WO2024017305A1 - 含氰基取代的大环类化合物的用途 - Google Patents

含氰基取代的大环类化合物的用途 Download PDF

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WO2024017305A1
WO2024017305A1 PCT/CN2023/108205 CN2023108205W WO2024017305A1 WO 2024017305 A1 WO2024017305 A1 WO 2024017305A1 CN 2023108205 W CN2023108205 W CN 2023108205W WO 2024017305 A1 WO2024017305 A1 WO 2024017305A1
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drug
substance
formula
mass ratio
intracranial
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李永国
隗维
叶未
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广州嘉越医药科技有限公司
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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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • the invention belongs to the technical field of biomedicine, and specifically relates to the use of a cyano-substituted macrocyclic compound.
  • Glioma also known as glioblastoma, is the most common primary central nervous system tumor, accounting for approximately half of all intracranial primary tumors. Glioma is a primary tumor of the central nervous system with the highest incidence rate (annual incidence rate is about 3 to 8 people per 100,000 population) and mortality rate (5-year survival rate is less than 3% to 7%). Patients with glioma may experience symptoms such as headaches, personality changes, nausea, and stroke-like symptoms. Symptoms often worsen rapidly, and in severe cases, they may develop unconsciousness. Gliomas often relapse despite intensive treatment, and the typical survival period after diagnosis is 12 to 15 months. Without treatment, survival is short, usually only 3 months.
  • ROS1 inhibitors currently in clinical use are multi-kinase inhibitors, which have strong inhibition of ALK and/or Trk kinases, but do not have highly selective inhibition of ROS1. It has been clinically proven that ALK inhibitors generally have target-related side effects such as pulmonary toxicity (such as interstitial lung disease), and Trk inhibitors generally have neurological-related target side effects (such as abnormal taste, cognitive impairment, dizziness, and coma). disorders, weight gain, mood disorders, sleep disorders and pain after drug withdrawal, etc.) (Liu D, Flory J, Lin A, et al. Characterization of on-target adverse events caused by TRK inhibitor therapy. Annals of Oncology. 2020, 31 (9):1207-1215.).
  • target-related side effects such as pulmonary toxicity (such as interstitial lung disease)
  • Trk inhibitors generally have neurological-related target side effects (such as abnormal taste, cognitive impairment, dizziness, and coma). disorders, weight gain, mood disorders, sleep disorders and pain after drug withdrawal, etc
  • Entritinib has a strong inhibitory effect on Trk kinase.
  • Trk kinase In the STARTRK (355 patients) clinical trial, there were multiple side effects related to the nervous system. The most common side effects included loss of taste (44%), dizziness (38%), and hypoesthesia. (34%) and cognitive impairment (27%), among which cognitive impairment of grade three or above reaches (4.5%) (https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf). Similar to entritinib, the most common side effects of TPX-0005 in the TRIDENT-1 clinical trial were dizziness (62%) and loss of taste (33%) (BCCho et al.
  • the technical problem to be solved by the present invention is that existing drugs for treating ROS1 fused intracranial tumors have strong side effects.
  • the present invention provides the use of cyano-substituted macrocyclic compounds, which compounds can treat and/or prevent intracranial tumors. Furthermore, the compound of the present invention has high safety in treating and/or preventing intracranial tumors.
  • the present invention provides the use of substance A in the preparation of medicines.
  • the substance A is a compound shown in formula I or a pharmaceutically acceptable salt thereof;
  • the medicine is a medicine for treating and/or preventing intracranial tumors;
  • the intracranial tumor may be a ROS1 fused intracranial tumor.
  • the intracranial tumor may be a neuroglioma and/or a non-small cell brain metastasis, such as a ROS1 fusion neuroglioma or a ROS1 fusion non-small cell brain metastasis.
  • the drug includes substance A and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier can be a conventional carrier in the art.
  • the administration frequency of the drug may be 1 time/day, 2 times/day or 3 times/day.
