WO2023221828A1 - 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 PDF

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WO2023221828A1
WO2023221828A1 PCT/CN2023/093156 CN2023093156W WO2023221828A1 WO 2023221828 A1 WO2023221828 A1 WO 2023221828A1 CN 2023093156 W CN2023093156 W CN 2023093156W WO 2023221828 A1 WO2023221828 A1 WO 2023221828A1
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acid
pharmaceutically acceptable
acceptable salt
sesquiterpene derivative
sesquiterpene
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PCT/CN2023/093156
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French (fr)
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杨诚
杨光
周红刚
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天津济坤医药科技有限公司
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Priority to AU2023270628A priority Critical patent/AU2023270628A1/en
Priority to EP23806780.5A priority patent/EP4342900A1/en
Priority to KR1020237044225A priority patent/KR20240012513A/ko
Publication of WO2023221828A1 publication Critical patent/WO2023221828A1/zh

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    • 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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    • 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
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
    • A61K39/39541—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against normal tissues, cells
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    • 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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
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    • C07C55/08—Malonic acid
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C55/10—Succinic acid
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
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    • C07C57/15—Fumaric acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/01—Saturated compounds having only one carboxyl group and containing hydroxy or O-metal groups
    • C07C59/08—Lactic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/255—Tartaric acid
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    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
    • C07C63/04—Monocyclic monocarboxylic acids
    • C07C63/06—Benzoic acid
    • C07C63/08—Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to the field of medicinal chemistry, and in particular to a sesquiterpene derivative, its pharmaceutical composition, its preparation method and use.
  • tumors depend on a variety of mechanisms, among which immune escape (ie, avoiding recognition and elimination by the immune system) is a very important mechanism.
  • immune escape ie, avoiding recognition and elimination by the immune system
  • the body's immune system can monitor "non-self" mutated cells and specifically eliminate them through the cellular immune mechanism to maintain the stability of the body's internal environment.
  • tumors escape from the body's immune surveillance and undergo immune escape, and their malignant biological behavior will be further accelerated, thus promoting tumor proliferation, invasion and metastasis.
  • Programmed death receptor-1 is an important immunosuppressive transmembrane protein expressed on the surface of T cells.
  • T cells are induced to highly express PD-1 molecules, while tumor cells express their ligands PD-L1 or PD-L2.
  • PD-L1 or PD-L2 binds to PD-1, T cells are unable to detect tumors and send signals to the immune system to attack the tumors. Therefore, the PD-1 monoclonal antibody immunotherapy strategy of blocking the PD-1/PD-L1 signaling pathway and restoring the immune killing function of T cells has also emerged.
  • PD-1 antibodies According to statistics, there are 154 companies around the world researching and developing PD-1 antibodies, including many well-known companies such as Merck, BMS, Junshi, Innovent and Hengrui. Currently, there are 6 PD-1 antibodies approved for marketing in China, including more than ten indications such as non-small cell lung cancer, gastric cancer, breast cancer, and renal cell cancer.
  • PD-1 antibodies have certain limitations in clinical application. Among them, the most prominent problem is the low response rate in tumor patients. According to clinical statistics, PD-1 antibodies have the best response rate for melanoma patients, about 40%, followed by non-small cell lung cancer, about 25-30%, and the response rate for liver cancer is about 20%, while for most other tumors The response rate is generally less than 15%. In particular, it is basically unresponsive to pancreatic cancer (response rate is less than 1%). The reasons for the low response rate of PD-1 antibodies in tumor patients are relatively complex, and the mechanism is unclear and is still under study.
  • the chemotherapy drug paclitaxel, platinum chemotherapy drugs, radiotherapy, etc. combined with PD-1 antibodies to treat tumors can significantly improve the response of patients' tumor lesions to PD-1 and improve the effectiveness of treatment.
  • targeted drugs such as EGFR and VEGFR combined with PD-1 antibody therapy have also achieved good therapeutic effects, benefiting patients significantly.
  • the object of the present invention is to provide a sesquiterpene derivative or a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing it and a PD-1 antibody, and their use in preparing drugs for treating tumors. use.
  • the sesquiterpene derivatives of the present invention or pharmaceutically acceptable salts thereof can significantly enhance the response and efficacy of PD-1 antibodies to tumors, and their combined administration with PD-1 antibodies shows an obvious synergistic effect, showing Exhibited strong anti-tumor activity.
  • the present invention provides the following technical solutions:
  • the present invention provides a sesquiterpene derivative or a pharmaceutically acceptable salt thereof, the sesquiterpene derivative having a structure shown in formula (I):
  • R 1 and R 2 are independently selected from: alkyl and hydroxyalkyl, provided that: R 1 and R 2 are not methyl at the same time.
