CN103687597A - 用于治疗cipn的parp抑制剂 - Google Patents
用于治疗cipn的parp抑制剂 Download PDFInfo
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- CN103687597A CN103687597A CN201280028608.4A CN201280028608A CN103687597A CN 103687597 A CN103687597 A CN 103687597A CN 201280028608 A CN201280028608 A CN 201280028608A CN 103687597 A CN103687597 A CN 103687597A
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- Prior art keywords
- alkyl
- purposes
- chemotherapeutant
- compound
- carbonyl
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Abstract
本发明涉及使用聚(ADP-核糖)聚合酶(PARP)抑制剂治疗需要其的受试者中的化疗诱导的神经病变的方法。
Description
发明领域
本发明涉及聚(ADP-核糖)聚合酶(PARP)抑制剂用于治疗和/或预防化疗诱导的周围神经病变(CIPN)的用途。
发明背景
化疗诱导的周围神经病变(CIPN)是许多化学治疗剂的致残副作用。症状为感觉或感觉和运动的组合并且包括麻木、刺痛、四肢发麻、灼热、减少或改变的感觉、手足疼痛敏感性增加和/或运动无力。(Hausheer F.H.等人,Semin Oncol 2006 33:15-49)。CIPN能为急性或持续性的并导致日常工作和生活质量受损。(Postma T.J.等人,European Journal of Cancer 2005 41:1135-1139)。
CIPN与化学治疗剂如铂基试剂、长春花生物碱类和紫杉烷类有关,并且常为这些试剂的剂量限制副作用。(Hausheer F.H.等人,Semin Oncol 2006 33:15-49)。CIPN的发病率高度可变并且能依赖许多因素,包括剂量、累积剂量、化疗的持续时间、与其它化学治疗剂的联合治疗以及年龄和高危既存疾病状态的存在,例如糖尿病。(Wolf S.,等人,European Journal of Cancer 2008 44:1507-1515;Nurgalieva Z.,等人,American Journal of Therapeutics 2010 17:148-158;Hausheer F.H.等人,Semin Oncol 2006 33:15-49)。例如,卡铂标签上报道的CIPN的发病率为6%至42%,且紫杉醇标签上报道的CIPN的发病率为42%至79%。
没有用于预防CIPN或治疗已确定的CIPN的有效策略。目前,标准疗法由减少暴露于有毒物质,随后症状和支持治疗组成,例如,三环抗抑郁药、抗惊厥药、用于疼痛和其它症状的阿片类物质或NSAIDs。(Kaley, T.J.等人,British Journal of Haematology 2009 145:3-13)。因此,CIPN的发展能导致剂量改变和中断,延迟或甚至完全停止化学治疗,不利影响恶性肿瘤的治疗和患者结果。
亟需用于治疗、预防性治疗和/或减轻CIPN及其症状的有效方法。此外,亟需用于治疗、预防性治疗和/或减轻CIPN及其症状而不干扰化疗的抗肿瘤活性的有效方法。
发明简述
本发明涉及用于治疗受试者中的化疗诱导的周围神经病变的方法,其包括给予受试者有效量的式(I)化合物或其药物可接受的盐或溶剂化物:
(I)
其中
R1、R2和R3独立地选自氢、烯基、烷氧基、烷氧基羰基、烷基、炔基、氰基、卤代烷氧基、卤代烷基、卤素、羟基、羟基烷基、硝基、NRARB和(NRARB)羰基;
A为包含1或2个氮原子和任选一个硫或氧原子的非芳香族4、5、6、7或8-元环,其中所述非芳香族环被1、2或3个选自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷氧基羰基烷基、烷基、炔基、芳基、芳基烷基、环烷基、环烷基烷基、氰基、卤代烷氧基、卤代烷基、卤素、杂环、杂环烷基、杂芳基、杂芳基烷基、羟基、羟基烷基、硝基、NRCRD、(NRCRD)烷基、(NRCRD)羰基、(NRCRD)羰基烷基、(NRCRD)磺酰基和氧代的取代基任选取代;且
RA、RB、RC和RD独立地选自氢、烷基和烷基羰基。
本发明涉及用于预防性治疗受试者中的化疗诱导的周围神经病变的方法,其包括给予受试者有效量的式(I)化合物。
本发明涉及用于减轻化学治疗剂的神经毒性作用的方法,其包括给予受试者有效量的式(I)化合物。
本发明涉及用于治疗受试者中的化疗诱导的神经病变性疼痛的方法,其包括给予受试者有效量的式(I)化合物。
本发明还涉及用于治疗受试者中的化疗诱导的周围神经病变的方法,其包括给予受试者有效量的式(II)化合物或其药物可接受的盐或溶剂化物:
其中
R101、R104和R105为H;
R103为F;
R102选自吡咯烷基、噁唑基、咪唑烷基、异噻唑烷基、哌啶基、哌嗪基和氮杂环庚烷基,其中R102被一个或两个(O)取代基取代。
本发明涉及用于预防性治疗受试者中的化疗诱导的周围神经病变的方法,其包括给予受试者有效量的式(II)化合物。
本发明涉及用于减轻化学治疗剂的神经毒性作用的方法,其包括给予受试者有效量的式(II)化合物。
本发明涉及用于治疗受试者中的化疗诱导的神经病变性疼痛的方法,其包括给予受试者有效量的式(II)化合物。
附图简述
图1显示通过预防长春新碱介导的疼痛证明的2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物A)对长春新碱介导的神经病变的预防作用。
图2显示通过预防长春新碱介导的疼痛证明的6-氟-2-(2-甲基吡咯烷-2-基)-1H-苯并咪唑-4-甲酰胺(化合物B)对长春新碱介导的神经病变的预防作用。
图3显示通过减轻奥沙利铂介导的机械性触诱发痛证明的2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C)对奥沙利铂介导的神经病变的预防作用。
图4显示通过减轻奥沙利铂介导的冷触诱发痛证明的2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C)对奥沙利铂介导的神经病变的预防作用。
图5显示通过减轻顺铂介导的机械性触诱发痛证明的2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C)对顺铂介导的神经病变的预防作用。
图6显示通过减轻顺铂介导的热痛觉过敏证明的2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C)对顺铂介导的神经病变的预防作用。
