CN111132688B - 环孢菌素类似物及其用途 - Google Patents
环孢菌素类似物及其用途 Download PDFInfo
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- CN111132688B CN111132688B CN201880061440.4A CN201880061440A CN111132688B CN 111132688 B CN111132688 B CN 111132688B CN 201880061440 A CN201880061440 A CN 201880061440A CN 111132688 B CN111132688 B CN 111132688B
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Abstract
一种用于治疗或预防急性或慢性炎性紊乱的化合物,其中所述化合物是式1的化合物或其盐:其中n是2‑5,并且R1和R2独立地选自H或C1‑C4烷基,其中R1和R2可以连接在一起形成C3‑C5杂烷基环。
Description
发明领域
本发明涉及用于治疗或预防疾病或紊乱的环孢菌素类似物。特别地,但不排他地,本发明涉及式1的环孢菌素类似物在治疗或预防急性或慢性炎性紊乱中的用途,所述急性或慢性炎性紊乱包括急性肾损伤、慢性或急性胰腺炎和缺血再灌注损伤。
急性炎症被公认为涉及多种细胞(中性粒细胞、巨噬细胞)和细胞外因子(补体、组胺)的复杂相互作用,这些因子响应PAMP(病原体活化的分子模式)信号和DAMP(损伤活化的分子模式)信号起作用以解决最初的损害。亲环蛋白A已经被证明作为趋化因子起作用以促进白细胞迁移而支持炎性应答,并且亲环蛋白A的阻断在急性炎症的动物模型中被示出是有益的。最近描述了伴随细胞死亡和组织坏死的严重的炎症形式。现在大量的证据支持线粒体膜处的一个孔,称为线粒体通透性转换孔(MPTP)的开放对于这种坏死性炎症的发生和维持至关重要。这种MPTP开放的关键调节因子是亲环蛋白D(CypD),并且CypD抑制剂在预防坏死性炎症相关的组织损害方面已经示出了良好的活性。MPTP的开放和随后坏死性细胞死亡的开始是由升高的细胞内钙水平触发的,该升高的细胞内钙水平由多种因素引起,包括氧化应激、缺氧、胆盐毒素等。值得注意的是,发现CypD的遗传消融或药理学抑制对于由于心脏组织的缺血再灌注损伤引起的组织降解具有保护作用,这表明抑制CypD更普遍地是缺血再灌注损伤的可行的药物靶点。
肾缺血由动脉闭塞、休克和肾移植引起,并且可以导致肾细胞死亡和肾衰竭。与缺血相关的组织损害的另外的来源发生在器官移植过程期间。在取出供体器官后,由于血流损失,组织不可避免地经历氧气匮乏(oxygenstarvation),并且对缺血组织的损害跟随到流动重新开始时。能够防止再灌注过程期间的组织损伤的化合物将提高被移植的器官的存活力。待用作组织保护剂的化合物的优选特征谱将包括有效抑制CypD,阻止缺血性应激后MPTP的开放,以及足够的溶解度,这样的溶解度使其以足以保护组织的高浓度被添加至器官运输期间通常使用的保存溶液中。
在使用亲环蛋白D敲除小鼠以及亲环蛋白抑制剂的药理学策略进行的研究中,已经明确证明线粒体通透性转换孔(MPTP)(线粒体内膜中的非特异性通道)的开放是多种形式的急性胰腺炎的基础,并且验证了MPTP为该疾病的药物靶点(Mukherjee R,等人Gut2016;65:1333–1346)。体外研究已经证明,胰腺腺泡细胞的损伤是引发急性胰腺炎相关的坏死性组织变性的关键事件。具体地,用毒性损伤物质诸如胆盐、酒精或激素受体过度刺激剂(急性胰腺炎发作的关键触发因子)处理分离的腺泡细胞导致了取决于线粒体通透性转换孔的活化的坏死性细胞死亡。从其中亲环蛋白D基因被缺失的小鼠中分离的胰腺腺泡细胞显示出对这些毒性挑战具有抗性。将这些发现转化到动物模型显示出,亲环蛋白D敲除动物被保护免受这些胰腺毒素的影响。使用亲环蛋白D抑制剂的研究进一步支持将靶向亲环蛋白D作为可能治疗急性胰腺炎的途径。
发明背景
环孢菌素A是一种以其免疫抑制特性而被众所周知的化合物,但也已经描述了其他生物学特性。环孢菌素A具有以下化学结构:
还已经制备了环孢菌素A的生物活性衍生物。例如,US 6,583,265、EP 0 484 281和EP 0 194 972描述了具有多种特性的环孢菌素衍生物,所述多种特性包括免疫抑制特性、抗寄生虫特性和抗病毒特性。
US 6,583,265描述了在环孢菌素大环的3位进行了修饰的环孢菌素衍生物。特别地,US 6,583,265公开了化合物1:
该化合物是专利US 6,583,265中的实施例27,该专利包括数百个在环周围不同位置处具有修饰的已命名的化合物。然而,没有描述对于该化合物或相关类似物的生物测试数据或特定用途。当申请人试图合成所述化合物时,使用US 6,583,265中公开的用于制备化合物27的路线,该方法是无效的。为了重复US 6,583,265中的方法进行了许多尝试,但没有取得大的成功。不受理论束缚,认为二甲基氨基基团(为碱性的)优先与酸催化剂反应。酸催化剂由此被阻止激活离去基团的失去,抑制反应的进展。因此,对于实施例27之前是否被合成得到存在一些疑问,并且因此对于该现有技术对于制备化合物1的公开内容是否实际上可实施存在疑问。