  • the alkyl group is a C1-C4 alkyl group, preferably a C1-C3 alkyl group.
  • the hydroxyalkyl group is a C1-C4 hydroxyalkyl group, preferably a C1-C3 hydroxyalkyl group.
  • the sesquiterpene derivative is a compound selected from the following:
  • the pharmaceutically acceptable salt of the sesquiterpene derivative is a salt formed by the sesquiterpene derivative and an inorganic acid or organic acid;
  • the inorganic acid is selected from the group consisting of: hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid;
  • the organic acid is selected from the group consisting of: citric acid, maleic acid, D-malic acid, L-malic acid, DL-malic acid, D-lactic acid, L-lactic acid, DL-lactic acid, oxalic acid, Methanesulfonic acid, p-toluenesulfonic acid, tartaric acid, malonic acid, succinic acid, fumaric acid, benzoic acid or substituted benzoic acid.
  • the pharmaceutically acceptable salt of the sesquiterpene derivative is the fumarate salt of the sesquiterpene derivative.
  • the pharmaceutically acceptable salt of the sesquiterpene derivative is selected from the following:
  • the present invention provides a method for preparing the sesquiterpene derivative or a pharmaceutically acceptable salt thereof as described in the first aspect, and its synthesis route is as follows:
  • the Sol. is a solvent selected from dichloromethane, chloroform, tetrahydrofuran, methanol, ethanol, toluene, acetonitrile, ethyl acetate, N,N'-dimethylformamide, dimethyl sulfoxide, One or more species in water.
  • the present invention provides a pharmaceutical composition, which includes: a sesquiterpene derivative or a pharmaceutically acceptable salt thereof as described in the first aspect; PD-1 antibody, preferably PD-1 monoclonal Antibodies; and pharmaceutically acceptable carriers and/or excipients.
  • the sesquiterpene derivative or a pharmaceutically acceptable salt thereof is used as the first active component
  • the PD-1 antibody is used as the second active component; in a preferred embodiment, the sesquiterpene derivative or a pharmaceutically acceptable salt thereof is used as the first active component.
  • the hemiterpene derivative or a pharmaceutically acceptable salt thereof is in the same preparation unit as the PD-1 antibody, or in a different preparation unit.
  • the mass ratio of the sesquiterpene derivative or its pharmaceutically acceptable salt to the PD-1 antibody is: (1-20):1, more preferably 10:1.
  • the present invention provides a sesquiterpene derivative or a pharmaceutically acceptable salt thereof as described in the first aspect above or a pharmaceutical composition as described in the third aspect above when prepared for the treatment of tumors. uses in medicines.
  • the tumor is selected from the group consisting of melanoma, lung cancer, pancreatic cancer, liver cancer, colorectal cancer, gastric cancer, and glioma.
  • the sesquiterpene derivative of the present invention or its pharmaceutically acceptable salt can significantly enhance the response and therapeutic effect of PD-1 antibodies to tumors, and its combined administration with PD-1 antibodies shows obvious synergistic effects. It shows extremely strong anti-tumor activity, provides a new way for clinical treatment of tumors, and has potential clinical application value and broad clinical application prospects.
  • Example 7 Anti-tumor effect of combination therapy with the compound of the present invention and PD-1 monoclonal antibody
  • mice used in this experiment were purchased from Beijing Vital River Laboratory (Beijing, China).
  • the different types of tumor cells mentioned above were inoculated into different mouse types to generate corresponding tumor-bearing mice, as follows:
  • B16F10 uses 6-8 weeks old C57BL/6 female mice
  • LLC uses 6-8 weeks old Balb/c female mice
  • PAN02 uses 6-8 weeks old C57BL/6J female mice
  • H22 uses 6-8 weeks old C57BL /6 female mice
  • CT26 uses 6-8 week old Balb/c female mice
  • MFC uses 6-8 week old BALB/c-nu/nu female mice
  • GL261 uses 6-8 week old C57BL/6 female mice. mouse.
  • mice Inoculate the above cell suspension into the axilla of the forelimb of the mouse at an inoculation volume of 1 ⁇ 10 6 tumor cells per mouse (i.e., 100 ⁇ L cell suspension/mouse); when the average tumor volume exceeds 100cm 3 ( The difference in tumor volume between individuals does not exceed 10%), and the mice were randomly divided into the following groups (8 mice in each group):
  • Small molecule drug group Compounds 4, 5, 6, and 7 (compound 7 is the control compound), administered orally at a dose of 150 mg/kg body weight every day;
  • PD-1 monoclonal antibody group PD-1 monoclonal antibody, intraperitoneal injection once every three days, 10 mg/kg body weight each time;
  • mice were administered small molecule drugs and PD-1 monoclonal antibodies in combination.
  • mice were euthanized, the tumor tissues were collected, and their volume and weight were tested to calculate the tumor inhibition rate.
  • Tumor inhibition rate (1-tumor weight of treatment group/tumor weight of control group)*100%
  • the tumor inhibition rate was increased by about 9 times compared with the PD-1 monoclonal antibody group alone; and, compared with the compound group alone, Comparatively, the tumor inhibition rate in the group treated with compounds 4, 5, 6 and PD-1 monoclonal antibody can be increased by about 4 times; in addition, the tumor inhibition rate in the group treated with compounds 4, 5, 6 and PD-1 monoclonal antibody combined
  • the inhibition rate is also much higher than that of the control compound 7 and PD-1 monoclonal antibody combined administration group; these all show that the combined administration of the compound of the present invention and PD-1 monoclonal antibody can significantly enhance the response of tumor cells to PD-1 monoclonal antibody.
  • the tumor inhibitory effect was also significantly improved compared to the compound group alone, that is, the combination therapy showed an obvious synergistic effect and showed extremely strong anti-tumor activity.

