CN102892770A - 酪氨酸激酶三甲氧苯基抑制剂 - Google Patents
酪氨酸激酶三甲氧苯基抑制剂 Download PDFInfo
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Abstract
本发明涉及新的酪氨酸激酶三甲氧苯基抑制剂,其药物组合物,以及其使用方法。
Description
本申请要求2010年2月24日提交的美国临时申请61/307,742号的优先权,其公开的内容在此以引用的方式并入,视同其整体写入本发明。
本文公开了新的三甲氧苯基化合物和组合物及它们作为药物用于治疗疾病的应用。也提供了在受试者中抑制酪氨酸激酶活性的方法用于治疗疾病如类风湿关节炎、特发性血小板减少性紫癜、实体瘤、B细胞淋巴瘤、T细胞淋巴瘤、血管球性肾炎、溶血性贫血、急性髓细胞性白血病、结直肠癌、非小细胞肺癌、头颈癌、肝癌、肾癌、嗜铬细胞瘤、甲状腺癌、肝细胞癌、和肾细胞癌。
福他替尼(Fostamatinib)(NSC-745942、R-788、R-935788、Tamatinibfosdium、CAS# 901119-35-5)即6-[[5-氟-2-[(3,4,5-三甲氧苯基)氨基]-4-嘧啶基]氨基]-2,2-二甲基-4-[(磷酰氧基)甲基]-2H-吡啶并[3,2-b]-1,4-噁嗪-3(4H)-酮是酪氨酸激酶抑制剂R-406(CAS# 841290-80-0)即6-[[5-氟-2-[(3,4,5-三甲氧苯基)胺基]-4-嘧啶基]氨基]-2,2-二甲基-2H-吡啶并[3,2-b]-1,4-噁嗪-3(4H)-酮的前药。目前正在研究将福他替尼用于治疗类风湿关节炎、特发性血小板减少性紫癜、实体瘤、B细胞淋巴瘤、T细胞淋巴瘤、血管球性肾炎、溶血性贫血、急性髓细胞性白血病、结直肠癌、非小细胞肺癌、头颈癌、肝癌、肾癌、嗜铬细胞瘤、甲状腺癌、肝细胞癌、和肾细胞癌。WO 2005/012294;WO 2008/064274;WO2006/078846;Weinblatt等,Arthritis Rheum.,2008,58(11),3309-3318;Cha等,J.Pharmacol.Exp.Ther.,2006,317(2),57l-578;;Bajhat等,Arthritis &Rheumatism,2008,58(5),1433-1444;以及Brasselmann等,J.Pharmacol.Exp.Ther.,2006,319(3),998-1008。福他替尼也显示出了用于治疗淋巴癌、过敏反应、类过敏反应、花粉热、过敏性结膜炎、过敏性鼻炎、过敏性哮喘、过敏性皮炎、湿疹、荨麻疹、粘膜疾病、结缔组织病、骨性关节炎、炎症性肠病、溃疡性结肠炎、克罗恩病、特发性炎症性肠道疾病、肠易激综合征、结肠痉挛、浅层疤痕、硬皮病、纤维化、瘢痕、手术后疤痕、肺纤维化、血管痉挛、偏头痛、再灌注损伤、后心肌梗死、干燥复征或综合征、肺部肌肉改变或重塑、慢性阻塞性肺病、桥本甲状腺炎、自身免疫性溶血性贫血、自身免疫性恶性贫血萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、Goodpasture症、自身免疫性血小板减少症、交感性眼炎、重症肌无力、甲亢病、原发性胆汁性肝硬化、慢性侵袭性肝炎、溃疡性结肠炎和膜性肾病、系统性红斑狼疮、口眼干燥综合征、Reiter综合征、多发性肌炎-皮肌炎、系统性硬皮病、结节性多动脉炎、多发性硬化症、大疱性类天疱疮、自身免疫性脱发、I型糖尿病、和甲状腺炎的前景。WO 2005/012294;WO 2008/064274;和WO 2006/078846。
福他替尼由磷酸酶快速转变成R406,并且口服施用后仅在人血浆中观察到少量福他替尼,而R-406为血浆中观察到的主要药物相关化合物。Sweeny等,Drug Metab.Disp.,2010,38(7),1166-1176。R406在对甲氧基处经历肝细胞色素P450s氧化去甲氧基化以及与葡萄糖醛酸或无机硫酸盐缀合。Sweeny等,Drug Metab.Disp.,2010,38(7),1166-1176和Sweeny等,Xenobiotica,2010,40(6),415-423。3,5-苯二醇代谢物从粪便中分离并且认为因肠道中厌氧细菌去甲基化和去羟基化作用而产生。Sweeny等,Drug Metab.Disp.,2010,38(7),1166-1176和Sweeny等,Xenobiotica,2010,40(6),415-423。与福他替尼有关的副作用包括肠胃不适、腹泻、血压升高、中性粒细胞减少、转氨酶升高、和感染增加。
氘动力学同位素效应
为清除外来物质如治疗药剂,动物体表达多种酶,如细胞色素P450酶(CYP)、酯酶、蛋白酶、还原酶、脱氢酶、和单胺氧化酶,以与这些外来物质反应并将其转化为更有极性的中间体或代谢物以便肾脏排泄。这类代谢反应经常包括将碳-氢(C-H)键氧化成碳-氧(C-O)或碳-碳(C-C)π-键。得到的代谢物在生理条件下可以是稳定或不稳定的,并可能相对母体化合物具有显著不同的药代动力学、药效学以及急性和长期毒性特性。对于大多数药物,此类氧化一般是迅速的并且最终导致施用多次或高的每日剂量。
活化能和反应速率之间的关系可以由Arrhenius方程,k=Ae-Eact/RT量化。Arrhenius方程说明,在给定的温度,化学反应的速率以指数方式取决于活化能(Eact)。
反应中的过渡态是在反应途径中的短寿状态,在此期间初始键延伸至其极限。根据定义,某反应的活化能Eact是达到该反应的过渡态所需要的能量。一旦达到过渡态,分子可以恢复到初始反应物,或形成新键,从而生成反应产物。催化剂通过降低产生过渡态的活化能来促进反应过程。酶是生物催化剂的例子。
碳-氢键强度完全与键的基态振荡能的绝对值成正比。这种振荡能取决于形成键的原子的质量,并随形成键的一个或两个原子的质量增加而增加。由于氘(D)具有氕(1H)两倍的质量,故而C-D键比相应的C-1H键更强。如果C-1H键在化学反应中的速率决定步骤(即,具有最高过渡态能量的步骤)期间破坏,则氘代替氕会引起反应速率的降低。这种现象称为氘动力学同位素效应(DKIE)。DKIE的幅度可以表述为其中C-1H键遭破坏的给定反应的速率和其中氘代替氕的相同反应的速率之间的比值。DKIE范围可以从约1(无同位素效应)到非常大的数字,如50或更大。以氚代替氢得到甚至比氘更强的键,并产生数值更大的同位素效应。
氘(2H或D)是氢的稳定非放射性同位素,其具有约两倍于氕(1H)(氢最常见同位素)的质量。氧化氘(D2O或“重水”)看起来和尝起来像H2O,但具有不同的物理学特性。
将纯D2O给予啮齿动物时,它轻易地被吸收。引起毒性所需的氘量是非常高的。当约0-15%的身体水被D2O替代时,动物是健康的但不能像对照(未处理)组一样快地增长体重。当约15-20%的身体水被D2O替代时,动物变得容易兴奋。当约20-25%的身体水被D2O替代时,动物变得如此容易兴奋,以至于受刺激时发生频繁抽搐。出现皮肤损伤、爪和口鼻部上溃疡以及尾部坏死。动物也变得非常有攻击性。当约30%的身体水被D2O替代时,动物拒绝进食并变得昏睡。它们的体重剧烈下降,而其代谢速率降到远低于正常,同时在约30%到约35%的D2O替代死亡发生。这些影响是可逆的,除非超过百分之三十的先前体重已因D2O失去。研究也显示使用D2O可以延迟癌细胞的生长并增强特定抗肿瘤药的细胞毒性。
将药物氘化以改善药代动力学(PK)、药效学(PD)和毒性特性先前已经用某些类别的药物证明过。例如,使用DKIE来降低氟烷的肝毒性,这推测是通过限制反应性物质(如三氟乙酰氯)的产生来实现。然而,这种方法可能不适用于所有药物类别。例如,引入氘可能导致代谢改变。当被第一相酶螯合的外来反应物在化学反应(如氧化)之前,以各种不同构象短暂结合或再结合时,代谢改变发生。代谢改变由许多第一相酶中相对大尺寸的结合袋以及许多代谢反应的复杂性质引起。代谢改变可能导致不同比例的已知代谢物和同时产生的新代谢物。这种新的代谢特性可能引起或多或少的毒性。这样的缺陷是不明显并且对于任何药物类别不是可预见的先验。
福他替尼是酪氨酸激酶抑制剂。福他替尼的碳-氢键包括氢同位素的天然存在分布,即1H或氕(约99.9844%),2H或氘(约0.0156%),3H或氚(范围在每1018氕原子约0.5个和67个氚原子之间)。增加的氘引入水平可能产生可检测的氘动力学同位素效应(DKIE),与具有天然存在氘水平的化合物相比,其可能影响福他替尼的药代动力学,药效学和/或毒性特性。
基于我们实验室中做出的发现,并考虑文献,福他替尼在人中可能在O-甲基和孪位环甲基上代谢。目前的方法具有防止在这些位点上代谢的潜力。该分子上的其他位点也可能经历变换,从而导致具有尚且未知的药理学/毒理学性质的代谢物。限制这些代谢物的产生具有降低施用此类药物的危险的潜力,并甚至可以允许剂量增加和/或增加的疗效。所有这些变换可能因多态性表达的酶而发生,从而加剧患者间变异。此外,某些疾病在受试者全天或长时间用药时得到最好治疗。由于所有上述原因,半衰期较长的药物可能产生更大的疗效和费用节约。各种氘化模式可以用来(a)减少或消除有害的代谢物;(b)增加母药的半衰期;(c)降低达到想要效果所需的给药次数;(d)降低达到想要效果所需的给药量;(e)如果任何活性代谢物形成,则增加其形成;(f)降低特定组织中有害代谢物的产生,和/或(g)产生更有效的药物和/或更安全的药物以多重用药,无论多重用药是否是有意的。氘化方法具有强潜力来减慢福他替尼代谢病并且可减少患者间差异。
