CN1780615A - 氮杂环丁烷羧酰胺衍生物在疗法中的用途 - Google Patents
氮杂环丁烷羧酰胺衍生物在疗法中的用途 Download PDFInfo
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- CN1780615A CN1780615A CNA2004800117556A CN200480011755A CN1780615A CN 1780615 A CN1780615 A CN 1780615A CN A2004800117556 A CNA2004800117556 A CN A2004800117556A CN 200480011755 A CN200480011755 A CN 200480011755A CN 1780615 A CN1780615 A CN 1780615A
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- UHNVNVCYDWXEBN-UHFFFAOYSA-N 1-benzhydryl-3-[[3-(trifluoromethyl)phenyl]methoxy]azetidine Chemical compound FC(F)(F)C1=CC=CC(COC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 UHNVNVCYDWXEBN-UHFFFAOYSA-N 0.000 description 4
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Abstract
通式(I)的化合物或其药学上可接受的盐或前药在生产治疗由CB1受体介导的疾病的药物中的用途,其中:R1是芳基;R2是H、烷基或芳基;和R3是氢或烷基。
Description
技术领域
本发明主要涉及氮杂环丁烷-1-羧酰胺在治疗大麻素CB1受体介导的疾病中的用途,尤其是肥胖和其它与过量食物摄取有关的进食失调疾病的治疗。
发明背景
已经认识到,肥胖是受环境因素影响的疾病进程,其中,传统节食和运动的减肥方法应补充治疗药物(S.Parker,″Obesity:Trends and Treatments″,ScripReports,PJB Publications Ltd,1996)。
通常,基于身体质量指数(BMI)来确定某人归类为超重或肥胖,由体重(kg)除以身高的平方(m2)计算身体质量指数。因此,BMI的单位为kg/m2,并且,可在生命的每十年计算与最小的死亡率有关的BMI范围。BMI在25-30kg/m2范围内定义为超重,BMI大于30kg/m2定义为肥胖。这种定义的问题在于,它没有考虑身体质量的比例即肌肉与脂肪(脂肪组织)的比例。考虑到这一因素,也可基于身体脂肪含量定义肥胖:分别是男性大于25%和女性大于30%。
随着BMI的身高,多种不依赖于其它危险因素的原因导致的死亡危险增加。与肥胖有关的最常见的疾病是心血管疾病(尤其是高血压)、糖尿病(肥胖加重糖尿病的进程)、胆囊疾病(尤其是癌症)和生育的疾病。研究表明,即使是体重的微小降低也可明显降低冠心病发展的危险。
作为抗肥胖药物销售的化合物包括Orlistat(Reductil)和Sibutramine。Orlistat(脂肪酶抑制剂)直接抑制脂肪吸收,倾向于产生不适(虽然相对无害)的副作用如腹泻的高发生率。Sibutramine(混合的5-HT/去甲肾上腺素再摄取抑制剂)在一些患者中可使血压升高,心率增加。已报道5-羟色胺释放剂/再摄取抑制剂芬氟拉明(Pondimin)和右芬氟拉明(ReduxTM)可长时间(大于6个月)降低食物摄取和体重。然而,在报道了与它们的使用有关的心瓣膜异常后,撤销了这两种药物。因此,需要发展一种更安全的抗肥胖药物。
现在,存在广泛的临床前和临床研究数据,支持将CB1受体拮抗剂/逆激动剂应用于肥胖的治疗。
大麻制剂(Cannabis sativa)在药用和娱乐目的中的使用已超过5000年。已鉴定大麻中的主要精神活性成分是Δ9-四氢大麻酚(Δ9-THC),是从该植物中分类得到的超过60种相关大麻素化合物的一种。已表明,Δ9-THC通过与大麻素(CB)受体的激动相互作用发挥效果。目前,已鉴定了两种大麻素受体亚型(CB1和CB2)。发现CB1受体亚型主要存在于中枢神经系统中,在外周神经系统和多种外周器官中存在较少。发现CB2受体亚型主要存在于淋巴组织和细胞中。迄今为止,已鉴定了三个与CB1和CB2受体相互作用的内源性激动剂(内大麻素)(anandamide,2-花生四烯酰甘油和noladin ether)。
遗传性肥胖大鼠和小鼠在脑区显示与摄食行为有关的明显升高的内大麻素水平(Di Marzo等2001 Nature 410:822-825)。而且,在正常偏瘦动物禁食状态下也观察到内大麻素水平的升高(Kirkham等,British Journal of Pharmacology,2002,136(4),550-557)。内大麻素的外源性应用导致与用Δ9-THC处理观察到的相同的生理效应,包括食欲刺激(Jamshida等,British Journal of Pharmacology,2001,134:1151-1154)、镇痛、行进缓慢、低体温和僵住。
已使用CB1(CB1 -/-)和CB2(CB2 -/-)受体敲除小鼠来阐明两种大麻素受体亚型的特异作用。而且,对于对两种受体都以激动剂起效的配基如Δ9-THC,这些小鼠可用于鉴别哪一个受体亚型介导特异的生理效应。CB1 -/-,而不是CB2 -/-,小鼠可抵抗激动剂如Δ9-THC的行为效应。CB1 -/-动物还显示可抵抗与长期进食高脂饮食相关的体重增加,以及急性食物剥夺的食欲刺激作用。
这些结果提示,内源性和外源性大麻素受体激动剂通过选择性激活CB1受体亚型在增加食物摄取和体重中明显的作用。
已广泛地综述了大麻素受体配基的治疗潜力(Exp.Opin.Ther.Pat.1998,8,301-313;Exp.Opin.Ther.Pat.2000,10,1529-1538;Trendsin Phann.Sci.2000,21,218-224;Exp.Opin.Ther.Pat.2002,12(10),1475-1489)。
