CN106317043A - 一种新的大麻素受体2激动剂 - Google Patents
一种新的大麻素受体2激动剂 Download PDFInfo
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- CN106317043A CN106317043A CN201610688694.1A CN201610688694A CN106317043A CN 106317043 A CN106317043 A CN 106317043A CN 201610688694 A CN201610688694 A CN 201610688694A CN 106317043 A CN106317043 A CN 106317043A
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- indole
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- diazole
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Abstract
本发明涉及一种式Ⅰ所示的亚乙基联结的哌啶基噁二唑与吲哚‑2‑甲酰胺衍生物和/或它们的可药用盐及其制备方法，以及含有所述化合物的药物组合物。式Ⅰ所示的化合物是一种潜在的大麻素受体2(CB2)激动剂，可用于治疗和/或预防炎症、炎性肠病、青光眼、糖尿病、肾病、心肌病等疾病。其中，R1为芳基、杂芳基，R2为H、(C1‑C6)直链或支链烷基，R3为吲哚基、取代的吲哚基。
Description
技术领域
本发明属于药物化学领域，具体涉及到权利要求中所述的一种亚乙基联结的哌啶基噁二唑与吲哚-2-甲酰胺类化合物及其生理上可接受的盐，它们的制备及它们在预防和/或治疗疼痛、炎症、炎性肠病、青光眼、糖尿病、糖尿病性视网膜病变、动脉粥样硬化、老年性黄斑退化症、急性肝衰竭、肝纤维化、肺纤维化、肾纤维化、系统性纤维化、缺血-再灌注损伤、急性同种异体移植排斥、慢性同种异体移植肾病、糖尿病肾病、肾小球肾病、心肌病、心力衰竭、心肌缺血、心肌梗死、系统性硬化、热损伤、烧伤、肥大性疤痕、龈炎发热、肝硬化或肿瘤、骨质疏松、神经变性、卒中等大麻素受体2(CB2)激动剂相关疾病中的用途。
技术背景
大麻素(cannabinoid，CB)是大麻中起治疗作用和精神作用的化学物质，1964年，Gaoni等首次对植物大麻的主要活性成分四氢大麻酸，进行了分离及立体结构的确证(Gaoni,Y.et.al,J.Am.Chem.Soc,1964,86,1646)。随后研究者们又分离和合成得到一系列大麻素类化合物(Felder,C.C.et.al,Mol.Interv,2006,6,149)。传统的大麻素类化合物主要包括五类：1、以四氢大麻酸为代表的经典大麻素类化合物,该类化合物是从天然植物中提取的大麻素类物质及其类似物，三环母核为其共同结构特征；2、以AEA和2-AG为代表的内源性大麻素；3、以CP55940为代表的非经典大麻素类化合物，该类化合物为经典大麻素的开环衍生物；4、以WIN55212-2为代表的氨烷基吲哚类化合物；5、以SR141716A为代表的二芳基吡唑类化合物(Howlett,A.C.et.al,Pharmacol.Rev,2002,54,161)。
同时，人们对大麻素类化合物的作用机制也进行了广泛的研究。大麻素类物质作用于大麻素受体(cannabinoid receptor，CB-R)以实现其生理活性，目前研究证明，大麻素受体包括两个亚型：大麻素受体1(cannabinoid receptor 1,CB1受体)和大麻素受体2(cannabinoid receptor 2，CB2)。1990年，Matsuda等在大鼠大脑皮质cDNA文库中成功克隆出CB1受体(Matsuda,L.A.et.al,Nature,1990,346,561)；CB2受体则于1993年由Munro等在人类的早幼粒细胞白血病细胞HL60CDNA文库中成功克隆(Munro,S.et.al,Nature,1993,365,61)。CB1受体和CB2受体同属G蛋白偶联受体(G-protein coupled receptor,GPCR)的视紫红质样家族,具有典型的7段a-螺旋跨膜结构，两种受体完整的氨基酸序列有44％的同源性，在相对保守的跨膜区两者的氨基酸序列有68％的同源性(Pacher,P.et.al,Pharmacol.Rev,2006,58,389)。其中，CB2主要在免疫系统的细胞，如巨噬细胞和T-细胞和胃肠系统外周表达，CB2受体还广泛分布在脑中，其中它主要发现于小胶质细胞而非神经元上。