已经发现了新的化合物和药物组合物,已发现其中某些抑制酪氨酸激酶,以及合成和使用这些化合物的方法,包括在患者中通过施用这些化合物来治疗酪氨酸激酶介导的疾病的方法。
在本发明的某些实施方式中,化合物具有结构式I:
或是其盐,其中
R1-R3独立的选自由氢、氘、-CH3、-CH2D、-CD2H、和-CD3组成的组;
R4-R5独立的选自由-CH3、-CH2D、-CD2H、和-CD3组成的组;
R6-R12和R14-R15独立的选自由氢、氘组成的组;
R13选自由氢、氘、和
组成的组;以及
R1-R15至少之一为氘或含有氘。
本文公开的某些化合物可能具备有用的酪氨酸激酶抑制活性,并可以用于治疗或预防其中酪氨酸激酶起到积极作用的疾病。因此,某些实施方式也提供了包含一种或多种本文公开的化合物和药学可接受载体的药物组合物,以及制备和使用所述化合物和组合物的方法。某些实施方式提供了抑制酪氨酸激酶的方法。其他实施方式提供了用于在需要这种治疗的患者中治疗酪氨酸激酶介导的疾病的方法,包括向所述患者施用治疗有效量的本发明化合物或组合物。也提供了本文公开的特定化合物用于制造药物的用途,所述药物用于预防或治疗因抑制酪氨酸激酶而改善的疾病。
如本文公开的化合物也可以含有其他元素的较不占优的同位素,包括,但不限于,碳的13C或14C,硫的33S、34S或36S,氮的15N,以及氧的17O或18O。
在某些实施方式中,假设如本文公开的化合物中的所有C-D键经代谢并作为D2O或DHO释放,本文公开的化合物可以使患者暴露于最大约0.000005%的D2O或约0.00001%的DHO。在某些实施方式中,显示在动物中引起毒性的D2O水平远大于甚至因施用如本文公开的富氘化合物所引起的最大暴露限值。因此,在某些实施方式中,本文公开的富氘化合物不应当因药物代谢时D2O或DHO的形成而引起任何另外的毒性。
在某些实施方式中,本文公开的氘代化合物保持了相应非同位素富集分子的有益方面,同时大幅增加了最大耐受剂量、降低毒性、增加半衰期(T1/2)、降低最低有效剂量(MED)的最大血浆浓度(Cmax)、降低有效剂量并由此降低非机制相关的毒性和/或降低药物-药物相互作用的可能性。
在某些实施方式中,如果R1是-CD3,则R4-R15至少之一是氘或含有氘。
在某些实施方式中,如果R1是-CD3并且R2是-CH3,则R3-R15至少之一是氘或含有氘。
在某些实施方式中,如果R1-R3各自是-CD3,则R4-R15至少之一是氘或含有氘。
在某些实施方式中,如果R2是-CD3,则R4-R15至少之一是氘或含有氘。
在某些实施方式中,如果R14-R15各自是氘,则R1-R1至少2之一是氘或含有氘。
在某些实施方式中,如果R9是氘,则R1-R8或R10-R15至少之一是氘或含有氘。
在某些实施方式中,如果R4和R5各自是-CD3,则R1-R3或R6-R15至少之一是氘或含有氘。
在某些实施方式中,如果R4是-CD3,则R1-R3或R6-R15至少之一是氘或含有氘。
本发明中引用的所有出版物和参考文献明确地以参考方式整体并入本发明。然而,对于在并入的出版物或参考文献中出现并在本文件中明确提出或定义的任何相似或相同术语,在所有方面应以本文件中明确提出的这些术语的定义或含义为准。
在本发明中使用时,下面的术语具有指出的含义。
除非另有具体规定,单数形式“a”、“an”和“the”可以指复数的物品。
如本发明中使用的术语“约”旨在限定它修饰的数值,从而将这种值表示为误差范围内的变量。当没有提到在数据图或表中给出的平均值的具体误差范围(如标准差)时,术语“约”应当理解为意指包括所指值的范围和通过对该数字四舍五入以及考虑有效数字而包括的范围。
当公开值的范围时并且使用“n1到n2”或“n1-n2”的方式,其中n1和n2是数字,而除非另有具体规定,该方式是指包括数字自身和它们之间的范围。该范围可以是末端值之间并包括末端值的整数部分或连续部分。
术语“氘富集度”是指在分子中给定位置氢处引入氘的百分数。例如,在给定位置处1%的氘富集度意为给定样品中1%的分子在指定的位置含有氘。由于自然存在的氘分布为约0.0156%,在使用非富集起始材料合成的化合物在任何位置的氘富集度为约0.0156%。可以使用本领域一般技术人员知晓的常规分析方法确定氘富集度,包括质谱和核磁共振谱。
术语“是/是氘”当用于描述分子中的给定位置如R1-R15时,或者符号“D”当用于表示分子结构图中的给定位置时,意为指定的位置氘富集超过氘的天然存在分布。在一个实施方式中在指定位置的氘富集不小于约1%,在另一个中不小于约5%,在另一个中不小于约10%,在另一个中不小于约20%,在另一个中不小于约50%,在另一个中不小于约70%,在另一个中不小于约80%,在另一个中不小于约90%,或者在另一个中不小于约98%的氘。
术语“同位素富集”是指在分子中指定位置处掺入某元素的更少见同位素以替换该元素的更普遍同位素的百分数。
术语“非同位素富集的”是指其中各种同位素的百分数与天然存在的百分数基本上相同的分子。
不对称中心存在于本文公开的化合物中。依照手性碳原子周围取代物的构型,这些中心以符号“R”或“S”表示。应当理解,本发明包含所有的立体异构体形式,包括非对映体、对映体和差相异构体形式,以及d-异构体和1-异构体,及其混合物。化合物的个别异构体可以从含有手性中心的市售起始材料合成地制备,或通过制备对映体产物混合物,随后拆分(如转化为非对映体混合物),接着拆分或重结晶、色谱技术、直接在手性色谱柱上拆分对映体,或本领域已知的任何其他适合方法来制备。特定立体化学的起始化合物是市售的或可以通过本领域已知的技术制备和解析。此外,本文公开的化合物可以作为几何异构体存在。本发明包括所有的顺式、反式、同式(syn)、逆式(anti)、E型(entgegen)(E)、和Z型(zusammen)(Z)异构体以及其适合的混合物。此外,化合物可以作为互变异构体存在;所有互变异构体由本发明提供。此外,本文公开的化合物可以以非溶剂化形式,以及以具有药学可接受溶剂如水、乙醇等的溶剂化形式存在。通常,认为溶剂化形式等同于非溶剂化形式。
术语“键”是指两个原子之间的共价连接,或者当由该键接合的原子视为为更大亚结构的一部分时,指两个部分之间的共价连接。除非另有规定,键可以是单键、双键或三键。分子的附图中两个原子之间的虚线表示额外的键可以在这个位置存在或不存在。
如本文中所用的术语“疾病”意图一般与术语“疾病”和“病情”(如医学病情下)同义并与其可交换地使用,在于它们均反映人体或动物体或其部分之一的妨碍正常功能的异常状况,其通常由区别性体征和症状来表现。
术语“治疗”、“治疗的”和“治疗”意在包括减轻或消除疾病或与疾病相关的一个或多个症状;或者减轻或根除疾病本身的病因。如本文中所用,对疾病“治疗”的称谓意图包括预防。术语“预防”、“预防的”和“预防”指延迟或排除疾病的发作;和/或其伴随症状,阻止受试者患上疾病或减轻受试者患上疾病的风险的方法。
术语“治疗有效量”是指化合物的量,当施用时,所述的量足以阻止正在治疗的疾病进展,或一定程度上减轻该疾病的一个或多个症状。术语“治疗有效量”也指这样的化合物量,其足以引起由研究者、兽医、医疗医师或临床医生正在研究的细胞、组织、系统、动物或人的生物学或医学反应。
术语“受试者”指动物,包括,但不限于灵长类(如人、猴、黑猩猩、大猩猩等)、啮齿类(如大鼠、小鼠、沙鼠、仓鼠、貂等)、兔、猪(如家猪、小型猪)、马、犬、猫等。术语“受试者”和“患者”在本发明中可交换地例如指称哺乳动物受试者,如人患者。
术语“联合治疗”意为施用两种或更多种治疗药剂,以治疗本文公开中所描述的治疗性疾病。这种施用包括以基本同时的方式共同施用这些治疗药剂,如在具有固定比例的活性成分的单个胶囊中,或在每种活性成分的多个独立胶囊中。此外,这种施用也包括以顺序方式使用每个类型的治疗药剂。在任何情况下,治疗方案将在治疗本发明描述的疾病中提供药物联合的有益效果。
术语“酪氨酸激酶”指能够将磷酸基团从ATP转移到蛋白质中酪氨酸残基的酶。酪氨酸激酶对蛋白质的磷酸化是调节酶活性和细胞事件如细胞存活或增殖的信号转导的重要机制。由本文公开的化合物抑制的特定酪氨酸激酶包括SYK激酶和FLT3。FMS样酪氨酸激酶3(FLT3)是由不成熟的造血细胞表达的受体酪氨酸激酶并且对干细胞和免疫系统的正常发育重要。SYK主要在造血组织中表达,而Syk的异常功能已与造血系统恶性肿瘤和多种过敏性和自身免疫性疾病的几种情况相关。
术语“酪氨酸激酶介导的疾病”指以受到调节时引起其他异常生物过程改善的异常酪氨酸激酶活性或酪氨酸激酶活性为特征的疾病。酪氨酸激酶介导的疾病可以完全或部分由调节酪氨酸激酶介导。尤其,酪氨酸激酶介导的疾病是在其中抑制酪氨酸激酶对潜在疾病产生一些效果的疾病,如施用酪氨酸激酶抑制剂在至少正在治疗的某些患者中导致一些改善。
