CN117229291A - 内体-溶酶体转运靶向嵌合体降解剂及其制备方法与应用 - Google Patents
内体-溶酶体转运靶向嵌合体降解剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,涉及内体‑溶酶体转运靶向嵌合体降解剂及其制备方法与应用。具体地,本发明提供式I的化合物、其异构体或其药学上可接受的盐,PE‑L‑ML246式I;其中:PE是α1A‑肾上腺素能受体的激动剂去氧肾上腺素;ML246是自噬诱导剂;L是连接链,PE和ML246通过L经过化学键连接。本发明提供的化合物能够作为内体‑溶酶体转运靶向嵌合体降解剂,实现基于内体‑溶酶体途径的蛋白降解。
Description
技术领域
本发明属于生物医药技术领域,涉及内体-溶酶体转运靶向嵌合体降解剂(ETTAC)及其制备方法与应用。
背景技术
公开该背景技术部分的信息仅仅旨在增加对本发明的总体背景的理解,而不必然被视为承认或以任何形式暗示该信息构成已经成为本领域一般技术人员所公知的现有技术。
目前靶向蛋白降解技术有蛋白水解靶向嵌合体分子(Proteolysis TargetingChimeric Molecules,PROTACs)、基于抗体的PROTACs(Antibody-based PROTACs, AbTACs)以及基于共价纳米抗体的PROTACs(Covalent nanobody-based PROTACs, GlueTACs)。PROTAC技术主要针对细胞内蛋白,而LYTACs、AbTACs以及GlueTACs技术可以降解细胞外分泌蛋白和膜蛋白。虽然这些降解技术的出现可以克服现有治疗方式的一些局限性,但它们的临床前和临床期开发仍然面临着多重挑战。例如,泛素蛋白酶体系统作为PROTAC降解机制的核心,可能会限制其在特定细胞类型或蛋白酶体抗性蛋白上的潜在应用。
除基于泛素-蛋白酶体的蛋白降解剂外,还有基于溶酶体降解途径的蛋白降解剂。溶酶体降解途径包括自噬和内体-溶酶体途径。自噬途径已被用来开发蛋白降解药物,包括国外报道的自噬靶向嵌合体(AUTAC)技术和国内复旦大学报道的自噬小体绑定化合物(ATTEC)技术,而基于内体-溶酶体途径的蛋白降解剂仍然在探究阶段。
因此,基于内体-溶酶体途径的蛋白降解剂是十分急需的。
发明内容
本发明的一个目的在于提供一种新的化合物,以作为内体-溶酶体转运靶向嵌合体降解剂,能够实现基于内体-溶酶体途径的蛋白降解,从而进一步开发G蛋白偶联受体(GPCRs)降解剂。
本发明的另一个目的在于提供所述化合物的制备方法。
本发明的另一个目的在于提供所述化合物的应用。
一方面,本发明提供了一种式I的化合物、其异构体或其药学上可接受的盐,
PE-L-ML246;
式I;
其中:
(a) PE是α1A-肾上腺素能受体的激动剂去氧肾上腺素(Phenylephrine, PE);
(b) ML246是自噬诱导剂;
(c) L是连接链, PE和ML246通过L经过化学键连接。
在内体-溶酶体降解途径中,激动剂结合细胞膜上GPCR受体通过激活G蛋白启动信号传导,然后通过GPCR激酶(GRK)选择性磷酸化激活的受体。受体的磷酸化和随后受体与β-arrestin蛋白结合阻止受体与G蛋白的后续相互作用,从而有效终止G蛋白介导的信号转导并促进与β-arrestin结合的受体的内吞作用。然而,通过这种保守的细胞机制,GPCR内吞的功能后果是多种多样的。通过快速循环途径转运内化的GPCR回到细胞膜上可恢复质膜中功能性受体,并促进受体的快速增敏。相反,将内化的GPCR分选到溶酶体降解途径可促进受体下调,导致细胞信号转导的长期衰减。
本发明研究发现α1A-肾上腺素能受体(α1A-ARs)作为G蛋白偶联受体(GPCRs)的重要成员,暴露在长时间的激动剂刺激下,通过与GPCR相关分选蛋白1 (GASP1)和自噬相关蛋白Beclin 2形成一个“Beclin 2-GASP1-α1A-AR”三元复合物进而被分选到溶酶体降解。本发明所描述的内体-溶酶体转运靶向嵌合体(ETTAC)包含了α1A-AR的靶向激动剂和自噬诱导部分,显著增强了“Beclin 2-GASP1-α1A-AR”三元复合物的形成,强烈消除了细胞中α1A-AR的表达,并缓解了前列腺相关疾病的病理症状。
本发明的一些方案中,PE为α1A-肾上腺素能受体的激动剂去氧肾上腺素(Phenylephrine, PE)。PE的结构式如下所示:
。
本发明的一些方案中,自噬诱导小分子化合物ML246。ML246的结构式如下所示:
。
本发明的一些方案中所述的化合物、其异构体或其药学上可接受的盐,其中,所述化合物包含但不限于式II所示结构:
;
其中,n为1~10的整数,例如1、2、3、4、5、6、7、8、9、10。
本发明的一些方案中,所述的化合物、其异构体或其药学上可接受的盐,其中,所述化合物选自:
、/>、
。
本发明所述的“药学上可接受的”针对那些化合物、材料、组合物和/或剂型而言,它们在可靠的医学判断的范围之内,适用千与人类和动物的组织接触使用,而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症,与合理的利益/风险比相称。
本发明所述的药学上可接受的盐是指本发明化合物的盐,由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸,碳酸氢根,磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等类似的酸;还包括氨基酸(如精氨酸等)的盐,以及如葡萄糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。
本发明所述的异构体是指本发明的化合物可以存在特定的几何或立体异构体形式。包括顺式和反式异构体等。
