CN102834388A - Cgrp受体拮抗剂 - Google Patents
Cgrp受体拮抗剂 Download PDFInfo
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- CN102834388A CN102834388A CN2011800168882A CN201180016888A CN102834388A CN 102834388 A CN102834388 A CN 102834388A CN 2011800168882 A CN2011800168882 A CN 2011800168882A CN 201180016888 A CN201180016888 A CN 201180016888A CN 102834388 A CN102834388 A CN 102834388A
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Abstract
本发明一般地涉及式I化合物，(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺，包括可药用盐，其为CGRP-受体拮抗剂。本发明还涉及药物组合物和在治疗CGRP相关障碍中使用所述化合物的方法，所述障碍包括偏头痛、神经性血管舒张、神经性炎症、热损伤、循环性休克、与绝经相关的潮红、气道炎性疾病如哮喘、慢性阻塞性肺病(COPD)和癌症。
Description
相关申请的交叉引用
本专利申请要求2010年3月30日提交的美国临时专利申请61/319,015的优先权。
技术领域
本公开一般地涉及化合物(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺(化合物I或式I化合物)，包括可药用盐，其为CGRP-受体拮抗剂。本公开还涉及药物组合物和在治疗CGRP相关障碍中使用所述化合物的方法，所述CGRP相关障碍包括偏头痛、神经性血管舒张、神经性炎症、热损伤、循环性休克、与绝经相关的潮红、气道炎性疾病如哮喘、慢性阻塞性肺病(COPD)和癌症。
背景技术
降钙素基因相关肽(Calcitonin gene-related peptide；CGRP)为一种最初于1982年(Amara,S.G.等人，Science 1982,298,240-244)鉴别的天然存在的含有37个氨基酸的肽。该肽表达为两种形式(αCGRP及βCGRP)，其在大鼠及人类中的不同分别为1个及3个氨基酸。该肽广泛分布于外周神经系统(PNS)与中枢神经系统(CNS)中，主要位于感官传入及中枢神经元中，且显示许多生物作用，包括血管舒张。
当自细胞释放时，CGRP与特异性细胞表面G蛋白偶联受体结合且主要通过活化细胞内腺苷酸环化酶而发挥其生物作用(Poyner,D.R.等人，Br JPharmacol 1992,105,441-7；Van Valen,F.等人，Neurosci Lett 1990,119,195-8.)。已基于肽片段CGRP(8-37)的拮抗剂性质及CGRP的线性类似物活化CGRP2受体的能力提出两种CGRP受体CGRP1及CGRP2(Juaneda,C.等人，TiPS 2000,21,432-438)。然而，缺乏CGRP2受体的分子证据(Brain,S.D.等人，TiPS 2002,23,51-53)。CGRP1受体具有3种组分：(i)7跨膜降钙素受体样受体(CRLR)；(ii)1型单跨膜受体活性修饰蛋白(RAMP1)；及(iii)细胞内受体组分蛋白(RCP)(Evans B.N.等人，J Biol Chem.2000,275,31438-43)。RAMP1为CRLR转运至质膜及配体与CGRP受体结合所需(McLatchie,L.M.等人，Nature 1998,393,333-339)。RCP为信号转导所需(Evans B.N.等人，J Biol Chem.2000,275,31438-43)。小分子拮抗剂与CGRP受体的结合存在已知物种特异性差异，发现拮抗人类受体的亲和力通常大于拮抗其他物种的亲和力(Brain,S.D.等人，TiPS 2002,23,51-53)。RAMP1的氨基酸序列决定物种选择性，具体地，氨基酸残基Trp74负责人类受体的表型(Mallee等人，J Biol Chem 2002,277,14294-8)。
假定受体水平上的CGRP抑制剂可用于已发生CGRP受体过度活化的病理生理病症。这些病症中的一些包括神经性血管舒张、神经性炎症、偏头痛、丛集性头痛(cluster headache)及其它头痛、热损伤、循环性休克、绝经期潮红及哮喘。CGRP受体活化已牵涉于偏头痛的发病机制中(Edvinsson L.CNSDrugs 2001;15(10):745-53；Williamson,D.J.Microsc.Res.Tech.2001,53,167-178.；Grant,A.D.Brit.J.Pharmacol.2002,135,356-362.)。在偏头痛期间，CGRP的血清含量升高(Goadsby PJ等人，Ann Neurol 1990;28:183-7)且用抗偏头痛药物进行治疗使CGRP含量恢复正常，同时减轻头痛(Gallai V.等人，Cephalalgia 1995;15:384-90)。相较于对照，偏头痛患者呈现基础CGRP含量升高(Ashina M等人，Pain 2000,86(1-2):133-8.2000)。静脉内CGRP输注引起偏头痛患者持续头痛(Lassen LH等人，Cephalalgia 2002年2月；22(1):54-61)。在狗及大鼠中进行的临床前研究报导，用肽拮抗剂CGRP(8-37)全身性阻断CGRP不会改变静止全身性血流动力学及区域血流量(Shen,Y-T.等人，JPharmacol Exp Ther 2001,298,551-8)。因此，CGRP受体拮抗剂可提供避免与非选择性5-HT1B/1D激动剂‘triptans’(例如舒马普坦(sumatriptan))相关的心血管主动血管收缩倾向的偏头痛新颖治疗。
CGRP拮抗剂在人类临床试验中已经显示出效力。参见Davis CD,Xu C.CurrTop Med Chem.20088(16):1468-79;Benemei S,Nicoletti P，Capone JG，Geppetti P.CurrOpin Pharmacol.20099(1):9-14.Epub 2009Jan 20;Ho TW，Ferrari MD,Dodick DW，Galet V，Kost J,Fan X,Leibensperger H,Froman S,Assaid C,Lines C,Koppen H,Winner PK.Lancet.2008372:2115.Epub 2008Nov 25;Ho TW，Mannix LK,Fan X,Assaid C,Furtek C,Jones CJ,Lines CR,Rapoport AM;Neurology 200870:1304.Epub 2007Oct 3。
本发明提供技术优势，例如，所述化合物是新化合物并且抑制CGRP。另外，所述化合物提供医药用途的优势，例如，关于它们的作用机制、结合、抑制效力、靶标选择性、溶解度、安全特征或生物利用度中的一个或多个。
CGRP受体拮抗剂已经在PCT公开中披露，包括WO2003/104236。
发明内容
本发明包括(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺(化合物I或式I化合物)和药物组合物以及用于调节CGRP和治疗具有与异常水平的CGRP或CGRP受体信号相关的医学病症的患者的方法。
本发明包括所述化合物的所有可药用盐形式。可药用盐是其中的抗衡离子不明显地促进化合物的生理活性或毒性的盐，并相应地用作药理学等价物。这些盐可采用市售试剂根据常见有机化学技术制备。一些阴离子盐形式包括乙酸盐、醋硬脂酸盐(acistrate)、苯磺酸盐、溴化物、氯化物、柠檬酸盐、反丁烯二酸盐、葡萄糖醛酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、碘化物、乳酸盐、顺丁烯二酸盐、甲磺酸盐、硝酸盐、双羟萘酸盐、磷酸盐、丁二酸盐、硫酸盐、酒石酸盐、甲苯磺酸盐及羟萘甲酸盐(xinofoate)。一些阳离子盐形式包括铵盐、铝盐、苄星青(benzathine)、铋盐、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、锂盐、镁盐、葡甲胺(meglumine)盐、4-苯基环己胺盐、哌嗪盐、钾盐、钠盐、氨丁三醇(tromethamine)盐及锌盐。
本发明意欲包括存在于本发明化合物中的原子的所有同位素。同位素包括具有相同原子序数但质量数不同的那些原子。举例而言且不加限制，氢同位素包括氘及氚。碳同位素包括13C及14C。本发明的同位素标记化合物一般可通过本领域技术人员已知的常规技术或通过与本申请所述方法类似的方法，使用适当同位素标记的试剂替代否则采用的非标记试剂加以制备。这些化合物可具有多种潜在用途，例如在测定生物活性中用作标准物及试剂。在稳定同位素的情况下，这些化合物可具有有利地改变生物、药理学或药代动力学性质的潜力。
