CN104487422A - 脲类化合物及其作为酶抑制剂的用途 - Google Patents
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Abstract
本发明公开了一种下列结构的化合物或其药学上可接受的盐或衍生物。其可用于治疗或者预防下列紊乱:食欲调节、肥胖、代谢异常、恶病质、厌食、疼痛、发炎、神经毒性、神经外伤、中风、多发性硬化症、脊髓损伤、帕金森症、左旋多巴诱发的运动障碍、亨廷顿氏舞蹈症、Tourette’s综合症、迟发性运动障碍、肌张力障碍、肌萎缩性脊髓侧索硬化症、阿尔兹海默病、癫痫、精神分裂、焦虑、抑郁、失眠、恶心、呕吐、酒精失常、如鸦片类、尼古丁、可卡因、酒精和精神兴奋剂的药物成瘾、高血压、循环性休克、心肌再灌注损伤、动脉粥样硬化、哮喘、青光眼、视网膜病、癌症、炎症性肠病、如肝炎和肝硬化的急慢性肝病、关节炎和骨质疏松。
Description
技术领域
本发明涉及化合物及其用途,特别是化合物及其在治疗或预防与底物相关的病况中的治疗用途,例如神经传导物大麻素,其被脂肪酸酰胺水解酶(FAAH)分解。
背景技术
FAAH酶分解脂肪酸酰胺,诸如,大麻素(N-花生四烯酰乙醇胺)、N-油酰乙醇胺、N-棕榈酰乙醇胺及油酰胺。大麻素,亦称为N-花生四烯酰乙醇胺或AEA,是一种内源性大麻素神经传导物质,发现于动物和人类器官,特別是脑部。研究还发现大麻素与辣椒素受体结合。大麻素被脂肪酸酰胺水解酶(FAAH)降解成乙醇胺及花生四烯酸。因此,FAAH的抑制剂将导致大麻素水平的升高。
大麻素是内源性大麻素系统中的神经传导物质,且刺激大麻素受体。大麻素受体,例如CB1及CB2均是G蛋白偶联受体。研究发现CB1主要位于中枢神经系统,而CB2主要位于周围组织。内源性大麻素系统涉及到越来越多的中枢和周围神经系统及周围器官的生理功能。调节内源性大麻素系统的活性已显示出对各种不同疾病及病理病况具有潜在的治疗效果。因此,内源性大麻素系统,且特別是FAAH酶,已成为开发可能治疗多种疾病的治疗靶点。内源性大麻素系统已涉及到食欲调节、肥胖、代谢异常、恶病质、厌食、疼痛、发炎、神经毒性、神经外伤、中风、多发性硬化症、脊髓损伤、帕金森症、左旋多巴诱发的运动障碍、亨廷顿氏舞蹈症、Gilles de la tourette综合症、迟发性运动障碍、肌张力障碍、肌萎缩性脊髓侧索硬化症、阿尔兹海默病、癫痫、精神分裂症、焦虑、抑郁、失眠、恶心、呕吐、酒精失常、诸如鸦片类、尼古丁、可卡因、酒精和精神兴奋剂的药物成瘾、高血压、循环性休克、心肌再灌注损伤、动脉粥样硬化、哮喘、青光眼、视网膜病、癌症、炎症性肠病、诸如肝炎和肝硬化的急慢性肝病、关节炎和骨质疏松症。Pacher等人在(2006)Pharmacol.Rev.58:389-462中详细讨论了内源性大麻素系统及其相关病况。
为了调节内源性FAAH底物的水平,例如大麻素,该底物反过来调节内源性大麻素系统,已经开发出了FAAH酶抑制剂。这至少能部分治疗或预防与内源性大麻素系统有关的病况及疾病。
由于FAAH的底物与其他受体结合,例如辣椒素受体,和/或涉及其他信号通路,FAAH抑制剂至少也可能部分治疗或预防与其他通路或系统有关的病況或疾病,例如辣椒素系统。
WO 2010/074588公开了FAAH抑制剂化合物。等人(HeikkiMikko J.AnnaAntti O.Kataja、Susanna M.Saario、Tapio Nevalainen、Ari M.P.Koskinen和Antti Poso.Chem Med Chem2010,5(2),213-231)公开了作为FAAH抑制剂的氨基甲酸酯类化合物。特別地,化合物6b是一个含有咪唑结构的FAAH抑制剂。但是,与本文中描述的且不含咪唑结构的许多其它氨基甲酸酯化合物相比,该化合物的FAAH抑制作用较弱。
发明内容
第一方面,本发明提供了一种具有下列结构的化合物:
或其药学上可接受的盐或衍生物。
研究发现本发明的化合物可调节脂肪酸酰胺水解酶(FAAH)的活性。进一步,已证明其具有相对有效性、相对较高的周围选择性(也即是说,与中枢神经系统组织相比,其对周围组织中的FAAH抑制程度更大)和相对代谢稳定性。特別地,与WO 2010/074588中公开的化合物相比,本发明的化合物已显示出在一种或多种性质上有更好的结果。
本发明化合物的“其药学上可接受的盐”包含无机碱的盐、有机碱的盐、无机酸的盐、有机酸的盐和与酸性或碱性氨基酸的盐。特别地,在一些实施例中可使用与酸成的盐。典型的盐包括盐酸盐、乙酸盐、三氟乙酸盐、甲磺酸盐、2-羟基丙烷-1,2,3-三羧酸盐、(2R,3R)-2,3-二羟基琥珀酸盐、磷酸盐、硫酸盐、苯甲酸盐、2-羟基-苯甲酸盐、S-(+)-扁桃酸盐、S-(-)-苹果酸盐、S-(-)焦谷氨酸盐、丙酮酸盐、对甲苯磺酸盐、1-R-(-)-樟脑磺酸盐、富马酸盐和草酸盐。本发明的化合物可以是溶剂化物(例如,水合物)形式或非溶剂化物(例如,非水合物)形式。当是溶剂化物形式时,另外的溶剂可为醇,例如,异丙醇。
本发明化合物的“其药学上可接受的衍生物”是指化合物中一个或多个基团与其他分子反应进行修饰得到的衍生物。例如,衍生物包含修饰NH2基团形成NHR或NR2,其中,R可为C1-18烷基(例如,C1-6烷基)、芳基、杂芳基、C3-8环烷基或其组合。这类衍生物可依据下列方法制备。
例如,衍生物包含4-(3-氨基苯基)-N-环戊基-N-甲基-1H-咪唑-1-甲酰胺的NH2基团与R-N=C=O异氰酸酯反应(参见R.G.Arnold,J.A.Nelson,J.J.Verbanc:Recent Advances in Isocyanate Chemistry Chemical Reviews,57(1),47-76,1957及其引用文献)形成NH-(C=O)-NHR衍生物,或与Cl-(C=O)-Cl和NHR2反应(参见H.Babad,A.G.Zeiler;Chemistry of Phosgene ChemicalReviews,73(1),75-91,1973及其引用文献)形成NH-(CO)-NR2,其中,R可为C1-18烷基(例如,C1-6烷基)、芳基、杂芳基、C3-8环烷基或其组合。药学上可接受的衍生物可以任何合适的方法制备,基于有机和药物化学众所周知的原理,其制备方法对于本领域技术人员来说是显而易见的(例如,Vogel的教科书实用有机化学,第5版,朗文出版社,1989中公开的合适的方法)。显然,所述的衍生物应该能抑制FAAH且应显示出周围选择性,也即是说,其需要与上述结构具有相似的性质。测试这些化合物性质的合适的方法是本领域技术人员熟知的,且在此也有描述。
