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WO2021228146A1 - 一种lsd1抑制剂的用途 - Google Patents

一种lsd1抑制剂的用途 Download PDF

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Publication number
WO2021228146A1
WO2021228146A1 PCT/CN2021/093362 CN2021093362W WO2021228146A1 WO 2021228146 A1 WO2021228146 A1 WO 2021228146A1 CN 2021093362 W CN2021093362 W CN 2021093362W WO 2021228146 A1 WO2021228146 A1 WO 2021228146A1
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Prior art keywords
lung cancer
compound
small cell
cell lung
drug
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English (en)
French (fr)
Inventor
李家印
林红梅
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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Priority to CN202180034448.3A priority Critical patent/CN115551501B/zh
Publication of WO2021228146A1 publication Critical patent/WO2021228146A1/zh
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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

  • This patent application relates to the field of medicine, in particular to the use of an LSD1 inhibitor in the preparation of drugs for the prevention and/or treatment of cell proliferative diseases, a combination product containing the LSD1 inhibitor and the prevention and/or treatment of cell proliferation Methods of sexual diseases.
  • Tumor disease is one of the most common diseases in modern times and a common cause of unnatural death.
  • Tumors include benign tumors and malignant tumors.
  • the risk of malignant tumors is very high.
  • Most of the malignant tumors are life-threatening.
  • the methods of treatment of malignant tumors include surgical resection, radiotherapy, drug chemotherapy, and targeted therapy.
  • SCLC small cell lung cancer
  • Lung cancer is called primary bronchial lung cancer, which is a malignant tumor derived from the trachea, bronchial mucosa or glands. Lung cancer is the most common malignant tumor in the world, and its morbidity and mortality rate ranks first among all kinds of cancer. In 2018, there were 2.09 million new cases of lung cancer worldwide, accounting for 11.6% of all new cancers, and 1.76 million deaths, accounting for 18.4% of all cancer deaths. Lung cancer is also the number one cancer in China in terms of morbidity and mortality, of which about 15% are small cell lung cancer (SCLC). Small cell lung cancer is a heterogeneous neuroendocrine tumor originating from the bronchial mucosal epithelium. There are more than 270,000 new cases of SCLC worldwide each year.
  • SCLC small cell lung cancer
  • small cell lung cancer Compared with non-small cell lung cancer, small cell lung cancer generally has a faster doubling time, a high proliferation ratio and widespread metastasis earlier. Most patients will have hematological metastasis, so the survival time of small cell lung cancer is significantly shorter than that of non-small cell lung cancer.
  • AJCC Seventh Edition Tumor Staging Manual reported in 2010 the results of a meta-analysis of 2664 SCLC patients. The data showed that: the 5-year survival rate of stage I SCLC patients is about 50%; stage II is about 25%; stage III is reduced to 10% About; Stage IV is less than 3%. This result is similar to the statistical result of SCLC survival rate in my country.
  • Small cell lung cancer can be divided into limited stage and extensive stage.
  • the median survival time of limited-stage SCLC receiving radiotherapy or chemotherapy is 16 to 24 months. However, more than two-thirds of patients are already in the extensive stage at the time of diagnosis, and can only be treated with a comprehensive treatment plan based on chemotherapy.
  • the median survival period is usually 7 to 12 months, and the recurrence rate of extensive stage small cell lung cancer is very high.
  • comprehensive treatment based on chemotherapy is adopted for extensive-stage small cell lung cancer.
  • Etoposide combined with platinum is the standard first-line chemotherapy.
  • Irinotecan combined with platinum is also an effective first-line treatment for extensive-stage small cell lung cancer.
  • Post-translational modifications of human histones include processes such as methylation, acetylation, phosphorylation, and ubiquitination. They are important regulatory means of epigenetics and affect gene expression by changing the structure of chromatin. The methylation status of histones is regulated by histone methyltransferase and histone demethylase. Lysine specific demethylase (LSD1, also known as KDM1A) is the first reported histone lysine demethylase, which regulates the methylation of histone lysine It is widely involved in transcriptional regulation and affects many physiological processes such as cell proliferation and differentiation, and the pluripotency of embryonic stem cells.
  • LSD1A Lysine specific demethylase
  • LSD1 also regulates the methylation status of some non-histone substrates, including the tumor suppressor gene p53 and DNA methyltransferase 1 (DNMT1).
  • DNMT1 DNA methyltransferase 1
  • LSD1 inhibitors can affect the expression of differentiation-related genes by regulating the monomethylation and dimethylation status of histones H3K4 and H3K9, promote the differentiation of cancer stem cells, inhibit tumor growth, and enhance the sensitivity of small cell lung cancer to chemotherapy. Therefore, LSD1 inhibitors have good application prospects for the treatment of poorly differentiated malignant tumors such as small cell lung cancer.
  • GSK2879552 is an irreversible LSD1 inhibitor developed by GlaxoSmithKline, which is intended for the treatment of small cell lung cancer.
  • GSK2879552 started a phase I clinical study for the treatment of relapsed/refractory small cell lung cancer in February 2014. From February 4, 2014 to April 18, 2017, a total of 29 patients were enrolled, and a total of 22 patients completed the study; 7 patients withdrew from the study, mainly due to adverse events (AEs). Among them, 8 cases were taken to reduce the dose of the trial drug or to discontinue the treatment due to grade 3 or severe thrombocytopenia. 9 patients reported 12 serious adverse events (SAEs); 6 cases were considered treatment-related, of which the most common was encephalopathy (4 SAEs).
  • SAEs serious adverse events
  • Compound A is a new type of LSD1 inhibitor. This compound and its preparation method are disclosed in Example 144 of WO2018137644A1. WO2020015745A1 discloses the dihydrochloride salt of compound A. However, it is still unclear whether compound A or its pharmaceutically acceptable salt is used in clinical practice, the important risk and exact efficacy, its use in specific diseases, and the combination of compound A or its pharmaceutically acceptable salt with other drugs Effect. Therefore, it is necessary to study the safety and effectiveness of compound A or its pharmaceutically acceptable salt in clinical application, in order to provide reference for clinical medication.
  • the purpose of the present invention is to provide compound A or a pharmaceutically acceptable salt thereof in the preparation of drugs for the prevention and/or treatment of cell proliferative diseases, especially cancer application.
  • the structure of the compound A is shown in the following formula (I):
  • the cancer is selected from lung cancer, wherein the lung cancer is preferably small cell lung cancer.
  • the present invention also provides a medicine containing a preventive and/or therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, which is used to prevent and/or treat cell proliferation.
  • Diseases especially cancer drugs.
  • the cancer is selected from lung cancer, wherein the lung cancer is preferably small cell lung cancer.
  • the present invention also provides a method for preventing and/or treating cell proliferative diseases, especially cancer.
  • the cancer is selected from lung cancer, wherein the lung cancer is preferably small cell lung cancer.
  • the present invention provides a combination product comprising Compound A or a pharmaceutically acceptable salt thereof, and another targeted drug or chemotherapeutic drug
  • the additional targeted drug or Chemotherapy drugs are selected from platinum drugs and topoisomerase inhibitors, including but not limited to cisplatin, carboplatin, lobaplatin, nedaplatin, cycloplatin, oxaliplatin, teniposide, etoposide, topo At least one of Tecan and Irinotecan.
  • the additional targeted drug or chemotherapeutic drug is selected from at least one of etoposide and cisplatin.
  • Figure 1 The effect of compound A on the expression of neuroendocrine-related genes ASCL1 and GRP.
  • pharmaceutically acceptable salt refers to a salt of a free acid or a free base, preferably the hydrochloride.
  • prevention refers to when used for a disease or condition (e.g., cancer), when compared with a subject who has not been administered a compound or drug (e.g., a combination product claimed in this application), the compound or Drugs can reduce the frequency or delay the onset of medical symptoms in subjects.
  • a disease or condition e.g., cancer
  • a compound or drug e.g., a combination product claimed in this application
  • treatment refers to alleviating, alleviating or ameliorating the symptoms of a disease or disorder, ameliorating the symptoms caused by potential metabolism, inhibiting the disease or symptom, such as preventing the development of the disease or disorder, alleviating the disease or disorder, or causing the disease Or the regression of the disease, the alleviation of the condition caused by the disease or disease, or the prevention of the symptoms of the disease or disease.
  • cell proliferative disease refers to a condition in which the growth rate of the cell population is lower than or higher than the expected rate under a given physiological state and condition.
  • cancer refers to a new organism or tumor caused by abnormal uncontrolled cell growth. Non-limiting examples include those exemplary cancers described in the detailed description of the invention.
  • cancer includes diseases involving both premalignant cancer cells and malignant cancer cells.
  • subject as used herein is meant to include humans (e.g., patients) and animals (e.g., mice, rats, dogs, cats, rabbits, chickens, or monkeys, etc.).
  • animals e.g., mice, rats, dogs, cats, rabbits, chickens, or monkeys, etc.
  • an "effective amount” or “preventively and/or therapeutically effective amount” as used herein refers to a sufficient amount (eg, dose) of a drug or compound administered, which will reduce the disease or condition being treated to a certain extent One or more symptoms. The result may be to shrink and/or alleviate the condition or cause of the disease or any other desired changes in the biological system.
  • an "effective amount” for therapeutic use is an amount that provides a compound or drug (for example, a combination product claimed in the present application) that significantly reduces the clinical symptoms of a disease or disorder without causing excessive toxic and side effects.
  • dose refers to the weight of the active substance per kilogram (kg) of the subject's body weight (e.g., milligrams (mg)), or the weight of the active substance taken by each subject at once (e.g., Milligrams (mg)).
  • room temperature refers to 25°C ⁇ 5°C. At the same time, if the experiment temperature is not specified, it is room temperature.
  • the term "about” refers to ⁇ 10% of the value modified by the term, more preferably ⁇ 5%, and most preferably ⁇ 2%. Therefore, those of ordinary skill in the art can clearly refer to the modified value.
  • the numerical value determines the range of the term "about”.
  • the compound A of the present invention or a pharmaceutically acceptable salt thereof can be prepared according to the methods disclosed in the prior art.
  • Example 144 of WO2018137644A1 to prepare compound A
  • WO2020015745A1 to prepare compound A dihydrochloride.
  • the full texts of WO2018137644A1 and WO2020015745A1 are incorporated into the present invention by reference.
  • in vitro studies of the present invention use Compound A as the test drug; in vivo pharmacodynamic studies, pharmacokinetic studies, toxicology studies and clinical studies are administered in the form of Compound A dihydrochloride.
  • the drug doses are all calculated with compound A.
  • test materials used in the present invention including but not limited to control drugs, test reagents, etc.
  • test materials used in the present invention are all commercially available.
  • the reference compound INCB059872 was prepared according to the method described in Example 6 of WO2017184934 (purity 99.33%).
  • the object of the present invention is to provide the use of compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicine for preventing and/or treating cell proliferative diseases, especially cancer.
  • the structure of the compound A is shown in the following formula (I):
  • the cancer is selected from lung cancer, wherein the lung cancer is preferably small cell lung cancer.
  • the small cell lung cancer is preferably extensive-stage small cell lung cancer or relapsed and/or metastatic small cell lung cancer; further preferably, small cell lung cancer that has failed or is intolerant to standard treatments.
  • the standard treatment plan for small cell lung cancer of the present invention includes but is not limited to: (1) Extensive-stage small cell lung cancer: Comprehensive treatment based on chemotherapy is recommended for extensive-stage small cell lung cancer. For those with local symptoms or brain metastases, it is recommended to be based on chemotherapy Combine radiotherapy or other treatment methods.
  • the chemotherapy regimen recommends etoposide combined with cisplatin (EP), etoposide combined with carboplatin (EC), irinotecan combined with cisplatin (IP), irinotecan combined with carboplatin (IC), or etoposide combined with loplatin ( EL) program.
  • EP etoposide combined with cisplatin
  • EC etoposide combined with carboplatin
  • IP irinotecan combined with cisplatin
  • IC irinotecan combined with carboplatin
  • EL etoposide combined with loplatin
  • Relapsed small cell lung cancer Topotecan, irinotecan, gemcitabine, temozolomide or paclitaxel are recommended for recurrence or progression within 3 months after first-line chemotherapy; Topotecan is recommended for recurrence or progression within 3 to 6 months Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine; patients who relapse or progress after 6 months can choose the initial treatment plan.
  • Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine
  • the small cell lung cancer of the present invention includes treatment with cisplatin, carboplatin, etoposide, lobaplatin, topotecan, irinotecan, gemcitabine, temozolomide, paclitaxel, docetaxel, vinorelbine, etc.
  • the small cell lung cancer of the present invention refers to small cell lung cancer with high expression of ASCL1 and/or GRP.
  • the drug has good tolerance and no obvious adverse reactions.
  • the medicine contains a preventive and/or therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the preventive and/or therapeutic effective amount is preferably 0.001-1000 mg and the range between the following amounts: 0.01 mg, 0.1 mg, 0.5 mg, 1 mg, 1.5 mg, 3 mg, 6 mg, 9 mg, 11 mg, 12 mg, 13 mg, 20 mg , 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1000mg, including but not limited to: 0.01-1000mg, 0.1-1000mg, 0.1 -900mg, 0.1-800mg, 0.1-700mg, 0.1-600mg, 0.1-500mg, 0.1-400mg, 0.1-300mg, 0.1-200mg, 0.1-100
  • the medicament in addition to Compound A or a pharmaceutically acceptable salt thereof as an active ingredient, also contains at least one pharmaceutically acceptable carrier, excipient and/or diluent.
  • the medicament can be prepared at a suitable dosage level in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically prepared auxiliary agent in a known manner.
  • the preferred formulations are suitable for oral administration.
  • the forms of administration include, for example, pills, tablets, film tablets, coated tablets, capsules, powders and depots.
  • the present invention also includes preparations for parenteral administration, including dermal, intradermal, intradermal, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, transdermal, rectal,
  • parenteral administration including dermal, intradermal, intradermal, intravascular, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabuccal, transdermal, rectal,
  • the formulation also contains Compound A and/or a pharmaceutically acceptable salt thereof as active ingredients.
  • the compounds of the present invention can be administered as a monotherapy or together with other active agents, especially targeted drugs, chemotherapeutics or anti-tumor antibodies. In addition, they can also be used in conjunction with surgery and/or irradiation.
