WO2022083745A1 - Utilisation d'un inhibiteur de la tyrosine kinase de bruton - Google Patents

Utilisation d'un inhibiteur de la tyrosine kinase de bruton Download PDF

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WO2022083745A1
WO2022083745A1 PCT/CN2021/125756 CN2021125756W WO2022083745A1 WO 2022083745 A1 WO2022083745 A1 WO 2022083745A1 CN 2021125756 W CN2021125756 W CN 2021125756W WO 2022083745 A1 WO2022083745 A1 WO 2022083745A1
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lymphoma
cell lymphoma
compound
btk
administration
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PCT/CN2021/125756
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Chinese (zh)
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张翱
丁健
耿美玉
谢华
刘喜宝
杨汉煜
高娜
张阳
杨凤娇
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中国科学院上海药物研究所
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the application belongs to the field of medicine, and in particular, relates to the use of a Bruton's tyrosine kinase BTK inhibitor, especially the use of the compound in the preparation of a medicine for the treatment of BTK-related tumor diseases.
  • B cell receptor (BCR) signaling plays a crucial role in normal B cell development and adaptive immunity, and activation of this signaling pathway contributes to the occurrence and development of B cell malignancies and autoimmune diseases. develop.
  • Bruton's tyrosine kinase (BTK) is a non-receptor tyrosine kinase belonging to the TEC tyrosine kinase family and is a key regulator in the B cell receptor (BCR) signaling pathway. It is mainly expressed in various developmental stages of B lymphocytes (except plasma cells at the end of B lymphocyte development), and has an important effect on the proliferation, differentiation and apoptosis of B cells.
  • Ibrutinib (trade name Imbruvica) is the first BTK small molecule inhibitor to be marketed and belongs to the first generation of BTK inhibitors. It was approved by the US FDA in 2013 for Clinical treatment of Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL), etc. Since then, ibrutinib has continued to expand its indications.
  • the currently approved indications also include 17p deletion chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/Small Lymphocytic Lymphoma, SLL), Waldenstrom Macroglobulinemia (WM), marginal zone lymphoma (Marginal Zone Lymphoma, MZL), chronic graft-resistant Host disease (chronic Graft-Versus-Host Disease, cGVHD).
  • Ibrutinib can form covalent binding with cysteine 481 (Cys481) in the ATP-binding domain of BTK kinase, irreversibly inhibit BTK activation, block BTK signaling pathway, thereby inhibiting the proliferation and survival of B lymphoma cells. achieve the purpose of tumor treatment.
  • Ibrutinib has achieved substantial efficacy in clinical treatment. However, due to the poor target selectivity of ibrutinib, there are certain toxic and side effects in clinical practice.
  • Acalabrutinib (ACP-196, trade name Calquence) was approved for the treatment of MCL and CLL in 2017 and belongs to the second generation of BTK targeted drugs. Compared with ibrutinib, acaltinib is more selective for BTK and has lower off-target toxicity.
  • Zanubrutinib Zanubrutinib (Zabrutinib, BGB-3111), developed by BeiGene Biotechnology Co., Ltd., was approved by the FDA in November 2019 for the treatment of adult MCL patients, becoming the first Chinese local antibody to receive FDA breakthrough therapy designation.
  • Tirabrutinib (ONO-4059) developed by Japan's Ono Pharmaceutical Co., Ltd. was approved by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) in March 2020 for relapsed or refractory primary central nervous system lymphoma (PCNSL) and treatment of lymphoplasmacytic lymphoma (LPL).
  • PCNSL central nervous system lymphoma
  • LPL lymphoplasmacytic lymphoma
  • the first-generation inhibitors have high inhibitory activity against BTK, but the target selection and bioavailability are poor; the second-generation inhibitors have good selectivity, but the inhibition rate of BTK is lower than that of the first-generation inhibitors.
  • the core skeleton of currently marketed BTK drugs is mainly a bicyclic system.
  • pyrimido[5,4-b]indolizine compounds S1 and S10 and pyrimido[5,4-b]pyrine compounds S18, S19 and S20 showed higher BTK inhibitory activity, and further work
  • the S-configuration compounds of S18, S19 and S20 ie S18s, S19s and S20s
  • were also synthesized [Yu Xue, et al.
