CN110740993B - 用作钠通道调节剂的氘代吡啶酮酰胺及其前药 - Google Patents
用作钠通道调节剂的氘代吡啶酮酰胺及其前药 Download PDFInfo
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- CN110740993B CN110740993B CN201880037064.5A CN201880037064A CN110740993B CN 110740993 B CN110740993 B CN 110740993B CN 201880037064 A CN201880037064 A CN 201880037064A CN 110740993 B CN110740993 B CN 110740993B
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Abstract
提供了用作钠通道抑制剂的化合物及其药学上可接受的盐。该混合物具有式(I)其中R为H或CH2OPO(OH)2。还提供了包含所述化合物或药学上可接受的盐的药物组合物,以及用于治疗不同障碍包括疼痛的药物组合物。
Description
相关申请的交叉引用
本申请要求2017年5月16日提交的美国临时申请号62/507,172和2017年8月18日提交的美国临时申请号62/547,718的权益,其通过引用整体并入。
背景
疼痛是使健康动物避免组织损害及防止受伤组织的进一步损害的保护机制。然而,存在许多疼痛持续超出其有用性的情况或患者从抑制疼痛获得益处的情况。神经病变性疼痛是一种由对感觉神经的损伤引起的慢性疼痛形式(Dieleman,J.P.等人,Incidencerates and treatment of neuropathic pain conditions in the generalpopulation.Pain,2008.137(3):p.681-8)。神经病变性疼痛可以分为两类:由对神经的广泛性代谢损害引起的疼痛及由离散神经损伤引起的疼痛。代谢性神经病包括疱疹后神经病、糖尿病性神经病变及药物引起的神经病。离散神经损伤适应症包括截肢手术后疼痛、外科手术后神经损伤疼痛及神经挤压损伤(如神经性背痛)。
电压门控型钠通道(Nav)在疼痛信号传导中起关键作用。Nav是电信号传导的关键生物介体,因为它们介导许多可兴奋细胞类型(例如神经元、骨骼肌细胞、心肌细胞)的动作电位的快速上升。这些通道在正常生理现象中作用的证据、由钠通道基因突变造成的病理状态、动物模型中的临床前研究及已知钠通道调节剂的临床药理学均指向Nav在痛觉中的中心作用(Rush,A.M.和T.R.Cummins,Painful Research:Identiffcation of a Small-Molecule inhibitor that Selectively Targets NaV1.8Sodium Channels.Mol Interv,2007.7(4):p.192-5);England,S.,Voltage-gated sodium channels:the search forsubtype-selective analgesics.Expert Opin Investig Drugs 17(12),p.1849-64(2008);Krafte,D.S.和Bannon,A.W.,Sodium channels and nociception:recentconcepts and therapeutic opportunities.Curr Opin Pharmacol 8(1),p.50-56(2008))。Nav介导许多可兴奋细胞类型(例如神经元、骨骼肌细胞、心肌细胞)的动作电位的快速上升,因此牵涉这些细胞中信号传导的起始(Hille,Bertil,Ion Channels ofExcitable Membranes,第三版(Sinauer Associates,Inc.,Sunderland,MA,2001))。由于Nav在神经元信号的起始及传播中所起的作用,减少Nav电流的拮抗剂可防止或减少神经信号传导,且Nav通道已视为在观测到过度兴奋的症状中减少疼痛的可能标靶(Chahine,M.,Chatelier,A.,Babich,O.和Krupp,J.J.,Voltage-gated sodium channels inneurological disorders.CNS Neurol Disord Drug Targets 7(2),p.144-58(2008))。若干临床上有用的止痛剂已鉴别为Nav通道的抑制剂。局部***(例如利多卡因)通过抑制Nav通道来止痛,且已提出其他化合物(例如卡马西平、拉莫三嗪及已证明可有效减少疼痛的三环抗抑郁剂)通过钠通道抑制起作用(Soderpalm,B.,Anticonvulsants:aspects oftheir mechanisms of action.Eur J Pain 6Suppl A,p.3-9(2002);Wang,G.K.,Mitchell,J.和Wang,S.Y.,Block of persistent 1ate Na+ currents byantidepressant sertraline and paroxetine.J Membr Biol 222(2),p.79-90(2008))。
Nav形成电压门控型离子通道大家族中的亚家族,并包含9种同种型,它们被命名为Nav1.1至Nav1.9。九种同种型的组织定位不同。Nav1.4是骨骼肌的主要钠通道,Nav1.5是心肌细胞的主要钠通道。Nav1.7、1.8及1.9主要定位于外周神经***,而Nav1.1、1.2、1.3及1.6为在中枢神经***及外周神经***二者中发现的神经元通道。九种同种型的功能性质类似,但它们的电压依赖性及动力学性质的细节不同(Catterall,W.A.,Goldin,A.L.和Waxman,S.G.,International Union of Pharmacology.XLVII.Nomenclature andstructure-function relationships of voltage-gated sodium channels.PharmacolRev 57(4),p.397(2005))。
在它们发现之时,将NaV1.8通道鉴别为为镇痛的可能标靶(Akopian,A.N.,L.Sivilotti,and J.N.Wood,A tetrodotoxin-resistant voltage-gated sodiumchannel expressed by sensory neurons.Nature,1996.379(6562):p.257-62)。从那以后,显示Nav1.8为维持小DRG神经元中动作电位产生的钠电流的载体(Blair,N.T.和B.P.Bean,Roles of tetrodotoxin(TTX)-sensitive Na+current,TTX-resistant Na+current,and Ca2+current in the action potentials of nociceptive sensoryneurons.J Neurosci.,2002.22(23):p.10277-90)。Nav1.8对于受损神经元(如驱动神经病变性疼痛的神经元)中的自发性产生是必要的(Roza,C.等人,The tetrodotoxin-resistant Na+channel Nav1.8is essential for the expression of spontaneousactivity in damaged sensory axons of mice.J.Physiol.,2003.550(Pt 3):p.921-6;Jarvis,M.F.等人,A-803467,a potent and selective Nav1.8sodium channel blocker,attenuates neuropathic and inflammatory pain in the rat.Proc Natl Acad Sci.US A,2007.104(20):p.8520-5;Joshi,S.K.等人,Involvement of the TTX-resistantsodium channel Nav1.8in inflammatory and neuropathic,but not post-operative,pain states.Pain,2006.123(1-2):pp.75-82;Lai,J.等人,Inhibition of neuropathicpain by decreased expression of the tetrodotoxin-resistant sodium channel,Nav1.8.Pain,2002.95(1-2):p.143-52;Dong,X.W.等人,Small interfering RNA-mediated selective knockdown of Na(v)1.8tetrodotoxin-resistant sodium channelreverses mechanical allodynia in neuropathic rats.Neuroscience,2007.146(2):p.812-21;Huang,H.L.等人,Proteomic profiling of neuromas reveals alterationsin protein composition and local protein synthesis in hyper-excitablenerves.Mol Pain,2008.4:p.33;Black,J.A.等人,Multiple sodium channel isoformsand mitogen-activated protein kinases are present in painful humanneuromas.Ann Neurol,2008.64(6):p.644-53;Coward,K.等人,Immunolocalization ofSNS/PN3 and NaN/SNS2 sodium channels in human pain states.Pain,2000.85(1-2):p.41-50;Yiangou,Y.等人,SNS/PN3and SNS2/NaN sodium channel-1ikeimmunoreactivity in human adult and neonate injured sensory nerves.FEBS Lett,2000.467(2-3):p.249-52;Ruangsri,S.等人,Relationship of axonal voltage-gatedsodium channel 1.8(Nav1.8)mRNA accumulation to sciatic nerve injury-inducedpainful neuropathy in rats.J Biol Chem.286(46):p.39836-47)。表达Nav1.8的小DRG神经元包括牵涉疼痛信号传导的痛觉感受器。Nav1.8介导背根神经节的小神经元中的大振幅动作电位(Blair,N.T.和B.P.Bean,Roles of tetrodotoxin(TTX)-sensitive Na+current,TTX-resistant Na+current,and Ca2+ current in the action potentials ofnociceptive sensory neurons.J Neurosci.,2002.22(23):p.10277-90)。Nav1.8对于痛觉感受器中的快速重复动作电位及受损神经元的自发性活动是必要的。(Choi,J.S.和S.G.Waxman,Physiological interactions between Nav 1.7and Nav 1.8sodiumchannels:a computer simulation study.J Neurophysiol.106(6):p.3173-84;Renganathan,M.,T.R.Cummins和S.G.Waxman,Contribution of Na(v)1.8sodiumchannels to action potential electrogenesis in DRG neurons.J Neurophysiol.,2001.86(2):p.629-40;Roza,C.等人,The tetrodotoxin-resistant Na+channel Nav1.8is essential for the expression of spontaneous activity in damaged sensoryaxons of mice.J Physiol.,2003.550(Pt 3):p.921-6)。在去极化或受损DRG神经元中,Nav1.8看起来是过度兴奋的驱动物(Rush,A.M.等人,A single sodium channel mutationproduces hyper-or hypoexcitability in different types of neurons.Proc NatlAcad Sci USA,2006.103(21):p.8245-50)。在一些动物疼痛模型中,已显示Nav1.8mRNA表达水平在DRG中增加(Sun,W.等人,Reduced conduction failure of the main axon ofpolymodal nociceptive C-fibers cohtributes to painful diabetic neuropathy inrats.Brain.135(Pt 2):p.359-75;Strickland,I.T.等人,Changes in the expressionof NaV1.7,Nav1.8and Nav1.9in a distinct population of dorsal root gangliainnervating the rat knee joint in a model of chronic inflammatory jointpain.Eur J Pain,2008.12(5):p.564-72;Qiu,F.等人,Increased expression oftetrodotoxin-resistant sodium channels Nav1.8and Nav1.9within dorsal rootganglia in a rat model of bone cancer pain.Neurosci.Lett.512(2):p.61-6)。
已知Nav抑制剂的主要缺点是它们的治疗窗较差,这可能是它们缺乏同种型选择性的结果。由于Nav1.8主要局限于感受疼痛的神经元,故选择性Nav1.8阻断剂不太可能诱导非选择性Nav阻断剂所常见的不良反应。因此,本领域仍然需要研发另外的Nav通道调节剂,优选更对Nav1.8更有效和有选择性、代谢稳定性增加、溶解度增加和副作用更少的Nav通道调节剂。
在国际公开号WO 2014/120808 A9和美国公开号2014/0213616 A1中描述了一类可用作Nav1.8钠通道抑制剂的吡啶酮酰胺化合物,并且在国际公开号WO 2015/089361 A1和美国公开号2015/0166589 A1中描述了这些化合物的前药,通过引用并入它们的全部内容。那些吡啶酮酰胺化合物解决了现有Nav1.8抑制剂的某些缺点,但仍可以进一步改进。
概述
一方面,本发明涉及式I的化合物:
或其药学上可接受的盐,其中R为H或CH2OPO(OH)2。
另一方面,本发明涉及式I的化合物,其为
或其药学上可接受的盐。
另一方面,本发明涉及式I的化合物,其为
另一方面,本发明涉及式I的化合物,其为
或其药学上可接受的盐。
另一方面,本发明涉及式I的化合物,其为
另一方面,本发明涉及药物组合物,其包含式I的化合物或其药学上可接受的盐和一种或多种药学上可接受的载体或介质。
