CN117015526A - 作为食欲素受体激动剂的芳基磺酰胺 - Google Patents
作为食欲素受体激动剂的芳基磺酰胺 Download PDFInfo
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Abstract
本公开提供新颖芳基磺酰胺化合物作为本公开的实施例。这些化合物被认为是食欲素受体激动剂,其可用于治疗由食欲素活性降低引起的疾病和病症。
Description
技术领域
本公开提供新颖芳基磺酰胺化合物作为本公开的实施例。这些化合物被认为是食欲素受体激动剂,其可用于治疗由食欲素活性降低引起的疾病和病症。
背景技术
食欲素是下丘脑中产生的神经肽。食欲素有两种类型:食欲素-A和食欲素-B,其也可分别称为下丘脑分泌素1和下丘脑分泌素2。表达食欲素的神经元数量有限,并主要位于外侧下丘脑的一小块区域中。然而,食欲素神经元的神经纤维会投射到整个中枢神经系统(CNS),并且它们的传入神经会被发送到皮质、边缘和脑干回路的脑部区域。食欲素系统已被证明可调节多种重要的生物过程,包括睡眠/觉醒、摄食、运动活动、应激激素分泌、能量稳态以及学习和记忆。
举例来说,食欲素的一个作用是控制睡眠和清醒。释放食欲素的神经元在日间最活跃。为了让我们保持清醒,这些神经肽会刺激其他神经元释放促进警觉性的神经递质,诸如多巴胺、血清素和去甲肾上腺素。如果没有足够的食欲素,身体就很难保持清醒和警觉。被诊断患有1型发作性睡病的人的产生食欲素的神经元数量减少85%至95%。这种产生食欲素的神经元的丧失会导致发作性睡病的症状,包括日间过度嗜睡、睡眠麻痹、幻觉和猝倒。该产生食欲素的神经元的丧失会导致发作性睡病与猝倒,这是一种无法治愈的慢性神经疾病,其严重影响患病个体的日常生活。虽然体重增加并非发作性睡病的症状,但患有这种病症的人也更有可能超重。研究表明,发作性睡病与体重增加之间的联系可能与食欲素在调节身体活动中的作用有关。
食欲素对于身体应激反应很重要。产生食欲素的神经元接收来自环境的信号,通过激发提高心率和血压的其他神经元来对压力作出反应,从而帮助身体从静息状态转变为准备做出反应和移动的状态。由于激励反应的化学信号较少,食欲素缺乏与缺乏身体活动和肥胖有关。动物研究表明,失去产生食欲素的神经元的小鼠的体力活动较少,能量代谢下降,并且更有可能罹患肥胖和糖尿病,即使它们消耗的热量较少也是如此。
食欲素还能使对于调节情绪很重要的神经元激发。食欲素活性过多或过少与抑郁和其他心理健康状况有关,诸如焦虑、恐慌症、成瘾和创伤后应激障碍。这些神经肽还通过其在脑中称为海马体的部分中的功能来影响情绪。食欲素促进在海马体中产生新神经元,这对于学习、记忆力和空间能力很重要。如果没有足够的食欲素,人们就会产生学习和记忆力问题。
与食欲素的多方面作用一致,食欲素缺乏也与年龄相关疾病有关。在阿尔茨海默氏病和帕金森氏病患者以及老年人和小鼠中发现了食欲素神经元和/或食欲素肽的丧失。多项研究证明,外源性食欲素-A在发作性睡病动物中成功恢复了正常食欲素功能并改善了学习和记忆力。此外,使用食欲素/脊髓小脑共济失调蛋白-3(O/A3)转基因小鼠(一种类似于人类发作性睡病的小鼠模型),急性OXA治疗和慢性OXA治疗二者都逆转了记忆力减退。参见例如,Hara,J.;Beuckmann,C.T.;Nambu,T.;Willie,J.T.;Chemelli,R.M.;Sinton,C.M.;Sugiyama,F.;Yagami,K.;Goto,K.;Yanagisawa,M.;Sakurai,T.,Genetic ablation oforexin neurons in mice results in narcolepsy,hypophagia,and obesity.Neuron2001,30(2),345-5以及Mavanji,V.;Butterick,T.A.;Duffy,C.M.;Nixon,J.P.;Billington,C.J.;Kotz,C.M.,Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice.Neurobiol.Learn.Mem.2017,146,21-30,其每一者关于此类背景的内容都通过引用并入。
在所有食欲素替代疗法中,适合于全身施用的食欲素激动剂将是一种针对食欲素缺乏相关病症的有前景的策略。
迄今为止,由于食欲素在调节睡眠和觉醒中的作用,针对食欲素系统的药物最初集中于拮抗剂。双重食欲素受体拮抗剂(DORA)是一类针对人体食欲素系统的处方助眠剂。这些药物通过充当食欲素受体拮抗剂发挥作用,这意味着它们可阻断体内食欲素的作用,包括OX1/2R双重拮抗剂和亚型选择性拮抗剂,以减少保持清醒的动力并促进睡眠。美国食品药品监督管理局(FDA)目前批准了两种类型的DORA用于治疗成人失眠:苏沃雷生(suvorexant)和莱博雷生(lemborexant)。
相比之下,食欲素受体的活化主要使用食欲素肽,特别是食欲素A(33AA)来完成。迄今为止仅公开了有限数量的小分子食欲素激动剂。
举例说来,Yan7874是US 2010/0150840中报道的一种小分子:
然而,Yan7874后来被发现是两种食欲素受体的弱激动剂(EC50>3.2μM),并且不幸的是,表现出与食欲素受体无关的细胞毒性。参见例如,Turku,A.;Rinne,M.K.;Boije AfGennas,G.;Xhaard,H.;Lindholm,D.;Kukkonen,J.P.,Orexin receptor agonist Yan7874 is a weak agonist of orexin/hypocretin receptors and shows orexinreceptor-independent cytotoxicity.PloS one 2017,12(6),e0178526。
最近,已报道了几个系列的小分子,并且分别以YNT-185和TAK-925为代表。这些激动剂似乎表现出选择性,即以良好的效力活化OX2R,而在OX1R处显示极少甚至没有活性。WO2020/167706中报道了另外的OX2R激动剂。这些化合物,即5-烷基吡咯烷类似物,以其中的化合物37为代表。
更详细地说来,YNT-185显示出良好的OX2R效力和选择性(EC50=28nM,与之相比,在OX1R处则为2750nM)。腹膜内(i.p.)施用YNT-185(40mg/kg,盐形式)促进野生型小鼠的觉醒而不影响体温,而在食欲素KO和食欲素神经元消融的小鼠中,YNT-185则抑制猝倒样发作。参见,Irukayama-Tomobe,Y.;Ogawa,Y.;Tominaga,H.;Ishikawa,Y.;Hosokawa,N.;Ambai,S.;Kawabe,Y.;Uchida,S.;Nakajima,R.;Saitoh,T.;Kanda,T.;Vogt,K.;Sakurai,T.;Nagase,H.;Yanagisawa,M.,Nonpeptide orexin type-2receptor agonistameliorates narcolepsy-cataplexy symptoms in mouse models.Proc.Natl.Acad.Sci.U.S.A.2017,114(22),5731-5736。在另一项研究中,如通过EEG变化和行为测量(包括运动活动和惊吓反应延迟时间)所评定,YNT-185在大鼠中减弱了吗啡诱导的镇静作用,但不影响吗啡的镇痛作用。参见,Toyama,S.;Shimoyama,N.;Tagaito,Y.;Nagase,H.;Saitoh,T.;Yanagisawa,M.;Shimoyama,M.,Nonpeptide Orexin-2 ReceptorAgonist AttenuatesMorphine-induced Sedative Effects in Rats.Anesthesiology 2018,128(5),992-1003。
然而,本发明人探寻双重食欲素激动的药理学概况。本公开的化合物表现出作为双重食欲素A/B(替代地表征为双重OX1R/OX2R)激动剂的治疗效果的独特结构属性。
发明内容
本公开的一个实施例包括一种式(I)化合物:
或其药学上可接受的盐,
其中
A是C2-6亚烷基、C2-6亚烯基、C2-6亚炔基、亚苯基,或二价4元至7元环烷基或杂环基环,任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子;
B是C2-6亚烷基、C2-6亚烯基、C2-6亚炔基、亚苯基,或二价4元至7元环烷基或杂环基环,任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子;
X是O或NH;
R1是(CH2)m-杂芳基;
m是0、1、2、3、4、5或6;
R2是氢或C1-6烷基;
X是键、O、C(O)、NH、NHC(O)或C(O)NH;
Y是键、C2-6亚烷基、C2-6亚烯基、C2-6亚炔基、任选地具有一个或多个不饱和度的二价4元至7元环烷基环,或二价4元至7元杂环基环,任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子;
Z是键、O、C(O)、NH、NHC(O)或C(O)NH;
R3是C1-10烷基、C2-10烯基、C2-10炔基、(CH2)n-C3-6环烷基、(CH2)n-苯基、(CH2)n-萘基或(CH2)n-(4元至7元杂环基环),其中此类环任选地具有一个或多个不饱和度,并且含有1至3个选自由O、N或S组成的组的杂原子,
其中每个R3可以经一个或多个选自以下项的取代基取代:C1-6烷基、C2-6烯基、C2-6炔基、卤素、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、NH2、NHC1-6烷基、N(C1-6烷基)2、CN、NO2、OH、O(C1-6烷基)、SH、S(C1-6烷基)和=O;并且
每个n独立地是0、1、2或3。
在一个方面,R1是(CH2)m-吡啶基。在一个方面,m是1。在一个方面,R2是C1-6烷基。在一个方面,R2是CH3。在一个方面,A是亚苯基。在一个方面,B是亚苯基。在一个方面,B是二价吡啶基。在一个方面,X是NH。在一个方面,X是O。在一个方面,Y是C2-6亚烷基。在一个方面,Y是CH2CH2。在一个方面,Y是二价4元至7元杂环基环,其任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子。在一个方面,杂环基环含有至少一个N原子。在一个方面,Z是NHC(O)。在一个方面,Z是C(O)。在一个方面,X、Y和Z中的每一个是键。在一个方面,R3是C1-10烷基、(CH2)n-C3-6环烷基或(CH2)n-苯基,其中每个n独立地是0、1、2或3。在一个方面,R3是C9烷基、C8烷基、C7烷基、C6烷基、C5烷基、C4烷基、C3烷基、CH2CH3或CH3。在一个方面,R3是C9烷基、C8烷基、C7烷基、C6烷基或C5烷基。在一个方面,R3是(CH2)n-C3-6环烷基。在一个方面,R3是(CH2)n-C5-6环烷基。在一个方面,R3是(CH2)1-C6环烷基、(CH2)2-C6环烷基或(CH2)3-C6环烷基。在一个方面,R3是(CH2)n-苯基。在一个方面,n是0。在一个方面,R3经一个或多个选自以下项的取代基取代:C1-6烷基、C2-6烯基、C2-6炔基、卤素、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、NH2、NHC1-6烷基、N(C1-6烷基)2、CN、NO2、OH、O(C1-6烷基)、SH、S(C1-6烷基)和=O。在一个方面,R3经一个或多个C1-6烷基取代。
本公开的一个实施例包括一种化合物,其选自由实例中的一个或多个组成的组。
本公开的一个实施例包括一种药物组合物,其包含本公开的化合物和一种或多种药学上可接受的赋形剂。
本公开的一个实施例包括一种用于治疗受试者中由食欲素活性降低引起的疾病或病症的方法,其包括施用有效量的本公开的化合物。在一个方面,该疾病或病症是以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、血压调节、缺血事件、氧化应激事件和癌症。
本公开的一个实施例包括本公开的化合物用于制备药物的用途,该药物用于治疗受试者中由食欲素活性降低引起的疾病或病症,包括施用有效量的该化合物。在一个方面,该疾病或病症是以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
本公开的一个实施例包括一种本公开的化合物,其用作活性治疗物质。
本公开的一个实施例包括一种本公开的化合物,其用于治疗受试者中由食欲素活性降低引起的疾病或病症。在一个实施例中,该疾病或病症是以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
本公开的一个实施例包括一种治疗以下项中的一者或多者的方法:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症,该方法包括施用本公开的化合物。
本公开的一个实施例包括本公开的化合物用于制备药物的用途,该药物用于治疗以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
本公开的一个实施例包括一种本公开的化合物,其用于治疗以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
本公开的范围包括本文所描述的方面、实施例和优选项的所有不同组合。
附图说明
图1图解说明了外周注射RTIOXA-47(40mg/kg,i.p.)或盐水(n=8只/组,**p<0.01***p<0.005)后12月龄的小鼠在TWAA(左图)和CORT(右图)任务中认知的改善。
具体实施方式
本公开包括可用作双重食欲素受体激动剂的新颖芳基磺酰胺。
以下定义意在澄清但不限于所定义的术语。如果本文中使用的特定术语没有明确定义,则此术语不应被视为不确定的。相反,术语在其可接受的含义范围内使用。
如本说明书通篇所用,优选的原子(诸如碳原子)数将由例如短语“Cx-y烷基”表示,其是指如本文所定义的含有指定数目的碳原子的烷基。类似的术语也将适用于其他优选术语和范围。因此,例如,C1-4烷基表示含有一至四个碳原子的直链或支链烃。
如本文所用,单独或与任何其他术语组合的术语“烷基”是指直链或支链烃。如本文所用,“烷基”的实例包括但不限于甲基、乙基、丙基、异丙基、异丁基、正丁基、叔丁基、仲丁基、异戊基、正戊基、正己基等。
如本文所用,术语“烯基”是指含有一个或多个碳-碳双键的直链或支链脂肪族烃,其可任选地被取代,其中允许多个取代度。如本文所用,“烯基”的实例包括但不限于乙烯基和烯丙基。
如本文所用,术语“亚烷基”是指任选经取代的直链二价烃基。如本文所用,“亚烷基”的实例包括但不限于亚甲基、亚乙基、正亚丙基、正亚丁基等。
如本文所用,术语“炔基”是指含有一个或多个碳-碳三键的直链或支链脂肪族烃,其可任选地被取代,其中允许多个取代度。如本文所用,“炔基”的实例包括但不限于乙炔基。
如本文所用,术语“环烷基”是指完全饱和的任选经取代的单环、双环或桥接烃环,其中允许多个取代度。如本文所用,例示性“环烷基”基团包括但不限于环丙基、环丁基、环戊基、环己基和环庚基。
如本文所用,术语“芳基”是指可任选经取代的单苯环或稠合苯环系统,其中允许多个取代度。如所用,“芳基”基团的实例包括但不限于苯基、2-萘基、1-萘基、蒽和菲。优选的芳基环具有五元至十元。
如本文所用,术语“芳基”内涵盖的稠合苯环系统包括稠合多环烃,即其中具有小于最大数量的非累积双键的环状烃,例如其中饱和烃环(环烷基,诸如环戊基环)与芳香族环(芳基,诸如苯环)稠合以形成例如基团,诸如茚满基和苊烯基(acenaphthalenyl),并且还包括作为非限制性实例的基团,诸如二氢萘和四氢萘。
如本文所用,术语“杂环基”是指单环五元至七元部分或完全饱和的环,或是指包含两个此类环的稠合双环系统,其可任选地经取代,其中允许多个取代度。优选地,此类环含有五元至十元。这些杂环基环含有一个或多个氮、硫和/或氧原子,其中N-氧化物、氧化硫和二氧化物是容许的杂原子取代基。如本文所用,“杂环基”基团的实例包括但不限于环氧乙烷、四氢呋喃、四氢吡喃、二恶烷、乙烯亚胺、吡咯烷、哌啶、环硫乙烷、四氢噻吩、四氢噻喃和吗啉。
如本文所用,术语“杂芳基”是指单环五元至七元芳香族环,或是指包含两个此类芳香族环的稠合双环芳香族环系统,其可任选地经取代,其中允许多个取代度。优选地,此类环含有五元至十元。这些杂芳基环含有一个或多个氮、硫和/或氧原子,其中N-氧化物、氧化硫和二氧化物是容许的杂原子取代基。如本文所用,“杂芳基”基团的实例包括但不限于呋喃、噻吩、吡咯、咪唑、吡唑、三唑、四唑、噻唑、恶唑、异恶唑、恶二唑、噻二唑、异噻唑、吡啶、哒嗪、吡嗪、嘧啶、喹啉、异喹啉、苯并呋喃、苯并恶唑、苯并噻吩、吲哚、吲唑、苯并咪唑、咪唑并吡啶、吡唑并吡啶和吡唑并嘧啶。
如本文所用,术语“卤素”是指氟、氯、溴或碘。
如本文所用,术语“卤代烷基”是指如本文所定义的经至少一个卤素取代的烷基基团。如本文所用,支链或直链“卤代烷基”基团的实例包括但不限于独立地经一个或多个卤素(例如氟、氯、溴和碘)取代的甲基、乙基、丙基、异丙基、正丁基和叔丁基。术语“卤代烷基”应解释为包括诸如全氟烷基基团的取代基,诸如-CF3。
通常但非绝对地,本公开的盐是药学上可接受的盐。术语“药学上可接受的盐”内涵盖的盐是指本公开的化合物的无毒盐。本公开的化合物的盐可以包括酸加成盐。代表性的盐包括乙酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、硫酸氢盐、酒石酸氢盐、硼酸盐、依地酸钙、樟脑磺酸盐、碳酸盐、克拉维酸盐、柠檬酸盐、二盐酸盐、乙二磺酸盐、依托酸盐、乙磺酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、谷氨酸盐、乙醇酰基氨基苯胂酸盐(glycollylarsanilate)、己基间苯二酚酸盐、海巴明(hydrabamine)、氢溴酸盐、盐酸盐、羟基萘甲酸盐、碘化物、羟乙磺酸盐、乳酸盐、乳糖酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、硫酸甲酯、马来酸单钾、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺、草酸盐、双羟萘酸盐(思波酸盐)、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、聚半乳糖醛酸盐、水杨酸钾、硬脂酸钠、次乙酸盐、琥珀酸盐、硫酸盐、丹宁酸盐、酒石酸盐、茶氯酸盐、甲苯磺酸盐、三乙碘化物、三甲基铵和戊酸盐。药学上不可接受的其他盐可用于制备本公开的化合物,并且这些盐应被视为形成本公开的另一方面。
式(I)化合物可以以多于一种的形式结晶,这种特征被称为多晶型现象,并且此类多晶型形式(“多晶型物”)在式(I)的范围内。多晶型现象通常可以作为对温度、压力或这两者的变化的反应而发生。多晶型现象也可能由结晶过程中的变化引起。多晶型物可以通过本领域已知的各种物理特征来区分,这些物理特征诸如X射线衍射图、溶解度和熔点。
如本文所用,术语“有效量”意指例如研究人员或临床医生正在寻求的将引发组织、系统、动物或人的生物或医学应答的药物或药剂的量。术语“治疗有效量”意指如下任何量,与未接受该任何量的相应受试者相比,该任何量引起对疾病、病症或副作用的改进的治疗、治愈、预防或改善,或引起疾病或病症的进展速度降低。该术语在其范围内还包括可有效增强正常生理功能的量。
为了在疗法中使用,治疗有效量的式(I)化合物以及其盐或溶剂化物可以作为化学原料施用。另外,活性成分可以以药物组合物存在。
因此,本公开进一步提供药物组合物,其包括有效量的一种或多种式(I)化合物或者其盐或溶剂化物,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。式(I)化合物或者其盐或溶剂化物如本文所述。在与调配物的其它成分相容并且对药物组合物的接受者无害的意义上,载体、稀释剂或赋形剂必须是可接受的。
本公开的化合物可以通过多种方法制备,包括众所周知的标准合成方法。下文列出了说明性的一般合成方法,然后在工作实例中制备了本公开的具体化合物。
在下文描述的所有实例中,根据合成化学的一般原理,必要时采用针对敏感基团或反应基团的保护基团。根据有机合成的标准方法对保护基进行操作(T.W.Green和P.G.M.Wuts(1999)Protecting Groups in Organic Synthesis,第3版,John Wiley&Sons,关于保护基通过引用并入)。这些基团在化合物合成的方便阶段使用本领域技术人员显而易见的方法进行去除。工艺以及反应条件和其执行顺序的选择应与本公开的化合物的制备一致。
本公开还提供一种合成式(I)化合物的方法以及在制备本公开的化合物中可用作合成中间体的新颖化合物。
这些化合物可以根据下述方法使用容易获得的起始材料和试剂来制备。在这些反应中,可以使用本领域普通技术人员已知的变体,但这些变体没有更详细地提及。
除非另外说明,否则本文中所描绘的结构还意指包括不同之处仅在于存在一个或多个同位素富集原子的化合物。除了氢原子由氘或氚替代或碳原子由13C或14C富集碳替代之外具有本发明结构的化合物在本公开的范围内。例如,氘已广泛用于检验生物活性化合物的药代动力学和代谢。尽管从化学角度来看,氘的行为与氢相似,但氘-碳键和氢-碳键之间的键能和键长存在显著差异。因此,在生物活性化合物中用氘替换氢可能会产生一种化合物,其通常保留其生化效力和选择性,但与其无同位素的对应物相比,表现出显著不同的吸收、分布、代谢和/或排泄(ADME)特性。因此,氘取代可以引起一些生物活性化合物的药物功效、安全性和/或耐受性改善。
根据本公开的另一方面,还提供了一种制备药物调配物的方法,其包括将式(I)化合物或其盐、溶剂化物和生理功能衍生物与一种或多种药学上可接受的载体、稀释剂或赋形剂混合。
