WO2021208295A1 - Utilisation de l'inhibiteur pde4 dans la préparation d'un médicament destiné au traitement de la leucémie - Google Patents

Utilisation de l'inhibiteur pde4 dans la préparation d'un médicament destiné au traitement de la leucémie Download PDF

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WO2021208295A1
WO2021208295A1 PCT/CN2020/106205 CN2020106205W WO2021208295A1 WO 2021208295 A1 WO2021208295 A1 WO 2021208295A1 CN 2020106205 W CN2020106205 W CN 2020106205W WO 2021208295 A1 WO2021208295 A1 WO 2021208295A1
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leukemia
cells
drug
proliferation
cell
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PCT/CN2020/106205
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English (en)
Chinese (zh)
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赵子建
毛萍
李芳红
赵正刚
李玉玉
周素瑾
李美蓉
张馨丹
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广州华真医药科技有限公司
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Publication of WO2021208295A1 publication Critical patent/WO2021208295A1/fr

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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

Definitions

  • the present invention belongs to the field of anti-tumor drugs, especially leukemia drugs. Specifically, the present invention provides the application of PDE4 inhibitor ZL-n-91 in the preparation of drugs for treating leukemia.
  • Leukemia is a malignant disease of the hematopoietic system, which is characterized by the extensive and uncontrolled proliferation of a large number of leukemia cells in the body and the infiltration of normal bone marrow and other organs and tissues. Its etiology and pathogenesis are complex, and it is still not very clear.
  • the mortality rate of leukemia in China is roughly 4.8 per 100,000 population, and that in European and American countries is 6.2 per 100,000. It is one of the ten high-incidence malignant tumors in China, and it is also the malignant tumor with the highest morbidity and mortality among people under the age of 35.
  • Acute leukemia is more common than chronic leukemia in China, while the situation is the opposite in European and American countries.
  • Acute myeloid leukemia is more common in adults, and acute lymphoblastic leukemia is more common in children. It is slightly more common in men than in women.
  • the prognosis of leukemia is poor, and the treatment is mainly combination and supportive therapy. Because non-solid hematological tumors represented by leukemia are quite different from solid tumors in drug metabolism, cancer cell distribution, heterogeneity, and efficacy judgments, the current types of drugs for treating leukemia are far less than solid tumors, and their efficacy is generally limited. Seeking high efficiency The therapeutic drugs are of great significance.
  • Phosphodiesterase (abbreviated as PDEs) has the function of hydrolyzing the second messenger cAMP or cGMP in the cell, thereby affecting the signal pathway mediated by these second messengers and regulating cell functions.
  • PDEs are divided into 11 subtypes, in which phosphodiesterase 4 (PDE4) specifically hydrolyzes cAMP.
  • PDE4 is mainly distributed in various inflammatory cells, including mast cells, macrophages, lymphocytes, epithelial cells, etc.
  • PDE4 inhibitors have anti-inflammatory, anti-allergic, and anti-platelet activation effects.
  • Its mechanism of action mainly involves: 1) inhibiting the release of various inflammatory mediators/cytokines, which can inhibit the expression of IL-4 and IL-5 genes; 2) inhibiting the activation of white blood cells (such as respiratory burst) and inhibiting the migration of white blood cells; 3 ) Inhibit the expression or up-regulation of cell adhesion factor (CAM); 4) induce the production of cells with inhibitory activity, such as IL-6; 5) induce apoptosis; 6) stimulate the release of endogenous hormones and catecholamines.
  • the diseases targeted by PDE4 inhibitors that have been developed or are being developed are mainly chronic obstructive pulmonary disease (COPD), asthma, inflammatory bowel disease, arthritis and so on.
  • COPD chronic obstructive pulmonary disease
  • PDE4 inhibitors also have a significant inhibitory effect on malignant tumors.
  • Patricia Goldhoff xenotransplanted nude mice into human brain astroblastoma cells U87 the use of PDE4 inhibitors can prolong the survival of the mice.
  • Motoshi Narita discovered that PDE4i can inhibit the growth of human melanoma cells.
  • Petros X.E. Mouratidis discovered that the addition of PDE4 inhibitors CC-8075 and CC-8062 to pancreatic cancer cells can reduce cell proliferation and increase cell apoptosis.
  • the existing PDE4 inhibitors mainly include Rolipram, Cilomilast, and Roflumilast.
  • Rolipram and Cilomilast caused dizziness, headache, nausea, vomiting and other gastrointestinal adverse reactions, which affected the clinical promotion and application of the drug.
  • One of the possible reasons for gastrointestinal adverse reactions is poor specificity of PDE4 inhibitors, thereby moderately and selectively inhibiting the entire PDE family.
  • the Ki of Cilomilast to PDE4 92nM, which is only 500 to 1000 times the Ki of PDE1, 2, 3, and 5. Therefore, the use of higher doses of Cilomilast will interact with other members of the PDE family and cause side effects. In fact, for most PDE4 inhibitors, the side effect of vomiting at high doses is common.
  • Roflumilast has been approved by the US FDA for the treatment of COPD, it can reduce lung inflammation, resist oxidative stress, effectively alleviate lung fibrosis, enhance mucosal clearance, and airway remodeling. But there are also adverse reactions, mainly manifested as diarrhea, weight loss, nausea, atrial fibrillation, and aggravation of mental illness (such as insomnia, anxiety, depression) and so on.