另一方面,本发明涉及通过对受试者施用所述式I的化合物、药学上可接受的盐或药物组合物抑制该受试者的电压门控型钠通道的方法。
另一方面,本发明涉及一种通过对受试者施用所述式I的化合物、药学上可接受的盐或药物组合物治疗受试者的多种疾病、障碍或病症或减轻其严重性的方法,该疾病、障碍或病症包括(但不限于)慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛(例如囊肿切除术疼痛或腹壁整形术疼痛)、内脏痛、多发性硬化、沙-马-图综合征、失禁、病理性咳嗽和心律失常。
附图描述
图1为在大鼠肝微粒体存在下温育期间化合物7和10剩余百分比随时间变化的示意图。
图2为在狗肝微粒体存在下温育期间化合物7和10剩余百分比随时间变化的示意图。
图3为在猴肝微粒体存在下温育期间化合物7和10剩余百分比随时间变化的示意图。
图4为在人肝微粒体存在下温育期间化合物7和10剩余百分比随时间变化的示意图。
图5为施用于雄性Sprague Dawley大鼠后化合物7和化合物10的血浆浓度随时间变化的示意图。
详细描述
一方面,本发明涉及式I的化合物:
或其药学上可接受的盐,其中R为H或CH2OPO(OH)2。
另一方面,本发明涉及式I的化合物,其为
或其药学上可接受的盐。
另一方面,本发明涉及式I的化合物,其为
另一方面,本发明涉及式I的化合物,其为
或其药学上可接受的盐。
另一方面,本发明涉及式I的化合物,其为
R为CH2OPO(OH)2的式I的化合物及其药学上可接受的盐为R为H的母体化合物的前药。
如本说明书所用,术语“前药”是指作为药物前体的化合物,其在施用及吸收后在活体内通过一些代谢过程释放药物。一般而言,前药所具有的生物活性小于其母体药物。前药还可改良母体药物的物理特性及/或其还可改良总体药物功效,例如通过控制药物的吸收、血液含量、代谢分布及细胞吸收而减小药物的毒性及不期望的作用。
如本说明书所用,术语“母体化合物”或“母体药物”是指在施用前药后通过代谢过程或分解代谢过程的酶促作用或通过化学过程释放的生物活性实体。母体化合物还可以为用于制备其相应前药的起始物质。
出于本发明的目的,化学元素根据元素周期表,CAS版,Handbook of Chemistryand Physics,第75版来鉴别。另外,有机化学的一般原理描述于“Organic Chemistry,”Thomas Sorrell,University Science Books,Sausalito:1999,和“March's AdvancedOrganic Chemistry,”第5版,Ed.:Smith,M.B.和March,J.,John Wiley&Sons,New York:2001,该文献的全部内容引入本说明书作参考。
如本说明书所用,术语“本发明的化合物”是指式I的化合物及其如本说明书所述的其所有实施方案。
如本说明书所用,当涉及本发明的化合物时,术语“化合物”是指具有相同化学结构的分子的集合,除了在分子的组成原子之间可能存在同位素变化之外。术语“化合物”包括这样的分子集合,而与包含分子集合的给定样品的纯度无关。因此,术语“化合物”包括纯形式或与一种或多种其他物质的混合物(例如溶液,悬浮液或胶体)的分子的这种集合。
在本说明书和权利要求书中,除非另有说明,否则在本发明的任何化合物中未特别指定为特定同位素的任何原子意在表示指定元素的任何稳定同位素。在实施例中,其中原子在本发明的任何化合物中均未特别指定为特定的同位素,未作任何努力使该原子在特定的同位素中富集,因此,本领域普通技术人员将理解该原子可能以接近指定元素的自然丰度同位素组成存在。
如本说明书所用,当提及同位素时,术语“稳定”是指未知同位素会发生自发放射性衰变。稳定的同位素包括但不限于在V.S.Shirley&C.M.Lederer,Isotopes Project,Nuclear Science Division,Lawrence Berkeley Laboratory,Table ofNuclides(1980年1月)中未鉴定衰变模式的同位素。
如本说明书在说明书和权利要求书中所使用的,“H”是指氢并且包括氢的任何稳定同位素。在实施例中,其中一个原子被称为“H”,未尝试使该原子富集于氢的特定同位素中,因此,本领域普通技术人员将理解,这种氢原子可能以接您氢的自然丰度同位素组成存在。
如本说明书所用,“D”和“d”均指的是氘(2H)。
在一些实施方案中,本发明的化合物及其药学上可接受的盐包括一个或多个原子,其原子质量或质量数不同于指定元素最丰富的同位素的原子质量或质量数(“同位素标记的”化合物和盐)。可商购并适用于本发明的稳定同位素的实例包括但不限于氢,碳,氮,氧和磷的同位素,例如分别为2H、13C、15N、18O、17O和31p。
同位素标记的化合物和盐可以多种有益方式使用,包括用作药物。在一些实施方案中,同位素标记的化合物和盐是氘(2H)-标记的。氘(2H)-标记的化合物和盐可用于治疗,与非(2H)-标记的化合物相比具有潜在的治疗优势。通常,由于下述动力学同位素效应,与未同位素标记的那些相比,氘(2H)-标记的化合物和盐可以具有更高的代谢稳定性。较高的代谢稳定性直接转化为增加的体内半衰期或较低的剂量,这在大多数情况下将代表本发明的优选实施方案。同位素标记的化合物和盐通常可以通过进行合成方案、实施例和相关描述中公开的方法,用容易获得的同位素标记的反应物代替非同位素标记的反应物制备。
氘(2H)-标记的化合物和盐可以通过主要的动力学同位素效应来控制化合物的氧化代谢速率。主要的动力学同位素效应是化学反应速率的变化,该变化是由同位素核的交换引起的,而同位素核的交换又是由参与反应的共价键的基态能变化引起的。较重的同位素的交换通常会降低化学键的基态能量,从而减少限速键的断裂。如果沿着多产物反应的坐标在鞍点区域内或附近发生键断裂,则产物分布比可以大为改变。为了解释:如果氘在不可交换的位置与碳原子键合,则kH/kD=2-7的速率差是典型的。有关进一步的讨论,请参见S.L.Harbeson和R.D.Tung,Deuterium In Drug Discovery and Development,Ann.Rep.Med.Chem.2011,46,403-417,通过引用将其全部内容并入本申请。
在本发明的同位素标记的化合物或其药学上可接受的盐的给定位置处掺入的同位素(例如,氘)的浓度可以由同位素富集因子定义。如本说明书所用,术语“同位素富集因子”是指同位素标记的化合物(或盐)中给定位置的同位素丰度与同位素的自然丰度之比。
当本发明化合物中的原子或其药学上可接受的盐被指定为氘时,此类化合物(或盐)具有的同位素富集因子至少为3000(掺入45%氘)。在一些实施方案中,同位素富集因子是在以下条件下至少3500(氘掺入52.5%),至少4000(氘掺入60%),至少4500(氘掺入67.5%),至少5000(掺入75%氘)。至少5500(掺入82.5%氘),至少6000(掺入90%氘),至少6333(掺入95%氘),至少6466.7(掺入97%氘),至少6600(掺入99%氘),或至少6633.3(掺入99.5%氘)。
在一些实施方案中,在本发明的化合物中未具体指定为“D”,“d”或“氘”的位置应理解为在其天然丰度同位素组成方面有氢。
盐、组合物、用途、制剂、施用和另外的活性剂
药学上可接受的盐和组合物
如本说明书所论述,本发明提供作为电压门控型钠通道的抑制剂的化合物,且因此本发明化合物可用于治疗包括但不限于以下的疾病、障碍及病症:慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛)、内脏痛、多发性硬化症、沙-马-图综合症、失禁、病理性咳嗽或心律失常。相应地,在本发明的另一个实施方案中,提供药学上可接受的组合物,其中该组合物包含任一本说明书所阐述的化合物,且任选包含药学上可接受的载体、佐剂或赋形剂。在某些实施方案中,这些组合物任选进一步包含一种或多种其他治疗剂。在一些实施方案中,所述其他治疗为钠通道抑制剂。
如本说明书所用,术语“药学上可接受的盐”是指在合理医学判断范围内适于与人类和低等动物组织接触使用而无过高毒性、刺激性、过敏反应等且与合理益处/风险比相称的那些盐。本发明化合物的“药学上可接受的盐”意指本发明的任一如下的无毒盐:其在向接受者给予后能够直接或间接提供本发明化合物或其抑制活性代谢物或残余物。本说明书所用的术语“其抑制活性代谢物或残余物”意指其代谢物或残余物也是电压门控型钠通道的抑制剂。
药学上可接受的盐为本领域内所熟知。例如,S.M.Berge等人在J.PharmaceuticalSciences,1977,66,1-19中详细阐述的药学上可接受的盐,该文献以引用方式并入本说明书。本发明化合物的药学上可接受的盐包括衍生自适宜无机和有机酸和碱的那些。药学上可接受的无毒酸加成盐的实例是无机酸(例如,盐酸、氢溴酸、磷酸、硫酸及高氯酸)或有机酸(例如,乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)或通过使用本领域内所用的其他方法(例如,离子交换)与氨基形成的盐。其他药学上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、已酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。衍生自适当碱的盐包括碱金属盐、碱土金属盐、铵盐及N+(C1-4烷基)4盐。本发明还涵盖本说明书所公开化合物的任一碱性含氮基团的季铵化。可通过这样的季铵化获得水或油可溶性或可分散性产物。代表性碱金属盐或碱土金属盐包括钠盐、锂盐、钾盐、钙盐、镁盐等。若适当,其他药学上可接受的盐包括无毒铵、季铵及胺阳离子,其是使用例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根及芳基磺酸根等抗衡离子形成的。
在一些实施方案中,的药学上可接受的盐具有式:/>其中X为-PO(OH)O-M+、-PO(O-)2·2M+或-PO(O-)2·D2+;M+为药学上可接受的一价阳离子;且D2+为药学上可接受的二价阳离子。
如本说明书所用,术语“一价阳离子”(M+)是指带有单个正电荷单元的阳离子。一价阳离子包括铵(例如,N(R9)4其中R9是H或C1-C4烷基),碱金属离子,例如钠,锂和钾离子,二环己基胺离子和N-甲基-D-葡糖胺离子。已经认识到,如果存在定义2M+,则M+各自可以相同或不同。
如本说明书所用,术语“二价阳离子”(D2+)是指带有两个正电荷单元的阳离子。二价阳离子包括碱土金属离子,例如钙和镁离子,以及二价铝离子。
术语“一价阳离子”和“二价阳离子”包括氨基酸阳离子,例如精氨酸,赖氨酸,鸟氨酸等的一价或二价离子。碱性含氮基团可以被质子化或可以被诸如以下的试剂季铵化:低级烷基卤化物,例如甲基,乙基,丙基和丁基氯化物,溴化物和碘化物;二烷基硫酸盐,如二甲基,二乙基,二丁基;二戊基硫酸盐;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;芳烷基卤化物,例如苄基溴等。
如本说明书所阐述,本发明的药学上可接受的组合物额外包含药学上可接受的载体、佐剂或赋形剂,如本说明书所使用,其包括适于所期望的特定剂型的任一种及所有溶剂、稀释剂或其他液体赋形剂、分散液或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。Remington's Pharmaceutical Sciences,第16版,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)公开了用于配制药学上可接受的组合物的各种载体及制备其的已知技术。任何常用载体介质的使用均涵盖于本发明范围内,除非该常用载体介质与本发明化合物不兼容,例如产生任何不期望的生物学效应或另外以有害方式与药学上可接受的组合物中的任何其他组分相互作用。一些可用作药学上可接受的载体的材料的实例包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如,人类血清白蛋白)、缓冲物质(例如,磷酸盐、甘氨酸、山梨酸或山梨酸钾)、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁)、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、羊毛脂、糖(例如,乳糖、葡萄糖及蔗糖);淀粉,例如玉米淀粉及马铃薯淀粉;纤维素及其衍生物,例如羧甲基纤维素钠、乙基纤维素及醋酸纤维素;黄蓍胶粉;麦芽;明胶;滑石粉;赋形剂,例如可可脂及栓剂蜡;油,例如花生油、棉籽油;红花油;芝麻油;橄榄油;玉米油及大豆油;二醇;例如丙二醇或聚乙二醇;酯,例如油酸乙酯及月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁及氢氧化铝;海藻酸;无热原的水;等渗盐水;格氏试剂;乙醇及磷酸盐缓冲溶液,以等无毒相容性润滑剂(例如,月桂基硫酸钠及硬脂酸镁),以及根据制剂者的判断,该组合物中还可以存在着色剂、释放剂、包衣剂、甜味剂、矫味剂及芳香剂、防腐剂及抗氧化剂。
另一方面,本发明的特征在于药物组合物,其包含本发明的化合物或其药学上可接受的盐和药学上可接受的载体。
另一方面,本发明的特征在于药物组合物,其包含治疗有效量的化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体或介质。
化合物和药学上可接受的盐和组合物的用途
在另一个实施方案中,本发明的特征为一种抑制受试者的电压门控钠通道的方法,其包括对受试者施用本发明的化合物或其药学上可接受的盐或其药物组合物。另一方面,电压门控钠通道为Nav1.8。
另一方面,本发明的特征在于治疗受试者的如下疾病或减轻其严重性:慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛)、内脏痛、多发性硬化、沙-马-图综合征、失禁、病理性咳嗽或心律失常,其包含施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于治疗受试者的如下疾病或减轻其严重性:慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛、囊肿切除术疼痛、多发性硬化、沙-马-图综合征、失禁或心律失常,其包含施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
在另一个实施方案中,本发明的特征为一种治疗受试者的肠痛或减轻其严重性的方法,其中肠痛包括炎性肠病、克罗恩病疼痛或间质性膀胱炎疼痛,其中该方法包括施用有效量的本发明的化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗受试者的神经病变性疼痛或减轻其严重性的方法,该方法包括施用有效量的本发明的化合物,其药学上可接受的盐或其药物组合物。在一些方面,神经病变性疼痛包括疱疹后神经痛或特发性小纤维神经病。如本说明书所用,短语“特发性小纤维神经病”应理解为包括任何小纤维神经病。
在另一个实施方案中,本发明的特征为一种治疗受试者的神经病变性疼痛或减轻其严重性的方法,其中神经病变性疼痛包括疱疹后神经痛、糖尿病性神经痛、疼痛性HIV相关感觉神经病、三叉神经痛、灼口综合症、截肢手术后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、摩顿氏(Morton′s)神经瘤、神经挤压损伤、椎管狭窄、腕管综合症、神经根痛、坐骨神经痛;神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合症、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、脊髓损伤后疼痛、特发性小纤维神经病、特发性感觉神经病或三叉自主神经性头痛,其中该方法包括施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗减轻受试者的骨骼肌疼痛或其严重性的方法,包括给予有效量的本发明的化合物、其药学上可接受的盐或其药物组合物。在一些方面,肌肉骨骼疼痛包括骨关节炎疼痛。