本公开的化合物可在有此需要的受试者(诸如哺乳动物)中用作食欲素受体活性的双重激动剂。除了灵长类动物,尤其是人类之外,还可以根据本公开的方法治疗多种其他哺乳动物。本公开涉及一种本公开的化合物或其药学上可接受的盐,其用于药物中。本公开进一步涉及一种本公开的化合物或其药学上可接受的盐用于制造药物的用途,该药物用于在人和动物中拮抗食欲素受体活性或治疗本文所指出的病症和疾病。本发明方法和用途中治疗的受试者通常是哺乳动物,诸如人类,男性或女性。术语“治疗有效量”意指研究人员、兽医、医生或其他临床医生正在寻求的将引发组织、系统、动物或人的生物学或医学应答的本主题化合物的量。应认识到,本领域的技术人员可以通过治疗目前患有神经和精神病症的患者或通过用有效量的本公开的化合物预防性治疗患有神经和精神病症的患者来影响这些神经和精神病症。如本文所用,术语“治疗(treatment/treating)”是指其中可以减缓、中断、阻止、控制或停止本文所述的神经和精神病症的进展的所有方法,但不一定表示完全消除所有病症症状,以及对上述病症的预防性治疗,特别是在对于易患此类疾病或病症的患者中。术语化合物的“施用(administration)”和或“施用(administering)”化合物应理解为意指向有此需要的个体提供本公开的化合物或本公开的化合物的前药。
如本文所用,术语“组合物”旨在涵盖包含特定量的特定成分的产物,以及由特定量的特定成分的组合直接或间接产生的任何产物。与药物组合物相关的该术语旨在涵盖包含活性成分和构成载体的惰性成分的产物,以及直接或间接由任何两种或更多种成分的组合、络合或聚集,或由一种或多种成分的解离,或由一种或多种成分的其他类型的反应或相互作用产生的任何产物。
因此,本公开的药物组合物涵盖通过混合本公开的化合物和药学上可接受的载体制备的任何组合物。“药学上可接受的”是指载体、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。
所选择的剂量取决于所需的治疗效果、施用途径和治疗的持续时间。取决于疾病的性质和严重程度、患者的体重、患者随后遵循的特殊饮食、同时用药以及本领域技术人员将认识到的其他因素,剂量将因患者而异。
一般说来,每天向患者(例如人和老年人)施用0.0001至10mg/kg体重之间的剂量水平以获得食欲素受体的有效拮抗作用。剂量范围一般将为每患者每天约0.5mg至1.0g,其可以单剂量或多剂量施用。在一个实施例中,剂量范围将为每患者每天约0.5mg至500mg;在另一实施例中,为每患者每天约0.5mg至200mg;并且在又一实施例中,为每患者每天约5mg至50mg。
本公开的药物组合物可以固体剂量调配物的形式提供,该调配物诸如包含约0.5mg至500mg活性成分,或包含约1mg至250mg活性成分。药物组合物可以固体剂量调配物的形式提供,该调配物包含约1mg、5mg、10mg、25mg、30mg、50mg、80mg、100mg、200mg或250mg活性成分。对于口服施用,组合物可以以片剂的形式提供,这些片剂含有1.0至1000毫克活性成分,诸如1、5、10、15、20、25、50、75、100、150、200、250、300、400、500、600、750、800、900和1000毫克活性成分,用于待治疗患者的剂量的症状性调整。
可以按照每天1至4次(诸如每天一次或两次)的方案施用化合物。可以在睡前施用化合物。例如,可以在睡前约1小时、睡前约30分钟、睡前约15分钟或紧接在睡前施用化合物。
如所指出,本公开的化合物的治疗有效量将取决于许多因素。例如,接受者的物种、年龄和体重,需要治疗的确切病症和其严重程度,调配物的性质以及施用途径全部都是待考虑的因素。治疗有效量最终应由主治医师或兽医决定。该量可以每天单次剂量或每天多次(诸如两次、三次、四次、五次或更多次)亚剂量的形式给予,使得每日总剂量相同。盐或其溶剂化物的有效量可以确定为式(I)化合物本身的有效量的比例。类似的剂量应该适合于治疗本文所提到的其他病症。药物调配物可以单位剂量形式存在,每单位剂量含有预定量的活性成分。优选的单位剂量调配物是含有如上文所述的日剂量或亚剂量或其适当分数的活性成分的那些。此类药物调配物可以通过药学领域众所周知的任何方法制备。
药物调配物可适合于通过任何适当的途径施用,例如通过口服(包括颊内或舌下)、直肠、鼻、局部(包括颊内、舌下或经皮)、阴道或肠胃外(包括皮下、肌内、静脉内或皮内)途径施用。此类调配物可以通过药学领域已知的任何方法来制备,例如通过使活性成分与载体或赋形剂结合来制备。举例来说但并不意味着限制本公开内容,对于本公开的化合物被认为对其有用的某些病状和病症,某些途径将比其他途径更优选。此外,在延迟或延长的暴露将改善疗法的情况下,药物调配物可用于允许延迟或延长暴露于式(I)化合物。
适合于口服施用的药物调配物可以以离散单位的形式存在,诸如胶囊或片剂;粉末或颗粒;溶液或悬浮液,各自含有水性或非水性液体;可食用泡沫或搅拌沫(whip);或水包油液体乳液或油包水液体乳液。例如,对于呈片剂或胶囊形式的口服施用,活性药物组分可与口服、无毒、药学上可接受的惰性载体(诸如乙醇、甘油、水等)组合。一般说来,通过将化合物粉碎至合适的细小尺寸并与适当的药物载体(诸如可食用碳水化合物(例如淀粉或甘露糖醇))混合来制备粉末。还可以存在调味剂、防腐剂、分散剂和着色剂。
通过制备粉末、液体或悬浮液混合物并用明胶或一些其他适当的壳材料封装来制备胶囊。可以在封装之前将助流剂和润滑剂(诸如胶体二氧化硅、滑石、硬脂酸镁、硬脂酸钙或固体聚乙二醇)添加到混合物中。还可以添加崩解剂或增溶剂,诸如琼脂、碳酸钙或碳酸钠,以提高胶囊被摄取时药物的利用度。此外,当需要或必要时,也可将合适的粘合剂、润滑剂、崩解剂和着色剂掺入混合物中。合适的粘合剂的实例包括淀粉、明胶、天然糖(诸如葡萄糖或β-乳糖)、玉米甜味剂、天然树胶和合成树胶(诸如阿拉伯树胶、黄芪胶或海藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。可用于这些剂型中的润滑剂包括例如油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
例如,通过制备粉末混合物、造粒或压碎(slugging)、添加润滑剂和崩解剂并压制成片剂来调配片剂。可以通过将适当粉碎的化合物与如上文所述的稀释剂或碱混合来制备粉末混合物。任选的成分包括粘合剂,诸如羧甲基纤维素、藻酸盐、明胶或聚乙烯吡咯烷酮;溶液阻滞剂,诸如石蜡;再吸收促进剂,诸如季盐,和/或吸收剂,诸如膨润土、高岭土或磷酸二钙。粉末混合物可以用粘合剂,诸如糖浆、淀粉糊、阿拉伯胶粘液(acadia mucilage)或者纤维素或聚合物材料的溶液湿法造粒,并强制其通过筛网。作为造粒的替代方案,可以使粉末混合物通过压片机,并且结果是将不完美成型的压块碎成颗粒。可以借助于添加硬脂酸、硬脂酸盐、滑石或矿物油来润滑颗粒以防止粘附到片剂成型模具上。然后将润滑的混合物压制成片剂。本公开的化合物还可与自由流动的惰性载体组合并直接压制成片剂,而不经过造粒或压碎步骤。可以提供由虫胶密封涂层、糖或聚合物材料涂层和蜡抛光涂层组成的透明或不透明保护涂层。可以将染料添加到这些涂层中以区分不同的单位剂量。
口服液体,诸如溶液、糖浆和酏剂,可以以剂量单位形式制备,使得给定量含有预定量的化合物。例如,可以通过将化合物溶解于适当调味的水溶液中来制备糖浆,而酏剂通过使用无毒的醇媒剂来制备。通常可以通过将化合物分散于无毒媒剂中来调配悬浮液。还可以添加增溶剂和乳化剂,诸如乙氧基化异硬脂醇和聚氧乙烯山梨糖醇醚;防腐剂;风味添加剂,诸如薄荷油;或天然甜味剂,糖精或其他人造甜味剂;等等。
在适当的情况下,用于口服施用的剂量单位调配物可以经微囊化。还可以制备调配物以延长或维持释放,如例如通过将颗粒材料涂布或嵌入聚合物、蜡等中来制备。
适合于在口腔中局部施用的药物调配物包括锭剂、糖果锭剂和漱口剂。
本公开包括在本公开内容的一般范围内的具有作为食欲素-1受体和/或食欲素-2受体激动剂的活性的化合物。相对于其他食欲素调节剂,本发明化合物表现出意料之外的特性,诸如关于双重激动、提高的口服生物利用度、代谢稳定性、降低的代谢酶抑制(诸如降低的细胞色素P450 3A4(CYP3A4)抑制)、降低的转运体抑制(诸如降低的p-糖蛋白/PGP抑制)和/或相对于其他受体的选择性。
食欲素受体与广泛范围的生物学功能有关。这表明这些受体在人或其他物种的多种疾病过程中具有潜在作用。本公开的化合物可用于治疗、预防、改善、控制与食欲素受体相关的多种神经疾病和精神疾病或降低其风险,这些神经疾病和精神疾病包括以下病症或疾病中的一者或多者:睡眠障碍、减少夜间觉醒,尤其是晨间早醒,增加日间警觉性;减少白天的睡意;治疗或减少白天过度嗜睡、发作性睡病、睡眠中断、睡眠呼吸暂停、觉醒、夜间肌阵挛、REM睡眠中断、时差反应、轮班工作者睡眠障碍、睡眠异常、夜惊、与抑郁相关的失眠、情感/情绪障碍、阿尔茨海默氏病或认知障碍,以及梦游和遗尿,以及伴随衰老的睡眠障碍;阿尔茨海默氏病日落现象;与昼夜节律相关的病症,以及与跨时区旅行和轮班工作安排相关的精神和身体病症,因药物引起的导致REM睡眠减少作为副作用的病症;纤维肌痛;表现为非恢复性睡眠和肌肉疼痛或睡眠呼吸暂停(与睡眠期间呼吸障碍有关)的综合征;睡眠质量下降引起的病症;增进学习;增强记忆力;增强记忆保持;与过量食物摄入相关的饮食失调和其相关并发症、强迫性饮食失调、肥胖(由于任何原因,无论是遗传还是环境)、肥胖相关病症(包括暴饮暴食和神经性贪食症)、高血压、糖尿病、血浆胰岛素浓度升高和胰岛素抵抗、血脂异常、高脂血症、子宫内膜癌、乳腺癌、前列腺癌和结肠癌、骨关节炎、阻塞性睡眠呼吸暂停、胆石症、胆结石、心脏病、异常心律和心律失常、心肌梗塞、充血性心力衰竭、冠心病、猝死、中风、多囊卵巢病、颅咽管瘤、普瑞德-威利综合征、弗勒利希氏综合征、GH缺乏者(GH-deficient subject)、正常变异型身材矮小、特纳氏综合征和其他显示代谢活动减少或静息能量消耗作为去脂总质量百分比的降低的病理病症,例如儿童急性淋巴细胞白血病、代谢综合征(也称为X综合征)、胰岛素抵抗综合征、生殖激素异常、性和生殖功能障碍,诸如生育能力受损、不育、男性性腺功能减退症和女性多毛症,与母性肥胖相关的胎儿缺陷、胃肠动力障碍、肠动力障碍、肥胖相关胃食管反流、下丘脑疾病、脑下垂体疾病、呼吸系统病症,诸如肥胖通气不足综合征(匹克威克综合征)、呼吸困难、心血管疾病、炎症,诸如脉管系统的全身炎症,动脉硬化、高胆固醇血症、高尿酸血症、腰痛、胆囊疾病、痛风、肾癌、麻醉风险增加、降低肥胖次要结果的风险,诸如降低左心室肥厚的风险;脑中出现异常振荡活动的疾病或病症,包括抑郁症、偏头痛、神经性疼痛、帕金森氏病、精神病和精神分裂症,以及活动异常耦合的疾病或病症,特别是通过丘脑的活动异常耦合;增强认知功能,包括认知功能障碍,其包括在正常、健康、年轻人、成人或老年人群体中短暂或长期发生的所有类型的注意力、学习和记忆功能缺陷,以及在精神、神经、心血管和免疫病症中短暂或长期发生的上述缺陷;增强记忆力;增进记忆保持;增强免疫反应;增强免疫功能;潮热;盗汗;延长寿命;精神分裂症;由神经系统施加的兴奋/松弛节律控制的与肌肉相关的病症,诸如心律和心血管系统的其他病症;与细胞增殖相关的病症,诸如血管舒张或血管收缩和血压;癌症;心律失常;高血压;充血性心力衰竭;生殖/泌尿系统病症;性功能和生育力障碍;肾功能充足;对麻醉药的反应;情绪障碍,诸如抑郁症或更具体地忧郁症,例如单次发作性或复发性重度抑郁症和心境恶劣障碍,或双相情感障碍,例如双相I型障碍、双相II型障碍和循环性情绪障碍、由于一般医学状况引起的情绪障碍和物质诱发的情绪障碍;焦虑症,其包括急性应激障碍、广场恐惧症、广泛性焦虑症、强迫症、惊恐发作、恐慌症、创伤后应激障碍、离别焦虑障碍、社交恐惧症、特定恐惧症、物质引起的焦虑症和由于一般医学状况引起的焦虑;急性神经和精神病症,诸如心脏搭桥手术和移植后的脑缺损、中风、缺血性中风、脑缺血、脊髓创伤、头部创伤、围产期缺氧、心脏骤停、低血糖神经元损伤;亨廷顿舞蹈病;肌萎缩侧索硬化症;多发性硬化症;眼部损伤;视网膜病变;认知障碍;特发性和药物诱发的帕金森氏病;肌肉痉挛和与肌肉痉挛状态相关的病症,包括震颤、癫痫、抽搐、癫痫病、失神发作、复合部分性癫痫发作和全身性癫痫发作;雷诺-加斯特奥综合征;认知障碍,包括痴呆(与阿尔茨海默氏病、缺血、创伤、血管问题或中风、HTV疾病、帕金森氏病、亨廷顿病、皮克病、克雅氏病、围产期缺氧、其他一般医学状况或物质滥用有关);谵妄、遗忘症或与年龄相关的认知能力下降;精神分裂症或精神病,包括精神分裂症(偏执型、紊乱型、紧张性或未分化型)、类精神分裂症、精神分裂情感性障碍、妄想性障碍、短暂性精神障碍、共有性精神障碍、由于一般医学状况引起的精神障碍和物质诱发的精神障碍;解离性障碍,包括多重人格综合征和心因性遗忘症;物质相关障碍、物质使用、物质滥用、物质寻求、物质恢复、所有类型的心理和身体成瘾和成瘾行为、奖励相关行为(包括物质诱发的谵妄、持久性痴呆、持久性遗忘症、精神障碍或焦虑症;对包括酒精、安非他明、大麻、可卡因、致幻剂、吸入剂、吗啡、尼古丁、阿片类药物、苯环己哌啶、镇静剂、安眠药或抗焦虑药的物质的耐受性、成瘾性摄入、依赖性、戒断或复发);运动障碍,包括运动不能和运动不能-强直综合征(包括帕金森氏病、药物诱发的帕金森氏症、脑炎后帕金森氏症、进行性核上性麻痹、多系统萎缩、皮质基底节变性、帕金森氏症-ALS痴呆综合征和基底神经节钙化)、慢性疲劳综合征、疲劳,包括帕金森氏疲劳、多发性硬化症疲劳、睡眠障碍或昼夜节律障碍引起的疲劳、药物诱发的帕金森氏症(诸如抗精神病药诱发的帕金森氏症、抗精神病药恶性综合征、抗精神病药诱发的急性肌张力障碍、抗精神病药诱发的急性静坐不能、抗精神病药诱发的迟发性运动障碍和药物诱发的姿势性震颤)、Gilles de Ia Tourette综合征、癫痫和运动障碍[包括震颤(诸如静止性震颤、特发性震颤、姿势性震颤和意向性震颤)、舞蹈病(诸如西登哈姆氏舞蹈病、亨廷顿病、良性遗传性舞蹈病、神经棘红细胞增多症、症状性舞蹈病、药物诱发的舞蹈病和偏身颤搐)、肌阵挛(包括全身性肌阵挛和局灶性肌阵挛)、抽动(包括简单性抽动、复杂性抽动和症状性抽动)、不宁腿综合征和肌张力障碍(包括全身性肌张力障碍,诸如特发性肌张力障碍、药物诱发的肌张力障碍、症状性肌张力障碍和阵发性肌张力障碍,以及局灶性肌张力障碍,诸如眼睑痉挛、口下颌肌张力障碍、痉挛性烦躁不安、痉挛性斜颈、轴性肌张力障碍、肌张力障碍性书写痉挛和偏瘫性肌张力障碍);注意力缺陷/多动障碍(ADHD);品行障碍;偏头痛(包括偏头痛性头痛);头痛;痛觉过敏;疼痛;对疼痛的敏感性增强或过度,诸如痛觉过敏、灼痛和异常性疼痛;急性疼痛;烧伤疼痛;非典型面部疼痛;神经性疼痛;背疼;复杂区域疼痛综合征I和II;关节炎疼痛;运动损伤疼痛;与感染有关的疼痛,例如HIV、化疗后疼痛;中风后疼痛;术后疼痛;神经痛;呕吐(emesis)、恶心、呕吐(vomiting);胃运动障碍;胃溃疡;卡尔曼氏综合征(嗅觉丧失症);与内脏疼痛相关的病症,诸如肠易激综合征和心绞痛;饮食失调;尿失禁;物质耐受、物质戒断(包括诸如阿片类药物、尼古丁、烟草制品、酒精、苯二氮卓类药物、可卡因、镇静剂、安眠药等的物质);精神病;精神分裂症;焦虑(包括广泛性焦虑症、恐慌症和强迫症);情绪障碍(包括抑郁症、躁狂症、双相情感障碍);三叉神经痛;听力损失;耳鸣;神经元损伤,包括眼部损伤;视网膜病变;眼睛黄斑变性;呕吐;脑水肿;疼痛,包括急性和慢性疼痛状态、剧烈疼痛、顽固性疼痛、炎性疼痛、神经性疼痛、创伤后疼痛、骨关节疼痛(骨关节炎)、重复性运动疼痛、牙科疼痛、癌症疼痛、肌筋膜疼痛(肌肉损伤、纤维肌痛)、围术期疼痛(普外科、妇科)、慢性疼痛、神经性疼痛、创伤后疼痛、三叉神经痛、偏头痛和偏头痛性头痛。因此,在具体实施例中,本公开提供了用于以下的方法:提高睡眠质量;加强睡眠维持;增加REM睡眠;增加第2阶段睡眠;减少睡眠模式的碎片化;治疗失眠和所有类型的睡眠障碍;治疗或控制与诸如神经疾病(包括神经性疼痛和不宁腿综合征)的疾病相关的睡眠障碍;治疗或控制成瘾性病症;治疗或控制精神活性物质使用和滥用;增强认知;增加记忆保持;治疗或控制肥胖;治疗或控制糖尿病以及食欲、味觉、饮食或饮酒障碍;治疗或控制下丘脑疾病;治疗或控制抑郁症;治疗、控制、改善或降低癫痫(包括失神性癫痫)的风险;治疗或控制疼痛,包括神经性疼痛;治疗或控制帕金森氏病;治疗或控制精神病;治疗或控制心境恶劣、情绪、精神病和焦虑症;治疗或控制抑郁症,包括重度抑郁和重度抑郁症;治疗或控制双相情感障碍;或在有此需要的哺乳动物患者中治疗、控制、改善或降低精神分裂症的风险,其包括向患者施用治疗有效量的本公开的化合物。本主题化合物进一步可用于预防、治疗、控制、改善本文所指出的疾病、病症和病状或降低其风险的方法。本公开的组合物中的活性成分的剂量可以变化,然而,活性成分的量必须使得获得合适的剂型。活性成分可以以将提供最佳药效的剂量施用于需要此类治疗的患者(动物和人)。
本公开的化合物可以与一种或多种其他药物组合用于治疗、预防、控制、改善疾病或病症,或降低其风险,对于这些疾病或病症,本公开的化合物或其他药物可具有效用,其中药物组合在一起比单独使用任何一种药物更安全或更有效。此类其他药物可以通过其常用途径和量与本公开的化合物同时或依次施用。当本公开的化合物与一种或多种其他药物同时使用时,考虑呈单位剂型的含有此类其他药物和本公开的化合物的药物组合物。组合疗法还可以包括本公开的化合物和一种或多种其他药物以不同的重叠时间表施用的疗法。还考虑当与一种或多种其他活性成分组合使用时,本公开的化合物和其他活性成分可以以比各自单独使用时更低的剂量使用。
因此,本公开的药物组合物包括除了本公开的化合物之外还含有一种或多种其他活性成分的那些。上述组合包括本公开的化合物不仅与一种其他活性化合物的组合,还包括与两种或更多种其他活性化合物的组合。
同样地,本公开的化合物可以与用于预防、治疗、控制、改善疾病或病症,或降低其风险的其他药物组合使用,对于这些疾病或病症,本公开的化合物可有用。此类其他药物可以通过其常用途径和量与本公开的化合物同时或依次施用。当本公开的化合物与一种或多种其他药物同时使用时,考虑除了本公开的化合物之外还含有此类其他药物的药物组合物。因此,本公开的药物组合物包括除了本公开的化合物之外还含有一种或多种其他活性成分的那些。
本公开的化合物可以与本领域已知可用于治疗或预防睡眠障碍(包括发作性睡病)的其他化合物组合施用,这些其他化合物包括例如镇静剂、安眠药、抗焦虑药、抗精神病药、抗焦虑剂、抗组胺药、苯二氮卓类药物、巴比妥类药物、环吡咯酮、GABA激动剂、5HT-2拮抗剂(包括5HT-2A拮抗剂和5HT-2A/2C拮抗剂)、组胺拮抗剂(包括组胺H3拮抗剂、组胺H3反向激动剂、咪唑并吡啶、弱安定剂、褪黑激素激动剂和拮抗剂、褪黑激素能药剂、其他食欲素拮抗剂、食欲素激动剂、前动力蛋白激动剂和拮抗剂、吡唑并吡啶类、T型钙通道拮抗剂、三唑并吡啶类等,诸如:阿地唑仑(adinazolam)、二烯丙巴比妥(allobarbital)、阿洛米酮(alonimid)、阿普唑仑(alprazolam)、阿米替林、异戊巴比妥(amobarbital)、阿莫沙平(amoxapine)、阿莫达非尼(armodafinil)、APD-125、苯他西泮(bentazepam)、苯佐他明(benzoctamine)、溴替唑仑(brotizolam)、安非他酮(bupropion)、丁丙酮(busprione)、仲丁巴比妥(butabarbital)、布他比妥(butalbital)、卡普莫瑞林(capromorelin)、卡普脲(capuride)、卡波氯醛(carbocloral)、氯醛甜菜碱(chloral betaine)、水合氯醛(chloralhydrate)、利眠宁(chlordiazepoxide)、氯米帕明(clomipramine)、氯硝西泮(clonazepam)、氯哌喹酮(cloperidone)、氯氮(clorazepate)、氯乙双酯(clorethate)、氯氮平(clozapine)、康西泮(conazepam)、环丙西泮(cyprazepam)、地昔帕明(desipramine)、代克拉莫(dexclamol)、地西泮(diazepam)、二氯醛安替比林(dichloralphenazone)、双丙戊酸(divalproex)、苯海拉明、多虑平(doxepin)、EMD-281014、依利色林(eplivanserin)、艾司唑仑(estazolam)、艾司佐匹克隆(eszopiclone)、乙氯维诺(ethchlorynol)、依托咪酯(etomidate)、非诺班(fenobam)、氟硝西泮(flunitrazepam)、氟西泮(flurazepam)、氟伏沙明、氟西汀、膦西泮(fosazepam)、加波沙朵(gaboxadol)、格鲁米特(glutethimide)、哈拉西泮(halazepam)、羟嗪(hydroxyzine)、伊布莫伦(ibutamoren)、丙咪嗪(imipramine)、茚地普隆(indiplon)、锂、劳拉西泮(lorazepam)、氯甲西泮(lormetazepam)、LY-156735、马普替林(maprotiline)、MDL-100907、甲氯喹酮(mecloqualone)、褪黑激素、甲苯比妥(mephobarbital)、甲丙氨酯(meprobamate)、甲喹酮(methaqualone)、甲普隆(methyprylon)、咪达氟(midaflur)、咪达唑仑(midazolam)、莫达非尼(modafinil)、奈法唑酮(nefazodone)、NGD-2-73、尼索氨酯(nisobamate)、硝西泮(nitrazepam)、去甲替林(nortriptyline)、奥去甲替林(ornortriptyline)、奥沙西泮(oxazepam)、三聚乙醛(paraldehyde)、帕罗西汀(paroxetine)、戊巴比妥(pentobarbital)、哌拉平(perlapine)、奋乃静(perphenazine)、苯乙肼、苯巴比妥(phenobarbital)、普拉西泮(prazepam)、异丙嗪、丙泊酚(propofol)、普罗替林(protriptyline)、夸西泮(quazepam)、雷美替胺(ramelteon)、瑞氯西泮(reclazepam)、洛利米特(roletamide)、司考巴比妥(secobarbital)、舍曲林、舒普罗酮(suproclone)、TAK-375、替马西帕尼(temazepani)、硫利达嗪(thioridazine)、噻加滨(tiagabine)、曲卡唑酯(tracazolate)、反苯环丙嗪(tranylcypromaine)、曲唑酮(trazodone)、三唑仑(triazolam)、曲匹泮(trepipam)、三甲氧苯酯酰胺(tricetamide)、三氯福司(triclofos)、三氟拉嗪(trifluoperazine)、曲美托嗪(trimetozine)、曲米帕明(trimipramine)、乌达西泮(uldazepam)、文拉法辛(venlafaxine)、扎来普隆(zaleplon)、唑拉西泮(zolazepam)、佐匹克隆(zopiclone)、唑吡坦(zolpidem)以及其盐和其组合等,或者本公开的化合物可以与使用物理方法(诸如光疗法或电刺激)结合施用。
