WO2023241738A2 - Composé de 1,4-benzodiazépine et utilisation associée dans la préparation d'un médicament antitumoral - Google Patents
Composé de 1,4-benzodiazépine et utilisation associée dans la préparation d'un médicament antitumoral Download PDFInfo
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- WO2023241738A2 WO2023241738A2 PCT/CN2023/112421 CN2023112421W WO2023241738A2 WO 2023241738 A2 WO2023241738 A2 WO 2023241738A2 CN 2023112421 W CN2023112421 W CN 2023112421W WO 2023241738 A2 WO2023241738 A2 WO 2023241738A2
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- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N benzyl carbamate Chemical compound NC(=O)OCC1=CC=CC=C1 PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
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- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
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- 230000008878 coupling Effects 0.000 description 1
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- 239000003405 delayed action preparation Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- MAFQLJCYFMKEJJ-UHFFFAOYSA-N ethyl 4-aminobutanoate Chemical compound CCOC(=O)CCCN MAFQLJCYFMKEJJ-UHFFFAOYSA-N 0.000 description 1
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- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- DGMWFJYEDNCJDN-UHFFFAOYSA-N n-[(4-bromophenyl)carbamoyl]-2-chloroacetamide Chemical compound ClCC(=O)NC(=O)NC1=CC=C(Br)C=C1 DGMWFJYEDNCJDN-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
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- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
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- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
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- 235000020183 skimmed milk Nutrition 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
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- ZMCBYSBVJIMENC-UHFFFAOYSA-N tricaine Chemical compound CCOC(=O)C1=CC=CC(N)=C1 ZMCBYSBVJIMENC-UHFFFAOYSA-N 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- 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
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
- C07D243/28—Preparation including building-up the benzodiazepine skeleton from compounds containing no hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Definitions
- the invention belongs to the fields of medicinal chemistry and medical technology and pharmaceuticals, and relates to 1,4-benzodiazepine.
- Compounds and their use in preparing anti-tumor drugs, specifically involving 1,4-benzodiazepine The use of analog compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, or pharmaceutical compositions thereof and medically acceptable carriers in the preparation of ANXA3 degradation agents and in the preparation of prevention and/or treatment of cancer uses in medicines.
- Cancer is a common malignant tumor in clinical practice, characterized by rapid disease progression and high mortality.
- the latest report from the World Health Organization shows that there will be 19.3 million new cancer patients and 10 million deaths from cancer in the world in 2020 (CA: a cancer journal for clinicians, 2021, 71(3):209-249). It is expected that by 2040, the number of new cancer patients worldwide will reach 28.4 million, an increase of 47% from 2020. Therefore, cancer has become one of the major diseases that seriously endangers human health around the world.
- Targeted drugs have become a hot area of anti-tumor drug research and development in recent years because they can specifically act on abnormally expressed proteins in tumor cells and thereby induce specific death of tumor cells without affecting surrounding normal cells.
- targeted drugs can be mainly divided into various types such as macromolecular antibodies, small molecule inhibitors, small molecule agonists, and small molecule degraders. So far, small molecule inhibitors are one of the important types of targeted therapy, but they still have obvious shortcomings and limitations.
- small molecule degraders have subverted the previous concept of "difficult to drug" targets. These small molecule degraders not only have small dosages and high selectivity, but also greatly reduce off-target effects (Cell Chemical Biology. 2017, 24(9): 1181-1190). In addition, small molecule degraders have unique catalytic mechanisms, especially the ability to target traditional "difficult-to-drug" targets and solve pain points such as drug resistance.
- small molecule degraders have become a hot spot and frontier field in the current research and development of new drugs, and has achieved rapid development. Judging from the clinical research and development pipeline that has been advanced, small molecule degraders have excellent performance in terms of efficacy and safety, and have broad application value especially in the field of malignant tumor treatment. Therefore, the development of small molecule degraders with new targets has become an important research direction in the research and development of anti-tumor drugs, which is expected to meet the urgent unmet clinical needs of cancer patients.
