CN112805000A - 作为ppargc1a激活剂用于治疗神经退行性疾病的2-芳基苯并咪唑 - Google Patents
作为ppargc1a激活剂用于治疗神经退行性疾病的2-芳基苯并咪唑 Download PDFInfo
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- CN112805000A CN112805000A CN201980065941.4A CN201980065941A CN112805000A CN 112805000 A CN112805000 A CN 112805000A CN 201980065941 A CN201980065941 A CN 201980065941A CN 112805000 A CN112805000 A CN 112805000A
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Abstract
Description
技术领域
本申请涉及2-芳基苯并咪唑、2-芳基苯并恶唑、2-芳基苯并噻唑、2-芳基咪唑并[1,2-a]吡啶及其前药衍生物作为Ppargc1a的化学激活剂用于治疗神经退行性疾病的用途。
背景技术
肌萎缩性脊髓侧索硬化症
肌萎缩性脊髓侧索硬化症(ALS)是一种致死性的神经退行性疾病,其特征在于运动神经元的丢失,导致运动机能的逐步下降并最终导致死亡。ALS的运动症状包括肌无力、抽搐和消瘦,进而导致说话、吞咽和呼吸困难。ALS中运动神经元死亡的原因尚不清楚,并且5-10%的ALS病例是遗传的。
已经提出中枢和外周神经系统中免疫细胞的激活是ALS中疾病进展的关键决定因素(Phani等人,Front Pharmacol,3:150,2012)。具体而言,已表明小胶质细胞和巨噬细胞在该疾病的神经炎症的构成中发挥不同的作用(Dibaj等人,PLoS One,6(3):e17910,2011;Boillee等人,Science,312:1389-92,2006)。值得注意的是,已经证明骨髓移植(BMT)替代宿主髓系细胞在ALS动物模型中可延长生存期,这被认为是通过替代CNS小胶质细胞介导的(Beers等人,Proc Natl Acad Sci U S A.103:16021-6,2006)。但是,最近的研究表明,这些细胞不是从骨髓细胞发育而来,而是从更原始的卵黄囊祖细胞发育而来的(Ginhoux等人,Science,330:841-5,2110),表明上述研究中介导BMT治疗效果的骨髓源性细胞更有可能是外周或脑血管周巨噬细胞。然而,ALS中导致固有免疫细胞介导炎症的特定信号传导途径仍未完全了解。
目前,还无法治愈ALS。某些疗法,例如利鲁唑、骨髓移植(Deda,Cytotherapy,11:18-25,2009)和无创通气(McDeRmott等,BMJ,336:658-62,2008)已显示出在提高生活质量和延长生存期方面具有一定的作用,但没有疗法能够治愈或提供明显益处。
阿尔茨海默氏病
阿尔茨海默氏病(AD)是一种退行性脑疾病,其临床特征是运动机能的逐渐丧失,同时伴有记忆、认知、推理、判断和情感稳定性的丧失,逐渐导致严重的神经退化并最终导致死亡。已经提出氧化应激形式的神经元代谢功能障碍是AD中神经变性的根本原因(Friedland-Leuner等人,Mol Biol Transl Sci,127:183-201,2014)。
尽管对每个个体而言,AD的发展都不尽相同,但仍有许多常见症状。早期症状经常被错误地认为是与年龄相关的问题或压力表现。在早期阶段,最常见的症状是运动能力下降,难以记住最近发生的事情,这被称为短期记忆丧失(Buchman等人,Exp Rev Neurother,11:665-76,2011)。当怀疑患有AD时,诊断通常基于评估行为和思维能力的测试,如果可能的话,通常还会进行脑部扫描。但是,需要进行脑组织检查才能明确诊断。随着疾病的发展,症状可能包括思维混乱、易怒、攻击性、情绪波动、语言障碍和长期记忆力减退。随着个人状况的恶化,他/她会经常逃避家庭和社会。然后,身体的功能逐渐丧失,最终导致死亡。
帕金森氏病
帕金森氏病(PD)也称为特发性或原发性帕金森病,是中枢神经系统的退行性神经系统疾病。PD的运动症状是由中脑区域黑质中多巴胺生成细胞的死亡引起的,这种细胞死亡的原因尚不清楚。在疾病的早期,最明显的症状是与运动有关的。这些症状包括颤抖、僵硬、运动缓慢以及难以进行精细动作运动、行走困难和步态异常。后来,可能会出现思维和行为问题,痴呆症通常发生在疾病的晚期,而抑郁症是最常见的精神症状。其他症状包括感官、睡眠和情绪问题。
PD的特征是渐进性运动损伤和由小胶质细胞引起的神经炎症,其中小胶质细胞是中枢神经系统的固有免疫细胞(Aguzzi等人,Science,339:156-61,2013)。已显示功能异常的小胶质细胞产生的炎性介质可导致神经元细胞死亡,这是神经退行性疾病中认知和行为表现逐渐损害的基础(Czirr等人,J Clin Invest,122:1156-63,2012)。然而,导致小胶质细胞介导的炎症的特定信号传导途径仍然难以捉摸。
亨廷顿舞蹈病
亨廷顿舞蹈病(HD)是中枢神经系统的常染色体显性退行性疾病,其中亨廷顿基因突变。HD是一种遗传性疾病,会导致大脑中神经细胞的逐步衰竭(退化)。HD对人的功能能力具有广泛的影响,通常会导致运动、思维(认知)和精神疾病。
不同患者的HD的症状有所不同,但是,疾病的进展相对可预测(Mason S等人,JNeurol,2015)。在疾病的早期,症状是轻微的,例如情绪变化。之后,可能会出现认知和运动问题,痴呆通常发生在疾病的晚期。舞蹈病(非自愿运动)是最常见的运动症状。其他并发症包括肺炎、心脏病和摔倒造成的身体伤害。
目前尚无HD治愈的方法,病情发展至晚期的患者需要全职护理。
额颞叶变性
额颞叶变性(FTD)是与AD密切相关的疾病,AD的渐进性退化发生在大脑的额叶和颞叶。在人和动物FTD模型中已经记录了小胶质细胞的胶质增生和炎性激活(Cagnin等人Annals of Neurol,2004 6:894-897;Yi等人J.Exp.Med,2010.1:117-128)。FTD患者的行为和语言能力逐渐下降,记忆力通常相对保持。随着疾病的进展,对患者来说,开展活动、举止得体和照顾自己变得越来越困难。目前尚无任何减缓或阻止疾病进展的治疗方法。
路易体痴呆
路易体痴呆(DLB)是一种与PD相关的痴呆。这种疾病的标志是患者的大脑中存在α突触核蛋白聚集体。这些患者会经历类似PD的症状,包括驼背、肌肉僵硬、步态扭曲和移动困难,以及理智和思维的变化,记忆力减退(但不及AD明显)。由于路易氏体也存在于PD中,因此这两种疾病可能与大脑处理蛋白质α-突触核蛋白的方式上相同的潜在异常相关。此外,类似于PD,DLB患者的大脑中也存在小胶质细胞相关的神经炎症,尽管这种病理特征更广泛地发生(Iannaccone等人,Parkinsonism Relat.Disord,2013 19:47-52)。
运动神经元疾病
运动神经元疾病(MND)是类似于ALS的神经系统疾病,它会选择性地影响运动神经元,运动神经元是控制自主性肌肉活动(包括说话、行走、吞咽和运动活动)的细胞,目前尚无有效的MND治疗方法。它们本质上是神经变性,并导致渐进性残疾和死亡。此外,在MND的动物模型中,一种被称作颗粒蛋白前体的特定通路可以触发小胶质细胞的炎症激活,并且该通路的基因消融可延缓疾病进展(Philips等人,J Neuropathol Exp Neurol,2010 69:1191-200)。
脱髓鞘疾病
脱髓鞘疾病,例如格林-巴利综合征和多发性硬化症(MS),是退行性疾病,在这些疾病中神经元的髓鞘受到损害。这种损害削弱了受影响神经的信号传导性,导致感觉、运动、认知或其他功能不足,这些疾病无法治愈。它最著名的形式是MS,一种涉及免疫系统的细胞亚群的疾病。例如,持续的脱髓鞘作用通常与循环中T细胞和巨噬细胞的渗透以及小胶质细胞的炎症激活有关(Kutzelnigg等人,Handb.Clin.Neurol,2014,122:15-58)。
本文所述的化合物可激活Ppargc1a,并可用于治疗上述的神经退行性疾病。
发明内容
现已发现2-芳基苯并咪唑、2-芳基苯并恶唑、2-芳基苯并噻唑和2-芳基咪唑并[1,2-a]吡啶可激活Ppargc1a。这些化合物及其前药衍生物可用于治疗神经退行性疾病,例如肌萎缩性脊髓侧索硬化症(ALS)、阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、额颞叶变性、路易体痴呆、运动神经元疾病和脱髓鞘疾病。
第一方面,本申请涉及如下式(I)所示的化合物:
其中:
W2是N或C-R2;
W3是N或C-R3;
W4是N或C-R4;
W5是N或C-R5;
W6是N或C-R6;
W7是N或C-R7;
W8是N或C-R8;
R1选自-CH2OC(=O)R30、-CH2OP(=O)OR40OR41、-C(=O)OR42和-C(=O)R43;
其中:
R30选自(C1-C10)烃基、被氨基取代的(C1-C10)烃基、被(C1-C4)烷氧基羰基取代的(C1-C10)烃基、被羧基取代的(C1-C10)烃基、羧基、(C1-C6)烷氧基羰基、(C1-C6)烷氧基羰基氨基、甲硫基、杂环基、(C1-C10)氧杂烷基、CHR44NHR45和胍基;
其中:
R44选自任何天然存在的氨基酸侧链;和
R45选自H、甲基和(C1-C4)烷氧基羰基;和
R40和R41独立地选自氢和(C1-C6)烃基;
R42是(C1-C5)烷基;和
R43是(C1-C3)烷基;和