在另一实施例中,本主题化合物可以与本领域已知的其他化合物组合使用,单独施用或在同一药物组合物中施用,这些其他化合物包括但不限于:胰岛素增敏剂,包括(i)PPARγ拮抗剂,诸如格列酮类(例如西格列酮(ciglitazone);达格列酮(darglitazone);恩格列酮(englitazone);伊格列酮(isaglitazone)(MCC-555);吡格列酮(pioglitazone);罗格列酮(rosiglitazone);曲格列酮(troglitazone);图拉里克(tularik);BRL49653;CLX-0921;5-BTZD、GW-0207、LG-100641和LY-300512等);(iii)双胍类,诸如二甲双胍和苯乙双胍;(b)胰岛素或胰岛素模拟物,诸如biota、LP-100、novarapid、地特胰岛素、赖脯胰岛素、甘精胰岛素、胰岛素锌悬浮液(慢效和超慢效);Lys-Pro胰岛素、GLP-I(73-7)(胰岛素调理素(insulintropin));和GLP-I(7-36)-NH2;(c)磺酰脲类,诸如醋酸己脲(acetohexamide);氯磺丙脲(chlorpropamide);特泌胰(diabinese);格列本脲(glibenclamide);格列吡嗪(glipizide);格列苯脲(glyburide);格列美脲(glimepiride);格列齐特(gliclazide);格列戊脲(glipentide);格列喹酮(gliquidone);格列索脲(glisolamide);妥拉磺脲(tolazamide);和甲苯磺丁脲(tolbutamide);(d)α-葡萄糖苷酶抑制剂,诸如阿卡波糖(acarbose)、脂解素;卡格列波糖(camiglibose);乙格列酯;米格列醇;伏格列波糖;普那米星-Q;沙巴他汀;CKD-71;MDL-25,637;MDL-73,945;和MOR 14等;(e)胆固醇降低剂,诸如(i)HMG-CoA还原酶抑制剂(阿托伐他汀(atorvastatin)、伊伐他汀(itavastatin)、氟伐他汀(fluvastatin)、洛伐他汀(lovastatin)、普伐他汀(pravastatin)、利伐他汀(rivastatin)、瑞舒伐他汀(rosuvastatin)、辛伐他汀(simvastatin)和其他他汀类药物),(ii)胆汁酸吸收剂/螯合剂,诸如考来烯胺(cholestyramine)、考来替泊(colestipol)、交联葡聚糖的二烷基氨基烷基衍生物;等,(ii)烟醇、烟酸或其盐,(iii)增殖物活化受体α激动剂,诸如非诺贝酸衍生物(吉非贝齐(gemfibrozil)、氯贝特(clofibrate)、非诺贝特(fenofibrate)和苯扎贝特(benzafibrate)),(iv)胆固醇吸收抑制剂,诸如甾烷醇酯、β-谷甾醇、甾醇甙,诸如替奎安(tiqueside);以及氮杂环丁酮类,诸如依折麦布(ezetimibe)等,和(酰基CoAxholesterol酰基转移酶(ACAT))抑制剂,诸如阿瓦西米(avasimibe)和美林那胺(melinamide),(v)抗氧化剂,诸如普罗布考(probucol),(vi)维生素E,和(vii)拟甲状腺素药;(f)PPARa激动剂,诸如贝氯贝特(beclofibrate)、苯扎贝特、环丙贝特(ciprofibrate)、氯贝特、依托贝特、非诺贝特和吉非贝齐;以及其他纤维酸衍生物,诸如/>和/>等,以及PPARα激动剂;(h)PPARα/δ激动剂,诸如莫格列扎(muraglitazar);(i)抗肥胖剂,诸如(1)生长激素促分泌素或生长激素促分泌素受体激动剂/拮抗剂;(2)蛋白酪氨酸磷酸酶-IB(PTP-IB)抑制剂;(3)大麻素受体配体;(4)抗肥胖血清素能药剂;(5)β3-肾上腺素受体激动剂;(6)胰脂肪酶抑制剂;(7)神经肽Yl拮抗剂;(8)神经肽Y5拮抗剂;(9)黑色素浓集激素(MCH)受体拮抗剂;(10)黑色素浓集激素1受体(MCHlR)拮抗剂;(11)黑色素浓集激素2受体(MCH2R)激动剂/拮抗剂;(12)食欲素受体拮抗剂;(13)5-羟色胺再摄取抑制剂,诸如氟西汀、帕罗西汀和舍曲林;(14)黑皮质素激动剂,诸如Melanotan II;(15)Mc4r(黑皮质素4受体)激动剂;(16)5HT-2激动剂;(17)5HT2C(5-羟色胺受体2C)激动剂;(18)甘丙肽拮抗剂;(19)CCK激动剂;(20)CCK-A(胆囊收缩素-A)激动剂;(21)GLP-1激动剂;(22)促肾上腺皮质激素释放激素激动剂;(23)组胺受体-3(H3)调节剂;(24)组胺受体-3(H3)拮抗剂/反向激动剂;(25)β-羟基类固醇脱氢酶-1抑制剂(β-HSD-1);(26)PDE(磷酸二酯酶)抑制剂;(27)磷酸二酯酶-3B(PDE3B)抑制剂;(28)NE(去甲肾上腺素)转运抑制剂;(29)生长素释放肽受体拮抗剂;(30)瘦素,其包括重组人瘦素(PEG-OB,Hoffman La Roche)和重组甲硫氨酰人瘦素(Amgen);(31)瘦素衍生物;(32)BRS3(铃蟾肽受体亚型3)激动剂;(33)CNTF(睫状神经营养因子);(34)CNTF衍生物,诸如阿索开(axokine)(Regeneron);(35)单胺再摄取抑制剂;(36)UCP-1(解偶联蛋白-1、2或3活化剂);(37)甲状腺激素β激动剂;(38)FAS(脂肪30酸合成酶)抑制剂;(39)DGATl(二酰基甘油酰基转移酶1)抑制剂;(40)DGAT2(二酰基甘油酰基转移酶2)抑制剂;(41)ACC2(乙酰-CoA羧化酶-2)抑制剂;(42)糖皮质激素拮抗剂;(43)酰基-雌激素;(44)二肽基肽酶IV(DPP-IV)抑制剂;(45)二羧酸转运体抑制剂;(46)葡萄糖转运体抑制剂;(47)磷酸盐转运体抑制剂;(48)二甲双胍(49)托吡酯(Topiramate)/>(50)肽YY、PYY 3-36、肽YY类似物、衍生物和片段;(51)神经肽Y2(NPY2)受体激动剂;(52)神经肽Y4(NPY4);(53)环氧合酶-2;(54)神经肽Yl(NPYl)拮抗剂;(55)阿片拮抗剂;(56)1lβHSD-I(11-β羟基类固醇脱氢酶1型)抑制剂;(57)阿米雷司(aminorex);(58)双氯乙醛(amphechloral);(59)安非他明;(60)苄非他明(benzphetamine);(61)氯苯丁胺;(62)氯苄雷司;(63)氯福雷司;(64)氯氨雷司;(65)氯特胺;(66)环己异丙甲胺;(67)右旋安非他命;(68)二苯甲哌啶乙醇,(69)N-乙基安非他命;(70)芬布酯(fenbutrazate);(71)非尼雷司(fenisorex);(72)芬普雷司(fenproporex);(73)氟多雷司(fludorex);(74)氟氨雷司(fluminorex);(75)糠基甲基苯丙胺;(76)左旋苯丙胺;(77)左法哌酯;(78)美芬雷司;(79)甲胺苯丙酮;(80)甲基苯丙胺;(81)去甲伪麻黄碱;(82)喷托雷司;(83)苯二甲吗啉;(84)苯甲吗啉;(85)匹西雷司;(86)植物药(phytopharm);和(87)唑尼沙胺(zonisamide),(88)神经调节肽;(89)胃泌酸调节素;以及(90)神经激肽-1受体拮抗剂(NK-1拮抗剂)。
在另一实施例中,本主题化合物可以与抗抑郁剂或抗焦虑剂组合使用,这些抗抑郁剂或抗焦虑剂包括去甲肾上腺素再摄取抑制剂(包括叔胺类三环类药物和仲胺三环类药物)、选择性5-羟色胺再摄取抑制剂(SSRI)、单胺氧化酶抑制剂(MAOI)、单胺氧化酶可逆抑制剂(RIMA)、血清素和去甲肾上腺素再摄取抑制剂(SNRI)、促肾上腺皮质激素释放因子(CRF)拮抗剂、α-肾上腺素受体拮抗剂、神经激肽-1受体拮抗剂、非典型抗抑郁剂、苯二氮卓类药物、5-HTI A激动剂或拮抗剂(尤其是5-HTI A部分激动剂)和促肾上腺皮质激素释放因子(CRF)拮抗剂。具体药剂包括:阿米替林(amitriptyline)、氯米帕明(clomipramine)、多塞平(doxepin)、丙咪嗪(imipramine)和曲米帕明(trimipramine);阿莫沙平(amoxapine)、地昔帕明(desipramine)、马普替林(maprotiline)、去甲替林(nortriptyline)和普罗替林(protriptyline);西酞普兰(citalopram)、度洛西汀(duloxetine)、氟西汀(fluoxetine)、氟伏沙明(fluvoxamine)、帕罗西汀(paroxetine)和舍曲林(sertraline);异卡波肼(isocarboxazid)、苯乙肼(phenelzine)、反苯环丙胺(tranylcypromine)和司来吉兰(selegiline);吗氯贝胺(moclobemide):文拉法辛(venlafaxine);阿瑞匹坦(aprepitant);安非他酮(bupropion)、锂、奈法唑酮(nefazodone)、曲唑酮(trazodone)和维洛嗪(viloxazine);阿普唑仑(alprazolam)、利眠宁(chlordiazepoxide)、氯硝西泮(clonazepam)、二钾氯氮卓(chlorazepate)、地西泮(diazepam)、哈拉西泮(halazepam)、劳拉西泮(lorazepam)、奥沙西泮(oxazepam)和普拉西泮(prazepam);丁螺环酮(buspirone)、氟辛克生(flesinoxan)、吉哌隆(gepirone)和伊沙匹隆(ipsapirone),以及其药学上可接受的盐。
在另一实施例中,本主题化合物可以与以下项组合使用:抗阿尔茨海默氏病药剂;β-分泌酶抑制剂;γ-分泌酶抑制剂;生长激素促分泌素;重组生长激素;HMG-CoA还原酶抑制剂;NSAID,其包括布洛芬;维生素E;抗淀粉样蛋白抗体;CB-I受体拮抗剂或CB-I受体反向激动剂;抗生素,诸如多西环素和利福平;N-甲基-D-天冬氨酸(NMDA)受体拮抗剂,诸如美金刚;胆碱酯酶抑制剂,诸如加兰他敏、卡巴拉汀、多奈哌齐和他克林;生长激素促分泌素,诸如伊布莫伦、甲磺酸伊布莫伦和卡普莫瑞林;组胺H3拮抗剂;AMPA激动剂;PDE IV抑制剂;GABAA反向激动剂;或神经元烟碱激动剂。
在另一实施例中,本主题化合物可以与以下项组合使用:镇静剂、催眠药、抗焦虑药、抗精神病药、抗焦虑剂、环吡咯酮类、咪唑并吡啶类、吡唑并嘧啶类、弱安定剂、褪黑激素激动剂和拮抗剂、褪黑激素能药剂、苯二氮卓类药物、巴比妥类药物、5HT-2拮抗剂等,诸如:阿地唑仑、二烯丙巴比妥、阿洛米酮、阿普唑仑、阿米替林、异戊巴比妥、阿莫沙平、苯他西泮、苯佐他明、溴替唑仑、安非他酮、丁丙酮、仲丁巴比妥、布他比妥、卡普脲、卡波氯醛、氯醛甜菜碱、水合氯醛、利眠宁、氯米帕明、氯硝西泮、氯哌喹酮、氯氮、氯乙双酯、氯氮平、环丙西泮、地昔帕明、代克拉莫、地西泮、二氯醛安替比林、双丙戊酸、苯海拉明、多虑平、艾司唑仑、乙氯维诺、依托咪酯、非诺班、氟硝西泮、氟西泮、氟伏沙明、氟西汀、膦西泮、格鲁米特、哈拉西泮、羟嗪、丙咪嗪、锂、劳拉西泮、氯甲西泮、马普替林、甲氯喹酮、褪黑激素、甲苯比妥、甲丙氨酯、甲喹酮、咪达氟、咪达唑仑、奈法唑酮、尼索氨酯、硝西泮、去甲替林、奥沙西泮、三聚乙醛、帕罗西汀、戊巴比妥、哌拉平、奋乃静、苯乙肼、苯巴比妥、普拉西泮、异丙嗪、丙泊酚、普罗替林、夸西泮、瑞氯西泮、洛利米特、司考巴比妥、舍曲林、舒普罗酮、替马西泮、硫利达嗪、曲卡唑酯、反苯环丙嗪、曲唑酮、三唑仑、曲匹泮、三甲氧苯酯酰胺、三氯福司、三氟拉嗪、曲美托嗪、曲米帕明、乌达西泮、文拉法辛、扎来普隆、唑拉西泮、唑吡坦以及其盐和其组合等,或者本主题化合物可以与使用物理方法(诸如光疗法或电刺激)结合施用。
在另一实施例中,本主题化合物可以与以下项组合使用:左旋多巴(levodopa)(有或没有选择性脑外脱羧酶抑制剂,诸如卡比多巴(carbidopa)或苄丝肼(benserazide));抗胆碱能药,诸如比哌立登(任选作为其盐酸盐或乳酸盐)和盐酸苯海索(安坦(benzhexol));COMT抑制剂,诸如恩他卡朋;MOA-B抑制剂;抗氧化剂;A2a腺苷受体拮抗剂;胆碱能激动剂;NMDA受体拮抗剂;血清素受体拮抗剂;和多巴胺受体激动剂,诸如阿乐替莫、溴隐亭(bromocriptine)、非诺多泮(fenoldopam)、麦角乙脲(lisuride)、那高利特(naxagolide)、培高利特(pergolide)和普拉克索(pramipexole)。
在另一实施例中,本主题化合物可以与以下项组合使用:醋奋乃静(acetophenazine)、阿仑替莫(alentemol)、安坦、溴隐亭、比哌立登、氯丙嗪、氯普噻吨、氯氮平、地西泮、非诺多泮、氟奋乃静、氟哌啶醇、左旋多巴、左旋多巴与苄丝肼、左旋多巴与卡比多巴、麦角乙脲、洛沙平、美索达嗪、莫林多龙(molindolone)、那高利特、奥氮平、培高利特、奋乃静、匹莫齐特、普拉克索、利培酮、舒必利、丁苯那嗪、苯海索、硫利达嗪(thioridazine)、替沃噻吨(thiothixene)或三氟拉嗪(trifluoperazine)。
在另一实施例中,本主题化合物可以与来自以下项的化合物组合使用:吩噻嗪、噻吨、杂环二苯并氮杂卓、丁酰苯、二苯基丁基哌啶和吲哚酮类精神安定药。吩噻嗪的合适实例包括氯丙嗪、美索达嗪(mesoridazine)、硫利达嗪(thioridazine)、醋奋乃静、氟奋乃静、奋乃静和三氟拉嗪。噻吨类的合适实例包括氯普噻吨和替沃噻吨。二苯并氮杂卓的实例是氯氮平。丁酰苯的实例是氟哌啶醇。二苯基丁基哌啶的实例是匹莫齐特。吲哚酮的实例是吗茚酮(molindolone)。其他精神安定药包括洛沙平、舒必利和利培酮。在另一实施例中,本主题化合物可以与以下项组合使用:尼古丁激动剂或尼古丁受体部分激动剂,诸如伐尼克兰(varenicline);阿片类拮抗剂(例如纳曲酮(naltrexone))、多巴胺能药剂(例如阿朴吗啡(apomorphine))、ADD/ADHD药剂(例如盐酸哌甲酯(例如和/>)、托莫西汀(atomoxetine)(例如/>)、单胺氧化酶抑制剂(MAOI)、安非他明(例如/>))和抗肥胖剂,诸如apo-B/MTP抑制剂,1lβ-羟基类固醇脱氢酶-1(1lBeta-HSD 1型)抑制剂、肽YY3-36或其类似物、MCR激动剂、CCK-A激动剂、单胺再摄取抑制剂、拟交感神经药、β3肾上腺素能受体激动剂、多巴胺受体激动剂、黑素细胞-刺激激素受体类似物、5-HT2c受体激动剂、黑色素浓缩激素受体拮抗剂、瘦素、瘦素类似物、瘦素受体激动剂、甘丙肽受体拮抗剂、脂肪酶抑制剂、铃蟾肽受体激动剂、神经肽-Y受体拮抗剂(例如NPY Y5受体拮抗剂)、拟甲状腺剂、脱氢表雄酮或其类似物、糖皮质激素受体拮抗剂、其他食欲素受体拮抗剂、胰高血糖素样肽-1受体激动剂、睫状神经营养因子、人刺豚鼠相关蛋白拮抗剂、生长素释放肽受体拮抗剂、组胺3受体拮抗剂或反向激动剂和神经调节肽U受体激动剂以及其药学上可接受的盐。
在另一实施例中,本主题化合物可以与以下项组合使用:食欲剂,诸如阿米雷司(aminorex)、安非氯醛(amphechloral)、安非他明(amphetamine)、苄非他明(benzphetamine)、氯苯丁胺(chlorphentermine)、氯苄雷司(clobenzorex)、氯福雷司(cloforex)、氯氨雷司(clominorex)、邻氯苯丁胺(clortermine)、环己异丙甲胺(cyclexedrine)、右芬氟拉明(dexfenfluramine)、右旋安非他明(dextroamphetamine)、二乙胺苯丙酮、二苯甲哌啶乙醇(diphemethoxidine)、N-乙基安非他明、芬布酯(fenbutrazate)、芬氟拉明(fenfluramine)、非尼雷司(fenisorex)、芬普雷司(fenproporex)、氟多雷司(fludorex)、氟氨雷司(fluminorex)、糠基甲基安非他明、左苯丙胺(levamfetamine)、左法哌酯(levophacetoperane)、马吲哚(mazindol)、美芬雷司(mefenorex)、甲胺苯丙酮(metamfepramone)、甲基苯丙胺、去甲伪麻黄碱(norpseudoephedrine)、喷托雷司(pentorex)、苯甲曲嗪(phendimetrazine)、苯甲吗啉(phenmetrazine)、苯丁胺(phentermine)、苯丙醇胺(phenylpropanolamine)、匹西雷司(picilorex)和西布曲明(sibutramine);选择性血清素再摄取抑制剂(SSRI);卤化安非他明衍生物,其包括氯苯丁胺、氯福雷司、氯特胺、右芬氟拉明、芬氟拉明、匹西雷司和西布曲明;以及其药学上可接受的盐。
在另一实施例中,本主题化合物可以与以下项组合使用:阿片激动剂、脂氧合酶抑制剂(诸如5-脂氧合酶抑制剂)、环氧合酶抑制剂(诸如环氧合酶-2抑制剂)、白细胞介素抑制剂(诸如白细胞介素-1抑制剂)、NMDA拮抗剂、一氧化氮抑制剂或一氧化氮合成抑制剂、非类固醇抗炎药或细胞因子抑制性抗炎药,例如与诸如以下项的化合物组合使用:对乙酰氨基酚、阿司匹林、可二烯、芬太尼、布洛芬、吲哚美辛、酮咯酸、吗啡、萘普生、非那西丁、吡罗昔康、类固醇镇痛药、舒芬太尼、舒林酸、替尼达等。类似地,本主题化合物可以与以下项一起施用:止痛药;增效剂,诸如咖啡因、H2拮抗剂、西甲硅油、氢氧化铝或氢氧化镁;减充血药,诸如去氧肾上腺素、苯丙醇胺、伪麻黄碱、羟甲唑啉、肾上腺素、萘甲唑啉、赛洛唑啉、环己丙甲胺或左旋脱氧麻黄碱;镇咳药,诸如可待因、氢可酮、卡米芬、喷托维林或右美沙芬;利尿剂;以及镇静或非镇静抗组胺药。
本公开的化合物可以通过口服、肠胃外(例如,肌内、腹膜内、静脉内、ICV、脑池内注射或输注、皮下注射或植入)、通过吸入喷雾、鼻、阴道、直肠、舌下或局部施用途径施用,并且可以单独或一起调配成含有适合于每种施用途径的常规无毒的药学上可接受的载体、佐剂和媒剂的合适的剂量单位调配物。除了治疗温血动物(诸如小鼠、大鼠、马、牛、羊、狗、猫、猴等)之外,本公开的化合物对于用于人也可有效。
制备本公开的化合物的几种方法在以下方案和实例中说明。根据本领域已知的程序或如本文所说明制备起始材料。
本公开的化合物或者其盐或溶剂化物可以单独使用或与其他治疗剂组合使用。式(I)化合物和其他药物活性剂可以一起或分开施用,并且当分开施用时,施用可以同时或以任何顺序依序发生。选择式(I)化合物和其他药物活性剂的量以及相对施用时序以实现所需的组合治疗效果。式(I)化合物或者其盐或溶剂化物与其他治疗剂的组合施用可以以组合形式按以下同时施用:(1)包括化合物组合的单一药物组合物;或(2)各自包括本公开的化合物的单独药物组合物。替代地,组合可以以依序方式单独施用,其中首先施用一种治疗剂,其次施用另一种,或反之亦然。此类依序施用可以在时间上接近或在时间上较远。
有机合成领域的技术人员将理解,存在多种生产本公开的化合物的方法,这些化合物用适合于各种用途的放射性同位素标记。
实验部分
缩写:
如本文所用,这些工艺、方案和实例中使用的符号和惯例与当代科学文献(例如《美国化学学会杂志(Journal of the American Chemical Society)》或《生物化学杂志(Journal of Biological Chemistry)》)中使用的符号和惯例一致。具体地,可以在实例和整个说明书中使用以下缩写:
g(克); mg(毫克);
L(升); mL(毫升);
μL(微升); psi(磅/平方英寸);
M(摩尔); mM(毫摩尔);
Hz(赫兹); MHz(兆赫);
mol(摩尔); mmol(毫摩尔);
RT或rt(室温); hr(小时);
min(分钟); TLC(薄层色谱法);
mp(熔点); RP(反相);
Tr(保留时间); TFA(三氟乙酸);
TEA(三乙胺); THF(四氢呋喃);
TFAA(三氟乙酸酐); CD3OD(氘代甲醇);
CDCl3(氘代氯仿); DMSO(二甲亚砜);
SiO2(硅胶); atm(气氛);
EtOAc(乙酸乙酯); CHCl3(氯仿);
HCl(盐酸); Ac(乙酰基);
DMF(N,N-二甲基甲酰胺); Me(甲基);
Cs2CO3(碳酸铯); EtOH(乙醇);
Et(乙基); t-Bu(叔丁基);
MeOH(甲醇) p-TsOH(对甲苯磺酸);
DCM(二氯甲烷) DCE(二氯乙烷)
Et2O(二乙醚) K2CO3(碳酸钾);
Na2CO3(碳酸钠); i-PrOH(异丙醇)
NaHCO3(碳酸氢钠); ACN(乙腈);
Pr(丙基); i-Pr(异丙基);
PE(石油醚); Hex(己烷);
H2SO4(硫酸); HCl(盐酸);
Et3N(三乙胺); Na2SO4(硫酸钠);
MTBE(甲基叔丁基醚); Boc(叔丁氧基羰基);
DIPEA(二异丙基乙胺); IPA(异丙醇);
HMDS(六甲基二硅氮烷) NH4Cl(氯化铵)
NH4CO3(碳酸铵) MgSO4(硫酸镁)
NH4OH(氢氧化铵)
除非另有指示,否则所有温度均以℃(摄氏度)表示。除非另外指出,否则所有反应均在室温下进行。
所有目标化合物的合成如方案1-11中所示。所有化合物均通过1H NMR和LC-MS进行表征,并如通过HPLC所评定,其纯度>95%。
方案1.表1中的化合物的合成路线