  • IC 50 reaches 18nM. It has been tried at home and abroad to treat lung diseases, such as COPD and even lung cancer and prostate cancer, with good results. In the process of further expanding the PDE4 inhibitor to treat PDE4-related diseases, whether it is effective for other cancers, especially non-solid tumors, such as blood/lymphoid tumors, has not been verified by any research.
  • the present invention provides the application of the PDE4 inhibitor ZL-n-91 in the preparation of drugs for the treatment of non-solid tumors.
  • the non-solid tumor is leukemia.
  • the leukemia is lymphocytic leukemia.
  • the drug inhibits the proliferation of leukemia.
  • the drug is administered at a dose of 10 mg ⁇ kg-1.
  • the medicine is an oral dosage form.
  • the present invention provides a pharmaceutical composition for treating leukemia, which contains ZL-n-91 as the sole active ingredient.
  • the leukemia is lymphocytic leukemia.
  • the drug is administered at a dose of 10 mg ⁇ kg-1.
  • the pharmaceutical composition is an oral dosage form.
  • the present invention provides a method of treating non-solid tumors, comprising administering ZL-n-91 to a subject in need.
  • the non-solid tumor is leukemia.
  • the leukemia is lymphocytic leukemia.
  • the ZL-n-91 inhibits the proliferation of leukemia.
  • the ZL-n-91 is administered at a dose of 10 mg ⁇ kg-1.
  • ZL-n-91 The chemical structure of ZL-n-91 described in this application has been disclosed, and those skilled in the art can refer to prior art documents (such as Ruihong Ma, Bin-yan Yang, Chang-you Wu. A selective phosphodiesterase 4(PDE4) inhibitor Zl-n-91 suppresses IL-17 production by human memory Th17 cells. International Immunopharmacology, 2008, 8(10): 1408-1417.) and conventional techniques in the field of organic chemistry use synthesis, purchase, and application for gifts to obtain suitable purity The ZL-n-91.
  • PDE4 phosphodiesterase 4
  • the leukemia described in this application includes various specific types of leukemia, including, but not limited to, acute/chronic leukemia, myeloid/granulocyte/lymphocytic leukemia, and childhood/adult leukemia.
  • the dosage forms that can be used in the present invention include but are not limited to tablets, capsules, oral liquids, injections, powder injections, etc.
  • oral and injection dosage forms those skilled in the art can also design or select according to needs and common knowledge in the pharmaceutical field Other dosage forms.
  • the prepared medicine may contain various pharmaceutically acceptable excipients and excipients, including but not limited to coating materials, solvents, solubilizers, adhesives, stabilizers, and antioxidants. , PH adjusters, flavoring agents, etc.
  • the technical solution claimed by the present invention does not exclude the use of other known Chinese and Western medicines/therapies for the treatment of leukemia.
  • These medicines include but are not limited to chemotherapeutic drugs, biological targeted drugs, radiotherapy, immunotherapy, stem cell therapy, ZL-n -91 can be prepared in the same pharmaceutical composition with these drugs or used in combination as a single drug.
  • the selective PDE4 inhibitor ZL-n-91 of the present invention can significantly inhibit the proliferation of tumor cells, indicating that the phosphodiesterase 4 inhibitor ZL-n-91 is expected to become an important target for anti-leukemia proliferation research.
  • the preparation of anti-leukemia proliferation drugs provides a basis and has good development and application prospects.
  • the inhibitory strength of ZL-n-91 on PDE4B and PDE4D is more than 5000 times that of other PDE family members. Compared with other PDE4 inhibitors, the compound has higher selectivity for PDE4B and PDE4D, strong specificity, less side effects such as vomiting, and has good clinical adaptability and safety when it is extended to the treatment of leukemia.
  • Figure 1 The inhibitory effect of ZL-n-91 on the proliferation of leukemia cells
  • (a) The proliferation results of L1210, HL-60, K562 and JurKat cells treated with ZL-n-91 at different concentrations for 48 hours;
  • Figure 2 The morphological changes of L1210, HL-60, K562 and JurKat cells treated with different concentrations of ZL-n-91 for 48 hours.
  • Figure 3 The effect of ZL-n-91 on the cell cycle distribution of leukemia
  • Figure 4 ZL-n-91 induces apoptosis of leukemia cells
  • (a) Flow cytometric detection of apoptosis in L1210, HL-60, K562 and JurKat cells treated with different concentrations of ZL-n-91 for 48 hours;
  • (b) L1210 , HL-60, K562 and JurKat, the total apoptosis rate of different groups. All data are expressed as mean ⁇ standard deviation. (n 3), *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.001 and****P ⁇ 0.0001 are all compared with the solvent control group.
  • Example 1 CCK8 method to detect the effect of ZL-n-91 on the proliferation of leukemia cells.
  • Example 2 Changes in the morphology of leukemia cells after 48 hours of treatment with ZL-n-91
  • Example 3 Flow cytometry to detect the influence of Zl-n-91 on cell cycle distribution of leukemia
  • ZL-n-91 can significantly induce apoptosis of L1210, HL-60, K562 and JurKat leukemia cells.
  • Cell preparation Culture the leukemia cell L1210 to the logarithmic growth phase, wash twice with PBS and resuspend, and count the cells. The final injection volume is about 5*10 4 /100 ⁇ l/cell.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Oncology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Plant Substances (AREA)

