CN106470999A - 叔丁啡二聚体及其在治疗肠胃失调中的应用 - Google Patents
叔丁啡二聚体及其在治疗肠胃失调中的应用 Download PDFInfo
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- CN106470999A CN106470999A CN201580023367.8A CN201580023367A CN106470999A CN 106470999 A CN106470999 A CN 106470999A CN 201580023367 A CN201580023367 A CN 201580023367A CN 106470999 A CN106470999 A CN 106470999A
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Abstract
本发明提供了叔丁啡二聚体化合物,其中两个叔丁啡部分通过乙烯间隔基团进行连接,其中,所述间隔基团通过醚键键合于两个阿片分子。本发明还公开包括所述叔丁啡二聚体药物的药物组合物,以及所述化合物在常规治疗胃肠痛觉过敏,特别是腹泻型肠易激综合征中的应用。
Description
相关申请的交叉引用
本申请根据35U.S.C.§119(e)要求于2014年4月28日提交的美国临时申请序列号61/985,207、2015年1月9日提交的美国临时申请序列号62/101,768以及2015年1月9日提交的美国临时申请序列号62/176,883的优先权,各申请的披露内容通过引用并入本文。
关于对在联邦政府资助的研发下作出的发明的权利的声明
不适用。
关于光盘递交的“序列表”、表格或计算机程序清单附件的引用
不适用。
背景技术
叔丁啡
叔丁啡是半合成的、混合μ激动剂-κ-拮抗剂阿片受体调节剂,用于以较高剂量治疗阿片类成瘾,以较低剂量控制非阿片类药物耐受的个体中度急性疼痛,并且以甚至更小剂量控制中度慢性疼痛。它的结构为:
目前显示,叔丁啡以静脉内、舌下和经皮剂量形式用于治疗疼痛。还显示,叔丁啡用于治疗阿片成瘾。尽管叔丁啡具有长半衰期,可以每日给药一次,但由于大量的系统前提取作用(presystemic extraction),叔丁啡的口服生物利用度是很低的。因此,叔丁啡需要舌下给药从而获得临床上有效的的全身血浆浓度。即使使用舌下给药,仅约30%叔丁啡可用于全身循环。
腹泻型肠易激综合征
腹泻型肠易激综合征(IBS-D)是非常普遍的胃肠疾病,除了腹泻,常伴有内脏和躯体痛觉过敏(来自结直肠和躯体刺激增强的疼痛),不适,腹胀和放气。
根据国际功能性胃肠病基金会,预计IBS-D影响25-45百万美国人。它是由肠胃病医师作出的最常见的诊断,且是最经常由初级保健医生治疗的疾病之一。
肠道易激综合症对生活质量具有非常重大的影响,并具有高的社会成本。该病有波动趋势,但往往是慢性或亚慢性的。尽管没有证据表明IBS的存在涉及危害患者的预期寿命,它显著降低与健康相关的生活质量和工作效率。在更严重的情况下,患者可能经历每天发作数次的腹痛和腹泻,从而造成工作场所和关系的严重受损。
IBS-D的治疗
胆汁酸粘合剂、阿米替林、益生菌、肥大细胞稳定剂和5-ASA已经以非标识方式被用于IBS-D的治疗,虽然没有令人信服的慢性功效的证据。防腹泻的洛哌丁胺(一种合成的阿片类药物),已经类似应用,但它的未抑制的完全μ阿片激动剂活性往往造成严重的便秘。
在为IBS-D研发的药物中,一种药物是LX 1033,它是胃肠道内血清素合成的抑制剂,目前正由莱斯康(Lexicon)药物公司开发。但是,它的作用机制不支持疼痛减轻。DNK-333(诺华),一种神经激肽拮抗剂,已经在针对疗效的II期研究后从IBS-D研究中退出。艾波度坦(Ibodutant)(梅纳里尼公司),另一种处于II期临床试验中神经激肽拮抗剂,在全部人群中没有体现出超过安慰剂的功效,并且仅在女性展开进一步测试。利福昔明(Salix制药公司)已经被用于研究IBS-D,表现出中等的活性,但对于导致抗生素抗性和持续效力存在严重的关注。
盐酸阿洛司琼(Latronex)(阿洛司琼,普罗米修斯实验室公司)是在美国批准用于IBS-D的唯一药物,虽然只针对女性。它没有表现出镇痛性质。重要的是,它具有对于严重不良作用(具体地包括缺血性结肠炎)的黑框警告。
迄今为止,在美国没有药物被批准用于IBS-D的慢性,不受限治疗。