图7显示通过预防长春新碱介导的疼痛证明的2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物A)对长春新碱介导的神经病变的预防作用。
图8显示通过使用2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物A)治疗来预防皮肤中长春新碱介导的PAR水平的增加。
图9显示2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C)对顺铂-诱导的指神经SNAP记录中振幅降低的预防作用。
发明详述
定义
除非本文另外定义,关于本发明使用的科学和技术术语应具有本领域一般技术人员通常理解的含义。术语的含义和范围应当清楚,然而,如果发生任何潜在的不明确,本文提供的定义优先于任何字典或外来定义。在本申请中,除非另外规定“或者”的使用是指“和/或”。此外,术语“包括”以及其它形式如“包括(includes)”和“包括(included)”的使用不受限制。在本专利申请(包括权利要求)中关于词语“包括(comprise)”或“包括(comprises)”或“包括(comprising)”的使用,申请人注意除非上下文另外规定,使用那些词语基于和清楚解释它们被理解为包含地而非排除地,并且申请人意图在解释本专利申请包括下列权利要求中那些词语中的每一个都被如此理解。对于在任何取代基中或在本发明的化合物中或本文任何其它公式中出现大于一次的变量,它在每次出现时的定义独立于它在每次其它出现时的定义。
本文使用的术语“烯基”是指含2至10个碳并且包含至少一个通过去除两个氢形成的碳-碳双键的直链或支链烃。烯基的代表性实例包括但不限于乙烯基、2-丙烯基、2-甲基-2-丙烯基、3-丁烯基、4-戊烯基、5-己烯基、2-庚烯基、2-甲基-1-庚烯基和3-癸烯基。
本文使用的术语“烷氧基”是指通过氧原子附加于母体分子部分的本文定义的烷基。烷氧基的代表性实例包括但不限于甲氧基、乙氧基、丙氧基、2-丙氧基、丁氧基、叔丁氧基、戊氧基和己氧基。
本文使用的术语“烷氧基烷基”是指通过本文定义的烷基附加于母体分子部分的至少一个本文定义的烷氧基。烷氧基烷基的代表性实例包括但不限于叔丁氧基甲基、2-乙氧基乙基、2-甲氧基乙基和甲氧基甲基。
本文使用的术语“烷氧基羰基”是指通过本文定义的羰基附加于母体分子部分的本文定义的烷氧基。烷氧基羰基的代表性实例包括但不限于甲氧基羰基、乙氧基羰基和叔丁氧基羰基。
本文使用的术语“烷氧基羰基烷基”是指通过本文定义的烷基附加于母体分子部分的本文定义的烷氧基羰基。
本文使用的术语“烷基”是指含1至10个碳原子的直链或支链烃。烷基的代表性实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正庚基、正辛基、正壬基和正癸基。
本文使用的术语“烷基羰基”是指通过本文定义的羰基附加于母体分子部分的本文定义的烷基。烷基羰基的代表性实例包括但不限于乙酰基、1-氧代丙基、2,2-二甲基-1-氧代丙基、1-氧代丁基和1-氧代戊基。
本文使用的术语“烷基羰基氧基”是指通过氧原子附加于母体分子部分的本文定义的烷基羰基。烷基羰基氧基的代表性实例包括但不限于乙酰氧基、乙基羰基氧基和叔丁基羰基氧基。
本文使用的术语“烷基硫基”是指通过硫原子附加于母体分子部分的本文定义的烷基。烷基硫基的代表性实例包括但不限于甲基硫基、乙基硫基、叔丁基硫基和己基硫基。
本文使用的术语“烷基硫基烷基”是指通过本文定义的烷基附加于母体分子部分的本文定义的烷基硫基。烷基硫基烷基的代表性实例包括但不限于甲基硫基甲基和2-(乙基硫基)乙基。
本文使用的术语“炔基”是指含2至10个碳原子并且包含至少一个碳-碳三键的直链或支链烃基。炔基的代表性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基、3-丁炔基、2-戊炔基和1-丁炔基。
本文使用的术语“芳基”是指苯基或萘基。
本发明的芳基能被一个、两个、三个、四个或五个独立地选自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷基、烷基羰基、烷基羰基氧基、烷基硫基、烷基硫基烷基、炔基、羧基、氰基、甲酰基、卤代烷氧基、卤代烷基、卤素、羟基、羟基烷基、巯基、硝基、-NRERF和(NRERF)羰基的取代基任选取代。
本文使用的术语“芳基烷基”是指通过本文定义的烷基附加于母体分子部分的本文定义的芳基。芳基烷基的代表性实例包括但不限于苄基、2-苯基乙基、3-苯基丙基、1-甲基-3-苯基丙基和2-萘-2-基乙基。
本文使用的术语“羰基”是指-C(O)-基团。
本文使用的术语“羧基”是指-CO2H基团。
本文使用的术语“氰基”是指-CN基团。
本文使用的术语“环烷基”是指含3至8个碳的饱和环烃基团,环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
本发明的环烷基被1、2、3或4个选自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷基、烷基羰基、烷基羰基氧基、烷基硫基、烷基硫基烷基、炔基、羧基、氰基、甲酰基、卤代烷氧基、卤代烷基、卤素、羟基、羟基烷基、巯基、氧代、-NRERF和(NRERF)羰基的取代基任选取代。
本文使用的术语“环烷基烷基”是指通过本文定义的烷基附加于母体分子部分的本文定义的环烷基。环烷基烷基的代表性实例包括但不限于环丙基甲基、2-环丁基乙基、环戊基甲基、环己基甲基和4-环庚基丁基。
本文使用的术语“甲酰基”是指-C(O)H基团。
本文使用的术语“卤代”或“卤素”是指-Cl、-Br、-I或-F。
本文使用的术语“卤代烷氧基”是指通过本文定义的烷氧基附加于母体分子部分的至少一个本文定义的卤素。卤代烷氧基的代表性实例包括但不限于氯甲氧基、2-氟乙氧基、三氟甲氧基和五氟乙氧基。
本文使用的术语“卤代烷基”是指通过本文定义的烷基附加于母体分子部分的至少一个本文定义的卤素。卤代烷基的代表性实例包括但不限于氯甲基、2-氟乙基、三氟甲基、五氟乙基和2-氯-3-氟戊基。
本文使用的术语“杂芳基”是指单环杂芳基环或二环杂芳基环。单环杂芳基环为5或6元环。5元环具有两个双键并且包含一个、两个、三个或四个独立地选自N、O和S的杂原子。6元环具有三个双键并且包含一个、两个、三个或四个独立地选自N、O和S的杂原子。二环杂芳基环由与苯基基团稠合的5或6元杂芳基环组成或者5或6元杂芳基环与另一5或6元杂芳基环稠合。杂芳基内包含的氮杂原子可任选被氧化为N-氧化物。杂芳基通过杂芳基内包含的任何碳原子与母体分子部分连接同时保持适当化合价。杂芳基的代表性实例包括但不限于苯并噻吩基、苯并噁二唑基、噌嗪基、氟吡啶基(furopyridinyl)、呋喃基、咪唑基、吲唑基、吲哚基、异噁唑基、异喹啉基、异噻唑基、萘啶基、噁二唑基、噁唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡唑基、吡咯基、吡啶鎓N-氧化物、喹啉基、四唑基、噻二唑基、噻唑基、噻吩并吡啶基(thienopyridinyl)、噻吩基、三唑基和三嗪基。