已知至少一种表征为CB1受体拮抗剂/逆激动剂化合物(SR-141716A)在临床试验中用于治疗肥胖。
WO 00/15609,WO 01/64632,WO 01/64633和WO 01/64634公开了作为CB1受体拮抗剂的氮杂环丁烷衍生物。WO 02/28346公开了结合CB1受体拮抗剂氮杂环丁烷衍生物和西布曲明,用于肥胖的治疗。
仍然存在对具有合适的药动学和药效学性质以使其适合作为药物使用的低分子量CB1受体拮抗剂/逆激动剂的药用需求。还存在对CB1受体介导的疾病、尤其是进食失调疾病、尤其是肥胖的新治疗方法的药学需求。本发明的目的是提供上述药物和治疗方法。
现在,已发现某些氮杂环丁烷-1-羧酰胺作为抗肥胖药物具有意想不到的效果。这些化合物过去在WO-A-99/37612中描述,用于治疗焦虑和癫痫。已经表明,这些氮杂环丁烷-1-羧酰胺可以高亲和力选择性结合CB1受体亚型。已发现,这些化合物在小鼠中可剂量依赖性地阻断外源性应用的大麻素受体激动剂(如Δ9-THC)的作用。而且,已发现这些化合物在大鼠和小鼠的进食行为模型中可降低食物摄取和体重增加。
发明内容
根据本发明,提供了通式(I)化合物或其药学上可接受的盐或前药在生产治疗CB1受体介导的疾病的药物中的用途。
其中,
R1是芳基;
R2是H、烷基或芳基;
R3是氢或烷基。
通式(I)的活性化合物是大麻素-1(CB1)受体的拮抗剂和/或逆激动剂,可用于治疗、预防和抑制CB1受体介导的疾病。本发明涉及使用这些化合物来选择性拮抗CB1受体,例如,治疗肥胖和其它疾病。
本说明书中引用的“烷基”是指支链或直链、环状或非环状、饱和或不饱和(例如链烯基(包括烯丙基)或炔基(包括炔丙基))的烃基。环状或非环状烷基时,优选C1-C12,更优选C1-C8(如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、异戊基、己基、庚基、辛基)。因此,本文所用术语“烷基”包括:烷基(直链或支链)、烯基(直链或支链)、炔基(直链或支链)、环烷基、环烯基和环炔基。环状烷基也可是单桥键或多桥键的环状烷基。在优选的实施例中,环状烷基优选C3-C12,更优选C5-C8,非环状烷基优选C1-C10,更优选C1-C6,更优选甲基、乙基、丙基(正丙基或异丙基)、丁基(正丁基、异丁基、叔丁基或伯丁基)或戊基(包括正戊基和异戊基),更优选甲基。
如本文所用,术语“低级烷基”是指直链或支链、环状或非环状、饱和或不饱和(如烯基或炔基)的烃基,其中,所述环状低级烷基是C5、C6或C7,所述非环状低级烷基是C1、C2、C3或C4。因此,本文所用术语“低级烷基”宜包括:低级烷基(直链或支链)、低级烯基(直链或支链)、低级炔基(直链或支链)、环状低级烷基、环状低级烯基和环状低级炔基。优选地,低级烷基优选选自:甲基、乙基、丙基(正丙基或异丙基)或丁基(正丁基、异丁基、仲丁基或叔丁基),优选甲基。
本说明书引用的“芳基”是指单或二环芳族基团,例如苯基或萘基,优选单环芳族基团。
本说明书引用的“杂芳基”是指含有一个或多个杂原子的芳族基团,优选1、2或3个杂原子,优选1或2个杂原子。优选的杂原子选自O、S和N,优选选自O和N。优选的杂芳基包括5或6元环系统。杂芳基优选是单环或二环系统,优选单环。例子包括:噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡啶基、吡嗪基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基和异苯并呋喃基。
本说明书引用的非芳族杂环基团是指含有1、2或3个选自N、O和S杂原子的饱和或部分不饱和的4、5、6或7元环,优选1或2个杂原子,优选选自N和O。例子包括哌啶基、吗啉基、哌嗪基和吡咯烷基。
烷基和芳基可被取代或未取代。在一个实施例中,只有R1-R3和R9-R13所表示的烷基和芳基可被取代。取代时,通常存在1-3个取代基,优选1或2个取代基。取代基包括:
含碳基团如:烷基,芳基,芳烷基(如取代和未取代的苯基、取代和未取代的苄基);
卤原子和含卤素的基团如:卤烷基(如三氟甲基);
含氧基团溶如:醇(如羟基、羟烷基、(芳基)(羟基)烷基),醚(如烷氧基、烷氧基烷基、芳氧基烷基),醛(甲醛基),酮(如烷基羰基、烷基羰基烷基、芳基羰基、芳烷基羰基、芳基羰基烷基),酸(如羧基、羧基烷基),酸衍生物如酯(如烷氧基羰基、烷氧基羰基烷基、烷基羰氧基、烷基羰氧基烷基)和酰胺(如氨基羰基、单或二烷基氨基羰基、氨基羰基烷基、单或二烷基氨基羰基烷基、芳基氨基羰基);
含氮基团如:胺(如氨基、单或二烷基氨基、氨基烷基、单或二烷基氨基烷基),叠氮化合物,腈(如氰基、氰基烷基),硝基;
含硫基团如:巯基、巯醚、亚砜和砜(如烷硫基、烷基亚磺酰基、烷基磺酰基、烷基硫烷基、烷基亚磺酰基烷基、烷基磺酰基烷基、芳硫基、芳基亚磺酰基、芳基磺酰基、芳基硫烷基、芳基亚磺酰基烷基、芳基磺酰基烷基);
以及含一个或多个,优选一个杂原子的杂环基团(如噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、吡咯烷基、吡咯啉基、咪唑烷基、咪唑啉基、吡唑烷基、四氢呋喃基、吡喃基、吡喃酮基、吡啶基、吡嗪基、哒嗪基、哌啶基、哌嗪基、吗啉基、硫代萘基、苯并呋喃基、异苯并呋喃基、吲哚基、羟吲哚基、异吲哚基、吲唑基、吲哚满基、7-氮杂吲哚基、异吲唑基、苯并吡喃基、香豆素基、异香豆素基、喹啉基、异喹啉基、二氮杂萘基、噌啉基、喹唑啉基、吡啶并吡啶基、苯并噁嗪基、喹噁啉基(quinoxadinyl)、色原烯基、色满基、异色满基和咔啉基)。
当芳基是苯基时,苯基可被相邻的取代基取代,形成任选含有1或2个杂原子,优选选自N、O和S,优选选自N和O的5或6元饱和环。当饱和环含有2个氮原子时,环优选是6元环。当饱和环含有2个氧原子时,环可是5或6元环。例子包括:2,3-二氢苯并[b]呋喃-7-基、2,3-二氢苯并[b]噻吩-6-基、1,2,3,4四氢萘-5-基、2,3-二氢苯并[1,4]氧杂环己烯-6-基和1,2,3,4四氢异喹啉-8-基。
优选的取代基包括烷基(包括卤烷基)、烷氧基(包括卤烷氧基)、芳基、氰基或卤素。优选的含卤素基团包括三氟甲基。
