WO2023030437A1 - 一种pi3k抑制剂与btk抑制剂在制备治疗淋巴瘤的药物中的用途 - Google Patents

一种pi3k抑制剂与btk抑制剂在制备治疗淋巴瘤的药物中的用途 Download PDF

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WO2023030437A1
WO2023030437A1 PCT/CN2022/116476 CN2022116476W WO2023030437A1 WO 2023030437 A1 WO2023030437 A1 WO 2023030437A1 CN 2022116476 W CN2022116476 W CN 2022116476W WO 2023030437 A1 WO2023030437 A1 WO 2023030437A1
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lymphoma
once
dosage
inhibitor
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张晓静
施薇
冒文君
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江苏恒瑞医药股份有限公司
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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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the disclosure belongs to the field of pharmacy, and provides a use of a PI3K inhibitor and a BTK inhibitor in the preparation of a drug for treating lymphoma.
  • Phosphatidylinositol 3-kinases is a kind of intracellular phosphatidylinositol, which can catalyze the phosphorylation of the 3-hydroxyl of phosphatidylinositol, and transmit and amplify the signal step by step through the kinase cascade reaction , and ultimately regulate a series of activities such as cell proliferation, differentiation, metabolism, and apoptosis.
  • PI3K ⁇ a subclass of PI3K, is an intracellular signaling component expressed primarily in the blood cell lineage.
  • BCR signaling pathway Abnormal activation of the BCR signaling pathway is an important pathogenesis of B-cell non-Hodgkin's lymphoma, and continuous activation of BCR signaling through the PI3K pathway is crucial for the survival of some subtypes of B-cell non-Hodgkin's lymphoma. Blocking BCR signaling by PI3K inhibitors has been shown to effectively inhibit the growth of some tumors.
  • CN104557872B relates to a compound of formula (I), namely N-[5-[6-fluoro-8-[[4-(2-hydroxypropan-2-yl)piperidin-1 base]methyl]-2-mol Lin-4-yl-quinazolin-4 base]-2-methoxypyridin-3 base]methanesulfonamide, the structure is as follows:
  • BTK is the key signal for the activation of B lymphocyte-specific receptor BCR after activation. It promotes the survival of B lymphocytes by activating anti-apoptotic signals such as BCL, and activates transcriptional signals such as NF-kb to promote the production of various immune factors.
  • B-cell lymphoma due to the overexpression and mutation of CD79b, SYK and other genes in the BCR signaling pathway, BTK signaling is continuously activated, thereby maintaining the proliferation of B-lymphoma cells.
  • BTK inhibitors such as Ibrutinib have been approved for the treatment of B-cell lymphoma.
  • Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma in adults, accounting for 25% to 30% of all lymphomas.
  • WO2016007185 relates to a compound of formula (II), namely (R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4-(2,6- Difluorophenoxy)phenyl)-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one, the compound is a novel BTK kinase inhibitor with kinase selectivity, clinical The efficacy, indications, and safety have all been improved, and its structure is as follows:
  • the present disclosure provides a use of a PI3K inhibitor in combination with a BTK inhibitor in the preparation of a drug for treating lymphoma
  • the PI3K inhibitor is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof
  • the BTK The inhibitor is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof
  • the lymphoma is relapsed or refractory lymphoma.
  • the lymphoma is non-Hodgkin's lymphoma.
  • the lymphoma is B-cell non-Hodgkin's lymphoma.
  • the lymphoma is relapsed or refractory B-cell non-Hodgkin's lymphoma.
  • the lymphoma is diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is ABC type diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is relapsed or refractory diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is relapsed diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is refractory diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is relapsed or refractory ABC diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is relapsed ABC diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is refractory ABC diffuse large B-cell lymphoma (DLBCL).
  • DLBCL diffuse large B-cell lymphoma
  • the lymphoma is relapsed or refractory lymphoma previously treated with anti-CD20 targeted drugs.
  • the lymphoma is relapsed or refractory lymphoma after at least 2 lines of treatment.
  • the lymphoma is relapsed diffuse large B-cell lymphoma previously treated with anti-CD20 targeted drugs.
  • the lymphoma is refractory diffuse large B-cell lymphoma previously treated with anti-CD20 targeted drugs.
  • the lymphoma is relapsed diffuse large B-cell lymphoma after at least 2 lines of therapy.
  • the lymphoma is refractory diffuse large B-cell lymphoma after at least 2 lines of therapy.