本发明的杂芳基被0、1、2、3或4个独立地选自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷基、烷基羰基、烷基羰基氧基、烷基硫基、烷基硫基烷基、炔基、羧基、氰基、甲酰基、卤代烷氧基、卤代烷基、卤素、羟基、羟基烷基、巯基、硝基、-NRERF和(NRERF)羰基的取代基取代。
本文使用的术语“杂芳基烷基”是指通过本文定义的烷基附加于母体分子部分的本文定义的杂芳基。杂芳基烷基的代表性实例包括但不限于吡啶基甲基。
本文使用的术语“杂环”或“杂环的”是指单环或二环杂环。单环杂环由含至少一个独立地选自O、N和S的杂原子的3、4、5、6、7或8元环组成。3或4元环包含1个选自O、N和S的杂原子。5元环包含零个或一个双键和一个、两个或三个选自O、N和S的杂原子。6或7元环包含零个、一个或两个双键和一个、两个或三个选自O、N和S的杂原子。二环杂环由与环烷基稠合的单环杂环或与苯基稠合的单环杂环或与另一单环杂环稠合的单环杂环组成。杂环通过杂环内包含的任何碳或氮原子与母体分子部分连接同时保持适当化合价。杂环的代表性实例包括但不限于氮杂环丁烷基、氮杂环庚烷基、氮杂环丙烷基、二氮杂环庚烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,3-二硫杂环戊烷基、1,3-二噻烷基、咪唑啉基、咪唑烷基、异噻唑啉基、异噻唑烷基、异噁唑啉基、异噁唑烷基、吗啉基、噁二唑啉基、噁二唑烷基(oxadiazolidinyl)、噁唑啉基、噁唑烷基、哌嗪基、哌啶基、吡唑啉基、吡唑烷基、吡咯啉基、吡咯烷基、四氢呋喃基、四氢吡喃基、四氢噻吩基、噻二唑啉基、噻二唑烷基、噻唑啉基、噻唑烷基、硫代吗啉基、1,1-二氧代硫代吗啉基(硫代吗啉砜)、硫代吡喃基和三噻烷基。
本发明的杂环被0、1、2或3个独立地选自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷基、烷基羰基、烷基羰基氧基、烷基硫基、烷基硫基烷基、炔基、羧基、氰基、甲酰基、卤代烷氧基、卤代烷基、卤素、羟基、羟基烷基、巯基、硝基、-NRERF和(NRERF)羰基的取代基取代。
本文使用的术语“杂环烷基”是指通过本文定义的烷基附加于母体分子部分的本文定义的杂环。
本文使用的术语“羟基”是指-OH基团。
本文使用的术语“羟基烷基”是指通过本文定义的烷基附加于母体分子部分的至少一个本文定义的羟基。羟基烷基的代表性实例包括但不限于羟基甲基、2-羟基乙基、3-羟基丙基、2,3-二羟基戊基和2-乙基-4-羟基庚基。
本文使用的术语“巯基”是指-SH基团。
本文使用的术语“硝基”是指-NO2基团。
本文使用的术语“非芳香族”是指包含零个双键的4元非芳香族环、包含零个或一个双键的5元非芳香族环、包含零个、一个或两个双键的6、7或8元非芳香族环。
本文使用的术语“NRARB”是指通过氮原子附加于母体分子部分的两个基团RA和RB。RA和RB各自独立地为氢、烷基和烷基羰基。NRARB的代表性实例包括但不限于氨基、甲基氨基、乙酰基氨基和乙酰基甲基氨基。
本文使用的术语“(NRARB)羰基”是指通过本文定义的羰基附加于母体分子部分的本文定义的NRARB基团。(NRARB)羰基的代表性实例包括但不限于氨基羰基、(甲基氨基)羰基、(二甲基氨基)羰基和(乙基甲基氨基)羰基。
本文使用的术语“NRCRD”是指通过氮原子附加于母体分子部分的两个基团RC和RD。RC和RD各自独立地为氢、烷基和烷基羰基。NRCRD的代表性实例包括但不限于氨基、甲基氨基、乙酰基氨基和乙酰基甲基氨基。
本文使用的术语“(NRCRD)羰基”是指通过本文定义的羰基附加于母体分子部分的本文定义的NRCRD基团。(NRCRD)羰基的代表性实例包括但不限于氨基羰基、(甲基氨基)羰基、(二甲基氨基)羰基和(乙基甲基氨基)羰基。
本文使用的术语“(NRCRD)羰基烷基”是指通过本文定义的烷基附加于母体分子部分的本文定义的(NRCRD)羰基基团。
本文使用的术语“(NRCRD)磺酰基”是指通过本文定义的磺酰基附加于母体分子部分的本文定义的NRCRD基团。(NRCRD)磺酰基的代表性实例包括但不限于氨基磺酰基、(甲基氨基)磺酰基、(二甲基氨基)磺酰基和(乙基甲基氨基)磺酰基。
本文使用的术语“NRERF”是指通过氮原子附加于母体分子部分的两个基团RE和RF。RE和RF各自独立地为氢、烷基和烷基羰基。NRERF的代表性实例包括但不限于氨基、甲基氨基、乙酰基氨基和乙酰基甲基氨基。
本文使用的术语“(NRERF)羰基”是指通过本文定义的羰基附加于母体分子部分的本文定义的NRERF基团。(NRERF)羰基的代表性实例包括但不限于氨基羰基、(甲基氨基)羰基、(二甲基氨基)羰基和(乙基甲基氨基)羰基。
本文使用的术语“氧代”是指=O部分。
术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”是指减轻或消除疾病和/或它的伴随症状的方法。
“药物可接受的”意思是载体、稀释剂或赋形剂必需与制剂的其它成分相容并且不有害于其受体。
化合物的“溶剂化物”是指溶质(化合物)和溶剂的分子复合物。
本文定义的“受试者”包括动物如哺乳动物,包括但不限于灵长类(例如,人)、牛、羊、山羊、马、狗、猫、兔、大鼠、小鼠等。在优选的实施方案中,所述受试者为人。
如本文使用的 “化学治疗剂(chemotherapeutic agent)”或“化学治疗剂(chemotherapy agent)”或“抗肿瘤剂(antineoplastic agent)”是指以药物有效量减少、预防和/或延迟转移或肿瘤的生长,或直接通过坏死或细胞凋亡杀死肿瘤细胞以减少、预防和/或延迟患有肿瘤疾病的受试者中的转移或肿瘤的生长的试剂。
“化疗”是指使用化学治疗剂、化学治疗剂(chemotherapy agents)或抗肿瘤剂治疗。
关于式(I)或(II)的化合物或组合物的“有效量”或“药物有效量”是指足以诱导受试者中期望的生物学、药理学或治疗结果的量。
“化疗诱导的周围神经病变”是由化学治疗剂直接损伤周围神经系统导致的毒性神经病变。CIPN能为急性或慢性的。CIPN能为感觉、运动、自主的,或任何三种类别的混合物。
“神经毒性作用”和“神经毒性”是指改变神经系统的正常活动的有毒物质。
“神经病变性疼痛”是由周围或中枢神经系统的功能紊乱导致的难治性疼痛。
本发明提供了治疗受试者中化疗诱导的周围神经病变的方法,其包括给予受试者治疗有效量的式(I)或(II)化合物或其药物可接受的盐或溶剂化物。
在另一方面中,本发明提供了用于预防性治疗受试者中化疗诱导的周围神经病变的方法,其包括给予受试者有效量的式(I)或(II)化合物。
在另一方面中,本发明提供了用于减轻化学治疗剂的神经毒性作用的方法,其包括给予受试者有效量的式(I)或(II)化合物。