  • Compound A or a pharmaceutically acceptable salt thereof can be used in combination with one or more of other targeted drugs or chemotherapeutic drugs.
  • the other targeted drugs or chemotherapeutic drugs refer to targeted drugs or chemotherapeutic drugs that are clinically used to treat tumor-related diseases, such as platinum drugs and topoisomerase inhibitors, including but not limited to cisplatin, carboplatin, and chemotherapeutics. At least one of platinum, nedaplatin, cycloplatin, oxaliplatin, teniposide, etoposide, topotecan, and irinotecan. More preferably, the targeted drug or chemotherapeutic drug is selected from at least one of etoposide and cisplatin.
  • the present invention also provides a medicine containing a preventive and/or therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, which is used to prevent and/or treat cell proliferation.
  • Diseases especially cancer drugs.
  • the cancer is selected from lung cancer, wherein the lung cancer is preferably small cell lung cancer.
  • the small cell lung cancer is preferably extensive-stage small cell lung cancer or relapsed and/or metastatic small cell lung cancer; further preferably, small cell lung cancer that has failed or is intolerant to standard treatments.
  • the standard treatment plan for small cell lung cancer of the present invention includes but is not limited to: (1) Extensive-stage small cell lung cancer: Comprehensive treatment based on chemotherapy is recommended for extensive-stage small cell lung cancer. For those with local symptoms or brain metastases, it is recommended to be based on chemotherapy Combine radiotherapy or other treatment methods.
  • the chemotherapy regimen recommends etoposide combined with cisplatin (EP), etoposide combined with carboplatin (EC), irinotecan combined with cisplatin (IP), irinotecan combined with carboplatin (IC), or etoposide combined with loplatin ( EL) program.
  • EP etoposide combined with cisplatin
  • EC etoposide combined with carboplatin
  • IP irinotecan combined with cisplatin
  • IC irinotecan combined with carboplatin
  • EL etoposide combined with loplatin
  • Relapsed small cell lung cancer Topotecan, irinotecan, gemcitabine, temozolomide or paclitaxel are recommended for recurrence or progression within 3 months after first-line chemotherapy; Topotecan is recommended for recurrence or progression within 3 to 6 months Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine; patients who relapse or progress after 6 months can choose the initial treatment plan.
  • Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine
  • the small cell lung cancer of the present invention includes treatment with cisplatin, carboplatin, etoposide, lobaplatin, topotecan, irinotecan, gemcitabine, temozolomide, paclitaxel, docetaxel, vinorelbine, etc.
  • the small cell lung cancer of the present invention refers to small cell lung cancer with high expression of ASCL1 and/or GRP.
  • the present invention provides a medicament for the prevention and/or treatment of small cell lung cancer, which is characterized in that it contains a preventive and/or therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, and optionally, pharmaceutically acceptable Accepted excipients, carriers and/or diluents.
  • the medicine is prepared into clinically accepted preparations, such as oral preparations, injection preparations, topical administration preparations or external preparations.
  • the drug may also contain one or more of other targeted drugs or chemotherapeutic drugs.
  • the other targeted drugs or chemotherapeutic drugs refer to targeted drugs or chemotherapeutic drugs that are clinically used to treat tumor-related diseases, such as platinum drugs and topoisomerase inhibitors, including but not limited to cisplatin, carboplatin, and chemotherapeutics. At least one of platinum, nedaplatin, cycloplatin, oxaliplatin, teniposide, etoposide, topotecan, and irinotecan. More preferably, the targeted drug or chemotherapeutic drug is selected from at least one of etoposide and cisplatin.
  • the medicament of the present invention is as described in the first aspect of the present invention.
  • another object of the present invention also includes providing a method for preventing and/or treating small cell lung cancer, the method comprising administering to a subject a preventive and/or therapeutically effective amount of Compound A Or a pharmaceutically acceptable salt thereof.
  • the administration may be oral administration, injection administration, topical administration or in vitro administration.
  • compound A or a pharmaceutically acceptable salt thereof is prepared into clinically accepted preparations and then administered.
  • the preparations include oral preparations, injection preparations, topical administration preparations, topical preparations, and the like.
  • the small cell lung cancer is preferably extensive-stage small cell lung cancer or relapsed and/or metastatic small cell lung cancer; further preferably, small cell lung cancer that has failed or is intolerant to standard treatments.
  • the standard treatment plan for small cell lung cancer of the present invention includes but is not limited to: (1) Extensive-stage small cell lung cancer: Comprehensive treatment based on chemotherapy is recommended for extensive-stage small cell lung cancer. For those with local symptoms or brain metastases, it is recommended to be based on chemotherapy Combine radiotherapy or other treatment methods.
  • the chemotherapy regimen recommends etoposide combined with cisplatin (EP), etoposide combined with carboplatin (EC), irinotecan combined with cisplatin (IP), irinotecan combined with carboplatin (IC), or etoposide combined with loplatin ( EL) program.
  • EP etoposide combined with cisplatin
  • EC etoposide combined with carboplatin
  • IP irinotecan combined with cisplatin
  • IC irinotecan combined with carboplatin
  • EL etoposide combined with loplatin
  • Relapsed small cell lung cancer Topotecan, irinotecan, gemcitabine, temozolomide or paclitaxel are recommended for recurrence or progression within 3 months after first-line chemotherapy; Topotecan is recommended for recurrence or progression within 3 to 6 months Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine; patients who relapse or progress after 6 months can choose the initial treatment plan.
  • Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine
  • the small cell lung cancer of the present invention includes treatment with cisplatin, carboplatin, etoposide, lobaplatin, topotecan, irinotecan, gemcitabine, temozolomide, paclitaxel, docetaxel, vinorelbine, etc.
  • the small cell lung cancer of the present invention refers to small cell lung cancer with high expression of ASCL1 and/or GRP.
  • the method also includes providing a safe and effective dose and dose frequency of Compound A or a pharmaceutically acceptable salt thereof for the treatment of small cell lung cancer.
  • a suitable dosage range of Compound A or a pharmaceutically acceptable salt thereof is from about 0.001 mg/kg to about 1000 mg/kg; preferably, from about 0.01 mg/kg to about 100 mg/kg.
  • the dose of compound A or its pharmaceutically acceptable salt per administration is 0.001mg-1000mg; further preferably, the dose per administration is 0.01mg-100mg, or 0.1mg-50mg, most preferably 0.5-25mg . It is administered in a single dose or in divided doses; it can be administered continuously or at intervals.
  • the dosage and dosage frequency are: once a week, 0.5-13mg, 0.5-12mg, 0.5-11mg, 0.5-9mg, 0.5-6mg, 0.5-3mg, 0.5- 1.5mg, 1.5-13mg, 1.5-12mg, 1.5-11mg, 1.5-9mg, 1.5-6mg, 1.5-3mg, 3-13mg, 3-12mg, 3-11mg, 3-9mg, 3-6mg, 6-13mg , 6-12mg, 6-11mg, 6-9mg, 9-13mg, 9-12mg, 9-11mg, 11-13mg, 11-12mg, 12-13mg, for example, 0.5, 1.5, 3, 6, 9, 11 , 12, 13 mg, etc., preferably 6 mg to 9 mg.
  • the dosage of Compound A or its pharmaceutically acceptable salt of the present invention is all based on Compound A.
  • the present invention provides a combination product comprising Compound A or a pharmaceutically acceptable salt thereof, and another targeted drug or chemotherapeutic drug
  • the additional targeted drug or Chemotherapy drugs are selected from platinum drugs and topoisomerase inhibitors, including but not limited to cisplatin, carboplatin, lobaplatin, nedaplatin, cycloplatin, oxaliplatin, teniposide, etoposide, topo At least one of Tecan and Irinotecan.
  • the additional targeted drug or chemotherapeutic drug is selected from at least one of etoposide and cisplatin.
  • the present invention provides a combination product comprising Compound A or a pharmaceutically acceptable salt thereof and cisplatin, or Compound A or a pharmaceutically acceptable salt thereof and cisplatin and etoposide.
  • the combination product is in the form of a pharmaceutical composition.
  • the compound A or a pharmaceutically acceptable salt thereof and another targeted drug or chemotherapeutic drug are each in the form of a separate preparation. Further, the compound A or a pharmaceutically acceptable salt thereof and another targeted drug or chemotherapeutic drug can be administered simultaneously or sequentially.
  • the combination product contains a preventive and/or therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof, wherein the preventive and/or therapeutically effective amount is preferably 0.001-1000 mg, and the range between the following amounts: 0.01 mg, 0.1mg, 0.5mg, 1mg, 1.5mg, 3mg, 6mg, 9mg, 11mg, 12mg, 13mg, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 200mg, 300mg, 400mg, 500mg , 600mg, 700mg, 800mg, 900mg, 1000mg, including but not limited to: 0.01-1000mg, 0.1-1000mg, 0.1-900mg, 0.1-800mg, 0.1-700mg, 0.1-600mg, 0.1-500mg, 0.1-400mg, 0.1 -300mg, 0.1-200mg
  • the combination product further comprises at least one pharmaceutically acceptable carrier, excipient and/or diluent.
  • the combination product can be prepared in a known manner in a conventional solid or liquid carrier or diluent and a conventional pharmaceutically-prepared adjuvant at a suitable dosage level.
  • the preferred formulations are suitable for oral administration.
  • the forms of administration include, for example, pills, tablets, film tablets, coated tablets, capsules, powders, and reservoirs.
  • the combination product is used to prevent and/or treat cell proliferative diseases, especially cancer.
  • the cancer is selected from lung cancer, wherein the lung cancer is preferably small cell lung cancer.
  • the small cell lung cancer is preferably extensive-stage small cell lung cancer or relapsed and/or metastatic small cell lung cancer; further preferably, small cell lung cancer that has failed or is intolerant to standard treatments.
  • the standard treatment plan for small cell lung cancer of the present invention includes but is not limited to: (1) Extensive-stage small cell lung cancer: Comprehensive treatment based on chemotherapy is recommended for extensive-stage small cell lung cancer. For those with local symptoms or brain metastases, it is recommended to be based on chemotherapy Combine radiotherapy or other treatment methods.
  • the chemotherapy regimen recommends etoposide combined with cisplatin (EP), etoposide combined with carboplatin (EC), irinotecan combined with cisplatin (IP), irinotecan combined with carboplatin (IC), or etoposide combined with loplatin ( EL) program.
  • EP etoposide combined with cisplatin
  • EC etoposide combined with carboplatin
  • IP irinotecan combined with cisplatin
  • IC irinotecan combined with carboplatin
  • EL etoposide combined with loplatin
  • Relapsed small cell lung cancer Topotecan, irinotecan, gemcitabine, temozolomide or paclitaxel are recommended for recurrence or progression within 3 months after first-line chemotherapy; Topotecan is recommended for recurrence or progression within 3 to 6 months Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine; patients who relapse or progress after 6 months can choose the initial treatment plan.
  • Drug therapy such as Kang, irinotecan, gemcitabine, docetaxel, temozolomide or vinorelbine
  • the small cell lung cancer of the present invention includes treatment with cisplatin, carboplatin, etoposide, lobaplatin, topotecan, irinotecan, gemcitabine, temozolomide, paclitaxel, docetaxel, vinorelbine, etc.
  • the small cell lung cancer of the present invention refers to small cell lung cancer with high expression of ASCL1 and/or GRP.
  • compound A can effectively treat small cell lung cancer with good clinical safety.
  • combination of compound A and cisplatin or cisplatin + etoposide can significantly enhance the anti-tumor effect, produce a synergistic effect, and provide support for clinical combined treatment programs.
  • the enzyme used in this test is human LSD1, the standard substrate is histone H3(1-21) K4me2 peptide (10 ⁇ M), and INCB059872 is used as the reference compound.
  • LSD1 buffer composition 50mM Tris-HCl, pH 7.5, 0.05% CHAPS, 1% DMSO.
  • Compound A inhibits the proliferation of small cell lung cancer cell lines NCI-H1417 and NCI-H526
  • the Cell Titer Glo experimental method was used to analyze the effects of LSD1 inhibitor compound A and the reference compound INCB059872 on the proliferation of small cell lung cancer cell lines NCI-H1417 and NCI-H526.
  • Cell culture medium for experiment Add 10% fetal bovine serum, 1% penicillin/streptomycin double antibody, and 1% L-glutamine to RPMI1640 cell culture medium at 4°C for later use.
  • the suspended cells After the suspended cells are evenly pipetted, count them with a Vi-cell cytometer, prepare 3000 cells/90 ⁇ L of NCI-H1417 cell suspension with culture medium, and add it to a 96-well cell culture plate, 90 ⁇ L/well.
  • the reference compound INCB059872 and the test compound A were diluted with DMSO into a 10mM stock solution, and then using this concentration as the starting concentration, the compound was diluted 3 times with DMSO 9 times to obtain 10 concentrations, which were diluted with culture medium.
  • the compound was diluted 100 times, and at the same time, the same volume of DMSO as the compound solution was diluted 100 times in the medium, and 10 ⁇ L of the diluted mixture was transferred to the corresponding cell plate (ie 10-fold dilution), and the DMSO dilution was Transfer to F and G rows of the control group.
  • the final concentration of the compound was 10 ⁇ M as the initial concentration, and 10 concentrations were diluted in 3 folds, mixed and centrifuged, and placed in a cell incubator containing 5% CO 2 at 37° C. for 10 days. Take out the 96-well cell culture plate, add CTG reagent, 50 ⁇ L/well, mix and centrifuge, and incubate at room temperature for 10 minutes. Use Envison multi-marker analyzer to read.
  • the NCI-H526 cell test uses the formula: Vsample/Vvehicle control x100% to calculate the cell survival rate. Among them, Vsample is the reading of the drug treatment group, and Vvehicle control is the average value of the solvent control group. Using GraphPad Prism 5.0 software, a non-linear regression model was used to draw the S-type dose-survival rate curve and calculate the IC50 value.
  • Small cell lung cancer is a neuroendocrine tumor of the lung. About 75% of small cell lung cancer patients express ASCL1. ASCL1 is a neuroendocrine-related transcription factor and a potential target for the treatment of highly malignant neuroendocrine lung cancer. Gastrin-releasing peptide (GRP) is a gastrointestinal hormone that is widely distributed in the nervous system, gastrointestinal tract and lungs. Small cell lung cancer cells can secrete GRP, and the detection of GRP expression is helpful for disease monitoring.
