CN112424159A - 新颖的p62配体化合物及包含其的用于预防、改善或治疗蛋白质构象病的组合物 - Google Patents
新颖的p62配体化合物及包含其的用于预防、改善或治疗蛋白质构象病的组合物 Download PDFInfo
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- CN112424159A CN112424159A CN201980047606.1A CN201980047606A CN112424159A CN 112424159 A CN112424159 A CN 112424159A CN 201980047606 A CN201980047606 A CN 201980047606A CN 112424159 A CN112424159 A CN 112424159A
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Abstract
本发明涉及一种新颖的p62配体化合物或者其立体异构体、水合物、溶剂化物或前药;以及包含其作为活性成分的用于预防或治疗蛋白质构象病的药物或食品组合物。根据本发明的p62配体化合物可有效地用作通过活化细胞中的自噬且因此选择性地消除活体内蛋白质、细胞器合聚集体来预防、改善或治疗各种蛋白质构象病的药物组合物。
Description
技术领域
本发明涉及新颖的p62配体化合物及包含其的用于预防或治疗蛋白质构象病的药物或食品组合物。
背景技术
N端规则路径为蛋白分解系统,其中蛋白质的特定N端残基充当降解信号(图1)。N端规则降解信号通过包括N端精氨酸(Nt-Arg)、赖氨酸(Nt-Lys)及组氨酸(Nt-His)的I型碱性残基;以及包括苯丙氨酸(Nt-Phe)、亮氨酸(Nt-Leu)、色氨酸(Nt-Trp)、酪氨酸(Nt-Tyr)及异亮氨酸(Nt-Ile)的II型疏水性残基来例示。这些N端残基与特定N识别子(下文称作N配体)结合。
本发明发明人首次发现或克隆了先前已知的N识别子,即UBR1、UBR2、UBR4及UBR5,并发现它们利用UBR盒作为底物识别结构域(Tasaki,T.等,Mol Cell Biol 25,7120-36(2005))。发明人还发现,UBR盒与诸如N端精氨酸残基的I型N端规则配体(Nt-Arg、Nt-Lys、Nt-His)结合以识别底物且将泛素链连接至该底物。进一步发现UBR1及UBR2具有在2型N端规则配体(Nt-Trp、Nt-Phe、Nt-Tyr、Nt-Leu及Nt-Ile)的结合中起重要作用的N结构域(Sriram,S.M.,Kim,B.Y.&Kwon,Y.T.,Nat Rev Mol Cell Biol 12,735-47(2011))。由N识别子与N端规则配体之间的结合产生的泛素化底物被递送至蛋白酶体,该泛素化底物在其中被降解成短肽。在此过程中,特定N端残基(Nt-Arg、Nt-His、Nt-Lys、Nt-Trp、Nt-Phe、Nt-Tyr、Nt-Leu、Nt-Leu)为结合的基本决定因素,因为N识别子提供靶向N端规则底物所需氢键的大部分(Sriram,S.M.&Kwon,Y.T.,Nat Struct Mol Biol 17,1164-5(2010))。
若细胞中折叠不良的错误折叠蛋白质滞留很长时间,则其经聚集且阻断蛋白酶体功能或减少引起细胞毒素物质的其他细胞功能,且因此错误折叠蛋白质由泛素接合酶泛素化并被递送至蛋白酶体以进行降解(Ji,C.H.&Kwon,Y.T.,Mol Cells 40,441-449(2017))。在正常细胞中,此过程是平稳的且将由错误折叠蛋白质所引起的损伤降至最低,而在衰老神经元中,此过程经减缓以使得泛素化错误折叠蛋白质累积且这些过剩蛋白质废弃物被转换回聚集体(Ciechanover,A.&Kwon,Y.T.,Exp Mol Med 47,e147(2015))。此外,患有退行性脑疾病诸如亨廷顿氏病、帕金森氏病、人疯牛病及葛雷克氏病(Lou Gehrig's disease)等的患者的神经元细胞甚至在蛋白质构象病中具有将特定突变蛋白质转换成聚集体的较强特性,且因此不通过上文所描述的蛋白酶体降解。其原因在于,由于蛋白酶体具有约13埃的窄内径,因此错误折叠蛋白质必须去折叠,而当蛋白质聚集时,其不会去折叠。
同时,自噬(autophagy)是除了泛素-蛋白酶体系统之外的主要胞内蛋白质降解系统。自噬为通过降解衰老或受损细胞的细胞器或损伤或非正常折叠的蛋白质来基本维持细胞体内平衡及基因稳定性的蛋白质降解过程(Ji,C.H.&Kwon,Y.T.,Mol Cells 40,441-449(2017))。特别地,当错误折叠蛋白质聚集体在细胞质中累积时,其可能变为细胞毒素物质,且因此应该通过自噬来接收且降解。自噬的机制主要划分成大自噬(macroautophagy)、小自噬(microautophagy)及伴随蛋白介导的自噬,且其视降解胞内底物的目的而划分成主体自噬及选择性自噬(Dikic,I.&Elazar,Z.,Nat Rev Mol Cell Biol 19,349-364(2018))。其中,选择性自噬及伴随蛋白介导的自噬引起非所需胞内蛋白质及功能异常细胞器选择性降解。通过诱导选择性自噬,基于累积病理学上错误折叠蛋白质及功能异常细胞器的疾病的新疗法的发展目前正在建立新的范例。p62/SQSTM1/Sequestosome-1蛋白对于启动在选择性自噬的机制中作为介质的自噬小体的形成且递送内含物而言至关重要。此时,p62/SQRSM1/Sequestosome-1与错误折叠蛋白质及其聚集体结合,从而递送至自噬小体。p62在将错误折叠蛋白质递送至自噬小体时作为关键过程经历自身寡聚合(Ji&Kwon,Y.T.,MolCells 40,441-449(2017))。此时,将错误折叠蛋白质浓缩在一起以减少体积,从而利用自噬促进降解。PB1区域调节p62的自身寡聚合,但其调节机制不熟知。递送至自噬小体的错误折叠蛋白质-p62共轭物可在自噬小体与溶酶体结合时利用溶酶体酶降解。经由上文所描述的机制,自噬对于通过调节损伤蛋白质及细胞的细胞器中的胞内变化来维持细胞体内平衡至关重要。当自噬功能减弱时,其导致错误折叠蛋白质累积及聚集,从而产生蛋白质构象病(proteinopathy)(Ciechanover,A.&Kwon,Y.T.,Exp Mol Med 47,e147(2015))。本发明的关键技术在于提供一种用于有效地消除引起蛋白质构象病的错误折叠蛋白质或其聚集体的方法。出于此目的,有必要仅活化选择性自噬而不活化对各种生物路径具有广泛效果的主体自噬。
对于活化自噬以治疗蛋白质构象病已进行了积极的研究。正常抑制主体自噬的调节因子是mTOR。使用mTOR抑制剂活化自噬的方法是使用最广泛的(Jung,C.H.,Ro,S.H.,Cao,J.,Otto,N.M.&Kim,D.H.,FEBS Lett 584,1287-95(2010))。特别地,通过使用雷帕霉素(rapamycin)治疗,在过表达APP的AD动物模型中消除淀粉样蛋白β(Ab)及tau蛋白且同时提高认知能力(Caccamo,A.,Majumder,S.,Richardson,A.,Strong,R.&Oddo,S.,J BiolChem 285,13107-20(2010));在过表达tau蛋白的AD动物模型中消除tau蛋白(Rodriguez-Navarro,J.A.等人,Neurobiol Dis 39,423-38(2010));以及在PD小鼠模型中消除过表达的突变α-突触核蛋白蛋白质聚集体(Webb,J.L.,Ravikumar,B.,Atkins,J.,Skepper,J.N.&Rubinsztein,D.C.,J Biol Chem 278,25009-13(2003))。经确认,在HD小鼠中,亨廷顿蛋白聚集体通过使用CCI-779(雷帕霉素样物质)来有效地消除,从而改良动物行为及认知能力(Ravikumar,B.,Duden,R.&Rubinsztein,D.C.,Hum Mol Genet 11,1107-17(2002))。然而,mTOR在各种包括NF-kB的胞内路径中发挥极其重要的作用。因此,虽然其展现出极好的消除蛋白质构象疾病的错误折叠蛋白质聚集体的活性,但存在一定限制,原因在于这些主体自噬活化剂(已知用于调节主体自噬的mTOR是药物靶标)用作治疗剂。
如上文所描述,目前不存在治疗大部分蛋白质构象病的有效治疗剂。在泛素连接酶配体用于消除作为主要原因的错误折叠蛋白质的情况下,当错误折叠蛋白质聚集时难以将其消除。此外,mTOR抑制剂(其是最常用的作为主体自噬活化剂的化合物)除调节自噬之外,在响应于各种外部环境的刺激而调节细胞中的总体基因表达中起广泛作用,因此其就不适合作为治疗剂而言具有缺点。因此,需要开发一种通过活化p62(选择性自噬的关键调节因子)来消除错误折叠蛋白质聚集体而不降低mTOR(主体自噬的调节因子)的活性的方法。
发明内容
在这些情况下,发明人进行了大量研究,发现了一种蛋白质构象病的预防及治疗剂,其使用独立于mTOR而活化自噬的材料,且因此发现与p62、更特别地与p62的ZZ结构域结合的配体与LC3结合且活化自噬,从而导致有效消除诸如突变亨廷顿蛋白及α-突触核蛋白的病原性蛋白质聚集体,且由此其可用于预防、改善或治疗各种蛋白质构象病。已基于这些发现完成本发明。
本发明的目的是提供一种诱导p62蛋白质的活化及寡聚合的新颖的p62配体化合物。
本发明的另一目的是提供一种通过使用前述新颖化合物来将p62及结合p62的错误折叠蛋白质递送至自噬小体且最后将其递送至溶酶体进行消除的方法。
本发明的另一目的是提供一种通过使用前述新颖化合物经由p62蛋白质来增加大自噬活性的方法。
本发明的又一目的是提供一种用于消除错误折叠蛋白质聚集体的药物或食品组合物,其包含作为活性成分的前述新颖化合物。
本发明的另一目的是提供一种用于预防、改善或治疗蛋白质构象病的药物或食品组合物,其包含作为活性成分的前述新颖化合物。
为实现以上目的,本发明的一个实施方式提供一种充当p62蛋白质配体的新颖的化合物。优选地,根据本发明的新颖的p62配体与p62的ZZ结构域结合。
本发明的另一实施方式提供一种用于预防及治疗诸如神经退行性疾病的蛋白质构象病的药物组合物;或一种用于预防或改善蛋白质构象病的健康功能性食品,其包含作为活性成分的与p62蛋白质的ZZ结构域结合的配体。
本发明的另一实施方式提供:(1)诱导p62寡聚合和结构活化的方法;(2)增强p62-LC3结合的方法;(3)增加p62向自噬小体的递送的方法;(4)活化自噬的方法;以及(5)消除错误折叠蛋白质聚集体的方法,该方法包括用与p62的ZZ结构域结合的配体来治疗细胞或p62蛋白质的步骤。
本发明的又一实施方式提供一种通过活化将错误折叠蛋白质聚集体直接递送至自噬小体的p62来消除错误折叠蛋白质聚集体(其为退行性脑疾病的致病因子)的技术。
本发明的关键技术在于,通过同时活化p62和自噬来有效地消除错误折叠蛋白质聚集体(其引起退行性脑疾病)。
本发明的药代动力学及关键技术概括于图1中。