- Annexin A3 is a member of the Annexin (ANX) family. It can bind to acidic phospholipids in a Ca 2+ -dependent manner and participate in a series of Ca 2+ changes on the cell membrane surface. Dependent physiological activities, including vesicle trafficking, membrane fusion during exocytosis, signal transduction, formation of Ca 2+ channels, and interactions between cytoskeletal proteins (Nature reviews Molecular cell biology, 2005, 6(6) :449-461.), but the biochemical function of the ANXA3 protein is largely unknown. Normally, ANXA3 protein is expressed in differentiated cells of myeloid cell lines.
- ANXA3 protein in many cancers, such as breast cancer, There is scientific evidence of abnormal expression of ANXA3 protein in ovarian cancer, lung adenocarcinoma, prostate cancer, kidney cancer, colon cancer, pancreatic cancer and liver cancer, and the abnormal expression of ANXA3 protein is closely related to the progression of these cancers (Clinical and Translational Oncology,2013,15(2):106-110). For example, many studies have been dedicated to revealing the important role of ANXA3 in the development and progression of breast cancer.
- ANXA3 is highly expressed in breast tumor samples, especially in many triple-negative breast cancer (TNBC) tumor samples, with a positive expression rate of 79.66%, which is significantly higher than that of other types of breast cancer patients, and high expression levels of ANXA3 are closely related to poor prognosis.
- TNBC triple-negative breast cancer
- ANXA3 is highly expressed in breast tumor samples, especially in many triple-negative breast cancer (TNBC) tumor samples, with a positive expression rate of 79.66%, which is significantly higher than that of other types of breast cancer patients, and high expression levels of ANXA3 are closely related to poor prognosis.
- TNBC triple-negative breast cancer
- ANXA3 silencing the expression of ANXA3 not only significantly inhibited the growth of TNBC transplanted tumors at the animal level in vivo, but also effectively inhibited the lung metastasis of TNBC orthotopic transplanted tumors, while reducing the resistance of TNBC cells to the chemotherapy drug doxorubicin.
- Medicinal properties Pathology-Research and Practice, 2018, 214 (10): 1719-1725; Cell Death & Disease, 2018, 9 (2): 1-11). It is speculated that the development of selective degraders targeting ANXA3 to induce ANXA3 protein degradation may be a promising new anti-tumor treatment strategy.
- ANXA3 as a new class of drug targets, there have been no reports so far of small chemical molecules that can target and degrade ANXA3 and exhibit anti-tumor pharmacological activity.
- this application provides 1,4-benzodiazepine Compounds and their use in preparing anti-tumor drugs, specifically involving 1,4-benzodiazepine
- This application discovered the original 1,4-benzodiazepine through structure-activity relationship screening of the self-constructed small molecule compound library targeting ANXA3 binding activity and degradation activity, as well as research on anti-tumor cell activity.
- the compound can target and degrade ANXA3 and exhibit anti-tumor pharmacological activity.
- the first object of the present invention is to provide 1,4-benzodiazepine compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof;
- the 1,4-benzodiazepine Compounds are compounds or salts with a structure shown in formula (I),
- R 1 is selected from a hydrogen atom or a methyl group
- X is a linking group, selected from: Where, R 2 is selected from:
- R 3 to R 7 are each independently selected from hydrogen, halogen, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, dimethylamino, nitro, cyano or acetyl;
- R 8 to R 11 are each independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl or methoxy;
- R' 8 -R' 11 are each independently selected from hydrogen, halogen, cyano, nitro, trifluoromethyl or methoxy;
- R 12 to R 14 are each independently selected from hydrogen or halogen
- R' 12 to R' 14 are each independently selected from hydrogen or trifluoromethyl
- R 12 to R” 14 are each independently selected from hydrogen
- Aromatic five-membered heterocycle its structure is:
- A is selected from nitrogen, oxygen or sulfur
- B is selected from carbon or nitrogen
- C is selected from carbon or nitrogen
- D is selected from carbon or nitrogen
- E is selected from nitrogen or oxygen
- F is selected from carbon or nitrogen
- R 15 to R 18 are each independently selected from hydrogen, methyl or trifluoromethyl
- R' 15 to R' 17 are each independently selected from hydrogen or methyl
- G is selected from carbon or nitrogen
- R 19 is selected from methoxy or ethylene glycol.
- pharmaceutically acceptable salts refer to salts of compounds that are suitable for use within the range of reliable medical evaluation. Contact with tissues of humans or lower animals without undue toxicity, irritation and allergic reactions, etc., with a reasonable ratio of benefits to risks, usually water or oil soluble or dispersible, and can be effectively used for its intended use.