  • GRP Gastrin-releasing peptide
  • Real-time quantitative PCR was used to determine the changes in the expression of ASCL1 and GRP in NCI-H1417 cells after drug treatment.
  • Real-time fluorescent quantitative PCR adopts the SYBR Green method. 5 ⁇ L of SYBR Green is added to the qPCR reaction system. SYBR Green binds to double-stranded DNA and emits fluorescence. The PCR product amplification amount is detected by detecting the fluorescence intensity of SYBR Green in the reaction system. The Ct values of the target gene and the internal reference gene were analyzed, and the ⁇ CT method was used to calculate the expression of the target gene relative to the control group. Based on this data, statistical analysis was performed to evaluate differences between groups. The comparison between two groups was analyzed by T-test, and the comparison between three or more groups was analyzed by one-way ANOVA.
  • Test results Compared with the control group, the mRNA expression levels of ASCL1 and GRP in the compound A and INCB059872 added group decreased, and the mRNA expression of ASCL1 and GRP in the compound A added group decreased in a dose-dependent manner. See Figure 1 for details.
  • Cell culture Human small cell lung cancer NCI-H1417 (ATCC, Manassas, Virginia, catalog number: CRL-5869) cells are cultured in a monolayer in vitro, and the culture conditions are RPMI-1640 medium plus 10% fetal bovine serum, 37 Cultivation and passage at 5% CO 2. When the cell saturation is 80%-90%, the cells are collected by trypsin-EDTA digestion, counted, adjusted to 10 ⁇ 10 7 cells/mL and resuspended in PBS.
  • NCI-H1417 cells (with Matrigel, volume 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached about 100-150mm 3 and randomly grouped , Start the administration.
  • Routine inspections include observation of tumor growth and drug treatment's influence on the daily behavior of animals, such as behavioral activities, food and water intake (visual inspection only), and weight changes (weekly Measure your body weight twice), physical signs or other abnormalities. Based on the number of animals in each group, the number of animal deaths and side effects in the group were recorded.
  • Tumor measurement Measure the diameter of the tumor with a vernier caliper twice a week.
  • the anti-tumor efficacy of the compound was evaluated by TGI (%) or relative tumor growth rate T/C (%).
  • Relative tumor proliferation rate T/C(%) TRTV / CRTV ⁇ 100% ( TRTV : treatment group RTV; C RTV : negative control group RTV). Calculate the relative tumor volume (RTV) according to the results of tumor measurement.
  • TGI ⁇ 100%
  • T weight and C weight represent the tumor weight of the administration group and the vehicle control group, respectively.
  • PK sampling and analysis After the last administration, the animal's whole blood, plasma, lung and tumor tissues were collected for in vitro PK/PD experiments.
  • Compound A showed good tolerance at all doses, and no animal died in all treatment groups.
  • the effect of the drug on blood cells was also investigated.
  • the three dose groups of compound A were used alone or in combination with cisplatin.
  • the blood routine was tested 35 days after administration, and there were no key blood routine indicators such as white blood cells, red blood cells, platelets, monocytes, neutrophils, and reticulocytes. Significant impact, showing good hematological safety.
  • Cell culture human small cell lung cancer NCI-H526 (ATCC, Manassas, Virginia, catalog number: CRL-5811) cells, suspension culture in vitro, culture condition is RPMI-1640 medium plus 10% fetal bovine serum, 100U /mL penicillin and 100 ⁇ g/mL streptomycin, culture and subculture at 37°C with 5% CO 2. When the cell saturation is 80%-90%, count, adjust 10 ⁇ 10 7 cells/mL and resuspend in PBS.
  • NCI-H526 cells Take 5 BABL/c nude mice and inoculate 0.1 mL (5 ⁇ 10 6 cells) NCI-H526 cells in the subcutaneous position of the right back of each animal. When the tumor volume is close to 500 mm 3 , remove the tumor for use Organize vaccination. After removing the necrotic tissue, the tumor tissue was cut into small pieces (20-30mm 3 ), and subcutaneously inoculated on the right back of each mouse to wait for the tumor to grow. When the average tumor volume reached about 90mm 3 , they were randomly divided into groups and the drug was started.
  • Routine inspections include observation of tumor growth and drug treatment's influence on the daily behavior of animals, such as behavioral activities, food and water intake (visual inspection only), and weight changes (weekly Measure your body weight twice), physical signs or other abnormalities. Based on the number of animals in each group, the number of animal deaths and side effects in the group were recorded.
  • Tumor measurement Measure the diameter of the tumor with a vernier caliper twice a week.
  • the anti-tumor efficacy of the compound was evaluated by TGI (%) or relative tumor growth rate T/C (%).
  • Relative tumor proliferation rate T/C(%) TRTV / CRTV ⁇ 100% ( TRTV : treatment group RTV; C RTV : negative control group RTV). Calculate the relative tumor volume (RTV) according to the results of tumor measurement.
  • TGI ⁇ 100%
  • T weight and C weight represent the tumor weight of the administration group and the vehicle control group, respectively.
  • the King’s formula was used to evaluate the combined effects of compound A with cisplatin and etoposide.
  • Q ⁇ 0.85 has an antagonistic effect
  • 0.85 ⁇ Q ⁇ 1.15 has an additive effect
  • Q>1.15 has a synergistic effect.
  • the results show that: as shown in Table 4, in the small cell lung cancer NCI-H526 cell subcutaneous xenograft mouse model, the compound A (1.5 mg/kg) single administration group and the INCB059872 (1.5 mg/kg) single administration group
  • the average tumor volume of the tumors was 1,427 and 1,571mm 3 , respectively, and there was no significant tumor suppressor effect.
  • the combined administration of Cisplatin and Etoposide had a certain inhibitory effect.
  • the average tumor volume was 999 mm 3
  • the T/C value was 50.15%
  • the TGI value was 53.33%.
  • the pharmacokinetic properties of Compound A in male and female SD rats include: (1) 0.5 mg/kg single intravenous injection study; (2) 0.5, 1.5 and 5 mg/kg intragastric dose escalation studies; (3) ) Study on repeated intragastric administration once every 3 days, 1.5 mg/kg each time, 3 consecutive times.
  • the animals of the first group were given 0.5 mg/kg compound A by a single intravenous injection, and the vehicle was 10% HP- ⁇ -CD ( ⁇ -cyclodextrin aqueous solution).
  • the animals of group 2 and group 4 were given 0.5 and 5 mg/kg compound A by single gavage, respectively.
  • the animals in the third group were given 3 consecutive intragastric administrations, once every 3 days, 1.5 mg/kg compound A each time.
  • the first group of animals collected plasma samples before and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 36 and 48 hours after administration.
  • Plasma samples were collected from animals in groups 2 and 4 before administration and 0.25, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after administration, respectively.
  • Group 3 animals were collected plasma samples before the first and third doses, 0.25, 1, 2, 4, 6, 8, 12, 24, 36, and 48 hours after the dose and before the second dose.
  • the concentration of compound A in the plasma sample was determined using the LC-MS/MS method.
  • Studies on the pharmacokinetic properties of compound A in female and male beagle dogs include (1) 0.1 mg/kg single intravenous injection study; (2) 0.1, 0.3 and 0.6 mg/kg oral dose escalation studies; (3) 0.3 mg The oral administration study was repeated once a week at the dose of /kg for 3 consecutive weeks.
  • Plasma samples were collected at 72, 96, 120, and 168 hours. Animals in group 3 were administered 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 168 before and after administration in the first and third weeks (the second Plasma samples were collected one hour before administration. The concentration of compound A in the plasma sample was determined by the LC-MS/MS method.
  • the purpose of this experiment was to study the pharmacokinetic properties of a single oral 0.2mg/kg compound A capsule in male and female beagle dogs, to investigate the bioavailability after oral administration, and to compare the differences between male and female.
  • Three male and three female beagle dogs were selected, each of which was orally administered 1 capsule of compound A (each capsule contains 2mg of active ingredient compound A), 0.25, 0.5, 1, 2 before and after administration , 4, 6, 8, 12, 24, 48, 72, 96, 120, 168 hours to collect plasma samples.
  • the concentration of compound A in the plasma sample was determined by the LC-MS/MS method.
  • the AUC0-inf and Cmax were 689 ⁇ 334h ⁇ nM and 12.8 ⁇ 5.87nM, respectively.
  • the peak time appeared at 11.3 ⁇ 1.63h after administration.
  • Bioavailability The degree is 101%.
  • the ratio of female to male AUC0-last was 1.75, and there was no significant gender difference in system exposure.
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used, cisapride was used as a positive control compound, and electrophysiological manual patch clamp technology was used to investigate the inhibitory effect of compound A on hERG potassium channels.
  • the inhibitory percentage of compound A on hERG potassium current is 55.8% after being administered at a concentration of 40 ⁇ M for 1 minute. Under these conditions, the compound has an IC50 value of 34.5 ⁇ M for inhibiting hERG potassium current, and the risk of cardiovascular side effects is low.
  • This test uses cisapride as a positive control compound.
  • the IC50 value of cisapride inhibition of hERG potassium current ranges from 5 to 66 nM.
  • the IC50 value obtained from cisapride detection on the same day in this test is 32.6 nM, indicating that the test system is stable and reliable, and the test results precise.
  • MTD maximum tolerated dose
  • Beagle dogs were given a single intragastric administration of Compound A 0.3mg/kg, 1mg/kg and 3mg/kg to recover for 21 days with toxicokinetic experiment, the maximum tolerated dose (MTD) was 3mg/kg (AUC0-120h: ⁇ 4778.05) ng ⁇ h/mL, ⁇ 6647.67ng ⁇ h/mL), the changes related to the test substance are mainly manifested as skin toxicity and gastrointestinal reactions, accompanied by weight loss and poor food intake.
  • MTD maximum tolerated dose
  • Hematology can see white blood cells and their classification, Changes in red blood cell-related indicators, platelet-related indicators, as well as lymphopenia with small thymus and extramedullary hematopoiesis in red marrow with enlarged spleen.
  • SD rats were administered by oral gavage repeatedly 9 times (twice a week, on the 1st and 4th day respectively), administered 0.6, 2, and 6 mg/kg of compound A. The drug was stopped and recovered for 4 weeks. No toxicity was seen in both males and females.
  • Response dose is 0.6mg/kg
  • male maximum tolerated dose is 2mg/kg (D29: AUC0-48h: ⁇ 75.56ng ⁇ h/mL)
  • female maximum tolerated dose (MTD) is 6mg /kg (D29: AUC0-48h: ⁇ 383.60ng ⁇ h/mL).
  • the toxic changes related to the test substance are mainly manifested as erythema, swelling and crusting.
  • the blood system shows changes in white blood cell classification, erythroid indicators, and platelet-related indicators. Histopathology shows lymphopenia (thymus, spleen) and increased extramedullary hematopoiesis ( Spleen, liver), multiple organs/tissue hemorrhage (testicular interstitium, epididymal interstitium, eyeball, stomach, ovarian corpus luteum, lung alveoli, thymus, pancreas); liver bile duct hyperplasia, bone marrow (sternum and femur) bone new bones can also be seen Increased metaphyseal bone trabeculae decreased and megakaryocytes increased, ovarian atresia follicles increased and new corpus luteum decreased, lung macrophage aggregation and fibrosis, pancreatic acinar atrophy/necro
  • Beagle dogs were given 5 times by oral gavage (administered on the first day of the week) 0.075, 0.25, 0.75 mg/kg compound A was administered, and the drug was stopped and recovered for 4 weeks.
  • the NOAEL dose was 0.075 mg /kg
  • the highest non-serious toxic dose (HNSTD) is 0.25mg/kg
  • the minimum lethal dose (MLD) is 0.75mg/ kg (D29: AUC0-120h: ⁇ 1826.43ng ⁇ h/mL, ⁇ 701.55ng ⁇ h/mL).
  • the toxic changes related to the test substance are mainly manifested as gastrointestinal toxicity, malaise and reduced activity.
  • the blood system can see changes in white blood cell classification, red blood cell-related indicators, and platelet-related indicators.
  • Drug-related histopathological changes are seen in hematopoietic-lymphoid organs/ Tissues, digestive tract, adrenal glands, lungs, liver, muscles.
  • the drug was stopped and recovered for 4 weeks.
  • the above changes showed a complete recovery or a trend of recovery, and no other drug-related toxic reactions were seen. It is basically consistent with the toxicity of the same target drug.
  • the equivalent human dose is about 5.35 mg-16.05 mg (based on 60 kg body weight). Based on the above-mentioned pharmacodynamic and toxicological research results, the human equivalent dose is calculated by converting the effective dose of mouse 1mg/kg and the long-term toxicity test MTD dose (male 2mg/kg, female 6mg/kg) into the human equivalent to calculate the safety of compound A
  • the window is 4.5 times for males and 13.6 times for females, indicating that compound A is well tolerated.
  • This trial is an open, dose escalation and dose expansion phase I clinical study for patients with extensive-stage small cell lung cancer. It aims to evaluate the safety, tolerability, and pharmacokinetics of compound A in patients with extensive-stage small cell lung cancer. Characteristics and preliminary anti-tumor activity. The anti-tumor activity was carried out in accordance with the Evaluation Criteria for Efficacy of Solid Tumors (RECIST) V1.1.
  • This study is conducted in two stages, the first stage (Stage I) is a dose escalation study, and the second stage (Stage II) is a dose expansion study.
  • the initial dose of compound A was set at 0.5 mg/week, and five dose groups were initially planned: 0.5, 1.5, 3, 6, and 9 mg.
  • the preset maximum escalating dose is 9 mg/week. This study will follow the "3+3" dose escalation plan.
  • the target dose group dose expansion study and the exploration study of different dosing schedules can be carried out when necessary.
  • Sponsors and investigators will continue to conduct safety evaluations, and based on the available data of previous dose levels, determine the drug dose level and dosing schedule during the expansion period.
  • the initial dose of compound A was set at 0.5 mg, and the preset highest escalating dose was 9 mg.
  • This study adopts an increasing proportion of 200%, 100%, 100%, and 50%.
  • the slope plan is designed as 0.5, 1.5, 3, 6, 9 mg.