如本文所用,术语“烷氧基”是指烷基-O-,“烷酰基”是指烷基-CO-。
如本文所用,术语“卤素”是指氟、氯、溴或碘基团,优选氟或氯基团。
通式(I)化合物可存在许多非对映异构体和/或对映异构体形式。除非另有说明,本说明书引用的“通式(I)化合物”是指所有该化合物的立体异构体形式,包括混合物中未分离的立体异构体、外消旋或非外消旋以及其纯的立体异构体。
在通式(I)化合物中,优选R1是取代或未取代的苯基或萘基(优选苯基),更优选R1是取代的苯基或萘基(优选苯基),更优选R1是含1-3个取代基的苯基或萘基(优选苯基),最优选R1是含1或2个取代基的苯基或萘基(优选苯基)。优选的取代基包括烷基、卤素、含卤素的基团如卤烷基(尤其是卤甲基、如三氟甲基)、硫烷基、烷氧基、烷基磺酰基以及、单或二烷基氨基羰基。尤其优选的取代基是烷基、卤素和含卤素的基团如卤烷基(尤其是卤甲基如三氟甲基);更优选卤素和含卤素的基团如卤烷基(尤其是卤甲基如三氟甲基)。
在本发明一个实施例中,R2是芳基,优选取代或未取代的苯基,更优选取代苯基,更优选含有1-3个取代基的苯基,最优选含有1或2个取代基的苯基。优选的取代基包括烷基、卤素、含卤素的基团如卤烷基(尤其是卤甲基如三氟甲基)、硫烷基、烷氧基、烷基磺酰基和单或二烷基氨基羰基。尤其优选的取代基是烷基、卤素、含卤素的基团如卤烷基(尤其是卤甲基、如三氟甲基);更优选卤素和含卤素的基团如卤烷基(尤其是卤甲基如三氟甲基)。
在一个可选的实施例中,R2是H或烷基(环状或非环状)。
在优选的实施例中,R3是烷基、优选选自烯基、炔基、羟烷基、烷氧基烷基或未取代的饱和环状或非环状烃基。优选R3是非环状烃基,优选低级烷基,在一个实施例中是取代的。可存在一个或两个取代基团,优选一个取代基团。优选的取代基如上所述,尤其是羟基、烷氧基、硫烷基、氨基、单或二烷基氨基、烷氧基羰基、芳基(优选苯基),以及杂环基团包括杂芳基和非芳族杂环基团。当R3是非环状烷基时,其可被环状烷基取代;当R3是环状烷基时,它可被非环状烷基取代。当取代基是杂芳基时,优选杂芳基是含一个或多个N、O或S原子的5或6元环,优选基团包括噻吩基、呋喃基、异噁唑基、噻唑基和苯并噻吩基。其它优选的取代基包括:二氢苯并呋喃基、二氢苯并-1,4-氧杂环己烯基、四氢呋喃基、吡咯烷基、氧代吡咯啉基和苯并-1,3-二氧杂环戊烯基。
在一个实施例中,R3选自:
-(CHR9)n(CH2)mCR10R11R12
其中,n为0或1;
m为0、1、2或3;
R9、R10、R11和R12选自:氢、烷基(优选低级烷基)、羟基、烷氧基(优选低级烷氧基)、硫烷基(优选硫代低级烷基)、氨基、单和二烷基氨基(优选低级烷基氨基)、烷氧基羰基(优选低级烷氧基羰基)和R13;
其中,R13选自:芳基、杂芳基和非芳族杂环,任选被一个或多个(优选1或2个,优选1个)基团取代,取代基优选选自烷基(优选低级烷基、优选甲基)、卤素(优选氟、氯和溴)、烷氧基(优选低级烷氧基、优选甲氧基)、氧代、芳基、杂芳基和非芳族杂环。
优选地,m为0或1或2,优选0或1,优选0。
优选n为0。
在一个实施例中,至少一个或更优选两个R10、R11和R12选自H。在另一个实施例中,至少一个或更优选至少两个R10、R11和R12选自甲基。
在另一个实施例中,R3选自:环烷基,包括环戊基、环己基、降冰片基和金刚烷基,优选环戊基和环己基。优选的R3是叔丁基、仲丁基、异丁基、异丙基、正丙基和乙基,尤其优选叔丁基、异丁基、仲丁基和异丙基,尤其是叔丁基。
通式(I)化合物包括:
R1 | R2 | R3 |
4-C1-C6H44-C1-C6H4 | 4-C1-C6H44-C1-C6H4 | 烯丙基2-羟丙基 |
根据本发明的另一方面,提供了治疗CB1受体介导的疾病的方法,包括给予需要这种治疗的受试者以治疗优选剂量的通式(I)化合物,或其药学上可接受的盐或前药。
本发明涉及的疾病和病症为:精神病、精神分裂症、认知障碍、注意力缺陷障碍、胃肠道病症(如胃肠蠕动功能障碍或腹泻)、戒烟、肥胖和其它与食物摄取过量有关的进食障碍疾病(包括食欲过盛和强迫性进食障碍疾病)以及相关的健康并发症包括非胰岛素依赖性糖尿病。本发明具体涉及肥胖和其它与食物摄取过量有关的进食障碍疾病以及相关的健康并发症包括非胰岛素依赖性糖尿病,尤其涉及肥胖和其它与食物摄取过量有关的进食障碍疾病,尤其涉及肥胖。
在本发明可选的实施例中,本发明涉及戒烟及其简易化。
在本发明可选的实施例中,本发明涉及胃肠道疾病(如胃肠嚅动功能障碍或腹泻)。
本发明可应用于人或动物受试对象,更优选哺乳动物,更优选人受试对象。
如本文所用,术语“治疗”包括预防性治疗。
如本文所用,术语“前药是指通式(I)化合物任何药学上可接受的尤其。例如,可以前药的形式制备通式(I)化合物,其中,用合适的基团(该基团可包括如烷基、芳基、磷酸酯、糖、胺、乙二醇、磺酸酯或酸官能团)衍生化(例如,通过酯键、酰胺键或磷酸酯键)游离-OH,衍生化后的基团适当地不稳定,给药后某个时间或接触所需的生物环境后可被除去/断裂(例如水解),以暴露通式(I)化合物。
如本文所用,术语“药学上可接受的盐”是指任何通式(I)化合物的药学上可接受的盐。可由药学上可接受的无毒性的酸和碱包括无机和有机酸和碱来制备盐。酸包括:醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙烯磺酸、二氯醋酸、反丁烯二酸、葡糖酸、谷氨酸、马尿酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、粘酸、硝酸、巴莫酸、泛酸、磷酸、琥珀酸、硫酸、酒石酸、草酸、 对甲苯磺酸等。尤其优选盐酸、氢溴酸、磷酸、硫酸和甲磺酸,最优选甲磺酸盐。可接受的碱盐包括碱金属(如钠、钾)、碱土金属(如钙、镁)和铝盐。
通式(I)化合物可结合对治疗上述疾病有用的一种或多种附加的药物使用,组分可在同一制剂中或不同制剂中,同时或相继给予。