本文使用的术语“Cx-y烷基”是指一个含有x到y个碳原子的直链或支链饱和烃基。例如,C1-6烷基是指一个含有1至6个碳原子的直链或支链饱和烃基。C1-6烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基和己基。较佳地,烃基为直链。
本文使用的术语“芳基”是指其中至少一个环是芳香环的C6-12单环或双环烃环。此基团的例子包括苯基、萘基和四氢萘基。
本文使用的术语“杂芳基”是指5-6元单环芳香环或稠合的8-10元双环芳香环,此单环或双环含有1至4个选自氧、氮及硫的杂原子。此类单环芳香环的例子包括噻吩基、呋喃基、呋吖基、吡咯基、三唑基、四唑基、咪唑基、噁唑基、噻唑基、噁二唑基、异噻唑基、异噁唑基、噻二唑基、吡喃基、吡唑基、嘧啶基、哒嗪基、吡嗪基、吡啶基、三嗪基、四嗪基等类似物。此类双环芳香环的例子包含喹啉基、异喹啉基、喹唑啉基、喹喔啉基、喋啶基、噌嗪基、酞嗪基、萘啶基、吲哚基、异吲哚基、氮杂吲哚基、吲哚嗪基、吲唑基、嘌呤基、吡咯并吡啶基、呋喃并吡啶基、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噻唑基、苯并异噻唑基、苯并噁二唑基、苯并噻二唑基和咪唑并吡啶基。
双环情况下,术语“双环”“稠合”是指两个环经两个原子间的键连接在一起(例如,萘),经一系列原子结合在一起形成一桥(例如,奎宁环)或单个原子在一起形成螺环化合物(例如,1,4-二氧杂-8-氮杂-螺[4.5]癸烷及N,3,3-二甲基-1,5-二氧杂螺[5.5]十一烷-9-基)。
本文使用的术语“Cx-y环烷基”是指一个具有x至y个碳原子的饱和烃环,其可为单环、双环或三环。例如,C3-8环烷基是指一个具有3至8个碳原子的饱和单环、双环或三环烃环。C3-8环烷基基团的例子包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
用于制备盐及衍生物的通用方法是本领域熟练技术人员熟知的。盐及衍生物的药学可接受性取决于多种因素,包括制剂加工特征和体内活性行为,且技术人员能够容易评估有关于本发明披露的这些因素。
本发明的化合物可能存在可替代的互变异构形式(例如,酮/烯醇、酰胺/亚胺酸),本发明的化合物涉及分离后的单个互变异构体,和所有比例的互变异构体混合物。
根据本发明的第二方面,本发明提供了一种药物组合物,包括本发明第一方面所述的化合物和一种或多种药学上可接受的辅料。
本发明的药物组合物包括任何本发明第一方面的化合物,及任何药学上可接受的载体、佐剂,或媒介物。可用于本发明药物组合物的药学上可接受的载体、佐剂,或媒介物是药学制剂领域常规使用的,包括但不限于糖、糖醇、淀粉、离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白,例如,人血清白蛋白,缓冲物质,例如,磷酸盐,甘油、山梨酸、山梨酸钾、饱和蔬菜脂肪酸的部份甘油酯混合物、水、盐或电解质,例如,鱼精蛋白硫酸盐、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、以纤维素为主之物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段共聚物、聚乙二醇和羊毛脂。
本发明的药物组合物可以通过口服、肠外、雾化吸入、直肠、鼻、脸颊、阴道,或经植入储集层给药。口服给药较佳。本发明的药物组合物可含有任何常规的无毒性药学可接受的载体、佐剂或媒介物。此处所用术语肠外包含皮下、皮内、静脉内、肌肉内、关节内、滑膜内、胸骨内、鞘内、病灶内及颅内的注射或灌注技术。
药物组合物可以是无菌注射剂制剂的形式,例如,作为一无菌注射水或油悬浮液。此悬浮液可依据此领域已知技术,使用适合的分散或湿化剂(例如,Tween 80)及悬浮剂制得。无菌注射剂制剂也可以是在无毒性肠外可接受的稀释剂或溶剂中的无菌注射液或悬浊液,例如,1,3-丁二醇溶液。可被使用的可接受媒介物及溶剂有甘露醇、水、林格氏溶液和等渗氯化鈉溶液。此外,无菌不挥发油为常规使用的溶剂或悬浮介质。为了此目的,任何无刺激性的不挥发油均可使用,包括合成的单或双甘油酯。脂肪酸,例如油酸及其甘油酯衍生物可用于制备注射剂中,因为它们是天然的药学可接受的油类,例如橄榄油或蓖麻油,特別是以其聚氧乙烯化形式。这类油溶液或悬浮液也可含有一长链醇稀释剂或分散剂例如Ph.Helv中所述的醇,或类似醇。
本发明的药物组合物可以任何口服可接受剂型口服给药,包括但不限于胶囊、片剂、粉剂、颗粒剂和水性悬浮液及溶液。这类剂型依据药物制剂领域熟知技术制备。以片剂口服给药的情況中,常用的载体包括乳糖及玉米淀粉。通常也添加诸如硬脂酸镁等润滑剂。以胶囊形式口服给药的情况中,有用的稀释剂包含乳糖和干燥的玉米淀粉。当以水性悬浮液口服给药时,活性成分与乳化剂及悬浮剂结合。若需要的话,也可添加一些甜味剂和/或增香剂和/或着色剂。
本发明的药物组合物也可以直肠给药的栓剂形式给药。这类组合物可通过将本发明的一种化合物与一种合适的无刺激性赋形剂混合而制备得到,该赋形剂常温下是固体,但直肠温度下是液体,因而可在直肠中融化释放出活性成分。这类材料包括但不限于可可脂、蜂蜡和聚乙二醇。
本发明的药学组合物可用鼻用气雾剂或吸入剂给药。这类组合物可依据药物制剂领域众所周知的技术制备,且可在生理盐水中,使用苯甲醇或其它合适的防腐剂,提高生物利用度的吸收促进剂、氟碳化物,和/或本领域熟知的其他助溶剂或分散剂制备成溶液。
本发明的化合物可以每剂约1至约20,000μg/kg的剂量给药,例如,根据被治疗或预防的情况,以及摄入化合物的主体的特征,每剂的剂量约1至约10000μg/kg,约1至约5000μg/kg,约1至约3000μg/kg,约1至约2000μg/kg,约1至约1500μg/kg,约1至约1000μg/kg,约1至约500μg/kg,约1至约250μg/kg,约1至约100μg/kg,约1至约50μg/kg或约1至约25μg/kg。在许多情况下,每剂的剂量可为约1至约10μg/kg。对于特別的实施例,每剂的剂量可为约250μg/kg,约100μg/kg,约50μg/kg或约10μg/kg。对于特定化合物的给药方案可由能够获得此披露内容的技术人员决定。
