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WO2025087460A1 - 一种吡啶并吡唑衍生物药物组合物及其应用 - Google Patents

一种吡啶并吡唑衍生物药物组合物及其应用 Download PDF

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Publication number
WO2025087460A1
WO2025087460A1 PCT/CN2024/141727 CN2024141727W WO2025087460A1 WO 2025087460 A1 WO2025087460 A1 WO 2025087460A1 CN 2024141727 W CN2024141727 W CN 2024141727W WO 2025087460 A1 WO2025087460 A1 WO 2025087460A1
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ethyl
methyl
compound
cyano
administered
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French (fr)
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徐骏
李阳光
王菊
严庞科
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Haisco Pharmaceutical Group Co Ltd
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Haisco Pharmaceutical Group Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a pharmaceutical composition and an application thereof, in particular to a pyridopyrazole derivative pharmaceutical composition and an application thereof in treating tumor diseases, belonging to the technical field of pharmaceutical compositions.
  • Maintaining genome stability is essential for maintaining the normal functioning of various organs in the human body.
  • the body has a set of response mechanisms to deal with DNA damage. Mutations in important proteins in the DNA damage pathway, such as BRCA1, BRCA2, and ATM, are associated with cancer susceptibility. These important proteins in the DNA damage response signaling pathway have many feedback controls and cross-responses in the response pathway, making the DNA damage response pathway a complex network system.
  • homologous recombination repair HR uses homologous sister chromatids as templates to synthesize new chains, thereby accurately repairing broken double-stranded DNA.
  • BRCA1 and BRCA2 play an important role in the HR repair pathway. Their gene mutations can significantly weaken the HR repair ability of cells and cause genomic instability.
  • PARP plays an important role in repairing DNA single-strand breaks (SSBs). PARP inhibitors can make it difficult for cells to repair DNA single-strand damage. If the cell has BRCA1 or BRCA2 mutations at this time, the cell cannot repair DNA through the HR repair pathway, which will cause the cell to die due to DNA damage that cannot be repaired. Due to this synthetic lethal mechanism, PARP inhibitors have been approved for the treatment of breast cancer or ovarian cancer with BRCA1 and BRCA2 mutations. However, studies have found that PARP inhibitors can cause drug resistance and reduce efficacy, partly due to the stabilization of DNA replication forks.
  • USP1 is a type of deubiquitinase that can remove ubiquitination modifications on specific proteins. Studies have found that USP1 inhibitors can increase the ubiquitination of PCNA proteins on DNA replication forks, leading to DNA replication fork blockage and reduced replication fork stability. Therefore, USP1 inhibitors can solve the PARP inhibitor resistance caused by DNA replication fork stabilization and enhance the therapeutic effect of PARP inhibitors.
  • WO2023155866A1 describes a compound of formula (I), which has good USP1 inhibitory activity.
  • the present invention provides a pharmaceutical composition of a compound of formula (I) and application thereof in treating tumors with a sensitized PARP inhibitor.
  • the pharmaceutical composition has a good tumor-suppressing effect.
  • the present invention provides a pharmaceutical composition comprising:
  • the compound of formula (I) is:
  • the Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • R 1 and R 9 are each independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;
  • R 2 is selected from
  • R3 and R4 are each independently selected from H, F, Cl, Br, I, methyl, ethyl;
  • R 5 is selected from
  • R 5 is selected from
  • R8 is selected from F, Cl.
  • the compound of formula (I) is selected from one of the following structures:
  • the PARP inhibitor is selected from at least one of Olaparib, Niraparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, BGB-290 or pharmaceutically acceptable salts thereof, preferably at least one of Olaparib, Niraparib, Talazoparib, Veliparib and Rucaparib.
  • the compound of formula (I) is selected from compound 1 of the following structure:
  • the pharmaceutical composition further comprises:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • the content of Compound 1 or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the unit dosage of the pharmaceutical composition is selected from 1 mg-2000 mg, 20 mg-1600 mg, 20 mg-1200 mg, 20 mg-800 mg, 20 mg-400 mg, preferably 20 mg-1600 mg, calculated as C 30 H 33 F 4 N 7 O.
