CN116710469A - 线性Apelin受体激动剂 - Google Patents
线性Apelin受体激动剂 Download PDFInfo
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- CN116710469A CN116710469A CN202180081794.7A CN202180081794A CN116710469A CN 116710469 A CN116710469 A CN 116710469A CN 202180081794 A CN202180081794 A CN 202180081794A CN 116710469 A CN116710469 A CN 116710469A
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Abstract
本文的公开内容涉及式(1)的新型化合物及其盐,以及它们在治疗、预防、改善、控制或降低与Apelin受体相关的疾病的风险中的用途:其中Q、X、AA1、AA2、AA3、AA4、AA5、AA6、AA7、AA8、AA9、AA10、AA11、AA12、AA13、R1、R2和n如本文所定义。
Description
技术领域
本发明涉及一类新型肽化合物、其盐、含有其的药物组合物以及其在人体治疗中的用途。特别地,本发明涉及一类这样的化合物,其是Apelin受体的激动剂。本发明还涉及这些化合物和组合物的制备以及这些化合物和组合物在预防或治疗涉及Apelin受体的疾病中的用途。
这些化合物涉及代谢稳定的apelin类似物,涵盖G蛋白依赖性和独立药理学特征的范围,以及它们在急性和慢性给药方案下的用途,用于预防或治疗由apelin受体介导的疾病,特别是心血管疾病(心力衰竭、肾衰竭、高血压、肺动脉高压、急性和慢性肾损伤和血栓性疾病)、糖尿病、肝脏和胃肠道疾病。
背景技术
Apelin是apelin受体(也称为APJ、APLNR或血管紧张素受体样1)的内源性配体。Apelin受体是位于11号染色体上的A类GPCR,由377个氨基酸构成。迄今为止,在哺乳动物中仅鉴定出一种apelin受体,尽管两栖动物和鱼类中存在两种亚型,并且不存在密切相关的
(同源)基因。
在人类中,APLN基因存在于X染色体上,编码77个氨基酸的前体preproapelin,该前体随后被蛋白水解切割以产生若干种异构体:
apelin-36、apelin-17、apelin-13和[Pyr1]apelin-13。在异构体[Pyr1]中,apelin-13是在人心脏和血浆中检测到的主要异构体,然而apelin的血浆半衰期非常短(<5分钟),因此可能存在具有替代结构和/或药理学性质的其他短寿命异构体是可行的,并可能促进与母体肽apelin-36相关的生理效应。apelin与apelin受体的结合可导致由Gαi/o、Gα13和可能的Gαq G蛋白介导的多种细胞内信号通路的激活,导致若干种信号转导级联的募集,包括但不限于:磷脂酶C(PLC)、蛋白激酶C(PKC)、AMP活化蛋白激酶(AMPK)、内皮型一氧化氮合酶、调节ERK1/2磷酸化和PI3K/Akt/p70S6激酶信号转导。
已经鉴定出54个氨基酸的第二种肽Elabela/Toddler(ELABELA或ELA,也称为Toddler或Apela),其也激活apelin受体。ELA的主要氨基酸序列与APJ地区没有相似之处,但与APJ类似,ELA也经历快速蛋白水解切割以产生较短的异构体。这两种配体都是心血管发育和功能的关键调节因子。
内源性配体激活apelin受体也被证明会产生β-arrestin,这是一种启动受体内化、脱敏以及下游信号转导的蛋白质。β-arrestin的募集会导致明显的短持续时间反应和对配体介导的进一步激活无效的apelin受体群。在各种实施方案中,所识别的实例可以单独或与β-arrestin的募集结合和/或激活G蛋白信号转导,从而提供可用于治疗与apelin功能障碍相关疾病的独特药理学特征。
apelin和APJ在中枢神经系统(CNS)、外周组织和血液中的表达均相对广泛,这表明其在多个复杂的生理过程中发挥作用。基于多篇文献出版物,apelin系统与中枢神经系统疾病、体温调节、血糖稳态、血管生成、糖尿病、胰腺炎、心血管功能、肝功能和肾功能、癌症(包括但不限于胶质母细胞瘤和结肠癌)密切相关。
APJ受体及其配体(apelin和ELA)与人类心力衰竭的病理生理学有关。Apelin受体存在于内皮细胞、血管平滑肌细胞和心肌细胞上。初步研究确定apelin是迄今为止通过直接作用于心肌细胞收缩力而没有心脏肥大的证据的最有效的正性肌力药物之一。Apelin也被证明可以增加左心室收缩力。
已证明Apelin的表达在心血管疾病的情况下会改变。在心力衰竭早期阶段,在患者的血浆中观察到apelin免疫反应性增加,而在后期,更严重的阶段观察到降低。此外,已证明在大鼠肥大和衰竭的心脏中,apelin受体mRNA减少。Apelin基因缺陷小鼠被证明会出现与衰老和压力超负荷相关的心脏收缩力受损和进行性心力衰竭。因此,apelin系统的下调似乎与心脏功能的下降相吻合,这增加了apelin可能成为心脏功能保护剂的可能性。
在啮齿动物和人类中全身注射apelin已被证明可以通过产生一氧化氮显著降低大鼠的血压(BP)。这些数据表明,apelin在体内具有降压作用。然而,这些对血压和肌力心输出量的影响是短暂的,仅持续几分钟,并显示出一定程度的脱敏(也称为钝化作用),使apelin受体对进一步刺激无效。
在右心室衰竭的慢性模型中,apelin具有正性肌力作用,长期治疗使右心室质量改善、收缩力增加、心脏负荷和血流动力学测量降低。与这些发现一致的是,在肺动脉高压(PAH)的多种临床前模型中,apelin输注已被证明可以改善肺血管血流动力学,并且这些益处已被证实可转化(translate into)在PAH患者中。
在斑马鱼中,ELA信号转导是正常心脏和脉管系统发育所必需的,其缺乏会导致心脏发育和淋巴生成的严重缺陷。在人类中,ELA在成人胚胎干细胞和肾脏中表达,并在其抑制cAMP产生和诱导ERK1/2磷酸化和钙动员的活性方面激活人apelin受体。Elabela在功能上刺激人类HUVEC中的血管生成,并放松小鼠主动脉血管。
除了apelin的心血管作用外,已在所有肾脏区域中检测到apelin受体mRNA,最丰富的是在外髓质的内带中、在肾小球中,并且在所有肾单位段(nephron segments)中观察到适度表达,特别是在集合管中。与这种定位一致,以增加的剂量静脉内(iv)注射apelin,利尿性剂量依赖性地增加。
Apelin表达在人内皮组织中也得到了证实,其中通过apelin诱导的转录因子叉头框蛋白O1(FOXO1)的失活和随后的内皮脂肪酸结合蛋白4(FABP4)表达的抑制,在控制跨内皮层的脂肪酸转运中起到关键作用。这些作用与预测的对2型糖尿病(T2DM)等疾病的葡萄糖利用和胰岛素敏感性改善的益处一致。
Apelin受体激动剂可单独使用和/或与当前标准护理治疗联合用于治疗肺动脉高压(PAH)增加心输出量、降低肺血管高压、减少炎症、改善肺组织重塑和保留右心室功能。PAH是一种罕见的进行性疾病,其特征是肺动脉(肺动脉(pulmonary artery))无明显原因的高血压(高血压(hypertension))。PAH的症状包括尤其是在运动时呼吸短促(呼吸困难)、胸痛和昏厥发作。PAH的确切原因尚不清楚,虽然可以治疗,但目前还没有治愈这种疾病的方法。PAH在女性中的发生率是男性的两倍。它往往影响30至60岁的女性。据估计,在美国,每年每百万人中有一到两个人发生新病例。据估计,欧洲的发病率相似。在美国,每年约有500-1000例新发PAH病例被诊断出来。目前还没有已知哪个种族或族裔群体的PAH患者发病率更高。患有PAH的个体可能多年没有诊断,要么是因为他们的症状是轻微的,非特异性的,要么只在剧烈运动时出现。然而,治疗PAH很重要,因为如果不进行治疗,肺部的高血压会导致右心更加努力地工作,随着时间的推移,这种心肌可能会减弱或衰竭。这种疾病的进行性意味着个人一开始可能只出现轻微的症状,但最终将需要治疗和医疗护理来维持正常的生活方式。