对于一特定实施例,本发明的药物组合物还包含一种或多种额外的活性药物成分。本发明的化合物可与一种或多种额外的活性药物成分一起给药,诸如,大麻素、油酰基乙醇酰胺或棕榈酰基乙醇酰胺。这可以是包含本发明化合物和一种或多种额外的活性药物成分的单个组合物形式。或者,也可以是两种或多种各自独立地组合物,其中本发明化合物可包含在一种组合物中,而一种或多种额外的活性药物成分包含在一种或多种独立地组合物中。
因而,本发明化合物可与一种或多种额外的活性药物成分同时或者错开给药。
第三方面,本发明提供一种用于治疗的如本发明第一方面所述的化合物,或一种如第二方面所述的组合物。
第四方面,本发明提供一种用于治疗或预防发展或症状与FAAH酶的底物有关的病况的如本发明第一方面所述的化合物,或如第二方面所述的组合物。
本发明也提供了一种如本发明第一方面所述的化合物,或如第二方面所述的组合物用于制备治疗或预防发展或症状与FAAH酶的底物有关的病况的药物。
其发展或症状与FAAH酶的底物有关的一系列病况为技术人员众所周知的。其中的一些在上文已有讨论。
第五方面,本发明也提供了一种治疗或预防发展或症状与FAAH酶的底物有关的病况的方法,所述的方法包括给需要此治疗或预防的主体摄入治疗有效量的依据本发明第一方面的化合物,或依据第二方面的组合物。
如第四方面所述的化合物,或如第五方面所述的方法,其中,所述病况是一种与内源性大麻素系统有关的紊乱。
在某些实施例中,能够治疗的病况可选自:
(i)疼痛,特別是急性或慢性神经源性疼痛,诸如,偏头痛及神经性疼痛(例如,糖尿病神经性疼痛、疱疹后神经痛、三叉神经痛);偏头痛;急性或慢性炎症性疼痛,诸如,与炎症性疾病有关的,诸如,关节炎、风湿性关节炎、骨关节炎、骨质疏松症、脊椎炎、痛风、血管炎、克罗恩氏病和肠道易激综合症;急性或慢性周围疼痛、癌症疼痛;
(ii)头晕、呕吐及恶心,特別是化疗造成的;
(iii)饮食失调,特別是食欲异常、代谢异常、厌食症及各种性质的恶质病;
(iv)神经及精神疾病,诸如,颤抖、异动症、肌张力障碍、恶心、呕吐、成瘾性(诸如,对药物或酒精成瘾)、痉挛、强迫症、Tourette’s综合症、任何性质及起源的所有形式的抑郁和焦虑、失眠、情绪异常,及精神病,诸如,精神分裂;
(v)急性和慢性神经退行性疾病,诸如,帕金森病、阿尔兹海默病、老年痴呆症、亨廷顿氏舞蹈症、与脑缺血及颅和骨髓创伤有关的病变;
(vi)癫痫;
(vii)睡眠障碍,包括睡眠窒息;
(viii)心血管疾病诸如心脏衰竭、高血压、循环性休克、心肌再灌注损伤、心律不齐、动脉硬化/动脉粥状硬化、心脏病、缺血性心脏病、血管炎和肾缺血;
(ix)癌症,例如,良性皮肤肿瘤、脑瘤及乳头状瘤、前列腺肿瘤和颅内肿瘤(胶质母细胞瘤、髓上皮瘤、髓母细胞瘤、神经母细胞瘤、胚胎起源性肿瘤、星状细胞瘤、星状母细胞瘤、室管膜瘤、少突胶质细胞瘤、丛肿瘤、神经上皮瘤、骨骺肿瘤、室管膜母细胞瘤、恶性脑膜瘤、肉瘤病、恶性黑色素瘤及神经鞘瘤);
(x)免疫系统异常,特別是自身免疫疾病,诸如,牛皮癣、红斑性狼疮、结缔组织疾病或胶原疾病,综合症、强直性脊椎炎、未分化脊椎炎、白塞氏病、自身免疫性溶血性贫血、多发性硬化症、肌萎缩性脊髓侧索硬化症、淀粉样变性病、移植排斥、影响浆细胞株的疾病、过敏性疾病、即发或迟发性过敏症、过敏性鼻炎或结膜炎、接触性皮炎;
(xi)寄生虫、病毒或细菌感染疾病,诸如,AIDS和脑膜炎;
(xii)炎症性疾病,特別是,关节疾病,诸如,关节炎、风湿性关节炎、骨关节炎、脊椎炎、痛风、血管炎、克罗恩氏病、炎症性肠道激惹综合症、哮喘;
(xiii)骨质疏松症;
(xiv)眼部病况,诸如,高眼压症、视网膜病变及青光眼;
(xv)肺部病况,包含呼吸道疾病、支气管痉挛、咳嗽、气喘、慢性支气管炎、慢性呼吸道阻塞及肺气肿;
(xvi)肠胃疾病,诸如,炎症性肠道激惹综合症、炎症性肠道疾病、溃疡、腹泻、尿失禁和膀胱炎;
(xvii)急性及慢性肝病,诸如,肝炎及肝硬化;
(xviii)神经异常,诸如,神经外伤、中风、多发性硬化症、脊髓损伤、帕金森症、左旋多巴诱发的运动障碍、亨廷顿氏症/舞蹈病、Gilles de la tourette综合症、迟发性运动障碍、肌张力障碍、肌萎缩性脊髓侧索硬化症、阿尔兹海默病和癫痫。
本发明的第六方面,提供了一种合成N-甲基环戊胺的酸式盐的方法,所述的方法包括:将环戊胺,与氯甲酸酯或碳酸二叔丁酯进行反应,形成环戊基氨基甲酸酯,然后还原、酸化得N-甲基环戊胺的酸式盐。
第六方面的方法可用于有效率地制备N-甲基环戊胺的酸式盐,其是制备式A化合物的一个关键中间体。本方法收率高、产品品质好。酸式盐较佳地为盐酸盐。但是,其它无机及有机酸盐亦可行。
在实施例中,环戊基氨基甲酸酯是在碱性条件下,例如,无机碱,诸如,NaOH(例如,3M)、NaHCO3、Na2CO3或K2CO3,或有机碱,诸如,三乙胺、二异丙基乙基胺,在有机溶剂中,诸如,THF、甲基THF、二氧六环、甲基叔丁基醚或二氯甲烷中形成。用于此步骤的氯甲酸酯可为,例如,C1-4的氯甲酸酯,诸如,乙基氯甲酸酯。还原步骤可在诸如THF或甲基THF的有机溶剂中,使用氢化铝锂(LAH)进行还原。温度范围从30℃到溶剂回流温度,较佳地为60℃。为了分离产物,添加无机酸诸如(例如,浓酸)或有机酸,诸如乙酸,以便形成N-甲基环戊胺的相对应的酸式盐。
第七方面,本发明也提供了一种合成N-甲基环戊胺的酸式盐的方法,所述的方法包括在甲胺酸盐的存在下,将环戊酮进行还原胺化反应。
第七方面的实施例中,还原反应是在催化量的负载于碳上的贵金属存在下,(诸如,Pd/C(例如,5%或10%))例如,有机碱(诸如,三乙胺或二异丙基乙基胺),及醇类溶剂(诸如,甲醇、乙醇、丙醇或丁醇)中,氢气存在的下进行。压力可从大气压至10巴(bar)变化。可使用约50~80℃(或60-70)的温度。第七方面的较佳地酸式盐是盐酸盐,其中,该方法使用甲胺盐酸盐。但是,其它无机及有机酸盐亦可行。因此,诸如HBr、HI的无机酸盐,或诸如乙酸的有机酸盐可通过类似方法制备。
依据第六或第七方面制备的N-甲基环戊胺盐(诸如,盐酸盐)其后可用于制备式A化合物,此处使用所述的制备该化合物的任何方法。因此本发明还提供了一种式A化合物的制备方法,其中,包含第六或第七方面所述的方法。本发明还提供了一种通过该方法获得或能够获得的式A化合物。