  • the anti-CD20 targeting drug is selected from Rituximab, Ibritumomab, Tositumomab, ofatumumab, Ocrelizumab, Veltuzumab, Obinutuzumab, TG-101 and AME-133v.
  • the dosage of the PI3K inhibitor described in the present disclosure is selected from 1-1000 mg, and the frequency of administration is selected from once a day, twice a day, three times a day, once a day, once a day, or once a day. once a week.
  • the dosage of the PI3K inhibitor described in the present disclosure is selected from 1-500 mg, and the frequency of administration is selected from once a day, twice a day, three times a day, once a day, once a day, or once a day once a week.
  • the dosage of the PI3K inhibitor is selected from 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275mg, 280mg
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the dosage is once a day or twice a day.
  • the dosage of the PI3K inhibitor is selected from 60 mg, and the frequency of administration is once a day.
  • the dosage of the PI3K inhibitor is selected from 80 mg, and the dosage frequency is once a day.
  • the dosage of the BTK inhibitor in the present disclosure is selected from 1-1000 mg, and the frequency of administration is selected from once a day, twice a day, three times a day, once every two days, once every three days or once a week.
  • the dosage of the BTK inhibitor is selected from 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg, 255mg, 260mg, 265mg, 270mg, 275m
  • the dosage of the BTK inhibitor is selected from 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 155mg, 160mg, 165mg, 170mg, 175mg, 180mg, 185mg, 190mg, 195mg, 200mg, 205mg, 210mg, 215mg, 220mg, 225mg, 230mg, 235mg, 240mg, 245mg, 250mg,
  • the frequency of administration is once a day or twice a day.
  • the dosage of the BTK inhibitor is selected from 50 mg, 100 mg, 150 mg, 200 mg or 250 mg, and the dosage is once a day or twice a day.
  • the dosage of the BTK inhibitor is 150 mg, and the frequency of administration is once a day or twice a day.
  • the dosage of the BTK inhibitor is 200 mg, and the frequency of administration is once a day or twice a day.
  • the unit dose of the BTK inhibitor is 150 mg.
  • the unit dose of the BTK inhibitor is 200 mg.
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the frequency of administration is once a day or twice a day; the administration of the BTK inhibitor The dosage is selected from 50mg, 100mg, 150mg, 200mg or 250mg, and the administration frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is 50 mg, and the dosage is once a day or twice a day; the dosage of the BTK inhibitor is selected from 50 mg, 100 mg, 150 mg, and 200 mg Or 250mg, the dosing frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is 60 mg, and the dosage is once a day or twice a day; the dosage of the BTK inhibitor is selected from 50 mg, 100 mg, 150 mg, and 200 mg Or 250mg, the dosing frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is 70 mg, and the dosage is once a day or twice a day; the dosage of the BTK inhibitor is selected from 50 mg, 100 mg, 150 mg, and 200 mg Or 250mg, the dosing frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is 80 mg, and the dosage is once a day or twice a day; the dosage of the BTK inhibitor is selected from 50 mg, 100 mg, 150 mg, and 200 mg Or 250mg, the dosing frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is 90 mg, and the dosage is once a day or twice a day; the dosage of the BTK inhibitor is selected from 50 mg, 100 mg, 150 mg, and 200 mg Or 250mg, the dosing frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is 100mg, and the dosage is once a day or twice a day; the dosage of the BTK inhibitor is selected from 50mg, 100mg, 150mg, 200mg Or 250mg, the dosing frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the frequency of administration is once a day or twice a day; the administration of the BTK inhibitor The dosage is 50mg, and the administration frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the frequency of administration is once a day or twice a day; the administration of the BTK inhibitor The dosage is 50mg, and the administration frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the frequency of administration is once a day or twice a day; the administration of the BTK inhibitor The dosage is 100 mg, and the administration frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the frequency of administration is once a day or twice a day; the administration of the BTK inhibitor The dosage is 150mg, and the administration frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the frequency of administration is once a day or twice a day; the administration of the BTK inhibitor The dosage is 200 mg, and the administration frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is selected from 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg, and the frequency of administration is once a day or twice a day; the administration of the BTK inhibitor The dosage is 250mg, and the administration frequency is once a day or twice a day.
  • the dosage of the PI3K inhibitor is 60 mg, and the dosage is once a day; the dosage of the BTK inhibitor is 200 mg, and the dosage is once a day.
  • the dosage of the PI3K inhibitor is 80 mg, and the dosage is once a day; the dosage of the BTK inhibitor is 150 mg, and the dosage is once a day.