  • BTK kinase inhibitors with excellent BTK inhibitory activity and selectivity, high in vivo antitumor activity, and excellent oral administration performance and metabolic stability is very important for the treatment of BTK-related tumor diseases.
  • the purpose of the present invention is to provide the use of a Bruton's tyrosine kinase BTK inhibitor compound A or a pharmaceutically acceptable salt thereof in the preparation of a medicine for the treatment of BTK-related tumor diseases, the compound A has the following structure:
  • the BTK-related tumor diseases include hematological tumors and solid tumors.
  • the above-mentioned hematological tumors are lymphomas and leukemias.
  • the above-mentioned lymphoma is a B-cell lymphoma.
  • the BTK-related tumor diseases include histiocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma , Burkitt lymphoma, or Waldenstrom's macroglobulinemia.
  • the diffuse large B-cell lymphoma is selected from the group consisting of non-special types of diffuse large B-cell lymphoma, other large B-cell lymphomas, high-grade B-cell lymphomas with MYC and/or Bcl gene abnormalities, and non-specific types of diffuse large B-cell lymphomas.
  • the other large B-cell lymphomas include T-cell/histiocyte-rich DLBCL, primary central nervous system DLBCL, primary cutaneous DLBCL (leg type), EBV-positive DLBCL, unspecified DLBCL, chronic inflammation Associated large B-cell lymphoma, lymphomatoid granuloma, large B-cell lymphoma with IRF4 rearrangement, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B Cell lymphoma, plasmablastic lymphoma, HHV8-positive DLBCL, primary exudative lymphoma, etc.;
  • the high-grade B-cell lymphoma with MYC gene abnormality is one or more selected from the group consisting of high-grade B-cell lymphoma with MYC gene amplification and high-grade B-cell lymphoma with MYC gene fusion
  • the high-grade B-cell lymphoma with abnormal Bcl gene is selected from high-grade B-cell lymphoma with abnormal Bcl2 and/or Bcl6 gene
  • the high-grade B-cell lymphoma with abnormal Bcl2 and/or Bcl6 gene is selected from Bcl2 gene 1 in the group consisting of amplified high-grade B-cell lymphoma, Bcl2-fused high-grade B-cell lymphoma, Bcl6-amplified high-grade B-cell lymphoma, and Bcl6-fused high-grade B-cell lymphoma or more.
  • the diffuse large B-cell lymphoma involved in the present invention can also be a diffuse large B-cell lymphoma carrying abnormal chromosomes.
  • the mantle cell lymphoma is one or more selected from the group consisting of classic mantle cell lymphoma, leukemia-like non-scarring mantle cell lymphoma and Cyclin D1 positive mantle cell lymphoma.
  • the mantle cell lymphoma is selected from Bcl gene abnormal mantle cell lymphoma; preferably Bcl1 and/or Bcl2 gene abnormal mantle cell lymphoma; more preferably Bcl1 gene fusion or rearrangement mantle cell lymphoma or Mantle cell lymphoma with Bcl2 gene fusion or rearrangement.
  • the mantle cell lymphoma involved in the present invention may also be a mantle cell lymphoma carrying abnormal chromosomes.
  • the Burkitt lymphoma is a Burkitt lymphoma carrying abnormal chromosomes.
  • the gene abnormality refers to gene mutation, gene fusion or rearrangement and/or gene amplification.
  • the abnormal chromosome refers to a chromosome that has undergone amplification, deletion, fragmentation, rearrangement and/or translocation.
  • the medicament may also contain one or more other targeted drugs or chemotherapeutic drugs.
  • the other targeted drugs or chemotherapeutic drugs refer to targeted drugs or chemotherapeutic drugs clinically used for the treatment of tumor-related diseases.
  • the medicine is prepared into clinically acceptable preparations, such as oral preparations, injection preparations, external preparations and the like.
  • the medicine contains a therapeutically effective dose of Compound A or a pharmaceutically acceptable salt thereof, and the therapeutically effective dose is preferably 0.001-1000 mg per day, more preferably 0.01-500 mg per day, and more More preferably the daily dose is 0.1-200mg, still more preferably the daily dose is 0.5-100mg, still more preferably the daily dose is 0.5-50mg, still more preferably the daily dose is 0.5-30mg, even more preferably The daily dose is 0.5-20 mg.
  • Administration can be single dose or divided doses.