具体实施方式
合成方法
缩写一般遵循本领域中使用的惯例。说明书及实施例中使用的化学缩写如下进行定义：“NaHMDS”表示二(三甲基甲硅烷基)氨基钠；“DMF”表示N,N-二甲基甲酰胺；“MeOH”表示甲醇；“NBS”表示N-溴代丁二酰亚胺；“Ar”表示芳基；“TFA”表示三氟乙酸；“LAH”表示氢化锂铝；“BOC”；“DMSO”表示二甲亚砜；“h”表示小时；“rt”表示室温或保留时间(上下文将指示)；“min”表示分钟；“EtOAc”表示乙酸乙酯；“THF”表示四氢呋喃；“EDTA”表示乙二胺四乙酸；“Et2O”表示乙醚；“DMAP”表示4-二甲基氨基吡啶；“DCE”表示1,2-二氯乙烷；“ACN”表示乙腈；“DME”表示1,2-二甲氧基乙烷；“HOBt”表示1-羟基苯并三唑水合物；“DIEA”表示二异丙基乙胺，“Nf”表示CF3(CF2)3SO2-；且“TMOF”表示原甲酸三甲酯。
如本申请所用的缩写如下进行定义：“1×”表示1次，“2×”表示2次，“3×”表示3次，“℃”表示摄氏度，“eq”表示当量，“g”表示克，“mg”表示毫克，“L”表示升，“mL”或“ml”表示毫升，“μL”表示微升，“N”表示当量，“M”表示摩尔浓度，“mmol”表示毫摩尔，“min”表示分钟，“h”表示小时，“rt”表示室温，“RT”表示保留时间，“atm”表示大气压，“psi”表示磅/平方英寸，“conc.”表示浓缩物，“sat”或“sat'd”表示饱和，“MW”表示分子量，“mp”表示熔点，“ee”表示对映异构过量，“MS”或“Mass Spec”表示质谱，“ESI”表示电喷雾电离质谱，“HR”表示高分辨率，“HRMS”表示高分辨率质谱，“LCMS”表示液相色谱质谱，“HPLC”表示高压液相色谱，“RP HPLC”表示反相HPLC，“TLC”或“tlc”表示薄层色谱，“NMR”表示核磁共振光谱法，“1H”表示质子，“δ”表示德耳塔(delta)，“s”表示单峰，“d”表示二重峰，“t”表示三重峰，“q”表示四重峰，“m”表示多重峰，“br”表示宽峰，“Hz”表示赫兹，且“α”、“β”、“R”、“S”、“E”及“Z”为本领域技术人员熟知的立体化学符号。
化合物I可根据方案1制备。此合成具有14个化学步骤且高度收敛，在最后3步中偶合3个主要片段。因而，合成以制备主要片段A(方案2)及B(方案3)开始。
方案1
片段A的合成以N-Boc-4-哌啶酮与自膦酰基乙酸三甲酯产生的叶立德试剂(ylide)的霍纳尔-埃蒙斯反应(Horner-Emmons reaction)开始，以极佳产率得到4-(2-甲氧基-2-氧代亚乙基)哌啶-1-甲酸叔丁酯(方案2)。由钯/碳介导的催化氢化还原不饱和双键。用LDA处理4-(2-甲氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯，产生烯醇化物，其在用2-硝基苯甲醛捕获之后提供硝基醇。于乙酸中用铁还原硝基，随后于二噁烷中用氯化氢处理，完成片段A的合成。
方案2
吲唑氨基酸B的合成以在一氯化碘作用下进行2,6-二甲基苯胺的碘化开始(方案3)。此中间体暂时闲置。N-CBZ-L-丝氨酸甲酯经历一锅煮甲烷磺酰化/消除反应，得到N-CBZ-去氢丙氨酸甲酯。使用现有的碘化物及去氢丙氨酸，它们在使用乙酸钯(II)的情况下于海克偶合(Heck coupling)中有效偶合，以65%产率得到产物。此时，利用(-)-四氟硼酸1,2-二((2R,5R)-2,5-二乙基磷杂环戊烷基)苯(环辛二烯)铑(I)((-)-1,2-bis((2R,5R)-2,5-diethylphospholano)bezene(cyclooctadiene)rhodium(I)tetrafluoroborate)及氢气(60psi)，使用催化不对称氢化安装手性中心，得到约96%ee的手性氨基酸。接着在亚硝酸异戊酯作用下形成吲唑环。所得吲唑具有高度结晶性。自丙酮/己烷重结晶一次，得到极佳纯度且具有改良的99.8%ee的吲唑氨基酸。在氢化条件下移除CBZ保护基，完成片段B的制备。吲唑氨基酸B也可使用外消旋氨基酸或酮酸的酶促拆分加以制备(Hanson,Ronald L.;Davis,Brian L.;Goldberg,StevenL.;Johnston,Robert M.;Parker,William L.;Tully,Thomas P.;Montana,MichaelA.;Patel,Ramesh N.Process Research and Development,Bristol-Myers Squibb,New Brunswick,NJ,USA.Organic Process Research&Development(2008),12(6),1119-1129.)。
方案3
片段A及B在使用碳酸N,N'-二丁二酰亚氨酯的情况下有效偶合以安装脲部分，产率为78%(方案4)。用氢氧化锂使甲酯皂化，产生接近定量产率的羧酸。酸与1-(1-甲基哌啶-4-基)哌嗪的
介导的偶合完成化合物I的合成。快速色谱法得到呈无定形粉末状的产物，其可自丙酮中结晶，得到呈精细白色结晶粉末状的化合物I。
方案4
4-(2-甲氧基-2-氧代亚乙基)哌啶-1-甲酸叔丁酯。将在矿物油中的氢化钠(60％，7.92g，198.02mmol)用己烷洗涤，接着悬浮于二甲基甲酰胺(220mL)中。冷却混合物至0℃。逐滴添加膦酰基乙酸三甲酯(29.0mL，189.82mmol)至搅拌的反应混合物中。在0℃20分钟之后，向混合物中逐滴添加N-叔丁氧基羰基-4-哌啶酮(30.41g，152.62mmol)于二甲基甲酰胺(80mL)中的溶液。反应混合物在室温搅拌3小时且接着用乙醚(650mL)稀释。混合物用水洗涤1次且水层用乙醚萃取1次。合并的有机层用水洗涤4次且弃去水相。有机相用盐水洗涤且经硫酸镁干燥，过滤且浓缩至干燥。以92%产率获得呈白色固体状的标题化合物。1H-NMR(300MHz,CDCl3):δ=5.68(s,1H),3.66(s,3H),3.40-3.51(m,4H),2.90(t,J=5.49,2H),2.25(t,J=5.49,2H),1.44(s,9H)。
4-(2-甲氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯。用50%潮湿的10%钯/碳(3.3g)小心处理4-(2-甲氧基-2-氧代亚乙基)哌啶-1-甲酸叔丁酯(35.71g，140mmol)于1:1乙酸乙酯/甲醇混合物(220mL)中的溶液。向反应容器中装入55psi的氢气且在室温在Parr装置上震荡混合物16小时。接着过滤反应混合物以移除催化剂且真空浓缩滤液。以97%产率获得呈澄清无色油状的标题化合物。1H-NMR(300MHz,CDCl3):δ=4.04(d,J=10.25,2H),3.64(s,3H),2.68(t,J=12.44,2H),2.21(d,J=6.95,2H),1.98-1.77(m,1H),1.64(d,J=13.54,2H),1.41(s,9H),1.25-0.99(m,2H)。
4-[2-羟基-1-甲氧基羰基-2-(2-硝基-苯基)-乙基]-哌啶-1-甲酸叔丁酯。将N,N-二异丙胺(4.40mL，31.3mmol)溶解于四氢呋喃(50mL)中。冷却混合物至-78℃。逐滴添加丁基锂(2.5M，于己烷中，12.4mL，31mmol)至搅拌的溶液中。在-78℃搅拌30分钟之后，向混合物中逐滴添加4-(2-甲氧基-2-氧代乙基)哌啶-1-甲酸叔丁酯(6.65g，25.8mmol)于四氢呋喃(15mL)中的溶液。在-78℃继续搅拌1小时。接着向混合物中逐滴添加2-硝基苯甲醛(3.90g，25.8mmol)于四氢呋喃(20mL)中的溶液，且接着在-78℃再继续搅拌2.5小时。反应混合物用冷氯化铵水溶液淬灭且接着用水稀释。混合物用乙酸乙酯萃取2次且弃去水相。物质经干燥(硫酸镁)，过滤且浓缩至干燥。硅胶色谱法以94%产率得到呈浅黄色泡沫状的所要产物。MS m/e(M-C4H8+H)+=353.1。
4-(4-羟基-2-氧代-1,2,3,4-四氢-喹啉-3-基)-哌啶-1-甲酸叔丁酯。在配备有氮气入口、温度计及机械搅拌器的3颈烧瓶中，将4-[2-羟基-1-甲氧基羰基-2-(2-硝基-苯基)-乙基]-哌啶-1-甲酸叔丁酯(9.93g，24.3mmol)溶解于乙酸(1.75mol，100mL)中。在搅拌下添加铁粉(8.90g，159mmol)至容器中。将搅拌的混合物缓慢加热至80℃，保持30分钟，且接着冷却至室温。其接着用乙酸乙酯稀释且通过硅藻土垫过滤。依次用20%甲醇/乙酸乙酯及甲醇洗涤固体。浓缩滤液且使残余物在乙酸乙酯与碳酸氢钠水溶液之间分配。分离各层。所得水相用乙酸乙酯萃取2次。合并有机层。混合物用水洗涤2次且弃去水相。物质经干燥(硫酸镁)，过滤且浓缩至干燥。硅胶色谱法以77%产率得到呈浅黄色泡沫状的标题化合物。MS m/e(M-H)-=345.1。
