CN102065859A - 用于神经纤维瘤病的取代的苯并咪唑类 - Google Patents
用于神经纤维瘤病的取代的苯并咪唑类 Download PDFInfo
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Abstract
本发明涉及苯并咪唑衍生物在制备用于治疗神经纤维瘤病的药物中的用途。
Description
发明概述
本发明涉及取代的苯并咪唑类在治疗非癌性的良性脑肿瘤、尤其是在治疗性和/或预防性治疗脑膜瘤、神经鞘瘤、颅咽管瘤、皮样囊肿、表皮样瘤、成血管细胞瘤、脉络丛乳头状瘤和松果体区肿瘤、尤其是与1型和2型神经纤维瘤病有关的那些肿瘤和沿颅底发生的肿瘤中的用途以及在制备用于上述治疗的药物中的用途。
发明背景
神经纤维瘤病(NF)是侵袭骨、软组织、皮肤和神经系统的遗传病。它分为1型神经纤维瘤病(NF1)和2型神经纤维瘤病(NF2),它们分别在3,000个出生者中有约1个发生和在50,000个出生者中有约1个发生。这些紊乱是由于遗传缺陷而发生的,NF1和NF2分别由位于染色体17和染色体22上的基因发生突变所引起。
NF1还称为冯·雷克林豪森病(von Recklinghausen Disease),它是在美国在4,000个活出生者中有约1个发生的遗传性疾病。NF1的特征为咖啡(café-au-lait)斑(皮肤变色)、皮肤神经纤维瘤和虹膜利舍小结的三联征。该紊乱的其它特征可包括骨骼发育不良、血管发育不良、学习能力缺失、癫痫发作和神经嵴来源的其它肿瘤如嗜铬细胞瘤。此外,约10-15%的NF1患者患有低级星形细胞瘤和较少见的室管膜瘤(ependymoas)或脑膜瘤。
NF2的特征为两侧前庭神经鞘瘤伴有耳鸣、听力丧失和平衡功能障碍的相关症状。其它发现包括其它颅神经和外周神经的神经鞘瘤、脑膜瘤和幼年型后囊下白内障(juvenile posterior subcapsular contaract)。
NF的两种形式的特征均为称为神经纤维瘤的良性肿瘤的生长。这些肿瘤可以在体内有神经细胞的任何地方生长。这包括正好在皮肤表面下的神经以及体内较深的神经、脊髓和/或脑神经。神经纤维瘤通常起源于外周神经纤维。
在NF1中,神经纤维瘤最常见在皮肤上或在眼神经上生长。在眼神经上生长的肿瘤称为视神经胶质瘤,如果它生长得足够大,则可以引起视觉问题,包括失明。
如果不进行治疗,则神经纤维瘤可以引起严重的神经损害,导致由该神经兴奋的区域的功能丧失,例如长骨畸形、脊柱弯曲、身材矮小和生长激素缺乏。在视神经上的肿瘤可以引起视力丧失,在胃肠道上的肿瘤可以引起出血或梗阻,在脑上的肿瘤可以导致学习困难(语言问题)、行为问题(学习能力缺失或智力迟钝)、听觉问题、癫痫风险增加。
原癌基因的Ras家族(N-Ras、K-Ras和H-Ras)作为促进细胞生长、分化和存活信号的信号传导介导剂起作用。激活的Ras以GTP-结合状态存在,随着GTP水解为GDP而发生失活。Ras突变与多种人类恶性病相关,并且导致GTP水解速率的降低,导致持续的激活。
NF1基因编码GTP酶活化蛋白(GAP),GTP酶活化蛋白的功能是用作Ras的负调节剂。因此,损失NF1导致Ras和下游信号传导途径如Raf/MEK/ERK途径和PI3K/AKT途径的激活增加。靶向于这些下游信号传导途径的治疗性干预代表了治疗这种疾病的潜在途径。
如美国专利7,071,216和美国专利申请11/513,959中所记载的苯并咪唑类是Raf激酶的小分子抑制剂,它们已经被证明优先地抑制表达Ras或B-Raf的突变或激活形式的肿瘤细胞中的Raf/MEK/ERK信号传导途径。
作为Raf/MEK/ERK信号传导途径的抑制剂,苯并咪唑衍生物具有有益于治疗NF的潜能。
发明概述
本发明涉及式(I)苯并咪唑(下文称为“苯并咪唑衍生物”)或其互变异构体或立体异构体或该化合物、互变异构体或立体异构体的可药用盐在治疗或预防神经纤维瘤病(NF)引起的病症中的用途:
其中:
R1各自独立地选自羟基、卤素、C1-6烷基、C1-6烷氧基、(C1-6烷基)硫基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
R2是C1-6烷基或卤代(C1-6烷基);
R3各自独立地选自卤素、C1-6烷基和C1-6烷氧基;
R4各自独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨基羰基、C1-6烷基氨基羰基、腈、环烷基、杂环烷基、杂环烷基羰基、苯基和杂芳基;
其中R1、R2、R3和R4可以任选地被一个或多个独立地选自羟基、卤素、C1-6烷基、卤代(C1-6烷基)、C1-6烷氧基和卤代(C1-6烷氧基)的取代基取代;
a是1、2、3、4或5;
b是0、1、2或3;且
c是1或2。
上下文所用的一般术语在本公开内容的上下文中优选具有下述含义,另有说明除外。
在另一方面,本发明提供了在需要该治疗的人或动物受治疗者中治疗Raf相关性紊乱的方法,该方法包括给所述受治疗者施用有效降低或阻止该受治疗者中肿瘤生长的量的式(I)、(II)或(III)化合物以及至少一种用于治疗癌症的其它活性剂。在本发明的方法中考虑了大量意欲用作组合治疗的适宜抗癌剂。确实,本发明非限制性地考虑了施用各种抗癌剂,例如诱导细胞凋亡的活性剂;聚核苷酸,如核酶;多肽,如酶;药物;生物模拟物;生物碱;烷化剂;抗肿瘤抗生素;抗代谢物;激素;铂化合物;与抗癌药、毒素和/或放射性核素结合的单克隆抗体;生物应答调节剂,例如干扰素,如IFN-a等;和白细胞介素,例如IL-2等,继承性免疫治疗活性剂;造血生长因子;诱导肿瘤细胞分化的活性剂,例如全反式视黄酸等;基因治疗试剂;反义治疗试剂和核苷酸;肿瘤疫苗;血管生成抑制剂;等等。适于与所公开的式(I)、(II)或(III)化合物共同施用的化学治疗化合物和抗癌治疗的各种其它实例是本领域技术人员已知的。
在优选的实施方案中,意欲用于与本发明的化合物组合的抗癌剂包括诱导或刺激细胞凋亡的活性剂。诱导细胞凋亡的活性剂包括但不限于放射;激酶抑制剂,如表皮生长因子受体(EGFR)激酶抑制剂、血管生长因子受体(VGFR)激酶抑制剂、成纤维细胞生长因子受体(FGFR)激酶抑制剂、血小板衍生生长因子受体(PGFR)I激酶抑制剂和Bcr-Abl激酶抑制剂,如STI-571、Gleevec和Glivec;反义分子;抗体,例如赫赛汀和rituxan;抗雌激素药,例如雷洛昔芬和他莫昔芬;抗雄激素药,例如氟他胺、比卡鲁胺、非那雄胺、氨鲁米特(amino-glutethamide)、酮康唑和皮质类固醇;环加氧酶2(COX-2)抑制剂,例如塞来考昔、美洛昔康、NS-398和非甾体抗炎药(NSAIDs);以及癌症化学治疗药物,例如伊立替康(Camptosar)、CPT-11、氟达拉滨(Fludara)、达卡巴嗪(DTIC)、地塞米松、米托蒽醌、麦罗塔(mylotarg)、VP-16、顺铂、5-FU、多柔比星(doxrubicin)、泰索帝或紫杉醇;细胞信号传导分子;神经酰胺和细胞因子;以及星孢素(staurosprine);等等。
在其它方面,本发明提供了包含单独或与其它抗癌剂组合的至少一种式(I)、(II)或(III)化合物或其可药用盐以及适于施用于人或动物受治疗者的可药用载体的药物组合物。
“Raf抑制剂”在本文中用于指就Raf激酶活性而言显示出不高于约100μM和更通常不高于约50μM的IC50的化合物,如在下文概述的Raf/Mek过滤分析中所测定的那样。其中本发明的化合物将被证明抑制它们的Raf激酶的优选同工型包括A-Raf、B-Raf和C-Raf(Raf)1)。“IC50”是导致酶如Raf激酶活性降低至最大水平一半的抑制剂浓度。已经发现代表性的本发明化合物显示出对抗Raf的抑制活性。本发明的化合物就Raf而言优选显示出不高于约10μM、更优选不高于约5μM、甚至更优选不高于约1μM、最优选不高于约200nM的IC50,如在下文概述的Raf激酶分析中所测定的那样。
