CN110546148A - 作为钠通道抑制剂的4-哌啶-n-(嘧啶-4-基)色满-7-磺酰胺衍生物 - Google Patents
作为钠通道抑制剂的4-哌啶-n-(嘧啶-4-基)色满-7-磺酰胺衍生物 Download PDFInfo
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Abstract
本发明提供了作为钠通道调节剂的4‑哌啶‑色满‑7‑磺酰胺衍生物及其盐,以及含有此类化合物或盐的组合物和使用此类化合物、盐或组合物的治疗方法。
Description
背景技术
本发明涉及可用于对哺乳动物进行治疗的有机化合物,尤其是涉及可用于治疗钠通道介导的疾病或病患,例如疼痛,以及其它与钠通道调节相关的疾病和病患的钠通道(例如,NaV1.7)抑制剂。
电压门控钠通道是引发神经、肌肉和其它电兴奋细胞中的动作电位的跨膜蛋白,并且是正常感觉、情感、思想和运动的必要组分(Catterall,W.A.,Nature(2001),第409卷,988-990页)。这些通道由与辅助β亚基缔合的高度加工的α亚基组成。孔形成α亚基足以实现通道功能,但通道门控的动力学和电压依赖性部分被β亚基改变(Goldin等,Neuron(2000),第28卷,第365–368页)。电生理记录、生化纯化和分子克隆已鉴定出10种不同的钠通道α亚基和4种β亚基(Yu,F.H.等,Sci.STKE(2004),253;和Yu,F.H.等,Neurosci.(2003),20:7577-85)。
蛋白质的钠通道家族已得到广泛研究,并且已被证明参与许多至关重要的人体功能。该领域的研究已鉴定出导致通道功能和活性发生重大变化,从而最终可导致重大病理生理病患的α亚基变体。该蛋白质家族的成员表示为NaV1.1至NaV1.9。
NaV1.7是由SCN9A基因编码的河豚毒素敏感性电压门控钠通道。首先从神经内分泌细胞(Klugbauer,N.等,1995EMBO J.,14(6):1084-90.)克隆人NaV1.7,然后从嗜铬细胞瘤PC12细胞系(Toledo-Aral,J.J.等,Proc.Natl.Acad.Sci.USA(1997),94:1527–1532)和大鼠背根神经节(Sangameswaran,L.等,(1997),J.Biol.Chem.,272(23):14805-9)克隆大鼠NaV1.7。NaV1.7主要在周围神经系统,尤其是在伤害感受器和嗅觉神经元以及交感神经元中表达。NaV1.7的抑制或阻断已被证明会导致镇痛活性。在主要感受伤害结果的感觉神经元的亚组中敲除NaV1.7表达导致了对炎性疼痛的抵抗(Nassar等,同上)。同样地,人类中的功能丧失性突变导致对疼痛的先天性冷漠(CIP),在这种情况下个体对炎性疼痛和神经病理性疼痛均有抵抗力(Cox,J.J.等,Nature(2006);444:894-898;Goldberg,Y.P.等,Clin.Genet.(2007);71:311-319)。相反,已在两种人遗传性疼痛病患(原发性红斑性肢痛症和家族性直肠痛)中确定了NaV1.7的功能获得性突变(Yang,Y.等,J.Med.Genet.(2004),41(3):171-4)。另外,对通道门控的时间和电压依赖性具有非常细微的影响的单核苷酸多态性(R1150W)对疼痛感知有很大影响(Estacion,M.等,2009.Ann Neurol 66:862-6;Reimann,F.等,Proc Natl Acad Sci U S A(2010),107:5148-53)。患有各种疼痛疾患的患者中约10%具有赋予更高的疼痛敏感性的等位基因,因此更可能对NaV1.7的阻断作出反应。由于NaV1.7在感觉神经元和交感神经元中都有表达,因此人们可以预期疼痛感知的增强将伴随心血管异常(诸如高血压),但尚无相关报道。因此,CIP突变和SNP分析均表明,人疼痛响应对NaV1.7电流的变化比对自主功能的扰动更为敏感。
钠通道阻断剂已被证明可用于治疗疼痛(参见,例如,Wood,J.N.等,J.Neurobiol.(2004),61(1),55-71)。遗传和功能研究已提供了证据来证明NaV1.7活性是哺乳动物中疼痛信号传导的主要贡献者(参见Hajj等,Nature Reviews Neuroscience;2013,第14卷,49-62;以及Lee等Cell;2014,vol 157;1-12)。目前临床上仅有有限数量的有效钠通道阻断剂用于治疗疼痛且具有最小的不良副作用。因此仍然需要可为治疗提供更大的治疗指数的选择性电压门控钠通道调节剂(例如,NaV1.7的调节剂)。还需要具有强效的体内活性并且具有良好代谢稳定性的选择性电压门控钠通道调节剂。
发明内容
一方面,本发明提供了可用于治疗疼痛的具有钠通道阻断活性的新型化合物。本发明的某些化合物具有强效的体内活性和良好的代谢稳定性。
在第一实施方案中,本发明提供式I化合物,其选自由以下组成的组:
(S)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
(S)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺;以及
(S)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
或其药学上可接受的盐。
在另一方面,本发明提供了药物组合物,其包含式I化合物或其药学上可接受的盐以及药学上可接受的赋形剂。
在另一个方面,本发明提供了治疗哺乳动物的疾病或病患的方法,该疾病或病患选自由以下组成的组:疼痛、抑郁、心血管疾病、呼吸系统疾病和精神病,以及其组合,该方法包括对哺乳动物施用治疗有效量的式I化合物或其药学上可接受的盐。在本发明的另一方面,所述疾病或病患选自由以下组成的组:神经病理性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、术后疼痛、分娩疼痛、产前阵痛(labor pain)、神经原性膀胱、溃疡性结肠炎、慢性疼痛、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢疼痛、牙齿疼痛、周围神经损伤,或其组合。在本发明的另一方面,所述疾病或病患选自由以下组成的组:与HIV相关的疼痛、HIV治疗引起的神经病变、三叉神经痛、疱疹后神经痛、急性痛(eudynia)、热敏感性、结节病(tosarcoidosis)、肠易激综合征、克罗恩病、与多发性硬化症(MS)相关的疼痛、肌萎缩侧索硬化症(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿性关节炎、骨关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、与钠通道毒素相关的疾病、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛、癌症、癫痫、局部和全身性强直性癫痫发作(partial and general tonic seizures)、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、快速型心律失常、心房纤颤和心室纤颤。
在另一方面,本发明提供了通过抑制哺乳动物中的通过电压依赖性钠通道的离子通量来治疗哺乳动物的疼痛的方法,其中所述方法包括向哺乳动物施用治疗有效量的式I化合物或其药学上可接受的盐。
在另一方面,本发明提供了减少哺乳动物细胞中的通过电压依赖性钠通道的离子通量的方法,其中所述方法包括使细胞与式I化合物或其药学上可接受的盐接触。
在另一方面,本发明提供了治疗哺乳动物的瘙痒症的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的式I化合物或其药学上可接受的盐。
在另一方面,本发明提供了治疗哺乳动物的癌症的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的式I化合物或其药学上可接受的盐。
在另一方面,本发明提供了治疗但不预防哺乳动物的疼痛的方法,其中所述方法包括向哺乳动物施用治疗有效量的式I化合物或其药学上可接受的盐。在本发明的另一方面,所述疼痛选自由以下组成的组:神经病理性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、术后疼痛、分娩疼痛、产前阵痛、神经原性膀胱、溃疡性结肠炎、慢性疼痛、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢疼痛、牙齿疼痛、周围神经损伤,或其组合。在本发明的另一个方面,所述疼痛与选自由以下组成的组的疾病或病患相关:HIV、HIV治疗引起的神经病变、三叉神经痛、疱疹后神经痛、急性痛、热敏感性、结节病、肠易激综合征、克罗恩病、与多发性硬化症(MS)相关的疼痛、肌萎缩侧索硬化症(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿关节炎、骨关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、与钠通道毒素相关的疾病、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛、癌症、癫痫、局部和全身性强直性癫痫发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、快速型心律失常(tach-arrhythmias)、心房纤颤和心室纤颤。
在另一方面,本发明提供了用于治疗或预防动物的疼痛、抑郁、心血管疾病、呼吸系统疾病或精神病,或其组合的方法,所述方法包括施用有效量的式(I)的化合物或其药学上可接受的盐。
在另一方面,本发明提供了式I化合物或其药学上可接受的盐,其用作治疗选自由以下组成的组的疾病和病症的药剂:疼痛、抑郁、心血管疾病、呼吸系统疾病和精神病,或其组合。
在另一方面,本发明提供了式I化合物或其药学上可接受的盐用于制造药剂的用途,所述药剂用于治疗选自由以下组成的组的疾病和病症:疼痛、抑郁、心血管疾病、呼吸系统疾病和精神病,或其组合。
在另一方面,本发明提供了如本文所述的发明。
具体实施方式
定义
如本文中所用,术语“手性”是指具有镜像配偶体的不重叠性特性的分子,而术语“非手性”是指可重叠在其镜像配偶体上的分子。
如本文中所用,术语“立体异构体”是指具有相同化学组成,但关于原子或基团的空间排列不同的化合物。
如本文中所用,在化学结构中与键相交的波浪线指示该波浪键在化学结构中与分子的其余部分相交的键的连接点。
“非对映异构体”是指具有两个或更多个手性中心并且其分子并非彼此的镜像的立体异构体。非对映异构体具有不同的物理性质,例如熔点、沸点、光谱性质和反应性。可以在高拆分率分析程序(诸如电泳和色谱法)下分离非对映异构体的混合物。
“对映异构体”是指彼此为非重叠性镜像的化合物的两种立体异构体。
本文使用的立体化学定义和惯例一般遵循S.P.Parker,编辑,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;以及Eliel,E.和Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994。本发明的化合物可含有不对称或手术中心,因此以不同的立体异构形式存在。意图本发明化合物的所有立体异构形式(包括但不限于非对映异构体、对映异构体和阻转异构体及其混合物,诸如外消旋混合物)形成本发明的一部分。许多有机化合物以光学活性形式存在,即,它们具有使平面偏振光的平面旋转的能力。在描述光学活性化合物时,使用前缀D和L或者R和S表示分子围绕其一个或多个手性中心的绝对构型。使用前缀d和l或(+)和(-)来指定由化合物引起的平面偏振光的旋转方向,其中(-)或l表示化合物是左旋的。以(+)或d为前缀的化合物是右旋的。对于给定的化学结构,除它们为彼此的镜像外,这些立体异构体是相同的。特定的立体异构体还可称为对映异构体,以及此类异构体的混合物常常称为对映异构体混合物。对映异构体的50:50混合物称为外消旋混合物或外消旋物,其可在化学反应或过程中一直没有立体选择性或立体特异性的情况下产生。术语"外消旋混合物"和"外消旋物"是指无光学活性的两种对映异构体种类的等摩尔混合物。
当以非立体化学方式(例如平面)绘制本文中的化合物式(compound formula)中的键时,与键连接的原子包括所有立体化学可能性。当以确定的立体化学方式(例如,粗体、粗体-楔形、虚线或虚线-楔形)绘制本文中的化合物式中的键时,应理解立体化学键所连接的原子富含所描绘的绝对立体异构体,除非另有说明。在一个实施方案中,所述化合物可至少51%为所描绘的绝对立体异构体。在另一个实施方案中,所述化合物可至少80%为所描绘的绝对立体异构体。在另一个实施方案中,所述化合物可至少90%为所描绘的绝对立体异构体。在另一个实施方案中,所述化合物可至少95%为所描绘的绝对立体异构体。在另一个实施方案中,所述化合物可至少97%为所描绘的绝对立体异构体。在另一个实施方案中,所述化合物可至少98%为所描绘的绝对立体异构体。在另一个实施方案中,所述化合物可至少99%为所描绘的绝对立体异构体。
如本文中所用,术语“互变异构体”或“互变异构形式”是指具有不同能量的结构异构体,它们可通过低能垒相互转化。例如,质子互变异构体(也称为质子异变互变异构体(prototropic tautomers))包括通过质子迁移进行的互相转化,诸如酮-烯醇和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组来进行的互相转化。
如本文中所用,术语“溶剂化物”是指一种或多种溶剂分子与本发明化合物的缔合或复合。形成溶剂化物的溶剂的实例包括但不限于水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸和乙醇胺。术语“水合物”是指溶剂分子为水的复合物。
如本文中所用,术语"保护基团"是指通常用于封闭或保护化合物上特定官能团的取代基。例如,"氨基保护基团"是连接至氨基的取代基,其封闭或保护化合物中的的氨基官能团。合适的氨基保护基团包括但不限于乙酰基、三氟乙酰基、叔-丁氧基羰基(BOC)、苄基氧基羰基(CBZ)和9-芴基亚甲基氧基羰基(Fmoc)。类似地,“羟基保护基团”是指羟基的取代基,其封闭或保护羟基官能团。合适的保护基包括乙酰基和甲硅烷基。“羧基保护基团”是指羧基的取代基,其封闭或保护羧基官能团。常见的羧基保护基包括苯基磺酰基乙基、氰基乙基、2-(三甲基甲硅烷基)乙基、2-(三甲基甲硅烷基)乙氧基甲基、2-(对-甲苯磺酰基)乙基、2-(对-硝基苯基亚磺酰基)乙基、2-(二苯基膦基)-乙基、硝基乙基等。有关保护基团及其用途的一般描述,参见P.G.M.Wuts和T.W.Greene,Greene's Protective Groups in OrganicSynthesis第4版,Wiley-Interscience,New York,2006。
如本文所用,术语“哺乳动物”包括但不限于人、小鼠、大鼠、豚鼠、猴、狗、猫、马、牛、猪和绵羊。