发明的详细说明
本发明将通过实施例的方式进行更详细地说明。
1.合成方法
用于合成本发明化合物的方法通过下面的一般流程式进行说明。所有化合物及中间体由核磁共振(NMR)进行表征。用于制备这些化合物的起始原料和试剂均可商业获得,或由本领域技术人员通过显而易见的方法制得。这些一般流程式仅说明本发明化合物的可通过这些方法合成,也可对这些流程式进行各种不同的修改,且将给关注此披露的本领域技术人员建议。
下列流程式中的室温所指从20℃至25℃的温度范围。
合成N-环戊基-N-甲基-4-(3-脲基苯基)-1H-咪唑-1-甲酰胺(化合物1)的一般流程式
2-溴-1-(3-硝基苯基)乙酮
室温下,滴加苯基三甲基三溴化铵(50.1g,133mmol)的THF(200mL)溶液至搅拌的1-(3-硝基苯基)乙酮(20g,121mmol)的THF(200mL)溶液中。此反应混合物在室温下搅拌1小时。过滤白色悬浮物,滤饼用THF洗涤,滤液真空中浓缩得到黄色油状物。残留物溶于EtOAc后,用水洗。有机层干燥(MgSO4)后,真空中浓缩得到黄色油状物,其固化成黄色固体。固体在异丙醇中重结晶,分离得到的最终产物为灰白色固体。2-溴-1-(3-硝基苯基)乙酮(20.5g,收率70%)。
(1H,600MHz,20℃,CDCl3)δ:8.83(1H,t,J=2Hz),8.49(1H,ddd,J=1.0,2.3,8.2Hz),8.34(1H,ddd,J=1.0,1.7,7.8Hz),7.75(1H,t,J=8.1Hz),4.49(2H,s)。
(13C,150MHz,20℃,CDCl3)δ:189.3,148.5,135.1,134.4,130.2,128.1,123.8,29.9。
熔点(mp):90-91℃。
溴化反应的另一条路线如下:
3-硝基苯乙酮(1wt,1eq)的乙酸(10vol)溶液中加入溴素(0.34vol,1.08eq),保持温度低于30℃,时间不少于2小时。在25℃到30℃的温度之间搅拌1小时后,检测反应完成情况。反应完成后加入冷水(12vol),形成白色沉淀。悬浮液在15℃再搅拌1小时后过滤。滤饼用水(4.5vol)洗涤。产品在不高于45℃下真空干燥直到干燥失重<1.0%。溴化产物的分离收率约为66%。此可选路线更适宜于放大。
4-(3-硝基苯基)-1H-咪唑
搅拌下,向2-溴-1-(3-硝基苯基)乙酮(57.1g,234mmol)和甲酰胺(116mL,2.9mol)的悬浮液中加入水(8mL)。混合物在140℃下搅拌5小时。棕色残留物倾倒至300毫升水中,形成的沉淀过滤分离后,用1M HCl水溶液洗涤。滤液用50%NaOH碱化,形成的黄色沉淀经过过滤分离后,水洗。固体干燥后用异丙醇重结晶。4-(3-硝基苯基)-1H-咪唑(7.05g,收率44%)。
(1H,600MHz,20℃,DMSO)δ:12.37(1H,s,br),8.58(1H,mt,J=2.0Hz),8.21(1H,ddd,J=1.0,1.6,7.8Hz),8.02(1H,ddd,J=1.0,2.5,8.2Hz),7.88(1H,dd,J=1.2Hz),7.79(1H,dd,J=1.1Hz),7.64(1H,t,J=8.1Hz)。
(13C,150MHz,20℃,DMSO)δ:148.4,137.9,136.8,136.6,130.5,130.0,120.5,118.3,114.6。
熔点:221℃(分解)。
在该方法此步骤的改进中,研究发现,反应温度增加到140℃至170℃,单独使用甲酰胺(即无水)作为悬浮介质可以提高收率(高达80%)。改进的方案如下:
2-溴-1-(3-硝基苯基)乙酮(1wt,1eq)的甲酰胺(10vol)溶液加热至170℃,且搅拌时间不超过4小时。搅拌4小时后,检测反应完成情况。反应完成后,混合物冷却到室温,加入水(15vol)。悬浮液过滤后,滤饼用3N HCl(2vol)清洗,母液再次过滤。加入50%NaOH(2vol)调节pH至14,保持混合物温度在0℃到5℃之间。悬浮液在0/5℃搅拌不少于(NLT)30分钟后,过滤,用水(5vol)洗滤饼。产物在不高于45℃下真空干燥直到干燥失重<1.0%。
环戊基(甲基)胺甲酰氯
在0℃下,N-甲基环戊胺(10g,101mmol)的THF(126mL)溶液滴加到光气溶液(63.7mL,121mmol,20%甲苯溶液)中得到白色悬浮液。反应混合物室温搅拌1小时。溶液倒至冰内。有机层用EtOAc稀释,用1M HCl洗涤后分开,干燥(MgSO4),真空浓缩得到清澈透明的可流动性油状物。环戊基(甲基)胺甲酰氯(13.1g,收率80%)。
(1H,600MHz,20℃,CDCl3)δ:4.65(1H,m),3.0,2.93(3H,2单峰),1.92(2H,m),1.73(2H,m),1.59(4H,m)。
(13C,150MHz,20℃,CDCl3)δ:149.7,149.3,61.1,59.5,33.1,31.1,28.8,28.5,24.0。
胺甲酰化步骤亦使用三光气/DCM及碳酸钠进行,如下:
将三光气(1.2wt,0.4eq)的DCM(10vol)溶液冷却至0/5℃下搅拌不超过10分钟。加入N-甲基环戊胺(1wt,1eq)的DCM(5vol)溶液,保持反应温度低于10℃。加入胺溶液之后,加入Na2CO3(2.14wt,2eq),加热至室温。搅拌2小时后,过滤反应混合物,滤饼用DCM(1vol)洗涤。浓缩至干后得到黄色油状物,不经过进一步处理直接使用。
N-环戊基-N-甲基-4-(3-硝基苯基)-1H-咪唑-1-甲酰胺
0℃下,向搅拌的4-(3-硝基苯基)-1H-咪唑(20g,106mmol)的THF(500mL)悬浮液中分批加入氢化钠(5.1g,127mmol,60%分散在矿物油中)。黄色悬浮液变成深红色悬浮液。混合物在室温下搅拌30分钟后,加入环戊基(甲基)胺甲酰氯(25.6g,159mmol)的THF(26mL)溶液。然后,悬浮液在室温下搅拌2小时。0℃下加入水,蒸发掉THF。有机残留物用DCM萃取,分出有机层后,干燥(MgSO4),真空中浓缩得到米黄色固体。固体用异丙醇磨碎。N-环戊基-N-甲基-4-(3-硝基苯基)-1H-咪唑-1-甲酰胺(25.18g,收率76%)。