在另一方面中,本发明提供了用于治疗受试者中化疗诱导的神经病变性疼痛的方法,其包括给予受试者有效量的式(I)或(II)化合物。
式(I)化合物是聚(ADP-核糖)聚合酶(PARP)的抑制剂并且以前描述于WO 2006-110816中。相似地,式(II)化合物是PARP抑制剂并且以前描述于WO 2008/083027中。聚(ADP-核糖)聚合酶在促进DNA修复、控制RNA转录、介导细胞死亡和调节免疫反应中具有重要作用。这些作用使PARP抑制剂靶向广泛的病症。(Virag L.等人,Pharmacol. Rev. 2002 54(3):375-429)。在各种临床前癌症模型和人临床试验中,PARP抑制剂已被证明通过增加癌症细胞的细胞凋亡、限制肿瘤生长、减少转移和延长肿瘤携带受试者的生存时间加强辐射和化疗。(WO 2007-084532;Donawho C.K.,等人,Clin Cancer Res 2007 13(9):2728-37;Kummar S.等人,J Clin Oncol. 2009 27(16):2705-11)。
在一个实施方案中,本发明提供了式(I)化合物或其药物可接受的盐或溶剂化物
(I)
其中
R1、R2和R3独立地选自氢、烯基、烷氧基、烷氧基羰基、烷基、炔基、氰基、卤代烷氧基、卤代烷基、卤素、羟基、羟基烷基、硝基、NRARB和(NRARB)羰基;
A为包含1或2个氮原子和任选一个硫或氧原子的非芳香族4、5、6、7或8-元环,其中所述非芳香族环被1、2或3个选自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷氧基羰基烷基、烷基、炔基、芳基、芳基烷基、环烷基、环烷基烷基、氰基、卤代烷氧基、卤代烷基、卤素、杂环、杂环烷基、杂芳基、杂芳基烷基、羟基、羟基烷基、硝基、NRCRD、(NRCRD)烷基、(NRCRD)羰基、(NRCRD)羰基烷基、(NRCRD)磺酰基和氧代的取代基任选取代;且
RA、RB、RC和RD独立地选自氢、烷基和烷基羰基。
n为0;R6选自氢、烯基、烷氧基烷基、烷氧基羰基、烷氧基羰基烷基、烷基、炔基、芳基、芳基烷基、环烷基、环烷基烷基、杂环、杂环烷基、杂芳基、杂芳基烷基、羟基烷基、(NRCRD)烷基、(NRCRD)羰基、(NRCRD)羰基烷基和(NRCRD)磺酰基;且RC和RD独立地选自氢和烷基。
n为0;R1、R2和R3为氢或卤素;R6选自氢、烷基、(NRCRD)磺酰基、芳基烷基、环烷基、环烷基烷基、杂环和杂芳基烷基且RC和RD独立地选自氢和烷基。
n为0;R1、R2和R3为氢或卤素;且R6为氢。
在本发明的另一实施方案中,式(I)化合物为2-(2-甲基吡咯烷-2-基)-1H-苯并咪唑-4-甲酰胺。在本发明的另一实施方案中,式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。在本发明的另一实施方案中,式(I)化合物为2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在本发明的另一实施方案中,式(I)化合物为6-氟-2-(2-甲基吡咯烷-2-基)-1H-苯并咪唑-4-甲酰胺。
本发明的另一实施方案提供了式(II)化合物或其药物可接受的盐或溶剂化物:
其中
R101、R104和R105为H;
R103为F;且
R102选自吡咯烷基、噁唑基、咪唑烷基、异噻唑烷基、哌啶基、哌嗪基和氮杂环庚烷基,其中R102被一个或两个(O)取代基取代。
在本发明的另一实施方案中,式(II)化合物为1-(2-氟-5-((4-氧代-3,4,5,6,7,8-六氢二氮杂萘-1-基)甲基)苯基)哌啶-2,6-二酮。在本发明的另一实施方案中,式(II)化合物为1-(2-氟-5-((4-氧代-3,4,5,6,7,8-六氢二氮杂萘-1-基)甲基)苯基)吡咯烷-2,5-二酮。
式(I)或(II)化合物可包含R或S构型的不对称取代的碳原子,其中术语“R”和“S”在Pure Appl. Chem.(1976) 45, 13-10中进行定义。具有不对称取代的碳原子以及等量的R和S构型的化合物在那些原子处是外消旋的。将具有一种构型比另一种过量的原子指定为过量的构型,优选过量为约85%-90%,更优选过量为约95%-99%,并且还更优选过量大于约99%。因此,本发明意思包括外消旋混合物和其化合物的相对和绝对非对映异构体。
本发明还部分涉及式(I)或(II)化合物的所有盐和它们的使用方法。化合物的盐可能由于一种或多种盐的性质而为有利的,例如,在不同温度和湿度中增强的药物稳定性或在水或其它溶剂中期望的溶解度。在意图将盐给予患者的情况下(与例如,在体外背景中使用相反),所述盐优选为药物可接受的和/或生理学相容的。在本专利申请中作形容词使用术语“药物可接受的”是指所修饰的名词适于用作药物产品或作为药物产品的一部分。药物可接受的盐包括通常用于形成碱金属盐和用于形成游离酸或游离碱的加成盐的盐。通常,通过例如使合适的酸或碱与本发明的化合物反应的常规方法制备这些盐。
能从无机酸或有机酸制备式(I)或(II)化合物的药物可接受的酸加成盐。通常,合适的无机酸的实例包括盐酸、氢溴酸、氢碘酸、硝酸、碳酸、硫酸和磷酸。合适的有机酸通常包括例如有机酸的脂肪族酸、环脂肪族酸、芳香族酸、芳脂肪族酸(araliphatic)、杂环、羧酸和磺酸类。通常,合适的有机酸的具体实例包括乙酸、三氟乙酸、甲酸、丙酸、琥珀酸、乙醇酸、葡糖酸、二葡糖酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、葡糖醛酸、马来酸、延胡索酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、邻氨基苯甲酸、甲磺酸、硬脂酸、水杨酸、对羟基苯甲酸、苯乙酸、扁桃酸、双羟萘酸(扑酸)、乙磺酸、苯磺酸、泛酸、2-羟基乙磺酸、磺胺酸、环己基氨基磺酸、海藻酸、β-羟基丁酸、粘酸、半乳糖醛酸、己二酸、海藻酸、重硫酸、丁酸、樟脑酸、樟脑磺酸、环戊烷丙酸、十二烷基硫酸、糖庚酸、甘油磷酸、庚酸、己酸、烟酸、草酸、palmoate、果胶酸、2-萘磺酸、3-苯基丙酸、苦味酸、三甲基乙酸、硫氰酸、甲苯磺酸和十一烷酸。
式(I)或(II)化合物的药物可接受的碱加成盐包括例如金属盐和有机盐。优选的金属盐包括碱金属(第Ia族)盐、碱土金属(第IIa族)盐和其它生理学可接受的金属盐。这类盐可由铝、钙、锂、镁、钾、钠和锌制成。优选的有机盐能由胺制成,所述胺例如氨丁三醇、二乙胺、N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因。能使用试剂如低级烷基(C1-C6)卤化物(例如,甲基、乙基、丙基和丁基氯化物、溴化物和碘化物)、二烷基硫酸酯(例如,二甲基、二乙基、二丁基和二戊基硫酸酯)、长链卤化物(例如,癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物)、芳基烷基卤化物(例如,苄基和苯乙基溴化物)等将碱性含氮基团季铵化。