  • the dosage of the PI3K inhibitor is 60 mg, and the dosage is once a day; the dosage of the BTK inhibitor is 150 mg, and the dosage is once a day.
  • the dosage of the PI3K inhibitor is 80 mg, and the dosage is once a day; the dosage of the BTK inhibitor is 200 mg, and the dosage is once a day.
  • “Pharmaceutically acceptable salt” refers to the salt of the disclosed compound, which is safe and effective when used in mammals, and has proper biological activity. Salts can be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate group with a suitable base or acid.
  • Bases commonly used to form pharmaceutically acceptable salts include inorganic bases, such as sodium hydroxide and potassium hydroxide, and organic bases, such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.
  • the present disclosure provides a pharmaceutical composition comprising the above-mentioned PI3K inhibitor and BTK inhibitor.
  • the pharmaceutical composition contains one or more pharmaceutically acceptable excipients in addition to the PI3K inhibitor and BTK inhibitor.
  • the pharmaceutical composition described in this disclosure can be prepared as tablet, capsule, pill, granule, solution, suspension, syrup, injection (including injection, sterile powder for injection and concentrated solution for injection) , suppositories, inhalants or sprays, etc.
  • the mode of administration of the combinations described in the present disclosure is selected from simultaneous administration, separate formulation and co-administration or separate formulation and sequential administration.
  • the administration route of the combination in the present disclosure is selected from oral administration, parenteral administration, and transdermal administration, and said parenteral administration includes but not limited to intravenous injection, subcutaneous injection, and intramuscular injection.
  • the present disclosure provides a method for treating lymphoma, comprising administering to a patient a therapeutically effective dose of the aforementioned PI3K inhibitor and a therapeutically effective dose of the aforementioned BTK inhibitor.
  • the present disclosure provides a PI3K inhibitor for lymphoma, and the PI3K inhibitor is used in combination with a BTK inhibitor.
  • the present disclosure provides a BTK inhibitor for lymphoma, and the BTK inhibitor is used in combination with a PI3K inhibitor.
  • the administration is oral administration on an empty stomach.
  • the administration is oral administration 1 hour before a meal or 2 hours after a meal
  • relapse refers to remission after the last treatment, and relapse more than 6 months after the end of treatment.
  • the "refractory” mentioned in the present disclosure means that remission is not achieved after the last line of treatment, or relapse occurs within 6 months after the end of treatment.
  • tautomer or tautomeric form refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • lactam-lactim equilibrium is between A and B as shown below.
  • the compound represented by formula (II) of the present disclosure can be drawn as Form A or Form B.
  • the naming of compounds does not exclude any tautomers.
  • a “therapeutically effective amount” refers to the amount of a therapeutic agent that produces the desired effect for which it is administered. In some embodiments, the term refers to an amount sufficient to treat a disease, disorder, and/or condition when administered according to a regimen to a population suffering from or susceptible to the disease, disorder, and/or condition. In some embodiments, a therapeutically effective amount is an amount that reduces the incidence and/or severity of, and/or delays the onset of, one or more symptoms of a disease, disorder, and/or condition. Those of ordinary skill in the art will appreciate that the term “therapeutically effective amount” need not actually be used to achieve successful treatment in a particular individual.
  • a therapeutically effective amount may be an amount that, when administered to a patient in need of such treatment, provides a specific desired pharmacological response in a substantial number of subjects.
  • a reference to a therapeutically effective amount may refer to, for example, a specific tissue (e.g., tissue affected by a disease, disorder, or condition) or fluid (e.g., blood, saliva, serum, sweat, tears, The amount measured in urine, etc.).
  • tissue e.g., tissue affected by a disease, disorder, or condition
  • fluid e.g., blood, saliva, serum, sweat, tears, The amount measured in urine, etc.
  • a therapeutically effective amount of a particular agent or therapy may be formulated and/or administered in a single dose.
  • a therapeutically effective agent may be formulated and/or administered in multiple doses.
  • the "combination" described in this disclosure is a mode of administration, which refers to the administration of at least one dose of a PI3K inhibitor or a pharmaceutically acceptable salt thereof and a BTK inhibitor within a certain period of time, wherein both drugs are Show pharmacological effects.
  • the time period can be within one administration cycle, preferably within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours.
  • the PI3K inhibitor or a pharmaceutically acceptable salt thereof and the BTK inhibitor can be administered simultaneously or sequentially. This term includes treatments wherein the PI3K inhibitor or a pharmaceutically acceptable salt thereof and the BTK inhibitor are administered by the same route of administration or by different routes of administration.
