CN101039671A - 非肽类缓激肽拮抗剂及其药物组合物 - Google Patents
非肽类缓激肽拮抗剂及其药物组合物 Download PDFInfo
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Abstract
本发明涉及具有作为缓激肽(BK)B2受体选择性拮抗剂活性的非肽类化合物。这些化合物的化学特征在于存在环状基团α取代的氨基酸和四烷基铵基团。
Description
技术领域
本发明涉及具有季铵基团的对缓激肽(BK)B2受体具有特异性拮抗活性的非肽类化合物、包含这些化合物的药物组合物以及这些化合物在治疗涉及缓激肽B2受体活化的所有病症中的用途。
背景技术
缓激肽(BK)属于激肽并且与赖氨酰缓激肽和T-激肽一起形成激肽的亚类，其存在于哺乳动物中。激肽作为疼痛和炎症的介质在中枢和外周神经系统中起着重要作用。具体地讲，缓激肽是由机体在病理生理条件下产生的非肽(H-Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9-OH)。
存在两种类型的激肽受体：B1和B2。B1受体的主要特征在于其比组成型更易诱导。其在炎症或压力条件下在组织中表达。另一方面，B2是通常存在于所有组织中的组成型受体并且在炎性过程中用作介质。缓激肽和赖氨酰缓激肽通过称为激肽原酶的蛋白水解酶自其蛋白前体(称为激肽原)中释放。其中，通过激肽释放酶发挥主要作用，但是一旦通过前体释放，其作用只能发挥很短的时间，因为它们很快会被一系列循环酶和通常被定义为激肽酶的膜所破坏。这些激肽酶之一在C末端精氨酸处裂解缓激肽，从而形成用作B1受体激动剂的des-Arg-BK。
缓激肽B1和B2受体的活化诱导血管肌舒张(伴有随后的低血压)，增加血管渗透性，使肠道和呼吸道平滑肌收缩，刺激感受伤害的神经元，改变离子的上皮分泌，产生硝基化物并且通过来自不同细胞类型的白细胞和类花生酸释放细胞因子。因此，BK受体的拮抗剂化合物可以被认为是可能作用于多种障碍的一类新药。所述拮抗剂的可能的治疗应用为炎性、过敏性和自身免疫性障碍，例如哮喘和慢性支气管炎(也包括由刺激物诱导的)、过敏性鼻炎、血管舒缩性鼻炎和病毒性鼻炎、阻塞性肺部疾病(COPD)、类风湿性关节炎、肠部慢性炎性疾病(克隆病和溃疡性结肠炎)、肾小球肾炎、银屑病、疹、急性和慢性膀胱炎、具有纤维化特征的退行性疾病(例如肝硬化、肾小球病和肺纤维化)、动脉硬化；由于它们的镇痛活性，所以可以治疗急性和慢性疼痛，例如烧伤、头痛、昆虫咬伤、癌症患者的慢性疼痛；治疗心血管装置障碍(例如脓毒症、过敏性和创伤后休克)和肝肾综合征引起的肝硬化；其可以用作抗癌药和抗血管生成药；用于治疗低血压和脱发。
缓激肽B2受体的不同的肽类和非肽类拮抗剂在文献中是已知的。WO03103671公开了许多种对缓激肽B2受体具有拮抗活性的化合物。本发明化合物尽管包含于WO03103671的通式中，但在所述文献中没有描述或叙述其特征。
发明内容
本发明涉及对B2受体具有高亲和力和拮抗活性的非肽类化合物，其具有通式(I)及其与可药用酸的盐：
其中：
R为氢或甲基；
W为单键或氧原子；
n＝3、4；
X为氢或-NR1R2氨基基团，其中R1和R2可以独立地为氢或选自以下的基团：甲基、乙基、正丙基、异丙基；
Y为-NR3R4R5季铵基团，其中R3、R4和R5可以独立地选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基。
优选的是，化合物(I)与无机或有机酸成盐，该酸选自盐酸、氢溴酸、氢碘酸、硫酸、磷酸、乙酸、三氟乙酸、丙酸、草酸、苹果酸、马来酸、琥珀酸、丙二酸、天冬氨酸、谷氨酸。另外，由于手性中心的存在，本发明也包括两种对映异构体或它们的任何比例的混合物，包括外消旋混合物。
通式(I)化合物对B2受体的体内和体外拮抗活性高于在WO03103671中描述的结构上相似的类似物。
优选如下定义的通式(I)化合物，其中：
n＝3；
X＝氢或-NH2基团；
Y＝-N(CH3)3 +季铵基团；
其它取代基如上定义。
特别优选如下定义的化合物(I)，其中：
R为氢或甲基；
W为氧原子；
n＝3；
X为氢或基团-NH2；
Y为-N(CH3)3 +季铵基团。
可以根据众所周知的合成路线制备本发明的目标化合物。