在另一个实施方案中,本发明的特征为一种治疗受试者的肌肉骨骼痛或减轻其严重性的方法,其中肌肉骨骼痛包括骨关节炎痛、背痛、冷痛、烧伤痛或牙痛,其中该方法包括施用有效量的本发明的化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗受试者的炎性疼痛或减轻其严重性的方法,其中炎性疼痛包括类风湿性关节炎疼痛或外阴痛,其中所述方法包括施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗或减轻受试者的炎性疼痛的严重性的方法,其中炎性疼痛包括类风湿性关节炎疼痛,其中所述方法包括施用有效量的本发明化合物、其可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗受试者特发性疼痛或减轻其严重性的方法,其中特发性疼痛包括纤维肌痛,其中所述方法包括施用有效量的本发明化合物、药学上可接受的其盐或其药物组合物。
另一方面,本发明特征在于一种治疗患者的病理性咳嗽或减轻其严重性的方法,其中所述方法包括施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗受试者的急性疼痛或减轻其严重性的方法,该方法包括施用有效量的本发明的化合物、其药学上可接受的盐或其药物组合物。在一些方面,急性疼痛包括急性手术后疼痛。
另一方面,本发明的特征在于一种治疗受试者的手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛)或减轻其严重性的方法,该方法包括施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗或减轻受试者的拇囊炎切除术疼痛的严重程度的方法,该方法包括施用效量的本发明的化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗或减轻受试者的腹部成形术疼痛的程度的方法,该方法包括施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗或减轻对象的内脏痛的严重程度的方法,该方法包括施用效量的本发明的化合物,其药学上可接受的盐或其药物组合物。在一些方面,内脏痛包括来自腹部成形术的内脏痛。
另一方面,本发明特征在于一种方法,其中在用有效量的化合物、药学上可接受的盐或药物组合物治疗同时,之前或之后,用一种或多种另外的治疗剂治疗受试者。在一些实施方案中,另外的治疗剂为钠通道抑制剂。
另一方面,本发明的特征在于一种抑制生物样品中的电压门控钠通道的方法,该方法包括使生物样品与有效量的本发明化合物、其药学上可接受的盐或其药物组合物接触。另一方面,电压门控钠通道是Nav1.8。
另一方面,本发明的特征在于一种治疗受试者的如下疾病或减轻其严重性的方法:急性疼痛,慢性疼痛,神经病变性疼痛,炎性疼痛,关节炎,偏头痛,丛集性头痛,三叉神经痛,疱疹性神经痛,普通神经痛的方法,癫痫,癫痫病,神经退行性疾病,精神病,焦虑症,抑郁症,躁郁症,肌强直,心律不齐,运动障碍,神经内分泌失调,共济失调,多发性硬化,肠易激综合征,失禁,病理性咳嗽,内脏痛,骨关节炎疼痛,带状疱疹后神经痛,糖尿病性神经病,神经根痛,坐骨神经痛,背部疼痛,头部疼痛,颈部疼痛,严重疼痛,顽固性疼痛,伤害性疼痛,突破性疼痛,手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛),癌症疼痛,中风,脑缺血,外伤性脑损伤,肌萎缩性侧索硬化症,应激性心绞痛,运动性心绞痛,心悸,高血压或胃肠道蠕动异常,包括施用效量的本发明化合物、其药学上可接受的盐或其药物组合物。
另一方面,本发明的特征在于一种治疗或减轻受试者如下疾病的严重性的方法;股骨癌疼痛;非恶性慢性骨痛;类风湿关节炎;骨关节炎;椎管狭窄;神经性腰痛;肌筋膜疼痛综合征;纤维肌痛;颞下颌关节痛;慢性内脏痛,腹痛;胰腺疼痛;IBS疼痛;慢性和急性头痛;偏头痛;紧张性头痛;丛集性头痛;慢性和急性神经病变性疼痛,疱疹后神经痛;糖尿病性神经病;艾滋病毒相关的神经病;三叉神经痛;沙-马-图(Charcot-Marie-Tooth)神经病;遗传性感觉神经病;周围神经损伤;痛性神经瘤;异位近端和远端放电;神经根病;化疗引起的神经病变性疼痛;放疗引起的神经病变性疼痛;***切除术后的疼痛;中枢性疼痛;脊髓损伤疼痛;中风后疼痛;丘脑痛;复杂性局部疼痛综合征;幻肢痛;顽固性疼痛;急性疼痛,急性手术后疼痛;急性肌肉骨骼疼痛;关节痛;机械性腰痛;颈部疼痛;肌腱炎;伤痛;运动疼痛;急性内脏痛;肾盂肾炎;阑尾炎;胆囊炎;肠梗阻;疝气;胸痛,心脏痛;骨盆痛,肾绞痛,急性产科痛,分娩痛;剖宫产疼痛;急性炎性疼痛,烧伤痛,创伤痛;急性间歇性疼痛,子宫内膜异位;带状疱疹急性疼痛;镰状细胞性贫血;急性胰腺炎;突破性疼痛;口面部疼痛;鼻窦炎疼痛;牙齿疼痛;多发性硬化症(MS)疼痛;抑郁症疼痛;麻风痛;***疼痛;肥胖症;静脉炎痛;Guillain-Barre疼痛;腿部和脚趾移动疼痛;Haglund综合征;红毛痛;布里氏病疼痛;膀胱和泌尿生殖***疾病;尿失禁,病理性咳嗽;膀胱过度活动症;膀胱疼痛综合征;间质性膀胱炎(IC);***炎;I型复杂区域性疼痛综合征(CRPS),II型复杂性区域疼痛综合征(CRPS);广泛性疼痛,阵发性极端疼痛,瘙瘁,耳鸣或绞痛诱发的疼痛,包括施用有效量的本发明化合物、其药学上可接受的盐或其药物组合物。
应用的化合物、药学上可接受的盐和组合物
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用作药剂。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于抑制受试者的电压门控型钠通道的方法中。另一方面,电压门控型钠通道为Nav1.8。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的如下疾病或减轻其严重性的方法中:慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛)、内脏痛、多发性硬化、沙-马-图综合征、失禁、病理性咳嗽或心律失常。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的如下疾病或减轻其严重性的方法中:慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛、囊肿切除术疼痛、多发性硬化、沙-马-图综合征、失禁或心律失常。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗或减轻受试者的肠痛或减轻其严重性的方法中,其中肠痛包括炎性肠病、克罗恩病疼痛或间质性膀胱炎疼痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗或减轻神经病变性疼痛的受试者的严重程度的方法中。在一些方面,神经病变性疼痛包括疱疹后神经痛或特发性小纤维神经病。如本说明书所用,短语“特发性小纤维神经病”应理解为包括任何小纤维神经病。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的神经病变性疼痛或减轻其严重性的方法中,其中神经病变性疼痛包括疱疹后神经痛、糖尿病性神经痛、疼痛性HIV相关感觉神经病、三叉神经痛、灼口综合症、截肢手术后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、摩顿氏神经瘤、神经挤压损伤、椎管狭窄、腕管综合症、神经根痛、坐骨神经痛;神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合症、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、脊髓损伤后疼痛、特发性小纤维神经病、特发性感觉神经病或三叉自主神经性头痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗或减轻受试者的骨骼肌疼痛的严重性的方法中。在一些方面,肌肉骨骼疼痛包括骨关节炎疼痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的肌肉骨骼痛或减轻其严重性的方法中,其中肌肉骨骼痛包括骨关节炎痛、背痛、冷痛、烧伤痛或牙痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的炎性疼痛或减轻其严重性的方法中,其中炎性疼痛包括类风湿性关节炎疼痛或外阴痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的炎性疼痛或减轻其严重性的方法中,其中炎性疼痛包括类风湿性关节炎疼痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的特发性疼痛或减轻其严重性的方法中,其中特发性疼痛包括纤维肌痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗或受试者的病理性咳嗽或减轻其严重性的方法中。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的急性疼痛或减轻其严重性的方法中。在一些方面,急性疼痛包括急性手术后疼痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的手术后疼痛或减轻其严重性的方法中(例如,囊肿切除术疼痛或腹部成形术疼痛)。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的囊肿切除术疼痛或减轻其严重性的方法中。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的腹部成形术疼痛或减轻其严重性的方法中。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的内脏痛或减轻其严重性的方法中。在一些方面,内脏痛包括来自腹部成形术的内脏痛。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于一种方法中,其中在用有效量的化合物、药学上可接受的盐或药物组合物治疗同时,之前或之后,用一种或多种另外的治疗剂治疗受试者。在一些实施方案中,另外的治疗剂为钠通道抑制剂。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于抑制生物样品中的电压门控钠通道的方法,该方法包括使生物样品与有效量的本发明化合物、其药学上可接受的盐或其药物组合物接触。另一方面,电压门控钠通道是Nav1.8。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的如下疾病或减轻其严重性的方法:急性疼痛,慢性疼痛,神经病变性疼痛,炎性疼痛,关节炎,偏头痛,丛集性头痛,三叉神经痛,疱疹性神经痛,普通神经痛的方法,癫痫,癫痫病,神经退行性疾病,精神病,焦虑症,抑郁症,躁郁症,肌强直,心律不齐,运动障碍,神经内分泌失调,共济失调,多发性硬化,肠易激综合征,失禁,病理性咳嗽,内脏痛,骨关节炎疼痛,带状疱疹后神经痛,糖尿病性神经病,神经根痛,坐骨神经痛,背部疼痛,头部疼痛,颈部疼痛,严重疼痛,顽固性疼痛,伤害性疼痛,突破性疼痛,手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛),癌症疼痛,中风,脑缺血,外伤性脑损伤,肌萎缩性侧索硬化症,应激性心绞痛,运动性心绞痛,心悸,高血压或胃肠道蠕动异常。
另一方面,本发明的特征在于本发明的化合物或其药学上可接受的盐或其药物组合物,用于治疗受试者的如下疾病或减轻其严重性的方法中:股骨癌疼痛;非恶性慢性骨痛;类风湿关节炎;骨关节炎;椎管狭窄;神经性腰痛;肌筋膜疼痛综合征;纤维肌痛;颞下颌关节痛;慢性内脏痛,腹痛;胰腺疼痛;IBS疼痛;慢性和急性头痛;偏头痛;紧张性头痛;丛集性头痛;慢性和急性神经病变性疼痛,疱疹后神经痛;糖尿病性神经病;艾滋病毒相关的神经病;三叉神经痛;Charcot-Marie-Tooth神经病;遗传性感觉神经病;周围神经损伤;痛性神经瘤;异位近端和远端放电;神经根病;化疗引起的神经病变性疼痛;放疗引起的神经病变性疼痛;***切除术后的疼痛;中枢性疼痛;脊髓损伤疼痛;中风后疼痛;丘脑痛;复杂性局部疼痛综合征;幻肢痛;顽固性疼痛;急性疼痛,急性手术后疼痛;急性肌肉骨骼疼痛;关节痛;机械性腰痛;颈部疼痛;肌腱炎;伤痛;运动疼痛;急性内脏痛;肾盂肾炎;阑尾炎;胆囊炎;肠梗阻;疝气;胸痛,心脏痛;骨盆痛,肾绞痛,急性产科痛,分娩痛;剖宫产疼痛;急性炎性疼痛,烧伤痛,创伤痛;急性间歇性疼痛,子宫内膜异位;带状疱疹急性疼痛;镰状细胞性贫血;急性胰腺炎;突破性疼痛;口面部疼痛;鼻窦炎疼痛;牙齿疼痛;多发性硬化症(MS)疼痛;抑郁症疼痛;麻风痛;***疼痛;肥胖症;静脉炎痛;Guillain-Barre疼痛;腿部和脚趾移动疼痛;Haglund综合征;红毛痛;布里氏病疼痛;膀胱和泌尿生殖***疾病;尿失禁,病理性咳嗽;膀胱过度活动症;膀胱疼痛综合征;间质性膀胱炎(IC);***炎;I型复杂区域性疼痛综合征(CRPS),II型复杂性区域疼痛综合征(CRPS);广泛性疼痛,阵发性极端疼痛,瘙痒,耳鸣或绞痛诱发的疼痛。
药剂生产
另一方面,本发明提供本发明的化合物或其药学上可接受的盐或其药物组合物在制备药剂中的用途。
另一方面,本发明提供本发明的化合物或其药学上可接受的盐或其药物组合物在制备用于抑制电压门控型钠通道的药剂中的用途。另一方面,电压门控型钠通道为Nav1.8。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的如下疾病或减轻其严重性的药剂中的用途:慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛)、内脏痛、多发性硬化、沙-马-图综合征、失禁、病理性咳嗽或心律失常。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的如下疾病或减轻其严重性的药剂中的用途:慢性疼痛、肠痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛、囊肿切除术疼痛、多发性硬化、沙-马-图综合征、失禁或心律失常。