R2、R3、R4和R5独立地选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基;
R6和R10独立地选自氢、氘、卤素、(C1-C3)烷基、全氟(C1-C3)烷基、羟基、(C1-C3)烷氧基、全氟(C1-C3)烷氧基和氨基;
R7和R9独立地选自氢、氘、羟基、氰基、氨基、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基和卤代(C1-C4)烷氧基;和
R8选自氢、氘、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、氰基、苯基、苯氧基、苄氧基和氨基。
第二方面,本申请涉及如下式(II)所示的化合物:
其中:
W1选自O、S和N-R1,或者当W9是N时,W1可以另外是C-R50;
W2是N或C-R2;
W3是N或C-R3;
W4是N或C-R4;
W5是N或C-R5;
W9是C,或者当W1是C-R50时;W9可以是N;
其中:
R1选自H、(C1-C3)烷基、-CH2OC(=O)R30、-CH2OP(=O)OR40OR41、-C(=O)OR42和-C(=O)R43;
其中:
R30选自(C1-C10)烃基、被氨基取代的(C1-C10)烃基、被(C1-C4)烷氧基羰基取代的(C1-C10)烃基、被羧基取代的(C1-C10)烃基、羧基、(C1-C6)烷氧基羰基、(C1-C6)烷氧基羰基氨基、甲硫基、杂环基、(C1-C10)氧杂烷基、CHR44NHR45和胍基;
其中:
R44选自任何天然存在的氨基酸侧链;和
R45选自H、甲基和(C1-C4)烷氧基羰基;和
R40和R41独立地选自氢和(C1-C6)烃基;
R42是(C1-C5)烷基;和
R43是(C1-C3)烷基;和
R50是H或(C1-C3)烷基;和
R2、R3、R4和R5独立地选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基;
条件是仅当:
W9是C;
W1是N-R1;和
R1不是H或者(C1-C3)烷基时,
第三方面,本申请涉及一种治疗神经退行性疾病的方法,包括施用如下式(III)所示的化合物:
其中:
W1选自O、S和N-R1,或者当W9是N时,W1可以另外是C-R50;
W2是N或C-R2;
W3是N或C-R3;
W4是N或C-R4;
W5是N或C-R5;
W6是N或C-R6;
W7为N或C-R7;
W8是N或C-R8;
W9是C,或者当W1是C-R50时;W9可以是N;
其中:
R1选自H、(C1-C3)烷基、-CH2OC(=O)R30、-CH2OP(=O)OR40OR41、-C(=O)OR42和-C(=O)R43;
其中:
R30选自(C1-C10)烃基、被氨基取代的(C1-C10)烃基、被(C1-C10)烷氧基羰基取代的(C1-C10)烃基、被羧基取代的(C1-C10)烃基、羧基、(C1-C10)烷氧基羰基、(C1-C6)烷氧基羰基氨基、甲硫基、杂环基、(C1-C10)烷氧基、CHR44NHR45和胍基;
其中:
R44选自任何天然存在的氨基酸侧链;和
R45选自H、甲基和(C1-C4)烷氧基羰基;和
R40和R41独立地选自氢和(C1-C6)烃基;
R42是(C1-C5)烷基;和
R43是(C1-C3)烷基;和
R50是H或(C1-C3)烷基;
R2、R3、R4和R5独立地选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基;
R6和R10独立地选自氢、氘、卤素、(C1-C3)烷基、全氟(C1-C3)烷基、羟基、(C1-C3)烷氧基、全氟(C1-C3)烷氧基和氨基;
R7和R9独立地选自氢、氘、羟基、氰基、氨基、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基和卤代(C1-C4)烷氧基;和
R8选自氢、氘、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、氰基、苯基、苯氧基、苄氧基和氨基;
条件是,当下述情况时,R8不是氢或(C1-C4)烷基:
(a)W1是N-R1;
(b)R1是氢;
(c)W2、W3、W4、W5、W6和W7是C-H;
(d)W8是C-R8;
(e)W9是C;和
(f)R9和R10是氢。
第四方面,本申请涉及如上述式I、II或III所示的化合物、或包含如式I、II或III所示的化合物的药物组合物在医学中的方法和用途,特别是用于神经退行性疾病的治疗。此类神经退行性疾病包括肌萎缩性脊髓侧索硬化症(ALS)、阿尔茨海默氏病、帕金森氏病、亨廷顿舞蹈病、额颞叶变性、路易体痴呆、运动神经元疾病和脱髓鞘疾病。该方法包括施用有效量的本文所述的化合物或药物组合物。
第五方面,本申请涉及如上述式I、II或III所示的化合物、或包含如式I、II或III所示的化合物的药物组合物在医学中的方法和用途,特别是用于治疗患者与衰老相关的认知障碍和神经炎症。这些方法包括向患者施用治疗有效量的本文所述的化合物的药物组合物。
附图说明
图1示出了前药实例6-P、8-P和11-P的血浆API水平。
图2示出了前药实例6-P、8-P和11-P的脑组织API水平。
图3示出了前药实例6-P、8-P和11-P的肝脏API水平。
具体实施方式
取代基通常在引入时定义,并在整个说明书和所有独立权利要求中均保持该定义。
在第一组成方面,本申请涉及如本文所述的下式(I)所示的化合物:
在第二组成方面,本申请涉及如本文所述的下式(II)所示的化合物:
在方法方面,本申请涉及如本文所述的下式(III)所示的化合物:
在下面描述的实施例中,除非另有说明,化合物可以是如式I、II或III所示的化合物。
在式II和III的一些实施例中,W1是N-R1。在式II和III的其他实施例中,W1是O。在式II和III的另一些实施例中,W1是S。在式II和III的又一些实施例中,优选地,当W9是N时,W1是C-R50。在W1是C-R50的一些实施例中,R50是H。在W1是C-R50的其他实施例中,R50是(C1-C3)烷基。
在式I、II和III的一些实施例中,R1是-CH2OC(=O)R30;其中R30选自(C1-C10)烃基、被氨基取代的(C1-C10)烃基、被(C1-C4)烷氧基羰基取代的(C1-C10)烃基、被羧基取代的(C1-C10)烃基、羧基、(C1-C6)烷氧基羰基、(C1-C6)烷氧基羰基氨基、甲硫基、杂环基、(C1-C10)氧杂烷基和胍基。
在一些实施例中,当R1是-CH2OC(=O)R30时,R30选自:(a)(C1-C6)烷基;(b)被(C1-C4)烷基氨基取代的苯基;(c)天然氨基酸的去羧基残基;(d)被羧基取代的(C1-C3)烃基;(e)(C1-C5)氧杂烷基;和(d)吡啶基。
在式II和III的一些实施例中,R1是H。在式II和III的其他实施例中,R1是(C1-C3)烷基。
在式I、II和III的一些实施例中,W2是N。在式I、II和III的其他实施例中,W2是C-R2。在一些实施例中,W2选自C-H、C-F、C-D、C-CF3、C-CH3、C-Cl、C-Br、C-OH、C-OCH3、C-NH2、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-CONH2。在一些实施例中,W2选自C-H、C-F、C-D、C-CF2H、C-CD3和C-CF3。
在W2是C-R2的实施例中,R2选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基。
在W2是C-R2的一些实施例中,R2选自氢、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、氨基、羟基、腈、卤素或甲酰胺。在一些实施例中,R2选自氢、三氟甲基、甲基、乙基、甲氧基、三氟甲氧基、氨基、羟基、腈、卤素或甲酰胺。在一些实施例中,R2选自氢、卤素和全氟(C1-C3)烷基。
在式I、II和III的一些实施例中,W3是N。在式I、II和III的其他实施例中,W3是C-R3。在一些实施例中,W3选自N、C-H、C-NH2、C-F、C-CF3、C-D、C-OCH3、C-CN、C-OH、C-Cl、C-CH3、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-Br。在一些实施例中,W3选自N、C-H、C-NH2、C-F、C-CF3、C-CF2H、C-CD3和C-D。
在W3是C-R3的一些实施例中,R3选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基。
在W3是C-R3的一些实施例中,R3选自氢、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、氨基、羟基、腈、卤素或甲酰胺。在W3是C-R3的一些实施例中,R3选自氢、三氟甲基、甲基、乙基、甲氧基、三氟甲氧基、氨基、羟基、腈、卤素或甲酰胺。在W3是C-R3的一些实施例中,R3选自H、卤素和全氟(C1-C3)烷基。
在式I、II和III的一些实施例中,W4是N。在式I、II和III的其他实施例中,W4是C-R4。在一些实施例中,W4选自N、C-H、C-NH2、C-F、C-CF3、C-D、C-OCH3、C-CN、C-OH、C-Cl、C-CH3、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-Br。在一些实施例中,W4选自N、C-H、C-NH2、C-F、C-CF3、C-CF2H、C-CD3和C-D。