Apelin受体激动剂是可用于治疗如下心血管疾病的药物:如心力衰竭、急性失代偿性心力衰竭、充血性心力衰竭、心肌病、缺血、缺血/再灌注损伤、液体稳态、肾衰竭、高血压、肺动脉高压、多囊肾病、低钠血症和SIADH,从而增加心输出量、改善心脏功能、稳定心脏功能、限制心脏功能进一步下降、降低系统性和门静脉高压、促进缺血组织中的血管生成和新血管形成、治疗血栓形成和血小板功能异常、改善肾功能和利尿。心力衰竭是一个主要且日益严重的健康负担。欧洲至少有1,500万心力衰竭患者,而在美国,心力衰竭影响着近580万人。65岁以后,心力衰竭发病率接近每1,000人10例。心力衰竭在美国每年导致28万人死亡,2010年心力衰竭的直接和间接成本估计为392亿美元。治疗方案取决于心力衰竭的类型、原因、症状和严重程度,包括治疗根本原因和改变生活方式。许多药物是针对心力衰竭的,大多数患者会服用一种以上的药物。Apelin受体激动剂可能会在现有药物的基础上使用。尽管在药物治疗方面取得了进步,但心力衰竭的死亡率仍然很高:几乎50%被诊断患有心力衰竭的人将在5年内死亡。
血小板功能异常与一系列血栓性疾病有关,如外周动脉疾病(PAD)、急性冠脉综合征(ACS)、心肌梗塞(Ml)、心脏病发作(HA)、中风和动脉粥样硬化。Apelin和APJNR在人和小鼠血小板中表达,并且Apelin敲除小鼠表现出血小板凝集增加的血栓前原表型。用apelin刺激血小板已被证明参与与钙、一氧化氮和血栓素产生相关的信号转导通路,这与这些情况下的预期益处一致。
Apelin受体激动剂也是可用于治疗和管理以下疾病的药物:糖尿病和相关代谢疾病、糖尿病并发症(例如糖尿病肾病、视网膜病变、神经病变、非酒精性脂肪肝病、非酒精性脂肪变性、门静脉高压)以及肌肉群的刺激和/或生长和/或耐力可能被认为是有益的疾病。Apelin已被证明在内皮细胞中表达,并改善葡萄糖耐量,增强肌肉对葡萄糖的利用,增加肌肉对胰岛素的敏感性,并改善局部血液供应不足的组织中的血管生成。Apelin-神经保护,其中apelin肽的施用促进神经元存活和/或神经元数量的增加,将在神经元功能丧失的情况下中有用,例如糖尿病神经病变。
apelin在血液循环中的半衰期约为一分钟,本发明旨在设计、合成和测试激活apelin/apelin受体通路的新型有效和稳定的药物。本文中的实施方案举例说明了以独立于β-arrestin激活的方式特异性激活细胞内信号转导通路的潜力,并且在没有脱敏和/或钝化作用的情况下与持续的受体激活一致。这种化合物构成了治疗由本发明所述的apelin受体介导的疾病的潜在新治疗剂。
发明内容
本发明涉及在Apelin受体上具有激动剂活性的新型化合物、包含这些新型化合物的药物组合物、以及该化合物用于制备用于治疗疾病的药物的用途。
因此,在一个实施方案中,本发明提供了一种式(1)的化合物或其互变异构体或立体化学异构形式或其前药、盐或两性离子:
其中:
Q选自苯基或单环杂芳基环,其各自可以任选地被一个或多个Rq基团取代;或Q是式-(OCH2CH2)mOCH3的聚醚链,其中m为1至5;
Rq选自卤素、羟基、氨基或C1-6烷基,所述C1-6烷基具有任选包含一个或多个选自O、N或S的杂原子的烷基链;
n为1至3;
R1和R2独立地选自氢或C1-6烷基,或与它们所连接的碳一起结合形成C3-8环烷基或杂环基;
X是-DArg-或键;
AA1是-NHCR3aR3bCO-或-N(Me)CR3aR3bCO-;其中R3a是氢或C1-3烷基;并且R3b是-CH2(CH2)pCONH2或-(CH2)p苄基,其中p是0或1;
AA2是-Arg-、-DArg-或高精氨酸残基;
AA3是选自以下的残基:
AA4是-Arg-或-DArg-;
AA5是-NHCH(CH2R4)CO-或-N(Me)CH(CH2R4)CO-;其中R4是C1-6烷基、C1-6环烷基或C1-6支链烷基;
AA6是-Aib-、-DAla-或-Ser-;
AA7是-NHCR5aR5bCO-或-N(Me)CR5aR5bCO-;其中R5a是氢或C1-3烷基,并且R5b是C1-3烷基、CH2芳基或CH2杂芳基,其任选被一个或多个卤代基团或C1-3烷基取代;
AA8是以下的残基:
AA9是-Gly-、-Ala-、-DAla-或N-甲基甘氨酸残基;
AA10是以下的残基:
AA11是-NHCHR6CO-;其中R6是任选被一个或多个卤代基团取代的C1-6烷基、苄基、-CH2萘基或-CH2联苯基;
AA12是选自以下的残基:
AA13是-NHCR7aR7bCO-或-N(Me)CR7aR7bCO-;其中R7a是氢或C1-3烷基,并且R7b是C1-10烷基、-CH2萘基、-CH2联苯基或苄基,其任选被一个或多个R8基团取代,其中R8选自卤素、-O-芳基或-O-苄基;
其中AA13的C端是羧基或甲酰胺基。
具体实施方式
本发明涉及新型化合物。本发明还涉及新型化合物作为Apelin受体激动剂的用途。本发明还涉及在制备用作Apelin受体激动剂或用于治疗与Apelin受体相关的病症的药物中的新型化合物的用途。
本发明还涉及可用于治疗与Apelin受体相关的病症的化合物、组合物和药物。这些病症包括心血管疾病、急性失代偿性心力衰竭、充血性心力衰竭、心肌梗塞、心肌病、缺血、缺血/再灌注损伤、肺动脉高压、糖尿病、肥胖症、癌症、转移性疾病、液体稳态、病理性血管生成、视网膜病变、HIV感染,治疗肺动脉高压(PAH)从而增加心输出量、降低肺血管高血压、减少炎症、改善肺组织重塑、保留右心室功能,心力衰竭、充血性心力衰竭、心肌病、缺血、缺血/再灌注损伤、液体稳态、肾衰竭、高血压、肺动脉高压、多囊肾病、低钠血症、SIADH,血小板功能与一系列血栓性疾病有关如外周动脉疾病(PAD)、急性冠脉综合征(ACS)、心肌梗塞(Ml)、心脏病发作(HA)、中风、动脉粥样硬化,糖尿病的治疗和管理以及相关联的代谢病症、糖尿病并发症(例如糖尿病肾病、视网膜病变、神经病变、非酒精性脂肪肝病、非酒精性脂肪变性、门静脉高压症)以及肌肉群的刺激和/或生长和/或耐力可能被认为有益的病症。
本发明的另一方面是治疗各种形式的中枢神经系统病症的症状的方法,所述中枢神经系统病症包括:痴呆,包括老年性痴呆和脑血管性痴呆、抑郁症、运动过度(轻微脑损伤)综合征、意识障碍、焦虑症、精神分裂症、恐惧症、癫痫、肌萎缩侧索硬化症;生长激素分泌和/或功能受损,包括但不限于过食症、多食症、高胆固醇血症、高甘油三酯血症、高脂血症、高催乳素血症、低血糖症、垂体功能减退症、垂体性侏儒症;癌症、胰腺炎、肾脏疾病、Turner综合征、类风湿性关节炎、脊髓损伤、脊髓小脑变形(spinocerebellardeformation)、骨折、创伤、特应性皮炎、骨质疏松症、哮喘、不孕症、动脉硬化、肺气肿、肺水肿、乳汁分泌不足,还可用作催眠镇静剂、术后营养状况改善剂、HIV感染、艾滋病等的预防或治疗药物等等,包括将Apelin作用多肽给予有需要的患者。
所述化合物可能对其有益的疾病或病症包括选自下组中的那些:治疗肺动脉高压(PAH)从而增加心输出量、降低肺血管高血压、减少炎症、改善肺组织重塑、保留右心室功能,心力衰竭、充血性心力衰竭、心肌病、缺血、缺血/再灌注损伤、液体稳态、肾衰竭、高血压、肺动脉高压、多囊肾病、低钠血症和SIADH,糖尿病的治疗和管理以及相关联的代谢病症、糖尿病并发症(例如糖尿病肾病、视网膜病变、神经病变、非酒精性脂肪肝病、非酒精性脂肪变性、门静脉高压症)以及肌肉群的刺激和/或生长和/或耐力的病症。
在进一步的方面,本发明提供了如上所述的化合物用于制备用于治疗上述任何适应症的药物的用途。
因此,在一个实施方案中,本发明提供了式(1)的化合物或其互变异构体或立体化学异构形式或其前药、盐或两性离子:
其中;
Q选自苯基或单环杂芳基环,其各自可以任选地被一个或多个Rq基团取代;或Q是式-(OCH2CH2)mOCH3的聚醚链,其中m为1至5;
Rq选自卤素、羟基、氨基或C1-6烷基,所述C1-6烷基具有任选包含一个或多个选自O、N或S的杂原子的烷基链;
n为1至3;