优选的是，如上定义的通式(I)化合物通过在适当的缩合剂存在下将通式(II)的中间体(按照WO03103671中公开的方法获得的)
(II)
与式(10)化合物或其衍生物(其中羧基是适当地活化的)缩合来制备。
合成方法在流程图1中说明
流程图1
式(2)化合物如J.Med.Chem.2001，44，1674-1689中描述的通过将相应的甲苯衍生物溴化来制备，该甲苯衍生物如J.Fluorine Chemistry，2000.101：85-89中描述的依次获得。
第一步涉及亚磺酰氨键(4)的形成，其通过将中间体(2)和(3)缩合获得。该反应在室温下，优选为在乙腈/水(2∶1)中，在碳酸氢钠(NaHCO3)存在下进行。该反应通过在苄基位点上与氯和溴交换来进行：产生的产物混合物直接应用于随后的步骤。卤素衍生物混合物与二取代的羟基喹啉(5)的反应是在碳酸钾(K2CO3)和碘化钾(KI)的存在下，在丙酮中回流进行的，得到酯衍生物(6)。
式(5)化合物(即2，4-二甲基-8-羟基喹啉)，其中R4＝R5＝CH3，按照WO9640639中公开的方法制备。
式(6)的甲酯在碱性条件下水解生成羧酸(7)，该羧酸与式Boc-哌嗪(8)缩合，得到中间体(9)。该缩合反应根据已知的肽合成方法进行，应用羟基苯并三唑以活化羧基，应用缩合剂例如1-乙基-3-(3’-二甲基丙基)-碳二亚胺以及一定量的叔胺，即二异丙基乙基胺(其为缩合剂的三倍当量)。化合物(II)通过中间体(9)中的Boc基团的裂解获得，其通过在二烷中的盐酸溶液(4N)以及分离游离的胺而非盐酸盐代替来进行。
衍生物(11)是通过将中间体(10)与氨基酸(11)缩合(根据从(7)到(9)的制备方法)而获得。任何存在的Boc基团可以用在二烷中的盐酸溶液(4N)自中间体(11)中除去，从而获得最终的化合物。当三烷基铵基团不存在于任何可商购的中间体中时，其可以应用已知的方法自相应的胺开始合成(Rapoport等人，J.Org.Chem，1977，42：139-141；Chen等人，J.Biochem.，1978，56：150-152)。
本发明化合物用于治疗其中缓激肽受体的活化被阻断或减少的所有障碍。它们特别适合治疗炎性、过敏性和自身免疫性障碍，例如哮喘和慢性支气管炎、过敏性、血管舒缩性和病毒性鼻炎、慢性阻塞性肺部疾病(COPD)、类风湿性关节炎、肠部慢性炎性疾病(克隆病和溃疡性结肠炎)、肾小球肾炎、银屑病、疹、急性和慢性膀胱炎、肝硬化、肾小球病和肺纤维化、动脉硬化、急性和慢性疼痛、脓毒症、过敏性和创伤后休克、肝肾综合征引起的肝硬化、低血压、脱发或其可以用作抗癌药和抗血管生成药。
为治疗需要，将本发明化合物适当与可药用载体/赋形剂一起配制。优选的是适合口服施用的药物形式，例如片剂、胶囊剂、颗粒剂、散剂、溶液剂、混悬剂、糖浆剂等。这些药物制剂可以通过常规的方法制备，应用本领域中已知的成分，例如配体、崩解剂、润滑剂、填充剂、稳定剂、稀释剂、染色剂、矫味剂、润湿剂以及其它本领域中已知的赋形剂。口服制剂也包括缓释形式，例如肠衣片剂或颗粒剂。固体口服组合物可以用常规的混合、填充或压制方法制备。液体口服制剂可以为例如水混悬剂或油混悬剂或溶液剂、乳剂、糖浆剂的形式，或可以以干燥产物存在，该干燥产物在使用前用水或其它的适合的溶媒复制。
剂量可以取决于患者的年龄和通常的条件、疾病或障碍的性质和严重程度以及施用的途径和类型。通常，在口服适用于成年患者的情况下，本发明化合物将通常以每日总剂量为1-1000mg的范围施用，优选为5-300mg，该施用以单剂量或分剂量进行。
具体实施方式
以下实施例更详细地说明本发明。
实施例1
(4-(S)-氨基-5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]四氢吡喃-4-羰基}哌嗪-1-基)-5-氧代-戊基)三甲基-氯化铵，二盐酸盐
(通式I化合物，其中R＝CH3、W＝-O-、X＝NH2、n＝3、Y＝N(CH3)3 +Cl-)。
该化合物按照流程图2中说明的合成路线进行合成
实施例1
流程图2
通用方法：分析HPLC：流速：1mL/分钟；流动相：A-0.1％三氟乙酸的水溶液，B-0.1％三氟乙酸的乙腈溶液；柱：Zorbax Eclipse XDBC8，5微米，150×4.6mm。
中间体(2)2，4-二氯-3-溴甲基-苯磺酰氯