  • Figure 1 Tumor volume growth curves of mice in the DLCM164 model.
  • Figure 2 Body weight change curves of mice in the DLCM164 model.
  • Example 1 Anti-tumor effect of compound 1 and compound 2 used alone or in combination in PDX model DLCM164 mouse model
  • This experiment on the DLCM164 model used compound 2-10mpk QD po administration and compound 1-30mpk QD po administration.
  • the tumors grew to 145 ⁇ 7mm 3 size, they were divided into groups, 7 mice in each group, and then continuously administered After 21 days of treatment, tumor volume and mouse body weight were measured twice a week.
  • the tumor volume inhibition rate of compound 2-10mpk QD monotherapy for 21 days was 21%, and the tumor volume inhibition rate of compound 1-30mpk QD monotherapy for 21 days was 44%.
  • the drug effect was weak, and there was no statistical difference compared with the control group.
  • the tumor volume inhibition rate for 21 days of continuous treatment was 109.4%, which was significantly different from that in the control group (p ⁇ 0.001), and compared with the compound 2 single-drug group (p ⁇ 0.001) and the compound 1 single drug group (p ⁇ 0.001) have statistical differences, the combination of the two drugs shows a more effective tumor inhibitory effect than the single drug or superposition, indicating that the combination of the two drugs has Significant synergistic therapeutic effects (see Table 1 and Figure 1).
  • mice in the control group was 8% ⁇ 2%
  • the average weight changes of the mice in the compound 2 single drug group and the compound 1 single drug group were 4% ⁇ 2%.
  • the average body weight change of the mice in the two-drug combination group was -2% ⁇ 1%, and no obvious abnormalities such as death were found in the signs and activities of the mice in each group, indicating that the mice combined with the two drugs at this dose were well tolerated (See Table 1 and Figure 2).
  • Example 2 A phase I/II clinical study of compound 1 combined with compound 2 in relapsed/refractory B-cell non-Hodgkin's lymphoma
  • This clinical trial is an open-label, two-drug combination, dose exploration and phase I/II clinical trial of clinical expansion.
  • Dose exploration stage the subject will receive the compound of formula (I) combined with formula (II). Every 28 days is a treatment cycle, until the disease progresses, the toxicity is intolerable, the subjects withdraw their knowledge or the investigator judges that the drug must be terminated.
  • Clinical expansion stage a 1:1 randomized, open, controlled study is adopted, and random stratification is carried out according to the patient's response to the last treatment and pathological type.
  • the test group receives compound 1 and compound 2 double drug therapy, and the control group receives GemOx ( Gemcitabine + oxaliplatin) regimen chemotherapy. 27 subjects were enrolled in the experimental group and the control group respectively.
  • Experimental group Administer compound 1 and compound 2 according to the recommended dose selected in the dose exploration stage, orally on an empty stomach, once a day, 1 hour before meal or 2 hours after meal, simultaneous administration is allowed, 28 days as a period cycle.
  • Control group GemOx (gemcitabine + oxaliplatin) chemotherapy regimen, 14 days as a cycle of administration.
  • Evaluation indicators were ORR (CR+PR), DoR, DCR (CR+PR+SD), PFS and OS.