在W4是C-R4的一些实施例中,R4选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基。
在W4是C-R4的一些实施例中,R4选自氢、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、氨基、羟基、腈、卤素或甲酰胺。在W4是C-R4的一些实施例中,R4选自氢、三氟甲基、甲基、乙基、甲氧基、三氟甲氧基、氨基、羟基、腈、卤素或甲酰胺。在W4是C-R4的一些实施例中,R4选自H、卤素和全氟(C1-C3)烷基。
在式I、II和III的一些实施例中,W5是N。在式I、II和III的其他实施例中,W5是C-R5。在一些实施例中,W5选自C-H、C-F、C-D、C-CF3、C-CH3、C-Cl、C-Br、C-OH、C-OCH3、C-NH2、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-CONH2。在一些实施例中,W5选自CH、CF、CD、C-CF2H、C-CD3和C-CF3。
在W5是C-R5的实施例中,R5选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基。
在W5是C-R5的一些实施例中,R5选自氢、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、氨基、羟基、腈、卤素或甲酰胺。在一些实施例中,R5选自氢、三氟甲基、甲基、乙基、甲氧基、三氟甲氧基、氨基、羟基、腈、卤素或甲酰胺。在一些实施例中,R5选自氢、卤素和全氟(C1-C3)烷基。
在式I和III的一些实施例中,W6是N。在式I和III的其他实施例中,W6是C-R6,优选为C-H。
在W6是C-R6的一些实施例中,R6选自氢、氘、卤素、(C1-C3)烷基、全氟(C1-C3)烷基、羟基、(C1-C3)烷氧基、全氟(C1-C3)烷氧基和氨基。
在式I和III的一些实施例中,W7是N。在式I和III的其他实施例中,W7是C-R7。在W7是C-R7的一些实施例中,R7选自氢、氘、羟基、氰基、氨基、卤素、卤素(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基和卤素(C1-C4)烷氧基。在W7是C-R7的一些实施例中,R7是氢或(C3-C4)烷基。
在式I和III的一些实施例中,W8是N。在式I和III的其他实施例中,W8是C-R8。在W8是C-R8的一些实施例中,R8选自氢、氘、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、氰基、苯基、苯氧基、苄氧基和氨基。在W8是C-R8的一些实施例中,R8选自H、(C1-C4)烷基、氨基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和羟基。在W8是C-R8的一些实施例中,R8选自H、叔丁基、氨基和甲氧基,当W7为N或R7为氢时,R8优选为叔丁基。
在式II和III的一些实施例中,当W1是CR50时,W9是N。在式II和III的其他实施例中,当W1是NR1、O或S时,W9是C。
在式I和III的一些实施例中,R9选自氢、氘、羟基、氰基、氨基、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基和卤代(C1-C4)烷氧基。在优选的实施例中,当R7是氢且R8是H时,R9是叔丁基。
在式I和III的一些实施例中,R10选自氢、氘、卤素、(C1-C3)烷基、全氟(C1-C3)烷基、羟基、(C1-C3)烷氧基、全氟(C1-C3)烷氧基和氨基,优选H。
经审查会发现某些种类和属对于本申请的发明人来说是不能获得专利权的。在这种情况下,在申请人的声明要求中将这些种类和属排除在外是为了符合专利审查的要求,不反映发明人对其发明的构思或描述,这包括所有不为公众所有的属I、属II和属III的成员。
如本文中所使用的,并且如本领域技术人员将理解的,除非明确地进一步限制,否则“化合物”一词旨在包括该化合物的盐。在一个具体的实施例中,术语“通式化合物”是指该化合物或其药学上可接受的盐。
术语“药学上可接受的盐”是指由药学上可接受的无毒酸或无毒碱(包括无机酸和无机碱以及有机酸和有机碱)制备的盐。当本申请的化合物是碱性时,盐可以由药学上可接受的无毒酸(包括无机酸和有机酸)制备。用于本申请化合物的合适的药学上可接受的酸加成盐包括乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸(苯磺酸盐)、苯甲酸、硼酸、丁酸、樟脑酸、樟脑磺酸、碳酸、柠檬酸、乙二磺酸、乙磺酸、乙二胺四乙酸、甲酸、富马酸、葡庚糖酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、氢碘酸、羟基萘酸、羟乙磺酸、乳酸、乳糖酸、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲基磺酸、粘酸、萘磺酸、硝酸、油酸、扑酸、泛酸、磷酸、三甲基乙酸、多聚半乳糖醛酸、水杨酸、硬脂酸、琥珀酸、硫酸、单宁酸、酒石酸、特拉克酸(Teoclatic)、对甲苯磺酸等。当化合物包含酸性侧链时,适用于本申请化合物的药学上可接受的碱加成盐包括但不限于由铝、钙、锂、镁、钾、钠和锌制成的金属盐或由赖氨酸、精氨酸、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因制成的有机盐。在适当的情况下,进一步地,药学上可接受的盐包括,无毒的铵阳离子和与具有1至20个碳原子的烷基连接的羧酸盐、磺酸盐和膦酸盐阴离子。
虽然式I、II和III的化合物有可能作为原料化学品施用,但是优选将它们作为药物组合物存在。根据另一方面,本申请提供了一种药物组合物,其包含式I或式II的化合物或其药学上可接受的盐,以及一种或多种其药学上可接受的载体,以及任选地一种或多种其他治疗成分。载体必须是“可接受的”,即与制剂的其他成分相容并且对其接收者无害。
制剂包括适于口服、肠胃外(包括皮下、皮内、肌内、静脉内和关节内)、直肠和局部(包括皮肤、颊、舌下和眼内)给药的制剂。最合适的途径取决于接收者的状况和病症。所述制剂可以方便地以单位剂型提供,并且可以通过药学领域公知的任何方法制备。所有方法都包括使式I、II或III的化合物或其药学上可接受的盐(“活性成分”)与构成一种或多种辅助成分的载体相结合的步骤。通常,通过将活性成分与液体载体或细分的固体载体或两者均匀且紧密地结合在一起,然后如果需要,将产品成型为所需制剂来制备制剂。
本申请适用于口服给药的制剂可以离散单元提供,例如胶囊、扁囊剂或片剂,每个均包含预定量的活性成分;粉末或颗粒;在水性液体或非水性液体中的溶液或悬浮液;或者水包油型液体乳剂或油包水型液体乳剂。活性成分也可以丸剂、栓剂或糊剂的形式提供。
片剂可以通过压制或模制,任选地与一种或多种辅助成分一起制成。压制的片剂可以通过在合适的机器中将自由流动形式的活性成分例如粉末或颗粒压缩,任选地与粘合剂、润滑剂、惰性稀释剂、润滑剂、表面活性剂或分散剂混合来制备。模制片剂可以通过在合适的机器中模制用惰性液体稀释剂润湿的粉末状化合物的混合物来制备。片剂可以任选地被包衣或刻痕,并且可以将其配制以提供其中的活性成分的持续释放、延迟释放或控制释放。
用于肠胃外给药的制剂包括水性的和非水性的无菌注射溶液,其可以含有抗氧化剂、缓冲剂、抑菌剂和溶质,使制剂与预期接受者的血液保持等渗状态。肠胃外给药的制剂还包括水性的和非水性的无菌悬浮液,其可以包括悬浮剂和增稠剂。上述制剂可以多剂量容器的单位剂量提供,例如密封的安瓿瓶和小瓶,并且可以存储在冷冻干燥(冻干)条件,仅需要在使用前立即添加无菌液体载体,例如生理盐水、磷酸缓冲盐水(PBS)。应急用注射溶液和悬浮液可以由前述类型的无菌粉末、颗粒和片剂制备。
应当认识到,本申请的化合物可以以放射性标记的形式存在,即,该化合物可以包含一个或多个原子,该原子的原子质量或质量数不同于自然界中通常发现的原子质量或质量数。氢、碳、磷、氟和氯的放射性同位素分别包括2H、3H、13C、14C、15N、35S、18F和36Cl。包含这些放射性同位素和/或其他原子的其他放射性同位素的化合物在本申请的范围内。氚(即3H)和碳-14(即14C),由于其易于制备和可检测性而特别优选。包含同位素11C、13N、15O和18F的化合物非常适合于正电子发射型计算机断层扫描。本申请的式I、II和III的放射性标记的化合物及其前药通常可以通过本领域技术人员众所周知的方法来制备。方便地,可以通过下述实施例和方案中公开的方法,通过用容易获得的放射性标记试剂代替非放射性标记试剂来制备这样的放射性标记化合物。
本文提供的化合物可用于治疗患者的神经退行性疾病,该方法包括向患者施用治疗有效量的式I、II或III的化合物。
除非另有定义,本文中使用的所有技术和科学术语具有与本申请所属领域的普通技术人员通常所理解的相同的含义。有机化学家(即本领域普通技术人员)使用的缩写的完整列表出现在《有机化学杂志》每卷的第一期中。该列表通常在标题为“缩写标准列表”的表中呈现,在此通过引用并入。如果本文所引用的术语有多种定义,除非另有说明,否则以本节中的定义为准。
如本文中所使用的,术语“包括”或其语法变体将被视为指定所陈述的特征、整数、步骤或组件,但不排除添加一个或多个附加特征、整数、步骤、组件或组。该术语包括术语“由……组成”和“基本上由……组成”。
当在本文中使用时,短语“基本上由……组成”或其语法变体应被视为指定所陈述的特征、整数、步骤或组件,但不排除添加一个或多个另外的特征、整数、步骤、组件或其组合(仅当附加特征、整数、步骤、组件或其组合没有实质性地改变所要求保护的组合物或方法的基本和新颖特征时)。