“烷基”指不含有杂原子的饱和烃基,包括直链烷基如甲基、乙基、丙基、丁基、戊基、己基、庚基、辛基、壬基、癸基、十一烷基、十二烷基等。烷基还包括直链烷基的支链异构体,包括但不限于如下以举例方式提供的那些:-CH(CH3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3)、-CH2CH(CH2CH3)2、-CH2C(CH3)3、-CH2C(CH2CH3)3、-CH(CH3)-CH(CH3)(CH2CH3)、-CH2CH2CH(CH3)2、-CH2CH2CH(CH3)(CH2CH3)、-CH2CH2CH(CH2CH3)2、-CH2CH2C(CH3)3、-CH2CH2C(CH2CH3)3、-CH(CH3)CH2CH(CH3)2、-CH(CH3)CH(CH3)CH(CH3)2、-CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3)等。因而,烷基包括伯烷基、仲烷基和叔烷基。短语“C1-12烷基”指具有1至12个碳原子的烷基。短语“C1-6烷基”指具有1至6个碳原子的烷基。
“烷氧基”指其中R为烷基的RO-。如本文所用的短语“C1-6烷氧基”指其中R为C1-6烷基的RO-。C1-6烷氧基的代表性实例包括甲氧基、乙氧基、叔丁氧基等。
“(C1-6烷氧基)羰基”指酯-C(=O)-OR,其中R是C1-6烷基。
“氨基羰基”在本文中指-C(O)-NH2。
“C1-6烷基氨基羰基”指-C(O)-NRR′,其中R是C1-6烷基且R′选自氢和C1-6烷基。
“羰基”指二价基团-C(O)-。
“羧基”指-C(=O)-OH。
“氰基”或“腈”指-CN。
“腈(C1-6烷基)”指被-CN取代的C1-6烷基。
“环烷基”指单环或多环烷基取代基。典型的环烷基具有3至8个环碳原子。代表性的环烷基包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
“卤素”或“卤代”指氯、溴、氟和碘基团。
“卤代(C1-6烷基)”指被一个或多个卤素原子、优选一至五个卤素原子取代的C1-6烷基。更优选的卤代(C1-6烷基)是三氟甲基。
“卤代(C1-6烷基)苯基”指被卤代(C1-6烷基)取代的苯基。
“卤代(C1-6烷氧基)”指被一个或多个卤素原子、优选一至五个卤素原子取代的烷氧基。更优选的卤代(C1-6烷氧基)是三氟甲氧基。
“卤代(C1-6烷基)磺酰基”和“卤代(C1-6烷基)硫基”指被卤代(C1-6烷基)取代的磺酰基和硫基,其中磺酰基和硫基如本文所定义。
“杂芳基”指在芳香环中具有1至4个杂原子作为环原子且其余环原子为碳原子的芳香族基团。适用于本发明的化合物的杂原子有氮、氧和硫,其中氮和硫原子可以任选地被氧化。示例性的杂芳基具有5至14个环原子,包括例如苯并咪唑基、苯并噻唑基、苯并唑基、二氮杂基、呋喃基、吡嗪基、吡唑基、吡啶基、哒嗪基、嘧啶基、吡咯基、唑基、异唑基、咪唑基、吲哚基、吲唑基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噻唑基、噻吩基和三唑基。
“杂环烷基”在本文中指在环结构中具有1至5个、更通常地具有1至2个杂原子的环烷基取代基。适用于本发明的化合物的杂原子有氮、氧和硫,其中氮和硫原子可以任选地被氧化。代表性的杂环烷基部分包括例如吗啉基或吗啉代基、哌嗪基、哌啶基等。
“(C1-6烷基)杂环烷基”指被C1-6烷基取代的杂环烷基。
“杂环烷基(C1-6烷基)”指被杂环烷基取代的C1-6烷基。
“杂环烷基羰基”在本文中指-C(O)-R10,其中R10是杂环烷基。
“(C1-6烷基)杂环烷基羰基”指-C(O)-R11,其中R11是(C1-6烷基)杂环烷基。
“羟基”指-OH。
“羟基(C1-6烷基)”指被羟基取代的C1-6烷基。
“羟基(C1-6烷基氨基羰基)”指被羟基取代的C1-6烷基氨基羰基。
“磺酰基”在本文中指-SO2-。
“硫基”在本文中指-S-。“烷基磺酰基”指具有-SO2R12结构的取代的磺酰基,其中R12是烷基。“烷基硫基”指具有-SR12结构的取代的硫基,其中R12是烷基。本发明的化合物中所用的烷基磺酰基和烷基硫基包括(C1-6烷基)磺酰基和(C1-6烷基)硫基。因此,典型的基团包括例如甲基磺酰基和甲基硫基(即其中R12是甲基)、乙基磺酰基和乙基硫基(即其中R12是乙基)、丙基磺酰基和丙基硫基(即其中R12是丙基)等。
“羟基保护基”指用于OH基团的保护基。如本文所用的该术语还指酸COOH的OH基团的保护。适宜的羟基保护基以及适于保护和脱保护具体官能团的条件是本领域熟知的。例如,T.W.Greene和P.G.M.Wuts,Protecting Groups in Organic Synthesis,第3版,Wiley,纽约(1999)中记载了大量这类保护基。这类羟基保护基包括C1-6烷基醚、苄基酯、对甲氧基苄基酯、甲硅烷基醚等。
“任选被取代”或“取代”指一个或多个氢原子被单价或二价基团所替换。
当取代的取代基包括直链基团时,取代情况可以在链内发生,例如2-羟基丙基、2-氨基丁基等;或者在链末端发生,例如2-羟基乙基、3-氰基丙基等。取代的取代基可以是直链、支链或环状排列的共价键合的碳原子或杂原子。
可以理解,上述定义不意欲包括不可能的取代模式,例如被5个氟基团取代的甲基或者被另一个卤素原子取代的卤素原子。这种不可能的取代模式是本领域技术人员所熟知的。
式(I)范围内的化合物以及制备它们的方法在美国专利7,071,216、美国专利申请11/513,959和美国专利申请11/513,745中公开,这些文献引入本申请作为参考。优选的化合物是式(II)的1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基苯基)-胺及其可药用盐:
或者具有式(III)的式(II)化合物的互变异构体或该互变异构体的可药用盐:
当特别为苯并咪唑衍生物化合物而引用专利申请或科学出版物时,其终产物、药物制剂和权利要求的主题在此处通过参考这些出版物的方式引入本申请。
由代码、通用名或商品名确定的活性剂的结构可以从标准目录“默克索引”的现行版本或从数据库、例如国际专利(Patents International)如IMS世界出版物(IMS World Publications)中获得。其相应的内容引入本文作为参考。
现在已经出人意料地发现苯并咪唑衍生物具有治疗性质,这使它们可用于治疗非癌性的良性脑肿瘤、尤其是神经纤维瘤病。
因此,本发明涉及苯并咪唑衍生物在制备用于治疗非癌性的良性脑肿瘤、尤其是神经纤维瘤病的药物中的用途。
本发明更特别涉及苯并咪唑衍生物在制备用于治疗非癌性的良性脑肿瘤、尤其是神经纤维瘤病的药物中的用途。
在另一项实施方案中,本发明提供了用于治疗非癌性的良性脑肿瘤、尤其是NF的方法,该方法包括给需要该治疗的哺乳动物施用治疗有效量的苯并咪唑衍生物或其可药用盐或前药。
本发明优选提供了用于治疗患有非癌性的良性脑肿瘤、尤其是NF的哺乳动物、尤其是人的方法,该方法包括给需要该治疗的哺乳动物施用抑制量的1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基苯基)-胺(化合物(II))或其可药用盐。
该方法优选用于治疗NF1或NF2。
在另一项实施方案中,本发明涉及苯并咪唑衍生物在制备用于治疗非癌性的良性脑肿瘤、尤其是NF的药物组合物中的用途。
在本说明书中,术语“治疗”包括预防性或防止性治疗以及治疗性或疾病抑制性治疗,包括治疗有患病危险或被怀疑已经患病的患者以及患病的患者。该术语还包括用于延缓疾病发展的治疗。
本文所用的术语“治疗性”表示在治疗涉及非癌性的良性脑肿瘤、尤其是NF的正在进行的发作中的效能。