如本文中所用,术语“药学上可接受的盐”意在包括活性化合物的盐,所述活性化合物的盐根据本文所述的化合物上存在的特定取代基用相对无毒的酸或碱来制备。当本发明的化合物含有相对酸性的官能团时,可通过使此类化合物的中性形式与足够量的纯的或在合适的惰性溶剂中的所需碱接触而获得碱加成盐。衍生自药学上可接受的无机碱的盐的实例包括铝、铵、钙、铜、铁、亚铁、锂、镁、锰、二价锰、钾、钠、锌等的盐。衍生自药学上可接受的有机碱的盐包括伯胺、仲胺和叔胺的盐,所述伯胺、仲胺和叔胺包括取代的胺、环状胺、天然存在的胺等,诸如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡糖胺、葡糖胺、组氨酸、哈胺、异丙基胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。当本发明的化合物包含相对碱性的官能团时,可通过使此类化合物的中性形式与足够量的纯的或在合适的惰性溶剂中的所需酸接触而获得酸加成盐。药学上可接受的酸加成盐的实例包括衍生自诸如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢氟酸或亚磷酸等无机酸的盐,以及衍生自相对无毒的诸如乙酸、丙酸、异丁酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对-甲苯磺酸、柠檬酸、酒石酸、甲烷磺酸等有机酸的盐。还包括诸如精氨酸等氨基酸的盐,以及诸如葡糖醛酸或半乳糖醛酸等有机酸的盐(参见,例如,Berge,S.M.等,"Pharmaceutical Salts",Journal of Pharmaceutical Science,1977,66,1-19)。本发明的某些特定化合物含有使得化合物能够转化成碱加成盐或酸加成盐的碱性官能团和酸性官能团二者。
化合物的中性形式可通过使所述盐与碱或酸接触并以常规方式分离母体化合物来再生。化合物的母体形式在某些物理特性方面(诸如在极性溶剂中的溶解度方面)与各种盐形式不同,但出于本发明的目的,这些盐在其它方面等同于化合物的母体形式。
除了盐形式以外,本发明还提供了呈前药形式的化合物。如本文中所用,术语“前药”是指在生理条件下容易经历化学变化以提供本发明的化合物的那些化合物。另外,可在离体环境中通过化学或生化方法将前药转化为本发明的化合物。例如,当将前药与合适的酶或化学试剂一起置于透皮贴片储库中时,前药可缓慢转化为本发明的化合物。
本发明的前药包括这样的化合物,其中氨基酸残基或两个或更多个(例如,两个、三个或四个)氨基酸残基的多肽链通过酰胺或酯键与本发明的化合物的自由氨基、羟基或羧基共价连接。氨基酸残基包括但不限于通常由三字母符号来命名的20种天然存在的氨基酸,并且还包括磷酸丝氨酸、磷酸苏氨酸、磷酸酪氨酸、4-羟基脯氨酸、羟基赖氨酸、锁链素、异锁链素、γ-羧基谷氨酸、马尿酸、八氢吲哚-2-羧酸、抑胃酶氨酸、1,2,3,4-四氢异喹啉-3-羧酸、青霉胺、鸟氨酸、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸、高丝氨酸、甲基-丙氨酸、对-苯甲酰基苯丙氨酸、苯基甘氨酸、炔丙基甘氨酸、肌氨酸、甲硫氨酸砜和叔-丁基甘氨酸。
还涵盖另外类型的前药。举例来说,本发明化合物的自由羧基可被衍生为酰胺或烷基酯。作为另一个实例,包含自由羟基的本发明化合物可通过将羟基转化成诸如但不限于磷酸酯、半琥珀酸酯、二甲基氨基乙酸酯或磷酰基氧基甲基氧基羰基的基团而衍生为前药,如Fleisher,D.等,(1996)Improved oral drug delivery:solubility limitationsovercome by the use of prodrugs Advanced Drug Delivery Reviews,19:115中所概述的。还包括具有羟基和氨基的氨基甲酸酯前药,具有羟基的碳酸酯前药、磺酸酯和硫酸酯也被包括在内。还涵盖羟基衍生为(酰基氧基)甲基醚和(酰基氧基)乙基醚,其中所述酰基可以是任选地被包括但不限于醚、胺和羧酸官能团的基团取代的烷基酯,或者其中酰基是如上所述的氨基酸酯。这种类型的前药描述于J.Med.Chem.,(1996),39:10中。更具体的实例包括醇基的氢原子被诸如以下基团替换:(C1-6)烷酰基氧基甲基、1-((C1-6)烷酰基氧基)乙基、1-甲基-1-((C1-6)烷酰基氧基)乙基、(C1-6)烷氧基羰基氧基甲基、N-(C1-6)烷氧基羰基氨基甲基、琥珀酰基、(C1-6)烷酰基、α-氨基(C1-4)烷酰基、芳基酰基和α-氨基酰基或α-氨基酰基-α-氨基酰基,其中每个α-氨基酰基均独立选自天然存在的L-氨基酸、P(O)(OH)2、-P(O)(O(C1-6)烷基)2或糖基(由碳水化合物的半缩醛形式的羟基移除而产生的基团)。
有关前药衍生物的另外实例,参见,例如,a)Design of Prodrugs,H.Bundgaard编,(Elsevier,1985)和Methods in Enzymology,第42卷,第309-396页,K.Widder等人编(Academic Press,1985);b)A Textbook of Drug Design and Development,Krogsgaard-Larsen和H.Bundgaard编,第5章"Design and Application of Prodrugs,"H.Bundgaard,第113-191页(1991);c)H.Bundgaard,Advanced Drug Delivery Reviews,8:1-38(1992);d)H.Bundgaard等人,Journal of Pharmaceutical Sciences,77:285(1988);以及e)N.Kakeya等人,Chem.Pharm.Bull.,32:692(1984),其中的每一篇均具体地通过引用并入本文。
另外,本发明提供了本发明化合物的代谢物。如本文中所用,“代谢物”是指由指定的化合物或其盐在体内代谢产生的产物。此类产物可以例如由所施用化合物的氧化、还原、水解、酰胺化、去酰胺化、酯化、去酯化、酶促裂解等产生。
代谢产物通常通过以下过程来进行鉴定:制备本发明化合物的放射性标记(例如14C或3H)同位素,将其以可检测的剂量(例如,大于约0.5mg/kg)肠胃外施用给动物诸如大鼠、小鼠、豚鼠、猴子或施用给人,允许代谢进行足够的时间(通常约30秒到30个小时),并从尿液、血液或其它生物样品中分离出其转化产物。这些产物由于它们已被标记而易于分离(通过使用在代谢物中继续存活的能够结合表位的抗体来分离其它产物)。以常规方式,例如通过MS、LC/MS或NMR分析来确定代谢物的结构。一般来说,以与本领域技术人员公知的常规药物代谢研究相同的方式进行代谢物的分析。代谢产物可用于对本发明化合物的治疗性给药进行诊断测定,只要其不以其它方式存在于体内即可。
本发明的某些化合物可以以非溶剂化物形式以及包括水合形式在内的溶剂化物形式存在。一般来说,溶剂化物形式等效于非溶剂化物形式,并且旨在包括在本发明的范围内。本发明的某些化合物可以多种晶体或无定形形式存在。一般来说,所有物理形式对于本发明所考虑的用途是等效的,并且意图落入本发明的范围内。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋物、非对映异构体、几何异构体、区域异构体和单个异构体(例如,单独的对映异构体)均旨在涵盖在本发明的范围内。
术语“进行治疗(treat)”和“治疗(treatment)”是指治疗性治疗和/或防治性治疗或预防性措施,其中目的是预防或减缓(减轻)不希望的生理变化或病症,诸如例如癌症的发展或扩散。出于本发明的目的,有益的或期望的临床结果包括但不限于可检测或不可检测的症状缓和、疾病或病症范围的减小、疾病或病症状态的稳定(即,不恶化)、疾病进展的延迟或减慢、疾病状态或病症的改善或减缓以及缓解(无论是局部缓解还是完全缓解)。“治疗”还可意指相比于未接受治疗的预期生存期,延长生存。需要治疗的那些包括已经患有疾病或病症的那些患者,以及易于患疾病或病症的那些或要预防疾病或病症的那些。
短语“治疗有效量”或“有效量”意指本发明的化合物(i)治疗或预防本文所述的特定的疾病、病患或病症、(ii)减弱、改善或消除本文所述的特定的疾病、病患或病症的一个或多个症状,或(iii)预防或延迟本文所述的特定的疾病、病患或病症的一个或多个症状的发作的量。对于癌症治疗,可以例如通过评估疾病进展时间(TTP)和/或确定反应速率(RR)来测量功效。
化合物
在一个方面,本发明提供了如本文所述的以下化合物:
(S)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
(S)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺;以及
(S)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
或其药学上可接受的盐。
本文提供的化合物可通过本领域普通技术人员已知的任何可行的合成途径,例如通过下面的方案1中阐明的方法来制备。
方案1
药物组合物和施用
除了一种或多种上文提供的化合物(或其立体异构体、几何异构体、互变异构体、溶剂化物、代谢物、同位素、药学上可接受的盐或前药)之外,本发明还提供了包含式I化合物或/和其实施方案以及至少一种药学上可接受的载体、稀释剂或赋形剂的组合物和药剂。本发明的组合物可用于选择性抑制患者(例如人)中的NaV1.7。
如本文中所用,术语“组合物”旨在涵盖包含指定量的指定成分的产品,以及直接或间接地由指定量的指定成分的组合产生的任何产品。“药学上可接受的”意指载体、稀释剂或赋形剂必须与制剂的其它成分相容并且对其接受者无害。
在一个实施方案中,本发明提供了药物组合物(或药剂),其包含式I化合物或其实施方案以及它的立体异构体、几何异构体、互变异构体、溶剂化物、代谢物、同位素、药学上可接受的盐或其前药以及药学上可接受的载体、稀释剂或赋形剂。在另一个实施方案中,本发明提供了制备包含本发明化合物的组合物(或药剂)。在另一个实施方案中,本发明提供了向有需要的患者(例如,人患者)施用式I化合物或其实施方案以及包含式I化合物或其实施方案的组合物。
以与良好医学实践一致的方式对组合物进行配制、给药和施用。在此背景下考虑的因素包括正在治疗的特定疾病、正在治疗的特定哺乳动物、个体患者的临床病患、病症的原因、剂的递送部位、施用方法、施用时程以及从业医生已知的其它因素。待施用的化合物的有效量将由此类考虑因素决定,并且是抑制NaV1.7活性以预防或治疗不期望的疾病或病症(例如,疼痛)所需的最小量。例如,这种量可以低于对正常细胞或整个哺乳动物有毒的量。
在一个实例中,每剂肠胃外施用的本发明化合物的治疗有效量为约0.01-100mg/kg患者体重/日,或者约例如0.1至20mg/kg患者体重/日,其中所用的化合物的典型初始范围为0.3至15mg/kg/日。在某些实施方案中,每日剂量以每日剂量单次施用的方式提供或者以分次剂量每天施用两次至六次的方式提供,或以持续释放形式提供。在70kg的成年人的情况下,每日总剂量一般为约7mg至约1400mg。可以调整该剂量方案以提供最佳的治疗反应。化合物可以每天1-4次,优选每天一次或两次的方案施用。
本发明的化合物可以以任何方便的施用形式(例如片剂、粉剂、胶囊、溶液、分散体、悬浮液、糖浆剂、喷雾剂、栓剂、凝胶剂、乳剂、贴片等)施用。此类组合物可在药物制剂中含有常规组分,例如稀释剂、载体、pH调节剂、甜味剂、填充剂和此外的活性剂。
本发明的化合物可通过任何合适的方式施用,包括口服、外用(包括颊部和舌下)、直肠、阴道、经皮、肠胃外、皮下、腹膜内、肺内、真皮内、鞘内和硬膜外以及鼻内施用,以及在需要局部治疗时进行的病灶内施用。肠胃外输注包括肌内、静脉内、动脉内、腹膜内、脑内、眼内、病灶内或皮下施用。
通常根据标准药学实践将包含式I化合物或其实施方案的组合物配制成药物组合物。通过混合本发明化合物和稀释剂、载体或赋形剂来制备典型制剂。合适的稀释剂、载体和赋形剂是本领域技术人员公知的,并详细地描述在例如Ansel,Howard C.等,Ansel’sPharmaceutical Dosage Forms and Drug Delivery Systems.Philadelphia:Lippincott,Williams&Wilkins,2004;Gennaro,Alfonso R.等Remington:The Scienceand Practice of Pharmacy.Philadelphia:Lippincott,Williams&Wilkins,2000以及Rowe,Raymond C.Handbook of Pharmaceutical Excipients.Chicago,PharmaceuticalPress,2005中。该制剂还可包含一种或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、避光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂、稀释剂和其它已知的添加剂,以提供药物(即,本发明化合物或其药物组合物)的精致外观或帮助制造药物产品(即,药剂)。
合适的载体、稀释剂和赋形剂是本领域技术人员公知的,并且包括诸如以下的材料:碳水化合物、蜡、水溶性和/或水溶胀性聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。所使用的特定载体、稀释剂或赋形剂将视施加本发明化合物的方式和目的而定。一般基于本领域技术人员公认对哺乳动物施用安全(GRAS)的溶剂来选择溶剂。一般来说,安全溶剂是无毒的水性溶剂,诸如水和其它可溶于水或与水混溶的无毒溶剂。合适的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如,PEG 400、PEG 300)等及其混合物。所述制剂还可包括一种或多种缓冲剂、稳定剂、表面活性剂、润湿剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、避光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其它已知的添加剂以提供药物(即,本发明化合物或其药物组合物)的精致外观或帮助制造药物产品(即,药剂)。
可接受的稀释剂、载体、赋形剂和稳定剂在所使用的剂量和浓度下对接受者无毒性,并且包括诸如磷酸盐、柠檬酸盐和其它有机酸的缓冲剂;包括抗坏血酸和甲硫氨酸的抗氧化剂;防腐剂(诸如十八烷基二甲基苄基氯化铵;氯化六烃季铵;氯化苯甲烃铵、苄索氯铵;苯酚、丁醇或苄醇;诸如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯的对羟基苯甲酸烷基酯;儿茶酚;间苯二酚;环己醇;3-戊醇;及间甲酚);低分子量(少于约10个残基)多肽;诸如血清白蛋白、明胶或免疫球蛋白的蛋白质;诸如聚乙烯吡咯烷酮的亲水性聚合物;诸如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸的氨基酸;单糖、二糖及其它碳水化合物,包括葡萄糖、甘露糖或糊精;诸如EDTA的螯合剂;诸如蔗糖、甘露醇、海藻糖或山梨糖醇的糖类;诸如钠的成盐反离子;金属络合物(例如,Zn-蛋白络合物);和/或诸如TWEENTM、PLURONICSTM或聚乙二醇(PEG)的非离子表面活性剂。也可将本发明的活性药物成分(例如,式I化合物或其实施方案)以胶体药物递送系统(例如,脂质体、白蛋白微球、微乳液、纳米颗粒和纳米胶囊)形式或以粗乳液(macroemulsion)形式包埋在例如通过凝聚技术或通过界面聚合制备的微胶囊(分别例如羟基甲基纤维素或明胶微胶囊和聚(甲基丙烯酸甲酯)微胶囊)中。此类技术公开于Remington:The Science and Practice of Pharmacy:Remingtonthe Science and Practice of Pharmacy(2005)第21版,Lippincott Williams&Wilkins,Philidelphia,PA中。