- Some of the compounds of the present invention or their stereoisomers contain basic groups such as amine groups, which can form salts with acids, and can form acid salts with inorganic and/or organic acids, including zwitterionic salts (inner salts), and Quaternary ammonium salts, such as alkylammonium salts.
- These salts may be obtained directly from the final isolation and purification of the compound, or its stereoisomers. It can also be obtained by appropriately mixing the compound, or its stereoisomer, with a certain amount of acid (for example, equivalent amounts).
- These salts may form a precipitate in the solution and be collected by filtration, or may be recovered after evaporation of the solvent, or may be obtained by reacting in an aqueous medium and then freeze-drying.
- Pharmaceutically acceptable salts described in the present invention include organic acid salts such as citrate, benzenesulfonate, acetate, propionate, succinate, oxalate, malate, and succinate. acid salt, fumarate, maleate, tartrate or trifluoroacetate, etc.; inorganic acid salts such as hydrochloride, sulfate, hydrobromide, hydrofluoride, hydroiodide, hydrogen iodide, etc. Chlorate, phosphate, etc.; or with amino acids, such as glutamic acid or aspartic acid, can form glutamate or aspartate.
- organic acid salts such as citrate, benzenesulfonate, acetate, propionate, succinate, oxalate, malate, and succinate.
- acid salt fumarate, maleate, tartrate or trifluoroacetate, etc.
- inorganic acid salts such as hydrochloride, sulfate, hydrobromide, hydro
- 1,4-benzodiazepine of the present invention Solvates of similar compounds also fall within the protection scope of the present invention.
- the solvents are preferably water, alcohol or alcohol-water mixtures.
- the alcohol here is methanol or ethanol.
- the second object of the present invention is to provide 1,4-benzodiazepine represented by formula (I)
- the binding activity test based on surface plasmon resonance showed that the 1,4-benzodiazepine represented by formula (I)
- the compound has submicromolar ANXA3 binding activity, and the activity results are shown in Table 1.
- Experiments based on Western blot testing showed that the compound can induce ANXA3 protein degradation in TNBC cells, with activity at the micromolar level, and the results are shown in Table 1.
- the degradation activity results of representative isomer compounds I-9a19, (R)-I-9a19 or (S)-I-9a19 are shown in Figure 1.
- a further object of the present invention is to provide 1,4-benzodiazepine represented by formula (I)
- Table 1 In vitro anti-tumor activity tests on various tumor cells show that the compound has anti-tumor activity at the micromolar level, and the activity results are shown in Table 1.
- compound I-9a19 can significantly inhibit the cloning, migration and invasion of TNBC cells.
- the activity results are shown in Figure 2.
- compound I-9a19 showed effective therapeutic effects and induced the degradation of ANXA3 protein in tumor tissue in the in vivo TNBC transplanted tumor model.
- the activity results are shown in Figure 3.
- the above-mentioned medicines may also contain one or more pharmaceutically acceptable carriers.
- the carriers include conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, and absorbers in the pharmaceutical field. Accelerators, surfactants, adsorption carriers, lubricants, etc., and flavors, sweeteners, etc. can also be added if necessary.
- the present invention also provides an anti-tumor pharmaceutical composition that exerts an anti-tumor effect by acting as an annexin ANXA3 degrading agent.
- the anti-tumor pharmaceutical composition is a tablet, capsule, pill, injection, sustained-release preparation, or spray. Or nano drug delivery system.
- the beneficial effect of the present invention lies in the 1,4-benzodiazepine provided Compounds are a class of structurally novel ANXA3
- the small molecule degrader not only has sub-micromolar ANXA3 binding effect, but also shows obvious ANXA3 degradation activity in TNBC cells and animal levels. Moreover, it can significantly inhibit the proliferation, cloning, migration and invasion of TNBC cells in vitro.
- TNBC cells through the orthotopic xenograft tumor model of human MDA-MB-231 cells in female BALB/c nude mice, it has been confirmed that the anti-tumor function is better in vivo.
- TNBC has good potential and application prospects, and can be further prepared into drugs for the treatment of cancers, such as breast cancer, cervical cancer, ovarian cancer, intestinal cancer, gastric cancer, pancreatic cancer, lung cancer, esophageal cancer, and liver cancer.