术语“预防性”表示防止涉及非癌性的良性脑肿瘤、尤其是NF的疾病的发作或复发。
本文所用的术语“延缓发展”表示给处于待治疗疾病的前期或早期的患者施用活性化合物,在这些患者中例如诊断出相应疾病的预先形成,或者这些患者处于将有可能发展相应疾病的状况(例如在医学治疗期间)或由意外引起的状况下。
这种不可预料的性质范围意味着苯并咪唑衍生物在制备用于治疗非癌性的良性脑肿瘤、尤其是NF的药物中的用途是特别重要的。
为了证明苯并咪唑衍生物特别适用于治疗非癌性的良性脑肿瘤、尤其是NF并具有良好的治疗范围和其它优点,可按照技术人员已知的方法进行临床试验。
用于抑制非癌性的良性脑肿瘤、尤其是NF的苯并咪唑衍生物的准确剂量取决于若干个因素,包括宿主、所治疗病症的性质和严重性、施用方式。式(I)化合物可以通过任意途径来施用,所述的途径包括口服、胃肠道外(例如腹膜内、静脉内、肌内、皮下、瘤内或直肠)或肠内。优选式(I)化合物经口服施用,优选以1-300mg/kg体重的日剂量或者对于多数较大的灵长类动物而言以50-5000mg、优选500-3000mg的日剂量施用。
通常,开始时施用小剂量,剂量逐渐增大直到确定对所治疗宿主而言的最佳剂量。剂量的上限受副反应影响并且可以通过对正在治疗的宿主进行的试验来确定。
式(I)化合物可以与一种或多种可药用载体和任选的一种或多种其它常规药物佐剂合并,并且可以以片剂、胶囊剂、胶囊形片剂等形式经肠内(例如口服)或者以无菌注射溶液或混悬液的形式经胃肠道外(例如腹膜内或静脉内)施用。肠内和胃肠道外组合物可以通过常规方法来制备。
苯并咪唑衍生物可以单独使用或者与至少一种其它用于这些病状的药物活性化合物组合使用。组合组分包括抗增殖性化合物。这类抗增殖性化合物包括但不限于:芳香酶抑制剂;抗雌激素药;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管活性化合物;烷化剂化合物;组蛋白脱乙酰酶抑制剂;诱导细胞分化过程的化合物;环加氧酶抑制剂;MMP抑制剂;mTOR抑制剂;抗肿瘤性抗代谢物;铂化合物;靶向于/降低蛋白激酶或脂激酶活性的化合物和其它抗血管生成性化合物;靶向于、降低或抑制蛋白磷酸酶或脂质磷酸酶活性的化合物;戈那瑞林激动剂;抗雄激素药;甲硫氨酸氨肽酶抑制剂;双膦酸化合物;生物应答调节剂;抗增殖性抗体;类肝素酶抑制剂;Ras致癌同工型抑制剂;端粒酶抑制剂;蛋白酶体抑制剂;用于治疗血液学恶性疾病的化合物;靶向于、降低或抑制Flt-3活性的化合物;Hsp90抑制剂如17-AAG(17-烯丙基氨基格尔德霉素,NSC330507)、17-DMAG(17-二甲基氨基乙基氨基-17-去甲氧基-格尔德霉素,NSC707545)、IPI-504、CNF1010、CNF2024、CNF1010,来自Conforma Therapeutics;替莫唑胺驱动蛋白纺锤体蛋白抑制剂,如来自GlaxoSmithKline的SB715992或SB743921或来自CombinatoRx的喷他脒/氯丙嗪;MEK抑制剂,如来自Array PioPharma的ARRY142886、来自AstraZeneca的AZD6244、来自Pfizer的PD181461,和亚叶酸。
本文所用的术语“芳香酶抑制剂”涉及抑制雌激素产生、即底物雄烯二酮和睾酮分别转化成雌酮和雌二醇的化合物。该术语包括但不限于类固醇、尤其是阿他美坦、依西美坦和福美坦;且特别是非类固醇、尤其是氨鲁米特、罗谷亚胺、吡鲁米特、曲洛司坦、睾内酯、酮康唑、伏氯唑、法倔唑、阿那曲唑和来曲唑。依西美坦可以例如以其市售形式、例如以商标AROMASIN施用。福美坦可以例如以其市售形式、例如以商标LENTARON施用。法倔唑可以例如以其市售形式、例如以商标AFEMA施用。阿那曲唑可以例如以其市售形式、例如以商标ARIMIDEX施用。来曲唑可以例如以其市售形式、例如以商标FEMARA或FEMAR施用。氨鲁米特可以例如以其市售形式、例如以商标ORIMETEN施用。包含作为芳香酶抑制剂的化疗剂的本发明的组合可特别用于治疗激素受体阳性肿瘤如乳腺肿瘤。
本文所用的术语“抗雌激素药”涉及在雌激素受体水平拮抗雌激素作用的化合物。该术语包括但不限于他莫昔芬、氟维司群、雷洛昔芬和盐酸雷洛昔芬。他莫昔芬可以例如以其市售形式、例如以商标NOLVADEX施用。盐酸雷洛昔芬可以以其市售形式、例如以商标EVISTA施用。氟维司群可以如美国专利US 4,659,516中公开的那样配制,或者其可以例如以其市售形式、例如以商标FASLODEX施用。包含作为抗雌激素药的化疗剂的本发明的组合可特别用于治疗雌激素受体阳性肿瘤、例如乳腺肿瘤。
本文所用的术语“抗雄激素药”涉及能够抑制雄性激素的生物作用的任意物质,其包括但不限于比卡鲁胺(CASODEX),比卡鲁胺可以例如如美国专利US 4,636,505中所公开的那样配制。
本文所用的术语“戈那瑞林激动剂”包括但不限于阿巴瑞克、戈舍瑞林和醋酸戈舍瑞林。戈舍瑞林在美国专利US 4,100,274中公开,可以例如以其市售形式、例如以商标ZOLADEX施用。阿巴瑞克例如可以如美国专利US 5,843,901中公开的那样进行配制。
本文所用的术语“拓扑异构酶I抑制剂”包括但不限于托泊替康、吉马替康(gimatecan)、伊立替康、喜树碱及其类似物、9-硝基喜树碱和大分子喜树碱共轭物PNU-166148(WO 99/17804中的化合物A1)。伊立替康可以例如以其市售形式、例如以商标CAMPTOSAR施用。托泊替康可以例如以其市售形式、例如以商标HYCAMTIN施用。
本文所用的术语“拓扑异构酶II抑制剂”包括但不限于蒽环类如多柔比星(包括脂质体制剂,例如CAELYX)、柔红霉素、表柔比星、伊达比星和奈莫柔比星(nemorubicin);蒽醌类米托蒽醌和洛索蒽醌;和鬼臼毒素依托泊苷和替尼泊苷。依托泊苷可以例如以其市售形式、例如以商标ETOPOPHOS施用。替尼泊苷可以例如以其市售形式、例如以商标VM26-BRISTOL施用。多柔比星可以例如以其市售形式、例如以商标ADRIBLASTIN或ADRIAMYCIN施用。表柔比星可以例如以其市售形式、例如以商标FARMORUBICIN施用。伊达比星可以例如以其市售形式、例如以商标ZAVEDOS施用。米托蒽醌可以例如以其市售形式、例如以商标NOVANTRON施用。
术语“微管活性剂”涉及微管稳定化合物、微管去稳定化合物和微管蛋白聚合抑制剂,包括但不限于紫杉烷类(taxanes),例如紫杉醇和多西他赛;长春花生物碱,例如长春花碱,尤其是硫酸长春花碱、长春花新碱,尤其是硫酸长春花新碱和长春瑞滨;淅皮海绵内酯(discodermolides);秋水仙碱;和埃坡霉素及其衍生物,例如埃坡霉素B或D或其衍生物。紫杉醇可以例如以其市售形式、例如以TAXOL施用。多西他赛可以例如以其市售形式、例如以商标TAXOTERE施用。硫酸长春花碱可以例如以其市售形式、例如以商标VINBLASTIN R.P.施用。硫酸长春花新碱可以例如以其市售形式、例如以商标FARMISTIN施用。淅皮海绵内酯可以例如如US5,010,099中所公开的那样得到。还包括WO 98/10121、美国专利6,194,181、WO 98/25929、WO 98/08849、WO 99/43653、WO 98/22461和WO 00/31247中所公开的埃坡霉素衍生物。尤其优选埃坡霉素A和/或B。
本文所用的术语“烷化剂”包括但不限于环磷酰胺、异环磷酰胺、美法仑或亚硝基脲(BCNU或Gliadel)。环磷酰胺可以例如以其市售形式、例如以商标CYCLOSTIN施用。异环磷酰胺可以例如以其市售形式、例如以商标HOLOXAN施用。