伊卢多啉(Eluxadoline,森林实验室公司)是μ阿片受体激动剂和δ阿片受体拮抗剂,在三阶段测试中已满足粪便稠度改进和腹痛减轻的主要终点指标。它对疼痛减轻的效果在最好的情况下是适度的,对减轻导致痛觉过敏的结肠过敏没有可展示效果。此外,几例严重的胰腺炎(一种潜在的威胁生命的疾病),已在二期试验中报道过。甚至将已知胆道疾病史的患者排除出临床研究登记名单后,仍然有胰腺炎的病例的报导。通常,μ激动剂对奥狄氏括约肌(一种调节胆汁和胰液从胆管流入十二指肠的肌肉阀)具有收缩作用。叔丁啡,因其部分μ激动剂作用和κ拮抗剂作用,不会导致奥狄氏括约肌的收缩或增加的伸缩性。我们期望叔丁啡二聚体,与叔丁啡具有相同的受体药理学,也将不会对奥狄氏括约肌产生收缩作用。
因此,长期需要一种IBS-D的长期治疗手段,它可降低肠道蠕动从而降低腹泻的发生率,是镇痛型的,与胰腺炎不相关,并且不仅仅是治疗症状,能够解决与IBS-D相关的潜在的超敏反应和导致的痛觉过敏。
发明内容
在一方面,本发明提供一种新型的二聚体或其药学上可接受的盐或其溶剂化物,所述二聚体包括两个叔丁啡药物分子,经它们的酚基通过O-烷基化相互结合,从而获得式(I)的结构:
在式(I)中,化合物是2,2’-((4aR,4a’R,6S,6’S,7S,7’S,12bR,12b’R)-9,9’-(乙-1,2-二基二(氧))二(3-(环丙基甲基)-7-甲氧基-1,2,3,4,5,6,7,7a-八氢-4a,7-亚乙基-4,12-亚甲基苯并呋喃[3,2-e]异喹啉-9,6-二基))二(3,3-二甲基-丁-2-醇)(化合物1或叔丁啡二聚体)。它的分子量是961.28。
最初,我们合成该叔丁啡二聚体是为了获得防止滥用的前药。通过在它们的酚氢位置二聚化母化合物,我们相信阿片活性将被减轻,直到肝脏中首过代谢导致释放母化合物。我们相信,当它们与连接到二聚体的酚氧分子的亚甲基碳相互作用时,细胞色素P-450酶(CYP 3A4和CYP2D6)将促进药物代谢。发生的O-脱烷基化最终会释放叔丁啡进入全身循环。
关于常规偶联于酚氢的文献,支持了我们的期望,虽然不是用我们独有的连接基团。传统知识是这样的:通过用更少的亲水性取代基取代氢而对吗啡酮的酚基进行衍生化,会显著降低所得阿片样物质的阿片效力。参见Feinberg Andrew F等人.美国国家科学院院刊(Proc Natl Acad Sci.USA)73卷11号,第4215-4219页(1976)。根据R.Richards,阿片类 镇痛剂(www.faculty.smu.edu):“游离酚基对于镇痛作用是至关重要的(A free phenolgroup is crucial for analgesic activity)”。在麻醉与镇痛(Anesth Analg)1984;63;143‐51第145页以及以下部分中,D.H.Thorpe描述到,“被认为与受体相互作用的吗啡分子的另一部分是酚基。采用甲基封闭游离羟基会降低效力超出十倍…”。作者继续引用其他研究,表明较大烷基具有更为不利的影响,得出的结论是“大体积…导致了下降的结合效果”。还参见美国专利号8,183,376和8,461,171。
尽管有这些期望,但是所得二聚体变成具有完全意想不到的性质,不适合作为前体药的用途,但它适合用于与我们最初预计非常不同的适应症。叔丁啡部分,完全没有展示我们预期的空间位阻,保留了它们特有的阿片受体药理学。二聚体证明了在胃肠环境抗酶促代谢。它也是高度抗篡改的,例如通过游离碱进行篡改。当口服给药时,它是基本上不吸收,因此不进入全身循环。这些偶然观察使我们设想新的适应症,即通过这些性能可获益的适应症,如通过外周对胃肠道镇痛。
本发明的新型化合物解决了有效治疗IBS-D的长期需要,它解决了疼痛和腹泻,减少内脏(结肠)过敏,不具有用于此目的其它药剂的缺点,且可以安全长期开药。因此,本发明包括使用所述化合物用于IBS-D的治疗,特别是当存在内脏过敏和痛觉过敏时。所述化合物也可以作为辅剂应用,与其他药物如替度鲁肽用于治疗其他肠道疾病如短肠综合征,从而安全地降低肠道转运时间。根据本发明的药物组合物,含有式(I)的叔丁啡二聚体,它可配制为口服片剂或胶囊、缓释口服片剂或胶囊剂、肌内或皮下长效注射剂、或透皮贴剂。
附图说明
图1为柱状图,示出在辅助因子存在或不存在下,当暴露于CYP酶时,叔丁啡二聚体的稳定性。
图2为柱状图,示出叔丁啡二聚体对水性条件以及酸性和碱性条件的稳定性,各个分别在室温和在140°F经过一段指定时间。
图3为叔丁啡二聚体受体结合实验–μ受体结果图。
图4为叔丁啡二聚体受体结合实验–κ受体结果图。
图5为叔丁啡二聚体μ激动剂功能试验结果图。
图6为叔丁啡二聚体μ拮抗剂功能试验结果图。
图7为叔丁啡和叔丁啡二聚体的口服和静脉内给药的生物利用度结果图。
图8和图9提供根据实施例7评价的应激诱导的雄性小鼠的粪便量图。
图10示出叔丁啡二聚体以剂量依赖性方式降低粪便量。
图11示出根据实施例7,在炎症后模型中叔丁啡二聚体对胃肠蠕动的作用。
具体实施方式