特别地,如图1中所示,蛋白质构象病的主要病原性蛋白质诸如突变亨廷顿蛋白及α-突触核蛋白被转换成不溶于水的错误折叠蛋白质,且随后彼此聚集并且生长成寡聚聚集体。这些错误折叠蛋白质进一步生长同时充当神经元中的细胞毒素物质,且随后生长成大型寡聚或纤维状聚集体,最终形成包涵体。在上文过程中,诸如BiP的内质网伴随蛋白(①)通过ATE1 R-转移酶经由N端精氨酸化(②)产生大量Nt-Arg,且随后使精氨酸化的BiP(R-BiP)易位至细胞质中并与错误折叠的亨廷顿蛋白或α-突触核蛋白(③)结合。作为配体,R-BiP的Nt-Arg与p62的ZZ结构域结合。由于所述结合,p62的不正常活化的闭合形式被改变为开放形式,从而导致结构活化(④),且因此暴露PB1和LC3结合的区域。此活化由于p62的二硫键(⑤)导致寡聚物及高分子量聚集体的形成,以及与最后递送至自溶酶体(⑥)的自噬小体标志物LC3结合增强。此外,与N端精氨酸结合的p62迁移至内质网膜且活化PI3P介导的自噬小体生物合成(⑦),从而增强胞内自噬(⑧)。
p62为本发明人所提出的用于自噬活化的第一类靶标(图1,⑧)。此外,此前没有完成过提出p62作为用于退行性脑疾病中自噬活化或消除蛋白质聚集体的药物靶标的研究。
自噬是用来降解或回收细胞中非所需或耗尽的细胞组分的机制,且在诸如营养素及能量缺失的条件下,其可对生物合成过程中所使用的能量及代谢物的产生起作用。自噬的机制主要划分成大自噬、小自噬及伴随蛋白介导的自噬,且其视降解胞内基质的目的而划分成主体自噬及选择性自噬。其中,选择性自噬及伴随蛋白介导的自噬引起非所需胞内蛋白质及功能异常细胞器选择性降解。通过诱导选择性自噬,基于累积错误折叠蛋白质及功能异常细胞器的疾病的新疗法的发展目前正建立新范例。
p62蛋白质对于启动自噬小体(在选择性自噬的机制中作为介质)的形成和递送内含物而言至关重要。观测到根据本发明的新颖p62配体的显著p62活化诱导p62自身寡聚合。另外,鉴于经由此自身寡聚合增加p62的自噬小体靶向的事实,这表明根据本发明的新颖的p62配体可通过胞内自噬诱导p62蛋白质的靶向及降解。这些结果意味着根据本发明的新颖的p62配体化合物可用作现有抗蛋白质疾病药物的更有效的或补充替代物。
蛋白分解靶向嵌合体(PROteolysis Targeting Chimera;PROTAC)是识别靶蛋白的配体及识别E3泛素酶的配体的化合物嵌合体。由于用于疾病的现有治疗剂的范例是抑制蛋白质酶,因此开发一种针对无法用现有治疗剂靶向的蛋白质错误折叠的疾病的新治疗剂非常重要。从这些角度而言,PROTAC是相对于无法利用常规酶抑制方法进行靶向的蛋白质通过在泛素-蛋白酶体系统下实现选择性降解的有吸引力的新疗法开发方法。然而,目前对PROTAC的研究仅限于通过仅利用识别E3泛素酶的配体的泛素-蛋白酶体系统,且因此具有与前述蛋白酶体系统中的错误折叠蛋白质相关的折叠问题。相反,由于根据本发明的新颖的p62配体能够不仅诱导胞内自噬,而且诱导与p62相互作用的负荷底物蛋白质的自噬小体靶向,因此其可提供能够在无法利用常规酶抑制方法进行靶向的蛋白质自噬机制下进行选择性降解的新颖的治疗剂。
根据本发明的新颖的化合物充当与p62蛋白质的ZZ结构域结合的配体,促进p62向自噬小体的递送,活化自噬,并消除错误折叠蛋白质聚集体,且因此适用作供预防、改善及治疗各种蛋白质构象病用的药物。
附图说明
图1为说明利用N端规则精氨酸化的蛋白质与p62 ZZ结构域结合且经由胞内自噬活性降解诸如蛋白质等胞内物质的示意图。
图2为展示增加根据本发明的p62配体化合物(YOK-1104、YOK-2204、YOK-3304、YOK-1204、YOK-4404、YOK-1107、YOK-1109、YOK-2207、YOK-2209、YT-4-1、YT-4-2、YT-6-1、YT-6-2、YT-6-7、YT-6-8、YT-9-1及YT-9-2)的p62蛋白质寡聚合活性的效果的免疫印迹测定结果。
图3为展示增加根据本发明的p62配体化合物(YOK-1107、YOK-4404、3301、3302及YOK-1104)的自噬活性的效果的免疫印迹测定结果。
图4为展示增加根据本发明的p62配体化合物(YOK-1106、YOK-1107、YOK-1204、YOK-1304、YOK-2204、YOK-4404)的自噬活性的效果的免疫印迹测定结果。
图5为确认对照化合物(1101、1102、1103、1201、1202、1203、1301、1302、YTK-1105-1、4402、1401、1402、2201及2202)不会增加自噬活性的免疫印迹测定结果。
图6a及6b为确认根据本发明的p62配体化合物(YOK-1106、YOK-1204、YOK-1504、YOK-2204、YOK-3304及YOK-4404)使得p62蛋白质活化及寡聚合,且随后展示将其递送至自噬小体且同时增加自噬活性的效能的免疫荧光染色测定结果。
图7为确认对照化合物(YOK-A-1104、YOK-G-1104、YTK-1005及YTK-1105-1)使得p62蛋白质活化及寡聚合且随后展示将其递送至自噬小体且同时增加自噬活性的效能的免疫荧光染色测定结果。
图8a及8b以及图9a及9b为展示递送靶蛋白以自噬的效能的免疫荧光染色测定结果。其为展示用化合物处理后,就p62蛋白质与胞内斑点的共存而言,靶蛋白、FK2(图8a及8b)或亨廷顿Q103-GFP(图9a及9b)的标志物逐渐增加的结果。
具体实施方式
在下文中将更详细地描述本发明。
详细描述本文中所使用的基团的定义。除非另外指出,否则各基团具有以下定义。
如本文中所使用,术语“卤基”包括氟、氯、溴及碘。
如本文中所使用,“烷基”是指直链或支链脂族烃基,且可优选为具有1至6个碳原子的烷基,更优选为具有1至4个碳原子的烷基。这些烷基的实例包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、1-乙基丙基、己基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基及2-乙基丁基。
在本发明的一个方面,提供一种由以下化学式1表示的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药:
[化学式1]
在化学式1中,
W为C6至C10芳基;
L为-O-(CH2)n1-CH(OH)-,条件是-O-(CH2)n1-CH(OH)-中的O与苯环结合,其中n1为1至4的整数;
m为0至2的整数;
Ra为R1或-OR1,
其中R1为氢或-(CH2)n2-R'1,
R'1为未经取代或经以下取代的苯基:羟基、卤素、C1-4烷基、C1-4烷氧基、硝基、氨基、(C1-4烷基)氨基或二(C1-4烷基)氨基,
n2为1至6的整数;
Rb为-OR2,
其中R2为氢或-(CH2)n3-R'2,
R'2为未经取代或经以下取代的苯基:羟基、卤素、C1-4烷基、C1-4烷氧基、硝基、氨基、(C1-4烷基)氨基或二(C1-4烷基)氨基,
n3为1至6的整数;
Rc为-(CH2)n4-OH、-(CH2)n4-NH-C(=NH)NH2、-C(=NH)NH2、C1-6烷基、-CH(R3)-COO-R4或-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n4-O-(CH2)n4-OR4、-CONH(CH2)n4-OR4、-CO(CH2)n5-OR4、-(CH2)n5-CH(NH2)-COOR4、-(CH2)n5-CONHR4,
n4为2至4的整数,
n5为1至4的整数,
R3为氢或C1-4烷基,以及
R4为氢或C1-4烷基。
优选地,W可为苯基。
优选地,n1可为1或2。
优选地,Ra可为氢或-O-(CH2)n2-R'1。
优选地,R'1可为未经取代或经以下取代的苯基:羟基、氟、氯、溴、甲基、乙基、甲氧基、乙氧基、硝基、氨基或二甲氨基。
优选地,n2可为1至4的整数。
优选地,Rb可为羟基或-O-(CH2)n3-R'2。
优选地,R'2可为未经取代或经以下取代的苯基:羟基、氟、氯、溴、甲基、乙基、甲氧基、乙氧基、硝基、氨基或二甲氨基。
优选地,n3可为1至4的整数。
优选地,Rc可为-(CH2)n4-OH、-(CH2)n4-NH-C(=NH)NH2、-C(=NH)NH2、甲基、乙基或异丙基。
优选地,n4可为2至3的整数。
优选地,n5可为1至3的整数。优选地,R4可为氢或甲基。
具体地,由化学式1表示的化合物的代表性实例如下:
1)(R)-1-(3,4-(双(苯甲氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YOK-1106);
2)(R)-1-(3,4-(双((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-1);
3)(R)-1-(3-((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-2);
4)(R)-1-(3-((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-7);
5)(R)-1-(3-((4-氟苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-8);
6)(R)-1-(2-((3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-1109);
7)(R)-1-(2-((3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-2209);
8)(R)-1-(2-((3-(3,4-双(4-氯苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-1);
9)(R)-1-(2-((3-(3,4-双(4-氟苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-2);
10)(R)-1-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)胍(YOK-1107);
11)(R)-1-(3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)胍(YOK-2207);
12)(R)-1-(3,4-双(苯甲氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1104);
13)(R)-1-(3,4-二苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-2204);
14)(R)-1-(3,4-双(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-3304);
15)(R)-1-(3,4-双(4-苯基丁氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-4404);
16)(R)-1-(4-(苯甲氧基)-3-苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1204);
17)(R)-1-(4-(苯甲氧基)-3-(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1304);
18)(R)-1-(3,4-双((4-氯苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-1);以及
19)(R)-1-(3,4-双((4-氟苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-2)。