  • the content of Olaparib in the unit dosage of the pharmaceutical composition calculated as C 24 H 23 FN 4 O 3 is selected from 0.1 mg-1000 mg, 1 mg-1000 mg, 10 mg-800 mg, 10 mg-600 mg, 10 mg-400 mg, 10 mg-200 mg, preferably 10 mg-400 mg.
  • the pharmaceutical composition of the present invention has a dosage form selected from tablets, capsules, pills, granules, or injections, and the injections include injection solutions, sterile powders for injection, and concentrated solutions for injection.
  • the present invention also provides the use of the pharmaceutical composition in the preparation of a drug for treating tumor diseases.
  • it can be administered alone or in combination with one or more other anti-tumor drugs;
  • the combined administration is selected from simultaneous administration, independent configuration and co-administration, or independent configuration and sequential administration;
  • the combined administration adopts an administration route selected from oral administration, parenteral administration or transdermal administration, and the parenteral administration is selected from intravenous injection, subcutaneous injection or intramuscular injection;
  • the tumor disease is selected from ovarian cancer, pancreatic cancer, castration-resistant prostate cancer, non-small cell lung cancer, breast cancer and other tumors with homologous recombination repair defects.
  • the present invention also provides a medicine packaging box, which comprises the medicine composition of the present invention.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition in the preparation of anti-tumor drugs:
  • the administration frequency of (i) is once a day, twice a day, once a week or once every two weeks, and the administration frequency of (ii) is once a day, twice a day or once a week;
  • (i) and (ii) may be administered simultaneously or separately in sequence;
  • (i) and (ii) may be formulated independently and co-administered or formulated independently and administered sequentially;
  • preparations made from (i) and (ii) may be co-administered in the same preparation or in separate different preparations.
  • the above application further includes:
  • the (i), (ii) and (iii) can be administered simultaneously or separately in sequence;
  • (i), (ii) and (iii) may be formulated independently and co-administered or formulated independently and administered sequentially.
  • the present invention also provides pharmaceutical compositions of other USP1 inhibitors and PARP inhibitors and their use in treating tumor diseases, wherein the other USP1 inhibitors are selected from KSQ-4279, ISM3091, TNG-438, FT-3171, SJB3-019A, or pharmaceutically acceptable salts thereof; the PARP inhibitors can be selected from Olaparib, Niraparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, BGB-290, or pharmaceutically acceptable salts thereof.
  • the present invention also provides the use of (i) a compound of formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in combination with (ii) a PARP inhibitor for treating cancer,
  • the compound of formula (I) is:
  • Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • R 1 and R 9 are each independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;
  • R 2 is selected from
  • R3 and R4 are each independently selected from H, F, Cl, Br, I, methyl, ethyl;
  • R 5 is selected from
  • R 5 is selected from
  • R8 is selected from F, Cl.
  • the present invention also provides use of (i) a compound of formula (I) or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in combination with (ii) a PARP inhibitor in the preparation of a drug for treating cancer.
  • the compound of formula (I) is:
  • Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • R 1 and R 9 are each independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;
  • R 2 is selected from
  • R3 and R4 are each independently selected from H, F, Cl, Br, I, methyl, ethyl;
  • R 5 is selected from
  • R 5 is selected from
  • R8 is selected from F, Cl.
  • the present invention also provides a method for treating cancer, wherein a therapeutically effective amount of (i) a compound of formula (I) or its stereoisomer, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and (ii) a PARP inhibitor are administered to a patient in combination.
  • the compound of formula (I) is:
  • Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • Cy is selected from The Cy is optionally further substituted with 0 to 4 substituents selected from H, F, Cl, Br, I, cyano, CH 2 F, CHF 2 , CF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy or cyclopropyl;
  • R 1 and R 9 are each independently selected from H, F, Cl, Br, I, cyano, methyl or ethyl;
  • R 2 is selected from
  • R3 and R4 are each independently selected from H, F, Cl, Br, I, methyl, ethyl;
  • R 5 is selected from
  • R 5 is selected from
  • R8 is selected from F, Cl.
  • (i) and (ii) may be formulated independently and co-administered or formulated independently and administered sequentially;
  • the administration frequency of (i) is once a day, twice a day, once a week or once every two weeks, and the administration frequency of (ii) is once a day, twice a day or once a week;
  • (i) and (ii) may be co-administered in the same formulation or in separate different formulations.