本发明的叔丁啡二聚体表现出母体叔丁啡的部分μ-受体激动剂和全部κ-受体拮抗剂活性特性。κ-受体拮抗剂活性是非常重要的,因为它表现出有多种功能。由于本文描述的μ-受体激动剂二聚体还具有κ受体拮抗剂作用,因此肠道蠕动的μ-受体激动剂减少作用是缓和的,减少了显著便秘的可能性。另外,κ受体拮抗剂效应可防止对奥迪氏括约肌的平滑肌组织收缩性μ-受体激动剂作用,从而避免胰腺炎的可能性。在动物和人类研究中,已经显示出叔丁啡也降低结肠和皮肤过敏和痛觉过敏。内脏过敏是IBS-D的病因学的重要组成部分,我们相信叔丁啡二聚体的κ-受体拮抗作用将在症状减轻中发挥重要作用。目前我们在动物模型中也进一步证明了,所述的叔丁啡二聚体由于同时保留叔丁啡受体药理学和非全身性吸收(即,没有从肠道吸收),因而适合于IBS-D的慢性治疗,同时基本上消除滥用前景。这个惊人的发现表明,本发明所述的二聚体优于用于治疗IBS-D的可用药剂,因为它(1)解决IBS-D潜在内脏(结肠)过敏和随之发生的痛觉过敏性,(2)将回避与伊卢多啉相关的造成胰腺炎的可能性,(3)将减轻腹泻,没有便秘的风险,和(4)将实现前述事项,并且没有归因于叔丁啡本身的麻烦的全身和中枢神经系统的不利影响。
如上所述,本发明提供了叔丁啡的二聚体形式,其中两个叔丁啡分子在各个叔丁啡分子的酚(3-羟基)官能团和乙烯接头之间通过共价键连接。乙烯接头用作两个叔丁啡分子之间的间隔基团,并且被认为防止了两个大的叔丁啡分子经由分子上其它官能团之间共价的、离子的或范德华相互作用而采用封闭环的构象。
令人惊奇的是,当两个药物分子通过乙烯间隔基团彼此相连时,其中所述间隔基团经由醚键连接到每个药物分子的苯环,已发现所得二聚体在化学和代谢上是稳定的,且暴露于代谢酶时不会被解开。此外,令人惊讶和意外的是,二聚体保留母体化合物的药理活性,并且口服给药时还具有可忽略的全身暴露量。
与叔丁啡不同,如本文描述制备的叔丁啡二聚体,已发现在口服施用后不被吸收,进而在形式和用法上保持阿片μ和κ活性,即既不损害受体的亲和力,也不损害活性。此外,本发明所述的叔丁啡二聚体在体内和体外实验中对于代谢是相对稳定。叔丁啡二聚体呈现出代谢稳定性,甚至暴露于活体小鼠的肝脏(在静脉注射之后)。因此,令人惊奇和意外的是,尽管缺乏胃肠道吸收和代谢失活证明了吸收性质的损失,但是二聚体的阿片功能并没有失去,其胃肠阿片效应表现为口服给药后减弱的肠胃运动和抗腹泻反应。在由身体和心理压力的组合所产生的导致腹泻(增加排泄粪粒)的小鼠模型中,胃肠道反应与剂量成正比。在另一由炎性损伤敏化结肠的小鼠模型实验中,良好反应持续超出急性期,达到急性损伤后的三周,这可能表明二聚体在降低小鼠结肠膜的过敏和痛觉过敏中的效果。
更进一步地,还发现,叔丁啡二聚体选择性地仅保留了叔丁啡的μ和κ功能,但显著去除了其δ功能。换言之,与叔丁啡不同,叔丁啡二聚体是一种选择性的μ和K活性分子而没有明显的δ活性。
叔丁啡二聚体的合成
在室温或升高的温度下,在无机碱(如氢氧化钠、碳酸钾、碳酸钠、碳酸铯、碳酸氢钾和碳酸氢钠)或有机碱(如三乙胺、Hunig碱、DMAP和吡啶)存在下,在有机溶剂(如乙腈、DMF、DMSO、NMP、DCM、THF、1,4-二氧六环)中,通过常规O-烷基化反应,可进行本发明提供的叔丁啡二聚体的合成。能够使用的合适的烷基化试剂包括:二碘、二溴、二氯、二甲苯磺酸酯、二甲磺酸酯和二三氟甲磺酸酯试剂(例如,1,2-亚乙基二甲苯磺酸酯,1,2-亚乙基二甲磺酸酯)。叔丁啡的游离碱或盐可用作合成的原料。
二聚体的药物组合物–概述
在一些实施方式中,本文提供包括式(I)的叔丁啡二聚体的组合物。药物组合物还可以包括药学上可接受的载体。下文描述了说明性的药学上可接受的载体和剂型。这些药物组合物可以用于治疗腹泻型IBS。
应理解,在本文讨论的任一或全部组合和治疗方法中,二聚体的药学上可接受的盐可以用来替代二聚体或作为二聚体的补充。因此,在具体实施方式中,二聚体的药学上可接受的盐(即任何二聚体的药学上可接受的盐)可用于本发明的方法。例如,可以在化合物的最终分离和纯化过程中原位制备这些盐,或各自通过将游离碱形式的纯化化合物与合适的有机或无机酸反应并分离由此形成的盐来制备。在一些实施方式中,采用乙酸、海藻酸、氨茴酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、糠酸、半乳糖醛酸、葡糖酸、葡糖醛、谷氨酸、乙醇酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、苯乙酸、磷酸、丙酸、水杨酸、硬脂酸、琥珀酸、对氨基苯磺酸、硫酸、酒石酸或对甲苯磺酸,来制备叔丁啡二聚体药学上可接受的盐。对于可以用于本文描述方法中的药学上可接受的盐的其他描述,参见,例如S.M.Berge等人,“药用盐(Pharmaceutical Salts),”1977,J.Pharm.Sci.66:1-19,该文献通过引用全部并入本文。
