CN117295523A - 靶向pxr的双官能protac型化合物、其制备方法及其治疗用途 - Google Patents
靶向pxr的双官能protac型化合物、其制备方法及其治疗用途 Download PDFInfo
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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Abstract
本申请涉及同时结合靶蛋白PXR和E3‑泛素连接酶的新颖的双官能PROTAC型化合物、其制备方法及其用于治疗过表达PXR的癌症的用途。
Description
技术领域
本发明涉及癌症的治疗,更具体地涉及过表达PXR核受体的癌症(诸如结直肠癌)的治疗。
背景技术
结直肠癌(CRC)是第三大最常见的癌症,并且是第三大癌症死亡原因。目前的治疗包括手术、放射疗法和化学疗法,有时结合显示出较小改善的靶向治疗。然而,这些治疗的功效由于经常出现抗药性而严重受损,这导致患者在治疗停止后复发(50%的患者)。近年来,研究表明,肿瘤细胞亚群(癌症干细胞(CSC))参与肿瘤的起始、转移发展和对药物的抗药性,从而导致肿瘤复发。
本发明人现已证明,PXR(NR1I2)核受体在癌症干细胞中优先被激活,并且通过RNA干扰(shRNA)消除其表达使该细胞群体(通常对化学疗法耐受)敏化,并且显著延迟小鼠中的肿瘤复发。因此,PXR(NR1I2)核受体的抑制使得将癌症干细胞对目前的治疗敏化成为可能。
然而,迄今为止发现的PXR拮抗剂(L-萝卜硫素、酮康唑和SAP-70)在使PXR失活所必需的浓度下不是非特异性的和/或有毒的,就是尚未被批准用于临床。
PROTAC(“蛋白水解靶向嵌合体”)是同时结合靶蛋白和E3-泛素连接酶的双官能分子。这导致靶蛋白的多泛素化,从而通过蛋白酶体复合物降解成小肽和氨基酸。因此,PROTAC方法是化学蛋白敲除策略。
因此,需要提供能够根据PROTAC策略诱导PXR的靶向蛋白水解的双官能嵌合配体。
发明内容
根据第一主题,本发明涉及符合通式(I)的双官能化合物:
L(PXR)-连接基-L(E3连接酶)
(I)
其中:
L(PXR)是能够与PXR核受体结合的配体,
L(E3连接酶)表示E3-泛素连接酶的配体,并且
连接基表示使L(PXR)与L(E3连接酶)共价结合成为可能的基团。
泛素-蛋白酶体途径(UPP)是必需的细胞途径,该细胞途径调节关键的调节蛋白并降解错误折叠或异常的蛋白。UPP是几个细胞过程的核心。如果该途径是有缺陷的或不平衡的,则其会导致各种疾病的发病机制。泛素与特定蛋白底物的共价连接是通过E3-泛素连接酶的作用获得的。这些连接酶包括多于500种的不同蛋白,并且被分类成由这些连接酶的E3功能活性的结构元素所定义的几类。
构成本发明化合物的功能形式的E3连接酶配体与E3-泛素连接酶结合。连接酶催化泛素与靶蛋白的共价结合,这进而诱导靶蛋白被天然蛋白酶体降解。因此,本发明的化合物是以利用天然细胞降解过程的方式设计的,但是其中降解作用是针对与疾病的病因有关的不期望的靶蛋白。
与常规化学抑制剂不同,根据本发明的PROTAC充当具有超化学计量作用能力的降解酶。
因此,根据本发明的化合物具有多种优点:
1)它们在低于单独的抑制剂的浓度的浓度下是有活性的,这需要高水平的全身暴露以获得靶标的饱和,
2) 它们可进行多个降解循环,从而导致靶蛋白的降解,
3)与抑制剂在其靶标上的快速离解动力学相比,在由PROTAC诱导的降解后恢复蛋白功能需要细胞重新合成蛋白,这需要更长的时间,因此增加了PROTAC作用的持续时间。
L(PXR)是与PXR结合的本发明化合物的功能形式。在一些实施方案中,靶向配体是PXR JMV6845配体的类似物:
根据一个实施方案,L(PXR)可选自式(II)的基团:
其中表示基团与连接基的连接;
或药学上可接受的盐。
因此,根据本发明的化合物可符合下式(l-1):
其中连接基、L(E3连接酶)如上文或下文所定义,或药学上可接受的盐。
根据一个实施方案,E3连接酶配体与小脑蛋白结合。L(E3连接酶)特别可选自:
-式(IIIA)的基团:
以及
-式(IIIB)的基团:
或药学上可接受的盐,
在式(IIIA)和(IIIB)中:
X是NH;
X'是-C(O)-或-CH2-;
Y表示H或C1-C6烷基基团;
表示基团与连接基的连接。
因此,根据本发明的化合物可特别符合式(I-2)或(I-3):
其中连接基、L(PXR)、L(E3连接酶)、X、X’、Y如上文或下文所定义;
或药学上可接受的盐。
更具体地,根据本发明的化合物可符合下式(I-4)和(I-5)中的一者:
其中L(PXR)、连接基如上文或下文所定义;
或药学上可接受的盐。
连接基提供靶向配体与E3连接酶配体的共价结合。根据一个实施方案,连接基表示C1-C20亚烷基基团,该亚烷基基团任选地被以下基团中的一个基团中断或任选地在一端和/或两端上终止:-O-、-S-、-N(R')-、-C(O)-、-C(O)O-、-OC(O)-、-OC(O)O-、-C(NOR')-、-C(O)N(R')-、-C(O)N(R')C(O)-、-C(O)N(R')C(O)N(R')-、-N(R')C(O)-、-N(R')C(O)N(R')-、-N(R')C(O)O-、-OC(O)N(R')-、-C(NR')-、-N(R')C(NR')-、-C(NR')N(R')-、-N(R')C(NR')N(R')-、-S(O)2-、-OS(O)-、-S(O)O-、-S(O)-、-OS(O)2-、-N(R')S(O)2-、-S(O)2N(R')-、-N(R')S-、-S(O)N(R')-、-N(R')S(O)2N(R')-、-N(R')S(O)N(R')-、C3-C12亚环烷基、包含1、2或3个选自N、O、S的杂原子的3元至12元亚杂环基、包含1、2或3个选自N、O、S的杂原子的5元至12元杂亚芳基或它们的任何组合,并且其中R’相同或不同,表示H或C1-C6烷基基团。
因此,根据一个具体实施方案,连接基可选自C4-C20亚烷基基团,该亚烷基基团任选地被选自-NH-、-O-、-C(O)-、哌啶基、亚哌嗪基的一个或多个基团中断和/或被该一个或多个基团终止。
更具体地,连接基可在式(IV)的基团中表示:
其中L1和L2相同或不同,表示具有1至12个碳原子的亚烷基基团,该亚烷基基团任选地被包含1、2或3个选自N、O、S的杂原子的3元至12元亚杂环基中断或终止;
L1与L(PXR)结合,并且与L(E3连接酶)结合;
Z表示H或C1-C6烷基基团。
根据一个更具体的实施方案,L1是C7-亚烷基基团(-C7H14-)。
根据一个更具体的实施方案,L2是任选地被哌啶基基团中断的C2-C8亚烷基基团。
根据一个实施方案,根据本发明的化合物可符合下式(V):
其中L2表示任选地被哌啶基基团中断的C2-C8直链亚烷基基团,并且L(E3连接酶)如上文或下文所定义。
本文所示的式(I)、(II)、(IIIA)、(IIIB)、(IV)、(V)还涵盖其药学上可接受的盐、其同位素衍生物及其立体异构体。
除非另有说明,如上文和下文中所用:
“烷基”表示在链中具有约1至约20个碳原子的直链或支链脂族烃基团。优选的烷基基团在链中具有1至约12个碳原子,特别是1至6个碳原子。支链是指一个或多个低级烷基基团(诸如甲基、乙基或丙基)与直链烷基链结合。“低级烷基”是指在可以是直链或支链的链中具有约1至约4个碳原子。烷基可被一个或多个“烷基基团取代基”取代,该烷基基团取代基可以相同或不同并且包括卤素、环烷基、羟基、烷氧基、氨基、酰基氨基、芳酰基氨基、羧基、烷氧基羰基、芳烷基氧羰基、杂芳烷氧基羰基或Y1Y2NCO-,其中Y1和Y2独立地是氢、任选取代的烷基、任选取代的芳基、任选取代的芳烷基或任选取代的杂芳烷基,或者Y1和Y2与Y1和Y2经由其结合的N一起考虑,形成4元至7元杂环基。烷基基团的典型示例包括甲基、三氟甲基、环丙基甲基、环戊基甲基、乙基、正丙基、异丙基、正丁基、叔丁基、正戊基、3-戊基、甲氧基乙基、羧甲基、甲氧基羰基乙基、苄氧基羰基甲基、吡啶基甲氧基羰基甲基。