  • (i), (ii) and (iii) may be administered simultaneously or separately in sequence;
  • (i), (ii) and (iii) may be independently formulated and co-administered or independently formulated and administered sequentially;
  • (i), (ii) and (iii) may be co-administered in the same formulation or in separate different formulations.
  • the route of administration adopted is selected from oral administration, parenteral administration or transdermal administration, and the parenteral administration is selected from intravenous injection, subcutaneous injection or intramuscular injection;
  • the tumor disease is selected from ovarian cancer, pancreatic cancer, castration-resistant prostate cancer, non-small cell lung cancer, breast cancer and other tumors with homologous recombination repair defects.
  • the PARP inhibitor is selected from at least one of Olaparib, Niraparib, Talazoparib, Veliparib, Rucaparib, CEP-8983, BGB-290 or pharmaceutically acceptable salts thereof, preferably at least one of Olaparib, Niraparib, Talazoparib, Veliparib and Rucaparib.
  • the compound of formula (I) is selected from compound 1 having the following structure:
  • the "combination" is a mode of administration, which refers to the administration of at least one dose of USP1 inhibitor and at least one dose of PARP inhibitor within a certain time period, wherein the administered drugs all show pharmacological effects.
  • the time period may be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 3 weeks, within 1 week or within 24 hours, more preferably within 12 hours.
  • the USP1 inhibitor and the PARP inhibitor or a pharmaceutically acceptable salt thereof may be administered simultaneously or sequentially. This period includes treatments in which the USP1 inhibitor and the PARP inhibitor or a pharmaceutically acceptable salt thereof are administered by the same administration route or different administration routes.
  • the combined administration mode of the present invention selects simultaneous administration, independent configuration and co-administration, or independent configuration and sequential administration.
  • the term “optional” or “optionally” means that the event or environment described later may but need not occur, and the description includes occasions where the event or environment occurs or does not occur.
  • the present invention administers a USP1 inhibitor and a PARP inhibitor or a pharmaceutically acceptable salt thereof in combination, thereby enhancing the anti-tumor activity and improving the therapeutic effect of tumor diseases.
  • USP1 inhibitor and PARP inhibitor or pharmaceutical composition
  • USP1 inhibitor and PARP inhibitor or pharmaceutical composition
  • the combined use of USP1 inhibitor and PARP inhibitor (or pharmaceutical composition) provided by the present invention has significant synergistic effects in both in vitro and in vivo experiments, and is superior to the use of USP1 or PARP inhibitor alone.
  • FIG1 is a graph showing the results of USP1 inhibitors increasing the sensitivity of PARP inhibitors in an MDA-MB-436 cell growth assay in Example 1 of the present invention
  • FIG2 is a graph showing the results of USP1 inhibitors increasing the sensitivity of PARP inhibitors in a CAOV3 cell growth assay in Example 2 of the present invention
  • FIG3A is a graph showing the effect of the test substance in Example 3 of the present invention on the body weight of nude mice bearing human breast cancer MDA-MB-436 cells;
  • FIG3B is a graph showing the effect of the test substance in Example 3 of the present invention on the tumor volume of subcutaneous transplanted tumors of human breast cancer MDA-MB-436 cells.
  • the drug information used in the related research of the present invention is as follows: Compound 1, prepared according to the method described in WO2023155866A1; Olaparib, purchased from Chengdu Huajieming Biotechnology Co., Ltd.
  • This example studies the effect of administering Compound 1 in combination with the PARP inhibitor Olaparib on the growth of the PARP inhibitor-sensitive breast cancer cell line MDA-MB-436.
  • the trial was divided into three groups, including:
  • Control group no drug treatment.
  • Olaparib group cells were treated with different concentrations of Olaparib.
  • Combination group cells were simultaneously administered with different concentrations of compound 1 and different concentrations of Olaparib.
  • USP1 inhibitor compound 1 can significantly enhance the sensitivity of cells to PARP inhibitors.
  • the cell growth inhibition of the combination group was significantly stronger than that of the Olaparib group.
  • the concentration of compound 1 was 63nM and the concentration of Olaparib was 0.4nM
  • the cell growth inhibition rate was 62.75%
  • the concentration of Olaparib was 0.4nM
  • the cell growth inhibition rate was 24.79%.