3-(哌啶-4-基)喹啉-2(1H)盐酸盐。用HCl/二噁烷(4N，40mmol，10mL)处理4-(4-羟基-2-氧代-1,2,3,4-四氢-喹啉-3-基)-哌啶-1-甲酸叔丁酯(5.60g，16.2mmol)于乙酸乙酯(70mL)中的搅拌的溶液。在室温搅拌混合物45分钟。接着再添加HCl/二噁烷(4N，120mmol，30mL)且在室温继续搅拌16小时。通过过滤收集所得固体且用乙酸乙酯洗涤。接着将其悬浮于5%水-异丙醇(100mL)中且将混合物升温至回流并搅拌20分钟。将混合物冷却至室温且在室温搅拌16小时。通过过滤收集固体，用异丙醇洗涤，且在高真空下干燥。以75%产率获得呈白色固体状的标题化合物。1H-NMR(DMSO-d6)δ11.85(s,1H),9.02(bs,1H),8.88(bs,1H),7.70(t,J=3.81Hz,2H),7.53-7.30(d,J=8.24Hz,1H),7.17(t,J=7.48Hz,2H),3.36(d,J=12.51Hz,2H),3.10-2.94(m,3H),2.01(d,J=13.43Hz,2H),1.87-1.73(m,2H)；MS m/e(M+H)+=229.0。
4-碘-2,6-二甲基苯胺盐酸盐。在室温经1小时向碳酸氢钠(126g，1.5mol)及2,6-二甲基苯胺(61.5mL，500mmol)于甲醇(700mL)中的悬浮液中添加一氯化碘(1.0M，于二氯甲烷中，550mL，550mmol)。在完成添加后，继续搅拌3小时。过滤反应混合物以移除过量碳酸氢钠且真空移除溶剂。将残余物再溶解于乙醚(1.5L)中且用盐酸(2M，于乙醚中，375mL，750mmol)处理。将所得悬浮液于冷冻器(-15℃)中储存过夜。过滤固体且用乙醚洗涤直至其变为无色，得到126.5g(89%)灰绿色粉末。1H-NMR(DMSO-d6)δ2.33(s,6H),7.48(s,2H),9.05(bs,3H)；13C-NMR(DMSO-d6)δ17.4,91.5,133.1,131.2,136.9。
2-(苯甲氧基羰基)丙烯酸甲酯。向经火焰干燥的配备有机械搅拌器的3颈圆底烧瓶中添加(S)-2-(苯甲氧基羰基)-3-羟基丙酸甲酯(129g，509mmol)、无水二氯甲烷(2L)及甲烷磺酰氯(49.3mL，636mmol)。将混合物冷却至-15℃且用三乙胺(213mL，1527mmol)逐滴处理以确保反应混合物的温度不超过0℃。添加第一当量的三乙胺会放热。在添加三乙胺之后，在0℃搅拌混合物30分钟。移除冷却浴且在室温搅拌混合物1.5小时。通过添加甲醇(21mL)淬灭反应。用0.5%硫酸氢钾水溶液洗涤混合物直至洗涤液的pH值为5，接着用饱和碳酸氢钠及盐水洗涤，经硫酸钠干燥且浓缩。快速色谱法(硅胶，1:9乙酸乙酯/己烷)得到111g(92%)粘性无色油状物，其在静置时结晶。1H-NMR(DMSO-d6)δ3.71(s,3H),5.10(s,2H),5.60(s,1H),5.76(s,1H),7.39-7.35(m,5H),8.96(s,1H)；13C-NMR(DMSO-d6)δ52.3,65.9,127.8,128.1,128.3,128.8,133.3,136.3,153.5,163.7。
(Z)-3-(4-氨基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙烯酸甲酯。将4-碘-2,6-二甲基苯胺盐酸盐(55g，194mmol)、2-(苯甲氧基羰基)丙烯酸甲酯(59.2g，252mmol)、氯化四丁铵(59.2g，213mmol)、乙酸钯(II)(4.34g，19.4mmol)及四氢呋喃(1.2L，用氮气流脱气30分钟)装入2L圆底烧瓶中。搅拌混合物以使得形成悬浮液且接着用氮气流脱气30分钟。添加三乙胺(110mL，789mmol)且在回流下加热所得混合物3小时。冷却至室温后，反应混合物通过硅藻土垫过滤，用四氢呋喃(2×100mL)洗涤，且浓缩。将残余物溶解于二氯甲烷中，用水(3×)及盐水(2×)洗涤，经硫酸钠干燥，且浓缩。快速色谱法(硅胶，使用1:9乙酸乙酯/二氯甲烷)得到褐色固体。使固体自温热甲醇(210mL)及水(100mL)中重结晶。混合物在室温保持过夜，接着在0℃保持2小时，且最终在-15℃保持2小时。将所得固体过滤，用冰冷1:1甲醇/水洗涤且在高真空下干燥过夜，得到44.7g(65%)浅褐色固体，其为Z/E异构体(73:27)的混合物。1H-NMR(DMSO-d6)δ,2.05(s,6H),3.61(s,0.8H),3.68(s,2.2H),5.00(s,0.54H),5.13(s,1.46H),5.24(s,2H),7.40-7.21(m,8H),8.51(s,0.27H),8.79(s,0.73H)；13C-NMR(DMSO-d6)δ17.8,51.7,65.3,119.4,120.0,120.3,127.3,127.7,128.3,130.9,135.8,137.2,146.9,154.7,166.0。
(R)-3-(4-氨基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙酸甲酯。向经火焰干燥的2L Parr氢化瓶中装入(Z)-3-(4-氨基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙烯酸甲酯(84.5g，239mmol)、二氯甲烷(300mL)及甲醇(300mL)。将瓶涡旋以使得形成浅棕色悬浮液。使用氮气流使混合物脱气30分钟。向此混合物中快速添加(-)-四氟硼酸1,2-二((2R,5R)-2,5-二乙基磷杂环戊烷基)-苯(环辛二烯)铑(I)([(2R,5R)-Et-DuPhosRh]BF4)(2.11g，3.20mmol)。立即将瓶连接至Parr氢化器。在氢气(60psi)及真空的5个循环后，将瓶加压至65psi且在室温搅拌悬浮液16小时。反应混合物已变得均质。浓缩反应混合物，且通过快速色谱法(硅胶，1:9乙酸乙酯/二氯甲烷)纯化所得残余物，得到82.9g(98%)。1H-NMR(DMSO-d6)δ2.04(s,6H),2.65(dd,J=13.4,9.8Hz,1H),2.82(dd,J=13.7,5.2Hz,1H),3.62(s,3H),4.15-4.10(m,1H),4.41(s,2H),5.00(s,2H),6.68(s,2H),7.37-7.28(m,5H),7.70(d,J=7.9Hz,1H)；13C-NMR(DMSO-d6)δ17.7,35.9,51.7,56.1,65.3,120.4,124.0,127.5,127.7,128.2,128.3,136.9,142.6,155.9,172.5。
(R)-2-(苯甲氧基羰基)-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯。将(R)-3-(4-氨基-3,5-二甲基苯基)-2-(苯甲氧基羰基)丙酸甲酯(50.0g，140mmol)称量入经火焰干燥的5L3颈圆底烧瓶中，随后添加甲苯(2.4L)及冰醋酸(120mL，2.1mol)。机械搅拌混合物以形成澄清溶液，且接着添加乙酸钾(103g，1.05mol)。在室温向所得白色悬浮液中逐滴添加亚硝酸异戊酯(20.7mL，154mmol)，且在室温搅拌所得混合物16小时。添加饱和碳酸氢钠(1L)，随后小心添加固体碳酸氢钠以中和乙酸。用二氯甲烷(2L)与盐水(1.5L)的混合物萃取混合物。分离后，用二氯甲烷(500mL)萃取水层。合并的有机层经无水硫酸钠干燥且过滤。移除溶剂，得到褐色固体，用己烷(2L)及甲苯(150mL)将其洗涤。使固体自热丙酮(260mL)及己烷(700mL)中重结晶。使略微混浊的混合物缓慢冷却至室温，接着冷却至0℃，保持1.5小时，且最终冷却至-15℃，保持1.5小时。过滤所得固体且用冰冷丙酮/己烷(1∶1，200mL)洗涤，得到39.1g(76%产率)。分析性HPLC显示UV纯度>98%。对映异构过量(ee)测定为99.8%(条件：ChiralpakAD柱，4.6×250mm，10μm；A=乙醇，B=0.05%二乙胺/庚烷；85%B，在1.0mL/min下，保持55分钟。R的保留时间为44.6分钟且S的保留时间为28.8分钟)。1H-NMR(DMSO-d6)δ2.48(s,3H),2.93(dd,J=13.4,10.7Hz,1H),3.10(dd,J=13.7,4.9Hz,1H),3.63(s,3H),4.32-4.27(m,1H),4.97(s,2H),7.03(s,1H),7.24-7.22(m,2H),7.29-7.27(m,3H),7.41(s,1H),7.83(d,J=8.2Hz,1H),7.99(s,1H),13.1(s,1H)；13C-NMR(DMSO-d6)δ16.7,36.5,51.8,56.0,65.3,117.6,119.6,122.7,127.2,127.4,127.6,128.2,129.3,133.4,136.8,139.2,155.9,172.4。质谱：368.16(MH)+。