(1H,600MHz,20℃,CDCl3)δ:8.63(1H,mt,J=2.0Hz),8.16(1H,ddd,J=1.0,1.6,7.8Hz),8.14(1H,ddd,J=1.0,2.3,8.2Hz),7.96(1H,d,J=1.3Hz),7.65(1H,dd,J=1.3Hz),7.58(1H,t,J=8.1Hz),4.45(1H,m),3.03(3H,s),1.98(2H,m),1.80(2H,m),1.73(2H,m),1.66(2H,m)。
(13C,150MHz,20℃,CDCl3)δ:151.3,148.7,140.1,137.3,134.9,130.9,129.7,122.1,119.9,114.6,59.4,31.3,28.9,24.4。
熔点:121-122℃。
4-(3-胺基苯基)-N-环戊基-N-甲基-1H-咪唑-1-甲酰胺
氩气气氛下,将乙酸乙酯(160mL)和EtOH(160mL)的混合物加入到湿Pd/C(0.846g,0.795mmol,10%)中。N-环戊基-N-甲基-4-(3-硝基苯基)-1H-咪唑-1-甲酰胺(5g,15.91mmol)分批加入到混合物中,且悬浮液在氢气气氛下室温搅拌过夜。混合物经氩气沖洗,硅藻土(celite)过滤,硅藻土用DCM洗涤。滤液真空浓缩得到清澈透明的油状物,固化成无色透明固体。固体用异丙醇重结晶。4-(3-胺基苯基)-N-环戊基-N-甲基-1H-咪唑-1-甲酰胺(3.62g,收率80%)。
(1H,600MHz,20℃,DMSO)δ:8.06(1H,d,J=1.3Hz),7.77(1H,d,J=1.1Hz),7.08(1H,t,J=1.9Hz),7.0(1H,t,J=7.8Hz),6.98(1H,md,J=7.7Hz),6.45(1H,ddd,J=1.2,2.3,7.7Hz),5.07(2H,s),4.37(1H,m),2.92(3H,s),1.87(2H,m),1.68(4H,m),1.53(2H,m)。
(13C,150MHz,20℃DMSO)δ:151.2,148.8,141.4,137.3,133.8,129.0,113.7,112.9,112.8,110.4,58.4,31.2,28.2,24.0。
熔点:108-109℃。
另一可选实施例中,该步骤的产物苯胺衍生物可不经纯化直接用于后续反应,也即是说可以缩短此步和后续步骤。
N-环戊基-N-甲基-4-(3-脲基苯基)-1H-咪唑-1-甲酰胺(化合物1)
0℃下,搅拌的4-(3-胺基苯基)-N-环戊基-N-甲基-1H-咪唑-1-甲酰胺(1.3g,4.57mmol)的2N氯化氢(2.286mL,4.57mmol)与水(4mL)的混合溶液中分批加入氰酸钾(0.445g,5.49mmol)。混合物在室温下搅拌24小时。加入氰酸钾(0.220g,2.74mmol)后,混合物在室温下再搅拌一夜。加入水,有机层用7:3的DCM/异丙醇混合物稀释。分出有机层,用1N HCl水溶液洗涤。有机层分出后,干燥(MgSO4),真空浓缩得到无色泡沫状物。产物经柱色谱(硅胶,DCM/MeOH 5%,10%)纯化,分离得到无色固体。固体在0℃下用EtOH重结晶。N-环戊基-N-甲基-4-(3-脲基苯基)-1H-咪唑-1-甲酰胺(0.403g,收率26%)。
本发明的上述化合物通过熔点及如下所述的NMR表征。NMR谱通过Bruker 600MHz Avance III光谱仪记录,其以溶剂作为内标。13C谱记录于150MHz,且1H谱记录于600MHz。数据按下列顺序报道:近似化学位移(ppm),质子数,多重性(br,宽峰;d,双峰;m,多重峰;s,单峰,t;三重峰),及偶合常数(Hz)。
化合物1(熔点:204℃)。
(13C,150MHz,20℃,DMSO)δ:156,151.1,140.9,140.8,137.5,133.7,128.9,117.9,116.6,114.2,114.2,58.4,31.2,28.2,24。
(1H,600MHz,20℃,DMSO)δ:8.55(1H,s),8.09(1H,d,J=1.2Hz),7.86(1H,d,J=1.2Hz),7.85(1H,t,J=1.8Hz),7.35(1H,md),7.34(1H,md),7.22(1H,t,J=7.8Hz),5.84(2H,s),4.36(1H,m),2.93(3H,s),1.87(2H,m),1.69(4H,m),1.54(2H,m)。
此最后一步的改进(苯环上脲基的形成)包括使用乙酸替代水作为4-(3-胺基苯基)-N-环戊基-N-甲基-1H-咪唑-1-甲酰胺的溶剂。这会导致收率的改善(约78%),及改进分离方案。改进的步骤如下所述:室温下,将4-(3-胺基苯基)-N-环戊基-N-甲基-1H-咪唑-1-甲酰胺溶于AcOH(8.8vol)中。室温下加入氰酸钾(0.65wt,2.5eq)的水(0.9vol)溶液。所得溶液室温搅拌至反应完成为止(起始原料<0.1%)。1小时内,产生脲类产物的沉淀物。水(5vol)加入所得浆状物中,出现更多固体。然后,米黄色悬浊液室温放置1小时,过滤。水(10vol)洗米黄色固体后,真空干燥至干燥失重<1.5%。
若此改进步骤(使用乙酸)导致N-乙酰化苯胺杂质,可进行重结晶。可如下所示:
室温下,向脲类产物(1wt)的乙酸(5vol)溶液中,逐滴加入水(5vol);滴加时间在30分钟以上。播入晶种后,加入水(2vol),将浆状物于室温下放置1小时。冷却至10℃,10℃下搅拌至少1小时后过滤。灰白色固体用水/乙酸9:1的混合物(2vol),水(10vol)洗涤,55℃下真空烘箱内干燥。然后,在室温下,将灰白色固体(0.82wt)溶于乙酸(3.96vol),逐滴加入水(4.1vol),滴加时间在30分钟以上。然后,播入晶种到此溶液,再添加水(1.6vol)。得到的浆状物在室温下搅拌至少1小时,然后,冷却至10℃。10℃下放置至少1小时,过滤固体,用水/乙酸9:1的混合物(1.6vol),水(10vol)洗涤,55℃下真空烘箱中干燥至干燥失重<1.5%。
2.生物疗效
体内测试按照下述方案实施。BRh(脑匀浆)显示中枢神经组织中的抑制作用,在这种情况下指脑部,且LVh(肝匀浆)显示周围组织中的抑制作用,在这种情况下指肝脏。对照组是反应混合物减去测试化合物。因此,测试化合物的数值低显示其为一个强抑制剂。数值100表明无法测得抑制作用。
体内方案
动物处理
