CN104053648A - 治疗癌症的哌嗪基衍生物 - Google Patents
治疗癌症的哌嗪基衍生物 Download PDFInfo
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- CN104053648A CN104053648A CN201280064255.3A CN201280064255A CN104053648A CN 104053648 A CN104053648 A CN 104053648A CN 201280064255 A CN201280064255 A CN 201280064255A CN 104053648 A CN104053648 A CN 104053648A
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- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 26
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Abstract
本发明涉及式(I)的哌嗪基衍生物及其作为药物,特别是治疗癌症的药物的用途,含有所述衍生物的药物组合物,及其合成方法。
Description
技术领域
本发明涉及特别用于治疗癌症的哌嗪基化合物,含有其的组合物及它们的制备方法。
背景技术
随着生存期延长,世界死亡率主要原因之一的癌症影响着越来越多的人并且依然很难治疗。
对抗癌剂的发展的耐药是极其限制多类型癌症治疗的严重问题。对一种药剂降低的耐受通常伴随对各种其它药剂的交叉耐药。这种对抗癌剂的多重耐药称为多药耐药(MDR),其由多种机制引起,这些机制中仅有一小部分被很好的特征化。这些机制包括药物排出的增加、细胞排毒能力的增加、被这些抗癌剂影响的分子靶点的变化、DNA(法文缩写为l’ADN)修复系统的修饰和凋亡途径的修饰(Baguley,Mol.Biotechnol.,2010,46,308–316;Gatti等人,Methods Mol.Med.2005,111,127–148;Longley等人,J.Pathol.2005,205,275–292;Kohno等人,Eur.J.Cancer2005,41,2577–2586)。
能够避免这些耐药机制的抗癌治疗的开发是一个重要挑战,并且直到目前所启动的试验已经给出很少的结果。
WO2009/150248中描述了更特别地旨在治疗化疗耐受(résistant à unechimiothérapie)癌症的抗癌剂。它们对应于以下通式(I):
其中R1和R2与其连接的氮原子一起,可以形成任选取代的杂环,例如哌嗪基,唯一的示例性化合物是在哌嗪的氮原子上任选取代。
该专利申请的发明人令人惊讶地发现在哌嗪第二个氮原子的α位插入取代基X(见下面的通式(I))能够改善化合物的物理化学性质,特别是其溶解性、药代动力学特性和生物活性。
发明内容
因此,本发明的主题更特别地为一种以下通式(I)的取代的哌嗪基化合物:
及其药学上可接受的盐、其立体异构体或任何比例的立体异构体混合物,特别是对映异构体混合物,尤其是外消旋混合物,
其中:
–X是(C1–C6)烷基、苯基、苄基、C(O)OR5或C(O)NHR5基团;
–R1是氢原子或C(O)H、C(O)R6或C(O)OR6基团;
–R2是氢原子或(C1–C6)烷基基团;
或者R2与R1或X一起形成饱和烃链以形成5或6元环,特别是5元环;
–R3是氢或卤素原子或(C1–C6)烷基或(C1–C6)烷氧基基团;
–R4是氢或卤素原子、CN、NO2、或(C1–C6)烷基、(C1–C6)烷氧基、芳氧基、苄氧基或杂芳氧基基团,所述基团任选被一个或多个卤素原子取代;
–Ar是任选被一个或多个卤素原子取代的苯硫基基团或苯基基团;和
–R5和R6彼此独立地为(C1–C6)烷基、芳基–(C1–C6)烷基或芳基基团,所述基团任选被一个或多个卤素原子取代。
本发明所述的“卤素”是指氟、溴、氯或碘原子。有利地其为氟、溴或氯原子。
本发明所述的“烷基”基团是指任何饱和的、直链或支链烃基,有利地具有1至6个,优选1至4个碳原子。其可以特别地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基,新戊基或正己基。有利地其为甲基、乙基、异丙基、叔丁基或异丁基。
在某些情况下,烷基可以任选地被一个或多个卤素原子取代,特别是溴、氯和氟,有利地为氟。在这种情况下,所述基团特别地为–CF3基团。
本发明所述的“烷氧基”基团是指通过氧原子与分子的其余部分连接的如上所定义的烷基。烷氧基基团的实例是甲氧基、乙氧基、异丙氧基或叔丁氧基。有利地其为甲氧基或叔丁氧基,进一步有利地为甲氧基。
在某些情况下,烷氧基基团可以被一个或多个氟原子取代。在这种情况下,其有利地为–OCHF2或–OCF3基团,特别是–OCF3。
本发明所述的“芳基”基团是指芳香基团,其优选具有5至10个碳原子并且含有一个或多个稠合环。有利地其为苯基基团。
本发明所述的“杂芳基”基团是指其中一个或多个碳原子被一个或多个杂原子,有利地为1至4个,更有利地为1至2个杂原子替换的任何如上所定义的芳基基团,所述杂原子例如硫、氮或氧原子。有利地其为呋喃基、苯硫基基、吡啶基、嘧啶基、喹啉基、1,2,3–噻二唑基苯并咪唑基、吲唑基或1,2,3–苯并三氮唑基。
本发明所述的“芳氧基”基团是指通过氧原子与分子的其余部分连接的如上所定义的芳基基团。其有利地为苯氧基基团。
本发明所述的“杂芳氧基”基团是指通过氧原子与分子的其余部分连接的如上所定义的杂芳基基团。其有利地为吡啶氧基基团。
本发明所述的“芳基–(C1–C6)烷基”基团是指通过如上所定义的具有1至6个碳原子的烷基与分子的其余部分连接的如上所定义的芳基基团。有利地,其为苄基或1–苯乙基,更有利地为苄基。
本发明中的“药学上可接受的”是指其有用于制备通常是安全、无毒性并且既无生物学上不需要的又无其它不需要的方面,并且对于兽医使用和人类药典使用是可接受的药物组合物。
本发明中化合物的“药学上可接受的盐”是指其是本文所定义的药学上可接受的并具有母体化合物的预期药物活性的盐。这样的盐包括:
(1)水合物和溶剂化物;
(2)与无机酸形成的酸式加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等;或与有机酸形成的酸式加成盐,所述有机酸例如乙酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙烷磺酸、富马酸、葡庚糖酸、葡糖酸、谷氨酸、羟基乙酸、羟基萘甲酸、2-羟乙基磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘康酸、2-萘磺酸、丙酸、水杨酸、琥珀酸、联苯甲酰基–L–酒石酸、酒石酸、对甲苯磺酸、三甲基乙酸、三氟乙酸等,有利地为盐酸;和
(3)当存在于母体化合物的酸质子或者被金属离子例如碱金属离子(例如Na+、K+或Li+)、碱土金属离子(例如Ca2+或Mg2+)或铝离子替换,或者与有机或无机碱调配时所形成的盐。可以接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等。可以接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠。
本发明中的“立体异构体”是指非对映异构体或对映异构体。因此,它们是光学异构体。彼此不为镜像的立体异构体被称为“非对映异构体”,且成不可重叠的镜像的立体异构体被称为“对映异构体”。
连接于四个不同取代基的碳原子称为手性中心。
两个对映异构体的等摩尔混合物称为外消旋混合物。
本发明的化合物可以特别地对应于下式(I–bis):
则携带X基团的氮原子为(S)构型。
有利地X为(C1–C6)烷基,特别是(C1–C4)烷基,苯基或苄基基团。
有利地R1为氢原子或C(O)R6或C(O)OR6基团,特别是氢原子。
有利地R2为氢原子或(C1–C6)烷基基团,例如甲基。
有利地R3为氢原子或(C1–C6)烷基基团,例如甲基。
有利地R4为氢或卤素原子、或(C1–C6)烷基、(C1–C6)烷氧基或芳氧基基团,所述基团任选被一个或多个卤素原子特别是氟取代。