可根据反应过程1(其中,P是氮保护基团)制备通式(I)化合物。R1、R2和R3如上文所定义。氮杂环丁醇(II)与芳基烷醇(III,X=OH)和偶氮二羧酸二乙酯和三苯基膦或与芳烷基的氯化物、溴化物、碘化物、甲磺酸酯或甲苯磺酸酯(III,X=Cl,Br,I,甲磺酸酯,甲苯磺酸酯)和强碱如氢化钠反应,形成醚(IV)。(IV)与合适的氮脱保护剂反应,形成氮杂环丁烷(V)。例如,如果P是二苯基甲基,那么,可通过用氯甲酸1-氯乙酯处理,再用甲醇处理,进行脱保护反应。氮杂环丁烷(V)与N-烷基异氰酸酯或N-烷基氨甲酰氯和碱如三乙胺或碳酸钾反应,形成脲(I)。可选地,不分离中间产物如伯胺(V),直接从氮杂环丁烷(IV)制备脲。例如,当P是二苯基甲基时,可通过用碳酰氯处理,再用胺R3NH2处理氮杂环丁烷(IV),直接得到脲(I)。
反应过程1
可根据反应过程2(其中P是氮保护基团)制备通式(I)化合物,其中,R1、和R2是芳基。R1、R2和R3如上文所定义。氮杂环丁醇(II)与二苯甲醇(III,X=OH)反应,除去水(例如,在标准Dean-Stark条件下共沸除去水),形成醚(IV)。也可通过氮杂环丁醇(II)与合适的离去基团取代的二苯甲基(III,X=Cl,Br,I,甲磺酸酯,甲苯磺酸酯)和强碱如氢化钠反应,形成醚(IV)。(IV)与合适的氮脱保护剂反应,得到氮杂环丁烷(V)。例如,如果P是二苯甲基时,那么,可通过用氯甲酸1-氯乙酯处理,再用甲醇处理,进行脱保护反应。可以盐酸盐或碱化后以游离碱的形式,直接分离脱保护的氮杂环丁烷(V)。氮杂环丁烷(V)与N-烷基异氰酸酯或N-烷基氨基甲酰氯和碱如三乙胺或碳酸钾反应,形成脲(I)。可选地,不分离中间产物如氮杂环丁烷(V),直接从保护的氮杂环丁烷(IV)制备脲。例如,当P是二苯基甲基时,可通过用碳酰氯处理,再用胺R3NH2处理氮杂环丁醚(IV),直接得到脲(I)。用例如三碳酰氯处理,氮杂环丁烷(V)也可转化为相应的氨甲酰氯(VI)。该中间体氨甲酰氯(VI)可与胺R3NH2反应,得到脲(I)。
反应过程2
本发明还提供了含有效量通式(I)化合物与药学上可接受的载体或赋形剂的药物组合物,以及制备该含有效量通式(I)化合物与药学上可接受的载体或赋形剂的组合物的方法。
为了进一步增加疗效,该组合物可含有组分如葡聚糖或环糊精或其醚衍生物,以增加稳定性和分散性,降低活性成分的代谢。
对于由环糊精或其醚衍生物构成药学上可接受的载体的组合物,活性成分与环糊精或其醚衍生物水溶液充分混合,在所述混合之前、同时或之后任选地再加入药学上可接受的成分。这样,所得到的溶液任选地冻干,冻干残留任选地用水重新溶解。
在本发明的一个实施例中,组合物还包含缓冲系统、去离子剂和水。
可以适用于口服,如片剂、胶囊、水或油溶液、混悬剂或乳剂;包括透过粘膜和透皮应用的局部应用,如乳膏、软膏、凝胶、水或油溶液或混悬液、油膏、胶布或硬膏剂;鼻腔应用,如鼻腔吸入剂、鼻腔喷雾剂或滴鼻剂;阴道或直肠应用,如栓剂;吸入给药,如细分粉末或液体气雾剂;舌下或含服应用,如片剂或胶囊;非胃肠道应用(包括静脉内、皮下、肌内、血管内或滴注),如无菌水溶液或油溶液或混悬液的形式给予通式(I)化合物。通常,可使用药学领域技术人员公知的标准技术,用常规赋形剂,以常规方式制备上述组合物。
对于口服给药,通常以片剂或胶囊或水溶液或混悬液的形式提供通式(I)化合物。
口服片剂可包含与药学上可接受的辅料如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、矫味剂、着色剂和防腐剂混合的活性成分。合适的惰性稀释剂包括碳酸钠和碳酸钙、磷酸钠和磷酸钙、乳糖,而玉米淀粉和海藻酸是合适的崩解剂。粘合剂可包括淀粉和明胶,如果存在润滑剂,润滑剂通常是硬脂酸镁、硬脂酸或滑石粉。需要时,片剂可用如单硬脂酸甘油酯或二硬脂酸甘油酯包衣的物质包衣,在胃肠道中延迟吸收。
口服应用的胶囊包括活性成分与固体稀释剂混合的硬明胶胶囊,以及活性成分与水或油如花生油、液体石蜡或橄榄油混合的软胶囊。可选地,活性成分可与赋形剂、表面活性剂或增溶剂如Labrafil、Labrasol、或Miglyol,或它们合适的混合物混合。
对于肌内、腹膜内、皮下和静脉内应用,通常以无菌水溶液或混悬液,缓冲调节至合适的pH和渗透压的形式提供通式(I)混合物。合适的水性载体包括:Ringer氏溶液和氯化钠等渗溶液。水性混悬液可包括混悬剂如纤维素衍生物、海藻酸钠、聚乙烯基吡咯烷酮和西黄蓍胶,以及润湿剂如卵磷脂。水性混悬液合适的防腐剂包括乙基和正丙基对羟苯甲酸。
希望可根据所用的混合物、患者所显示的症状的严重程度以及患者的体重,在较大的范围内改变所使用的剂量水平。
现在,将结合以下药理实施例具体描述本发明。实施例是示例性的,而不是限制本发明的范围。
实施例
合成实施例
1-(二苯基甲基)-3-氮杂环丁醇的制备
根据Anderson和Lok(J.Org.Chem.,1972,37,3953,其内容通过引用包括在此)制备该化合物,m.p.111-112 C(lit.m.p.113 C)。
3-(4-氯苯甲氧基-1-(二苯甲基)氮杂环丁烷(1)的制备
0℃下,将1-二苯甲基-3-氮杂环丁醇(25mmol)的DMF(100mL)溶液加入到NaH(60%在油中分散,30mmol)的DMF(50mL)混悬液中。室温下搅拌反应混合物1小时,然后0℃下逐滴加入4-氯苄基氯(25mmol),室温下继续搅拌反应混合物3小时。用水终止反应,乙酸乙酯(3×50mL)萃取,用水和盐水洗萃取物,干燥(MgSO4)并真空浓缩。色谱法[SiO2;己烷-乙酸乙酯(9∶1)]纯化残留物,得到黄色油状产物(7.3g,80%)。无需进一步纯化,该物质可用于下一步骤。
实施例1 3-(4-氯苯甲氧基)-N-(2-丙烯基)氮杂环丁烷-1-羧酰胺(2)
0℃下,将碳酰氯溶液(1.75-M甲苯溶液,24mmol)加入到化合物(1)(20mmol)的CH2Cl2(40mL)中。室温下搅拌反应混合物90分钟,真空浓缩,然后再溶解于CH2Cl2(40mL)中,0℃下用烯丙胺(42mmol)处理。室温下搅拌反应混合物4小时,然后,加入水(40mL),分离水层。在用CH2Cl2(2×40mL)萃取亲水层。用稀HCl(20mmol)和盐水洗有机层,干燥(MgSO4)并真空浓缩。用乙醚研磨残留物,得到结晶固体形式的产物(2)(3.5g,60%),m.p.110-111℃。测定值:C,59.84;H,6.11;N,9.98。C14H17ClN2O2理论值:C,59.89;H,9.6.10;N,9.97%。
3-(3,4-二氯苯甲氧基)-1-(二苯甲基)氮杂环丁烷(3)的制备