发明陈述
申请人已经合成了先前现有技术中教导的化合物,并且出乎意料地发现,一个小的亚组的化合物是特别良好的亲环蛋白D抑制剂。因此,下文描述的化合物可以用于治疗得利于对亲环蛋白D活性的抑制的状况。根据本发明的方面,提供了用于治疗或预防急性或慢性炎性紊乱的化合物,其中该化合物是式1的化合物:
或其盐,
其中n是2-5,并且
R1和R2独立地选自H或C1-C4烷基,其中R1和R2可以连接在一起形成C3-C5杂烷基环。
在实施方案中,急性或慢性炎性紊乱是例如急性肾损伤。
在实施方案中,急性或慢性炎性紊乱是例如慢性胰腺炎。
在实施方案中,急性或慢性炎性紊乱是例如急性胰腺炎。
在实施方案中,急性或慢性炎性紊乱是例如缺血再灌注损伤。
在实施方案中,化合物可以用于在重接之前保存离断的身体部分。离断的身体部分可以是肢体、手、脚、手指或脚趾。
在优选的实施方案中,化合物是:
根据本发明的另一个方面,提供了治疗患有或易患急性或慢性炎性紊乱的患者的方法,其中该方法包括向所述患者施用式1的化合物:
在实施方案中,治疗患有或易患急性或慢性炎性紊乱的患者的方法包括向所述患者施用化合物1。
根据本发明的一个方面,提供了式1的化合物用于制备用于治疗或预防急性或慢性炎性紊乱的药物的用途。
在实施方案中,化合物1的用途是用于制备用于治疗或预防急性或慢性炎性紊乱的药物。
已经发现化合物1在治疗或预防急性肾损伤、缺血再灌注损伤(IRI)和胰腺炎方面均出乎意料地有效。
式1的化合物可以用于治疗或预防急性或慢性炎性紊乱,包括急性肾损伤和缺血再灌注损伤。式1的化合物可以用于治疗或预防急性肾损伤。式1的化合物可以用于治疗与重接离断的身体部分相关的缺血再灌注损伤。本申请提供的数据在图1和图2中以图示出,表明化合物1明显优于已经建立的比较实例环孢菌素A和其他密切相关的类似物,包括在式1的范围内的那些类似物。事实上,在所进行的挑战性测试中,其中持续30分钟去除器官中的血液,化合物1给出了出乎意料地良好的结果,确实显示出几乎完全逆转了对受影响器官的预期损害。
化合物1显示出作为亲环蛋白D抑制剂的显著效力。如表1可见,化合物1(条目4)显示出针对亲环蛋白D的24nM的EC50。将N原子上的一个甲基基团替换为H(条目1简单地是与NMe2对比的NHMe)使效力降低约100倍,具有>2000nM的EC50。因此,化合物1是亲环蛋白D和线粒体通透性转换(MPT)的出乎意料地有效的抑制剂。
在如上文提及的化合物、方法或用途的实施方案中,化合物的剂量是0.1mg/kg至10mg/kg。在如上文提及的化合物、方法或用途的实施方案中,化合物的剂量是1mg/kg至3mg/kg。在这些剂量范围内,本发明的化合物是特别有效的。
本发明的盐可以由向式1的化合物或化合物1中添加酸来产生。得到的酸加成盐包括用乙酸、2,2-二氯乙酸、柠檬酸、乳酸、扁桃酸、乙醇酸、己二酸、海藻酸、芳基磺酸(例如,苯磺酸、萘-2-磺酸、萘-1,5-二磺酸和对甲苯磺酸)、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(cyclamic acid)、十二烷基硫酸、乙烷-1,2-二磺酸、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、葡糖酸(例如D-葡糖酸)、葡糖醛酸(例如D-葡糖醛酸)、谷氨酸(例如L-谷氨酸)、α-氧代戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸(isethionic acid)、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)、(±)-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、单宁酸、酒石酸(例如(+)-L-酒石酸)、硫氰酸、十一碳烯酸和戊酸形成的那些酸加成盐。
特别地,酸加成盐包括衍生自无机酸、有机酸的那些酸加成盐,所述无机酸诸如盐酸、氢溴酸、磷酸、偏磷酸、硝酸和硫酸;所述有机酸诸如酒石酸、乙酸、柠檬酸、苹果酸、乳酸、富马酸、苯甲酸、乙醇酸、葡糖酸、琥珀酸、芳基磺酸。
本发明的化合物可以与一种或更多种另外的活性物质一起施用。
根据本发明的一个方面,提供了用于在器官移植至新个体或重接身体部分之前保存从受试者取出或离断的身体部分的化合物,其中该化合物是式1的化合物:
或其盐,
其中n是2-5,并且
R1和R2独立地选自H或C1-C4烷基,其中R1和R2可以连接在一起形成C3-C5杂烷基环。
根据本公开内容的一个方面,提供了用于在器官移植或重接之前保存从受试者取出或离断的器官的方法,该方法包括将器官暴露于式1的化合物:
或其盐,
其中n是2-5,并且
R1和R2独立地选自H或C1-C4烷基,其中R1和R2可以连接在一起形成C3-C5杂烷基环。
根据本公开内容的一个方面,提供了化合物用于制备用于在移植或重接之前保存从受试者取出或离断的身体部分的药物的用途,其中该化合物是式1的化合物:
或其盐,
其中n是2-5,并且
R1和R2独立地选自H或C1-C4烷基,其中R1和R2可以连接在一起形成C3-C5杂烷基环。