CB2受体激动剂相关的化合物已经在许多疾病中表现出较好的活性，这些疾病包括疼痛(Beltramo,M.Mini Rev Med Chem,2009,9,11)、炎症(Cabral,G.A.et.al,J LeukocBiol,2005,78,1192)、结肠炎(林思思等，中国病理生理杂志，2015,10,195)、青光眼(Hampson,A.J.et.al,PNAS,1998,95,8268)、肝纤维化(Julien,B.et.al.Gastroenterology,2005,128,742)、脑缺血再灌注损伤(Lopez,R.A,CerebCortex,2011,21,2046；孙竞等，中国药科大学学报，2013,44,167)、肿瘤(邓远斐，广东医学，2016,8,1109)、心肌病(胡文星等，心脏杂志，2014,3,265)等。
CB2受体激动剂多种多样的临床应用价值显示出其在医药领域的广阔前景，然而到目前为止，尚无CB2受体激动剂成为上市药物，因此，发现新型高活性、高选择性且具有较好成药性的CB2受体激动剂对于该领域具有非常重要的意义。
发明概述
本发明描述了式I化合物，和/或它们的可药用盐
其中，R1为芳基、杂环芳基，R2为H、(C1-C6)直链或支链烷基。
优选的，R1选自2-三氟甲氧基苯基、4-三氟甲氧基苯基、2,4-二三氟甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2,4-二甲氧基苯基、2-甲基苯基、4-甲基苯基、2,4-二甲基苯基、2-氟苯基、4-氟苯基、2,4-二氟苯基、2-氯苯基、4-氯苯基、2,4-二氯苯基、2-吡啶基；R2选自H、甲基；R3选自吲哚-2-基、3-硝基吲哚-2-基、5-硝基吲哚-2-基、6-硝基吲哚-2-基、3-甲基吲哚-2-基、4-甲基吲哚-2-基、5-甲基吲哚-2-基、7-甲基吲哚-2-基、5-甲氧基吲哚-2-基、5-溴吲哚-2-基、5-氯吲哚-2-基、5-氟吲哚-2-基、5-三氟甲基吲哚-2-基、吲哚-3-基。
对于R1取代基来说，有代表性的例子如下，
星号(*)表示该键与哌啶环4位的碳原子相连。
对于R3取代基来说，有代表性的例子如下，
星号(*)表示该键与羰基上的碳原子相连。
本发明还涉及用作药物(或药剂)的式I化合物和/或其可药用盐用于预防和/或治疗疼痛、炎症、炎性肠病、青光眼、糖尿病、糖尿病性视网膜病变、动脉粥样硬化、老年性黄斑退化症、急性肝衰竭、肝纤维化、肺纤维化、肾纤维化、系统性纤维化、缺血-再灌注损伤、急性同种异体移植排斥、慢性同种异体移植肾病、糖尿病肾病、肾小球肾病、心肌病、心力衰竭、心肌缺血、心肌梗死、系统性硬化、热损伤、烧伤、肥大性疤痕、龈炎发热、肝硬化或肿瘤、骨质疏松、神经变性、卒中。
本发明还涉及药物制剂(或药物组合物)，其含有有效量的至少一种式I化合物和/或其可药用盐、生理学耐受的赋形剂和载体，以及在适当时还有其他添加剂和/或其他活性成分。药物可以口服施用，例如以丸剂、片剂、喷涂片、包衣片、颗粒剂、硬和软明胶胶囊、溶液、糖浆、乳剂、混悬剂或气雾混合物形式。但是，施用也可以如下进行：经直肠给药，例如以栓剂形式；或胃肠外给药，例如经静脉内、肌内或皮下以注射溶液或输注溶液、微囊、植入剂或植入棒的形式；或经皮或局部给药，例如以软膏剂、溶液或酊剂形式；或以其他途径给药、例如以气雾剂或鼻喷雾剂形式。