术语“组蛋白脱乙酰酶抑制剂”或“HDAC抑制剂”涉及抑制组蛋白脱乙酰酶和具有抗增殖活性的化合物。其包括WO 02/22577中公开的化合物,尤其是N-羟基-3-[4-[[(2-羟基乙基)[2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙酰胺、N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙酰胺及其可药用盐。其还尤其包括辛二酰苯胺异羟肟酸(SAHA)。
术语“抗肿瘤性抗代谢物”包括但不限于5-氟尿嘧啶或5-FU、卡培他滨、吉西他滨、DNA去甲基化化合物如5-氮杂胞苷和地西他滨、甲氨蝶呤和依达曲沙以及叶酸拮抗剂如培美曲塞。卡培他滨可以例如以其市售形式、例如以商标XELODA施用。吉西他滨可以例如以其市售形式、例如以商标GEMZAR施用。
本文所用的术语“铂化合物”包括但不限于卡铂、顺铂、顺铂和奥沙利铂。卡铂可以例如以其市售形式、例如以商标CARBOPLAT施用。奥沙利铂可以例如以其市售形式、例如以商标ELOXATIN施用。
本文所用的术语“靶向于/降低蛋白激酶或脂激酶活性或者担保磷酸酶或脂质磷酸酶活性的化合物;或者其它抗血管生成性化合物”包括但不限于蛋白酪氨酸激酶和/或丝氨酸和/或苏氨酸激酶抑制剂或者脂激酶抑制剂,例如:
a)靶向于、降低或抑制血小板衍生生长因子受体(PDGFR)活性的化合物,例如靶向于、降低或抑制PDGFR活性的化合物,尤其是抑制PDGF受体的化合物,例如N-苯基-2-嘧啶-胺衍生物,例如伊马替尼、SU101、SU6668和GFB-111;
b)靶向于、降低或抑制成纤维细胞生长因子受体(FGFR)活性的化合物;
c)靶向于、降低或抑制胰岛素样生长因子受体I(IGF-IR)活性的化合物,例如靶向于、降低或抑制IGF-IR活性的化合物,尤其是抑制IGF-I受体的激酶活性的化合物,例如WO 02/092599中公开的那些化合物;或者靶向于IGF-I受体或其生长因子的胞外域的抗体;
d)靶向于、降低或抑制Trk受体酪氨酸激酶家族活性的化合物;或肝配蛋白(ephrin)B4抑制剂;
e)靶向于、降低或抑制Axl受体酪氨酸激酶家族活性的化合物;
f)靶向于、降低或抑制Ret受体酪氨酸激酶活性的化合物;
g)靶向于、降低或抑制Kit/SCFR受体酪氨酸激酶活性的化合物;如伊马替尼;
h)靶向于、降低或抑制C-kit受体酪氨酸激酶(PDGFR家族的一部分)活性的化合物,例如靶向于、降低或抑制c-Kit受体酪氨酸激酶家族活性的化合物,尤其是抑制c-Kit受体的化合物,例如伊马替尼;
i)靶向于、降低或抑制c-Abl家族成员和它们的基因-融合产物(例如BCR-Abl激酶)和突变体活性的化合物,例如靶向于、降低或抑制c-Abl家族成员和它们的基因-融合产物活性的化合物,例如N-苯基-2-嘧啶-胺衍生物,例如伊马替尼或尼罗替尼(nilotinib)(AMN107);PD180970;AG957;NSC 680410;来自ParkeDavis的PD173955;或达沙替尼(dasatinib)(BMS-354825);
j)靶向于、降低或抑制蛋白激酶C(PKC)和丝氨酸/苏氨酸激酶Raf家族成员以及MEK、SRC、JAK、FAK、PDK1、PKB/Akt和Ras/MAPK家族成员和/或细胞周期蛋白依赖性激酶家族(CDK)成员活性的化合物,尤其是US 5,093,330中所公开的那些星孢素衍生物,例如米哚妥林;其它化合物的实例例如包括UCN-01、沙芬戈、BAY 43-9006、苔藓抑素1、哌立福辛;伊莫福新;RO 318220和RO 320432;GO 6976;Isis 3521;LY333531/LY379196;异喹啉化合物,例如WO 00/09495中所公开的那些;FTIs;PD184352或QAN697(P13K抑制剂)或AT7519(CDK抑制剂);
k)靶向于、降低或抑制蛋白酪氨酸激酶抑制剂活性的化合物,例如靶向于、降低或抑制蛋白酪氨酸激酶抑制剂活性的化合物,包括甲磺酸伊马替尼(GLEEVEC)或tyrphostin。Tyrphostin优选是低分子量(Mr<1500)化合物,或其可药用盐,尤其是选自亚苄基丙二腈类或者S-芳基苯丙二腈或双底物喹啉类化合物的化合物,更尤其是选自下组的任意化合物:Tyrphostin A23/RG-50810;AG 99;Tyrphostin AG 213;Tyrphostin AG1748;Tyrphostin AG 490;Tyrphostin B44;Tyrphostin B44(+)对映异构体;Tyrphostin AG 555;AG 494;Tyrphostin AG 556、AG957和adaphostin(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷基酯;NSC680410,adaphostin);
l)靶向于、降低或抑制受体酪氨酸激酶的表皮生长因子家族(EGFR、ErbB2、ErbB3、ErbB4,为均聚物或杂二聚物)和它们的突变体的活性的化合物,例如靶向于、降低或抑制表皮生长因子受体家族活性的化合物,尤其是抑制EGF受体酪氨酸激酶家族成员例如EGF受体、ErbB2、ErbB3和ErbB4或者与EGF或EGF相关性配体结合的化合物、蛋白质或抗体,特别是概括地和具体地在下列文献中公开的那些化合物、蛋白质或单克隆抗体:WO 97/02266,例如实施例39的化合物,或者EP 0564 409、WO 99/03854、EP 0520722、EP 0 566 226、EP 0 787 722、EP0 837 063、US 5,747,498、WO 98/10767、WO 97/30034、WO 97/49688、WO 97/38983、尤其是WO 96/30347(例如被称为CP 358774的化合物)、WO 96/33980(例如化合物ZD 1839)和WO 95/03283(例如化合物ZM105180);例如曲妥单抗(HerceptinTM)、西妥昔单抗(ErbituxTM)、Iressa、Tarceva、OSI-774、CI-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3或E7.6.3和WO 03/013541中所公开的7H-吡咯并[2,3-d]嘧啶衍生物;和
m)靶向于、降低或抑制c-Met受体活性的化合物,例如靶向于、降低或抑制c-Met活性的化合物,尤其是抑制c-Met受体的激酶活性的化合物,或者靶向于c-Met的胞外域或与HGF结合的抗体。
其它抗血管生成性化合物包括具有其它活性机理的化合物,例如与蛋白激酶或脂激酶抑制作用无关的机理,例如沙利度胺(THALOMID)和TNP-470。
靶向于、降低或抑制蛋白磷酸酶或脂质磷酸酶活性的化合物有例如磷酸酶1、磷酸酶2A或CDC25的抑制剂,例如冈田酸(okadaicacid)或其衍生物。
诱导细胞分化过程的化合物有例如视黄酸、α-、γ-或δ-生育酚或者α-、γ-或δ-生育三烯酚。
本文所用的术语“环加氧酶抑制剂”包括但不限于例如COX-2抑制剂、5-烷基取代的2-芳基氨基苯基乙酸与衍生物,例如塞来考昔(CELEBREX)、罗非考昔(VIOXX)、艾托考昔、伐地考昔或5-烷基-2-芳基氨基苯基乙酸(例如5-甲基-2-(2’-氯-6’-氟苯氨基)苯基乙酸)、芦米考昔。
本文所用的术语“双膦酸化合物”包括但不限于依替膦酸(etridonicacid)、氯膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、伊班膦酸、利塞膦酸和唑来膦酸。“依替膦酸”可以例如以其市售形式、例如以商标DIDRONEL施用。“氯膦酸”可以例如以其市售形式、例如以商标BONEFOS施用。“替鲁膦酸”可以例如以其市售形式、例如以商标SKELID施用。“帕米膦酸”可以例如以其市售形式、例如以商标AREDIATM施用。“阿仑膦酸”可以例如以其市售形式、例如以商标FOSAMAX施用。“伊班膦酸”可以例如以其市售形式、例如以商标BONDRANAT施用。“利塞膦酸”可以例如以其市售形式、例如以商标ACTONEL施用。“唑来膦酸”可以例如以其市售形式、例如以商标ZOMETA施用。