根据本公开内容的一个方面,提供了化合物用于在移植或重接之前保存从受试者取出或离断的身体部分的用途,其中该化合物是式1的化合物:
或其盐,
其中n是2-5,并且
R1和R2独立地选自H或C1-C4烷基,其中R1和R2可以连接在一起形成C3-C5杂烷基环。
缺血性损伤发生在组织的某一区域的血液供应被切断时。缺血性损伤的发生是大量的:心肌梗死、中风和其他血栓事件,并且这些仅在美国每年就影响超过130万的个体。
此外,缺血性损伤也发生手术期间当血管被阻断(cross-clamped)时以及用于移植的器官中。虽然组织能够经得住氧气匮乏的时间长度不同,但最终缺血组织变成坏死的。
再灌注(复氧)损伤是缺血或氧缺乏(缺氧症、低氧)一段时间后将血液供应返回到组织时造成的组织损害。不受理论束缚,认为缺血期间血液中氧和营养物的缺乏造成了其中循环恢复导致炎症和氧化损害的状况。
在器官移植中,从去除器官的供体血液供应直到将该器官与供体接受者的血液供应重新连接之间存在一段时间。在该时间段,存在缺血再灌注损伤的可能性。在一些情况下,器官可能需要长距离运输至手术地点,增加了器官损害的可能性。
在涉及离断的肢体的事故中,在身体部分与血液供应离断直到身体部分与血液供应重新连接之间存在一段时间。在该时间段,存在缺血再灌注损伤的可能性。在一些情况下,身体部分和患者可能需要长距离运输至手术地点,增加了重接之前、期间和之后损害的可能性。
本发明提供了施用本发明化合物以防止对身体部分和器官的这种损害。特别是在去除身体部分或器官的供体血液供应到重新连接至供体接受者的血液供应(或者在离断的身体部分的情况下,重接)之间的时间段内。技术人员将明了本发明的化合物可施用至从个体取出的身体部分的方式,无论这些个体是器官供体还是事故受害者。例如,本发明的化合物可以被添加至(或包含在)放置器官的流体中;和/或本发明的化合物可以被添加至(或包含在)在器官/身体部分中再循环和/或再循环通过器官/身体部分的流体中。
在如上文提及的化合物、方法或用途的实施方案中,在从个体取出器官之后并且在移植或重接之前,将本发明的化合物施用至该器官。可选择地,或除此之外,将本发明的化合物在取出供体器官之前施用至供体。例如,化合物可以全身施用。注射是施用本发明化合物的全身剂量的一种方式。本发明的化合物也可以在器官移植之后施用至接受者,或者在重接之后施用至事故受害者。
全身剂量的本发明化合物可以在器官取出之前施用至器官供体。这允许器官在被取出之前接受保护性剂量的化合物,从而通过在取出期间并且直至移植到供体接受者体内以及在移植到供体接受者体内的过程期间保护器官免受损害来保存器官。在从供体取出多于一个器官的情况下,该全身剂量确保每个器官都接受一定剂量的化合物。全身剂量也更有可能向待移植的器官组织提供均匀剂量的化合物。在供体法定死亡的情况下,剂量可以大于将通常给予存活受试者的剂量。
化合物可以在手术前不久或在手术期间施用。例如,本发明的化合物可以在手术前多达8小时、7小时、6小时、5小时、4小时、3小时、2小时或1小时施用。
此外,或可选择地,器官接受者或事故受害者可以在接受器官或经历重接手术之前接受一定剂量的本发明化合物,使得他们的血液供应包含保护性剂量的本发明化合物,从而保存移植的或重接的身体部分在手术后免受损害。
身体部分可以离断并且重接至同一个体,或者可以作为移植物给予第二个体。在身体部分从受试者离断的情况下,断离可以是完全的或部分的。部分离断可以是例如血液供应的离断,但身体部分保持附接,例如经由皮肤、骨或肌肉组织附接。化合物可以(i)施用至离断的身体部位;和/或(ii)在重接身体部分之前施用至受试者;和/或(iii)在重接身体部分期间或之后施用至受试者。
本发明还在非人类受试者,例如猫、犬、马和猪方面具有应用。本发明还在转基因动物(例如转基因猪)中具有应用,其中这样的动物具有适合用于人类移植的器官。
在如上文提及的化合物、方法或用途的实施方案中,化合物是化合物1:
化合物1在本申请中已经显示出在治疗急性肾损伤和预防或治疗IRI方面是特别有效的。化合物1在本申请中已经显示出在治疗急性肾损伤以及慢性和急性胰腺炎方面均是特别有效的。
表1中展示的结果证明,化合物1(条目4)对亲环蛋白D的抑制和对MPT的抑制相对于本领域中也已知的相似的类似物(条目1-3和5-7)出乎意料地高。相对于其他三种密切相关的化合物(条目1、5和7),观察到MPT的100倍改善,并且相对于次优表现的类似物(条目3),观察到超过25倍的改善。化合物1还显示出优异的亲环蛋白D抑制,相对于所有测试的其他类似物,具有至少50倍的改善。
在如上文提及的化合物、方法或用途的实施方案中,器官可以是肾、胰腺、肝、心脏、肺或肠。在离断的身体部分的情况下,身体部分可以是肢体、手、脚、手指或脚趾。
在如上文提及的化合物、方法或用途的实施方案中,化合物的剂量是0.1mg/kg至10mg/kg;并且任选地是1mg/kg至3mg/kg。在器官或身体部分浸在包含本发明化合物的流体中,或者该流体正在再循环的情况下,化合物的浓度可以根据需要要求而更高或更低。
在如上文提及的化合物、方法或用途的实施方案中,化合物被配制在Cremophor/盐水/DMSO中。
根据本公开内容的一个方面,提供了制备式1的化合物的方法,该方法包括产物形成反应,该反应包括三氟甲磺酸铜和式2的氨基醇:
其中n是2-5,并且
R1和R2独立地选自H或C1-C4烷基,其中R1和R2可以连接在一起形成C3-C5杂烷基环。
出乎意料地,已经发现通过上文提及的方法可容易地制备获得本发明的化合物。例如,本申请人进行重复US 6,583,265中公开的方法的许多尝试都失败了,并且最终放弃了US 6,583,265中的方法,该方法是行不通的。
在实施方案中,反应包括干燥剂和/或在大体上无水的条件下进行。任选地,干燥剂是分子筛。任选地,分子筛是3A分子筛。
在实施方案中,氨基醇是N,N-二甲基氨基乙醇。这种氨基醇产生化合物1。
在实施方案中,氨基醇与包含不稳定基团的环孢菌素前体化合物反应,其中该不稳定基团在反应中失去。任选地,不稳定基团通过-S-键与前体化合物键合。还任选地,不稳定基团是硫代吡啶基基团或巯基苯并噻唑-2-基硫代基团。
附图简述
图1示出了通过测量血清肌酸酐浓度,化合物1和比较化合物CsA对在大鼠中的诱导的急性肾损伤的抑制性作用和/或保护性作用。
图2示出了通过测量血尿素氮(BUN)浓度,化合物1和比较化合物CsA对在大鼠中的诱导的急性肾损伤的抑制性作用和/或保护性作用。
图3示出了化合物1对于LPS诱导的急性肾损伤的抑制性作用和/或保护性作用。
详细描述
现在将通过以下实施例来说明本发明。
实验方法和结果
技术人员将认识到,式1的化合物可以以多种方式制备。下文的路线仅仅说明了可以用于合成化合物1的方式。尽管如此,US 6,583,265中用于制备化合物1的路线是无效的。为了重复US 6,583,265中的方法进行了许多尝试,但没有取得大的成功。不受理论束缚,认为二甲基氨基基团(为碱性的)优先与酸催化剂反应。由此酸催化剂被阻止活化离去基团的失去,抑制反应的进展。
通式1的化合物可以使用若干种途径方便地制备。在一种情况下(方案1),其中R是低级烷基的化合物2与羰基化合物和还原剂的反应可以进行还原胺化程序,以产生期望的化合物。优选地,羰基化合物是低级烷基醛或低级烷基酮,并且还原剂是金属硼氢化物。更优选地,醛是甲醛、乙醛或丙醛,并且酮是丙酮、2-丁酮等。优选地,还原剂是三乙酰氧基硼氢化钠或氰基硼氢化钠。
胺化合物2可以方便地由适当保护的其中R是氢或低级烷基的乙醇胺化合物诸如3制备,通过用已知的条件处理所述化合物以去除保护基团并且产生游离胺化合物。可以在分子中存在其他官能团的情况下被去除的合适的保护基团包括叔丁氧羰基(BOC)、9-芴甲氧羰基(FMOC)等。优选地,保护基团是叔丁氧羰基(BOC),并且用于去除BOC基团的条件包括用酸诸如三氟乙酸处理。
步骤1:[2’-(2-硫代吡啶基)-Sar]3-环孢菌素A的制备
[2’-(2-硫代吡啶基)-Sar]3-环孢菌素A(1a)
向干燥的1L烧瓶中添加环孢菌素A(20g,16.6mmol)、无水氯化锂(21.1g,499mmol)和无水THF(500mL),对烧瓶冲氩气并且将混合物冷却至-45℃。在分开的烧瓶中,将二异丙胺(13.5g,133mmol)溶解在无水THF(120mL)中并且冷却至-78℃。向该烧瓶中添加正丁基锂(53.2mL的2.5M溶液,133mmol)并且将得到的溶液在-78℃搅拌20min。使用套管,将二异丙基氨基锂的溶液转移至环孢菌素的溶液中,并且将得到的混合物在-45℃搅拌90min。逐滴添加2-吡啶基二硫化物(11g,49.9mmol)在无水THF(20mL)中的溶液,并且允许得到的混合物升温至室温过夜。通过小心添加饱和NaCl溶液(200mL)将反应猝灭,并分离得到的有机层。将水层用乙酸乙酯(3×100mL)萃取,并且将合并的有机级分用3N NaOH(2×100mL)、饱和NH4Cl(100mL)和饱和NaCl(100mL)洗涤,随后经无水Na2SO4干燥并且蒸发。通过硅胶色谱法分离作为固体的标题化合物,7.18g。
1H NMR(400MHz,氯仿-d)d 8.45(ddd,J=0.88,1.73,4.90Hz,1H),7.98(d,J=9.66Hz,1H),7.65-7.73(m,1H),7.59(dt,J=1.85,7.71Hz,1H),7.51(ddd,J=0.76,1.68,6.44Hz,OH),7.45(d,J=8.54Hz,1H),735(ddd,J=1.73,6.97,8.77Hz,OH),7.25(s,0H),7.17(d,J=7.96Hz,1H),7.09-7.15(m,2H),6.72(dt,J=1.17,6.71Hz,OH),5.70(dd,J=4.29,10.88Hz,1H),5.50(d,J=6.39Hz,1H),5.32-5.38(m,1H),5.28(dd,J=3.88,11.74Hz,1H),5.13(d,J=10.88Hz,1H),4.97-5.11(m,2H),4.84(dq,J=7.03,7.24Hz,1H),4.69(t,J=9.15Hz,1H),4.54(五重峰,J=7.31Hz,1H),4.13(q,J=7.16Hz,0H),3.81(dt,J=1.00,5.75Hz,1H),3.59-3.72(m,1H),3.50(s,2H),3.38(s,2H),3.26(s,2H),3.13(s,5H),2.70(d,J=1.07Hz,5H),2.34-2.54(m,1H),1.92-2.23(m,4H),1.55-1.85(m,11H),1.19-1.54(m,11H),1.12(d,J=6.54Hz,2H),0.78-1.07(m,30H),0.73(d,3H)。