  • Grouping dose Increment Subject 1 0.5mg - 1 2 1.5mg 200% 3+3 3 3mg 100% 3+3 4 6mg 100% 3+3 5 9mg 50% 3+3
  • the dose escalation will start from the initial dose (0.5mg), and only 1 patient will be evaluated in the initial dose group. From the second dose group (1.5mg), follow the "3+3 principle", and each dose group will be included in the group 3 ⁇ 6 subjects. After all subjects have completed a certain dose of the drug test, the sponsor and the investigator jointly decide whether to increase to the next dose level.
  • MTD definition Refers to the current dose group after ⁇ 33% of subjects in the high-dose group have DLT, and 0/6 or 1/6 of the current dose group has DLT, then the current dose group is defined as MTD.
  • MTD is not found in all planned dose groups, the sponsor will further discuss with the investigator whether to conduct a higher dose group study.
  • each dose group may be enrolled in 3 subjects at an early stage On the basis of this, additional new subjects were enrolled.
  • the principle of case supplement is as follows:
  • Subjects who have signed the informed consent form but have not received research intervention can be replaced.
  • substitutes will be allowed if they meet the following conditions:
  • Non-DLT causes the dose in the first cycle to be less than 75% of the planned dose.
  • Subjects who have completed the treatment and observation of the core trial period are judged by the investigator that the subject has benefit and can tolerate the study drug treatment, and can enter the subsequent treatment period according to the subject's wishes. The same subject entering the subsequent treatment period is not allowed to increase to the next higher dose group.
  • the selection criteria for the first part of the trial patients with small cell lung cancer diagnosed histologically, who have failed or are intolerant to the standard treatment, and have at least one measurable lesion according to the RECIST1.1 standard;
  • the selection criteria for the second part of the trial patients with small cell lung cancer diagnosed histologically, who have failed or are intolerant to standard therapies (etoposide combined with platinum regimens have progressed or become intolerant after at least one treatment) , And at least one focus can be measured according to the RECIST1.1 standard.
  • cardiovascular events occurred within 6 months before the first administration, including: acute coronary syndrome, congestive heart failure, stroke or other cardiovascular events of grade 3 or above;
  • the left ventricular ejection fraction is less than 60%.
  • 1 subject has been enrolled in the 0.5 mg dose group and 3 subjects have been enrolled in the 1.5 mg dose group, all of which have completed the enrollment and DLT observation period.
  • One subject in the 3mg dose group has been enrolled and completed the DLT observation period. All subjects had no DLT, no SAE, and no adverse events of special concern.
  • TNM stage was IVB stage, and the VALG stage was extensive stage.
  • Irinotecan+cisplatin second-line chemotherapy was started on August 12, 2020, and the best curative effect was PD.
  • the informed consent form was signed.
  • the TNM staging was the IVB stage, and the VALG staging was the extensive stage.
  • a 63-year-old male was diagnosed with small cell lung cancer in October 2017, with metastatic lymph nodes.
  • the TNM staging at the first diagnosis was unknown, and the VALG staging was unknown.
  • a right lower lobectomy and systemic lymph node dissection were performed.
  • Received etoposide + cisplatin combined postoperative adjuvant chemotherapy from November 6, 2017 to March 1, 2018, with the best effect SD.
  • Received whole brain radiotherapy from March 30 to April 4, 2018.
  • Received etoposide + cisplatin combined chemotherapy from April 20th to August 17th, 2019, the best curative effect was PR, and the disease progressed on November 21st, 2019.
  • Received second-line etoposide single-agent chemotherapy from December 6, 2019 to February 9, 2020. The best efficacy is unknown.
  • the informed consent form will be signed on February 24, 2021.
  • the TNM staging was the IVB stage, and the VALG staging was the extensive stage. From March 3, 2021, take Compound A 3mg once a week.
  • the anti-tumor efficacy evaluation of C1D28 on March 30, 2021 is SD, and follow-up treatment and efficacy evaluation are in progress.
  • Adverse events that occurred during the study included double pneumonia, right emphysema, right pleural effusion, liver cyst, decreased lymphocyte count, increased GGT, increased LDH, sinus tachycardia, insomnia, and weight loss.
  • the CTCAE grade of all adverse events was 1-2, and they were judged not to be related to the study drug.

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Abstract

一种LSD1抑制剂化合物A或其药学上可接受的盐在制备用于预防和/或治疗细胞增殖性疾病的药物中的应用，以及含有该化合物A或其药学上可接受的盐以及另外的靶向药物或化疗药物的组合产品。所述细胞增殖性疾病是癌症，特别是小细胞肺癌，优选广泛期小细胞肺癌或复发转移的小细胞肺癌，尤其是标准治疗失败或对标准治疗不耐受的小细胞肺癌。

Description

一种LSD1抑制剂的用途 技术领域
本专利申请涉及医药领域，具体涉及一种LSD1抑制剂在制备用于预防和/或治疗细胞增殖性疾病的药物中的用途，含有所述LSD1抑制剂的组合产品以及预防和/或治疗细胞增殖性疾病的方法。
背景技术
1.小细胞肺癌
肿瘤疾病是现代最常见的疾病之一，也是非自然死亡的常见原因。肿瘤包括良性肿瘤和恶性肿瘤两种类型，恶性肿瘤的危险性非常高，大部分的恶性肿瘤都会危及生命。目前，治疗恶性肿瘤的方法包括手术切除、放射治疗、药物化疗以及靶向治疗等，然而现有的治疗手段对包括小细胞肺癌(SCLC)在内的多种中晚期肿瘤患者难以产生较好的疗效。
肺癌全称为原发性支气管肺癌，是来源于气管、支气管黏膜或腺体的恶性肿瘤。肺癌是世界范围内最常见的恶性肿瘤，其发病率和死亡率位居各癌种之首。2018年，全球肺癌新发病例209万，占所有新发癌症的11.6％，死亡病例176万，占所有死亡癌症的18.4％。肺癌也是中国发病率和死亡率第一位的癌症，其中约15％为小细胞肺癌(Small cell lung cancer，SCLC)。小细胞肺癌是一种起源于支气管黏膜上皮的异源性神经内分泌肿瘤，全球每年SCLC新发病例超过27万。与非小细胞肺癌相比，小细胞肺癌普遍倍增时间快，增殖比高且更早发生广泛转移，大部分患者会出现血行转移，故小细胞肺癌的生存期显著短于非小细胞肺癌。AJCC第七版肿瘤分期手册于2010年报道了2664例SCLC患者荟萃分析的结果，数据显示：Ⅰ期SCLC患者5年生存率约为50％；Ⅱ期约为25％；Ⅲ期降至10％左右；Ⅳ期不足3％。该结果与我国SCLC生存率统计结果类似。
小细胞肺癌可分为局限期和广泛期，局限期SCLC接受放疗或化疗的中位生存期为16～24个月。但是超过2/3的病人确诊时已处于广泛期，只能采用化疗为主的综合治疗方案，中位生存期通常为7～12个月，且广泛期的小细胞肺癌复发率很高。目前，广泛期小细胞肺癌采取以化疗为主的综合治疗，依托泊苷联合铂类为标准一线化疗方案，伊立替康联合铂类也是广泛期小细胞肺癌的有效一线治疗方案。尽管小细胞肺癌对于初始治疗非常敏感，但大多数小细胞肺癌患者在一线常规化疗后出现复发或耐药。这些患者在接受后续的化疗后中位生存时间只有4～5个月。临床治疗方案近三十年来经过屡屡尝试，但没有太大改善，复发或耐药小细胞肺癌的治疗存在极大的未满足的临床需求。
2.LSD1抑制剂
人类组蛋白翻译后修饰包括甲基化、乙酰化、磷酸化、泛素化等过程，是表观遗传学的重要调控手段，通过改变染色质结构影响基因表达。组蛋白的甲基化状态由组蛋白甲基转移酶和组蛋白去甲基化酶共同调控。赖氨酸特异性去甲基化酶(Lysine specific demethylase 1，LSD1，又名KDM1A)是第一个被报道的组蛋白赖氨酸去甲基化酶，通过调控组蛋白赖氨酸的甲基化状态，广泛参与转录调控，影响细胞增殖和分化、胚胎干细胞多能性等诸多生理过程。此外，LSD1还调控部分非组蛋白底物的甲基化状态，包括抑癌 基因p53和DNA甲基转移酶1(DNA methyltransferase 1，DNMT1)等。LSD1的异常表达在多种肿瘤中被报道，与肿瘤的发生发展和预后不良密切相关。