根据化合物(1)所述的制备方法,由1-二苯甲基-3-氮杂环丁醇(6.0g)和α,3,4-三氯甲苯制备该化合物(产率92%)。
实施例2 3-(3,4-二氯苯甲氧基)-N-(2-丙烯基)氮杂环丁烷-1-羧酰胺(4)
根据制备化合物(2)所述的方法,由化合物(3)(9.2g)制备该化合物(产率75%),m.p.88-89℃。测定值:C,53.43;H,5.18;N,8.85,C14H17ClN2O2理论值:C,53.35;H,5.12;N,8.88%。
3-(3-(三氟甲基)苯甲氧基)-1-(二苯甲基)氮杂环丁烷(5)的制备
根据制备化合物(1)所述的方法,由1-二苯甲基-3-氮杂环丁醇(5g)和α′-溴-α,α,α-三氟间二甲苯(产率91%)制备。
实施例3 3-(3-(三氟甲基)苯甲氧基)-N-(2-丙烯基)氮杂环丁烷-1-羧酰胺(6)的制备
根据制备化合物(1)所述的方法,由化合物(5)(7.5g)制备该化合物(产率64%),m.p.108℃。测定值:C,57.29;H,5.44;N,8.87,C15H17F3N2O2理论值:C,57.32;H,5.45;N,8.91%。
3-(4-(三氟甲基)苯甲氧基-1-(二苯甲基)氮杂环丁烷(7)的制备
根据制备化合物(1)所述的方法,由1-二苯甲基-3-氮杂环丁醇(6.0g)和α′-溴-α,α,α-三氟对二甲苯制备该化合物(产率77%)。
实施例4 3-(4-(三氟甲基)苯甲氧基)-N-(2-丙烯基)氮杂环丁烷-1-羧酰胺(8)的制备
根据制备化合物(2)所述的方法,由化合物(7)(7.7g)制备该化合物(产率72%),m.p.120℃。测定值:C,57.27;H,5.45;N,8.86。C15H17F3N2O2理论值:C,57.32;H,5.45,N,8.91%。
3-(4-氟苯甲氧基-1-(二苯甲基)氮杂环丁烷(9)的制备
根据制备化合物(1)所述的方法,由1-二苯甲基-3-氮杂环丁醇(6.0g)和4-氟苄基溴制备该化合物(产率83%)。
实施例5 3-(4-氟苯甲氧基)-N-(2-丙烯基)氮杂环丁烷-1-羧酰胺(10)的制备
根据制备化合物(2)所述的方法,由化合物(9)制备该化合物,m.p.97-99℃。测定值:C,63.57;H,6.59;N,10.66。C14H17ClN2O2理论值:C,63.62;H,6.48;N,10.59。
3-(二(4-氯苯基)甲氧基-1-二苯甲基)氮杂环丁烷(11)的制备
在Dean-Stark装置中回流4,4′-二氯二苯甲醇(25mmol),对甲苯磺酸(18.4mmol)和1-(二苯甲基)-3-氮杂环丁醇(8.4mmol)的苯溶液3小时。冷却溶液,用碳酸氢钠洗(饱和水溶液,100mL),干燥(MgSO4)并真空浓缩。色谱法[SiO2;己烷-乙醚(5∶1)]纯化残留物,得到稠厚油状产物(11)(2.4g,62%),该产物在保存中可结晶。
实施例6 3-(二(4-氯苯基)甲氧基)-N-(2-丙烯基)氮杂环丁烷-1-羧酰胺(12)
根据制备化合物(2)所述的方法,由化合物(11)制备结晶固体形式的该化合物(产率17%)。测定值:C,56.38;H,5.10;N,6.51。C20H20C12N2O2·2H2O理论值:C,56.21;H,5.66;N,6.56%。
实施例7 (R)-3-(二(4-氯苯基)甲氧基)-N-(2-羟丙基)氮杂环丁烷-1-羧酰胺(13)
根据制备化合物(2)所述的方法,由化合物(11)和(R)-(-)-1-氨基-2-丙醇制备结晶固体形式的该化合物(产率57%)。测定值:C,58.74;H,5.42;N,6.84。C20H22Cl12N2O3理论值:C,58.69;H,5.42;N,6.84%。
实施例8 3-(3-三氟甲基)苯甲氧基-N-氮杂环丁烷-1-羧酰胺(14)
0℃下,在3-(3-三氟甲基)苯甲氧基-1-(二苯甲基)氮杂环丁烷(5)(5.3mmol)的二氯甲烷(15mL)溶液中加入碳酰氯溶液(1.75M甲苯溶液,6.4mmol)。室温下搅拌该反应混合物2小时,真空浓缩,然后再溶解于THF(15mL)中,0℃下加入一部分氢氧化铵(5mL)处理。室温下剧烈搅拌反应混合物15小时,然后加入水(50mL)和乙酸乙酯(40mL),分层。用乙酸乙酯(2×40mL)萃取亲水层,干燥(MgSO4)并真空浓缩。用乙酸乙酯(10mL)研磨残留物,得到固体形式的(14)(0.91g,63%),mp.167℃(乙酸乙酯)。测定值:C,52.44;H,4.72;N,10.23。C14H17CIN2O2理论值:C,52.56;H,4.78;N,10.21。
3-(1-(3-三氟甲基苯基)乙氧基)-1-(二苯甲基)氮杂环丁烷(15)的制备
冷却至0℃,氮气下,在α-甲基-3-三氟甲基苄醇(53mmol),二异丙基乙胺(105mmol)的二氯甲烷溶液(150mL)中,10分钟内逐滴加入甲烷磺酰氯(63.1mmol)。搅拌反应混合液15小时。加入水(200mL)并所得混合液搅拌10分钟,倒入碳酸钾中(10%wt/wt水溶液,200mL)并用二氯甲烷(3×150mL)萃取。合并的有机萃取物用盐水(50mL)洗一次,然后干燥(Na2SO4),过滤并真空浓缩。残留物溶解于乙醚中并冲洗通过一段二氧化硅,用更多的乙醚洗脱。滤过液真空浓缩。如下所示,可直接应用该物质。
0℃下,用移液管将1-二苯甲基-3-氮杂环丁醇(42mmol)的二甲基甲酰胺溶液(20mL)加入到NaH(60%在油中分散,50mmol)的二甲基甲酰胺混悬液中(80mL)。室温下搅拌该反应混合液15分钟,0℃下将得到的粗品(假定53mmol)以溶液的形式逐滴加入到二甲基甲酰胺(30mL)中,室温下继续搅拌反应混合液2小时。将反应液倒入水中(200mL)并用乙酸乙酯(3×50mL)萃取,用水(200mL)和盐水(50mL)冲洗萃取物,干燥(MgSO4)并真空浓缩。色谱法(SiO2;己烷/乙酸乙酯9/1)纯化残留物,得到黄色油状的3-(1-(3-三氟甲基苯基)乙氧基)-1-(二苯甲基)氮杂环丁烷(15)(11.2g,产率65%)。该物质无需进一步纯化可用于下一步骤中。
实施例9 3-(1-(3-三氟甲基苯基)乙氧基)-氮杂环丁烷-1-羧酰胺(16)