本文所使用的“患者”包括人类和其他动物,特别是哺乳动物。因此,该方法适用于人类治疗和兽医应用。在一些实施例中,患者是哺乳动物,例如灵长类动物。在一些实施例中,患者是人。
治疗可以包括向诊断患有疾病的患者施用本文所述的化合物,并且可以包括向没有有效症状的患者施用该化合物。相反,治疗可能包括将所述组合物给予处于发生特定疾病风险的患者,或向患有疾病的一种或多种生理症状的患者给药,即使可能尚未作出该疾病的诊断。
关于本申请剂型的术语“施用”是指将剂型引入需要治疗的受试者系统中的行为。当本申请的剂型与一种或多种其他活性剂(以它们各自的剂型)组合给予时,“施用”及其变体应理解为包括同时和/或依次引入该剂型和另一种活性剂。任何所述剂型的施用包括平行施用、共同施用或依次施用。在某些情况下,这些治疗方法在大约相同的时间实施,例如彼此相差大约几秒钟到几小时。
本文所述化合物的“治疗有效”量通常是足以实现所需效果的量,并且可以根据疾病状况的性质和严重程度以及化合物的效力而变化。应当理解,可以采用与治疗活动性疾病不同的浓度来进行预防。通过减轻与基础疾病相关的一种或多种生理症状来获得治疗益处,从而尽管患者仍可能患有基础疾病,但可观察到状况有所改善。
在整个说明书中,术语和取代基保持其定义。
C1-C20烃包括烷基、环烷基、多环烷基、烯基、炔基、芳基,以及它们的组合。实例包括苄基、苯乙基、环己基甲基、金刚烷基、樟脑基和萘基乙基。烃基是指由氢和碳作为唯二元素组成的任何取代基。脂肪烃是没有芳香性的烃;它们可以是饱和或不饱和的、环状的、直链的或支链的。脂族烃的实例包括异丙基、2-丁烯基、2-丁炔基、环戊基、降冰片基等。芳族烃包括苯(苯基)、萘(萘基)、蒽等。
除非另有说明,否则烷基(或亚烷基)旨在包括直链或支链的饱和烃结构及其组合。烷基是指包括1至20个碳原子,优选1至10个碳原子,更优选1至6个碳原子的烷基。烷基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基等。
环烷基是烃的一个子集,包括3至8个碳原子的环状烃基。环烷基的实例包括环丙基、环丁基、环戊基、降冰片基等。
除非另有说明,否则术语“碳环”旨在包括其中环原子都是碳,但不具有任何氧化态的环系统。因此,(C3-C10)碳环是指非芳族系统和芳族系统,包括环丙烷、苯和环己烯等体系;(C8-C12)碳多环是指诸如降莰烷、十氢化萘、二氧化茚和萘的系统。除非另外限定,碳环是指单环、双环和多环。
杂环是指其中1-4个碳原子被选自包含N、O和S的杂原子取代的脂肪族或芳族的碳环残基。氮和硫的杂原子可任选地被氧化,并且氮杂原子可以任选地被季铵化。除非另有说明,否则杂环可以是非芳族的(杂脂族基)或芳族的(杂芳基)。杂环的实例包括吡咯烷、吡唑、吡咯、吲哚、喹啉、异喹啉、四氢异喹啉、苯并呋喃、苯并二恶烷、苯并间二氧杂环戊烯(当作为取代基出现时,通常称为亚甲基二氧苯基)、四唑、吗啉、噻唑、吡啶、哒嗪、嘧啶、噻吩、呋喃、恶唑、恶唑啉、异恶唑、二恶烷、四氢呋喃等。杂环基残基的实例包括哌嗪基、哌啶基、吡唑烷基、咪唑基、咪唑啉基、咪唑烷基、吡嗪基、恶唑烷基、异恶唑烷基、噻唑烷基、异噻唑基、奎宁环基、异噻唑烷基、苯并咪唑基、噻二唑基、苯并吡喃基、苯并噻唑基、四氢呋喃基、四氢吡喃基、噻吩基(历史上也称为苯硫基)、苯并噻吩基、噻吗啉基、恶二唑基、三唑基和四氢喹啉基。
烃氧基或烷氧基是指通过氧与母体结构相连的具有1-20个碳原子(优选1-10个碳原子,更优选1-6个碳原子)的直链或支链构型的基团。实例包括甲氧基、乙氧基、丙氧基、异丙氧基等。低级烷氧基是指含有1-4个碳的基团。对于本申请,烷氧基和低级烷氧基包括亚甲基二氧基和亚乙基二氧基。
氧杂烷基是指其中一个或多个碳(以及它们关联的氢)已被氧取代的烷基残基。实例包括甲氧基丙氧基、3,6,9-三氧杂癸基等。术语“氧杂烷基”如本领域所理解的[参见美国化学学会出版的化学文摘的化学物质的命名和索引(Naming and Indexing of ChemicalSubstances for Chemical Abstracts),196,但不受127(a)的限制],即,它是指其中氧通过单键与其相邻原子结合(形成醚键)的化合物;它不是指如在羰基基团中发现的双键结合的氧。类似地,硫代烷基和氮杂烷基是指其中一个或多个碳分别被硫或氮取代的烷基残基。实例包括乙基氨基乙基和甲硫基丙基。
术语“卤素”是指氟、氯、溴或碘原子。在一个实施例中,卤素可以是氟或氯原子。
除非另有说明,酰基是指甲酰基,以及通过羰基官能团与母体结构相连的具有1、2、3、4、5、6、7和8个碳原子的直链、支链、环状构型、饱和、不饱和以及芳族的基团和它们的组合。实例包括乙酰基、苯甲酰基、丙酰基、异丁酰基等。低级酰基是指含有1-4个碳的基团。当双键结合的氧本身被称为取代基时,其被称为“氧代”。
如本文中所使用的,术语“任选取代的”可以与“未取代或取代的”互换使用。术语“取代的”是指用特定基团取代特定基团中的一个或多个氢原子。例如,取代的烷基、芳基、环烷基、杂环基等是指这样的烷基、芳基、环烷基或杂环基,其中每个残基中的一个或多个H原子被以下基团取代:卤素、卤代烷基、烷基、酰基、烷氧基烷基、羟基低级烷基、羰基、苯基、杂芳基、苯磺酰基、羟基、低级烷氧基、卤代烷氧基、氧杂烷基、羧基、烷氧基羰基[-C(=O)O-烷基]、烷氧基羰基氨基[HNC(=O)O-烷基]、氨基羰基(也称为甲酰胺基)[-C(=O)NH2]、烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、烷基氨基、二烷基氨基、(烷基)(芳基)氨基烷基、烷基氨基烷基(包括环烷基氨基烷基)、二烷基氨基烷基、二烷基氨基烷氧基、杂环基烷氧基、巯基、烷硫基、亚砜、砜、磺酰胺基、烷基亚磺酰基、烷基磺酰基、酰胺基烷基、酰胺基烷氧基、酰胺基、脒基、芳基、苄基、杂环基、杂环基烷基、苯氧基、苄氧基、杂芳氧基、羟基亚氨基、烷氧基亚氨基、氧杂烷基、磺酰胺、三苯甲基、脒基、胍基、脲基、苄氧基苯基和苄氧基。在“任选取代的”所指的取代基中还包括“氧代”;本领域技术人员将理解,由于氧代是二价基团,所以会存在它不适于作为取代基的情况(例如在苯基上)。在一个实施例中,1、2或3个氢原子被特定基团取代。在烷基和环烷基的情况下,三个以上的氢原子可以被氟取代;实际上,所有可用的氢原子都可以被氟取代。
取代基Rn通常在引入时定义,并且在整个说明书和所有独立权利要求中都保持该定义。对于显示或要求保护的任何和所有可能存在互变异构体的化合物,是指包括所有可能的互变异构体。
实验部分
制备化合物可能涉及各种化学基团的保护和脱保护。本领域技术人员可以容易地确定是否需要保护和脱保护以及选择合适的保护基团。适用于该目的的合适基团在化学领域的标准教科书中进行了讨论,例如在T.W.Greene和P.G.M.Wuts的《有机合成保护基团》(Protective Group in Organic Synthesis)(John Wiley&Sons,纽约,1999年)、在《化学保护基团》(Protecting Group in Chemistry,第1版,牛津大学出版社,2000年),以及在《March高等有机化学:反应、机理和结构》(March’s Advanced Organic chemistry:Reactions,Mechanisms,and Structure,第5版,Wiley-Interscience出版,2001年)中都有讨论。
苯并咪唑类化合物可通过以下任一方法合成:i)在亚硫酸氢钠存在下使任选取代的2-硝基苯胺与芳基醛反应(D.Fokas等人的《合成》(Synthesis)2005,1,47-56.);ii)酰氯与任选取代的1,2-苯二胺反应,然后使中间体酰胺环缩合。
方法A–2-硝基苯胺与芳醛反应生成苯并咪唑
实例1:2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑
将在乙醇(20mL)中的2-硝基苯胺(691mg,5.00mmol)和4-叔丁基苯甲醛(836μL,5.00mmol,1.0当量)溶液用新鲜配制的1M亚硫酸氢钠水溶液(15mL,15.0mmol,3.0当量)处理,并将混合物在70℃下加热14小时。将混合物冷却至环境温度,添加5M氢氧化铵水溶液(10mL)淬灭,并过滤收集形成的固体,以及用水洗涤几次。通过乙醇-水重结晶来纯化产物,得到灰白色固体(739mg,59%)。1H NMR(500MHz,DMSO-d6):δ12.84(1H,br s),8.10(2H,d,J=8.4Hz),7.57(4H,app d,J=8.4Hz,overlapping br),7.21-7.17(2H,m),1.33(9H,s);LCMS:rt 2.48-2.52min,+ve ESI m/z 250.8([M+H]+,100%),-ve ESI m/z 248.7(M–H]-,100%)。
方法B–酰氯与1,2-苯二胺反应后进行中间体酰胺的环缩合反应生成苯并咪唑类化合物
实例2:2-(4-(叔丁基)苯基)-1H-咪唑并[4,5-c]吡啶
向在二甲基甲酰胺(DMF)(15mL)中的3,4-二氨基吡啶(437mg,4.00mmol)和三乙胺(669μL,4.80mmol,1.2当量)的冷却(0℃)溶液滴加在DMF(1mL)中的4-叔丁基苯甲酰氯(781μL,4.00mmol,1.0当量)。使混合物升温至环境温度,并搅拌12小时。将混合物缓慢加入到剧烈搅拌的冰水(240mL)中,并过滤收集形成的固体。通过快速色谱法(己烷-EtOAc,100:0至0:100)纯化,得到白色固体N-(4-氨基吡啶-3-基)-4-(叔丁基)苯甲酰胺(369mg,34%)。1HNMR(500MHz,DMSO-d6):δ9.66(1H,s),8.09(1H,s),7.89(2H,d,J=8.4Hz),7.80(1H,d,J=5.2Hz),7.55(2H,d,J=8.4Hz),7.44(1H,d,J=5.2Hz),5.17(2H,s),1.32(9H,s);LCMS:rt2.46-2.50min,+ve ESI m/z 269.7([M+H]+,100%),-ve ESI m/z 267.7(M–H]-,100%)。
