CN114127054B - 作为用于治疗炎性气道或纤维化疾病的自分泌运动因子(atx)调节剂的n-甲基、n-(6-(甲氧基)哒嗪-3-基)胺衍生物 - Google Patents
作为用于治疗炎性气道或纤维化疾病的自分泌运动因子(atx)调节剂的n-甲基、n-(6-(甲氧基)哒嗪-3-基)胺衍生物 Download PDFInfo
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Abstract
本发明涉及N‑甲基、N‑(6‑(甲氧基)哒嗪‑3‑基)胺衍生物,其作为自分泌运动因子(ATX)调节剂用于治疗炎性气道或纤维化疾病,例如像特发性肺病(IFF)或系统性硬化症(SSc)。本说明书公开了示例性化合物的制备(例如,第37至45页;实施例1.1至1.13)及其相关生物学数据(例如,第12至17页,表1至9)。示例性化合物是例如l‑[4‑(4‑{l‑[(6‑{[6‑(三氟甲基)吡啶‑3‑基]甲氧基}哒嗪‑3‑基)氨基]环丙基}‑苯基)哌嗪‑1‑基]乙‑l‑酮(实施例1.1)。
Description
技术领域
本发明涉及新型哒嗪、其制备方法、含有它们的药物组合物以及其在疗法中的用途,特别是在治疗和/或预防由自分泌运动因子介导的疾病和障碍中的用途。
背景技术
自分泌运动因子(Autotaxin)(ATX;ENPP2)是一种分泌酶,其负责通过其溶血磷脂酶D活性将溶血磷脂酰胆碱(LPC)水解为生物活性的脂质溶血磷脂酸(LPA)。进而,LPA通过与六种GPCR(LPA受体1-6,LPAR1-6)相互作用发挥其作用(Houben AJ,2011)。ATX-LPA信号传导与例如血管生成、慢性炎症、自身免疫性疾病、纤维化疾病、癌症进展和肿瘤转移有关。例如,LPA作用于LPAR1,诱导肺成纤维细胞迁移、增殖和分化;调节上皮和内皮屏障功能;并且促进肺上皮细胞凋亡(Budd,2013)。ATX抑制、LPAR1基因缺失和选择性LPAR1拮抗剂已显示在肺和皮肤纤维化的临床前模型中有效(Tager AM,2008;Swaney J,2010,CasetelinoFV,2016)。
在特发性肺纤维化(IPF)患者中,支气管肺泡灌洗液中的LPA水平增加(Tager等人,2008,Nat.Med.),并且在人纤维化肺组织中检测到ATX浓度增加。(Oikonomou等人,2012,AJRCMB)。IPF受试者的呼出气冷凝物中的LPA水平升高(Montesi等人,2014_BMCPM),并且稳定IPF患者的血清中的LPC增加2倍(Rindlisbacher等人,2018,Resp.Res.)。
因此,增加的ATX水平和/或增加的LPA水平、改变的LPA受体表达和改变对LPA的反应可能影响与ATX-LPA信号传导相关的许多病理生理病症。
间质性肺病(ILD)的特征在于间质、组织、和肺的肺泡之间的空间的炎症和纤维化(du Bois,Nat.Rev.Drug Discov.2010,9,129-140)。当肺部损伤触发异常愈合反应时,可能发生OLD。因此,ILD还包括进行性纤维化间质性肺病(PFILD),其中对肺损伤的反应变得进行性、自我维持并且独立于最初的临床关联或触发。最突出的PF-ILD是特发性肺纤维化(IPF)和系统性硬化症-ILD(SSc-ILD)。
IPF是一种慢性纤维化不可逆且最终致命的肺部疾病,其特征在于肺间质中的进行性纤维化,导致肺容量减少和进行性肺功能不全。IPF的特征还在于被称为常见间质性肺炎(UIP)的特定组织病理学模式(Raghu等人,Am.J.Respir.Crit.Care Med.183:788-824.)。
系统性硬化症(SSc)也称为硬皮病,是一种免疫介导的复杂病因的风湿性疾病。它是一种多器官异源性疾病,其特征在于广泛的纤维化、血管病变和针对各种细胞抗原的自身抗体,死亡率高。它是一种少见的障碍,即具有医疗需求高度未满足的罕见疾病。SSc的早期临床体征可能不同。雷诺(Raynaud)现象和胃食管反流通常在疾病早期出现(Rongioletti F等人,J Eur Acad Dermatol Venereol 2015;29:2399-404)。一些患者呈现出炎性皮肤病、手指浮肿和肿胀、肌肉骨骼炎症或诸如疲劳的体质表现。患者皮肤中过多的胶原蛋白沉积使皮肤变厚且坚韧。在一些患者中,观察到基于器官的疾病表现,如肺纤维化、肺动脉高压、肾功能衰竭或胃肠道并发症。另外,免疫参与的最常见表现之一是存在针对自身细胞核的自身免疫抗体(抗核抗体或ANA)水平异常,这在几乎每个SSc患者中可见(Guiducci S等人,Isr Med Assoc J 2016;18:141-43)。ILD和肺动脉高压(PAH)是SSc患者最常见的死亡原因(Tyndall AJ等人.Ann Rheum Dis 2010;69:1809-15)。
SSc患者分类为两个主要疾病亚群:弥漫性皮肤系统性硬化症和局限性皮肤系统性硬化症(LeRoy EC等人,J Rheumatol 1988;15:202-5)。三个临床特征-过度纤维化(结疤)、血管病变和自身免疫-似乎是导致表征SSc的不同表现的过程的基础。SSc目前被认为是结缔组织损伤修复失调或功能障碍的表现(Denton CP等人,Lancet 2017;390:1685-99)。
因此希望提供有效力的ATX抑制剂。
D.Castagna等人(J.Med.Chem.2016,59,5604-5621)综述了各种结构类别的ATX抑制剂。WO 2014/139882公开了作为ATX抑制剂的化合物,具有通用结构式