另一方面,一种药物组合物,包括式I的化合物、其异构体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。
另一方面,一种药物制剂,包括式I的化合物、其异构体或其药学上可接受的盐,和至少一种其他药理学活性物质。
另一方面,一种试剂盒,包含:
第一药物组合物或剂型,其包含式I的化合物、其异构体或其药学上可接受的盐和药学上可接受的载体、赋形剂;
第二药物组合物或剂型,其包含另一种药理学活性物质和药学上可接受的载体、赋形剂。
本发明的所述的药理学活性物质选自以下任何一种或多种:
激素、激素类似物和抗激素物(例如他莫昔芬、托瑞米芬、氨鲁米特、醋酸环丙孕酮、比卡鲁胺、雷洛昔芬、氟维司群、氟他胺、尼鲁米特、氟氢可的松、氟甲睾酮、非那雄胺、醋酸布舍瑞林、醋酸甲地孕酮、甲羟孕酮、奥曲肽)、LHRH激动剂和拮抗剂(例如鲁珀若利得(luprolide)、醋酸戈舍瑞林)、芳香酶抑制剂(例如阿那曲唑、来曲唑、伏氯唑、依西美坦、阿他美坦、利阿唑等)等。
用于施用本发明化合物的合适制剂将对于本领域普通技术人员而言是显而易见的,并且包括例如片剂、吸入剂、溶液剂、栓剂、糖锭剂、糖浆、乳液、可分散粉剂、扁囊剂、酏剂、丸剂、胶囊或锭剂;其中,溶液剂例如注射(皮下、静脉内、肌内)溶液、输注(注射剂)用溶液等。一种或多种药物活性化合物的含量的范围应该是作为整体的组合物的0.1至90wt.%、优选0.5至50wt.%,即,其量足以实现以下指定的剂量范围。如有必要,指定的剂量可以每天给予若干次。其递送方式可通过已知的方式施用至体内。例如通过静脉全身递送或者局部注射递送到感兴趣组织中。可选地经由静脉内、经皮、鼻内、粘膜或其他递送方法进行施用。这样的施用可以经由单剂量或多剂量来进行。本领域技术人员理解的是,本发明中有待施用的实际剂量可以在很大程度上取决于多种因素而变化,如靶细胞、生物类型或其组织、待治疗受试者的一般状况、给药途径、给药方式等等。
所述药物施用对象可以是人和非人哺乳动物,如小鼠、大鼠、豚鼠、兔、狗、猴、猩猩等。
本发明所述的片剂可以例如通过将本发明的一种或多种活性物质与已知的赋形剂混合来获得,所述赋形剂例如填充剂、载体、结合剂、表面活性剂、润滑剂、崩解剂和/或佐剂;例如乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯胶、藻酸盐、明胶、磷酸钙、硅酸钙、纤维素、甲基纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油等。
另一方面,一种上述式I的化合物、其异构体或其药学上可接受的盐、药物组合物、药物制剂或试剂盒在制备抗肿瘤药物和或/治疗炎症药物中的应用。
本发明的一些方案中,肿瘤为前列腺肿瘤。
本发明的一些方案中,炎症为前列腺炎症。
另一方面,一种上述式I的化合物、其异构体或其药学上可接受的盐、药物组合物、药物制剂或试剂盒在制备治疗前列腺相关疾病药物中的应用。
本发明的一些方案中,所述前列腺相关疾病包括与α1A-肾上腺素能受体、GASP1或Beclin 2相关的疾病。
另一方面,一种治疗肿瘤、炎症、前列腺相关疾病的方法,所述方法包括向受试者施用治疗有效量的上述化合物、药物组合物、药物制剂或试剂盒。
所述受试者是指已经是治疗、观察或实验的对象的动物,优选指哺乳动物,最优选指人。
所述“治疗有效量”是指包括本发明化合物在内的活性化合物或药剂的量,该量可引起研究者、兽医、医生或其他医疗人员所追求的组织系统、动物或人的生物学或医学响应,这包括减轻或部分减轻受治疗的疾病、综合征、病症或障碍的症状。
本领域的研究者、兽医、医生或其他医疗人员可根据临床试验或者本领域其他公知的手段获知可使用的治疗有效量的范围。
另一方面,本发明还提供了一种中间体及其制备方法。所述的中间体包括但不限于:上述制备所述的化合物、其异构体或其药学上可接受的盐的合成路线中的任一中间体。优选地,所述中间体具有与式I的化合物、其异构体或其药学上可接受的盐相同的基本结构单元(基本相同的基本核心部分或者基本的环),或者中间体的基本结构单元包含在了式I的化合物、其异构体或其药学上可接受的盐的化学结构中。
本发明的有益效果为:
本发明提供的化合物作为内体-溶酶体转运靶向嵌合体降解剂具有启动GPCR分选和靶向溶酶体降解的双重功能。ETTACs是通过将自噬诱导部分连接到α1A-AR靶向激动剂上设计的。首先,这些ETTACs分别通过其靶向激动剂和自噬诱导部分触发α1A-AR的内化和激活自噬。其次,Beclin 2/Bcl-2复合物的破坏与Beclin 2-GASP1-α1A-AR三元复合物的形成同时发生。三元Beclin 2-GASP1-α1A-AR复合体数量的增加是通过将释放的Beclin2从自噬途径“转移”到GPCR降解途径来实现的。第三,ETTACs利用独立于泛素化和ESCRT机制的内体-溶酶体转运途径显著促进α1A-AR的靶向降解。
通过实验表明,本发明提供的化合物具有体内抗前列腺增生的作用,同时具有显著的体内抗前列腺肿瘤的作用,且在治疗前列腺肿瘤过程中不会引起体重的明显变化。
本发明可以作为开发GPCRs降解剂的普遍策略,为生物医药研究提供了一个强大的工具。
附图说明
构成本发明的一部分的说明书附图用来提供对本发明的进一步理解,本发明的示意性实施例及其说明用于解释本发明,并不构成对本发明的不当限定。
图1为本发明实施例制备的ETTAC的合成路线。
图2为本发明实施例制备的ETTAC降解GPCR机制示意图。
图3为本发明实施例中免疫共沉淀实验证明Beclin 2-GASP1-α1A-AR三元复合物的形成。
图4为本发明实施例中ETTAC(PMA-37)在不同的浓度下对稳定转染α1A-AR的HEK293细胞(A和B)和PC-3细胞(C和D)中α1A-AR蛋白水平的影响.