“亚烷基”表示如上文所定义的二价烷基基团。优选的亚烷基基团是具有1至约6个碳原子的低级亚烷基基团。亚烷基基团的典型示例包括亚甲基和亚乙基。
“环烷基”是指具有约3至约10个碳原子,优选地约5至约10个碳原子的非芳族单环环系或多环环系。环系的环的优选环尺寸包括约5至约6个环原子,任选地被一个或多个取代基取代。示例性单环环烷基包括环戊基、环己基、环庚基等。示例性多环环烷基包括1-萘烷基、降莰烷基、金刚烷-1-基或金刚烷-2-基等。
“亚环烷基”是指如上文所定义的饱和二价环烷基基团,诸如特别是亚环己基。
“杂环基”是指具有约3至约10个碳原子,优选地约5至约10个碳原子的非芳族饱和单环环系或多环环系,其中环系中的碳原子中的一个或多个碳原子是除碳以外的一种或多种杂元素,例如氮、氧或硫。环系的环的优选环尺寸包括约5至约6个环原子。在杂环基之前指定氮杂、氧杂或硫杂为前缀定义了为分别存在至少一个氮、氧或硫原子作为环原子。杂环基可任选地被一个或多个取代基取代,该一个或多个取代基可以相同或不同,并且如本文所定义。杂环基的氮原子可以是碱性氮原子。杂环基的氮或硫原子也可任选地被氧化成相应的N-氧化物、S-氧化物或S,S-二氧化物。示例性单环杂环基环包括哌啶基、吡咯烷基、哌嗪基、吗啉基、硫代吗啉基、噻唑烷基、1,3-二氧戊环基、1,4-二噁烷基、四氢呋喃基、四氢噻吩基、四氢噻喃基等。
术语“亚杂环基”表示如上文所定义的二价杂环基自由基。
“杂芳基”是指具有约5至约14个碳原子、优选地约5至约10个碳原子的单环芳环系或多环芳环系,其中该环系中的碳原子中的一个或多个碳原子是除碳以外的一种或多种杂元素,例如氮、氧或硫。环系的环的优选环尺寸包括约5至约6个环原子。“杂芳基”还可被一个或多个取代基取代。在杂芳基之前指定氮杂、氧杂或硫杂为前缀定义了为分别存在至少一个氮、氧或硫原子作为环原子。杂芳基的氮原子可以是碱性氮原子,也可任选地被氧化成相应的N-氧化物。示例性取代的杂芳基基团和杂芳基基团包括吡嗪基、噻吩基、异噻唑基、噁唑基、吡唑基、呋咱基、吡咯基、1,2,4-噻二唑基、哒嗪基、喹喔啉基、酞嗪基、咪唑并[1,2-a]吡啶、咪唑并[2,1-b]噻唑基、苯并呋咱基、氮杂吲哚基、苯并咪唑基、苯并噻吩基、噻吩并吡啶基、噻吩并嘧啶基、吡咯并吡啶基、咪唑并吡啶基、苯并氮杂吲哚、1,2,4-三嗪基、苯并噻唑基、呋喃基、咪唑基、吲哚基、吲哚嗪基、异噁唑基、异喹啉基、异噻唑基、噁二唑基、吡嗪基、哒嗪基、吡唑基、吡啶基、嘧啶基、吡咯基、喹唑啉基、喹啉基、1,3,4-噻二唑基、噻唑基、噻吩基和***基。优选的杂芳基基团包括吡嗪基、噻吩基、吡啶基、嘧啶基、异噁唑基和异噻唑基。
“杂亚芳基”表示如上文所定义的二价杂芳基自由基。
“取代基”表示选自卤素、氰基、环烷基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、芳酰基氨基、羧基、烷氧基羰基、芳烷氧基羰基、杂芳烷氧基羰基的一个或多个相同或不同的基团。
本发明的化合物可以是游离酸或游离碱或药学上可接受的盐的形式。
表述“药学上可接受的盐”是指本发明的化合物的相对无毒的无机和有机酸加成盐以及碱加成盐。这些盐可在化合物的最终分离和纯化过程中原位制备。具体地,酸加成盐可通过将纯化形式的纯化化合物分别与有机酸或无机酸反应并分离由此形成的盐来制备。酸加成盐的示例有氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、氨基磺酸盐、丙二酸盐、水杨酸盐、丙酸盐、亚甲基双-b-羟基萘甲酸盐、龙胆酸、羟乙基磺酸盐、二-对甲苯酰酒石酸盐、甲烷磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和喹啉磺酰基磺酸盐等。(参见例如S.M.Berge等人的《药用盐(Pharmaceutical Salts)》,《药物科学杂志(Journal of Pharmaceutical Science)》66:第1-19页(1977),其以引用方式并入本文)。酸加成盐还可通过将酸形式的纯化化合物分别与有机碱或无机碱反应并分离由此形成的盐来制备。酸加成盐包括胺和金属盐。合适的金属盐包括钠盐、钾盐、钙盐、钡盐、锌盐、镁盐和铝盐。钠盐和钾盐是优选的。合适的碱性无机加成盐由金属碱制备,该金属碱包括氢化钠、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化铝、氢氧化锂、氢氧化镁、氢氧化锌。合适的碱性加成盐由胺制备,该胺具有足够的碱度以形成稳定的盐,并且优选地包括由于它们的低毒性和它们对于医疗用途的可接受性而通常用于药物化学中的胺:氨、乙二胺、N-甲基-葡糖胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N'-二苄基乙二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苄基苯乙胺、二乙胺、哌嗪、三(羟甲基)-氨基甲烷、四甲基氢氧化铵、三乙胺、二苄胺、麻黄胺、脱氢枞胺、N-乙基哌啶、苄胺、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、乙胺、碱性氨基酸(例如赖氨酸和精氨酸)和二环己基胺等。
本发明的化合物可具有至少一个手性中心,因此可以是立体异构体的形式,如本文所用,该立体异构体涵盖单个化合物的所有异构体,这些异构体的区别仅在于它们的原子在空间中的取向。术语立体异构体包括化合物的镜像异构体(包括化合物的(R-)或(S-)构型的对映异构体)、几何化合物(顺式/反式异构体或E/Z异构体、R/S异构体)的镜像异构体的混合物(对映异构体和外消旋体或外消旋混合物的物理混合物)以及具有多于一个手性中心且互不为镜像的化合物的异构体(非对映异构体)。化合物的手性中心可在体内发生差向异构化;因此,对于这些化合物,其(R-)形式的化合物的给药被认为等同于其(S-)形式的化合物的给药。因此,本发明的化合物可以单个异构体的形式和基本上不含其他异构体的形式制造和使用,或以各种异构体的混合物的形式(例如立体异构体的外消旋混合物)制造和使用。
在一些实施方案中,下列化合物适用于结合小脑蛋白和PXR:
[表1]
最特别地,根据本发明的化合物可选自符合下式中的一者的化合物:
根据进一步的主题,本发明还涉及用于制备根据本发明的化合物的方法。
通式(I)的化合物可通过应用或修改任何本身已知的方法和/或在本领域技术人员的能力范围内的方法来制备,特别是由Larock在《综合有机转化(ComprehensiveOrganic Transformations)》(VCH出版,1989年)中描述的那些方法,或者通过应用或修改以下示例中描述的方法来制备。
根据本发明,所述方法包括将式(B)的化合物和式(C)的化合物偶联:
使得L(PXR)和L(E3连接酶)如上文所定义,并且T和T’是两组连接基前体,也就是说,该两组连接基前体的偶联使得产生连接基基团成为可能,使得L(PXR)和L(E3连接酶)各自分别具有互补的反应性末端官能团。
本文中“互补的反应性官能团”表示能够一起反应以形成确保T和T'之间的共价键的官能团的两个官能团。因此,典型地,T和T'使得T具有胺类末端官能团并且T'具有羧酸类末端官能团。
因此,典型地,T表示式(T-B)的基团:
-L1-NH2
(T-B)
并且T'表示式(T-C)的基团:
其中L1和L2如上文所定义。
所述偶联可有利地在肽偶联剂诸如BOP(苯并***-1-基氧基三(二甲基氨基)鏻六氟磷酸盐)的存在下进行,典型地在有机碱诸如胡宁氏碱N,N-二异丙基乙胺(DIPEA或DIEA)的存在的情况下进行。
根据一个实施方案,化合物(B)符合式(A):
根据一个实施方案,化合物(C)符合式(C-1):
其中L2和L(E3连接酶)如上文所定义。
任选地,所述方法还可包括由分离获得的式(I)的产物组成的步骤。