可以制备本发明化合物(例如,式I化合物或其实施方案)的持续释放制品。持续释放制品的合适实例包括含有式I化合物或其实施方案的固体疏水性聚合物的半透性基质,该基质呈成形物品(例如薄膜或微胶囊)的形式。持续释放基质的实例包括聚酯、水凝胶(例如,聚(甲基丙烯酸2-羟基乙酯)或聚(乙烯醇))、聚丙交酯(美国专利第3,773,919号)、L-谷氨酸与L-谷氨酸γ-乙酯的共聚物(Sidman等,Biopolymers22:547,1983)、不可降解的乙烯-乙酸乙烯酯(Langer等,J.Biomed.Mater.Res.15:167,1981)、诸如LUPRON DEPOTTM(由乳酸-乙醇酸共聚物和醋酸亮丙瑞林组成的可注射微球)的可降解的乳酸-乙醇酸共聚物和聚-D-(-)-3-羟基丁酸(EP 133,988A)。持续释放组合物还包括通过脂质体包埋的化合物,其可通过本身已知的方法制备(Epstein等,Proc.Natl.Acad.Sci.U.S.A.82:3688,1985;Hwang等,Proc.Natl.Acad.Sci.U.S.A.77:4030,1980;美国专利第4,485,045号和第4,544,545号;以及EP 102,324A)。通常,脂质体属于小的(约200-800埃)单层类型,其中脂质含量为大于约30mol%胆固醇,调整选定的比例以用于最佳治疗。
制剂包括适合于本文详述的施用途径的那些制剂。所述制剂可以方便地以单位剂型呈现,并且可以通过制药领域公知的任何方法制备。技术和制剂一般可在Remington:TheScience and Practice of Pharmacy:Remington the Science and Practice ofPharmacy(2005)第21版,Lippincott Williams&Wilkins,Philidelphia,PA中找到。此类方法包括将活性成分与构成一种或多种辅助成分的载体结合的步骤。
一般来说,通过如下方式制备制剂:将活性成分与液体载体、稀释剂或赋形剂或细粉状固体载体、稀释剂或赋形剂或两者均匀且密切地结合,然后,如果需要,使产物成形。通过将本发明化合物与载体、稀释剂或赋形剂混合来制备典型的制剂。可使用常规溶解和混合程序来制备制剂。例如,将散装原料药(即,本发明化合物或该化合物的稳定化形式(例如,与环糊精衍生物或其它已知络合剂的络合物))在一种或多种上述赋形剂存在的情况下溶解于合适的溶剂中。通常将本发明化合物配制成药物剂型,以使药物的剂量易于控制并且使患者能够依从规定的方案。
在一个实例中,可通过将式I化合物或其实施方案在环境温度下在合适的pH下并且以所需程度的纯度与生理上可接受的载体(即,在所采用的剂量和浓度下对接受者无毒的载体)混合来配制成盖仑制剂(galenical)施用形式。制剂的pH主要取决于特定用途及化合物浓度,但优选在从约3至约8的任何范围内。在一个实例中,在pH为5的乙酸盐缓冲液中配制式I化合物(或其实施方案)。在另一个实施方案中,式I化合物或其实施方案是无菌的。可将该化合物例如以固体或无定形组合物、冻干制剂或水溶液形式储存。
可将适于口服施用的本发明化合物(例如式I化合物或其实施方案)的制剂制备成离散单位诸如丸剂、胶囊、扁囊剂或片剂,它们各自含有预定量的本发明化合物。
可通过在合适的机器中压制呈自由流动形式(如粉末或颗粒)的活性成分来制备压制片剂,所述活性成分任选地与粘结剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合。可通过在适合的机器中模制用惰性液体稀释剂润湿的粉状活性成分的混合物来制备模制片剂。可任选地为片剂包衣或刻线,并且可将片剂配制成使得活性成分从其中缓慢或受控地释放。
可制备片剂、锭剂、糖锭剂、水性或油性悬浮液、分散性粉末或颗粒、乳液、硬胶囊或软胶囊(例如,明胶胶囊)、糖浆剂或酏剂用于口服使用。旨在用于口服使用的本发明化合物(例如,式I化合物或其实施方案)的制剂可以根据本领域已知的用于制造药物组合物的任何方法来制备,并且此类组合物可含有一种或多种剂(包括甜味剂、调味剂、着色剂和防腐剂)以提供可口的制品。含有与适合于制造片剂的无毒药学上可接受的赋形剂混合的活性成分的片剂是可接受的。这些赋形剂可以是例如惰性稀释剂,诸如碳酸钙或碳酸钠、乳糖、磷酸钙或磷酸钠;成粒剂和崩解剂,诸如玉米淀粉或海藻酸;粘结剂,诸如淀粉、明胶或阿拉伯胶;以及润滑剂,诸如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的,或者可通过包括微囊化在内的已知技术进行包衣,以延迟在胃肠道中的崩解和吸收,从而在更长的时间内提供持续的作用。例如,可采用诸如单独的或与蜡在一起的甘油单硬脂酸酯或甘油二硬脂酸酯的延时材料。
合适的口服施用形式的实例是含有约1mg、5mg、10mg、25mg、30mg、50mg、80mg、100mg、150mg、250mg、300mg和500mg的本发明化合物与约90-30mg无水乳糖、约5-40mg交联羧甲基纤维素钠、约5-30mg聚乙烯吡咯烷酮(PVP)K30和约1-10mg硬脂酸镁混配的片剂。首先将粉状成分混合在一起,然后与PVP溶液进行混合。可使用常规设备将所得的组合物干燥、制粒、与硬脂酸镁混合并压制成片剂形式。气溶胶制剂的实例可通过如下方式制备:将本发明的化合物(例如5-400mg)溶解在合适的缓冲液(例如磷酸盐缓冲液)中,如果需要,加入张力调节剂(例如盐,诸如氯化钠)。可以例如使用0.2微米的过滤器过滤溶液以除去杂质和污染物。
为了治疗眼部或其它外部组织,例如嘴和皮肤,可优选地将制剂作为含有例如0.075至20%w/w的量的一种或多种活性成分的外用膏剂或霜剂形式施用。当配制成膏剂时,可将活性成分与石蜡基料或水混溶性膏剂基料一起使用。或者,可将活性成分与水包油霜剂基料一起配制成霜剂。如果需要,霜剂基料的水相可包含多元醇,即具有两个或更多个羟基的醇,诸如丙二醇、丁烷1,3-二醇、甘露醇、山梨糖醇、甘油和聚乙二醇(包括PEG 400)及其混合物。外用制剂可理想地包括增强活性成分穿过皮肤或其它受影响区域的吸收或渗透的化合物。此类皮肤渗透增强剂的实例包括二甲基亚砜及相关类似物。
本发明乳液的油相可由已知成分以已知方式构成。尽管所述相可仅包含乳液,但它理想地包含至少一种乳化剂与脂肪或油或与脂肪和油两者的混合物。优选地,可将亲水性乳化剂与用作稳定剂的亲脂性乳化剂一起包括在内。还优选包括油和脂肪两者。含有一种(多种)稳定剂或者不含一种(多种)稳定剂的一种(多种)乳化剂构成所谓的乳化蜡,并且所述蜡与油和脂肪一起构成所谓的乳化膏剂基料,该乳化膏剂基料形成霜剂制剂的油性分散相。适用于本发明的制剂的乳化剂和乳液稳定剂包括60、80、鲸蜡硬脂醇、苄醇、肉豆蔻醇、单硬脂酸甘油酯和月桂基硫酸钠。
在外用施加的一个方面,期望向与待治疗的周围神经元相邻的靶区域(例如皮肤表面、粘膜等)施用有效量的根据本发明的药物组合物。该量一般在每次施用约0.0001mg至约1g本发明化合物的范围内,这取决于待治疗的区域,用途是诊断性的、预防性的还是治疗性的,症状的严重度以及所采用的外用媒介物的性质。优选的外用制品是膏剂,其中每cc的膏剂基料使用约0.001至约50mg活性成分。可将药物组合物配制成透皮组合物或透皮递送装置(“贴片”)。此类组合物包括例如背衬、活性化合物储库、控制膜、衬垫和接触粘合剂。此类透皮贴片可用于提供连续的脉动或需要时按需递送本发明化合物。
本发明化合物(例如,式I化合物或其实施方案)的水性悬浮液含有与适合于制造水性悬浮液的赋形剂混合的活性物质。此类赋形剂包括悬浮剂,诸如羧基甲基纤维素钠、交联羧甲基纤维素、聚维酮、甲基纤维素、羟丙基甲基纤维素、海藻酸钠、聚乙烯吡咯烷酮、黄蓍树胶和阿拉伯胶,以及分散剂或湿润剂(诸如天然存在的磷脂(例如,卵磷脂)、氧化烯与脂肪酸的缩合产物(例如,聚氧乙烯硬脂酸酯)、氧化乙烯与长链脂族醇的缩合产物(例如,十七亚乙基氧基鲸蜡醇)、氧化乙烯与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如,聚氧乙烯脱水山梨糖醇单油酸酯)。水性悬浮液还可含有一种或多种防腐剂诸如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯、一种或多种着色剂、一种或多种调味剂,以及一或多种甜味剂(诸如蔗糖或糖精)。
本发明化合物(例如,式I化合物或其实施方案)的制剂可呈无菌注射制剂(诸如无菌注射水性悬浮液或油性悬浮液)的形式。这种悬浮液可以根据已知技术使用上面已经提到的那些合适的分散剂或湿润剂以及悬浮剂来配制。无菌注射制品还可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如在1,3-丁二醇中的溶液,或者被制备成冻干粉末。可采用的可接受的媒介物和溶剂有水、林格氏溶液和等渗氯化钠溶液。另外,可将无菌不挥发性油方便地用作溶剂或悬浮介质。出于此目的,可采用任何温和不挥发性油,包括合成的单甘油酯或二甘油酯。另外,脂肪酸(诸如油酸)同样可用于制备注射剂。
可与载体物质组合以产生单一剂型的活性成分的量将取决于所治疗的宿主和特定施用方式。例如,旨在供人口服施用的定时释放制剂可含有与适当且方便的量的载体物质混配的约1至1000mg活性物质,所述载体材料的量可在总组合物的约5%至约95%(重量:重量)之间变化。可制备药物组合物以提供可容易测量的施用量。例如,旨在用于静脉内输注的水溶液可含有每毫升溶液约3至500μg的活性成分,以便合适体积的输注可以以约30mL/hr的速率产生。
适用于胃肠外施用的制剂包括水性和非水性等渗无菌注射溶液,其可含有抗氧化剂、缓冲剂、抑菌剂和使制剂与预期受者血液等渗的溶质;以及水性和非水性无菌悬浮液,其可包括助悬剂和增稠剂。
适合于外用施用于眼部的制剂还包括滴眼剂,其中活性成分溶解或悬浮在适合于活性成分的载体,尤其水性溶剂中。活性成分优选以约0.5%w/w至20%w/w,例如约0.5%w/w至10%w/w,例如约1.5%w/w的浓度存在于此类制剂中。
适合于外用施用于口的制剂包括在调味基料(通常为蔗糖和阿拉伯胶或黄芪胶)中包含活性成分的糖锭剂;在惰性基质(诸如明胶和甘油,或蔗糖和阿拉伯胶)中包含活性成分的软锭剂(pastilles);在适当的液体载体中包含活性成分的漱口水。
用于直肠施用的制剂可利用包含例如可可脂或水杨酸酯的合适基料以栓剂形式存在。
适用于肺内或经鼻施用的制剂具有例如在0.1微米至500微米范围内的粒度(包括在增量为微米的介于0.1微米与500微米之间的范围内的粒度,诸如0.5微米、1微米、30微米、35微米等),所述制剂通过经由鼻通道快速吸入或者通过经口吸入从而达到肺泡囊来进行施用。合适的制剂包括活性成分的水性或油性溶液。适于气溶胶或干燥粉末施用的制剂可根据常规方法制备,并且可与诸如如下文所述迄今为止用于治疗病症的化合物的其它治疗剂一起递送。
可将制剂包装在单位剂量或多剂量容器,例如密封安瓿瓶和小瓶中,并且可将其在冷冻干燥(冻干)条件下储存,仅需要在临用前添加无菌注射用液体载体,例如水。临时注射溶液和悬浮液是由先前所述的种类的无菌粉末、颗粒剂和片剂制备。优选的单位剂量制剂为含有如本文上文所述的日剂量或单位日次剂量或其合适分量的活性成分的那些。
当结合靶位于大脑中时,本发明的某些实施方案提供了用于穿过血脑屏障的式I化合物(或其实施方案)。某些神经变性疾病与血脑屏障的渗透性增加有关,使得式I化合物(或其实施方案)可容易地被引入到大脑中。当血脑屏障保持完整时,存在几种本领域已知的途径用于将分子运输穿过血脑屏障,所述方法包括但不限于物理方法、基于脂质的方法以及基于受体和通道的方法。
将式I化合物(或其实施方案)运输穿过血脑屏障的物理方法包括但不限于完全绕开血脑屏障或通过在血脑屏障中产生开口。
绕开方法包括但不限于直接注射到大脑中(参见,例如,Papanastassiou等,GeneTherapy 9:398-406,2002)、间质输注/对流增强型递送(例如,参见Bobo等,Proc.Natl.Acad.Sci.U.S.A.91:2076-2080,1994)以及将递送装置植入脑中(参见,例如,Gill等,Nature Med.9:589-595,2003;以及Gliadel WafersTM,GuildfordPharmaceutical)。在屏障中产生开口的方法包括但不限于超声波(参见,例如,美国专利公开第2002/0038086号)、渗透压(例如,通过施用高渗性甘露糖醇来进行(Neuwelt,E.A.,Implication of the Blood-Brain Barrier and its Manipulation,第1和2卷,PlenumPress,N.Y.,1989)),以及通过例如缓激肽或透化剂A-7进行透化(参见,例如,美国专利第5,112,596号、第5,268,164号、第5,506,206号和第5,686,416号)。
将式I化合物(或其实施方案)运输穿过血脑屏障的基于脂质的方法包括但不限于将式I化合物(或其实施方案)包封在偶联至结合于血脑屏障血管内皮上的受体的抗体结合片段的脂质体中(参见,例如,美国专利申请公开第2002/0025313号),以及将式I化合物(或其实施方案)包覆于低密度脂蛋白颗粒(参见,例如,美国专利申请公开第2004/0204354号)或阿朴脂蛋白E(参见,例如,美国专利申请公开第2004/0131692号)中。
将式I化合物(或其实施方案)运输穿过血脑屏障的基于受体和通道的方法包括但不限于使用糖皮质激素阻断剂来增加血脑屏障的渗透性(参见,例如,美国专利申请公开第2002/0065259号、第2003/0162695号和第2005/0124533号);激活钾通道(参见,例如,美国专利申请公开第2005/0089473号),抑制ABC药物转运蛋白(参见,例如,美国专利申请公开第2003/0073713号);用转铁蛋白包覆式I化合物(或其实施方案)并调节一种或多种转铁蛋白受体的活性(参见,例如,美国专利申请公开第2003/0129186号),以及使抗体阳离子化(参见,例如,美国专利第5,004,697号)。
对于脑内使用,在某些实施方案中,可通过输注至CNS的储液室中来连续施用化合物,但是推注是可以接受的。可将抑制剂施用至脑室或以其它方式引入CNS或脊髓液中。可通过使用留置导管和连续施用装置(诸如泵)进行施用,或者它可通过植入,例如持续释放媒介物的大脑内植入来施用。更具体地,可通过长期植入的套管或在渗透性微型泵的帮助下长期输注来注射抑制剂。皮下泵是可用的,其将蛋白质通过小的管道递送至脑室。通过皮肤可重新灌注高度精密的泵,并且可在无手术干预的情况下设置该泵的递送速率。涉及皮下泵装置或通过完全植入的药物递送系统进行的连续脑室内输注的合适的施用方案和递送系统的实例是用于向阿尔茨海默症患者和帕金森病动物模型施用多巴胺、多巴胺激动剂和胆碱能激动剂的那些,如Harbaugh,J.Neural Transm.增刊24:271,1987;和DeYebenes等,Mov.Disord.2:143,1987所描述的。
将本发明中使用的式I化合物(或其实施方案)以与良好医学实践一致的方式配制、给药和施用。在此背景下考虑的因素包括受治疗的特定病症、受治疗的特定哺乳动物、个体患者的临床病患、病症的起因、药剂的递送部位、施用方法、施用时程以及从业医生已知的其它因素。不需要但任选地将式I化合物(或其实施方案)与当前用于预防或治疗所讨论的病症的一种或多种剂一起配制。此类其它剂的有效量取决于制剂中存在的本发明化合物的量、病症或治疗的类型以及上面讨论的其它因素。
这些剂一般以与如本文所述的剂量相同的剂量和如本文所述的施用途径使用,或以本文所述剂量的约1%-99%使用,或以经验上/临床上确定合适的任何剂量和任何途径使用。