本文所用的术语“类肝素酶抑制剂”指靶向于、降低或抑制硫酸肝素降解的化合物。该术语包括但不限于PI-88。
本文所用的术语“生物应答调节剂”指淋巴因子或干扰素,例如干扰素γ。
本文所用的术语“Ras致癌同工型抑制剂”(如H-Ras、K-Ras或N-Ras)指靶向于、降低或抑制Ras的致癌活性的化合物,例如“法尼基转移酶抑制剂”,例如L-744832、DK8G557或RI 15777(Zarnestra)。
本文所用的术语“端粒酶抑制剂”指靶向于、降低或抑制端粒酶活性的化合物。靶向于、降低或抑制端粒酶活性的化合物尤其是抑制端粒酶受体的化合物,例如telomestatin(替莫美他汀)。
本文所用的术语“甲硫氨酸氨肽酶抑制剂”指靶向于、降低或抑制甲硫氨酸氨肽酶活性的化合物。靶向于、降低或抑制甲硫氨酸氨肽酶活性的化合物有例如bengamide(比格麦德)或其衍生物。
本文所用的术语“蛋白酶体抑制剂”指靶向于、降低或抑制蛋白酶体活性的化合物。靶向于、降低或抑制蛋白酶体活性的化合物包括例如Bortezomid(VelcadeTM)和MLN 341。
本文所用的术语“基质金属蛋白酶抑制剂”或(“MMP”抑制剂)包括但不限于胶原拟肽和非拟肽抑制剂、四环素衍生物,例如异羟肟酸拟肽抑制剂巴马司他和其口服可生物利用的类似物马立马司他(BB-2516)、普啉司他(AG3340)、metastat(马他司他)(NSC 683551)BMS-279251、BAY12-9566、TAA211、MMI270B或AAJ996。
本文所用的术语“用于治疗血液学恶性疾病的化合物”包括但不限于FMS-样酪氨酸激酶抑制剂,例如靶向于、降低或抑制FMS-样酪氨酸激酶受体(Flt-3R)活性的化合物;干扰素、1-b-D-阿拉伯呋喃糖基胞嘧啶(ara-c)和白消安(bisulfan);和ALK抑制剂,例如靶向于、降低或抑制间变性淋巴瘤激酶的化合物。
靶向于、降低或抑制FMS-样酪氨酸激酶受体(Flt-3R)活性的化合物尤其是抑制Flt-3R受体激酶家族成员的化合物、蛋白质或抗体,例如PKC412、米哚妥林、星孢素衍生物、SU11248和MLN518。
本文所用的术语“HSP90抑制剂”包括但不限于靶向于、降低或抑制HSP90的内源性腺苷三磷酸酶活性的化合物;经由遍在蛋白质蛋白酶体途径降解、靶向于、降低或抑制HSP90客户蛋白(client protein)的化合物。靶向于、降低或抑制HSP90的内源性腺苷三磷酸酶活性的化合物尤其是抑制HSP90的腺苷三磷酸酶活性的化合物、蛋白质或抗体,例如17-烯丙基氨基,17-去甲氧基格尔德霉素(17AAG)-格尔德霉素衍生物;其它与格尔德霉素相关的化合物;根赤壳菌素和HDAC抑制剂。
本文所用的术语“抗增殖性抗体”包括但不限于曲妥单抗(HerceptinTM)、曲妥单抗-DM1、爱比妥、贝伐单抗(AvastinTM)、利妥昔单抗、PRO64553(抗-CD40)和2C4抗体。“抗体”意指例如完整的单克隆抗体、多克隆抗体、由至少2个完整抗体形成的多特异性抗体和抗体片段,只要它们表现出所需的生物学活性即可。
术语“抗白血病化合物”包括例如嘧啶类似物Ara-C,它是脱氧胞苷的2′-α-羟基核糖(阿糖胞苷)衍生物。还包括嘌呤类似物次黄嘌呤、6-巯基嘌呤(6-MP)和磷酸氟达拉滨。
靶向于、降低或抑制组蛋白脱乙酰酶(HDAC)抑制剂活性的化合物如丁酸钠和辛二酰苯胺异羟肟酸(SAHA)抑制组蛋白脱乙酰酶的活性。具体的HDAC抑制剂包括MS275、SAHA、FK228(以前称为FR901228)、曲古抑菌素A和US 6,552,065中所公开的化合物,特别是N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺或其可药用盐和N-羟基-3-[4-[(2-羟基乙基){2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺或其可药用盐,尤其是乳酸盐。
如本文所用的促生长素抑制素受体拮抗剂指靶向于、降低或抑制促生长素抑制素受体的化合物,例如奥曲肽和SOM230。
肿瘤细胞损害手段指诸如电离放射等手段。上下文中所提及的术语“电离放射”意指以电磁射线(如X-射线和γ射线)或粒子(如α和β粒子)形式发生的电离放射。电离放射是在放射疗法中提供的,但是不限于此,并且是本领域已知的。参见Hellman,Principles of Radiation Therapy,Cancer,Principles and Practice of Oncology,Devita等人编辑,第4版,第1卷,248-275页(1993)。
本文所用的术语“EDG结合剂”指调节淋巴细胞再循环的免疫抑制剂类,如FTY720。
术语“核糖核苷酸还原酶抑制剂”指嘧啶或嘌呤核苷类似物,包括但不限于氟达拉滨和/或阿糖胞苷(ara-C);6-硫鸟嘌呤;5-氟尿嘧啶;克拉屈滨;6-巯基嘌呤(尤其是与ara-C组合用于抗ALL)和/或喷司他丁。核糖核苷酸还原酶抑制剂尤其是羟基脲或2-羟基-1H-异吲哚-1,3-二酮衍生物,例如Nandy等人,Acta Oncologica,第33卷,第8期,第953-961页(1994)中提及的PL-1、PL-2、PL-3、PL-4、PL-5、PL-6、PL-7或PL-8。
本文所用的术语“S-腺苷甲硫氨酸脱羧酶抑制剂”包括但不限于US5,461,076中公开的化合物。
还包括特别是WO98/35958中所公开的那些化合物、蛋白质或VEGF的单克隆抗体,例如1-(4-氯苯氨基)-4-(4-吡啶基甲基)酞嗪或其可药用盐,例如琥珀酸盐,或者在WO00/09495、WO00/27820、WO00/59509、WO98/11223、WO00/27819和EP0 769 947中公开的那些;如下述文献中所述的那些:Prewett等人,Cancer Res,第59卷,第5209-5218页(1999);Yuan等人,Proc Natl Acad Sci U S A,第93卷,第14765-14770页(1996);Zhu等人,Cancer Res,第58卷,第3209-3214页(1998);和Mordenti等人,Toxicol Pathol,第27卷,第1期,第14-21页(1999);WO00/37502和WO94/10202;血管抑素(ANGIOSTATIN),O’Reilly等人,Cell,第79卷,第315-328页(1994)中所述;内皮抑素(ENDOSTATIN),O’Reilly等人,Cell,第88卷,第277-285页(1997)中所述;邻氨基苯甲酸酰胺;ZD4190;ZD6474;SU5416;SU6668;见伐单抗;或抗-VEGF抗体或抗-VEGF受体抗体,如rhuMAb和RHUFab、VEGF适体如Macugon;FLT-4抑制剂、FLT-3抑制剂、VEGFR-2 IgG1抗体、Angiozyme(RPI 4610)和贝伐单抗(AvastinTM)。
如本文所用的“光动力疗法”指采用某些被称为光敏化合物来治疗或预防癌症的疗法。光动力疗法的实例包括用诸如维替泊芬(VISUDYNE)和卟吩姆钠的药物进行的治疗。
本文所用的“血管抑制性类固醇”指阻断或抑制血管发生的化合物,如阿奈可他、曲安西龙、氢化可的松、11-α-epihydrocotisol、去氧可的松、17α-羟孕酮、皮质酮、脱氧皮质酮、睾酮、雌酮和地塞米松。
含有皮质类固醇的植入物指诸如氟轻松和地塞米松的化合物。
其它化疗化合物包括但不限于植物生物碱、激素化合物和拮抗剂;生物应答调节剂、优选淋巴因子或干扰素;反义寡核苷酸或寡核苷酸衍生物;shRNA或siRNA;或混杂化合物(miscellaneous compounds)或具有其它作用机理或未知作用机理的化合物。