- cancers such as breast cancer, cervical cancer, ovarian cancer, intestinal cancer, gastric cancer, pancreatic cancer, lung cancer, esophageal cancer, and liver cancer.
- leukemia and melanoma preferably, leukemia and melanoma.
- the anti-tumor drug is an anti-triple-negative breast cancer drug.
- 1,4-benzodiazepine provided by the invention
- the structures of similar compounds and their pharmaceutically acceptable salts have not been reported by Scifinder. They are a class of ANXA3 small molecule degraders with novel structures. This type of compound exerts anti-tumor therapeutic effects in vitro and in vivo by directly binding to ANXA3 and inducing its degradation. It solves the lack of small molecule drugs that can directly bind to ANXA3 and exhibit anti-tumor activity in the existing technology, and provides a basis for clinical use. It provides new treatment options and medication regimens for the treatment of tumors.
- Figure 1 Detection of the effects of compounds I-9a19, (R)-I-9a19 and (S)-I-9a19 on ANXA3 protein levels;
- Figure 3 In vivo anti-TNBC efficacy study of compound I-9a19 and detection of ANXA3 degradation in tumor tissue.
- Compound I-9a3 was synthesized according to the method of step 1.3 in Example 1, replacing the raw materials with the same equivalent of 8a3.
- 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 11.53(s,1H),11.20(s,1H),10.73(s,1H),8.09(s,1H),7.68(s,5H),7.59- 7.43(m,5H),7.30(s,2H),5.94(s,1H),4.25(s,2H),3.37(s,3H) .
- Compound I-9b1 was synthesized according to the method of step 1.3 in Example 1, replacing the raw materials with the same equivalent of 8b1.
- 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 11.54(s,1H),11.14(s,1H),10.69(s,1H),8.28(s,2H),7.92(s,2H),7.79( s,2H),7.68(s,3H),7.51(m,8H),7.30(s,3H),7.11(s,1H),5.94(s,1H),4.24(s,3H),3.37(s ,4H) .
- Compound I-9d1 was synthesized according to the method of step 1.3 in Example 1, replacing the raw materials with the same equivalent of 8d1.
- Compound I-10a5 was synthesized according to the method of step 1.3 in Example 1.
- 1 H NMR 400MHz, DMSO-d 6 ) ⁇ 11.49(s,1H),11.16(s,1H),11.04-10.96(m,1H),10.71(s,1H),8.31(s,1H), 7.96(s,1H),7.82(s,1H),7.66(s,1H),7.58-7.45(m,5H),7.36-7.22(m,3H),7.14(s,1H),5.92(s, 1H),4.30(s,2H) .
- 1,4-Benzodiazepine according to the present invention Binding activity test of similar compounds to ANXA3 protein.
- 1,4-Benzodiazepine according to the present invention Test of the degradation activity of similar compounds on ANXA3 protein.
- protease inhibitor (Swiss Roche Company), BCA protein quantitative detection kit (American Thermo Fisher Scientific Company), ECL chromogenic solution (WBKLS0500, American Milipore Company), Tubulin antibody (HC101-02, Beijing Full Gold Biological Company), ANXA3 antibody (11804-1-AP, Proteinteach Company of the United States), secondary antibodies (HS201-01, HS101-01, Beijing Quanshijin Biotechnology Company).
- Experimental steps 1.5*10 4 cells were seeded in a 6cm culture dish. After 24 hours, compound formula I solution was added to the cells to form the experimental group. Culture medium containing 0.1% DMSO was added to the cells as a control group. After incubation for 24 hours, cells were collected, RIAP solution was added and lysed on ice for 30 minutes, and then centrifuged at 12,000 rpm for 15 minutes at 4°C and the supernatant was collected. The BCA kit detects the total protein concentration. The total protein loading amount is 50 ⁇ g. The stacking gel electrophoresis voltage is 80V and the separation gel electrophoresis voltage is 120V. Then the film is transferred at a constant voltage of 110V for 90 minutes.
- 1,4-Benzodiazepine according to the present invention In vitro experiments on the inhibition of tumor cell viability by similar compounds.