为了预防或治疗疾病,式I化合物(或其实施方案)(当单独使用或与其它剂组合使用时)的适当剂量将取决于待治疗的疾病类型、化合物的性质、疾病的严重度和病程、是为预防目的还是治疗目的而施用所述化合物、既往治疗、患者的临床病史和对该化合物的响应以及主治医师的判断。适当地一次性或历经一系列治疗将所述化合物施用于患者。根据疾病的类型和严重度,例如,无论通过一次或多次单独施用还是通过连续输注,约1μg/kg至15mg/kg(例如0.1mg/kg-10mg/kg)的化合物可为施用于患者的初始候选剂量。一种典型的日剂量范围可以为约1μg/kg至100mg/kg或更高,这取决于上面提到的因素。对于视病患而定的历经数天或更长时间的重复施用,该治疗一般将会持续,直至出现期望的疾病症状压制。式I化合物(或其实施方案)的一个示例性剂量范围将为约0.05mg/kg至约10mg/kg。因此,可向患者施用约0.5mg/kg、2.0mg/kg、4.0mg/kg或10mg/kg(或其任意组合)中的一种或多种剂量。可以间断地施用此类剂量,例如每周进行或每三周进行(例如,使得患者接受约两剂至约二十剂,或例如约六剂的抗体)。可施用初始较高的加载剂量,然后施用一种或多种较低剂量。示例性给药方案包括施用约4mg/kg的初始加载剂量,随后施用约2mg/kg化合物的每周维持剂量。然而,其它给药方案可以是有用的。本治疗的进程易于通过常规技术和测定加以监测。
其它典型的日剂量范围可为例如约1g/kg至高达100mg/kg或更高(例如、约1μg/kg至1mg/kg、约1μg/kg至约5mg/kg、约1mg/kg至10mg/kg、约5mg/kg至约200mg/kg、约50mg/kg至约150mg/mg、约100mg/kg至约500mg/kg、约100mg/kg至约400mg/kg以及约200mg/kg至约400mg/kg),这取决于上面提到的因素。通常,临床医生将施用化合物,直至达到改善或最佳地,消除所治疗的疾病或病患的一种或多种症状的剂量。本治疗的进程易于通过常规测定加以监测。可将本文提供的一种或多种剂一起施用或在不同时间施用(例如,一种剂是在第二种剂施用之前施用)。可使用不同的技术将一种或多种剂施用于受试者(例如,可口服施用一种剂,而通过肌内注射或鼻内施用第二种剂)。可施用一种或多种剂,使得所述一种或多种剂同时在受试者中产生药理学效应。或者,可施用一种或多种剂,使得首先施用的剂的药理活性在施用一种或多种其次施用的剂(例如1种、2种、3种或4种其次施用的剂)之前终止。
适应症和治疗方法
本发明化合物调节,优选抑制哺乳动物(例如,人)中的通过电压依赖性钠通道的离子。任何此类调节(无论其是部分还是完全抑制或阻止离子通量),在本文中有时都称为“阻断”,并且相应的化合物被称为“阻断剂”或“抑制剂”。一般来说,本发明的化合物通过抑制钠通道的电压依赖性活性来向下调节钠通道的活性,和/或通过阻止钠通道活性(诸如离子通量)来减少或阻止穿过细胞膜的钠离子通量。
因此,本发明的化合物是钠通道阻断剂,因此可用于治疗哺乳动物例如人和其它生物体的疾病和病患,包括所有由于电压依赖性钠通道生物活性异常而导致的或者可通过调节电压依赖性钠通道的生物活性而得到改善的疾病和病患。特别地,本发明的化合物,即式(I)化合物以及实施方案和(或其立体异构体、几何异构体、互变异构体、溶剂化物、代谢物、同位素、药学上可接受的盐或前药)可用于治疗哺乳动物,例如人的由于电压依赖性NaV1.7生物活性异常而导致的或者可通过调节,优选抑制NaV1.7生物活性而得到改善的疾病和病患。在某些方面,与NaV1.5相比,本发明的化合物选择性地抑制NaV1.7。
如本文所定义,钠通道介导的疾病或病患是指在调节钠通道后得到改善的哺乳动物,优选人的疾病或病患,其包括但不限于疼痛、中枢神经病患,诸如癫痫、焦虑、抑郁和双相疾病;心血管病患,诸如心律失常、心房纤颤和心室纤颤;神经肌肉病患,诸如不宁腿综合征和肌肉麻痹或破伤风;针对中风、神经创伤和多发性硬化的神经保护;以及通道病变,诸如红斑性肢痛症和家族性直肠疼痛综合征。
在一个方面,本发明涉及化合物、药物组合物,以及使用所述化合物和药物组合物治疗哺乳动物,优选人的钠离子通道介导的疾病和优选与以下有关的疾病和疾患的方法:疼痛、中枢神经病患,诸如癫痫、焦虑、抑郁和双相疾病;心血管病患,诸如心律失常、心房纤颤和心室纤颤;神经肌肉病患,诸如不宁腿综合征和肌肉麻痹或破伤风;针对中风、神经创伤和多发性硬化的神经保护;以及通道病变,诸如红斑性肢痛症和家族性直肠疼痛综合征,所述方法通过向需要此种治疗的哺乳动物,例如人施用有效量的钠通道阻断剂调节剂,尤其抑制剂来实现。
钠通道介导的疾病或病患还包括与HIV相关的疼痛、HIV治疗引起的神经病变、三叉神经痛、舌咽神经痛、转移性浸润继发性神经病变、痛性肥胖症(adiposis dolorosa)、丘脑病变、高血压、自身免疫性疾病、哮喘、药物成瘾(例如,鸦片剂、苯并二氮安非他明、可卡因、酒精、丁烷吸入)、阿尔茨海默症、痴呆、年龄相关记忆损伤、科尔萨科夫综合征(Korsakoff syndrome)、再狭窄、泌尿功能障碍、失禁、帕金森病、脑血管缺血、神经官能症、胃肠道疾病、镰状细胞性贫血、移植排斥、心力衰竭、心肌梗塞、再灌注损伤、间歇性跛行(intermittant claudication)、心绞痛、惊厥、呼吸系统病症、脑或心肌缺血、长QT综合征、儿茶酚胺能多形性室性心动过速、眼部疾病、痉挛、痉挛性截瘫、肌病、重症肌无力、先天性副肌强直、高钾性周期性瘫痪、低钾性周期性瘫痪、脱发、焦虑症、精神病、躁狂症、妄想症、季节性情感障碍、恐慌症、强迫症(OCD)、恐惧症、自闭症、阿斯伯格综合症、瑞特综合征、崩解症、注意力缺陷障碍、攻击性、冲动控制障碍、血栓形成、子痫前期、充血性心力衰竭、心脏骤停、弗里德里希共济失调、脊髓小脑性共济失调、骨髓病、神经根病、系统性红斑狼疮、肉芽肿病、橄榄-桥脑-小脑萎缩(olivo-ponto-cerebellar atrophy)、脊髓小脑性共济失调、发作性共济失调、肌纤维颤搐、进行性苍白球萎缩、进行性核上性麻痹和痉挛、外伤性脑损伤、脑水肿、脑积水、脊髓损伤、神经性厌食症、贪食症、普拉德-威利综合症、肥胖、视神经炎、白内障、视网膜出血、缺血性视网膜病变、色素性视网膜炎、急性和慢性青光眼、黄斑变性、视网膜动脉闭塞、舞蹈症、亨廷顿舞蹈症、脑水肿、直肠炎、疱疹后神经痛、急性痛、热敏感性、结节病、肠易激综合征、妥瑞氏综合征(Tourette syndrome)、莱施-奈恩综合征、布鲁格达综合征(Brugado syndrome)、利德尔综合征、克罗恩病、多发性硬化和与多发性硬化(MS)相关的疼痛、肌萎缩侧索硬化症(ALS)、弥散性硬化症、糖尿病性神经病变、周围神经病变、夏-马-图三氏综合征(charcot marie tooth syndrome)、关节炎、类风湿关节炎、骨关节炎、软骨钙化病、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、肌强直性营养不良、肌肉营养不良、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、心理障碍、甲状腺功能减退症、双相性抑郁、焦虑、精神分裂症、与钠通道毒素相关的疾病、家族性红斑性肢痛症、原发性红斑性肢痛症、直肠疼痛、癌症、癫痫、局部和全身性强直性癫痫发作、发热性癫痫发作、失神性癫痫发作(癫痫小发作)、肌阵挛性癫痫发作、失张力性癫痫发作、阵挛性癫痫发作、雷格氏病(Lennox Gastaut)、West综合征(婴儿痉挛症)、多重耐药性发作、癫痫发作预防(抗癫痫发作)、家族性地中海热综合征、痛风、不宁腿综合征、心律失常、纤维肌痛、由中风或神经外伤引起的局部缺血状态下的神经保护、快速型心律失常、心房纤颤和心室纤颤以及呈全身或局部麻醉状态。
如本文中所用,术语“疼痛”是指所有类别的疼痛,并且被认为包括但不限于神经病理性疼痛、炎性疼痛、伤害性疼痛、特发性疼痛、神经源性疼痛(neuralgic pain)、口面痛、烧伤疼痛、灼口综合征、躯体疼痛、内脏疼痛、肌筋膜疼痛、牙齿疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、术后疼痛、分娩疼痛、产前阵痛、慢性区域性疼痛综合征(CRPS)、反射性交感神经营养不良、臂丛根性撕脱(brachial plexus avulsion)、神经原性膀胱、急性疼痛(例如,骨骼肌痛和术后疼痛)、慢性疼痛、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、家族性偏瘫性偏头痛、与头痛相关的病患、鼻窦头痛、紧张性头痛、幻肢疼痛、周围神经损伤、中风后疼痛、丘脑病变、神经根病、HIV痛、疱疹后疼痛、非心脏性胸痛、肠易激综合征和与肠道病症和消化不良相关的疼痛及其组合。
此外,除了疼痛以外,钠通道阻断剂还具有临床用途。因此,本发明还涉及化合物、药物组合物以及使用所述化合物和药物组合物治疗诸如癌症和瘙痒症(发痒)的疾病或病患的方法。
瘙痒症通常称为发痒,是一种常见的皮肤病。虽然瘙痒症的确切原因是复杂的并且尚未完全了解,但长期以来已有证据表明,发痒牵涉到与介导疼痛的那些感觉神经元类似的感觉神经元,尤其是C纤维(Schmelz,M.等,J.Neurosci.(1997),17:8003-8)。特别地,据信钠通过电压门控钠通道流入对于皮肤的发痒感觉传播是必不可少的。发痒冲动的传输导致令人不快的感觉,从而引发搔抓的欲望或反射。
已知多种原因和电学通路引起发痒。在人中,瘙痒可由组胺或激活C纤维的独特群体的PAR-2激动剂(诸如黎豆因(mucunain))引起(Namer,B等,J.Neurophysiol.(2008),100:2062-9)。已知多种神经营养肽在动物模型中介导发痒(Wang,H.和Yosipovitch,G.,International Journal of Dermatology(2010),49:1-11)。发痒也可由鸦片类药物引起,这是与疼痛响应的药理学不同的药理学证据。
在发痒与疼痛响应之间存在复杂的相互作用,所述相互作用部分产生于来自皮肤的重叠感觉输入(Ikoma,A.等,Arch.Dermatol.(2003),139:1475-8),并且也产生于疼痛和瘙痒两者的不同病因学。疼痛响应可通过增强中枢致敏而使瘙痒加剧或者导致疼痛性搔抓的抑制。当疼痛响应不存在时,特别严重形式的慢性发痒就会出现,正如在疱疹后发痒的情况下一般(Oaklander,A.L.等,Pain(2002),96:9-12)。
本发明的化合物也可用于治疗瘙痒症。用电压门控钠通道,尤其是NaV1.7的抑制剂治疗发痒的基本原理如下:
感觉嘌呤兴奋剂(pruritinergic stimulant)的C纤维中的电活性的传播需要钠通过电压门控钠通道进入。
NaV1.7在人体皮肤中的C纤维和角质形成细胞中表达(Zhao,P.等人,Pain(2008),139:90-105)。
NaV1.7(L858F)的引起红斑性肢痛症的功能获得性突变也引起慢性发痒(Li,Y.等,Clinical and Experimental Dermatology(2009),34:e313-e4)。
可通过用钠通道阻断剂,诸如局部麻醉剂利多卡因治疗来缓解慢性发痒(Oaklander,A.L.等,Pain(2002),96:9-12;Villamil,A.G.等,The American Journal ofMedicine(2005),118:1160-3)。在这些报道中,当静脉内或外用(Lidoderm贴片)施用时,利多卡因是有效的。当全身施用时利多卡因在所达到的血浆浓度下可具有多种活性,但当外用施用时,血浆浓度仅为约1μM(药物评估和研究中心NDA 20-612)。在这些浓度下,利多卡因对于钠通道阻断为选择性的并且抑制动物模型中的C纤维和疼痛响应中的自发性电活性(Xiao,W.H.,和Bennett,G.J..Pain(2008),137:218-28)。发痒或皮肤刺激的类型包括但不限于:
银屑病性瘙痒症,由血液透析(hemodyalisis)引起的发痒,水因性瘙痒症(aguagenic pruritus)以及由皮肤病症(例如,接触性皮炎)、全身性病症、神经病、精神性因素或其混合物引起的发痒;
由过敏反应、虫咬、超敏反应(例如,干性皮肤、痤疮、湿疹、银屑病)、炎性病患或损伤引起的发痒;
与外阴前庭炎相关的发痒;以及
由另一治疗剂诸如,例如,抗生素、抗病毒药和抗组胺的施用产生的皮肤刺激或炎性作用。
本发明化合物也可用于治疗哺乳动物,优选人的某些癌症,诸如激素敏感性癌症,诸如前列腺癌(腺癌)、乳腺癌、卵巢癌、睾丸癌和甲状腺瘤形成。已经证实电压门控钠通道在前列腺癌细胞和乳腺癌细胞中表达。新生的NaV1.5作为人乳腺癌的转移过程中的不可分割的部分而存在,并且可用作转移表型和治疗靶标两者的新型标志物(Clin.Cancer Res.(2005),Aug.1;11(15):5381-9)。电压门控钠通道α-亚基,尤其NaV1.7的功能表达与体外前列腺癌(CaP)的强的转移潜力相关。使用对钠通道α亚基具特异性的抗体进行的电压门控钠通道α-亚基免疫染色在前列腺组织中是明显的并且相较于非CaP患者在CaP中显著更强(Prostate Cancer Prostatic Dis.,2005;8(3):266-73)。另见Diss,J.K.J.等,Mol.Cell.Neurosci.(2008),37:537–547和Kis-Toth,K.等,The Journal of Immunology(2011),187:1273–1280。
考虑到以上情况,在一个实施方案中,本发明提供了用于治疗哺乳动物的钠通道-介导的疾病,尤其是疼痛,或保护哺乳动物免于发展钠通道-介导的疾病,尤其是疼痛的方法,所述方法包括向哺乳动物,尤其是人施用治疗有效量的本发明化合物或包含治疗有效量的本发明化合物的药物组合物,其中所述化合物调节一种或多种电压依赖性钠通道的活性。
本发明的另一个实施方案为治疗哺乳动物,优选人的疾病或病患的方法,其中所述疾病或病患选自由以下组成的组:疼痛、抑郁、心血管疾病、呼吸系统疾病和精神病,以及其组合,并且其中所述方法包括向哺乳动物施用治疗有效量的如上所阐述的本发明化合物的实施方案(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),或包含治疗有效量的如上所阐述的本发明化合物(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),以及药学上可接受的赋形剂的药物组合物。
这个实施方案的一个实施方案为其中所述疾病或病患选自由以下组成的组的实施方案:急性疼痛、慢性疼痛、神经病理性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、术后疼痛、分娩疼痛、产前阵痛、神经原性膀胱、溃疡性结肠炎、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢疼痛、周围神经损伤及其组合。
这个实施方案的另一个实施方案为其中所述疾病或病患选自由以下组成的组的实施方案:与HIV相关的疼痛、HIV治疗引起的神经病变、三叉神经痛、疱疹后神经痛、急性痛、热敏感性、结节病、肠易激综合征、克罗恩病、与多发性硬化症(MS)相关的疼痛、肌萎缩侧索硬化症(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿关节炎、骨关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、与钠通道毒素相关的疾病、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛、癌症、癫痫、局部和全身性强直性癫痫发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、快速型心律失常、心房纤颤和心室纤颤。
本发明的另一个实施方案为治疗但并不预防哺乳动物的疼痛的方法,其中所述方法包括向哺乳动物施用治疗有效量的如上所阐述的本发明化合物(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),或包含治疗有效量的如上所阐述的本发明化合物(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),以及药学上可接受的赋形剂的药物组合物。