在室温、磁力搅拌下，历经2小时，在10mL氯磺酸中滴加4.8mL2，6-二氯甲苯。加入完成后，将混合物在40℃加热2小时，从而获得紫色溶液，将该溶液冷却并且小心倾倒至冰水(0.5L)中，剧烈搅拌。将分离的白色固体过滤，研碎，用水洗涤，经KOH干燥并且通过用正己烷洗涤而纯化，在剧烈搅拌下加入200mL溶剂。将混合物过滤，除去固体并且将溶剂蒸干以获得2，4-二氯-3-甲基-苯磺酰氯，其为结晶的白色固体。产率：85％。
HPLC纯度：86％(30％B，3％/分钟，保留时间＝19.7分钟)。
1H-NMR(CDCl3)：δ(ppm)2.6(s，3H)，7.5(d，1H)，7.95(d，1H)；
ESI(+)MS：m/z 260[M+H]+。
将该中间体在以下条件下溴化：将20mmol 2，4-二氯-3-甲基-苯磺酰氯溶于乙腈中。在室温、搅拌下，加入2当量的NBS直至NBS完全溶解。最后，加入0.1当量偶氮-二异丁腈(AIBN)并且将混合物在70℃加热约6小时。将溶液蒸发，残留物用乙酸乙酯溶解，用H2O和5％NaHCO3洗涤，经干燥的Na2SO4干燥并且过滤。将有机相蒸发从而获得粘稠状、浅色液体，该液体溶于石油醚中。将残留物过滤，溶液产生(2’)，为浅色结晶固体。
HPLC纯度：95％(50％B至5％/分钟，保留时间＝18.72)。
1H-NMR(CDCl3)：δ(ppm)4.85(s，2H)，7.58(d，1H)，8.08(d，1H)；
ESI(+)MS：m/z 338.1[M+H]+。
中间体(3’)4-氨基-四氢吡喃-4-甲酸甲酯盐酸盐
将4-氨基-四氢吡喃-4-甲酸盐酸盐(0.025mol)混悬于13mL CH3OH中，冷却至-60℃并且在搅拌下滴加SOCl2(3当量)。加入完成后，将混合物温至室温，然后逐渐加热至沸腾以获得澄清溶液(约2小时)，将该溶液冷却，过滤残留物并且在真空下浓缩。
产率80％。纯度(NMR)：85％。
1H-NMR(DMSO-d6)：δ(ppm)1.91-2.04(m，4H)，3.78(s，3H)，3.60-3.85(m，4H)，9.00(s，3H)。ESI(+)MS：m/z 160.1[M+H]+。
中间体(4’)4-(3-溴甲基-2，4-二氯-苯磺酰基氨基)-四氢吡喃-4-甲酸甲酯
将中间体(3’)(1.1当量)与4当量的K2CO3一起溶于水中。在该溶液中加入1当量(10mmol)中间体(2)的乙腈溶液并且在室温下搅拌直至形成沉淀(4小时)。将溶剂蒸发除去并且将残留物溶解于乙酸乙酯和0.1M HCl(1/1)中。将有机相分离并且经Na2SO4干燥。将溶剂蒸发除去，产生的固体用环己烷洗涤，从而获得白色固体，其中氯/溴衍生物以10/1的比例存在。产率：60％。
HPLC纯度：88％(20％B，3％/分钟；保留时间＝14.11(Br)和14.47(Cl))。
1H-NMR(CDCl3)：δ(ppm)1.81-1.99(2H，m)，2.07-2.25(2H，m)，3.49-3.71(7H，m)，4.81(1.5H，s，[Br])，4.94(0.3H，s，[Cl])，5.30(1H，brs)，7.47-7.53(1H，m)，[7.49(d，J 8.5Hz，X＝Br)，7.51(d，J 8.5Hz，X＝Cl)]，7.91-7.98(1H，m)，[7.94(d，J 8.5Hz，X＝Br)，7.96(d，J 8.5Hz，X＝Cl)]。
中间体(6’)4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]四氢吡喃-4-甲酸甲酯
在氮气、室温下，将喹啉(5’)(0.48mmol)和LiOH(2.5当量)在甲基乙基酮(MEK)中混合。混合物在搅拌和氮气下保持90分钟。将中间体(4)溶于MEK/干燥的DMF(2/1)(42mL，12mL/mmol)中，在搅拌下，将含有喹啉的溶液滴加至反应混合物中。保持搅拌16小时。将反应混合物在真空下浓缩并且将残留物溶于乙酸乙酯(50mL，100mL/mmol)中。有机相用pH＝4.2的缓冲溶液洗涤(3×50mL)，经Na2SO4干燥，过滤并在真空下浓缩以获得黄色油状物。产率：33％。HPLC纯度：77％(20％B，3％/分钟；保留时间＝9.54)。