另一方面,本发明提供本说明书所述的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的肠痛或减轻其严重性的药剂中的用途,其中肠痛包括炎性肠病、克罗恩病疼痛或间质性膀胱炎疼痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的神经病变性疼痛或减轻其严重性的药剂中的用途。在一些方面,神经病变性疼痛包括疱疹后神经痛或特发性小纤维神经病。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的神经病变性疼痛或减轻其严重性的药剂中的用途,其中神经病变性疼痛包括疱疹后神经痛、糖尿病性神经痛、疼痛性HIV相关感觉神经病、三叉神经痛、灼口综合症、截肢手术后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、摩顿氏神经瘤、神经挤压损伤、椎管狭窄、腕管综合症、神经根痛、坐骨神经痛;神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合症、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、脊髓损伤后疼痛、特发性小纤维神经病、特发性感觉神经病或三叉自主神经性头痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的肌肉骨骼疼痛或减轻其严重性的药剂中的用途。在一些方面,肌肉骨骼疼痛包括骨关节炎疼痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的肌肉骨骼疼痛或减轻其严重性的药剂中的用途,其中肌肉骨骼疼痛包括骨关节炎疼痛、背痛、冷痛、烧伤痛或牙痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的炎性疼痛或减轻其严重性的药剂中的用途,其中炎性疼痛包括类风湿性关节炎疼痛或外阴痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的炎性疼痛或减轻其严重性的药剂中的用途,其中炎性疼痛包括类风湿性关节炎疼痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的特发性疼痛或减轻其严重性的药剂中的用途,其中特发性疼痛包括纤肌痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的病理性咳嗽或减轻其严重性的药剂中的用途。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的急性疼痛或减轻其严重性的药剂中的用途。在一些方面,急性疼痛包括急性手术后疼痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛)或减轻其严重性的药剂中的用途。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的囊肿切除术疼痛或减轻其严重性的药剂中的用途。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的腹部成形术疼痛或减轻其严重性的药剂中的用途。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的内脏痛或减轻其严重性的药剂中的用途。在一些方面,内脏痛包括来自腹部成形术的内脏痛。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备药剂中的用途,其中在用所述化合物或药物组合物治疗同时,之前或之后,用一种或多种另外的治疗剂治疗受试者。在一些实施方案中,另外的治疗剂为钠通道抑制剂。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的如下疾病或减轻其严重性的药剂中的用途:急性疼痛,慢性疼痛,神经病变性疼痛,炎性疼痛,关节炎,偏头痛,丛集性头痛,三叉神经痛,疱疹性神经痛,普通神经痛的方法,癫痫,癫痫病,神经退行性疾病,精神病,焦虑症,抑郁症,躁郁症,肌强直,心律不齐,运动障碍,神经内分泌失调,共济失调,多发性硬化,肠易激综合征,失禁,病理性咳嗽,内脏痛,骨关节炎疼痛,带状疱疹后神经痛,糖尿病性神经病,神经根痛,坐骨神经痛,背部疼痛,头部疼痛,颈部疼痛,严重疼痛,顽固性疼痛,伤害性疼痛,突破性疼痛,手术后疼痛(例如,囊肿切除术疼痛或腹部成形术疼痛),癌症疼痛,中风,脑缺血,外伤性脑损伤,肌萎缩性侧索硬化症,应激性心绞痛,运动性心绞痛,心悸,高血压或胃肠道蠕动异常。
另一方面,本发明提供本发明的化合物、其药学上可接受的盐或其药物组合物在制备用于治疗受试者的如下疾病或减轻其严重性的药剂中的用途:股骨癌疼痛;非恶性慢性骨痛;类风湿关节炎;骨关节炎;椎管狭窄;神经性腰痛;肌筋膜疼痛综合征;纤维肌痛;颞下颌关节痛;慢性内脏痛,腹痛;胰腺疼痛;IBS疼痛;慢性和急性头痛;偏头痛;紧张性头痛;丛集性头痛;慢性和急性神经病变性疼痛,疱疹后神经痛;糖尿病性神经病;艾滋病毒相关的神经病;三叉神经痛;Charcot-Marie-Tooth神经病;遗传性感觉神经病;周围神经损伤;痛性神经瘤;异位近端和远端放电;神经根病;化疗引起的神经病变性疼痛;放疗引起的神经病变性疼痛;***切除术后的疼痛;中枢性疼痛;脊髓损伤疼痛;中风后疼痛;丘脑痛;复杂性局部疼痛综合征;幻肢痛;顽固性疼痛;急性疼痛,急性手术后疼痛;急性肌肉骨骼疼痛;关节痛;机械性腰痛;颈部疼痛;肌腱炎;伤痛;运动疼痛;急性内脏痛;肾盂肾炎;阑尾炎;胆囊炎;肠梗阻;疝气;胸痛,心脏痛;骨盆痛,肾绞痛,急性产科痛,分娩痛;剖宫产疼痛;急性炎性疼痛,烧伤痛,创伤痛;急性间歇性疼痛,子宫内膜异位;带状疱疹急性疼痛;镰状细胞性贫血;急性胰腺炎;突破性疼痛;口面部疼痛;鼻窦炎疼痛;牙齿疼痛;多发性硬化症(MS)疼痛;抑郁症疼痛;麻风痛;***疼痛;肥胖症;静脉炎痛;Guillain-Barre疼痛;腿部和脚趾移动疼痛;Haglund综合征;红毛痛;布里氏病疼痛;膀胱和泌尿生殖***疾病;尿失禁,病理性咳嗽;膀胱过度活动症;膀胱疼痛综合征;间质性膀胱炎(IC);***炎;I型复杂区域性疼痛综合征(CRPS),II型复杂性区域疼痛综合征(CRPS);广泛性疼痛,阵发性极端疼痛,瘙瘁,耳鸣或绞痛诱发的疼痛。
药学上可接受的盐和组合物的施用
在本发明的某些实施方案中,本发明的化合物、其药学上可接受的盐或其组合物的“有效量”是可有效治疗或减轻上述病症的一种或多种的严重性的量。
根据本发明方法,该化合物及组合物可使用有效治疗一种或多种本说明书中所列举的疼痛或非疼痛疾病或减轻其严重性的任何量和任何给药途径给药。所需确切量可随个体而变化,取决于个体的物种、年龄及一般状况、感染的严重性、特定药物、其给药模式等。本发明化合物优选配制为剂量单位形式以便于给药和统一剂量。本说明书所使用的表述“剂量单位形式”是指适于欲治疗患者的药剂的物理离散单位。然而,应了解,本发明化合物及组合物的总日用量可由主治医生在合理医学判断范围内决定。任意特定个体或生物体的具体有效剂量水平将取决于多种因素,包括所治疗的疾病以及疾病的严重性;所用具体化合物的活性;所用具体组合物;个体的年龄、体重、一般健康状况、性别及饮食;所用具体化合物的给药时间、给药途径及***速率;治疗持续时间;与所用具体化合物组合或同时使用的药物;及药学领域中众所周知的类似因素。本说明书所用的术语“个体”或“患者”意指动物,优选哺乳动物,最优选人类。
根据所治疗的病况的严重性,可以通过以下方式将本发明的药学上可接受的组合物施用给人和其它动物:口服、经直肠、胃肠外、经脑池内、经***内、经腹膜内、局部(如通过粉剂、软膏或滴剂)、经口腔(如口服喷雾或鼻喷雾)等。在某些实施方案中,本发明的化合物盐和组合物可以以有效获得所期望的治疗效应的每天约0.001mg/kg受试者体重到约100mg/kg受试者体重或每天约0.01mg/kg受试者体重到约50mg/kg受试者体重的剂量水平,每天一次或多次,口服或胃肠外给药。
用于口服给药的液体剂型包括但不限于药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆及酏剂。除活性化合物外,液体剂型可含有本领域内常用的惰性稀释剂(例如水或其他溶剂)、增溶剂及乳化剂,例如,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(具体地为棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油及芝麻油)、甘油、四氢糠醇、聚乙二醇及山梨糖醇酐的脂肪酸酯及其混合物。除惰性稀释剂外,口服组合物还可包括佐剂,例如,润湿剂、乳化剂及悬浮剂、甜味剂、矫味剂及芳香剂。
可根据已知技术使用适宜分散剂或润湿剂及悬浮剂来配制注射剂,例如,无菌可注射水性或油性悬浮液。无菌注射剂还可以是在无毒的胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮液或乳液,例如在1,3-丁二醇中的溶液。可采用的可接受的赋形剂及溶剂尤其为水、格氏溶液、U.S.P.及等渗氯化钠溶液。另外,通常采用无菌不挥发性油作为溶剂或悬浮介质。出于此目的,可采用包括合成单甘油酯或二甘油酯的任何温和不挥发性油。另外,在注射剂中可使用例如油酸等脂肪酸。
注射剂可例如通过经细菌截留滤器过滤或通过引入灭菌剂来进行灭菌,该灭菌剂呈可在使用前溶解或分散于无菌水或其他无菌可注射介质中的无菌固体组合物形式。
为延长本发明化合物的效应,通常期望从皮下或肌内注射来减缓该化合物的吸收。这可以通过使用具有较差水溶性的晶体或无定形材料的液体悬浮液来实现。因此,化合物的吸收速率取决于其溶解速率,而溶解速率进而可取决于晶体大小及晶型。或者,通过将化合物溶解或悬浮于油性赋形剂中来实现胃肠外给药化合物形式的延迟吸收。通过在生物可降解聚合物(例如,聚丙交酯-乙交酯)中形成化合物的微囊基质来制备可注射的储库形式。视化合物与聚合物的比及所用特定聚合物的性质而定,可控制化合物的释放速率。其他生物可降解聚合物的实例包括聚(原酸酯)及聚(酸酐)。还可通过将化合物装入与身体组织兼容的脂质体或微乳液中来制备储库型注射剂。
用于直肠或***给药的组合物优选为栓剂,其可通过将本发明化合物与适宜的无刺激性赋形剂或载体(例如可可脂、聚乙二醇或栓剂蜡)混合来制备,该赋形剂或载体在环境温度下为固体但在体温下为液体,因此其可在直肠或***腔内融化并释放活性化合物。
口服给药的固体剂型包括胶囊、片剂、丸剂、粉剂及颗粒。在该固体剂型中,活性化合物与至少一种药学上可接受的惰性赋形剂或载体(例如,柠檬酸钠或磷酸二钙)及/或以下物质混合:a)填充剂或增量剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇及硅酸,b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖及***胶,c)保湿剂,例如甘油,d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐及碳酸钠,e)溶液阻滞剂,例如石蜡,f)吸收促进剂,例如季铵化合物,g)润湿剂,例如鲸蜡醇及甘油单硬脂酸酯,h)吸收剂,例如高岭土及膨润土,及i)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物。在胶囊、片剂及丸剂的情况下,剂型还可包含缓冲剂。
在使用例如乳糖以及高分子聚乙二醇等赋形剂的软明胶胶囊及硬明胶胶囊中,还可采用类似类型的固体组合物作为填充剂。片剂、糖衣片、胶囊、丸剂及颗粒的固体剂型可使用包衣及包壳制备,例如肠溶包衣及药物制剂领域中熟知的其他包衣。该剂型可任选含有遮光剂且还可为任选以延迟方式仅(或优先)在肠道的某一部分中释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物质及蜡。在使用例如乳糖以及高分子量聚乙二醇等赋形剂的软和硬明胶胶囊中,还可采用相似类型的固体组合物作为填充剂。
活性化合物或盐还可呈具有一种或多种上述赋形剂的微囊化形式。片剂、糖衣片、胶囊、丸剂及颗粒的固体剂型可使用包衣及包壳来制备,例如肠溶包衣、控释包衣及药物制剂领域中熟知的其他包衣。在该固体剂型中,可将活性化合物与至少一种惰性稀释剂(例如,蔗糖、乳糖或淀粉)混合。该剂型除惰性稀释剂以外还可以像通常实践那样包含其他物质,例如压片润滑剂等压片助剂(例如硬脂酸镁及微晶纤维素)。在胶囊、片剂及丸剂的情况下,该剂型还可包含缓冲剂。该剂型可任选含有遮光剂且还可为任选以延迟方式仅(或优先)在肠道的某一部分中释放活性成分的组合物。可使用的包埋组合物的实例包括聚合物质及蜡。
用于局部或经皮给药本发明化合物的剂型包含软膏、糊剂、乳剂、洗剂、凝胶、粉剂、溶液、喷雾剂、吸入剂或贴片。根据需要,可在无菌条件下将活性成分与药学上可接受的载体及任何需要的防腐剂或缓冲剂混合。眼用制剂、滴耳剂及滴眼剂也涵盖于本发明范围内。另外,本发明涵盖使用经皮贴片,其具有向身体提供化合物的受控递送的额外优点。该剂型可通过将化合物溶解或分散于适当介质中制得。还可使用吸收促进剂来增加该化合物经过皮肤的通量。速率可通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中来控制。
如上文所述,本发明化合物可用作电压门控型钠通道的抑制剂。在一个实施方案中,本发明的化合物及组合物为Nav1.8的抑制剂,因此,不希望受任何特定理论限制,所述化合物、盐和组合物特别用于治疗疾病、病症或障碍(其中该疾病、病症或障碍涉及Nav1.8的激活或活性过高)或减轻其严重性。当特定的疾病、病症或障碍中涉及Nav1.8的激活或活性过高时,该疾病、病症或障碍还可称为“Nav1.8介导的疾病、病症或障碍”。因此,另一方面,本发明提供治疗疾病、病症或障碍或减轻其严重性的方法,其中该疾病状态涉及Nav1.8的激活或活性过高。
本发明中用作Nav1.8抑制剂的化合物的活性可根据国际公开号WO 2014/120808A9和美国公开号2014/0213616 A1一般所述的方法、本说明书所述的方法和根据本领域技术人员已知和可利用的另外的方法测定,通过引用并入所述文献的全部内容。
另外的治疗剂
还应理解,本发明的化合物及药学上可接受的组合物可用于组合疗法,即,该化合物及药学上可接受的组合物可与一种或多种其他期望的治疗剂或医学操作同时、之前或之后给予。在组合方案中使用的特定疗法(治疗剂或操作)组合将考虑期望治疗剂及/或操作的相容性及想要达成的期望的治疗效果。还应理解,所用疗法可对相同疾病达成期望效果(例如,本发明化合物可与用于治疗相同疾病的另一药剂同时给药),或它们可达成不同效果(例如,控制任何不良效应)。如本说明书中所使用的,将通常给药以治疗或预防特定疾病或病症的其他治疗剂看作“适于被治疗的疾病或病症”。例如,实例性的其他治疗剂包括但不限于:非阿片样镇痛药(吲哚类,例如依托度酸、吲哚美辛、舒林酸、托美丁;萘基烷酮类,例如萘丁美酮;昔康类,例如吡罗昔康;对氨基苯酚衍生物,例如醋氨酚;丙酸类,例如非诺洛芬、氟比洛芬、布洛芬、酮洛芬、萘普生、萘普生钠、奥沙普秦;水杨酸盐类,例如阿司匹林、三水杨酸胆碱镁、二氟尼柳;芬那酸,例如甲氯芬那酸、甲芬那酸;及吡唑类,例如保泰松);或阿片样物质(***)激动剂(例如可待因、芬太尼、氢***酮、左啡诺、哌替啶、***、***、羟考酮、羟***酮、右丙氧芬、丁丙诺啡、布托啡诺、地佐辛、纳布啡及喷他佐辛)。另外,非药物镇痛方法可以与给药一种或多种本发明化合物联合使用。例如,也可以使用麻醉(脊柱内输注、神经阻断术)、神经外科(CNS通路的神经松解术)、神经刺激术(经皮电刺激神经疗法、脊柱刺激)、理疗(物理疗法、矫正装置、透热疗法)或心理学(认知方法-催眠术、生物反馈或行为方法)方法。其他适当的治疗剂或方法概述于The Merck Manual,第19版,Ed.Robert S.Porter和Justin L.Kaplan,Merck Sharp&Dohme Corp.,a subsidiary ofMerck&Co.,Inc.,2011和Food and Drug Administration website,www.fda.gov中,通过引用将其全部内容并入本说明书。
在另一个实施方案中,另外适当的治疗药选自如下:
(1)阿片类镇痛药,例如***、氢***酮、羟***酮、左啡诺、左洛啡烷、***、哌替啶、芬太尼、可待因、双氢可待因、羟可酮、氢可酮、丙氧芬、纳美芬、烯丙***、纳洛酮、纳曲酮、丁丙诺啡、布托啡诺、纳布啡或喷他佐辛;
(2)非甾体类抗炎药(NSAID),例如阿司匹林、双氯芬那、二氟尼柳、依托度酸、芬布芬、非诺洛芬、氟苯柳、氟比洛芬、布洛芬、吲哚美辛、酮洛芬、酮咯酸、甲氯芬那酸、甲芬那酸、美洛昔康、萘丁美酮、萘普生、尼美舒利、硝基氟吡洛芬、奥沙拉秦、奥沙普秦、保泰松、吡罗昔康、柳氮磺胺吡啶、舒林酸、托美丁或佐美酸;
(3)巴比妥盐镇静剂,例如异戊巴比妥、阿普比妥、仲丁比妥、布他比妥、甲苯比妥、美沙比妥、美索比妥、戊巴比妥、***、司可巴比妥、他布比妥、硫戊巴比妥或硫喷妥钠;
(4)具有镇静剂作用的苯二氮杂类例如氯眠宁、氯氮/>***、氟西泮、劳拉西泮、奥沙西泮、替马西泮或***仑;