  • the trial was divided into three groups, including:
  • Control group no drug treatment.
  • Olaparib group cells were treated with different concentrations of Olaparib.
  • Combination group cells were simultaneously administered with different concentrations of compound 1 and different concentrations of Olaparib.
  • Compound 1 group Compound 1 was administered alone at a concentration of 30 mg/kg, once a day.
  • Olaparib group Olaparib was administered alone at a concentration of 50 mg/kg once a day.
  • Combination group I Compound 1 and Olaparib were co-administered at concentrations of 5 mg/kg and 50 mg/kg, respectively, once a day.
  • Combination group II Compound 1 and Olaparib were co-administered at concentrations of 10 mg/kg and 50 mg/kg, respectively, once a day.
  • TGI tumor growth inhibition rate
  • the combination of the USP1 inhibitor of the present invention and the PARP inhibitor has a significant synergistic effect in the subcutaneous transplant tumor model, and the synergistic effect achieves a reduction in drug dosage, showing a strong anti-tumor effect at a significantly lower dose. This result is consistent with the results of in vitro detection of tumor cell lines.

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Abstract

本发明提供一种式(I)所示吡啶并吡唑衍生物药物组合物及其在制备抗肿瘤药物中的应用，所述药物组合物包括式(I)化合物和PARP抑制剂。

Description

一种吡啶并吡唑衍生物药物组合物及其应用 技术领域
本发明涉及一种药物组合物及其应用，具体涉及一种吡啶并吡唑衍生物药物组合物及其在治疗肿瘤疾病中的应用，属于药用组合物技术领域。
背景技术
恶性肿瘤是危害人们生命健康的重大疾病。近年来，随着肿瘤生物学及相关学科的飞速发展，针对肿瘤细胞内异常信号系统靶点的特异性抗肿瘤药物是新药研发的焦点。同时，多种抗肿瘤药物联合用于治疗肿瘤疾病也是科学研究的热点。
保持基因组稳定性对于维持人体各个器官的正常工作至关重要。机体有一套应答机制来应对DNA损伤。DNA损伤通路中的重要蛋白如BRCA1、BRCA2和ATM的突变都与癌症易感性相关DNA损伤应答信号通路中这些重要蛋白在应答通路中存在着许多反馈调控以及交叉应答，使得DNA损伤应答通路成为一个复杂的网络系统。在真核生物中，同源重组修复(Homologous recombination，HR)利用同源的姐妹染色单体为模板进行新链的合成，从而精准的修复断裂的双联DNA。BRCA1及BRCA2在HR修复通路中扮演了重要的作用，其基因突变会显著削弱细胞的HR修复能力，引起基因组不稳定。而PARP在修复DNA单链断裂(SSB)过程中发挥重要作用，PARP抑制剂会导致细胞难以对DNA单链损伤进行修复，而若此时细胞存在BRCA1或BRCA2突变，细胞亦无法通过HR修复通路进行DNA修复，将导致细胞因无法得到修复的DNA损伤而发生死亡。由于此合成致死机制，PARP抑制剂已被批准用于BRCA1、BRCA2突变的乳腺癌或卵巢癌的治疗中。然而研究发现PARP抑制剂会部分因为DNA复制叉稳定化的原因产生耐药，降低疗效。
USP1是一类去泛素酶，可以去除特定蛋白上的泛素化修饰。已有研究发现，USP1抑制剂会导致DNA复制叉上的PCNA蛋白泛素化增加，从而导致DNA复制叉阻滞，降低复制叉的稳定性。因而USP1抑制剂可以解决由DNA复制叉稳定化导致的PARP抑制剂耐药，增强PARP抑制剂的治疗效果。