有利地Ar为被一个或多个氟原子取代的苯硫基基团或苯基基团,例如4–氟–苯基。
根据本发明的一个特别的实施方案,X是(C1–C6)烷基、苯基、苄基、C(O)OR5、C(O)NHR5基团;R1是氢原子;R2是氢原子或(C1–C6)烷基基团,有利地为(C1–C4)烷基,或者R2与R1或X一起形成饱和烃链以形成5元环;R3是氢或卤素原子或(C1–C6)烷基基团,特别是(C1–C3)烷基,或(C1–C6)烷氧基例如甲氧基;R4是卤素原子、CN、NO2或(C1–C6)烷基、(C1–C6)烷氧基、芳氧基、苄氧基或杂芳氧基基团,所述基团任选被一个或多个卤素原子取代;Ar是任选被卤素取代的苯硫基基团或苯基基团;并且R5和R6彼此独立地为(C1–C6)烷基、芳基–(C1–C6)烷基或芳基基团,所述基团任选被一个或多个卤素原子取代。
更有利地,X是(C1–C6)烷基、苯基、苄基、C(O)OR5、C(O)NHR5基团;R1是氢原子;R2是氢原子或(C1–C6)烷基,有利地为(C1–C4)烷基;R3是氢或卤素原子或(C1–C6)烷基基团,特别是(C1–C3)烷基,或(C1–C6)烷氧基,例如甲氧基;R4是卤素原子或(C1–C6)烷基、(C1–C6)烷氧基、芳氧基、苄氧基或杂芳氧基基团,所述基团任选被一个或多个卤素原子取代;Ar是任选被卤素取代的苯硫基基团或苯基基团;并且R5和R6彼此独立地为(C1–C6)烷基、芳基–(C1–C6)烷基或芳基基团,所述基团任选地被一个或多个卤素原子取代。
进一步有利地,X是(C1–C6)烷基、苯基或苄基;R1和R2是氢原子;R3是氢或卤素原子或(C1–C6)烷基基团,特别是(C1–C3)烷基;R4是卤素原子或(C1–C6)烷基、(C1–C6)烷氧基、芳氧基或苄氧基基团,所述基团任选被一个或多个卤素原子取代;Ar是任选被卤素取代的苯硫基基团或苯基基团;并且R5和R6彼此独立地为(C1–C6)烷基、芳基–(C1–C6)烷基或芳基基团,所述基团任选被一个或多个卤素原子取代。
优选地,X是(C1–C6)烷基、苯基或苄基;R1和R2是氢原子;R3是氢原子或(C1–C6)烷基基团,特别是(C1–C3)烷基;R4是卤素原子或(C1–C6)烷基、(C1–C6)烷氧基、芳氧基或苄氧基,所述基团任选被一个或多个卤素原子取代;Ar代表任选被氟原子取代的苯硫基基团或苯基基团,例如4-氟-苯基;并且R5和R6彼此独立地为(C1–C6)烷基、芳基–(C1–C6)烷基或芳基基团,所述基团任选被一个或多个氟原子取代。
特别地,其是以下实施例部分所描述的实施例I-1a至I-63中的化合物之一,或其药学上可接受的盐、其立体异构体或任意比例的立体异构体混合物,特别是对映异构体混合物,尤其是外消旋混合物之一。
本发明还涉及如上所定义的式(I)的化合物,其用作特别是旨在治疗或预防癌症的药物,并且特别是治疗化疗耐受癌症的药物。
本发明还涉及如上所定义的式(I)的化合物在制备特别是旨在治疗或预防癌症的药物,特别是治疗化疗耐受癌症的药物中的用途。
本发明还涉及一种治疗或预防癌症,特别是化疗耐受癌症的方法,其包含向需要其的患者施用有效量的式(I)化合物。
本发明的另一主题是一种药物组合物,其含有至少一种如上所定义的式(I)化合物和一种或多种药学上可接受的赋形剂。
在一个特别的实施方案中,该组合物可以含有至少一种其它活性成分。
特别地,这个或这些活性成分可以是常规用于治疗癌症的抗癌剂。这些抗癌剂可以特别地选自顺铂及其衍生物,例如卡铂和奥沙利铂;紫杉烷类,例如紫杉酚、泰索帝、紫杉醇和多西他赛;长春花生物碱类,例如长春花碱、长春新碱和长春瑞滨;嘌呤类似物,例如硫嘌呤、硫鸟嘌呤、喷司他丁和2–氯脱氧腺苷;拓扑异构酶I抑制剂,例如喜树碱化合物如伊立替康和拓扑替康;拓扑异构酶II抑制剂,例如表鬼臼毒素、足叶草毒素及其衍生物例如依托泊苷和替尼泊苷;抗肿瘤核苷衍生物,例如5–氟尿嘧啶、亚叶酸、吉西他滨或卡培他滨;烷化剂,例如氮芥类如环磷酰胺、二氯甲基二乙胺、苯丁酸氮芥和美法仑,亚硝基脲类例如卡莫司汀、洛莫司汀和链脲菌素,烷基磺酸盐类例如白消安,乙烯亚胺类(éthylènimines)和甲基三聚氰胺类例如塞替派和六甲基三聚氰胺,和四嗪类例如达卡巴嗪;抗肿瘤蒽环类衍生物,例如道诺霉素、阿霉素、多喜、伊达比星和米托蒽醌;靶向于IGF–I受体的分子,例如足叶苦素;替曲卡星衍生物,例如替曲卡星A;皮质类固醇类,例如强的松;抗体类,例如曲妥单抗(抗–HER2抗体)、利妥昔单抗(抗–CD20抗体)、吉妥单抗(gemtuzamab)、西妥昔单抗、帕妥珠单抗和贝伐单抗;雌激素受体的拮抗剂或选择性调节剂,例如他莫昔芬、氟维司群、托瑞米芬、屈洛昔芬、伐索戴司(faslodex)和雷洛昔芬;芳香酶抑制剂,例如依西美坦、阿那曲唑、来曲唑和伏罗唑;分化剂,类视黄醇类如维甲酸和维生素D和阻断维甲酸代谢的试剂如异维甲酸;DNA甲基转移酶抑制剂,例如氮杂胞苷和地西他滨;抗叶酸类,例如培美曲塞二钠;抗生素类,例如抗霉素D、博来霉素、丝裂霉素C、放线菌素D、洋红霉素、道诺霉素和普卡霉素;抗代谢物类,例如氯法拉滨、氨嘌呤、阿糖胞苷、氟脲苷和甲氨蝶呤;Bcl–2抑制剂的细胞凋亡诱导剂和抗血管生成剂,例如YC137、BH312、ABT737、棉子酚、HA14–1、TW37和癸酸;结合于微管蛋白的试剂,例如考布他汀、秋水仙碱衍生物和诺考达唑;激酶抑制剂,例如佛罗匹多(flavoperidol)、甲磺酸伊马替尼、埃罗替尼和吉非替尼;法尼基转移酶抑制剂,例如替吡法尼;组蛋白脱乙酰基酶抑制剂,例如丁酸钠、辛二酰苯胺异羟肟酸、缩酚酸肽、NVP-LAQ824、R306465、JNJ–26481585和曲古抑菌素A;泛素-蛋白酶体系统抑制剂,例如MLN.41、硼替佐米和曲贝替定(l’yondelis);和端粒酶抑制剂,例如替莫美他汀。
可以通过口服、舌下、肠胃外、皮下、肌肉内、静脉内、经皮、局部或直肠途径给予本发明的化合物。
在用于口服、舌下、肠胃外、皮下、肌肉内、静脉内、经皮、局部或直肠途径的本发明药物组合物中,可以单位施用形式,在与常规药物载体的混合物中,将活性成分施用于动物或人类。合适的单位施用形式包括通过口服途径的形式,例如片剂、胶囊剂、粉末剂、颗粒剂和口服溶液或混悬剂;舌下和口腔含化施用形式;肠胃外、皮下、肌肉内、静脉内、鼻内或眼内施用形式;和直肠施用形式。
当将固体组合物制成片剂形式时,将主要的活性成分与药物载体例如明胶、淀粉、乳糖、硬脂酸镁、滑石粉、阿拉伯胶或其类似物混合。可以用蔗糖或其它合适的材料包衣片剂,或可以处理片剂以使其具有持续的或延缓的释放和连续释放预先确定量的活性成分。
通过将活性成分与稀释剂混合并将获得的混合物倒入软或硬胶囊中获得胶囊制剂。
糖浆或酏剂形式的制剂可以包含活性成分和甜味剂、防腐剂和味觉提高剂、以及合适的着色剂。
水可分散性粉末剂或颗粒剂可以包含活性成分与分散剂或湿润剂、或悬浮剂、以及味觉提高剂或甜味剂的混合物。
对于直肠施用,求助于用在直肠温度可以熔化的粘合剂,例如可可脂或聚乙二醇制备的栓剂。
对于肠胃外、鼻内或眼内施用,使用包含药理学上相容的分散剂和/或湿润剂的水性混悬剂、盐水等渗溶液或无菌、注射溶液。
活性成分也可以任选与一种或多种添加剂载体制成微囊形式。
可以每天0.01mg至1000mg之间的剂量使用本发明的化合物,以每天单剂量或每天数个剂量例如等剂量一日两次给予。每天施用的剂量有利地在5mg至500mg之间,更有利地在10mg至200mg之间。可能有必要使用这些范围以外的剂量,本领域技术人员知晓怎样确定该剂量。
本发明的另一个主题是一种药物组合物,其包含:
(i)至少一种如上所定义的式(I)化合物;和
(ii)至少一种其它活性成分
作为组合产品用于同时、分别或错时使用。
用双联或三联治疗法治疗癌症通常是有效的。特别是将本发明的分子与一种或多种抗癌化合物联合(第一种允许治疗癌症和第二种预防出现耐药癌细胞)可能是有用的。