实验所用动物是从Interfauna Ibérica(西班牙)获得的雄性NMRI小鼠(重27-44g)。小鼠在可控的环境条件下(12小时光照/黑暗循环,室温22±1℃),每笼放置5只。食物及自来水通过自由采食获取,实验都在白天进行。
使用动物喂食不锈钢弯曲针(Perfectum,U.S.A.)通过口服途径给动物摄入30mg/kg或3mg/kg的本发明化合物或对比化合物(8mL/kg,悬浮于0.5%羧甲基纤维素(CMC)或溶于水中)或媒介物(对照组)。动物处死前15分钟,用戊巴比妥60mg/kg,经腹腔内给药进行麻醉。移除部分肝脏、左肺叶和无小脑的脑部,置于含有膜缓冲溶液(3mM MgCl2,1mM EDTA,50mM TrisHCl pH 7.4)的塑料小瓶内。将组织在-30℃储存至分析为止。
动物在摄入化合物之前通常要禁食过夜,除了时间点>18小时,此时食物在摄入当日上午移除且化合物在当日下午摄入。然后,除了水,没有别的东西供给动物。
所有动物程序严格按照《用于实验和其它科学目的的脊椎动物保护欧洲公约》的法规(86/609CEE)及葡萄牙法律(Decreto-Lei 129/92,Portarias 1005/92e 1131/97)进行。使用动物的数量符合现行规定和科学道德的最小可能值。
试剂及溶液
大麻素[乙醇胺-1-3H-](40-60Ci/mmol)从American Radiochemicals获得。所用其它试剂从Sigma-Aldrich获得。Optiphase Supermix从Perkin Elmer获得,活性炭从Sigma-Aldrich获得。
组织制备
组织在冰上解冻且在10倍体积量的膜缓冲溶液(3mM MgCl2,1mMEDTA,50mM Tris HCl pH 7.4)内用Potter-Elvejhem(脑-8个行程,500rpm)或Heidolph Diax(肝脏-2行程,置于位置5,20秒,30秒停顿)均质化。
组织内的总蛋白质经BioRad蛋白质分析(BioRad)使用BSA标准曲线确定(50-250μg/ml)。
酶分析
反应混合物(总体积200μL)包含:2μM AEA(2μM AEA+5nM 3H-AEA),0.1%无BSA脂肪酸,15μg(脑),5μg(肝脏)或50μg(肺)蛋白,在1mM EDTA,10mM Tris中,pH 7.6。37℃下预培养15分钟,反应在加入底物溶液(冷的AEA+放射性标记的AEA+BSA)后开始。反应进行10分钟(脑和肺)或7分钟(肝脏)后,加入400μl活性炭的悬浮液(8g活性炭,置于32mL 0.5M HCl,持续搅拌)而终止。室温搅拌培养30分钟后,活性炭由microfuge离心处理(10分钟,13000rpm)而沉降。200μL上清液加入到预先分布在24孔板的800μLOptiphase Supermix闪烁鸡尾酒。每分钟的计数由一MicrobetaTriLux闪烁计数器测定。
每次分析,制备空白组(无蛋白质)。
剩余酶活性的百分比由减去空白组后相对于对照组计算得到。
ED50测定
测试化合物以渐增的剂量(10、3、1、0.3、0.03及0.01mg/kg)提供给动物,且摄入8小时后,依据前述体内方案测定FAAH活性,然后,ED50值由“Prisma”软件以95%的置信区间计算。
CYPs代谢稳定性分析
测试化合物的稳定性在NADPH存在或不存在的MLM(小鼠肝微粒体)或HLM(人肝微粒体)中完成。
使用含有1mg/mL的总蛋白质、MgCl25mM和50mM K-磷酸盐缓冲溶液的培养混合物(总体积100μl)测试稳定性。NADPH 1mM存在或不存在样品培养中。反应预培养5分钟,反应以测试的化合物开始(HLM 5μM,MLM50μM)。样品在37℃的摇动的水浴中培养60分钟。通过加入100μL乙腈停止反应。然后,样品经离心,过滤,上清液注入HLPC-MSD内。测试化合物溶于DMSO,且反应中DMSO最后浓度小于0.5%(v/v)。在T0,加入乙腈,然后加入化合物。所有进行实验的样品一式两份。
测试化合物1-(N-环戊基-N-甲基-4-(3-脲基苯基)-1H-咪唑-1-甲酰胺;也称为如上述式A化合物)。而且,还测试了WO 2010/074588公开的两个对比化合物。如下所示:
对比化合物1-N-环己基-4-(3-胍其苯基)-N-甲基-1H-咪唑-1-甲酰胺。
对比化合物2-N-环戊基-4-(4-氟-3-羟基苯基)-N-甲基-1H-咪唑-1-甲酰胺。
对比化合物1与化合物1虽然结构相似,但是二者明显不同。对比化合物2虽然与化合物1结构也相似,但是二者也明显不同。
由上表可看出,对于肝脏内的FAAH抑制作用而言,化合物1是最有效的化合物。特別地,化合物1比对比化合物1更有效。
周围选择性由肝脏内的FAAH活性除以脑内的FAAH活性计算得到。如此计算时,较低数值表明化合物更具周围选择性。结果列于下表中:
/ | 周围选择性 |
化合物1 | 0.008 |
对比化合物1 | 0.235 |
对比化合物2 | 0.017 |
此结果表明化合物1是最具周围选择性的化合物,两倍以上。进一步地,化合物1比对比化合物1更具周围选择性。
化合物1和对比化合物2在不同浓度下FAAH活性有关的其它数据列于下表中:
可看出,对于所有剂量,摄入化合物1后,FAAH活性大大低于对比化合物2。特別地,剂量为0.1mg/kg,8小时后,化合物1的FAAH活性显著低于对比化合物2。这表明化合物1相比对比化合物2显著有效。在0.1mg/kg,化合物1相比对比化合物2效果高出10倍。效力上的重大差异是出乎意料的。此数据也是化合物1代谢稳定的证据,因为当进行体内抑制实验时,化合物的代谢稳定性对于抑制作用的水平及抑制作用发生的时间跨度也非常重要。
下表表明了对小鼠口服给药后,化合物FAAH抑制作用的ED50值(半数有效量,在肝脏中产生50%的FAAH抑制作用所需的化合物剂量)。包括置信区间(95%)。
化合物 | 肝脏ED50(95CI)(mg/kg) | 时间(小时) |
化合物1 | 0.03(0.02;0.04) | 1 |
对比化合物2 | 0.17(0.13;0.23) | 8 |
下表表明化合物1及对比化合物2的代谢稳定性。稳定性数据是在MLM或HLM中暴露1小时后,产生的剩余化合物的%。100%是指没有任何代谢反应,0%对应酶完全降解。“CYP-”是指不存在对CYP代谢反应非常重要的辅助因子(NADPH)。因此,“CYP-”可被视为对照值。“CYP+”是指存在辅助因子,且酶降解依据测试化合物的稳定性而发生。可以看出,在MLM及HLM二者中,化合物1都比对比化合物2更稳定。