本发明还部分涉及式(I)或(II)化合物的所有组合物和它们的使用方法。可在含有或不含有赋形剂的情况下给予具有式(I)或(II)的化合物。赋形剂包括但不限于封装剂和添加剂如吸收加速剂、抗氧化剂、粘结剂、缓冲剂、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、增量剂、填充剂、调味剂、润湿剂、润滑剂、香料、防腐剂、推进剂、释放剂、灭菌剂、甜味剂、增溶剂、湿润剂、其混合物等。
用于制备待口服给予的包含式(I)化合物的组合物的赋形剂包括但不限于琼脂、海藻酸、氢氧化铝、苄醇、苯甲酸苄酯、1,3-丁二醇、卡波姆、蓖麻油、纤维素、醋酸纤维素、胶体氧化硅、可可油、玉米淀粉、玉米油、棉籽油、交联聚维酮、甘油二酯、乙醇、乙基纤维素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明胶、胚芽油、葡萄糖、甘油、落花生油、羟基丙基甲基纤维素、异丙醇、等渗盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、微晶纤维素、甘油单酯、橄榄油、花生油、磷酸钾盐、土豆淀粉、聚维酮、丙二醇、林格氏溶液、红花油、芝麻油、羧甲基纤维素钠、磷酸钠盐、月桂基硫酸钠、山梨醇钠、大豆油、硬脂酸、硬脂酰富马酸盐、蔗糖、表面活性剂、滑石、二氧化钛、黄芪胶、四氢糠醇、甘油三酯、水、其混合物等。
以单一剂量或分开剂量形式给予人或其它哺乳动物宿主的本发明组合物的总每日剂量可为例如,0.0001至300 mg/kg体重每天且更通常1至300 mg/kg体重的量。可每天给予两次0.0001至300 mg/kg体重的剂量。
在本发明的一个实施方案中,式(I)或(II)化合物或其药物可接受的盐或溶剂化物的剂量为5 mg至400 mg、10 mg至200 mg、10 mg至100 mg或10 mg至50 mg。在本发明另外的实施方案中,式(I)或(II)化合物或其药物可接受的盐或溶剂化物的剂量为约5 mg、10 mg、20 mg、40 mg、50 mg、60 mg、80 mg或100 mg。能每天给予一次或两次所述剂量。或者,能每周给予两次所述剂量。或者,能每周给予一次所述剂量。
在一个实施方案中,化疗诱导的周围神经病变为感觉的。在一个实施方案中,神经病变以远端轴突病变的形式出现。在另一实施方案中,神经病变以触物感痛、感觉异常、灼热、麻木和/或疼痛的形式出现。
在一个实施方案中,化疗诱导的周围为运动的。在另一实施方案中,神经病变以肌萎缩形式出现。在另一实施方案中,神经病变伴随丧失远端深部腱反射出现。
在一个实施方案中,化疗诱导的周围神经病变为自主的。
在一个实施方案中,受试者具有形成化疗诱导的周围神经病变的高风险。具有形成CIPN的高风险的受试者具有先前存在的疾病状态包括糖尿病、营养不良、酒精中毒和先前暴露于神经毒性化疗。在另一实施方案中,受试者具有神经病变的病史。先前的神经病变可能由糖尿病、营养不良、酒精中毒、遗传性疾病和/或神经毒性化疗引起。
在一个实施方案中,本发明还包括给予一种或多种化学治疗剂的步骤。
一种或多种化学治疗剂可包括例如,抗代谢药(即,叶酸拮抗剂、嘌呤拮抗剂和嘧啶拮抗剂)、博来霉素、DNA烷基化试剂(即,亚硝基脲、交联剂和烷基化试剂)、激素、芳香酶抑制剂、单克隆抗体、抗生素、铂复合物、蛋白酶体抑制剂、紫杉烷类似物、长春花生物碱、拓扑异构酶抑制剂(即,蒽环类、喜树碱、鬼臼毒素)、酪氨酸激酶抑制剂或其组合。
在另一实施方案中,化学治疗剂可包括例如,铂复合物、长春花类似物、紫杉烷类似物、烷基化试剂、抗代谢药、蛋白酶体抑制剂或其组合。
铂复合物可包括例如,顺铂、奥沙利铂、依铂、洛铂、奈达铂、卡铂、沙铂、吡铂等。
长春花生物碱可包括例如,长春新碱、长春花碱、长春瑞滨、长春地辛等。
紫杉烷可包括例如,紫杉醇、多西他赛和其各种制剂和类似物。
烷基化试剂可包括例如,达卡巴嗪、甲基苄肼、替莫唑胺、噻替派、氮芥、苯丁酸氮芥、L-苯丙氨酸氮芥、美法仑、异环磷酰胺、环磷酰胺、mefosphamide、培磷酰胺、氯乙环磷酰胺、白消安、卡莫司汀、洛莫司汀、噻替派、司莫司汀等。
抗代谢药包括培美曲塞二钠、5阿扎胞苷、卡培他滨、卡莫氟、克拉屈滨、氯法拉滨、阿糖胞苷、阿糖胞苷烷磷酯、阿糖胞苷(cytosine arabinoside)、地西他滨、去铁胺、去氧氟尿苷、伊洛尼塞、依诺他滨、ethnylcytidine、氟达拉滨、单独或结合亚叶酸的5 氟尿嘧啶、吉西他滨、羟基脲、美法仑、巯基嘌呤、6 巯基嘌呤核苷、甲氨蝶呤、麦考酚酸、奈拉滨、诺拉曲塞、烷磷酯(ocfosfate)、pelitrexol、喷司他丁、雷替曲塞、利巴韦林、triapine、三甲曲沙、S-1、噻唑羧胺核苷(tiazofurin)、替加氟、TS-1、阿糖腺苷、UFT等。
蛋白酶体抑制剂可包括例如,硼替佐米。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、becatecarin、贝洛替康、伊立替康盐酸盐、喜树碱、右旋丙亚胺、二氟替康、edotecarin、表柔比星、依托泊苷、依沙替康、10-羟基喜树碱、吉马替康、勒托替康、米托蒽醌、鲁比替康(orathecin)、吡柔比星、匹杉琼、鲁比替康、索布佐生、SN-38、他氟泊苷、拓扑替康等。
在另一实施方案中,化学治疗剂为硼替佐米、卡铂、顺铂、吉西他滨、米索硝唑、奥沙利铂、甲基苄肼、沙利度胺、多西他赛、六甲蜜胺、紫杉醇、长春新碱、长春花碱或长春瑞滨。
在本发明的一个实施方案中,化学治疗剂为卡铂且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。另一实施方案还包括化学治疗剂拓扑替康。另一实施方案还包括化学治疗剂环磷酰胺。
在本发明的一个实施方案中,化学治疗剂为顺铂且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。另一实施方案还包括化学治疗剂环磷酰胺。
在本发明的一个实施方案中,化学治疗剂为奥沙利铂且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。另一实施方案还包括化学治疗剂卡培他滨。另一实施方案还包括化学治疗剂5-氟尿嘧啶和亚叶酸。
在本发明的一个实施方案中,化学治疗剂为紫杉醇且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。另一实施方案还包括化学治疗剂顺铂。另一实施方案还包括化学治疗剂多柔比星和环磷酰胺。
在本发明的一个实施方案中,化学治疗剂为多西他赛且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。另一实施方案还包括化学治疗剂多柔比星和环磷酰胺。另一实施方案还包括化学治疗剂顺铂和氟尿嘧啶。
在本发明的一个实施方案中,化学治疗剂为长春瑞滨且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。另一实施方案还包括化学治疗剂顺铂。