图5为本发明实施例中ETTAC(PMA-37)在小鼠前列腺增生模型中的治疗效果,实验结果表明ETTAC(PMA-37)具有良好的体内缓解前列腺增生的作用:其中,A为不同处理时间小鼠体重变化情况,B为治疗结束时小鼠前列腺重量与体重的比值大小,C为治疗结束时小鼠前列腺组织切片IHC染色深浅统计学分析。
图6为本发明实施例中ETTAC(PMA-37)在小鼠前列腺肿瘤异种移植模型中的抗肿瘤活性,实验结果表明ETTAC(PMA-37)具有显著的体内抗前列腺肿瘤的作用:其中,A为不同处理时间小鼠体重变化情况,B为不同处理时间肿瘤体积生长情况,C为治疗结束时小鼠肿瘤组织切片IHC染色深浅统计学分析。
具体实施方式
为了使得本领域技术人员能够更加清楚地了解本发明的技术方案,以下将结合具体的实施例详细说明本发明的技术方案。下列实施例中为注明具体条件的试验方法,通常按照常规条件进行。
实施例1:化合物PMA-19的制备方法,如图1中n=1合成路线所示。
化合物1a的合成
在0℃下,将丙炔醇乙氧基化物(1 g, 10 mmol)溶解于二氯甲烷(30 mL),向反应液中依次加入三乙胺(2.02 g, 20 mmol)和甲磺酰氯(1.72 g, 15 mmol),室温下反应1小时。用饱和碳酸氢钠水溶液(50 mL)稀释混合物,分离有机层,用二氯甲烷(30 mL,三次)提取水层,并用饱和氯化钠水溶液洗涤三次。有机相用无水硫酸钠干燥。将干燥的溶液过滤,并将滤液浓缩以获得油状物。粗产物用二氯甲烷(DCM)和甲醇(100:1)进行硅胶柱层析纯化,得到1.61克淡黄色的油作为化合物1a,产率90%。1H NMR (400 MHz, CDCl3) δ 4.40(dq,J= 4.3, 1.7 Hz, 2H), 4.22 (d,J= 2.3 Hz, 2H), 3.82 (dq,J= 4.2, 1.8 Hz,2H), 3.07 (d,J= 1.4 Hz, 3H), 2.51 (t,J= 2.3 Hz, 1H). ESI-MS: m/z [M + NH4]+calcd for C6H14NO4S+196.03, found 196.3.
化合物2的合成
在室温下,盐酸去氧肾上腺素(5 g, 24.5 mmol)溶解在50 mL四氢呋喃中,向反应液中加入溶于50 mL水中的氢氧化钠(3.93 g, 98.2 mmol)。约30分钟后,向反应溶液中加入二碳酸二叔丁酯(21.43 g, 98.20 mmol)。在室温下搅拌一夜后,将溶液浓缩,在减压下去除四氢呋喃。水相用二氯甲烷 (30 mL, 3次)提取。合并有机相,用盐水洗涤三次。无水Na2SO4干燥后,将干燥后的溶液过滤,浓缩成油。最后粗产物通过硅胶柱色谱分离纯化(二氯甲烷:甲醇=40:1)得到产物2共3.07克,为无色粘性油,产率46.9%。1H NMR (400 MHz,CDCl3) δ 7.17 (t,J= 7.8 Hz, 1H), 6.94 – 6.70 (m, 4H), 4.87 (s, 1H), 4.45 (s,1H), 3.62 – 3.26 (m, 2H), 2.91 – 2.74 (m, 3H), 1.52 – 1.32 (m, 9H). ESI-MS:m/z [M + H]+calcd for C14H22NO4 +268.15, found 268.2.
化合物3a的合成
将化合物1a (2 g, 11.2 mmol)、化合物2 (1.5 g, 15.61 mmol)和碳酸钾 (1.94g, 14.0 mmol)加入到乙腈(40 mL)中,在82℃下氮气回流20小时。加入水(50 mL)后,减压除去溶剂。水层用二氯甲烷 (50 mL, 3次)提取。合并的有机层用盐水洗涤三次,无水Na2SO4干燥。将干燥的溶液过滤,并将滤液浓缩得油状物。粗产物经硅胶柱色谱分离纯化,以二氯甲烷(DCM)和甲醇(50:1)为展开剂,得到淡黄色的油状液体化合物3a共1.92克。产率98%。1HNMR (400 MHz, CDCl3) δ 7.23 (t,J= 7.9 Hz, 1H), 6.93 (dd,J= 17.8, 9.7 Hz, 2H),6.82 (dd,J= 8.2, 2.5 Hz, 1H), 4.87 (s, 1H), 4.25 (d,J= 2.4 Hz, 2H), 4.14 (t,J= 4.7 Hz, 2H), 3.88 (dd,J= 5.7, 3.8 Hz, 2H), 3.53 – 3.25 (m, 2H), 3.04 (s,1H), 2.92 – 2.68 (m, 3H), 2.49 (dt,J= 5.0, 2.4 Hz, 1H), 1.44 (d,J= 12.0 Hz,9H). ESI-MS: m/z [M + H]+calcd for C19H28NO5 +350.19, found 350.4.
化合物4a的合成
在室温下,将化合物3a (1 g,2.87 mmol)和乙酸酐(586 mg, 5.74 mmol)溶于二氯甲烷(20 mL)中,向反应液中依次加入Et3N (581 mg, 5.74 mmol)和DMAP (37 mg, 0.3mmol),搅拌1 h,反应液用二氯甲烷(80 mL)稀释后,依次用H2O、0.4N HCl、饱和盐水洗涤。用无水Na2SO4干燥后,将干燥后的溶液过滤,浓缩成油。最后,在硅胶上用二氯甲烷和甲醇(60:1)分离纯化得到1.12克产物4a,为淡黄色粘性油。产率:99%。1H NMR (400 MHz, CDCl3)δ 7.29 – 7.21 (m, 1H), 6.94 – 6.82 (m, 2H), 6.04 – 5.80 (m, 1H), 4.27 (d,J=2.4 Hz, 2H), 4.21 – 4.07 (m, 2H), 3.90 (t,J= 4.8 Hz, 2H), 3.06 (s, 1H), 2.86(d,J= 10.0 Hz, 3H), 2.47 (t,J= 2.5 Hz, 1H), 2.09 (d,J= 2.9 Hz, 3H), 1.44 (s,9H). ESI-MS: m/z [M + NH4]+calcd for C21H33N2O6 +409.20, found 409.4.