其中的实施例2在N.Desroy等人(J.Med.Chem.2017,60,3580-3590,作为实施例11)中进一步公开为一流的ATX抑制剂,正在接受针对治疗特发性肺纤维化的临床评估。在C.Kuttruff等人(ACS Med.Chem.Lett.2017,8,1252-1257)中,公开了ATX抑制剂BI-2545(实施例19),其显著降低体内LPA水平。
具体实施方式
本发明提供了新型哒嗪,所述哒嗪是令人惊讶地有效力的自分泌运动因子抑制剂(测定A),其进一步特征在于
-人全血中的高效力(测定B),以及
-体内LPA的血浆浓度水平在几个小时内显著降低(测定C)。
本发明的化合物可用作治疗或预防疾病或病症的药剂,在所述疾病或病症中ATX活性和/或LPA信号传导参与,涉及疾病的病因或病理,或以其他方式与疾病的至少一种症状相关。ATX-LPA信号传导与例如血管生成、慢性炎症、自身免疫性疾病、纤维化疾病、癌症进展和肿瘤转移有关。
本发明的化合物在以下参数组合方面优于现有技术中公开的那些:
-作为ATX抑制剂的效力,
-在人全血中作为ATX抑制剂的效力,
-体内LPA的血浆浓度水平在几个小时内降低。
ATX是可溶性血浆蛋白,其在肝素化全血中具有活性。其底物LPC非常丰富,其浓度在μM范围内。因此,生理底物浓度的全血测定是一种高度相关的测定,可预测ATX抑制剂在体内的功效。
通过在口服本发明化合物后测量LPA的血浆浓度来确定体内LPA的减少。LPA是非常强的生物活性脂质,其通过LPA受体1-6以浓度依赖性方式有效地激活下游通路。通过在化合物给药后8小时测量LPA减少的程度来评估通过ATX抑制对LPA形成的显著且持续的阻断。因此,在8h时血浆LPA的高度减少高度表明体内的功效和持续的作用持续时间以及LPA受体的持续靶标接合。
本发明的化合物在结构上与WO 2014/139882中的实施例2和12和ACSMed.Chem.Lett.2017,8,1252-1257中的实施例19的不同之处在于它们含有在3位和6位具有取代基的中央哒嗪核心。这种结构差异出乎意料地导致以下的较优组合:(i)ATX的抑制,(ii)人全血中ATX的抑制,和(iii)在几小时内降低体内LPA的血浆浓度水平。
因此,本发明的化合物证明了高的体内靶标接合并且可以预期在人体中具有更高的功效。
本发明提供了根据式(I)的新型化合物
其中
A是被由氟和F1-7-氟-C1-3-烷基组成的组中的一个或两个成员取代的吡啶基;
E选自苯基和吡啶基,任选被由氟和C1-3-烷基组成的组中的一个或两个成员取代;
K选自
R3选自R4(O)C-和R5(O)C(CH3)N-;
R4是甲基;
R5是甲基;
L和M独立地选自
H、甲基和HOH2C-,
或L和M与它们所连接的碳一起形成环丙基环。
本发明的另一个实施方案涉及式(I)的化合物,其中A是被F1-3-氟-C1-烷基中的一个或两个取代的吡啶基;并且取代基E、K、L和M如前述实施方案所定义。
本发明的另一个实施方案涉及式(I)的化合物,其中A是被由F2HC和F3C组成的组中的一个或两个成员取代的吡啶基;并且取代基E、K、L和M如前述实施方案所定义。
本发明的另一个实施方案涉及式(I)的化合物,其中A选自
并且取代基E、K、L和M如前述实施方案中任一项所定义。
本发明的另一个实施方案涉及式(I)的化合物,其中E选自苯基和吡啶基,任选被由氟和甲基组成的组中的一个或两个成员取代;
并且取代基A、K、L和M如在任何前述实施方案中任一项所定义。
本发明的另一个实施方案涉及式(I)的化合物,其中E选自
并且取代基A、K、L和M如在任何前述实施方案中任一项所定义。
优选的是根据本发明的式(I)化合物,其选自:
另一个实施方案涉及一种药物组合物,其包含根据本发明的至少一种式I的化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂。
另一个实施方案涉及根据本发明的式(I)的化合物,其用作药剂。
所用的术语和定义
在本文中未明确定义的术语应当被理解为具有本领域技术人员根据本披露和上下文能得出的含义。然而,如在本说明书中所用,除非有相反说明,以下术语具有所指示的含义并且遵循以下惯例。
在以下定义的基团(group、radical)或部分中,碳原子数目通常在基团之前指定,例如,C1-6烷基是指具有1到6个碳原子的烷基或烷基。通常,在像HO、H2N、(O)S、(O)2S、NC(氰基)、HOOC、F3C等基团中,技术人员可以从基团本身的自由化合价中看出与分子的一个或多个基团附接点。对于包含两个或更多个子基团的组合基团,最后命名的子基团是自由基附接点,例如,取代基“芳基-C1-3-烷基-”意指芳基与C1-3-烷基-基团结合,后者与核心或与取代基所附接的基团结合。
在本发明化合物以化学名称的形式或作为结构式进行描述时,在任何不一致的情况下,应以所述结构式为准。星号可以用于在子式中指示连接至如所定义的核心分子的键。
取代基的原子的编号开始于与核心或与取代基所附接的基团最靠近的原子。
例如,术语“3-羧基丙基-基团”表示以下取代基:
其中羧基与丙基的第三碳原子附接。术语“1-甲基丙基-”、“2,2-二甲基丙基-”或“环丙基甲基-”基团表示以下基团:
星号在子式中可以用于指示与所定义核心分子连接的键。
如本文所用的术语“取代的”是指指定原子上的任何一个或多个氢被指定基团的选择替换,其条件是不超过指定原子的正常化合价,并且取代产生稳定化合物。
术语“C1-n-烷基”(其中n是选自2、3、4、5或6的整数,优选4或6),单独或与另一个基团组合,表示具有1至n个C原子的无环、饱和、支链或直链烃基。例如,术语C1-5-烷基包括以下基团:H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2-、H3C-C(CH3)2-、H3C-CH2-CH2-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-和H3C-CH2-CH(CH2CH3)-。