术语“酪氨酸激酶抑制剂”是指本文公开的化合物改变酪氨酸激酶功能的能力。抑制剂可以通过在抑制剂和酪氨酸激酶之间形成可逆或不可逆的共价键,或者通过形成非共价结合的复合物来阻断或降低酪氨酸激酶的活性。这样的抑制可能仅在特定类型细胞中表现或可能出现在特定生物事件中。术语“抑制”或“抑制”也指通过降低酪氨酸激酶和自然底物之间形成复合物的几率,来改变酪氨酸激酶的功能。在某些实施方式中,可以使用WO 2005/012294;WO 2008/064274;WO 2006/078846;Weinblatt等,Arthritis Rheum.,2008,58(11),3309-3318;Cha等,J.Pharmacol.Exp.Ther.,2006,317(2),571-578;Bajhat等,Arthritis & Rheumatism,2008,58(5),1433-1444;和Brasselmann等,J.Pharmacol.Exp.Ther.,2006,319(3),998-1008中描述的方法评估酪氨酸激酶的抑制。
术语“治疗可接受的”是指适合用于接触患者组织而没有过多毒性,刺激性,过敏反应,免疫原性,与合理的收益/风险比相当,以及对其预定用途有效的那些化合物(或盐、前药、互变异构体、两性形式等)。
术语“药学可接受的载体”,“药学可接受的辅料”,“生理可接受的载体”或“生理可接受的辅料”是指药学可接受的材料、组合物或载剂,如液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊材料。每种成分必须在与药物制剂中其他成分相容的意义上是“药学可接受的”。它必须适合用于与人或动物的组织或器官接触而没有过的多毒性、刺激性、过敏反应、免疫原性或其他问题或并发症,与合理的收益/风险比相当。见Remington:The Science and Practice ofPharmacy,第21版;Lippincott Williams & Wilkins:Philadelphia,PA,2005;Handbook of Pharmaceutical Excipients,第5版;Rowe等编著,ThePharmaceutical Press and the American Pharmaceutical Association:2005;和Handbook of Pharmaceutical Additives,第3版;Ash and Ash Eds.,GowerPublishing Company:2007;Pharmaceutical Preformulation and Formulation,Gibson Ed.,CRC Press LLC:Boca Raton,FL,2004)。
术语“活性成分”、“活性化合物”和“活性物质”是指单独或与一种或多种药学可接受辅料或载体联合施用给受试者,以治疗、预防或减轻疾病的一种或多种症状的化合物。
术语“药物”、“治疗药剂”和“化疗药剂”是施用给受试者以治疗,预防,或减轻疾病的一种或多种症状的化合物或其药物组合物。
术语“控释辅料”是指辅料,相比于常规立即释放剂型,其主要功能是调整活性物质从剂型中释放的持续时间或位置。
术语“非控释辅料”是指辅料,相比于常规立即释放剂型,其主要功能不包括调整活性物质从剂型中释放的持续时间或位置。
术语“前药”是指本文公开的化合物的化合物功能性衍生物,其轻易在体内转变为母体化合物。前药通常有用,因为在某些情况下,它们比母体化合物更容易施用。例如,它们可以通过口服施用而是生物可利用的,而母体化合物不可以。前药也可能在药物组合物中具有比母体化合物增强的溶解性。前药可以通过各种机制(包括酶促过程和代谢水解)转变成母体药。见Harper,Progressin Drug Research 1962,4,221-294;Morozowich等.在“Design ofBiopharmaceutical Properties through Prodrugs and Analogs,”Roche Ed.,APHAAcad.Pharm.Sci.1977中;“Bioreversible Carriers in Drug in Drug Design,Theoryand Application,”Roche Ed.,APHA Acad.Pharm.Sci.1987;“Design ofProdrugs,”Bundgaard,Elsevier,1985;Wang等,Curr.Pharm.Design 1999,5,265-287;Pauletti等,Adv.Drug.Delivery Rev.1997,27,235-256;Mizen等,Pharm.Biotech.1998,11,345-365;Gaignault等,Pract.Med.Chem.1996,671-696;Asgharnejad在“Transport Processes in Pharmaceutical Systems,”Amidon等,Ed.,Marcell Dekker,185-218,2000中;Balant等,Eur.J.Drug Metab.Pharmacokinet.1990,15,143-53;Balimane和Sinko,Adv.Drug Delivery Rev.1999,39,183-209;Browne,Clin.Neuropharmacol.1997,20,1-12;Bundgaard,Arch.Pharm.Chem.1979,86,1-39;Bundgaard,Controlled Drug Delivery 1987,17,179-96;Bundgaard,Adv.Drug Delivery Rev.1992,8,1-38;Fleisher等,Adv.Drug Delivery Rev.1996,19,115-130;Fleisher等,Methods Enzymol.1985,112,360-381;Farquhar等,J.Pharm.Sci.1983,72,324-325;Freeman等,J.Chem.Soc.,Chem.Commun.1991,875-877;Friis和Bundgaard,Eur.J.Pharm.Sci.1996,4,49-59;Gangwar等,Des.Biopharm.Prop.Prodrugs Analogs,1977,409-421;Nathwani和Wood,Drugs 1993,45,866-94;Sinhababu和Thakker,Adv.DrugDelivery Rev.1996,19,241-273;Stella等,Drugs 1985,29,455-73;Tan等,Adv.Drug Delivery Rev.1999,39,117-151;Taylor,Adv.Drug Delivery Rev.1996,19,131-148;Valentino和Borchardt,Drug Discovery Today 1997,2,148-155;Wiebe和Knaus,Adv.Drug Delivery Rev.1999,39,63-80;Waller等,Br.J.Clin.Pharmac.1989,28,497-507。
本文公开的化合物可以作为药学可接受的盐存在。如本发明中使用的术语“药学可接受的盐”,表示本文公开的化合物的盐或两性形式,它们如本发明定义是药学上可接受的。可以在化合物的最终分离和纯化期间,或者单独通过将适合的化合物与适合的酸或碱反应来制备盐。药学可接受的盐包括酸和碱的加成盐。对于制备和选择盐的更完整讨论,参考“Handbook of PharmaceuticalSalts,Properties,and Use”Stah和Wermuth编著;(Wiley-VCH and VHCA,Zurich,2002)以及Berge等,J.Pharm.Sci.1977,66,1-19。
用于制备药学可接受盐的适合酸包括,但不仅限于、乙酸、2,2-二氯乙酸、酰化氨基酸、己二酸、褐藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、硼酸、(+)-樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、环己基氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、粘酸、龙胆酸、葡庚糖酸、D-葡萄糖酸、D-葡萄糖醛酸、L-谷氨酸、α-酮戊二酸、甘醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、(+)-L-乳酸、(±)-DL-乳酸、乳糖酸、月桂酸、马来酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘-2-磺酸、萘-1,5-二磺酸、1-羟基-2-萘酸、烟碱酸、硝酸、油酸、乳清酸、草酸、棕榈酸、扑酸、高氯酸、磷酸、L-焦谷氨酸、砂糖酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸、十一烯酸和戊酸。