将在冰醋酸(5mL)中的N-(4-氨基吡啶-3-基)-4-(叔丁基)苯甲酰胺(135mg,0.50mmol)溶液在70℃下加热14小时。将溶液冷却至环境温度,并倒入乙酸乙酯(50mL)中。用水(2×5mL)、饱和碳酸氢钠水溶液(2×5mL)、盐水(5mL)洗涤有机层,进行干燥(Na2SO4),并减压蒸发溶剂。将残余物重悬于少量乙酸乙酯(~0.5mL)中,并在搅拌下滴加己烷进行处理,过滤并干燥形成的沉淀物,得到白色固体2-(4-(叔丁基)苯基)-1H-咪唑[4,5-c]吡啶(34mg,27%)。1H NMR(500MHz,CD3OD):δ8.88(1H,s),8.32(1H,d,J=5.6Hz),8.09(2H,d,J=8.4Hz),7.64(3H,app d,J=8.4Hz,overlapping),1.39(9H,s);LCMS:rt 2.41-2.45min,+ve ESI m/z 251.8([M+H]+,100%),-ve ESI m/z 249.7(M–H]-,100%)。
使任选取代的2-氨基苯硫酚与酰氯反应,然后加热,合成苯并噻唑类化合物。
方法C–酰氯与2-氨基苯硫酚反应生成苯并噻唑类化合物
实例3:2-(4-叔丁基苯基)-1,3-苯并噻唑
向在NMP(20mL)中的2-氨基苯硫酚(1.070mL,10mmol)溶液滴加4-叔丁基苯甲酰氯(2.930mL,15mmol,1.5当量),并将溶液加热至100℃保持6小时。将冷却的反应物倒入冰水(300mL)中,并通过加入浓NH4OH水溶液将pH调节至9-10。将混合物过滤并用水洗涤几次。通过快速色谱法(己烷-EtOAc,100:0至70:30)纯化,得到白色结晶固体(1.831g,65%)。1HNMR(500MHz,CDCl3):δ8.07(1H,d,J=8.1Hz),8.03(2H,d,J=8.4Hz),7.90(1H,d,J=8.1Hz),7.52(2H,d,J=8.4Hz),7.49(1H,td,J=7.8,0.8Hz),7.37(1H,td,J=7.8,0.8Hz),1.37(9H,s);LCMS:rt 4.58-4.62min,+ve ESI m/z 268.1([M+H]+,100%)。
任选取代的2-氨基苯酚与酰氯反应,然后加热,合成苯并恶唑类化合物。
方法D–酰氯与2-氨基苯酚反应生成苯并恶唑
实例4:2-(4-叔丁基苯基)-1,3-苯并恶唑
向在NMP(5mL)中的2-氨基苯酚(1.091mL,10mmol)的冷却(0℃)溶液滴加4-叔丁基苯甲酰氯(1.953mL,10mmol,1.0当量),然后添加吡啶(1.011mL,12.5mmol,1.25当量),并将溶液在180℃下搅拌3小时。将反应物倒入水-MeOH(80:20,20mL)中,并将混合物冷却至0℃。过滤沉淀的产物,并通过快速色谱法(己烷-EtOAc,100:0至75:25)纯化,得到白色固体(1.977g,75%)。1H NMR(500MHz,CDCl3):δ8.19(2H,d,J=8.5Hz),7.79-7.75(1H,m),7.59-7.57(1H,m),7.55(2H,d,J=8.5Hz),7.36-7.33(2H,m),1.38(9H,s);LCMS:rt 4.38-4.42min,+ve ESI m/z 252.1([M+H]+,100%)。
在碱的存在下将2-氨基吡啶与2-溴-1-苯基乙醇-1-酮加热,合成咪唑并[1,2-a]吡啶。
方法E–2-氨基吡啶与2-溴-1-苯基乙醇-1-酮反应生成咪唑并[1,2-a]吡啶
实例5:2-(4-叔丁基苯基)咪唑并[1,2-a]吡啶
将吡啶-2-胺(63.8mg,0.68mmol)和2-溴-1-(4-叔丁基苯基)乙酮(0.136mL,0.68mmol)加入烧瓶中并溶于乙腈(2.7mL),然后加入碳酸氢钠(114mg,1.36mmol)。将反应物回流1小时并然后冷却。通过过滤除去沉淀物,并减压蒸发滤液。用快速色谱法(50:50EtOAC:己烷)纯化粗产物,得到黄色固体2-(4-叔丁基苯基)咪唑并[1,2-a]吡啶(0.061g,35%)。1H NMR(500MHz,CD3OD):δ8.42(1H,d,J=6.9Hz),8.16(1H,s),7.85(2H,d,J=8.4Hz),7.55(1H,d,J=9.1Hz),7.49(2H,d,J=8.4Hz),7.32(1H,t,J=7.9Hz),6.92(1H,t,J=6.8Hz),1.36(9H,s);LCMS:rt 2.51-2.55min,+ve ESI m/z 250.8([M+H]+,100%)。
方法F–苯并咪唑类化合物的烷基化获得1-烷基-苯并咪唑
在碳酸氢钠或碳酸钠的存在下滴加烷基卤来合成1-烷基-苯并咪唑。
实例6:2-(4-叔丁基苯基)-1-甲基-苯并[d]咪唑
白色固体。1H NMR(500MHz,CD3OD):δ7.73(2H,d,J=8.4Hz),7.68(1H,d,J=7.9Hz),7.65(2H,d,J=8.4Hz),7.55(1H,d,J=7.9Hz),7.35(1H,t,J=7.8Hz),7.31(1H,t,J=7.8Hz),3.90(3H,s),1.40(9H,s);LCMS:rt 2.63-2.67min,+ve ESI m/z 264.8([M+H]+,100%)。
表1示出了实例7-78的化合物名称、结构、光谱数据和合成方法(S.M.)。
表1
苯并咪唑前药通过下述的方法G和方法H合成。
方法G–卤代甲基酯和卤代碳酸甲酯反应生成苯并咪唑前药
苯并咪唑前药是通过在回流丙酮时在碘化钠和碳酸钠的存在下将苯并咪唑与氯甲基酯加热来制备的;或者,苯并咪唑前药可以在回流丙酮时在碘化钠和碳酸钠的存在下通过将苯并咪唑与氯代甲烷碳酸盐加热来制备(实例6-P至9-P和11-P)。
在下文所述的典型步骤中,将在丙酮(10mL)中的苯并咪唑(1.0mmol)溶液用碳酸钠(2.0–3.0mmol)、碘化钠(1.0–1.5mmol)和任选地受保护的氯甲基酯(1.0-1.5mmol)处理。在回流状态下加热混合物直到反应完成。然后将混合物过滤并将溶剂蒸发,然后使用硅胶快速色谱法纯化。使用本领域已知的标准方案(实例10-P和12-P)完成产物的脱保护。
另外,用氢化钠处理苯并咪唑,然后加入溴代甲基酯,得到所需前药(实例5-P)。
实例1-P:(2-4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)乙酸甲酯
将在DMF(5mL)中的2-(4-叔丁基苯基)-1H-苯并咪唑(250mg,1.00mmol)的冷却(0℃)溶液用氢化钠(60%分散在矿物油中,40毫克,1.00毫摩尔,1.0当量)分批处理,并在环境温度下搅拌1小时。将混合物冷却至0℃,滴加乙酸溴甲酯(98uL,1.00mmol,1.0当量),并在环境温度下搅拌48小时。将反应物倒入水(100mL)中,并用EtOAc(4×25mL)萃取。合并的有机层用盐水(25mL)洗涤、干燥(Na2SO4),并在减压下蒸发溶剂。通过硅胶快速色谱纯化粗残余物,用己烷-EtOAc(100:0至60:40)洗脱,得到标题化合物,为白色结晶固体(108mg,32%)。1H NMR(500MHz,CDCl3):δ7.83-7.81(1H,m),7.80(2H,d,J=8.4Hz),7.62-7.60(1H,m),7.57(2H,d,J=8.4Hz),7.36-7.33(2H,m),6.18(2H,s),2.18(3H,s),1.38(9H,s).LCMS:rt 3.27-3.47min,+ve ESI m/z 322.8([M+H]+,100%)。
实例2-P:(2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)丁酸甲酯
将在丙酮(20mL)中的2-(4-叔丁基苯基)-1H-苯并咪唑(501mg,2.00mmol)、碳酸钠(636mg,6.00mmol,3.0当量)和碘化钠(450mg,3.00mmol,1.5当量)的混合物用丁酸氯甲酯(382μL,3.00mmol,1.5当量)处理,并将混合物加热回流24小时。将混合物冷却至环境温度,过滤,并在减压下蒸发溶剂。通过快速色谱法纯化残余物(己烷-EtOAc,100:0至70:30),得到蜡状固体,用己烷研磨,得到白色固体(143mg,20%)。1H NMR(500MHz,CDCl3):δ7.83-7.81(1H,m),7.80(2H,d,J=8.4Hz),7.62-7.60(1H,m),7.56(2H,d,J=8.4Hz),7.35-7.33(2H,m),6.18(2H,s),2.41(2H,t,J=7.4Hz),1.74-1.67(2H,app.sextet,J=7.4Hz),1.38(9H,s),0.96(3H,t,J=7.4Hz);LCMS:rt 3.62-3.78min,+ve ESI m/z 350.9([M+H]+,100%)。
实例3-P:(2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)异丁酸甲酯
