WO2022007745A1 - 西奥罗尼及其联合用药治疗非霍奇金淋巴瘤的用途 - Google Patents
西奥罗尼及其联合用药治疗非霍奇金淋巴瘤的用途 Download PDFInfo
- Publication number
- WO2022007745A1 WO2022007745A1 PCT/CN2021/104503 CN2021104503W WO2022007745A1 WO 2022007745 A1 WO2022007745 A1 WO 2022007745A1 CN 2021104503 W CN2021104503 W CN 2021104503W WO 2022007745 A1 WO2022007745 A1 WO 2022007745A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- chidamide
- lymphoma
- hodgkin
- derivative
- cioronitrile
- Prior art date
Links
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 title claims abstract description 37
- BRKWREZNORONDU-UHFFFAOYSA-N n-(2-aminophenyl)-6-(7-methoxyquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=1C=NC2=CC(OC)=CC=C2C=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=CC=C1N BRKWREZNORONDU-UHFFFAOYSA-N 0.000 title abstract 4
- 239000000890 drug combination Substances 0.000 title abstract 3
- 238000011282 treatment Methods 0.000 title description 15
- WXHHICFWKXDFOW-BJMVGYQFSA-N n-(2-amino-5-fluorophenyl)-4-[[[(e)-3-pyridin-3-ylprop-2-enoyl]amino]methyl]benzamide Chemical compound NC1=CC=C(F)C=C1NC(=O)C(C=C1)=CC=C1CNC(=O)\C=C\C1=CC=CN=C1 WXHHICFWKXDFOW-BJMVGYQFSA-N 0.000 claims abstract description 48
- 229950009221 chidamide Drugs 0.000 claims abstract description 46
- 239000003814 drug Substances 0.000 claims abstract description 24
- 238000002360 preparation method Methods 0.000 claims abstract description 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 11
- 239000013078 crystal Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 10
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229940079593 drug Drugs 0.000 abstract description 17
- 239000000203 mixture Substances 0.000 abstract description 3
- 206010028980 Neoplasm Diseases 0.000 description 14
- 102000003964 Histone deacetylase Human genes 0.000 description 11
- 108090000353 Histone deacetylase Proteins 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 11
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 7
- -1 AuroraB Proteins 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 230000002159 abnormal effect Effects 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 206010025323 Lymphomas Diseases 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 3
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 3
- 210000001165 lymph node Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 230000011278 mitosis Effects 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000009097 single-agent therapy Methods 0.000 description 3
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- 108010077544 Chromatin Proteins 0.000 description 2
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 2
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 2
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 2
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 210000003483 chromatin Anatomy 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- 201000003444 follicular lymphoma Diseases 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 2
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 201000011649 lymphoblastic lymphoma Diseases 0.000 description 2
- 201000007924 marginal zone B-cell lymphoma Diseases 0.000 description 2
- 208000021937 marginal zone lymphoma Diseases 0.000 description 2
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000000822 natural killer cell Anatomy 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 2
- 229960001796 sunitinib Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- 229940122815 Aromatase inhibitor Drugs 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 102000004269 Granulocyte Colony-Stimulating Factor Human genes 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 1
- 102100039999 Histone deacetylase 2 Human genes 0.000 description 1
- 102100021455 Histone deacetylase 3 Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 101500025419 Homo sapiens Epidermal growth factor Proteins 0.000 description 1
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 1
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 description 1
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101001035694 Homo sapiens Polyamine deacetylase HDAC10 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 102100039388 Polyamine deacetylase HDAC10 Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 108700005075 Regulator Genes Proteins 0.000 description 1
- 230000009102 absorption Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000005441 aurora Substances 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000007969 cellular immunity Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009261 endocrine therapy Methods 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 230000008995 epigenetic change Effects 0.000 description 1
- 230000006718 epigenetic regulation Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000019691 hematopoietic and lymphoid cell neoplasm Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 229940116978 human epidermal growth factor Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000019569 negative regulation of cell differentiation Effects 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000003909 protein kinase inhibitor Substances 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
Images
Classifications
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
-
- 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 invention relates to the field of biomedicine, in particular to the use of cioronib and its combination drug for treating non-Hodgkin's lymphoma.
- Non-Hodgkin's lymphoma is a cancer originating from the lymph nodes of the body, accounting for about 80% to 90% of all lymphomas, of which two-thirds are primary in the lymph nodes, and one-third 1. Primary in organs or tissues outside the lymph nodes, such as digestive and respiratory tract, lungs, skin, salivary glands, thyroid and central nervous system.
- non-Hodgkin lymphoma In my country, non-Hodgkin lymphoma accounts for about 90% of all lymphomas, and the incidence is increasing year by year. According to the natural history of non-Hodgkin's lymphoma, it can be classified into three major clinical types, namely highly aggressive non-Hodgkin's lymphoma, aggressive non-Hodgkin's lymphoma and indolent non-Hodgkin's lymphoma. Highly aggressive non-Hodgkin lymphoma includes Burkitt lymphoma (BL), lymphoblastic lymphoma (LBL) and mantle cell lymphoma (MCL), etc.