1H-NMR(DMSO-d6)：δ(ppm)1.80-1.95(m，4H)，2.56(s，3H)，2.64(s，3H)，3.32-3.40(m，2H)，3.42-3.55(m，2H)，3.60(s，3H)，5.57(s，2H)，7.30(s，1H)，7.39(d，1H)，7.50(dd，1H)，7.67(d，1H)，7.78(d，1H)，8.02(d，1H)，8.77(bs，1H)；ESI(+)MS：m/z 553.1[M+H]+。
中间体(7’)4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]四氢吡喃-4-甲酸
将式(6’)中间体溶于THF中并且在该溶液中加入10当量1M LiOH的水溶液。在40℃下，将混合物搅拌4小时，然后蒸发除去溶剂。将残留物溶于水中并且加入0.1M HCl至pH＝4。将水相用二氯甲烷萃取并且有机相经Na2SO4干燥。将溶剂蒸发除去以获得黄色固体残留物。产率：90％。HPLC纯度：99％(20％B，3％/分钟；保留时间＝7.72)。
1H-NMR(DMSO-d6)：δ(ppm)1.75-1.90(m，4H)，2.56(s，3H)，2.64(s，3H)，3.10-3.35(m，2H)，3.38-3.50(m，2H)，5.58(s，2H)，7.30(s，1H)，7.37(d，1H)，7.46(t，1H)，7.67(d，1H)，7.75(d，1H)，8.03(d，1H)，8.64(bs，1H)。ESI(+)MS：m/z 539.1[M+H]+。
中间体(9’)4-叔丁氧基羰基-((4-(2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)苯磺酰基氨基)-四氢吡喃-4-羰基)-哌嗪-1-基)
在氮气下，在100mL圆底烧瓶中，将(7’)(1.3mmol)和HOBt(1.1当量)混悬于50mL干燥的DMF中。将混合物冷却至+4℃并且在搅拌下加入EDCI.HCl(1.1当量)。在+4℃下连续搅拌1小时，然后在搅拌下加入DIPEA(2当量)和Boc-哌嗪(1当量)并且将混合物温至室温，12小时后将溶剂蒸发除去，将残留物溶于40mL DCM中并且有机相用盐水(20mL)洗涤并经Na2SO4干燥。将溶剂蒸发除去以获得油状物，该油状物在Varian Mega Bond(快速主系统)70g柱(乙酸乙酯，Rf＝0.50)上纯化，从而获得黄色固体。
产率：96％。HPLC纯度：98％(20％B，3％B/分钟，保留时间＝11.14)。
1H-NMR(CDCl3)：δ(ppm)1.45(s，9H)；1.55-1.80(m，2H)，2.05-2.20(m，4H)，2.56(s，3H)，2.64(s，3H)，3.38-3.90(m，10H)，5.58(s，2H)，7.10(s，1H)，7.30(s，1H)，7.37(d，1H)，7.46(t，1H)，7.67(d，1H)，7.75(d，1H)，8.03(d，1H)，8.64(bs，1H)。ESI(+)MS：m/z 707.2[M+H]+。
中间体(1’)(4-(2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基)-四氢吡喃-4-羰基)-哌嗪-1-基
在0.62mmol(9’)中加入10mL HCl/二烷4M并且将混合物搅拌3小时。将溶剂蒸发除去并且将残留物冷冻干燥，以获得盐酸盐(1’)，为黄色固体。产率：98％。HPLC纯度：92％(20％B，3％/分钟；保留时间＝5.34)。
1H-NMR(D2O)：δ(ppm)1.55-2.10(m，7H)，2.90-3.10(m，9H)，3.20-3.55(m，9H)，6.0(s，2H)，7.60-8.10(m，8H)，8.95(d，1H)。
ESI(+)MS：m/z 609.1[M+H]+。
中间体(10’)(4-叔丁氧基羰基氨基-4-羧基-丁基)-三甲基铵
将10mmol Boc-Orn-OH混悬于甲醇(20mL)中并且在混悬液中加入44mmol异脲。将烧瓶密封并且在室温下搅拌2天。产生的溶液用TLC(洗脱液：CHCl3/CH3OH/NH4OH 40/54/6；Boc-Orn-OH Rf＝0.29；(10’)Rf：0.11，用KMnO4检测)监控。