WO2023155866A1中记载了一种式(I)化合物，该化合物具有良好的USP1抑制活性。
本发明提供一种式(I)化合物的药物组合物及其在增敏PARP抑制剂治疗肿瘤中的应用，该药物组合物具有良好的抑瘤效果。
发明内容
本发明提供一种药物组合物，其包含：
(i)式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶；
(ii)PARP抑制剂；
其中式(I)化合物为：
Cy选自
所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
R2选自
R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
R5选自
或者R5选自
R8选自F、Cl。
优选地，式(I)化合物选自如下结构之一：
在一些实施方案中，所述PARP抑制剂选自Olaparib(奥拉帕尼)、Niraparib(尼拉帕尼)、Talazoparib(他拉唑帕尼)、Veliparib(维利帕尼)、Rucaparib(鲁卡帕尼)、CEP-8983、BGB-290或其药学上可接受的盐中的至少一种，优选Olaparib(奥拉帕尼)、Niraparib(尼拉帕尼)、Talazoparib(他拉唑帕尼)、Veliparib(维利帕尼)、Rucaparib(鲁卡帕尼)中的至少一种。
在一些实施方案中，所述式(I)化合物选自如下结构的化合物1：
在一些实施方案中，所述药物组合物还包含：
(iii)任选地，其它药物活性成分，例如一种或多种抗肿瘤药物；和
(iv)药学上可接受的载体。
进一步地，本发明还提供一种药物组合物，其包含：
(i)化合物1或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
(ii)Olaparib；
(iii)药学上可接受的载体。
在一些实施方案中，所述药物组合物其单位计量中化合物1或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以C30H33F4N7O计的含量选自1mg-2000mg、20mg-1600mg、20mg-1200mg、20mg-800mg、20mg-400mg，优选自20mg-1600mg。
在一些实施方案中，所述药物组合物其单位计量中Olaparib以C24H23FN4O3计的含量选自0.1mg-1000mg、1mg-1000mg、10mg-800mg、10mg-600mg、10mg-400mg、10mg-200mg，优选自10mg-400mg。
本发明所述药物组合物，其剂型选自片剂、胶囊剂、丸剂、颗粒剂、或注射剂，所述注射剂包括注射液、注射用无菌粉末与注射用浓溶液。
本发明还提供所述药物组合物在制备治疗肿瘤疾病药物中的应用，任选地，其可单独给药，或与一种或多种其他抗肿瘤药物联合给药；所述联合给药选自同时给药、独立地配置并共给药或独立地配置并相继给药；所述联合给药采用的给药途径选自经口给药、胃肠外给药或经皮给药，所述胃肠外给药选自静脉注射、皮下注射或肌肉注射；所述肿瘤疾病选自卵巢癌、胰腺癌、去势抵抗前列腺癌、非小细胞肺癌、乳腺癌及其他具有同源重组修复缺陷的肿瘤。
本发明还提供一种药物包装盒，其包括本发明药物组合物。
本发明还提供上述药物组合物在制备抗肿瘤药物中的应用：
任选地，(i)的给药频率为一日一次、一日两次、一周一次或两周一次，(ii)的给药频率为一日一次、一日两次或一周一次；
任选地，(i)和(ii)可同时给药或依次顺序地分开给药；
任选地，(i)和(ii)可独立地配制并共给药或独立地配制并相继给药；
任选地，由(i)和(ii)制成的制剂可以同一制剂形式或以分开的不同制剂形式联合给药。
进一步地，上述应用，其还包括：
(iii)其他抗肿瘤药物；
所述(i)、(ii)和(iii)可同时给药或依次顺序地分开给药；
任选地，(i)、(ii)和(iii)可独立地配制并共给药或独立地配制并相继给药。
本发明还提供其他USP1抑制剂与PARP抑制剂的药物组合物及其在治疗肿瘤疾病中的应用，所述其他USP1抑制剂选自KSQ-4279、ISM3091、TNG-438、FT-3171、SJB3-019A，或其可药用盐；PARP抑制剂可选自Olaparib、Niraparib、Talazoparib、Veliparib、Rucaparib、CEP-8983、BGB-290，或其可药用盐。
本发明还提供(i)式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶与(ii)PARP抑制剂联合用于治疗癌症的用途，
其中式(I)化合物为：
Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
R2选自
R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
R5选自
或者R5选自
R8选自F、Cl。