步骤2:[2’-(2-二甲基氨基乙氧基)-Sar]3-环孢菌素A(化合物1)的制备
[2’-(2-二甲基氨基乙氧基)-Sar]3-环孢菌素A(1)
将三氟甲磺酸铜(0.291g,0.8mmol)和3埃分子筛添加至烧瓶中,添加无水THF(3mL),并且对烧瓶冲氩气。在分开的烧瓶中,将[2’-(2-硫代吡啶基)-Sar]3-环孢菌素A(1a)(0.293g,0.223mmol)、二甲基氨基乙醇(0.086g,0.96mmol)和3A分子筛在无水THF(2mL)中的混合物搅拌30分钟,并且然后添加至三氟甲磺酸铜溶液中。允许反应在室温搅拌过夜。添加饱和NaHCO3溶液(10mL),并且将混合物通过硅藻土(celite)过滤。将硅藻土用乙酸乙酯(3×25mL)洗涤,并且添加至滤液中。将有机层分离;将水溶液用EtOAc(2×25mL)萃取,并且将合并的有机级分经无水Na2SO4干燥并且蒸发。将粗制物质在硅胶上纯化提供了标题化合物,86.4mg。
1H NMR(400MHz,氯仿-d)d7.92(d,J=9.61Hz,1H),7.75(d,J=7.32Hz,1H),7.22(d,J=8.15Hz),7.15(d,J=7.86Hz,),6.01(s,1H),5.70(dd,J=4.22,10.86Hz,1H),5.46(d,J=6.10Hz,1H),5.35(q,J=4.77Hz,1H),5.27(dd,J=4.15,11.42Hz,1H),5.14(d,J=10.83Hz,1H),5.05-5.11(m,1H),4.94-5.04(m,1H),4.77-4.90(m,1H),4.73(s),4.66(t,J=8.83Hz,1H),4.46-4.57(m,1H),3.71-3.81(m,1H),3.58-3.67(m,J=5.15,5.64,5.64,5.83Hz,1H),3.53-3.58(m,1H),3.51(s,2H),324(s,2H),3,20(s,2H),3.13(d,J=2.10Hz,3H),2.71(d,J=6.54Hz,3H),2.49-2.67(m,2H),2.33-2.46(m,1H),2.27(s,4H),1.88-2.20(m,4H),1.74(d,J=0.29Hz,6H),1.57-1.68(m,5H),1.38-1.52(m,2H),1.35(d,J=7.27Hz,3H),1.26(d,J=2.88Hz,4H),0.77-1.12(m,30H),0.70(d,2H)。
例如,技术人员将理解化合物1的类似物可以通过使用不同的氨基醇试剂来制备。例如,醇和胺基团之间的碳原子数目可以增加或减少(连接基团的实例包括亚甲基、亚乙基、亚丙基、亚丁基、亚戊基,并且可以包括其分枝形式,诸如异亚丙基、仲亚丁基、叔亚丁基、2-甲基亚丁基、2,2-二甲基亚丙基)。可选择地,或另外,氨基醇上的N-氨基取代基也可以被改变以产生化合物1另外的类似物(N-氨基取代基的实例包括甲基、乙基、丙基、异丙基、正丁基、仲丁基、叔丁基)。
[2’-(2-N-Boc-氨基乙氧基)-Sar]3-环孢菌素A的制备
将三氟甲磺酸铜(4.95g,13.7mmol)和3A分子筛悬浮在无水THF(50mL)中,并且在氩气下搅拌30min。将[2’-(2-硫代吡啶基)-Sar]3-环孢菌素A(1)(5.0g,3.82mmol)和N-Boc-乙醇胺(2.64g,16.4mmol)在无水THF(10mL)中的溶液经3A分子筛干燥30min,并且然后添加至三氟甲磺酸铜悬浮液中。将得到的混合物在室温搅拌过夜。添加饱和NaHCO3(2×50mL),并且将混合物通过硅藻土过滤。将硅藻土垫用EtOAc(4×100mL)洗涤,并且将有机层分离。将水相用EtOAc(2×50mL)萃取,并且将合并的有机级分用饱和NaCl(50mL)洗涤,经无水Na2SO4干燥并且蒸发。将粗制物质在二氧化硅上纯化,得到标题化合物4.18g。
1H NMR(400MHz,氯仿-d)d ppm 0.72(ddd,2H)0.91(m,31H)1.32(m,8H)1.48(dddd,J=3.95,3.07,2.23,0.95Hz,2H)1.69(m,10H)2.10(m,4H)2.39(m,1H)2.70(m,4H)2.95(m,2H)3.12(d,J=7.42Hz,4H)3.17(d,J=9.37Hz,1H)3.20(s,2H)3.25(s,2H)3.29(m,J=6.69,3.02,1.45,0.76,0.63Hz,1H)3.41(m,1H)3.51(s,2H)3.61(m,1H)3.75(dddd,J=7.73,1.54,1.02,0.73Hz,1H)4.13(q,J=7.11Hz,1H)4.50(m,1H)4.65(dd,J=18.06,0.44Hz,1H)4.98(m,4H)5.30(m,2H)5.47(m,1H)5.70(m,1H)5.93(d,J=0.34Hz)7.21(m,1H)7.71(m)8.03(m)
[2’-(2-氨基乙氧基)-Sar]3-环孢菌素A的制备