(5)具有镇静剂作用的组胺(H1)拮抗剂,例如苯海拉明、吡拉明、异丙嗪、氯苯那敏或氯环利嗪;
(6)镇静剂,例如格鲁米特、甲丙氨酯、甲喹酮或氯醛比林;
(7)骨骼肌松弛剂,例如巴氯芬、卡立普多、氯唑沙宗、环苯扎林、美索巴莫或奥芬那君;
(8)NMDA受体拮抗剂,例如右美沙芬((+)-3-羟基-N-甲基***烷)或其代谢物右啡烷((+)-3-羟基-N-甲基***烷)、***、美金刚、吡咯并喹啉奎宁、顺式-4-(膦酰基甲基)-2-哌啶甲酸、布他品、EN-3231***与右美沙芬的组合制剂)、托吡酯、奈拉美生或培净福太,包括NR2B拮抗剂,例如艾芬地尔、曲索罗地或(-)-(R)-6-{2-[4-(3-氟苯基)-4-羟基-1-哌啶基]-1-羟乙基-3,4-二氢-2(1H)-喹啉酮;
(9)α-肾上腺素能药,例如多沙唑嗪、坦洛新、可乐定、胍法辛、右美托咪定、***或4-氨基-6,7-二甲氧基-2-(5-甲烷-磺酰氨基-1,2,3,4-四氢异喹啉-2-基)-5-(2-吡啶基)喹唑啉;
(10)三环抗抑郁剂,例如地昔帕明、丙咪嗪、阿米替林或去甲替林;
(11)抗惊厥药,例如卡马西平拉莫三嗪、托吡酯、拉科沙胺或丙戊酸盐;
(12)速激肽(NK)拮抗剂,具体可举出,NK-3、NK-2或NK-1拮抗剂,例如(αR,9R)-7-[3,5-双(三氟甲基)苄基]-8,9,10,11-四氢-9-甲基-5-(4-甲基苯基)-7H-[1,4]二氮杂环辛并[2,1-g][1,7]-萘啶-6-13-二酮(TAK-637)、5-[[(2R,3S)-2-[(1R)-1-[3,5-双(三氟甲基)苯基]乙氧基-3-(4-氟苯基)-4-吗啉基]-甲基]-1,2-二氢-3H-1,2,4-***-3-酮(MK-869)、阿瑞吡坦、拉奈匹坦、达匹坦或3-[[2-甲氧基-5-(三氟甲氧基)苯基]-甲基氨基]-2-苯基哌啶(2S,3S);
(13)毒蕈碱拮抗剂,例如奥昔布宁、托特罗定、丙哌维林、曲司氯铵、达非那新、索非那新、替米维林及异丙托铵;
(14)COX-2选择性抑制剂,例如塞来昔布、罗非昔布、帕瑞考布、伐地考昔、地拉考昔、艾托考昔或鲁米考昔;
(15)煤焦油镇痛药,具体可举出扑热息痛;
(16)安定药,例如氟哌利多、氯丙嗪、氟哌啶醇、奋乃静、硫利哒嗪、美索达嗪、三氟拉嗪、氟奋乃静、氯氮平、奥氮平、利培酮、齐拉西酮、喹硫平、舍吲哚、阿立哌唑、索奈哌唑、布南色林、伊潘立酮、哌罗匹隆、雷氯必利、佐替平、联苯芦诺、阿塞那平、鲁拉西酮、氨磺必利、巴拉皮利酮(Balaperidone)、帕林多尔、依利色林、奥沙奈坦、利莫那班、美兰纳坦、或沙立佐坦;
(17)野香草受体激动剂(例如树脂毒素或Civamide)或拮抗剂(例如辣椒平,GRC-15300);
(18)p-肾上腺素能药,例如***;
(19)局部麻醉剂,例如美西律;
(20)皮质类固醇,例如***;
(21)5-HT受体激动剂或拮抗剂,具体可举出5-HT1B/1D激动剂,例如依来曲普坦、舒马普坦、那拉曲坦、佐米曲普坦或利扎曲普坦;
(22)5-HT2A受体拮抗剂,例如R(+)-α-(2,3-二甲氧基-苯基)-1-[2-(4-氟苯基乙基)]-4-哌啶甲醇(MDL-100907);
(23)胆碱性(烟碱)镇痛药,例如异丙克兰(TC-1734)、(E)-N-甲基-4-(3-吡啶基)-3-丁烯-1-胺(RJR-2403)、(R)-5-(2-氮杂环丁基甲氧基)-2-氯吡啶(ABT-594)或烟碱;
(24)曲马多ER(Ultram/>)、他喷他多ER/>
(25)PDE5抑制剂,例如5-[2-乙氧基-5-(4-甲基-1-哌嗪基-磺酰基)苯基]-1-甲基-3-正丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮(西地那非)、(6R,12aR)-2,3,6,7,12,12a-六氢-2-甲基-6-(3,4-亚甲基二氧基苯基)-吡嗪并[2′,1′:6,1]-吡啶并[3,4-b]吲哚-1,4-二酮(IC-351或他达拉非)、2-[2-乙氧基-5-(4-乙基-哌嗪-1-基-1-磺酰基)-苯基]-5-甲基-7-丙基-3H-咪唑并[5,1-f][1,2,4]三嗪-4-酮(伐地那非)、5-(5-乙酰基-2-丁氧基-3-吡啶基)-3-乙基-2-(1-乙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、5-(5-乙酰基-2-丙氧基-3-吡啶基)-3-乙基-2-(1-异丙基-3-氮杂环丁基)-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、5-[2-乙氧基-5-(4-乙基哌嗪-1-基磺酰基)吡啶-3-基]-3-乙基-2-[2-甲氧基乙基]-2,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮、4-[(3-氯-4-甲氧基苄基)氨基]-2-[(2S)-2-(羟甲基)吡咯烷-1-基]-N-(嘧啶-2-基甲基)嘧啶-5-甲酰胺、3-(1-甲基-7-氧代-3-丙基-6,7-二氢-1H-吡唑并[4,3-d]嘧啶-5-基)-N-[2-(1-甲基吡咯烷-2-基)乙基]-4-丙氧基苯磺酰胺;
(26)α-2-δ配体,例如加巴喷丁加巴喷丁GR/>加巴喷丁酯/>普瑞巴林/>3-甲基加巴喷丁、(1[α],3[α],5[α])(3-氨基-甲基-双环[3.2.0]庚-3-基)-乙酸、(3S,5R)-3-氨基甲基-5-甲基-庚酸、(3S,5R)-3-氨基-5-甲基-庚酸、(3S,5R)-3-氨基-5-甲基-辛酸、(2S,4S)-4-(3-氯苯氧基)脯氨酸、(2S,4S)-4-(3-氟苄基)-脯氨酸、[(1R,5R,6S)-6-(氨基甲基)双环[3.2.0]庚-6-基]乙酸、3-(1-氨基甲基-环己基甲基)-4H-[1,2,4]噁二唑-5-酮、C-[1-(1H-四唑-5-基甲基)-环庚基]-甲胺、(3S,4S)-(1-氨基甲基-3,4-二甲基-环戊基)-乙酸、(3S,5R)-3-氨基甲基-5-甲基-辛酸、(3S,5R)-3-氨基-5-甲基-壬酸、(3S,5R)-3-氨基-5-甲基-辛酸、(3R,4R,5R)-3-氨基-4,5-二甲基-庚酸及(3R,4R,5R)-3-氨基-4,5-二甲基-辛酸;
(27)***素,例如KHK-6188;
(28)亲代谢性谷氨酸盐亚型1受体(mGluRl)拮抗剂;
(29)5-羟色胺再摄取抑制剂,例如舍曲林、舍曲林代谢物去甲基舍曲林、氟西汀、诺氟西汀(氟西汀去甲基代谢物)、氟伏沙明、帕罗西汀、西酞普兰、西酞普兰代谢物去甲基西酞普兰、依他普仑、d,1-芬氟拉明、非莫西汀、伊福西汀、氰基度硫平(cyanodothiepin)、利托西汀、达泊西汀、萘法唑酮、西文氯胺及曲唑酮;
(30)去甲肾上腺素(正肾上腺素)再吸收抑制剂,例如马普替林、洛非帕明、米氮平、羟丙替林、非唑拉明、托莫西汀、米色安林、安非他酮、安非他酮代谢物羟基安非他酮、诺米芬辛及维洛沙秦尤其可举出选择性去甲肾上腺素再吸收抑制剂,例如瑞波西汀,具体地可举出(S,S)-瑞波西汀;
(31)5-羟色胺-去甲肾上腺素双重再吸收抑制剂,例如文拉法辛、文拉法辛代谢物O-去甲基文拉法辛、氯米帕明、氯米帕明代谢物去甲基氯米帕明、度洛西汀米那普仑及丙咪嗪;
(32)诱生型一氧化氮合酶(iNOS)抑制剂,例如S-[2-[(1-亚氨基乙基)氨基]乙基]-L-高半胱氨酸、S-[2-[(1-亚氨基乙基)-氨基]乙基]-4,4-二氧代-L-半胱氨酸、S-[2-[(1-亚氨基乙基)氨基]乙基]-2-甲基-L-半胱氨酸、(2S,5Z)-2-氨基-2-甲基-7-[(1-亚氨基乙基)氨基]-5-庚酸、2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)-丁基]硫代]-S-氯-S-吡啶甲腈;2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)丁基]硫代]-4-氯苯甲腈、(2S,4R)-2-氨基-4-[[2-氯-5-(三氟甲基)苯基]硫代]-5-噻唑丁醇、2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)丁基]硫代]-6-(三氟甲基)-3-吡啶甲腈、2-[[(1R,3S)-3-氨基-4-羟基-1-(5-噻唑基)丁基]硫代]-5-氯苯甲腈、N-[4-[2-(3-氯苄基氨基)乙基]苯基]噻吩-2-甲脒、NXN-462或胍基乙基二硫化物;
(33)乙酰胆碱酯酶抑制剂,例如多奈哌齐;
(34)***素E2亚型4(EP4)拮抗剂,例如N-[({2-[4-(2-乙基-4,6-二甲基-1H-咪唑并[4,5-c]吡啶-1-基)苯基]乙基}氨基)-羰基]-4-甲基苯磺酰胺或4-[(15)-1-({[5-氯-2-(3-氟苯氧基)吡啶-3-基]羰基}氨基)乙基]苯甲酸;
(35)白三烯B4拮抗剂;例如1-(3-联苯-4-基甲基-4-羟基-色满-7-基)-环戊烷甲酸(CP-105696)、5-[2-(2-羧乙基)-3-[6-(4-甲氧基苯基)-5E-己烯基]氧基苯氧基]-戊酸(ONO-4057)或DPC-11870;
(36)5-脂氧合酶抑制剂,例如齐留通、6-[(3-氟-5-[4-甲氧基-3,4,5,6-四氢-2H-吡喃-4-基])苯氧基-甲基]-1-甲基-2-喹诺酮(ZD-2138)或2,3,5-三甲基-6-(3-吡啶基甲基)-1,4-苯醌(CV-6504);
(37)钠通道阻断剂,例如利多卡因、利多卡因加丁卡因乳膏(ZRS-201)或乙酸艾司利卡西平;
(38)Nav1.7阻断剂,例如XEN-402,XEN403,TV-45070,PF-05089771,CNV1014802,GDC-0276,RG7893,和例如公开在如下文献中的那些:WO2011/140425(US2011/306607);WO2012/106499(US2012196869);WO2012/112743(US2012245136);WO2012/125613(US2012264749);WO2012/116440(US2014187533);WO2011026240(US2012220605);US8883840;US8466188;或WO2013/109521(US2015005304),通过引用将每一申请的全部内容并入本说明书。
(38a)Nav1.7阻断剂,例如(2-苯甲基螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基)-(4-异丙氧基-3-甲基-苯基)甲酮、2,2,2-三氟-1-[1′-[3-甲氧基-4-[2-(三氟甲氧基)乙氧基]苯甲酰基]-2,4-二甲基-螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]乙酮、[8-氟-2-甲基-6-(三氟甲基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]-(4-异丁氧基-3-甲氧基-苯基)甲酮、1-(4-二苯甲基哌嗪-1-基)-3-[2-(3,4-二甲基苯氧基)乙氧基]丙-2-醇、(4-丁氧基-3-甲氧基-苯基)-[2-甲基-6-(三氟甲基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]甲酮、[8-氟-2-甲基-6-(三氟甲基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]-(5-异丙氧基-6-甲基-2-吡啶基)甲酮、(4-异丙氧基-3-甲基-苯基)-[2-甲基-6-(1,1,2,2,2-五氟乙基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]甲酮、5-[2-甲基-4-[2-甲基-6-(2,2,2-三氟乙酰基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-羰基]苯基]吡啶-2-甲腈、(4-异丙氧基-3-甲基-苯基)-[6-(三氟甲基)螺[3,4-二氢-2H-吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]甲酮、2,2,2-三氟-1-[1′-[3-甲氧基-4-[2-(三氟甲氧基)乙氧基]苯甲酰基]-2-甲基-螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]乙酮、2,2,2-三氟-1-[1′-(5-异丙氧基-6-甲基-吡啶-2-羰基)-3,3-二甲基-螺[2,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]乙酮、2,2,2-三氟-1-[1′-(5-异戊氧基吡啶-2-羰基)-2-甲基-螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]乙酮、(4-异丙氧基-3-甲氧基-苯基)-[2-甲基-6-(三氟甲基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]甲酮、2,2,2-三氟-1-[1′-(5-异戊氧基吡啶-2-羰基)-2,4-二甲基-螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]乙酮、1-[(3S)-2,3-二甲基-1′-[4-(3,3,3-三氟丙氧基甲基)苯甲酰基]螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]-2,2,2-三氟-乙酮、[8-氟-2-甲基-6-(三氟甲基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]-[3-甲氧基-4-[(1R)-1-甲基丙氧基]苯基]甲酮、2,2,2-三氟-1-[1′-(5-异丙氧基-6-甲基-吡啶-2-羰基)-2,4-二甲基-螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]乙酮、1-[1′-[4-甲氧基-3-(三氟甲基)苯甲酰基]-2-甲基-螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-6-基]-2,2-二甲基-丙-1-酮、(4-异丙氧基-3-甲基-苯基)-[2-甲基-6-(三氟甲基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]甲酮、[2-甲基-6-(1-甲基环丙烷羰基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]-[4-(3,3,3-三氟丙氧基甲基)苯基]甲酮、4-溴-N-(4-溴苯基)-3-[(1-甲基-2-氧代-4-哌啶基)氨磺酰基]苯甲酰胺或(3-氯-4-异丙氧基-苯基)-[2-甲基-6-(1,1,2,2,2-五氟乙基)螺[3,4-二氢吡咯并[1,2-a]吡嗪-1,4′-哌啶]-1′-基]甲酮。
(39)Nav1.8阻断剂,例如PF-04531083、PF-06372865,以及例如公开于如下所述文献中的Nav1.8阻断剂:WO2008/135826(US2009048306),WO2006/011050(US2008312235),WO2013/061205(US2014296313),US20130303535,WO2013131018,US8466188,WO2013114250(US2013274243),WO2014/120808(US2014213616),WO2014/120815(US2014228371)WO2014/120820(US2014221435),WO2015/010065(US20160152561)和WO2015/089361(US20150166589),将每一申请的全部内容作为用于并入本说明书。