在本发明的一个实施方案中,化学治疗剂为卡铂和多西他赛且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在本发明的一个实施方案中,化学治疗剂为顺铂和多西他赛且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在本发明的一个实施方案中,化学治疗剂为卡铂和紫杉醇且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。另一实施方案还包括化学治疗剂贝伐单抗。
在本发明的一个实施方案中,化学治疗剂为顺铂和紫杉醇且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在本发明的一个实施方案中,化学治疗剂为卡铂和吉西他滨且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在本发明的一个实施方案中,化学治疗剂为顺铂和吉西他滨且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在本发明的一个实施方案中,化学治疗剂为顺铂和长春瑞滨且式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
在另一实施方案中,给予一种或多种化学治疗剂用于癌症的治疗。
在本发明的一个实施方案中,受治疗的癌症为听神经瘤、急性白血病、急性淋巴细胞白血病、急性髓细胞白血病(单核细胞、成髓细胞、腺癌、血管肉瘤、星形细胞瘤、髓单核细胞和早幼粒细胞)、急性t-细胞白血病、基底细胞癌、胆管癌、膀胱癌、脑癌、乳腺癌、支气管癌、子宫颈癌、软骨肉瘤、脊索癌、绒毛膜癌、慢性白血病、慢性淋巴细胞白血病、慢性髓细胞(粒细胞)白血病、慢性髓细胞性白血病、结肠癌、结直肠癌、颅咽管瘤、囊腺癌、弥漫大B-细胞淋巴瘤、异常增殖(dysproliferative)变化(发育不良和化生)、胚胎癌、子宫内膜癌、内皮肉瘤、室管膜瘤、上皮癌、红白血病、食管癌、雌激素受体阳性乳腺癌、原发性血小板增多症、尤文氏瘤、纤维肉瘤、滤泡性淋巴瘤、生殖细胞睾丸癌、神经胶质瘤、重链病、成血管细胞瘤、肝细胞瘤、肝细胞癌、激素不敏感前列腺癌、平滑肌肉瘤、脂肪肉瘤、肺癌、淋巴管内皮肉瘤(lymphagioendotheliosarcoma)、淋巴管肉瘤、成淋巴细胞白血病、淋巴瘤(霍奇金和非霍奇金),膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增殖性病症、T-细胞或B-细胞源的淋巴恶性肿瘤、白血病、淋巴瘤、髓样癌、成神经管细胞瘤、黑素瘤、脑膜瘤、间皮瘤、多发性骨髓瘤、髓细胞性白血病、骨髓瘤、粘液肉瘤、成神经细胞瘤、非小细胞肺癌、少突神经胶质瘤、口腔癌、骨源性肉瘤、卵巢癌、胰腺癌、乳头状腺癌、乳头状癌、松果体瘤、真性红细胞增多症、前列腺癌、直肠癌、肾细胞癌、视网膜母细胞瘤、横纹肌肉瘤、肉瘤、皮脂腺癌、精原细胞瘤、皮肤癌、小细胞肺癌、实体瘤(癌和肉瘤)、小细胞肺癌、胃癌、鳞状细胞癌、滑膜瘤、汗腺瘤、甲状腺癌、瓦尔登斯特伦巨球蛋白血症、睾丸肿瘤、子宫癌和维尔姆斯瘤。
在本发明的另一实施方案中,受治疗的癌症选自卵巢癌、子宫颈癌、结直肠癌、前列腺癌、乳腺癌、胃腺癌、头颈癌、睾丸癌、白血病、成神经细胞瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤和非小细胞肺癌。
式(I)或(II)化合物或其药物可接受的盐或溶剂化物及其组合物和制剂的给药可在一种或多种化学治疗剂的给药之前、之前立即、期间、随后立即或随后。可在CIPN建立之前预防性或用于治疗已建立的CIPN给予式(I)或(II)化合物。已建立的CIPN能为急性或慢性的。
能以1、2、3、4、5、6、7或8的周期以20 mg/m2至140 mg/m2的范围给予顺铂。例如,能以20 mg/m2每天给予顺铂达五天每周期。能以75 mg/m2至100 mg/m2每周期给予一次顺铂,所述周期为每四周(1天)。能以50 mg/m2至70 mg/m2每周期给予一次顺铂,所述周期为每三至四周(1天)。
能以约300 mg/m2或更少或以约360 mg/m2或更少每周期给予一次卡铂,所述周期为每三至四周(1天)。能以1、2、3、4、5、6、7或8的周期给予卡铂。
能以约85 mg/m2或更少每周期给予一次奥沙利铂,所述周期为每2周。能以1、2、3、4、5、6、7或8的周期给予奥沙利铂。
能以1、2、3、4、5、6、7或8的周期以约60 mg/m2至约100 mg/m2给予多西他赛。例如,能以75 mg/m2每周期给予一次多西他赛,所述周期为每三周(1天)。
能以1、2、3、4、5、6、7或8的周期以约100 mg/m2至约175 mg/m2的范围给予紫杉醇。能以约100 mg/m2每周期给予一次紫杉醇,所述周期为每三周(1天)。能以约135 mg/m2每周期给予一次紫杉醇,所述周期为每三周(1天)。能以约175 mg/m2每周期给予一次紫杉醇,所述周期为每三周(1天)。
能以约0.4 mg/m2至1.4 mg/m2每周期给予一次长春新碱,所述周期为每一至四周(1天)。能以1、2、3、4、5、6、7或8的周期给予长春新碱。
能以约3.7 mg/m2至约18.5 mg/m2每周期给予一次长春花碱,所述周期为每一至四周(1天)。例如,能以3.7 mg/m2、5.5 mg/m2、 7.4 mg/m2、9.25 mg/m2或11.1 mg/m2给予长春花碱。能以1、2、3、4、5、6、7或8的周期给予长春花碱。
能以约25 mg/m2至约120 mg/m2的范围每周期给予一次长春瑞滨,所述周期为每一至六周(1天)。例如,能以30 mg/m2给予长春瑞滨。能以1、2、3、4、5、6、7或8的周期给予长春瑞滨。
在一个实施方案中,在治疗周期过程中每天给予一次式(I)或(II)化合物及其组合物和制剂,其中在周期的第1天给予一种或多种化学治疗剂,其中周期为5天、1周、2周、3周、4周、5周或6周。
在一个实施方案中,在治疗周期过程中每天给予两次式(I)或(II)化合物及其组合物和制剂,其中在周期的第1天给予一种或多种化学治疗剂,其中周期为5天、1周、2周、3周、4周、5周或6周。
在一个实施方案中,在治疗周期过程中每周给予两次式(I)或(II)化合物及其组合物和制剂,其中在周期的第1天给予一种或多种化学治疗剂,其中周期为5天、1周、2周、3周、4周、5周或6周。
在一个实施方案中,在治疗周期过程中每周给予一次式(I)或(II)化合物及其组合物和制剂,其中在周期的第1天给予一种或多种化学治疗剂,其中周期为5天、1周、2周、3周、4周、5周或6周。
在一个实施方案中,在治疗周期过程中每周给予一次式(I)或(II)化合物及其组合物和制剂,其中在周期的第1天给予一种或多种化学治疗剂,其中周期为5天、1周、2周、3周、4周、5周或6周。