将[2’-(2-N-Boc-氨基乙氧基)-Sar]3-环孢菌素A(3)(3.0g,2.2mmol)在无水CH2Cl2(30mL)中的溶液冷却至0℃,并且逐滴添加三氟乙酸(6.54mL,10.03g,88mmol),并且将混合物搅拌30min。将溶剂蒸发,并且将粗制物质在二氧化硅上纯化,得到标题化合物1.99g。
[2’-(2-二甲基氨基乙氧基)-Sar]3-环孢菌素A(2)的制备
将[2’-(2-氨基乙氧基)-Sar]3-环孢菌素A(0.273g,0.216mmol)溶解在CH2Cl2(5mL)中,并且添加甲醛(37%水溶液,0.048mL,0.69mmol),随后添加NaB(OAc)3H(0.138g,0.649mmol),并且允许反应在约室温搅拌18h。将反应混合物通过小硅胶垫过滤,将小硅胶垫用90∶9∶1 CH2Cl2∶MeOH∶浓氨水(cone.NH4OH)(5×100mL)洗涤。蒸发溶剂,并且将产物通过色谱法在硅胶上分离,得到标题化合物0.214g。
亲环蛋白抑制性结合测量
本文公开的化合物对亲环蛋白抑制性结合是使用竞争性ELISA来确定的,所述竞争性ELISA改编自Quesniaux等人(Eur.J Immunol.,1987,17:1359-1365)描述的方法。与D-Lys8-环孢菌素A(D-Lys8-Cs)结合的琥珀酰基间隔基的活化酯通过8位的D-赖氨酰基残基与牛血清白蛋白(BSA)偶联。将BSA溶解在0.1M硼酸盐缓冲液,pH 9.0中(4mg于1.4ml中)。在剧烈搅拌下,将溶解在二甲基甲酰胺(0.6ml)中的100倍摩尔过量的D-Lys8-Cs逐滴添加至BSA中。将偶联反应在温和搅拌下在室温进行2小时至3小时,并且将缀合物针对磷酸盐缓冲盐水(PBS,pH 7.4)充分透析。在丙酮沉淀缀合蛋白的等分试样之后,丙酮溶液中没有共价结合的D-Lys8-Cs残留,并且计算环孢菌素共价结合的程度。
将微量滴定板包被D-Lys8-Cs-BSA缀合物(2μg/ml于PBS中,在4℃持续24小时)。将板用洗涤并且用单独的PBS洗涤。为了阻断非特异性结合,将2%BSA/PBS(pH7.4)添加至孔中,并且允许在37℃孵育2小时。在单独的微量滴定板中,在乙醇中制备待测试化合物的五倍稀释系列。使用人类重组亲环蛋白的测定的起始浓度是0.1mg/mL。将198μL的0.1μg/mL亲环蛋白溶液添加至微量滴定板中,随后立即添加2μL的稀释的环孢菌素A(用作参考化合物)或本发明的化合物。包被的BSA-Cs缀合物、单独的环孢菌素A和亲环蛋白之间的反应被允许在4℃平衡过夜。亲环蛋白用稀释在含1%BSA的PBS中的抗亲环蛋白兔抗血清检测,并且在4℃孵育过夜。将板如上文描述洗涤。然后通过稀释在1%BSA-PBS中的与碱性磷酸酶缀合的山羊抗兔IgG检测结合的兔抗体,并且允许在37℃孵育2小时。将板如上文描述洗涤。在与4-硝基苯基磷酸盐(1g/l于二乙醇胺缓冲液,pH 9.8中)在37℃孵育1小时至2小时之后,使用分光光度计在405nm处通过分光光度法测量酶反应。结果表示为EC50,EC50是实现50%抑制所需的本发明化合物的浓度。针对亲环蛋白A、亲环蛋白B和亲环蛋白D,化合物1具有小于100nM的EC50值。
PPI酶抑制
测定使用Agilent 8453分光光度计,基本上如Janowski等人{Jankowski等人Anal.Biochem.(1997),252:299-307}描述的‘解偶联测定’进行。将由35mM HEPES pH 7.8和50μM DTT组成的测定缓冲液在精密玻璃比色杯中冷却至10℃(在搅拌下),并且添加来自100%DMSO储备溶液的抑制剂。获得空白光谱,并且然后添加纯化的His加标签的重组人类亲环蛋白酶(f/c2nM)和四肽底物,即溶解在于三氟乙醇中的0.5M LiCl中的Suc-Ala-Ala-Pro-Phe-对硝基苯胺(Bachem,f/c 60μM),并且在330nM处测量经5min的吸光度变化。将一阶速率方程拟合到吸光度数据以获得速率常数(由于混合,前10s至15s被去除)。催化速率由酶速率减去背景速率来计算。抑制剂的Ki是从相对于抑制剂浓度绘制的速率常数获得的。
线粒体通透性转换
线粒体通透性转换(MPT)通过测量Ca2+诱导的线粒体溶胀来确定。该程序改编自Blattner等人,2001,Analytical Biochem,295:220描述的方法。线粒体使用标准方法由已经用磷酸盐缓冲盐水(PBS)灌注去除血液的大鼠肝制备,所述标准方法利用在蔗糖基缓冲液中的温和均质化和之后的差速离心,以先去除细胞碎片,并然后沉淀线粒体。溶胀由150微摩尔Ca2+(从CaCl2的浓溶液中添加)诱导,并且通过测量535nm-540nm处的散射来监测。在诱导溶胀前5分钟添加代表性化合物。EC50通过比较存在和不存在本文公开的化合物时的溶胀来确定。化合物1抑制线粒体溶胀,具有小于0.2uM的EC50。
急性肾损伤
化合物1和环孢菌素A制剂通过将这些化合物与Cremophor/盐水/DMSO混合来准备。
