CN104387372A - 氧代吖丁啶衍生物、其制备方法及其在人类医药和美容品中的用途 - Google Patents
氧代吖丁啶衍生物、其制备方法及其在人类医药和美容品中的用途 Download PDFInfo
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- CN104387372A CN104387372A CN201410498368.5A CN201410498368A CN104387372A CN 104387372 A CN104387372 A CN 104387372A CN 201410498368 A CN201410498368 A CN 201410498368A CN 104387372 A CN104387372 A CN 104387372A
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Classifications
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Abstract
本发明涉及对应于以下通式(I)的衍生自氧代吖丁啶的新颖化合物:
Description
本申请是申请号2009801446981、申请日2009年11月4日、发明名称“氧代吖丁啶衍生物、其制备方法及其在人类医药和美容品中的用途”的中国专利申请的分案申请。
技术领域
本发明涉及作为调节一种或多种黑皮质素受体的产品的新颖化合物。本发明还涉及其制备方法及其治疗用途。
背景技术
黑皮质素组成调整肽家族,其通过转译后加工激素阿片皮质素原(POMC-131长链氨基酸)合成。POMC导致生成三类激素:黑皮质素、促皮质素激素和各种内啡肽,诸如促脂素(ligotropin)(Cone,等,Recent Prog.Horm.Res.,51:287-317,(1996);Cone等,Ann.N.Y.Acad.Sd.,31:342-363(1993))。
黑皮质素受体(MCR)形成7-跨膜域GPCR超家族的一部分。迄今为止,在哺乳动物中已经鉴定了5种受体亚型MC1-5R。肽的内源组在激动剂或拮抗剂作用下结合MCR,诸如促黑素细胞激素(MSH)、促皮质素激素(ACTH)和刺鼠蛋白质及其衍生物。然而,一个例外是MC2R受体,其仅与ACTH结合(ACTH受体与其它黑皮质素受体的主要药理学区别(Major pharmacological distinction ofthe ACTH receptor from other melanocortin receptors),Schioth等,Life sciences(1996),59(10),797-801)。
MCR在生理学水平下具有不同作用。MC1R调控皮肤中的黑色素形成且对免疫***调控具有作用。MC2R调控肾上腺水平下的皮质类固醇生成。MC3R和MC4R受体在控制食物摄取和性行为中起作用。MC5R涉及外分泌腺调控(Wikberg,Jarl E.S.,黑皮质素受体:用于新药物的前景(Melanocortin receptors:perspectives fornovel drugs).European Journal of Pharmacology(1999),375(1-3),295-310。Wikberg,Jarl E.S.,黑皮质素受体:药物发现中的新机遇(Melanocortin receptors:new opportunities in drug discovery),ExpertOpinion on Therapeutic Patents(2001),11(1),61-76)。
MCR作为药物(旨在治疗诸如肥胖症、糖尿病、炎性疾病和性功能障碍的显著病理组成)的靶标的潜在用途产生了对针对特定亚型显示出极大特异性的化合物的需要。然而,对针对稍微不同的受体亚型具有选择性的药物建模(modelling)是一项艰难的任务,如果可以得到关于配体-受体相互作用的决定因素的详细知识,则该任务将被简化。
本申请人现在已经出乎意料且令人惊讶地发现如下文定义的通式(I)的新颖化合物对黑皮质素受体显示出很好的活性,且具体地说某些化合物对MC1R具有高度选择性。
尤其已经证明MC1R是调控黑素细胞中黑色素合成的关键蛋白质之一。
MC1R在黑素细胞中表达且涉及到皮肤色素沉着、动物毛皮着色和黑素细胞功能。黑皮质素因此可用以治疗白斑病(hypopigmentary)和黄褐斑病症(hyperpigmentary disorder)。MC1R基因多态性数据与褐色头发表型及恶性和非恶性皮肤癌有关(Xu X等,Nat Genet 1996;14:384;Van Der Velden PA等,Am J Hum Gent2001;69;774-779;Valverde P等,Hum Mol Genet 1996;5;1663-1666;Schioth HB Biochem Biophys Res Commun 1999;260:488-491;Scott MC等,J Cell Sci 2002;115;2349-2355)。因此,在MC1R和黑素瘤之间存在关联;结果,MC1R在预防和治疗某些形式的皮肤癌中可具有重要性(Stockfleth E等,Recent Results CancerRes 2002;160;259-268;Stander等,Exp Dermatol 2002;11:42-51)。MC1R还在以下细胞中表达:巨噬细胞和单核细胞(Star等,Proc.Natl.Acad.Sci.USA 92;8016-8020;Hartmeyer等,J.Immunol.159;1930-1937)、中性粒细胞(Catania等,Peptides 17;675-679)、内皮细胞(Hartmeyer等,J.Immunol.159;1930-1937)、胶质瘤细胞和星形细胞(Wong等,Neuroimmunomodulation 4,37-41)、成纤维细胞(Boston和Cone,Endocrinology 137,2043-2050)及角质细胞(Luger等,J.Invest Dermatol.Symp.Proc.2,87-93)。MC1R在这些细胞中的定位与MSH衍生肽抑制炎性过程的能力有关。具体地说,α-MSH在肠炎、关节炎、局部缺血、接触性过敏症以及皮炎的慢性模型中已经显示出强烈的炎症抑制作用,且还能够诱发对半抗原的耐受性(Ceriana等,Neuroimmunomodulation 1,28-32;Chiao等,Clin.Invest.99,1165-1172;Huh和Lipton Neurosurgery 40,132-139;Luger等,J.Invest Dermatol.Symp.Proc.2,87-93;Rajora等,Peptides 18,381-385;J.Neurosci.17,2181-2196;Lipton等,Neuroimmunomodulation 5,178-183)。黑皮质素因此可用以治疗炎性病症和免疫病症。已经提出MC1R信号转导途径在疼痛感知中起作用且MC1R的功能变化与高疼痛耐受性有关(Mogil等,J MedGenet.2005Jul;42(7):583-7)。
在人类头发颜色和MC1R变体之间存在强烈相关性(Valverde等,Nat Genet.1995Nov;11(3):328-30)。MC1R的功能变化与褐色头发颜色有关。
还已知皮脂腺表达MC1R(Ganceviciene等,Exp Dermatol.2007Jul;16(7):547-52)和MC5R(Zhang等,Peptides.2006Feb;27(2):413-20)两者。也已有报道,在痤疮情况下,MC1R在皮脂腺过度表达。
这些化合物在人类医药中、尤其是在皮肤病学中和在美容领域中获得应用。
在已知的氧代吖丁啶衍生物之中,已经描述其中一些具有抗细菌性(WO9709328、WO04045616、WO04087697)、作为CCR5拮抗剂的抗病毒性质(WO04055016、WO08034731)和止痛性质(Journal of Medicinal Chemistry(1968),11,466-470)。
专利WO9810653公开了用于促进在人类和动物体内合成生长激素的某些哌啶、吡咯烷和六氢-1H-氮杂化合物。
专利WO9635713和WO9638471公开了用于刺激生长激素合成的某些二肽。
药物化学志(Journal of Medicinal Chemistry)(2003),46,1123-1126中的出版物描述了“具有抗炎性质的基于酪氨酸的有效且选择性MC1R受体小分子拮抗剂的发现(discovery oftyrosine-based potent and selective MC1R receptor small-moleculeagonists with anti-inflammatory properties)”。
专利WO02070511、WO02079146和WO02069905要求保护化合物作为黑皮质素受体、更具体地MC1R和MC4R的调节剂的用途。
发明内容
现在,本申请人已经出乎意料且令人惊讶地发现某些式(I)化合物(其为本发明的主题)为一种或多种黑皮质素受体的调节剂,且具体地说,一些化合物对MC1R具有高度选择性。
因此,本发明涉及以下通式(I)的化合物:
其中:
R1代表芳基、被取代的芳基或环烷基;
R2代表氢原子、羟基、低碳数烷基、被取代的低碳数烷基、高碳数烷基、被取代的高碳数烷基、环烷基、环烷基烷基、低碳数烷氧基、被取代的低碳数烷氧基、高碳数烷氧基、被取代的高碳数烷氧基、环烷基烷氧基或酰氧基;
R3代表芳烷基或被取代的芳烷基;
R4代表杂烷基、被取代的杂芳烷基、杂烷基或被取代的杂烷基;
R5代表氢原子、羟基、氨基、酰氨基或磺酰胺;
以及通式(I)化合物的相应盐和对映异构体。
具体实施方式
在具有医药学上可接受的酸的通式(I)化合物的加成盐之中,可优选提到用有机酸或用无机酸制成的盐。
合适无机酸的实例有氢卤酸,诸如盐酸或氢溴酸;硫酸;或硝酸。
合适有机酸的实例有苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、柠檬酸、草酸或酒石酸。
通式(I)化合物也可以与水或溶剂的水合物或溶剂合物形式存在。
用于形成溶剂合物或水合物的适当溶剂的实例有醇,诸如乙醇或异丙醇;或水。
根据本发明,术语“芳基”表示未被取代的苯基或萘基。
根据本发明,术语“被取代的芳基”表示用选自烷基、烷氧基、卤素、羟基、氰基、三氟甲基和硝基的一个或多个原子团取代的苯基或萘基。
根据本发明,术语“环烷基”表示含有3-7个碳原子的基于环状饱和烃的链。
根据本发明,术语“羟基”表示OH基团。
根据本发明,术语“氨基”表示NH2基团。
根据本发明,术语“酰基”表示甲酰基或用烷基取代的羰基。
根据本发明,术语“磺酰基”表示用烷基取代的砜。
根据本发明,术语“低碳数烷基”表示含有1-4个碳原子的基于直链或支链饱和烃的链或含有2-4个碳原子的基于直链或支链不饱和烃的链。
根据本发明,术语“烷基”表示被取代或未被取代的低碳数烷基或高碳数烷基。
根据本发明,术语“被取代的低碳数烷基”表示用一个或多个卤素原子或用羟基取代的含有1-4个碳原子的基于直链或支链饱和烃的链或含有2-4个碳原子的基于直链或支链不饱和烃的链,具体地说例如为甲基、乙基、丙基、异丙基或丁基。
根据本发明,术语“高碳数烷基”表示具有5-10个碳原子的基于直链或支链、饱和或不饱和烃的链。
根据本发明,术语“被取代的高碳数烷基”用来指含有5-10个碳原子且用一个或多个卤素或用羟基取代的基于直链或支链、饱和或不饱和烃的链。
根据本发明,术语“环烷基烷基”表示用环烷基取代的烷基。
根据本发明,术语“低碳数烷氧基”表示用低碳数烷基取代的氧原子,且具体地例如为甲氧基、乙氧基、丙氧基、异丙氧基或丁氧基。
根据本发明,术语“被取代的低碳数烷氧基”表示用被取代的低碳数烷基取代的氧原子。
根据本发明,术语“高碳数烷氧基”表示用高碳数烷基取代的氧原子。
根据本发明,术语“被取代的高碳数烷氧基”表示用被取代的高碳数烷基取代的氧原子。
根据本发明,术语“环烷基烷氧基”表示用环烷基烷基取代的氧原子。
根据本发明,术语“酰氧基”表示用酰基取代的氧原子。
根据本发明,术语“芳烷基”表示用芳基取代的烷基。
根据本发明,术语“被取代的芳烷基”表示用被取代的芳基取代的烷基。
根据本发明,术语“卤素原子”表示氯、氟、碘和溴原子。
根据本发明,术语“杂环”表示包含一个或多个选自O、S和N的杂原子的基于饱和或不饱和、环状或双环烃的链。
根据本发明,术语“被取代的杂环”表示用一个或多个烷基取代的包含一个或多个选自O、S和N的杂原子的基于饱和或不饱和、环状或双环烃的链。
根据本发明,术语“杂芳基”表示芳族杂环。
根据本发明,术语“被取代的杂芳基”表示用一个或多个烷基取代的芳族杂环。
根据本发明,术语“杂芳烷基”表示用杂芳基取代的烷基。
根据本发明,术语“被取代的杂芳烷基”表示用被取代的杂芳基取代的烷基。
根据本发明,术语“杂烷基”表示用杂环取代的烷基。
根据本发明,术语“被取代的杂烷基”表示用被取代的杂环取代的烷基。
根据本发明,术语“酰氨基”表示用酰基取代的胺。
根据本发明,术语“磺酰胺基”表示用磺酰基取代的胺。
在属于本发明的范围的通式(I)化合物之中,具体地可提到以下化合物:
-丁酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-苯基吖丁啶-3-基酯
-N-[(S)-1-[(S)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-1-[(S)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-乙酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-邻甲苯基吖丁啶-3-基酯
-丁酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-(4-氟苯基)吖丁啶-3-基酯
-N-[(S)-1-[(S)-2-(3-环己基-3-羟基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-1-[(S)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-1-[(S)-2-[3-丁氧基-3-(3-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-2-(3-环己基-3-羟基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(S)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(3,4-二氯苄基)-2-(3-羟基-3-苯基吖丁啶-1-基)-2-氧代乙基]-3-(1H-咪唑-4-基)-丙酰胺
-N-[(S)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)-丙酰胺
-N-[(S)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(S)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-环己基甲基-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(2,4-二氯苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(S)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-己氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环丙基甲氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(3-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-{(R)-1-苄基-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-2-氧代乙基}-3-(4H-咪唑-2-基)丙酰胺
-N-[(R)-1-苄基-2-(3-丁氧基-3-苯基吖丁啶-1-基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H[1,2,3]***-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-[1,2,4]***-3-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺
-N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)-3-戊基吖丁啶-1-基]-2-氧代乙基}-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-苄基-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙烯酰胺
-N-[(R)-2-[3-(2,4-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)-1-(3-三氟甲基苄基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)-1-(4-三氟甲基苄基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(3,4-二氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(3,4-二氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(3-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(3-氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(2-氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(2,4-二氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(4-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,5-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,6-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)戊酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2,4-二氯苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺
-N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
-(S)-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-2-羟基-3-(1H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
-N-[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环己基甲氧基-3邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-邻甲苯基-3-(4,4,4-三氟丁氧基)吖丁啶-1-基]乙基丙酰胺
-N-[(R)-2-(3-环丁基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
-N-{(R)-1-(4-甲氧基苄基)-2-[3-(3-甲基丁-2-烯基氧基)-3-邻甲苯基吖丁啶-1-基]-2-氧代乙基}-3-(5-甲基-1H-咪唑-4-基丙酰胺
-3-(1H-咪唑-4-基)-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-苯基吖丁啶-1-基)乙基]丙酰胺
-N-[(R)-2-[3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)吖丁啶-1-基]-2-氧代乙基}丙酰胺
-N-[(R)-2-[3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-苯基-3-(4,4,4-三氟丁基)吖丁啶-1-基]乙基}丙酰胺