(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯。向Parr氢化瓶中装入(R)-2-(苯甲氧基羰基)-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯(11.0g，29.9mmol)及甲醇(75mL)。悬浮液用氮气净化且用钯(10%，于炭上，700mg)处理。在氢气(15psi)下将瓶震荡过夜。通过硅藻土垫过滤混合物以移除催化剂。浓缩洗脱剂，得到7.7g(定量)油状物，其不经进一步纯化即使用。1H-NMR(CD3OD)δ2.54(s,3H),2.98(dd,J=13.5,7.0Hz,1H),3.09(dd,J=13.5,5.9Hz,1H),3.68(s,3H),3.75(dd,J=7.0,6.2Hz,1H),7.01(s,1H),7.39(s,1H),7.98(s,1H)。质谱：232.34(M-H)-。
(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰氨基)丙酸甲酯。在室温向(R)-2-氨基-3-(7-甲基-1H-吲唑-5-基)丙酸甲酯盐酸盐(7.26g，27.0mmol)于二甲基甲酰胺(50mL)中的溶液中依次添加碳酸N,N'-二丁二酰亚氨酯(7.60g，29.7mmol)及三乙胺(11.29mL，81mmol)。将所得混合物搅拌30分钟且以逐份方式用3-(哌啶-4-基)喹啉-2(1H)-酮(6.77g，29.9mmol)处理。使反应混合物搅拌24小时。将混合物浓缩，溶解于乙酸乙酯中，且依次用水、盐水及0.5N HCl(2×)洗涤。有机相经硫酸镁干燥，过滤且浓缩。通过快速色谱法(硅胶，20:1乙酸乙酯/甲醇)纯化所得残余物，得到11.9g(78%)。1H-NMR(CD3OD)δ13.0(s,1H),11.8(s,1H),7.98(s,1H),7.63(d,J=7.6Hz,1H),7.57(s,1H),7.45-7.41(m,2H),7.27(d,J=8.2Hz,1H),7.16(t,J=7.9Hz,1H),7.03(s,1H),6.85(d,J=7.9Hz,1H),4.31-4.26(m,1H),4.10-4.08(m,2H),3.60(s,3H),3.07-3.01(m,2H),2.93-2.88(m,1H),2.77-2.67(m,2H),2.48(s,3H),1.78-1.72(m,2H),1.34-1.26(m,2H)。质谱：488.52(MH)+。
(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰氨基)丙酸。将(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰氨基)丙酸甲酯(5.50g，11.3mmol)于四氢呋喃(50mL)及甲醇(10mL)中的溶液冷却至0℃。经15分钟向此溶液中逐滴添加单水合氢氧化锂(0.95g，22.6mmol)于水(20mL)中的冷(0℃)溶液。在室温再搅拌反应混合物3小时。浓缩混合物以移除有机溶剂。将所得残余物溶解于少量水中，冷却至0℃，且用冷(0℃)1N HCl处理直至达到pH 2。通过过滤收集所得固体，用冷水及乙醚洗涤，且接着在高真空下干燥过夜，得到5.0g(94%)白色固体。1H-NMR(DMSO-d6)δ13.05(bs,1H),11.77(s,1H),7.98(s,1H),7.62(d,J=8.0Hz,1H),7.55(s,1H),7.44(d,J=8.2Hz,1H),7.42(s,1H),7.27(d,J=8.2Hz,1H),7.16(t,J=7.6Hz,1H),7.05(s,1H),6.65(d,J=7.9Hz,1H),4.27-4.22(m,1H),4.10-4.07(m,2H),3.12-3.07(m,1H),3.03-2.99(m,1H),2.93-2.88(m,1H),2.77-2.66(m,2H),2.47(s,3H),1.77-1.74(m,2H),1.34-1.27(m,2H)。质谱：474.30(MH)+。
(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺(I)。向烧瓶中装入(R)-3-(7-甲基-1H-吲唑-5-基)-2-(4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰氨基)丙酸(2.9g，6.11mmol)、三乙胺(3.00mL，21.5mmol)、1-(1-甲基哌啶-4-基)哌嗪(1.23g，6.72mmol)及二甲基甲酰胺(10mL)。以逐份方式用四氟硼酸2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓(2.26g，7.03mmol)处理所得溶液。在室温使反应混合物搅拌过夜。在真空下浓缩混合物以移除二甲基甲酰胺。将粗产物溶解于7%甲醇/二氯甲烷中且使用含有2%氢氧化铵水溶液的7%甲醇/二氯甲烷作为洗脱剂通过快速色谱法纯化。收集纯级份且在真空下移除溶剂。使所要产物自热丙酮中结晶，以77%产率得到化合物I。分析性HPLC显示230nm下的UV纯度为99.0%。对映异构过量(ee)测定为>99.9%(条件：Chiralpak AD柱，4.6×250mm，10μm；洗脱剂：70%(0.05%二乙胺)/庚烷/30%乙醇；在1.0mL/min下，保持45分钟。R的保留时间为18.7分钟且S的保留时间为28.1分钟)。1H-NMR(500MHz,DMSO-d6)δppm 13.01(s,1H),11.76(s,1H),7.96(s,1H),7.62(d,J=7.10Hz,1H),7.60(s,1H),7.42(m,1H),7.36(s,1H),7.26(d,J=8.25Hz,1H),7.14(m,1H),7.00(s,1H),6.69(d,J=8.25Hz,1H),4.78(q,J=7.79Hz,1H),4.14(d,J=12.37Hz,2H),3.54(dd,J=9.16,4.58Hz,1H),3.24(m,1H),3.11(m,1H),2.97(m,1H),2.89(m,2H),2.69(m,4H),2.32(m,1H),2.21(m,1H),2.07(m,4H),1.95(t,J=8.25Hz,1H),1.87(m,J=11.28,11.28,3.55,3.44Hz,1H),1.76(t,J=12.03Hz,2H),1.68(t,J=11.11Hz,2H),1.53(t,J=8.25Hz,1H),1.32(m,4H),1.16(m,2H)；13C-NMR(DMSO-d6)δ16.80,27.30,30.51,30.51,30.67,35.50,38.04,41.74,44.00,44.16,45.35,45.78,48.14,48.39,51.45,54.76,54.76,60.61,114.53,117.79,119.29,119.34,121.57,122.78,127.46,127.79,129.29,129.79,133.31,133.72,136.98,137.41,139.12,156.50,161.50,170.42。精确质量分析：m/z 639.3770，[MH]+，Δ=-0.2ppm。旋光度：-27.36°(在589nm下)，浓度=4.71mg/mL(于甲醇中)。
生物方法及其它性质
方案5：化合物I及比较化合物II及III。
水溶性。将固体游离碱与碳酸盐及乙醇胺缓冲液混合。用HCl调节第三样品的pH值。使用封闭在设定至25℃的孵育箱内的混合器混合固体与媒介物。平衡后，取出上清液样品，适当时加以稀释，且通过HPLC进行分析。
于水性介质中的溶解度，pH值依赖性。在测量pH值溶解度特征期间结晶化合物I转化成凝胶相。不存在与水平衡的结晶相会妨碍对可将化合物I配制成热力学稳定溶液的pH值范围进行可靠评估。产生化合物I的于水中可平衡的结晶游离碱形式的努力正在进行中。收集的关于凝胶相的数据列于表1中。
表1：在25℃化合物I于水性介质中的溶解度
| 媒介物 | 溶解度(mg/mL) |
| 碳酸盐缓冲液，pH=10.4 | 0.2 |
| 乙醇胺缓冲液，pH=9.4 | 0.5 |
| 用HCl部分滴定化合物I，pH=8.5 | 105 |
| pH<8.5 | >300 |
溶液状态稳定性。化合物I的溶液状态稳定性评估为温度、pH值、高强度光照(HIL)、缓冲液浓度及药物浓度的函数。所用实验矩阵展示于表2中。
表2：溶液状态稳定性矩阵
丁二酸盐缓冲液用于所有溶液。对于曝露于光中的样品，根据ICH准则(1.2×106勒克司小时(1.2million lux hour)曝露于可见光且200瓦特小时/平方米(200watt hour/m2)曝露于UV)使用光稳定性腔室。在4、8及12周进行分析。