(39a)Nav1.8阻断剂,例如4,5-二氯-2-(4-氟-2-甲氧基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺、2-(4-氟-2-甲氧基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(全氟乙基)苯甲酰胺、4,5-二氯-2-(4-氟苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺、4,5-二氯-2-(3-氟-4-甲氧基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺、2-(4-氟-2-甲氧基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-5-(三氟甲基)苯甲酰胺、N-(2-氧代-1,2-二氢吡啶-4-基)-2-(4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰胺、2-(4-氟苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(全氟乙基)苯甲酰胺、5-氯-2-(4-氟-2-甲氧基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺、N-(2-氧代-1,2-二氢吡啶-4-基)-2-(4-(三氟甲氧基)苯氧基)-5-(三氟甲基)苯甲酰胺、2-(4-氟-2-甲基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-5-(三氟甲基)苯甲酰胺、2-(2-氯-4-氟苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-5-(三氟甲基)苯甲酰胺、5-氯-2-(4-氟-2-甲基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺、4-氯-2-(4-氟-2-甲基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺、5-氯-2-(2-氯-4-氟苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)苯甲酰胺、2-((5-氟-2-羟基苯甲基)氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺、N-(2-氧代-1,2-二氢吡啶-4-基)-2-(邻甲苯氧基)-5-(三氟甲基)苯甲酰胺、2-(2,4-二氟苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺、N-(2-氧代-1,2-二氢吡啶-4-基)-2-(2-(三氟甲氧基)苯氧基)-5-(三氟甲基)苯甲酰胺、2-(4-氟苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-5-(三氟甲基)苯甲酰胺,在一个实施方案中,化合物为3-(4-氟-2-甲氧基苯氧基)-N-(3-(甲基磺酰基)苯基)喹喔啉-2-甲酰胺、3-(2-氯-4-氟苯氧基)-N-(3-氨磺酰基苯基)喹喔啉-2-甲酰胺、3-(2-氯-4-甲氧基苯氧基)-N-(3-氨磺酰基苯基)喹喔啉-2-甲酰胺、3-(4-氯-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)喹喔啉-2-甲酰胺、4-(3-(4-(三氟甲氧基)苯氧基)喹喔啉-2-甲酰氨基)吡啶甲酸、2-(2,4-二氟苯氧基)-N-(3-氨磺酰基苯基)喹啉-3-甲酰胺、2-(4-氟-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)喹啉-3-甲酰胺、3-(2,4-二氟苯氧基)-N-(3-氨磺酰基苯基)喹喔啉-2-甲酰胺、N-(3-氨磺酰基苯基)-2-(4-(三氟甲氧基)苯氧基)喹啉-3-甲酰胺、N-(3-氨磺酰基苯基)-3-(4-(三氟甲氧基)苯氧基)喹喔啉-2-甲酰胺、3-(4-氯-2-甲基苯氧基)-N-(3-氨磺酰基苯基)喹喔啉-2-甲酰胺、5-(3-(4-(三氟甲氧基)苯氧基)喹喔啉-2-甲酰氨基)吡啶甲酸、3-(4-氟-2-甲氧基苯氧基)-N-(2-氧代-2,3-二氢-1H-苯并[d]咪唑-5-基)喹喔啉-2-甲酰胺、3-(4-氟-2-甲氧基苯氧基)-N-(吡啶-4-基)喹喔啉-2-甲酰胺、3-(4-氟苯氧基)-N-(3-氨磺酰基苯基)喹喔啉-2-甲酰胺、N-(3-氰基苯基)-3-(4-氟-2-甲氧基苯氧基)喹喔啉-2-甲酰胺、N-(4-氨基甲酰基苯基)-3-(4-氟-2-甲氧基苯氧基)喹喔啉-2-甲酰胺、4-(3-(4-(三氟甲氧基)苯氧基)喹喔啉-2-甲酰氨基)苯甲酸、N-(4-氰基苯基)-3-(4-氟-2-甲氧基苯氧基)喹喔啉-2-甲酰胺、5-(4,5-二氯-2-(4-氟-2-甲氧基苯氧基)苯甲酰氨基)吡啶甲酸、5-(2-(2,4-二甲氧基苯氧基)-4,6-双(三氟甲基)苯甲酰氨基)吡啶甲酸、4-(4,5-二氯-2-(4-氟-2-甲氧基苯氧基)苯甲酰氨基)苯甲酸、5-(2-(4-氟-2-甲氧基苯氧基)-4,6-双(三氟甲基)苯甲酰氨基)吡啶甲酸、4-(2-(4-氟-2-甲氧基苯氧基)-4-(全氟乙基)苯甲酰氨基)苯甲酸、5-(2-(4-氟-2-甲氧基苯氧基)-4-(全氟乙基)苯甲酰氨基)吡啶甲酸、4-(2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)苯甲酸、5-(4,5-二氯-2-(4-氟-2-甲氧基苯氧基)苯甲酰氨基)吡啶甲酸、4-(2-(2-氯-4-氟苯氧基)-4-(全氟乙基)苯甲酰氨基)苯甲酸、4-(2-(4-氟-2-甲基苯氧基)-4-(全氟乙基)苯甲酰氨基)苯甲酸、4-(4,5-二氯-2-(4-(三氟甲氧基)苯氧基)苯甲酰氨基)苯甲酸、4-(4,5-二氯-2-(4-氯-2-甲基苯氧基)苯甲酰氨基)苯甲酸、5-(4-(四叔丁基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰氨基)吡啶甲酸、5-(4,5-二氯-2-(4-(三氟甲氧基)苯氧基)苯甲酰氨基)吡啶甲酸、4-(4,5-二氯-2-(4-氟-2-甲基苯氧基)苯甲酰氨基)苯甲酸、5-(4,5-二氯-2-(2,4-二甲氧基苯氧基)苯甲酰氨基)吡啶甲酸、5-(4,5-二氯-2-(2-氯-4-氟苯氧基)苯甲酰氨基)吡啶甲酸、5-(4,5-二氯-2-(4-氟-2-甲基苯氧基)苯甲酰氨基)吡啶甲酸、4-(4,5-二氯-2-(4-氯-2-甲氧基苯氧基)苯甲酰氨基)苯甲酸、5-(4,5-二氯-2-(2,4-二氟苯氧基)苯甲酰氨基)吡啶甲酸、2-(4-氟苯氧基)-N-(3-氨磺酰基苯基)-5-(三氟甲基)苯甲酰胺、2-(4-氟苯氧基)-N-(3-氨磺酰基苯基)-4-(三氟甲基)苯甲酰胺、2-(2-氯-4-氟苯氧基)-N-(3-氨磺酰基苯基)-5-(三氟甲基)苯甲酰胺、2-(4-氟苯氧基)-N-(3-氨磺酰基苯基)-4-(三氟甲基)苯甲酰胺、2-(2-氯-4-氟苯氧基)-N-(3-氨磺酰基苯基)-6-(三氟甲基)苯甲酰胺、2-(2-氯-4-氟苯氧基)-5-(二氟甲基)-N-(3-氨磺酰基苯基)苯甲酰胺、2-(4-氟苯氧基)-4-(全氟乙基)-N-(3-氨磺酰基苯基)苯甲酰胺、2-(4-氯-2-甲氧基苯氧基)-4-(全氟乙基)-N-(3-氨磺酰基苯基)苯甲酰胺、2-(4-氟-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)-5-(三氟甲基)苯甲酰胺、5-氯-2-(4-氟-2-甲基苯氧基)-N-(3-氨磺酰基苯基)苯甲酰胺、4,5-二氯-2-(4-氟-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)苯甲酰胺、2,4-二氯-6-(4-氯-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)苯甲酰胺、2,4-二氯-6-(4-氟-2-甲基苯氧基)-N-(3-氨磺酰基苯基)苯甲酰胺、2-(4-氟-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)-4,6-双(三氟甲基)苯甲酰胺、2-(4-氟-2-甲基苯氧基)-N-(3-氨磺酰基苯基)-4,6-双(三氟甲基)苯甲酰胺、5-氯-2-(2-氯-4-氟苯氧基)-N-(3-氨磺酰基苯基)苯甲酰胺、2-(4-氟-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)-4-(三氟甲氧基)苯甲酰胺、2-(4-氟-2-甲氧基苯氧基)-N-(3-氨磺酰基苯基)-4-(三氟甲基)苯甲酰胺、4,5-二氯-2-(4-氟苯氧基)-N-(3-氨磺酰基苯基)苯甲酰胺、2-(4-氟-2-甲氧基苯氧基)-4-(全氟乙基)-N-(3-氨磺酰基苯基)苯甲酰胺、5-氟-2-(4-氟-2-甲基苯氧基)-N-(3-氨磺酰基苯基)苯甲酰胺、2-(2-氯-4-氟苯氧基)-4-氰基-N-(3-氨磺酰基苯基)苯甲酰胺或N-(3-氨磺酰基苯基)-2-(4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰胺。
(40)组合的Nav1.7及Nav1.8阻断剂,例如DSP-2230或BL-1021;
(41)5-HT3拮抗剂,例如昂丹司琼;
(42)TPRV 1受体激动剂,例如辣椒碱及其药学上可接受的盐及溶剂合物;
(43)烟碱性受体拮抗剂,例如伐尼克兰;
(44)N型钙通道拮抗剂,例如Z-160;
(45)神经生长因子拮抗剂,例如他尼珠单抗;
(46)内肽酶刺激剂,例如Senrebotase;
(47)血管紧张素II拮抗剂,例如EMA-401;
在一个实施方案中,其他适当的治疗剂选自V-116517、普瑞巴林、控释普瑞巴林、依佐加滨(Ezogabine)***/阿米替林局部乳膏/>AVP-923、吡仑帕奈(E-2007)、拉非酰胺、经皮布比卡因/>CNV1014802、JNJ-10234094(卡立氨酯)、BMS-954561或ARC-4558。
在另一个实施方案中,其他适当治疗剂选自N-(6-氨基-5-(2,3,5-三氯苯基)吡啶-2-基)乙酰胺;N-(6-氨基-5-(2-氯-5-甲氧基苯基)吡啶-2-基)-1-甲基-1H-吡唑-5-甲酰胺;或3-((4-(4-(三氟甲氧基)苯基)-1H-咪唑-2-基)甲基)氧杂环丁烷-3-胺。
在另一个实施方案中,另外的治疗剂为钠通道抑制剂(也称作钠通道阻断剂),例如上述鉴定的Nav1.7和Nav1.8阻断剂。
存在于本发明组合物中的其他治疗剂的量将不超过在包含该治疗剂作为唯一活性剂的组合物中正常给药的量。存在于本说明书所述组合物中的其他治疗剂的量将在包含该药剂作为唯一治疗活性剂的组合物中所正常存在量的约10%-100%的范围。
还可将本发明化合物或其药学上可接受的组合物并入用于包覆可植入医疗器械(例如假肢、人工瓣膜、人造血管、支架及导管)的组合物中。因此,在另一个实施方案中,本发明包括用于涂覆可植入装置的组合物,该组合物包含上文所概述并在本说明书中以类别和亚类阐述的本发明化合物及适于涂覆该可植入装置的载体。在又一个实施方案中,本发明包括涂覆有组合物的可植入装置,该组合物包含上文所概述并在本说明书中以类别和亚类阐述的本发明化合物及适于涂覆该可植入装置的载体。适宜的涂层及被包覆的可植入装置的一般制备记载于美国专利6099562;5886026;及5304121中。涂层通常是生物相容性聚合材料,例如水凝胶聚合物、聚甲基二硅氧烷、聚己内酯、聚乙二醇、聚乳酸、乙烯-乙酸乙烯酯及其混合物。该涂层可任选进一步被氟硅酮、多糖、聚乙二醇、磷脂或其组合的适宜顶涂层覆盖以使该组合物具有控释特性。
本发明的另一方面涉及抑制生物样品或受试者的Nav1.8活性,该方法包括施用给受试者本发明的化合物、其药学上可接受的盐或其组合物,或使所述生物样品接触它们。本说明书所用的术语“生物样品”包括(但不限于)细胞培养物或其提取物;由哺乳动物获得的活组织检查材料或其提取物;及其血液、唾液、尿、粪便、***、眼泪或其他体液或其提取物。
抑制生物样品中的Nav1.8活性适用于本领域技术人员已知的多种目的。此类目的的实例包括(但不限于)研究生物学和病理学现象中的钠通道、以及比较评估新的钠通道抑制剂。
实施例
通用方法。以在适合的氘代溶剂例如二甲亚砜-d6(DMSO-d6)中的溶液形式得到了1H NMR(400MHz)波谱。
通过LC/MS分析,采用两种方法:方法A和方法B之一测定了化合物纯度、保留时间和电喷雾质谱(ESI-MS)数据。
LC/MS方法A。如下进行LC/MS分析:采用Waters Acquity Ultra Performance LC***,通过反相UPLC,使用由Waters(pn:186002349)制造的Acquity UPLC BEH C18柱(30×2.1mm,1.7μm颗粒)和双重梯度运行1-99%流动相B,1.2分钟。流动相A=H20(0.05%CF3CO2H)。流动相B=CH3CN(0.035%CF3CO2H)。流速=1.5mL/min,注射体积=1.5μL,且柱温=60℃。
LC/MS方法B。如下进行LC/MS分析:采用Waters Acquity Ultra Performance LC***,通过反相UPLC,使用由Waters(pn:186002350)制造的Acquity UPLC BEH C18柱(50×2.1mm,1.7μm颗粒)和双重梯度运行1-99%流动相B,3.0分钟。流动相A=H2O(0.05%CF3CO2H)。流动相B=CH3CN(0.035%CF3CO2H)。流速=1.2nL/min,注射体积=1.5μL,且柱温=60℃。
缩写
除非另有注解,或上下文中另有指示,否则应理解下列缩写具有如下含义:
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实施例1
2-(4-氟-2-甲基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(10)
2-(4-氟-2-甲基苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(10)的合成描述在国际公开号WO 2014/120808 A9和美国公开号2014/0213616A1中,通过引用并入这两篇文献的全部内容。
实施例2
磷酸二氢(4-(2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲酯(20)
磷酸二氢(4-(2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲酯(20)的合成描述在WO 2015/089361 A1和美国公开号2015/0166589 A1中,通过引用并入这两篇文献的全部内容。
实施例3
2-(4-氟-2-(甲基-d3)苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(7)
如方案1中所示合成了2-(4-氟-2-(甲基-d3)苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(7)。1-氟-4-甲氧基-苯(1)三氘代甲基化得到4-氟-1-甲氧基-2-(甲基-d3)苯(2),使(2)进行脱甲基化,得到4-氟-2-(甲基-d3)苯酚(3)。单独地,使2-氟-4-(三氟甲基)苯甲酸(4)与2-甲氧基吡啶-4-胺偶联,得到2-氟-N-(2-甲氧基-4-吡啶基)-4-(三氟甲基)苯甲酰胺(5),使(5)进行脱甲基化,得到2-氟-N-(2-氧代-1H-吡啶-4-基)-4-(三氟甲基)苯甲酰胺(6)。用4-氟-2-(甲基-d3)苯酚(3)在碱存在下处理2-氟-N-(2-氧代-1H-吡啶-4-基)-4-(三氟甲基)苯甲酰胺(6),得到2-(4-氟-2-(甲基-d3)苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(7)。详细实验方法和分析数据提供如下。