-N-[(R)-2-[3-(5-氟戊基)-3-苯基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环丙基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环丙基甲基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-(S)-2-羟基-3-(1H-咪唑-4-基)-N-[1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]丙酰胺
-(S)-2-氨基-3-(1H-咪唑-4-基)-N-[1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丁酰胺
-(S)-N-[2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)-2-甲烷磺酰基氨基丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
以及其对应盐和对映异构体。
通式(I)化合物根据以下提供的反应方案1制备。
根据方案1,通式(IV)化合物可通过在常规肽偶联条件下使用例如1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐或羟基苯并***或TBTU作为偶联剂和使用三乙胺或二异丙基乙胺作为碱在诸如二氯甲烷或二甲基甲酰胺的溶剂中偶联式(II)中间体和式(III)氨基酸(其胺官能团用保护基Pg(例如Boc、CBz或Fmoc基团)保护)来制备。
通式(IV)氨基酸可以购得或通过文献(Williams,R.M.,光学活性α-氨基酸的合成(Synthesis of optically active α-amino acids),Pergamon Press,Oxford,1989)中描述的方法制备。
通式(V)化合物通过用选自本领域技术人员已知方法的方法使通式(IV)化合物的胺官能团去保护得到。这些方法特别包括例如在用Boc基团保护的情况下使用三氟乙酸或在二氯甲烷或乙酸乙酯中的盐酸;例如在用CBz基团保护的情况下,用在四氢呋喃或甲醇中的适当金属氢化;和例如在用Fmoc基团保护的情况下使用在乙腈中的哌啶。
在最后阶段,通式(I)化合物通过在常规肽偶联条件下使用例如1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐或羟基苯并***或TBTU作为偶联剂和三乙胺或二异丙基乙胺作为碱在诸如二氯甲烷或二甲基甲酰胺的溶剂中偶联式(V)胺和式(VI)酸来制备。
通式(VI)化合物可以购得或根据文献中所述或本领域技术人员已知、根据取代基R4和R5的性质修改的方法来制备。根据R4和R5的性质,下文中的方案2、3和4提供制备通式(VI)化合物的实例。
例如,当R5包含用1,2,3-***杂环取代的烷基时,化合物(VI)可根据方案2制备:
方案2:
通式(VIII)化合物通过利用选自本领域技术人员已知方法的方法使通式(VII)化合物的酸官能团酯化得到。所述方法特别包括例如使用在甲醇中的硫酸。由式(VIII)化合物得到的式(IX)化合物通过文献(Loren J.C.,Synlett,2005,2847-2850)中描述的方法制备,接着在碱性介质中在例如氢氧化钠存在下在水/甲醇混合物中裂解,从而产生***化合物(VI)。
例如,当R5包含用咪唑杂环取代的烷基时,化合物(VI)根据方案3制备:
方案3:
通式(X)化合物可以购得或根据文献中描述的或本领域技术人员已知的方法制备。通式(VI)化合物例如通过在可为在甲醇中的钯/炭的催化剂存在下使化合物(X)氢化得到。
例如,当R5包含用杂环取代的烷基时,化合物(VI)可根据方案4制备:
方案4:
通式(XVIII)化合物例如通过在可为六甲基二硅氮烷锂的碱存在下在诸如四氢呋喃的溶剂中叶立德(ylide)(XVII)和用醛(XVI)取代的杂环之间的维狄希(Wittig)反应来得到。通式(VI)化合物例如通过在可为钯/炭的催化剂存在下在例如乙酸的酸性介质中使化合物(XVIII)氢化得到。
通式(II)化合物根据在文献中描述或本领域技术人员已知的根据取代基R1和R2的性质修改的方法来制备。在下文中的方案5和6提供制备通式(II)化合物的实例。
例如,当R2包含烷氧基链时,化合物(II)可根据方案5制备:
方案5:
通式(XII)化合物例如通过向N-boc-吖丁啶酮(XI)(商用)中加入衍生自R1的卤化镁来得到,接着在例如可为氢化钠的碱和衍生自R2的卤代衍生物存在下使叔醇烷基化,从而得到化合物(XIII)。通式(II)化合物通过例如在三氟乙酸或在二氯甲烷或乙酸乙酯中的盐酸存在下使通式(XIII)化合物的胺官能团去保护得到。
例如,当R2包含烷基链时,通式(II)化合物根据方案6制备:
方案6:
通式(XV)化合物可例如通过在衍生自R2的卤代衍生物存在下加入诸如氢化钠的碱来得到。通式(XIX)的伯醇在例如氢化钠的碱和多聚甲醛存在下由腈衍生物(XV)合成。化合物(XIX)的伯醇官能团例如在可为三乙胺的碱或甲苯磺酰氯存在下转化为磺酸盐。通式(II)的吖丁啶化合物通过例如在氢化铝锂存在下还原腈官能团之后得到的胺官能团和通式(XX)化合物的甲苯磺酸盐官能团之间的分子内环化来合成。
根据本发明,特别优选的通式(I)化合物为如下化合物,其中:
-R1代表芳基、被取代的芳基或环烷基;
-R2代表羟基、低碳数烷基、被取代的低碳数烷基、高碳数烷基、被取代的高碳数烷基、碳数烷氧基、被取代的低碳数烷氧基、高碳数烷氧基、被取代的高碳数烷氧基或环烷基烷氧基;
-R3代表芳烷基或被取代的芳烷基;
-R4代表杂芳烷基或被取代的杂芳烷基;
-R5代表氢或酰氨基;
以及通式(I)化合物的相应盐和对映异构体。
优选的化合物有:
-N-[(S)-1-[(S)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-1-[(S)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(S)-1-[(S)-2-[3-丁氧基-3-(3-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(2,4-二氯苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(3-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-苄基-2-(3-丁氧基-3-苯基吖丁啶-1-基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-[1,2,4]***-3-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺
-N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)-3-戊基吖丁啶-1-基]-2-氧代乙基}-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-苄基-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,4-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(3-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(2,4-二氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,5-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,6-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)戊酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
-(S)-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-2-羟基-3-(1H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环己基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-邻甲苯基-3-(4,4,4-三氟丁氧基)吖丁啶-1-基]乙基丙酰胺
-N-[(R)-2-(3-环丁基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
-N-{(R)-1-(4-甲氧基苄基)-2-[3-(3-甲基丁-2-烯基氧基)-3-邻甲苯基吖丁啶-1-基]-2-氧代乙基}-3-(5-甲基-1H-咪唑-4-基丙酰胺
以及其对应盐和对映异构体。
根据本发明,特别优选的通式(I)化合物为如下化合物,其中:
-R1代表芳基、被取代的芳基或环烷基;
-R2代表低碳数烷氧基、高碳数烷氧基、环烷基烷氧基、低碳数烷基或高碳数烷基;
-R3代表被取代的芳烷基;
-R4代表被取代的咪唑或未被取代的咪唑;
-R5代表氢;以及通式(I)化合物的相应盐和对映异构体。
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺
-N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)-3-戊基吖丁啶-1-基]-2-氧代乙基}-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,4-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(3-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,5-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-[3-(2,6-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺,
-N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
-N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
-N-[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
-N-[(R)-2-(3-环己基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
-3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-邻甲苯基-3-(4,4,4-三氟丁氧基)吖丁啶-1-基]乙基丙酰胺
-N-[(R)-2-(3-环丁基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
-N-{(R)-1-(4-甲氧基苄基)-2-[3-(3-甲基丁-2-烯基氧基)-3-邻甲苯基吖丁啶-1-基]-2-氧代乙基}-3-(5-甲基-1H-咪唑-4-基丙酰胺;
以及其对应盐和对映异构体。
根据本发明的化合物具有黑皮质素受体调节性质。术语“黑皮质素受体调节性质”用以指黑皮质素受体激动剂或拮抗剂性质。对MCR的该活性在转活化试验中测量且通过50%有效浓度(EC50)量化,如实施例10中所述。
优选所述化合物为至少调节MCR、相对于亚型1(MC1R)具有选择性的化合物,即,MC1R相对于其它MCR,它们的EC50比大于或等于10。优选该比率大于或等于10、有利地大于或等于20、更有利地大于或等于50。
有利的是,本发明的化合物相对于MC1受体显示出小于或等于10μM且更具体地小于或等于1μM的50%有效浓度(EC50)值。
本发明因此涉及至少一种如上定义的通式(I)化合物制备药物组合物或美容组合物的用途,其中所述化合物对一种或多种黑皮质素受体且尤其是对亚型1、3、4和5具有调节活性。
在本发明的一个特定实施方案中,本发明中的通式(I)化合物具有MC1R选择性活性且特别适用于治疗色素沉着病症及炎性和免疫病症。本发明的某些其它化合物具有MC4R选择性且特别适用于治疗饮食和新陈代谢病症以及神经退行性疾病。
本发明还涉及治疗学或美容治疗方法,其包括施用包含作为一种或多种黑皮质素受体、尤其是亚型1、3、4和5的调节剂的所述化合物的医药或美容组合物。在一个特定的实施方案中,本发明还涉及治疗或美容方法,其包括施用包含所述化合物的医药或美容组合物以便治疗色素沉着病症及炎性和免疫病症。在本发明的一个实施方案中,所述化合物为亚型1选择性调节剂。
本发明还涉及如上定义的通式(I)化合物在制备用于治疗与MC1R的功能障碍有关的病症的药物中的用途。
具体地说,根据本发明使用的化合物特别适合治疗和/或预防选自以下的病症和/或疾病:
-消化道的炎性疾病,尤其包括肠(且特别是结肠,在过敏性肠综合征、溃疡性结肠炎或克罗恩氏病(Crohn’s disease)的情况下)的炎性疾病;胰腺炎、肝炎(急性和慢性)、膀胱的炎性病理学病状和胃炎;
-运动***的炎性疾病,包括类风湿性关节炎、骨关节炎、骨质疏松症、创伤性关节炎、感染后关节炎、肌肉退化病、皮肌炎;
-泌尿生殖***的炎性疾病,尤其是肾小球性肾炎;
-心脏***的炎性疾病,尤其是心包炎和心肌炎,和包括炎症作为基础因素的那些疾病的疾病。这些疾病包括但不限于动脉粥样硬化、移植动脉粥样硬化、周围血管疾病、炎性血管疾病、间歇性跛行或磕绊、再狭窄、中风、短暂性脑缺血发作、心肌局部缺血和心肌梗塞。这些化合物还可用于治疗高血压、高脂血、冠状动脉疾病、不稳定型心绞痛(angina)(或心绞痛(angina pectoris))、血栓形成、凝血酶诱发的血小板凝聚和/或血栓形成和/或动脉粥样斑形成的后果;
-呼吸和ENT***的炎性疾病,尤其包括哮喘、急性呼吸窘迫综合征、花粉热、过敏性鼻炎和慢性阻塞性肺病。根据本发明的化合物还可用于治疗过敏症;
-中枢神经***的炎性疾病,尤其是阿茨海默氏病(Alzheimer’s disease)和任何形式的痴呆、帕金森氏病(Parkinson’sdisease)、克雅氏病(Creutzfeldt-Jacob disease)、多发性硬化、脑膜炎;
-炎性皮肤疾病,尤其是荨麻疹、硬皮病、接触性皮炎、特异性皮炎、牛皮癣、鳞癣、痤疮及其它形式的毛囊炎、红斑痤疮和秃发症;
-自体免疫疾病,尤其是红斑狼疮、甲状腺病状、肾上腺的自体免疫疾病和自体免疫胃炎、白斑病和斑秃;
-伴随细菌、病毒或真菌感染的炎症,尤其是肺结核、败血病、热病、HIV(无论什么位置感染)、疱疹、巨细胞病毒、甲型肝炎、乙型肝炎和丙型肝炎;
-移植或移植排斥,诸如肾、肝、心脏、肺、胰腺、骨髓、角膜、肠、皮肤(皮肤同种异体移植、自体移植和异种移植等)。
另外,这些化合物可用来治疗无论起源在哪里的疼痛:术后疼痛、神经肌肉疼痛、头痛、癌症相关疼痛、牙痛、骨关节痛。
这些化合物可用于调节色素沉着,因此用于:
-治疗具有色素沉着病症的疾病,尤其是良性皮肤病,诸如白斑病、白化病、黑斑病、痣、雀斑、黑素细胞痣和所有炎症后色素沉着;以及色素沉着肿瘤,诸如黑素瘤和局部转移(渗透根瘤)、区域转移或其全身性转移;
-出于预防目的的光照保护以免受日光影响:
-日光的有害影响,诸如光化红斑、皮肤老化、皮肤癌(棘细胞、基底细胞(basocellular)和黑素瘤),尤其是其中日光加速发病的疾病(着色性干皮病、基底细胞痣综合征、家族性黑素瘤);
-由于外源感光剂引起的光线性皮肤病(photodermatoses),尤其是通过接触感光剂(例如呋喃香豆素、卤代水杨酰苯胺和衍生物、及局部硫酰胺和衍生物)引起的光线性皮肤病或由感光剂通过全身性路径(例如补骨脂素、四环素、硫酰胺、吩噻嗪、萘啶酮酸、三环抗忧郁药)引起的光线性皮肤病;
-具有光敏性的皮肤病发作,尤其是
-光加重的皮肤病(例如红斑狼疮、复发性疱疹、先天性皮肤异色病(congenital poikilodermal)或具有光敏性的毛细血管扩张(telangiectasic)病状(布卢姆综合症(bloom syndrome)、科凯恩综合症(Cockayne syndrome)、罗思蒙德-汤姆森二氏综合征(Rothmund-Thomson syndrome))、光化扁平癣、光化肉芽瘤、播散浅表性光线性汗孔角化症、红斑痤疮、少年痤疮(juvenile acne)、大疱皮肤病、这里埃病(Darier’s disease)、皮肤淋巴瘤、牛皮癣、特异性皮炎、接触性皮炎、卵泡粘蛋白沉积症、多形性红斑、固定药物红斑、皮肤淋巴细胞瘤、具有粘蛋白沉积症的网状红斑、黑斑病),
-具有因黑色素形成或分布异常的保护***缺陷引起的光敏性的皮肤病(例如眼皮白化病、苯丙酮酸尿症、前垂体功能不全、白斑病、斑驳)和具有DNA修复***缺陷的皮肤病(例如着色性干皮病、科凯恩综合症),
-具有由新陈代谢异常引起的光敏性的皮肤病,诸如皮肤卟啉病(例如晚期皮肤卟啉病、混合型卟啉病、生血性原卟啉病、先天性红细胞生成性卟啉病(京特病(Günther’s disease))、红细胞生成性粪卟啉病)、糙皮病或类糙皮病红斑(例如,糙皮病、类糙皮病红斑和色氨酸新陈代谢病症);
-自发性光照性皮肤病发作,尤其是PMLE(多态性光线疹)、良性夏季光线疹、光化痒疹、持久性光过敏(光线性类网状细胞增生病(actinoreticulosis)、慢性光线性皮肤病、感光湿疹)、日光性荨麻疹、牛痘样水疱病、青年春季疹、日光性瘙痒),
-调节皮肤或头发和身体毛发的颜色,尤其是因黑色素合成增加引起皮肤变褐色或因妨碍黑色素合成使皮肤变白;而且预防头发和身体毛发变白或变灰(例如灰发症和斑驳);
-在美容适应症中改变头发和身体毛发的颜色。
这些化合物可用于调节皮脂腺功能,以便:
-治疗具有皮脂分泌过多的病状,尤其是痤疮、脂溢性皮炎、多油脂性皮肤和多油脂性头发、帕金森氏病和癫痫中的皮脂分泌过多和雄激素过多症;
-治疗具有减少的皮脂分泌的病状,尤其是干燥病和所有干燥性皮肤;
-调节良性或恶性皮脂腺细胞和皮脂腺增生;
-治疗毛囊皮脂腺滤泡的炎性疾病,尤其是痤疮、疖、痈和毛囊炎。
本发明还涉及如上定义的通式(I)化合物用于制备用于治疗与MC4R功能障碍有关的病症的药物中的用途。
本发明的化合物还可用于治疗神经退行性疾病,包括抑郁症、焦虑症、强迫症(诸如强迫性障碍)、神经病、精神病、失眠和睡眠障碍、睡眠呼吸暂停和药物滥用。
这些化合物可用于治疗男性或女性性功能障碍。男性性功能障碍包括但不限于阳痿、***减退和***功能障碍。
女性性功能障碍包括但不限于性刺激障碍或与欲望相关的病症、性接受程度、***高潮和性功能要点的障碍。女性性功能障碍还可包括疼痛、早产、痛经、月经过多和子宫内膜异位。
根据本发明的化合物还可用于治疗与体重相关的病症,所述病症但不限于肥胖症和食欲缺乏(诸如食欲改变或受损、脾脏新陈代谢、脂肪或碳水化合物的无害摄取);糖尿病(由于葡萄糖剂量耐受性和/或胰岛素抵抗性降低)。
所述化合物还可用于治疗癌症,尤其是肺癌、***癌、结肠癌、乳腺癌、卵巢癌和骨癌,或包括实体肿瘤的形成或生长的血管形成病症。
本发明的主题还在于尤其用于治疗上述病状的药物组合物,且其特征在于其包含在与选择用于所述组合物的施用方法相容的医药学上可接受的载体中的通式(I)化合物或其对映异构体或其与医药学上可接受的酸的盐。
术语“医药学上可接受的载体”用以指与皮肤、粘膜和皮肤附件相容的介质。
根据本发明的组合物的给药可经口服、肠内、肠胃外、局部或经眼进行。优选所述药物组合物调节为适于局部施用的形式。
当用于口服给药时,所述组合物可呈如下形式:片剂、凝胶胶囊、锭剂、糖浆、混悬剂、溶液剂、粉剂、颗粒剂、乳液、微球或纳米球的混悬剂或脂质或聚合物泡囊以便于受控释放。当用于肠胃外给药时,所述组合物可以溶液剂或混悬剂形式以便于输注或注射。
根据本发明的组合物通常以约0.01mg/kg-100mg/kg体重的日剂量以一次或多次摄取经口服给药或全身性给药。
所述化合物以相对于组合物的总重量通常为0.001%-10%重量、优选0.01%-1%重量的浓度全身性使用。
当局部给药时,根据本发明的药物组合物更特别适用于治疗皮肤和粘膜,且可以液体、糊状物或固体形式,更特别地以药膏、乳膏、乳液、软膏、粉剂、浸渗垫、去污剂(syndet)、溶液剂、凝胶、喷雾剂、泡沫剂、混悬剂、贴剂(stick)、洗发精或洗涤基质形式。其还可以微球或纳米球的混悬剂、或脂质或聚合物泡囊、或聚合物或凝胶贴剂的形式以便受控释放。
用于局部给药的组合物具有相对于组合物的总重量通常为0.001%-10%重量、优选为0.01%-5%重量的浓度的根据本发明的化合物。
根据本发明的通式(I)化合物还在美容领域、尤其是在预防日光的有害影响中获得应用,用于预防和/或抗击皮肤和皮肤附件的光诱发或自然的老化。