本发明的叔丁啡二聚体,可以是以非溶剂化的,或与药学上可接受的溶剂如水、乙醇等以溶剂化(物)的形式存在。出于本发明的目的,通常认为溶剂化形式与非溶剂化形式是等价的。在一具体实施方式中,二聚体的溶剂化形式是水合物。
通常,盐形式可以提高所得治疗剂的使用期。恰当的盐合成可提供结晶的、不易氧化和易于处理的产物。可以制备各种盐,从而获得稳定结晶化合物。几个例子是盐酸盐、硫酸盐、对甲苯磺酸盐、甲磺酸盐、丙二酸盐、反丁烯二酸盐和抗坏血酸盐。
在一些具体实施方式中,这样的药物组合物可被配制成口服片剂或胶囊、延长释放的口服片剂或胶囊(硬明胶胶囊、软明胶胶囊)、舌下片剂或薄膜、或延长释放的舌下片剂或膜。在下面更详细地描述这些说明性的可药用载体和制剂。
治疗方法–概述
在具体实施方式中,本发明提供了一种通过减轻患者腹泻、疼痛和肠过敏和痛觉过敏,治疗腹泻型肠易激综合征的方法,包括口服施用治疗有效量的所述二聚体。治疗有效量是在具有统计学显著数目的患者中产生可观的和有益效果的量。在一些实施方式中,患者是人。在某些具体实施方式中,患者是家养哺乳动物如狗、猫、或马。
药物组合物,给药途径和剂量
本发明所提供的IBS-D药物可以常规制剂形式口服给药于对象,如胶囊、微胶囊、片剂、颗粒、粉末、锭剂、丸剂、栓剂、口服悬浮液、糖浆、口服凝胶剂、喷雾剂、溶液和乳剂。合适的制剂可通过通常使用的方法来制备,并使用常规的有机或无机添加剂,如赋形剂(例如,蔗糖、淀粉、甘露醇、山梨醇、乳糖、葡萄糖、纤维素、滑石粉、磷酸钙或碳酸钙),粘合剂(例如,纤维素、甲基纤维素、羟甲基纤维素、聚丙基吡咯烷酮、聚乙烯吡咯烷酮、明胶、阿拉伯胶、聚乙二醇、蔗糖或淀粉),崩解剂(如淀粉、羧甲基纤维素、羟丙基淀粉、低取代的羟丙基纤维素、碳酸氢钠、磷酸钙或柠檬酸钙),润滑剂(例如,硬脂酸镁、轻质无水硅酸、滑石粉或月桂基硫酸钠),矫味剂(例如,柠檬酸、薄荷醇、甘氨酸或橘粉),防腐剂(例如,苯甲酸钠、亚硫酸氢钠、对羟基苯甲酸甲酯或对羟基苯甲酸丙酯),稳定剂(如柠檬酸、柠檬酸钠或乙酸),悬浮剂(例如,甲基纤维素、聚乙烯吡咯烷酮或硬脂酸铝),分散剂(如羟丙基甲基纤维素),稀释剂(例如,水)和底蜡(如可可脂、白凡士林或聚乙二醇)。
可施用给患者的本发明所提供的叔丁啡二聚体的剂量,是相当广泛可变的,并可经保健医生的判断。剂量可根据受治疗者的年龄、体重和医疗状况以及给药的类型适当改变。在一实施方式中,每天给予一剂。在任何给定的情况下,施用本发明提供的二聚体的量将取决于多种因素,例如活性成分的溶解度、所使用的剂型和给药途径。药物组合物中本发明所提供的叔丁啡二聚体药物的有效量,是会处于显示出预期效果的水平,优选地,用于口服给药的单位计量为,例如,约0.15毫克/千克IBS-D患者体重至约7.2毫克/千克患者体重,更优选约0.7毫克/公斤IBS-D患者体重到约3.0毫克/千克患者体重,和还更优选约1.5毫克/千克患者体重。或者,约10-约500毫克,优选约50-约300毫克,更优选约100毫克,被施用于IBS-D患者。
本发明提供的叔丁啡二聚体,可以每天给药如一次、两次或三次,优选每天一次。方便起见,本发明提供的二聚体可以口服给药。在一实施方式中,当口服给药时,本发明提供的二聚体与膳食和水一起食用。在另一实施方式中,本发明提供的二聚体分散于水或果汁中(例如,苹果汁或橙汁)并作为悬浮液口服。
或者,本发明提供的叔丁啡二聚体也可以直肠给药或通过其他透粘膜途径给药。给药方式可由保健医生决定。
在一实施方式中,本发明提供胶囊,它包含二聚体,而无其他的载体、赋形剂或介质。
在另一实施方式中,本发明提供了组合物,它包括有效量的二聚体和药学上可接受的载体或介质,其中,药学上可接受的载体或介质包括赋形剂、稀释剂或它们的混合物。
口服组合物可以是片剂,可咀嚼片剂、胶囊、溶液、锭剂和悬浮液等的形式。组合物可配制成在一个剂量单位中含有每日剂量或每日剂量的合适部分,其可以是单个药片或胶囊或适当体积的液体。在一实施方式中,用水溶性的盐,例如盐酸盐制备溶液。在一般情况下,可根据药物化学中公知的方法制备所有的组合物。胶囊可以通过本文提供的二聚体和合适的载体或稀释剂并将合适量的混合物充入胶囊进行制备。常规的载体和稀释剂包括(但不限于):惰性粉状物质,如很多不同种类的淀粉,粉状纤维素,特别是结晶和微晶纤维素,糖例如果糖、甘露糖醇和蔗糖,谷物粉和类似的可食用粉末。
可以通过直接压制,通过湿法制粒,或通过干法制粒来制备片剂。它们的制剂通常包括稀释剂、粘合剂、润滑剂和崩解剂以及所述化合物。典型的稀释剂包括,例如,各种类型的淀粉、乳糖、甘露糖醇、高岭土、磷酸钙或硫酸钙,无机盐如氯化钠和粉状糖。粉状纤维素衍生物也是有用的。典型的片剂粘合剂是例如淀粉、明胶,以及糖如乳糖、果糖、葡萄糖等的物质。天然和合成胶也是实用的,包括阿拉伯胶、海藻酸、甲基纤维素、聚乙烯吡咯烷酮等。聚乙二醇、乙基纤维素和蜡也可以作为粘合剂。