在下文所述的反应中,可能有必要保护反应性官能基团,例如羟基、氨基、亚氨基、硫基、羧基(当它们在最终产物中是期望的时),以避免它们不期望地参与反应。可根据标准惯例使用常规保护基团,例如参见T.W.Green和P.G.M.Wuts的《有机化学中的保护基团(Protective Groups in Organic Chemistry)》,约翰威立国际出版集团(John Wiley andSons),1991年;J.F.W.McOmie的《有机化学中的保护基团》,普伦姆出版社(Plenum Press),1973年。
这样制备的化合物可通过常规方法从反应混合物中回收。例如,可通过蒸馏反应混合物的溶剂来回收化合物,或者如果必要,在蒸馏溶液混合物的溶剂之后,通过将剩余物倒入水中,随后用与水不混溶的有机溶剂萃取并通过从萃取物中蒸馏溶剂来回收化合物。除此之外,如果需要,可通过各种技术进一步纯化产物,诸如重结晶、再沉淀或各种色谱技术,特别是柱色谱或制备薄膜色谱。
可以看出,根据本发明的有用化合物可含有不对称中心。这些不对称中心可独立地为R或S构型。对本领域技术人员显而易见的是,某些有用的根据本发明的化合物也可具有几何异构性。应当理解,本发明包括上文中的式(I)的化合物的单个几何异构体和立体异构体及其混合物,包括外消旋混合物。这种类型的异构体可通过应用或修改已知的方法(例如色谱技术或重结晶技术)从它们的混合物中分离出来,或者这种类型的异构体从它们的中间体的适当异构体中单独制备。
所使用的碱产品或试剂是可商购的和/或可通过应用或修改已知方法来制备,例如如参考实施例中所述的方法或其明显的化学等效物。
根据本发明的方法可实施新颖的式(A)的中间体。
根据进一步的主题,本发明因此还涉及式(A)的化合物:
式(A)的化合物可通过偶联以下化合物来制备:
典型地,该偶联可通过应用或修改实施例1中所述的步骤来进行。
根据本发明,式(I)的化合物能够诱导PXR的靶向蛋白水解。因此,式(I)的化合物可用于治疗和/或预防癌症,特别是过表达PXR的癌症。
因此,本发明还涉及包含根据本发明的化合物以及药学上可接受的赋形剂的药物组合物。
优选地,所述组合物含有有效量的根据本发明的化合物。
根据进一步的主题,本发明还涉及通式(I)的化合物,该化合物用于治疗和/或预防癌症,特别是过表达PXR的癌症。
过表达PXR的癌症特别是结直肠癌,以及胰腺癌、肝癌和乳腺癌。
典型地,根据本发明的化合物可与抗癌剂联合使用。此类抗癌剂特别可选自5氟尿嘧啶(5-FU)、伊立替康(CPT11)、奥沙利铂、顺铂、他莫昔芬、紫杉醇、多柔比星、长春碱(Vonblastin)、环磷酰胺(CPA)、异环磷酰胺(IFO)。
优选地,用所述组合物对有此需要的患者进行给药。所述患者特别是对上述抗癌剂有抗药性的患者。
本发明的药物组合物的制剂类型取决于给药方式,该给药方式可包括可以是肠内(例如,口服)、胃肠外(例如,皮下(sc)、静脉内(iv)、肌内(im)和胸骨内)的注射,或可以是静脉内或动脉、髓内、鞘内、心室内、经皮、皮内、直肠、***内、腹膜内、局部粘膜、鼻、口、舌下、气管内滴注、支气管滴注和/或吸入的输注技术。通常,最合适的给药途径取决于多种因素,特别是药剂的性质(例如,其在消化道环境中的稳定性)和/或受试者的状态(例如,如果受试者能够耐受口服给药)。在一些实施方案中,组合物被配制用于口服给药或静脉内给药(例如,全身静脉内注射)。
本领域已知的表述“药学上可接受的载体”表示适用于用本发明的化合物对哺乳动物进行给药的药学上可接受的材料、组合物或载体。合适的支持物可包括例如液体(水性和非水性两者及其组合)、固体、包封材料、气体及其组合(例如,半固体),其用于将化合物从一个器官或身体部位运输或转运到另一个器官或身体部位。支持物是“可接受的”,意思是它是生理学惰性的并且与制剂的其他组分相容,并且对受试者或患者是无毒的。基于制剂的类型,
因此,式I的化合物可被配制为固体组合物(例如,粉剂、片剂、可分散颗粒、胶囊、圆片和栓剂)、液体组合物(例如,化合物溶解于其中的溶液、化合物颗粒分散于其中的悬浮液、含有脂质体、胶束或纳米颗粒的乳剂和溶液、糖浆剂和酏剂);半固体组合物(例如,凝胶、悬浮液和乳膏);以及气体(例如,用于气溶胶组合物的推进剂)。化合物还可被配制用于快速释放、中间释放或延长释放。
适用于固体给药的赋形剂是纤维素或微晶纤维素的衍生物、碱土金属碳酸盐、磷酸镁、淀粉、改性淀粉、固体形式的乳糖。对于肠胃外使用,水、水性溶质、生理血清、等渗溶质是最方便使用的载体。
剂量可根据治疗适应症和给药途径以及受试者的年龄和体重在较大范围内变化。
附图说明
图1描绘了通过RT-FRET测定的前PROTAC JMV6944的PXR亲和力。
图2示出了前PROTAC JMV6944对PXR的激活以及由此产生的如通过置于CYP3A4启动子(PXR的靶基因)控制下的荧光素酶报告基因所测定的PROTAC。
图3A和图3B描绘了前PROTAC JMV6944对PXR的靶基因(即CYP3A4)的诱导以及由此产生的通过RT-qPCR测定的PROTAC。
图4A和图4B示出并描绘了PROTAC JMV7048和PROTAC JMV7965通过蛋白印迹法对CYP34诱导的作用。
图5A和图5B示出了PROTAC对衍生自结肠癌的各种细胞系(LS174T,FIT29)和原代培养物(CRC1)中的细胞活力的影响。
图6A至图6E描绘了通过蛋白印迹法测定的PROTAC对LS174T细胞中PXR蛋白降解的影响。
图7A和图7B分别描绘了通过蛋白印迹法测定的PROTAC对FIEPG2(图7A)和ASPC1(图7B)细胞中PXR蛋白降解的影响。
图8A至图8B示出了蛋白酶体途径在通过蛋白印迹法测定的PROTAC对PXR蛋白降解的影响中的重要作用。
图9A至图9C分别描绘了JMV7048对SCID小鼠中LS174T细胞异种移植物中PXR蛋白体内降解的影响。
图10A至图10D分别描绘了PROTAC对癌症干细胞群的作用:抑制ALDFI活性(图10A)、抑制它们的自我更新能力(图10B)以及对化学疗法的敏化作用(图10C和图10D)
图11示出了JMV6944与hPXR的LBD的相互作用模式。(图11A)复合物的整体结构。显示了活化螺旋H12。箭头表示随后合成的PROTAC的延伸部分。(图11B)JMV6944的输出途径的扩大和与hPXR-LBD/SR12813复合物的结构的重叠。H2’螺旋的末端(残基206至209)在配体存在下重新排列。(图11C)JMV6944与hPXR结合口袋残基的残基的相互作用以及配体的电子密度的描绘(省略类型差异图)。
具体实施方式
以下实施例说明本发明,但不限制本发明。所用的起始产品是已知产品或根据已知步骤制备的产品。
结合在各种工作实施例中描述的合成图,将更好地理解本发明的化合物,该合成图示出了可制备本发明的化合物的非限制性方法。除非另有说明,百分比以重量表示。
实施例1:JMV6944的合成
步骤1:N1-苄基-4-硝基苯-1,2-二胺
将K2CO3(13.28g,96.08mmol)加入到含有2-氟-5-硝基苯胺(5g,32.03mmol)和苄胺(7.01ml,64.05mmol)的DMF(50ml)溶液中。将反应介质在100℃下搅拌24小时。将反应介质在乙酸乙酯/H2O混合物中稀释。依次用水、1N KHSO4、饱和NaCl洗涤有机相,并用硫酸镁干燥。蒸发后,将产物在***中研磨并沥干。获得黄色固体形式的化合物1N1-苄基-4-硝基苯-1,2-二胺,质量为7.5g(产率96%)。ESI:M+H 244.1。
步骤2:N-{2-[4-(1-苄基-5-硝基-1H-1,3-苯并二唑-2-基)丁氧基]乙基}氨基甲
酸(9H-芴-9-基)甲酯
将TFA(0.91ml,12.28mmol)加入到含有N1-苄基-4-硝基苯-1,2-二胺(0.747g,3.07mmol)和N-[8-(1H-1,2,3-苯并***-1-基)-8-氧代辛基]氨基甲酸(9H-芴-9-基)甲酯(1.63g,3.37mmol)的甲苯/DMF(9/1)混合物(45ml/5ml)溶液中。将反应介质在60℃下搅拌6小时。将反应介质冷却至室温,然后冷却至0℃。将固体沥干,然后用***洗涤两次。将粉末溶解在乙酸中并加热至100℃持续18小时。蒸发后,获得黄色油状形式的化合物2N-{2-[4-(1-苄基-5-硝基-1H-1,3-苯并二唑-2-基)丁氧基]乙基}氨基甲酸(9H-芴-9-基)甲酯,0.55g(产率30%)。ESI:M+H 589.2。