将甲醇在真空下蒸发除去并且将残留物在150mL水中溶解并且过滤。用水(2×50mL)洗涤圆底烧瓶和固体并且将所有洗涤水溶液合并，然后在真空下浓缩(40mL)。将残留固体(4.068g)混悬于水(40mL)中，过滤(以除去任何痕量脲)，并且通过FCC在反相LiChroprepRP-18(40-63微米)上纯化。柱(19×7cm)用3％CH3CN的水溶液洗脱并且通过TLC分析级分(约100mL)。将含有纯产物的级分(500mL)合并，在真空下浓缩以除去CH3CN，冷冻干燥，最后自150mL无水乙醇中蒸发，以得到442mg白色、极易吸湿的固体。产率：16％。
1H-NMR(DMSO-d6)：δ(ppm)1.38(s，9H)1.58-1.75(m，4H)，3.03(s，9H)，3.29(m，2H)，3.45(m，1H)，6.49(d，d，1H)；ESI(+)MS：m/z 275.2[M+H]+。
中间体(11’)(4-(S)-叔丁氧基羰基氨基-5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)苯磺酰基氨基]四氢吡喃-4-羰基}哌嗪-1-基)-5-氧代-戊基)三甲基-氯化铵
将中间体(10’)1.2mmol溶于DMF中并且在该溶液中加入二环己基碳二亚胺(1.2当量)和HOBt(1.2当量)。将混合物搅拌30分钟，然后加入二异丙基氨基甲基聚苯乙烯(1.5当量)和中间体(1’)(1当量)。将混合物搅拌24小时。过滤树脂，将溶剂蒸发除去并且将残留物溶于水和乙酸乙酯中。将水相分离并且冷冻干燥。将粗产物通过制备HPLC(柱Vydac 218TP，C18，250×50mm，流速60mL/分钟，10％至70％CH3CN/0.1％TFA梯度洗脱120分钟，240nm UV检测，收集55至75分钟)纯化，从而得到中间体(11’)，将其冷冻干燥为白色固体。产率：46％。HPLC纯度：98％(20％B，3％/分钟；保留时间＝7.68)。
1H NMR(DMSO-d6)δ：1.4(s，9H)，1.8-1.45(m，6H)，1.95-1.85(m，2H)，2.81(m，6H)，3.08(s，9H)，3.70-3.18(m，7H)，4.01-3.56(5H，m)，4.57-4.45(m，1H)，5.59(s，2H)，7.25(d，1H)，7.90-7.43(m，4H)，8.02(d，1H)，8.85(s，1H)。ESI(+)MS：m/z 863.2[M+H]+。
(4-(S)-氨基-5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]四氢吡喃-4-羰基}哌嗪-1-基)-5-氧代-戊基)三甲基-氯化铵，二盐酸盐
在0.45mmol(11’)中加入10mL HCl/二烷4M。将混合物搅拌6小时，将溶剂蒸发除去并且将残留物冷冻干燥，从而获得最终的化合物，为白色固体。产率：87％。HPLC纯度：98％(20％B，3％/分钟；保留时间＝5.14)。
1H NMR(DMSO-d6)δ：1.95-1.60(m，8H)，2.81(m，6H)，3.08(s，9H)，3.70-3.18(m，12H)，4.57-4,45(m，1H)，5.59(s，2H)，7.90-7.60(m，4H)，8.02(d，1H)，8.5(s，3H)，8.85(s，1H)。
ESI(+)MS：m/z 763.1[M+H]+。
实施例2
(4-(S)-氨基-5-(4-(4-(2，4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基)四氢吡喃-4-羰基)-哌嗪-1-基-)5-氧代-戊基)-三甲基氯化铵，盐酸盐
1H NMR(DMSO-d6)δ：8.90(1H，s)，8.47-8.34(4H，m)，8.02(1H，d)，7.81(1H，d)，7.73-7.37(4H，m)，5.62(2H，s)，4.57-4.45(1H，m)，4.01-3.56(5H，m)，3.43-3.18(7H，m)，3.06(9H，s)，2.78-2.61(4H，m)，2.89(1H，s)，1.97-1.60(9H，m)。HPLC：保留时间＝9.26分钟。MS：[M]+749。
实施例3
[5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]四氢吡喃-4-羰基}哌嗪-1-基)-5-氧代-戊基]-三甲基三氟乙酸铵。