同时,本发明的化合物可以药学上可接受的盐形式存在。作为盐,可使用通过药学上可接受的游离酸所形成的加成盐。本文中所使用的术语“药学上可接受的盐”是指由化学式1表示的化合物的任何有机或无机加成盐,其中由盐所引起的不良作用并不损害在对患者展现相对无毒的和非有害的有效活性的浓度下的化合物的有益效果。
酸加成盐可通过常用方法,例如通过将化合物溶解于过量的酸水溶液中且使用水可混溶性有机溶剂(诸如甲醇、乙醇、丙酮或乙腈)沉淀所得盐来制备。作为另选,可加热含等摩尔量的化合物和酸的水或醇(例如,乙二醇单甲醚),且随后所得混合物可通过蒸发来干燥或经沉淀的盐可在抽吸下过滤。
在此情况下,游离酸可为无机酸或有机酸。无机酸的实例包括但不限于盐酸、磷酸、硫酸、硝酸及锡酸。有机酸的实例包括但不限于甲磺酸、对甲苯磺酸、乙酸、三氟乙酸、顺丁烯二酸、丁二酸、草酸、苯甲酸、酒石酸、反丁烯二酸、杏仁酸、丙酸、柠檬酸、乳酸、乙醇酸、葡糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡糖醛酸、天冬氨酸、抗坏血酸、碳酸、香草酸及氢碘酸。
此外,可使用碱制备药学上可接受的金属盐。碱金属或碱土金属盐可例如通过将化合物溶解于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐且随后蒸发过滤物直至干燥来获得。此时,作为金属盐,特别是钠、钾或钙盐在药学上是合适的,但本发明不限于此。此外,相应的银盐可通过用适当银盐(例如,硝酸银)使碱金属或碱土金属盐反应来获得。
除非本文中另外指出,否则本发明的化合物的药学上可接受的盐包括酸性或碱性基团的盐,其可存在于化学式1的化合物中。例如,药学上可接受的盐包括羟基的钠、钙及钾盐;以及氨基的其他药学上可接受的盐,包括氢溴酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、磷酸二氢盐、乙酸盐、丁二酸盐、柠檬酸盐、酒石酸盐、乳酸盐、杏仁酸盐、甲磺酸盐(methanesulfonate/mesylate)及对甲苯磺酸盐(p-toluenesulfonate/tosylate)。可使用现有技术中已知的盐制备方法来制备盐。
本发明的化学式1的化合物的盐为药学上可接受的盐,且可不经特别限制使用,只要其为化学式1的化合物的盐即可,该盐展现出等效于化学式1的化合物的药理学活性,例如可通过经由p62的配体诱导胞内神经退行性疾病及肿瘤相关的蛋白质的自噬性降解来预防或治疗神经退行性疾病。
此外,根据本发明的由化学式1表示的化合物包括但不限于,不仅其药学上可接受的盐,而且所有溶剂化物或水合物以及可由其制备的所有可能的立体异构体。本发明化合物的所有立体异构体(例如,可由于各种取代基上的不对称碳而存在的那些),包括对映异构体形式及非对映异构体形式,均涵盖于本发明的范围内。本发明的化合物的个别立体异构体可例如基本上不含其他异构体(例如,作为具有指定活性的纯或基本上纯的光学异构体)或可例如作为外消旋体或与所有其他立体异构体或其他选出的立体异构体共混。本发明的化合物的手性中心可具有如由IUPAC 1974建议所定义的S或R构型。外消旋形式可通过物理方法分析,诸如非对映异构体衍生物的分步结晶、分离或结晶,或通过手性柱层析分离。个别光学异构体可由外消旋体通过任何适合的方法来获得,包括但不限于用光学活性酸形成盐然后结晶。
由化学式1表示的化合物的溶剂化物及立体异构体可由化学式1表示的化合物使用现有技术中已知的方法来制备。
此外,根据本发明的由化学式1表示的化合物可以结晶形式或非结晶形式制备,当化合物以结晶形式制备时,其可任选地为水合或溶剂化的。在本发明中,化学式1的化合物可不仅包括化学计量的水合物,而且包括含有各种水量的化合物。根据本发明的化学式1的化合物的溶剂化物既包括化学计量溶剂化物也包括非化学计量溶剂化物。
根据本发明的化学式1的化合物可通过与反应式1至5中相同的方法(其为下文示例性方法)来制备,且其具体实例与以下实施例中所描述的那些相同。
[反应式1]
[反应式2]
[反应式3]
[反应式4]
[反应式5]
在本发明的制备方法中,反应式中所使用的反应物可为可商购的化合物,或可通过进行一或多个其在此项技术中已知的反应或通过适当修改所述反应来合成。例如,考虑到骨架结构中所含有的反应性官能团及/或杂元素的存在、类型及/或位置,反应物可通过以一系列顺序进行一个或多个反应来合成,但不限于此。
根据本发明的化学式1的化合物通过充当与p62的ZZ结构域结合的配体且因此活化p62的功能来表征。通过活化p62的功能,根据本发明的化学式1的化合物可活化自噬。
因此,在另一方面,本发明提供一种用于自噬活化的药物组合物,其包含化学式1的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药。
根据本发明的化学式1的化合物由于自噬的活化作用可消除与错误折叠蛋白质聚集相关的疾病有关的聚集蛋白质。此外,化学式1的化合物为p62配体,其与p62ZZ结构域结合且活化p62蛋白的PB1区域及LIR区域,使得其诱导p62寡聚合及聚集体形成以及通过诱导p62聚集体形成来增加自噬小体形成。通过以上过程,可有效地消除错误折叠蛋白质(参见图1)。这些蛋白质可为蛋白质构象病的主要蛋白质,更优选为选自由以下组成的组的至少一种:朊病毒蛋白(prion protein)、淀粉样蛋白前体蛋白(amyloid precursor protein;APP)、α-突触核蛋白、超氧化歧化酶1、tau蛋白(tau)、免疫球蛋白、淀粉样蛋白A、甲状腺素运载蛋白、β2-微球蛋白、胱抑素C、载脂蛋白A1、TDP-43、胰岛淀粉样蛋白多肽、ANF、胶溶素、胰岛素、溶菌酶、血纤维蛋白原、亨廷顿蛋白、α-1-抗胰蛋白酶Z、晶状体球蛋白、c9开放阅读框72(c9orf72)、胶质纤维酸性蛋白、囊性纤维化跨膜传导调节蛋白、视紫质(rhodopsin)及脊髓小脑性共济失调蛋白(ataxin)以及具有聚-Q延伸的其他蛋白质。
因此,在又一方面,本发明提供一种用于预防、改善或治疗蛋白质构象病的药物组合物,该药物组合物包含以下化学式1的p62配体化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药。
根据本发明的术语“聚集(aggregation)”是指典型地一种或多种类型的蛋白质的寡聚或多聚复合物的形成,其可伴随着将额外生物分子如碳水化合物、核酸及脂质整合至复合物中。这些聚集蛋白质可在特定组织中,更优选在神经组织或大脑组织中形成沉积物。聚集的程度视特定疾病而定。
如本文中所使用的术语“蛋白质构象病(proteinopathy)”或“与蛋白质聚集有关的疾病”是指其特征在于存在聚集蛋白质的这些疾病,其实例包括但不限于神经退行性疾病、α-1抗胰蛋白酶缺乏症、角膜病变、色素性视网膜炎、2型糖尿病和囊性纤维化等。
本文中的神经退行性疾病优选选自由以下组成的组:莱姆疏螺旋体病(Lymeborreliosis)、致死性家族性失眠症、库贾氏病(Creutzfeldt-Jakob Disease;CJD)、多发性硬化(MS)、痴呆、阿兹海默氏病、癫痫症、帕金森氏病、中风、亨廷顿氏病、皮克氏病、肌肉萎缩性侧索硬化(ALS)、脊髓小脑共济失调、其他聚-Q疾病、遗传性脑淀粉样血管病、家族性淀粉样多发性神经病、原发性全身性淀粉样变性(AL淀粉样变性)、反应性全身性淀粉样变性(AA淀粉样变性)、注射局部淀粉样变性、β-2微球蛋白淀粉样变性、遗传性非神经病性淀粉样变性、亚历山大氏病(Alexander disease)及芬兰型遗传性全身性淀粉样变性。
本发明的药物组合物的剂量可视患者的体重、年龄、性别或健康状况、饮食、施用时期、施用方法、排泄物及疾病的严重程度而在较宽广范围内变化。然而,有效剂量通常为约1ng至10mg/天,且尤其针对成年人(60kg)为约1ng至1mg/天。由于剂量可视各种条件而变化,对于相关领域技术人员将显而易见的是可增加或减少剂量。因此,本发明的范围不受前述剂量以任何方式限制。关于施用的次数,可在所需范围内进行每天一次或经划分的若干次施用,且施用时期抑或不受特定限制。
如本文中所使用,术语“治疗”是指通过施用本发明的药物组合物来缓解或有利地改变各种与错误折叠蛋白质聚集有关的疾病(诸如蛋白质构象病)的症状的所有措施。
如上文所描述,本发明的化合物展现以下效果:(1)诱导p62寡聚合及结构活化;(2)增强p62-LC3结合,及(3)增强p62向自噬小体的递送;(4)活化自噬;以及最后(5)消除错误折叠蛋白质聚集体。因此,含有作为活性成分的此化合物的药物组合物可用于预防、改善或治疗与各种错误折叠蛋白质聚集有关的疾病。
例如,本发明的组合物可进一步包括药学上可接受的载剂、稀释剂或赋形剂。组合物可以各种形式使用,诸如粉剂、颗粒剂、锭剂、胶囊、悬浮液、乳液、糖浆、喷雾剂的口服剂型及无菌可注射溶液的注射,其根据预期用途中的每一种的目的通过常规方法来配制。组合物可经由各种途径施用,包括口服施用或静脉内、腹膜内、皮下、经直肠及局部施用。可包括于此组合物中的适合载剂、赋形剂或稀释剂的实例可包括乳糖、右旋糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藻糖醇、麦芽糖醇、淀粉、阿拉伯胶、橡胶、海藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯啶酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁和矿物油等。此外,本发明的组合物可进一步包括填充剂、抗凝血剂、润滑剂、保湿剂、芳香剂、乳化剂和防腐剂等。
用于口服施用的固体制剂包括锭剂、丸剂、粉剂、颗粒剂和胶囊等,且这些固体剂型通过使本发明的组合物与一或多种赋形剂,诸如淀粉、碳酸钙、蔗糖、乳糖和明胶等混合来调配。此外,可使用除简单赋形剂以外的润滑剂,诸如硬脂酸镁及滑石。
用于口服施用的液体制剂可说明为悬浮液、溶液、乳液和糖浆等,且可包括各种赋形剂,诸如保湿剂、甜味剂、芳香剂和防腐剂等以及作为常用稀释剂的水及液体石蜡。
用于胃肠外施用的制剂包括无菌水溶液、非水性溶剂、悬浮剂、乳液试剂、冻干剂及栓剂。非水性溶剂及悬浮剂可包括丙二醇、聚乙二醇、诸如橄榄油的植物油及诸如油酸乙酯的可注射酯。作为栓剂的基质,可使用Witepsol、聚乙二醇、Tween 61、可可脂、月桂酯或甘油明胶等。在另一方面,注射剂可包括常规添加剂,诸如助溶剂、等张剂、悬浮剂、乳化剂、稳定剂或防腐剂。
制剂可根据常规混合、颗粒化或涂布方法来制备,且含有对医学治疗、尤其对于预防、改善或治疗与错误折叠蛋白质聚集有关的疾病有效的量的活性成分。
在此情况下,本发明的组合物以药学有效量施用。如本文中所使用的术语“药学有效量”是指在适用于任何医学治疗的合理权益/风险比下足以治疗疾病而且不足以引起副作用的量。有效量的水平可视患者的健康状况、疾病类型、疾病的严重程度、药物的活性、对药物的灵敏度、施用方法、施用时间、施用途径、排泄速率、治疗持续时间、组合、包括同时使用其他药品的因素及医学领域中熟知的其他因素而测定。本发明的组合物可作为个别治疗剂或与其他治疗剂组合施用,且其可与常规治疗剂同时或依次施用,并且施用一次或多次。考虑所有以上因素,施用可提供最大效果而无副作用的最少量为至关重要的,其可由本领域技术人员容易地测定。
例如,剂量可视施用途径、疾病的严重程度、性别、体重和年龄等而增加或减少,且本发明的范围不受前述剂量以任何方式限制。