R1和R2独立地选自氢或C1-6烷基,或与它们所连接的碳一起结合形成C3-8环烷基或杂环基;
X是-DArg-或键;
AA1是-NHCR3aR3bCO-或-N(Me)CR3aR3bCO-;其中R3a是氢或C1-3烷基;并且R3b是-CH2(CH2)pCONH2或-(CH2)p苄基,其中p是0或1;
AA2是-Arg-、-DArg-或高精氨酸残基;
AA3是选自以下的残基:
AA4是-Arg-或-DArg-;
AA5是-NHCH(CH2R4)CO-或-N(Me)CH(CH2R4)CO-;其中R4是C1-6烷基、C1-6环烷基或C1-6支链烷基;
AA6是-Aib-、-DAla-或-Ser-;
AA7是-NHCR5aR5bCO-或-N(Me)CR5aR5bCO-;其中R5a是氢或C1-3烷基,并且R5b是C1-3烷基、CH2芳基或CH2杂芳基,其任选被一个或多个卤代基团或C1-3烷基取代;
AA8是以下的残基:
AA9是-Gly-、-Ala-、-DAla-或N-甲基甘氨酸残基;
AA10是以下的残基:
AA11是-NHCHR6CO-;其中R6是任选被一个或多个卤代基团取代的C1-6烷基、苄基、-CH2萘基或-CH2联苯基;
AA12是选自以下的残基:
AA13是-NHCR7aR7bCO-或-N(Me)CR7aR7bCO-;其中R7a是氢或C1-3烷基,并且R7b是C1-10烷基、-CH2萘基、-CH2联苯基或苄基,其任选被一个或多个R8基团取代,其中R8选自卤素、-O-芳基或-O-苄基;
其中所述AA13 C端是羧基或甲酰胺基。
Q可以选自:
Q可以是咪唑环。
Q可以是:
n可以是1。n可以是2。n可以是3。
R1和R2可以独立地选自氢或C1-6烷基。R1可以是氢或C1-6烷基。R2可以是氢或C1-6烷基。R1和R2均可以是甲基。R1可以是甲基。R2可以是甲基。
X可以是-DArg-。X可以是键。
AA1可以是谷氨酰胺残基、D-谷氨酰胺残基、高苯丙氨酸残基、或下式的N-甲基谷氨酰胺残基:
AA1可以是谷氨酰胺残基。
AA2可以是-Arg-。AA2可以是-DArg-。AA2可以是高精氨酸残基。
AA3可以是:
AA3可以是:
AA4可以是-Arg-。AA4可以是-DArg-。
AA5可以是是亮氨酸残基、D-亮氨酸残基、叔丁基丙氨酸残基、环丁基丙氨酸残基、或N-甲基亮氨酸残基。AA5可以是亮氨酸残基。
AA6可以是-Aib-。AA6可以是-DAIa-。AA6可以是-Ser-。
AA7可以是2-氨基异丁酸残基、组氨酸残基、4-溴苯丙氨酸残基、或者是选自以下的残基:
AA7可以是组氨酸残基。
AA9可以是-Gly-。AA9可以是-Ala-。AA9可以是-DAla-。AA9可以是N-甲基甘氨酸残基;
AA11可以是是苯丙氨酸残基、2-萘基丙氨酸残基、3-氯苯丙氨酸残基、4-溴苯丙氨酸残基、4-氯苯丙氨酸残基、正亮氨酸残基或4-苯基苯丙氨酸残基。AA11可以是4-溴苯丙氨酸残基。
AA12可以是:
AA12可以是:
AA13可以是O-苄基-D-酪氨酸残基、4-溴-D-苯丙氨酸残基、4-苯氧基-D-苯丙氨酸残基、2-萘基-D-丙氨酸残基、4-苯基-D-苯丙氨酸残基、N-甲基-4-苯基-D-苯丙氨酸残基或β-环己基-D-丙氨酸残基。AA13可以是4-苯基-D-苯丙氨酸残基。
AA13的C端可以是甲酰胺基团。AA13的C端可以是羧基。
以下部分
的特定示例包括如下所示的CAP1-7,其中COOH基团与肽X或AA1的胺偶联,其中X是键:
该化合物可以选自表1所示的实施例1至62中的任何一种。
化合物的具体实例包括具有Apelin受体激动剂活性的化合物。
本发明化合物可用于包含本发明化合物和药学上可接受的赋形剂的药物组合物中。
本发明的化合物可用于医药。
本发明的化合物可用于治疗与上面列出的Apelin受体相关的病症。
定义
在本申请中,除非另有说明,否则适用以下定义。
除非另有说明,否则术语“烷基”、“芳基”、“卤素”、“环烷基”、“杂环基”和“杂芳基”按其传统意义使用(例如IUPAC Gold Book中的定义)。
与本文所述的任何化合物(包括式(1)的化合物)的用途相关的术语“治疗”用于描述任何形式的干预,其中将化合物施用于患有所述疾病或病症、或有患所述疾病或病症的风险、或有患所述疾病或病症的潜在风险的受试者。因此,术语“治疗”包括预防性(预防)治疗和显示疾病或病症的可测量或可检测症状的治疗。
本文所用的术语“有效治疗量”(例如与治疗病症、疾病或病情的方法相关)是指有效产生所需治疗效果的化合物的量。例如,如果病症是疼痛,那么有效治疗量是足以提供所需程度的疼痛缓解的量。所需程度的疼痛缓解可以是,例如,完全消除疼痛或降低疼痛的严重程度。
就所描述的任何化合物具有手性中心而言,本发明的适用范围扩及这些化合物的所有光学异构体,无论是外消旋体形式还是拆分的对映体形式。本文描述的发明涉及任何公开的化合物的所有晶体形式、溶剂化物和水合物,无论如何制备。就本文公开的任何化合物具有酸或碱中心如羧酸盐或氨基而言,所述化合物的所有盐形式都包括在本文中。在药物用途的情况下,该盐应被视为药学上可接受的盐。
可以提及的盐或药学上可接受的盐包括酸加成盐和碱加成盐。此类盐可以通过常规方法形成,例如通过游离酸或游离碱形式的化合物与一或多当量的合适的酸或碱反应,任选在溶剂中,或在盐不溶的介质中进行反应,然后使用标准技术(例如在真空中,通过冷冻干燥或过滤)除去所述溶剂或所述介质。盐也可以通过用另一种抗衡离子交换盐形式的化合物的抗衡离子来制备,例如使用合适的离子交换树脂。
药学上可接受的盐的实例包括衍生自无机酸和有机酸的酸加成盐,以及衍生自金属(如钠、镁、钾和钙)的盐。
酸加成盐的实例包括与以下酸形成的酸加成盐:乙酸、2,2-二氯乙酸、己二酸、藻酸、芳基磺酸(例如苯磺酸、2-萘磺酸、1,5-萘二磺酸和对甲苯磺酸)、抗坏血酸(例如L抗坏血酸)、L-天冬氨酸、苯甲酸、4-乙酰氨基苯甲酸、丁酸、(+)樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环己基氨基磺酸、十二烷基硫酸、1,2-乙二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、葡萄糖酸(例如D-葡萄糖酸)、葡萄糖醛酸(例如D-葡萄糖醛酸)、谷氨酸(例如L-谷氨酸)、α-氧戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、乳酸(例如(+)-L-乳酸和(±)-DL-乳酸)、乳糖酸、马来酸、苹果酸(例如(-)-L-苹果酸)、丙二酸、(±)-DL-扁桃酸、偏磷酸、甲磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、帕莫酸、磷酸、丙酸、L-焦谷氨酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、酒石酸(例如,(+)-L-酒石酸)、硫氰酸、十一烯酸和戊酸。
还包括这些化合物及其盐的任何溶剂化物。优选的溶剂化物是通过向本发明化合物的固态结构(例如晶体结构)中掺入无毒的药学上可接受的溶剂分子(以下称为溶剂化溶剂)而形成的溶剂化物。此类溶剂的例子包括水、醇类(如乙醇、异丙醇和丁醇)和二甲亚砜。溶剂化物可以通过用含有溶剂化溶剂的溶剂或溶剂混合物重结晶本发明的化合物来制备。在任何给定的情况下是否已经形成溶剂化物可以通过使用众所周知的标准技术如热重分析(TGA)、差示扫描量热法(DSC)和X射线结晶学对化合物的晶体进行分析来确定。
溶剂化物可以是化学计量或非化学计量的溶剂化物。特定的溶剂化物可以是水合物,并且水合物的例子包括半水合物、一水合物和二水合物。关于溶剂化物和用于制备和表征它们的方法的更详细的讨论,参见Bryn等,Solid-State Chemistry of Drugs,SecondEdition,published by SSCI,Inc of West Lafayette,IN,USA,1999,ISBN 0-967-06710-3。