其中，研究发现在小细胞肺癌的98％样本中发现LSD1的高表达，参与维持小细胞肺癌的肿瘤干细胞样基因的表达，是导致疾病难治和复发的重要原因之一。LSD1抑制剂可以通过调控组蛋白H3K4和H3K9的一甲基化和二甲基化状态，影响分化相关基因的表达，促进肿瘤干细胞分化，抑制肿瘤生长，同时提升小细胞肺癌对化疗的敏感性。因此，LSD1抑制剂用于治疗小细胞肺癌等低分化类恶性肿瘤具有良好的应用前景。然而，目前国内外尚没有LSD1抑制剂上市，仅有多个制药公司的小分子药物处于临床阶段，主要用于小细胞肺癌等疾病的治疗。其中，INCB059872、ORY-1001、CC-90011和GSK2879552四种药物的研发方向包含小细胞肺癌这一适应症。
GSK2879552是GlaxoSmithKline公司开发的不可逆LSD1抑制剂，拟用于小细胞肺癌的治疗。GSK2879552于2014年2月开展治疗复发/难治性小细胞肺癌的I期临床研究。2014年2月4日至2017年4月18日，共入组29名患者，共有22名患者完成了研究；7名患者退出研究，主要原因是不良事件(AEs)。其中8例因3级或严重的血小板减少而采取试验药物减量或中断治疗。9名患者报告了12例严重不良事件(SAEs)；6例被认为与治疗有关，其中最常见的是脑病(4例SAEs)。3名患者死亡；1名死亡与SAEs有关。评价16周的疾病控制率仅为14％(4/29)。根据临床Ⅰ期结果，目前该药物已经停止研发。CC-90011在临床I期研究(NCT02875223)中也发现与药物相关的3/4级不良反应为血小板减少(9％)。以上药物的临床研究结果提示，LSD1抑制剂用于小细胞肺癌存在较为严重的安全性缺陷，血小板减少是LSD1抑制剂的主要不良反应之一。目前在研的LSD1抑制剂药物距离临床应用还需相当长的研究历程。
化合物A是一种新型的LSD1抑制剂，在WO2018137644A1实施例144中公开了该化合物及其制备方法。WO2020015745A1公开了化合物A的二盐酸盐。但目前尚不清楚化合物A或其药学上可接受的盐用于临床的重要风险和确切疗效，其在特定疾病中的用途，以及化合物A或其药学上可接受的盐与其他药物联用的效果。因此，有必要对化合物A或其药学上可接受的盐临床应用的安全性和有效性进行研究，以期为临床用药提供参考。
发明内容
基于上述现有技术缺陷，在本发明的第一方面，本发明的目的在于提供化合物A或其药学上可接受的盐在制备预防和/或治疗细胞增殖性疾病，尤其是癌症的药物中的应用。所述化合物A的结构如下式(Ⅰ)所示：
Figure PCTCN2021093362-appb-000001
所述癌症选自肺癌，其中所述肺癌优选小细胞肺癌。
在本发明的第二方面，本发明还提供了一种含有预防和/或治疗有效量的化合物A或其药学上可接受的盐的药物，所述药物用于预防和/或治疗细胞增殖性疾病，尤其是癌症的药物。进一步地，所述癌症选自肺癌，其中所述肺癌优选小细胞肺癌。
在本发明的第三方面，本发明还提供一种预防和/或治疗细胞增殖性疾病，尤其是癌症的方法。进一步地，所述癌症选自肺癌，其中所述肺癌优选小细胞肺癌。
在本发明的第四方面，本发明提供一种组合产品，所述组合产品包含化合物A或其药学上可接受的盐，以及另外的靶向药物或化疗药物，所述另外的靶向药物或化疗药物选自铂类药物和拓扑异构酶抑制剂，包括但不仅限于顺铂、卡铂、洛铂、奈达铂、环铂、奥沙利铂、替尼泊苷、依托泊苷、拓扑替康、伊立替康中的至少一种。优选地，另外的靶向药物或化疗药物选自依托泊苷和顺铂中的至少一种。
附图说明
图1化合物A对神经内分泌相关基因ASCL1和GRP表达的影响。
图2临床Ⅰ期方案流程图。
发明详述
定义
在本文中使用的术语“药学上可接受的盐”是指游离酸或游离碱的盐，优选盐酸盐。
在本文使用的术语“预防”是指当用于疾病或病症(例如癌症)时，与未施用化合物或药物(例如，本申请要求保护的组合产品)的受试者相比，所述化合物或药物能降低受试者体内的医学病症症状的频率或推迟其发病。
在本文中使用的术语“治疗”是指减轻、缓解或改善疾病或病症的症状，改善潜在的代谢引起的症状，抑制疾病或症状，例如阻止疾病或病症的发展、缓解疾病或病症、引起疾病或病症的消退、缓解疾病或病症引起的病况、或阻止疾病或病症的症状。
在本文中使用的术语“细胞增殖性疾病”是指其中的细胞群生长速率低于或高于给定生理状态和条件下的预期速率的病症。
在本文中使用的术语“癌症”是指由异常的不受控制的细胞生长引起的新生物或肿瘤。非限制性的例子包括那些在发明详述中所描述的示例性癌症。术语“癌症”包括同时涉及恶化前癌细胞和恶性癌细胞的疾病。
在本文中使用的术语“受试者”是指包括人类(例如，患者)和动物(例如，小鼠、大鼠、犬、猫、兔、鸡或猴等)。
在本文中使用的术语“有效量”或“预防和/或治疗有效量”是指施用的药物或化合物的足够量(例如，剂量)，其将在一定程度上减轻被治疗的疾病或病症的一种或多种症状。结果可以是缩小和/或减轻病症或疾病原因或任意其它期望的生物系统的改变。例如，用于治疗用途的“有效量”是提供以使疾病或病症的临床症状显著减轻、而不产生过度的毒副作用的化合物或药物(例如，本申请要求保护的组合产品)的量。
在本文中使用的术语“剂量”是指每千克(kg)受试者体重的活性物质的重量(例如，毫克(mg))，或者每位受试者一次服用的活性物质的重量(例如，毫克(mg))。
在本文中使用的术语“室温”是指25℃±5℃。同时，若没有具体指明实验温度，均为室温。
在本文中使用的术语“约”是指该术语所修饰的数值的±10％，更优选为±5％，最优选为±2％，因此本领域的普通技术人员能够清楚地根据所修饰的数值确定术语“约”的范围。
在本文中，本发明所述化合物A或其药学上可接受的盐可以按照现有技术已公开的方法制备得到。例如参照WO2018137644A1实施例144制备化合物A，参照WO2020015745A1 制备化合物A二盐酸盐。WO2018137644A1和WO2020015745A1的全文被引入本发明作为参考。
在本文中，本发明体外研究以化合物A作为受试药物；体内药效学研究、药代动力学研究、毒理学研究和临床研究以化合物A二盐酸盐形式给药。药物剂量均以化合物A计算。
在本文中，如无特别说明，本发明使用的试验材料(包括但不仅限于对照药物、试验试剂等)均为商购获得。参比化合物INCB059872参照WO2017184934实施例6所述方法制备得到(纯度99.33％)。
在本发明的第一方面，本发明的目的在于提供化合物A或其药学上可接受的盐在制备预防和/或治疗细胞增殖性疾病，尤其是癌症的药物中的应用。所述化合物A的结构如下式(Ⅰ)所示：
Figure PCTCN2021093362-appb-000002
所述癌症选自肺癌，其中所述肺癌优选小细胞肺癌。
所述小细胞肺癌优选广泛期小细胞肺癌或者复发和/或转移的小细胞肺癌；进一步优选标准治疗失败或对标准治疗不耐受的小细胞肺癌。本发明所述的小细胞肺癌标准治疗方案包括但不限于：(1)广泛期小细胞肺癌：广泛期小细胞肺癌推荐化疗为主的综合治疗，有局部症状或伴脑转移者推荐在化疗基础上联合放疗或其他治疗方法。化疗方案推荐依托泊苷联合顺铂(EP)、依托泊苷联合卡铂(EC)、伊立替康联合顺铂(IP)、伊立替康联合卡铂(IC)或依托泊苷联合洛铂(EL)方案。(2)复发的小细胞肺癌：一线化疗后3个月内复发或进展者推荐拓扑替康、伊立替康、吉西他滨、替莫唑胺或紫杉醇等药物治疗；3～6个月复发或进展者推荐拓扑替康、伊立替康、吉西他滨、多西他赛、替莫唑胺或长春瑞滨等药物治疗；6个月后复发或进展者可选择初始治疗方案。
进一步优选的，本发明所述的小细胞肺癌包括对顺铂、卡铂、依托泊苷、洛铂、拓扑替康、伊立替康、吉西他滨、替莫唑胺、紫杉醇、多西他赛、长春瑞滨等药物中的一种或多种治疗失败或治疗不耐受的小细胞肺癌。
进一步优选的，本发明所述小细胞肺癌是指ASCL1和/或GRP高表达的小细胞肺癌。
进一步优选的，在本发明所述的应用中，所述药物具有良好的耐受性、无明显不良反应。
优选的，本发明所述的应用，所述药物含有预防和/或治疗有效量的化合物A或其药学上可接受的盐。所述预防和/或治疗有效量优选0.001-1000mg以及下述各量之间的范围：0.01mg、0.1mg、0.5mg、1mg、1.5mg、3mg、6mg、9mg、11mg、12mg、13mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg，其中包括但不限于：0.01-1000mg、0.1-1000mg、0.1-900mg、0.1-800mg、0.1-700mg、0.1-600mg、0.1-500mg、0.1-400mg、0.1-300mg、0.1-200mg、0.1-100mg、0.1-90mg、0.1-80mg、0.1-70mg、0.1-60mg、0.1-50mg、0.1-40mg、0.1-30mg、0.1-20mg、0.1-15mg、0.1-10mg、0.5-1000mg、0.5-900mg、0.5-800mg、0.5-700mg、0.5-600mg、0.5-500mg、0.5-400mg、0.5-300mg、0.5-200mg、0.5-100mg、0.5-90mg、0.5-80mg、0.5-70mg、0.5-60mg、0.5-50mg、0.5-40mg、0.5-30mg、0.5-20mg、0.5-15mg、0.5-10mg、0.5-13mg、 0.5-12mg、0.5-11mg、0.5-9mg、0.5-6mg、0.5-3mg、0.5-1.5mg、1.5-13mg、1.5-12mg、1.5-11mg、1.5-9mg、1.5-6mg、1.5-3mg、3-13mg、3-12mg、3-11mg、3-9mg、3-6mg、6-13mg、6-12mg、6-11mg、6-9mg、9-13mg、9-12mg、9-11mg、11-13mg、11-12mg、12-13mg。可以单剂量施用或分剂量施用。所述药物制成临床接受的制剂，例如口服制剂、注射制剂、局部给药制剂或外用制剂等。
进一步地，除了化合物A或其药学上可接受的盐作为活性成分外，所述药物还包含至少一种药学上可接受的载体、赋形剂和/或稀释剂。所述药物可以以已知的方式在常规的固体或液体载体或稀释剂和常规的药学上制备的辅助剂中以合适的剂量水平制备。优选的制剂适合用于口服施用。所述施用的形式包括例如丸剂、片剂、薄膜片剂、包衣片剂、胶囊、粉剂和贮库。
此外，本发明还包括用于胃肠外施用的制剂，包括真皮、真皮内、皮内、血管内、静脉内、肌肉内、腹膜内、鼻内、阴道内、颊内、经皮、直肠、皮下、舌下、局部或透皮施用，除了典型的媒介物和/或稀释剂以外，所述制剂还含有化合物A和/或其药学上可接受的盐作为活性成分。
本发明的化合物可以作为单一疗法施用，或与其它活性剂、特别是靶向药物、化疗药物或抗肿瘤抗体一起施用。此外，它们也可以与外科手术和/或辐照联合使用。
进一步地，本发明所述的应用，化合物A或其药学上可接受的盐可与其他靶向药物或化疗药物中的一种或多种联合使用。所述的其他靶向药物或化疗药物是指临床用于治疗肿瘤相关疾病的靶向药物或化疗药物，例如铂类药物和拓扑异构酶抑制剂，包括但不仅限于顺铂、卡铂、洛铂、奈达铂、环铂、奥沙利铂、替尼泊苷、依托泊苷、拓扑替康、伊立替康中的至少一种。更优选地，所述靶向药物或化疗药物选自依托泊苷和顺铂中的至少一种。
在本发明的第二方面，本发明还提供了一种含有预防和/或治疗有效量的化合物A或其药学上可接受的盐的药物，所述药物用于预防和/或治疗细胞增殖性疾病，尤其是癌症的药物。进一步地，所述癌症选自肺癌，其中所述肺癌优选小细胞肺癌。
所述小细胞肺癌优选广泛期小细胞肺癌或者复发和/或转移的小细胞肺癌；进一步优选标准治疗失败或对标准治疗不耐受的小细胞肺癌。本发明所述的小细胞肺癌标准治疗方案包括但不限于：(1)广泛期小细胞肺癌：广泛期小细胞肺癌推荐化疗为主的综合治疗，有局部症状或伴脑转移者推荐在化疗基础上联合放疗或其他治疗方法。化疗方案推荐依托泊苷联合顺铂(EP)、依托泊苷联合卡铂(EC)、伊立替康联合顺铂(IP)、伊立替康联合卡铂(IC)或依托泊苷联合洛铂(EL)方案。(2)复发的小细胞肺癌：一线化疗后3个月内复发或进展者推荐拓扑替康、伊立替康、吉西他滨、替莫唑胺或紫杉醇等药物治疗；3～6个月复发或进展者推荐拓扑替康、伊立替康、吉西他滨、多西他赛、替莫唑胺或长春瑞滨等药物治疗；6个月后复发或进展者可选择初始治疗方案。
进一步优选的，本发明所述的小细胞肺癌包括对顺铂、卡铂、依托泊苷、洛铂、拓扑替康、伊立替康、吉西他滨、替莫唑胺、紫杉醇、多西他赛、长春瑞滨等药物中的一种或多种治疗失败或治疗不耐受的小细胞肺癌。
进一步优选的，本发明所述小细胞肺癌是指ASCL1和/或GRP高表达的小细胞肺癌。
本发明提供了一种预防和/或治疗治疗小细胞肺癌的药物，其特征在于，含有预防和/或治疗有效量的化合物A或其药学上可接受的盐，以及任选的，药学上可接受的赋形剂、载体和/或稀释剂。所述药物制成临床接受的制剂，例如口服制剂、注射制剂、局部给药 制剂或外用制剂等。所述药物中还可含有其他靶向药物或化疗药物中的一种或多种。所述的其他靶向药物或化疗药物是指临床用于治疗肿瘤相关疾病的靶向药物或化疗药物，例如铂类药物和拓扑异构酶抑制剂，包括但不仅限于顺铂、卡铂、洛铂、奈达铂、环铂、奥沙利铂、替尼泊苷、依托泊苷、拓扑替康、伊立替康中的至少一种。更优选地，所述靶向药物或化疗药物选自依托泊苷和顺铂中的至少一种。
进一步地，本发明的药物如在本发明第一方面所述。
在本发明的第三方面，本发明的另一个发明目的还包括提供一种预防和/或治疗小细胞肺癌的方法，所述方法包括给受试者施用预防和/或治疗有效量的化合物A或其药学上可接受的盐。所述施用可以是口服施用、注射施用、局部施用或体外施用。相应的，化合物A或其药学上可接受的盐制成临床接受的制剂后施用，所述制剂包括口服制剂、注射制剂、局部给药制剂、外用制剂等。
所述小细胞肺癌优选广泛期小细胞肺癌或者复发和/或转移的小细胞肺癌；进一步优选标准治疗失败或对标准治疗不耐受的小细胞肺癌。本发明所述的小细胞肺癌标准治疗方案包括但不限于：(1)广泛期小细胞肺癌：广泛期小细胞肺癌推荐化疗为主的综合治疗，有局部症状或伴脑转移者推荐在化疗基础上联合放疗或其他治疗方法。化疗方案推荐依托泊苷联合顺铂(EP)、依托泊苷联合卡铂(EC)、伊立替康联合顺铂(IP)、伊立替康联合卡铂(IC)或依托泊苷联合洛铂(EL)方案。(2)复发的小细胞肺癌：一线化疗后3个月内复发或进展者推荐拓扑替康、伊立替康、吉西他滨、替莫唑胺或紫杉醇等药物治疗；3～6个月复发或进展者推荐拓扑替康、伊立替康、吉西他滨、多西他赛、替莫唑胺或长春瑞滨等药物治疗；6个月后复发或进展者可选择初始治疗方案。
进一步优选的，本发明所述的小细胞肺癌包括对顺铂、卡铂、依托泊苷、洛铂、拓扑替康、伊立替康、吉西他滨、替莫唑胺、紫杉醇、多西他赛、长春瑞滨等药物中的一种或多种治疗失败或治疗不耐受的小细胞肺癌。
进一步优选的，本发明所述小细胞肺癌是指ASCL1和/或GRP高表达的小细胞肺癌。
所述方法还包括提供化合物A或其药学上可接受的盐治疗小细胞肺癌的安全有效剂量和剂量频率。