术语“卤素”表示氯、溴、碘和氟。术语“卤素”添加到“烷基”、“亚烷基”或“环烷基”基团(饱和或不饱和)上是这样的烷基或环烷基,其中一个或多个氢原子被卤素原子取代,所述卤素原子选自氟、氯或溴,优选氟和氯,特别优选氟。实施例包括:H2FC-、HF2C-、F3C-。
术语苯基是指以下环的基团
术语吡啶基是指下列环的基团
术语哒嗪是指以下环
术语环丙基是指以下环
除非明确指示,否则贯穿整个说明书和所附权利要求书,给定的化学式或名称应当包括互变异构体和所有立体异构体、光学异构体和几何异构体(例如对映异构体、非对映异构体、E/Z异构体等)及其外消旋体以及处于不同比例的单独的对映异构体的混合物、非对映异构体的混合物、或任何前述形式的混合物,其中存在此类异构体和对映异构体,以及盐,包括其药学上可接受的盐及其溶剂化物,例如像水合物,包括游离化合物的溶剂化物或化合物的盐的溶剂化物。
一般而言,可根据本领域技术人员已知的合成原理,例如通过分离相应的混合物、通过使用立体化学纯的起始材料和/或通过立体选择性合成获得基本上纯的立体异构体。本领域已知如何制备光学活性形式,诸如通过拆分外消旋形式或通过合成,例如从光学活性起始材料开始和/或通过使用手性试剂。
本发明的对映异构体纯的化合物或中间体可以通过不对称合成制备,例如通过制备和随后分离适当的非对映异构体化合物或中间体,其可以通过已知方法(例如,通过色谱分离或结晶)和/或通过使用诸如手性原料、手性催化剂或手性助剂的手性试剂来分离。
此外,本领域技术人员已知如何从相应的外消旋混合物制备对映异构体纯的化合物,例如通过在手性固定相上色谱分离相应的外消旋混合物;或通过使用适当的拆分剂拆分外消旋混合物,例如借助用光学活性的酸或碱进行外消旋化合物的非对映异构体盐形成、随后拆分所述盐并且从所述盐中释放所希望的化合物或通过用光学活性的手性助剂衍生化相应的外消旋化合物、随后进行非对映异构体分离并且除去手性辅助基团;或通过对外消旋体的动力学拆分(例如,通过酶促拆分);通过在合适的条件下从对映形态晶体的聚集物对映选择性结晶或通过在光学活性手性助剂的存在下从合适的溶剂中(分级)结晶。
短语“药学上可接受的”在本文中用于指代如下的那些化合物、材料、组合物和/或剂型,它们在合理的医学判断范围内适合使用,而没有过度的毒性、刺激、过敏反应或者其他问题或并发症,并且与合理的收益效益/风险比相称。
如本文所用,“药学上可接受的盐”是指所公开的化合物的衍生物,其中母体化合物与酸或碱形成盐或复合物。
与含有碱性部分的母体化合物形成药学上可接受的盐的酸的例子包括无机酸或有机酸,诸如苯磺酸、苯甲酸、柠檬酸、乙磺酸、富马酸、龙胆酸、氢溴酸、盐酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、4-甲基-苯磺酸、磷酸、水杨酸、琥珀酸、硫酸和酒石酸。
与含有酸性部分的母体化合物形成药学上可接受的盐的阳离子和碱的例子包括Na+、K+、Ca2+、Mg2+、NH4 +、L-精氨酸、2,2'-亚氨基双乙醇、L-赖氨酸、N-甲基-D-谷氨酰胺或三(羟甲基)-氨基甲烷。
本发明的药学上可接受的盐可以通过常规化学方法从含有碱性或酸性部分的母体化合物合成。通常,此类盐可以通过使这些化合物的游离酸或碱形式与足量的适当的碱或酸在水中或在有机稀释剂(诸如醚、乙酸乙酯、乙醇、异丙醇或乙腈或其混合物)中反应来制备。
除上文所提及的那些酸以外的酸的盐也构成本发明的一部分,其例如可用于纯化或分离本发明的化合物(例如三氟乙酸盐)。
生物学测定
化合物的生物学活性通过以下方法确定:
测定A:生化ATX测定
将5nM重组ATX(Cayman Chemicals)补充到含有3mM KCl、1mM CaCl2、1mMMgCl20.14mM NaCl和0.1%牛血清白蛋白的50mM Tris缓冲液(pH 8.0)中。将测试化合物溶解在DMSO中并且在0.1nM至10μM的范围内进行测试。通过添加2.5μL 10μM 18:1LPC(AvantiLipids,美国亚拉巴马州阿拉巴斯特(Alabaster))开始酶反应(22.5μL)。在室温下孵育2h后,通过添加20μL水(含有500nM 20:4LPA作为内标和100μL 1-丁醇用于提取LPA)来停止反应。随后,将板以4000rpm、4℃离心2min。所得上层丁醇相直接用于注射在RapidFire系统(Agilent)中。
将RapidFire自动进样器与二元泵(Agilent 1290)和Triple Quad 6500(ABSciex,加拿大多伦多)偶联。此系统配备有10-μL环、5-μL Waters Atlantis HILIC筒柱(Waters,英国埃尔斯特里)、含有10mM乙酸铵的90%乙腈作为洗脱液A、和含有10mM乙酸铵的40%乙腈作为洗脱液B。细节参见(Bretschneider等人,SLAS Discovery,2017)。1MS在负模式下运行,其中源温度为550℃,气帘气=35,气体1=65,并且气体2=80。确定了各个LPA的以下跃迁和MS参数(DP:去簇电势和CE:碰撞能量):
18:1LPA,处在435.2/152.8,DP=-40,CE=-28,并且20:4LPA,处在457.2/152.8,DP=-100,CE=-27)。
监测18:1LPA的形成并且和评价为与20:4LPA的比率。
表1:如在测定A中获得的本发明化合物的生物学数据
表2:如在测定A中获得的现有技术化合物的生物学数据(WO 2014/139882中的实施例2和12)。
表3:如在测定A中获得的现有技术化合物(ACS Med.Chem.Lett.2017,8,1252-1257中的实施例19)的生物学数据