根据本发明的化合物的优选剂量可根据患者的病况及体重、疾病的严重程度、药物的类型以及施用途径及持续时间而改变,但其可由本领域技术人员适当选择。
在又一方面,本发明提供用于预防、改善或治疗与错误折叠蛋白质聚集相关的疾病的方法,其包括向有需要的受试者施用根据本发明的药物组合物。
如本文中所使用,术语“受试者”指包含人类、猴、牛、马、绵羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或豚鼠的所有动物,其具有与错误折叠蛋白质聚集有关的疾病。与错误折叠蛋白质聚集有关的疾病可通过向受试者施用本发明的药物组合物来有效地预防、改善或治疗。此外,因为本发明的药物组合物充当p62配体以活化自噬,由于自噬活化从而消除错误折叠蛋白质的聚集体,且因此展现与这些聚集蛋白质有关的疾病的预防或治疗效果,其可通过与现有治疗剂组合施用来展现协同效果。
如本文中所使用,术语“施用”是指以某些适当方法将物质的处方量引入至患者中,且本发明的组合物可经由通用途径中的任一者施用,只要其可达至靶组织即可。例如,可进行腹膜内施用、静脉内施用、肌肉内施用、皮下施用、皮内施用、口服施用、局部施用、鼻内施用、肺内施用及直肠内施用,但本发明不限于这些例示的施用模式。此外,本发明的药物组合物可使用任何能够将活性成分递送至靶细胞的装置施用。优选施用模式及制剂为静脉内注射、皮下注射、皮内注射、肌肉内注射或静脉内滴注等。可注射制剂可使用盐水、诸如林格氏溶液的水溶液及非水性溶液,诸如植物油、高脂肪酸酯(例如,油酸乙酯等)、醇(例如,乙醇、苯甲醇、丙二醇、甘油等)来制备。可注射制剂可包括药学载剂,包括用于预防退化症的稳定剂(例如,抗坏血酸、亚硫酸氢钠、焦亚硫酸钠、BHA、生育酚、EDTA等)、乳化剂、用于pH控制的缓冲剂及用于抑制微生物生长的防腐剂(例如,硝酸苯汞、硫柳汞、苯扎氯铵、苯酚、甲酚、苯甲醇等)。
在另一方面,本发明提供一种用于预防或改善错误折叠蛋白质相关疾病的食品组合物,其包含化学式1的p62配体化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药。食品组合物为健康功能性食品且其可经由制剂自身使用或作为健康功能性食品的添加剂包含于其他健康功能性食品中。健康功能性食品是指具有诸如疾病的预防或改善、生物防御、免疫、康复的恢复、衰老抑制等身体调节功能的食品,且其在长期服用时应对人体无害。活性成分的混合量可适当地视使用的目的(预防、保健或治疗性处理)而定。
食品的种类不受特定限制。可添加以上物质的食品的实例为肉、香肠、面包、巧克力、糖果、点心、甜饼、披萨饼、拉面、其他面条、胶状物、包括冰淇淋的乳制品、汤类、饮料、茶、饮品、酒精饮料及维生素复合物等,且其包括常识中的所有保健功能性食品。
本发明的食品组合物可包含在制备食品或食品添加剂中所使用的常用成分,特别是,调味剂;天然甜味剂,诸如,如葡萄糖、果糖等单糖,如麦芽糖、蔗糖等双糖,及作为天然碳水化合物的糊精、环糊精,或合成甜味剂,诸如糖精、阿斯巴甜;营养素;维生素;电解质;着色剂;有机酸;保护性胶体粘性剂;pH调节剂;稳定剂;防腐剂;甘油;酒精;碳酸饮品上所使用的碳酸化剂等。
在本发明的具体实施方式中,新合成实施例1至19的化合物,其为由化学式1表示的新颖的p62配体。此外,为评估根据本发明的新颖的p62配体化合物是否可增加经培养细胞中的自噬现象,海拉细胞系(HeLa cell line)(其为来源于子宫颈癌患者的细胞系)用根据本发明的新颖的p62配体化合物处理并培养,并且随后经培养细胞中的自噬活性通过免疫印迹法来确认。因此,应确认LC3(其为自噬活性的标记物)的水平根据用本发明的p62配体化合物处理的时间而逐渐增加,且根据本发明的p62配体化合物活化并寡聚p62蛋白质并且经递送至自噬小体并同时增强自噬活性,从而有效地消除错误折叠蛋白质聚集体。
实施例
在下文中,将参考实施例更详细地描述本发明。然而,这些实施例仅出于说明性目的而提供,且本发明不意欲受限于这些实施例。
通过根据以下实施例1至19的方法来制备下文表1中所示的化合物。
[表1]
就用于合成本发明的化合物的起始材料而言,已知各种合成方法,且若可在市场上获得,则起始材料可购自供货商。试剂供货商的实例包括Sigma-Aldrich、TCI、Wako、Kanto、Fluorchem、Acros、Alfa和Fluka等,但不限于此。
本发明的化合物可使用以下通用方法及程序由可容易获得的起始材料来制备。关于典型或优选工艺条件(亦即反应温度、时间、反应物的莫耳比、溶剂、压力)等,除非另外说明,否则亦可使用其他工艺条件。最佳反应状态可视所使用的特定反应物或溶剂而变化。这些条件可由本领域技术人员通过常规优化程序来确定。
在下文中,描述实施例1至19的制备方法。
制备例1)实施例1、2、3、12、13、14、15、18及19的化合物通过下文反应式1中所示的方法来合成。
[反应式1]
实施例1:制备(R)-1-(3,4-(双(苯甲氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YOK-1106)
步骤1)制备3,4-双(苯甲氧基)苯酚(1102)
在将二氯甲烷(15ml)添加至3,4-双(苯甲氧基)苯甲醛(1101,1.00g,3.0mmol,1当量)且溶解于其中之后,将mCPBA(0.78g,4.5mmol,1.5当量)添加至反应中并且在室温下搅拌4小时。反应混合物用乙酸乙酯稀释并且用碳酸钠饱和水溶液洗涤,且分离有机层。有机层用氯化钠水溶液洗涤,随后用无水硫酸钠脱水且在减压下过滤。将过滤的溶液经浓缩且随后再次溶解于甲醇(10ml)中,且添加6N NaOH并且在室温下搅拌30分钟。将4N HCl溶液添加至反应中,且进一步搅拌30分钟。反应混合物用乙酸乙酯(50ml)稀释,用盐水洗涤,且随后用无水硫酸钠脱水,并且在减压下过滤。过滤的溶液经浓缩且随后通过柱层析(己烷/乙酸乙酯比率=7/3)纯化以得到3,4-双(苯甲氧基)苯酚(1102,0.87g,产率:90%)。
1H-NMR(CDCl3,300MHz):δ7.25-7.42(m,10H),6.80(d,1H,J=9.0Hz),6.48(d,1H,J=3.0Hz),6.29(dd,1H,J=3.0and 9.0Hz),5.08(d,4H,J=15Hz),4.55(s,1H);ESIMS m/z:307.25[M+H]+。
步骤2)制备R-2-((3,4-双(苯甲氧基)苯氧基)甲基)环氧乙烷(1103)
3,4-二苯甲氧基苯酚(1102,306mg,1.0mmol)用乙醇(10ml)稀释,且随后依次添加KOH水溶液(KOH 66mg,1.2mmol,1ml)及(R)-2-(氯甲基)环氧乙烷(410μl,5.0mmol)。将反应混合物在室温下搅拌5小时,且随后在减压下移除有机溶剂。经浓缩的反应混合物再次用乙酸乙酯稀释,用水洗涤且随后用盐水洗涤。经萃取的有机层用无水硫酸钠脱水且随后在减压下过滤。过滤的有机层经浓缩且通过柱层析纯化以得到纯R-2-((3,4-双(苯甲氧基)苯氧基)甲基)环氧乙烷(1103,297mg,产率:82%)。ESIMS m/z:363.5[M+H]+。
步骤3)R-2-((3,4-双(苯甲氧基)苯氧基)甲基)环氧乙烷(1103,9mg,25nmol)用无水乙醇(1ml)稀释,且随后向其中添加2-氨基乙-1-醇(7.6μL,125nmol)并且在室温下搅拌4小时。在通过TLC确认反应之后,在减压下浓缩反应溶剂,将水添加至经浓缩的反应产物中且用二氯甲烷(3×5mL)萃取。经萃取的有机层用无水硫酸钠脱水且随后在减压下过滤。过滤的有机层经浓缩且通过柱层析(二氯甲烷:甲醇=19:1)纯化以得到(R)-1-(3,4-(双(苯甲氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YOK-1106,9.0mg,产率:85%)。1H NMR(CDCl3,300MHz):δ7.42-7.40(m,2H),7.33-7.27(m,8H),6.82(d,1H,J=9.0Hz),6.42(d,1H,J=3.0Hz),6.28(dd,1H,J=3.0and 9.0Hz),5.09(d,1H,J=12.9Hz),5.06(s,2H),4.93(d,1H,J=12.9Hz),4.35-4.25(m,1H),3.94(dd,1H,J=3.6and 9.9Hz),3.89-3.72(m,3H),3.34(t,1H,J=11.4Hz),2.93(brS,2H),2.80(d,1H,J=10.8Hz);ESIMS m/z:424.67[M+H]+。
实施例2:制备(R)-1-(3,4-(双((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-1)
(R)-1-(3,4-(双((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-1)以与实施例19的制备方法中相同的方式,通过使用3,4-双((4-氯苯甲基)氧基)苯甲醛(1101-1)而非3,4-双(苯甲氧基)苯甲醛(1101)作为起始材料来合成。1H NMR(400MHz,DMSO-d6)δ(ppm)2.59(m,4H),3.45(s,2H),3.81(m,3H),4.50(b,1H),4.85(b,1H),5.01(s,2H),5.11(s,2H),6.42(dd,J=8Hz and 2.8Hz,1H),6.66(d,J=2.8Hz,1H),6.92(d,J=8Hz,1H),7.42(s,4H),7.45(s,4H);C25H27Cl2NO5[M+2]+的m/z的ESI-MS计算值493.90,实验值492.39
实施例3:制备(R)-1-(3,4-(双((4-氟苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-2)
(R)-1-(3,4-(双((4-氟苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-2)以与实施例19的制备方法中相同的方式,通过使用3,4-双((4-氟苯甲基)氧基)苯甲醛(1101-2)而非3,4-双(苯甲氧基)苯甲醛(1101)作为起始材料来合成。1H NMR(400MHz,CDCl3)δ(ppm)2.82(m,4H),3.69(t,J=5.2Hz,2H),3.91(m,2H),4.05(m,1H),5.00(s,2H),5.06(s,2H),6.41(m,1H),6.58(d,J=2.8Hz,1H),6.84(d,J=8Hz,1H),7.03(m,4H),7.37(m,4H);C25H27F2NO5 M+2]+的m/z的ESI-MS计算值[461.0,实验值459.49
实施例12:制备(R)-1-(3,4-双(苯甲氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1104)
(R)-1-(3,4-双(苯甲氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1104)通过使用异丙胺而非实施例1的制备步骤3中的2-氨基乙-1-醇来合成。1H NMR(300MHz,CDCl3)δ(ppm)1.12(d,J=6Hz,6H),2.81(m,5H),3.88(d,J=3Hz,2H),4.04(m,1H),5.09(d,J=15Hz),6.38(dd,J=9Hz and 3Hz,1H),6.59(s,1H),6.85(d,J=9Hz,1H),7.35(m,10H;C26H31NO4[M+H]+的m/z的ESI-MS计算值422.42,实验值421.54