所述预防和/或治疗有效量可治疗或缓解所述受试者的肿瘤疾病。化合物A或其药学上可接受的盐合适的剂量范围为每次从约0.001mg/kg至约1000mg/kg；优选的，从约0.01mg/kg至约100mg/kg。优选的，化合物A或其药学上可接受的盐每次给药剂量为0.001mg-1000mg；进一步优选的，每次给药剂量为0.01mg-100mg，或者0.1mg-50mg，最优选0.5-25mg。以单剂量或分剂量施用；可以连续给药，也可以间隔给药。示例性的，所述给药剂量和剂量频率为：每周给药一次，每次给药0.5-13mg、0.5-12mg、0.5-11mg、0.5-9mg、0.5-6mg、0.5-3mg、0.5-1.5mg、1.5-13mg、1.5-12mg、1.5-11mg、1.5-9mg、1.5-6mg、1.5-3mg、3-13mg、3-12mg、3-11mg、3-9mg、3-6mg、6-13mg、6-12mg、6-11mg、6-9mg、9-13mg、9-12mg、9-11mg、11-13mg、11-12mg、12-13mg，例如，0.5、1.5、3、6、9、11、12、13mg等，优选6mg～9mg。
本发明所述的化合物A或其药学上可接受的盐的剂量，均以化合物A计。
在本发明的第四方面，本发明提供一种组合产品，所述组合产品包含化合物A或其药学上可接受的盐，以及另外的靶向药物或化疗药物，所述另外的靶向药物或化疗药物选自铂类药物和拓扑异构酶抑制剂，包括但不仅限于顺铂、卡铂、洛铂、奈达铂、环铂、奥沙 利铂、替尼泊苷、依托泊苷、拓扑替康、伊立替康中的至少一种。更优选地，另外的靶向药物或化疗药物选自依托泊苷和顺铂中的至少一种。还更优选地，本发明提供一种组合产品，包含化合物A或其药学上可接受的盐和顺铂，或化合物A或其药学上可接受的盐和顺铂以及依托泊苷。
所述组合产品呈药物组合物的形式。在一些实施方案中，在所述组合产品中，所述化合物A或其药学上可接受的盐与另外的靶向药物或化疗药物各自呈单独的制剂形式。进一步地，所述化合物A或其药学上可接受的盐与另外的靶向药物或化疗药物可以同时或先后施用。
所述组合产品含有预防和/或治疗有效量的化合物A或其药学上可接受的盐，其中所述预防和/或治疗有效量优选0.001-1000mg，以及下述各量之间的范围：0.01mg、0.1mg、0.5mg、1mg、1.5mg、3mg、6mg、9mg、11mg、12mg、13mg、20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg、100mg、200mg、300mg、400mg、500mg、600mg、700mg、800mg、900mg、1000mg，其中包括但不限于：0.01-1000mg、0.1-1000mg、0.1-900mg、0.1-800mg、0.1-700mg、0.1-600mg、0.1-500mg、0.1-400mg、0.1-300mg、0.1-200mg、0.1-100mg、0.1-90mg、0.1-80mg、0.1-70mg、0.1-60mg、0.1-50mg、0.1-40mg、0.1-30mg、0.1-20mg、0.1-10mg、0.5-1000mg、0.5-900mg、0.5-800mg、0.5-700mg、0.5-600mg、0.5-500mg、0.5-400mg、0.5-300mg、0.5-200mg、0.5-100mg、0.5-90mg、0.5-80mg、0.5-70mg、0.5-60mg、0.5-50mg、0.5-40mg、0.5-30mg、0.5-20mg、0.5-15mg、0.5-10mg、0.5-13mg、0.5-12mg、0.5-11mg、0.5-9mg、0.5-6mg、0.5-3mg、0.5-1.5mg、1.5-13mg、1.5-12mg、1.5-11mg、1.5-9mg、1.5-6mg、1.5-3mg、3-13mg、3-12mg、3-11mg、3-9mg、3-6mg、6-13mg、6-12mg、6-11mg、6-9mg、9-13mg、9-12mg、9-11mg、11-13mg、11-12mg、12-13mg。所述组合产品制成临床接受的制剂，例如口服制剂、注射制剂、局部给药制剂或外用制剂等。
进一步地，所述组合产品还包含至少一种药学上可接受的载体、赋形剂和/或稀释剂。所述组合产品可以以已知的方式在常规的固体或液体载体或稀释剂和常规的药学上制备的辅助剂中以合适的剂量水平制备。优选的制剂适合用于口服施用。所述施用的形式包括例如丸剂、片剂、薄膜片剂、包衣片剂、胶囊、粉剂和贮库等。
进一步地，所述组合产品用于预防和/或治疗细胞增殖性疾病，尤其是癌症。进一步地，所述癌症选自肺癌，其中所述肺癌优选小细胞肺癌。
所述小细胞肺癌优选广泛期小细胞肺癌或者复发和/或转移的小细胞肺癌；进一步优选标准治疗失败或对标准治疗不耐受的小细胞肺癌。本发明所述的小细胞肺癌标准治疗方案包括但不限于：(1)广泛期小细胞肺癌：广泛期小细胞肺癌推荐化疗为主的综合治疗，有局部症状或伴脑转移者推荐在化疗基础上联合放疗或其他治疗方法。化疗方案推荐依托泊苷联合顺铂(EP)、依托泊苷联合卡铂(EC)、伊立替康联合顺铂(IP)、伊立替康联合卡铂(IC)或依托泊苷联合洛铂(EL)方案。(2)复发的小细胞肺癌：一线化疗后3个月内复发或进展者推荐拓扑替康、伊立替康、吉西他滨、替莫唑胺或紫杉醇等药物治疗；3～6个月复发或进展者推荐拓扑替康、伊立替康、吉西他滨、多西他赛、替莫唑胺或长春瑞滨等药物治疗；6个月后复发或进展者可选择初始治疗方案。
进一步优选的，本发明所述的小细胞肺癌包括对顺铂、卡铂、依托泊苷、洛铂、拓扑替康、伊立替康、吉西他滨、替莫唑胺、紫杉醇、多西他赛、长春瑞滨等药物中的一种或多种治疗失败或治疗不耐受的小细胞肺癌。
进一步优选的，本发明所述小细胞肺癌是指ASCL1和/或GRP高表达的小细胞肺癌。
为评价化合物A或其药学上可接受的盐治疗小细胞肺癌的疗效和安全性，本申请的发明人开展LSD1体外活性抑制试验、体外培养肿瘤细胞增殖试验、体内抑瘤试验、药代动力学试验、安全毒理学试验、临床Ⅰ期研究，结果显示化合物A作用机理明确，能显著抑制LSD1蛋白的活性，在小细胞肺癌体外细胞培养和体内移植瘤模型中抑制肿瘤生长效果明显，毒理研究显示该药物安全可耐受。在临床Ⅰ期研究中化合物A可安全有效地治疗广泛期小细胞肺癌。可见，化合物A能有效治疗小细胞肺癌，临床安全性良好。并且，化合物A与顺铂或顺铂+依托泊苷联用，能显著增强抗肿瘤作用，产生协同效应，为临床联合治疗方案提供了支持。
具体实施方式
以下列举的实施例是为了更好地对本发明的内容进行说明，但并不是本发明的内容仅限于所举实施例。本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
一、体外研究
1.化合物A对LSD1的抑制作用
本试验采用的酶为人源LSD1，标准底物为组蛋白H3(1-21)K4me2肽(10μM)，并以INCB059872为参比化合物，采用酶荧光偶联法，通过辣根过氧化酶(HPR)和荧光试剂Amplex Red联合检测LSD1与FAD相结合产生去甲基化活性后生成的H 2O 2的方法测定化合物的活性。从10μM开始3倍稀释，检测化合物以及对照化合物INCB059872的10个浓度下IC50值。化合物在加入底物开始反应前，先与酶预孵化30分钟。荧光检测器：EnVision，激发波长：Ex/Em＝535/590nM。
具体测试条件如下：
LSD1缓冲液成分：50mM Tris-HCl,pH 7.5,0.05％CHAPS,1％DMSO。
反应时间：室温反应1小时
反应过程：
1.将酶加入新鲜制备的缓冲液中。
2.使用纳升级的Acoustic Technology(Echo 550,LabCyte Inc.Sunnyvale,CA)将化合物的DMSO溶液加入酶混合物中，室温孵育30分钟。
3.将底物加入新鲜制备的缓冲液中。
4.室温孵育1小时。
5.准备检测混合液。
6.使用Perkin Elmer Envision读取数据。
7.使用Excel和GraphPad Prism软件分析数据。
结果显示：如表1中所示，化合物A对LSD1有显著抑制作用，IC50＝8.0nM，并且其抑制作用优于参比化合物INCB059872(IC50＝12.5nM)。
表1化合物A对LSD1的抑制作用
Figure PCTCN2021093362-appb-000003
Figure PCTCN2021093362-appb-000004
2.化合物A对小细胞肺癌细胞株NCI-H1417和NCI-H526的增殖抑制作用
本次实验用Cell Titer Glo实验方法分析LSD1抑制剂化合物A及参比化合物INCB059872对小细胞肺癌细胞株NCI-H1417和NCI-H526细胞增殖的影响。
实验材料：RPMI 1640培养基，胎牛血清，青霉素链霉素双抗，左旋谷氨酰胺，Promega CellTiter-Glo试剂盒，二甲基亚砜(DMSO)。Envision多标记分析仪(PerkinElmer 2104)。
实验方法：
实验用细胞培养液：在RPMI1640细胞培养基中添加终浓度为10％的胎牛血清，1％的青霉素/链霉素双抗，1％的左旋谷氨酰胺，4℃保存备用。
悬浮细胞吹打均匀后，用Vi-cell细胞计数仪计数，用培养基制成3000个细胞/90μL的NCI-H1417细胞悬液，加入96孔细胞培养板，90μL/孔。参考化合物INCB059872及受试化合物A用DMSO将化合物稀释成10mM的储存液，然后以该浓度为起始浓度，用DMSO将化合物3倍递减稀释9次，得到10个浓度，用培养基将稀释好的化合物进行100倍稀释，并同时同样以培养基100倍稀释与化合物溶液等体积的DMSO，将稀释好的混合液10μL分别转移至相应的细胞板中(即10倍稀释)，DMSO稀释液则转入对照组F、G排。化合物终浓度为10μM为起始浓度，3倍递减稀释10个浓度，混匀离心，置于含5％CO 2的细胞培养箱中37℃培养10天。取出96孔细胞培养板，加入CTG试剂，50μL/孔，混匀离心，室温孵育10分钟。使用Envison多标记分析仪读数。
使用同样方法针对NCI-H526细胞进行试验。
数据分析：NCI-H1417细胞试验，利用方程式(1-(样品值-最小值)/(最大值-最小值))*100将原始数据换算成抑制率，计算IC50采用的是四参数剂量-响应模型，公式为Y＝Bottom+(Top-Bottom)/(1+10^((logEC50-x)*HillSlope))。NCI-H526细胞试验，利用公式：Vsample/Vvehicle control x100％计算细胞存活率。其中Vsample为药物处理组的读数，Vvehicle control为溶剂对照组的平均值。应用GraphPad Prism 5.0软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。
结果显示：如表2中所示，化合物A对NCI-H1417有显著的增殖抑制作用，IC50＝207.8nM，并且其抑制活性优于参比化合物INCB059872(IC50＝421.0nM)。化合物A对NCI-H526有显著的增殖抑制作用，IC50＝610.6nM，显著优于参比化合物INCB059872(IC50＞1000.0nM)。
表2化合物A对NCI-H1417和NCI-H526的增殖抑制作用
Figure PCTCN2021093362-appb-000005
3.化合物A对神经内分泌相关基因ASCL1和GRP表达的影响
小细胞肺癌是一种肺部神经内分泌肿瘤，约75％的小细胞肺癌病人表达ASCL1。ASCL1是一种神经内分泌相关的转录因子，也是治疗高度恶性的神经内分泌肺癌的潜在靶标。胃泌素释放肽(gastrin-releasing peptide，GRP)是一种胃肠激素，在神经系统、胃肠道和肺部广泛分布。小细胞肺癌细胞可以分泌GRP，检测GRP表达有助于疾病的监控。
本实验通过实时定量PCR测定NCI-H1417细胞加药处理后ASCL1和GRP表达量的变化。实时荧光定量PCR采用SYBR Green法，在qPCR反应体系中添加SYBR Green 5μL，SYBR Green与双链DNA结合后发出荧光，通过检测反应体系中的SYBR Green荧光强度，检测PCR产物扩增量。分析得到靶基因和内参基因的Ct值，运用ΔΔCT法计算靶基因相对于对照组的表达量。基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析。
试验结果：与对照组相比，化合物A和INCB059872加药组ASCL1和GRP的mRNA表达水平均有所下降，且化合物A加药组中ASCL1和GRP的mRNA减少呈剂量依赖性。详情见图1。
二、体内药效研究
1.化合物A在小细胞肺癌NCI-H1417细胞皮下异种移植小鼠模型的体内药效学研究
试验方法与步骤：
细胞培养：人小细胞肺癌NCI-H1417(ATCC，马纳萨斯，弗吉尼亚州，货号：CRL-5869)细胞体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，37℃5％CO 2培养传代。当细胞饱和度为80％-90％时，用胰酶-EDTA消化收取细胞，计数，调整10×10 7个细胞/mL重悬于PBS。
细胞接种：0.2mL(10×10 6个)NCI-H1417细胞(加基质胶，体积1：1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约100-150mm 3时随机分组，开始给药。
试验动物日常观察：每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响，如行为活动、摄食摄水量(仅目测)、体重变化(每周测量两次体重)、外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。
肿瘤测量：每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝T RTV/C RTV×100％(T RTV：治疗组RTV；C RTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即D0)测量所得肿瘤体积，Vt为对应小鼠某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
在实验结束后检测肿瘤重量，并计算T weight/C weight百分比，T weight和C weight分别表示给药组和溶媒对照组的瘤重。
本试验还同时观察了药物在肺组织和血液中的分布情况。PK取材和分析：在最后一次给药后，采集动物的全血、血浆、肺和肿瘤组织，用于体外PK/PD实验。
统计分析：包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)。治疗组在试验结束时(给药后第35天)表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。三组或多组间比较用one-way ANOVA进行分析，本实验中RTV和瘤重统计的F值都有显著性差异，应用Games-Howell法进行检验。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