- BL Burkitt lymphoma
- LBL lymphoblastic lymphoma
- MCL mantle cell lymphoma
- Aggressive non-Hodgkin lymphoma includes diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma, anaplastic large cell lymphoma (ALCL) and angioimmunoblastic T-cell lymphoma, etc., indolent non-Hodgkin lymphoma including follicular lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma and marginal zone lymphoma (MZL).
- DLBCL diffuse large B-cell lymphoma
- ACL anaplastic large cell lymphoma
- angioimmunoblastic T-cell lymphoma etc.
- indolent non-Hodgkin lymphoma including follicular lymphoma, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), lymphoplasmacytic lymphoma and marginal zone lymph
- Cioroni is a new protein kinase inhibitor with complete intellectual property rights independently developed by Shenzhen Microchip Biotechnology Co., Ltd. Cioroni is a small-molecule anti-tumor drug targeting multi-protein kinases. It has anti-tumor angiogenesis, high selective inhibitory activity against VEGFR/PDGFR/c-Kit, AuroraB, and CSF-1R targets. The three-way anti-tumor synergistic mechanism of inhibiting tumor cell mitosis and regulating tumor inflammatory microenvironment plays a comprehensive anti-tumor effect.
- cioronib Compared with traditional VEGFR targeted inhibitors (such as sunitinib/Sunitinib, sorafenib/Sorafenib, etc.), the inhibitory activity of cioronib on mitosis key enzyme Aurora B is unique and has potential The effect of reducing the genomic instability of tumor tissue and inhibiting tumor cell metastasis. Cioroni exerts antitumor activity by inhibiting three complementary mechanisms of tumor angiogenesis, cell mitosis and tumor inflammatory microenvironment, and its high target selectivity also reduces the risk of side effects caused by off-target effects.
- CN200910223861.5 discloses cioroni compound, which specifically discloses a derivative of naphthalene amide, its preparation method and application.
- the compounds have both protein kinase inhibitory activity and histone deacetylase inhibitory activity, and can be used to treat diseases related to abnormal protein kinase activity or abnormal activity of histone deacetylase, including inflammation, autoimmune disease, cancer , neurological and neurodegenerative diseases, cardiovascular diseases, metabolic diseases, allergies, asthma, and hormone-related diseases.
- CN201610856945.2 discloses unsolvated crystals A, B, C of Cioroni and their preparation methods, and also relates to a pharmaceutical composition containing said crystals, and said crystals are used in the preparation of treatment and abnormal protein kinase activity Or the application of medicines for diseases related to abnormal histone deacetylase activity.
- CN201811550290.1 discloses a new use of cioronib in the preparation of a drug for the treatment of acute myeloid leukemia, and the new use is that cioronib or a pharmaceutically acceptable salt, ester or solvate thereof is used in the preparation of preventive and/or Use in a medicament for the treatment of acute myeloid leukemia.
- Cioroni inhibits the growth, apoptosis and colony formation of acute myeloid leukemia cells through Src/Fyn/p38 and Erk/MEK signaling pathways.
- Chidamide is also a new molecular body independently developed by Shenzhen Microchip Biotechnology Co., Ltd. with global patent protection. It is the world's first subtype-selective histone deacetylase (HDAC) oral inhibitor. Chidamide mainly targets subtypes 1, 2, and 3 of class I HDACs and subtype 10 of class IIb, and has a regulatory effect on abnormal epigenetic functions of tumors.
- HDAC histone deacetylase
- Chidamide triggers chromatin remodeling by inhibiting related HDAC isoforms to increase the acetylation level of chromatin histones, resulting in changes in gene expression (ie, epigenetic changes) for multiple signaling pathways, and then It inhibits tumor cell cycle, induces tumor cell apoptosis, and has overall regulatory activity on the body's cellular immunity, and induces and enhances the tumor killing effect mediated by natural killer cells (NK) and antigen-specific cytotoxic T cells (CTL).
- NK natural killer cells
- CTL antigen-specific cytotoxic T cells
- Chidamide also has functions such as inducing tumor stem cell differentiation and reversing the epithelial-mesenchymal phenotype transition (EMT) of tumor cells through epigenetic regulation mechanisms, thereby restoring the sensitivity of drug-resistant tumor cells to drugs and inhibiting tumors. It plays a potential role in metastasis and recurrence.
- EMT epithelial-mesenchymal phenotype transition
- Chidamide's first indication is for relapsed and refractory peripheral T-cell lymphoma.
- Chidamide was approved in combination with an aromatase inhibitor for hormone receptor-positive, human epidermal growth factor receptor-2-negative, postmenopausal, locally advanced or metastatic breast cancer that has recurred or progressed on endocrine therapy Indications for cancer patients.