实施例13:制备(R)-1-(3,4-二苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-2204)
(R)-1-(3,4-二苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-2204)以与实施例1的制备方法中相同的方式合成,不同之处在于:在实施例1的制备方法的步骤1中,使用3,4-二苯乙氧基苯甲醛(2201)作为起始材料而非3,4-双(苯甲氧基)苯甲醛(1101),且在步骤3中,使用异丙胺而非2-氨基乙-1-醇。1H NMR(300MHz,CDCl3)δ(ppm)1.17(d,J=6Hz,6H),2.79(dd,J=9Hz and 3Hz,1H),2.95(m,2H),3.08(m,4H),3.34(b,2H),3.89(m,2H),4.13(m,5H),6.37(dd,J=6Hz and 3Hz,1H),6.52(d,J=3Hz,1H),6.78(d,J=9Hz,1H),7.25(m,10H);C28H35NO4[M+H]+的m/z的ESI-MS计算值451.00,实验值449.59
实施例14:制备(R)-1-(3,4-双(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-3304)
(R)-1-(3,4-双(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-3304)以与实施例1的制备方法中相同的方式合成,不同之处在于:在实施例1的制备方法的步骤1中,使用3,4-双(3-苯基丙氧基)苯甲醛(3301)作为起始材料而非3,4-双(苯甲氧基)苯甲醛(1101),且在步骤3中,使用异丙胺而非2-氨基乙-1-醇。1H NMR(300MHz,CDCl3)δ(ppm)1.21(d,J=6Hz,6H),2.12(m,4H),2.83(t,J=9Hz,5H),3.01(m,2H),3.30(b,3H),3.93(m,6H),4.18(m,1H),6.38(dd,J=6Hz and 3Hz,1H),6.52(d,J=3Hz,1H),6.80(d,J=9Hz,1H),7.25(m,10H);C30H39NO4[M+H]+的m/z的ESI-MS计算值479.09,实验值477.65
实施例15:制备(R)-1-(3,4-双(4-苯基丁氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-4404)
(R)-1-(3,4-双(4-苯基丁氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-4404)以与实施例1的制备方法中相同的方式合成,不同之处在于:在实施例1的制备方法的步骤1中,使用3,4-双(4-苯基丁氧基)苯甲醛(4401)作为起始材料而非3,4-双(苯甲氧基)苯甲醛(1101),且在步骤3中,使用异丙胺而非2-氨基乙-1-醇。1H NMR(300MHz,CDCl3)δ(ppm)1.26(dd,J=6Hz and 3Hz,8H),1.81(m,7H),2.66(t,J=6Hz,4H),2.85(m,1H),3.06(m,2H),3.46(b,2H),3.93(m,6H),4.24(m,1H),6.36(dd,J=6Hz and 3Hz,1H),6.52(d,J=3Hz,1H),6.78(d,J=9Hz,1H),7.23(m,10H),C32H43NO4[M+H]+的m/z的ESI-MS计算值505.70,实验值503.45
实施例18:制备(R)-1-(3,4-双((4-氯苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-1)
(R)-1-(3,4-双((4-氯苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-1)以与实施例1的制备方法中相同的方式合成,不同之处在于:在实施例1的制备方法的步骤1中,使用3,4-双(4-氯苯甲氧基)苯甲醛(1101-1)作为起始材料而非3,4-双(苯甲氧基)苯甲醛(1101),且在步骤3中,使用异丙胺而非2-氨基乙-1-醇。1H NMR(400MHz,CDCl3)δ(ppm)1.08(d,J=6.4Hz,6H),2.68(dd,J=12Hz and 8Hz,1H),2.83(m,2H),3.88(d,J=5.2Hz,2H),3.95(m,1H),5.01(s,2H),5.06(s,2H),6.40(dd,J=8Hz and 4Hz,1H),6.56(d,J=2.8Hz,1H),6.82(d,J=8Hz,1H),7.31(m,8H);C26H29Cl2NO4[M+H]+的m/z的ESI-MS计算值491.40,实验值490.42
实施例19:制备(R)-1-(3,4-双((4-氟苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-2)
(R)-1-(3,4-双((4-氟苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-2)以与实施例1的制备方法中相同的方式合成,不同之处在于:在实施例1的制备方法的步骤1中,使用3,4-双(4-氟苯甲氧基)苯甲醛(1101-2)作为起始材料而非3,4-双(苯甲氧基)苯甲醛(1101),且在步骤3中,使用异丙胺而非2-氨基乙-1-醇。1H NMR(400MHz,CDCl3)δ(ppm)1.08(d,J=6.4Hz,6H),2.68(dd,J=12Hz and 8Hz,1H),2.83(m,2H),3.89(d,J=4Hz,2H),3.95(m,1H),5.00(s,2H),5.05(s,2H),6.40(dd,J=8Hz and 2.8Hz,1H),6.59(d,J=2.8Hz,1H),6.83(d,J=9.6Hz,1H),7.03(m,4H),7.37(m,4H);C26H29F2NO4[M+H]+的m/z的ESI-MS计算值457.90,实验值457.52
制备例2)实施例6至11的化合物根据下文反应式2中所示的方法来合成。
[反应式2]
实施例6:制备(R)-1-(2-((3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-1109)
步骤1)在将R-2-((3,4-双(苯甲氧基)苯氧基)甲基)环氧乙烷(1103,500mg,1.38mmol)溶解于甲醇(10ml)中之后,向其中添加2-氨基乙基胺甲酸第三丁酯(442mg,2.76mmol)且在50℃下搅拌10小时。当反应完成时,在减压下浓缩反应溶剂。
步骤2)在将(R)-(2-((3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)氨基)乙基)胺甲酸第三丁酯(1105,600mg,1.15mmol)溶解于甲醇(3ml)中之后,向其中添加甲醇/盐酸(3N,2ml)且随后在室温下搅拌4小时。当反应完成时,在减压下浓缩反应混合物(白色固体,1106)且不经纯化即用作下一步骤中的起始材料。
步骤3)将(R)-1-((2-氨基乙基)氨基)-3-(3,4-双(苯甲氧基)苯氧基)丙-2-醇(1106,400g,0.95mmol)溶解于DMF(3ml)中,且随后向其中另外添加1H-吡唑-1-甲脒盐酸盐(553mg,3.8mmol)及二异丙基乙胺(0.3g,2.4mmol)。将反应混合物在30℃下搅拌12小时,在减压下浓缩且通过高分辨率液相色谱纯化以合成呈白色固体状的(R)-1-(2-((3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-1109,22mg)。1H NMR(400MHz,DMSO+D2O)δ(ppm)3.13(m,4H),3.47(s,2H),3.89(s,2H),5.04(s,2H),5.12(s,2H),6.46(d,J=8Hz,1H),6.67(s,1H),6.97(d,J=8Hz,1H),7.39(m,10H);C26H32N4O4[M+H]+的m/z的ESI-MS计算值465.00,实验值464.57。
实施例7:制备(R)-1-(2-((3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-2209)
(R)-1-(2-((3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-2209)以与实施例6的制备方法中相同的方式合成,不同之处在于:使用R-2-((3,4-二苯乙氧基苯氧基)甲基)环氧乙烷(2203)而非实施例6的制备方法的步骤1中的R-2-((3,4-双(苯甲氧基)苯氧基)甲基)环氧乙烷(1103)。1H NMR(400MHz,CD3OD)δ(ppm)3.00(t,J=6.8Hz,2H),3.06(t,J=6.8Hz,2H),3.23(m,1H),3.28(m,3H),3.62(t,J=6.4Hz,2H),6.46(dd,J=8Hz and2.8Hz,1H),6.60(d,J=2.8Hz,1H),6.85(d,J=8Hz,1H),7.25(m,10H);C28H36N4O4[M+H]+的m/z的ESI-MS计算值493.00,实验值492.62
实施例8:制备(R)-1-(2-((3-(3,4-双(4-氯苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-1)
(R)-1-(2-((3-(3,4-双(4-氯苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-1)以与实施例6的制备方法中相同的方式合成,不同之处在于:使用R-2-((3,4-双(4-氯苯甲基)氧基)苯氧基)甲基)环氧乙烷(1103-1)而非实施例6的制备方法的步骤1中的1103。1H NMR(400MHz,DMSO+D2O)δ(ppm)3.13(m,4H),3.47(t,J=6Hz,2H),3.90(m,2H),4.13(m,1H),5.03(s,2H),5.10(s,2H),6.47(dd,J=8Hz and 2Hz,1H),6.66(d,J=2.4Hz,1H),6.97(d,J=8.8Hz,1H),7.42(s,4H),7.45(s,4H);C26H30Cl2N4O4[M+H]+的m/z的ESI-MS计算值532.90,实验值533.45
实施例9:制备(R)-1-(2-((3-(3,4-双(4-氟苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-2)