本发明的药物制剂以本身已知并且为本领域技术人员所熟悉的方式制备，除了式I化合物和/或它们的可药用盐和/或它们的前药外，使用可药用的惰性无机和/或有机载体物质和/或添加剂。对于丸剂、片剂、包衣片和硬明胶胶囊的制备而言，可能使用例如乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐等。软明胶胶囊和栓剂的载体物质有例如脂肪、蜡、半固体和液体多元醇、天然或硬化油等。适合于制备溶液、例如注射溶液或乳剂或糖浆剂的载体物质有例如水、盐水、醇、甘油、多元醇、蔗糖、转化糖、葡萄糖、植物油等。适合用于微囊、植入剂或植入棒的载体物质，例如羟乙酸和乳酸的共聚物。药物制剂通常含有约0.5至约90％重量的式I化合物和/或它们的可药用盐和/或它们的前药。药物制剂中的活性成分式I化合物和/或它们的可药用盐和/或它们的前药的量通常约0.5至约1000mg、优选约1至约500mg。
除了式I的活性成分和/或它们的可药用盐以及载体物质外，药物制剂可含有一种或多种添加剂，如填充剂、崩解剂、粘合剂、润滑剂、润湿剂、稳定剂、乳化剂、防腐剂、甜味剂、着色剂、矫味剂、芳香剂、增稠剂、稀释剂、缓冲物质、溶剂、增溶剂、获得储库效果的试剂、改变渗透压的盐、包衣剂或抗氧化剂。它们也可以含有两种或多种式I化合物和/或它们的可药用盐。在药物组合物含有两种或更多种式I化合物时，对个别化合物的选择可依据药物制剂的特定总体药理学性质。例如，作用持续时间较短的高度强效化合物可以与功效较低的长效化合物组合。就式I化合物中取代基选择而言所允许的灵活性使得能够对化合物的生物学和物理化学性质进行众多控制，由此能够选择这类所需化合物。此外，除了至少一种式I化合物和/或其可药用盐外，药物制剂还可含有一种或多种其他治疗性或预防性的活性成分。
当使用式I化合物时，剂量可在宽限度内并且按照常规的和医生已知的而变化，剂量应适合于每种个例的个体情况。其取决于例如所应用的具体化合物、所治疗疾病的性质和严重程度、施用方式和方案或所治疗的是急性还是慢性病症或是否进行预防。适合的剂量可利用医学领域已知的临床方法建立。一般而言，在重约75kg的成人中获得所需结果的日剂量是约0.01至约100mg/kg、优选约0.1至约50mg/kg、特别约0.1至约10mg/kg(在每种情况下以mg/kg体重计)。特别在施用相对大量的情况下，日剂量可以分为若干部分，例如2、3或4部分施用。通常，根据个体行为，可能有必要向上或向下偏离所述的日剂量。
此外，式I化合物可用作制备其他化合物、特别是其他药物活性成分的合成中间体，其可由式I化合物例如通过引入取代基或修饰官能团获得。
在大多数情况下，对含有式I的最终化合物或中间体的反应混合物进行后处理，如果有必要，将产物通过本领域技术人员已知的常规方法纯化。例如，所合成的化合物可利用熟知的方法如结晶、色谱或反相高效液相色谱法(RP-HPLC)或基于例如化合物大小、电荷或疏水性的其他分离方法进行纯化。类似地，熟知的方法如NMR、IR和质谱法(MS)可以用于表征本发明化合物。
因此，以下实施例是本发明的一部分，用于阐明而非限制本发明。
应当指明的是，未实质性影响本发明各种实施方案活性的修饰包括在本文所公开的本发明范围内。
实施例：
第一步：4-[2-(三氟甲氧基)苯基]哌啶-1-腈的制备
将4-[2-(三氟甲氧基)苯基]哌啶(10.0g，40.8mmol)，碳酸钾(11.1g，80.2mmol)加于100mL二氯甲烷/水(1:1)中，搅拌，降温至0℃。将溶于20mL二氯甲烷的氰基溴(5.3g，50.0mmol)缓慢滴入上述溶液中，0℃下反应30min，恢复至室温继续反应2h，分离有机层，用饱和碳酸氢钠溶液，饱和氯化钠溶液洗涤有机层，无水硫酸镁干燥，减压浓缩有机相，粗产品用硅胶柱层析(石油醚/乙酸乙酯＝7/3)得4-[2-(三氟甲氧基)苯基]哌啶-1-腈8.7g(收率：80％)。
1H-NMR(400MHz,CDCl3):δ7.12-7.03(m,2H),6.69-6.51(m,2H),3.52(d,J＝12.0Hz,2H),3.17-3.04(m,2H),2.70-2.68(m,1H),1.98-1.83(m,2H),1.70-1.61(m,2H)；LC/MS(M+1)+＝271.1.