本公开的化合物可以根据Nagahara及其同事描述的程序来合成。如上文所示,将市售1-氟-3-硝基苯与过量乙二胺在120℃反应12小时,得到经取代的苯胺,其立即与Boc2O反应得到化合物1-1。快速色谱法后,在DMF中在碳酸钾存在下用BnBr处理化合物1-1,得到关键中间体1-2。使用铁还原中间体1-2,得到化合物1-3。在三乙胺和催化DMAP存在下,将THF中的5-溴-2-甲氧基苯磺酰氯缓慢添加到DCM中的化合物1-3,得到化合物1-4,该化合物与不同的硼酸进行Susuki偶合,之后进行酸助剂Boc脱保护和酰胺偶合,得到中间体1-6。随后对中间体1-6中的苄基脱保护,得到所需产物。
方案2-1.表2中的化合物的合成路线
本公开的化合物可以根据与本文所描述的程序类似的程序来合成。将市售1-氟-3-硝基苯与过量的具有不同烷基链长度的二胺在120℃反应12小时,得到经取代的苯胺,其立即与Boc2O反应得到化合物2-1。快速色谱法后,在DMF中在碳酸钾存在下用BnBr处理化合物2-1,得到关键中间体2-2。使用铁还原中间体2-2,得到化合物2-3。在三乙胺和催化DMAP存在下,将THF中的5-溴-2-甲氧基苯磺酰氯缓慢添加到DCM中的化合物2-3,得到化合物2-4,该化合物与不同的硼酸进行Susuki偶合,之后进行酸助剂Boc脱保护和酰胺偶合,得到中间体2-6。随后对中间体2-6中的苄基脱保护,得到所需产物。
方案2-2.表2中的化合物的合成路线
本公开的化合物可以如下合成:将市售的1-氟-3-硝基苯与过量的二胺和1,4-哌嗪在120℃反应12小时,得到经取代的苯胺,其立即与Boc2O反应得到化合物2-1-3。快速色谱法后,在EtOH中用铁和氯化铵以回流处理化合物2-1-3,得到化合物2-3-3。在三乙胺和催化DMAP存在下,将THF中的5-溴-2-甲氧基苯磺酰氯缓慢添加到DCM中的化合物2-3-3中,得到化合物2-4-3,该化合物与N,N-二甲基苯甲酰胺-3-硼酸进行Susuki偶合,之后进行酸助剂Boc脱保护和酰胺偶合,得到中间体2-5-3。随后对中间体2-5-3中的苄基脱保护,得到所需产物。
这些化合物的合成主要遵循如Nagahara及其同事概述的化合物1(YNT-185)的合成程序。参见,Nagahara,T.;Saitoh,T.;Kutsumura,N.;Irukayama-Tomobe,Y.;Ogawa,Y.;Kuroda,D.;Gouda,H.;Kumagai,H.;Fujii,H.;Yanagisawa,M.;Nagase,H.,Design andSynthesis of Non-Peptide,Selective Orexin Receptor 2Agonists.J.Med.Chem.2015,58(20),7931-7,其对于此类合成教示有帮助并通过引用并入。
方案3.表3中的化合物、表2中的化合物12的合成路线:
本公开的化合物可以按照如针对化合物1(YNT-185)所指出的经修改的程序来合成。因此,将市售1-氟-3-硝基苯与过量乙二胺在120℃反应12小时,得到经取代的苯胺,其立即与Boc2O反应得到化合物3-1。快速色谱法后,用二恶烷中的4N HCl处理化合物3-1,得到关键中间体3-2。在化合物3-2和3-甲基苯甲酸之间进行酰胺偶合,之后使用铁还原,得到化合物3-4。在DIPEA存在下,将THF中的5-溴-2-甲氧基苯磺酰氯缓慢添加到DCM中的化合物3-4中,得到化合物3-5,其中选择性酰化受阻较小的苯胺,产率中等。随后的Miyaura硼化反应得到硼酸频哪醇酯3-6,其很容易与不同的卤代芳香族化合物反应以提供最终产物。
方案4.表4中的化合物的合成路线:
本公开的化合物可以按照与表3中的程序类似的程序来合成。将氟化氨基吡啶与乙二胺在密封管中于150℃反应过夜,得到中间体4-1,其与3-甲基苯甲酸进行酰胺偶合,得到关键中间体4-2。在三乙胺和DMAP存在下,5-溴-2-甲氧基苯磺酰氯与4-2在DMF和THF混合物中反应,以合理的产率实现化合物4-3。随后的Miyaura硼化反应以及Suzuki反应产生了所需的最终产物28、29和30。值得注意的是,Miyaura硼化反应和Suzuki反应可以使用不同的钯催化剂和反应时间在一锅中完成(更多详细信息请参见SI)。在其余目标化合物的后续合成中遵循这一具有必要修改的一般顺序。
方案5.表5中的化合物的合成
本公开的化合物可以按照表2中的程序合成。化合物2-4经历Miyaura硼化,之后与相应的卤代芳香族酰胺进行Suzuki反应,得到所需化合物。
方案6-1.表6中的化合物41和42的合成:
化合物41和42的合成可以经由化合物3-4与5-溴-2-甲氧基苯甲酸酰氯之间的酰胺偶合,之后进行Miyaura硼化和Suzuki反应来完成。
方案6-2.表6中的43和44的合成:
通过3-硼-5-氟吡啶和过量乙二胺反应得到中间体6-A,然后将其与3-甲基苯甲酸偶合来获得中间体6-B。为了合成6-C,在5-溴-3-吡啶醇和N-Boc-乙醇胺之间进行Mitsunobu反应,之后进行后续酸性脱保护和酰胺偶合。经由肼羧硫代酰胺和5-溴邻茴香酸在回流POCl3中之间的反应来获得1,3,4-噻二唑6-3。对6-3进行Miyaura硼化反应,之后与3-溴-N-甲基-N-(4-吡啶基甲基)-苯甲酰胺进行Suzuki反应,得到6-5。可以经由6-5和6-B之间的Buchwald偶合容易地以合理的产率获得化合物43。类似地,6-5与6-E反应产生化合物44。
方案7-1.表7中的47、48、49、50、53、54的合成路线:
表7-1中的化合物的合成按照与之前的路线不同的路线进行。对于化合物47、48、49、50、53和54,通过5-溴-2-甲氧基苯磺酰氯与氢氧化铵在饱和碳酸氢钠的存在下之间的反应获得中间体7-A。将化合物7-A在苯中与各种经取代的甲基丙二酰氯回流,得到化合物7-1,随后使其经历水解和酰胺偶合,得到中间体7-3。对化合物6-4中的Boc进行酸性脱保护,之后与3-甲基苯甲酸进行酰胺偶合,得到化合物7-5。最后,7-5经由Miyaura硼化反应和Suzuki反应转化为最终产物。
方案7-2.表7中的化合物45、46、51、52的合成路线:
化合物51、52、45和46按照类似的程序合成,其中中间体7-E或7-F在如下一锅顺序反应中制备:在3-甲基苯甲酸和N-Boc-乙二胺之间进行酰胺偶合,之后进行酸性处理,得到中间体7-C。化合物7-C和不同的N-Boc氨基酸之间的第二次酰胺偶合得到化合物7-D,使其经历酸性脱保护,得到7-E或7-F。在7-E或7-F与5-溴-2-甲氧基苯磺酰氯之间形成磺酰胺,产生7-7,其通过后续Miyaura硼化反应和Suzuki反应顺利转化为最终产物。
方案8.表8中的化合物55、56、57和58的合成:
为了提高效率,在表8中的化合物的制备中采用了修改的合成方法,其中在磺酰胺官能团处将支架分为两部分。对于右侧部分,首先使用CDI在二氯甲烷中将醇与3-甲基苯甲酸偶联,得到8-A,使其经历SNAr反应,得到8-B。对于左侧部分,7-A经历Miyaura硼化反应,之后进行Suzuki反应,得到中间体8-2。然后,使用tBuXphos作为催化剂,经由Buchwald交叉偶合使化合物8-2与8-B或6-C反应,得到最终产物。
方案9-1.表9中的38和59的合成:
化合物38和59的合成可以容易地通过针对表3中的化合物所述的程序完成。对中间体3-6进行Miyaura硼化,之后进行Suzuki反应,产生化合物38和59。
方案9-2.表9中的60和61的合成:
由7-A和6-B在Buchwald交叉偶合条件下反应,之后进行Miyaura硼化反应和Suzuki反应获得化合物60和61。
实例
合成。所有溶剂和化学物质均为试剂级。除非另有说明,否则所有试剂和溶剂均购自商业供应商并按原样使用。使用预填充柱在Teledyne ISCO CombiFlash Rf系统上进行快速柱色谱法。所使用的溶剂包括己烷、乙酸乙酯(EtOAc)、二氯甲烷、甲醇和氯仿/甲醇/氢氧化铵(80:18:2)(CMA-80)。通过HPLC、TLC、质谱和NMR分析的组合确定化合物的纯度和表征。通过Mel-Temp II仪器(Laboratory Devices Inc.,U.S.)记录熔点。1H和13C NMR光谱在Bruker Avance DPX-300(300MHz)光谱仪上记录,并在氯仿-d、DMSO-d6或甲醇-d4中以四甲基硅烷(TMS)(0.00ppm)或溶剂峰作为内部参考进行测定。化学位移以相对于参考信号的ppm为单位报告,并且偶合常数(J)值以赫兹(Hz)为单位报告。在EMD预涂硅胶60F254板上进行薄层色谱法(TLC),并用UV光或碘染色使斑点可视化。使用Waters Alliance HT/Micromass ZQ系统(ESI)获得低分辨率质谱。如通过HPLC在Agilent 1100系统上使用Agilent Zorbax SB-Phenyl(2.1mm×150mm,5μm)柱,使用5-95%溶剂B以1mL/min进行15分钟梯度洗脱,之后为以95%溶剂B进行10分钟(溶剂A,含有0.1% TFA的水;溶剂B,含有0.1% TFA和5%水的乙腈;在220和280nm处监测吸光度)进行测定,所有测试化合物的纯度均大于95%。
化合物1-1的合成的一般程序:
将3-硝基氟苯(5.0mmol,35.4mmol)和乙二胺(11.8mL,177.2mmol)在密封管中混合,并将反应物加热至120℃过夜。冷却后,在60℃在减压下蒸发挥发物。然后将残余物重新溶解于THF(30mL)和水(30mL)的混合物中,随后添加碳酸钾(14.7g,106.2mmol)和Boc酸酐(19.3g,88.5mmol)。然后将反应物搅拌过夜并通过盐水(150mL)稀释。然后添加乙酸乙酯(150mL),并且分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。6.28g棕色油状物,产率:63%。1H NMR(300MHz,氯仿-d)d 7.51(dd,J=1.60,8.01Hz,1H),7.37(t,J=2.26Hz,1H),7.22-7.31(m,1H),6.87(dd,J=2.07,8.10Hz,1H),4.78-4.94(m,1H),4.56-4.73(m,1H),3.36-3.50(m,2H),3.21-3.34(m,2H),1.38-1.50(m,9H)。
化合物1-2的合成的一般程序:
将化合物1-1(6.28g,22.30mmol)溶解于DMF(110mL)中,之后添加碳酸钾(6.17g,44.65mmol)和苄基溴(3.2mL,26.79mmol)。然后将反应物加热至60℃过夜。添加水(500mL)和乙酸乙酯(200mL),并且分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。5.11g橙色糖浆,产率:62%。1H NMR(300MHz,氯仿-d)d 7.46-7.59(m,2H),7.34-7.40(m,1H),7.26-7.34(m,3H),7.17(d,J=7.16Hz,2H),7.02(d,J=6.22Hz,1H),4.58-4.76(m,3H),3.57-3.72(m,2H),3.37(q,J=6.47Hz,2H),1.35-1.48(m,9H)。
化合物1-3的合成的一般程序:
将化合物1-2(5.11g,13.76mmol)溶解于乙醇和水(55mL/22mL)的混合物中,之后添加氯化铵(7.36g,137.6mmol)和铁粉(5.38g,96.3mmol)。然后将反应物以回流加热3小时。冷却后,添加DCM(100mL)并将混合物经由硅藻土过滤。然后分离有机层并加以干燥。然后在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。4.61g棕色油状物,产率:98%。1H NMR(300MHz,氯仿-d)d 7.08-7.46(m,6H),6.98(t,J=8.19Hz,1H),6.02-6.26(m,2H),4.62-4.77(m,1H),4.40-4.60(m,2H),3.41-3.58(m,2H),3.22-3.39(m,2H),1.55-2.23(m,2H),1.32-1.53(m,9H)。
化合物1-4的合成的一般程序:
在氮气保护下,将化合物1-3(3.52g,10.31mmol)于0℃溶解于无水DCM(50mL)中,添加吡啶(1mL,12.37mmol),之后添加2-甲氧基-5-溴苯磺酰氯(3.24g,11.34mmol)。使反应物升温至室温并搅拌过夜。通过饱和NaHCO3(30mL)猝灭反应并添加DCM(100mL)。分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。5.46g灰白色固体,产率:90%。1H NMR(300MHz,氯仿-d)d 7.87(d,J=2.45Hz,1H),7.55(dd,J=2.45,8.85Hz,1H),7.18-7.35(m,4H),7.10(d,J=6.59Hz,2H),7.00(t,J=8.38Hz,1H),6.90(br.s.,1H),6.78(d,J=8.85Hz,1H),6.49(d,J=8.48Hz,1H),6.39(d,J=4.71Hz,2H),4.59-4.73(m,1H),4.48(s,2H),3.84(s,3H),3.41-3.53(m,2H),3.19-3.34(m,2H),1.36-1.47(m,9H)。
表1中的最终化合物合成的一般程序:
将化合物1-4(1.0当量)、硼酸(1.2当量)、Pd(PPh3)4(0.1当量)和碳酸钾(2.0当量)置于具有高效冷凝器的圆底烧瓶中。然后用氮气冲洗系统并添加1,4-二恶烷/水(4/1,0.1M)的混合物。将反应物回流2小时。冷却后,添加DCM(50ml),并且分离有机层并加以干燥。然后去除溶剂并将残余物溶解于1,4-二恶烷中的4N HCl(10当量)中。将反应物在室温下搅拌2小时,然后在减压下去除溶剂。然后将残余物溶解于DMF(0.1M)中,之后添加2-二甲氨基苯甲酸(1.1当量)、HATU(1.2当量)和DIPEA(1.5当量)。将反应物在室温下搅拌过夜并通过饱和NaHCO3猝灭。添加DCM(50mL),并且分离有机层并加以干燥。在减压下去除溶剂,得到粗产物,然后将其与MeOH(0.1M)中的Pd/C(0.1当量)在氢气气氛(40psi)下混合12小时。过滤反应混合物,并且在减压下去除滤液中的溶剂。通过ISCO纯化残余物,得到纯的所需最终产物。
化合物1:四步产率:45%。1H NMR(300MHz,氯仿-d)δ9.89(br.s.,1H),8.00-8.17(m,2H),7.64(dd,J=1.88,8.67Hz,1H),7.48-7.58(m,2H),7.25-7.46(m,3H),7.10-7.23(m,3H),7.01(d,J=8.67Hz,1H),6.94(t,J=8.01Hz,1H),6.45(br.s.,1H),6.34(dd,J=8.01,14.79Hz,2H),4.33(br.s.,1H),3.94-4.09(m,3H),3.54-3.73(m,2H),3.28(br.s.,2H),2.86-3.20(m,6H),2.42-2.66(m,6H)。
化合物2:四步产率:36%。1H NMR(300MHz,氯仿-d)d 9.67-9.90(m,1H),8.03(d,J=2.07Hz,2H),7.65-7.74(m,1H),7.56-7.65(m,1H),7.36-7.56(m,6H),7.31(s,2H),7.07(s,2H),6.92(br.s.,2H),6.79-6.87(m,1H),4.04(s,3H),3.79(br.s.,4H),3.44(br.s.,4H),3.14(s,6H),1.69(br.s.,4H),1.44-1.59(m,2H)。
化合物3:四步产率:39%。1H NMR(300MHz,氯仿-d)d 9.90(br.s.,1H),7.99-8.15(m,2H),7.59-7.71(m,2H),7.49-7.55(m,1H),7.35-7.47(m,3H),7.10-7.22(m,2H),6.86-7.07(m,3H),6.44(s,1H),6.34(dd,J=4.71,7.54Hz,2H),4.23-4.39(m,1H),4.06(s,3H),3.56-3.72(m,8H),3.42(t,J=6.50Hz,2H),3.29(t,J=5.65Hz,2H),2.82(d,J=8.10Hz,2H),2.56(s,6H),1.94-2.03(m,2H),1.85-1.91(m,2H)。
化合物4:四步产率:32%。1H NMR(300MHz,氯仿-d)d 9.87(br.s.,1H),7.97-8.17(m,3H),7.90(s,1H),7.63-7.75(m,2H),7.57(d,J=7.72Hz,1H),7.33-7.49(m,2H),7.10-7.23(m,2H),7.02(d,J=4.33Hz,1H),6.88-6.98(m,1H),6.51(br.s.,1H),6.44(s,1H),6.32(t,J=6.59Hz,2H),4.30(br.s.,1H),4.05(s,3H),3.60(q,J=5.78Hz,2H),3.43(q,J=6.47Hz,2H),3.26(br.s.,2H),2.76-2.83(m,6H),1.60-1.71(m,2H),0.98(t,J=7.44Hz,3H)。
化合物5:四步产率:29%。1H NMR(300MHz,氯仿-d)d 9.90(br.s.,1H),8.07-8.16(m,1H),7.97-8.06(m,2H),7.65(dd,J=2.26,8.67Hz,1H),7.46-7.54(m,2H),7.41(t,J=7.54Hz,2H),7.30(d,J=7.35Hz,1H),7.12-7.22(m,2H),7.03(d,J=8.67Hz,1H),6.95(t,J=8.01Hz,1H),6.44(s,1H),6.34(d,J=5.09Hz,2H),4.31(t,J=5.27Hz,1H),4.07(s,3H),3.65(q,J=5.84Hz,2H),3.55(br.s.,2H),3.17-3.36(m,4H),2.75-2.99(m,6H),1.26(br.s.,3H),1.11(br.s.,3H)。
化合物6:四步产率:41%。1H NMR(300MHz,氯仿-d)d 9.91(br.s.,1H),8.11(dd,J=1.70,7.91Hz,1H),8.05(d,J=2.26Hz,1H),7.65(dd,J=2.35,8.57Hz,1H),7.37-7.45(m,1H),7.28-7.36(m,3H),7.20(d,J=7.35Hz,2H),7.08-7.16(m,1H),7.02(d,J=8.67Hz,1H),6.94(t,J=8.10Hz,1H),6.89(s,1H),6.45(t,J=2.07Hz,1H),6.33(td,J=2.28,8.05Hz,2H),4.17-4.54(m,1H),4.05-4.09(m,3H),3.64(q,J=5.97Hz,2H),3.29(t,J=5.75Hz,2H),2.87-2.99(m,1H),2.54(s,6H),1.27(d,J=6.97Hz,6H)。
化合物7:四步产率:35%。1H NMR(300MHz,CDCl3)d 9.92(br.s.,1H),8.11(d,J=7.72Hz,1H),8.05(d,J=2.26Hz,1H),7.66(dd,J=2.26,8.48Hz,1H),7.31-7.51(m,1H),7.06-7.24(m,3H),6.84-7.05(m,3H),6.73-6.84(m,2H),6.70(d,J=10.17Hz,1H),6.45(s,1H),6.31(d,J=7.91Hz,2H),3.97-4.09(m,3H),3.53-3.69(m,2H),3.29(t,J=5.75Hz,2H),2.29-3.06(m,12H)。
化合物8:四步产率:32%。1H NMR(300MHz,氯仿-d)d 9.93(br.s.,1H),8.11(dd,J=1.70,7.91Hz,1H),8.04(d,J=2.26Hz,1H),7.64(dd,J=2.26,8.67Hz,1H),7.36-7.46(m,1H),7.07-7.24(m,3H),7.00(d,J=8.67Hz,1H),6.87-6.96(m,2H),6.69-6.77(m,2H),6.65(d,J=8.10Hz,1H),6.45(d,J=2.07Hz,1H),6.27-6.38(m,2H),4.05(s,3H),3.64(q,J=5.97Hz,2H),3.38(q,J=7.16Hz,3H),3.29(t,J=5.75Hz,2H),2.43-2.60(m,6H),1.17(t,J=7.06Hz,6H)。
化合物9:四步产率:33%。1H NMR(300MHz,氯仿-d)d 9.93(br.s.,1H),8.11(dd,J=1.70,7.72Hz,1H),8.03(d,J=2.45Hz,1H),7.63(dd,J=2.35,8.57Hz,1H),7.40(dt,J=1.70,7.72Hz,1H),7.10-7.24(m,3H),7.01(d,J=8.67Hz,1H),6.93(t,J=8.01Hz,1H),6.88(s,1H),6.65-6.73(m,2H),6.61(dd,J=2.26,8.29Hz,1H),6.44(t,J=2.07Hz,1H),6.27-6.36(m,2H),4.05(s,3H),3.64(q,J=5.84Hz,1H),3.16-3.33(m,4H),2.49-2.58(m,6H),1.57-1.64(m,4H),0.93(t,J=7.44Hz,6H)。
化合物10:四步产率:39%。1H NMR(300MHz,氯仿-d)d 9.77-10.00(m,1H),8.11(dd,J=1.60,7.82Hz,1H),8.04(d,J=2.26Hz,1H),7.65(dd,J=2.35,8.57Hz,1H),7.47(s,1H),7.39(dd,J=1.70,7.54Hz,1H),7.32-7.37(m,1H),7.28-7.31(m,1H),7.26(s,1H),7.15-7.22(m,1H),7.12(d,J=8.10Hz,1H),7.03(d,J=8.67Hz,1H),6.88-6.99(m,2H),6.43-6.49(m,1H),6.27-6.38(m,2H),4.06(s,3H),3.57-3.70(m,2H),3.29(t,J=5.84Hz,2H),2.42-2.60(m,6H),1.29-1.38(m,9H)。