本发明的主题因此还在于包含在美容学上可接受的载体中的至少一种通式(I)化合物的组合物。术语“美容学上可接受的介质”用以指与皮肤、粘膜和皮肤附件相容的介质。
本发明的主题还在于包含至少一种通式(I)化合物的组合物用于预防和/或治疗老化和/或皮肤的病征的美容用途。
本发明的主题还在于包含至少一种通式(I)化合物的组合物用于身体或头发卫生的美容用途。
包含在美容学上可接受的载体中的通式(I)化合物或其对映异构体或其与医药学上可接受的酸的盐的根据本发明的美容组合物尤其可以如下形式:乳膏、乳液、凝胶、微球或纳米球的混悬剂或脂质或聚合物泡囊、浸渗垫、溶液剂、喷雾剂、泡沫体、贴剂、皂、洗涤基质或洗发精。
在所述美容组合物中通式(I)化合物的浓度相对于所述组合物的总重量优选为0.001%-10%重量。
如上所述的药物组合物和美容组合物还可包含惰性添加剂或者甚至药效学活性添加剂(在药物组合物方面)或这些添加剂的组合,尤其是:
-湿润剂;
-增香剂;
-防腐剂,诸如对羟基苯甲酸酯;
-稳定剂;
-水分调控剂;
-pH调控剂;
-渗透压力调节剂;
-乳化剂;
-UV-A和UV-B掩蔽剂;
-抗氧化剂,诸如α-生育酚、丁基羟基苯甲醚或丁基羟基甲苯、超氧化物歧化酶、泛醌醇(ubiquinol);
-软化剂;
-保湿剂,诸如甘油、PEG 400、噻吗啉酮和其衍生物或尿素;
-抗皮脂溢剂或抗痤疮剂,诸如S-羧甲司坦、S-苄基半胱胺、其盐或其衍生物、或过氧化苯甲酰。
当然,本领域的技术人员将慎重选择加到这些组合物中的任选化合物,从而使得与本发明内在相关的有利性质不受或基本不受所预计添加的损害。
现将通过举例说明而决不是在本质上限制的方式给出得到根据本发明的通式(I)化合物和这些化合物的生物活性结果的数个实施例。
以下实施例描述根据本发明一些化合物的制备。这些实施例不是限制、而仅仅是举例说明本发明。所例示的化合物的编号回头参阅下文表I中给出的化合物,表I说明了根据本发明的一些化合物的化学名称和物理性质。
使用以下缩写:
-TBTU:四氟硼酸N,N,N’,N’-四甲基-O-(苯并***-1-基)脲
-HOBt:1-羟基-1,2,3-苯并***
-EDC:1-乙基-(3-二甲氨基丙基)碳化二亚胺盐酸盐
-BOC:叔丁氧基羰基
-CBz:苄氧基羰基
-Fmoc:6-芴基甲氧基羰基
-Tos:对甲苯磺酰基
-DMF:二甲基甲酰胺
-DCM:二氯甲烷
-DIEA:二异丙基乙胺
术语“构象异构体”对于立体异构体给出,其通过围绕键(由电子的双重态提供的单键)旋转从一种构象转变为另一构象。
材料和方法
HPLC方法:
方法A
管柱:Gemini 150×3mm,3μm
UV检测器:220-420nm
流速:0.5ml/min
溶剂A:CH3CN+0.05TFA
溶剂B:H2O+0.05TFA
梯度:
方法B
管柱:Gemini 150×3mm,3μm
UV检测器:220-420nm
流速:0.5ml/min
溶剂A:CH3CN+0.05TFA
溶剂B:H2O+0.05TFA
梯度:
方法C
管柱:Atlantis C18 150×3.2mm,3μm
UV检测器:220-420nm
流速:0.3ml/min
溶剂A:CH3CN+0.1TFA
溶剂B:H2O+0.1TFA
梯度:
方法D
管柱:Gemini 150×3mm,3μm
UV检测器:220-420nm
流速:0.5ml/min
溶剂A:CH3CN
溶剂B:H2O+0.02TFA
梯度:
方法E
管柱:Xbridge phenyl 150×2.1mm,3.5μm
UV检测器:220-420nm
流速:1.0ml/min
溶剂A:95%MeOH/5%水+25mM NH4OAc
溶剂B:H2O+25mM NH4OAc
梯度:
方法F
管柱:Xbridge phenyl 250×4.6mm,5μm
UV检测器:220-420nm
流速:1.0ml/min
溶剂A:90%MeOH/10%水+25mM NH4OAc
溶剂B:H2O+25mM NH4OAc
梯度:
方法G
管柱:Xbridge phenyl 250×4.6mm,5μm
UV检测器:220-420nm
流速:1.0ml/min
溶剂A:90%MeOH/10%水+25mM NH4OAc
溶剂B:H2O+25mM NH4OAc
梯度:
方法H
管柱:Gemini C18 150×3mm,3μm
UV检测器:220-420nm
流速:0.3ml/min
溶剂A:94%MeOH/6%水+10mm NH4OAc
溶剂B:H2O+10mm NH4OAc
梯度:
方法I
管柱:Gemini C18 150×3mm,3μm
UV检测器:220-420nm
流速:0.3ml/min
溶剂A:H2O+0.05%TFA
溶剂B:CH3CN+0.05%TFA
梯度:
方法J
管柱:Gemini C18 150×3mm,3μm
UV检测器:220-420nm
流速:0.5ml/min
溶剂A:MeOH+0.1%TFA
溶剂B:H2O+0.02%TFA
梯度:
方法K
管柱:Gemini C6-phenyl 150×3mm,3μm
UV检测器:220-420nm
流速:0.5ml/min
溶剂A:H2O+0.05%TFA
溶剂B:CH3CN+0.05%TFA
梯度:
方法L
管柱:Gemini C18 150×3mm,3μm
UV检测器:220-420nm
流速:0.5ml/min
溶剂A:CH3CN+0.1%HCOOH
溶剂B:H2O+0.1%HCOOH
梯度:
方法M
管柱:ThermoHypersil Hypurity C18 150×4.6mm,5μm
UV检测器:220-420nm
流速:0.5ml/min
溶剂A:H2O+0.05%TFA
溶剂B:CH3CN+0.05%TFA
梯度:
方法N
管柱:Atlantis T3 150×2.1mm,3μm
UV检测器:220-420nm
流速:0.3ml/min
溶剂A:H2O+0.05%TFA
溶剂B:CH3CN+0.05%TFA
梯度:
方法O
管柱:Atlantis T3 150×4.6mm,5μm
UV检测器:220-420nm
流速:0.3ml/min
溶剂A:H2O+0.05%TFA
溶剂B:CH3CN+0.05%TFA
梯度:
方法P
管柱:Atlantis T3 150×4.6mm,5μm
UV检测器:190-420nm
流速:0.25ml/min
溶剂A:H2O+0.05%TFA
溶剂B:CH3CN+0.05%TFA
梯度:
方法Q
管柱:Atlantis T3 150×4.6mm,5μm
UV检测器:190-420nm
流速:0.3ml/min
溶剂A:H2O+0.05%TFA
溶剂B:CH3CN+0.05%TFA
梯度:
方法R
管柱:Gemini C6-phenyl 150×3mm,3μm
UV检测器:190-420nm
流速:0.3ml/min
溶剂A:CH3CN+0.05%TFA
溶剂B:H2O+0.05%TFA
梯度:
方法S
管柱:Eclipse XDB C8 150×4.6mm,5μm
UV检测器:190-420hm
流速:1ml/min
溶剂A:CH3CN+0.1%HCOOH
溶剂B:H2O+0.1%HCOOH
梯度:
方法T
管柱:Gemini C6-phenyl 150×3mm,3μm
UV检测器:190-420nm
流速:0.3ml/min
溶剂A:CH3CN+0.05%TFA
溶剂B:H2O+0.05%TFA
梯度:
方法U
管柱:Atlantis T3 150×4.6mm,5μm
UV检测器:190-420nm
流速:0.3ml/min
溶剂A:CH3CN+0.05%TFA
溶剂B:H2O+0.05%TFA
梯度:
方法V
管柱:Xbridge C18 250×4.5mm,5μm
UV检测器:190-420nm
流速:1ml/min
溶剂A:CH3CN+0.05%TFA
溶剂B:H2O+0.05%TFA
梯度:
方法W
管柱:Xbridge Phenyl 150×3mm,3μm
UV检测器:190-420nm
流速:1ml/min
溶剂A:CH3CN+0.05%TFA
溶剂B:H2O+0.05%TFA
梯度:
方法X
管柱:Atlantis 150×2.1mm,3μm
UV检测器:190-420nm
流速:0.3ml/min
溶剂A:CH3CN+0.02%TFA
溶剂B:H2O+0.02%TFA
梯度:
方法Y
管柱:Xbridge Phenyl 250×4mm,3μm
UV检测器:190-420hm
流速:0.8ml/min
溶剂A:CH3CN+5%THF+0.02%TFA
溶剂B:H2O+0.02%HCOOH
梯度:
方法Z
管柱:Atlantis T3 150×2.1mm,3μm
UV检测器:190-420nm
流速:0.3ml/min
溶剂A:CH3CN+0.02%TFA
溶剂B:H2O+0.02%TFA
梯度:
实施例1:N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺(化合物编号3;表I)
1-1 (S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酸
将5.07g(15.8mmol)TBTU加到包含在30ml DMF中的4.05g(15.6mmol)(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酸的溶液中。使反应介质在环境温度下搅拌15分钟。逐滴加入在20ml DMF中的3g(14.3mmol)(S)-2-氨基-3-(4-甲氧基苯基)丙酸甲酯和7.5ml DIEA并在环境温度下搅拌4小时。反应通过加入水来终止,并将有机产物用二氯甲烷萃取。将有机相在硫酸镁存在下干燥。过滤之后,蒸出溶剂。得到6.56g浅黄色固体并将其溶解于100ml THF中。加入29ml的1N LiOH溶液。将反应介质在环境温度下搅拌16小时。加入20ml氯化铵饱和溶液,接着用***萃取。水相用1N HCl溶液酸化到pH 5。滤出得到的白色沉淀物并在真空下在40℃下将其烘干。得到5.6g(12.8mmol)(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酸,产率88%。
1-2 N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
1-2-1 3-羟基-3-苯基-1-(叔丁氧基羰基)吖丁啶
将3.9ml(11.7mmol)苯基溴化镁在***中的3M溶液逐滴加到浸没在-50℃浴中的包含在10ml THF中的500mg(2.92mmol)3-氧代-1-(叔丁氧基羰基)吖丁啶的溶液中。将介质在-50℃下搅拌1小时且通过加入氯化铵饱和溶液来水解。在回到环境温度之后,加入1N盐酸溶液,接着用乙酸乙酯萃取。将有机相干燥并蒸干。将得到的粗产物在二氧化硅上以7/3庚烷/乙酸乙酯混合物纯化。得到253mg的白色粉末形式的产物,产率35%。
1-2-2 3-丁氧基-3-苯基-1-(叔丁氧基羰基)吖丁啶
将1g(4.0mmol)3-羟基-3-苯基-1-(叔丁氧基羰基)吖丁啶溶解于5ml DMF中的溶液逐滴加到浸没在0℃浴中的300mg的60%NaH在3ml DMF中的悬浮液中。逐滴加入2.5ml碘正丁烷。使反应介质在0℃下搅拌10分钟并在环境温度下搅拌72小时。介质通过加入氯化铵饱和溶液水解,接着用乙酸乙酯萃取。将有机相干燥并蒸干。将得到的粗产物在二氧化硅上以7/3庚烷/乙酸乙酯混合物纯化。得到500mg淡黄色油形式的产物,产率41%。
1-2-3 3-丁氧基-3-苯基吖丁啶三氟乙酸盐
将1ml三氟乙酸加到包含溶解于5ml二氯甲烷中的500mg(1.64mmol)3-丁氧基-3-苯基-1-(叔丁氧基羰基)吖丁啶的溶液中。将反应介质在环境温度下搅拌3小时,随后浓缩。得到的粗产物通过硅胶色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到400mg浅黄色粉末形式的产物,产率76%。
1-3 N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
将1ml 3/2二氯甲烷/三氟乙酸溶液加到200mg(0.343mmol)(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酸中。在环境温度下搅拌1小时之后,将溶剂蒸出。将得到的残余物溶解于5ml DMF中,且加入110mg(0.343mmol)TBTU和2.37ml DIEA。使反应介质在环境温度下搅拌15分钟。逐滴加入溶解于5ml 1/4 DCM/DMF溶液中的47mg(0.147mmol)3-丁氧基-3-苯基吖丁啶三氟乙酸盐并在环境温度下搅拌16小时。加入5%柠檬酸溶液,接着用二氯甲烷萃取。将有机相用碳酸氢钾饱和溶液洗涤。将有机相干燥并蒸干。得到的粗产物通过硅胶色谱法(洗脱剂:9/1二氯甲烷/甲醇)纯化。得到55mg白色粉末形式的N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺,产率60%。
HPLC:(方法A);2个峰(构象异构体的混合物):保留时间:16.44min和16.60min,(34+57)%,M+H:624。
实施例2:丁酸[1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-(4-氟苯基)吖丁啶-3-基]酯(化合物编号6;表I):
2-1 3-(4-氟苯基)-3-羟基-1-(叔丁氧基羰基)吖丁啶
将6ml(11.7mmol)4-氟苯基溴化镁在***中的2M溶液逐滴加入浸没于-50℃浴中的包含在10ml THF中的500mg(2.92mmol)3-氧代-1-(叔丁氧基羰基)吖丁啶的溶液中。将介质在-50℃下搅拌1小时,且通过加入氯化铵饱和溶液水解。在回到环境温度之后,加入1N盐酸溶液,接着用乙酸乙酯萃取。将有机相干燥并蒸干。得到的粗产物通过硅胶色谱法(洗脱剂:7/3庚烷/乙酸乙酯)纯化。得到333mg白色粉末形式的产物,产率43%。
2-2 3-丁酰基氧基-3-(4-氟苯基)-1-(叔丁氧基羰基)吖丁啶
将23mg(0.188mmol)DMAP和0.03ml吡啶加到包含在1ml二氯甲烷中的50mg(0.187mmol)3-丁酰基氧基-3-(4-氟苯基)-1-(叔丁氧基-羰基)吖丁啶的溶液中。在环境温度下搅拌10分钟之后,引入0.06ml丁酸酐。3小时后,加入氯化铵饱和溶液,接着用二氯甲烷萃取。将有机相干燥并蒸干。得到的粗产物通过硅胶色谱法(洗脱剂:7/3庚烷/乙酸乙酯)纯化。得到61mg无色油形式的产物,产率97%。
2-3 丁酸3-(4-氟苯基)吖丁啶-3-基酯三氟乙酸盐
将2ml三氟乙酸加到包含溶解于8ml二氯甲烷中的61mg(0.181mmol)3-羟基-3-(4-氟苯基)-1-(叔丁氧基羰基)吖丁啶的溶液中。将反应介质在环境温度下搅拌3小时,随后浓缩。得到的粗产物通过硅胶色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到40mg浅黄色油形式的产物,产率63%。
2-4 丁酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-(4-氟苯基)吖丁啶-3-基酯
将1ml 3/2二氯甲烷/三氟乙酸溶液加到109mg(0.252mmol)(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酸(参照程序1-1)中。在环境温度下搅拌1小时之后,将溶剂蒸出。将得到的残余物溶解于5ml DMF中,且加入8mg(0.252mmol)TBTU和1.74ml DIEA。使反应介质在环境温度下搅拌15分钟。逐滴加入溶解于5ml 1/4二氯甲烷/二甲基甲酰胺溶液中的40mg(0.114mmol)丁酸3-(4-氟苯基)吖丁啶-3-基酯三氟乙酸盐并在环境温度下搅拌16小时。加入5%柠檬酸溶液,接着用二氯甲烷萃取。将有机相用碳酸氢钾饱和溶液洗涤。将有机相干燥并蒸干。得到的粗产物通过硅胶色谱法(洗脱剂:9/1二氯甲烷/甲醇)纯化。得到19mg白色粉末形式的丁酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-(4-氟苯基)吖丁啶-3-基酯,产率25%。
HPLC:(方法B):2个峰(构象异构体的混合物):保留时间:13.51min和13.72min,(28+55)%,M+H:656。
实施例3:N-[(S)-1-[(S)-2-(3-环己基-3-羟基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺(化合物编号7;表I)
3-1 3-环己基-3-羟基-1-(叔丁氧基羰基)吖丁啶
将0.5ml乙酸和40mg 5%铑/氧化铝加到包含溶解于4ml甲醇中的117mg(0.470mmol)3-羟基-3-苯基-1-(叔丁氧基-羰基)吖丁啶(参照程序1-2-1)的溶液中。将反应介质置于4巴氢气中并在85℃下加热4小时。将催化剂滤出,用甲醇洗涤且将溶剂蒸出。得到120mg浅褐色粉末形式的产物,产率100%。
3-2 3-环己基吖丁啶-3-醇三氟乙酸盐
将1ml三氟乙酸加到包含溶解于3ml二氯甲烷中的120mg(0.47mmol)3-环己基-3-羟基-1-(叔丁氧基羰基)吖丁啶的溶液中。将反应介质在环境温度下搅拌1小时,随后浓缩至干燥并在不进一步纯化的情况下使用。
3-3 N-[(S)-1-[(S)-2-(3-环己基-3-羟基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
将1ml 3/2二氯甲烷/三氟乙酸溶液加到84mg(0.193mmol)(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酸(参照程序1-1)中。在环境温度下搅拌1小时后,将溶剂蒸出。将得到的残余物溶解于1ml DMF中,且加入79mg(0.246mmol)TBTU和15滴DIEA。逐滴加入溶解于1ml DCM溶液中的0.235mmol 3-环己基吖丁啶-3-醇三氟乙酸盐并在环境温度下搅拌2小时。加入碳酸氢钾饱和溶液,接着用二氯甲烷萃取。将有机相用碳酸氢钾饱和溶液洗涤。将有机相干燥并蒸干。得到的粗产物通过硅胶色谱法(洗脱剂:85/15二氯甲烷/甲醇混合物)纯化。得到35mg黄色粉末形式的N-[(S)-1-[(S)-2-(3-环己基-3-羟基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺,产率32%。
HPLC:(方法B):2个峰(构象异构体的混合物):保留时间:10.68min和10.94min,(36+62)%,M+H:574。
实施例4:N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺(化合物编号24;表I)
4-1 3-戊氧基-3-邻甲苯基-1-(叔丁氧基羰基)吖丁啶将3.53g(13.4mmol)3-羟基-3-苯基-1-(叔丁氧基羰基)吖丁啶(参照程序1-2-1)的溶液逐滴加到浸没在0℃浴中的1.07g(26.8mmol)60%NaH在17ml DMF中的悬浮液中。逐滴加入9.0ml碘正戊烷。使反应介质在0℃下搅拌15分钟且在环境温度下搅拌24小时。介质通过加入氯化铵饱和溶液水解,接着用乙酸乙酯萃取。将有机相干燥并蒸干。得到的粗产物通过硅胶色谱法(洗脱剂:7/3庚烷/乙酸乙酯)纯化。得到3.41g淡黄色油形式的产物,产率76%。
4-2 3-戊氧基-3-苯基吖丁啶三氟乙酸盐
将5.5ml三氟乙酸加到包含溶解于10ml二氯甲烷中的3.34g(10mmol)3-戊氧基-3-苯基-1-(叔丁氧基羰基)吖丁啶的溶液中。将反应介质在环境温度下搅拌2小时30分钟,随后浓缩。得到的粗产物通过硅胶色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到3.5g浅黄色油形式的产物,产率100%。
4-3 [(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]氨基甲酸叔丁酯
将2.93g(9.93mmol)(R)-2-叔丁氧基羰基氨基-3-(4-甲氧基苯基)丙酸溶解于10ml DMF中。随后加入2.08g(10.9mmol)EDC、1.47g(10.9mmol)HOBt和3.45g(9.93mmol)3-戊氧基-3-苯基吖丁啶三氟乙酸盐在15ml DMF中的溶液。加入7ml(40.2mmol)DIEA。将反应介质在环境温度下搅拌2小时30分钟,随后用乙酸乙酯萃取。将有机相用1N氢氧化钠洗涤,随后经硫酸镁干燥、过滤并蒸发。得到的粗产物通过硅胶色谱法(洗脱剂:6/4庚烷/乙酸乙酯)纯化。得到2.83g白色粉末形式的产物,产率56%。
4-4 (R)-2-氨基-3-(4-甲氧基苯基)-1-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)丙-1-酮三氟乙酸盐