  • the present invention also provides a method for treating BTK-related tumor diseases, characterized by administering to a subject or patient a drug containing a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the BTK-related tumor diseases include hematological tumors and solid tumors.
  • the above-mentioned hematological tumors are lymphomas and leukemias.
  • the above-mentioned lymphoma is a B-cell lymphoma.
  • the BTK-related tumor diseases include histiocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma , Burkitt lymphoma, or Waldenstrom's macroglobulinemia.
  • the diffuse large B-cell lymphoma is selected from the group consisting of non-special types of diffuse large B-cell lymphoma, other large B-cell lymphomas, high-grade B-cell lymphomas with MYC and/or Bcl gene abnormalities, and non-specific types of diffuse large B-cell lymphomas.
  • the other large B-cell lymphomas include T-cell/histiocyte-rich DLBCL, primary central nervous system DLBCL, primary cutaneous DLBCL (leg type), EBV-positive DLBCL, unspecified DLBCL, chronic inflammation Associated large B-cell lymphoma, lymphomatoid granuloma, large B-cell lymphoma with IRF4 rearrangement, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B Cell lymphoma, plasmablastic lymphoma, HHV8-positive DLBCL, primary exudative lymphoma, etc.;
  • the high-grade B-cell lymphoma with MYC gene abnormality is one or more selected from the group consisting of high-grade B-cell lymphoma with MYC gene amplification and high-grade B-cell lymphoma with MYC gene fusion
  • the high-grade B-cell lymphoma with abnormal Bcl gene is selected from high-grade B-cell lymphoma with abnormal Bcl2 and/or Bcl6 gene
  • the high-grade B-cell lymphoma with abnormal Bcl2 and/or Bcl6 gene is selected from Bcl2 gene
  • the diffuse large B-cell lymphoma involved in the present invention can also be a diffuse large B-cell lymphoma carrying abnormal chromosomes.
  • the mantle cell lymphoma is selected from one or more of the group consisting of classic mantle cell lymphoma, leukemia-like non-scarring mantle cell lymphoma and Cyclin D1 positive mantle cell lymphoma.
  • the mantle cell lymphoma is selected from Bcl gene abnormal mantle cell lymphoma; preferably Bcl1 and/or Bcl2 gene abnormal mantle cell lymphoma; more preferably Bcl1 gene fusion or rearrangement mantle cell lymphoma or Bcl2 gene fusion or rearrangement of mantle cell lymphoma.
  • the mantle cell lymphoma involved in the present invention may also be a mantle cell lymphoma carrying abnormal chromosomes.
  • the Burkitt lymphoma is a Burkitt lymphoma carrying abnormal chromosomes.
  • the gene abnormality refers to gene mutation, gene fusion or rearrangement and/or gene amplification.
  • the abnormal chromosome refers to a chromosome that has undergone amplification, deletion, fragmentation, rearrangement and/or translocation.
  • the administration may be oral administration, injection administration, topical administration or in vitro administration, preferably oral administration or injection administration.
  • 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 per day; preferably, from about 0.01 mg/kg to about 100 mg/kg; further preferably, from about 0.02 mg/kg to about 50 mg/kg; even more preferably, from about 0.03 mg/kg to about 20 mg/kg.
  • the daily dose of Compound A or a pharmaceutically acceptable salt thereof is 0.001 mg-1000 mg, further preferably, the daily dose of Compound A or its pharmaceutically acceptable salt is 0.01-500 mg; even more preferably , the daily dose of Compound A or its pharmaceutically acceptable salt is 0.1-200 mg; more preferably, the daily dose of Compound A or its pharmaceutically acceptable salt is 0.5-100 mg; more preferably, the compound The daily dose of A or its pharmaceutically acceptable salt is 0.5-50 mg; more preferably, the daily dose of Compound A or its pharmaceutically acceptable salt is 0.5-30 mg; even more preferably, Compound A or A pharmaceutically acceptable salt thereof is administered in a daily dose of 0.5-20 mg; administered in single or divided doses.
  • the present invention also provides a method of treating a disorder in a patient, whose disorder is a BTK-related tumor disease, by administering to the patient a drug containing a therapeutically effective amount of Compound A or a pharmaceutically acceptable salt thereof.
  • the BTK-related tumor diseases include hematological tumors and solid tumors.
  • the above-mentioned hematological tumors are lymphomas and leukemias.
  • the above-mentioned lymphoma is a B-cell lymphoma.