(R)-1-(2-((3-(3,4-双(4-氟苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-2)以与实施例6的制备方法中相同的方式合成,不同之处在于:使用R-2-((3,4-双(4-氟苯甲基)氧基)苯氧基)甲基)环氧乙烷(1103-2)而非实施例6的制备方法的步骤1中的1103。1H NMR(400MHz,DMSO-d6)δ(ppm)3.13(m,4H),3.45(t,J=6Hz,2H),3.89(m,2H),4.15(m,1H),5.01(s,2H),5.09(s,2H),6.46(dd,J=8Hz and 2.8Hz,1H),6.68(d,J=2.8Hz,1H),6.96(d,J=9.2Hz,1H),7.20(m,4H),7.46(m,4H);C26H30Cl2N4O4[M+H]+的m/z的ESI-MS计算值501.00,实验值500.55
实施例10:制备(R)-1-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)胍(YOK-1107)
步骤1)在将R-2-((3,4-双(苯甲氧基)苯氧基)甲基)环氧乙烷(1103,500mg,1.38mmol)溶解于甲醇(10ml)中之后,向其中添加氨水/甲醇((2N,3ml)且在50℃下搅拌10小时。当反应完成时,在减压下浓缩反应溶剂。
步骤2)将(R)-1-氨基-3-(3,4-双(苯甲氧基)苯氧基)丙-2-醇(1107,300mg,0.8mmol)溶解于DMF(3ml)中,且随后依次添加1H-吡唑-1-甲脒盐酸盐(570mg,3.9mmol)及二异丙基乙胺(0.3g,2.4mmol)。将反应混合物在30℃下搅拌12小时,在减压下浓缩且通过高分辨率液相色谱纯化以合成(R)-1-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)胍(YOK-1107,23mg)。1H NMR(400MHz,DMSO-d6)δ(ppm)3.20(m,1H),3.31(m,1H),5.03(s,2H),5.12(s,2H),6.44(dd,J=8.8Hz and 2.8Hz,1H),6.68(d,J=2.8Hz,1H),6.95(d,J=8Hz,1H),7.38(m,10H);C24H27N3O4[M+H]+的m/z的ESI-MS计算值422.00,实验值421.50。
实施例11:制备(R)-1-(3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)胍(YOK-2207)
(R)-1-(3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)胍(YOK-2207,25mg)以与实施例10的制备方法中相同的方式合成,不同之处在于:使用R-2-((3,4-二苯氧基苯氧基)甲基)环氧乙烷(2203)而非实施例10的制备方法的步骤1中的1103。1H NMR(400MHz,CD3OD)δ(ppm)3.00(t,J=8Hz,2H),3.06(t,J=8Hz,2H),3.33(m,1H),3.42(dd,J=24Hz and 4Hz,1H),3.91(m,2H),4.08(m,3H),4.16(t,J=6.4Hz,2H),6.46(dd,J=8Hz and 2Hz,1H),6.60(d,J=2.8Hz,1H),6.84(d,J=8Hz,1H),7.25(m,10H);C26H31N3O4[M+H]+的m/z的ESI-MS计算值450.00,实验值449.55。
制备例3)实施例4及5的化合物通过下文反应式3中所示的方法来合成。
[反应式3]
实施例4:制备(R)-1-(3-((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-7)
步骤1)将1,3-二羟基苯(5.0g,45.4mmol)溶解于乙腈(100ml)中且随后向其中添加K2CO3。随后,将1-(溴甲基)-4-氯苯(9.3g,45.4mmol)添加至反应中且随后在80℃下搅拌16小时。在冷却至室温之后,在减压下浓缩反应溶剂。将水添加至经浓缩的残余物中,接着用乙酸乙酯萃取。有机层用无水硫酸钠脱水且在减压下过滤。取出过滤物,在减压下浓缩,且随后通过柱层析(乙酸乙酯/石油醚1:15至1:8)纯化以合成呈淡黄色油状的3-((4-氯苯甲基)氧基)苯酚(2011,2.3g)。1H NMR(400MHz,CD3OD)δ(ppm)5.03(s,2H),6.35-6.43(m,3H),7.04(t,1H),7.45(s,4H),9.41(s,1H)。
步骤2)在将3-((4-氯苯甲基)氧基)苯酚(2011,1.0g,4.2mmol)溶解于乙醇(10ml)中之后,添加(R)-2-(氯甲基)环氧乙烷(1.17g,12.7mmol)、纯化水(1ml)及KOH(0.24g,4.2mmol),且随后在室温下搅拌16小时。将水(30ml)添加至反应中且用乙酸乙酯(30ml)萃取。水层用乙酸乙酯萃取多于两次,且随后有机层用无水硫酸钠脱水且在减压下过滤。经过滤的溶液在减压下浓缩且通过柱层析(乙酸乙酯/石油醚1:15至1:8)纯化以合成呈无色油状的(R)-2-((3-((4-氯苯甲基)氧基)苯氧基)甲基)环氧乙烷(3011,0.85g)。1H NMR(400MHz,CD3OD)δ(ppm)2.74(m,1H),2.90(m,1H),3.34(m,1H),3.91-3.95(m,1H),4.18-4.22(m,1H),5.01(s,2H),6.52-6.59(m,3H),7.16-7.26(m,1H),7.35(s,4H)。
步骤3)将(R)-2-((3-((4-氯苯甲基)氧基)苯氧基)甲基)环氧乙烷(3011,300mg,1.03mmol)溶解于甲醇(5ml)中,且随后向其中添加2-氨基乙醇(189mg,3.09mmol)。将反应混合物在65℃下搅拌5小时。在冷却至室温之后,反应溶剂在减压下浓缩且通过高分辨率液相色谱纯化以合成呈白色固体状的(R)-1-(3-((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-7,15mg)。1H NMR(400MHz,CDCl3)δ(ppm)2.83(m,4H),3.69(m,2H),2.96(m,2H),4.08(m,1H),5.00(s,2H),6.55(m,3H),7.18(t,J=8Hz,1H),7.35(s,4H);C18H22ClNO4[M]+的m/z的ESI-MS计算值352.00,实验值351.83
实施例5:制备(R)-1-(3-((4-氟苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-8)
(R)-1-(3-((4-氟苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-8,20mg)以与实施例4的制备方法中相同的方式合成,不同之处在于:使用1-(溴甲基)-4-氟苯而非实施例4的制备方法的步骤1中的1-(溴甲基)-4-氯苯。1H NMR(400MHz,CDCl3)δ(ppm)2.03(b,3H),2.83(m,4H),3.69(t,J=4.8Hz,2H),3.96(m,2H),4.08(m,1H),4.99(s,2H),6.56(m,3H),7.07(m,2H),7.18(t,J=8Hz,1H),7.40(m,2H);C18H22FNO4[M+H]+的m/z的ESI-MS计算值336.00,实验值335.38
制备例4)实施例16及17的化合物通过下文反应式4所示的方法来合成。
[反应式4]
实施例16:制备(R)-1-(4-(苯甲氧基)-3-苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1204)
步骤1)在将4-(苯甲氧基)-3-苯乙氧基苯甲醛(1201,332mg,1.0mmol)溶解于二氯甲烷中之后,向其中添加间氯过苯甲酸(mCPBA,260mg,1.5mmol)且随后在室温下搅拌4小时。将过量的乙酸乙酯添加至反应中且随后用碳酸钠饱和水溶液洗涤,并且分离有机层。有机层用氯化钠水溶液洗涤,随后用无水硫酸钠脱水且在减压下过滤。过滤的溶液经浓缩且再次溶解于甲醇(10ml)中,随后添加6N NaOH并且在室温下搅拌30分钟。将4N HCl溶液添加至反应中且随后进一步搅拌30分钟。反应混合物用乙酸乙酯(50ml)稀释,随后用盐水洗涤,用无水硫酸钠脱水,且在减压下过滤。过滤的溶液经浓缩且随后通过柱层析(己烷/乙酸乙酯比率=7/3)纯化以得到4-(苯甲氧基)-3-苯乙氧基苯酚(1202,310mg,产率:90%)。1HNMR(CDCl3,300MHz)δ(ppm):7.23-7.42(m,10H),6.77(d,1H,J=9.0Hz),6.46(d,1H),6.28(dd,1H,J=3.0and 9.0Hz),4.98(s,2H),4.58(s,1H),4.20(t,2H,J=6Hz),3.14(t,2H,J=6Hz)。
步骤2)4-(苯甲氧基)-3-苯乙氧基苯酚(1202,320mg,1.0mmol)用乙醇(5ml)稀释,且随后依次添加KOH水溶液(KOH 66mg,1.2mmol,1ml)及(R)-2-(氯甲基)环氧乙烷(410μl,5.0mmol)。将反应混合物在室温下搅拌5小时,且随后在减压下移除有机溶剂。经浓缩的反应混合物再次用乙酸乙酯稀释,用水然后用盐水洗涤。经萃取的有机层用无水硫酸钠脱水且随后在减压下过滤。过滤的有机层经浓缩且通过柱层析纯化以得到纯R-2-((4-(苯甲氧基)-3-苯乙氧基苯氧基)甲基)环氧乙烷(1203,308mg,产率:82%)。1H NMR(300MHz,CDCl3)δ(ppm)7.44-7.47(m,2H),7.26-7.39(m,5H),7.19-7.22(m,3H),6.84(d,1H,J=6.0Hz),6.54(d,1H,J=3.0Hz),6.36(dd,1H),5.07(s,2H),4.15(dd,1H),4.00(t,2H,J=6.0Hz),2.84(t,2H,J=9.0Hz),2.73(dd,1H),2.10-2.19(m,2H);ESIMS m/z:363.5[M+H]+。
步骤3)在R-2-((4-(苯甲氧基)-3-苯乙氧基苯氧基)甲基)环氧乙烷(1203,9.4mg,25nmol)用无水乙醇(1ml)稀释之后,向其中添加异丙胺(10μL,125nmol)且在室温下搅拌4小时。在通过TLC确认反应之后,在减压下浓缩反应溶剂,且将水添加至经浓缩的反应产物并且用二氯甲烷(3×5mL)萃取。经萃取的有机层用无水硫酸钠脱水且随后在减压下过滤。过滤的有机层经浓缩且通过柱层析(二氯甲烷:甲醇=19:1)纯化以得到(R)-1-(4-(苯甲氧基)-3-苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1204,9.3mg,产率:86%)。1H NMR(300MHz,CDCl3)δ(ppm)1.15(d,J=6Hz,6H),2.71(m,4H),2.80(m,2H),3.14(t,J=6Hz,2H),3.91(d,J=3Hz,2H),4.09(m,1H),4.21(t,J=6Hz,2H),4.99(s,2H),6.35(dd,J=6Hzand 3Hz,1H),6.54(d,J=3Hz,1H),6.82(d,J=9Hz,1H),7.26(m,10H);C27H33NO4[M+H]+的m/z的ESI-MS计算值437.00,实验值435.56。
实施例17:制备(R)-1-(4-(苯甲氧基)-3-(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1304)