化合物11:四步产率:31%。1H NMR(300MHz,氯仿-d)d 9.91(br.s.,1H),8.11(dd,J=1.70,7.91Hz,1H),8.04(d,J=2.45Hz,1H),7.70(s,1H),7.61-7.68(m,2H),7.55-7.60(m,1H),7.52(d,J=7.54Hz,1H),7.42(dt,J=1.79,7.68Hz,1H),7.20(d,J=7.72Hz,1H),7.14(d,J=8.10Hz,1H),7.06(d,J=8.67Hz,1H),6.89-6.99(m,2H),6.39-6.49(m,1H),6.34(d,J=8.10Hz,2H),4.21-4.57(m,1H),4.06-4.13(m,3H),3.65(q,J=5.97Hz,2H),3.29(t,J=5.75Hz,2H),2.48-2.62(m,6H)。
化合物2-1的合成的一般程序:
将3-硝基氟苯(1当量)和乙二胺(5当量)在密封管中混合,并将反应物加热至120℃过夜。冷却后,在60℃在减压下蒸发挥发物。然后将残余物重新溶解于THF(30mL)和水(30mL)的混合物中,随后添加碳酸钾(3.0当量)和Boc酸酐(2.5当量)。然后将反应物搅拌过夜并通过盐水(150mL)稀释。然后添加乙酸乙酯(150mL),并且分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。
化合物2-1-1:产率:72%。1H NMR(300MHz,氯仿-d)d 7.50(dd,J=1.60,8.01Hz,1H),7.39(t,J=2.26Hz,1H),7.25-7.30(m,1H),6.88(dd,J=2.07,8.10Hz,1H),4.56-4.69(m,1H),3.25(dq,J=3.58,6.34Hz,4H),2.72(d,J=7.16Hz,1H),1.79(t,J=6.50Hz,2H),1.45(s,9H)。
化合物2-1-2:产率:30%。1H NMR(300MHz,氯仿-d)d 7.47-7.52(m,2H),7.35(t,J=2.26Hz,2H),7.24-7.29(m,1H),6.87(dd,J=1.88,8.10Hz,1H),4.78-4.87(m,1H),4.46-4.59(m,1H),3.92-4.03(m,1H),3.21(s,2H),3.06-3.15(m,1H),2.74-2.92(m,1H),1.40-1.47(m,9H),1.24-1.28(m,3H)。
化合物2-2的合成的一般程序:
将化合物2-1(1当量)溶解于DMF(0.2M)中,之后添加碳酸钾(2当量)和苄基溴(1.2当量)。然后将反应物加热至60℃过夜。添加水和乙酸乙酯,并且分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。
化合物2-2-1:产率:84%。1H NMR(300MHz,氯仿-d)d 7.46-7.54(m,2H),7.28-7.39(m,3H),7.25-7.27(m,1H),7.18(d,J=6.78Hz,2H),6.86-6.96(m,1H),4.60(s,2H),3.45-3.58(m,1H),3.21(d,J=6.40Hz,1H),1.82-1.94(m,2H),1.44(s,9H)。
化合物2-2-2:产率:81%。1H NMR(300MHz,氯仿-d)d 7.58(br.s.,1H),7.48(dd,J=1.51,7.91Hz,1H),7.37(d,J=4.33Hz,1H),7.25-7.32(m,4H),7.17(s,1H),6.97-7.12(m,1H),4.59-4.77(m,3H),4.27-4.50(m,1H),4.09(d,J=6.97Hz,1H),3.21-3.82(m,2H),1.31-1.46(m,9H)。
化合物2-3的合成的一般程序:
将化合物2-2(1当量)溶解于乙醇和水的混合物(5:2,0.2M)中,之后添加氯化铵(10当量)和铁粉(7当量)。然后将反应物以回流加热3小时。冷却后,添加DCM(100mL)并将混合物经由硅藻土过滤。然后分离有机层并加以干燥。然后在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。
化合物2-3-1:产率:92%。1H NMR(300MHz,氯仿-d)d 7.27-7.40(m,2H),7.18-7.25(m,3H),6.97(t,J=8.01Hz,1H),5.98-6.21(m,3H),4.49(m,3H),3.29-3.45(m,2H),3.15(d,J=6.22Hz,2H),1.74-1.88(m,2H),1.43(s,9H)。
化合物2-3-2:产率:92%。1H NMR(300MHz,氯仿-d)d 7.37(d,J=4.33Hz,1H),7.26-7.32(m,2H),7.18(t,J=6.69Hz,2H),6.96(t,J=8.10Hz,1H),6.23(dd,J=2.45,8.29Hz,1H),6.12-6.19(m,1H),6.06(dd,J=1.51,7.72Hz,1H),4.49-4.73(m,2H),4.35-4.48(m,1H),3.95-4.09(m,1H),3.45-3.69(m,2H),3.08-3.22(m,1H),1.29-1.48(m,9H),1.18(d,J=6.78Hz,3H)。
化合物2-4的合成的一般程序:
在氮气保护下,将化合物2-3(1当量)于0℃溶解于无水DCM(0.2当量)中,添加吡啶(1.2当量),之后添加2-甲氧基-5-溴苯磺酰氯(1.1当量)。使反应物升温至室温并搅拌过夜。通过饱和NaHCO3(10mL)猝灭反应并添加DCM(30mL)。分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。
化合物2-4-1:产率:85%。1H NMR(300MHz,氯仿-d)d 7.88(d,J=2.64Hz,1H),7.55(dd,J=2.64,8.85Hz,1H),7.28(d,J=7.54Hz,2H),7.23(s,1H),7.11(d,J=6.59Hz,2H),6.97(d,J=8.10Hz,1H),6.92(s,1H),6.79(d,J=8.85Hz,1H),6.37-6.46(m,2H),6.33(d,J=8.67Hz,1H),4.54-4.64(m,1H),4.44(s,2H),3.85(s,3H),3.30-3.42(m,2H),3.15(d,J=6.22Hz,2H),1.70-1.83(m,2H),1.44(s,9H)。
化合物2-4-2:产率:83%。1H NMR(300MHz,氯仿-d)d 7.86(d,J=2.64Hz,1H),7.54(dd,J=2.45,8.85Hz,1H),7.25-7.30(m,3H),7.07(d,J=6.59Hz,2H),6.99(t,J=8.10Hz,1H),6.90(br.s.,1H),6.70-6.83(m,1H),6.52(d,J=8.48Hz,1H),6.34-6.46(m,2H),4.42-4.64(m,2H),4.33(d,J=12.06Hz,1H),3.90-4.05(m,1H),3.79-3.88(m,3H),3.58(br.s.,1H),3.18(br.s.,1H),1.37(s,9H),1.16(d,J=6.59Hz,2H)。
表2中的最终化合物(化合物13、14、15和16)的合成的一般程序:
将化合物2-4(1.0当量)、硼酸(1.2当量)、Pd(PPh3)4(0.1当量)和碳酸钾(2.0当量)置于具有高效冷凝器的圆底烧瓶中。然后用氮气冲洗系统并添加1,4-二恶烷/水(4/1,0.1M)的混合物。将反应物回流2小时。冷却后,添加DCM(50ml),并且分离有机层并加以干燥。然后去除溶剂并将残余物溶解于1,4-二恶烷中的4N HCl(10当量)中。将反应物在室温下搅拌2小时,然后在减压下去除溶剂。然后将残余物溶解于DMF(0.1M)中,之后添加相应的苯甲酸(1.1当量)、HATU(1.2当量)和DIPEA(1.5当量)。将反应物在室温下搅拌过夜并通过饱和NaHCO3猝灭。添加DCM(50mL),并且分离有机层并加以干燥。在减压下去除溶剂,得到粗产物,然后将其与MeOH(0.1M)中的Pd/C(0.1当量)在氢气气氛(40psi)下混合12小时。过滤反应混合物,并且在减压下去除滤液中的溶剂。通过ISCO纯化残余物,得到纯的所需最终产物。
化合物12:1H NMR(300MHz,氯仿-d)δ9.89(br.s.,1H),8.00-8.17(m,2H),7.64(dd,J=1.88,8.67Hz,1H),7.48-7.58(m,2H),7.25-7.46(m,3H),7.10-7.23(m,3H),7.01(d,J=8.67Hz,1H),6.94(t,J=8.01Hz,1H),6.45(br.s.,1H),6.34(dd,J=8.01,14.79Hz,2H),4.33(br.s.,1H),3.94-4.09(m,3H),3.54-3.73(m,2H),3.28(br.s.,2H),2.86-3.20(m,6H),2.42-2.66(m,6H)。
化合物13:四步产率:29%。1H NMR(300MHz,氯仿-d)δ9.71(br.s.,1H),7.97-8.15(m,2H),7.62-7.80(m,2H),7.50-7.57(m,2H),7.30-7.48(m,4H),7.14-7.22(m,2H),7.02-7.10(m,1H),6.88-6.97(m,2H),6.39-6.53(m,1H),6.20-6.37(m,2H),4.03-4.10(m,3H),3.31-3.54(m,2H),2.78-3.21(m,12H),2.38-2.64(m,2H),1.74-1.90(m,2H)。
化合物14:四步产率:22%。1H NMR(300MHz,氯仿-d)δ9.70-9.79(m,1H),8.01-8.11(m,2H),7.64(dd,J=2.45,8.67Hz,1H),7.49-7.56(m,2H),7.38-7.47(m,2H),7.30-7.37(m,1H),7.11-7.23(m,2H),6.97-7.06(m,2H),6.93(t,J=8.01Hz,1H),6.42(t,J=1.98Hz,1H),6.25-6.38(m,2H),4.35-4.46(m,1H),4.06(s,3H),3.13-3.20(m,2H),2.85-3.06(m,7H),2.80(s,6H),1.28(d,J=6.78Hz,3H)。
化合物15:四步产率:32%。1H NMR(300MHz,氯仿-d)δ8.08(d,J=2.45Hz,1H),7.71-8.04(m,1H),7.67(dd,J=2.35,8.57Hz,1H),7.57(s,1H),7.52(td,J=1.53,3.53Hz,3H),7.29-7.45(m,3H),7.04(d,J=8.85Hz,2H),6.85-6.98(m,2H),6.48(d,J=1.88Hz,1H),6.25-6.35(m,2H),4.13(s,1H),4.02-4.08(m,4H),3.36(q,J=6.22Hz,2H),2.76-3.23(m,14H),2.35(s,3H),1.69-1.74(m,3H)。
化合物16:四步产率:19%。1H NMR(300MHz,氯仿-d)d 8.09(d,J=2.45Hz,1H),8.01(s,1H),7.65(dd,J=2.45,8.67Hz,1H),7.48-7.59(m,4H),7.41(t,J=7.72Hz,1H),7.30-7.35(m,1H),7.24(s,1H),7.11(s,1H),7.01(d,J=8.67Hz,1H),6.90(t,J=8.01Hz,1H),6.72(d,J=8.10Hz,1H),6.46(t,J=1.98Hz,1H),6.29(dt,J=1.79,7.86Hz,2H),4.39-4.47(m,1H),4.02(s,3H),3.00(s,2H),2.80(s,6H),2.32(s,3H),1.25(d,J=6.78Hz,3H)。
化合物2-1-3的合成的一般程序:
将3-硝基氟苯(5.0mmol,35.4mmol)和哌嗪(9.16g,106.31mmol)在密封管中混合,并将反应物加热至120℃过夜。冷却后,在60℃在减压下蒸发挥发物。然后将残余物重新溶解于THF(30mL)和水(30mL)的混合物中,随后添加碳酸钾(14.7g,106.2mmol)和Boc酸酐(19.3g,88.5mmol)。然后将反应物搅拌过夜并通过盐水(150mL)稀释。然后添加乙酸乙酯(150mL),并且分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。5.30g黄色固体,产率:49%。化合物2-1-3:1H NMR(300MHz,氯仿-d)d 7.64-7.76(m,2H),7.40(t,J=8.10Hz,1H),7.16-7.24(m,1H),3.54-3.67(m,2H),3.19-3.30(m,4H),1.49(s,9H)。
化合物2-3-3的合成的一般程序:
将化合物2-1-3(5.35g,17.41mmol)溶解于乙醇和水(70mL/30mL)的混合物中,之后添加氯化铵(9.31g,174.1mmol)和铁粉(6.81g,121.8mmol)。然后将反应物以回流加热3小时。冷却后,添加DCM(100mL)并将混合物经由硅藻土过滤。然后分离有机层并加以干燥。然后在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。4.15g棕色油状物,产率:86%。化合物2-3-3:1H NMR(300MHz,氯仿-d)d 6.98-7.11(m,1H),6.32-6.39(m,1H),6.20-6.30(m,2H),3.58-3.85(m,2H),3.49-3.58(m,4H),3.07-3.14(m,4H),1.47-1.50(m,9H)。
化合物2-4-3的合成的一般程序:
在氮气保护下,将化合物2-3-3(3.04g,10.96mmol)于0℃溶解于无水DCM(55mL)中,添加吡啶(1.06mL,13.15mmol),之后添加2-甲氧基-5-溴苯磺酰氯(3.44g,12.06mmol)。使反应物升温至室温并搅拌过夜。通过饱和NaHCO3(30mL)猝灭反应并添加DCM(100mL)。分离有机层并加以干燥。在减压下去除溶剂,并通过ISCO纯化残余物,得到纯的所需产物。4.61g棕色固体,产率:80%。化合物2-4-3:1H NMR(300MHz,氯仿-d)d 7.94(d,J=2.45Hz,1H),7.58(dd,J=2.54,8.76Hz,1H),7.26(s,3H),7.07(t,J=8.10Hz,1H),6.82-6.93(m,2H),6.69-6.76(m,1H),6.64(d,J=8.29Hz,1H),6.41(d,J=7.91Hz,1H),4.01(s,3H),3.48-3.62(m,4H),3.00-3.16(m,4H),1.48(s,9H)。
表2中的最终化合物(化合物17和18)的合成的一般程序:
将化合物2-4-3(1.0当量)、硼酸(1.2当量)、Pd(PPh3)4(0.1当量)和碳酸钾(2.0当量)置于具有高效冷凝器的圆底烧瓶中。然后用氮气冲洗系统并添加1,4-二恶烷/水(4/1,0.1M)的混合物。将反应物回流2小时。冷却后,添加DCM(50ml),并且分离有机层并加以干燥。然后去除溶剂并将残余物溶解于1,4-二恶烷中的4N HCl(10当量)中。将反应物在室温下搅拌2小时,然后在减压下去除溶剂。然后将残余物溶解于DMF(0.1M)中,之后添加相应的苯甲酸(1.1当量)、HATU(1.2当量)和DIPEA(1.5当量)。将反应物在室温下搅拌过夜并通过饱和NaHCO3猝灭。添加DCM(50mL),并且分离有机层并加以干燥。在减压下去除溶剂,得到粗产物,将其通过ISCO纯化,得到纯的所需产物。
化合物17:四步产率:36%。1H NMR(300MHz,CDCl3)δ8.04(d,J=2.07Hz,1H),8.03(d,J1=9.0Hz,J2=177Hz,1H),7.72(d,J=8.67Hz,1H),7.52(d,J=12.06Hz,2H),7.42(t,J=7.54Hz,1H),7.30-7.37(m,2H),7.22(d,J=7.16Hz,1H),7.02-7.12(m,2H),6.89-6.99(m,3H),6.77(s,1H),6.62(d,J=8.10Hz,1H),6.48(d,J=7.54Hz,1H),4.08(s,3H),3.93(br.s.,1H),3.84(br.s.,1H),2.94-3.22(m,10H),2.73-2.86(m,8H)。
化合物18:四步产率:41%。1H NMR(300MHz,氯仿-d)δ8.04(d,J=2.26Hz,1H),7.71(dd,J=2.35,8.57Hz,1H),7.48-7.60(m,2H),7.42(t,J=7.54Hz,1H),7.31-7.37(m,1H),7.21-7.30(m,4H),7.17(d,J=7.16Hz,1H),7.08(d,J=8.85Hz,2H),6.97-7.04(m,1H),6.78(s,1H),6.62(d,J=8.29Hz,1H),6.49(d,J=7.72Hz,1H),4.07(s,3H),3.83(br.s.,2H),3.54(br.s.,2H),2.90-3.25(m,10H),2.38(s,3H)。
化合物3-2的合成。
将1-氟-3-硝基苯(14.10g,100mmol)与乙二胺(75mL)混合,并将混合物加热至120℃过夜。然后将反应物冷却至室温并添加甲苯(100mL)。然后在减压下去除挥发物,并将残余物重新溶解于乙酸乙酯(100mL)和饱和碳酸氢钠(100mL)的混合物中。添加二碳酸二叔丁酯(32.7g,150mmol),然后将反应物搅拌过夜。将有机层分离并通过无水MgSO4干燥。然后通过减压去除溶剂并通过ISCO纯化残余物,得到3-1,将其溶解于最少量的乙酸乙酯中并添加于二恶烷中的4N HCl(50mL)。然后将混合物搅拌2小时直至没有气泡释放。添加己烷(100mL)以沉淀任何固体并过滤悬浮液。将所收集的固体用二乙醚冲洗并在真空中干燥过夜,得到纯的所需产物。17g棕褐色固体,产率:78%。1H NMR(300MHz,DMSO-d6)d 8.12(br.s.,4H),7.29-7.50(m,3H),6.91-7.17(m,1H),3.38(t,J=6.40Hz,2H),2.87-3.06(m,2H)。
化合物3-4的合成。
将3-甲基苯甲酸(2.73g,20mmol)和1,1′-羰基二咪唑(3.25g,20mmol)在DCM中混合并搅拌15分钟。然后一次性添加化合物3-2(2.62g,10mmol),之后添加DIPEA(10.5mL,60mmol)。然后通过TLC监测反应。完成后,添加饱和NaHCO3以猝灭反应。然后分离有机层并通过无水MgSO4干燥。在减压下去除溶剂,然后将残余物重新溶解于EtOH(80mL)和水(30mL)的混合物中,之后添加氯化铵(10.7g,0.2mol)和铁粉(7.84g,0.14mol)。然后使反应物回流2小时。冷却至室温后,过滤反应混合物并浓缩滤液。将乙酸乙酯(200mL)和盐水(200mL)添加到残余物中,并且分离有机层并加以干燥。在减压下去除溶剂并对残余物进行ISCO,得到纯的所需化合物。3.33g棕色油状物,产率:62%。1H NMR(300MHz,d6-DMSO)d 8.56(m,2H),7.54-8.22(m,3H),7.10-7.50(m,2H),7.02(br.s,2H),3.60-3.20(m,4H),2.35(s,3H)。
化合物3-5的合成。
将化合物3-4(3.33g,12.4mmol)溶解于DCM(100mL)中并添加三乙胺(3.5mL,24.7mmol),之后添加催化DMAP(302mg,2.47mmol)。然后将混合物冷却至0℃,并经20分钟的时间段缓慢添加THF(10mL)中的5-溴-2-甲氧基苯磺酰氯(3.86g,13.0mmol)。使反应物升温至室温并搅拌过夜。将反应物通过饱和NaHCO3(50mL)猝灭并添加乙酸乙酯(100mL)。分离有机层并加以干燥。在减压下去除溶剂并对残余物进行ISCO,得到纯的所需化合物。4.84g浅黄色泡沫,产率:76%。1H NMR(300MHz,氯仿-d)d 7.94(d,J=2.45Hz,1H),7.47-7.60(m,3H),7.29-7.36(m,2H),6.97(t,J=8.01Hz,1H),6.80-6.92(m,2H),6.45(d,J=2.07Hz,2H),6.33-6.40(m,1H),6.29(d,J=9.23Hz,1H),4.21(br.s.,1H),4.00(s,3H),3.66(q,J=5.90Hz,2H),3.32(t,J=5.65Hz,2H),2.39(s,3H)。
Miyaura硼化反应的一般程序:
将卤代芳香族化合物(1.0当量)溶解于1,4-二恶烷(0.1M)中,并且添加双(频那醇)二硼(1.5当量),之后添加PdCl2(dppf)(0.1当量)和KOAc(2当量)。然后将反应物加热至90℃过夜。冷却至室温后,将反应混合物通过硅藻土过滤,并将滤液在减压下浓缩。对残余物进行ISCO,得到所需产物。
Suzuki偶合反应的一般程序:
将硼酸频哪醇酯(1.0当量)、化合物2(1.0当量)和K2CO3(2.0当量)溶解于1,4-二恶烷和水的混合物(v/v=4:1,0.04M)中。将混合物脱气并用氮气吹扫三次。然后添加Pd(PPh3)4(0.1当量),并且将反应物在90℃搅拌1小时。然后将反应物冷却并用盐水猝灭。然后添加乙酸乙酯,并且分离有机层并加以干燥。在减压下去除溶剂并对残余物进行ISCO,得到纯的所需产物。
连续Miyaura硼化和Suzuki偶合反应的一般程序:
将卤代芳香族化合物(1.0当量)溶解于1,4-二恶烷(0.1M)中,并且添加双(频那醇)二硼(1.5当量),之后添加PdCl2(dppf)(0.1当量)和KOAc(2当量)。然后将反应物加热到90℃持续6小时。添加脱气水(1,4-二恶烷/水:v/v=4:1),之后添加K2CO3(2.0当量)和Pd(PPh3)4(0.1当量)。然后将反应物在90℃继续搅拌1小时。然后将反应物冷却并用盐水猝灭。然后添加乙酸乙酯,并且分离有机层并加以干燥。在减压下去除溶剂并对残余物进行ISCO,得到纯的所需产物。