Abstract

本公开提供一种PI3K抑制剂与BTK抑制剂联合在制备治疗淋巴瘤的药物中的用途。具体而言，本公开所述PI3K抑制剂为式(I)所示的化合物或其药学上可接受的盐，所述BTK抑制剂为式(II)所示的化合物或其药学上可接受的盐。

Description

一种PI3K抑制剂与BTK抑制剂在制备治疗淋巴瘤的药物中的用途
本申请要求申请日为2021年9月1日的中国专利申请2021110187387的优先权。本申请引用上述中国专利申请的全文。
技术领域
本公开属于药学领域，提供了一种PI3K抑制剂与BTK抑制剂在制备治疗淋巴瘤的药物中的用途。
背景技术
磷酯酰肌醇3-激酶(Phosphatidylinositol 3-kinases,PI3K)是一种胞内磷脂酰肌醇，可催化磷脂酰醇的3位羟基磷酸化，通过激酶级联反应将信号逐级传递并放大，最终调节细胞的增殖、分化、代谢、凋亡等一系列活动。PI3Kδ是PI3K的一个亚类，是一种细胞内信号转导组分，主要表达在血细胞谱系中。BCR信号通路异常激活是B细胞非霍奇金淋巴瘤的重要发病机制，持续性通过PI3K途径激活BCR信号传导对于B细胞非霍奇金淋巴瘤一些亚型的肿瘤细胞生存至关重要。通过PI3K抑制剂阻断BCR信号传导已被证明能有效抑制一些肿瘤的生长。CN104557872B涉及一种式(I)化合物，即N-[5-[6-氟-8-[[4-(2-羟基丙烷-2-基)哌啶-1基]甲基]-2-吗啉-4-基-喹唑啉-4基]-2-甲氧基吡啶-3基]甲磺酰胺，结构如下所示：
Figure PCTCN2022116476-appb-000001
BTK是B淋巴细胞特异性受体BCR活化后激活的关键信号，通过活化BCL等抗凋亡信号来促进B淋巴细胞存活，并活化NF-kb等转录信号来促进多种免疫因子的产生。在B细胞淋巴瘤中，由于BCR信号通路上的CD79b、SYK等基因发生过表达及突变，导致BTK信号发生持续活化，从而维持B淋巴瘤细胞的增殖。目前多种BTK抑制剂如Ibrutinib已获批用于治疗B细胞淋巴瘤。弥漫性大B细胞淋巴瘤(DLBCL)是成人中最常见的非霍奇金淋巴瘤，占所有淋巴瘤的25％至30％。
WO2016007185涉及一种式(II)化合物，即(R)-4-氨基-1-(1-(丁-2-炔酰基)吡咯烷-3-基)-3-(4-(2,6-二氟苯氧基)苯基)-1,6-二氢-7H-吡咯并[2,3-d]哒嗪-7-酮，该化合物为新型BTK激酶抑制剂，在激酶选择性，临床疗效或适应症，及安全性等方面均有所改善，其结构如下所示：
Figure PCTCN2022116476-appb-000002
发明内容
本公开提供一种PI3K抑制剂与BTK抑制剂联合在制备治疗淋巴瘤的药物中的用途，所述PI3K抑制剂为式(I)所示的化合物或其药学上可接受的盐，所述BTK抑制剂为式(II)所示的化合物或其药学上可接受的盐，
Figure PCTCN2022116476-appb-000003
在一些实施方案中，其中所述的淋巴瘤为复发或难治性淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为非霍奇金淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为B细胞非霍奇金淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为复发或难治性B细胞非霍奇金淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为ABC型弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为复发或难治性弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为复发性弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为难治性弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为复发或难治性ABC型弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为复发性ABC型弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为难治性ABC型弥漫性大B细胞淋巴瘤(DLBCL)。
在一些实施方案中，其中所述的淋巴瘤为既往接受过抗CD20靶向药物治疗的复发或难治性淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为经过至少2线治疗后复发或难治性淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为既往接受过抗CD20靶向药物治疗的复发性弥漫性大B细胞淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为既往接受过抗CD20靶向药物治疗的难治性弥漫性大B细胞淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为经过至少2线治疗后的复发性弥漫性大B细胞淋巴瘤。
在一些实施方案中，其中所述的淋巴瘤为经过至少2线治疗后的难治性弥漫性大B细胞淋巴瘤。
在一些实施方案中，其中抗CD20靶向药物选自Rituximab、Ibritumomab、Tositumomab、ofatumumab、Ocrelizumab、Veltuzumab、Obinutuzumab、TG-101和AME-133v。