将Sprague-Dawley大鼠分为六组:组(i),假手术组,用不含活性物质的Cremophor/盐水/DMSO给药;组(ii),对照组,用不含活性物质的Cremophor/盐水/DMSO给药;组(iii),用化合物1(3mg/kg)给药;组(iv),用CsA(3mg/kg)给药;组(v),用化合物1(10mg/kg)给药;组(vi),用CsA(10mg/kg)给药。除了组(i),即‘假手术组’之外,通过结扎双侧肾动脉持续30min并且然后解除结扎,在大鼠中诱导了肾缺血再灌注诱导的急性肾损伤(AKI)。
对照组和处理组的动物施用腹膜内注射三次(结扎前1h,结扎后4h和8h)。在结扎/解除程序后24小时从动物采血,并且分析血清肌酸酐和血尿素氮(BUN)浓度,作为对肾损伤的量度。
这些实验的结果在下文中示出,并且在图1和图2中直观地显示。
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表1–对亲环蛋白A抑制、亲环蛋白D抑制和线粒体通透性转换(MPT)的测量。
表1中显示的结果证明,化合物1(条目4)对亲环蛋白D的抑制和对MPT的抑制相对于相似的类似物(条目1-3和5-7)出乎意料地高。相对于其他三种化合物(条目1、5和7),观察到MPT的100倍改善,并且相对于次优表现的类似物(条目3),观察到超过25倍的改善。化合物1还显示出优异的亲环蛋白D抑制,具有相对于所有测试的其他类似物至少50倍的改善。
表2-对组(i)至组(vi)的血清肌酸酐和BUN浓度的测量
在小鼠(C57)中通过腹膜内注射LPS(15mg/kg)诱导了LPS诱导的急性肾损伤(AKI)。将20只小鼠随机分为两组。对照组中的动物接受媒介物(Cremophor/盐水/DMSO),而治疗组接受化合物1(3mg/kg,于Cremophor/盐水/DMSO中),每只动物经腹膜内给药。将动物用媒介物或化合物1给药三次(LPS注射前1h以及LPS注射后4h和8h),并且在LPS注射后12h从动物采血。化合物的活性通过升高的存活率和通过评估肾功能的标志来确定。
结果讨论
在图1中,血清肌酸酐浓度指示肾损害。‘假手术组’是没有诱导的AKI的大鼠。‘对照组’代表具有诱导的AKI并且未经治疗的大鼠。因此,可以看出,诱导的AKI导致肌酸酐水平从25umol/ml(组1)增加至195umol/ml(组2)。
与组2相比,用3mg/kg的CsA治疗具有诱导的AKI的大鼠(组4)导致肌酸酐水平从195umol/ml降至115umol/ml。因此,应理解,CsA起防止缺血再灌注损伤的作用。
出乎意料地,当用3mg/kg的化合物1治疗具有诱导的AKI的大鼠时(组3),这给出了肌酸酐水平的非常显著的降低,从195umol/ml降至60umol/ml(与组2相比),60umol/ml接近‘假手术组’(组1)即没有诱导的AKI的大鼠中观察到的肌酸酐水平。当化合物1和CsA的剂量从3mg/ml(组3和组4)增加至10mg/ml(组5和组6)时,似乎CsA和化合物1的益处降低,而化合物1仍然比CsA表现更好。
在图2中,血尿素氮(BUN)浓度指示肾损害。
图2遵循与图1中观察到的相同的趋势。也就是说,3mg/kg的CsA导致BUN水平下降(组4相比于组2),而3mg/kg的化合物1示出BUN水平的非常显著的下降(组3相比于组2),接近‘假手术组’(组1)中观察到的BUN水平。将化合物1和CsA的浓度从3mg/kg(组3和组4)增加至10mg/kg(组5和组6)证明不太有效。该结果支持图1中观察到的结果。
通过碘化丙啶测定鼠胰腺腺泡细胞的坏死性细胞死亡
为了评估坏死性细胞死亡途径的活化,使用1μM碘化丙啶(PI;λex:543nm,λem:610nm-690nm)评估质膜破裂。为了评估潜在药物对坏死的抑制,将从CD1小鼠中新鲜分离的胰腺腺泡细胞(PAC)分成以下四组:
1.对照组;将PAC与HEPES钠和媒介物(0.5%DMSO)一起孵育。
2.牛磺石胆酸硫酸盐(Taurolithocholate acid sulphate)(TLCS)组;将PAC与500μM TLCS和媒介物一起孵育。
3.单独的潜在药物组(用于细胞毒性测试);将PAC与潜在药物一起孵育。
4.潜在药物+TLCS组;将PAC在500μM TLCS的存在下与潜在药物一起孵育。
对于每个组,在温和震荡下在室温孵育PAC 30分钟。对于每个组,在共聚焦显微镜下对每个小鼠分离物拍摄8个随机选择的视野(每个视野通常大多包含超过100个细胞),并且计数每个视野显示PI摄取的细胞的总数,以给出每个视野的百分比,取跨多个视野的平均值,并转化为每个实验组最少3只小鼠的平均值和平均值的标准误差。整个测定以盲法进行,这样的方式使得选择视野的观察者和进行图像分析的观察者不知道治疗组。
体内小鼠TLCS急性胰腺炎模型
该实验测量了化合物在小鼠模型中救治胆酸、牛磺石胆酸硫酸盐(taurolithocholylsulphate)(TLCS)诱导的急性胰腺炎的能力。体内动物方案得到了英国内政部(UK Home Office)的批准。C57BL6/J小鼠(Charles River UK Ltd)在体内实验前适应持续至少1周。化合物被制成适当的制剂。如先前描述的[Laukkarinen等人,2007],通过逆行胰管注射3mM TLCS来诱导TLCS-AP。化合物通常通过腹膜内(i.p.)注射施用,并且然后在24h后处死动物。如先前描述的[Mukherjee等人,2016],观察组织学,并且测量血清淀粉酶、白细胞介素6和髓过氧化物酶活性。