  • the BTK-related tumor diseases include histiocytic lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma, marginal zone lymphoma, and follicular lymphoma , Burkitt lymphoma, or Waldenstrom's macroglobulinemia.
  • the diffuse large B-cell lymphoma is selected from the group consisting of non-special types of diffuse large B-cell lymphoma, other large B-cell lymphomas, high-grade B-cell lymphomas with MYC and/or Bcl gene abnormalities, and non-specific types of diffuse large B-cell lymphomas.
  • the other large B-cell lymphomas include T-cell/histiocyte-rich DLBCL, primary central nervous system DLBCL, primary cutaneous DLBCL (leg type), EBV-positive DLBCL, unspecified DLBCL, chronic inflammation Associated large B-cell lymphoma, lymphomatoid granuloma, large B-cell lymphoma with IRF4 rearrangement, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B Cell lymphoma, plasmablastic lymphoma, HHV8-positive DLBCL, primary exudative lymphoma, etc.;
  • the high-grade B-cell lymphoma with MYC gene abnormality is one or more selected from the group consisting of high-grade B-cell lymphoma with MYC gene amplification and high-grade B-cell lymphoma with MYC gene fusion
  • the high-grade B-cell lymphoma with abnormal Bcl gene is selected from high-grade B-cell lymphoma with abnormal Bcl2 and/or Bcl6 gene
  • the high-grade B-cell lymphoma with abnormal Bcl2 and/or Bcl6 gene is selected from Bcl2 gene
  • the diffuse large B-cell lymphoma involved in the present invention can also be a diffuse large B-cell lymphoma carrying abnormal chromosomes.
  • the mantle cell lymphoma is selected from one or more of the group consisting of classic mantle cell lymphoma, leukemia-like non-scarring mantle cell lymphoma and Cyclin D1 positive mantle cell lymphoma.
  • the mantle cell lymphoma is selected from Bcl gene abnormal mantle cell lymphoma; preferably Bcl1 and/or Bcl2 gene abnormal mantle cell lymphoma; more preferably Bcl1 gene fusion or rearrangement mantle cell lymphoma or Bcl2 gene fusion or rearrangement of mantle cell lymphoma.
  • the mantle cell lymphoma involved in the present invention may also be a mantle cell lymphoma carrying abnormal chromosomes.
  • the Burkitt lymphoma is a Burkitt lymphoma carrying abnormal chromosomes.
  • the gene abnormality refers to gene mutation, gene fusion or rearrangement and/or gene amplification.
  • the abnormal chromosome refers to a chromosome that has undergone amplification, deletion, fragmentation, rearrangement and/or translocation.
  • the therapeutically effective amount, administration dose or administration dose of Compound A or a pharmaceutically acceptable salt thereof of the present invention are all calculated as Compound A.
  • DLBCL diffuse large B-cell lymphoma
  • non-special types of DLBCL include morphologically including centroblastoid variant, immunoblastoid variant, anaplastic variant and other rare variants (such as spindle cell variant, signet ring cell variant), etc.; other large B-cell lymphocytes Tumors include T-cell/histiocyte-rich DLBCL, primary central nervous system DLBCL, primary cutaneous DLBCL (leg type), EBV-positive DLBCL, unspecified DLBCL, chronic inflammation-related large B-cell lymphoma, lymphoma Granuloma-like, large B-cell lymphoma with IRF4 rearrangement, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma , HHV8-positive DLBCL, primary effusion lymphoma, etc.; high-grade B-cell lymphoma includes high-grade B-cell lymphom
  • Diffuse large B-cell lymphoma carrying abnormal chromosomes refers to diffuse large B-cell lymphoma carrying abnormal chromosomes (eg, chromosomal amplification, deletion, breakage, rearrangement and/or translocation, etc.).
  • Cellular lymphomas such as Pfeiffer cells mentioned in this application (there are multiple chromosomal abnormalities, including translocation of chromosome t(14;18)(q32;q21)) and the like. (Source: ATCC official website information and DSMZ official website information)
  • mantle cell lymphoma carrying abnormal chromosomes refers to mantle cell lymphomas carrying abnormal chromosomes (eg, chromosomal translocations, chromosomal fusions, chromosomal deletions, etc.), such as Z mentioned in this application.
  • abnormal chromosomes eg, chromosomal translocations, chromosomal fusions, chromosomal deletions, etc.