呈白色固体状的(R)-1-(4-(苯甲氧基)-3-(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1304,9.5mg,产率:85%)以与实施例16的制备方法中相同的方式,通过使用4-(苯甲氧基)-3-(3-苯基丙氧基)苯甲醛(1301,346mg,1.0mmol)而非实施例16的制备方法的步骤1中的4-(苯甲氧基)-3-苯乙氧基苯甲醛(1201)作为起始材料来合成。1H NMR(300MHz,CDCl3)δ(ppm)1.13(d,J=6Hz,6H),2.15(m,2H),2.33(b,3H),2.80(m,5H),3.91(d,J=6Hz,2H),4.01(m,3H),5.07(s,2H),6.36(dd,J=6Hz and 3Hz,1H),6.53(d,J=3Hz,1H),6.84(d,J=9Hz,1H),7.33(m,10H);C28H35NO4[M+H]+的m/z的ESI-MS计算值451.00,实验值449.59。
制备例5)比较例1及2的化合物通过下文反应式5中所示的方法来合成。
[反应式5]
比较例1:制备(R)-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)甘氨酸甲酯(YOK-G-1104)
(R)-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)甘氨酸甲酯(YOK-G-1104)以与实施例19的制备方法中相同的方式合成,不同之处在于:使用甘氨酸甲酯而非实施例19的制备方法的步骤3中的2-氨基乙-1-醇。1H NMR(300MHz,DMSO-d6)δ(ppm)2.55(m,1H),2.81(m,1H),3.51(s,2H),3.66(s,3H),4.05(m,1H),4.20(m,2H),5.16(s,2H),5.18(s,2H),5.37(brs,1H),5.52(br s,1H),6.57(s,1H),6.67(d,1H),6.96(d,1H),7.32-7.48(m,10H)。
比较例2:制备(R)-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)丙氨酸乙酯(YOK-A-1104)
(R)-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)丙氨酸乙酯(YOK-A-1104)以与实施例19的制备方法中相同的方式合成,不同之处在于:使用丙氨酸乙酯而非实施例19的制备方法的步骤3中的2-氨基乙-1-醇。1H NMR(300MHz,DMSO-d6)δ(ppm)1.21(t,3H),1.27(m,3H),2.56-2.81(m,2H),3.56(m,1H),4.05(m,1H),3.95-4.20(m,4H),5.16(s,2H),5.18(s,2H),5.37(br s,1H),6.57(s,1H),6.67(d,1H),6.96(d,1H),7.32-7.48(m,10H)。
实验例1.利用免疫印迹评估经培养细胞中的p62蛋白质的寡聚合活性
为利用化合物(实施例1至19)评估p62蛋白质寡聚合活性效能,收集HEK293细胞系(其为人类胚胎肾衍生的细胞)。作为当前化合物中的代表性化合物,选择YOK-1104、YOK-2204、YOK-3304、YOK-1204、YOK-4404、YOK-1107、YOK-1109、YOK-2207、YOK-2209、YT-4-1、YT-4-2、YT-6-1、YT-6-2、YT-6-7、YT-6-8、YT-9-1、YT-9-2。为根据用这些所选择代表性化合物处理来测量胞内p62蛋白质活化及寡聚合,将对应的细胞分配至100pi培养皿中。在进一步培养24小时之后收集细胞,使得细胞完全附着至盘的表面。将100μl的溶解缓冲液(20mMTris,pH 7.4)、150mM NaCl、1%Triton X-100、2mM NaF、2mM EDTA、2mMβ-甘油磷酸盐、5mM原钒酸钠、1mM PMSF、亮抑酶肽、抑肽酶)注射至各样品中并溶解细胞。基于所测量的总蛋白质浓度,各样品在室温下用测试化合物处理2小时,随后添加样品缓冲液并且使其在95℃下反应10分钟。在反应后自样品取出25μl且分配至丙烯酰胺凝胶的各孔中,随后进行免疫印迹。免疫印迹展示来自三个或多于三个独立实验的代表性结果。结果展示于图2中。
如图2中所见,当用根据本发明的p62配体化合物处理时,确认用化合物处理导致p62蛋白质的单体减少且同时寡聚物及高分子聚集体增加。
实验例2.利用免疫印迹评估经培养细胞中的自噬活性
为利用化合物(实施例1至19)评估自噬活性效能,在具有5%二氧化碳的培养箱中使用含有10%FBS及1%链霉素/青霉素的DMEM培养基培养海拉细胞系(其为自子宫颈癌患者衍生的细胞系)。作为当前化合物中的代表性化合物,选择YOK-1107、YOK-4404及YOK-1104。为根据用这些所选择代表性化合物处理来测量自噬活性,将对应的细胞分配至6孔盘中。进行额外培养24小时,使得细胞完全附着至盘的表面。为发现对应化合物可增加自噬现象下的浓度,将测试化合物稀释至1、2、5、10及20μM且进行处理。在用对应化合物处理后,将细胞再次培养在细胞培养箱中24小时,随后收集细胞。为自收集的细胞萃取蛋白质,将100μl的溶解缓冲液(20mM Tris(pH 7.4)、150mM NaCl、1%Triton X-100、2mM NaF、2mM EDTA、2mMβ-甘油磷酸盐、5mM原钒酸钠、1mM PMSF、亮抑酶肽、抑肽酶)注射至各样品中并溶解细胞。基于所测量的总蛋白质浓度,将样品缓冲液添加至各样品中且使其在100℃下反应5分钟。在反应后自样品取出5μl且分配至丙烯酰胺凝胶的各孔中,随后进行免疫印迹。免疫印迹展示来自三个或多于三个独立实验的代表性结果。结果展示于图3中。
如图3中所见,当用根据本发明的p62配体化合物处理时,确认LC3(大自噬活性的标志物)的水平根据化合物的浓度而逐渐增加。
实验例3.利用免疫印迹评估经培养细胞中的自噬活性
为利用化合物(实施例1至19)研究自噬活性效能,以与实验例2中相同的方式,使用LC3作为标志物来进行免疫印迹。关于差异,为评估活化所需的处理时间及活性保留时间,作为选自本发明化合物的代表性化合物,将5μM的YOK-1107、YOK-1204、YOK-1304、YOK-2204、YOK-3304、YOK-4404处理1、3、6、12、24、48小时,。在另一方面,作为选自本发明的化合物的代表性化合物,将10μM的YOK-1107、YOK-1109、YOK-2207、YOK-2209、YT-4-1、YT-4-2、YT-6-1、YT-6-2、YT-6-8、YT-6-7、YT-9-1、YT-9-2处理24小时。免疫印迹展示来自三个或多于三个独立实验的代表性结果。结果展示于图4中。如图4中所见,当用根据本发明的p62配体化合物处理时,确认LC3(大自噬活性的标志物)的水平根据用化合物处理而逐渐增加。
实验例4.利用免疫印迹评估经培养细胞中的自噬活性
为研究对照化合物的自噬活性效能,以与实验例2中相同的方式,通过使用LC3作为标志物来进行免疫印迹。作为对照化合物,使用具有以下结构的化合物。
[表2]
前述化合物通过在不同浓度下和不同时间的处理来确认,且免疫印迹展示来自三个或多于三个独立实验的代表性结果。结果展示于图5中。如图5中所示,确认对照化合物无论处理时间或浓度如何并未增加LC3(大自噬活性的标志物)的水平。
实验例5.利用免疫荧光染色及共焦显微镜评估经培养细胞中的自噬活性
为利用化合物(实施例1至19)确认p62蛋白质活性及自噬现象的活性水平,使用p62及LC3作为标志物来进行免疫荧光染色。为利用经培养细胞中的新p62配体及其异构体确认p62活性及自噬现象的活性水平,将海拉细胞系(其为来源于子宫颈癌患者的细胞系)用新颖的p62配体化合物(YOK-1106、YOK-1204、YOK-1504、YOK-2204、YOK-3304、YOK-4404、YOK-1107、YOK-1109、YOK-2207、YOK-2209、YT-4-1、YT-4-2、YT-6-1、YT-9-1及YT-9-2)处理并培养。此后,作为自噬现象的标志物,观测LC3斑点的表达水平及位置以及与p62斑点的局部共存。
对于免疫荧光染色,将玻璃罩置于24孔板上,将细胞分配,培养24小时,且随后用5μM根据本发明的新颖的p62配体处理。为使化合物发挥作用,进行额外培养24小时,随后移除培养基。在室温下使用甲醛固定细胞。为防止非特异性染色,使细胞与阻断溶液在室温下反应1小时,随后用以特定比率使用阻断溶液稀释的LC3抗体处理,并且使其在室温下反应1小时。抗体处理的细胞用PBS洗涤三次,且以特定比率使用阻断溶液稀释山羊衍生的二级抗体,且随后使其在室温下反应30分钟。细胞再次用PBS洗涤三次,且对于胞内细胞核染色,在DAPI染色后,经由共焦显微镜观测p62及LC3的表达水平、胞内斑点形成及胞内共存水平。结果展示于图5中。免疫荧光染色展示来自三个或多于三个独立实验的代表性结果。
如图6中所见,确认在用根据本发明的p62配体化合物处理后,p62蛋白质的胞内斑点形成,作为自噬小体标志物的LC3的胞内斑点及局部共存增加,且LC3的胞内斑点形成增加。
实验例6.利用免疫荧光染色及共焦显微镜评估经培养细胞中的自噬活性
为确认对照化合物(YOK-A-1104、YOK-G-1104、YTK-1005、YTK-1105-1)的p62蛋白质活性及自噬现象的活性水平,以与实验例4中相同的方式,通过使用p62及LC3作为标志物来进行免疫荧光染色。YOK-A-1104及YOK-G-1104为具有以下结构的化合物。
[表3]
在不同浓度下处理化合物,且利用共焦显微镜观测p62或LC3的胞内斑点(即,自噬小体形成且递送p62的程度)。结果展示于图7中。免疫荧光染色展示来自三个或多于三个独立实验的代表性结果。
如图7中所示,确认无论用对照化合物处理的浓度如何,p62蛋白质的胞内斑点形成,作为自噬小体标志物的LC3的胞内斑点及局部共存增加,且LC3的胞内斑点形成不增加。
实验例7.利用免疫荧光染色及共焦显微镜评估经培养细胞中P62介导的自泛素化蛋白质递送以自噬的活性
为确认在用化合物(实施例1至19)处理后,经培养细胞中P62介导的自泛素化蛋白质递送以自噬的活性水平,以与实验例4中相同的方式通过使用p62及FK2作为标志物来进行免疫荧光染色。作为化合物,使用YT-4-1、YT-4-2、YT-6-1、YT-6-7、YT-6-8、YOK-4404、YOK-1106、YOK-1107、YOK-1109、YOK-1204及YOK-1204。在用化合物处理后,利用共焦显微镜观测p62或FK2的胞内斑点(即,将p62及泛素化蛋白递送至自噬小体的程度)。结果展示于图8a及8b中。免疫荧光染色展示来自三个或多于三个独立实验的代表性结果。
如图8a及8b中所示,确认在用根据本发明的p62配体化合物处理后,FK2(p62蛋白质及泛素化蛋白质的标志物)的胞内斑点形成,且斑点的局部共存增加。
实验例8.利用免疫荧光染色及共焦显微镜评估经培养细胞中P62介导的错误折叠的亨廷顿蛋白递送以自噬的活性