  • the drug may be administered orally.
  • the dosage form of the drug may be a conventional dosage form in this field.
  • the concentration of the compound represented by Formula I in the drug can be 0.5-1.5 mg/mL; preferably, it is 0.5 mg/mL or 1.5 mg/mL.
  • the unit dose of the drug can be determined according to the effective dose of the subject/patient.
  • the unit dose of the substance A can be 10-600 mg, such as 10 mg, 40 mg, 100 mg, 200 mg, 250 mg, 300 mg. , 400mg or 600mg.
  • the single dose of the drug can be determined according to the actual therapeutic effect of the subject/patient.
  • the single dose of the drug is the substance A.
  • the mass ratio may be 1.8-30 mg/kg, preferably 5-15 mg/kg, such as 5 mg/kg or 15 mg/kg.
  • the daily dose of the drug can be determined according to the actual therapeutic effect of the subject/patient.
  • the daily dose of the drug is the substance A.
  • the mass ratio of the subject/patient the mass ratio may be 1.8-120 mg/kg, preferably 10-30 mg/kg, such as 10 mg/kg or 30 mg/kg.
  • the mass fraction of the compound represented by Formula I in the drug is 5-80%, preferably 5-50%.
  • the present invention also provides a pharmaceutical composition, which includes substance A and a pharmaceutically acceptable carrier; the substance A is a compound shown in Formula I or a pharmaceutically acceptable salt thereof;
  • the mass fraction of the compound represented by formula I is 5-80%.
  • the mass fraction of the compound represented by formula I may be 5-50%.
  • the present invention also provides the use of the pharmaceutical composition as described above in the preparation of drugs for treating and/or preventing intracranial tumors.
  • the intracranial tumor is a ROS1 fusion intracranial tumor.
  • the intracranial tumor is a neuroglioma and/or a non-small cell brain metastasis, such as a ROS1 fusion neuroglioma or a ROS1 fusion non-small cell brain metastasis.
  • a neuroglioma and/or a non-small cell brain metastasis such as a ROS1 fusion neuroglioma or a ROS1 fusion non-small cell brain metastasis.
  • the present invention also provides a drug method for treating and/or preventing intracranial tumors.
  • the method includes: administering a therapeutically effective amount of substance A or a drug to a subject/patient, and the drug includes substance A and a pharmaceutically acceptable drug.
  • Acceptable carrier; the substance A is a compound shown in Formula I or a pharmaceutically acceptable salt thereof;
  • the intracranial tumor may be a neuroglioma and/or a non-small cell brain metastasis, such as a ROS1 fusion neuroglioma or a ROS1 fusion non-small cell brain metastasis.
  • the intracranial tumor may be a ROS1 fused intracranial tumor.
  • the pharmaceutically acceptable carrier can be a conventional carrier in the art.
  • the administration frequency of the drug may be 1 time/day, 2 times/day or 3 times/day.
  • the drug may be administered orally.
  • the dosage form of the drug can be a conventional dosage form in this field.
  • the concentration of the compound represented by Formula I in the drug can be 0.5-1.5 mg/mL; preferably, it is 0.5 mg/mL or 1.5 mg/mL.
  • the unit dose of the drug can be determined according to the effective dose of the subject/patient.
  • the unit dose of the substance A can be 10-600 mg, such as 10 mg, 40 mg, 100 mg, 200 mg, 250 mg, 300 mg. , 400mg or 600mg.
  • the single dose of the drug can be determined according to the actual therapeutic effect of the subject/patient.
  • the single dose of the drug is the substance A.
  • the mass ratio may be 1.8-30 mg/kg, preferably 5-15 mg/kg, such as 5 mg/kg or 15 mg/kg.
  • the daily dose of the drug can be determined according to the actual therapeutic effect of the subject/patient.
  • the daily dose of the drug is the substance A.