- clinical studies of Chidamide alone and in combination with other anti-tumor drugs against other hematological tumors, solid tumors and HIV are being carried out simultaneously in the United States, Japan, China, Taiwan and other countries and regions.
- CN03139760.3 discloses chidamide compound, specifically discloses a benzamide-type histone deacetylase inhibitor with differentiation and anti-proliferation activity and the preparation method and application of its medicinal preparation, which discloses the structure The general formula defines the substituents. These compounds, as histone deacetylase inhibitors, can be used to treat differentiation and proliferation-related diseases such as cancer and psoriasis.
- CN201210489178.8 discloses two crystalline forms of Chidamide, namely Chidamide crystalline form A and Chidamide crystalline form B, and a preparation method of a new crystalline form of Chidamide.
- the Chidamide crystalline form A and Chidamide crystalline form B have excellent performance in oral absorption and inhibition of cell differentiation and proliferation, and have weak toxicity, good storage and handling stability, and can be used for preparation Drugs to treat disorders related to cell differentiation and proliferation.
- CN201410136761.X discloses an E-configuration benzamide compound and its medicinal preparation and application, the E-configuration benzamide compound is Chidamide, and its chemical name is N-(2-amino- 4-Fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl]benzamide, in its structural formula, the configuration of 3-pyridineacryloyl is E type.
- the E-configuration Chidamide has subtype-selective histone deacetylase inhibitory activity, mainly inhibiting HDAC1, HDAC2, HDAC3 in class I HDACs and HDAC10 in class IIb HDACs.
- the E-configuration chidamide can be used to treat diseases related to abnormal activity of histone deacetylase, such as cancer, including lymphoma, solid tumor and hematological tumor.
- CN201810892420.3 discloses a combined drug for the treatment of leukemia, including Chidamide and DCAG drugs with effective doses for simultaneous, separate or sequential administration, and the DCAG drugs are decitabine,
- the combined medicine of glycocytidine, aclarithromycin and granulocyte colony-stimulating factor provides the use of Chidamide combined with DCAG in the preparation of a medicine for treating acute myeloid leukemia, and the beneficial effects are:
- the complete remission rate (CR) of AML patients with relapsed and refractory acute myeloid leukemia reached 43.6%
- the objective response rate (ORR) reached 58.2%.
- CN201911129472.6 discloses the application of Chidamide, specifically proposes the application of Chidamide with therapeutic effect on B-cell lymphoma, and has verified through clinical trials that Chidamide monotherapy treats diffuse large B-cell lymphoma Cell lymphomas and relapsed or refractory follicular lymphomas with specific epigenetic regulatory gene mutations have a more prominent effect, and the application can more efficiently treat B-cell lymphoma patients.
- the purpose of the present invention is to provide a cioronib and its combined drug composition which can effectively prevent and/or treat non-Hodgkin's lymphoma, and especially have high efficacy and safety within a specific dosage range.
- the present invention provides the use of ciorone or its derivatives in preparing a medicament for preventing and/or treating non-Hodgkin's lymphoma, preferably, the content of said cioroni or its derivatives is 10 -65mg, preferably 20-50mg.
- the Cioroni derivative includes Cioroni, its pharmaceutically acceptable salts, and its unsolvated crystals A, B and C.
- the unsolvated crystals A, B and C of Cioroni are disclosed in CN201610856945.2, the full content of which is incorporated into the present invention.
- the present invention also provides the use of a pharmaceutical composition comprising ciorone or its derivative and chidamide or its derivative in preparing a medicament for preventing and/or treating non-Hodgkin's lymphoma.
- the content of the cioronitrile or its derivatives is 10-65 mg, preferably 20-50 mg, and the content of the chidamide or its derivatives is 5-60 mg, preferably 10-30 mg.
- the Cioroni derivative includes Cioroni, its pharmaceutically acceptable salts and its unsolvated crystals A, B and C.
- the unsolvated crystals A, B and C of Cioroni are disclosed in CN201610856945.2, the full content of which is incorporated into the present invention.
- the Chidamide derivatives include Chidamide, its pharmaceutically acceptable salts, its enantiomers, and its crystal forms A and B.
- the enantiomers of Chidamide are disclosed in CN201410136761.X, the full content of which is incorporated into the present invention, and the crystal forms A and B of Chidamide are disclosed in CN201210489178.8, the full content of which is incorporated into the present invention .
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising ciorone or its derivative and chidamide or its derivative, wherein the content of said cioroni or its derivative is 10- 65 mg, preferably 20-50 mg, and the content of the Chidamide or its derivatives is 5-60 mg, preferably 10-30 mg.
- the Cioroni derivative includes Cioroni, its pharmaceutically acceptable salts and its unsolvated crystals A, B and C.
- the unsolvated crystals A, B and C of Cioroni are disclosed in CN201610856945.2, the full content of which is incorporated into the present invention.
- the Chidamide derivatives include Chidamide, its pharmaceutically acceptable salts, its enantiomers, and its crystal forms A and B.