本发明还提供(i)式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶与(ii)PARP抑制剂联合在制备用于治疗癌症的药物中的用途，
其中式(I)化合物为：
Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
R2选自
R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
R5选自
或者R5选自
R8选自F、Cl。
本发明还提供一种治疗癌症的方法，其中，向患者联合施用治疗有效量的(i)式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶与(ii)PARP抑制剂，
其中式(I)化合物为：
Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
R2选自
R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
R5选自
或者R5选自
R8选自F、Cl。
进一步地，上述用途或方法中，(i)和(ii)可同时给药或依次顺序地分开给药；
任选地，(i)和(ii)可独立地配制并共给药或独立地配制并相继给药；
任选地，(i)的给药频率为一日一次、一日两次、一周一次或两周一次，(ii)的给药频率为一日一次、一日两次或一周一次；
任选地，(i)和(ii)可以同一制剂形式或以分开的不同制剂形式联合给药。
进一步地，上述用途或方法中，(i)、(ii)还可以与(iii)其他抗肿瘤药物联用；
任选地，所述(i)、(ii)和(iii)可同时给药或依次顺序地分开给药；
任选地，(i)、(ii)和(iii)可独立地配制并共给药或独立地配制并相继给药；
任选地，(i)、(ii)和(iii)可以同一制剂形式或以分开的不同制剂形式联合给药。
进一步地，上述用途或方法中，在联合施用时，采用的给药途径选自经口给药、胃肠外给药或经皮给药，所述胃肠外给药选自静脉注射、皮下注射或肌肉注射；所述肿瘤疾病选自卵巢癌、胰腺癌、去势抵抗前列腺癌、非小细胞肺癌、乳腺癌及其他具有同源重组修复缺陷的肿瘤。
进一步地，上述用途或方法中，式(I)化合物选自如下结构之一：
进一步地，上述用途或方法中，所述PARP抑制剂选自Olaparib(奥拉帕尼)、Niraparib(尼拉帕尼)、Talazoparib(他拉唑帕尼)、Veliparib(维利帕尼)、Rucaparib(鲁卡帕尼)、CEP-8983、BGB-290或其药学上可接受的盐中的至少一种，优选Olaparib(奥拉帕尼)、Niraparib(尼拉帕尼)、Talazoparib(他拉唑帕尼)、Veliparib(维利帕尼)、Rucaparib(鲁卡帕尼)中的至少一种。
进一步地，上述用途或方法中，所述式(I)化合物选自如下结构的化合物1：
本发明中，所述的“联合”是一种给药方式，是指一定时间期限内给予至少一种剂量的USP1抑制剂和至少一种剂量的PARP抑制剂，其中给予的药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内、3周内、3周内、1周内或24小时以内，更优选12小时以内。可以同时或依次给予USP1抑制剂以及PARP抑制剂或其可药用盐。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给与USP1抑制剂和PARP抑制剂或其可药用盐。本发明所述联合的给药方式选择同时给药、独立地配置并共给药或独立地配置并相继给药。
本发明中，所述“任选”或“任选地”是指随后所描述地事件或环境可以但不必发生，该说明包括该时间或环境发生或不发生的场合。
本发明将USP1抑制剂和PARP抑制剂或其可药用盐联合给药，从而增强了抗肿瘤活性，以及改善了肿瘤疾病的治疗效果。
缩略语和关键术语定义：
本发明的有益效果：
本发明提供的USP1抑制剂与PARP抑制剂联合用药(或药物组合物)在体外和体内的实验中均具有显著的协同作用，优于USP1或PARP抑制剂单独用药。
附图说明
图1为本发明实施例1MDA-MB-436细胞生长试验中USP1抑制剂增加PARP抑制剂敏感性结果图；
图2为本发明实施例2CAOV3细胞生长试验中USP1抑制剂增加PARP抑制剂敏感性结果图；
图3A为本发明实施例3受试物对人乳腺癌MDA-MB-436细胞荷瘤裸小鼠动物体重的影响结果图；
图3B为本发明实施例3受试物对人乳腺癌MDA-MB-436细胞皮下移植瘤肿瘤体积的影响结果图。
具体实施方式
本发明相关研究采用的药品信息如下：化合物1，按WO2023155866A1中记载的方法制备得到；Olaparib，采购自成都华捷明生物科技有限公司。
实施例1
本实施例研究了施用化合物1与PARP抑制剂Olaparib联用对PARP抑制剂敏感的乳腺癌细胞株MDA-MB-436生长的影响。
试验分为三组，包括：
对照组：不进行药物处理。
Olaparib组：细胞施用不同浓度的Olaparib进行处理。