  • the mass ratio may be 1.8-120 mg/kg, preferably 10-30 mg/kg, such as 10 mg/kg or 30 mg/kg.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases wait. These matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine. Additional information regarding vectors may be found in Remington: The Science and Practice of Pharmacy, 21 st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • treatment refers to therapeutic therapy.
  • treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that causes or causes the condition or (b) ) one or more biological manifestations of a condition, (3) amelioration of one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slow the progression of a condition or one or more biological manifestations of a condition.
  • prevention refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • terapéuticaally effective amount refers to an amount of a compound sufficient to effectively treat a disease or condition described herein when administered to a patient.
  • the “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted as necessary by one skilled in the art.
  • patient refers to any animal, preferably mammals, most preferably humans, to which a compound is or has been administered in accordance with embodiments of the present invention.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the compounds of the present invention can treat and/or prevent intracranial tumors. Furthermore, the compound of the present invention has high safety in treating and/or preventing intracranial tumors.
  • Figure 1 is Example 1, a survival curve diagram during the drug efficacy test in mice
  • Figure 2 is Example 1, the percentage change in body weight of mice during the in vivo drug efficacy test in mice.
  • DMSO purchased from Sigma
  • FBS purchased from GIBCO
  • PRMI1640 purchased from GIBCO
  • Trypsin purchased from GIBCO
  • Cell culture Cells are cultured in a monolayer in vitro.
  • the culture conditions are RPMI1640 medium plus 10% fetal calf serum, 100U/mL penicillin and 100ug/mL streptomycin, 37°C, 5% CO 2 , 95% relative humidity.
  • the cells were cultured under low temperature and digested with trypsin twice a week for passage. When the cells were in the logarithmic growth phase, the digested cells were used for inoculation.
  • mice BALB/c nude mice (Beijing Huafukang Biotechnology Co., Ltd.), female, 6-8 weeks old (the age of mice when tumor cells were inoculated), weighing 18-20g, 32 in total.
  • Tumor inoculation Place 0.2 mL of BAF3-GOPC-ROS1 cell suspension with a processed cell concentration of 2.5 ⁇ 10 7 cells/ml on ice, pipet until uniform, and fix the mouse on the mouse brain stereotaxic apparatus. , use a microsyringe to inoculate 2 ⁇ L of cell suspension into the mouse brain, 5 ⁇ 10 4 cells/mouse.
  • the subjects were randomly divided into groups on the seventh day after vaccination. The administration and treatment after grouping are as follows in Table 1.
  • Solvent 10% DMSO (the volume of DMSO accounts for the percentage of the volume of the solution) + 10% solutol (the volume of polyethylene glycol-15 hydroxystearate accounts for the percentage of the volume of the solution) + 80% water;
  • mice treated with compound I were longer than that of mice treated with TPX-0005.
  • the median survival period of mice in each treatment group and solvent control group is shown in Table 2.
  • compound I significantly prolonged the minimum survival period and improved the survival rate of mice at the end of the experiment. As shown in table 2.
  • test compound I has a significant inhibitory effect on the growth of BAF3-GOPC-ROS1 intracranial brain orthotopic transplantation tumors in nude mice, and significantly prolongs the median survival period of mice.
  • Compound I has a better tumor inhibition tendency compared with TPX-0005.
  • a patient with lung adenocarcinoma who was diagnosed by pathology was confirmed to have a ROS1 gene fusion mutation by NGS testing.
  • This patient was previously resistant to multiple lines of treatment, such as first-line icotinib, second-line crizotinib, third-line pemetrexed combined with carboplatin, and fourth-line fororitinib succinate, among which crizotinib and crizotinib were combined.
  • Foritinib diacid is an inhibitor targeting ROS1.
  • Subjects who have become resistant to multiple lines of therapy will participate in a Phase I clinical study of the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of Compound I in patients with ROS1 gene fusion-positive locally advanced/metastatic solid tumors. .