测定B:全血ATX测定
向45μL人全血中补充5μL溶解在磷酸盐缓冲盐水中的测试化合物(浓度范围0.12nM-100μM)。将此混合物在37℃下孵育1h,并且通过添加100μL 40mM磷酸氢二钠缓冲液停止,所述缓冲液含有30mM柠檬酸(pH 4)和1μM 17:0LPA(内标)。通过添加500μL 1-丁醇,然后在4℃下以4000rpm离心10min来提取LPA。从所得有机上清液中,将200μL等分试样转移到96深孔板中,并且转移至基于RapidFire的MS/MS测量。
将RapidFire自动进样器与二元泵(Agilent 1290)和Triple Quad 6500(ABSciex,加拿大多伦多)偶联。此系统配备有10-μL环、5-μL Waters Atlantis HILIC筒柱(Waters,英国埃尔斯特里)、含有10mM乙酸铵的90%乙腈作为洗脱液A、和含有10mM乙酸铵的40%乙腈作为洗脱液B。细节参见(Bretschneider等人,SLAS Discovery,2017,22,425-432)。MS在负模式下运行,其中源温度为550℃,气帘气=35,气体1=65,并且气体2=80。确定了各个LPA的以下跃迁和MS参数(DP:去簇电势和CE:碰撞能量):18:2LPA,处在433.2/152.8,DP=-150,CE=-27,并且17:0LPA,处在423.5/152.8,DP=-100。
监测18:2LPA的形成并且和评价为与17:0LPA的比率。
表4:如在测定B中获得的本发明化合物的生物学数据。
表5:如在测定B中获得的现有技术化合物的生物学数据(WO 2014/139882中的实施例2和12)。
表6:如在测定B中获得的现有技术化合物(ACS Med.Chem.Lett.2017,8,1252-1257中的实施例19)的生物学数据。
测定C:体内
将测试物质溶解在补充有0.015%Tween 80的0.5%纤维素羟乙基醚(natrosol)中,以5mg/kg的剂量口服应用于大鼠。在化合物施用前和使用EDTA作为凝血剂在冰上应用后8小时收集血液样品。随后,通过离心制备血浆并且储存在-20℃直到进行分析。
通过使用由Scherer等人(Clinical chemistry 2009,55,1218-22)所述的程序从血浆样品中提取LPA。将35μL肝素化血浆与200μL 40mM磷酸氢二钠缓冲液混合,所述缓冲液含有30mM柠檬酸(pH 4)和1μM 17:0LPA(内标。随后,添加500μL丁醇并且剧烈摇晃10min。此后将样品在4000rpm、4℃下离心10min。将500μL有机上层相转移到新鲜的96深孔板中,并且在15psi的温和氮气流下蒸发45min。在LC-MS分析之前,将所得残余物溶解在100μL乙醇中。
用于分析体内样品的LC-MS方法
Triple Quad 6500(ABSciex,加拿大多伦多ABSciex)配备有Agilent 1290LC系统(Agilent,加利福尼亚州圣克拉拉)、CTC自动进样器和Atlantis 50×2.1-mm、3-μm HILICLC柱(Waters,英国埃尔斯特里)。洗脱液A含有在水中的0.2%甲酸和50mM甲酸铵,而洗脱液B由在乙腈中的0.2%甲酸组成。LC梯度从95%溶剂B开始,并且在1.5min内下降到75%并且在0.2min内下降到50%溶剂B,并且流速从500进一步增加至700μL·min–1。在1.8min时,将溶剂B设置回95%,并且保持恒定0.7min,以使柱重新平衡。对以下LPA物质进行监测(DP:去簇电势和CE:碰撞能):16:0LPA,处在409.2/152.8,DP=-150,CE=-28;18:0LPA,处在437.3/152.8,DP=-60,CE=-28;18:1LPA,处在435.2/152.8,DP=-40,CE=-28;18:2LPA,处在433.2/152.8,DP=-150,CE=-28;20:4LPA,处在457.2/152.8,DP=-100,CE=-29,并且17:0LPA,处在423.5/152.8,DP=-100,CE=-36。
LPA消耗百分比是基于测试化合物应用前的基线LPA水平计算的。LPA之和指物质16:0;18:0;18:1;18:2和20:4。
表7:如在测定C中获得的本发明化合物的生物学数据。
表8:如在测定C中获得的现有技术化合物的生物学数据(WO 2014/139882中的实施例2和12)。
表9:如在测定C中获得的现有技术化合物(ACS Med.Chem.Lett.2017,8,1252-1257中的实施例19)的生物学数据。
治疗方法
本发明涉及通式(I)的化合物,其可用于预防和/或治疗与ATX和/或LPA的生物活性相关的或由其调节的疾病和/或病症,包括但不限于治疗和/或预防炎性病症、纤维化疾病、呼吸系统病症、肾脏病症、肝脏病症、血管和心血管病症、癌症、眼部病症、代谢病症、胆汁淤积和其他形式的慢性瘙痒以及急性和慢性器官移植排斥反应和神经系统病症。