步骤3:N-[7-(5-氨基-1-苄基-1H-1,3-苯并二唑-2-基)庚基]氨基甲酸(9H-芴-9-
基)甲酯
将SnCl2(1.2g,6.34mmol)加入到含有N-{2-[4-(1-苄基-5-硝基-1H-1,3-苯并二唑-2-基)丁氧基]乙基}氨基甲酸(9H-芴-9-基)甲酯(0.75g,1.27mmol)的乙醇(30ml)溶液中。将反应介质在80℃下搅拌2小时。将反应介质在乙酸乙酯/NaHCO3混合物中稀释并通过硅藻土过滤。回收有机相并在MgSO4上干燥。蒸发后,获得黄色粉末形式的化合物3N-[7-(5-氨基-1-苄基-1H-1,3-苯并二唑-2-基)庚基]氨基甲酸(9H-芴-9-基)甲酯,0.55g(产率77%)。ESI:M+H559.3。
步骤4:N-[2-(7-氨基庚基)-1-苄基-1H-1,3-苯并二唑-5-基]-2,4,6-三甲基苯-
1-磺酰胺
在0℃下,将每份2-均三甲苯基磺酰氯(0.166g,0.75mmol)加入到含有N-[7-(5-氨基-1-苄基-1H-1,3-苯并二唑-2-基)庚基]氨基甲酸(9H-芴-9-基)甲酯(0.386g,0.69mmol)的吡啶/DCM(1/1)混合物(5ml/5ml)溶液中。将反应介质升至室温并搅拌18小时。向反应介质中加入二乙胺(2ml)并搅拌2小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,0.201g(产率56%)。ESI:M+H 519.4。1H NMR(600MHz,DMSO-d6):δ10.53(s,1H),7.77(m,3H),7.64(d,J=8.92Hz,1H),7.33(m,4H),7.20(d,J=6.81Hz,2H),7.10(dd,J=1.79,8.88Hz,1H),7.01(s,2H),5.63(s,2H),3.08(m,2H),2.75(m,2H),2.58(s,6H),2.21(s,3H),1.66(m,2H),1.48(m,2H),1.26(m,6H)。
13C NMR(125MHz,DMSO-d6):δ155.3,142.7,139.2,135.8,135.4,133.9,132.3,129.4,129.3,129.3,128.5,127.3,117.7,113.7,47.7,39.4,39.2,28.6,28.4,27.3,26.5。
实施例2:JMV7048的合成
步骤1:2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚-1,3-二酮
将在乙酸(50ml)中含有4-氟邻苯二甲酸酐(2.43g,14.63mmol)和3-氨基哌啶-2,6-二酮(2.38g,14.63mmol)以及乙酸钠(2.4g,29.26mmol)的反应介质加热至100℃持续24小时。冷却至室温后,向反应混合物中加入水(150mL),将混合物沥干,用***洗涤数次。在干燥器中于50℃放置过夜,获得粉红色固体形式的化合物1,2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮,质量为4g(产率99%)。ESI:M+H 277.2。1H NMR(600MHz,DMSO-d6):δ11.15(s,1H),8.03-8.00(dd,J=4.59,8.02Hz,1H),7.87-7.85(dd,J=2.29,8.02Hz,1H),7.75-7.71(t,J=2.29,4.59,8.02Hz,1H),5.19-5.16(dd,J=5.51,13.03,1H),2.94-2.87(m,1H),2.64-2.59(m,1H),2.58-2.51(m,1H),2.10-2.05(m,1H);13C NMR(125MHz,DMSO-d6)δ173.2,173.2,170.2,170.1,167.4,166.6,166.6,166.3,165.4,134.7,134.6,127.9,126.7,126.7,122.3,122.1,112.0,111.8,49.6,31.3,22.4。
步骤2:4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-5-基)哌嗪-1-羧酸叔
丁酯
在室温下将化合物2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(500mg,1.81mmol)溶解于NMP(7ml)中。加入DIEA(0.89ml,5.43mmol)和1-哌嗪-羧酸叔丁酯(370.9mg,1.99mmol),将混合物在140℃搅拌24小时。将溶液用水(100ml)稀释。用乙酸乙酯萃取两次,用饱和NaCl洗涤有机相,并且用硫酸镁干燥。蒸发后,将获得的油状物在硅胶上用石油醚/乙酸乙酯洗脱液(3/1)纯化。获得黄色固体形式的4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-5-基)哌嗪-1-羧酸叔丁酯,质量为655mg(产率82%)。ESI:M+H443.1。1H NMR(600MHz,DMSO-d6):δ11.09(s,1H),7.70(d,J=8.56Hz,1H),7.35(d,J=2.08Hz,1H),7.26-7.24(dd,J=2.08,8.56Hz,1H),5.08(m,1H),3.47(s,8H),2.93-2.86(m,1H),2.61-2.48(m,2H),2.03(m,1H),1.43(s,9H)。13C NMR(125MHz,DMSO-d6)δ173.2,170.5,167.9,167.4,155.4,154.3,134.3,125.3,119.0,118.3,108.5,79.6,49.2,47.0,31.4,28.5,22.6。
步骤3:2-(2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮
将4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-5-基)哌嗪-1-羧酸叔丁酯(464mg,1.04mmol)化合物溶解于4N HCl的二噁烷(4ml)溶液中,将该反应介质在室温下搅拌2小时,然后浓缩并与***一起研磨。获得黄色粉末形式的固体,质量为323mg(产率90%)。ESI:M+H 343.1。1H NMR(600MHz,DMSO-d6):δ11.09(s,1H),9.71(m,2H),7.73(d,J=8.61Hz,1H),7.44(d,J=2.08Hz,1H),7.32(dd,J=2.08,8.61Hz,1H),5.09(m,1H),3.73(m,4H),3.19(m,4H),2.89(m,1H),2.61-2.48(m,2H),2.03(m,1H)。13C NMR(125MHz,DMSO-d6)δ173.2,170.4,167.8,167.3,154.8,134.2,125.4,120.0,119.0,109.2,49.2,44.5,42.4,31.4,22.6。
步骤4:6-(4-(2-(2,6-二氧代哌啶-3-基)-1.3-二氧代吲哚啉-5-基)哌嗪-1-基)
己酸
将化合物2-(2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮(100g,0.29mmol)溶解于乙腈(5ml)中。加入6-溴己酸(152mg,0.73mmol)和DIEA(0.193ml,1.16mmol),将混合物在60℃搅拌24小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,质量为90mg(产率65%)。ESI:M+H 457.3。1H NMR(600MHz,DMSO-d6):δ12.08(m,1H),11.04(s,1H),9.73(m,1H),7.77(d,J=8.50Hz),7.50(d,J=1.90Hz),7.37(dd,J=1.90,8.50Hz),5.10(m,1H),4.23(m,2H),3.59(m,2H),3.25(m,2H),3.14(m,4H),2.90(m,1H),2.59(m,2H),2.25(m,2H),2.04(m,1H),1.69(m,2H),1.55(m,2H),1.33(m,2H)。13C NMR(125MHz,DMSO-d6)δ174.7,173.2,170.4,167.8,167.3,154.6,134.2,125.4,120.4,119.2,109.4,55.7,50.7,49.3,44.8,33.7,31.4,25.9,24.3,23.4。