本发明上下文中的术语“药物组合物”是指包含活性剂且另外包含一种或以上药学上可接受的载体的组合物。根据施用方式和剂型的性质,组合物可以进一步包含选自以下的成分:例如稀释剂、佐剂、赋形剂、载体、防腐剂、填充剂、崩解剂、湿润剂、乳化剂、悬浮剂、甜味剂、调味剂、芳香剂、抗细菌剂、抗真菌剂、润滑剂和分散剂。所述组合物可以采取以下形式:例如片剂、糖衣丸、粉剂、酏剂、糖浆、包括悬浮液的液体制剂、喷雾剂、吸入剂、片剂、锭剂、乳剂、溶液剂、扁囊剂、颗粒剂、胶囊剂和栓剂,以及注射用液体制剂,包括脂质体制剂。
本发明的化合物可以包含一个或以上同位素取代,并且提及特定元素在其范围内包括该元素的所有同位素。例如,提及氢在其范围内包括1H、2H(D)和3H(T)。类似地,提及碳和氧在其范围内分别包括12C、13C和14C以及16O和18O。以类似的方式,除非上下文另有说明,否则提及特定官能团在其范围内也包括同位素变体。例如,提及烷基如乙基或烷氧基如甲氧基时,也包括基团中一个或以上氢原子为氘或氚同位素形式的变体,例如乙基中所有五个氢原子均为氘同位素形式(全氘乙基)或甲氧基中所有三个氢原子均为氘同位素形式(三氘甲氧基)。同位素可以是放射性的或非放射性的。
治疗剂量可以根据患者的要求、所治疗病情的严重程度和所用的化合物而变化。确定特定情况下的适当剂量在本领域的技术范围内。通常,治疗以小于化合物最佳剂量的较小剂量开始。此后,以小增量增加剂量,直到达到最佳效果的情况。为了方便起见,如果需要的话,总的日剂量可以在一天中分成几份施用。
当然,化合物有效剂量的大小将随着所治疗病情的严重程度以及特定化合物及其施用途径而变化。合适剂量的选择在本领域普通技术人员的能力范围内,不存在不适当的负担。通常,日剂量范围可以是人和非人动物每千克体重约10μg至约30mg,优选人和非人动物每千克体重约50μg至约30mg,例如人和非人动物每千克体重约50μg至约10mg,例如人和非人动物每千克体重约100μg至约30mg,例如人和非人动物每千克体重约100μg至约10mg,并且最优选人和非人动物每千克体重约100μg至约1mg。
药物制剂
虽然活性化合物可以单独施用,但优选以药物组合物(例如制剂)的形式存在。
因此,在本发明的另一个实施方案中,提供了一种药物组合物,其包含至少一种如上定义的式(1)化合物以及至少一种药学上可接受的赋形剂。
该组合物可以是适于用于注射的组合物。注射可以是静脉内(IV)注射或皮下注射。该组合物可以以无菌缓冲溶液形式提供,或者作为可以悬浮或溶解在注射用无菌缓冲液中的固体提供。
药学上可接受的赋形剂可选自例如载体(例如固体、液体或半固体载体)、佐剂、稀释剂(例如固体稀释剂,如填料或填充剂;和液体稀释剂,如溶剂和助溶剂)、成粒剂、粘合剂、助流剂、包衣剂、控释剂(例如延迟释放或延缓释放的聚合物或蜡状物)、结合剂、崩解剂、缓冲剂、润滑剂、防腐剂、抗真菌剂和抗细菌剂、抗氧化剂、缓冲剂、张力调节剂、增稠剂、调味剂、增甜剂、色素、增塑剂、掩味剂、稳定剂或药物组合物中常规使用的任何其他赋形剂。
本文所用术语“药学上可接受的”是指化合物、材料、组合物和/或剂型,其在合理的医学判断范围内,适合用于与受试者(例如人类受试者)的组织接触,而没有过度的毒性、刺激、过敏反应或其他问题或并发症,具有合理的效益/风险比。每种赋形剂还必须是“可接受的”,即与制剂的其他成分相容。
含有式(1)化合物的药物组合物可以根据已知技术配制,参见例如Remington'sPharmaceutical Sciences,Mack Publishing Company,Easton,PA,USA。
合适的制剂通常包含0-20%(w/w)缓冲剂、0-50%(w/w)助溶剂和/或0-99%(w/w)注射用水(WFI)(取决于剂量和是否冻干)。肌内长效制剂也可以含有0-99%(w/w)的油。
式(1)化合物通常以单位剂量形式存在,因此通常含有足够的化合物以提供所需水平的生物活性。例如,制剂可以包含1纳克至2克的活性成分,例如1纳克至2毫克的活性成分。在这些范围内,化合物的特定子范围为0.1毫克至2克活性成分(更通常为10毫克至1克,例如50毫克至500毫克),或1微克至20毫克(例如1微克至10毫克,例如0.1毫克至2毫克活性成分)。
活性化合物将以足以达到所需治疗效果的量(有效量)施用给有需要的患者(例如人或动物患者)。施用化合物的精确量可由主管医师根据标准程序确定。
实施例
现在通过参考以下实施例中描述的具体实施方案来阐释本发明,但不限于此。
实施例1至62
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已经制备了下面表1中所示的实施例1至62的化合物。它们的LCMS特性和用于制备它们的方法如表2所示。除非另有说明,否则每个实施例的原料均是可商购的。
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在适当的情况下,在表1中使用标准氨基酸符号。在无标准符号可用的情况下,将使用以下表示法:
在适当的情况下,在表1中使用标准氨基酸符号。在无标准符号可用的情况下,将使用以下表示法:
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一般程序
如果没有包括制备路线,则相关的中间体是可商购的。无需进一步纯化使用商购试剂。室温(rt)是指大约20℃至27℃。在Bruker仪器上在400MHz下记录1H NMR光谱。化学位移值以百万分率(ppm)表示,即(δ)-值。以下缩写用于NMR信号的多重性:s=单重峰,br=宽峰,d=双重峰,t=三重峰,q=四重峰,quin=五重峰,td=双三重峰,tt=三三重峰,qd=双四重峰,ddd=双双双重峰,ddt=三双双重峰,m=多重峰。耦合常数以J值列出,单位为Hz。NMR和质谱结果被校正以说明背景峰。
色谱法是指使用60至120目硅胶,并在氮气压力(快速色谱法)条件下进行的柱色谱法。
分析方法
化合物的LCMS分析是在电喷雾条件下进行的
LCMS方法A
仪器:Waters Acquity UPLC,Waters 3100PDA检测器,SQD;柱:Acquity HSS-T3,1.8微米,2.1x 100mm;梯度[时间(min)/溶剂B的A溶液(%)]:0.00/10、1.00/10、2.00/15、4.50/55、6.00/90、8.00/90、9.00/10、10.00/10;溶剂:溶剂A=0.1%的三氟乙酸水溶液;溶剂B=乙腈;进样量1L;检测波长:214nm;柱温30℃;流速:0.3mL/min。
分析方法B
使用以下LCMS方法在电喷雾条件下测定MS离子,使用以下HPLC方法测定HPLC保留时间(RT),通过HPLC测定的纯度>95%,除非另有说明。
LCMS:Agilent 1200 HPLC&6410B Triple Quad,柱:Xbridge C18 3.5μm 2.1*30mm。梯度[时间(min)/溶剂B(%)]:0.0/10、0.9/80、1.5/90、8.5/5、1.51/10。(溶剂A=1mLTFA在1000mL水中的溶液;溶剂B=1mL TFA在1000ml MeCN中的溶液);进样量5μL(可变);紫外检测:220nm、254nm、210nm;柱温25℃;1.0mL/min。
HPLC:Agilent Technologies 1200,柱:Sepax GP-C18 5μm 120A 4.6*150mm。梯度[时间(min)/溶剂B(%)]:0.0/40、20/55、20.1/90、23/90。(溶剂A=1mL TFA在1000mL水中的溶液;溶剂B=1mL TFA在1000mL 80%MeCN+20%H2O中的溶液);进样量30μL(可变);紫外检测:220nm;柱温25℃;1.0mL/min。
分析方法C
使用以下LCMS方法在电喷雾条件下测定MS离子,使用以下HPLC方法测定HPLC保留时间(RT),通过HPLC测定的纯度>95%,除非另有说明。
LCMS:Agilent 1200 HPLC&6410B Triple Quad,柱:Xbridge C18 3.5μm 2.1*30mm。梯度[时间(min)/溶剂B(%)]:0.0/10、0.9/80、1.5/90、8.5/5、1.51/10。(溶剂A=1mLTFA在1000mL水中的溶液;溶剂B=1mL TFA在1000mL MeCN中的溶液);进样量5μL(可变);紫外检测:220nm、254nm、210nm;柱温25℃;1.0mL/min。