通式(I)的化合物可用于预防和/或治疗炎性病症,包括但不限于肖格伦综合征、关节炎、骨关节炎、多发性硬化、系统性红斑狼疮、炎性肠病、炎性气道疾病诸如慢性阻塞性肺疾病(COPD)和慢性哮喘;纤维化疾病,包括但不限于间质性肺病(ILD),包括进行性纤维化间质性肺病(PFILD)诸如特发性肺纤维化(IPF)和SSC-ILD、家族性间质性肺病心肌和血管纤维化、肾纤维化、肝纤维化、肺纤维化、皮肤纤维化、胶原血管疾病,包括系统性硬化症(SSc)和包裹性腹膜炎;呼吸系统病症,包括但不限于不同病因的弥漫性实质性肺病,包括医源性药物诱导的纤维化、职业和/或环境诱导的纤维化、系统性疾病和血管炎、肉芽肿性疾病(结节病、过敏性肺炎)、肾病症,包括但不限于急性肾损伤和伴有或不伴有蛋白尿的慢性肾病,包括终末期肾病(ESRD)、局灶节段性肾小球硬化、IgA肾病、血管炎/系统性疾病以及急性和慢性肾移植排斥反应;肝脏病症,包括但不限于肝硬化、肝淤血、胆汁淤积性肝病,包括瘙痒、原发性胆汁性胆管炎、非酒精性脂肪性肝炎和急性和慢性肝移植排斥;血管病症,包括但不限于动脉粥样硬化、血栓性血管疾病以及血栓性微血管病、增生性动脉病(诸如周围有粘液性细胞外基质的肿胀的肌内膜细胞和结节增厚)、内皮功能障碍;心血管病症,包括但不限于急性冠脉综合征、冠心病、心肌梗死、动脉和肺动脉高压、心律失常诸如心房颤动、中风和其他血管损害;癌症和癌症转移,包括但不限于乳腺癌、卵巢癌、肺癌、前列腺癌、间皮瘤、胶质瘤、肝癌、胃肠道癌及其进展和转移性侵袭;眼部病症,包括但不限于增殖性和非增殖性(糖尿病性)视网膜病变、干和湿性年龄相关性黄斑变性(AMD)、黄斑水肿、中央动脉/静脉阻塞、创伤性损伤、青光眼;代谢病症,包括但不限于肥胖症、血脂异常和糖尿病;神经系统病症,包括但不限于神经病理性疼痛、阿尔茨海默病、精神分裂症、神经炎症(例如,星形胶质细胞增生)、周围和/或自主(糖尿病性)神经病变。
因此,本发明涉及作为药剂的通式(I)的化合物。
此外,本发明涉及通式(I)的化合物用于治疗和/或预防与ATX和/或LPA的生物活性相关或由其调节的疾病和/或病症的用途。
此外,本发明涉及通式(I)的化合物用于治疗和/或预防与ATX和/或LPA的生物活性相关或由其调节的疾病和/或病症的用途,所述疾病和/或病症包括但不限于炎性病症、纤维化疾病、呼吸系统病症、肾脏病症、肝脏病症、血管和心血管病症、癌症、眼部病症、代谢病症、胆汁淤积和其他形式的慢性瘙痒以及急性和慢性器官移植排斥反应和神经系统病症。
此外,本发明涉及通式(I)的化合物用于治疗和/或预防炎性病症的用途,所述炎性病症包括但不限于肖格伦综合征、关节炎、骨关节炎、多发性硬化、系统性红斑狼疮、炎性肠病、炎性气道疾病诸如慢性阻塞性肺疾病(COPD)和慢性哮喘;纤维化疾病,包括但不限于间质性肺病(ILD),包括进行性纤维化间质性肺病(PFILD)诸如特发性肺纤维化(IPF)和SSC-ILD、家族性间质性肺病心肌和血管纤维化、肾纤维化、肝纤维化、肺纤维化、皮肤纤维化、胶原血管疾病,包括系统性硬化症(SSc)和包裹性腹膜炎;呼吸系统病症,包括但不限于不同病因的弥漫性实质性肺病,包括医源性药物诱导的纤维化、职业和/或环境诱导的纤维化、系统性疾病和血管炎、肉芽肿性疾病(结节病、过敏性肺炎)、肾病症,包括但不限于急性肾损伤和伴有或不伴有蛋白尿的慢性肾病,包括终末期肾病(ESRD)、局灶节段性肾小球硬化、IgA肾病、血管炎/系统性疾病以及急性和慢性肾移植排斥反应;肝脏病症,包括但不限于肝硬化、肝淤血、胆汁淤积性肝病,包括瘙痒、原发性胆汁性胆管炎、非酒精性脂肪性肝炎和急性和慢性肝移植排斥;血管病症,包括但不限于动脉粥样硬化、血栓性血管疾病以及血栓性微血管病、增生性动脉病(诸如周围有粘液性细胞外基质的肿胀的肌内膜细胞和结节增厚)、内皮功能障碍;心血管病症,包括但不限于急性冠脉综合征、冠心病、心肌梗死、动脉和肺动脉高压、心律失常诸如心房颤动、中风和其他血管损害;癌症和癌症转移,包括但不限于乳腺癌、卵巢癌、肺癌、前列腺癌、间皮瘤、胶质瘤、肝癌、胃肠道癌及其进展和转移性侵袭;眼部病症,包括但不限于增殖性和非增殖性(糖尿病性)视网膜病变、干和湿性年龄相关性黄斑变性(AMD)、黄斑水肿、中央动脉/静脉阻塞、创伤性损伤、青光眼;代谢病症,包括但不限于肥胖症、血脂异常和糖尿病;神经系统病症,包括但不限于神经病理性疼痛、阿尔茨海默病、精神分裂症、神经炎症(例如,星形胶质细胞增生)、周围和/或自主(糖尿病性)神经病变。
在另一方面,本发明涉及通式(I)的化合物,其用于治疗和/或预防上述疾病和病症。
在另一方面,本发明涉及通式(I)的化合物用于制备治疗和/或预防上述疾病和病症的药剂的用途。
在本发明的另一方面,本发明涉及用于治疗或预防上述疾病和病症的方法,所述方法包括向人类施用有效量的通式(I)的化合物。
药物组合物
用于施用式(I)的化合物的合适制剂对于本领域普通技术人员来说将是显而易见的,并且包括例如片剂、丸剂、胶囊、栓剂、锭剂、糖锭、溶液、糖浆、酏剂、小药囊、注射剂、吸入剂和散剂等。
合适的片剂可以例如通过将一种或多种根据式I的化合物与已知的赋形剂混合获得,所述赋形剂例如惰性稀释剂、载体、崩解剂、佐剂、表面活性剂、粘合剂和/或润滑剂。
组合疗法
根据本发明的化合物可以与本领域已知使用的其他治疗选项组合,使得有效量的至少两种活性化合物用于同时治疗本发明对其有用的适应症。尽管组合疗法优选包括同时向患者施用两种活性化合物,但同时向患者施用化合物不是必须的,尽管有效量的单独化合物将同时存在于患者中。根据本发明的化合物可以与一种或多种组合伴侣一起施用,如本文另外所述。
因此,本发明提供了根据前述实施方案中任一项所述的式(I)的化合物,其特征在于除了用来自由IL6调节剂、抗IL6R调节剂和IL13/IL-4JAKi调节剂组成的列表中的一种或多种抗炎分子治疗外,还施用式(I)的化合物。
根据另一方面,本发明提供了根据前述实施方案中任一项所述的式(I)的化合物,其特征在于除了用来自由CB2激动剂、TGF调节剂、FGFR调节剂、VEGFR抑制剂、PDGFR抑制剂、FGF调节剂、αvβ6整合素调节剂、抗CTGF抗体、ROCK2抑制剂、rhPTX-2(穿透素-2)、JNK1抑制剂、LOXL2抑制剂、半乳糖凝集素3抑制剂、MK2抑制剂、Wnt通路抑制剂、TGFR抑制剂、PDE4调节剂、TRPA1抑制剂和微RNA调节剂组成的列表的中的一种或多种抗纤维化分子治疗外,还施用式(I)的化合物。