在一些实施方案中，本公开中所述PI3K抑制剂的给药剂量选自1-1000mg，给药频次选自一日一次、一日二次、一日三次、二日一次、三日一次或一周一次。
在一些实施方案中，本公开中所述PI3K抑制剂的给药剂量选自1-500mg，给药频次选自一日一次、一日二次、一日三次、二日一次、三日一次或一周一次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg，给药频次为一日一 次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自60mg，给药频次为一日一次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自80mg，给药频次为一日一次。
本公开中所述BTK抑制剂的给药剂量选自1-1000mg，给药频次选自一日一次、一日二次、一日三次、二日一次、三日一次或一周一次。
可选的实施方案中，所述BTK抑制剂的给药剂量选自10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg、255mg、260mg、265mg、270mg、275mg、280mg、285mg、290mg、295mg、300mg、305mg、310mg、315mg、320mg、325mg、330mg、335mg、340mg、345mg、350mg、355mg、360mg、365mg、370mg、375mg、380mg、385mg、390mg、395mg、400mg、405mg、410mg、415mg、420mg、425mg、430mg、435mg、440mg、445mg、450mg、455mg、460mg、465mg、470mg、475mg、480mg、485mg、490mg、495mg、500mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述BTK抑制剂的给药剂量选自50mg、55mg、60mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、105mg、110mg、115mg、120mg、125mg、130mg、135mg、140mg、145mg、150mg、155mg、160mg、165mg、170mg、175mg、180mg、185mg、190mg、195mg、200mg、205mg、210mg、215mg、220mg、225mg、230mg、235mg、240mg、245mg、250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述BTK抑制剂的给药剂量为150mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述BTK抑制剂的给药剂量为200mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述BTK抑制剂的单位剂量为150mg。
可选的实施方案中，所述BTK抑制剂的单位剂量为200mg。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为50mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为60mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为70mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为80mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为90mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量为50mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量为50mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量为100mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量为150mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量为200mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次；所述BTK抑制剂的给药剂量为250mg，给药频次为一日一次或一日二次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为60mg，给药频次为一日一次；所述BTK抑制剂的给药剂量为200mg，给药频次为一日一次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为80mg，给药频次为一日一次； 所述BTK抑制剂的给药剂量为150mg，给药频次为一日一次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为60mg，给药频次为一日一次；所述BTK抑制剂的给药剂量为150mg，给药频次为一日一次。
可选的实施方案中，所述PI3K抑制剂的给药剂量为80mg，给药频次为一日一次；所述BTK抑制剂的给药剂量为200mg，给药频次为一日一次。
