CN114773356A - 一种倍半萜衍生物、其药物组合物及其制备方法和用途 - Google Patents
一种倍半萜衍生物、其药物组合物及其制备方法和用途 Download PDFInfo
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- CN114773356A CN114773356A CN202210527640.2A CN202210527640A CN114773356A CN 114773356 A CN114773356 A CN 114773356A CN 202210527640 A CN202210527640 A CN 202210527640A CN 114773356 A CN114773356 A CN 114773356A
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- acid
- pharmaceutically acceptable
- acceptable salt
- sesquiterpene derivative
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Classifications
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2818—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD28 or CD152
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
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- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/06—Oxalic acid
- C07C55/07—Salts thereof
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明涉及一种式(I)所示的倍半萜类衍生物或其药学上可接受的盐,包含其与PD‑1抗体作为活性组分的药物组合物,以及其制备方法和用途。本发明的倍半萜类衍生物或其药学上可接受的盐可以显著增强PD‑1抗体对肿瘤的响应和治疗效果,其与PD‑1抗体的联合施用表现出明显的协同增效作用,显示出了极强的抗肿瘤活性,为临床治疗肿瘤提供了一条新途径,具有潜在的临床应用价值和广阔的临床应用前景。
Description
技术领域
本发明涉及药物化学领域,具体涉及一种倍半萜衍生物、其药物组合物以及其制备方法和用途。
背景技术
肿瘤的发生和发展有赖于多种机制,其中,免疫逃逸(即,躲避免疫系统的识别和消灭)是十分重要的一种机制。机体的免疫系统可以对“非己”的突变细胞发挥监视作用,并可通过细胞免疫机制特异性地将其清除,以保持机体内环境的稳定。然而,在各种因素作用下,肿瘤脱离机体免疫的监控后发生免疫逃逸,其恶性生物学行为将会进一步加快,从而促进肿瘤的增殖、侵袭和转移。
程序性死亡受体-1(PD-1)是表达在T细胞表面的一种重要的免疫抑制跨膜蛋白。在肿瘤的微环境中,会诱导T细胞高表达PD-1分子,而肿瘤细胞表达其配体PD-L1或者PD-L2。当配体PD-L1或者PD-L2与PD-1联接以后,T细胞就不能够发现肿瘤和向免疫系统发出攻击肿瘤的信号。因此,阻断PD-1/PD-L1信号通路,恢复T细胞的免疫杀伤功能的PD-1单克隆抗体免疫治疗策略也应运而生。根据统计数据,全球有154个企业在研究开发PD-1抗体,其中不乏默沙东、BMS、君实、信达和恒瑞等知名企业。目前,国内获批上市的PD-1抗体已达6款,其中包含了非小细胞肺癌、胃癌、乳腺癌、肾细胞癌等十余种适应症。
然而,PD-1抗体在临床应用中具有一定的局限性,其中,最突出的问题是对肿瘤患者的响应率低。据临床统计,PD-1抗体对黑色素瘤患者的响应率最好,约为40%,其次是非小细胞肺癌,大约25-30%,对肝癌的响应率在20%左右,而对其他多数肿瘤的响应率普遍低于15%,尤其是,其对胰腺癌基本不响应(响应率小于1%)。关于PD-1抗体对肿瘤患者响应率低的原因相对复杂,机制不明确,目前还在研究中。
目前,已经有一些联用方案可以适当提高PD-1抗体的抗肿瘤效果。例如,化疗药物紫杉醇,铂类化疗药物,放射治疗等联合PD-1抗体对肿瘤进行治疗,可以显著提高患者肿瘤病灶对于PD-1的响应,提高治疗的效果。另外,EGFR和VEGFR等靶向药物联合PD-1抗体治疗也收到的较好的治疗效果,使患者受益显著。