本发明的化合物也可用作辅助治疗化合物用于与其它药物组合使用,如抗炎药、支气管扩张药或抗组胺药,特别是用于治疗阻塞性或炎性气道疾病,例如上文所述的那些疾病,例如作为该类药物治疗活性的增效剂或者作为降低该类药物所需给药剂量或可能副作用的手段。本发明的化合物可以在固定药物组合物中与其它药物混合,或者可以在其它药物施用前、施用同时或者施用后被独立地施用。因此,本发明包括上文所述的本发明的化合物与抗炎药、支气管扩张药、抗组胺药或镇咳药的组合,所述的本发明的化合物和所述的药物在相同或不同的药物组合物中。
适宜的抗炎药物包括类固醇,特别是糖皮质激素如布地奈德、丙酸倍氯米松、丙酸氟替卡松、环索奈德或莫米松糠酸酯,或下述文献中所述的类固醇:WO02/88167、WO02/12266、WO02/100879、WO02/00679(尤其是实施例3、11、14、17、19、26、34、37、39、51、60、67、72、73、90、99和101中的那些)、WO03/035668、WO03/048181、WO03/062259、WO03/064445、WO03/072592,非类固醇类糖皮质激素受体激动剂,如下述文献中所述的那些:WO00/00531、WO02/10143、WO03/082280、WO03/082787、WO03/104195、WO04/005229;
LTB4拮抗剂,如LY293111、CGS025019C、CP-195543、SC-53228、BIIL 284、ONO 4057、SB 209247和US 5451700中所述的那些;LTD4拮抗剂,如孟鲁司特和扎鲁司特;PDE4抑制剂,如西洛司特GlaxoSmithKline)、罗氟司特(Byk Gulden)、V-11294A(Napp)、BAY19-8004(Bayer)、SCH-351591(Schering-Plough)、阿罗茶碱(AlmirallProdesfarma)、PD189659/PD168787(Parke-Davis)、AWD-12-281(AstaMedica)、CDC-801(Celgene)、SelCID(TM)CC-10004(Celgene)、VM554/UM565(Vernalis)、T-440(Tanabe)、KW-4490(Kyowa Hakko Kogyo)和下述文献中所述的那些:WO 92/19594、WO 93/19749、WO93/19750、WO 93/19751、WO 98/18796、WO 99/16766、WO 01/13953、WO 03/104204、WO 03/104205、WO 03/39544、WO 04/000814、WO04/000839、WO 04/005258、WO 04/018450、WO 04/018451、WO 04/018457、WO 04/018465、WO 04/018431、WO 04/018449、WO 04/018450、WO 04/018451、WO 04/018457、WO 04/018465、WO 04/019944、WO04/019945、WO 04/045607和WO 04/037805;A2a激动剂,如下述文献中所述的那些:EP 409 595 A2、EP 1 052 264、EP 1 241 176、WO 94/17090、WO 96/02543、WO 96/02553、WO 98/28319、WO 99/24449、WO 99/24450、WO 99/24451、WO 99/38877、WO 99/41267、WO 99/67263、WO 99/67264、WO 99/67265、WO 99/67266、WO 00/23457、WO 00/77018、WO 00/78774、WO 01/23399、WO 01/27130、WO 01/27131、WO 01/60835、WO 01/94368、WO 02/00676、WO 02/22630、WO 02/96462、WO 03/086408、WO04/039762、WO 04/039766、WO 04/045618和WO 04/046083;A2b拮抗剂,如WO02/42298中所述的那些;和β-2肾上腺素受体激动剂,如阿布叔醇(沙丁胺醇)、奥西那林、特布他林、沙美特罗、非诺特罗、丙卡特罗和尤其是福莫特罗及其可药用盐,以及WO0075114的式I化合物(游离或盐或溶剂合物形式),该文献引入本文作为参考,优选其实施例的化合物,尤其是下式化合物及其可药用盐:
以及WO04/16601的式I化合物(游离或盐或溶剂合物形式)和WO04/033412的化合物。
适宜的支气管扩张药包括抗胆碱能或抗毒蕈碱化合物,特别是异丙托溴铵、氧托溴铵、噻托铵盐和CHF 4226(Chiesi),和格隆铵,还有WO01/04118、WO 02/51841、WO 02/53564、WO 03/00840、WO 03/87094、WO 04/05285、WO 02/00652、WO 03/53966、EP 424021、US 5171744、US 3714357、WO 03/33495和WO 04/018422中所述的那些。
适宜的抗组胺药物包括盐酸西替利嗪、对乙酰氨基酚、富马酸氯马斯汀、异丙嗪、氯雷他定、地氯雷他定、苯海拉明和盐酸非索非那定、阿伐斯汀(activastine)、阿司咪唑、氮斯汀、依巴斯汀、依匹斯汀、咪唑斯汀和特芬那定(tefenadine)以及WO 03/099807、WO 04/026841和JP2004107299中所公开的那些。
本发明化合物与抗炎药的其它有用组合是与趋化因子受体拮抗剂的组合,例如CCR-1、CCR-2、CCR-3、CCR-4、CCR-5、CCR-6、CCR-7、CCR-8、CCR-9和CCR10、CXCR1、CXCR2、CXCR3、CXCR4、CXCR5、特别是CCR-5的拮抗剂,如Schering-Plough的拮抗剂SC-351125、SCH-55700和SCH-D、Takeda的拮抗剂如N-[[4-[[[6,7-二氢-2-(4-甲基苯基)-5H-苯并环庚三烯-8-基]羰基]氨基]苯基]甲基]四氢-N,N-二甲基-2H-吡喃-4-氯化铵(TAK-770)和以下文献中所述的CCR-5拮抗剂:US 6166037(特别是权利要求18和19)、WO 00/66558(特别是权利要求8)、WO 00/66559(特别是权利要求9)、WO 04/018425和WO 04/026873。
由代码号、通用名或商品名确定的活性化合物的结构可以从标准汇编“默克索引”的现行版本或者从数据库、例如国际专利(Patents International)如IMS世界出版物(IMS World Publications)中获得。
上述可以与式(I)化合物组合使用的化合物可以如现有技术、例如上文所引用的文献中所描述的那样进行制备和施用。
式(I)化合物还可以有利地用于与已知的治疗过程组合,例如激素施用或者尤其是放射的施用。
式(I)化合物可以特别用作放射致敏剂,尤其是用于治疗对放射疗法敏感性差的肿瘤。
“组合”意指一种剂量单位形式的固定组合,或者用于组合施用的成套药盒,其中式(I)化合物和组合伴侣可以在同一时间独立施用或者在一定的时间间隔内分别施用,所述时间间隔尤其允许各组合伴侣显示出合作作用,例如协同作用。
用以上组合治疗非癌性的良性脑肿瘤、尤其是NF可以是所谓的一线治疗,即治疗新诊断的疾病而先前没有使用任何化学疗法等,或者它还可以是所谓的二线治疗,即先用伊马替尼或苯并咪唑衍生物治疗后再进行的疾病治疗,这取决于疾病的严重性或阶段以及患者的综合状况等。
结果:
化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺显示出对B-Raf、c-Raf和突变型B-Raf(V600E)活性的强效抑制(IC50<0.1μM),如下表1中所示。