这个实施方案的一个实施方案为一种方法,其中所述疼痛选自由以下组成的组:神经病理性疼痛、炎性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、术后疼痛、分娩疼痛、产前阵痛、牙齿疼痛、慢性疼痛、持续性疼痛、外周介导性疼痛、中枢介导性疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢疼痛、周围神经损伤、三叉神经痛、疱疹后神经痛、急性痛、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠痛或纤维肌痛及其组合。
这个实施方案的另一个实施方案为一种方法,其中所述疼痛与选自由以下组成的组的疾病或病患相关:HIV、HIV治疗引起的神经病变、热敏感性、结节病、肠易激综合征、克罗恩病、多发性硬化、肌萎缩侧索硬化症、糖尿病性神经病变、周围神经病变、类风湿关节炎、骨关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、与钠通道毒素相关的疾病、神经原性膀胱、溃疡性结肠炎、癌症、癫痫、局部和全身性强直性癫痫发作、不宁腿综合征、心律失常、由中风或神经创伤引起的局部缺血病患、快速型心律失常、心房纤颤和心室纤颤。
本发明的另一个实施方案为治疗哺乳动物,优选人的疼痛的方法,该方法通过抑制哺乳动物中的通过电压依赖性钠通道的离子通量来实现,其中所述方法包括向哺乳动物施用治疗有效量的如上所阐述的本发明化合物的实施方案(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),或包含治疗有效量的如上所阐述的本发明化合物(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),以及药学上可接受的赋形剂的药物组合物。
本发明的另一个实施方案为治疗哺乳动物,优选人的瘙痒症的方法,其中所述方法包括向哺乳动物施用治疗有效量的如上所阐述的本发明化合物的实施方案(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),或包含治疗有效量的如上所阐述的本发明化合物(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),以及药学上可接受的赋形剂的药物组合物。
本发明的另一个实施方案为治疗哺乳动物,优选人的癌症的方法,其中所述方法包括向哺乳动物施用治疗有效量的如上所阐述的本发明化合物的实施方案(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),或包含治疗有效量的如上所阐述的本发明化合物(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式),以及药学上可接受的赋形剂的药物组合物。
本发明的另一个实施方案为减少哺乳动物细胞中的通过电压依赖性钠通道的离子通量的方法,其中所述方法包括使所述细胞与如上所阐述的本发明化合物的实施方案(其呈现为其立体异构体、对映异构体或互变异构体或它们的混合物,或其药学上可接受的盐、溶剂化物或前药的形式)接触。
本发明的另一个实施方案为在哺乳动物中相对于第二电压门控钠通道选择性抑制第一电压门控钠通道的方法,其中所述方法包括向哺乳动物施用抑制量的式(I)化合物或式(I)化合物的实施方案。
本发明的另一个实施方案为与NaV1.5相比选择性抑制哺乳动物或哺乳动物细胞中的NaV1.7的方法,其中所述方法包括向哺乳动物施用抑制量的式(I)化合物或其实施方案的实施方案。
对于与治疗哺乳动物的疾病和病患相关的上述实施方案中的每一个,本发明还相关地考虑了用作治疗此类疾病和病患的药剂的式I化合物或其实施方案。
对于与治疗哺乳动物的疾病和病患相关的上述实施方案中的每一个,本发明还相关地考虑了式I化合物或其实施方案用于制造治疗此类疾病和病患的药剂的用途。
本发明的另一个实施方案为在体外或体内测定中使用式(I)化合物作为标准或对照来确定测试化合物调节电压依赖性钠通道的功效的方法。
在本发明的另一个实施方案中,式(I)化合物是通过使其中的一个或多个原子被具有不同原子质量或质量数的原子替换来进行同位素标记的。此类同位素标记的(即,放射性标记的)式(I)化合物被认为在本发明的范围内。可掺入至式(I)化合物中的同位素的实例分别包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,诸如但不限于2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。这些同位素标记的化合物将可用于通过表征例如钠通道上的作用位点或作用方式,或对钠通道,尤其是NaV1.7上的药学上重要的作用位点的结合亲和力来帮助确定或测量化合物的有效性。某些经同位素标记的式(I)化合物,例如,掺入有放射性同位素的那些,可用于药物和/或底物组织分布研究。放射性同位素氚,即3H和碳-14,即,14C,特别可用于该目的,因为它们易于掺入并且具有方便的检测手段。
诸如氘,即2H的较重同位素取代可以提供由较高的代谢稳定性带来的某些治疗优势,例如,体内半衰期延长或剂量需要减少,并因此在一些情况下可能是优选的。
诸如11C、18F、15O及13N的正电子发射同位素取代可用于正电子发射断层扫描(PET)研究以检查基质受体占有率。经同位素标记的式(I)化合物一般可通过本领域技术人员已知的常规技术来制备,或者通过与如下文阐述的实施例中描述的那些工艺类似的工艺使用适当的同位素标记的试剂代替先前使用的未标记的试剂来制备。
测试化合物
对本发明化合物在介导,特别是抑制钠通道离子通量方面的评估可使用下文描述的测定来确定。或者,对化合物在治疗人的病患和疾病方面的评估可以在用于证明化合物治疗疼痛的功效的产业标准动物模型中建立。已经开发了人神经病理性疼痛病患动物模型,其在一段持续时间内产生可通过感觉测试评价的可复现感觉短缺(异常性疼痛、痛觉过敏和自发性疼痛)。通过确定所存在的机械、化学和温度诱导的异常性疼痛和痛觉过敏的程度,可将在人中观察到的若干病理生理学病患模型化,从而允许评价药物疗法。
在外周神经损伤大鼠模型中,损伤神经的异位活性对应于疼痛的行为体征。在这些模型中,以不影响一般行为和运动功能的浓度静脉内施用钠通道阻断剂和局部麻醉剂利多卡因,可压制异位活性并逆转触觉异常性疼痛(Mao,J.和Chen,L.L,Pain(2000),87:7-17)。将在这些大鼠模型中有效的剂量按异速比例(allometric scaling)转化为与被证明在人体中有效的那些剂量类似的剂量(Tanelian,D.L.和Brose,W.G.,Anesthesiology(1991),74(5):949-951)。此外,以皮肤贴片形式施用的利多卡因当前被FDA批准用于疱疹后神经痛治疗(Devers,A.和Glaler,B.S.,Clin.J.Pain(2000),16(3):205-8)。
本发明容易提供许多用于鉴定可用作治疗剂的钠通道调节剂的不同手段。可使用例如,测量电流、测量膜电位、测量离子通量(例如,钠或胍盐)、测量钠浓度、测量第二信使和转录水平的多种体外和体内测定,并且使用例如电压敏感染料、放射性示踪剂和贴片钳电生理学来对钠通道调节剂的鉴定进行评估。
一种此类方案牵涉筛选能够调节钠通道活性的化学药剂,从而鉴定其为调节剂。
在Bean等人,J.General Physiology(1983),83:613-642和Leuwer,M.等人,Br.J.Pharmacol(2004),141(1):47-54中描述的典型测定使用贴片钳技术来研究通道的行为。此类技术对于本领域技术人员来说是已知的,并且可使用当前技术研制成用于评价化合物调节钠通道行为的能力的低通过量测定或中通过量测定。
在选择待使用的筛选测定时,测试化合物的通过量是一个重要的考虑因素。在一些要测试数十万种化合物的策略中,使用低通过量方式是不可取的。然而,在其它情况下,对于鉴定有限数目的化合物之间的重要差异,低通过量是令人满意的。经常将需要合并测定类型以鉴定特定的钠通道调节化合物。
使用贴片钳技术的电生理学测定被公认为用于钠通道化合物相互作用的详细表征的金标准并且如Bean等人(同上)和Leuwer,M.等人(同上)中所描述。存在手动的低通过量筛选(LTS)方法,所述方法可每天比较2-10种化合物;最近开发的系统,所述系统用于按每天20-50个贴片(即化合物)进行自动化中通过量筛选(MTS);以及来自MolecularDevices Corporation(Sunnyvale,CA)的技术,所述技术允许按每天1000-3000个贴片(即化合物)进行自动化高通过量筛选(HTS)。
一种自动化贴片钳系统采用平面电极技术来加快发现药物的速率。平面电极能够实现高阻抗、细胞粘附密封,随后实现与常规记录相当的稳定的低噪音全细胞记录。合适的仪器为PatchXpress 7000A(Axon Instruments Inc.,Union City,CA)。对多种细胞系和培养技术(其包括粘附细胞以及在悬浮液中自发生长的细胞)按密封成功率和稳定性进行了等级划分。可使稳定表达高水平的相关钠离子通道的永生化细胞(例如HEK和CHO)适应高密度悬浮培养。
可选择允许研究人员鉴定阻断通道的特定状态,诸如开启状态、闭合状态或静息状态,或阻断从开启状态至闭合状态、闭合状态至静息状态或静息状态至开启状态的过渡的化合物的其它测定。本领域技术人员一般熟悉此类测定。
也可用结合测定。设计包括可获得自Evotec OAI集团的公司(Hamburg,Germany)的基于常规放射性过滤器的结合测定或基于共聚焦的荧光系统,这两者均为HTS。
也可使用放射性通量测定。在本测定中,用藜芦定或乌头碱刺激通道打开,并利用毒素将通道保持在稳定开启状态,并且根据它们阻止离子流入的能力鉴定通道阻断剂。所述测定可使用放射性22[Na]和14[C]胍离子作为示踪剂。活细胞中的FlashPlate&Cytostar-T板避免分离步骤并适合于HTS。闪烁板技术还已经将该方法推进至HTS适合性。由于所述测定的功能方面,所以所述信息内容相当好。
然而另一形式使用可获得自Molecular Dynamics(Amersham Biosciences的一个部门,Piscataway,NJ)的FLIPR系统膜电位试剂盒(HTS)测量膜电位的重新分布。该方法受限于缓慢的膜电位变化。一些问题可能来自化合物的荧光背景。测试化合物也可能直接影响细胞膜的流动性并导致细胞内染料浓度升高。另外,由于所述测定的功能方面,所述信息内容相当好。
可使用钠染料来测量钠离子通过通道流入的速率或量。鉴于可能的通道阻断剂,这种类型的测定提供非常高的信息内容。所述测定为功能性的并且将直接测量Na+流入量。CoroNa Red、SBFI和/或钠绿(sodium green)(Molecular Probes,Inc.Eugene OR)可用于测量Na流入量;它们全部为Na响应性染料。可将它们与FLIPR仪器组合使用。这些染料在筛选中的用途先前未在文献中进行描述。以这种形式,钙染料也可能具有潜力。
在另一个测定中,使用基于FRET的电压传感器来测量测试化合物直接阻断Na流入的能力。商购可得的HTS系统包括VIPRTM II FRET系统(Life Technologies,或AuroraBiosciences Corporation,San Diego,CA,Vertex Pharmaceuticals,Inc.的一个部门),所述系统可以与FRET染料结合使用,所述FRET染料也可获自Aurora Biosciences。这种测定测量对电压变化的亚秒响应。不存在对通道功能的修饰剂的需要。所述测定测量去极化和超极化,并提供用于定量的成比例输出。这种测定的稍微不太昂贵的MTS版本利用与来自Aurora Biosciences的FRET染料结合的FLEXstationTM(Molecular DevicesCorporation)。测试本文公开的所述化合物的其它方法也是本领域技术人员容易知道的并且是本领域技术人员可获得的。
然后在多种体内模型中测试如此鉴定的调节剂以便确定它们是否能减轻疼痛,尤其是慢性疼痛或其它病患诸如癌症和瘙痒症(发痒)而具有最小的不良事件。以下生物测定部分中所描述的测定可用于评估本发明的化合物的生物活性。
通常,本发明化合物的功效以其IC50值(“抑制浓度–50%”)表示,其为在特定时段内实现目标钠通道活性受到50%抑制所需的化合物的量的量度。例如,本发明的代表性化合物已经在本文所述的贴片电压钳NaV1.7电生理学测定中显示出在小于100纳摩尔至小于10微摩尔范围内的IC50。
在本发明的另一方面,可在体外或体内研究中使用本发明化合物作为用于比较目的示例性剂,以发现也可用于治疗本文公开的各种疾病或防止其发生的其它化合物。
本发明的另一方面涉及抑制生物样品或哺乳动物,优选人中的NaV1.1、NaV1.2、NaV1.3、NaV1.4、NaV1.5、NaV1.6、NaV1.7、NaV1.8或NaV1.9活性,优选NaV1.7活性,所述方法包括将式(I)化合物或包含式(I)化合物的药物组合物施用于哺乳动物,优选人,或者使所述生物样品与式(I)化合物或包含式(I)化合物的药物组合物接触。如本文中所用,术语“生物样品”包括但不限于细胞培养物或其提取物;获自哺乳动物的活组织检查材料或其提取物;以及血液、唾液、尿、粪便、精液、眼泪或其它体液或其提取物。
生物样品中NaV1.1、NaV1.2、NaV1.3、NaV1.4、NaV1.5、NaV1.6、NaV1.7、NaV1.8或NaV1.9活性的抑制可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生物和病理现象中钠离子通道的研究;以及新的钠离子通道抑制剂的比较性评价。
本发明化合物(或其立体异构体、几何异构体、互变异构体、溶剂化物、代谢物、同位素、药学上可接受的盐或前药)和/或本文描述的包含药学上可接受的赋形剂和一种或多种本发明化合物的药物组合物可用于制备用于治疗哺乳动物的钠通道-介导的疾病或病患的药剂。
组合治疗
在治疗钠通道-介导的疾病和病患时,可将本发明化合物与一种或多种其它的本发明化合物或一种或多种其它治疗剂或以其任何组合的形式有效地组合。例如,本发明化合物可以与其它治疗剂组合同时施用、依序施用或单独施用,所述的其它治疗剂包括但不限于:
鸦片剂镇痛剂,例如,吗啡、海洛因、可卡因、氧化吗啡、左啡诺、左洛啡烷、羟考酮、可待因、双氢可待因、丙氧芬、纳美芬、芬太尼、氢可酮、氢吗啡酮、美利皮定(meripidine)、美沙酮、烯丙吗啡、纳洛酮、纳曲酮、丁丙诺啡、布托啡诺、纳布啡和喷他佐辛;
非鸦片剂镇痛剂,例如,乙酰美尼芬(acetomeniphen)、水杨酸盐(如,阿司匹林);
非甾体抗炎药物(NSAID),例如,布洛芬、萘普生、非诺洛芬、酮洛芬、塞来昔布、双氯芬酸、氟苯水杨酸(diflusinal)、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(nitroflurbiprofen)、奥沙拉秦、奥沙普秦、保泰松、吡罗昔康、柳氮磺胺吡啶、舒林酸、托美丁和佐美酸;
抗惊厥药,例如,卡马西平、奥卡西平、拉莫三嗪、丙戊酸盐、托吡酯、加巴喷丁和普瑞巴林;
抗抑郁药诸如三环抗抑郁药,如,阿米替林、氯米帕明、去甲丙咪嗪(despramine)、丙米嗪和去甲替林;
COX-2选择性抑制剂,例如,塞来昔布、罗非昔布、帕瑞考昔、伐地考昔、地拉考昔、依托考昔和鲁米考昔;
α-肾上腺素能药物,例如,多沙唑嗪、坦洛新、可乐定、胍法辛、地塞托咪定(dexmetatomidine)、莫达非尼和4-氨基-6,7-二甲氧基-2-(5-甲烷磺酰胺基-1,2,3,4-四氢异喹啉-2-基)-5-(2-吡啶基)喹唑啉;
巴比妥酸盐镇静药,例如,异戊巴比妥、阿普比妥、仲丁巴比妥(butabarbital)、布他比妥(butabital)、甲苯比妥、美沙比妥、美索比妥、戊巴比妥、苯巴比妥(phenobartital)、司可巴比妥、他布比妥、硫戊巴比妥(theamylal)和硫喷妥;