用于制备药学可接受盐的适合碱包括,但不仅限于,无机碱,如氢氧化镁、氢氧化钙、氢氧化钾、氢氧化锌、或氢氧化钠;和有机碱,如一级、二级、三级、和四级的、脂肪族和芳香族胺类,包括L-精氨酸、苯乙苄胺、苄星、胆碱、地阿诺、二乙醇胺、二乙胺、二甲胺、二正丙胺、二异丙胺、2-(二乙氨基)-乙醇、乙醇胺、乙胺、乙二胺、异丙胺、N-甲基葡萄糖胺、海巴明、1H-咪唑、L-赖氨酸、吗啉、4-(2-羟乙基)吗啉、甲胺、哌啶、哌嗪、丙胺、吡咯烷、1-(2-羟乙基)吡咯烷、吡啶、奎宁环、喹啉、异喹啉、二级胺、三乙醇胺、三甲胺、三乙胺、N-甲基-D-葡萄糖胺、2-氨基-2-(羟甲基)-1,3-丙二醇和氨基丁三醇。
尽管本发明的化合物可以作为原始化学品施用,但也可以将它们作为药物组合物提供。因此,本发明提供了药物组合物,其包含一种或多种本文公开的特定化合物,或其一种或多种药学可接受盐、前药或溶剂化物,连同其一种或多种药学可接受载体和可选地一种或多种其他治疗成分。适合的剂型取决于选择的施用途径。任何公知的技术、载体和辅料可以如合适和如本领域(例如,雷明顿药学大全)所理解那样使用。本文公开的药物组合物可以按本领域已知的任何方式制造,如通过常规的混合、溶解、造粒、制造糖衣丸、研粉、乳化、包囊、包埋、或挤压方法。药物组合物也可以配制为改良的释放剂型、包括延迟释放、延长释放、长期释放、持续释放、脉冲释放、控释释放、加速释放和快速释放、定向释放、程序释放和胃停留剂型。这些剂型可以按照本领域技术人员已知的常规方法和技术制备(见Remington:The Science and Practice ofPharmacy,supra;Modified-Release Drug Deliver Technology,Rathbone等编著,Drugs and the Pharmaceutical Science,Marcel Dekker,Inc.:New York,NY,2002;Vol.126)。
尽管最适合的途径可能取决于例如接受者的状况和疾病,但是所述组合物包括适合口服、肠胃外(包括皮下、皮内、肌肉、静脉、关节和髓内)、腹内、经粘膜、透皮、直肠和局部(包括皮肤、口腔、舌下和眼内)施用的那些组合物。组合物可以以单位剂量形式方便地给出,并可以通过药学领域公知的任何方法来制备。通常,这些方法包括将本发明化合物或其药学盐、前药或溶剂化物(“活性成分”)与一种或多种辅助成分所构成的载体结合的步骤。在一般情况下,通过以下方式制备组合物:将活性成分与液体载体或精细分散的固体载体或两者均匀而紧密的结合,并随后,如果必要,将该产物成型为想要的制剂。
适合口服施用的本文公开的化合物的制剂可以作为离散单位,如含有预定量活性成分的胶囊剂、扁囊剂或片剂;作为散剂或颗粒剂;作为水性液体或非水性液体中的溶液剂或悬液剂;或作为水包油液体乳液剂或油包水液体乳液剂来提供。活性成分也可以作为丸剂、糖膏剂或糊剂来提供。
可以口服使用的药物制品包括片剂、由明胶制成的推入配合胶囊剂,以及由明胶和增塑剂(如甘油或山梨醇)制成的密封软胶囊剂。片剂可以通过压缩和模塑,可选地与一种或多种辅助成分一起进行制造。可以通过在适合的机器中压缩自由流动形式(如粉末或颗粒)的活性成分来制备挤压片剂,所述活性成分可选地与粘合剂、惰性稀释剂、或润滑剂、表面活性剂或分散剂混合。模塑的片剂可以通过在适合的机器中模塑用惰性液体稀释剂湿润的粉末状化合物的混合物来制备。片剂可以可选地经包衣或刻痕,并可以如此配制,以提供其中活性成分的缓释或控释。所有口服施用的剂型应当处于适合这种施用的剂量。推入配合胶囊剂可以含有与填料如乳糖、粘合剂如淀粉和/或润滑剂如滑石粉或硬脂酸镁以及可选地与稳定剂混合的活性成分。在软胶囊剂中,活性化合物可以溶解或悬浮于适合的液体(如脂肪油、液体石蜡或液体聚乙二醇)中。此外,可以加入稳定剂。糖衣丸芯配有适合的包衣。为此目的,可以使用浓缩的糖溶液,其可以可选地含有阿拉伯树胶、滑石粉、聚乙烯吡咯烷酮、卡波姆凝胶、聚乙二醇和/或二氧化钛、漆溶液,以及适合的有机溶剂或溶剂混合物。可以向片剂或糖衣丸包衣中加入染料或颜料,以识别或标记活性化合物药剂的不同组合。
化合物可以配制用于通过注射(例如通过快速浓注或连续输注)的肠胃外施用。用于注射的制剂可以按单位剂量形式(如在安瓿或多剂量容器中)在带有添加的防腐剂的情况下提供。组合物可以采用此类形式,如在油性或水性溶媒中的混悬剂、溶液剂或乳液剂,并可以含有配制剂,如助悬剂、稳定剂和/或分散剂。制剂可以在单位剂量容器或多剂量容器(例如密封的安瓿和小药瓶)中提供,并且可以按粉末形式或在冷冻-干燥(冻干)状态下储存,仅需要在马上使用之前加入无菌液体载体,例如,盐水或无菌的无热原水。临时注射溶液剂和混悬剂可以从先前描述种类的无菌散剂、颗粒剂和片剂制备。
用于肠胃外施用的制剂包括活性化合物的水性和非水性(油性)无菌注射溶液剂,其可以包含抗氧化剂、缓冲剂、抑菌剂和使制剂与预期接受者的血液等渗的溶质;以及可以包括水性和非水性的无菌悬液,其包含助悬剂和增稠剂。适合的脂溶性溶剂或溶媒包括脂肪油(如芝麻油)或合成性脂肪酸酯(如油酸乙酯或甘油三酯)或脂质体。水性注射混悬剂可以包含增加混悬剂粘度的物质,如羧甲基纤维素钠、山梨醇或右旋糖酐。可选地,混悬剂也可以含有适合的稳定剂或增加化合物溶解度的试剂以允许制备高浓缩的溶液剂。
除了前面描述的剂型,化合物也可以配制为储库制品。此类长效制剂可以通过植入(例如皮下或肌肉内植入)或者肌内注射施用。因此,例如,化合物可以与适合的聚合或疏水材料(例如配制为可接受的油中的乳剂)或离子交换树脂配制,或作为难溶性衍生物(例如,作为难溶性盐)配制。
对口腔和舌下施用,组合物可以采用以常规方式配制的片剂、锭剂、软锭剂、或凝胶剂形式。这样的组合物可以包含在有味基质(如蔗糖和阿拉伯树胶或黄蓍胶)中的活性成分。
化合物也可以配制在例如含有常规栓剂基质(如可可脂、聚乙二醇或其他甘油酯)直肠用组合物,如栓剂或滞留灌肠剂。
本文公开的某些化合物可以局部施用,即通过非全身施用法施用。这包括将本文公开的化合物外在施加至表皮或颊腔,以及将这种化合物灌输到耳、眼和鼻中,以化合物不明显地进入血流。相反,全身施用是指口服、静脉内施用,腹内和肌内施用。
适于局部施用的剂型包括适合经皮肤渗透到炎症部位的液体或半液体制品,如凝胶剂、搽剂、洗剂、霜剂、软膏或糊剂,和适于施用至眼、耳或鼻的滴剂。
对吸入施用,化合物可以从吹药器、雾化器加压包或递送气溶胶喷雾的其他方便手段递送。加压包可以包含适合的推进剂,如二氯二氟甲烷、三氯氟甲烷、二氯四氟甲烷、二氧化碳或其他合适的气体。在压缩的气雾剂情况下,剂量单位可以通过提供阀以递送计量的量来确定。另外,对于吸入或吹入施用,本发明的化合物可以采用干散剂组合物的形式,例如化合物和适合的散剂基体(如乳糖或淀粉)的散剂末混合物。散剂组合物可以按单位剂量提供,例如在胶囊、药盒、明胶或气泡包中给出,从中可以借助吸药器或吹药器施用散剂。
优选的单位剂量剂型是含有如本发明下面叙述的有效剂量或其适合份数的活性成分的那些剂型。
化合物可以口服地或通过注射以每日0.1到500mg/kg的剂量施用。成人的剂量范围一般是5mg到2g/日。片剂或以离散单位提供的其他形式可以方便的含有一定量的一种或多种化合物,所述量在这样的剂量下有效或者在相同的多个单位下有效,例如,所述单位含有5mg到500mg,通常约10mg到200mg。
可以与载体材料结合以产生单一剂形式的活性成分的量将会依据治疗的宿主和特定施用模式变化。
化合物可以按不同的模式(如口服、局部或通过注射)施用。施用至患者的化合物的准确量将是巡诊医生的责任。用于任何特定患者的具体剂量取决于多种因素,包括使用的具体化合物的活性、年龄、体重、总体健康状况、性别、饮食、施用时间、施用途径、排泄率、药物组合、所治疗的准确疾病、和所治疗疾病的严重性。施用途径也根据疾病及其严重程度变化。
在患者的病情没有改善的情况下,按医生的考虑,可以长期施用化合物,即,施用较长的时间,包括患者的整个生命续存间,以缓解或以其他方式控制或限制患者疾病的症状。
在患者病情改善的情况下,按医生的考虑,化合物的施用可以持续地给予或暂时停顿一定长度的时间(即,“药物假期”)。
一旦患者的情况改善已经出现,如果需要,施用维持剂量。随后,施用剂量或频率或两者,作为症状的函数,可以降低到维持改善的疾病的水平。然而,任何症状复发时,患者可能需要基于长期的间歇性治疗。
本文公开了治疗酪氨酸激酶介导疾病的方法,其包括向患有或疑似患有这种疾病的受试者施用治疗有效量的本文公开的化合物,或其药学可接受的盐、溶剂化物或前药。
酪氨酸激酶介导的疾病包括但不限于类风湿关节炎、特发性血小板减少性紫癜、实体瘤、B细胞淋巴瘤、T细胞淋巴瘤、血管球性肾炎、溶血性贫血、急性髓细胞性白血病、结直肠癌、非小细胞肺癌、头颈癌、肝癌、肾癌、嗜铬细胞瘤、甲状腺癌、肝细胞癌、肾细胞癌、淋巴癌、过敏反应、过敏类反应、花粉热、过敏性结膜炎、过敏性鼻炎、过敏性哮喘、过敏性皮炎、湿疹、荨麻疹、粘膜疾病、结缔组织病、骨性关节炎、炎症性肠病、溃疡性结肠炎、克罗恩病、特发性炎症性肠道疾病、肠易激综合征、结肠痉挛、浅层疤痕、硬皮病、纤维化症、瘢痕、手术后疤痕、肺纤维化症、血管痉挛、偏头痛、再灌注损伤、后心肌梗死、干燥复征或综合征、肺部肌肉改变或重塑、慢性阻塞性肺病、桥本甲状腺炎、自身免疫性溶血性贫血、自身免疫性恶性贫血萎缩性胃炎、自身免疫性脑脊髓炎、自身免疫性睾丸炎、Goodpasture症、自身免疫性血小板减少症、交感性眼炎、重症肌无力、甲亢病、原发性胆汁性肝硬化、慢性侵略性肝炎、溃疡性结肠炎和膜性肾病、系统性红斑狼疮、口眼干燥综合征、Reiter综合征、多发性肌炎-皮肌炎、系统性硬皮病、结节性多动脉炎、多发性硬化症、大疱性类天疱疮、自身免疫性脱发、I型糖尿病、甲状腺炎,和/或可以通过使用酪氨酸激酶抑制剂来减轻、缓解或预防的任何疾病。