表1:化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺对抗Raf活性的体外效力
如上表1所示,化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺呈现出对抗野生型同工型B-Raf、野生型同工型c-Raf和突变型B-Raf(V600E)Raf激酶的强抑制活性。在MAPK途径中,Raf激酶被Ras激活,使Mek1和Mek2磷酸化和活化,继而使有丝分裂原激活激酶1和2(MAPK)活化。已知Raf激酶影响和调控细胞增殖、分化、存活、致癌性转化和细胞凋亡。已经证明B-Raf同工型是在信号传导中涉及的Raf的最具有活性的形式,在传播Ras信号传导中是关键的。
如下表2所示,化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺是VEGFR-2、c-Kit、PDGFR-β和CSF-1R的强抑制剂。
表2:化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺对酪氨酸激酶的抑制
还使用了基于细胞的分析如下测定了化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺对抗表2中所示的靶分子的活性。
用化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺处理后的HEK-KDR-93细胞中的靶调控显示了对VEGF介导的VEGFR-2磷酸化的抑制,其EC50为0.19μM,如通过ELISA测定磷酸-VEGFR的降低所测定的那样(未显示)。
用化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺处理后对Mo7e细胞中的c-Kit抑制进行了分析,显示以1.1μM的EC50抑制c-Kit磷酸化,如通过ELISA测定磷酸-c-Kit的降低所测定的那样。
用化合物1-甲基-5-[2-(5-三氟甲基-1H-咪唑-2-基)-吡啶-4-基氧基]-1H-苯并咪唑-2-基}-(4-三氟甲基-苯基)-胺处理后对MG63细胞中的PDGFR-β抑制进行了分析,显示以0.7μM的EC50抑制磷酸-PDGFR-β,如通过ELISA测定磷酸-PDGFR-β的降低所测定的那样。
ST88细胞系(NF1+/-)含有升高水平的Ras-GTP,通常用作NF1的临床前模型。Novartis内部数据表明,用RAF265处理ST88细胞导致磷酸-MEK和磷酸-ERK的水平降低,随后导致增殖的抑制。
在ST88细胞中RAF265的途径抑制和抗增殖活性
这些数据表明,RAF265具有与表达突变型B-Raf(B-RafV600E)或N-Ras(N-RasQ61R)的细胞系相似的对抗NF1缺陷肿瘤细胞系的效力。虽然这是有限的数据组,但是通过抑制Ras靶下游来治疗NF1缺陷神经纤维瘤在文献中是优先的。例如,用MEK抑制剂CI-1040处理ST88和NF90细胞(均NF1+/-)降低了磷酸-ERK的水平和抑制了增殖(Mattingly等人,2005)。
由于VEGFR-2的抑制,RAF265还具有抗血管生成活性,其还可以在治疗神经纤维瘤中提供治疗益处。为了证实RAF265体内抑制新血管的生长(即血管生成),给小鼠植入了含有过表达VEGF的中国仓鼠卵巢细胞(CHO)的,然后用RAF265的剂量范围或赋形剂对照处理小鼠(第1和4天)。在该模型中,从CHO细胞中表达的VEGF在栓中诱导了血管生成。在第5天切出栓,采用Drabkin’s试剂分析血红蛋白,作为血管生成程度的度量。
如图XX所示,VEGF-CHO细胞清楚地诱导了血管生成,因为植入了细胞的Matrigel具有比未植入VEGF-CHO细胞的Matrigel高得多的血红蛋白水平。RAF265引起血红蛋白含量呈剂量依赖性的降低,在5mg/kg时产生最大抑制。这些数据表明,RAF265具有体内抗血管生成活性,在NF1肿瘤中可以提供额外的抗肿瘤活性。
Claims (12)
1.治疗或预防神经纤维瘤病引起的病症的方法,该方法包括施用式(I)苯并咪唑衍生物或其互变异构体或立体异构体或该化合物、互变异构体或立体异构体的可药用盐:
其中:
R1各自独立地选自羟基、卤素、C1-6烷基、C1-6烷氧基、(C1-6烷基)硫基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
R2是C1-6烷基或卤代(C1-6烷基);
R3各自独立地选自卤素、C1-6烷基和C1-6烷氧基;
R4各自独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨基羰基、C1-6烷基氨基羰基、腈、环烷基、杂环烷基、杂环烷基羰基、苯基和杂芳基;
其中R1、R2、R3和R4可以任选地被一个或多个独立地选自羟基、卤素、C1-6烷基、卤代(C1-6烷基)、C1-6烷氧基和卤代(C1-6烷氧基)的取代基取代;
a是1、2、3、4或5;
b是0、1、2或3;且
c是1或2。
2.根据权利要求1的方法,其中神经纤维瘤病引起的病症选自非癌性的良性脑肿瘤、脑膜瘤、神经鞘瘤、颅咽管瘤、皮样囊肿、表皮样瘤、成血管细胞瘤、脉络丛乳头状瘤和松果体区肿瘤。
3.根据权利要求1的方法,其中神经纤维瘤病选自1型或2型神经纤维瘤病。
4.根据权利要求1的方法,其中式(I)化合物是式(II)的4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-N-[5-(4-甲基-1H-咪唑-1-基)-3-(三氟甲基)苯基]苯甲酰胺:
或者具有式(III)的式(II)化合物的互变异构体或该互变异构体的可药用盐:
其中:
R1各自独立地选自羟基、卤素、C1-6烷基、C1-6烷氧基、(C1-6烷基)硫基、(C1-6烷基)磺酰基、环烷基、杂环烷基、苯基和杂芳基;
R2是C1-6烷基或卤代(C1-6烷基);
R3各自独立地选自卤素、C1-6烷基和C1-6烷氧基;
R4各自独立地选自羟基、C1-6烷基、C1-6烷氧基、卤素、羧基、(C1-6烷氧基)羰基、氨基羰基、C1-6烷基氨基羰基、腈、环烷基、杂环烷基、杂环烷基羰基、苯基和杂芳基;
其中R1、R2、R3和R4可以任选地被一个或多个独立地选自羟基、卤素、C1-6烷基、卤代(C1-6烷基)、C1-6烷氧基和卤代(C1-6烷氧基)的取代基取代;
a是1、2、3、4或5;
5.式(I)化合物或其互变异构体或立体异构体或该化合物、互变异构体或立体异构体的可药用盐在制备用于治疗神经纤维瘤病引起的病症的药物组合物中的用途:
b是0、1、2或3;且
c是1或2。
6.根据权利要求4的用途,其中神经纤维瘤病引起的病症选自非癌性的良性脑肿瘤、脑膜瘤、神经鞘瘤、颅咽管瘤、皮样囊肿、表皮样瘤、成血管细胞瘤、脉络丛乳头状瘤和松果体区肿瘤。
7.根据权利要求4的用途,其中神经纤维瘤病选自1型或2型神经纤维瘤病。
9.根据权利要求7的用途,其中神经纤维瘤病引起的病症选自非癌性的良性脑肿瘤、脑膜瘤、神经鞘瘤、颅咽管瘤、皮样囊肿、表皮样瘤、成血管细胞瘤、脉络丛乳头状瘤和松果体区肿瘤。
10.根据权利要求7的用途,其中神经纤维瘤病选自1型或2型神经纤维瘤病。
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BR (1) | BRPI0915106A2 (zh) |
CA (1) | CA2726376A1 (zh) |
MX (1) | MX2010013683A (zh) |
RU (1) | RU2011100106A (zh) |
TW (1) | TW201004621A (zh) |