根据制备化合物(14)所述的方法,由化合物(15)制备结晶固体形式的该化合物(产率62%),mp.130.5-131.5℃(二异丙醚)。测定值:C,54.24;H,5.26;N,9.69。C14H17ClN2O2理论值:C,54.17;H,5.24;N,9.71。
使用相同的制备化合物16所述的全合成方法,但是用手性醇,来制备实施例9的各个对映异构体。由合适的手性1-(3-三氟甲基)苯基乙醇制备实施例9的R-对映异构体。由3′-三氟甲基-苯乙酮通过立体选择性还原,例如使用硼烷和合适的手性助剂或手性催化剂制备手性醇(见Corey,EJ;Bakshi,RK;Shibata S.J.Amer.Chem.Soc.,1987,109,5551-5553或Pickard,ST和Smith,HE.J.Amer.Chez.Soc.,1990,112,5741-5747)。
实施例10-43见表1
使用制备化合物(2)所述的方法制备这些化合物。
表1
表1的脚注
脚注a:IR:3296,2980,2943,2877,1638,1545,1400,1377,1330,1203,1166,1127,1073,706cm-1。
脚注b:IR:3319,2963,2872,1634,1549,1469,1403,1327,1269,1184,1130,1083,818cm-1。
实施例44 3-((3-氯苯基)甲氧基)-氮杂环丁烷-1-羧酰胺(51)
使用制备化合物(14)所述的方法,由化合物(1)制备结晶固体形式的该化合物(产率87%),m.p.163-165.5℃(二异丙醚)。测定值:C,55.49;H,5.45;N,11.40。C11H13ClN2O2理论值:C,54.89;H,5.44;N,11.63。
分析试验
与CB1受体结合
参考Rinaldi-Carmona等所述的方法(Rinaldi-Carmona,M.,Pialot,F.,Congy,C.,Redon,E.,Barth,F.,Bachy,A.,Breliere,J.C.,Soubre,P.,LeFur,G.,Life Sci.1996,58(15),1239-1247),通过标准方法,体外测定通式I化合物与重组人CB1受体的结合。由表达重组hCB1受体的HEK293细胞制备膜。在总体积250μL,含[3H]-SR-141716A(1nM终浓度)的膜和受试化合物中进行结合试验。用CP55,940(10μM)测定非特异结合。从受试化合物10mM的DMSO溶液开始进行连续稀释。在10-10M-10-5M浓度范围内试验化合物,根据Cheng-Prusoff方程,由IC50值计算Ki值。
因而确定的通式(I)化合物的活性见表2
表2
实施例 | Ki(hCB1)nM |
实施例6 | 285 |
在小鼠中阻断Δ9-THC诱导的行动迟缓
在雄性C57B1/6小鼠中,研究通式(I)化合物对快速全身给予Δ9-THC所诱导的运动行为的减慢的拮抗能力,评价其体内活性。方法如下。
以剂量30mg/kg快速口服或腹膜内给予后,评价受试化合物。所有试验采用受试者间的设计(典型地,n=8)并比较试验药物与其载体和阳性对照之间的剂量的效应。
试验化合物的给药途径,药物体积以及注射试验间隔取决于所采用的化合物。试验前10分钟,通过i.p.途径给予小鼠3mg/kg剂量的Δ9-THC(或载体)。使用自动化仪器(AM-1052行动监测盒,Benwick Electronics,LintonInstrumentation),记录光电光束中断作为行动能力的尺度。光束排列在金属格子7×4的矩阵上。16个格子串联,带有扁平孔的Perspex盒,20(宽)×40(长)×20(高)cm,Perspex盖置于每个格子内。将小鼠单独置于Perspex盒中,并记录同时开始的所有16个盒子中的行动。15分钟内不打扰小鼠,以探究该新型行动监测盒,同时记录光束。
以药物处理作为受试对象间的因素,对行动能力数据进行单因素方差分析(ANOVA)。进行Dunnett′s试验分析,显示明显的主效应,以评价哪种处理方式与对照平均值之间存在显著性差异。Newman-Keuls分析显示,载体/Δ9-THC组和试验化合物/Δ9-THC组之间存在显著性差异。使用Statistica软件Version6.0(Statsoft Inc.)和Microsoft Excel 7.0(Microsoft Corp.)进行所有统计学分析。
进食行为的调节
在雄性禁食Lister-hooded大鼠中,通过测定食物消耗,研究通式(1)化合物调节进食行为的能力,以评价其体内活性,方法如下。
快速给药后评价试验化合物。所有试验采用受试对象间设(典型地,n=8)并比较试验药物与载体和阳性对照间的剂量的效应。
食欲抑制药sibutramine或对照CB1受体拮抗剂SR-141716A通常作为阳性对照。给药途径、药物体积以及注射试验间隔取决于所使用的化合物。注射试验间隔是指给药与进食间的时间。通常,禁食动物以使再给予食物时,食物已消耗18小时。在预先指定的时间点(通常是给药后1、2和4小时)分析食物消耗。以药物作为受试对象间的因素,对食物摄取数据进行单因素方差分析(ANOVA)。进行Dunnett′s试验分析,显示明显的主效应,以评价哪种处理方式与对照平均值之间存在显著性差异。使用Statistica软件Version 6.0(StatsoftInc.)和Microsoft Excel 7.0(Microsoft Corp.)进行所有统计学分析。
Claims (13)
2.如权利要求1所述的用途,其特征在于,R1是取代或未取代的苯基或萘基。
3.如权利要求1或2所述的用途,其特征在于,R1具有1、2或3个取代基。
4.如权利要求1、2或3所述的用途,其特征在于,R1是氯苯基或(三氟甲基)苯基。
5.如权利要求1、2、3或4所述的用途,其特征在于,R2是芳基。
6.如权利要求1-5中任一项所述的用途,其特征在于,R3是烷基。
7.如权利要求1所述的用途,其特征在于,所述化合物选自:
3-(二(4-氯苯基)甲氧基)-N-(2-丙烯基)氮杂环丁烷-1-羧酰胺;和
(R)-3-(二(4-氯苯基)甲氧基)-N-(2-羟丙基)氮杂环丁烷-1-羧酰胺。
8.如上述权利要求中任一项所述的用途,其特征在于,所述药物包含药学上可接受的载体和作为活性成分的有效量的通式(I)的化合物。