化合物3-6的合成。使用化合物3-5作为起始材料,根据Miyaura硼化反应的一般程序进行制备,产率:87%。1H NMR(300MHz,氯仿-d)d 8.29(d,J=1.51Hz,1H),8.15-8.27(m,1H),7.85-7.95(m,1H),7.45-7.65(m,2H),7.28-7.34(m,2H),6.89-7.00(m,3H),6.84(s,1H),6.20-6.53(m,3H),4.10-4.22(m,1H),4.03(s,3H),3.64(d,J=6.03Hz,2H),3.33(br.s.,2H),2.34-2.41(m,3H),1.26-1.31(m,12H)。
使用化合物3-6和相应的卤代芳香族酰胺作为起始材料,根据Suzuki偶合反应的一般程序制备表2中的化合物12、表3中的19-27和表5中的31-40:
化合物12,产率:78%。1H NMR(300MHz,氯仿-d)d 8.12(d,J=2.26Hz,1H),7.69(dd,J=2.45,8.67Hz,1H),7.57(br.s.,3H),7.46-7.54(m,2H),7.42(t,J=7.54Hz,1H),7.30-7.35(m,1H),7.23(s,1H),7.14(br.s.,1H),7.04(d,J=8.85Hz,1H),6.93(t,J=8.01Hz,1H),6.85(s,1H),6.42-6.49(m,1H),6.32(d,J=8.10Hz,1H),6.23(d,J=7.72Hz,1H),4.37-4.50(m,1H),4.04(s,3H),3.61(q,J=5.97Hz,2H),3.21(t,J=5.56Hz,2H),2.99-3.16(m,6H),2.34(s,3H)。
化合物19,产率:78%。1H NMR(300MHz,氯仿-d)d 8.64(d,J=4.90Hz,1H),8.43(d,J=2.45Hz,1H),8.25(dd,J=2.35,8.76Hz,1H),7.67(s,1H),7.55(s,1H),7.47(d,J=6.59Hz,1H),7.33-7.20(m,2H),7.15(dd,J=1.41,4.99Hz,1H),7.08(d,J=8.85Hz,1H),6.91-6.98(m,2H),6.84-6.90(m,1H),6.46-6.52(m,1H),6.31(d,J=8.10Hz,1H),6.23(d,J=9.04Hz,1H),4.27-4.44(m,1H),4.07(s,3H),3.61(d,J=5.46Hz,2H),3.25(t,J=5.56Hz,2H),3.15(s,3H),2.98(s,3H),2.35(s,3H)。
化合物20,产率:80%。1H NMR(300MHz,氯仿-d)d 8.78(d,J=2.26Hz,1H),8.60(d,J=1.88Hz,1H),8.08(d,J=2.45Hz,1H),7.89(t,J=2.17Hz,1H),7.70(dd,J=2.45,8.67Hz,1H),7.57(s,1H),7.50(d,J=6.41Hz,1H),7.09(d,J=8.67Hz,1H),6.95-7.03(m,1H),6.86-6.95(m,1H),6.46-6.51(m,1H),6.34(d,J=8.10Hz,1H),6.25(d,J=7.72Hz,1H),4.07(s,3H),3.60-3.70(m,2H),3.26(t,J=5.75Hz,2H),3.15(s,3H),3.06(s,3H),2.35(s,3H)。
化合物21,产率:83%。1H NMR(300MHz,氯仿-d)d 8.59(d,J=5.27Hz,1H),8.19(d,J=2.26Hz,1H),7.77(d,J=2.07Hz,1H),7.74(d,J=2.45Hz,1H),7.58(s,1H),7.51(d,J=6.41Hz,1H),7.47(dd,J=1.88,5.27Hz,1H),7.08(d,J=8.67Hz,1H),6.92(t,J=8.01Hz,1H),6.86(s,1H),6.48(s,1H),6.32(d,J=8.29Hz,1H),6.20(d,J=9.23Hz,1H),4.43-4.59(m,1H),4.07(s,3H),3.61-3.71(m,2H),3.24(t,J=5.56Hz,2H),3.15(d,J=3.58Hz,6H),2.34(s,3H)。
化合物22,产率:85%。1H NMR(300MHz,氯仿-d)d 8.58(d,J=2.45Hz,1H),8.15(d,J=8.67Hz,1H),7.77(d,J=7.72Hz,1H),7.70(s,1H),7.56(s,1H),7.48(d,J=6.41Hz,2H),7.06(d,J=8.85Hz,1H),6.86-6.98(m,1H),6.82(s,2H),6.46(s,1H),6.21-6.35(m,2H),4.28-4.44(m,1H),4.06(s,3H),3.57(d,J=5.65Hz,2H),3.22(d,J=5.46Hz,2H),3.17(s,3H),3.11(s,3H),2.37(s,3H)。
化合物23,产率:68%。1H NMR(氯仿-d,300MHz):d=8.01-8.04(m,1H),7.62-7.68(m,1H),7.55(d,J=1.5Hz,2H),7.47-7.52(m,1H),7.45(s,1H),7.30(s,2H),7.00-7.05(m,1H),6.91-6.99(m,1H),6.79-6.83(m,1H),6.58-6.66(m,1H),6.46-6.50(m,1H),6.31-6.37(m,1H),6.24-6.30(m,1H),4.21-4.34(m,1H),4.05(s,3H),3.25-3.33(m,2H),3.10-3.24(m,2H),2.38ppm(s,3H)。
化合物24,产率:88%。1H NMR(300MHz,氯仿-d)d 8.08(d,J=2.26Hz,1H),7.64(dd,J1=2.35Hz,J2=8.57Hz,1H),7.56(s,1H),7.46-7.52(m,1H),7.35(s,1H),7.33-7.34(m,1H),6.99(d,J=8.67Hz,1H),6.92(d,J=8.29Hz,1H),6.83-6.88(m,1H),6.81(s,1H),6.48(s,1H),6.30-6.37(m,1H),6.21-6.27(m,1H),4.34-4.47(m,1H),4.04(s,3H),3.64(d,J=5.84Hz,2H),3.26(s,2H),3.11(br.s.,6H),2.37(s,3H)。
化合物25,产率:70%。1H NMR(300MHz,氯仿-d)d 8.31(d,J=2.26Hz,1H),7.99-8.07(m,1H),7.63-7.73(m,1H),7.57(s,1H),7.51-7.56(m,1H),7.45-7.50(m,2H),7.28-7.33(m,2H),7.06(d,J=8.67Hz,1H),6.95(m,1H),6.84(s,1H),6.48(s,1H),6.37-6.43(m,1H),4.08(s,3H),3.57-3.67(m,5H),3.24-3.33(m,2H),3.17(s,3H),2.38(s,3H)。
化合物26,产率:63%。1H NMR(300MHz,氯仿-d)d 8.03(d,J=2.26Hz,1H),7.46-7.59(m,5H),7.28-7.34(m,2H),6.91-7.01(m,2H),6.73-6.85(m,2H),6.50-6.58(m,1H),6.44(s,1H),6.24-6.38(m,2H),4.13-4.32(m,1H),4.04(s,3H),3.65(d,J=5.84Hz,2H),3.29(s,2H),3.14(s,3H),3.04(s,3H),2.39(s,3H)。
化合物27,产率:67%。1H NMR(300MHz,氯仿-d)d 7.64(d,J=2.26Hz,1H),7.58(s,1H),7.52(br.s.,1H),7.28-7.36(m,3H),6.95(t,J=8.01Hz,1H),6.89(d,J=8.29Hz,1H),6.83(s,1H),6.67-6.75(m,1H),6.43(s,1H),6.35(s,1H),6.28(d,J=7.54Hz,1H),3.98(s,3H),3.64(d,J=5.65Hz,2H),3.30(t,J=5.75Hz,2H),2.81-2.92(m,8H),2.49-2.57(m,2H),2.39(s,3H)。
化合物31,产率:72%。1H NMR(300MHz,氯仿-d)d 8.12(d,J=2.26Hz,1H),7.69(dd,J1=2.35Hz,J2=8.57Hz,1H),7.58(br.s.,3H),7.53(s,2H),7.38-7.47(m,2H),7.30-7.37(m,2H),7.15(br.s.,2H),7.04(d,J=8.67Hz,1H),6.93(t,J=8.01Hz,2H),6.46(s,1H),6.32(d,J=7.91Hz,1H),6.23(d,J=9.23Hz,1H),4.04(s,3H),3.65-3.74(m,1H),3.55-3.64(m,2H),3.31-3.42(m,1H),3.17-3.26(m,2H),3.11(br.s.,1H),3.04(br.s.,2H),2.61-2.71(m,1H),2.41-2.50(m,1H),2.34(s,6H),2.08(br.s.,3H)。
化合物32,产率:75%。1H NMR(300MHz,氯仿-d)d 8.14(d,J=2.45Hz,1H),8.02(s,1H),7.78-7.84(m,1H),7.66-7.73(m,2H),7.63(s,1H),7.55(br.s.,2H),7.49(d,J=3.20Hz,2H),7.20(br.s.,2H),7.04(d,J=8.67Hz,1H),6.93(t,J=7.91Hz,2H),6.55(s,1H),6.31(d,J=8.10Hz,1H),6.23(d,J=6.22Hz,1H),4.03(s,3H),3.65(d,J=5.65Hz,2H),3.47-3.58(m,2H),3.26(br.s.,2H),2.57(t,J=5.75Hz,1H),2.52(d,J=6.03Hz,1H),2.31(s,6H),2.25(s,3H)。
化合物33,产率:78%。1H NMR(300MHz,氯仿-d)d 8.36-8.40(m,1H),8.24-8.33(m,2H),8.18-8.22(m,1H),7.70-7.76(m,1H),7.59-7.62(m,1H),7.56-7.59(m,1H),7.53-7.56(m,1H),7.50-7.52(m,1H),7.47-7.50(m,1H),7.44-7.47(m,1H),7.30-7.39(m,2H),7.21(s,1H),7.18(s,1H),7.02-7.07(m,1H),6.89-6.96(m,1H),6.79-6.83(m,1H),6.49-6.58(m,2H),6.27-6.33(m,1H),6.14-6.22(m,1H),4.04(s,3H),3.90(s,3H),3.63-3.73(m,2H),3.23-3.35(m,2H),2.28(s,3H)。
化合物34,3步产率:56%。1H NMR(300MHz,氯仿-d)d 8.13(br.s.,1H),7.48-7.75(m,5H),7.30-7.46(m,6H),6.99-7.21(m,3H),6.93(t,J=7.91Hz,1H),6.85(s,1H),6.45(s,1H),6.32(d,J=8.10Hz,1H),6.23(d,J=7.72Hz,1H),4.49-4.82(m,2H),4.04(s,3H),3.58(br.s.,2H),3.21(br.s.,2H),2.76-3.11(m,3H),2.33(br.s.,3H)。
化合物35,产率:84%。1H NMR(300MHz,氯仿-d)d 8.56-8.69(m,1H),8.00-8.17(m,1H),7.67-7.77(m,2H),7.47-7.66(m,5H),7.42(br.s.,3H),7.01-7.13(m,2H),6.93(t,J=8.01Hz,1H),6.84(br.s.,1H),6.46(s,1H),6.32(d,J=8.10Hz,1H),6.17-6.27(m,1H),4.88(s,1H),4.62(s,1H),4.04(br.s.,3H),3.59(br.s.,2H),3.21(br.s.,2H),3.09(d,J=15.82Hz,3H),2.34(br.s.,3H)。
化合物36,产率:62%。1H NMR(300MHz,氯仿-d)d 8.52-8.60(m,1H),8.14(d,J=2.45Hz,1H),8.04(s,1H),7.78(d,J=7.72Hz,2H),7.61-7.72(m,3H),7.44-7.56(m,3H),7.06-7.14(m,1H),6.98-7.05(m,2H),6.88-6.98(m,1H),6.55(s,1H),6.27-6.36(m,1H),6.19-6.26(m,1H),4.72(d,J=4.90Hz,2H),4.25-4.48(m,1H),4.00(s,3H),3.65(d,J=5.46Hz,2H),3.29(br.s.,2H),2.30(s,3H)。
化合物37,产率:68%。1H NMR(300MHz,甲醇-d4)d 8.40-8.62(m,1H),7.86-8.07(m,1H),7.31(s,12H),7.10-7.23(m,1H),6.84-6.92(m,1H),6.45-6.51(m,1H),6.35-6.42(m,1H),6.24-6.35(m,1H),3.99(s,3H),3.40-3.48(m,2H),3.21(m,2H),2.94-3.08(m,3H),2.36(s,3H)。
化合物38(RTIOX-43),产率:80%。1H NMR(300MHz,甲醇-d4)d 8.43-8.57(m,2H),7.91-8.09(m,1H),7.62-7.86(m,2H),7.49-7.60(m,3H),7.37-7.47(m,2H),7.23-7.37(m,3H),7.10-7.23(m,1H),6.83-6.94(m,1H),6.43-6.52(m,1H),6.35-6.42(m,1H),6.26-6.35(m,1H),3.92-4.02(m,3H),3.36-3.49(m,2H),3.15-3.24(m,3H),2.88-3.13(m,4H),2.36(s,3H)
化合物39,产率:85%。1H NMR(300MHz,甲醇-d4)d 8.25(dd,J1=159.0Hz,J2=3.0Hz,1H),7.95(d,J=33.0Hz,1H),7.73–7.84(m,1H),7.58(dd,J1=63.0Hz,J2=9.0Hz,1H),7.18–7.62(m,9H),7.03(t,J=6.0Hz,1H),6.91(t,J=6.0Hz,1H),6.48-6.83(m,2H),6.42(t,J=9.0Hz,1H),6.26-6.36(m,1H),4.03(d,J=12.0Hz,3H),3.91(t,J=6.0Hz,1H),3.71(t,J=6.0Hz,1H),3.35-3.58(m,2H),3.08-3025(m,7H),2.37(s,3H)。
化合物40,产率:70%。1H NMR(300MHz,氯仿-d)d 8.55(br.s.,1H),8.25-8.36(m,1H),7.95-8.11(m,1H),7.30-7.75(m,6H),6.68-7.22(m,8H),6.49(br.s.,1H),6.31(br.s.,2H),4.04(s,3H),3.83(br.s.,1H),3.59(br.s.,4H),3.12-3.29(m,3H),3.03(br.s.,1H),2.90(br.s.,3H),2.34(s,3H)。
化合物28、29和30的合成的一般程序:
将氟化氨基吡啶(1.0当量)与乙二胺(10.0当量)混合并在密封管中加热至150℃过夜。然后在减压下去除挥发物。然后将残余物悬浮于DCM中并添加DIPEA(5当量)。在另一圆底烧瓶中装入DCM(1.0M)中的3-甲基苯甲酸(1.0当量),之后添加1,1′-羰基二咪唑(CDI)(1.0当量)。将混合物搅拌15分钟,随后将其添加到上述悬浮液中。使反应继续过夜,并在减压下去除溶剂,得到粘性油状物,对其直接进行ISCO,得到中间体4-2。
化合物28的中间体4-2-1。1H NMR(300MHz,氯仿-d)d 7.62-7.71(m,2H),7.24-7.34(m,3H),6.07(dd,J=2.07,7.16Hz,1H),6.00(d,J=2.07Hz,1H),3.75(br.s.,4H),3.54-3.62(m,2H),3.40-3.47(m,2H),2.40(s,3H)。
化合物29的中间体4-2-2无需进一步纯化即可用于下一步。
化合物30的中间体4-2-3。1H NMR(300MHz,甲醇-d4)d 7.93-8.01(m,1H),7.90(s,1H),7.55-7.66(m,3H),7.27-7.33(m,2H),3.45-3.55(m,3H),2.86(s,3H)。
将中间体4-2(1.0当量)溶解于DMF/THF的混合物(v/v=1:2,0.5M)中,之后添加三乙胺(4.0当量)和催化DMAP(0.4当量)。将混合物冷却至0℃,并且缓慢添加THF(0.5M)中的5-溴-2-甲氧基苯磺酰氯(1.2当量),然后将反应物升温至室温并搅拌过夜。添加饱和NaHCO3以猝灭反应并用DCM萃取水相。分离有机层并用无水硫酸镁干燥。然后通过减压去除溶剂并对残余物进行ISCO,得到中间体4-3。
化合物28的中间体4-3-1。1H NMR(300MHz,甲醇-d4)d 8.02(d,J=2.45Hz,1H),7.61-7.67(m,1H),7.59(br.s.,4H),7.34(s,2H),7.01-7.07(m,1H),6.29-6.36(m,1H),6.26(s,1H),3.86(s,3H),3.46-3.55(m,2H),3.41(s,3H),2.38(s,3H)。
化合物29的中间体4-3-2无需进一步纯化即可用于下一步。
化合物30的中间体4-3-3。1H NMR(300MHz,甲醇-d4)d 8.08(d,J=2.45Hz,1H),7.59-7.65(m,1H),7.47-7.53(m,1H),7.39-7.44(m,1H),7.30(s,3H),6.95(s,1H),6.03-6.19(m,2H),3.81(s,3H),3.52(d,J=5.84Hz,2H),3.46(d,J=5.65Hz,2H),2.36(s,3H)。
然后使用相应的卤代芳香族酰胺对中间体4-3进行连续的Miyaura硼化和Suzuki偶合反应的一般程序,得到化合物28、29和30。
化合物28,两步产率:64%。1H NMR(300MHz,氯仿-d)d 8.19(d,J=2.26Hz,1H),7.93(br.s.,1H),7.73(d,J=2.26Hz,2H),7.70(d,J=2.26Hz,1H),7.60(br.s.,2H),7.56(s,2H),7.52(br.s.,1H),7.46(t,J=7.63Hz,1H),7.34-7.38(m,1H),7.19-7.24(m,2H),7.02(d,J=8.67Hz,1H),6.30(d,J=6.03Hz,1H),6.24(s,1H),3.93(s,3H),3.54(br.s.,2H),3.45(br.s.,2H),3.14(s,3H),3.02(s,3H),2.32(s,3H)。
化合物29,两步产率:61%。1H NMR(300MHz,氯仿-d)d 8.10(d,J=2.45Hz,1H),7.69(d,J=2.64Hz,3H),7.51-7.62(m,6H),7.45(d,J=2.26Hz,2H),7.31-7.38(m,1H),7.04(d,J=8.67Hz,2H),6.82(s,1H),4.87-5.01(m,1H),4.04(s,3H),3.65(d,J=5.09Hz,2H),3.14(m,5H),2.96-3.09(m,5H),2.32(s,3H)。
化合物30,两步产率:70%。1H NMR(300MHz,氯仿-d)d 8.21(d,J=2.26Hz,1H),7.57-7.68(m,3H),7.53(s,1H),7.44-7.51(m,2H),7.35-7.41(m,2H),7.11-7.18(m,1H),7.06(d,J=7.72Hz,1H),6.79(d,J=7.91Hz,2H),6.64(d,J=8.85Hz,1H),5.98(d,J=8.29Hz,1H),3.61(s.,3H),3.38(br.s.,2H),3.23(br.s.,2H),3.16(s,3H),3.04(s,3H),2.20(s,3H)。
化合物41和42的合成的一般程序:
将中间体3-4(539mg,2.0mmol)溶解于DCM(20mL)中并添加三乙胺(0.56mL,4.0mmol)。然后引入催化DMAP(25mg,0.4mmol)并将反应混合物冷却至0℃。在此温度下,缓慢添加THF(10mL)中的5-溴-2-甲氧基苯甲酰氯(499mg,2.0mmol)。然后将反应物在此温度下搅拌1小时并使其升温至室温过夜。添加饱和碳酸氢钠(50mL)以猝灭反应并用乙酸乙酯(50mL)萃取反应物。分离有机层并加以干燥。在减压下去除溶剂,并对残余物进行ISCO,得到所需产物6-1。(579mg,60%)
化合物6-1。1H NMR(300MHz,氯仿-d)d 9.61(s,1H),8.35(d,J=2.64Hz,1H),7.47-7.62(m,3H),7.21-7.35(m,4H),7.12(t,J=8.01Hz,1H),6.90(d,J=8.85Hz,1H),6.75(d,J=7.91Hz,1H),6.65(br.s.,1H),6.43(dd,J=1.70,8.10Hz,1H),4.15-4.27(m,1H),4.02(s,3H),3.69(q,J=5.97Hz,2H),3.32-3.50(m,2H),2.36(s,3H)。