在另一实施方案中,在化疗之前至少一天给予式(I)或(II)化合物及其组合物和制剂。在另一实施方案中,在化疗之前两天给予式(I)或(II)化合物及其组合物和制剂。在另一实施方案中,在化疗之前一周给予式(I)化合物及其组合物和制剂。在另一实施方案中,在每次化疗治疗之前立即给予式(I)或(II)化合物及其组合物和制剂。在另一实施方案中,在每次化疗治疗同时给予式(I)或(II)化合物及其组合物和制剂。在另一实施方案中,在化疗之后给予式(I)或(II)化合物及其组合物和制剂。
本发明还允许给予更高剂量的化疗。此外,本发明允许给予另外的化疗周期。本发明还允许减少化疗周期之间的时间。
以等级即,0、1、2、3或4反映CIPN发病率的严重程度。尺度从等级0,正常和无症状,逐步升至等级4,致残和/或威胁生命。(Postma T.J.,Annals of Oncology 1998 9:739-744)。等级3需要纠正措施,包括剂量减少和/或延迟。
有用于临床实践以评价CIPN严重程度的多个常见毒性标准(CTC)尺度:世界健康组织(WHO)尺度、东方协作肿瘤组织(ECOG)尺度、国家癌症研究所 – 常见毒性标准(NCI-CTC)和Ajani尺度。(Cavaletti G.,等人,European Journal of Cancer 2010 46:479-494)。尺度代表CIPN作用的客观评价和患者感觉的结合。
本发明的一个实施方案提供了使用式(I)化合物治疗,包括预防治疗化疗诱导的周围神经病变的方法,其中等级3或4 CIPN的发病率降低。在另一实施方案中,等级1或2 CIPN的发病率降低。在另一实施方案中,等级3或4 CIPN的发病率降低至等级1或2 CIPN。在另一实施方案中,等级2 CIPN的发病率降低至等级1。
本发明还提供了用于减轻化学治疗剂的神经毒性作用的方法,其中等级3或4 CIPN的发病率降低。在另一实施方案中,等级1或2 CIPN的发病率降低。在另一实施方案中,等级3或4 CIPN的发病率降低至等级1或2 CIPN。在另一实施方案中,等级2 CIPN的发病率降低至等级1。
或者,能使用生命质量评价来评估CIPN。一种这样的评价为欧洲癌症研究和治疗组织(EORTC) QLQ-CIPN20问卷。(Cavaletti G.,等人,European Journal of Cancer 2010 46:479-494)。
在本发明的一个实施方案中,CIPN在EORTC QLQ-CIPN 20问卷上改善。
本发明的一个实施方案提供了使用式(I)或(II)化合物治疗化疗诱导的神经病变性疼痛的方法。神经病变性疼痛是由周围或中枢神经系统的功能紊乱导致的难治性疼痛。
能使用生命质量评价来评估疼痛。一种这样的评价为欧洲癌症研究和治疗组织(EORTC) EORTC QLQ-C30/L13 问卷。
在本发明的一个实施方案中,基于EORTC QLQ-C30/L13 问卷的评价疼痛减少。
在本发明的一个实施方案中,疼痛为周围神经病变性疼痛或中枢神经病变性疼痛。
在本发明的另一实施方案中,疼痛为慢性或急性的。
在本发明的另一实施方案中,减少疼痛的支持性护理的使用。支持性护理包括例如,NSAIDS或阿片类物质。
本文引用的所有参考文献,包括公开、专利申请和专利以相同程度通过引用并入,如同各个参考文献单独地和特别地指出通过引用并入并且在本文以其整体内容阐述。
术语“一个(a)”和“一个(an)”和“该(the)”以及描述本发明(特别是在下列权利要求的上下文中)的上下文中的相似指代物的使用被解释为包括单数和复数二者,除非本文另外规定或通过上下文明确否定。术语“包括(comprising)”、“具有(having)”、“包括(including)”和“包含(containing)”被解释为开放式术语(即,意思是“包括但不限于”),除非另外规定。本文值的范围的表述仅意图充当单独提及属于所述范围的各个单独值的速记方法,除非本文另外规定,并且各个单独值被并入本说明书如同本文单独引用它。能以任何适当的顺序进行本文描述的所有方法,除非本文另外规定或通过上下文另外明确否定。本文提供的任何和所有实施例或示例性语言(例如,“例如”)的使用仅意图更好地阐明本发明并且不形成对本发明范围的限制,除非另外规定。说明书中没有文字应被解释为规定任何未要求保护的元素作为实施本发明必需的。
本发明的优选实施方案,包括用于进行本发明的发明人已知的最佳方式在本文进行描述。在阅读前述描述后,那些优选实施方案的变化对于本领域一般技术人员而言可能变得显而易见。发明人期望技术人员适当使用这样的变化,并且发明人意图以与本文具体描述不同的形式实施本发明。因此,如由适用的法律允许的,本发明包括在此附加的权利要求中列举的主旨的所有修改和等效物。此外,本发明包括在其所有可能的变化中上述元素的任何组合,除非本文另外规定或通过上下文另外明确否定。
实施例
实施例1
在开始长春新碱之前,以25 mg/kg/天或50 mg/kg/天(i.p.)的剂量给予大鼠PARP抑制剂2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物A)或6-氟-2-(2-甲基吡咯烷-2-基)-1H-苯并咪唑-4-甲酰胺(化合物B)时间为两天。在两天后或用PARP抑制剂预给药后,将两个微型泵植入大鼠。通过皮下微渗透泵给予长春新碱,所述泵递送30 ug/kg/天(i.v)时间为十二天。通过皮下微渗透泵给予PARP抑制剂化合物A或化合物B或媒介物,所述泵递送25 mg/kg/天、50 mg/kg/天或媒介物(i.p.),时间为十二天。接受长春新碱的阳性对照组的大鼠在试验的每一天快速给予吗啡(6 mg/kg,i.p.)。阴性对照组的大鼠接受盐水。对于化合物A在开始长春新碱给药后的第5、9和12天(分别为化合物递送的第7、11和14天),并且对于化合物B在开始长春新碱给药后的第3、6和10天(分别为化合物递送的第5、8和12天)使用von Frey单丝测定所有大鼠的机械阈值。与原始组相比,在使用长春新碱治疗的大鼠中,在所有试验日观察到机械性触诱发痛。在所有试验日吗啡完全逆转机械性触诱发痛。在化疗诱导的疼痛的长春新碱模型中,PARP抑制剂化合物A或化合物B减弱机械性触诱发痛的发展(图1和图2)。
实施例2
在开始顺铂之前,以25 mg/kg/天或50 mg/kg/天(i.p.)的剂量给予小鼠PARP抑制剂2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C),时间为两天。在奥沙利铂给药之前给予(i.p.) 50 mg/kg剂量的化合物C时间为两天。在用PARP抑制剂预给药的两天后,共同给予小鼠化合物C与顺铂或奥沙利铂时间为5天(每天注射,i.p.),随后5天停止,随后5天每天注射(i.p.)。顺铂的累积剂量为23 mg/kg。奥沙利铂的累积剂量为30 mg/kg。在给药之前,然后在第3、6和8周在所有组的小鼠上进行行为检验。行为检验包括使用von Frey单丝测定机械阈值、测定从辐射热源的缩爪的潜伏期和从冷板抬爪的次数。在第3、6和8周在顺铂模型中并在第3和6周在奥沙利铂模型中化合物C减弱机械性触诱发痛的发展(图3和图4)。在第3和6周,在顺铂模型中化合物C减弱热痛觉过敏的发展。在第6周,在奥沙利铂模型中化合物C减弱冷痛觉过敏的发展(图5和图6)。