1H-NMR(DMSO-d6)：δ(ppm)1.53(s，2H，m)；1.69(m，4H)；1.90(m，2H)；2.45(t，2H)；2.78(m，6H)；3.04(9H，s)；3.23-3.57(7H，m)；5.68(2H，s)；7.38-8.18(5H，m)；8.04(1H，d，J＝8.42Hz)；8.82(1H，s)。HPLC：保留时间＝5.65分钟。MS：[M]+748。
实施例4
[4-(S)-氨基-5-(4-{1-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]环戊烷羰基}哌嗪-1-基)-5-氧代-戊基]-三甲基-氯化铵，二盐酸盐。
1H NMR(DMSO-d6)δ：8.90(1H，s)，8.48(3H，s)，8.02(1H，d)，7.95-7.63(3H，m)，5.59(2H，s)，4.57-4.45(1H，m)，3.97-3.24(10H，m)，3.08(9H，s)，2.95-2.61(5H，m)，1.97-1.72(8H，m)，1.42(4H，s)；HPLC：保留时间＝5.88分钟。MS：[M]+747.2。
生物活性
本发明化合物的B2受体亲和力的评价是通过研究与在CHO细胞中表达的人B2受体的结合进行的，其按照在Bellucci等人，Br.J.Pharmacol.2003，140：500-506中描述的方法进行；结合值用pKi表示。
拮抗活性(以pA2表示)被评价为在用B2人受体转染的CHO细胞中对缓激肽诱导的肌醇的产生的抑制，其根据在Bellucci等人，Br.J.Pharmacol.2003，140：500-506中描述的方法进行。
本发明化合物的体内活性被评价为在抑制豚鼠的BK诱导的支气管痉挛中的效力(Tramontana等人，J.Pharmacol.Exp.Therap.，296：1051-1057，2001)，测量it(it＝气管内施用)(以nmol/kg为单位)剂量，该剂量抑制80％支气管狭窄至少210分钟。
| 实施例 | W | R | X | Y | n | pKi | pA2 | it剂量 |
| WO03103671实施例55 | 键 | H | NH2 | NHC(＝NH)NH2 | 3 | 8.7 | 8.4 | 300 |
| WO03103671实施例63 | 键 | CH3 | NH2 | NH2 | 4 | 9.1 | 8.9 | 300 |
| WO03103671实施例57 | 键 | H | NH2 | N(CH3)2 | 4 | 8.8 | 8.3 | 300 |
| WO03103671实施例59 | 键 | CH3 | NH2 | N(CH3)2 | 4 | 8.8 | 9.0 | 300 |
| WO03103671实施例44 | 键 | CH3 | NH2 | NHC(＝NEt)NHEt | 3 | 10.1 | 9.0 | 300 |
| WO03103671实施例88 | 键 | CH3 | N(CH3)3 | N(CH3)3 | 4 | 9.7 | 8.2 | - |
| 实施例1 | O | CH3 | NH2 | N(CH3)3 | 3 | 10.3 | 10.3 | 30 |
| 实施例2 | O | H | NH2 | N(CH3)3 | 3 | 10.2 | 9.7 | 100 |
| 实施例3 | O | CH3 | H | N(CH3)3 | 3 | 10.1 | 9.5 | 100 |
| 实施例4 | 键 | CH3 | NH2 | N(CH3)3 | 3 | 10.1 | 9.4 | 100 |
将优选的本发明化合物与在WO03103671中公开的结构上非常相似的化合物进行比较。可以令人惊奇地发现本发明化合物的体内和体外活性高于在WO03103671中描述的结构上相关的类似物。用人受体转染的细胞的拮抗活性试验和体内试验均为人类治疗应用的预期剂量提供了高度预测。
缩略语