特别地,这个或这些活性成分可以是通常用于治疗癌症的抗癌剂。这些抗癌剂可以特别地选自顺铂及其衍生物,例如卡铂和奥沙利铂;紫杉烷类,例如紫杉酚、泰索帝、紫杉醇和多西他赛;长春花生物碱类,例如长春花碱、长春新碱和长春瑞滨;嘌呤类似物,例如硫嘌呤、硫鸟嘌呤、喷司他丁和2–氯脱氧腺苷;拓扑异构酶I抑制剂,例如喜树碱化合物如伊立替康和拓扑替康;拓扑异构酶II抑制剂,例如表鬼臼毒素、足叶草毒素和其衍生物如依托泊苷和替尼泊苷;抗肿瘤核苷衍生物,例如5–氟尿嘧啶、亚叶酸、吉西他滨或卡培他滨;烷化剂,例如氮芥类如环磷酰胺、二氯甲基二乙胺、苯丁酸氮芥和美法仑,亚硝基脲类如卡莫司汀,洛莫司汀和链脲菌素,烷基磺酸盐类如白消安,乙烯亚胺类和甲基三聚氰胺类如塞替派和六甲基三聚氰胺,和四嗪类如达卡巴嗪;抗肿瘤蒽环类衍生物,例如道诺霉素、阿霉素、多喜、伊达比星和米托蒽醌;靶向于IGF–I受体的分子,例如足叶苦素;替曲卡星衍生物,例如替曲卡星A;皮质类固醇类,例如强的松;抗体类,例如曲妥单抗(抗–HER2抗体)、利妥昔单抗(抗–CD20抗体)、吉妥单抗、西妥昔单抗、帕妥珠单抗和贝伐单抗;雌激素的受体拮抗剂或选择性调节剂,例如他莫昔芬、氟维司群、托瑞米芬、屈洛昔芬、伐索戴司和雷洛昔芬;芳香酶抑制剂,例如依西美坦、阿那曲唑、来曲唑和伏罗唑;分化剂,例如类视黄醇类如维甲酸和维生素D和维甲酸代谢阻断剂,例如异维甲酸;DNA甲基转移酶抑制剂,例如氮杂胞苷和地西他滨;抗叶酸类,例如培美曲塞二钠;抗生素类,例如抗霉素D、博来霉素、丝裂霉素C、放线菌素D、洋红霉素、道诺霉素和普卡霉素;抗代谢物类,例如氯法拉滨、氨嘌呤、阿糖胞苷、氟脲苷和甲氨蝶呤;Bcl–2抑制剂的细胞凋亡诱导剂和抗血管生成剂,例如YC137、BH312、ABT737、棉子酚、HA14–1、TW37和癸酸;微管蛋白结合剂,例如考布他汀、秋水仙碱衍生物、诺考达唑;激酶抑制剂,例如佛罗匹多、甲磺酸伊马替尼、埃罗替尼、吉非替尼;法尼基转移酶抑制剂,例如替吡法尼;组蛋白脱乙酰基酶抑制剂,例如丁酸钠、辛二酰苯胺异羟肟酸、缩酚酸肽、NVP-LAQ824、R306465、JNJ–26481585和曲古抑菌素A;泛素-蛋白酶体系统抑制剂,例如MLN.41、硼替佐米和曲贝替定;和端粒酶抑制剂,例如替莫美他汀。
本发明的另一个主题是一种如上所定义的药物组合物,其用作治疗或预防癌症,特别是化疗耐受癌症的药物。
本发明还涉及一种制备如上所定义的式(I)化合物的方法,其包含以下连续的步骤:
a)在碱的存在下,将下式(II)的胺与氯乙酰氯反应得到其中R1≠H的式(I)化合物,
其中X、R1、R2、R3、R4和Ar如前所定义,R1不代表氢原子;和
b)任选地,将携带R1≠H基团的氮原子脱保护,得到其中R1=H的式(I)化合物。
步骤a):
该步骤所使用的碱优选弱碱,例如NaHCO3。
可以通过将下式(III)的哌嗪与下式(IV)的酸反应获得式(II)的胺,
其中X、R1和R2如前所定义,R1不代表氢原子,
其中R3、R4和Ar如前所定义。
可以在本领域技术人员熟知的肽偶联条件下进行该反应。
因此,偶联优选在偶联剂的存在下任选与偶联佐剂联合进行,所述偶联剂例如,二异丙基碳二亚胺(DIC)、二环己基碳二亚胺(DCC)、1–(3–二甲基氨丙基)–3–乙基碳二亚胺盐酸盐(EDC)、羰基二咪唑(CDI)、2–(1H–苯并三氮唑–1-基)–1,1,3,3–四甲基脲六氟磷酸盐(HBTU)、2–(1H–苯并三氮唑–1-基)–1,1,3,3–四甲基脲四氟硼酸盐(TBTU)或O–(7–偶氮苯并三氮唑–1-基)–1,1,3,3–四甲基脲六氟磷酸盐(HATU),所述偶联佐剂例如,N–羟基琥珀酰亚胺(NHS)、N–羟基苯并三氮唑(HOBt)、3,4–二氢–3–羟基–4–氧代–1,2,3–苯并三氮唑(HOOBt)、l–羟基–7–偶氮苯并三氮唑(HAt)或N–羟基硫代琥珀酰亚胺(硫代NHS)。优选HBTU。
还可以存在碱,例如二异丙基乙基胺(DIPEA)。
可以商购获得或根据本领域技术人员熟知的以下方法制备式(III)的哌嗪。
可以使用以下连续的步骤制备式(IV)的酸:
i)将下式(V)的酮酯与下式(VI)的苯胺反应得到下式(VII)的亚胺,
其中Ar如前所定义,且R代表(C1–C6)烷基基团,例如乙基,
其中R3和R4如前所定义,
其中R、R3、R4和Ar如前所定义;
ii)将在前述步骤获得的式(VII)的亚胺还原得到下式(VIII)的胺,
其中R、R3、R4和Ar如前所定义;和
iii)皂化在前述步骤获得的式(VIII)化合物的酯官能团得到式(IV)的酸。
可以在酸例如对甲苯磺酸(PTSA,法文缩写为APTS)的存在下进行步骤i)。可以在极性溶剂例如甲苯中进行该反应。优选使用Dean–Stark装置,在回流下加热反应介质,以除去反应过程中形成的水。
可以商购获得或通过使用乙基草酰氯和对应的芳香剂在路易斯酸如三氯化铝AlCl3的存在下的傅克(Friedel–Crafts)反应制备获得该反应所使用的酮酯(V)。
可以商购获得或使用本领域技术人员熟知的方法制备获得该反应所使用的苯胺(VI)。
可以在本领域技术人员熟知的还原剂如氰基硼氢化钠的存在下进行还原步骤 ii)。
可以在本领域技术人员熟知的条件下,特别地在碱如NaOH、KOH或LiOH的存在下,进行皂化步骤iii)。
步骤b):
优选使用其中R1=CO2R6例如CO2tBu的式(I)化合物,通过用酸如HCl的处理,进行该步骤。
可以使用本领域技术人员熟知的方法,例如通过萃取、溶剂蒸发或通过沉淀和过滤,从反应介质中分离由此获得的化合物。
如需要,可以使用本领域技术人员熟知的技术,例如通过重结晶(如果化合物是晶体)、通过蒸馏、通过硅胶色谱法或高效液相色谱法(HPLC)纯化化合物。
制备其中R1≠H的本发明化合物的本发明的方法示于以下反应方案:
以下实施例阐明本发明,但并不限制其范围。
附图说明
图1显示通过静脉内途径(IV)以10mg/kg的剂量或通过口服途径(PO)以30mg/kg的剂量向小鼠施用给定的化合物I-43dia2的时间—血浆浓度曲线。
具体实施方式
实施例
I–本发明化合物的合成
在以下章节中,当分离出本发明化合物的两个非对映异构体时,采用两种不同的命名法:
-a/b每一个指定单一个非对映异构体的特定结构;
-dia1/dia2分别指定在使用的色谱体系中的最小极性和最大极性的非对映异构体。
没有确定每个非对映异构体的特定立体化学。因此,不能够对每一个分离的非对映异构体dia1和dia2分配特定结构a和b。这是为什么使用双重命名法。
在本章节中使用以下缩写:
TLC(法文缩写为CCM) 薄层色谱法
DCM 二氯甲烷
DIEA 二异丙基乙基胺
HBTU 2–(1H–苯并三氮唑–1-基)–1,1,3,3–四甲基脲六氟磷酸盐
LCMS 液相色谱偶联质谱仪
NMR(法文缩写为RMN) 核磁共振
RT(法文缩写为TA) 室温
实施例I–1a和I–1b:4–[2–[(2–氯-乙酰基)–(4–苯氧基–苯基)–氨基]–2–(4–氟–苯基)–乙酰基]–(S)–2–异丙基–哌嗪–1–羧酸叔丁酯的非对映异构体。
步骤1:(4–氟–苯基)–氧代–乙酸乙酯(1):
于0℃,氩气下,经10min,向三氯化铝(21.13g;160mmol)在DCM(200mL)中的溶液滴加乙基草酰氯(17.9mL;160mmol)。将介质搅拌10分钟。于0℃滴加稀释于30mL DCM中的氟代苯(14.7mL;160mmol)。于室温将介质搅拌12小时。用水洗涤介质,并用MgSO4干燥有机相。蒸发后,通过硅胶上闪式色谱法纯化回收的油状物,用环己烷–乙酸乙酯90:10洗脱。
回收得黄色油状物(17.08g;54%)。
1H NMR(300MHz,CDCl3):δ8.04–8.14(m;1.8H);7.15–7.24(m;1.9H);4.46(q;J=7.2Hz;2.0H);1.44(t;J=7.2Hz;3.0H)。
步骤2:(4–氟–苯基)–[(Z)–4–苯氧基–苯亚氨基]–乙酸乙酯(2):
在分子筛的存在下,向1(3.92g;20mmol)在甲苯中的溶液(25mL)连续加入对甲苯磺酸(200mg;1mmol)和4–苯氧基苯基–苯胺(3.70g;20mmol)。在DeanStark装置中,在回流下,放置介质20小时。在水中洗涤介质并用MgSO4干燥有机相。蒸发后,通过闪式硅胶色谱法纯化回收的油状物,用环己烷–乙酸乙酯90:10洗脱。
回收得到黄色油状物(6.27g;86%)。
LCMS[M+H]=364(C22H18FNO3)
步骤3:(4–氟–苯基)–(4–苯氧基–苯基氨基)–乙酸乙酯(3):