将在丙酮(20mL)中的2-(4-叔丁基苯基)-1H-苯并咪唑(501mg,2.00mmol)、碳酸钠(636mg,6.00mmol,3.0当量)和碘化钠(450mg,3.00mmol,1.5当量)的混合物用2-甲基丙酸甲酯(379μL,3.00mmol,1.5当量)处理,并将混合物加热回流24小时。将混合物冷却至环境温度,过滤并在减压下蒸发溶剂。通过快速色谱法纯化残余物(己烷-EtOAc,100:0至70:30),得到蜡状固体,用己烷研磨,得到白色固体。实例4-P:(2-(4-(叔丁基苯基)-1H-苯并[d]咪唑-1-基)新戊酸甲酯
将在丙酮(10mL)中的2-(4-叔丁基苯基)-1H-苯并咪唑(250mg,1.00mmol)、碳酸钠(159mg,1.50mmol,1.5当量)和碘化钠(165mg,1.10mmol,1.1当量)的混合物用新戊酸氯甲酯(159μL,1.10mmol,1.1当量)处理,并将混合物加热回流24小时。将混合物冷却至环境温度,过滤并在减压下蒸发溶剂。通过快速色谱法(己烷-EtOAc,100:0至70:30)纯化残余物,得到白色固体(41mg,11%)。LCMS:rt 3.87-3.91min,+ve ESI m/z 364.9([M+H]+,100%)。
实例5-P:叔丁基((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基)琥珀酸酯
将在丙酮(40mL)中的2-(4-叔丁基苯基)-1H-苯并咪唑(1001mg,4.00mmol)、碳酸钠(848mg,8.00mmol,2.0当量)和碘化钠(660mg,4.40mmol,1.1当量)的混合物用叔丁基氯甲基琥珀酸酯(ClCH2OC(=O)CH2CH2C(=O)OC(CH3)3)(980mg,4.40mmol,1.1当量)处理并将混合物加热回流48小时。将混合物冷却至环境温度,过滤,并在减压下蒸发溶剂。通过快速色谱法(己烷-EtOAc,100:0至70:30)纯化残余物,得到蜡状固体,用己烷研磨,得到白色固体(487mg,28%)。1H NMR(500MHz,CDCl3):δ7.83-7.80(3H,m,overlapping),7.61-7.59(1H,m),7.57(2H,d,J=8.4Hz),7.35-7.33(2H,m),6.20(2H,s),2.69(2H,t,J=6.5Hz),2.60(2H,t,J=6.5Hz),1.41(9H,s),1.38(9H,s);LCMS:rt 3.80-3.90min,+ve ESI m/z 437.1([M+H]+,100%)。
实例6-P:4-((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲氧基)-4-氧代丁酸
将在二氯甲烷(0.5mL)中的叔丁基((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基)琥珀酸酯(实例9-P,87mg,0.200mmol)用三氟乙酸(0.5mL)处理,并将溶液在环境温度下搅拌4小时。将该溶液减压蒸发并在高真空下干燥,得到白色结晶固体(70mg,92%)。1H NMR(500MHz,CDCl3):δ8.02(1H,m),7.92(2H,d,J=8.1Hz),7.86-7.84(1H,m),7.71(2H,d,J=8.1Hz),7.61-7.60(2H,m),6.32(2H,s),6.01(1H,br s),2.73(4H,s),1.39(9H,s).LCMS:rt 2.90-2.94min,+ve ESI m/z 380.9([M+H]+,100%)。
实例7-P:(2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基4-(((叔丁氧羰基)氨基)甲基)苯甲酸酯
将在丙酮(40mL)中的2-(4-叔丁基苯基)-1H-苯并咪唑(1001mg,4.00mmol)、碳酸钠(1272mg,12.00mmol,3.0当量)和碘化钠(660mg,4.40mmol,1.1当量)的混合物用4-(((叔丁氧基羰基)氨基)甲基)苯甲酸酯(1319mg,4.40mmol,1.1当量)处理,并将混合物加热回流48小时。将混合物冷却至环境温度,过滤,并在减压下蒸发溶剂。通过快速色谱法(己烷-EtOAc,100:0至70:30)纯化残余物,得到白色固体(532mg,26%)。1H NMR(500MHz,CDCl3):δ8.04(2H,d,J=8.3Hz),7.87-7.83(3H,m,overlapping),7.68-7.66(1H,m),7.58(2H,d,J=8.3Hz),7.39-7.34(4H,m,overlapping),6.43(2H,s),4.93(1H,br s),4.38(2H,d,J=5.2Hz),1.46(9H,s),1.38(9H,s);LCMS:rt 3.88-3.92min,+ve ESI m/z 514.1([M+H]+,100%)。
实例8-P:(4-(((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲氧基)羰基)-苯基)甲胺盐酸盐
将在乙酸乙酯(13.5mL)中的(2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基4-(((叔丁氧基羰基)氨基)甲基)苯甲酸酯的溶液(462mg,0.90mmol)用在乙醇中的2.5M氯化氢的溶液(3.6mL,9.00mmol,10.0当量)处理,并将该溶液在环境温度下搅拌24小时。在减压下蒸发溶液,并在真空下干燥。将获得的固体从甲醇-乙醚中重结晶,得到细小的白色针状物(337mg,93%)。1H NMR(500MHz,CD3OD):δ8.24-8.22(1H,m),8.14(2H,d,J=8.3Hz),8.01-7.99(2H,m),7.90-7.87(3H,m),7.76-7.70(2H,m),7.63-7.60(2H,m),6.69(2H,s),4.21(2H,s),1.45(9H,s).LCMS:rt 2.66-2.70min,+ve ESI m/z 414.0([M+H]+,20%)。
方法H–与二烷基氯甲基磷酸酯反应生成苯并咪唑前药
通过用过量的氢化钠处理苯并咪唑,然后用二烷基氯甲基磷酸酯处理来制备苯并咪唑前药。在二叔丁基氯甲基磷酸酯的情况下,可以将所得产物进行酸介导的水解以获得磷酸二氢前药。该方法根据Chassaing等人(J Med Chem.2008,51,1111)和Flores-Ramos等人(Bioorg Med Chem Lett.2014,24,5814)报道的方法做了调整。
实例9-P:二叔丁基((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基)磷酸酯
向在DMF(35mL)中的2-(4-叔丁基苯基)-1H-苯并咪唑(2.00g,8.00mmol)的冷却(0℃)溶液中,分批加入氢化钠(60%的油分散液,1.12g,28.0mmol,3.5当量),并将混合物在环境温度下搅拌1h。将混合物冷却(0℃),滴加在DMF(5mL)中的二叔丁基氯甲基磷酸酯(2.41mL,10.4mmol,1.3当量)溶液,并在环境温度下搅拌12h。将混合物冷却(0℃),用DCM(150mL)稀释,并小心滴加和之后用水(50mL)分批处理。分离各层,并用水(3×50mL)、盐水(2×50mL)洗涤有机层,干燥(Na2SO4)并蒸发溶剂。通过硅胶快速色谱法(己烷-EtOAc,100:0至50:50)纯化粗产物,所得油状物在-20℃下结晶过夜。将结晶物质用己烷(3×10mL)研磨,得到白色固体(2.54g,64%)。1H NMR(500MHz,CDCl3):δ7.87(2H,d,J=8.4Hz),7.82-7.80(1H,m),7.76-7.74(1H,m),7.56(2H,d,J=8.4Hz),7.36-7.32(2H,m),6.00(2H,d,J=8.2Hz),1.43(18H,s),1.38(9H,s);LCMS:rt 3.7-3.8min,+ve ESI m/z 473.0([M+H]+,100%)。
实例10-P:二氢((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基)磷酸酯
在室温下,向在1,4-二恶烷(0.5mL)中的二叔丁基((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基)磷酸酯(118mg,0.25mmol)溶液滴加到在1,4-二恶烷(0.5mL)中4M氯化氢溶液中,并将混合物搅拌20小时。用1,4-二恶烷(0.5mL)稀释反应混合物,并过滤沉淀物,用冷的二恶烷(1.0mL)、冷的二乙醚(1.0mL)洗涤,并在高真空下干燥,得到白色晶体(69mg,73%)。1H NMR(500MHz,DMSO-d6):δ8.04(1H,d,J=7.9Hz),7.96(2H,d,J=8.4Hz),7.87(1H,d,J=7.9Hz),7.76(2H,d,J=8.4Hz),7.62-7.56(2H,m),6.05(2H,d,J=9.0Hz),1.37(9H,s);LCMS:rt 2.1-2.2min,+ve ESI m/z 360.8([M+H]+,100%),-ve ESI m/z358.7([M-H]-,100%)。
实例11-P:((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基]甲基)磷酸二钠