- the enantiomers of Chidamide are disclosed in CN201410136761.X, the full content of which is incorporated into the present invention, and the crystal forms A and B of Chidamide are disclosed in CN201210489178.8, the full content of which is incorporated into the present invention .
- the present invention provides a kit comprising the aforementioned pharmaceutical composition.
- the present invention provides a method of preventing and/or treating non-Hodgkin's lymphoma, which comprises administering the aforementioned cioronib or its derivative, pharmaceutical composition or kit to a patient in need thereof.
- Chidamide can be used alone for the treatment of non-Hodgkin's lymphoma in the prior art, but no reports and studies have shown that ciorone is effective for the treatment of non-Hodgkin's lymphoma alone.
- the present invention verifies for the first time that 50 mg of cioronib alone in some patients with relapsed and refractory NHL plays a certain role in delaying the recurrence and progression of the disease, and the test shows that 50 mg of cioronib alone in the treatment of relapsed and refractory NHL, the overall risk Controllable, no new safety signals found.
- the process of tumor treatment is very complicated. Combination of drugs with different targets will cause drug interactions, which may lead to enhanced drug efficacy or reduced side effects, as well as weakened drug efficacy or unwanted side effects. It is of great significance to study the efficacy and safety of the combined drug. However, it is completely unpredictable what effect the combination of the two drugs will have.
- the present invention is the first time that the combination of ciorone and chidamide is used for the treatment of non-Hodgkin's lymphoma. The test results show that 15-20 mg of chidamide combined with 50 mg of cioroni is used for non-Hodgkin's lymphoma. It has a significant therapeutic effect, and at the same time, the present invention verifies for the first time that the medication risk of 20 mg chidamide combined with 50 mg cioroni does not exceed expectations, and the main adverse events are controllable.
- Example 1 Evaluation of the efficacy of cioronib monotherapy in the treatment of non-Hodgkin's lymphoma
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
提供西奥罗尼或其衍生物在制备用于预防和/或治疗非霍奇金淋巴瘤的药物中的用途、包含西奥罗尼或其衍生物和西达本胺或其衍生物的药物组合物在制备用于预防和/或治疗非霍奇金淋巴瘤的药物中的用途、以及联合用药组合物。所述的西奥罗尼以及联合用药组合物能够有效预防和/或治疗非霍奇金淋巴瘤,尤其在特定用量范围内具有较高的有效性和安全性。
Description
本发明涉及生物医药领域,具体涉及西奥罗尼及其联合用药治疗非霍奇金淋巴瘤的用途。