尽管如此,联合治疗的手段依然非常有限,对原本低响应肿瘤类型依然效果不佳。因此,筛选与开发可以增效免疫治疗的化合物具有重要的临床意义。
公开于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,而不应当被视为承认或以任何形式暗示该信息构成已为本领域一般技术人员所公知的现有技术。
发明内容
发明目的
本发明的目的在于提供一种倍半萜类衍生物或其药学上可接受的盐、其制备方法、包含其和PD-1抗体的药物组合物以及它们在制备用于治疗肿瘤的药物中的用途。本发明的倍半萜类衍生物或其药学上可接受的盐可以显著增强PD-1抗体对肿瘤的响应和疗效,其与PD-1抗体的联合施用表现出明显的协同增效作用,显示出了极强的抗肿瘤活性。
解决方案
为实现本发明目的,本发明提供了以下技术方案:
第一方面,本发明提供了一种倍半萜类衍生物或其药学上可接受的盐,所述倍半萜类衍生物具有如式(I)所示的结构:
其中,R1和R2独立地选自:烷基和羟烷基,条件是:R1和R2不同时为甲基。
在优选的实施方案中,所述烷基为C1-C4烷基,优选为C1-C3烷基。
在优选的实施方案中,所述羟烷基为C1-C4羟烷基,优选为C1-C3羟烷基。
进一步优选地,所述倍半萜类衍生物为选自以下的化合物:
在优选的实施方案中,所述倍半萜类衍生物的药学上可接受的盐为所述倍半萜类衍生物与无机酸或有机酸所形成的盐;
优选地,所述无机酸选自由以下组成的组:氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸;
优选地,所述有机酸选自由以下组成的组:柠檬酸、马来酸、D-苹果酸、L-苹果酸、DL-苹果酸、D-乳酸、L-乳酸、DL-乳酸、草酸、甲磺酸、对甲苯磺酸、酒石酸、丙二酸、丁二酸、富马酸、苯甲酸或取代苯甲酸。
进一步优选地,所述倍半萜类衍生物的药学上可接受的盐为所述倍半萜类衍生物的富马酸盐。
在优选的具体实施方案中,所述倍半萜类衍生物的药学上可接受的盐选自以下:
第二方面,本发明提供了一种如上述第一方面所述倍半萜类衍生物或其药学上可接受的盐的制备方法,其合成路线如下:
其中,所述Sol.为溶剂,选自二氯甲烷、三氯甲烷、四氢呋喃、甲醇、乙醇、甲苯、乙腈、乙酸乙酯、N,N’-二甲基甲酰胺、二甲基亚砜、水中的一种或多种。
第三方面,本发明提供了一种药物组合物,其包括:如上述第一方面所述倍半萜类衍生物或其药学上可接受的盐;PD-1抗体,优选PD-1单克隆抗体;以及药学上可接受的载体和/或赋形剂。
上述药物组合物中,所述倍半萜类衍生物或其药学上可接受的盐作为第一活性组分,PD-1抗体作为第二活性组分;在优选的实施方案中,所述倍半萜类衍生物或其药学上可接受的盐与所述PD-1抗体在同一制剂单元中,或者在不同的制剂单元中。
此外,作为优选,所述倍半萜类衍生物或其药学上可接受的盐与所述PD-1抗体的质量比为:(1~20):1,进一步优选为10:1。
第四方面,本发明提供了一种如上述第一方面所述的倍半萜类衍生物或其药学上可接受的盐或者如上述第三方面所述的药物组合物在制备用于治疗肿瘤的药物中的用途。
在具体实施方案中,所述肿瘤选自由以下组成的组:黑色素瘤、肺癌、胰腺癌、肝癌、结直肠癌、胃癌和脑胶质瘤。
有益效果
本发明的倍半萜类衍生物或其药学上可接受的盐可以显著增强PD-1抗体对肿瘤的响应和治疗效果,其与PD-1抗体的联合施用表现出明显的协同增效作用,显示出了极强的抗肿瘤活性,为临床治疗肿瘤提供了一条新途径,具有潜在的临床应用价值和广阔的临床应用前景。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
另外,为了更好的说明本发明,在下文的具体实施方式中给出了众多的具体细节。本领域技术人员应当理解,没有某些具体细节,本发明同样可以实施。在一些实施例中,对于本领域技术人员熟知的原料、元件、方法、手段等未作详细描述,以便于凸显本发明的主旨。
除非另有其它明确表示,否则在整个说明书和权利要求书中,术语“包括”或其变换如“包含”或“包括有”等等将被理解为包括所陈述的元件或组成部分,而并未排除其它元件或其它组成部分。
以下实施例中所使用的实验方法如无特殊说明,均为常规方法。
以下实施例中所用的材料或试剂等,如无特殊说明,均可通过商购获得。
实施例1:化合物1的制备
化合物1的结构如下:
其制备过程如下:
0℃下,将二氧化硒(2.86g,25.8mmol)溶解在二氯甲烷(250mL)中,加入过氧化叔丁醇(15.5mL),搅拌反应30分钟后,将异土木香内酯(30g,0.129mol)的二氯甲烷(250mL)溶液缓慢地加入到上述体系中,室温下搅拌8小时,然后用饱和硫代硫酸钠水溶液(500mL)淬灭反应,分液后,水相用二氯甲烷萃取(300mL×3),将有机相合并、干燥、浓缩,用石油醚/乙酸乙酯混合溶剂重结晶,得到中间体1(白色固体,19.5g,产率61%),其随后直接用于下一步。
0℃下,将化合物中间体1(19.5g,78.5mmol)溶解在二氯甲烷(100mL)中,缓慢将间氯过氧苯甲酸(16.3g,94.2mmol)的二氯甲烷(300mL)溶液滴加到上述体系中,室温下反应2小时,然后用饱和硫代硫酸钠(300mL)淬灭反应,水相用乙酸乙酯萃取(3×200mL),有机相用NaHCO3饱和溶液(100mL)洗涤一次,再用无水Na2SO4干燥,过滤除去固体,将母液浓缩,得到化合物CP0105粗品;所得化合物CP0105粗品用乙酸乙酯/石油醚重结晶,得到化合物CP0105(16.8g,产率81%)。
将化合物CP0105(1.00g,3.78mmol)溶解在四氢呋喃(16mL)中,向体系中加入N-甲基氨基乙醇(1.42g,18.9mol),25℃下将反应体系搅拌4小时,反应结束后,减压浓缩除去四氢呋喃,得到化合物1的粗产物;然后通过硅胶快速柱色谱(二氯甲烷∶甲醇=20∶1)纯化粗产物,得到化合物1(白色固体,1.13g,产率88%)。
对化合物1进行检测,其NMR数据如下:
1H NMR(400MHz,DMSO)δ4.76(d,J=4.3Hz,1H),3.90(t,J=5.2Hz,1H),3.75(t,J=6.3Hz,2H),3.46(d,J=2.9Hz,1H),3.38(dt,J=10.4,5.4Hz,1H),3.22(t,J=5.2Hz,1H),3.02(d,J=4.5Hz,1H),2.89–2.72(m,7H),2.67(dt,J=12.7,6.4Hz,2H),2.36(dd,J=13.0,2.3Hz,1H),2.30–2.15(m,1H),2.07–1.93(m,1H),1.92–1.69(m,3H),1.60(ddd,J=13.7,5.9,2.5Hz,1H),1.52–1.39(m,1H),1.11(s,3H),0.91(q,J=12.9Hz,1H).13C NMR(100MHz,DMSO)δ177.5,77.5,71.1,60.8,59.3,58.6,56.4,52.5,50.4,48.0,44.4,42.2,38.4,36.8,34.2,27.7,17.9,15.5.HRMS(ESI):m/z calcd for C18H29NO5Na+[M+Na]+362.1938,found 362.1933.
实施例2:化合物1的富马酸盐——化合物4的制备
化合物4的结构如下:
将实施例1所制备的化合物1(1.08g,3.19mmol)溶解在四氢呋喃中(20mL)中,搅拌均匀后,向体系中加入富马酸(352mg,3.03mmol),室温下搅拌反应3小时,反应结束后,减压浓缩除去四氢呋喃,然后向反应体系中加入乙酸乙酯(100mL),得到悬浊液,抽滤后得到化合物4(白色固体,1.26g,产率83%)。
对化合物4进行检测,其NMR数据如下:
1H NMR(400MHz,DMSO)δ6.80(s,2H),4.76(d,J=4.3Hz,1H),3.90(t,J=5.2Hz,1H),3.75(t,J=6.3Hz,2H),3.46(d,J=2.9Hz,1H),3.38(dt,J=10.4,5.4Hz,1H),3.22(t,J=5.2Hz,1H),3.02(d,J=4.5Hz,1H),2.89–2.72(m,7H),2.67(dt,J=12.7,6.4Hz,2H),2.36(dd,J=13.0,2.3Hz,1H),2.30–2.15(m,1H),2.07–1.93(m,1H),1.92–1.69(m,3H),1.60(ddd,J=13.7,5.9,2.5Hz,1H),1.52–1.39(m,1H),1.11(s,3H),0.91(q,J=12.9Hz,1H).13C NMR(100MHz,DMSO)δ177.5,167.4,134.8,77.5,71.1,60.8,59.3,58.6,56.4,52.5,50.4,48.0,44.4,42.2,38.4,36.8,34.2,27.7,17.9,15.5.HRMS(ESI):m/z calcd forC18H29NO5Na+[M+Na]+362.1938,found 362.1933.