向2(6.27g;17.26mmol)在甲醇(75mL)和乙酸(7.5mL)中的溶液加入氰基硼氢化钠(1.63g;26mmol)。于RT,在搅拌下放置介质1小时。部分蒸发甲醇,用Na2CO3中和溶液(如果必要,加水)。用DCM萃取介质,并用MgSO4干燥有机相。蒸发后,通过硅胶上的闪式色谱法纯化回收的油状物,用环己烷–乙酸乙酯95:5洗脱。
回收得到黄色油状物(5.91g;93%)。
LCMS[M+H]=366(C22H20FNO3)
1H NMR(300MHz,CDCl3):δ7.45–7.54(m;1.9H);7.23–7.31(m;1.9H);6.97–7.11(m;2.9H);6.81–6.94(m;3.9H);6.54(d;J=9.0Hz;2.0H);5.01(br;1.0H);4.90(br;0.9H);4.10–4.32(m;2.0H);1.23(t;J=7.0Hz;3.0H)。
步骤4:(4–氟–苯基)–(4–苯氧基–苯基氨基)–乙酸(4):
向3(8.04g;22mmol)在130mL乙腈中的溶液加入66mL1M LiOH(3eq)溶液。搅拌下放置反应介质2至3小时,通过TLC(环己烷–乙酸乙酯60:40)控制反应的完全。部分蒸发乙腈,用1M HCl溶液酸化介质,并加入200mL水。过滤介质,并用水洗涤回收的固体三次,在P2O5存在下,在干燥箱中真空干燥。
回收得到白色粉末(7.17g;97%)。
LCMS[M+H]=338(C20H16FNO3)
1H NMR(300MHz,DMSO):δ7.55(dd;J=8.5Hz;J=5.6Hz;2.1H);7.28(t;J=7.9Hz;2.1H);7.20(t;J=8.5Hz;2.1H);6.99(t;J=7.0Hz;1.1H);6.74–6.90(m;4.0H;6.62–6.70(m;2.0H);5.10(s1.0H)。
步骤5:4–[2–(4–氟–苯基)–2–(4–苯氧基–苯基氨基)–乙酰基]–(S)–2–异丙基–哌 嗪–1–羧酸叔丁酯(5):
向4(7.17g;21.2mmol)在DCM(150mL)中的溶液(存在一当量的DIEA(3.7mL))加入叔丁氧羰基–α–(S)–异丙基–哌嗪盐酸盐(5.63g;21.26mmol)在50mLDCM中的溶液(存在1eq DIEA(3.7mL)),然后加入HBTU(8.06g;21.2mmol)。在搅拌下放置介质12小时。用水洗涤介质并用MgSO4干燥有机相。蒸发后,通过硅胶上的闪式色谱法纯化回收的油状物,用环己烷–乙酸乙酯80:20洗脱。
回收得到白色泡沫状物(11.90g;100%)。
LCMS[M+H]=548(C32H38FN3O4)
步骤64–[2–[(2–氯-乙酰基)–(4–苯氧基–苯基)–氨基]–2–(4–氟–苯基)–乙酰
基]–(S)–2–异丙基–哌嗪–1–羧酸叔丁酯
向5(11.86g;22.66mmol)在250mL DCM中的溶液(存在NaHCO3(7.30g;87.0mmol))加入氯乙酰氯(3.45mL;43.3mmol)。在搅拌下放置介质12小时。用水洗涤介质并用MgSO4干燥有机相。蒸发后,通过硅胶上的闪式色谱法纯化回收的油状物,用环己烷–乙酸乙酯梯度95–5’至50–50洗脱以分别得到无色泡沫状的两个非对映异构体:
最小极性的非对映异构体(I–1dia1)
(3.80g;28%)
LCMS[M+H]=625(C34H39ClFN3O5)
1H NMR(300MHz,CDCl3):δ7.92–8.01(m;1.0H);7.30–7.40(m;2.0H);7.10–7.18(m;1.1H);7.01–7.09(m;1.1H);6.84–7.00(m;6.1H);6.55–6.65(m;1.1H);6.32–6.48(m;2.1H);4.72(d;J=13.5Hz;0.5H)4.63(d;J=13.5Hz;0.4H);3.52–3.96(m;4.0H);3.10–3.27(m;0.5H);2.85–3.07(m;0.4H);2.23–2.85(m;0.5H+0.7H+0.4H);1.87–2.14(m;0.6H);1.42(s;8.7H);1.17(d;J=6.6Hz;1.0H);1.03(d;J=6.6Hz;1.3H);0.88(d;J=6.6Hz;1.1H);0.69(d;J=6.6Hz;1.3H)。
最大极性的非对映异构体(I–1dia2)
(3.29g;24%)
LCMS[M+H]=625(C34H39ClFN3O5)
1H NMR(300MHz,CD2Cl2):δ7.85–8.00(m;1.0H);7.36(t;J=7.6Hz;2.1H);6.99–7.21(m;3.2H);6.81–6.98(m;5.2H);6.63(br;1.1H);6.35–65.5(m;2.1H);4.65(d;J=13.1Hz;0.6H)4.42(d;J=13.1Hz;0.3H);3.50–4.16(m;4.9H);3.00–3.43(m;0.9H);2.57–2.90(m;1.9H);1.98–2.18(m;0.7H);1.36–1.49(m;10.0H);1.73(d;J=6.5Hz;2.1H);0.90(d;J=6.5Hz;2.1H);0.63(d;J=6.5Hz;1.0H);0.20(d;J=6.5Hz;0.9H)。
实施例I–2a和I–2b:4–[–2–[(2–氯-乙酰基)–(4–苯氧基–苯基)–氨基]–2–(4–氟–苯基)–乙酰基]–(R)–2–异丙基–哌嗪–1–羧酸叔丁酯的非对映异构体。
步骤1:4–[2–(4–氟–苯基)–2–(4–苯氧基–苯基氨基)–乙酰基]–(R)–2–异丙基–哌 嗪–1–羧酸叔丁酯(6):
向(4–氟–苯基)–(4–苯氧基–苯基氨基)–乙酸4(253mg;0.75mmol)在DCM(10mL)中的溶液(存在一当量DIEA(131μL))加入叔丁氧羰基–α–(R)–异丙基–哌嗪(171mg;0.75mmol)在5mL DCM中的溶液(存在1eq DIEA(131μL)),然后加入HBTU(285mg;0.75mmol)。在搅拌下放置介质12小时。用水洗涤介质并用MgSO4干燥有机相。蒸发后,通过硅胶上的闪式色谱法纯化回收的油状物,用环己烷–乙酸乙酯80:20洗脱。
回收得到白色泡沫状物(369mg;90%)。
LCMS[M+H]=548(C32H38FN3O4)
步骤2:4–[–2–[(2–氯-乙酰基)–(4–苯氧基–苯基)–氨基]–2–(4–氟–苯基)–乙酰
基]–(R)–2–异丙基–哌嗪–1–羧酸叔丁酯:
根据实施例1中(步骤6)的制备相同的操作模式从6分离两个非对映异构体。
分别回收得到无色泡沫状形式的两个非对映异构体。
最小极性的非对映异构体(I–2dia1)(195mg;42%)
LCMS[M+H]=625(C34H39ClFN3O5)
1H NMR(300MHz,CD2Cl2):δ7.85–8.00(m;1.0H);7.36(t;J=7.6Hz;2.0H);6.99–7.21(m;3.1H);6.81–6.98(m;4.9H);6.63(br;1.0H);6.35–6.55(m;2.1H);4.65(d;J=13.0Hz;0.7H)4.42(d;J=13.0Hz;0.2H);3.50–4.16(m;4.9H);3.00–3.43(m.;0.8H);2.57–3.90(m;2.0H);1.98–2.18(m;0.8H);1.36–1.49(m;10.5H);1.73(d;J=6.5Hz;2.0H);0.90(d;J=6.5Hz;2.0H);0.63(d;J=6.5Hz;0.8H);0.20(d;J=6.5Hz;0.8H)。
最大极性的非对映异构体(I–2dia2)(122mg;26%)
LCMS[M+H]=625(C34H39ClFN3O5)
1H NMR(300MHz,CDCl3):δ7.92–8.01(m;1.0H);7.30–7.40(m;2.0H);7.10–7.18(m;1.0H);7.01–7.09(m;1.1H);6.84–7.00(m;6.0H);6.55–6.65(m;1.1H);6.32–6.48(m;2.1H);4.72(d;J=13.5Hz;0.4H)4.63(d;J=13.5Hz;0.3H);3.52–3.96(m;4.7H);3.10–3.27(m;0.7H);2.85–3.07(m;0.5H);2.23–2.85(m;0.5H+0.6H+0.8H);1.87–2.14(m;0.9H);1.42(s;8.6H);1.17(d;J=6.6Hz;1.4H);1.03(d;J=6.6Hz;2.1H);0.88(d;J=6.6Hz;2.1H);0.69(d;J=6.6Hz;1.6H)。