  • vital signs, physical examination, ECOG physical score, infectious disease markers, blood routine, urine routine, coagulation function, liver function, kidney function, electrolytes, fasting blood glucose, blood lipids, 12-lead electrocardiogram and other examinations are eligible for inclusion. condition.
  • the location and size of the target lesions determined by imaging before enrollment were (1) right upper lung, with a diameter of 15mm, (2) left upper lung, with a diameter of 15.5mm; (3) lymph nodes (right neck), with a diameter of 25.4mm, (4) ) lymph node (in front of the superior vena cava), with a diameter of 28.5mm, (5) brain (left frontal lobe) 13.6mm, with a total diameter of 97.8mm.
  • the specific administration method was as follows: Compound I tablets, taken orally on an empty stomach, once a day, 300 mg each time, continuously. And perform vital signs, physical examination, routine blood tests, routine urine tests, liver function, kidney function, electrolytes, and fasting every week (within the first month after taking the medicine) or every two weeks (after the first month after taking the medicine).

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Abstract

本发明公开了一种含氰基取代的大环类化合物的用途。本发明提供一种物质A在制备药物中的应用，所述物质A为如式Ⅰ所示化合物或其药学上可接受的盐；所述药物为治疗和/或预防颅内肿瘤的药物；如式Ⅰ所示化合物治疗和/或预防颅内肿瘤安全性高。

Description

含氰基取代的大环类化合物的用途
本申请要求申请日为2022/7/20的中国专利申请2022108617733的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明属于生物医药技术领域，具体涉及一种含氰基取代的大环类化合物的用途。
背景技术
神经脑胶质瘤(glioma)简称胶质瘤，也称为胶质细胞瘤，是最常见的原发性中枢神经系统肿瘤，约占所有颅内原发肿瘤的一半。胶质瘤是发病率(年发病率约为3～8人/10万人口)、病死率(5年生存率小于3％～7％)最高的一种中枢神经系统原发性肿瘤。神经胶质瘤患者可能会出现头痛、人格改变、觉得恶心、有类似中风的等症状，且症状通常会快速加重，严重者还可能会发展为意识不清。神经胶质瘤在全力治疗下仍通常会复发，确诊后的典型生存期为12～15个月。在未经治疗的情况下，生存期短，通常仅剩3个月。