采用金氏公式评价化合物A与顺铂(Cisplatin)的联合作用，具体方法如下：Q＝E(a+b)/[E(a)+E(b)-E(a)*E(b)](其中E(a+b)：a、b两药联合给药后的抑瘤率；E(a)：a单独给药时的抑瘤率；E(b)：b单独给药时的抑瘤率。Q<0.85具有拮抗作用，0.85≤Q≤1.15具有相加作用，Q>1.15具有协同作用。
结果显示：如表3中所示，在小细胞肺癌NCI-H1417细胞皮下异种移植小鼠模型中，单用化合物A在1mg/kg、1.5mg/kg和3mg/kg剂量下均具有显著抑瘤作用，并具有剂量依赖性，TGI分别为81.9％、99.2％和115.6％，T/C分别为40.6％、27.0％和15.1％。
化合物A(1mg/kg，PO QD或3mg/kg，PO BIW)与顺铂(1mg/kg，IP BIW)联合治疗时与溶剂对照组和顺铂组相比都产生了显著的抑瘤作用，TGI分别为130.1％和134.5％，计算得到Q值分别为1.34和1.31。可见，化合物A与顺铂联合治疗时在抑瘤方面产生了协同作用。
表3化合物A对NCI-H1417细胞皮下异种移植瘤的抑制作用
Figure PCTCN2021093362-appb-000006
末次给药后药代动力学数据显示，化合物A(1mg/kg)在4h和24h肺组织全血药物浓度比分别为125和140，表明药物能够在肺组织富集，预计对肺癌的治疗具有一定优势。
化合物A在所有剂量下都显示出良好的耐受性，所有治疗组均无动物死亡。在NCI-H1417体内药效试验中也同时考察了药物对血细胞的影响。化合物A三个剂量组单用或与顺铂联合用药，给药35天之后测试血常规，对白细胞、红细胞、血小板、单核细胞、中性粒细胞和网织红细胞等关键血常规指标均无显著影响，表现出良好的血液学安全性。
2.化合物A在小细胞肺癌NCI-H526细胞皮下异种移植小鼠模型的体内药效学研究试验方法和步骤：
细胞培养：人小细胞肺癌NCI-H526(ATCC，马纳萨斯，弗吉尼亚州，货号：CRL-5811)细胞，体外悬浮培养，培养条件为RPMI-1640培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃5％CO 2培养传代。当细胞饱和度为80％-90％时，计数，调整10×10 7个细胞/mL重悬于PBS。
细胞接种：取5只BABL/c裸小鼠，每只动物于右后背皮下位置接种0.1mL(5×10 6个)NCI-H526细胞，当肿瘤体积接近500mm 3时，取出肿瘤，用于组织接种。将肿瘤组织剔除坏死组织后切成(20-30mm 3)的小块，皮下接种于每只小鼠的右后背等待肿瘤生长，肿瘤平均体积达到约90mm 3时随机分组，开始进行给药。
试验动物日常观察：每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响，如行为活动、摄食摄水量(仅目测)、体重变 化(每周测量两次体重)、外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。
肿瘤测量：每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)或相对肿瘤增殖率T/C(％)评价。相对肿瘤增殖率T/C(％)＝T RTV/C RTV×100％(T RTV：治疗组RTV；C RTV：阴性对照组RTV)。根据肿瘤测量的结果计算出相对肿瘤体积(relative tumor volume，RTV)，计算公式为RTV＝Vt/V0，其中V0是分组给药时(即D0)测量所得肿瘤体积，Vt为对应小鼠某一次测量时的肿瘤体积，T RTV与C RTV取同一天数据。TGI(％)，反映肿瘤生长抑制率。TGI(％)＝[(1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。
在实验结束后检测肿瘤重量，并计算T weight/C weight百分比，T weight和C weight分别表示给药组和溶媒对照组的瘤重。
统计分析：包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)。治疗组在试验结束时(给药后第21天)表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。三组或多组间比较用one-way ANOVA进行分析，本实验中RTV和瘤重统计的F值都有显著性差异，应用Games-Howell法进行检验。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
采用金氏公式评价化合物A与顺铂(Cisplatin)、依托泊苷的联合作用，具体方法如下：Q＝E(a+b)/[E(a)+E(b)-E(a)*E(b)](其中E(a+b)：a、b两药联合给药后的抑瘤率；E(a)：a单独给药时的抑瘤率；E(b)：b单独给药时的抑瘤率。Q<0.85具有拮抗作用，0.85≤Q≤1.15具有相加作用，Q>1.15具有协同作用。
结果显示：如表4中所示，在小细胞肺癌NCI-H526细胞皮下异种移植小鼠模型中，化合物A(1.5mg/kg)单独给药组和INCB059872(1.5mg/kg)单独给药组的平均肿瘤体积分别为1,427和1,571mm 3，无显著的抑瘤作用。顺铂(Cisplatin)加依托泊苷(Etoposide)联合给药组和溶剂对照组相比具有一定的抑瘤作用，平均肿瘤体积为999mm 3，T/C值为50.15％，TGI值为53.33％。化合物A(1.5mg/kg，PO QD或3mg/kg，PO BIW)与顺铂(Cisplatin)加依托泊苷(Etoposide)三药联用时，与溶剂对照组以及化疗组合给药相比，均具有显著的抑瘤作用(T/C＝11.38％和19.01％，TGI＝90.36％和80.46％)。所有给药组动物耐受性均良好，无显著体重下降或动物死亡。化合物A(1.5mg/kg，PO QD)与顺铂(Cisplatin)+依托泊苷(Etoposide)三药联用时，Q值为1.33，可见化合物A与顺铂和依托泊苷联合治疗时在抑瘤方面产生了协同作用。
表4化合物A对NCI-H526细胞皮下异种移植瘤的抑制作用
Figure PCTCN2021093362-appb-000007
三、药代动力学研究
1.化合物A在啮齿类动物SD大鼠的药代动力学研究
化合物A在雌雄SD大鼠体内的药代动力学性质研究包括：(1)0.5mg/kg单次静脉注射给药研究；(2)0.5、1.5和5mg/kg灌胃剂量递增研究；(3)每3天一次、每次1.5mg/kg、连续3次重复灌胃给药研究。
试验方法：
将24只SD大鼠，雌雄各半，按体重相近分成4组，每组3雄3雌。第1组动物单次静脉注射给药0.5mg/kg化合物A，溶媒为10％HP-β-CD(β环糊精水溶液)。第2组和第4组动物分别单次灌胃施用0.5和5mg/kg化合物A。第3组动物连续3次灌胃给药，每3天1次，每次1.5mg/kg化合物A。第1组动物于给药前及给药后0.083、0.25、0.5、1、2、4、6、8、12、24、36和48小时采集血浆样品。第2组和第4组动物分别于给药前及给药后0.25、1、2、4、6、8、12、24、36和48小时采集血浆样品。第3组动物于第1次和第3次给药前及给药后0.25、1、2、4、6、8、12、24、36和48小时以及第2次给药前采集血浆样品。血浆样本中化合物A的浓度使用LC-MS/MS方法测定。
结果显示：(1)单次静脉注射给药0.5mg/kg后，化合物A在雌雄SD大鼠中的血浆清除率(CL)为88.6±6.29mL/min/kg，稳态表观分布容积(Vdss)为63.7±10.4L/kg，消除半衰期(T1/2)为8.71±0.532h，暴露量(AUC0-last)是263±19.7nM·h。
(2)雌雄SD大鼠单次灌胃给药0.5mg/kg化合物A后，其生物利用度为29.9％。雌雄SD大鼠单次灌胃给药0.5、1.5和5mg/kg化合物A后，AUC0-last值分别为78.6±21.0、315±60.4和1470±227nM·h，达峰浓度(Cmax)分别为5.24±1.56、22.1±3.95和102±24.1nM，达峰时间(Tmax)分别出现在给药后5.33±2.07h、3.33±2.07h和3.50±2.74h。
(3)SD大鼠每3天1次、每次1.5mg/kg、连续3次灌胃给药后，系统暴露量均未见药物蓄积。在0.5至5mg/kg剂量范围内，雌雄大鼠AUC0-last和Cmax均随剂量增加成比例增长，各剂量组下无明显性别差异。
2.化合物A在比格犬的药代动力学研究
2.1化合物A雌雄比格犬静脉注射及经口给药后的药代动力学研究
化合物A在雌雄比格犬体内的药代动力学性质研究包括(1)0.1mg/kg单次静脉注射研究；(2)0.1，0.3及0.6mg/kg口服剂量递增研究；(3)0.3mg/kg剂量下连续3周，每周1次重复口服给药研究。
试验方法:
将24只比格犬分成4组，每组6只，雌雄各半。第1组动物单次静脉注射0.1mg/kg化合物A，第2和4组动物分别单次口服给药0.1和0.6mg/kg的化合物A溶液。第3组动物连续3周口服给药，每周1次，每次口服0.3mg/kg的化合物A溶液。静脉注射组的溶媒为10％HP-β-CD(β环糊精)水溶液。口服组的溶媒为0.5％MC(甲基纤维素)水溶液。第1，2和4组的动物于给药前及给药后0.0833(仅第1组，即静脉注射组)，0.25，0.5，1，2，4，6，8，12，24，48，72，96，120，168小时采集血浆样品。第3组动物于第1周和第3周给药前及给药后0.25，0.5，1，2，4，6，8，12，24，48，72，96，120，168(第2次给药前)小时采集血浆样品。血浆样本中化合物A的浓度用LC-MS/MS方法测定。
结果显示：(1)雌雄比格犬单次静脉注射0.1mg/kg的化合物A后，CL为17.0±10.3mL/min/kg，Vdss为45.1±25.2L/kg，T1/2和0点到无穷大时间点血浆浓度曲线下面积(AUC0-inf)分别为31.9±3.32h和338±127nM·h。雌雄比格犬单次口服0.1mg/kg的化合物A溶液后，暴露量AUC0-inf为248±88.0nM·h，生物利用度为73.4％。
(2)雌雄比格犬单次口服给药0.1，0.3及0.6mg/kg的化合物A溶液后，AUC0-last分别为234±83.2，900±248和1490±432nM·h，Cmax分别为5.88±1.96，21.1±7.48和30.5±13.1nM，Tmax分别出现在给药后9.33±2.07，7.33±2.42和9.00±2.45h。在0.1至0.6mg/kg剂量范围内，雌雄性比格犬的系统暴露量(Cmax和AUC0-last)均呈剂量相关线性增长，且未见明显性别差异。
(3)连续3周，每周1次口服0.3mg/kg的化合物A溶液后，与第1周相比，雌雄比格犬的系统暴露量(Cmax和AUC0-last)均未出现明显变化。
2.2化合物A雌雄比格犬静脉注射及经口给药后的药代动力学研究
本实验旨在研究单次口服0.2mg/kg化合物A胶囊在雌雄比格犬体内的药代动力学性质，考察经口给药后的生物利用度，并比较雌雄差异。
试验方法：
选取3只雄性和3只雌性比格犬，每只单次口服施用1颗化合物A胶囊(每颗胶囊含有2mg活性成分化合物A)，于给药前及给药后0.25，0.5，1，2，4，6，8，12，24，48，72，96，120，168小时采集血浆样品。血浆样本中化合物A的浓度用LC-MS/MS方法测定。
雌雄比格犬单次口服0.2mg/kg的化合物A胶囊后，AUC0-inf和Cmax分别为689±334h·nM和12.8±5.87nM，达峰时间出现在给药后11.3±1.63h，生物利用度为101％。雌性与雄性AUC0-last比值为1.75，系统暴露量无明显性别差异。
四、毒理学研究
1.安全药理学试验
单次经口灌胃施用SD大鼠化合物A 0.5mg/kg、1.5mg/kg和5mg/kg剂量下，各剂量组在24h观察范围内未见对大鼠神经系统功能相关指标明显药物相关性影响。
比格犬单次经口灌胃施用化合物A 0.075mg/kg、0.25mg/kg和0.75mg/kg组对心血管系统和呼吸系统未见明显药物相关影响。
2.化合物A对hERG钾通道电流的影响
采用稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，使用cisapride作为阳性对照化合物，用电生理手动膜片钳技术，考察化合物A对hERG钾通道的抑制作用。化合物A在40μM浓度给药1分钟后对hERG钾电流的抑制百分率为55.8％，在此条件下，该化合物抑制hERG钾电流的IC50值为34.5μM，心血管副作用风险较低。
本次测试使用cisapride作为阳性对照化合物，文献报到cisapride对hERG钾电流抑制的IC50值范围在5～66nM，本次试验同一天内检测cisapride得到的IC50值为32.6nM，说明试验系统稳定可靠，测试结果准确。
3.急性毒性试验
SD大鼠单次经口灌胃施用化合物A 6、20、50mg/kg恢复14天毒性实验，最大耐受剂量(MTD)为50mg/kg，受试物相关的改变主要表现为皮肤红斑、红肿以及脾脏红髓髓外造血。
比格犬单次灌胃施用化合物A 0.3mg/kg、1mg/kg和3mg/kg恢复21天伴随毒代动力学实验，最大耐受剂量(MTD)为3mg/kg(AUC0-120h：♂4778.05ng·h/mL、♀6647.67ng·h/mL)，受试物相关的改变主要表现为皮肤毒性反应及胃肠道反应，伴有体重降低和摄食情况差，血液学可见白细胞及其分类、红细胞相关指标、血小板相关指标改变，以及淋巴细胞减少伴胸腺小和红髓髓外造血伴脾脏增大。
4.长期毒性试验
4.1化合物A用于SD大鼠的长期毒性试验
SD大鼠经口灌胃重复给药9次(每周2次，分别为第1天和第4天)施用0.6、2、6mg/kg化合物A，停药恢复4周，雌雄动物未见毒性反应剂量(NOAEL)均为0.6mg/kg，雄性最大耐受剂量(MTD)为2mg/kg(D29：AUC0-48h：♂75.56ng·h/mL)，雌性最大耐受剂量(MTD)为6mg/kg(D29：AUC0-48h：♀383.60ng·h/mL)。
受试物相关的毒性改变主要表现为红斑、红肿和结痂，血液系统可见白细胞分类、红系指标、血小板相关指标改变，组织病理学可见淋巴细胞减少(胸腺、脾脏)、髓外造血增多(脾脏、肝脏)、多脏器/组织出血(睾丸间质、附睾间质、眼球、胃、卵巢黄体、肺脏肺泡、胸腺、胰腺)；还可见肝脏胆管增生，骨髓(胸骨和股骨)骨干新生骨增多、干骺端骨小梁减少和巨核细胞增多，卵巢闭锁卵泡增加和新生黄体减少，肺脏巨噬细胞聚集和纤维化，胰腺腺泡萎缩/坏死和胰岛周围纤维化。停药恢复4周，以上改变可见完全恢复或恢复趋势，未见其他供试品相关毒性反应。与同靶点药物毒性反应基本一致。
4.2化合物A用于比格犬的长期毒性试验