在环境温度下向在甲醇(5mL)中的((2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基)磷酸二氢酯的悬浮液(180mg,0.500mmol)滴加到在甲醇中的0.5M甲醇钠溶液(2mL,1.00mmol,2.0当量)中。在减压下蒸发所得透明溶液,并在高真空下干燥,得到白色固体(196mg,96%)。1H NMR(500MHz,D2O):δ7.92-7.89(3H,m,overlapping),7.79-7.77(3H,m,overlapping),7.50(1H,t,J=7.5Hz),7.46(1H,t,J=7.5Hz),5.88(2H,d,J=4.3Hz),1.40(9H,s);LCMS:rt 2.06-2.10min,+ve ESI m/z 360.8([M+H]+,100%),-ve ESI m/z 358.7([M-H]-,100%)。
合成的其他前药衍生物如下所示。氨基甲酸酯的实例通常是通过在吡啶/二氯甲烷中用适当的氯甲酸酯处理苯并咪唑前体而形成的。
实例12-P:(2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)甲基(叔丁氧基羰基)-L-丙氨酸酯
实例13-P:2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-羧酸乙酯
实例14-P:2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-羧酸甲酯
实例15-P:2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-羧酸乙酯
实例16-P:2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-羧酸丙酯
实例17-P:1-(2-(4-(叔丁基)苯基)-1H-苯并[d]咪唑-1-基)乙-1-酮
生物测定
氧化代谢对骨髓细胞表型发挥抗炎作用(O'Neill LA,Front Immunol.2014),Ppargc1a可以促进这种能量代谢途径(Spiegelman BM,Novartis Found Symp.2007)。因此,可以预期Ppargc1a的药理激活会抑制骨髓细胞的炎症反应。该现象可通过TNF-α抑制试验在培养物中测量。
测量TNF-α抑制作用的细胞试验方法
在补充有10%胎牛血清和1%L-谷氨酰胺1%青霉素的RPMI 1640培养基(Cat#11875119,Gibco)中培养鼠骨髓细胞BV2或人外周血单核细胞(PBMC)。然后经24小时用100ng/ml脂多糖(LPS,O111:B4,Cat#L2630,Sigma)刺激这些细胞。LPS刺激导致BV2细胞或PBMC分泌炎性细胞因子TNF-α,可根据制造商的方法(BV2的货号为Cat#558273,PBMC、BD生物科学的货号为Cat#558299)通过ELISA定量。为了确定示例化合物1-78是否抑制BV2细胞或PBMC产生的TNF-α,在不同浓度的化合物存在下培养细胞,并测定在二甲基亚砜(作为载体对照)存在下培养的同一细胞中TNF-α的产量相对于TNF-α的产量的下降比例。结果示于表2。
表2–TNF-抑制作用
对本申请所选择的化合物进行微粒体稳定性试验和Caco-2渗透性试验。
微粒体稳定性试验方法
将人肝微粒体(Corning#452117批号38291)或小鼠肝微粒体(Corning#452701批号6328004)以11.25mg蛋白质/化合物的最终浓度分别与KxPO4 pH 7.4(100mM)、MgCl2(10mM)和受试化合物(1μM)混合并预培养(10分钟,37℃)。接下来,添加NADPH(1mM)以开始反应(总体积100μL)。在各个时间点(0、10、20和40分钟),用在乙腈中的Clem终止溶液(100μL,625ng/mL)(Cyprotex)淬灭反应。将样品以4000g离心20分钟,稀释(将75μL溶于75μL的0.1%甲酸水溶液),并通过LC-MS/MS进行分析。结果示于表3。
Caco-2渗透性试验方法
将Caco-2细胞保持在5%的CO2气体下的DMEM中。为了进行运输实验,将5×105细胞/孔的细胞接种在聚碳酸酯滤器衬垫上,并使其生长和分化21±4天,然后将细胞单层用于实验。确定在有和没有存在elacridar作为转运蛋白抑制剂的情况下,A→B和B→A方向的表观渗透系数。将多达三个测试项目和参照化合物溶解在pH 7.4的Hank平衡盐溶液中,最终浓度为10μM。在含有25mM HEPES(pH 7.4)的HBSS中于37℃进行试验。在研究之前,将单层细胞在预热的HBSS中洗涤。在实验开始时,将包含受试项目的预热HBSS添加到单层的供体侧,将没有受试项目的HBSS添加到接收器侧。在2小时的温育期间内取出接收器侧的等分试样;在0小时和2小时取等分的供体侧。等份试样用等体积的甲醇/水和含有内标物的0.1%甲酸稀释。通过LC-MS/MS分析混合物。表观渗透系数(Papp)使用以下公式计算:Papp=(dCrec/dt)/(A×C0,donor)]×106,其中dCrev/dt是接收器隔间中浓度随时间的变化,C0,donor为0时供体隔间中的浓度,A为隔间中细胞的面积。结果示于表3。
表3–微粒体稳定性和Caco-2渗透性
对本申请实例1、6-P、8-P和11-P化合物进行了药代动力学研究(小鼠)。实例1、6-P、8-P和11-P化合物在小鼠中的剂量为10mg/kgp.o.(n=2)。在0.5小时、1小时、2小时和4小时进行血浆、脑组织和肝脏取样。通过LCMS分析样品以确定实例1化合物的水平,即前药实例6-P、8-P和11-P的活性药物成分(API)。
图1示出了前药实例6-P、8-P和11-P的血浆API水平。
图2示出了前药实例6-P、8-P和11-P的脑组织API水平。
图3示出了前药实例6-P、8-P和11-P的肝脏API水平。
一般而言,图1-3显示在小鼠PK研究中,前药实例6-P、8-P和11-P导致血浆、脑组织和肝脏中的API含量可测量。
尽管出于说明的目的已经提出了典型的实施例,但是上述描述和实例不应被认为是对本申请范围的限制。因此,在不脱离本申请的精神和范围的情况下,本领域的技术人员可以想到各种修改、变更和替换。
Claims (27)
1.下式(I)的化合物:
其中:
W2是N或C-R2;
W3是N或C-R3;
W4是N或C-R4;
W5是N或C-R5;
W6是N或C-R6;
W7是N或C-R7;
W8是N或C-R8;
其中:
R1选自-CH2OC(=O)R30、–CH2OP(=O)OR40OR41、-C(=O)OR42和-C(=O)R43;
其中:
R30选自(C1-C10)烃基、被氨基取代的(C1-C10)烃基、被(C1-C4)烷氧基羰基取代的(C1-C10)烃基、被羧基取代的(C1-C10)烃基、羧基、(C1-C6)烷氧基羰基、(C1-C6)烷氧基羰基氨基、甲硫基、杂环基、(C1-C10)氧杂烷基、CHR44NHR45和胍基;
其中:
R44选自任何天然存在的氨基酸侧链;和
R45选自H、甲基和(C1-C4)烷氧基羰基;和
R40和R41独立地选自氢和(C1-C6)烃基;
R42是(C1-C5)烷基;和
R43是(C1-C3)烷基;和
R2、R3、R4和R5独立地选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基;
R6和R10独立地选自氢、氘、卤素、(C1-C3)烷基、全氟(C1-C3)烷基、羟基、(C1-C3)烷氧基、全氟(C1-C3)烷氧基和氨基;
R7和R9独立地选自氢、氘、羟基、氰基、氨基、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基和卤代(C1-C4)烷氧基;和
R8选自氢、氘、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、氰基、苯基、苯氧基、苄氧基和氨基。
2.根据权利要求1所述的化合物,其中:
W6是C-H;W8是C-R8;
R9和R10是氢;
R7是H或(C3-C4)烷基;和
R8选自H、(C1-C4)烷基、氨基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和羟基。
3.根据权利要求2所述的化合物,其中:
W2和W5分别是C-R2和C-R5;
R2、R3、R4和R5独立地选自H、卤素和全氟(C1-C3)烷基;和
R1是-CH2OP(=O)OR40OR41。
4.根据权利要求2所述的化合物,其中:
W2和W5分别是C-R2和C-R5;
R2、R3、R4和R5独立地选自H、卤素和全氟(C1-C3)烷基;
R1为-CH2OC(=O)R30;和
R30选自:
(a)(C1-C6)烷基;
(b)被(C1-C4)烷基氨基取代的苯基;
(c)天然氨基酸的脱羧基残基;
(d)被羧基取代的(C1-C3)烃基;
(e)(C1-C5)氧杂烷基;和
(d)吡啶基。
5.根据权利要求1所述的化合物,其中:
W2和W5独立地选自C-H、C-F、C-D、C-CF3、C-CH3、C-Cl、C-Br、C-OH、C-OCH3、C-NH2、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-CONH2;
W3选自N、C-H、C-NH2、C-F、C-CF3、C-D、C-OCH3、C-CN、C-OH、C-Cl、C-CH3、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-Br;
W4选自N、C-H、C-NH2、C-F、C-CF3、C-D、C-OCH3、C-CN、C-OH、C-Cl、C-CH3、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-Br;