方案1。化合物7的合成
4-氟-2-(甲基-d3)苯酚(3)的制备。在-10℃向1-氟-4-甲氧基-苯(1)(1.02g,8.09mmol)在THF(10mL)中的溶液中加入n-BuLi(2.38g 2.5M的己烷溶液,8.75mmol),历时20分钟,同时维持内部温度为-5℃。将该溶液温热至室温,然后搅拌1小时。将该混合物冷却至0℃,通过滴加碘甲烷-d3(1.30g,8.97mmol,99.5%D掺入)处理,同时维持内部温度在5℃以下。使该反应体系达到室温,搅拌45分钟。用***和冷水稀释该反应混合物,分离各层。用盐水洗涤合并的有机层,用硫酸钠干燥,过滤,浓缩。进行硅胶色谱法(0-10%乙酸乙酯/己烷),得到4-氟-1-甲氧基-2-(甲基-d3)苯(2)(160mg,14%)。1H NMR(400MHz,DMSO-d6)δ7.03-6.97(m,1H),6.95(dd,J=8.4,3.2Hz,1H),6.90(dd,J=8.9,4.8Hz,1H),3.76(s,3H)ppm。LC/MS保留时间(方法A):0.60分钟(1分钟运行)。
在0℃向4-氟-1-甲氧基-2-(甲基-d3)苯(2)(160mg,1.12mmol)在二氯甲烷(2mL)中的溶液中滴加BBr3(2.3mL 1M的二氯甲烷溶液,2.3mmol),历时5分钟。从冰浴中取出反应体系,使其达到室温,搅拌1小时。用二氯甲烷稀释该反应混合物,用水和盐水洗涤。用硫酸钠干燥有机层,过滤,浓缩,得到粗4-氟-2-(甲基-d3)苯酚(3)(125mg,87%),将其直接用于下一反应。LC/MS保留时间(方法A):0.43分钟(1分钟运行)。
2-氟-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(6)的制备。在40℃用T3P溶液(23mL在乙酸乙酯中50%w/v,36mmol),随后用吡啶(5.7g,5.8mL,72mmol)、三乙胺(7.3g,10mL,72mmol)和2-甲氧基吡啶-4-胺(3.3g,26mmol)处理2-氟-4-(三氟甲基)苯甲酸(4)(5.0g,24mmol)在2-甲基四氢呋喃(30mL)中的溶液。将该反应体系在40℃加热16小时。加入水(50mL),搅拌该混合物。分离得到的层,用50mL 0.1N HCl、50mL 10%KOH和50mL盐水洗涤有机层。用硫酸钠干燥该溶液,过滤,蒸发,得到2-氟-N-(2-甲氧基-4-吡啶基)-4-(三氟甲基)苯甲酰胺(5)(7.1g,94%)。ESI-MS m/z计算值314.07,测定值315.2(M+1)+。LC/MS保留时间(方法B):1.21分钟(3分钟运行)。1H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.14-8.07(m,1H),7.96-7.88(m,2H),7.76(dd,J=8.1,1.6Hz,1H),7.22(d,J=4.7Hz,2H),3.85(s,3H)ppm。
向2-氟-N-(2-甲氧基-4-吡啶基)-4-(三氟甲基)苯甲酰胺(5)(6.44g,20.5mmol)在乙酸(39mL)中的混悬液中加入HBr的乙酸溶液(25mL 33%w/v,103mmol),将该反应体系在100℃搅拌16小时。将该反应混合物冷却至28℃,用甲苯(15mL)处理。将该混合物搅拌10分钟,过滤,用甲苯(15mL)洗涤得到的固体,在40℃真空干燥,得到3.42g产物。通过依次过滤母液和用甲苯(15mL)冲洗得到的固体,得到第二批(0.35g)和第三批(0.40g)产物。合并固体,得到2-氟-N-(2-氧代-1H-吡啶-4-基)-4-(三氟甲基)苯甲酰胺(6)(4.17g,70%)。ESI-MS m/z计算值300.05,测定值301.1(M+1)+。LC/MS保留时间(方法B):1.05分钟(3分钟运行)。1H NMR(400MHz,DMSO-d6)δ11.81(br s,1H),10.86(s,1H),7.96-7.87(m,2H),7.76(dd,J=8.2,1.6Hz,1H),7.48(dd,J=7.1,1.8Hz,1H),6.96(d,J=2.1Hz,1H),6.56(dd,J=7.2,2.1Hz,1H)ppm。
2-(4-氟-2-(甲基-d3)苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(7)的制备。将2-氟-N-(2-氧代-1H-吡啶-4-基)-4-(三氟甲基)苯甲酰胺(6)(265mg,0.883mmol)、K2CO3(366mg,2.645mmol)和4-氟-2-(甲基-d3)苯酚(3)(125mg,0.968mmol)合并在无水DMSO(2.5mL)中,在75℃加热16小时。用水(10mL)稀释该反应体系,过滤,用水(10mL)洗涤得到的固体,风干。将固体在乙酸异丁酯中搅拌成浆液,过滤,得到期望的产物,为黄白色固体(200mg)。浓缩母液,通过硅胶色谱法纯化(1-15%甲醇/二氯甲烷),又得到60mg产物。将两批溶于二氯甲烷,浓缩溶剂,风干得到的固体,得到2-(4-氟-2-(甲基-d3)苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(7)(260mg,72%)。ESI-MS m/z计算值409.11,实测值410.2(M+1)+。LC/MS保留时间(方法B):1.59分钟(3分钟运行)。1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),10.61(s,1H),7.88-7.78(m,1H),7.60(dt,J=8.1,1.1Hz,1H),7.31(d,J=7.2Hz,1H),7.22(ddd,J=9.2,2.5,1.0Hz,1H),7.12-7.07(m,2H),6.97(d,J=1.6Hz,1H),6.75(d,J=2.0Hz,1H),6.38(dd,J=7.2,2.1Hz,1H)ppm。
实施例4
磷酸二氢(4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲酯(13)
如方案2中所示合成了磷酸二氢(4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲酯(13)。用氯甲酸氯甲酯使2-(4-氟-2-(甲基-d3)苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(7)氯甲基化,得到N-[1-(氯甲基)-2-氧代-1,2-二氢吡啶-4-基]-2-[4-氟-2-(甲基-d3)苯氧基]-4-(三氟甲基)苯甲酰胺(11),然后用二叔丁氧基磷酰氧基钾处理,得到((4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲基)磷酸二叔丁酯(12)。水解化合物12,得到磷酸二氢(4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲酯(13)。详细实验方法和分析数据提供如下。
方案2。化合物13的合成
N-[1-(氯甲基)-2-氧代-1,2-二氢吡啶-4-基]-2-[4-氟-2-(甲基-d3)苯氧基]-4-(三氟甲基)苯甲酰胺(11)的制备。向2-(4-氟-2-(甲基-d3)苯氧基)-N-(2-氧代-1,2-二氢吡啶-4-基)-4-(三氟甲基)苯甲酰胺(7)(1.9g,4.642mmol)在DCE(20mL)和DMF(1mL)中的浆液中加入DABCO(265mg,2.362mmol)。向该浆液中滴加氯甲酸氯甲酯(620μL,6.972mmol),历时5min。将该混合物在60℃搅拌1hr。将淡黄色浆液冷却至环境温度,用水(50mL)和DCM(50mL)稀释。分离有机相,用DCM(50mL)萃取水相。用盐水洗涤合并的有机相。用MgSO4干燥有机相,过滤,用硅藻土过滤,浓缩,得到N-[1-(氯甲基)-2-氧代-1,2-二氢吡啶-4-基]-2-[4-氟-2-(甲基-d3)苯氧基]-4-(三氟甲基)苯甲酰胺(11)(2.1g,99%)。不经进一步纯化将产物用于下一步。ESI-MS m/z计算值457.08957,测定值458.1(M+1)+;LC/MS保留时间(方法B):2.06分钟(3分钟运行)。
((4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲基)磷酸二叔丁酯(12)的制备。向N-[1-(氯甲基)-2-氧代-1,2-二氢吡啶-4-基]-2-[4-氟-2-(甲基-d3)苯氧基]-4-(三氟甲基)苯甲酰胺(11)(2.1g,4.587mmol)在EtOAc(25mL)中的混悬液中加入碘化叔丁基铵(30mg,0.08122mmol),然后觉得二叔丁氧基磷酰氧基钾(1.3g,5.236mmol),将该混合物加热至70℃3hr。通过倾倒在冰水(50mL)上并用EtOAc(100mL)稀释使反应停止。分离有机相,用盐水洗涤。用EtOAc(100mL)萃取水相,用MgSO4干燥合并的有机相,过滤,浓缩。使用反相色谱法纯化粗产物(50-100%水/ACN),得到((4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲基)磷酸二叔丁酯(12)(1.75g,60%)。ESI-MS m/z计算值631.21497,测定值632.2(M+1)+;LC/MS保留时间(方法B):2.25分钟(3分钟运行)。
磷酸二氢(4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲酯(13)的制备。向((4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲基)磷酸二叔丁酯(12)(1.5g,2.375mmol)在异丙醇(9mL)和水(3mL)中的混合物中加入HOAc(4.5mL)。将该混合物在70℃加热4.5hr。浓缩该混合物至约2mL油状物,用10mL ACN稀释,得到浑浊溶液,进一步用10mL异丙醇稀释。浓缩溶剂至约2mL,得到颗粒状固体。用中孔漏斗采集固体,用5mL丙酮洗涤3X。风干固体15min,然后在真空烘箱中在40℃16小时,得到磷酸二氢(4-(2-(4-氟-2-(甲基-d3)苯氧基)-4-(三氟甲基)苯甲酰氨基)-2-氧代吡啶-1(2H)-基)甲酯(13)(150mg,12%)。ESI-MS m/z计算值519.0898,测定值520.0(M+1)+;LC/MS保留时间(方法B):1.99分钟(3分钟运行)。1H NMR(400MHz,DMSO-d6)δ11.51(s,2H),10.75(s,1H),7.86(d,J=7.9Hz,1H),7.61(dd,J=7.2,1.7Hz,2H),7.22(ddd,J=9.3,2.5,1.0Hz,1H),7.15-7.06(m,2H),6.98(d,J=1.5Hz,1H),6.89(d,J=2.3Hz,1H),6.44(dd,J=7.6,2.3Hz,1H),5.53(d,J=9.7Hz,2H)ppm。
实施例5
前药转化成母体化合物的评价:体外肝细胞测定法
材料。冷藏保存的人肝细胞和冷藏保存的肝细胞恢复培养基(CHRMTM)购自LifeTechnologies(Carlsbad,CA)。GibcoTM Leibovitz′s L-15培养基购自Fisher Scientific(Waltham,MA)。
方法。用DMSO中制备10mM的含有化合物20和化合物13的储备溶液。将等体积的两种10mM储备溶液混合,以形成包含浓度分别为5mM的化合物20和化合物13的组合储备溶液。将5mM组合储备液稀释至DMSO中每种化合物的浓度为50μM(“50μM组合储备液”)。将冷藏保存的人肝细胞在CHRMTM培养基中融化,并制成温育培养基(含葡萄糖、HEPES缓冲液和NaHCO3的补充剂的L-15培养基)中的悬浮液,最终细胞浓度为62.5万细胞/毫升。在48孔板中,向每个孔中加入1μL的50μM组合储备液,然后添加199μL的肝细胞悬液(62.5万个细胞/毫升)。覆盖板,并在培养箱中于37℃温和摇动(50rpm)温育。通过加入200μL含内标的冰冷淬灭溶液(ACN∶MeOH∶0.1%甲酸水溶液,2∶2∶1),在0、0.25、0.5、1和2小时时间点(每个时间点n=3)使反应淬灭。离心淬灭的样品,并通过LC-MS/MS分析上清液分析剩余的化合物20和化合物13的量,以及形成的化合物10和化合物7的量。如下进行LC-MS/MS分析:使用PhenomenexLuna C8色谱柱(3微米,2mm直径x 30mm长,在室温下)进行洗脱,该梯度由0.1%甲酸水溶液和0.1%在乙腈中的甲酸的流动相组成,总流速为0.6mL/min,总运行时间为4.5分钟。通过多重反应监测(MRM)模式的MS/MS与电喷雾电离(ESI)检测分析物。进样量为10μL。
结果。通过LC-MS/MS分析来分析与人肝细胞一起温育的化合物20和化合物13的样品时,对应于化合物20和化合物13的峰迅速下降,同时对应于化合物10和化合物7的峰升高,表示化合物20和化合物13分别被快速转化成化合物10和化合物7。人肝细胞中化合物20和化合物13的t1/2<0.5 hr。表1报告了在与人肝细胞一起温育期间每个时间点剩余的化合物20和化合物13的百分比。
表1.肝细胞测定期间剩余化合物20和化合物13的百分比
时间(hr) | %剩余(化合物20) | %剩余(化合物13) |
0 | 100 | 100 |
0.25 | 75.1 | 73.8 |
0.5 | 32.7 | 33.2 |
1 | 11.2 | 11.1 |
2 | 11.6 | 11.8 |
实施例6
检测和测定Nav抑制特性的E-VIPR测定法
钠离子通道是电压依赖性蛋白,其可以通过施加电场诱导膜电压变化而被激活。在国际公开号WO 2002/008748 A3和C.-J.Huang等人Characterization of voltage-gated sodium channel blockers by electrical stimulation and fluorescencedetection of membrane potential,24 Nature Biotech.439-46(2006)中描述了被称作E-VIPR的电刺激仪器和使用方法,通过引用并入上述文献二者的全部内容。该仪器包含微量滴定板处理器、用于激发香豆素染料同时记录香豆素和氮杂菁(oxonol)发射的光学***、波形发生器、电流或电压控制的放大器以及***测定板孔中的平行电极对。在集成计算机控制下,该仪器将用户编程的电刺激方案传递至微量滴定板孔内的细胞。
在E-VIPR上进行测定前16-20小时,将表达人Nav 1.8的HEK细胞以25,000个细胞/孔的密度接种到预先涂有基质胶的384孔板(Greiner#781091-1B)中。在接种到细胞板中之前,将5%KIR2.1Bacmam病毒添加到最终的细胞悬液中。使HEK细胞在补充有10%FBS(胎牛血清,合格;Sigma#F4135),1%NEAA(非必需氨基酸,Life Tech#11140),1%HEPES(LifeTech#15630),1%Pen-Strep(青霉素-链霉素;Life Tech#15640)和5μg/ml稻瘟素(Gibco#R210-01)的DMEM培养基中生长(确切的组成对于每种细胞类型和Nav亚型而言都是特定的)。在具有95%湿度和5%CO2的通风盖烧瓶中使细胞展平。
试剂和储备溶液:
100mg/mL Pluronic F-127(Sigma#P2443),在无水DMSO中
化合物板:Corning 384孔聚丙烯圆底#3656
细胞板:384孔组织培养处理的板。Greiner#781091-1B
5%KIR 2.1Bacmam病毒(内部产生),如J.A.Fornwald等人Gene Expression inMammalian Cells Using BacMam,a Modified Baculovfrus System,1350Methods inMolecular Biology 95-116(2016)的3.3节中所述制备,通过引用并入其全部内容。