在片剂制剂中可能需要润滑剂以防止染色时药片和冲压器粘连。润滑剂可以选自光滑的固体,如滑石、硬脂酸镁和硬脂酸钙、硬脂酸和氢化植物油。片剂崩解剂是遇湿膨胀从而分解药片并释放化合物的物质。它们包括淀粉、粘土、纤维素、藻胶和树胶。更具体地说,例如,可以使用玉米和土豆淀粉、甲基纤维素、琼脂、膨润土、木纤维素、粉状天然海绵、阳离子交换树脂、藻酸、瓜尔胶、柑橘果肉和羧甲基纤维素,以及使用月桂醇硫酸钠。片剂可以包覆有糖作为调味剂和密封剂,或用成膜保护剂进行包衣以改变片剂的溶出性质。组合物也可以配制成可咀嚼的片剂,例如,通过在制剂中使用如甘露醇的物质。
当希望以栓剂施用本发明所提供的药物时,可以使用典型的基质。可可脂是传统的栓剂基质,可以通过加入蜡来改性以稍微提高其熔点。可与水混合的栓剂基质,其中包括特别是各种分子量的聚乙二醇,已被广泛使用。
本发明所提供的药物的作用,可以通过适当的制剂被延迟或者延长。例如,可以制备二聚体的缓慢溶解的颗粒并掺入片剂或胶囊,或者作为缓释的可植入装置。该技术还包括:制作数个不同溶解速率粒料并将粒料混合物填入胶囊。片剂或胶囊可涂覆有在预定时间内抵抗溶解的膜。
实施例
提供以下实施例用于说明,但不用于限制要求保护的发明。
实施例1:
合成
如下所示合成叔丁啡二聚体。
将叔丁啡盐酸盐(5.0g,10.68毫摩尔,1当量)和碳酸钾(42.73毫摩尔,4当量)加入三口圆底烧瓶,随后加入无水DMSO(50ml,10体积)。将混合物加热至60摄氏度,并缓慢加入1,2-二溴乙烷(9.2mL,106.8毫摩尔,10当量)。在60摄氏度搅拌反应混合物16小时,然后冷却至室温,用水稀释并用二氯甲烷萃取。采用盐水洗涤合并的有机部分,干燥(无水Na2SO4),过滤并减压浓缩,从而获得粘性液体。通过硅胶色谱采用0-5%MeOH/DCM纯化粗产物,从而获得4.2g(69%)中间体1,为米白色泡沫状固体。
将叔丁啡盐酸盐(1.74g,3.72毫摩尔)和碳酸钾(2.0g,14.87毫摩尔,4当量)加入三口圆底烧瓶,随后加入无水DMSO(10mL)。将混合物加热至60摄氏度并经2小时滴加溶于7mL无水DMSO的中间体1(3g,5.22毫摩尔,1.4当量)。在60摄氏度搅拌反应混合物16小时,然后冷却至室温,用水稀释并用二氯甲烷萃取。采用盐水洗涤有机层,干燥(无水Na2SO4),过滤并减压浓缩,从而获得粘性液体。通过硅胶色谱采用0-5%MeOH/DCM纯化粗产物,从而获得叔丁啡二聚体-FB(游离碱),为泡沫状固体(2.8g,77%)。
在氮气下,于室温,将5.5g(5.7毫摩尔)双共轭物(叔丁啡二聚体-FB)溶于50mL乙酸乙酯。室温滴加3.43mL(6.9毫摩尔,1.2当量)乙醚中的2N HCl。在室温下再搅拌反应混合物一小时,过滤获得固体。进一步用100mL乙酸乙酯洗涤固体并真空干燥,从而获得叔丁啡二聚体(二盐酸盐),为白色固体(5.8g,98%)。1H NMR(300MHz,DMSO-d6):δ9.75(br,2H),6.88(d,J=9.2Hz,2H),6.67(d,J=9.2Hz,2H),4.66(s,2H),4.23-4.42(m,4H),3.84-3.92(m,2H),3.40(s,6H),3.21-3.35(m,5H),2.98-3.20(m,7H),2.64-2.85(m,4H),2.12-2.26(m,4H),1.72-1.94(m,4H),1.38-1.52(m,4H),1.26(s,6H),0.99(s,20H),0.48-0.76(m,10H),0.32-0.42(m,4H);MS:m/z 962(M+1)+。
实施例2:
说明性的药物组合物
以下成分可以用于叔丁啡二聚体的口服片剂。
表1
实施例3–试验
体外试验:叔丁啡二聚体的代谢稳定性
采用帝肯(Tecan)液体处理系统或等效系统,于37±1℃在有或无辅助因子,NADPH-生成系统,在包含磷酸钾缓冲液(50mM,pH 7.4)、MgCl2(3mM)和EDTA(1mM,pH 7.4)的0.2mL孵育混合物(终体积)中,在96孔板指示的终浓度下进行二聚体(例如,1μM)和人肝微粒体(例如,1毫克蛋白质/毫升)的孵育。NADPH-生成系统由NADP(1mM,pH7.4)、葡萄糖-6-磷酸(5mM,pH 7.4)和葡萄糖-6-磷酸脱氢酶(1单位/mL)组成。二聚体溶于甲醇水溶液(甲醇0.5%v/v或更低)。通常通过加入辅助因子开始反应,并通过进入等体积的终止试剂(例如,乙腈,0.2mL含内标)在四个指定的时间点(例如,至多120分钟)停止反应。零点时间孵育作为100%的值,以确定底物百分比损失。除了零点时间样本(一式四份进行孵育)外,一式三份进行孵育。零-辅助因子(无NADPH)孵育,是在零时间和最长的时间点进行。样本经离心(例如,920x g,10min,10℃),并通过LC-MS/MS分析上清部分。采用微粒体和标记的底物(例如,右美沙芬,以监测底物损失)作为阳性对照,进行额外的孵育从而确定测试系统是否能够代谢。