在某些实施方式中,治疗酪氨酸激酶介导疾病的方法包括向受试者施用治疗有效量的本文公开的化合物,或其药学可接受的盐、溶剂化物或前药,从而导致:(1)降低的化合物或其代谢物的血浆水平的个体间变化;(2)每剂量单位中增加的化合物的平均血浆水平或降低的化合物的至少一种代谢物的平均血浆水平;(3)受试者中至少一种细胞色素P450或单胺氧化酶同工型的抑制降低和/或由其所致的代谢降低;(4)借助受试者中至少一种多态表达的细胞色素P450同工型降低代谢;(5)至少一种统计学显著改善的疾病控制和/或疾病根除终点;(6)疾病治疗期间改进的临床效果;(7)作为主要临床益处,预防复发或延迟异常消化道或肝功能参数的消退或出现;或(8)与相应的非同位素富集的化合物相比,在任何诊断性肝胆功能终点中的有害变化降低或消除。
在某些实施方式中,与相应的非同位素富集的化合物相比,本文公开的化合物或其代谢物的血浆水平的个体间变化降低;本文公开的化合物的平均血浆水平增加;本文公开的化合物的代谢物的平均血浆水平降低;本文公开化合物对细胞色素P450或单胺氧化酶同工型的抑制降低;或至少一种多态表达的细胞色素P450同工型对本文公开化合物的代谢降低大于约5%、大于约10%、大于约20%、大于约30%、大于约40%或大于约50%。
可以使用Li等.Rapid Communications in Mass Spectrometry 2005,19,1943-1950,Sweeny等.,Drug Metab.Disp.,2010,38(7),1166-1176,and Sweeny等,Xenobiotica,2010,40(6),415-423中描述的方法来测定本文公开的化合物或其代谢物的血浆水平。
哺乳动物受试者中细胞色素P450同工型的例子包括,但不限于CYP1A1、CYP1A2、CYP1B1、CYP2A6、CYP2A13、CYP2B6、CYP2C8、CYP2C9、CYP2C18、CYP2C19、CYP2D6、CYP2E1、CYP2G1、CYP2J2、CYP2R1、CYP2S1、CYP3A4、CYP3A5、CYP3A5P1、CYP3A5P2、CYP3A7、CYP4A11、CYP4B1、CYP4F2、CYP4F3、CYP4F8、CYP4F11、CYP4F12、CYP4X1、CYP4Z1、CYP5A1、CYP7A1、CYP7B1、CYP8A1、CYP8B1、CYP11A1、CYP11B1、CYP11B2、CYP17、CYP19、CYP21、CYP24、CYP26A1、CYP26B1、CYP27A1、CYP27B1、CYP39、CYP46和CYP51。
哺乳动物受试者中单胺氧化酶同工型的例子包括,但不限于MAOA和MAOB。
通过Ko等(British Journal of Clinical Pharmacology,2000,49,343-351)的方法测定细胞色素P450同工型的抑制。通过Weyler等(J.Biol Chem.1985,260,13199-13207)的方法测定MAOA同工型的抑制。通过Uebelhack等(Pharmacopsychiatry,1998,31,187-192)的方法测定MAOB同工型的抑制。
哺乳动物受试者中多态性表达的细胞色素细胞色素P450同工型的例子包括,但不限于CYP2C8、CYP2C9、CYP2C19和CYP2D6。
通过本发明中描述的方法测量肝微粒体、细胞色素P450同工型和单胺氧化酶同工型的代谢活性,。
改善的疾病控制和/或疾病根除终点,或改善的临床效果的例子包括,但不限于,美国风湿病学会20、50或70标准(ACR20,ACR50,或ACR70[20%,50%,或70%临床改善的ACR标准]),其需要脆弱和肿胀的关节计数上有20%,50%,或70%的改善,以及下列5个参数中3个参数20%,50%,或70%的的改善:患者的整体评估,医生的整体评估,患者的疼痛评估,残疾程度,和急性期反应物水平;Paulu标准;放射学进展;Sharp评分;疼痛;CRP水平;修改的健康评估问卷[M-HAQ]评分;患者和医生整体评估;个体ACR标准组成部分的改善;28个关节的疾病活动度评分(DAS28);总体反应率;临床受益率;SELENA-SLEDAI评分的改善;和医生总体评估评分。WO 2008/064274;Weinblatt等,Arthritis Rheum.,2008,58(11),3309-3318;和www.clinicaltrials.gov。
诊断性肝胆功能终点的例子包括,但不限于,谷丙转氨酶(“ALT”)、血清谷氨酸丙酮酸转氨酶(“SGPT”)、谷草转氨酶(“AST”、“SGOT”)、ALT/AST的比值、血清醛缩酶、碱性磷酸酶(“ALP”)、氨水平、胆红素、γ-谷氨酰转肽酶(“GGTP”,“γ-GTP”、“GGT”)、亮氨酸氨基肽酶(“LAP”)、肝活检、肝脏超声、肝核素扫描、5′-核苷酸酶和血蛋白。肝胆终点与如“Diagnostic andLaboratory Test Reference”,第4版,Mosby,1999中给出的规定正常水平相比较。这些测试按照标准方案由认可达标的实验室进行。
除了用于人类治疗,本文公开的特定化合物和制剂也可以用于包括哺乳动物、啮齿动物等在内的伴侣动物,珍奇动物和家畜的兽医治疗。更优选的动物包括马、犬和猫。
联合治疗
本文公开的化合物也可以与用于治疗酪氨酸激酶介导的疾病的其他药剂组合或在组合下使用。或者,仅通过举例,可以通过施用佐剂(即,佐剂本身可能仅有最小的治疗益处,但与另一种治疗药剂组合时,患者的总体治疗益处增强)来增强本发明描述的化合物之一的治疗有效性。
这样其他的药剂、佐剂或药物可以通过其常用的途径并按其常用的量,同时或顺序地,与本文公开的化合物一起施用。当本文公开的化合物与一种或多种其他药物同时使用时,可以使用除本文公开的化合物外还含有这些其他药物的药物组合物,但这不是必须的。
在某些实施方式中,本文公开的化合物可以与一种或多种烷化剂、抗代谢剂、有丝分裂抑制剂、酪氨酸激酶抑制剂、拓扑异构酶抑制剂、癌免疫治疗单克隆抗体、抗肿瘤抗生素、抗癌药、非甾体类抗炎药、苯胺类镇痛药、调节疾病的抗风湿药、糖皮质激素和免疫抑制剂组合。
在某些实施方式中,本文公开的化合物可以与选自由苯丁酸氮芥、氮芥、环磷酰胺、异环磷酰胺、苯丙氨酸氮芥、卡氮芥、福莫司汀、洛莫司汀、链脲霉素、卡铂、顺铂、奥沙利铂、BBR3464、白消安、达卡巴嗪、苯卡巴肼、替莫唑胺、噻替哌、尿嘧啶氮芥组成的组的烷化剂组合。
在某些实施方式中,本文公开的化合物可以与选自由氨基蝶呤、甲氨蝶呤、培美曲塞、雷替曲塞、克拉屈滨、安妥明、氟达拉滨、巯基嘌呤、喷司他丁、硫鸟嘌呤、阿糖胞苷、氟脲嘧啶、氟尿苷、替加氟、卡莫氟、卡培他滨、和吉西他滨组成的组的抗代谢剂组合。
在某些实施方式中,本文公开的化合物可以与选自由多西紫杉醇、紫杉醇、长春碱、长春新碱、长春地辛、和长春瑞滨组成的组的有丝分裂抑制剂组合。
在某些实施方式中,本文公开的化合物可以与伊马替尼、BIBW-2992、BIBF-1120、达沙替尼、埃罗替尼、吉非替尼、拉帕替尼、培利替尼、尼罗替尼、索拉非尼和舒尼替尼组成的组的酪氨酸激酶抑制剂组合。
在某些实施方式中,本文公开的化合物可以与选自由依托泊苷、依托泊苷磷酸盐、替尼泊苷、喜树碱、拓扑替康和伊立替康组成的组的拓扑异构酶抑制剂组合。
在某些实施方式中,本文公开的化合物可以与选自由利妥昔单抗、阿仑单抗、贝伐单抗、西妥昔单抗、吉妥单抗、帕尼单抗、托西莫单抗和曲妥单抗组成的组的癌免疫治疗单克隆抗体组合。
在某些实施方式中,本文公开的化合物可以与选自由柔红霉素、阿霉素、表阿霉素、去甲氧柔红霉素、米托蒽醌、戊柔比星、更生霉素、博莱霉素、丝裂霉素、光辉霉素和羟基脲组成的组的抗肿瘤抗生素组合。
在某些实施方式中,本文公开的化合物可以与选自由安吖啶、天门冬酰胺酶、六甲蜜胺、羟基脲、氯尼达明、喷司他丁、米替福新、马索罗酚、雌氮芥、维甲酸、米托胍腙、拓扑替康、噻唑呋林、伊立替康、阿维甲酸、米托坦、培门冬酶、蓓萨罗丁、三氧化二砷、伊马替尼、地尼白介素、硼替佐米、塞来昔布和阿那格雷组成的组的抗癌药组合。
在某些实施方式中,本文公开的化合物可以与选自由醋氯芬酸、阿西美辛、阿洛泼林、阿司匹林、阿扎丙宗、贝诺酯、溴芬酸、卡洛芬、塞来昔布、胆碱镁水杨酸、双氯芬酸、二氟尼柳、依托度酸、依托考昔、faislamine、芬布芬、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、氯诺昔康、洛索洛芬、罗美昔布、美洛昔康、甲氯灭酸、甲芬那酸、美洛昔康、安乃近、水杨酸甲酯、水杨酸镁、萘丁美酮、萘普生、尼美舒利、羟基保泰松、帕瑞昔布、保泰松、吡罗昔康、双水杨酸酯、舒林酸、磺吡酮、舒洛芬、替诺昔康、噻洛芬酸、和托美丁组成的组的非甾体类抗炎药组合。
在某些实施方式中,本文公开的化合物可以与选自由对乙酰氨基酚和非那西丁组成的组的苯胺类镇痛药组合。