将2.81g(5.5mmol)[(R)-1-(4-甲氧基-苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]氨基甲酸叔丁酯溶解在10ml二氯甲烷中。将反应介质冷却到0℃。随后引入6.5ml三氟乙酸。回到环境温度之后,将反应介质搅拌5小时,随后浓缩至干燥。得到的粗产物通过硅胶色谱法(洗脱剂:9/1二氯甲烷/甲醇)纯化。得到2.81g白色粉末形式的产物,产率97%。
4-5 N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
将670mg(2.08mmol)TBTU、0.8ml三乙胺和1.0g(1.91mmol)(R)-2-氨基-3-(4-甲氧基苯基)-1-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)丙-1-酮三氟乙酸盐加到包含在15ml二甲基甲酰胺中的370mg(2.10mmol)去氨基-组氨酸盐酸盐的溶液中。将反应介质在环境温度下搅拌21小时。反应通过加入1N氢氧化钠溶液停止,随后用二氯甲烷进行萃取。将有机相合并且经硫酸钠干燥。过滤之后,将溶剂蒸出且残余物随后通过硅胶色谱法(洗脱剂90/10二氯甲烷/甲醇)纯化。得到598mg白色粉末形式的N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺,产率59%。
HPLC:(方法M);保留时间:18.20min,99%,M+H:533。
实施例5:N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺(化合物编号26;表I)
5-1 (R)-2-氨基-3-(4-甲氧基苯基)丙酸甲酯
将20ml硫酸经30分钟的时间逐滴加入包含在150ml甲醇中的13g(66.6mmol)(R)-2-氨基-3-(4-甲氧基-苯基)丙酸的溶液中。在环境温度下搅拌24小时之后,反应介质通过引入10N氢氧化钠和碳酸氢钠饱和溶液而碱化到pH 8-9,接着用二氯甲烷萃取。将有机相经硫酸钠干燥,过滤并蒸发。得到12.8g浅黄色油形式的产物,产率92%。
5-2 (R)-2-(3-1H-咪唑-4-基丙酰基氨基)-3-(4-甲氧基苯基)丙酸甲酯
将35.5ml DIEA加到包含在100ml DMF中的13.2g(74.7mmol)去氨基-组氨酸盐酸盐和24g(74.7mmol)TBTU的溶液中。在环境温度下搅拌15分钟之后,加入在150ml DMF中的14.2g(67.9mmol)(R)-2-氨基-3-(4-甲氧基苯基)-丙酸甲酯。使反应介质搅拌16小时,随后通过引入1N氢氧化钠和碳酸氢钠饱和溶液碱化到pH=8-9,接着用二氯甲烷萃取。将有机相经硫酸钠干燥,过滤并蒸发。得到的粗产物通过硅胶色谱法(洗脱剂:85/15二氯甲烷/甲醇混合物)纯化。得到11.0g橙色油形式的产物,产率49%。
5-3 (R)-2-(3-1H-咪唑-4-基丙酰基氨基)-3-(4-甲氧基苯基)丙酸
将40ml 1N氢氧化锂水溶液加到包含在100ml THF中的11.0g(33.3mmol)(R)-2-(3-1H-咪唑-4-基丙酰基氨基)-3-(4-甲氧基苯基)丙酸甲酯的溶液中。搅拌16小时之后,将反应介质浓缩。残余物通过硅胶色谱法(洗脱剂:70/30/1二氯甲烷/甲醇/三乙胺)纯化。得到8.4g白色粉末形式的产物,产率79%。
5-4-1 2-苯基庚腈
将5g(42.7mmol)苯基乙腈逐滴加到冷却到0℃的2g 60%NaH在50ml DMF中的悬浮液中。在0℃下搅拌30分钟之后,逐滴加入5.32ml(42.7mmol)溴戊烷。将反应介质在环境温度下搅拌16小时,随后用冰处理并用***萃取。将有机相用碳酸氢钠饱和水溶液洗涤,经硫酸钠干燥,过滤并在压力下蒸发。得到橙黄色油且其通过在减压(70-75℃,1×10-1毫巴)下分级蒸馏纯化。得到5.14g橙色油形式的产物,产率64%。
5-4-2 2-羟基甲基-2-苯基庚腈
将5.14g(27.4mmol)2-苯基庚腈加到冷却到0℃的1.34g 60%NaH在50ml DMF中的悬浮液中。搅拌30分钟之后,逐部分加入7.6g(220mmol)多聚甲醛。使反应介质在环境温度下搅拌6小时,随后用冰水解并用***萃取。将有机相用碳酸氢钠饱和水溶液洗涤,经硫酸钠干燥,过滤并在压力下蒸发。得到的粗产物通过硅胶色谱法(洗脱剂:8/2庚烷/乙酸乙酯)纯化。得到4.24g浅黄色油形式的产物,产率71%。
5-4-3 甲苯-4-磺酸2-氰基-2-苯基庚酯
将4.1g(21.5mmol)对甲苯磺酰氯和6ml三乙胺加到包含在25ml二氯甲烷中的4.24g(19.5mmol)2-羟基甲基-2-苯基庚腈的溶液中。使反应介质在环境温度下搅拌15小时,随后用1N盐酸溶液处理并用二氯甲烷萃取。将有机相经硫酸钠干燥,过滤并在压力下蒸发。得到黄色油并使其从9/1庚烷/二异丙醚混合物中沉淀。将所形成的沉淀物滤出并用二异丙醚漂洗。得到5.26g浅褐色粉末形式的产物,产率72%。
5-4-4 3-戊基-3-苯基吖丁啶
在氮下将600mg(15.52mmol)粉末状LiAlH4小心加到包含在25ml THF中的5.26g(14.15mmol)甲苯-4-磺酸2-氰基-2-苯基庚酯的溶液中。使反应介质在环境温度下搅拌1小时,随后用硫酸钠水溶液处理。在环境温度下搅拌30分钟之后,将所形成的盐滤出并在减压下蒸发滤液。将残余物在二氯甲烷中处理并用1N氢氧化钠水溶液洗涤。将有机相经硫酸钠干燥,过滤并在减压下蒸发。得到2.90g无色油形式的产物并在不进一步纯化的情况下用于下一阶段。
5-4-5 N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
将70mg(0.345mmol)3-戊基-3-苯基吖丁啶和100mg(0.315mmol)(R)-2-(3-1H-咪唑-4-基丙酰基氨基)-3-(4-甲氧基苯基)丙酸溶解在1ml DMF中。将67mg(0.345mmol)EDC和47mg(0.345mmol)HOBT加到该溶液中。将整体搅拌4小时,随后用1N氢氧化钠处理并用二氯甲烷萃取。将有机相经硫酸钠干燥,过滤并在压力下蒸发。得到的粗产物通过硅胶色谱法(洗脱剂:9/1二氯甲烷/甲醇)纯化。得到85mg白色粉末形式的N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺,产率49%。
HPLC:(方法L);保留时间:22.96min,97%,M+H:503。
实施例6:N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-[1,2,3]***-4-基)丙酰胺(化合物编号39;表I)
6-1 3-(1H-[1,2,3]***-4-基)丙酸
将39mg 10%的钯/炭加到包含在3ml甲醇中的390mg(1.7mmol)3-(1-苄基-1H[1,2,3]***-4-基)丙酸的溶液中。将反应混合物置于10巴的氢气压力下并在60℃下搅拌16小时。经硅藻土过滤之后,将溶剂蒸出,残余物随后通过硅胶色谱法(洗脱剂:95/5二氯甲烷/甲醇)纯化。得到159.8mg白色粉末形式的3-(1H[1,2,3]***-4-基)丙酸,产率67%。
6-2 (R)-2-氨基-3-(4-甲氧基苯基)-1-(3-丁基氧基-3-邻甲苯基吖丁啶-1-基)丙-1-酮盐酸盐
将6ml在乙酸乙酯中的4N盐酸溶液加到615mg(1.24mmol)[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯(程序与4-3相同)中。将反应混合物在环境温度下搅拌2小时。将得到的沉淀物滤出,用***洗涤,随后溶解于甲醇中,接着蒸发溶剂。得到441mg白色粉末形式的(R)-2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮盐酸盐,产率82%。
6-3 N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H[1,2,3]***-4-基)丙酰胺
将在2ml二甲基甲酰胺中的146mg(0.34mmol)(R)-2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮盐酸盐加到47mg(0.34mmol)3-(1H[1,2,3]***-4-基)丙酸、119mg(0.37mmol)TBTU和0.15ml(1.1mmol)三乙胺在2ml二甲基甲酰胺中的溶液中。将反应混合物在环境温度下搅拌2小时。反应通过加入10ml水终止,随后用乙酸乙酯萃取。将有机相合并,用1N氢氧化钠溶液洗涤,随后用氯化钠饱和溶液洗涤并经硫酸钠干燥。过滤之后,将溶剂蒸出,残余物随后通过硅胶色谱法(洗脱剂:90/10乙酸乙酯/庚烷)纯化。得到78.6mg白色粉末形式的N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H[1,2,3]***-4-基)丙酰胺,产率为45%。
HPLC:(方法M);保留时间:19.03min,93%,M+H:520。
实施例7:N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺(化合物编号41;表I):
7-1 3-(5-甲基-3H-咪唑-4-基)丙酸
将50mg 10%的钯/炭加到在10ml 0.5N氢氧化钠溶液中的500mg(2.65mmol)3-(5-甲基-3H-咪唑-4-基)丙烯酸氯化物中。将反应混合物置于6巴的氢气压力下并在80℃下搅拌72小时。在已经经硅藻土滤出催化剂之后,残余物用盐酸酸化到pH 2,浓缩至干燥并在乙醇中处理。将不溶性物质滤出并将滤液浓缩至干燥。得到102mg白色粉末形式的3-(5-甲基-3H-咪唑-4-基)丙酸氯化物,产率16%。
7-2 N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺
将溶解在2ml二甲基甲酰胺中的146mg(0.34mmol)(R)-2-氨基-3-(4-甲氧基-苯基)-1-(3-丁基氧基-3-邻甲苯基吖丁啶-1-基)丙-1-酮盐酸盐加到64mg(0.34mmol)3-(5-甲基-3H-咪唑-4-基)丙酸氯化物、119mg(2.34mmol)TBTU和0.15ml(1.1mmol)三乙胺在2ml二甲基甲酰胺中的溶液中。将反应混合物在环境温度下搅拌2小时。反应通过加入10ml水来终止,随后用乙酸乙酯萃取。将有机相合并,用1N氢氧化钠溶液洗涤,随后用氯化钠饱和溶液洗涤并经硫酸钠干燥。过滤之后,将溶剂蒸出,残余物随后通过硅胶色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到154mg白色粉末形式的N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺,产率为86%。
HPLC:(方法M);保留时间:17.65min,96%,M+H:533。
实施例8:N-[(S)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺(化合物编号11;表I)
8-1 3-羟基-3-苯基吖丁啶三氟乙酸盐
将1ml三氟乙酸加到包含溶解于4ml二氯甲烷中的50mg(0.19mmol)3-羟基-3-苯基吖丁啶-1-甲酸叔丁酯的溶液中。将反应介质在环境温度下搅拌3小时,随后浓缩。得到的粗产物通过硅胶色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到36mg白色粉末形式的产物,产率68%。
8-2 N-[(S)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺三氟乙酸盐
将2ml DMF、106mg(0.33mmol)TBTU和1ml DIEA加到105mg(0.33mmol)(R)-2-(3-1H-咪唑-4-基丙酰基氨基)-3-(4-甲氧基-苯基)丙酸中。使反应介质在环境温度下搅拌15分钟。逐滴加入溶解于5ml 1/4DCM/DMF溶液中的36mg(0.13mmol)3-羟基-3-苯基吖丁啶三氟乙酸盐并在环境温度下搅拌16小时。加入5%柠檬酸溶液,接着用二氯甲烷萃取。将有机相用碳酸氢钾饱和溶液洗涤。将有机相干燥并蒸干。得到的粗产物通过硅胶色谱法(洗脱剂:9/1二氯甲烷/甲醇)纯化。得到6mg白色粉末形式的N-[(S)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺三氟乙酸盐,产率10%。
HPLC:(方法D);保留时间:9.25min,89%,M+H:463。
实施例9:N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺(化合物编号38;表I)
9-1-1 (4-氟苯基)庚腈
将5g(37.0mmol)(4-氟苯基)乙腈逐滴加到冷却到0℃的1.62g60%NaH在50ml DMF中的悬浮液中。在0℃下搅拌30分钟之后,逐滴加入4.62mmol(37.0mmol)溴戊烷。将反应介质在环境温度下搅拌16小时,随后用冰处理并用二氯甲烷萃取。将有机相经硫酸钠干燥,过滤并在压力下蒸发。得到橙黄色油并将其按原样用于下一阶段。
9-1-2 2-羟基甲基-2-(4-氟苯基)庚腈
将阶段9-1-1得到的粗(4-氟苯基)庚腈加到冷却到0℃的1.62g60%NaH在50ml DMF中的悬浮液中。搅拌30分钟之后,逐部分加入8.9g(296mmol)多聚甲醛。使反应介质在环境温度下搅拌3小时,随后用冰水解并用二氯甲烷萃取。将有机相经硫酸钠干燥,过滤并在压力下蒸发。得到的粗产物通过硅胶色谱法(洗脱剂:8/2庚烷/乙酸乙酯)纯化。得到3.85g浅黄色油形式的产物,产率44%。
9-1-3 甲苯-4-磺酸2-氰基-2-(4-氟苯基)庚酯
将3.43g(18.0mmol)对甲苯磺酰氯和5ml三乙胺加到包含在40ml二氯甲烷中的3.85g(16.4mmol)2-羟基甲基-2-(4-氟苯基)庚腈的溶液中。使反应介质在环境温度下搅拌15小时,随后用1N盐酸溶液处理并用二氯甲烷萃取。将有机相经硫酸钠干燥,过滤并在压力下蒸发。得到黄色油并使其从8/2二氯甲烷/二异丙醚混合物中沉淀。将所形成的沉淀物滤出。得到4.4g浅褐色粉末形式的产物,产率65%。
9-1-4 3-戊基-3-(4-氟苯基)吖丁啶
在氮下将471mg(12.4mmol)粉末状LiAlH4小心加到包含在40ml THF中的4.4g(11.3mmol)甲苯-4-磺酸2-氰基-2-(4-氟苯基)庚酯的溶液中。使反应介质在环境温度下搅拌1小时,随后用硫酸钠水溶液处理。在环境温度下搅拌30分钟之后,将所形成的盐滤出并在减压下蒸发滤液。将残余物在二氯甲烷中处理并用1N氢氧化钠水溶液洗涤。将有机相经硫酸钠干燥,过滤并在减压下蒸发。得到2.02g黄色油形式的产物并在不进一步纯化的情况下用于下一阶段。
9-2 [(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-(4-氟苯基)吖丁啶-1-基)乙基]氨基甲酸叔丁酯
将606mg(2.05mmol)(R)-2-叔丁氧基-羰基氨基-3-(4-甲氧基苯基)丙酸和500mg(2.26mmol)3-戊基-3-(4-氟苯基)吖丁啶溶解于10ml DMF中。将473mg(2.46mmol)EDC、333mg(2.46mmol)HOBt和0.6ml(4.5mmol)三乙胺加到该溶液中。将反应介质在环境温度下搅拌5小时,随后用二氯甲烷萃取。将有机相用1N氢氧化钠洗涤,随后经硫酸镁干燥、过滤并蒸发。得到的粗产物通过硅胶色谱法(洗脱剂:6/4庚烷/乙酸乙酯)纯化。得到780mg白色粉末形式的产物,产率76%。
9-3 (R)-2-氨基-3-(4-甲氧基苯基)-1-(3-戊基-3-(4-氟苯基)吖丁啶-1-基)-丙-1-酮
将780mg(1.56mmol)[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-(4-氟苯基)吖丁啶-1-基)乙基]氨基甲酸叔丁酯溶解在10ml二氯甲烷中。引入4ml三氟乙酸。将反应介质搅拌1小时,随后浓缩至干燥。将残余物在1N氢氧化钠水溶液中处理并用二氯甲烷萃取,随后将所得产物经硫酸镁干燥,过滤并蒸发。
得到590mg无色树脂形式的产物,产率95%。
9-4 N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
将600mg(1.86mmol)TBTU和0.45ml三乙胺加到包含在5ml二甲基甲酰胺中的330mg(1.86mmol)去氨基-组氨酸盐酸盐的溶液中。搅拌15分钟之后,加入溶解在5ml二甲基甲酰胺中的590mg(1.55mmol)(R)-2-氨基-3-(4-甲氧基苯基)-1-(3-戊基-3-(4-氟苯基)吖丁啶-1-基)-丙-1-酮。将反应介质在环境温度下搅拌3天。反应通过加入1N氢氧化钠溶液来停止,随后用1/1庚烷/乙酸乙酯混合物萃取。将有机相合并且经硫酸钠干燥。过滤之后,将溶剂蒸出,残余物随后通过硅胶色谱法(洗脱剂:85/15二氯甲烷/甲醇)纯化。得到490mg白色粉末形式的N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)-丙酰胺,产率为61%。
HPLC:(方法O);保留时间:15.85min,99%,M+H:521。
实施例10:N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺(化合物编号62;表I)
10-1-1 6-(1-三苯甲基-1H-咪唑-4-基)己-5-烯酸
将13.5ml(14.3mmol)的六甲基二硅氮烷锂在THF中的1.06M溶液加到冷却到-75℃的悬浮在45ml THF中的3.27g(7.38mmol)(4-羧丁基)三苯基溴化中。将反应介质在-75℃下搅拌20分钟,随后在0℃下搅拌15分钟。在回到-75℃之后,引入悬浮在15ml THF中的1.50g(4.43mmol)1-三苯甲基-1H-咪唑-4-甲醛。在回到环境温度之后,将反应介质搅拌20小时,随后在90℃下微波加热5分钟。将反应介质过滤并在旋转蒸发器中浓缩,随后在1/1庚烷/EtOAc中处理。将有机相用NaHCO3饱和水溶液洗涤。得到的水相用5%的柠檬酸水溶液酸化到pH=5,随后用1/1庚烷/EtOAc混合物萃取。将有机相经MgSO4干燥,过滤并在旋转蒸发器中浓缩。得到0.58g灰褐色粉末形式的6-(1-三苯甲基-1H-咪唑-4-基)己-5-烯酸,产率31%。
10-1-2 6-(1H-咪唑-4-基)己-5-烯酸三氟乙酸盐
将2ml三氟乙酸加到悬浮在8ml二氯甲烷中的0.58g(1.37mmol)6-(1-三苯甲基-1H-咪唑-4-基)己-5-烯酸中。在溶剂已经蒸出之后,将得到的油在二氧化硅管柱(洗脱剂:8/2 DCM/MeOH)上纯化。分离到240mg黄色油形式的6-(1H-咪唑-4-基)己-5-烯酸三氟乙酸盐,产率60%。
10-1-3 6-(1H-咪唑-4-基)己酸三氟乙酸盐
将4ml乙酸和80mg 10%的钯/炭加到218mg(0.741mmol)6-(1H-咪唑-4-基)己-5-烯酸三氟乙酸盐中。将反应介质置于大气压力下的氢气氛下。13小时之后,将反应介质经硅藻土过滤。在溶剂已经蒸出之后,得到175mg黄色油形式的6-(1H-咪唑-4-基)己酸三氟乙酸盐,产率80%。
10-2 N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺
将60mg(0.186mmol)TBTU、0.1ml(0.715mmol)三乙胺和79mg(0.155mmol)2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮三氟乙酸盐(参照程序4-4)在1ml DMF中的溶液加到溶解在1ml DMF中的55mg(0.186mmol)6-(1H-咪唑-4-基)己酸三氟乙酸盐中。将反应介质搅拌66小时,用1/2庚烷/EtOAc混合物萃取,随后用1N氢氧化钠洗涤。将有机相经MgSO4干燥,过滤并浓缩。将得到的粗产物在二氧化硅管柱(洗脱剂:8/2 DCM/MeOH)上纯化。得到白色粉末形式的40.8mg N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺,产率47%。
HPLC:(方法V);保留时间:18.05min,99%,M+H:561。
实施例11:N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺(化合物编号64;表I)
11-1-1 碘化5-(2-甲氧基羰基乙基)-1-甲基-3-三苯甲基-3H-咪唑-1-鎓
将720mg(5.2mmol)碳酸钾和0.34ml(5.72mmol)碘甲烷加到1g(2.6mmol)N-1-三苯甲基-去氨基-组氨酸在10ml DMF中的溶液中。将反应介质在60℃下加热3小时。在回到环境温度之后,将反应介质用水和乙酸处理(达到pH 4-5)并用二氯甲烷萃取。将有机相经MgSO4干燥,过滤并蒸发。得到的残余物通过二氧化硅色谱法(洗脱剂:8/2 DCM/MeOH)纯化。得到970mg碘化5-(2-甲氧基羰基乙基)-1-甲基-3-三苯甲基-3H-咪唑-1-鎓,产率69%。