HPLC:Agilent Technologies 1200,柱:Gemini-NX C18 5μm110A 150*4.6mm。梯度[时间(min)/溶剂B(%)]:0.0/30、20/60、20.1/90、23/90。(溶剂A=1mL TFA在1000mL水中的溶液;溶剂B=1mL TFA在1000mL MeCN中的溶液);进样量5μL(可变);紫外检测:220nm、254nm;柱温25℃;1.0mL/min。
分析方法D
仪器:Thermo Scientific Orbitrap Fusion;柱:Phenomenex Kinetex Biphenyl2.6μm,2.1x50mm;梯度[时间(min)/溶剂B在A中的溶液(%)]:0.001/10、0.30/10、0.40/60、1.10/90、1.70/90、1.75/10、1.99/10、2.00/10;溶剂:溶剂A=0.1%甲酸的水溶液;溶剂B=0.1%甲酸的乙腈溶液;进样量5μL;柱温25℃;流速0.8mL/min。
中间体和化合物的合成
提供以下实施例是为了说明本发明的优选方面,而不是为了限制本发明的范围。
中间体的合成
除中间体1至7外,所有Fmoc氨基酸均可商购,中间体的合成概述如下
3-((4-氟苄基)氨基)-2,2-二甲基-3-氧代丙酸(中间体1)的合成
步骤1:合成2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(2):在室温下向2,2-二甲基-1,3二噁烷-4,6-二酮(1,20.0g,138.8mmol)在ACN(200mL)中的溶液中加入K2CO3(96g,694.0mmol)和MeI(26mL,416.6mmol),并将反应混合物回流10小时。完成后,将反应混合物冷却至室温,通过celite垫过滤,用EtOAc(3x 50mL)洗涤。有机层用10%Na2S2O3水溶液(100mL)洗涤,干燥(Na2SO4),并真空浓缩,得到呈黄色固体的2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(2,21g,88%)。将粗残留物用于下一步骤,而不进行进一步纯化。
1H-NMR(400MHz;CDCl3):δ1.63(s,6H),1.73(s,6H)。
步骤2:合成3-((4-氟苄基)氨基)-2,2-二甲基-3-氧代丙酸(中间体1):在75℃下加热2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(2,99g,57.0mmol)在甲苯(60mL)中的搅拌溶液。将反应混合物在相同温度下搅拌10分钟,并在10分钟内滴加Et3N(34.6mL,240mmol)和(4-氟苯基)甲胺(1,6g,48.0mmol)在甲苯(60mL)中的溶液。将反应混合物进一步在相同温度搅拌16小时。完成后,将反应混合物真空浓缩。将残留物在二乙醚(70mL)中研制,并滗掉乙醚。将所得材料真空干燥,得到呈黄色固体的3-((4-氟苄基)氨基)-2,2-二甲基-3-氧代丙酸(中间体1,1.58g,14%)。
LCMS(方法A):m/z 240.13[M+H]+(ES+),在4.77分钟时,98.85%。
1H-NMR(400MHz;DMSO-d6):δ1.31(s,6H),4.25(d,J=5.8Hz,2H),7.07-7.15(m,2H),7.20-7.30(m,2H),8.23(br s,1H),12.49(br s,1H)。
2,2-二甲基-3-氧代-3-(苯乙氨基)丙酸(中间体2)的合成
步骤1:合成2,2-二甲基-3-氧代-3-(苯乙氨基)丙酸(中间体2):将2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(1,5.1g,29.7mmol)在甲苯(30mL)中的搅拌溶液在75℃下加热。将反应混合物在相同温度下搅拌10分钟,并在10分钟内滴加Et3N(16.4mL,123.7mmol)和2-苯基乙-1-胺(2,3.1g,24.7mmol)在甲苯(50mL)中的溶液。将所得混合物在相同的温度下进一步搅拌3小时。消耗原料后,将反应混合物真空浓缩,得到粗产物。用二乙醚(80mL)研制粗材料,并滗掉乙醚。将所得材料在真空下干燥,得到呈白色固体的2,2-二甲基-3-氧代-3-(苯乙氨基)丙酸(中间体2,3.2g,55%)。
LCMS(方法A):m/z 236.18[M+H]+(ES+),在5.01分钟时,99.61%。
1H-NMR(400MHz;DMSO-d6):δ1.24(s,6H),2.70(t,J=7.6Hz,2H),3.24(t,J=7.6Hz,2H),7.17-7.20(m,3H),7.26-7.29(m,2H),7.72(br s,1H),12.48(br s,1H)。
2,2-二甲基-3-氧代-3-((2-(吡啶-2-基)乙基)氨基)丙酸(中间体3)的合成
步骤1:合成2,2-二甲基-3-氧代-3-((2-(吡啶-2-基)乙基)氨基)丙酸(中间体3):在75℃下,加热2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(1,3.3g,19.6mmol)在甲苯(30mL)中的搅拌溶液。反应混合物在相同温度下搅拌10分钟,并在10分钟内滴加Et3N(11.4mL,81.9mmol)和2-(吡啶-2-基)乙-1-胺(2,2g,16.4mmol)在甲苯(50mL)中的溶液。反应混合物在同一温度下进一步搅拌3小时。消耗原料后,将反应混合物真空浓缩,得到粗物质,用二乙醚(50mL)研制,并滗掉乙醚。将所得物质真空干燥,得到呈白色固体的2,2-二甲基-3-氧代-3-((2-(吡啶-2-基)乙基)氨基)丙酸(中间体3,1.9g,50%)。
LCMS(方法A):m/z 237.23[M+H]+(ES+),在4.07分钟时,97.85%。
1H-NMR(400MHz;DMSO-d6):δ1.22(s,6H),2.80-2.90(m,2H),3.33-3.43(m,2H),7.18-7.22(m,2H),7.61-7.71(m,1H),7.79(br s,1H),8.45(d,J=4.4Hz,1H),12.00(br s,1H)。
2,2-二甲基-3-氧代-3-((3-(1-三苯甲基-1H-咪唑-4-基)丙基)氨基)丙酸(中间体4)的合成
步骤1:合成1-三苯甲基-1H-咪唑-4-甲醛(2):向1H-咪唑-4-甲醛(1,10.0g,104mmol)在DCM(100mL)中的溶液中加入Et3N(28.9mL,110mmol)。将反应混合物在0℃下搅拌10分钟,并在相同温度下加入三苯基氯甲烷(34.7g,124.0mmol)。将所得混合物进一步搅拌16小时。完成后,加入水,并用DCM(3x 100mL)萃取水层。将合并的有机层用盐水洗涤,用Na2SO4干燥并真空浓缩以得到粗材料。将所得材料用己烷(200mL)研制,并滗掉己烷。将所得材料在真空下干燥,得到呈灰白色固体的1-三苯甲基-1H-咪唑-4-甲醛(2,11.2g,32%)。
1H NMR(400MHz;DMSO-d6):δ7.06-7.18(m,6H),7.37-7.50(m,9H),7.65(s,1H),7.79(s,1H),9.72(s,10H)。
步骤2:合成(1-三苯甲基-1H-咪唑-4-基)甲胺(3):将1-三苯甲基-1H-咪唑-4-甲醛(2,4.0g,11.8mmol)溶于EtOH(100mL)中,并转移到parr装置中,然后加入雷尼镍(1.5g),接着加入乙醇氨(100mL)。将所得混合物在H2气氛(72Psi)下于45℃搅拌10小时。消耗原料后,通过celite垫过滤反应混合物,用MeOH洗涤并真空浓缩,得到(1-三苯甲基-1H-咪唑-4-基)甲胺(3,4.1g,99%)。粗产物用于下一步反应,无需纯化。