在某些实施方式中,本文公开的化合物可以与选自由硫唑嘌呤、环孢素A、D-青霉胺、金盐、羟氯喹、来氟米特、甲氨蝶呤、米诺环素、柳氮磺胺吡啶、环磷酰胺、依那西普、英夫利昔、阿达木单抗、阿那白滞素、美罗华、和阿贝西普组成的组的调节疾病的抗风湿药组合。
在某些实施方式中,本文公开的化合物可以与选自由倍氯米松、布地奈德、氟尼缩松、倍他米松、氟替卡松、曲安西龙、艾洛松、环索奈德、氢化可的松、醋酸可的松、泼尼松、泼尼松龙、甲泼尼龙和地塞米松组成的组的糖皮质激素组合。
在某些实施方式中,本文公开的化合物可以与选自由芬戈莫德、环孢素A、硫唑嘌呤、地塞米松、他克莫司、西罗莫司、吡美莫司、霉酚酸盐、依维莫司、巴利昔单抗、达珠单抗、抗胸腺细胞球蛋白、抗淋巴细胞球蛋白、CTLA4IgG和CP-690550组成的组的免疫抑制剂组合。
本文公开的化合物可以与其他类化合物联合施用,其他类化合物包括,但不限于去甲肾上腺素再摄取抑制剂(NRIs),如阿托西汀;多巴胺再摄取抑制剂(DARIs),如哌醋甲酯;羟色胺去甲肾上腺素再摄取抑制剂(SNRIs),如米那普伦;镇静剂,如地西泮;去甲肾上腺素-多巴胺再摄取抑制剂(NDRIs),如安非他酮;羟色胺-去甲肾上腺素-多巴胺再摄取抑制剂(SNDRIs),如文拉法辛;单胺氧化酶抑制剂,如司来吉兰;下丘脑磷脂;内皮素转换酶(ECE)抑制剂,如磷酸阿米酮;阿片类药物,如曲马多;血栓素受体拮抗剂,如伊非曲班;钾通道开放剂;凝血酶抑制剂,如水蛭素;下丘脑磷脂;生长因子抑制剂,如PDGF活性调节物;血小板活化因子(PAF)拮抗剂;抗血小板药剂,如GPIIb/IIIa阻滞剂(如阿昔单抗、依替巴肽、替罗非班)、P2Y(AC)拮抗剂(如氯吡格雷、噻氯匹定和CS-747),与阿司匹林;抗凝血剂,如华法令;低分子量肝素,如依诺肝素;因子VIIa抑制剂和因子Xa抑制剂;肾素抑制剂;中性肽链内切酶(NEP)的抑制剂;血管肽酶抑制剂(双NEP-ACE抑制剂),如奥帕曲拉和格莫曲拉;HMG CoA还原酶抑制剂,如普伐他汀,洛伐他汀,阿托伐他汀,辛伐他汀,NK-104(又名伊伐他汀、尼伐他汀、或nisbastatin),与ZD-4522(又称瑞舒伐他汀,或阿托伐司他汀或visastatin);角鲨烯合成酶抑制剂;贝特类药物;胆汁酸螯合剂,如消胆胺;烟酸;抗动脉粥样硬化剂,如ACAT抑制剂;MTP抑制剂;钙通道阻滞剂,如苯磺酸氨氯地平;钾通道激活剂;α-毒蕈碱剂、β-毒蕈碱剂,如卡维地洛和美托洛尔;抗心律失常药剂;利尿剂、如氯噻嗪、氢氯噻嗪、氟甲噻嗪、氢氟甲噻嗪、苄氟噻嗪、甲基氯噻嗪、三氯噻嗪、多噻嗪、苯并噻嗪、利尿酸、tricrynafen、氯噻酮、furosenilde、musolimine、布美他尼、氨苯喋啶、阿米洛利和安体舒通;血栓溶解剂,如组织型纤溶酶原激活剂(tPA)、重组tPA、链激酶、尿激酶、尿激酶原和乙酰化纤溶酶原链激酶激活剂复合物(APSAC);抗糖尿病药剂,如双胍类(如二甲双胍)、糖苷酶抑制剂(如阿卡波糖)、胰岛素、氯茴苯酸类(如瑞格列奈)、磺脲类(如格列美脲、格列本脲、和格列吡嗪)、噻唑烷二酮类(如曲格列酮、罗格列酮和吡格列酮)、与PPAR-γ激动剂;盐皮质激素受体拮抗剂,如螺内酯和依普利酮;促生长激素分泌药剂;aP2抑制剂;磷酸二酯酶抑制剂,如PDEIII抑制剂(如,西洛他唑)和PDE V抑制剂(如西地那非、他达拉非、伐地那非);蛋白酪氨酸激酶抑制剂;抗炎药;抗增殖药剂,如甲氨蝶呤,FK506(他克莫司、普乐可复),霉酚酸酯;化疗药物;免疫抑制剂;抗癌药和细胞毒性药剂(例如烷化剂,如氮芥、烷基磺酸盐、亚硝基脲、乙烯亚胺类、与三氮烯类);抗代谢药物,如叶酸拮抗剂、嘌呤类似物和吡啶类似物;抗生素,如蒽环类抗生素、博莱霉素、裂霉素、更生霉素和光辉霉素;酶,如L-门冬酰胺酶;法尼基蛋白转移酶抑制剂;激素制剂,如糖皮质激素(如可的松)、雌激素/抗雌激素、雄激素/抗雄激素、孕激素和促黄体激素释放激素拮抗剂以及醋酸奥曲肽;微管干扰药剂,如海鞘素类;微管稳定药剂,如紫杉醇,多西紫杉醇和埃博霉素A-F;源自植物的产物,如,长春花生物碱类,表鬼臼毒素类,紫杉烷类;和拓扑异构酶抑制剂;异戊烯基蛋白转移酶抑制剂;和环孢菌素类;类固醇,如泼尼松龙和地塞米松;细胞毒性药物,如硫唑嘌呤和环磷酰胺;TNF-α抑制剂,如替尼达普、抗TNF抗体或可溶性TNF受体,如依那西普、雷帕霉素和米氟米特;和环氧合酶-2(COX-2)抑制剂,如塞来昔布和罗非昔布;以及其他药剂,如羟基脲、甲苄肼、米托坦、六甲三聚氰胺、金化合物、铂配位络合物,如顺铂、赛特铂和卡铂。
因此,另一方面,某些实施方式提供了在需要这样治疗的人或动物受试者中治疗酪氨酸激酶介导疾病的方法,其包括与至少一种本领域已知的治疗所述疾病的另外药剂相联合,给所述对象施用有效量的本文公开的化合物以减轻或预防对象的所述疾病。在相关的方面,某些实施方式提供了治疗组合物,其包括与一种或多种治疗酪氨酸激酶介导疾病的另外药剂相联合的,至少一种本文公开的化合物。
制备化合物的一般合成方法
氢同位素可以通过使用氘代试剂的合成方法,由此预先确定引入率;和/或通过其中引入率由平衡条件决定的交换技术引入如本文公开的化合物,并可以根据反应条件高度可变。其中通过已知同位素含量的氚代或氘代试剂直接和特异插入氚或氘的合成技术可以产生高的氚或氘丰度,但可能被所需化学反应限制。另一方面,交换技术可以产生较低的氚或氘引入率,其中同位素经常分布于分子上的许多位点。
如本文公开的化合物可以通过本领域技术人员已知的方法及其路线修改形式,和/或遵循与本发明实施例部分中描述那些过程及其路线修改形式,和/或在通过引用方式在此完整并入的WO 2004/014382;WO 2005/012294;WO2008/064274;WO 2006/078846;Gong等,Bioorg.Med.Chem.,2009,17,3414-3425;Clauson-Hass等,Acta Chem.Scand.,1969,23,2322-2324及其中所引用参考文献中的过程及其修改路线来制备。
下面的方案可以用来实施本发明。任何显示为氢的位置可以可选地以氘替换。
方案I
化合物1在高温用适合的氯化剂(如氧氯化磷和五氯化磷的组合)处理以产生化合物2。化合物2与化合物3在适合的溶剂(如水和甲醇的混合物)中反应以产生化合物4。化合物4与化合物5在适合的溶剂(如水和甲醇的混合物中)在高温反应以产生式I的化合物6。化合物6在适合的碱(如碳酸铯)存在下与化合物7在适合的溶剂(如二甲基甲酰胺)中反应以产生化合物8。化合物8在高温用适合的脱保护剂(如醋酸和水的混合物)处理以产生化合物9。化合物9用适合的碱(如氢氧化钠)在适合的溶剂(如水)中处理以产生式I的化合物10。
按照方案I所示的合成过程,通过使用适合的氘代中间体,将氘合成地引入不同的位置。例如,为了在R9引入氘,可以使用具有相应氘取代的化合物1。为了在R4-R5和R11-R12的一个或多个位置引入氘,可以使用具有相应氘取代的化合物3。为了在R1-R3和R6-R7的一个或多个位置引入氘,可以使用具有相应氘取代的化合物5。为了在R14-R15的一个或多个位置引入氘,可以使用具有有相应氘取代的化合物7。
通过质子-氘平衡交换,可以将氘引入具有可交换质子的不同位置,如胺N-Hs。例如,为了在R8,R10,和R13引入氘,可以通过本领域已知的质子-氘交换方法用氘选择性或非选择性地替换这些质子。
方案II
化合物11与化合物12在适合的碱(如氢化钠)存在下在适合的溶剂(如二甲基亚砜)中反应以产生化合物3。
按照方案II所示的合成过程,通过使用适合的氘代中间体,将氘合成地引入不同的位置。例如,为了在R11-R12引入氘,可以使用具有有相应氘取代的化合物11。为了在R4-R5的一个或多个位置引入氘,可以使用具有相应氘取代的化合物12。
方案III
化合物13与化合物14在适合的碱(如碳酸钾)存在下在适合的溶剂(如丙酮)中反应以产生化合物15。化合物15用适合的碱(如氢氧化钠)在适合的溶剂(如乙醇和水的混合物)中处理以产生化合物16。化合物16用适合的硝化剂,(如硝酸)在适合的溶剂(如醋酸)中处理以产生化合物17。化合物17用适合的还原剂(如水合肼和适合的催化剂(如钯碳)的组合)在适合的溶剂(如乙醇)中处理以产生化合物5。
按照方案III所示的合成过程,通过使用适合的氘代中间体,将氘合成地引入不同的位置。例如,为了在R6-R7引入氘,可以使用具有有相应氘取代的化合物13。为了在R1-R3的一个或多个位置引入氘,可以使用具有有相应氘取代的化合物14。
通过下面的例子进一步说明本发明。所有IUPAC名称是使用CambridgeSoft的ChemDraw 10.0生成。
下列化合物一般可以使用上述方法制造。预期当制造出来时,这些化合物会具有与上面例子中所描述的化合物相似的活性。
使用下面的测定法,可以显示与其非同位素富集的类似物相比,本文公开的化合物的代谢特性的变化。预测上面列出的还未制造和/或测试过的化合物已经改变一个或多个代谢特性,如这些测定法所显示。
生物活性测定法
体外肝微粒体稳定性测定法