目前所有临床上的ROS1抑制剂都是多激酶抑制剂，对ALK和/或Trk激酶有强抑制，但对ROS1无高选择性抑制。而临床证实ALK抑制剂普遍有肺毒性等靶点相关的毒副作用(例间质性肺病)，Trk抑制剂普遍存在神经相关的靶点毒副作用(例味觉异常、认知障碍、头晕、共济失调、体重增加、情绪障碍、睡眠障碍和停药后疼痛等)(Liu D,Flory J,Lin A,et al.Characterization of on-target adverse events caused by TRK inhibitor therapy.Annals of Oncology.2020,31(9):1207-1215.)。Entritinib对Trk激酶有强抑制作用，在STARTRK(355个病人)临床实验中，存在多个与神经系统相关的副作用，最常见的副作用包括味觉丧失(44％)、头晕(38％)、感觉迟钝(34％) 和认知障碍(27％)等，其中三级以上认知障碍达到(4.5％)(https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212725s000lbl.pdf)。与Entritinib相似，TPX-0005在TRIDENT-1临床实验中，最常见的副作用为头晕(62％)和味觉丧失(33％)等(B.C.Cho et al.MA11.07 Phase 1/2 TRIDENT-1 Study of Repotrectinib in Patients with ROS1+or NTRK+Advanced Solid Tumors,Journal of Thoracic Oncology Vol.16No.3S)。对于ROS1基因融合的病人来说，除了需要承担靶点相关的副作用外，还需要额外承担由于脱靶带来的副作用，这将会影响到治疗效果和病人体验。
因此对于ROS1基因融合的神经脑胶质瘤的临床治疗，迫切需要一类能降低药物副作用的有效化合物。
发明内容
本发明所要解决的技术问题是现有治疗ROS1融合颅内肿瘤的药物副作用强。本发明提供了含氰基取代的大环类化合物的用途，该类化合物能够治疗和/或预防颅内肿瘤。进一步，本发明的化合物治疗和/或预防颅内肿瘤安全性高。
本发明提供了一种物质A在制备药物中的应用，所述物质A为如式Ⅰ所示化合物或其药学上可接受的盐；所述药物为治疗和/或预防颅内肿瘤的药物；
所述应用中，所述颅内肿瘤可为ROS1融合颅内肿瘤。
所述应用中，所述颅内肿瘤可为神经脑胶质瘤和/或非小细胞脑转移瘤，例如ROS1融合神经脑胶质瘤或ROS1融合非小细胞脑转移瘤。
所述应用中，所述药物包含物质A和药学上可接受的载体。
所述应用中，所述药学上可接受的载体可为本领域常规载体。
所述应用中，所述药物的施用频率可为1次/日、2次/日或3次/日。
所述应用中，所述药物可经口服施用。
所述应用中，所述药物的剂型可为本领域常规剂型。
所述应用中，所述如式Ⅰ所示化合物在药物中的浓度可为0.5-1.5mg/mL；优选为0.5mg/mL或1.5mg/mL。
所述应用中，所述药物的单位剂量可根据受试者/患者的起效量来确定，所述物质A的单位剂量可为10-600mg，例如10mg、40mg、100mg、200mg、250mg、300mg、400mg或600mg。
所述应用中，每次施用所述药物时，所述药物的单次剂量可根据受试者/患者的实际治疗效果来确定，较佳地，所述药物的单次剂量为所述物质A与受试者/患者的质量比，所述质量比可为1.8-30mg/kg，优选为5-15mg/kg，例如5mg/kg或15mg/kg。
所述应用中，每次施用所述药物时，所述药物的日用剂量可根据受试者/患者的实际治疗效果来确定，较佳地，所述药物的日用剂量为所述物质A与受试者/患者的质量比，所述质量比可为1.8-120mg/kg，优选为10-30mg/kg，例如10mg/kg或30mg/kg。
所述应用中，所述如式Ⅰ所示化合物占所述药物的质量分数为5-80％，优选为5-50％。
本发明还提供一种药物组合物，其包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物或其药学上可接受的盐；
所述如式Ⅰ所示化合物的质量分数为5-80％。
所述药物组合物中，所述如式Ⅰ所示化合物的质量分数可为5-50％。
本发明还提供一种如前所述药物组合物在制备治疗和/或预防颅内肿瘤的药物中的应用。
