大最常见癌症:2016年,美国有约22,280例新病例和14,240例死亡。在中国,每年有超过100,000例卵巢癌新病例。吉西他滨(静脉内给药)是卵巢癌的第二线SOC。如下所示,在A2780模型中,相比吉西他滨(IV给药),实例2(口服给药)具有更好的功效。
组 | 小鼠 | 药剂 | mg/kg | 途径 | 时间表 | 肿瘤体积 |
1 | 5 | 媒剂 | 媒剂 | po | q4d×7 | 2710mm<sup>3</sup> |
2 | 5 | 吉西他滨 | 120 | IV | qw×4 | 442mm<sup>3</sup> |
3 | 5 | 实例2 | 75 | po | q4d×7 | 65mm<sup>3</sup> |
Claims (4)
2.根据权利要求1所述的化合物或其N-氧化物或所述化合物或其N-氧化物的药学上可接受的盐、溶剂化物、多晶型物或互变异构体,其中所述化合物是
异丁酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
缬氨酸((2R,3R,5R)-3-((L-缬氨酰基)氧基)-4,4-二氟-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
L-缬氨酸((2R,3R,5R)-4,4-二氟-3-(异丁酰氧基)-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸((2R,3R,5R)-4,4-二氟-3-(异丁酰氧基)-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
异丁酸(2R,3R,5R)-4,4-二氟-2-((异丁酰氧基)甲基)-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-3-基酯,
L-缬氨酸((2R,3R,5R)-3-((L-缬氨酰基)氧基)-4,4-二氟-5-(2-氧代-4-(((戊氧基)羰基)氨基)嘧啶-1(2H)-基)四氢呋喃-2-基)甲酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-5-(4-(((己氧基)羰基)氨基)-2-氧嘧啶-1(2H)-基)-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-5-(4-((丁氧基羰基)氨基)-2-氧嘧啶-1(2H)-基)-4,4-二氟-2-((异丁酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-5-(2-氧代-4-(2-丙基戊酰胺基)嘧啶-1(2H)-基)-2-((新戊酰氧基)甲基)四氢呋喃-3-基酯,
L-缬氨酸(2R,3R,5R)-4,4-二氟-5-(4-(((己氧基)羰基)氨基)-2-氧嘧啶-1(2H)-基)-2-((新戊酰氧基)甲基)四氢呋喃-3-基酯。
3.一种药物组合物,其包括根据权利要求1所述的式(I)化合物或其N-氧化物或所述式(I)化合物或其N-氧化物的药学上可接受的盐、溶剂化物、多晶型物、互变异构体、立体异构体、同位素形式或前药以及药学上可接受的稀释剂或载体。
4.一种治疗肿瘤疾病的方法,所述方法包括向有需要的受试者施用有效量的根据权利要求1所述的式(I)化合物或其N-氧化物或所述式(I)化合物或其N-氧化物的药学上可接受的盐、溶剂化物、多晶型物、互变异构体、立体异构体、同位素形式或前药。
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Title |
---|
DAVID M. BENDER ET AL: ""Synthesis, Crystallization, and Biological Evaluation of an Orally Active Prodrug of Gemcitabine"", 《J. MED. CHEM》, vol. 52, no. 22, pages 6958 - 6961, XP055058643, DOI: 10.1021/jm901181h * |
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