11-1-2 3-(3-甲基-3H-咪唑-4-基)丙酸甲酯三氟乙酸盐
将0.5ml三氟乙酸加到200mg(0.37mmol)碘化5-(2-甲氧基羰基乙基)-1-甲基-3-三苯甲基-3H-咪唑-1-鎓在2ml二氯甲烷中的溶液中。使反应介质在环境温度下搅拌过夜并将溶剂蒸出。残余物通过二氧化硅色谱法(洗脱剂:9/1 DCM/MeOH)纯化。得到80mg 3-(3-甲基-3H-咪唑-4-基)丙酸甲酯三氟乙酸盐,产率76%。
11-1-3 3-(3-甲基-1H-咪唑-4-基)丙酸盐酸盐
将2ml 30%的氢氧化钠水溶液加到320mg(1.13mmol)3-(3-甲基-3H-咪唑-4-基)丙酸甲酯三氟乙酸盐在10ml THF中的溶液中。将反应介质在环境温度下搅拌16小时,随后冷却到0℃,逐滴加入浓盐酸直到达到pH 1。过滤之后,将滤液蒸发。得到87mg 3-(3-甲基-1H-咪唑-4-基)丙酸盐酸盐,产率39%。
11-2 N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
将0.17ml(1.23mmol)三乙胺小心加到包含在1ml DMF中的87mg(0.45mmol)3-(3-甲基-1H-咪唑-4-基)丙酸盐酸盐和160mg(0.49mmol)TBTU的溶液中。在环境温度下搅拌60分钟之后,加入200mg(0.32mmol)(R)-2-氨基-3-(4-甲氧基苯基)-1-(3-戊基-3-苯基吖丁啶-1-基)丙-1-酮三氟乙酸盐(参照程序9-3)且使反应介质搅拌3天。将反应介质用2庚烷/8EtOAc混合物和1N氢氧化钠水溶液处理。将有机相经MgSO4干燥,过滤并蒸发。得到的残余物通过二氧化硅色谱法(洗脱剂:9DCM/1 MeOH)纯化。得到21mgN-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺,产率9%。
HPLC:(方法W);保留时间:18.04min,96%,M+H:517。
实施例号12:N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺(化合物编号66;表I)
12-1 3-环己基-3-戊基吖丁啶草酸盐
将254mg 5%的铑/氧化铝加到在13ml水和6.5ml THF中的652mg(2.62mmol)3-戊基-3-苯基吖丁啶草酸盐(参照)中。将介质置于处于6巴压力的氢气氛下并在80℃下加热。在23小时之后,将反应介质经硅藻土过滤并将溶剂蒸出。得到0.43g 3-环己基-3-戊基吖丁啶草酸盐,产率64%。
12-2 [(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯
将0.36g(1.98mmol)EDC、0.25g(1.85mmol)HOBt和0.51g(1.73mmol)(R)-2-叔丁氧基-羰基氨基-3-(4-甲氧基苯基)丙酸加到溶解于8ml DMF中的0.43g(1.69mmol)3-环己基-3-戊基吖丁啶草酸盐中。5分钟后,加入0.9ml(6.5mmol)三乙胺。1小时30分钟之后,将反应介质用1/1 EtOAc/庚烷混合物萃取并用1N盐酸溶液、1N氢氧化钠溶液和水洗涤。将有机相经MgSO4干燥,过滤并浓缩。将残余物在二氧化硅管柱(洗脱剂:6/4庚烷/EtOAc)上纯化。得到0.48g无色油形式的[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯,产率59%。
12-3 (R)-2-氨基-1-(3-环己基-3-戊基吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮
在0℃下将2.5ml三氟乙酸加到溶解于10ml二氯甲烷中的0.48g(0.99mmol)[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯。2小时之后,蒸出溶剂。将残余物在二氯甲烷中处理并用1N氢氧化钠洗涤。将有机相合并,经MgSO4干燥,过滤并浓缩。得到327mg(R)-2-氨基-1-(3-环己基-3-戊基吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮,产率86%。
12-4 N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
将100mg(0.311mmol)TBTU和0.1ml(0.715mmol)三乙胺加到在1ml DMF中的55mg(0.311mmol)3-(1H-咪唑-4-基)丙酸盐酸盐。10分钟之后,加入溶解于1ml DMF中的99mg(0.256mmol)(R)-2-氨基-1-(3-环己基-3-戊基吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮。在环境温度下搅拌118小时之后,将反应介质用1/2庚烷/EtOAc混合物萃取并用1N氢氧化钠和饱和氯化钠溶液洗涤。将有机相经MgSO4干燥,过滤并浓缩。将残余物在二氧化硅管柱(洗脱剂:9/1DCM/MeOH)上纯化。得到72mg白色粉末形式的N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺,产率55%。
HPLC:(方法Y);保留时间:18.34min,98%,M+H:509。
实施例13:N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
13.1:3-(2-氟苯基)-3-羟基-1-(叔丁氧基羰基)吖丁啶
将3.1ml(6.1mmol)的异丙基氯化镁在四氢呋喃中的2M溶液加到预先冷却到-25℃的1.1g(6.2mmol)1-溴-2-氟苯在4ml四氢呋喃中的溶液中。在-25℃下搅拌30分钟之后,加入0.65g(3.7mmol)3-氧代-1-(叔丁氧基羰基)吖丁啶在7.5ml四氢呋喃中的溶液。将反应介质搅拌30分钟,随后加入氯化铵饱和水溶液。将有机化合物用1/1庚烷/乙酸乙酯混合物萃取。将有机相经硫酸镁干燥,随后过滤并蒸发。粗产物通过硅胶色谱法纯化,用5/5庚烷/乙酸乙酯混合物进行洗脱。得到白色固体形式的135mg 3-(2-氟苯基)-3-羟基-1-(叔丁氧基羰基)-吖丁啶,产率14%。
13.2:3-丁氧基-3-(2-氟苯基)-1-(叔丁氧基羰基)吖丁啶
在氮下在0℃下将在2ml二甲基甲酰胺中以80%的135mg(0.4mmol)3-(2-氟苯基)-3-羟基-1-(叔丁氧基羰基)吖丁啶加到65mg(1.6mmol)氢化钠在1.5ml二甲基甲酰胺中的60%悬浮液中。在0℃下搅拌20分钟之后,加入0.2ml(1.5mmol)碘丁烷。将反应介质在环境温度下搅拌1小时30分钟,随后用水并用氯化铵饱和水溶液水解且用1/2庚烷/乙酸乙酯混合物萃取。将有机相合并,用水洗涤,经硫酸镁干燥,过滤并蒸发。粗产物通过硅胶色谱法纯化,用8/2庚烷/乙酸乙酯混合物进行洗脱。得到黄色油形式的104mg 3-丁氧基-3-(2-氟苯基)-1-(叔丁氧基羰基)吖丁啶,产率79%。
13.3:3-丁氧基-3-(2-氟苯基)吖丁啶三氟乙酸盐
在0℃下将1ml三氟乙酸加到包含在3ml二氯甲烷中的104mg(0.3mmol)3-丁氧基-(2-氟苯基)-1-(叔丁氧基羰基)吖丁啶的溶液中。搅拌30分钟之后,将反应介质在在氮气流下蒸发。得到126mg浅黄色油形式的3-丁氧基-3-(2-氟苯基)吖丁啶三氟乙酸盐,产率100%。
13.4:[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯
在氮下将68mg EDC(0.3mmol)、45mg(0.3mmol)HOBt和100mg(0.33mmol)Boc-D-甲氧基苯基丙氨酸依次加到在1.5ml二甲基甲酰胺中的126mg(0.3mmol)3-丁氧基-3-(2-氟苯基)吖丁啶三氟乙酸盐。搅拌5分钟之后,加入0.2ml(13mmol)三乙胺。随后将反应介质在环境温度下搅拌23小时并在1N氢氧化钠水溶液存在下用1/1乙酸乙酯/庚烷混合物萃取。将有机相用1N盐酸水溶液洗涤,随后用水洗涤,经硫酸镁干燥,过滤并蒸发。得到94mg黄色油形式的[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯,产率58%。
13.5:(R)-2-氨基-1-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-3-(4-甲氧基苯基)丙-1-酮三氟乙酸盐
将1ml三氟乙酸加到预先冷却到0℃的94mg(0.2mmol)[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯在10ml二氯甲烷中的溶液中。在环境温度下搅拌1小时30分钟之后,将反应介质在氮气流下蒸发。得到119mg黄色油形式的(R)-2-氨基-1-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-3-(4-甲氧基-苯基)丙-1-酮三氟乙酸盐,产率100%。
13.6:N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
将81mg(0.3mmol)TBTU和0.1ml(0.6mmol)三乙胺加到42mg(0.25mmol)去氨基-组氨酸盐酸盐在1ml二甲基甲酰胺中的溶液中。在搅拌10分钟之后,加入119mg(0.2mmol)(R)-2-氨基-1-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-3-(4-甲氧基苯基)丙-1-酮三氟乙酸盐并将反应介质在环境温度下搅拌64小时。在用1/2庚烷/乙酸乙酯混合物萃取之后,将有机相用1N氢氧化钠水溶液和氯化钠饱和水溶液洗涤,经硫酸镁干燥,过滤并蒸发。粗产物通过硅胶色谱法纯化,用90/10二氯甲烷/甲醇混合物进行洗脱。得到59mg白色固体形式的N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺,产率57%。
1H NMR/DMSO d6 100℃:δ=0.78(t,J=7.2-7.6Hz,3H);1.23(六重峰,J=6.8-7.2Hz,2H);1.37(五重峰,J=6.4-7.6Hz,2H);2.38-2.42(m,2H);2.68-2.94(m,7H);3.10(bt,J=5.6-6.4,2H);4.00-4.40(m,4H);4.50(q,J=7.2-7.6Hz,1H);6.67-6.80(m,3H);7.09-7.24(m,4H);7.30-7.43(m,4H);7.70-7.90(m,1H)。
实施例14:N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
14.1 (E)-3-(1-甲基-1H-咪唑-4-基)丙烯酸甲酯
将1ml(5.5mmol)二乙基膦酰乙酸甲酯加到冷却到0℃的220mg(5.5mmol)氢化钠在5ml四氢呋喃中的60%悬浮液中。在搅拌1小时之后,加入500mg(4.5mmol)1-甲基-1H-咪唑-4-甲醛,将混合物在环境温度下搅拌4小时,随后用水水解并用乙酸乙酯萃取。将有机相用碳酸氢钠饱和水溶液洗涤,经硫酸镁干燥,过滤并蒸发。使得到的产物从庚烷中沉淀并将其过滤。得到430mg黄色粉末形式的(E)-3-(1-甲基-1H-咪唑-4-基)丙烯酸甲酯,产率57%。
14.2 3-(1-甲基-1H-咪唑-4-基)丙酸盐酸盐
将50mg 10%的钯/炭加到100mg(0.6mmol)(E)-3-(1-甲基-1H-咪唑-4-基)丙烯酸甲酯在5ml 1N氢氧化钠水溶液中的溶液中。将反应介质用氮气吹扫,随后在氢气氛下搅拌24小时。在经硅藻土过滤之后,用浓盐酸水溶液使滤液的pH回到2,加入甲苯并将介质浓缩至干燥。将得到的残余物在丙酮中处理并将沉淀的盐滤出。浓缩滤液。得到固体形式的160mg 3-(1-甲基-1H-咪唑-4-基)丙酸盐酸盐,产率32%。
14.3 N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
将84mg(0.3mmol)TBTU和0.1ml(0.5mmol)三乙胺加到50mg(0.3mmol)3-(1-甲基-1H-咪唑-4-基)丙酸盐酸盐在2ml二甲基甲酰胺中的溶液中。在环境温度下搅拌1小时之后,加入90mg(0.2mmol)(R)-2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮盐酸盐(如实施例6.2中所述制备)。将反应介质在环境温度下搅拌72小时,用2/8庚烷/乙酸乙酯混合物萃取,随后用1N氢氧化钠水溶液洗涤。将有机相经硫酸镁干燥,过滤并蒸发。
粗产物通过硅胶色谱法纯化,用97/3二氯甲烷/甲醇混合物进行洗脱。得到22mg灰褐色粉末形式的N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺,产率23%。
HPLC:(方法U);保留时间:15.28min,96.5%,M+H:533。
实施例15:N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
15.1:2-苄氧基-4-甲氧基苯甲醛
将160ml(1.3mmol)溴化苄和(1.3mmol)碳酸钾加到2g(1.3mmol)2-羟基-4-甲氧基苯甲醛在20ml丙酮中的溶液中。将混合物在回流下搅拌6小时,随后蒸发。加入50ml 1N氢氧化钠水溶液并将介质用二氯甲烷萃取。将有机相经硫酸镁干燥,过滤并蒸发。使得到的残余物从1庚烷/乙酸乙酯混合物(95/5)中沉淀。得到2.75g白色粉末形式的2-苄氧基-4-甲氧基苯甲醛,产率86%。
15.2:(E)-3-(2-苄氧基-4-甲氧基苯基)-2-(叔丁氧基羰基)氨基丙烯酸甲酯
将1.8g(5.4mmol)1,8-二氮杂双环[5.4.0]十一碳-7-烯加到预先冷却到0℃的1.8g(6.2mmol)(±)-Boc-α-膦酰基甘氨酸三甲基酯在10ml二氯甲烷中的溶液中。将混合物在0℃下搅拌10分钟,随后加入1g(4.1mmol)2-苄氧基-4-甲氧苯甲醛在5ml二氯甲烷中的溶液,随后将反应介质在环境温度下搅拌18小时。在二氯甲烷已经蒸出之后,将残余物在50ml乙酸乙酯中处理。将有机相用氯化铵饱和水溶液和水洗涤,经硫酸镁干燥,过滤并蒸发。得到的残余物通过硅胶色谱法(洗脱剂:70/30庚烷/乙酸乙酯)纯化。得到1.5g灰褐色粉末形式的(E)-3-(2-苄氧基-4-甲氧基苯基)-2-(叔丁氧基羰基氨基)丙烯酸甲酯,产率85%。
15.3:2-叔丁氧基羰基氨基-3-(2-羟基-4-甲氧基苯基)丙酸甲酯
将350mg 10%的钯/炭加到包含在15ml甲醇中的1.5g(3.5mmol)(E)-3-(2-苄氧基-4-甲氧基苯基)-2-(叔丁氧基羰基-氨基)丙烯酸甲酯的溶液中。在氢气氛下搅拌4小时之后,将反应介质经硅藻土过滤并将滤液蒸发。得到850mg灰白色粉末形式的2-叔丁氧基羰基氨基-3-(2-羟基-4-甲氧基苯基)-丙酸甲酯,产率74%。
15.4:2-叔丁氧基羰基氨基-3-(2-羟基-4-甲氧基苯基)丙酸
将5ml1N氢氧化钠水溶液加到850mg(2.6mmol)2-叔丁氧基羰基氨基-3-(2-羟基-4-甲氧基苯基)-丙酸甲酯在10ml四氢呋喃中的溶液中。将反应介质在环境温度下搅拌4小时,随后加入1N盐酸水溶液直到pH为1,并将介质用二氯甲烷萃取。将有机相经硫酸镁干燥,过滤并蒸发。以定量产率得到820mg灰褐色粉末形式的2-叔丁氧基羰基氨基-3-(2-羟基-4-甲氧基-苯基)丙酸。
15.5:3-丁氧基-3-邻甲苯基吖丁啶三氟乙酸盐
将1ml三氟乙酸加到包含溶解于5ml二氯甲烷中的500mg(1.65mmol)3-丁氧基-3-邻甲苯基-吖丁啶-1-(叔丁氧基羰基)吖丁啶的溶液中。将反应介质在环境温度下搅拌3小时,随后浓缩。得到的粗产物通过硅胶色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到400mg浅黄色粉末形式的产物,产率76%。
15.6:[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯
将74mg(0.4mmol)EDC和52mg(0.4mmol)HOBt加到100mg(0.3mmol)2-叔丁氧基羰基氨基-3-(2-羟基-4-甲氧基苯基)-丙酸在5ml二甲基甲酰胺中的溶液中。将混合物搅拌15分钟并加入107mg(0.3mmol)3-丁氧基-3-邻甲苯基吖丁啶三氟乙酸盐。在环境温度下另外搅拌15分钟之后,加入0.3ml(1.3mmol)二异丙基-乙胺。将反应介质搅拌2小时,随后加入10ml 1N盐酸水溶液并将介质用乙酸乙酯萃取。将有机相用水洗涤,随后经硫酸镁干燥,过滤并蒸发。残余物经硅胶(洗脱剂:70/30庚烷/乙酸乙酯)过滤。得到220mg黄色油形式的[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯并将其以粗产物用于下一阶段。
15.7:2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(2-羟基-4-甲氧基苯基)丙-1-酮三氟乙酸盐
将1ml三氟乙酸加到在2ml二氯甲烷中的220mg(0.4mmol)[2-(3-丁氧基-3-邻甲苯基-吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯中。在环境温度下搅拌1小时之后,将反应介质在真空下浓缩。以定量产率得到250mg黄色油形式的2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(2-羟基-4-甲氧基苯基)丙-1-酮三氟乙酸盐。
15.8:N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
将0.25ml(0.6mmol)三乙胺加到90mg(0.6mmol)去氨基-组氨酸和207mg(0.6mmol)TBTU在2ml二甲基甲酰胺中的溶液中。在环境温度下搅拌1小时之后,加入250mg(0.4mmol)2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(3-羟基-4-甲氧基苯基)丙-1-酮三氟乙酸盐并将混合物在环境温度下搅拌72小时。随后将10ml碳酸氢钠饱和水溶液倾入反应介质中,将其用20/80庚烷/乙酸乙酯混合物萃取。将有机相经硫酸镁干燥,过滤并浓缩。产物通过制备型薄层色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到30mg灰褐色粉末形式的N-[2-(3-丁氧基-3-邻甲苯基-吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐,产率11%。
HPLC:(方法A1):保留时间:14.39min,94.2%,M+H:535。
实施例16:(S)-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-2-羟基-3-(1H-咪唑-4-基)丙酰胺
将0.1ml(0.8mmol)三乙胺加到包含在2ml二甲基甲酰胺中的50mg(0.3mmol)(S)-2-羟基-3-(1H-咪唑-4-基)丙酸和100mg(0.3mmol)TBTU的溶液中。在环境温度下搅拌1小时之后,加入128mg(0.3mmol)(R)-2-氨基-1-(3-丁氧基-3-邻甲苯基-吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮盐酸盐(在实施例6.2中描述)并将混合物在环境温度下搅拌72小时。加入1N氢氧化钠水溶液并将介质用20/80庚烷/乙酸乙酯混合物萃取。将有机相经硫酸镁干燥,过滤并浓缩。粗产物通过制备型薄层色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到17mg白色粉末形式的(S)-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-2-羟基-3-(1H-咪唑-4-基)丙酰胺,产率13%。
1H NMR/DMSO d6 100℃:δ=0.78(t,J=7.2Hz,3H);1.23(六重峰,J=7.3Hz,2H);1.36(五重峰,J=6.7Hz,2H);2.12(s,3H);2.55-2.75(m,1H);2.86-2.98(m,7H);3.68(bs,3H);3.90-4.30(m,4H);4.54(bq,J=6.4Hz,1H);5.25-5.45(m,1H);6.55-6.95(m,3H);7.09-7.27(m,6H);7.43(bs,1H);7.50-7.65(m,1H)。