使用化合物6-1作为起始材料,根据Miyaura硼化反应的一般程序合成化合物6-2:
DZ14171-190(化合物5-2),产率:>99%。1H NMR(300MHz,氯仿-d)d 9.57(s,1H),8.70(d,J=1.51Hz,1H),7.91(dd,J=1.60,8.19Hz,1H),7.51-7.66(m,2H),7.42(s,1H),7.22-7.35(m,3H),7.12(t,J=8.01Hz,1H),7.01(d,J=8.29Hz,1H),6.73(d,J=7.91Hz,1H),6.63(br.s.,1H),6.44(d,J=7.91Hz,1H),4.05(s,3H),3.72(q,J=5.65Hz,2H),3.37-3.52(m,2H),2.37(s,3H),1.33(s,12H)。
使用化合物6-2作为起始材料,根据Suzuki偶合反应的一般程序合成化合物41和42:
化合物41,产率:78%。1H NMR(300MHz,氯仿-d)d 9.77(s,1H),8.53(d,J=2.26Hz,1H),7.73(dd,J=2.45,8.48Hz,1H),7.66(s,2H),7.58(s,1H),7.54(br.s.,1H),7.47(t,J=7.91Hz,1H),7.34-7.42(m,3H),7.29(d,J=4.71Hz,2H),7.09-7.21(m,3H),6.79(d,J=8.48Hz,1H),6.46(d,J=8.10Hz,2H),4.13-4.22(m,1H),4.10(s,3H),3.68-3.78(m,2H),3.47(t,J=5.75Hz,3H),2.93-3.19(m,7H),2.38(s,3H)。
化合物42,产率:72%。1H NMR(300MHz,氯仿-d)d 9.75(br.s.,1H),8.62(d,J=6.03Hz,2H),8.40-8.57(m,1H),7.69(d,J=7.72Hz,3H),7.36-7.60(m,5H),7.28-7.34(m,3H),7.06-7.22(m,3H),6.72-6.83(m,1H),6.46(d,J=7.91Hz,1H),4.78(br.s.,2H),4.10(s,3H),3.74(q,J=5.84Hz,2H),3.41-3.53(m,2H),2.90-3.16(m,3H),2.37(s,3H)。
化合物43和44的合成的一般程序:
将3-溴-5-氟吡啶(1当量)溶解于乙二胺(20当量)中,并将反应物在密封管中加热至150℃过夜。冷却至室温后,在80℃在减压下去除挥发物。然后将残余物重新溶解于乙酸乙酯中并添加碳酸钾。将该溶液搅拌1小时并过滤。在减压下去除溶剂,得到粘性油状物,将其重新溶解于DCM(0.25M)中。
将3-甲基苯甲酸(1当量)和1,1′-羰基二咪唑(1当量)在DCM(0.1M)中混合并搅拌15分钟。将混合物逐滴添加到上述溶液中并搅拌反应物过夜。添加盐水以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂并通过ISCO纯化残余物,得到呈灰白色固体状的化合物6-B。
中间体6-B,产率:59%。1H NMR(300MHz,氯仿-d)d 7.98(d,J=1.70Hz,1H),7.94(d,J=2.26Hz,1H),7.59(s,1H),7.53(br.s.,1H),7.33(d,J=5.09Hz,2H),7.04(t,J=2.17Hz,1H),6.36-6.50(m,1H),4.57-4.74(m,1H),3.75(q,J=5.97Hz,2H),3.38(d,J=5.65Hz,2H),2.40(s,3H)。
化合物6-D的合成。
将N-Boc-乙醇胺(1.3当量)溶解于THF(0.5M)中并添加偶氮二甲酸二异丙酯(1.03当量)。将反应混合物在室温下搅拌30分钟并添加3-溴-5-羟基吡啶(1.0当量),之后添加三苯基膦(1.5当量)。然后将反应物搅拌过夜。然后将反应物冷却至0℃并添加浓HCl(V反应混合物/V浓HCl=2:1)。将反应物升温至室温并搅拌30分钟直至停止冒泡。然后用DCM洗涤酸性水溶液3次。通过碳酸钾(pH>10.0)使水溶液呈碱性并引入乙酸乙酯。然后添加Boc2O(1.2当量)并将反应物搅拌2小时。然后分离有机层并通过无水硫酸镁干燥。过滤后,在减压下去除溶剂,并通过ISCO纯化残余物,得到化合物6-C。
化合物6-C,白色固体,产率:82%。1H NMR(300MHz,氯仿-d)d 8.30(d,J=1.88Hz,1H),8.24(d,J=2.45Hz,1H),7.37(t,J=2.17Hz,1H),4.88-5.08(m,1H),4.06(t,J=5.09Hz,2H),3.55(q,J=5.27Hz,2H),1.46(s,9H)。
用4N HCl处理化合物6-C(1当量),得到化合物6-D。将3-甲基苯甲酸(1当量)和1,1′-羰基二咪唑(1当量)在DCM(0.1M)中混合并搅拌15分钟。添加中间体6-D(1当量)并将反应物搅拌过夜。添加盐水以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂,得到化合物6-E,其无需进一步纯化即可用于下一步。
将市售氨基硫脲(1.0当量)和5-溴-2-甲氧基苯甲酸(1.0当量)在POCl3(14.0当量)中混合,并将反应物在75℃加热半小时。冷却至室温后,缓慢添加水(VH2O/VPOCl3=4:1)并使反应物回流4小时。冷却至室温后,通过在搅拌下逐滴添加50% NaOH溶液将混合物碱化至pH 8.0。通过过滤收集沉淀物,得到呈白色固体状的纯化合物6-3。
化合物6-3,产率:76%。1H NMR(300MHz,DMSO-d6)d 8.18(d,J=2.64Hz,1H),7.55-7.63(m,1H),7.30(s,2H),7.20(s,1H),3.93(s,3H)。
使用化合物6-3作为起始材料,根据连续Miyaura硼化和Suzuki偶合反应的一般程序合成化合物6-5:
化合物6-5,两步产率:56%。1H NMR(300MHz,DMSO)d 8.50-8.63(m,2H),8.26-8.47(m,1H),7.74-7.84(m,2H),7.47-7.64(m,2H),7.16-7.42(m,5H),4.51-4.86(m,2H),3.99(s,3H),2.92-2.99(m,3H)。
化合物43和44的合成的一般程序:
在氮气下,将化合物6-5(1.0当量)、t-BuBrettphos(0.132当量)、Pd2(dba)3(0.03当量)和碳酸钾(1.4当量)在密封管中混合。然后引入化合物6-B或化合物6-E(1.0当量),之后引入无水t-BuOH(0.1M)。然后将反应混合物脱气并用氮气重新填充三次。然后将反应物密封并加热至100℃过夜。冷却至室温后,将反应混合物用乙酸乙酯稀释并过滤。然后用水和盐水洗涤滤液。将有机层干燥并在减压下去除溶剂。然后通过ISCO纯化残余物,得到所需产物。
化合物43,灰白色固体,产率:71%。1H NMR(300MHz,氯仿-d)d 8.60(d,J=5.27Hz,3H),8.18(s,1H),8.10(s,1H),7.93(d,J=2.26Hz,1H),7.56-7.80(m,5H),7.35-7.55(m,3H),7.32(br.s.,2H),7.06(s,3H),4.80(br.s.,2H),4.26(t,J=5.18Hz,2H),4.01(br.s.,3H),3.88(t,J=5.18Hz,2H),2.94-3.18(m,3H),2.39(s,3H)。
化合物44,灰白色固体,产率:68%。1H NMR(300MHz,CDCl3)d 10.42(br.s.,1H),8.47-8.74(m,2H),7.75-8.43(m,1H),7.29-7.74(m,8H),6.78-7.26(m,8H),4.30-5.09(m,3H),3.62-4.03(m,3H),3.45-3.62(m,2H),3.37(br.s.,2H),2.86-3.19(m,3H),2.31(s,3H)。
化合物7-A的合成:
将5-溴-2-甲氧基苯磺酰氯(2.85g,10.0mmol)溶解于乙腈(25mL)中,并在0℃添加氢氧化铵溶液(4mL)。然后将反应物升温至室温并搅拌2小时。添加水(50mL)并通过过滤收集白色沉淀物并在空气中干燥过夜。
化合物7-A,2.66g白色固体,产率:100%。1H NMR(300MHz,甲醇-d4)d 7.91(d,J=2.45Hz,1H),7.69(dd,J=2.64,8.85Hz,4H),7.14(d,J=8.85Hz,2H),3.87-4.03(m,6H)。
中间体7-5的合成的一般程序:
将化合物7-A(1.0当量)悬浮于无水苯(0.8M)中并添加相应的经取代的甲基丙二酰氯(1.0当量)。然后使混合物回流过夜。然后去除溶剂,并且残余物(化合物6-2)不经进一步纯化即用于下一步。
将化合物7-1(1.0当量)溶解于MeOH/THF/水的混合物(v/v/v=15:5:3,0.2M)中,并添加LiOH·H2O(6.0当量)。然后在室温下搅拌反应物2小时。添加2N HCl(10当量)以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂,得到通常为白色的固体(化合物7-2),其无需进一步纯化即可用于下一步。
将化合物7-2(1.0当量)悬浮于DCM(0.1M)中并添加1,1′-羰基二咪唑(1.0当量)。将反应物在室温下搅拌1小时直至混合物变得均匀。然后一次性添加N-Boc-乙二胺(1.2当量)并将反应物搅拌过夜。添加1N HCl(10当量)以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂,得到中间体7-3,将其用二恶烷中的4N HCl(20当量)处理30分钟。然后去除溶剂,得到中间体7-4,其无需进一步纯化即可用于下一步。
将3-甲基苯甲酸(1当量)和1,1′-羰基二咪唑(1当量)在DCM(0.1M)中混合并搅拌15分钟。将来自上一步的中间体7-4悬浮于DCM(0.1M)中,向其中逐滴添加上述反应混合物。然后将反应物在室温下搅拌过夜。添加1N HCl(10当量)以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂,得到化合物7-5。
化合物47和48的中间体7-5-1,5步产率:21%。1H NMR(300MHz,甲醇-d4)d 8.00(d,J=2.45Hz,1H),7.73(dd,J=2.54,8.95Hz,1H),7.51-7.64(m,2H),7.25-7.39(m,2H),7.12(d,J=8.85Hz,1H),3.87-3.98(m,3H),3.45(d,J=5.84Hz,2H),3.39(d,J=5.46Hz,2H),3.20-3.27(m,2H),2.39(s,3H)。
化合物49和50的中间体7-5-2:5步产率:19%。1H NMR(300MHz,甲醇-d4)d 7.93-8.02(m,1H),7.74(dd,J=2.54,8.95Hz,1H),7.51-7.66(m,2H),7.34(d,J=5.65Hz,2H),7.11(d,J=9.04Hz,1H),3.85-3.97(m,3H),3.45-3.56(m,2H),3.43(d,J=5.65Hz,2H),2.29-2.43(m,3H),1.38-1.54(m,4H)。
化合物53和54的中间体7-5-3:5步产率:25%。1H NMR(300MHz,甲醇-d4)d 7.82(d,J=2.64Hz,1H),7.56-7.75(m,3H),7.27-7.40(m,2H),7.16(d,J=8.85Hz,1H),4.01(s,3H),3.51-3.60(m,2H),3.33-3.41(m,2H),2.38(s,3H),1.80(br.s.,4H),1.32(d,J=17.52Hz,4H),1.17(br.s.,2H)。
使用化合物7-5作为起始材料,根据连续Miyaura硼化和Suzuki偶合反应的一般程序合成化合物47、48、49、50、53和54:
化合物47,两步产率:70%。1H NMR(300MHz,氯仿-d)d 8.19(m,1H),7.72(d,J=7.54Hz,2H),7.50-7.67(m,6H),7.42(m,1H),7.34(m,1H),7.20(m,1H),7.01(d,J=8.67Hz,2H),3.91(s,3H),3.51(br.s.,2H),3.41(br.s.,2H),3.23(m,2H),3.07-3.14(m,3H),2.98(m,3H),2.33(m,3H)。
化合物48,两步产率:61%。1H NMR(300MHz,甲醇-d4)d 8.49-8.60(m,2H),8.10-8.28(m,1H),7.84-7.96(m,1H),7.61(s,10H),7.27(s,4H),4.42-4.79(m,2H),3.99(s,3H),3.65-3.78(m,1H),3.43(s,2H),3.39(d,J=5.46Hz,2H),3.17-3.26(m,1H),3.03(br.s.,3H),2.34(s,3H)。
化合物49,两步产率:65%。1H NMR(300MHz,甲醇-d4)d 8.13-8.21(m,1H),7.82-7.93(m,1H),7.69-7.76(m,2H),7.62-7.68(m,2H),7.56-7.61(m,1H),7.51-7.55(m,1H),7.36-7.44(m,1H),7.33(s,1H),7.20-7.29(m,1H),3.93(s,3H),3.40-3.55(m,4H),3.13(s,3H),3.03(s,3H),2.37(s,3H),1.43(s,4H)。
化合物50,两步产率:58%。1H NMR(300MHz,甲醇-d4)d 8.46-8.61(m,2H),8.10-8.25(m,1H),7.69-7.94(m,3H),7.54-7.67(m,3H),7.41-7.53(m,2H),7.27-7.40(m,3H),7.06-7.27(m,1H),4.52-4.80(m,2H),3.91(s,3H),3.42-3.56(m,4H),3.02-3.14(m,3H),2.35(s,3H),1.31(d,J=6.59Hz,4H)。
化合物53,两步产率:76%。1H NMR(300MHz,氯仿-d)d 8.04(d,J=2.26Hz,1H),7.74-7.82(m,1H),7.62-7.72(m,3H),7.53-7.60(m,2H),7.46-7.51(m,1H),7.43(s,1H),7.34(d,J=7.72Hz,2H),7.13(d,J=8.85Hz,1H),7.04-7.10(m,1H),5.50(s,1H),4.09(s,3H),3.63(br.s.,2H),3.40(br.s.,2H),3.14(br.s.,3H),3.02(br.s.,3H),2.34(s,3H),1.84(br.s.,4H),1.46(br.s.,4H),0.83-0.93(m,2H)。
化合物54,两步产率:69%。1H NMR(300MHz,氯仿-d)d 8.62(d,J=5.46Hz,2H),7.90-8.11(m,1H),7.52-7.87(m,5H),7.30-7.52(m,3H),7.28-7.30(m,1H),7.25(br.s.,2H),7.10(d,J=16.58Hz,3H),5.52(s,1H),4.47-4.85(m,2H),4.09(s,3H),3.64(br.s.,2H),3.43(br.s.,2H),2.98(br.s.,3H),2.34(s,3H),1.72-1.99(m,4H),1.45(br.s.,4H),1.05(br.s.,2H)。
化合物45、46、51和52的合成的一般程序:
将3-甲基苯甲酸(1当量)溶解于DCM(0.1M)中并添加1,1′-羰基二咪唑(1.0当量)。然后将反应物在室温下搅拌15分钟,其后添加N-Boc-乙二胺(1.2当量)。将反应物搅拌过夜。添加1N HCl(10当量)以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂,得到中间体7-B,将其用二恶烷中的4N HCl(20当量)处理,得到中间体7-C。
将具有不同烷基链长度的N-Boc-氨基酸(1.0当量)溶解于DCM(0.1M)中并添加1,1′-羰基二咪唑(1.0当量)。然后将反应物在室温下搅拌15分钟,其后添加来自上一步的中间体7-C,之后添加DIPEA(3.0当量)。将反应物搅拌过夜。添加1N HCl(10当量)以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂,得到中间体7-D,将其用二恶烷中的4N HCl(20当量)处理,得到中间体7-E或7-F。
在0℃,将中间体7-E或7-F(1当量)悬浮于DCM(0.1M)中并添加三乙胺(4.0当量)。然后引入催化DMAP(0.4当量)。在此温度下,缓慢添加THF(10mL)中的5-溴-2-甲氧基苯磺酰氯(1.0当量)。然后将反应物在此温度下搅拌1小时并使其升温至室温过夜。添加饱和碳酸氢钠(50mL)以猝灭反应并用乙酸乙酯(50mL)萃取反应物。分离有机层并加以干燥。在减压下去除溶剂,并对残余物进行ISCO,得到所需产物7-7。
化合物51和52的中间体7-7-1:5步产率:25%。1H NMR(300MHz,甲醇-d4)d 7.93-8.02(m,1H),7.74(dd,J=2.54,8.95Hz,1H),7.51-7.66(m,2H),7.34(d,J=5.65Hz,2H),7.11(d,J=9.04Hz,1H),3.85-3.97(m,3H),3.45-3.56(m,2H),3.43(d,J=5.65Hz,2H),2.29-2.43(m,3H),1.38-1.54(m,4H)。
化合物45和46的中间体7-7-2:5步产率:28%。1H NMR(300MHz,甲醇-d4)d 7.82(d,J=2.64Hz,1H),7.56-7.75(m,3H),7.27-7.40(m,2H),7.16(d,J=8.85Hz,1H),4.01(s,3H),3.51-3.60(m,2H),3.33-3.41(m,2H),2.38(s,3H),1.80(br.s.,4H),1.32(d,J=17.52Hz,4H),1.17(br.s.,2H)。
使用中间体7-7作为起始材料,根据连续Miyaura硼化和Suzuki偶合反应的一般程序合成化合物45、46、51和52:
化合物45,两步产率:60%。1H NMR(300MHz,氯仿-d)d 8.10(d,J=2.26Hz,1H),7.75(dd,J=2.35,8.57Hz,1H),7.50-7.65(m,4H),7.40-7.50(m,1H),7.37(d,J=7.54Hz,1H),7.29(d,J=4.33Hz,2H),7.00-7.14(m,2H),6.61(br.s.,1H),5.91(t,J=6.40Hz,1H),3.95-4.03(m,3H),3.57(br.s.,2H),3.46(d,J=5.09Hz,2H),2.95-3.26(m,8H),2.32-2.47(m,5H)。
化合物46,两步产率:70%。1H NMR(300MHz,氯仿-d)d 8.61(br.s.,2H),8.12(br.s.,1H),7.36-7.85(m,7H),7.29(d,J=4.71Hz,3H),6.94-7.20(m,3H),6.56(br.s.,1H),5.91(br.s.,1H),4.49-4.86(m,2H),4.00(s,3H),3.59(br.s.,2H),3.49(br.s.,2H),2.93-3.25(m,5H),2.42(t,J=5.65Hz,2H),2.37(s,3H)。
化合物51,两步产率:62%。1H NMR(300MHz,氯仿-d)d 8.07(d,J=2.26Hz,1H),7.73-7.82(m,1H),7.62(s,1H),7.50-7.59(m,3H),7.44(s,1H),7.36(s,1H),7.29(br.s.,1H),7.14-7.23(m,1H),7.10(d,J=8.67Hz,3H),5.78(s,1H),4.02(s,3H),3.57(d,J=5.84Hz,4H),3.45(br.s.,2H),2.95-3.18(m,6H),2.37(s,3H)。
化合物52,两步产率:68%。1H NMR(300MHz,氯仿-d)d 8.61(br.s.,2H),7.70-8.18(m,2H),7.52-7.68(m,4H),7.42(br.s.,3H),7.17(br.s.,4H),5.81(s,1H),4.51-4.84(m,2H),4.01(br.s.,3H),3.40-3.65(m,6H),2.91-3.20(m,3H),2.37(s,3H)。
化合物33、34、35和36的合成的一般程序:
将3-甲基苯甲酸(1当量)和1,1′-羰基二咪唑(1当量)在DCM(0.1M)中混合并搅拌15分钟。添加不同大小的环胺醇(1当量)并将反应物搅拌过夜。添加1N HCl(10当量)以猝灭反应并通过乙酸乙酯萃取反应物。然后分离有机层并加以干燥。在减压下去除溶剂,得到中间体8-A,其无需进一步纯化即可用于下一步。
将中间体8-A(1当量)溶解于DMF(0.25M)中并将溶液冷却至0℃。以使内部温度不超过10℃的速率分几次添加NaH(60%于油中,1.2当量)。在0℃搅拌30分钟后,逐滴添加DMF(0.5M)中的3-溴-5-氟吡啶(1.0当量),并且将反应物升温至室温并搅拌过夜。通过水猝灭反应并添加乙酸乙酯。然后分离有机层并加以干燥。在减压下去除溶剂,得到粘性油状物,将其通过ISCO纯化,得到所需产物。
化合物56的中间体8-B-1,两步产率:53%。1H NMR(300MHz,氯仿-d)d 8.35(d,J=1.88Hz,1H),8.12(d,J=2.45Hz,1H),7.47(s,1H),7.40(d,J=3.96Hz,1H),7.28-7.35(m,2H),7.23(t,J=2.17Hz,1H),4.95-5.08(m,1H),4.63(dd,J=6.50,10.08Hz,2H),4.31(br.s.,2H),2.39(s,3H)。