速激肽(NK)拮抗剂,特别是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]二氮芳辛并(diazocino)[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-1,2,4-三唑-3-酮(MK-869)、阿瑞匹坦、拉奈匹坦(lanepitant)、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);
煤焦油镇痛剂,特别是对乙酰氨基酚;
血清素再摄取抑制剂,例如,帕罗西汀、舍曲林、诺氟西汀(诺氟西汀去甲基代谢物)、代谢产物去甲基舍曲林、'3氟伏沙明、帕罗西汀、西酞普兰、西酞普兰代谢产物去甲基西酞普兰、依地普仑、d,l-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、奈法唑酮、西文氯胺、曲唑酮和氟西汀;
去甲肾上腺素(降肾上腺素)再摄取抑制剂,例如,马普替林、洛非帕明、米氮平(mirtazepine)、羟丙替林、非唑拉明、托莫西汀、米安色林、安非他酮(buproprion)、安非他酮代谢产物羟基安非他酮、诺米芬辛和维洛沙秦尤其是选择性去甲肾上腺素再摄取抑制剂诸如瑞波西汀,特别是(S,S)-瑞波西汀和文拉法辛度洛西汀精神安定药镇静药/抗焦虑剂;
双重血清素-去甲肾上腺素再摄取抑制剂,诸如文拉法辛、文拉法辛代谢产物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、米那普仑和丙咪嗪;
乙酰胆碱酯酶抑制剂,诸如多奈哌齐;
5-HT3拮抗剂,诸如昂丹司琼;
促代谢性谷氨酸盐受体(mGluR)拮抗剂;
局部麻醉剂,诸如美西律和利多卡因;
皮质类固醇诸如地塞米松;
抗心律不齐药,例如,美西律和苯妥英;
毒蕈碱拮抗剂,例如,托特罗定、丙哌维林、曲司氯铵、达非那新、索利那辛、替米维林和异丙托铵;
大麻素类;
辣椒素受体激动剂(例如,树胶脂毒素(resinferatoxin))或拮抗剂(例如,辣椒平(capsazepine));
镇静药,例如,格鲁米特、甲丙氨酯、甲喹酮和氯醛比林;
抗焦虑剂诸如苯二氮类,
抗抑郁药诸如米氮平,
外用剂(例如,利多卡因、辣椒碱和树胶脂毒素(resiniferotoxin));
肌肉松弛药诸如苯二氮类、巴氯芬、卡立普多、氯唑沙宗、环苯扎林、美索巴莫和奥芬那君(orphrenadine);
抗组胺或H1拮抗剂;
NMDA受体拮抗剂;
5-HT受体激动剂/拮抗剂;
PDEV抑制剂;
胆碱能(烟碱(nicotinic))镇痛剂;
α-2-δ配体;
前列腺素E2亚型拮抗剂;
白三烯B4拮抗剂;
5-脂氧合酶抑制剂;以及
5-HT3拮抗剂。
可使用此类组合治疗和/或预防的钠通道-介导的疾病和病患包括但不限于疼痛、伴有相关疼痛的中枢和外周介导的急性、慢性、神经病性疾病以及其它疾病,以及其它中枢神经病症诸如癫痫、焦虑、抑郁和双相疾病;或心血管病症诸如心律失常、心房纤颤和心室纤颤;神经肌肉病症诸如不宁腿综合征和肌肉麻痹或破伤风;针对中风、神经创伤和多发性硬化的神经保护;以及通道病变诸如红斑性肢痛症和家族性直肠疼痛综合征。
如本文中所用,“组合”是指一种或多种本发明化合物与一种或多种其它的本发明化合物或一种或多种另外的治疗剂的任何混合物或排列组合。除非上下文另外清楚说明,否则“组合”可以包括将本发明化合物与一种或多种治疗剂同时递送或依序递送。除非上下文另外清楚说明,否则“组合”可包括本发明化合物加上另一种治疗剂的剂量形式。除非上下文另外清楚说明,否则“组合”可包括本发明化合物加上另一种治疗剂的施用途径。除非上下文清楚说明,否则“组合”可包括本发明化合物加上另一种治疗剂的制剂。剂量形式、施用途径和药物组合物包括但不限于本文描述的那些。
通过参考以下实施例将更充分地理解本发明。然而,所述实施例不应解读为限制本发明的范围。
实施例
这些实施例用于给技术人员制备和使用本发明的化合物、组合物以及方法提供指导。尽管描述了本发明的特定实施方案,但技术人员将理解可在不脱离本发明精神和范围的情况下进行各种变化和修改。
实施例中描述的化学反应可容易地被修改以制备许多其它的本发明化合物,并且用于制备本发明化合物的可替代方法被认为在本发明的范围内。例如,可通过对本领域技术人员显而易见的修改,例如,通过利用本领域已知的其它合适试剂适当地保护干扰基团,例如,通过利用除所描述的那些试剂以外的本领域已知的其它合适试剂来适当地保护干扰基团,和/或通过对反应条件作出常规修改而成功地执行对根据本发明的非示例性化合物的合成。
在以下实施例中,除非另外指出,否则所有温度以摄氏度形式阐述。商购可得的试剂购自供应商诸如Aldrich Chemical Company,Lancaster,TCI或Maybridge并且除非另外指出,否则未进一步纯化即使用。通常在正氮气或氩气压力下或使用干燥管(除非另外说明)在无水溶剂中进行下文所阐述的反应,并且反应烧瓶通常配有橡胶隔片以经由注射器引入底物和试剂。玻璃器皿经烘干和/或加热干燥。使用三甲基甲硅烷(TMS)或残留的非氘化溶剂峰作为参考标准在氘化的CDCl3、d6-DMSO、CH3OD或d6-丙酮溶剂溶液(以ppm报告)中获得1H NMR光谱。当报告峰多重性时,使用以下缩写:s(单峰),d(双峰),t(三重峰),q(四重峰),m(多重峰),br(变宽),dd(双峰的双峰),dt(三重峰的双峰)。耦合常数,当给出时,以Hz(赫兹)报告。
用于描述试剂、反应条件或设备的所有缩写旨在与“标准缩写和首字母缩写列表”中所阐述的定义相一致。使用ChemDraw命名程序的结构命名特征来获得离散(discrete)的本发明化合物的化学名称。
LCMS分析方法
使用三种不同的LC/MS条件分析最终化合物,其中使用UV检测器在214nm和254nm处进行监测,并且使质谱仪以ESI+电离模式扫描110-800amu。
LC/MS方法A:(LC-MS运行8.0min):XBridge C18柱(4.6×50mm,3.5μm,40℃);流动相:A=10mM在水中的碳酸氢铵,B=乙腈;梯度:0.0-8.0min,5%-95%B;流速=1.2mL/min。
LC/MS方法B:(LC-MS运行8.0min):XBridge C18柱(4.6×50mm,3.5μm,40℃);流动相:A=0.1%在水中的氨,B=乙腈;梯度:0.0-8.0min,5%-95%B;流速=1.2mL/min。
LC/MS方法C:(LC-MS运行8.0min):XBridge C18柱(4.6×50mm,3.5μm,40℃);流动相:A=0.1%在水中的TFA,B=乙腈;梯度:0.0-8.0min,5%-95%B;流速=1.2mL/min。
LC/MS方法D:Agilent SB C18,2.1x30mm,1.8μm;流动相:A水(0.05%TFA),BCH3CN(0.05%TFA);梯度:3%B(0.3min),随后3-95%B(6.5min),95%B(1.5min);流速:0.4mL/min;柱箱温度25℃。
LC/MS方法E:Acquity BEH C18,2.1x50mm,1.8μm;流动相:A水(0.1%FA),B CH3CN(0.1%FA);梯度:3%B(0.4min),随后3-95%B(7.5min),95%B(0.5min);流速:0.5mL/min;柱箱温度25℃。
缩写
MeCN 乙腈
EtOAc 乙酸乙酯
DCE 二氯乙烷
DCM 二氯甲烷
DIPEA 二异丙基乙胺
DEA 二乙胺
DMAP 4-二甲基氨基吡啶
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
FA 甲酸
IPA 异丙醇
TFA 三氟乙酸
EDCI 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐
HCl 盐酸
HPLC 高压液相色谱
LCMS 液相色谱质谱
MeOH 甲醇
NMP N-甲基-2-吡咯烷酮
RPHPLC 反相高压液相色谱
RT 保留时间
SFC 超临界流体色谱
THF 四氢呋喃
TEA 三乙胺
实施例1:
(S)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
步骤1:
(R,Z)-2-甲基-N-(1-(吡啶-2-基)亚乙基)丙烷-2-亚磺酰胺
在氮气氛下向(R)-2-甲基丙烷-2-亚磺酰胺(105g,0.86mol)与1-(吡啶-2-基)乙酮(95g,0.78mol)在DCM(1.5L)中的混合物中缓慢加入乙醇钛(IV)(322mL,1.57mol)。将反应混合物加热至40℃,持续16小时。冷却至室温后,加入饱和NaHCO3水溶液(350mL),通过无水Na2SO4的短垫过滤,用DCM(3L)洗涤。将有机层真空浓缩。通过硅胶色谱(石油醚/EtOAc=5:1)纯化粗残余物,得到呈黄色固体形式的标题化合物(85g,48%)。1H NMR(400MHz,CDCl3)δ8.66(d,J=4.4Hz,1H),8.14(d,J=8.0Hz,1H),7.81-7.73(m,1H),7.43-7.33(m,1H),2.88(s,3H),1.34(s,9H)。
步骤2:
(S,Z)-5-(((R)-叔-丁基亚磺酰基)亚氨基)-5-(吡啶-2-基)-3-(三氟甲基)戊酸乙酯
向-78℃下的(R,Z)-2-甲基-N-(1-(吡啶-2-基)亚乙基)丙烷-2-亚磺酰胺(85g,0.38mol)在无水THF(850mL)中的溶液中加入二异丙基氨基化锂(2.0M,199mL,0.40mmol)。将反应混合物在-78℃下搅拌2h,加入在无水THF(100mL)中的4,4,4-三氟丁-2-烯酸乙酯(67g,0.40mol)。将反应混合物在30分钟的时间内加温至0℃,并在0℃搅拌3h。用饱和氯化铵水溶液(500mL)淬灭反应,用EtOAc(1L x 2)萃取,用盐水(500mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。通过硅胶色谱(石油醚/EtOAc=5:1)纯化粗残余物,得到呈黄色油状物形式的标题化合物(47g,32%)。1H NMR(400MHz,CDCl3)δ8.67(d,J=4.8Hz,1H),8.00(s,1H),7.81-7.74(m,1H),7.43-7.35(m,1H),4.09-3.92(m,3H),3.64-3.46(m,2H),2.68(d,J=6.0Hz,2H),1.36(s,9H),1.17(t,J=7.2Hz,3H)。
步骤3:
(S)-5-氧代-5-(吡啶-2-基)-3-(三氟甲基)戊酸乙酯
向(S,Z)-5-(((R)-叔-丁基亚磺酰基)亚氨基)-5-(吡啶-2-基)-3-(三氟甲基)戊酸乙酯(47g,0.12mol)在EtOH(400mL)中的溶液中加入HCl水溶液(4.0M,150mL,0.60mol)。将反应混合物在40℃搅拌3h。在冷却至室温后,加入EtOAc(1L),用饱和Na2CO3水溶液(500mLx 2)、盐水(500mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。通过硅胶色谱(石油醚/EtOAc=10:1)纯化粗残余物,得到呈黄色油状物的标准化合物(31g,89%)。LCMS M/Z(M+H)290。
步骤4:
(3R)-1-(吡啶-2-基)-3-(三氟甲基)戊烷-1,5-二醇
在氮气氛下向0℃下的氢化铝锂(10g,0.27mol)在无水THF(450mL)中的溶液中滴加在无水THF(50mL)中的(S)-5-氧代-5-(吡啶-2-基)-3-(三氟甲基)戊酸乙酯(26.3g,90.9mmol)。将反应混合物在0℃搅拌1h。用水(11mL)和15%NaOH水溶液(11mL)淬灭反应,经无水MgSO4干燥,过滤。将滤液真空浓缩,得到无需进一步纯化的呈浅黄色油状物形式的标题化合物(13g,57%)。LCMS M/Z(M+H)250。
步骤5:
(R)-5-氧代-5-(吡啶-2-基)-3-(三氟甲基)戊醛
向0℃下的(3R)-1-(2-吡啶基)-3-(三氟甲基)戊烷-1,5-二醇(12.0g,48.15mmol)在N,N-二甲基甲酰胺(240mL)中的混合物中加入戴斯-马丁氧化剂(Dess-Martinperiodinane)(42.89g,101.11mmol)。将混合物在室温下搅拌16h。用EtOAc(3L)稀释混合物,用饱和Na2CO3水溶液(1L x 2)和水(1L x 2)水涤,经无水Na2SO4干燥,过滤并真空浓缩。通过硅胶色谱(石油醚/EtOAc=5:1)纯化残余物,得到呈黄色油状物形式的标题化合物(3R)-5-氧代-5-(2-吡啶基)-3-(三氟甲基)戊醛(7.8g,66%)。1H NMR(400MHz,CDCl3)δ9.79(s,1H),8.69(d,J=4.4Hz,1H),8.09-8.02(m,1H),7.91-7.83(m,1H),7.55-7.49(m,1H),3.73-3.59(m,2H),3.49-3.38(m,1H),2.88-2.79(m,1H),2.69-2.60(m,1H)
步骤6:
(S)-N-(2,4-二甲氧基苄基)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
在氮气氛下向(3R)-5-氧代-5-(2-吡啶基)-3-(三氟甲基)戊醛(992mg,4.05mmol)和(S)-4-氨基-N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)色满-7-磺酰胺(1.2g,2.53mmol)在甲苯(40mL)中的溶液中加入异丙醇钛(IV)(1.87mL,6.32mmol)。将反应混合物在室温下搅拌3h。将三乙酰氧基硼氢化钠(8.04g,37.93mmol)加入到该混合物中,并在室温下再搅拌16h。加入EtOAc(100mL),并用水(50mL x 2)、盐水(50mL)洗涤。将有机层经无水MgSO4干燥,过滤并真空浓缩。通过硅胶色谱(DCM/EtOAc=2:1)纯化粗残余物,得到呈白色固体形式的标题化合物(1.5g,54%)。LCMS M/Z(M+H)688。
步骤7:
(S)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
将(S)-N-(2,4-二甲氧基苄基)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺(1.5g,1.35mmol)与甲酸(15mL)的混合物在室温下搅拌1h。将混合物真空浓缩。通过反相色谱(乙腈55-75%/含0.225%甲酸的水)纯化残余物,得到呈白色固体形式的标题化合物(427mg,59%)。1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.51(d,J=4.8Hz,1H),8.25-8.24(m,1H),7.82-7.76(m,1H),7.66(d,J=8.0Hz,1H),7.56(d,J=10.8Hz,1H),7.32-7.26(m,1H),7.14(d,J=6.0Hz,1H),7.00(d,J=4.0Hz,1H),4.28-4.21(m,1H),3.90-3.78(m,2H),3.56-3.52(m,1H),2.58-2.54(m,2H),2.44-2.32(m,1H),2.07-1.94(m,1H),1.91-1.70(m,4H),1.53-1.51(m,1H)。LCMS M/Z(M+H)538。
实施例2:
(S)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
步骤1:
2-(4-氟苯基)-4-氧代-3,4-二氢吡啶-1(2H)-羧酸苄酯