实施例17:N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
17.1:[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]氨基甲酸叔丁酯
将205mg(1.1mmol)EDC和145mg(1.1mmol)HOBt加到250mg(0.9mmol)(R)-2-叔丁氧基羰基氨基-3-(4-羟基苯基)-丙酸在5ml二甲基甲酰胺中的溶液中。在环境温度下搅拌15分钟之后,加入300mg(1.1mmol)3-丁氧基-3-邻甲苯基吖丁啶三氟乙酸盐(在实施例15.5中描述)和0.5ml(3.6mmol)三乙胺。将反应介质在环境温度下搅拌2小时,随后加入1N盐酸水溶液并将混合物用乙酸乙酯萃取。将有机相用水洗涤,随后经硫酸镁干燥,过滤并蒸发。残余物通过硅胶色谱法纯化,用60/40庚烷/乙酸乙酯混合物进行洗脱。得到410mg[2-(3-丁氧基-3-邻甲苯基-吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺,产率90%。
17.2:2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-羟基苯基)丙-1-酮三氟乙酸盐
将2ml三氟乙酸加到410mg(0.8mmol)[2-(3-丁氧基-3-邻甲苯基-吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]氨基甲酸叔丁酯在5ml二氯甲烷中的溶液中。在环境温度下搅拌1小时后,将溶剂蒸出。以定量产率得到440mg 2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-羟基苯基)丙-1-酮三氟乙酸盐。
17.3:N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
将0.35ml(2.6mmol)三乙胺加到包含在5ml DMF中的225mg(1.3mmol)去氨基-组氨酸盐酸盐和410mg(1.3mmol)TBTU的溶液中。在环境温度下搅拌1小时之后,加入440mg(0.9mmol)2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-羟基苯基)丙-1-酮三氟乙酸盐。在环境温度下搅拌72小时之后,将反应介质用碳酸氢钠饱和水溶液处理,随后用20/80庚烷/乙酸乙酯混合物萃取。将有机相经硫酸镁干燥,过滤并浓缩。产物通过制备型薄层色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到白色粉末形式的205mg N-[2-(3-丁氧基-3-邻甲苯基-吖丁啶-1-基)-1-(4-羟基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺,产率47%。
1H NNR/DMSO d6 100℃:δ=0.80(t,J=7.6Hz,3H,);1.22(m,2H);1.36(五重峰,J=6.4Hz,2H,);2.23(s,3H);2.40(t,J=8.8Hz,2H);2.82-2.70(m,4H);2.97(t,J=6.4Hz,2H);4.09(d,J=10Hz,2H);4.23(d,J=7.6Hz,2H);4.50(q,J=7.6Hz,1H);6.63(m,2H);6.70(s,1H);6.99(m,2H);7.26-7.20(m,4H);7.49(s,1H);7.75(s,1H)。
实施例18:N-[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]-3-(1H-咪唑-4-基)丙酰胺
18.1:2-氨基-3-(4-甲氧基苯基)-3-氧代丙酸乙酯盐酸盐
将溶解于20ml四氢呋喃中的5g(18.6mmol)N-(二苯基亚甲基)甘氨酸乙酯加到冷却到-70℃的18.7ml(18.6mmol)在20ml四氢呋喃中的1N叔丁氧基钾溶液中。在搅拌30分钟之后,在-70℃下将该混合物加到包含在20ml四氢呋喃中的3.2g(18.6mmol)4-甲氧基苯甲酰氯的溶液中。添加之后1小时,将反应介质用1N盐酸水溶液水解并浓缩。将残余物在水中处理并用***萃取。将有机相经硫酸镁干燥,随后将溶剂蒸出。以定量产率得到5.5g 2-氨基-3-(4-甲氧基苯基)-3-氧代-丙酸乙酯盐酸盐
18.2:2-叔丁氧基羰基氨基-3-(4-甲氧基-苯基)-3-氧代丙酸乙酯
在0℃下将4g(18.3mmol)二碳酸二叔丁酯和2.6ml(18.3mmol)三乙胺加到溶解于60ml四氢呋喃中的5g(18.3mmol)2-氨基-3-(4-甲氧基苯基)-3-氧代-丙酸乙酯盐酸盐中。在环境温度下搅拌3小时之后,将混合物用水处理并用乙酸乙酯萃取。将有机相用1N硫酸氢钠水溶液和水洗涤,随后经硫酸镁干燥,过滤并浓缩。得到4.1g黄色油形式的2-叔丁氧基羰基氨基-3-(4-甲氧基苯基)-3-氧代-丙酸乙酯,产率66%。
18.3:2-叔丁氧基羰基氨基-3-羟基-3-(4-甲氧基苯基)丙酸乙酯
将461mg(0.7mmol)硼氢化钠小心加到冷却到-78℃的4.1mg(12.2mmol)2-叔丁氧基羰基氨基-3-(4-甲氧基苯基)-3-氧代-丙酸乙酯在40ml乙醇中的溶液中。搅拌15分钟之后,将反应介质用氯化铵饱和水溶液水解。将乙醇蒸出并将水相用二氯甲烷萃取。将有机相经硫酸镁干燥,过滤并浓缩。残余物通过硅胶色谱法纯化,用70/30庚烷/乙酸乙酯混合物进行洗脱。得到3g黄色油形式的2-叔丁氧基羰基氨基-3-羟基-3-(4-甲氧基-苯基)丙酸乙酯,产率72%。
18.4:2-叔丁氧基羰基氨基-3-羟基-3-(4-甲氧基苯基)丙酸
将15ml 1N氢氧化钠水溶液加到包含在40ml四氢呋喃中的3g(8.4mmol)2-叔丁氧基羰基氨基-3-羟基-3-(4-甲氧基苯基)-丙酸的溶液中。将混合物在环境温度下搅拌4小时,用1N盐酸水溶液处理直到pH为1,随后用二氯甲烷萃取。将有机相经硫酸镁干燥,过滤并浓缩。使残余物从1/1***/庚烷混合物中沉淀。得到2.2g白色粉末形式的2-叔丁氧基羰基氨基-3-羟基-3-(4-甲氧基苯基)-丙酸,产率84%。
18.5:[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]氨基甲酸叔丁酯
将740mg(3.5mmol)EDC和1.2g(9.6mmol)4-二甲基氨基吡啶加到冷却到0℃的1g(3.2mmol)2-叔丁氧基羰基氨基-3-羟基-3-(4-甲氧基苯基)丙酸、11g(3.5mmol)3-丁氧基-3-邻甲苯基吖丁啶三氟乙酸盐和480mg(3.5mmol)HOAT在10ml二氯甲烷中的溶液中。在环境温度下搅拌24小时之后,将反应介质用1N氢氧化钠水溶液处理,随后用乙酸乙酯萃取。将有机相用1N盐酸水溶液和水依次洗涤,随后经硫酸镁干燥,过滤并浓缩。得到的残余物通过硅胶色谱法(洗脱剂:60/40庚烷/乙酸乙酯)纯化。得到1.4g无色油形式的[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]氨基甲酸叔丁酯,产率87%。
18.6:2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-羟基-3-(4-甲氧基苯基)丙-1-酮三氟乙酸盐
将10ml三氟乙酸加到包含在20ml二氯甲烷中的1.4g(2.8mmol)[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基-苯基)乙基]氨基甲酸叔丁酯的溶液中。在环境温度下搅拌1之后,浓缩反应介质。以定量产率得到1.5g灰褐色粉末形式的2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-羟基-3-(4-甲氧基-苯基)丙-1-酮三氟乙酸盐。
18.7:N-[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]-3-(1H-咪唑-4-基)丙酰胺
将0.2ml(1.5mmol)三乙胺加到包含在5ml二甲基甲酰胺中的100mg(0.6mmol)去氨基-组氨酸盐酸盐和180mg(0.6mmol)TBTU的溶液中。在环境温度下搅拌1小时之后,加入200mg(0.4mmol)2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-羟基-3-(4-甲氧基-苯基)丙-1-酮三氟乙酸盐。将反应介质在环境温度下搅拌48小时,随后用1N氢氧化钠水溶液处理并用20/80庚烷/乙酸乙酯混合物萃取。将有机相经硫酸镁干燥,过滤并浓缩。残余物通过制备型薄层色谱法(洗脱剂:90/10二氯甲烷/甲醇)纯化。得到80mg灰褐色粉末形式的N-[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基-苯基)乙基]-3-(1H-咪唑-4-基)丙酰胺,产率39%。
1H NMR/DMSO d6 100℃:δ=0.78(t,J=7.6Hz,3H);1.23(六重峰,J=7.3Hz,2H);1.37(五重峰,J=6.7Hz,2H);2.25(s,3H);2.40-2.50(m,2H);2.75(m,2H);3.01(t,J=12Hz,2H);3.70-3.80(bs,3H);4.10-4.50(m,6H);4.55(m,1H);4.73(m,1H);6.82(m,2H);7.10-7.40(m,8H);7.86(m,1H)。
实施例19:N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
19.1:3-羟基-3-(1-三苯甲基-1H-咪唑-4-基)丙酸叔丁酯
将2.15ml(14.5mmol)溴乙酸叔丁酯逐滴加到在20ml四氢呋喃中的1g(15.3mmol)20目锌的溶液中,搅拌15分钟,加入几滴三甲硅烷氯化物。在环境温度下搅拌15分钟之后,使混合物的温度保持在50℃下1小时。在回到环境温度之后,加入包含在10ml THF中的1.2g(3.6mmol)1-三苯甲基-1H-咪唑-4-甲醛的溶液。将反应介质在环境温度下搅拌6小时,随后用1N盐酸水溶液处理并用乙酸乙酯萃取。将有机相用碳酸氢钠饱和水溶液且随后用水依次洗涤。在经硫酸镁干燥并过滤之后,将溶剂蒸出。使得到的残余物从二异丙醚中沉淀并将其滤出。得到1.4g白色粉末形式的3-羟基-3-(1-三苯甲基-1H-咪唑-4-基)丙酸叔丁酯,产率84%。
19.2:3-羟基-3-(1H-咪唑-4-基)丙酸
将3ml三氟乙酸加到1.4g(3mmol)3-羟基-3-(1-三苯甲基-1H-咪唑-4-基)丙酸叔丁酯在7ml二氯甲烷中的溶液中。在环境温度下搅拌4小时之后,浓缩反应介质。将0.5g粗产物直接用于下一阶段。
19.3:N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
将0.5ml(3mmol)三乙胺加到包含在2ml二甲基甲酰胺中的0.5g(3mmol)3-羟基-3-(1H-咪唑-4-基)丙酸和1.0g(3mmol)TBTU的溶液中。在环境温度下搅拌1小时之后,加入1.5g(3mmol)(R)-2-氨基-1-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-甲氧基苯基)-丙-1-酮盐酸盐(如实施例6.2中所述制备)。将反应介质在环境温度下搅拌24小时,用1N氢氧化钠水溶液处理并用20/80庚烷/乙酸乙酯混合物萃取。将有机相经硫酸镁干燥,过滤并浓缩。产物通过硅胶色谱法纯化,用97/3二氯甲烷/甲醇混合物进行洗脱。得到72mg灰褐色粉末形式的N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺,产率5%。
1H NMR/DMSO d6 100℃:δ=0.78(t,J=7.2Hz,3H);1.23(六重峰,J=7.3Hz,2H);1.36(五重峰,J=6.7Hz,2H);2.21(s,3H);2.55-2.65(m,2H);2.70-2.90(m,3H);2.90-3.00(m,2H);3.68(bs,3H);3.90-4.40(m,5H);454(bq,J=7.2Hz,1H);4.92(bs,1H);6.60-6.80(m,3H);7.00-7.30(m,6H);7.46(bs,1H);7.81(bs,1H)。
实施例20:N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
20.1:3-羟基-3-邻甲苯基吖丁啶-1-甲酸叔丁酯
将60ml(60mmol)在THF中的1M邻甲苯基氯化镁逐滴加到冷却到-78℃的7.4g(43mmol)3-氧代吖丁啶-1-甲酸叔丁酯在60ml四氢呋喃中的溶液中。环境温度下搅拌1小时30分钟之后,将混合物用氯化铵饱和水溶液水解,随后用乙酸乙酯萃取。将有机相经硫酸钠干燥,过滤并浓缩。得到的灰褐色固体通过硅胶色谱法纯化,用50/50庚烷/乙酸乙酯混合物进行洗脱。得到8.9g白色固体形式的3-羟基-3-邻甲苯基吖丁啶-1-甲酸叔丁酯,产率79%。
20.2:3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-甲酸叔丁酯
将1ml(11.4mmol)1-溴-2-丁炔加到预先冷却0℃的1.4g(34.2mmol)氢化钠在14ml二甲基甲酰胺中的60%悬浮液中。搅拌1小时之后,逐滴加入在20ml二甲基甲酰胺中的3g(11.4mmol)3-羟基-3-邻甲苯基吖丁啶-1-甲酸叔丁酯,随后将反应混合物搅拌1小时30分钟。在用水并用氯化铵饱和水溶液水解之后,将反应介质用1/1庚烷/乙酸乙酯混合物萃取。将有机相经硫酸钠干燥,过滤并浓缩。得到的残余物通过硅胶色谱法纯化,用80/20庚烷/乙酸乙酯混合物进行洗脱。得到2.9g黄色油形式的3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-甲酸叔丁酯,产率81%。
20.3:3-丁-2-炔基氧基-3-邻甲苯基吖丁啶盐酸盐
将2.8g(9mmol)3-丁-2-炔基氧基-3-邻甲苯基-吖丁啶-1-甲酸叔丁酯溶解在40ml(120mmol)盐酸在乙酸乙酯中的3M溶液中。在环境温度下搅拌1小时30分钟之后,在真空下浓缩反应介质。得到2.2g灰褐色固体形式的3-丁-2-炔基氧基-3-邻甲苯基吖丁啶盐酸盐,产率96%。
20.4:[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基-吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯
将1.9g(10.2mmol)EDC、1.4g(10.2mmol)HOBt和3.8ml(27.2mmol)三乙胺加到包含在55ml二甲基甲酰胺中的2.7g(9.2mmol)Boc-D-甲氧基苯基丙氨酸的溶液中。搅拌1小时之后,将2.2g(8.7mmol)3-丁-2-炔基氧基-3-邻甲苯基吖丁啶盐酸盐在35ml二甲基甲酰胺中的溶液加到混合物中。随后将反应介质在环境温度下搅拌38小时。随后将其用1/1庚烷/乙酸乙酯混合物萃取。将有机相用1N氢氧化钠水溶液、随后用1N盐酸水溶液依次洗涤,经硫酸钠干燥,过滤并浓缩。得到的残余物通过硅胶色谱法纯化,用60/40庚烷/乙酸乙酯混合物进行洗脱。得到1.8g白色固体形式的[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯,产率41%。
20.5:(R)-2-氨基-1-(3-丁-2-炔基氧基-3-邻甲苯基-吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮
将1.7g(3.5mmol)[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]氨基甲酸叔丁酯溶解在45ml(135mmol)的盐酸在乙酸乙酯中的3M溶液中。在环境温度下搅拌3小时之后,浓缩混合物。以定量产率得到1.6g灰褐色固体形式的(R)-2-氨基-1-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-甲氧基苯基)-丙-1-酮。
206:N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
将732mg(2.3mmol)TBTU和1ml(7mmol)三乙胺加到408mg(2.3mmol)去氨基-组氨酸盐酸盐在6ml二甲基甲酰胺中的溶液中。搅拌60分钟之后,加入在6ml二甲基甲酰胺中的751mg(1.8mmol)(R)-2-氨基-1-(3-丁-2-炔基氧基-3-邻甲苯基-吖丁啶-1-基)-3-(4-甲氧基苯基)丙-1-酮。将反应介质在环境温度下搅拌115小时,随后加入1N氢氧化钠水溶液且将介质用1/1庚烷/乙酸乙酯混合物萃取。将有机相经硫酸钠干燥,过滤并浓缩。得到的残余物通过硅胶色谱法纯化,用90/10二氯甲烷/甲醇混合物进行洗脱。得到362mg白色固体形式的N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺,产率40%。
1H NMR/DMSO d6 100℃:δ=1.74(bs,3H);2.21(s,3H);2.39-2.43(m,2H);2.69-3.10(m,4H);3.68(m,5H);4.10-4.40(m,4H);4.52(q,J=7.2-8.0Hz,1H);6.67-6.85(m,3H);7.05-7.15(m,2H);7.18-7.29(m,4H);7.41(s,1H);7.75-7.85(m,1H)。
实施例21:N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
21.1:3-(5-甲基-1H-咪唑-4-基)丙酸盐酸盐
将60mg 10%的钯/炭加到387mg(1.1mmol)(E)-3-(5-甲基-1H-咪唑-4-基)丙烯酸盐酸盐在1/1四氢呋喃/水混合物中的溶液中。将反应介质置于氢气氛下并搅拌19小时,随后经硅藻土过滤。将滤液在真空下浓缩。在搅拌下将得到的残余物在庚烷/二异丙醚混合物中处理2小时。将所形成的白色沉淀物滤出,随后干燥。得到326mg白色固体形式的3-(5-甲基-1H-咪唑-4-基)丙酸盐酸盐,产率83%。
21.2:N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
将389mg(1.2mmol)TBTU和0.5ml(3.7mmol)三乙胺加到包含在4ml二甲基甲酰胺中的229mg(1.2mmol)3-(5-甲基-1H-咪唑-4-基)丙酸盐酸盐的溶液中。5分钟之后,加入溶解于4ml二甲基甲酰胺中的402mg(0.9mmol)(R)-2-氨基-1-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-3-(4-甲氧基苯基)-丙-1-酮。随后将反应介质在环境温度下搅拌90小时,随后加入1N氢氧化钠水溶液并将介质用1/1庚烷/乙酸乙酯混合物萃取。将有机相用氯化钠饱和水溶液洗涤,随后经硫酸钠干燥,过滤并浓缩。得到的残余物通过硅胶色谱法纯化,用88/12二氯甲烷/甲醇混合物进行洗脱。得到45mg白色固体形式的N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基-吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺,产率9%。
1H NMR/DMSO d6 100℃:δ=1.74(s,3H);2.06(s,3H);2.21(s,3H);2.30-2.45(m,2H);2.55-2.70(m,2H);2.74-3.10(m,2H);3.55-3.80(m,5H);4.00-4.45(m,4H);4.50(bq,J=8.0Hz,1H);6.65-6.85(m,2H);7.00-7.15(m,2H);7.15-7.35(m,5H);7.75-7.90(m,1H)。
表I举例说明根据本发明的化合物的实例。
在该表中:
-在“盐”列中,TFA代表以三氟乙酸盐形式的化合物,
-纯度(%)代表通过HPLC得到的产物纯度,
-质量(M+H)代表来源于质谱的质量+1(氢),与预期产物的HPLC峰有关。
表I:
实施例22:转活化试验:黑皮质素受体:
细胞:将HEK293细胞系用pCRE-Luc和hMC1R、hMC3R、hMC4R或hMC5R载体转染。将细胞在37℃、5%CO2下在补充有10%胎牛血清的DMEM培养基中培养。
试验原理:在活化剂(激动剂)存在下,黑皮质素受体将活化cAMP途径,其经由CRE-Luc载体将导致合成荧光素酶。在加入包含荧光素酶的发光底物的裂解缓冲液之后,将可以测量与活化程度或受体抑制程度成比例的发光。