化合物57的中间体8-B-2,两步产率:52%。1H NMR(300MHz,氯仿-d)d 8.28-8.37(m,1H),8.12-8.28(m,1H),7.27-7.42(m,4H),7.19-7.26(m,1H),4.86-5.08(m,1H),3.55-4.09(m,4H),2.33-2.43(m,3H),2.06-2.31(m,2H)。
化合物58的中间体8-B-3,两步产率:60%。1H NMR(300MHz,CDCl3)d 8.03-8.36(m,2H),7.20(br.s.,5H),4.32(br.s.,2H),3.59(br.s.,3H),2.32(br.s.,3H),1.98(br.s.,4H)。
使用化合物7-A作为起始材料,根据连续Miyaura硼化和Suzuki偶合反应的一般程序合成化合物8-2:
化合物8-2,灰白色固体,两步产率;93%。1H NMR(300MHz,氯仿-d)d 8.46-8.63(m,2H),7.87-8.10(m,2H),7.64-7.81(m,2H),7.42-7.61(m,2H),7.24-7.41(m,3H),7.03-7.22(m,2H),4.64-4.79(m,1H),4.45-4.63(m,1H),3.95(s,3H),2.83-3.02(m,3H)。
化合物55、56、57和58的合成的一般程序:
将化合物8-2(1当量)置于密封管中。置入tBuXphos(0.1当量),之后引入化合物6-C或化合物8-B(1当量)。然后添加碳酸铯(2.4当量),之后注入1,4-二恶烷(0.1M)。然后将混合物脱气并用氮气重新填充三次。然后添加Pd2(dba)3(0.05当量)。然后将管密封并加热至100℃过夜。冷却至室温后,将反应混合物用乙酸乙酯稀释并过滤。然后用水和盐水洗涤滤液。将有机层干燥并在减压下去除溶剂。通过ISCO纯化残余物,得到所需产物。
化合物55,产率:62%。1H NMR(300MHz,氯仿-d)d 8.62(d,J=6.03Hz,2H),8.04(d,J=2.64Hz,2H),7.85(d,J=2.07Hz,1H),7.78(s,1H),7.49-7.63(m,4H),7.35-7.48(m,2H),7.29(br.s.,2H),6.99-7.22(m,3H),6.75-6.91(m,1H),4.49-4.80(m,2H),4.13(t,J=6.0Hz,2H),4.07(br.s.,3H),3.83(dd,J1=6.0Hz,J2=3.0Hz,2H),2.91-.3.15(m,3H),2.37(s,3H)。
化合物56,产率:78%。1H NMR(300MHz,氯仿-d)d 8.64(m,2H),7.66-8.15(m,4H),7.29-7.65(m,7H),7.01-7.26(m,6H),4.69-5.04(m,2H),4.53(br.s.,1H),4.01-4.18(m,3H),3.83-3.99(m,1H),3.51-3.80(m,4H),2.88-3.20(m,3H),2.28-2.40(m,3H),2.07-2.24(m,2H)。
化合物57,产率:59%。
1H NMR(300MHz,氯仿-d)d 8.62(d,J=5.65Hz,2H),7.65-8.15(m,4H),7.30-7.64(m,5H),6.90-7.25(m,8H),4.50-4.85(m,2H),4.25-4.40(m,1H),4.09(br.s.,3H),3.30-3.70(m,3H),2.88-3.15(m,3H),2.05-2.45(m,7H)。
化合物58,产率:69%。1H NMR(300MHz,氯仿-d)d 8.62(d,J=5.09Hz,2H),7.94-8.09(m,1H),7.90(s,2H),7.33-7.82(m,9H),7.28-7.32(m,2H),6.68-7.20(m,3H),4.98(br.s.,1H),4.77(br.s.,1H),4.57(br.s.,3H),4.30(br.s.,1H),4.19(br.s.,1H),4.07(br.s.,3H),2.91-3.20(m,3H),2.37(s,3H)。
使用化合物3-6作为起始材料,根据连续Miyaura硼化和Suzuki偶合反应的一般程序合成化合物59(也可以通过此程序获得化合物38):
化合物59(RTIOX-45),两步产率:58%。1H NMR(300MHz,氯仿-d)d 8.61(d,J=6.41Hz,1H),8.56(d,J=6.03Hz,1H),8.33(d,J=2.26Hz,1H),8.13-8.19(m,0H),7.64-7.87(m,3H),7.61(d,J=6.59Hz,1H),7.56(br.s.,1H),7.50(br.s.,1H),7.31(d,J=6.03Hz,1H),7.09(d,J=8.85Hz,0H),6.89-7.00(m,2H),6.84(d,J=8.85Hz,1H),6.49(d,J=13.37Hz,1H),6.33(d,J=8.48Hz,1H),6.24-6.30(m,1H),4.77(d,J=18.08Hz,2H),4.05(d,J=19.78Hz,3H),3.59(dd,J=5.75,11.77Hz,2H),3.25(dd,J=5.56,10.46Hz,2H),3.12(d,J=7.35Hz,3H),2.36(d,J=2.07Hz,3H)
60和61的合成的一般程序:
将化合物7-A(1当量)和化合物6-B(1当量)在密封管中混合。然后添加tBuXphos(0.1当量)和碳酸铯(2.4当量),之后注入1,4-二恶烷(0.1M)。然后将混合物脱气并用氮气重新填充三次。然后添加Pd2(dba)3(0.05当量)。然后将管密封并加热至110℃过夜。冷却至室温后,将反应混合物用乙酸乙酯稀释并过滤。然后用水和盐水洗涤滤液。将有机层干燥并在减压下去除溶剂。将残余物重新溶解于DCM中,并使溶液通过短硅胶,得到澄清溶液。然后在减压下去除溶剂,得到粗中间体9-1,其无需进一步纯化即可用于下一步。
使用化合物9-1作为起始材料,根据连续Miyaura硼化和Suzuki偶合反应的一般程序实现60和61的合成:
化合物60(RTIOX-46),3步产率:48%。1H NMR(300MHz,氯仿-d)d 8.57(d,J=6.0Hz,1H),8.500(dd,J1=129.0Hz,J2=3.0Hz,1H),8.495(dd,J1=129.0Hz,J2=3.0Hz,1H),8.05(ddd,J1=141.0Hz,J2=9.0Hz,J3=3.0Hz,1H),7.98-7.89(m,1H),7.89-7.83(m,1H),7.63-7.53(m,5H),7.47(d,J=3.0Hz,1H),7.40(d,J=3.0Hz,1H),7.37-7.29(m,2H),7.17(dd,J1=69.0Hz,J2=9.0Hz,1H),6.89(dd,J1=12.0Hz,J2=3.0Hz,1H),4.00(d,J=14.13Hz,3H),3.42(br,2H),3.21(br,2H),3.12(d,J=2.64Hz,3H),2.37(s,3H)。
化合物61(RTIOX-47),3步产率:52%。1H NMR(300MHz,甲醇-d4)d 8.50-8.58(m,2H),7.99-8.15(m,1H),7.79-7.90(m,1H),7.77(s,1H),7.65-7.70(m,1H),7.60(br.s.,5H),7.38-7.49(m,2H),7.32(s,3H),7.12-7.24(m,1H),6.83-6.94(m,1H),4.25-4.75(m,2H),4.00(s,3H),3.44-3.52(m,2H),3.18-3.29(m,2H),2.95-3.15(m,4H),2.38(s,3H)。
生物学实例
OX1R和OX2R钙动员测定。
利用经工程改造以稳定表达人OX1或人OX2受体的CHO RD-HGA16细胞(MolecularDevices)测定目标化合物在人OX1和OX2受体处的活性。将细胞维持在补充有10%胎牛血清、100单位青霉素和链霉素以及100μg/mL normocinTM的Ham’s F12中。为了进行测定,将细胞以25,000个细胞/孔涂铺,并在37℃、5% CO2下孵育过夜。第二天,用测定缓冲液洗涤细胞并加载Calcium 5染料(Molecular Devices)。45分钟后,用9% DMSO溶液预处理细胞15分钟。我们的小组已发现,这种预处理孵育期大大减少了DMSO介导的荧光增加。然后将测试化合物(8点浓度反应曲线)添加到1% DMSO溶液中,同时使用FlexStation II测量荧光。在此测定平台中,受体活化通过荧光的增加来测量,荧光的增加与内部钙的增加成正比。测试化合物EC50值通过非线性回归分析确定,并且值为至少三个重复运行的独立实验的平均值±S.E.M.。
OX1R和OX2R钙动员测定中的效力。
使用过表达OX1R或OX2R的CHO细胞在钙动员测定中,对所有合成的化合物的激动效力进行表征。参考German,N.A.;Decker,A.M.;Gilmour,B.P.;Thomas,B.F.;Zhang,Y.,Truncated Orexin Peptides:Structure-Activity Relationship Studies.ACSmedicinal chemistry letters 2013,4(12),1224-1227,关于此类测定并入本文。EC50列于表1-12中。
进行结构活性阐明以确定所示化合物左侧上末端芳香族环的模式是否可用。用其他几种烷基酰胺替换二甲氨基酰胺,但没有观察到效力的改善。当羰基官能团被去除时,观察到活性完全丧失,证实了其对于食欲素受体活化的重要性。
表1.
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对最右侧部分上的芳香族酰胺以及乙基进行了探索。乙基上的甲基取代基略微降低了两种受体处的效力。乙基延伸至3-碳丙基导致效力几乎没有变化。3-甲基苯基似乎在OX1R和OX2R处都提供了更好的效力,并因此被用于后续SAR研究中。当乙基转化为刚性哌嗪基团时,所有活性均丧失。
表2.
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左侧上的第一个苯环经一系列芳香族环替换。作为一个实施例,2,6-取代的吡啶基改善了OX1R和OX2R两者处的效力。对两个5元环即噻唑和恶唑进行了检查,并且它们的效力显著较低。乙烯和乙基类似物在两种受体处均无活性。
SAR表3:
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探索中心苯环并用吡啶基替换。虽然3,5-吡啶基在OX2R处的效力较小,但其在两种受体处的效力相同。这表明该3,5-吡啶基上的氮可能具有有利于OX1R的相互作用。此外,氮的引入降低了芳香族环的电子密度,这可能使其不易被氧化,从而产生更好的PK特性。
SAR表4:
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鉴于左侧上酰胺官能团处的羰基的重要性,保留了该酰胺并探索了该位置处的进一步取代。酰胺上的甲基经二甲氨基乙基替换,这提供了与二甲氨基形成盐的位点以提高溶解度。然而,观察到效力略有下降。值得注意的是,去除氮上的另一个甲基导致OX2R处的效力急剧下降(31对比32),并且OX1R处的效力完全丧失。引入吡啶基或苄基代替二甲氨基上的甲基导致两种受体处的效力显著降低,大部分在OX1R处无活性。然而,当引入2-吡啶甲基时,效力完成逆转,在OX1R和OX2R两者处均显示出与化合物1(YNT-185)相似的效力。这表明吡啶基和OX受体之间可能存在氢键结或极性间相互作用。同样,去除二甲氨基上的另一甲基再次导致OX1R效力完全丧失(35对比36)。接下来,检查了不同的吡啶基甲基。虽然3-吡啶基甲基的效力显示略有下降,但令人兴奋的是,具有4-吡啶基甲基的化合物38在OX1R和OX2R两者处均显示出较高且相同的效力,显著比化合物1(YNT-185)更有效。事实证明,用更长的吡啶基乙基替换吡啶基甲基并没有提高效力(化合物39和40)。
SAR表5:
/>
磺酰胺官能度被证明对于活性很重要,并且这通过41得到证实,该化合物在OX1R处无活性并且在OX2R处具有微摩尔效力。酰胺处的吡啶基甲基显著增加了OX1R和OX2R,但并未恢复效力。然后我们考虑用1,3,4-噻二唑取代它,1,3,4-噻二唑可以被认为是酰胺或磺酰胺的生物等排体。然而,两种化合物(43和44)均无活性。这进一步证实了磺酰胺对于获得食欲素受体处的活性的重要性。
SAR表6:
/>
然后用烷基或二羰基替换与磺酰胺氮相连的中心苯基,以研究是否可以在该区域引入柔性。然而,这些化合物大多没有活性。
SAR表7:
/>
乙基接头被证明对活性很重要(表2)。由于存在有利的吡啶基甲基,我们再次重新检查了该区域。我们首先用氧原子替换氮,这导致OX1R和OX2R两者处的效力降低约20倍。当引入脂肪族环以获得更多的柔性应变时,这些类似物并没有导致效力的提高,但56在OX2R处的效力与38相似。
SAR表8:
最后,合成了几种类似物,它们结合了意想不到的关键结构要素,从而使得食欲素受体(特别是OX1R)处的效力提高(表9)。这些关键要素包括但不限于:(1)Ar1处的4-吡啶基,其为OX1活性所必需;(2)Ar2处的2,6-吡啶基,其有利于OX1R和OX2R两者处的效力的提高;和(3)Ar3处的3,5-吡啶基,其可能有助于通过降低电子密度来提高代谢稳定性。在所有类似物中,一个实施例即化合物61(RTIOX-47)被证明具有择优的总体特性。
SAR表9:
/>
评定了三种最有效的化合物的ADME特性。在pH为2时,所有化合物均呈盐形式并且具有优异的水溶性。虽然化合物1(YNT-185)、RTIOXA-43和RTIOXA-45在大鼠肝微粒体(RLM)中具有适度的代谢稳定性,但RTIOXA-47显示出显著延长的半衰期(t1/2)。如与其他3种化合物相比,主要结构差异是在RTIOXA-47中吡啶基与磺酰胺相连。用吡啶基替换苯基降低了该芳香族环的电子密度。本发明人的一种假设是,这可能导致代谢氧化的易感性降低。
表10.食欲素激动剂的实施例的ADME特性
SAR表11:
SAR表12:
/>
分析
YNT-185是最早报道的小分子食欲素激动剂之一。YNT-185主要活化OX2R,而在OX1R处具有最小的激动活性。通过多个位点处的广泛SAR研究,本公开展示了几种OX1R/OX2R双重激动剂,包括RTIOX-47。这些是迄今为止发现的第一种也是唯一一种小分子双重食欲素激动剂。除了在两种食欲素受体处具有出色的激动效力外,RTIOXA-47当与YNT-185相比时还表现出显著改善的代谢稳定性。
观察到的特异性药理应答可以根据或依据所选择的特定活性化合物或是否存在药物载体以及所采用的调配物的类型和施用模式而变化,并且根据本公开的实践设想了结果的这种预期变化或差异。
尽管本文详细说明和描述了本公开的具体实施例,但本公开不限于此。以上详细描述作为本公开的示例提供,并且不应被解释为构成本公开的任何限制。修改对于本领域技术人员来说将是显而易见的,并且所有不偏离本公开的精神的修改都旨在包含在所附权利要求的范围内。
Claims (39)
1.一种式(I)化合物:
或其药学上可接受的盐,
其中
A是C2-6亚烷基、C2-6亚烯基、C2-6亚炔基、亚苯基,或二价4元至7元环烷基或杂环基环,任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子;
B是C2-6亚烷基、C2-6亚烯基、C2-6亚炔基、亚苯基,或二价4元至7元环烷基或杂环基环,任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子;
X是O或NH;
R1是(CH2)m-杂芳基;
m是0、1、2、3、4、5或6;
R2是氢或C1-6烷基;
X是键、O、C(O)、NH、NHC(O)或C(O)NH;
Y是键、C2-6亚烷基、C2-6亚烯基、C2-6亚炔基、任选地具有一个或多个不饱和度的二价4元至7元环烷基环,或二价4元至7元杂环基环,任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子;
Z是键、O、C(O)、NH、NHC(O)或C(O)NH;
R3是C1-10烷基、C2-10烯基、C2-10炔基、(CH2)n-C3-6环烷基、(CH2)n-苯基、(CH2)n-萘基或(CH2)n-(4元至7元杂环基环),其中此类环任选地具有一个或多个不饱和度,并且含有1至3个选自由O、N或S组成的组的杂原子,
其中每个R3可以经一个或多个选自以下项的取代基取代:C1-6烷基、C2-6烯基、C2-6炔基、卤素、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、NH2、NHC1-6烷基、N(C1-6烷基)2、CN、NO2、OH、O(C1-6烷基)、SH、S(C1-6烷基)和=O;并且
每个n独立地是0、1、2或3。
2.根据权利要求1所述的化合物,其中R1是(CH2)m-吡啶基。
3.根据权利要求2所述的化合物,其中m是1。
4.根据权利要求1或2所述的化合物,其中R2是C1-6烷基。
5.根据权利要求4所述的化合物,其中R2是CH3。
6.根据权利要求1至5中任一项所述的化合物,其中A是亚苯基。
7.根据权利要求1至6中任一项所述的化合物,其中B是亚苯基。
8.根据权利要求1至6中任一项所述的化合物,其中B是二价吡啶基。
9.根据权利要求1至8中任一项所述的化合物,其中X是NH。
10.根据权利要求1至8中任一项所述的化合物,其中X是O。
11.根据权利要求1至10中任一项所述的化合物,其中Y是C2-6亚烷基。
12.根据权利要求11所述的化合物,其中Y是CH2CH2。
13.根据权利要求1至10中任一项所述的化合物,其中Y是二价4元至7元杂环基环,任选地具有一个或多个不饱和度并且含有1至3个选自由O、N或S组成的组的杂原子。
14.根据权利要求13所述的化合物,其中所述杂环基环含有至少一个N原子。
15.根据权利要求1至14中任一项所述的化合物,其中Z是NHC(O)。
16.根据权利要求1至14中任一项所述的化合物,其中Z是C(O)。
17.根据权利要求1至8中任一项所述的化合物,其中X、Y和Z中的每一个是键。
18.根据权利要求1至17中任一项所述的化合物,其中R3是C1-10烷基、(CH2)n-C3-6环烷基或(CH2)n-苯基,其中每个n独立地是0、1、2或3。
19.根据权利要求18所述的化合物,其中R3是C9烷基、C8烷基、C7烷基、C6烷基、C5烷基、C4烷基、C3烷基、CH2CH3或CH3。
20.根据权利要求19所述的化合物,其中R3是C9烷基、C8烷基、C7烷基、C6烷基或C5烷基。
21.根据权利要求18所述的化合物,其中R3是(CH2)n-C3-6环烷基。
22.根据权利要求21所述的化合物,其中R3是(CH2)n-C5-6环烷基。
23.根据权利要求22所述的化合物,其中R3是(CH2)1-C6环烷基、(CH2)2-C6环烷基或(CH2)3-C6环烷基。
24.根据权利要求18所述的化合物,其中R3是(CH2)n-苯基。
25.根据权利要求24所述的化合物,其中n是0。
26.根据权利要求1至25中任一项所述的化合物,其中R3经一个或多个选自以下项的取代基取代:C1-6烷基、C2-6烯基、C2-6炔基、卤素、C1-6卤代烷基、C2-6卤代烯基、C2-6卤代炔基、NH2、NHC1-6烷基、N(C1-6烷基)2、CN、NO2、OH、O(C1-6烷基)、SH、S(C1-6烷基)和=O。
27.根据权利要求26所述的化合物,其中R3经一个或多个C1-6烷基取代。
28.一种化合物,其选自由实例中的一个或多个组成的组。
29.一种药物组合物,其包含根据权利要求1至28中任一项所述的化合物以及一种或多种药学上可接受的赋形剂。
30.一种用于治疗受试者中由食欲素活性降低引起的疾病或病症的方法,其包括施用有效量的根据权利要求1至28中任一项所述的化合物。
31.根据权利要求30所述的方法,其中所述疾病或病症是以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、血压调节、缺血事件、氧化应激事件和癌症。
32.根据权利要求1至28中任一项所述的化合物用于制备药物的用途,所述药物用于治疗受试者中由食欲素活性降低引起的疾病或病症,包括施用有效量的所述化合物。
33.根据权利要求32所述的用途,其中所述疾病或病症是以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
34.根据权利要求1至28中任一项所述的化合物,其用作活性治疗物质。
35.根据权利要求1至28中任一项所述的化合物,其用于治疗受试者中由食欲素活性降低引起的疾病或病症。
36.根据权利要求35所述的化合物,其中所述疾病或病症是以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
37.一种治疗以下项中的一者或多者的方法:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症,所述方法包括施用根据权利要求1至28中任一项所述的化合物。
38.根据权利要求1至28中任一项所述的化合物用于制备药物的用途,所述药物用于治疗以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
39.根据权利要求1至28中任一项所述的化合物,其用于治疗以下项中的一者或多者:睡眠障碍、发作性睡病、猝倒、失眠、睡眠状态调节、呼吸暂停、觉醒状态调节、睡眠-苏醒循环、麻醉后加速恢复、时差反应、食欲调节、摄食调节、饮食失调、胃肠道运动、能量平衡、代谢紊乱、肥胖、记忆力、思维清晰度、认知障碍、阿尔茨海默氏病、注意力缺陷、痴呆、轻度认知障碍、帕金森氏病、认知功能障碍、脑损伤、认知障碍、成瘾、药物成瘾、血压调节、缺血事件、氧化应激事件和癌症。
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