联用组：细胞同时施用了不同浓度的化合物1与不同浓度的Olaparib。
实验结果如附图1所示，USP1抑制剂化合物1可以显著增强细胞对PARP抑制剂的敏感性。相同化合物1浓度下，联用组的细胞生长抑制显著强于Olaparib组。例如当化合物1浓度为63nM时，Olaparib浓度为0.4nM时，细胞生长抑制率为62.75％，而在Olaparib组中，Olaparib浓度为0.4nM时，细胞生长抑制率为24.79％。
由此可见，USP1抑制剂化合物1与PARP抑制剂的联用，可以显著增强肿瘤细胞对PARP抑制剂的敏感性。
实施例2
本实施例研究了施用化合物1与Olaparib联用对PARP抑制剂耐药的卵巢癌细胞株CAOV3生长的影响。
试验分为三组，包括：
对照组：不进行药物处理。
Olaparib组：细胞施用不同浓度的Olaparib进行处理。
联用组：细胞同时施用了不同浓度的化合物1与不同浓度的Olaparib。
实验结果如附图2所示，USP1抑制剂化合物1可以显著增强细胞对PARP抑制剂的敏感性。相同化合物1浓度下，联用组的细胞生长抑制显著强于Olaparib组。例如当化合物1浓度为8nM时，Olaparib浓度为938nM时，细胞生长抑制率为84.5％，而在Olaparib组中，Olaparib浓度为938nM时，细胞生长抑制率为25.84％。
由此可见，USP1抑制剂化合物1与PARP抑制剂的联用，可以显著增强肿瘤细胞对PARP抑制剂的敏感性。这一结果与在MDA-MB-436细胞株中的结果一致。
实施例3
化合物1与Olaparib联合用药对人乳腺癌MDA-MB-436细胞荷瘤裸小鼠皮下移植瘤的药效作用研究。
试验分为如下五组：
对照组：不进行药物处理。
化合物1组：单独施用化合物1，浓度为30mg/kg，一天一次。
Olaparib组：单独施用Olaparib，浓度为50mg/kg，一天一次。
联用组I：联合施用化合物1和Olaparib，浓度分别为5mg/kg和50mg/kg，分别一天一次给药。
联用组II：联合施用化合物1和Olaparib，浓度分别为10mg/kg和50mg/kg，分别一天一次给药。
1)受试物对人乳腺癌MDA-MB-436细胞荷瘤裸小鼠动物体重的影响
在整个试验周期内，动物行为正常。溶剂组与化合物1和Olaparib单独施用组及联合用药组体重无明显下降，无明显由于联用导致的毒性。详细结果见附图3A。
2)受试物对人乳腺癌MDA-MB-436细胞皮下移植瘤肿瘤体积的影响
结果如附图3B所示，与对照组相比，单独施用化合物1或Olaparib，小鼠肿瘤生长速度有一定程度下降；而两种药物化合物1和Olaparib联合用药，可以更加有效的抑制肿瘤生长，联合用药后小鼠的肿瘤生长受到显著的抑制，5mg/kg或10mg/kg化合物1与50mg/kg Olaparib联用的肿瘤生长抑制率(TGI)分别为89.6％和99.0％，几乎完全抑制肿瘤生长。
因此，本发明的USP1抑制剂与PARP抑制剂联用在皮下移植瘤模型中具有显著的协同作用，并通过协同效应实现了药物剂量的降低，在明显更低的剂量下即展现出强劲的抗肿瘤作用。这一结果与肿瘤细胞株体外检测的结果是一致的。

Claims (14)

  1. 一种药物组合物，其包含：
    (i)式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶；
    (ii)PARP抑制剂；
    其中式(I)化合物为：
    Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
    R2选自
    R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
    R5选自
    或者R5选自
    R8选自F、Cl。
  2. 如权利要求1所述的药物组合物，其进一步包含：
    (iii)任选地，其它药物活性成分，例如一种或多种抗肿瘤药物；和
    (iv)药学上可接受的载体。
  3. 如权利要求1或2所述的药物组合物，所述PARP抑制剂选自奥拉帕尼、尼拉帕尼、他拉唑帕尼、维利帕尼、鲁卡帕尼、CEP-8983、BGB-290或其药学上可接受的盐中的至少一种，优选自奥拉帕尼、尼拉帕尼、他拉唑帕尼、维利帕尼、鲁卡帕尼中的至少一种。
  4. 如权利要求1-3中任一项所述的药物组合物，所述式(I)化合物选自化合物1：
  5. 如权利要求4所述的药物组合物，其包含：
    (i)化合物1或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，
    (ii)奥拉帕尼；
    (iii)药学上可接受的载体。
  6. 如权利要求5所述的组合物，单位计量中化合物1或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶以C30H33F4N7O计的含量选自1mg-2000mg、20mg-1600mg、20mg-1200mg、20mg-800mg、20mg-400mg，优选自20mg-1600mg。