根据另一方面,本发明提供了根据前述实施方案中任一项所述的式(I)的化合物,其特征在于除了尼达尼布外,还施用式(I)的化合物。
根据另一方面,本发明提供了根据前述实施方案中任一项所述的式(I)的化合物,其特征在于除了吡非尼酮外,还施用式(I)的化合物。
制备
根据本发明的化合物可以使用本领域技术人员已知并且在有机合成文献中描述的合成方法获得。优选地,化合物类似地通过在下文中更加全面解释(特别是如在实验部分中所述)的制备方法获得。
用于制备根据本发明的化合物的通用方法对研究以下方案的本领域技术人员而言将变得明显。起始材料可通过文献或本文中所述的方法制备或可以类似或相似方式制备。可使用常规保护基团来保护起始材料或中间体中的任何官能基团。这些保护基团可在反应序列中的适当阶段中使用本领域技术人员熟悉的方法来再次裂解。
通过哒嗪基卤化物或三氟甲磺酸酯(III)与胺(II)(其中X是离去基团诸如Cl、Br、I或OTf(三氟甲磺酸酯))的钯介导的布赫瓦尔德(Buchwald)反应或铜介导的乌尔曼(Ullmann)反应获得通式(I)的化合物。
用于胺(II)的合成路线取决于取代基L和M。例如,由腈(IV)经由Kulinkovich-Szymoniak反应得到中间体(V)(其中X是离去基团,例如表示Cl、Br、I或OTf(三氟甲磺酸酯),然后与胺(K)的钯介导的布赫瓦尔德反应或铜介导的乌尔曼反应来制备通式(VI)的化合物。
可替代地,通过以下方式制备胺(II):由羧酸(VII)通过柯提斯(Curtius)重排得到中间体(VIII),然后将Boc-基团去保护以获得胺(V)。后者可以通过以下方式转化为胺(VI):芳基卤化物与胺(K)的钯介导的布赫瓦尔德反应或铜介导的乌尔曼反应,其中X是离去基团,诸如Cl、Br、I或OTf(三氟甲磺酸酯)。
另一方面,通过酮(IX)的还原胺化在一个步骤中获得呈外消旋混合物的胺(XII)。它们也可以在三步骤过程中通过与对映异构体纯形式的叔丁基亚磺酰胺(X)缩合以提供叔丁基亚磺酰基亚胺(X)来以对映异构体纯形式来制备。后者被还原成胺(XI)。随后用例如甲醇HCl裂解N-叔丁基亚磺酰基来提供胺(XII)。
实施例
实验部分
以下的实施例旨在说明本发明而不限制本发明。术语“环境温度”和“室温”可互换使用,并指定为约20℃的温度。
缩写:
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起始化合物的制备
实施例I
实施例I.1
3-{[6-(二氟甲基)吡啶-3-基]甲氧基}-6-碘哒嗪
将在25mL THF中的17.7g(53.3mmol)3,6-二碘哒嗪(CAS号20698-04-8)和8.50g(53.41mmol)[6-(二氟甲基)吡啶-3-基]甲醇(CAS号946578-33-2)冷却至0℃并且添加2.33g(53.3mmol)氢化钠(55%纯度)。将反应混合物在室温下搅拌过夜并且在减压下浓缩。将残余物用水稀释。将沉淀物过滤,用水和tBME洗涤,并且在50℃下在真空中干燥过夜以得到17.5g产物。
C11H8F2IN3O (M=363.1g/mol)
ESI-MS: 364[M+H]+
Rt(HPLC): 0.90min(方法A)
根据上述通用程序(实施例I.1)制备以下化合物:
实施例II
1-(6-溴吡啶-3-基)环丙-1-胺
将732mg(4.00mmol)6-溴吡啶-3-甲腈(CAS号139585-70-9)用30mL乙醚稀释并且在室温下逐滴添加1.37mL(4.67mmol)四异丙醇钛。在冷却在15℃-20℃下,向混合物中添加2.95mL(8.84mmol)乙基溴化镁(在乙醚中3M)。将反应混合物在室温下搅拌30min。在冷却下,将1.26mL(9.97mmol)三氟化硼-乙醚合物添加到混合物中并且将其在室温下搅拌45min。在冷却下将反应混合物用20mL 2N NaOH淬灭,在室温下搅拌2h并且通过硅藻土过滤。将滤饼用乙醚洗涤。将滤液的水相用乙醚萃取,并且将所有有机层在真空中还原。将残余物通过HPLC纯化以得到203mg产物。
C8H9BrN2 (M=436.3g/mol)
ESI-MS: 214/216Br[M+H]+
Rt(HPLC): 0.92min(方法B)
实施例III
[1-(4-溴-2-氟-苯基)-环丙基]-氨基甲酸叔丁酯
将在氩气气氛下的在5mL叔丁醇中的0.50g(1.93mmol)1-(4-溴-2-氟苯基)环丙烷-1-甲酸(CAS编号872422-15-6)用0.43mL(2.51mmol)DIPEA和0.50mL(2.32mmol)二苯基磷酰基叠氮化物处理。将反应混合物回流过夜。将反应混合物在减压下浓缩。将残余物溶解在200ml乙酸乙酯中;将有机相用150mL 5%柠檬酸、饱和NaHCO3-溶液、饱和NaCl-溶液洗涤,干燥并且蒸发成粗产物。将残余物通过柱色谱法(硅胶:Cy/EE=4/1)纯化以得到541mg产物。
C14H17BrFNO2 (M=330.2g/mol)
ESI-MS: 331/333Br[M+H]+
Rt(HPLC): 1.17min(方法D)
实施例IV
实施例IV.1
N-{1-[4-(4-乙酰基哌嗪-1-基)苯基]环丙基}氨基甲酸叔丁酯
将在50mL 1,4-二噁烷中的4.50g(14.4mmol)N-[1-(4-溴苯基)环丙基]氨基甲酸叔丁酯(CAS号360773-84-8)、2.22g(17.3mmol)1-(哌嗪-1-基)乙-1-酮(CAS号13889-98-0)、0.18g(0.22mmol)RUPHOS环钯配合物(CAS号1028206-60-1)和2.08g(21.6mmol)叔丁醇钠在80℃下搅拌10min。将反应混合物用EtOAc稀释并且用半浓K2CO3溶液洗涤。将有机层用Na2SO4干燥并且在真空中浓缩。将残余物通过柱色谱法纯化(硅胶;DCM/MeOH(95:05))以得到3.30g产物。