步骤5:JMV7048
将BOP(52mg,0.12mmol)加入到含有N-[2-(7-氨基庚基)-1-苄基-1H-1,3-苯并二唑-5-基]-2,4,6-三甲基苯-1-磺酰胺(41mg,0.079mmol)(实施例1,JMV6944)、6-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚-5-基)哌嗪-1-基)己酸(34mg,0.079mmol)和DIEA(0.039ml,0.237mmol)的DMF(5ml)溶液中。将反应介质在室温下搅拌两个小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,质量为52mg(产率66%)。ESI:M+H 958.0。1H NMR(600MHz,DMSO-d6):δ11.02(s,1H),10.42(m,1H),9.78(m,1H),7.69(d,J=8.49Hz,1H),7.65(m,1H),7.54(d,J=8.89Hz,1H),7.41(d,J=2.01Hz,1H),7.29-7.20(m,5H),7.11(m,2H),7.00(dd,J=2.01,8.89Hz,1H),6.93(s,2H),5.02(dd,J=5.53,13.14Hz,1H)。
实施例3:JMV7505的合成
步骤1:7-{4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-
基]哌嗪-1-基}庚酸
将化合物2-(2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮(100mg,0.29mmol)(实施例2,步骤3)溶解于乙腈(5ml)中。加入7-溴庚酸(155mg,0.73mmol)和DIEA(0.193ml,1.16mmol),将混合物在60℃搅拌24小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,质量为93mg(产率65%)。ESI:M+H471.3。
步骤2:
将BOP(52mg,0.12mmol)加入到含有N-[2-(7-氨基庚基)-1-苄基-1H-1,3-苯并二唑-5-基]-2,4,6-三甲基苯-1-磺酰胺(41mg,0.079mmol)(实施例1,JMV6944)、6-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚啉-5-基)哌嗪-1-基)庚酸(34mg,0.079mmol)和DIEA(0.039ml,0.237mmol)的DMF(5ml)溶液中。将反应介质在室温下搅拌两个小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得白色粉末,质量为52mg(产率68%)。ESI:M+H 971.5。1H NMR(600MHz,DMSO-d6):δ11.02(s,1H),10.42(m,1H),9.78(m,1H),7.69(d,J=8.49Hz,1H),7.65(m,1H),7.54(d,J=8.89Hz,1H),7.41(d,J=2.01Hz,1H),7.29-7.20(m,5H),7.11(m,2H),7.00(dd,J=2.01,8.89Hz,1H),6.93(s,2H),5.53(s,2H),5.02(dd,J=5.53,13.14Hz,1H)。
实施例4:JMV7506的合成
步骤1:8-{4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-
基]哌嗪-1-基}辛酸
将2-(2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮化合物(100mg,0.29mmol)(实施例2,步骤3)溶解于乙腈(5ml)中。加入8-溴辛酸(160mg,0.73mmol)和DIEA(0.193ml,1.16mmol),将混合物在60℃搅拌24小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,质量为101mg(产率67%)。ESI:M+H 485.6。
步骤2:
将BOP(52mg,0.12mmol)加入到含有N-[2-(7-氨基庚基)-1-苄基-1H-1,3-苯并二唑-5-基]-2,4,6-三甲基苯-1-磺酰胺(41mg,0.079mmol)(实施例1,JMV6944)、6-(4-(2-(2,6-二氧代哌啶-3-基)-1,3-二氧代吲哚-5-基)哌嗪-1-基)辛酸(36mg,0.079mmol)和DIEA(0.039ml,0.023mmol)的DMF(5ml)溶液中。将反应介质在室温下搅拌两个小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得白色粉末,质量为45mg(产率61%)。ESI:M+H 985.5。
1H NMR(600MHz,DMSO-d6):δ11.02(s,1H),10.42(m,1H),9.78(m,1H),7.69(d,J=8.49Hz,1H),7.65(m,1H),7.54(d,J=8.89Hz,1H),7.41(d,J=2.01Hz,1H),7.29-7.20(m,5H),7.11(m,2H),7.00(dd,J=2.01,8.89Hz,1H),6.93(s,2H),5.54(s,4H),5.02(dd,J=5.53,13.14Hz,1H)。
实施例5:JMV7965的合成
步骤1:4-({4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基}甲基)哌啶-1-羧酸叔丁酯
将3ml MeOH加入到含有2-(2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮(100mg,0.29mmol)(实施例2,步骤3)和4-甲酰基哌啶-1-羧酸叔丁酯(112mg,0.53mmol)的DCE溶液中。将反应介质在室温下搅拌30分钟。分批加入三乙酰氧基硼氢化钠,并将反应介质在室温下搅拌18小时。将反应介质浓缩,并进行制备型HPLC。冷冻干燥后,获得黄色粉末,质量为85mg(产率53%)。ESI:M+H 540.2。
步骤2:2-(2,6-二氧代哌啶-3-基)-5-{4-[(哌啶-4-基)甲基]哌嗪-1-基}-2,3-二
氢-1H-异吲哚-1,3-二酮
将4-({4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基}甲基)哌啶-1-羧酸叔丁酯化合物(100mg,0.19mmol)溶解于DCM(50ml)中。将TFA(5ml)逐滴加入反应介质中,并在室温下搅拌5小时。在减压下浓缩溶液。将获得的油状物(75mg,产率92%)直接用于步骤3。ESI:M+FI 440.3。
步骤3:2-[4-({4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲 哚-5-基]哌嗪-1-基}甲基)哌啶-1-基]乙酸叔丁酯
在DIEA(0.14ml,0.88mmol)的存在下,将化合物2-(2,6-二氧代哌啶-3-基)-5-{4-[(哌啶-4-基)甲基]哌嗪-1-基}-2,3-二氢-1H-异吲哚-1,3-二酮(128mg,0.29mmol)溶解于DCM中。加入溴乙酸叔丁酯(0.043ml,0.29mmol)并在室温下搅拌18小时。将反应介质浓缩,并进行制备型HPLC。冷冻干燥后,获得黄色粉末,质量为85mg(产率53%)。ESI:M+H 554.4。