比格犬经口灌胃重复给药5次(每周第1天给药)施用0.075、0.25、0.75mg/kg化合物A，停药恢复4周，未见毒性反应剂量(NOAEL)为0.075mg/kg，最高非严重毒性剂量(HNSTD)为0.25mg/kg(D29：AUC0-120h：♂126.53ng·h/mL，♀150.65ng·h/mL)，最小致死剂量(MLD)为0.75mg/kg(D29：AUC0-120h：♂1826.43ng·h/mL，♀701.55ng·h/mL)。
受试物相关的毒性改变主要表现为胃肠道毒性反应、精神萎靡和活动减少，血液系统可见白细胞分类、红细胞相关指标、血小板相关指标改变，药物相关性组织病理学改变见 于造血-淋巴器官/组织、消化道、肾上腺、肺脏、肝脏、肌肉。停药恢复4周，以上改变可见完全恢复或恢复趋势，未见其他药物相关毒性反应。与同靶点药物毒性反应基本一致。
小鼠体内药效试验显示，化合物A 1-3mg/kg剂量对小细胞肺癌具有显著的抑制作用，换算人体等效剂量约为5.35mg-16.05mg(按60kg体重计)。综合上述药效学、毒理学研究结果，以小鼠药效剂量1mg/kg、大鼠长期毒性试验MTD剂量(雄性2mg/kg、雌性6mg/kg)换算人体等效剂量，计算化合物A的安全窗为雄性4.5倍、雌性13.6倍，说明化合物A安全耐受性较好。
五、化合物A临床Ⅰ期研究
1.方案设计
1.1试验流程
本试验为一项针对广泛期小细胞肺癌患者的开放、剂量递增及剂量扩展的Ⅰ期临床研究，旨在评价化合物A在广泛期小细胞肺癌患者中的安全性、耐受性、药代动力学特征以及初步抗肿瘤活性。抗肿瘤活性参照实体瘤疗效评价标准(RECIST)V1.1进行。
本研究分两阶段进行，第一阶段(Stage I)为剂量递增(Dose escalation)研究，第二阶段(Stage II)为剂量扩增(Dose expansion)研究。
第一阶段(Stage I)：剂量递增研究
化合物A的起始给药剂量定为0.5mg/周，初步拟定5个剂量组：0.5、1.5、3、6、9mg。预设的最高递增剂量为9mg/周。本研究将遵循“3+3”剂量递增方案。
完成核心给药期给药后，评估受试者的安全性、耐受性、药代动力学特征及抗肿瘤活性。如受试者耐受性良好且本人同意，则可继续进行治疗，直至疾病进展，或出现不可耐受的毒性，或其他原因终止研究。
第二阶段(Stage II)：剂量扩增研究
可根据剂量递增研究获得的安全性、耐受性及有效性等数据，必要时进行目标剂量组剂量扩增研究和不同给药方案的探索研究。申办者和研究者将持续进行安全性评价，基于既往剂量水平的可用数据，确定扩增期间的用药剂量水平和给药方案。
以上两个阶段的Ⅰ期临床实验，共拟纳入广泛期小细胞肺癌患者34-71例。
1.2递增剂量组的设置
化合物A的起始给药剂量定为0.5mg，预设的最高递增剂量为9mg。在确保安全的前提下，避免过多受试者暴露在无效剂量下，同时密切监测受试者的安全性指标，本研究采取200％、100％、100％、50％的比例递增，即爬坡方案设计为0.5、1.5、3、6、9mg。
如果剂量递增至预设的最高剂量组时，该剂量组安全性和耐受性仍良好，则可由研究者和申办者共同讨论决定是否尝试更高剂量，例如以20％或30％增幅调整剂量。具体的剂量递增阶段的剂量组设置参见表5：
表5剂量递增阶段的剂量组设置
分组 剂量 递增幅度 受试者
1 0.5mg - 1
2 1.5mg 200％ 3+3
3 3mg 100％ 3+3
4 6mg 100％ 3+3
5 9mg 50％ 3+3
6(如有必要) 待定 待定 3+3
1.3剂量递增原则
剂量递增将从初始剂量(0.5mg)开始，在初始剂量组将仅评价1例患者，从第二个剂量组(1.5mg)开始遵循“3+3原则”，每个剂量组入组3～6例受试者。在所有受试者完成了某个剂量的药物试验以后，由申办方和研究者共同决定是否递增至后一个剂量水平。
在初始剂量组完成后是否进行后续剂量组试验根据以下规则判断：
(1)若患者出现2级及以下AE(非DLT)，即可递增至后一个剂量组；
(2)若患者出现3级及以上AE(非DLT)，由研究者判断与药物相关者，需扩增至3例继续观察；
(3)若患者出现与研究药物相关的DLT，则应在此剂量组再入组5例患者(共6例)，继续观察安全耐受性。若≥2/6患者出现DLT，则考虑降低剂量或终止研究；
在后续各剂量组中，每个剂量组完成后是否进行后一剂量组试验根据以下规则判断：
(1)如果某剂量组3例患者均未出现DLT，则递增至后一剂量组；
(2)如果某剂量组3例患者中有2例及以上出现DLT，则递减至前一个剂量组；
(3)如果某剂量组3例患者中有1例出现DLT，则该剂量组再增补3例患者，如有1/6患者出现DLT，则递增至后一剂量组，如有≥2/6患者出现DLT，则递减至前一个剂量组；
(4)当递减至前一个剂量组时，若此剂量组只有3例患者，则再增补3例患者。若此剂量组已有6例患者，则剂量递增试验结束，此剂量为MTD。
MTD定义：指当前剂量组的后一个高剂量组有≥33％的受试者出现DLT，且当前剂量组的0/6或1/6受试者出现DLT，则当前剂量组定义为MTD。
如果完成所有计划剂量组仍未发现MTD，申办方将与研究者进一步讨论是否进行更高剂量组的研究。
1.4病例增补
考虑到研究中的核心试验期(第1周期)可能会出现病例的脱落而导致无足够的可评估病例(如疾病的早期进展)，因此每剂量组可能会在早期入组3例受试者的基础上再额外入组新的受试者。病例增补原则如下：
已签署知情同意书但未接受研究干预治疗的受试者可重新替补。对于签署了知情同意书并已接受研究干预治疗，但随后中止研究的受试者，符合以下情况将允许替补：
1)在剂量递增试验期间，受试者因非DLT原因未能完成核心治疗期观察；
2)非DLT原因导致第一周期的给药剂量小于计划给药剂量的75％。
1.5患者内剂量递增
完成核心试验期治疗与观察的受试者，经研究者判断，受试者有获益且可耐受研究药物治疗，依据受试者意愿，可进入后续治疗期。进入后续治疗期的同一受试者不允许递增到后一较高剂量组。
2.入排标准
2.1入选标准
有资格参加本次研究的受试者必须符合下列各条入选标准：
①男性或女性，年龄18～70岁(至获取知情同意书的时间)。
②疾病诊断明确：
试验第一部分受试者的入选标准：经组织学确诊的小细胞肺癌患者，且标准治疗失败或对标准治疗不耐受，且依据RECIST1.1标准至少有一处可供测量的病灶；
试验第二部分受试者的入选标准：经组织学确诊的小细胞肺癌患者，且标准治疗失败或对标准治疗不耐受(至少经过一次依托泊苷联合铂类方案治疗进展或不耐受)，且依据RECIST1.1标准至少有一处可供测量的病灶。
③ECOG评分：0或1分。
④已从既往治疗的毒性中恢复，脱发和色素沉着除外，(根据CTCAE 5.0判定为0-1级)。
⑤预计生存期超过3个月。
⑥主要器官功能在治疗前7天内，符合下述表6标准(在研究药物给药前14天内未接受过输血)：
表6入选受试者的主要器官功能的标准
Figure PCTCN2021093362-appb-000008
⑦有生育能力的合格患者(男性和女性)必须同意在试验期间和末次用药后至少6个月内与其伴侣一起使用可靠的避孕方法(激素或屏障法或禁欲)；育龄期的女性患者在入选前7天内的血妊娠试验必须为阴性。
⑧受试者自愿加入本研究，签署知情同意书，依从性好。
2.2排除标准
以下任何一条均可将受试者剔除，不入选研究：
①合并小细胞肺癌以外其他原发性恶性肿瘤者，已治愈2年以上的的皮肤基底细胞癌和宫颈原位癌除外。
②经影像学评估确定存在中枢神经系统转移(如脑转移或脑膜转移)者；
③不能控制的需要反复引流的胸腔积液、心包积液或腹水的患者。
④在首次使用研究药物前4周内接受以下任一抗肿瘤治疗，包括：化疗、放疗(缓解症状的局部放疗除外)、生物治疗、靶向治疗、免疫治疗。
⑤曾使用过任何LSD1抑制剂治疗者。
⑥无法口服吞咽药物，或存在经研究者判断严重影响胃肠道吸收的状况。
⑦患有临床上显著的心血管疾病，包括但不限于：
--严重心律失常，或需服用抗心律失常的药物(不包括抗凝药物，服用抗凝药物相关凝血指标必须满足入选标准)；
--基线期心电图QT/QTc间期延长者(QTc>480ms,Fridericia公式:QTc＝QT/RR0.33)；
--首次给药前6个月内发生以下任一心血管事件，包括：急性冠脉综合征、充血性心力衰竭、脑卒中或其他3级及以上心血管事件；
--心力衰竭，纽约心脏病学会(NYHA)分级为II级及以上；
--通过超声心动图检测，左室射血分数＜60％。
⑧有其它严重的系统性疾病史，经研究者判断不适合参加临床试验的患者。
⑨研究者判断的严重的自身免疫性疾病史、免疫缺陷病史，包括HIV检测阳性，或患有其他获得性先天性免疫缺陷疾病，或有器官移植史。
⑩乙型肝炎病毒HBsAg阳性、丙型肝炎病毒抗体阳性或梅毒抗体阳性者。
Figure PCTCN2021093362-appb-000009
化合物A首次给药前2周内使用过CYP3A4肝代谢酶的强抑制剂或诱导剂且仍需继续使用该类药物者(具体见附录C)。
Figure PCTCN2021093362-appb-000010
精神障碍者或依从性差者。
Figure PCTCN2021093362-appb-000011
妊娠或哺乳期妇女。
Figure PCTCN2021093362-appb-000012
参加本次试验前4周内作为受试者参加其他临床试验并使用了研究药物者。
Figure PCTCN2021093362-appb-000013
研究者认为受试者存在其他原因而不适合参加本临床研究。
3.研究结果：
目前，0.5mg剂量组入组1例受试者，1.5mg剂量组入组3例受试者，均已经完成入组和DLT观察期。3mg剂量组已有1例受试者入组并完成DLT观察期。所有受试者未发生DLT，未发生SAE，未发生特别关注的不良事件。
0.5mg剂量组1例受试者服药1周期，抗肿瘤疗效评价为SD，服药2周期治疗结束访视疗效评估PD。治疗期间发生13次不良事件，均判定与研究药物无关。
1.5mg剂量组3例受试者服药1周期疗效评价均为PD，治疗期间发生33次不良事件，其中8次不良事件判定与研究药物可能有关，分别为GGT增高(2次)、呼吸困难、发热(2次)、LDH增高、ALP增高、D-Di增高，CTCAE等级均为1-2级。
3.0mg剂量组受试者已完成一周期服药，疗效评价SD，目前继续治疗中。研究期间发生的不良事件CTCAE等级均为1-2级，均判定与研究药物无关。
4.典型病例
4.1病例1
女性，63岁，2020年1月22日诊断为小细胞肺癌，转移部位肝脏和淋巴结，初诊时TNM分期为IVB期，VALG分期为广泛期。2020年2月19日至4月7日接受3个周期的依托泊苷+卡铂联合化疗，5月19日至6月3日接受3个周期的依托泊苷单药治疗，最佳疗效PR。2020年8月12日开始伊立替康+顺铂二线化疗，最佳疗效PD。2020年9月签署知情同意书。筛选时TNM分期为IVB期，VALG分期为广泛期。2020年9月23日至11月4日服用化合物A 0.5mg每周一次。2020年10月18日C1D28抗肿瘤疗效评估为SD， 2020年11月27日末次访视抗肿瘤疗效评估为PD。研究期间发生的不良事件有淋巴细胞计数降低、低白蛋白血症、乏力、低钠血症、排痰性咳嗽、低钾血症、体重降低、双侧肋骨疼、高血糖症、白细胞数降低、中性粒细胞计数降低、血小板数降低。所有不良事件CTCAE等级均为1-2级，均判定与研究药物无关。
4.2病例2
男性，63岁，2017年10月诊断为小细胞肺癌，转移部位淋巴结，初诊时TNM分期为未知，VALG分期为未知。2017年10月10日行右肺下叶切除术及系统淋巴结清除术。2017年11月6日至2018年3月1日接受依托泊苷+顺铂联合术后辅助化疗，最佳疗效SD。2018年3月30日至4月4日接受全脑放疗。2019年4月20日至8月17日接受依托泊苷+顺铂联合化疗，最佳疗效PR，2019年11月21日疾病进展。2019年12月6日至2020年2月9日接受依托泊苷单药二线化疗，最佳疗效未知，2020年3月4日疾病进展。2020年3月11日至2020年4月15日接受伊利替康单药三线化疗，最佳疗效未知。2020年5月13日-6月17日，接受食管后方放疗。
2021年2月24日签署知情同意书。筛选时TNM分期为IVB期，VALG分期为广泛期。2021年3月3日起服用化合物A 3mg每周一次。2021年3月30日C1D28抗肿瘤疗效评估为SD，后续治疗和疗效评估正在进行中。研究期间发生的不良事件有双肺炎、右肺气肿、右侧胸腔积液、肝囊肿、淋巴细胞计数降低、GGT增高、LDH增高、窦性心动过速、失眠、体重下降。所有不良事件CTCAE等级均为1-2级，均判定与研究药物无关。
缩略语列表
Figure PCTCN2021093362-appb-000014
Figure PCTCN2021093362-appb-000015

Claims (10)

  1. 化合物A或其药学上可接受的盐在制备用于预防和/或治疗细胞增殖性疾病的药物中的应用，所述化合物A的结构如下式(Ⅰ)所示：
    Figure PCTCN2021093362-appb-100001
  2. 根据权利要求1所述的应用，其特征在于：所述细胞增殖性疾病是癌症，优选所述癌症是肺癌，更优选所述肺癌是小细胞肺癌。
  3. 根据权利要求2所述的应用，其特征在于，所述小细胞肺癌是广泛期小细胞肺癌；或者，所述小细胞肺癌是复发和/或转移的小细胞肺癌；或者，所述小细胞肺癌是标准治疗失败或对标准治疗不耐受的小细胞肺癌；或者，所述的小细胞肺癌是对顺铂、卡铂、依托泊苷、洛铂、拓扑替康、伊立替康、吉西他滨、替莫唑胺、紫杉醇、多西他赛、长春瑞滨等药物中的一种或多种治疗失败或治疗不耐受的小细胞肺癌；或者，所述小细胞肺癌为ASCL1和/或GRP高表达的小细胞肺癌。
  4. 根据权利要求1-3任一项所述的应用，其特征在于：所述药物含有预防和/或治疗有效量的化合物A或其药学上可接受的盐，以及任选的，药学上可接受的赋形剂、载体和/或稀释剂；所述预防和/或治疗有效量为0.001-1000mg。
  5. 根据权利要求1-3任一项所述的应用，其特征在于：所述药物制成临床接受的制剂，优选口服制剂、注射制剂、局部给药制剂或外用制剂。
  6. 根据权利要求1-3任一项所述的应用，其特征在于：所述药物中还含有其他靶向药物或化疗药物中的一种或多种，所述其它靶向药物或化疗药物选自铂类药物和拓扑异构酶抑制剂。
  7. 根据权利要求1-3中任一项所述的应用，其特征在于：所述药物每次施用剂量为0.01mg-100mg。
  8. 一种组合产品，所述组合产品包含化合物A或其药学上可接受的盐，以及另外的靶向药物或化疗药物，所述另外的靶向药物或化疗药物选自铂类药物和拓扑异构酶抑制剂，所述化合物A的结构如下式(Ⅰ)所示：
    Figure PCTCN2021093362-appb-100002
  9. 根据权利要求8所述的组合产品，其特征在于：所述组合产品呈组合物的形式，或所述化合物A或其药学上可接受的盐与另外的靶向药物或化疗药物各自呈单独的制剂形式。
  10. 根据权利要求8-9中任一项所述的组合产品在制备用于预防和/或治疗细胞增殖性疾病的药物中的应用。
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