9.一种治疗由CB1受体介导的疾病的方法,所述方法包括给予需要这种治疗的受试者有效量的如权利要求1-8中任一项所述的通式(I)的化合物,或其药学上可接受的盐或前药。
10.如上述权利要求中任一项所述的用途或方法,其特征在于,所述疾病选自:精神病、精神分裂症、认知障碍、注意力缺陷障碍、胃肠道病症(如胃肠蠕动功能障碍或腹泻)、戒烟、肥胖和其它与食物摄取过量有关的进食障碍疾病以及非胰岛素依赖性糖尿病。
11.如权利要求1-10中任一项所述的用途或方法,其特征在于,所述疾病是肥胖。
12.如权利要求1-10所述中任一项所述用途和方法被用于戒烟。
13.如权利要求1-10所述中任一项的用途或方法,其特征在于,所述疾病是胃肠道病症。
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US7504522B2 (en) * | 2003-05-01 | 2009-03-17 | Vernalis Research Limited | Azetidinecarboxamide derivatives and their use in the treatment of cb1 receptor mediated disorders |
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US8846666B2 (en) | 2011-03-08 | 2014-09-30 | Sanofi | Oxathiazine derivatives which are substituted with benzyl or heteromethylene groups, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
US8871758B2 (en) | 2011-03-08 | 2014-10-28 | Sanofi | Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof |
WO2012120057A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2012120054A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
US8901114B2 (en) | 2011-03-08 | 2014-12-02 | Sanofi | Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof |
US8809325B2 (en) | 2011-03-08 | 2014-08-19 | Sanofi | Benzyl-oxathiazine derivatives substituted with adamantane and noradamantane, medicaments containing said compounds and use thereof |
EP2683699B1 (de) | 2011-03-08 | 2015-06-24 | Sanofi | Di- und trisubstituierte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
WO2012120050A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Neue substituierte phenyl-oxathiazinderivate, verfahren zu deren herstellung, diese verbindungen enthaltende arzneimittel und deren verwendung |
WO2012120053A1 (de) | 2011-03-08 | 2012-09-13 | Sanofi | Verzweigte oxathiazinderivate, verfahren zu deren herstellung, ihre verwendung als medikament sowie sie enthaltendes arzneimittel und deren verwendung |
US11141404B1 (en) | 2020-11-18 | 2021-10-12 | Anebulo Pharmaceuticals, Inc. | Formulations and methods for treating acute cannabinoid overdose |
WO2023064225A1 (en) * | 2021-10-11 | 2023-04-20 | Anebulo Pharmaceuticals, Inc. | Crystalline forms of a cannabinoid receptor type 1 (cb1) modulator and methods of use and preparation thereof |
Family Cites Families (9)
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US4261990A (en) * | 1979-03-09 | 1981-04-14 | Ciba-Geigy Corporation | N-alkyleneiminoalkyl-dicarboximides as antiallergics and antiasthmatics |
JPH03264562A (ja) * | 1989-05-22 | 1991-11-25 | Hokuriku Seiyaku Co Ltd | ピペリジン誘導体 |
JP3194355B2 (ja) * | 1996-10-24 | 2001-07-30 | 宇部興産株式会社 | ピペリジン化合物及びその製法 |
PT1049672E (pt) * | 1998-01-23 | 2004-02-27 | Vernalis Res Ltd | Derivados de azetidinocarboxamida para o tratamento de disturbios do snc |