血清淀粉酶水平使用Roche自动化临床化学分析仪(Roche)来确定。
血清IL-6水平通过Quantikine小鼠ELISA试剂盒(R&D systems)来确定。
髓过氧化物酶(MPO)活性被用作中性粒细胞浸润的标志物,并且按所描述的进行确定。首先将胰腺组织和肺组织均质化并且重悬在含有蛋白酶抑制剂的100mM磷酸钾缓冲液(pH 7.4)中,在重复离心和重悬2-3次后,然后进一步重悬在含有0.5%十六烷基三甲基溴化铵、10mM EDTA和蛋白酶抑制剂的100mM磷酸钾缓冲液(pH 5.4)中,然后冻融3次,超声处理30秒,并且最后在16,000×g离心15min。收集上清液,并且使用H2O2来测量对一般过氧化物酶底物3,3,5,5-四甲基联苯胺的MPO活性。在655nm处测量吸光度。匀浆蛋白水平使用BCA测定试剂盒检测。基于每个样品的蛋白水平和TLCS组的平均值对MPO活性归一化。
组织学
对于形态学检查,将胰腺组织在10%福尔马林中固定,包埋在石蜡中,并且用苏木精和伊红(H&E)染色。通过盲法由两名独立的研究者对每个载玻片的10个随机视野(×10个高倍视野)进行组织病理学评估,将水肿、炎性浸润和坏死的等级和程度分成从0至3[5]的等级,计算总和平均值±s.e.m.。
结果讨论
综上,发现化合物1在治疗或预防胰腺炎方面当与类似化合物比较时出乎意料地有效。
整体总结而言,发现化合物1,特别是在较低浓度水平,在治疗或预防缺血再灌注损伤方面出乎意料地有效。所述化合物对于急性肾损伤和胰腺炎也特别有效。
Claims (6)
1.化合物在制备用于治疗或预防急性或慢性炎性紊乱的药物中的用途,其中所述化合物是化合物1:
或其盐;
其中所述化合物以0.1mg/kg至3mg/kg的剂量使用,
并且其中所述紊乱选自急性肾损伤、慢性或急性胰腺炎和缺血再灌注损伤,其中所述缺血再灌注损伤发生在重接离断的身体部分之后或器官移植过程期间。
2.根据权利要求1所述的用途,其中所述紊乱是急性肾损伤。
3.根据权利要求1所述的用途,其中所述紊乱是缺血再灌注损伤,所述缺血再灌注损伤发生在重接离断的身体部分之后或器官移植过程期间。
4.根据权利要求1所述的用途,其中所述紊乱是慢性或急性胰腺炎。
5.根据权利要求1至4中任一项所述的用途,其中所述化合物的剂量是0.1mg/kg至1mg/kg。
6.根据权利要求1至4中任一项所述的用途,其中所述化合物的剂量是1mg/kg至3mg/kg。
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PCT/GB2018/052066 WO2019016572A1 (en) | 2017-07-21 | 2018-07-23 | CICLOSPORINE ANALOGUES AND USES THEREOF |
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TW202128211A (zh) * | 2019-10-12 | 2021-08-01 | 大陸商睿諾醫療科技(上海)有限公司 | 腎毒素引起的腎損傷的治療和預防 |
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CA3172689A1 (en) * | 2020-03-26 | 2021-09-30 | Ching-Pong Mak | Cyclophilin inhibitors and uses thereof |
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WO2012103520A1 (en) * | 2011-01-28 | 2012-08-02 | Board Of Regents Of The University Of Nebraska | Methods and compositions for modulating cyclophilin d |
CN106902347A (zh) * | 2015-12-23 | 2017-06-30 | 中美华世通生物医药科技(武汉)有限公司 | 亲环孢素抑制剂的用途 |
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CN118005743A (zh) | 2024-05-10 |
EP3655012A1 (en) | 2020-05-27 |
ES2950455T3 (es) | 2023-10-10 |
GB201711749D0 (en) | 2017-09-06 |
CN115299430A (zh) | 2022-11-08 |
WO2019016572A1 (en) | 2019-01-24 |
CN111132688A (zh) | 2020-05-08 |
US20220072093A1 (en) | 2022-03-10 |
EP3655012B1 (en) | 2023-07-05 |
US20200171122A1 (en) | 2020-06-04 |
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