非霍奇金淋巴瘤(NHL,Non-Hodgkin's lymphoma)是一种源于机体淋巴结的癌症,约占所有淋巴瘤的80%~90%,其中有三分之二原发于淋巴结,三分之一原发于淋巴结外器官或组织,如消化和呼吸道、肺、皮肤、涎腺、甲状腺及中枢神经系统等。
在我国,非霍奇金淋巴瘤占全部淋巴瘤的90%左右,并且发病率逐年升高。根据非霍奇金淋巴瘤的自然病程,可以归为三大临床类型,即高度侵袭性非霍奇金淋巴瘤、侵袭性非霍奇金淋巴瘤和惰性非霍奇金淋巴瘤。高度侵袭性非霍奇金淋巴瘤包括Burkitt淋巴瘤(BL),淋巴母细胞淋巴瘤(LBL)和套细胞淋巴瘤(MCL)等,侵袭性非霍奇金淋巴瘤包括弥漫大B细胞淋巴瘤(DLBCL),外周T细胞淋巴瘤,间变性大细胞淋巴瘤(ALCL)和血管免疫母细胞性T细胞淋巴瘤等,惰性非霍奇金淋巴瘤包括滤泡性淋巴瘤,慢性淋巴细胞性白血病(CLL),小淋巴细胞淋巴瘤(SLL),淋巴浆细胞淋巴瘤和边缘区淋巴瘤(MZL)等。
西奥罗尼是深圳微芯生物科技股份有限公司自主研发的具有完全知识产权的全新蛋白激酶抑制剂。西奥罗尼是以多蛋白激酶为靶点的小分子抗肿瘤靶向药物,通过对VEGFR/PDGFR/c-Kit、AuroraB、CSF-1R靶点的高选择抑制活性,具有抗肿瘤血管生成、抑制肿瘤细胞有丝分裂、调控肿瘤炎性微环境等三通路 抗肿瘤协同作用机制,发挥综合抗肿瘤作用。与传统的VEGFR类靶向抑制剂(如舒尼替尼/Sunitinib、索拉菲尼/Sorafenib等)相比,西奥罗尼对有丝分裂关键酶Aurora B的抑制活性是其所特有的,具有潜在的降低肿瘤组织基因组不稳定性及抑制肿瘤细胞转移的作用。西奥罗尼通过抑制肿瘤血管生成、细胞有丝分裂和肿瘤炎性微环境三种互补的作用机制发挥抗肿瘤活性,同时其高靶标选择性也降低了因脱靶效应带来的副作用风险。
CN200910223861.5公开了西奥罗尼化合物,其具体公开了一种萘酰胺的衍生物、其制备方法及应用。该类化合物同时具有蛋白激酶抑制活性和组蛋白去乙酰化酶抑制活性,可以用于治疗与蛋白激酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病,包括炎症、自身免疫性疾病、癌症、神经系统疾病和神经退化性疾病、心血管疾病、代谢病、过敏、哮喘以及与激素相关的疾病。
CN201610856945.2公开了西奥罗尼的的非溶剂化晶体A、B、C及其制备方法,还涉及含有所述晶体的药物组合物,以及所述晶体在制备用于治疗与蛋白激酶活性异常或组蛋白去乙酰化酶活性异常相关的疾病的药物中的应用。
CN201811550290.1公开了西奥罗尼在制备治疗急性髓系白血病药物的新用途,所述新用途为西奥罗尼或其药学上可接受的盐、酯、溶剂合物在制备预防和/或治疗急性髓系白血病的药物中的用途。西奥罗尼通过Src/Fyn/p38和Erk/MEK信号通路抑制急性髓系白血病细胞生长、诱导其凋亡及集落形成。
目前尚未有关于西奥罗尼单用或联用于治疗非霍奇金淋巴瘤的研究和报道。
西达本胺也是深圳微芯生物科技股份有限公司自主研发的具全球专利保护的全新分子体,其是国际首个亚型选择性组蛋白去乙酰化酶(HDAC)口服抑制剂。西达本胺主要针对第I类HDAC中的1、2、3亚型和第IIb类的10亚型, 具有对肿瘤异常表观遗传功能的调控作用。西达本胺通过抑制相关HDAC亚型以增加染色质组蛋白的乙酰化水平来引发染色质重塑,并由此产生针对多条信号传递通路基因表达的改变(即表观遗传改变),进而抑制肿瘤细胞周期、诱导肿瘤细胞凋亡,同时对机体细胞免疫具有整体调节活性,诱导和增强自然杀伤细胞(NK)和抗原特异性细胞毒T细胞(CTL)介导的肿瘤杀伤作用。西达本胺还通过表观遗传调控机制,具有诱导肿瘤干细胞分化、逆转肿瘤细胞的上皮间充质表型转化(EMT)等功能,进而在恢复耐药肿瘤细胞对药物的敏感性和抑制肿瘤转移、复发等方面发挥潜在作用。
西达本胺首个适应症为复发及难治性的外周T细胞淋巴瘤。2019年11月,西达本胺获批联合芳香化酶抑制剂用于激素受体阳性、人表皮生长因子受体-2阴性、绝经后、经内分泌治疗复发或进展的局部晚期或转移性乳腺癌患者的适应症。同时,西达本胺单药及联合其他抗肿瘤药物针对其他血液肿瘤、实体瘤及HIV的临床研究正在美国、日本、中国及中国台湾等国家和地区同步开展。
CN03139760.3公开了西达本胺化合物,具体公开了一种具有分化和抗增殖活性的苯甲酰胺类组蛋白去乙酰化酶抑制剂及其药用制剂的制备方法与应用,其公开了结构通式,对取代基进行了定义。该类化合物作为组蛋白去乙酰化酶抑制剂,可以用于治疗与分化和增殖相关的疾病如癌症和牛皮癣。
CN201210489178.8公开了西达本胺的两种结晶形式,即西达本胺晶型A和西达本胺晶型B,以及西达本胺新的结晶形式的制备方法。所述西达本胺晶型A和西达本胺晶型B在口服吸收性和抑制细胞的分化和增殖的方面性能优异,并且其毒性弱,具有良好的储存和处理稳定性,可用于制备治疗与细胞分化和增殖相关的疾病的药物。
CN201410136761.X公开了一种E构型苯甲酰胺类化合物及其药用制剂与应 用,所述E构型苯甲酰胺类化合物为西达本胺,其化学名称为N-(2-氨基-4-氟苯基)-4-[N-[(E)-3-(3-吡啶)丙烯酰基]氨甲基]苯甲酰胺,在其结构式中,3-吡啶丙烯酰基的构型为E型。所述E构型西达本胺具有亚型选择性组蛋白去乙酰化酶抑制活性,主要抑制第I类HDAC中的HDAC1、HDAC2、HDAC3和第IIb类HDAC中的HDAC10。所述E构型西达本胺可以用于治疗与组蛋白去乙酰化酶活性异常相关的疾病,如癌症,包括淋巴瘤、实体肿瘤和血液系统肿瘤等。
CN201810892420.3公开了一种用于治疗白血病的联合用药物,包括用于同时、分别或依次给药的具有有效剂量的西达本胺和DCAG药物,所述DCAG药物为地西他滨、阿糖胞苷、阿克拉霉素和粒细胞集落刺激因子的组合药物,其提供了西达本胺联合DCAG在制备用于治疗急性髓性白血病的药物中的用途,其有益效果是:解决了现有AML联合化疗方案的复发难治问题,其治疗复发难治的急性髓性白血病患者的完全缓解率(CR)达到了43.6%,客观缓解率(ORR)达到了58.2%。