W6为C-H;
W7为N或C-H;
W8为C-R8;
R8选自H、(C1-C4)烷基、氨基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基和羟基;
R9是H或(C1-C4)烷基;和
R10是H。
6.根据权利要求5所述的化合物,其中:
W2和W5独立地选自C-H、C-F、C-D、C-CF2H、C-CD3和C-CF3;
W3选自N、C-H、C-NH2、C-F、C-CF3、C-CF2H、C-CD3和C-D;
W4选自N、C-H、C-NH2、C-F、C-CF3、C-CF2H、C-CD3和C-D;
W7是C-H;
R8选自H、叔丁基、氨基和甲氧基;和
R9是H或叔丁基。
7.根据权利要求1所述的化合物,其中W2、W3、W4和W5中的1-4个为C-D或C-F。
8.根据权利要求1所述的化合物,其中R2、R3、R4和R5中的一个是全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、氨基、羟基、腈、卤素或甲酰胺,其余为氢。
9.根据权利要求8所述的化合物,其中R2、R3、R4和R5中的一个是三氟甲基、甲基、乙基、甲氧基、三氟甲氧基、氨基、羟基、腈、卤素或甲酰胺。
10.根据权利要求1所述的化合物,其中W3或W4中的一个为N,另一个连同W2和W5是C-H。
11.根据权利要求1所述的化合物,其中W2、W3、W4、W5、W6和W7为C-H。
12.根据权利要求1-11任一项所述的化合物,其中R8是叔丁基。
13.下式(II)的化合物:
其中:
W1选自O、S和N-R1,或者,当W9是N时,W1可以另外是C-R50;
W2是N或C-R2;
W3是N或C-R3;
W4是N或C-R4;
W5是N或C-R5;
W9是C,或者当W1是C-R50时;W9可以是N;
其中:
R1选自H、(C1-C3)烷基-CH2OC(=O)R30;CH2OP(=O)OR40OR41、-C(=O)OR42和-C(=O)R43;
其中:
R30选自(C1-C10)烃基、被氨基取代的(C1-C10)烃基、被(C1-C4)烷氧羰基烷氧基羰基取代的(C1-C10)烃基、被羧基取代的(C1-C10)烃基、羧基、(C1-C6)烷氧羰基烷氧基羰基、(C1-C6)烷氧羰基烷氧基羰基氨基、甲硫基、杂环基、(C1-C10)氧杂烷氧基、CHR44NHR45和胍基;
其中:
R44选自任何天然存在的氨基酸侧链;和
R45选自H、甲基和(C1-C4)烷氧基羰基;和
R40和R41独立地选自氢和(C1-C6)烃基;
R42是(C1-C5)烷基;和
R43是(C1-C3)烷基;和
R50是H或(C1-C3)烷基;和
R2、R3、R4和R5独立地选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基;
条件是仅当:
W9是C;
W1是N-R1;和
R1不是H或者(C1-C3)烷基时,
14.根据权利要求13所述的化合物,其中:
W2和W5分别是C-R2和C-R5;和
R2、R3、R4和R5独立地选自H、氘、卤素、(C1-C3)烷氧基、全氟(C1-C3)烷氧基、腈、氨基、羟基、氨基羰基、(C1-C3)烷基和全氟(C1-C3)烷基。
15.根据权利要求13所述的化合物,其中:
R2、R3、R4和R5独立地选自H、卤素和全氟(C1-C3)烷基。
16.根据权利要求15所述的化合物,其中:
W1是N-H或C-H;
W2和W5独立地选自C-H、C-F、C-D、C-CF3、C-CH3、C-Cl、C-Br、C-OH、C-OCH3、C-NH2、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-CONH2;
W3选自N、C-H、C-NH2、C-F、C-CF3、C-D、C-OCH3、C-CN、C-OH、C-Cl、C-CH3、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-Br;和
W4选自N、C-H、C-NH2、C-F、C-CF3、C-D、C-OCH3、C-CN、C-OH、C-Cl、C-CH3、C-CF2H、C-OCF3、C-OCF2H、C-CD3和C-Br。
17.根据权利要求16所述的化合物,其中:
W2和W5独立地选自C-H、C-F、C-D、C-CF2H、C-CD3和C-CF3;
W3选自N、C-H、C-NH2、C-F、C-CF3、C-CF2H、C-CD3和C-D;
W4选自N、C-H、C-NH2、C-F、C-CF3、C-CF2H、C-CD3和C-D。
18.根据权利要求13所述的化合物,其中W2、W3、W4和W5中的1-4个为C-D或C-F。
19.根据权利要求13所述的化合物,其中R2、R3、R4和R5中的一个是全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、氨基、羟基、腈、卤素或甲酰胺,其余为氢。
20.根据权利要求19所述的化合物,其中R2、R3、R4和R5中的一个是三氟甲基、甲基、乙基、甲氧基、三氟甲氧基、氨基、羟基、腈、卤素或甲酰胺。
21.根据权利要求13所述的化合物,其中W3或W4中的一个是N,另一个连同W2和W5是C-H。
22.根据权利要求13所述的化合物,其中W2、W3、W4和W5是C-H。
23.一种药物组合物,包括药学上可接受的载体和根据权利要求1-11和13-22中任一项所述的化合物。
24.一种药物组合物,包括药学上可接受的载体和根据权利要求12所述的化合物。
25.一种治疗神经退行性疾病的方法,包括向患有神经退行性疾病的受试者施用有效量的下式(III)的化合物:
其中:
W1选自O、S和N-R1,或者当W9是N时,W1可以另外是C-R50;
W2是N或C-R2;
W3是N或C-R3;
W4是N或C-R4;
W5是N或C-R5;
W6是N或C-R6;
W7为N或C-R7;
W8是N或C-R8;
W9是C,或者当W1是C-R50时,W9可以是N;
其中:
R1选自H、(C1-C3)烷基、-CH2OC(=O)R30、-CH2OP(=O)OR40OR41、-C(=O)OR42和-C(=O)R43;
其中:
R30选自(C1-C10)烃基、被氨基取代的(C1-C10)烃基、被(C1-C4)烷氧基羰基烷氧基羰基取代的(C1-C10)烃基、被(C1-C4)烷氧羰基烷氧基羰基取代的(C1-C10)烃基、羧基、(C1-C10)烷氧基羰基烷氧基羰基、(C1-C6)烷氧羰基烷氧基羰基氨基、甲硫基、杂环基、(C1-C10)氧杂烷氧基、CHR44NHR45和胍基;
其中:
R44选自任何天然存在的氨基酸侧链;和
R45选自H、甲基和(C1-C4)烷氧基羰基;和
R40和R41独立地选自氢和(C1-C6)烃基;
R42是(C1-C5)烷基;和
R43是(C1-C3)烷基;和
R50是H或(C1-C3)烷基;
R2、R3、R4和R5独立地选自氢、氘、卤素、全氟(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、全氟(C1-C4)烷氧基、(C1-C4)酰基、(C1-C4)烷氧基(C1-C4)烷基、羟基(C1-C4)烷基、羟基、羧基、(C1-C4)烷氧基羰基氨基[-HNC(=O)O-烷基]、甲酰胺基[-C(=O)NH2]、(C1-C4)烷基氨基羰基[-C(=O)NH-烷基]、氰基、乙酰氧基、硝基、氨基、(C1-C4)烷基氨基、二(C1-C4)烷基氨基、巯基、(C1-C4)烷硫基、氨基磺酰基、(C1-C4)烷基磺酰基和(C1-C4)酰胺基;
R6和R10独立地选自氢、氘、卤素、(C1-C3)烷基、全氟(C1-C3)烷基、羟基、(C1-C3)烷氧基、全氟(C1-C3)烷氧基和氨基;
R7和R9独立地选自氢、氘、羟基、氰基、氨基、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基和卤代(C1-C4)烷氧基;和
R8选自氢、氘、卤素、卤代(C1-C4)烷基、(C1-C4)烷基、(C1-C4)烷氧基、卤代(C1-C4)烷氧基、氰基、苯基、苯氧基、苄氧基和氨基;
条件是:当下述情况时,R8不是氢或(C1-C4)烷基:
(a)W1是N-R1;
(b)R1是氢;
(c)W2、W3、W4、W5、W6和W7是C-H;
(d)W8是C-R8;
(e)W9是C;和
(f)R9和R10是氢。
26.根据权利要求25所述的方法,其中所述神经退行性疾病选自:肌萎缩性脊髓侧索硬化症(ALS)、阿尔茨海默氏病、帕金森氏病、亨廷顿氏病、额颞变性、路易体痴呆、运动神经元疾病和脱髓鞘疾病。
27.一种治疗衰老相关的认知障碍和神经炎症的方法,包括向患有衰老相关的认知障碍和神经炎症的受试者施用有效量的如权利要求25所定义的式III的化合物。
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JP2021534099A (ja) | 2021-12-09 |
EP3833344A1 (en) | 2021-06-16 |
IL280664A (en) | 2021-03-25 |
US20200299244A1 (en) | 2020-09-24 |
US10851066B2 (en) | 2020-12-01 |
US11111217B2 (en) | 2021-09-07 |
TW202019410A (zh) | 2020-06-01 |
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