  7. 如权利要求5所述的组合物，单位计量中奥拉帕尼以C24H23FN4O3计的含量选自0.1mg-1000mg、1mg-1000mg、10mg-800mg、10mg-600mg、10mg-400mg、10mg-200mg，优选自10mg-400mg。
  8. 如权利要求1-7中任一项所述的组合物，其剂型选自片剂、胶囊剂、丸剂、颗粒剂、或注射剂，所述注射剂包括注射液、注射用无菌粉末与注射用浓溶液。
  9. 权利要求1-8中任一项所述组合物在制备治疗肿瘤疾病药物中的应用；其可单独给药，或与一种或多种其他抗肿瘤药物联合给药；所述联合给药选自同时给药、独立地配置并共给药或独立地配置并相继给药；所述联合给药采用的给药途径选自经口给药、胃肠外给药或经皮给药，所述胃肠外给药选自静脉注射、皮下注射或肌肉注射；所述肿瘤疾病选自卵巢癌、胰腺癌、去势抵抗前列腺癌、非小细胞肺癌、乳腺癌及其他具有同源重组修复缺陷的肿瘤。
  10. 如权利要求9所述的应用：
    任选地，(i)的给药频率为一日一次、一日两次、一周一次或两周一次，(ii)的给药频率为一日一次、一日两次或一周一次；
    任选地，(i)和(ii)可同时给药或依次顺序地分开给药；
    任选地，(i)和(ii)可独立地配制并共给药或独立地配制并相继给药；
    任选地，由(i)和(ii)制成的制剂可以同一制剂形式或以分开的不同制剂形式联合给药。
  11. 一种药物包装盒，其包括权利要求1-8中任一项所述的药物组合物。
  12. 式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶与PARP抑制剂联合用于治疗癌症的用途，
    其中式(I)化合物为：
    Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
    R2选自
    R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
    R5选自
    或者R5选自
    R8选自F、Cl。
  13. 式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶与PARP抑制剂联合在制备用于治疗癌症的药物中的用途，
    其中式(I)化合物为：
    Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
    R2选自
    R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
    R5选自
    或者R5选自
    R8选自F、Cl。
  14. 一种治疗癌症的方法，其中，向患者联合施用治疗有效量的式(I)化合物或其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶与PARP抑制剂，
    其中式(I)化合物为：
    Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    或者Cy选自 所述的Cy任选进一步被0至4个选自H、F、Cl、Br、I、氰基、CH2F、CHF2、CF3、甲基、乙基、丙基、异丙基、甲氧基、乙氧基或环丙基的取代基所取代；
    R1和R9各自独立地选自H、F、Cl、Br、I、氰基、甲基或乙基；
    R2选自
    R3和R4各自独立地选自H、F、Cl、Br、I、甲基、乙基；
    R5选自
    或者R5选自
    R8选自F、Cl。
PCT/CN2024/141727 2023-10-25 2024-12-24 一种吡啶并吡唑衍生物药物组合物及其应用 Pending WO2025087460A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115066235A (zh) * 2020-02-14 2022-09-16 Ksq治疗公司 包含泛素特异性加工蛋白酶1(usp1)抑制剂和多聚(adp-核糖)聚合酶(parp)抑制剂的治疗组合
WO2023155866A1 (zh) * 2022-02-18 2023-08-24 四川海思科制药有限公司 一种吡唑并吡啶衍生物及其在医药上的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115066235A (zh) * 2020-02-14 2022-09-16 Ksq治疗公司 包含泛素特异性加工蛋白酶1(usp1)抑制剂和多聚(adp-核糖)聚合酶(parp)抑制剂的治疗组合
WO2023155866A1 (zh) * 2022-02-18 2023-08-24 四川海思科制药有限公司 一种吡唑并吡啶衍生物及其在医药上的应用

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