化合物5的合成
在氮气保护下,将安息香(1 g, 4.71 mmol)、3-溴苄胺(1.31 g, 7.06 mmol)和三氟乙酸(0.57 g, 5.0 mmol, 0.05 equiv.)溶于甲苯(40 mL),111℃回流2小时。向混合物中加入丙二腈(311 mg, 4.71 mmol),继续在氮气下加热回流17 h。然后用乙酸乙酯稀释反应混合物(50 mL)。有机相用饱和碳酸氢钠和盐水洗涤,用无水Na2SO4干燥,浓缩。所得粗产物用甲醇精制,在真空干燥箱中45℃干燥,得到1.31克黄色固体化合物5。产率65%。M.p.:196.5-199.8 ℃.1H NMR (400 MHz, DMSO-d 6) δ 7.42 – 7.38 (m, 1H), 7.32 – 7.18(m, 6H), 7.16 – 7.10 (m, 3H), 7.09 – 7.00 (m, 3H), 6.81 (d,J= 7.7 Hz, 1H),6.23 (s, 2H), 4.98 (s, 2H). ESI-MS: m/z [M + H]+calcd for C24H19BrN3 +428.07,found 428.07.
化合物6的合成
将化合物5 (1 g, 2.34 mmol)溶于含10 %乙酸的原甲酸三乙酯(17.4 g, 0.117mol)中,在75℃下加热4小时。然后用乙酸乙酯(50 mL)稀释反应混合物。有机相用饱和碳酸氢钠和盐水洗涤,用无水硫酸钠干燥。在真空中去除多余的原甲酸三乙酯。所得粗产物从甲醇中重结晶,在真空干燥箱中45℃干燥,得到878毫克黄色固体化合物6。产率78%。M.p.:134.6-135.2 °C.1H NMR (400 MHz, DMSO-d 6) δ 8.56 (s, 1H), 7.43 – 7.30 (m, 4H),7.29 – 7.11 (m, 8H), 7.03 (t,J= 1.9 Hz, 1H), 6.83 (d,J= 7.7 Hz, 1H), 5.05 (s,2H), 4.32 (q,J= 7.1 Hz, 2H), 1.29 (t,J= 7.1 Hz, 3H). ESI-MS: m/z [M + H]+calcd for C27H23BrN3O+484.09, found 484.05.
化合物7的合成
将化合物6(500 g, 1.04 mmol)、反式-4-氨基环己醇(238 g, 2.07 mmol)和叔丁醇钾(349 g, 3.11 mmol)的甲醇溶液(20 mL)在50℃下加热20小时,然后冷却到室温并过滤。沉淀物用甲醇(10 mL,两次)清洗。固体用甲醇精制,在45°C的真空干燥箱中干燥,得到378毫克的化合物7,为白色固体。产率66%。M.p.:233.7-235.0 °C.1H NMR (400 MHz,DMSO-d 6) δ 8.07 (s, 1H), 7.38 (d,J= 8.0 Hz, 1H), 7.34 – 7.16 (m, 9H), 7.11(dd,J= 7.1, 2.4 Hz, 2H), 7.05 (s, 1H), 6.84 (d,J= 7.7 Hz, 1H), 6.20 (s, 1H),5.23 (s, 2H), 4.90 (p,J= 8.0 Hz, 1H), 4.65 (s, 1H), 3.51 (tt,J= 10.3, 4.1 Hz,1H), 1.94 (dd,J= 12.4, 4.2 Hz, 2H), 1.80 (dt,J= 11.1, 5.7 Hz, 4H), 1.29 (p,J=10.7 Hz, 2H). ESI-MS: m/z [M + H]+calcd for C31H30BrN4O+553.15, found 553.37.
化合物8a的合成
在氮气保护下,化合物7 (200 mg, 0.362 mmol)、化合物4a (425 mg, 1.09mmol)、碘化铜(I) (42 mg, 0.216 mmol)和[1,1′-双(二苯基膦)二茂铁]二氯化钯(II)(80 mg, 0.108 mmol)溶解于N,N-二甲基甲酰胺(DMF) (20 ml)中。通过注射器缓慢加入二异丙基乙胺(1 mL),在回流下加热5小时。将反应混合物冷却至室温,并用二氯甲烷(50 mL)稀释。有机溶液用水、饱和碳酸氢钠和盐水洗涤,用无水Na2SO4干燥,浓缩。粗产物经硅胶柱层析纯化(二氯甲烷:甲醇=20:1),得到棕色固体化合物8a共218毫克。产率70%。M.p.:97.2-106.2 °C.1H NMR (400 MHz, DMSO-d 6) δ 8.81 (s, 1H), 7.43 – 7.20 (m, 12H), 7.16(d,J= 7.5 Hz, 2H), 6.97 (s, 1H), 6.89 (q,J= 7.6 Hz, 4H), 5.90 – 5.78 (m, 1H),5.38 (s, 2H), 4.77 (d,J= 4.3 Hz, 1H), 4.67 (p,J= 7.9 Hz, 1H), 4.43 (s, 2H),4.15 (t,J= 4.4 Hz, 2H), 3.82 (t,J= 4.5 Hz, 2H), 3.64 – 3.42 (m, 3H), 2.78 (s,3H), 2.09 – 1.97 (m, 7H), 1.94 (d,J= 12.7 Hz, 2H), 1.49 (q,J= 13.5 Hz, 2H),1.40 – 1.29 (m, 10H). ESI-MS: m/z [M + H]+calcd for C52H58N5O7 +864.43, found864.66.
化合物9a的合成
将化合物8a (200mg, 0.231 mmol)溶解于10 mL甲醇中,与甲醇钠 (270 mg, 5mmol)在室温下搅拌12小时。用甲醇过滤和洗涤反应混合物。浓缩滤液,粗产物用(二氯甲烷:甲醇=25:1)硅胶柱层析纯化,得到190毫克白色固体化合物9a。产率72%。M.p.:106.8-113.8 °C.1H NMR (400 MHz, DMSO-d 6) δ 8.07 (s, 1H), 7.60 – 7.16 (m, 12H), 7.14– 7.06 (m, 2H), 6.95 (s, 1H), 6.92 – 6.79 (m, 4H), 6.20 (s, 1H), 5.45 (s,1H), 5.22 (s, 2H), 4.93 – 4.83 (m, 1H), 4.69 (t,J= 6.3 Hz, 1H), 4.44 (s, 2H),4.19 – 4.02 (m, 2H), 3.82 (t,J= 4.5 Hz, 2H), 3.49 (t,J= 9.9 Hz, 1H), 3.30 –3.07 (m, 2H), 2.77 (d,J= 11.1 Hz, 3H), 1.93 (d,J= 12.3 Hz, 2H), 1.81 (d,J=8.9 Hz, 4H), 1.37 (s, 2H), 1.29 (s, 9H). ESI-MS: m/z [M + H]+calcd forC50H56N5O6 +822.42, found 822.29.