较佳地，所述颅内肿瘤为ROS1融合颅内肿瘤。
较佳地，所述颅内肿瘤为神经脑胶质瘤和/或非小细胞脑转移瘤，例如ROS1融合神经脑胶质瘤或ROS1融合非小细胞脑转移瘤。
本发明还提供了一种治疗和/或预防颅内肿瘤的药物的方法，所述方法包括：向受试者/患者施用治疗有效量物质A或药物，所述药物包含物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物或其药学上可接受的盐；
所述方法中，所述颅内肿瘤可为神经脑胶质瘤和/或非小细胞脑转移瘤，例如ROS1融合神经脑胶质瘤或ROS1融合非小细胞脑转移瘤。
所述方法中，所述颅内肿瘤可为ROS1融合颅内肿瘤。
所述方法中，所述药学上可接受的载体可为本领域常规载体。
所述方法中，所述药物的施用频率可为1次/日、2次/日或3次/日。
所述方法中，所述药物可经口服施用。
所述方法中，所述药物的剂型可为本领域常规剂型。
所述方法中，所述如式Ⅰ所示化合物在药物中的浓度可为0.5-1.5mg/mL；优选为0.5mg/mL或1.5mg/mL。
所述方法中，所述药物的单位剂量可根据受试者/患者的起效量来确定，所述物质A的单位剂量可为10-600mg，例如10mg、40mg、100mg、200mg、250mg、300mg、400mg或600mg。
所述方法中，每次施用所述药物时，所述药物的单次剂量可根据受试者/患者的实际治疗效果来确定，较佳地，所述药物的单次剂量为所述物质A与受试者/患者的质量比，所述质量比可为1.8-30mg/kg，优选为5-15mg/kg，例如5mg/kg或15mg/kg。
所述方法中，每次施用所述药物时，所述药物的日用剂量可根据受试者/患者的实际治疗效果来确定，较佳地，所述药物的日用剂量为所述物质A与受试者/患者的质量比，所述质量比可为1.8-120mg/kg，优选为10-30mg/kg，例如10mg/kg或30mg/kg。
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、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，适用于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。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质 等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化，但可由本领域技术人员根据需要进行调整。
术语“患者”是指根据本发明的实施例，即将或已经接受了该化合物给药的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：
本发明化合物能够治疗和/或预防颅内肿瘤。进一步，本发明的化合物治疗和/或预防颅内肿瘤安全性高。
附图说明
图1为实施例1，小鼠体内药效测试过程中的生存曲线图；
图2为实施例1，小鼠体内药效测试过程中小鼠的体重变化百分率。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
实施例1化合物在小鼠体内的药效测试
实验目的：评价测试药对BaF3-GOPC-ROS1细胞在Balb/c裸小鼠颅内脑原位的抗肿瘤作用，并研究对小鼠生存期的影响。
实验材料：DMSO(购于Sigma)、FBS(购于GIBCO)、PRMI1640(购于GIBCO)、Trypsin(购于GIBCO)。
实验模型：BaF3-GOPC-ROS1细胞在Balb/c裸小鼠颅内脑原位模型。
实验方法：
细胞培养：细胞体外单层培养，培养条件为RPMI1640培养基中加10％胎牛血清，100U/mL的青霉素和100ug/mL的链霉素，37℃，5％CO2，95％相对湿度条件下培养，一周两次用胰酶消化传代，当细胞处于对数生长期时，消化细胞用于接种。
实验动物：BALB/c裸小鼠(北京华阜康生物科技股份有限公司)，雌性，6-8周(肿瘤细胞接种时的小鼠周龄)，体重18-20g，共32只。