上述样品通过LC-MS/MS进行分析。在各孵育溶液中对样品进行分析。通过在实验时间过程比较峰比率(通常被报告为“%亲本剩余”)确定结果。
采用LIMS(包括伽利略(Galileo),赛默飞世尔科技公司(Thermo FisherScientific Inc.)和报告工具,水晶报表(Crystal Reports),SAP),电子制表软件计算机程序微软Excel(Microsoft Corp.)或等价物,计算数据。采用LIMS,“分析员仪器控制和数据处理软件”(AB SCIEX)或等价物,基于分析物/内标物(IS)峰面积比,评价未改变母体化合物的量(以确定各孵育中底物残留的大概百分数)。
结果:结果示于图1,表明在测试期间在微粒体酶存在下,叔丁啡二聚体是相对稳定的。微粒体酶通常负责药物如叔丁啡的代谢。在微粒体存在下,以及有或无辅助因子存在下,二聚体是稳定的。在2小时终止反应,因为在37℃孵育温度超过2小时后,酶通常不稳定。
稳定性试验
实验室研究的目的,是评估患者从二聚体得到叔丁啡并因此危害其滥用遏制性的容易性。
本研究帮助理解潜在滥用者使用家用化学品如小苏打、酸或在水中简单加热从而裂解二聚体的难易程度。于室温,在未处理的自来水且在酸(1N HCl)或碱(5%碳酸氢钠水溶液)存在下,评估叔丁啡二聚体的稳定性。在那些条件下,二聚体相对稳定,且在这些条件下没有观察到降解为叔丁啡。参见图2。
结果:如图2所示,在室温或在升高的温度,在极端pH,甚至长达30分钟,叔丁啡二聚体保持稳定,没有降解释放叔丁啡。
这些研究也助于理解二聚体在IBS-D患者和健康对象两者的胃肠道(沿其长度呈现梯度pH)中的稳定性。pH值范围为:从因胃壁细胞盐酸排泄导致的pH 1至结肠内pH8。胃肠道的近端部分是酸性最大的,而远端是酸性最小的。
实施例4–受体结合活性
本实施例阐明本发明提供的叔丁啡二聚体与以下受体的结合:μ-阿片受体、κ-阿片受体和δ-阿片受体。
人μ阿片受体结合试验
采用玻璃组织研磨机、特氟龙研棒和固定搅拌器(飞世尔科技)在测试缓冲液(50mM Tris,pH 7.5,含5mM MgCl2)中,将表达人μ阿片受体中国仓鼠卵巢细胞的膜(珀金埃尔默#RBHOMM400UA)进行匀浆。在测试板(96孔圆底聚丙烯板)内,将膜浓度调节至300μg/mL。待测试的化合物溶于DMSO(Pierce),10mM,然后在测试缓冲液中稀释至3.6nM。在第二个96孔圆底聚丙烯板(被称为预混物板)内,将60μL的6X化合物与60μL 3.6nM 3H-纳洛酮混合。从预混板转移50μL至含有膜的测试板,一式两份。测试板在室温下孵育2小时。采用0.3%聚乙烯亚胺预处理GF/C 96孔过滤板(珀金埃尔默#6005174)30分钟。使用帕卡德过滤(Packard Filtermate)收集器,通过过滤板过滤测试板中的内容物,在4℃采用0.9%盐水洗涤3次。干燥过滤板,底面密封,将30μL Microscint 20(Packard#6013621)加入各孔。采用Topcount-NXT微板闪烁记数器(Packard)检测2.9到35KeV的发射能量。将结果与最大结合(没有抑制的孔)进行比较。在50μM未标记纳洛酮的存在下,测定非特异性结合。二聚体的生物学活性示于图3。
结果:图3的图示出二聚体对阿片μ受体具有显著的亲合力。在10-8M(~10ng),叔丁啡二聚体的阿片μ受体亲合力及曲线和叔丁啡的类似。
人κ阿片受体结合试验
采用玻璃组织研磨机、特氟龙研棒和固定搅拌器(飞世尔科技)在测试缓冲液(50mM Tris,pH 7.5,含5mM MgCl2)中,将表达人κ阿片受体的克隆的HEK-293细胞的膜(英国安玛西亚生物科学有限公司.6110558 200U)进行匀浆。在测试板(96孔圆底聚丙烯板)内将膜浓度调节至300μg/mL。待测试的化合物溶于DMSO(Pierce),10mM,然后在测试缓冲液中稀释至3.6nM。在第二个96孔圆底聚丙烯板(被称为预混物板)内,将60μL的6X化合物与60μL3.6nM 3H-二丙诺啡混合。从预混板转移50μL至含有膜的测试板,一式两份。测试板在室温下孵育18小时。采用0.3%聚乙烯亚胺预处理GF/C 96孔过滤板(珀金埃尔默#6005174)30分钟。使用帕卡德过滤(Packard Filtermate)收集器,通过过滤板过滤测试板中的内容物,在4℃采用0.9%盐水洗涤3次。干燥过滤板,底面密封,将30μL Microscint 20(Packard#6013621)加入各孔。采用Topcount-NXT微板闪烁记数器(Packard)检测2.9到35KeV的发射能量。将结果与最大结合(没有抑制的孔)进行比较。在50μM未标记纳洛酮的存在下测定非特异性结合。二聚体的生物学活性示于图4。