在氮气氛下向-20℃下的4-甲氧基吡啶(10.0g,91.63mmol)在无水THF(250mL)中的溶液中缓慢加入氯甲酸苄酯(17.01mL,119mmol)。将反应混合物在室温下搅拌1h。将-20℃下的在THF中的(4-氟苯基)溴化镁(1.0M,146.61mL,146.61mmol)加入到该混合物中,并在相同温度下再搅拌1h。用3%盐酸水溶液(40mL)淬灭混合物,并用甲苯(40mL)萃取。用4.5%NaHCO3水溶液(40mL)洗涤有机层,经无水Na2SO4干燥,过滤并真空浓缩。将异丙醇(15mL)加入到该混合物中,并在室温下搅拌1h。通过过滤分离固体。用异丙醇(5mL x 3)洗涤滤饼并真空干燥,得到呈白色固体形式的标题化合物(14g,47%)。1H NMR(400MHz,DMSO-d6)δ8.06(d,J=8.4Hz,1H),7.42-7.30(m,5H),7.27-7.22(m,2H),7.20-7.12(m,2H),5.74(d,J=7.2Hz,1H),5.36-5.17(m,3H),3.32-3.20(m,1H),2.62(d,J=16.8Hz,1H)。LCMS M/Z(M+H)326。
步骤2:
2-(4-氟苯基)-4-氧代哌啶-1-羧酸苄酯
将2-(4-氟苯基)-4-氧代-3,4-二氢吡啶-1(2H)-羧酸苄酯(14.0g,43.03mmol)和锌粉(28.14g,430.33mmol)在乙酸(100mL)中的混合物在室温下搅拌24h。过滤该混合物,并用乙酸(30mL x 3)洗涤滤饼。将滤液真空浓缩。通过硅胶色谱(石油醚/EtOAc=3:1)纯化粗残余物,得到呈无色油状物形式的标题化合物(14g,99%)。LCMS M/Z(M+H)328。
步骤3:
(反式)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯及(顺式)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯
向0℃下的2-(4-氟苯基)-4-氧代哌啶-1-羧酸苄酯(12.0g,36.66mmol)在无水THF(200mL)中的溶液中加入(三氟甲基)三甲基甲硅烷(19.06mL,47.66mmol)和在THF中的氟化四丁基铵(1.0M,3.67mL,3.67mmol)。将反应混合物在室温下搅拌16h。加入水(50mL)并用EtOAc(50mL)萃取。将有机层经无水Na2SO4干燥,过滤并真空浓缩。通过硅胶色谱(石油醚/EtOAc=10:1)纯化粗残余物,得到呈白色固体形式的(反式)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯外消旋-5B(3.4g,在TLC上极性较小)和呈白色固体形式的(顺式)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯外消旋-5A(0.88g,在TLC上极性较大)。反式异构体:1H NMR(400MHz,CDCl3)δ7.31-7.25(m,3H),7.22-7.16(m,2H),7.11-7.05(m,2H),7.03-6.96(m,2H),5.15-4.97(m,3H),4.33-4.25(m,1H),3.42-3.28(m,1H),2.55(s,1H),2.27-2.12(m,2H),2.06-1.99(m,1H),1.97-1.86(m,1H)。LCMS M/Z(M+H)398。顺式异构体:1H NMR(400MHz,CDCl3)δ7.30-7.24(m,3H),7.22-7.15(m,2H),7.11-7.05(m,2H),7.03-6.95(m,2H),5.15-4.97(m,3H),4.35-4.22(m,1H),3.41-3.29(m,1H),2.57(s,1H),2.28-2.12(m,2H),2.08-1.98(m,1H),1.97-1.84(m,1H)。LCMS M/Z(M+H)398。
步骤4:
(2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯及(2R,4R)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯
通过使用手性SFC(Whelk-01 250mm*30mm,10UM,超临界CO2/MeOH+DEA=70/30;70ml/min)分离(顺式)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯(0.88g),得到呈白色固体形式的(2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯(0.37g,第一峰)和呈白色固体形式的(2R,4R)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯(0.38g,第二峰)。
步骤5:
(2S,4S)-2-(4-氟苯基)-4-(三氟甲基)哌啶-4-醇
向(2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-羧酸苄酯(1.2g,3.02mmol)在EtOH(20mL)中的溶液中加入20%的负载于碳上的氢氧化钯(1.09g)。将混合物在室温下在氢气氛(1 5psi)下搅拌1h。过滤该混合物,并将滤液真空浓缩,得到无需进一步纯化的呈白色固体形式的标题化合物(700mg,粗产物)。1H NMR(400MHz,CDCl3)δ7.37-7.35(m,2H),7.04-7.00(m,2H),4.02-3.98(m,1H),3.19-3.12(m,2H),1.90-1.65(m,4H)。
步骤6:
(R)-7-(N-(2,4-二甲氧基苄基)-N-(嘧啶-4-基)氨磺酰基)-6-氟色满-4-基甲磺酸酯
向0℃下的(R)-N-(2,4-二甲氧基苄基)-6-氟-4-羟基-N-(嘧啶-4-基)色满-7-磺酰胺(800mg,1.68mmol)和三乙胺(0.7mL,5.05mmol)在DCM(10mL)中的溶液中加入在DCM(3mL)中的甲磺酸酐(586mg,3.36mmol)。将所得混合物在室温下搅拌2h。用DCM(30mL)稀释该混合物,用10%柠檬酸水溶液(20mL)、饱和NaHCO3水溶液(20mL)、盐水(10mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到无需进一步纯化的呈黄色固体形式的标题化合物(750mg,粗产物)。1H NMR(400MHz,CDCl3)δ8.80(s,1H),8.47(d,J=6.0Hz,1H),7.54(d,J=6.0Hz,1H),7.27-7.18(m,3H),6.43-6.41(m,2H),5.75-5.73(m,1H),5.27(s,2H),4.42-4.38(m,1H),4.31-4.25(m,1H),3.79(s,3H),3.78(s,3H),3.10(s,3H),2.40-2.36(m,1H),2.35-2.18(m,1H)。
步骤7:
(S)-N-(2,4-二甲氧基苄基)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺及(R)-N-(2,4-二甲氧基苄基)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
向(2S,4S)-2-(4-氟苯基)-4-(三氟甲基)哌啶-4-醇(190mg,0.72mmol)和(R)-7-(N-(2,4-二甲氧基苄基)-N-(嘧啶-4-基)氨磺酰基)-6-氟色满-4-基甲磺酸酯(799mg,1.44mmol)在EtOAc(4mL)中的溶液中加入N,N-二异丙基乙胺(0.6mL,3.61mmol)。在氮气氛下将混合物加热到80℃,持续16h。在冷却至室温后,将混合物真空浓缩。通过硅胶色谱(石油醚/EtOAc=5:1)纯化残余物,得到呈无色油状物形式的(R)-N-(2,4-二甲氧基苄基)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺(70mg,13.5%,在TLC上极性较小)和(S)-N-(2,4-二甲氧基苄基)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺(170mg,33%,在TLC上极性较大)。LCMS M/Z(M+H)721。
步骤8:
(S)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
将(S)-N-(2,4-二甲氧基苄基)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺(300mg,0.42mmol)和甲酸(5mL)的混合物在室温下搅拌1h。将该混合物真空浓缩。通过反相色谱(乙腈40-70%/含0.225%甲酸的水)纯化残余物,得到呈白色固体形式的标题化合物(50mg,21%)。1H NMR(400MHz,DMSO-d6)8.56(s,1H),8.25(d,J=2.0Hz,1H),7.59-7.49(m,3H),7.18-7.13(m,3H),6.99(s,1H),6.03(s,1H),4.27-4.24(m,1H),3.96-3.93(m,1H),3.82-3.79(m,1H),3.67-3.63(m,1H),2.68-2.63(m,1H),2.36-2.33(m,1H),2.03-1.94(m,1H),1.86-1.76(m,4H),1.68-1.65(m,1H)。LCMS M/Z(M+H)571。
实施例3:
(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺
步骤1:
(反式)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯及(顺式)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯
向2-(4-氟苯基)-4-羟基-哌啶-1-羧酸苄酯(20.0g,60.72mmol)在乙腈(200mL)中的溶液中加入CuI(2.32g,12.16mmol)。将该混合物加热至45℃。然后历经0.5h滴加2,2-二氟-2-(氟磺酰基)乙酸(21.64g,121.44mmol)。将该混合物加热至45℃,再保持2h。在冷却至室温后,将混合物真空浓缩。加入EtOAc(200mL),用盐水(100mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩。通过硅胶色谱(石油醚/EtOAc=5:1)纯化残余物,得到呈无色油状物形式的(反式)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯(4.3g,19%,在TLC上极性较小)和(顺式)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯(6g,粗产物,在TLC上极性较大)。通过反相色谱(乙腈55-85%/含0.225%甲酸的水)再纯化顺式-产物(6g,粗产物),得到呈无色油状物的(顺式)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯(3g,13%)。反式异构体:1H NMR(400MHz,CDCl3)δ7.44-7.28(m,5H),7.23-7.16(m,2H),7.09-7.01(m,2H),6.45-6.03(m,1H),5.67(s,1H),5.71-5.62(m,1H),5.71-5.62(m,1H),5.22(s,2H),4.40-4.18(m,2H),2.89-2.76(m,1H),2.73-2.61(m,1H),2.04-1.92(m,2H),1.75-1.62(m,1H)。LCMS M/Z(M+H)380。顺式异构体:1H NMR(400MHz,CDCl3)δ7.37-7.24(m,5H),7.21-7.14(m,2H),7.03-6.95(m,2H),6.19-5.79(m,1H),5.45-5.35(m,1H),5.20-5.12(m,2H),4.66-4.59(m,1H),4.19-4.08(m,1H),3.37-3.25(m,1H),2.57-2.47(m,1H),2.22-2.13(m,1H),1.97-1.78(m,2H)。LCMS M/Z(M+H)380。
步骤2:
(2R,4S)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯及(2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯
通过手性SFC(Chiralpak OJ(250mm*50mm,10um)、超临界CO2/IPA+0.1%NH4OH=85/15;180mL/min)分离(顺式)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯(3.0g,7.91mmol),得到呈黄色油状物形式的(2R,4S)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯(1.2g,40%,第一峰)和(2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯(1.3g,43%,第二峰)。LCMS M/Z(M+H)380。
步骤3:
(2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶
向(2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-羧酸苄酯(1.3g,3.43mmol)在MeOH(20mL)中的溶液中加入20%的负载于碳上的氢氧化钯(500mg)。将混合物在室温下在氢气氛(15psi)下搅拌1h。过滤该混合物,并真空浓缩滤液,得到呈白色固体形式的标题化合物(800mg,95%)。LCMS M/Z(M+H)246
步骤4:
(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-N-(2,4-二甲氧基苄基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺及(R)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-N-(2,4-二甲氧基苄基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺
向(2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶(300mg,1.23mmol)和N,N-二异丙基乙胺(1.01mL,6.12mmol)在乙酸乙酯(12mL)中的溶液中加入(R)-7-(N-(2,4-二甲氧基苄基)-N-(嘧啶-4-基)氨磺酰基)-6-氟色满-4-基甲磺酸酯(1.31g,2.45mmol)。将该混合物在氮气氛下加热至80℃,保持16h。在冷却至室温后,将该混合物真空浓缩。通过制备-TLC(含50%EtOAc的石油醚)纯化残余物,得到呈白色固体形式的(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-N-(2,4-二甲氧基苄基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺(155mg,18%,在TLC上极性较大)和(R)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-N-(2,4-二甲氧基苄基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺(160mg,19%,在TLC上极性较小)。LCMS M/Z(M+H)703。