化合物PMA-19的合成
在室温下,化合物9a (200mg, 0.243 mmol)在饱和氯化氢的乙酸乙酯溶液(5ml)中搅拌5小时。然后,沉淀经过过滤,用乙酸乙酯洗涤,甲醇和乙酸乙酯重结晶,得到120毫克白色固体化合物PMA-19。产率69%。M.p.:151.9-158.8 °C.1H NMR (400 MHz, DMSO-d 6) δ9.36 (s, 1H), 8.88 (s, 2H), 7.60 – 7.20 (m, 12H), 7.17 (d,J= 7.3 Hz, 2H),7.05 – 6.93 (m, 3H), 6.87 (dt,J= 9.1, 4.7 Hz, 2H), 6.23 (d,J= 4.4 Hz, 1H),5.40 (s, 2H), 5.05 – 4.92 (m, 1H), 4.91 – 4.71 (m, 2H), 4.44 (s, 2H), 4.15(dd,J= 5.9, 3.2 Hz, 2H), 3.83 (dd,J= 5.7, 3.2 Hz, 2H), 3.57 (s, 1H), 3.09 (d,J= 12.4 Hz, 1H), 2.95 (t,J= 11.3 Hz, 1H), 2.56 (s, 3H), 2.03 (q,J= 9.4 Hz,4H), 1.91 (t,J= 6.5 Hz, 2H), 1.58 (td,J= 11.8, 4.5 Hz, 2H).13C NMR (101 MHz,DMSO) δ 170.83, 158.91, 151.39, 145.79, 144.00, 143.78, 137.94, 137.53,131.83, 131.26, 131.21, 130.89, 130.32, 129.98, 129.79, 129.54, 129.48,129.05, 129.02, 128.74, 127.76, 122.51, 118.62, 116.60, 114.08, 112.48,100.26, 86.91, 85.72, 68.35, 67.95, 67.26, 60.24, 58.65, 57.67, 55.26, 46.09,34.25, 33.12, 30.20, 21.26, 14.57. ESI-MS: m/z [M + H]+calcd for C45H48N5O4 +722.37, found 722.37. HPLC purity: 99.4 %. [α]20 D= - 14.00 (c = 0.1, MeOH).
实施例2:化合物PMA-37的制备,方法如图1中n=2合成路线所示。
化合物1b的合成
化合物1b使用与1a相同的方法合成,除了使用丙炔基-二聚乙二醇(1.44 g, 10mmol)。收率:1.89克,85%。1H NMR (400 MHz, CDCl3) δ 4.42 – 4.35 (m, 2H), 4.19 (d,J= 2.3 Hz, 2H), 3.81 – 3.74 (m, 2H), 3.70 (s, 4H), 3.08 (s, 3H), 2.45 (t,J=2.3 Hz, 1H). ESI-MS: m/z [M + H]+calcd for C8H15O5S+ 223.06, found 223.20.
化合物3b的合成
除使用化合物1b (2.49 g, 11.2 mmol)外,使用3a所述的方法合成了化合物3b。产率:2.03克,92%。1H NMR (400 MHz, CDCl3) δ 7.24 (t,J= 7.8 Hz, 1H), 7.01 – 6.90(m, 2H), 6.83 (dd,J= 8.6, 2.4 Hz, 1H), 4.96 – 4.83 (m, 1H), 4.42 – 4.35 (m,2H), 4.19 (d,J= 2.3 Hz, 2H), 3.86 (t,J= 4.9 Hz, 2H), 3.70 (s, 4H), 3.39 (s,1H), 3.07 (s, 3H), 2.94 – 2.73 (m, 3H), 2.45 (d,J= 2.5 Hz, 1H), 1.47 (s, 9H).ESI-MS: m/z [M + NH4]+calcd for C21H35N2O6+ 411.22, found 411.5.
化合物4b的合成
除了使用化合物3b (1.25 g, 2.87 mmol)外,还使用与4a相同的方法合成了化合物4b。产率:1.19克,95%。1H NMR (400 MHz, CDCl3) δ 7.29 – 7.21 (m, 1H), 6.98 –6.81 (m, 3H), 6.05 – 5.82 (m, 1H), 4.42 – 4.34 (m, 2H), 4.22 (d,J= 2.4 Hz,2H), 3.86 (t,J= 4.9 Hz, 2H), 3.70 (s, 4H), 3.57 – 3.37 (m, 2H), 2.86 (d,J=8.3 Hz, 3H), 2.44 (q,J= 2.3 Hz, 2H), 2.09 (s, 3H), 1.44 (s, 9H). ESI-MS: m/z[M + Na]+calcd for C23H33NO7Na+458.23, found 458.18.
化合物8b的合成
除使用化合物4b (473 mg, 1.09 mmol)外,化合物8b采用所述8a的方法合成。产率:213毫克,65%。M.p.:77.9-88.2 °C.1H NMR (400 MHz, DMSO-d 6) δ 8.79 (s, 1H),7.64 – 7.47 (m, 1H), 7.44 – 7.19 (m, 11H), 7.15 (d,J= 7.4 Hz, 2H), 6.97 (s,1H), 6.87 (t,J= 9.2 Hz, 4H), 5.84 (d,J= 7.0 Hz, 1H), 5.37 (s, 2H), 4.77 (d,J=4.3 Hz, 1H), 4.67 (s, 1H), 4.37 (s, 2H), 4.09 (t,J= 4.7 Hz, 2H), 3.75 (t,J=4.6 Hz, 2H), 3.63 (d,J= 7.7 Hz, 4H), 3.56 (s, 2H), 3.49 (d,J= 6.3 Hz, 1H),2.77 (s, 3H), 2.12 – 1.90 (m, 9H), 1.48 (d,J= 13.2 Hz, 2H), 1.41 – 1.28 (m,9H). ESI-MS: m/z [M + H]+calcd for C54H62N5O8 +908.45, found 908.62.