MS(ESI+ve):341.24
1H NMR(400MHz;DMSO-d6):δ3.40-3.50(m,2H),4.08(br s,2H),6.71(s,1H),7.00-7.11(m,6H),7.24(s,1H),7.30-745(m,9H)。
步骤3:合成2,2-二甲基-3-氧代-3-(((1-三苯甲基-1H-咪唑-4-基)甲基)氨基)丙酸(中间体4):在75℃下,加热2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(4,3.1g,18.1mmol)在甲苯(30mL)中的搅拌溶液。将反应混合物在相同温度下搅拌10分钟,并在10分钟内滴加Et3N(8.4mL,60.4mmol)和(1-三苯甲基-1H-咪唑-4-基)甲胺(3,4.1g,12.1mmol)在甲苯(50mL)中的溶液。将反应混合物进一步在相同温度下继续反应3小时。完成后,将反应混合物真空浓缩。将残留物溶于氯仿(80mL)中,用10%的柠檬酸水溶液(pH~6至6.5)洗涤。有机层用Na2SO4干燥并真空浓缩。在二乙醚/正己烷(35mL)中研制获得的残留物,并将悬浮液在室温下搅拌16小时。过滤固体,用甲醇(30mL)洗涤,真空干燥,得到呈白色固体的2,2-二甲基-3-氧代-3-((3-(1-三苯甲基-1H-咪唑-4-基)丙基)氨基)丙酸(中间体4,1.7g,43%)。
LCMS(方法A):m/z 454.26[M+H]+(ES+),在4.73分钟时,99.42%。
1H-NMR(400MHz;DMSO-d6):δ1.20(s,6H),4.11(d,J=4.8Hz,2H),6.68(s,1H),6.98-7.10(m,6H),7.25(s,1H),7.30-7.50(m,2H),8.00(br s,1H),12.33(br s,1H)
2,2-二甲基-3-氧代-3-((2-(1-三苯甲基-1H-咪唑-4-基)乙基)氨基)丙酸(中间体5)的合成
步骤1:合成2,2,2-三氟-N-(2-(1-三苯甲基-1H-咪唑-4-基)乙基)乙酰胺(2):在室温下,向2-(1H-咪唑4-基)乙基-1-胺二盐酸盐(1,25.0g,136.6mmol)的MeOH(100mL)溶液中加入Et3N(67mL,464.4mmol),将反应混合物冷却至0℃。将三氟乙酸乙酯(20mL,164.0mmol)的MeOH(50mL)溶液在0℃下经30分钟添加到反应混合物中,并将反应混合物在室温下搅拌4小时。用干燥的DCM(200mL)和Et3N(60mL,409.8mmol)稀释该反应混合物,并将该反应混合物冷却至0℃。逐份加入Tr-Cl(76g,273.2mmol),将所得反应混合物在室温下搅拌16小时。完成后,用水(300mL)骤冷反应混合物,并用氯仿(3x 150mL)萃取水层。将有机层合并、干燥(Na2SO4)并在真空中浓缩。用正己烷研制粗残留物,得到呈白色固体的2,2,2-三氟-N-(2-(1-三苯甲基-1H-咪唑-4-基)乙基)乙酰胺(2,50.10g,81%)。
MS(ESI+ve):450
1H-NMR(400MHz;CDCl3):δ2.75(t,J=5.9Hz,2H),3.60-3.65(m,2H),6.61(s,1H),7.08-7.15(m,6H),7.31-7.38(m,9H),7.40(s,1H),8.41(br s,1H)。
步骤2:合成2-(1-三苯甲基-1H-咪唑-4-基)乙-1-胺(3):在0℃下向2,2,2-三氟-N-(2-(1-三苯甲基-1H-咪唑-4-基)乙基)乙酰胺(2,50.0g,111.3mmol)在THF(150mL)和MeOH(180mL)中的溶液中缓慢加入NaOH(22.0g,556.7mmol)的水(100mL)溶液,并在室温下搅拌反应混合物2小时。完成后,用水(300mL)骤冷反应混合物,并用氯仿(3x 150mL)萃取水层。合并有机层,干燥(Na2SO4)并真空浓缩,得到呈黄色粘性固体的2-(1-三苯甲基-1H-咪唑-4-基)乙-1-胺(3,34.0g,86%)。将粗残留物用于下一步骤,而不进行进一步纯化。
MS(ESI+ve):354
1H-NMR(400MHz;CDCl3):δ1.53(bs,2H),2.65(t,J=6.5Hz,2H),2.95(t,J=6.5Hz,2H),6.58(s,1H),7.11-7.16(m,6H),7.28-7.38(m,10H)。
步骤4:合成2,2-二甲基-3-氧代-3-((2-(1-三苯甲基-1H-咪唑-4-基)乙基)氨基)丙酸(中间体5):在75℃下,在60分钟内将2-(1-三苯甲基-1H-咪唑-4-基)乙-1-胺(3,8.0g,22.6mmol)和Et3N(16.0mL,113.0mmol)在甲苯(100mL)中的溶液逐滴加入2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(5,5.8g,29.76mmol)的甲苯(50mL)溶液中。将反应混合物在相同温度下进一步搅拌3小时。完成后,将反应混合物真空浓缩。将残留物溶于氯仿(100mL)中,用10%柠檬酸水溶液(pH~6至6.5)洗涤。将有机层干燥(Na2SO4)并真空浓缩。用热氯仿(150mL)和正己烷(75mL)研制得到的粗残留物,并将悬浮液在室温下搅拌16小时。过滤固体,用氯仿:正己烷(1:1,2x 50mL)洗涤,并真空干燥,得到呈白色固体的2,2-二甲基-3-氧代-3-((2-(1-三苯甲基-1H-咪唑-4-基)乙基)氨基)丙酸(中间体5,6.8g,64%)。
LCMS(方法A):m/z 468[M+H]+(ES+),在5.38分钟时,99.31%
1H-NMR(400MHz;DMSO-d6):δ1.21(s,6H),2.57(t,J=6.8Hz,2H),3.22-3.27(m,2H),6.66(s,1H),7.06-7.11(m,6H),7.28(s,1H),7.35-7.42(m,8H),7.64(t,J=5.4Hz,1H),8.31(s,1H),12.44(br s,1H)。
2,2-二甲基-3-氧代-3-((3-(1-三苯甲基-1H-咪唑-4-基)丙基)氨基)丙酸(中间体6)的合成
步骤1:合成3-(1H-咪唑-4-基)丙酸甲酯·HCl(2):在0℃下,向3-(1H-咪唑4-基)丙酸(2,5g,38.7mmol)在MeOH(80mL)中的混合物中加入SOCl2(7.7mL,107.1mmol)。在室温下使得反应混合物反应后,将反应进一步回流下加热5小时。完成后,真空浓缩反应混合物,并用二乙醚(200mL)研制反应混合物,得到呈白色固体的3-(1H-咪唑-4-基)丙酸甲酯·HCl(2,7g,97%)。
MS(ESI+ve):155.14。
步骤2:合成3-(1-三苯甲基-1H-咪唑-4-基)丙酸甲酯(3):向3-(1H-咪唑-4-基)丙酸甲酯·HCl盐(2,7g,44.02mmol)在DCM(80mL)中的溶液中加入Et3N(19mL,132mmol)。在0℃下搅拌10分钟后,在相同温度下加入三苯基氯甲烷(18.3g,66mmol),并将反应进一步搅拌2小时。完成后,加入水,并用DCM(3x 100mL)萃取水层。将合并的有机层用盐水洗涤,用Na2SO4干燥并真空浓缩。用己烷(200mL)研制粗材料,并且滗掉己烷。将所得材料在真空下干燥,得到呈白色固体的3-(1-三苯甲基-1H-咪唑-4-基)丙酸甲酯(3,15g,88%)。
MS(ESI+ve):397
1H NMR(400MHz;DMSO-d6):δ2.51-2.73(m,4H),3.52(s,3H),6.60(s,1H),7.00-7.11(m,6H),7.17-745(m,10H)。
步骤3:合成3-(1-三苯甲基-1H-咪唑-4-基)丙-1-醇(4):在0℃下向3-(1-三苯甲基-1H-咪唑4-基)丙酸甲酯(3,15g,37.8mmol)的THF(300mL)溶液中缓慢加入LAH(2.5M的THF溶液,60mL,151.2mmol)。在0℃下搅拌10分钟后,使反应在室温下保温2小时。完成后,用饱和NH4Cl溶液(60mL)猝灭反应,并通过celite垫过滤固体悬浮液,并用乙酸乙酯(200mL)洗涤。将滤液真空浓缩,得到呈白色固体的3-(1-三苯甲基-1H-咪唑-4-基)丙-1-醇(4,10.2g,73%)。粗产物在没有纯化的情况下用于下一步反应。