结果:图4描述叔丁啡单体和二聚体的阿片κ受体激动剂图。叔丁啡单体或叔丁啡二聚体没有损失κ受体亲合力。定性地,同叔丁啡一样,叔丁啡二聚体结合至阿片κ受体随浓度增加。据估计在约1μg,二聚体的阿片κ受体亲合力曲线与叔丁啡类似。
人δ阿片受体结合试验
设计试验检测化合物干预氚代纳曲吲哚与人δ亚型2阿片受体结合的能力。采用玻璃组织研磨机、特氟龙研棒和固定搅拌器(飞世尔科技)在测试缓冲液(50mM Tris,pH 7.5,含5mM MgCl2)中,将表达人δ亚型2阿片受体中国仓鼠卵巢细胞的膜(珀金埃尔默#RBHODM400UA)进行匀浆。在测试板(96孔圆底聚丙烯板)内将膜浓度调节至100μg/mL。待测试的化合物溶于DMSO,10mM,然后在测试缓冲液中稀释至6x所需终浓度。配体(3H-纳曲吲哚)(珀金埃尔默#NET-1065)也在测试缓冲液中稀释至6nM。从预混板转移等份的3H-纳曲吲哚(50μL)至含有膜的测试板,一式两份。测试板在室温下孵育30分钟。采用0.3%聚乙烯亚胺预处理GF/C 96孔过滤板(珀金埃尔默#6005174)30分钟。使用帕卡德过滤(PackardFiltermate)收集器,通过过滤板过滤测试板中的内容物,在4℃采用0.9%盐水洗涤3次。干燥过滤板,底面密封,将30μL MictoS=scint20(Packard#6013621)加入各孔。采用Topcount-NXT微板闪烁记数器(Packard)检测2.9到35KeV的发射能量。将结果与最大结合(没有抑制的孔)进行比较。在1μM未标记的纳曲吲哚的存在下测定非特异性结合。叔丁啡二聚体的生物学活性在下表2中示出。
表2
化合物 IC50 Ki
叔丁啡二聚体 7.6nM 2.87nM
相对于μ和κ阿片受体,二聚体具有弱的δ受体亲合力。
实施例5-受体刺激活性
本实施例说明本发明提供的叔丁啡二聚体刺激μ-阿片受体-介导的信号转导的能力。
μ阿片受体激动剂和拮抗剂功能试验:
表达人μ受体中国仓鼠卵巢(CHO-hMOR)细胞膜的[35S]GTPγS结合试验
简而言之,从受体生物公司(Baltimore Md)购买CHO-hMOR细胞膜。将约10mg/ml膜蛋白悬浮于10mM TRIS-HCl pH 7.2,2mM EDTA,10%蔗糖,悬浮液保持在冰上。1毫升膜加入15mL冷结合分析缓冲液,其包含50mM HEPES,pH 7.6,5mM MgCl2,100mM NaCl,1mM DTT和1mM EDTA。膜悬浮液采用匀浆器进行均质,并在3000rpm离心10分钟。然后在18000rpm离心上清20分钟。采用匀浆器将沉淀重悬于10毫升分析缓冲液。
于25℃,在分析缓冲液中,膜与小麦胚芽凝集素包被的SPA珠(阿莫仙(Amersham))一起预孵育45分钟。然后在分析缓冲液中,将偶联有膜(10μg/ml)的SPA珠(5mg/ml)和0.5nM[35S]GTPγS进行孵育。基线结合是在没有加入测试化合物的情况下发生的结合,这个未调节结合被认为是100%,激动剂刺激结合升高至明显高于该值的水平。一系列浓度范围的受体激动剂SNC80被用来刺激[35S]GTPγS结合。在不存在激动剂下,测试基线和非特异性结合两者,非特异性结合检测包括10μM未标记的GTPγS。
通过采用D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2(CTOP)作为标准品,评价其抑制激动剂刺激的GTPγS结合的潜力,从而测试叔丁啡二聚体作为拮抗剂的功能。采用帕卡德计数器量化放射性。计算以下参数:
%刺激=[(测试化合物cpm-非特异性cpm)/(基线cpm–非特异性cpm)]×100
%抑制=(%由1μM SNC80刺激-%在测试化合物存在下由1μM SNC80刺激)×100/(%由1μM SNC80刺激-100)。
采用GraphPad Prism计算EC50。测试化合物的图示于图5和6。
结果:图5示出的数据表明,叔丁啡二聚体是有效的μ激动剂。结果也表明,在10-6M(~1μg)时,二聚体的阿片μ受体活性与叔丁啡类似。图6的数据表明,叔丁啡二聚体不能作为μ-拮抗剂。
实施例6
体内药代动力学研究