CN201911129472.6公开了西达本胺的应用,具体提出了对B细胞淋巴瘤具备治疗作用的给予西达本胺的治疗方案应用,并通过临床试验验证了西达本胺单药治疗弥漫大B细胞淋巴瘤和伴有特定表观遗传调控基因突变的复发或难治性滤泡性淋巴瘤具备更加突出的效果,所述应用能够更高效的治疗B细胞淋巴瘤患者。
目前尚未有将西达本胺与西奥罗尼联用于治疗非霍奇金淋巴瘤的研究和报道。
发明内容
本发明的目的是提供一种能够有效预防和/或治疗非霍奇金淋巴瘤的西奥罗尼及其联合用药组合物,尤其在特定用量范围内具有较高的有效性和安全性。
本发明提供了西奥罗尼或其衍生物在制备用于预防和/或治疗非霍奇金淋巴瘤的药物中的用途,优选的,所述西奥罗尼或其衍生物的含量为10-65mg,优选为20-50mg。
所述西奥罗尼衍生物包括西奥罗尼、其可药用盐以及其非溶剂化晶体A、B和C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中,其全文内容被引入本发明。
本发明还提供了一种包含西奥罗尼或其衍生物和西达本胺或其衍生物的药物组合物在制备用于预防和/或治疗非霍奇金淋巴瘤的药物中的用途。
其中,所述西奥罗尼或其衍生物的含量为10-65mg,优选为20-50mg,所述西达本胺或其衍生物的含量为5-60mg,优选为10-30mg。
优选的,所述西奥罗尼衍生物包括西奥罗尼、其可药用盐以及其非溶剂化晶体A、B和C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中,其全文内容被引入本发明。
优选的,所述西达本胺衍生物包括西达本胺、其可药用盐、其对映异构体以及其晶型A和晶型B。西达本胺的对映异构体公开于CN201410136761.X中,其全文内容被引入本发明,西达本胺的晶型A和晶型B公开于CN201210489178.8,其全文内容被引入本发明。
另一方面,本发明提供了一种药物组合物,其包含西奥罗尼或其衍生物和西达本胺或其衍生物,其中所述西奥罗尼或其衍生物的含量为10-65mg,优选为20-50mg,所述西达本胺或其衍生物的含量为5-60mg,优选为10-30mg。
优选的,所述西奥罗尼衍生物包括西奥罗尼、其可药用盐以及其非溶剂化晶体A、B和C。西奥罗尼的非溶剂化晶体A、B和C公开于CN201610856945.2中,其全文内容被引入本发明。
优选的,所述西达本胺衍生物包括西达本胺、其可药用盐、其对映异构体以及其晶型A和晶型B。西达本胺的对映异构体公开于CN201410136761.X中,其全文内容被引入本发明,西达本胺的晶型A和晶型B公开于CN201210489178.8,其全文内容被引入本发明。
再一方面,本发明提供了一种药盒,其包含前述的药物组合物。
最后,本发明提供了一种预防和/或治疗非霍奇金淋巴瘤的方法,其包括向有需要的患者施用前述的西奥罗尼或其衍生物、药物组合物或药盒。
本发明的有益效果:
(1)现有技术中西达本胺可单用于非霍奇金淋巴瘤的治疗,但西奥罗尼并未有报道和研究显示其单用于治疗非霍奇金淋巴瘤有效。本发明首次验证了50mg西奥罗尼单用在部分复发难治NHL患者中对于延缓疾病的复发进展起到一定作用,并且,试验显示西奥罗尼单药50mg治疗复发难治NHL,总体风险可控,未发现新的安全信号。
(2)肿瘤治疗的过程十分复杂,不同靶点的药物联用,会产生药物相互作用,可能导致药效加强或副作用减轻,也可使药效减弱或出现不应有的毒副作用,因而在进行联合用药时,对其药效以及安全性研究具有重要意义,然而,两种药物联用会出现何种效果是完全无法预期的。本发明首次将西奥罗尼与西达本胺联用于非霍奇金淋巴瘤的治疗,试验结果显示,15-20mg西达本胺联合50mg西奥罗尼用于非霍奇金淋巴瘤具有显著的治疗作用,同时,本发明首次验证了20mg西达本胺联合50mg西奥罗尼用药风险未超出预期,主要的不良事件可控。
图1靶病灶最佳反应较基线变化瀑布图
以下进一步通过非限制性实例来说明本发明,其不旨在限制本发明所涵盖的范围。
除非另有定义,否则本文中使用的所有技术和科学术语均具有与本领域一般技术人员通常所理解的含义相同的含义。
实施例一西奥罗尼单药治疗非霍奇金淋巴瘤研究有效性评价
实施例二西奥罗尼单药治疗非霍奇金淋巴瘤研究安全性评价
实施例三西奥罗尼联合西达本胺治疗非霍奇金淋巴瘤研究有效性评价
实施例四西奥罗尼联合西达本胺治疗非霍奇金淋巴瘤研究安全性评价
以上对本发明进行了详细的介绍,本文中应用了具体个例对本发明的原理及实施方式进行了阐述,以上实施例的说明只是用于帮助理解本发明的方法及其核心思想,包括最佳方式,并且也使得本领域的任何技术人员都能够实践本发明,包括制造和使用任何装置或系统,和实施任何结合的方法。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。本发明专利保护的范围通过权利要求来限定,并可包括本领域技术人员能够想到的其他实施例。如果这些其他实施例具有不是不同于权利要求文字表述的结构要素,或者如果它们包括与权利要求的文字表述无实质差异的等同结构要素,那么这些其他实施例也应包含在权利要求的范围内。
Claims (10)
- 西奥罗尼或其衍生物在制备用于预防和/或治疗非霍奇金淋巴瘤的药物中的用途。
- 包含西奥罗尼或其衍生物和西达本胺或其衍生物的药物组合物在制备用于预防和/或治疗非霍奇金淋巴瘤的药物中的用途。
- 根据权利要求1或2所述的用途,其特征在于,所述西奥罗尼或其衍生物的含量为10-65mg,优选为20-50mg。
- 根据权利要求2或3所述的用途,其特征在于,所述西达本胺或其衍生物的含量为5-60mg,优选为10-30mg。
- 根据权利要求1-3任一项所述的用途,其特征在于,所述西奥罗尼衍生物包括西奥罗尼、其可药用盐以及其非溶剂化晶体A、B和C。
- 根据权利要求2-5任一项所述的用途,其特征在于,所述西达本胺衍生物包括西达本胺、其可药用盐、其对映异构体以及其晶型A和晶型B。
- 一种药物组合物,其特征在于,包含西奥罗尼或其衍生物和西达本胺或其衍生物,其中,所述西奥罗尼或其衍生物的含量为10-65mg,优选为20-50mg,所述西达本胺或其衍生物的含量为5-60mg,优选为10-30mg。