  • -138 cells with chromosomal abnormalities, such as chromosome t(11;14)(q13;q32) translocation and/or chromosome del(5)(p15) deletion, etc.
  • Mino cells with chromosomal abnormalities, such as chromosome del(6) ) (q16) deletion, etc.
  • REC-1 cells chromosomal abnormalities such as chromosome t(11;14)(q13;q32) translocation, etc.
  • Bcl gene abnormal mantle cell lymphoma refers to a mantle cell lymphoma with Bcl gene abnormality (eg, gene mutation, gene amplification, gene rearrangement or/fusion, abnormal gene activation, etc.), It can lead to overexpression of Bcl-related proteins, such as the Jeko-1 cells mentioned in this application (with Bcl-1 gene rearrangement) and the like. (Source: ATCC official website information)
  • Burkitt lymphoma carrying abnormal chromosomes refers to Burkitt lymphomas carrying abnormal chromosomes (eg, abnormalities in chromosomal size and/or number, chromosomal translocations, chromosomal fusions, chromosomal deletions, etc.), such as Raji cells referred to in this application (abnormal size and/or number of chromosomes 1 or 4).
  • abnormal chromosomes eg, abnormalities in chromosomal size and/or number, chromosomal translocations, chromosomal fusions, chromosomal deletions, etc.
  • the pharmaceutically acceptable salts of the compounds can be conventional non-toxic salts formed by the reaction of the compounds with inorganic acids, organic acids, inorganic bases or organic bases.
  • DCM dichloromethane
  • DIAD diisopropyl azodicarboxylate
  • DIPEA diisopropylethylamine
  • DMF N,N-dimethylformamide
  • EA ethyl acetate
  • HATU 2-(7 -benzotriazole oxide)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • NBS N-bromosuccinimide
  • NIS N-iodosuccinimide Amine
  • PdCl 2 (dppf) [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium
  • PdCl 2 Palladium dichloride
  • Pd(OAc) 2 palladium acetate
  • Pd(PPh 3 ) 2 Cl 2 bistripheny
  • S1, S10, S18s and S19s are easy to be oxidized at the 4-position of the terminal phenyl group, have many kinds of metabolites, and have poor metabolic stability. S18s can only retain 51% of the prototype drug after incubation with rat liver microsomes.
  • Compound A effectively overcomes the hydroxylation of the terminal benzene ring of the diphenyl ether structure in the above compounds through structural modification, and can be detected in different species of liver microsomes (HLM: human liver microsomes; RLM: rat liver microsomes; MLM: mouse liver microsomes). Under the action of microsomes), the types and proportions of metabolites are small, and the prototype drugs are basically the main ones (60min: 84%-98%), and the metabolic stability is better.
  • compound A has good BTK inhibitory activity and tumor inhibitory effect, and has low in vivo clearance rate, good oral bioavailability, and stable metabolism, which has important clinical application value.
  • Figure 1 Schematic diagram of the experimental results of the REC-1 xenograft tumor model.
  • Figure 2 Schematic diagram of experimental results of the TMD8 xenograft tumor model.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • the above reaction system was placed in a shaker at 37°C (100 rpm) for 1 hour, then the plate was washed three times with T-PBS, and the primary antibody PY99 100 ⁇ L/well (Santa Cruz) was added, and the reaction was shaken at 37°C for 0.5 hour. After washing the plate with T-PBS, 100 ⁇ L/well of horseradish peroxidase-labeled goat anti-mouse secondary antibody diluent was added, and the reaction was shaken at 37°C for 0.5 hours. After washing the plate with T-PBS, add 100 ⁇ L/well of 2 mg/mL OPD chromogenic solution, and react at 25°C for 1-10 minutes in the dark. Then, 50 ⁇ L/well of 2M H 2 SO 4 was added to stop the reaction, and the reaction was read with a tunable wavelength microplate reader SPECTRA MAX Plus384 with a wavelength of 490 nm.
  • Compounds S1, S10, ibrutinib, acalatinib, S18s, S19s and S20s are used as positive control compounds, wherein compounds S1, S10, S18s, S19s and S20s adopt the methods disclosed in the prior art (eg CN108101905A) or similar methods, ibrutinib and acalatinib were purchased from Selleck Company.
  • the IC 50 value was obtained by four-parameter regression using the software attached to the microplate reader. The results are listed in Table 1 below.