实施例3:化合物2的制备
化合物2的结构如下:
其制备过程如下:
使用乙二醇胺(1.99g,18.9mmol),按照实施例1中化合物1的合成步骤,获得目标化合物2(白色固体,879mg,产率63%)。
对化合物2进行检测,其NMR数据如下:
1H NMR(400MHz,DMSO)δ4.48(s,1H),3.47(q,J=5.3,4.8Hz,3H),3.18(s,1H),3.13–3.04(m,1H),2.86–2.53(m,7H),2.49–2.34(m,2H),2.08(d,J=12.7Hz,1H),1.95(d,J=15.3Hz,1H),1.82–1.67(m,1H),1.64–1.45(m,3H),1.34(dd,J=14.0,5.2Hz,1H),1.20(d,J=12.5Hz,1H),0.83(s,3H),0.63(q,J=12.7Hz,1H).13C NMR(100MHz,DMSO)δ177.6,77.4,71.1,60.8,58.8,58.6,56.3,50.0,48.0,41.3,38.4,36.8,34.7,34.2,27.7,17.9,15.5.HRMS(ESI):m/z calcd for C19H31NO6Na+[M+Na]+392.2044,found392.2039.
实施例4:化合物2的富马酸盐——化合物5的制备
化合物5的结构如下:
使用实施例3所制备的化合物2(878mg,2.38mmol)和富马酸(262g,2.26mol),按照实施例2中化合物4的合成步骤获得目标化合物5(白色固体,674mg,产率58%)。
对化合物5进行检测,其NMR数据如下:
1H NMR(400MHz,DMSO)δ6.61(d,J=3.2Hz,2H),4.48(s,1H),3.47(q,J=5.3,4.8Hz,3H),3.18(s,1H),3.13–3.04(m,1H),2.86–2.53(m,7H),2.49–2.34(m,2H),2.08(d,J=12.7Hz,1H),1.95(d,J=15.3Hz,1H),1.82–1.67(m,1H),1.64–1.45(m,3H),1.34(dd,J=14.0,5.2Hz,1H),1.20(d,J=12.5Hz,1H),0.83(s,3H),0.63(q,J=12.7Hz,1H).13C NMR(100MHz,DMSO)δ177.6,166.2,134.1,77.4,71.1,60.8,58.8,58.6,56.3,50.0,48.0,41.3,38.4,36.8,34.7,34.2,27.7,17.9,15.5.HRMS(ESI):m/z calcd for C19H31NO6Na+[M+Na]+392.2044,found 392.2039.
实施例5:化合物3的制备
化合物3的结构如下:
其制备过程如下:
使用N-甲基氨基丙醇(1.65g,18.9mmol),按照实施例1中化合物1的合成步骤获得目标化合物3(白色固体,1.32g,产率99%)。
对化合物3进行检测,其NMR数据如下:
1H NMR(400MHz,DMSO)δ5.11–4.48(m,1H),3.67(q,J=6.2,5.3Hz,2H),3.50–3.31(m,3H),3.21–2.96(m,2H),2.96–2.69(m,7H),2.67(q,J=6.1,5.6Hz,2H),2.39–2.28(m,1H),2.26–2.14(m,1H),2.07–1.69(m,6H),1.62–1.51(m,1H),1.44(qt,J=10.6,7.2,6.4Hz,1H),1.07(s,3H),0.88(q,J=12.8Hz,1H).13C NMR(101MHz,DMSO)δ177.3,77.6,71.1,60.9,59.1,54.1,52.0,48.1,44.1,41.5,41.3,38.5,36.8,34.7,34.3,29.2,27.7,18.0,15.6.HRMS(ESI):m/z calcd for C19H31NO5Na+[M+Na]+376.2094,found 376.2093.