Abstract

La présente divulgation concerne l'utilisation de l'inhibiteur de phosphodiestérase 4 ZL-n-91 dans la préparation d'un médicament destiné au traitement de la leucémie. Des expériences de cytologie in vitro et des expériences chez l'animal montrent que l'inhibiteur de phosphodiestérase 4 ZL-n -91 peut inhiber significativement la prolifération de cellules leucémiques, ce qui montre que l'inhibiteur de phosphodiestérase 4 ZL-n-91 devrait devenir une cible importante dans les études concernant la prolifération anti-leucémie, et qu'il présente de bonnes perspectives en termes de développement futur et d'application.
PCT/CN2020/106205 2020-04-16 2020-07-31 Utilisation de l'inhibiteur pde4 dans la préparation d'un médicament destiné au traitement de la leucémie WO2021208295A1 (fr)

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CN202010302022.9 2020-04-16
CN202010302022.9A CN113521053B (zh) 2020-04-16 2020-04-16 Pde4抑制剂在制备治疗白血病的药物中的应用

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016621A1 (fr) * 1998-09-24 2000-03-30 Boston Medical Center Corporation Traitement de la leucemie lymphoide chronique et compositions a cet effet
CN107041880A (zh) * 2016-02-05 2017-08-15 赵子建 磷酸二酯酶4抑制剂ZL-n-91在制备抗肺癌增殖与转移药物中的应用
CN107714686A (zh) * 2016-08-10 2018-02-23 赵子建 磷酸二酯酶4抑制剂ZL‑n‑91在制备治疗前列腺癌增生和转移药物中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016621A1 (fr) * 1998-09-24 2000-03-30 Boston Medical Center Corporation Traitement de la leucemie lymphoide chronique et compositions a cet effet
CN107041880A (zh) * 2016-02-05 2017-08-15 赵子建 磷酸二酯酶4抑制剂ZL-n-91在制备抗肺癌增殖与转移药物中的应用
CN107714686A (zh) * 2016-08-10 2018-02-23 赵子建 磷酸二酯酶4抑制剂ZL‑n‑91在制备治疗前列腺癌增生和转移药物中的应用

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GONG SI-JIA, LIN YAN, LI XIAO-XI, ZHOU SU-JIN, ZHAO ZHENG-GANG, LAI YI-MEI, SHI HUI, DING NING, LI FANG-HONG, ZHAO ZI-JIAN: "Effects of a Selective Phosphodiesterase 4 Inhibitor, ZL-n-91, on the Human Prostate Cancer PC-3 Cells and Xenografts in Nude Mice", PROGRESS IN MODERN BIOMEDICINE, XIAN DAI SHENG WU YI XUE JIN ZHAN BIAN JI BU, CN, vol. 16, no. 24, 30 August 2016 (2016-08-30), CN , pages 4601 - 4604, XP009513645, ISSN: 1673-6273, DOI: 10.13241/j.cnki.pmb.2016.24.001 *
MOON E-Y, LERNER A: "PDE4 inhibitors activate a mitochondrial apoptotic pathway in chronic lymphocytic leukemia cells that is regulated by protein phosphatase 2A", BLOOD, AMERICAN SOCIETY OF HEMATOLOGY, US, vol. 101, no. 10, 15 May 2003 (2003-05-15), US , pages 4122 - 4130, XP003013050, ISSN: 0006-4971, DOI: 10.1182/blood-2002-10-3208 *
NORMAN P: "PDE4 inhibitors: Sustained patenting activity as leading drugs near the market", EXPERT OPINION ON THERAPEUTIC PATENTS, TAYLOR & FRANCIS, GB, vol. 10, no. 9, 1 January 2000 (2000-01-01), GB , pages 1415 - 1427, XP002235905, ISSN: 1354-3776, DOI: 10.1517/13543776.10.9.1415 *

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