实施例I–3a和I–3b:2–氯-N–[1–(4–氟–苯基)–2–((S)–3–异丙基–哌嗪–1-基)–2–氧代–乙基]–N–(4–苯氧基–苯基)–乙酰胺非对映异构体的盐酸盐。
向I–1dia2非对映异构体(3.24g;5.2mmol)在50mL DCM中的溶液,鼓吹加入HCl气体。于RT,在搅拌下放置反应介质12小时。蒸发DCM并在醚中沉淀残余油状物。
过滤后得到白色粉末形式的实施例I–3dia2:(2.53g;87%)。
LCMS[M+H]=524(C29H32Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.60–9.35(m;1.6H);7.77(br;0.8H);7.30–7.40(m;2.0H);7.00–7.23(m;5.1H);6.80–7.00(m;3.1H);6.54–6.76(m;3.0H);4.56(d;J=13.3Hz;1.0H);3.88–4.16(m;3.0H);3.00–3.30(m;3.1H);2.65–2.96(m;1.7H);1.52–2.00(m;1.6H);1.00(t;J=7.4Hz;2.4H);0.59(dd;J=15.6Hz;J=6.7Hz;3.5H)。
应用相同的程序,从实施例I–1dia1过滤后获得白色粉末形式的实施例I–3dia1:(63mg)。
LCMS[M+H]=524(C29H32Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.65–9.6(br;1.2H);7.77(br.;0.8H);7.30–7.40(m;2.0H);6.36–7.25(m;11.7H);4.40–4.60(m;0.8H);4.00–4.12(m;2.0H);3.76–3.98(m;0.9H);3.37–3.63(m;0.9H);2.65–3.30(m;4.0H);1.77–2.06(m;1.6H);0.89–1.06(m;6.1H)。
实施例I–4a和I–4b:2–氯-N–[1–(4–氟–苯基)–2–((R)–3–异丙基–哌嗪–1-基)–2–氧代–乙基]–N–(4–苯氧基–苯基)–乙酰胺非对映异构体的盐酸盐。
从每一个非对映异构体I–2a和I–2b起始,接着进行如实施例I–3a和I–3b的相同方案。
起始于实施例I–2的第一个非对映异构体(I–4dia1):
过滤后回收得到白色粉末:(95mg)
LCMS[M+H]=524(C29H32Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.65–9.6(br;1.3H).;7.77(br;0.4H);7.30–7.40(m;2.0H);6.36–7.25(m;11.8H);4.40–4.60(m;0.9H);4.00–4.12(m;2.0H);3.76–3.98(m;1.0H);3.37–3.63(m;1.0H);2.65–3.30(m;3.8H);1.77–2.06(m;1.8H);0.89–1.06(m;6.1H)。
起始于实施例I–2的第二个对映异构体(I–4dia2):
过滤后回收得到白色粉末:(95mg)
LCMS[M+H]=524(C29H32Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.60–9.35(m;1.7H);7.77(br;0.9H);7.30–7.40(m;2.0H);7.00–7.23(m;5.0H);6.80–7.00(m;3.0H);6.54–6.76(m;2.9H);4.56(d;J=13.3Hz;1.0H);3.88–4.16(m;3.0H);3.00–3.30(m;3.1H);2.65–2.96(m;1.7H);1.52–2.06(m;1.9H);1.00(t;J=7.2Hz;2.4H);0.59(dd;J=15.4Hz;J=6.7Hz;3.3H)。
实施例I–5a和I–5b:4–[–2–[(2–氯-乙酰基)–(2–甲基–4–苯氧基–苯基)–氨基]–2–(4–氟–苯基)–乙酰基]–(S)–2–异丙基–哌嗪–1–羧酸叔丁酯的非对映异构体。
步骤1:4–[2–(4–氟–苯基)–2–(2–甲基–4–苯氧基–苯基氨基)–乙酰基]–(S)–2–异 丙基–哌嗪–1–羧酸叔丁酯(8):
向(4–氟–苯基)–(2–甲基–4–苯氧基–苯基氨基)–乙酸(9.29g;26.4mmol)在DCM(150mL)中的溶液(存在一当量的DIEA(4.6mL))加入叔丁氧羰基–α–(S)–异丙基–哌嗪盐酸盐(7.00g;26.4mmol)在50mL DCM中的溶液(存在1eq DIEA(4.6mL)),然后加入HBTU(10.00g;26.4mmol)。在搅拌下放置介质12小时。用水洗涤介质并用MgSO4干燥有机相。蒸发后,通过硅胶上的闪式色谱法纯化回收的油状物,用环己烷–乙酸乙酯80:20洗脱。
回收得到白色泡沫状物(14.13g;95%)。
LCMS[M+H]=562(C33H40FN3O4)
步骤2:4–[–2–[(2–氯-乙酰基)–(2–甲基–4–苯氧基–苯基)–氨基]–2–(4–氟–苯
基)–乙酰基]–(S)–2–异丙基–哌嗪–1–羧酸叔丁酯
向8(14.13g;25.1mmol)在250mL DCM中的溶液(存在NaHCO3(8.40g;100.0mmol))加入氯乙酰氯(4.00mL;50.0mmol)。在搅拌下放置介质12小时。用水洗涤介质并用MgSO4干燥有机相。蒸发后,通过硅胶上的闪式色谱法纯化回收的油状物,用环己烷–乙酸乙酯90:10逐渐升至50:50洗脱。
回收得到无色泡沫状形式的两个非对映异构体:
最小极性的非对映异构体(I–5dia1)(3.83g;24%)
LCMS[M+H]=639(C35H41ClFN3O5)
1H NMR(300MHz,CD2Cl2):δ7.94–8.57(m;1.0H);7.35(t;J=7.9Hz;2.0H);7.07–7.27(m;3.0H);6.74–6.95(m;5.0H);6.58(br d;J=2.6Hz;1.1H);6.51(br s;0.2H);6.41(s;0.8H);6.31(br s;0.3H);4.62(d;J=13.5Hz;0.7H)4.39(d;J=13.5Hz;0.3H);3.53–4.05(m;4.8H);3.04–3.46(m;0.8H);2.41–2.96(m;2.1H);2.04–2.23(m;0.8H);1.82–1.95(m;2.2H);1.43(br s;10.1H);1.07(d;J=6.5Hz;2.1H);0.90(d;J=6.5Hz;2.3H);0.63(d;J=6.5Hz;1.0H);0.29(d;J=6.5Hz;0.8H)。
最大极性的非对映异构体(I–5dia2)(4.40g;27%)
LCMS[M+H]=639(C35H41ClFN3O5)
1H NMR(300MHz,CDCl3):δ8.00–8.10(m;1.0H);7.30–7.40(m;2.1H);6.98–7.18(m;3.2H);6.73–6.90(m;5.3H);6.52–6.58(m;1.0H);6.34–6.39(m;1.0H);4.71(d;J=13.5Hz;0.7H);4.49(d;J=13.5Hz;0.4H);3.50–4.00(m;4.7H);3.10–3.30(m;0.7H);2.86–3.07(m;0.4H);2.54–2.85(m;1.5H);2.30–2.47(m;0.4H);1.80–1.87(m;2.8H);1.54–1.60(m;2.5H);1.42(br s;8.8H);1.19(d;J=6.6Hz;1.1H);1.00(d;J=6.6Hz;1.5H);0.88(d;J=6.6Hz;1.2H);0.64(d;J=6.6Hz;1.5H)。