实施例6:化合物3的富马酸盐——化合物6的制备
化合物6的结构如下:
使用实施例5所制备的化合物3(1.32g,3.74mmol)和富马酸(412mg,3.56mol),按照实施例2中化合物4的合成步骤获得目标化合物6(白色固体,1.42g,产率81%)。
对化合物6进行检测,其NMR数据如下:
1H NMR(400MHz,DMSO)δ6.82(s,2H),5.11–4.48(m,1H),3.67(q,J=6.2,5.3Hz,2H),3.50–3.31(m,3H),3.21–2.96(m,2H),2.96–2.69(m,7H),2.67(q,J=6.1,5.6Hz,2H),2.39–2.28(m,1H),2.26–2.14(m,1H),2.07–1.69(m,6H),1.62–1.51(m,1H),1.44(qt,J=10.6,7.2,6.4Hz,1H),1.07(s,3H),0.88(q,J=12.8Hz,1H).13C NMR(101MHz,DMSO)δ177.3,166.6,134.4,77.6,71.1,60.9,59.1,54.1,52.0,48.1,44.1,41.5,41.3,38.5,36.8,34.7,34.3,29.2,27.7,18.0,15.6.HRMS(ESI):m/z calcd for C19H31NO5Na+[M+Na]+376.2094,found 376.2093.
对比例:对照化合物7的制备
化合物7的结构如下:
其制备过程如下:
将化合物CP0105(1.00g,3.78mmol,可按照实施例1中记载的有关方法制得)溶解在四氢呋喃(16mL)中,向其中加入二甲胺(2M in THF,9.46mL,18.9mol),25℃下将反应体系搅拌4小时,反应结束后,旋转蒸发以除去溶剂,所得产物浓缩后再次溶解在四氢呋喃中(20mL),搅拌均匀后,向体系中加入富马酸(346mg,2.98mmol),室温下搅拌反应3小时,反应结束后,减压浓缩除去四氢呋喃,加入乙酸乙酯(100mL),得到悬浊液,抽滤后得到化合物7(白色固体,951mg,产率52%)。
对化合物7进行检测,其NMR数据如下:
1H NMR(400MHz,CDCl3)δ6.58(s,2H),4.50(q,J=2.8,2.0Hz,1H),3.24–3.05(m,2H),2.75(d,J=4.5Hz,1H),2.62(dd,J=12.8,10.4Hz,1H),2.50–2.45(m,3H),2.44–2.37(m,1H),2.26(s,6H),2.08(dd,J=13.0,2.4Hz,1H),1.96(dd,J=15.4,2.0Hz,1H),1.74(tt,J=15.3,3.6Hz,1H),1.63–1.46(m,3H),1.30(ddd,J=13.6,5.8,2.4Hz,1H),1.25–1.14(m,1H),0.83(s,3H),0.64(q,J=12.9Hz,1H).13C NMR(100MHz,CDCl3)δ177.6,167.0,134.8,78.0,71.5,61.3,54.1,48.5,45.1,44.7,41.7,38.9,37.2,35.2,34.7,28.2,18.4,16.0.HRMS(ESI):m/z calcd for C17H27NO4Na+[M+Na]+332.1832,found 332.1838.