肿瘤接种：将处理好的细胞浓度为2.5×107细胞/毫升的BAF3-GOPC-ROS1细胞悬液0.2mL，置于冰上，吹打至均匀，将小鼠固定在小鼠脑立体定位仪上，用微量注射器在小鼠脑部接种2μL细胞悬液，5×104细胞/只。接种第七天后随机分组，分组后给药处理如下表1。
表1小鼠的给药情况

备注：
溶媒：10％DMSO(DMSO体积占溶液的体积的百分数)+10％solutol(聚乙二醇-15羟基硬脂酸酯的体积占溶液体积的百分数)+80％水；
实验结果：
1)化合物Ⅰ在5mg/kg和15mg/kg剂量下平均中位生存期都大于49天，与对照组相比，均显著延长小鼠中位生存期(P＝0.032和P＝0.007)。
2)TPX-0005组的平均中位生存期为45天，与溶剂对照组相比有延长小鼠中位生存期的趋势，但无统计学意义(0.177)。此外，化合物Ⅰ处理后的小鼠中位生存期长于TPX-0005处理后小鼠，各治疗组和溶剂对照组小鼠中位生存期情况见表2。
3)在给药终点时，与对照组相比，TPX-0005处理后小鼠体重显著下降，平均体重变化百分率为-11.48％(P<0.05)，而化合物Ⅰ(5mg/kg和15mg/kg)处理后的小鼠体重下降少，平均体重变化百分率分别为-4.99％(P＝0.254)和-0.81％(P<0.05)。与TPX-0005相比，化合物Ⅰ明显延长最短生存期和提高实验终点时小鼠存活率。如表2所示。
表2.小鼠中位生存期

表3小鼠体重变化率
实验结论：受试物化合物Ⅰ对裸鼠BAF3-GOPC-ROS1颅内脑原位移植瘤的生长有显著抑制作用，并显著延长小鼠的生存中位期。在该脑原位小鼠模型中，与TPX-0005相比，化合物Ⅰ具有更优的抑癌趋势。
从小鼠体重变化百分率来看，化合物Ⅰ在两个剂量(5mg/kg和15mg/kg)下，小鼠的体重略有减少；而对照化合物TPX-0005在3mg/kg剂量下表现出体重的逐步下降以及不可耐受趋势。结果表明相比于TPX-0005(3mg/kg)，化合物Ⅰ的安全性更高。如图2所示。
从最短生存时间和实验终点时存活小鼠的数量来看，化合物Ⅰ在两个剂 量(5mg/kg和15mg/kg)下，最短存活时间要明显长于溶剂对照组和TPX-005组，实验完成时小鼠存活率相比于对照组也高很多，如图1所示。说明化合物Ⅰ对裸鼠BAF3-GOPC-ROS1颅内脑原位移植瘤的生长有显著抑制作用。
实施例2
经病理学明确诊断的一例肺腺癌患者，NGS检测明确为ROS1基因融合突变。该患者既往经过多线治疗耐药，如一线埃克替尼，二线克唑替尼，三线培美曲塞联用卡铂，四线丁二酸复瑞替尼，其中克唑替尼与丁二酸复瑞替尼为靶向ROS1的抑制剂。受试者多线治疗耐药后参加化合物Ⅰ在ROS1基因融合阳性局部晚期/转移性实体瘤患者中安全性、耐受性、药代动力学特征及初步有效性的I期临床研究的临床试验。基线期进行生命体征、体格检查、ECOG体力评分、感染性疾病标志物、血常规、尿常规、凝血功能、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查符合入组条件。入组前影像学确定靶病灶位置与大小为(1)右上肺，直径为15mm，(2)左上肺，直径为15.5mm；(3)淋巴结(右颈部)，直径为25.4mm，(4)淋巴结(上腔静脉前)，直径为28.5mm，(5)脑(左侧额叶)13.6mm，总直径为97.8mm。
受试者接受化合物Ⅰ单药治疗后，具体给药方法如下：化合物Ⅰ片，空腹口服，每日1次，每次300mg，连续给药。并于每周(服药后第一个月内)或每两周(服药后第一个月以后)进行生命体征、体格检查、血常规检查、尿常规检查、肝功能、肾功能、电解质、空腹血糖、血脂、12导联心电图等检查，用药期间无出现任何严重副作用；经化合物Ⅰ单药治疗后，影像学肿瘤评估，(1)右上肺，直径为8.5mm，(2)左上肺，直径为10.5mm；(3)淋巴结(右颈部)，直径为19.9mm，(4)淋巴结(上腔静脉前)，直径为26.5mm，(5)脑(左侧额叶)8.7mm，总直径为74.1mm。与基线比较，肿瘤总体直径缩小24.2％，脑部肿瘤转移灶总体直径缩小36％。