  • DLBCL diffuse large B-cell lymphoma
  • FBS fetal bovine serum
  • 2-mercaptoethanol 2-mercaptoethanol
  • the cell suspension (Ramos: 10,000 cells/well; TMD8: 12,000 cells/well) was inoculated into a 96-well plate, and left for 2 hours in a 37°C incubator until the cells were in a stable state, and then different concentrations of test compounds were added to each well. (3 duplicate wells for each concentration), and a blank control (well containing only culture medium, no cells), negative control (well with only cells, no compound) and positive compound control were set at the same time.
  • the inhibition rate of the compound was calculated by the following formula:
  • the IC 50 value was obtained by four-parameter regression using the software attached to the microplate reader. The experiment was repeated 3 times independently and the results are listed in Table 2 below.
  • the compounds S1, S10, ibrutinib, acalatinib, S18s, S19s and S20s described above were also used as positive control compounds.
  • DLBCL diffuse large B-cell lymphoma
  • FL follicular lymphoma
  • MCL mantle cell lymphoma
  • PMBCL primary mediastinal B-cell lymphoma
  • CCK8 Cell Counting Kit-8, #D3100L4057, Shanghai Liji Biotechnology Co., Ltd. staining method was used to detect the proliferation inhibitory activity of the compounds on cells.
  • a cell suspension of an appropriate density was inoculated into a 96-well plate, 95 ⁇ L per well. Incubate at 37°C for 2-4h until the cells are in a stable state, then add 10 ⁇ L of compound with the desired concentration of gradient dilution in sequence, set 3 duplicate wells for each dose, and set solvent control and cell-free blank control wells at the same time. Incubate in a carbon dioxide incubator at 37°C for 72h.
  • Inhibition rate % (OD value of control group-OD value of administration group)/OD value of control group ⁇ 100%.
  • the IC 50 value of the median inhibitory dose was calculated by the four-parameter method. Each experiment was independently repeated 3 times, and the average IC 50 value of each experiment was obtained as the final indicator of inhibitory ability.
  • the inhibitory activity of compound A on OCI-LY10 and REC-1 is better than that of the positive control drugs ibrutinib and acalatinib, and the inhibitory activity on other B lymphoma cells
  • the inhibitory activity is comparable to that of ibrutinib, or is between ibrutinib and acalatinib, suggesting that Compound A of the present invention is expected to be able to treat diseases treated by ibrutinib and acalatinib, such as Chronic lymphocytic leukemia, chronic lymphocytic leukemia with 17p deletion/small lymphocytic lymphoma, Waldenstrom's macroglobulinemia, marginal zone lymphoma, chronic graft-versus-host disease.
  • diseases treated by ibrutinib and acalatinib such as Chronic lymphocytic leukemia, chronic lymphocytic leukemia with 17p deletion/small lymphocytic lymphoma, Waldenstrom's macroglob
  • Cell culture Human lymphoma TMD8 cells were cultured in vitro in suspension, and the culture conditions were RPMI 1640 medium (supplier: gibco; product number: 22400-089; production batch number: 4868546) with 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g /mL streptomycin, incubate at 37°C with 5% CO 2 . Routine treatment passaging was performed twice a week. When the cell saturation was 80%-90%, cells were harvested, counted, and seeded.
  • Human mantle cell lymphoma REC-1 cells were cultured in vitro in suspension in RPMI 1640 medium (supplier: gibco; product number: 22400-089; production batch number: 1868795) with 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, 37 °C 5% CO2 culture. Routine treatment passaging was performed twice a week. When the cell saturation was 80%-90%, cells were harvested, counted, and seeded.
  • Tumor Measurements and Experimental Indicators examine whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with vernier calipers three times a week.
  • the formula for calculating tumor volume is:
  • V 0.5a ⁇ b 2 .
  • a and b represent the long and short diameters of the tumor, respectively.
  • TGI % or relative tumor proliferation rate T/C (%).
  • TGI % reflecting tumor growth inhibition rate.
  • TGI(%) [1-(average tumor volume at the end of administration of a certain treatment group-average tumor volume at the beginning of administration of this treatment group)/(average tumor volume at the end of treatment in the solvent control group-average at the beginning of treatment in the solvent control group Tumor volume)] ⁇ 100%.