5mM在无水DMSO中的DiSBAC6(3)(电压敏感性氮杂菁接受体)(Aurora#00-100-010)
5mM在无水DMSO中的CC2-DMPE(膜结合的香豆素磷脂FRET供体)(Aurora#00-100-008)
89mM在H20中的VABSC-1
人血清(HS,Millipore#S1P1-01KL,批号2706671A)
Bath1缓冲液:
氯化钠160mM(9.35g/L)、氯化钾4.5mM(0.335g/L)、葡萄糖10mM(1.8g/L)、氯化镁(无水)1mM(0.095g/L)、氯化钙2mM(0.222g/L)、HEPES 10mM(2.38g/L)水溶液。
Na/TMA Cl Bath1缓冲液:
氯化钠96mM(5.61g/L)、氯化钾4.5mM(0.335g/L)、四甲基铵(TMA)-Cl 64mM(7.01g/L)、葡萄糖10mM(1.8g/L)、氯化镁(无水)1mM(0.095g/L)、氯化钙2mM(0.222g/L)HEPES 10mM(2.38g/L)水溶液。
己基染料溶液(2X):
包含0.5%β-环糊精(每次使用前新鲜制备,Sigma#C4767),8μM CC2-DMPE和2μMDiSBAC6(3)的Bath1缓冲液。通过添加等于CC2-DMPE和DiSBAC6(3)合并体积的10%P1uronicF127储备液,制备了该溶液。制备顺序为先将Pluronic和CC2-DMPE混合,然后添加DiSBAC6(3),然后在涡旋混合的同时添加Bath1/β-环糊精。
化合物荷载缓冲液(2X):Na/TMA C1 Bath1缓冲液,其包含50%的HS(在没有HS的情况下进行的实验中省略了它),VABSC-1 1mM,BSA 0.2%(在Bath-1中),KC1 9mM,DMSO0.75%。
测定方案:
1)将400nL的测试化合物(化合物7或化合物13)以11点剂量响应,3倍稀释度(纯DMSO)以400x所需的最终浓度预滴入聚丙烯化合物板中,导致最高剂量为细胞板中终浓度为3μM。将介质对照(纯DMSO)和阳性对照(化合物10(用化合物7的测定)或化合物20(用化合物13的测定),在DMSO中测定中最终为25μM)分别手动添加到每个板的最外层柱中。将化合物以1∶1的比例转移到细胞板中后,用每孔80ul/孔化合物荷载缓冲液回填化合物板,导致化合物稀释400倍(步骤6)。测定中所有孔的最终DMSO浓度为0.625%(将0.75%DMSO补充到化合物荷载缓冲液中以使最终DMSO浓度为0.625%)。
2)制备己基染料溶液。
3)制备细胞板。在测定当天,抽吸培养基,并用80μL Bath-1缓冲液洗涤细胞3次,并维持每个孔中25μL的残留体积。
4)将每孔25μL的己基染料溶液分配到细胞板中。将细胞在室温或环境条件下在黑暗中温育20分钟。
5)将每孔80μL的化合物荷载缓冲液分配到化合物板上。
6)将细胞板用每孔Bath-1缓冲液80μL洗涤3次,剩余25μL残留体积。然后将每孔25uL的化合物板转移到每个细胞板上。将该混合物在室温/环境条件下温育30分钟。
7)使用电流控制放大器在E-VIPR上读数板,以使用以下方案传递刺激波脉冲:1.25Amps,2.5ms脉冲宽度双相波形,10Hz 10秒,扫描速率为200Hz。进行刺激前记录0.5秒,以获得未刺激的强度基线。在刺激波形之后,为0.5秒的刺激后记录,以检查松弛到静止状态。
数据分析:
分析数据并将其报告为在460nm和580nm通道中测得的发射强度的标准化比率。将响应值作为时间的函数报告为使用以下公式获得的比率:
通过计算初始(Ri)和最终(Rf)比率进一步还原了数据。这些是部分或全部预刺激期间以及刺激期间采样点期间的平均比率值。然后计算荧光比(Rf/Ri),并报告为时间的函数。
通过在阳性对照(化合物10或化合物20)存在下和不存在药理学试剂(DMSO介质阴性对照)的情况下进行测定来获得对照响应值。如上计算对阴性(N)和阳性(P)对照的响应。然后将化合物拮抗剂%活性A定义为:
其中X是测试化合物的比例响应。使用这种分析方法,绘制了剂量响应曲线,并生成了IC50和Max%活性值。
结果:
将对化合物7和化合物13测定的IC50和Max%活性值分别报告在表2和3中。
表2.E-VIPR测定法中化合物7的IC50和Max%活性
Nav1.8IC50(uM) | Nav1.8Max%活性(%) |
0.35 | 98 |
表3.E-VIPR测定法中化合物13的IC50和Max%活性
Nav1.8IC50(uM) | Nav1.8Max%活性(%) |
1.2 | 99 |
实施例7
代谢稳定性的评价:体外微粒体测定法
材料。大鼠、狗、猴和人肝微粒体(20mg/mL)得自Xenotech,LLC(Lenexa,KS)。还原形式的P-烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、氯化镁(MgCl2)和二甲亚砜(DMSO)购自Sigma-A1drich。
方法。在DMSO中制备了10mM含有测试化合物(化合物10或化合物7)的储备溶液。将10mM储备溶液在DMSO中稀释至100μM。在每个聚簇聚丙烯试管中,添加190.7μL的100mM磷酸盐缓冲液,pH 7.4,然后添加2.5μL肝脂质体(20mg/mL,大鼠,狗,猴或人),然后加入100μM测试化合物的2μL等分试样,并将混合物预热10分钟。通过添加4.8μL预热的NADPH溶液(在100mM磷酸盐缓冲液中为100mM)启动反应。最终反应体积为200μL,并在0.1M磷酸钾缓冲液(pH 7.4)中包含0.25mg/mL大鼠,狗,猴或人肝微粒体,1.0μM测试化合物和2.4mM NADPH。将反应混合物在37℃下温育,并通过加入包含内标的200uL冰冷的淬灭溶液(ACN∶MeOH∶0.1%甲酸的水溶液2∶2∶1)在0、15、30和60分钟淬灭反应,每个时间点n=3。将试管离心,并通过LC-MS/MS分析上清液中剩余的测试化合物的量。HPLC***包括Phenomenex Luna C8色谱柱,3微米,2mm直径x 30mm长,用梯度流动相洗脱,该梯度流动相由0.1%甲酸的水溶液或乙腈溶液组成。通过多反应监测(MRM)模式的MS/MS和电喷雾电离(ESI)检测分析物。进样量为10μL。
结果。与大鼠、狗、猴和人肝微粒体温育期间每个时间点剩余的化合物7和化合物10的百分比报告在图1(大鼠)、2(狗)、3(猴)和4(人)中。下表4a(大鼠)、4b(狗)、4c(猴)和4d(人)中也报告了该数据。
表4a.化合物7和化合物10的大鼠肝微粒体数据
时间 | 化合物10(%剩余) | 化合物7(%剩余) |
0分钟 | 100 | 100 |
15分钟 | 108 | 109 |
30分钟 | 102 | 105 |
60分钟 | 87.4 | 92.2 |
表4b.化合物7和化合物10的狗肝微粒体数据
时间 | 化合物10(%剩余) | 化合物7(%剩余) |
0分钟 | 100 | 100 |
15分钟 | 85.9 | 86.1 |
30分钟 | 85.4 | 85.8 |
60分钟 | 85.7 | 87.5 |
表4c.化合物7和化合物10的猴肝微粒体数据
时间 | 化合物10(%剩余) | 化合物7(%剩余) |
0分钟 | 100 | 100 |
15分钟 | 96.4 | 97.0 |
30分钟 | 92.4 | 93.3 |
60分钟 | 91.4 | 92.5 |
表4d.化合物7和化合物10的人肝微粒体数据
时间 | 化合物10(%剩余) | 化合物7(%剩余) |
0分钟 | 100 | 100 |
15分钟 | 110 | 109 |
30分钟 | 105 | 105 |
60分钟 | 106 | 106 |
实施例8
体内药物动力学研究
一般方法。使用高效液相色谱/串联质谱法(HPLC/MS/MS)确定血浆中待测化合物的浓度。通过用乙腈(血浆/乙腈比例为1∶25)直接进行蛋白质沉淀从血浆(20μL)中提取测试化合物以及内标(IS)。离心后,将上清液(10μL)注入LC/MS/MS***。HPLC***包括Phenomenex Luna C8色谱柱,该色谱柱为3微米,2min直径x 30mm长,用梯度流动相洗脱,该梯度流动相由0.1%甲酸的水溶液或乙腈溶液组成。通过多反应监测(MRM)模式的MS/MS和电喷雾电离(ESI)检测分析物。定量下限(LLOQ)为1.00ng/mL。测定的线性范围是1至3000ng/mL。测定准确度在标称值的20%以内。
首先用DMSO稀释,然后用空白血浆稀释,最终稀释倍数为1000倍,然后用类似的HPLC/MS/MS方法测定了测试化合物的盒式剂量制剂样品。
使用Watson,第7.4.2版(Thermo Scientific)中的PK模块通过非房室药物动力学方法分析测试化合物的血浆浓度-时间曲线。确定了包括AUC全部、AUC0-∞、C0、Cl、Vss和t1/2在内的药物动力学参数。
使用Microsoft Excel 2010计算血浆浓度和药物动力学参数估计值的描述性统计数据,包括平均值,标准偏差(SD)和变异系数(%CV)。
大鼠IV研究。化合物7和化合物10分别通过颈静脉插管以单次静脉推注方式施用于雄性Sprague Dawley大鼠(n=3)。每种化合物的标称剂量为0.5mg/kg。将盒式定量给药溶液在D5W中与添加剂一起配制。在给药之前和之后,动物可以自由获得食物和水。在给药前和给药后0(剂量前)、5分钟、10分钟、0.25小时、0.5小时、1小时、2小时、4小时、8小时、12小时、24小时通过颈动脉导管收集血样(每次约0.25mL)。将每个血样收集到管中,该管保持在湿冰上并包含EDTA钾作为抗凝剂。分离血浆并在约-70℃下保存直至分析。
使用液相色谱/串联质谱法(LC/MS/MS)分析血浆样品和给药溶液,以测定化合物7和化合物10的浓度,其定量下限(LLOQ)为1.00ng/mL。将化合物7和化合物10的平均血浆浓度绘制在图5中,并以表格形式显示在表5中。
表5.大鼠IV血浆浓度(ng/mL)与时间(小时)的关系
时间(小时) | 化合物10(ng/mL) | 化合物7(ng/mL) |
0.083 | 391 | 420 |
0.167 | 349 | 399 |
0.25 | 316 | 371 |
0.5 | 239 | 301 |
1 | 174 | 256 |
2 | 111 | 208 |
4 | 51.6 | 154 |
8 | 14.3 | 91.3 |
12 | 4.27 | 47.6 |
24 | 7.57 |
对血浆浓度与时间关系的数据进行非房室药物动力学(PK)分析。将该分析的结果提供在表6中。将化合物7和化合物10的测定剂量也记录在表6中。为了确定每种化合物的测定剂量,在给药时将剂量制剂(50uL)等分到簇管中。然后将450uL DMSO添加到试管中以稀释10倍。然后将稀释的加药溶液以100x稀释量分入大鼠空白血浆中。使用相同的LC/MS/MS方法,将所得血浆样品与从用化合物给药的大鼠收集的血浆样品一起进行分析。
表6.来自大鼠IV研究的药物动力学数据
如表6中所示,在大鼠中,与化合物10相比,化合物7具有较低的清除率和较长的t1/2。
对本领域技术人员而言明显的是,可以在不脱离本发明范围的情况下对本说明书所述的实施方案进行许多修改和变化。本说明书中所描述的具体实施方案仅以举例的方式提供。
Claims (25)
1.式I的化合物:
或其药学上可接受的盐,其中R为H或CH2OPO(OH)2。
2.权利要求1的化合物,或其药学上可接受的盐,其中式I的化合物为:
3.权利要求1的化合物,其中式I的化合物为:
4.权利要求1的化合物,或其药学上可接受的盐,其中式I的化合物为:
5.权利要求1的化合物,其中式I的化合物为:
6.药物组合物,它包含治疗有效量的权利要求1、2或4的化合物或其药学上可接受的盐或权利要求3或5的化合物以及一种或多种药学上可接受的载体或介质。
7.药物组合物,它包含权利要求1、2或4的化合物或其药学上可接受的盐或权利要求3或5的化合物以及一种或多种药学上可接受的载体或介质。
8.权利要求1、2或4的化合物或其药学上可接受的盐或权利要求3或5的化合物或权利要求6或7的药物组合物在制备用于抑制受试者中电压门控型钠通道的药物中的用途。
9.权利要求8的用途,其中所述的电压门控型钠通道为Nav1.8。
10.权利要求1、2或4的化合物或其药学上可接受的盐或权利要求3或5的化合物或权利要求6或7的药物组合物在制备用于治疗受试者的如下病症或减轻其严重性的药物中的用途:慢性疼痛、神经病变性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、特发性疼痛、手术后疼痛、内脏痛、多发性硬化、沙-马-图综合征、失禁、病理性咳嗽或心律失常。
11.权利要求1、2或4的化合物或其药学上可接受的盐或权利要求3或5的化合物或权利要求6或7的药物组合物在制备用于治疗受试者的肠痛或减轻其严重性的药物中的用途。
12.权利要求10的用途,其中所制备的药物用于治疗受试者的神经病变性疼痛或减轻其严重性。
13.权利要求12的用途,其中所述的神经病变性疼痛包含疱疹后神经痛。
14.权利要求12的用途,其中所述的神经病变性疼痛包含特发性细纤维神经病。
15.权利要求12的用途,其中所述的神经病变性疼痛包含糖尿病性神经痛。
16.权利要求10的用途,其中所制备的药物用于治疗受试者的肌肉骨骼痛或减轻其严重性。
17.权利要求16的用途,其中所述的肌肉骨骼痛包含骨关节炎疼痛。
18.权利要求10的用途,其中所制备的药物用于治疗受试者的急性疼痛或减轻其严重性。
19.权利要求18的用途,其中所述的急性疼痛包含急性手术后疼痛。
20.权利要求10的用途,其中所制备的药物用于治疗受试者的手术后疼痛或减轻其严重性。
21.权利要求20的用途,其中所述的手术后疼痛包含囊肿切除术疼痛。
22.权利要求20的用途,其中所述的手术后疼痛包含腹壁整形术疼痛。
23.权利要求10的用途,其中所制备的药物用于治疗受试者的内脏痛或减轻其严重性。
24.权利要求8至23任一项的用途,其中用一种或多种另外的治疗剂治疗所述的受试者,在用所述化合物、药学上可接受的盐或药物组合物治疗的同时、在其之前或之后施用所述一种或多种另外的治疗剂。
25.化合物,其选自
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MA49137A (fr) | 2021-04-21 |
WO2018213426A1 (en) | 2018-11-22 |
US20210155643A1 (en) | 2021-05-27 |
EP3625214A1 (en) | 2020-03-25 |
AU2018271110A1 (en) | 2019-12-05 |
CL2019003239A1 (es) | 2020-04-17 |
MX2019013574A (es) | 2019-12-18 |
CA3063901A1 (en) | 2018-11-22 |
IL270680B (en) | 2022-06-01 |
JP7104070B2 (ja) | 2022-07-20 |
UA124857C2 (uk) | 2021-12-01 |
CN110740993A (zh) | 2020-01-31 |
BR112019024016A2 (pt) | 2020-06-09 |
EP3625214B1 (en) | 2022-07-06 |
CO2019013021A2 (es) | 2020-04-01 |
JP2020519661A (ja) | 2020-07-02 |
US11358977B2 (en) | 2022-06-14 |
ZA201907619B (en) | 2022-03-30 |
ES2927712T3 (es) | 2022-11-10 |
KR20200006128A (ko) | 2020-01-17 |
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