3.化合物1IC50的测定
3.1材料和方法
a)试剂和溶液
大麻素[乙醇胺-1-3H-]从American Radiochemicals获得,其具有60Ci/mmol的特定活性。所有其它试剂从Sigma-Aldrich获得。OptiphaseSupermix从Perkin Elmer获得,且活性炭从Sigma获得。
b)组织制备
来自4只Wistar大鼠的冷冻脑部在20mL 1mM MgCl2、20mMHEPES(4-(2-羟基乙基)-1-哌嗪乙烷磺酸)pH 7.0中用Potter-Elvejhem(8个行程,500rpm)均质化。匀浆在36000g 4℃下离心20分钟(Beckman,70Ti rotor)。形成的小球重新悬浮于15mL相同的缓冲溶液内,37℃下培养15分钟,然后,在36000g 4℃下离心20分钟。之后,每一小球再次悬浮于10mL的3mMMgCl2、1mM EDTA(乙二胺四乙酸)、50mM三(2-胺基-2-羟基甲基-丙-1,3-二醇)pH 7.4中,蛋白质经BioRad蛋白质分析检测(BioRad)使用BSA(牛血清白蛋白)标准曲线确定(50~250μg/mL)。
将膜悬浮液进行等分,于-30℃下储存。
c)酶分析
反应混合物(总体积200μL)包含:2μM AEA(2μM AEA+5nM 3H-AEA),0.1%无BSA脂肪酸,5或10μg蛋白质,在1mM EDTA,10mM Tris中,pH 7.6,及各种不同浓度的化合物1。储备溶液(10mM)在100%DMSO(二甲亚砜)中制备,在测试中DMSO的浓度为0.1%。37℃下预培养15分钟,反应在加入底物溶液(冷的AEA+放射性标记的AEA+BSA)后开始。反应进行10分钟,加入400μL活性炭的悬浮液(8g活性炭,置于32mL 0.5M HCl,持续搅拌)终止。室温搅拌培养30分钟后,活性炭由microfuge离心处理(10分钟,15000g)而沉降。200μL上清液加入到预先分布在24孔板的800μLOptiphase Supermix闪烁鸡尾酒。每分钟的计数或每分钟的分解量由一MicrobetaTriLux闪烁计数器测定。
对于每次分析,均存在空白组(无蛋白质)和对照组(无化合物)。
d)测试系统
Wallac 1450MicrobetaTriLux闪烁计数器。
e)测试方法
计数条件如下:
标签: | H-3 |
卡匣类型: | 24孔,4×6 |
计数模式: | CPM或DPM |
样品类型: | 常规 |
使用Paralux: | 否 |
计数时间: | 10分钟 |
CPM norm.: | 对于CPM是Norm_H3(0),或者对于DPM是3H AEA标准化 |
状态: | n |
修正 | / |
BGND corr.: | 关闭 |
CLM corr.: | 关闭 |
Autoquench corr.: | 对于CPM是No,对于DPM是NA |
计数控制 | / |
准确度: | 0.2 |
重复: | 1 |
循环: | 1 |
循环延迟: | 0 |
板延迟: | 0 |
板位向: | 常规 |
检测器设置: | 常规 |
窗口1: | 5-360 |
f)其它设备
SpectramaxPRO软件,3.0版
g)数据采集和分析
通过软件“Microbeta TriLux Windows workstation,4.01版”进行采集原始数据。
使用Prism 5for Windows软件,5.02版(GraphPad Software Inc.,SanDiego,CA)进行数据分析。化合物1的IC50值通过将实验数据与log(抑制剂)对规格化响应-变化斜率方程式拟合进行测定:
3.2结果
使用此方案,测定化合物1的IC50为27nM。
由以上所有结果可看出,与对比化合物1或2相比,化合物1具有更显著的效果,周围选择性,和/或代谢稳定性。
4.N-甲基环戊基胺盐酸盐的合成
4.1氨基甲酸酯还原方法
步骤1:形成氨基甲酸乙酯
0℃下,环戊胺(3mL,30.3mmol)的THF(20ml)溶液中,分別加入3M氢氧化钠(15.15ml,45.5mmol)和氯甲酸乙酯(3.47ml,36.4mmol)。所得两相混合物室温下搅拌4小时。MTBE(30mL)和氢氧化铵(5mL)稀释反应混合物。所得混合物室温搅拌10分钟,然后分离。有机层用水、0.5M HCl洗涤,Na2SO4干燥,过滤。滤液在减压下浓缩。得到无色油状物环戊基氨基甲酸乙酯(4.35g),收率95%,未经进一步纯化直接用于下一步。
此反应能很好地进行,产率高和产品的品质好。
步骤2:还原氨基甲酸乙酯
氨基甲酸酯还原成相应的甲胺是一般是众所周知的。此还原通常需要过量氢化铝锂(LAH)在THF中回流。然而,大规模使用氢化铝锂后处理较为复杂。因此,使用更安全更简单的Fieser后处理方法(对于x克LAH,使用x毫升水,x毫升15到25%的NaOH,然后再用3x毫升水)处理。首次尝试使用LAH还原氨基甲酸叔丁酯成功,Fieser后处理后加入浓HCl形成盐酸盐。分离后得到N-甲基环戊基胺盐酸盐,收率为63%。基于首次尝试得到的品质和收率,从而进行氨基甲酸乙酯的重复实验,摩尔收率83%,且NMR品质范围:>98%。
室温,氮气气氛下,氨基甲酸乙酯(2g,12.72mmol)的THF(8mL)溶液在20分钟内加入到LAH(2.414g,63.6mmol,5eq)的THF(20mL)悬浮液中。注意:有气体逸出。滴液漏斗用THF(2mL)冲洗干净。反应混合物加热到65℃(内温,回流)6小时。悬浮液冷却到0℃(冰水浴)。MTBE(30mL)稀释悬浮液。2.4mL水滴加到悬浮液中(观察到强烈地气体和热量释放),滴加3.6mL 10%NaOH(需要有良好地搅拌),最后滴加7.2mL水。所得浆状物加热到室温,室温搅拌30分钟。白色悬浮液中加入MgSO4(10g)。所得浆状物搅拌10分钟,过滤。MTBE(20mL)洗涤固体。