C20H29N3O3 (M=359.5g/mol)
ESI-MS: 360[M+H]+
Rt(HPLC): 0.71min(方法D)
根据上述通用程序(实施例IV.1)制备以下化合物:
实施例V
实施例V.1
1-{4-[4-(1-氨基环丙基)苯基]哌嗪-1-基}乙-1-酮
将2.42g(6.73mmol)2-(4-氰基苯基)-2,7-二氮杂螺[3.5]壬烷-7-甲酸叔丁酯(实施例IV.1)用50mL DCM稀释并且添加5mL TFA。将反应混合物在室温下搅拌过夜。将混合物蒸发并且将残余物溶解在MeOH中。将溶液用NaHCO3碱化,过滤并且蒸发。将粗产物通过柱色谱法纯化(硅胶;DCM/MeOH/NH3(9:1:0.1)),然后用HPLC纯化以得到650mg产物。
C15H21N3O (M=259.3g/mol)
ESI-MS: 260[M+H]+
Rt(HPLC): 0.72min(方法A)
根据上述通用程序(实施例V.1)制备以下化合物:
实施例VI
实施例VI.1
N-{1-[4-(1-氨基环丙基)苯基]哌啶-4-基}-N-甲基乙酰胺
将380mg(1.22mmol)N-[1-(4-溴苯基)环丙基]氨基甲酸叔丁酯(CAS号360773-84-8)和570mg(3.65mmol)N-甲基-N-(哌啶-4-基)乙酰胺(CAS号83180-55-6)用1,4-二噁烷稀释,并且添加870mg(2.68mmol)碳酸铯和50mg(0.06mmol)XPHOS Pd G3。将反应混合物在80℃下搅拌2.5h,过滤并且用EtOAc稀释。将有机层用半浓NaHCO3-溶液洗涤,用PTK干燥并且在减压下浓缩。将残余物通过HPLC纯化。将粗中间体用2mL在1,4-二噁烷中的4N HCl溶解,并且将混合物在室温下搅拌30min。将反应混合物在真空中蒸发,并且将残余物通过HPLC纯化以得到48.0mg产物。
C17H25N3O (M=287.4g/mol)
ESI-MS: 288[M+H]+
Rt(HPLC): 0.78min(方法A)
根据上述通用程序(实施例VI.1)制备以下化合物:
实施例VII
实施例VII.1
(R)-N-[(1E)-1-[4-(4-乙酰基哌嗪-1-基)苯基]亚乙基]-2-甲基丙烷-2-亚磺酰
胺
将1.00g(4.06mmol)1-[4-(4-乙酰基苯基)哌嗪-1-基]乙-1-酮(CAS号104080-54-8)、0.98g(8.12mmol)(R)-2-甲基丙烷-2-亚磺酰胺(CAS号196929-78-9)和2.97mL(12.2mmol)乙醇钛(85%)在10mL THF中的混合物在80℃下搅拌过夜。冷却后,将反应混合物用半浓NaCl溶液和EtOAc稀释。将沉淀物过滤,并且分离两层滤液。将有机层用Na2SO4干燥并且在减压下蒸发。将残余物通过柱色谱法纯化(硅胶;DCM/MeOH(9:1))以得到1.30g产物。
C18H27N3O2S (M=349.5g/mol)
ESI-MS: 350[M+H]+
Rt(HPLC): 0.91min(方法D)
根据上述通用程序(实施例VII.1)制备以下化合物:
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实施例VIII
实施例VIII.1
(R)-N-[(1R)-1-[4-(4-乙酰基哌嗪-1-基)苯基]乙基]-2-甲基丙烷-2-亚磺酰胺
向1.30g(3.72mmol)(R)-N-[(1E)-1-[4-(4-乙酰基哌嗪-1-基)苯基]-亚乙基]-2-甲基丙烷-2-亚磺酰胺(实施例VII.1)在2mL THF中的溶液中添加水,并且冷却至-50℃。将反应混合物用0.42g(11.2mmol)硼氢化钠处理并且温热至室温。向混合物中添加半浓NaHCO3-溶液,并且分离有机相,干燥并且在真空中浓缩。将残余物通过HPLC纯化以得到0.50g所希望的非对映异构体。
C18H29N3O2S (M=351.5g/mol)
ESI-MS: 352[M+H]+
Rt(HPLC): 0.82min(方法D)
根据上述通用程序(实施例VIII.1)制备以下化合物:
实施例IX
实施例IX.1
1-(4-{4-[(1R)-1-氨基乙基]苯基}哌嗪-1-基)乙-1-酮
将550mg(1.56mmol)(R)-N-[(1R)-1-[4-(4-乙酰基哌嗪-1-基)苯基]乙基]-2-甲基-丙烷-2-亚磺酰胺(实施例VIII.1)溶解在10mL THF中并且用0.98mL(3.91mmol)在1,4-二噁烷中的4N氯化氢处理。将反应混合物在室温下搅拌30min。将沉淀物过滤并且用THF洗涤。将固体溶解在MeOH中并且添加碱性树脂。将树脂滤出,并且在减压下蒸发滤液以得到0.33g产物。
C14H21N3O (M=247.3g/mol)
ESI-MS: 231[M+H-NH3]+
Rt(HPLC): 0.59min(方法D)
根据上述通用程序(实施例IX.1)制备以下化合物:
实施例X
1-{4-[4-(1-氨基乙基)苯基]哌嗪-1-基}乙-1-酮
将在10mL MeOH中的0.90g(3.65mmol)1-[4-(4-乙酰基哌嗪-1-基)苯基]乙-1-酮(CAS号104080-54-8)用2.82g(36.54mmol)乙酸铵和0.28g(4.38mmol)氰基硼氢化钠处理。将反应混合物在80℃下搅拌1h,用甲基-THF稀释并且用浓K2CO3-溶液洗涤。将有机相用Na2SO4干燥并且在真空中浓缩至干以得到650mg产物。
C14H21N3O (M=247.3g/mol)