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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

一种倍半萜衍生物、其药物组合物及其制备方法和用途
本申请要求于2022年05月16日提交中国专利局、申请号为202210527640.2、发明名称为“一种倍半萜衍生物、其药物组合物及其制备方法和用途”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
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，18.9mmol)，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,found362.1933.
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(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 for C18H29NO5Na+[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,9H),2.49–2.34(m,4H),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(262mg，2.26mmol)，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,9H),2.49–2.34(m,4H),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(100MHz,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，3.56mmol)，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：
1HNMR(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(100MHz,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,found376.2093.
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 inTHF，9.46mL，18.9mmol)，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 forC17H27NO4Na+[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 (18)

  1. 一种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，且R1和R2不同时为甲基。
  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；
    和/或，所述羟烷基为C1-C4羟烷基。
  3. 根据权利要求2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-C3烷基。
  4. 根据权利要求2或3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：所述羟烷基为C1-C3羟烷基。
  5. 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为选自以下的化合物：
  6. 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；
    所述无机酸选自：氢氟酸、盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、碳酸；
    所述有机酸选自：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. 根据权利要求6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的富马酸盐。
  8. 根据权利要求7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选自以下：
  9. 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的制备方法，所述倍半萜类衍生物的合成路线如下：
    其中，所述Sol.为溶剂。
  10. 根据权利要求9所述的制备方法，其特征在于，所述倍半萜类衍生物的富马酸盐的合成路线如下：
    其中，所述Sol.为溶剂。
  11. 根据权利要求9或10所述的制备方法，其特征在于：所述Sol.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。
  12. 一种药物组合物，其包括：如权利要求1-8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；以及药学上可接受的载体和/或赋形剂。
  13. 根据权利要求12所述的药物组合物，其特征在于：所述PD-1抗体为PD-1单克隆抗体。
  14. 根据权利要求12或13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。
  15. 根据权利要求14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10：1。
  16. 根据权利要求14或15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抗体在同一制剂单元中，或者在不同的制剂单元中。
  17. 权利要求1-8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权利要求12-16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。
  18. 根据权利要求17所述的用途，其特征在于，所述肿瘤选自：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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