化合物9b的合成
除化合物8b (210mg, 0.231 mmol)外,化合物9b采用与9a相同的方法合成。产率:140毫克,70%。M.p.:83.9-89.8 °C.1H NMR (400 MHz, DMSO-d 6) δ 8.06 (s, 1H), 7.61 –7.46 (m, 1H), 7.38 – 7.14 (m, 11H), 7.13 – 7.04 (m, 2H), 6.94 (s, 1H), 6.91 –6.74 (m, 4H), 6.19 (s, 1H), 5.44 (s, 1H), 5.21 (s, 2H), 4.89 (s, 1H), 4.67(d,J= 6.3 Hz, 1H), 4.37 (s, 2H), 4.07 (s, 2H), 3.75 (t,J= 4.6 Hz, 2H), 3.63(d,J= 7.4 Hz, 4H), 3.50 (s, 1H), 3.17 (s, 3H), 2.77 (d,J= 9.6 Hz, 3H), 1.93(d,J= 12.5 Hz, 2H), 1.80 (d,J= 9.1 Hz, 4H), 1.36 (s, 2H), 1.26 (d,J= 17.5 Hz,9H). ESI-MS: m/z [M - H]-calcd for C52H58N5O7 -864.44, found 864.35.
化合物PMA-37的合成
除使用化合物10b (210 mg, 0.243 mmol)外,使用所述的PMA-19方法合成了化合物PMA-37。产率:119毫克,64%。M.p.:136.1-144.3 °C.1H NMR (400 MHz, DMSO-d 6) δ 9.36(s, 1H), 8.88 (s, 2H), 7.39 (d,J= 6.6 Hz, 5H), 7.31 (dt,J= 12.1, 5.0 Hz, 5H),7.27 – 7.20 (m, 2H), 7.16 (d,J= 7.2 Hz, 2H), 6.96 (d,J= 12.0 Hz, 3H), 6.86(d,J= 7.7 Hz, 2H), 6.21 (d,J= 4.3 Hz, 1H), 5.39 (s, 2H), 4.96 (d,J= 9.7 Hz,1H), 4.81 (s, 2H), 4.37 (s, 2H), 4.10 (t,J= 4.2 Hz, 2H), 3.76 (dd,J= 5.6, 3.3Hz, 2H), 3.64 (s, 4H), 3.57 (s, 1H), 3.09 (d,J= 12.5 Hz, 1H), 2.95 (t,J= 11.3Hz, 1H), 2.56 (s, 3H), 2.12 – 1.97 (m, 5H), 1.97 – 1.88 (m, 2H), 1.56 (d,J=11.7 Hz, 2H).13C NMR (101 MHz, DMSO) δ 158.96, 151.39, 145.80, 143.97, 143.77,137.95, 137.51, 131.83, 131.26, 131.20, 130.89, 130.31, 129.95, 129.78,129.53, 129.48, 129.04, 129.01, 128.75, 127.74, 122.55, 118.57, 116.60,114.10, 112.48, 100.26, 87.04, 85.58, 70.17, 69.43, 69.19, 68.36, 67.95,67.54, 58.57, 57.69, 55.28, 46.09, 34.24, 33.13, 31.43, 30.20, 22.54, 14.45.ESI-MS: m/z [M + H]+calcd for C47H52N5O5 +766.39, found 766.39. HPLC purity: 99.7%. [α]20 D= - 11.47 (c = 0.1, MeOH).
实施例3:化合物PMA-43的制备,方法如图1中n=3合成路线所示。
化合物1c的合成
除了使用丙炔基-三聚乙二醇(1.88 g, 10 mmol)外,还使用与1a相同的方法合成了化合物1c。产率:2.18克,82%。1H NMR (400 MHz, CDCl3) δ 4.42 – 4.35 (m, 2H), 4.20(d,J= 2.4 Hz, 2H), 3.81 – 3.74 (m, 2H), 3.67 (h,J= 2.7 Hz, 8H), 3.08 (s, 3H),2.45 (t,J= 2.4 Hz, 1H). ESI-MS: m/z [M + H]+calcd for C10H19O6S+ 267.08, found267.15.
化合物3c的合成
除使用化合物1c (2.98 g, 11.2 mmol)外,化合物3c采用上述方法合成8a。产率:2.11克,86%。1H NMR (400 MHz, CDCl3) δ 7.24 (t,J= 7.8 Hz, 1H), 6.95 (d,J= 13.9Hz, 2H), 6.86 – 6.79 (m, 1H), 4.90 (s, 1H), 4.42 – 4.35 (m, 2H), 4.14 (t,J=4.9 Hz, 2H), 3.86 (t,J= 4.8 Hz, 2H), 3.69 (d,J= 5.6 Hz, 8H), 3.36 (d,J= 14.0Hz, 1H), 3.08 (s, 2H), 2.94 – 2.73 (m, 3H), 2.46 – 2.44 (m, 1H), 1.47 (s,9H). ESI-MS: m/z [M + Na]+calcd for C23H35NO7Na+460.24, found 460.01.
化合物4c的合成
除了使用化合物3c (1.13 g, 2.87 mmol)外,使用与4a相同的方法合成了化合物4c。产率:1.27克,92%。1H NMR (400 MHz, CDCl3) δ 7.27 – 7.20 (m, 1H), 6.98 – 6.81(m, 3H), 6.01 – 5.87 (m, 1H), 4.12 (t,J= 4.9 Hz, 2H), 3.86 (t,J= 4.9 Hz, 2H),3.74 (dd,J= 6.0, 3.5 Hz, 2H), 3.69 (d,J= 4.8 Hz, 8H), 3.49 (qd,J= 15.1, 8.0Hz, 2H), 2.86 (d,J= 8.6 Hz, 3H), 2.44 (dt,J= 4.8, 2.4 Hz, 2H), 2.09 (s, 3H),1.44 (s, 9H). ESI-MS: m/z [M + Na]+calcd for C25H37NO8Na+502.25, found 502.00.