产物试验:将产物以10mM溶解在DMSO中。在0.1%的最终DMSO浓度下以剂量-反应形式对它们进行试验。范围包括10个点,且零值是在4倍稀释下在10μM处开始。对于测试激动剂,仅测试了产物。对于测定拮抗剂的行为,在1nM NDP-MSH(参照激动剂)存在下测试目标产物。将细胞在无血清DMEM培养基中以5000个细胞/孔(384孔板)的速率接种,并在37℃、5%CO2下培养过夜。
在随后的几天加入产物和参照配位体(NDP-MSH),并将板在37℃、5%CO2下再培养6小时。在加入包含荧光素的裂解缓冲液之后,将板在Top-Count仪器上读数。结果使用100%(细胞+NDP-MSH,在10nM下)和0%(仅细胞)对照来标准化为%活性。对于各产物使用XLFit软件计算EC50。结果以nM给出。
实施例编号 | EC50 hMC1R(nM) | EC50 hMC4R(nM) |
1 | 500 | NT |
2 | 30 | 8000 |
3 | 60 | 4000 |
4 | 250 | 4000 |
5 | 4000 | 8000 |
6 | 2000 | 8000 |
7 | 500 | 4000 |
8 | 120 | 4000 |
9 | 120 | 1000 |
10 | 8000 | IA |
11 | 4000 | 8000 |
12 | 8000 | IA |
13 | 2000 | 15000 |
14 | 2000 | 15000 |
15 | 120 | 4000 |
16 | 2000 | 15000 |
17 | 250 | 8000 |
18 | 8000 | 8000 |
19 | 2000 | 120 |
20 | 120 | 4000 |
21 | 4000 | IA |
22 | 120 | 10000 |
23 | 60 | 1000 |
24 | 250 | 4000 |
25 | 1000 | 8000 |
26 | 500 | 4000 |
27 | 500 | 8000 |
28 | 1000 | 8000 |
29 | 1000 | IA |
31 | 500 | 4000 |
32 | 1000 | 4000 |
33 | 500 | 2000 |
34 | 1000 | 2000 |
35 | 500 | 2000 |
36 | 1000 | 3000 |
37 | 250 | 2000 |
38 | 250 | NT |
39 | 8000 | 2000 |
40 | 8000 | 500 |
41 | 120 | 1000 |
42 | 60 | 30 |
43 | 30 | NT |
44 | 30 | NT |
45 | 2000 | 2000 |
46 | 1000 | 4000 |
47 | 500 | 4000 |
48 | 4000 | 500 |
49 | 15 | 2000 |
50 | 1000 | 500 |
51 | 1000 | IA |
52 | 2000 | 250 |
53 | 1000 | 4000 |
54 | 250 | NT |
55 | 120 | 1000 |
56 | 4000 | 8000 |
57 | 1000 | 4000 |
58 | 2000 | 500 |
59 | NT | IA |
60 | 120 | 100 |
61 | 120 | 100 |
62 | 4000 | 500 |
63 | 500 | 500 |
64 | 2000 | 500 |
65 | IA | 100 |
66 | 250 | 250 |
67 | 500 | 500 |
68 | 60 | 2000 |
69 | 1000 | 8000 |
70 | 4000 | IA |
71 | 60 | 4000 |
72 | 2000 | IA |
73 | 500 | 8000 |
74 | 250 | 8000 |
75 | 60 | 4000 |
76 | 30 | 4000 |
77 | 120 | 2000 |
78 | 120 | 2000 |
79 | 15 | 1000 |
80 | 15 | 4000 |
IA:无活性
NT:未测试
Claims (18)
1. 通式(I)化合物以及所述通式(I)化合物的相应盐和对映异构体,
(I)
其中:
R1代表芳基、被取代的芳基或环烷基;
R2代表氢原子、羟基、低碳数烷基、被取代的低碳数烷基、高碳数烷基、被取代的高碳数烷基、环烷基、环烷基烷基、低碳数烷氧基、被取代的低碳数烷氧基、高碳数烷氧基、被取代的高碳数烷氧基、环烷基烷氧基或酰氧基;
R3代表芳烷基或被取代的芳烷基;
R4代表杂芳烷基、被取代的杂芳烷基、杂烷基或被取代的杂烷基;
R5代表氢原子、羟基、氨基、酰氨基或磺酰胺。
2. 权利要求1的通式(I)化合物以及所述通式(I)化合物的相应盐和对映异构体,其中:
- R1代表芳基、被取代的芳基或环烷基;
- R2代表羟基、低碳数烷基、被取代的低碳数烷基、高碳数烷基、被取代的高碳数烷基、低碳数烷氧基、被取代的低碳数烷氧基、高碳数烷氧基、被取代的高碳数烷氧基或环烷基烷氧基;
- R3代表芳烷基或被取代的芳烷基;
- R4代表杂芳烷基或被取代的杂芳烷基;
- R5代表氢或酰氨基。
3. 权利要求2的通式(I)化合物以及所述通式(I)化合物的相应盐和对映异构体,其中:
- R1代表芳基、被取代的芳基或环烷基;
- R2代表低碳数烷氧基、高碳数烷氧基、环烷基烷氧基、低碳数烷基或高碳数烷基;
- R3代表被取代的芳烷基;
- R4代表被取代和未被取代的咪唑基;
- R5代表氢原子。
4. 权利要求1-3中任一项的化合物,其特征在于所述通式(I)化合物选自:
- 丁酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-苯基吖丁啶-3-基酯
- N-[(S)-1-[(S)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-1-[(S)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- 乙酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-邻甲苯基吖丁啶-3-基酯
- 丁酸1-[(S)-2-[(S)-2-苯甲酰基氨基-3-(1H-咪唑-4-基)丙酰基氨基]-3-(4-甲氧基苯基)丙酰基]-3-(4-氟苯基)吖丁啶-3-基酯
- N-[(S)-1-[(S)-2-(3-环己基-3-羟基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-1-[(S)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-1-[(S)-2-[3-丁氧基-3-(3-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-2-(3-环己基-3-羟基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(S)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(3,4-二氯苄基)-2-(3-羟基-3-苯基吖丁啶-1-基)-2-氧代乙基]-3-(1H-咪唑-4-基)-丙酰胺
- N-[(S)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)-丙酰胺
- N-[(S)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(S)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-环己基甲基-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(2,4-二氯苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(S)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-己氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环丙基甲氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-羟基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(3-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-{(R)-1-苄基-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-2-氧代乙基}-3-(4H-咪唑-2-基)丙酰胺
- N-[(R)-1-苄基-2-(3-丁氧基-3-苯基吖丁啶-1-基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H[1,2,3]***-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H[1,2,4]***-3-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺
- N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)-3-戊基吖丁啶-1-基]-2-氧代乙基}-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-苄基-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙烯酰胺
- N-[(R)-2-[3-(2,4-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)-1-(3-三氟甲基苄基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)-1-(4-三氟甲基苄基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(3,4-二氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(3,4-二氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(3-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(3-氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(2-氟苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(2,4-二氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(4-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,5-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,6-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)戊酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2,4-二氯苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺
- N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)-丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
- (S)-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-2-羟基-3-(1H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基-苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
- N-[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环己基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- 3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-邻甲苯基-3-(4,4,4-三氟丁氧基)吖丁啶-1-基]乙基丙酰胺
- N-[(R)-2-(3-环丁基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
- N-{(R)-1-(4-甲氧基苄基)-2-[3-(3-甲基丁-2-烯基氧基)-3-邻甲苯基吖丁啶-1-基]-2-氧代乙基}-3-(5-甲基-1H-咪唑-4-基丙酰胺
- 3-(1H-咪唑-4-基)-N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-苯基吖丁啶-1-基)乙基]丙酰胺
- N-[(R)-2-[3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- 3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)吖丁啶-1-基]-2-氧代乙基}丙酰胺
- N-[(R)-2-[3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- 3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-苯基-3-(4,4,4-三氟丁基)吖丁啶-1-基]乙基}丙酰胺
- N-[(R)-2-[3-(5-氟戊基)-3-苯基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环丙基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环丙基甲基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- (S)-2-羟基-3-(1H-咪唑-4-基)-N-[1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]丙酰胺
- (S)-2-氨基-3-(1H-咪唑-4-基)-N-[1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丁酰胺
- (S)-N-[2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)-2-甲烷磺酰基氨基丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
以及其对应盐和对映异构体。
5. 权利要求1-4中任一项的化合物,其特征在于所述通式(I)化合物选自:
- N-[(S)-1-[(S)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-1-[(S)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-1-[(S)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(S)-1-[(S)-2-[3-丁氧基-3-(3-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基氨基甲酰基]-2-(1H-咪唑-4-基)乙基]苯甲酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(2,4-二氯苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(3-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-苯基吖丁啶-1-基)-1-(4-氟苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-苄基-2-(3-丁氧基-3-苯基吖丁啶-1-基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-[1,2,4]***-3-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺
- N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)-3-戊基吖丁啶-1-基]-2-氧代乙基}-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-苄基-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,4-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(3-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(2,4-二氯苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,5-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,6-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)己酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)戊酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(3-甲基-3H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
- (S)-N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-2-羟基-3-(1H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基-苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环己基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- 3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-邻甲苯基-3-(4,4,4-三氟丁氧基)吖丁啶-1-基]乙基丙酰胺
- N-[(R)-2-(3-环丁基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
- N-{(R)-1-(4-甲氧基苄基)-2-[3-(3-甲基丁-2-烯基氧基)-3-邻甲苯基吖丁啶-1-基]-2-氧代乙基}-3-(5-甲基-1H-咪唑-4-基丙酰胺
以及其对应盐和对映异构体。
6. 权利要求1-5中任一项的化合物,其特征在于所述通式(I)化合物选自:
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-乙氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环丙基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-丙氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-丁氧基-3-(4-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊氧基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁基-3-苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-1-(4-甲氧基苄基)-2-氧代-2-(3-戊基-3-邻甲苯基吖丁啶-1-基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(4-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-3H-咪唑-4-基)丙酰胺