实施例7:本发明化合物与PD-1单抗联合疗法的抗肿瘤效果
收集生长状态良好的肿瘤细胞B16F10、LLC、PAN02、H22、CT26、MFC和GL261,(购自Biological Industries)分别用1×PBS洗涤2次,用细胞计数仪计算细胞总数,用1×PBS将细胞液稀释成1×107个细胞/ml的细胞悬浮液。
本实验所使用小鼠均购自北京Vital River实验室(中国北京)。上述不同种类的肿瘤细胞分别接种于不同的小鼠类型以产生各自相应的荷瘤小鼠,具体如下:
B16F10选用6-8周龄C57BL/6雌性小鼠,LLC选用6-8周龄Balb/c雌性小鼠,Pan02选用6-8周龄C57BL/6J雌性小鼠,H22选用6-8周龄C57BL/6雌性小鼠,CT26选用6-8周龄Balb/c雌性小鼠,MFC选用6-8周龄BALB/c-nu/nu雌性小鼠,GL261选用6-8周龄C57BL/6雌性小鼠。
按每只小鼠1×106个肿瘤细胞的接种量(即,100μL细胞悬浮液/只小鼠),将上述细胞悬浮液接种至小鼠前肢腋窝处;待肿瘤平均体积超过100cm3时(个体间肿瘤体积差异不超过10%),将小鼠随机分为以下几组(每组8只):
小分子药物组:化合物4、5、6、7(其中,化合物7为对照化合物),按150mg/kg体重,每天口服灌胃给药;
PD-1单抗组:PD-1单抗,每三天腹腔注射一次,每次10mg/kg体重;
联合给药组:按照上述给药方式与剂量,对小鼠联合施用小分子药物与PD-1单抗。
实验结束后,用安乐死的方式处死小鼠,收集肿瘤组织,并对其体积、重量进行测试,计算肿瘤抑制率。
肿瘤抑制率=(1-治疗组瘤重量/对照组瘤重量)*100%
实验结果如下表1所示。
表1、各测试组对一系列肿瘤的抑制率
由表1可知,化合物4、5、6与PD-1单抗的联合施用,使原本对PD-1单抗不响应或低响应的小鼠肿瘤细胞B16F10、LLC、PAN02、H22、CT26、MFC和GL261都能显著地响应PD-1单抗的免疫治疗,特别是,使得原本对PD-1单抗完全无响应的PAN02细胞或者对PD-1单抗极低响应的GL261细胞,产生了高达89%的肿瘤抑制率(联合使用化合物6组),即便对于其他肿瘤细胞而言,其肿瘤抑制率也较单独使用PD-1单抗组增加了高达9倍左右;并且,与单独使用化合物组相比,化合物4、5、6与PD-1单抗联合给药组的肿瘤抑制率可增加高达4倍左右;此外,化合物4、5、6与PD-1单抗联合给药组的肿瘤抑制率也远远高于对照化合物7与PD-1单抗联合给药组;这些均表明:本发明化合物与PD-1单抗的联合施用可显著增强肿瘤细胞对PD-1单抗的响应,并且较单独使用化合物组的肿瘤抑制效应也显著提高,即,该联合疗法表现出明显的协同增效作用,显示出了极强的抗肿瘤活性。
最后应说明的是:以上实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明技术方案的精神和范围。
Claims (10)
2.根据权利要求1所述的倍半萜类衍生物或其药学上可接受的盐,其特征在于:所述烷基为C1-C4烷基,优选为C1-C3烷基;
和/或,所述羟烷基为C1-C4羟烷基,优选为C1-C3羟烷基。
4.根据权利要求1所述的倍半萜类衍生物或其药学上可接受的盐,其特征在于:所述倍半萜类衍生物的药学上可接受的盐为所述倍半萜类衍生物与无机酸或有机酸所形成的盐;
优选地,所述无机酸选自由以下组成的组:氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸;
优选地,所述有机酸选自由以下组成的组:柠檬酸、马来酸、D-苹果酸、L-苹果酸、DL-苹果酸、D-乳酸、L-乳酸、DL-乳酸、草酸、甲磺酸、对甲苯磺酸、酒石酸、丙二酸、丁二酸、富马酸、苯甲酸或取代苯甲酸。
7.一种药物组合物,其包括:如权利要求1-5任一项所述的倍半萜类衍生物或其药学上可接受的盐;PD-1抗体,优选PD-1单克隆抗体;以及药学上可接受的载体和/或赋形剂。
8.根据权利要求7所述的药物组合物,其特征在于:所述倍半萜类衍生物或其药学上可接受的盐与所述PD-1抗体的质量比为:(1~20):1,优选为10:1;
优选地,所述倍半萜类衍生物或其药学上可接受的盐与所述PD-1抗体在同一制剂单元中,或者在不同的制剂单元中。
9.根据权利要求1-5任一项所述的倍半萜类衍生物或其药学上可接受的盐或者根据权利要求7-8任一项所述的药物组合物在制备用于治疗肿瘤的药物中的用途。
10.根据权利要求9所述的用途,其特征在于,所述肿瘤选自由以下组成的组:黑色素瘤、肺癌、胰腺癌、肝癌、结直肠癌、胃癌和脑胶质瘤。
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