WO (1) | WO2009152288A1 (zh) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2012103165A2 (en) | 2011-01-26 | 2012-08-02 | Kolltan Pharmaceuticals, Inc. | Anti-kit antibodies and uses thereof |
NZ630363A (en) | 2012-07-25 | 2018-09-28 | Celldex Therapeutics Inc | Anti-kit antibodies and uses thereof |
JP6768639B2 (ja) | 2014-05-23 | 2020-10-21 | セルデックス セラピューティクス,インコーポレーテッド | 好酸球又はマスト細胞関連障害の治療 |
KR101880015B1 (ko) | 2017-12-08 | 2018-07-19 | 아주대학교산학협력단 | 인터페론 감마를 유효성분으로 함유하는 신경섬유육종 예방 또는 치료용 조성물 |
US11976052B2 (en) | 2019-01-11 | 2024-05-07 | Naegis Pharmaceuticals Inc. | Leukotriene synthesis inhibitors |
WO2022268158A1 (zh) * | 2021-06-23 | 2022-12-29 | 正大天晴药业集团股份有限公司 | 作为c-Met激酶抑制剂的化合物治疗I型神经纤维瘤病的用途 |
CA3233383A1 (en) * | 2021-10-08 | 2023-04-13 | Luc OTTEN | Benzimidazole derivatives for use in the treatment or prevention of a histiocytosis or a craniopharyngioma |
Family Cites Families (7)
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IL164302A0 (en) * | 2002-03-29 | 2005-12-18 | Chiron Corp | Substituted benzazoles and use thereof as raf kinase inhibitors |
TWI387592B (zh) * | 2005-08-30 | 2013-03-01 | Novartis Ag | 經取代之苯并咪唑及其作為與腫瘤形成相關激酶之抑制劑之方法 |
GB0609378D0 (en) * | 2006-05-11 | 2006-06-21 | Novartis Ag | Organic compounds |
PE20080766A1 (es) * | 2006-08-30 | 2008-06-15 | Novartis Ag | Sales de benzimidazolil piridil eteres y formulaciones que las contienen |
US20100074897A1 (en) * | 2006-12-01 | 2010-03-25 | University Of Utah Research Foundation | Methods and Compositions related to HIF-1 alpha |
JP5479337B2 (ja) * | 2007-07-30 | 2014-04-23 | アルディア バイオサイエンス,インク. | Mek阻害剤およびrafキナーゼ阻害剤の組み合わせ、ならびにその使用 |
US20110033461A1 (en) * | 2008-03-12 | 2011-02-10 | Vladimir Ratushny | Combination Therapy for the Treatment of Cancer |
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2009
- 2009-06-11 US US12/997,770 patent/US20110092546A1/en not_active Abandoned
- 2009-06-11 CA CA2726376A patent/CA2726376A1/en not_active Abandoned
- 2009-06-11 WO PCT/US2009/046971 patent/WO2009152288A1/en active Application Filing
- 2009-06-11 AU AU2009257487A patent/AU2009257487B2/en not_active Ceased
- 2009-06-11 CN CN2009801221827A patent/CN102065859B/zh not_active Expired - Fee Related
- 2009-06-11 MX MX2010013683A patent/MX2010013683A/es not_active Application Discontinuation
- 2009-06-11 RU RU2011100106/15A patent/RU2011100106A/ru not_active Application Discontinuation
- 2009-06-11 JP JP2011513674A patent/JP2011524362A/ja not_active Withdrawn
- 2009-06-11 KR KR1020117000776A patent/KR20110025827A/ko not_active Application Discontinuation
- 2009-06-11 BR BRPI0915106A patent/BRPI0915106A2/pt not_active IP Right Cessation
- 2009-06-11 EP EP09763578A patent/EP2288354A1/en not_active Ceased
- 2009-06-12 TW TW098119822A patent/TW201004621A/zh unknown
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RU2011100106A (ru) | 2012-10-27 |
US20110092546A1 (en) | 2011-04-21 |
CA2726376A1 (en) | 2009-12-17 |
CN102065859B (zh) | 2012-10-03 |
KR20110025827A (ko) | 2011-03-11 |
BRPI0915106A2 (pt) | 2016-02-10 |
AU2009257487B2 (en) | 2013-01-31 |
MX2010013683A (es) | 2011-04-26 |
AU2009257487A1 (en) | 2009-12-17 |
TW201004621A (en) | 2010-02-01 |
EP2288354A1 (en) | 2011-03-02 |
JP2011524362A (ja) | 2011-09-01 |
WO2009152288A1 (en) | 2009-12-17 |
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