MS(ESI-ve):367
1H NMR(400MHz;DMSO-d6):δ1.60-1.70(m,2H),2.40-2.53(m,2H),3.30-3.42(m,2H),4.40(bs,1H),6.57(s,1H),7.00-7.11(m,6H),7.24(s,1H),7.30-745(m,9H)。
步骤4:合成3-(1-三苯甲基-1H-咪唑-4-基)甲磺酸丙酯(5):向3-(1-三苯甲基-1H-咪唑-4-基)丙-1-醇(4,10g,27.1mmol)在DCM(60mL)中的溶液中加入Et3N(5.9mL,29.8mmol)。在0℃下搅拌10分钟后,加入甲磺酰氯(3.08mL,47mmol),并在相同温度下进一步搅拌反应1小时。消耗原料后,加入水并用DCM(3x 100mL)萃取。将合并的有机层用盐水洗涤,用Na2SO4干燥并真空浓缩,得到呈粘性液体的3-(1-三苯甲基-1H-咪唑-4-基)甲磺酸丙酯(5,14g粗品)。粗产物在没有纯化的情况下用于下一步反应。
步骤5:合成2-(3-(1-三苯甲基-1H-咪唑-4-基)丙基)异吲哚啉-1,3-二酮(7):向3-(1-三苯甲基-1H-咪唑-4-基)甲磺酸丙酯(5,14g,28mmol)在DMF(50mL)中的溶液中加入NaI(1.2g,8.4mmol)和酞酰亚胺钾(potassium pthalimide)(6,7.3g,39.2mmol)。将所得混合物在室温下搅拌16小时。消耗原料后,加入水并过滤固体。将滤液真空干燥,得到呈白色固体的2-(3-(1-三苯甲基-1H-咪唑-4-基)丙基)异吲哚啉-1,3-二酮(7,7.5g,51%)。粗产物在没有纯化的情况下用于下一步反应。
MS(ESI+-ve):498.31
1H NMR(400MHz;DMSO-d6):δ1.80-1.90(m,2H),2.80-3.00(m,4H),6.40(s,1H),7.00-7.11(m,3H),7.12 -7.47(m,16H),7.82(s,1H)。
步骤6:合成3-(1-三苯甲基-1H-咪唑-4-基)丙-1-胺(8):向2-(3-(1-三苯甲基-1H-咪唑-4-基)丙基)异吲哚啉-1,3-二酮(7,7.5g,15.1mmol)在EtOH:THF(2:1,75mL)中的溶液中滴加一水合肼(9.4mL),然后在75℃下加热反应4小时。完成后,过滤反应混合物并真空浓缩滤液。残留物通过快速柱色谱法纯化[正相,硅胶(100-200目),梯度2%,MeOH在DCM(饱和NH4OH)中的溶液,得到呈白色固体的3-(1-三苯甲基-1H-咪唑-4-基)丙-1-胺(8,3g,54%)。
1H NMR(400MHz;DMSO-d6):δ1.50-1.60(m,2H),2.20-2.30(m,2H),2.48-2.67(m,2H),4.08(bs,2H),6.56(s,1H),7.00-7.12(m,6H),7.22(s,1H),7.32 -7.45(m,9H)。
步骤7:合成2,2-二甲基-3-氧代-3-((3-(1-三苯甲基-1H-咪唑-4-基)丙基)氨基)丙酸(中间体6):在75℃下,将2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮[1](9,2.1g,12.2mmol)在甲苯(30mL)中的搅拌溶液加热。将反应混合物在相同温度下搅拌10分钟,并在75℃下在10分钟内加入Et3N(5.8mL,40.8mmol)和3-(1-三苯甲基-1H-咪唑-4-基)丙-1-胺(8,3g,8.1mmol)在甲苯(50mL)中的溶液。将反应混合物在相同温度下进一步搅拌3小时。完成后,将反应混合物真空浓缩。将残留物溶于氯仿(100mL)中,并用10%的柠檬酸水溶液(pH~6至6.5)洗涤。有机层用Na2SO4干燥并真空浓缩。用二乙醚(50mL)洗涤粗材料,并滗掉乙醚。将所得材料真空干燥,得到呈白色固体的2,2-二甲基-3-氧代-3-((3-(1-三苯甲基-1H-咪唑-4-基)丙基)氨基)丙酸(中间体6,1.7g,43%)。
LCMS(方法A):m/z 482.09[M+H]+(ES+),在4.98分钟时,97.99%。
1H-NMR(400MHz;DMSO-d6):δ1.24(s,6H),2.70(t,J=7.6Hz,2H),3.24(t,J=7.6Hz,2H),7.17-7.24(m,3H),7.23-7.33(m,2H),7.72(br s,1H)。
19,19-二甲基-18-氧代-2,5,8,11,14-五氧杂-17-氮杂二十烷-20-酸(中间体7)的合成
合成19,19-二甲基-18-氧代-2,5,8,11,14-五氧杂-17-氮杂二十烷-20-酸(中间体7):在75℃下,加热2,2,5,5-四甲基-1,3-二噁烷-4,6-二酮(1,986mg,5.73mmol)在甲苯(30mL)中的搅拌溶液。将反应混合物在相同温度下搅拌10分钟,并在10分钟内滴加Et3N(3.0mL,23.4mmol)和2,5,8,11,14-五氧杂十六烷-16-胺(2,1.2g,4.71mmol)在甲苯(30mL)中的溶液。将反应混合物进一步在相同温度搅拌18小时。完成后,将反应混合物真空浓缩。残留物用二乙醚(50mL)研制,并滗掉乙醚。将所得材料真空干燥,得到呈黄色粘稠液体的19,19-二甲基-18-氧代-2,5,8,11,14-五氧杂-17-氮杂二十烷-20-酸(中间体7,1.9g,90%)。
LCMS(方法A):m/z 383.2[M+H]+(ES+),在3.85分钟时,99.3%。
1H-NMR(400MHz;DMSO-d6):δ1.04(t,J=7.1Hz,1H),1.25(s,6H),2.70-2.85(m,2H),3.15-3.23(m,2H),3.23(s,1H),3.32-3.45(m,6H),3.46-3.55(m,7H),7.80(br s,1H),12.00(br s,1H)。
实施例1至62的合成
使用标准Fmoc固相肽合成(SPPS)来合成线性肽,然后将其从树脂上切割并纯化。
肽合成的一般方法:
肽是使用标准的Fmoc化学合成的。
方法a–通过实例39的合成举例说明
1)向装有CTC树脂的容器中加入DCM(sub:0.35mmol/g,5mmol,14.29g)并溶胀2小时。
2)沥干并用DMF洗涤树脂(5次,每次洗涤之间沥干)。
3)加入20%哌啶的DMF溶液,用N2鼓泡搅拌30分钟。
4)沥干并用DMF洗涤(5次,每次洗涤之间沥干)。
5)加入Fmoc氨基酸溶液(DMF溶液,2.0当量)并混合30秒,然后加入活化缓冲液(HBTU(1.9当量)和DIEA(4当量)的DMF溶液),用N2鼓泡搅拌1小时。
6)通过茚三酮试验监控偶联反应
7)如果需要,在出现低效偶联时,对相同的氨基酸偶联重复步骤4至5
8)对下一个氨基酸偶联重复步骤2至6。
注:对于下表中的氨基酸,使用了不同的当量和偶联剂
来自C端的氨基酸 | 材料 | 偶联试剂 |
14 | 中间体5(1.5当量) | HOAT(1.5当量)和DIC(1.5当量) |
9)将树脂用MeOH洗涤三次,并在真空中干燥。
肽切割和纯化:
1)在室温下,将切割缓冲液(92.5%TFA/2.5%EDT/2.5%TIS/2.5%H2O)加入烧瓶中,所述烧瓶含有在树脂上保护侧链的肽,并搅拌3小时。
2)用冷的叔丁基甲基醚沉淀肽,并离心(在3000rpm下离心3分钟)。
3)过滤反应混合物,收集滤液并在真空中还原。
4)残留物用叔丁基甲基醚洗涤(2次)。
5)将粗肽在真空中干燥2小时。