步骤4:2-[4-({4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲 哚-5-基]哌嗪-1-基}甲基)哌啶-1-基]乙酸
将2-[4-({4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基}甲基)哌啶-1-基]乙酸叔丁酯化合物(83mg,0.19mmol)溶解于DCM(25ml)中。将TFA(5ml)逐滴加入反应介质中,并在室温下搅拌5小时。在减压下浓缩溶液。将获得的油状物(70mg,产率93%)直接用于步骤3。ESI:M+H 498.3。
步骤5:
将BOP(27mg,0.0603mmol)加入到含有N-[2-(7-氨基庚基)-1-苄基-1H-1,3-苯并二唑-5-基]-2,4,6-三甲基苯-1-磺酰胺(21mg,0.0402mmol)(实施例1,JMV6944)、2-[4-({4-[2-(2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基}甲基)哌啶-1-基]乙酸(20mg,0.0402mmol)和DIEA(0.020ml,0.12mmol)的DMF(5ml)溶液中。将反应介质在室温下搅拌两个小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,质量为25mg(产率62%)。ESI:M+H 998.3。
实施例6:JMV7605的合成
步骤1:4-{4-[(2,6-二氧代哌啶-3-基)氨基甲酰基]苯基}哌嗪-1-羧酸叔丁酯
将BOP(1.11g,2.53mmol)加入到含有4-[4-(叔丁氧基羰基)哌嗪]苯甲酸(0.775g,2.53mmol)、3-氨基哌啶-2,6-二酮盐酸盐(0.50g,3.03mmol)和DIEA(1.25ml,7.59mmol)的DMF(50ml)溶液中。
将反应介质在室温下搅拌两个小时。向反应介质中加入水,用乙酸乙酯萃取。依次用1N HCl、饱和NaHCO3和饱和NaCl洗涤有机相。用MgSO4干燥有机相,过滤并在减压下浓缩。获得白色粉末,质量为0.4g(产率38%)。ESI:M+H 417.3。
步骤2:N-(2,6-二氧代哌啶-3-基)-4-(哌嗪-1-基)苯甲酰胺
将4-{4-[(2,6-二氧代哌啶-3-基)氨基甲酰基]苯基}哌嗪-1-羧酸叔丁酯(0.4g,0.96mmol)化合物溶解于4N HCl的二噁烷(6ml)溶液中,将该反应介质在室温下搅拌2小时,然后浓缩并与***一起研磨。获得白色粉末形式的固体,质量为0.285mg(产率94%)。
将反应介质在室温下搅拌两个小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得白色粉末,质量为45mg(产率52%)。ESI:M+H 317.3。
步骤3:7-(4-{4-[(2,6-二氧代哌啶-3-基)氨基甲酰基]苯基}哌嗪-1-基)庚酸
将N-(2,6-二氧代哌啶-3-基)-4-(哌嗪-1-基)苯甲酰胺化合物(50mg,0.15mmol)溶解于DMF(5ml)中。加入7-溴庚酸(66mg,0.31mmol)和DIEA(0.078ml,0.47mmol),将混合物在100℃搅拌24小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,质量为38mg(产率55%)。ESI:M+H 445.1。
步骤4:
将BOP(44mg,0.101mmol)加入到含有N-[2-(7-氨基庚基)-1-苄基-1H-1,3-苯并二唑-5-基]-2,4,6-三甲基苯-1-磺酰胺(35mg,0.067mmol)(实施例1,JMV6944)、7-(4-{4-[(2,6-二氧代哌啶-3-基)氨基甲酰基]苯基}哌嗪-1-基)庚酸(30mg,0.067mmol)和DIEA(0.033ml,0.20mmol)的DMF(5ml)溶液中。将反应介质在室温下搅拌两个小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得白色粉末,质量为41mg(产率65%)。ESI:M+H 945.8。
实施例7:JMV7159的合成(比较例)
步骤1:5-氟-2-(1-甲氧基-2,6-二氧代哌啶-3-基)-2,3-二氢-1H-异吲哚-1,3-二
酮
将化合物2-(2,6-二氧代哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(250mg,0.90mmol)溶解与无水DMF(5ml)中,搅拌反应介质并升温至0℃。分批加入NaH并搅拌20分钟。加入甲基碘并搅拌2小时。用NH4Cl溶液停止反应。用乙酸乙酯萃取,并且用饱和NaCl洗涤有机相两次。用MgSO4干燥,过滤并在减压下浓缩。获得白色粉末形式的化合物5-氟-2-(1-甲基-2,6-二氧代哌啶-3-基)-2,3-二氢-1H-异吲哚-1,3-二酮,质量为253mg(产率96%)。ESI:M+H291.1。
步骤2:4-[2-(1-甲基-2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲
哚-5-基]哌嗪-1-羧酸叔丁酯
在室温下将化合物5-氟-2-(1-甲基-2,6-二氧代哌啶-3-基)-2,3-二氢-1H-异吲哚-1,3-二酮(250mg,0.86mmol)溶解于NMP(4ml)中。加入DIEA(0.42ml,2.58mmol)和1-哌嗪-羧酸叔丁酯(176mg,0.94mmol),将混合物在140℃搅拌24小时。将溶液用水(100ml)稀释。用乙酸乙酯萃取两次,用饱和NaCl洗涤有机相,并且用硫酸镁干燥。蒸发后,将获得的油状物在硅胶上用石油醚/乙酸乙酯洗脱液(3/1)纯化。获得黄色固体形式的4-[2-(1-甲基-2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-羧酸叔丁酯,质量为338mg(产率86%)。ESI:M+H 457.3。
步骤3:2-(1-甲基-2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基)-2,3-二氢-1H-异吲
哚-1,3-二酮
将4-[2-(1-甲基-2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-羧酸叔丁酯(250mg,0.54mmol)化合物溶解于4N HCl的二噁烷(4ml)溶液中,将该反应介质在室温下搅拌2小时,然后浓缩并与***一起研磨。获得黄色粉末形式的固体,质量为175mg(产率90%)。ESI:M+H 357.3。
步骤4:6-{4-[2-(1-甲基-2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基}己酸
将化合物2-(1-甲基-2,6-二氧代哌啶-3-基)-5-(哌嗪-1-基)-2,3-二氢-1H-异吲哚-1,3-二酮(100mg,0.28mmol)溶解于乙腈(5ml)中。加入6-溴己酸(136mg,0.70mmol)和DIEA(0.139ml,0.84mmol),将混合物在60℃搅拌24小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得黄色粉末,质量为85mg(产率65%)。ESI:M+H471.3。
步骤5:
将BOP(36mg,0.082mmol)加入到含有N-[2-(7-氨基庚基)-1-苄基-1H-1,3-苯并二唑-5-基]-2,4,6-三甲基苯-1-磺酰胺(28mg,0.055mmol)(实施例1,JMV6944)、6-{4-[2-(1-甲基-2,6-二氧代哌啶-3-基)-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基}己酸(26mg,0.055mmol)和DIEA(0.165ml,0.165mmol)的DMF(5ml)溶液中。将反应介质在室温下搅拌两个小时。在减压下浓缩溶液。将获得的油状物通过制备型HPLC纯化。冷冻干燥后,获得白色粉末,质量为30mg(产率56%)。ESI:M+H 971.6。