实施例I–6a和I–6b:4–[–2–[(2–氯-乙酰基)–(4–苯氧基–苯基)–氨基]–2–(4–氟–苯基)–乙酰基]–(R)–2–异丙基–哌嗪–1–羧酸叔丁酯的非对映异构体
以与前述实施例相同的方式制备无色泡沫状形式的这两个非对映异构体:
最小极性的非对映异构体(I–6dia1)(97m;30%)
LCMS[M+H]=639(C35H41ClFN3O5)
1H NMR(300MHz,CD2Cl2):δ7.94–8.57(m;0.9H);7.35(t;J=7.9Hz;1.9H);7.05–7.25(m;3.1H);6.72–6.93(m;5.0H);6.58(br d;J=2.6Hz;1.1H);6.41(s;0.8H);6.31(br s;0.3H);4.63(d;J=13.5Hz;0.8H)4.40(d;J=13.5Hz;0.3H);3.51–4.06(m;4.8H);3.03–3.45(m;1.0H);2.41–2.96(m;1.6H);2.02–2.21(m;0.8H);1.82–1.95(m;2.1H);1.43(br s;10.1H);1.07(d;J=6.5Hz;2.1H);0.90(d;J=6.5Hz;2.3H);0.63(d;J=6.5Hz;1.0H);0.29(d;J=6.5Hz;0.8H)。
最大极性的非对映异构体(I–6dia2)(90mg;28%)
LCMS[M+H]=639(C35H41ClFN3O5)
1H NMR(300MHz,CDCl3):δ8.00–8.10(m;1.0H);7.30–7.40(m;2.1H);6.98–7.18(m;3.1H);6.73–6.90(m;5.1H);6.52–6.58(m;1.0H);6.34–6.39(m;1.0H);4.70(d;J=13.5Hz;0.7H);4.49(d;J=13.5Hz;0.4H);3.50–4.00(m;4.8H);3.10–3.30(m;0.7H);2.86–3.07(m;0.4H);2.54–2.85(m;1.5H);2.30–2.47(m;0.4H);1.80–1.87(m;2.8H);1.54–1.60(m;2.6H);1.42(br s;8.6H);1.20(d;J=6.6Hz;1.1H);1.01(d;J=6.6Hz;1.5H);0.89(d;J=6.6Hz;1.2H);0.64(d;J=6.6Hz;1.5H)。
实施例I–7a和I–7b:2–氯-N–[–1–(4–氟–苯基)–2–((S)–3–异丙基–哌嗪–1-基)–2–氧代–乙基]–N–(2–甲基–4–苯氧基–苯基)–乙酰胺非对映异构体的盐酸盐
向非对映异构体I–5a和I–5b之一在50mL DCM中的溶液鼓吹加入HCl气体。于RT,在搅拌下放置反应介质12小时。蒸发DCM和在乙醚中沉淀残余油状物。
起始于实施例I–5的第一个非对映异构体(I–7dia1):
过滤后回收得到白色粉末:(26mg)
LCMS[M+H]=538(C30H34Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.79–9.33(m;1.3H);7.83(t;J=9.0Hz;1.0H);7.24–7.40(m;4.0H);6.97–7.15(m;3.1H);6.73–6.89(m;3.2H);6.64(d;J=2.7Hz;0.9H);6.51–6.59(m;1.0H);4.40–4.55(br m;1.1H);3.86–4.09(m;3.6H);3.45–3.60(m;0.7H);2.78–3.05(m;2.8H);1.79–2.00(m;4.5H);1.61–1.77(m;0.7H);0.97(d;J=6.7Hz;6.0H)。
起始于实施例I–5的第二个非对映异构体(I–7dia2):
过滤后回收得到白色粉末:(2.62g)
LCMS[M+H]=538(C30H34Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.78–9.51(m;1.9H);7.82(t;J=8.9Hz;0.9H);7.20–7.41(m;4.0H);6.97–7.16(m;3.1H);6.71–6.90(m;3.1H);6.61–6.70(m;1.9H);4.46–4.60(br m;1.0H);3.85–4.15(m;3.1H);3.00–3.30(m;3.0H);2.57–2.96(m;1.8H);1.43–1.98(m;4.3H);1.00(dd;J=8.8Hz;J=7.0Hz;2.7H);0.71(d;J=6.8Hz;1.6H);0.65(d;J=6.8Hz;1.5H)。
实施例I–8:2–氯-N–[–1–(4–氟–苯基)–2–((R)–3–异丙基–哌嗪–1-基)–2–氧代–乙基]–N–(2–甲基–4–苯氧基–苯基)–乙酰胺盐酸盐
起始于实施例I–6的每个非对映异构体,接着进行如前述实施例相同的方案。
起始于实施例I–6的第一个非对映异构体(I–8dia1):
过滤后回收得到白色粉末:(34mg;56%)
LCMS[M+H]=538(C30H34Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.79–9.33(m;1.3H);7.83(t;J=9.0Hz;0.9H);7.24–7.40(m;4.0H);6.97–7.15(m;3.1H);6.73–6.89(m;3.1H);6.64(d;J=2.7Hz;1.0H);6.51–6.59(m;1.0H);4.41–4.56(br m;1.1H);3.86–4.09(m;3.4H);3.45–3.60(m;0.7H);2.78–3.05(m;2.8H);1.79–2.00(m;4.4H);1.61–1.77(m;0.8H);0.97(d;J=6.7Hz;6.0H)。
起始于实施例I–6的第二个非对映异构体(I–8dia2):
过滤后回收得到白色粉末:(30mg;54%)
LCMS[M+H]=538(C30H34Cl2FN3O3)
1H NMR(300MHz,DMSO):δ8.78–9.51(m;1.5H);7.82(t;J=8.9Hz;1.0H);7.20–7.41(m;4.0H);6.97–7.16(m;3.1H);6.71–6.90(m;3.2H);6.61–6.70(m;1.9H);4.46–4.60(br m;1.0H);3.85–4.15(m;3.1H);3.00–3.30(m;2.9H);2.57–2.96(m;1.8H);1.43–1.98(m;4.3H);1.00(dd;J=8.8Hz;J=7.0Hz;2.7H);0.71(d;J=6.8Hz;1.6H);0.65(d;J=6.8Hz;1.5H)。
使用如上相同的操作模式和相同的通过硅胶色谱法的分离模式,从各种取代的苯胺和哌嗪制备以下实施例。它们或者以两个或四个非对映异构体的形式(一个实施例编号对应相同的化学结构)或者以单独的非对映异构体形式被分离。在后一种情况下,命名法a/b用于指定每一个非对映异构体。
通过用噻吩-2-乙醛酸乙酯代替(4–氟–苯基)–氧代–乙酸乙酯,并根据之前相同的操作模式,得到以下实施例。
II-本发明化合物的药理学研究
1)细胞毒性试验
在不同组织来源(MCF–7:乳腺癌,MCF–7/adr阿霉素–耐受乳腺癌,HL–60:急性早幼粒细胞性白血病,HL–60/R10:阿霉素–耐受急性早幼粒细胞性白血病,HT29:结肠癌,Mia Paca2:胰腺肿瘤,Panc–1:胰腺外分泌肿瘤,SK–OV–3:顺铂-和阿霉素耐受卵巢癌)的不同人类癌症细胞株上研究本发明化合物对癌症细胞增殖的作用。于37℃,在以不同浓度添加于培养基中的一种本发明化合物的存在下,孵育用于本研究的癌细胞。