- MTT American Sigma Company
- fetal calf serum Ausbian Company, Australia
- DMEM culture medium American Gibco Company
- Compound I-9a19 of the present invention inhibits tumor cell colony formation in vitro.
- the main reagents in the experiment Matrigel Matrigel (BD Company, USA), RIPA lysis buffer (Thermo Fisher Scientific Company, USA).
- mice Inject 1 ⁇ 10 6 cells into the fourth pair of breast pads of female BALB/c nude mice. After the tumor volume reaches approximately 100 mm 3 , the nude mice are randomly divided into blank solvent group and control drug docetaxel (DTX). ) group and compound I-9a19 treated group. Administration was started on the first day, and after 19 consecutive days of administration, the nude mice were sacrificed, tumor tissues were obtained, weighed, and TGI was calculated. Then take 10 mg of tumor, add RIPA lysis buffer, and then centrifuge, collect the supernatant, use the BCA method for protein quantification, and perform subsequent operations according to the Western blot experiment.
- DTX control drug docetaxel
- the binding activity test based on surface plasmon resonance shows that the 1,4-benzenediazepine represented by formula (I)
- the compound has submicromolar ANXA3 binding activity, and the activity results are shown in Table 1.
- Experiments based on Western blot testing showed that the compound can induce ANXA3 protein degradation in TNBC cells, with activity at the micromolar level, and the results are shown in Table 1.
- the degradation activity results of representative isomer compounds I-9a19, (R)-I-9a19 or (S)-I-9a19 are shown in Figure 1.
- Affinity K D , degradation activity DC 50 and half inhibitory concentration IC 50 *: >100 ⁇ M, **: 10-100 ⁇ M, ***: 1-10 ⁇ M, ****: ⁇ 1 ⁇ M.
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Abstract
La présente invention appartient au domaine technique de la chimie pharmaceutique et des médicaments, se rapportant à un composé de 1,4-benzodiazépine et une utilisation associée dans la préparation d'un médicament antitumoral, en particulier, une utilisation du composé de 1,4-benzodiazépine dans la préparation d'un agent de dégradation de l'annexine A3 (ANXA3) et une utilisation du composé de 1,4-benzodiazépine dans la préparation d'un médicament pour le traitement de cancers. En particulier, l'invention concerne une utilisation du composé de 1,4-benzodiazépine, ou d'un sel pharmaceutiquement acceptable ou d'un stéréoisomère associé, ou d'une composition pharmaceutique utilisant le composé en tant que principe actif dans la préparation d'un médicament pour la prévention et le traitement de tumeurs. Le composé peut se lier à la protéine ANXA3, induire une dégradation de la protéine ANXA3, inhiber la prolifération, le clonage, la migration, l'invasion et d'autres fonctions des cellules tumorales, et exercer un effet de traitement antitumoral in vivo. La méthode peut être utilisée pour traiter des tumeurs solides, des tumeurs sanguines et d'autres maladies, et les tumeurs impliquées comprennent le cancer du sein, le cancer du col de l'utérus, le cancer de l'ovaire, le cancer de l'intestin, le cancer de l 'estomac, le cancer du pancréas, le cancer du poumon, le cancer de l'œsophage, le cancer du foie, la leucémie et le mélanome.
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CN202210680501.3A CN117263873A (zh) | 2022-06-15 | 2022-06-15 | 1,4-苯二氮䓬类化合物及其在制备抗肿瘤药物中的用途 |
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EP1089980A1 (fr) * | 1998-06-22 | 2001-04-11 | Elan Pharmaceuticals, Inc. | Composes d'inhibition de la liberation du peptide beta-amyloide et/ou de sa synthese |
DE60007960T2 (de) * | 1999-04-30 | 2004-10-21 | Univ Michigan Ann Arbor | Therapeutische Anwendungen von pro-apoptotischen Benzodiazepinen |
NZ532463A (en) * | 2001-11-13 | 2007-02-23 | Dimensional Pharm Inc | Substituted 1,4-benzodiazepines and uses thereof for the treatment of cancer |
SE0104250D0 (sv) * | 2001-12-14 | 2001-12-14 | Astrazeneca Ab | Heterocyclic compounds |
JP2015529252A (ja) * | 2012-09-21 | 2015-10-05 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | フルオロアルキル−1,4−ベンゾジアゼピノン化合物 |
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