实施例3
在开始长春新碱之前,以25 mg/kg/天或50 mg/kg/天(i.p., bid)的剂量给予大鼠PARP抑制剂2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物A)时间为两天。在两天后或用ABT-888预给药后,将两个微型泵植入大鼠。通过皮下微渗透泵给予长春新碱,所述泵递送30 ug/kg/天(i.v)时间为十二天。通过皮下微渗透泵给予化合物A或媒介物,所述泵递送25 mg/kg/天或50 mg/kg/天(i.p.)时间为十二天。接受长春新碱的阳性对照组的大鼠在试验的每一天快速给予吗啡(6 mg/kg,i.p.)。阴性对照组的大鼠接受盐水。在开始长春新碱给药后的第5、9和12天(分别为化合物递送的第7、11和14天)使用von Frey单丝测定所有大鼠的机械阈值。与原始组相比,在使用长春新碱治疗的大鼠中,在所有试验日观察到机械性触诱发痛。在所有试验日吗啡完全逆转机械性触诱发痛。在化疗诱导的疼痛的长春新碱模型中化合物A减弱机械性触诱发痛的发展(图7)。
实施例4
在实施例3中第12天的行为试验之后,从原始、长春新碱和长春新碱 + 化合物A组(n=5 每组)中的大鼠的无毛后爪皮肤进行皮肤活组织检查。如前面描述的(Liu等人,2008),使用ab ELISA检验评价PAR水平以检测pADPr。与盐水组相比,长春新碱增加了皮肤中的PAR水平。使用化合物A预治疗(25 mg/kg和50 mg/kg)显著减少大鼠无毛皮肤中长春新碱介导的PAR激活(图8)。
实施例5
在开始顺铂之前,以25 mg/kg/天或50 mg/kg/天(i.p.,bid)的剂量给予小鼠PARP抑制剂2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C),时间为两天。在两天后或用化合物C预给药后,共同给予小鼠PARP抑制剂(25 mg/kg/天或50 mg/kg/天)和顺铂(2.3 mg/kg/天,i.p.)。给药方案由5天每天共同注射,随后5天停止,然后重复5天每天共同注射组成。在第3周中最后注射之后进行神经传导研究。从指神经形成感觉神经动作电位(SNAP)记录。顺铂导致来自指神经的SNAP记录的振幅减小,通过2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺(化合物C)治疗预防的结果(图9)。
Claims (23)
1. 式(I)化合物或其药物可接受的盐或溶剂化物在制备用于治疗受试者中的化疗诱导的周围神经病变的方法的药物中的用途
(I),
其中
R1、R2和R3独立地选自氢、烯基、烷氧基、烷氧基羰基、烷基、炔基、氰基、卤代烷氧基、卤代烷基、卤素、羟基、羟基烷基、硝基、NRARB和(NRARB)羰基;
A为包含1或2个氮原子和任选一个硫或氧原子的非芳香族4、5、6、7或8-元环,其中所述非芳香族环被1、2或3个选自烯基、烷氧基、烷氧基烷基、烷氧基羰基、烷氧基羰基烷基、烷基、炔基、芳基、芳基烷基、环烷基、环烷基烷基、氰基、卤代烷氧基、卤代烷基、卤素、杂环、杂环烷基、杂芳基、杂芳基烷基、羟基、羟基烷基、硝基、NRCRD、(NRCRD)烷基、(NRCRD)羰基、(NRCRD)羰基烷基、(NRCRD)磺酰基和氧代的取代基任选取代;且
RA、RB、RC和RD独立地选自氢、烷基和烷基羰基。
2. 如权利要求1所述的用途,其中所述治疗为预防性治疗。
4. 如权利要求1-3中任一项所述的用途,其中R1、R2和R3独立地为氢或卤素;
R6为氢;且
n为0。
5. 如权利要求1-4中任一项所述的用途,其中式(I)化合物为2-(2-甲基吡咯烷-2-基)-1H-苯并咪唑-4-甲酰胺。
6. 如权利要求1-4中任一项所述的用途,其中式(I)化合物为2-[(2R)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
7. 如权利要求1-4中任一项所述的用途,其中式(I)化合物为2-[(2S)-2-甲基吡咯烷-2-基]-1H-苯并咪唑-4-甲酰胺。
8. 如权利要求1-7中任一项所述的用途,其中所述治疗还包括一种或多种化学治疗剂的给药。
9. 如权利要求8所述的方法,其中所述一种或多种化学治疗剂用于癌症的治疗。
10. 如权利要求8或9所述的用途,其中所述化学治疗剂选自硼替佐米、卡铂、顺铂、吉西他滨、米索硝唑、奥沙利铂、甲基苄肼、沙利度胺、多西他赛、六甲蜜胺、紫杉醇、长春新碱、长春花碱或长春瑞滨。
11. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为卡铂。
12. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为顺铂。
13. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为紫杉醇。
14. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为长春瑞滨。
15. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为顺铂和多西他赛。
16. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为卡铂和多西他赛。
17. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为顺铂和吉西他滨。
18. 如权利要求8-10中任一项所述的用途,其中所述化学治疗剂为卡铂和吉西他滨。
19. 如权利要求8-18中任一项所述的用途,其中所述癌症选自卵巢癌、子宫颈癌、结直肠癌、前列腺癌、乳腺癌、睾丸癌、白血病、成神经细胞瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤和非小细胞肺癌。
20. 如权利要求8-18中任一项所述的用途,其中所述癌症选自卵巢癌、乳腺癌和非小细胞肺癌。
21. 如权利要求8-20中任一项所述的用途,其中在所述化学治疗剂的给药之前给予式(I)化合物。
22. 如权利要求8-20中任一项所述的用途,其中在所述化学治疗剂的给药期间给予式(I)化合物。
23. 如权利要求8-20中任一项所述的用途,其中在所述化学治疗剂的给药之后给予式(I)化合物。
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US20140287021A1 (en) * | 2013-03-21 | 2014-09-25 | Panacea Pharmaceuticals | Treatment of chemotherapy-induced peripheral neuropathy |
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