在溶液稳定性研究期间发现10种降解物。储存12周后于样品中发现的各降解物的百分比列于表3中。应注意在初始时间点时，降解物B及G为仅有的存在的降解物且其初始浓度分别为0.17%及0.06%。
对以足以允许质量测定的量存在的那些降解物进行质谱评估。结果列于表4中。在降解物B下列有两个峰，因为发现两种降解物未由当前HPLC方法充分分离。降解物A及C对应于水解产物。
在所研究的最有利条件(表2中的条件I)下，化合物I显示在40℃12周后仅有0.3%降解。这表明，可找到满足化学稳定性的ICH准则至少1年的含水制剂。
表3：在12周时所见的降解物的面积百分比及其保留时间(分钟)
表4：降解物分子量
方案6
溶液稳定性：温度影响。温度影响总结于表5中。降解速率随温度增加主要归因于水解增强。在最高温度下，降解自始至终发生，直至产物C，但在较低温度下，降解停在产物A处。
表5：溶液稳定性及温度
溶液稳定性：光照影响。光照对稳定性的影响总结于表6中。对于曝露于光中的样品，注意到有7种降解物，其中3种不出现在于任何其它条件下储存的样品中。水解(降解物A)因曝露于光中而得以增强。
表6：溶液稳定性及光照
| pH值 | 温度(℃) | 光照条件 | 总降解物 |
| 5 | 25 | 黑暗 | 2.3% |
| 5 | 25 | 光照 | 72% |
溶液稳定性：pH值影响。pH值对降解速率的影响总结于表7中。降解速率的增加与pH值呈相反变化且受水解增强支配。在pH 4下，降解发生直至水解产物C，但在pH 5及6下，降解停在水解产物A处。
表7：溶液稳定性及pH值
| pH值 | 总降解物 |
| 4 | 12.5% |
| 5 | 2.2% |
| 6 | 0.62% |
溶液稳定性：缓冲液浓度影响。丁二酸盐缓冲液的较高浓度倾向于产生水解成降解物A的较高速率(表8)。
表8：溶液稳定性及丁二酸盐缓冲液浓度
溶液稳定性：药物浓度的影响。高药物加载量使水解速率减缓且限制水解形成降解物A(表9)。在研究期间，降解物G(其仅在高浓度样品中检测到)的浓度不显著增长且可能仅为杂质。降解物J仅可在最终时间点时检测到。
表9：溶液稳定性及化合物I浓度
结合[125I]CGRP的竞争
结合测定。SK-N-MC细胞膜组织匀浆充当受体源。人类神经母细胞瘤SK-N-MC细胞用于活体外测定，因为其内源性表达与克隆的人类CGRP受体具有一致序列的CGRP受体(Aiyar等人，2001)。在37℃于5%CO2中，使细胞生长于由补充有10%胎牛血清的含有厄尔氏盐(Earle's salt)及L-谷氨酰胺的MEM组成的培养基中，直至达到融合。通过用磷酸盐缓冲盐水冲洗2次收集细胞，且在4℃于由10mM Tris(pH 7.4)及5mM EDTA组成的低张裂解缓冲液中孵育5-10分钟。收集细胞并转移至聚丙烯管中，且使用polytron加以均质化。组织匀浆在32,000×g下离心30分钟。使团粒再悬浮于含有0.1%哺乳动物蛋白酶抑制剂混合剂的冷低张裂解缓冲液中，且测定蛋白质浓度。接着等分(aliquoted)膜组织匀浆且储存在-80℃直至测定当天。
使用放射性配体竞争测定测量化合物I竞争放射性标记的([125I]CGRP，Amersham Biosciences)内源性肽人类αCGRP(hαCGRP)的能力。化合物I首先溶解于100%DMSO中且使用100%DMSO进行连续稀释。将化合物于测定缓冲液(50mM Tris-Cl(pH 7.5)，5mM MgCl2，0.005%Triton X-100)中进一步稀释25倍且转移(50μl)入96孔测定板中。于测定缓冲液中稀释[125I]-CGRP至600pM，且添加50μl体积至各孔中(测定中的最终浓度为15pM)。解冻SK-N-MC膜团粒，于含有新鲜0.1%哺乳动物蛋白酶抑制剂混合剂的测定缓冲液中稀释，且如先前所述加以均质化。接着以100μl体积添加每孔5至10μg蛋白质。接着在室温(25℃)孵育测定板2小时。通过添加过量冷洗涤缓冲液(20mMTris-Cl(pH 7.5)，0.1%BSA)终止测定，随后即刻经预浸泡于0.5%PEI中的玻璃纤维过滤器过滤。非特异性结合以1μM β-CGRP加以定义。使用γ闪烁计数器测量蛋白质结合放射性。IC50定义为抑制50%放射性配体结合所需的化合物浓度。
结果。化合物I显示以浓度依赖性方式抑制[125I]CGRP与在SK-N-MC细胞膜中内源性表达的CGRP受体结合。平均Ki为22.7±1.6pM。
与CGRP肽的相互作用
方法。使用饱和结合实验详细研究内源性CGRP肽与化合物I之间的相互作用的性质。简而言之，在不存在化合物I(对照条件)或存在两种浓度(30pM及100pM)之一的化合物I(测试条件)的情况下，用浓度递增的[125I]CGRP测量[125I]CGRP与SK-N-MC细胞膜制备物的结合。使用Kell软件(Biosoft,Cambridge,UK)用双曲线方程分析饱和数据，以估计解离常数(Kd)及最大结合位点数(B最大)。测量并比较添加化合物I对[125I]CGRP的结合参数(Kd、B最大)的影响。
结果。化合物I以浓度依赖性方式使[125I]CGRP结合的解离常数Kd增加(使其亲和力降低)，而不显著改变[125I]CGRP结合的最大结合位点数(B最大)。这表明了化合物I抑制[125I]CGRP在人类受体处结合的竞争机制(表10)。
表10：存在或不存在化合物I的情况下[125I]CGRP与SK-N-MC细胞膜制备物结合的Kd、B最大。
| 对照 | 30pM化合物I | 100pM化合物I | |
| Kd(pM) | 23.1±5.0 | 58.0±19.6 | 129.7±31.9 |
| B最大(飞摩尔/毫克蛋白质) | 142.6±10.6 | 112.1±20.6 | 146.8±6.4 |
细胞功能性测定-环AMP测定
方法。使CGRP受体复合物与Gs种类的G蛋白偶联。CGRP与此复合物的结合导致通过腺苷酸环化酶的Gs依赖性活化而产生环AMP(3',5'-环单磷酸腺苷)。
化合物I的功能性拮抗作用通过以下方法测定：测量其在所附着的整个SK-N-MC细胞中抑制CGRP刺激的环AMP形成的能力。SK-N-MC细胞在室温与单独的0.3nM CGRP一起孵育30分钟，或与各种浓度的化合物I一起预孵育15分钟，随后添加0.3nM CGRP且接着再孵育30分钟。使用“裂解试剂(LysisReagent)”提取产生的环AMP(cAMP)，且使用RPA559cAMP SPA直接筛选测定试剂盒(Direct Screening Assay Kit)(Amersham Pharmacia Biotech)通过放射免疫测定来测定其浓度。IC50值定义为抑制50%的0.3nM CGRP刺激的cAMP产生所需的化合物浓度。Y最大定义为0.3nM CGRP刺激的cAMP产生的最大抑制百分比。
结果。化合物I显示以浓度依赖性方式在所附着的整个SK-N-MC细胞中抑制CGRP刺激的cAMP产生，其中IC50为38.6±4.2pM，且Y最大为95.4(±1.3)%。所观察到的最大(约100%)抑制表明在CGRP受体处的完全拮抗。
谢尔德(Schild)分析
方法。谢尔德分析用于表征化合物I的拮抗作用的性质。用单独CGRP或在各种浓度的化合物I存在下用CGRP产生CGRP刺激的cAMP产生的剂量应答。具体地，在存在5种不同浓度的化合物I或不存在化合物I的情况下，测定CGRP对cAMP的剂量依赖性刺激。在X轴上相对于Y轴上的剂量比率减1绘制化合物I的浓度(剂量比率定义为在化合物I存在下CGRP的EC50除以单独CGRP的EC50)。接着进行线性回归，将X轴与Y轴对数变换。不显著不同于数目1的斜率表明竞争性拮抗作用。Kb为拮抗剂解离常数。
结果。化合物I的谢尔德分析揭示，平均斜率为1.02±0.04且平均拮抗剂解离常数Kb为21.5±9.4pM。在递增浓度的化合物I存在下CGRP浓度-应答的平行向右移位表明化合物I对CGRP刺激的cAMP产生的竞争性拮抗作用。来自谢尔德曲线的1.02的斜率进一步支持在化合物I和CGRP功能之间的竞争性相互作用。21.5pM的Kb与结合Ki(22.7pM)一致。
逆转离体人类颅内动脉中CGRP诱导的扩张
为了提供模拟临床条件(其中偏头痛相关的CGRP在起始疗法之前释放)的离体测量，首先通过CGRP扩张血管且接着用化合物I逆转扩张。在此逆转规程中，拮抗剂后处理逆转CGRP诱导的动脉扩张(使用单次激动剂剂量及多次拮抗剂剂量)。简而言之，将安装有电线的动脉环(wire mounted artery rings)用钾离子收缩(以模拟内源性张力)，用CGRP充分扩张，且用递增浓度的CGRP拮抗剂化合物I逆转扩张。化合物I后处理有效逆转所产生的CGRP诱导的离体人类颅内动脉扩张。
组织样品。自组织采购供货商获得人类动脉的剖检样品。所有血管皆于冰冷HEPES缓冲液(组成(mM)：NaCl 130、KCl 4、KH2PO4 1.2、MgSO4 1.2、CaCl21.8、葡萄糖6、NaHCO34、HEPES 10、EDTA 0.025)中加以运输。接收后，将血管置于用碳合氧(carbogen)(5%CO2及95%氧气)饱和的冷克雷伯氏缓冲液(Kreb's buffer)(组成(mM)：NaCl 118.4、KCl 4.7、KH2PO4 1.2、MgSO41.2、CaCl2 1.8、葡萄糖10.1、NaHCO3 25)中。