该研究表明，化合物Ⅰ可以缩小脑转移肺腺癌患者的整体肿瘤体积，尤其是脑部的肿瘤体积。此外，患者未表现出任何严重副作用。综上说明，对于有脑转移的ROS1融合突变的肺腺癌患者，化合物Ⅰ的治疗有临床获益(表现出有效性，且安全性高)。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不违背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (11)

  1. 一种物质A在制备药物中的应用，其特征在于，所述物质A为如式Ⅰ所示化合物或其药学上可接受的盐；所述药物为治疗和/或预防颅内肿瘤的药物；
  2. 如权利要求1所述应用，其特征在于，
    所述颅内肿瘤为ROS1融合颅内肿瘤，
    和/或，所述颅内肿瘤为神经脑胶质瘤和/或非小细胞脑转移瘤，例如ROS1融合神经脑胶质瘤或ROS1融合非小细胞脑转移瘤。
  3. 如权利要求1所述应用，其特征在于，所述应用满足如下条件中的一种或多种：
    ①所述药物包含物质A和药学上可接受的载体；
    ②所述药物的施用频率为1次/日、2次/日或3次/日；
    ③所述药物经口服施用；
    ④所述物质A的单位剂量为10-600mg，例如10mg、40mg、100mg、200mg、250mg、300mg、400mg或600mg；
    和⑤所述如式Ⅰ所示化合物在药物中的浓度为0.5-1.5mg/mL；优选为0.5mg/mL或1.5mg/mL。
  4. 如权利要求1-3任一项所述应用，其特征在于，所述应用中，
    所述药物的单次剂量为所述物质A与受试者/患者的质量比，所述质量比为1.8-30mg/kg，优选为5-15mg/kg，例如5mg/kg或15mg/kg；
    较佳地，所述应用中，
    所述药物的日用剂量为所述物质A与受试者/患者的质量比，所述质量比为1.8-120mg/kg，优选为10-30mg/kg，例如10mg/kg或30mg/kg。
  5. 如权利要求1-3任一项所述应用，其特征在于，所述如式Ⅰ所示化合物占所述药物的质量分数为5-80％，优选为5-50％。
  6. 一种药物组合物，其特征在于，包括物质A和药学上可接受的载体；所述物质A为如式Ⅰ所示化合物或其药学上可接受的盐；
    所述如式Ⅰ所示化合物的质量分数为5-80％。
  7. 如权利要求6所述药物组合物，其特征在于，所述如式Ⅰ所示化合物的质量分数为5-50％。
  8. 一种如权利要求6所述药物组合物在制备治疗和/或预防颅内肿瘤的药物中的应用，
    较佳地，所述颅内肿瘤为ROS1融合颅内肿瘤；
    和/或，所述颅内肿瘤为神经脑胶质瘤和/或非小细胞脑转移瘤，例如ROS1融合神经脑胶质瘤或ROS1融合非小细胞脑转移瘤。
  9. 一种治疗和/或预防颅内肿瘤的方法，其特征在于，所述方法包括：向受试者/患者施用治疗有效量物质A或药物；
    所述药物包含物质A和药学上可接受的载体；
    所述物质A为如式Ⅰ所示化合物或其药学上可接受的盐；
  10. 如权利要求9所述方法，其特征在于，所述方法满足如下条件中的一种或多种：
    ①所述颅内肿瘤为ROS1融合颅内肿瘤，
    ②所述颅内肿瘤为神经脑胶质瘤和/或非小细胞脑转移瘤，例如ROS1融合神经脑胶质瘤或ROS1融合非小细胞脑转移瘤；
    ③所述药物的施用频率为1次/日、2次/日或3次/日；
    ④所述药物经口服施用；
    ⑤所述物质A的单位剂量为10-600mg，例如10mg、40mg、100mg、200mg、250mg、300mg、400mg或600mg；
    和⑥所述如式Ⅰ所示化合物在药物中的浓度为0.5-1.5mg/mL；优选为0.5mg/mL或1.5mg/mL。
  11. 如权利要求9或10所述方法，其特征在于，所述方法中，
    所述药物的单次剂量为所述物质A与受试者/患者的质量比，所述质量比为1.8-30mg/kg，优选为5-15mg/kg，例如5mg/kg或15mg/kg；
    较佳地，所述方法中，
    所述药物的日用剂量为所述物质A与受试者/患者的质量比，所述质量比为1.8-120mg/kg，优选为10-30mg/kg，例如10mg/kg或30mg/kg。
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