化合物8c的合成
除化合物4c (523 mg, 1.09 mmol)外,化合物8c采用所述8a方法合成。产率:214毫克,62%。M.p.:71.8-79.7 °C.1H NMR (400 MHz, DMSO) δ 8.81 (s, 1H), 7.63 – 7.46(m, 1H), 7.44 – 7.19 (m, 11H), 7.15 (d,J= 6.9 Hz, 2H), 6.97 (s, 1H), 6.87 (t,J= 8.8 Hz, 4H), 5.94 – 5.80 (m, 1H), 5.38 (s, 2H), 4.78 (d,J= 4.3 Hz, 1H),4.65 (s, 1H), 4.36 (s, 2H), 4.08 (t,J= 4.4 Hz, 2H), 3.74 (t,J= 4.6 Hz, 2H),3.58 (dh,J= 9.3, 4.0 Hz, 9H), 3.49 (d,J= 5.8 Hz, 2H), 2.78 (s, 3H), 2.14 –1.88 (m, 9H), 1.48 (d,J= 11.4 Hz, 2H), 1.32 (s, 9H). ESI-MS: m/z [M + H]+calcd for C56H66N5O9 +952.48, found 952.66.
化合物9c的合成
除化合物8c (220mg, 0.231 mmol)外,化合物9c采用与9a相同的方法合成。产率:137毫克,65%。M.p.:67.2-76.1 °C.1H NMR (400 MHz, DMSO) δ 8.32, 7.30, 7.23,7.11, 7.04, 6.94, 6.85, 6.79, 5.76, 5.44, 5.39, 5.26, 4.78, 4.69, 4.35, 4.29,4.04, 3.72, 3.58, 3.54, 3.49, 3.23, 3.16, 2.76, 1.87, 1.35, 1.28, 1.23. ESI-MS: m/z [M + Na]+calcd for C54H63N5O8Na+932.47, found 932.11.
化合物PMA-43的合成
除使用化合物10c (221 mg, 0.243 mmol)外,使用所述PMA-19的方法合成了化合物PMA-43。产率:108毫克,55%。M.p.:118.8-127.6 °C.1H NMR (400 MHz, DMSO) δ 9.49(s, 1H), 8.89 (s, 2H), 7.39 (d,J= 6.6 Hz, 5H), 7.33 (t,J= 5.9 Hz, 4H), 7.29(s, 1H), 7.24 (d,J= 6.8 Hz, 2H), 7.16 (d,J= 7.2 Hz, 2H), 6.96 (d,J= 13.5 Hz,3H), 6.86 (d,J= 6.5 Hz, 2H), 6.22 (s, 1H), 5.39 (s, 2H), 4.97 (d,J= 9.7 Hz,1H), 4.88 (s, 2H), 4.36 (s, 2H), 4.08 (t,J= 4.6 Hz, 2H), 3.73 (t,J= 4.4 Hz,2H), 3.62 – 3.51 (m, 9H), 3.07 (s, 1H), 2.94 (d,J= 9.7 Hz, 1H), 2.55 (d,J=4.9 Hz, 3H), 2.03 (q,J= 11.0 Hz, 4H), 1.95 – 1.87 (m, 2H), 1.59 (d,J= 12.0Hz, 2H).13C NMR (101 MHz, DMSO) δ 158.96, 151.40, 145.77, 143.99, 143.82,137.91, 137.51, 131.88, 131.25, 130.90, 130.32, 129.90, 129.77, 129.49,129.03, 128.76, 127.74, 122.57, 118.56, 116.60, 114.08, 112.49, 100.28,87.06, 85.56, 70.40, 70.28, 70.05, 69.42, 69.16, 68.35, 67.97, 67.55, 58.54,57.72, 55.47, 55.39, 46.10, 34.19, 33.10, 31.42, 30.23, 22.53, 14.44. ESI-MS:m/z [M + H]+calcd for C49H56N5O6 +810.42, found 810.42. HPLC purity: 98.5 %. [α]20 D=- 21.40 (c = 0.1, MeOH).
ETTAC降解GPCR机制如图2所示,ETTACs分别通过其靶向激动剂和自噬诱导部分触发α1A-AR的内化和激活自噬,Beclin 2/Bcl-2复合物的破坏与Beclin 2-GASP1-α1A-AR三元复合物的形成同时发生,将释放的Beclin2从自噬途径“转移”到GPCR降解途径,以增加三元Beclin 2-GASP1-α1A-AR复合体数量,ETTACs利用独立于泛素化和ESCRT机制的内体-溶酶体转运途径显著促进α1A-AR的靶向降解。
实施例4:免疫共沉淀实验
样品的制备:稳定表达Flag表位标记α1A-AR受体的HEK293细胞在含有蛋白酶抑制剂的Western及IP裂解液中裂解。4℃12000 rpm离心10分钟去除细胞碎片。用BCA蛋白浓度测定试剂盒将每组的蛋白样品定量为等体积等浓度等质量的。每组取出60 μL作为Input组。Anti-Flag磁珠的准备:用移液器轻轻吹打重悬Anti-Flag磁珠,取25μL Anti-Flag磁珠悬浊液至一洁净Ep管中,加入500 μL 1× TBS至最终体积。用移液器轻轻吹打重悬Anti-Flag磁珠。置于磁力架上分离10秒,去除上清。重复上述步骤两次。用25 μL 1 × TBS重悬Anti-Flag磁珠。免疫沉淀:加入磁珠与孵育。将离心后的上清液中加入清洗好的25 μL磁珠悬浊液,置于旋转混合仪,4℃孵育过夜。磁分离:孵育完毕后,置于磁力架上分离10秒,去除上清。洗涤:加入500 μL的1 × TBS,用移液器轻轻吹打重悬磁珠。置于磁力架上分离10秒,去除上清。重复洗涤三次。洗脱: 加入100 μL 1 × SDS-PAGE上样缓冲液,95℃加热5分钟。置于磁力架上分离10秒,取上清进行Western blot检测。