肝微粒体稳定性测定法在1mg/mL肝微粒体蛋白浓度下,使用2% NaHCO3中的NADPH生成系统(2.2mM NADPH,25.6mM葡萄糖-6-磷酸,6单位/mL葡萄糖-6-磷酸脱氢酶和3.3mM MgCl2)进行。将测试化合物制备为20%乙腈-水中的溶液并添加至分析混合物中(最终分析浓度5微克/mL)并且在37℃下温浴。本测定法中的乙腈最终浓度应当是<1%。在0、15、30、45和60分钟时间取出等份(50μL)并以冰冷的乙腈(200μL)稀释以终止反应。将样品在12,000RPM离心10分钟以沉淀蛋白质。将上清液转移到微量离心管中并贮存用于测试化合物的降解半衰期的LC/MS/MS分析。
使用人细胞色素P
450
酶的体外代谢
使用杆状病毒表达系统(BD Biosciences,San Jose,CA),从相应的人cDNA表达细胞色素P450酶。将100毫摩尔磷酸钾(pH 7.4)中的0.25毫升反应混合物在37℃下温浴20分钟,所述反应混合物含有0.8毫克每毫升蛋白、1.3毫摩尔NADP+、3.3毫摩尔葡萄糖-6-磷酸、0.4U/mL葡萄糖-6-磷酸脱氢酶、3.3毫摩尔氯化镁以及0.2毫摩尔的式I化合物、相应的非同位素富集化合物或标准品或者对照。温育之后,反应通过添加适合的溶剂(如,乙腈、20%三氯乙酸、94%乙腈/6%冰醋酸、70%高氯酸、94%乙腈/6%冰醋酸)终止并且离心(10,000g)3分钟。通过HPLC/MS/MS分析上清液。
细胞色素P450 | 标准 |
CYP1A2 | 非那西丁 |
CYP2A6 | 香豆素 |
CYP2B6 | [13C]-(S)-美芬妥英 |
CYP2C8 | 紫杉醇 |
CYP2C9 | 双氯芬酸 |
CYP2C19 | [13C]-(S)-美芬妥英 |
CYP2D6 | (+/-)-丁呋洛尔 |
CYP2E1 | 氯唑沙宗 |
CYP3A4 | 睾酮 |
CYP4A | [13C]-月桂酸 |
单胺氧化酶A抑制和氧化循环
该过程使用Weyler,Journal of Biological Chemistry 1985,260,13199-13207描述的方法进行,所述文献因而通过引用的方式完整并入。通过监测氧化犬尿胺时314nm处光吸收的增加伴随4-羟基喹啉形成,以分光光度方式测量单胺氧化酶A的活性。测量在30℃在1mL总体积中的pH 7.2的50mM NaPi缓冲液(单胺氧化酶测试缓冲液)的中进行,所述缓冲液含有0.2% Triton X-100外加1mM犬尿胺以及所需量的酶。
单胺氧化酶B抑制和氧化周转
该过程如Uebelhack,Pharmacopsychiatry 1998,31(5),187-192中所述那样进行,所述文献因而通过引用的方式完整并入。
反向被动Arthus反应模型
该过程如WO 2005/012294、WO 2008/064274和2006/078846中所述那样进行,所述文献因而通过引用的方式完整并入。
动物毒性测定法
该过程如WO 2008/064274和2006/078846中所述那样进行,所述文献因而通过引用的方式完整并入。
FcεRI依赖性肥大细胞激活
该过程如WO 2008/064274和2006/078846中所述那样进行,所述文献因而通过引用的方式完整并入。
反向被动Arthus反应模型
该过程按照WO 2008/064274和2006/078846中所述那样进行,所述文献因而通过引用的方式完整并入。
胶原抗体诱导关节炎模型
该过程按照WO 2008/064274和2006/078846中所述那样进行,所述文献因而通过引用的方式完整并入。
胶原诱导关节炎模型
该过程按照WO 2008/064274和2006/078846中所述那样进行,所述文献因而通过引用的方式完整并入。
口服生物利用度测定法
该过程按照WO 2008/064274和2006/078846中所述那样进行,所述文献因而通过引用的方式完整并入。
人类风湿关节炎试验
该过程如Weinblatt等,Arthritis Rheum.,2008,58(11),3309-3318中所述那样进行,所述文献因而通过引用的方式完整并入。
小鼠狼疮模型
该过程如Bajhat等,Arthritis & Rheumatism,2008,58(5),1433-1444中所述那样进行,所述文献因而通过引用的方式完整并入。
Syk激酶抑制研究
该过程如Brasselmann等,J.Pharmacol.Exp.Ther.,2006,319(3),998-1008所述那样进行,所述文献因而通过引用的方式完整并入。
福他替尼和R-406人药代动力学研究
该过程如Sweeny等,Drug Metab.Disp.,2010,38(7),1166-1176中所述那样进行,所述文献因而通过引用的方式完整并入。
福他替尼和R-406在食蟹猴中的药代动力学研究
该过程如Sweeny等,Xenobiotica,2010,40(6),415-423中所述那样进行,所述文献因而通过引用的方式完整并入。
从上面的描述中,本领域技术人员可以容易地确定本发明的实质特征,并且在不背离本发明精神和范围的情况下,可以对本发明作出各种变化和修改,以使其适应于各种用途和情况。
Claims (49)
2.如权利要求1中所述的化合物,其中R1-R15至少之一独立地具有不小于约10%的氘富集度。
3.如权利要求1中所述的化合物,其中R1-R1至少5之一独立地具有不小于约50%的氘富集度。
4.如权利要求1中所述的化合物,其中R1-R15至少之一独立地具有不小于约90%的氘富集度。
5.如权利要求1中所述的化合物,其中R1-R15至少之一独立地具有不小于约98%的氘富集度。
8.如权利要求7中所述的化合物,其中每个表示为D的位置具有不小于10%的氘富集度。
9.如权利要求7中所述的化合物,其中每个表示为D的位置具有不小于50%的氘富集度。
10.如权利要求7中所述的化合物,其中每个表示为D的位置具有不小于90%的氘富集度。
11.如权利要求7中所述的化合物,其中每个表示为D的位置具有不小于98%的氘富集度。
13.如权利要求7中所述的化合物,其中所述化合物具有结构式:
15.如权利要求7中所述的化合物,其中所述化合物具有结构式:
16.如权利要求7中所述的化合物,其中所述化合物具有结构式:
22.药物组合物,其包含如权利要求1中所述的化合物连同药学可接受载体。
23.治疗酪氨酸激酶介导的疾病的方法,包括施用治疗有效量的如权利要求1中所述的化合物至需要其的患者。
24.如权利要求19中所述的方法,其中所述疾病选自由类风湿关节炎,特发性血小板减少性紫癜、实体瘤、B细胞淋巴瘤、T细胞淋巴瘤、血管球性肾炎、溶血性贫血、急性髓细胞性白血病、结直肠癌、非小细胞肺癌、头颈癌、肝癌、肾癌、嗜铬细胞瘤、甲状腺癌、肝细胞癌、和肾细胞癌组成的组。
25.如权利要求19中所述的方法,进一步包括施用另外的治疗剂。
26.如权利要求21中所述的方法,其中所述另外的治疗剂选自由烷化剂、抗代谢剂、有丝分裂抑制剂、酪氨酸激酶抑制剂、拓扑异构酶抑制剂、癌免疫治疗单克隆抗体、抗肿瘤抗生素、抗癌药、非甾体类抗炎药、苯胺类镇痛药、调节疾病的抗风湿药、糖皮质激素、和免疫抑制剂组成的组。
27.如权利要求22中所述的方法、其中所述烷化剂选自由苯丁酸氮芥、氮芥、环磷酰胺、异环磷酰胺、苯丙氨酸氮芥、卡氮芥、福莫司汀、洛莫司汀、链脲霉素、卡铂、顺铂、奥沙利铂、BBR3464、白消安、达卡巴嗪、苯卡巴肼、替莫唑胺、噻替哌、尿嘧啶氮芥组成的组。
28.如权利要求22中所述的方法,其中所述抗代谢剂选自由氨基蝶呤、甲氨蝶呤、培美曲塞、雷替曲塞、克拉屈滨、安妥明、氟达拉滨、巯基嘌呤、喷司他丁、硫鸟嘌呤、阿糖胞苷、氟脲嘧啶、氟尿苷、替加氟、卡莫氟、卡培他滨、和吉西他滨组成的组。
29.如权利要求22中所述的方法,其中所述有丝分裂抑制剂选自由多西紫杉醇、紫杉醇、长春碱、长春新碱、长春地辛、和长春瑞滨组成的组。
30.如权利要求22所述的方法,其中所述酪氨酸激酶抑制剂选自由伊马替尼、BIBW-2992、BIBF-1120、达沙替尼、埃罗替尼、吉非替尼、拉帕替尼、培利替尼、尼罗替尼、索拉非尼、和舒尼替尼组成的组。
31.如权利要求22中所述的方法,其中所述拓扑异构酶抑制剂选自由依托泊苷、依托泊苷磷酸盐、替尼泊苷、喜树碱、拓扑替康、和伊立替康组成的组。
32.如权利要求22中所述的方法,其中所述癌免疫治疗单克隆抗体选自由利妥昔单抗、阿仑单抗、贝伐单抗、西妥昔单抗、吉妥单抗、帕尼单抗、托西莫单抗、和曲妥单抗组成的组。
33.如权利要求22中所述的方法,其中所述抗肿瘤抗生素选自由柔红霉素、阿霉素、表阿霉素、去甲氧柔红霉素、米托蒽醌、戊柔比星、更生霉素、博莱霉素、丝裂霉素、光辉霉素、和羟基脲组成的组。
34.如权利要求22中所述的方法,其中所述抗癌药选自由安吖啶、天门冬酰胺、六甲蜜胺、羟基脲、氯尼达明、喷司他丁、米替福新、马索罗酚、雌氮芥、维甲酸、米托胍腙、拓扑替康、噻唑呋林、伊立替康、阿维甲酸、米托坦、天门冬酰胺酶、蓓萨罗丁、三氧化二砷、伊马替尼、硼替佐米、地尼白介素、塞来昔布、和阿那格雷组成的组。
35.如权利要求22中所述的方法,其中所述非甾体类抗炎药选自由醋氯芬酸、阿西美辛、阿洛泼林、阿司匹林、阿扎丙宗、贝诺酯、溴芬酸、卡洛芬、塞来昔布、胆碱镁水杨酸、双氯芬酸、二氟尼柳、依托度酸、依托考昔、faislamine、芬布芬、非诺洛芬、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、氯诺昔康、洛索洛芬、罗美昔布、美洛昔康、甲氯灭酸、甲芬那酸、美洛昔康、安乃近、水杨酸甲酯、水杨酸镁、萘丁美酮、萘普生、尼美舒利、羟基保泰松、帕瑞昔布、保泰松、吡罗昔康、双水杨酸酯、舒林酸、磺吡酮、舒洛芬、替诺昔康、噻洛芬酸、和托美丁组成的组。