“药学上可接受的盐”是指本公开化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。可以在化合物的最终分离和纯化过程中，或通过使合适的基团与合适的碱或酸反应来单独制备盐。通常用于形成药学上可接受的盐的碱包括无机碱，例如氢氧化钠和氢氧化钾，以及有机碱，例如氨。通常用于形成药学上可接受的盐的酸包括无机酸以及有机酸。
本公开提供一种包含上述PI3K抑制剂和BTK抑制剂的药物组合物，所述药物组合物除含有PI3K抑制剂和BTK抑制剂外，另含有一种或多种可药用的赋型剂。
本公开中所述的药物组合物可以制备为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂等。
本公开所述联合的给药方式选自同时给药、独立地配制并共给药或独立地配制并相继给药。
本公开所述联合的给药途径选自经口给药、胃肠外给药、经皮给药，所述胃肠外给药包括但不限于静脉注射、皮下注射、肌肉注射。
本公开提供一种治疗淋巴瘤的方法，包括给与患者治疗有效量的上述PI3K抑制剂和治疗有效量的上述BTK抑制剂。
可选的实施方案中，本公开提供一种用于淋巴瘤的PI3K抑制剂，所述PI3K抑制剂与BTK抑制剂联合使用。
可选的实施方案中，本公开提供一种用于淋巴瘤的BTK抑制剂，所述BTK抑制剂与PI3K抑制剂联合使用。
可选的实施方案中，所述的给药为空腹口服给药。
可选的实施方案中，所述的给药为餐前1小时或餐后2小时口服给药
本公开中所述的“复发”是末次治疗获得缓解，治疗结束后6个月以上复发。
本公开中所述的“难治”是末线治疗结束后未获得缓解，或治疗结束6个月以内复发。
本公开的化合物还可以以不同的互变异构体形式存在，所有的互变异构形式均在本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。内酰胺-内酰亚胺平衡实例是在如下所示的A和B之间。
Figure PCTCN2022116476-appb-000004
在某些实施方式中，本公开的式(II)所示化合物可以被画成A型或B型。化合物的命名不排除任何互变异构体。
“治疗有效量”指产生它为了其施用的所需效应的治疗剂的量。在一些实施方案中，该术语指当根据方案施用于患有或易患疾病、病症和/或状况的群体时，足以治疗所述疾病、病症和/或状况的量。在一些实施方案中，治疗有效量是降低疾病、病症和/或状况的一种或多种症状的发生率和/或严重性，和/或延迟其发作的量。本领域普通技术人员将了解，术语“治疗有效量”实际上不需要实现在特定个体中的成功治疗。相反，治疗有效量可以是当施用于需要此类治疗的患者时，在大量受试者中提供特定的所需药理学应答的量。在一些实施方案中，提及治疗有效量可以指如在一种或多种特定组织(例如，受疾病、病症或状况影响的组织)或流体(例如，血液、唾液、血清、汗液、泪、尿等)中测量的量。本领域普通技术人员将了解，在一些实施方案中，治疗有效量的特定试剂或疗法可以以单一剂量配制和/或施用。在一些实施方案中，治疗有效试剂可以以多个剂量配制和/或施用。
本公开中所述的“联合”是一种给药方式，是指在一定时间期限内给予至少一种剂量 的PI3K抑制剂或其药学上可接受的盐和BTK抑制剂，其中两种药物都显示药理学作用。所述的时间期限可以是一个给药周期内，优选4周内，3周内，2周内，1周内，或24小时以内。可以同时或依次给予PI3K抑制剂或其药学上可接受的盐和BTK抑制剂。这种期限包括这样的治疗，其中通过相同给药途径或不同给药途径给予PI3K抑制剂或其药学上可接受的盐和BTK抑制剂。
附图说明
图1：小鼠在DLCM164模型中的肿瘤体积生长曲线。
图2：小鼠在DLCM164模型中的体重变化曲线。
具体实施方式
以下结合实施例用于进一步描述本公开，但这些实施例并非限制本公开的范围。
实施例1化合物1和化合物2单用或联用在PDX模型DLCM164小鼠模型中的抗肿瘤作用
一、实验设计
本实验在一例ABC型DLBCL的PDX模型DLCM164上进行(该模型为通过合作方式从北京肿瘤医院淋巴肿瘤内科获得，经过病理及诊断确认)。该PDX模型接种于NOD-SCID鼠生长后，进行化合物2联合化合物1的药效学实验。
本次在DLCM164模型上的实验采用化合物2-10mpk QD po给药以及化合物1-30mpk QD po给药，肿瘤在生长至145±7mm 3大小时进行分组，每组7只小鼠，随后连续给药21天，每周两次测量肿瘤体积以及小鼠体重。
二、实验药物
化合物1，
Figure PCTCN2022116476-appb-000005
参照CN104557872B中方法制备。
化合物2，
Figure PCTCN2022116476-appb-000006
参照WO2016007185中方法制备。
三、实验结果
在本次实验中，化合物2-10mpk QD单药连续治疗21天的肿瘤体积抑制率为21％，化合物1-30mpk QD单药连续治疗21天的肿瘤体积抑制率为44％，两者单药药效较弱，相比于对照组均无统计学差异。
而当两药剂量不变进行联合治疗时，连续治疗21天的肿瘤体积抑制率为109.4％，相比于对照组有显著统计学差异(p<0.001)，同时相比于化合物2单药组(p<0.001)以及化合物1单药组(p<0.001)均有统计学差异，两药物的联用体现出相比各自单药或叠加更为有效的肿瘤抑制作用，表明两药联用具有显著协同治疗效应(见表1和图1)。
本次实验中，在21天处理后对照组组小鼠体重变化平均值为8％±2％，化合物2单药组以及化合物1单药组小鼠体重变化平均值均为4％±2％，而两药联用组小鼠体重变化平均值为-2％±1％，各组小鼠体征活动未见死亡等明显异常，表明两药在该剂量下联用的小鼠耐受性良好(见表1和图2)。
表1化合物2、化合物1在PDX模型DLCM164小鼠模型中的抗肿瘤作用