第二步：(E)-N-羟基-4-[2-(三氟甲氧基)苯基]哌啶-1-甲脒的制备
将4-[2-(三氟甲氧基)苯基]哌啶-1-腈(8.0g，30.0mmol)溶于异丙醇/水(4/1)30mL中，室温下加入盐酸羟胺(10.4g，150.0mmol)，90℃下搅拌5h，冷却至室温，向溶液中加入6N HCl水溶液，乙醚洗涤，用碳酸钠水溶液将水相调pH值至弱碱性，乙醚萃取，收集有机相，干燥，减压浓缩得(E)-N-羟基-4-[2-(三氟甲氧基)苯基]哌啶-1-甲脒8.0g(收率：89％)。LC/MS(M+1)+＝304.1。
第三步：2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基氨基甲酸叔丁基酯的制备
向含有羰基二咪唑(4.5g，27.6mmol)的50mL无水N,N-二甲基甲酰胺中，缓慢滴加含有3-(N-叔丁氧羰基氨基)丙酸(5.7g，30.0mmol)的30mL无水N,N-二甲基甲酰胺溶液，室温下搅拌1h，向溶液中缓慢加入(E)-N-羟基-4-[2-(三氟甲氧基)苯基]哌啶-1-甲脒(7.0g，23.0mmol)，反应在110℃下搅拌5h，冷却后，减压蒸馏除去溶剂。剩余物用硅胶柱层析(PE/EA＝1/1)得2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基氨基甲酸叔丁基酯6.7g(收率：64％)。
1H-NMR(400MHz,CDCl3):δ7.14-7.05(m,2H),6.63-6.51(m,2H),6.45(br,1H),3.47-4.43(m,2H),3.17(t,J＝7.6Hz,2H),3.12-3.04(m,2H),2.72-2.70(m,1H),2.67(t,J＝7.6Hz,2H),1.98-1.71(m,4H),1.42(s,9H)；LC/MS(M+1-100)+＝357.1.
第四步：2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙胺基三氟乙酸盐的制备
2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基氨基甲酸叔丁基酯(6.5g，14.2mmol)加入80mL三氟乙酸/二氯甲烷(1:5)中，在室温下搅拌6h，减压除去溶剂得到2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙胺基三氟乙酸盐6.4g(收率：100％)。LC/MS(M+1)+＝357.1。
第五步：N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺的制备
将1H-吲哚-2-甲酸(2.5g，15.6mmol)加入到60mL二氯甲烷中，向溶液中加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDCI，3.0g，15.6mmol)，1-羟基苯并三唑(HOBt,2.1g,15.6mmol)，三乙胺(3.2g，31.2mmol)，室温搅拌30min，向反应液中加入2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙胺基三氟乙酸盐(6.4g，14.2mmol)，反应在室温下搅拌过夜，停止反应，二氯甲烷相用水，饱和食盐水洗涤，收集有机相，无水硫酸钠干燥，过滤，减压浓缩得粗品，粗品经硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化得N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺5.9g(收率：83％)。
1H-NMR(400MHz,CDCl3):δ9.62(s,1H),7.66-7.05(m,7H),6.67-6.58(m,2H),6.42(s,1H),3.48-3.41(m,2H),3.19(t,J＝7.2Hz,2H),3.12-3.04(m,2H),2.71-2.69(m,1H),2.62(t,J＝7.2Hz,2H),1.99-1.88(m,2H),1.81-1.78(m,2H)；LC/MS(M+1)+＝500.2.
符合专利权要求的式I化合物均可以采用与上述实施例近似的合成方法得到，只需变更不同的起始物料即可。有代表性的化合物如下：
N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-[4-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-[2,4-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-[2-(甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-[4-(甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-[2,4-(甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(2-甲基苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(4-甲基苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(2,4-甲基苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(2-氯苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(4-氯苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(2,4-氯苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(2-氟苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(4-氟苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(2,4-氟苯基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-(2-吡啶基)哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
3-硝基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