ESI-MS: 231[M+H-NH3]+
Rt(HPLC): 0.69min(方法A)
最终化合物的制备
实施例1.1
1-[4-(4-{1-[(6-{[4-(三氟甲基)苯基]甲氧基}哒嗪-3-基)氨基]环丙基}-苯基)
哌嗪-1-基]乙-1-酮
将106mg(0.28mmol)3-碘-6-{[6-(三氟甲基)吡啶-3-基]甲氧基}-哒嗪(实施例I.2)、60.0mg(0.23mmol)1-{4-[4-(1-氨基环丙基)苯基]-哌嗪-1-基}乙-1-酮(实施例V.1)、8.8mg(46.3μmol)碘化铜、18.6mg(0.09mmol)[(2,6-二氟苯基)氨基甲酰基]甲酸(CAS号1018295-42-5)和147mg(0.69mmol)磷酸钾在3mL DMSO中的混合物在80℃下搅拌。15min后,将反应混合物用EtOAc稀释并且用NH4Cl溶液/氨-溶液(9:1)洗涤。将有机相用Na2SO4干燥并且在真空中还原。将残余物通过HPLC纯化以得到23.0mg产物。
C26H27F3N6O2 (M=512.5g/mol)
ESI-MS: 513[M+H]+
Rt(HPLC): 0.79min(方法A)
1H NMR(400MHz,DMSO-d6)δ8.84(d,J=1.14Hz,1H),8.13(dd,J=1.46,8.05Hz,1H),7.91(d,J=7.98Hz,1H),7.54(s,1H),7.07(d,J=8.74Hz,1H),7.00(d,J=9.51Hz,1H),6.89(s,1H),6.79-6.88(m,3H),5.47(s,2H),3.54(br d,J=3.30Hz,4H),3.04-3.10(m,2H),2.96-3.04(m,2H),2.02(s,3H),1.14-1.23(m,2H),1.08-1.14(m,2H)。
根据上述通用程序(实施例1.1)制备以下化合物:
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分析型HPLC方法
方法A
分析柱:XBridge C18(Waters)2.5μm;3.0x 30mm;柱温:60℃
方法B
分析柱:Stable Bond(Agilent)1.8μm;3.0x 30mm;柱温:60℃
方法C
分析柱:XBridge C18_3.0x 30mm_2.5μm(Waters);柱温:60℃
方法D
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Claims (21)
1.一种根据式(I)的化合物
其中
A是被由氟和F1-3-氟-C1-3-烷基组成的组中的一个或两个成员取代的吡啶基;
E选自苯基和吡啶基,任选被由氟和C1-3-烷基组成的组中的一个或两个成员取代;
K选自
R3选自R4(O)C-和R5(O)C(CH3)N-;
R4是甲基;
R5是甲基;
L和M独立地选自H、甲基和HOH2C-,
或L和M与它们所连接的碳一起形成环丙基环。
2.根据权利要求1所述的式(I)的化合物,其中A是被F1-3-氟-C1-烷基中的一个或两个取代的吡啶基。
3.根据权利要求1所述的式(I)的化合物,其中A选自
4.根据权利要求1至3中任一项所述的式(I)的化合物,其中E选自苯基和吡啶基,任选被由氟和甲基组成的组中的一个或两个成员取代。
5.根据权利要求1至3中任一项所述的式(I)的化合物,其中E选自
6.根据权利要求1所述的式(I)的化合物,其选自
7.下式化合物
8.下式化合物
9.下式化合物
10.下式化合物
11.下式化合物
12.下式化合物
13.下式化合物
14.下式化合物
15.下式化合物
16.下式化合物
17.一种根据权利要求1至16中的任一项所述的化合物的盐。
18.根据权利要求17所述的盐,其中所述盐是药学上可接受的盐。
19.一种药物组合物,其包含根据权利要求1至16中任一项所述的至少一种式I的化合物或根据权利要求17或18所述的盐和一种或多种药学上可接受的赋形剂。
20.根据权利要求1至16中任一项所述的化合物或根据权利要求17或18所述的盐在制备用于治疗或预防炎性气道疾病或纤维化疾病的药物中的用途。
21.根据权利要求1至16中任一项所述的化合物或根据权利要求17或18所述的盐在制备用于治疗或预防IPF或系统性硬化症(SSc)的药物中的用途。
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CA3145960A1 (en) | 2021-01-28 |
US20220281838A1 (en) | 2022-09-08 |
JP7240554B2 (ja) | 2023-03-15 |
WO2021013833A1 (en) | 2021-01-28 |
EP4003978B1 (en) | 2024-05-01 |
BR112021026267A2 (pt) | 2022-05-31 |
MX2022000955A (es) | 2022-02-14 |
CL2022000111A1 (es) | 2022-10-21 |
EP4003978A1 (en) | 2022-06-01 |
AU2020318697A1 (en) | 2022-01-27 |
KR20220035950A (ko) | 2022-03-22 |
IL289800A (en) | 2022-03-01 |
CN114127054A (zh) | 2022-03-01 |
JP2022541613A (ja) | 2022-09-26 |
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