it＝气管内施用；iv＝静脉内施用；eq＝当量；DCM＝二氯甲烷；MeOH＝甲醇；THF＝四氢呋喃；DMSO＝二甲亚砜；DMF＝二甲基甲酰胺；AcOEt＝乙酸乙酯；AcOH＝乙酸；TFA三氟乙酸；NBS＝Nα-溴琥珀酰亚胺；bpo＝苯甲酰基过氧化物；Boc＝叔丁氧基羰基；HOBt＝1-羟基-苯并三唑；EDC＝1-乙基-3-(3’-二甲基丙基)碳二亚胺；DIPEA＝二异丙基乙基胺；HPLC＝高压液相色谱；TLC＝薄层色谱；NMR＝核磁共振；ESI＝电喷雾电离；MS＝质谱；FCC＝快速柱色谱；Rt＝保留时间。
Claims (10)
1.通式(I)化合物及其可药用盐、对映异构体和对映异构体混合物。
其中：
R为氢或甲基；
W为单键或氧原子；
n＝3、4；
X为氢或-NR1R2氨基基团，其中R1和R2可以独立地为氢或选自以下的基团：甲基、乙基、正丙基、异丙基；
Y为-NR3R4R5季铵基团，其中R3、R4和R5可以独立地选自甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基。
2.通式(I)化合物与无机或有机酸的盐，其中该酸选自盐酸、氢溴酸、氢碘酸、硫酸、磷酸、乙酸、三氟乙酸、丙酸、草酸、苹果酸、马来酸、琥珀酸、丙二酸、天冬氨酸、谷氨酸。
3.权利要求1或2中所述的化合物，其中：
W为单键；
n＝3；
X选自氢或-NH2基团；
Y为-N(CH3)3 +季铵基团；
其它的取代基如权利要求1中定义。
4.权利要求1或2中所述的化合物，其中：
R选自氢或甲基；
W为氧原子；
n＝3；
X选自氢或-NH2基团；
Y为-N(CH3)3 +季铵基团；
其它的取代基如权利要求1中定义。
5.权利要求3中所述的以下化合物：
[4-(S)-氨基-5-(4-{1-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)苯磺酰基氨基]-环戊烷羰基}哌嗪-1-基)-5-氧代-戊基]三甲基-氯化铵，二盐酸盐。
6.权利要求4中所述的以下化合物：
(4-(S)-氨基-5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)苯磺酰基氨基]四氢吡喃-4-羰基}-哌嗪-1-基)-5-氧代-戊基)三甲基-氯化铵，二盐酸盐；
(4-(S)-氨基-5-(4-(4-(2，4-二氯-3-(2-甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基)-四氢吡喃-4-羰基)-哌嗪-1-基-)5-氧代-戊基)-三甲基-氯化铵，盐酸盐；
[5-(4-{4-[2，4-二氯-3-(2，4-二甲基-喹啉-8-基氧基甲基)-苯磺酰基氨基]四氢吡喃-4-羰基}哌嗪-1-基)-5-氧代-戊基]三甲基-三氟乙酸铵。
7.药物组合物，该药物组合物包含作为活性剂的权利要求1-6中所述的化合物以及可药用赋形剂。
8.权利要求1-6中所述的化合物在制备用于治疗涉及缓激肽B2受体活化的所有病症的药物组合物中的用途。
9.权利要求8中所述的化合物在制备用于治疗炎性、过敏性和自身免疫性病症的药物组合物中的用途。
10.权利要求8中所述的化合物在制备用于治疗下列疾病的药物组合物中的用途：哮喘和慢性支气管炎、过敏性、血管舒缩性和病毒性鼻炎、慢性阻塞性肺部疾病(COPD)、类风湿性关节炎、肠部慢性炎性疾病(克隆病和溃疡性结肠炎)、肾小球肾炎、银屑病、疹、急性和慢性膀胱炎、肝硬化、肾小球病和肺纤维化、动脉硬化、急性和慢性疼痛、脓毒症、过敏性和创伤后休克、肝硬化引起的肝肾综合征、低血压、脱发、癌症和抗血管生成性疾病。
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| CN102088975B (zh) * | 2008-07-11 | 2013-08-21 | 意大利卢索药品研究有限公司 | 基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 |
| CN113906018A (zh) * | 2019-05-23 | 2022-01-07 | 法瓦里斯有限责任公司 | 用于治疗皮肤病的缓激肽（bk）b2受体拮抗剂的1-((s)-1-(3-氯-5-氟-2-((4-(1h-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-咪唑啶-2,4-二酮衍生物及其相关化合物 |