方法。将血管清除掉结缔组织且切割成长度为4-5mm的圆柱形区段。接着将血管在组织浴中安放于两个不锈钢钩之间；其中一个钩被固定且另一个钩与力位移传感器(force displacement transducer)相连。使用数据采集系统(Powerlab,AD Instruments,Mountain View,CA)连续记录血管张力。控制含有克雷伯氏缓冲液及所安放血管的组织浴的温度(37℃)及pH值(7.4)且用碳合氧对所述组织浴连续鼓泡。使动脉区段平衡约30-45分钟，直至实现稳定静止张力(0.25至0.5g)。在测定之前，用100mM KCl灌注(调节)血管且随后洗涤。
为了测试化合物I的抗扩张作用，首先用10mM氯化钾(KCl)收缩血管以模拟内源性张力，接着用1nM hαCGRP充分扩张，且最终通过以半对数单位(允许计算EC50)累积添加递增浓度的化合物I使扩张逆转。在各浓度下，药物作用表示为各血管中CGRP诱导扩张的逆转百分比。单独地进行各血管的数据分析，通过非线性回归分析将浓度-应答数据拟合至4参数逻辑函数，以估计EC50值。
结果。化合物I显示有效且完全逆转CGRP诱导的离体人类颅内动脉扩张，EC50=880±50pM。
谢尔德分析：离体人类颅内动脉中CGRP浓度-应答曲线的抑制
为了评估对于一定范围的CGRP浓度的功能性拮抗作用，将化合物I与单独动脉环一起在组织浴中预孵育且接着产生CGRP浓度-应答曲线以实现充分扩张(使用多次激动剂及多次拮抗剂剂量)。拮抗剂的浓度较高会引起CGRP浓度-应答曲线中的‘右移’，从而需要较大浓度的激动剂来克服拮抗剂的存在且实现充分扩张。简而言之，将安装有电线的动脉环与拮抗剂一起预孵育，接着用KCl收缩(以模拟内源性张力)，且随后添加递增浓度的CGRP以实现充分松弛。化合物I预处理有效抑制CGRP诱导的离体人类颅内动脉扩张，且显示CGRP浓度-应答曲线的平行向右移位。
方法。将各安装有电线的动脉环与单一浓度(0.1-30nM)的拮抗剂化合物I一起预孵育30分钟，接着用10mM KCl收缩(以模拟内源性张力)，随后添加递增浓度的CGRP以实现充分松弛。使KCl收缩稳定，以使得在施用CGRP之前，总拮抗剂预处理时间为约45分钟。
结果。化合物I引起离体人类颅内动脉中CGRP浓度-应答曲线的平行向右移位。谢尔德分析揭示91pM的Kb。这些结果有利地与活体外结合(Ki=22.7pM)及功能性(Kb=21.5pM)测定相当。
化合物I在狨猿面部血流量方面的活体内效力
为了评估新颖CGRP受体拮抗剂的活体内效力，狨猿接受一系列的4次hαCGRP静脉内注射(间隔45分钟)。首次注射充当基线对照，且随后皮下递送测试物品。随后3次CGRP激发提供对活体内功能性CGRP拮抗作用的评估。在本研究中，化合物I证明具有稳固的持续性CGRP拮抗作用。
方法。将狨猿麻醉，且面部血流量因以45分钟时间间隔(-30、15、60及105分钟)静脉内(IV)给药hαCGRP而增加。通过激光多普勒血流测定仪(laserDoppler flowmetry)测量在0分钟递送的测试化合物对hαCGRP诱导的面部血流量变化的影响。有效化合物将抑制在15、60及105分钟所见的hαCGRP诱导的面部血流量增加(相较于在-30分钟所见的基线hαCGRP影响)。
受试者：重量为350-650g的成年雄性及雌性普通狨猿(狨毛猴(Callithrixjacchus))充当受试者。
麻醉及准备：动物通过于吸气室中吸入异氟烷(4-5%快速吸气，以1-2.5%维持；Solomon等人，1999)而被麻醉。麻醉通过以下方法维持：通过插管及通风递送恒定供应的空气:氧气(50:50)及异氟烷(同时监测血气)。通过置放在自动温度控制表面上用直肠探针将体温维持在38±0.5℃。通过施用脱毛乳膏及/或剃毛，自面部的一侧或两侧除去小面积的软毛(fur)(约1.5平方厘米)。修剪手术区域且用聚烯吡酮磺(betadine)进行准备。将静脉内管线置于隐静脉中以给药测试化合物及CGRP受体激动剂hαCGRP。另外，此静脉内管线为取出血液样品(最大2.5ml，10%)用于监测血气及分析化合物血浆含量做准备。静脉内给药5%右旋糖的溶液以维持血糖含量。麻醉深度通过以下方法监测：分别使用非侵入性臂套测压法及脉搏血氧计测量血压及心率。静脉内给予5-10mg/kg胍乙啶(需要时静脉内补充5mg/kg)以稳定面部血流量的峰通量，否则其会在重复刺激后显示渐进性减小(Escott等人，1995)。微血管血流量通过以下方法监测：将自粘激光多普勒流量探针附着于面部皮肤。探针记录穿过两个激光束的路径的红血细胞数目，乘以其速度(报导为通量的变化)。
药物递送：在颈背中皮下给药测试化合物(0.1-0.6ml/kg)。以10μg/kg的剂量静脉内递送CGRP受体激动剂hαCGRP(1ml/kg)。
测试规程：为了评估活体内效力及作用持续时间，通过在药物递送之前30分钟(-0.5小时)给药hαCGRP(10μg/kg，静脉内)来诱导面部血流量的对照增加。接着在时间零点(0分钟)给药化合物I且以45分钟时间间隔持续约2小时重复递送hαCGRP(在给药后0.25、1及1.75小时收集数据)。化合物I以0.003、0.01及0.03mg/kg皮下给药。在各hαCGRP即将给药之前获得血浆样品。在测试之后，使动物返回至置放在温度受控表面上的运输笼中，该表面使动物保持温暧直至完全苏醒及可走动。可在14-21天的休息及清除期之后再次测试动物。
结果。化合物I(0.003-0.03mg/kg，皮下)显示以剂量依赖性方式抑制CGRP诱导的狨猿面部血流量增加。在0.03mg/kg下，在给药后0.25、1及1.75小时观察到稳固(53-80%)抑制。在0.01mg/kg下，在整个所有给药后测试时间内可见显著(35-40%)抑制。在0.003mg/kg下，在0.25小时观察到温和(20%)但显著的抑制，在随后的测试时间无作用。
比较效力相对于暴露(exposure)的关系，对于化合物I而言，血浆含量≥8nM与显著活体内效力相关且含量≥25nM与最大效力相关。
大鼠中的鼻内刺激研究
化合物I及化合物III：大鼠中的1周比较鼻内刺激研究。进行此研究以比较化合物I与化合物III当向雄性大鼠鼻内给予1周时的潜在鼻刺激。用化合物I或化合物III溶液(25、75或175mg/L，225mM丁二酸，0.02%苯扎氯铵，1.25%无水右旋糖，pH 5.8-6.2)以每鼻孔100μL的剂量体积每日1次对雄性大鼠(10只/组)鼻内滴注。使用此给药范式，每日递送固定剂量的5、15或35mg测试物品。因此，相对于体重标准化的剂量因大鼠生长而随时间减小。对1个对照组给予丁二酸盐媒介物，且对假对照组通过鼻内滴注给予盐水。评估的参数包括临床观察、体重、食物消耗、毒物动力学及鼻组织的组织学评估。
毒物动力学参数的值展示于表11中。
表11：获得的关于化合物I的毒物动力学数据。
1由于长期暴露而未测出。
2在静脉内给药1mg/kg之后，在大鼠中基于7.7μM·h的AUC0-24h的绝对生物利用度。
3估计的大鼠鼻粘膜表面积=14cm2
化合物I的鼻内给药提供大鼠中24小时的全身性暴露，且在此1周研究中的首天与末天给药之间几乎未观察到差异。
鼻内给药化合物I耐受良好；在所有剂量组及媒介物对照中的活体内研究结果受限于流涎增加，且可能与用于研究的给药体积过大有关。在给予盐水的大鼠中未观察到流涎。
对于两种化合物均观察到鼻刺激，但在整个剂量范围内，化合物I明显导致比化合物III较少的嗅上皮萎缩(表12)。观察的损害类型与先前对化合物II所作的观察一致。鼻研究结果的严重程度及发病率证明，化合物I的鼻毒性特征优于化合物III的鼻毒性特征。
表12：在大鼠中鼻滴注化合物III或化合物I之后嗅上皮萎缩的发病率及严重程度
化合物I及化合物II：大鼠中的1周探索性鼻内刺激研究。也直接比较化合物I与化合物II的鼻内刺激。用化合物I或化合物II溶液(75或175mg/L，225mM丁二酸，1.25%无水右旋糖，pH 5.8-6.2)以每鼻孔12.5、25或100μL的剂量体积每日1次对雄性大鼠(6只/组)鼻内滴注。此研究中评估的唯一终点为鼻甲的组织学评估。
在评估的各剂量(体积×浓度)下，由化合物I引起的嗅上皮萎缩的严重程度明显小于由化合物II产生的严重程度(表13)。
表13：化合物I及化合物II的嗅上皮毒性、严重程度评分。
化合物II的剂量-应答关系与在其它研究中观察到的剂量-应答关系一致。体积增加与浓度增加两者均促成更显著的鼻毒性，但浓度可能为更重要的因素。
总而言之，相较于化合物II，化合物I显示关于鼻刺激的优越性。
鼻递送的潜力。CGRP拮抗剂的鼻内(IN)给药途径具有吸引力，因为其提供具有快速起作用的潜力的非侵入性递送。高渗透性鼻上皮障壁、良好灌注的粘膜组织及有限的代谢能力/组织保留时间是支持鼻内递送呈现非常差的口服吸收的化合物如化合物I的潜在有用特征。