Figure PCTCN2022116476-appb-000007
实施例2一项化合物1联合化合物2在复发/难治B细胞非霍奇金淋巴瘤中的I/II期临床研究
1.研究目的
评估化合物1联合化合物2在复发/难治B细胞非霍奇金淋巴瘤受试者中的有效性、安全性及耐受性。
2.研究设计
2.1研究方案
本临床试验为开放、两药联用、剂量探索和临床拓展的I/II期临床试验。
1)剂量探索阶段：受试者将接受式(I)化合物与式(II)联合给药。每28天为一个治疗周期，直至疾病进展、毒性不可耐受、受试者撤回知情或研究者判断必须终止用药。
方案1：化合物2(200mg QD)+化合物1(80mg QD)；
方案2：化合物2(200mg QD)+化合物1(60mg QD)；
方案3：化合物2(150mg QD)+化合物1(80mg QD)；
方案4：化合物2(200mg QD)+化合物1(40mg QD)；
方案5：化合物2(150mg QD)+化合物1(60mg QD)；
方案6：化合物2(150mg QD)+化合物1(40mg QD)；
方案7：化合物2(100mg QD)+化合物1(60mg QD)；
方案8：化合物2(100mg QD)+化合物1(40mg QD)。
2)临床拓展阶段：采用1:1随机、开放、对照研究，根据患者对末次治疗的反应情况以及病理类型进行随机分层，试验组接受化合物1和化合物2双药治疗，对照组接受GemOx(吉西他滨+奥沙利铂)方案化疗。试验组和对照组各入组27例受试者。
试验组：根据剂量探索阶段选出的推荐剂量给药化合物1及化合物2，空腹口服，每日1次，在餐前1小时或餐后2小时口服给药，允许同时服用，28天为一周期。
对照组：GemOx(吉西他滨+奥沙利铂)化疗方案，14天为一个给药周期。
2.2入组标准
1.经过至少2线系统治疗后复发或难治的患者，经过1个周期化疗后因不耐受换方案者，不视为一个治疗线数，a)复发：末次治疗获得缓解，治疗结束后6个月以上复发；b)难治：末线治疗结束后未获得缓解，或治疗结束6个月以内复发。
2.既往接受过抗CD20靶向药物充分治疗，按病理类型和疾病分期要求完成CD20单抗联合化疗足周期治疗，或CD20单抗单药治疗按375mg/m 2每周一次注射至少4次；若诱导治疗期间进展则利妥昔单抗联合化疗治疗或单药治疗至少完成了一个周期；若维持治疗期间进展则至少完成了一剂注射。
2.3有效性评估：
评价指标为ORR(CR+PR)、DoR、DCR(CR+PR+SD)、PFS和OS。
计算ORR和DCR的点估计，及其95％置信区间(Clopper-Pearson法)。
对PFS、DoR和OS，采用Kaplan-Meier法绘制生存曲线，并估计中位生存时间及相应的95％置信区间(基于log-log变换的Brookmeyer-Crowley方法，标准误采用Greenwood公式进行计算)。
3研究结果
目前，化合物2(150mg QD)+化合物1(60mg QD)剂量组共入组11例患者，其中9 例弥漫大B细胞淋巴瘤。在这9例患者中，2例CR，3例PR，2例SD，2例PD，ORR为55％。
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 (12)

  1. 一种PI3K抑制剂与BTK抑制剂联合在制备治疗淋巴瘤的药物中的用途，所述PI3K抑制剂为式(I)所示的化合物或其药学上可接受的盐，所述BTK抑制剂为式(II)所示的化合物或其药学上可接受的盐，
    Figure PCTCN2022116476-appb-100001
  2. 根据权利要求1所述的用途，其中所述的淋巴瘤为复发或难治性淋巴瘤。
  3. 根据权利要求1或2所述的用途，其中所述的淋巴瘤为非霍奇金淋巴瘤，优选为B细胞非霍奇金淋巴瘤。
  4. 根据权利要求1至3中任一项所述的用途，其中所述的淋巴瘤为弥漫性大B细胞淋巴瘤，优选为ABC型弥漫性大B细胞淋巴瘤。
  5. 根据权利要求1至4中任一项所述的用途，其中所述的淋巴瘤为复发或难治弥漫性大B细胞淋巴瘤，优选为复发或难治性ABC型弥漫性大B细胞淋巴瘤。
  6. 根据权利要求1至5中任一项所述的用途，其中所述的淋巴瘤为既往接受过抗CD20靶向药物治疗的复发或难治性淋巴瘤。
  7. 根据权利要求1至6中任一项所述的用途，其中所述的淋巴瘤为经过至少2线治疗后复发或难治性淋巴瘤。
  8. 根据权利要求1至7中任一项所述的用途，其中PI3K抑制剂的给药剂量选自1-1000mg，给药频次选自一日一次、一日二次、一日三次、二日一次、三日一次或一周一 次。
  9. 根据权利要求1至8中任一项所述的用途，其中PI3K抑制剂的给药剂量选自50mg、60mg、70mg、80mg、90mg或100mg，给药频次为一日一次或一日二次。
  10. 根据权利要求1至9中任一项所述的用途，其中BTK抑制剂的给药剂量选自1-1000mg，给药频次选自一日一次、一日二次、一日三次、二日一次、三日一次或一周一次。
  11. 根据权利要求1至10中任一项所述的用途，其中BTK抑制剂的给药剂量选自50mg、100mg、150mg、200mg或250mg，给药频次为一日一次或一日二次。
  12. 一种包含权利要求1-11任一项所述的PI3K抑制剂和BTK抑制剂的药物组合物，进一步含有一种或多种可药用的赋型剂。
PCT/CN2022/116476 2021-09-01 2022-09-01 一种pi3k抑制剂与btk抑制剂在制备治疗淋巴瘤的药物中的用途 WO2023030437A1 (zh)

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