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| JP5406722B2 (ja) * | 2006-10-16 | 2014-02-05 | グリュネンタール・ゲゼルシャフト・ミト・ベシュレンクテル・ハフツング | ブラジキニン１受容体モジュレータとしての置換されたスルホンアミド誘導体 |
| TWI407960B (zh) | 2007-03-23 | 2013-09-11 | Jerini Ag | 小分子緩激肽ｂ２受體調節劑 |
| ITMI20072225A1 (it) * | 2007-11-23 | 2009-05-24 | Luso Farmaco Inst | "composizioni farmaceutiche a base di antagonisti della bradichinina ed acido ialuronico e loro uso" |
| WO2015155323A1 (en) * | 2014-04-10 | 2015-10-15 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Br2 antagonist for use in the prevention of the hypotensive effect of patient treated with angiotensin-converting enzyme inhibitors (acei) |
| US11340237B2 (en) * | 2016-09-16 | 2022-05-24 | Takeda Pharmaceutical Company Limited | Metabolite biomarkers for diseases associated with the contact activation system |
| SI3713928T1 (sl) | 2017-11-24 | 2022-09-30 | Pharvaris Netherlands B.V. | Novi antagonisti receptorja bradikinina B2 |
| AR118983A1 (es) | 2019-05-23 | 2021-11-17 | Pharvaris Gmbh | Antagonistas cíclicos del receptor b2 de bradiquinina |
| WO2023180575A1 (en) | 2022-03-25 | 2023-09-28 | Pharvaris Gmbh | Solid composition comprising solubilised bradykinin b2-receptor antagonists |
| TW202345810A (zh) | 2022-03-25 | 2023-12-01 | 瑞士商帕法瑞斯有限責任公司 | 包含緩激肽ｂ２受體拮抗劑之固態延長釋放組成物 |
| WO2023180577A1 (en) | 2022-03-25 | 2023-09-28 | Pharvaris Gmbh | Therapeutic uses of bradykinin b2-receptor antagonists |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102088975B (zh) * | 2008-07-11 | 2013-08-21 | 意大利卢索药品研究有限公司 | 基于激肽b2受体拮抗剂和皮质类固醇的药物组合物及其用途 |
| CN113906018A (zh) * | 2019-05-23 | 2022-01-07 | 法瓦里斯有限责任公司 | 用于治疗皮肤病的缓激肽（bk）b2受体拮抗剂的1-((s)-1-(3-氯-5-氟-2-((4-(1h-吡唑-1-基)-2-甲基喹啉-8-基氧基)甲基)苯基)乙基)-咪唑啶-2,4-二酮衍生物及其相关化合物 |
| CN113906018B (zh) * | 2019-05-23 | 2024-04-12 | 法瓦里斯有限责任公司 | 缓激肽b2受体拮抗剂 |
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