36.如权利要求22中所述的方法,其中所述苯胺类镇痛药选自由对乙酰氨基酚和非那西丁组成的组。
37.如权利要求22中所述的方法,其中所述调节疾病的抗风湿药选自由硫唑嘌呤、环孢素A、D-青霉胺、金盐、羟氯喹、来氟米特、甲氨蝶呤、米诺环素、柳氮磺胺吡啶、环磷酰胺、依那西普、英夫利昔、阿达木单抗、阿那白滞素、美罗华、和阿贝西普组成的组。
38.如权利要求22中所述的方法,其中所述糖皮质激素选自由倍氯米松、布地奈德、氟尼缩松、倍他米松、氟替卡松、曲安西龙、艾洛松、环索奈德、氢化可的松、醋酸可的松、泼尼松、泼尼松龙、甲泼尼龙、和地塞米松组成的组。
39.如权利要求22中所述的方法,其中所述免疫抑制剂选自由芬戈莫德、环孢素A、硫唑嘌呤、地塞米松、他克莫司、西罗莫司、吡美莫司、霉酚酸盐、依维莫司、巴利昔单抗、达珠单抗、抗胸腺细胞球蛋白、抗淋巴细胞球蛋白、CTLA4IgG、和CP-690550组成的组。
40.如权利要求19中所述的方法,进一步引起至少一种效果选自由:
a与非同位素富集的化合物相比,降低的所述化合物或其代谢物的血浆水平的个体间变化;
b与非同位素富集的化合物相比,每剂量单位增加的所述化合物的平均血浆水平;
c与非同位素富集的化合物相比,每剂量单位降低的所述化合物的至少一种代谢物的平均血浆水平;
d与非同位素富集的化合物相比,每剂量单位增加的所述化合物的至少一种代谢物的平均血浆水平;和
e与非同位素富集的化合物相比,每剂量单位在所述受试者中治疗期间改进的临床效果;
组成的组。
41.如权利要求19中所述的方法,进一步引起至少两种效果选自由:
a与非同位素富集的化合物相比,降低的所述化合物或其代谢物的血浆水平个体间变化;
b与非同位素富集的化合物相比,每剂量单位增加的所述化合物的平均血浆水平;
c与非同位素富集的化合物相比,每剂量单位降低的所述化合物的至少一种代谢物的平均血浆水平;
d与非同位素富集的化合物相比,每剂量单位增加的所述化合物的至少一种代谢物的平均血浆水平;和
e与非同位素富集的化合物相比,每剂量单位在受试者中治疗期间改进的临床效果;
组成的组。
42.如权利要求19中所述的方法,其中与相应非同位素富集的化合物相比,所述方法通过受试者中至少一种多态表达的细胞色素P450同工型引起化合物按其每剂量单位的代谢降低。
43.如权利要求38中所述的方法,其中细胞色素P450同工型选自由CYP2C8、CYP2C9、CYP2C19、和CYP2D6组成的组。
44.如权利要求19中所述的方法,其中所述化合物特征在于,与非同位素富集的化合物相比,其每剂量单位对所述受试者中至少一种细胞色素P450或单胺氧化酶同工型的抑制降低。
45.如权利要求19中所述的方法,其中所述细胞色素P450或单胺氧化酶同工型选自由CYP1A1、CYP1A2、CYP1B1、CYP2A6、CYP2A13、CYP2B6、CYP2C8、CYP2C9、CYP2C18、CYP2C19、CYP2D6、CYP2E1、CYP2G1、CYP2J2、CYP2R1、CYP2S1、CYP3A4、CYP3A5、CYP3A5P1、CYP3A5P2、CYP3A7、CYP4A11、CYP4B1、CYP4F2、CYP4F3、CYP4F8、CYP4F11、CYP4F12、CYP4X1、CYP4Z1、CYP5A1、CYP7A1、CYP7B1、CYP8A1、CYP8B1、CYP11A1、CYP11B1、CYP11B2、CYP17、CYP19、CYP21、CYP24、CYP26A1、CYP26B1、CYP27A1、CYP27B1、CYP39、CYP46、CYP51、MAOA和MAOB组成的组。
46.如权利要求19中所述的方法,其中与相应非同位素富集的化合物相比,所述方法减少诊断性肝胆功能终点的变化。
47.如权利要求42中所述的方法,其中诊断性肝胆功能终点选自由谷丙转氨酶(“ALT”)、血清谷氨酸丙酮酸转氨酶(“SGPT”)、谷草转氨酶(“AST”、“SGOT”)、ALT/AST的比值、血清醛缩酶、碱性磷酸酶(“ALP”)、氨水平、胆红素、γ-谷氨酰转肽酶(“GGTP”、“γ-GTP”、“GGT”)、亮氨酸氨基肽酶(“LAP”)、肝脏活组织检查、肝脏超声检查、肝核素扫描、5′-核苷酸酶、和血液蛋白质组成的组。
48.如权利要求1中所述的化合物,其用作药物。
49.如权利要求1中所述的化合物,其用于制造用以预防或治疗通过抑制酪氨酸激酶来改善的疾病的药物。
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CN116635030A (zh) * | 2020-11-24 | 2023-08-22 | 广州君赫生物科技有限公司 | 化合物在制备调降runx2表达试剂中的应用 |
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WO2013142817A2 (en) | 2012-03-23 | 2013-09-26 | Dennis Brown | Compositions and methods to improve the therapeutic benefit of indirubin and analogs thereof, including meisoindigo |
MX367055B (es) | 2012-06-26 | 2019-08-02 | Del Mar Pharmaceuticals | El uso de una composición que comprende dianhidrogalactitol, diacetildianhidrogalactitol, y dibromodulcitol, y análogos o derivados de cada uno para el tratamiento de malignidades resistentes a inhibidores de tirosina cinasa. |
BR112015005894B1 (pt) | 2012-09-18 | 2022-03-29 | Auspex Pharmaceuticals, Inc | Composto, composição farmacêutica, método para tratar um distúrbio mediado por vmat2 e formulação farmacêutica de liberação prolongada |
US9550780B2 (en) | 2012-09-18 | 2017-01-24 | Auspex Pharmaceuticals, Inc. | Formulations pharmacokinetics of deuterated benzoquinoline inhibitors of vesicular monoamine transporter 2 |
US11491154B2 (en) | 2013-04-08 | 2022-11-08 | Dennis M. Brown | Therapeutic benefit of suboptimally administered chemical compounds |
KR20160104612A (ko) | 2013-07-26 | 2016-09-05 | 업데이트 파마 인코포레이트 | 비산트렌의 치료 효과 개선용 조성물 |
MX369956B (es) | 2013-12-03 | 2019-11-27 | Auspex Pharmaceuticals Inc | Metodos para preparar compuestos de benzoquinolina. |
EA201691582A1 (ru) | 2014-02-07 | 2017-01-30 | Оспекс Фармасьютикалз, Инк. | Новые фармацевтические препараты |
US20150284327A1 (en) * | 2014-04-04 | 2015-10-08 | Auspex Pharmaceuticals, Inc. | Oxindole inhibitors of tyrosine kinase |
CN114796209A (zh) | 2015-03-06 | 2022-07-29 | 奥斯拜客斯制药有限公司 | 氘代丁苯那嗪或包含氘代丁苯那嗪的组合物 |
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WO2011106248A3 (en) | 2012-01-05 |
KR20120120970A (ko) | 2012-11-02 |
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