- 根据权利要求7所述的药物组合物,其特征在于,所述西奥罗尼衍生物包括西奥罗尼、其可药用盐以及其非溶剂化晶体A、B和C;所述西达本胺衍生物包括西达本胺、其可药用盐、其对映异构体以及其晶型A和晶型B。
- 一种药盒,其特征在于,包含权利要求7-8任一项所述的药物组合物。
- 预防和/或治疗非霍奇金淋巴瘤的方法,其特征在于,向有需要的患者施用西奥罗尼或其衍生物或者根据权利要求7-8任一项所述的药物组合物或者权利要求9所述的药盒。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010654215 | 2020-07-08 | ||
CN202010654215.0 | 2020-07-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022007745A1 true WO2022007745A1 (zh) | 2022-01-13 |
Family
ID=79232827
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2021/104503 WO2022007745A1 (zh) | 2020-07-08 | 2021-07-05 | 西奥罗尼及其联合用药治疗非霍奇金淋巴瘤的用途 |
Country Status (3)
Country | Link |
---|---|
CN (1) | CN113908159A (zh) |
TW (1) | TW202214242A (zh) |
WO (1) | WO2022007745A1 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115177620A (zh) * | 2022-07-18 | 2022-10-14 | 厦门大学附属第一医院 | 西奥罗尼或其药学上可接受的盐在制备预防或治疗滤泡淋巴瘤的药物中的应用 |
WO2023193705A1 (zh) * | 2022-04-07 | 2023-10-12 | 深圳微芯生物科技股份有限公司 | 西奥罗尼在抗胰腺癌中的用途 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN116637182A (zh) * | 2022-02-24 | 2023-08-25 | 康方药业有限公司 | 包含抗ctla4-抗pd-1双特异性抗体和西奥罗尼的药物组合 |
CN115322171B (zh) * | 2022-08-30 | 2023-03-17 | 深圳微芯生物科技股份有限公司 | 一种trka(g667c)和flt3靶点抑制剂及其与西达本胺的组合物 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109908143A (zh) * | 2018-12-18 | 2019-06-21 | 厦门大学附属第一医院 | 西奥罗尼在制备治疗急性髓系白血病药物的新用途 |
CN110833544A (zh) * | 2018-08-17 | 2020-02-25 | 深圳微芯生物科技股份有限公司 | 组蛋白去乙酰化酶抑制剂与蛋白激酶抑制剂之组合及其制药用途 |
CN111214475A (zh) * | 2020-02-25 | 2020-06-02 | 厦门大学附属第一医院 | 一种抗双重打击淋巴瘤的联合用药物组合物及其应用 |
-
2021
- 2021-07-05 WO PCT/CN2021/104503 patent/WO2022007745A1/zh active Application Filing
- 2021-07-05 CN CN202110755354.7A patent/CN113908159A/zh active Pending
- 2021-07-07 TW TW110125049A patent/TW202214242A/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110833544A (zh) * | 2018-08-17 | 2020-02-25 | 深圳微芯生物科技股份有限公司 | 组蛋白去乙酰化酶抑制剂与蛋白激酶抑制剂之组合及其制药用途 |
CN109908143A (zh) * | 2018-12-18 | 2019-06-21 | 厦门大学附属第一医院 | 西奥罗尼在制备治疗急性髓系白血病药物的新用途 |
CN111214475A (zh) * | 2020-02-25 | 2020-06-02 | 厦门大学附属第一医院 | 一种抗双重打击淋巴瘤的联合用药物组合物及其应用 |
Non-Patent Citations (1)
Title |
---|
ZHAO ZHENGYANG, QI SHUYUE; LI HUIMIN: "Application of rNPV in Pharma Enterprises Listed in STAR Market", APPRAISAL JOURNAL OF CHINA, 31 December 2019 (2019-12-31), pages 24 - 29, XP055886340 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023193705A1 (zh) * | 2022-04-07 | 2023-10-12 | 深圳微芯生物科技股份有限公司 | 西奥罗尼在抗胰腺癌中的用途 |
CN115177620A (zh) * | 2022-07-18 | 2022-10-14 | 厦门大学附属第一医院 | 西奥罗尼或其药学上可接受的盐在制备预防或治疗滤泡淋巴瘤的药物中的应用 |
Also Published As
Publication number | Publication date |