实施例8:生物化学和结晶学
人PXR受体配体结合域(hPXR-LBD,残基130-434)在大肠杆菌BL21-DE3细菌中以重组蛋白的形式产生。蛋白在亲和柱上纯化,然后通过尺寸排除色谱法纯化。浓缩后,在JMV6944配体存在下使hPXR-LBD结晶。通过分子置换法由放射性结晶学确定hPXR-LBD/JMV6944复合物的结构,然后基于电子密度(在格勒诺布尔的ERF同步加速器收集的衍射数据)来进行重建和改进。其结构如图11所示。在A中,复合物的整个结构显示JMV6944的结合模式。JMV6944的独创性在于添加到母体分子JMV6845的延伸部分的位置及其离开蛋白结构域的途径。不同于所有基于拮抗剂配体修饰的其他核受体的已知PROTAC,接枝在JMV6845拮抗剂上的延伸部分不向H12螺旋延伸,而是指向H2’螺旋、H6螺旋和H7螺旋与S1链之间的相反方向,以便最终到达LBD的外表面。烷基/NH臂(被B包围)的存在诱导H2'末端的构象变化,这允许该配体从结合口袋中被提取出来,并且与表面残基C207(C)特异性地相互作用。在配体的结合口袋中,JMV6944还与H407和S247建立氢键,以及与L411和F428以及与“π-陷阱”区域的残基(F288,W299,Y306)建立疏水相互作用。
实施例9:生物结果
9.1测定前PROTAC/PXR亲和性
借助于LanthaScreen TR-FRET PXR竞争性结合测定试剂盒(英杰(Invitrogen)),通过FRET定量JMV6944(前PROTAC)与PXR配体结合域(LBD)之间的结合亲和性。在荧光参照配体的存在下,将分子与PXR LBD在室温下培养1小时30分钟。由前PROTAC或PXR SR12813配体引起的荧光配体的置换通过在PHERA-Star设备(BMG LABTECH)上在337nm处激励之后读取在520nm和495nm处的发射来测定。结果示于图1中,该图示出了分子JMV6944是亲和性为18.38nm的PXR配体。
9.2测定PROTAC对PXR(报告基因)转录活性的影响
用编码PXR蛋白的表达载体、置于CYP3A4启动子控制下的荧光素酶报告基因(PXR靶基因)和置于CMV启动子控制下的编码GFP蛋白的表达盒稳定转染的LS174T细胞的处理用于信号的标准化。将细胞用5μM的分子JMV6944(前PROTAC)、PROTAC JMV7048和PROTACJMV7605以及利福平(5μM,PXR配体)处理48小时。在处理结束时,通过在PHERA-Star设备(BMG LABTECH)上测定的荧光素酶/GFP信号的比率来测定PXR的转录活性。图2示出了只有前PROTAC JMV6944和利福平能够激活PXR的转录活性。
9.3测定PROTAC对PXR转录活性(CYP3A4 mRNA表达)的影响
在存在或不存在最终浓度为5μM的利福平(PXR配体)的情况下,用55μM的分子JMV6944(前PROTAC)、JMV7048、JMV7505或JMV5159(在CNBR连接酶泛素配体上添加甲基基团后JMV7048的失活等效物)将LS174T细胞处理48小时。在裂解细胞并纯化总RNA(凯杰RNeasy)后,制备互补DNA(在6个核苷酸的随机引物存在下的SuperScript II,英杰)。在存在SyberGreen(密理博(Millipore))的情况下,在LC480设备(罗氏(Roche))上通过RT-qPCR测定CYP3A4 mRNA和RPLO以及肌动蛋白管家基因的表达。根据RQ=相对定量=2-ΔΔCt方法计算相对表达水平,未处理的细胞用作设定为1的校准品。图3A和图3B示出了如果前PROTAC和失活的PROTAC(JMV7159)对CYP3A4 mRNA的表达具有加成效应,则PROTAC JMV7048和PROTAC JMV7965显著降低由利福平介导的CYP3A4的诱导。
9.4测定PROTAC对PXR的转录活性(CYP3A4的表达)的影响
在存在或不存在最终浓度为5mM的利福平(PXR配体)的情况下,用5mM JMV7048将LS174T细胞处理48小时。在裂解细胞(RIPA+抗蛋白酶)后,纯化并分析蛋白,然后在10%SDS-PAGE凝胶上沉积(90μg)。在迁移到凝胶上之后,将这些蛋白转移到硝化纤维素膜(通用电气医疗(GE Healthcare))上,然后用针对CYP3A4(sc-53850,圣克鲁斯(Santa Cruz))和β-肌动蛋白(A5441,西格玛(Sigma)或Ab-253283,艾博抗(AbCAm))的抗体暴露,然后用与过氧化物酶偶联的二抗(抗小鼠HRP,圣克鲁斯)暴露。通过相机(BioRad MP Touch)测定信号的强度。图4A和图4B示出PROTAC JMV7048和PROTAC JMV7965降低由利福平介导的CYP3A4酶的诱导。
9.5测定PROTAC对细胞活力的影响
已经在各种细胞系CRC1、HT29和LS174T上测试了PROTAC对细胞活力的影响。在用磺基罗丹明B(西格玛)固定和标记之前,将细胞在浓度递增的分子存在下培养72小时。在洗涤和裂解细胞后,由细胞释放的掺入着色剂与细胞生物量成正比。用96孔板分光光度计(Técan)在565nM处测定。将未处理细胞获得的信号设定为100%。图5A示出了PROTAC JMV7048、PROTAC JMV7505和PROTAC JMV7605对LS174T细胞系不存在毒性。在图5B中,可以看出,PROTAC JMV7048不影响HT29细胞或CRC1原代培养物(来源于结肠癌患者)的生存力。
9.6通过体外蛋白印迹法测定PROTAC对LS174T细胞中PXR降解的影响
通过蛋白印迹法研究PROTAC对PXR蛋白的表达水平的影响。在不存在或存在50nM靶向PXR的siRNA(siPXR:NR1I2 Silencer,赛默飞世尔(Thermofischer))的情况下移植LS174T细胞或用PROTAC处理该细胞。在裂解细胞(RIPA+抗蛋白酶)后,纯化并分析蛋白,然后在10% SDS-PAGE凝胶上沉积(90μg)。在迁移到凝胶上之后,将这些蛋白转移到硝化纤维素膜(通用电气医疗)上,然后用针对PXR(sc-48340,圣克鲁斯)、GAPDH(sc-32233,圣克鲁斯)和β-肌动蛋白(A5441,西格玛或Ab-253283,艾博抗)的抗体暴露,然后用与过氧化物酶偶联的二抗(抗小鼠HRP,圣克鲁斯)暴露。通过相机(BioRad MP Touch)测定信号的强度。图6A至图6C示出了在5μM下处理24小时后,PROTAC JMV7048、PROTAC JMV7505、PROTACJMV7506、PROTAC JMV7605和PROTAC JMV7965显著降低了PXR蛋白的表达水平,这与JMV7048的失活突变体(即JMV7159)不同。图6D和图6E示出了基于处理时间(处理3小时后达到最大效果)和所用浓度(根据剂量降低,从500nM观察到最大效果)的JMV7048对PXR的表达水平的影响。
9.7通过体外蛋白印迹法测定PROTAC对HEPG2和ASPC1细胞中PXR降解的影响
通过蛋白印迹法研究了PROTAC(5mM,处理24小时)对HepG2(肝细胞癌,ATCC#HB-8065TM)或ASPC1(人胰腺癌细胞系,ATCC#CRL-1682)细胞中的PXR蛋白的表达水平的影响。在裂解细胞(RIPA+抗蛋白酶)后,纯化并分析蛋白,然后在10% SDS-PAGE凝胶上沉积(90μg)。在迁移到凝胶上之后,将这些蛋白转移到硝化纤维素膜(通用电气医疗)上,然后用针对PXR(sc-48340,圣克鲁斯)、GAPDH(sc-32233,圣克鲁斯)和β-肌动蛋白(A5441,西格玛或Ab-253283,艾博抗)的抗体暴露,然后用与过氧化物酶偶联的二抗(抗小鼠HRP,圣克鲁斯)暴露。图7A和图7B示出了PROTAC JMV7048和PROTAC JMV7965对肝癌细胞(图7A)或胰腺癌细胞(图7B)中PXR的表达水平的影响。