在约翰·霍普金斯医学研究所进行动物药代动力学研究。使用的动物为CD-1小鼠(约35克,n=3,每个时间点)。测试的药物是叔丁啡和叔丁啡二聚体。剂量10毫克/千克静脉内和口服给药。在时间0时,30分钟和1、2、6和24小时收集血液。获得血浆后,如下通过LC/MS/MS分析药物血液样本。
采用掺入任一试验药物(10-25000nM)的小鼠血浆,制备标准曲线。采用包含作为内标的氯沙坦或叔丁啡-d4的300μL乙腈萃取血浆样本(50μL)。于4℃在16000x g离心提取物5分钟。将上清转移至新管并在45℃在氮气下干燥1小时。采用100μL的30%乙腈重构样本,涡旋并离心。将上清(90μL)转移至LC小瓶,将10μL注入LC/MS。参见图7。
结果:图7描述了10mg口服和静脉内给药后叔丁啡二聚体的血浆浓度曲线。曲线图表明,口服和静脉内给药后如浓度曲线下面积比所测定的,二聚体的绝对生物利用度为1%或更小,而单体为约30%。
实施例7
体内试验:应激诱导粪便量
研究中采用的动物是雄性CD-1小鼠,平均体重约30至35克,每剂量组平均5只小鼠。小鼠通常装在群笼中,其中在聚碳酸酯笼中每笼3只,随意饮食和饮水。在实验的当天,运送小鼠到操作室,在试验化合物灌胃后,它们被单独放在配备有金属丝网的20厘米宽×20厘米深×15厘米高的笼子里。在测试过程中,动物随意饮食和饮水。以金属丝网为底的高笼,产生诱导小鼠应激的新环境。以小时为单位检测排泄颗粒的数量。结果示于图8-10。
结果:图8和图9显示,叔丁啡二聚体口服给药,相对于空白剂(载体),显著地降低小鼠粪便量。研究的剂量为每千克25毫克和50毫克。即使从分析中去除表明极端敏感性零粪便量的动物,结果也不发生变化。图10显示小鼠粪便量随剂量发生降低,这标志真正的药理作用。
体内试验:对炎症后改变的GI通过时间的影响
设计本试验以检测测试物质对伴随炎症发生的胃肠过敏的影响。通过注射新打开的芥末油(95%纯异硫氰酸烯丙酯,0.5%在乙醇中)诱导雄性CD-1小鼠炎症后改变的GI运送。应激对GI收缩的作用,在3-4周后进行评估,此时尽管不再有炎症,但GI段处于高度敏感的状态。口服给药(灌胃)并通过将动物放入配有金属丝网底的20厘米宽×20厘米深×15厘米高的笼内,使动物经受环境应激后,检测测试物质的效果。在测试过程中,动物随意饮食和饮水。以金属丝网为底的高笼,产生诱导小鼠应激的新环境。每小时到每两小时检测排泄颗粒的数量。见图11。
如图11所示,在25毫克/千克情况下,根据后炎症模型中的粪便量测定,叔丁啡二聚体显著地降低胃肠蠕动。该图还示出,没有用芥子油处理的小鼠粪便量的增加是短暂的,持续时间不超过1小时。芥子油处理动物增加的粪便量甚至在2小时仍然存在。甚至在2小时,二聚体继续控制胃肠蠕动,而结果是统计学显著的。
可以理解的是本文描述的实施例和实施方式仅用于说明目的,各种明显修改或改变将被建议给本领域的技术人员并且被包括在本申请的精神和范围以及所附的权利要求的范围之内。如果在先申请和本申请间存在冲突到一定程度,那么以本申请优先来消除任何不一致之处。本文引用的所有出版物和专利通过引用以其整体为所有目的并入本文。
Claims (7)
1.一种具有式(I)的叔丁啡二聚体化合物或其药学上可接受的盐或其溶剂化物:
2.如权利要求1所述的叔丁啡二聚体化合物,其特征在于,所述化合物是药学上可接受的盐的形式。
3.一种药物组合物,其特征在于,它包括药学上可接受的载体或赋形剂以及权利要求1所述的叔丁啡二聚体化合物。
4.一种治疗或管理胃肠痛觉过敏的方法,其特征在于,所述方法包括:向有需要的患者施用治疗有效量的权利要求1所述的叔丁啡二聚体化合物。
5.一种治疗有需要患者的腹泻型肠易激综合征的方法,所述方法包括:向所述患者施用治疗有效量的权利要求1所述的叔丁啡二聚体化合物。
6.如权利要求5所述的方法,其特征在于,所述患者是人类,且施用剂量是约0.1mg/kg患者体重至约7.2mg/kg患者体重。
7.如权利要求5所述的方法,其特征在于,所述患者是人类,且施用剂量是每天约10至约50毫克。
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CN201580023367.8A Active CN106470999B (zh) | 2014-04-28 | 2015-04-27 | 叔丁啡二聚体及其在治疗肠胃失调中的应用 |
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WO2021011327A1 (en) * | 2019-07-12 | 2021-01-21 | Orphomed, Inc. | Compound for treating cystic fibrosis |
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