5-硝基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
6-硝基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
3-甲基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
4-甲基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
5-甲基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
7-甲基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
5-甲氧基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
5-溴-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
5-氯基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
5-氟基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
5-三氟甲氧基-N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-2-甲酰胺；
N-[2-[3-[4-[2-(三氟甲氧基)苯基]哌啶-1-基]-1,2,4-噁二唑-5-基]乙基]-1H-吲哚-3-甲酰胺。
活性测定
进行以下试验以确定式(I)化合物的活性。
放射性配体结合测定
本发明化合物对大麻素CB1受体的亲和性使用建议量的表达人CNR1或CNR2受体的人胚胎肾(HEK)细胞的膜制品(PerkinElmer)各自分别结合1.5或2.6nM[3H]-CP-55，940(Perkin Elmer)作为放射性配体确定。结合在总体积为0.2ml的结合缓冲液(对于CB1受体：50mM Tris，5mMMgCl2，2.5mM EDTA，和0.5％(wt/vol)无脂肪酸BSA，PH7.4，和对于CB2受体：50mM Tris，5mM MgCl2，2.5mM EGTA，和0.1％(wt/vol)无脂肪酸BSA，pH 7.4)中进行，在30℃震荡1h。通过经涂布有0.5％聚乙烯亚胺的微过滤板(UniFilter GF/B过滤板；Packard)快速过滤将反应终止。对于Ki使用非线性回归分析(Activity Base,ID BusinessSolution,Limited)来分析结合的放射性，对于[3H]CP55,940的Kd值从饱和试验确定。式(I)化合物显示对于CB2受体的优异的亲和性，亲和性低于20μM。
根据式I的化合物在上述测定中的活性(Ki)特别是1nM至10μM，更特别是1nM至2μM。
cAMP测定
将表达人CB1或CB2受体的CHO细胞在实验之前17-24小时以50.000细胞/孔接种在具有透明平底的黑色96孔平板(Corning Costar#3904)中、在DMEM(Invitrogen No.31331)中，补充1x HT，具有10％胎牛血清，并在湿润的培养箱中在5％CO2和37℃下温育30分钟。加入化合物至最终测定体积为100μl，并且在30℃温育30分钟。使用cAMP-Nano-TRF检测试剂盒(Roche Diagnostics)，通过加入50μl裂解试剂(Tris，NaCl，1.5％Triton X100，2.5％NP40，10％NaN3)和50μl检测溶液(20μM mAb Alexa700-cAMP 1：1，和48μM钌-2-AHA-cAMP)终止测定，并且室温振荡2h。通过装备有ND：YAG激光器作为激光源的TRF读出器(EvotecTechnologies GmbH)测量时间分辨能量转移。将平板测量两次，在355nm激发和分别在730(带宽30nm)或645nm(带宽75nm)以100ns的延迟和100ns的门(gate)发射，总暴露时间是10s。FRET信号计算如下：FRET＝T730-Alexa730-P(T645-B645)，P＝Ru730-B730/Ru645-B645，其中T730是在730nM测量的测试孔，T645是在645nM测量的测试孔，B730和B645是分别在730nM和645nM的缓冲液对照。cAMP含量从跨度为从10μM至0.1nM cAMP的标准曲线的函数来测定。
使用Activity Base分析(ID Business Solution，Limited)测定EC50值。从该测定产生的宽范围的大麻素激动剂的EC50值与科学文献中公开的值吻合。根据本发明的所有化合物均为CB2激动剂，其EC50低于5uM，特别地低于2uM。例如，以下化合物在上述功能cAMP测定中显示以下人EC50值(以uM表达)：
Claims (5)
1.式I化合物，和/或它们的可药用盐
其中，R1为芳基、杂芳基，R2为H、(C1-C6)直链或支链烷基，R3为吲哚基、取代的吲哚基。
2.依据权利要求1的式I化合物，其中R1选自2-三氟甲氧基苯基、4-三氟甲氧基苯基、2,4-二三氟甲氧基苯基、2-甲氧基苯基、4-甲氧基苯基、2,4-二甲氧基苯基、2,4-二甲基苯基、2-氟苯基、4-氟苯基、2,4-二氟苯基、2-氯苯基、4-氯苯基、2,4-二氯苯基、2-吡啶基；R2选自H、甲基；同时R3选自吲哚-2-基、3-硝基吲哚-2-基、5-硝基吲哚-2-基、6-硝基吲哚-2-基、3-甲基吲哚-2-基、4-甲基吲哚-2-基、5-甲基吲哚-2-基、7-甲基吲哚-2-基、5-甲氧基吲哚-2-基、5-溴吲哚-2-基、5-氯吲哚-2-基、5-氟吲哚-2-基、5-三氟甲基吲哚-2-基、吲哚-3-基。
3.依据权利要求1和2中任意一项所述的至少一种式I化合物和/或其可药用盐用于预防和/或治疗疼痛、炎症、炎性肠病、青光眼、糖尿病、糖尿病性视网膜病变、动脉粥样硬化、老年性黄斑退化症、急性肝衰竭、肝纤维化、肺纤维化、肾纤维化、系统性纤维化、缺血-再灌注损伤、急性同种异体移植排斥、慢性同种异体移植肾病、糖尿病肾病、肾小球肾病、心肌病、心力衰竭、心肌缺血、心肌梗死、系统性硬化、热损伤、烧伤、肥大性疤痕、龈炎发热、肝硬化或肿瘤、骨质疏松、神经变性、卒中。
4.权利要求3中所述的用途，其中的疾病指的炎症、炎性肠病、青光眼、糖尿病、肾病、心肌病。
5.药物，其包含有效量的权利要求1和2中任意一项所述的至少一种式I化合物和/或其可药用盐、生理学耐受的赋形剂和载体，以及在适当时还有其他添加剂和/或其他活性成分。
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