鼻递送的可行性在鼻内兔模型中通过以下方法评估：比较经鼻递送与通过静脉内途径递送的化合物I的血浆浓度-时间特征及药代动力学参数(C最大、T最大、AUC及生物利用度)。给药溶液浓度及递送体积包括在各研究的数据表中。媒介物组成描述于表下方的脚注中。
方法。各组3只重量在3-3.5kg的范围内的雄性新西兰白兔(New ZealandWhite rabbit)以下列治疗之一接受单次剂量的药物：0.5mg/kg，经30秒静脉内弹丸注射；或0.3-3mg/kg，用针筒微型喷雾器(syringe microsprayer)鼻内给药。在鼻内给药之前，用吸入麻醉剂七氟烷使兔稍微镇静以实现麻醉的目的。兔在2-5分钟内恢复意识。在给药前、给药后2、5、10、15、30分钟及1、2、4、6及24小时连续收集血液样品于含肝素的采血管(vacutainers)中。将血液样品立即在4℃离心且分离的血浆储存在-80℃直至通过LC/MS/MS测定进行进一步分析。
结果。药代动力学特征表明，化合物I在以溶液形式喷雾时自兔的鼻腔快速吸收。在所研究的所有剂量下，达到峰浓度的时间(T最大)皆发生在0.2-0.3小时(15-20分钟)内。在0.3、1及3mg/kg下，绝对生物利用度在13至30%范围内且C最大在0.12至2.0μM范围内(表14)。
表14：静脉内及鼻内给药之后化合物I在兔中的药代动力学参数。
静脉内制剂：50mM丁二酸盐缓冲液/D5W媒介物，pH 5。
鼻内制剂：50mM丁二酸盐缓冲液，pH 5-6。
化合物I在兔中的鼻内吸收极其快速。在5分钟内测量到血浆含量>10nM。给药后持续至少6小时且在高剂量下多达24小时在血浆中检测到药物。
先前，就化合物II而言，当鼻内递送体积而非给药浓度改变时，存在较大线性偏差。通过保持化合物I递送体积恒定且改变给药溶液浓度，鼻内AUC及C最大显示出朝向剂量依赖性线性的趋势(表15)。这些参数的变化性也随剂量增加而增加。经仔细检查，对于测试的3种剂量而言，鼻内生物利用度似乎随剂量(或给药浓度)增加而增加(表15)。
表15：鼻内化合物I在兔中的剂量线性
给药浓度为10、30及100mg/ml，于50mM丁二酸盐缓冲液媒介物(pH 5)中。
总而言之，相较于口服途径，化合物I的鼻内给药途径提供快速全身性吸收及相对延长的血浆含量。高水溶性及改良的溶液稳定性有利地支持鼻用喷雾产品于适当喷雾装置中的耐久性(viability)。预期药物溶液在人类鼻腔中的递送及其沉积比用临床前鼻内动物模型可能获得的结果更稳固及更可再现。化合物I制剂计划以可重复使用的多次剂量或一次性单位剂量鼻用喷雾装置加以递送。
药物组合物及治疗方法
本发明的另一方面为包含化合物I与可药用辅料、载体或稀释剂的药物组合物。
化合物I将一般以包含治疗有效量的化合物I或可药用盐及可药用载体且可含有常规赋形剂的药物组合物形式给出。治疗有效量为本领域技术人员确定的提供有意义的患者益处所需的量。可药用载体为具有可接受的安全特征的那些通常已知载体。组合物涵盖所有常见固体及液体形式，包括胶囊剂、片剂、锭剂及粉剂以及液体混悬剂、糖浆剂、酏剂及溶液剂。固体组合物可按定时释放或持续释放制剂形式形成。组合物使用常见配制技术及常规赋形剂(诸如粘合剂及湿润剂)及媒介物(诸如水及醇)制备。
固体组合物通常以每剂量提供约1至约1000mg活性成分的剂量单位配制。固体剂量单位的一些实例为0.1mg、1mg、10mg、100mg、500mg及1000mg。液体组合物的单位剂量范围一般为1-100mg/mL。液体剂量单位的一些实例为0.1mg/mL、1mg/mL、10mg/mL、25mg/mL、50mg/mL及100mg/mL。
本发明涵盖所有常规给药模式，包括口服、肠胃外、鼻内、舌下及经皮方法。通常，每日剂量将为每日每公斤体重0.01-100毫克。一般而言，口服给药需要较多化合物且肠胃外给药需要较少化合物。然而，具体给药方案应由医师使用合理医学判断来确定。
本发明的另一方面为鼻内给药。
假定受体水平上的CGRP抑制剂可用于已发生CGRP受体过度活化的病理生理病症。这些病症中的一些包括神经性血管舒张、神经性炎症、偏头痛、丛集性头痛及其它头痛、热损伤、循环性休克、绝经期潮红及哮喘。CGRP受体活化已牵涉于偏头痛的发病机制中(Edvinsson L.CNS Drugs2001;15(10):745-53;Williamson,D.J.Microsc.Res.Tech.2001,53,167-178.;Grant,A.D.Brit.J.Pharmacol.2002,135,356-362.)。在偏头痛期间，CGRP的血清含量升高(Goadsby PJ等人Ann Neurol 1990;28:183-7)且用抗偏头痛药物进行治疗使CGRP含量恢复正常，同时减轻头痛(Gallai V.et al.Cephalalgia1995;15:384-90)。相较于对照，偏头痛患者呈现基础CGRP含量升高(AshinaM,et al.,Pain 2000,86(1-2):133-8.2000)。静脉内CGRP输注引起偏头痛患者持续头痛(Lassen LH等人Cephalalgia 2002Feb;22(1):54-61)。在狗及大鼠中进行的临床前研究报导，用肽拮抗剂CGRP(8-37)全身性阻断CGRP不会改变静止全身性血流动力学及区域血流量(Shen,Y-T.等人J Pharmacol Exp Ther 2001,298,551-8)。因此，CGRP受体拮抗剂可提供避免与非选择性5-HT1B/1D激动剂‘triptans’(例如舒马普坦)相关的心血管主动血管收缩倾向的偏头痛新颖治疗。
本发明的另一方面为抑制CGRP受体的方法，其包括使CGRP受体与式I化合物或其可药用盐接触。
本发明的另一方面为治疗与异常水平的CGRP或CGRP受体信号相关的病症的方法，其包括向患者给药治疗有效量的式I化合物。
本发明的另一方面为式I化合物在制造用于治疗与异常水平的CGRP或CGRP受体信号相关的病症的药剂中的用途。
本发明的另一方面为治疗偏头痛或头痛的方法。
本发明的另一方面为治疗神经性疼痛的方法。
本发明的另一方面涉及治疗以下病症的方法：炎症(尤其神经性炎症)、疼痛、热损伤、循环性休克、糖尿病、雷诺综合征(Reynaud's syndrome)、周围动脉供血不足(peripheral arterial insufficiency)、蛛网膜下腔(subarachnoid)/颅出血、肿瘤生长、与绝经相关的潮红及可通过给药包含本申请定义的式I化合物的药物组合物拮抗CGRP受体而实现治疗的其它病症。
本发明的另一方面涉及选自以下的方法：(a)肠粘膜中的免疫调节；(b)对抗心脏过敏性损伤的保护作用；(c)刺激或防止骨质吸收的白介素-1b(IL-1b)刺激；(d)调节脊神经元中NK1受体的表达及(e)气道炎性疾病及慢性阻塞性肺病，包括哮喘。参见(a)Calcitonin Receptor-Like Receptor Is Expressed onGastrointestinal Immune Cells.Hagner,Stefanie;Knauer,Jens;Haberberger,Rainer;Goeke,Burkhard;Voigt,Karlheinz;McGregor,Gerard Patrick.Instituteof Physiology,Philipps University,Marburg,Germany.Digestion(2002),66(4),197-203；(b)Protective effects of calcitonin gene-related peptide-mediatedevodiamine on guinea-pig cardiac anaphylaxis.Rang,Wei-Qing;Du,Yan-Hua;Hu,Chang-Ping;Ye,Feng;Tan,Gui-Shan;Deng,Han-Wu;Li,Yuan-Jian.Schoolof Pharmaceutical Sciences,Department of Pharmacology,Central SouthUniversity,Xiang-Ya Road 88,Changsha,Hunan,Naunyn-Schmiedeberg′sArchives of Pharmacology(2003),367(3),306-311；(c)The experimental study onthe effect calcitonin gene-related peptide on bone resorption mediated byinterleukin-1.Lian,Kai;Du,Jingyuan;Rao,Zhenyu;Luo,Huaican.Department ofOrthopedics,Xiehe Hospital,Tongji Medical College,Huazhong University ofScience and