从ATCC(美国模式培养物保藏所)获得癌细胞株MCF–7,从de la PitiéSalpetrière获得癌细胞株MCF–7/adr,和从Oncodesign(Dijon,法国)获得癌细胞株HL–60、HL–60/R10、HT29、MiaPaCa2、Panc–1和SK–OV–3。在含有2mM L-谷氨酰胺并补充有10%胎牛血清(Lonza;Verviers,比利时)的RPMI1640基质中培养这些细胞株。于37℃,在含有5%CO2的湿润气氛下,培养所有细胞株。使用联合检测试剂盒(Lonza;Verviers,比利时),按照制造商的说明,评估细胞增殖。在100μl培养基中,以每孔5000至10000个细胞的比例,将细胞接种于兼容荧光读数的96孔板(具有透明底的白板)中。于37℃预孵育24小时后,以每孔0.5μl的比例将溶解于二甲基亚砜(DMSO)的本发明化合物独立地添加于每个孔中。在含有5%CO2的湿润气氛下,于37℃孵育72小时后,将50μl裂解缓冲液添加于每孔中,15分钟后添加100μl ATP测试试剂。在光度计下读取孔板以评估细胞活力。用计算机处理获得的数据以获得EC50值,即与对照值(仅有0.5%DMSO)相比,诱导50%细胞活力的每个化合物的浓度值。
以下表1和2中给出了获得的结果。
表1:细胞株HL–60、HL60/R10、MCF–7和MCF–7/adr获得的结果(以nM表示的EC50)
nd=未确定
表2:其它细胞株获得的结果(以nM表示的EC50)
以下表3和4阐明与未取代的哌嗪和/或在哌嗪的其它位置取代相比,具有在哌嗪的氮4的α位取代的哌嗪的化合物获得了对于耐受HL60/R10株的细胞毒活性的增加。该取代的绝对构型(S)获得最佳的细胞毒活性。
表3:哌嗪的不同取代获得的结果
表4:哌嗪的不同取代获得的结果
2)水溶性测定
水溶性是分子中改善ADME性质(吸收、分布、代谢和排泄)的主要物理化学参数(Drug–like properties:concepts,structure design and methods,Edward HarvelKerns,Li Di;Academic Press,2008)。
于pH7.4测定每个化合物的水溶性。在于20℃的温度,搅拌24小时后用过量的化合物饱和介质后离心,使用HPLC测定该离心获得的上清液。自动化制备和处理样品。
表5显示与未取代的哌嗪和/或在其它位置取代相比,本发明I-58的化合物获得了的水溶性的增加。
表5:不同哌嗪取代获得的水溶性
3)小鼠中的药代动力学参数
化合物的药代动力学行为对于其体内实验中的合理使用是先决条件。通过静脉内途径(IV)或口服途径(PO)向balb/c小鼠给予DMSO溶液中的化合物。从5分钟至6小时的时间范围内采取血液样品,收集血浆,并通过LC/MS/MS分析每个样品中的化合物浓度。获得的数据允许绘出时间-浓度曲线并确定基本参数例如化合物的血浆半衰期(T1/2),给定时间下的曲线下面积(AUCt)和所获得的最大浓度(Cmax)。表6显示由哌嗪取代所贡献的以10mg/kg的剂量静脉内途径施用的化合物的药代动力学参数的增加。
图1给出通过IV和PO途径施用I-43dia2后,小鼠中的时间-血浆浓度曲线。因此,化合物I–43dia2显示在小鼠中,特别是经过口服途径的良好的生物利用度。
表6:各种哌嗪取代获得的药代动力学参数
Claims (17)
1.以下通式(I)的化合物:
及其药学上可接受的盐、其立体异构体或任何比例的立体异构体混合物,特别是对映异构体混合物,并且特别是外消旋混合物,
其中:
–X是(C1–C6)烷基、苯基、苄基、C(O)OR5或C(O)NHR5基团;
–R1是氢原子或C(O)H、C(O)R6或C(O)OR6基团;
–R2是氢原子或(C1–C6)烷基基团;
或R2与R1或X一起形成饱和烃链以形成5-或6元环,特别是5元环;
–R3是氢或卤素原子或(C1–C6)烷基或(C1–C6)烷氧基基团;
–R4是氢或卤素原子、CN、NO2、或(C1–C6)烷基、(C1–C6)烷氧基、芳氧基、苄氧基或杂芳氧基基团,所述基团任选被一个或多个卤素原子取代;
–Ar是任选被一个或多个卤素原子取代的苯硫基基团或苯基基团;和
-R5和R6彼此独立地为(C1–C6)烷基、芳基–(C1–C6)烷基或芳基基团,所述基团任选被一个或多个卤素原子取代。
2.根据权利要求1所述的化合物,其特征在于,其对应于以下式(I-bis):
3.根据权利要求1和2任一项所述的化合物,其特征在于,Ar是被一个或多个氟原子取代的苯硫基基团或苯基基团,例如4-氟-苯基。
4.根据权利要求1至3任一项所述的化合物,其特征在于,R4是氢或卤素原子或(C1–C6)烷基、(C1–C6)烷氧基或芳氧基基团,所述基团任选被一个或多个卤素原子特别是氟原子取代。
5.根据权利要求1至4任一项所述的化合物,其特征在于,R3是氢原子或(C1–C6)烷基基团,例如甲基。
6.根据权利要求1至5任一项所述的化合物,其特征在于,X是(C1–C6)烷基、苯基或苄基;R1和R2是氢原子;R3是氢原子或(C1–C6)烷基基团,特别是(C1–C3)烷基;R4是卤素原子或(C1–C6)烷基、(C1–C6)烷氧基、芳氧基或苄氧基基团,所述基团任选被一个或多个卤素原子取代;Ar是任选被氟原子取代的苯硫基基团或苯基基团,例如4–氟–苯基;和R5和R6彼此独立地为(C1–C6)烷基、芳基–(C1–C6)烷基或芳基基团,所述基团任选被一个或多个氟原子取代。
7.根据权利要求1所述的化合物,其特征在于,所述化合物选自:
8.根据权利要求1至7任一项所述的通式(I)的化合物,其用作药物。
9.根据权利要求1至7任一项所述的通式(I)的化合物,其用于预防或治疗癌症和化疗耐受癌症。
10.一种药物组合物,其包含至少一种根据权利要求1至7任一项所述的通式(I)的化合物,和一种或多种药学上可接受的赋形剂。
11.根据权利要求10所述的药物组合物,其特征在于,其包含至少一种其它活性成分,例如抗癌剂。
12.根据权利要求11所述的药物组合物,其特征在于,所述活性成分选自顺铂和其衍生物,例如卡铂和奥沙利铂;紫杉烷类,例如紫杉酚、泰索帝、紫杉醇和多西他赛;长春花生物碱类,例如长春花碱、长春新碱和长春瑞滨;嘌呤类似物,例如硫嘌呤、硫鸟嘌呤、喷司他丁和2–氯脱氧腺苷;拓扑异构酶I抑制剂,例如喜树碱化合物如伊立替康和拓扑替康;拓扑异构酶II抑制剂,例如表鬼臼毒素、足叶草毒素和其衍生物如依托泊苷和替尼泊苷;抗肿瘤核苷衍生物,例如5–氟尿嘧啶、亚叶酸、吉西他滨或卡培他滨;烷化剂,例如氮芥类如环磷酰胺、二氯甲基二乙胺、苯丁酸氮芥和美法仑,亚硝基脲类如卡莫司汀、洛莫司汀和链脲菌素,烷基磺酸盐类如白消安,乙烯亚胺类和甲基三聚氰胺类如塞替派和六甲基三聚氰胺,和四嗪类如达卡巴嗪;抗肿瘤蒽环类衍生物,例如道诺霉素、阿霉素、多喜、伊达比星和米托蒽醌;靶向于IGF–I受体的分子,例如足叶苦素;替曲卡星衍生物,例如替曲卡星A;皮质类固醇类,例如强的松;抗体类,例如曲妥单抗(抗–HER2抗体)、利妥昔单抗(抗–CD20抗体)、吉妥单抗、西妥昔单抗、帕妥珠单抗和贝伐单抗;雌激素受体的拮抗剂或选择性调节剂,例如他莫昔芬、氟维司群、托瑞米芬、屈洛昔芬、伐索戴司和雷洛昔芬;芳香酶抑制剂,例如依西美坦、阿那曲唑、来曲唑和伏罗唑;分化剂,例如类视黄醇类如维甲酸和维生素D和维甲酸代谢阻断剂,例如异维甲酸;DNA甲基转移酶抑制剂,例如氮杂胞苷和地西他滨;抗叶酸类,例如培美曲塞二钠;抗生素类,例如抗霉素D、博来霉素、丝裂霉素C、放线菌素D、洋红霉素、道诺霉素和普卡霉素;抗代谢物类,例如氯法拉滨、氨嘌呤、阿糖胞苷、氟脲苷和甲氨蝶呤;Bcl–2抑制剂的细胞凋亡诱导剂和抗血管生成剂,例如YC137、BH312、ABT737、棉子酚、HA14–1、TW37和癸酸;微管蛋白结合剂,例如考布他汀、秋水仙碱衍生物和诺考达唑;激酶抑制剂,例如佛罗匹多、甲磺酸伊马替尼、埃罗替尼和吉非替尼;法尼基转移酶抑制剂,例如替吡法尼;组蛋白–脱乙酰酶抑制剂,例如丁酸钠、辛二酰苯胺异羟肟酸、缩酚酸肽、NVP-LAQ824、R306465、JNJ–26481585和曲古抑菌素A;泛素-蛋白酶体系统抑制剂,例如MLN.41、硼替佐米和曲贝替定;和端粒酶抑制剂,例如替莫美他汀。
13.一种药物组合物,其包含:
(i)至少一种根据权利要求1至7任一项所述的式(I)化合物;和
(ii)至少一种其它活性成分,例如抗癌剂,
作为组合产品用于同时、分别或错时使用。