GB9917386D0 (en) * | 1999-07-23 | 1999-09-22 | Cerebrus Ltd | Chemical compounds-II |
FR2805817B1 (fr) * | 2000-03-03 | 2002-04-26 | Aventis Pharma Sa | Compositions pharmaceutiques contenant des derives d'azetidine, les nouveaux derives d'azetidine et leur preparation |
US6566356B2 (en) * | 2000-03-03 | 2003-05-20 | Aventis Pharma S.A. | Pharmaceutical compositions containing 3-aminoazetidine derivatives, novel derivatives and their preparation |
FR2805810B1 (fr) * | 2000-03-03 | 2002-04-26 | Aventis Pharma Sa | Compositions pharmaceutiques contenant des derives de 3- amino-azetidine, les nouveaux derives et leur preparation |
US7504522B2 (en) * | 2003-05-01 | 2009-03-17 | Vernalis Research Limited | Azetidinecarboxamide derivatives and their use in the treatment of cb1 receptor mediated disorders |
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2004
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- 2004-04-29 BR BRPI0409959-1A patent/BRPI0409959A/pt not_active IP Right Cessation
- 2004-04-29 WO PCT/GB2004/001812 patent/WO2004096209A1/en active IP Right Grant
- 2004-04-29 EA EA200501703A patent/EA200501703A1/ru unknown
- 2004-04-29 MX MXPA05011472A patent/MXPA05011472A/es active IP Right Grant
- 2004-04-29 AU AU2004233644A patent/AU2004233644A1/en not_active Abandoned
- 2004-04-29 KR KR1020057020651A patent/KR20060017763A/ko not_active Application Discontinuation
- 2004-04-29 DE DE602004014484T patent/DE602004014484D1/de not_active Expired - Fee Related
- 2004-04-29 CN CNA2004800117556A patent/CN1780615A/zh active Pending
- 2004-04-29 NZ NZ543322A patent/NZ543322A/xx unknown
- 2004-04-29 AT AT04730286T patent/ATE398449T1/de not_active IP Right Cessation
- 2004-04-29 US US10/552,574 patent/US20060276452A1/en not_active Abandoned
- 2004-04-29 CA CA002524245A patent/CA2524245A1/en not_active Abandoned
- 2004-04-29 EP EP04730286A patent/EP1617839B1/en active Active
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2005
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BRPI0409959A (pt) | 2006-04-25 |
US20060276452A1 (en) | 2006-12-07 |
NO20055655L (no) | 2006-01-31 |
KR20060017763A (ko) | 2006-02-27 |
EA200501703A1 (ru) | 2006-06-30 |
NO20055655D0 (no) | 2005-11-30 |
MXPA05011472A (es) | 2005-12-12 |
ATE398449T1 (de) | 2008-07-15 |
ZA200508835B (en) | 2006-12-27 |
WO2004096209A1 (en) | 2004-11-11 |
JP2006525297A (ja) | 2006-11-09 |
CA2524245A1 (en) | 2004-11-11 |
AU2004233644A1 (en) | 2004-11-11 |
DE602004014484D1 (de) | 2008-07-31 |
EP1617839B1 (en) | 2008-06-18 |
EP1617839A1 (en) | 2006-01-25 |
NZ543322A (en) | 2009-03-31 |
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