  • T/C% T RTV /C RTV ⁇ 100% (T RTV : relative tumor volume of the treatment group; C RTV : relative tumor volume of the negative control group).
  • Statistical analysis including mean and standard error (SEM) of tumor volume for each time point for each group.
  • the treatment group showed the best therapeutic effect on the 15th day (REC-1 xenograft tumor model) and 17th day (TMD8 xenograft tumor model) after administration, so a statistical analysis was performed based on this data to evaluate between groups difference.
  • One-way ANOVA was used for comparison among three or more groups, and if there was a significant difference in F value, the Games-Howell method was used to test. All data analyses were performed with SPSS 17.0. p ⁇ 0.05 was considered a significant difference.
  • the in vivo efficacy of compound A in the human mantle cell lymphoma REC-1 xenograft tumor model is shown in Table 7 and FIG. 1 .
  • the tumor volume of Compound A 15mg/kg and 30mg/kg groups were 1034 and 680mm 3 , respectively, which had a significant tumor inhibitory effect compared with the solvent control group (T/C values were 30% and 19%, respectively, TGI values were 73 % and 83%, both p values were less than 0.01), compared with the positive drug ibrutinib 25 mg/kg group, the compound A 15 mg/kg group had better tumor-inhibiting effect.
  • TGI(%) [1-(T 15 -T 0 )/(V 15 -V 0 )] ⁇ 100);
  • the in vivo efficacy of Compound A in the human lymphoma TMD8 xenograft tumor model is shown in Table 8 and FIG. 2 .
  • 17 days after the start of administration the tumor volume of the tumor-bearing mice in the solvent control group reached 1852 mm 3 , and the tumor volume of the ibrutinib 25 mg/kg group was 661 mm 3 .
  • the tumor volume of compound A 5mg/kg and 10mg/kg groups were 912mm 3 and 553mm 3 , respectively, which had a significant tumor inhibitory effect compared with the solvent control group (T/C values were 49.27% and 29.85%, TGI values were 53.78% and 74.35%, both p values were less than 0.01), compared with the positive drug ibrutinib 25 mg/kg group, the compound A 10 mg/kg group had better tumor-inhibiting effect.
  • TGI(%) [1-(T 17 -T 0 )/(V 17 -V 0 )] ⁇ 100);
  • Mode of administration once a day.
  • CMC-Na carboxymethylcellulose sodium
  • Tween 80 0.5% DMSO/5% Tween 80/90% physiological saline was formulated into a solution, and the dose concentration was 0.2 mg/mL.
  • Oral administration 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;
  • Intravenous administration 5 minutes, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 hours after administration;
  • venous blood was collected from the retroocular venous plexus of rats, placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 minutes, and the plasma was separated and frozen in a -20°C refrigerator.
  • the concentration of Compound A in rat plasma was determined by LC/MS/MS method.
  • the peak concentration Cmax and the peak time Tmax are measured values
  • AUC 0-t value of the area under the drug-time curve calculated by trapezoidal method
  • AUC 0- ⁇ AUC 0-t +C t / ke ,
  • C t is the blood drug concentration at the last measurable time point
  • ke is the elimination rate constant
  • Mean residence time MRT AUMC/AUC.
  • Absolute bioavailability F (AUC gavage ⁇ D vein )/(AUC vein ⁇ D gavage ) ⁇ 100%
  • Compound A is a novel, oral, highly selective and highly active BTK inhibitor with significantly better in vitro and in vivo activity than the currently marketed BTK inhibitors. At the same dose, it inhibits tumor growth. The activity is significantly better than that of the positive control drug ibrutinib, which is of great development value.

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Abstract

L'invention concerne l'utilisation du composé A ou d'un sel pharmaceutiquement acceptable de celui-ci en tant qu'inhibiteur de la tyrosine kinase de Bruton (BTK) dans la préparation de médicaments pour le traitement de maladies tumorales associées à la BTK. Le composé A a une bonne activité inhibitrice sur la BTK, a une bonne activité inhibitrice sur les cellules de lymphomes à cellules B humaines hautement exprimées par la BTK, et a également une bonne activité anti-tumorale in vivo. Le composé A a de bonnes propriétés pharmacocinétiques et une bonne stabilité métabolique, et peut être utilisé pour développer des préparations pharmaceutiques pour le traitement de maladies tumorales associées à la BTK.
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Citations (3)

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