6)通过制备型HPLC(A:0.5% ACOH的H2O溶液,B:MeCN)纯化粗肽。制备型HPLC的条件:Gilson 281。溶剂:A-0.075%TFA的H2O溶液,B-乙腈,柱:Luna C18(200×25mm;10μm)和Gemini C18(150*30mm;5μm)串联。梯度[时间(min)/溶剂B(%)]:0.0/25、60.0/55、60.1/90、70/90、70.1/10。然后通过制备型HPLC(A:0.5%ACOH的H2O溶液,B:MeCN)进行再纯化,制备型HPLC的条件:仪器:Gilson 281。溶剂:A-0.5% AcOH在H2O中的溶液,B-乙腈,柱:LunaC18(200×25mm;10μm)和Gemini C18(150*30mm;5μm)串联。梯度[时间(min)/溶剂B(%)]:0.0/25、60.0/55、60.1/90、70/90、70.1/10,得到实施例39(2.94g,产率28.04%)。
表2-实施例1至23代表的纯化肽的HRMS和LCMS特性
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ND–未测定
生物活性
提供以下实施例以说明本发明的优选方面,而非限制本发明的范围。
实施例A.Apelin肽的体外药理学表征-人Apelin受体的功能激动作用,cAMP积累测定:
cAMP功能测定。使用均相时间分辨荧光(HTRF)cAMP动态-2测定法(Cisbio,France)对cAMP的产量进行定量。将稳定表达人Apelin受体的CHO细胞以12,500个细胞/孔的密度接种在实心壁96孔半区板(Costar)中。在37℃孵育16小时后,移除培养基,将细胞在37℃下在含有500μM IBMX(Tocris)、3μM forskolin的无血清培养基中孵育30分钟,以提高cAMP水平并增加试验激动剂的浓度。在PheraStar荧光平板阅读器(BMG LabTech)上读取平板之前,按照制造商的说明测定cAMP的产量,并使用Graphpad Prism测定EC50值。
实施例B.Apelin肽的体外药理学表征-人Apelin受体的功能激动作用,β-arrestin累积测定:
β-arrestin测定。将经工程改造以过表达人Apelin受体和β-arrestin(DiscoverRx)的CHO-K1细胞以12,500个细胞/孔的密度接种在实心壁96孔半区板(Costar)中。在37℃下孵育16小时后,移除培养基,并将细胞在37℃下在含有不断增加的测试激动剂浓度的无血清培养基中孵育90分钟。通过加入检测试剂(DiscoveRx)并在黑暗中孵育60分钟来终止测定反应。然后在PheraStar荧光平板阅读器(BMG LabTech)上测量受体激活水平,并使用Graphpad Prism测定EC50值。仅报告活性化合物的Emax值。
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Claims (24)
1.一种包括式(1)的序列的化合物或其互变异构体或立体化学异构形式或其前药、盐或两性离子:
其中:
Q选自苯基或单环杂芳基环,其各自可以任选地被一个或多个Rq基团取代;或Q是式-(OCH2CH2)mOCH3的聚醚链,其中m为1至5;
Rq选自卤素、羟基、氨基或C1-6烷基,所述C1-6烷基具有任选包含一个或多个选自O、N或S的杂原子的烷基链;
n为1至3;
R1和R2独立地选自氢或C1-6烷基,或与它们所连接的碳一起结合形成C3-8环烷基或杂环基;
X是-DArg-或键;
AA1是-NHCR3aR3bCO-或-N(Me)CR3aR3bCO-;其中R3a是氢或C1-3烷基;并且R3b是-CH2(CH2)pCONH2或-(CH2)p苄基,其中p是0或1;
AA2是-Arg-、-DArg-或高精氨酸残基;
AA3是选自以下的残基:
AA4是-Arg-或-DArg-;
AA5是-NHCH(CH2R4)CO-或-N(Me)CH(CH2R4)CO-;其中R4是C1-6烷基、C1-6环烷基或C1-6支链烷基;
AA6是-Aib-、-DAla-或-Ser-;
AA7是-NHCR5aR5bCO-或-N(Me)CR5aR5bCO-;其中R5a是氢或C1-3烷基,并且R5b是C1-3烷基、CH2芳基或CH2杂芳基,其任选被一个或多个卤代基团或C1-3烷基取代;
AA8是以下的残基:
AA9是-Gly-、-Ala-、-DAla-或N-甲基甘氨酸残基;
AA10是以下的残基:
AA11是-NHCHR6CO-;其中R6是C1-6烷基、苄基、-CH2萘基或-CH2联苯基,其任选被一个或多个卤代基团取代;
AA12是选自以下的残基:
AA13是-NHCR7aR7bCO-或-N(Me)CR7aR7bCO-;其中R7a是氢或C1-3烷基,并且R7b是C1-10烷基、-CH2萘基、-CH2联苯基或苄基,其任选被一个或多个R8基团取代,其中R8选自卤素、-O-芳基或-O-苄基;
其中所述AA13的C端是羧基或甲酰胺基。
2.根据权利要求1所述的化合物,其中Q选自:
3.根据权利要求2所述的化合物,其中Q是:
4.根据权利要求3所述的化合物,其中n是2。
5.根据权利要求1至4中任一项所述的化合物,其中R1和R2独立地选自氢或C1-6烷基。
6.根据权利要求5所述的化合物,其中R1和R2都是甲基。
7.根据权利要求1至6中任一项所述的化合物,其中X是-DArg-。
8.根据权利要求1至6中任一项所述的化合物,其中X是键。
9.根据权利要求1至8中任一项所述的化合物,其中AA1是谷氨酰胺残基、D-谷氨酰胺残基、高苯丙氨酸残基或者下式的N-甲基谷氨酰胺残基:
10.根据权利要求9所述的化合物,其中AA1是谷氨酰胺残基。
11.根据权利要求1至10中任一项所述的化合物,其中AA5是亮氨酸残基、D-亮氨酸残基、叔丁基丙氨酸残基、环丁基丙氨酸残基或N-甲基亮氨酸残基。
12.根据权利要求11所述的化合物,其中AA5是亮氨酸残基。
13.根据权利要求1至12中任一项所述的化合物,其中AA7是2-氨基异丁酸残基、组氨酸残基、4-溴苯丙氨酸残基或者是选自以下的残基:
14.根据权利要求13所述的化合物,其中AA7是组氨酸残基。
15.根据权利要求1至14中任一项所述的化合物,其中AA11是苯丙氨酸残基、2-萘基丙氨酸残基、3-氯苯丙氨酸残基、4-溴苯基丙氨酸残基、4-氯苯基丙氨酸残基、正亮氨酸残基或4-苯基苯丙氨酸残基。
16.根据权利要求15所述的化合物,其中AA11是4-溴苯丙氨酸残基。
17.根据权利要求1至16中任一项所述的化合物,其中AA13是O-苄基-D-酪氨酸残基、4-溴-D-苯丙氨酸残基、4-苯氧基-D-苯丙氨酸残基、2-萘基-D-丙氨酸残基、4-苯基-D-苯丙氨酸残基、N-甲基-4-苯基-D-苯丙氨酸残基或β-环己基-D-丙氨酸残基。
18.根据权利要求17所述的化合物,其中AA13是4-苯基-D-苯丙氨酸残基。
19.根据权利要求1至18中任一项所述的化合物,其中AA13的C端是羧基。
20.根据权利要求1所述的化合物,所述化合物选自:
21.根据权利要求1至20中任一项所述的化合物,其具有apelin受体激动剂活性。
22.一种药物组合物,其包含如权利要求1至21中任一项所定义的化合物和药学上可接受的赋形剂。
23.根据权利要求1至22中任一项所述的化合物在医药中的用途。
24.根据权利要求1至23中任一项所述的化合物或组合物用于治疗以下疾病的用途:心血管疾病、急性失代偿性心力衰竭、充血性心力衰竭、心肌梗塞、心肌病、缺血、缺血/再灌注损伤、肺动脉高压、糖尿病、肥胖症、癌症、转移性疾病、液体稳态、病理性血管生成、视网膜病变、HIV感染,治疗肺动脉高压(PAH)从而增加心输出量、降低肺血管高血压、减少炎症、改善肺组织重塑、保留右心室功能,心力衰竭、充血性心力衰竭、心肌病、缺血、缺血/再灌注损伤、液体稳态、肾衰竭、高血压、肺动脉高压、多囊肾病、低钠血症、SIADH、血小板功能与一系列血栓性疾病有关如外周动脉疾病(PAD)、急性冠脉综合征(ACS)、心肌梗塞(Ml)、心脏病发作(HA)、中风、动脉粥样硬化,糖尿病的治疗和管理以及相关联的代谢病症、糖尿病并发症(例如糖尿病肾病、视网膜病变、神经病变、非酒精性脂肪肝疾病、非酒精性脂肪变性、门静脉高压症)以及肌肉群的刺激和/或生长和/或耐力可能被认为有益的病症。
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