为确认P62介导的错误折叠的亨廷顿蛋白(Htt-Q103)(亨廷顿氏病的主要蛋白质)递送的活性水平,在用化合物(实施例1至19)治疗退化性脑疾病后,以与实验例4中相同的方式通过使用p62及Htt-Q103-GFP作为标志物来进行免疫荧光染色。作为化合物,使用YOK-1106、YOK-1107、YOK-1109、YOK-1204、YOK-2204、YOK-4404、YT-4-1、YT-4-2、YT-6-1、YT-6-7及YT-9-1。在用化合物处理后,利用共焦显微镜观测p62或Htt-Q103-GFP的胞内斑点(即,将p62及错误折叠的亨廷顿蛋白递送至自噬小体的程度)。结果展示于图9a及9b中。免疫荧光染色展示来自三个或多于三个独立实验的代表性结果。
如图9a及9b中所示,在用根据本发明的p62化合物处理后,确认FK2(p62蛋白质及泛素化蛋白质的标志物)的胞内斑点形成及斑点的局部共存增加。
Claims (19)
1.一种由以下化学式1表示的p62配体化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药:
[化学式1]
在化学式1中,
W为C6至C10芳基;
L为-O-(CH2)n1-CH(OH)-,条件是该-O-(CH2)n1-CH(OH)-中的O与苯环结合,其中n1为1至4的整数;
m为0至2的整数;
Ra为R1或-OR1,
其中R1为氢或-(CH2)n2-R'1,
R'1为未经取代或经以下取代的苯基:羟基、卤素、C1-4烷基、C1-4烷氧基、硝基、氨基、(C1-4烷基)氨基或二(C1-4烷基)氨基,
n2为1至6的整数;
Rb为-OR2,
其中R2为氢或-(CH2)n3-R'2,
R'2为未经取代或经以下取代的苯基:羟基、卤素、C1-4烷基、C1-4烷氧基、硝基、氨基、(C1-4烷基)氨基或二(C1-4烷基)氨基,
n3为1至6的整数;
Rc为-(CH2)n4-OH、-(CH2)n4-NH-C(=NH)NH2、-C(=NH)NH2、C1-6烷基、-CH(R3)-COO-R4或-CH(COO-R4)-CH2CH2CH2-NH-C(=NH)NH2、-(CH2)n4-O-(CH2)n4-OR4、-CONH(CH2)n4-OR4、-CO(CH2)n5-OR4、-(CH2)n5-CH(NH2)-COOR4、-(CH2)n5-CONHR4,
n4为2至4的整数,
n5为1至4的整数,
R3为氢或C1-4烷基,且
R4为氢或C1-4烷基。
2.如权利要求1所述的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药,其中,W为苯基且n1为1或2。
3.如权利要求1所述的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药,其中,Ra为氢或-O-(CH2)n2-R'1,R'1为未经取代或经以下取代的苯基:羟基、氟、氯基、溴、甲基、乙基、甲氧基、乙氧基、硝基、氨基或二甲氨基,且n2为1至4的整数。
4.如权利要求1所述的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药,其中,Rb为羟基或-O-(CH2)n3-R'2,R'2为未经取代或经以下取代的苯基:羟基、氟、氯、溴、甲基、乙基、甲氧基、乙氧基、硝基、氨基或二甲氨基,且n3为1至4的整数。
5.如权利要求1所述的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药,其中,Rc为-(CH2)n4-OH、-(CH2)n4-NH-C(=NH)NH2、-C(=NH)NH2、甲基、乙基或异丙基,且n4为2至3的整数。
6.如权利要求1所述的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药,其中,化学式1的化合物选自由以下化合物1)至19)组成的组:
1)(R)-1-(3,4-(双(苯甲氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YOK-1106);
2)(R)-1-(3,4-(双((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-1);
3)(R)-1-(3-((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-2);
4)(R)-1-(3-((4-氯苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-7);
5)(R)-1-(3-((4-氟苯甲基)氧基)苯氧基)-3-((2-羟乙基)氨基)丙-2-醇(YT-6-8);
6)(R)-1-(2-((3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-1109);
7)(R)-1-(2-((3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)氨基)乙基)胍(YOK-2209);
8)(R)-1-(2-((3-(3,4-双(4-氯苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-1);
9)(R)-1-(2-((3-(3,4-双(4-氟苯甲基)氧基)苯氧基)-2-羟丙基)氨基)乙基)胍(YT-9-2);
10)(R)-1-(3-(3,4-双(苯甲氧基)苯氧基)-2-羟丙基)胍(YOK-1107);
11)(R)-1-(3-(3,4-二苯乙氧基苯氧基)-2-羟丙基)胍(YOK-2207);
12)(R)-1-(3,4-双(苯甲氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1104);
13)(R)-1-(3,4-二苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-2204);
14)(R)-1-(3,4-双(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-3304);
15)(R)-1-(3,4-双(4-苯基丁氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-4404);
16)(R)-1-(4-(苯甲氧基)-3-苯乙氧基苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1204);
17)(R)-1-(4-(苯甲氧基)-3-(3-苯基丙氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YOK-1304);
18)(R)-1-(3,4-双((4-氯苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-1);和
19)(R)-1-(3,4-双((4-氟苯甲基)氧基)苯氧基)-3-(异丙氨基)丙-2-醇(YT-4-2)。
7.一种用于预防、改善或治疗蛋白质构象病的药物组合物,其包含权利要求1至6中任一项所述的化学式1的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药。
8.如权利要求7所述的药物组合物,其中,所述蛋白质构象病为神经退行性疾病、α-1抗胰蛋白酶缺乏症、角膜病变、色素性视网膜炎、2型糖尿病或囊性纤维化。
9.如权利要求8所述的药物组合物,其中,所述神经退行性疾病为选自由以下组成的组的至少一种:莱姆疏螺旋体病、致死性家族性失眠症、库贾氏病(CJD)、多发性硬化(MS)、痴呆、阿兹海默氏病、癫痫症、帕金森氏病、中风、亨廷顿氏病、皮克氏病、肌肉萎缩性侧索硬化(ALS)、脊髓小脑共济失调、其他聚-Q疾病、遗传性脑淀粉样血管病、家族性淀粉样多发性神经病、原发性全身性淀粉样变性(AL淀粉样变性)、反应性全身性淀粉样变性(AA淀粉样变性)、2型糖尿病、注射局部淀粉样变性、β-2微球蛋白淀粉样变性、遗传性非神经病性淀粉样变性以及芬兰型遗传性全身性淀粉样变性。
10.一种用于增强错误折叠蛋白质的自噬活性的药物组合物,其包含权利要求1至6中任一项所述的化学式1的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药。
11.如权利要求10所述的药物组合物,其中,所述蛋白质为选自由以下组成的组的至少一种:癌症诱导性蛋白、朊病毒蛋白、淀粉样前体蛋白(APP)、α-突触核蛋白、超氧化歧化酶1、tau蛋白、免疫球蛋白、淀粉样蛋白A、甲状腺素运载蛋白、β2-微球蛋白、胱抑素C、载脂蛋白A1、TDP-43、胰岛淀粉样多肽、ANF、胶溶素、胰岛素、溶菌酶、血纤维蛋白原、亨廷顿蛋白及脊髓小脑共济失调蛋白以及具有聚-Q延伸的其他蛋白质。
12.一种用于预防、改善或治疗蛋白质构象病的食品组合物,其包含权利要求1至6中任一项所述的化学式1的化合物、其药学上可接受的盐、立体异构体、水合物、溶剂化物或前药。
13.如权利要求12所述的食品组合物,其中,所述蛋白质构象病为神经退行性疾病、α-1抗胰蛋白酶缺乏症、角膜病变、色素性视网膜炎、2型糖尿病或囊性纤维化。
14.如权利要求13所述的食品组合物,其中,所述神经退行性疾病为选自由以下组成的组的至少一种:莱姆疏螺旋体病、致死性家族性失眠症、库贾氏病(CJD)、多发性硬化(MS)、痴呆、阿兹海默氏病、癫痫症、帕金森氏病、中风、亨廷顿氏病、皮克氏病、肌肉萎缩性侧索硬化(ALS)、脊髓小脑共济失调、其他聚-Q疾病、遗传性脑淀粉样血管病、家族性淀粉样多发性神经病、原发性全身性淀粉样变性(AL淀粉样变性)、反应性全身性淀粉样变性(AA淀粉样变性)、2型糖尿病、注射局部淀粉样变性、β-2微球蛋白淀粉样变性、遗传性非神经病性淀粉样变性、亚历山大氏病以及芬兰型遗传性全身性淀粉样变性。
15.一种用于增加错误折叠蛋白质聚集体降解的方法,其包括用权利要求1至6中任一项所述的p62配体化合物处理细胞或p62蛋白。
16.一种用于活化自噬的方法,其包括用权利要求1至6中任一项所述的p62配体化合物处理细胞或p62蛋白。
17.一种用于预防、改善或治疗蛋白质构象病的方法,其包括用权利要求1至6中任一项所述的p62配体化合物处理细胞或p62蛋白,包括向有需要的受试者施用该化合物。
18.如权利要求17所述的方法,其中,所述蛋白质构象病为癌症、神经退行性疾病、α-1抗胰蛋白酶缺乏症、角膜病变、色素性视网膜炎、2型糖尿病或囊性纤维化。
19.如权利要求18所述的方法,其中,所述神经退行性疾病为选自由以下组成的组的至少一种:莱姆疏螺旋体病、致死性家族性失眠症、库贾氏病(CJD)、多发性硬化(MS)、痴呆、阿兹海默氏病、癫痫症、帕金森氏病、中风、亨廷顿氏病、皮克氏病、肌肉萎缩性侧索硬化(ALS)、脊髓小脑共济失调、其他聚-Q疾病、遗传性脑淀粉样血管病、家族性淀粉样多发性神经病、原发性全身性淀粉样变性(AL淀粉样变性)、反应性全身性淀粉样变性(AA淀粉样变性)、2型糖尿病、注射局部淀粉样变性、β-2微球蛋白淀粉样变性、遗传性非神经病性淀粉样变性、亚历山大氏病以及芬兰型遗传性全身性淀粉样变性。
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WO2020256444A1 (ko) * | 2019-06-18 | 2020-12-24 | 서울대학교산학협력단 | p62 리간드 화합물 및 이의 ER-파지 촉진 용도 |
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