Technology,Wuhan,Peop.Rep.China.Journal of Tongji MedicalUniversity(2001),21(4),304-307；(d)Calcitonin gene-related Peptide regulatesexpression of neurokininl receptors by rat spinal neurons.Seybold VS,McCarsonKE,Mermelstein PG,Groth RD,Abrahams LG.J.Neurosci.200323(5):1816-1824.epartment of Neuroscience,University of Minnesota,Minneapolis,Minnesota 55455,及Department of Pharmacology,Toxicology,and Therapeutics,University of Kansas Medical Center,Kansas City,Kansas 66160；(e)Attenuationof antigen-induced airway hyperresponsiveness in CGRP-deficient mice.Aoki-Nagase,Tomoko;Nagase,Takahide;Oh-Hashi,Yoshio;Shindo,Takayuki;Kurihara,Yukiko;Yamaguchi,Yasuhiro;Yamamoto,Hiroshi;Tomita,Tetsuji;Ohga,Eijiro;Nagai,Ryozo;Kurihara,Hiroki;Ouchi,Yasuyoshi.Department ofGeriatric Medicine,Graduate School of Medicine,University of Tokyo,Tokyo,Japan.American Journal of Physiology(2002),283(5,Pt.1),L963-L970；(f)Calcitonin gene-related peptide as inflammatory mediator.Springer,Jochen;Geppetti,Pierangelo;Fischer,Axel;Groneberg,David A.ChariteCampus-Virchow,Department of Pediatric Pneumology and Immunology,Division of Allergy Research,Humboldt-University Berlin,Berlin,Germany.Pulmonary Pharmacology&Therapeutics(2003),16(3),121-130；及(g)Pharmacological targets for the inhibition of neurogenic inflammation.Helyes,Zsuzsanna;Pinter,Erika;Nemeth,Jozsef；Szolcsanyi,Janos.Department ofPharmacology and Pharmacotherapy,Faculty of Medicine,University of Pecs,Pecs,Hung.Current Medicinal Chemistry:Anti-Inflammatory&Anti-AllergyAgents(2003),2(2),191-218。
本发明的另一方面涉及治疗癌症及增生性疾病及病症的方法。也已提出，CGRP拮抗剂显示出治疗向脑转移的恶性疾病，尤其对抗神经胶质瘤及乳癌的效用。CGRP拮抗剂尤其可用于对抗低氧性肿瘤及预防转移性植入。参见PCT申请公开WO2010006168。
本发明的另一方面涉及使用式I化合物与一种或多种用于治疗偏头痛的药物的组合的治疗方法，所述用于治疗偏头痛的药物选自COX-2抑制剂、NSAIDS、阿司匹林、醋氨酚、triptans、麦角胺及咖啡因。
“偏头痛”、“头痛”及相关术语如医学技术人员所了解。偏头痛涵盖所有种类的偏头痛，包括普通型偏头痛、典型偏头痛、群集性偏头痛、闪电状偏头痛、偏瘫性偏头痛、眼肌麻痹型偏头痛及眼型(opthomalmic)偏头痛。
“治疗有效”是指如医学技术人员所了解的存在有意义的患者益处。
“患者”是指如医学技术人员所确定的可从治疗受益的个人。
对于本领域技术人员显而易见的是，本公开不限于前述说明性实施例，以及它可在不脱离其基本属性的情况下体现在其它具体形式中。因此，希望实施例在所有方面中皆被视为具有说明性而非限制性，参考所附权利要求而非前述实施例，且因此，意欲落在具有权利要求相等性的含义及范围内的所有变化皆包括在本发明中。
Claims (7)
1.化合物(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺，或其可药用盐
2.药物组合物，其包含治疗有效量的(R)-N-(3-(7-甲基-1H-吲唑-5-基)-1-(4-(1-甲基哌啶-4-基)哌嗪-1-基)-1-氧代丙-2-基)-4-(2-氧代-1,2-二氢喹啉-3-基)哌啶-1-甲酰胺，以及可药用辅料、载体或稀释剂。
3.治疗与异常水平的CGRP或CGRP受体信号相关的病症的方法，其包括将治疗有效量的权利要求1的化合物或其可药用盐给药于患者。
4.权利要求3的方法，其中所述病症为偏头痛。
5.权利要求3的方法，其中所述病症为神经性疼痛。
6.治疗增生性疾病的方法，其包括将治疗有效量的权利要求1的化合物或其可药用盐给药于患者。
7.权利要求6的方法，其中所述增生性疾病为乳癌或神经胶质瘤。
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| CN101495480A (zh) * | 2006-05-03 | 2009-07-29 | 百时美施贵宝公司 | 作为降钙素基因相关肽受体拮抗剂的受限化合物 |
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| US7220862B2 (en) | 2002-06-05 | 2007-05-22 | Bristol-Myers Squibb Company | Calcitonin gene related peptide receptor antagonists |
| WO2005084672A1 (de) | 2004-03-03 | 2005-09-15 | Boehringer Ingelheim International Gmbh | Ausgewählte cgrp-antagonisten, verfahren zu deren herstellung sowie deren verwendung als arzneimittel |
| US7834007B2 (en) | 2005-08-25 | 2010-11-16 | Bristol-Myers Squibb Company | CGRP antagonists |
| WO2010006168A2 (en) | 2008-07-09 | 2010-01-14 | University Of Rochester | Methods of treating cancer using and agent that modulates activity of the calcitonin-gene related peptide ("cgrp") receptor |
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| CN101495480A (zh) * | 2006-05-03 | 2009-07-29 | 百时美施贵宝公司 | 作为降钙素基因相关肽受体拮抗剂的受限化合物 |
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| CN112888438A (zh) * | 2018-10-13 | 2021-06-01 | 拜尔哈文制药股份有限公司 | Cgrp拮抗剂的前药 |
| WO2024046223A1 (zh) * | 2022-08-30 | 2024-03-07 | 熙源安健医药（上海）有限公司 | 吲唑甲酰胺类衍生物及其制备方法和用途 |
| CN116003387A (zh) * | 2022-11-20 | 2023-04-25 | 药康众拓(北京)医药科技有限公司 | 一种氘代吲唑丙酰胺类化合物、药物组合物和用途 |
| CN116003387B (zh) * | 2022-11-20 | 2024-03-26 | 药康众拓(北京)医药科技有限公司 | 一种氘代吲唑丙酰胺类化合物、药物组合物和用途 |
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