浓盐酸(1.272mL,15.27mmol,1.2eq)加入到合并的滤液中。所得混合物室温搅拌过夜,然后浓缩至干。残留物溶于异丙醇(20mL)后浓缩到2倍体积(4mL)。然后,所得溶液加入MTBE(12mL)。出现白色晶状固体。浆状物室温搅拌1小时,之后,收集固体,MTBE(4mL)洗涤,50℃真空烘箱中干燥4小时。得到第一批白色针状物(884mg)。合并的母液和洗涤液浓缩至干,残留物中加入异丙基乙酸酯(iPrOAc),开始出现白色晶体。加入更多iPrOAc,但一些固体粘在瓶壁上。加入一些DCM,得到清澈透明的固体。移除DCM后,白色固体出现,过滤,iPrOAc洗涤。白色晶状固体在50℃的真空烘箱内干燥4小时。得到第二批白色针状物(547mg)。得到N-甲基环戊胺盐酸盐白色针状物,摩尔收率83%。
4.2还原胺化方法
研究发现,在65℃,甲醇中,氢气气氛下,在催化量的三乙胺及Pd/C存在下,使用环戊酮及N-甲胺盐酸盐产生最佳结果。在这些条件下,分离得到N-甲基环戊胺盐酸盐白色固体,收率49%。
测试钯的来源和试剂当量来提高产品的收率和品质(去除甲胺盐酸盐)。使用Pd/C(JM,5R39糊状物)及稍微过量的甲胺盐酸盐(1.1eq),可使产率提高到至69%。
注意甲胺盐酸盐的去除可以在有碳酸钠存在二氯甲烷中,悬浮N-甲基环戊胺盐酸盐,之后蒸馏而进行。最终产物中未检测出甲胺。
方案描述
在5%钯/碳,5R 39糊状物(0.75g,0.176mmol,0.001eq)中,相继加入MeOH(105mL),甲胺盐酸盐(13.24g,196mmol),环戊酮(15.77mL,178mmol),最后是三乙胺(0.621mL,4.46mmol)。所得浆状物置于高压釜中,施加5bar氢气。高压釜加热65℃搅拌过夜。反应混合物缓慢冷却,TLC(展开剂PE/EA 8:2,高锰酸盐浸泡)显示没有起始原料。硅藻土过滤黑色浆状物,MeOH(10mL)洗涤。除去甲醇后,用异丙醇(60mL)替代。溶液浓缩到2倍体积后,加入异丙醚(60mL)。所得混合物室温搅拌。观察到白色固体,将浆状物在0℃下搅拌1小时,然后过滤。固体用异丙醚/异丙醇9:1(30mL)洗涤,真空烘箱干燥过夜。得到白色晶状固体N-甲基环戊基胺盐酸盐(16.9g,收率69.5%)。
Claims (11)
1.一种具有下列结构的化合物:
或其药学上可接受的盐或衍生物。
2.一种药物组合物,其特征在于,其包含如权利要求1所述的化合物和一种或多种药学上可接受的辅料。
3.如权利要求2所述的药物组合物,其特征在于,所述的药物组合物进一步包括一种或多种额外的活性药物成分,诸如大麻素、油酰基乙醇酰胺或者棕榈基乙醇酰胺。
4.一种用于治疗的如权利要求1所述的化合物或者如权利要求2或3所述的药物组合物。
5.一种用于治疗或预防发展或症状与FAAH酶的底物相关病况的用途的如权利要求1所述的化合物或者如权利要求2或3所述的药物组合物。
6.一种用于治疗或预防发展或症状与FAAH酶的底物相关的病况的方法,其特征在于,所述的方法包括对需要治疗或预防的主体摄入治疗有效量的如权利要求1所述的化合物或者如权利要求2或3所述的药物组合物。
7.一种如权利要求5所述用途的化合物或如权利要求6所述的方法,其特征在于,所述的病况是指与内源性大麻素系统相关的紊乱。
8.如权利要求7所述的化合物或方法,其特征在于,所述的紊乱选自食欲调节、肥胖、代谢异常、恶病质、厌食、疼痛、发炎、神经毒性、神经外伤、中风、多发性硬化症、脊髓损伤、帕金森症、左旋多巴诱发的运动障碍、亨廷顿氏舞蹈症、Gilles de la tourette综合症、迟发性运动障碍、肌张力障碍、肌萎缩性脊髓侧索硬化症、阿尔兹海默病、癫痫、精神分裂症、焦虑、忧郁、失眠、恶心、呕吐、酒精失常、诸如鸦片类、尼古丁、可卡因、酒精和精神兴奋剂的药物成瘾、高血压、循环性休克、心肌再灌注损伤、动脉粥样硬化、哮喘、青光眼、视网膜病、癌症、炎症性肠病、诸如肝炎和肝硬化的急慢性肝病、关节炎和骨质疏松症。
9.一种合成N-甲基环戊基胺的酸式盐的方法,其特征在于,所述的方法包含:将环戊胺,与氯甲酸酯或者碳酸二叔丁酯进行反应,得到环戊基氨基甲酸酯,然后还原所述的环戊基氨基甲酸酯,酸化,得到N-甲基环戊基胺的酸式盐。
10.一种合成N-甲基环戊基胺的酸式盐的方法,其特征在于,所述的方法包括在甲胺酸盐的存在下,对环戊酮进行还原胺化。
11.一种合成如权利要求1所述化合物的方法,其特征在于,其包含如权利要求9或10所述的方法。
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CN102333568A (zh) * | 2008-12-24 | 2012-01-25 | 比亚尔-珀特拉和Ca股份公司 | 药物化合物 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102333568A (zh) * | 2008-12-24 | 2012-01-25 | 比亚尔-珀特拉和Ca股份公司 | 药物化合物 |
WO2012015324A1 (en) * | 2010-07-29 | 2012-02-02 | Bial - Portela & Ca, S.A. | Process for the synthesis of substituted urea compounds |
Non-Patent Citations (2)
Title |
---|
HEIKKI KASNANEN等: "3-Heterocycle-Phenyl N-Alkylcarbamates as FAAH Inhibitors: Design, Synthesis and 3D-QSAR Studies", 《CHEMMEDCHEM》, vol. 5, no. 2, 18 December 2009 (2009-12-18), pages 213 - 231, XP055083059, DOI: doi:10.1002/cmdc.200900390 * |
RENATO A. DA SILVA等: "Zinc-promoted, iridium catalyzed reductive alkylation of primary amines with aliphatic ketones in aqueous medium", 《TETRAHEDRON LETTERS》, vol. 51, no. 4, 29 November 2009 (2009-11-29), pages 689 - 691, XP026815296 * |
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