- N-{(R)-1-(4-甲氧基苄基)-2-[3-(2-甲氧基苯基)-3-戊基吖丁啶-1-基]-2-氧代乙基}-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2-氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,4-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(3,4-二氯苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(3-氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,5-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-[3-(2,6-二氟苯基)-3-戊基吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环己基-3-戊基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺,
- N-[(R)-2-[3-丁氧基-3-(2-氟苯基)吖丁啶-1-基]-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1-甲基-1H-咪唑-4-基)丙酰胺
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(2-羟基-4-甲氧基苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺三氟乙酸盐
- N-[2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-羟基-苄基)-2-氧代乙基]-3-(3H-咪唑-4-基)丙酰胺
- N-[1-(3-丁氧基-3-邻甲苯基吖丁啶-1-羰基)-2-羟基-2-(4-甲氧基苯基)乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-羟基-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-丁-2-炔基氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
- N-[(R)-2-(3-环己基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(1H-咪唑-4-基)丙酰胺
- 3-(1H-咪唑-4-基)-N-{(R)-1-(4-甲氧基苄基)-2-氧代-2-[3-邻甲苯基-3-(4,4,4-三氟丁氧基)-吖丁啶-1-基]乙基丙酰胺
- N-[(R)-2-(3-环丁基甲氧基-3-邻甲苯基吖丁啶-1-基)-1-(4-甲氧基苄基)-2-氧代乙基]-3-(5-甲基-1H-咪唑-4-基)丙酰胺
- N-{(R)-1-(4-甲氧基苄基)-2-[3-(3-甲基丁-2-烯基氧基)-3-邻甲苯基吖丁啶-1-基]-2-氧代乙基}-3-(5-甲基-1H-咪唑-4-基)丙酰胺
以及其对应盐和对映异构体。
7. 权利要求1-6中任一项的化合物,其用作药物。
8. 权利要求1-7中任一项的化合物在制造用于治疗和/或预防病症和/或疾病的组合物中的用途,所述病症和/或疾病选自:
- 消化道的炎性疾病,尤其包括肠(且特别是结肠,在过敏性肠综合征、溃疡性结肠炎或克罗恩氏病的情况下)的炎性疾病;胰腺炎、肝炎(急性和慢性)、膀胱的炎性病理学病状和胃炎;
- 运动***的炎性疾病,包括类风湿性关节炎、骨关节炎、骨质疏松症、创伤性关节炎、感染后关节炎、肌肉退化病、皮肌炎;
- 泌尿生殖***的炎性疾病,尤其是肾小球性肾炎;
- 心脏***的炎性疾病,尤其是心包炎和心肌炎,和包括炎症作为基础因素的那些疾病的疾病(诸如动脉粥样硬化、移植动脉粥样硬化、周围血管疾病、炎性血管疾病、间歇性跛行或磕绊、再狭窄、中风、短暂性脑缺血发作、心肌局部缺血和心肌梗塞)或高血压、高脂血、冠状动脉疾病、不稳定型心绞痛(或心绞痛)、血栓形成、凝血酶诱发的血小板凝聚和/或血栓形成和/或动脉粥样斑形成的后果;
- 呼吸和ENT***的炎性疾病,尤其包括哮喘、急性呼吸窘迫综合征、花粉热、过敏性鼻炎、慢性阻塞性肺病或过敏症;
- 中枢神经***的炎性疾病,尤其是阿茨海默氏病和任何其它形式的痴呆、帕金森氏病、克雅氏病、多发性硬化症、脑膜炎;
- 炎性皮肤疾病,尤其是荨麻疹、硬皮病、接触性皮炎、特异性皮炎、牛皮癣、鳞癣、痤疮及其它形式的毛囊炎、红斑痤疮和秃发症;
- 自体免疫疾病,尤其是红斑狼疮、甲状腺病状、肾上腺的自体免疫疾病和自体免疫胃炎、白斑病和斑秃;
- 伴随细菌、病毒或真菌感染的炎症,尤其是肺结核、败血病、热病、HIV(无论什么位置感染)、疱疹、巨细胞病毒、甲型肝炎、乙型肝炎和丙型肝炎;
- 移植或移植排斥,诸如肾、肝、心脏、肺、胰腺、骨髓、角膜、肠、皮肤(皮肤同种异体移植、自体移植和异种移植等);;
- 治疗无论起源在哪里的疼痛:术后疼痛、神经肌肉疼痛、头痛、癌症相关疼痛、牙痛、骨关节痛;
- 调节色素沉着,以便治疗:
- 具有色素沉着病症的疾病,尤其是良性皮肤病,诸如白斑病、白化病、黑斑病、痣、雀斑、黑素细胞痣和所有炎症后色素沉着;以及色素沉着肿瘤,诸如黑素瘤和局部转移(渗透根瘤)、区域转移或其全身性转移;
- 出于预防目的的光照保护以免受日光影响:
- 日光的有害影响,诸如光化红斑、皮肤老化、皮肤癌(棘细胞、基底细胞和黑素瘤),尤其是其中日光加速发病的疾病(着色性干皮病、基底细胞痣综合征、家族性黑素瘤);
- 由于外源感光剂引起的光线性皮肤病,尤其是通过接触感光剂(例如呋喃香豆素、卤代水杨酰苯胺和衍生物、及局部硫酰胺和衍生物)引起的光线性皮肤病或由感光剂通过全身性路径(例如补骨脂素、四环素、硫酰胺、吩噻嗪、萘啶酮酸、三环抗忧郁药)引起的光线性皮肤病;
- 具有光敏性的皮肤病发作,尤其是
- 光加重的皮肤病(例如红斑狼疮、复发性疱疹、先天性皮肤异色病或具有光敏性的毛细血管扩张病状(布卢姆综合症、科凯恩综合症、罗思蒙德-汤姆森二氏综合征)、光化扁平癣、光化肉芽瘤、播散浅表性光线性汗孔角化症、红斑痤疮、少年痤疮、大疱皮肤病、达里埃病、皮肤淋巴瘤、牛皮癣、特异性皮炎、接触性皮炎、卵泡粘蛋白沉积症、多形性红斑、固定药物红斑、皮肤淋巴细胞瘤、具有粘蛋白沉积症的网状红斑、黑斑病),
- 具有因黑色素形成或分布异常的保护***缺陷引起的光敏性的皮肤病(例如眼皮白化病、苯丙酮酸尿症、前垂体功能不全、白斑病、斑驳)和具有DNA修复***缺陷的皮肤病(例如着色性干皮病、科凯恩综合症),
- 具有由新陈代谢异常引起的光敏性的皮肤病,诸如皮肤卟啉病(例如晚期皮肤卟啉病、混合型卟啉病、生血性原卟啉病、先天性红细胞生成性卟啉病(京特病)、红细胞生成性粪卟啉病)、糙皮病或类糙皮病红斑(例如,糙皮病、类糙皮病红斑和色氨酸新陈代谢病症);
- 自发性光照性皮肤病发作,尤其是PMLE(多态性光线疹)、良性夏季光线疹、光化痒疹、持久性光过敏(光线性类网状细胞增生病、慢性光线性皮肤病、感光湿疹)、日光性荨麻疹、牛痘样水疱病、青年春季疹、日光性瘙痒),
- 调节皮肤或头发和身体毛发的颜色,尤其是因黑色素合成增加引起皮肤变褐色或因妨碍黑色素合成使皮肤变白;而且预防头发和身体毛发变白色或变灰(例如灰发症和斑驳);以及在美容适应症中改变头发和身体毛发的颜色;
- 调节皮脂腺功能,尤其是治疗:
- 具有皮脂分泌过多的病状,尤其是痤疮、脂溢性皮炎、多油脂性皮肤和多油脂性头发、帕金森氏病和癫痫中的皮脂分泌过多和雄激素过多症;
- 具有降低的皮脂分泌的病状,尤其是干燥病和所有干燥性皮肤;
- 调节良性或恶性皮脂腺细胞和皮脂腺增生;
- 毛囊皮脂腺滤泡的炎性疾病,尤其是痤疮、疖、痈和毛囊炎;
- 神经退行性疾病,包括抑郁症、焦虑症、强迫症(诸如强迫性障碍)、神经病、精神病、失眠和睡眠障碍、睡眠呼吸暂停和药物滥用;
- 男性或女性性功能障碍;男性性功能障碍包括但不限于阳痿、***减退和***功能障碍;女性性功能障碍包括但不限于性刺激障碍或与欲望相关的病症、性接受程度、***高潮和性功能要点的障碍;疼痛、早产、痛经、月经过多和子宫内膜异位;
- 与体重相关的病症,所述病症但不限于肥胖症和食欲缺乏(诸如食欲改变或受损、脾脏新陈代谢、脂肪或碳水化合物的无害摄取);糖尿病(由于葡萄糖剂量耐受性和/或胰岛素抵抗性降低);
- 癌症,尤其是肺癌、***癌、结肠癌、乳腺癌、卵巢癌和骨癌,或包括实体肿瘤的形成或生长的血管形成病症。
9. 权利要求1-8中任一项的化合物在制造用于治疗和/或预防病症和/或疾病中的用途,所述病症和/或疾病选自:
- 皮肤疾病,尤其是荨麻疹、硬皮病、接触性皮炎、特异性皮炎、牛皮癣、鳞癣、痤疮及其它形式的毛囊炎、红斑痤疮和秃发症;
- 自体免疫疾病,尤其是红斑狼疮、甲状腺病状、肾上腺的自体免疫疾病和自体免疫胃炎、白斑病和斑秃;
- 具有色素沉着病症的疾病,尤其是良性皮肤病,诸如白斑病、白化病、黑斑病、痣、雀斑、黑素细胞痣和所有炎症后色素沉着;以及色素沉着肿瘤,诸如黑素瘤和局部转移(渗透根瘤)、区域转移或其全身性转移;
- 出于预防目的的光照保护以免受日光影响:
- 日光的有害影响,诸如光化红斑、皮肤老化、皮肤癌(棘细胞、基底细胞和黑素瘤),尤其是其中日光加速发病的疾病(着色性干皮病、基底细胞痣综合征、家族性黑素瘤);
- 由于外源感光剂引起的光线性皮肤病,尤其是通过接触感光剂(例如呋喃香豆素、卤代水杨酰苯胺和衍生物、及局部硫酰胺和衍生物)引起的光线性皮肤病或由感光剂通过全身性路径(例如补骨脂素、四环素、硫酰胺、吩噻嗪、萘啶酮酸、三环抗忧郁药)引起的光线性皮肤病;
- 具有光敏性的皮肤病发作,尤其是
- 光加重的皮肤病(例如红斑狼疮、复发性疱疹、先天性皮肤异色病或具有光敏性的毛细血管扩张病状(布卢姆综合症、科凯恩综合症、罗思蒙德-汤姆森二氏综合征)、光化扁平癣、光化肉芽瘤、播散浅表性光线性汗孔角化症、红斑痤疮、少年痤疮、大疱皮肤病、达里埃病、皮肤淋巴瘤、牛皮癣、特异性皮炎、接触性皮炎、卵泡粘蛋白沉积症、多形性红斑、固定药物红斑、皮肤淋巴细胞瘤、具有粘蛋白沉积症的网状红斑、黑斑病),
- 具有因黑色素形成或分布异常的保护***缺陷引起的光敏性的皮肤病(例如眼皮白化病、苯丙酮酸尿症、前垂体功能不全、白斑病、斑驳)和具有DNA修复***缺陷的皮肤病(例如着色性干皮病、科凯恩综合症),
- 具有由新陈代谢异常引起的光敏性的皮肤病,诸如皮肤卟啉病(例如晚期皮肤卟啉病、混合型卟啉病、生血性原卟啉病、先天性红细胞生成性卟啉病(京特病)、红细胞生成性粪卟啉病)、糙皮病或类糙皮病红斑(例如,糙皮病、类糙皮病红斑和色氨酸新陈代谢病症);
- 自发性光照性皮肤病发作,尤其是PMLE(多态性光线疹)、良性夏季光线疹、光化痒疹、持久性光过敏(光线性类网状细胞增生病、慢性光线性皮肤病、感光湿疹)、日光性荨麻疹、牛痘样水疱病、青年春季疹、日光性瘙痒);
- 调节皮肤或头发和身体毛发的颜色,尤其是因黑色素合成增加引起皮肤变褐色或因妨碍黑色素合成使皮肤变白;而且预防头发和身体毛发变白色或变灰(例如灰发症和斑驳);
- 在美容适应症中改变头发和身体毛发的颜色。
10. 权利要求1-7中任一项的化合物在制造用于治疗和/或预防病症和/或疾病的组合物中的用途,所述病症和/或疾病选自:
- 具有皮脂分泌过多的病状,尤其是痤疮、脂溢性皮炎、多油脂性皮肤和多油脂性头发、帕金森氏病和癫痫中的皮脂分泌过多和雄激素过多症;
- 具有减少的皮脂分泌的病状,尤其是干燥病和所有干燥性皮肤;
- 调控良性或恶性皮脂腺细胞和皮脂腺增生;
- 毛囊皮脂腺滤泡的炎性疾病,尤其是痤疮、疖、痈和毛囊炎。
11. 权利要求9的用途,其特征在于所述病症选自:
- 皮肤疾病,尤其是荨麻疹、硬皮病、接触性皮炎、特异性皮炎、牛皮癣、鳞癣、痤疮及其它形式的毛囊炎、红斑痤疮和秃发症;
- 具有色素沉着病症的疾病,尤其是良性皮肤病,诸如白斑病、白化病、黑斑病、痣、雀斑、黑素细胞痣和所有炎症后色素沉着;以及色素沉着肿瘤,诸如黑素瘤和局部转移(渗透根瘤)、区域转移或其全身性转移。
12. 药物组合物,其特征在于其包含在生理学上可接受的载体中的至少一种权利要求1-7中任一项的通式(I)化合物。
13. 权利要求12的组合物,其特征在于通式(I)化合物的浓度相对于所述组合物的总重量为0.001%-10%重量。
14. 权利要求12或13的组合物,其特征在于用于局部施用的通式(I)化合物的浓度相对于所述组合物的总重量为0.01%-5%重量。
15. 美容组合物,其特征在于其包含在美容学上可接受的载体中的至少一种权利要求1-7中任一项的通式(I)化合物。
16. 权利要求15的组合物,其特征在于通式(I)化合物的浓度相对于所述组合物的总重量为0.001%-3%重量。
17. 权利要求15和16中任一项的组合物用于预防和/或治疗老化和/或皮肤的病征的美容用途。
18. 权利要求15和16中任一项的组合物用于身体或头发卫生的美容用途。
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FR0857496A FR2937972B1 (fr) | 2008-11-04 | 2008-11-04 | Derives d'oxoazetidine, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
CN2009801446981A CN102203081A (zh) | 2008-11-04 | 2009-11-04 | 氧代吖丁啶衍生物、其制备方法及其在人类医药和美容品中的用途 |
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FR2939135B1 (fr) * | 2008-12-02 | 2010-12-03 | Galderma Res & Dev | Nouveaux composes 4-(azacycloalkyl)-benzene-1,3-diol comme inhibiteurs de la tyrosinase, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
FR2969494B1 (fr) * | 2010-12-22 | 2013-11-08 | Expanscience Lab | Extrait de parties aeriennes de gynandropsis gynandra ou cleome gynandra et compositions cosmetiques, dermatologiques le comprenant |
FR2981933B1 (fr) * | 2011-11-02 | 2013-11-15 | Galderma Res & Dev | Derives d'oxoazetidine, leur procede de preparation et leur utilisation en medecine humaine ainsi qu'en cosmetique |
FR2984167B1 (fr) | 2011-12-16 | 2014-01-17 | Galderma Res & Dev | Association d'un agoniste des recepteurs des prostaglandines et d'un agoniste du recepteur mc1r pour le traitement et/ou la prevention de desordres de la pigmentation |
WO2013135880A1 (en) | 2012-03-15 | 2013-09-19 | Galderma Research & Development | Combination of a mc1r receptor agonist and uvb for the treatment and/or prevention of pigmentation disorders |
FR2992317B1 (fr) | 2012-06-22 | 2016-05-13 | Diverchim | Procede de preparation de peptides chiraux |
FR3027900B1 (fr) * | 2014-11-05 | 2018-02-23 | Centre National De La Recherche Scientifique | Utilisation de derives halogenes de l'histidine a titre de sel d'electrolyte dans une cellule photovoltaique a colorants |
CA2968836A1 (en) | 2016-06-13 | 2017-12-13 | Gilead Sciences, Inc. | Fxr (nr1h4) modulating compounds |
US20200246436A1 (en) * | 2017-02-01 | 2020-08-06 | Clinuvel Pharmaceuticals Ltd | Alpha-msh analogues used in the treatment of xeroderma pigmentosum |
JP6906626B2 (ja) | 2017-03-28 | 2021-07-21 | ギリアード サイエンシーズ, インコーポレイテッド | 肝疾患を処置するための治療的組み合わせ |
AU2020225225B2 (en) | 2019-02-19 | 2022-12-22 | Gilead Sciences, Inc. | Solid forms of FXR agonists |
MX2023002974A (es) | 2020-09-14 | 2023-05-25 | Regeneron Pharma | Conjugados de anticuerpo-farmaco que comprenden peptidomimeticos glp1 y usos de los mismos. |
US20230330254A1 (en) | 2022-03-11 | 2023-10-19 | Regeneron Pharmaceuticals, Inc. | Anti-glp1r antibody-tethered drug conjugates comprising glp1 peptidomimetics and uses thereof |
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MX2011004068A (es) | 2011-05-31 |
AU2009312818A1 (en) | 2010-05-14 |
BRPI0916069A2 (pt) | 2015-11-10 |
US8871187B2 (en) | 2014-10-28 |
FR2937972A1 (fr) | 2010-05-07 |
WO2010052253A1 (en) | 2010-05-14 |
US20150045559A1 (en) | 2015-02-12 |
EP2342194B1 (en) | 2018-08-08 |
CA2738785A1 (en) | 2010-05-14 |
RU2011122637A (ru) | 2012-12-20 |
CN102203081A (zh) | 2011-09-28 |
RU2569886C2 (ru) | 2015-12-10 |
AU2009312818B2 (en) | 2014-11-06 |
US20110274638A1 (en) | 2011-11-10 |
KR101689042B1 (ko) | 2016-12-22 |
RU2671189C1 (ru) | 2018-10-30 |
AR074275A1 (es) | 2011-01-05 |
BRPI0916069B1 (pt) | 2019-11-05 |
US9630949B2 (en) | 2017-04-25 |
CA2738785C (en) | 2017-05-16 |
BRPI0916069C1 (pt) | 2021-05-25 |
EP2342194A1 (en) | 2011-07-13 |
FR2937972B1 (fr) | 2013-03-29 |
CN104387372B (zh) | 2018-06-26 |
JP2012507491A (ja) | 2012-03-29 |
BRPI0916069B8 (pt) | 2019-12-17 |
JP5798486B2 (ja) | 2015-10-21 |
KR20110088555A (ko) | 2011-08-03 |
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