9.8蛋白酶体途径对PROTAC对PXR降解的影响的重要作用。
通过蛋白印迹法研究了PROTAC对PXR蛋白的表达水平的影响中的蛋白酶体途径的参与。在存在或不存在CNBR泛素连接酶(MLN4924)或蛋白酶体抑制剂(硼替佐米)的情况下,用JMV7048将LS174T细胞处理24小时。图8A和图8B证实了蛋白酶体途径对降低由PROTACJMV7048诱导的PXR蛋白的表达水平起到的重要作用:CRBN泛素连接酶抑制剂(MLN4924,图8A)或26S蛋白酶体抑制剂(硼替佐米,Bz;图8B)逆转了JMV7048诱导的PXR的表达水平的降低,而JMV7048的突变体(即JMV7159,不允许CNBR的募集)不引起PXR的表达水平的降低。
9.9通过体内蛋白印迹法测定PROTAC对PXR降解的影响
通过蛋白印迹法从SCID小鼠中的LS174T细胞异种移植物体内研究了PROTAC对PXR蛋白的表达水平的影响。一旦肿瘤达到100mm3,每24小时通过I.V.用5% EtOH溶剂、在D5W中的20% Solutol或PROTAC(25mg/kg)治疗10只小鼠,持续4天。每天对小鼠称重。在最后一次治疗后四小时,切除肿瘤,然后用Fast-Prep 24(MP-Bio)设备借助陶瓷珠(裂解介质D,MP-Bio)在RIPA缓冲液中裂解。纯化并分析蛋白,然后在10% SDS-PAGE凝胶上沉积(90μg)。在迁移到凝胶上之后,将这些蛋白转移到硝化纤维素膜(通用电气医疗)上,然后用针对PXR(sc-48340,圣克鲁斯)、GAPDH(sc-32233,圣克鲁斯)和β-肌动蛋白(A5441,西格玛或Ab-253283,艾博抗)的抗体暴露,然后用与过氧化物酶偶联的二抗(抗小鼠HRP,圣克鲁斯)暴露。通过相机(Biorad MP Touch)测定信号的强度。在图9A中可以看出,以25mk/kb治疗4天没有显著改变小鼠的体重。图9B和图9C证实了该治疗能够诱导肿瘤内PXR蛋白的表达水平的显著下降。
9.10测定PROTAC对结肠癌干细胞的自我更新和化学抗性的影响
在体外对从患者分离的HT29细胞系或癌细胞(CRC1)上研究了PROTAC对结肠癌干细胞存活和自我更新的影响。在分析之前,用5μM PROTAC将细胞处理48小时或者不对细胞进行处理:Aldefluor标记,酶活性优先存在于癌症干细胞中(图10A);在无菌和非粘附条件下形成肿瘤球(图10B),最后对化学疗法产生抗性(图10C和图10D)。
图10A示出了与未经处理的细胞相比,PROTAC JMV7048、PROTAC JMV7505、PROTACJMV7506和PROTAC JMV7965显著降低了CRC1细胞离解并用AldefluorTM(加拿大干细胞技术有限公司(STEMCELL Technologies))标记后ALDH阳性细胞的百分比。图10B示出了分子JMV7048和JMV7965显著减少能够使失巢凋亡存活并且能够诱导肿瘤球(球形成细胞)形成的HT29细胞的数量。在处理和在100μL耗尽的BCS培养基中每孔培养200个细胞(预先用poly2Hema处理以防止任何细胞粘附)后10天,对直径大于50μM的肿瘤球进行计数。这些培养条件仅允许癌症干细胞存活。图10C和图10D示出了PROTAC JMV7048和PROTAC JMV7965对HT29细胞的存活率(图10C)和形成肿瘤球能力(图10D)的影响,该HT29细胞在不同浓度的5-FU和SN38(Folfiri 1X=50μg 5-FU+500nM SN38)存在的情况下维持,并在用poly2Hema预处理的培养皿中的100μL耗尽的BCS培养基中培养,以防止任何细胞粘附。接种200个细胞/孔后10天,对直径大于50μM的肿瘤球进行计数。因此,图10A至图10D显示了用PROTACJMV7048和PROTAC JMV7965在5μM下处理2天显著降低了结肠癌细胞系中干细胞的存活率和化学抗性。
Claims (15)
1.一种具有通式(I)的双官能化合物:
L(PXR)-连接基-L(E3连接酶)
(I)
其中:
L(PXR)是能够与PXR核受体结合的配体,
L(E3连接酶)表示E3-泛素连接酶的配体,并且
连接基表示使L(PXR)与L(E3连接酶)共价结合成为可能的基团。
2.根据权利要求1所述的双官能化合物,其中:
L(PXR)是式(II)的基团:
其中表示所述基团与连接基的连接;
或药学上可接受的盐。
3.根据权利要求1或2所述的化合物,其中L(E3连接酶)选自:-式(IIIA)的基团:
以及
-式(IIIB)的基团:
或药学上可接受的盐,
其中:
X是NH;
X'是-C(O)-或-CH2-;
Y表示H或C1-C6烷基基团;
表示所述基团与连接基的连接。
4.根据前述权利要求中的任一项所述的化合物,其中连接基表示C1-C20亚烷基基团,所述亚烷基基团任选地被以下基团中的一个基团中断或任选地在一端和/或两端上终止:-O-、-S-、-N(R')-、-C(O)-、-C(O)O-、-OC(O)-、-OC(O)O-、-C(NOR')-、-C(O)N(R')-、-C(O)N(R')C(O)-、-C(O)N(R')C(O)N(R')-、-N(R')C(O)-、-N(R')C(O)N(R')-、-N(R')C(O)O-、-OC(O)N(R')-、-C(NR')-、-N(R')C(NR')-、-C(NR')N(R')-、-N(R')C(NR')N(R')-、-S(O)2-、-OS(O)-、-S(O)O-、-S(O)-、-OS(O)2-、-N(R')S(O)2-、-S(O)2N(R')-、-N(R')S-、-S(O)N(R')-、-N(R')S(O)2N(R')-、-N(R')S(O)N(R')-、C3-C12亚碳环基、包含1、2或3个选自N、O、S的杂原子的3元至12元亚杂环基、包含1、2或3个选自N、O、S的杂原子的5元至12元杂亚芳基或它们的任何组合,并且其中R'相同或不同,表示H或C1-C6烷基基团。
5.根据前述权利要求中任一项所述的化合物,其中连接基表示基团(IV)
其中L1和L2相同或不同,独立地表示具有1至12个碳原子的亚烷基基团,所述亚烷基基团任选地被包含1、2或3个选自N、O、S的杂原子的3元至12元亚杂环基中断或终止;
L1与L(PXR)连接,并且与L(E3连接酶)连接;
Z表示H或C1-C6烷基基团。
6.根据前述权利要求中任一项所述的化合物,其中所述化合物符合下式(I-4)和(I-5)中的一者:
其中L(PXR)、连接基根据权利要求1至5中任一项所定义;
或药学上可接受的盐。
7.根据前述权利要求中任一项所述的化合物,使得所述化合物符合下式(V):
其中L2表示任选地被哌啶基基团中断的C2-C8直链亚烷基基团,并且L(E3连接酶)如根据权利要求1至6中任一项所定义。
8.根据前述权利要求中任一项所述的化合物,其中所述化合物符合下式中的一者:
9.一种用于制备根据前述权利要求中任一项所述的化合物的方法,所述方法包括将式(B)的化合物和式(C)的化合物偶联:
其中L(PXR)和L(E3连接酶)如根据权利要求1至7中任一项所定义,并且T和T'是两组连接基前体,使得L(PXR)和L(E3连接酶)各自分别具有互补的反应性末端官能团。
10.根据权利要求9所述的方法,其中所述化合物(B)符合式(A):
并且所述化合物(C)符合式(C-1):
其中L2和L(E3连接酶)如根据权利要求1至7中任一项所定义。
11.一种式(A)的化合物:
。
12.一种药物组合物,所述药物组合物包含根据权利要求1至7中任一项所述的化合物和至少一种药学上可接受的赋形剂。
13.根据权利要求1至7中任一项所述的化合物,所述化合物用于治疗和/或预防过表达PXR核受体的癌症。
14.根据权利要求13所述的用于所述用途的化合物,所述化合物与抗癌剂联合使用。
15.根据权利要求13或14中任一项所述的用于所述用途的化合物,所述化合物用于向对抗癌剂有抗药性的患者给药。
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