步骤5:
(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺
将(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-N-(2,4-二甲氧基苄基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺(155mg,0.22mmol)与甲酸(3mL)的混合物在室温下搅拌1h。将该混合物真空浓缩。通过反相色谱(乙腈30-60%/含0.225%甲酸的水)纯化残余物,得到呈白色固体形式的标题化合物(75mg,62%)。1H NMR(400MHz,DMSO-d6)δ8.57(s,1H),8.31-8.20(m,1H),7.52-7.42(m,2H),7.19(d,J=10.4Hz,1H),7.15-7.06(m,3H),7.03-6.95(m,1H),6.89-6.48(m,1H),4.22-4.08(m,3H),3.90-3.75(m,2H),2.72-2.67(m,1H),2.28-2.17(m,1H),2.02-1.90(m,3H),1.83-1.73(m,1H),1.68-1.54(m,2H)。LCMS M/Z(M+H)553。
实施例4:
(S)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
步骤1:
(2S,3R)-2-乙酰基-5-氧代-3-(3-(三氟甲基)苯基)戊酸叔丁酯
向(E)-3-(3-(三氟甲基)苯基)丙烯醛(1.27g,6.32mmol)在水(12mL)中的混合物中加入(S)-2-(双(3,5-双(三氟甲基)苯基)((三甲基甲硅烷基)氧基)甲基)吡咯烷(378mg,0.63mmol)和3-氧代丁酸叔丁酯(1.0g,6.32mmol)。将反应混合物在室温下搅拌16h。用EtOAc(100mL)稀释该混合物,用水(50mL)和盐水(50mL)洗涤,经无水Na2SO4干燥,过滤并真空浓缩,得到呈黄色油状物形式的标题化合物(2.25g,粗产物)。1H NMR(400MHz,CDCl3)δ9.64-9.59(m,1H),7.56-7.38(m,4H),4.10-4.01(m,1H),3.87-3.84(m,1H),2.96-2.76(m,2H),2.06-2.04(m,3H),1.16-1.12(m,9H)。
步骤2:
(R)-5-氧代-3-(3-(三氟甲基)苯基)己醛
将(2S,3R)-2-乙酰基-5-氧代-3-(3-(三氟甲基)苯基)戊酸叔丁酯(1.0g,2.79mmol)在2,2,2-三氟乙酸(5mL)和二氯甲烷(5mL)中的溶液在室温下搅拌1h。用NaHCO3(50mL)淬灭反应,用EtOAc(50mL)萃取。将有机层经无水Na2SO4干燥,过滤并真空浓缩,得到呈黄色油状物形式的标题化合物(720mg,粗产物)。
步骤3:
(S)-N-(2,4-二甲氧基苄基)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
在氮气氛下向(R)-5-氧代-3-(3-(三氟甲基)苯基)己醛(327mg,1.26mmol)和(S)-4-氨基-N-(2,4-二甲氧基苄基)-N-(1,2,4-噻二唑-5-基)色满-7-磺酰胺(400mg,0.84mmol)在甲苯(10mL)中的溶液中加入异丙醇钛(IV)(0.62mL,2.1mmol)。将反应混合物在室温下搅拌3h。将三乙酰氧基硼氢化钠(1.79g,8.42mmol)加入到该混合物中,并在室温下再搅拌16h。加入EtOAc(100mL)并用水(50mL x 2)、盐水(50mL)洗涤。将有机层经无水MgSO4干燥,过滤并真空浓缩。通过反相色谱(乙腈75-100%/含0.05%氢氧化铵的水)纯化粗残余物,得到呈白色固体形式的标题化合物(50mg,8%)。1H NMR(400MHz,CDCl3)δ8.78(s,1H),8.44(d,J=5.6Hz,1H),7.52-7.44(m,3H),7.43-7.39(m,3H),7.30(d,J=5.2Hz,1H),7.23(d,J=8.0Hz,1H),6.45-6.39(m,2H),5.31(s,2H),4.52-4.45(m,1H),4.19-4.04(m,2H),3.81(s,3H),3.78(s,3H),2.95-2.87(m,1H),2.78-2.58(m,3H),2.30-2.18(m,1H),2.15-2.07(m,1H),1.94-1.74(m,3H),1.53-1.41(m,1H),0.74(s,3H)。LCMS M/Z(M+H)701。
步骤4:
(S)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺
将(S)-N-(2,4-二甲氧基苄基)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺(50mg,0.07mmol)与甲酸(1mL)的混合物在室温下搅拌1h。真空浓缩该混合物。通过反相色谱(乙腈26-56%/含0.225%甲酸的水)纯化残余物,得到呈白色固体形式的标题化合物(26mg,67%)。1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.25(d,J=6.0Hz,1H),7.61-7.51(m,4H),7.49-7.40(m,1H),7.17(d,J=6.0Hz,1H),6.98(d,J=6.4Hz,1H),4.46-4.38(m,1H),4.24-4.08(m,2H),2.94-2.83(m,1H),2.78-2.64(m,3H),2.15-2.01(m,2H),1.85-1.67(m,3H),1.49-1.36(m,1H),0.71(s,3H)。LCMS M/Z(M+H)551。
实施例5:氚化化合物与从异源表达hNav1.7和β1亚基的细胞中分离的膜的结合
含有重组表达的钠通道的膜的制备:将冷冻的重组细胞沉淀物在冰上解冻,并用冰冷的50mM Tris HCl,pH 7.4缓冲液稀释至细胞沉淀物重量的4倍。使用机动化玻璃杜莎匀浆器(dounce homogeniser)在冰上将细胞悬浮液匀质化。用冰冷的50mM Tris HCl,pH7.4缓冲液将匀浆进一步稀释8.4倍,然后在4℃以200x g离心15分钟。收集上清液,并在10000x g下于4℃离心50分钟。然后将沉淀物重悬于含有1%v/v蛋白酶抑制剂(Calbiochem)的100mM NaCl,20mM Tris HCl,pH 7.4缓冲液中,并在冰上再均质化。然后通过配备有26号针头的注射器处理均化的膜。通过Bradford测定法测定蛋白质浓度,并将膜于-80℃下储存。
放射性配体结合研究:饱和实验。对具有甲基的竞争性NaV1.7抑制剂氚化。掺入三个氚来代替甲基氢以生成[3H]化合物。在室温下于5mL硼硅酸盐玻璃试管中进行这种放射性配体的结合。通过将膜加入到在含有0.01%w/v牛血清白蛋白(BSA)的100mM NaCl,20mMTris HCl,pH7.4缓冲液中的渐增浓度的[3H]化合物中保持18h来引发结合。在1μM未标记的化合物存在的情况下确定非特异性结合。在18h之后,将反应物通过预浸在0.5%w/v聚乙烯亚胺中的GF/C玻璃纤维过滤器过滤。将过滤器用15mL冰冷的含有0.25%BSA的100mM NaCl,20mM Tris HCl,pH7.4缓冲液洗涤以将结合的配体与游离配体分离。通过液体闪烁计数定量结合于过滤器的[3H]化合物。
竞争性结合实验:结合反应在室温下于96孔聚丙烯板中进行18h。以360μL,将膜与100pM[3H]化合物和渐增浓度的测试化合物一起孵育。在1μM未标记的化合物存在的情况下界定非特异性结合。将反应物转移并通过用0.5%聚乙烯亚胺预浸的96孔玻璃纤维/C过滤板过滤。将过滤的反应物用200μL冰冷的含有0.25%BSA的缓冲液洗涤5次。通过液体闪烁计数测定结合的放射性。
数据分析:对于饱和实验,将非特异性结合从总结合中扣除以提供特异性结合,并且依据每毫克蛋白质所结合的配体的皮摩尔数来重新计算这些数值。构建饱和曲线并使用单位点配体结合模型计算解离常数:Beq=(B最大*X)/(X+Kd),其中Beq为平衡时结合的配体的量,B最大为最大受体密度,Kd为配体的解离常数,并且X为游离配体浓度。对于竞争研究,确定抑制百分比并使用4参数logistic模型(抑制%=(A+((B-A)/(1+((x/C)^D))))利用XL拟合计算IC50值,其中A和B分别为最大抑制和最小抑制,C为IC50浓度并且D为(Hill)斜率。
当在抑制的此模型或另一个代表性模型中测试时,代表化合物表现出如下表1中所阐述的体外NaV1.7抑制。
实施例6:体内药代动力学实验(化合物在大鼠中的清除率)
测量某些化合物的体内清除率(CLp),以评估这些化合物是否可能是用于开发的良好候选物。雄性大鼠在受控温度和湿度下以交替的12小时光照/黑暗周期圈养,并随意获取食物和水。所有体内研究均根据机构动物护理和使用委员会的指导原则进行,并与实验室动物护理和使用指南相一致。向大鼠静脉内施用化合物。从在化合物施用后的不同时间点收集自每只动物的血液样品中收集血浆。通过质谱仪确定化合物的血浆浓度,并使用Phoenix WinNonlin,利用非房室法进行药代动力学分析。口服施用后,通过将从时间0至每次口服剂量后获得的最后测量浓度的血浆浓度-时间曲线(AUC0-t最后)下的剂量标准化面积除以通过静脉内注射给药的动物的平均剂量标准化AUC0-t最后来确定每只动物的生物利用度百分比。
当在该模型中测试时,代表性化合物表现出如下表1所阐述的药代动力学(“PK”)性质(CLp)。在实施例6的模型中表现出约40mL/min/kg或更低的CLp值的化合物被认为是从体内低到中度清除的,这意味着化合物可能合理地暴露于待治疗如本文提供的疾病或病症的受试者。实施例6中高于约40mL/min/kg的CLp值被认为是在向受试者施用化合物后从体内高度清除的,这意味着该暴露可能不足以治疗本文所提供的疾病或病症。表1的每种化合物均表现出如由小于30mL/min/kg的CLp值所证明的良好稳定性。
表1
表2给出被鉴定为强效的NaV1.7抑制剂的另外的代表性化合物,但它们在上文实施例6中所述的方法中令人惊讶地表现出差的药代动力学性质(即,CLp)。
表2
本说明书中提及的所有美国专利、美国专利申请公布、美国专利申请、国外专利、国外专利申请和非专利公布均通过引用整体并入本文。
尽管为了促进理解已经详细描述了上述发明,但将显而易见的是可以在所附权利要求书的范围内实践某些变化和修改。因此,所述的实施方案将被认为是示例性的且是非限制性的,并且本发明并不限于本文给定的详细内容,但是可以在所附权利要求书的范围和等同形式内修改。
Claims (14)
1.一种选自由以下组成的组的化合物:
(S)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
(S)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺:以及
(S)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺;
或其药学上可接受的盐。
2.如权利要求1所述的化合物,所述化合物为:
(S)-6-氟-4-((2S,4R)-2-(吡啶-2-基)-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺或其药学上可接受的盐。
3.如权利要求1所述的化合物,所述化合物为:
(S)-6-氟-4-((2S,4S)-2-(4-氟苯基)-4-羟基-4-(三氟甲基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺或其药学上可接受的盐。
4.如权利要求1所述的化合物,所述化合物为:
(S)-4-((2S,4R)-4-(二氟甲氧基)-2-(4-氟苯基)哌啶-1-基)-6-氟-N-(嘧啶-4-基)色满-7-磺酰胺或其药学上可接受的盐。
5.如权利要求1所述的化合物,所述化合物为:
(S)-6-氟-4-((2R,4R)-2-甲基-4-(3-(三氟甲基)苯基)哌啶-1-基)-N-(嘧啶-4-基)色满-7-磺酰胺或其药学上可接受的盐。
6.一种药物组合物,其包含如权利要求1-5中任一项所述的化合物或其药学上可接受的盐以及药学上可接受的赋形剂。
7.一种治疗哺乳动物的疾病或病患的方法,所述疾病或病患选自由以下组成的组:疼痛、抑郁、心血管疾病、呼吸系统疾病和精神病,以及其组合,其中所述方法包括向所述哺乳动物施用治疗有效量的如权利要求1-5中任一项所述的化合物或其药学上可接受的盐。
8.如权利要求7所述的方法,其中所述疾病或病患选自由以下组成的组:急性疼痛、慢性疼痛、神经病理性疼痛、炎性疼痛、急性疼痛、慢性疼痛、内脏疼痛、癌症疼痛、化疗疼痛、创伤疼痛、手术疼痛、术后疼痛、分娩疼痛、产前阵痛、神经原性膀胱、溃疡性结肠炎、持续性疼痛、外周介导的疼痛、中枢介导的疼痛、慢性头痛、偏头痛、窦性头痛、紧张性头痛、幻肢疼痛、牙齿疼痛、周围神经损伤,或其组合。
9.如权利要求7所述的方法,其中所述疾病或病患选自由以下组成的组:与HIV相关的疼痛、HIV治疗引起的神经病变、三叉神经痛、疱疹后神经痛、急性痛、热敏感性、结节病、肠易激综合征、克罗恩病、与多发性硬化症(MS)相关的疼痛、肌萎缩侧索硬化症(ALS)、糖尿病性神经病变、周围神经病变、关节炎、类风湿关节炎、骨关节炎、动脉粥样硬化、阵发性肌张力障碍、肌无力综合征、肌强直、恶性高热、囊性纤维化、假性醛固酮增多症、横纹肌溶解症、甲状腺功能减退症、双相抑郁、焦虑、精神分裂症、与钠通道毒素相关的疾病、家族性红斑性肢痛症、原发性红斑性肢痛症、家族性直肠疼痛、癌症、癫痫、局部和全身性强直性癫痫发作、不宁腿综合征、心律失常、纤维肌痛、由中风或神经创伤引起的局部缺血状态下的神经保护、快速型心律失常、心房纤颤和心室纤颤。
10.一种通过抑制哺乳动物中的通过电压依赖性钠通道的离子通量来治疗所述哺乳动物的疼痛的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的如权利要求1-5中任一项所述的化合物或其药学上可接受的盐。
11.一种减少哺乳动物细胞中的通过电压依赖性钠通道的离子通量的方法,其中所述方法包括使所述细胞与如权利要求1-5中任一项所述的化合物或其药学上可接受的盐接触。
12.一种治疗哺乳动物的瘙痒症的方法,其中所述方法包括向所述哺乳动物施用治疗有效量的如权利要求1-5中任一项所述的化合物或其药学上可接受的盐。
13.如权利要求1-5中任一项所述的化合物或其药学上可接受的盐用于制造药剂的用途,所述药剂用于治疗选自由以下组成的组的疾病和病症:疼痛、抑郁、心血管疾病、呼吸系统疾病和精神病,或其组合。
14.一种如上文中所述的发明。
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TW201838987A (zh) | 2018-11-01 |
JP2020511511A (ja) | 2020-04-16 |
US20210107895A1 (en) | 2021-04-15 |
EP3601273A1 (en) | 2020-02-05 |
EP3601273B1 (en) | 2021-12-01 |
WO2018175707A1 (en) | 2018-09-27 |
US10793550B2 (en) | 2020-10-06 |
US20200017469A1 (en) | 2020-01-16 |
AR111255A1 (es) | 2019-06-19 |
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