14.根据权利要求13所述的药物组合物,其特征在于,所述活性成分选自顺铂和其衍生物,例如卡铂和奥沙利铂;紫杉烷类,例如紫杉酚、泰索帝、紫杉醇和多西他赛;长春花生物碱类,例如长春花碱、长春新碱和长春瑞滨;嘌呤类似物,例如硫嘌呤、硫鸟嘌呤、喷司他丁和2–氯脱氧腺苷;拓扑异构酶I抑制剂,例如喜树碱化合物如伊立替康和拓扑替康;拓扑异构酶II抑制剂,例如表鬼臼毒素、足叶草毒素和其衍生物如依托泊苷和替尼泊苷;抗肿瘤核苷衍生物,例如5–氟尿嘧啶、亚叶酸、吉西他滨或卡培他滨;烷化剂,例如氮芥类如环磷酰胺、二氯甲基二乙胺、苯丁酸氮芥和美法仑,亚硝基脲类如卡莫司汀、洛莫司汀和链脲菌素,烷基磺酸盐类如白消安,乙烯亚胺类和甲基三聚氰胺类如塞替派和六甲基三聚氰胺,和四嗪类如达卡巴嗪;抗肿瘤蒽环类衍生物,例如道诺霉素、阿霉素、多喜、伊达比星和米托蒽醌;靶向于IGF–I受体的分子,例如足叶苦素;替曲卡星衍生物,例如替曲卡星A;皮质类固醇类,例如强的松;抗体类,例如曲妥单抗(抗–HER2抗体)、利妥昔单抗(抗–CD20抗体)、吉妥单抗、西妥昔单抗、帕妥珠单抗和贝伐单抗;雌激素受体的拮抗剂或选择性调节剂,例如他莫昔芬、氟维司群、托瑞米芬、屈洛昔芬、伐索戴司和雷洛昔芬;芳香酶抑制剂,例如依西美坦、阿那曲唑、来曲唑和伏罗唑;分化剂,例如类视黄醇类如维甲酸和维生素D和维甲酸代谢阻断剂,例如异维甲酸;DNA甲基转移酶抑制剂,例如氮杂胞苷和地西他滨;抗叶酸类,例如培美曲塞二钠;抗生素类,例如抗霉素D、博来霉素、丝裂霉素C、放线菌素D、洋红霉素、道诺霉素和普卡霉素;抗代谢物类,例如氯法拉滨、氨嘌呤、阿糖胞苷、氟脲苷和甲氨蝶呤;Bcl–2抑制剂的细胞凋亡诱导剂和抗血管生成剂,例如YC137、BH312、ABT737、棉子酚、HA14–1、TW37和癸酸;微管蛋白结合剂,例如考布他汀、秋水仙碱衍生物和诺考达唑;激酶抑制剂,例如佛罗匹多、甲磺酸伊马替尼、埃罗替尼和吉非替尼;法尼基转移酶抑制剂,例如替吡法尼;组蛋白–脱乙酰酶抑制剂,例如丁酸钠、辛二酰苯胺异羟肟酸、缩酚酸肽、NVP-LAQ824、R306465、JNJ–26481585和曲古抑菌素A;泛素-蛋白酶体系统抑制剂,例如MLN.41、硼替佐米和曲贝替定;和端粒酶抑制剂,例如替莫美他汀。
15.根据权利要求10至14任一项所述的药物组合物,其用作药物,所述药物旨在治疗或预防癌症,特别是治疗化学耐受癌症。
16.一种制备根据权利要求1至7任一项所述的式(I)化合物的方法,其包含以下连续的步骤:
a)在碱的存在下,将下式(II)的胺与氯乙酰氯反应得到其中R1≠H的式(I)化合物,
其中X、R1、R2、R3、R4和Ar如权利要求1所定义,R1不代表氢原子;和
b)任选地,将携带R1≠H基团的氮原子脱保护,得到其中R1=H的式(I)化合物。
17.根据权利要求16所述的方法,其包含以下连续的步骤:
i)将下式(V)的酮酯与下式(VI)的苯胺反应得到下式(VII)的亚胺;
其中Ar如权利要求1所定义,且R代表(C1–C6)烷基基团,例如乙基,
其中R3和R4如权利要求1所定义,
其中R、R3、R4和Ar如权利要求1所定义;
ii)将在前述步骤获得的式(VII)的亚胺还原得到下式(VIII)的胺:
其中R、R3、R4和Ar如权利要求1所定义;
iii)皂化在前述步骤获得的式(VIII)化合物的酯官能团得到下式(IV)的酸:
其中R3、R4和Ar如权利要求1所定义;
iv)将在前述步骤获得的式(IV)的酸与下式(III)的哌嗪反应得到根据权利要求16的式(II)的胺,
其中X、R1和R2如权利要求1所定义,R1不代表氢原子;
v)在碱的存在下,将在前述步骤获得的式(II)的胺与氯乙酰氯反应得到其中R1≠H的式(I)化合物;和
vi)任选地,将携带R1≠H基团的氮原子脱保护,得到其中R1=H的式(I)化合物。
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FR1162586A FR2985256B1 (fr) | 2011-12-30 | 2011-12-30 | Derives piperazinyles pour le traitement de cancers |
PCT/EP2012/077059 WO2013098393A1 (fr) | 2011-12-30 | 2012-12-28 | Derives piperazinyles pour le traitement de cancers |
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CN101010315A (zh) * | 2004-04-30 | 2007-08-01 | 拜耳制药公司 | 用于治疗癌症的取代的吡唑基脲衍生物 |
WO2009150248A1 (en) * | 2008-06-13 | 2009-12-17 | Cytomics Systems | Compounds which can be used for the treatment of cancers |
CN101687863A (zh) * | 2007-05-04 | 2010-03-31 | 阿斯利康(瑞典)有限公司 | 氨基-噻唑基-嘧啶衍生物及其治疗癌症的用途 |
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CN101687863A (zh) * | 2007-05-04 | 2010-03-31 | 阿斯利康(瑞典)有限公司 | 氨基-噻唑基-嘧啶衍生物及其治疗癌症的用途 |
WO2009150248A1 (en) * | 2008-06-13 | 2009-12-17 | Cytomics Systems | Compounds which can be used for the treatment of cancers |
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US20140356360A1 (en) | 2014-12-04 |
IL233414A0 (en) | 2014-08-31 |
NZ627149A (en) | 2015-08-28 |
RU2629115C2 (ru) | 2017-08-24 |
EP2797898B1 (fr) | 2016-09-14 |
FR2985256A1 (fr) | 2013-07-05 |
US9321778B2 (en) | 2016-04-26 |
CA2859721A1 (fr) | 2013-07-04 |
EP2797898A1 (fr) | 2014-11-05 |
BR112014015991A8 (pt) | 2017-07-04 |
IL233414A (en) | 2015-11-30 |
CA2859721C (fr) | 2020-01-07 |
HK1202118A1 (zh) | 2015-09-18 |
FR2985256B1 (fr) | 2016-03-04 |
KR102086732B1 (ko) | 2020-03-09 |
KR20140117456A (ko) | 2014-10-07 |
CN104053648B (zh) | 2016-09-28 |
EP2797898B9 (fr) | 2021-05-26 |
JP2015505308A (ja) | 2015-02-19 |
ES2606289T3 (es) | 2017-03-23 |
WO2013098393A1 (fr) | 2013-07-04 |
BR112014015991A2 (pt) | 2017-06-13 |
RU2014131001A (ru) | 2016-02-20 |
ZA201405068B (en) | 2015-11-25 |
BR112014015991B1 (pt) | 2022-11-16 |
AU2012360815A1 (en) | 2014-07-31 |
SG11201403727YA (en) | 2014-09-26 |
JP6105625B2 (ja) | 2017-03-29 |
AU2012360815B2 (en) | 2017-02-02 |
PL2797898T3 (pl) | 2017-03-31 |
HUE030951T2 (en) | 2017-06-28 |
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