---|---|
CN113908159A (zh) | 2022-01-11 |
TW202214242A (zh) | 2022-04-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022007745A1 (zh) | 西奥罗尼及其联合用药治疗非霍奇金淋巴瘤的用途 | |
Yan et al. | Targeting autophagy to sensitive glioma to temozolomide treatment | |
Armando et al. | New drugs are not enough‑drug repositioning in oncology: An update | |
JP2015536964A (ja) | B−raf阻害剤とヒストン脱アセチル化酵素阻害剤を含む医薬組合せおよび増殖性疾患の治療におけるそれらの使用 | |
Heffeter et al. | The ruthenium compound KP1339 potentiates the anticancer activity of sorafenib in vitro and in vivo | |
JP5969255B2 (ja) | 炎症関連疾患の治療法 | |
KR102033305B1 (ko) | 아스피린 및 다중 키나아제 억제제를 포함하는 항암제 내성 치료용 조성물 | |
WO2017200969A1 (en) | Combination therapy with notch and pd-1 or pd-l1 inhibitors | |
KR20160126984A (ko) | 아필리모드 조성물 및 이를 사용하기 위한 방법 | |
WO2023072010A1 (zh) | Ppar激动剂在制备治疗急性髓细胞白血病的药物中的应用 | |
He et al. | BIIB021, an Hsp90 inhibitor: A promising therapeutic strategy for blood malignancies | |
CA3062741A1 (en) | Methods for the treatment of recurrent glioblastoma (rgbm) | |
NL2033623A (en) | Use of lenvatinib plus anti-pd-1 monoclonal antibody in preparation of anti-hepatoma drug | |
Zhu et al. | Synergistic antitumor effect of dual PI3K and mTOR inhibitor NVP‑BEZ235 in combination with cisplatin on drug‑resistant non‑small cell lung cancer cell | |
JP2019505555A (ja) | がん治療における抗エストロゲン剤有効性の増強のための擬絶食の使用 | |
WO2024120523A1 (zh) | 一种治疗前列腺癌的药物组合及其应用 | |
JP7113826B2 (ja) | プロテインキナーゼ阻害剤および追加的化学療法剤の組み合わせ | |
Gu et al. | Effects of low‑dose bufalin combined with hydroxycamptothecin on human castration‑resistant prostate cancer xenografts in nude mice | |
US20190183893A1 (en) | Low dose of sildenafil as an antitumor drug | |
US11406627B2 (en) | Combinations of MDM2 inhibitors with inhibitors of ERK for treating cancers | |
Zhong et al. | Preclinical evaluation of the HDAC inhibitor chidamide in transformed follicular lymphoma | |
US20040127571A1 (en) | Method of Treating Leukemia with a Combination of Suberoylanilide Hydromaxic Acid and Imatinib Mesylate | |
WO2023280244A1 (zh) | 西奥罗尼及其联合用药治疗乳腺癌的用途 | |
CN115364231B (zh) | 一种增强ezh2抑制剂抗肿瘤作用的药物组合物及其用途 | |
TW202029961A (zh) | Ar拮抗劑聯合parp抑制劑在製備治療前列腺癌的藥物中的用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 21836962 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
32PN | Ep: public notification in the ep bulletin as address of the adressee cannot be established |
Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 14/06/2023) |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 21836962 Country of ref document: EP Kind code of ref document: A1 |