结果如图3所示,G蛋白偶联受体相关分选蛋白1 (GASP1)分别与α1A-AR和自噬相关蛋白Beclin 2结合,通过形成“Beclin 2-GASP1-α1A-AR”三元复合物,参与α1A-AR的溶酶体转运。
实施例5:Western blot实验
用化合物对稳定转染α1A-AR的HEK293细胞和PC-3细胞进行不同浓度的处理后,通过Western blot实验测定细胞内α1A-AR蛋白的水平。首先提取细胞蛋白并进行蛋白定量:用RIPA细胞裂解液(加蛋白酶抑制剂)裂解细胞,收集蛋白,并用BCA蛋白定量测定试剂盒进行定量,定量成同一浓度。蛋白变性:将蛋白置于100℃水浴8分钟,使蛋白变性。上样并跑胶:每孔上样量一般为20 μL,上层浓缩胶的电泳电压为75 V,下层分离胶的电泳电压为120 V,待40 KD的蛋白 marker下至凝胶末端处1 cm左右,停止电泳。转膜:使用湿转转膜仪进行转膜,PVDF膜要事先用甲醇浸泡,恒流250 mA,转膜90分钟。封闭:将PVDF膜置于BSA封闭液中封闭1 h(摇床慢摇)。 孵育一抗:按照说明书稀释一抗,加入一抗后,4℃孵育过夜。洗膜:用TBST洗膜液洗涤3次,每次洗涤10分钟。孵育二抗:加入二抗后,室温下摇床孵育1 h。洗膜:用TBST洗膜液洗涤3次,每次洗涤10分钟。曝光:将ECL显影液A液和B液等体积混合,进行曝光。
用小分子ETTACs处理稳定转染α1A-AR的HEK293细胞和PC-3细胞24h后,Westernblot结果(图4)表明 α1A-AR蛋白水平均呈剂量依赖性降低,其中化合物PMA-37的降解活性最好,诱导稳定转染α1A-AR的HEK293细胞和PC-3细胞中α1A-AR降解的DC50值(导致50%蛋白质降解的药物浓度)分别约为185 nM和59.7 nM。以上结果说明了基于内体-溶酶体转运途径成功的建立了一种新的蛋白降解方法。
实施例6:小鼠体内抗前列腺增生实验
C57BL/6雄性小鼠(7周龄)购自北京维通利华实验动物科技有限公司。取25只体重20-25 g的小鼠,分为对照组(n=10)和模型组(n=15)。模型组小鼠连续皮下注射丙酸睾酮(5 mg/kg) 21天,对照组小鼠每天只注射橄榄油。第21天,处死对照组和模型小鼠各5只,立即切除前列腺组织并称重。前列腺叶切片用4%多聚甲醛固定进行组织学分析。根据前列腺重量指数及组织学特征,造模成功后停用丙酸睾酮。将10只丙酸睾酮诱导的前列腺增生小鼠和5只对照组小鼠分为3组:对照组、BPH-载体组、BPH-ETTAC组。BPH-ETTAC组小鼠腹腔注射ETTAC(PMA-37)(10 mg/kg),对照组和BPH-载体组给药(5% DMSO + 25% PEG400 + 70%生理盐水,ip),每日1次,连续给药7天。在本实验中,最后一次给药24小时后采集小鼠前列腺组织进行进一步分析。
根据图5可知,靶向降解α1A-AR的ETTAC(PMA-37)能够显著缓解丙酸睾酮诱导的小鼠前列腺增生的病理症状,该实验说明本申请设计合成的靶向α1A-AR的ETTAC(PMA-37)具有体内抗前列腺增生的作用。
实施例7:小鼠体内前列腺肿瘤异种移植实验
4周龄雄性裸鼠购自北京北京维通利华实验动物科技有限公司。适应性饲养7天后,每只裸鼠皮下注射5×106个PC-3细胞。当肿瘤体积达到100-200 mm3,每天分别给药(5%DMSO + 25% PEG400 + 70%生理盐水,ip)和ETTAC(PMA-37) (10 mg/kg, ip)。ETTAC(PMA-37)治疗PC-3异种移植瘤模型小鼠2周,每天每次给药前测量小鼠体重和肿瘤体积(体积=长×宽2/2)。治疗结束时,处死小鼠,收集小鼠的肿瘤用于进一步分析。
根据图6可知,靶向降解α1A-AR的ETTAC(PMA-37)具有显著的体内抗前列腺肿瘤的作用,且在治疗过程中小鼠的体重未发生明显变化。
以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种化合物、其异构体或其药学上可接受的盐,其中所述化合物具有式I所示结构,
PE-L-ML246;
式I;
其中:
PE是α1A-肾上腺素能受体的激动剂去氧肾上腺素,其化学结构式为;
ML246是自噬诱导剂,其化学结构式为;
L是连接链,PE和ML246通过L经过化学键连接。
2.如权利要求1所述的化合物、其异构体或其药学上可接受的盐,其中:所述化合物具有式II所示结构:
;
其中,n为1~10的整数。
3.如权利要求1所述的化合物、其异构体或其药学上可接受的盐,其中:所述化合物选自:
、/>、
。
4.一种药物组合物,其中,包括权利要求1~3任一所述的化合物、其异构体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。
5.一种药物制剂,其中,包括权利要求1~3任一所述的化合物、其异构体或其药学上可接受的盐,和至少一种其他药理学活性物质。
6.一种试剂盒,包含:
第一药物组合物或剂型,其包权利要求1~3任一所述的化合物、其异构体或其药学上可接受的盐和药学上可接受的载体、赋形剂;
第二药物组合物或剂型,其包含另一种药理学活性物质和药学上可接受的载体、赋形剂。
7.一种权利要求1~3任一所述的化合物、其异构体或其药学上可接受的盐、权利要求4所述的药物组合物、权利要求5所述的药物制剂或权利要求6所述的试剂盒在制备抗肿瘤药物和或/治疗炎症药物中的应用。
8.如权利要求7所述的应用,其特征是,肿瘤为前列腺肿瘤;炎症为前列腺炎症。
9.一种权利要求1~3任一所述的化合物、其异构体或其药学上可接受的盐、权利要求4所述的药物组合物、权利要求5所述的药物制剂或权利要求6所述的试剂盒在制备治疗前列腺相关疾病药物中的应用。
10.如权利要求9所述的应用,其特征是,所述前列腺相关疾病包括与α1A-肾上腺素能受体、GASP1或Beclin 2相关的疾病。
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